Note: Descriptions are shown in the official language in which they were submitted.
8408
PRIOR ART
Depressive disorders have with more or less success been treated
with various compounds. Many types of chemical substances have been used,
- among these amphetamine with the structure
fH2-CH-NH2
'
~ However, the euphoretic effect and the risk for dependence have to a great
~ extent restricted the use of amphetamine in the therapy.
The medical use of amphetamine is nowadays mainly restricted to
the treatment of narcolepsy and asthenic states in aged people.
, 10 OUTLINE OF INVENTION
a) General outline
We have found that by a proper modification of the amphetamine
molecule the euphoric or central stimulant effect of the substance can be
diminished or completely abolished. The pharmacological profile of the com-
pounds of the invention suggests a potential value of the compounds as anti-
depressants and also as a new type of anxiolytics.
The compounds of the invention are characterized by the general
formula
Rl~CH2- H-NH2
R3
~ N
R3 \ R4
20 or a pharmaceutically acceptable salt thereof, in which formula Rl and R2 arethe same or different and each represents a hydrogen atom, a lower alkyl group
or a halogen atom, R3 represents a lower alkyl group or a benzyl grou~
represents a hydrogen atom, a lower alkyl group ~ abenzyl group, provided
that Rl and/or R2 represents a lower alkyl group or a halogen atom when R3
1~7840~3
and R4 represents a methyl group.
Rl and R2 may be situated at any free position on the phenyl
nucleus.
Illustrative examples of radicals included in the above definitions
are lower alkyl group: methyl, ethyl, n-propyl and isopropyl halogen atom:
chlorine, bromine, iodine and fluorine.
By the expression "lower alkyl group" in this application is to be understood
alkyl groups with 1 to 5 carbon atoms, inclusive.
The new compounds of this invention may be used therapeutically ~ ~
; 10 as the racemic mixtures of ~)- and ~-)-forms, which are obtained by synthesis. ~ -
They may also be resolved into the corresponding optically active modifications
which, likewise, may be used in therapy. The compounds of this invention may
be administered in the form of free bases or their salts with non-toxic acids.
Some typical examples of these salts are the hydrobromide~ hydrochloride,
phosphate, sulphate, citrate, tartrate.
b) Pharmaceutical preparations
In clinical practice the compounds of the present invention will
normally be administered orally, rectally or by injection, in the form of
pharmaceutical preparations comprising the active ingredient either as a free
base or as a pharmaceutically acceptable non-toxic, acid addition salt, e.g.
the hydrochloride, hydrobromide, lactate, acetate, sulphate, sulphamate and
the like in association with a pharmaceutically acceptable carrier. According-
ly, terms relating to the novel compounds of this invention whether generical-
ly 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 between 0.1 and 99%
by weight of the preparation, more specifically between 0.5 and 20% by weight
for preparation intencled for injection and between 2 and 50% by weight for
preparations suitable for oral administration.
-- 2 --
. . ~ - - . . . . ~ , . ~
78~0~3
.
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, or gelatine, 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 di-
oxide, and the like. Alternatively, the tablet can be coated with a lacquer
dissolved in a readily volatile organic solvent or mixture of organic solvents.
Dyestuffs may be added to these coatings in order to readily distinguish
between tablets containing different active substances or different amounts
of the active compound.
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 combina-
tion with solid, pulverulent carriers such as lactose, saccharose, sorbitol,
mannitol, starches (e.g. potatoe starch, corn starch or amylopectin),
cellulose derivatives or gelatine.
Dosage units for rectal application can be prepared in the form of
suppositories comprising the active substance in admixture with a neutral
fatty base, or gelatine rectal capsules comprising the active substance in
admixture with vegetable oil or paraffin oil.
Liquid preparations for oral application may be in the form of
syrups or suspensions for example, solutions containing from about 0.2% to
20% by weight of the active substance herein described, the balance being
sugar and a mixture of ethanol, water, glycerol, and propyleneglycol. Op-
tionally 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
- 3 _
78~08
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 10o by weight. These solutions may also contain stabilizing agents
and/or buffering agents and may conveniently be provided in various dosages
unit ampoules.
Suitable peroral doses of the compounds of the invention are 2-20
mg, preferably 5-15 mg given 1 to 3 times a day~ preferably 2 times a day.
c) Preferred embodiment
The preferred compound of the invention has the formula
I
CH2-CH2-CH-NH2 .
Cl ~
N
CH3 \CH3
Preferably these compounds will be prepared and used in the form of their
dihydrochloride salt.
d) Methods of preparation
.
A. Reduction of a compound of the formula
Rl A-C=N-OH
~ ~,."."''.
R2 ~ II
R3 ~ \R4
wherein Rl, R2, R3 and R4 are as previously described, and A is -CH2CH2- or
-CH=CH- to the format:ion of a compound of the formula I.
The reduction can be effected by catalytic hydrogenation, using a
metal catalyst such as Raney nickel or palladium on charcoal. The reaction
is conducted in a suitable solvent e.g. methanol or acetic acid preferably
in the presence of a mineral acid. If the reaction mixture becomes sluggish,
. - . . .. : .. , - : : , ::
~7~34(~3
additional catalyst may be introduced thereinto. l~hen no more hydrogen is
absorbed the catalyst is removed by filtration, and the filtrate is concen-
trated. The residue is recrystallized from a suitable solvent.
B. Heating a ketone of the ~ormula
fH3
R ~ ~
R3 / \ 4
Nherein Rl, R , R3 and R4 are as previously described, with Eormamide,
ammonium formate or formamide and formic acid according to the Leuckart reac-
tion to the formation of a compound of the formula I. In case the product
obtained is a N-formyl derivative of the amine, hydrolysis will yield the
compound of the formula I.
- C. Reductive amination of a ketone of the formula
Rl -CH2-C=
R2~
R3 / \ R4
wherein Rl, R2, R3 and R4 are as previously described, with ammonia in the
presence of a catalyst ~e.g. a metal catalyst) to the formation of a compound
of the formula I.
D. Direc~ halogenation of a compound of the formula
CIH3
R \ CH2CH2CH-NH2
R2 _~
~ N
~$78408
wherein R3 and R4 are as previously described and either Rl or R2 or both are
` hydrogen, to the formation of a compound of the formula I wherein Rl or R2 or
both are a halogen atom.
e) Intermediates
For the preparation of the compounds of the formula I it has been
found that a compound of the formula
1 3
Rl~=N-OH 11
R2 N -
R3~ \ R4
in which formula A is -CH2CH2- or -CH=CH-, Rl and R2 are the same or different
and each represents a hydrogen atom, a lower alkyl group or a halogen atom,
R3 represents aloweralkyl group or a benzyl group, R4 represents a hydrogen
atom, a lower alkyl group or a benzyl group, provided that Rl and/or R2
represents a lower alkyl group or a halogen atom when R3 and R4 represents a
methyl group, is a valuable starting material.
The preparation of the oxime II is effected by treating a ketone
of the formula
A-C = 0
Rl ~ 3
R2 ~ III
3~ \ 4
wherein A, Rl, R2, R3 and R4 are the same as above, with a hydroxylamine salt
according to known procedures. The reaction is performed at elevated tempera-
tures in a suitable solvent, e.g. ethanol or acetic acid and preferably in the
presence of sodium acetate.
The ketones of the formula III are prepared as outlined below:
: '
-- 6 --
- , . ... ~ . . . .
1C~784~8
l CHO
R2 ~ ~ R ~ CH3COCH3
'
3 ~ \ 4 R3~ \R4
CH3 1 -
2 ~ 2 ,~
`3 ~ \ 4 ~N
R R
The formylation of the substituted aniline according to the
Vilsmeyer-Haack reaction gives in a first step the corresponding aldehyde.
The formylation is effected by using a mixture of dimethylformamide and phos-
phorus oxychloride. Alternatively the preparation is achieved by using a
mixture of phosphorus tribromide and dimethylformamide (Acta Pharm3 Suecica 7
87, 1970).
The procedure involving the condensation of the aldehyde with ace-
tone in a second step gives the intermediate benzylideneacetone. The condensa-
tion is performed in a suitable solvent or with excess of acetone, in the
presence of a base e.g. sodium hydroxide.
- In a third step the benzylideneacetone is subjected to catalytic
hydrogenation to yield a 4-phenyl-2-butanone. The catalytic hydrogenation is
performed using a metal catalyst such as platinum. The reaction is conducted
in a suitable solvent e.g. ethyl acetate and ethanol.
~Ci78408
f) ~orking examples
Preparation of starting materials
___ ________________________~____ ~
Example 1. 4-Dimethylamino-2-chlorobenzalacetone oxime
____ __________________________________________________
(a) 4-Dimethylamino-2-chlorobenzylide-n-acetone
To a solution of 50 g of 2-chloro-4-dimethylaminobenzaldehyde
in 200 ml of acetone was added dropwise 75 ml of 10% NaOH solution. The mix-
ture was stirred over night at room temperature and then poured on 1.5 1 of
ice water. The obtained precipitate was collected by suction filtration and
air-dried.
Yield 62.5 g. M.p. 70-75C. Recrystallization from dimethylformamide-water
yields 39.5 g ~65%). M.p. 80-81C.
Analysis. Calculated for C12H14ClN0: C 64.43, H 6.31, Cl 15.85, N 6.25,
0 7.15.
; Found: C 64.3, H 6.20, Cl 16.1, N 6.07, 0 7.26.
~) 4-Dimethylamino-2-chlorobenzylideneacetone oxime
A mixture of 22.4 g ~0.1 mole) of 4-dimethylamino-2-chlorobenzal-
acetone, 18 g of CH3COONa . 3H20 and 7.2 g hydroxylamine hydrochloride in
250 ml of abs. ethanol was refluxed for 4 hours. The mixture was then poured
in 1 litre of ice water. The obtained precipitate was collected by suction
filtration and washed with water. M.p. 160-166C. Yield 26.5 g. After
recrystallization from ethanol the product melted at 170-171.5C. Yield 17.5
g ~73%). Calculated equivalent weight 238.73. Found equivalent weight 239.
Analysis. Calculated for C12H15N20Cl: C 60.37, H 6.33, N 11.73, 0 6.70,
Cl 14.85. Found: C 60.3, H 6.37, N 11.5, 0 6.98, Cl 15.1.
Example 2. 4-Dimethylamino-2-methylbenzylideneacetone oxime
____________________________________________________________
(a) 4-Dimethylamino-2-methylbenzylideneacetone
To a solution of 32.7 g of 4-dimethylamino-2-methylbenzaldehyde in
135 ml of acetone was added dropwise while stirring 49 ml of 10% NaOH solu-
tion. The mixture was stirred overnight at room temperature and then poured
into 1.5 1 of ice water. The obtained precipitate was collected by filtration,
. ' ~ .
, . . . .
~07~408
.
washed ~ith ice water and air-dried.
Yield: 38.6 g ~95%). M.p. 65-75C.
Recrystallization from ligroin-ethanol yielded 22.4 g of the product ~55%).
hl p. 77-79C.
Analysis. Calculated for C13H17N0: C 76.81, H 8.43, N 6.89, 0 7.87.
Found: C 76.6, H 8.37, N 6.76, 0 8.020
(b) 4-Dimethylamino-2-methylbenzylideneacetone oxime
A mixture of 4.1 g of 4-dimethylamino-2-methylbenzylideneacetone,
1.44 g of hydroxylamine hydrochloride and 3.72 g of sodium acetate trihydrate
in 50 ml of ethanol was refluxed for 7 h. The mixture was then poured into
;~ 1 litre of ice water. The obtained precipitate was filtered off and dried.
Yield: 2.8 g ~64%). M. p. 155-157C.
After recrystallization from aqueous ethanol the product melted at 155-
156.5C. Yield: 2.6 g ~60%).
Analysis. Calculated for C13H18N20: C 71.58, H 8.31, N 12.84, 0 7.33.
Found: C 71.20, H 8.25, N 12.6, 0 7.7.
Example ~ 4-(4-Dimethylamino-o-tolyl)-2-butanone
A solution of 10.15 g of 4-dimethylamino-2-methylbenzylidene-
acetone in 250 ml of ethyl acetate was hydrogenated in presence of 0.42 g of
platinum dioxide at room temperature and normal pressure. The catalyst was
filtered off and the filtrate was evaporated. The residual oil was distilled
at 114-123/0.3 mm, yielding 7.1 g (69%) of the compound.
Neut. equiv. (determined by potentiometric titration with perchloric acid in
acetic acid). Calc. for C13H19N0: 205.30. Found 205.
Example 4. 4-~Dimethylamino-o-tolyl)-2-butanone oxime
______________________________________________________
A mixture of 8.24 g of 4-(dimethylamino-o-tolyl)-2-butanone,
2.88 g of hydroxylami-ne hydrochloride and 7.44 g of sodium acetate trihydrate
in 100 ml of ethanol was refluxed for 5 h. The mixture was then poured into
1 litre of ice water and left overnight at 0C. The obtained precipitate was
filtered off and dried.
_ g _
.
784~3
. .
Yield: 4.9 g ~56%). M.p. 83-90C.
After recrystallization from aqueous ethanol the product melted at 87-89C.
Yield: 3.6 g.
Analysis. Calculated for C13H20N20: C 70.87, H 9.15, N 12.72, 0 7.26.
Found: C 70.87, H 9.3, N 12.4, 0 7.0
Preparation of end compounds
Example 5. 4-(3-Aminobutyl)-3-chloro-N,N-dimethylaniline
dihydrochloride. Method A.
_ _ _ _ _ _ _ . .
A solution of 4.8 g (0.02 mole) of 4-dimethylamino-2-chloro-benzal-
acetone oxime in 150 ml of acetic acid and 4 ml of concentrated HCl was
hydrogenated with H2/Pd-C 5% at room temperature and normal pressure. The
consumption of H2 stopped at 900 ml (2.5 hours). The catalyst was filtered
off and the filtrate was evaporated. The residue was recrystallized from
ethanol-ether. M.p. 200-202C (decomposition). Yield 1.2 g (20~). The pro-
duct was recrystallized from ethanol-isopropylether. M.p. 204-205C
~decomposition). Yield 0.8 g. A further recrystallization yielded 0.5 g of
the product. M.p. 206-207C (decomposition~.
Analysis. Calculated for C12HlgClN2 . 2HCl: C 48.09, H 7.06, Cl 23.66, ; ,
` Cl+Cl 35.49, N 9.35.
Found: C 48.2, H 7.77, Cl 23.4, Cl+Cl 34.9, N 9.14.
Example 6. 4-(3-Aminobutyl~-N,N-dimethyl-m-toluidine dihydro-
chloride. Method A.
____________________________________________.________________
A solution of 10.92 g of 4-dimethylamino-2-methylbenzylidene-
acetone oxime in 200 ml of acetic acid and 8 ml of concentrated hydrochloric
acid was hydrogenated in presence of 2 g Pd-C 10% at room temperature and
normal pressure. The catalyst was filtered off and the filtrate was evaporat-
ed. The residue was dissolved in 200 ml of water and the solution was ex-
tracted with ether and evaporated. The residue was recrystallized from
aqueous ethanol-isopropylether.
Yield: 6.7 g ~48%). M.p. 220.5-222.5C. A further recrystallization yielded
_ 10 -
1C! 78~618
; 3.6 g of the product melting at 227-228C.
Analysis. Calculated for C13H22N2 . 211Cl: C 55.91, H 8.66, N 10.03,
Cl 25.39. Found: C 55.6, H 8.6, N 9.8, Cl 25Ø
Example 7. 4-(3-Aminobutyl)-N,N-dimethyl-m-toluidine dihydro-
chloride. Method B
--_ _____ ____________________________
A solution of 8.21 g of 4-~4-dimethylamino-o-tolyl)-2-butanone in
15.2 g of formamide was heated at 200C for 20 h. After the addition of 25
ml of 30% NaOH solution the mixture was refluxed for 12 h. An equal volume
of water was added and the solution was extracted with ether. The ether layer
was separated and extracted with 2 N hydrochloric acid. The extracts were
alkalized with sodium hydroxide solution and extracted with ether. The ether
layer was separated, dried with sodium sulphate and evaporated. The residue
was distilled at about 150/0.6 mm yielding 2.05 g o~ the crude base. The
product was treated with anhydrous hydrogen chloride in ether and the obtained
crude, semicrystalline hydrochloride salt was recrystallized twice from aqueous
ethanol-isopropylether.
Yield: 1.5 g ci3%). ~I.p. 219.5-223C.
g) Pharmacological tests
It is not possible by experimental means to induce depressions in
laboratory animals. In order to evaluate a possible antidepressive effect of
new substances biochemical-pharmacological test methods must be resorted to.
One such method, which seems to give a good indic.ation of the potential anti-
depressive effects of the test substances, is described in Europ. J. Pharmacol.
_, 107, 1972. This method involves the measurement of the potentiation of
the syndromes produced by 5-hydroxytryptophan ~5-llTP) in a laboratory animal.
The lack of euphoric effects, that is lack of central stimulatory
activity, is tested by measuring the motor activity in mice after administra-
tion of the test substance.
Potential anxiolytic activity is tested by measuring the anti-
aggressivity in isolated mice after administration of the test substance. In
- 11 -
,
7~4~8
'
thi5 test not amphetamine but Valiu ~ - a well-known anYiolytic substance -
is used as a reference.
5-HTP response potentiation test
Inhibition of the uptake of 5-HI` potentiates the effects of
administered 4-hydroxytryptophan (S-HTP) probably by increasing the amount of
5-HT at the receptor. Three mice are given the test drugs one hour ~or 4,
24 hours) before dl-5-HTP~ 90 mg/kg i.v. 5-HTP alone gives only a weak
behavioural syndrome but in pretreated mice there is seen a characteristic
behavioural syndrome, which comes within five minutes: tremor, lordosis,
abduction of the hindlegs, head-twitches.
The absence or presence of respective syndrome is scored in groups
of ten mice. The compound was administered in at least five doses and the
quantal responses were analysed by probit analysis and ED50 determined accor-
ding to the method of Litchfield and Wilcoxon.
~lotor activity in mice
______________________
The exploratory activity of mice was recorded in a locomotion cage
in which the movements were counted each time the animals cross-circuits an
electrical current in the bottom plate. The activity was recorded for ten
minutes one hour after the administration of the drug. The animals were test-
ed individually. Groups of six mice were used and the mice were only used
once. The activity was expressed in per cent of the activity of control
groups ran simultaneously. The compounds were administered in at least four
doses. The increase C+) or decrease ~-) of the activity compared to control
groups was determined from log dose response curves.
Aggressive behaviour in mice
_ _ _ _ _ _
Male mice kept isolated for 3 weeks or longer develop an aggres-
sive behaviour when caged together. The method used follows that o
Valzelli et al. ~Europ. J. Pharmacol. 2, 144, 1967);
- lla -
~;~ .. .
, '.
.. . .
- ~78408
with the exception that 2 mice were tested on each other. The aggressive-
ness was scored during a 5 minute test according to the following schedule:
O the animals show no interest in each other except occasional nosing
frequent vigorous nosing and tail rattling, the animals assume a
fighting position and occasionally attack each other - no more
than 3-4 times in the 5 minute period
tail rattling, powerful attacks - no more than 10 times in the test
period
the animals follow their partners, attacking and biting for most of
the time
lO0 attacks over the entire period.
Controls administered with the solvent were tested, the repeated
testing did not influence on the aggressiveness. The animals were used for
several experiments but with intervals of at least one week. Groups of 10
mice were used.
ED50 is the dose which reduces the aggressiveness score by 50%.
TABLE
Pharmacological effects
CH2cH2-cH-NH2
R
R2~
R3~ \ R4
Compound Potentiation of Motor activity Antiaggressive
Rl R2 R3 R4 5-HTP + = increase behaviour in mice
ED50 mg/kg i.p. - - decrease ED50 mg/kg i.p.
Vali~n** 2.5
Amphetamine ~ 5 +-~+ x
p-Aminoamphetamine 11.5 5-10
p-Chloroamphetamine 0.8 ++ 0.3
H 3-Cl CH3 CH3 1.6 o 3.4
H 3-CH3 CH3 CH3 2.0
x not tested, due to interference with motor activity
**Trade Mark
- 12 -
-
~ ~.,
., ;,
1C!7~3408
As can be seen from the test values of the Table the tested
substance of the invention differs considerably in activity from amphet-
amine both qualitatively and quantitatively. In contrast to amphetamine
the tested compound of the invention strongly potentiates the 5-HTP
response. Furthermore the tested compound lacks the central stimulation
which is pronounced after amphetamine ancl p-chloroamphetamine. Thus,
the potential antidepressive activity as indicated by the potentiation
of 5-HTP and the lack of central stimulatory activity may give the com-
pounds of this invention value as potential antidepressive agents.
The tested compound antagonizes the aggressive behaviour of
male mice which have been kept isolated for one month or more. The com-
pound is almost as active as Valium* in this test which may indicate that
the compound may have therapeutic value as an anxiolytic compound.
*Trade ~lark.
- 13 -
