CA2009501A1 - Pyradazine derivatives, method of preparation and pharmaceutical compositions in which they are present - Google Patents
Pyradazine derivatives, method of preparation and pharmaceutical compositions in which they are presentInfo
- Publication number
- CA2009501A1 CA2009501A1 CA002009501A CA2009501A CA2009501A1 CA 2009501 A1 CA2009501 A1 CA 2009501A1 CA 002009501 A CA002009501 A CA 002009501A CA 2009501 A CA2009501 A CA 2009501A CA 2009501 A1 CA2009501 A1 CA 2009501A1
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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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/04—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/20—Nitrogen atoms
-
- 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
- C07D401/04—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Abstract
ABSTRACT OF DISCLOSURE
The present invention relates to pyridazine derivatives of formula :
(I) in which - Ar is a group a pyridyl or a thienyl ;
- R1 and R2 independently are each hydrogen, a halogen atom, a hydroxyl group, a trifluoromethyl group, a C1-C4 alkoxy group or a C1-C4 alkyl group ;
- R3 is a C1-C4 alkyl-group or a phenyl ; and R4 is :
- a group in which Alk is C1-C6 alkylene group, R5 is hydrogen or a C1-C6 alkyl group and R6 is a C1-C4 alkyl group, a benzyl or a C3-C7 cycloalkyl, or R5 and R6 form, with the nitrogen atom to which they are bonded, a heterocycle selected from morpholine, thiomorpholine, pyrrolidine, N-methylpiperazine and piperidine which is unsubstituted or substituted by one more methyl groups, by a hydroxyl, by a phenyl or by a benzyl ;
- a group in which Alk' is a C1-C3 alkylene group and R7 is a C1-C4 alkyl group ; or - a group
The present invention relates to pyridazine derivatives of formula :
(I) in which - Ar is a group a pyridyl or a thienyl ;
- R1 and R2 independently are each hydrogen, a halogen atom, a hydroxyl group, a trifluoromethyl group, a C1-C4 alkoxy group or a C1-C4 alkyl group ;
- R3 is a C1-C4 alkyl-group or a phenyl ; and R4 is :
- a group in which Alk is C1-C6 alkylene group, R5 is hydrogen or a C1-C6 alkyl group and R6 is a C1-C4 alkyl group, a benzyl or a C3-C7 cycloalkyl, or R5 and R6 form, with the nitrogen atom to which they are bonded, a heterocycle selected from morpholine, thiomorpholine, pyrrolidine, N-methylpiperazine and piperidine which is unsubstituted or substituted by one more methyl groups, by a hydroxyl, by a phenyl or by a benzyl ;
- a group in which Alk' is a C1-C3 alkylene group and R7 is a C1-C4 alkyl group ; or - a group
Description
Pyridazine derivative~ have been proposed a~
drugs for many years.
In a large number of case~, the~e are sub~tance~
which are active on the cardiova~cular sy~tem and have in 06 particular a hypoten~ive or vasodilative efect, in other cases, an ~ntiinflammatory and analgesic action ha~ been mentioned for pyridazine derivative~.
Finally, French patents 2 141 697, 2 610 997 and 2 510 998 di~clo~e pyridazine derivatives which are variously ~ub~tituted on the pyridazine ring and all carry, in the 3-po~ition, an amino sub~tituent of the typ~
-NH-alkyl-N
y in which X and Y independently are hydrogen or an alkyl group or form~ with the nitrogen atom to which they are bonded, a heterocycle such as morpholine.
All the~e compounds are active on the central nervous sy tem a~ antidepres~ant~.
According to the pre~ent invention, it ha~ now been found that by modifying the nature and~or position 26 of the substituents on the pyridazine ring, compound are obtained which have lo~t their antidapre3sant activity and ac~uired a valuable activity a~ M~-type muYcarinic cholinergic ligand~
According to a fir t feature, the pre~ent inven-tion relate~ to novel pyridazine derivative~ of thegeneral formula 36 Ar_~ NH~R4 ( I~
s~
in which - Ar is a group R ~
a pyridyl or a thienyl, - R1 and Rz independently are each hydrogen, a halogen atom, a hydroxyl group, a trifluoro~ethyl group, a C~-C4 alkoxy group or a C1-C4 alkyl group;
- R3 iæ a C1-C4 alkyl group or a phenyl; and - R4 is:
1~ - a group -Alk-N
R~
in which Alk i~ a C1-Ca alkylene group, R6 i~
hydrogen or a Cl-Cs alkyl group and R~ i8 a C1-C4 alkyl group, a benzyl or a C3-C7 cycloalkyl, or R6 and R~ form, with the nitrogen atom to which they are bonded, a heterocycle selected from morpholine, thio-morpholine, pyrrolidine, N-methylpi~erazine and piperidine which is unsub~tituted or substituted by one or more methyl groups, by a hydroxyl, by a phenyl or by a benzyl;
- a group -Alk' sq;~
in which Alk' is a Cl-c3 alkylene group and R7 i8 a C1-C~ alkyl group; or - a group -A1~' ~
in which Alk' is a~ defined abov0 and substitute~ the pyridine in the 2-, 3- or 4-position, with the limitation that R1 and Rz are not simultane-ously hydrogen when R4 i~ a group (CHz)2NR~Rs, and to the salts of the compound~ of formula (I) with mineral or organic acid~.
The compounds (I) according to the invention in which Ar i~ a group Rl~
are preferred.
Among these, particularly preferred compounds are those in which R~ is one of the following group~:
~(CH2)n ~ N or ~~CH2)m ~R6 N
in which R~, R6 and R7 are as defined above for (I~, n is between 1 and 6, and preferably equal to 2, 3 or 4 and m is between 1 and 3, preferably equal to 1 or 2.
When the compound (I) has an a~ym~etric carbon, the 2 stereoi80mer~ form part of the invention.
According to ~ second feature 7 the pre3ent inven-- 4 - ~~5 tion relates to a method of preparing the oompound~ o~
formula (I) which i5 repre~ented by the ~ollowing reac-tion scheme:
05 IHO R3 ~H
coOC2Hs /CH - CH~
Ar - C-CH2-R3 ~ Ar - C C = O
~1 /
~ Ar - C\ C = O ~Ar - C C = O
N - N N-N
H H
POCl3 /C~c~ R4NH2 C_C\
- ~ Ar - C C-Cl - ~ Ar - C C-NH-R4 N-N N=N
S (I) Heatin8 the ketone 1 with ethyl glyoxylate at a temperature of between 80 and 140C gives the hydroxy-ketoester 2. The crude reaction mixture is then taken up in an inert ~olvent such as n-butanol, and hydrazlne hydrate is added. Refluxing for 24 hour~, give~ the hydroxypyridazinone ~, which, when heated in an acid medium, yields the 2H-pyridazin-3-one ~ by dahydration.
Heating the latter with excess pho~phoru~ oxy-chloride gives the 3-chlorop~ridazine 5. The reaction i~
;~$~
carried out without a solvent or in the pre~ence of an inert ~olvent such as acetonitrile.
Finally, heating the chlorine derivative 5 with a large exces~ of amine R4NHz at a temperature of between 05 100 and 150C~ in the presence of a ~mall amount of ammonium chloride, yield~ the compound ~I). The reaction i~ carried out without a sol~ent or in an inert solvent such as n-butanol. The product (I) i~ i~olated by ex-traction and purified by chromatography.
If desired, the resulting ba3e can be converted to a ~alt by a known method and e~pecially by reaction with an equimolecular amount of acid in a ~uitable ~ol-vent.
The compounds (I) in which Ar i~ a hydroxyphenyl or dihydroxyphenyl group are prepared from the corre~pon-ding compounds (I) in which Ar i~ a methoxyphenyl or di-methoxyphenyl ~roup by demethylation in an acid medium.
The following Example~ illustrate the preparation of compounds of formula (I) without implying a limita-tion.
drugs for many years.
In a large number of case~, the~e are sub~tance~
which are active on the cardiova~cular sy~tem and have in 06 particular a hypoten~ive or vasodilative efect, in other cases, an ~ntiinflammatory and analgesic action ha~ been mentioned for pyridazine derivative~.
Finally, French patents 2 141 697, 2 610 997 and 2 510 998 di~clo~e pyridazine derivatives which are variously ~ub~tituted on the pyridazine ring and all carry, in the 3-po~ition, an amino sub~tituent of the typ~
-NH-alkyl-N
y in which X and Y independently are hydrogen or an alkyl group or form~ with the nitrogen atom to which they are bonded, a heterocycle such as morpholine.
All the~e compounds are active on the central nervous sy tem a~ antidepres~ant~.
According to the pre~ent invention, it ha~ now been found that by modifying the nature and~or position 26 of the substituents on the pyridazine ring, compound are obtained which have lo~t their antidapre3sant activity and ac~uired a valuable activity a~ M~-type muYcarinic cholinergic ligand~
According to a fir t feature, the pre~ent inven-tion relate~ to novel pyridazine derivative~ of thegeneral formula 36 Ar_~ NH~R4 ( I~
s~
in which - Ar is a group R ~
a pyridyl or a thienyl, - R1 and Rz independently are each hydrogen, a halogen atom, a hydroxyl group, a trifluoro~ethyl group, a C~-C4 alkoxy group or a C1-C4 alkyl group;
- R3 iæ a C1-C4 alkyl group or a phenyl; and - R4 is:
1~ - a group -Alk-N
R~
in which Alk i~ a C1-Ca alkylene group, R6 i~
hydrogen or a Cl-Cs alkyl group and R~ i8 a C1-C4 alkyl group, a benzyl or a C3-C7 cycloalkyl, or R6 and R~ form, with the nitrogen atom to which they are bonded, a heterocycle selected from morpholine, thio-morpholine, pyrrolidine, N-methylpi~erazine and piperidine which is unsub~tituted or substituted by one or more methyl groups, by a hydroxyl, by a phenyl or by a benzyl;
- a group -Alk' sq;~
in which Alk' is a Cl-c3 alkylene group and R7 i8 a C1-C~ alkyl group; or - a group -A1~' ~
in which Alk' is a~ defined abov0 and substitute~ the pyridine in the 2-, 3- or 4-position, with the limitation that R1 and Rz are not simultane-ously hydrogen when R4 i~ a group (CHz)2NR~Rs, and to the salts of the compound~ of formula (I) with mineral or organic acid~.
The compounds (I) according to the invention in which Ar i~ a group Rl~
are preferred.
Among these, particularly preferred compounds are those in which R~ is one of the following group~:
~(CH2)n ~ N or ~~CH2)m ~R6 N
in which R~, R6 and R7 are as defined above for (I~, n is between 1 and 6, and preferably equal to 2, 3 or 4 and m is between 1 and 3, preferably equal to 1 or 2.
When the compound (I) has an a~ym~etric carbon, the 2 stereoi80mer~ form part of the invention.
According to ~ second feature 7 the pre3ent inven-- 4 - ~~5 tion relates to a method of preparing the oompound~ o~
formula (I) which i5 repre~ented by the ~ollowing reac-tion scheme:
05 IHO R3 ~H
coOC2Hs /CH - CH~
Ar - C-CH2-R3 ~ Ar - C C = O
~1 /
~ Ar - C\ C = O ~Ar - C C = O
N - N N-N
H H
POCl3 /C~c~ R4NH2 C_C\
- ~ Ar - C C-Cl - ~ Ar - C C-NH-R4 N-N N=N
S (I) Heatin8 the ketone 1 with ethyl glyoxylate at a temperature of between 80 and 140C gives the hydroxy-ketoester 2. The crude reaction mixture is then taken up in an inert ~olvent such as n-butanol, and hydrazlne hydrate is added. Refluxing for 24 hour~, give~ the hydroxypyridazinone ~, which, when heated in an acid medium, yields the 2H-pyridazin-3-one ~ by dahydration.
Heating the latter with excess pho~phoru~ oxy-chloride gives the 3-chlorop~ridazine 5. The reaction i~
;~$~
carried out without a solvent or in the pre~ence of an inert ~olvent such as acetonitrile.
Finally, heating the chlorine derivative 5 with a large exces~ of amine R4NHz at a temperature of between 05 100 and 150C~ in the presence of a ~mall amount of ammonium chloride, yield~ the compound ~I). The reaction i~ carried out without a sol~ent or in an inert solvent such as n-butanol. The product (I) i~ i~olated by ex-traction and purified by chromatography.
If desired, the resulting ba3e can be converted to a ~alt by a known method and e~pecially by reaction with an equimolecular amount of acid in a ~uitable ~ol-vent.
The compounds (I) in which Ar i~ a hydroxyphenyl or dihydroxyphenyl group are prepared from the corre~pon-ding compounds (I) in which Ar i~ a methoxyphenyl or di-methoxyphenyl ~roup by demethylation in an acid medium.
The following Example~ illustrate the preparation of compounds of formula (I) without implying a limita-tion.
3-[(N-Ethylpyrrolidin-2-yl)methylamino]-5-methyl-6-phenylpyridazine (SR 96185) (I) R1 = R2 = H R3 = C~3 R4 = -CH2 n N
A) 3-Chloro-5-methyl-6-phenylpyridazine l Ethyl 2-hydroxy-3-methyl-4-phenyl-4-oxobutyrate A mixture of 13.4 ~ of propiophenone and 15.3 of ethyl glyoxylate i8 heated at 135C for 5 hour3~
The resultin~ product is u~ed as ~uch for the next operation.
2 5-Methyl-6-phenyl-2H-pyridazin-3-one The crud0 product obtained above i~ di3~01ved in 150 ml of n-butanol, 9 44 ml of hydrazine hydrate are then added and the mixture is refluxed for 24 hours.
05 Part of the n-butanol i~ di~tilled at ordinary pressure in order to remove the water formed in the reaction as an azeotrope. The mixture is then concen-trated to dryness under vacuum. The residue i8 taken up in a mixture of 100 ml of acetic acid and 10 ml of con-centrated hydrochloric acid. The mixture i~ heated at 100C for 4 hours. The ~olution i8 poured into cold water and left to crystallize.
The solid is filtered off and dried.
Weight: 11.6 g M p : 218C.
3. 3-Chloro-5-methyl-6-phenylpyridazine 50 ml of pho phorus oxychloride are added to 12 g of the pyridazinone obtained above and the mixture i~
heated at 80C for 4 hour~.
The mixture is poured 510wly on to ice and ren-dered alkaline with a 20% solution of sodium hydroxide.
The precipitate is filtered off, wa~hed copiously with water and recry~tallized from i~opropanol.
9.9 g of the expected product are obtained.
M.p.: 122C.
B) SR 96185 A mixture of 2 g of the chlorine derivativ~
obtained above, 5 g of 2-aminomethyl-1-ethylpyrrolidine and 0.5 g of ammonium chloride i8 heated at 130C ~or 3 hours under an inert atmo~phere. The reaction mixture i~
poured into water and extracted with ethyl acet~te. The solution is dried and the solvent i~ evaporated off to dryness. The re~idue i~ chromatographed on a 3ilica column. Elution with an ethyl aoetate/methanol mixture (95/5 vol/vol) give3 an oil, which cry~tallizes from a small ~uantity of ethyl acetate.
~ 7 ~ 2~
Weight: 2 ~ M~p.: 92C.
3-(2-Diethylaminoethylamino)-5-methyl-6-(4-05 methoxyphenyl)pyridazine dioxalate (SR 96194 A) ~C2H5 tI) Rl = -OCH3(4), R2 = H, R3 = CH3, R4 =-CH2CH2N
A) 3-Chloro-5-methyl-6-(4-methoxyphenyl)pyridazine 1. Ethyl 2-hydroxy-3-methyl-4-(4-methoxyphenyl)-4-oxo-butyrate A mixture of 82 g of 4-methoxypropiophenone and 76.6 g of ethyl glyoxylate is heated at 135C for 15 hours.
The resulting product is u3ed as such for the next operation.
2. 5-Methyl-6-(4-methoxyph0nyl)-2H-pyridazin-3-one The crude product obtained ahove i~ di~olved in 250 ml of n-butanol, 38 g of hydrazine hydrate are then added and the mixture is refluxed for 24 hours.
Part of the n-butanol is di~tilled at ordinary pressure in order to remo~e the water formed in the reaction as an azeotrope. The mixture i5 then concen-trated to dryne~s under vacuum. The residue is taken up in a mi~ture of~460 ml of acetic acid and 50 ml of con-centrated hydrochloric acid. The mixture is heated at 100C for 4 hours. The ~olution i~ poured into cold water and left to crystallize.
The solid i~ filtered off and dried.
Weight: 40 g M~p.: 216C.
3. 3-Chloro-5-methyl-6-(4-methoxyphenyl)pyridazine 2~0 ml of phosphorus oxychloride are added to 10 g of the pyridazinone obtained above and the mixture Z~?5q~
is heated at 80C for 10 hours.
The mixture is poured ~lowly on to ice and ren-dered alkaline with a 20% solution of sodium hydroxide.
The precipitate is filtered o~f, wa~hed copiou ly 05 with water and recrystallized from methanol.
9 g of the expected product are obtained.
M.p.: 132C.
B) SR 96194 A
A mixture of 2.3 g of the chlorine derivative obtained above, 5 g o~ N,N-diethylethylenediamine and 0.6 g of ammonium chloride is heated at 135C for 4 hours ~nder an inert atmo~phere. The reaction mixture is poured into water and extracted with et~yl acetate. The solution is dried and the solvent is evaporated of to dryness.
Wei~ht: 2.3 g.
n~Q~La~
The above base is dissolved in hot isopropanol~
and a solution of 2.2 equivalents of oxalic acid in the minimum quantity of boiling i~opropanol is added. The dioxalate precipitates on cooling. It is filtered off and recrystallized rom ab~olute ethanol.
M.p.: 136C.
A) The 3-chloropyridazines collated in Tables 1 and 2 below are obtained by followin~ the procedure indicated in Example lA, but varying the starting ketone:
- 9 - ~
A) 3-Chloro-5-methyl-6-phenylpyridazine l Ethyl 2-hydroxy-3-methyl-4-phenyl-4-oxobutyrate A mixture of 13.4 ~ of propiophenone and 15.3 of ethyl glyoxylate i8 heated at 135C for 5 hour3~
The resultin~ product is u~ed as ~uch for the next operation.
2 5-Methyl-6-phenyl-2H-pyridazin-3-one The crud0 product obtained above i~ di3~01ved in 150 ml of n-butanol, 9 44 ml of hydrazine hydrate are then added and the mixture is refluxed for 24 hours.
05 Part of the n-butanol i~ di~tilled at ordinary pressure in order to remove the water formed in the reaction as an azeotrope. The mixture is then concen-trated to dryness under vacuum. The residue i8 taken up in a mixture of 100 ml of acetic acid and 10 ml of con-centrated hydrochloric acid. The mixture i~ heated at 100C for 4 hours. The ~olution i8 poured into cold water and left to crystallize.
The solid is filtered off and dried.
Weight: 11.6 g M p : 218C.
3. 3-Chloro-5-methyl-6-phenylpyridazine 50 ml of pho phorus oxychloride are added to 12 g of the pyridazinone obtained above and the mixture i~
heated at 80C for 4 hour~.
The mixture is poured 510wly on to ice and ren-dered alkaline with a 20% solution of sodium hydroxide.
The precipitate is filtered off, wa~hed copiously with water and recry~tallized from i~opropanol.
9.9 g of the expected product are obtained.
M.p.: 122C.
B) SR 96185 A mixture of 2 g of the chlorine derivativ~
obtained above, 5 g of 2-aminomethyl-1-ethylpyrrolidine and 0.5 g of ammonium chloride i8 heated at 130C ~or 3 hours under an inert atmo~phere. The reaction mixture i~
poured into water and extracted with ethyl acet~te. The solution is dried and the solvent i~ evaporated off to dryness. The re~idue i~ chromatographed on a 3ilica column. Elution with an ethyl aoetate/methanol mixture (95/5 vol/vol) give3 an oil, which cry~tallizes from a small ~uantity of ethyl acetate.
~ 7 ~ 2~
Weight: 2 ~ M~p.: 92C.
3-(2-Diethylaminoethylamino)-5-methyl-6-(4-05 methoxyphenyl)pyridazine dioxalate (SR 96194 A) ~C2H5 tI) Rl = -OCH3(4), R2 = H, R3 = CH3, R4 =-CH2CH2N
A) 3-Chloro-5-methyl-6-(4-methoxyphenyl)pyridazine 1. Ethyl 2-hydroxy-3-methyl-4-(4-methoxyphenyl)-4-oxo-butyrate A mixture of 82 g of 4-methoxypropiophenone and 76.6 g of ethyl glyoxylate is heated at 135C for 15 hours.
The resulting product is u3ed as such for the next operation.
2. 5-Methyl-6-(4-methoxyph0nyl)-2H-pyridazin-3-one The crude product obtained ahove i~ di~olved in 250 ml of n-butanol, 38 g of hydrazine hydrate are then added and the mixture is refluxed for 24 hours.
Part of the n-butanol is di~tilled at ordinary pressure in order to remo~e the water formed in the reaction as an azeotrope. The mixture i5 then concen-trated to dryne~s under vacuum. The residue is taken up in a mi~ture of~460 ml of acetic acid and 50 ml of con-centrated hydrochloric acid. The mixture is heated at 100C for 4 hours. The ~olution i~ poured into cold water and left to crystallize.
The solid i~ filtered off and dried.
Weight: 40 g M~p.: 216C.
3. 3-Chloro-5-methyl-6-(4-methoxyphenyl)pyridazine 2~0 ml of phosphorus oxychloride are added to 10 g of the pyridazinone obtained above and the mixture Z~?5q~
is heated at 80C for 10 hours.
The mixture is poured ~lowly on to ice and ren-dered alkaline with a 20% solution of sodium hydroxide.
The precipitate is filtered o~f, wa~hed copiou ly 05 with water and recrystallized from methanol.
9 g of the expected product are obtained.
M.p.: 132C.
B) SR 96194 A
A mixture of 2.3 g of the chlorine derivative obtained above, 5 g o~ N,N-diethylethylenediamine and 0.6 g of ammonium chloride is heated at 135C for 4 hours ~nder an inert atmo~phere. The reaction mixture is poured into water and extracted with et~yl acetate. The solution is dried and the solvent is evaporated of to dryness.
Wei~ht: 2.3 g.
n~Q~La~
The above base is dissolved in hot isopropanol~
and a solution of 2.2 equivalents of oxalic acid in the minimum quantity of boiling i~opropanol is added. The dioxalate precipitates on cooling. It is filtered off and recrystallized rom ab~olute ethanol.
M.p.: 136C.
A) The 3-chloropyridazines collated in Tables 1 and 2 below are obtained by followin~ the procedure indicated in Example lA, but varying the starting ketone:
- 9 - ~
4 `~r C 1 R1 _R:~ Phy~3ical con~tant~
.
C1(4) H CH3 M.p.: 178-180C
Cl(4) H CH~CH3 M.p.: 86C
Cl(2) Clt4) CH3 M.p.: 116C
C1(3) H CH3 M.p.: 95C
CF3(3) H CH3 M p.: 120~C
F(4) H CH3 M.p.: 153C
CH3(4~ H CH3 M.p.: 165-166C
Cl(4) H CH~CH2CH3 M.p.: 95C
OCH3 ( 4 ) H CH2CH2CH3 M . p .: 68-69 C
H H CH;3 M . p .: 123- 124 C
H H phenyl M . p .: 1 15 C
Cl(3) Cl(!ij CH3 M.p.: 104C
Cl(3) Cl(4~ CH3 M.p.: 167C
H H CHxClH2CHs M . p .: 60 C
OCU3 ( 2 ) _ CH3 M . p . 74 C
- 10 ~
05 Ar ~ Cl Ar Rs Physical constant~
Pyrid-2-yl CH3 135C
Pyrid-3-yl CH3 142C
Thien-2-yl CH3 99C
B) The compounds (I) collated in Tab~ 8S 3 and 4 are ob-tained from the chlorine derivative~ of Example~ lA, 2A
and 3A by ollowing the techni~ue of Example lB, varying the amines used. These compounds are characterized by their meltin~ ~oint (M.p.) or their optical rotation 20 ~a]~.
, , .
~s~
05 4 ~ ~i ~ NH-R4 Rl N=N
Ex SR ref. Rl R2 R3 R4 Salt or base n n M.p. or [a]~
3 96181 H H(CHz3z-CH3 C~2 _~ Ba~e 94C
4 96198 Cl(4) H CH3 .. .. Ba~e 90C
96222 Cl(2)Cl(4) CH3 .. .. Base 113C
6 46004A CFs(3) H CH3 ~, .. Dihydro-chloride 0.5H~0 180C
tdOno)mpo~i-7 96204A H H CH3 CH2~ ~ Dihydro-N ~ 2h21ocide 8 96240A Cl(4) H CH3 ~, .. Dihydro-. chloride 9 46005A Cl(3) H CHa .. .. Hydro-chloride lHzO 182C
45991A Cl(43 H CHzCH3 " .. Dihydro-chloride . 21~-217C
ll 96220A H H CH3 CH2 ~ Dihydro-_N ClHlOrlod9C
05 12 96205A H H CH3 (CH2)2 ~ Dihydro-N chloride . lHzO 133C
13 96239A Cl(4) H CH3 ,. .. Dihydro-chloride 14 46035A Cl(3) H CH3 CH2 n Dihydro-N ClHlOrlde2C
46079A Cl(4) H CH2CH3 .. Fu6m3arla65~ec 16 96193A oCH3(4) H CH3 CH2CH2-N 0 Dihydro-V 2hl900cide 2~
17 96197A Cl(4) H CH3 .. .. Dihydro-chloride 0.5HzO 247C
18 96223A Cl(2) Cl(4) CH3 .. .. Dihydro-250C (de-composition) 19 45964A CF3(3) H CH3 ., .. Dihydro-chloride 45944A Gl(3) H CH3 .. ,. cDhhloYrdrde 1.5HzO 212C
21 46179A Cl(3) Cl(5) CH3 ., " Dhhlyrride lHzO 198C
- 13 - ~ S~3~
22 46197A Cl(4) H CHzCHaCH2-c~J2-N ~ Difumarate ~ 168-17~C
05 23 46222A F(4) H CHa " .. Dihydro-chloride 24 46223A CH3(4) H CH3 ,. ,. Fumarate 46224A Cl(3~ Cl(4) CH3 ., ,. cDhhlYodride ~28-230C
26 46405A Cl(4~ H CH3CHz-CHz-N(iPr) 2 Dihydro-lChlOride 157-160~C
27 46534A Cl(4) H n.CaH7 .. .. Oum5Har20t~
28 46431A Cl(4) H CHaCH2-CH2-N ~ O Dihydro-~ H 2h26or228Oec 29 46432A Cl(4) H CH3CH2-CH2-N 3 chloride ~
46514A Cl(4) H CHaCHz-CH2-N Dihydro-chloride 31 46637ACl(4~ H n.C3H7 ll ll Dihydro-chloride lHzO 205C
32 46636A H H n.C3H7 ll ll Dihydro-chloride lHzO 207C
33 96224A Clt4) H C~l3 CH2CHz-N 1D3loxclate 34 96230A Cl(2) Cl(4) CH3 " .. Dioxalate 05 lHzO 106C
96194A OCH3(4) H CH3 ., " Dio~alate 36 96266A Cl(3) H CH3 " ., Dioxalate ~CH3 37 96232A Cl(4) H CH3 CH2CH2N Dihydro-. CH3 c2h58or259ec 38 46010A Cl(4) H CH2CH3 " " Dihydro-chloride 0.3H~0 . 223-22~C
39 46081A F(4) H CH3 " " Dihydro-chloride ~0 . 233-235C
46082A CH3 (4) H CH3 ., " Dihydro-chloride . CH3 235-237C
41 45960A Cl(4) H CH3 (cH2)3-N Dihydro-CH3 chloride 42 46080A Cl(4) H CH~CH3 " " Dihydro-chloride 0.5H20 202C
CH3 ~
43 46731A Cl(4) H CH3 CH2-CHz-N \ Fumarate ~ 213-215C
44 46730A H H n. C3H7 " " 2 5 Fumarate - 15 - ~ 3 ~
~45 96231A Cl(4) H CH3CHzCHz~H-CHa OlHXzala~e 05 /__~
46 46961A Cl(4) H CHa(CH233-N O Dihydro-\_/ 2hQ-25i2deC
47 45988A Cl(4) H CH3(cH2)4-N Dihydro-\CH3 chloride 48 45989ACl(4) H CHzCH3 ,l ,l Dihydro-2HhlOride 49 46377A H H n. C3H7( CHz~z~CH2C6H6 Dihydro-Pr chloride 0.5H20 5Q 46532A H H n.CaH7CH2-CH2- 18~-184 C
N ~ 152C
\/
51 46728ACl(4) H CHa (CH2)z- Dihydro-~ chlorido -N -CH2C6H5 0.5H20 \_ 224-226C
52 9629QA H H CHaCH2-CH~-N S Diox~late ~ 181 C
.
2~ 5~.
53 96291 H H C~3 (C~z)z- Ba~e 98C
0~
54 46352A H H n.CaH7 CHz-CHz-N(iPr)z Fumarate 46359A H H ,. (CHz)z-~CHzCH3 Fumarate (~Hz)3CHa 113~114C
56 46378A H H .l (CHz)2 N(nBu)z Fumarate 57 46533A H H " (CHz)z-N(nPr)z Fumarate 58 46180Cl(3) Cl(5) CH3 CH2 ~ Dihydro-N chloride 59 46195Cl(4) H CzH~ CH2 / N Fumarate 46196CH3(4) H CH3 CH2- ~ Ba~e 106C
61 96268Cl(4~ H CH3 C(+2) ~ a~ 65 N (2% CHCl3) 62 96269Cl(4) H CH3 CH2 ~ Yallow oil C2H5 (2% CHCl3;
63 96272 H H n.C3H7(3 D;.hydro-. 218C
64 46433 H H n.CaH7CH2- ~/ a22 = +68.6 C2H5 ~HCl3) 46434 H H n.C3H7( ~ a2l = _70o C2H5 CHCl3) 66 46430 F(4) H CH3CH2 ~ Dhhlydrride 67 46514 Cl~4) H CH3 r-~ Dihydro-CH2-CH2-N ~ chloride \ ~ lH20 174C
B8 46636 H H n.C3H7 / ~ Dihydro-. CH2-CH2-N ~ chloride ~ lH20 207C
69 46637 Cl(4) H n.C3H7CH2-CH2-N ~ chlorid~
~ lH20 205C
~7046 ~ U H ~ C~Hc~2~3 ~ He lf~=~r~te 2~5~
¦71 47186 H H C~H6 CH2- ~ Fumarate C2~15 05 .
72 47226 H H CsH~ CH2-CH2- ~ Se~qui-CH3 f1~1acate 73 96305OH(2) H CH3 CH2 ~ 0.3H20 C~Hs 74 96306ACl(4) H CH3 CH3 0 DchhlYdide 0 5Hz3 96307ACl(4) H CH3 CH2CH2N ~ 0179Hocate 76 96308A H H CH3 CH2CH2N ~ Hydro-B chloride . _ 196C
Ar ~ ~ NH-Alk-N
05 N_N R6 ~x. SR ref. Ar R~ ~R6 Salt or base n' Alk- ~ M.p.
7746457A Pyrid-2-yl CH3CHz-CHz-N(iPr)z Fumarate 1~ 7846578A Pyrid-3-yl CHa \ Fumarate 7946640A Pyrid-2-yl CH3CH2-CH2-N ~ 146C
8046641A Thien-2-yl CH3 .l .l Dihydro-~ ~ 0.5HzO
The product~ acoording to the invention were studied or their pharmacological propertie~ and in par ticular for their affinity for the mu~carinic choliner~ic receptors.
In vitro, the compounds (I) were te~ted according to the technique de~cribed by Wat~on J.D. et al. (Life Science, 1982, ~1, 2019-2029) for their activity on the Ml-type receptor~, and according to the techni~ue de3-cribed by Hammer R. et al. ~Nature, 1980, 2~, 90-92) and Hulme E.C. et al. (Molecular Pharmacology~ 1978, 1~, 737-3~ 750) for their activity on the M2-type receptor~
~d~ 5~
The compounds according to the inventlon ha~e a good affinity for the Ml-type receptor~ and a marked specificity for the Ml-kype central receptor~ campared with the M~-type peripheral receptors.
05 By way of example, the compound SR 96181 ~howed a 50% inhibitory concentration, expre~ed in micromol, of 0.03 on the ligand or the Ml receptor~ and 0.35 on the li~and for the Mz receptor~.
Likewi~e, the compound SR 96204 A showed 50% in-hibitory concentrations of 0.75 and 50 on the ligand for the Ml and M2 receptor~ re~pectively.
In vivo, the compounds according to the invention were 3ubjected to the te~t for the rotation~ induced by pirenzepine, de3cribed by Wormæ P. et al. (Psychopharma-cology, 1987, ~3, 489-493), with the modification that oral admini~tration of the product~ took place 4 hours before instead of 30 minutes before the injection of pirenzepine.
At a do~e of 3 mg per kg of body weight, the product~ according to the invention stron~ly inhibit the number of rotation~ induced by pirenzepine.
Thus, by way of example, the compound~ SR 96181 ~nd SR 96204 A inhibit the rotation~ induced by piren-zepine to the extent of 71% and 67% respectively.
Furthermore, the re~ult~ obtained with variou~
compound~ of formula (I3 will be found in Table 5.
Thi~ Table ~hows the re3ult3 obtained with the only compound of French patent n~ 2 510 998 ~ub~tituted by an alkyl group in the 5-po~ition and described in said patent a~ an antidepre~ant.
Thi~ compound ha~ the formula c~3 ~ </ ~/- NH - Cll2Cll2N ~ 0 Compound A
Product % inhibition of pirenzepine-induced n rotations at a dose of 3 mg/kg per os SR 96197 A -70% ~*
SR 96224 A -59% **
15 SR 96231 A -40% *~
SR 96232 A -40% **
SR 96223 A -74%
SR 96230 A -41% *~
SR 46964 A -3B% ~*
Compound A -20% *
Student t te~t 2 * P < ~.05 5 ** p c o Ol At a dose of 3 mgfkg per 08, the compound~
accordin~ to the invention inhibit the number of rota-tions induced by pirenzepine wi-th an inten~ity 2 to 3.5 times greater than the compound o the prior art.
Finally, the compounds accordin~ to the invention showed no signs of toxicity at the dose~ at which they are active.
Conse~uently, the compounds (I~ can be used as drug~.
- 22 ~
The re~ult3 indicated make it pos~ible to con-sider using the products according to the invention in all cases where a cholinergic deficiency is Pvident, especially for the treatment of memorY and cognitive 05 disorders and degenerative syndromes associ~ted with senescence and with ~enile dementia.
According to another of it~ features, the pre~ent patent application therefore relates to pharmaceutical compositions in which at least one of the compounds of formula (I) or one of their pharmaceutically acceptable salts is present as the active ingredient.
In the pharmaceutical compo~itions of the pre~ent invention for oral, sublingual, percutaneous or rectal admini~tration, the active ingredients of formula (I) above can be administered to humans in unit forms of adminiætration, mixed with the conventional pharmaceuti-cal excipients, especially for the treatment of senile dementia. Appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powder~, granules and solutions or suspensions to be taken orally, forms for sublingual and buccal administr~tion, form~ for subcutaneous, intra-muscular or intravenous administration and forms for rectal admini~tration.
To obtain the desired effect, the dose of active ~principle can vary between 20 and 500 mg per day.
Each unit dose can contain from 5 to 200 mg of active ingredient in combination with a pharmaceutioal excipient. This unit dose can b~ administered 1 to 4 times a day.
I~ a solid compo~ition in the form of tablets iæ
prepared, the main active ingredient i~ mixed with a pharmaceutical vehicle ~uch as gelatin, starch, lactose, magne~ium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or othsr appropriate S~
substance~ or they can be treated 80 a~ ko have a pro-longed or delayed activity and 80 a~ to release a pre-determined a,~ount of active principle continuou~lY~
A preparation in the form o~ gelatin capsules i~
05 obtained by mixing the active ingredient with a diluent and pouring the re~ulting mixture into 30ft or hard gelatin capsule~.
WatPr-dispersible granule~ or powder3 can contain the active ingredient mixed with disper~ant~ or wetting agent~ or with su~pending agentc ~uch a~ polyvinylpyr-rolidone, as well a~ with sweetener~ or ta~te corrector~.
Rectal administration i~ effected using ~upposi-tories which are prepared with binder3 melting at the rectal temperature, ~or example cacao butter or poly-ethylene glycols.
Parenteral administration is effected ucingaqueou~ ~u~pen~ion~ otonic 3aline solution~ or ~terile and inJectable ~olutions which contain pharmacologically compatible disperAant~ and~or wetting agent~, example~
bein~ propylene glycol and butylene glycol.
The active principle can al~o be formulated as microcapsule~, if appropriate with one or more excipientæ
or additive~.
A~ pharmaceutical preparation~, it is po~ible to prepare ths following gelatin cap~ule~:
SR 96204 A 0.010 g Lacto~e 0.050 g Magne~ium stearate 0.005 g The above ingredient~ are intimately mixed and the mix-ture i~ poured into hard gelatin cap~ule~.
SR 96197 A 0.010 g Lacto~e 0.050 g Magnesium stearate 0.005 g ~0
.
C1(4) H CH3 M.p.: 178-180C
Cl(4) H CH~CH3 M.p.: 86C
Cl(2) Clt4) CH3 M.p.: 116C
C1(3) H CH3 M.p.: 95C
CF3(3) H CH3 M p.: 120~C
F(4) H CH3 M.p.: 153C
CH3(4~ H CH3 M.p.: 165-166C
Cl(4) H CH~CH2CH3 M.p.: 95C
OCH3 ( 4 ) H CH2CH2CH3 M . p .: 68-69 C
H H CH;3 M . p .: 123- 124 C
H H phenyl M . p .: 1 15 C
Cl(3) Cl(!ij CH3 M.p.: 104C
Cl(3) Cl(4~ CH3 M.p.: 167C
H H CHxClH2CHs M . p .: 60 C
OCU3 ( 2 ) _ CH3 M . p . 74 C
- 10 ~
05 Ar ~ Cl Ar Rs Physical constant~
Pyrid-2-yl CH3 135C
Pyrid-3-yl CH3 142C
Thien-2-yl CH3 99C
B) The compounds (I) collated in Tab~ 8S 3 and 4 are ob-tained from the chlorine derivative~ of Example~ lA, 2A
and 3A by ollowing the techni~ue of Example lB, varying the amines used. These compounds are characterized by their meltin~ ~oint (M.p.) or their optical rotation 20 ~a]~.
, , .
~s~
05 4 ~ ~i ~ NH-R4 Rl N=N
Ex SR ref. Rl R2 R3 R4 Salt or base n n M.p. or [a]~
3 96181 H H(CHz3z-CH3 C~2 _~ Ba~e 94C
4 96198 Cl(4) H CH3 .. .. Ba~e 90C
96222 Cl(2)Cl(4) CH3 .. .. Base 113C
6 46004A CFs(3) H CH3 ~, .. Dihydro-chloride 0.5H~0 180C
tdOno)mpo~i-7 96204A H H CH3 CH2~ ~ Dihydro-N ~ 2h21ocide 8 96240A Cl(4) H CH3 ~, .. Dihydro-. chloride 9 46005A Cl(3) H CHa .. .. Hydro-chloride lHzO 182C
45991A Cl(43 H CHzCH3 " .. Dihydro-chloride . 21~-217C
ll 96220A H H CH3 CH2 ~ Dihydro-_N ClHlOrlod9C
05 12 96205A H H CH3 (CH2)2 ~ Dihydro-N chloride . lHzO 133C
13 96239A Cl(4) H CH3 ,. .. Dihydro-chloride 14 46035A Cl(3) H CH3 CH2 n Dihydro-N ClHlOrlde2C
46079A Cl(4) H CH2CH3 .. Fu6m3arla65~ec 16 96193A oCH3(4) H CH3 CH2CH2-N 0 Dihydro-V 2hl900cide 2~
17 96197A Cl(4) H CH3 .. .. Dihydro-chloride 0.5HzO 247C
18 96223A Cl(2) Cl(4) CH3 .. .. Dihydro-250C (de-composition) 19 45964A CF3(3) H CH3 ., .. Dihydro-chloride 45944A Gl(3) H CH3 .. ,. cDhhloYrdrde 1.5HzO 212C
21 46179A Cl(3) Cl(5) CH3 ., " Dhhlyrride lHzO 198C
- 13 - ~ S~3~
22 46197A Cl(4) H CHzCHaCH2-c~J2-N ~ Difumarate ~ 168-17~C
05 23 46222A F(4) H CHa " .. Dihydro-chloride 24 46223A CH3(4) H CH3 ,. ,. Fumarate 46224A Cl(3~ Cl(4) CH3 ., ,. cDhhlYodride ~28-230C
26 46405A Cl(4~ H CH3CHz-CHz-N(iPr) 2 Dihydro-lChlOride 157-160~C
27 46534A Cl(4) H n.CaH7 .. .. Oum5Har20t~
28 46431A Cl(4) H CHaCH2-CH2-N ~ O Dihydro-~ H 2h26or228Oec 29 46432A Cl(4) H CH3CH2-CH2-N 3 chloride ~
46514A Cl(4) H CHaCHz-CH2-N Dihydro-chloride 31 46637ACl(4~ H n.C3H7 ll ll Dihydro-chloride lHzO 205C
32 46636A H H n.C3H7 ll ll Dihydro-chloride lHzO 207C
33 96224A Clt4) H C~l3 CH2CHz-N 1D3loxclate 34 96230A Cl(2) Cl(4) CH3 " .. Dioxalate 05 lHzO 106C
96194A OCH3(4) H CH3 ., " Dio~alate 36 96266A Cl(3) H CH3 " ., Dioxalate ~CH3 37 96232A Cl(4) H CH3 CH2CH2N Dihydro-. CH3 c2h58or259ec 38 46010A Cl(4) H CH2CH3 " " Dihydro-chloride 0.3H~0 . 223-22~C
39 46081A F(4) H CH3 " " Dihydro-chloride ~0 . 233-235C
46082A CH3 (4) H CH3 ., " Dihydro-chloride . CH3 235-237C
41 45960A Cl(4) H CH3 (cH2)3-N Dihydro-CH3 chloride 42 46080A Cl(4) H CH~CH3 " " Dihydro-chloride 0.5H20 202C
CH3 ~
43 46731A Cl(4) H CH3 CH2-CHz-N \ Fumarate ~ 213-215C
44 46730A H H n. C3H7 " " 2 5 Fumarate - 15 - ~ 3 ~
~45 96231A Cl(4) H CH3CHzCHz~H-CHa OlHXzala~e 05 /__~
46 46961A Cl(4) H CHa(CH233-N O Dihydro-\_/ 2hQ-25i2deC
47 45988A Cl(4) H CH3(cH2)4-N Dihydro-\CH3 chloride 48 45989ACl(4) H CHzCH3 ,l ,l Dihydro-2HhlOride 49 46377A H H n. C3H7( CHz~z~CH2C6H6 Dihydro-Pr chloride 0.5H20 5Q 46532A H H n.CaH7CH2-CH2- 18~-184 C
N ~ 152C
\/
51 46728ACl(4) H CHa (CH2)z- Dihydro-~ chlorido -N -CH2C6H5 0.5H20 \_ 224-226C
52 9629QA H H CHaCH2-CH~-N S Diox~late ~ 181 C
.
2~ 5~.
53 96291 H H C~3 (C~z)z- Ba~e 98C
0~
54 46352A H H n.CaH7 CHz-CHz-N(iPr)z Fumarate 46359A H H ,. (CHz)z-~CHzCH3 Fumarate (~Hz)3CHa 113~114C
56 46378A H H .l (CHz)2 N(nBu)z Fumarate 57 46533A H H " (CHz)z-N(nPr)z Fumarate 58 46180Cl(3) Cl(5) CH3 CH2 ~ Dihydro-N chloride 59 46195Cl(4) H CzH~ CH2 / N Fumarate 46196CH3(4) H CH3 CH2- ~ Ba~e 106C
61 96268Cl(4~ H CH3 C(+2) ~ a~ 65 N (2% CHCl3) 62 96269Cl(4) H CH3 CH2 ~ Yallow oil C2H5 (2% CHCl3;
63 96272 H H n.C3H7(3 D;.hydro-. 218C
64 46433 H H n.CaH7CH2- ~/ a22 = +68.6 C2H5 ~HCl3) 46434 H H n.C3H7( ~ a2l = _70o C2H5 CHCl3) 66 46430 F(4) H CH3CH2 ~ Dhhlydrride 67 46514 Cl~4) H CH3 r-~ Dihydro-CH2-CH2-N ~ chloride \ ~ lH20 174C
B8 46636 H H n.C3H7 / ~ Dihydro-. CH2-CH2-N ~ chloride ~ lH20 207C
69 46637 Cl(4) H n.C3H7CH2-CH2-N ~ chlorid~
~ lH20 205C
~7046 ~ U H ~ C~Hc~2~3 ~ He lf~=~r~te 2~5~
¦71 47186 H H C~H6 CH2- ~ Fumarate C2~15 05 .
72 47226 H H CsH~ CH2-CH2- ~ Se~qui-CH3 f1~1acate 73 96305OH(2) H CH3 CH2 ~ 0.3H20 C~Hs 74 96306ACl(4) H CH3 CH3 0 DchhlYdide 0 5Hz3 96307ACl(4) H CH3 CH2CH2N ~ 0179Hocate 76 96308A H H CH3 CH2CH2N ~ Hydro-B chloride . _ 196C
Ar ~ ~ NH-Alk-N
05 N_N R6 ~x. SR ref. Ar R~ ~R6 Salt or base n' Alk- ~ M.p.
7746457A Pyrid-2-yl CH3CHz-CHz-N(iPr)z Fumarate 1~ 7846578A Pyrid-3-yl CHa \ Fumarate 7946640A Pyrid-2-yl CH3CH2-CH2-N ~ 146C
8046641A Thien-2-yl CH3 .l .l Dihydro-~ ~ 0.5HzO
The product~ acoording to the invention were studied or their pharmacological propertie~ and in par ticular for their affinity for the mu~carinic choliner~ic receptors.
In vitro, the compounds (I) were te~ted according to the technique de~cribed by Wat~on J.D. et al. (Life Science, 1982, ~1, 2019-2029) for their activity on the Ml-type receptor~, and according to the techni~ue de3-cribed by Hammer R. et al. ~Nature, 1980, 2~, 90-92) and Hulme E.C. et al. (Molecular Pharmacology~ 1978, 1~, 737-3~ 750) for their activity on the M2-type receptor~
~d~ 5~
The compounds according to the inventlon ha~e a good affinity for the Ml-type receptor~ and a marked specificity for the Ml-kype central receptor~ campared with the M~-type peripheral receptors.
05 By way of example, the compound SR 96181 ~howed a 50% inhibitory concentration, expre~ed in micromol, of 0.03 on the ligand or the Ml receptor~ and 0.35 on the li~and for the Mz receptor~.
Likewi~e, the compound SR 96204 A showed 50% in-hibitory concentrations of 0.75 and 50 on the ligand for the Ml and M2 receptor~ re~pectively.
In vivo, the compounds according to the invention were 3ubjected to the te~t for the rotation~ induced by pirenzepine, de3cribed by Wormæ P. et al. (Psychopharma-cology, 1987, ~3, 489-493), with the modification that oral admini~tration of the product~ took place 4 hours before instead of 30 minutes before the injection of pirenzepine.
At a do~e of 3 mg per kg of body weight, the product~ according to the invention stron~ly inhibit the number of rotation~ induced by pirenzepine.
Thus, by way of example, the compound~ SR 96181 ~nd SR 96204 A inhibit the rotation~ induced by piren-zepine to the extent of 71% and 67% respectively.
Furthermore, the re~ult~ obtained with variou~
compound~ of formula (I3 will be found in Table 5.
Thi~ Table ~hows the re3ult3 obtained with the only compound of French patent n~ 2 510 998 ~ub~tituted by an alkyl group in the 5-po~ition and described in said patent a~ an antidepre~ant.
Thi~ compound ha~ the formula c~3 ~ </ ~/- NH - Cll2Cll2N ~ 0 Compound A
Product % inhibition of pirenzepine-induced n rotations at a dose of 3 mg/kg per os SR 96197 A -70% ~*
SR 96224 A -59% **
15 SR 96231 A -40% *~
SR 96232 A -40% **
SR 96223 A -74%
SR 96230 A -41% *~
SR 46964 A -3B% ~*
Compound A -20% *
Student t te~t 2 * P < ~.05 5 ** p c o Ol At a dose of 3 mgfkg per 08, the compound~
accordin~ to the invention inhibit the number of rota-tions induced by pirenzepine wi-th an inten~ity 2 to 3.5 times greater than the compound o the prior art.
Finally, the compounds accordin~ to the invention showed no signs of toxicity at the dose~ at which they are active.
Conse~uently, the compounds (I~ can be used as drug~.
- 22 ~
The re~ult3 indicated make it pos~ible to con-sider using the products according to the invention in all cases where a cholinergic deficiency is Pvident, especially for the treatment of memorY and cognitive 05 disorders and degenerative syndromes associ~ted with senescence and with ~enile dementia.
According to another of it~ features, the pre~ent patent application therefore relates to pharmaceutical compositions in which at least one of the compounds of formula (I) or one of their pharmaceutically acceptable salts is present as the active ingredient.
In the pharmaceutical compo~itions of the pre~ent invention for oral, sublingual, percutaneous or rectal admini~tration, the active ingredients of formula (I) above can be administered to humans in unit forms of adminiætration, mixed with the conventional pharmaceuti-cal excipients, especially for the treatment of senile dementia. Appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powder~, granules and solutions or suspensions to be taken orally, forms for sublingual and buccal administr~tion, form~ for subcutaneous, intra-muscular or intravenous administration and forms for rectal admini~tration.
To obtain the desired effect, the dose of active ~principle can vary between 20 and 500 mg per day.
Each unit dose can contain from 5 to 200 mg of active ingredient in combination with a pharmaceutioal excipient. This unit dose can b~ administered 1 to 4 times a day.
I~ a solid compo~ition in the form of tablets iæ
prepared, the main active ingredient i~ mixed with a pharmaceutical vehicle ~uch as gelatin, starch, lactose, magne~ium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or othsr appropriate S~
substance~ or they can be treated 80 a~ ko have a pro-longed or delayed activity and 80 a~ to release a pre-determined a,~ount of active principle continuou~lY~
A preparation in the form o~ gelatin capsules i~
05 obtained by mixing the active ingredient with a diluent and pouring the re~ulting mixture into 30ft or hard gelatin capsule~.
WatPr-dispersible granule~ or powder3 can contain the active ingredient mixed with disper~ant~ or wetting agent~ or with su~pending agentc ~uch a~ polyvinylpyr-rolidone, as well a~ with sweetener~ or ta~te corrector~.
Rectal administration i~ effected using ~upposi-tories which are prepared with binder3 melting at the rectal temperature, ~or example cacao butter or poly-ethylene glycols.
Parenteral administration is effected ucingaqueou~ ~u~pen~ion~ otonic 3aline solution~ or ~terile and inJectable ~olutions which contain pharmacologically compatible disperAant~ and~or wetting agent~, example~
bein~ propylene glycol and butylene glycol.
The active principle can al~o be formulated as microcapsule~, if appropriate with one or more excipientæ
or additive~.
A~ pharmaceutical preparation~, it is po~ible to prepare ths following gelatin cap~ule~:
SR 96204 A 0.010 g Lacto~e 0.050 g Magne~ium stearate 0.005 g The above ingredient~ are intimately mixed and the mix-ture i~ poured into hard gelatin cap~ule~.
SR 96197 A 0.010 g Lacto~e 0.050 g Magnesium stearate 0.005 g ~0
Claims (9)
1. A compound of the formula (I) in which - Ar is a group a pyridyl or a thienyl, - R1 and Rz independently are each hydrogen, a halogen atom, a hydroxyl group, a trifluoromethyl group, a C1-C4 alkoxy group or a C1-C4 alkyl group, - R3 is a C1-C4 alkyl group or a phenyl; and - R4 is:
-a group in which Alk is a C1-C6 alkylene group, R6 is hydrogen or a C1-C6 alkyl group and R6 is a C1-C4 alkyl group, a benzyl or a C3 -C7 cycloalkyl, or R5 and R6 form, with the nitrogen atom to which they are bonded, a heterocycle selected from morpholine, thio-morpholine, pyrrolidine, N-methylpiperazine and piperidine which is unsubstituted or substituted by one or more methyl groups, by a hydroxyl, by a phenyl or by a benzyl;
- a group in which Alk' is a C1-C3 alkylene group and R7 is a C1-C4 alkyl group; or - a group in which Alk' is as defined above and substitutes the pyridine in the 2-, 3- or 4-position, with the limitation that R1 and R2 are not simultane-ously hydrogen when R4 is a group (CHz)zNR6R5) and its salts with mineral or organic acids.
-a group in which Alk is a C1-C6 alkylene group, R6 is hydrogen or a C1-C6 alkyl group and R6 is a C1-C4 alkyl group, a benzyl or a C3 -C7 cycloalkyl, or R5 and R6 form, with the nitrogen atom to which they are bonded, a heterocycle selected from morpholine, thio-morpholine, pyrrolidine, N-methylpiperazine and piperidine which is unsubstituted or substituted by one or more methyl groups, by a hydroxyl, by a phenyl or by a benzyl;
- a group in which Alk' is a C1-C3 alkylene group and R7 is a C1-C4 alkyl group; or - a group in which Alk' is as defined above and substitutes the pyridine in the 2-, 3- or 4-position, with the limitation that R1 and R2 are not simultane-ously hydrogen when R4 is a group (CHz)zNR6R5) and its salts with mineral or organic acids.
2. A compound according to claim 1 in which Ar is a group
3. A compound according to claim 1 or claim 2 of the formula in which R1, Rz, R3, R5 and R6 are as defined in claim 1 and n is between 1 and 6, with the limitation that R
and Rz are not simultaneously hydrogen when n = 2
and Rz are not simultaneously hydrogen when n = 2
4. A compound according to claim 3, wherein n is equal to 2, 3 or 4.
5. A compound according to claim 1 or claim 2 of the formula in which R1, R2, R3 and R7 are as defined in claim 1 and m is an integer between 1 and 3.
6. A compound according to claim 5, wherein m is equal to 1 or 2.
7. A method of preparing the compounds of formula (I) according to any one of claims 1 to 6, which comprises:
- heating an appropriately substituted ketone of the formula Ar-COCH2-R3 with ethyl glyoxylate to form the hydroxyester of the formula - heating the ester 2 with hydrazine hydrate to form the hydroxypyridazinone of the formula - dehydrating the resulting product, by heating in an acid medium, to. form the 2H-pyridazin-3-one of the formula 4 - treating the resulting product with excess phosphorus oxychloride, under the action of heat, to form the 3-chloropyridazine of the formula 5 - heating the chlorine derivative 5 with an excess of amine R4NHz, if appropriate in the presence of ammonium chloride, to give the compound (I); and - if appropriate, converting the compound (I) to a salt with a mineral or organic acid by a known method.
- heating an appropriately substituted ketone of the formula Ar-COCH2-R3 with ethyl glyoxylate to form the hydroxyester of the formula - heating the ester 2 with hydrazine hydrate to form the hydroxypyridazinone of the formula - dehydrating the resulting product, by heating in an acid medium, to. form the 2H-pyridazin-3-one of the formula 4 - treating the resulting product with excess phosphorus oxychloride, under the action of heat, to form the 3-chloropyridazine of the formula 5 - heating the chlorine derivative 5 with an excess of amine R4NHz, if appropriate in the presence of ammonium chloride, to give the compound (I); and - if appropriate, converting the compound (I) to a salt with a mineral or organic acid by a known method.
8. A pharmaceutical composition in which a compound of formula (I) or one of its pharmaceutically acceptable salts is present as the active principle, in combination with a pharmaceutically acceptable vehicle.
9. A pharmaceutical composition according to claim 8 which are in the form of unit dosages containing 5 to 200 mg of active principle.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8901547 | 1989-02-07 | ||
| FR8901548 | 1989-02-07 | ||
| FR8901548A FR2642757B1 (en) | 1989-02-07 | 1989-02-07 | NOVEL PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| FR8901547A FR2642754B1 (en) | 1989-02-07 | 1989-02-07 | NOVEL PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2009501A1 true CA2009501A1 (en) | 1990-08-07 |
Family
ID=26227154
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002009501A Abandoned CA2009501A1 (en) | 1989-02-07 | 1990-02-07 | Pyradazine derivatives, method of preparation and pharmaceutical compositions in which they are present |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0382634B1 (en) |
| JP (1) | JPH02250871A (en) |
| CA (1) | CA2009501A1 (en) |
| DE (1) | DE69008566T2 (en) |
| PT (1) | PT93060B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI399373B (en) * | 2005-10-26 | 2013-06-21 | Janssen Pharmaceutica Nv | Fast dissociating dopamine 2 receptor antagonists |
| US8791120B2 (en) | 2007-02-13 | 2014-07-29 | Janssen Pharmaceutica Nv | Fast-dissociating dopamine 2 receptor antagonists |
| US8895562B2 (en) | 2008-07-31 | 2014-11-25 | Janssen Pharmaceutica Nv | Piperazin-1-yl-trifluoromethyl-substituted-pyridines as fast dissociating dopamine 2 receptor antagonists |
| US8906921B2 (en) | 2007-04-23 | 2014-12-09 | Janssen Pharmaceutica Nv | 4-alkoxypyridazine derivatives as fast dissociating dopamine 2 receptor antagonists |
| US8933101B2 (en) | 2007-04-23 | 2015-01-13 | Janssen Pharmaceutica Nv | Thia(dia)zoles as fast dissociating dopamine 2 receptor antagonists |
| WO2022166890A1 (en) * | 2021-02-08 | 2022-08-11 | 南京明德新药研发有限公司 | Substituted pyridazine phenol derivatives |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5461053A (en) * | 1989-02-07 | 1995-10-24 | Sanofi | Pyridazine derivatives |
| FR2642648B1 (en) * | 1989-02-07 | 1991-06-21 | Sanofi Sa | USE OF ALKYL-5 PYRIDAZINE DERIVATIVES AS ACTIVE MEDICAMENTS ON THE CHOLINERGIC SYSTEM |
| FR2663326B2 (en) * | 1989-11-17 | 1992-10-16 | Sanofi Sa | 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. |
| GB9707693D0 (en) * | 1997-04-16 | 1997-06-04 | Smithkline Beecham Plc | Novel method of treatment |
| US20030176437A1 (en) | 2001-08-31 | 2003-09-18 | D.M. Watterson | Anti-inflammatory and protein kinase inhibitor compositions and related methods for downregulation of detrimental cellular responses and inhibition of cell death |
| WO2006050359A2 (en) | 2004-11-02 | 2006-05-11 | Northwestern University | Pyridazine compounds and methods |
| BRPI0517947A (en) | 2004-11-02 | 2008-10-21 | Univ Northwestern | pyridazine compound, compositions and methods |
| AU2007243280A1 (en) | 2006-04-28 | 2007-11-08 | Northwestern University | Formulations containing pyridazine compounds for treating neuroinflammatory diseases |
| EP2015750A2 (en) | 2006-04-28 | 2009-01-21 | Northwestern University | Compositions and treatments using pyridazine compounds and cholinesterase inhibitors |
| US9447075B2 (en) * | 2011-08-02 | 2016-09-20 | The Brigham And Women's Hospital, Inc. | Pyridazine derivatives as EAAT2 activators |
| AR119731A1 (en) | 2019-05-17 | 2022-01-05 | Novartis Ag | NLRP3 INFLAMASOME INHIBITORS |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1345880A (en) | 1971-06-18 | 1974-02-06 | Cepbepe | Pyridazine derivatives |
| FR2510998B1 (en) | 1981-08-07 | 1986-01-10 | Sanofi Sa | NOVEL AMINO DERIVATIVES OF PYRIDAZINE, PROCESS FOR THEIR PREPARATION AND DRINKING ACTS THEREOF |
| FR2510997A1 (en) | 1981-08-10 | 1983-02-11 | Sanofi Sa | NOVEL DERIVATIVES OF METHYL-4-PHENYL-6-PYRIDAZINE, PROCESS FOR THEIR PREPARATION AND ACTIVE MEDICINES ON CENTRAL NERVOUS SYSTEM CONTAINING THE SAME |
| US4590194A (en) | 1981-10-05 | 1986-05-20 | Sterling Drug Inc. | 3-[methyl or dimethyl)amino]-6-(pyridinyl)pyridazines and their cardiotonic use |
| FR2539742B1 (en) | 1983-01-24 | 1986-09-05 | Sanofi Sa | AMINO DERIVATIVES OF PYRIDAZINE SUBSTITUTED IN POSITION 6 BY A HETEROCYCLE OR ALICYCLE, SAID DERIVATIVES Being ACTIVE ON THE CENTRAL NERVOUS SYSTEM |
-
1990
- 1990-02-05 PT PT93060A patent/PT93060B/en not_active IP Right Cessation
- 1990-02-07 CA CA002009501A patent/CA2009501A1/en not_active Abandoned
- 1990-02-07 JP JP2028149A patent/JPH02250871A/en active Pending
- 1990-02-07 DE DE69008566T patent/DE69008566T2/en not_active Expired - Fee Related
- 1990-02-07 EP EP90400334A patent/EP0382634B1/en not_active Expired - Lifetime
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI399373B (en) * | 2005-10-26 | 2013-06-21 | Janssen Pharmaceutica Nv | Fast dissociating dopamine 2 receptor antagonists |
| US8940743B2 (en) | 2005-10-26 | 2015-01-27 | Janssen Pharmaceutica Nv | Piperidin-4-yl-pyridazin-3-ylamine derivatives as fast dissociating dopamine 2 receptor antagonists |
| US9468640B2 (en) | 2005-10-26 | 2016-10-18 | Janssen Pharmaceutica Nv | Piperidin-4-yl-pyridazin-3-ylamine derivatives as fast dissociating dopamine 2 receptor antagonists |
| US9751860B2 (en) | 2005-10-26 | 2017-09-05 | Janssen Pharmaceutica Nv | Piperidin-4YL-pyridazin-3-ylamine derivatives as fast dissociating dopamine 2 receptor antagonists |
| US8791120B2 (en) | 2007-02-13 | 2014-07-29 | Janssen Pharmaceutica Nv | Fast-dissociating dopamine 2 receptor antagonists |
| US9422296B2 (en) | 2007-02-13 | 2016-08-23 | Janssen Pharmaceutica Nv | Fast-dissociating dopamine 2 receptor antagonists |
| US8906921B2 (en) | 2007-04-23 | 2014-12-09 | Janssen Pharmaceutica Nv | 4-alkoxypyridazine derivatives as fast dissociating dopamine 2 receptor antagonists |
| US8933101B2 (en) | 2007-04-23 | 2015-01-13 | Janssen Pharmaceutica Nv | Thia(dia)zoles as fast dissociating dopamine 2 receptor antagonists |
| US8895562B2 (en) | 2008-07-31 | 2014-11-25 | Janssen Pharmaceutica Nv | Piperazin-1-yl-trifluoromethyl-substituted-pyridines as fast dissociating dopamine 2 receptor antagonists |
| WO2022166890A1 (en) * | 2021-02-08 | 2022-08-11 | 南京明德新药研发有限公司 | Substituted pyridazine phenol derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| DE69008566T2 (en) | 1994-12-01 |
| JPH02250871A (en) | 1990-10-08 |
| EP0382634B1 (en) | 1994-05-04 |
| PT93060A (en) | 1990-08-31 |
| PT93060B (en) | 1995-12-29 |
| EP0382634A1 (en) | 1990-08-16 |
| DE69008566D1 (en) | 1994-06-09 |
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