CA1111041A - Primary diarylalkyl amines having antidepressive activity - Google Patents

Abstract

Abstract of the Disclosure A limited number of useful compounds having anti-depressive or tranquilizing activity are known. The present invention expands upon the known compounds by providing a compound of the general formula I

wherein the dotted line represents an optional double bond and Ar represents the group

Description

The present invention is related to new compounds of the diarylalkyl-amine type having therapeutic. activity, to methods for preparing such compounds, to pharmaceutical preparations comprising such compounds and to methods of treatment employing such compounds. The invention is also related to inter-mediates useful in preparation of such therapeutically active compounds.
The object of the invention is to obtain compounds having a therapeu-tical activity in the central nervous system, especially an anti-depressive or a tranquilizing activity.
British Patent 1429068 discloses compounds corresponding to the general formula:
Br ~
: Rl ~\ fCH3 ~ CH-CH2 -CH2 -N~

N
having anti-depressive activity. Belgian Patent 835.802 discloses compounds of the general formula:
Br R ~ / C=CH-CH2-N

having anti-depressive activity.
Compounds following ~ithin the general formula H~
C RIII

CH-CH
NHR

are disclosed by prior publications as follows: R =CH30, R =OH, R =RIV=H

and R =Cl, R =OH~ R =CH3~ R V=H having hypotensive properties, by British Patent 765~881; RI=RII=RIII=RIV=H by French Patent 2~215~973; R =R sR =H~

RIV=tertiary butyl having spasmolytic properties, by British Patent 923~942;

R =R =R =H, R V=CH3 having spasmolytic properties, by U.S. Patent 2~46~522.
r - 2 -,"~
.

South African Patent 62/~15~ discloses i.a. a compound having theformula CF

/ \
CH3 CH3-N(CH3)2 claimed to have a therapeutic utility especially as an anti-tussive.
In J. Med. Chem. 1~ 161 (1971) a compound of the formula ~`lCI~

is disclosed as an antidepressant.
General Outline of the Invention According to the present invention it has been found that compounds of the general formula below have advantageous, therapeutic properties:
Ar R
Cll.... CH2-CH-NH2(HA)n X

In these compounds the dotted line represents an optional double bond. These compounds may be divided into two groups defined by the formulae Ar R
~ CH-cH2-cH-NH2(HA)n Ia X
Ar R
- C=CH-CH-NH2~HA)n Ib X

-.. .
. In the compounds of formula I Ar represents the group wherein Y is bound in the 2-, 3- or 4-position and represents a lower alkyl group, a lower alkoxy group, a halogen, a trifluoromethyl group, or Ar represents a pyridyl group bound in the 2-, 3- or 4-position, X represents hydrogen, a lower alkyl group, a lower alkoxy group, a halogen, a trifluoro-methyl group, R is a lower alkyl group, n is zero or 1 and A is an anion of a pharmaceutically acceptable acid, provided that when the symbol represents a single bond, X and Y are both fluorine atoms in the 4-position `~ 10 and R is a methyl group~ n is not zero. By lower alkyl and alkoxy groups are meant groups comprising up to 3 carbon atoms. Halogen may be any of the elements F, Cl, Br or I. Therapeutically acceptable salts and bioprecursors of the compounds of the invention as well as differently hydrated or anhydrous forms of such compounds or salts are within the scope of the invention. By a bioprecursor of a therapeutically active compound is meant a compound which is structurally different from the therapeutically active compound but which ~ on administration to an animal or human is converted in the body to the ; therapeutically active compound.
The compounds of formula Ia above wherein Ar is identical to the group ~ X
contain one asymmetric carbon atom. The remaining compounds of formula Ia ; contain two asymmetric carbon atoms and can therefore exist in two diastereo-; meric forms which can be separated by methods known in the art. Further the : compounds of formula Ia above may be resolved into their optical enantiomers by using optically active acids such as i.a. tartaric acid, mandelic acid, dibenzoyl tartaric acid as known in the art. The compounds of the invention may be used as mixtures of diastereomeric forms or as racemic mixtures of the pure diastereomers or as the pure - : , , .

.-: ,' . :- ~ - :
.: .. . : -.
enantiomers mentioned above. The therapeutic properties may reside to a greater or lesser extent in one of the enantiomers or mixtures mentioned above.
Due to the lack of free rotation in the double bond the compound of formula Ib in which the group Ar is not identical with the group X~

may exist in different stereoisomeric forms, that is in cis-trans isomers or, according to the IUPAC nomenclature ~J. Org. Chem. 35, 2849-2867, September 1970), in an E-form and a Z-form. The compound may be used therapeutically as a mixture of geometrical isomers or in pure E or Z form. The pure geo-metrical isomers may be prepared from an isomer mixture, from an isomer-pure starting material or directly by a stereoselective synthesis.
It should be noted that in the IUPAC nomenclature compounds of formula Ib in the form of pure geometrical isomers which are similar in structure may be named the E-form for one subgroup of compounds and the Z-form for another subgroup. The two structural formulas below illustrate this fact.

Br f H / CH-NH

E-form Z-form 5 _ : :: ::
- ,.

4 ~
;
All the compounds of formula Ib further contain one asymmetric carbon atom.
The compounds of formula Ib may be resolved into their optical enantiomers by using optically active acids such as i.e. tartaric acid, mandelic acid, dibenzoyl tartaric acid as known in the art. The compounds of formula Ib may be used as mixtures especially racemic mixtures, or as the pure enantio-mers of the geometrical isomers mentioned above. The therapeutic properties may reside to a greater or lesser extent in one of the enantiomers or mix-tures mentioned above.
The compounds of the invention show an activity in the central 1~ nervous system which makes them useful as neuropharmacological agents for treatment of various diseases in animals including man. The compounds are expected to be especially useful as anti-depressive, anxiolytic or tranquil-. izing agents in man.

~; Preferred embodiment of the inventionOf the compounds of the invention defined by formula I above those wherein Ar is are to be specially mentioned. Of those the compounds ~herein X is hydrogen are preferred and especially those wherein Y is F, Br or CH30-.
As preferred individual compounds should be mentioned:
~)-3-~4-~lurophenyl)-1-methyl-3-phenylpropylamine, ~)-3-~4-bromophenyl)-1-methyl-3-phenylpropylamine, ` ~a)-3-~4--methoxyphenyl)-1-methyl-3-phenylpropylamine, and ~)-3-~3-bromophenyl)-1-methyl-3-phenylpropylamine being non-selective inhibitors of neuronal noradrenaline and 5-hydroxytryp-tamine uptake;
~a)-3-~2-bromophenyl)-1-methyl-3-phenylpropylamine, .

~,~
' (E)-3-amino-1-(3-bromophenyl)-1-phenylbutene, and ~Z)-3-amino-1-~3-bromophenyl)-1-phenylbutene being selective inhibitors of neuronal noradrenaline uptake; and 3-amino-1,1-di-~4-methoxyphenyL)-l-butene, 3,3-di-(4-fluorophenyl)-1-metllylpropylamine, ` - 6a -- ~ . :: ' : ' ~ ' :

3-(4-methoxyphenyl)-1-methyl-3-phenylpropylamine, and (E)-3-amino-1-(4-bromophenyl)-1-phenylbutene, being selective inhibitors of neuronal 5-hydroxytryptamine uptake; as well as salts and precursors of said compounds. The neuronal uptake mechanisms are discussed further in the chapter "Pharmacological evaluation" below.
Generally preferred in all classes of the compounds of the invention are those wherein R represents a methyl group.
Methods of Preparation The compounds of the invention may be prepared by (a) reducing a compound of the formula Ar R
CH-CH -C=N-OR' II

wherein Ar, X and R have the meaning defined above and R' is a hydrogen atom or an alkyl, an acyl or an alkylsulfonyl group having 1 to 3 carbon atoms, to obtain a compound of formula Ia. The reduction may be carried out by known methods e.g. employing a hydride reagent such as lithium aluminium hydride, (b) reacting a reactive ester of an alcohol of the formula Ar R

.~ X
wherein Ar, X and R have the meaning defined above and reacting the ester obtained with ammonia. The reactive ester may be obtained by treating the alcohol with a halogenating agent such as thionyl chloride, thionyl bromide or phosphorus tribromide, or with an arylsulphonyl halide such as p-toluene-sulphonyl chloride, (c) reducing a compound of the formula Ar R

X C=CH-CH-NH2 Ib ~ .
,~,1 wherein Ar, X and R have the meaning defined above. The reduction may be carried out by methods known in the art e.g. by catalytical hydrogenation using catalysts SUC}I as Raney nickel, palladium on charcoal, platinum dioxide or rhodium, (d) reacting aketone of the formula Ar R

~ CH-C}12-C--O IV
.' X

wherein Ar, X and R have the meaning defined above, with ammoniumformate or methylammoniumformate according to Leuckart-~allach. The formate may be added as such, or obtained by formation in situ from formamide or methyl formamide, or from formic acid and ammonia or methylamine.
The intermediates of formulae II, III, and IV above are novel.
The intermediates of formula II may be prepared by reacting the ketone of the formula IV above with a hydroxylamine derivative of formula NH20R', wherein R' has the meaning defined above.
The intermediate of formula III may be prepared by hydride reduc-tion of the compound of formula IV which, in turn, may be obtained by 1) reacting an alpha, beta-unsaturated ketone of the formula X ~ CH=CH-C=O
wherein X and R have the meaning defined above, with a metal-organic reagent, such as magnesium, lithium or sodium derivative of an arylhalide of the formula Ar-Y', wherein Ar has the meaning defined above and Y' is a chlorine, bromine or iodine atom, in the presence of catalytic amounts of cuprous ions,

2) reacting a diarylcarbinol of the formula H-Ar VI
X OH

wherein Ar and X have the meaning defined above, first withthionylchloride, then with ethyl acetoacetate in the presence of suitable condensation catalyst such as sodium acetate or the like.

~' i ~ - 8 -4:L

The compounds of formula Ia are preferably prepared by method a).
The reaction according to method a) is preferably performed in diethyl ether with a slight excess of lithium aluminium hydride under inert atmosphere.
The new compounds of :Eormula Ia may be used therapeutically as the racemic mixtures of ~+)- and (-)-forms, which in the usual case are obtained ; at the synthesis. Isomer mixtures obtained may be resolved by methods known per se into the corresponding optically active modifications. If desired, the optically active modification may be prepared by way of direct synthesis, e.g. via an optically active compound as described above.
; 10 The compounds of the formula I of the invention may be prepared by:
~e) Dehydration of a carbinol of the formula Ar R

~ 1 2 2 VII
X 0}1 to a compo~md of formula Ib.
The dehydration of the starting material may be done by means of treatment with hydrochloric acid HCl and heating of the reacting mixture.
The dehydration of the starting material may also be done by means of other types of acid-catalysis, such as by means of sulfuric acid H2S04, phosphoric acid H3P04, potassium hydrogen sulphate KHS04, or oxalic acid ~COOH)2. Other methods for the dehydration of the starting material to the formation of a compound of the formula I are dehydration using phosphoroxichloride POC13 in pyridine, and dehydration with thionylchloride, SOC12, in pyridine. Also a catalytic dehydration of the starting material may be used. The dehydration is in this case carried out at a temperature of about 300 to 500~C using a catalyst such as kaolin, alumina or aluminium oxide.

~ _ 9 _ (f) Reaction of a compo~md of the formula Ar R
X ~ C=CH-CH-Z VIII
wherein Z is a leaving group such as F, Cl, Br, I, OS02R , wherein R is alkyl, aralkyl or aryl, with ammonia or with a derivative thereof such as hexamethylenetetraamine, alkaliphtalimide, lithium bisbenzenesulfeneamide, guanidine, sodium cyanate, sodium azide, a carboxamide or a sulfoneamide.
IVhen an amine derivative is alkylated the product obtained is subsequently hydrolyzed or in some other way converted into a primary amine of formula Ib.
A preferred amine derivative is potassium phtalimide.
This reaction is also useful for preparation of the compounds of formula Ia by employing as a starting material a saturated compound corres-ponding to the compound of formula VIII.
(g) Oxidation (halogenation) of the benzylic carbon atom of a com-pound of formula IX
Ar R R"
~ CH-CH2-CH-N / IX
X R"' e.g. with N-bromosuccinimide, R", R"' being protective groups for the amino function preferably joined as the group R~ .

: O
or alternatively corresponding to one of the amine derivatives specified under f) above, followed by elimination of the group formed by oxidation at the benzyl carbon atom, giving a compound of the formula Ar R R"
C=CII-CH-N
X R"' which is transformed into the compound of formula Ib by splitting off the groups R" and R"', e.g. by hydrolysis or hydrazinolysis. In this manner it is possible to synthesize the compounds of formula Ib from the corresponding saturated compo~mds of formula Ia, by introducing in those compounds protec-tive groups R" and R"~ in a kno~n manner to the obtention of a compound of formula IX.
Obtained compounds of formula I can be converted, if required, into therapeutically acceptable acid addition salts, in anhydrous form or in any 10degree of hydration, by reaction with an acid HA wherein A is as defined above.
The intermediates of formulae VII, VIII, IX and X above are novel.
.: The intermediate of formula VII may be obtained by preparing a Grignard or lithium compound from a halobenzene of the formula .; ~ Hal Hal = Br, Cl : X
and reacting it with an ester of the formula Il I
.~ R" - 0-C-CH2-CH-NH2 wherein R" is an alkyl, aralkyl or aryl group.

The intermediate of formula VII may be isolated (cf. Example 14) 20and subsequently dehydrated or alternatively the crude product in the prepar-ation of formula VII may be dehydrated directly (cf. Example 16).

The intermediate of formula VIII may be obtained fro~ a compound of formula X ~ C=CH-CH -R XI

~ . . .--wherein X, Ar and R haYe the meaning defined above, by oxidation of the allylic carbon to the formation of a compound of the formula Ar R
X ~ C=cH-cll-zl III:l wherein Z represents Z or OH, e.g. by reaction with N-bromosuccinimide (Z = Br) or selenium dioxide ~zl = OH). The latter compound may be trans-formed to a reactive derivative III by treatment with an agent such as SOC12, SOBr2 or PBr3 or with ClS02Rl.

Pharmaceutical preparations In clinical practice the compounds of the present invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, e.g.
the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulphate, sul-phamate, citrate, tartrate, oxalate and the like in association with a phar-maceutically acceptable carrier. Accordingly, terms relating to the novel compounds of this invention whether generically or specifically are intended to include both the free amine base and the acid addition salts of the free base, unless the context in which such terms are used, e.g. in the specific examples would be inconsistent with the broad concept. The carrier may be a solid, semi-solid or liquid diluent or capsule. These pharmaceutical pre-parations constitute a further aspect of this invention. Usually the active substance will constitute from 0.1 to 99 % by weight of the preparation, more specifically between 0.5 and 20 % by weight for preparations intended for in-jection and between 2 and 50 % by weight for preparations suitable for oral administration.

To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for oral application the selected ':
- compound may be mixed with a solid pulverulent carrier, e.g. lactose, sac-charose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinyl-pyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes, and the like, and then compressed to form tablets.
If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solu-tion which may contain, e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet can be coated with a lacquer dissolved in a readily volatile organic 1~ solvent or mixture of organic solvents. Dyestuffs may be added to these coat-ings in order to readily distinguish between tablets containing different active substances or different amounts of the active compounds.
~or the preparation of soft gelatine capsules (pearlshaped closed capsules) consisting of gelatine and for example, glycerol or similar closed capsules, the active substance may be admixed with a vegetable oil. Hard gelatine capsules may contain granulates of the active substance in combina-tion with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.
Dosage units for rectal application can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing from about 0.2 % to about 20 % by weight of the active substance herein described the balance being sugar and a mixture of ethanol, water, glycerol, and propyleneglycol.
Optionally such liquid preparations may contain colouring agents, flavouring agents, saccarine and carboxymethylcellulose as a thickening agent.
Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of .

the active substance preferably in a concentration of from about 0.5 % to about 10 % by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
Suitable daily doses of the compounds of the invention in thera-peutic treatment is 25 to 250 mg for peroral administration, preferably 50 - to 150 mg, and 5 to 50 mg for parenteral administration preferably 10 to 30 mg. A preparation in dosage unit form for oral administration may contain 10 to 50 mg, preferably 10 to 25 mg of active substance per dosage unit.
~orking examples Example 1. PTeparation of 4-(3-bromophenyl)-4-phenylbutan-2-one To 2.4 g ~0.10 mol) of magnesium turnings, covered with 20 ml of anhydrous diethyl ether and treated with some crystals of iodine under nitro-gen atmosphere, 23.5 g ~0.10 mol) of 1.3-dibromobenzene in 80 ml of ether was added. The rate of addition was adjusted, to maintain a gentle reflux of the solvent. When the Mg turnings had disappeared ~30 min) 0.75 g ~0.005 mol) of cuprous bromide was added and the mixture was stirred for 10 min at room temperature. A solution of 13.6 g (0.09 mol) of benzalacetone in 100 ml of ether was added dropwise at ~10C. Then the reaction mixture was al-lowed to reach room temperature for 2 h. The mixture was poured into 400 ml of a 10 % aqueous solution of ammonium chloride, the aqueous layer was sep-arated and the product was extracted with 2 x 200 ml of ether. The ethereal layer was washed with water, dried with Na2S04 and the solvent was evaporated.
The crude 3-~3-bromophenyl)-3-phenylbutan-2-one obtained (26.5 g, 0.086 mol) was added to a solution of 20 g ~0.28 mol) of hydroxylamine hydrochloride in 300 ml of ethanol and 100 ml of anhydrous pyridine. The mixture was heated under reflux for 4 h. After cooling the solvent was evaporated in vacuo and the ketoxime was extracted with ether from an aqueous solution. Washing of the extract with water and drying followed by evaporation of the solvent gave 27.5 g of 4-~3-bromophenyl)-4-phenylbutan-2-one oxime.

. X

Example 2. Preparation of 3-~3-bromophenyl)-1-methyl-3-phenyl-propylamine oxalate. (Method a) To the oxime obtained according to Example 1 ~27.5 g) 100 ml of carbon tetrachloride was added and evaporated twice in order to remove traces of water. The residue was dissolved in a mixture of 300 ml of anhydrous ether and 150 ml of anhydrous tetrahydrofuran. To the stirred mixture 3.5 g ~0.0086 mol) of lithium al~1minum hydride was added in portions under nitrogen atmo-sphere at room temperature. The reaction mixture was stirred for 8 h. Then 25 ml of 2 M NaOH was dropwise added and the precipitated inorganic salts were removed by filtration. The filtrate was shaken with 3 x 300 ml of 1 M
HCl and the combined aqueous layers were made alkaline by addition of 35 ml of 30 % NaOH. Extraction with 3 x 200 ml of methylene chloride, washing, dry-ing and evaporation of the solvent gave 8.9 g of the primary amine as an oil.
To a hot solution of 7.9 g ~0.026 mol) of the amine in 100 ml of isopropyl-alcohol 1.1 g (0.014 mol) of oxalic acid in 10 ml of ethanol was added. 6.2 g of the diamine oxalate was collected. Recrystallization from 160 ml of a mixture of ethanol and isopropylalcohol ~1:1) yielded 4.43 g, mp 134-138C.
Analysis: C calcd 58.5 %, found 58.7 %; H calcd 5.48 %, found 5.80 %; N calcd 4.01 %, found 4.07 %.
Example 3. Separation of 3-~3-bromophenyl)-1-methyl-3-phenyl-propylamine into its diastereomers.
The free amine ~2.9 g, 0.009 mol) obtained from 3.8 g of the oxa-late prepared according to Example 2, was dissolved in 40 ml of ethyl acetate.
A hot solution of 1.1 g ~0.009 mol) of maleic acid in 20 ml of ethanol was added. There was obtained 1.3 g of the maleate. Recrystallization from 18 ml of isopropylalcohol gave 0.65 g of the pure alpha isomer, mp 163-165 C.
The high field part of the NMR spectrum ~COC13) displayed a triplet at 4.1 ppm ~J=7.8 Hz), a quartet at 2.8 ppm ~J=6.2 Hz), a double dublet at 2.0 ppm ttwo protons) and a dublet at 1.5 ppm ~J=6.1 Hz) ~three protons).
Analysis: C calcd 57.15 %, found 57.45 %, H calcd 5.28 %, found 5.35 %; Br calcd 19.01 %, found 19.05 %; N calcd 3.33 %, found 3.20 %; O calcd 15.23 %, found 15.00 %.

4 i The solvents of the first mother liquors of the diamine oxalate prepared accordin~ to example 2 were evaporated and the residue was extracted with ether from an alkaline solution. There was obtained 1.2 g of free amine.
The fumarate was prepared in ethyl acetate from half an equivalent of fumaric acid and recrystallized twice from acetonitrile-isopropylalcohol affording 0.28 g of the pure beta isomer as the diamine fumarate, mp 184-186C.
Analysis: C calcd 59.7 %, found 60.3 %, H calcd 5.6 %, found 5.7 %;
N calcd 3.9 %, found 3.7 %.
Example 4 ~a)-3-~4-fluorophenyl)-1-methyl-3-phenylpropylamine oxalate, mp 186-188 C ~EtOH-EtOAc, 1:1) and ~)-3-~4-fluorophenyl)-1-methyl-3-phenyl-propylamine hydrochloride, mp 171-172C ~EtOAc) were prepared from 4-~3-fluorophenyl)-4-phenylbutan-2-one oxime in accordance with Examples 2 and 3.
Example 5 ~a)-3-~4-bromophenyl)-1-methyl-3-phenylpropylamine maleate, mp 168-170 C ~EtOH-EtOAc, 1:1) and ~)-3-(4-bromophenyl)-1-methyl-3-phenyl-propylamine maleate; mp 161-162C ~i-PrOH-EtOAc, 3:1) were prepared from 4-~4-bromophenyl)-4-phenylbutan-2-one oxime in accordance with Examples 2 and 3.
Example 6 ~a)-3-~4-methoxyphenyl)-1-methyl-3-phenylpropylamine maleate, mp 146-148C ~i-PrOH) and ~)-3-~4-methoxyphenyl)-1-methyl-3-phenylpropylamine maleate, mp 124-133C ~EtOAc) were prepared from 4-~4-methoxyphenyl)-4-phenyl-` butan-2-one oxime in accordance with Examples 2 and 3.
Example 7 ~a)-l-methyl-3-~4-trifluoromethylphenyl)-3-phenylpropylamine maleate, mp 165-166C.
; and ~ l-methyl-3-(4-trifluoromethylphenyl)-3-phenylpropylamine maleate, mp 165-167C.
were prepared from 4-~4-trifluoromethylphenyl)-4-phenylbutan-2-one oxime in accordance with Examples 2 and 3.

Example 8. Preparation of 4-(2-bromophenyl)-4-phenylbutan-2-one To a solution of 24.3 g ~0.13 mol) of 2-bromobenzaldehyde in 80 ml of acetone, 1.0 ml of 10 M NaOH was slowly added at OC. The reaction mixture was allowed to reach room temperature and stirred for another 2 h. Then it was poured into 400 ml of water, to which 10 ml of 2 M HCl had been added.
- Extraction with ether, drying and evaporation of the solvent gave 18.9 g of 2-bromobenzalacetone as an oil. This was dissolved in 150 ml of ether and added to a Grignard reagent prepared from 1,1 g (0.045 mol~ of magnesium turnings 6.6 g ~0.042 mol) of bromobenzene and 0.2 g of CuBr in 150 ml of ether. The mixture was stirred under nitrogen atmosphere for 2 h. It was poured into 450 ml of ice-water to which 18 g of ammonium chloride had been added. Extraction with ether gave 11.0 g of the desired ketone as an oil.
Example 9 (~)-3-~2-bromophenyl)-1-methyl-3-phenylpropylamine maleate, mp 145-146 C ~i-PrOH) and ~)-3-(2-bromophenyl)-1-methyl-3-phenyl-propylamine maleate, mp 135-137C ~EtOH-EtOAc, 1:4) were prepared from 4-~2-bromophenyl)-4-phenylbutan-2-one oxime in accordance with Examples 2 and 3.
Example 10. Preparation of 3-(3-bromophenyl)-1-methyl-3-phenyl-propylamine ~Method d) A mixture of 22.1 g ~0.074 mol) of 4-(3-bromophenyl)-4-phenylbutan-2-one and 230 ml o~ formamide was heated for 8 h at 180C. After cooling water was added and the product was taken up in ether. Drying and evaporation of the solvent gave 30.5 g of a residue.
To this residue 85 ml of conc. hydrochloric acid was added and the mixture was heated under refluxing conditions for 3 h. Water was added and the non basic materials were removed by shaking the reaction mixture with 100 ml of ether. The aqueous layer was separated and made alkaline by addition of 120 ml of 10 M NaOH. Extraction with 3 x 200 ml of ether, drying ~Na2SO4) and evaporation of the solvent gave 12.9 g of the desired amine.

,~

o~

The maleate was prepared by addition of a hot ethanolic solution of 4.9 g of maleic acid into a warm solution of the amine in 100 ml of ethyl acetate. P.ecrystallization from EtOH-EtOAc gave 8.4 g of the maleate, mp 158-161C.
Analysis: C calcd 57.2 %, found 57.5 %; H calcd 5.28 %, found 5.35 %; Br calcd 19.0 %, found 19.1 %; N calcd 3.33 %, found 3.20 %; O calcd 15.2 %, found 15.0 %.
Example 11. Preparation of 3,3-di-~4-fluorophenyl)-1-methyl-propylamine hydrochloride (Mekhod c)

3,3-di-~4-fluorophenyl)-1-methylallylamine (0.9 g, 0.003 mol) as dissolved in 100 ml of ethanol and transferred to a Parr hydrogenation flask.
1.0 ml of concentrated hydrochloric acid was added followed by 0.2 g of 5 %
palladium on charcoal. The hydrogenation was effectuated at a pressure of 3.9 atm for 5.5 h. The reaction mixture was filtered to remove the catalyst and the solvent of the filtrate was evaporated. Crystallization from EtOAc-i-Pr2O gave 0.75 g of the desired product, mp 225-229C.
Analysis: C calcd 64.5 %, found 64.5 %; H calcd 6.09 %, found 6.11 %; C1 calcd 11.9 %, found 11.8 %; F calcd 12.8 %, found 12.7 %; N calcd

4.70 %, found 4.55 %.
By the same method there were prepared from the appropriate ally-lamines:
Example 12.
By the method of Example 11 3,3-di-(4-methoxyphenyl)-1-methyl-propylamine fumarate, mp 153-157C, (~tOH-i-Pr2O) was prepared from the cor-responding allylamine.
Example 13.
By the method of Example 11 1,3', 3"-trimethyl-3,3-diphenyl-propy-lamine oxalate, mp 214-215C, (EtOH-EtOAc) was prepared from the corresponding allylamine.

Example 14~ ~reparation of 4,4-di~(4-bromophenyl)-4-hydroxy-2-butylamine oxalate A solution of 81.5 g ~0.35 mol) 1,4-dibromobenzene in 500 ml of diethyl ether was added to a stirred mixture of 8.3 g ~0.35 mol) magnesium turnings in 25 ml diethyl ether at such a rate that reflux was maintained.
After an additional stirring for 1.5 h at room temperature the mixture was cooled in an ice-bath and a solution of 11.3 g ~0.11 mol) of ethyl 3-amino-butyrate in 25 ml of diethyl ether was added during 15 min.
The mixture was stirred for 1.25 h at ice-cooling and then for 2.5 h at reflux. An aqueous cold solution of 25 g ammonium chloride was slowly added, and after stirring ~he mixture was extracted twice with ether. The ethereal layer was dried over sodium sulphate and the amine was precipitated ~10.9 g, 20 % yield) with oxalic acid dissolved in ether. M.p. 191-194C.
Elemental analysis: C18lll9Br2NO5: Found: C 44.5, H 4.0, N 2.7, and D 16.8 %. Calculated: C 44.20, H 3.91, N 2.86 and 0 16.35 ~.
Examp-le 15. Preparation of 3-amino-1,1-di(4-bromophenyl)-1-butene hydrochloride_~hlethod e) A solution of 3.8 g 4,4-di(4-bromophenyl)-4-hydroxy-2-butylamine oxalate, 25 ml acetic acid and 5 ml conc. aqueous hydrogen chloride was heated under reflux for 30 min. The solvent was evaporated and the residue was made alkaline with sodium hydroxide and extracted twice with ether. The ethereal layer was dried over sodium sulphate and the solvent was evaporated. Ace-tonitrile and hydrogen chloride in ether were added and the hydrochloride of the title compound (1.7 g) was obtained after recrystallization from ace-tonitrile/ether. M.p. 216-220 C.
Elemental analysis: C16H16Br2ClN; Found: C 46.7, H 3.9, Cl 8.8 and N 3.1 %. Calculated: C 46.02, 11 3.86, Cl 8.49 and N 3.35 %.
Example 16. Preparation of 3-amino-1 1-di(4-methoxyphenyl)-1-.

butene fumarate (Method e) A solution of 58.0 g (0.31 mol) of 4-bromoanisole in 300 ml diethyl ether was added dropwise to a stirred mixture of 7.78 g (0.32 mol) magnesium turnings in 250 ml of diethyl ether during 2 h. The mixture was stirred at room temperature for another 1.5 h and then he&ted under reflux for 1.5 h.
The mixture was cooled in an ice-ba~h and a solution o~ 10.3 g ~0.10 mol) ethyl ~-aminobutyrate in 25 ml diethyl ether was added during 20 min. After stirring over night at room temperature an aqueolls solution of 16.6 g (0.31 mol) ammonium chloride was slowly added. The mixture was stirred and then ; made alkaline and filtered. After separation of the ether phase the aqueous phase was extracted with ether. The combined ethereal layers were extracted twice with 2 M hydrogen chloride. The aqueous phase was made alkaline and extracted with ether and dried over sodium sulphate. After evaporation of the solvent 10.1 g of yellow oil was obtained, which was dissolved in 75 ml of acetic acid and 15 ml of conc. aqueous hydrogen chloride.
The solution was heated under reflux for 30 min and then the solvent was evaporated. The residue was made alkaline and extracted with ether. The ethereal layer was washed with water and extracted with 0.5 M hydrogen chlo-ride. The aqueous phase was washed with ether, made alkaline and extracted with ether. After drying over sodium sulphate the ether was evaporated to give 5.9 g of the title compound as an oil in 21 % yield.
The amine was converted to the fumarate, which was recrystallized twice from ethanol/ethyl acetate/hexane to give 6.2 g (17 % yield) of the fumaric acid salt in the form C18H21N2 3/4C4H~04- M-p- 167-167-5 C-Elemental analysis: C21H24NO5: Found: C 67.8, H 6.52, N 3.89and 0 21.5 %. Calculated: C 68.09, H 6.53, N 3.78 and 0 21.60 %.
Example 17 3-amino-1,1-di-(4-fluorophenyl)-1-butene fumarate was prepared according to Example 16. M.p. 225-231C.
Example 18 3-amino-1,1-di-(3-methyiphenyl)-1-butene hydrochloride was prepared according to Example 16. M.p. 216-217.5C.

.~

' Example 19. Preparation of l-(4-bromophenyl~ phenyl-butene Sodium dimethylsulfoxide in DMS0, prepared by heating 3.8 g (0.08 mol) sodium hydride (50 ~ in oil) in lO0 ml dimethylsulfoxide at 80C for 40 min, was mixed with 27.0 g (0.07 mol) propyltriphenyl-phosphonium bromide, prepared by heating propylbromide and triphenyl-phosphine in toluene at re-flux temperature for 14 h. The mixture was stirred under nitrogen atmosphere at room temperature for 1.5 h. Then a solution of 13.1 g (0.05 mol) of 4-bromobenzophenone, in a mixture of 100 ml dimethylsulfoxide and 100 ml of anhydrous tetrahydrofuran was added at room temperature. The reaction mix-ture was stirred for 2 h, then it was poured into l.000 ml of ice-water.
The product was extracted with 3 x 300 ml of ether, the combined ethereal layer was washed with 100 ml of water. Vrying (Na2S04) and evaporation of the solvent gave 18 g of oily residue. After trituration with lO0 ml of di-isopropylether crystals of triphenyl-phosphinoxide was separated by filtration.
Distillation of the filtrate at 4 Pa gave 12.2 g of 1-(4-bromophenyl)-1-phenyl-butene, b.p. 120-130C. Yield 85 %.
Example 20. Preparation of 3-(4-bromophenyl)-3-phenyl-1-methyl-- allylbromide.
To a solution of 22.6 g (0.0786 mol) of 1-(4-bromophenyl)-1-phenyl-butene in 800 ml of carbontetrachloride 14.0 g (0.0787 mol) of N-bromo-succinimide was added. The mixture was heated to reflux temperature after the addition of 0.7 g of alpha, alpha-azabis-butyronitrile. After 3.5 h all NBS had been consumed and the reaction mixture was cooled and filtered. 7.8 g of succinimide was separated and the volume~of the filtrate was reduced to 50 ml by evaporation at 35 C. TLC of a sample on silica in diisopropyl-etherhexane (1:1) showed a new spot at Rf 0.62 (the starting olefin had Rf 0.55). The material was being used without further isolation or purifica-tion due to its hi~h reactivity with nucleophilic agents.

': ' :

:
Example 21. Preparation of 3~ phtalimido)~ 4-bromophenyl)-l-phenylbutene ~Method f) A solution of crude 3-~4-bromophenyl)-3-phenyl~l-methylallyl-bromide (29 g, 0.08 mol) in 50 ml carbon tetrachloride was mixed with 15.0 g (0.08 mol) of N-potassiumphtalimide and 120 ml of anhydrous dimethylformamide.
The mixture was stiTTed at 50 C foT 14 houTs.
Dilution with wateT ~excess) and extTaction of the product with diethylether gave 18 g of an oil after drying and evapoTation of the solvent.
Column chromatogTaphy on silica with diisopropyletheT as the eluent afforded the geometrical isomers: 2.6 g of the ~Z)-form, R~ = 0.30, and 3.7 g of the (E)-form, Rf = 0.26 in diisopropylether-hexane ~1:1).
Example 22. PTepaTation of ~Z)-3-amino-1-~4-bromophenyl)-1-phenylbutene maleate To a stirTed solution of 0.43 g ~0.001 mol) of ~Z)-3-phtalimido-1-~4-bTomophenyl)-l-phenylbutene in 30 ml of methanol 0.25 g ~0.005 mol) of hydTazine hydrate was added at Toom temperatuTe. In ordeT to dissolve all the phtalimide 10 ml of carbon tetTachloride was added. The mixture was stirred and heated at 60C for 2 h. After cooling the solvent was removed in vacuo and the residue was taken up in ether. The product was extracted with 3 x 50 ml of 0.5 M HCl, the combined aqueous layer was made alkaline with 10 M NaOH and extracted with 2 x 50 ml of ether. Drying and evaporation of the solvent gave 0.23 g of the title compound as an oil. The maleate had m.p. 174-176C from ethanol. The UV spectrum in ethanol had ~ max 237 nm.
Elemental analysis: C20H20BrN04; Found: C 57.1, H 4.80, BT 20.3, N 3.10 and 0 15.2 %. Calculated: C 57.43, H 4.82, BT 19.10, N 3.35 and 0 15.30 %.
Example 23 ~E)-3-amino-1-~4-bTomophenyl)-l-phenylbutene oxalate was prepared fTom the coTresponding phtalimide according to Example 22. M.p. 145-148 C.

- . ' :

.

Example 24. Preparation of (Z)-3-amino-1-(3-bromophenyl)-1-phenylbut-l-ene maleàte (Method f) To a stirred solution of 0.43 g (0.001 mol) of (Z)-3-phtalimido-1-~3-bromophenyl)-1-phenylbutene in 40 ml of methanol 0.35 g (0.007 mol) of hydrazine hydrate was added at room temperature. The mixture was heated under reflux for 2.5 h. The solvent was evaporated and the residue was taken up in ether. Extraction with 3 x 25 ml of 0.5 M IICl followed by alkalization of the combined aqueous layer with 10 M NaOH and extraction with 2 x 50 ml of ether gave 0.19 g of residue after drying and evaporation of the solvent.
The maleate was prepared from 15 ml ethylacetate - ethanol (2:1) to give 0.12 g (28 %~. M.p. 198-200C.
Elemental analysis: C20H20BrN04; Found: C 56.3, H 4.7, and N 3.2 %. Calculated C 57.43, H 4.82 and N 3.35 %.
Example 25 (E)-3-amino-1-(3-bromophenyl)-1-phenylbutene hydrochloride was pre-pared from the corresponding phtalimide according to Example 24. M.p. 118-123C.
Example 26 (Z)-3-amino-1-(4-bromophenyl)-1-(3-pyridyl)-butene oxalate was pre-pared from the corresponding phtalimide according to Example 24. M.p.
Example 27. Preparation of 3-(N-Phtalimido)-1-(4-bromophenyl)-1-phenylbutane 3-(4-bromophenyl)-1-methyl-3-phenylpropylamine as the free base (41.2 g, 0.136 mol) was dissolved in 350 ml of acetic acid. Phtalic anhydride (20.0 g, 0.136 mol) was added and the mixture was heated with stirring under refl~x (bath temperature 120C) for 2 h. After cooling the solvent was evap-orated in vacuo. The residue was shaken with a mixture of 800 ml of ether and 500 ml of 2 M Na3H. The ethereal layer was separated and washed with 100 ml 1 M hydrochloric acid. Drying and evaporation gave 49.5 g of a tan oil.
Thin layer chromatography on silica in diisopropylether showed one spot of :

Rf 0.42. NMR showed a four proton multiplet at 7.7 ppm from T~S, character-istic of phtalimides. The material was used without further purification.
Yield 83 %.
Example 28 Preparation of 3-~N-phtalimido)-1-(4-bromophenyl)-` l-phenylbut-l-ene ~Method g) To a stirred solution of 24.6 g ~0.057 mol) 3-~N-phtalimido)-l-~4-bromophenyl)-1-phenylbutane in 400 ml of carbon tetrachloride 10.0 g (0.057 mol) of N-bromosuccinimide was added. The mixture was stirred and 0.5 g of alpha, alpha-azaisobutyronitrile was added as radical initiator. Stirring was continued under reflux temperature for 2.5 h. The reaction mixture was cooled and filtered. Upon evaporation of the solvent 32.4 g of a residue Nas obtained. NhlR of a sample in COC13 showed a double quartet at 5.0 ppm from T~S and a doublet at 6.6 ppm. TLC on silica in diisopropylether showed a spot with Rf 0.28, identical with the Rf-value of the material prepared according to Example 22.
The following examples illustrate how the compound of the present invention may be included in pharmaceutical preparations.
Example 29. Preparation of soft gelatin capsules.
500 g of active substance were mixed with 500 g of corn oil, where-upon the mixture was filled in soft gelatin capsules, each capsule containing100 mg of the mixture ~i.e. 50 mg of active substance).
Example 30. Preparation of soft gelatin caRsules.
` 500 g of active substance were mixed with 750 g of peanut oil, where-; upon the mixture was filled in soft gelatin capsules, each capsule containing 125 mg of the mixture ~i.e. 50 mg of active substance).
Example 3l. Preparation of tablets.
` 50 kg of active substance were mixed with 20 kg of silicic acid of the trade mark Aerosil. 45 kg of potato starch and 50 kg of lactose were mixed therewith and the mixture was moistened with a starch paste prepared from 5 kg of potato starch and distilled water, whereupon the mixture was gran-ulated through a sieve. The granulate was dried and sieved, whereupon 2 kg of magnesium stearate was mixed into it. Finally the mixture was pressed in-to tablets each weighing 172 mg.
Example 32. Preparation of an emulsion.
100 g of active substance were dissolved in 2500 g of peanut oil.From the solution thus obtained, 90 g of ~lm arabic, aroma och colouring agents (q.s.) and 2500 g of water an emulsion was prepared.
Example 33. Preparation of a syrup.
100 g of active substance were dissolved in 300 g of 95 % ethanol, whereupon 300 g of glycerol, aroma and colouring agents (q.s.) and 1000 ml ; of water were mixed therein. A syrup was obtained.

Example 34. Preparation of a solution.
100 g of active substance were dissolved in 2000 g o~ polyoxyethy-lene sorbitane monooleate, whereupon flavouring agents and colouring agents (q.s.) and water to 5000 ml was mixed therein. A drop solution was obtained.
Example 35. Preparation of effervescing tablets.
100 g of active substance, 140 g of finely divided citric acid, 100 g of finely divided sodium hydrogen carbonate, 3.5 g of magnesium stear-ate and flavouring agents (q.s.) were mixed and the mixture was pressed into tablets each containing 100 mg of active substance.
Example 36. Preparation of a drop solution.

100 g of active substance were mixed with 300 g of ethanol, where-upon 300 g of glycerol, water to 1000 ml, aroma and flavouring agents (q.s.) and 0.1 N sodium hydroxide solution (to pH 4.5 to 5.5) was added while stir-ring. A drops solution was obtained.
Example 37. Preparation of a sustained release tablet.
200 g of active substance were melted together with 50 g of stearic acid and 50 g of carnauba wax. The mixture thus obtained was cooled and ground to a particle size of at most 1 mm in diameter. The mixture thus ob-tained was mixed wilth 5 g of magnesium stearate and pressed into tablets each weighing 305 mg. Each tablet thus contains 200 mg of active substance.

- 24a -" ~

Phar~acological evaluation Depressions are considered to be connected with changes in the bio-chemical processes of the brain which processes control the mood. The nature of these biochemical processes are largely unkno~in but in depressive states there is evidence for a decreased activity of - 24b -~5 monoaminergic brain neurons. The monoamines, noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT), are of great interest in this respect.
It has been demonstrated that NA, DA and 5-~T is localised in three different types of neurons and may function as transmittors in the central nervous system. The monoamines are stored in special structures, granules, situated in enlargements of the nerve endings, varicosities. The varicosity is separated from the effector neuron by a space, the synaptic cleft or spatium. As-a result of a nerve stimulation the transmittor is released from the granule into the synaptic cleft and reaches the receptor of the eFfector neuron and generates a nerve impulse. After impulse generation the amines are inactivated by mainly two mechanisms: a re-uptake mechanisrn at the cell membrane and enzymatic conversion by catechol-0-methyltransferas to form methylated metabolites. There is also an inactivating enzyme within the varicosities, monoamine oxidase (MA0), that is stored in the mitochondria and inactivates the amines intracellular-ly. I
When MA0-inhibitors are administered, an increased amount of transmittor substance becomes available for release at the nerve ending.
Another way o-f increasing the amine levels at the receptor is exerted by the tricyclic antidepressants. It has been shown that this type of compOund~inhibits the re-uptake mechanism of NA
and 5-HT, and the antidepresseive action is assumed to be related to the uptake inhibition of NA and 5-HT.
It has been proposed, that some depressions are caused by deficiency in either one of the neurotransmittors and so~e of deficiency in both.
- An antidepressant effect should thus be obtained with compounds which are able to inhibit the re-uptake of one or both NA and

5-HT.
Pharmacological methods The test method described in Europ.J. Pharmacol. 17, 107, 1972.
This method involves the mesurement of the decrease in the uptake - of 14C-5-hydroxytryptamine (14C-5-HT) and H-noradrenaline ~3H-NA) in brain slices from mice after in vivo and in vitro administ ration of the test substance.

'' .

, ~6 Inhibition of the uptake o-F 14C-5-HT and 3H-NA in vitro and i~n vivo The test substances were administered intraperitoneally half an hour before the animals were killed. The midbrain was taken ou-t, sliced and incubated in a mixture consisting of 0.2 nmole of 14C-5-HT, 0.2 nmole of 3H-NA and 11 ~umole of glucose in Z ml of Krebs Henseleit-buffer, pH 7.4,per 100 mg of brain slices. The in- ;
cubation time was 5 minutes with 5 minutes of preincubation before the labelled amines were added.The slices were diSsolved in Soluene@ and the amounts of radioactive amines taken up were determined by liquid scintillation. The doses producing 50 per cent decrease of the active uptake ~ED50) of 14C-5-HT and 3H-NA were - determined graphically from dose response curves. Active uptake is defined as that part of the radioactive uptake which is inhibited by a high concentration of cocaine.
: In the vitro administration method slices of mouse midbrain were preincubated for 5 minutes with solutiOn of the compound to be tested and then incubated as described above. The concentration producing 50 per cent inhibition of the active uptake IC50 f 14c-5 HTand 3-H-NA was determined graphically from dose response curves.
The test results are given in Table I.

l~L~
:
.
Q~ ~
O b~ . (r) ~11 ) CJ) ~) CJ~ (D N
4 > v c~ Q) O ~ O

D -`' C Q O Z N ';r ~ N o ) H 0 111 (r) ~1 ~ N ~ 1~ 10 N
`` 'O O) ' O
. ~ L I c~cc ~ o ~ N
~ Ll ~ ~ 1\1 ~I N U~
c O~ U) O O N O' O O O O
11 O C~_ ~1-.1 L o V
.~ ~ ~ ) o ~ u~ tD ~ ~ m >1 C ~ Ul Cl U~ N tO N O ~ N
o C C Q O Z~ O C O O N O O O
-O L
c ~Y .

LLIO E . 0 oX I
o u~
Q4- .,, OU~
c . . ~ I I I II I I I

O ,1 X I I I II I I I
O r~ ~ IL LL ma~ L ~ h h s L c'S ¢;~

. >

c ~
~ O ~ .
-O 1 ) L, I ~.
C C , I Ir~ O U~l 1~ U~ ~t U~l ~ ' o ' o ~ ~ ~ ~ ~ ~, IQ~ YQQ~ Q

34:~
~ ~ ~n o ~ o I rn rn ~ r~ ~ rD "~
c ,_ In ~ ~
rD Q ~
~ Q ~ O
o ~ - ~
~rl O O
c tD > E r ~ ~r, ~ r~ rr o C r~ r~ o~ r~ Ln ~n ~ o H ~ ~ -- Z
4 L l_ ~ C r5 O Ln 0~,1 I I~ I~ rr) ~ ~ I~
c o UD N O O O 0 o o ~1 rD t~
H
_O ~ O
' C ~ ~ C ~ U ~ G~
. H~ > -- Z: ~ ~ O O r-: G o rD rD rD ro rD
rn ~ ~ ~ ~
c h O E
o ~ ~ ~ rn rn - -rq-. o~ I I I I I I I
. ~ ~
' ' t~r-~
I I
LL
. - X I I I I
,' . . - O O O
LL LL I I
L~

. C ~ rr~ .
. c L

c ,~ Z
c c~
4o L I
T~ ~nCC -C C . l ~rn tn ~r~
O O ~1 D) ~ tDtD tD
o o ~ o ¦ Q Q t~ ~ J
~ t~ X t~ l_~ t~ t ) t_~ lL l.L IL

;
J ~ _ ~ . 1 :

' 3 1~ 4:L

c -n ~
O r1 0 I ~ r~ D OCD ~; CJ~
LlJ I . (D ~D (-OCJ ) a~ ~t r-l CJl CD
o C~ . /\ ,_~

D ~ ~1 c a~ ~ E r~ ~ tDtD ~DCD Ll~ ~ cr) C C ~1 ~ Cl U- O O u~ '1 N CO
H +' > `-- Z .~ ~1 /~
,_ c a~ ~
o ~ I u~ ~ O~D ~D 1~ N
C ~ O U7 ~\1 0 0 ~-- ~ O O O O
o V U~
.,1 ~L
O ~ O
.,1 L-C ~ ~ CD 1~ U~~t O ~D ~ ('') ~D
~_C r-l C
H ~ ~ Z ~ l-- ~ N N N ~1 ~I r~
:~:
., E ~ ~ ~ ~ ~
x ~ t~ x O I L~ 1~ I ~ O ~: I O

O II I I ~ LL ~ LL r~
.~ m . (D
cl:
.

.: ~ ~
I I I I I I I I I
tY
I ~
L c~ I L
m o 1l o I I I I m , . X
I Ir L, O I L L L L
m o LL o m m m m >~
L
c , ~ >~

. c L

.~

+~ I
~ ~:
O

TJ _~J L~ CD O
~ ~ I O ~ ~ ~ Ll-l O .--1 .--1 O O ~Q ~D ~D ID ~D ~ ~ N ~ ,_~
E c~ ~ ~ C ~5 '1: Cl ~ ~ ~' ~ CL
o o \ o ~ ~ ~ J
~ ~ -X ~ ILLL~

f~ .~4~

o C Ln ~
O rl O I Ln ~ a) o O
LL~ I I~ o C o~ ~-- Ln `. , ~ `' ~ ~o ." ,~ Q v . ~ ~
~ Q r~ O~
n, ~
~rl O O
c o > E o Ln t\l o o C_C~ ~ Ln ~ O Ln Ln H +~ >--~ Z .--I H
., ,_ o ~ 2` I Ln Ln r I O (~I
C W o Ln O ~ o o o .. ~1 10 t~
+? H
~: ~1 Q
n ~ D
.,, L o c o ~ Ln cn Ln C_C rl ~1 .. . H ~ > Z O O -1 0 h h o~
o o o L~
.. ~ .. ~ .
H LU 1~1 '~S I ~11 . ..
.' ~ `
~ , . Q~ I i ,_ h >, ~ L
>1 Q
C ~ ` . .
. __ tO ~
~1 1 Q ~1 : E
L c rl . CLQ~ ~ -D
. >~CL E L
. ~ o E h o) ~ -C ~, ~ ~
CL I ~t E c L) -D H iD E
o >~ , h E h c E o ~
cIr) CL ~ ~
11 L c~I E ~,1 E
c a3 Q >~ ~ c o ~ ~I E
E h ~ E E C~ o LL
o L, ~ * *

~, ,.

: 31 ~h~
` The pharmacological tests show that the compounds are able -to inhibit the uptake of noradrenaline and 5-hydroxytryptamine.
A pronounced non-selective activity is shown for -the compounds having codes CPK 170, CPK 171, CPK 130 and CPK 184. A pronounced selective activity on uptake of noradrenaline is seen in compounds CPK 185, CPK 215 and CPK 217 while a pronounced selective activity on uptake of 5-hydroxytryptamine is seen in compounds FLA 611, FLA 615, CPK 198 and CPK 204.
A strong non-selective activity is considered to be especially advantageous, as compounds having such activity may be employed in the treatment of depressions in which the neurotransmittor 1.
deficiency is unknown as well as in those cases wherein it is established that the deficiency pertains to both noradrenaline and 5-hydroxytryptamine .

. .
.

Claims (41)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the general formula I
wherein the symbol represents either a single or double bond and Ar represents the group wherein Y is bound in the 2-, 3- or 4-position and represents a lower alkyl or lower alkoxy group, a halogen or a trifluoromethyl group or Ar represents a pyridyl group bound in the 2-, 3- or 4-position, X represents hydrogen, a lower alkyl or lower alkoxy group, a halogen or a trifluoromethyl group, R represents a lower alkyl group, n is 0 or 1 and A is an anion of a pharmaceutically acceptable acid wherein "lower" indicates a group having up to 3 carbon atoms, provided that when the symbol represents a single bond, X and Y are both fluorine atoms in the 4-position and R is a methyl group n is not zero, which process comprises a) reducing a compound of the formula II
wherein Ar, X and R have the meaning as defined above and R' is a hydrogen atom or an alkyl, an acyl or an alkylsulfonyl group having 1 - 3 carbon atoms, to obtain a compound of formula Ia, or b) reacting a reactive ester of an alcohol of the formula I
wherein Ar, X and R have the meaning defined above, with ammonia or c) reducing a compound of the formula Ib wherein Ar, X and R have the meaning defined above or d) reacting a ketone of the formula IV
wherein Ar, X and R have the meaning defined above with ammonium formate or methyl ammonium formate according to Leuckert-Wallach, e) dehydrating a carbinol of the formula VII
to a compound of formula Ib, as defined above f) reacting a compound of the formula VIII

wherein Ar, X and R have the meaning defined above and Z is a leaving group with ammonia or a derivative thereof to form a primary amine of formula Ib above, or (g) oxidizing the benzylic carbon atom of a compound of the formula IX

wherein Ar, X and R have the meaning defined above and R" and R"' are pro-tective groups for the amino function, followed by elimination of the group formed by oxidation at the benzyl carbon atom, giving a compound of the formula X

which is transformed into the compound of formula Ib by removing the pro-tective groups R" and R"'; and, if required, converting the primary amine ob-tained into a therapeutically acceptable acid addition salt thereof in anhy-drous form or any degree of hydration possible, by reaction with an acid HA
wherein A is as defined above.

2. A process according to claim 1 wherein process (b) is used and the reactive ester is obtained by reacting the alcohol of formula III with a halogenating agent.

3. A process according to claim 1 wherein process (b) is used and the reactive ester is obtained by reacting the alcohol of formula III with thionyl chloride, thionyl bromide, phosphorus tribromide or p-toluenesulphonyl chloride.

4. A process according to claim 1 wherein process (c) is used and the starting material of formula Ib is obtained by process (e), (f) or (g) of claim 1.

5. A process according to claim 1 wherein X and Y are not both fluorine atoms in the 4-position of respective phenyl groups.

6. A process according to claim 1 or 5 wherein process (a), (b), (c) or (d) is used to obtain a compound of formula I in which the symbol represents a single bond.

7. A process according to claim 1 or 5 wherein process (a), (b), (c) or (d) is used to obtain a compound of formula I in which the symbol represents a single bond and wherein X is hydrogen.

8. A process according to claim 1 or 5 wherein process (e), (f) or (g) is used to obtain a compound of formula I in which the symbol represents a double bond.

9. A process according to claim 1 wherein X is hydrogen and Y is fluorine, bromine or a methoxy group.

10. A compound of formula I as defined in claim 1 when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

11. A process according to claim 1 wherein R is methyl, X is hydrogen and the symbol ? represents a single bond.

12. A process according to claim 11 wherein Y is a phenyl ring substi-tuted in the 4-position by a fluorine atom.

13. A process according to claim 11 wherein Y is a phenyl ring substi-tuted in the 4-position by a bromine atom.

14. A process according to claim 11 wherein Y is a phenyl ring substi-tuted in the 4-position by a methoxy group.

15. A process according to claim 11 wherein Y is a phenyl ring substi-tuted in the 3-position by a bromine atom.

16. A process according to claim 11 wherein Y is a phenyl ring substi-tuted in the 2-position by a bromine atom.

17. A process according to claim 1 wherein R is methyl X is hydrogen, the symbol ? represents a double bond and Y is a phenyl ring substituted in the 3-position by a bromine atom.

18. A process according to claim 1 wherein R is methyl, X is methoxy in the 4-position, the symbol ? represents a double bond and Y is a phenyl group substituted in the 4-position by a methoxy group.

19. A process for preparing (.beta.)-3-(4-fluorophenyl)-1-methyl-3-phenyl-propylamine or its hydrochloride salt which comprises reducing 4-(4-fluoro-phenyl)-4-phenylbutan-2-one oxime and, if required, reacting the product with hydrogen chlcride to obtain the hydrochloride salt.

20. A process for preparing (.beta.)-3-(4-bromophenyl)-1-methyl-3-phenyl-propylamine or its maleate salt which comprises reducing 4-(4-bromophenyl)-4-phenylbutan-2-one oxime and, if required, reacting the product with maleic acid to obtain the maleate salt.

21. A process for preparing (.alpha.)-3-(4-methoxyphenyl)-1-methyl-3-phenyl-propylamine or its maleate salt which comprises reclucing 4-(4-methoxyphenyl)-4-phenylbutan-2-one oxime and, if required, reacting the product with maleic acid to obtain the maleate salt.

22. A process for preparing (.beta.)-3-(3-bromophenyl)-1-methyl-3-phenyl-propylamine or its fumarate salt which comprises reducing 4-(3-bromophenyl)-4-phenylbutan-2-one oxime and, if required, reacting the product with fumaric acid to obtain the fumarate salt.

23. A process for preparing (.beta.)-3-(3-bromophenyl)-1-methyl-3-phenyl-propylamine or its maleate salt which comprises reacting 4-(3-bromophenyl)-4-phenylbutan-2-one with formamide, and, if required, reacting the product with maleic acid to obtain the maleate salt.

24. A process for preparing (.alpha.)-3-(2-bromophenyl)-1-methyl-3-phenyl-propylamine or its maleate salt which comprises reducing 4-(2-bromophenyl)-3-phenylbutan-2-one oxime and, if required, reacting the product with maleic acid to obtain the maleate salt.

25. A process for preparing (E)-3-amino-1-(3-bromophenyl)-1-phenyl-butene or its hydrochloride salt which comprises reacting (E)-3-phthalimido-1-(3-bromophenyl)-1-phenylbutene with hydrazine hydrate and, if required, reacting the product with hydrogen chloride to obtain the hydrochloride salt.

26. A process for preparing (Z)-3-amino-1-(3-bromophenyl)-1-phenylbut-l-ene or its maleate salt which comprises reacting (Z)-3-phthalimido-1-(3-bromophenyl)-1-phenylbutene with hydrazine hydrate and, if required, reacting the product with maleic acid to obtain the maleate salt.

27. A process for preparing 3-amino-1,1-di-(4-methoxyphenyl)-1-butene or its fumarate salt which comprises dehydrating 3-amino-1-hydroxy-1,1-di-(4-methoxyphenyl)-butane and, if required, reacting the product with fumaric acid to obtain the fumarate salt.

28. A process for preparing the hydrochloride salt of 3,3-di-(4-fluorophenyl)-1-methylpropylamine which comprises reducing 3,3-di-(4-fluoro-phenyl)-1-methyl-allylamine in the presence of hydrochloric acid.

29. A process for preparing (.beta.)-3-(4-methoxyphenyl)-1-methyl-3-phenyl-propylamine or its maleate salt which comprises reducing 4-(4-methoxyphenyl)-4-phenylbutan-2-one oxime and, if required, reacting the product with maleic acid to obtain the maleate salt.

30. A process for preparing (E)-3-amino-1-(4-bromophenyl)-1-phenyl-butene or its oxalate salt which comprises reacting (E)-3-phthalimido-1-(4-bromophenyl)-1-phenylbutene with hydrazine hydrate and, if required, reacting the product with oxalic acid to obtain the oxalate salt.

31. The compound (.beta.)-3-(4-fluorophenyl)-1-methyl-3-phenylpropylamine or its hydrochloride salt when prepared by a process according to claim 19 or an obvious chemical equivalent thereof.

32. The compound (.beta.)-3-(4-bromophenyl)-1-methyl-3-phenylpropylamine or its maleate salt when prepared by a process according to claim 20 or an ob-vious chemical equivalent thereof.

33. The compound (.alpha.)-3-(4-methoxyphenyl-1-methyl-3-phenylpropylamine or its maleate salt when prepared by a process according to claim 21 or an ob-vious chemical equivalent thereof.

34. The compound (.beta.)-3-(3-bromophenyl)-1-methyl-3-phenylpropylamine or its fumarate or maleate salt when prepared by a process according to claim 22 or 23 or an obvious chemical equivalent thereof.

35. The compound (.alpha.)-3-(2-bromophenyl)-1-methyl-3-phenylpropylamine or its maleate salt when prepared by a process according to claim 24 or an ob-vious chemical equivalent thereof.

36. The compound (E)-3-amino-1-(3-bromophenyl)-1-phenylbutene or its hydrochloride salt when prepared by a process according to claim 25 or an obvious chemical equivalent thereof.

37. The compound (Z)-3-amino-1-(3-bromophenyl)-1-phenylbut-1-ene or its maleate salt when prepared by a process according to claim 26 or an obvious chemical equivalent thereof.

38. The compound 3-amino-1,1-di-(4-methoxyphenyl)-1-butene or its fumarate salt when prepared by a process according to claim 27 or an obvious chemical equivalent thereof.

39. The hydrochloride salt of 3,3-di-(4-fluorophenyl)-1-methylpropyl-amine when prepared by a process according to claim 28 or an obvious chemical equivalent thereof.

40. The compound (.beta.)-3-(4-methoxyphenyl)-1-methyl-3-phenylpropylamine or its maleate salt when prepared by a process according to claim 29 or an obvious chemical equivalent thereof.

41. The compound (E)-3-amino-1-(4-bromophenyl)-1-phenylbutene or its oxalate salt when prepared by a process according to claim 30 or an obvious chemical equivalent thereof.