Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
3~
Depressive disorders have with more or less success been treated
with various compounds.
The antidepressive agents having the most widespread7 clinical
use are the tricyclic tertiary amines imipramine having the st~ctural
formula
I CH
CH2CH2CH2-~<
H3
and amitriptyline having the structural formula
~ ':.
CHCH2CH2-N < 3
Secondary amines such as desipramine having the structural formula
~ ~ ~ ~ / H
CH2CH2CH2-N
and nortriptyline having the structural formula
~ H
CHCH2CH2N ~ CH
~ -
are used to a somewhat less extent. These substances have, however, side
effects that are not desired at therapeutic use, such as orthostatism,
. ,~ ,
anticholinergic effects and above all, an arrhythmogenic i.e. heart arrhythmia
developing effect, on administration in large doses to elderly patients.
Moreover,all the substances mentioned show the disadvantage that the
-1- , ,:
~56~
antidepressive effect starts first after some weeks of treatmentO
Further, it is known from the literature that certain l,l-diphenyl-
3-aminoprop-1-enes~ such as the compound haYing the formula
\
(~CHCH2 \
~ / C~3
have an antidepressive effect; see J. Med. Chem. 14, 161-4 (19
Compounds having the formula
~ '~ - .' ' ,. "
X ~ R
CHch2C~
.'
wherein X is chlorine or bromine and R is hydrogen or methyl~ are described
to have antidepressive effect, see United States Patent No. 3,423,510. These
: . .
compounds however also have a strong antihistaminic effect. From the
literature it is also known that a compound having the formula
Br ~
CH3
C=CHCH2N'\
C 3
M
' ' ',' '' '
has an antidepressi~e activity in animals see Belgian Patent Specification ;
No. ~81glO5.
In clinical practice different types of depressive disorders are
' ~'
_2- :
3L/~
recognized. Depressed patients respond in different ways to the various
anti-depressants clinically used. Most of these substances inhibit the
neuronal uptake of noradrenaline, and some of them additionally inhibit
the uptake of 5-hydroxytryptamine. It is believed that inhibition of the
uptake of 5-hydroxy~ryptamine is the mechanism behind a mood eleva~ing
property seen in some of these anti-depressants. In addition to the
absolute values for inhibition of the uptake of either 5 hydroxytryptamine
or noradrenaline the selectivity towards uptake of either of these two amines
is of great interest.
The present invention seeks to provide a new compo~d having a
good antidepressive effect. The invention also seeks to provide a compound
having an antidepressive effect, and giving rise to only minor side-effects,
in particular arrhythmogenic effects; additionally this compound usefully
has a therapeutical effect against an~iety.
The compound of the invention is characterized by the formula
~r
Il /H
CHCH2N
Pharmaceutically a¢ceptable salts of this compound are included
within this invention.
Due to the lack of free rotation in the double bond the compound
of this invention may exist in different stereoisomeric forms, that is in
cis-trans isomers or, according to the IUPAC nomenclature (J. Org. Chem.
35~ 2849~2867, September 1970)~ in an E-form and a Z-form. The compound
may be used therapeutically as a mixture of geometrical isomers or in pure
E or Z form. The pure geometrical isomers may be prepared from an isomer
, ,,, ~ , ~ ., , . .
. , . - , . . .
~S~3'~
mixture~ from an isomer-pure starting material or directly by a
stereoselective synthesis.
The compound of this invention may be administered in the form of
a Eree base or as a salt thereof. Some typical examples of these salts are
the hydrobromide, hydrochloride, phosphate, sulphate, sulphamate, lactate,
acetate~ citrate, tartrate, malate and maleate.
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, acid addition salt, e~g. as one of
those suggested abo-ve in association with a pharmaceutically acceptable
carrier. ~ccordingly, terms relating to the novel compound of this
invention 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 a
capsule. These pharmaceutical preparations constitute a further aspect of
this inventionO Usually the active substance will constitute from 0 1 to 95%
by weight of the preparation, more specifically from 0.5 to 20% by weight for
preparations intended for injection and from 2 to 50% by weight for
preparations suitable for oral administration.
To produce pharmaceutical preparations containing a compound of
the invention in the form of dosage units for oral application, the selected ~-
compound may be mixed with a solid pulverulent carrier, eOg, lactose,
saccharose, sorbitol, mannitol, starches such as potato starch, corn starch
or amylopectin, cellulose derivatives, or gelatine, and a lubricant such as
magnesium stearate, calcium stearate or polyethylene glycol waxes, and then
compressed to form tablets. If coated tablets are required, the cores,
prepared as described above~ may be coated with a concentrated sugar ~ ;
3~
solution which may contain, e.g. gum arabic, gelatine, talcum or titanium
dioxide. Alternatively, the tablet can be coated with a lacquer dissolved
in a readily volatilc organic solvent or mixture of organic sol~ents.
Dyestuffs may be added to these coatings in order to readily distinguish
between tablets containing different active substances of different amounts
of the active compo~md.
For the preparation of soft gelatine capsules (pearl-shaped closed
capsules) consisting of gelat~ne 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, pulve~ulent carriers such as lactose, saccharose,
sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin)~
cellulose derivatives or gelatiMe.
Dosage units for rectal application can be prepared in the form
of suppositories comprising the active substa~cein admixture with a neutral
fatty base, or gelatine rectal capsules comprising the active substance in
admixture with ~egetable oil or paraffin oil.
Liquid preparations for oral application may be in the form of -
syrups or suspensions for example, solutions containing from about nO2% to
about 2G% 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, saccharine and carboxymethylcellulose as a thickening agent.
Solutions for parenteral applications by injection can be prepared
in an aqueous solution of a water-soluble pharmaceutically acceptable salt
of the active substance preferably in a concentration of from about 0.5% to
about 10% by ~eight~ These solutions may also contain stabilizing agents
and/or buffering agents and may conveniently be provided in various dosage
unit ampoules.
,, , ., , ,: . :
- . :, ............ .
Suitable daily doses of the compo~mds of the invention at
therapeutical treatment is 25 to 250 mg at peroral administration, preferably
50 to 150 mg and 5 to 50 mg at parenteral administra~ion, preferably 10 to
30 mg. A preparation in dosage unit form for oral administration may
contain 10-50 mg, preferably 10 to 25 mg of active substance per dosage
unit.
The preferred isomer of the compound of the invention is the Z-
isomer having the structural formula
~ ~ '
C
/ \ -
CH3NHCH2 H
Preferably the compound of the invention will be prepared and used in the
~orm of its salt.
Method of ~re~aration
.
A. Dehydration of a compound of the formula
~3~ e)fBr
;~
HO CH2CH2NHCH3
to a compound of the form~la I. ;
The dehydration of the starting material may for example be done
by means of treatment with sulphuric acid 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 hydrochloric acid, HCl~
phosphoric acid, H3P04, potassium hydrogen sulphate, KHS04, or oxalic acid
~COOH)2. Other methods for the dehydration of the starting material to
~3~ 3~ :
the formation of a compound of the formula I are dehydration using phosphor-
oxichloride PoC13 in pyridine, and dehydration with thionylchloride,
SOC12~ in pyridine. Also a catalytic dehydration of the starting material
may be used. The dehydration is in this case carried out at a temperature
of about 300 to 500 C using a catalyst such as kaolin, alumina or aluminium
oxide.
B. Demethylation of a compound of the formula
Br
C
1I CH
CHCH2N ~ ' : '
to the formation of a compound of the formula I.
C. AIkylation of monomethylamine with a compound of the formula
r
CHCH2-Y
wherein Y is a leaving group to the formation of a compound of the formula I.
Illustrative examples of Y are halogens such as Cl, Br and I or
sulphonates such as methanesulphonate, toluenesulphonate and benzene-
sulphonate.
D. Introduction of a methyl group into a compound of the formula
13~
CHCH2NH2
18 to the formation of a compound of the formula I.
.
` ~1S~3~
E. Treatment under hydrolytic conditions of an acyl or sulphonyl
compound of the fomula
~ Br
/\
HO CN2CH2-NCH3-Z
wh0rein Z is an acyl or sulphonyl group to a compound of the fo = la I
either directly or via an intermediate of the fo = la
~C~~
` CHCH NCH -Z
::: :- .
Illustrative examples of Z are acetyl, benzoyl, methanesulphonyl,
benzoylmethanesulphonyl and toluenesulphonyl.
Intermediates
For the preparation of the compounds of formNla I it has been found
that certain hitherto unlmown compounds may be valuable.
: When preparing the compounds of fo = la I according to process A,
the compound
C .- :. .
HO CH2C~ZEHCH3
. . .
` is used as starting material.
. .
This starting materia1 can be prepared according to the reaction ~-
scheme . ~
::: ' . . -
-8~
'
/~ + Y-C~12COO-~
O HO CH2COOR
red >
/C\ / \ ,
HO CH2CONHCH3HO CH2CH2NHR
In the reaction scheme Y has the previously given definition and R
is a lower alkyl group with 1-5 carbon atoms, preferably an ethyl group.
The reduction in the last step is preferably carried out with a hydride
reagen~.
When preparing the compounds of the formula I according to process
C compounds of the formula
~f ~
CHCH~-Y
wherein Y is a leaving group are used as star~ing material.
Thls starting material can be prepared according to the reaction
scheme
> ~ ~
HO CH2COOR HO 2 2
dehydration and ~ ~ "Br
introduction of a
leaving group Y ~ N ~ ~
Il .
In the reaction scheme above Y and R have the previously given
definition. The reduction in the first step is preferably carried out using
LiAlH4. The last step is preferably accomplished using PBr3, which means
that the leaving group Y is Br.
The same starting material in which the leaving group is a halogen
may also be obtained by the following reaction scheme:
Br ~ Br
~ ~ Br CHCH
allylic halogenati,on N ,l ~ ,J
, _ ..... ,~ ~ \~ ~ ~.
CHCH2Y
wherein ~ is a halogen such as Cl, Br and I. The allylic halogenation is
carried out with a suitable halogenating agen1; such as a halogen succinimide.
When preparing the compound of the in~ention aceording to process
D a compound o~ the formula
3~Br
. .
11 '` . ':
CHCH2NH2
:. ... . .
is used as starting material. This compound may be prepared aecording to
methods similar to methods A, B, C and E described in paragraph d). '~r. .. ,, -.
Still further methods exist for the preparation of the starting
materials, so for instance according to the reaction seheme:
;' ' ',
"
--10~
3~
Li CH2CN
ll H0 CH2CN
O .'' . ~:
r ~ ~ ~ dr
~' ~ ~ ~ N
H0 CH2CH2NH2 H0 CH2 ~H2
NHC00-aIkyl 3
Examples
Pr~paration of intermediates
_ _ _ _ _ _ _ _ _ _ _ _
Example A.
Step 1
BrC1~2COalC2Hs ~ )3~ Br
Cl / \
0 H0 2 2 5
A mixture of 4-bromophenyl-3-p~ridyIketone ~CA 66, 37125 (1967); 50 g, 0.19
moles] and activated zinc (20 g~ in benzene (100 ml) was heated to reflux.
Ethyl bromoacetate (56 g, 0.35 moles) dissolved in benzene (50 ml) was
added carefully during 30 minutes. Another portion of zinc ~50 g) was
added and the ixture was refluxed~for 14 hours. After cooling and filtration,
benzene (300 ~1) was added to the ~iltrate, which was washed three times with
10% aqueous acetic acid solution.
Ethyl ether (200 ml)was added and the solution acidified with
10% hydrochloric acid. The precipitate was filtered off~ washed with ether
and dried. Yield: 75%. M.p~ 168-175 C~ -
' ,: ' '
3~
LiAlH4 ~ ~
~C\ / C ~ . .
HO CH2COOC2H5 HO CH2CH2OH
The base (9.5 g, 0.027 moles) from ethyl 3-(4-bromophenyl)-3-
-hydroxy-3-(3-pyridyl~propanoate hydrochloride (step 1) was prepared and
dissolved in ethyl ether (50 ml). This solution was added dropwise to an
ice-cold mixture of lithium aluminum hydride (1.0 g, 0.027 moles) and ethyl
ether (150 ml). The reaction mixture was refluxed for 5 hours, cooled and
a saturated sodium sulphate solution was added until a white precipitate ~-
was formed. This was filtered off and the ~iltrate evaporated. The residue
was crystallized from chloroform. 1-(4-bromophenyl)-1-(3-pyridyl)-1,3-
propanediol was obtained. Yield: 39%. M.p. 130-132 C.
~xam~_e B
Step 1
J~ ~C
C /\
/ \ HO CH2CONHCH
HO~ ~CH2COOC2N5
3 ~4-bromophenyl)-3-h~droxy-N-meth~1-3-(3-pyridyl)-propionamide
19,4 g (0.05 mole) of ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-
,
_pyridyl)-propanoate, 200 ml of 40% solution of methylamine in water and
30 ml of absolute ethanol was stirred for 24 hours at room temperature.
The precipitate was ~iltered off and recrystallized from isopropyl alcohol,
which ga~e 13.2 g (79%~ of the amide. M.p~ 188-191 C. The formula
C15H15BrN202 was yerified through elemental analysis. (The elemental
.~ . .
analyses throughout this application were carried out for all elements of the
,:
'..'.
-12-
3~ :~
compounds prepared, and are within ~ 0.4 per cent of the theoretical ~alues
if not otherwise stated.)
~ r ~ ~ r
HO \ CH CONHCH / \
~ 3 HO CH2CH2NHCH3
3-(4-bromophenyl)-3-hydroxy-N-meth~1-3-~pyridyl)-propylamine
To 1.0 g (3.1 mmole) of 3-(4-bromophenyl)-3 hydroxy-N-methyl-
-3-(3-pyridyl)-propionamide and 0.8 g (0.02 mole) of sodium borohydride in
60 ml of dry tetrahydrofuran at 0 and under N2, was added dropwise over 20
minutes 4.6 g (0.03 mole) of boron trifluoride ethyl etherate in 20 ml of
dry tetrahydrofuran. The mixture was stirred over night at room temperature,
and then cautiously hydrolyzed with water. Alcalization with 2M NaOH and
extraction with ether gave after evaporation C)~9 g of a semicrytsalline
residue. Recrystallization from ether-petroleumether gave 2.0 g (23%) of
the amine. M.p. 81-88 C.
Example C
~ ~ '.
Br
/.C C ',
HO CH2COOC2H5 HO CH2CONH2
3-(4~bromop_enyl)-3-hydroxy-3_(3 pyr dyl)-propionamide
0.8 g (2.5 mmole) of ethyl 3-(4-bromophenyl)-3-hydroxy-3_(3_
-pyridyl)-propanoate, 50 ml of aqueous an~lonia and lO ml of absolute ethanol
.
was stirred at room temperature for 24 hours. The white precipitate
obtained was collected by filtration. Recrystalli ation from isopropyl
: ~ ',.
-13-
';
, ~ . : . : . . . .
3~
alcohol gave 0~45 g (56%), m.p~ 213-214 C. The formula C14H13BrN202 was
verified through elemental analysis, C calculated 52r4, found 51.9.
Ste~p 2
N
HO CH2CONH2 HO CH2CH2N~2
3-(4-bromo~henyl)-3-hydrox~ 3-pyridyl~-propylamine
To loO g (3.1 mmole) of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-
-propionamide and 0.8 g ~0~02 mole) of sodium borohydride in 60 ml of dry
tetrahydrofuran at O C and under N2, was added dropwise over 20 minutes
4.6 g (0.03 mole) of boron trifluoride ethyl etherate in 20 ml of dry
tetrahydrofuran. The mixture was stirred for ~8 hours at room temperature,
and then cautiously hydrolyzed with water. ALcalization with 2M NaOH and
extraction with ether gave after evaporation a semi-crystalline residue.
Recrystallization from ether-petroleumether gave 0.6 g (63~) of the amine,
m.p. 95-115 C NMR-spectrum (COC13); 2H(2.4~ 1-CH2)m: 2H(3-0, 2-CH2) :
.
3H~3.6~ -OH, -NH2)b : 6H(7.1-8.0 ArH)m: 2H(8.6)m ~ -
Step 3
Ac~O ~
/ \ CHCH NH
HO \ CH2CH2~H2 2 2
3-(4-bromo~henvl~ 3-~3-~vridvl)-allYlamine
~..... . .
The raw product of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)- ~ -
-propylam~e (from 0.4 g of 3-(4-bromophenyl)-3-hydroxy-3_pyridyl)_
-propionamide) was added with stirring to 50 ml of acetic anhydride and
0.2S ml of concentrated sulphuric acid and the mixture was heated at 130
,.''~ :
-14-
~35~13~
for 45 minutes The mixture was then cooled, poured on to crushed ice,
alcalized with 30% NaOH and extracted with ether. Evaporation gave 0.36
g of an oil. After hydrolysis with 15 ml of concentrated hydrochloric acid
for four hours 0.2S g of an oil was obtained, thin layer chromatography
showed two spots with Rf=O.l and 0.8. CO1D chromatography on Silica Gel
with methanol as eluant gave 0.06 g of the faster moving fraction and 0.19
g of the slower one, which was the amine. The oxalate of this compound was
prepared. It was recrystallized from ethanol~ M.p. 153.5-155.5 C.
The NMR spectrum shows the vinyl proton as a double triplet at
lo 6.1-6.5 ppm indicating an isomer ratio 1:1.
The formula: C14H13BrN2 . 1 H~O was ~erified through elemental analysisO
The oxalate was further recrystallized from a mixture of equal
volumes of methanol and isopropyl alcohol and once from pure methanol. A
substance melting at 160-162 C was obtained. The NMR spectrum showed it to
be the Z isomer.
Example D
S_e~_l
W ~.W ~ ~r
HO 2
3-~-bromophenyl~-3-hydroxy-3-(3-p2~idyl)-propionit_ile
A mixture of 6.5 g (0.16 mole) of acetonitrile and SO ml of dry
tetrahydrofuran (T~F) was slowly added under N2-atm to a mixture of 100 ml
of 1.5 M n-buthyllithium in hexane and 50 ml of dry THF at -50C. After
stirring for 35 minutes a solution of 36.5 g (0.14 mole) of 4-bromophenyl-3-
pyridylketone in 250 ml of dry THF was added at -50 C. The temperature was
kept at -70 C for 15 minutes, then the reaction mixture became viscous and
it was allowed to reach ambient temperature. The product was poured into a
-15-
3 ~
stirred mixture of 500 g of ice-water and 500 ml of methylene chloride. The
layers were separated and the a~ous layer was extracted with 2x200 ml of
CH2C12. The combined organic layers were washed with water and dried. The
solvent was evaporated giving 39.7 g of an oil. It was dissolved in 550 ml
of hot i-PrOH a~d a solution of 35 ml of 4M HCl-ether (0.14 mole~ in 100 ml
of i-PrOH was added, After coolirg there was collected 34.6 (74 %) of the
hydrochloride of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propionitrile.
M.p. 158-161 C.
Step 2
~ ~ Br
2C
3-(4-bromophenyl-3-hydroxy-3-(3-pyridyl3-propylamine
17.2 g (0.056 mole) of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-
propionitrile was dissolved in 175 ml of T~ and diluted with 200 ml of
ether. The solution was cooled ~o -35 C and 4.0 g (0.112 mole) of LiAlH4 was
added in portions under N2-atm. The mixture was held at 0C for 2 hours then
at 15 C for 2 hours. 20ml of a solution o~ saturated Na2S04 was slowly added.
After 30 minutes the mixture was filtered and the inorganic salts were
washed with 2xlOO ml of ether. The filtrate was collected and the solvent -
was evaporated giving 14.7 g of an oil. It was diluted with 500 ml of hot
i-PrOH and 4.3 g ~0.048 mole~ of oxalic acid in 300 ml of hot i PrOH was
dropwise added. After cooling over night 11.8 g of crystals, m.p.
98-105 C were collected. An analytical sample of the free amine had m.p.
118-120 C from i-PrOH. Yield 51%.
-]6-
.
3'~
Step 3
~ ~Br ~ r
HO CH2CH2NH2 2 2
3-(4-bromophenyl)-3-(3-pyridyl)-allylamine
To 0.80 g (0.002 mole) of the oxalate of 3-(4-bromophenyl)-3-
-hydroxy-3-(3-pyridyl)-propylamine was added 6 ml of 70% H2S04 for 35 minutes.
Ice-waker was added, then 30 ml of 30% NaOH and the mixture was extracted
with 3xlOO ml of ether. Drying and evaporation of the solvent gave O.62 g
of an oil. This was dissolved in 10 ml of hot ethanol and a hot solution
of 0.20 g of oxalic acid in 5 ml of ethanol was added. Upon cooling 0.49 g
of crystals were collected. NMR showed the product to be a mixture of the
. .
E and z isomers of 3-(4-bromophenyl)-3-(3-pyridyl)-allylamine as in Example
C step 3.
Preparation of the end product
Example 1~ (Method C)
C NH2CH3 lC
\ CHCH,NHCH
HO CH2C~2H 3
1-(4-bromophenyl)-1-(3-pyrid~1)-1,3-propanediol (prepared in accordance with
Example A, 7.2 g, 0.023 moles) was dissolved in dry acetone (70 ml)7 Hydrogen
bromide was bubbled through the solution and the solvent was removed in
~acuum. Methylene chloride (50 ml) and phosphorus tribromide (6~4 g, 0.047
mole) w0re added to the residue and the mixture was refluxed for 14 hours,
poured into ice and made aIkaline with sodium carbonate, Methanol (50 ml) ;
was added to the organic phase and the solution was evaporated in vacuum at
~30 C to 30 ml, The solution was heated with monomethylamine (14 g, 0.47 -~ -
.. ~: .
: ' ' ' ' .
-17-
~ f~
mole~ in an autoclave at 110C for 15 hours. After coo]ing, the solvent was
evaporated and the residue was dissolved in ether (25 ml) and water (25 ml).
~he pH of the mixture was adjusted to 9.0 with ammonia and the layers were
separated. Another portion of water was added to the etheral layer and pH
was adjusted to 2.1 with HCl. The water-phase was treated with carbon black
and then made alkaline with ammonia and extracted with ether. The organic-
phase was dried with sodium sulphate and evaporated in vacuum. The residual
base was dissolved in ether (40 ml) and cooled on an ice bath. Hydro-
chloric acid in ether was added dropwise whereby a slightly yellow
lo precipitate was obtained. The precipitate was filtered off, washed with
ether and dried in vacuum. The hydrochloride of 3-~(4-bromophenyl)-N-methyl-
3~(3-pyridyl) ally~Lamine was obtained.
Yield: 43%. M.p. 138-1~4 C.
Example 2. (Method A~
H SO ~ ~ Br ~ :
N ~ ~ 2 4 ~ ~ ~
C\ 11
HO 2 2 3 CHCH2NHCH3
The raw product of 3-(4-bromophenyl~-3-hydroxy-N-methyl_3_(3_pyridyl)
_prop~lamine (prepared in accordance with Example B from 5.0 g of 3-(4-
bromophenyl)-3-hydroxy-N-methyl-3-pyridyl~-propionamide) was added with
stirring to 50% sulphuric acid (50 ml) and the mixture was heated at 110
for 10 minutes. me mixture was then cooled, poured on to crushed ice,
basified by the addition of 30% NaOH and extracted with ether~ Evaporation
gave 4~9 g of semicrystalline residue. lSG ml acetone was added and the
solution was clarified by filtration. 0.9 g (0.01 mole) of oxalic acid
dissolved in 25 ml of acetone was added dropwise to the filtrate. The white
precipitate was collected and recrystallized from 350 ml isopropyl alcohol to
yield 1.7 g of white crystals of the oxalate of 3-~4-bromophenyl)-N-methyl-3-
~ ''
_18-
J, ' ' ~ ' '.
~35~3~
(3-pyridyl)-allylamine. M.p. 180-208 CO The NMR spectrum shows the vinyl
proton as a double triplet at 6.1-6~4 ppm, indicating a mixture of E and Z
isomers.
Isolation of the Z-isomer: After recrystallization three times
from ethanol 0.5 g substance was obtained. M.p. 202-205C. The NMR spectrum
sho~s the vinyl proton as a single triplet with J = 3.4 Hz ~nd in a position
which indicates that the compound is the Z-isomer.
The amine oxalate obtained was converted into the corresponding
hydrochloride via the free base. Recrystallization from acetonitrile
containing a few per cent of water gave a compound melting at 161-165 C.
Elemental analysis showed it to be a dihydrochloride with the composition
C15H15BrN2 2HCl H20.
Isolation of the ~-isomer: Mother liquors from the isolation of
the Z isomer, containing both isomers in a ratio of about 60:40 E and Z
respectively~ was used. The oxalate of this amine mixture was recrystalli~ed
three times from acetonitrile containing 15% of water, giving a substance
melting at 198-201C. According to the NMR spectrum this substance was the
E~isomer.
Pharmacolo~cal tes~s
-
It is not possible by experimental means to induce depressions in
laboratory animals. In order to evaluate a possible anti-depressive effect of
new substances biochemical-pharmacological test methods must be resorted to.
One such method, which seems to give a good indication of the potential anti- ;
depressive e~fects o~ the test substances, is described in Europ. JO Pharmacol.
7~ 1~7~ 1972.
This method involves the measurement of the decrease in the uptake
of C-S-hydroxytryptamine ( C-5-HT) and H-noradrenaline ( H-NA) in brain ;~
slices from mice after in vivo and in vitro administration of the test
substance O '
~19-- ., .,. : .
...... ,,,, .. ,, .. , ,, ., , , , ; . . . .
., , .. , , . , ~ , . . .. .. ..
Inhibition of the uptake of C-5-HT and H-NA in vitro and in
vivo, is measured as follows:
The test substances were administered intraperitoneally half an
hour before the animals were killed. The midbrair. was taken out, sliced
and incubated in a mixture consisting of 0.2 nmole of C-5-HT, 0.2 nmole of
H-NA and ll,umole of glucose in 2 ml of Krebs-Henseleit buffer, pH 7.4 per
loo 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 radio-active amines taken up were
` 10 determined by liquid ~cintillationO The doses producing 50 per cent decrease ~ -
of the active uptake (ED50) of C-5-HT and H-NA were de~ermined graphically
from dose response curves. Active uptake is defined as that part of the
radioactive uptake which is inhibited by a high concentration of cocaine.
In the in vitro method slices of mouse midbrain were preincubated
for 5 minutes with solution of the compound to be tes~ed and then incubated
as described above.
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As can be seen from the Table the compounds of the invention are
potent inhibitors of the neuronal uptake of 5-hydroxytryptamine and
noradrenaline. The Z-form of the compound of the invention shows a stronger
inhibition of the uptake of 5-HT in vivo than do any of the prior art
compounds tested.
The Z-form of the compound of the invention tested as the
hydrochloride, is further a more potent inhibitor of the uptake of 5-HT in vitro
than any of the prior art compounds. ~The difference appearing between the ~-
oxalate and the hydrochloride is believed to be due to the fact that the
hydrochloride was prepared from the oxalate whereby a more pure Z-isomer was
obtained). The E-form of the compound of the invention primarily inhibits the
uptake of noradrenaline. The inhibition of neuronal uptake of 5-
hydroxytryptamine and noradrenaline disclosed, may give the compounds of the
invention value as anti-depressive agents. Likewise the compounds of the
invention may be useful as anxiolytic agents.
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-22-
