NO157975B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC ACTIVE PROPYLAMINE DERIVATIVES. - Google Patents

Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. A compound of the general formula I see diagramm : EP0102929,P33,F1 Wherein each of R1 and R2 independently of the other represents hydrogen or lower alkyl ; or R1 and R2 together with the adjacent nitrogen atom represent piperidino or pyrrolidino or a five- or six-membered saturated heterocyclic ring containing NH, N-lower alkyl, O or S ; R3 represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl ; Ar represents phenyl or phenyl substituted by one to three substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, halogen and trifluoromethyl, or by on lower alkylenedioxy ; and X represents O, S or N-lower alkyl ; and n represents an integer 1, 2 or 3 ; or an N-oxide thereof ; an acid addition salt thereof ; of an N-lower alkyl or N-benzyl quaternary salt thereof ; with the exception of the compound of formula I wherein R1 and R2 represent ethyl, R3 represents hydrogen, Ar represents phenyl, X represents O, and n is 3, or a salt thereof ; with the groups qualified by the term "lower" containing at most 7 carbon atoms. For the Contracting State : AT 1. A process for the preparation of a novel propylamine derivative of the general formula I see diagramm : EP0102929,P37,F1 Wherein each of R1 and R2 independently of the other represents hydrogen or lower alkyl ; or R1 and R2 together with the adjacent nitrogen atom represent piperidono or pyrrodino or a five- or six-membered saturated heterocyclic ring containing NH, N-lower alkyl, O or S ; R3 represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl ; Ar represents phenyl or phenyl substituted by one to three substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, halogen and trifluoromethyl, or by on lower alkylenedioxy ; and X represents O, S or N-lower alkyl ; and n represents an integer 1, 2 or 3 ; or of an N-oxide thereof ; an acid addition salt thereof ; of an N-lower alkyl or N-benzyl quaternary salt thereof ; with the exception of the compound of formula I wherein R1 and R2 represent ethyl, R3 represents hydrogen, Ar represents phenyl, X represents O, and n is 3, or a salt thereof ; with the groups qualified by the term "lower" containing at most 7 carbon atoms ; which process comprises a) condensing a compound of the formula II see diagramm : EP0102929,P37,F2 or an acid addition salt thereof, with a compound of the formula III AR-Y(III) wherein R1 , R2 , R3 , n and Ar are as defined above, one of the symbols W and Y represents a group XH or XH in a metal salt from, in which X is as defined above, and the other one represents the group XH in a reactive esterified form thereof or as an N,N'-disubstituted isourea or isothiourea derivative ; or b) alkylating an amine of the formula IV see diagramm : EP0102929,P37,F3 or an acid addition salt thereof, with a compound of the formula V see diagramm : EP0102929,P38,F4 in which Z is a hydrogen atom together with a reactive esterified hydroxyl group of the oxo group and Ar, X, R3 and n are as defined above, and if Z is the oxo group, said alkylation is carried out under reductive conditions ; or c) reducing a compound structurally analogous to a compound of formula I as defined above, wherein an oxo group is present on at least one carbon atom adjacent to the amino nitrogen ; or d) saturating with hydrogen a multiple bond or multiple bonds in a compound structurally analogous to the compound of formula I as defined above and wherein one or two double bonds are present in the aliphatic moiety of the molecule inclusive of the amino group ; or e) removing the radial R0 from a compound of the formula VI see diagramm : EP0102929,P38,F5 wherein R2 , R3 , X, n and Ar are as defined above and R0 is an amino proctective group, to obtain a compound of formula in which R1 is hyrogen ; or f) reducing a compound of the formula VII see diagramm : EP0102929,P38,F5 wherein T represents cyano or azidomethyl ; and R3 , X, n and Ar are as defined above to obtain a compound of formula I wherein R1 and R2 are hydrogen ; or g) condensing a compound of the formula VIIA see diagramm : EP0102929,P39,F6 with a compound of the formula VIIB see diagramm : EP0102929,P39,F6 wherein one of the groups Q and M represents a removable group, and the other represents a metal or halometal radical, and Ar, X, R1 to R3 and n are as defined above, if necesseray while temporarily protecting any interfering reactive group in all these processes, and isolating the resultant compound of formula ; and/or, if required, converting a resultant compound of formula I into another compound of formula I, and/or, if require, converting a resultant free compound into a salt or a resultant salt into the free compound or into another salt, and/or, if required, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if required, resolving a racemate obtained into the optical antipodes.

Description

The French patent application 2,148,001 £oq also those i

the substantially equivalent Canadian, Belgian and British descriptions (975 375, 786 450 and 1 343 527 respectively) relate to such compounds which are designated as certain 2-(aryl, aralkynyl or aralkyl)-3-(aryl or alk)-oxypropylamines. These compounds have an effect on the cardiovascular system. In Example 60, a compound whose structure corresponds to that of 2-benzyl-3-phenoxy-N,N-diethyl-propylamine has been shown. By repeating the procedure of Example 60 in the French patent application 2 148 001, it had now been found that the product according to example 60 essentially essentially consists of a compound which does not have the attributed structure

trip. Instead of the assumed structure, this compound has the structure of 3-phenoxymethyl-3-phenyl-N,N-diethyl-propyl-amines.

The invention relates to analogue methods for the production of therapeutically active new compounds with the general formula I

in which each of the symbols R^ and R2 means hydrogen or lower alkyl, or and R2 stands together with the nitrogen atom of piperidino, R^ means hydrogen or halogen, Ar stands for optionally with one or two substituents of the group lower-

alkyl, lower alkoxy, lower alkenyloxy, lower alkyl alkoxy, lower alkenyloxy, lower alkyl mercapto, lower alkylsulfinyl, halogen, trifluoromethyl, or with a lower alkylenedioxy substituted phenyl, X means an oxygen atom or a sulfur atom,

their acid addition salts, especially their therapeutically useful acid addition salts, and their N-lower alkyl or N-benzyl quaternary salts.

In particular, the present invention relates to compounds of the general formula I, in which each of the symbols R^ and R2 means hydrogen or lower alkyl, or R^ and R2 stand together with the nitrogen atom for piperidino, R^ means hydrogen, halogen, Ar stands for optionally with one or two substituents from the group of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkyl mercapto, lower alkyl sulfinyl, halogen and trifluoromethyl, or with a lower alkylenedioxy substituted phenyl, X means a sulfur atom or an oxygen atom, their acid addition salts, especially their therapeutically useful acid addition salts, and their N-lower alkyl- or N-benzyl quaternary salts.

Preferred are compounds of the general formula I, in which R 1 and R 2 mean independently of each other hydrogen or lower alkyl, or R 1 and R 2 stand together with the nitrogen atom of piperidino; R 1 , Ar and X have the meanings given above, and their acid addition salts, especially their therapeutically useful salts, with the exception of the compound of formula I, in which each of the symbols R 1 and R 2 is ethyl, R 2 is hydrogen, Ar is phenyl , X stands for an oxygen atom and n means 3, and their salts.

As an illustration of the above-mentioned preferred compounds, mention is made of those with the general formula I, in which and R2 independently of each other means hydrogen, methyl or ethyl, R^ stands for hydrogen or chlorine, Ar means optionally with one or two substituents of the group methyl , methoxy, allyloxy, methylthio, methylsulfinyl, chlorine, bromine or trifluoromethyl or with a methylenedioxy substituted phenyl,

X represents 0 or S, and their acid addition salts, especially therapeutically useful salts, with the exception of the compound of formula I, in which each of the symbols R₁ and R₂ is ethyl, R₂ is hydrogen, Ar is phenyl, X is an oxygen atom and n means 3, and their salts.

Highly preferred are compounds of formula I,

in which R-^ and R 2 independently of each other mean hydrogen or lower alkyl, or R^ and R 2 mean together with the nitrogen atom piperidino, R^ means hydrogen or halogen or trifluoromethyl, X means oxygen, sulfur or N-lower alkyl, Ar stands

for a phenyl radical, which is substituted with one or two substituents from the group of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkyl mercapto, lower alkylsulfinyl, halogen and trifluoromethyl, or substituted with a lower alkylenedioxy, and their acid addition salts, especially their therapeutically useful acid addition salts.

Particularly important are compounds of formula IB

wherein and R2 independently of each other means hydrogen or lower alkyl, R^ stands for hydrogen or halogen, Ar means phenyl which is substituted with one or two, the same or different substituents from the group of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkyl mercapto, lower alkylsulfinyl, halogen or trifluoromethyl; and their acid addition salts, especially their therapeutically useful salts.

Very preferred are compounds of formula IB, in which R.j means hydrogen or alkyl with 1-4 carbon atoms; R 2 stands for alkyl of 1-4 carbon atoms; R 1 means hydrogen or chlorine; Ar stands for phenyl, which is monosubstituted with alkyl, alkoxy or alkyl mercapto of each 1-4 carbon atoms, chlorine or trifluoromethyl, and their acid addition salts, especially their therapeutically useful salts.

Further preferred compounds are those of formula IB, in which R 1 is hydrogen, R 2 means alkyl of 1-4 carbon atoms; R^ represents hydrogen or chlorine; Ar means phenyl which is monosubstituted with alkyl, alkoxy or alkyl mercapto of each 1-4 carbon atoms, chlorine or trifluoromethyl, and their acid addition salts, especially their therapeutically useful salts.

In all the aforementioned compounds of formula IB, Ar preferably means phenyl, which is di- or mono-substituted in the 3- and/or 4-position in the phenyl ring with the above-mentioned substituents.

As examples of the above-mentioned preferred compounds, mention should be made of those of formula IB, in which R. means hydrogen or methyl; R 2 stands for methyl; R 3 means hydrogen or chlorine in the 3- or 4-position; Ar stands for phenyl, which is monosubstituted. with methoxy, methyl, methylthio, chlorine or trifluoromethyl, and their acid addition salts, especially therapeutically useful salts. Further preferred of these compounds are those: in which Ar means phenyl, which is substituted in the 3- or 4-position, preferably in the 4-position, with methoxy, methylthio or trifluoromethyl, and their acid addition salts, especially their therapeutically useful salts.

A particularly valuable group of compounds are those of formula I, in which R 1 is hydrogen or methyl, R 2 stands for methyl; R 3 means hydrogen, X means oxygen and Ar stands for unsubstituted phenyl, and their acid addition salts, especially their therapeutically useful salts.

The general definitions used here have in the frame

of the present invention the following meaning.

The term "lower" is defined in the above or subsequently mentioned organic residues or compounds of this type with at most 7, preferably 4, especially 1 or 2 carbon atoms.

A lower alkyl group preferably contains 1-4 carbon atoms and means e.g. ethyl, propyl, butyl or preferably methyl.

)

Lower oxy is preferably ethoxy, propoxy, iso-propoxy or especially methoxy.

Lower alkylthio is preferably ethylthio, propylthio or preferably methylthio. 5 Lower alkylsulfinyl is especially ethylsulfinyl, propylsulfinyl or preferably methylsulfinyl.

Lower alkylsulfonyl is preferably ethylsulfonyl, propylsulfonyl or especially methylsulfonyl.

A lower alkenyl group as such or as, for example, present in alkenyloxy means straight-chain or branched alkenyl, preferably with up to 7 carbon atoms, especially up to and including 4 carbon atoms, e.g. 2-propenyl (allyl), 2-butenyl, 2-methyl-2-propenyl or 2-methyl-2-butenyl.

Halogen is preferably chlorine, but can also be bromine, iodine or fluorine.

The aforementioned compounds of formula I form acid addition salts which are preferably those of therapeutically usable inorganic or organic acids, such as, for example, of strong mineral acids, e.g. halogenated acids, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; aliphatic or aromatic carboxylic acids or sulphonic acids, e.g. ant, vinegar, propion, amber, glycol, milk, apple, wine, glucone, lemon, maleic, fumar, pyrrhotite, phenyl acetic, benzo, 4-aminobenzo, anthra-nyl-, 4-hydroxybenzo-, salicylic-, 4-aminosalicylic-, pamoe-, nicotine-; methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanil, cyclohexylsulfamic acid; or of ascorbic acid.

Acid addition salts, e.g. those of other strong inorganic or organic acids, e.g. perchloric acid or picric acid, can also be used in the isolation, purification and characterization of the compounds of formula I.

The compounds prepared according to the present invention exhibit valuable pharmacological properties, e.g. particularly regulatory effects on the central nervous system, specifically such effects that refer to antidepressant effects. These come i.a. to be seen by selective inhibition of serotonin uptake by the brain nerve cells. The compounds according to the invention also inhibit the neuronal uptake of norepinephrine (NE).

The above-mentioned properties can be demonstrated by in vitro or in vivo animal experiments, preferably on mammals, such as mice, rats, guinea pigs, rabbits or monkeys as test subjects. The said compounds can be administered enterally or parenterally, preferably orally, or subcutaneously, intravenously or intraperitoneally, e.g. with gelatin capsules either in the form of starch containing suspensions or aqueous solutions or suspensions. The dose used can range from approx. between 0.1 and 100 mg/kg/day, preferably approx. 1 and 50 mg/kg/day, especially approx. 5 and 30 mg/kg/day.

The inhibition of serotonin (5-HT) uptake, which refers to the potential antidepressant effect, is determined in vitro, on synaptosomes of the midbrain of the rat as follows: Synaptosomes of the midbrain section of the rat are prepared and <3>H-5 is determined -The HT recording according to Baumann and Maitre, Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 31 , (1977). The concentration of 5-HT in the incubation medium is 2.5 x 10~<9>M and the incubation lasts 10 minutes. A concentration of a compound according to the invention is determined which inhibits serotonin uptake by 50%, i.e. the IC^ value.

As examples of the intermediates produced according to the invention, mention should be made of N,N-dimethyl-2-benzyl-3-(4-methylthiophenoxy)-propylamine-oxalate, N,N-dimethyl-2-benzyl-3-(4-trifluoromethyl -phenoxy)-propylamine oxalate and N-methyl-2-benzyl-3-(4-trifluoromethyl-phenoxy)-propylamine oxalate, which inhibit the uptake of <3>H-5-HT into the synaptosome of the rat midbrain with IC5Q -values of approx. 3 x 10<-8>M, 1.5 x 10<_8>M respectively. 1 x 10~<8>M.

The inhibition of norepinephrine (NE) uptake is determined in vitro on rat midbrain synaptosomes as follows:

It prepares synaptosomes of the midbrain zone

in rats and 3H-NE uptake is measured according to Baumann and Maitre, Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 31 (1977). The concentration of NE in the incubation medium is 1 x 10 — 8M and the incubation lasts 20 minutes. A concentration of a new compound that inhibits norepinephrine uptake by 50% is determined, i.e. iCg-Q^vérdiehy

As examples of the compounds produced according to the invention, mention should be made of N,N-dimethyl-2-benzyl-3-(4-methylthio-phenoxy)-propylamine-oxalate, N,N-dimethyl-2-benzyl-3(4-trifluoromethyl-phenoxy )-propylamine oxalate and N-methyl-2-benzyl-3-(4-trifluoromethyl-phenoxy)-propylamine oxalate, which inhibit the uptake of <3>H-NE in the synaptosome of the rat midbrain with IC50 values of approx. . 5 x 10~<7>M, 3 x 10<-6>M respectively. 2 x 10~<6>M.

The inhibition of serotonin (5 HT) uptake is also determined in rats, which have been pre-treated with compounds according to the present patent application.

As examples of the compounds produced according to the invention, mention should be made of N,N-dimethyl-2-benzyl-3-(4-methylthio-phenoxy)-propylamine-oxalate and N,N-dimethyl-2-benzyl-3-(4- The trifluoromethyl-phenoxy)-propylamine oxalate, which shows at an oral dose of 30 mg/kg an 80% resp. 60% inhibition of <3>H-5HT uptake. The N-methyl-2-benzyl-3-(4-trifluoromethyl-phenoxy)-propylamine oxalate gives an approx. 50% inhibition of <3>H-5HT uptake at a dose of 10 mg/kg p.o.

The inhibition of the serotonin uptake or property

by activation of serotonin by the compounds according to the invention refers to the antidepressant effect. This is determined in rabbits by the reversal of reserpine-induced ptosis (ie contraction of the eyelid).

The rabbits are administered by intravenous injection

2 mg/kg reserpine 90 minutes before the intravenous infusion of a 0.2% active substance solution into the ear veins, according to the method of J. Mizoule et al., /J. Pharmacol., 8, 3, 269-285,

(1977)_7. The complete opening of the eyelid is considered the criterion for the reversal of the reserpine-induced ptosis. The results are expressed in terms of the mean dose of the test compound which induces the complete opening of the eyelid of the reserpine-treated rabbits. Examples of compounds produced according to the invention are N,N-dimethyl-2-benzyl-3-(4-methylthio-phenoxy)-propylamine-oxalate, N,N-dimethyl-2-benzyl-3-(4-trifluoromethyl- the phenoxy)-propylamine oxalate and the N-methyl-2-benzyl-3-(4-trifluoromethyl-phenoxy)-propylamine oxalate, which show the described effect at an i.v. dose of approx. 7.7, 12.6 respectively. 12.9 mg/kg.

The compounds produced according to the invention also inhibit the serotonin secretion of the induced effect of 3-hydroxy-4-methyl-α-ethylphenethylamine (H 75/12) in the rat brain. The test is carried out essentially according to Carlsson, Corrodi, Fuxe and Hoekfelt, Europ. J. Pharmacol. 5, 357 (1969).

The compound selected for testing is administered orally 30 minutes before H 75/12 (25 mg/kg s.c.) and the animals are decapitated 4 hours later. The brains are immediately removed, the serotonin content is determined as above and the ED50~ value is calculated. The effect of a compound according to the invention in inhibiting the effect of H 75/12, which promotes serotonin secretion, is an indirect measure of the ability to inhibit serotonin uptake.

As examples of the illustration of the inhibitory effect of the compounds produced according to the invention on serotonin uptake, the ED,-Q values in the above-mentioned H 75/12 test for N,N-dimethyl-2-(3-chlorobenzyl)- The 3-(4-methylthio-phenoxy)-propylamine oxalate and for the N-methyl-2-benzyl-3-(4-trifluoromethyl-phenoxy)-propylamine oxalate, which lies at approx. 1.4 respectively 1.8 mg/kg p.o. The ED^ values for the N,N-dimethyl-2-benzyl-3-(4-methylthio-phenoxy)-propylamine oxalate and for the N,N-dimethyl-2-benzyl-3-(4-trifluoromethyl-phenoxy)- The propylamine oxalate is approx. 2.3 respectively 4.5 mg/kg p.o.

Therefore, the compounds prepared according to the present invention can be used alone or in combination in mammals in the treatment of psychotropic diseases, especially depression. The compounds according to the invention can also be used for the treatment of other disorders in the central nervous system, which promote the regulation of brain serotonin, e.g. minimal functional disorders of the brain, inordinate appetite, anxiety, schizophrenia and dementia. The new compounds can also be used as an analgesic and for the production of other valuable products, especially pharmacologically active preparations.

The compounds of formula I can be prepared according to

in and of themselves known methods, ie

a) a compound of formula II

or an acid addition salt thereof, is condensed with a compound of formula III

in which R^, , R-^ and Ar have the above meaning, one of the symbols W and Y means the group -XH, in which X has the above meaning, and the other means the group XH in reactive esterified form, preferably as an N,N' -disubstituted isourea or isothiourea derivative, or

b) an amine of formula IV

or an acid addition salt thereof, is condensed under reducing conditions with a compound of formula V

where Ar, X and R^ have the above meanings, or

c) a compound of formula XII

wherein R1, R3, Ar and X have the above meaning, are reduced or

d) in a compound with formula VI

wherein R 2 , R 1 , x and Ar have the above meaning, and R means

an amino protecting group, the group R is cleaved off, and a compound of formula I is formed, in which R1 means hydrogen, and the compounds of formula I formed are isolated, and/or if desired, a compound of formula I is converted

to another compound of formula I, and/or if desired, a formed free compound is transferred to a salt or a formed salt to the free compound or to another salt.

The condensation according to method a) is carried out as described below. The group XH is a hydroxy or mercapto-(thiol) group. The metal salt form of such a group is preferably derived from an alkali metal (e.g. potassium, lithium or especially sodium) or, in the case of the marcapto group, also derived from monovalent or divalent copper.

The condensation according to method a) is preferably carried out using a reactive functional converted hydroxy group or thiol group, which are derived from carbodiimide. This group can be an 0-(or S)-derivative of an N,N<1->disubstituted isourea (or isothiourea) with the characteristic formula in which X has the above meaning and a and b mean optionally substituted hydrocarbon residues, e.g. e.g. especially cyclohexyl. Preferably, the reactive ester of this type is produced in situ and reacted. It is heated, e.g. a mixture of a reagent to be esterified, especially an N,N'-disubstituted derivative of carbodiimide, e.g. preferably N,N'-dicyclohexylcarbodiimide and the starting substances II and III, in which W and Y are in the form of a free hydroxy or thiol group. In other cases, one of the starting materials, preferably at a temperature between 50° and 200°C, can be reacted with the N,N'-substituted carbodiimide, preferably in the presence of copper I chloride, and the isourea or isourea derivative is prepared. The second starting material is then added and heated further to produce the product mixture.

The condensation according to method a) can also be carried out according to a further known method. A reactive esterified form of a group XH is preferably one in which hydroxy or the thiol group is esterified with a strong organic acid, e.g. an aliphatic or aromatic sulfonic acid (e.g. a lower alkanesulfonic acid, especially methanesulfonic, trifluoromethanesulfonic and ethanesulfonic acids, or with an arylsulfonic acid, especially benzenesulfonic, p-toluenesulfonic, p-bromobenzenesulfonic and p-nitrobenzenesulfonic acids) or with a strong inorganic acid, e.g. especially sulfuric acid or a hydrohalic acid, e.g. hydrobromic, hydroiodic or preferably hydrochloric acid, or if it is bound to an Ar residue, especially with hydrofluoric acid. If the symbol W or Y means a group XH esterified with a halogen hydrogen acid, then it actually stands for the corresponding halogen atom, namely for a bromine atom, iodine atom or preferably chlorine atom, in connection with a residue Ar, for a fluorine atom.

If in a starting substance ArY the symbol Y means a halogen atom, especially fluorine, then it is advantageous when an activating group is in the ortho or para position, e.g. trifluoromethyl, alkylsulfonyl or alkylsulfinyl. A particularly favorable starting material is p-fluoro-benzotrifluoride (p-trifluoromethyl-fluoro-benzene). If the condensation according to method a) is carried out as described above, then one works at temperatures between 0°C and the boiling point of the reaction mixture, preferably between room temperature and 100°C. Preferably, the reaction is carried out in the presence of a solvent inert to the reagents, e.g. in an acyclic or cyclic ether (such as diethyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran), and especially in the presence of a tert..-amide (which has a low molecular weight), e.g. N,N-dimethylformamide, N-methylpyrrolidone, N-ethylpiperidone and hexamethylphosphoric triamide. If a strong acid is released during the condensation, it is preferably bound by the addition of an acid-binding agent, e.g. an alkali metal carbonate or hydroxide, or especially a very strong base, e.g. an alkali metal hydride (eg sodium or potassium hydride), or alkoxide (eg sodium methoxide or ethoxide, potassium tert-butoxide) or amide (eg lithium diisopropylamide). Starting from a compound of formula II, in which W means halogen (preferably chlorine), it is advantageous to convert the corresponding reactant of formula III, in this case the phenol, first, into the corresponding phenoxide, especially alkali metal phenoxide (e.g. sodium phenoxide). One works here with an equivalent amount of sodium hydride in a polar, aprotic solvent, e.g. in one of the above mentioned, and carries out the condensation with this salt. By the condensation of the starting material with the formulas II and III, in which the reactive esterified. hydroxy group is formed in situ by the action of an N,N<1->disubstituted carbodiimide, e.g. N,N<1->dicyclohexylcarbodiimide, one works under conditions known per se.

The starting substances of formula III are generally known, or if they are new, they can be easily prepared according to the methods described for the known compounds.

The starting substances of formula II are generally new. They can be produced according to conventional organic syntheses known per se. Thus, one can e.g. condense an α-benzyl acrylic acid lower alkyl ester of formula VIII

in which R^ has the above meaning and R is lower alkyl / for the preparation see R.B. Miller and B.F. Smith, Synth. Commun. 3_, 359 (1973)_7, with an above-defined secondary amine of formula IV. One works in a lower alkanol under the conditions of Michael addition, and the formed α-benzyl-B-amino-propionic acid lower alkyl ester with the formula

in which R 1 , R 2 and R 2 have the meaning given above and R is lower alkyl, is reduced with a complex hydride, preferably lithium aluminum hydride or an equivalent carbonyl reducing agent, to the corresponding alcohol, namely to a compound of formula II, in which W means hydroxy. If desired, this hydroxy group can be converted by conventional means into a reactive esterified form. One an-

facing e.g. for the preparation of the preferred chloride (W = Cl) the reaction with thionyl chloride, phosphorus trichloride, phosphorus oxychloride or a similar reagent.

The intermediates of formula IX can also be formed by

a) transfer of e.g. a lower alkyl ester of B-(NR^R2)-substituted propionic acid in an α-metallated derivative, e.g. in

the α-lithium derivative with lithium diisopropylamide and, b) subsequent reaction of the α-metallated derivative formed with a compound of the formula IXA

in which R 3 has the meaning given above and P means a reactive esterified hydroxy group defined above, especially halogen, e.g. chlorine. One works in a suitable solvent, e.g. tetrahydrofuran, optionally in the presence of another solvating agent, e.g. hexamethylphosphorus amide.

Method b) is carried out according to methods known per se, which are referred to as alkylation of amines. In the starting substances with the formula V, the group Z (replaceable with amino) can mean in particular a hydrogen atom together with a reactive esterified hydroxy group, or mean the oxo group. In the former case, the amine alkylation takes place under the general conditions for substitutive alkylation of amines, while in the second case the conditions for reductive alkylation of amines are used.

The condensation according to method b)

is carried out under the conditions of the reductive alkylation of amines in a manner known and used per se. A compound of the formula V, in which Z means the oxo group and X, Ar, R 1 and n have the meanings given above, is used as an alkylating agent. This is traded with what. starting material

used amine IV, and in the same or subsequent reaction step reacted with a reducing agent. Among the reducing agents used at the same time as the alkylating agent, mention should be made of the complex metal hydrides, such as sodium cyanoborohydride. Such reducing agents which are mainly used in a separate subsequent step should be mentioned the diborane and complex metal hydrides, such as sodium borohydride and sodium cyanoborohydride, which are preferably used in the primary reaction mixture, without isolation of the intermediate product. In this case, the alkylation is preferably carried out in a solvent inert to the reducing agent. These are aliphatic or cyclic ethers (e.g. diethyl ester, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran) or an aliphatic alcohol (e.g. methanol, ethanol, isopropyl alcohol, glycol, glycol monomethyl ether or diethylene glycol), which are preferably used at approx. 0°-80°C. They are, however, the most important reducing agent that can be used both simultaneously and subsequently, hydrogen, especially catalytically activated hydrogen. The catalysts are the conventionally used hydrogenation catalysts, preferably those from the group of noble metals (e.g. palladium, platinum and rhodium), on a support material (e.g. carbon black, calcium carbonate, aluminum oxide or barium sulfate), in a finely dispersed suspension without carrier material, or in the form of complexes, in a homogeneous phase. Also finely dispersed transition metals, e.g. Raney nickel are very suitable catalysts for the reductive alkylation. The specific reaction conditions are highly dependent on the hydrogenation catalyst in question and on its specific activity. They do not differ from those known for their hydration. The temperature range between room temperature and 150°C and a hydrogen pressure between atmospheric and approx. 300 atmospheres can be used according to the usual standard methods. In addition to the inert solvents mentioned above in connection with the hydride reduction, lower molecular amides can also be used, especially tertiary amides (e.g. N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N-ethylpiperidone and hexamethylphosphoric acid triamide) as well as formamide and acetamide, as a suitable solvent. Special preparations must be made for starting substances with formula V, where X means sulphur. As most hydrogenation catalysts are inactivated by sulfur compounds, other reducing agents (e.g. the above-mentioned complex metal hydrides, especially sodium cyanoborohydride) are to be preferred in this case.

The amines of formula IV used as starting materials are known compounds. The new starting materials of the formula V can be obtained according to conventional synthetic methods. E.g. starting from a compound with the formula X

in which R-j, X and Ar have the meanings mentioned above, and R means hydrogen or lower alkyl, compounds of formula V are obtained.

Intermediates of the formula X can more advantageously be prepared by condensation of a compound of the formula VIII with a compound of the formula Ar-XH, in which X stands for 0, S or N-lower alkyl, or their alkali metal salts, under the general conditions of the Michael addition.

Procedure c) can also be carried out in a manner known per se, under conventional conditions. The double bond in the starting materials in method c) can either be between the nitrogen atom and a neighboring carbon atom or between two carbon atoms. Thus, a carbon bond can be between the nitrogen atom and any of the neighboring carbon atoms, while a further carbon-carbon double bond can be on the central carbon atom. Such starting materials can also be used in which only one carbon-carbon double bond is present. In these, the double bond is between the central carbon atom and any of the neighboring carbon atoms. The starting materials for method 5) can be indicated with the formula Xlla in which R1, R3, Ar and X have the meanings given above, and the dotted lines mean a possibly present double bond, or with the formula Xllb

in which Ry n, Ar and X have the meanings given above, R^ means a lower alkylidene residue and the dotted lines mean a possibly present double bond, or with the formula

XIII

in which R.j , B.^ > R3» Ar °9 x have the meanings indicated above and the dotted lines mean a double bond.

Method d) can be carried out in a manner known per se, in particular under the conditions of cleavage of an amino protecting group. Suitable protecting groups as well as methods for their introduction and cleavage are sufficiently known from the literature. These have especially been developed in detail as general methods for the synthesis of peptides. Reference should be made, e.g. to Houben-Weyl: Methoden der organischen Chemie, 4th edition, vol. 15/1 and II, E. Wunsch (publisher): Synthese von Peptiden (Georg Thieme Verlag, Stuttgart, 1974).

Suitable amino-protecting groups (RQ) are especially those which can be cleaved by reduction. Special mention should be made of such groups, e.g. the benzyl or benzyloxycarbonyl groups which in the aromatic part may be substituted with halogen, lower alkoxy, lower alkyl and preferably with nitro groups. In other cases, the amino protecting group is isonicotinyloxycarbonyl.

The benzyl, benzyloxycarbonyl and isonicotinyloxycarbonyl amino protecting groups can be easily cleaved in the usual way by hydrogenolysis, especially over a noble metal catalyst. Such groups containing isonicotinyl residues (e.g. isonicotinyloxycarbonyl) and especially substituted benzyl residues, primarily 4-nitrobenzyl residues of any kind, can preferably be cleaved by reduction with zinc, usually in the presence of an acid, preferably acetic acid, and with or without addition of an inert solvent, usually at room temperature.

The use of RQ groups which are cleavable by acidolysis is also possible. Such are cyan, tert.-butyloxy-carbonyl and analogous groups, but also those of the aralkyl type such as benzhydryl, di-(4-methoxy)-benzhydryl and triphenylmethyl (trityl), or certain araloxycarbonyl groups of the type to 2-(p-biphenylyl )-2-propoxycarbonyl type, which are described in Swiss patent document 509 266. The removal of the protective group by hydrolysis in an acidic medium (acidolysis) is carried out by the groups of the tert.-butyl type with acids such as hydrochloric, hydrofluoric or trifluoroacetic acid, and in the case of acid-sensitive protecting groups mainly with lower aliphatic carboxylic acids such as formic and/or acetic acid, in the presence of water, and, optionally in the presence of a polyhalogenated lower alkanol or lower alkane, e.g.

1,1,1,3,3,3-hexafluoropropan-2-ol or hexafluoroacetone. In this way, it is possible e.g. to cleave off an N-trityl group

with an organic acid, e.g. formic acid, acetic acid, chloroacetic acid or trifluoroacetic acid, in aqueous solutions or in absolute trifluoroethanol as solvent (cf. BRD official document DT 2 346 147) or with aqueous acetic acid.

Furthermore, e.g. The tert.-butoxycarbonyl group is cleaved off with trifluoroacetic acid or hydrochloric acid; The 2-(p-biphenylyl)-isopropoxycarbonyl group can be cleaved with aqueous acetic acid or e.g. with a mixture of acetic acid-formic acid (82.8%)-water (7:1:2) or according to the method according to DT 2 346 147. An advantageous amino-protecting group RQ is also the ethoxycarbonyl group, which in the 3-position carries a silyl group substituted with three hydrocarbon residues, e.g. triphenylsilyl, dimethylbutylsilyl or especially trimethylsilyl. A 3-(trihydrocarbyl-silyl)-ethoxycarbonyl group of this type, e.g. a 3-(tri-lower alkyl-silyl)-ethoxy-carbonyl group, e.g. in particular the 3-(trimethylsilyl)-ethoxycarbonyl forms with the amino group to be protected, a corresponding 6-trihydrocarbylsilyl-ethoxycarbonylamino group (e.g. ^<:->trimethylsilyl-ethoxycarbonylamino group).

These can preferably be cleaved with reagents that release fluoride ions, e.g. with fluorides of quaternary organo-

isic bases, e.g. tetraethylammonium fluoride. Cyan-

the group is preferably split off by hydrolysis with a strong mineral acid, e.g. concentrated hydrogen chloride

acid, according to Chem. Pray. 68, 2291 (1935).

The starting materials for method d), namely

the compounds of formula VI defined above are new. They can be obtained according to a method already described above, preferably method a). The only difference is that the starting materials carry nitrogen-

the atom the group -NR-^R,, instead of the residue R^ carries the amino protecting group Ro>

The isolation of the desired product with

the formula I is carried out according to separation procedures known per se, e.g. by fractional

distillation or crystallization, thin-layer

chromatography or high pressure liquid chromatography.

Compounds according to the invention,

which are obtained according to any of the methods described above, can be converted in another according to conventional methods corresponding to the state of the art or, for example, as described below.

Compounds of the formula I, in which R1 and/or R2 means hydrogen, can be converted into compounds of the formula I, in which R1 and/or R2 stand for lower alkyl, as they are reacted with a reactive ester of a lower alkanol, e.g. with a lower alkyl halide. The formed compound of formula I is preferably isolated as the corresponding acid addition salt. But you can also alkylate reductively, e.g. with formaldehyde and formic acid, whereby compounds of the formula I are obtained, in which R 1 and/or R 2 means methyl.

Compounds of formula I, in which R 1 and R 2 mean lower alkyl, preferably methyl, can be converted into compounds of formula I, in which R 1 or R 2 stands for hydrogen, by catalytic air oxidation, e.g. with palladium-on-charcoal, using an alcohol as solvent, e.g. methanol, preferably at room temperature. But you can also react with haloformic acid lower alkyl esters, e.g. chloroformic acid ethyl ester. N-acyl derivatives are obtained, which can be hydrolysed to the aforementioned unsubstituted compounds, such as those with R1 or R2 = H, e.g. with a base, such as an alkali metal hydroxide, e.g. with a sodium hydroxide solution in aqueous alcohol.

Compounds with the formula I, in which R 1 and/or R 2 mean methyl, can be obtained from the corresponding compounds, in which R 1 and/or R 2 stand for hydrogen, by reaction with haloformic acid lower alkyl esters or phenyl lower alkyl esters, e.g. haloformic acid ethyl ester, is converted into compounds of the formula I, in which or R 2 is alkoxycarbonyl or phenyl-alkoxycarbonyl. After reduction of this acyl derivative with simple or complex light metal hydrides, e.g. lithium aluminum hydride, sodium tri-tert.-butoxy aluminum hydride or sodium bis-(2-methoxyethoxy) aluminum hydride, the compounds are obtained in which R1 and/or R2 means methyl.

Unsaturated compounds, e.g. such which contain an alkenyl or alkynyl residue can be converted with catalytically activated hydrogen into the compounds of formula I or intermediates which have the corresponding alkyl residue.

In all of the above-mentioned reactions, it can be advantageous to protect the potential reactants, e.g. amino, carboxy or other interfering substituents, according to the protection methods known per se. The work will e.g. as illustrated below, to avoid the disturbing reactions. Such substituents are protected before the desired reaction and, if desired, the protecting groups are later cleaved off, whereby the desired compounds are obtained, e.g. those of formula I or intermediates. Thus, e.g. a free basic amino group, the group -NR^R2, which contains at least one hydrogen atom on the nitrogen atom, is protected in the form of easily cleavable amides, e.g. as acyl derivative as benzyloxycarbonyl (carbobenzyloxy-) or as tert.-butyloxycarbonyl derivative or with other easily cleavable N-protecting groups as described above.

In an analogous way, a carboxy group can be protected in the form of an easily cleavable ester, e.g. benzyl ester, butyl ester, or another commonly used ester. In a formed protected compound of formula I or in an intermediate product, in which one or more functional groups are protected, the protected functional groups, e.g. amino or carboxy groups, are released according to methods known per se, e.g. solvolysis, especially hydrolysis with an acid or by reduction, especially hydrogenolysis.

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

The compounds produced according to the present invention are finally obtained either free or in the form of their salts. Each base formed can be converted into a corresponding acid addition salt, preferably using a therapeutically acceptable acid or an anion exchanger. Formed salts can be converted into the corresponding free bases, e.g. using a stronger base, for example a metal or ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchanger. These or other salts, such as picrates, can also be used for purification of the formed bases, as one transfers the bases into salts, separates them and cleans them, and frees the bases again from the salts. Due to the close relationship between the free compounds and their salts, in this context free compounds are also always possibly the corresponding salts. The compounds and their salts can also be obtained in the form of their hydrates, or they can comprise other solvents used for crystallization.

The preparations deal with those for enteral, oral or rectal use, as well as for parenteral administration to mammals, including humans.

The pharmaceutical preparations according to the invention contain at least one compound of formula I, or one of their therapeutically acceptable salts as active ingredient, possibly together with one or more therapeutically acceptable carriers.

The pharmacological compounds used can be used for the production of pharmaceutical preparations, which contain an effective amount of active substance together with or in mixture with carriers, which are suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules are used which contain the active substance together with fbr thinner, e.g. lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and/or glycine, and lubricants, e.g. diatomaceous earth, 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 pastes, gelatins, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, explosives, e.g. starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or fizzy mixes or adsorbents, colourants, flavorings and sweeteners. Injectable preparations are preferably isotonic solutions or suspensions and suppositories are primarily fat emulsions or suspensions. The pharmacological preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting and/or emulsifying agents, solubility mediators, salts for regulating the osmotic pressure and/or buffer. The present pharmaceutical preparations, which, if desired, can contain further pharmacologically valuable substances are produced on

in and of itself known way, e.g. using conventional mixing, granulating or coating methods, and contains from approx. 0.1% to approx. 75%, especially from approx. 1% to approx. 50% active ingredient.

The compounds prepared according to the present invention can be used for the treatment of psychotropic disorders, especially depression. The dosage of the active substance depends on the nature of the warm-blooded creature, its body weight, age and individual condition as well as the method of application. Single doses for mammals with a weight of approx. 50-70 kg can contain between approx. 10-100 mg of the active ingredient.

The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporation operations are carried out at reduced pressure, preferably between approx. 15 and 100 mm Hg.

Example_el_1

A mixture of 4.2 g of 2-benzyl-3-dimethylaminopropanol, 4.6 g of dicyclohexylcarbodiimide and 0.2 g of copper (I) chloride is kept for 40 hours at 80°C. 5.0 g of 4-trifluoromethylphenol is then added and the mixture is allowed to stand for a further 12 hours at 130°C. The reaction mixture is cooled and 100 ml of ether is added. The insoluble components are filtered off and the filtrate is extracted with 2-n. hydrochloric acid (3 x 100 ml). The acidic extracts are combined and made basic by the addition of concentrated aqueous ammonia solution. The aqueous solution is extracted three times with 150 ml of ether each time, the combined extracts are dried over magnesium sulfate and evaporated in vacuo, whereby the desired ether is obtained as a yellow oil. This is converted into the oxalate by dissolving it in ether and adding the calculated amount of oxalic acid dihydrate, dissolved in ether. Filtration gives N,N-dimethyl-2-benzyl-3-(4-trifluoromethyl-phenoxy)propylamine oxalate. Melting point 147-149°C.

The starting material is prepared as follows: A solution of 30.0 g of α-benzyl acrylic acid methyl ester, prepared according to the method according to R.B. Miller and B.F. Smith /Synth. Commun. 3, 359 (1973)_7, in 50 ml of methanol is added to 71.0 g of dimethylamine, dissolved in 210 ml of methanol, and the mixture is stirred for 48 hours at room temperature. The solvent is evaporated in vacuo and 2-benzyl-3-dimethylaminopropionic acid methyl ester is obtained as a yellow oil which is used further without purification; NMR: δ 7.14 (s, 5H), 3.52 (s, 3H), 2.82 (m, 3H), 2.17 (s, 6H), 2.63-2.17 (m, other H).

A solution of 60.0 g of 2-benzyl-3-dimethylamino-propionic acid methyl ester in 300 ml of ether is slowly added dropwise in a nitrogen atmosphere with stirring to a suspension of 28.0 g of lithium aluminum hydride in 700 ml of ether. The reaction mixture is boiled for 4 hours under reflux and then stirred for 18 hours at room temperature. The mixture is cooled to 0°C and carefully, first drop by drop, 30 ml of water and then 60 ml of 10% aqueous sodium hydroxide solution are added. The solid inorganic components are filtered off and the filtrate is dried over magnesium sulphate. After evaporation of the solvent in vacuo, 2-benzyl-3-dimethylaminopropanol is obtained as an oil which is used without further purification; NMR (CDCl 3 ): δ 7.12 (m, 5H), 5.62 (broad s, 1H), 3.57 (m, 2H).

Example_el_2

A mixture of 5.0 g of 2-(3-chlorobenzyl)-3-dimethylamino-propanol, 3.3 g of 4-methylmercaptophenol and 4.5 g of dicyclohexylcarbodiimide is kept for 72 hours at 180°C. The reaction mixture is cooled to room temperature and 100 ml of ether and 120 ml of 1-n are added. hydrochloric acid. The aqueous phase is separated, washed further with 100 ml of ether, then made basic by the addition of concentrated aqueous ammonia solution and extracted with 2 x 100 ml of ether. The last ether extracts are combined, dried over potassium carbonate and the solvent evaporated in vacuo. By treating the oil formed with oxalic acid, dissolved in ether, N,N-dimethyl-2-(3-chlorobenzyl)-3-(4-methylmercaptophenoxy)-propylamine oxalate is obtained, melting point 122-124°C.

Example_3

In an analogous way, according to the methods described in examples 1 and 2, the following compounds of formula I are obtained, which are isolated and characterized in the form of their oxalates (Me = methyl; Ph = phenyl):

The new starting materials are produced as follows:

a) a-(chlorobenzyl)acrylic acid ethyl ester is prepared as follows: A solution of 26 g of potassium hydroxide in 375 ml of abs. ethanol is added over the course of 30 minutes to an ice-cold solution of 112 g of 3-chlorobenzylmalonic acid diethyl ester in 375 ml abs. ethanol. The solution is stirred for 18 hours at room temperature and then the solvent is drawn off under vacuum. The residue is dissolved in 1200 ml of water and the solution thus formed is cooled in an ice bath. 29 ml of concentrated hydrochloric acid are added and the solution is extracted with 2 x 350 ml of ether. The combined ether extracts are washed with 250 ml of water, dried over magnesium sulphate. and evaporated in vacuo, whereby 3-chlorobenzylmalonic acid monoethyl ester is obtained as an oil; NMR (CDCl 2 ): <S 10.13 (s, 1H), 7.2 (m, 4H), 4.15 (q, 2H), 3.5 (m, 3H), 1.21

(t, 3H).

In a flask that is cooled with a water bath, 27.6 g (39 ml) of diethylamine are added dropwise while shaking to 90.0 g of 3-chloro-benzylmalonic acid monoethyl ester /Chem. Pray. 92^, 203

(1959)_7. While maintaining the cooling, 38 ml of an aqueous formaldehyde solution (37%) is also carefully added while shaking. Gas formation is observed and the color of the reaction mixture becomes light. The elanding is stirred for 65 hours: at room temperature, then 500 ml of water is added, after which the solution is extracted with 2 x 350 ml of ether. The combined ether extracts are first washed with 300 ml of water, then 2 times with each time 200 ml of 3-n. hydrochloric acid and further with 300 ml of water. The ether solution is dried over magnesium sulfate and the solvent is removed in vacuo, whereby α-(3-chlorobenzyl) acrylic acid ethyl ester is obtained as a yellow oil. NMR (CDCl 2 ): 7.15 (m, 4H), 6.22 (s, 1H), 5.45 (m, 1H), 4.13 (q, 2H), 3.58 (s, 2H) , 1.23 (t, 3H). o-(4-Chlorobenzyl)acrylic acid ethyl ester is prepared according to an analogous method, whereby one starts from 4-chlorobenzylmalonic acid diethyl ester (J.Med.Chem. V7, 732 (1974); NMR (CDCl3): <5 7.15 (m, 4H) , 6.17 (s, 1H), 5.38 (m, 1H), 4.11 (q, 2H), 3.55 (s, 2H), 1.20 (t, 3H). b) The following esters are prepared according to the method described in example 1 under the reaction conditions indicated below: c) The following alcohols are prepared according to the method described in example 1:

Eczema gel_4

A solution of 25.0 g of N-carbethoxy-N-methyl-2-benzyl-3-(4-trifluoromethylphenoxy)propylamine and 25.0 g of potassium hydroxide in 200 ml of isopropanol is refluxed for 48 hours. The reaction mixture is cooled to room temperature and the solvent is evaporated in vacuo. 250 ml of water is added and the mixture is extracted with 2 x 150 ml of dichloromethane. The combined dichloromethane extracts are washed with 150 ml of water, dried over magnesium sulphate and the solvent is evaporated in vacuo, whereby an oil is obtained. This is dissolved in 500 ml of ether and dry hydrogen chloride is introduced until no further solid is precipitated. The solid is filtered off, washed with 250 ml of ether, dried and N-methyl-2-benzyl-3-(4-trifluoromethylphenoxy)propylamine hydrochloride is obtained. Melting point 161-162°C, a compound of formula I, in which R1 is methyl, R2 and R3 are hydrogen and Ar is 4-trifluoromethylphenyl. The oxalate which is prepared in the usual way has a melting point of 173-175°C.

The starting material is produced as follows:

A solution of 22.0 g of N,N-dimethyl-2-benzyl-3-(4-trifluoromethylphenoxy)propylamine and 34.1 g (30.0 ml) of ethyl chloroformate in 200 ml of dry toluene is refluxed for 72 hours . The reaction mixture is cooled to room temperature and the solvent is evaporated in vacuo. 200 ml of water are added and the mixture is extracted with 2 x 150 ml of dichloromethane. The combined dichloromethane extracts are washed with 200 ml of 2-n hydrochloric acid and 200 ml of water and then dried over magnesium sulphate. The solvent is evaporated in vacuo and N-carbethoxy-N-methyl-2-benzyl-3-(4-trifluoromethylphenoxy)propylamine is obtained as an oil, which is further used without purification.

Example_el_5

A solution of 7.0 g of N-benzyl-N-methyl-2-benzyl-3-(3-methoxyphenoxy)propylamine in 100 ml of ethanol is hydrogenated at room temperature and at atmospheric pressure until the hydrogen uptake ceases, whereby as a catalyst 2.0 g 10% palladium-on-charcoal catalyst. The catalyst is filtered off and the solvent is evaporated in vacuo, whereby N-methyl-2-benzyl-3-(3-methoxyphenoxy)propylamine is obtained as an oil which is reacted with oxalic acid, dissolved in ether, to N-methyl-2-benzyl-3-( 3-Methoxyphenoxy)propylamine oxalate, melting point 127-129°C.

The starting material, as oxalate, which is produced according to the method in example 2, has a melting point of 79-81°C.

Eczema gel_6

The following compounds of formula I, in which R^ is hydrogen and X is oxygen, and which are isolated and characterized as oxalates, are prepared in a similar manner to the compounds in examples 4 and 5, analogously to the methods described there (Me = methyl, Ph = phenyl ):

A starting material for example 6/1 is N,2-dibenzyl-N-methyl-3-(4-methoxyphenoxy)propylamine oxalate, melting point 147-149°C.

Example_el_7

4.2 g of a 50% sodium hydride dispersion in mineral oil are washed 3 times with 100 ml of petroleum ether each time and dried in a dry stream of nitrogen. 65 ml of dimethylformamide which has been dried with a molecular sieve (4Å) is added. A solution of 14 g of 2-benzyl-3-dimethylaminopropanol in 30 ml of dry dimethylformamide is also added while stirring. Stirring is continued for 10 minutes at room temperature and then for a further 1 hour at 55°C. A solution of 12.0 g of 4-fluorobenzotrifluoride in 25 ml of dry dimethylformamide is then carefully added dropwise, the reaction mixture is stirred for 6 hours at 60°C and then for a further 18 hours at room temperature. 300 ml of water is added and the solution is extracted with 2 x 200 ml of ether. The combined ether extracts are extracted with 2 x 150 ml of 3-n. hydrochloric acid. The combined acidic extracts are washed with 200 ml of ether and made basic by the addition of concentrated aqueous ammonia solution. The aqueous solution is extracted with 2 x 250 ml of ether, the combined ether extracts are washed with 100 ml of water and dried over magnesium sulphate. The solvent evaporates

in vacuum and you get N,N-dimethyl-2-benzyl-3-(4-trifluoromethyl-phenoxy)propylamine which is identical to the compound from example 1 and which can be converted to N,N-dimethyl-2-benzyl-3- (4-trifluoromethylphenoxy)propylamine oxalate as described in Example 1.

Example_el_8

A mixture of 2.0 g of 10% palladium-on-charcoal catalyst and N,N-dimethyl-2-benzyl-3-(2-methoxyphenoxy)propylamine - 2 g of the oxalate melting at 76 is used -79°C during cleavage - in 300 ml methanol is stirred for 18 hours in an open flask at room temperature. The catalyst is filtered off and the solvent is evaporated in vacuo. The remaining oil is reacted with an equivalent amount of oxalic acid, dissolved in ether, to N-methyl-2-benzyl-3-(2-methoxyphenoxy)propylamine oxalate, melting point 135-139°C.

Example_el_9

A solution of 12.6 g of N-methyl-N-acetyl-2-benzyl-3-(4-methylthiophenoxy)propylamine in 100 ml of dry ether is carefully added dropwise to a stirred suspension of 4.0 g of lithium aluminum hydride in 250 ml of dry ether. The reaction mixture is boiled for 18 hours under reflux and then cooled to 0°C. Carefully add 3 ml of water, then 3 ml of 15% caustic soda and several times 9 ml of water. The inorganic salts are filtered off, washed with 150 ml of ether and the combined ether extracts are dried over magnesium sulphate. The solvent is evaporated in vacuo and N-methyl-N-ethyl-2-benzyl-3-(4-methylthiophenoxy)propylamine is obtained. Melting point 98-100°C.

The starting material is prepared as follows: By reacting N-methyl-2-benzyl-3-(4-methylthiophenoxy)propylamine with acetyl chloride in dichloromethane at room temperature in the presence of triethylamine, N-methyl-N-acetyl-2- benzyl-3-(4-methylthiophenoxy)propylamine.

Example_el_1_0

A solution of 3.0 g of N,N-dimethyl-2-benzyl-3-(4-methylthiophenoxy)propylamine in 350 ml of methanol is added dropwise under nitrogen over 30 minutes to a solution of 4.8 g of sodium periodate in 160 ml of water . After complete addition, the reaction mixture is stirred for 4 hours at room temperature, added to 500 ml of water and extracted with 2 x 250 ml of ether. The combined ether extracts are dried over potassium carbonate and the solvent is evaporated in vacuo, whereby an oil is obtained. After reaction with an equivalent amount of oxalic acid, dissolved in ether, and 3 times crystallization of the formed salt from methanol/ether, N,N-dimethyl-2-benzyl-3-(4-methyl-sulfinylphenoxy)-propylamine is obtained -oxalate, melting point 112-115°C.

Example_el_1_1_

The following compounds of formula I are prepared essentially according to the methods in the above-mentioned examples:

The starting materials are prepared according to the above-mentioned examples: 2-benzyl-3-dimethylamino-propionic acid methyl ester

(see example 1) is also advantageously produced as follows:

1800 ml of methanol is cooled to -35° and added

the one with 500 g of liquid dimethylamine. A solution of 500 g of acrylic acid methyl ester in 850 ml of methanol is then added, whereby the temperature is kept between -50° and -60°. The reaction mixture is kept for 2 hours at -50 to -60° and then overnight at room temperature. The solvent is evaporated in vacuo and the residue is distilled under reduced pressure. The 3-dimethylaminopropionic acid methyl ester is obtained, which boils at 60-70°/16 mm Hg.

A solution of 101 g of diisopropylamine in 200 ml of tetrahydrofuran is cooled under nitrogen to -78° and, at this temperature, 2.1 M n-butyllithium in tetrahydrofuran (470 ml) is added dropwise. The reaction mixture is stirred at this temperature for 1 hour, a solution of 179 g of hexamethylphosphoramide in 200 ml of tetrahydrofuran is added and further stirred at -78° for an hour.

At the same temperature, it is added drop by drop

with a solution of 125 g of N,N-dimethylamino-propionic acid methyl ester in 200 ml of tetrahydrofuran and stirred for a further 20 minutes. At -78°C, a solution of 171 g of benzyl bromide in 300 ml of tetrahydrofuran is then added. The solution is stirred at this temperature for 2 hours, then 250 ml of saturated aqueous ammonium chloride solution and then 250 ml of saturated aqueous sodium chloride solution are added. The mixture is added with 1500 ml of ether. The layers are separated and the aqueous layer is extracted with 4 x 200 ml of ether. The ether extracts are dried over magnesium sulphate and evaporated to dryness. The oil formed is dissolved again in 300 ml of ether, the ether solution is washed with 100 ml of water and the aqueous layer is extracted again with 3 x 100 ml of ether. The combined ether solutions are dried over magnesium sulfate and evaporated to dryness. You get an oil that is purified by fractional distillation. The 2-benzyl-3-dimethylaminopropionic acid methyl ester is obtained, which boils at 104°/0.2-0.4 mm Hg.

Example_el_1_2

The compounds in the above examples are tested for their ability to block the in vitro uptake of tritium-labeled serotonin at rat whole-brain syhaptosomal nerve endings, essentially working according to that of Thornburg and Moore in Res. Comm. Chem. Pathol. Pharmacol. 5_, 81 (1973) described method. The pre-incubation period of the test compound (used in ethanolic solution) with cerebrum synaptosomes suspension in a Krebs buffer solution is 5 minutes. The incubation time after the addition of tritium-labelled serotonin (3H-5-HT) until

-7

a final concentration of approx. 1 x 10 M is 4 minutes. The concentration of the test compound required to reduce serotonin uptake by 50% of a control value, i.e. the IC^Q value, is determined graphically and given in micromolar concentration. The concentration of test compound necessary to reduce norepinephrine (NE) uptake by 50% of a control value, i.e. the ICcri value, is determined similarly

bu 2 way, using tritium-labeled norepinephrine (H-NE) and expressing the value likewise in micromolar concentration.

Example_el_13

Ni,N-dimethyl;2-benzyl 3-^4-me tox

A solution of dimethylamine (2.7 g) and 2-benzyl-3-(4-methoxyphenylthio)-propionaldehyde (5.52 g) in ethanol is hydrogenated completely using 10% palladium on charcoal (0.5 g) as catalyst . The catalyst is filtered off, and the solvent is removed under reduced pressure to give 2-benzyl-3-(4-methoxyphenylthio)-N,N-dimethylpropylamine, purified as oxalate salt, melting point 124-127°C.

The starting material is produced as follows:

A mixture of p-methoxythiophenol (14.0 g), 2-benzylprop-2-enal (M. Brink and E. Schanberg, J. Prakt. Chem. 323, 836 (1981)) (15.0 g) and triethylamine (1 g) is kept at 80°C for 2 4 hours under a nitrogen atmosphere. The reaction mixture is distributed between water (300 ml) and ether (300 ml). The organic phase is washed with saturated aqueous sodium bicarbonate (200 mL) and water (200 mL), dried over sodium sulfate and evaporated under reduced pressure to give 2-benzyl-3-(4-methoxy-phenylthio)-propionaldehyde as an oil, which is used without;, further purification for transfer to the propylamine derivative.

Compounds of the general formula I (X = 0) can be obtained in a similar manner, but the Michael addition is carried out in the presence of a 1 molar equivalent of sodium methoxide.

Example_el_14

Ni5§tYlz2-benzYl;,3-^4-methoxyYf §22?S§YilE£2EYi5mi!}z23S§Si§t

A solution of methylamine (2.2 g), 2-benzyl-3-(4-methoxyphenoxy)-propionaldehyde (5.4 g) and di-n-butyltin dichloride (0.1 g) in dichloromethane (75 ml) is refluxed for 18 hours using a water separator. The solvent is removed under reduced pressure to give the crude imine, which is reduced to the saturated derivative without further purification.

A solution of the imine (6.2 g) in ethanol (75 ml) is completely hydrogenated at room temperature and atmospheric pressure, using 5% palladium on charcoal as catalyst. The catalyst is filtered off and the solvent is removed

to give products like an oil. The substance is transferred to the oxalate salt in a manner known per se, melting point 142-144°C.

The starting material is produced as follows:

A mixture of p-methoxyphenol (12.4 g), 2-benzyl-prop-2-enal (M. Brink and E. Schanberg, J. Prak. Chem. 323, 136 (1981)) (15.0 g) and sodium methoxide (5.4 g) kept at 80°C for 24 hours under a nitrogen atmosphere. The reaction mixture is distributed between water (300 ml) and ether (300 ml). The organic phase is washed with saturated aqueous sodium bicarbonate (200 mL) and water (200 mL), dried over sodium sulfate and evaporated under reduced pressure to give 2-benzyl-3-(4-methoxy-phenoxy)-propionaldehyde as an oil, which is used without further purification for transfer to the propylamine derivative.

Example_el_15

N-dimethyl-2-benzyl-3-4-methoxy

A solution of N,N-dimethyl-2-benzyl-3-(4-methoxyphenoxy)-propionamide (3.1 g) in ether (240 mL) is added dropwise with stirring over 30 minutes to lithium aluminum hydride (1, 2 g) in ether (150 ml) under a dry nitrogen atmosphere. The reaction mixture is refluxed in 6

hours and then cooled to 0°C. The reaction mixture is worked up and the solvent is removed under reduced pressure to give 2-benzyl-3-(4-methoxyphenoxy)-N,N-dimethyl-propylamine, purified as oxalate salt, melting point 120-121°C.

The starting material is produced as follows:

A solution of 2-benzyl-3-(4-methoxyphenoxy)-propionaldehyde (12.0 g), prepared as described in example 3)

in acetone (200 ml) and sulfuric acid (25 ml) is treated with chromium trioxide (7 g) with stirring at room temperature for 24 hours. The reaction mixture is poured onto ice (500 g) and ether (500 ml)

and the ether layer is washed with saturated aqueous sodium bicarbonate (2 x 200 ml) and water (200 ml). The ether solution is evaporated under reduced pressure and the residue is transferred directly to the acid chloride.

A solution of 2-benzyl-3-(4-methoxyphenoxy)-propionic acid (7 g) in thionyl chloride (100 ml) is refluxed for 4 hours. The reaction mixture is evaporated under reduced pressure and the acid chloride is used without purification.

A solution of dimethylamine (3.0 g) and 2-benzyl-3-(4-methoxyphenoxy)-propionyl chloride (6.1 g) in dichloromethane (350 ml) is stirred at room temperature for 18 hours and then poured into saturated aqueous sodium bicarbonate ( 350 ml). The organic phase is washed with water (150 ml), dried over magnesium sulfate and the solvent is removed under reduced pressure to give N,N-dimethyl-2-benzyl-3-(4-methoxyphenoxy)-propionamide which is obtained crystalline after trituration with ether.

Claims (1)

Analogy method for the production of new terra therapeutically active propylamine derivatives of the general formula I wherein each of the symbols R 1 and R 2 means hydrogen or lower alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached mean piperidino, R 2 means hydrogen or halogen, Ar means optionally with one or two substituents from the group lower alkyl, lower alkoxy, lower alkenyloxy, lower alkyl mercapto, lower alkyl sulfinyl, halogen, trifluoromethyl or lower alkylenedioxy substituted phenyl, X means an oxygen atom or sulfur atom, their acid addition salts and their N-lower alkyl or N-benzyl quaternary salts, characterized in that a) a compound of formula II or an acid addition salt thereof, is condensed with a compound of formula III in which R-^, R2, R^ and Ar have the above meaning, one of the symbols W and Y means the group -XH, in which X has the above meaning, and the other means the group XH in reactive esterified form, preferably as an N,N'-disubstituted isourea or isothiourea derivative, or b) an amine of formula IV or an acid addition salt thereof, is condensed under reducing conditions with a compound of formula V wherein Ar, X and R₂ have the above-mentioned meanings, or c) a compound of formula XII in which R^, R'3, Ar and X have the above meaning, is reduced or d) in a compound of formula VI in which / R3, X and Ar have the above meaning, and RQ means an amino protecting group, the group RQ is cleaved off, and a compound of formula I, in which R^ means hydrogen, and the formed compounds of formula I are isolated, and/or if desired, a formed compound of formula I is converted into another compound of formula I, and/or if desired, a formed compound is transferred free compound to a salt or a formed salt to the free compound or to another salt.