[0001] The present invention is related to new compounds of the diarylalkylamine 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 intermediates useful in preparation of such therapeutically
active compounds.
[0002] The object of the invention is to obtain compounds having a therapeutical activity
in the central nervous system, especially an anti-depressive or a tranquilizing activity.
Prior Art
[0003] British Patent 1 429 068 disel the general Formule : corresponding to

having anti-depressive activity. Belgian Patent 835.802 discloses compounds of the
general formula: -

having anti-depressive activity.
[0004] Compounds following within the general formula

are disclosed by prior publications as follows : R
I=CH
3O, R
II= =OH, R
III=R
IV =H, and R
I =Cl, R
II =OH, RIII=CH
3, R
IV =H having hyme- tensive properties, by British Patent 755, 881 ; R
I =R
II =R
III =8
IV= =H by French Patent 2, 215, 973; R
I=R
II=R
III=H, R
IV=tertiary butyl having spasmolytic properties, by British Patent 923, 942 ; R
I=R
II=R
III =H, R
IV=CH
3 having spasmolytic properties, by US Patent 2? 446? 522.
[0005] South African Patent 62/415 discloses i.a. a compound having the formula

claimed to have a therapeutic utility especially as an anti- tussive.
[0006] In J. Med. Chem. 14 161 (1971) a compound of the formula

is disclosed as an antidepressant.
General Outline of the Invention
[0007] According to the present invention it has been found that compounds of the general
formula below have advantageous, therapeutic properties:

[0008] In these compounds the dotted line represents an optional double bond. These compounds
may be divided into two groups defined by the formulae

[0009] 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 an amino or a mono- or
di-lower alkyl amino 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 trifluoromethyl group, an amino group or a mono- or di-lower alkyl amino group,
R is a lower alkyl group and R is hydrogen or a lower alkyl group. 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. Therapautically acceptable salts and biopre- cursors
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.
[0010] The compounds of formula Ia above wherein Ar is identical to the group

contain one asymmetric carbon atom. The remaining compounds of formula Ia contain
two asymmetric carbon atoms and can therefore exist in two diastereomeric 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 residue to a greater or lesser extent in one
of the enantiomers or mixtures mentioned above.
[0011] Due to the lack of free rotation in the double bond the compound of formula I5 in
which the group Ar is not identical with the group

may exist in different stereoisomeric forms, that is in cis- trans isomers or, according
to the IUPAC nomencleture (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 geometrical isomers may be prepared from
an isomer mixture, from an isomer-pure starting material or directly by a stereoselective
synthesis.
[0012] 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.

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.a. 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 enantiomers of the geometrical isomers mentioned above. The
therapeutic properties may reside to a greater or lesser extent in one of the enantiomers
or mixtures mentioned above.
[0013] The compounds of the invention show an activity in the central nerwous 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 tranquilizing agents in man.
Preferred Embodiment of the Invention
[0014] Of the compounds of the invention defined by formula I above those wherein Ar is

are to be specially mentioned. Of those the compounds wherein X is hydrogen are preferred
and especially those wherein Y is F, Br or CH
3O-.
[0015] As preferred individual compounds should be mentioned:
(β)-3-(4-flurophenyl)-1-methyl-3-phenyloropylamine,
(β)-3-(4-bromophenyl)-1-methyl-3-phenyloropylamine,
(α)-3-(4-methoxyphenyl)-1-methyl-3-phenylprobylamine, and
(β) -3-(3-bromophenyl)-1-methyl-3-phenylpropylamine being non-selective inhibitors
of neuronal noradroneline and 5-hydroxytryoptamine uptake;
(α)-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)-1-butene,
3, 3-di-(4-fluorophenyl)-1-methylpropylamine,
(β)-3-(4-methoxyphenyl)-1-methyl-3-phenylpropylamine, and
(E)-3-aminc-1-(4-bromophenyl)-1-phenylbutene,
being selective inhibitors of neuronal 5-hydroxytryptamine uptake; as well as salts
and precursors of said compounds.
[0016] The neuronal uptake mechanism are discussed further in the chapter "Pharmacological
evaluation" below.
[0017] Generally preferred in all classes of the compounds of the invention are those wherein
R
1 represents hydrogen and R represents a methyl group.
Methods of Preparation
[0018] The compounds of the invention may be prepared by
a) reducing a compound of the formula

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 1-3 carbon atoms, to the obtention
of a compound of formula Ia in which R1 is hydrogen, and if of formula Ia in which R1 is hydrogen, and if desired converting this primary amine to a secondary amine in
a manner known in the art. The reduction may be carried out by known methods e.g.
employing a hydride reagent such as lithium aluminium hydride,
b) preparing a reactive ester of an alcohol of the formula

wherein Ar, X and R have the meaning defined above and reacting the ester obtained
with an amine of the formula NH2R1, wherein R1 has the meaning defined above. The reactive ester wherein R1 has the meaning defined above. 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-toluenesulphonyl chloride,
c) reducing a compound of the formula

wherein Ar, X, R and R1 have the meaning defined above. The reduction may be carried out by methods known
in the art e.g. by catalytical hydrogenation using catalysts such as Raney nickel,
palladium on charcoal, platinum dioxide or rhodium,
d) reacting a ketone of the formula

wherein Ar, X and R have the meaning defined above, with ammoniumformate or methylammoniumformate
according to Leuckart-Wallach. 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.
[0019] The intermediates of formulae II, III, and IV above are novel.
[0020] The intermediates of formula II may be prepared by reacting the ketone of the formula
IV above with a hydroxylamine de- rivative of formula NH
2OR
1, wherein R
1 has the meaning defined above.
[0021] The intermediate of formula III may be prepared by hydride reduction of the compound
of fcrmula IV which, in burn, may be obtained by
1) reacting an alpha, beta-unsaturated ketone of the formula

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 diary learbinol of the formula

wherein Ar and X have the meaning defined above, first with tionylchloride. then with
ethyl acetoacetate in the presence of suitable condensation catalyst such as sodium
acetate or the like.
[0022] 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.
[0023] The new compounds of formual Ia may be used therepeutically 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 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.
[0024] The compounds of the formula I in the invention may be prepared by:
e) Dehydration of a carbinol of the formula

to a compound of formula Ib.
[0025] The dehydration of the starting material may be done by means of treatment with hydrochloric
acid HC1 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 H
2SO
4, phosphoric acid H
3PO
4. potassium hydrogen sulphate KHSO
4, 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 POCI
3 in pyridine,'and dehydration with thionylchloride, SOCI
2, 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.
[0026] f) Reaction of a compound of the formula

wherein Z is a leaving group such as F, Cl, Br, I, OSO
2R
1, wherein R
1 is alkyl, aralkyl or aryl, with an amine of the formula NH
2R
1 or with a derivative thereof such as hexa- methylenetetraamine, alkaliphtalimide,
lithium bisbenzene- sulfeneamide, guanidine, sodium cyanate, sodium azide, a carboxamide
or a sulfonsamide. When an amine derivative is alkylated the product obtained is subsequently
hydrolyzed or in some other way converted into a primary or secondary amine of formula
Ib. A preferred amine derivative is potassium phtalimide.
[0027] This reaction is also useful for preparation of the compounds of formula Ia by employing
as a starting material a saturated compound corresponding to the compound of formula
VIII.
[0028] g) Oxidation (halogenation) of the benzylic carbon atom of a compound of formula
IX

e.g. with N-bromosuccinimide, R", R'" being protective groups for the amino function
preferably joined as the group

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 compoundof the formula

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 compounds cf formula
Ia, by introducing in those compounds protective groups R" and R'" in a known manner
to the obtenti of a compound of formula IX.
[0029] The intermediates of formulae VII, VIII, IX and X above are novel.
[0030] The intermediate of formula VII may be obtained by preparing a Grignard or lithium
compound from a halobenzene of the formula

and reacting it with an ester of the formula

wherein R" is an alkyl, aralkyl or aryl group.
[0031] The intermediate of formula VIII may be isolated (of. Example 15) and subsequently
dehydrated or alternatively the crude product in the preparation of formula VII may
be dahydrated directly (of. Example 17).
[0032] The intermediate of formula VIII may be obtained from a compound of formula

wherein X, Ar and R have the meaning defined above, by oxidation of the allylic carbon
to the formation of a compound of the formula

wherein Z
1 represents Z or OH, e.g. by reaction with N-bromosuccinimide (Z
1 = Br) or selenium dioxide (Z
1 = OH). The latter compound may be transformed to a reactive derivative III by treatment
with an agent such as SOCl
2, SOBr
2 or PBr
3 or with ClSO
2R
1.
Pharmaceutical Preparations
[0033] 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, sulphamate, citrate, tartrate, oxalate and the like in association with
a pharmaceutically 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, semisolid or liquid diluant or capsule.
These pharmaceutical preparations 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 injection
and between 2 and 50 % by weight for preparations suitable for oral administration.
[0034] 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, saccharose, sorbitol, mannitol, starches
such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder
such as gelatine or polyvinylpyrrolidone, 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 solution which may contain, e.g. gum arabic,
gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet can be
coated with a lacquer in a readily volatile organic solvent or mixture of organic
solvents. Dyestuff may be added to these coatings in order to readily distinguish
between tablets containing different active substances or different amounts of the
active compounds.
[0035] For 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 combination with solid, pulverulent carriers such as lactose,
saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin),
cellulose derivatives or gelatine.
[0036] Dosage units for rectal application can be prepared in the form of suppositories
comprising the active substance in ed- mixture witha neutral fatty base, or gelatine
rectal capsules comprising the active substance in admixture with vegetable oil or
paraffin oil.
[0037] 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 ceing 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.
[0038] 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.
[0039] Suitable daily doses of the compounds of the invention in therapeutic 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.
Working Examples
Example 1. Preparation of 4-(3-bromophenyl)-4-phenylbutan-2-one
[0040] 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 nitrogen atmosphere, 23.5 g (0.10
mol) of 1,3--dibromobenzene in 30 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 bensalacetone in
100 ml of ether was added dropwise at +10°C. Then the reaction mixture was allowed
to reach room temperature for 2 hours. The mixture was poured into 400 ml of 10 %
aqueous solution of ammonium chloride, the aqueous layer was separated and the product
was extracted with 2 x 200 ml of ether. The ethereal layer was washed with water,-dried
with NA
2SO
4 and the solvent was evaporated. The crude 3-(3-bromophenyl)-3-phenylbutan-2-one obtained
(28.5 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 hours. 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 3-(3--bromophenylbutan-2-one
oxime.
Example 2. Preparation of 3-(3-bromophenyl)-1-methyl-3-phenyl- propylamine oxalate.
(Method a)
[0041] 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 aluminium hydride was added in
portions under nitrogen atmosphere at room temperature. The reaction mixture was stirred
for 8 hours. Then 25 ml of 2 M NaOH was dropwise added and the precipitated inorganic
salts were removes 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, drying and evaporation
of the solvent gave 8.9 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 isopropylalcohol 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
134-138°C.
[0042] 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-(bromophenyl-1-methyl-3-chanyl- propylamine into its diastereomers
[0043] The free amine (2.9 g, 0.009 mol) obtained from 3.3 g of the oxalate 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 (COC1
3) 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 (two protons) and a dublet at 1.5 ppm (J=6.1 Hz) (three protons).
[0044] Analysis: C calcd 57.15 %, found 57.45 %; H caled 5.28 %. found 5.35 %; Br calcd
19.01 %, found 19.05 %; N calcd 3.33 %, found 3.20. %; 0 calcd 15.23 %, found 15.00
%.
[0045] The solvents of the first mother liquors pf the diamine oxalate prepared according
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 184-186°C.
[0046] Analysis: C calcd 59.7 %, found 60.3 %; H calcd 5.5 %, found 5.7 %; N caled 3.9 %,
found 3.7 %.
Example 4
[0047] (α)-3-(4-fluorophenyl)-1-methyl-3-phenylpropylamine oxalate, mp 186-188°C (EtOH-EtOAc,
1:1) and (β)-3-(4-fluorophenyl)-1--methyl-3-phenylpropylamine hydrochloride, mp 171-172°C
(EtOAc) were prepared from 3-(3-fluorophenyl)-3-phenylbutan-2-one oxime in accordance
with Examples 2 and 3.
Example 5
[0048] (α)-3-(4-bromophenyl)-1-methyl-3-phenylaropylamine maleate, mp 168-170°C (EtOH-EtOAc,
1:1) and (β)-3-(bromophenyl)-1-methyl--3-phenylpropylamine maleate, mp 161-162°C (1-PrPH-EtOAc,
3:1) were prepared from 3-(4-bromophenyl)-3-phenylbutan-2-one exime in accordance
with Examples 2 and 3.
Example 6
[0049] (α)-3-(4-methoxyphenyl]-1-methyl-3-phenylpropylamine maleate, mp 146-148°C (i-PrOH)
and (β)-3-(4-methoxyphenyl)-1-methyl-3--phenylpropylamine maleate, mp 124-133°C (EtOAc)
were prepared from 3-(4-methoxyphenyl)-3-phenylbutan-2-one oxime in accordance with
Examples 2 and 3.
Example 7
[0050] (α)-1-methyl-3-(4-trifluoromethylphenyl)-3-phenylpropylamine maleate, mp 165-166°C
and (β)-1-methyl-3-(4-trifluoromethylphenyl)-3-phenylpropylamine maleate, mp 165-157°C
were prepared from 3-(4-trifluoromethylphenyl)-3-phenylbutan-2-one oxime in accordance
with Examples 2 and 3.
Example 8. Preparation of 4-(2-bromophenyl)-4-phenylbutan-2-one
[0051] To a solution of 24.3 g (0.13 mol) of 2-bromobenzeldehyde in 60 ml of acetone, 1.0
ml of 10 M NaOH was slowly added at 0°C. The reaction mixture was allowed to reach
room temperature and stirred for another 2 hours. Then it was poured into 400 ml of
water, to which 10 ml of 2 M HC1 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 1,1g (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 hours. 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
[0052] (α)-3-(2-bromophenyl)-1-methyl-3-phenylpropylamine maleate, mp 145-146°C (i-PrOH)
and (β)-3-(2-bromophenyl)-1-methyl-3--phenyl-propylamine maleate, mp 135-137°C (EtCH-EtOAc,
1:4) were prepared from 3-(2-bromophenyl)-3-phenylbutan-2-one oxime in accordance
with Examples 2 and 3.
Example 10. Preparation of N, 1-dimethyl-3(4-bromophenyl)--3-phenylpropylamine
[0053] The free base of 3-(4-bromophenyl)-1-methyl-3-phenylpropyi- amine (0.07 g, 0.0023
mol) was dissolved in 50 ml of chloroform. 1.2 ml (0.0024 mol) of 2 M NaOH and 0.25
g (0.0024 mol) of ethyl chloroformate were added separately and dropwise with vigorous
stirring at 15°C. Stirring was continued for 2 hours at room temperature.
[0054] Then 25 ml of water was added and the organic layer was separated, dried, and the
solvent was evaporated to give 1.0 g of N-ethoxycarbonyl-3-(4-bromophenyl)-1-methyl-3--phenylpropylamine
as a colourless oil.
[0055] Treatment of the carbamate with 0.25 g (0.006 mol) of LiAlH
4 in 60 ml of ether for 14 hours gave 0.20 g of the secondary amine after extraction.with
ether/hydrochloride and NaOH/ /ether. The hydrochloride was prepared and recrystallized
from 18 ml of acetone to give 0.12 g, mp 146-148°C.
[0056] The oxalate had mp 106-111°C from acetone.
Example 11. Preparation of 3-(3-bromopnenyl)-1-methyl-3--phenylpropylamine. (Method
d)
[0057] A mixture of 22.1 g (0.073 mol) of 4-(3-bromophenyl)-4--phenylbutan-2-one and 230
ml of formamide was heated for 8 hours at 180°C. After cooling water was added and
the product was taken up in ether. Drying and evaporaticn of the solvent gave 30.5
g of a residue.
[0058] To this residue 35 ml of conc. hydrochloric acid was added and the mixture was heated
under refluxing conditions for 3 hours. Water was added and the non basic materials
were removed by shaking the reaction mixture with 180 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 cf ether, drying (Na2SO4) and evaporation of the solvent gave 12.9 g of
the desired amine.
[0059] The maleate was prepared by addition of a hot ethanolic solution of 4.9 g of maleic
acid intc a warm solution of the amine in 100 ml of ethyl acetate. Recrystallization
from EtOH-EtOAc gave 8.4 g of the maleate, mp 158-181°C.
[0060] Analysis: C calcd 57.2 %, found 57.5 %; H caled 5.28 %, found 5.35 %; Br calcd 19.0
%, found 19.1 %; N caled 3.33 %, found 3.20 %; 0 calcd 15.2 %, found 15.0 %.
Example 12. Preparation of 3,3-di-(4-fluorophenyl)-1-methylpropylamine hydrochloride
(Method c)
[0061] 3,3-di-(4-fluorophenyl)-1-methylallylamine (0.9 g, 0.003 mol) was dissolved in 100
ml of ethanol end 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 hours. The reaction mixture was filtered
to remove the catalyst and the solvent of the filtrate was evaporated Crystallisation
from EtOAC-i-Pr
2O gave 0.75 g of the desired product, mp 225-229°C.
[0062] Analysis: C caled 64.5 %, found 64.5 %; H caled 6.09 %, found 6.11 %; Cl calcd 11.9
%, found 11.8 %; F caled 12.3 %, found 12.7 %; N calcd 4.70 %, found 4.55 %.
[0063] By the same method there were prepared from the appropriate allylamines :
Example 13
[0064] By the method of Example 12 3,3-di-(4-methoxyphenyl)-1-methyl--propylamine fumarate,
mp 163-157°C, (EtOH-i-Pr
2O) was prepared from the corresponding allylamine.
Example 14
[0065] By the method of Example 12 1,3', 3"-trimethyl-3,3-diphenyl- propylamine oxalate,
mp 214-215°C, (EtOH-EtOAc) was prepared from the corresponding allylamine.
Example 15. Preparation of 4,4-di-(4-bromophenyl)-4-hydroxy--2-butylamine oxalate
[0066] A solution of 61.5 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 hours at room temperature the mixture was cooled in an ice-bath and a solution
of 11.3 g (0.11 mol) of ethyl 3-aminobutyrate in 25 ml of diethyl ether was added
during 15 min.
[0067] The mixture was stirred for 1.25 hours at ice-cooling and then for 2.5 hours at reflux.
An aqueous cold solution of 25 g ammonium chloride was slowly added, and after stirring
the 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. 191-194°C.
[0068] Elemental analysis: C
18H
19Br
2NO
5: Found: C 44.5, H 4.0, N 2.7, and 0 16.8 %. Calculated: C 44.20, H 3.91, N 2.86 and
G 16.35 %.
Example 16. Preparation of 3-amino-1,1-di(4-bromophenyl)-1--butene hydrochloride (Method
e)
[0069] A solution of 3.8 g 4,4-di(4-bromophenyl)-4-hydroxy-2-butylamine oxalate, 25 ml acetic
acid and 5 ml cone. 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. Acetonitrile and hydrogen chloride in ether were added
and the hydrochloride of the title compound (1.7 g) was obtained after recrystallization
from acetonitrile/ether. M.o. 215--220°C.
[0070] Elemental analysis: C
16H
15Br
2C1N; Found: C 46.7, H 3.9, Cl 8.8 and N 3.1 %. Calculated: C 40.02, H 3.86 Cl 3,49
and N 3.35 %.
Example 17. Preparation of 3-amino-1,1-di(4-methoxyphenyl)--1-butene fumarate (method
e)
[0071] A solution of 53.0 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 hours. The mixture was stirred at room temperature for another
1.5 hours and then heated under reflux for 1.5 hours. The mixture was cooled in an
ice-bath and a solution of 10.3 g (0.10 mol) ethyl 3-aminobutyrate in 25 ml diethyl
ether was added during 20 min. After stirring over night at room temperature an aqueous
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.
[0072] The solution was heated under reflux for 30 min and then the solvent was evaporated.
The residue was made alakline and extracted with ether. The ethereal layer was washed
with water and extracted with 0.5 M hydrogen chloride. 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.
[0073] 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 C
18H
21NO
2 . 3/4C
4H
4O
4 . M.p. 167-167.5°C.
[0074] Elemental analysis: C
21H
24NO
5 : Found: C 67.8, H 6.52, N 3.89 and 0'21.5 %. Calculated: C 68.09, H 6.53, N 3.78
and 0 21.60 %.
Example 18
[0075] 3-amino-1,1-di-(4-fluorphenyl)-1-butene fumarate was prepared according to Example
17. M.p. 225-231°C.
Example 19
[0076] 3-amino-1,1-di-(3-methylphenyl)-1-butene hydrochloride was prepared according tc
Example 17. M.p. 216-217.5°C.
Example 20. Preparation of 1-(4-bromophenyl)-1-phenyl-butene
[0077] Sodium dimethylsulfoxide in DMSO, prepared by heating 3.8 g 0.08 mol) sodium hydride
(50 % in oil) in 100 ml dimethylsulfoxide at 80°C for 40 min, was mixed with 27.0
g (0.07 mol) propyltriphenylphosphonium bromide, prepared by heating propyl- bromide
and triphenylphosphine in toluene at reflux temperature for 14 hours. The mixture
was stirred under nitrogen atomos- phere at room temperature for 1.5 hours. Then a
solution of 13.1 g (0.05 mol) of 4-bromobenzohenone, in a mixture of 100 ml dimethylsuphoxideand
100 ml of anhydrous tetrahydrofuran was added at room temperature. The reaction mixture
was stirred for hours , then it was poured into 1.000 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. Drying (Na
2SO
4) and evaporation of the solvent gave 18 g of oily re- sidue. After trituration with
100 ml of diisopropylether crystals of triphenylphosphinoxide 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 - 130°C Yield 85 %.
Examople 21. preparation of 3-(4-bromophenyl)-3-phenyl-1- -methylellylbromide
[0078] To a solution of 22.8 g (0.0787 mol) of 1-(4-bromophenyl)-1--phenylbutene in 300
ml of carbontetrachloride 14.0 g (0,0787 mol) oF N-bromosuccinimide was added. The
mixture was heated to reflux temperature after the addition of 0.7 g. of alpha, alpha-anabisoutyronitrile.
After 3.5 hours all NBS had beenconsumed and the reaction mixture was cooled and filtered.
7.8 g of succinimide was separated and the volume of the filtrade was reduced to 511
ml by evaporation at 35°C. TLC of campis on silice in diisopropylether-hexane (1:1)-showed
a new spot at RF 0.62 (the starting olefin had Rf 0.55). The material was beeing used
without further isolation or purification due to its high reactivity with nucleophilic
agents.
Example 22. Preparation of 3-(N-phtalimido)-1-(4-bromophenyl)--1-phenylbutene method
f)
[0079] A solution of crude 3-(4-bromophenyl)-3-phenyl-1-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 stirred at 50°C for 14
hours.
[0080] Dilution with water (excess) and extraction of the product with diethylether gave
18 g of an oil after drying and evaporation of the solvent. Column chromatography
on silica with diisopropylether as the eluent afforded the geometrical isomers:
2.5 g of the (Z)-form, Rf. =0.30, and 3.7 g of the (E)-form, Rf = 0.26 in diisopropylether-hexane (1:1).
Example 23. preparation of (Z)-3-amino-1-(4-bromophenyl)-1--phenylbutene maleate
[0081] To a stirred solution of 0.43 g (0.001 mol) of (Z)-3-phtali- mido-1-(4-bromophenyl)-1-phenylbutene
in 30 ml of methanol 0.25 g (0.05 mol) of hydrazine hydrate was added at room temperature.
In order to dissolve all the phtalimide 10 ml of carbon tetrachloride was added. The
mixture was stirred and heated at 60°C for 2 hours. 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. 174-175°C from
ethanol. The UV spectrum in ethanol had λ max 237 nm.
[0082] Elemental analysis: C
20H
20BrNO ; Found: C 57.1, H 4.80, Br 20.3, N 3.10 and 0 15.2 %. Calculated: C 57.43, H
4.82, Br 19.10, N 3.35 and 0 15.30 %.
Example 24
[0083] (E)-3-amino-1-(4-bromophenyl)-1-phenylbutene oxalate was pr
e- pared from the corresponding phtalimide according to Example 23.. M.p. 145-148°C.
Example 25. Preparation of-(Z)-3-amino-1-(3-bromoohenyl)-1--phenylbut-1-ene maleate
(Method f)
[0084] To a stirred solution of 0.43 g (0.001 mol) of (Z)-3-phtali- mido-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 hours. The solvent was evaporated and
the residue was taken up in ether. Extraction with 3 x 25 ml of 0.5 M Hcl followed
by alkalization of the ccmbined 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. 138-200°C .
[0085] Elemental analysis: C
20H
20BrNO
4 ;Found: C 56.3, H 4.7, and N 3.2 %. Calculated: C 57.43, H 4.32 and N 3.35 %.
Example 26
[0086] (E)-3-amino-1-(3-bromophenyl-1-phenylbutene hydrochloride was prepared from the corresponding
phtalimide according to Example 25. M.p. 116-123°C. 25. M.p. 118-123°C .
Example 27
[0087] (Z)-3-amino-1-(4-bromophenyl)-1-(3-pyridyl)-butane oxalate was prepared from the
corresponding phtalmide according to Example 25. M.p. 25. M.p.
Example 28. Preparation of 3-(N-Phtalmide)-1-(4-bromophenyl)--1-phenylbutane
[0088] 3-(4-bromophenyl)-1-methyl-3-phenylprocylamine as the free base (41.2 g, 0.136 mol)
was dissolved in 350 ml of acetic acid. phtalic anhydride (20.0 g, 0.135 mol was added
and the mixture was heated with stirring under reflux (bath temperature 120°C) for
2 hours. After cooling the solvent was evaporated in vacuo. The residue was shaken
with a mixture of 300 ml of ather and 500 ml of 2 M NaOH. 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 TMS, characteristic
of phtalmides. The material was used without further purification. Yield: 83 %.
Example 29. preparation of 3-(N-phtalimido)-1-(4-bromophenyl)-1-phenylvbut-1-ene Method
g)
[0089] To a stirred solution of 24.6 g (0.057 mol) 3-(N-phtalimido)--1(-4-bromophenyl)-1-phenylbutane
in 400 ml of carbon tetrachloride 10.0 g 0.057 mol) of N-bromosuccinimida was added.
The mixture was stirred and 0.5 g of alpha, alpha-ezaiso- butyronitrils was added
as radical initiator. Stirring was continued under reflux temperature for 2.5 hours.
The reaction mixture was cooled and filtered. Upon evaporation of the solvent 32.4
g of a residue was obtained. NMR of a sample in 001, snowed a double quartet at 5.0
ppm from TMS and a doublet at 8.5 ppm TLC on silica in disiopropylether showed a spot
with Rf 0.25, identical witn the Rf-value of the material prepared according to Example
22.
[0090] The following examples illustrate how the compound of the present invention may be
included in pharmaceutical preparations .
Example 30. preparation of soft gelatin capsules
[0091] 500 g of active substance were mixed withe 500 g of corn oil 500 g active substance
were mixed with 500 g of corn oil, where upon the mixture was filied in soft gelatin
capsules, each capsules containing 100 mg of the mixture (i.e. 50 mg of active substance)
.
Example 31 .preparationof soft relation capsules
[0092] 500 g of active substance were mixed with 750 g of pea nut oil, whereupon the mixture
was filled in soft gelatin capsules . each capsules containing 125 mg of the mixture
(i.e. 50 mg of active substance) .
Example 32. Preparation of tablets
[0093] 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
destilled water, whereupon the mixture was granulated through a sieve. The granulate
was dried and sieved, whereupon 2 kg of magnesium stearate was mixed into it. Finally
the mixture was pressed into tablets each weighing 172 mg.
Example 33. Preparation of an emulsion
[0094] 100 g of active substance were dissolved in 2500 g of pea nut oil. From the solution
thus obtained, 90 g of gum arabic, aroma and colouring agents (q.s.) and 2500 g of
water an emulsion was prepared.
Example 34. Preoaration of a syrup
[0095] 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 35. Preparation of a solution
[0096] 100 g of active substance were dissolved in 2000 g of polyoxyethylene 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
[0097] 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 stearate and flavouring agents (q.s.)
were mixed and the mixture was pressed into tablets each containing 100 mg of active
substance.
Examole 37. Preparation of a drop solution
[0098] 100 g of active substance were mixed with 300 g of ethanol, whereupon 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 stirring. A drop solution was obtained.
Example 38. Preparation of a sustained release tablet
[0099] 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 obtained was mixed with 5 g of magnesium stearate and pressed into tablets
each weighing 305 mg. Each tablet thus contains 200 mg of active substance.
Pharmacological Evaluation
[0100] Depressions are considered to be connected with changes in the biochemical processes
of the brain which processes control the mood. The nature of these biochemical processes
are largely unknown but in depressive states there is evidence for a decreased activity
of monoaminergic brain neurons. The monoamines, noradrenaline (NA), dopamine (DA)
and 6-hydroxytryptamine (5-HT), are of great interest in this respect.
[0101] It has been demonstrated that NA, DA and 5-HT is localised in three different type
son neurons and may function as trans- mittors 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 space, the synantic cleft or spatium. As a result of a nerve stimulation the transmittor
is released from the granule into the synantic cleft and reaches the receptor of the
effector neuron and generates a nerve imoulse. After impulse generation the amines
are inactivated by mainly two mechanisme: a re-uptaka mechanism at the cell membrane
and enzymatic conversion by catechol-8-methyltransferas to form methylated metabolites.
There is also an inactivating enzyme within the vericosties, monoamine oxidase (MAD),
that is stored in the mitochondrie and inactivates the amines intracellularly,
[0102] When MAS-inhibitors are administered, an increased amount of transmittor substance
becomes available for release at the nerve ending.
[0103] Another way of increasing the amine levels at the receptor is exerted by the tricyclic
antidepressants. It has' been shown that this type of compounds inhibits the re-uptake
mechanism of NA and 5-HT, and the antidepressive action is assumed to be related to
the uptake inhibition of NA and 5-HT.
[0104] It has been proposed, that some depressions are caused by deficiency in either one
of the neurotransmittors and some of deficiency in both.
[0105] 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
[0106] The test method described in Europ. J. Pharmacol. 17, 107, 1972. This method involves
the measurement of the decrease in the uptake of
14C-5-hydroxytryptamine (
14C-5-HT) and
3H- -noradrenaline (
3H-NA) in brain slices from mice after in vivo and in vitro administration of the test
substance.
Inhibition of the uptake of 14C-5-HT and 3H-NA in vitro and in vivo
[0107] The test substances were administered intraperitoneally half an hour before the animals
were killed. The midbrain was taken out, sliced and incubated in a mixture consisting
of 0.2 nmole of
14C-5-HT, 0.2 nmole of
3H-NA and 11 µmole of glucose in 2 ml of Krebs Henseleit-buffer, pH 7.4 per 100 mg
of brain slices. The incubation 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 u
p were determined by liquid scintillation. The doses producing 50 per cent decrease
of the active uptake (ED
50) 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.
[0108] 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 IC
50 of
14C-5-HT and 3-H-NA was determined graphically from dose response curves.
[0110] 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 160 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.
[0111] 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
neurotransmit- tor deficiency is unknown as well as in those cases wherein it is established
that the deficiency pertains to both noradrenaline and 5-hydroxytryptamine.
[0112] The invention is summarized in the following clauses:
A. A compound cf the general formula

wherein the dotted line represents an optional 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, a trifluoromethyl group or an amino, mono- or di-lower alkylamino
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, a trifluoromethyl group
or an amino, mono- or di-lower alkylamino group, R represents a lower alkyl group,
and R1 represents hydrogen or a lower alkyl group, whereby and represents hydrogen or a
lower alkyl group, whereby "lower" indicates a group having up to 3 carbon atoms;
or a therapeutically acceptable acid addition salt thereof, in anhydrous form or in
any degree of hydration possible, or a bioprecursor thereof.
B. A compound of the general formula

wherein Ar, X, R, and R1 have the meaning defined in clause A, or a salt or bioprecursor thereof as defined
in clause A.
C. A compound of the general formula

wherein Ar, X, R and R have the meaning defined in clause A, or a salt or bioprecursor
thereof as defined in clause A.
D. A compound according to caluse B in the form of a pure diasteromer.
E. A compound according to clause C in the form of a pure geomatrical isomer.
F. A compound according to clause A in the form of a pure optical enentiomer.
G. A compound according to clause A wherein Ar represents the group

H. A compound according to clause G wherein X represents hydrogen.
J. A compound according to clause H wherein Y represents F, Br, or CH3O-.
K. A compound selected from the group consisting of:
(β)-3-(4-fluorophenyl)-1-methyl-3-phenylpropylamine,
(β)-3-(4-bromophenyl)-1-methyl-3-phenylpropylamine,
(α)-3-(4-methoxyphenyl)-1-methyl-3-phenylpropylamine,
(β)-3-(3-bromophenyl)-1-methyl-3-phenylpropylamine,
(α)-3-(2-bromophenyl )-1-methyl-3-phenylpropylamine,
(E)-3-amino-1-(3-bromophenyl)-1-phenylbutene,
(Z)-3-amino-1-(3-bromophenyl)-1-phenylbutene,
3-amino-1,1-di-(4-methoxyphenyl)-1-butene,
3, 3-di-(4-fluorophenyl ) -1-methylpropylamine,
(β) -3- (4-methoxyphenyl)-1-methyl-3-phenylpropylamine, and
(E) -3-amino-1-(4-bromorhenyl)-1-phenylbutene,
or a salt or bioprecursor thereof as defined in clause A.
L. A compound according to one or more of the precading clauses wherein R is a methyl
group.
M. A compound according to one or more of the preceding clauses wherein R is hydrogen.
N. A process for preparing a compound of the general formula

wherein the dotted line represents an optional 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, a trifluoromethyl group or an amino, mono- or di-lower
alkylamino 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, a trifluoromethyl
group or an amino, mono-or di-lower alkylamino group, R represents a lower alkyl group,
and R1 represents hydrogen or a lower alkyl group, whereby "lower" indicates a group having
up to 3 carbon atoms, character ized in
a) reducing a compound of the formula

wherein Ar, X and R have the meaning defined in clause A and R is a hydrogen atom
or an alkyl, an acyl or an alkylsulfonyl group having 1-3 carbon atoms, to the obtention
of a compound of formula Ia, in which R1 is hydrogen, or
b) preparing a reactive ester of an alcohol of the formula

wherein Ar, X, and R have the meaning defined in clause A, and reacting the ester
obtained with an amine of the formula NH2R1, wherein R1 has the meaning defined in clause A, or
c) reducing a compound of the formula

wherein Ar, X, R, and R1 have the meaning defined in clause A ord) reacting a ketone of the formula


wherein Ar, X, and R have the meaning defined in clause A, with ammoniumformate or
methylammoniumformate according to Leuckart-Wallach,
e) dehydrating a carbinol of the formula

to a compound of formula Ib.
f) reacting a compound of the formula

wherein Ar, X, and R have the meaning defined above and Z is a leaving group with
an amine of the formula NH2R1 or a derivative thereof to the formation of a primary or secondary amine of formula
Ib above, which formation involves conversion of an amine derivative when a derivative
of an amine of the formula NH2R1 is employed, or
g) oxidizing the benzylic carbon atom of a compound of the formula

wherein Ar, X, and R have the meaning defined above and R" and R"' are protective
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

which is transformed into the compound of formula Ib by splitting; and if desired
converting a primary amine obtained according to any process alternatives a) to g)
above into the corresponding secondary amine by methylation, and if desired converting
the primary or secondary amine obtained into a therapeutically acceptable acid addition
salt thereof in anhydrous form or any degree of hydration possible.
P. A compound useful as an intermediate in preparation of the compound defined in
clause A, characterized by the formula

wherein Ar, X, and R have the meaning defined in clause A and R' is a hydrogen atom
or an alkyl, an acyl or an alkylsulfonyl group having 1-3 carbon atoms.
Q. A compound useful as an intermediate in preparation of the compound defined in
clause A, characterized by the formula

wherein Ar, X, and R have the meaning defined in clause A.
S. A compound useful as an intermediate in preparation of the compound defined in
clause A, characterized by the formula

wherein Ar, X, and R have the meaning defined in clause A.
T. A compound useful as an intermediate in preparation of the compound defined in
claim 1, characterized by the formula

wherein Ar, X, R, and R1 have the meaning defined in clause A,
U. A compound useful as an intermediate in preparation of the compound defined in
clause A, characterized by the formula

wherein Ar, X, R1, and R have the meaning defined in clause A and Z represents F, Cl, Br, I, OS02R; wherein R' is an anlkyl, aralkyl, or aryl group.
V. A compound useful as an intermediate in preparation of the compound defined in
clause A, characterized by the formula

wherein Ar, X, and R have the meaning defined in clause A, and R" and R'" are protective
groups for the amino function.
AA. A compound useful as an intermediate in preparation of the compound defined in
clause A, characterized by the formula

wherein Ar, X , and R .°, have the meaning defined in clause A .
AB. A compound useful as an intermediate in preparation of the compound defined in
clause A, characterized by the formula

wherein Ar, X, and R have the meaning defined in clause A .
AC. A pharmaceutical preparation which comprises as active ingredient a therapeutically
effective amount of a compound defined in clause A or a pharmaceutically acceptable
salt thereof, in association with a pharmaceutically acceptable carrier.
AD . A method for the treatment of depressions, characterized in administration to
a host suffering from such ailment a therapeutically acceptable amount of a compound
defined in clause .A or a pharmaceutically acceptable salt thereof.
AE. A method for the treatment of anxiety, characterized in administration to a host
suffering from such ailment a thara- peutically acceptable amount of a compound defined
in clause A or a pharmaceutically acceptable salt thereof.
AF.. A compound, a process for preparing a compound, a compound useful as an intermediate,
a pharmaceutical preparation and a method of treatment as defined in any of clauses
A to AF and substantially as described.