CA2030133A1 - Pyridazine derivatives, process for their preparation and pharmaceutical compositions containing them - Google Patents

Pyridazine derivatives, process for their preparation and pharmaceutical compositions containing them

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Publication number
CA2030133A1
CA2030133A1 CA002030133A CA2030133A CA2030133A1 CA 2030133 A1 CA2030133 A1 CA 2030133A1 CA 002030133 A CA002030133 A CA 002030133A CA 2030133 A CA2030133 A CA 2030133A CA 2030133 A1 CA2030133 A1 CA 2030133A1
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methyl
phenyl
substituted
group
propyl
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CA2030133C (en
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Robert Boigegrain
Roger Brodin
Jean Paul Kan
Dominique Olliero
Camille Georges Wermuth
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    • C07D451/00Heterocyclic 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
    • C07D451/02Heterocyclic 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
    • C07D451/04Heterocyclic 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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    • A61K31/00Medicinal preparations containing organic active ingredients
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    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/50Pyridazines; Hydrogenated pyridazines
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    • C07D401/04Heterocyclic 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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    • C07D451/02Heterocyclic 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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    • C07D487/02Heterocyclic 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
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Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to pyridazine derivatives of formula :
(I) in which :
-Ar represents a phenyl group substituted by R1 and R2 or a heterocyclic radical such as a pyridyl group, unsubstituted or substituted by methyl or methoxy, or a thienyl group, unsubstituted or substituted by chlorine, methyl or methoxy ;
-R1 and R2 each independently denotes hydrogen, halogen, trifluoromethyl, hydroxyl, C1-C4 alkoxy or C1-C4 alkyl ;
-R3 represents linear or branched C1-C4 alkyl, C3-C7 cycloalkyl, benzyl, phenethyl or the Ar' radical, Ar' being phenyl substituted by R1 and R2 ;
-R4 represents :

a group, with n = 0 or 1 in which X1 represents hydrogen or methyl ;
-R5 represents a C1-C6 linear alkyl group ;
-R6 represents a C1-C6 linear alkyl group, or R5 and R6 also constitute with the nitrogen atom to which they are attached a heterocycle selected from morpholine, pyrrolidine or piperidine ;
as well as its salts with mineral or organic acids.
The above compounds are useful as drugs, notably as drugs active on the cholinergic receptors of type M1.

Description

203~ 3~

P~RIDAZINE DERIVATIVES, PROCESS FOR_THEIB PREPARATION
A~D PHARMACEUTICAL COMPOSITIONS CONTAINING T~EM
~or many years pyridazine derivatives have been sug~ested as ~edicines, in particular medicines active on the cardiovascular system or on the central nervous system.
In particular, French patent 2 510 99~ and European patent 72 726 disclose pyridazine derivatives variously substituted on the pyridazine ring and all bearing at position 3 an amine substituent of the type ~ -alkylene-,`~l in which X and Y independently represent hydrogen, alkyl or form together with the nitrogen atom to which they are attached a heterocycle such as morpholine.
.~11 of these co~pounds exilibit an activity on the central nervous system as antidepressants.
-~ccording to the present invention, novel derivatives o~
pyridazine have now been discovered which have lost their antidepressant activity and acquired a useful activity as li~ands of cholinergic receptors, in particular receptors of the Ml type.
In accordance with a first feature, the object of the prescnt invention is novel derivatives of pyridazine corresponding to the formula:

Ar ~ ~ NH-~4 (I) in which - Ar represents a phenyl group substituted by Rl and R2 or a hetero-cyclic radical such as a pyridyl group, unsubstituted or substituted by methyl or methoxy, or a thienyl group, unsubstituted or substituted by chlorine, methyl or methoxy;
~ Rl and ~2 each independently denotes hydrogen, halogen, trifluoro-methyl, hydroxy, C1-C4 alkoxy or Cl-C4 alkyl;
- R3 represents a C1-C4 linear or branched allcyl, C3-C7 cycloalkyl, benzyl, phenethyl or the ~r' radical, I~r' being phenyl substituted by P~l and g2;

..
.- . - - . - :
- . . :.

.. ,, . . , ~ .
:,.. - ~ , : . . . . :

': . . - ~

203~3~

- R4 re?resents:

Cl~2Xl R5 a ~ CH2 - C - (Cl~2)n ~ N \ group9 with n = 0 or 1 CH2X1 ~6 in ~/hich ~1 represents hydrogen or methyl;
- R5 represents a Cl-C6 linear alkyl group;
- !?~ represents a Cl-C, linear al'.cyl group, or R5 and R6 also constitute together with the nitrogell atom to which they are attached a hetero-cycle selected from morpholine, pyrroli(line or piperidine;
as well as their salts with organic or mineral acids.
Preferentially, .~r represents phenyl, unsubstituted or mono-substituted at position 2, more particularly ~r represents a group selected from phenyl, 2-'nalo~phenyl, in particular 2-chloro-pll~llyl, 2-metho~y-phenyl or 2-hydro~y-phenyl, ?~3 represents phenyl or n-propyl, T-5 and R~ each represents ethyl, n = 0 and ~1 = H.
The followin~ co;npounds ~re particularly preferred:
3-(2-diethylamino-2-methyl-propyl)amino-6-phenyl-5-propyl-pyridazine and its salts;
3-(2-cliethylamino-2-methyl-propyl)amino-5,6-diphenyl-pyridazine and its salts.
The salts of the compounds of formula I accorcling to the present inventiotl includes those with both mineral and organic acids 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-napht~alene sulfonate.
In accordance with a second feature, the present invention relates to a process for the preparation of the compounds of formula (I).
.~ccording to the present invention, the process for the preparation of the compounds of Eormula (I) is characterized in that an amine ~4N7~2 is reacted with a 6-chloro pyridazine of formula:

: ' :

203~33 Ar--<~Cl (II) N_N
in which Ar and R3 have the meanin2s indicated above Eor (I) and, optionally, the compound thus obtained is converted into a salt with a mineral or orOanic acid.
The substitution reaction of the 6-chloro pyrida2ine (II) by the amille R4~H2 is carried out between 100 and 150C, 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. ~le product (I) is isolated by extraction and purified, for example, by chromato~raphy.
The product oE formula I thus obtained is isolated in the form of the free base or a salt according to standard techniques.
'lhen the compound of formula I is obtained in the Eorm 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 oE the selected acid in the same solvent, the correspondin~ 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 Eumarate and the 2-naphthalene sulfonate are prepared.
At the end o-E 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 neutraliæation 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.
~lhen Rl andjor R2 represent a hydroxyl group, the compound according to the invention is obtained startino from compound ~I) in which Rl and/or R2 denote alkoxy and all of the other substituents :

, . . , ~ - - -- . - - : :: ~
~ : ' i - : ~: :

203~3~

have the above definitions, I)y deallcylation using 1cno~/n methods.
The 6-chloro pyridazines (II), used as startino materials, are prepared from the correspon(ling 211-pyrldazin-3-ones (III) by reaction ~ith an e~cess of hot phosphorus oxychloride in the absence oE a solvent or in the presence of an inert solvent such as acetonitrile, accordino to the :Eollot~ing reaction scheme:

Ar ~\ ~ O POCl3 ~II) N-N -->
H

(III) 15The 2EI-pyridazin-3-ones ~III) are known or prepared by known methods.
Tl1us, when P~3 is a Ar' radical, the 211-pyridazin-3-ones are obtainetl according to the method described by P.SCf{MIDT et al. in llelv .
Chim. Acta, l954, 15, 134-140, starting Erom malonic acid tliethyl ester 20antl a hydrazone derivative according to the follo~ino reaction scheme:
Ar'-CO-C-Ar + CH2-CO2C2H5 25Ar~ C02C2Hs Ar~ COOH

- > Ar ~ O - > Ar ~ O
N-N N-H H

Ar' :

- > Ar ~ ~ O :
-N :
1 ~: :

(III) ~ -. .- . ~

2~3~3~

11hen ~3 represents an alkyl or cycloallcyl radical, the compoun(1s ~III) are prepared ~rom a ketone Ar-CO-C~2R3 (1):
CllO R3 OH
COOC2Hs CH-CH
5 Ar-C-C112-R3 -> Ar - C C = O
l 1~sC20 2 lO NH2NH2 CH-CH\ C=C
-----> Ar - C C = O > Ar - C\\ C = O ~
N - N N - ~ -3 ~ (III) H

The hydro~y keto ester 2 is obtained from the ketone 1 by heating it with ethyl ~lyoxylate at a temperature between 80 and 140C.
The crude reaction mixture is then taken up in an inert solvent such as n-butanol and hydrazine hydrate is added. By heating at refluc for 24 hours, the 4,5-dihydro 4-hydro~y pyridazin-3-one 3 is obtained which, when heated in an acidic medium, leads by dehydration to the 211-pyridazin-3-one (III).
The amines R4N112 are known or prepared by lcnown methods.
Thus, when n = O, they rnay be prepared from a cyano derivative of formula:
XlCHz OH
C (IV) XlCH2 CN

By reaction with an amine H~R5R6 by heating at a temperature between 40 and 80C, optionally in the presence of a salt of a strong acid such as sodium sulfate or magnesium sulfate, a compound of formula:
X lCH2 NR5R6 C ~V) XlCH2 CN

:
--. :

, . . - ~ . . ~ .

2~3~3~

is first prepared, then this compound is hydrated by reaction with a strong acid such as hot sulEuric acid in order to produce the corresponding aMide:
XlCH2 / NR5R6 C \ (VI) XlCH2 CONH2 Finally, reduction by heating with a metal hydride such as boron hydride or lithium aluminium hydride leads to the formation of the amine R4Nll2.
~ lhen n = O, the amine P~4N!12 may also be prepared from a chloronitroso derivative (VII) accordino to the procedure described in J. Prakt. Chem., 1978, 320 (3), 433-451.

Xl,CH2 XlCH2 C1 - C - CH2NO + R5R6NH2 - ~ R6RsN - C - CH = NOH
XlCH2 XlCH2 : `

(VII) (VIII) Li Al H4 XlCH2 > R6R5N - C - CH2 - NH2 X lCH2 The compound of formula (VII) may be used in the form o:E
a dimer (VIIa) which is obtained by reaction of nitrosyl chloride with the appropriate olefin (IX) according to the procedure described in J. Prakt. ChemO, 1965, 29 (4), 123.

,C,112 C1~l2Xl ~ O C~2~1 C + NOCl > Cl - C - CH2 - N = N - CH2 - C - Cl X lCH2 CH2X 1 CH2X 1 C112X 1 (IX) (VII a ) ~: . . . -2~3~33 Finally, when n = 1, the amine R4NH2 may be prepared according to the mcthod described in ~eilstein 4 (3)I 5~6, i.e. by reaction o lithiuln aluminium hydride on the oxime (X):

CII2X1 LiAlH4 CI12Xl IIo - N = CH - C - C~Iz - NR5a6 > H2N - CH2 - C - CH2- NRsR6 (X) ine ~II2 ~ CX2C(CI3)2 ~ CH2-~(C~I3)2 is commercially available.
The following exaIllples illustrate the invention without in any way limiting it. The compounds are characterized by their melting point (~I.p.) expressed in degrees centigrade.

E~A,IPLE 1 3-(2-diethylamino-2-methyl-propyl)amino-6-phenyl-5-propyl-pyridazine sesquifumarate: SR 46559 ,~.
A~ 6-chloro-3-phenyL-4-propyl-pyridazine.
1. Ethyl 2-hydroxy-4-oxo-4-phenyl-3-propyl-butyrate.
A mixture of 48.c,7 g of valerophenone and 45.94 g of ethyl ~lyoxylate is heated at 120C Eor 15 hours.
The crucle reaction product is used as such in the following step, 2. 6-phenyl-5-propyl-2rl-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 -Eor 24 hours.
The n-butanol is evaporated ~d2r 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 100C for 3 hours. The solution is poured into cold water and the product is left to crystallize.
The solid is filtered off ancl dried.
I,~eight: 44 g M.p.: 160C.

, .: : . - - . .

- : .

2~3~3~

Yield : 69~
3. 6-chloro-3-pllenyl-4-propyl-pyridazine.
250 ml of phosph~s oxychloride are added to 44 g of pyridazinone obtained above and the mi~ture is heated at 80~C for ~
hours. After being left to stan~ o~erni~ht at room temperature, the reaction mixture is concentrated to 3/4 and then poured slowly onto ice. Tl-e mixture is extracted twice with 300 ml of dichloro!nethane, the e~tracts are tlried over sodiwn sul~ate and concentrated.
Chrolna~ography on silica is then carried out by elutin~ h an ethyl acetate-r,lethylene chloride mixture (50/50 v/v).
After recrystallization ~rom isopropyl ether, 43.7 g of the expected product are obtaine~d.
I.p. : 60C
Yield: 9~%.
~) 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, S5.7 g of magnesium sulfate are added and the mixture is heated under gentle reflux for 20 hours with stirrin~.
The sulfate mass which is formed is filtered off and washed with ether.
The filtrate is concentrated and tllen distilled.
86.S g of the expected product are recovered.
Yieltl : 62%
3.p. = 68-70C at 15 mm of mercury.
2. 2-diethylamino 2-methyl propionamide.
To 95.9 g of the nitrile prel~ared in the preceding step 450 ml of sulfuric acid and 70 ml or water are added with stirring and the mixture is heated on an oil bath at 100-110C for 2 hours. The reaction mixture is poured slowly during one hour into 1.4 1 of a 20%
~0 ammonia solution and 400 ml of water cooled in a Dry Ice/acetone bath. The mixture is extracted 3 times with S00 ml of methylene chloride, the extracts are dried over sodium sulEate and concentrated. -The expected product is obtained by distillation.
I1eight : 102.5 g Yield : 95%

, . .:

: - -: . : ~. :: . :
:' : ~ - :: - : - ~ .:

- 2~3~;~3~

B.p. : 13~-139C at 15 mm of mercury.
3. 2-diethylamino-2-me~hyl-propylamine.
A mixture containil~, 52.4 g~ of the ami(l~ prepared in the preceding step and ~0 ml of tetrahydroftlran are heated at 45-50C.
So ml of the borane-dimethylsulEide complex are added under an atmosphere of nitro~en durino one hour and heating is continued for 3 hours on an oil bath at ~0-~5C.
After being left overnight at room temperature, the mixture is cooled in an ice bath, then 315 ml of 6~ llydrochloric acid are added slowly during 3 hours and the mixture is heated again at 135C for 3 hours. After being left overnight at room temperature, the reaction mixture is cooled whilst 200 ml of 30~O~ sodium hydroxide are added.
The mixture is extracted 3 times with 250 ml of ether, the extracts are dried over sodiu,n sulfate and concentrated.
The expected product is obtained by distillation.
~eight: 23 Yield : 48%
3.p. = 71-73C at 15 mm of mercury.
C) SP~ 46559 A
- t~ mixture oE 2.5 g of the chloro derivative obtained above in step A and 4.6 g oE the ~iamine obtained in step B are heated at 120C 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.
Chromatotgraphy 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.
.-I.p. = 75-77C
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 ~ of fumaric acid in 150 ml of ace~one are added. The mixture is filtered hot. The total volume recovered .

.
- , : ~ ~:
- ~ :
- ~ .
.

2~3~.~33 (175 ml) is concentrated to 130 ml. The product i9 allowed to crystallize, the crystals are filtered off and then ~ashed witll acetone.
.l g of the expec~ed product are obtained.
Overall yield of step C = 74,~
`I.p. = 151~C

rXA;~IPL~ 2 S?~ 46559 .~
Aj 6-chloro-3-?henyl-4-propyl-pyridazine, described in e~ample 1.
B) 2-diethylamino-2-methyl--propylannine.
1. Pre?aration of the compound of formula ~VII a) with ~1 = H.
47.14 g of isobutylene are dissolved in 150 ml oE n-heptane, the mixture is cooled to a temperature bet-~een -10 and -20C and 50 g of nitrosyl chloride are added. The temperature is allowed to rise~+5C) during one and a half hours, then the temperature is brought to between 10C and 20C and the mixture is stirred for one and a half hours. The precipitate formed is filteretl off, washed with heptane and then dried.
;I.p. = 102-104C
m = G4 g 2. Preparation oE the compound of forlnula VIII~ 5 = ~6 = C2~15 21.7 g of the compound prepared in the preceding step are suspellded in 150 ml of a~solute alcohol, 39.17 g of diethylamine are added antl the mixture is heated at 60C for 6 hours. An oil is obtained which solidifies.
m = 19.5 g ~ I.p. ~ 50C
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 l hour. After being stirred for one and a half hours at room temperature, the mixture is refluxed for 4 hours. r~hile the mixture is maintained between 0C and -10C, 7.1 ml of water are added during 1 hour, 7.1 i711 of sodium hydroxide durino 30 minutes and 21.3 ml of water during 3G minutes. After being stirred for 2 hours at room :: , . :
:

20~3~

temperature, the solution is filtered, the precipitate is washed ~ith anhydrous ether, the filtrate is dried over sodium sulfate and the solvents are removed un~ervacuum. The pro~uct is distilled:
~.p. = 72-75C at 15 mrn of mercury.
m = 4.2 ~
C) SR 46559 A is then prepared as described in example 1.

EX~`IPLE 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-pilenyl) 5-propyl pyridazine and 6 ml of 2-diethylalDino 2-methyl propylamine are heated at 110C
under nitro~en for 20 hours.
After evaporation unde~ vacuum, the mixture is talcen up in dichloromethane and uashed with a solution of sodium bicarbonate. The organic phase is decanted, dried over magnesium sulfate, filtered and concentrated undsrvacuum. The residue is chromatographed on silica nel, eluant: dichloromethane/methanol 98/2.
The conccntration of the pure fractions gives an oil ~hich is dissolved in 10 ml of methanol. Fumaric acid is added, the methanol is evaporated under vacuum and the sesquifumarate crystallizes from ether.
m = l.G ~
~I.p. = 144~C.
E~ lPL~ 4 3-(2-diethylamino-2-methyl-propyl)amino-6-(2-methoxy-phenyl)-5-methyl-pyridazine.
1.6 g of 3-chloro-o-~2-methoxy-phenyl)-5-methyl pyrida~ine, 4 g of 2-diethylamino-2-methyl-propylamine and 0.36 o of ammonium chloride are melted together at 120C 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 2~3~3 The orgaIlic phase is separated, ~ried over ~gS0~. filtered and evaporated to Iryness in a vacuum.
The residue is chromatol7rapIled on alumina, eluent: ethyl acetate +2~o of triethylamine.
The concentration of the pure fractions g~ives the e~pected product. Tlle structure is confirZ~Ied by ~iR spectral analysis.

E~A`PL~ 5 3-(2-diethylamino-2-methyl-propyl)amino-5-methyl-6-(2-hydroxy-phenyl)-pyridazine. SR 96376.
1 g oE the product obtained previously in e~ample 4 is dissolved in 50 ml of 4~O hydrobromic acid and the mixture is heated at reflu~ for 4~ hours. After this time, the Ieac-~.on mixture is evaporated to dryness under vacuum, the residue is made allcaline with an aqueous solution of potassium carbonate and the solution is extracted with dicIlloromethane. The org7anic phase is decanted, dried over-i~IOS04.
filtered and evaporated to dryness ~der vacuum.
The residue is chromatographed on alumina, eluent: ethyl acetate/methanol 9/1 + 2% of triethylamine.
The concentration of the pure fractions ~ives a residue which is crystallized from isopropanol.
m = 200 mg ~ 59.2C

~'~A`IPLES 6 T0 35 A) By using the procedure indicated in e~ample lA, but by varying the starting ketone, the 6-chloro-pyridazines assembled in the tables 1 and 2 are obtained.

.: . .~ .

.- , . :

2 ~

OS ~ >\ ~ Cl ___________________________________________________ , : R1 : R2 : R3 : Physical : : constan~s H H -CH2CH2CH3 M.p.: 52-53C

Cl (4) H . -CH3 M.p; 178-180C ;

lS Cl (4) H -CH2CHzCH3 ;M.p; 95C

OCH3 (4) }I ; -CH2CH2C1l3 M.p~ 68-!69C

: H : I{ : CH3 :M.p: 123-124C :

: H H phenyl M.p:. 115C

H H : cyclopropyl M,p.119C

: F (4): H isopropyl :M.p-.89-90C
-. :
: Gl (2) : H : CH2CH2CH3 : oil, NMR ~ :
:
: OCH3(2) : H : CH3 NMR
: : : : :
: H : H : benzy~ :M.p; 92C
:

- 20~13~

Cl (4~ H ; C1-4 phenyl M p... 118-119C

: H : H : Cl-4 phenyl :M.p_ 130C
:
OS : Cl (4) : H : phenyl :M.p; 125C

Cl ~2) Cl (4) CH2CH2CH3 M.p; 71-72C

: Cl (3) : H : CH2cl~2cl~3 :M.p; 48C

: CH3 (4) : H : Cl-4 phenyl :M.p'. 140C
:
: OCI13(2) : ll : C1l2CII2CH3 :oil~ NMR

: OCH3(3) : H : Cll2CH2CH3 :oil, NMR
:
: F ~4) : H : Cl-4 phenyl :M.p. 139C
____ _ ____________________________________________ NMR : NM~ spectral analysis enables the structure of ~he above compounds to be confirmed.

.:

203~33 Ar_\ ~ Cl N-N

: : : Physical Ar : R3 : constants : 2-thienyl : phenyl :M.p: 148C

: 2-C1 5-thienyl . phenyl . NMR
3-pyridyl : phenyl :M.F. 184C

: 2-pyridyl : phenyl : M.p. 138C

: 4-pyridyl : phényl : M.p 193~C
--------------------------------------~~~~~~~~~~~
B) Starting ~rom the chloro derivatives of table 1 and by followinn ~he procedure e~nployed in evample 1, the co~pounds according to the invention assembled in table 3 belo~ are obtained by ~tarying the amines `.lll2~4 use(!.

~ :

, ~ - :
., -:, ~3~3~
4 ~ ~ NH-R4 05 Rl N_N

____________________________________________________________________ :SR No. : sal~ or base:
:Ex. No. : Rl R2 : R3 : R4 : M.p.

: : : : CH3 : di`nydro-I ~ chloride : 46729A : Cl(4) : H : CH3 : CH2C-N > ; - :
: 6 : : : : CH3 ~ : 240-242~ :

: : : : : : sesqui-: 46732A : }I : H : nC3H7 : : fumarate : 7 : : : : : lS9-161C

CH3/C2Hs : Fumarate : 46733A :C1(4) ~ }I : CH3 CH2-C-N\ : 138-140C
: 8 : : : : CH3 C2Hs : 47020A : H : H : CH3 t- ~ : sesquifuma- :
: 9 : : : : : rate 161C
- . . . . . .
: 47047A : H : H : phenyl. " " : fumarate : 10 : : : : : 193C
:- : : : : :
: 47054A : Cl(4) : H : nC3H7 : : sesqui-: 11 : : : : : fumarate :
: : : : : 152-154C
:

: . :. . . :

- , : . . .. : . . ..
, ~ . , , . - . ' - , :
- , : ; . : . -. : , :, 2 ~

: 47068 : oCH3~4): H : nC3H7 : " " : 65-66C base:
: 12 : : : :
:
: 47069A : OH(4) : H : nC3H7 : : hydrobromide:
05 : 13 : : : : : 179-181C
:
: 47097A : H : H : cyclo- : " " : sesqui-: 14 : : : propyl : : fumarate : : : : : : 158-160C

: : : : : : sesqui-: 47098A : F(4) : H : iPr : " " : fumarate : 15 : : : : : hemihydrate :
: : : : : : 143-145C

: : : CH3 ~ : sesqui-: 47138A : H : H : nC3H7 : CII2-C-N O : fumarate : 16 : : : : CH3 ~ : 149-151C
:
: : C1~l3 C~l3 : 164C
: 47153A : H H : phenyl : CH2-c-c~2-~ : sesqui-: 17 : : : : CH3 CH3 : fumarate :
: : : : : CH3/C2Hs : fumarate : 47227A : H : H : benzyl : CH2-C-N~ : 163C
: -18 ~H3 C2H5 : 47297A : Cl (4) : H : Cl-4 : : dihydro-: 19 : . : : phenyl : a~l~ide 138C
: : : : : : hydrate :
: 47608A : H - : H : " : : dihydro-:20 : ~id~ 147C

'' . :- . ' . ' .

, .

--.

2~3~3~

: 47609A : Cl (4) : H : phenyl : " " :d~hydlo 21 chl~id~470c .
: 47655A : Cl (2) :Cl-~4): nC3H7 : " " : sesquifuma- :
05 : 22 : : : : : rate : : : : : : 165-166C
:
: : : : : C2Hs CH3 : base : 47673 : H : H : nC3H7 : CH2-C-N. : oil 1023 : : : : C2Hs CH3 : ~MR
:
: : : : : CH3 C2Hs : sesquifuma- :
: 47878A : Cl (3) : H : nC3H7 : CH2-C-N : rate 146C
: 24 : : : : C~13 C2l~s : 47890A : CH3 (4) : H : Cl-4 : " " dihydro-: 25 : : : phenyl : Chloridle O
:
: 47967 : F (4) : H : Cl-4 : : 98C
: 26 : : phenyl : : base : 48079A : OCH3 (Z) ': H : nC3~17 : : sesquifuma- :
: 27 : : .: : : rate 95C

: 48080 : OH (2) : H : nC3H7 : : 15g,5 C
: 28 : : : : : base : 4808lA : OCH3 (3) : H : nC3H7 : ' dihydro-: 29 : : : : chloride : 48082 : OH (3) : H : nC3H7 : : 166~C
30 : : : : base ________________________________________________ ___________________ :

- : . . . . : : :
;, ,. ~ ~

~ ~ 3 ~

.`r;lR spectrurIl of SR 47673 ~D:IS0 d6; 200 `-~Tz) 0.70 (t: 3 11); O.S0 ~t; 6TI); 1~JO (q; 21l); 1.50 (m; 411);
2.30 (s; ~)ll~; 2.40 (m; 2M); 3,40 (m; 211); 6.20 (In; lll); 6.S0 (s;
lH); 7.35 (s; 5M).
~I~IR spectrum of SR 4SOSl ~
(D`IS0 d; 200 lI!lz) 0.3d (t; 3TM~; 1.40 (m; 31.1); 1.5 (s; 61T); 2.56 ~q; 211);
3.40 (b.s. ; 4Tl); 3,30 (s ; 3~1); 4.00 (d ; 21'); 7.02 (In; 3~1); 7.40 lO (t; l1l~; 7.S3 (b.s.; lM).
The following abbreviations are used for the analysis of a ~ s~ectruIn.
s = singlet ; I).s. : broa(l sin;,let; d : doublet; t : triplet;
q : quadruplet; ;n : multiplet.
15 C) Starting from the chloro derivatives of table 2 and by l~ollowing the pro^edure described in e:cample 1, the compounds according- to the invention asseml)led in table 4 belo~ are obtained by varying the amines .'~112R4 used.

,, .
~, :. . , . : ' . ~ . , .
.
'' ~ ' . ' ' . ' ' ..

2~3~:~33 TA~LE 4 Ar ~ NH R4 ~___________________________________________________________________ : SR No. : Ar : R3 : R4 : Salt or ~ase:
: Ex. No. : : : : :

:: : : CH3 C2H5 : dihydro- : -:47674 A : 2-thienyl : phenyl ~ : CH2-C-N \ Chlrilde3C
:31 : : : CH3 C2H5 : : .

47675 A : 5-Cl : phenyl : " " : dihydro-:32 2-thienyl chloride 130C
:: : : : decomposi-: tion : 47802 A : 3-pyridyl : phcnyl : " " : trihydro- :
33 ' ' , chlnride 225C , : 47803 A : 2-pyridyl : ph~nyl : " " trihydro-: 34 : : ~ oride233C

~5 : 47804 A : 4-pyridyl : phenyl : " " : ~rih~d~o-. :
: 3S : 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 .
of type ;~1l and ~12-In vitro, the compounds (I) were assayed according to the technique described by '.~1atson J.D. et al. (Life Science.s, 19S2, 31, . .

.
;

2~3~3~

2019-2029) as far as their affinity for the receptors of type ~ll is concerned and according to the technique described by ~lanmmer 1>~. et al. (`-ature, 19S0, 2S3, 90-92) and llulme I~.C. et al. (~`~olecular Pharmacology, 1973~, 14, 737-750! as far as their af Einity for the receptors of the ~'~2 type is concerned.
The compounds accordino to the invention exhibit good affinity for the receptors of type ~1l and a mar~ced specificity for the central receptors o E type `:ll as opposed to receptors of type li2.
As an exainple, the co npound SR 46559 A showed an inhibitin~ -concentration 50 expressed in micromoles of 0.11 and 2.2, respectively, on the ~ll and i l2 receptors .
Similarly, the compound SR~ 47047 A showed inhibitin~
concentrations 50 o 0.04 and 0.9, respectively, on the `11 and ~t2 receptors .
In vivo, the compollnds accordin~ to the invention were assayed for their effect on the rotations induced by intrastriatal pirenzepine in the test tlescribed by r?orms P, et al. (Psychopharinacology, 19S7, 93, 4S9-493) modified in that the adlninistration of the compounds by the oral route toolc place 4 hours before, instea(l o~ 30 minutes before, the injection of pirenzepirle.
At a dose o E 3 m;-g per Icg of body wei-r,ht, the compoullds according to the invention strongly inhibit the number of rotations induced by pirenzepine. Thus, as an exainple, the compound SR 4G559 A
inhibits the rotations induced by pirenzepine by 73%.
Furtherlllore, the coalpounds according to the invention were shown to be active in the passive avoidance tests in the rat described by Jarvik ;il.E. et al. in Psychol. :led., 19S7, 21, 221-224 and by l~orms P . et al . in Psychopharmacol ., 19S9, 9S , 2~$-2~33.
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~!cg and the amnesia induced by Ipirenzepine administered intraperitoneally at 75 mg/lcg.
For example, SP~ 46559 A exhibits an oral efficien~ dose 50 of 0.25 mg/kg and 0.027 m~,/lcg, respectively,in each of these tests.
'loreover, some compounds according to the invention were - , ', 2~3~3~ .

studied in se~veral predictive models oE antidepressant activity such as the forced suimming test described by Porsolt et al. (Arch. Intern.
Pharmacodyn., 1977, 229, 327-33S) and the test of antagonism of reserpine-induced ptosis described by Gouret et al. (J. Pharmacol.
(Paris), 1977, o, 333-350). S~ 46559 A in particular was shown to be inactive in these tests at oral doses varyillg from 0.1 to 10 mg/lcg.
linally,the compounds according to the invention did not sho~ any sign of toxicity at the doses at which tlley are active.
Consequently, the compounds ~I) may be used as medicines.
The results indicated show that the compoun(ls according to the invention e~hibit 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 accordillO to the invention to be contemplated in all cases in which a cholinergic deficit is indicated and particularly Eor the treatinent 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 compoull(ls of formula (I) or one oE 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 oE cognitive or memory ;-disorders or degenerative syndromes. ~he 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.

: :

.

, :. ~

2 ~ 3 ~

Each unit dose may contain from 0.1 to 100 mo of active inoredient in combination with a pharmaceutical vehicle. This unit dose may be administered 1 to 5 times per clay.
~Ihen 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 num arabic, or si;nilar substances. The tablets may be coated with sucrose or other suitable materials or they may be treatetl so that they have sustained or clelayed activity and so that they release continuously a predetermined amount of active ingredient.
t~ preparation oi- capsules is obtained by nixinO the active ingredient ~ith a diluent and ~y pourino the mixture obtained into soft or hard capsules.
The powders or granules dispe~sible 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 me~tino at the rectal ten~perature, for example cocoa butter or polyethylene glycols.
~or parenteral administration aclueous suspensiolls, isotonic saline solutions or sterile ancl injectable solutions which contain pharmacologically compatible wetting andfor 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 oe prepared containing:
SR 46559 l~ 0.010 8 ~0 Lactose 0.050 g .~iagnesium stearate 0.005 g by mixing the aboYe ingredients intima~ely and pouring the mixture into gelules of hard gelatine.

.:
. ~ .
. ' ~.
, .

Claims (7)

1. Compound of formula:
(I) in which :
- Ar represents a phenyl group substituted by R1 and R2 or a hetero-cyclic radical such as a pyridyl group, unsubstituted or substituted by methyl or methoxy, or a thienyl group, unsubstituted or substituted by chlorine, methyl or methoxy.
- R1 and R2 each independently denotes hydrogen, halogen, trifluoro-methyl, hydroxyl, C1-C4 alkoxy or C1-C4 alkyl;
- R3 represents linear or branched C1-C4 alkyl, C3-C7 cycloalkyl, benzyl, phenethyl or the Ar' radical, Ar' being phenyl substituted by R1 and R2;
- R4 represents:

a group, with n = O or 1 in which X1 represents hydrogen or methyl;
- R5 represents a C1-C6 linear alkyl group;
- R6 represents a C1-C6 linear alkyl group, or R5 and R6 also constitute with the nitrogen atom to which they are attached a heterocycle selected from morpholine, pyrrolidine or piperidine;
as well as its salts with mineral or organic acids.
2. Compound according to Claim 1 in which:
- Ar represents phenyl, unsubstituted or substituted at position 2 by chlorine, hydroxyl or methoxy;
- R3 represents phenyl or n-propyl;
- R5 and R6 each represents ethyl;
n = O and X1 = II;
as well as its salts with mineral or organic acids.
3. 3-N-(2-diethylamino 2-methyl propyl) 6-phenyl 5-propyl pyridazinamine and its salts.
4. 3-N-(2-diethylamino 2-methyl propyl) 5,6-diphenyl pyridazinamine and its salts.
5. Process for the preparation of a compound according to Claim 1, characterized in that an amine R4NH2 reacts with a 6-chloro pyridazine of formula:

(II) in which Ar and R3 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.
6. Pharmaceutical composition characterized in that it contains as active ingredient one compound according to any one of the Claims 1 to 4.
7. Pharmaceutical composition according to Claim 6, characterized in that it contains from 0.5 to 100 mg of active ingredient per dosage unit.
CA002030133A 1989-11-17 1990-11-16 Pyridazine derivatives, process for their preparation and pharmaceutical compositions containing them Granted CA2030133A1 (en)

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FR8915137 1989-11-17
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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PT93060B (en) * 1989-02-07 1995-12-29 Sanofi Sa METHOD FOR OBTAINING PYRIDAZINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022166890A1 (en) * 2021-02-08 2022-08-11 南京明德新药研发有限公司 Substituted pyridazine phenol derivatives
CN116867769A (en) * 2021-02-08 2023-10-10 南京明德新药研发有限公司 Substituted pyridazine phenol derivatives

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IL96384A0 (en) 1991-08-16
IE75697B1 (en) 1997-09-10
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EP0429344B1 (en) 1996-09-18
EP0429344A1 (en) 1991-05-29
IL96384A (en) 1995-10-31
HU907178D0 (en) 1991-05-28
NO178967B (en) 1996-04-01
FI905663A7 (en) 1991-05-18
NO904984L (en) 1991-05-21
FR2663326B2 (en) 1992-10-16
HU211351A9 (en) 1995-11-28
ES2094146T3 (en) 1997-01-16
PT95902B (en) 1998-01-30
NO178967C (en) 1996-07-10
CA2030133C (en) 1991-05-18
HU207852B (en) 1993-06-28
GR3021933T3 (en) 1997-03-31
DK0429344T3 (en) 1997-03-03
NZ236107A (en) 1992-10-28
JPH03170465A (en) 1991-07-24
KR0164599B1 (en) 1999-01-15
HK1000597A1 (en) 1998-04-09
NO904984D0 (en) 1990-11-16
DE69028602T2 (en) 1997-04-03
AU6667290A (en) 1991-05-23
ATE143010T1 (en) 1996-10-15
LV11972A (en) 1998-02-20
DE69028602D1 (en) 1996-10-24
HUT56078A (en) 1991-07-29
PT95902A (en) 1991-09-13
IE904145A1 (en) 1991-05-22
AU639043B2 (en) 1993-07-15
FR2663326A2 (en) 1991-12-20
FI905663A0 (en) 1990-11-15
AR247557A1 (en) 1995-01-31
LV11972B (en) 1998-04-20

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