FR2498596A1 - NOVEL PHENYLALCOYLAMINES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Abstract

PHENYLALCOYLAMINES OF GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH R IS OH OR AMINO POSSIBLY SUBSTITUTED; R AND R ARE HALOGEN ATOMS, CF, CN OR NO OR ONE OF THE REMAINS R OR R IS ALSO H; R IS H OR ALKYL; R IS H, ALKYL, CYCLOALCOYL, ALKENYL OR ARALCOYL; A IS METHYLENE, ETHYLENE OR HYDROXYMETHYLENE; AND B IS POSSIBLY SUBSTITUTED ARALCOYL, THE METHYLENE BOUND TO THE PHENYL CORE COULD BE REPLACED BY O, S OR SULFINYL OR SULFONYL, THEIR DIFFERENT OPTICAL DERIVATIVES AND SALTS WITH ACIDS. THESE COMPOUNDS CAN BE USED IN PARTICULAR IN THE TREATMENT OF HEART AND CIRCULATION DISEASES.

Description

Phenylalkylamine News, Preparation and use thereof

as medicines.

  The subject of the present invention is new phenylalkylamines of the general formula

R2 A -CH -N 5 I

  RR their optically active antipodes, their diastereoisomeric racemates and their optical antipodes, as well as their addition salts with acids, in particular their physiologically tolerable addition salts with inorganic or organic acids,

  medicines containing them and processes for their preparation.

  The new compounds offer valuable

  pharmacological properties, in particular an activity on

the heart and the circulation.

  In the general formula I above

  R1 represents a hydroxy group, an amino group possibly

  optionally substituted by an alkanoyl group with 1 to 3 carbon atoms or an alkoxycarbonyl group with altogether 2 to 4 carbon atoms, an alkylamino or dialkylamino group in which each alkyl part may contain

  1 to 3 carbon atoms and each time

  substituted by a phenyl group, R2 and R3 which may be the same or different,

  represent halogen atoms, trifluoromeric groups,

  romethyl, cyano or nitro or one of the radicals R2 or R3 also represents a hydrogen atom, R4 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, R represents a hydrogen atom, a group straight or branched alkyl with 1 to 4 carbon atoms, a

  cycloalkyl group with 3 to 6 carbon atoms, a group of

  eg alkenyl with 2 to 5 carbon atoms or an aral group

  Coyle with 7 to 10 carbon atoms,

  A represents the methylene, ethylene or hydro-

  xymethylene and B represents a group according to formulas R8

-CH- (CH 2) -D

  -CH- (CH 2) n D 'R 6 R 7 or - E R 6 R 6 R 6 represents a hydrogen or halogen atom, a hydroxy group, an alkoxy group with 1 to 3 carbon atoms optionally substituted with a phenyl group, a alkylsulfenyl or alkylsulphinyl group with in each case 1 to 3 carbon atoms, R7 represents a hydrogen atom, a hydroxyl group or an alkoxy group with 1 to 3 carbon atoms or R6 and R7 together represent the methylenedioxy group,

  R represents a hydrogen atom or a group

  Coyle with 1 to 3 carbon atoms,

  D represents an oxygen or sulfur atom, a group

  For example, where n is the number 1 or 2 and E is a straight alkylene group with 3 to 5 carbon atoms, optionally substituted with one or two alkyl groups. with each 1 to 3 carbon atoms or, when A represents a methylene or ethylene group and / or R1 represents an amino group substituted by a group

  alkanoyl with 1 to 3 carbon atoms or an alkoxy group

  carbonyl with a total of 2 to 4 carbon atoms, hydroxy, alkylamino or dialkylamino in which each alkyl moiety may contain 1 to 3 carbon atoms and each substituted with a phenyl group, and / or R2 represents a trifluoromethyl group , cyano or nitro and / or R3 represents a fluorine atom and / or R4 represents an alkyl group with 1 to 3 carbon atoms and / or R5 represents an alkyl group with 1 to 4 carbon atoms.

  carbon, a cycloalkyl group with 3 to 6 carbon atoms

  bone, an alkenyl group with 2 to 5 carbon atoms or an aralkyl group with 7 to 10 carbon atoms and / or

  R6 represents a fluorine or chlorine atom, a group

  eg alkylsulfenyl or alkylsulphinyl with in each case 1 to 3 carbon atoms, an ethylene group or also, when A represents the methylene group, a group of formula R9 I

  - CH - CH2 -, in which R9 represents

  is an alkyl group with 1 to 3 carbon atoms.

  As meanings to be mentioned in the first place in the case of the definition of radicals R1 to R9 and E, there may be mentioned for example for R1 that of the hydroxyl, amino, methylamino group,

  ethylamino, propylamino, isopropylamino, ben-

  zylamino, 1-phenylethylamino, 2-phenylethyl-

  amino, 3-phenylpropylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino,

  dibenzylamino, di- (2-phenylethyl) -amino, di-

  (3-phenylpropyl) -amino, methyl-ethylamino, methyl-propylamino, methylisopropylamino, ethyl-isopropylamino, methyl-benzylamino,

  ethyl-benzylamino, propyl-benzylamino, pyrrolidine

  lidino, piperidino, hexamethylene-imino,

  mylamino, acetylamino, propionylamino, methyl

  thoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino or isopropoxycarbonylamino,

  for R2 and R3, which may be the same or different

  in each case that of the atom of

  fluorine, chlorine, bromine or iodine, of the tri-

  fluoromethyl, cyano or nitro or for R2 or R3 also that of the hydrogen atom,

  for R4 and R8 which may be the same or different

  in each case that of the atom of hy-

  from the group methyl, ethyl, propyl or isopropyl,

  for R5 that of the hydrogen atom, of the methyl group

  thyl, ethyl, propyl, isopropyl, butyl,

  isobutyl, tert. butyl, cyclopropyl, cy-

  clobutyl, cyclopentyl, cyclohexyl, allyl, crotyl, pentenyl, benzyl, 1-phenylethyl,

  2-phenylethyl, 3-phenylpropyl or 4-phenyl

  butyl, for R6 that of the hydrogen atom of fluorine, chlorine or bromine, that of the hydroxy group,

  methoxy, ethoxy, propoxy, isopropoxy, methyl

  sulfenyl, ethylsulfenyl, methylsulfinyl, propylsulfinyl, benzyloxy, 2-phenylethoxy or 3-phenylpropoxy,

  for R7 that of the hydrogen atom, the hydrogen group

  xy, methoxy, ethoxy, propoxy or isopropoxy or

  for R6 and R7 together that of the methyl group

  for R9 that of methyl, ethyl, propyl or isopropyl and

  for E that of the ethylene, n-propylene, n-butyl-

  lene, n-pentylene, 1-methyl-n-propylene, 1-ethyl-n-propylene, 1-propyl-npropylene, 1,1-dimethyl-n-propylene, 1,1-diethyl-n-propylene,

  1,1-dipropyl-n-propylene, 1-methyl-1-ethyl-

  n-propylene, 1-methyl-1-propyl-n-propylene,

  1-ethyl-1-propyl-n-propylene, 1-methyl-n-

  butylene or 1-methyl-n-pentylene.

  In this case the compounds of general formula I in which

  R1 represents an optionally substituted amino group

  killed by a benzyl group or an alkoxycarbonyl group

  with a total of 2 to 4 carbon atoms, an alkylamino group

  no or dialkylamino in which each alkyl part may contain 1 to 3 carbon atoms, R2 represents a hydrogen, chlorine, bromine or iodine atom, a trifluoromethyl, cyano or nitro group, R3 represents a fluorine atom, of chlorine or bromine or a cyano group, R4 represents a hydrogen atom or a methyl group, R5 represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms optionally substituted with a phenyl group, an allyl group or cyclopropyl,

  A represents the methylene, ethylene or hydro-

  xymethylene and B represents a group corresponding to formulas R8

I R 6

-CH- (CH2) n-D R OR

E

  R 7, R 8, D and n are defined as indicated at the beginning, R 6 represents a hydrogen, fluorine or chlorine atom, a hydroxy, methoxy, ethoxy, benzyloxy, methylsulfenyl or methylsulfinyl group; R 7 represents a hydrogen atom; hydrogen or a group

  methoxy or R6 and R7 together represent the group

thylenedioxy and

  E represents the n-propylene group, 1-methyl-n-pro-

  pylene, 1,1-dimethyl-n-propylene or n-butylene or, when A represents the methylene or ethylene group and / or

  R1 represents an optionally substituted amino group

  killed by a benzyl group or an alkoxycarbonyl group with altogether 2 to 4 carbon atoms, an alkylamino or dialkylamino group, in which each alkyl part may contain 1 to 3 carbon atoms, and / or R2 represents a trifluoromethyl, cyano group; or nitro and / or R3 represents a fluorine atom and / or R5 represents an alkyl group with 1 to 3 carbon atoms optionally substituted by a phenyl group, the allyl or cyclopropyl group, also the ethylene group,

  have particularly favorable properties.

  Particularly preferred compounds of the above-mentioned general formula I, however, are those in which R 1 represents an amino group optionally substituted by an ethoxycarbonyl group, an alkylamino or dialkylamino group, in which each alkyl part may contain 1 to 3 carbon atoms, R 2 represents a chlorine or bromine hydrogen atom or the cyano group, R3 represents a fluorine or chlorine atom or the cyano group, R4 represents a hydrogen atom or the methyl group, R5 represents a hydrogen atom, a group alkyl with 1 to 3 carbon atoms optionally substituted with phenyl, allyl or cyclopropyl, A represents methylene or hydroxymethylene and B represents a group of formula ER6 R7 o

  E represents the n-propylene group, 1-methyl-n-pro-

  pylene, 1,1-dimethyl-n-propylene, n-butylene or, where R1 is ethoxycarbonylamino and / or R2 is cyano and / or R3 is fluorine and / or R5 is alkyl with 1 with 3 carbon atoms optionally substituted by a phenyl group, the allyl or cyclopropyl group, also the ethylene group, R 6 represents a hydrogen atom, a hydroxyl or methoxy group and R 7 represents a hydrogen atom or a group

methoxy.

  According to the invention, the novel compounds are obtained according to the following processes: a) reduction of a compound of general formula R (II)

R2 X -N B

  R in which R1 to R3, R5 and B are defined as at the beginning and X is a group corresponding to the formulas R

- CO - CH -,

OH R4

I 4

- CH - CH-,

0-acyl

- I

- CH - CO -,

CH2 - CO-,

Z R4

-CH - CH- or

Z R

I - | I- o R is

-CH CH2 CH- 4

defined as at the beginning, -

  Acyl represents an organic acyl group such as the acetyl, propionyl or benzoyl group and Z represents a reducing cleavable group such as a bromine or iodine atom or a carboxylic acid ester residue such as the methoxycarbonyloxy group

or ethoxycarbonyloxy.

  According to the meaning of radical X the reduction is carried out in a suitable solvent such as methanol, methanol / water, ethanol, ethanol / water, isopropanol, trifluoroacetic acid, butanol, ethyl ether ,

  tetrahydrofuran, tetrahydrofuran / water, dioxane

  or hexamethyl phosphotriamide, advantageously with a hydride, with aluminum isopropoxide in the presence of a primary or secondary alcohol, with hydrogen catalytic activity or with nascent hydrogen

  at temperatures between -200C and the temperature

  boiling point of the reaction mixture, for example at

  temperatures between -200C and 1000C.

  To prepare a compound of general formula I in

  which A represents the hydroxymethylene group, the

  The reaction is advantageously carried out for example with a complex metal hydride such as sodium borohydride or lithium aluminum hydride in a suitable solvent such as methanol or methanol / water.

  ethyl ether or tetrahydrofuran. at temperatures

  The reduction with aluminum isopropoxide is advantageously carried out in isopropanol at boiling point and, by removing the acetone formed by distillation, the reduction by catalytically activated hydrogen is preferably carried out between -200 ° C. and 500 ° C. advantageously carried out with hydrogen in the presence of a catalyst such as platinum, palladium, Raney nickel or Raney cobalt at room temperature and under a hydrogen pressure of 1-5 bar, and the reduction with

  the incipient hydrogen is advantageously effected for example

  with activated aluminum metal and water or with zinc and hydrochloric acid, at temperatures up to the boiling point of the solvent

used.

  If in this case X represents, in a compound of

  general mule It, the group -CO-CHR4-, the reaction is

  advantageously carried out at temperatures comprised between

  0 and 50 ° C., preferably at room temperature, for example with sodium borohydride in methanol / water, ethanol / water or isopropanol or with lithium aluminum hydride in ether. ethyl or tetrahydrofuran as solvent, or if X is O-Acyl

  group - CH - CO-, the reaction is advantageously effected

  killed with a hydride in a suitable solvent such as ether, tetrahydrofuran or dioxane, for example with diborane or lithium aluminum hydride in tetrahydrofuran at temperatures

  from low to slightly high, for example to

  res between 0 and 100 C, but advantageously

  at the boiling temperature of the reaction mixture.

  To prepare a compound of general formula I wherein A represents methylene or ethylene,

  the reduction is advantageously carried out with a water

  such as sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride or pyridine borane in a suitable solvent such as

  ethanol, isopropanol, tetrahydrofuran, dioxane

  ne, trifluoroacetic acid or hexamethyl phosphotria-

  mide at temperatures between 0 and 1000 C.

  If then X represents in a compound of formula

  the group -CH2-CO-, the reaction is pre-

  If the reaction is carried out at increased temperatures, for example with lithium aluminum hydride in tetrahydrofuran at the boiling temperature of the reaction mixture, or if X is hydroxyethylene, the reaction is preferably carried out with pyridine. -borane in trifluoroacetic acid

  at temperatures between 25 and 100 C,

  posers of the reaction being advantageously combined with

  low temperatures, for example -10 C, or if X is

Z R4 Z R

  has a -CH-CH- or -CH-CH2-CH- group, the reaction is preferably carried out with sodium borohydride, sodium cyanoborohydride or lithium double hydride and

  of aluminum in a suitable solvent such as isopropanol

  hexamethylphosphotriamide, tetrahydrofuran or dioxane at temperatures between 20 and

1000C.

  b) reaction of an optionally formed carbonyl compound in the reaction mixture, of general formula:

K - L, (III)

  in which: 11 K, together with a neighboring hydrogen atom in the alkovyl portion of the L radical, represents an oxygen atom, L has the meanings mentioned at the beginning for B or, at the expense of that of the atom of hydrogen, nour R5, or represents a group of formula: R4

- CH - A '

- CH - A '

  R1 to R4 are defined as in the beginning, and A 'represents the carbonyl, methylene or ethylene group, or its aldehyde hydrate with an amine of general formula: ## STR2 ## wherein:

  M and Q. which are different, possess the meanings

  fications mentioned at the beginning for B and R5 or one of the radicals M or Q represents the group of formula: R4

- CH - A

  R2 o R1 35. R3 R1 to R4 and A are defined as at the beginning, and

with a discount agent.

  The reaction is preferably carried out in a suitable solvent such as methanol, methanol / water,

  ethanol, ethanol / water, butanol, ethyl ether

  that, tetrahydrofuran or dioxane in the presence of a reducing agent at temperatures

  between -20 and 50 C, preferably, however,

  temperatures between 0 and 250C. As a reducing agent, it is possible to use a hydride in this case.

  complex metal or catalytically active hydrogen

matically.

  If the reaction is carried out with a secondary amine

  of general formula IV, it is however preferably carried out in tetrahydrofuran as a solvent and with sodium cyanoborohydride at pH <7, for example at pH 6-6.5 and then with

  sodium borohydride at room temperature.

  If the reaction is carried out with a primary amine

  mayor of general formula IV, the Schiff base formed in the reaction mixture is preferably reduced by means of a complex metal hydride such as sodium borohydride or lithium aluminum hydride in a suitable solvent such as methanol, methanol / water, ethyl ether or tetrahydrofuran at temperatures between

  -200C and the boiling point of the solvent used

  for example at temperatures between

  0 and 800C, or with catalytically activated hydrogen-

  for example with hydrogen in the presence of a catalyst such as platinum, palladium, nickel

  of Raney or Raney's cobalt, at temperatures of

  between 0 and 1000C, preferably at room temperature, and under hydrogen pressure

from 1-5 bars.

  Methylation can also be performed at

  medium of formaldehyde and formic acid as

  gent reduction at increased temperatures, by

  example at the boiling temperature of the reaction mixture

tional.

  If the reaction is carried out with an ingredient of general formula

  in which R 1 represents an amino or alkylamino group with 1 to 3 carbon atoms and with

  a carbonyl compound of the general formula III in the

  which L has the meaning relative to R5, it can be alkylated in particular using

a corresponding excess.

  (c) cleavage of one or more groups

  from a compound of the general formula R4

1 R '

R2 A CH N

B ', (V)

  R 'R3 in which R2, R3 and R4 are defined as in the beginning, R1' has the meanings mentioned at the beginning for R1 or represents a hydroxyl or amino group protected by a protective radical, A "has the meanings mentioned at the beginning for A or represents a hydroxymethylene group protected by a protective group, R5 'has the meanings mentioned at the beginning for R5 or represents a protective group for an amino group, and B' has the meanings mentioned at the beginning for B or represents a group corresponding to the formulas:

R8 R

-CH- (CH2) n-D R6 '

7

  or R 'R' o R8, D, E and n are defined as at the beginning and

  R6 'and R7', which may be the same or different

  have the meanings mentioned at the beginning for R6 and R7 or represent hydroxy groups protected by protective radicals, at least one of the radicals R1 ', A ", R5' and / or B 'to be resorent

  or respectively contain one of the pro-radicals

mentioned above.

  As protective groups, acyl radicals, such as ethoxycarbonyl, acetyl, propionyl or benzoyl or benzyl, and

  for acetyl, methoxycarbonyl or ethoxy-

carbonyl.

  The cleavage of one of the abovementioned acyl and / or alkoxycarbonyl radicals is preferably carried out hydrolytically in an aqueous solvent, by

  example in water, isopropanol / water, tetrahydro-

  furan / water or dioxane / water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkaline base such as sodium hydroxide or potassium hydroxide at temperatures

  between 0 and 1000 C, preferably at room temperature.

  boiling point of the reaction mixture.

  The cleavage of a benzyl radical takes place preferably

  hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium on charcoal, in a solvent such as methanol, ethanol, ethyl acetate or acetic acid optionally crystallizable presence

  an acid such as hydrochloric acid at temperatures of

  between 0 and 50 C, preferably

  at room temperature, and under a hydrogen pressure of 1 to 7 bar, preferably

3 to 5 bars.

  d) to prepare a compound of general formula I in which one of the radicals R2 or R3 represents a hydrogen atom: dehalogenation of a compound of general formula: ## STR1 ## in which: R1, R3 to R5 , A and B are defined as at the beginning

  and Hal represents a chlorine, bromine or iodine atom.

  The dehalogenation takes place preferably in a solvent, advantageously with triphenylphosphine in benzene or toluene, with hydrogen in

  methanol, ethanol, ethyl acetate or tetra-

  hydrofuran and in the presence of a hydrogen

  nation or with a complex metal hydride such as lithium aluminum hydride or with the

  diethoxyaluminum-sodium hydride in tetrahydro-

  furan, dioxane or toluene. Depending on the method used, the reaction is carried out at room temperature or at an increased temperature, for example at temperatures between 600 ° C. and 150 ° C., and at normal pressure or under a slight overpressure; when using Raney nickel or palladium on carbon for example dehalogenation takes place at

  the ambient temperature and under normal pressure.

  e) Alkylation of a Compound of General Formula

R4 R

R2 A-CH-N, (VII)

  In which: R1 to R4 and A are defined as in the beginning, R5 "has the meanings mentioned at the beginning for R5 or represents a hydrogen atom, and B" has the meanings mentioned at the beginning nour B, it being understood that when R5 "does not represent a hydrogen atom, at least one of the radicals R6 or R7 must

  represent a hydroxyl group or Ri a possible amino group

  is substituted by an alkyl group with 1 to 3 atoms

  carbon monoxide, the alkyl group being

  be substituted with a phenyl radical.

  The reaction is carried out in a solvent such as water / methanol, ethanol / water, tetrahydrofuran, dioxane, acetone or dimethylsulfoxide with an alkylating agent such as methyl iodide, sodium sulfate and the like. dimethyl, ethyl bromide, sulphate

  of diethyl, benzyl bromide, bromide of 2-

  phenylethyl or methyl p-toluenesulfonate, possibly

  in the presence of a base such as sodium hydroxide or potassium carbonate advantageously

  at temperatures between -10 and 50 C, preferably

  However, the temperature can be between 0 and 30 C. However, the reaction can also be

performed in the absence of solvent.

  The alkylation of the nitrogen atom may also be effected by means of formaldehyde / formic acid at increased temperature, for example at the boiling temperature of the reaction mixture, or with a compound

  corresponding carbonyl and a metal hydride

  plex, preferably with sodium cyanoborohydride at pH <7, for example at pH 6-6.5, in a solvent such as water / methanol, ethanol, ethanol / water or tetrahydrofuran at temperatures between 0 and 50 ° C, preferably, however, at room temperature. Alkylation of a phenolic hydroxy group can

* in addition be carried out with a diazoalkane correspon-

  in a solvent such as ethyl ether or tetrahydrofuran at temperatures between 0 ° and 50 ° C, preferably, however, at room temperature.

room.

  f) To prepare a compound of general formula I wherein R 1 represents an amino group substituted with an alkanoyl group with 1 to 3 carbon atoms or alkoxycarbonyl with altogether 2 to 4 carbon atoms and R 5 does not represent a hydrogen atom : acylation of a compound of the general formula

R.4 R5

R2

R2 A - CH - N, (VIII)

30. B

  H2N R in which: R2 R5, A and B are defined as at the beginning, by means of a compound of general formula:

Y - CO - R10 (IX)

  in which: R10 represents a hydrogen atom, a methyl or ethyl group or an alkoxy group with 1 to 3 carbon atoms and

  Y represents a group that can be exchanged

  cleophile such as a halogen atom, a nitro-

  phenyl, an imidazolyl group or a radical of formula

-O-COR10.

  The reaction is carried out for example with acetyl chloride, acetic anhydride, anhydride

  propionic acid or a corresponding ester of chloroacid

  roformic, for example ethyl chloroformate, which can also serve at the same time solvent,

  optionally in a solvent such as water / tetra-

  hydrofuran, ethyl ether, tetrahydrofuran, or methylene chloride, optionally in the presence of a base such as triethylamine or pyridine, a tertiary organic base which can also be used at the same time as a solvent, at temperatures ranging from

  between 0 and 100 C, preferably at

  ambient temperature. The reaction can also be

performed in the absence of solvent.

  g) To prepare a compound of general formula I in which D represents a sulfinyl or sulphonyl group: oxidation of a compound of general formula

- R

R4

R2 A-CH - N

C CH - (CH2) n - S0X 352 n D F

R1 R

  {7 R3 in which: R1 to R8, A and n are defined as at the beginning and

m represents the number O or 1.

  The oxidation is preferably carried out in a solvent, for example in water, water / pyridine,

  thanol, methanol, acetone, acetic acid

  formisable, formic acid, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidizing agent advantageously used at temperatures including

between -80 and 100 C.

  To prepare a sulfinyl compound of the general formula I, the oxidation is advantageously carried out with one equivalent of the oxidation agent used, for example

  example with hydrogen peroxide in acetic acid

  crystallizable acid, trifluoroacetic acid or formic acid at 0 to 200C or in acetone at 0 to 600C, with a peracid such as performic acid

  in glacial acetic acid or trihydric acid

  fluoroacetic acid at 0 to 50 C or with m-chloro

  perbenzoate in methylene chloride or chlo-

  roform at -20 to 60 C, with sodium metaperiodate

  in methanol or aqueous ethanol at 15 to 25 C.

  To prepare a sulfonyl compound of the general formula I, the oxidation is advantageously carried out with one or two or more equivalents of the oxidation agent used, for example with the

  hydrogen peroxide in crystalline acetic acid

  sand, trifluoroacetic acid or in the form of

  at 20 to 100 ° C. or in acetone at 0 to 60 ° C., with a peracid such as performic acid or acid

  m-chloro-perbenzoic acid in crystalline acetic acid

  sand, trifluoroacetic acid, methyl chloride,

  thylene or chloroform at temperatures between 0 and 60 C or with potassium permanganate

  in glacial acetic acid, water / sulfur acid

  furic acid or in acetone at 0 to 20 C.

  h) For preparing a compound of general formula I in which D represents an oxygen or sulfur atom and R5 does not represent a hydrogen atom: reaction of a compound of general formula R.

R4 R5

I (I

R2 A H N CH (CH) -V Y (XI)

I 2 n

R1 R8

  R3 wherein: R1 to R5, R8 and n are defined as at the beginning,

  V represents a group that can be exchanged

  cleophile such as a halogen atom or a sulphonic acid ester residue, for example an atom of

  chlorine, bromine or iodine, a p-toluenesulphone group

  nyloxy or methanesulfonyloxy, and A '' 'represents methylene or ethylene, with a compound of the general formula: R

H - Of 6, (XII)

  R in which: R6 and R7 are defined as at the beginning and D 'represents an oxygen or sulfur atom,

  or its alkaline or alkaline earth salts.

  The reaction is advantageously carried out in

  a solvent such as chloroform, tetrahydrofuran

  preferably dioxane or toluene, preferably

  in an anhydrous aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide, optionally in the presence of an alkaline base such as sodium carbonate, potassium carbonate,

  sodium hydroxide, sodium hydride or tert.

  butylate at temperatures between -10 ° C and the boiling point of the solvent used, for example at temperatures between

  -10 and 100 C, preferably, however, at temperatures below

  res between 0 and 500C. The reaction may, however,

  should also be carried out in the absence of solvent.

  A compound according to the invention obtained of general formula I which contains 1, 2 or 3 optically active carbon atoms can then be separated into its

  optically active antipodes, its diastereo-

  isomers and the optical antipodes thereof,

  according to conventional methods.

  Cleavage of a racemate of a compound of formula

  General I above, preferably takes place through the

  mediate a fractional crystallization of a mixture of its diastereoisomeric salts with an optically acid

  active ingredient, for example D (-) - tartaric acid, L (+) -

  tartaric acid, dibenzoyl-D-tartaric acid, di-

  benzoyl -L-tartaric acid, (+) - kampfer-10-sulfonic acid, L (-) malic acid, L (+) - mandelic acid, da-bromo-kampfer-n-sulfonic acid or 1-chinasic acid and subsequent release of the optically active base in each case. Racemate cleavage can, however, also take place by column chromatography

  on an optically active support, for example on

tylcellulose.

  Esracématesdiastéréoisomèrespurs obtained for example by fractional crystallization and / or

  column chromatography on an inert support.

  In addition, a new compound thus obtained can then, if desired, be converted into its physiologically tolerable salts with inorganic or organic acids. As suitable acids for this purpose,

  for example, hydrochloric acid, acetic acid,

  hydrobromic acid, sulfuric acid, phosphoric acid,

  fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and

of maleic.

  Compounds of general formulas II to XII used

  as starting materials are partly new.

  They are obtained according to known methods for oneself and

in itself.

  Thus, for example, a compound of formula

  the general II in which X represents a group

  -CO-CHR4-, by reaction of a-halo-ketone corres-

  with a corresponding amine and a compound of general formula II in which X represents the

  -CH2-CO- group, by reaction of a ph

  corresponding nylacetic acid with a corresponding amine.

  We obtain a compound used as

  starting material, of general formula III in the

  which A 'represents the carbonyl group and R4 represents

  a hydrogen atom, for example by oxidation

  selenium dioxide of an acetophenone corresponding to

  or a compound of the general formula III in which A 'represents a methylene group or

  ethylene by transformation of a hydroxy compound

  corresponding to a corresponding halogenated compound or respectively by acylation of a corresponding hydroxy compound with a corresponding chloroformic acid ester. A compound used as starting material of general formula V is obtained, for example by reaction of a corresponding o-phenylalkyl halide with

a corresponding amine.

  A compound of general formulas VI, VII and VIII, used as starting material for example, is obtained

  by reduction of a corresponding carboxylic acid amide

  or a corresponding aminoacetophenone.

  A compound of general formula X is obtained

  as starting material, for example by alkylation

  corresponding mercapto compound and, where appropriate,

  subsequent oxidation. A compound of general formula XI is obtained

  used as a starting material for example by alkylation

  lation of a corresponding phenylalkylamine.

  As already mentioned at the beginning, the new

  have a low acute toxicity and low secondary activities, valuable pharmacological properties, namely an activity on the heart and circulation, especially an activity on blood pressure, anti-arrhythmic activity and / or

tonic-cardio.

  For example, the following compounds:

  A = 1- (4-amino-3,5-dichlorophenyl) -2-N- [3- (4-methoxy) -2-

phenyl) -propyl7-amino7-ethanol,

  B = 1- (4-amino-3-cyano-5-fluoro-phenyl) -2- [N- [3- (4-methyl) -2-

  methoxy-phenyl) -propyl7-methylamino] -ethanol,

  C = 1- (4-amino-3,5-dichlorophenyl) hydrochloride

  ZF (3-phenyl-propyl) -2-propylamino] -ethanol,

  D = 1- (4-amino-3,5-dichloro-phenyl) -2- [N-f3- (4-hydroxy);

  phenyl) -1-methyl-propyl7-méthylamino7-ethanol,

  E = N-Z1-methyl-2- (4-amino-3,5-dichlorohydrochloride)

  ro-phenyl) -ethyl] -N-3- (4-methoxy-phenyl) -propyl7-

amine,

  F = N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl-N-13- (4-

  chloro-phenyl) -propyl7-isopropylamine,

  G = N - / - (4-chloro-phenyl) -propyl] -N-Z2- (3,5-dichloro)

  4-isopropyl-amino-phenyl) -ethyl-isopropylamine and

  H = N - / - (4-amino-3-bromo-5-cyano-phenyl) -ethyl7-N-

  [4- (4-methoxy-phenyl) -butyl-7-methylamine have been studied as follows with respect to their biological activities: 1. Measurement of the contractility parameter dp / dtmax or respectively of the heart rate on

narcotized cats.

  Male and female cats with a weight of

  2-4 kg were narcotized with sodium pentobarbital (40 mg / kg intraperitoneally) and

  maintain the narcosis, it has been continuously infused

  sodium pentobarbital (8 mg / kg per hour).

  The animals breathed spontaneously.

  Body temperature was maintained at 380C

  with a heating pad and a thermostat.

  The pressure in the left ventricle of the heart was recorded by means of a setting device

  (Millar PC 350) introduced into the ventrum

  left by the right aorta and it was determined continuously by means of a

  differentiation, the rate of increase of

  dp / dt from the pressure signal.

  Heart rate was measured continuously

  using a grass tachograph (model 7P4).

  The triggering signal was either an electrocardiogram or the left ventricular pressure curve. Saving settings

  took place on a Grass polygraph.

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

i.v.

  The maximum activity and the time after application were given up to which the activity returned to the

half of the maximum effect.

  The following tables contain the found values

TABLE I

  Substance% increase in half-time dp / dtmax in minutes

A + 93 38

B + 124> 140

C + 83 112

D + 105> 100

TABLE II

  Substance% Decrease Time Half Value Heart Rate in Minutes

E - 27 39

F - 17 150

G - 13> 90

H - 14> 52

2. Acute toxicity.

  Male and female mice with a weight of about

  20 g were given a dose of each of the test substances in a V. saphena (0.1 or 0.2 ml / 10 g body weight) respectively in the stomach respectively. After an observation period of 14 days, the LD50 was determined according to the method of Lichtfield and Wilcoxon: Substance LD50 mg / kg

i.v. p.o.

A 19> 100

C 32,250

26 -

  Because of their pharmacological properties, the compounds prepared according to the invention are suitable for

  treatment of heart disease and circulation.

  Thus, the compounds which act in a positively inotropic manner are particularly suitable for the treatment

  heart failure, and the compounds that lower

  heart rate are particularly suitable

  for the treatment of cardiac rhythm disturbances

  that and coronary heart disease.

  For this purpose, the new compounds, possibly in combination with other active substances, can be converted into the usual galenic preparations such as tablets, tablets, powders, suppositories, suspensions, ampoules or drops. The unit dose in adults is then from 5 to 75 mg, preferably from 10 to 50 mg, and administered from

1 to 4 times a day.

  The following examples serve to illustrate the in-

  without limiting its scope

Example 1

  1- (4-amino-3,5-dichloro-phenyl) -2- / N-Z3- (4-methoxy

  Phenyl) -provyl7-methylamino - ethanol.

  To a solution of 3.45 g (9 mmol) of 4'-amino-

  3 ', 5'-dichloro-2- [N- / 3- (4-methoxy-phenyl) -propyl] J-Me

  thylamino-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 value is during this

  maintained between 3 and 6 by means of hydrochloric acid

  2N. When the addition is complete, stirring is continued for 30 minutes and the solution is concentrated on a rotary evaporator. The residue obtained is partitioned between 100 ml of ether and 100 ml of ammonia solution.

  2N. The ethereal phase is washed with water, dried over

  sodium fate and concentrated. The remaining oil is

  Mapped on silica gel fiMacherey and Nagel 0.062 to 0.210 mm (70 230 mesh ASTM)] with chloride

  methylene: methanol = 19: 1 as eluent.

  The fractions which contain the desired compound are combined, evaporated and the oil obtained is freed

  solvent residues, under vacuum at 40 C.

  IR (methylene chloride) spectrum: -1 OH 3610 cm -1 NH 3400 + 3490 cm 1

2 -

  CH2 2850 + 2940 cm OCH3 2830 cm-1 -1 N-alkyl 2800 cm C = C 1610 cm1 UV spectrum (ethanol): X max. 243 nm (0.23) 280 nm (0.08) 300 nm (0.08)

Example 2

  1- (4-amino-3,5-dichlorophenyl) -2-fN- hydrochloride

  (3-Dhényl-DroDYl) -méthylamino7-ethanol.

  g (0.035 mole) of 4'-amino-2-bromo-3 ', 5'-dichlo-

  ro-acetophenone, 6.7 g (0.036 mol) of N- (3-phenylpropyl) methylamine hydrochloride 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 left to stand overnight at room temperature, washed with water, dried

  on sodium sulphate and evaporated under vacuum with evaporation

  rotator. The oily residue, consisting of 4'-amino

  3 ', 51'-dichloro-2- [N- (3-phenylpropyl) -méthylamino_-acetic

  crude tophenone is dissolved in 100 ml of 90% ethanol.

  5 g of sodium borohydride are added portionwise under

  stirring and cooling on the outside with water.

  The mixture is left standing for one hour at room temperature and the excess sodium borohydride is decomposed with

  acetone. After dilution with water, extract with chlorine

  methylene chloride. The methylene chloride phase is separated off, washed with water, dried over sodium sulphate and concentrated under vacuum on a rotary evaporator. The yellowish oily residue is chromatographed on silica gel with methylene chloride: ethyl acetate = 4: 1 as eluent. The fractions which contain the desired compound are evaporated. The remaining oily residue is dissolved in isopropanol, acidified with ethereal hydrochloric acid and added to it.

  ether until crystallization begins.

  A colorless crystalline product is obtained.

  Melting point: from 85oC (with sintering).

Example 3

  1- (4-Amino-3,5-dichlorophenyl) -2-FN-Z3- (4-hydroxy-phenol)

  nyl) -l-methyl-proDvl / methylamino / -ethanol. To a solution cooled by ice water of 0.1

  mole of 4'-amino-3 ', 5'-dichloro-2- [N- / 3- (4-hydroxy-phenyl) -2-

  nyl) -1-methyl-propyl-7-methylamino] -acetophenone in 300 ml of tetrahydrofuran and 50 ml of water, 0.2 mol of sodium borohydride is added portionwise and with stirring. The reaction solution is further stirred for 60 minutes at room temperature and after

  acidification with 2N hydrochloric acid,

  Trahydrofuran is distilled off by evaporation.

  rotator. The residue obtained in a hydrochloric acid medium

  Aqueous hydrite is extracted twice with 250 ml portions of ether after addition of 8.5 N ammonia to basic reaction, the ethereal extract is then

  washed twice with 75 ml portions of water and

  on magnesium sulphate. The filtrate is concentrated

  by rotary evaporator and the evaporation residue ob-

  held is purified on silica gel 60 / Macherey and Nagel) 0.062 to 0.210 mm (70 - 230 mesh ASTM)]. As

  that eluent, a mixture of methyl chloride

  lene: methanol = 30: 1. The evaporation residue obtains

  after fractionation and evaporation concentration

  rotator crystallizes after seeding. Screams-

* Crude levels are recrystallized from the chloride of

  thylene and are in the form of a 1: 1 mixture

  diastereoisomeric racemates.

Melting point: 112-115 C.

Example 4

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

  phenyl) -l-methyl-Dropyl7-methylamino] -ethanol.

  0.02 mole of 1- (4-amino-3,5-dichlorophenyl) -2-

  [N-3- (4-hydroxy-phenyl) -1-methyl-propyl7-méthylamino7-

  Ethanol are dissolved in 22 ml of 1N sodium hydroxide solution and 10 ml of water. To this solution, 0.022 moles of dimethyl sulphate are added dropwise with stirring and cooling with ice-water and stirred.

  the reaction solution 20 hours at room temperature

  after addition of 50 ml of tetrahydrofuran.

  Then 100 ml of ether are added, the organic phase is separated off, washed with 50 ml of 0.5N sodium hydroxide solution, three times with 75 ml portions of water and dried.

  on magnesium sulfate. The organic phase is concentrated

  rotary evaporator and the evaporation residue obtained is purified on 60 ml silica gel and 0.022 to 0.210 mm (70 - 230 mesh ASTM)

  methylene chloride: methanol = 30: 1 as

  luant. The oily evaporation residue obtained is

  collected with solvent residues under vacuum and with sulfur acid.

  furique. The oil obtained is in the form of a

  1: 1 mixture of diastereoisomeric racemates.

  IR spectrum (methylene chloride): OH 3200 - 3500 cm 1 broad (as NH2) NH2 3480 + 3390 cm -1 CH2 2930, 2850 cm OCH3 2830 cm1 -1 N-alkyl 2800 cm1 -1 C = C 1580, 1510, 1485 cm -1 C = C + NH2 deformation 1620 cm UV spectrum (ethanol): X max. 244 nm (0.27) 280 nm (0.08) 300 nm (0.08)

Example 5

  1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2-

  [N- / N- (4-methoxy-phenyl) -proDovl-amino] -ethanol. In a solution of 1.16 g (0.01 mol) of selenium dioxoxide in 12 ml of dioxane and 0.7 ml of water, the mixture is stirred into portions at 60 ° C. with stirring.

  0.5 g of celite and then 2.5 g (0.01 mole) of 4'-ethylene

  xycarbonylamino-3'-cyano-5'-fluoro-acetophenone. Ensui-

  you heat for 4 hours at the temperature of

  flow and the insolubles are then removed by filtration.

  In the thus obtained solution of 4'-ethoxy-carbonyl-

  amino-3'-cyano-5'-fluoro-phenylglyoxal, introduced

  drip, after cooling and cooling

  freezing with ice, 2.01 g (0.01 mol) of 3- (4-methoxy-phenyl) -propylamine hydrochloride and 1.01 g (0.01 mol) of triethylamine> dissolved in 12 ml

  ethanol. The solution containing 4'-ethoxycarbonyl-

  amino-3'-cyano-5'-fluoro-phenyl-glyoxylidène-3- (4-Me

  thoxy-phenyl) -propylamine is added by

  portions with 1.5 g of sodium borohydride, under stirring

  ice-cooling and allowed to stand overnight at room temperature. Then we

  breaks down excess sodium borohydride by

  tone, concentrate under vacuum to a small volume,

  water is added and extracted with methyl chloride.

  lene. The methylene chloride solution is washed with water, dried over sodium sulphate and evaporated under vacuum to dryness. The remaining oily residue is chromatographed on 200 g of silica gel with methylene chloride: methanol = 20: 1 as eluent. Fractions that contain the product

  searched are evaporated. We obtain a crystalline product

tallin colorless.

Melting point: 111-112 C.

Example 6.

  1- (4-éthoxvcarbonylamino-3-cyano-5-fluoro-phény1) -2-

  N- (3- (4-methoxy-phenyl) -propyl-methylaminoethanol.

  In a solution of 6.6 g (0.06 mol) of dioxygen

  of selenium in 60 ml of dioxane and 2 ml of water are added in portions, at 60 C and stirring, 15 g

  (0.06 mole) 4'-ethoxycarbonylamino-3'-cyano-5'-fluoro

  ro-acetophenone. Then, the mixture is heated for 4 hours at reflux temperature and then diluted with 100 ml of tetrahydrofuran and the insolubles are removed by

  filtration. To the thus obtained solution of 4'-ethoxy-

  Carbonylamino-3'-cyano-5'-fluoro-phenylglyoxal is added after cooling to room temperature

  7 g (0.06 mole) of N-t3- (4-methoxy-phenyl) -propyl-7-

  Methylamine dissolved in 100 ml of tetrahydrofuran.

  To this solution is added portionwise 8 g (0.13 mol) of sodium cyanoborohydride, while maintaining the solution at pH 6 by dropwise addition of acid

  2N hydrochloric acid. One night is allowed to rest at

  at room temperature, 5 g of sodium borohydride are added.

  dium and let it rest for 5 hours at room temperature.

  ambient temperature. Subsequently, the excess sodium borohydride is decomposed with acetone, diluted with water and extracted with methylene chloride. The methylene chloride phase is washed with water, dried over sodium sulphate and evaporated under vacuum to dryness. The remaining oily residue is chromatographed on 700 g of

  silica with ethyl acetate as eluent.

  The fractions which contain the desired compound are combined, evaporated and the oil obtained is freed

  under vacuum at 40 C solvent remains.

  IR spectrum (methylene chloride): -1 OH 3600 cm -1 NH 3400 cm -! CH2 2930 cm -1OCH3 2830 cm 0CH3 2830 cm N-alkyl 2800 cm1

CN 2220 cm-

  NHCOOC2H5 1735 cm1 UV spectrum (ethanol): X max. 228 nm (shoulder, 0.19) 240 nm (shoulder, 0.12) 285 nm (0.06) UV spectrum (ethanol + KOH): X 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 ester dihydrochloride

  N-z3- (4-methoxy-phenyl) -propoyl7-methylamine. 2.9 g (0.077 mol) of lithium aluminum hydride are suspended in 100 ml of

  absolute tetrahydrofuran in a nitrogen atmosphere.

  A solution of 14.4 g (0.031 g) is added dropwise.

  mole) of 4-amino-3,5-dibromo-N- / 3- (4-methoxy-phenyl) -

  propyl7-N-methyl-phenylacetamide in 100 ml of tetrahydrofuran

  absolute hydrofuran, with stirring at room temperature. Then, refluxing for one hour. Excess lithium aluminum hydride is decomposed with ethyl acetate and water and 1N sodium hydroxide solution is added dropwise until the inorganic material precipitates in the form of granules. . The supernatant tetrahydrofuran phase

  is separated by decantation, dried over sodium sulfate

  dium and concentrated on the rotary evaporator. One chroma-

  Macherey and Nagel silica gel plot 0.062 to 0.210 mm (70-230 mesh ASTM) with methylene chloride: methanol = 19: 1 as eluent. The fractions with the desired product are combined and concentrated. The oil obtained is dissolved in a little absolute ethanol and the crystalline dihydrochloride is obtained using ethanolic hydrochloric acid in

Z498596

adding ether.

  Melting point: 168-171 ° C. (decomp.).

Example 8.

  N-Z2- (4-amino-3,5-dibromo-phenyl) -éthyl7-N-4- (4-methodical

  xv-phenyl) -butvl7-methylamine. 2.9 g (0.077 mol) of lithium aluminum hydride are suspended in 100 ml of

  absolute tetrahydrofuran in a nitrogen atmosphere.

  Stirring is added dropwise at room temperature

  a solution of 15.0 g (0.031 mol) of 4-amino

  3,5-dibromo-N- [4- (4-methoxy-phenyl) -butyj-N-methylphenyl

  acetamide in 100 ml of absolute tetrahydrofuran. Then we heat up

  an hour to reflux. Lithium and alumina double hydride in ex-

  This is decomposed with ethyl acetate and water and 1N sodium hydroxide solution is added dropwise until

  that the mineral material precipitates in the form of

  Nules. The supernatant tetrahydrofuran phase is separated by decantation, dried over sodium sulphate

  and concentrated on the rotary evaporator. We chromatograph

  on silica gel [Macherey and Nagel., 0.062 to 0.210 mm (70-230 mesh ASTM)) with methylene chloride: methanol = 19: 1 as eluent. The fractions with the desired product are combined and concentrated. The oil obtained is freed under vacuum

at 40 C solvent remains.

  IR spectrum (methylene chloride): -1 NH 2 3380 + 3470 cm -1 N-alkyl 2790 cm -1 OCH 3 2830 cm -1 CH 2 aliphat 2850 cm -1 2930 cm -1 C = C 1610 cm UV spectrum (ethanol): X max. 246 nm (0.24) 281 nm (0.08) 305 nm (0.09)

Example 9.

  N- [2- (4-amino-3-chloro-5-cyano-phenyl) -ethyl] -N-Z-3- (4-

  methoxy-phenyl) -propyl-methylamine.

  6.6 g (0.014 mol) of 1- (ethoxycarbonyloxy) -1- (4-

  amino-3-chloro-5-cyano-phenyl) -2-N-zr3- (4-methoxy-phe-

  nyl) -propyl-7-methylamino-2-ethane are dissolved in 70 ml of isopropanol and stirred overnight at room temperature.

  with 5.5 g (0.14 mol) of sodium borohydride.

  The solution obtained is concentrated to dryness and taken up in 100 ml of water. Sodium borohydride

  excess is decomposed with 50 ml of 2N hydrochloric acid.

  Then, the mixture is made basic again with 2N aqueous ammonia and extracted twice with 150 ml of ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated. The oil obtained is chromatographed on silica gel [Macherey and Nagel,

  0.062 to 0.210 mm (70 - 230 mesh ASTM) J with chlorine

  methylene chloride: methanol = 19: 1 as eluent.

  The fractions which contain the desired compound are combined and evaporated and the oil obtained is freed

  under vacuum at 40 C solvent remains.

  IR spectrum (methylene chloride): -1 NH 2 3400 + 3500 cm 1 2-1 N-alkyl 2800 cm -1 CH 2 aliphat. - 2860 + 2940 cm -1 C = C aromat. 1600 cm -1 deformation of NH2 1625 cm 1 UV spectrum (ethanol): X max. 244 nm (0.23) 278 nm (0.06) 330 nm (0.13)

Example 10

  N-Z2- (4-amino-3-chloro-5-cyano-phenyl) -éthvl7-N- / A- (4-

  methoxy-phenyl) -propyl7-methylamine.

  1.3 g (0.0027 mole) of 1- (4-amino-3) iodide

  chloro-5-cyano-phenyl) -2- / N- [3- (4-methoxy-phenyl) -Pro

  pyl7-methylamino2-ethyl are dissolved in 30 ml of

  méthylphosphotriamide. To this solution is added 0.25 g (0.004 mol) of sodium cyanoborohydride and heated

  then 3 hours at 70 ° C. After cooling,

  read with 100 ml of water and extracted with ether. The solution

  ethereal solution is washed with water, dried over

  sodium and concentrated under vacuum to dryness. The re

  The remaining oily residue is chromatographed on silica gel with methylene chloride: methanol = 20: 1

  as an eluent. The oily evaporation residue ob-

  held is vacuum removed solvent residues.

  Mass spectrum M: found 357/59.

Molecular Weight 357.8.

Example 11

  1- (4-amino-3-fluoro-phenyl) -2-N- [3- (4-methoxphenyl)] -

  propvl7-méthylamino7-ethanol. 2 g of 10% palladium on carbon are added

  to a solution of 3.9 g (0.0095 mole) of 1- (4-amino-3-

  bromo-5-fluoro-phenyl) -2- / N-f (4-methoxy-phenyl) -Pro

  2-methylamino-ethanol in 50 ml of methanol and is autoclaved at room temperature and

  under a pressure of 3.5 bar. When the theo-

  Hydrogen was fixed, filtered off and the filtrate concentrated on a rotary evaporator. The 4 g of oil then obtained are chromatographed on gel

  of silica [Macherey and Nagel, 0.0062 to 0.210 mm (70-

  230 mesh ASTM)] with chloroform: methanol = 19: 1 as eluent. Fractions containing the desired substance are pooled and concentrated. The resulting oil is dissolved in isopropanol and the hydrochloride is precipitated with isopropanol hydrochloric acid and ethyl acetate. The crystals are dewatered, washed with a little cold isopropanol and dried under vacuum.

Melting point: 110 C (decomp.).

Example 12.

  1 -. (4-éthoxvcarbonvlamino-3-bromo-phenyl) -2- / N - I4- (4-Me

  methoxy-phenyl) -butyl7-methylamino - ethanol.

  To a solution of 5.1 g (0.0125 mol) of 1- (4-

  amino-3-bromo-phenyl) -2-jÂi- [44- (4-methoxy-phenyl) -butyl] -

  Methylamino-ethanol in 40 ml of absolute pyridine, 1.5 ml (0.015 mole) of ethyl chloroformate was added while cooling with ice to OC. The resulting solution is kept in the refrigerator cabinet at + 40C overnight. The pyridine is then distilled off on a rotary evaporator C. The oil obtained is dissolved in 100 ml of methylene chloride and washed twice with 100 ml of water. The organic phase is dried over sodium sulphate

  sodium, filtered and evaporated on a rotary evaporator.

  The oil obtained is chromatographed on silica gel úMacherey and Nagel, 0.0062 to 0.210 mm (70 - 230 mesh ASTM)] with methylene chloride: methanol = 9: 1

  as an eluent. Fractions that contain the sub-

  stance are gathered and concentrated. The oil obtained is freed from the solvent residues under

empty at 40OC.

  IR spectrum (methylene chloride): OH 3610 cm1 -! NH 3400 cm -1 OCH 3 2830 cm -1 N-alkyl 2800 cm -1 - CH 2 aliphat. 2860 + 2940 cm -1 -1 C = O 1735 cm -1 C = C aromat. 1610 cm UV spectrum (ethanol): X max. 224 nm (0.42) 240 nm (0.29) 280 nm (0.04)

Example 13

  N- [2- (4-amino-3,5-dichloro-ohenyl) -ethyl) -N- [3- (4-hydroxy) -N

  N-phenyl-1-methyl-9-dimethyl-methylamine.

  0.012 mole N-f2- (4-amino-3,5-dichlorophenyl)

  ethyl 7-N- [3- (4-hydroxy-phenyl) -1-methyl-propyl] -amine are dissolved in 13 ml of 1N sodium hydroxide solution. We

  add dropwise to the solution 0.014 mol of sulphate

  dimethyl fate by cooling with ice water

  After a short time, the product of the pre-reaction

  cipite in the fatty state; it is dissolved by addition

  150 ml of tetrahydrofuran. The reaction solution

  It is stirred for 24 hours at room temperature and then extracted twice with 1 ml portions of ether. The organic extracts are washed with water, dried over magnesium sulphate and concentrated under vacuum. The purification of the evaporation residue obtained is carried out on silica gel (Polygosil

  -1525; Macherey and Nagel) with chloride of

  thylene: methanol / concentrated ammonia = 19: 1: 0.1.

  The oily evaporation residue is freed under

  empty, on potassium hydroxide solvents retained.

  IR (methylene chloride) spectrum: -1 OH 3580 cm -1 -NH 2 3480 + 3380 cm 1 CH 2 2930, 2960, 2850 cm -1 N-alkyl 2790 cm -1 C = C 1580, 1510, 1480 cm -1 C = C + NH2 deformation 1610 cm -1 UV spectrum (ethanol): X max. 240 nm (0.26, shoulder) 288 nm (0.08) 301 nm (0.08) UV spectrum (ethanol + KOH): X max. 241 nm (0.56) 299 nm (0.17)

Example 14.

  1- (4-amino-3,5-dichloro-phenyl) -2 - /} N-Z- (4-methoxy-Dhé-

  nylsulfinyl) -éthyl7-méthylamino7-ethanol.

  7.0 g of 1- (4-amino-3,5-dichlorophenyl) -2-N-

  / 2- (4-methoxy-phenyl-sulfenyl) -éthyl7-méthylaminoj-

  Ethanol are dissolved in 100 ml of glacial acetic acid and added dropwise, with stirring at room temperature, 2.0 g of 30% hydrogen peroxide. The mixture is stirred overnight at the same temperature and the solution is then evaporated in vacuo. The residue is taken up in the water

  and added with potassium carbonate until

  basic It is extracted with dichloromethane, the organic phase is washed with water, dried over magnesium sulphate and evaporated in vacuo. The residue is purified by chromatography (column: 40 × 200 mm, silica gel 60 from E. Merck, grain size:

  0.06 - 0.2 mm, methylene chloride: methanol = 50: 1).

  After evaporation under vacuum of the desired fractions,

  it remains the substance mentioned in the form of oil.

  IR spectrum (methylene chloride): -1 NH 2 3390 + 3480 cm CH 2 2940 cm -1 OCH 3 2840 cm -1 -1 N-alkyl 2800 cm C = C 1590, 1-510 + 1480 cm -1 S = 0 1040 cm -1 (shoulder) UV spectrum (ethanol): 1 max. 244 nm (0.54) 300 nm (0.07; shoulder)

Example 15

  1- (4-Amino-3,5-dichloro-n-phenyl) -2- / N- [2- (4-methoxy) -phenyl) -2-

  nylsulfonyl) -ethyl-7-methylamino-ethanol.

  7.0 g of 1- (4-amino-3,5-dichlorophenyl) -2-fN-

  2- (4-methoxy-phenyl-sulfenyl) -éthyl7-methylamino] -

  ethanol are converted to sulfinyl derivative as described in Example 14. The residue (4.7 g) obtained after

  Evaporation of the dichloromethane extract is

  under 100 ml of dioxane and 30 ml of water and add

  4.0 g of magnesium sulphate. We add

  2.5 g of potassium permanganate per

  checked, with stirring. When the addition is complete

  The mixture is stirred for a further 2 hours and then the insolubles are removed by filtration through celite. Hunting

  dioxane under vacuum and shared between the dichloro-

  methane and water. The evaporation residue of the

  dried organic phase is purified twice

  Matography (1. column: 60 x 300 mm, Al203 II neutral,

  methylene chloride: tetrahydrofuran = 5: 1; 2.

  column: 35 x 300 mm, silica gel 60 from E. Merck, grain size: 0.015 - 0.025 mm, dichloromethane, 8.5 bar). After evaporation under vacuum of the desired fractions, it remains the substance mentioned

in the form of oil.

  IR spectrum (methylene chloride): -1

NH2 3395 + 3480 cm.

  -1 CH 2 2940 cm -1 OCH 3 2840 cm -1 N-alkyl 2800 cm -1 C = C 1595, 1520 + 1495 cm -1 S0 1150 + 1315 cm UV spectrum (ethanol): X max. 241 nm (0.59) 300 nm (0.09)

Example 16

  1- (4-amino-3,5-dichloro-phenyl) -2 - N-Z3- (4-hvdroxy-

  DhénYl) -proyl17-méthylamino7-ethanol.

  9.2 g of 1- (4-amino-3,5-dichlorophenyl) -2-ZN-

  B- (4-Benzyloxy-phenyl) -propyl] -methylamino) -ethanol are dissolved in 150 ml of methanol. The solution is supplemented with 1 g of 5% palladium on carbon

  and hydrogenated at room temperature under a

  5 bars of hydrogen. When the quantity

  hydrogen abutment has been absorbed, the catalyst is

  separated by filtration, the solution is evaporated

  to dryness on a rotary evaporator and the oily residue is chromatographed on silica gel with

  methylene chloride / methanol = 20: 1 as eluent.

  Fractions that contain the desired compound

  are combined, evaporated, and the resulting oil is

  packed with the solvent remains under vacuum at 40 C.

  IR (methylene chloride) spectrum: OH 3580 cm -1 OH 3580 cm NH 2 3395 + 3495 cm -1

NH2 1

N-alkyl 2800 cm-1

Example 17

  1- (4-amino-3-bromo-phenyl) -2- [N] -4- (4-methoxyphenyl) -

butyl7-méthylamino7-ethanol.

  3 g of 1- (4-acetamino-3-bromo-phenyl) -2-ZN-Z-4- (4-

  methoxy-phenyl) -butyl-methylamino] -ethanol are heated

  at reflux temperature for 1 hour in ml of half-concentrated hydrochloric acid. After cooling, the medium is made alkaline with 1N sodium hydroxide solution, extracted with methylene chloride, the methylene chloride solution is washed with water, dried over sodium sulfate and concentrated.

  to dryness on a rotary evaporator. The oil remains

  aunt is chromatographed on silica gel with

  methylene chloride / methanol = 20: 1 as eluent.

  From the fractions which contain the compound

  sought, we get this one in the form of oil by

evaporation under vacuum at 400C.

  IR (methylene chloride) spectrum: -1 OH 3590 cm NH 2 3380 + 3470 cm -1 -1 N-alkyl 2800 cm -1 OCH 3 2830 cm

3 -1

  CH2 aliph. 2850 + 2930 cm -1 C = C arom. 1620 cm UV Spectrum (ethanol): At max. 224 nm (O, 20) 243 nm (0.14) 280 nm (0.04) 300 nm (0.04)

Example 18.

  1- (4-amino-3-cyano-5-fluorophenyl) -2) / N-Z3- (4-methoxy

  phenyl) -proDyl1-methylamino] -ethanol.

  Prepared from 4'-amino-3'-cyano-5'-fluoro

  2- [N- [3- (4-methoxy-phenyl) -propylj-methylamino] -acéto-

  phenone and sodium borohydride in methanol

24 9'8596

  at 90% in a similar manner to Example 1.

  IR spectrum (methylene chloride): -1HeO 3590 cm1

NH2 3400 + 3490

CH2 2850 + 2940

  -1 OCH3 2830 cm -1 N-alkyl 2800 cm -1 CEN 2210 cm deformation of NH2 1635 cm C = C aromat. 1610 cm1 UV spectrum (ethanol): 1 max. 242 nm (0.3) 325 nm (0.14) cm -1 cm

* Example 19.

  1- (4-amino-3-bromo-5-cyano-phény1Y-2-Fn / 3- (4-methoxy-

  Phenyl) -propvl7-méthylamino7-ethanol.

  Prepared analogously to Example 1 from

  of 4'-amino-3'-bromo-5'-cyano-2- [N-Z3- (4-methoxy-phenyl)

  nyl) -propyl-7-methylamino] -acetophenone and borohy-

  sodium chloride in 80% methanol.

  IR spectrum (methylene chloride): -1 OH 3590 cm low -1 NH2 3400 + 3480 cm CH2 2850 + 2930 cm -1 CEN 2200 cm1

C = 1640 cm C

  UV spectrum (ethanol): X max. 243 nm (0.20) 280 nm (0.04) 334 nm (0.12)

Example 20.

  1- (4-amino-3,5-dibromo-phenyl) -2-EN-3- (4-methoxy-Dhé-

  nyl) -Dropyl - methylamino] ethanol. Prepared analogously to Example 1, from

  4'-amino-3 ', 5'-dibromo-2- [N-Z3- (4-methoxy-phenyl) -

  propyl-methylamino-7-acetophenone and borohydride

sodium in 80% methanol.

  IR (methylene chloride) spectrum: -1H, 3590 cm -1 NH 2 3380 + 3460 cm -1 -1 N-alkyl 2800 cm OCH 3 2830 cm -1 CH 2 aliphat. 2850 + 2940 cm C = C 1610 cm 1 UV spectrum (ethanol): At max. 244 nm (0.16) 303 nm (0.06)

Example 21.

  1- (4-Amino-3,5-dichloro-phenyl) -2- / ZN-R1, 1-dimethyl-3-

  (4-methoxy-phenyl) -propl17-amino7-ethanol.

  Prepared in a similar way to Example 13,

  1- (4-amino-3,5-dichlorophenyl) -2-FN-Z1, 1-dimethylamine

  thyl-3- (4-hydroxy-phenyl) -propyl] -amino] -ethanol, tetrahydrofuran, sodium hydroxide solution and sulphate

of dimethyl. Oil.

  IR spectrum (methylene chloride): 1 OH 3600 cm 1 NH 2 3390 + 3490 cm CH 2 2860 + 2960 cm -1 OCH 3 2830 cm C = C 1580 + 1620 cm UV spectrum (ethanol): max. 243 nm (0.23) 280 nm (0.08) 300 nm (0.08)

Example 22.

  1- (4-amino-3,5-dichloro-ohényl) -2-fN-1l, 1-dimethyl-3-

  (4-methoxy-phenyl) -proDyl / methylamino / -ethanol.

  Prepared in a similar way to Example 13,

  1- (4-amino-3,5-dichlorophenyl) -2-ZN-Zl, 1-di-

  methyl-3- (4-hydroxy-phenyl) -propyl-7-amino-ethanol, tetrahydrofuran, sodium hydroxide solution and sulphate

of dimethyl. Oil.

  Calculated: C 61.31 H 6.86 C1 17.24 N 6.81 Found: 61.13 6.99 17.25 6.75

Example 23.

  1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-Fn / n

  (4-methoxyphenyl) propyl, 7-methylamino / -ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3'-chloro-5'-trifluoromethyl-2-ZN - [- (4-methoxy-phenyl) propyl] -methylaminoacetophenone and sodium borohydride in 80 X methanol. IR spectrum (methylene chloride): 1 OH 3590 cm -1 NH 2 3410 + 3510 cm -1 N-alkyl 2800 cm -1 OCH 3 2830 cm 2 CH 2 aliphat. 2850 + 2940 cm -1 C = C 1630 cm UV spectrum (ethanol): X max. 225 nm (0.36) 245 nm (0.31) 280 nm (0.05) 310 nm (0.1)

Example 24.

  1- (3,5-dichloro-4-hydroxy-phenyl) -2-fN-z- (4-methoxy

  phenyl) -prop1l7-méthylamino7-ethanol.

  Prepared in a similar manner to Example 1,

  3 ', 5'-dichloro-4'-hydroxy-2- [N-L3- (4-methoxy) -2-

  phenyl) -propyl-7-methylamino] -acetophenone and boron

  sodium hydride in 80% methanol.

Melting point: 156-157 C.

Example 25

  1- (3,5-dibromo-4-hydroxy-phenyl) -2-fN-a3 (4-methoxy

  Phenyl) -propyl 17-methylamino-ethanol.

  Prepared in a similar manner to Example 1,

  3 ', 5'-dibromo-4'-hydroxy-2- [N-Z3- (4-methoxy) -2-

  phenyl) -propyl-methylaminol-acetophenone and boron

  sodium hydride in 80% methanol.

  Melting point of the hydrochloride: 159-162 C.

Example 26.

  1- (4-amino-3-bromo-5-fluoro-phenyl) -2-fN-3- (4-methoxy

  Dhényl) - "ropyl / 7-méthylamino7-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3'-bromo-5'-fluoro-2- [N-Z- (4-methoxy) -2-

  phenyl) propyll) methylamino} -acetophenone and boron

  sodium hydride in 80% methanol. Melting point of the hydrochloride (amorphous): from

60 C.

Example 27.

  1- (4-amino-3-chloro-5-fluoro-phenyl) -2-fN-3- (4-methodical

  xv-phenyl) propyl / -méthvlamino7-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3'-chloro-5'-fluoro-2-N-L3- (4-methoxy)

  phenyl) -propyl-2-methylamino-7-acetophenone and boron

  sodium hydride in 80% methanol.

  Melting point of the hydrochloride: 103-108 ° C (decomp.).

Example 28.

  1- (4-amino-3-chloro-5-cyano-phenyl) -2-Fn / A- (4-methoxy

  phenyl) -DroDpYl] -méthylamino7-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3'-chloro-5'-cyano-2- [N-Z3- (4-methoxy) -2-

  phenyl) -propyl-2-methylamino] -acetophenone and boron

  sodium hydride in methanol at 80 S. IR spectrum (methylene chloride): -1 OH 3590 cm -1 -1 NH 2 - 3400 + 3500 cm -1 N-alkyl 2800 cm 1 -OCH 3 2830 cm 2 CH 2 aliphat. 2850 + 2940 cm -1 CaN 2210 cm -1 C = C 1625 cm 1 UV spectrum (ethanol): A max. 245 nm (0.26) 278 nm (0.06) 332 nm (0.16)

Example 29

  1- (4-Amino-3-chloro-5-nitro-phenyl) -2-N- [3- (4-methoxy) -1-

  phenyl) -propylJ-méthvlaminoq / -ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3'-chloro-5'-nitro-2- / IN-3- (4-methoxy)

  phenyl) -propyl-7-methylamino] -acetophenone and boron

  sodium hydride in 80% methanol.

  IR (methylene chloride) spectrum: -1H OH 3590 cm -1 NH 2 3390 + 3500 cm 1 N-alkyl 2800 cm -1 OCH 3 2830 cm -1 -1 CH 2 aliphat. 2850 + 2940 cm C = C 1630 cm1 NO2 1330 + 1515 cm UV spectrum (ethanol): X max. 227 nm (0.64) 280 nm (0.16) 400 nm (0.12)

Example 30

  1- (4-amino-3-chloro-phenyl) -2 .-- N-T3- (4-methoxy-phenyl) -

propyvl7-méthylaminoj-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3'-chloro-2-ZN-f3- (4-methoxy-phenyl) -

  propyl / -methylamino] -acetophenone and borohydride

sodium in 80% methanol.

  IR (methylene chloride) spectrum: -1 OH 3600 cm -1 NH 2 3380 + 3470 cm 1 N-alkyl 2800 cm -1 OCH 3 2830 cm -1 -1 CH 2 aliphat. 2850 + 2940 cm C = C 1620 cm-1 UV spectrum (ethanol): 1 max. 225 nm (0.44) 243 nm (0.36) 280 nm (0.09) 295 nm (0.08)

Example 31.

  1- (4-amino-3-bromo-phenyl) -2-fN-z3- (4-methoxy-phenyl) -

1-methylamino-ethanol prop.

  Prepared in a similar manner to Example 1,

  4'-amino-3'-bromo-2- [N- [3- (4-methoxy-phenyl)) -

  propyl7-methylamino] -acetophenone and borohydride

  of sodium in 80% methanol.

  Melting point of the dihydrochloride: 1370C (decomp.).

Example 32.

  1- (4-amino-3,5-dicyano-phénl1) -2-rN-Z3- (4-methoxy

  phenyl) -propylj-méthylamino7-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3 ', 5'-dicyano-2- [N-13- (4-methoxy-phenyl) -2-

  nyl) -propyl-7-methylamino-2-acetophenone and borohy-

  sodium chloride in 80% methanol.

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

Example 33.

  1- (4-amino-3-bromo-phenyl) -2-EN-4- (4-methoxyphenyl) -

butyl 7-methylamino, ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3'-bromo-2-rN-Z4- (4-methoxyphenyl) - firing

  butyl7-methylamino7-acetophenone and borohydride

sodium in 80% methanol.

  IR (methylene chloride) spectrum: -1 OH 3590 cm NH2 3380 + 3470 cm

NH2 -1

N-alkyl 2800 cm -1

OCH 2830 cm-

- CH2 aliphat. 2850 + 2930 cm -1

C = C 1620 cm-

  UV spectrum (ethanol): X 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- / 2- (4-methoxy-phenyl) -

éthvl7-methylamino] ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3'-bromo-2- [N- [2- (4-methoxy-phenyl)] -

  ethyl-7-methylamino] -acetophenone and borohydride

sodium in 80% methanol.

  IR spectrum (methylene chloride): -: 1 OH 3590 cm NH2 3380 + 3470 cm -1 N-alkyl 2800 cm

OCH3 2830 cm-

  -1 CH2 aliphat. 2840 + 2940 cm -1 C = C 1620 cm UV spectrum (ethanol): A max. 225 nm (0.43) 243 nm (0.36) 280 nm (0.08) 296 nm (0.08)

Example 35

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

  phenyl) -butyl7-methylamino] -ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3 ', 5'-dichloro-2- [N- [4- (4-methoxy) phenyl)

  nyl) -butyl-7-methylamino-7-acetophenone and borohydride

  of sodium in 80% methanol.

  IR (methylene chloride) spectrum: -1 OH 3590 cm -1 NH 2 3390 + 3490 cm 1 N-alkyl 2800 cm -1

OCH3 2830 cm-

  -1 CH2 aliphat. 2850 + 2930 cm -1 C = C 1610 cm UV spectrum (ethanol): X max. 245 nm (0.25) 320 nm (0.48)

Example 36.

  1- (4-amino-3-bromo-5-cyano-phenyl) -2-one-zr4- (4-methoxy

  phenyl) -butyl7-méthylaminoQ7-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3'-bromo-5'-cyano-2-N- [4- (4-methoxymethyl) -2-

  phenyl) -butyl] -methylamino-7-acetophenone and boron

  sodium hydride in 80% methanol.

  IR (methylene chloride) spectrum: -1H OH 3590 cm -1 NH 2 3390 + 3490 cm 1 N-alkyl 2800 cm -1 OCH 3 2830 cm 2 CH 2 aliphat. 2850 + 2930 cm-1 CEN 2210 cm1 C = C 1620 cm-1 UV spectrum (ethanol): X max. 245 nm (0.27) 278 nm (0.08) 330 nm (0.15)

Example 37

  1- (4-amino-3-bromo-5-cyano-phenyl) -2-fN-Z2- (4-methoxy

  phenyl) -éthvl7-méthvlamino7-ethanol.

  Prepared in a similar manner to Example 1,

  firing of 4'-amino-3'-bromo-5'-cyano-2- [N- [2- (4-methoxy)]

  phenyl) -ethyl-7-methylamino-7-acetophenone and boron

  sodium hydride in 80% methanol.

  IR spectrum (methylene chloride): OH 3590 cm -1 -1 NH 2 3390 + 3490 cm

2 -1

  N-alkyl 2800 cm -1 OCH 3 2830 cm -1 CH 2 aliphat. 2850 + 2950 cm -1 C-N 2210 cm C = C 1620 cm1 UV spectrum (ethanol): max. 245 nm (0.25) 277 nm (0.09) 331 nm (0.10)

Example 38.

  1- (4-amino-3,5-dichloro-phenyl) -2-Fn / 2- (4-methoxy-

  phenyl) -éthvl7-méthylamino7-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3 ', 5'-dichloro-2-ZN-Z2- (4-methoxy-phenol)

  nyl) -ethyl-7-methylamino-7-acetopheenone and borohy-

  sodium chloride in 80% methanol.

  IR (methylene chloride) spectrum: -1H OH 3590 cm NH 2 3390 + 3490 cm -1 N-alkyl 2800 cm OCH 3 2830 cm -1 CH 2 aliphat. 2850 + 2930 cm -1 C = C 1610 cm

EXAMPLE 39

  1- (4-Amino-3-chloro-5-cyano-dienyl) -2-FN-Z4- (4-methox)

  phenyl) -butyvl7-méthylamino7-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3'-chloro-5'-cyano-2- [N- [4- (4-methoxy) -2-

  phenyl) -butyl-7-methylamino-acetophenone and boron

  sodium hydride in 80% methanol.

  IR spectrum (methylene chloride): OH 3590 cm -1 NH2 3400 + 3500 cm

2 -1

  N-alkyl 2800 cm OCH3 2830 cm -1 CH2 aliphat. 2850 + 2930 cm -1 CZN 2210 cm C = C 1625 cmx1 UV spectrum (ethanol): X max. 245 nm (0.23) 280 nm (0.05) 332 nm (0.13)

Example 40.

  1- (4-amino-3-chloro-5-cyano-phenyl) -2-FN-2- (4-methoxy

  phenyl) -éthyl7-methylamino - ethanol.

  Prepared in a similar manner to Example 1, i

  4'-amino-3'-chloro-5'-cyano-2-N- [2- (4-methoxy) -2-methyl-3'-chloro-5'-cyano-2-N-

  phenyl) -ethyl-7-methylamino] -acetophenone and boron

  sodium hydride in 80% methanol.

  IR (methylene chloride) spectrum: -1 OH 3590 cm -1 NH 3390 + 3490 cm Nay 2 20c-1 N-alkyl 2800 cm -1 OCH 3 2830 cm CH 2 2850 + 2940 cm -1 CEN 2210 cm C = C 1620 cm1 UV spectrum (ethanol): X max. 245 nm (0.24) 280 nm (0.04) 332 nm (0.13)

Example 41.

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

  phénylsulfényl) -éthyL7-méthylaminol-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3 ', 5'-dichloro-2-Z- [2- (4-methoxy) phenyl)

  nylsulfenyl) -ethyl-methylamino-7-acetophenone and sodium borohydride in tetrahydrofuran: water:

methanol = 25: 5: 10. Oil.

  IR spectrum (methylene chloride): -OH 3200-2500 cm-1 (as NH2)

NH2 3480 + 3390 cm-

  -1 CH2 2940 cm N-alkyl 2800 cm OCH3 2830 cm -1 C = C 1580 + 1490 cm1 UV spectrum (ethanol): X max. 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-phe-

  phenoxy) -éthyl7-methylamino ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3 ', 5'-dichloro-2-N- [2- (4-methoxy) phenyl)

  noxy) -ethyl-7-methylamino-acetophenone and borohy-

  sodium chloride in tetrahydrofuran: water: methanol =

: 5: 3. Oil.

  IR (methylene chloride) spectrum: OH 3200-3500 cm 1 (as NH2) NH2 3480 + 3390 c-1 NH 2 3480 + 3390 cm CH2 2940 cm-1

2 1

N-alkyl 2790 cm -1 OCH3 2830 cm1

C = C 1580, 1505 + 1485 cm.

  -1 C-O-aryl 1250 cm- UV spectrum (ethanol): X max. 230 nm (0.32, shoulder) 244 nm (0.26, shoulder)

294 nm (0.12).

Example 43

  1- (4-amino-3,5-dichloro-phenyl) -2- [N-f] - (4-methoxy) -phenyl)

  nyl) -propyl-17-amino-propanol (1).

  Prepared in a similar manner to Example 1,

  4'-amino-3 ', 5'-dichloro-2-ZN- / 3- (4-methoxy-phenol)

  nyl) -propyl] -7-amino] propiophenone and borohydride

sodium.

  Melting point of the hydrochloride: 201-202 C (decomp.).

Example 44.

  1- (4-amino-3,5-dichloro-phenyl) -2-fN-3- (4-methoxy

  phenyl) -propy17-2-propvlamino7-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3 ', 5'-dichloro-2- [N-] - (4-methoxyphenol)

  nyl) propyl-2-propylamino-acetophenone and boron

sodium hydride. Oil.

  IR (methylene chloride) spectrum: -1 OH 3600 cm -1 NH2 3400 + 3490 cm 1 OCH3 2830 cm UV spectrum (ethanol): X max. 243 nm (0.13) 280 nm (0.03) 300 nm (0.03)

Example 45.

  1- (4-amino-3,5-dichloro-phenyl) -2-fN-3- (4-methoxy

  phenyl) -propyl - éthvlamino7-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3 ', 5'-dichloro-2-N- [3- (4-methoxy-phenyl) -2-

  nyl) -propyl-ethylamino-acetophenone and borohydride

sodium.

  IR (methylene chloride) spectrum: -1 OH 3600 cm -1 -1 NH 2 3395 + 3490 cm

2 1

  OCH3 2830 cm-1 UV spectrum (ethanol): A max. 243 nm (0.13) 280 nm (0.04) 300 nm (0.04)

Example 46.

  1- (4-amino-3,5-dichloro-phenyl) -2-Fn / 3- (4-methoxy-

  phenyl) -propylpropylamino-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3 ', 5'-dichloro-2- [N-Z3- (4-methoxy-phenol)

  nyl) -propyl-7-propylamino-7-acetophenone and borohy-

sodium drure. Oil.

  IR spectrum (methylene chloride): OH 3600 cm -1 -1 NH 2 3395 + 3495 cm OCH 3 2850 cm UV spectrum (ethanol): At max. 245 nm (0.10) 280 nm (0.03) 300 nm (0.03)

Example 47

1- (4-Amino-3,5-dichloro-phenyl) -2- [N-f3- (4-methoxy) -2-

  phenyl) -oropyl7-cvclopropylamino7-ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3 ', 5'-dichloro-2- [N-13- (4-methoxy-phenol)

  nyl) -propyl7-cyclopropylamino] -acetophenone and boron

sodium hydride. Oil.

  IR spectrum (methylene chloride): -! OH 3590 cm -1 -1 NH 2 3395 + 3495 cm 1 OCH 3 2850 cm UV spectrum (ethanol): 1 max. 245 nm (0.12) 280 nm (0.04) 300 nm (0.04)

Example 48.

  1- (4-amino-3,5-dichloro-phenyl) -2-fN-Z3- (4-methoxy

  phenyl) -propyl-7-methylamino-7-propanol (1), B-isomer.

  Prepared in a similar way to Example 2,

  N-Z3- (4-methoxy-phenyl) -propyl-methylamine, from

  4'-amino-2-bromo-3 ', 5'-dichloro-pro.piophenone, tris

  ethylamine and sodium borohydride. Oil.

  IR spectrum (methylene chloride): OH 3600 + 3680 cm

NH2 3390 + 3490 cm-

  -1 OCH3 2835 + 2940 cm Aromat. 1510, 1585 + 1610 cm 1 UV spectrum (ethanol): X max. 246 nm (0.14) 278 nm (0.08) 285 nm (0.08) 300 nm (0.08) NMR spectrum (CDCl3 / D20): Proton signal on the carbon atom 1 of the propanol part : doublet at 4.1 ppm

(J = 10 Hz).

Example 49.

  1- (4-amino-3,5-dichloro-phenyl) -2- / N-Z3- (4-methoxy-phe-

  nyl) -propyl-methylamino-propanol- (1), isomer A.

  Prepared in a similar way to Example 2,

  N- [3- (4-methoxy-phenyl) -propyl] -7-methylamine

  4'-amino-3 ', 5'-dichloro-2-bromo-propiophenone, of tri-

  ethylamine and sodium borohydride.

  Melting point of the hydrochloride: 178-181 ° C.

  NMR spectrum of the base (CDC13 / D20): proton signal

  on the carbon atom 1 of the propanol part: dou-

4.6 ppm (J = 4.5 Hz).

Example 50.

  1- (4-amino-3,5-dichloro-Dhényl) -2-fN-3- (4-ethoxy-

  phenyl) -propyl7-methylamino] -ethanol.

  Prepared in a similar way to Example 2,

  4'-amino-3 ', 5'-dichloro-2-bromoacetophenone,

  1- (4-ethoxy-phenyl) -3-methylaminohydrochloride

  propane, triethylamine and sodium borohydride.

  -Oil. IR spectrum (methylene chloride): OH 3590 cm -1 NH 2 3395 + 3495 cm -1 N-alkyl 2800 cm UV spectrum (ethanol): A max. 245 nm (0.13) 280 nm (0.04) 300 nm (0.04)

Exempt 51.

  1- (4-amino-3,5-dichloro-phenyl) -2-FN - / - (4-benzyloxy)

  phenyl) -propyl7-methylamino / -ethanol.

  Prepared in a similar way to Example 2,

  4'-amino-3 ', 5'-dichloro-2-bromoacetophenone,

  1- (4-benzyloxy-phenyl) -3-methylaminohydrochloride

  no-propane, triethylamine and sodium borohydride

dium. Oil.

  IR spectrum (methylene chloride): OH 3590 cm-1 -1 NH2 3395 + 3495 cm N-alkyl 2800 cm

Example 52.

  1- (4-amino-3-iodo-5-fluoro-phenyl) -2-N-z- (4-methoxy)

  phenyl) -propyl 7-methylaminoethanol.

  Prepared in a similar way to Example 2,

  4'-amino-3'-iodo-5'-fluoro-2-bromoacetophenone,

  1- (4-methoxy-phenyl) -3-methylaminohydrochloride

  propane, triethylamine and sodium borohydride.

  Oil. IR (methylene chloride) spectrum: -1 OH 3590 cm -1 NH 2 3395 + 3495 cm -1 N-alkyl 2800 cm

Example 53.

  1- (4-amino-3-cyano-5-fluoro-Dhényl) -2- / N-3- (4-methoxy

  phenyl) -DropylD7-2-Dropylamino] -ethanol.

  Prepared in a similar way to Example 2,

  4'-amino-3'-cyano-5'-fluoro-2-bromoacetophenate

  none of 1- (4-methoxy-phenyl) -3- (2-

  propylamino) -propane and sodium borohydride.

  Oil. IR (methylene chloride) spectrum: -1 OH 3600 cm -1 NH 2 3395 + 3495 cm -1 OCH 3 2830 cm -1 N-alkyl 2800 cm -1 C N 2220 cm

Example 54

  1- (4-amino-3,5-dichlorophenyl) -2- / N- hydrochloride

  3- (2-methoxyphenyl) -propyl1méthylamino] -ethanol.

  Prepared in a similar way to Example 2,

  4'-amino-3'-5'-dichloro-2-bromoacetophenone, 1- (2-methoxy-phenyl) -3-methylaminohydrochloride

  propane, triethylamine and sodium borohydride.

  Melting point: from 75 C (with sintering).

Example 55.

  1- (4-amino-3,5-dichloro-phenyl) -2 - N- / 3- (3,4-dimethoxy-

  Dhényl) -propyl1-méthylamino7-ethanol.

  Prepared in a similar way to Example 2,

  4'-amino-3 ', 5'-dichloro-2-bromoacetophenone,

  1- (3,4-dimethoxy-phenyl) -3-methylhydrochloride

  amino-propane, triethylamine and sodium borohydride. IR spectrum (methylene chloride): -1 OH 3600 cm NH2 3390 + 3485 cm1 -1 OCH3 2830 cm -1 N-alkyl 2800 cm

Example 56.

  1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- / N-2-

  (4-methoxy-phenyl) -ethyl / -méthylaminol-ethanol.

  Prepared in a similar manner to Example 1,

  firing of 4'-amino-3'-chloro-5'-trifluoromethyl-2-ZN- / 2-

  (4-methoxy-phenyl) -ethyl] methylamino] acetophenone

  and sodium borohydride in 80% methanol.

  IR (methylene chloride) spectrum: -1 OH 3600 cm NH2 3410 + 3510 cm1 -1 N-alkyl 2800 cm -1 O-CH3 2830 cm1 -1 CH2 aliphat. 2850 + 2940 cm -1 C = C 1630 cm UV spectrum (ethanol): X max. 225 nm (0.38) - 244 nm (0.34) 280 nm (0.07) 307 nm (0.10)

EXAMPLE 57

  1- (4-amino-3,5-dichlorophenyl) -2-fN- hydrochloride

  3- (4-methoxy-phenyl) -propvll7-amino7-ethanol.

  Prepared in a similar manner to Example 1,

  firing of 4'-amino-3 ', 5'-dichloro-2- [N-L- (4-methoxy)

  phenyl) -propyl-7-amino-acetophenone and borohydride

  of sodium in 90% ethanol.

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

Example 58.

  1- (4-Amino-3,5-dichloro-phenyl) -2-PN-hydrochloride

  (3-phenylpropyl) -2-propyl-amino / -ethanol.

  Prepared in a similar way to Example 2,

  4'-amino-3 ', 5'-dichloro-2-bromoacetophenone, 1-phenyl-3- (2-propylamino) -propane hydrochloride,

  triethylamine and sodium borohydride.

Melting point: 124-128 C.

Example 59.

  1- (4-amino-3,5-dichlorophenyl) -2-fN- hydrochloride

  /3-(4-fluoro-phényl)-propyl.-méthylamino/-éthanol.

  Prepared in a similar way to Example 2,

  4'-amino-3 ', 5'-dichloro-2-bromoacetophenone,

  1- (4-fluoro-phenyl) -3-methylaminohydrochloride

  propane, triethylamine and sodium borohydride.

  Melting point: 185-188 ° C (decomp.)

Example 60.

  1- (4-amino-3,5-dichlorophenyl) -2- [N- [3- (4-hydroxyphenyl) -1-methylpropyl] amino] ethanol.

  Prepared in a similar way to Example 4,

  4'-amino-3 ', 5'-dichloro-2-FN-β- (4-hydroxy)

  phenyl) -l-methyl-propyl-7-amino] -acetophenone and

  sodium borohydride in aqueous tetrahydrofuran.

  As an eluent for chromatographic purification

  that on silica gel, a mixture of dichlo-

  romomethane / methanol / concentrated ammonia = 19: 1: 0.05.

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

  IR spectrum (KBr): OH 2300 - 3500 cm (broad, associated) -1 NH 2 3460 + 3370 cm -1 CH 2 2920 + 2960 cm C = C 1580, 1510 + 1480 cm UV spectrum (ethanol): x max. 244 nm (0.28) 280 nm (0.08) 300 nm (0.08) UV spectrum (ethanol + KOH): X max. 243 nm (0.54) 299 nm (0.15)

Example 61

  1- (4-amino-3,5-dichloro-phenyl) -2-fN-Z3- (4-methoxy

  Phenyl) -l-methyl-amino-propyl7 / -ethanol.

  Prepared in a similar way to Example 4,

  4'-amino-3 ', 5'-dichloro-2-ZN- / 3- (4-methoxy)

  phenyl) -l-methyl-propyl-7-amino-7-acetophenone and

  sodium borohydride in aqueous tetrahydrofuran.

  Oil. The compound is in the form of a mixture

  1: 1 diastereoisomeric racemates.

  IR spectrum (methylene chloride): -1. OH 3600 cm 1 NH 2 3480 + 3390 cm -1 CH 2 2930 cm -1 OCH 3 2830 cm 1

C = C 1580, 1510 + 1485 cm.

  UV spectrum (ethanol): X max. 244 nm (0.28) 280 nm (0.08) 300 nm (0.09)

Example 62.

  1- (4-Amino-3-cyano-5-fluoro-Dhenyl) hydrochloride

  N- [2- (3,4-dimethoxy-phenyl) ethyl] amino] ethanol.

  Prepared in a similar way to Example 5,

  4'-amino-3'-fluoro-5'-cyanoacetophenone, from

  selenium dioxide, 2- (3,4-dimethoxy-phenyl) -ethyl-

amine and sodium borohydride.

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

Example 63.

  1- (4-Amino-3-fluoro-5-iodo-phenyl) -2-chlorhydrate

  N- / 2- (3,4-dimethoxy-phenyl) -ethyl / -amino7-ethanol.

  Prepared in a similar way to Example 5,

  4'-amino-3'-fluoro-5'-iodo-acetophenone, from

  selenium dioxide, 2- (3,4-dimethoxy-phenyl) -ethyl-

amine and sodium borohydride.

  Melting point: 192-193oC (decomp.)

Example 64.

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

  N- [n- (3,4-dimethoxy-phenyl) -ethyl] amino] ethanol.

  Prepared in a similar way to Example 5,

  firing of 4'-amino-3'-chloro-5'-fluoroacetophenone,

  selenium dioxide, 2- (3,4-dimethoxy-phenyl) -ethyl-

amine and sodium borohydride.

  Melting point: 184-186oC (decomp.).

Example 65.

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

  IN- / 2- (3,4-Dimethoxy-phenyl) -ethyl / -amino7-ethanol.

  Prepared in a similar way to Example 5,

  4'-amino-3'-bromo-5'-fluoroacetophenone, from

  selenium dioxide, 2- (3,4-dimethoxy-phenyl) -

  ethylamine and sodium borohydride.

  Melting point: 194-1950C (decomp.)

Example 66.

  1- (4-amino-3-fluoro-5-cyanophenyl) -2 - N-Z3- (4-methoxy

phenyl) -propY17-amino7-ethanol.

  Prepared in a similar way to Example 5,

  4'-amino-3'-fluoro-5'-cyanoacetophenone, from

  selenium dioxide, 3- (4-methoxy-phenyl) -propyl-

amine and sodium borohydride.

Melting point: 119-121oC.

Example 67

  1- (4-amino-3,5-dichloro-phenyl) -2-fN-chlorohydrate

(3-phenyl-prop1l) -amino7-ethanol.

  Prepared in a similar way to Example 5,

  firing of 4'-amino-3 ', 5'-dichloroacetophenone, dioxygen

  of selenium, 3-phenyl-propylamine and borohy-

sodium drure.

  Melting point: 180-181oC (decomp.).

Example 68.

  1- (4-Amino-3-chloro-5-fluoro-phenyl) dihydrochloride

  Fn-2 (1-methyl-2-phenoxy-ethyl) -amino7-ethanol.

  Prepared in a similar way to Example 5,

  4'-amino-3'-chloro-5'-fluoroacetophenone, selenium dioxide, 1-methyl-2-phenoxyethylamine

and sodium borohydride.

  Melting point: 158-160 ° C (decomp.).

Example 69.

  1- (4-amino-3-cyano-5-fluoro-phenyl) hydrochloride

  Fn (1-methyl-2-phenoxy-ethyl) -amino-ethanol.

  Prepared in a similar way to Example 5,

  firing of 4'-amino-3'-cyano-5'-fluoroacetophenone, selenium dioxide, 1-methyl-2-phenoxyethylamine

and sodium borohydride.

  Melting point: 178-184oC (decomp.).

Example 70.

  1- (4-Amino-3-bromo-5-fluoro-phenyl) dihydrochloride

  Fn-2 (1-methyl-2-phenoxy-ethyl) -amino / -ethanol. Prepared analogously to Example 5, from 4'-amino-3'-bromo-5'-fluoroacetophenone, selenium dioxide, 1-methyl-2-phenoxyethylamine

and sodium borohydride.

  Melting point: 156-158 ° C (decomp.).

Example 71.

  N-2- (4-amino-3. 5-dibromo-Dhényl) -éthyl7-N- / 3- (4-Me

  thoxv-phenyl) -propyl7-methylamine.

  Prepared analogously to Example 7,

  shot of 4-amino-3,5-dibromo-N-Z3- (4-methoxy-phenyl) -

  propyl7-N-methyl-phenylacetamide and double hydride

of lithium and aluminum.

  Melting point of the hydrochloride: 149-153 C.

Example 72.

  N-12- (4-amino-3,5-dichloro-phenyl) -éthy1 / -N-3- (4-methodical

xy-phenyl) -propyl7-methylamine.

  Prepared analogously to Example 7,

  4-amino-3,5-dichloro-N- [3- (4-methoxyphenyl)) -

  propyl-N-methyl-phenylacetamide and double hydride

of lithium and aluminum.

  Melting point of the hydrochloride: 90-94 C.

Example 73.

  N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl] -N- / 2- (4-Me

  thoxv-phenyl) -éthyl7-methylamine.

  Prepared analogously to Example 8,

  4-amino-3,5-dichloro-N- [2- (4-methoxyphenyl)) -

  ethyL7-N-methyl-phenylacetamide and double hydride

of lithium and aluminum.

  IR spectrum (methylene chloride): -1 NH 2 3380 + 3470 cm -1 N-alkyl 2780 cm -1 OCH 3 2830 cm -1 CH 2 aliphat. 2850 + 2930 cm C = C 1610 cm-! UV spectrum (ethanol): X max. 245 nm (0.24) 281 nm (0.08) 305 nm (0.07)

Example 74.

  N- / 2- (4-amino-3,5-dichloro-phenyl) -éthvl7-N- / 4- (4-Me

methoxy-phenyl) -butyl7-methylamine.

  Prepared analogously to Example 8,

  4-amino-3,5-dichloro-N- [4- (4-methoxyphenyl)] -

  butyl7-N-methyl-phenylacetamide and double hydride

of lithium and aluminum.

  IR spectrum (methylene chloride): -1 NH 2 3380 + 3480 cm OCH 3 2830 cm -1 CH 2 Aliphat. 2850 + 2930 cm1 NH 2100 - 2500 cm -1 C = C 1630 cm UV spectrum (ethanol): A max. 245 nm (0.22) 280 nm (0.07) 304 nm (0.08)

EXAMPLE 75

  N- / 3- (4-amino-3,5-dichlorophenyl) hydrochloride

  DroDYl / -2- (3,4-dimethoxy-phenyl) -ethylamine.

  Prepared in a similar way to Example 7,

  3- (4-amino-3,5-dichloro-phenyl) -N-Z2- (3,4-dimethyl) -2-

  thoxy-phenyl) -ethyl] -propionamide and double hydride

of lithium and aluminum.

Melting point: 142-145C.

Example 76.

  N- / 3- (4-amino-3,5-dichloro-phenyl) -propyl7 / N- / 2- (3,4

  dimethoxy-phenyl-ethyl-methylamine.

  Prepared analogously to Example 8,

  3- (4-amino-3,5-dichlorophenyl) -N-2- (3,4-di-

  methoxy-phenyl) -ethyl-N-methyl-propionamide and hy-

  double drums of lithium and aluminum. Oil.

  IR spectrum (methylene chloride): NH2 3400 + 3500 cm-1 OCH3 2835 + 2960 cm

3 1

* NCH3 2800 cm-1 flavor. 1510 + 1590/1615 cm1 UV spectrum (ethanol): 1 max. 239 nm (shoulder) 281 nm (0.11) 300 nm (0.08)

EXAMPLE 77

  N-n3- (4-amino-3-bromo-phenyl) propyl-7-hydrochloride

  2- (3,4-dimethoxy-phenyl) -ethylamine.

  Prepared in a similar way to Example 7,

  3- (4-amino-3,5-dibromo-phenyl) -N-Z2- (3,4-dimethyl) -2-

  thoxy-phenyl) -ethyl-propionamide and double hydride

of lithium and aluminum.

Melting point: 131-134C.

Example 78.

  N-2- (4-amino-3,5-dichloro-phenyl) -éthyl7-N- / 3- (4-hydroxy

  droxy-phenyl) -l-methyl-propyl7-amine.

  Prepared analogously to Example 8,

  4-amino-3,5-dichloro-N-Z3- (4-hydroxy-phenyl) -

  1-methyl-propyl-phenylacetamide and double hydride

  of lithium and aluminum in tetrahydrofuran.

  Chromatographic purification takes place by means of a

  medium pressure chromatography, on a gel of

  lice (grain size: 0.015 - 0.025 mm) with methylene chloride: methanol: concentrated ammonia =

  19: 1: 0.1 as an eluent. Foam.

  IR (methylene chloride) spectrum: -1 OH 3580 cm -1 -1 NH2 3480 + 3385 cm -1 CH2 2920 cm

2 -1

  C = C 1580, 1510 + 1480 cmx UV spectrum (ethanol): 1 max. 242 nm (0.24, shoulder) 280 nm (0.07) 303 nm (0.08) UV spectrum (ethanol + KOH): X max. 242 nm (0.53) 300 nm (0.16)

Example 79.

  N- / 2- (4-amino-3,5-dichloro-phenyl) -éthyl1-N- / 3- (4-Me

  thoxy-phenyl) -1-methyl-propyl-amine.

  Prepared analogously to Example 8,

  4-amino-3,5-dichloro-N --- (4-methoxy-phenyl) -

  1-methyl-propyl-phenylacetamide and double hydride

  of lithium and aluminum in tetrahydrofuran.

  Oil. IR (methylene chloride) spectrum: NH 2 3480 + 3385 cm 2 CH 2 2930 cm -1 OCH 3 2830 cm 1 C = C 1580, 1510 + 1485 cm UV spectrum (ethanol): X max. 242 nm (0.25, shoulder) 280 nm (0.07) 302 nm (0.08)

Example 80.

  N- / 2- (4-amino-3,5-dichloro-phenyl) -éthyL7-N-F3- (4-ben-

  zyloxy-phenyl) propyl! methylamine.

  Prepared analogously to Example 8,

  4-amino-3,5-dichloro-N - / - (4-benzyloxyphenyl) -

  propyl7-N-methyl-phenylacetamide and double hydride

of lithium and aluminum. Oil.

  IR spectrum (methylene chloride): -1 NH 2 3390 + 3490 cm -1 N-alkyl 2800 cm UV spectrum (ethanol): X max. 245 nm (0.10) 280 nm (0.04) 300 nm (0.04)

Example 81.

  N-Z2- (4-amino-3,5-dichloro-phenyl) -ethyl-N-Z3-

  dimethoxy-phenyl) -propyl1-methylamine.

  Prepared in a similar way to Example 8,

  4-amino-3,5-dichloro-N-3- (3,4-dimethoxy-phenyl) -

  propyl7-N-methyl-phenylacetamide and double hydride

lithium and aluminum. Oil.

  IR (methylene chloride) spectrum: NH2 3395 + 3495 cm1 -1 OCH3 2830 cm N-alkyl 2800 cm-1 UV spectrum (ethanol): X max. 230 nm (shoulder, 0.18) 245 nm (shoulder, 0.12) 282 nm (0.04) 302 nm (0.03)

Example 82.

  N-f2- (4-amino-3,5-dichlorophenyl) hydrochloride

  éthyL7-N-3- (2-methoxy-phenyl) -propyl7-methylamine.

  Prepared in a similar way to Example 7,

  4-amino-3,5-dichloro-N-L3- (2-methoxy-phenyl) -

  propyl] -N-methyl-phenylacetamide and double hydride

of lithium and aluminum.

Melting point: 160-164 ° C.

Example 83.

  N- [2- (4-amino-3,5-dichloro-Dhenyl) -ethyl] -N- (3-phenol)

propyl) -methylamine.

  Prepared in a similar way to Example 8,

  4-amino-3,5-dichloro-N- (3-phenylpropyl) -N-methylamine

  thyl-phenylacetamide and lithium double hydride

el aluminum. Oil.

  IR spectrum (methylene chloride): -1 NH 2 3390 + 3490 cm -1 N-alkyl 2800 cm UV spectrum (ethanol): X max. 245 nm (0.12) 300 nm (0.03)

Example 84.

  N- / 2- (4-amino-3,5-dichlorophenyl) hydrochloride

  ethyl / -N- / 3- (4-methoxy-phenyl) propyl / -amine.

  Prepared in a similar way to Example 7,

  4-amino-3,5-dichloro-N- [3- (4-methoxyphenyl)] -

  propyl7-phenylacetamide and lithium double hydride

and aluminum.

Melting point: 203-2050C.

Example 85.

  N- [2- (4-amino-3,5-dichloro-phenyl) -ethyl] -N- (4-methyl);

  thoxv-Dhenyl) -propyl / -cyclo-propylamine.

  Prepared analogously to Example 8,

  4-amino-3,5-dichloro-N-Z3- (4-methoxy-phenyl) -

  propyl7-N-cyclopropyl-phenylacetamide and hydride

  double of lithium and aluminum. Oil.

  IR (methylene chloride) spectrum: NH2 3390 + 3490 cm -1 -1 OCH3 2830 cm UV spectrum (ethanol): At max. 245 nm (0.15) 280 nm (0.04) 300 nm (0.05)

Example 86.

  N- [2- (4-amino-3,5-dichloro-phenyl) -ethyl] -N- [3- (4-methyl) -2-

  thoxv-phenyl) -proDpyl / -Dropylamine.

  Prepared analogously to Example 8,

  shot of 4-amino-3,5-dichloro-N - / - (4-methoxy-phenyl) -

  propyl7-N-propyl-phenylacetamide and double hydride

of lithium and aluminum. Oil.

  IR spectrum (methylene chloride): -1 NH 2 3390 + 3490 cm -1 OCH 3 2830 cm -1 N-alkyl 2800 cm UV spectrum (ethanol): X max. 243 nm (0.13) 280 nm (0.04) 300 nm (0.04)

Example 87.

  N- [2- (4-amino-3,5-dichloro-phenyl) -ethyl] -N- [3- (4-methoxy)]

xv-phenyl) -Dropyl-17-ethylamine.

  Prepared analogously to Example 8,

  4-amino-3,5-dichloro-N- [3- (4-methoxyphenyl)] -

  propyl / -N-ethyl-phenylacetamide and double hydride

of lithium and aluminum. Oil.

  IR spectrum (methylene chloride): -1 NH 2 3390 + 3490 cm -1 OCH 3 2830 cm -1 N-alkyl 2800 cm -1 UV spectrum (ethanol): A max. 243 nm (0.13) 280 nm (0.04) 300 nm (0.04)

Example 88.

  N-2- (4-amino-3,5-dichloro-phenyl) -ethyl / -N- / n- (4-Me

  thox-phenyl) -propyl-2-propylamine.

  Prepared analogously to Example 8,

  4-amino-3,5-dichloro-N-L3- (4-methoxy-phenyl) -

  propyl7-N- (2-propyl) -phenylacetamide and hydride dou-

  lithium and aluminum. Oil.

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

NH2 -1

  OCH3 2830 cm UV spectrum (ethanol): At max. 243 nm (0.13) 280 nm (0.04) 300 nm (0.04)

Example 89.

  N- / 2- (4-amino-3,5-dichloro-phenyl) -ethyl-N - / - (4-ethoxy)

xv-phenylpropyl-7-methylamine.

  Prepared analogously to Example 8,

  4-amino-3,5-dichloro-N-3 - (4-ethoxy-phenyl) -

  propyl-N-methyl-phenylacetamide and double hydride

of lithium and aluminum. Oil.

  IR spectrum (methylene chloride): NH 2 3390 + 3490 cm -1 -1 OCH 3 2830 cm -1 1 N-alkyl 2800 cm UV spectrum (ethanol): X max. 245 nm (0.12) 280 nm (0.03) 300 nm (0.04)

Example 90.

  N- / 2- (4-amino-3,5-dichloro-phenyl) -éthyL7-N- / 3- (4-Me

  methoxy-phenyl) -1-methyl-propylJ-methylamine.

  Prepared in a similar way to Example 9,

  shot of -1-ethoxycarbonyloxy-1- (4-amino-3,5-dichloro-

  phenyl) -2-N-Z3- (4-methoxy-phenyl) -1l-methyl-propyl7-

  methylamino] ethane and sodium borohydride in

isopropanol. Oil.

  IR (methylene chloride) spectrum: NH 2 3480 + 3380 cm -1 -1 CH 2 2930 cm -1 N-alkyl 2790 cm -1 -1 OCH 3 2840 cm -1 C = C 1580, 1510 + 1480 cm

Example 91.

  N- / 2- (4-amino-3-bromo-5-cyan0-phenyl) -éthyl7 / -N-f44- (4-

  methoxy-phenyl) -butyl7-methylamine.

  Prepared analogously to Example 9,

  firing of 1-ethoxycarbonyloxy-1- (4-amino-3-bromo-5-cyano-

  phenyl) -2- [N- [4- (4-methoxy-phenyl) -butyl7-méthylamino7-

  ethane and sodium borohydride.

  Analysis: Calculated: C 60.6 H 6.3 Br 19.2 N 10.1 Found: 60.5 6.1 19.2 10.1

Example 92.

  N-Z2- (4-amino-3-chloro-5-cyano-phenyl) -éthylJ-N-U2- (4-

  methoxphenyl) ethylmethylamine.

  Prepared analogously to Example 9,

  firing of 1-ethoxycarbonyloxy-1- (4-amino-3-chloro-5-cyano)

  phenyl) -2- / N-Z2- (4-methoxy-phenyl) -éthylJ-methylamino] -

  ethane and sodium borohydride.

  IR spectrum (methylene chloride): -1 NH 2 3400 + 3490 cm -1 N-alkyl 3790 cm

3 -1

  OCH32 aliphat. 2850 + 2940 cm CH2 aliphat. 2850 + 2940 cm-1 -1 C-N 2210 cm C = C 1620 cm-1 UV spectrum (ethanol): max. 244 nm (0.26) 280 nm (0.04) 335 nm (O0.15)

Exemole 93.

  N- / 2- (4-amino-3-bromo-5-cyano-nhényl) -ethyl, -N-Z3- (4-

  methoxy-phenyl) -DroDyl7-methylamine.

  Prepared analogously to Example 9,

  tiene-ethoxycarbonyloxy-1- (4-amino-3-brano-5-cyaphenyl) -2- [3- (4-methoxy-phenyl) -propyl] -methylamino-ethane and

sodium borohydride.

  IR (methylene chloride) spectrum: NH 2 3390 + 3490 cm -1 N-alkyl 3790 cm -1 OCH 3 3830 cm -1 CH 2 aliphat. 2850 + 2940 cm -1 C-N 2210 cm -1 C = C 1620 cm -1 UV spectrum (ethanol): max. 244 nm (0.2) 280 nm (0.04) 334 nm (0.13)

Example 94.

  N- / 2- (4-amino-3-chloro-5-cyano-nhényl) -éthvl7-N- / 4- (4-

  methoxy-phenyl) -butvl7-methylamine.

  Prepared analogously to Example 9,

  firing of 1-ethoxycarbonyloxy-1- (4-amino-3-chloro-5-

  cyano-phenyl) -2-N- [4- (4-methoxy-phenyl) -butyl] -methyl

  amino-ethane and sodium borohydride.

  Analysis: Calculated: C 67.5 H 7.3 Cl 9.53 N 11.25 Found: 67.5 7.14 9.65 11.34

Exemole 95.

  1- (4-Amino-3-chloro-5-trifluoromethyl-1-enin) -2-IN-f4-

  (4-methoxy-phenyl) -butyl7-methylamino / -ethanol.

  Prepared in a similar manner to Example 1,

  4'-amino-3'-chloro-5'-trifluoromethyl-2- [N- [4-

  (4-methoxy-phenyl) -butyl-7-methylaminof7-acetophenone and

  of sodium borohydride in 80% methanol.

  IR spectrum (methylene chloride): -1H OH 3590 cm NH 3410 + 3510 cm

2 _-1

  N-alkyl 2800 cm OCH3 2830 cm-1 -1 CH2 aliDhat. 2850 + 2930 cm C = C aromat. 1630 cm-1 UV spectrum (ethanol): x max. 225 nm (0.32) 245 nm (0.31) 280 nm (0.06) 308 nm (0.10)

Example 96.

  1- (4-amino-3-cyano-phenyl) -2-FN-3 (4-methoxy-phenyl) -

propyl7-méthylamino7-ethanol.

  Prepared in a similar way to Example 11,

  1- (4-amino-3-bromo-5-cyano-phenyl) -2- [N-Z '- (4-)

  methoxyphenyl) propyl-N-methylaminoethanol in the presence of

  the presence of palladium on carbon and hydrogen.

  IR (methylene chloride) spectrum: -1 OH 3610 cm -1 NH2 3400 + 3490 cm

2 1

N-alkyl 2800 cm -1 OCH 2830 cm

3 -1

  CH2 aliphat. 2850 + 2940 cm -1 CLN 2210 cm -1 C = C 1630 cm1 UV spectrum (ethanol): X max. 251 nm (0.31) 280 nm (0.6) 328 nm (0.12)

EXAMPLE 97

  N- / 2- (4-amino-3-chloro-phenyl) -éthyl7-N-Z3- (4-benzylo-

xv-Dhényl) -Dropyl7-methylamine.

  Prepared analogously to Example 11,

  N-Z2- (4-amino-3,5-dichloro-phenyl) -ethyl7-N-

  / 3- (4-Benzyloxy-phenyl) -propyl-7-methylamine and hy-

drogen. Oil.

  IR spectrum (methylene chloride): -1 NH 2 3390 + 3490 cm -1 N-alkyl 2790 cm

Example 98.

  N - / - (4-amino-3,5-dichloro-ohényl) -éthyl1-N-3- (4-

  hydroxy-phenyl) -α-β-methylamine.

  Prepared analogously to Example 16,

  N- [2- (4-amino-3,5-dichlorophenyl) ethyl] -N-

  / 3- (4-Benzyloxy-phenyl) -propyl] -methylamine and hy-

drogen. Oil.

  IR spectrum (methylene chloride): OH 3580 cm -1 -1 NH 2 3390 + 3490 cm -1 N-alkyl 2800 cm

Example 99.

  1- (4-Amino-3-fluoro-phenyl) -2- / N- (1-methyl) -substituted

2-phenoxy-ethyl) -amino] -ethanol.

  Prepared in a similar way to Example 17,

  1- (4-acetamino-3-fluoro-phenyl) -2- [N- (1-methyl) -2-

  2-phenoxy) -ethyl-7-aminoethanol and sodium hydroxide

dium.

Melting point: 124-128 C.

Example 100.

  N- (2-amino-3,5-dichlorophenyl) ethyl) -N-Z3- (4-methoxy) -N

phenoxy) -propyl7 / -methylamine.

  1.74 g (0.014 mole) of 4-methoxyphene was

  in 60 ml of dry tetrahydrofuran, the solution is cooled to -50 ° C. and 0.67 g is added with stirring.

  (0.014 mole) of a 50% dispersion of sodium hydride

  dium in the oil. The mixture is stirred for a further 2 hours at 0.degree.

  then, drop by drop, at the same temperature

  ture, a solution of 4.2 g of N- [2- (4-amino-3,5-di-)

  chloro-phenyl) -éthyJ / -N- (3-chloro-propyl) -methyl-amine