IE75697B1 - Pyridazine derivatives process for their preparation and pharmaceutical compositions containing them - Google Patents
Pyridazine derivatives process for their preparation and pharmaceutical compositions containing themInfo
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- IE75697B1 IE75697B1 IE414590A IE414590A IE75697B1 IE 75697 B1 IE75697 B1 IE 75697B1 IE 414590 A IE414590 A IE 414590A IE 414590 A IE414590 A IE 414590A IE 75697 B1 IE75697 B1 IE 75697B1
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- methylpropyl
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- diethylamino
- phenyl
- chlorophenyl
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- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
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- 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
- C07D237/14—Oxygen atoms
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- 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
- C07D237/20—Nitrogen atoms
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
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- 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
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention relates to pyridazine derivatives of the formula: in which: - Ar represents a phenyl substituted with R1 and R2 or a heterocyclic radical such as pyridyl, unsubstituted or substituted with a methyl or a methoxy, or thienyl unsubstituted or substituted with a chlorine, a methyl or a methoxy; - R1 and R2 each independently denote hydrogen, a halogen atom, a trifluoromethyl group, a hydroxyl group, a C1-C4 alkoxy group or a C1-C4 alkyl group; - R3 represents a linear or branched C1-C4 alkyl group, a C3-C7 cycloalkyl, a benzyl, a phenethyl or a radical Ar', Ar' being a phenyl substituted with R1 and R2; - R4 represents a group: with n = 0 or 1, in which X1 represents hydrogen or a methyl; - R5 represents a linear C1-C6 alkyl group; - R6 represents a linear C1-C6 alkyl group, or alternatively R5 and R6, with the nitrogen atom to which they are linked, form a heterocycle chosen from morpholine, pyrrolidine or piperidine; as well as its salts with inorganic or organic acids. Application: medicaments which are active with respect to type M1 cholinergic receptors.
Description
According to the present invention, novel derivatives of pyridazine have now been discovered which have lost their antidepressant activity and acquired a useful activity as ligands of cholinergic receptors, in particular receptors of the M-| type.
In accordance with a first feature, the object of the present invention is novel derivatives of pyridazine selected from : *3-(2-diethylamino-2-methylpropyl)amino-6-phenyl-5-propylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-(2-chlorophenyl)-5-propylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-(2-methoxyphenyl)-5methylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-(2-hydroxyphenyl)-5methylpyridazine; *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)-5methylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-phenyl-5-methylpyridazine; * 3-(2-diethylamino-2-methylpropyl)amino-5,6-diphenylpyrida2ine; *3-(2-diethylamino-2-methylpropyl)amino-6-(4-chlorophenyl)-5propylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-(4-methoxyphenyl)-5propylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-(4-hydroxyphenyl)-5propylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-5-cyclopropyl-6-phenylpyridazine; *3-(2-diethylamino-2-methylpropyi)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.
The following compounds are particularly preferred: 3-(2-diethylamino-2-methylpropyl)amino-6-phenyl-5-propylpyridazine and its salts; 3-(2-diethylamino-2-methylpropyl)amino-5,6-diphenylpyridazine and its salts.
The salts of the compounds according to the present invention include both those with mineral or organic acids which enable said compounds to be suitably separated or crystallized, such as picric acid or oxalic acid, and those which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methane sulfonate, methyl sulfate, maleate, fumarate, 2naphthalene sulfonate.
In accordance with a second feature, the present invention relates to a process for the preparation of the above compounds.
According to the present invention, the process for the preparation of the above compounds is 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 4chlorophenyl, a 4-methoxyphenyl or a 4-hydroxyphenyl; or * R3 is a methyl and Ar is a 2-methoxyphenyl or, if need be, a 2hydroxyphenyl, 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.
The substitution reaction of the 6-chloropyridazine (II) by the amine R4NH2 is carried out between 100*C and 150’C, optionally in the presence of ammonium chloride. The reaction is performed without solvent or in the presence of an inert solvent such as n-butanol. The pyridazine derivative according to the invention is isolated by extraction and purified, for example, by chromatography.
The thus obtained product is isolated in the form of the free base or a salt, according.to standard techniques.
When said product is obtained in the form of the free base, salt formation 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 according to standard techniques. In this way, the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the methane sulfonate, the methyl sulfate, the oxalate, the maleate, the fumarate and the 2-naphthalene sulfonate are prepared.
At the end of the reaction, the compound according to the invention may be isolated in the form of one of its salts, for example the hydrochloride; in this case, if necessary, the free base may be prepared by neutralization of the said salt with a mineral or organic base such as sodium hydroxide or triethylamine or an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.
When Ar represents a hydroxyphenyl, the compound according to the invention is obtained starting from the compound in which Ar denotes an alkoxyphenyl and all the other substituents have the above definitions, by dealkylation using known methods.
The 6-chloropyridazines (II), used as starting products, are prepared from the corresponding 2H-pyridazin-3-ones (III) by reaction with an excess of hot phosphorous oxychloride in the absence of a solvent or in the presence of an inert solvent such as acetonitrile, according to the following reaction scheme; The 2H-pyridazin-3-ones (III) are known or prepared by known methods.
Thus, when R3 is a phenyl Ar', the 2H-pyridazin-3-ones are obtained according to the method described by P. SCHMIDT et al. in Helv.
Chim. Acta, 1954, 15, 134-140, starting from malonic acid diethyl ester and a hydrazone derivative according to the following reaction scheme; * + CH--CO,C,Hc ι ί £ £ i Ar'-C0-C-Ar II n-nh2 (III) When R3 represents a methyl, propyl, isopropyl or cyclopropyl radical, the compounds (III) are prepared from a ketone Ar-Co-CHgRa* (1): Ar-C~CH -R 11 2 3 CHO COOC2H5 R, OH CH—CH.
H5C2O NH2NH2 CH-CH OH / Ar - C Ar - C -N I H A / /c=cx c k / N-N I H (III) = 0 The hydroxy keto ester 2 is obtained from the ketone 1 by heating it with ethyl glyoxylate at a temperature between 80 and 140*C. The crude reaction mixture is then taken up in an inert solvent such as nbutanol and hydrazine hydrate is added. By heating at reflux for 24 hours, the 4,5-dihydro 4-hydroxy pyridazin-3-one 3 is obtained which, when heated in an acidic medium, leads by dehydration to the 2H-pyridazin-3one (III).
The amines R4NH2 are known or prepared by known methods. Thus, they may be prepared from a cyano derivative of formula: CHi\ ZOH C CH^Z CN (IV) By reaction with an amine HNR5R6 (diethylamine, piperidine or morpholine) by heating at a temperature between 40 and 80’C, optionally in the presence of a salt of a strong acid such as sodium sulfate or magnesium sulfate, a compound of formula: CHK znr5R6 zc\ CH ' CN (V) is first prepared, then this compound is hydrated by reaction with a strong 25 acid such as hot sulfuric acid in order to produce the corresponding amide: CH, NRCR. 3\c/ 54 / \ CH^ C0NH2 (VI) Finally, reduction by heating with a metal hydride such as boron hydride or lithium aluminium hydride leads to the formation of the amine R4NH2.
The amine R4NH2 may also be prepared from a chloronitroso derivative (VII) according to the procedure described in J. Prakt. Chem., 1978, 320(3),433-451. ct - C - CH_N0 I 2 ft + RCRZNH- — J O c iHs ~* R6R5N " c - CH = NOH CHg (VII) (VIII) LiAlH -* R6R5N nh2 The compound of formula (VII) may be used in the form of a dimer (Vila) which is obtained by reaction of nitrosyl chloride with the appropriate olefin (IX) according to the procedure described in J. Prakt. Chem., 1965, 29(4), 123.
CH.
(IX) + NOCI Cl CH_ I 5 C - CH. I 1 ft· 0 t t N = N - CH2 ft rct CH(Vila, ) The following examples illustrate the invention. The compounds are characterized by their melting point (m.p.) expressed in degrees Celsius.
EXAMPLE 1 3-(2-diethylamino-2-methylpropyl)amino-6-phenyl-5propylpyridazine sesquifumarate: SR 46559 A.
A) 6-chloro-3-phenyl-4-propylpyridazine. 1. Ethyl 2-hydroxy-4-oxo-4-phenyl-3-propyl butyrate.
A mixture of 48.67 g of valerophenone and 45.94 g of ethyl glyoxylate is heated at 120*C for 15 hours.
The crude reaction product is used as such in the following step. Λ 2. 6-phenyl-5-propyl-2H-pyridazin-3-one. The crude product obtained above is dissolved in 450 ml of n- J 5 butanol, then 30 g of hydrazine hydrate are added and the mixture is heated at reflux for 24 hours. 10 The n-butanol is concentrated under vacuum. The residue is taken up in a mixture of 300 ml of acetic acid and 30 ml of concentrated hydrochloric acid. The mixture is heated at 100*C for 3 hours. The solution is poured into cold water and the product is left to crystallize. The solid is filtered off and dried. 15 Weight: 44 g. M.p.: 160’C. Yield: 69% 3. 6-chloro-3-phenyl-4-propylpyridazine. 250 ml of phosphorus oxychloride are added to 44 g of pyridazinone obtained above and the mixture is heated at 80’C for 4 hours. 20 After being left to stand overnight at room temperature, the reaction mixture is concentrated to 3/4 and then poured slowly onto ice. The mixture is extracted twice with 300 ml of dichloromethane, the organic phase is dried over sodium sulfate and concentrated. Chromatography on silica is then 25 carried out by eluting with an ethyl acetate-methylene chloride mixture (50/50 v/v). After recrystallization from isopropyl ether, 43.7 g of the expected product are obtained. M.p.: 60’C Yield: 92%. 30 B) Preparation of 2-diethylamino-2-methylpropylamine. 1. 2-diethylamino-2-methyl propionitrile. 85.1 g of distilled cyanohydrin of acetone and 73.1 g of diethylamine are mixed, 85.7 g of magnesium sulfate are added and the mixture is heated under gentle reflux for 20 hours with stirring. The sulfate mass which is formed is filtered off and washed with ether. The filtrate is • 35 concentrated and then distilled. 86.6 g of the expected product are recovered. Yield: 62% B.p. = 68-70*C at 1998 Pa (15 mm of mercury). 2. 2-diethylamino 2-methyl propionamide.
To 95.9 g of the nitrile prepared in the preceding step 450 ml of sulfuric acid and 70 ml of water are added with stirring and the mixture is heated in an oil bath at 100-110*C for 2 hours. The reaction mixture is poured slowly over one hour into 1.4 I of a 20% ammonia solution and 400 ml of water and cooled in a Dry Ice/acetone bath. The mixture is extracted 3 times with 600 ml of methylene chloride, the organic phase is dried over sodium sulfate and concentrated.
The expected product is obtained by distillation.
Weight: 102.5 g Yield: 95% B.p.: 134-139’C at 1998 Pa (15 mm of mercury). 3. 2-diethylamino-2-methylpropylamine.
A mixture containing 52.4 g of the amide prepared in the preceding step and 60 ml of tetrahydrofuran are heated at 45-50’C. 86 ml of the borane-dimethylsulfide complex are added under a nitrogen atmosphere over one hour and heating is continued for 3 hours in an oil bath at 80-85*C.
After being left overnight at room temperature, the mixture is cooled in an ice bath, then 315 ml of 6N hydrochloric acid are added very slowly over 3 hours and the mixture is heated again at 135*C for 3 hours. After being left overnight at room temperature, the reaction mixture is cooled whilst 200 ml of 30% sodium hydroxide are added. The mixture is extracted 3 times with 250 ml of ether, the organic phase is dried over sodium sulfate and concentrated.
The expected product is obtained by distillation.
Weight: 23 g Yield: 48% B.p. = 71-73*C at 1998 Pa (15 mm of mercury).
C) SR 46559 A A mixture of 2.5 g of the chloro derivative obtained above in step A and 4.6 g of the diamine obtained in step B are heated at 120*C overnight. 150 ml of ethyl acetate are added, then the mixture is extracted twice with 50 ml of hydrochloric acid. The mixture is then made alkaline by the addition of 50 ml of 30% sodium hydroxide and then extracted with ethyl acetate. The organic phase is washed with a sodium chloride solution, dried over sodium sulfate and concentrated. Chromatography on alumina is carried out by eluting with a methylene chloride-ethyl acetate mixture (70/30, v/v). 3.2 g of an oil is obtained which crystallizes.
M.p. = 75-77’C Yield: 87% Sesquifumarate 3.1 g of the base obtained in the preceding step are taken up in 50 ml of acetone and 1.6 g of fumaric acid in 150 ml of acetone are added. The mixture is filtered hot. The total volume recovered (175 ml) is concentrated to 130 ml. The product is allowed to crystallize, the crystals are filtered off and then washed with acetone. 4.1 g of the expected product are obtained.
Overall yield of step C = 74% M.p. = 151’C EXAMPLE 2 SR 46559 A A) 6-chioro-3-phenyl-4-propylpyridazine, described in example 1.
B) 2-diethyiamino-2-methylpropylamine 1. Preparation of the compound of formula (Vila). 47.14 g of isobutylene are dissolved in 150 ml of n-heptane, the mixture is cooled to a temperature between -10* and -20’C and 50 g of nitrosyl chloride are added. The temperature is allowed to rise (+5’C) over one and a half hours, then the temperature is brought to between 10’C and 20’C and the mixture is stirred for one and a half hours. The precipitate formed is filtered off, washed with heptane and then dried.
M.p. = 102-104’C m = 64 g 2. Preparation of the compound of formula VIII: R5 = Rg = C2H5 21.7 g of the compound prepared in the preceding step are suspended in 150 ml of absolute alcohol, 39.17 g of diethylamine are added and the mixture is heated at 60’C for 6 hours. An oil is obtained which solidifies. m = 19.5 g M.p. > 50’C. 3. 2-diethylamino-2-methylpropylamine 7.01 g of lithium aluminium hydride are added to 50 ml of an ethereal solution of the compound obtained in the preceding step over 1 hour. After being stirred for one and a half hours at room temperature, the mixture is refluxed for 4 hours. While the mixture is maintained between 0*C and -10*C, 7.1 ml of water are added over 1 hour, 7.1 ml of sodium hydroxide over 30 minutes and 21.3 ml of water over 30 minutes. After being stirred for 2 hours at room temperature, the solution is filtered, the precipitate is washed with anhydrous ether, the filtrate is dried over sodium sulfate and the solvents are concentrated. The product is distilled: B.p. = 72-75*C at 1998 Pa (15 mm of mercury), m = 4.2 g C) SR 46559 A is then prepared as described in example 1.
EXAMPLE 3 3-(2-diethylamino-2-methylpropyl)amino-6-(2-chlorophenyl)5-propylpyridazine sesquifumarate. SR 47863 A. 1.7 g of 3-chloro 6-(2-chlorophenyl)-5-propylpyridazine and 6 ml of 2-diethylamino-2-methylpropylamine are heated at 110‘C under nitrogen for 20 hours.
After evaporation under vacuum, the mixture is taken up in dichloromethane and washed with a solution of sodium carbonate. The organic phase is decanted, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is chromatographed on silica gel, eluent: dichloromethane/methanol 98/2.
The concentration of the pure fractions gives an oil which is dissolved in 10 ml of methanol. Fumaric acid is added, the methanol is concentrated under vacuum and the sesquifumarate crystallizes from ether. m = 1.6 g M.p. = 144 *C.
EXAMPLE 4 3- (2-diethy lamino-2-methyl propyl) ami no-6- (2-methoxyphenyl)-5-methylpyridazine. 1.6 g of 3-chloro-6-(2-methoxyphenyl)-5-methylpyridazine, 4 g of 2-diethylamino-2-methylpropylamine and 0.36 g of ammonium chloride are melted together 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 a saturated aqueous solution of sodium chloride.
The organic phase is decanted, dried over MgSO^ filtered and concentrated under vacuum.
The residue is chromatographed on alumina, eluent: ethyl acetate + 2% of triethylamine.
The concentration of the pure fractions gives the expected product. The structure is confirmed by NMR spectral analysis.
EXAMPLE 5 3-(2-diethylamino-2-methylpropyl)amino-5-methyl-6-(2hydroxyphenyl)-pyridazine. SR 96376. 1 g of the product obtained previously in example 4 is dissolved in 50 ml of 48% hydrobromic acid and the mixture is heated at reflux for 48 hours. After this time, the reaction mixture is concentrated under vacuum, the residue is made alkaline with an aqueous solution of potassium carbonate and the solution is extracted with dichloromethane. The organic phase is decanted, dried over MgSO4, filtered and concentrated under vacuum.
The residue is chromatographed on alumina, eluent: ethyl acetate/methanol 9/1 +2% of triethylamine.
The concentration of the pure fractions gives a residue which is recrystallized from isopropanol, m = 200 mg M.p. = 159.2’C EXAMPLES 6 TO 16 A) By using the procedure indicated in example 1A, but by varying the starting ketone, the 6-chloropyridazines collated in Table 1 are obtained.
Table 1 Ri r2 Ra Physical constants H H -CH2CH2CH3 M.p.: 52-53’C Cl (4) H -ch3 M.p.: 178-180*C Cl (4) H -ch2ch2ch3 M.p.: 95*C OCH3 (4) H -ch2ch2ch3 M.p.: 68-69‘C H H -ch3 M.p.: 123-124*0 H H phenyl M.p.: 115*C H H cyclopropyl M.p.: 119*C F(4) H isopropyl M.p.: 89-90*C Cl (2) H -CH2CH2CH3 oil, NMR* OCHa (2) K -CH3 NMR* * NMR: NMR spectral analysis enables the structure of the above compounds to be confirmed.
B) Starting from the chloro derivatives of Table 1 and by following the procedure employed in example 1, the compounds according to the invention collated in Table 2 below are obtained by varying the amines NH2R4 used.
Table 2 SR No. Ex. No. R1 R2 R3 R4 Salt or base M.p. 46729A 6 Cl (4) H ch3 CH, cH2-iO CH3 Dihydrochloride 240-242*C 46732A 7 H H nC3H7 N CH, Γ Hr sesquifumarate 159-161’C 46733A 8 Cl (4) H ch3 I 3 / 2 5 CH -C-fT 2 ' \ CH3xc2h5 Fumarate 138-140‘C 47020A 9 H H ch3 M sesquifumarate 161*C 47047A 10 H H phenyl H fumarate 193’C 47054A 11 Cl (4) H nC3H7 N sesquifumarate 152-154’C 47068 12 OCH3 (4) H nC3H7 65-66*C base Table 2 (continuation) SR No. Ex. No. R1 R2 R3 R4 Salt or base M.p. 47069A 13 OH (4) H ηΟβΗγ ft ,c2h5CH2TN\ ch3 c2hs hydrobromide 179-181*C 47097A 14 H H cyclopropyl sesquifumarate 158-160*C 47098A 15 F(4) H isopropyl R sesquifumarate hemihydrate 143-145*C 47138A 16 H H ηΟβΗγ CH- I 3/—κ CH--C-N 0 2 I ch3 sesquifumarate 149-151*0 The products according to the invention were studied with respect to their pharmacological properties and in particular with respect to their affinity for the muscarinic cholinergic receptors of type M-| and M2.
In vitro, the compounds according to the invention were assayed according to the technique described by Watson J.D. et al. (Life Science, 1982, 31, 2019-2029) as far as their affinity for the receptors of type M-, is concerned and according to 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) as far as their affinity for the receptors of the M2 type is concerned.
The compounds according to the invention exhibit good affinity for the receptors of type M-j and a marked specificity for the central receptors of type M-| as opposed to receptors of type M2.
As an example, the compound SR 46559 A showed an inhibiting concentration 50 expressed in micromoles of 0.11 and 2.2, respectively, on the M-j and M2 receptors.
Similarly, the compound SR 47047 A showed inhibiting 5 concentrations 50 of 0.04 and 0.9, respectively, on the M-| and M2 receptors.
In vivo, the compounds according to the invention were assayed on the rotations induced by intrastriatal pirenzepine in the test described by Worms P. et al. (Psychopharmacology, 1987, 93, 489-493) modified in that the administration of the products by the oral route took place 4 hours before, instead of 30 minutes before, the injection of pirenzepine.
At a dose of 3 mg per kg of body weight, the products according to the invention strongly inhibit the number of rotations induced by pirenzepine. Thus, as an example, the compound SR 46559 A inhibits the rotations induced by pirenzepine by 78%.
Furthermore, the compounds according to the invention were shown to be active in the passive avoidance tests in the rat 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 according to the invention counteract the amnesia induced by scopolamine administered by the intraperitoneal route at 0.5 mg/kg and the amnesia induced by pirenzepine administered intraperitoneally at 75 mg/kg. For example, SR 46559 A exhibits an oral efficient dose 50 of 0.25 mg/kg and 0.027 mg/kg, respectively, in each of these tests.
Moreover, some compounds according to the invention were studied in several predictive models of antidepressant activity such as the forced swimming test described by Porsolt et al. (Arch. Intern. Pharmacodyn., 1977, 229, 327-336) and the test of antagonism of reserpine-induced ptosis described by Gouret et al. (J. Pharmacol. (Paris), 1977, 8, 333-350). SR 46559 A in particular was shown to be inactive in these tests at oral doses varying from 0.1 to 10 mg/kg.
Finally, the compounds according to the invention did not show any sign of toxicity at the doses at which they are active.
Consequently, the compounds according to the invention may be used as medicines.
The results indicated show that the compounds according to the invention exhibit a good affinity for the muscarinic receptors and a good activity in the tests of amnesia induced by scopolamine or pirenzepine. They allow the use of the products according to the invention to be contemplated in all cases in which a cholinergic deficit is present and particularly for the treatment of cognitive and memory disorders, the degenerative syndromes associated with senescence and senile dementia.
In accordance with another of its features, the present application thus relates to pharmaceutical compositions containing at least one of the compounds according to the invention or one of their salts as active ingredient.
In the pharmaceutical compositions of the present invention for oral, sublingual, transdermal or rectal administration, the above active ingredients may be administered in unit forms of administration, in combination with the standard pharmaceutical carriers, to humans especially for the treatment of cognitive and memory disorders or degenerative syndromes. The appropriate unit forms of administration comprise the forms for the oral route such as tablets, capsules, powders, granules and oral solutions or suspensions, the forms for sublingual and buccal administration, the forms for subcutaneous, intramuscular or intravenous administration and the forms for rectal administration.
In order to obtain the desired effect, the dose of the active principle may vary between 0.5 and 500 mg per day.
Each unit dose may contain from 0.1 to 100 mg of active ingredient in combination with a pharmaceutical carrier. This unit dose may be administered 1 to 5 times per day.
When a solid composition is prepared 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 the like. The tablets may be coated with sucrose or other suitable materials or they may be treated so that they have sustained or delayed activity and so that they release continuously a predetermined amount of active principle.
A preparation in the form of capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
The powders or granules dispersible in water may contain the active ingredient mixed with dispersants or wetting agents or suspension • agents such as polyvinylpyrrolidone, as well as with sweeteners or taste modifiers.
In the case of rectal administration, suppositories are used which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.
For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol, are used.
The active principle may also be formulated in the form of microcapsules, with or without one or more additives or carriers.
As an example of a galenic preparation, capsules may be prepared containing: SR 46559 A 0.010 g Lactose 0.050 g Magnesium stearate 0.005 g by mixing the above ingredients intimately and pouring the mixture into hard gelatine capsules. > CLAIMS
Claims (11)
1. Pyridazine derivative, selected from:
2. Derivative according to claim 1, which is the 3-(2-diethylamino2-methylpropyl)amino-6-phenyl-5-propylpyridazine or a salt thereof with mineral or organic acids.
3. Derivative according to claim 1, which is the 3-(2-diethylamino2-methylpropyl)amino-5,6-diphenylpyridazine or a salt thereof with mineral or organic acids. 'f *3-(2-(morpholin-4-yl)-2-methylpropyl)amino-6-phenyl-5-propylpyridazine; and the salts thereof with mineral or organic acids. *3-(2-diethylamino-2-methylpropyl)amino-5-isopropyl-6-(4-fluorophenyl)pyridazine; *3-(2-diethylamino-2-methylpropyl)amino-5-cyclopropyl-6-phenylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-(4-hydroxyphenyl)-5propylpyridazine; * 3-(2-diethylamino-2-methylpropyl)amino-6-(4-methoxyphenyl)-5propylpyridazine; * 3-(2-diethylamino-2-methylpropyl)amino-5,6-diphenylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-(4-chlorophenyl)-5propylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-phenyl-5-methylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-(4-chlorophenyl)-5methylpyridazine; *3-(2-piperidino-2-methylpropyl)amino-6-phenyl-5-propylpyridazine; *3-(2-piperidino-2-methylpropyl)amino-6-(4-chlorophenyl)-5-methylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-(2-hydroxyphenyl)-5methylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-(2-methoxyphenyl)-5methylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-phenyl-5-propylpyridazine; *3-(2-diethylamino-2-methylpropyl)amino-6-(2-chlorophenyl)-5-propylpyridazine;
4. Process for the preparation of the derivatives according to claim 5. A process claimed in a preceding claim.
5. Pharmaceutical composition, characterized in that it contains as active principle a derivative according to any one of claims 1 to 3.
6. Pharmaceutical composition according to claim 5, characterized in that it contains as active principle the derivative according to claim 2. 30 7. Pharmaceutical composition according to claim 5, characterized in that it contains as active principle the derivative according to claim 3.
7. characterized in that it contains from 0.1 to 100 mg of active principle per dosage unit.
8. Pharmaceutical composition according to any one of claims 5 to
9. A process for the preparation of a compound according to claim 1 substantially as hereinbefore described and * exemplified.
10. A compound according to claim 1, whenever prepared by
11. A pharmaceutical composition according to claim 5, substantially as hereinbefore described and exemplified.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8915137A FR2654727B1 (en) | 1989-11-17 | 1989-11-17 | PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
| FR909007533A FR2663326B2 (en) | 1989-11-17 | 1990-06-15 | PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE904145A1 IE904145A1 (en) | 1991-05-22 |
| IE75697B1 true IE75697B1 (en) | 1997-09-10 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE414590A IE75697B1 (en) | 1989-11-17 | 1990-11-16 | Pyridazine derivatives process for their preparation and pharmaceutical compositions containing them |
Country Status (21)
| Country | Link |
|---|---|
| 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) |
| NZ (1) | NZ236107A (en) |
| PT (1) | PT95902B (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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. |
| AU717744B2 (en) * | 1996-01-15 | 2000-03-30 | Janssen Pharmaceutica N.V. | 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 |
| EP1381345B1 (en) | 2001-03-23 | 2008-07-09 | Advanced Bionutrition Corporation | Delivery of disease control in aquaculture using yeasts containing bioactive proteins |
| EP2258359A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
| JP2009506069A (en) | 2005-08-26 | 2009-02-12 | ブレインセルス，インコーポレイティド | Neurogenesis through modulation of muscarinic receptors |
| WO2007066601A1 (en) * | 2005-12-07 | 2007-06-14 | 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 |
| AR119731A1 (en) | 2019-05-17 | 2022-01-05 | Novartis Ag | NLRP3 INFLAMASOME INHIBITORS |
| EP4289823A1 (en) * | 2021-02-08 | 2023-12-13 | Medshine Discovery Inc. | Substituted pyridazine phenol derivatives |
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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 |
| PT93060B (en) * | 1989-02-07 | 1995-12-29 | Sanofi Sa | METHOD FOR OBTAINING PYRIDAZINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2642648B1 (en) * | 1989-02-07 | 1991-06-21 | Sanofi Sa | USE OF ALKYL-5 PYRIDAZINE DERIVATIVES AS ACTIVE MEDICAMENTS ON THE CHOLINERGIC SYSTEM |
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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 NO NO904984A patent/NO178967C/en unknown
- 1990-11-16 DK DK90403239.8T patent/DK0429344T3/da active
- 1990-11-16 AR AR90318401A patent/AR247557A1/en active
- 1990-11-16 CA CA002030133A patent/CA2030133A1/en active Granted
- 1990-11-16 DE DE69028602T patent/DE69028602T2/en not_active Expired - Fee Related
- 1990-11-16 JP JP2312597A patent/JPH03170465A/en active Pending
- 1990-11-16 NZ NZ236107A patent/NZ236107A/en unknown
- 1990-11-16 IE IE414590A patent/IE75697B1/en not_active IP Right Cessation
- 1990-11-16 AT AT90403239T patent/ATE143010T1/en not_active IP Right Cessation
- 1990-11-16 AU AU66672/90A patent/AU639043B2/en not_active Ceased
- 1990-11-16 EP EP90403239A patent/EP0429344B1/en not_active Expired - Lifetime
- 1990-11-16 ES ES90403239T patent/ES2094146T3/en not_active Expired - Lifetime
- 1990-11-16 HU HU907178A patent/HU207852B/en not_active IP Right Cessation
- 1990-11-17 KR KR1019900018663A patent/KR0164599B1/en not_active IP Right Cessation
- 1990-11-18 IL IL9638490A patent/IL96384A/en not_active IP Right Cessation
-
1995
- 1995-06-27 HU HU95P/P00450P patent/HU211351A9/en unknown
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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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