CS229924B2 - Production method of new phenylalkylamine - Google Patents

Abstract

Compounds of general formula I <IMAGE> wherein R1 represents a hydroxy group or an optionally substituted amino group; R2 and R3 each represents a halogen atom, a trifluoromethyl, cyano or nitro group or one of the radicals R2 or R3 represents a hydrogen atom; R4 represents a hydrogen atom or an alkyl group; R5 represents a hydrogen atom, an alkyl, cycloalkyl, alkenyl or aralkyl group; A represents a methylene, ethylene or hydroxymethylene group; and B represents an optionally substituted aralkyl group, in which the methylene group adjacent to the phenyl nucleus may be replaced by an oxygen or sulfur atom, or a sulfinyl or sulfonyl group; all optical isomers thereof, and mixtures of the aforesaid optical isomers; and acid addition salts thereof. Processes for the preparation of the new compounds as well as pharmaceutical compositions containing them are also objects of this invention. The new compounds show valuable pharmacological properties, especially effects on the heat and circulation.

Description

The present invention provides a process for the preparation of novel phenylalkylamines of the general formula I

their optically active antipodes, their diastereomeric racemates and their respective optical antipodes, as well as their addition salts with. acids, in particular physiologically compatible addition salts with inorganic or organic acids.

These novel compounds have valuable pharmacological properties, in particular an effect on the heart and blood circulation.

In the above general formula I

R 1 represents a hydroxyl group, an amino group optionally substituted by a C 1 -C 3 alkanoyl group or a C 2 -C 4 alkoxycarbonyl group, furthermore an alkylamino group. or a dialkylamino group in which each alkyl moiety contains 1 to carbon atoms, each of R2 ^and R3, which may be the same or different, represents a halogen atom, a trifluoromethyl group, a cyano group or a nitro group, where one of R2 or R3 may be also a hydrogen atom,

R 4 represents a hydrogen atom or a C 1 -C 3 alkyl group,

R 5 represents a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms, a cyclopropyl group, an alkenyl group having 2 to 5 carbon atoms or a benzyl group;

A represents a methylene group, an ethylene group or a hydroxymethylene group and

B represents the remainder of the formula

or

in which

R (i) represents a hydrogen or halogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, optionally substituted by a phenyl group, an alkylsulfenyl or an alkylsulfinyl group containing from 1 to 3 carbon atoms in each case,

R 7 represents a hydrogen atom, a hydroxyl group or an alkoxy group having from 1 to 3 carbon atoms or

R ₆ and R 7 together form methylenedioxy,

R ₈ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

D is an oxygen atom or a sulfonyl group, n is an integer of 1 or 2 and

E represents a straight C 3 -C 5 alkylene group optionally substituted by one or two C 1 -C 3 alkyl groups or, when A is a methylene or ethylene group, and / or

R 1 is an amino group substituted with C 1 -C 3 alkanoyl. or. alkoxycarbonyl having a total of 2 to 4 carbon atoms, hydroxyl, alkylamino or. . a dialkylamino group in which each. the alkyl moiety always contains 1 to 3 carbon atoms or a

R2 is trifluoromethyl, cyano or nitro, and / or

R 3 represents a fluorine atom, and / or

R 4 represents an alkyl group having 1 to 3 carbon atoms, and / or

R 8 represents a C 1 -C 4 alkyl group, a cyclopropyl group, a C 2 -C 5 alkenyl group or a benzyl group; and / or

R6 represents a fluorine or chlorine atom, an alkylsulphenyl or alkylsulphinyl group containing from 1 to 3 carbon atoms, then E represents an ethylene group or, in the case where A represents a methylene group, E represents a group of the formula

Ro

--CH - CH ₂ - wherein R 9 is C 1 -C 3 alkyl.

Examples of the meanings of the symbols Rt to R9 mentioned above are:

_t R for hydroxyl, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, 'diethylamino, dipropylamino, diisopropylamino, methylethylamino,' methylpropylamino, '.methylisopropylaminoskupina, ethylisopropylaminoskupina, pyrrolidinoskuplna, piperidino, hexamethyleneimino, formylamino, acetylamino, propionylamino, methoxykarbonylaminoskupina, ethoxycarbonylamino, propoxycarbonylamino or isopropoxycarbonylamino, for R2 and R1, which may be the same or different, in each case fluorine, chlorine, bromine or iodine, trifluoromethyl, cyano or nitro, or for R2 or R3; OM hydrogen for R 4 and R _s, which may be the same or different, hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group or- for R5 are hydrogen, methyl sku pin, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, allyl, crotyl, pentenyl or benzyl, for R (i), hydrogen, fluorine, chlorine or a bromine atom, hydroxyl, m-methoxy, ethoxy, propoxy, isopropoxy, methylsulphenyl, ethylsulphenyl, methylsulphinyl, propylsulphinyl, benzyloxy, 2-phenylethoxy, R, or 3-phenylpropoxy; methoxy, ethoxy, propoxy or isopropoxy, for R6 and R7 together, methylenedioxy, for R9, methyl, ethyl, propyl or isopropyl, and for. E ethylene. n-propylene, n-butylene, n-pentylene, 1-methyl-n-propylene, L-ethyl-n-propylene, 1-propyl-n-propylene,

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 a methyl-n-butylene group or a 1-methyl-n-pentylene group.

Particularly beneficial properties are those compounds of formula (I) above wherein:

R 1 represents an amino group, optionally substituted by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, an alkylamino group or a dialkylamino group, in which each alkyl part may each contain 1 to 3 'carbon atoms,

R2 represents a hydrogen atom, a chlorine atom, a bromine or iodine atom, a trifluoromethyl group, a cyano group or a nitro group,

R ₃ represents fluorine, chlorine, bromine or cyano,

R4 represents a hydrogen atom or a methyl group,

R 5 represents a hydrogen atom, a C 1 -C 3 alkyl group optionally substituted by a phenyl group, an allyl group or a cyclopropyl group,

A represents a methylene group, an ethylene group, or a hydroxymethylene group, and

B is a radical of the formula wherein each alkyl moiety each contains 1 to 3 carbon atoms,

R2 represents a hydrogen atom, a chlorine atom, a bromine atom or a cyano group,

R 3 represents a fluorine atom, a chlorine atom or a cyano group,

R4 represents a hydrogen atom or a methyl group,

R 5 represents a hydrogen atom, a C 1 -C 3 alkyl group optionally substituted by a phenyl group, an allyl group or a cyclopropyl group,

A represents a methylene group or a hydroxymethylene group and

B is a radical of the formula _C 8 ^ 7 ^ 0

-CHC-O- ^O

or where

Рл

in which

R 8, D and n are as defined above,

R ₆ represents a hydrogen atom, a fluorine atom, a halogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a benzyloxy group, a methylsulfonyl group or a methylsulfinyl group,

R ₇ represents a hydrogen atom or a methoxy group;

R _c and R 7 together form methylenedioxy a

E represents a n-propylene group, a 1-methyl-n-propylene group, a 1,1-dimethyl-n-propylene group or an n-butylon group, or A represents a methylene or ethylene group and / or

R1 represents an amino group, optionally substituted by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, an alkylamino group or a dialkylamino group, in which each alkyl moiety each contains 1 to 3 carbon atoms, and / or

R2 is trifluoromethyl, cyano or nitro, and / or

R 3 represents a fluorine atom, and / or

R 5 represents an alkyl group having 1 to 3 carbon atoms, optionally substituted by a phenyl group, an allyl group or a cyclopropyl group, then

E. represents an ethyl group.

Particularly preferred compounds are, however, compounds of the above general formula (I) in which:

R 1 represents an amino group, optionally substituted with an ethoxycarbonyl group, an alkylamino group, or a dialkylamino group. E represents' n-propylene group, 1-methyl-n-propylene group, 1,1-dimethyl-n-propylene group, n-butylenoyl group or li R. ethoxycarbonylaminoamino and / or

R2 is cyano; and / or

R 3 represents a fluorine atom, and / or

R 5 represents an alkyl group having 1 to 3 carbon atoms, optionally substituted by a phenyl group, an allyl group or a cyclopropyl group, then

E is also an ethylene group,

R represents a hydrogen atom, a hydroxyl group or a methoxy group and

R 7 represents a hydrogen atom or a methoxy group.

In accordance with the invention, the above novel compounds are obtained by reducing the compound of formula II

^R 3 (ID in which

Rj. to R3, R5 and B are as defined above and

X represents the remainder of the formula

--CO — CH-—

OH R4 —CH — CH

O-acyl — GH — CO—

-CI ^ r -CO ₄

I I —CH — CH— or

ZR-CH ₂ -CH -CH - wherein

R 4 is as defined above, acyl means an organic acyl group such as acetyl, propionyl or benzoyl; and

Z represents. a leaving group such as a bromine or iodine atom, or a carbonic acid ester residue such as a methoxycarbonyloxy or ethoxycarbonyloxy group. ’

Depending on the significance of the residue X, this reduction is carried out in a suitable solvent, such as methanol, aqueous methanol, ethanol, aqueous ethanol, isopropanol, trifluoroacetic acid, butanol, diethyl ether, tetrahydrofuran, aqueous tetrahydrofuran, dioxane or hexamethylphosphoric trihydride, suitably. aluminum isopropoxide in the presence of a primary or secondary alcohol, catalytically activated hydrogen, or hydrogen at birth, at a temperature between -20 ° C and the boiling point of the reaction mixture, for example at a temperature between -20 ° C and 100 ° C.

For the preparation of compounds of formula I in which A is a hydroxymethylene group, the reduction is conveniently carried out, for example, by treatment with a complex metal hydride such as sodium borohydride or lithium aluminum hydride in a suitable solvent such as methanol, aqueous methanol, diethyl ether or tetrahydrofuran. —20 ° C and 50 ° C, or by treatment with isopropoxide in isopropanol while boiling the reaction mixture and distilling off the resulting acetone, or catalytically activated hydrogen in the presence of a catalyst such as platinum, palladium, Raney-nickel or Raney-cobalt at room temperature under pressure hydrogen, or by treatment with hydrogen at birth, for example by activated metal aluminum and water or zinc and hydrochloric acid, at a temperature up to the boiling point of the solvent used.

When X in the compound of formula II is -CO-CHR 4 -, the reaction is conveniently carried out at a temperature between 0 and 50 ° C, preferably at room temperature, for example sodium borohydride in aqueous methanol, aqueous ethanol or isopropanol, or lithium aluminum hydride in diethyl ether or tetrahydrofuran as solvent.

When X is a radical of formula

The O-acyl-CH-CO reduction is preferably carried out with a hydride in a suitable solvent such as ether, tetrahydrofuran or. dioxane, for example diborane or lithium aluminum hydride in tetrahydrofuran at a lower to slightly elevated temperature, for example at a temperature between 0 and 100 degrees Celsius, but conveniently boiling the reaction mixture.

For the preparation of compounds of formula I in which A is a methylene or ethylene group, the reduction is conveniently carried out with a hydride such as sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride or pyridine-borane complex in a suitable solvent such as ethanol, isepropanol, tetrahydrofuran, dioxane, trifluoroacetic acid. or hexamethylphosphoric triamide, at a temperature between 0 and 100 ° C.

When X is a compound of formula. II group —CH2 —CO—, the reaction is preferably carried out at elevated temperature, for example by treatment with lithium aluminum hydride in tetrahydrofuran while boiling the reaction mixture. When X is a hydroxyethylene group, the reaction is preferably carried out with pyridine-borane complex. trifluoroacetic acid at temperatures between 25 and 100 ° C, the reaction components are suitably brought into contact at a lower temperature, for example at -10 ^Q C When X radical of the formula

R 4 is -CH-CH- or

ZR ₄ -CH-CH2-CH- the reaction is carried out preferably with sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride in a suitable solvent such as isopropanol, hexamethylfosfortriaminu, tetrahydrofuran or dioxane, at temperatures between 20 and 100 ° C.

The compounds of the formula I obtained by the process according to the invention containing one, two or three optically active carbon atoms can then be separated into the optically active antipodes, diastereomeric racemates and the corresponding optical antipodes by conventional methods.

The resolution of the racemic compound of formula (I) above is preferably carried out by fractional crystallization with mixtures of diastereo229924 specific salts of this compound with an optically active acid, for example with D 1 - tartaric acid, L (+) - tartaric, dibenzoyl-D-tartaric tartaric, (4-) -camphor-10-sulfonic, L (-) -malic, L (+) -mandelic, d-bromocapro-TT-sulfonic or 1-quinic, followed by release of the appropriate optically active base. However, resolution of the racemate can also be accomplished by column chromatography on an optically active adsorbent, for example acetylcellulose.

The diastoreomeric racemates in pure form are obtained, for example, by traction crystallization and / or column chromatography on an inert adsorbent.

The novel compounds thus obtained can then optionally be converted into physiologically compatible salts with inorganic or organic acids. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Some of the compounds of formula (II) used as starting materials are novel. These compounds can be obtained in a manner known per se.

Obočného example, a compound of formula II wherein X is --CO - -CHR ₄ -, is obtained by reacting the corresponding C-haloketone with the appropriate amine and compound of formula II wherein X is -CH ₂ -CO- is obtained by reacting the corresponding phenylacetic acid derivative with the corresponding amine.

As mentioned above, the novel compounds of the present invention exhibit valuable pharmacological properties, namely heart and blood circulation effects, in particular blood pressure, antiarrhythmic and / or cardtotonic effects, with low acute toxicity and minor side effects.

For example, the biological effects of the following compounds were investigated as follows:

A = 1- (4-amino-3,5-dichlorophenyl) -2- {N- [3- [4-methoxyphenyl] propylamino] ethanol,

N- [4-amino-3-cyano-5-fluorophenyl) -2-) N- [3- (4-methoxyphenyl) propyl] methylamine / ethanol,

C-1- (4-amino-3,5-dichlorophenyl) -2- [N- (3-phenylpropyl) -2-propylamino] ethanol hydrochloride,

D; 1- (4-Amino-3,5-dichlorophenyl) -2- {N- [3-

- [4-Hydroxyphenyl] -1-methylpropyl] methylamino] ethanod,

E = N- [1-methyl-2- (4-amino-3,5-dichlorophenyl) ethyl] -N- [3- (4-methoxyphenyl) propyl] amine hydrochloride,

F - N- [2- (4-amino-3,5-dichlorophenyl) ethyl] -N- [3- (4-chlorophenyl) propyl] isopropylamine,

G = N- [3- (4-chlorophenyl) propyl] -N- [2-

- (3,5-dichloro-4-isopropylaminophenyl) ethyl] isopropylamine a

H - N- [2- (4-amino-3-bram-5-cyanophenyl) ethyl] -N- [4-methoxyphenyl) blithyl] -methylamine.

1. Measurement of contractility parameters dp / dt _inax or heart rate in narcotized cats

Male and female cats weighing about 2 to 4 kg are anesthetized by intraperitoneal administration of 40 mg / kg sodium-pento-barbital and 8 mg / kg / h of nalnum-pentobarbital are continually and asphyxia to maintain the disease. Animals breathe spontaneously and their body temperature is maintained at 33 ° C using an electric pad and thermostat.

The pressure in the left ventricle is sensed by a pressure transducer (Millar PC 350j inserted through the right aorta into the left ventricle) and the pressure signals dp / dit are continuously evaluated from the pressure signals using a differentiator.

Heart rate is continuously measured with a Grass tachograph (model 7P4). Either the ECG or left ventricular pressure curve is used as a trigger signal. Parameter registration is performed using Grass printing.

All test substances are injected into Vena saphena in the form of a solution in water or polyethylene glycol 200. The intravenous dose is always 0.3 mg / kg.

The observed maximum effect values and the time after application when the effect returns to half of the maximum effect are shown in the following tables:

Table I

test substance % increase in dp / _{dti llax} time to half effect (min) A V C D + 93 38 + 124> 140 + 83 112 + 105> 100

Table II

test substance heart rate decrease (%) time to half effect (min) E F G H —27 39 —17 150 —13> 90 —14> 52 2. Acute toxicity weight), optionally into the stomach. After 14 days, the method described by Licht-

Male and female mice weighing approximately field and Wilcoxon weigh LD _5n .

The results obtained are summarized in the saphenous efficacy (0.1 or 0.2 ml / 10 g body weight):

test substance LD ₅ [mg / kg] intravenous administration oral administration AND 19 Dec > 100 C 32 250

Because of their pharmacological properties, the compounds produced by the process of the invention are useful in the treatment of cardiac and circulatory disorders. Those compounds which have a positively inotropic effect are particularly useful in the treatment of cardiac insufficiency, and compounds reducing heart rate are particularly useful in the treatment of heart rhythm disorders and coronary heart disease.

For this purpose, the novel compounds described may be formulated, optionally in combination with other active ingredients, into conventional pharmaceutical compositions such as dragees, tablets, powders, suppositories, suspensions, ampoules or drops. A unit dose for adults is 5 to 75 mg, preferably 10 to 50 milligrams, and is administered one to four times daily.

The invention is illustrated by the following non-limiting examples.

Example 1

1- (4-Amino-3,5-dichlorophenyl) -2- (N- [3- (4-methoxyphenyl) propyl] methylamino iothanol

To a solution of 3.45 g (9 mmol) of 4'-amino-3 ', 5'-dichloro-2- {N- [3- (4-methoxyphenyl) propyl] methyl, minoacetophenone in 40 ml of methanol and 15 ml of water was added. 0.5 grams (13.5 mmol) of sodium borohydride was added portionwise while maintaining the pH between 2N and 3 with 6 hydrochloric acid. After the addition was complete, the reaction mixture was stirred for 30 minutes, then evaporated on a rotary evaporator and the residue partitioned between. 100 ml ether and 100 ml 2N ammonia solution. The ether phase is washed with water and dried over sodium sulphate and evaporated. The oily residue is chromatographed on silica gel using methylene chloride / methanol (19: 1) as eluent. The fractions containing the desired compound were combined, evaporated and the oily residue freed from solvent by heating under vacuum at 40 ° C.

IR (methylene chloride):

OH 3610 cm ^-1

NH ₂ 3400 4- 3490 cm ^-1 CH9 2850 + 2940 cm ⁴ OCH3 2830 cm ¹

N-alkyl 2800 cm ^-1

C = C 1610 cm ^-1

UV spectrum (eithanol): λ _max

243 nm (0.23)

280 nm (0.08)

300 nm (0.08)

Example 2

1- (4-Amino-3,5-dichlorophenyl) -2- [N- (3-phenylpropyl) methylamino] ethanol hydrochloride

To 250 ml of methylene chloride was added 10 g (0.035 mol) 4 ^{t-amino-2-broim-3} \ 5'-dichloraceitoifenonu, 6.7 g (0.036 mole) of N- (3-phenylpropyl) meithylamin hydrochloride and

10.5 ml (0.075 mol) of triethylamine. The mixture was heated to reflux for one hour then allowed to stand overnight at room temperature, washed with water, dried over sodium sulfate and evaporated in vacuo on a rotary evaporator. The oily residue consisting of crude 4'-aimino-3 ', 5'-dichloro-2- [N- (3-phenylpropyl) methylamino] Jaco-phenone is dissolved in 100 ml of 90% ethanol and left to stand with cooling and cooling with water. 5 g of sodium borohydride are added in portions. The reaction mixture was allowed to stand at room temperature for 1 hour, then excess sodium borohydride was quenched with acetone. After dilution with water, the mixture is extracted with methylene chloride, the methylene chloride phase is separated, washed with water, dried over sodium sulphate and evaporated in vacuo on a rotary evaporator. The yellowish oily residue is chromatographed on silica gel using methylene chloride / ethyl acetate (4: 1) as eluent. The fractions containing the title compound were evaporated, the oily residue was dissolved in isopropanol, acidified with ethereal hydrochloric acid, and then ethec was added until crystallization began. A colorless crystalline product is obtained, m.p.

Example 3

4- [4- (4-chloro-1,5,5-dichloro) -4- (4'-furyl)] - {N- [3- (4-hydroxyphenyl-1-methylpropyl)] methylamino.ethanol

To a solution of 0.1 mol of 4'-amino-3 ', 5'-dichloro-2-N- [3- (4-hydroxyphenyl-1-methylpropyl) methylanomethoacetophenone] in 300 ml of tetrahydrofuran and 50 ml of water is added to the reaction mixture. The reaction solution was stirred at room temperature for 60 minutes, and after acidification with 2N hydrochloric acid, the tetrahydrofuran was distilled off on a rotary evaporator, and the remaining acidic aqueous residue was basified until basic. ether (2.times.75 ml) was added, the ether extracts were washed with water (2.times.75 ml), dried (MgSO4), filtered and the filtrate evaporated on a rotary evaporator.

The residue was purified by silica gel chromatography eluting with methylene chloride / methanol (30: 1). The fractions containing the title compound were evaporated on a rotary evaporator. The residue crystallizes after seeding. The crude crystalline product was recrystallized from methyl chloride. The product was a 1: 1 mixture of diastereomeric racemates, m.p. 112-115 ° C

Example 4

N- [2- (4-Amino-3-bromophenyl) ethyl] -N- [3- (4-methoxyphenyl) propyl] methylamine dihydrochiorici

2.9 g (0.077 mol) of lithium perhalodium hydride are suspended in 100 ml of absolute tetrahydrofuran under nitrogen and a solution of 14.4 g (0.031 mol) of 4-amino-3,5-dibromo is added dropwise under stirring at room temperature. N- [3- [4 - ^ <^ tho: ^^^ i ^ f ^ ^r ^^ l.1 propyl] -N-methyl-phenylacetamide in 100 ml of absolute tetrahydrofuran. the reaction mixture was heated 1 h under reflux for The reaction mixture was quenched with ethyl acetate and water and 10 N sodium hydroxide solution was added until the inorganic material precipitated as a granulate.The decanted tetrahydrofuran phase was decanted off, dried over sodium sulfate and evaporated on a rotary evaporator. The residue was chromatographed on silica gel using a mixture of methylene chloride and methanol (19: 1) as the eluent, and the fractions containing the desired product were combined, evaporated, the oily residue dissolved in a small amount of absolute ethanol and dissolved in a solution. Ethanolic hydrochloric acid is added and ether is added to give crystalline dihydrochloride melting at 168-171 ° C with decomposition.

Example 1 a d 5

N- [2- (4-amino-3,5-diphenylphenyl) ethyl] -N- [4- (4-mothoxyphenyl) butyl] methylamine

2.9 g (0.077%) of lithium aluminum hydride are suspended in 100 ml of absolute tetrahydrofuran under nitrogen atmosphere and a solution of 15.0 g (0.0-31 mol of 4-a · 4-a) is added dropwise under stirring at room temperature. 4- [4- (4-Ethoxyphenyl-butyl) -N-methyl-phenylacetamide in 100 ml of absolute tetrahydrofuran, the reaction mixture was heated under reflux for 1 hour, then the excess of trifluorohydride was decomposed with ethyl acetate and water, and 10 N sodium hydroxide solution is added dropwise until the inorganic material precipitates in the form of a granulate. The supernatant phase is decanted off, dried over sodium sulphate and evaporated on a rotary evaporator. The residue is chromatographed on silica gel using methylene chloride / methanol ( The fractions containing the desired product were combined and evaporated, and the oily residue was freed from solvent by heating under vacuum at 40 ° C.

IR (methylene chloride):

NH 2 3380 + 3470 cmN-alkyl 2790 cm ^-1

OCH ·, 2830 cm -1 aliphatic CH ₂ 2850 4- 2930 cm ¹ C = G 1610 cmIJV. Spectrum (ethanol): λ _ίΠΊΧ

246 nm (0.24)

281 nm (0.08)

305 nm (0.09)

229

Example 6

N- [2- (4-amino-3-chloro-5-cyanophenyl) ethyl] -N- [3- (4-methoxyphenyl) propyl] methylamine

1.3 g (0.0027 mol) of 1- (- amino-3-chloro-5-cyanophenyl) -2- (N- [3- (4-methoxyphenyl) propyl) methylamino] ethyl iodide are dissolved in 30 ml of hexamethylphosphoric triamide. 0.25 g (0.004 mol) of sodium cyanoborohydride was added and the mixture was heated at 70 ° C for 3 hours. After cooling, the reaction mixture was diluted with water (100 ml) and extracted with ether, washed with water, dried over sodium sulfate and evaporated. The oily residue is chromatographed on silica gel using methylene chloride / methanol (20: 1) as the eluent. The oily residue is then stripped of the solvent in vacuo.

Mass spectrum:

found M + 357/59.

Molecular Weight: 3'57,8.

Example 7 1- (4-Amino-3-cyano-5-fluorophenyl) -2- (N- (3- (4-methoxyphenyl) propyl) methylamino) thithanol

The title compound was prepared in an analogous manner to that in Example 1 from 4'-amino-3'-cyano-5'-fluoro-2- (N- [3- (4-methoxyphenyl) propyl] methylamin] acetenenone and sodium borohydride in 90%: methanol.

IR (methylene chloride):

OH 3590 · cm-1

NH 3, 3400 + 3490 cm

CH2 2850 + 2940 cm ¹

00¾ 2830 cm ^-1 N-alkyl 2800 cm ¹ PN 2210 cm

NH ₂ (deformation vibration) 1635 cm aromatic

C = C 1610 cm -1

UV spectrum (ethanol): Amax

242 nm (0.3)

325 nm (0.14).

Example 8

1- (4-amino-3-bromo-5-cyanophenyl) -2-N- [3- (4-methoxyphenyl) propyl] methylamino] ethanol

The title compound was prepared in an analogous manner to that in Example 1 from 4'-amine-3'-bromo-5'-cyano-2- {N- [3- (4-methoxyphenyl) propylmethylamino] acetophenone and sodium borohydride in 80% of methanol.

IR (methylene chloride):

OH 3590 cm-1 (thin strip)

NH ₂ 3400 + 3480 cm -1

CH2 2850 + 2930 cm @ -1

C = N 2200 cm &lt; -1 &gt;.

C = 1640 cm

UV spectrum (ethanol): Amax

243 nm (0.20)

280 nm (0.04)

334 nm (0.12)

Example 9

1- (4-Amino-3,4-dibromophenyl) -2- {N- [3- (4-methoxyphenyl) propyl] methylamino] ethanol

The title compound was prepared in an analogous manner to that in Example 1 from 4'-amino-3 ', 5'-dibromo-2- | N- [3- (4-methoxyphenyl) propyl] methylamino] acetufenone and sodium borohydride in 80% methanol. .

IR (methylene chloride):

OH 3590 cm ¹

NH ₂ 3380 + 3460 cm -1

N-alkyl 2800 cm

OCH3 2830 cm-1 aliphatic CH ₂ 2850 + 2940 cm- ¹ C = C 1610 cm-1

UV spectrum (ethanol): Amax

244 nm (0.16)

303 nm (0.06).

Example 10

1- (4-amino-3 -chloro-5-tri-trifluoromethylphenyl) -2- {N- [3- (4-methyl-phenyl thoxyι ⁱ⁾ prupyl] methyl-1-amine] ethanul

The title compound was prepared in an analogous manner to that in Example 1 from 4 '-' amino-3'-chloro-5'-trifluoromethyl-2 - N - (3- (4-methoxyphenyl) propyl] methylamino) acetufenone and sodium borohydride in 80% of methanol.

IR (methylene chloride):

OH 3590 cm @ -1

NH ₂ 3410 + 3510 cm -1

N-alkyl 2800 cm -1

OCH 3 2830 cm -1 aliphatic CH ₂ 2850 + 2940 cm C = C 1630 cm -1

UV spectrum (ethanol): Amax

225 nm (0.36)

245 nm (0.31)

280 nm · (0.05)

310 nm (0.1).

Example 11

1- (3,5-dichloro-4-hydroxyphenyl) -2-N- [3- (4-methoxyphenyl) propyl] methylamine;

The title compound was prepared in an analogous manner to Example 1 from

3 ^{<5 <-dichloro-4'-hydroxy-2-IFN-} [3- (4'methoxyf) propyl] methylaminojacetofenonu and sodium borohydride in a ^80:% methanol.

Melting point: 156-157 ° C.

Example 12 l [(3,5-dibromo-4-hydroxy-phenyl - 2- [N- [3- (4-methoxyphenyl 1} propyl] ^methyl-1 mino'ečhanol title compound having Prepared analogously -v of Example 1 from 3 ', 5' [dibi [omega] [hydroxy] 2 [(N- [3- (4 [methoxy [phenyl) propyl] methylamino] acetophenone and sodium borohydride in 80% methanol.

Melting point hydrochloride: 159-162 ° C.

Example 13

1- [4-Amino [3-bromo-5-fluorophenyl) -2- {N- [3- (4-methoxyphenyl) propyl] methylamino] ethanol

The title compound was prepared in an analogous manner to Example 1 from 4'-amino-3'-bromo-5'-fluoro [-2 '- (N [[3- (4-methoxyphenyl) propyl] methylamino) acetophenone and sodium borohydride in 80% methanol.

Melting point of the amorphous hydro-cord: from 60 ° C.

Example 14 (4 [amino [3 [chloro [5 [fluorophenyl]) -2- {N- [3- (4 [methoxyphenyl) propyl] methylamino] ethanol)

The title compound was prepared in an analogous manner to Example 1 from 4 '[amino-3' [Chloro [5 '] fluoro-2- (N [[3- (4-methylphenyl) propyl] methylamino] acetophenone and sodium borohydride at 80 ° C. 103 DEG-108 DEG C. [decomposition].

Example 15

1 · [4 [amino [3-chloro [5] cyanophenyl) -2- {N- [3- (4 [methoxyphonyl (propyl) methylamino] ethanol]

The title compound is prepared analogously to Example 1 from ^4'-amino: and 3'-ch1or [5 ^t-cyano-2- {N - 3- (4-methcxyfenyl) propyl jmethylaminojacetofenonu and sodium borohydride in 80% of methanol.

IR (methylene chloride):

OH 3590 cm

_NH2 3400 + 3500 cm ¹

N-alkyl 2800 cm ¹

OCH3 2830 cm ¹ aliphatic CH> 2850 + 2940 cm ⁴ C = N 2210 cm ¹

C = C 1625 cm ¹

UV spectrum (ethanol): Amax

245 _; nm (0.2 µl)

278 nm (0.061

- 2 nm (0.16).

EXAMPLE 16 1- (4-amino-3-chloro-5-nitrophenyl) -24N- [3- (4-methoxyphenyl) propyl] methylamino] ethane

The title compound was prepared in an analogous manner to that described in the example from Pan-10-chloro-S-nitro-1'-N-4-methoxy-phenyl-propyl-methylamino-acetophenone and sodium borohydride in 80% methanol.

IR (methylene chloride):

OH 3590 cm

NH ₂ 3390 - + 3500 - cm -1

N-alkyl 2800 cm

OCH 3 2830 cm -1 aliphatic C 1 - group 2850 + 2940 cm ^-1

C - C 1630 cm 1

NO2 1330- + 1515 cm ~ k

UV Spectrum (ethanol): λ _inax

227 nm (0.64)

280 nm (0.16)

400 nm [0.12]

Example 17

1- [4-Amino-5-chlorophenyl-2-; N- [3- (4-methoxyphenyl) propyl] methylamino] ethanol

The title compound was prepared in analogy to Example 1 from 4 z-amino-3--chloro-2-N- [3- (4-methoxyphenyl) propyl] methylamino] acetophenone and sodium borohydride in 80% methanol.

IR-spectrum (ιιοΙ · ’!! ^ '^! ^^):

OH 3600 cm -1

NH, 3380 + 3470 cm!

N-alkyl 2800 cm -1 ^!

OCH _? and 2830 - cm ^-1 CLD-aliphatic group 2850 2940 + CMC-C 1620 cm.

UV spectrum [ethanol]: _{2.1) a4}

225 nm (0.44)

243 nm (0.36)

280 nm

295 nm (0.08)

Example 18

1- (4-Amino-3) -2- {N- (3- (4-methoxyphenyl) propyl] methylamino) ethanol

The title compound was prepared according to the procedure in Example 1 from 4--amino-3‘-bromo-2-N-13- (4-methoxyphenyl) propylmethylamino-acetophenene and sodium borohydride in 80% methanol.

The dihydrochloride melts with decomposition at 137 degrees Celsius.

Example 19

1- (4-Amino-3,5-dicyanophenyl) -2- {N- [3- (4-methoxyphenyl) propyl] methyl laminoethanol

The title compound was prepared in an analogous manner to Example 1 from 4‘-amino-3-, 5‘-dicyano-2- [N- [3- (4-methoxyphenyl) propyl] methylamino] acetophenone and sodium borohydride in 80% methanol.

The hydrochloride has a melting point of 167-170 degrees Celsius.

Example 20

1- (4-Amino-3-bromophenyl) -2-N- [4- [4-methoxyphenyl) butyl] methylamino] ethanol

The title compound was prepared in an analogous manner to Example 1 from 4 z-amino-3‘-bromo-2- [N- (4- (4-methoxyphenyl) butyl) methylamino) acetophenone and sodium borohydride in 80% methanol.

IR (methylene chloride):

OH 3590 cm @ -1

NH-3380 + 3470 cm ^-1

N-alkyl 2800 cm @ -1

1 2830 cm ^-1 aliphatic CH 2 group 2850 + 2930 cm ¹ C — C 1620 cm -1.

UV spectrum (ethanol): Amax

224 nm (0.44)

243 nm (0.28)

280 nm (0.08)

300 nm (0.06)

Example 2 1

1- [4-Amino-3-bromophenyl) -2- {N- [2- [4-methoxyphenyl) ethyl] methylamino] ethanol

The title compound was prepared in an analogous manner to Example 1 from 4‘-amino-3‘-bromo-2- (N- [2- (4-methoxyphenyl) ethyl) methylamino-acetophenone and sodium borohydride in 80% methanol.

IC spectrum · (methylene chloride):

OH 3590 cm @ -1

NH2 3,380 · 3470 cm ⁴

N-alkyl 2800 cm @ -1

OCH- 2830 cm @ -1 aliphatic CH2 group 2840 + 2940 cm @ ^-1 C = C 1620 cm @ ^-1 ;

UV spectrum (ethanol): Amax

225 nm (0.43)

243 nm (0.36)

280 nm (0.08)

296 nm (0.08).

Example 22

1- (4-Amino-3,5-dichlorophenyl) -2-N- [4- (4-ethoxyphenyl) butyl] methylamino] ethanol

The title compound was prepared in an analogous manner to Example 1 from

4‘-amino-3 ‘, 5‘-dichloro-2- (N- [4- (4-methoxyphenyl) butyl] methylamino) acetophonone and sodium borohydride in 80% methanol.

IR (methylene chloride):

OH 3590 cm @ -1

NH2 3390 + 3490 cm ^-1

N-alkyl 2800 cm ^-1

OCH 3 2830 cm-CH 2 -group 2850 + 2930 cm ⁴ C = C 1610 cm -1.

UV spectrum (ethanol): Amax

245 nm (0.25)

320 nm · (0.48)

Example 23

1- (4-amino-3-bromo-5-cyanophenyl) -2- {N- [4- (4-methoxyoxyphenyl) butyl] methylamino] ethanol

The title compound was prepared in an analogous manner to Example 1, starting from 4'-amino-3'-bromo-5'-cyano-2-N - [4- [4-methoxyphenyl] butyl] methylamino] acetophenone and sodium borohydride in 80% o of methanol.

IR (methylene chloride):

OH 3590 cm @ -1

NH 2 3390 + 3490 cm -1

N-alkyl 2800 cm -1

OCH3 2830 cm -1 aliphatic CH 2 group 2850 + 2930 cm -1 CsN 2210 cm -1!

C = C 1620 cm @ -1.

UV spectrum (ethanol): A, _nax

245 nm (0.27)

278 nm (0.08)

330 nm (0.15)

Example 24

1- (4-Amino-3-bromo-5-cyanophenyl) -2-N- [2- (4-methoxyphenyl) ethyl] methylamino] ethanol

The title compound was prepared in analogy to Example 1 from 4'-amino-3'-bromo-5'-cyano-2- [N- (2- (4-methoxyphenyl) ethyl] methylamino) acetophenone and sodium borohydride in 80% of methanol.

IR (methylene chloride):

OH 3590 cm @ -1

NH 2 3390 4- 3490 cm -1 N-alkyl 2800 cm -1

OCH3 2830 cm @ -1 aliphatic CH2 group 2850 + 2950 cm @ -1

C = N 2210 cm -1

C = C 1620 cm -1

UV spectrum (ethanol):?,? _:?

245 .nm (0.25)

277 nm (0.09)

331 nm (0.10)

Example 25

1- (4-amino-2,3-dichlorophenyl) -2- (N- [2- (4-methoxyphenyl) ethyl] methylamino) ethanol

The title compound was prepared in an analogous manner to that in Example 1 from 4'-amirio-3 ', 5'-dichloro-2- {N- [2- (4-methoxyphenyl) ethyl] methylamino] acetophenone and sodium borohydride in 80% of methanol.

IC spectrum (methylene chloride):

OH 3590 cm ” ¹

_NH2 3390 + 3490 cm ¹

N-alkyl 2800 cm ¹

OCH.) 2830 cm ¹ aliphatic CH ₂ -group 2850 + 2930 cm ^-1 C-1610 cm -1.

Example 26 1- (4-amino-3-chloro-5-cyanophenyl) -2- [N- (4- (4-methoxyphenyl) butyl) methylamino] ethanol

The title compound was prepared in an analogous manner to that in Example 1 from 4'-amino-3'-chloro-5'-cyano-2- | N- [4- (4-methoxyphenyl) butyl] methylamino] acetophenone and sodium borohydride in 80% methanol.

IR spectrum [methylene chloride]:

OH 3590 cm ^- '

NH, 3400 + 3500 cm ¹

N-alkyl 2800 cm ¹

OCH _{: i} 2830 cm ¹ aliphatic CH _{2 -} group 2850-2930 cm ^-1

Ch = N 2210 cm ^-1

C = C 1625 cm ¹

UV spectrum (ethanol): A _inaK

245 nm (0.23)

280 nm (0.05)

332 nm (0.13)

Example 27 1- (4-Amino-3-chloro-5-cyanophenyl) -2- N- (2- (4-methoxyphenyl) ethyl) Imethylamino, ethanol

The title compound was prepared in an analogous manner to Example 1 from 4'-amino-3'-chloro-5'-cyano-2- {N- [2- (4-methoxyphenyl) ethyl] methylamino} acetophenone and sodium borohydride in 80% methanol.

IR (methylene chloride):

OH 3590 cm ¹

NH, 3390 + 3490 cm ^&lt; -1 ^&gt;.

N-alkyl 2800 cm ¹

TCH 2830 cm ¹

CH2 ₂ Z850 + 2940 cm ” ¹

UN 2210 cm ” ¹

C = C 1620 cm -1.

UV spectrum (ethanol): A _niax

245 nm (0.24)

280 nm (0.04)

332 n.m (0.13)

Example 28

1- (4-Amino-3,5-dichlorophenyl) -2- (N- [2- (4-methoxyphenylsulfenyl) ethyl] methylamino) ethanol

The title compound was prepared in oily form as described in Example 1 from 4'-amino-3 ', 5'-dichloro-2- {N- [2- (4-mothoxyphenylsulfenyl) ethyl] methyl lamino | acetophenone and sodium borohydride in tetrahydrofuran / water / methanol (25: 5: 10).

IR (methylene chloride):

OH 3200 - 2500 cm ¹ (below NH ₂ )

_NH2 3480 + 3390 cm ¹

CH ₂ 2940 cm- ¹

N-alkyl 2800 cm ¹

₍ 2830 cm ¹⁾

C = No. 1580 + 1490 cm ” ¹ .

UV spectrum (ethanol): λ _max

230 nm (0.58, arm)

245 nm (0.54)

298 nm (0.14)

Example 1 a d 2 9

1- (4-Amino-3,5-dichlorophenyl) -2- {N- [2- (4-methoxyphenoxy) ethyl] methylamino] ethanol

The title compound was prepared in an oily form in an analogous manner to Example 1 from 4'-amino-3 ', 5'-dichloro-2-) N- [2- (4-methoxyphenoxy) ethyl] methylamino) acetophenone and sodium borohydride in mixture of itetrahydrofuran, water and methanol (15: 5: 3).

IR (methylene chloride):

OH 3200—3500 cm ¹ (under NH,)

_NH2 3480 + 3390 cm ¹

CH ₂ 29 ¹ 2940 cm

N-alkyl 2790 cm ¹

OCH ₃ 2830 cm ¹

C = δ 1580, 1505 + 1485 cm ^-1

C-O-aryl 1250 cm ^-1

UV spectrum (ethanol): A _niax

230 nm (0.32; arm)

244 nm (0.26; arm)

294 nm (0.12)

Example 30

1- (4-amino-3,5-dichlorophenyl) -2- {N- [3- (4-methoxyphenyl) propyl] amino] propan-1-ol

The title compound was prepared in an analogous manner to Example 1 from 4 z-amino-3-, 5‘-dichloro-2- (N- [3- (4-methyl-oxyphenyl) propyl] -amino-propiophenone and sodium borohydride.

The hydrochloride melts at 201-202 ° C with decomposition.

Example 31

1- (4-amino-3,5-dichlorophenyl) -2- [N- (3- (4-methoxyphenyl) propyl) -2-propylamino] ethanol

The title compound was prepared in an oily form in a manner analogous to Example 1 from 4'-amino-3 ', 5'-dichloro-2- {N- [3- (4-methoxyphenyl) propyl] -2-pr opy 1ат1по (асе1о1е.по.пи and sodium borohydride.

IR (methylene chloride):

OH 3600 cm ¹

NH ₂ 3400 + 3490 cm ^-1

_{OCH t} 2830 ^cm-1

UV Spectrum (ethanol): A _liax

243 nm (0.13)

280 nm (0.03)

300 nm (0.03)

Example 32

1- (4-Amino-3,5-dichlorophenyl) -2- (N- [3- (4-methoxyphenyl) propyl) ethylamino] ethanol

The title compound was prepared in an analogous manner to that in Example 1 from 4 amino-amino-3‘, 5‘-dichloro-2-1H- [3- (4-methoxyphenyl) propyl] ethylamino] acetophenone and sodium borohydride.

IR (methylene chloride):

OH 3600 cm-1 ·

NH ₂ 3395 + 3490 cm ^-1

O'CH ₃ 2830 cm ¹ UV spectrum (ethanol): _{max max}

243 nm (0.13)

280 nm (0.04)

300 nm (0.04)

Example 33

1- (4-Amino-3,5-dichlorophenyl) -2- (N- [3- (4-methoxyphenyl) propyl] propylamino) ethanol

The title compound is prepared analogously to Example 1 from 4'-amino-3 ', 5'-dichloro-2- {N- [3- (4-methyl ^| methoxyphenyl) propyl jpropyiaminojacetofenonu and sodium borohydride. The product results in the form of an oil.

IR (methylene chloride):

OH 3600 cm ^-1

NH ₂ 3395 + 3495 cm ^-1

O, 2850 ^cm-1

UV spectrum (ethanol): A _max

245 nm (0.10)

280 nm (0.03)

300 nm (0.03).

Example 34

1- (4-Amino-3,5-dichlorophenyl) -2- (N- [3- (4-methoxyphenyl) propyl] cyclopropylaminoethanol

The title compound was prepared in an analogous manner to that in Example 1 from 4'-amino-3 ', 5'-dichloro-2- (N- [3- (4-methoxyphenyl) propyl] cyclopropylamino) acetophenone and sodium borohydride. .

IR (methylene chloride):

OH 3590 cm ¹

_NH2 3395 + 3495 cm ¹

_{OCH and} 2850 cmUV spectrum (ethanol): A _max

245 nm (0.12)

280 nm (0.04)

300 nm (0.04)

Example 35

1- (4-amino-3,5-dichlorophenyl) -2- [N- (3- (4-methoxyphenyl) propyl) methylamino] propan-1-ol, isomer V

The title compound was prepared in an analogous manner to Example 2 from N- [3- (4-methoxyphenyl) proipyl] methylamine, 4‘-amino-2-bromo-3 3, 5‘-dichloropropiophenone, triethylamine and sodium borohydride. The product results in the form of an oil.

IR (methylene chloride):

OH 3600 + 3680 cm ¹

NH ₂ 3390 + 3490 cm ^-1

OCH ₃ 2835 + 2940 cmaromatics 1510, 1585 + 1610 cm ^-1

UV spectrum (ethanol): λ _max

246 nm (0.15)

278 nm (0.08)

285 nm (0.08)

300 nm (0.08)

NMR spectrum (deuterochloroform / deuterium oxide):

proton signal at the carbon atom at position 1 of the propanol moiety: doublet at 4.1 ppm (J = 10 Hz).

Example 36

1- (4-amino-3,5-dichlorophenyl) -2- {N- [3- (4-methoxyphenyl) propyl] methylamino] propan-1-ol, isomer A

The title compound was prepared in an analogous manner to Example 2 from N- [3- (4-methoxyphenyl) propyl] methylamine, 4‘-amino-3-, 5‘-dichloro-2-bromopropiophenone, triethylamine and sodium borohydride.

The hydrochloride melts at 173-181 ° C.

The NMR spectrum of the throw (deuterochloroform / / deuterium oxide):

signal for proton on carbon atom in position 1 of the propanol part: doublet at 4.3 ppm (4.5 Hz).

Example 37

1- (4-amino-3,5-dichlorophenyl) -2- {N- [3- (4-ethoxyphenyl) propyl] methylamino'ethanol The title compound was prepared in an analogous manner to Example 2 of 4 '-amino-3', 5'-dCchloro-2-bromoacetophenone, 1- (4-ethoxyphenyl) -3-methylaminopropane hydrochloride, triethylamine and sodium bromide, The product is obtained as an oil.

IR (methylene chloride):

OH 3590 cm ¹

NH2 3395 - | - 3495 cm ¹

N-alkyl 2800 cm ¹ ·

UV spectrum (ethanol): _IR

245 nm (0.13)

280 nm (0.05)

300 nm (0.04)

Example 3 8 1- (4-Amino-3,5-dlphenylphenyl) -2- {N- [3- (4-benzyloxyphenyl) propyl] methylamino] ethanol

The title compound was prepared in an analogous manner as in Example 2 from 4 ^<-amino-3 ', 5'-dichlof 2-bromo ·? Etoíenrnu. 1- (4-benzyloxyphenyl) -4-methylaminopropane hydrochloride, triethylamine and sodium trihydrohydride. The product results in the form of an oil.

IR (methylene chloride):

OH 3590 cm ¹

NH2 3395 + 3495 cm ¹

N-alkyl 2800 cm- ⁴

Example 39 1- (4-Amino-3-iodo-5-fluorophenyl) -2- {N- [3- (4-methoxyphenyl) propyl] methylamino] ethanol

The title compound was prepared in an analogous manner to Example 2 from 4'-amino-3'-iodo-5'-fluoro-2-bromoacetophenone, 1- (4-methoxyphenyl) -3-methylaminopropane hydrochloride, triethylamine and sodium trihydrotrihydride. . The product results in the form of an oil.

IR (methylene chloride):

OH 3599 cm @ -1

NH2 3395 + 3495 cm ¹

N-alkyl 2800 cm ¹

Example 40

1- (4-: amino-3-cyano-5-fluorophenyl) -2- [N- [3- (4-methoxyphenyl) propyl] -2-trifluoromethylaminoethanol

The title compound was prepared in analogy to Example 2 from 4'-amino-3'-cyano-5'-flurr-2-bromoaceto ^: phenone, 1- (4-methoxyphenyl) -3- (2-pr opylamino) propane hydrochloride and sodium bromide. The product results in the form of an oil.

IR (methylene chloride):

OH 3600 cm @ -1

NH + ₂ 3395 ^3495-1

OCH2 2830 cm @ -1

N-alkyl 2800 cm @ -1

C = N 2220 cm @ -1

Example 41

1- (4- (3,5-trichloro-phenyl) -2-N- [3- (2-methoxyphenyl) propyl] methylamino) ethanol-hydrochloride

The title compound is prepared analogously to Example 2 from 4 ^<ζ-amino-3, 5'-dichlof 2 Br · omacetofenrnu, 1- (2-methyl (methoxy phenyl) -3-methylamino-propan-sulfide hydrochloride, triethylamine and sodium borohydride.

The product lays for sintering from 73 C.

Example 42

1- (4-Amino-3,5-dichlorophenyl) -2-N- [3- (3,4-dimethoxyphenyl) propyl] methylamino] ethanone

The title compound is prepared analogously to Example 2 from ^4-d -aminr з ', 5'-dichloro - 2-bfomacetofeοonu, 1- (3,4-d ImQthoxyfeuyl) ^ -methylammopropan hydrochloride, triethylamine and sodium borohydride .

IR spectrum 1

OH 3600 · cm ¹

NH ₂ · 3390 + 3485 cm ¹

OCH ₃ 2830 cm

N-alkyl 2800 cm ¹

Example 43 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-N- [2- (4-methoxy-phenyl) -ethyl] -methyl-amino-ethanol

The title compound was prepared in an analogous manner to Example 1 from

4‘-amino-3‘-chloro-5‘-trifluoromethyl-2- [N- [2- (4-methoxyphenyl) ethyl] methylamino] acetophenone and sodium borohydride in 80% methanol.

IC spectrum (methylene chloride):

OH 3600 ^cm-1

NH2 3410 + 3510 cm ¹

N-alkyl 2800 cm ¹

OCH3 2830 cm @ ¹ aliphatic CH2 group 2850 + 2940 cm @ ¹ C — C 1630 cm @ ¹

UV spectrum (ethanol): Amax

225 nm (0.38)

244 nm (0.34)

280 nm. (0,07)

307 nm (0.10)

Example 44

1- (4-Amino-3,5-dichlorophenyl) -2-N- [3- (4-methoxyphenyl) propyl] aminojethanol hydrochloride

The title compound was prepared in an analogous manner to Example 1 from 4 z-amino-3mo, 5‘-dichloro-2- [N- (3- (4-methoxyphenyl) propyl) amino] acetophenone and sodium borohydride in 80% ethanol.

The hydrochloride melts at 185-186 ° C after crystallization from an ethanol / ether mixture.

Example 45

1- (4-Amino-3,5-dichlorophenyl) -2- [N- (3-phenylpropyl) -2-propylamino] ethanol-hydrochloride

The title compound was prepared in an analogous manner to Example 2 from 4'-amino-3 ', 5' '- dichloro-2-bromoacetophenone, 1-phenyl-3- (2-propylamino) propane hydrochloride, triethylamine and sodium borohydride .

The product melts at 124-128 ° C.

Example 1 4

1- (4-amino-3,5-dichlorophenyl) -2- {N- [3- (4-fluorophenyl) propyl] methylamino] ethanol ethanol hydrochloride

The title compound was prepared in an analogous manner to Example 2 from 4‘-amino-3‘, 5‘-dichloro-2-bromoacetophenone, 1- (4-fluorophenyl) -3-methylaminopropane hydrochloride, triethylamine and sodium borohydride.

The product melts with decomposition at 185-188 degrees Celsius.

Example 47

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

The title compound was prepared in an analogous manner to Example 3 from 4'-amino-3 ', 5'-dichloro-2- [N- (3- (4-hydroxyphenyl) -1-methylpropyl) amino] acetophenone and sodium borohydride in aqueous tetrahydrofuran. A mixture of dichloromethane, methanol and concentrated ammonia (19: 1: 0.05) was used as the eluent in silica gel chromatography purification.

The product results in the form of an oil consisting of a mixture of equal parts of diastero-racemic racemates.

IC spectrum (KBrrtechnika):

OH 2300—3500 cm1 (wide band of coupled signals)

NH2 3460 + 3370 cm ¹

CH2 2920 + 2960 cm ^-1

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

UV spectrum (ethanol): λ _max

244 nm (0.28)

280 nm (0.08)

300 nm (0.08)

UV spectrum (ethanol + potassium hydroxide): ^λ inax

243 nm (0.54)

299 nm (0.15)

Example 48

1- (4-Amino-3,5-dichlorophenyl) -2- {N- [3- [4-methoxylphenyl] -1-methylpropyl] aminojethanol

The title compound was prepared in an analogous manner to that in Example 3 from 4'-amino-3 ', 5'-dichloro-2-N- [3- (4-methoxyphenyl) -1-methyl-propyl] -amino-acetonitrile and sodium borohydride in aqueous tetrahydrofuran. The product results in the form of an oil.

The resulting product is obtained as a 1: 1 mixture of diastereomeric racemates.

IC spectrum (methylene chloride):

OH 3600 cm ” ¹

_NH2 3480 + 3390 cm ¹

CH, 2930 · cm1 CHCH 2830 cm ¹

C = C 1580, 1510 + 1485 cm ¹

UV spectrum (ethanol): Amax

244 nm (0.28)

280 nm (0.08)

300 nm (0.09)

Example 1 4 9

N- [2- (4-amino-3,5-dibromophenyl) ethyl] -N- [3- (4-methoxyphenyl) propyl] methylamine

The title compound was prepared in an analogous manner to that described in Example 4 of

4-Amino-3,5-dibromo-N- [3- (4-methoxyphenyl) propyl] -4H-methylphenylalcohol and lithium aluminum hydride.

The hydrochloride melts at 149-153 ° C.

Example 1 a d 5 0

N- [2- (4-amino-3, l ^ - ^ ^and t ^ r ^ ll ^ i ^ i ^ (^ in ^ l) ethyl] - N- ^

- [3- (4-methoxyphenyl) propyl] methylamine

The title compound was prepared in an analogous manner to that in Example 4 from 4-amino-3,5-dichloro-1 - [- [- [3,4-methoxyphenyl] propyl] -N-methyl-phenylacetamide and lithium aluminum hydride.

The hydrogen steel melt melts at 90 to 94 ° C.

Example 5 1

N- [2- 3 4-Amino-0,5-dichloro-phenyl) -ethyl] -N-

- [2- (4-methoxyphenyl) ethyl] methylamine

The title compound was prepared in an analogous manner to that in Example 5 from 4-amino-0,5-dichloro-N- [2- (4-methoxy-phenyl) -ethyl] -N- (4-yl) -acetamide. and lithium aluminum hydride.

IR spectrum (methylene chloride):

NH, 3380 + 3470

N-alkyl 2780 cm ^-1

OCH3 2830 cm-1 aliphatic CH ₂ -group 2850 + 2930 cm -1

C = C 1610 cm ⁴

UV spectrum (ethane): A _{) Pax}

245 nm (0.24)

281 nm (0.08)

305 nm (0.07)

Example 5 2

N- [2- (4-amino-0,5-dichlorophenyl) ethyl] -N- (4- (4-methylbutyl) butyl) methylamine

The title compound was prepared in an analogous manner to that in Example 5 from 4-amino-0,3-dicelor-N- [4- (4-methoxy-phenyl) -butyl] -acetamide and lithium aluminum hydride.

IR spectrum (meteylencelorld):

NH ₂ 3380 + 3480 cm -1

OCHg 2830 cm “aliphatic CH group 2850 -h 2930 cm“ NH + 2100—2500 cm “1

C — C 1630 cm -1

3- (4-amino-0,5-dichloro-ynyl) -N- [2- (3,4-dimethylethyl-phenyl) -yl] -propionamide and lithium aluminum hydride.

The product melts at 142-145 ° C.

Example La d '5 4

N- [O- (4-amino-0,5-dichlorophenyl) propyl] -N- [2- (0,4-dimethoxyxenyl) ethyl] methylamine

The title compound was prepared in an analogous manner to that in Example 5 from O- (4-amino-0,5-dichlorophenyl) -N- [2- (3,4-dimethoxyXenyl) ethyl] -N-methyl-propionamide and lithium aluminum hydride.

The product results in the form of an oil.

IR spectrum (myyleylene chloride):

NH ₂ 3400 + 3500 cm “

OCHg 2835 + 2960 cm '

NCHg 2800 cm “1 aromatics 1510 + 1390/1613 cm“

UV spectrum (ethanol): Amax

239 nm (arm)

281 nm (0.11)

390 nm (0.08)

Example 55

N- [3- (4-Amino-O-bromo-ynyl) -propyl 1-2- (3,4-dimethoxy-phenyl) -ethylamine hydride

The title compound was prepared in a manner analogous to Example 4 starting from

3- (4-amino-3,5-dibromophenyl) -N- [2- (3,4-dimethoxyphenyl) ethyl] propionamide and lithium aluminum hydride.

The product melts at 131-134 ° C.

Example 56

N- [2- (4-amino-0,5-dichloro-ynyl) -ethyl] -N- (3- (4-hydroxy-ynyl) -1-methyl-propyl) -amine

The title compound was prepared in a manner analogous to Example 5 starting from

4-Amino-0,3-dicelor N - (3- (4-hydroxyphenyl) -1-methylpropyl) phenylacetamide and lithium aluminum hydride in tetrahydrofuran Chromatographic purification of the product is accomplished by medium pressure chromatography on silica gel (particle size 0.015 0,0 0.025 mm) eluting with a mixture of mythylyn chloride, methanol and concentrated ammonia (19: 1: 0.1) to give the product as a foam.

IR (methylene chloride):

OH 3580 cm *

NH, 3480 + 3335 cm ^-1

CH ₂ 2920 cm '

C = C 1580, 1510 + 1480 cm '

The title compound was prepared in a manner analogous to Example 4 starting from

UV spectrum (ethane): Am _ax

245 nm (0.22)

280 nm (0.07)

304 nm (0.08)

Example 5 3

N- [3- (4-amino-3,5-dicchorphenyl) propyl] -2- (3,4-dimethoxyphenyl) yteylamine hydrochloride

UV spectrum (ethanol): λ _max

242 nm (0.24, arm)

280 nm (0.07)

303 nm (0.08)

UV spectrum (ethanol + potassium hydroxide): Amax

242 nm (0.53)

300 nm (0.16)

Example 57

N- [2- (4-amino-3,5-dichlorophenyl) ethyl] -N- (3- (4-methoxyphenyl) -1-methylpropyl) amine

The title compound was prepared in an analogous manner to Example 5 from 4-amino-3,5-dichloro-N- [3- (4-methoxyphenyl) -1-methylpropyl] phenylacetamide and lithium aluminum hydride in tetrahydrofuran.

The product results in the form of an oil.

IR (methylene chloride):

NH ₂ . 3480 + 3385 cm ¹

CH ₂ 2930 cm ¹

OCH ·, 2830 cm ^-1

C = C 1580, 1510 + 1485 cm ^-1

UV spectrum (ethanol): λ _max

242 nm (0.25, arm)

280 nm (0.07)

302 nm (0.08)

Example 58

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

The title compound was prepared in analogy to Example 5 from 4-amino-3,5-dichloro-N- [3- (4-benzyloxyphenyl) propyl] -N-methylphenylacetamide and lithium aluminum hydride. The product results in the form of an oil.

IR (methylene chloride):

_NH2 3390 + 3490 cm ¹

N-alkyl 2800 cm ^-1

UV spectrum (ethanol): λ _max

245 nm (0.10)

280 nm (0.04)

300 nm (0.04)

Example 59

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

The title compound was prepared in an analogous manner to Example 5 from

4-amino-3,5-dichloro-N- [3- (3,4-dimethoxyphenyl) propyl] -N-methylphenylacetamide and lithium aluminum hydride.

The product results in the form of an oil.

IC spectrum (methylene chloride):

NH ₂ 3395 + 3495 cm ⁴

OCH ₃ 2830 cm ^-1

N-alkyl 2800 cm ¹

UV spectrum (ethanol): λ _max

230 nm (arm, 0.18)

245 nm (arm, 0.12)

282 nm (0.04)

302 nm (0.03)

Example 60

N- [2- (4-amino-3,5-dichlorophenyl) ethyl] -N- (3- (2-methoxyphenyl) propyl] methylamine hydrochloride

The title compound was prepared in an analogous manner to that in Example 4 from 4-amino-3,5-dichloro-N- [3- (2-methoxyphenyl) propyl] -N-methylphenylacetamide and lithium aluminum hydride.

The product melts at 160-164 ° C.

Example 61

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

The title compound was prepared in an analogous manner to Example 5 from 4-amino-3,5-dichloro-N- (3-phenylpropyl) -N-methyl-phenylacetamide and lithium aluminum hydride. The product results in the form of an oil.

IR (methylene chloride):

_NH2 3390 + 3490 cm ¹

N-alkyl 2800 cm ^-1

UV spectrum (ethanol): A, _nax

245 nm (0.12)

300 nm (0.03)

Example 62

N- [2- (4-amino-3,5-dichlorophenyl) ethyl] -N- (3- (4-methoxyphenyl) propyl] amine hydrochloride

The title compound was prepared in an analogous manner to that in Example 4 from 4-amino-3,5-dichloro-N- [3- (4-methoxyphenyl) propyl] phenylacetamide and lithium aluminum hydride.

The product melts at 203-205 ° C.

Example 63

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

The title compound was prepared in an analogous manner to Example 5 from

4-amino-3,5-dichloro-N- [3- (4-methoxyphenyl) propyl] -N-cyclopropylphenylacetamide and 11,29924 thium aluminum hydride. The product results in the form of an oil.

IC spectrum (methylene chloride):

NH ₂ 3390 4- 3490 cm ^-1

2830 _OCH3 tin ^-1

UV spectrum [ethanol]: λ _inax

245 nm (0.15)

280 nm (0.04)

300 nm (0.05)

Example 64

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

The title compound was prepared in an analogous manner to that in Example 5 from 4-amino-3,5-dichloro-N- [3- (4-methoxyphenyl) propyl] -N-propyl-phenylacetamide and lithium aluminum hydride. The product results in the form of an oil.

IC spectrum (methylene chloride):

NH ₂ 3390 -h 3490 cm ^-1

OCH3 2830 cm ¹

N-alkyl 2800 cm ^-1

UV Spectrum (ethanol): A _niaK

243 nm (0.13)

280 nm (0.04)

300 nm [0.04]

Example 65

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

The title compound was prepared in an analogous manner to Example 5 from 4-amino-3,5-dichloro-N- [3- (4-methoxyphenyl) propyl] -N-ethyl-phenylacetamide and lithium aluminum hydride. The product results in the form of an oil.

IR (methylene chloride):

NH ₂ 3390 4- 3490 cm ^-1

OCH ₃ 2830 cm ^-1

N-alkyl 2800 cm ⁴

UV spectrum (ethanol): λ _max

243 nm (0.13)

280 nm (0.04)

300 nm (0.04)

Example 66

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

The title compound was prepared in an analogous manner to Example 5 from

4-Amino-3,5-dichloro-N- [3- (4-methoxyphenyl) propyl] -N- (2-piperidinyl) phenylacetamide and lithium aluminum hydride. The product results in the form of an oil.

IC spectrum (methylene chloride):

NH ₂ 3390 4- 3490 cm ^-1

OCH ₃ 2830 cm ' ¹

UV spectrum (ethanol): A _max

243 nm (0.13)

280 nm (0.04)

300 nm (0.04)

Example 67

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

- [3- (4-ethoxyphenyl) propyl) methylamine

The title compound was prepared in an analogous manner to that in Example 5 from 4-amino-3,5-dichloro-N- [3- (4-ethoxyphenyl) propyl] -N-methylphenylacetamide and lithium aluminum hydride. The product results in the form of an oil.

IR (methylene chloride):

NH ₂ 3390 -b 3490 cm ^-1

OCH ₃ 2830 cm ^-1

N-alkyl 2800 cm ¹

UV spectrum (ethanol): λ _inax

245 nm (0.12)

280 nm (0.03)

300 nm (0.04)

Example 68

1- (4-Amino-3-chloro-5-trifluoromethylphenyl) -2- {N- [4- (4-methoxyphenyl) butyl] methylaminoethanol

The title compound was prepared in an analogous manner to Example 1 from 4 amino-amino-3--chloro-5 triflu-trifluoromethyl-2- {N- [4-

- (4-methoxyphenyl) butyl] methylamino-acetophenone and sodium borohydride in 80% methanol.

IR (methylene chloride):

OH 3590 cm ^-1

NHu 34.1.0 + 3510 cm ^-1

N-alkyl 2800 cm ^-1

OCH ₃ 2830 cm ^-1 aliphatic CH ₂ -group 2850 4- 2930 cm ^-1 aromatic C = C-group 1630 cm ^-1

UV spectrum, (ethanol): λ _max

225 nm (0.33)

245 nm (0.31)

280 nm (0.06)

308 nm (0.10)

Example 69

1- (4-Amino-3-cyano-5-fluorophenyl) -2- {N- [4-

- (4-methoxyphenyl) butyl] methylamino] ethanol

CH3 —CH2 — CH2 — CH—

The title compound was prepared in an analogous manner to that in Example 1 from 4'-amino-3'-cyano-5'-fluoro-2- {N- [4- (4-methoxyphenyl) butyl] methylamino] acetophenone and sodium borohydride in 80%. % methanol.

IC spectrum (meth-ylene chloride):

OH 3590 cm “i

_NH2 3400 + 3490 cm ¹

N-alkyl 2800 cmOCH3 2830 cm-1 aliphatic C1-4-group 2850 + 2930 cm- ¹

C = N 2210 cm -1

C = C 1635 cm UV spectrum (ethanol): Amax

241 nm (0.27)

280 nm (0.07)

322 nm (0.15)

Example 70

1- (4-acetamino-3-bromophenyl) -2- {N- [4- (4-methoxyphenyl) butyl] methylamino] ethanol

The title compound was prepared in an analogous manner to that in Example 1 from 4'-acetamino-3'-bromo-2- {N- [4- (4-methoxyphenyl) butyl] methylamino] acetophenone and sodium borohydride in 80% methanol. .

IC soektrum (methylene chloride):

OH 3590 cm @ -1

NH 3410 cm @ -1

N-alkyl 2800 cmOCI-II 2830 cm-1 aliphatic CH ₂ -group 2850 + 2930 cm -1 aromatic C = C-group 1610 cn ¹

C = O 1700 cm -1 amide II 1510 cm EXAMPLE 7 d

Racemates A and B of 1- (4-amino-3,5-dichlorophenyl) -2- {N- [3- (4-hydroxyphenyl) -1-] trans (4-methylpropyl) methylamino] ethanol g of a mixture of the same parts of 1- (4-amino-3,5-dichlorophenyl) -2- {N- [3- (4-hydroxyphenyl) -1-methylpropyl] -methylamino] ethanol are dissolved in parts of the di-tert-imide racemates A and B in ether and the solution. add 0.5 equivalents of 3N ethereal hydrogen chloride. the obtained crude crystalline hydrochloride of the racemate, and překrystaliije first from isopropanol and then recrystallized twice by dissolving in a large volume of methanol followed by ^evaporation, up to incipient crystallization.

The hydrochloride melts at 248-249 ° C with decomposition.

13 C NMR spectrum of the base (deuterochloroform / / deuteromethanol):

CH3

I —CH2 — CH2 — CH— \

CH — CH3 /

\

N — CH3 /

\

N — CH2— /

OH —CH—

37.50 ppm

58.36 ppm

13.91 ppm

36.33 ppm

61.03 ppm

68.89 ppm

35.61 ppm

59.21 ppm. 14.56 ppm

35.03 ppm

63.11 ppm

The isopropanol mother liquor is evaporated and the residue is partitioned between ether and 2N ammonia, the organic phase is dried, evaporated and the residue is subjected to high pressure liquid chromatography on silica gel (0.015 to 0.025 millimeters, ether-methanol 10) to isolate racemates B from racemate A: 1). The crystalline residue after evaporation of the eluate is recrystallized by dissolving in a large amount of ether and concentrating the solution by boiling. The product melts at 128-131 ° C.

13 C NMR (deuterochloroform / perdeuteromethanol):

CH3 ί —CH2 —CH2 —CH—

CHs

I —CH2 .....- CI-I2 - - ch \

CH — CPIa / \

N — CH3 /

\

N — CH2— / ‘”

OH

I —CH—

69.08 ppm

Example 72

1- (4-Amino-3-bromo-5-cyanophenyl) -2- [N - [4- (4-imino-4-yl) -butyl] benzylamino] -ethanol hydrochloride

The title compound was prepared in analogy to Example 1 from 4'-amino-3'-bromo-5'-cyano-2-N - [4- (4-methoxyphenyl) butyl] benzylamino] acetophenone and sodium borohydride in 90% - of methanol.

The hydrochloride melts at 122-126 ° C.

Example 7 3

1- (4-amino-3-bi'omR-cyanophenyl) -2-N- [4- (4-methoxyphenyl) butyl] allylamine;

The title compound -se prepared analogously to Example 1 from 4 ^{l-amino-3'-5'-biwn} k7an-2FN- [4- (4-methoxyphenyl) butyl] allylamino} acetophenone precursor and sodium borohydride in 90 % methanol. The product is a resin.

IC spectrum (methylene chloride):

NH2 3390 + 3490 cm ^-1

OCH3 2830 + 2940 cm ^-1

CN 2210 cm ^-1 aromatic C-C group 1610 cm ^-1

UV spectrum (ethanol) • Amax. 223 nm (0.43)

244 nm (arm, broad signal; 0.07)

330 nm (wide band, 0.05)

Example 74 1- (4-Amino-3-bromo-5-cyanophenyl) -2- [N- [4- (4-methoxyphenyl) butyl] isopropylamino] ethanol

The title compound was prepared in an analogous manner to that in Example 1 from 4'-amino-3'-bromo-5'-cyano-2-] N- [4- (4-methoxyphenyl) butyl] isopropylamino aminoacetophenone and sodium borohydride in 90% of methanol.

The hydrochloride melts with sintering from 40 ° C.

Analysis:

calculated

C, 55.6; H, 6.29; Br, 16.2; Cl, 2.14; N, 8.46;

found *

H, 6.37; Br, 15.4; Cl, 6.84; N, 8.83.

Example 75

1- (4-Amino-3-bromo-5-cyanophenyl) -2- {N- [4- (4-methoxyphenyl) butyl] -n-propylamino] ethanol hydrochloride

The title compound was prepared in an analogous manner to Example 1 from

4'-Amino-3'-br (om-5'-cyano-2-N- [4- (4-methoxyphenyl) butyl] -N-propylamino) acetophenone and sodium borohydride in 90% methanol.

The hydrochloride melts with sintering from 40 ° C.

Analysis:

calculated:

C 55.60, M 6.29, N 8.46; found:

H, 6.32; H, 8.39; N, 8.39.

Example 76

1- (4-Amino-3-bromo-5-cyanophenyl) -2- {N- [4- (4-methoxyphenyl) butyl] ethylamino] ethanol ethanol hydrochloride

The title compound was prepared in analogy to Example 1 from 4'-amino-3'-bromo-5'-cyano-2- [N- (4- (4-methoxyphenyl) butyl] ethylamino) acetophenone and sodium borohydride 90% methanol.

The hydrochloride melts at 139-142 ° C.

Example 77

1- (4-Amino-3-omo-5-trifluoromethylphenyl) -2-N- [3- (4-methoxyphenyl) propyl] methylamino] ethanol

The title compound was prepared in an analogous manner to that in Example 1 from 4'-amino-3'-bromo-5'-trifluoromethyl-N- [3- (4-methoxyphenyl) propyl] methylamino] acetophenone and sodium hydride in 90% of methanol. The product results in the form of an oil.

IC spectrum (methylene chloride):

NH2 3400 + 3490 cm ¹

OCH3 28) 40 + 2940 cm -1 aromatic C = C-group 1610 cmUV spectrum (ethanol): Amax

223 nm (0.26)

244 nm (0.1)

310 nm (very broad band, 0.04) Example 78

1- (4-Amino-3-bromo-5-cyanophenyl) -2- [N- (4-phenylbutyl) methylamino] ethanol hydrochloride

The title compound was prepared in an analogous manner to that in Example 1 from 4'-amino-3'-bromo-5'-cyano-12 [N- (4-phenylbutylmethylamino) acetophenone and sodium borohydride in 90% methanol.

The hydrochloride melts at 153-155 ° C.

Example 79

1- (4-amino-3-cyano-5-fluorophenyl) -2-N- [2- (4-methoxyphenyl) ethyl] methylamino] ethanrilohydride

2 9

The title compound was prepared in an analogous manner to that in Example 1 from 4'-amino-3'-cyano-5'-fluoro-2- [N- [2- (4-methoxycarbonyl) ethyl] methylamino] acetophenone and sodium borohydride in 90% methanol. .

The hydrochloride melts with sintering from 68 ° C.

Analysis:

calculated:

H, 6.12; H, 9.35; N, 11.05; found *

H, 6.07; H, 9.40; N, 10.69.

Example 80

1- (4-amino-3,5-dichlorophenyl) -2- (N- (3-phenylsulphenylpropyl) methylamino) ethanol

The title compound was prepared in an analogous manner to Example 2 from 4'-amino-2-bromo-3 ', 5'-dichloroacetophenone, N- [3- (4-methoxyphenylsulfenyl) propyl] methylamine and sodium borohydride in 80% methanol. The product results in the form of an oil.

IR (methylene chloride):

NH 2 3390 + 3490 cm ^-1

OH 3600 + 3680 cm ^-1

UV spectrum (ethanol): λ _max

246 nm (0.18)

300 nm (0.05)

Example 81

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

The title compound was prepared in an analogous manner to that in Example 3 from 4'-amino-3 ‘, 5 dichlor-dichloro-2- [N- [3- (4-hydroxyphenyl) propyl] amino [acetophenone and sodium borohydride in aqueous tetrahydrofuran. The product results in the form of an oil.

1C spectrum (KBr technology):

OH, NH2 3300 + 3600 cm ¹ aromatic C = C-group 1615 cm * ¹

UV spectrum (ethanol + potassium hydroxide): A _max

244 nm (0.26)

299 nm (0.08)

Example 82

1- (4-amino-3,5-dichlorophenyl) -2- {N- [3- (4-chlorophenyl) propyl] amino] ethanol

The title compound was prepared in a manner analogous to Example 3 starting from

4‘-amino-3 ‘, 5‘-dichloro-2- [N- (3- (4-chlorophenyl) propyl) amino] acetophenone and sodium borohydride in aqueous tetrahydrofuran.

The product melts at 103-106 ° C.

4

Example 83

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

The title compound was prepared in a manner analogous to Example 3, starting from 4‘-amino-3‘, 5‘-dichloro-2- {N- [3- (4-hydroxyphenyl) -1-methylpropyl] isopropylamino} acetophenone and sodium borohydride. The product results in the form of an oil.

Analysis:

calculated:

C 61.31, H 6.86, Cl 17.24, N 6.81; found:

% C, 61.67;% H, 6.86;% Cl, 16.67.

Example 84

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

The title compound was prepared in a manner analogous to Example 3, starting from 4‘-amino-3‘, 5‘-dichloro-2- {N- [3- (4-hydroxyphenyl) -1-methylpropyl] ethylamino] acetophenone and sodium borohydride. The product results in the form of an oil.

Analysis:

calculated:

H, 6.60; H, 17.85; N, 7.05; found:

% C, 60.45;% H, 6.76;% C, 17.70;

Example 85 1- (4-Methylamino-3,5-dichlorophenyl) -2- {N- [3- [4-hydroxyphenyl] -1-methylpropyl] methylamino] ethanol

The title compound was prepared in an analogous manner to that in Example 3 from 4'-methylamino-3 ', 5'-dichloro-2- (N- [3- (4-hydroxyphenyl) -1-methylpropyl] methylamino) acetophenone and sodium borohydride. The product results in the form of an oil.

Analysis:

calculated:

H, 6.60; H, 17.85; N, 7.05; found ·:

% C, 60.68;% H, 6.73;% C, 17.50;

Example 86

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

The title compound was prepared in an analogous manner to that in Example 3 from 4‘-dimethylamino-3‘, 5‘-dichloro-2- {N- [3- (4-hydroxyphenyl) -1-methylpropyl] methylamino] acetophenone and sodium borohydride. The product results in the form of an oil.

Analysis:

calculated:

% C, 61.31;% H, 6.36;% Cl, 17.24; found:

% C, 61.28;% H, 6.57;% C, 16.80;

Example 87 1- (4-Acetylamino-3,5-dichlorophenyl) -2- [N- [3-

(4-Hydroxyphenyl) -1-methylpropyl] methylamino] ethanol

The title compound was prepared in an analogous manner to that in Example 3 from 4-acetylamino-3 ‘, 5 dichlor-dichloro-2-N - [3- (4-hydroxyphenyl) -1-methylpropylmethylamino] acetophenone and sodium borohydride. The product results in the form of a masterlike substance.

IR (methylene chloride):

OH 3580 cm

NH 3410 cm

N-alkyl 2800 cm

0 = 0 1700 cm

C = C 1610, 1595 cm @ ¹ amide II 1515 cm @ -1

UV spectrum (ethanol) Amax

230 nm (0.3, arm)

280 nm (0.04)

UV spectrum (ethanol 4-potassium hydroxide) · Amax

243 nm (0.46)

294 nm (0.08)

Example 88

1- (4-ethoxycarbonylamino-3,5-dichlorophenyl) -2- {N- [3- (4-hydroxyphenyl) -1-methylpropyl] methylamino] ethanol

The title compound was prepared in an analogous manner to that in Example 3 from 4‘-ethoxycarbonylamino-3‘, 5‘-dichloro-2- [N-

- [3- (4-hydroxyphenyl) -1-methylpropyl] methylamino] acetophenone and sodium borohydride. The product results in the form of an oil.

Analysis:

calculated:

H, 6.20; H, 15.57; N, 6.15; found:

H, 6.32; H, 15.32; Cl, 6.03.

Example 89

1- (4-Amino-3-cyano-5-fluorophenyl) -2- {N- [1-methyl-3- (4-hydroxyphenyl) propyl] methylamino] ethanol ethanol racemate

The title compound was prepared in an analogous manner to that in Example 3 from 4'-amino-3'-cyano-5'-fluoro-2- (N- [1-methyl-3- [4-hydroxyphenyl) propyl] methylamino] acetophenone and sodium borohydride. The mixture of diastereomeric racemates obtained was separated by silica gel column chromatography using a mixture of methylene chloride, methanol and concentrated ammonia (50: 1: 0.1) as eluent.

Racemate A

M.p. 101-163 ° C.

¹⁵ C-NMR spectrum (perdeuterodimethylsulfoxicil:

CH ₃ .

CH ₂ - CHO · Cil - 37.17 ppm CH ₃ —CH ₂ —CH ₂ —CH— 57.91 ppm \ CH —- CH _S / 13.26 ppm \ N — CH ₄ / 35.74 ppm \ _N-CH2 - / nu 60.90 ppm 1 л 1 1 - • CH - 69.21 ppm

Racemate В

Melting point 92-98 ° C.

¹³ C-NMR spectrum (perdeuterodimethylsulfoxide):

СНз

CH ₂ —CH ₂ —CH— 36.52 ppm

CH ₃ —CH ₂ —CH ₂ —-CH - 57.78 ppm \

CH — СНз 13.19 ppm /

\

N — СНч.

/ \

n — ch ₂ - /

OH —CH—

35,74 ρριη

61.48 ppm

69.02 ppm

Example 90

1- (4-Amino-3-cyano-5-fluorophenyl) -2- (N- [1-methyl-3- (4-methoxyphenyl) propyl laminoethanol)

The title compound was prepared in an analogous manner to Example 3 from 4'-amino-3'-cyano-5'-fluoro-2- (N- [1-methyl-3- (4-methoxyphenyl) propyl]) aminojacetophenone and sodium borohydride.

The product melts at 108-110 ° C.

Example 91

1- (4-Amino-3-cyano-5-fluorophenyl) -2- (N- [1-methyl-3- (4-hydroxyphenyl) propyl] aminojethanol

The title compound was prepared in analogy to Example 3 from 4'-amino-3'-cyano-5'-fluoro-2- (N- [1-methyl-3- (4-hydroxyphenyl) propyl) ] aminojacetophenone and sodium borohydride.

The product melts at 162-164 ° C.

Example 92

N- [3- (4-Amino-3-bromophenyl) propyl] -N- [2- (3,4-dimethoxyphenyl) ethyl] methylamine hydrochloride

The title compound was prepared in an analogous manner to Example 4 from N-methyl-N- [2- (3,4-dimethoxyphenyl) ethyl] -3- (4-amino-3,5-dibromophenyl) ) propionamide and lithium aluminum hydride in absolute tetrahydrofuran.

The hydrochloride melts at 70-120 ° C for sintering.

IC spectrum (KBr - echnika):

NH + 2500-250 cm ^-1 alkyl 2800-3000 cm ^-1

UV spectrum (ethanol): Amax

234 nm (0.17)

280 nm (0.04)

300 nm (arm, 0.03)

Example 93

N- [2- (4-amino-3-chloro-phenyl) -ethyl] -N- (1-methyl-3-phenyl-phenyl) -isopropylamime

The title compound was prepared in an analogous manner to that in Example 4 from amine-3,5-dichloro-N-isopropyl-N- (1-methyl-3-femylpropyl) phenylacetamide and lithium aluminum hydride in tetrahydrofuran. The product results in the form of an oil.

IC spectrum (methylene chloride):

NH ₂ 3390 + 3490 cm -1

UV spectrum (ethanol): Amax

241 nm (0.15)

300 nm (0.03)

Example 94

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

- (1-methyl-3-fernylpropyl) isopropylamine

The title compound was prepared in an analogous manner to that in Example 4 from α-amine-N -dichloro-N-isopropyl-N- (1-methyl-3-phenylpropyl) phellylacetamide and lithium aluminum hydride in tetrahydrofuran. The product results in the form of an oil.

IC · spectrum (methylene chloride):

NH ₂ 3390 + 3490 cm ^-1

UV spectrum (ethanol): Amax

245 nm (0.15)

302 nm (0.04)

Example 95

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

The title compound was prepared in an analogous manner to that in Example 4 from α-amino-5-5-dichloro-N- [3- (4-fluorophenyl) propyl] phenylacetamide and lithium aluminum hydride in tetrahydrofuran.

The hydrochloride melts at 205-206 ° C.

Example 96

N- (2- (4-ammonio-3,5-dichlorophenyl) ethyl) -N-

- (1-methyl-3-phenylpropyl) methylamine

The title compound was prepared in an analogous manner to Example 4 from α-amino-5-5-dihydro-N- (1'-methyl-3-femylpropyl) phenylacetamide and lithium aluminum hydride in tetrahydrofuran. The product results in the form of an oil.

IC spectrum (methylene chloride):

NH ₂ 3390 + 3490 cm -1

UV spectrum (ethanol): Amax

243 nm (0.15)

300 nm (0.05)

Example 97

N- [2- (4-Amino-3,5-dichlorophenyl) ethyl] -N229924

- [3- (4-methoxyphenylsulfenyl) propyl] methylamine

The title compound was prepared in an analogous manner to that in Example 4 from 4-amino-3,5-difluoro-N- [3- (4-methoxyphenylsulfenyl) propyl] -N-methyl-1-phenylacetamide and lithium aluminum hydride in tetrahydrofuran. The product results in the form of an oil.

IR spectrum [methylene chloride]:

_NH2 3390 + 3490 cm ¹

UV spectrum [ethanol] Amax

245 nm (0.16)

300 nm (0.04)

Example 98

N- [2- (4-Amino-3-bromophenyl) ethyl] -N- [4-

- (4-methoxyphenyl) butyl] methylamine

The title compound was prepared in an analogous manner to Example 5 from 4-amino-3-bromo-N- [2- (4-methoxyphenyl) butyl] -N-methylphenylacetamide and lithium aluminum hydride in absolute tetrahydrofuran.

IC spectrum (methylene chloride):

NH ₂ 3380 4- 3470 cm ¹

OCH ₃ 2830 ⁴ 2930 cm -i- aromatic C = C-group 1620 cm ~ ^j

NMR spectrum (deuterochloroform, deuterium oxide):

aromatic protons 6.4-7.3 ppm (multiplet, 7H)

OCH 3 3.7 ppm (singlet, 3H)

NCH ₃ 2.2 ppm (singlet, 3H) aliphatic protons 1.3-2.8 ppm (multiplet, 8H)

Example 99

N- [2- (4-amino-3-bromophenyl) ethyl] -N- [2- (4-methoxyphenyl) ethyl] methylamine

The title compound was prepared in an analogous manner to that in Example 5 from 4-amino-3-bromo-N- [2- (4-methoxyphenyl) ethyl] -N-methylphenylacetamide and lithium aluminum hydride in absolute tetrahydrofuran.

IR (methylene chloride):

NH ₂ 3380 4- 3480 cm ^-1

OCH 3 2840 4- 2940 cm ^-1 aromatic C = C-group 1620 cm ^-1

UV spectrum (ethanol): λ _max

224 nm (0.24)

242 nm (0.15)

280 nm (wide band, 0.03)

300 nm (wide band, 0.03)

Example 100

N- [2- (4-Amino-3-fluorophenyl) ethyl] -N- [3-

- (4-methoxyphenyl) propyl] methylamine

The title compound was prepared according to the procedure in Example 5, starting from 4-amino-3-fluoro-N- [3- (4-methoxyphenyl) propyl] -N-methylphenylacetamide and lithium aluminum hydride in absolute tetrahydrofuran.

IC spectrum (methylene chloride):

NH ₂ 3390 4- 3460 cm ¹

OCH ₃ 2840 4- 2940 cm ^-1 aromatic C = C-group 1610 cm ^-1

UV spectrum (ethanol): λ _max

227 nm (0.3)

279 nm (0.06)

285 nm (0.06)

Example 101

N- [2- (4-Amino-3-chlorophenyl) ethyl] -N- [3-

- (4-methoxyphenyl] propyl] methylamine

The title compound was prepared in an analogous manner to that in Example 5 from 4-amino-3-chloro-N-methyl-N- [3- (4-methoxyphenyl) propyl] phenylacetamide and lithium aluminum hydride in absolute tetrahydrofuran. .

IC spectrum (methylene chloride):

NH ₂ 3390 4 3470 ^cm-1

OCH ₃ 2840 4- 2940 cm ^-1 aromatic C = C-group 1610 cm ^-1

UV spectrum (ethanol): λ _max

224 nm (0.25)

240 nm (0.18)

280 nm (0.04)

300 nm (0.03)

Example 102

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

- [3- (4-methoxyphenyl) propyl amine hydrochloride

The title compound was prepared in an analogous manner to Example 5 from 3- (4-amino-3,5-dichlorophenyl) -N- [3- (4-methoxyphenyl) propyl] propionamide and lithium aluminum hydride in absolute tetrahydrofuran.

The hydrochloride melts at 138-142 ° C.

Example 103

N- [3- [4-amino-3,5-dichloro-phenyl] -propyl] -N-

[2- (4-methoxyphenylethyl) methylamine dihydrochloride

The title compound was prepared in an analogous manner to Example 5 from

3- (4-Amino-3,5-dichlorophenyl) -N-methyl-N-

- [2- (4-methoxyphenyl) ethyl] propionamide and lithium aluminum hydride in absolute tetrahydrofuran.

The dihydrochloride melts at 147-157 ° C.

Example 104

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

- [4- (4-methoxyphenyl) butyl] amine hydrochloride

The title compound was prepared in an analogous manner to that in Example 5 from N- [2- (4-amino-3,5-dichloro-phenyl) -ethyl] -amide

4- (4-methoxyphenylbutyric acid) and lithium aluminum hydride in absolute tetrahydrofuran.

The hydrochloride melts at 186-189 ° C.

For example: ^ í ^ 5

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

- [3- (4-chlorophenyl) propyl] amine hydrochloride

The title compound was prepared in an analogous manner to Example 5 from α-amino-3,3, d-dichloro-N- [3- (4-chlorophenyl) propyl] phenylacetamide and lithium aluminum hydride in absolute tetrahydrofuran.

The hydrochloride melts at 186-190 ° C.

Example 106

N- [2- (4-Amino-3,5-dichlorophenyl) ethyl] -N- (4- (4-methoxyphenyl) butyl) isopropylamine

The title compound was prepared in an anologic manner as in Example 5 from N- [2- [4-amino-3,5-dichloro-phenylethyl] -N-isopropylamide of 4- (4-methoxyphenyl) butyric acid and lithium aluminum hydride in absolute tetrahydrofuran. The product results in the form of an oil.

IR (methylene chloride):

NH2 3390 + 3490 cm ¹

OCH3 2850 + 2930 cm ” ¹ aromatic C = C-group 1610 cm” ¹

UV spectrum (ethanol): Amax

242 nm [0.12]

280 nm [arm, 0.04]

301 nm [0.04]

Example 107

N- [2- [1-Amino-5-dichlorophenyl] ethyl] -N-

- [2- [4-methoxyphenyl] ethyl] isopropylamine

The title compound was prepared in an analogous manner to Example 5 from

N- [2- (4-Amino-3,5-chlorophenyl) ethyl] -N-C5-propyl-4-methoxyphenylacetamide and lithium aluminum hydride in absolute tetrahydrofuran, the product is obtained as an oil.

IR (methylene chloride):

NH ₂ 3390 + 3490 cm ^-1

OCH3 2830 + 2960 cm "aromatic C = C-group 1610 ^cm-1

UV spectrum [ethanol]: Amax

244 nm (arm, 0.12)

280 nm (arm, 0.05)

301 nm (0.05)

Example 108

N- [2- (4-Amino-3,5-dichlorophenyl) ethyl] -N- (2- (4-methoxyphenyl) ethyl) amine hydrochloride

The title compound was prepared in an analogous manner to Example 5 from 4-amino-3,3-dihydro-N- [2- (4-methoxyphenyl) ethyl] phenylacetamide and lithium aluminum hydride in absolute tetrahydrofuran.

The hydrochloride melts at 206-208 ° C.

10 9

N- [3- (4-Amino-3,3-dibromophenyl) propyl] -N- (2- (3,4-dimethoxyphenyl) ethyl) methylamine

The title compound was prepared in an analogous manner to that in Example 5 from N-methyl-N- [2- (3,4-dimethoxyphenyl) ethyl] -3- [4-amino-3,5-dibromophenyl] propionamide and 1CthCumalumCniumhydrochloride in absolute tetrahydrofuran. .

The product results in the form of an oil.

IR (methylene chloride):

NH-2 3480 + 3380 cm &lt; -1 &gt;.

OCH3 2840 + 2940 cm ”

NMR Spectrum [deutelΌchlhrhfolΊn / deuterium oxide]:

O — CH3 4.85 ppm [singlet, 6H]

N — CH3 2.25 ppm [singlet, 3H] aromatic protons 6.75 ppm [doublet, 3H)

7.2 ppm (singlet, 2H) aliphatic protons 1.5-2.9 ppm (multiplet, 12H)

Example 110

N- [2- (4-Amino-3,5-dichlorophenyl) ethyl] -3-phenylpropylamine hydrochloride

The title compound was prepared in an analogous manner to that in Example 5 from 4-amino-3,5-dichloro-N- (3-phenylpropyl) phenylacetamide and lithium aluminum hydride in tetrahydrofuran.

The hydride melts at 197-199 ° C.

Example 111

N- [2- (4-amino-3,5-dichlorophenyl) ethyl] -N229924

- [1,1-dimethyl-3- (4-hydroxyphenyl) propyl] methylamine

To a solution of 3 g [0.0075 mol] of 1- (4-amino-3,5-dlchlorophenyl) -2- {N- [1,1-dimethyl-3- (4-hydroxyphenyl) propyl] methylamino] ethanol in 12 ml of trifluoroacetic acid are added dropwise while stirring at -10 DEG C., 1.8 ml (0.018 mol) of pyridine-borane complex. After removal of the cooling bath, the reaction solution was warmed to room temperature over 30 minutes and then heated on a steam bath for 60 minutes with stirring. After evaporation of the trifluoroacetic acid on a rotary evaporator at 50 ° C under vacuum, 40 ml of 2N sodium hydroxide solution are added to the residue, the mixture is heated to 120 ° C with stirring for 30 minutes, then cooled, carefully acidified with concentrated hydrochloric acid until basic. Concentrated ammonia was added to the reaction and the resulting mixture was extracted twice with 75 ml of ether each time. The ether extracts were washed twice with 75 ml of ether each time. The ether extracts were washed with water (2 x 50 ml), combined, dried (MgSO4) and evaporated to dryness in vacuo on a rotary evaporator.

The residue was purified by silica gel column chromatography (70-230 mesh) using methylene chloride / methanol (2: 1 ^) as the eluent and then purified by chromatography on a neutral alumina column (activity III) using a mixture of ether and n. hexane (2: 1) as eluent, and the oily residue crystallized after a short time.

The product melts at 122-124 ° C.

Example 112

1- (3-chloro-4-piperidophenyl) -2- {N- [3- (4-methoxyphenyl) propyl] methylamino] ethanol ethanol hydrochloride

The title compound was prepared in an analogous manner to that in Example 1 from 3‘-chloro-4ino-piperidino-2- {N- [3- (4-methoxyphenyl) propyl] methylamino] acetophenone on sodium borohydride in aqueous methanol to give the product as an oily hydrochloride.

IC spectrum (methylene chloride):

OH 3600 cm -1

OCH3 2840 cm ¹

NH + 2300-2700 ^cm-1

UV spectrum (ethanol): Amax

258 nm (0.12)

283 nm (arm, 0.05)

Example 113

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

- [3- [4-hydroxyphenyl) -1-methylpropyl] ethyl amine

The title compound was prepared from 4'-amino-2-bromo-3 ^<, 5'-dichloroacetophenone, N- [3- (4-hydroxyphenyl) -1-methylpropyl] ethylamine and sodium carbonate in aqueous tetrahydrofuran, followed by reaction of The reaction product was purified by neutral alumina column activity III, eluting with ether: petroleum ether (2: 1).

The product results in the form of an oil.

IC spectrum (methylene chloride):

OH 3590 cm ¹

NH 2 3480 + 3390 cm ^-1

CH 2, CH 3 2960 + 2930 + 2860 cm ¹

N-alkyl 2310 cm ¹

C = C 1585 + 1510 + 1485 cm ^-1

UV spectrum (ethanol): Amax

241 nm (arm, 0.28)

280—302 nm (0.08)

UV spectrum (ethanol + potassium hydroxide): Amax

241 nm (0.56)

298 nm (0.17)

Example 114

1- (4-Amino-3,5-dichlorophenyl) -2- {N- [1,1-dimethyl-3- (4-hydroxyphenyl) propyl] methylamino] ethanol

The title compound is prepared from 4'-amino-2-bromo-3 ', 5'-dichloroacetophenone, N- [1,1-dimethyl-3- (4-hydroxyphenyl) propyl] methylamine and sodium carbonate, followed by reduction with sodium borohydride in aqueous tetrahydrofuran in analogy to Example 3. Pre-purification and final purification is carried out by chromatography on silica gel (70 to 230 mesh) using a mixture of ether and tetrahydrofuran (3: 1) as well as methylene chloride, methanol and concentrated ammonia (30: 1): 0.3) as eluent (Cmdel).

The product melts at 155-158 ° C.

Example 115 1- (4-Amino-3,5-dichloro-phenyl) -2- [N- [1,1-dimethyl-3- (4-hydroxy-phenyl) -propyl] -aminoethanol

The title compound was prepared from 4'-amino-2-bromo-3 ', 5'-dichloroacetophenone, 1,1-diethyl-3- (4-hydroxyphenyl) propylamine and sodium carbonate, followed by reduction with sodium borohydride in aqueous tetrahydrofuran in an analogous manner as in Example 3. Purification of the product is accomplished by chromatography on silica gel (70-230 mesh) using methylene chloride, metha229924.

124 DEG -128 DEG C. (phenoxyethyl) aninojethanotosylate;

1- (4-amino-3-cyano-5-fluorophenyl) -2- (N- [1-methyl-3- (4-methoxyphenyl) propyl] methylamino) ethanol in the form of an oil;

nol and concentrated ammonia (25: 1: 0.2) as eluent.

The product melts at 142-144 ° C.

The following compounds were prepared analogously to the previous examples:

1- (4-amino-3,5-dichlorophenyl) -2- {N- [3- (4-methoxyphenyl) -1-methylpropyl] methylaminoethanol as an oil;

IR (methylene chloride):

OH 3200—3500 cm1, wide belt (under NH ₂ )

NH 2 3480 -I- 3390 cm -1

_CH2 2930, 2850 cm

OCH) 2830 cm @ -1

N-alkyl 2800 cm

C = -C 1580, 1510, 1485 cm ^-1

C = C + NH ₂ deformation 1620 cm ^-1

UV spectrum (ethanol): _λwx

244 nm (0.27)

280 nm (0.08)

300 nm (0.08)

1- (4-Amino-3,5-dichloro-phenyl) -2- (N - [1,1-dimethyl-3- (4-methoxy-phenyl) -propyl] -methylamino-ethanol; as an oil;

Analysis:

calculated:

% C, 61.31;% H, 6.86;% N, 11.24; found:

% C, 61.13;% H, 6.99;% C, 17.25;% N, 6.75;

1- (4-amino-3-fluoro-5-cyanophenyl) -2- {N- [3- (4-methoxyphenyl) propyl] amino] ethanol, m.p. 119-121 ° C;

1- [4-amino-3,5-dichlorophenyl] -2- [N- (3-phenylpropyl) anine] ethanol hydrochloride melting at 180-181 ° C;

1- (4-amino-3-chloro-5-fluorophenyl) -2- [N- (1-methyl-2-phenoxyethyl) amino] ethanol dihydrochloride melting at 158-160 ° C;

1- (4-amino-3-bromo-5-fluorophenyl) -2- [N- (1-methyl-2-phenoxyethyl) amino] ethanol dihydrochloride, m.p. 156 DEG-158 DEG C .;

N- [2- (4-amino-3-bromo-5-cyanophenyl) ethyl] -N- [4- (4-methoxyphenyl) butyl] methylamine;

Analysis:

calculated:

% C, 60.6;% H, 6.3%; Br: 19.2%;

60.5% C, 6.1% H, 19.2% Br, 10.1% N;

1- (4-amino-3-fluorophenyl) -2- [N- (1-methyl-1-2C) spectrum (methylene chloride):

NH ₂ 3400 + 3500 cm -1

O - CH 3 2830 cm ^-1

N-alkyl 2800 cm

C = N 2210 cm -1

C = C 1580, 1510 cm

C- = C + NH ₂ deformation 1620 cm

UV spectrum (ethanol): A _innx

242 nm (0.27)

278 nm (0.05)

286 nm (0.05)

324 nm (0.12)

1- (4-amino-3,5-dichlorophenyl) -2- [N- (1-methyl-2-phenoxyethyl) amino] -ethanol hydrochloride as an amorphous substance;

IR (methylene chloride):

NH ₂ 3390 + 3490 cm

UV spectrum (ethanol): Amax

245 nm (0.15)

300 nm (0.04)

N- [3- (4- (Acetamino-3, 4 - [(1 R, 4 R)] -1 H -phenyl) propyl] -N- [2- (3,4-dimethoxyphenyl) ethyl] methylamine in the form of an oil;

IR (methylene chloride):

NH 3405 cm @ -1

OCH3 2330 + 2940 cm

CO 1700 cm ^-1

UV spectrum (ethanol): _λK , _x

228 nm (arm, 0.17)

280 nm (0.04)

1- ^(4-Am; no-3,5 - d.chlorf) -2- {N- [3- [4-hydroxyphenyl] -1-Roi hylpr PROPYL] allylamino) ethanol as an oil;

IR (methylene chloride):

OH 3580 cm @ -1

NH ₂ 3390 + 3480 cm ^-1 aliphatic CH ₂ -group 1850 + 2930 cm -1

CC 1615 cm @ -1

UV spectrum (ethanol): A _m ax

243 nm (0.26)

282 nm (0.08)

300 nm (0.08)

UV spectrum (ethanol + potassium hydroxide ^Ny nlax

242 nm (0.47)

298 nm (0.19)

N- [2- (4-amino-3,5-dichlorophenyl) ethyl] -N- [4- (4-methoxyphenyl) butyl] ethylamine as an oil;

IR (methylene chloride):

OCH ₃ 2860 + 2930 cm ^-1 aromatic C == C-group 1610 cm ^-1

UV spectrum (ethanol): _laxllax

245 nm (0.09)

278 nm (0.02)

282 nm (0.02)

300 nm (0.01)

N- [2- _(4-amino-3, 5-dichlorophenyl) ethyl] -N- [3- (4-chlorophenyl) propyl] isopropylamine as an oil;

IR (methylene chloride):

NH ₂ 3390 + 3480 ст ' ¹ aromatic C = C-group 1615 cm ^-1

UV spectrum (ethanol): A, _liax

241 nm (0.13)

300 nm (0.05)

N- [1-methyl-2- (4-amino-3,5-dichlorophenyl) ethyl] -N- [3- (4-methoxyphenyl) propyl] amine hydrochloride, m.p. 193-195 ° C;

1- (4-amino-3,5-dichlorophenyl) -2- [N- (1-methyl-3-phenylpropyl) methylamino] ethanol hydrochloride as an oil;

IR (methylene chloride):

NH-2,390 + 3490 cm ^-1

NH ⁺ 2300 ^- 2400 cm ^-1

OH 3580 cm ^-1

UV spectrum (ethanol): λ, _ax

245 nm (0.12)

302 nm (0.03)

1- (4-amino-3,5-dichlorophenyl) -2- [N- (1-methyl-3-phenylpropyl) methylamino] ethanol hydrochloride, m.p. 170-173 ° C;

1- (4-amino-3,5-dichlorophenyl) -2- [N- (1-methyl-3-phenylpropyl) propylamino] ethanol hydrochloride as an oil;

IR (methylene chloride):

_NH2 3390 + 3490 cm ¹

NH ⁺ 2300 ^- 2400 cm ^-1

OH 3590 + 3680 cm ^-1

UV spectrum (ethanol): λ _max

245 nm (0.12)

302 nm (0.03)

N- [2- (4-amino-3,5-dichlorophenyl) ethyl] -N- (3-phenylpropyl) -n-propylamine hydride chloride as an oil;

IR (methylene chloride):

_NH2 3390 + 3490 cm ¹

NH ⁺ 2300 ^- 2400 cm ^-1

OH 3600 + 3650 cm ¹

UV spectrum (ethanol): λ _max

245 nm (0.17)

302 nm (0.05)

1- (4-Amino-3-cyano-5-fluorophenyl) -2- {N- [2-

- (3,4-dimethoxyphenyl) ethyl] ethylamino-ethanol in the form of an oil;

IR (methylene chloride):

NH ₂ 3390 + 3490 cm ^-1

CN 2205 cm ^-1

UV spectrum (ethanol): A _niax

240 nm (arm, 0.16)

280 nm (0.04)

325 nm (0.06)

1- (4-Amino-3-chloro-5-fluorophenyl) -2- {N- [2-

- (3,4-methylenedioxyphenoxy) -1-methylethyl-ethylamino-ethanol-hydrochloride as an oil;

IR (methylene chloride):

NH ₂ 3390 + 3490 cm ^-1

NH ⁺ 2300 ^- 2450 cnr ¹

OH 3600 + 3680 cm ^-1

UV spectrum (ethanol): λ _max

243 nm (0.17)

287 nm (0.07)

1- (4-Amino-3-cyano-5-fluorophenyl) -2- [N- [3-

(4-Methoxyphenyl) propyl] ethylamino (ethanol hydrochloride as an oil;

IR (methylene chloride):

NH, 3390 + 3490 cm ^-1

NH ⁺ 2300 ^- 2500 cm ^-1

CN 2205 cm * ¹

OH 3590 + 3680 ^cm-1

UV spectrum (ethanol): λ _max

248 nm (0.11)

280 nm (0.03)

320 nm (0.06)

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

- [3- (4-fluorophenyl) propyl] -N-propylamine hydrochloride, m.p. 130-133 ° C;

N- [2- (4-amino-3,5-dichlorophenyl) ethyl] -N- (3- (4-fluorophenyl) propyl) ethylamine hydrochloride, m.p. 182 DEG-184 DEG C .;

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

- [3- (4-fluorophenyl) propyl] isopropylamine hydrochloride melting at 182-184 ° C;

1- (4-amino-3,5-dichlorophenyl) -2- [N- (1-methyl-3-phenylpropyl) ethylamino] ethanol as an oil;

IR (methylene chloride):

_NH2 3390 + 3490 cm ¹

UV spectrum (ethanol): A, _nax

245 nm (0.13)

300 nm (0.03) 1- (4-dimethylamino-3,5-dichlorophenyl) -2- [N- (3-phenyl-1-methylpropyl) methylamino] ethanol as an oil;

IR (methylene chloride):

OH 3600 + 3680 cm ^-1

N-alkyl 2800 cm ^-1

UV spectrum (ethanol): λ _max

275 nm (0.03)

1- (4-amino-3,5-dichlorophenyl) -2- {N- [3- (4-methylsulfinylphenyl) propyl] amino} ethanol, m.p. 127-129 ° C;

1- (4-amino-3,5-dichlorophenyl) -2- {N- [3- (4-methylsulfenylphenyl) propyl] amino] ethanol, m.p. 128-130 ° C;

1- (4-amino-3,5-dichlorophenyl) -2- (N- [3- (3-methoxyphenyl) propyl) amino] ethanol, m.p. 124 [deg.];

1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- [N- (3- (4-methoxyphenyl) propyl) amino] ethanol, m.p. 111-112 ° C;

N- [2- (4-amino-3,5-dichlorophenyl) ethyl] -N- (3-phenyl-1-methylpropyl) methylamine as an oily hydrochloride;

IR (methylene chloride):

NH ₂ 3390 + 3490 cm ^-1

CH ₂ 2930 cm ^-1

UV spectrum (ethanol): λ _max

243 nm (0.12)

300 nm (0.04)

N- [2- (4-amino-3,5-dichlorophenyl) ethyl] -N- (3-phenyl-1-methylpropyl) -N-propylamine as an oily hydrochloride;

IR (methylene chloride J):

_NH2 3390 + 3490 ^cm-1

CH ₂ 2930 cm ^-1

UV spectrum (ethanol): λ _inax

245 nm (0.11)

300 nm (0.04)

Claims (7)

1. A process for the preparation of the novel phenylalkylamines of the general formula I according to the invention A represents a methylene group, an ethylene group or a hydroxymethylene group and В represents the remainder of the formula in which R ₁ represents a hydroxyl group, an amino group optionally substituted by a C 1 -C 3 alkanoyl group or a C 2 -C 4 alkoxycarbonyl group, an alkylamino group or a dialkylamino group in which each alkyl moiety contains 1 to 3 carbon atoms each ₂ and R _:! Which may be the same or different, represents halogen, trifluoromethyl, cyano or nitro, wherein one of R ₂ or R ₂ may also represent hydrogen, R 1 represents a hydrogen atom or a C 1 -C 3 alkyl group, R 5 represents a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms, a cyclopropyl group, an alkenyl group having 2 to 5 carbon atoms or a benzyl group, or in which: R6 represents a hydrogen or halogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, optionally substituted by a phenyl group, an alkylsulfenyl or an alkylsulfinyl group containing in each case 1 to 3 carbon atoms, R ₇ is hydrogen, hydroxyl or C 1 -C 3 alkoxy; Rg and _R7 together form a methylenedioxy group, R 8 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, D represents an oxygen atom or a sulfonyl group, n is an integer of 1 or 2 and E represents a straight C 3 -C 5 alkylene group optionally substituted by one or two C 1 -C 3 alkyl groups or, when A is a methylene or ethylene group, and / or R 1 represents an amino group substituted by a C 1 -C 3 alkanoyl or C 2 -C 4 alkoxycarbonyl group, a hydroxyl group, an alkylamino group or a dialkylamino group in which each alkyl moiety each contains 1 to 3 carbon atoms and may in each case optionally be substituted by phenyl group, and / or R2 is trifluoromethyl, cyano or nitro, and / or R 3 represents a fluorine atom, and / or R 4 represents an alkyl group having 1 to 3 carbon atoms, and / or R 5 represents a C 1 -C 4 alkyl group, a cyclopropyl group, a C 2 -C 5 alkenyl group or a benzyl group and / or R6 represents a fluorine or chlorine atom, an alkylsulphenyl or alkylsulphinyl group containing from 1 to 3 carbon atoms, then E represents an ethylene group or, in the case where A represents a methylene group, E represents a group of the formula R 9 - CH - CH 2 - wherein R 9 represents a C 1 -C 3 alkyl group, their optically active antipodes, their diastereomeric racemates and their respective optical antipodes, as well as their acid addition salts, characterized in that a compound of the general formula is reduced II OH Ri I I -CH-CHO-acyl-CH-CO- -CH 2 -CO- Z Rl I I —CH — CH— or From R4 —CH — CH2 — CH— wherein R1 is as defined above, acyl means an organic acyl group, for example an acetyl, propionyl or benzoyl group, and Z is a reductively cleavable group such as iodine, bromine, methoxycarbonyloxy or ethoxycarbonyloxy, with the proviso that X is a radical of the formula defined above From R 1, CH is CH or From R4 —CHI — CH2 — CH - only when A represents a methylene or ethylene group, the compound of formula I obtained which contains one, two or three optically active antipodes, diastereomorphic racemates and / or the respective optical antipodes, and / or and optionally converting the compound of formula I obtained with an inorganic or organic acid into its physiologically tolerable acid addition salt. 2. The process according to item 1, for the preparation of novel phenylalkylamines of the general formula Ia R (UI) in which Rt to R; ₃ , R 5 and B are as defined above and X represents the remainder of the formula R1-CO-CH- by reducing a compound of formula (Iia) wherein: R _2, R b, R d and A are as defined in claim 1, R _it is a hydroxyl group or amino group optionally substituted by an alkanoyl group having 1-3 carbon atoms or an alkoxycarbonyl group containing 2 to 4 carbon atoms, R5a represents a hydrogen atom, a straight or carbon atom, a cyclopropyl group or a benzyl group, Ba represents a radical of the formula wherein (IIa) wherein R7, Rs, Dan have the meaning as in · point 1, R _R represents a hydrogen or halogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, optionally substituted phenyl, or • R ₆ and R 7 together form methylenedioxy, and E _a represents a straight C 3 -C 5 alkylene group, optionally substituted by a C 1 -C 3 alkyl group, or A represents a methylene or ethylene group and / or R _1a represents an amino group substituted by a C 1 -C 3 alkanoyl or C 2 -C 4 alkoxycarbonyl or hydroxyl group, and / or R2 is trifluoromethyl, cyano or nitro, and / or R 3 represents a fluorine atom, and / or R 4 represents an alkyl group having 1 to 3 carbon atoms, and / or R _15a represents a C 1 -C 4 alkyl group, a cyclopropyl group, a benzyl group, and / or R _6a represents a fluorine or chlorine atom, then Ea represents an ethylene group or, in the case where A represents a methylene group, Ea represents a group of the formula R 5 = CH-CH 2 -. wherein R 9 is a C 1 -C 3 alkyl group, their optically active antipodes, their diastereomeric racemates and their respective optical antipodes, as well as their acid addition salts, R 2 and R 3 are as defined in point 1, R 1a, R _5a and Ba are as defined above and _And X is a radical of formula R4 —CO — CH— O-acyl | —CH — CO— —CH2 — CO— From R4 —CH — CH— or Z Rl CH 2 CH 2 CH R 1, acyl and Z are as defined in 1, with the proviso that X _a is a radical of the formula defined above From R 1 = CH-CH- or From Ri II —CH — CH2 — CH— only when A represents a methylene or ethylene group, then the compound of formula (Ia) containing one, two or three optically active carbon atoms is resolved into optically active antipodes, diastereomeric racemates and / or the corresponding optical antipodes, and / or the compound of formula Ia obtained is optionally converted by treatment with an inorganic or organic acid into its physiologically tolerable acid addition salt. 3. The process according to claim 1, wherein the reaction is carried out in a solvent. 4. A process according to any one of claims 1 to 3, wherein the reduction is carried out by treatment with hydride, aluminum isopropoxide in the presence of a primary or secondary alcohol, catalytically activated hydrogen, or hydrogen at birth. 5. A process according to any one of claims 1 to 4, wherein the reaction is carried out at a temperature between -20 ° C and the boiling point of the reaction mixture, for example at a temperature between -20 ° C and 100 ° C. 6. A process according to any one of Claims 1 to 5 for the preparation of a compound of formula (I) wherein A is a hydroxymethylene group and the remaining symbols are as in 1 or 2, wherein the reduction is effected by treatment with a complex metal hydride, aluminum isopropoxide. , catalytically activated hydrogen, or hydrogen at birth. 7. A process according to any one of Claims 1 to 5 for the preparation of a compound of formula (I) wherein A is a methylene or ethylene group and the remaining symbols are as in 1 or 2, characterized in that the reduction is effected by treatment with a complex metal hydride. , such as sodium borohydride or lithium aluminum hydride, or by treatment with pyridine and borane.