DE2534339A1 - PROCESS FOR THE PRODUCTION OF NEW 1- (ARALCOXYPHENYL) -2- OR -3- (BIS-ARYLALKYLAMINO) -ALKANES - Google Patents

Description

CIBA-GEIGY AG, 4002 BASEL (SWITZERLAND)

Case 4-9540 / SU 614 / +

GERMANY

Process for the preparation of new 1- (aralkoxyphenyl) -2- or ~ 3- (bis-arylalkylamino) -alkanes.

The invention relates to the preparation of new 1- (aralkoxyphenyl) -2- or-3- (bis-arylalkylamino) alkanes of the general formula I.

CH ₀ ,, Ar ₀

in 2 + 1 2

Ar ₁ - CH ₀ - 0 - Ph - (ClL) ^ - CH - NH - CH ₀ - C - Ar _a (I), 1 m 2m 2 ^r ρ 2p ι 3 '

^R l

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wherein each of the symbols Ar ₁ , Ar ₉ and Ar "is an unsubstituted or by one or more lower alkyl, lower alkoxy, trifluoromethyl, nitro, amino, mono-lower alkylamino or di-lower alkylamino-j lower alkanoylamino, cyano, Carboxy, carbon-lower alkoxy, carbamoyl, aminomethyl, mono-lower alkylaminomethyl or di-lower alkylaminomethyl groups or one or more halogen atoms-substituted phenyl radicals, Ph stands for a phenylene radical which can optionally be substituted by one of the substituents mentioned for Ar, η denotes a number from 0 to 4 and each of the symbols m and ρ denotes a number from 1 to 4, r denotes the number 1 or 2, and R ₁ denotes hydrogen or hydroxy, and salts of these compounds.

The symbol Ar preferably denotes a substituted phenyl radical of up to five, primarily one or has two substituents. These are: lower alkyl, e.g. methyl, ethyl, n- or i-propyl or butyl; Lower alkoxy, e.g. methoxy, ethoxy, n- or i-propoxy or butoxy; Halogen, e.g., fluorine, chlorine or bromine; Trifluoromethyl; Nitro; Amino; Mono- or di-lower alkylamino, e.g. mono- or dimethylamines, mono- or diethylamino; Niederal-

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kanoylamino, for example acetylamino, propionylamino or pivaloylamino; Cyan; Carboxy; Carbo-lower alkoxy, for example carbomethoxy or carbethoxy; Carbamoyl; Aminomethyl; Mono- or di-lower alkylaminomethyl, for example mono- or dimethylaminomethyl. _{Each of the symbols Ar 1} and Ar preferably stands for unsubstituted phenyl or phenyl which has one of the substituents mentioned for the radical Ar 1.

The term "lower" is defined in the organic radicals or compounds mentioned above or below, those with at most 4, preferably 3, primarily with one or two carbon atoms.

The symbol Ph preferably stands for unsubstituted 1,4-phenylene, but also for 1,2- or 1,3-phenylene, or for those radicals which have a lower alkyl, lower alkoxy, halogen or trifluoromethyl substituent, for example one of the has substituents mentioned for the radical Ar _1. The symbol R preferably denotes hydrogen, but also hydroxyl.

The lower alkyl group CH "preferably denotes methyl, but also another lower alkyl group mentioned above. The lower alkylene group CH ₉ preferably represents (CH 2), in particular methylene

. ο to

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1,1- or 1,2-ethylene, 1,1-, 2,2-, 1,2- or 1,3-propylene or butylene. The group C HL is preferably (CH), in particular 1,2-ethylene, but also another of the above mentioned alkylene groups.

Salts of compounds of the general formula I are preferably therapeutically useful acid addition salts, e.g. those of the acids mentioned below.

The compounds of the invention show valuable pharmacological properties, primarily hypotensive, antihypertensive and heart rate lowering effects. These pharmacological properties can be tested on animals, preferably on mammals, such as rats, cats or monkeys, are detected as test objects. The animals can be normotensive or hypertensive, e.g. genetically or adrenal-regeneratively hypertensive rats. The new connections can them enterally or parenterally, preferably orally, or subcutaneously, intravenously, intraperitoneally or intraduodenally, e.g. by gelatin capsules or in the form of starch-containing suspensions or aqueous solutions will. The dose used can range from approximately between 0.1 and 100 mg / kg / day, preferably approximately 1 and 50 mg / kg / day, especially about 5 and 25 mg / kg / day.

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The antihypertensive effect is registered either directly with a catheter, which is inserted, for example, into the caudal artery of a rat or into the femoral artery of a dog, or indirectly by sphygmomanometry on the rat's tail and a transmission instrument. The blood pressure is determined in mm Hg before and after the administration of the active ingredient. For example, d, £ -1- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane, is a typical representative of compounds of the present invention, preferably in the form of its hydrochloride, or in particular, its levorotatory antipode, strongly effective in the above-mentioned hypertensive rats at a dose of 5 mg / kg / day or less, and no more than 24 hours after administration. Antihypertensive doses only slightly impair the sympathetic neural function in contrast to antihypertensive agents, which develop their effect through adrenergic neuron blockade. This can be determined by changes in pressure after electrical stimulation of the spinal nerve cord of rats whose spinal cord has been destroyed. The said compound also differs from certain centrally acting antihypertensive agents which induce sedation. Moreover, it calls

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said d, Λ, hydrochloride no release of cerebral catecholamine, as is the case with centrally acting agents; although it causes a secretion in peripheral tissues, such as the heart. Furthermore, no sedation can be found in monkeys at hypotensive doses, as evoked by oc-methyl-dopa. The compounds of the present invention can therefore be used as antihypertensive agents or as agents causing bradycardia, for example for the treatment of primary or secondary high blood pressure or angina pectoris. They can also be used as intermediate products for the production of other valuable, in particular pharmacologically active compounds or preparations.

Preferred compounds are those of the formula I in which each of the symbols Ar ₁ , Ar ₀ and Ar is phenyl, (lower alkyl) ■

1 line ό X

phenyl, (lower alkoxy) -phenyl, (halogen) -phenyl or "(tri-

X X

fluoromethyl) phenyl, Ph for 1,3- or 1,4-phenylene, (Lower alkyl) -1,3- or -1,4-phenylene, (lower alkoxy) -1,3- or "1,4-phenylene, (halogen) -1,3- or -1,4-phenylene or (trifluoromethyl) -1,3- or -1,4-phenylene, η is a number from 1 to 4 means each of the symbols m and ρ for one

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Number from 1 to 4, χ is a number from 1 to 5, r is the number 1 or 2, and L is hydrogen or Hydroxy, and their therapeutically useful acid addition salts.

Particularly noteworthy are compounds of the general formula II

(CH ₀ ) - O - ^v 2'm

H ₀ , η 2n + l

CH ₂ - CH

NH -

(CH ₂ ).

(II),

wherein each of the symbols R and R 'denotes hydrogen, methyl, methoxy, fluorine, chlorine, bromine or trifluoromethyl and each of the symbols m, η and ρ denotes the number 1 or 2, R ₁ denotes hydrogen or hydroxy, and their therapeutically useful Acid addition salts.

Preference is also given to the compounds of the general formula II in which R, m, η and ρ have the meanings given in the preceding paragraph, R is chlorine and R ¹

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stands for hydrogen, and their therapeutically useful Acid addition salts.

Particularly preferred are compounds of the general formula II in which R is chlorine, preferably in the meta or para position, R ₁ and R ^! stand for hydrogen, each of the symbols m and η means the number 1, and ρ stands for the number 2, and their therapeutically useful acid addition salts.

The compounds of the present invention can be prepared by methods known per se, preferably thereby be that one

1) Carbonyl compounds of the general formula III

(III) XCHY Ar ₉

Il | ^{n 2n + 1} Il

| Il I

^Ar l " ^C m ^H 2m- ° - ^Ph - ^C - <CH ₂ ) _r _ _r CH - Z - C - 0 _ρ _ _χ H ^ - C - Ar,

^R l in which one or both symbols X and Y denote oxygen or the other symbol _{denotes H 2} , and Z denotes a free or protected -NH group, reduced.

A slotted amino group Z is preferably one which can be released easily, for example by hydrolysis or hydrogenolysis Group, e.g. an amide or, preferably, benzyl group.

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Such are lower alkanoylamino, aralkanoylamino or a-aralky! Amino groups, e.g. C H "- - CON or Ar - C H"

CON. if Y = HL., or CH _0,. - CHAr ₁ - N if Y = O or H_. '2 η 2n + l 1

The reduction of ketones and / or amides of the formula III is carried out according to methods known per se. For example, the ketones are reduced by reaction with an arylsulfonyl hydrazide and then with sodium borohydride. Amides are preferably used with reducing agents, such as simple or complex light metal hydrides, e.g. boranes or aluminum hydrides, in particular alkali metal borohydrides or alkali metal aluminum hydrides, e.g. lithium aluminum hydride, sodium borohydride or lithium or sodium tri-lower alkoxy or bisalkoxy-alkoxy-aluminum hydrides, such as lithium tri-t-butoxy or sodium bis (2-methoxy-ethoxy) aluminum hydride, reduced.

The starting materials can be used in a manner known per se, preferably in accordance with those described in the examples Methods to be produced. For example, starting materials of the formula III can be prepared by reacting corresponding Phenolates, e.g. alkali metal, such as sodium or potassium salts of phenols of the formula

HO - Ph - CX - (CH ₂ ) ^ ₁ -CH (C _n H _{2n + 1} ) - Z-CY- C ^ H ^^ - CH (Ar "Ar) with reactive esters of alcohols of the formula

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- 16 -

Ar _n - CH ₀ - OH. This reactive 1 m 2 m ' ^ö

Esters are made from strong inorganic or organic acids, preferably hydrohalic acids, e.g. hydrochloric, Hydrobromic or hydroiodic acid or alkanesulphonic acids or benzenesulphonic acids, e.g. methane, p-toluene or derived from m-bromobenzene sulfonic acids. Raw materials of the formula III can also be obtained by reacting amines of the formula

Ar ₁ ■ C H. - 0 - Ph - CX - (CH ₀ ) -CH (CH ₀ ) - ZH 1 m 2m ^v 2 r-1 η 2n + l

with reactive functional derivatives of acids of the formula

HOOC - C _p _ _lH2p _ ₂ - CR ₁ (Ar ₂ AR ₃ ),

e.g. with their halides or anhydrides. The aforementioned phenols are either known or they can be obtained by condensation of in Belgian patent no. 660,217 compounds described, i.e. those of the general formula

HO - Ph - CO - CHNH ₀ - CH _{0 n} ,

Z Π ΔΧϊ + L

with the alcohol or acid derivatives mentioned above, in

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successive steps, and also according to the one here
further, under 3) mentioned conditions can be obtained.

Another process for the preparation of compounds of the formula I is that one

2) Olefins or Schiff bases of the general formula IV

CH ₀ Ar ₀ Ar_

in -2n + ls z _v / 3

^Ar l - ⁰ An-C ₁ - ° - ^Ph - ^(C Vr - ^{C (H} lu ^{) Z1} VW "*" ^R l

where one of the symbols q, s and ν is the number 2 and the
others are 0 or 2, u is zero, and Z is free or
is protected NH, or Z is nitrogen, u
stands for 1, ν stands for zero or 2 and the other indices
have the meanings given above, or Z is a nitrogen atom, u is zero. "., ν is the number 1 or 3 and the other indices have the meanings given above, reduced.

For compounds in which IL is hydrogen, this process consists in using olefins or Schiff's Bases of the general formula IVa

6Q9808 / 1093 '

? n ^H 2n + ls

Ar ₁ - CH, - O - Ph - (CH.) - C (H ₁ ) Z [C _in H _{o jn} ] _{/ TTr} ,

1 m 2m-q 2 ⁷ r 1-u 'p + 1 2p + lv \ (IVa)

^Ar 3

where one of the symbols q, s and ν is the number 2 and the others stand for 0 or 2, u is zero, and Z is free or is protected NH, or Z is a nitrogen atom, u is 1, ν is zero or 2 and the other indices have the meanings given above, or Z denotes a nitrogen atom, υ denotes zero, ν denotes the number 1 or 3 and the other indices have the meanings given above, reduced.

The starting materials of the formulas IV and IVa are reduced by methods known per se, for example with hydrogen in the presence of catalysts, for example platinum or nickel catalysts, or with nascent hydrogen, for example with electrolytically generated hydrogen, preferably in the case of the Schiff bases IV and IVa. These can also be reduced with the reducing agents mentioned above in process 1), preferably with simple light metal hydrides, for example boranes. Schiff bases, in which η denotes zero, u denotes 1, and ν denotes 1 (or 3), can also be used with CH ₉ _ - Grignard compounds

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fertilizers, e.g. lower alkyl magnesium halides. The adduct obtained is hydrolyzed with water or aqueous ammonium salts. Process products of the formula are obtained I, in which η is a number from 1 to 4 or the remainder

C H. represents a branched chain,
ρ 2p

The olefin starting materials of the formula IV and IVa can analogously to the carbonyl starting materials of the formula III abovementioned condensations, with corresponding unsaturated compounds, namely reactive esters of alcohols the general formula

Ar ₁ - CH ₀ - OH,
1 m 2 m-q '

or derivatives of acids of the formula
HOOC - [Cp ₁ H ₂ P ₂ ^] A

for the preparation of compounds of the formula IV or derivatives of acids of the formula
HOOC - [C _p H _2p1

for the preparation of starting materials of the formula IVa selects, and reduction of a carbonyl group in the amide compounds obtained with the reducing agents mentioned in process 1), preferably with complex light metal hydrides,

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e.g. lithium aluminum hydride. The ship Bases of the formula IV can be obtained from corresponding free or protected amines of the formula

HO-Ph- (CH ₂ ) _r - CHNH ₂ - Cy ^^

by condensation with aldehydes of the formula

^0CH - ^[C pl ^H 2p-2-v ^{] CR} 1 ^Ar 2 ^Ar 3

and then with a reactive ester of an alcohol the formula

Ar _n - CH ₀ - OH 1 m 2 m - q

can be obtained.

Schiff's bases of the formula IV can also, from corresponding free or slotted ketones of the formula

HO-Ph- (CH ₂ ) _r - CO - C _n

by condensation with amines of the formula

^H 2 ^{N [C} p ^{H 2p-v]} l ^{CR Ar} 2 ^Ar 3

and then with a reactive ester of an alcohol get the formula

Ar ₁ CH ₀ -OH 1 m 2m-q

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getting produced.

The ship's view bases of Formula IVa can be made from free or protected amines of the formula

HO-Ph- (CH ₂ ) _r - CHNH ₂ - C ^ _1. , By condensation with aldehydes of the formula

^0HC - [ ^C p ^H 2plv ^1Ar

and then with a reactive ester of an alcohol the formula

Ar ₁ - CH ₀ - OH 1 m 2 m-q

can be obtained. The ship's view bases of Formula IVa are also made from corresponding free or protected ketones of the formula

HO-Ph- (CH ₀ ) - CO - CH _{0 x1}

^v 2 r η 2n + ls

by condensation with amines of the formula H ₂ N - [Cp ₊₁ H ₂ P ₊₁ ^] Ar ₂ Ar ₃

and then with a reactive ester of an alcohol of the formula

Ar ₁ - CH "- OH 1 m Zm- q

manufactured.

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Another process for the preparation of compounds of general formula I is that one

3) Compounds of the general formulas V and VI

^Ar l - ^C m ^H 2m - ^{T And U} - ^C p ^H 2p "CR ₁ (Ar ₂₃ ) (V) (VI)

or their reactive salts, in which one of the symbols T and U for the group of the formula

(0 - Ph - (CH ₂ ) _r - CH (C _n H _{2n + 1} ) Z ") H,

where Z "signifies free or protected NH, and the other the symbols T and U represent a reactive esterified hydroxyl group denotes, or U denotes amino and T denotes the group mentioned, in which Z "denotes a reactive esterified one Hydroxy group, e.g. bromine, is condensed.

The reactive esters are made from strong inorganic or organic acids, preferably hydrohalic acids, e.g. hydrochloric, hydrobromic or hydroiodic acid or alkanesulphonic acids or benzenesulphonic acids, e.g. methane, p-toluene or m-bromobenzenesulfonic acids derived.

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The condensation of the starting materials V and VI is preferably carried out using reactive salts of phenols or amines, e.g. alkali metal salts such as sodium or potassium salts, or in the presence of condensing agents, the eliminated acids (TH, UH or Z ¹¹ H) being neutralized, and / or intercepts the water formed. Such agents are inorganic or organic (nitrogen) bases, for example alkali metal or alkaline earth metal carbonates or hydrogen carbonates, tri-lower alkylamines or pyridines, or anhydrous forms of salt hydrates or azeotropic solvents.

The starting materials of the formulas V and VI are similar like the starting materials described above, e.g. by condensation of compounds of the formula

HO-Ph- (CH ₀ ) - CH (CH ₀ ,,) Z " δ r η <cn-ri

with compounds of the formula Ar ₁ - CH _n - T or

1 m 2 m

U - CH ₉ - CH (Ar Ar), where T denotes a reactive esterified hydroxyl group, and one of the symbols U and Z "denotes T and the other denotes the primary amino group. The protection of the amino groups can be carried out in a manner known per se , for example similar to that described in French patents 2,013,686 and 2,013,689.

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Protected or metallized amino groups Z and Z "can either be used in the course of the above process 1) to 3) or subsequently, in a manner known per se, e.g. by hydrolysis of the amide groups, or by hydrogenolysis of α-aralkyl groups, either with water or preferably with aqueous acids or bases, in particular with aqueous mineral acids or alkali metal hydroxides, or a-aralkyl groups with catalytically activated hydrogen are released.

The compounds obtained according to the invention can be converted into one another in a manner known per se. For example, halogen compounds obtained can be either in the course of the hydrogenations described above or afterwards under more drastic conditions, e.g. with increased Temperature and / or pressure, dehalogenate. The course of these reactions can be determined by the amount of hydrogen consumed monitored and controlled.

The compounds of the invention can, depending on the reaction conditions, under which the process is carried out, can be obtained in free form or in the form of their salts. Salts obtained can in a manner known per se, for example with

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Ammonia, alkalis or ion exchangers in the free bases be transferred. Obtained free bases can be converted into their salts with acids, especially with those which are therapeutic usable acid addition salts are converted. Such acids are inorganic acids, e.g. mineral acids such as a hydrohalic acid, e.g. Hydrochloric or hydrobromic acid, or sulfuric, phosphoric, nitric or pex'chloric acid; or organic acids, such as aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, vinegar, propionic, amber, Glycol, milk, apple, wine, lemon, maleic, hydroxymalein Pyruvic, phenyl acetic, benzoin, aminobenzoic, anthranil, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, embon, nicotine, llethanesulfone, ethanesulfone, hydroxyethanesulfone, ethylene sulfone, Halobenzenesulfone, toluenesulfone, naphthalene sulfone, Sulfanil or cyclohexylsulfamic acid; Methionine, tryptophan, Lysine or arginine, or ascorbic acid. These or other salts, e.g. the picrates, can also be used in the torment of the free connections can be used.

As a result of the close relationships between the new compounds are in free form and in the form of their salts in the preceding and following under free compounds and salts, appropriately and appropriately, if necessary, also the to understand corresponding salts or free compounds.

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7 5 34339

Isomer mixtures obtained can be prepared by methods known per se, e.g. by fractional distillation, Crystallization and / or chromatography, can be separated into the individual isomers. Racemic products can be used in the • optical antipodes, e.g. when separating their diastereoisomeric salts, e.g. by fractional crystallization of the d- or ^ -Tartrate, to be separated.

The above reactions are carried out according to methods known per se, in the presence or absence of diluents, preferably in those which are inert to the reagents and dissolve them, catalysts, Condensation or neutralizing agents and / or in an inert atmosphere, with cooling, at room temperature or at elevated temperatures, preferably at the boiling point of the solvent used, at normal or elevated pressure carried out.

The invention also relates to modifications of the present method according to which one at any stage intermediate product obtained from the process is used as starting material and the remaining process steps are carried out

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or the proceedings are terminated at any stage becomes, or after which a starting material under the reaction conditions or in which a starting material in the form of a salt or optically pure antipode thereof is used will.

The pharmacologically acceptable compounds of the present invention can be used, for example, in the manufacture of pharmaceutical Preparations are used which contain an effective amount of the active ingredient together or in admixture with excipients which are suitable for enteral or parenteral administration. Tablets are preferably used or gelatin capsules, which contain the active ingredient together with diluents, e.g. lactose, dextrose, raw sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain "binders, e.g. magnesium aluminum silicate, starch pasta, gelatin, tragacanth, methyl cellulose, Sodium carboxymethyl cellulose and / or polyvinylpyrrolidone and, if desired, disintegrants, e.g. starches, agar, alginic acid or a salt thereof, such as sodium alginate, enzymes of the binders and / or effervescent mixtures, or adsorbents, dyes, Flavors and sweeteners. Injectable preparations

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are preferably isotonic aqueous solutions or suspensions and suppositories are primarily fat emulsions or suspensions. The pharmacological preparations can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, can contain further pharmacologically valuable substances, are produced in a manner known per se, for example by means of conventional mixing, granulating or coating processes, and contain from about 0.1% to about 75%, especially from about 1% to about 507 _o of the active ingredient.

The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius. Unless otherwise defined, the evaporation of solvents is carried out under reduced pressure.

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Example 1:

A mixture of 210 g of 1- [4- (3-chlorobenzyloxy) phenyl] -2-aminopropane, 158 g of β-phenyl-cinnamaldehyde and 1000 ml of dry benzene are in an apparatus that contains a water separator, refluxed while stirring until water ceases to form. The solution is then reduced under Evaporated pressure. The residue is triturated in 1000 ml of dry tetrahydrofuran and added dropwise, with stirring, in a nitrogen atmosphere to a cooled slurry of 86.5 g Lithium aluminum hydride in 1500 ml dry tetrahydrofuran given. The reaction mixture is stirred at room temperature for 20 hours, then cooled and until the excess is destroyed Hydrids treated with saturated aqueous ammonium chloride solution. The mixture is filtered and the filter cake extracted with chloroform. The extract and the filtrate are combined, washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. An oily product is obtained, which is the free base. This material is dissolved in acetone and acidified with ethereal hydrogen chloride. After cooling and adding small portions of dry Ether, one obtains the crystalline l- [4- (3-chlorobenzyloxy) -

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phenyl] -2- (3,3-diphenylpropylamino) propane hydrochloride. the Recrystallization from a mixture of methanol and ether results in the analytically pure hydrochloride, which melts at 157-160 °.

The starting material is prepared as follows: * A mixture of 244 g p-hydroxy-benzaldehyde, 360 g potassium carbonate, 32 g of potassium iodide, 1200 ml of 95% aqueous ethanol and 160 ml of water is slowly mixed with 367 g of m-chloro-benzyl chloride Stirring added. The mixture is stirred under reflux for 4 hours, cooled to 80 ° and mixed with 2000 ml of water at 80 ° with stirring. The reaction mixture is cooled, the one obtained Separated product, washed with water and extracted from methanol

recrystallized. The 4- (3-chlorobenzyloxy) benzaldehyde is obtained, which melts at 51-54 °.

A mixture of 200 g of 4- (3-chlorobenzyloxy) benzaldehyde, 40 g of ammonium acetate and 400 ml is heated under reflux Nitroethane 40 minutes and then let it cool. The precipitate obtained is filtered off, pressed to dryness and extracted Recrystallized ethanol. 1- [4- (3-chlorobenzyloxy) phenyl] -2-nitropropene, which melts at 110-114 °, is obtained. To Recrystallization from ethanol, the melting point rises

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117-118 °. The raw product is also suitable for the next step.

A cooled slurry of 57 g of lithium aluminum hydride in 750 ml of dry tetrahydrofuran is made in a nitrogen atmosphere with 91 g of 1- [4- (3-chlorobenzyloxy) phenyl] -2-nitropropene in 600 ml of dry tetrahydrofuran added dropwise. The mixture is stirred at room temperature for 18 hours and then remove the excess hydride while cooling by carefully adding dropwise a saturated aqueous ammonium chloride solution destroyed. The mixture is filtered and the precipitate extracted with chloroform. The filtrate and extracts are combined, washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The 1- [4- (3-chlorobenzyloxy) phenyl] -2-aminopropane is obtained as an oil which is used further. That Hydrochloride melts at 152-154 °.

Example 2:

In an analogous manner, according to Example 1, the d, Z 1- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane-hydrochloride is used. 178-180 °, via 4- (4-chlorobenzyloxy) -

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benzaldehyde (m.p. 73-75 °), 1- [4- (4-chlorobenzyloxy) phenyl] -2-nitropropene (M.p. 99-100 °) and 1- [4- (4-chlorobenzyloxy) phenyl] -2-aminopropane (melting point of the hydrochloride 199-201.5 °).

Example 3:

A solution of 85 g of 1- (4-hydroxyphenyl) -2- (3,3-diphenylpropylamino) propane hydrochloride (F. 204-207 °) made from the free base, which in turn according to Ehrhart et al., U.S. Patent 3,152,173) in 50 ml of dimethyl sulfoxide is mixed with 4.1 ml of a 10 normal aqueous sodium hydroxide solution offset. The reaction mixture is heated to 60 °, kept at this temperature for one hour, then with 4 g of 3,4-dichlorobenzyl chloride are added and at room temperature Vigorously stirred for 20 hours. The mixture is in 500 ml of ice water, which 5 ml of 10 normal aqueous sodium hydroxide solution contains, poured and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution washed, dried over sodium sulfate and. evaporated to dryness under reduced pressure. The residue is dissolved in a little isopropanol, with ethereal hydrogen chloride acidified and stored in the refrigerator. You get

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the white crystalline 1- [4- (3,4-dichlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane hydrochloride, which melts at 147-148 °.

Example 4:

In Example 3, the 3,4-dichlorobenzyl chloride is replaced by p-cyano-benzyl chloride, the 1- [4- (4-cyanobenzyloxy) phenyl] -2- (3,3-diphenyl-propylamino) -propane obtained. The extraction of the aqueous mixture with ethyl acetate gives the free base as a white crystalline material which melts at 132-138.5 °.

Example 5:

A mixture of 11.9 g of 4- (4-chlorobenzyloxy) phenyl acetone, 9.8 g of 3,3-diphenyl-3-hydroxypropylamine and 100 ml of absolute methanol are refluxed for one hour, cooled to room temperature and 6 g of sodium borohydride in 25 ml of water were added in portions while stirring. That The mixture is stirred for 18 hours and poured into ice water. The precipitate obtained is separated off and washed with water and recrystallized from isopropanol. The received

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Material is taken up in chloroform, the solution with activated charcoal treated, filtered, to dryness under reduced pressure evaporated and recrystallized from isopropanol. The pure 1- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenyl-3-hydroxypropylamino) propane is obtained, which melts at 125-127 °. The raw material is made as follows: A Mixture of 30.4 g of 1- [4- (4-chlorobenzyloxy) -phenylj-2-nitropropene (Intermediate product in Example 2), 80 g iron powder, 3.2 g iron III chloride, 40 ml concentrated hydrochloric acid, 400 ml of ethanol and 1200 ml of water are refluxed for 10 hours with vigorous stirring, cooled and filtered. The precipitate is extracted with methanol. The filtrate and extracts are combined and reduced under reduced pressure Pressure evaporated to dryness. The residue is dissolved in hot isopropanol, treated with activated charcoal and filtered and the filtrate kept in the refrigerator. The precipitate is separated off, washed with petroleum ether and dried. Man receives 4- (4-chlorobenzyloxy) phenylacetone, which melts at 76-80 °.

Example 6:

A mixture of 16 g of Ί-1- (4-hydroxyphenyl) -2- (3,3-diphenylpropylamino) propane hydrochloride, 50 ml of dimethyl sulf

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Oxide and 3.4 g of sodium hydroxide in 10 ml of water are stirred at 60 ° for one hour and then 7.2 g of 4-chlorobenzyl chloride are added. The reaction mixture is stirred overnight at room temperature, poured into 300 ml of 1 normal aqueous sodium hydroxide solution and extracted with methylene chloride. The extract is dried and evaporated. The residue is dissolved in 250 ml of ethyl acetate, the solution is mixed with that of 7 g of maleic acid in 25 ml of methanol, the mixture is stirred for one hour and filtered. The £ -1- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane maleate, which melts at 177-178 °, is obtained. [M] = -58.1 ° (5% in methanol).

The starting material is prepared as follows: A mixture of 23 g of .L -1- (4-hydroxyphenyl) -2-aminopropane, 31.2 g of 3,3-diphenylacrolein, 150 ml of anhydrous ethanol and 4 g of 10% palladium -Carbon catalyst is hydrogenated at 3.3 atmospheres for 6 hours. The reaction mixture is filtered, the filtrate is evaporated, the residue is dissolved in 400 ml of isopropanol and the solution is treated with 12.5 ml of concentrated hydrochloric acid. The mixture is left to stand overnight, the precipitate is separated off and washed with isopropanol and diethyl ether. The /i-1.- (4-hydroxyphenyl) -2- (3,3-di-

609808/1093

phenylpropylamino) propane hydrochloride, which melts at 244-247 °. [M] ₀ = -35.1 ° (5% in methanol).

The corresponding clockwise antipode is produced in an analogous manner. 244-246 °. [M] _β = + 31.9 ° (5% in methanol). As described above, it is converted into dl- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane maleate. F. 176-178 °, [M] _n = + 57.3 ° (5% in methanol)

Example 7:

A mixture of 11.85 g of 1- (4-hydroxyphenyl) -3- (3,3-diphenylpropylamino) butane (USP 3,262,977), 50 ml dimethyl sulfoxide and 3.1 ml 10 normal aqueous sodium hydroxide solution is stirred at 80 ° for half an hour and then mixed with 5.1 g of 4-chloro-benzyl chloride. The reaction mixture is stirred for 8 hours, taking it to room temperature lets cool down. The mixture is poured into 600 ml of ice-cold aqueous sodium hydroxide solution and mixed with a total of 700 ml of ethyl acetate extracted. The extract is washed with saturated aqueous sodium chloride solution, dried and evaporated. The residue is taken up in a minimal amount of anhydrous ethanol, the solution with that of 3.48 g of maleic acid added in ethanol, cooled and the precipitate

609808/1093

separated. 1- [4- (4-chlorobenzyloxy) phenyl] -3- (3,3-diphenylpropylamino) butane maleate, which ^{melts at 154-156 ° C.} , is obtained.

Example 8:

A mixture of 17.3 g of 1- (3-hydroxyphenyl) -2- (3,3-diphenyl-propylamino) propane, 100 ml of diethyl sulfoxide and 5 ml of 10 normal aqueous sodium hydroxide solution are used in Stirred at room temperature for half an hour, mixed with 8.05 g of 4 ~ chlorobenzyl chloride and stirred for a further 16 hours. That The reaction mixture is poured into water, extracted with ethyl acetate, the extract with saturated aqueous sodium chloride solution washed, dried and evaporated. The residue is taken up in diethyl ether and with hydrochloric acid in Isopropanol acidified. The precipitate is separated off and washed with diethyl ether. The 1- [3- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane hydrochloride is obtained, which melts at 184-189 °.

The 1- [3- (2-chloro-

benzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane hydrochloride, 165-167 ° and the 1- [2- (3-chlorobenzyloxy) phenyl] -2-

609808/1093

(3,3-diphenylpropylamino) propane hydrochloride, mp 144-145 °.

The starting material is prepared as follows: A mixture of 100 g of m-methoxyphenylacetone, 129 g of 3,3-diphenylpropylamine and 500 ml of anhydrous ethanol is refluxed for 2 hours, cooled to 20 ° and at room temperature, while stirring, a solution of 95 g of sodium borohydride in 300 ml of water is added dropwise. The mixture is over Stirred overnight, poured into water, extracted with methylene chloride, the extract dried and evaporated. The residue is taken up in diethyl ether, the solution is acidified with hydrogen chloride in isopropanol and the precipitate is separated off. The 1- (3-methoxyphenyl) -2- (3,3-diphenylprop'ylamino) propane hydrochloride is obtained, which melts at 95-98 °.

A mixture of 145 g of 1- (3-methoxyphenyl) -2- (3,3-diphenylpropylamino) propane hydrochloride and 1500 ml of 48% hydrobromic acid is refluxed for 45 minutes and left to stand overnight at room temperature. That The reaction mixture is poured onto 4000 g of ice and 1000 ml of concentrated ammonia and the mixture is extracted with methylene chloride. The extract is dried, evaporated and the residue is recrystallized from ethyl acetate. The 1 ~ (3-hydroxyphenyl) -

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2- (3,3-diphenylpropylamino) propane, which at 122-124 ° melts.

Substituting the (3-methoxy-4-hydroxyphenyl) -acetone with 3,3-diphenylpropylamine in order to reduce the Schiff ¹ obtained see Base as shown above and allowed to gesä'ttigte the compound with 3-trifluoromethyl-benzyl chloride to react, the 1- [3-methoxy-4- (3-trifluoromethylbenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane hydrochloride is obtained. After recrystallization from isopropanol, the product melts at 142-146 °.

Example 9:

A mixture of 7.18 g of 1- (3-methyl-4-hydroxyphenyl) ~ 2- (3,3-diphenylpropylamino) propane, 50 ml of dimethyl sulfoxide and 2 ml of a 10 normal aqueous sodium hydroxide solution is stirred at 60 ° for 1 hour . After cooling to room temperature, the reaction mixture is mixed with 3.32 g of 4-chlorobenzyl chloride and stirred overnight at this temperature. The mixture is then poured into water, extracted with ethyl acetate, the extract is dried and evaporated. The residue is taken up in isopropanol, the solution with chlorine water

609808/1093

acidified substance in isopropanol, separated the precipitate and washed with diethyl ether. The 1- [3-methyl-4- (4-chlorobenzyloxy) phenyl] -2- (3, 3-diphenylpropylamino) ~ propane hydrochloride, which melts at 166-168 °.

In an analogous manner, the 1- [3-fluoro-4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane hydrochloride, 183-187 °.

The starting material is obtained as follows: A mixture 100 g of 3-methyl-4-methoxy-benzaldehyde, 300 ml of nitroethane and 52 g of ammonium acetate are refluxed for 4 hours and evaporated. 1- (3-Methyl-4-methoxyphenyl) -2-nitropropene is obtained.

A solution of 185.9 g of 1- (3-methyl-4-methoxyphenyl) -2-nitropropene in 500 ml of tetrahydrofuran is added dropwise to a slurry of 76 g of lithium aluminum hydride in 250 ml of tetrahydrofuran added with stirring and cooling with ice-sodium chloride. That Stir overnight at room temperature in a nitrogen atmosphere continued. 300 ml of saturated aqueous ammonium chloride solution are slowly added to the mixture to obtain the To facilitate stirring, dilute with 2000 ml of diethyl ether and filter. The residue is mixed with a total of 1500 ml of diethyl ether

609808/1093

washed, the filtrate with saturated aqueous sodium chloride solution washed, dried and evaporated. The residue is taken up in diethyl ether, the solution with hydrogen chloride acidified in ethanol and separated off the precipitate. The l- (3-methyl-4-methoxyphenyl) -2-aminopropane hydrochloride is obtained, which melts at 200-205 °.

A solution of 4.93 g of sodium methylate in 300 ml of anhydrous ethanol is mixed with 19.7 g of 1- (3-methyl-4-methoxyphenyl) -2-aminopropane hydrochloride with stirring offset. After a few minutes, the mixture is filtered, the filtrate is evaporated and the residue is taken up in 500 ml of benzene. 19.01 g of 3,3-diphenylacrolein are added to the solution, refluxed using a water separator for 2 1/2 hours and evaporated. The residue is in 250 ml Tetrahydrofuran added, the solution with 14 g of lithium aluminum hydride added and then with stirring in a nitrogen atmosphere Boiled under reflux for 60 hours. 250 ml of saturated aqueous ammonium chloride solution are added to the mixture, filtered and the residue washed with diethyl ether and ethyl acetate. The filtrate is washed with saturated aqueous sodium chloride solution washed, dried and evaporated. The return

6098 0 8/109 3 '

stand is taken up in diethyl ether, the solution with Hydrogen chloride neutralized in ethanol and the precipitate recrystallized from isopropanol. The 1- (3-methyl-4-methoxyphenyl) -2- (3,3-diphenylpropylamino) propane hydrochloride is obtained, which melts at 174-179 °.

A mixture of 20.5 g of 1- (3-methyl-4-methoxyphenyl) -2- (3,3-Diphenylpropylamino) propane hydrochloride, 100 ml of methylene chloride and 50 g of boron tribromide is 9 hours at 0 ° and 9 hours stirred at room temperature. The reaction mixture is evaporated, the residue on ice and saturated ammonium hydroxide poured, the mixture filtered and the precipitate recrystallized from benzene. The 1- (3-methyl-4-hydroxyphenyl) -2- (3,3-diphenylpropylamino) propane is obtained, which melts at 115-118 °.

The analogously prepared 1- (3-fluoro-4-hydroxyphenyl) -2- (3,3-diphenylpropylamino) propane melts after recrystallization from methyl cellosolve at 186-188 °.

Example 10:

Starting from equivalent amounts of corresponding starting materials, according to the in the preceding examples,

609808/1093

preferably in the method 3) described methods, also the following racemic compounds are prepared:

1) 1- [4- (4-fluorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane maleate, 161-163 °;

2) 1- [4- (Pentafluorbenzyloxy) -phenyl] -2- (3, 3-diphenylpropylamino) -propane-inaleate, 156-158 °;

3) 1- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane maleate, 183-184 °;

4) 1- [4- (4-bromobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) ~ propane inaleate, 183-185 °;

5) 1- [4- (3-trifluoromethylbenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane maleate, 135-137 °;

6) 1- [4- (4-Cyanbenzyloxy) -phenyl] ~ 2- (SjS-diphei - ^ '- l-propylamino ^ propane-inaleate, 80-82 °;

7) 1- [4- (4-carbamoylbenzyloxy) phenyl] -2- (3, 3-diphenylpropylamino) propane maleate, 184-185 °.

Example 11:
A mixture of 4.8 g of 1- [4- (4-carbamoylbenzyloxy) -

609808/1093

phenyl] -2- (3,3-diphenylpropylamino) propane (made from the Maleate of Example 10/7 by extracting its suspension in 100 ml of 1 normal aqueous sodium hydroxide solution with Methylene chloride and evaporation of the extract), 25 ml of ethanol, 10 ml of water and 5.6 g of potassium hydroxide is in a nitrogen atmosphere Cooked under reflux for 18 hours. The reaction mixture is concentrated and the concentrate is diluted with 75 ml of water and acidified with 10 ml of concentrated hydrochloric acid. The precipitate is filtered off, washed with water, dried and triturated with diethyl ether. You get that 1- [4- (4-carboxybenzyloxy) -phenylj-2- (3,3-diphenylpropylamino) propane hydrochloride, which melts at 188-190 °.

Example 12:

Manufacture of 10,000 tablets, each containing 50 mg of the active substance:

609808/1093

Components:

/ £ -l- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenyl-

propylamino) propane inaleate 500 g

Milk sugar 1706 g

Corn starch 90 g

Polyethylene glycol 6000 90 g

Talc powder 90 g

Magnesium stearate 24 g

purified water q.s.

Procedure: All powdery components are sieved with a sieve with a mesh size of 0.6 mm. Then the active ingredient is mixed with lactose, talc, magnesium stearate and half of the starch in a suitable mixer. The other half of the starch is suspended in 45 ml of water and the suspension is added to the boiling solution of polyethylene glycol in 180 ml of water. The paste obtained is added to the powders and, if necessary, granulated with the addition of a further amount of water. The granules are dried overnight at 35 °, forced through a sieve with a mesh size of 1.2 mm and pressed into tablets with a diameter of 7.1 mm, which have a break groove.

609808/1093

Manufacture of 10,000 capsules containing 100 mg of the active substance:

Components:

d, ZI- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane hydrochloride 1000 g

Milk sugar 2800 g

Talc powder 200 g

Procedure: The powders are sieved with a sieve with a mesh size of 0.6 mm. Then the active ingredient is homogenized first with the talc and then with the milk sugar in a suitable mixer. Capsules No. 1 are each filled with 400 mg of the mixture using a filling machine.

Tablets or capsules with the other compounds of the examples are also produced in an analogous manner.

609808/109

Claims (1)

Patent claims: 1. Process for the production of new 1- (aralkoxyphenyl) 2-or-3- (bis-arylalkylamino) alkanes of the general formula I. CH ₀ Ar ₉ η 2 + 1 I. Ar- - C H. - O - Ph - (CH ₀ ) _r - CH - NH - CH - C - Ar (I), 1 m 2m 2 ^L ρ 2ρ j wherein each of the symbols Ar, Ar ₀ and Ar ~ is an unsubstituted or substituted by one or more lower alkyl, lower alkoxy, trifluoromethyl, nitro, amino, mono-lower alkylamino or di-lower alkylamino, lower alkanoylamino, cyano, Carboxy, carbo-lower alkoxy, carbamoyl, aminomethyl, mono-lower alkylaminomethyl or di-lower alkylaminomethyl groups or one or more halogen atoms-substituted phenyl radicals, Ph stands for a phenylene radical which can optionally be substituted by one of the substituents mentioned for Ar, η denotes a number from 0 to 4 and each of the symbols m and ρ denotes a number from 1 to 4, r the number 1 or 2 609808/1093 and R is hydrogen or hydroxy, and Salts of these compounds, characterized in that one 1) Carbonyl compounds of the general formula III (III) X C H. Y Ar_ ■ ι ι η 2η + 1 η ι 2 r ^C m ^H 2m- 0 - Fh - C - (CH.,) ^ - CH - Z - C - C ^ H., ^ - C - Ar ₃ ^R l wherein one or both symbols X and Y denote oxygen or the other symbol _{denotes H 0} , and Z denotes a free or protected -NH group, reduced, or 2) Olefins or Schiff bases of the general formula IV CH ₀ Ar ₀ Ar 1 η 2n + ls ^ v / 3 Ar _n - CH ₀ - 0 - Ph - (CH ₀ ) - C (H _n ) Z [CH ₀ JCR ₁ '1 in 2m-q Vx 1-u ρ 2p-v 1 where one of the symbols q, s and ν is the number 2 and the others stand for 0 or 2, u is zero, and Z is free or slotted NH denotes, or Z is a nitrogen atom, u denotes 1, ν denotes zero or 2 and the other indices have the meanings given above, or Z denotes a nitrogen atom, u stands for zero, ν denotes the number 1 or 3 and the other indices have the meanings given above, 609808/1093 reduced or 3) Compounds of the general formulas V and VI Ar ₁ - CH ₀ - T and U - CH ₀ - CR _n (Ar ₀ Ar.) 1 m 2m P 2p 12 3 (V) (VI) or their reactive salts, in which one of the symbols T and U represents the group of the formula (0 - Ph - (CH ₂ ) _r - CH (C _n H _{2n + 1} ) Z ") H, where Z "signifies free or protected NH, and the other the symbols T and U represent a reactive esterified hydroxyl group denotes, or U denotes amino and T denotes the group mentioned, in which Z "denotes a reactive esterified one Hydroxy group, condenses and, if necessary, liberates protected amino groups, and if desired, a retained one Converts the compound into another compound according to the invention, and / or, if desired, a free compound obtained into a salt or a salt obtained into the free compound or converted into another salt, and / or, if desired, a mixture of isomers or racemates obtained separates into the individual isomers or racemates, and / or, if desired, the racemates obtained into the optical antipodes splits. 609808/1093 2. The method according to claim 1, reaction 1), characterized in that starting materials are used in which the protected amino group Z is a group which can be released by hydrolysis or hydrogenolysis. 3. The method according to any one of claims 1 and 2, characterized in that in reaction 1) starting materials used, wherein the protected amino group Z is a lower alkanoylamino, aralkanoylamino or oc-aralkylamino group. 4. The method according to any one of claims 1 to 3, characterized in that the reduction of ketones of the reaction 1) with an Arylsulfonylhydrazld and then with sodium borohydride performs. 5. The method according to any one of claims 1 to 3, characterized in that the reduction of amides of the reaction 1) with simple or complex light metal hydrides. 6. The method according to claim 1, characterized in that that in reaction 2) starting materials are used in which the protected amino group Z is obtained by hydrolysis or hydrogenolysis releasable group is. 609808/1093 7. The method according to any one of claims 1 or 6, characterized in that the reduction in reaction 2) carries out with catalytically activated hydrogen. 8. The method according to claim 1, characterized in that in reaction 2) the Schiff's view bases with nascent Hydrogen or with simple or complex light metal hydrides reduced. 9. The method according to claim 1, characterized in that in reaction 2) the Schiff's view bases in which η means zero, u stands for 1, and ν means 1 or 3, reduced with C EL ,, - Grignard compounds and the obtained Hydrolyzed adduct. 10. The method according to any one of claims 1 and 6 to 9, characterized in that in reaction 2) for products, in which R, denotes hydrogen, starting materials of the formula IVa C H in 2n + ls _Ar ^Ar l - ^C m ^H 2 _ra - _q - 0 - Ph - (CH) - C (H mc ». \ ' \, ^H ^ r iu p + i 2p + lv ^J \ (IVa) 809808/1093 wherein all symbols have the meanings given in claim 1, used. 11. The method according to claim 1, characterized in that starting materials are used in reaction 3), wherein the protected amino group Z "is a group which can be released by hydrolysis or hydrogenolysis. 12. The method according to any one of claims 1 or 11, characterized in that in reaction 3) starting materials used in which a reactive esterified hydroxyl group from a strong inorganic or organic acid is derived. 13. The method according to any one of claims 1, 11 and 12, characterized in that the reaction of the starting materials of the formulas V and VI shown in claim 1 in the presence of condensing agents. 14. The method according to any one of claims 1 to 13, characterized in that the halogen compounds obtained are dehalogenated. 15. The method according to any one of claims 1 to 14, characterized in that one at any process stage 609808/1093 obtained intermediate used as starting material and carries out the remaining process steps, or terminates the process at any stage, or a starting material forms under the reaction conditions or used in the form of a salt or optically pure antipode. 16. The method according to any one of claims 1 to 15, characterized in that compounds of those shown in claim 1 are used Formula I, in which each of the symbols Ar_, Ar and Ar is phenyl, (Lower alkyl) phenyl, (lower alkoxy) phenyl, (halo) phenyl X X X or (trifluoromethyl) phenyl, Ph is 1,3- or 1,4-phenylene, (lower alkyl) -1,3- or -1,4-phenylene, (lower alkoxy) -1,3- or -1,4 -phenylene, (halogen) -1,3- or -1,4-phenylene or (trifluoromethyl) -1,3- or -1,4-phenylene, η is a number from 1 to 4, each of the symbols m and ρ is a number from 1 to 4, χ is a number from 1 to 5, r is the number 1 or 2, and R _{1 is} hydrogen or hydroxy, and prepares salts of these compounds. 17. The method according to any one of claims 1 to 15, characterized in that compounds of the general formula II 609808/1093 CH ₀ . • η 2η- (CH ₀ ) - O ^ν ζ'ιη CH ₂ - CH NH - (CH ₂ ) in which each of the symbols R and R ¹ denotes hydrogen, methyl, methoxy, fluorine, chlorine, bromine or trifluoromethyl and each of the symbols m, η and ρ denotes the number 1 or 2, R ^ denotes hydrogen or hydroxy, and salts of these compounds manufactures. 18. The method according to any one of claims 1 to 15, characterized in that compounds of the formula II shown in claim 17, wherein R ,, m, η and ρ have the meanings given in claim 17, R is chlorine and R ^{1 is} what - "is hydrogen, and produces salts of these compounds. 19. The method according to any one of claims 1 to 15, characterized in that compounds of those shown in claim 17 are made Formula II, in which R is chlorine in the meta or pafa position 609808/1093 means, IL and R ¹ stand for hydrogen, each of the symbols m and η stands for the number 1, and ρ stands for the number 2, and produces salts of these compounds. 20. The method according to any one of claims 1 to 13 and 15, characterized in that I- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane and makes its salts. 21. The method according to any one of claims 1 to 20, characterized in that the left-handed antipodes of in these claims mentioned compounds isolated. 22. The method according to any one of claims 1 to 20, characterized in that one of the clockwise antipodes compounds mentioned in these claims isolated. 23. The procedure described in Examples 6-11. 24. The method according to claim 1 for the preparation of compounds of the formula I shown in claim 1, wherein each of the symbols Ar ₁ , Ar ~ and A, r ~ is an unsubstituted or by one or more lower alkyl, lower alkoxy, trifluoromethyl, nitro , Amino, mono-lower alkylamino or di-lower alkylamino, lower alkanoylamino, cyano, carboxy, 809808/1093 Carbon-lower alkoxy, aminomethyl, mono-lower alkylaminomethyl or di-lower alkylaminomethyl groups or one or more halogen atoms substituted phenyl radicals, Ph stands for a 1,3- or 1,4-phenylene radical which may be substituted _{by one of the substituents mentioned for Ar 1} can, η denotes a number from 0 to 4 and each of the symbols m and ρ denotes a number from 1 to 4, r denotes the number 1 and R ₁ denotes hydrogen or hydroxy, and salts of these compounds, characterized in that man 1) Compounds of the formula III shown in claim 1, in which X is two hydrogen atoms, Y for one oxygen atom stands, r stands for the number 1, Z stands for a free or protected -NH group, and the other symbols are as above have given meanings, reduced or 2) Olefins or Schiff bases of the formula IV given in claim 1, in which r is the number 1, Ar .., Ar _? , Ar “and Ph have the meanings given above, and the other symbols have the meanings given in claim 1, reduced or 3) Compounds of the formulas V and VI shown in claim 1, in which Ar ₁ , Ar ", Ar" and Ph have the meanings given above JL £ m > J 609808/1093 have, r stands for 1, and the other symbols have the meanings given in claim 1, condensed, and, if necessary, releases protected amino groups and, if desired, converts one compound obtained into another according to the invention converts, and / or, if desired, an obtained free compound into a salt or a obtained salt into the free compound or another Salt converted, and / or, if desired, a mixture of isomers or racemates obtained into the individual isomers or separating racemates, and / or, if desired, separating the racemates obtained into the optical antipodes. 25. The method according to claim 24, reaction 1), characterized in that starting materials are used in which the protected amino group Z is a group which can be released by hydrolysis or hydrogenolysis. 26. The method according to any one of claims 24 or 25, characterized in that the reduction of amides of the Reaction 1) with simple or complex light metal hydrides. 27. The method according to claim 24, characterized in that starting materials are used in reaction 2) in which the protected amino group Z is a group which can be released by hydrolysis or hydrogenolysis. 60 9808/1093 ' 28. The method according to any one of claims 24 and 27, characterized in that the reduction in reaction 2) carries out with catalytically activated hydrogen. 29. The method according to claim 24, characterized in that in reaction 2) the Schiff's view bases with nascent hydrogen or with simple or complex light metal hydrides. 30. The method according to claim 24, characterized in that in reaction 2) the Schiff's bases in which η means zero, u stands for 1, and ν means 1 or 3, reduced with C H "- Grignard compounds and the result Hydrolyzed adduct. 31. The method according to any one of claims 24 and 27 to 30, characterized in that in reaction 2) for products, in which R, denotes hydrogen, starting materials of the formula IVa given in claim 10 are used, wherein ' all other symbols have the meanings given in claim 24. 32. The method according to claim 24, characterized in that starting materials are used in reaction 3) in which 809808/1093 the protected amino group Z "is a group which can be released by hydrolysis or hydrogenolysis. 33. The method according to any one of claims 24 and 32, characterized in that in reaction 3) starting materials used in which a reactive esterified hydroxyl group is derived from a strong inorganic or organic Acid derived. 34. The method according to any one of claims 24, 32 and 33, characterized in that reaction 3) is in the presence of condensing agents. 35. The method according to any one of claims 24 to 34, characterized in that the halogen compounds obtained dehalogenated. 36. The method according to any one of claims 24 to 35, characterized characterized in that an intermediate product obtained at any process stage is used as the starting material and carries out the remaining process steps, or the process stops at any stage, or forms a starting material under the reaction conditions or in Used in the form of a salt or optically pure antipode. 609808/1093 37. The method according to any one of claims 24 to 36, characterized in that compounds of the claim Formula I shown, wherein each of the symbols Ar, Ar and Ar Phenyl, (lower alkyl) phenyl, (lower alkoxy) phenyl, (halo- X X gen) -phenyl or (trifluoromethyl) -phenyl means Ph flir 1,3- or 1,4-phenylene, (lower alkyl) -1,3- or -1,4-phenylene, (Lower alkoxy) -1,3- or -1,4-phenylene, (halogen) -1,3- or -1,4-phenylene or (trifluoromethyl) -1,3- or -1,4-phenylene is, η is a number from 1 to 4, each of the symbols m and ρ is a number from 1 to 4, χ is a number from 1 to 5, r denotes the number 1, and R- denotes hydrogen or hydroxy, and prepares salts of these compounds. 38. The method according to any one of claims 24 to 36, characterized in that compounds of those specified in claim 17 are used Formula II, in which all symbols have the meanings given in claim 17, and salts of these compounds manufactures. 39. The method according to any one of claims 24 to 36, characterized in that compounds of the formula II shown in claim, in which R,, m, η and ρ have the meanings given in the claim, R is chlorine and R ^{1 is} hydrogen, and making salts of these compounds. «09808/1093 40. The method according to any one of claims 24 to 34 and 36, characterized in that 1- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane and makes its salts. 41. The procedure described in Examples 1-5. 609808/1093 Compounds of the general formula I ^Ar 2 ^Ar l ■ ^C , »V- ° - ^Ph - < ^CH 2> r - CH - KH - CMi ^ -C-Ar, (I), wherein each of the symbols Ar ₁ , Ar ~ and Ar «is an unsubstituted or by one or more lower alkyl, lower alkoxy trifluoromethyl, nitro, amino, mono-lower alkylamino or di-lower alkylamino, lower alkanoylamino, cyano, carboxy , Carbo-lower alkoxy, carbamoyl, aminomethyl, mono-lower alkylaminomethyl or di-lower alkylaminomethyl groups or one or more halogen atoms-substituted phenyl radicals, Ph stands for a phenylene radical which can optionally be substituted by one of the substituents mentioned for Ar, η is a number denotes from 0 to 4 and each of the symbols m and ρ denotes a number from 1 to 4, r denotes the number 1 or, and R ₁ denotes hydrogen or hydroxy, 43. Compounds of the formula I shown in claim 42, wherein each of the symbols Ar ₁ , Ar and Ar is phenyl, (lower alkyl) - JL * L ό X. phenyl, (lower alkoxy) -phenyl, (halogen) -phenyl or (tri- 9808/1093 fluoromethyl) phenyl is Ph for 1,3- or 1,4-phenylene, (Lower alkyl) -1,3- or -1,4-phenylene, (lower alkoxy) -1,3- or -1,4-phenylene, (halogen) -1,3- or -1,4-phenylene or (Trifluoromethyl) -1,3- or -1,4-phenylene, η denotes a number from 1 to 4, each of the symbols m and ρ denotes a Number from 1 to 4, χ denotes a number from 1 to 5, r denotes the number 1 or 2, and IL denotes hydrogen or Hydroxy stands. 44. Compounds of the general formula II (CH ₂ ) ,, - O C Η «ι τ η 2n-KL CH ₀ - CH NH - (CH ₂ ) wherein each of the symbols R and R ^! Denotes hydrogen, methyl, methoxy, fluorine, chlorine, bromine or trifluoromethyl and each of the symbols m, η and ρ denotes the number 1 or 2, and R ₁ denotes hydrogen or hydroxy. 609808/1093 45. Compounds of the formula II shown in claim 44, wherein R ₁ ; m, η and ρ have the meanings given in claim 44, R is chlorine and R ^{1 is} hydrogen. 46. Compounds of the formula II shown in claim 44, wherein R is chlorine in the meta or para position, R .. and R ^! stand for hydrogen, each of the symbols m and η stands for the number 1, and ρ stands for the number 2. 47. 1- [4- (3-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane. 48. d, ^ -l- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane. 49. 1- [4- (3,4-Dichlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane. 50. 1- [4- (4-Cyanobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane. 51. 1- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenyl-3-hydroxypropylamino) propane. 52. I -1- [4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane. 609808/1093 53. d-1- [4- (4-Chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane. 54. 1- [4- (4-chlorobenzyloxy) phenyl] -3- (3,3-diphenylpropylamino) butane. 55. 1- [3- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane. 56. 1- [3- (2-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino-propane. 57. 1- [2- (3-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane. 58. 1- [3-methoxy-4- (3-trifluoromethylbenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane. 59. 1- [3-methyl-4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) -propane. 60. 1- [3-fluoro-4- (4-chlorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) -propane. 61. 1- [4- (4-fluorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) -propane. 62. 1- [4- (pentafluorobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) - propane. 609808/1093 63. 1- [4- (4-bromobenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane. 64. 1- [4- (3-Trifluoromethyl-benzyloxy) -phenyl] -2- (3,3-diphenylpropylamino) -propane. 65. 1- [4- (4-Carbamoylbenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane. 66. 1- [4- (4-Carboxybenzyloxy) phenyl] -2- (3,3-diphenylpropylamino) propane. 67. Left-turning antipodes of the compounds mentioned in claims 42 to 66. 68. Clockwise antipodes of the compounds mentioned in claims 42 to 66. 69. The compounds mentioned in claims 42 to 68 in the form of their salts. 70. The compounds mentioned in claims 42 to 68 in the form of their therapeutically useful salts. 71. Pharmaceutical preparations characterized by a content of one of the claims 42 to 68 and named compounds. 609808/1093