Note: Descriptions are shown in the official language in which they were submitted.
t ~ 625~
DESCRIPTION
"NAPHT~ IDINE DERIVATIVES"
The present invention relates to
2,3,3a,4,5s6-hexahydro-lH-indolo[3,2,1-de]C1,5-
naphthyrldine~ derivatives, their addition salts with
pharmaceutically acceptable acids, their preparation
and pharmaceutical compositions containing -them.
The naphthyridine derivatives of the present
invention are those compounds of the general formula:
~ 3NH
1 o~J<R 2
R ~ (I)
1 9 ~ N~ "
in which Rl is in the 9- or 10-position and represents
a hydrogen atom. a halogen atom or a Cl ~ alkyl
or Cl ~ alkoxy radical and R2 represents a hydrogen atom
or a Cl 4 alkyl radical, and pharmaceutically acceptable
acid addition salts thereof.
~hese compounds contain an asymmetric
carbon atom in the 3a-position. The racemates and the
optically active isomers of the com~ounds of general
formula ~I) form part of the present invention.
~ J~4~
The preferred cornpounds of the invention are
those in which Rl represents a hydrogen, chlorine,
bromine or fluorine atom or the methyl or methoxy
radical and R2 represents a hydro~en atom or the methyl
radical and, more particularly, those in which Rl
represents a hydrogen, fluorine, chlorine or bromine
atom and R2 represents a hydrogen atorn.
The compounds of general formula (I) can be
prepared, for example, by reducing the compounds of
the general formula:
~ ~IEI R
in which Rl and R2 are as hereinbefore defined, or an
acid addition salt thereof, e.g. the hydrochloride.
The compounds of general formula (II) have
already been described in the literature, in particular by
R.G. Taborsky et al., J. Med. Chem. 7 (2). 135-41 (1964).
by G. Hahn et al., Ber. 71B, 2163-7S (1933), in French
Patent 2434165 and by ourselves in Canadian Patent 1072960.
~ 3~5~4
rFhe process of the invention consists in
reducing the compounds of general formula (II)
in accordance with a conventional method for the
conversion of the carbonyl group (~ C=0) to me-thylene
(i.e. -CH2-), for example by treating a compound of
general formula (II) with a hydride, such as lithium
aluminium hydride. in the presence of a Lewis acid
such as aluminium chloride. The reaction is generally
carried out at a temperature of from -40 to +80C in
an organic solvent such as an anhydrous ether.
Pharmaceutically acceptable acid addition
salts of the naphthyridine derivatives of general
formula (I), e.g~ methanesulphonates, mandelates,
fumarates, citrates and hydrochlorides, may be obtained
by methods known per se, for example by treatment of the
naphthyridine base in a solvent medium, e.g. an ether,
with the appropriate acid in a solvent medi~n. e.g. an
alkanol.
By the term~methods known per se' as used
in this specification is meant methods heretofore used
or described in the literature.
The following Examples illustrate the
preparation of naphthyridine derivatives of the present
invention.
The analyses and the IR and NMR spectra
confirm the structure of the compounds.
~ 1 62~
EXAMPLE 1
.
2,3,3a,~,5,6-Hexahydro~lH -indol~3,2.1-de][1,5-
naphthyr ~ and its methanesulphorlate
5.4 g (0.04 mol) of aluminium chloride are
placed in a one litre three-necked flask. 50 ml of
anhydrous diethyl ether are added all at once.
2.3 g (0.06 mol) of lithium aluminium hydride are
added gradually to the solution obtained. The
suspension obtained is stirred for 10 minutes.
A suspension of 5.3 g (0.02 mol) of 1.2,3,3a,4,5-hexa-
hydro-6H-indolo[3,2,1-de][1,5-naphthyridine]-6-one
hydrochloride in 70 ml of anhydrous tetrahydrofuran
is added gradually thereto. The mixture is stirred at
ambient temperature for 30 minutes. It is then cooled
in an ice-bath and 10 ml of water are added slowly.
The mixture is stirred for 10 minu-tes and 10 ml of
sodium hydroxide solution (d = 1.38), 150 ml of ethyl
acetate and 100 ml of water are then added successively.
The mixture is stirred for 15 minutes. The organic
phase is decanted. The aqueous phase is extracted
twice with 60 ml of ethyl acetate. The combined organic
extracts are washed with water, dried over sodium
sulphate and evaporated ln vacuo on a water-bath. This
yields an oil, which is dried by aæeotropic distillation
with toluene. The base obtained is pure according to
thin layer chromatography.
~ ~ ~2~
-- 5 --
This oil is soluhilised in 80 ml of
anhydrous diethyl e-ther. A solution of 2 g (0.02 mol)
of methanesulphonic acid in 20 ml of ethanol is added.
The mixture is stirred for 30 minutes at ambient
temperature. The white precipitate obtained is
filtered off, washed with diethyl ether and dried in
a desiccator. The methanesulphona-te salt of the
naphthyridine produc-t is recrys-tallised from 80 ml of
ethanol. Its melting point is 246-248C.
EXAMPLE 2
10-Chloro-2,3,3a,4,5,6-hexahydro-lH-indolo-
.~. .. _ _
[3,2,1-de~[1,5-naphthyridine~ and its methane-
. . . _ . _ _ _ _
sulphonate
2.25 g (0.0168 mol) of anhydrous aluminium
chloride, 25 ml of anhydrous diethyl ether and 0.96 g
(0.0252 mol) of lithium aluminium hydride are placed
in a 500 cc three-necked round-bottomed flask. A
suspension of 2.5 g (0.0084 mol) of 10-chloro-
1,2,3,3a,~,5-hexahydro-6H-indolo[3,2,1-de][1,5-
naphthyridine~-6-one hydrochloride in 60 ml of anhydrous
tetrahydrofuran is added to the resulting suspension,
whilst stirring. ~hen the introduction has ended, a
grey solution is obtained, which is stirred for half
an hour. The complete clisappearance of the starting
material is monitored by thin layer chromatography.
The complex is destroyed by slowly adding
5 ml of water and then 15 ml of sodium hydroxide
solution (d = 1.38). The mediurn is diluted with 150 ml
of water and extraction is then carried out three times
with 70 ml of ethyl acetate. The extract is washed
with water and then dried over sodium sulphate.
It is filtered.
A solution of 0.9 g (0.0093 mol) of
methanesulphonic acid in 2 ml of ethyl acetate is
added to the filtrate. The resulting precipitte
is filtered off, and recrystallised from about 50 ml
of methanol in the presence of decolorising charcoal.
The mixture is filtered hot. The filtrate deposits
crystals. These are fi]tered off and dried. The
methanesulphonate of the naphthyridine product melts
at 275-278C.
The following Table shows the compounds
of the invention which were prepared by way of
examples in accordance with the method described
above.
~ 3 ~5~
TABLE
~ NH
R
g ~----N~ "
_
CompoundRl R2 Base Melting
or point
salt (C)
1 H H m.s. 246-248
(Example 1)
lO_CN3 H baEe ~, 3
3 10-CH30 H m.s. 248-250
_ _
10-F H HCl >300
10-Cl H base 142-3
(Example 2) m.s. ~75-8
6 H CEI3 m. 9 . )~0
7 9-Cl H m.s. 251-253
10-Br H m.s. 265
9-CH30 H m.s. 214-6
(m.s. = methanesulphonate)
I :~ 625~4
The compourlds of the invention formed the
subject of a pharmacological study.
1. TOXICITY
The 50% le-thal dose (LD 50) o~ the compounds
is determined on mice of the CDl strain by a
graphical method. The LD 50 is from 120 to 500 mg/kg,
administered intraperitoneally.
2. HYPOXIA CAUSED BY PRESSURE REDUCTION
Mice of the CDl strain axe kept in an oxygen-
depleted atmosphere produced by _reating a partialvacuum (190 mm of mercury, corresponding to r3.25% of
oxyyen).
The survival -time of the animals is noted.
This time is increased by agents which are capable of
assisting the oxygenation of tissues and in particular
of the brain. The compounds studied are administered
intraperitoneally in several doses, 10 minutes before
the experiment. The percentage increases in the survival
time, relative to the values obtained for control
animals,are calculated. The mean active dose (MAD), that
is to say the dose which increases the survival time
by 100%, is determined graphically. Tne MAD is from
10 to 15 mg/kg.
3. ACTION ON THE DURATION OF THE "SLEEP" INDUCED BY
SODIUM 4-HYDRoxBuTYRArrE
This action was determined by the influence
~ ~ 6~54~
of a compound on the duration of the "sleep" induced
in curarised rats hy sodium 4-hydroxybutyrate (GMB).
The animals used are male rats of the
Charles River strain, weighing 200 + 20 g The
animals, which have been curarised with alloferine at
a rate of 1 mg/kg, administered intraperitoneally, are
placed under artificial respiration with the aid of a
mask applied to the snout (breathing rate: 50/minute,
breathing volume: 14 cc).
The oesophagus is ligated beforehand in
order to prevent air from entering the stomach.
Fronto-parietal and fronto-occipital
cortical electrodes make it possible to record the
electrocorticographic activi-ty on a model 79 P Grass
polygraph at a speed of 6 mm/second.
The animal is prepared under local
anaesthetic (2% strength xylocaine). The rats are
kept at constant temperature (37.5C) throughout the
experiment. Ten minutes after the rat has been
prepared, a 200 mgjkg dose of sodium 4-hydrox~butyrate
is injectecl intravenously into the tail.
A 10 mg/kg dose o the compound to be
studied is administered intraperitoneally, 3 minutes
after the administration of the sodium 4-hydroxybu-tyrate.
The graphs are evaluated at 15-minute
intervals for 75 minutes after the injection of the
1 ~62S4~
-- 10 --
"GHB". During this peri.od of analysis, the total.
duration of -the "sleep" is determined. A series of
15 controls makes it possi~le to specify the duration
of the "G~IB sleep".
Statis-tical analysis of the results is
carried out using the Mann-Whitney "U" test.
The reduction in the duration of the "sleep"
is from 25 to 40%.
The pharmacological study of the compounds
of the invention shows that -they are active in the
test for the hypoxia caused in mice by pressure
reduction, whilst at the same time being only
slightly toxic, and that they exert a significant
waking action in the test for the "sleep" induced by
sodium 4-hydroxybutyrate.
The compounds of the invention, which
possess an anti-anoxia action and a psychotropic
action, can be used in therapy for the treatment of
vigilance disorders, in particular for combating
the behavioural disorders which can be attributed
to cerebral vascular damage and to the cerebral
sclerosis encountered in geriatrics, and also for
the treatment of epileptic vertigo due to cranial
traumatisms, for the treatment of metabolic
encephalopathies and for the treatment of depressive
states.
I ~fi254~
The invention consequently includes
pharmaceu-tical compositions containing, as active
ingredient, a naphthyridine derivative of genera]
formula (I), or a pharmaceu-tically acceptable acid
addition salt thereof, in association with any
excipients which are suitable for their administration,
in particular their oral or parenteral administration.
~ he methods of administration can be oral
and parenteral.
The daily posology can range from 10 to 100 mg
of naphthyridine derivative. The dosage units can
therefore contain, for example, 2 to 50 mg doses of
active substance associated with customary excipients,
and can be presented in the form of tablets, coated
tablets, capsules, suspensions or solutions to be
taken orally or in~ected.
Particularly preferred naphthyridine
derivatives of the invention are 2,3,3a,4,5,6-
hexahydro-lM-indolo[3,2,1-de][1,5-naphthyridine~,
10-chloro-2,3,3a,4,5/6-hexahydro-lEI-lndolo[3,2,1-de]-
[1,5-naphthyridine], 10-fluoro-2,3,3a,4,5,6-
hexahydro-lH-indolo[3,2,1-de][1,5-naphthyridine~ and
10-bromo-2,3,3a,4,5,6-hexahydro-l~I-indolo[3,2~1-de]-
[1,5-naphthyridine], and their pharmaceutically
acceptable acid addition salts.
