IL96384A - Pyridazine derivatives their preparation and pharmaceutical compositions containing them - Google Patents

Pyridazine derivatives their preparation and pharmaceutical compositions containing them

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Publication number
IL96384A
IL96384A IL9638490A IL9638490A IL96384A IL 96384 A IL96384 A IL 96384A IL 9638490 A IL9638490 A IL 9638490A IL 9638490 A IL9638490 A IL 9638490A IL 96384 A IL96384 A IL 96384A
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phenyl
methyl
substituted
propyl
salts
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IL9638490A
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IL96384A0 (en
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Sanofi Sa
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Priority claimed from FR8915137A external-priority patent/FR2654727B1/en
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Publication of IL96384A0 publication Critical patent/IL96384A0/en
Publication of IL96384A publication Critical patent/IL96384A/en

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    • 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
    • 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
    • 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
    • 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
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    • 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
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
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    • 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
    • C07D237/14—Oxygen atoms
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    • 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
    • C07D237/20—Nitrogen atoms
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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
    • C07D401/04—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
    • 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
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    • 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
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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

Description

iniN ο>ϊ> ηη ηιηρη ^nom ιη,οη ,mN* T>A mTi>in Pyridazine derivatives, their preparation and pharmaceutical compositions containing them SANOFI C: 82114 For many years pyridazine derivatives have been suggested as medicines, in partipular medicines active on the cardiovascular system or on the central nervous system.
In particular, French Patent 2 510 998 and European Patent 72 726 corresponding to Israel Patent 66408, disclose pyridazine derivatives variously substituted on the pyridazine ring and all bearing at position 3 an amine substituent of the type -NH-alkylene-N H in which X represents hydrogen or (Ca-C4)alkyl.
IL 66409 describes pyridazine derivatives variously substituted on the pyridazine ring and all bearing at position -3 a substituent of the type All of these compounds exhibit an activity on the central nervous system as antidepressants. - la - 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 type.
In accordance with a first feature, the object of the present invention is novel derivatives of pyridazine corresponding to the ormula : in which - Ar represents a phenyl group substituted by R1 and o a hetero¬ 18. XI.90 cyclic radical such as a pyridyl group, unsubstitutsd or substituted only for by methyl or methoxy, or a thienyl group, unsubstitutsd or substituted underlined meanings - by chlorine, methyl or methoxy; R^ and ? each independently denotes hydrogen, halogen, trifluoro- nethyl, hydroxyl , C^-C^ alkoxy or C^-C^ alkyl; R0 represents a C^-C^ linear or branched alkyl, cycloalkyl, benzyl , henethyl or the Ar ' radical, Ar' being phenyl substituted by R, and R. 2 - R, represents: CH2Xi R5 ·ΧΙ·90 . a - CH2 - C - (CH2)„ - gr0up, with n = 0 or 1 CH2*1 6 — - in which represents hydrogen or methyl; - R,. represents a C^-C, linear alkyl group; - Rg represents a C^-C^ linear alkyl group, or and also constitute 0 together with the nitrogen atom to which they are attached a hetero- cycle selected from pyrrolidine or piperidine; as well as their salts with organic or mineral acids.
Preferentially, Ar represents phenyl, unsubstituted or mono- substituted at position 2, more particularly Ar represents a group 5 selected from phenyl, 2-halo-phenyl , in particular 2-chloro-phenyl , 2-methoxy-phenyl or 2-hydroxy-phenyl , ?^ represents phenyl or n-propyl, ^ and R^ each represents ethyl, n = 0 and = H.
The following compounds are particularly preferred: 3- (2-diethylamino-2-methyl-propyl) amino-6-phenyl-5-propyl-0 pyridazine and its salts; 3- (2-diethylamino-2-methyl-propyl)amino-5,6-diphenyl- pyridazine and its salts.
The salts of the compounds of formula I according to the present invention includes those with both mineral and organic acids 5 which enable the compounds of formula I to be separated or suitably crystallized, such as picric acid or oxalic acid, those which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide , sulfate, hydrogen sulfate, dihydrogen phosphate, methane sulfonate, methyl sulfate, maleate, fumarate, 2-naphthalene sulfonate. 0 In accordance with a second feature, the present invention relates to a process for the preparation of the compounds of formula (I).
According to the present invention, the process for the preparation of the compounds of formula (I) is characterized in that 5 an amine /NH„ is reacted with a 6-chloro pyridazine of formula: in which Ar and R^ have the meanings indicated above for (I) and, optionally, the compound thus obtained is converted into a salt with a mineral or organic acid.
The substitution reaction of the 6-chloro pyridazine (II) by the amine R^ ^ is carried out between 100° 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 product (I) is isolated by extraction and purified, for example, by chromatography.
The product of formula I thus obtained is isolated in the form of the free base or a salt according to standard techniques.
When the compound of formula I 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 of formula I 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 R^ and/or represent a hydroxyl group, the compound according to the invention is obtained starting from compound (I) in which R. and/or „ denote alkoxy and all of the other substituents 4 have the above definitions, by dealkylation using known methods.
The 6-chloro pyridazines (II), used as starting materials, are prepared from the corresponding 2!I-pyridazin-3-ones (III) by reaction with an excess of hot phosphorus oxychloride in the absence of a solvent or in the presence of an inert solvent such as acetonitrile, according to the following reaction scheme: (III) The 2H-pyridazin-3-ones (III) are known or prepared by known methods .
Thus, when is a Ar ' radical, the 2II-pyridazin-3-ones are obtained according to the method described by P. SCHMIDT et al . in Helv. Chim. Acta, 1954, 1_5, 134-140, starting from malonic acid diethyl ester and a hydrazone derivative according to the following reaction scheme: -CO-C-Ar CH2-CO2C2H5 il N-NH2 CO2C2H5 Ar* (III) 5 When represents an alkyl or cycloalkyl radical, the compounds (III) are prepared from a ketone Ar-CO-Cr^R^ (I) · CHO R3 OH COOC2H5 CH-CH Ar-C-CH2-R3 > Ar - C C = 0 0 1 0 II5C2O 2 R3 OH R3 H / NH2NH2 ^ CCHH--CCHH, c=C / \ C Ar - C^N C N - (III) J 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 n-butanol 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-3-one (III).
The amines R^NI^ are known or prepared by known methods.
Thus, when n = 0, they may be prepared from a cyano derivative of formula: By reaction with an amine HN ^ ^ 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 XICH2 NR5R6 (V) lCH2X VCN 6 is first prepared, then this compound is hydrated by reaction with a strong acid such as hot sulfuric acid in order to produce the corresponding amide: X1CH2 NR5R6 C (VI) X1CH2 CO H2 Finally, reduction by heating with a metal hydride such as boron hydride or lithium aluminium hydride leads to the formation of the amine R^NI^ .
When n = 0, the amine R^ I^ may also be prepared from a chloronitroso derivative (VII) according to the procedure described in J. Prakt. Chem., 1978, 320 (3), 433-451.
CI CH = NOH (VII) (VIII) Li Al H4 XiCH2 > R6R5N - C - CH2 - NH2 X1CH2 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.
CH2 CH2Xl 0 0 CH2Xl 11 I f Φ 1 C + N0C1 > CI - C - CH2 - N = N - CH2 - C - CI XlCH2 CH2X1 CH2X1 CH2X1 (IX) (VII a ) Finally, when n = 1, the amine R^ H? may be prepared according to the method described in Beilstein _ (3), 596, i.e. by reaction of lithium aluminium hydride on the oxime (X): CH2Xl L1AIH4 CH2Xl HO - N = CH - C - CH2 - NR5R6 > H2 - CH2 - C - CH2- NR5R6 CH2Xl · CH2Xi (X) The amine II? - CH2C(CH3)2 - CH?- (CH3)2 is commercially available.
The following examples illustrate the invention without in any way limiting it. The compounds are characterized by their melting point (m. p.) expressed in degrees centigrade.
EXAMPLE 1 3- (2-diethylamino-2-methyl-propyl )amino-6-pheny1-5-propyl-pyridazine sesquifumarate : SR 46559. A.
A) 6-chloro -3-phenyl-4-propyl-pyridazine. 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 . 2. 6-phenyl-5-propyl- 2H-pyridazin-3-one.
The crude product obtained above is dissolved in 450 ml of n-butanol, then 30 g of hydrazine hydrate are added and the mixture is heated at reflux for 24 hours.
The n-butanol is evaporated 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.
Weight: 44 g M.p. : 160°C.
Yield : 69% 3. 6-chloro-3-phenyl-4-propyl— yridazine. 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. 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 extracts are dried over sodium sulfate and concentrated.
Chromatography on silica is then 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%.
E) Preparation of 2-diethylamino-2-methyl-propylamine . 1. 2-diethylamino-2-methyl-propionitrile. 85.1 g of the cyanohydrin of distilled acetone and 73.1 g of diethylamine are mixed, 35.7 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 concentrated and then distilled. 86.6 g of the expected product are recovered.
Yield : 62% B.p. = 63-70°C at 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 nil of water are added with stirring and the mixture is heated on an oil bath at 100-110°C for 2 hours. The reaction mixture is poured slowly during one hour into 1.4 1 of a 20% ammonia solution and 400 ml of water cooled in a Dry Ice/acetone bath. The mixture is extracted 3 times with 600 ml of methylene chloride, the extracts are 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 15 mm of mercury. 3. 2-diethylamino-2-methy1— ropylamine .
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 an atmosphere of nitrogen during one hour and heating is continued for 3 hours on 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 adde slowly during 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 extracts are dried over sodium sulfate and concentrated.
The expected product is obtained by distillation.
Weight: 23 g Yield : 48% B.p. = 71-73°C at 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 extracts are washed with dilute salt 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.
H.p. = 15-11°C Yield: 87% Sesqui umarate 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 10 (175 ml) is concentrated to 130 ml. The product is allowed to crystallize, the crystals are filtered off and then washed v/ith acetone. 4.1 2 of the expected product are obtained.
Overall yield of step C = 74% M.p. = 151°C EXAMPLE 2 S 46559 A A) 6-chloro-3-phenyl-4-propyl-pyridazine , described in example 1.
B) 2-diethylamino-2-rnethyl—propylamine . 1. Preparation of the compound of formula (VII a) with X^ = H. 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) during 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: X^ = li; - i¾ - L2.I_ 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-methyl-propylamine 7.01 g of lithium aluminium hydride are added to 50 ml of an ethereal solution of the compound obtained in the preceding step during 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 during 1 hour, 7.1 ml of sodium hydroxide during 30 minutes and 21.3 ml of water during 30 minutes. After being stirred for 2 hours at room 11 temperature, the solution is filtered, the precipitate is washed with anhydrous ether, the filtrate is dried over sodium sulfate and the solvents are removed under vacuum. The product is distilled: B.p. = 72-75°C at 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-methyl-propyl)amino-6- (2-chloro-phenyl) -5-propyl-pyridazine sesquifumarate. SR 47863 A. 1.7 g of 3-chloro 6-(2-chloro-phenyl) 5-propyl pyridazine and 6 ml of 2-diethylamino 2-methyl propylamine 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 bicarbonate. The organic phase is decanted, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is chromatographed on silica gel, eluant: dichloromethane/methanol 93/2.
The concentration of the pure fractions gives an oil which s dissolved in 10 ml of methanol. Fumaric acid is added, the methanol is evaporated under vacuum and the sesquifumarate crystallizes from ether . m = 1.6 g M.p. = 144°C.
EXAMPLE 4 3- (2-diethylamino-2-methyl-propyl) amino-6- (2-methoxy-phenyl) -5-methyl-pyridazine . 1.6 g of 3-chloro-6-(2-methoxy-phenyl)-5-methyl pyridazine, 4 g of 2-diethylamino-2-methyl-propylamine 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. 12 The organic phase is separated, dried over MgSO^. filtered and evaporated to dryness in a 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-methyl-propyl) amino-5-methyl-6- (2-hydroxy-phenyl)-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 evaporated to dryness under vacuum, the residue is made alkaline with an aqueous solution of potassium carbonate and the solution is extracted with dichloro ethane. The organic phase is decanted, dried over MgSO^. filtered and evaporated to dryness 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 crystallized from isopropanol. m = 200 mg M.p. = 159.2°C EXAMPLES 6 TO 35 A) 3y using the procedure indicated in example 1A, but by varying the starting ketone, the 6-chloro-pyridazines assembled in the tables 1 and 2 are obtained.
TABLE 1 3 2 Rl : R2 : R3 : Physical : constants H : H : -CH2CH2CH3 :M.p.: 52-53°C CI (4) : H : -CH3 :M.p; 178-180°C CI (4) : H : -CH2CH2CH3 :M.p; 95°C OCH3 (4): H : -CH2CH2CH3 : .PV-68-^9°C H : H : CH3 :M.p:; 123-124°C H : H : phenyl : .p:. 115°C H : H : cyclopropyl : M.p. 119°C F (4) H : isopropyl : M.p.89-90°C CI (2) : H : CH2CH2CH3 : oil, NMR" : 0CH3(2) : H : CH3 : NMR* H : H : benzyl :M.p; 92°C • CI (4) H Cl-4 phenyl .p.: 118-119°C H H Cl-4 phenyl M.p 130°C CI (4) H phenyl M. i 125°C CI (2) CI (4) CH2CH2CH3 M . p ; 71-72°C CI (3) H CH2CH2CH3 M.p,- 48°C CH3 (4) H Cl-4 phenyl . M.p. 140°C OCIl3(2) II CH2CH2CH3 oil, NMR" OCH3O) H CH2CH2CH3 oil , NMR" F (4) H Cl-4 phenyl M.p. 139°C NMR : NMR spectral analysis enables the structure of the above compounds to be confirmed. 15 TABLE 2 Physical Ar R3 constants 2-thienyl phenyl .p: 148°C 2-Cl 5-thienyl : phenyl NMR 3-pyridyl phenyl : M.p. 1S4 2-pyridyl phenyl M.p: 138°C 4-pyridyl phenyl : M.p; 193°C Starting from the chloro derivatives of table 1 and by following the procedure employed in example 1, the compounds according to the invention assembled in table 3 below are obtained by varying the amines NH„R, used.
TABLE 3 3 2 : SR No. : : salt or base : Ex. No. : Ri : R2 : 3 : R4 : .p. : sesqui- II II : 46732A : H : H : nC3H7 : fumarate : 7 : : 159-161°C : CH3/C2H5 : Fumarate : 46733A : Cl(4) ί~ H : CH3 : CH2-C-N : 138-140°C 1 \ : 8 : : CH3 C2H5 : 47020A : 1» It H : H : CH3 : sesquifuma- : 9 : : rate 161°C : 47047A : It tl H : H : phenyl : fumarate : 10 : : 193°C It It : 47054A : Cl(4) : H : nC3H7 : sesqui- : 11 : : fumarate : 152-154°C - 17 - 47068 : OCH3(4): H : nC3H7 : 65-66°C base 12 : 47069A : 0H(4) : H : nC3H7 : hydrobromide: 13 : 179-181°C 47097A : H : H : cyclo- : sesqui- 14 : : propyl : fumarate 158-160°C sesqui- 47098A : F(4) : H : iPr : fumarate 15 : hemihydrate 143-145°C CH3 CH3 164°C 47153A : H : H : phenyl : CH2-C-CH2-N sesqui- 17 : CH3 CH3 fumarate CH3 C2H5 fumarate I / 47227A · H : H : benzyl : CH2-C-N^ 163°C 18 : £H3 C2H5 47297A CI (4) : H : Cl-4 : dihydro- 19 : phenyl : chloride 138°C hydrace 47608A H · : H dihydro- 20 clande 147°C 47609A CI (A) phenyl d_.hyd.ro 21 47655A CI (2) :Cl-(4) nC3H7 sesquifuma- 22 rate 165-166°C C2H5 CH3 base 47673 nC3H7 CH2-C-N oil » \ 23 C2H5 CH3 NMR* CH3 C2H5 sesquifutna 1 / 47878Λ CI (3) nC3H7 C-N rate 146°C 24 CH3 C2H5 47890A CH3 (4) Cl-4 dihydrochloride „ 25 phenyl 138°C 47967 F (4) Cl-4 98°C 26 phenyl base 48079A OCH3 (2) nC3H7 sesquifuma- 27 rate 95°C 48080 OH (2) nC3H7 159, 5°C 28 base 48081A OCH3 (3) nC3H7 dihydro-. chloride 29 NMR 48082 OH (3) nC3H7 166°C 30 base 19 NMR spectrum of SR 47673 (DMSO d6; 200 MHz) 0.70 (t : 3 II); 0.S0 (t ; 611); 1.30 (q ; 2H); 1.50 (m ; 4H); 2.30 (s ; 6H); 2.40 (m ; 2H); 3,40 (m ; 2H) ; 6.20 (m ; 111); 6.80 (s ; 1H); 7.35 (s ; 511).
NMR spectrum of SR 480S1 Λ (DMSO d6; 200 MHz ) 0.80 (t ; 3H); 1.40 (m ; 8H) ; 1.5 (s ; 6H); 2.56 (q ; 2H); 3.40 (b.s. ; 411); 3.30 (s ; 3H) ; 4.00 (d ; 2!I) ; 7.02 (m ; 3H) ; 7.40 (t ; III); 7.83 (b.s. ; III).
The following abbreviations are used for the analysis of a NMR spectrum. s = singlet ; b.s. : broad singlet; d : doublet; t : triplet; q : quadruplet; m : multiplet.
C) Starting from the chloro derivatives of table 2 and by following the procedure described in example 1, the compounds according to the invention assembled in table 4 below are obtained by varying the amines !LR, used. 20 TABLE 4 SR No. Ar R3 R4 : Salt or base Ex. No : dihydro- chloride _ 47 : 133°C 47675 A : 5-Cl phenyl : dihydro- 32 . chloride 130°C : 2-thienyl : decomposi- : tion 47802 A : 3-pyridyl phenyl : trihydro- 33 . chloride 225°C 47803 A : 2-pyridyl phenyl : trihydro- 34 : chloride 233°C 47804 A : 4-pyridyl phenyl : trihydro-.. 35 . chloride : 239°C The compounds 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 In vitro, the compounds (I) were assayed according to the technique described by Watson J.D. et al. (Life Sciences, 19S2, 31, 21 2019-2029) as far as their affinity for the receptors of type is concerned and according to the technique described by Hammer R. et al. (Nature, 1980, 2S3, 90-92) and Hulme S.C. et al. (Molecular Pharmacology, 1978, 14, 737-750) as far as their affinity for the receptors of the M? type is concerned.
The compounds according to the invention exhibit good affinity for the receptors of type and a marked specificity for the central receptors of type as opposed to receptors of type i-L^.
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 and !L^ receptors.
Similarly, the compound SR 47047 A showed inhibiting concentrations 50 of 0.04 and 0.9, respectively, on the and !-^ receptors .
In vivo, the compounds according to the invention were assayed for their effect on the rotations induced by intrastriatal pirenzepine in the test described by Worms P, et al. (Psychopharmacology , 1987, 93, 439-493) modified in that the administration of the compounds 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 compounds 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 73%.
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 compounds 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 22 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, he compounds according to the invention did not show any sign of toxicity at the doses at which they are active.
Consequently, the compounds (I) may be used as medicines.
The results indicated show that the compounds according to the invention exhibit good affinity for the muscarinic receptors and 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 indicated and particularly for the treatment of cognitive and memory disorders, and 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 of formula (I) or one of their salts as active ingredient.
In the pharmaceutical compositions of the present invention for oral, sublingual, transdermal or rectal administration, the active ingredients of formula I above may be administered in specific forms of administration, in combination with the standard pharmaceutical vehicles, to humans especially for the treatment of cognitive or memory disorders or degenerative syndromes. The appropriate specific forms of administration comprise the forms used for the oral route such as tablets, capsules, powders, granules and solutions or oral suspensions, the forms used 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 ingredient may vary between 0.5 and 500 mg per day. 23 Each unit dose may contain from 0.1 to 100 mg of active ingredient in combination with a pharmaceutical vehicle. This unit dose may be administered 1 to 5 times per day.
When a solid composition is prepared in the form of tablets, the principal active ingredient is mixed with a pharmaceutical vehicle such as gelatine, starch, lactose, magnesium stearate, talc, gum arabic, or similar substances. 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 ingredient.
A preparation 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 dispersing agents or wetting agents or suspending 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 wetting and/or dispersing agents, for example propylene glycol or butylene glycol, are used.
The active ingredient may also be formulated in the form of microcapsules, with or without one or more additives or supports.
As an example of a galenic preparation, capsules may be prepared containing: S 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 gelules of hard gelatine. 96384/2 24

Claims (1)

1. Compound of formula: in which : - Ar represents a phenyl group substituted by and or a hetero¬ 10 cyclic radical such as a pyridyl group, unsubstituted or substituted 8 . XI . 90 only for by methyl or methoxy, or a thienyl group, unsubstituted or substituted underlined by chlorine, methyl or methoxy. meanings R^ and 9 each independently denotes hydrogen, halogen, trifluoro- methyl, hydroxyl, ^-C^ alkoxy or C^-C/t alkyl; 15 R^ represents linear or branched C^-C^ alkyl, Cg-C-, cycloalkyl, benzyl, phenethyl or the Ar' radical, Ar' being phenyl substituted by and represents 20 CH2Xl Rs 8 . XI . 90 group, with n = 0 or 1 CH2Xl R6 in which represents hydrogen or methyl; - represents a C^-C, linear alkyl group; 25 - g represents a C^-C linear alkyl group, or and R^ also constitute with the nitrogen atom to which they are attached a heterocycle selected from pyrrolidine or piperidine; as well as its salts with mineral or organic acids. Compound according to Claim 1 in which: 30 - Ar represents phenyl, unsubstituted or substituted at position 2 by chlorine, hydroxyl or methoxy; - R3 represents phenyl or n-propyl; - g and g each represents ethyl; n = 0 and γ - 'Λ' 35 as well as its salts with mineral or organic acids. 25 3-N-(2-diethylamino 2-methyl propyl )v-6-phenyl-'5-propyl pyridazinamine and its salts. 3-N-(2-diethylamino 2-methyl propyl) 5, 6-diphenyl pyridazinamine \/ and its salts. Process for the preparation of a compound according to Claim characterized in that an amine R, Hn reacts with a 6-chloro 4 2 pyridazine of formula: R3 in which Ar and have the same meanings as in Claim 1 and, optionally, the compound thus obtained is converted into a salt with a mineral or organic acid. Pharmaceutical composition characterized in that it contains as active ingredient one compound according to any one of the Claims 1 to 4. Pharmaceutical composition according to Claim 6, characterized in that it contains from 0.5 to 100 mg of active ingredient per dosage unit . For the Applicants OR REINHOLD COHN AND PARTNERS By:
IL9638490A 1989-11-17 1990-11-18 Pyridazine derivatives their preparation and pharmaceutical compositions containing them IL96384A (en)

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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
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