Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D237/22—Nitrogen and oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the invention relates to substituted alkylaminopyridazinone derivatives, process for the preparation thereof and pharmaceutical composition containing the same.
• 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.
• sedative and amnestic side effects are a major disadvantage of these drugs especially in disorders affecting active, working populations.
• 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.
• 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.
• the object of the invention is to provide new substituted alkylaminopyridazinone derivatives having useful pharmaceutical properties and free of disturbing side-effects.
• a preferable subgroup of the invention compounds of the general Formula I are those derivatives, in which
• halogen means the fluorine, chlorine, bromine and iodine atoms, and is preferably chlorine.
• 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.
• alkoxy relates to straight or branched chained alkoxy groups, e.g. methoxy, ethoxy, isopropoxy or n-buthoxy, preferably methoxy.
• leaving group relates to halogen (e.g. chlorine, bromine) or alkylsulfonyloxy groups (e.g. methylsulfonyloxy) or arylsulfonyloxy groups (e.g. benzylsulfonyloxy, p-toluene-sulfonyloxy).
• halogen e.g. chlorine, bromine
• alkylsulfonyloxy groups e.g. methylsulfonyloxy
• arylsulfonyloxy groups e.g. benzylsulfonyloxy, p-toluene-sulfonyloxy
• 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.
• inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid etc.
• 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.
• 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 th Edition, John Wiley and Sons, New York, 1992].
• 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.
• an inorganic base such as sodium hydroxide or an organic base such as hydrazine, triethyl amine, diisopropyl ethyl amine etc.
• 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.
• the reaction temperature is 0-150° C., preferably 20-100° C.
• 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).
• 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)].
• 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].
• 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)].
• mice were implanted with transmitters (type: TL11M2-C50-PXT) that permitted continues monitoring of arterial blood pressure.
• transmitters type: TL11M2-C50-PXT
• 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).
• pentobarbital-Na 60 mg/kg, i.p.; Nembutal inj. Phylaxia-Sanofi, Budapest).
• pentobarbital-Na 60 mg/kg, i.p.; Nembutal inj. Phylaxia-Sanofi, Budapest).
• the animals were treated with an antibiotic (1 ml/kg i.m. Tardomyocel comp. inj. ad us.
• test substances or vehicle methyl cellulose 0.4% w/v
• vehicle methyl cellulose 0.4% w/v
• 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.
• Diazepam [7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one] was used as the reference substance.
• TABLE 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
• 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. Elevated Plus-maze Test in Rats
• mice 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:
• Diazepam 7.0 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.
• the substituted alkylaminopyridazinone derivatives of the general Formula I are effective in the treatment of various clinical patterns connected with anxiety.
• 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.
• the substituted alkylaminopyridazinone derivatives of the general Formula I do not have sedative, life quality deteriorating side-effects which are characteristic of benzodiazepines.
• mice 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%.
• 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 ⁇ 20 ⁇ 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 ⁇ 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.
• the experiment was performed on two consecutive days, in two sessions which were 24 h apart from each other.
• 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.
• 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.
• 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).
• 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.
• 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.
• 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.
• the compounds of the invention and pharmaceutically suitable acid addition salts thereof can be used as active ingredients in pharmaceutical compositions.
• the invention relates to a pharmaceutical composition
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• compositions suitable for parenteral administration consist of sterile solutions of the active ingredient, in general.
• Dosage forms listed above as well as other dosage forms are known per se, see e.g. Remington's Pharmaceutical Sciences, 18 th Edition, Mack Publishing Co., Easton, USA (1990).
• 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.
• 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.
• 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.
• the mixture is filtered while hot, and the catalyst is washed three times using 33 cm 3 of a 1:1 mixture of methanol and dichloromethane.
• the combined filtrates are evaporated, and the residue is dissolved in 25 cm 3 of a 8:1 filtered, and the filtrate is evaporated to the fifth of the original volume.
• 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° C. over phosphorus pentoxide in vacuo for 3 hours.
• the mixture is filtered while hot, and the catalyst is washed three times using 33 cm 3 of a 1:1 mixture of methanol and dichloromethane.
• the combined filtrates are evaporated, and the residue is dissolved in 15 cm 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.
• 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° C. over phosphorus pentoxide in vacuo for 3 hours.
• the mixture is filtered while hot, and the catalyst is washed three times using 33 cm 3 of a 1:1 mixture of methanol and dichloromethane.
• the combined filtrates are evaporated, and the residue is dissolved in 30 cm 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.
• 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° C. over phosphorus pentoxide in vacuo for 3 hours.
• the mixture is filtered while hot, and the catalyst is washed three times using 33 cm 3 of a 1:1 mixture of methanol and dichloromethane.
• the combined filtrates are evaporated, and the residue is dissolved in 28 cm 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.
• 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° C. over phosphorus pentoxide in vacuo for 3 hours.
• a mixture of 1.96 g (0.01 moles) of 1-(3-chlorophenyl)-piperazine, 8 cm 3 of dimethylformamide, 4.5 cm 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.
• a solution of 3.0 g of sodium hydrogen carbonate in 40 cm 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 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.

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