U.S. patent application number 10/490959 was filed with the patent office on 2005-02-24 for substituted alkylaminopyridazinone derivatives, process for the preparation thereof and pharmaceutical composition containing the same.
Invention is credited to Barkoczy, Jozsef, Egyed, Andras, Gacsalyi, Istvan, Harsing, Laszlo, Kompagne, Hajnalka, Kotay Nagy, Peter, Levay, Gyorgy, Leveleki, Csilla, Martonne Marko, Bernadett, Miklosne Kovacs, Aniko, Schmidt, Eva, Simig, Gyula, Szenasi, Gabor, Wellmann, Janos.
Application Number | 20050043314 10/490959 |
Document ID | / |
Family ID | 10975085 |
Filed Date | 2005-02-24 |
United States Patent
Application |
20050043314 |
Kind Code |
A1 |
Barkoczy, Jozsef ; et
al. |
February 24, 2005 |
Substituted alkylaminopyridazinone derivatives, process for the
preparation thereof and pharmaceutical composition containing the
same
Abstract
New substituted alkylaminopyridazinone derivatives of the
general Formula (I), (wherein R.sub.1 is hydrogen or alkyl having
1-4 carbon atoms; X is hydrogen or halogen; R.sub.2 is hydrogen or
alkyl having 1-4 carbon atoms; n is 1, 2 or 3; Q and W
independently from each other stand for --N.dbd. or --CH.dbd.; and
R.sub.4 and R.sub.5 independently from each other represent
hydrogen, halogen, trifluoromethyl or alkoxy having 1-4 carbon
atoms) and pharmaceutically acceptable acid addition salts thereof
possess useful anxiolytic and cognition enhancing properties.
Inventors: |
Barkoczy, Jozsef; (Budapest,
HU) ; Egyed, Andras; (Budapest, HU) ;
Gacsalyi, Istvan; (Budapest, HU) ; Harsing,
Laszlo; (Budapest, HU) ; Kompagne, Hajnalka;
(Budapest, HU) ; Kotay Nagy, Peter; (Vac, HU)
; Levay, Gyorgy; (Budakeszi, HU) ; Leveleki,
Csilla; (Budapest, HU) ; Martonne Marko,
Bernadett; (Budapest, HU) ; Miklosne Kovacs,
Aniko; (Budapest, HU) ; Schmidt, Eva;
(Budapest, HU) ; Simig, Gyula; (Budapest, HU)
; Szenasi, Gabor; (Budapest, HU) ; Wellmann,
Janos; (Budapest, HU) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Family ID: |
10975085 |
Appl. No.: |
10/490959 |
Filed: |
October 18, 2004 |
PCT Filed: |
September 26, 2002 |
PCT NO: |
PCT/HU02/00097 |
Current U.S.
Class: |
514/252.02 ;
544/238 |
Current CPC
Class: |
C07D 237/22 20130101;
C07D 403/12 20130101; A61P 25/22 20180101; C07D 401/12 20130101;
C07D 405/12 20130101; A61P 25/28 20180101; A61P 25/24 20180101;
A61P 25/00 20180101; A61P 25/14 20180101 |
Class at
Publication: |
514/252.02 ;
544/238 |
International
Class: |
A61K 031/501; C07D
043/14 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 27, 2001 |
HU |
P 0103912 |
Claims
What we claim is,
1. Compounds of the general Formula 6(wherein R.sub.1 is hydrogen
or alkyl having 1-4 carbon atoms; X is hydrogen or halogen; R.sub.2
is hydrogen or alkyl having 1-4 carbon atoms; n is 1,2 or 3; Q and
W independently from each other stand for --N.dbd. or --CH.dbd.;
and R.sub.4 and R.sub.5 independently from each other represent
hydrogen, halogen, trifluoromethyl or alkoxy having 1-4 carbon
atoms) and pharmaceutically acceptable acid addition salts
thereof.
2. Compounds according to claim 1 (wherein R.sub.1 is hydrogen; X
is hydrogen; n is 1; Q and W independently from each other stand
for --N.dbd. or --CH.dbd.; and R.sub.4 and R.sub.5 independently
from each other represent hydrogen, chlorine, fluorine,
trifluoromethyl or methoxy and pharmaceutically acceptable acid
addition salts thereof.
3.
5-{2-[4-(methoxytrifluoromethylphenyl)-piperazine-1-yl]-ethylamino}-2H--
pyridazine-3-one according to claim 1 and pharmaceutically
acceptable acid addition salts thereof.
4.
5-{2-[4-(2-fluorophenyl)piperazine-1-yl]ethyl-amino}-2H-pyridazine-3-on-
e according to claim 1 and pharmaceutically acceptable acid
addition salts thereof.
5. 5-{2-[4-phenylpiperazine-1-yl]ethylamino}-2H-pyridazine-3-one
according to claim 1 and pharmaceutically acceptable acid addition
salts thereof.
6.
5-[2-(4-pyridin-2-ylpiperazine-1-yl)ethylamino]-2H-pyridazine-3-one
according to claim 1 and pharmaceutically acceptable acid addition
salts thereof.
7.
5-[2-(4-pyrimidin-2-ylpiperazine-1-yl)ethylamino]-2H-pyridazine-3-one
according to claim 1 and pharmaceutically acceptable acid addition
salts thereof.
8.
5-{2-[4-(3-chlorophenyl)piperazine-1-yl]ethyl-amino}-2H-pyridazine-3-on-
e according to claim 1 and pharmaceutically acceptable acid
addition salts thereof.
9.
5-{2-[4-(4-fluorophenyl)piperazine-1-yl]ethyl-amino}-2H-pyridazine-3-on-
e according to claim 1 and pharmaceutically acceptable acid
addition salts thereof.
10. Process for the preparation of compounds of the general Formula
I (wherein R.sub.1 is hydrogen or alkyl having 1-4 carbon atoms; X
is hydrogen or halogen; R.sub.2 is hydrogen or alkyl having 1-4
carbon atoms; n is 1, 2 or 3; Q and W independently from each other
stand for --N.dbd. or --CH.dbd.; and R.sub.4 and R.sub.5
independently from each other represent hydrogen, halogen,
trifluoromethyl or alkoxy having 1-4 carbon atoms) and
pharmaceutically acceptable acid addition salts thereof which
comprises a) reacting a compound of the general Formula 7(wherein
L.sub.1 is leaving group and R.sub.1, R.sub.2, X and n are as
stated above) with an amine of the general Formula 8(wherein Q, W,
R.sub.4 and R.sub.5 are as stated above); or b) reacting a compound
of the general Formula 9(wherein Y is halogen and R.sub.1 and X are
as stated above) with a compound of the general Formula 10(wherein
R.sub.2, n, Q, W, R.sub.4 and R.sub.5 are as stated above); and, if
desired, subjecting a compound of the general Formula I, wherein X
stands for halogen, to catalytic dehalogenation to obtain a
compound of the general Formula I or its hydrochloride salt,
wherein X is hydrogen; and/or converting a compound of the general
Formula thus obtained into a pharmaceutically acceptable acid
addition salt thereof or setting free a compound of the general
Formula I from an acid addition salt.
11. Pharmaceutical composition comprising as active ingredient at
least one compound of the general Formula I or a pharmaceutically
acceptable acid addition salt thereof in admixture with suitable
inert pharmaceutical carriers and/or auxiliary agents.
12. Process for the preparation of pharmaceutical compositions
which comprises admixing a compound of the general Formula I
according to claim 1 or a pharmaceutically acceptable acid addition
salt thereof with suitable inert pharmaceutical carriers and/or
auxiliary agents.
13. Use of compounds of the general Formula I according to claim 1
or a pharmaceutically acceptable acid addition salt thereof as
pharmaceutical active ingredient.
14. Use of compounds of the general Formula I according to claim 1
or pharmaceutically acceptable acid addition salts thereof as
anxiolytic and cognition enhancing pharmaceutically active
ingredients.
15. Method of anxiolytic and cognition enhancing treatment of
anxiolytic conditions which comprises administering to the person
in need of such treatment a pharmaceutically effective amount of a
compound of the general Formula I according to claim 1 or a
pharmaceutically acceptable acid addition salt thereof.
Description
FIELD OF THE INVENTION
[0001] The invention relates to substituted alkylaminopyridazinone
derivatives, process for the preparation thereof and pharmaceutical
composition containing the same.
BACKGROUND OF THE INVENTION
[0002] Anxiety is a major CNS symptom accompanied by many
psychiatric disorders, medical and surgical conditions and stress
situations. Benzodiazepines such as diazepam, chlordiazepoxide, and
alprazolam etc. are the most commonly used agents in the anxiety
disorders. However, sedative and amnestic side effects are a major
disadvantage of these drugs especially in disorders affecting
active, working populations. Moreover, withdrawal symptoms may
occur following suspension of benzodiazepine administration after
long term therapy. Therefore, finding of an effective
anxiolytic/antistress compound without such undesirable side
effects, low addictive potential and good safety features still
remains one of the most challenging aims of CNS pharmacology
research these days.
[0003] Piperazinylalkylamino-3(2H)-pyridazinone derivatives having
blood pressure lowering effect and being suitable for the treatment
of heart failure and peripheral circulatory disturbances are known
from EP-A No. 372 305.
SUMMARY OF THE INVENTION
[0004] The object of the invention is to provide new substituted
alkylaminopyridazinone derivatives having useful pharmaceutical
properties and free of disturbing side-effects.
[0005] The above object is achieved with the aid of the present
invention.
[0006] According to the present invention there are provided new
alkylaminopyridazinone derivatives of the general Formula 1
[0007] (wherein
[0008] R.sub.1 is hydrogen or alkyl having 1-4 carbon atoms;
[0009] X is hydrogen or halogen;
[0010] R.sub.2 is hydrogen or alkyl having 1-4 carbon atoms;
[0011] n is 1, 2 or 3;
[0012] Q and W independently from each other stand for --N.dbd. or
--CH.dbd.; and
[0013] R.sub.4 and R.sub.5 independently from each other represent
hydrogen, halogen, trifluoromethyl or alkoxy having 1-4 carbon
atoms) and pharmaceutically acceptable acid addition salts
thereof.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0014] A preferable subgroup of the invention compounds of the
general Formula I are those derivatives, in which
[0015] R.sub.1 is hydrogen;
[0016] is hydrogen;
[0017] n is 1;
[0018] Q and W independently from each other stand for --N.dbd. or
--CH.dbd.; and
[0019] R.sub.4 and R.sub.5 independently from each other represent
hydrogen, chlorine, fluorine, trifluoromethyl or methoxy and
pharmaceutically acceptable acid addition salts thereof.
[0020] The following compounds of the general Formula I possess
particularly preferable pharmaceutical properties:
[0021]
5-{2-[4-(methoxytrifluoromethylphenyl)-piperazine-1-yl]-ethylamino}-
-2H-pyridazine-3-one;
[0022]
5-{2-[4-(2-fluorophenyl)piperazine-1-yl]ethyl-amino}-2H-pyridazine--
3-one;
[0023]
5-{2-[4-phenylpiperazine-1-yl]ethylamino}-2H-pyridazine-3-one;
[0024]
5-[2-(4-pyridin-2-ylpiperazine-1-yl)ethylamino]-2H-pyridazine-3-one-
;
[0025]
5-[2-(4-pyrimidin-2-ylpiperazine-1-yl)ethylaino]-2H-pyridazine-3-on-
e;
[0026]
5-{2-[4-(3-chlorophenyl)piperazine-1-yl]ethyl-amino}-2H-pyridazine--
3-one;
[0027]
5-{2-[4-(4-fluorophenyl)piperazine-1-yl]ethyl-amino}-2H-pyridazine--
3-one
[0028] and pharmaceutically acceptable acid addition salts
thereof.
[0029] The definition of the terms used throughout the body of the
specification and the claims is as follows:
[0030] The term "halogen" means the fluorine, chlorine, bromine and
iodine atoms, and is preferably chlorine.
[0031] The term "alkyl group having 1-4 carbon atoms" relates to
straight or branched chained alkyl groups, e.g. methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl
etc.
[0032] The term "alkoxy" relates to straight or branched chained
alkoxy groups, e.g. methoxy, ethoxy, isopropoxy or n-buthoxy,
preferably methoxy.
[0033] The term "leaving group" relates to halogen (e.g. chlorine,
bromine) or alkylsulfonyloxy groups (e.g. methylsulfonyloxy) or
arylsulfonyloxy groups (e.g. benzylsulfonyloxy,
p-toluene-sulfonyloxy).
[0034] The term "pharmaceutically suitable acid addition salt" of
the substituted alkylaminopyridazinone derivatives of the general
Formula I, relates to non-toxic acid addition salts of the compound
formed with inorganic acids such as hydrochloric acid, hydrobromic
acid, sulfuric acid, phosphoric acid etc. or organic acids such as
formic acid, acetic acid, maleic acid, fumaric acid, lactic acid,
tartaric acid, succinic acid, citric acid, benzenesulfonic acid,
p-toluenesulfonic acid, methanesulfonic acid etc.
[0035] According to a further feature of the present invention
there is provided a process for the preparation of compounds of the
general Formula I
[0036] (wherein
[0037] R.sub.1 is hydrogen or alkyl having 1-4 carbon atoms;
[0038] X is hydrogen or halogen;
[0039] R.sub.2 is hydrogen or alkyl having 1-4 carbon atoms;
[0040] n is 1, 2 or 3;
[0041] Q and W independently from each other stand for --N.dbd. or
--CH.dbd.; and
[0042] R.sub.4 and R.sub.5 independently from each other represent
hydrogen, halogen, trifluoromethyl or alkoxy having 1-4 carbon
atoms) and pharmaceutically acceptable acid addition salts thereof
which comprises
[0043] a) reacting a compound of the general Formula 2
[0044] (wherein
[0045] L.sub.1 is leaving group and R.sub.1, R.sub.2, X and n are
as stated above) with an amine of the general Formula 3
[0046] (wherein Q, W, R.sub.4 and R.sub.5 are as stated above);
or
[0047] b) reacting a compound of the general Formula 4
[0048] (wherein Y is halogen and R.sub.1 and X are as stated above)
with a compound of the general Formula 5
[0049] (wherein R.sub.2, n, Q, W, R.sub.4 and R.sub.5 are as stated
above);
[0050] and, if desired, subjecting a compound of the general
Formula I, wherein X stands for halogen, to catalytic
dehalogenation to obtain a compound of the general Formula I or its
hydrochloride salt, wherein X is hydrogen; and/or
[0051] converting a compound of the general Formula thus obtained
into a pharmaceutically acceptable acid addition salt thereof or
setting free a compound of the general Formula I from an acid
addition salt.
[0052] In case of processes (a) and (b) of the invention, the
reactions are carried out in a manner similar to the known
analogous processes, see e.g. March, J.: Advanced Organic
Chemistry, Reactions, Mechanism and Structure, 4.sup.th Edition,
John Wiley and Sons, New York, 1992.
[0053] When a substitued alkylaminopyridazinone derivative of the
Formula I, wherein X stands for halogen, preferably chlorine, is
subjected to catalytic hydrogenation, then dehalogenation proceeds
and the corresponding substituted alkylaninopyridazinone derivative
of the Formula I or its hydrochloride salt, wherein X stands for a
hydrogen atom is formed.
[0054] The catalytic hydrogenation is carried out in an analogous
manner as the processes described in the literature [e.g. March,
J.: Advanced Organic Chemistry, Reactions, Mechanism and Structure,
4.sup.th Edition, John Wiley and Sons, New York, 1992]. As the
hydrogen source, for example, hydrogen gas, hydrazine, hydrazine
hydrate, formic acid, a trialkylammonium formate or an alkali metal
formate can be used. The catalyst is suitably palladium, platinum
oxide, Raney nickel etc. The reaction can be performed in the
presence or absence of an acid binding agent. As the acid binding
agent, an inorganic base such as sodium hydroxide or an organic
base such as hydrazine, triethyl amine, diisopropyl ethyl amine
etc. can be used. The reaction can be carried out in an indifferent
protic or aprotic solvent or a mixture thereof. The protic solvent
is, for example, an alkanol, water or mixtures thereof, the aprotic
solvent is suitably dioxane, tetrahydrofuran or dichloromethane. In
general, the reaction temperature is 0-150.degree. C., preferably
20-100.degree. C.
[0055] The preparation of the acid addition salt from the free base
of the general Formula I and the liberation of the base from the
acid addition salt are carried out in a manner known per se.
[0056] The alkylamninopyridazinone derivatives of the general
Formula II used as the starting compounds can be prepared by the
process described in the International Patent Application No.
PCT/HU98/00054; (WO 99/64402).
[0057] The amines of the general Formula III are partly known
compounds. The novel ones can be prepared in an analogous way
[Pollard et al., J.Am.Chem.Soc., 56, 2199 (1934)].
[0058] The dihalopyridazinone derivatives of the general Formula IV
are partly known. The novel compounds can be prepared by using the
methods known from the literature [Homer et al., J. Chem. Soc.,
1948, 2194].
[0059] The compounds of the general Formula V can be prepared from
the corresponding amine of the general Formula III in a manner
knownper se [Shigenaga, S. et al., Arch. Pharm., 329(1), 3-10
(1996); Janssens, F. et al., J. Med. Chem., 28(12), 1934-1943
(1985); He Xiao Shu et al., Bioorg. Med. Chem. Lett., 7(18),
2399-2402 (1997)].
[0060] The pharmacological effect of the substituted
alkylaminopyridazinone derivatives of the general Formula I was
studied in the following test.
[0061] Methods and Results
[0062] Effects on Blood Pressure
[0063] The experiments were performed in conscious, freely moving,
male Wistar rats using a radiotelemetry system (Data Sciences
International, St. Paul, Minn., USA). Prior to treatments rats were
implanted with transmitters (type: TL11M2-C50-PXT) that permitted
continues monitoring of arterial blood pressure. Under sterile
surgical conditions, catheter of the transmitter was introduced
into the abdominal aorta for measurement of arterial blood pressure
and the transmitter was sutured to the abdominal wall of animals
anaesthetised with pentobarbital-Na (60 mg/kg, i.p.; Nembutal inj.
Phylaxia-Sanofi, Budapest). After surgery the animals were treated
with an antibiotic (1 ml/kg i.m. Tardomyocel comp. inj. ad us.
vet., Bayer AG Leverkusen Germany). A 7 day postoperative recovery
period was allowed. Radio signals emitted by the transmitters were
detected by RLA1000 type receivers placed under each animal's cage.
The data were collected, saved and evaluated using the Dataquest IV
software from Data Sciences. The computer was set to sample the
parameters for 10 seconds in every second minute.
[0064] The test substances or vehicle (methyl cellulose 0.4% w/v)
were administered orally by gavage in a volume of 1 ml/kg at about
10 a.m. The effects of test items were measured for 6 hours. The
effect of each compound was compared with that caused by vehicle
treatment using two-way analysis of variance for repeated measures
with Scheffe's post hoc test.
[0065] Data obtained are shown in the Table 1. None of the
compounds examined reduced blood pressure of the test animals.
1TABLE 1 Effects of different test items or vehicle on mean
arterial blood pressure for 6 hours after treatment in conscious
rats Mean blood pressure after treatment after treatment with test
with placebo compound Results of (mmHg) (mmHg) statistical Example
Mean S.E. Mean S.E. evaluation 7 92.6 3.3 92.7 3.2 N.S. S.E. =
Standard Error (of the mean); N.S. = Not significant statistically
(when compared to placebo)
[0066] According to data presented here the compounds of present
invention have no effect on blood pressure, indicating the lack of
antihypertensive potential.
[0067] Anxiolytic Effect
[0068] Vogel Lick-conflict
[0069] Experiments were performed in a PC operated system
(LIIKOSYS, Experimetria, Hungary) consisted of 8 test chambers (20
cm.times.20 cm.times.20 cm Plexiglas boxes) each of which was
equipped with a water fountain system mounted at appropriate height
on the wall of the chamber and metal grid floor for delivering
electric shocks. 160-180 g male Wistar rats (N.dbd.8) were deprived
of drinking water 48 h and fasted for 24 h prior to test. Test and
reference compounds or vehicle were administered intraperitoneally,
30 min prior to test. All procedures were carried out in a quiet,
air-conditioned room between 07:30 and 13:00 h at an ambient
temperature of 23.+-.2.degree. C. At the beginning of the test the
animals were placed in the test chamber where they had free access
to drinking water for a 30 s grace period. After that, electric
shocks (600 .mu.A, 0.6 s) were applied through the drinking spout
following every 20 licks during the 5 min test period (Vogel et al,
1971). Number of punished licks were recorded and stored by an IBM
compatible computer. Means.+-.SEM of numbers of tolerated shocks
were calculated in each group, statistical analysis of data was
performed by one way ANOVA followed by Duncan's test (STATISTICA).
The results obtained are shown in Table 2. Diazepam
[7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodia-
zepine-2-one] was used as the reference substance.
2TABLE 2 Vogel's drinking conflict test Compound (Example No.) MED
in mg/kg ip. 1 20.0 2 20.0 3 5.0 4 10.0 5 20.0 7 20.0 Diazepam
5.0
[0070] The data of Table 2 indicate that the substituted
alkylaminopyrinone derivatives of the general Formula I have
significant anxiolytic effect equivalent to that of diazepam.
[0071] Elevated Plus-maze Test in Rats
[0072] Test have been performed as described by Pellow and
co-workers [J.Neurosci. Methods, 14, 149 (1985)]. A wooden cross,
15 cm wide with 100 cm long arms was used for the experiments. The
sides and ends of two opposite arms of the cross were equipped with
40 cm high walls, however, the arms were open to the 15.times.5 cm
central area (closed arms). The two other opposite arms were not
encircled by walls (open arms).
[0073] Male Sprague-Dawley rats weighing 200-220 g were used for
the experiments. The animals were placed in the central area of the
equipment 60 min after treatment and the following four parameters
have been observed for the 5 min test time:
[0074] time spent in the open arms,
[0075] time spent in the closed arms,
[0076] number of entries into the open arms,
[0077] number of entries into the closed arms.
[0078] The effect was expressed as percent increase in either the
time (measured in sec) spent in the open arms or number of entries
into the open arms. MEDs (minimal effective dose) were determined
for each compound regarding the time spent in the open arms
[0079] The results obtained are summarized in Table 3. Buspirone
[8-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-8-azaspiro[4,5]decane-7,9-d-
ione] was used as the reference substance.
3TABLE 3 Elevated plus-maze test in rats Compound (Example No.) MED
in mg/kg po. 3 0.1 Buspirone 3.0
[0080] From Table 3 it is evident that the substituted
alkylaninopyridazinone derivatives of the general Formula I have
outstanding anxiolytic activity in the above test, considerably
exceeding the efficacy of the reference substance.
[0081] Sedative Effect
[0082] Inhibition of Spontaneous Motor Activity
[0083] The effect on spontaneous motor activity was investigated
according to Borsy and co-workers [Borsy, J. et al, Arch. Int.
Pharmacodyn., 124, 180-190 (1960)] in a ten channel Dews
instrument, with 1-1 animal in each channel. Animals were placed
into the instrument 60 min after per os treatment with either
vehicle or test compound, and interruptions of infrared beams were
recorded for 30 min. From these data, 50 per cent inhibitory doses
(ID.sub.50)have been determined by regression analysis. The results
obtained are shown in Table 4. Diazepam was used as the reference
substance.
4TABLE 4 Inhibition of spontaneous motility in mouse Compound
(Example No.) ID.sub.50 in mg/kg po. 2 21.0 3 60.0 5 >100.0
Diazepam 7.0
[0084] In contrast to the diazepam used as the reference substance,
the tested substitued alkylaminopyridazinone derivatives of the
general Formula I display sedative effect only in a relatively high
dose.
[0085] Based on the above test data, the substituted
alkylaminopyridazinone derivatives of the general Formula I are
effective in the treatment of various clinical patterns connected
with anxiety. In case of certain compounds, the anxiolytic
potential exceeds by several orders of magnitude the effect of the
marketed reference substances (diazepam, buspirone). Sedative
side-effect appears only in a dose that is multiple of the one
needed to produce the expected therapeutical effect. This means
that the substituted alkylaminopyridazinone derivatives of the
general Formula I do not have sedative, life quality deteriorating
side-effects which are characteristic of benzodiazepines.
[0086] Effect of Cognition and Memory
[0087] Male Wistar rats weighing 200-220 g were used. The animals
were obtained from Charles River Co. They were kept in a room with
normal 12-12 h light-dark cycle (light on: 06:00) at relative
humidity of 60.+-.10%.
[0088] The experiment was performed in a five-channel "step
through"-type passive avoidance learning apparatus. The equipment
consisted of two adjacent Plexi-glass boxes of 20.times.20.times.16
cm. One of them was made of regular transparent Plexi-glass and the
other one was made of black, non-transparent Plexi-glass. The boxes
were connected with a 7.5.times.8 cm passage way, equipped with a
computer-controlled guillotine-door. The passage of the rats
through the door was detected by infrared photocells arranged in
two parallel lines in the opening of the passage way. The door was
automatically closed when the animals passed through. The dark
compartment was equipped with stainless steel grid floor through
which electric foot shocks could have been delivered to the
animals. A 10 W light bulb was installed above the passage way in
the light compartment.
[0089] The experiment was performed on two consecutive days, in two
sessions which were 24 h apart from each other.
[0090] On Day 1 (Acquisition) the animals acquired information
about the situation (grid floor shock in the dark compartment), on
Day 2 (Retention) they recalled the acquired information to avoid
punishment ("if I go into the dark I will be punished, so I stay
outside in the light").
[0091] Day 1 (Acquisition)
[0092] The individually numbered animals were placed into the light
compartment of the equipment. After 30 s the guillotine door was
opened and the rats could freely pass to the dark (considered as
safe) compartment. Step through latency was automatically
determined. (Step-trough latency is the time period spanning from
door opening to the time when the animal passed into the dark
compartment.) The door was closed then, and the timer was
automatically stopped. An electric foot shock of 1.2 mA lasting 2.5
s was applied to the animal through the grid floor 3 s after the
door has been closed, except for rats in the absolute control group
(no shock+vehicle treated). Test animals were removed from the dark
compartment immediately after foot shock has been delivered. The
function of the absolute control group was to show that shocked
animals will remember the unpleasant foot shock as revealed by
increased latency time when compared to absolute control. That is
the essence of acquisition.
[0093] Day 2 (Retention)
[0094] After 24 h, the animals were placed again in the light
compartment of the test apparatus and step-through latency was
measured as described at Acquisition day, except that no foot shock
was applied to the animals in any group on the second day. A
maximum of 180 s time interval was available for the rats to pass
into the dark compartment. The animals were removed from the light
compartment if they did not pass to the dark compartment within the
180 s test period.
[0095] The investigators surprisingly found that the invention
compounds significantly increased step-through latency into the
dark compartment of the passive avoidance apparatus after Day 2
administration of the compound (FIG. 1). It is shown on FIG. 1 that
in absolute control group(no shock, untreated), step-trough latency
was approximately the same on both experimental days (meaning that
there was nothing to recall and avoid on the second day).
[0096] In the shocked, vehicle-treated control group the
unavoidable 1.2 mA foot shock resulted in a significantly increased
step-through latency on Day 2 when compared to absolute control.
The experimental animals recalled the annoying experience (foot
shock) in the dark, therefore, they pass into the dark compartment
with a significantly longer time (increased latency).
[0097] In the treated groups this augmented latency has been
further increased after the Day 2 treatment indicating that the
retention of memory has been improved.
[0098] These surprising effects are not evident since anxiolytic
compounds (i.e. diazepam) have a deleterious effect on memory.
[0099] From therapeutic point of view the advantageous effect of
compounds of general Formula I on learning and memory signifies
that the compounds could be appropriate for treating and/or
preventing diseases or conditions accompanying diseases wherein
learning or memory functions are suffering a loss or there is a
possibility to suffering a loss. Such diseases are, but not limited
to--as mentioned earlier--Alzheimer's disease, Korsakoff syndrome,
Huntington's disease, Parkinson's disease and mental decline due to
ageing processes, impairment of the cognitive functions or to
exposure to toxic substances as well.
SUMMARY
[0100] The compounds of general Formula I possess surprisingly
considerable anxiolytic properties without sedative side effects in
their anxiolytic dose range. In addition to the anxiolytic
efficacy, the compounds of general Formula I have advantageous
effects on cognition and memory. According to our studies the
compounds of general Formula I surprisingly have no
antihypertensive potential.
[0101] The compounds of the invention and pharmaceutically suitable
acid addition salts thereof can be used as active ingredients in
pharmaceutical compositions.
[0102] Furthermore, the invention relates to a pharmaceutical
composition comprising a substituted alkylaminopyridazinone
derivatives of the general Formula I or a pharmaceutically suitable
acid addition salt thereof and one or more conventional
carriers.
[0103] The pharmaceutical composition of the invention contains, in
general, 0.1 to 95 per cent by weight, preferably 1 to 50 per cent
by weight, suitably 5 to 30 per cent by weight of the active
ingredient.
[0104] The pharmaceutical composition of the invention is suitable
for peroral, parenteral, rectal or transdermal administration or
for local treatment, and can be solid or liquid.
[0105] The solid pharmaceutical compositions suitable for peroral
administration may be powders, capsules, tablets, film-coated
tablets, microcapsules etc., and can comprise binding agents such
as gelatine, sorbitol, poly(vinyl-pyrrolidone) etc.; filling agents
such as lactose, glucose, starch, calcium phosphate etc.; auxiliary
substances for tabletting such as magnesium stearate, talc,
poly(ethylene glycol), silica etc.; wetting agents such as sodium
laurylsulfate etc. as the carrier.
[0106] The liquid pharmaceutical compositions suitable for peroral
administration may be solutions, suspensions or emulsions and can
comprise e.g. suspending agents such as gelatine,
carboxymethylcellulose etc.; emulsifiers such as sorbitane
monooleate etc.; solvents such as water, oils, glycerol, propylene
glycol, ethanol etc.; preservatives such as methyl
p-hydroxybenzoate etc. as the carrier.
[0107] Pharmaceutical compositions suitable for parenteral
administration consist of sterile solutions of the active
ingredient, in general.
[0108] Dosage forms listed above as well as other dosage forms are
known per se, see e.g. Remington's Pharmaceutical Sciences,
18.sup.th Edition, Mack Publishing Co., Easton, USA (1990).
[0109] The pharmaceutical composition contains dosage unit, in
general. A typical dose for adult patients amounts to 0.1 to 1000
mg of the compound of the general Formula I or a pharmaceutically
suitable acid addition salt thereof calculated for 1 kg body
weight, daily. The daily dose can be administered in one or more
portions. The actual dosage depends on many factors and is
determined by the doctor.
[0110] The pharmaceutical composition is prepared by admixing a
compound of the general Formula I or a pharmaceutically suitable
acid addition salt thereof to one or more carrier(s), and
converting the mixture obtained to a pharmaceutical composition in
a manner known per se. Useful methods are known from the
literature, e.g. Remington's Pharmaceutical Sciences mentioned
above.
[0111] According to a further feature of the present invention
there is provided the use of compounds of the general Formula I or
a pharmaceutically acceptable acid addition salt thereof as
pharmaceutical active ingredient.
[0112] According to a preferred embodiment of the above feature of
the invention there is provided the use of compounds of the general
Formula I or pharmaceutically acceptable acid addition salts
thereof as anxiolytic and cognition enhancing pharmaceutically
active ingredients.
[0113] According to a still further feature of the present
invention there is provided a method of anxiolytic and cognition
enhancing treatment of anxiolytic conditions which comprises
administering to the person in need of such treatment a
pharmaceutically effective amount of a compound of the general
Formula I according to claim 1 or a pharmaceutically acceptable
acid addition salt thereof.
[0114] Further details of the present invention are to be found in
the following Examples without limiting the scope of protection to
said Examples.
EXAMPLES
Example 1
[0115] Preparation of
5-{2-[4-(methoxytrifluoromethylphenyl)-piperazine-1--
yl]-ethylamino}-2H-pyridazine-3-one trihydrochloride
[0116] 3.7 g (0.0086 moles) of
4-chloro-5-{2-[4-(methoxy-trifluoromethyl-p-
henyl)piperazine-1-yl]ethylamino}-H-pyridazine-3-one, 370 cm.sup.3
of methanol, 3.2 cm.sup.3 (0,018 moles) of diisopropyl-ethylamine
and 3.7 g of palladium on carbon catalyst consisting of 8% of Pd,
28% of C and 64% of H.sub.2O are transferred into an autoclave. The
reaction mixture is stirred at room temperature and under a
hydrogen pressure of 10 atm for 4 hours. Then, the excess hydrogen
is let out from the autoclave, the reaction mixture is heated to
reflux temperature and stirred at this temperature for 5 minutes,
then filtered while hot, and the catalyst is washed three times
using 33 cm.sup.3 of a 1:1 mixture of methanol and dichloromethane
each time. The combined filtrates are evaporated under reduced
pressure, and the residue is subjected to chromatography over a
silica gel column using a 19:1 mixture of chloroform and methanol
as the eluent. The fractions containing the product are evaporated,
the residue is dissolved in a mixture of ethyl acetate and diethyl
ether, and, to the solution obtained, ether containing hydrogen
chloride are added, drop by drop. The crystals that precipitate are
stirred for half an hour under cooling with ice water, then
filtered and washed with diethyl ether. The product is dried at
80.degree. C. over phosphorus pentoxide in vacuo for 3 hours.
[0117] Thus, 1.84 g (54%) of the title compound are obtained. M.p.:
238-240.degree. C.
[0118] Analysis: for C.sub.18H.sub.25Cl.sub.3F.sub.3N.sub.5O.sub.2
(506.79)
[0119] calculated: C 42.66%, H 4.97%, N 13.82%, Cl 20.99%;
[0120] found: C 42.53%, H 5.01%, N 13.63%, Cl 20.69%.
[0121] IR (KBr): 3294, 2340, 1630, 1330, 1115:
[0122] .sup.1H-NMR (DMSO-d.sub.6, i400): 13.23 (b, 1H), 11.49 (b,
1H), 8.43 (b, 1H), 7.90 (bs, 1H), 7.40 (d, J.dbd.8.5 Hz, 1H), 7.18
(d, J.dbd.8.7 Hz, 1H), 7.15 (s, 1H), 6.05 (bs, 1H), 3.89 (s, 3H),
3.13-3.75 (m, 12H).
[0123] .sup.3C-NMR (DMSO-d.sub.6, i400): 162.14, 154.81, 150.30,
139.98, 134.04, 124.68 (q, J.dbd.271.6 Hz), 121.51 (q, J.dbd.31.7
Hz), 120.92 (q), 114.81 (q), 112.22, 93.60, 56.13, 53.09, 51.30,
46.69, 36.49.
Example 2
[0124] Preparation of
5-{2-[4-(2-fluorophenyl)piperazine-1-yl]ethyl-amino}-
-2H-pyridazine-3-one
[0125] 2.5 g (0.0071 moles) of
4-chloro-5-{2-[4-(2-fluorophenyl)piperazine-
-1-yl]ethylamino}-2H-pyridazine-3-one, 400 cm.sup.3 of a 9:1
mixture of methanol and distilled water and 2.5 g of palladium on
carbon catalyst consisting of 8% of Pd, 28% of C and 64% of
H.sub.2O are weighed into an apparatus of 1000 cm.sup.3 volume
equipped with a reflux condenser connected to a bubbling device.
1.4 cm.sup.3 of hydrazine hydrate are added, drop by drop, to the
reaction mixture that is then stirred at reflux temperature for 1
hour. The mixture is filtered while hot, and the catalyst is washed
three times using 33 cm.sup.3 of a 1:1 mixture of methanol and
dichloromethane. The combined filtrates are evaporated, and the
residue is dissolved in 25 cm.sup.3 of a 8:1 filtered, and the
filtrate is evaporated to the fifth of the original volume. After
cooling, the crystals separated are stirred for further half an
hour under cooling with ice water, then filtered and washed with
diethyl ether. The product is dried at 40.degree. C. over
phosphorus pentoxide in vacuo for 3 hours.
[0126] Thus, 1.91 g (84.8%) of the title compound are obtained.
M.p.: 103-105.degree. C.
[0127] Analysis: for C.sub.16H.sub.20FN.sub.5O (317.37)
[0128] calculated: C 60.55%, H 6.35%, N 22.07%;
[0129] found: C 60.25%, H 6.34%, N 21.89%.
[0130] IR (KBr): 3272, 3122, 1633, 1550.
[0131] .sup.1H-NMR (DMSO-d6, i400): 11.87 (bs, 1H), 8.35 (d,
J.dbd.4.8 Hz, 2H), 7.48 (d, J.dbd.2.6 Hz, 1H), 6.85 (bt, J.dbd.5.1
Hz, 1H), 6.62 (t, J.dbd.4.7 Hz, 1H), 5.40 (.about.s, 1H), 3.73 (m,
4H), 3.14 (.about.q, J.dbd.6.0 Hz, 2H), 2.50 (m)
[0132] .sup.13C-NMR (DMSO-d.sub.6, i400): 162.42, 161.38, 158.08,
149.44, 131.73, 110.28, 94.38, 55.85, 52.71,43.40, 39.16.
Example 3
[0133] Preparation of
5-{2-[4phenylpiperazine-1-yl]ethylamino}2H-pyridazin- e-3-one
[0134] 3.3 g (0.01 moles) of
4-chloro-5-[2-(4-phenylpiperazine-1-yl)ethyla-
mino]-2H-pyridazine-3-one, 500 cm3 of a 9:1 mixture of methanol and
distilled water and 3.3 g of palladium on carbon catalyst
consisting of 8% of Pd, 28% of C and 64% of H.sub.2O are weighed
into an apparatus of 1000 cm.sup.3 volume equipped with a reflux
condenser connected to a bubbling device. 2 cm.sup.3 of hydrazine
hydrate are added, drop by drop, to the reaction mixture that is
then stirred at reflux temperature for 3 hours. The mixture is
filtered while hot, and the catalyst is washed three times using 33
cm.sup.3 of a 1:1 mixture of methanol and dichloromethane. The
combined filtrates are evaporated, and the residue is dissolved in
15 cm.sup.3 of a 8:1 mixture of ethanol and water under heating,
the solution is filtered, and the filtrate is evaporated to the
fourth of the original volume. After cooling, the crystals
separated are stirred for further half an hour under cooling with
ice water, then filtered and washed with diethyl ether. The product
is dried at 60.degree. C. over phosphorus pentoxide in vacuo for 3
hours.
[0135] Thus, 2.18 g (72.9%) of the title compound are obtained.
M.p.: 147-149.degree. C.
[0136] Analysis: for: C.sub.16H.sub.20FN.sub.5O (317.37)
[0137] calculated: C 64.19%, H 7.07%, N 23.39%;
[0138] found: C 63.74%, H 7.09%, N 22.89%.
[0139] IR (KBr): 3484, 3318, 1638, 1600.
[0140] .sup.1H-NMR (DMSO-d.sub.6, i400): 11.98 (bs, 1H), 7.52 (d,
J.dbd.2.3 Hz, 1H), 7.21 (.about.t, J.dbd.7.8 Hz, 2H), 6.91
(.about.d, J.dbd.8.5 Hz, 2H), 6.90 (bt, J.dbd.5.1 Hz, 1H), 6.77
(.about.t, J.dbd.7.2 Hz, 1H), 5.44 (d, J.dbd.2.3 Hz, 1H), 3.14 (m,
6H), 2.56 (m, 6H).
[0141] .sup.13C-NMR (DMSO-d.sub.6, i400): 162.46, 151.20, 149.47,
131.76, 129.11, 118.97, 115.52, 94.37, 55.87, 52.93, 48.30,
39.25.
Example 4
[0142] Preparation of
5-[2-(4-pyridin-2-ylpiperazine-;1-yl)ethylamino]-2H--
pyridazine-3-one
[0143] 3.2 g (0.0096 moles) of
4-chloro-5-[2-(4-pyridin-2-ylpiperazine-1-y-
l)-ethylamino]-2H-pyridazine-3-one, 500 cm.sup.3 of a 9:1 mixture
of methanol and distilled water and 3.2 g of palladium on carbon
catalyst consisting of 8% of Pd, 28% of C and 64% of H.sub.2O are
weighed into an apparatus of 1000 cm.sup.3 volume equipped with a
reflux condenser connected to a bubbling device. 1.6 cm.sup.3 of
hydrazine hydrate are added, drop by drop, to the reaction mixture
that is then stirred at reflux temperature for 2 hours. The mixture
is filtered while hot, and the catalyst is washed three times using
33 cm.sup.3 of a 1:1 mixture of methanol and dichloromethane. The
combined filtrates are evaporated, and the residue is dissolved in
30 cm.sup.3 of a 8:1 mixture of ethanol and water under heating,
the solution is filtered, and the filtrate is evaporated to the
fifth of the original volume. After cooling, the crystals separated
are stirred for further half an hour under cooling with ice water,
then filtered and washed with diethyl ether. The product is dried
at 80.degree. C. over phosphorus pentoxide in vacuo for 3
hours.
[0144] Thus, 2.44 g (85.0%) of the title compound are obtained.
M.p.: 150-152.degree. C.
[0145] IR (KBr): 3444, 1605, 1340, 1167.
[0146] .sup.1H-NMR (CDCl.sub.3, g200): 11.91 (bs, 1H), 8.11 (m,
1H), 7.51 (m Hz, 2H), 6.95 (b, 1H), 6.85 (m, 1H), 6.65 (m, 1H),
5.44 (s, 1H), 3.52 (m, 4H), 3.22 (m, 4H), 2.63 (m, 4H).
Example 5
[0147] Preparation of
5-[2-(4-pyrimidin-2-ylpiperazine-1-yl)ethylamino]-2H-
-pyridazine-3-one
[0148] 3.4 g (0.01 moles) of
4-chloro-5-[2-(4-pyrimidin-2-ylpiperazine-1-y-
l)-ethylamino]-2H-pyridazine-3-one, 500 cm.sup.3 of a 9:1 mixture
of methanol and distilled water and 3.4 g of palladium on carbon
catalyst consisting of 8% of Pd, 28% of C and 64% of H.sub.2O are
weighed into an apparatus of 1000 cm.sup.3 volume equipped with a
reflux condenser connected to a bubbling device. 1.7 cm.sup.3 of
hydrazine hydrate are added, drop by drop, to the reaction mixture
that is then stirred at reflux temperature for 1.5 hours. The
mixture is filtered while hot, and the catalyst is washed three
times using 33 cm.sup.3 of a 1:1 mixture of methanol and
dichloromethane. The combined filtrates are evaporated, and the
residue is dissolved in 28 cm.sup.3 of a 8:1 mixture of ethanol and
water under heating, the solution is filtered, and the filtrate is
evaporated to the fifth of the original volume. After cooling, the
crystals separated are stirred for further half an hour under
cooling with ice water, then filtered and washed with diethyl
ether. The product is dried at 80.degree. C. over phosphorus
pentoxide in vacuo for 3 hours.
[0149] Thus, 2.19 g (72.5%) of the title compound are obtained.
M.p.: 199-201.degree. C.
[0150] Analysis: for C.sub.14H.sub.19N.sub.7O (301.35)
[0151] calculated: C 55.80%, H 6.36%, N 32.54%;
[0152] found: C 55.71%, H 6.33%, N 32.41%;
[0153] IR (KBr): 3272, 3122, 1633, 1550.
[0154] .sup.1H-NMR (DMSO-d.sub.6, i400): 11.87 (bs, 1H), 8.35 (d,
J.dbd.4.8 Hz, 2H), 7.48 (d, J.dbd.2.6 Hz, 1H), 6.85 (bt, J.dbd.5.1
Hz, 1H), 6.62 (t, J.dbd.4.7 Hz, 1H), 5.40 (.about.s, 1H), 3.73 (m,
4H), 3.14 (.about.q, J.dbd.6.0 Hz, 2H), 2.50 (m).
[0155] .sup.13C-NMR (DMSO-d.sub.6, i400): 162.42, 161.38, 158.08,
149.44, 131.73, 110.28, 94.38, 55.85, 52.71, 43.40, 39.16.
Example 6
[0156] Preparation of
5-{2-[4-(3-chlorophenyl)piperazine-1-yl]ethyl-amino}-
-2H-pyridazine-3-one
[0157] A mixture of 1.96 g (0.01 moles) of
1-(3-chlorophenyl)-piperazine, 8 cm.sup.3 of dimethylformamide, 4.5
cm.sup.3 (0.014 moles) of triethylamine, 0.2 g of potassium iodide
and 1.9 g (0.009 moles) of
5-(2-chloroethylamino)-2H-pyridazine-3-one hydrochloride is stirred
at reflux temperature for 2 hours. To the reaction mixture, a
solution of 3.0 g of sodium hydrogen carbonate in 40 cm.sup.3 of
water is added, drop by drop. Due to the presence of the water, oil
separates. The water is decanted from the oil, and 10 cm.sup.3 of
dichloro-methane are added to the residue. The crystals separating
under stirring are filtered. The crude product is dissolved in
methanol at reflux temperature under stirring, treated with
charcoal, filtered, and the filtrate is evaporated to the fifth of
the original volume. The residue is stirred under cooling with ice
water, and. the precipitated crystals are filtered.
[0158] Thus, 1.21 g (40.5%) of the title compound are obtained.
M.p.: 187-189.degree. C.
[0159] Analysis: for C.sub.16H.sub.20CIN.sub.5O (333.82)
[0160] calculated: C 57.57%, H 6.04%, Cl 10.62%, N 20.98%;
[0161] found: C 57.09%, H 6,05%, Cl 10.38%, N 22.68%.
[0162] IR (KBr): 3410, 3277, 1624, 1599, 1240.
[0163] .sup.1H-NMR (DMSO-d.sub.6, i400): 11.93 (bs, 1H), 7.20
(.about.t, J.dbd.8.2 Hz, 1H), 6.89 (m, 1H), 6,87 (bt, J.dbd.5.2 Hz,
1H), 6.78 (m, 1H), 5.42 (d, J.dbd.2.5 Hz, 1H), 3.18 (m, 6H), 2.54
(m, 6H).
[0164] .sup.13C-NMR (DMSO-d.sub.6, i400): 162.38, 152.40, 149.42,
134.01, 131.70, 130.57, 118.17, 114.65, 113.78, 94.37, 55.80,
52.71, 47.74, 39.22.
Example 7
[0165] Preparation of
5-{2-[4-(4-fluorophenyl)piperazine-1-yl]ethyl-amino]-
-2H-pyridazine-3-one
[0166] 3.51 g (0.01 moles)
of4-chloro-5-{2-[4-(4-fluorophenyl)piperazine-1-
-yl]ethylamino}-2H-pyridazine-3-one, 350 cm.sup.3 of a 9:1 mixture
of methanol and distilled water, 0.44 g (0.011 moles) of sodium
hydroxide and 3.5 g of palladium on carbon catalyst consisting of
8% of Pd, 28% of C and 64% of H.sub.2O are transferred into an
autoclave. The reaction mixture is stirred at room temperature
under a hydrogen pressure of 10 atm for 3 hours. Then, the excess
hydrogen is let out from the autoclave, the reaction mixture is
heated to reflux temperature and stirred at this temperature for 5
minutes, then filtered while hot, and the catalyst is washed three
times using 50 cm.sup.3 of a 1:1 mixture of methanol and dichloro
methane each time. The combined filtrates are evaporated to a
volume of 20 cm.sup.3, the solution obtained is stirred for half an
hour under cooling with ice water, the crystals obtained are
filtered and washed with 10 cm.sup.3 of cooled methanol.
[0167] Thus, 2.98 g (81.7%) of the title compound are obtained.
M.p.: 96-98.degree. C.
[0168] Analysis: for: C.sub.16H.sub.20FN.sub.5O (317.37)
[0169] calculated: H 6.35%, N 22.07%;
[0170] found: H 6.30%, N 21.64%.
[0171] IR (KBr) 3433, 3243, 3081, 1618, 1507, 1226.
[0172] .sup.1H-NMR (DMSO-d.sub.6, i400): 11.95 (bs, 1H), 7.52 (d,
J.dbd.2.5 Hz, 1H), 7.02 (.about.t, J.dbd.8.9 Hz, 2H), 6.94 (dd,
J1.dbd.4.7 Hz, J2.dbd.9.3 Hz, 2H), 6.90 (bt, J.dbd.5.3 Hz, 1H),
5.43 (d, J.dbd.2.5 Hz, 1H), 3.15 (.about.q, J.dbd.6.0 Hz, 2H), 3.08
(m, 4H), 2.56 (m, 6H).
[0173] .sup.13C-NMR (DMSO-d.sub.6, i400): 162.42, 156.16 (d,
J.dbd.235.4 Hz), 149.45, 148.10 (d, J.dbd.1.9 Hz), 131.72, 117.23
(J.dbd.7.6 Hz), 115.42 (d, J.dbd.21.7 Hz), 94.35, 55.82, 52.91,
49.09, 39.25.
* * * * *