[0001] The present invention is related to new compounds of the diarylalkylamine type having
thereapeutic activity, to methods for preparing such compounds, to pharmaceutical
preparations comprising such compounds and to methods of treatment employing such
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 discloses compounds corresponding to the general formula:
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=CI, R
II=OH, R
III=CH
3, R
IV=H having hypotensive properties, by British Patent 765,881: R
I=R
II=R
III=R
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 62/4154 discloses i.a. a compound having the formula
claimed to have a therapeutic utility especially as an antitussive.
[0006] In J. Med. 14 161 (1971) a compound of the formula
is disclosed as an antidepressant.
[0007] Chemical Abstract vol. 82 (1975) 170339c discloses the compound of the formula
as a chemical intermediate.
Related patent application
[0008] Certain intermediates disclosed in the present specification are claimed in a European
divisional patent application having no. 80105028.7.
General Outline of the Invention
[0009] According to the present invention it has been found that compounds of the general
formula below have advantageous, therapeutic properties:
[0010] In these compounds the dotted line represents an optional double bond. These compounds
may be divided into two groups defined by the formulae
[0011] 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
1 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.
Therapeutically acceptable salts 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.
[0012] The compounds of formula la above wherein Ar is identical to the group
contain one asymmetric carbon atom. The remaining compounds of formula la 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 la
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.
[0013] 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
may exist in different stereoisomeric forms, that is in cis-trans isomers or, according
to the IUPAC nomenclature (J. Org. Chem. 35, 2849-2867, Sept. 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.
[0014] 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.
E-form
Z-form
[0015] 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.
[0016] The invention relates in one aspect to pharmaceutical compositions comprising as
active ingredient a therapeutically effective amount of a compound of the formula
I.
[0017] The invention relates also to compounds of the formula I for use in the treatment
of depressions and for use in the treatment of anxiety.
[0018] The invention also relates to such compounds per se of the formula I wherein X is
hydrogen.
[0019] The compounds of the invention show an activity in the central 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 tranquilizing agents in man.
Preferred Embodiment of the Invention
[0020] 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
30-.
[0021] As preferred individual compounds should be mentioned:
(β)-3-(4-fluorophenyl)-1-methyl-3-phenylpropylamine,
(β)-3-(4-bromophenyl)-1-methyl-3-phenylpropylamine,
(a)-3-(4-methoxyphenyl)-1-methyl-3-phenylpropylamine, and
(/3)-3-(3-bromophenyl)-1-methyl-3-phenylpropylamine being non-selective inhibitors
of neuronal noradrenaline and 5-hydroxytryptamine 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)-1-butene,
3,3-di-(4-fluorophenyl)-1 -methylpropylamine,
(β)-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 mechanism are discussed further
in the chapter "Pharmacological evaluation" below.
[0022] 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
[0023] The compounds of the formula I 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 la 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 NH2R', 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 catalytic 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 methylammonium-
formate 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.
[0024] The intermediates of formulae II, III, and IV above are novel.
[0025] The intermediates of formula II may be prepared by reacting the ketone of the formula
IV above a hydroxylamine derivative of formula NH
20R
I, wherein R
1 has the meaning defined above.
[0026] The intermediate of formula III may be prepared by hydride reduction of the compound
of formula IV which, in turn, 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 diarylcarbinol of the formula
wherein Ar and X have the meaning defined above, first with thionyl chloride, then
with ethyl acetoacetate in the presence of suitable condensation catalyst such as
sodium acetate or the like.
[0027] The compounds of formula la 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.
[0028] The new compounds of formula la 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 corresponding optically
active modifications. If desired, the optically active modifications may be prepared
by way of direct synthesis, e.g. via an optically active compound as described above.
[0029] 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 lb.
[0030] The dehydration of the starting material may be done by means of treatment with hydrochloric
acid HCI and heating of the reaction 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
3P0
4, potassium hydrogen sulphate KHS0
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.
f) Reaction of a compound of the formula
wherein Z is a leaving group such as F, Cl, Br, I, OSO2R1, wherein R1 is alkyl, aralkyl or aryl, with an amine of the formula NH2R1 or with a derivative thereof such as hexamethylenetetraamine, alkali phthalimide,
lithium bisbenzenesulfenamide, guanidine, sodium cyanate, sodium azide, a carboxamide,
or a sulfonamide. 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
lb. A preferred amine derivative is potassium phthalimide.
[0031] This reaction is also useful for preparation of the compounds of formula la by employing
as a starting material a saturated compound corresponding to the compound of formula
VIII.
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 compound of 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 of formula
la, by introducing in those compounds protective groups R" and R"' in a known manner
to the obtention of a compound of formula IX.
[0032] The intermediates of formulae VII, VIII, IX and X above are novel.
[0033] The intermediate of formula VII may be obtained by preparing a Grignard or lithium
compound from a halobenzene of the formula
Hal = Br, CI and reacting it with an ester of the formula
wherein R" is an alkyl, aralkyl or aryl group.
[0034] The intermediate formula VIII may be isolated (cf. Example 15) and subsequently dehydrated
or alternatively the crude product in the preparation of formula VII may be dehydrated
directly (cf. Example 17).
[0035] 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
[0036] In clinical practice the compounds of the formula I 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 compounds
of the formula I 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 diluent 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.
[0037] To produce pharmaceutical preparations containing a compound of the formula I 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 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 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.
[0038] For the preparation of soft gelatine capsules (pearl shaped 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] Suitable daily doses of the compounds of the formula I 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
[0043] 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 atomosphere, 23.5 g
(0.10 mol) of 1,3-dibromobenzene in 80 ml of ether was added. The rate of addition
was adjusted, to maintainn 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 +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 4-(3-bromophenyl)-4-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 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 4-(3-bromophenyl)-4-phenylbutan-2-one
oxime.
Example 2
Preparation of 3-(3-bromophenyl)-1-methyl-3-phenylpropylamine oxalate. (Method a)
[0044] 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 2M 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 HCI
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.
[0045] 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-phenylpropylamine into its diastereomers
[0046] The free amine (2.9 g, 0.009 mol) obtained from 3.8 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 (COCI,) 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 doublet at 1.5 ppm (J=6.1 Hz) (three protons).
[0047] Analysis: C calcd 57.15%, found 57.45%; H calcd 5.28%, found 5.35%; Br calcd 19.1%,
found 19.05%; N calcd 3.33%, found 3.20%; 0 calcd 15.23%, found 15.00%.
[0048] The solvents of the first mother liquors of 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.
[0049] Analysis: C calcd 59.7%, found 60.3%; H calcd 5.6%, found 5.7%; N calcd 3.9%, found
3.7%.
Example 4
[0050] (a1-3-(4-fluorophenyl)-1-methyl-3-phenylpropylamine oxalate, mp 186-188°C (EtOH-EtOAc,
1:1) and (f3)-3-(4-fluorophenyl)-1-methyl-3-phenylpropylamine hydrochloride, mp 171-172°C
(EtOAc) were prepared from 4-(3-fluorophenyl)-4-phenylbutan-2-one oxime in accordance
with Examples 2 and 3.
Example 5
[0051] (a)-3-(4-bromophenyl)-1-methyl-3-phenylpropylamine maleate, mp 168-170°C (EtOH-EtOAc,
1:1) and (β)-3-(4-bromophenyl)-1-methyl-3-phenylpropylamine maleate, mp 161-162°C
(i-PrPH-EtOAc, 3:1) were prepared from 4-(4-bromophenyl)-4-phenylbutan-2-one oxime
in accordance with Examples 2 and 3.
Example 6
[0052] (a)-3-(4-methoxyphenyll-1-methyl-3-phenylpropylamine maleate, mp 146-148°C (i-PrOH)
and (f3)-3-(4-methoxyphenyl)-1-methyl-3-phenylpropylamine maleate, mp 124-133°C (EtOAc)
were prepared from 4-4-methoxyphenyl)-4-phenylbutan-2-one oxime in accordance with
Examples 2 and 3.
Example 7
[0053] (a)-1-methyl-3-(4-trifluoromethylphenyl)-3-phenylpropylamine maleate, mp 165-166°C
and (β)-1-methyl-3-(4-trifluoromethylphenyl)-3-phenylpropylamine maleate, mp 165-167°C
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
[0054] 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 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 HCI had been added. Extraction with ether, drying and
evaporation of the solvent gave 18.9 g of 2-bromo- benzalacetone 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 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
[0055] (α)-3-12-bromophenyl)-1-methyl-3-phenylpropylamine maleate, mp 145-146°C (i-PrOH)
and (f3)-3-(2-bromophenyl)-1-methyl-3-phenyl-propylamine maleate, mp 135-137°C (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 N,1-dimethyl-3-(4-bromophenyl)-3-phenylpropylamine
[0056] The free base of 3-(4-bromophenyl)-1-methyl-3-phenylpropylamine (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.
[0057] 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.
[0058] Treatment of the carbamate with 0.25 g (0.006 mol) of LiAIH
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.
[0059] The oxalate had mp 106-111°C from acetone.
Example 11
Preparation of 3-(3-bromophenyl)-1-methyl-3-phenylpropylamine. (Method d)
[0060] 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 evaporation of the solvent gave 30.5
g of a residue.
[0061] To this residue 85 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 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 (Na
2S0
4) and evaporation of the solvent gave 12.9 g of the desired amine.
[0062] 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. Recrystallization
from EtOH-EtOAc gave 8.4 g of the maleate, mp 158-161 °C.
[0063] 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 12
Preparation of 3,3-di-(4-fluorophenyl)-1-methylpropylamine hydrochloride (Method c)
[0064] 3,3-di-(4-fluorophenyl)-1-methylallylamine (0.9 g, 0.003 mol) was 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 effected 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. Crystallization
from EtOAc-i-Pr
20 gave 0.75 g of the desired product, mp 225-229°C.
[0065] Analysis: C calcd 64.5%, found 64.5%; H calcd 6.09%, found 6.11%; CI calcd 11.9%,
found 11.8%; F calcd 12.8%, found 12.7%; N calcd 4.70%, found 4.55%.
[0066] By the same method there were prepared from the appropriate allylamines:
Example 13
[0067] By the method of Example 12 3,3-di-(4-methoxyphenyl)-1-methyl-propylamine fumarate,
mp 153-157°C, (EtOH-i-Pr
zO) was prepared from the corresponding allylamine.
Example 14
[0068] 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
[0069] 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 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-amino-butyrate in 25 ml of diethyl ether was added
during 15 min.
[0070] The mixture was stirred for 1.25 hours at ice-cooling and then for 2.5 hours at reflux.
A cold aqueous 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.
[0071] Elemental analysis: C
18H
19Br
2NO
5: Found: C 44.5, H 4.0, N 2.7, and O 16.8%. Calculated: C 44.20, H 3.91, N 2.86 and
0 16.35%.
Example 16
Preparation of 3-amino-1,1-di(4-bromophenyl)-1-butene hydrochloride (Method e)
[0072] 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. Acetronitrile 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.p. 216-220°C.
[0073] Elemental analysis: C
16H
16Br
2CIN; Found: C 46.7, H 3.9, CI 8.8 and N 3.1 %. Calculated: C 46.02, H, 3.86, CI 8.49
and N 3.35%.
Example 17
Preparation of 3-amino-1,1-di(4-methoxyphenyi)-1-butene fumarate (Method e)
[0074] 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 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.
[0075] 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 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.
[0076] 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. 167167.5°C.
[0077] 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
[0078] 3-amino-1,1-di-(4-fluorophenyl)-l-butene fumarate was prepared according to Example
17. M.p. 225-231 °C.
Example 19
[0079] 3-amino-1,1-di-(3-methylphenyl)-1-butene hydrochloride was prepared according to
Example 17. M.p. 216-217.5°C.
Example 20
Preparation of 1-(4-bromophenyl)-1-phenyl-butene
[0080] Sodium dimethylsulfoxide in DMSO, prepared by heating 3.8 g (0.08 mol) sodium hydride
(50% in oil) in 100 ml dimethylsolfoxide at 80°C for 40 min, was mixed with 27.0 g
(0.07 mol) propyltriphenylphosphonium bromide, prepared by heating propylbromide and
triphenylphosphine in toluene at reflux temperature for 14 hours. The mixture was
stirred under nitrogen atmosphere at room temperature for 1.5 hours. 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
mixture was stirred for 2 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 residue. After trituration with
100 ml of diisopropylether crystal of triphenylphosphine oxide was separated by filtration.
Distillation of the filtrate at 4 Pa gave 12.2 of 1-(4-bromophenyl)-1-phenyl-butene,
b.p. 120-130°C. Yield 85%.
Example 21
Preparation of 3-(4-bromophenyl)-3-phenyl-1-methylallylbromide
[0081] To a solution of 22.6 g (0.0787 mol) of 1-(4-bromophenyl)-1-phenylbutene in 800 ml
of carbon tetrachloride 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-azobisbutyronitrile.
After 3.5 hours 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 diisopropyletherhexane
(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 purification due to its high reactivity
with nucleophilic agents.
Example 22
Preparation of 3-(N-phtalimido)-1-(4-bromophenyl)-1-phenylbutene (Method f)
[0082] A solution of crude 3-(4-bromophenyl)-3-phenyl-1-methylallylbromide (29 g, 0.08 mol)
in 50 ml carbon tetrachloride was mixed with 15.0 g (0.08 mol) of N-potassiumpthalimide
and 120 ml of anhydrous dimethylformamide. The mixture was stirred at 50°C for 14
hours.
[0083] 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: 2.6
g of the (Z)-form, R
f = 0.30, and 3.7 g of the (E)-form, R
f = 0.26 in diisopropylether-hexane (1:1).
Example 23
Preparation of (Z)-3-amino-1-(4-bromophenyl)-1-phenylbutene maleate
[0084] To a stirred solution of 0.43 g (0.001 mol) of (Z)-3-phtalimido-1-(4-bromophenyl)-1-phenyl-
butene in 30 ml of methanol 0.25 g (0.005 mol) of hydrazine hydrate was added at room
temperature. In order to dissolve all the phtalimide 10 ml of carbon tetrachloride
was added.The mxiture 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 HCI, 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. 174-176°C
from ethanol. The UV spectrum in ethanol had λ max 237 nm.
[0085] Elemental analysis: C
20H
20BrNO
4; 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
[0086] (E)-3-amino-1-(4-bromophenyl)-1-phenylbutene oxalate was prepared from the corresponding
phthalimide according to Example 23. M.p. 145-148
0C.
Example 25
Preparation of (Z)-3-amino-1-(3-bromophenyl)-1-phenylbut-1-ene maleate (Method f)
[0087] To a stirred solution of 0.43 g (0.001 mol) of (Z)-3-phtalimido-1-(3-bromophenyl)-1-phenyl-
butene in 40 ml of methanol 0.35 g (0.007 mol) of hydrazine hydrate was added at room
temperature. The mixure 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 HCI 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. 198-200°C.
[0088] Elemental analysis: C
2oH
2oBrN0
4: Found: C 56.3, H 4.7 and N 3.2%. Calculated C 57.43, H 4.82 and N 3.35%.
Example 26
[0089] (E)-3-amino-1-(3-bromophenyl)-1-phenylbutene hydrochloride was prepared from the
corresponding phthalimide according to Example 25. M.p. 118-123°C.
Example 27
[0090] (Z)-3-amino-1-(4-bromophenyl)-1-(3-pyridyl)-butene oxalate was prepared from the
corresponding phthalimide according to Example 25. M.p.
Example 28
Preparation of 3-(N-Phthalimido)-1-(4-bromophenyl)-1-phenylbutane
[0091] 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. Phthalic anhydride (20.0 g, 0.136 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 800 ml of ether and 500 ml of 2 M NaOH. The ethereal layer was separated
and washed with 100 ml I 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 phthalimides. The material was used without further purification. Yield: 83%.
Example 29
Preparation of 3-(N-phthalimido)-1-(4-bromophenyl)-1-phenylbut-1-ene (Method g)
[0092] To a stirred solution of 24.6 g (0.057 mol) 3-(N-phthaiimido)-1-(4-bromophenyi)-1-phenyi-
butane 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-azoisobutyronitrile 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 CDCI
3 showed a double quartet at 5.0 ppm from TMS 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.
[0093] The following examples illustrate how the compound of the present invention may be
included in pharmaceutical preparations.
Example 30
Preparation of soft gelatin capsules
[0094] 500 g of active substance were mixed with 500 g of corn oil, whereupon the mixture
was filled in soft gelatin capsules, each capsule containing 100 mg of the mxiture
(i.e. 50 mg of active substance).
Example 31
Preparation of soft gelatin capsules
[0095] 500 g of active substance were mixed with 750 g of peanut oil, whereupon the mixture
was filled in soft gelatin capsules, each capsule containing 125 mg of the mixture
(i.e. 50 mg of active substance).
Example 32
Preparation of tablets
[0096] 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 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
[0097] 100 g of active substance were dissolved in 2500 g of peanut 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
Preparation of a syrup
[0098] 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
[0099] 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 dropping solution was obtained.
Example 36
Preparation of effervescing tablets
[0100] 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.
Example 37
Preparation of a dropping solution
[0101] 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 dropping solution was obtained.
Example 38
Preparation of a sustained release tablet
[0102] 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
[0103] 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 5-hydroxytryptamine (5-HT), are of great interest in this respect.
[0104] It has been demonstrated that NA, DA and 5-HT is localised in three different types
on 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 mechanism at the cell membrane
and enzymatic conversion by catechol-0-methyltransferase to form methylated metabolites.
There is also an inactivating enzyme within the varicosities, monoamine oxidase (MAO),
that is stored in the mitochondria and inactivates the amines intracellularly.
[0105] When MAO-inhibitors are administered, an increased amount of transmittor substance
becomes available for release at the nerve ending.
[0106] 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.
[0107] It has been proposed, that some depressions are caused by deficiency in either one
of the neuro- transmittors and some of deficiency in both.
[0108] 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
[0109] 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
[0110] 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 (Trade
Mark) and the amounts of radioactive amines taken up were determined by liquid scintillation.
The doses producing 50 percent 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.
[0111] 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.
[0113] 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 180 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.
[0114] 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 deficiency is unknown as well as in those cases wherein it is established
that the deficiency pertains to both noradrenaline and 5-hydroxytryptamine.
1. Composé, caractérisé en ce qu'il répond à la formule générale:
dans laquelle le trait en pointillé représente une double liaison facultative et Ar
représente le radical
où Y est fixé en position 2,3 ou 4 et représente un radical alkyle inférieur ou un
radical alcoxy inférieur, un atome d'halogène, un radical trifluorométhyle, ou un
radical amino ou mono- ou di-alkyl (inférieur)-amino, ou bien Ar représente un radical
pyridyle fixé en position 2, 3 ou 4, X représente un atome d'hydrogène, R représente
un radical alkyle inférieur et R
1 représente un atome d'hydrogène ou un radical alkyle inférieur, le terme "inférieur"
désignant un radical ayant jusqu'à 3 atomes de carbone, ou ses sels d'addition avec
des acides thérapeutiquement acceptables, sous forme anhydre ou hydratée.
2. Composé selon la revendication 1, caractérisé en ce qu'.il répond à la formule:
dans laquelle Ar, X, R et R
1 sont tels que définis dans la revendication 1, ou un sel d'addition de ce composé
avec un acide thérapeutiquement acceptable.
3. Composé selon la revendication 1, caractérisé en ce qu'il répond à la formule:
dans laquelle Ar, X, R et R
1 sont tels que définis dans la revendication 1, ou un sel d'addition de ce composé
avec un acide thérapeutiquement acceptable.
4. Composé selon l'une quelconque des revendications 1 à 3, caractérisé en ce qu'il
est sous la forme (a) d'un diastéréoisomère pur, (b) d'un isomère géométrique pur
ou (c) d'un énantiomère optique pur.
5. Composé selon l'une quelconque des revendications 1 à 3, caractérisé en ce que
Ar représente le radical
6. Composé selon la revendication 5, caractérisé en ce que Y représente F, Br ou CH30-.
7. Composé selon l'une quelconque des revendications 1 à 6, caractérisé en ce que
R est un groupe méthyle.
8. Composé selon l'une quelconque des revendications 1 à 7, caractérisé en ce que
R1 est de l'hydrogène.
9. Composé selon la revendication 1, caractérisé en ce qu'il est la (bêta)-3-(4-fluorophényl)-1-méthyl-3-phényl-propylamine.
10. Composé selon la revendication 1, caractérisé en ce qu'il est la (bêta)-3-(4-bromophényl)-1-méthyl-3-phényl-propylamine.
11. Composé selon la revendication 1, caractérisé en ce qu'il est l'(alpha)-3-(4-méthoxyphényl)-1-méthyl-3-phényl-propylamine.
12. Composé selon la revendication 1, caractérisé en ce qu'il est la (bêta)-3-(3-bromophényl)-1-méthyl-3-phényl-propylamine.
13. Composé selon la revendication 1, caractérisé en ce qu'il est l'(alpha)-3-(2-bromophényl)-1-méthyl-3-phényl-propylamine.
14. Composé selon la revendication 1, caractérisé en ce qu'il est 1'(E)-3-amino-1-(3-bromo-
phényl)-1-phényl-butène.
15. Composé selon la revendication 1, caractérisé en ce qu'il est le (Z)-3-amino-1-(3-bromo-
phényl)-1-phényl-butène.
16. Composé selon la revendication 1, caractérisé en ce qu'il est la (bêta)-3-(4-méthoxyphényl)-'
1-méthyl-3-phényl-propylamine.
17. Composé selon la revendication 1, caractérisé en ce qu'il est l'(E)-3-amino-1-(4-bromo-
phényl)-1-phényl-butène.
18. Préparation pharmaceutique, caractérisée en ce qu'elle comprend, à titre de constituant
actif, une quantité thérapeutiquement efficace d'un composé de formule
dans laquelle le trait en pointillé représente une double liaison facultative et Ar
représente le radical
où Y est fixé en position 2, 3 ou 4 et représente un radical alkyle inférieur ou un
radical alcoxy inférieur, un atome d'halogène, un radical trifluorométhyle, ou un
radical amino ou mono- ou di-alkyl (inférieur)-amino, ou bien Ar représente un radical
pyridyle fixé en position 2, 3 ou 4, X représente un atome d'hydrogène, un radical
alkyle inférieur ou alcoxy inférieur, un atome d'halogène, un radical trifluorométhyle,
ou un radical amino ou mono- ou di-alkyl (inférieur)-amino, R représente un radical
alkyle inférieur et R
1 représente un atome d'hydrogène ou un radical alkyle inférieur, le terme "inférieur"
désignant un radical ayant jusqu'à 3 atomes de carbone, ou ses sels d'addition avec
des acides thérapeutiquement acceptables, sous forme anhydre ou hydratée.
19. Préparation pharmaceutique selon la revendication 18, caractérisée en ce qu'elle
comprend à titre de constituant actif, un composé selon l'une quelconque des revendications
1 à 17.
20. Composé caractérisé en ce qu'il répond à la formule:
dans laquelle Ar, X, R et R
1 sont tels que déinis dans la revendication 18, et est destiné au traitement des dépressions.
21. Composé selon l'une quelconque des revendications 1 à 17, caractérisé en ce qu'il
est destiné au traitement des dépressions.
22. Composé, caractérisé en ce qu'il répond à la formule:
dans laquelle Ar, X, R et R
1 sont tels que définis dans la revendication 18, et est destiné au traitement de l'anxiété.
23. Composé selon l'une quelconque des revendications 1 à 17, caractérisé en ce qu'il
est destiné au traitement de l'anxiété.
24. Composés utiles commes intermédiaires dans la préparation du composé défini dans
la revendication 1, caractérisé en ce qu'il répond à la formule:
dans laquelle Ar, X et R sont tels que définis dans la revendication 1, et R" et R"'
sont des groupes protecteurs de la fonction amino;
dans laquelle Ar, X et R sont tels que définis dans la revendication 1, et R" et R"'
sont des groupes protecteurs de la fonction amino.
1. Verbindung der allgemeinen Formel
worin die gepunktete Linie eine eventuelle Doppelbindung bedeutet und Ar die Gruppe
bedeutet, worin Y in der 2-, 3- oder 4-Stellung gebunden ist und eine niedermolekulare
Alkylgruppe oder niedermolekulare Alkoxygruppe, ein Haloqenatom, eine Trifluormethylgruppe
oder eine Aminogruppe, Mono- oder Diniederalkylaminogruppe bedeutet, oder Ar eine
in der 2-, 3- oder 4-Stellung gebundenen Pyridylgruppe bedeutet, X ein Wasserstoffatom
bedeutet, R eine niedermolekulare Alkylgruppe bedeutet und R
1 Wasserstoff oder eine niedermolekulare Alkylgruppe bedeutet, worin "niedermolekular"
bzw. "nieder" eine Gruppe mit bis zu 3 Kohlenstoffatomen bedeutet, oder ein therapeutisch
verträgliches Säureadditionssalz derselben in wasserfreier oder hydratisierter Form.
2. Verbindung nach Anspruch 1 der Formel
worin Ar, X, R und R
1 die in Anspruch 1 angegebene Bedeutung haben, oder ein therapeutisch verträgliches
Salz derselben.
3. Verbindung nach Anspruch 1 der Formel
worin Ar, X, R und R
1 die in Anspruch 1 angegebene Bedeutung haben, oder ein therapeutisch verträgliches
Salz derselben.
4. Verbindung nach einem der Ansprüche 1, 2 und 3 in der Form
a) eines reinen Diastereoisomeren,
b) eines reinen geometrischen Isomeren oder
c) eines reinen optischen Enantiomeren.
5. Verbindung nach einem der Ansprüche 1, 2 und 3, worin Ar die Gruppe
bedeutet.
6. Verbindung nach Anspruch 5, worin Y, F, Br der CH30- bedeutet.
7. Verbindung nach einem der Ansprüche 1 bis 6, worin R eine Methylgruppe ist.
8. Verbindung nach einem der Ansprüche 1 bis 7, worin R1 Wasserstoff ist.
9. Verbindung nach Anspruch 1, bestehend aus (ß)-3-(4-Fluorphenyl)-1-methyl-3-phenylpropyl-
amin.
10. Verbindung nach Anspruch 1, bestehend aus (ß)-3-(4-Bromphenyl)-1-methyl-3-phenyl-
propylamin.
11. Verbindung nach Anspruch 1, bestehend aus (a)-3-(4-Methoxyphenyl)-1 -methyl-3-phenyl-
propylamin.
12. Verbindung nach Anspruch 1, bestehend aus (β)-3-(3-Bromphenyl)-1-methyl-3-phenyl-
propylamin.
13. Verbindung nach Anspruch 1, bestehend aus (a)-3-(2-Bromphenyl)-1-methyl-3-phenyl-
propylamin.
14. Verbindung nach Anspruch 1, bestehend aus (E)-3-Amino-1-(3-bromphenyl)-1-phenylbuten.
15. Verbindung nach Anspruch 1, bestehend aus (Z)-3-Amino-1-(3-bromphenyl)-1-phenylbuten.
16. Verbindung nach Anspruch 1, bestehend aus (ß)-3-(4-Methoxyphenyl)-1-methyl-3-phenyl-
propylamin.
17. Verbindung nach Anspruch 1, bestehend aus (E)-3-Amino-1-(4-bromphenyl)-1-phenylbuten.
18. Pharmazeutisches Präparat, das als aktiven Bestandteil eine therapeutisch wirksame
Menge einer Verbindung der Formel
worin die gepunktete Linie eine eventuelle Doppelbindung bedeutet und Ar die Gruppe
bedeutet, worin Y in der 2-, 3- oder 4-Stellung gebunden ist und eine niedermolekulare
Alkylgruppe
5 oder niedermolekulare Alkoxygruppe, eine Halogenatom, eine Trifluormethylgruppe oder
eine Aminogruppe, Mono- oder Diniederalkylaminogruppe bedeutet, oder Ar eine in der
2-, 3- oder 4-Stellung gebundenen Pyridylgruppe bedeutet, X Wasserstoffatom, eine
niedermolekulare Alkylgruppe oder niedermolekulare Alkoxygruppe, ein Halogenatom,
eine Trifluormethylgruppe oder eine Aminogruppe, Mono-oder Diniederalkylaminogruppe
bedeutet, R eine niedermolekulare Alkylgruppe bedeutet und R
1 Wasserstoff oder eine niedermolekulare Alkylgruppe bedeutet, worin "niedermolekular"
bzw. "nieder" eine Gruppe mit bis zu 3 Kohlenstoffatomen bedeutet, oder ein therapeutisch
verträgliches Säureadditionssalz derselben in wasserfreier oder hydratisierter Form
in Verbindung mit einem pharmazeutisch verträglichen Trägermaterial enthält.
19. Pharmazeutisches Präparat nach Anspruch 18, das als aktiven Bestandteil ein Verbindung
nach einem der Ansprüche 1 bis 17 enthält.
20. Verbindung der Formel
worin Ar, X, R und R
1 die in Anspruch 18 angegebene Bedeutung haben, für die Verwendung bei der Behandlung
von Depressionen.
21. Verbindung nach einem der Ansprüche 1 bis 17 für die Verwendung bei der Behandlung
von Depressionen.
22. Verbindung der Formel
worin Ar, X, R und R
1 die in Anspruch 18 angegebene Bedeutung haben, für die Verwendung bei der Behandlung
von Beklemmungen oder Angstzuständen.
23. Verbindung nach einem def-Ansprüche 1 bis 17 für die Verwendug bei der Behandlung
von Beklemmungen oder Angstzuständen.
24. Verbindungen, brauchbar als Zwischenprodukte bei der Herstellung der in Anspruch
1 definierten Verbindung, gekennzeichnet durch die Formel
worin Ar, X und R die in Anspruch 1 angegebene Bedeutung haben und R" und R"' Schutzgruppen
für die Aminofunktion sind, und durch die Formel
worin Ar, X und R die in Anspruch 1 angegebene Bedeutung haben und R" und R"' Schutzgruppen
für die Aminofunktion sind.