HK1000597B - Pyridazine derivatives, process for their preparation and pharmaceutical compositions containing them - Google Patents
Pyridazine derivatives, process for their preparation and pharmaceutical compositions containing them Download PDFInfo
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- HK1000597B HK1000597B HK97102147.2A HK97102147A HK1000597B HK 1000597 B HK1000597 B HK 1000597B HK 97102147 A HK97102147 A HK 97102147A HK 1000597 B HK1000597 B HK 1000597B
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Description
For many years, pyridazine derivatives have been proposed as drugs, particularly those active on the cardiovascular or central nervous system.
In particular, French patent 2 510 998 and European patent 72 726 disclosed pyridazine derivatives variously substituted on the pyridazine cycle and each bearing in position 3 an amino substituent of the type
where X is the hydrogen or a (C1-C4) alkyl group.
European patent 74 863 describes pyridazine derivatives which are variously substituted on the pyridazine cycle and all of which have an amino substituent of the type
where A is an alkylene in C2-C5.
All of these compounds have activity on the central nervous system as antidepressants.
According to the present invention, new pyridazine derivatives have now been found to have lost their antidepressant activity and have acquired interesting activity as ligands of cholinergic receptors, particularly M1-type receptors.
The present invention relates, first, to new pyridazine derivatives selected from:
3-di-di-di-ethylamino-2-methylpropyl) amino-6-phenyle-5-propylpyridazine;* 3-di-di-di-ethylamino-2-methylpropyl) amino-6-di-chlorophenyl) -5-propylpyridazine;* 3-di-di-di-ethylamino-2-methylpropyl) amino-6-amino-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl-propyl
The following compounds are particularly preferred:
3-diethylamino-2-methylpropyl) amino-6-phenyle-5-propyl-pyridazine and its salts; 3-diethylamino-2-methylpropyl) amino-5,6-diphenylepyridazine and its salts
Salts of compounds according to the present invention include both those with mineral or organic acids that allow proper separation or crystallization of these compounds, such as picric acid or oxalic acid, and those that form pharmaceutically acceptable salts such as hydrochloride, bromohydrate, sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulfonate, methyl sulphate, maleate, fumarate, naphthalene-2 sulfonate.
In a second respect, the present invention relates to a process for the preparation of the above compounds.
According to the present invention, the process of preparation of the above compounds is characterized by reacting an amine with formula R4NH2 in which R4 represents a 2-diethylamino-2-methylpropyl group or, if applicable, 2-pipéridino-2-methylpropyl or 2-morpholin-4-yl) 2-methylpropyl, with a chloro-6-pyridazine of formula:
in which:
* R3 is a propyl and Ar is a phenyl or, where appropriate, a 2-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl or 4-hydroxyphenyl;
or* R3 is a methyl and Ar is a 2-methoxyphenyle or, where applicable, a 2-hydroxyphenyle, a 4-chlorophenyl or a phenyl;
where R*3 is a phenyl and Ar is a phenyl;
where R*3 is a cyclopropyl and Ar is a phenyl;
or R*3 is an isopropyl and Ar a 4-fluorophenyl;
and possibly the resulting compound is salivated with mineral or organic acid.
The substitution reaction of chlorine-6 pyridazine (II) with the amine R4NH2 is carried out at 100°C to 150°C, possibly in the presence of ammonium chloride.
The resulting product is isolated, in the form of a free base or salt, by conventional techniques.
When the product is obtained as a free base, the salivation is carried out by treatment with the selected acid in an organic solvent. By treatment of the free base, dissolved for example in an alcohol such as isopropanol, with a solution of the selected acid in the same solvent, the corresponding salt is obtained which is isolated by conventional techniques. Thus, for example, hydrochloride, bromohydrate, sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulfonate, methyl sulphate, oxalate, maleate, fumarate, naphthalene-2 sulphate are prepared.
At the end of the reaction, the compound of the invention may be isolated as one of its salts, e.g. the hydrochloride; in this case, if necessary, the free base may be prepared by neutralizing the salt with a mineral or organic base such as sodium hydroxide or triethylamine or with an alkaline carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.
Where Ar represents a hydroxyphenyle, the compound of the invention is obtained from the compound in which Ar represents an alcohol-oxyphenyle and all other substituents have the above definitions by dealkylation using known methods.
Chloro-6 pyridazines (II), used as starting products, are prepared from the corresponding 2H-pyridazines-3 (III) by the action of an excess of phosphorus oxychloride on hot, operating without solvent or in the presence of an inert solvent such as acetonitrile, according to the reaction scheme:
- What?
2H-pyridazinones-3 (III) are known or prepared by known methods.
Thus, when R3 is a phenyl Ar', the 2H-pyridazinones-3 are obtained by the method described by P. SCHMIDT et al. in Helv. Chim. Acta, 1954, 15, 134-140, from the diethyl ester of malonic acid and a derivative of hydrazone according to the following reaction scheme:
When R3 is a methyl, propyl, isopropyl or cyclopropyl radical, the compounds (III) are prepared from an Ar-CO-CH2R3 ketone (1):
- What?
From ketone 1, by heating with ethyl glyoxylate at a temperature of 80 to 140 °C, hydroxy ketoester 2 is obtained. The raw reaction mixture is then taken up in an inert solvent such as n-butanol and hydrazine hydrate is added. By reflux heating for 24 hours, dihydro-4,5 hydroxy-4 pyridazinone-3 3 is obtained, which, heated in an acidic medium, is driven by dehydration to 2H-pyridazinone-3 (III).
The amines R4NH2 are known or prepared by known methods. Thus, they can be prepared from a cyan derivative of formula:
- What?
By heating an amine HNR5R6 (diethylamine, piperidine or morpholine) at a temperature of 40 to 80 °C, possibly in the presence of a salt of a strong acid such as sodium sulphate or magnesium sulphate, a compound of the formula:
The compound is then hydrated by the action of a strong acid such as sulphuric acid on hot water to obtain the corresponding amide:
- What?
Finally, the heat reduction by a metal hydride such as a boron hydride, or a lithium and aluminium hydride allows the amine R4NH2 to be obtained.
An amine R4NH2 can also be prepared from a chloronitrose (VII) derivative by the method described in J. Prakt. Chem., 1978, 320 (3), 433-451.
- What?
The compound of formula (VII) may be used as a dimer (VII bis), which is obtained by action of nitrosyl chloride on the appropriate olefin (IX) according to the method described in J. Prakt. Chem., 1965, 29 (4), 123
- What?
The following examples illustrate the invention: Compounds are characterized by their melting point (F) expressed in degrees Celsius.
The following shall be indicated in the list of active substances:
1. hydroxy-2 oxo-4 phenyl-4 propyl-3 ethyl butyrate.
Heat the mixture of 48.67 g of valerophenone and 45.94 g of ethyl glyoxylate at 120 °C for 15 hours.
- What?
The raw reaction product is used as is for the next operation.
The following is the list of active substances:
Dissolve the raw product obtained above in 450 ml of n-butanol, add 30 g hydrazine hydrate and heat at low temperature for 24 hours.
- What?
Concentrate the n-butanol in a vacuum, take the residue into a mixture of 300 ml of acetic acid and 30 ml of concentrated hydrochloric acid, heat the mixture at 100°C for 3 hours, pour the solution into cold water and let it crystallize.- What?
- What?
You just rip out the solid and dry it.
Weight: 44 g.
F: 160°C.
The yield is 69%.
The following is a list of the active substances in the active substance:
To the 44 g of pyridazinone obtained above, add 250 ml of phosphorus oxychloride and heat at 80°C for 4 hours.
- What?
After a night at room temperature, the reaction medium is concentrated at 3/4 and the mixture is slowly poured over ice. Two extractions per 300 ml of dichloromethane are made, dried on sodium sulphate and concentrated.7 g of the expected product.
F: 60°C.
The yield is 92%.
The following is a list of the active substances in the active substance:
85.1 g of distilled acetone cyanhydrin and 73.1 g of diethylamine are mixed, 85.7 g of magnesium sulfate is added and heated at low reflux for 20 hours under stirring, the resulting sulfate block is filtered and washed with ether, the filtrate is concentrated and then distilled.
- What?
We're collecting 86.6 grams of the expected product.
The yield is 62%.
The temperature of the water is 68-70°C at 1998 Pa (15 mm mercury).
The following is a list of the active substances in the active substance:
To 95.9 g of nitrile prepared in the previous step, add 450 ml of sulphuric acid and 70 ml of water by stirring and heat in an oil bath at 100-110 °C for 2 hours.The reaction mixture is slowly poured over 1 hour into 1.4 litres of a 20% ammonia solution and 400 ml of water, cooled by a carboglass bath in acetone, and methylene chloride is extracted 3 times per 600 ml, dried on sodium sulphate and concentrated.
- What?
The expected product is obtained by distillation.
Weight: 102.5 g.
The yield is 95 percent.
The temperature of the water is between 134-139°C at 1998 Pa (15 mm mercury).
The Commission has not yet adopted a proposal for a directive on the approximation of the laws of the Member States relating to the labelling of foodstuffs.
Heat to 45-50°C a mixture containing 52.4 g of the amide prepared in the previous step and 60 ml of tetrahydrofuran.86 ml of the borane dimethyl sulphide complex and continue heating for 3 hours in an oil bath at 80-85°C.
- What?
After a night at room temperature, cool in an ice bath and then add very slowly, in 3 hours, 315 ml of 6N hydrochloric acid and heat again at 135°C for 3 hours. After a night at room temperature, add 200 ml of soda at 30%, while cooling the reaction mixture. Extract 3 times per 250 ml of ether and then dry on sodium sulfate and concentrate.
- What?
The expected product is obtained by distillation.
Weight: 23 g.- What?
The yield is 48%.
The temperature of the water is approximately 71-73°C at 1998 Pa (15 mm mercury).
(c) SR 46559 A
The mixture of 2.5 g of the chlorinated derivative obtained in step A and 4.6 g of the diamine obtained in step B is heated overnight to 120 °C. 150 ml of ethyl acetate is added and extracted twice per 50 ml of hydrochloric acid. 50 ml of soda is then alkalized by adding 50 ml of 30% sodium and then extracted with ethyl acetate.(v/v)
You get 3.2 grams of oil that crystallizes.
F: 75 to 77 °C.
The yield is 87%.
The total volume of the liquid (175 ml) is concentrated to 130 ml. The crystals are allowed to crystallize, filtered and washed with acetone.
We get 4.1 grams of the expected product.
Overall efficiency of stage E: 74%.
F is 151 degrees.
A) Chloro-6-phenyl-3-propyl-4-pyridazine, described in example 1.B) Diethylamino-2-methyl-2-propylamine.1.
47.14 g isobutylene are dissolved in 150 ml n-heptane, the mixture is cooled to a temperature of -10° to -20°C and 50 g nitrosyl chloride is added. The temperature is raised (+5°C) for 1 hour and a half, the temperature is raised between 10°C and 20°C and the mixture is stirred for 1 hour and a half. The precipitate formed is filtered, washed with heptane and dried.
F = 102 to 104°C.
m: 64 g.
Preparation of the compound of formula VIII: R5 = R6 = C2H5
21, please.7 g of the compound prepared in the previous step are suspended in 150 ml of absolute alcohol, 39.17 g of diethylamine are added and heated at 60°C for 6 hours.
m = 19,5 g.
F > 50°C.
The Commission has not yet adopted a proposal for a directive on the approximation of the laws of the Member States relating to the labelling of foodstuffs.
To 50 ml of an ether solution of the compound obtained in the previous step, add 7.01 g lithium and aluminium hydride in 1 hour. After 1 hour and a half agitation at room temperature, reflux for 4 hours. Keeping the mixture between 0°C and -10°C, then add 7.1 ml of water in 1 hour,After 2 hours of stirring at room temperature, the solution is filtered, washed with anhydrous ether, dried on sodium sulphate and concentrated in solvents.
The test chemical is used to determine the concentration of mercury in the test medium.
m: 4.2 g.
C) SR 46559 A is then prepared as described in Example 1.
1.7 g of chlorine-3 (chloro-2 phenyl) - 6 propyl-5 pyridazine and 6 ml of diethylamino-2 methyl-2 propylamine are heated at 110 °C with nitrogen for 20 hours.
After evaporation under vacuum, the mixture is taken up again in dichloromethane and washed with a solution of sodium carbonate. The organic phase is decanted, dried on magnesium sulphate, filtered and concentrated under vacuum. The residue is chromatographed on silica gel, the electrolyte : dichloromethane/methanol 98/2.
The concentration of the pure fractions gives an oil which is dissolved in 10 ml of methanol.
m = 1,6 g.
F is 144 degrees.
1.6 g of chloro-3 (methoxy-2 phenyl) -6 methyl-5 pyridazine, 4 g of diethylamino-2 methyl-2 propylamine and 0.36 g of ammonium chloride are co-soluble at 120°C and the reaction mixture is left at this temperature for 24 hours.
The mixture is cooled to room temperature, extracted with ethyl acetate and washed with an aqueous solution saturated with sodium chloride.
The organic phase is decanted, dried to MgSO4, filtered and concentrated under vacuum.
The residue is chromatographed on alumina, electrolyte: ethyl acetate + 2% triethylamine.
The concentration of pure fractions provides the expected product.
1 g of the product obtained in example 4 is put into solution in 50 ml of 48% hydrobromic acid and the mixture is heated at low temperature for 48 hours. After this time the reaction mixture is concentrated under vacuum, the residue is alkalized with an aqueous solution of potassium carbonate and the solution is extracted with dichloromethane. The organic phase is settled, dried on MgSO4, filtered and concentrated under vacuum.
The residue is chromatographed on alumina, electrolyte: ethyl acetate/methanol 9/1 + 2% triethylamine.
The concentration of pure fractions provides a residue which is recrystallized into isopropanol.
m = 200 mg, where m is the mass of the test substance.
F is 159.2 degrees.
A) By operation as shown in Example 1A but by varying the starting ketone, the chlorine-6 pyridazines in Table 1 are obtained.
The products of the invention have been studied with respect to their pharmacological properties and in particular with respect to their affinity for muscarinic cholinergic receptors of type M1 and M2.
In vitro, the compounds of the invention were tested using the technique described by Watson J.D. et al. (Life Science, 1982, 31, 2019-2029) with respect to their affinity for M1-type receptors and using the technique described by Hammer R. et al. (Nature, 1980, 283, 90-92) and Hulme E.C. et al. (Molecular Pharmacology, 1978, 14, 737-750) with respect to their affinity for M2-type receptors.
The compounds of the invention have good affinity for M1 type receptors and strong specificity for M1 type central receptors to M2 type receptors.
As an example, SR 46559 A showed an inhibitory concentration 50 expressed in micromoles of 0.11 and 2.2 respectively at the M1 and M2 receptors.
Similarly, SR 47047 A showed inhibitory concentrations of 50 of 0.04 and 0.9 respectively at the M1 and M2 receptors.
In vivo, the compounds of the invention were tested on the intrastrial pyrenzepine-induced rotation test described by Worms P. et al. (Psychopharmacology, 1987, 93, 489-493) modified in that oral administration of the products was done 4 hours before, instead of 30 minutes before, the pyrenzepine injection.
At a dose of 3 mg/kg body weight, the products of the invention strongly inhibit the number of pyrenzepine-induced rotations, for example SR 46559A, which inhibits pyrenzepine-induced rotations by 78%.
In addition, the compounds of the invention were shown to be active in the rat passive avoidance tests described by Jarvik M.E. et al. in Psychol. Med., 1967, 21, 221-224 and by Worms P. et al. in Psychopharmacol., 1989, 98, 286-288.
Thus, according to the results of these tests, the products of the invention are opposed to amnesia induced by scopolamine administered intraperiotoneally at 0,5 mg/kg and amnesia induced by pirenzhepin administered intraperiotoneally at 75 mg/kg. For example, SR 46559A has an effective dose 50 of 0,25 mg/kg per bone and 0,027 mg/kg per bone in each of these tests respectively.
In addition, some compounds of the invention have been studied in several models predictive of antidepressant activity, such as the forced swim test described by Porsolt et al. (Arch. Intern. Pharmacodyn., 1977, 229, 327-336) and the ptosis-reserpine antagonism test described by Gouret et al. (J. Pharmacol. (Paris), 1977, 8, 333-350).
Finally, the compounds of the invention have shown no evidence of toxicity at the doses at which they are active.
Therefore, the compounds of the invention can be used as medicinal products.
The results indicated show that the compounds of the invention have good affinity for muscarinic receptors and good activity in the amnesia tests induced by scopolamine or pyrenzepine, and allow the use of the products of the invention to be considered in all cases of cholinergic deficiency, in particular for the treatment of cognitive mnemonic disorders, senescence-related degenerative syndromes and senile dementia.
In another aspect, the present application therefore concerns pharmaceutical formulations containing at least one of the compounds of the invention or one of their salts as an active ingredient.
In the pharmaceutical formulations of the present invention for oral, sublingual, transdermal or rectal administration, the above active ingredients may be administered as unit doses in combination with conventional pharmaceutical media to humans, particularly for the treatment of cognitive mnemonic disorders or degenerative syndromes. The appropriate unit doses include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral doses, subcutaneous, intramuscular or intravenous doses and rectal doses.
To achieve the desired effect, the active substance dose may vary between 0.5 and 500 mg per day.
Each unit dose may contain 0.1 to 100 mg of active ingredient in combination with a pharmaceutical carrier, which may be administered 1 to 5 times daily.
When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle, such as gelatine, starch, lactose, magnesium stearate, talc, gum arabic or analogues.
A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into the soft or hard capsules.
Water-dispersible powders or granules may contain the active ingredient mixed with dispersion agents or wetting agents, or suspension agents such as polyvinylpyrrolidone, as well as sweeteners or flavour enhancers.
For rectal administration, suppositories are used which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile solutions for injection containing dispersing agents and/ or pharmacologically compatible wetting agents, e. g. propylene glycol and butylene glycol, are used.
The active substance may also be formulated in the form of microcapsules, possibly with one or more media or additives.
As a galenic preparation, capsules may be prepared containing:
SR 46559 A0.010 gLactose0.050 gMagnesium stearate0.005 g by mixing the above ingredients closely and pouring the mixture into hard gelatine capsules.
Claims (8)
- Pyridazine derivative, selected from:* 3-(2-diethylamino-2-methylpropyl)amino-6-phenyl-5-propylpyrldazine;* 3-(2-diethylamino-2-methylpropyl)amino-6-(2-chlorophenyl)-5-propylpyridazine;* 3-(2-diethylamino-2-methylpropyl)amino-6-(2-methoxyphenyl)-5-methylpyridazine;* 3-(2-diethylamino-2-methylpropyl)amino-6-(2-hydroxyphenyl)-5-methylpyridazine;* 3-(2-piperidino-2-methylpropyl)amino-6-(4-chlorophenyl)-5-methylpyridazine;* 3-(2-piperidino-2-methylpropyl)amino-6-phenyl-5-propylpyridazine;* 3-(2-diethylamino-2-methylpropyl)amino-6-(4-chlorophenyl)-5-methylpyridazine;* 3-(2-diethylamino-2-methylpropyl)amino-6-phenyl-5-methylpyridazine;* 3-(2-diethylamino-2-methylpropyl)amino-5,6-diphenylpyridazine;* 3-(2-diethylamino-2-methylpropyl)amino-6-(4-chlorophenyl)-5-propylpyridazine;* 3-(2-diethylamino-2-methylpropyl)amino-6-(4-methoxyphenyl)-5-propylpyridazine;* 3-(2-diethylamino-2-methylpropyl)amino-6-(4-hydroxyphenyl)-5-propylpyridazine;* 3-(2-diethylamino-2-methylpropyl)amino-5-cyclopropyl-6-phenylpyridazine;* 3-(2-diethylamino-2-methylpropyl)amino-5-isopropyl-6-(4-fluorophenyl)pyridazine;* 3-(2-(morpholin-4-yl)-2-methylpropyl)amino-6-phenyl-5-propylpyridazine; and the salts thereof with mineral or organic acids.
- Derivative according to claim 1, which is the 3-(2-diethylamino-2-methylpropyl)amino-6-phenyl-5-propylpyridazine or a salt thereof with mineral or organic acids.
- Derivative according to claim 1, which is the 3-(2-diethylamino-2-methylpropyl)amino-5,6-diphenylpyridazine or a salt thereof with mineral or organic acids.
- Process for the preparation of the derivatives according to claim 1, characterized in that an amine of formula R4NH2 in which R4 is a 2-diethylamino-2-methylpropyl or, if need be, 2-piperidino-2-methylpropyl or 2-(morpholin-4-yl)-2-methylpropyl group, is reacted with a 6-chloropyridazine of formula: in which:* R3 is a propyl and Ar is a phenyl or, if need be, a 2-chlorophenyl, a 4-chlorophenyl, a 4-methoxyphenyl or a 4-hydroxyphenyl; or* R3 is a methyl and Ar is a 2-methoxyphenyl or, if need be, a 2-hydroxyphenyl, a 4-chlorophenyl or a phenyl; or* R3 is a phenyl and Ar is a phenyl; or* R3 is a cyclopropyl and Ar a phenyl; or* R3 is an isopropyl and Ar a 4-fluorophenyl; and, optionally, the compound thus obtained is converted into a salt with a mineral or organic acid.
- Process for the preparation of a pharmaceutical composition containing as active principle a derivative according to any one of claims 1 to 3, characterized in that it consists in mixing said derivative with at least one pharmaceutically acceptable excipient.
- Process according to claim 5, characterized in that the active principle used is the derivative according to claim 2.
- Process according to claim 5, characterized in that the active principle used is the derivative according to claim 3.
- Process according to any one of claims 5 to 7, characterized in that the pharmaceutical composition contains from 0.1 to 100 mg of active principle per dosage unit.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8915137 | 1989-11-17 | ||
| FR8915137A FR2654727B1 (en) | 1989-11-17 | 1989-11-17 | PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
| FR9007533 | 1990-06-15 | ||
| FR909007533A FR2663326B2 (en) | 1989-11-17 | 1990-06-15 | PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
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| Publication Number | Publication Date |
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| HK1000597B true HK1000597B (en) | 1998-04-09 |
| HK1000597A1 HK1000597A1 (en) | 1998-04-09 |
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| HK97102147A HK1000597A1 (en) | 1989-11-17 | 1997-11-10 | Pyridazine derivatives, process for their preparation and pharmaceutical compositions containing them |
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| EP (1) | EP0429344B1 (en) |
| JP (1) | JPH03170465A (en) |
| KR (1) | KR0164599B1 (en) |
| AR (1) | AR247557A1 (en) |
| AT (1) | ATE143010T1 (en) |
| AU (1) | AU639043B2 (en) |
| CA (1) | CA2030133A1 (en) |
| DE (1) | DE69028602T2 (en) |
| DK (1) | DK0429344T3 (en) |
| ES (1) | ES2094146T3 (en) |
| FI (1) | FI101881B (en) |
| FR (1) | FR2663326B2 (en) |
| GR (1) | GR3021933T3 (en) |
| HK (1) | HK1000597A1 (en) |
| HU (2) | HU207852B (en) |
| IE (1) | IE75697B1 (en) |
| IL (1) | IL96384A (en) |
| LV (1) | LV11972B (en) |
| NO (1) | NO178967C (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2665442B1 (en) * | 1990-07-31 | 1992-12-04 | Sanofi Sa | ALKYL-6 PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
| FR2676444B1 (en) * | 1991-05-16 | 1995-03-10 | Sanofi Elf | NOVEL AMINO-3 PYRIDAZINE DERIVATIVES ACTIVE IN THE CENTRAL NERVOUS SYSTEM, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
| ZA97288B (en) * | 1996-01-15 | 1998-07-14 | Janssen Pharmaceutica Nv | Angiogenesis inhibiting pyridazinamines |
| AU755421B2 (en) * | 1997-12-19 | 2002-12-12 | Amgen, Inc. | Substituted pyridine and pyridazine compounds and their pharmaceutical use |
| US6528529B1 (en) | 1998-03-31 | 2003-03-04 | Acadia Pharmaceuticals Inc. | Compounds with activity on muscarinic receptors |
| NZ528578A (en) | 2001-03-23 | 2006-06-30 | Advanced Bionutrition | Microbial feeds for aquaculture and agriculture using microbes containing bioactive proteins |
| EP1928437A2 (en) | 2005-08-26 | 2008-06-11 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
| EP2258359A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
| AU2006322707B2 (en) | 2005-12-07 | 2011-09-15 | Sumitomo Chemical Company, Limited | Pyridazine compound and use thereof |
| FR2904314A1 (en) * | 2006-07-26 | 2008-02-01 | Centre Nat Rech Scient | LINEAR PYRIDAZINIC AND PYRROLIC COMPOUNDS, METHODS OF OBTAINING AND APPLICATIONS |
| AR081331A1 (en) | 2010-04-23 | 2012-08-08 | Cytokinetics Inc | AMINO- PYRIMIDINES COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THE SAME |
| US9133123B2 (en) | 2010-04-23 | 2015-09-15 | Cytokinetics, Inc. | Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use |
| AR081626A1 (en) | 2010-04-23 | 2012-10-10 | Cytokinetics Inc | AMINO-PYRIDAZINIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME TO TREAT CARDIAC AND SKELETIC MUSCULAR DISORDERS |
| UY38687A (en) | 2019-05-17 | 2023-05-15 | Novartis Ag | NLRP3 INFLAMMASOME INHIBITORS, COMPOSITIONS, COMBINATIONS THEREOF AND METHODS OF USE |
| AR121669A1 (en) * | 2020-03-27 | 2022-06-29 | Astellas Pharma Inc | SUBSTITUTED PYRIDAZINE COMPOUND |
| CN116867769A (en) * | 2021-02-08 | 2023-10-10 | 南京明德新药研发有限公司 | Substituted pyridazine phenol derivatives |
| UY40374A (en) | 2022-08-03 | 2024-02-15 | Novartis Ag | NLRP3 INFLAMASOME INHIBITORS |
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| FR2510998B1 (en) * | 1981-08-07 | 1986-01-10 | Sanofi Sa | NOVEL AMINO DERIVATIVES OF PYRIDAZINE, PROCESS FOR THEIR PREPARATION AND DRINKING ACTS THEREOF |
| FR2540113A1 (en) * | 1983-01-27 | 1984-08-03 | Sanofi Sa | PYRIDAZINE DERIVATIVE ACIDS ACTIVE ON THE CENTRAL NERVOUS SYSTEM |
| DE3629929A1 (en) * | 1986-09-03 | 1988-03-10 | Thomae Gmbh Dr K | NEW SULFONAMIDO-AETHYL COMPOUNDS, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| FR2642648B1 (en) * | 1989-02-07 | 1991-06-21 | Sanofi Sa | USE OF ALKYL-5 PYRIDAZINE DERIVATIVES AS ACTIVE MEDICAMENTS ON THE CHOLINERGIC SYSTEM |
| PT93060B (en) * | 1989-02-07 | 1995-12-29 | Sanofi Sa | METHOD FOR OBTAINING PYRIDAZINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
-
1990
- 1990-06-15 FR FR909007533A patent/FR2663326B2/en not_active Expired - Lifetime
- 1990-11-15 FI FI905663A patent/FI101881B/en not_active IP Right Cessation
- 1990-11-15 PT PT95902A patent/PT95902B/en not_active IP Right Cessation
- 1990-11-16 DE DE69028602T patent/DE69028602T2/en not_active Expired - Fee Related
- 1990-11-16 AU AU66672/90A patent/AU639043B2/en not_active Ceased
- 1990-11-16 AT AT90403239T patent/ATE143010T1/en not_active IP Right Cessation
- 1990-11-16 DK DK90403239.8T patent/DK0429344T3/da active
- 1990-11-16 CA CA002030133A patent/CA2030133A1/en active Granted
- 1990-11-16 IE IE414590A patent/IE75697B1/en not_active IP Right Cessation
- 1990-11-16 HU HU907178A patent/HU207852B/en not_active IP Right Cessation
- 1990-11-16 ES ES90403239T patent/ES2094146T3/en not_active Expired - Lifetime
- 1990-11-16 AR AR90318401A patent/AR247557A1/en active
- 1990-11-16 JP JP2312597A patent/JPH03170465A/en active Pending
- 1990-11-16 NZ NZ236107A patent/NZ236107A/en unknown
- 1990-11-16 NO NO904984A patent/NO178967C/en unknown
- 1990-11-16 EP EP90403239A patent/EP0429344B1/en not_active Expired - Lifetime
- 1990-11-17 KR KR1019900018663A patent/KR0164599B1/en not_active Expired - Fee Related
- 1990-11-18 IL IL9638490A patent/IL96384A/en not_active IP Right Cessation
-
1995
- 1995-06-27 HU HU95P/P00450P patent/HU211351A9/en unknown
-
1996
- 1996-12-06 GR GR960403344T patent/GR3021933T3/en unknown
-
1997
- 1997-09-10 LV LVP-97-165A patent/LV11972B/en unknown
- 1997-11-10 HK HK97102147A patent/HK1000597A1/en not_active IP Right Cessation
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