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NEW PYRIDAZIN-3(2H)-0NE DERIVATIVES
The present invention relates to new therapeutically useful pyridazin-3(2n)-one derivatives, to processes for their preparation and to pharmaceutical compositions containing them. These compounds sre potent and selective inhibitors of
chosphodiesterase - (FCE4) and are :hus useful in the treatment, prevention or suppression of pathological conditions, diseases and disorders known io be susceptible of being improved cy inhibition*of PDE4.
Phosphodiesterases (PDEs) comprise a superfamily of enzymes responsible for the hydrolysis and inactivaticn of the second messengers cyclic adenosine monophosphate (cAfvlP) and cyclic guanosine monophosphate (cGMP). Eleven different PDE families have been identified-to date (PDE1 to PDE11) which differ in substrate preference, catalytic activity, sensitivity to endogenous activators and inhibitors, and encoding genes.-
The PDE4 isoenzyme family exhibits a high affinity for cyclic AMP but has weak affinity for cyclic GMP. Increased cyclic AMP levels-caused by PDE4 inhibition are associated with the suppression of cell activation in a wide range of inflammatory and immune cells, including lymphocytes, macrophages, basophils, neutrophils, and eosinophils. Moreover, PDE4 inhibition decreases the release of the cytokine Tumor Necrosis Factor a (TNFa). The biology cf PDE4 is described in several recent reviews, for example M. D. Houslay, Prog. Nucleic Acid Res. MoL Bid. 2001, 59, 249-315; J. E. Souness et aL Immunopharmacol. 2000 47, 127-162; or M. Conti and S. L. Jin, Prog. Nucleic Acid Res. MoL Biol. 1999, 63, 1-33.
in view of these physiological effects, PDE4 inhibitors of varied chemical structures have been recentlty disclosed for the treatment or prevention of chronic and acute inflammatory diseases and of ether pathological conditions, diseases and disorders known to be susceptible to amelioration by inhibition of PDE4. See, for example, US 5449636, US 5710170, WO 93/45268, WO 99/06404, WO 01/57025, WO 01/57036, WO 01/46184, WO 97/05105, WO 96/40636, JJS 5785354, US 5773467, US*5753666, US 5728712, US 5693659, US 5379696, US 5596013, US 5541219, US 5508300, US 5502072 or H. J. Dyke and J. G. Montana, Exp. Opin. invest Drugs 1999, 8, 1301-1325.
A few compounds having the capacity to selectively inhibit phosphodiesterase 4 are in active development. Examples of these compounds are cipamfylline (European Patent number 0 389 282 B1), arofyline (European patent number 0 435 811 Bl), cilomilast, roflumilast (European Patent number I 706 513 B1), mesopram (European Patent number 0 859 766 B1) and pumafentrre (PCT Patent application number 98/21208 A1).
We have now found that a novel series of pyridazin-3(2h')-one derivatives are potent and selective inhibitors of PDE4 and are therefore useful in the treatment or prevention of these pathological conditions, diseases and disorders, in particular asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritable bowel disease.
The compounds of the present invention can also be used in combination with other drugs known to be effective in the treatment of these diseases. For example, they can be used in combination with steroids or immunosuppressive agents, such as cyclosporin A, rapamycin orT-cell receptor blockers, in this case the administration of-; the compounds allows a reduction of the dosage of the other drugs, thus preventing the appearance of the undesired side effects associated with both steroids and immunosuppressants.
Like other PDE4 inhibitors (see references above) the compounds of the invention can also be used for blocking the ulcerogenic effects induced by a variety of etiological agents, such as antiinflammatory drugs (steroidal or non-steroidal antiinflammatory agents), stress, ammonia, ethanol and concentrated acids. They can be used aione or in combination with antacids and/or antisecretory drugs in the preventive and/or curative treatment of gastrointestinal pathologies like drug-induced ulcers, peptic ulcers, H. Pylori-related ulcers, esophagitis and gastroesophageal reflux disease.
They can also tje used in the treatment of pathological situations where damage to the cells or tissues is produced through conditions like anoxia or the production of an excess of free radicals. Examples of such beneficial effects are the protection of cardiac tissue after coronary artery occlusion or the prolongation of cell and tissue viability when the compounds of the invention are added to preserving solutions
intended for storage of transplant organs cr fluids such as blood or sperm. ; hey are also of benefit on tissue -epair and wcunc healing.
Accordingly, the present nver:;cn provides novel compounds cf formula (!.-:
wherein
R; and R: represent inceoendently from each other:
• a hydrogen atom;
• a group selected from" acyl. hydroxycarsonyi, alkoxycarbonyK carbamoyl. monoalkylcarbamoyl cr diaikylcarbamoyl;
• an alkyl, alkenyl or aikynyl group, which is optionally substituted by one or more, for
example 1, 2, 3 or 4. substituents selected from halogen atoms and hydroxy,
alkoxy, ar/loxy, alkyithio, oxo, amino, mono- or di-alkylamino, acylamino.
carbamoyl, mono- or diaikylcarbamoyl groups;
• an aryl or heteroaryl group which is optionally substituted by one or mere, for
example 1, 2, 3 or 4. substituents selected from halogen atoms and hydroxy,
hydroxyalkyl, hydroxycarbenyl, alkoxy, alkylenedioxy, alkoxyacyl, aryloxy, acyl,
acyloxy, alkyithio, amino, nitro, cyano, mono- or di-alkylamino, acylamino,
carbamoyl, mono-crdi-alkylcarbamoyl, difluoromethyl, trifluoromethyi,
difluoromethoxy or trifluoromethoxy groups;
• a saturated or unsaturated heterocyclic group which is optionally substituted by one
or more, for example 1, 2, 3 or 4, substituents selected from halogen atoms and
hydroxy, hydroxyalkyl, hydroxycarbonyl, alkoxy, alkylenedioxy, alkoxyacyl, aryicxy,
acyl, acyloxy, alkylthio, oxo, amino, nitro, cyano, mono- or di-alkylamino, acylamino,
carbamoyl, mono- cr di-alkylcarbamoyl, difluoromethyl, trifluoromethy-l,
difluoromethoxy or trifluoromethoxy groups;
• a group of formula
wherein n is an integer from 0 to 4 and R6 represents:
• a cycloalkyl or cyclca:kenyl group;
• an aryl group, which s cptionaily substituted by one or more, for example 1. 2, 3 or 4, subs:::uents seiec:ec from halogen atoms and alkyl, hydroxy, alkoxy, alkyleredioxy. alkylthic. amino, mono- or di-aikylamino, nitre, acyl. hydroxycarbcr/.i, aikcxycarccnyl, carbamoyl, mono- or di-alkylcarbamcyi, cyano, trifluorcmethyi. difluorcmethoxy or trifiuoromethoxy groups;
• or a 3- to 7-membered ring comprising from 1 to 4 heteroatoms selected from nitrogen, oxygen and $L ohur, which ring is optionally substituted by one or more, for example 1,2,3 or 4, substituents selected from halogen atoms and alky!, hycroxy, alkoxy, alkyienedioxy, amino, mono- or di-aikylamino, nitro. cyano cr trifiuoromethyl groups;
RJ represents a monocyclic or poiycyclic aryl or heteroaryl group, which is optionally substituted by one or more, for example 1, 2, 3 or 4T substituents selected from:
• halogen atoms;
• alkyl and alkylene groups, which are optionally substituted by one or more, for example 1, 2, 3 or 4, substituents selected from halogen atoms; and phenyl, hydroxy, hydroxyalkyl, alkoxy, aryioxy, alkylthio, oxo, amino, mono- ordi-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyi, carbamoyl, mono- or di-alkylcarbamoyl groups
• phenyl, hydroxy, hydroxyalkyl, alkoxy, cycloalkoxy, nitro, aryioxy, alkylthio, alkylsulphinyl, alkylsulphcnyl, aikylsulphamoyl, acyl, amino, mono- or di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyi, carbamoyl, mono- or di-alkylcarbamoyl, ureitio, N'-alkyiureido, N'.N'-dialkylureido, alkylsulphamido, aminosuphonyl, mono- cr di-alkylaminosulphonyl, cyano, difluoromethoxy or trifiuoromethoxy groups;
R° represents a group -COOR7 or a monocyclic or poiycyclic aryl or heteroaryl group, which is optionally substituted by one or mere, for example 1, 2,*3 or 4, substituents selected from:
• halogen atoms;
• alkyl and alkenyl croups, which are optionally substituted by one or more, for
examole 1. 2 3 Of 4 sf:h~fitll(antc calao+aH fi-rum holr^rran atomc onH r\h^^v,l
hydroxy, hydroxyalkyi. aikoxy. anyloxy, aikyithio, oxo, amino, mono- or di-aikylamino, acylaminc. hydrcxycarbonyl, aikoxycarbonyl. carbamoyl, more- :r di-alkylcarbamcyi"groups; y
A .
phenyl, hydroxy, alkvienedicxy. aikoxy, cycloalkyicxy. aikyithio, alkyisuiph;r\;. alkylsulphonyl, aikyls-lfamo;. t. amino, mono- or di-alkylarrino, acylaminc. n .'::■:. acyl, hydroxycarbony'. aikox\:3rbonyl, carbamoyl, mono- crdi-alkylcarbarrcy ureico, N'-aikyiureicc. N'.N'-cialkylureido. alkylsubhamico. aminQsupr.cn;.I. monc- ordi-slkyiamircsulphcnyl. cyano, diflucror:e:hoxy or trifiuorcmethc aroucs;
therein R: represents an aiky; group .vhich is optionally substituted by one or mere, ~cr example 1. 2, 3;or4.- substituents selected from halogen -[cms and hydroxy, aikcxy. aryloxy, aikyithio, oxo' amino, mono- or di-alkylamino, acylamino. hydroxycarbony;. aikoxycarbonyl, carbamoyl and mono- or di-alkylcarbamoyl groups or a group of ormula- ■.
-(CH2)n-Rd
therein n and R°are as defined above, and
represents:
a hydrogen atom;
a hydroxy, aikoxy, amino, mono- or di-alkylamino group;
an aikyl, alkenyl or alkynyl group which is optionally substituted by one or more.
for example 1, 2, 3 or 4, substituents selected from halogen atoms and hydroxy,
aikoxy, an/loxy, aikyithio, oxo, amino, mono- or di-alkylamino,. acylamino,
hydroxycarbonyt, aikoxycarbonyl, carbamoyl and-mono- or di-alkylcarbamoyl
groups;
or a group of formula
-(CH2)n-R6 wherein n and RQars as defined above.
as well as the N-oxides obtainable from the heteroaryl radicals present in the structure when these heteroradicals comprise N aroms and pharmaceutical^ acceptable salts
thereof,
with the proviso that when Rc is neithe- an optionally substituted heteroaryl group nor a group COOR\ then R3 is an :c:icnaiiy substituted heteroaryl group.
Certain pyricazin-3(2H)-or.e cerivatives of similar structure, which do not fall within the scope of the present invention, have been disclosed in J. Pharm. Sci. 1991, SO, 341-343 and J. Med. Chem. 1999. 42. 1394-; 900.
Further objectives of the present invention are to provide processes for preparing said compounds; pharmaceutical compositions comprising an effective-amount of. said.. compounds; the use of the compounds in the manufacture of a medicament.for the treatment of diseases susceptible of being improved by inhibition_pf PDE4; and methods of treatment of diseases susceptible to amelioration by inhibition of PDE4, which methods comprise the administration of the compounds of the invention to a subject in need of treatment.
As used- herein the term alkyl embraces optionally substituted, linear or branched radicals having 1 to 20 carbon atoms or, preferably 1 to 12 carbon atoms. More preferably alkyl radicals ara "Icwer alkyl" radicals having 1 to 3, preferably 1 to 3 and more preferably 1 to 4 carbon atoms.
Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyi, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyt, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyi, 1,3-dimethylbutyl, 2,2-dimethyibutyl, 2,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl and iso-hexyl radicals.
As used herein, the term alkenyl embraces optionally substituted, linear or branched, mono or polyunsaturated radicals having 1 to 20 carbon atoms or, preferably, 1 to 12 carbon atoms. More preferably alkenyl radicals are "lower alkenyl" radicals having 2 to 3, preferably 2 to 6 and more preferably 2 to 4 carbon atoms. In particular it is preferred that the alkenyl radicals are mono or diunsaturated.
Examples include vinyl, ailyl. 1-prccenyl, isopropenyl. T-bu:enyl. 2-butenyi, 3-butenyl, 1-penteryl, 2-pentenyl, 2-pentenyl and 4-pentenyl radicals.
As used herein, the term aikynyl ere'aces optionally substituted, linear or brancreb. mono cr polyunsaturated radicals h=.:ng 1 to 20 career atoms or. preferably. 1 tc J2 carbon acorns. Mere preferably, alkvrv/l radicals are "'ever aikvnvi" radicals navirc 2 :o 3. preferably 2 to 3 and more preferably 2 to 4 carbon, a:oms. In particular i: ;s zraiecrze thai: the aikynvi radicals are mono cr diunsaturated.
Examples include 1-propynyl, 2-prcc;~yl, 1-butynyl. 2-cutynyl and 3-butyny! radicals.
-VVhen:it is mentioned that alkyL aikenyl or aikynyl radical's may be optionally subsnuted "ir-is-meant to include linear or branched aikyl, alkenyi cr aikynyl radicals as defined :above,:which may be unsubstituted or substituted in any position by one Gr more
substituents, for example by 1, 2 or 3 substituents. When two or more substitutes are
present, each substituent may be the same or different.
A said optionally substituted aikenyl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms. Typically, substituents on an aikenyl group are themselves unsubstituted.
A said optionally substituted aikynyl croup is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms. Typically, substituents on an aikynyl group are themselves unsubstituted.
A said optionally substituted alkyl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and aikoxy groups having from 1 to 4 carbon atoms. Typically, substituents on an alkyl group are
themselves unsubstituted. Preferred optionally substituted alkyl groups are unsubstituted or substituted with 1. 2 or 3 fluorine atoms.
As used herein, the term aikylene embraces divalent aikyl moieties typically having from 1 to 6, for example from 1 :c -, careen atoms. Examples of C--Ca aikyiene radicals include methylene, ethylene, propylene, butyiere, pentylene and hexyiene radicals.
A said optionally substituted aikyiene group is typically unsubstituted or substituted with 1. 2 or 3 substituents wfticn may be the same or different. The substituenis are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and aikoxy groups having from 1 to - carbon atoms:
When an aikyiene radical is present as a substituent on-ahdther radical it shall be deemed to be a single substituent. rather than a radical-formed-by two substituents.
As used herein, the term alkoxy (or alkyioxy) embraces optionally substituted, linear or branched oxy-containing radicals each having alkyl portions of 1 to 10 carbon atoms. More preferred alkoxy racicals are lower aikoxy" radicals having 1 to 3, preferably 1 to 6 and more preferably 1 to 4 carbon atoms.
An alkoxy group is typically unsubstituted or substituted with" 1, 2 or 3 substituents which may be the same or different. The substituents are-preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms. Typically, the substituents on an alkoxy group are themselves unsubstituted.
Preferred alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxyT n-butoxy, sec-butoxy, t-butoxy, trifluoromethoxy, difluoromethoxy, hydroxynnethoxy, 2-hydroxyethoxy and 2-hydroxypropoxy.
As used herein, the term alkylthio embraces radicals containing an optionally substituted, linear or branched alkyl radicals of 1 to 10 carbon atoms attached to a divalent suifur atom. More preferred alkylthio radicals are lower alkylthio" radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms.
An aikylthio group is typically -^substituted or substituted. .vi:h 1, 2 or 3 substituents which may be the same or different, "he substituents are preferably selected from halogen atoms, preferably fiucine atoms, hydroxy groups and aikcxy groups nav~z :*rcm 1 to 4 carbon atoms. Tvbicaifv. me substituents en ar. ^ikvthic orouo are themselves unsubstituted.
Preferred optionally substituted aikyithio radicals include methyithic. echylihic, n-cropylthio, i-propy(thio. vbur/thio, sec-butyithio, t-butylthic. Tiflucromeihyithic. difluoromethvlthio, hvcrcxvmemvlthic. 2-hydroxvethvltnic and 2-hvdrcxvorocyithic.
As used herein, the term moncaikylamino embraces racicais containing an optionally substituted, linear or branched alkyl radicals of 1 to 10 carbon atoms attached to a divalent -NH- radical. More preferred monoaikylamino racicais are "lower monoaikylamino" radicals having 1 to 3, preferably 1 to 5 and mere preferably 1 to -c arbon atoms.
A monoaikylamino group typically contains an alkyl group which is unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected Torn halogen atoms, preferably fluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms. Typically, the substitutents on a moncalkyiamino group are themselves unsubstituted.
Preferred optionally substituted monoaikylamino radicals include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, sec-butylamino, t-butylamino, trifluoromethylamino, difiuoromethylamino, hydroxymethylamino, 2-hydroxyethylamino and 2-hydroxypropylamino.
As used herein, the term dialkvlamino embraces radicals containing a trivaient nitrogen atoms with two optionally substituted, linear or branched alkyl radicals of 1 to 10 carbon atoms attached thereto. More preferred dialkylamino radicals are "lower dialkylamino" -radicais having 1 to 3, preferably 1 to 3 and more preferably 1 to 4 carbon atoms in each alkyl radical.
A dialkylamino group typically contains two alkyl groups, each of which is unsubstitutec or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4 careen atoms. Typicaiiy, the substituents on a dialkylamino croup are themselves unsubstitutec;.
Preferred optionally substituted disikylarnino radicals induce dimethylamino, diethylamino, methyi(ethyl)aminc. difr-propyOamino. n-prcpyl(methyl)amino. r.-propyl(ethyi)amino, di(i-prccyi)am;no. :-oropyl(methyl)am;Po, i-propyl(ethyl)amiro, di(r-butyl)amino, n-butyl(methyl'amino. n-bu7l(ethyl)aminoT n-butyl(i-propyl)aminc. di(sec-butyi)amino, sec-butyl(meihyf)aiTiino, 3ec-butyl(-ethyl)amir.e. sec-butyl(n-prcpy famine. sec-butyl(i-propyl)amino, diit-butyi)anr.lno, t-butyl(methyl)arnino, t-butyl(ethyi}amino, t-butyl(n-propyl)amino, t-butyn-propyOamiho: tfifluoromethyl(methynamino? trifluoromethyi(ethyi)amino, :riflucromethyl(7V-propyl)aminc. :rifluorcmethyl(i-propyl)aminor trifluoromethyi(n-butyi)amind;;trinuoromethyl(sec-butyi)aminc, difIuoromethyl(methyl)aminc, difIuorcmechyl(ethyl)amino, cifluoromethyl(n-propyl)amino, difIuoromethy!(i-propyl)amino, dif!uoromethyi(^-bu^yl))amino, difluoromethyl(sec-butyl)amino, difluoromethyl(t-butyl)amino, difluoromethyl(trifIuoromethyi)aminot hydrcxymethyl(methyl)amino, ethyl(hydroxymethyl)amino. hydrcxymethyl(n-propyl)aminct hydroxymethyl(i-propyl)amino, n-butyl(hydrcxymethyl)amino, sec-butyl(hycroxymethyl)amino, t-butyl(hydroxymethyl)aminor difluoromethyl(hydroxymethyl}amino, hydroxymethyl(trifluoromethyl)amino, hydroxyethyi(methyl)amino, ethyl(hydroxyethyl)amino, hydroxyethyl(n-propyl)amino, hydroxyethyl(i-procyl)amino, n-butyi(hydroxyethyl)amino, sec-butyl(hydroxyethyl)amino, t-butyl(hydroxyethyl)amino, difluoromethyl(hydroxyethyi)amino, hydroxyethyl(trifIuoromethyl)am(nof hydroxypropyl(methyi)amino, ethyl(hydrcxypropyl)amino, hydroxypropyl(n-propyi)amino, hydroxypropyl(i-propyi)amino, n-butyl(hydroxypropyl)amino, sec-butyl(hydroxypropyl)amino, t-butyl(hydroxypropyl)amino, difluoromethyl(hydroxypropyl)amino, hydroxypropyl(trifluoromethyl)amino.
As-used herein, the term hydroxyalkyl embraces linear or branched aikyi radicals having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals.
Examples of such radicals include hydrcxymethyl, hycrcxyethyl. hydroxyprcpyl, hydroxybutyl and hydroxyhexyi.
As used herein, the term aikcxvcarbcr.yi embraces optionally substituted, linear c: branched radicals each having alkyl crrricns of 1 to ; - :arbon atoms and attached :c an oxycarocnyl radical. More preferred aikoxycarbor.y radicals are lower aikoxycarbonyl" radicals, in wh-ch the aik\-i moiety has ' to 3, preferably 1 ie 5 ar.-.: mere preferably 1 to 4 carbon atoms.
An alkoxycarbonyl group '.s typically ^substituted or sjostituted with 1, 2 cr 5 substituents whicn may oe the same cr different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkoxy groups having from 1 to - carbon atoms. Typically, the substituents on an alkoxycarbonyl group are themselves unsubstituted.
Preferred optionally substituted alkoxycarbonyl radicals Include methoxycarbenyi. ethoxycarbonyl, n-propcxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, trifluoromethoxycarbonyl, difluoromethoxycarbonyL hydroxymethoxycarbonyi, 2-hydroxyethoxycarbonyl and 2-hydroxypropoxycarbonyL
As used herein, the term monoalkylcarbamoyl embraces radicals containing an optionally substituted, linear or branched alkyl radicals cf 1 to 10 carbon atoms and attached to the nitrogen of a-NHCO- radical. More preferred monoalkylcarbamoyl radicals are "lower moncalkylcarbamoyl" radicals in which the alkyl moiety has 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms.
A monoalkylcarbamoyl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same cr different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms. Typically, the substituents on a monoalkylcarbamoyl group are themselves unsubstituted.
Preferred optionally substituted monoalkylcarbamoyl radicals include methyicarbamoyi, ethylcarbamoyl, n-propyicarbamoyl, i-propylcarbamoyl, n-butylcarbamoyl, sec-
burylcarbamoyl, t-butylcarbamcy;. trifluoromethylcarbamoyl, diflucromethylcarbamoyl, hydroxymethylcarbamoyl, 2-hycrcxyethyfcarbamoyl and 2-hydroxypropyfcarbamoyl.
As used herein, the term dialkylcarbamcyl embraces raclcais containing a racical NCO- where the nitrogen is attached -c two optionally substituted, linear or branched alky! radicals of 1 tc 10 carbon sterns. More preferred cialkylcarbamoyi radicals are ■'Ic'.ver dialkylcarbamoyl" radicals having 1 to 8, preferably 1 to 6 and more preferably 1 ro 4 carbon atoms in each aikvi -adical.
A cialkylcarbamoyi group is typically ur.suostituted or substituted //iih 1, 2 or 3 substituents which may be the_sa~ie or different. The substituents are preferably selected from halogen atoms; preferably fluorine atoms, hydroxy groups and alkcxy groups having from 1 to 4 carbon atoms. Typically, the substituents on a diaikylcarbamoyl group are themselves unsubstituted.
Preferred optionally substituted ciaikylcarbamoyl radicals induce dimethyicarbamcyl, diethylcarbamoyi, methyl(ethyl)carbamoyl, di(n-propyl)carbamoyl, n-propy!(methyl)carbamoyl;n-propy!(ethyl)carbamoylI di(i-propyl)carbamoyl, i-prcpyl(methyl)carbamoyl. i-propyi(ethyi)carbamoyl, di(n-butyl)carbamoyl, n-butyl(methyl)carbamoylt n-butyi(ethyl)carbamdyl, n-butyi(i-propyl)carbamoyl( ci(sec-butyl)carbamoyl, sec-butyl(methy:'.carbamoyl, sec-butyl(ethyl)carbamoyl, sec-butyl(n-prcpyl)carbamoyl, sec-butyI(i-procyl)carbamoy!f di(t-butyl)carbamoyl, t-butyi(methyl)carbamoylf t-butyl(e:hyl)carbamoyl, t-butyl(n-propyI)carbamoylt t-butyf(i-prcpyl)carbamoyl, triflucromethylfmethyQcarbamoyl, trifIuoromethyl(ethyl)carbamoyl, trifluoromethyl(n-propyl)carbamcylf trifluoromethyl(i-propyl)carbamoyl, trifluoromethyl(n-butyl)carbamoylf trifIuoromethyl(sec-butyl)carbamoyl, difluoromethyl(methyl)carbamoyl, difIuoromethyl(ethyl)carbamoyl, cifluoromethyl(n-propyl)carbamoylI difluoromethyi(i-' propyl)carbamoyl, difIuoromethy!fn-butyl))carbamoyl, difluoromethyl(s'ec-butyI)carbamoylf difIuoromethyl(t-butyl)carbamoyl,
difluoromethyi(trifluoromethyl)carc3moylf hydroxymethyl(methyl)carbamoyl, ' ethyl(hydroxymethyl)carbamoylT hydroxymethyi(n-propyl)carbamoyl, hydroxymethyl(i-propyl)carbamoyl, n-butyl(hydroxymethyl)carbamoylt sec-butyl(hydroxymethyl)carbamoyl, t-butyl(hydroxymethyl)carbamoyl, difluoromethyl(hydroxymethyl)carbamoyl, hydroxymethyl(trifluoromethyl)carbamoyl, hydroxyethyl(methyl)carbamovl, e:hvi(hvr!rnY\/Pth\/nrsrhamriwi hwHm^/mhwi/n
prcpyl)carbamoylf hydroxye:hyl(i-propyl}carbamoyl, r-butyi(hycrcxyethyl)carbamcy sec-butyl(hydroxyethyl)carbamoyL L-buryi(hydroxyethyf .carbamoyl, difiuoromethyl(hydroxyethyf carbamoyl, hydroxyethyi.tr;f!ucrome:hyl)carbamcyl, hydroxypropyl(methyl)carbsmoyl, ethytfhydroxyprocyrcarbamcyj, hydroxypropy!.^-prcpy!)carbamoyl, hydroxypr:cyl(i-crccyi)carbamoyL n-butyi(hy:rcxypropy!;carbam sec-bu^yl(hydroxyp^opyl)c3^:amovl. :oury!('hydroxypfccyi)carbamoyi, diflucromethyl(hydroxypropy! carbamoyl. hydroxyprcp>!(:rifluorcmethyl)carbamcyi.
As used herein, the term aik;.:sulfiny! embraces radicals containing an optionally substituted, linear or brancre: alky! radicals of 1 to 10 carbon atoms attached tea . divalent-SO- radical. More preferred alkylsulfinyl radicals are "lower alkylsufinyi" radicals having 1 to 3, preferaoly 1 to 5 and more preferably 1 :c -1 carbon atoms. -
An alkylsulfinyl group is typically unsubstituted or substituted wi:h 1, 2 or 3 subst;tue
which may be the same or different. The substituents are preferaoly selected frcm-
halcgen atoms, preferably fluorine atoms, hydroxy groups and aikoxy groups havinc
from 1 to 4 carbon atoms. Tycically, the substituents on a alkylsulfinyl group are
themselves unsubstituted. - - - •■:--:. ■•
Preferred optionally substituted alkylsuiphinyl radicals include methylsulphinyl, . ethyisulphinyl, n-propylsulphinyl, i-prcpyisulphinyl, n-butylsulphinyi, seobutyisulphin t-butylsulphinyl, trifluoromethyisulphinyl, difluoromethylsulphinyl, hydroxymethylsulphinyl, 2-hycroxyethylsulphinyl and 2-hydroxypropylsulphinyl.
As used herein, the term alkyisulfonyl embraces radicals containing an optionally substituted, linear or branched alkyl radicals of 1 to 10 carbon atoms attached to a divalent -S02- radical. More preferred alkyisulfonyl radicals are "lower alkyisulfonyl" radicals having 1 to 8T preferably 1 to 5 and more preferably 1 to 4 carbon atoms.
An alkyisulfonyl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkcxy groups having from 1 to 4 carbon atoms. Typically, the substituents on a
As used herein, the term monoalkylaminosulfonyl embraces radicals containing an optionally substituted, linear or branched alky! radicals of 1 to 10 carbon atoms and attached to the nitrogen of a-NHSGr radical. More preferred mcnoalkyiamincsulfcnyl radicals are lower moncsikylamincsuifcnvl" radicals havina 1 to 3, oreferablv 1 tc 5 and more preferably 1 tc 4 careen stems.
A moncalkviaminosuifcnv! crouc Is r.cicailv unsubstituted or substituted with 1. 2 cr 3 substituents.which may be the same z: different. The substituents are preferably selected from haicgen atoms, prefersriy fluorine atoms, hydroxy groups and aikoxy groups having, from-1 to -± careen atoms. Typically, the substituents on a monoalkylaminosulfonyl group are themselves unsubstituted.
Preferred optionally substituted mcncaikyiaminosulphonyl radicals include methylaminosulphonyl, ethylamincsuiphcnyl, n-propylaminosulphonyl, i-propylaminosulphonyl, n-buty!aminosuipnonyl, sec-butylaminosulphonyl, t-butylaminosulphonyl, trifluorcmethylaminosulphonyi, diflucromethylaminosulphonyi, hydroxymethylaminosulphonyl, 2-hydroxyethylaminosulphonyl and 2-hydroxyprppylaminos.ulphonyl.
As used, herein,ithe term dialkylaminosulfonyl embraces radicals containing a radical NS02- where-the-nitrogen is attached to two optionally substituted, linear or branched alkyl radicals-of.1 to 10 carbon atoms. More preferred dialkylaminosulfonyl radicals are "lower dialkylaminosulfonyl" radicals having 1 to 3, preferably 1 to 6 and more preferably 1 to 4 carbon atoms in each alkyl radical.
A dialkylaminosulfonyl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and aikoxy groups having from 1 to 4 carbon atoms. Typically, the substituents on a dialkylaminosulphonyl group are themselves unsubstituted.
Preferred optionally substituted dialkylaminosulphonyl radicals include dimethylaminosulphonyl, diethyiaminosulphonyl, methyl(ethyl)aminosulphcnyi, di(n-propyl)aminosulphonyl, n-propyl(methyl)aminosufphonyl, n-propyl(ethyi)amincsuIphonyl, di(i-propyi)aminosulphonylT i-
An aikylsulphamoyi group is typically unsubstituted or substituted with 1, 2 or 2 substituents which may.be the same cr different. The substituems are prefersc-iy selected from halogen atoms. preferac:y fluorine atoms, hydroxy croups anc aikcxv groups having from 1 to 4 careen atoms. Typically, the substituents on an 3:k;.:sulphamoyl group are :hemse!ves -^substituted.
F^er'erred optionally substituted aikylsuifamoyi radicals include methylsuiphamcyi. etryisulphamoyl, n-procyisuipha.royl. ;-oropyisulphamcvl. n-butylsuicnamcyi. sec-butyisulphamoyl, t-butylsulphamcyl, trif-oromethylsulphamcyl,
-cifiucromethyisulphamcyi. nycrcxyme:r/isuipnamoyl, 2-hydroxyethyisulphamcyi anc 2-hydroxypropylsulphamcy:.
-•As'jsed herein, the term alkyisuic-harrico embraces radicals containing an cpticna.ly -substituted, linear or branched a.kyl racicais of 1 to 10 carbon atoms and attached to one of the nitrogen atoms of a —\HSO:NH- radical. More preferred alkyisuichamicc racicais are "lower alkyisulphamido" radicals having 1 to 3, preferably 1 to 5 and more .preferably 1 to'4 carbon atoms.
An alkyisulphamido group is typically unsubstituted or substituted with 1, 2 or 3 ■ substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups anc aikoxy groups having from 1 to 4 carbon atoms. Typically, the substituents on an alkyisulphamido group are themselves unsubstituted.
Preferred optionally substituted alkyisulphamido radicals include methylsulphamidc, ethylsulphamido, n-propylsulphamido, i-propylsulphamido, n-butylsulphamido, sec-butylsulphamido, t-butyisulphamido, trifiuoromethylsuiphamido, difluoromethylsulphamidc, hydrcxymethylsulphamido, 2-hydroxyethyisulphamido and 2-hydroxysulphamido.
As used herein, the term N'-alkyiureido embraces radicals containing an optionally substituted, linear or branched aikyl radical of 1 to 10 carbon atoms attached to the terminal nitrogen of a -NHCONH- radical. More preferred N'-alkyiureido racicais ar^
"lower N'-alkylureido" radicals in which the alkyl moiety has 1 to 3. preferably 1 tc 5 and more preferably 1 to 4'carbon atoms.
An N'-alkyiureido group is typically unsubstituted or substituted .-vi:h 1, 2 or I substituents which may be the sane or different. The substituenrs are preferably selected from halocen a:cms. preferably flucrine atcms. hvcroxv croucs and alkrxv orcuos having from 1 tc -^ car:on atcms. Tvoicallv. the substituents on an N'-aikyiureido group are :hemse:ves unsubstituted.
*
Preferred optionally substituted N'-aikylureido radicals' inciude-iV-methylureido, iY-ethylureido, N'-n-propylureido. N'-i-prcpylureido, N'-n-buiyiureido. N'-sec-bur/lureico. N'-t-butylureido, N'-triflucromethylureido, N'-difiuoromethylureido.-N'-hydroxymethyiureido, N'-2-hycroxyethylureido and'N-'-2-hydroxyprcpylureidc.
As used herein, the term N'.N'-dialkylureido embraces-radicals,containing a radical -NHCON where the terminal nitrogen is attached to two opticnaily substituted, linear or branched alkyl radicals of 1 to 10 carbon atoms. More preferred N'.N'-dialkyiureido radicals are "lower N',N'-dialky!ureido" radicals having 1 to-8, preferably 1 to 3 and more preferably 1 to 4 carbon atoms in each alkyl radical.
A N'.N'-dialkylureido group is Typically unsubstituted or-substituted with 1, 2 or 3 substituents which may be the same cr different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkcxy groups having from 1 to 4 carbon atoms. Typically, the substituents on an N'.N'-dialkylureido group are themselves unsubstituted.
Preferred optionally substituted N'rN'-dialky!ureido radicals include N\N*-dimethylureido, N',N'-diethylureido, N'-methyl,N'-ethylureido, N',N'-di(n-propyl)ureido, N'-n-propyl,N'-methylureido, N'-n-propyl.N'-ethylureido, N\N'-di(i-propyl)ureido, N'-i-propyl,N'-methylureido, N'-i-propyl,N'-ethylureido, N',N'-di(n-butyl)ureido, N'-n-butyl,N'-methylureido, N'-n-but/LN'-ethyiureido, N'-n-butyl.N'-O-propyOureido, N\N'-di(sec-butyl)ureido, N'-sec-buf/l.N'-methylureido, N'-sec-butyl,N'-ethylureido, N'-sec-butyl.N'-(n-propyl)ureido, N'-sec-butyl,N'(i-propyl) ureido, N\N'ciit-butyl)ureidoT N'-t-butyl,N'-methylureido, N'-t-butyi.N'-ethylureido, N'-t-buiyl,N'-(n-propyl)ureido, N'-t-buiyUN'-fi-propyl)ureido, N'-triflucromethyi,N'-methylureido, N'-trifiuoromethyLN'-ethyiureido, N'-
tr;f!uoromethyi,N'-(n-propyi)ureido. N'-thfiuorcmethyl>iVi-propyl)ureido, N'-tr:fluorornethyl,N,-(n-bu^/i)ureiGC. N,-trifIuoromethyl,N,-(5ec-butyi)ureic!oI N'-diflucromethyLN'-methyiureido. M'-difiuororr.ethyl.N'-etrylureido, N'-difluoror.ethyLN';--propyOureico. N'-diflucromethyl.N'-iVpropyiJureido, N'-cifiuoromethyl^lXn-bur/Oureicc.
N^difluorcrriethyl.NXsec-butyDureidc. N,-difluoromethyi.iN'-(t-bubyl)ur9ido, N'-dirluoromethyljNI1 ■criflucrorriethytureido. N7-nydroxymethy!,N'-methyiureido, N'-ethyi,N'-rydroxymethylureido, N'-hycroxy-e^yi.N'-fn-propyOureidG, N'-hydroxymethyLN'-ij-cropyOureico, ^-n-buiyi.N'-nycroxymethyiureido, N'-sec-butyl.N'-hycroxymerhylureicc. M'-t-butyLM'-hydroxymeihyiureicc. N'-diflucrcnethyl.N'-nydroxyrriethylureidc. N'-hycroxymetnyLN'-triflucromethyiureido. N'-hydroxyethyl.N'-methyiureido, N'-ethyl.N'-hydroxyethylureico, N'-hydroxyethyLN'-'n-propyDureido. N'-hydroxyethyl,N'--i-propyOureido, NVn-bur/l)>i'4vydroxyeihylureico, N7sec-butyl),N'-hydroxyethylureido; N'-lt-butylj.N'-hydroxyethylureido. N'-difluoromethy^N'-nydroxyethylureido, N'-hydroxyethyl.N'-trifluorcmethytureido, N'-hydrcxypropyLN'-methylureido, N'-ethyl.N'-hydroxypropylureido, Nf-hydraxypropyl,N'-(n-propyl)ureido, N'-hydroxypropyl.N'-fi-propyl)ureido, N'-'n-butyO.N'-hydroxypropylureido, N'(sec-butyl),N'-hydroxypropyiureido, NT(t-bur/!),M'-hydroxypropylureido. N'-difluoromethyljY-hydroxypropylureido y N'-hydroxypropyl.N'-trifiuoromethylureido.
As used herein, the term acyl embraces optionally substituted, linear or branched radicals having 2 to 20 carbon atoms or, preferably 2 to 12 carbon atoms attached to a carbonyl radical More preferably acyl radicals are "lower acyl" radicals of formula -COR, wherein R is a hydrocarbon group, preferably an alkyl group, having 2 to 3. preferably 2 to 6 and more preferably 2 to 4 carbon atoms.
An acyl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and aikoxy groups having from 1 to 4 carbon atoms. Typically, the substituents on an acyl group are themselves unsubstituted.
Preferred optionaiiy substituted acyi radicals include "acetyl, propionyl, butiryl, tsocutiryi, isovaleryl, pivaloyii, valeryl, iauryl, myristyl, steanyl and paimityl,
As used herein, the term ar\ -adica! embraces typically a C5-C^ monocyclic or polycyclic aryl radical such as phenyl, naphthyl, anthranyi and phenanthr/l. Phenyl is preferred.
A said optionally substituted aryl races! is typically unsucstiiutec or substituted .v;:h
2 or 3 substituents which ma; os :he same or differen:. The sucstituents are creferab.v
selected from halogen atoms, preferably fluorine atoms, hydroxy groups,
alkoxycarbonyl groups in when the aikyl moiety has from 1 to 4 careen atc~3.
nydroxycarbonyl groups, car;amoy: groups, nitro groucs. cyano groups, C--C: a:ky!
groups, CT-04 alkoxy groups and C--3: hycroxyalkyl groups. When an aryl "adica,
carries 2 or more substituems. cne sucstituents mav be the same or differen-.. Unless
otherwise specified, the sucstituents. on: an 3r/l-grcup are typically themselves
unsubstituted. - ■
As used herein, the term he:eroanyl radical-embraces- typically a 5- to 14- membered ring system, preferably a 5-;: 10- membered ring system, comprising at least cne heteroaromatic ring and confining at least one heteroatom selected from 0. S and N. A h'eteroaryl radical may be a single ing or-two or more fused rings wherein at least one ring contains a heteroatom.
A said optionally substituted r.eteroar/l radical is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The sucstituents are preferably selected from halccen atoms, preferably fluorine, chlorine or bromine atoms, alkoxycarbonyl groups in which the alkyl moiety has from 1 to 4 carbon atoms, nitro groups, hydroxy groups, d-C- alkyl croups and CrC4 alkoxy groups. When an heteroaryl radical carries 2 cr more substituents, the substituents may be the same or different. Unless othen.vise specified, the substituents en a heteroanyl radical are typically themselves unsubstituted.
Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazciyl, benzoxazolyl, imidazolyl, benzimidazolyi, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, pyridinyl, benzothiazolyl, indclyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthaiazinyl, naphthyridinyl, quinoxalinyl, quinazoiinyi. cuinclizinv!, cinnoiinyl, triazolyi, indolizinyi. indolinyl, isoindolinyl, isoindolyl, imidazolidinyl. pteridinvl.
thianthrenyl, pyrazolyl, 2H-cyr3Zolo[3!4-djpyrimidinyl, 1H-pyrazoio[3,4-d]pyrimidinyl, thieno[2f3-d]'pyrimidnyl and the various pyrrolopyridyl radicals.
The mention of optionally substituted he£eroar/l radicals or rests within the present invention is intended to cover the N-cxides obtainable from these radicals when they comprise N-atoms.
Oxadiazolyi, oxazolyl, pyricyl. cyrrclyl. imicazoly!, thiazoiy!. thiadiazciyl, thienyi, furanyl. quinoiinyl, isoquinclinyl, incciyi. benzrxazolyi, naphthyricinyl, benzcfuranyi, pyrazinyl. pyrimidinvl and the various ovrrCiCcvrcvl radicals are oreferred.
As used herein, the term cycicalkyl embraces saturated carbccyclic radicals and, uniess otherwise specified, a cyclcalkyi radical typically has from 3 to 7 carbon arcms.
A cyclcalkyi radical is typicaily unsubstiiuted or substituted with 1, 2 or 3 substituents which may be the same or different. The subsiituents are preferably selected from halogen atoms, preferably fluorine atcms, hydroxy groups and aikoxy groups having from 1 -to-4 carbon atoms. When a cyclcalkyi radical carries 2 or more substituents, the substituents may be the same or different. Typically the substituents on a cycloalkyl group are themselves unsubstitutec.
Examples include cycioprcpyl, cyclcbutyl, cyclopentyl, cyclohexyl and cycloheptyl. It is preferably cyciopropyi, cyclccentyl and cyclohexyl.
As used herein, the term cycloalkenyl embraces partially unsaturated carbccyclic radicals and, unless otherwise specified, a cycloalkenyl radical typically has from 3 to 7 carbon atoms.
A cycloalkenyl radical is typically unsubstituted or substituted with 1, 2 or 3 substiruents which may be the same or different The substituents are preferably selected from halogen atoms, preferably fluorine atcms, hydroxy groups and.aikoxy groups having from 1 to 4 carbon atoms. When a cyclcalkenyl radical carries 2 or more substiruents, the substituents may be the same or different Typically, the substituents on a cycloalkenyl group are themselves unsubstituted.
bxarr.ples include cycicbutenyi, cyciopentenyl, cycichexenyl and cycfoheptenyl. Cyclopenteny! and cycichexenyl are preferred.
As used herein, the term heterccyciyi radical embraces typically 3 non-aromatic, saturated or unsaturated Cs-C- C3rcc-cyciic ring , sucn as a 5, 6 or 7 membered radical, in which one cr rnore. :or example 1, 2. 3 or 4 zf the carbon atoms creferacly lor 2 of the carbon atoms are replaced by a heteroatcm selected from N, 0 and S. .Saturated heterocyclyi radicals are preferred. A heterocyclic radical may be a s;rg;e ring or two or more fused rings therein at least one ring contains a heteroatcm. Vvuer a heterocyclyi radical carries,2 or more substituents. the substituents may be the same or different.
A said optionally substituted'heterocyclyi radical is typically unsubstituted cr substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from.halogen atoms, preferably fluorine atoms, hydroxy groups arc alkoxy groups having from 1 to 4 carbon atoms. Typically, the substituents on a heterocyclyi radical are themselves unsubstituted.
Examples of heterocyclic radicals include piperidyl, pyrroiidyl, pyrroiinyi, piperazinyi, morpholinyl, thicmorohclinyl, cyrrolyl, pyrazolinyl, pirazolidinyi, quinudidinyl, triazclyl, pyrazolyl, tetrazolyl, crcmanyl.-isocromanyl, imidazolidinyl, imidazolyl, oxirany!, azaridinyi, 4,5-dihydro-oxazoiyi and 3-aza-tetrahydrofuranyl."
Where a heterocyclyi radical carries 2 or more substituents, the substituents may be the same or different.
As used herein, some cf the atoms, radicals, moieties, chains and cycles present in the general structures of the invention are "optionally substituted". This means that these atoms, radicals, moieties, chains and cycles can be either unsubstituted or substituted in any poisition by one or more, for example 1, 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically acceptable atoms, radicals, moieties, chains and cycles. When two or mere substituents are present, each substituent may be the same or different. The substituents are typically themselves unsubstituted.
t ypically when a cyclic radical is bridged by an alkylene or alkylenedioxy radical, the bridging alkylene radical is attached ic the ring at non-adjacent atoms.
As used herein, the term halogen atom embraces chlorine, fluorine, bromine and iccine atoms. A halogen atom is r/picaiiy a fluorine, chicrine or bromine scon, most preferably chlorine or flucrine. The term halo when used as a prefix has the same meanina.
As used herein, an acyiamino group is typically a said acyi group attached to an amine group.
As used herein an alkylenedioxy g-oup is typically -0-R-0-, wherein R is a said
alkylene group. - -
As used herein, an alkoxyacyl group is typically a said aikoxy group attached to^asaid acyl group.
As used herein, an acyloxy group is typically a said acyi group attached to-an oxygen
atom.
As used herein, a cycioaikoxy group is typically a said cycloalkyl group attached tc-an-oxygen atom.
Compounds containing one or more chirai centre may be used in enantiomerically cr diastereoisomerically pure form, or in the form of a mixture of isomers.
As used herein, the term pharmaceutical/ acceptable salt embraces salts with a pharmaceutical acceptable acid or base. Pharmaceutical acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, "lydrobromic, hydroiodic and nitric acid and organic acids, for example citric, fumaric, naieic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, nethanesufphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid, ^harmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases, for example aikyl amines, arylalkyl amines and heterocyclic amines.
According to one embodiment of the present invention in the compounds d r'ormuia ! ■ R: represents a hydrogen atom or an aryl group, for example a phenyl group, which :s optionally substituted by one or mere, for example 1. 2, 3 cr 4. substituents selected from halogen atoms and nitre. Ci-C. alkcxy, C-Ci hycroxyalkyl and -C02~C--C, alkv-groups. Wore preferably, R- !s a h\:-cgen atom or a phenyl group which is unsubstitued or substituted .v::h 1 c: 2 unsuostituted SL-cstituenis seiected fr:m fluorine, chlorine, nitro. C.-C- hydrc;-;yaikyfand -CO:--C--C- aikyi) substiiuerts. Most preferably R2 is hydrogen.
In another embodimen: of the present invention in the compounds of formula (i) R: represents a group:se!ectec Torn:
- • ~a (Gi*4) alkyl group which is optionally substituted by one or mere, for "v "'-""'■■'■'e-xample'l, 2". 3 or 4 hydroxy groups; • a group of formula
-
wherein n is an integer from 1 to 3 and R6 represents a (C3.s) cycloalkyl group.
More preferably, RT is an unsuostituted C1-C4 alkyl, an unsuostituted CpCa hydroxyalkyl or an unsubstituted cyclopropyl-(Ci-C^ alkyl)- group.
In still another embodiment of the present invention in the compounds of formula (I) R2 represents a group selected from mcnocyclic or poiycyclic aryl or heteroanyl groups, which are optionally substituted by one or more, for example 1 f 2, 3 or 4, substituents selected from:
• halogen atoms;
• (C-.C4) alkyl groups, which are optionally substituted by one or more, for - • example 1, 2, 3 or 4 hydroxy groups; > .
• and'(C^Cd) alkoxy, nitro, hydroxy, hydroxycarbonyl, carbamoyl, (C-.C-alkoxy)-
carbonyi and cyano groups
in another embodiment of rhe present invention in the compounds of formula (I), R3 represents a monocyclic or pciycyciic aryl or heteroar/t group, which is optionally substituted by one or more, for example 1, 2, 3 or 4, subseituents selected from:
• halogen atoms:
• alkyl ^nd aikyiene croups. ;vh:cr are optionally substituted by one or mere, for example 1, 2, 3 or 4. suos::tuems selected from haic-aen atoms; and
• phenyl, hydroxy, hydroxycarbonyi, hydroxyaikyl, aikoxycarbcnyl, alkoxy, cycioalkoxy, nirro, ar/icxy. alkylthic, aikylsuiphinyl, aikyisulphcnyl. alkylsulphamoyl. acyi. amine, mono-or di-alkylamino, acyfamino, -hydroxycarbonyi, aikcxycarbcm-i. carbamoyl, mono- ordi-3lkylcarbamoyi. ureido, N'-alkylureido. N'.N'-diaikyiureido, alkylsulphamido, amindsupronyi, mono- or di-aikylarnir.osuphonyi. cyano, difluorcmethoxy or'tnrlucrcme'thoxy groups;
More preferably, RJ represents a ohenyi group, a naphthyl croup^6r"a"5-':to T--membered monocyiic or polycyciic heteroaryi group containing-1,- 2 or 3 heteroatcms selected from N, O and S, the phenyl, naphthyl and heteroaryi groups being unsubstituted or substituted with 1 or 2 unsubstituted substituehts selected from:
• halogen atoms, for example fluorine and chlorine atoms;
• Ci-C4 alkyl and C-rCi hydroxyaikyl groups; and ' "■ ' - : - ■■ '
• C-1-C4 alkoxy, nitro, hydroxy, hydroxycarbonyi, carbamoyl, (C1-C4. alkoxy)-carbonyl and cyano groups.
Still more preferably R3 represents a phenyl group, a naphtyl group or a substituted or unsubtituted heteroaryi group selected from substituted or unsubstituted oxadiazoly!, oxazoiyl, pyridyl, pyrrolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, furanyl, quinoiinyl, isoquinolinyl, indolyl, benzoxazolyi. naphthyridinyi, benzofuranyl, pyrazinyi, pyrimidinyl and the various pyrrolopyridyl radicals.
In another embodiment of the present invention in- the compounds of formula (I) R" represents ■ * -
• an unsubstituted mono-(C--C4 alkyi)amino or di-(d-C4 alkyl)amino group;
• a CrC- alkyl group which is unsubstituted or substituted by one or more, for example 1 or 2, substituents selected from hydroxy, C1-C4 alkoxy, amino, mono-(CrC4 alkyl)amino and di-fC-Ci alkyl)amino groups;
• an unsubstituted phenyl-(C-C- alkyl)- group; or • 3 group of formula
-(CH2)n-R6
wherein n is 2 and R° represents a radical seiected from phenyl, pyridyl and :nenv optionally substituted by :ne or ~zr~ substituents seiected from halogen atoms and aikyl, hydroxy, alkoxy. alkylenedioxy. amino, rncno-ordl-aikylaminc. nitre, ciano and trifluorcmethyi croups.
:L- ■;. More preferably, R~ represents ar aikyl group having from 1 to 6 carbon atoms arc -"which-is unsubstituted or substituted by one or more, far example 1, 2, 3 or 4, " substituents selected from halogen atoms and hydroxy groups.
: In yet another embodiment cf the present invention in the compounds of formula '[) R~ represents a group CCOR' cr a monocyclic or polycyciic aryl or heteroanyl group, which is optionally substituted by one or more substituents selected from halogen ■ atoms, Gi-C4 alkyl groups, C-Ci alkcxycarbonyi groups, a hydroxycarbonyl group and d-C^ alkoxy groups, wherein R' is as defined above.
In another preferred embodiment of the present invention in the compounds cf formula (i) R° represents a group -COGR7 or a monocyclic or poiycyclic aryl or heteroaryl group, which is optionally substituted by one or more, for example 1, 2, 3 or 4, substituents selected from halogen atoms and (VC4 alkoxy groups, wherein R7 has the meaning defined above.
More preferably, R° represents -C02R\ wherein R7 represents an unsubstituted C--C^ aikyl group, or R5 represents a phenyl group or a 5- to 10- membered monocyciic or polycyciic heteroaryl group containing 1 or 2 heteroatoms seiected from Nf 0 and S, the phenyl and heteroanyl groups being unsubstituted or substituted by 1 or 2 substituents selected from d-d alkoxy groups and halogen atoms, for example, chlorine and fluorine atoms.
Stiii more preferably R= represents a phenyl group, or a substituted or unsubtituted heteroanyl group selected from substituted or unsubstituted oxadiazolyl, oxazolyl,
pyridyl, pyrrolyl, imidazolyi, thiazolyl. thiadiazolyl, thienyl. furanyl, quinoiinyi, isccuinolinyl, indolyl, benzoxazoiyl. ".aphthyridinyl, benzofuranyl, pyrazinyi, pyrimicinyl and the various ovrrolccvridv! radicals.
Finaily in another embodiment of the present invention, \-vhen R3 represents a pcivcyclic heteroaryl group it is rycicaily a group of fcrmu;a (XXIII):
wherein Y represents an 0 atom. 2 3 atom or a -NH- group,jus U, 1 or 2 arc each R is the same or different and is a haicgen atom or a C-:CJ"ail
Particular individual compounds or the invention jnciude:
5-acetyf-2-ethyl-4-[(3-flucrophenyl>mino]-6-pyridin-3-ylpyridazin-3(2H)-one
5-acetyl-4-[(32-ethyi-5-pyridin-3-ylpyndazin-3(2H)-one
5-acetyl-4-[(3,5-dichlorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(
5-acebyl-2-ethyl-4-(1-naphthyiaminor5-pyridin-3-ylpyridazin-3(2H)-one
methyl 4-[(5-acety!-2-ethyl-3-oxo-e-pyndin-3'yl-2,3-dihydropyridazin-4-
yl)amino]benzoate
5-acetyl-2-ethyl-4-[(2-fluorophenyi;amino]-6-pyridin-3-ylpyhdazin-3(2H)-one
5-acetyl-4-[(2-chlorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one
5-acety(-2-ethy!-4-{[4-(hydroxymethyi)phenyl]amino}-6-pyridin-3-ylpyridazin-3(2H)-on9
3-[(5-acetyl-2-ethyl-3-oxo-5-pyridin-3-yl-2,3-dihydropyridazin-4-yl)amino]benzonitriIe
5-acetyl-4-[(3-chlorophenyi)amino]-2'(cyc!opropy(methyl)-6-pyridin-3-ylpyridazin-3(2H)-
one 5-acetyl-2-(cyclopropyimethyl)-4-[(3.5-dichlorophenyi)amino3-6-pyridin-3-yipyridazin-
3(2H)-one
5-ac8tyl-2-(cyclopropylmethyl)^.[(2-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-
one
5-acetyi-4-[(2-chlorophenyl)amino]-2-(cyciop
one
3-{[5-acetyl-2-(cyciopropyimethyl)-3-oxc-6-pyridin-3-yl-2I3-dihydropyridazin-4-
yl]amino}benzonitriie
5-acetyl-2-(cyclopropy]methylH^ cne
5-3C9tyi-2-9thyI-6-(4-fIucrop^
c-acatyl-o-nh-banzlmidazol^-y^
3-acetyl-3-(1l3-b9nzcxazGl-2-yi;;-4-['.3-chlcrophenyI)amincJ-2-ethylp^^^
3-3ceNi-5"{1I3-benzoxazoi-2-yi>2-etry!-4-[-'3-fiucrcphenyi)amino]pyridazin-3 2H}-one
5-ac3^yl-o-benzooxazci-2-yi-4-[c:5-(3-cnlorccheny!)-amino]-2-ethyl-pyri^
5-ac9tyl-o-benzooxazc!-2-yl-4-[bi5-(3-:1uoropheny!)-anir.c]-2-ethyl-p 2Hi-one
3-^5-3C8^yl-2-9thyi-3-cxo-5-py^;c!^-3-/l-2,3-dihyd^opyrid3zi^-4-yl)ami^Q]
5-=c9tyl-2-9thyI-4-(isccui^
5-ac9tyl-4-i(2"butylquirazciin-4-yi}arllro]-2-ethyl-6-ph9nyipyridazin-3
3-ac9tyl-4-(1,2-b9nziscthiazoJ-3-yianino)-2-9thyl-6-ph9nylpyridazin-3(2H)-ons
5-ac9byl-2-ethyI-6-phenyl-4-(pyricin-4-y!arr:ino)pyridazin-3f2H)-on9
5-ac9tyl-2-9thyI-4-[(2-hydrcxy^
5-acetyi-2-9thyl-o-pher.ylr4r(quir.azoiin-4-ylamino)pyridazin-3(2H)-on9
5-acetyl-4-[(4-chloro-1H-indazcl-3-yi)aminoh2-ethy[-5-phenylpyridazin-3(2
5-acetyl-4-[(7-chIorGquinoiin-4-yi;aminoi-2-ethyl-6-phenylpyridazin-3(2H)-one
5-3cetyl-4-[(4T6-dichlGrcpynmidin-2-yl)amino]-2-ethyl-6-phenyipyridazin-3(2H)-one
5-acetyl-2-9thyl-4-[(6-hydroxy-2H-pyrazQlo[3,4-d]pyrimidin-4-yl)amino]-6-
phenyipyridazin-3(2H)-cne -
5-acatyl-2-ethyl-4-((2-methylquinciin-4-yl)amino]-o-phenylpyridazin-3(2H)-one
5-3C3tyl-2-ethyl-4-(1H-imidazol-2-ylarnino)-6-phenylpyridazin-3(2H)-one
5-acetyl-2-ethyl-6-phenyl-4-(quinoIin-4-ylamino)pyridazin-3(2H)-one
5-acetyl-4-(cinnolin-4-ylamino)-2-ethyl-o-phenylpyridazin-3(2H)-on9
5-acatyl-2-ethyl-6-phenyl^{1H-pyrazcJo^
5-ac8tyl-2-ethyl-6-phenyl-4-(thieno[2,3-d]pyrimidin-4-ylamino)pyridazin-3(2H)-Gne
5-ac9tyl-2-ethyi-4-(1H4ndazol-6-yiarnino)-3-phenylpyridazin-3(2H)-on9
5-acetyl-4-{(3-ch!orophenyI)aminoj-2-eihyi-6-(2-methoxypyridin-4-yl)pyndazin-3(2H
one
5-ac8tyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-(6-methoxypyridin-3-
yl)pyridazin-3(2H)-ons
5-acstyr-2-ethy!-4~[(3-fT.etho>7ph^^
5-ac9tyl-6-(1-b9nzofuran-5-yl)-2-ethyl-4-[(3-fluorophenyl)amino]pyridazin-3(2H
1-ethyl-5-[(3-m9thoxyphenyl)amino]-nJn-dimethyl-6-oxo-3-pyridin-3-yi-1I6-
dihydropyridazine-4-Garboxamide
5-[{3~chlorophenyi)amino]-1-e^ 4-carooxamide
2-ethyi-4-[(3-fluorophenyi)afri^
2~thy!-44(3-fluorophenyi)arr^
5-[(dimethy(arTiino)ac5t\'i]-2-et'nyl-4-; 3-meLhoxyphe-y!:ar^inc!-coyridin-3-y:D7r;caz:n-
3(2H)-one
2-ethyl-4-[i3-fIuorophenyl)ar,.irlo]-5-[ nr,ethyiarriro;acs^i3-5-pyHcin-4-yipyr:d3z:n-3i.2H.
one
3-{[2-ethyl-3-cxo-5-(3-preny'o^^
yi]amino}benzamide
ethyl 4-ac9tyl-5-[(3-chIcrophar.yi)arr^
carboxyiate
ethyl 4-acetyl-5-amlno-1-ethyi-6-oxo-1,6-dihydropyridazine-3-c3rboxylate
5-acetyl-6-(1,3-benzoxazol-2-yi)-2-e^
one ~- —•.■■..:-■
5-acetyl-6-{1,3-benzcxazol-2-yi)-2-ethyl-4-{[4-(hydrcxymethyl)phenyl]am
3(2H)-one
5-acetyl-2-ethyl-4-(iscquinolin-4-ylamino)-6-phenylpyridazin-3(2H)-one .-..,.-. ...._.. .
5-acetyl-2-ethyi-4-(1T6-naphthyndin-3-ylarnino)-5-phenylpyridazin-3(2H)-one
5-acetyl-2-ethyt-4-[(5-methoxypyridir-3-yl)a'mino]-5-phenylpyridazin-3(2H)-cne
5-acety!-2-ethyl-o-pyndin-4-yl-4-{pyridin-3-ylamino)pyridazin-3(2H)-one •. .
5-acetyI-2-ethyI-4-[(4-methylpyridin-3-yI)amino]-6-pyridin-4-ylpyridazin-3(2H)-cne
5-acety!-2-ethyl-4-(isoquinolin-4-ylamino)-6-pyridin-4-ylpyridazin-3(2H)-Gne
5-acetyl-2-ethyl-6-pyridin-4-yl-4-[(3,4r54rifluorophenyi)amino]pyridazJn-3(2H
5-acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-pyridin-3-ylpyricazin-3(2H
5-acetyl-2-ethyi-4-{isoquinolin-4-ylamino)-6-pyridin-3-ylpyridazin-3(2H)-one
5-acetyl-2-ethyI-6-pyridin-3-y!-4H(3,4r54rif!uorophenyl)amino]pyridazin-3(2H)-cne
5-acetyl-2-ethyl-4-(quinoiin-5-ylamino)-6-thien-2-ylpyridazin-3(2H}-one
5-acetyl-2-ethyi-4-(pyridin-3-ylamino)-6-thien-2-ylpyridazin-3(2H)-one
4-[(5-acetyl-2-ethyl-3-oxo-6-thien-2-yl-2,3-dihydropyridazin-4-yl)amino]b9nzonitrile
5-acetyl-2-ethyl-6-thien-2-yI-4-[(314,5-trifIuorophenyl)amino]pyridazin-3(2H . ■
5-Acety!-4-(bis (4-cyanophenyl)amino)- 2-ethyl-5-thien-2-yIpyndazin-3(2H)-one
5-ac8tyl-2-(cyclopropylmethy!)-4-(qutnolin-5-ylamino)-6-thien-2-yipyrW
5-acetyl-2-(cycIopropylmethyi>4^
5-acetyl-2-ethyM-(quinolin-5-ylaminor6-thien-3-ylpyridazin-3(2H/-one
5~acetyi-4-[(3-chlorophenyl)arr:no]-2-ethyl-6-thien-3'yipyridazin-3(2H)-one 5-acetyl-2-ethyl^(pyrid^
4-f(5-acetyl-2-ethyl-3-oxo-6-tfr^ 5-3Cstyl-2-e
2-ethyl-6-phenyl-5-(3-pheny^^
2-ethyl-5-phenyl-5-{3-phenyipr:^^
2-ethyl-4HjsoquincIin-^-yla^
2-6thy!-6-phenyl-4-(quinol]^^
2-e^yl-3-phenyi-4-(pyHdin-3-yianirc--5-(3-thien-3-yiprcpano
5-3C8tyl-4-[(3-chiorcchenyi:anrare^^
3
5-acetyI-6-(l,3-benzoiniazoi-2-/V;-^-[.3-chlorophenyI)amino]-2-ethylpyri
5-acetyl-6-(1-benzofur3n-2--yl>4-;(3-crlcrophenyl)amino]-2-ethylpyridazi^
5-acstyl-2-ethyl~6-pyndin-3-y^
44(5-ac8tyi-2rethyi-3rOXO-5-pyr;din-3-yl-2t3-dihydropyridazin-4-yl)amino]benzoi^ acid
5-ac8tyl-2-ethyl-4-[(1-oxidcpyric;n-3-y!)amino]-6-phenylpyridazin-3(2H
ethyl 3-(5-ac9tyi-2-ettry1-3-oxo-6-oyri
3-{(5-acetyl-2rethyl-3-oxo-5-pyr;G!n-4-yl-2,3-dihydropyridazin-4-yl)amino]benzanide
5-acety!-2-ethyi-6-phenyl-4-(thieno[2f3-b]pyridin-3"ylamino)pyridazin-3(2H)-one
5-acetyl-2-ethyI-4-[(6-fiuoropyrid;n-3-y!)amino]-6-phenylpyridazin-3(2H}-one
5-ac8tyl-2-ethyl-4-[(2-methy!pyricin-3-yi)amino]-6-phenylpyridazin-3(2H)-one
5-acetyl-4-{[2-(dimethylamino)py
5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]pyridine-2-
carboxylic acid
5-ac8tyl-2-ethyl-4-[(2-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one
5-ac8ty[-2-ethyl-4-(1H-indazol-4-ylamino)-6-phenylpyridazin-3(2H)-one
5-acstyi-4-[(2-chlorcpyndin-3-yl)aminc]-2-ethyl-6-phenyipyridazin-3(2H)-one
5-ac8tyl-4-[(5-chloropyridin-3-yi)aminc]-2-ethyi-6-phenylpyridazin-3(2H)-on8
5-[(5-acetyi-2-ethyi-3-oxo-5-phenyl-2J3-dihydropyridazin-4-yf)amino]nicotinarnide
5-acetyl-2-8thyl-4-(17-naphthyridin-8-yiamino)-6-phenylpyridazin-3(2H)-one
2-ethyl-5-glycoioyW-[(2-methyipyridin-3-yl)amino]-6-phenyipyridazin-3(2H)-one
methyi 5-[(5-acetyl-2-ethyl-3-oxc-o-phenyl-2f3-dihydropyridazin-4-yl)arnino]nicotinat8
5-[(5-acetyl-2-sthyl-3-oxo-5-pher,yl-2f3-dihydropyridazin-4-yl)amino]nicotinic acid
5-ac9tyl-2-ethyl-4-(1,5-naprthyridin-3-yiamino)-6-phenylpyridazin-3(2H)-one
5-acetyl-2-ethyl-4-[(S-hydroxy one
5-acetyl-2-ethyl-5-phenyi-4-(trien-2-y)amino)pyndaz:n-3('2H)-one
5-ac3r/!-2-ethyl-o-phenyi-4-[t2-pheny[pyridin-3-yi)arri^^
ethyl {5-[(5-3cetyl-2-elhyi-3-exc-3^
yl}ace*3te
5-acer/l-2-ethyI-4-[(6-methylpyridin-3-yl)amincJ-5-phenyipy
5-aceTy!-2-ethyi-4-[(6-hydroxy?7
5-acs?y!^ethyl-4-[(2-fluoropyr;cm^^
5-aceryl-4-[(6-chloro-4-methyipyridirr3-yl)amino]-2-ethyl-6
5-aceiyl-2-6thyl-4-[(3-hydrcaypy -
5-acetyl-2-ethyl-4-[(4-nethoxypyridin-3-yl)amino]-6-phenyipyridazin-3(2H)-cn^ .J^
5-acetyl-2-ethyi-4-(isoquir.olin-3-ylamino)-5-phenylpyridazin-3(2H}-one ".:•:'-.:..:.:.-*
5-acer/i-2-ethyl-6-phenyI-4-(q!jinolin-7-ylamino)pyridazin-3(2H)-one-:■■*■-■;' -'---.: '■-■:--
5-acetyl-4-[(5-chioropyridin-3-yl)am
5-acebyl-2-ethyl-6-(4-fIuorophenyl)-^-^
5-acebyl-2-ethyl-6-(4-rluorophe^
5-acetyl-4-[(2-chioropyndin-3-yi)amino]-2-ethyl-6-(4-r1uoropheny!-)pyridazin-3(2H) .-
5-acstyi-2-ethyl-6-(4-fluorophenyi)-4-[(4-methyipyridin-3-yt)amino]pyridazin-3(2H
5-acety!-2-ethyl-6-(4-fluorophenylH^
5-ac8tyi-4-[(2-chloropyridin-3-yl)amino]-2-(cyclopropylmethyl)-6-(4- ■ : -•*-*■•-
fluorophenyl)pyridazih-3(2H)-one
5-acebyl-2-(cyclopropyimethyi)-6-(4-fiuorophenyl)-4-((2-methoxypyridin-3- ■
/()aminojpyridazin-3(2H)-one -
5-acetyl-2-(cyclopropy!methyl)-5-(4-fluorophenyl)-4-[(2-methylpyridin-3-
/l)amino]pyridazin-3(2H)-one 5-acetyl-2-(cyclopropylmethyl)-6-(4-r7uorophenyl)-4-[(2-fIuoropyridin-3-
/f)amino]pyridazin-3(2H)-one 5-acety[-2-(cyc!opropyimethyl)-5-(4-fluorophenyl)-4-[(4-methyIpyridin-3-
/l)amino]pyridazin-3(2H)-one 5-acetyU2-(cyciopropy!methyi)-8-(4-Tluorophenyt)-4-[(pyridin-3-yi)amino
3(2H)-one
5-acetyl-6-(3-chlorophenyl)-2-etty^
5-acebyl-6-(3-cnlorophenyI)-4-[(2-chloropyridin-3-y!)amino]-2-ethylpyridazin-3(2H)-one
5-3cetyl-5-(3-chloropheny|)-2-ethyl-4-[(4-methyipyridin-3-yi)am
methyl 5-[(5-acetyl-2-ethyl-3-c^
carboxylate
5-3C8tyl-2-ethyl-4-[(4-rr;ethylpyric:n-2-yl)arniV:0]-6-phenylp
5-3cetyi-2-ethyl-4-(iscquinoiin^
5-ac9tyi-2-ethyl-6K4-methoxyp
5-3cety[-2-ethyl-6-{4-methcxyphe^
5-acetyl-2-ethyl-6-(4-methoxy-oheny:'-4-(1-oxy-quinoiin-5-ylamino)-2H
5-3C3tyf-2-ethyl-4-(isoquinoiin-4-y!a^
5-ac8tyl-2-ethyl-6-(3-methoxyphenyr"-4Hpyricin-3-ylamino)pyridazin-3
5-scetyl-2-ethyl-6-(3-m9thoxyph3r^
5-acetyl-2-ethyl-6-(3-methcxyphenyf"-4-[(1-oxidoquinolin-5-yI)amino^
one ■ - ■-----'5-3cetyl-2'-ethyl-4-{isocuinolin---ylarr;ino)-6-(4-methylphenyl}pyridaz!n-3(2H)-cne " -
-5-3cetyl-2-ethyl-6-(4-methyIphenyl)-4-'pyridin-3-ylamino)pyridazi v5-3cety>2-ethyl-6-(4-methyiphe^^^
5-acetyl-2-ethyl-6-(4-methyIphenyl)---[(1-oxidoquinolin-5-yf)amino]p
5-acetyl-2-ethyl-5-(4-methylphenyl)-4-r(4-methylpyridin-3-yl)am ^•5-aeety!-2-ethyl-4-(isoqui^
5-acetyl-2-ethy[-6-(3-methyIphenyI)-4-^Dyridin-3-yiamino)pyridazin-3(2H)-on9
5-acety!-2-ethyl-6-(3-methylpnenyl^
5-acetyl-2-ethyl-6-(3-methylphenyl)-4-[(4-methylpyridin-3-yl)amino]p
methyl 4-[4-acety!-1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-1,6-dihydropyridazin-3-
yi]benzoate
methyl 4-[4-acetyl-1 -ethy(-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-
yljbenzoate
4-[4-acetyl-l -ethyi-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoic acid
methyl 4-{4-acetyl-1-ethyl-5-[(4-methy!pyridin-3-yl)amino]-6-oxo-1,6-dihydropyridazin-3-
yl}benzoate
4-{4-acetyl-1-ethyI-5-[(4-methy!pyridin-3-yl)amino]-6-oxo-1,6-dihydropyridazin-3-
yf}benzoic acid
methyl 3-[4-acetyi-l-ethyl-6-cxo-5-(pyridin-3-yiamino)-1T6-dihydropyridazin-3-
yljbenzoate - -
3-[4-aceb/!-1-ethyi-S-oxo-5-(p^
5-ac9tyl-4-[(3-chIoro-4-fiuorcph6nyi)amino]-2-ethyl-6-pyridin-4-yfpyndazin-3(2H)-one 5-acetyi-4-[bis(3-chloro-4-fluorc^^
5-ac3tyl-4-[(3
5-acaiyl-4-[bis(3-chlcr>a-fiucrop^
methyl [4-acetyl-6xc-3-pher\i-5-(qui^^
^-acsiyl-o^xo-S^her.yi-S-vCur.oH^ acic
5-acetyl-2-ethyl-4-[(3srieihy^
5-acaty!-2-eihyi-6-phenyl-4-0H-pyr3Z0i-3-yiarnino)pyrJG3Z!p-3(2H)-one
5-ac6tyl-2-ethyl-5-phenyi-4-(rH-purin-o-yiamino)pyric3zin-3(2H'i-one
5-acatyl-2-ethyi-4H(3-reethy^^
5-acetyl-2-ethyl-4-[(3-hydroxycuinc^
5-aceryl-2-ethyl-4-(1H4ndazci-^^
5-acety(-4-[(6-bromoqi:inolirr3-yl)a^
5-3cetyl-2-ethyl-4-{(5-methyliscxazot-3-yl)3mino]-8-phenyicyricaz:n-3(2H
5-acetyl-2-ethyl-4-(isoxazal-3-yiamino^
5-ac8tyl-2-(cyclopropy!methyiv-o-ph^^
5-acetyl-2-(cyclopropylmethyi;-Si3heny^^
5-acetyl-2-ethyl-4-[(1-methyMH-pyrazol^
5-acetyl-2-ethyl-4-[(1-oxidoqL,iroiin-5-yl)aminoI-6-pheny!pyridazin-3(2H)-one
5-ac8byl-2-ethyl-4-[(2-oxidoiscGuinoiin-5--yl)arninc]-8-pheny!pyrid3zin-3(2H)-or.e
5-acetyl-6-(3-chlorophenyl)'2-ethyl-4-(quinoiin-5-ylamino)pyridazin-3(2H)-one
5-ac8tyl-6-(3<:hlorophenyl>
5-acetyl-2-ethyi-6-pyridin-4-yi---{quinclin-5-ylamino)pyridazin-3(2H)-one
5-acetyl-2-eihyl-6-pyridin-3-yl-4-(quinoiin-5-ylamino)pyridazin-3(2H)-one
5-acetyl-2-ethyl-4-[(8-fiuoroquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one
5-acetyl-2-(cyclopropylmethyl;-5-(4-flLiorophenyl)-4-(quinolin-8-ylamino)pyridaz;n-
3(2H)-one
5-ac8tyl-2-ethyl-6-(4-fIuorophenyf)-4-(quinoiin-5-ylamino)pyridazin-3(2H)-one
5-ac8tyl-2-9thyi-6-(4-fluoropher,yl)-4-(quinolin-S-ylamino)pyridazin-3(2H)-one
5-acetyi-2-(cyclopropylmethyl)-5-(4-fluorophenyl)-4-(quinoIin-5-ylamino)pyricaz:r
3(2H)-one
5-acetyl-6-(3-chlorophenyi)-2-ethyl-4-[(1-oxidoquinoIin-5-yl)amino]pyrW
5-acetyl-2-9thyi-4-[(2-m9thy!q'j;noiin-5-yl)amino]-6-pheriyipyridaz!n-3(2H)-one
5-ac8tyl-5-(3-chloropnenyi)-2-ethyl-4-(isoquinolin-5-yIamino)pyridazin-3^
5-acetyl-2-9thyl-6-(4-fIuoropher//l)-4-[0^
5-acetyl-2-ethyl-6-(3-fluorophenyl)-4-(quinoIin-5-ylamino)pyridaz!n-3(2H)-one
5-acetyl-2-ethyl-6-(3-fluorophenyl)-4-^^
5-[(5-acetyl-2-ethyl-3-cxo-6-phenyi-2.3-dihyd carboxylic acid
and pharmaceutically acceptable sa'.s thereof.
Of outstanding interest are:
5-Acetyl-2-ethyl-4-[(3-^
5-Acetyl-2-ethyl-4-(1-naphthy;ar^
5-Ac8tyl-4-[(3-chloropnenyl)a^irc]-2-e'hyl-6-pyridin-4-y!pyridazin-3(2H)-one
5-Acetyl-2-ethyl-4-
5-Acetyl-2-ethyl-4-[(2-meihylpr^
5-AceWl-2-ethyl-4-[(3-nethoxypnenyi;3niino]-6-pyridin-4-ylpyridaz!n-3(2H)-one
4~[(5-Acety!-2-ethyi-3-cxo-6-pyntiin^^ acid
5-Acetyi-4-[(3-chlorophenyl)arniro]-2-2^
one
5-Acetyi-4-[(3-chlorcphenyl)anino]-2-eihyl-6-thien-2-ylpyridazin-3(2H)-one
5-Acetyl-2-ethyl-6-phenyl-4-(pyridin-3-yIamino)pyridazin-3(2H)-one
5-Acetyl-2-ethy!-5-phenyl-4-(quinolin-3-ylamino)pyridazin-3(2H)-one
5-Acetyl-2-ethyl-4-(1H-indol-4-ylamino)-5-phenylpyridazin-3(2H)-one
5-Acetyl-2-ethyl-6-phenyl-4-(quinoiin-5-ylamino)pyridazin-3(2H)-one
5-Acetyi-6-{3-fluorophenyl)-2-i3cprcpyi-4-(pyridin-3-ylamino)pyridazin-3(2H)-one
5-Acetyl-2-(cycIopropyimethyl;-o-(3-r1ucrophenyl)-4-(pyridin-3-yiamino)pyridazin-3(2H)-
one
5-Acetyl-2-ethyl-6-(4-fIuorophenyl)^-(pyridin-3-ylamino)pyridazin-3(2H)-one
5-Acetyl-2-ethyl-4-(isoquinolin-5-ylamino)-6-phenylpyridazin-3(2H)-one
5-Acetyl-6-(lI3-benzoxazol-2-yf)-2-ethyl-4-[(3-fIuorophenyl)amino]pyridazin-3(2H)-one
and pharmaceutically acceptable salts thereof.
The compounds of the present invention may be prepared by one of the orccesses iescribed below.
Compounds (i; may De cotamed as shown in Scheme* 1
An isoxazolo[3,4-d]pyridazin-7-(6H)rORe.of.formula-(ll)f wherein R\ R~ and R5- -are as hereinbefore defined, is hydrcgenated to yield an 4-aminopyridazin-3
Condensation of 4-aminopyridazin-3(2H)-ones (III) with an aryl or heteroaryl bromide of formula (A) wherein R3 is as hereinbefore defined, gives compounds (la), wherein R1, R3, R4 and R° are as hereinbefore defined. The reaction is carried out in the presence of a copper salt such as cuprous iodide and an inorganic base such as potassium phosphate, potassium carbonate or sodium carbonate and can also be performed in the presence, of an organic base, preferably a diamine base such as N, N'-dimethylethylenediamine in an inert solvent such as toluene, dioxane or dimethylformamide, at a temperature from -20°C to the boiling point of the solvent. It can also be performed neat.
Alternatively, condensation cf 4-aminopyridazin-3(2r/)-one derivative 'ill), wherein R\ R1 and R~ are as hereinbefore defined, with a boronic acid of formula (IVa.. wherein RJ is as hereinbefore defined, gives compound .la;, wherein R\ R:. R~ and Rf are as hereinbefore defined, "he reason is carried cut In the presence of a :ocper sal: such, as cupric acetate and an organic case, preferably an amine base such as •nethylamine, in an inert solvent sucn as cioxane, methylene chloride or ■ tetrahydrofuran, at a temperature from - 20° C to the bciiinc point of the solvent. Compounds (la) are equal to compounds (I) when R- is hydrogen.
Condensation of an 4-=nincpyr'dazin-3(2H)-cr.e derivative (la), wherein R\ R:. R" and R° are as hereinbefore defined, with a boronic acid (IVb), wherein R~ .:s as hereinbefore defined, gives compcuncs (1), wherein R\ R-, R3, R4 and R° are as hereinbefore defined. The reaction is carried out in the presence of a copper salt such as cupric acetate in the presence of an organic base, preferably an amine base such as tnethylamine, in an inert solvent such as dioxane, methylene chloride or tetrahydrofuran, at a temperature from - 20° C to the bciiing point of the solvent.
Alternatively, compounds (I) may be obtained as shown in Scheme 2.
Scheme 2
Oxidation of an isoxazclo[3,4-c]pyridazin-7(6/-/)-cne of formula (II), wherein R\ R*1 and R° are as hereinbefore defined, gives a 4-nitropyridazin-3(2H)-one derivative of formula (V), wherein R\ RT and R5 are as hereinbefore defined. The reaction may be performed using an oxidising agent such as cerium ammonium nitrate under acidic conditions by methods known per se, e. g. V. Dal Piaz et al. Synthesis, 1989, 213.
Condensation of the 4-niiropyridazin-3(2H)-cne derivative of formula V\ wherein R1, R4 and R~ are as hereinbefore defined, with the corresponding amine (711 wherein R~ and R~ are as hereinbefore defined, following methccs known ^er se. e. c. G. Ciciani etal. Farrr.aco 1991. 45, 373. Gives corrccurc M>. wherein R\ R: R:. R-and R= are as hereinbefore ce:':ned.
According to one aspect cf :he present inverr.ion seme scecifie come runes of formula (I) and in canicular :h:se cf formula i'XXIV msv also be cb-'ainec as shewn ;r Scheme 3.
- Scheme 3
Condensation of comp6unds"(Vll;)"jn which R' is an alkyl group, with an c-rtho-substituted aryl or heteroanylamine of formula (VIII), wherein each G1t G:, G- and G^ independently represent a nitrogen or carbon atom and -YH represents an amino, a mercapto or a hydroxy substituent, in the presence of a dehydrating agent such as trimethylaluminium, gives pyridazin-3(2H)-ones of formula (I) wherein R\ P/ and Ra are as hereinbefore defined and Y represents a sulphur atom, an oxygen atom cr a -NH-group. The reaction is preferably carried out in a solvent such as toluene at a temperature between -73 degrees and room temperature.
lscxazolo[3,4-a]pyridaz!n-7(6H)-ones of formula (II) may be obtained as shown in Scheme 4-.
Isoxazole derivatives of formula (IX), where R4 and R° are as hereinbefore defined and Ra is an alkyl group, are condensed with a hydrazine of formula (X), where R1 is as hereinbefore defined, by methods known per se, e. g. G. Renzi et al.f Gazz.... : Chim. Ital. 1965, 95, 1473, to give isoxazolo[3,4-c/]pyridazin-7(6/-/)-ones of formula (II) wherein R1, R4 and R° are as hereinbefore defined.
Alternatively, isoxazole derivatives of formula (IX), where R4 and R° are as hereinbefore defined and R3 is an alkyl group, are condensed with hydrazine, by methods known per se, e. g. G. Renzi et al.T Gazz. Chim. ItaL 1965, 95, 1473, to give isoxazolo[3,4-c/]pyridazin-7(6r/)-ones of formula (XI) wherein R4 and R° are as hereinbefore defined. Subsequent reaction with an alkylating agent of formula (XII), wherein R1 is as hereinbefore defined and X is a leaving group such as a chlorine or a bromine atom or a methanesulfonate, p-toluenesulfonate or a benzenesulfonate group by methods known per se, e. g. V. Dal Piaz et al. Drug Des. Discovery 1996, 14, 53; or condensation with an alcohol of formula (XII) wherein R1 is as hereinbefore described and X is a hydroxy group in :he presence of triphenylphosphine and diethyiazodicarboxylate by methods known per se, e. G. O. Mitsunobu et al. J. Am. Chem. Soc. 1972, 94, 379; gives isoxazolo[3,4-d]pyridazin-7(6H)-ones of formula (II) wherein R\ R4 and R° are as hereinbefore defined.
lsoxazolo[3,4-d]pyridsz:n-7(6W)-ones of formula HI) may also be obtained as shown in Scheme 5.
Scheme 5 .
Isoxazole derivatives of formula (XIII), wherein R4 is hereinbefore denned and R' and Ra are an alkyl croup, are condensed with hydrazine, by methods known per se, e. g. G. Renzi et al., Gazz. Chim. ItaL 1965, 95, 1473, to give isoxazo!o[3.4-cf]pyridazin-7(6H)-ones of formula (XIV) wherein R4 is as hereinbefore defined and R7 is an alkyl group. Subsequent reaction with an alkylating agent oi formula (XII), wherein R1 is as hereinbefore defined and X is a leaving group such as a chlorine or 3 bromine atom or a methanesuifonate, p-toluenesulfonate-ora benzenesulfonate group, by methods known per se, e. g. V. Dai Piaz et al. Drug Des. Discover/1996, ?4 53; or condensation with an alcohol oi formula (XII) wherein R* is as hereinbefore described and X is a hydroxy group in the presence of triphenylphosphine and diethylazodicarboxylate by methods known per se, e. g. O. Mitsunobu et al. J. Am. Chem. Soc. 1972, 94, 379; gives isoxazolo[3,4-cflpyridazin-7(6H)-ones of formula (XV), wherein R1 and R4 are as hereinbefore defined and R7 is an alkyl group. Comcounds (XV) are treated with sodium or potassium hydroxide and further neutralisation with an inorganic acid such as hydrochloric or sulfuric acid provides the corresponding carboxylic acid derivative of formula (XVI), wherein R1 and R4 are as hereinbefore
defined. The reaction is preferably carried out in a solvent such as methanol, ethan, tetrahydrofuran or an aqueous mixture of one of the above mentioned solvents at it: boiling point. Condensation of confounds (XVI) with an ertho-substituted ar/l or neteroarylamine of formula (VIII). '.vherein each G,, G:, G3 and G, independently represent a nitrogen or carbon ate-: and Y represents an amino, a mercapto or a hydroxy substituent, in the presence of a dehydrating agent such as polyphosphoric acid or trimethylsilylpolyphcsshste gives isoxazolo[3.4-Cjpyridazin-7(6H)-one5 of formula (!() wherein R\ R* and R5 23 as hereinbefore defined. The reaction is preferably carried out in a hichiy ceiling ccint solvent such as 1,2-dichlorobenzene at its boiling point.
Pyridazin-3(2H)-ones of fcrm.uia (VII) may be obtained as shown in Scheme 6
An 1soxaZolot314-d]Pyn^n-7(3H)-one of tarn* (XV). wherein R'and # are
• u .„„ defined and P.7 is an alkyl group, is hydrogenated to yield an 4-
" herS Z tZ rLva«vS (M,. wnerein * and tf are as nerein.e.ore
amin0pvn^n- ( H) Tne hydrogenation may be parted using (or
r;,^^, ™. 32. ™ *—a:;:— L.
mniiqhed bY transfer hydrogenation using an organic hydrogen
accomplished oyuc hvfira7ine by methods known per se, e
transfer agent such as amn-,cnlUmtorma,e or hydrate by .
g. V. Dal Piaz et ai. Heieroc. zles, 1991, 32, 1173. Condensation of an 4-arninopyridazin-3(2H)-one derivative (XVII), wherein R:. RJ and R4 are as hereinbefore defined and R' is an aikyl gr:up with an aryl or heteroami bromide of formula ;A
Isoxazole derivatives of formula (IX) and (XIII) may be obtained as shown in Scheme 7.
Reaction of a 1,3-dicarrcnyilc compound of general formula (XX), wherein R~ and R° are as hereinbefore defined, ar,d a 2-chioro-2-(hydroxyimino)acetate derivative of formula (XXI), wherein R3 is as here;nbefore denned, following methods known cer se, e. g. G. Renzi et al., Gazz. Chim. Hal. 1965, 55, 1478, gives isoxazofe derivatives of formula (IX), wherein R~ and R= are as hereinbefore defined and R3 is an alkyl group.
Reaction of a 2,4-dioxcester derivative of general formula (XXII), wherein PT is as hereinbefore defined and R' is an aikyl group, and a 2-chloro2-(hydroxyimino)acetate derivative of formula (XXI), wherein R3 is as hereinbefore defined, following methods known per se, e. g. G. Renzi et aL, Gazz. Chim. Hal. 1965, 95, 1478, gives isoxazole derivatives cf formula (XIII), wherein R4 is as hereinbefore defined and R' and R8 are an alky! group.
Scheme S
According to one aspect of the present invention some specific compounds of formula (!) and in particular those of formula (Ic) may also be obtained as shown in Scheme 3.
Reaction of a pyr'dlzincne of formula (lb; wherein R*. R:. R3 and ?: are as hereinbefore defined and R" is the 'est -CHR3R'C wr.e-ein are R- and RVja.!-'yi orar.i groups with an hyper/aler: iodine comoound by met;~:ds known per se (Mcriarty. R.M; Hu, H; Gupta S.C., Tetrahedron Le" 1931. 22, 1233--15) gives :he a-hydroxyiated derivative (Ic) wherein R\R-.R3 and R3 are as hereinbefore defined.
Scheme 9
4-Aminopyridazin-3(2H)-ones of formula (III) may also oe obtained as shewn ;n Scheme 9.
Condensation of an isoxazoio[3f4-Gf]pyriclazin-7(6/-;')-one of formula (lib) wherein R1 and R° are as defined above with an aldehyde or a ketone of formula R3COR10, by methods known per se, eg. G. Ciciani et al. // rarmaco 1991, 45, 873 leads to a substituted vinyl
derivative of formula (lie) which is then reduced using for example hydrogen in the presence of a catalyst such as palladium on charcoal in a solvent such as methanol. ethancl or ethyl acetate to yield ire corresponding 4-3minopyricaz:n-3(2H)-cne (III).
> When the defined crcucs ?.' :o R5 are susceptible to chemical reac;;cn under
the conditions of the hereinbefore described processes or are incompatible with said processes, conventional protecting croups may be used in accordance with standard practice, for example see T. VV. Greene and P. G. M. Wuts in 'Protective Groups in Organic Chemistry1, 3:J Edition, John Wiley & Sons (1399). It may oe that dec-erection wiil form the last step in the synthesis :f compounds of formula (I).
in still another aspect the present invention encompasses intermediate compounds of formula (XVII), (Vila) and (VII) usefui :n the synthesis of compounds of formula (1).
The compounds of formulae (IVa-, (IVb), (Vi),.(-X), (XII), Will), (XX). and (XXII) are known compounds or can be prepared by analogy with known methods.
PHARMACOLOGICAL ACTIVITY
PDE4 Assay Procedure
Compounds to be tested were resuspended in DMSO at a stock concentration of 1 mM. The compounds were tested at different concentrations varying from 10 u.M to 10 pM to calculate an IC50. These dilutions were done in 96-well plates. In some oases, plates containing diluted compounds were frozen before being assayed. In these cases, the plates were thawed at room temperature and stirred for 15 minutes.
Ten microliters of the diluted compounds were poured into a low binding" assay plate. Eighty microliters of reaction mixture containing 50 mM Tris pH 7.5, 3.3 mM MgCI2, 1.7 mM EGTA, and 15 nM [3H]-cAMP were added to each well. The reaction was initiated by adding ten microliters of a solution containing PDE4. The plate was then incubated under stirring fori hour at room temperature. After incubation the reaction was stopped with 50 microlitres of SPA beads, and the reaction was allowed to incubate for another 20 minutes at room temperature before measuring radioactivity using standard instrumentation.
i he reaction mixture was prepared by adding 90 ml of H:0 to :0 mi of 10X assay buffer (500 mM Tris cH 7.5. 53 mM MgCk 17 mivl EGTA), and 40 micrciitres ■ .-C.YLL [3H]-cAMP. SPA beacs soL::cn was prepared by accing 500 mc to 23 mi H:0 for a final concentration of 20 mc.mi beacs and 13 mM z:nc suiphare.
The results are shown, in Tazie 1.
It can be seen from Table 1 that the compounds of fcnmcia (I) are potent _ inhibitors of phosphodiesterase 4 (PDE 4). Preferred pyridazin-3(2/-/)-one derivatives of the invention possess an IC=:. value for the inhibition of PDE4 (determined as defined above) of less than 100 niM, preferably less than 50 nM and mcsr preferably less than
30 nM. The compounds are also caoable of blocking the production of some proinflammatory cytokines such as. for example, TNFa.
Thus, they can be usee "n the treatment of allergic, inflammatory and immunological diseases, as '.veil as :~ose diseases or conditions -vhere the bicckade of pro-inflammatory cytokines or tre se.active inhibition of PDE 4 cculd be of benefit. These disease states include aszr^.a. chronic obstructive pulmonary cisease, anergic rhinitis, rheumatoid arthritis, cstecarnritis. osteoporosis, bone-fematien disorders, glomeruloneohritis. multiple sclerosis, ankylosing spondylitis, Graves ephtaimepathy, myasthenia gravis, ciabetes :nsicicus. graft rejection, gastrointestinal disorders such as irritable bowel disease, ulcerative cc'ltis or Crohn disease, septic shock, aduit distress respiratory syndrome, and skin diseases'such as atopic dermatitis, contact dermatitis, acute dermatomyosuis and psoriasis. They can also be used as improvers of cerebrovascular function as v/ell as in the treatment of other CNS related diseases such as dementia, Alzheimer's disease/depression, and as nootropic agents.
The compounds of the present invention are also of benefit when administered in combination with other drugs such as steroids and immunosuppressive agents, such as cyclosporin A, rapamycin or T-ceii receptor blockers. In this case the administration of the compounds allows a reduction of the dosage of the other drugs, thus preventing the appearance of the undesired side" effects associated with both steroids and immunosuppressants.
Like other PDE4 inhibitors (see references above) the compounds of the invention can also be used for blocking, after preventive and/or curative treatment, the erosive and ulcerogenic effects induced by a variety of etiological agents, such as antiinflammatory drugs (steroidal or non-steroidal antiinflammatony agents), stress, ammonia, ethanoi and concentrated acids.
They can be used alone or in combination with antacids and/or antisecretory drugs in the preventive and/or curative treatment of gastrointestinal pathologies like ■ drug-induced ulcers, peptic ulcers, H. Pylori-related ulcers, esophagitis and gastroesophageal reflux disease.
They can also be used in the treatment of pathological situations where damage to the cells or tissues is produced through conditions like anoxia or the production c" =-, excess of free-radicals. Examples cf such beneficial effects are the protection of :ardiac 'issue after coronary artery occlusion or the prolongation of cell and tissue viability when the compounds of the invention are acced to preser/ing solutions Intended for storage of transplant organs or fluids such as blood or sperm. They are aiso of benefit on tissue repair and wound healing. '
Accordincly, the Dvridazin-2
The results.of table I show that the compounds of formula (I) are potent inhibitors cf phosphodiesterase 4 (PDE4) and are therefore useful in the treatment or prevention cf pathological conditions, diseases and disorders known to be susceptible of amelioration by inhibition of PDE4, such as asthma, chronic obstructive pulmonany disease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritable bowel disease.
The compounds of the present invention can also be used in combination with other drugs known to be effective in the treatment of these diseases. For example, in combination with steroids, immunosuppressive agents. T-cell receptor blockers and/or antiinflammatony drugs for simultaneous, separate or sequential use in the treatment of the human or animal body
Accordingly, another embodiment of he invention is the use of the compounds of formula (I) in the manufacture of a medicament for treatment or prevention of pathological conditions, diseases and disorders known to be susceptible of amelioration by inhibition of PDE4, as well as a method for treating a subject afflicted with a pathological condition or disease susceptible to amelioration by inhibition of PDE4, which comprises administering to said subject an effective amount of a compound of formula (I).
The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a pyridazin-3(2ry)-one derivative of formula (!) or a pharmaceutically acceotaoie salt 'hereof in association with at least cne pharmaceutically acceptable excicient such as a carrier or diluent. The active 5 ingredient may comprise 0.0C10- to 59% by weight, preferably 0.01% to 90% by weight, of the compositicn depending upcn the nature c; the formulation and whether further dilution is to be made prior ;c application. Preferably the compositions are mace up in a form suitable for oral, topical, nasal, rectai, percutaneous cr injectable administration. .
The pharmaceutically acceptable excipients which are admixed with the active compound, or salts of-such compound, tc form the compositions cf this invention are well-known-perse and the actual excipients used depend inter alia on the intended method of administering the compositions.
Compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid, preparations, such as mixtures, elixirs, syrups or suspensions, ail containing the compound of the invention; such preparations may be made by methods well-known in the art, ■.
The diluents which may be used in the preparation of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents, if desired. Tablets or capsules may conveniently contain between 2 and 500 mg of active ingredient or the equivalent amount of a salt thereof.
The liquid composition adapted for oral use may be in.the form of solutions cr suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent.
Compositions for parenteral injection may be prepared from soluble salts, which
may or may not be freeze-dried and which may be dissolved in pyrogen free acueous media or other appropriate parenteral" injection fluid.
Compositions for topical acmlnistraticn may take the form cf ointment, preams pr lotions, ail containing :he compound of the invention; such preparations ma;, pe made by methods well-known in the art.
Effective doses are r.crmalK ;n the range cf M-6C0 mg zf active r.grecienc ^~: day. Daily dosage may be acminister5d in one or mere treatments, preferably ~;cm ! to 4 treatments, per day.
The present invention will pe r'urther illustrated by the following examples.The--. •--.. -examples are given by way of illustration only and are not to be construed as.-a Smiting.
The syntheses of the compounds of the invention and of the intermediates for use therein are illustrated by the foiiowing Examples (including Preparation Examples (Preparations 1 to 99)) which do not limit the scope of the invention in.ar.y.v/ay^
1H Nuclear Magnetic Resonance Spectra were recorded on a Varian,Gemini 300 spectrometer.
Low P^esolution Mass Spectra (m/z) were recorded on a Micromass ZivlD mass spectrometer using ESI ionization.
Melting points were recorded using a Perkin Elmer DSC-7 apparatus.
The chromatographic separations were obtained using a Waters 2595 or 2795 system equipped with a Symmetry CIS (2.1 x 10 mm, 3.5 mM) column using one of the following methods:
Method A). The mobile phase wavs formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.46 mL), ammonia (0.115 mL) and water (1000 mL) (A): initially from 0% to 95% of B in 10.5 min at a flow rate of 0.4 ml/min, from 10.3 to 11.0 min the flow rate was linean/ increased to 0.3
ml/min and maintained in these conditions until minute 12.3. Reequilioration time cetwen two injections was 2 min. The injection volume was 5 microliter. Diode array chrcmatcgrams were collected at 2" J nM.
Method B) The mobile :rase .vas formic acid (0.- mL), ammonia (0.1 mL), methanol (500 mL) and ace::m:r;ie :C0 mL) (B) and forrv'c acid (0.45 mL), ammonia i.0.115 mL) and water (1000 mL;
PREPARATION EXAMPLES
PREP-PAT'QN 1 ^Scheme 7^ Ethyl 5-methyl-4-{pyridin-3-ylcarbcnyl)isoxaznle-3-carboxylat9
To an ice-cooled solution of scciurr etnoxice (5.S g. 1 '.0 mmoi) in absolute ethanci (150 mL) 1-pyridin-3-yl-butane-',2-C;cne (Ohta, S. ei a;.. Cham. Pharm. Bull.. 1981. ;;. 2762} (18.4 g. 100 mmcl) was added pcncnwise anc :he mixture was.stirrec at 0° :*:-30 min. A solution of ethyl chicrotoy^ximinolacetate 16.7 g. l-O-mmoi) in acsoiute ethanoi (50 mL) was added dropwise and" the finai mi;
o(CDCI3): 1.15 (t,3H), 2.53-'s. 3H). 4.13 (q, 2H;, 7.42 (m, 1H), 3.10 (m, 1H), 8.31 (m, 1H), 3.95 (m, 1H).
PREPARATION 2 (Scheme 7)
Ethyl 5-methyI-4-(pyridin-2-ylcarbonyl)isoxazole-3-cafboxyiate
Obtained as a yellow solid (99%) from 1-pyridin-2-yl-butane-1,3-dione (Chisweil et al.. Inorg. Chim. Acta 1972, 6, 623) and ethyl chioro(hydroximino)acetate following the experimental procedure described in Preparation 1. LRMS:m/Z261 (M+1)~.
PREPARATION 3 (Scheme 4)
3-Methyl-4-pyridin-3-ylisoxazoIo[3,4-d]pyridazin-7(6H)-one
Hydrazine monohydrate (6.0g, 120 mmol) was added dropwise to a solution of the title compound of Preparation 1 (25.0 g, 100 mmol) in -dry ethanoi (500 mL) and the resulting mixture was stirred overnicnt. After cooling with an ice bath, a precicitate was formed which was collected by filtration and washed with diethyl ether to yielc the title compound (17.2 gT 75% yield) as a yellow solid.
5(DMSO-d6): 2.57 (s. 3H), 7.53 (m, 1H), 3.10 (m. 1H), 3.72 (d, iH), 8,30 (sJH).
PREP-RATION 4 (Scheme 4)
3-Methyi-4-pyridin-2-ylisoxa2olo[3.--d]pyridazin-7(5H)-one
Obtained as a yellow solid (50%) frzn the title compound of Preparation 2 using the
experimental procedure described .r. Preparation 3.
5(DMSO-d6): 2.92 (s. 3H), ".53 (m, IH), 7.93 (m. 2H), 8.77 (m, 1H).
PREPARATION 5 (Scheme 4N.
6-EthyI-3-methyl-4-pyridin-3-ylisoxazo[o[3T4-d]pyridazin-7(6H)-one
To a suspension of the title compound of Preparation 3 (17.2 g, 75.6 mmol) and anhydrous potassium carbonate (62 g, 453 mmoi) in dry cimethylformamide (100 rr.L) was added ethyl bromide (57.0 g, 525 mmol) and the resulting mixture stirred at r.t. overnight. The mixture was concentrated and the residue thus obtained was suspended in dichloromethane, washed with water and brine, dried and concentrated to yield the title compound (3.44 g, AJ.% yield) as a yellow solid.
o(CDCI3): 1-42 (t, 3H), 2.53 (s, 3H), 4.23 (q, 2H), 7.55 (m.1H), 7.92 (m,1H), 3.30 (m, 2H).
PREPARATION 6 (Scheme 4)
6-Ethyi-3-methyI-4-pyridin-2-ylisoxazoIo[3,4-d]pyridazin-7{6H)-one
Obtained (27%) from the title compound from Preparation 4 following the experimental procedure described in Preparation 5.
8(CDCi3): 1.41 (t, 3H), 2.98 (s, 3H), 4.33 (q, 2H), 7.42 (mt1H)t 7.92 (m,1H), 3.05 (m, 1H), 3.63 (m, 1H).
-REPARATION 7.(Scheme ±) 6-Ethyl-3-methyl-4-pyridin-4-ylisoxa2olo[3,4-d]pyridarin-7(6H)-one
Obtained (32%) frc~ 3-metry-4-pypC!n-4-yl-5HHSCxazoio[3.4-d]cyr;Gaz:n-7-cre ;'.. Da! Piaz etai, J. P^ar-ac. S::\, 1SG1. 30, 341-34S' following ;ne experiment procedure describee .'n Preparation 5.
o(CDC!3): 1.35 (t, 3h% 2.53 :"s, Zr.), 4.31
-REPARATION 3 'Serene 4)
HCyclopropyImethyl)-3-methyl-4-pyridin-3-ylisoxa2oIo[3T4-d]pyrida2in-7(6H)-one
Dbtained (44%) freer. :he title compound'from Preparation'^ and cyclcprcpyimerhyi )romide following ine experimental procedure described in Preoaration 5.
5(DMSO-d6): 3.40 (m. -i.H). 1.32 (mf 1H), 2.58 (s. 3H), 4.C0 (dT 2H). 7.50 (m/,n\ 1.10 (mJH), 3.73 (m. 1H), 3.11 (m, 1H).
PREPARATION 9 (Scheme 4)
;-(Cyclopropylmethyl)-3-methyl-4-pyridin-2-ylisbxazolo[3(4-d]pyridazin-7(6H)-one
)btained (93%) from the title compound from Preparation 4 and cyclopropylmethyl romide following the experimental procedure described in Preparation 5.
5(CDCI3): 0.55 (m,4H), 1.42 (m, 1H), 2.93 (s, 3H), 4.03 (df 2H), 7.40 (m, 1H>. 7.32 (m,1H), 3.01 (m. 1H), 3.72 (m, 1H).
PREPARATION 10 (Scheme 4)
6-(Cyclopropylmethyl)-3-methyl-4-pyridin-4-ylisoxazoIo[3,4-d]pyridazin-7(6H)-one
Obtained (35%) from 3-methyl-4-pyridin-4-yl-6H-isoxazolo[3,4-d]pyridazin-7-cne ( V. Dal Piaz etai, J. Pharmac. Sci., 1.991, 30, 341-343) and cyclopropylmethyl bromide following the experimental procedure described in Preoaration 5.
5(DMSO-d3): 0.54 (m. 4H), 1.35 (m, 1H), 2.5S (s, 3H), 4.01 (d, 2H), 7.55 (d, 2H), 3.73 (d, 2H).
PRSP-.-ATlQN 11 (Scheme ->
6-(2-Hydroxyethyl)-3-methyl-4-pyridin-3-yiisoxazolo[3,4-d]pyridazin-7(6H)-one
Obtained (66%) from :he title comcrjnd from Preparation 3 and 2-brorrioethancl following the experimental procedLre described in Preparation 5.
o(DMSO-d,): 2.50 .'s. 3H), 4.35 -m, 2H), 4.41 (t, 2H), 7.52 -m,1H), 7.S5 m, 1H'. S.10 (m,1H), 8.60 (m, 2H).
PREPARATION 12 (Scheme -^
6-(2-Hydroxyethyl)-3-methyi-4-pyr:din-2-ylisoxazoIo[3,4-d]pyridazin-7(6H)-one
Obtained (92%) from the title compound from Preparation 4 and 2-bromoethanol following the experimental procedure described in Preparation 5.
5(CDCI3): 2.41 (m, 1H), 2.97 3, 3H), 4.13 (m, 2H), 4.43 (m, 2H). 7.42 (m, 1H), 7.35 (m,1H), 8.00 (m, 1H), 5.70 (m. 'H).'
PREPARATION 13 (Scheme 4)
6-(2-Hydroxyethyl)-3-methyl-4-pyridin-4-yIisoxazolo[3T4-d]pyndazin-7(6H)-one
Obtained (70%) from 3-methy!-4-pyrdin-4-yl-6H-isoxazolo[3,4-d]pyridazin-7-on9 ( V. Dal Piaz etal., J. Pharmac. ScL, 1991, 30, 341-343) and 2-bromoethanol follov/ing the experimental procedure described ir Preparation 5.
8(DMSO-d5): 2.60 (s, 3H), 3.73 (q, 2H), 4.18 (t, 2H), 4.83 (t, 1H), 7.68 (dt 2H), ,8.78 (d,2H).
PREPARATION 14 ,-scheme 1)
5-Acetyl-4-amino-2-ethyl-6.-pyridin-3-ylpyridasin-3(2H)-one
A mixture of the title compcunc of --epararicn 3 3.44 g, 33 mmci) and 10% :aiiadiu~ en charcoal (1.7 g) in ethane! —CO mL) was shaken under hydrogen at room temperature and 2 bar for 5 n. The catalysz -//as ""litered off and the solvent was removed under reduced pressure to yield the tii!e :ompcund (5.-3 g, 75% ye.-z).
3i'CDCI3): 1.-2(t,2H\ 1,32-s. 3H:-. 4.25 c 2H). 7.45 (m.-H), 7.30 (m/H). :TI = m,2H;.
PREPARATION 15 Scheme 1i
5-Acetyl-4-amino-2-ethyr-6-pyridin-2-ylpyridazin-3(2H)-one
Obtained after column chromatography purification (-10%) from the title product of Preparation 6 following the procedure described n Preparation 14.
o(CDC!3): 1.41 (t, 3H), 1.30 (s, 3H). 4.30 p, 2H), 7.05 (bs, 2H), 7.3S -. 1H). 7.82 (m, 2H)f 3.62 (m, 1H).
PREPARATION 15 Scheme 1)
5-AcetyI-4-amino-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one
Obtained (92%) from the title product of Preparation 7 following the procedure described in Preparation 14.
5(CDCI3): 1.37 (t. 3H), 1.32 (s, 3H), 4.24 (q, 2H), 7.44 (d, 2H), 3.70 -'d. 2H).
PREPARATION 17 ^Scheme 1)
5-Acetyl-4-amino-2-(cyclopropylmethyi)-6-pyridin-3-ylpyridazin-3(2H)-one
A mixture of the title compound of Preparation 9 TO g, 3.50 mmol) , 10% pai.'adium on charcoal (55 mg) and ammonium formate (3.97 g. 53 mmol) in methanol (30 ~L) was refluxed for 2 hours. Then the catalyst was filterec off and the solvent was removed
under reduced pressure. The resulting residue was partitioned between dichloromethane and water and the organic layer was washed with water twice. It was
cried and solvent removed uccer reduced pressure to yield the title compound (471 mg,47%).
o(CDC!3): 0.45 (m.^H;. I.r.'m. 1H)f 1.31 (s. 2H), 4.02 ;d, 2H),7.40 (m,1H), 7.30 (m,1H), 3.72 (m. 2H).
PREPARATION 13 (Scheme 1^
5-Acetyl-4-amino-2-(cyc!opropylmethyl)-6-pyridin-2-y!pyridazin-3(2H)-one
Obtained (90%) from [he title prcduc: cf Preparation 9 following the procedure described in Preparation 17.
3(CDCI3): 0.45 (m, ^H), 1.33 (m. 1H), 1.30 (s, 3H), 4.03 (d. 2H). 7.01 (bs, 2HV. " 7.52 (m, 1H)f 7.33 (m,2H), 3.52 (m. 1H).
PREPARATION 19 (Scheme 1)
5-Acetyl-4-amino-2-{cyclopropylmethyl)-6-pyridin-4-ylpyridazin-3(2H)-one
Obtained (96%) from the title produc: of Preparation 10 following the procedure described in Preparation 14.
5(DMSO-d6): 0.41 (m, 4H), 1.23 (m, 1H), 1.32 (s, 3H), 3.97 (d, 2H), 7.42 (d, 2H), 7.82 (bs, 2H), 3.55 (d, 2H).
PREPARATION 20 (Scheme 1) 5-Acetyl-4-amino-2-(2-hydroxyethyi)-6-pyridin-3-ylpyridazin-3(2H)-one
Obtained (50%) from the title product cf Preparation 11 following the procedure described in Preparation 17. It was refiuxed for 2 hours and then stirred at room temperature overnight.
o(CDCI3): 1.73 (s: 3H), 4.22 (m; 2H), 4.41 (m, 3H), 7.45 (m,1H), 7.80 (mf 1H), 8.78 (m,2H).
PREPARATION 21 (Scheme 1j
5-Ac9tyl-4-amino-2-(2-hydroxyethyl)-6-pyridin-2-ylpyrida2in-3(2H)-one
Obtained (64%) frcrr. the rltle produc; of Preparaacr. 12 following :he procedure described in Preparation 17.
5tCDCI2): 1.73 .'s. Zn . -.13 .,i. 2H), 4.40 (t. 2H'.. 7.10 (bs. 2H), 7.33 :rr.. 1h\ 7.32 (m. 2H),3.62;m. In'.
■• :" PREPARATION 22 -Scheme 1)
5-Acetyl-4-amino-2-(2-hydroxyethyl)-6-pyridin-^-ylpyridazin-3(2H)-one
Obtained (55%)'frcm :he"tit!e zroduct of Preparation 13 following the procedure described in Preparation-1A
o(DMSO-d5): 1.32 (s. 2H), 3.75 (m. 2H). 4.13 (t, 2H), 4.81 (bs, 1H). 7.^8 (d. 2H)( 7.85 (bs, 1H), 8.63 id. 2H).
PREPARATION 23 (Scheme 7) Ethyl 5-methyl-4-(thien-2"-ylcarbonyl)isoxazole-3-carboxylate
Obtained as a solid (50%) from 1-thicphen-2-yl-butane-1,3-dione (Gash. V.W.; Can J. Chem., 1967, 45, 2109-12) and ethyl chloro(hydroximino)acetate foilowing the experimental procedure described in Preparation 1.
o(CDCI3): 1.15 (t, 3H), 2.55 (s, 3H), 4.20 (q, 2H), 7,20-7.70 (m, 3H).
PREPARATION 24 (Scheme 4)
3-Methyl-4-thien-2-ylisoxa2oio[3,4-d]pyridazin-7(6H)-one
Obtained as a solid '.'37%)'from the title compound of Preparation 23 using the experimental procedure described in Preparation 3.
5(CDCI3): 2.73 (s, 3H), 7.18-7.59 (m, 3H), 9.62 (s, 1H).
PREPARATION 25 (Scheme^ 6-Ethyl-3-methyl-4-thien-2-ylisox3^olo[3,4-d]pyridazin-7(6H)-one
Obtained (33%) from the tit:e ccmcojnd from Preparation 24 following the experimental procedure described "n Preparation 5.
o(CDC!3): 1.41 (t, 3K, 2.73 s. 3H), 4.23 (q, 2H). ".13-7.59 (m, 3H).
PREP-RATION 25 (Scheme T
5-Acetyl-4-amino-2-ethyl-5-thien-2-yipyridazin-3(2H)-one
Obtained (50%) from the title product of Preparation 25 following the procedure described in Preparation-"14.
o(CDCI-3)':-1-:41 (t, 3HM.93 s. 3H), 4.22 (q, 2H), 7.10-7.41 (m, 3H).
PREPARATION 27 (Scheme 7^
Ethyl 4-(4-fIuorobenzoyI)-5-methylisoxazole-3-carboxylate
Obtained (95%)"from^1-(4-flucTocnenyl)butane-1I3-dione (Joshi, K.C.; Pathak, V.N.; Garg, U. J. Indian Chem. Sec. 1S33, 50, 1074-1076) and ethyl chloro(hydroximino)'acetate fcilowinc the experimental procedure described in Preparation 1.
5(CDCI3): 1.1 (t, 3H), 2.50 (s, 3H), 4.20 (q, 2H), 7.20 (m, 2H), 7.30 (m, 2H).
PREPARATION 23 ^Scheme 4) 4-(4-Fluorophenyl)-3-methy!isoxazoio[3,4-c/]pyridazin-7(6H)-one
Obtained (37%) from the title compound of Preparation 27, using the experimental -procedure described in Preparation 3.
8(CDCI3): 2.55 (s, 3H;( 7.30 (m. 2H)f 7.60 (m,2H).
PREPARATION 29 (Scheie 4V-
5-EthyI-4-{4-fluorophenyi)-3-methyiisoxazolo[3,4-a]pyridazin-7(6H)-one
To a suspension :f the title comccund of Preparation 23 (0.49 g. 2.0 mmGi' and anhydrous potassium carbonate (C.55 g, 4.0 mmoi; in on/ dimethyiformamice .5.3 ~L was added ethyl bromide (C.-4 g, -.33 mmol) and the resulting mixture heatec at 110°C for 40 minutes. Then 'ce-wa:er was added
PREPARATION 30 (Scheie 2)- . ---. .
5-Acetyl-2-ethyl-6-(4-fiuorophenyl)-4-nitropyridazin'-3(2H)-one
To a stirred suspension of the title compound of Preparation 29' (0.5 g, 1.33 mmol' in = mixture of acetic ac:d (7.3 ml), water (7.3 mL) and nitric acid (2.5 mL), cerium ammonium nitrate (5.0 g, 11 mmol) //as added portionwise during 40 min. Addition cf ice-cold water gave a crude precipitate which was filtered and washed with coid water to yield the title product (45% yield).
' o(CDCI3): 1 -43 (t, 3H), 2.20 s, 3H), 4.40 (q. 2H). 7.20 (m, 2H), 7.43 .'m. 2H).
PREPARATION 31 (Scheme 7) "
Ethyl 4-(3-fluorobenzoyi)-5-methylisoxazole-3-carboxylate
Obtained (79%) from 1-(3-fluorophenyl)butane-1,3-dione (Joshi, K.C.; Paiha.
o(CDCI3): 1.10 (t, 3H), 2.60 (sf 3H), 4.15 (q, 2H)f 7.30 (m. 4H).
PREPARATION 32 (Scheme ■*)
4-{3-FIuorophenyl)-3-methylisoxazolo[3,4-cQpyridazin-7(6H)-one.
Obtained (31%) from :he title comc-ound cf Preparation 31. following the expermental procedure described in Preparation 3.
o(CDCI3): 2.60 is, 3H). 7.3 m. 4H). 9.90 (5. 1H).
PREPARATION 33 fScheme ±)
5-Ethyl-4-(3-fIuorophenyl)-3-methylisoxazolo[3,4-c/]pyr!dazin-7(6f/)-on€
Obtained (84%) from the title comcound from Preparation 32 following the7, experimental procedure describee In Preparation 5.
5(CDCI3): 1-40 (t, 3H), 2.53 (s. 3H). 4.30 (q, 2H), 7.30 (m, 3H), 7.50tm/4H)/- ~-
PREPARATION 34 (Scheme 4)
6-(CycIopropyimethyl)^-(3-fIuorophenyI)-3-methyIispxazolo[3,4-d]pyridazin- - -
7(6H)-one
Obtained (37%) from the title compound from Preparation 32 and cycloprop'yimethyi ' bromide following the experimental procedure described in Preparation 5. The product was purified by column chromatography.
5(CDCI3): .0.52 (m, 4H), 1.33 (m, 1H), 2.58 (s, 3H), 4.07 (d, 2H), 7.30 (m, 3H)T 7.55 (m,1H).
PREPARATION 35 (Scheme 4) 4-(3-FIuorophenyl)-6-isopropyl-3-methylisoxazolo[3,4-d]pyridazin-7(6H}-one
To a stirred solution of the title compound of preparation 32 (2.0 g, 8.16 mmol) in 30 mL of dry TKF, triphenylphosphine (2.16 g, 3.24 mmol) and isopropanol (0.38 mL, 3.S7 mmol) were added. The mixture was ccoied to 0°C and then diethylazadicarboxylate (1.3 mL, 8.24 mmol) was added dropwise. The final mixture was let to warm up to rccm
temperature and the stirred -'cr 24h. Finally solvent was removed and the final pre due: was isolated by column chromatography in a 37% yield.
o(CDCI3): 1.33 id, 6H . 2.53 (s, 3H), 5.41 (h. 1H), 7.33 ■;-.. 3H). 7.52 'm, 1H:,
PREPARATION 36 'Scre-e 2'
5-Acetyl-2-ethyi-3-(3-fluorophenyl)-4-nitropyridaz:'n-3(2,:T,)-cne
Obtained (40%) from me titie :roduct of Preparation 33 following me experimental procedure describee in Preparation 30.
o(CDCI3): 1.50 (i, 3K , 2.20 (s. 3H), 4.40 (q. 2H'... 7.20
PREP A P. AT IO N 3 7 (S cheme 2)
5-Acatyl-2-(cyclopropylmethyl)-6-(3-fIuorophenyl)-4-nitropyridazin-3(2H)-one"-:;' ■
Obtained (23%) from the title product of Preparation 34 following the experimental procedure described in Preparation 30.
5(CDCI3): 0.54 (m, 4H), 1.51 (m, 1H), 2.21 (s, 3H)", 4.16 [c. 2H), 7.22 (m, 3H), 7.45 (m, 1H).
PREPARATION 38 ^Scheme 2)
5-Acetyl-6-{3-fluorophenyl)-2-isopropyl-4-nitropyridazin-3(2H)-one
Obtained (40%) from the title product of Preparation 35 following the experimental procedure described in Preparation 30.
5(CDCI3): 1.44 (d, 6H). 2.20 (s, 3H), 5.45 (h, 1H), 7.16 (m, 3H), 7.50 (m, 1H).
PREPARATION 39 (SchemeAl
4-(3-Chlorophenyl)-6-(cyclopropyImethyl)-3-methylisoxa2olo[3,4-d]pyridazin-7(6H)-one
Obtained (S7%) from 4-(3-ch!Cropher1yi)-3-merhyl-5H-iscx3z^lo[3t4-d]pyridaz!n-7-on6 [Dal Piaz, V etal, J. Med. Chem. JrrT*40, 1417) and cycicpropylmethyl bromice following the experimental procedure described in Preparation 5. The product was purified by column chromatography. LRMS: m/2 315 (M+V.
PREPARATION 4Q (Scheme 2)
5-Acetyl-6-(3-chlorophenyl)-2-(cyclopropyimethyl)-4-nitropyridazin-3(2H)-one
Obtained (21%) from the title product of Preparation 39 following the experimental procedure described in Preparation 30. LRMS: m/z343 (M+l)~.
PREPARATION 41 (Scheme 7)
Ethyl 4-[ethoxy(oxo)acetyf]-5-methylisoxazole-3-carboxylate
To a well stirred solution of sodium meihoxide (10.5 g, 0.15 mol) in 100 mL of dry ethanol, diethyl oxalate (21 mL, 0.15 mol) was added dropwise and the mixture was warmed to 45°C. Then dry acetone (45 mL, 0.60 mol) was added and after 30 min the final mixture was refluxed for 3 hours and stirred at room temperature overnight. Finally solvent was removed and ICO mL of fresh dry ethanol were added. The mixture was cooled to 0°C-and a solution of ethyl chioro(hydroximino)acetate (27.2g, 0.18 mol) in 25 mL of dry ethanol was added dropwise. Then it was stirred at 0°C for 30 min and at room temperature for 3 days. Finally solvent was removed and the crude thus obtained was partitioned between ethyl acetate and water. It was'dried and solvent removed to yield the desired product (90:/0) as an orange oil.
PREPARATION 42 (Serene 5)
Ethyl 3-methyl-7-oxo-6,7-dihydroisoxazolo[3,4-d]pyridasine-4-carboxylata
Obtained as a soiic (57%) frrm the :it!e compcunc c: -reparation 41 using Vre experimental procedure describee :n Preparation 3.
■3(CD'CI3): 1.41 ;t, 3H-. 3.0' .3, 3H)f 4.50 (q. 2H-. 6.30 Ts. 1H).
-REPARATION 43 '"Scheme 5>
Ethyi 6-ethyl-3-methyl-7-oxo-6,7-dihydroisoxa2olo[3,4-d]pyridazine-4-carboxy(at9
Obtained (90%) from the title compound of Preparation 42 following the experimental procedure described in Preparation 5.
o(CDCIo): 1.42(m.5K), 3.00 (s, 3H), 4.25 (q. 2n), 4.43 (q, 2H)
PREPARATION 44 (Scheme 5)
i
Ethyl 4-acetyl-5-amino-1-ethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate
Obtained (98%) from the title product of Preparation 43 following the procedure described in Preparation 14.
o(CDCI3): 1.33 (m, 6H), 2.30 (s, 3H), 4.22 (q, 2H), 4.42 (q, 2H),7.50 (bs, 2H).
PREPARATION 45 (Scheme 6)
Ethyl 4-acetyl-5-[{3-chlorophenyl)amino]-1-eth.yI-6-oxo-1,6-dihydropyridazine-3-carboxylate
A mixture of the title compound of Preparation 44 (506 mg, 2.0 mmol), 3-chlorophenyibpronic acid (625 mg, 4.0 mmol);anhydrous cupric acetate (540 mg, 3.0 mmol), triethyiamine (0.56 mL, 4.0 mmoi) and activated molecular sieves (1.5 g, 4 A) in dry dichloromethane (25 mL) was stirred under air exposure at room temperature for 43 h. The reaction was filtered and the solvent removed under reduced pressure. The resulting residue was recrystailized from ethyl acetate (202 mg, 54% yield).
o(CDC!3): 1.33 (t, 3H), 1.42 :. 3H). 2.01 (s, 3H), ^.42 (m, 4H), 6.97 (m, 1H), 7.16 (m, 1H), 7.35 (m. 2H), 7.05 (s. 1H).
PREPARATION 46 (Scheme 5)
6-Ethyl-3-methyl-7-oxo-6,7-dihydroH'soxazolo[3,4-d]pyridazin9-4-carboxyiic acic
Tc a stirred solution of :he title compound of preparation 43 :,2.73 g, 11 mrr.ci) in 9C rr of a 2:1 methancl/THF mixture, a sc-ution of lithium hydroxide (1.37 g, 45 mmci) in S mL of water was added dropwise. The final mixture was stirred at room temperature ; 5 hours and then diluted with some water snd acidified with HCi 2N. It was extracted with ethyl acetate, dried and solver.; removed to yield (3S%)ine title product. o(DMSO-d3): 1-35 (t, 3H), 2.53 (s, 3H), 4.15 (q, 2H).
PREPARATION 47 (Scheme 5)
4-(1,3-Ben20xa2ol-2-yl)-6-ethyl-3-methylisoxazolo[3,4-d]pyrida2in-7(6H)-one
To a 100°C pre-warmed suspension of PPSE (6g) in 10 mL of 1,2-dichlorobenzene, a solution of 2-aminophenol (0.48 g, 4.4 mmoi) in 10 mL of 1,2-dichlorobenzene was added and the'mixture was stirred fcr a while. Then the title compound of preparation 46 (1.08 g, 4.84 mmoi) was added in portions and the mixture was refiuxed overnight. Then it was let to cool down and poured onto ice-water vigorously stirring, it was neutralized with potassium carbonate and extracted with dichioromethane. The organi layer was dried and solvent removed to yield a crude product that was purified by column chromatography. The title product was isolated (44%).
5(CDCI3): 1.42 (t, 3H), 3.25 (s, 3H), 4.38 (q, 2H), 7.41 (m, 2H), 7.70 (m, 1H), 7.82 (m, 1H).
PREPARATION 43 (Scheme 1) 5-Acetyl-4-amino-6-(1l3-benzoxa2ol-2-yl)-2-ethylpyridazin-3(2H)-one
Obtained (93%) from the title product of Preparation 47 following the procedure de-
scribed in Preparation 14.
PREPARATION 49
5-Acetyl-4-amino-2-ethyl-6-phenylpyridazin-3(2i4)-one
A mixture of 5-ethyl-3-methyi-4-ph5nyIisoxazoiCi3.4-c^pyridaz:r.-7(5h')-one
PREPARATION 50
5-Acetyi-4-amino-6-thiophen-2-yl-2H-pyridazin-3-one
Obtained (73%) from.the title compound of Preparation 24 following the procedure described in Preparation 17.
5(CDCI3): 2.00 (s, 3H), 7.07-7.50 (m, 3H).
PREPARATION 51
5-Acetyl-4-amino-2-cyc!opropylmethyl-6-thiophen-2-yl-2H-pyridazin-3-one
Obtained (60%) from the title compound of Preparation 50 and cycloprcpyimeihyl bromide following the procedure described in Preparation 5.
o(CDCI3): 0.^2-0.62 (m, 4H), 1.40 (mt 1H)T 1.99 (s, 3H), 4.06 (d, 2H)f 7.04-7.50 (mf 3H).
-REPARATION 52
Ethyl 5-methyl-4-(thien-3-yIcarbcnyl)isoxa2ole-3-carboxylate
Obtained as a solid (70%) frcr. 1-:.- ;phen-3-yl-butane-1.2-dione (Harris, J; Levine, hi; J. Am. Chem. Soc. 1948, 7C. 326; arc ethyl cnloro(hydroximino)acetate following the experimental procedure descroec - Preparation 1.
o(CDC!3): 1.17 (t, 3H). 2.5c s. 3H), 4.20 (q, 2H), 7.26-7.70 (m, 3H).
PREPARATION 53 3-MethyI-4-thien-3-yIi5oxa20lo[3,-i-d]pyrida2in-7(6H)-one
Obtained as a solid (38%) from the r.:e compound of Preparation 52 using the experimental procedure described r Preparation 3.
5(CDCI3): 2.50 (s, 3H), 7.36-:.00 (m, 3H). 12.62 (s. 1H).
PREPARATION 54 6-EthyI-3-methy(-4-thien-3-ylisoxazo(o[3,4-d]pyridazin-7(6H)-one
Obtained (71%) from the title compcund from Preparation 53 following the experimental procedure described in Preparation 5.
5(CDC!3): 1 -42 (t, 3H), 2.57 (s. 3H), 4.26 (q, 2H), 7.30-7.62 (m, 3H).
PREPARATION 55
5-Acetyl-4-amino-2-ethyl-6-thien-3-ylpyridazin-3(2H)-one
Obtained (34%) from the title product of Preparation 54 following the procedure Jescribed in Preparation 14.
S(CDCt3): 1,41 (t, 3H), 1.23 (s. 3H), 4.26 (qf 2H), 7.17-7.48 (m, 3H).
PREPARATION 55 6-Ethy(-4-phenyl-3-3tyryl-6H-isox3zolo[3,4-d]pyridaziri-7"One
To a freshly prepared sciuticr of sc:ium metr.c/ide (113 mg. 1.95 rnmof. ;n re*har.oi
(2 mi), a solution of 6-e:hyl-2-~ethy:-^-phenyi-cn-is^ 'SCO
mg, 1.96 mmol) (Dal Piaz. V.; Gicvannoni, M.F.: Casie-lana. C: et ai J. A fee". Chen, 1997, 40. 1417-1421) in of zr; methanol (2 mi; .vas adzed and :he mixiure was siirrec for a while. Then, benzaidemce (O.-Q mi, 3.92 mmol) was adde^ drop-wise arc the final mixture was refluxed fcr 2 hours. The resu:::r.g suspension was !et to czz: dew-and the final product ( 514 mg. 76% yield) was elected by fiitra:ion.
o(CDCI3): 1.40 (t, 3k. 4.31'Ycr2H), 6.3C •:, 1H\ 7.35 (m. 5H). 7.63 i'm. 5H;.
'PREPARATION 57
6-Ethyl-4-phenyl-3-(2-thiophen-3-yl-vinyl)-6K-isoxazoIo[3,4-d]pyrida2in-7-one
Obtained (75%) from 6-9thy!-3-methyl-4-pheny!-cH-isoxazoio[3,4-d]pyridazin-7-or.e " (500 mg, 1.96 mmol) (Dal Piaz, V.; Gicvannoni. M.P.; Castellana, C; etal ,J. Med Chem. 1997, 40, 1417-1421)and ihiophene-S-carbalcehyde following the procedure described in Preparation 56.
o(CDCI3): 1.42 ft, 3H), 4.30 (q, 2H), 6.52 ,df 1H). 6.98 (d. 1H), 7.28 (m, 1H),
7.42 (m,1H), 7.63 (m, 6H). ■ •
PREPARATION] 58
4-Amino-2-ethyI-6-phenyl-5-(3-phenylpropionyl)pyridazin-3(2H)-one
A mixture of the title compound of preparation 35 (514 mg, 1.50 mmol) and 10% palladium on charcoal (100 mg) in ethanol (100 ml) was shaken under hydrogen at room temperature and 2 bar overnight. The caiaiyst was. filtered off and the solvent was' removed under reduced pressure to yield the ti:;e compound (437 mg, 95% yield).
m.p. 115.1-116.1°C
o(CDCi3): 1-40 (t, 3H,, 2.28 't, 2H), 2.68 :. 2H)t 4.25 (q, 2H), 6.73 (m, 2H), 7.05 •(m, 3H), 7.45 (m,5H).
PREPARATION 59 4-Amino-2-ethyl-6-phenyl-5-{3-thien-3-ylpropanoyl)pyrida2in-3(2H)-one
Obtained (67%) from the title :orr.?cunc of Preparation 3~ following the procedure
described in Preparation 53.
5(CDCi3): 1.41 [I 3H). 2.3C :, 2H). 2.70 (t. 2H\ 4.25 (q, 2H), 6.08 (d, 1H), 5.54-
5.62 (m, 2H). 7.03-7.53 (m, 7r).
- PREPARAT10N-6Q--
4-(3enzofuran-2-carbonyl)-5-rnethyl-isoxazoie-3-carboxylic acid ethyl ester
Obtained as a solid (30%; r'rom 1-benzofurari-2-yl-butane-1,3-dione (Richard. P.; Carreyre, H.; Coustard, J. M.; 3achmanrve-:;: Perot, G.. Tetrahedron 1993, 54(49), 14757-14766) and ethyl chloro(hydroximino;acstate following the experimental procedure described in Preparation 1.
o(CDCI3): 1-10 (I, 3H), 2.21 (s, 3H);4;15 (q:2H)', 7.16-7.30 (m, 5H).
PREPARATIONS ' 4-Benzofuran-2-yl-3-methyl-6H-isoxazo(o[3?4-d]pyridazin-7-one
Obtained as a solid (65%) from the title compound of Preparation 60 using the experimental procedure described in Preparation 3.
5(CDCI3): 2.99 (s, 3H), 7.29-7.49 (m, 3H), 7.70-7080 (m, 2H).
PREPARATION 62 4-Benzofuran-2-yl-6-ethyl-3-methyl-6H-isoxazolo[314-d]pyridazin-7-one
Obtained (67%) from the title compound from Preparation 61 following the experimental procedure deserted in Preparation 5.
5(CDCi3): 1.44 (tf 2H), 3.07 (s, 3H), 4.32 (q, 2H)t 7.27-7.76 (m, 5H).
PREPARATION 33 5-Acetyl-4-amino-6-benzofuran-2-y!-2-ethyl-2H-pyridazin-3-one
Obtained (90%) from the title crcduct of ^reparation 52 following the procedure described in Preparation 17.
o(CDC!3): 1.44 -'t. 3H\ 1.99 (sf 3H), 4.27 >c. 2K. 7.16(3. 1H), 7.27-7.*2 to. SH).
PREPARATION o^ . 6-(Cyclopropy[methyl)-4-(4-fIuorophenyi)-3-methylisoxazolo[374-d]pyridazin-7(6H)-one
Obtained (46%) from the title compound from Precara;ion-28 and cyclopropvirnethyi bromide following the experimental procedure described-in'Preparation 5. The product was purified by column chromatography.
o(CDCI:): 0.54 (m, 4H)t 1.38 (m, 1H), 2.53 (s, 3H), 4.08 (d. 2H)P 7.28 (d, 2H)t 7.57 (dd, 2H).
PREPARATION 55-
5-Acetyi-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-nitropyridazin-3(2H)-one
Obtained (37%) from the title product of Preparation 64 following the experimental procedure described in Preparation 30.
5(CDCI3): 0.46 (m, 2H), 0.62 (m, 2H), 1.45 (m, 1H)f 2.21 (s, 3H), 4.13 (d, 2H), 7.21 (m,2H), 7.45 (m, 2H).
PREPARATION 66
4:Nitro-[2,7]naphthyridin-1-oi
To a stirred solution of 2H-[2t7jnaphihyridin-1-one (300 mg, 2.05 mmoi; 'Baldwin, J. J.; Mensler, K.; Ponticeilo, G. S, J. Org. Chem. 1978, 43(25), 4378-30.) in 93% sulfuric acid (2 ml), 60% nitric acid (0.30 mi) was added droowise and :he mixing
was warmed to 85°C during 3 h. Addition of ice-cold water and basification to pH 7 gave a precipitate which was filtered and washed with ethyl ether to yield the title product as a yellow soiid :E7%).
o( DMSO-d6):3.23(d. :H), £.50 (c. 1H), 3.33 (s. 1H), 9.13 {d, 1H).
PREPARATION 57 4-Arnino-[2,7]naphthyridin-1 -ol
A mixture of the title ecr-pour: :f Preparation 55 f' tOO mg", 0.52 mrrioO and Ni-Raney (10 mg) in methanol (15 ml) was shaken under nydrcgen at rocm-.temperature and 1 aim overnight. Then catalyst was filtered off and the solvent was-re'mbved under reduced pressure to yield the tii.e compound (100%).
LRMS: m/Z 162 (M+1)"
PREPARATION 68 4-(4-Methoxy-benzoyl)-5-methyl-isoxazole-3-carboxylic acid ethyl ester
Obtained"as a yellow oil (63%) from 1-4-methoxy-phenyl)-butane-1r,3-dicne. (PopicV.V. etal., Synthesis 1991 (3), 1S5) and ethyl chlcro(hydroximino)acetate following the experimental procedure cescribed in Preparation 1.The final procuct was purified by column cromatography (n-Hex/EtOAc 9:1 to 1:1).
5(CDCI3): 1.18 (t, 3H), 2.53 (s, 3H)T 3.90 (s, 3H)t 4.20 (q, 2H), 6.95 (d, 2H), 7.30 (d, 2H).
PREPARATION 69 4-(4-Methoxy-phenyl)-3-methyl-6H-isoxa2o[o[3,4-d]pyridazin-7-one
Obtained as a white solid (91%) from the title compound of Preparation 63 using the experimental procedure described in Preparation 3.
8(DMSO-dQ): 2.54 (s, 3K/; 3.34 (3, 3H), 7.09 (d, 2H), 7.56 (d, 2H).
LRMS- (m/z): 253 (M+1V
r
PREPARATION 70 6-Ethyl-4-{4-methoxyphenyi)-3-rriethyl-5n-!SOxazoio[3,4-d]pyridazin-7-one
Obtained as a yellow solid ■"%; *r:^ the tii.e ccmcound from Preparation e2 "'ciicwr: the experimental procedure :escr:be: :r Preparation 5.
3(Dfv1SO-d^: -.30*:. 2H), 2.57
LRMS(m/z): 235 (i\^V,T
FR£?ARAT'ON 71 5-Acetyl-4-amino-2-ethyl-6-(4-methoxy-phenyi)-2H-pyridazirr-3-one
Obtained (34%) from the title product of Preparation 70 following the procedure" described in Preparation 14,
o( DMSO-d,): 1.29 (i/3H), 1.75 (s, 3H). 3.31 (s. 3H)( 4.10 (q, 2H), 7.03 ;d, 2H). 7.35 (d, 2H).
-REPARATION 72
4-(3-Methoxy-benzoyl)-5-methyl-isoxazole-3-carboxyIic acid ethyl ester
The title compound was synthesized (75%) from 1-(3-methoxy-phenyl)-butane-T3-dione (PopicTV.V. etal., Synthesis 1991 (3)t 195; following the procedure descrbed in Preparation 1.
5( DMSO-ds): TOO (t, 3H), 2.57 (s, 3H), 3.3 (s, 3H), 4.08(q, 2H)f 7.25-7.35 (m, 3H), 7.45 (m, 1H).
PREPARATION 73
t-(3-Methoxy-phenyf)-3-methy!-6H-isoxazolo[3T4-d]pyridazin»7-one
Obtained as a solid (69%) from the title compound of Preparation 72 using the experimental procedure described in Preparation 3.
5( DMSO-d6): 2.57 (s. 2H), 3.32 (s, 3H), 7.10 (d. 1H), 7.15-7.20 (m, 2H). 7.45 (t, In), 12.75 {s,NH).
PREPARATION 74
6-Ethyl-4-{3-methoxy-phenyi)-3-methyl-6H-isoxazoio[374-d]pyridazin-7-one
Obtained as a solid (30%) fre~ :he ::t!e compound of Preparation 73 using the experimental procedure descrbec > Preparation 5.
5( DMSO-d6): 1.35 (t. lr.\ 2.5" s. 3H), 3,32 (s, 3H), 4.15 (q, 2H), 7.10-7.25 (m, 3H), 7.45 (t, 1H).
PREPARATION 75
5-Acetyl-4-amino-2-ethyl-6-(3-methoxy-phenyi)-2H-pyridazin-3-one
Obtained as a solid (72%) from the title compound of Preparation 74 using the experimental procedure described in Preparation 14.
o( DMSO-ds): 1.35 (t, 3H), 1.73 (s, 3H), 3.32 (s, 3H), 4.10 (q, 2H), 6.90-7.10 (m, 3H), 7.40 (t, 1H), 7.73 (bs, 2H. NH:).
PREPARATION 76
5-Methyi-4-{4-methyl-benzoyl)-isoxazole-3-carboxylic acid ethyl ester
The title compound was synthesized (33%) from 1-p-tolyl-butane-1,3-dione (Popic.V.V. etaL, Synthesis 1991 (3), 1S5) following the procedure described in Preparation 1.
o(CDCU): 1.10 (t, 3H), 2.42 (s, 3H), 2.58 (s, 3H), 4.18 (q, 2H), 7.30 (d, 2H), 7.70 (d, 2H).
PREPARATION 77
3-Methyl-4-p-tolyl-6H-isox3Zolaf3,4-d]pyridazin-7-one
Obtained as a solid (33%) frcm the :;t!s compound of Preparation 75 using the experimental procedure describee in Preparation 3.
6-Ethyl-3-methyl-4-p-tolyl-6H-isoxazo!o[3T4-d]pyridazin-7-one
Obtained as a solid (39%) from (re title compounc of Preparation 77 using the experimental procedure described in Preparation 5.
o(CDCI3): 1.42 (t, 3H\ 2.-3 s, 3H), 2.53 (s. 3H). 4.30 (q. 2H). 7.35 (c. 2H). 7.4: id, 2H).
LRMS(m/z): 270 (M-M)".
Retention Time: 9.60 rnin.
-REPARATION 79
5-Acetyl-4-amino-2-ethyl-6-p-tolyi-2H-pyridazin-3-one
Obtained as a solid (91%) from the title compound of Preparation 73 using the experimental procedure described in Preparation 14.
5( CDCI3): 1.42 (tf 3H), 1.30 (s, 3H), 2.42 (s, 3H), 4.28 (q, 2H)f 7.30 (d. 2H),-7.33 (d, 2H).
LRMS(m/z):272(rvK1)7
Retention Time: 9.27 min.
PREPARATION 80
5-MethyI-4-{3-methyI-benzoyi)-isoxazole-3-carboxy!ic acid ethyl ester
The title compound was synthesized T3°o) from 1-m-tciy!-CLitane-1,3-dicne (PccicV.V. era/., Synthesis 1991 (3), 19: fcilcv/lrg :he procedure described in Preparation 1. 5{CDCI3): 1.10 (t, 3H}, Z.4C .s. 3H), 2.53 (s, 3H). 4.15 (q, 2H), 7.3G-7.5C m, 3H), 7.58 (m, 1H).
PREPARATION 81 3-MethyI-4-m-toiyl-6H-isoxazolo[3,4-d]pyridazin-7-one
Obtained as a solid (73%) frcm the :itie compound of Preparation 30 using the experimental procedure described in Preparation 3.
o(CDCI3): 2.45 (s, 3H), 2.53 is. 3H), 7.30-7.50 (mf 4H), 10.05 (bs, 1Hf NH).
PREPARATION 32
6-Ethyl-3-methyl-4-m-tolyI-6H-isoxazolo[3,4-d]pyridazin-7-one
Obtained as a solid (88%) from the title compound of Preparation 31 using the experimental procedure described in Preparation 5.
5(CDCI3): 1.42 (t, 3H), 2.45 (s, 3H), 2.58 (s, 3H), 4.30 (q, 2H), 7.30-7.50 (mT 4H).
PREPARATION 33
5-Acety!-4-amino-2-ethyl-6-m-tolyl-2H-pyridazin-3-one
Obtained as a solid (80%) from the title compound of Preparation 32 using the experimental procedure described in Preparation 14.
5( CDCI3): 1.42 (t, 3H), 1.30 (s, 2H), 2.42 (s, 3H), 4.28 (q, 2H), 7.20-7.40 (m, 4H).
■ LRMS(m/z):272(M+i;f. Retention Time: 9.25 min.
4-(3-Oxo-butyryl)-benzoic acid methyl ester
A solution of dimethyl terecrtnaiate «'10 gT 51.5 mncie; anc acetone ( 4.15 m.L, 5c.5 mmole) in a mixture of tolLere/dimethoxyethare 73mL'25 mL; .vas added to a suspension of NaH 500,o ;2.52 gT 55.9 mmoie; in zrj toiuene (25 mL) under argon. The mixture was heated at 1CG :C for- hcurs. The reaction mixture was cooied to ~ and 25 mL of water were added. The pH .'.as 3djustec :c 3-4 with HCI 2N and the mixture was poured-into water (300 mL;. Tie aqueous mixture was extracted with ethyl acetate (3x150 mL), dried over sodium suchate and evaoorated to afford a yellow soiid which was purified by column crcmatocrachy m-Hex.'EtOAc 9:1 to 7:3} to afford the title ccmD0und"(2.78 g. 25% vield) as a veilow soiid.
' -'5(-CDCi3): 2.25 (s, 2H), 3.95 (s. 3H), 6.22 -s, 1H), 7.90 (d. 2K), 3.10 (c. 2H).
LRMS(m/z): 221
Retention Time: 9.42 min.
PREPARATION 85 4-{44VIethoxycarbonyl-benzoyl)-5-methyI-isoxazoIe-3-carboxylic acid ethyl ester
The title compound was synthesized (54%) from the title compound of Preparation 34 following the procedure described in Preparation 1.
5(CDCI3): 1.10 (t, 3H), 2.53 's, 3H), 3.93 (s, 3H), 4.13 (q? 2H), 7.30 (d, 2H), 3.15 (d, 2H).
PREPARATION 86
4-{3-Methyl-7-oxo-6I7-dihydro-isoxazolo[3J4-d]pyrida2:in-4-yl)-benzoic acid methyl ester
Obtained as a solid (91%) from the title compound of Preparation 35 using the experimental procedure described in Preparation 3.
5(CDCI3): 2.58 (s, 3H), 3.93 (s, 3H). 7.52 (df 2H), 3.20 (d, 2H). 9.85 (bs. 1H,
NH).
PREPARATION 37
4-(5-EthyI-3-methyI-7-oxo-6,7-dihydro-isoxazoio[3,4-d]pyridazin-4-yi)-benzoic acid methyi ester
Obtained as a solid (70%) from the title compound of Preparation 86 using the experimental procedure-described in Preparation 5.
5(CDCI3): 1-:42-(t,;3H;, 2.53 (s, 2H), 3.93 (s, 3H), 4.30 (q, 2H), 7.62 (d, 2H), 3.20 (d. 2H).
PREPARATION 38
4-(4-Acetyl-5-amino-1-ethyl-5-oxo-176-dihydro-pyridazin-3-yl)-benzoic acid methyi ester
Obtained as a solid (97%) frcm the title compound of Preparation 37 using the experimental procedure described in Preparation 14.
8(CDCI3):-i:42"(t,:3H), 1.73 (s, 3H), 3.96 (s, 3H), 4.26 (q, 2H), 7.55 (d, 2H), 8.14 (d,2H).
LRMS(m/z):3'16 (M+1)*.
Retention Time: 8.80 min.
PREPARATION 89
3-(3-Oxo-butyryl)-benzoic acid methyl ester
A solution of dimethyl isophthalate (12 g, 51.85 mmole) and acetone ( 5 mL, 88 mmcle) in a mixture of toluene/dimethoyethane (90mL/30 mL) was added to a suspension of NaH 60% (2.97 g, 74.23 mmcle) in drytoluene (30 mL) under argon. The mixture was heated at 100 °C for 4 hours. The reaction mixture was cooled to rt and 25 mL of water were added. The mixture was poured into water (250 mL) and the pH was adjusted to 3-4 with HCI 2N. The aqueous mixture was extracted with ethyl acetate (2x250 rnL),
washed with brine, dried over sodium sulphate and evaporated to afford a yellow sciic which was purified bv column cromatocraDhv m-He; as a yellow solid.
o( CDCI-j: 2.23 (s. 3rX 3.56 (s, 3H), 5.25 (s. :H). 7.57 (d, 1H), 3.20 m. 2H), 3.51 (s, 1H).
LRMS irrJz): 221 \\wrr.
Retention Time: 9.22 rr.in.
-REPARATION SO
4-(3-Methoxycarbonyi-benzoyl)T5-methyl-isoxazole-3-carboxylic acid ethyl ester
The title compound was synthesized (62%) from the title compound of Preparation 39 following the procedure described in Preparation 1.
LRMS (m/z): 31S(M~i;f.- "'
Retention Time: 9.07 rnin.
PREPARATION 91
3-{3-Methyl-7-oxo-6,7-dihydro-isoxazolo[3,4-d]pyridazin-4-yf)-benzoic acid methyl ester
Obtained as a solid (30%) from the title compound of Preparation 90 using the experimental procedure described in Preparation 3.
LRMS (m/z): 286(M+1)+.
Retention Time: 7.73 min.
PREPARATION 92
3-(6-Ethyl-3-methyl-7-oxo-6,7-dihydro-isoxazolo[3,4-d]pyridazin-4-yl)-benzoic acid methyl ester
Obtained as a solid (99%) from the title compound of Preparation 91 using :r.e experimental procedure described in Preparation 5.
5(CDCI3): 1.42 (t. 3H), 2.53 ,3. 3H), 3.96 (s, 3H). 4.25 (q, 2H). 7.55 (dd, 1H), 7.30 (d, 1H), 8.20 (d, 1H), 8.25 3, 1H). LRMS(m/z): 314(M+1-'. Retention Time: 9.02 rrir.
PREPARATION 93
3-(4-Acatyl-5-amino-1-ethyl-o-oxo-1?5-dihydro-pyridazin-3-yi)-benzoic acid methyl ester
Obtained as a solid (93%) frcn :hs :;;;e compound.of Preparation 92 using the experimental procedure described \r, Preparation-^.
5(CDCI3): 1-42 (t, 3H), '.73 ..'s. 3H)r3'.96-(s,.3H), 4.25 (q, 2H), 7.45-7.70 (m, 4H), 8.15 (d, 1H), 3.13 (s, 1H).
LRMS(m/z): 316(M+ir.
Retention Time: 3.53 min.
PREPARATION'94 '
(3-Methyl-7-oxo-4-phenyl-7H-isox3zoIo[3,4-d]pyridazin-6-yl)-acetic acid methyl ester
Obtained as a white solid (39%) from S-methyM-phenylisoxazolop^-dlpyridazin-7(6H)-one (Renzi, G.; Pinzauti, S., II Farmaco Ed. Sci. 1969, 24, 885-889) and methyl bromoacetate following the exoerimental procedure described in Preparation 5. 5(CDCI3): 2.55 (s, 3H), 3.73 (s, 3H), 4.93 (s, 2H), 7.57 (m, 5H).
PREPARATION 95
(4-Acetyl-5-amino-6-oxo-3-phenyl-6H-pyridaz1n-1 -yl)-acetic acid methyl ester
Obtained as a white solid (99%) from the title compound of Preparation 94 following the experimental procedure described in Preparation 14.
5(CDCI3): 1.30 (s, 3H), 3.30 's, 3H), 4.92 (s, 2H), 7.42 (m, 5H).
PREPARATION 95 ■
e-Cyclopropylmethyl-S-methyl^-phenyi-oK-isoxazolotS^dJpyridazin-T-one
Obtained (31%) frcm 3-me:hyM-pnenyl-6h-oOX3Zcic[3.4d]pvr;cazin-7-one :Dai Plan. V. et al. J. Med. Chem.'VUT, -0. 1-17) arc cydoprccylmethy! bromide following :he experimental procedure described in Prepara'jon 5.
o(CDCI3): 0.30 (m. ±n\ 1.- (m. 1H)F 150 (s. 3H'-. 4.10 (c. 2H), 7.50 m. 5H).
PREPARATION 9^-
5-Acetyl-2-cyc!opropylmethyl-4-nitro-6-phenyl-2H-pyridazin-3-one.
Obtained (15.4%) from the :!tle compound ti ^reparation 96 following the experimental procedure described in Preparation; 30. The crude was purified by column, chromatography (siiica gel, hexane/ethyl ace:aie 3:1).
o(CDCI3): 0.50 (m. 2H), 0.70 (m, 2H;/T;4-(m; 1H), 2.20 (s, 3h), 4.20 (q, 2H). 7.50 (m, 5H).
PREPARATION 98
5-Nitroquinoline-3-carboxilic acid methyl ester.
To a stirred solution of 300 mg (1.375 mmol) of 5-nitroquinoline-S-carboxiiic acid (Breckenridge, J. G. Et al., Canadian J. of Research Sect S; 1947, 25, 49) in DMF (5 mL), 545 mg (3.850 mmci) of iodcmethane and 190 mg (1.375 mmol) cf potassium carbonate were adced. The resulting mixture was stirred at room temperature for one hour. Water (10 mL)" was added and the product collected by filtration. The residue was washed with water and dried to yield the title compound (250 mg, 78.4 %).
LRMS: m/Z233(M-M)* ' ■
o(CDCi3): 4705 (s, 3H), 7.70 (m, 1H), 8.00 (d, 1H), S.30 (d, 1H), 9.00 :z, 1H), 9.15 (m,1H).
PREPARATION 99 5-Aminoquinoline-3-carboxilic acid methyl ester.
A mixture of the title compcurc ;f Preparation 93 ;100 mg, 0.431 mmoi) and 1C : = palladium on charcoal ^46 rrc; ;.- eihancl (5 mL) was shaken under hydrogen at rcc~ temperature and 1 bar for 15 mnutes. The catalyst was filtered o~ and the sci'veri: removed under reduced pressure :c yieic ihe title compound (84 mg, 36 %) LRMS: m/Z203iM+V"
EXAMPLE 1 fScheme 1) 5-Acatyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-pyridin-3-ylpyrida2in-3(2H)-one
A mix:ure of the title compourc -zf Preparation 14 (520 mg, 2.0 mmol), 3-fluorcphenylboronic acid (560 ~c, 4.C mmol), anhydrous cupric acetate (540 mg, 3.0 mmol), triethylamine (0.55 mL -.0 mmei) and activated molecular sieves (1.5 g, 4 A) ;n dry dichloromethane (25 mL} was stirred under air exposure a; room temperature fcr 43 h. The reaction was filtered and the solvent removed under reduced pressure. The resulting residue was recrysta.iized frcm ethyl acetate (202 mg, 30% yieid).
m.p. 196.5-197.7°C.
5(CDCI3): 1.46 (t, 3H), 1,32 (s, 3H), 4.32 (q, 2H), 6.33 (m, 3H)f 7.31 (m, 1H), 7.49 (bs.1H), 7,37 (d, 1H), 3.15 (3.1H), 3.63 (bsT 2H).
EXAMPLE 2 (Scheme 1)
5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyi-6-pyridin-3-ylpyridazin-3(2H)-one
Obtained as a solid (27%) fron the title compound of Preparation 14 and 3-chlorophenylboronic acid following the procedure of Example 1.
m.p. 130.2-180.3°C.
5(CDCI3): 1-46 (t, 3H), 1.30 (s, 3H), 4.31 (q, 2H), 6.93 (d, 1H), 7.03 (m, 1H), 7.13 (m,1H), 7.25 (m, 1H), 7.41 (bs, 1H). 7.73 (d, 1H), 8.17 (s,1H), 3.67 (bs, 2H).
EXAMPLE 3 'Scheme 1)
5-Acetyl-4-[(3,5-dichlorophenyl)amino]-2-ethyl-6-pyridm-3-y!pyrida2in-3(2H)-on9
Obtained as a sciid (30%) :"rcm the :i:!e compound of Preparation 1- and 2.5-dicniorophenylbcronic acid r'cilowinc :he procedure of Example 1.
m.p. 219.9-220.4°C.
o(CDCI3}: 1.46 (t, 3H-, 1.83 [$. 3H), 4.31 (q, 2H), 6.93 (s, 2H;. 7.12 5. 1H). 7.13 (rn,1H). 7.50 (bs. HH), 3.02 rn, 1H). 3.17 (s.lri-. 3.72 (bs, 2H).
EXAMPLES 4-9 ^Scheme 1)
4. 5-Acetyl-2-ethyl-4-{1-naphthylamino)-6-pyridin-3-ylpyrida2in-3(2H}-one
5. Methyl 4-[(5-acetyl-2-ethyI-3-oxo-6-pyridin-3-yI-2,3-dihydropyridazin-4-
yl)amino]benzoate
6. 5-Acetyl-2-ethyl-4-[(2-fluorophenyl)aminoI-6-pyridin-3-ylpyrida2in-3(2H)-one
7. 5-AcetyI-4-[(2-chiorophenyl)amino]-2-ethyl-6-pyridin-3-yIpyridazin-3(2H)-one 3. 5-Acetyl-2-ethyI-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-3-ylpyridazin-
3(2H)-one 9. 3-[(5-Acety!-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-
yl)amino]benzonitriIe The title compounds were synthesized from the title compound of Preparazicn 14 and the corresponding boronic acid following the procedure of Example 1. The ESI/MS data and HPLC retention times are summarized in Table 2.
Table 2
EXAMPLE ESI/MS m/e (M+H)* Retention j Time (min)
4 385 8.1 i
i
5 393 7.2 |
[
0 353 7.1 i
7 369 7.7
3 365 5.7
360 6.3 i
EXAMPLES 10-14 (Scheme 1'.
10. 5-Acetyi-4-[(3-chlorophenyI)amino]-2-(cycIopropylrnethyi)-6-pyridin-3-ylpyridazin-3(2H)-one
11. 5-Acetyl-2-(cyclopropylmethy!)-4-[(3,5-dichlorophenyi)arnino]-5-pyridin-3-yipyridazin-3(2H)-one
12. 5-Acetyl-2-(cycIopropylmethyl}-4-[(2-fIuorophenyi)amino]-6-pyridin-3-ylpyridazin-3(2H)-one
13. 5-Acetyl-4-[(2-chlorophenyl)amino]-2-(cycIopropylmethyl)-6-pyridin-3-ylpyridazin-3(2H)-one
14. 3-{[5-Acetyl-2-(cyclopropylmethyl)-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazin-4-yI]amino}benzonitriIe
The title compounds were^synthesized from the title compound of Preparation 17 anc the corresponding borcnic acid following the procedure of Example 1- The ESI/MS ca:a and HPLC retention times are summarized in Table 3.
EXAMPLE 15-13 (Scheme 1)
15. Methyl 4-{[5-acetyl-2-{2-hydroxyethyl)-3-oxo-6-pyridin-3-yl-2,3-
dihydropyridazin-4-yi]amino}benzoate
16. 5-Acetyl-4-[(2-f!uorophenyl)amino]-2-(2-hydroxyethyl)'-6-pyridin-3-ylpyridazin-
3(2H)-one
17. 5-Acetyl-4-[(2-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazin-
3(2H)-one
13. 5-Acetyl-4-[{3-chIoroph9nyl)amino]-2-(2-hydroxyethyl)-6-pyridin-3-ylpyridazi 3(2H)-one
The title ccmpouncs were synthesized from the title compound of Preparation 20 anc 4-methoxycarbor.y:3henyl bconic ac'd following the procedure of Examp e T The 5 ESI/MS data anc HPLC retention tires are summarized in Tabie 4.
EXAMPLE 19 (Scheme 1)
5-Acetyl-4-[(3-chIorophenyl)amino]-2-ethyl-6-pyridin-2-yIpyridazin-3(2H)-one
Obtained as a solid (27%) from the title compound of Preparation 15 anc 3-chlorophenyibcror.ic acid following the procedure of Example 1.
LRMS: m/z369(M+1;T
5(CDCI3): 1.42 (t, 3H), 2.01 (s. 3H), 4.33 (q, 2H), 6.90 (m, 1H)T 7.20 (m, 4H), 7.32 (m,3H), 8.42 (d, 1H).
EXAMPLE 20 (Scheme 1)
S-KS-Acetyl^-ethyl-S-oxo-S-pyridin^-yi-Z.S-dihydropyridazin^-yl)amino]benzonitriIe
Obtained as a sciic (53%) from the title compound orPreparation 15 anc 3-cyanophenylbcronic acid following the procedure of Example 1.
5(DMSO-d:;: 1.37 (t, 2H), 2.09 (s, 3H), 4.22 (q, 2H), 7.42 (m, 5H . 7.52 (m, 2H) 3.49 (m, 1H), 8.29'5, 1H).
EXAMPLE 21 (Scheme II
5-Acetyl-2-ethyl-4-{[4-(hydroxymethy!)phenyl]amino}-6-pyridin-2-ylpyridazin-
3(2H)-one
Obtained as a solid (13°V) from the title compound of Preparation 15 and 4-hycroxymethyiphenylbcronic ac:c -"cslcwing the procedure of Example 1.
LRMS: m/Z 364^-1^1)".
Pvetention Time: 4.9 rrin.
•EXAMPLE 22 (Scheme 1)
3-{[5-Acetyl-2-(cyclopropyimethyl)-3-oxo-6-pyridin-2-yI-2.3-dihydropyridazin-4-yl]amino}benzonitrile -------
Obtained as a solid (40%) from the title compound of Preparation 13 and 3-cyanophenylboronic acid following the procedure of Example 1.
m.p. 168.1-169:5?C.
5(CD3OD): 0.49 (m, 2H), 0.59 (m, 2H), 1.36 (m, 1H), 2.11 (s, 3H), 4.13 (d, 2H)T 7.33 (m, 5H)f 7.92 (m, 32H), 3.4-1 'm. 1H).
EXAMPLE 23-25 (Scheme 1)
23. 5-Acetyl-4-{(3-chlorophenyl)amino]-2-(cyclopropyImethyl)-6-pyridin-2-yipyridazin-3(2H)-one
24. 5-Acetyl-2-(cycIopropylmethyl)-4-{[4-(hydroxyrnethyI)phenyl]amino}-6-pyridir 2-ylpyridazin-3(2H)-one
25. 5-Acetyl-2-(cyclopropyimethyl)-4-[(3,5-dichlorophenyl)amino]-6-pyridin-2-ylpyridazin-3(2H)-one
The title compounds were synthesized from the title compound of Preparation 13 and the corresponding boronic acid following the procedure of Example 1. The ESI/MS dat and HPLC" retention times are summarized in Table 5.
EXAMPLE 26 ( Scheie r
3-{[5-Acetyi-2-(2-hydroxyethyl)-3-oxo-5-pyridin-2-yl-2,3-dihydropyrida^;n-4-
yl]amino}benzonitrile - -" '
Obtained as a sc.id (26%) from the title'comcound'of Prepararicr 21 and 2-cyancphenylbcrcnic acid following the procedure of Example 1.
m.p. 194.2-195.0°C.
5(CD3OC : 2.10 (s,3H). 4.01 (t. 2H), 4.40 (t, 2H), 5.90 (m.LH), 7.25 -rn. SH). 7.92 (m, 2H), 3A5 (d, 1H).
EXAMPLE 27 (Scheme 1)
5-Acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydro_xyethyl)-6-pyridin-2-ylpyridazin-
3(2H)-one
Obtained as a sciid (22%) from the title compound of Preparation 21 and 3-chlorophenyiborcnic acid following the procedure of Example 1.
LRMS: ~Z385(M+1)".
Retention Time: 6.0 min.
EXAMPLES 23-29 (Scheme 1)
28. 5-Acetyl-4-f(3,5-dichIorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-j2-.
yipyridazin-3(2H)-one
29. 5-Acetyl-2-(2-hydroxyethyl)-4-{[4-(hydroxymethyi)phenyl]amino}-6-pyridin-2-
ylpyridazin-3(2H)-one
The title compounds were synthesized from the title compound of Preparation 21 and the corresponding boronic acid following the procedure of Example 1. The ESI/MS data and HPLC retention times are sumr.anzed in Table 5.
EXAMPLE 30 (Scheme 1V--
5-Acetyl-2-ethyl-4-[(3-fIuorophenyl)amino]-6:pyndinr4-ylpyridazin-3(2H)-one
Obtained as a solid (15%) from the title compound of Preparation 16 and 3-fluorophenylboronic acid following the procedure of Example 1.
m.p. 195.1-195.9°C.
5(DMSO-d6): 1.33 (i,3H), 1,37 (s, 3H), 4.13 "(q, 2H), 6.33 (mt 3H)f 7.28 (m, 1H)," 7.31 (d, 2H), S.58 (d, 2H), 9.24 (s, 1H). '.
EXAMPLE 31 (Scheme 1) .. 5-Acety(-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-4-yipyridazin-3(2H)-one
Obtained as a solid (63%) from the title compound of Preparation 16 and 3-chlorophenylboronic acid following :he procedure of Example 1.
m.p. 176.4-177.0°C.
5(DMSO-d5): 1.33 (t, 3H), 1.27 (s, 3H), 4.13 (q, 2H)f 7.01 (m, 3H), 7.29 (m, 3H), 8.60 (m, 2H), 9.24 (s, 1H).
EXAMPLE 32 (Scheme 1) - -
* -
5-Acetyl-2-ethyl-4-{1-naphthylamino)-6-pyridin-4-ylpyridazin-3(2H)-one
Obtained as a soiid (53%) from the title compound of Preparation 16 and r,aph:ha!ene-1-boronic acid fcilcwinc the crocedure of Examcie 1.
m.p. 177.5-
otLivlbO-c^ ■ 3"0»: i.o/ ;m. on), 4.23 \-z. _-\ /.2o (m, ort). t.o( ■ .. -rv. /.o4 *.. i i i. — iJ /, i.rj ijii. iiii. i'.«— . 111, 111'.'_'. J . .ill, i .;, O.J>J (in, wt i'. -j.uy [ii,. > .
^.Arilli LL 0U { OLW , — rT.b ! }
5-Ac8tyl-2-ethyi-4-[(2-methylphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)
Obtained as a send (17%) from the title compound of Preparation 15 anc 2- -methylphenylbcrcric acid following the procedure of Example 1.
m.p. 137,3-139.4°C. - • . . . .
5(CD3OC : 1.42 (t, 3H), 1.60 (s,3H), 2.29 (s, 3H), 4.30 (q. 2H)77~;:-m. 1H)t 7.14 (m, 2H), 7.25 ('m, 1H), 7.40 (m, 2H), S.54 (m. 2H). -
EXAMPLES 34-40 (Scheme 1)
34. Methyl 4-[(5-acetyI-2-ethyi-3-oxo-6-pyridin-4-yI-2,3-dihydropyridazin-4-yl)amino]benzoate
35. 5-AcetyI-2-ethyl-4-[(2-methoxyphenyl)arnino]-6-pyridin-4-ylpyridazin-3(2H)-one
36. 5-Acetyl-2-ethyl-4-[(3-methoxyphenyI)amino]-6-pyri(}in-4-yIpyridaz!n-3(2H)-one
37. 5-Acetyl-2-ethyI-4-[(2-fluorophenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one
33. 5-Acetyl-4-[(2-chlorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one
39. 3-[(5-Acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino] benzonitrile
40. 5-Acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyiJamino}-6-pyridin-4-yipyridazin-3(2H)-one
The title compounds were synthesized from the title compound of Preparation 16 and the corresponding boronic acid following the procedure of Example 1. The ESI/MS data and HPLC reten:ion times are summarized in Table 7.
EXAMPLE -1 fHvdrolisis: No scheme)
4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-4-y!-2,3-dihydropyrida2in-4-yl)arnino]ben2oic acid
To a stirred solution of the title product of example 34 (0.33 g, 0.97 mmbl) in 40 mL of a 3:2 MeOH/THF mixture a solution of lithium hydroxide (0.25 g, 5.83 mmol) in 4 mL of water was added and the mixture was stirred at room temperature overnight. It was acidified with HC! 2N until pH 5 and it was extracted with dichloromethane and washed with water and brine. It was dried on Na2S04 and solvent removed to yield a crude product that was purified by column chromatography on Si02 using CH2CI2/MeOH as eluent. The title product was obtained in a 16% yield.
m.p. 251.6-252.6°C.
5(DMSO-d6): 1.34 (m, 3H), 1.93 (s, 3H), 4.20 (q, 2H), 7.08 (d, 2H), 7.33 (d, 2H), 7.79 (d,2H), 8.60 (d, 2H), 9.33 (s,1H).
EXAMPLES 42-46 (Scheme 1)
42. 5-Acetyl-2-(cyc!opropylmethyl)-4-{(2-fIuorophenyi)amino]-6-pyridin-4-
\/In\/nrla7in-^nM\-nno
43. 5-Acetyl-4-[(2-ch!orophenyl)amino]-2-(cyciopropyimethyl)-6-pyridin-4-
ylpyridazin-3(2H)-one
44. 3-{[5-Acetyl-2-(cycIopropylmethyi)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-
4-yl]amino}benzonitriIe
45. 5-Acety!-2-(cyc!opropyImethyl)-4-{[4«(hydroxymethyI)phenyl]amino}-8 4-ylpyridazin-3(2H)-one
46. 5-Acetyi-4-[(3-chiorophenyi)amino]-2-{cyclopropy(methyl)-6-pyridin-4-ylpyridazin-3(2H)-one
The title compounds were synthesized frcm the title compound of Preparation 13 end the* corresponding borcnic acid following the procedure d Example 1. The ESI/MS data anc HPLC retention times are summarized in Table 3.
EXAMPLES 47-51 (Scheme 1)
47. 5-Acetyl-4-[(2-fluorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one
48. 5-AcetyI-4-[(2-chiorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one
49. 3-{[5-Acetyl-2-(2-hydroxyethyl)-3-oxo-6-pyridin-4-yl-2T3-dihydropyridazin-4-yl]amino}benzonitriie
50. 5-Acetyl-2-(2-hydroxyethyi)-4-{[4-(hydroxymethyl)phenyi]amino}-3-pyridin-4-yipyridazin-3(2H)-one
51. 5-Acetyl-4-[(3-chlorophenyJ)amino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one
The title compounds were synthesized from the title compound of Preparation 22 and the corresponding boronic acid following the procedure of Example 1. The ESI/MS data and HPLC retention times are summarized in Table 9.
EXAMPLE52 (Scheme 1)
5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethy!-6-thien-2-yIpyridazin-3(2H)-one
Obtained as a sciid (20%) from the title compound of Preparation 26 and 3-chlorophenylboronic acid following the procedure of Example 1. LRMS: m/Z374(M+1;_.
8(CDCU): 1.46 (tf 3H), 1.38 (s, 3H), 4.29 (q, 2H), 7.00 (m, 3H), 7.03 (m, 1H), 7.26 (mf 2H), 7.27 (m, 1H), 7.93 (m, 1H).
EXAMPLES 53-55 I Scheme 1)
53. 5-AcetyI-4-[bis(3-fluorophenyl)amino]-2-ethyl-6-pyridin-3-yIpyridazin-3(2H)-
one
54. 5-Acetyl-4-[bis-(4-methoxycarbonylphenyl)-amino]-2-ethyl-6-pyridin-3-
ylpyridazin-3(2H)-one
55. 5-Acetyl-4-{bis[4-(hydroxymethyI)phenyl]amino}-2-ethyl-6-pyridin-3-
ylpyridazin-3(2H)-one
The title compounds were synthesized from the title compound of Preparation 14 and an excess of the corresponding ar/lboronic acid following the experimental procedure described in example 1. The E3I/MS data and HPLC retention times are summarized in Table 10.
EXAMPLES 55-5" - Scheme 1)
56. 5-Acetyl-4-[bis(3-nitrophenyi)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one
57. 5-acetyl-4-[bis(3-fluorophenyl)amino]-2-ethyl-6-pyridin-4-yIpyridaz:n-3(2H)-one
The title compounds were synthesized from the title compound of Preparation 15 and an excess of the corresponding arylbcronic acid following the experimental procedure described in example 1. The ESI/MS data and HPLC retention times are summarized in Table 11.
EXAMPLES 58-59 (Scheme 1)
58. 5-Acetyl-4-[bis(3-chlorophenyl)amino]-2-(cycIopropylmethyl)-6-pyridin-3-y!pyridazin-3(2H)-one
59. 5-Acetyl-4-{bis(3,5-dichlorophenyI)amino]-2-(cyclopropylmethyl)-5-pyridin-3-ylpyridazin-3(2H)-one
The title compounds were synthesized from the title compound of Preparation 17 and an excess of the corresponding arylbcronic acid following the experiment procedure
described in example 1. The E3I/MS data and HPLC retention times are summarized in Table 12.
EXAMPLE 60 (Scheme 1)
5-Acetyl-4-fbis(4-methoxycarbonyipheny()arnino]-2-(2-hydroxyethyf)-6- pyridin-3-ylpyrida3:in-3(2H)-one
The title compound was synthesized from the title compound of Preparation 20 and an excess of 4-methoxycarbonylphenylbcronic acid following the experimental procedure described in example 1.
LRMS:m/Z542(M+1)~.
Retention Time: 3.0 min.
EXAMPLE 61 (Scheme 1)
5-Acetyl-4-[bis(3-chlorophenyi)amino]-2-(2-hydroxyethyl)-6-pyridin-2-ylpyrida2in-3
The title compound was synthesized from the title compound of Preparation 21 and an excess of 3-chlorophenylbcronic acid following the experimental procedure described n example 1.
LRMS:m/Z495(M-H)-.
Retention Time: 9.5 min.
EXAMPLE 52 Screme 1)
5-Acetyl-4-[bis(3-chlorophenyl)amino]-2-(cyclopropylrnethyl)-6-pyndin-i-ylpyridazin-3(2H)-one
The title compound was synthesized :r:n me :i:!e compound of Preparation 15 and an excess of 3-chicrcphenylboronic acic followir: the experimental procedure described in example 1.
LRMS: rr\I505 (M+lT.
Retention Time: 1C.2 min.
EXAMPLE 63 Sereme 2) 5-Acetyl-2-ethyl-6-phenyl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one
To a stirred solution of 200 mg (0.7 mmcl) of 5-acetyl-2-ethyl-4-nitro-6-phenyipyridazin-3(2H)-one (Dai Piaz, V etal, J. Med. Chem. : 557, 40, 1417) in ethanol (10 rr.L), 3-aminopyridine (0.09.8 mgT 1.04 mmol) was added portionwise. The resulting mixture was stirred at room temperature for five hours. The solvent was evaporated and the residue purified by column chromatography ^sMtca gei, dichloromethane/methanol 97:3) to yield the title compound (50 mg, 26% yield . m.p. 135.5-136.3 °C. . o(DMSO-d6): 1.34 (m, 3H), 1.72 (s, 3R. A1S (q, 2H), 7.29 (m, 3H), 7.41 (m, 4H) 3.26 (d, 1H), 3.33 (d, 1H), 9.10(s, 1H).
EXAMPLE 54 'Scheme 2)
5-Acetyl-4-[(3,5-dichioropyridin-4-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one
To a stirred suspension of 50 mg (1.25 mmol) of sodium hydride in 5 ml of THF , 100 mg (0.62 mmcl) of 4-amino-3,5-dichloropyridire in 5 ml of THF was added. The mixture was allowed stirring 30 minutes at room temperature and then cooled to 0°C. 150 mg (0.52 mmol) of 5-acetyl-2-ethyl-4-nitrc-6-phery!pyridazin-3(2h')-one (Dal Piaz, V etal, J. Med. Chem. 1997, 40, 1417) in 10 ml of THF was added. The reaction was allowed to warm to room temperature and to continue stirring for 12 hours. The mixture was acidified with 2N HCI to pH 2. Ethyl acetate was added and the organic layer was
washed with water, brineT dried over Na2S04 anhydride and evaporated. The residue obtained (210 mg) was purified by column chromatography (silica gel, hexane/erhyl acetate 1:1) to yield the title" compound (35 mgT 16.7 % yield).
m.p. 195.5-197.1 :C.
5( CDCU): 1.40 (m, 3H), 1.35 s. 3H), 4.10 (q, 2H), 7A5 (bs, 5H), 3.40 (s. 2H), 8.30 5, 1H).
EXAMPLE 65 {Scheme 2)
5-Acetyl-2-ethyl-S-phenyl-4-{pyrazin-2-yiamino)pyridazin-3(2H)-one
To a stirred solution of 75 mg (0.251 mmol) of 5-acetyl-2-ethyi-4-nitro-o-phenyipyridazin-3(2H)-one.(Dai Piaz, V at a/, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanoi, 37 mg (0.392"mniol) df'aminopyrazine was added. The resulting mixture was stirred at room temperature during 3 cays and the final product was collected by fiitrarion and washed with diethylether to yield the title compound (12 mg, 13.6 % yield).
m.p. 22S.9-229.7°C. '
5(DMSO-da): 1 ."34 (m; 3H), 1.34 (s, 3H), 4.21 (q, 2H), 7.34 (m, 2H), 7.43 (m, 3H) 3.12 (m, 2H), 3.67 (s, 1H)„9.93 (s, 1H).
-" 'EXAMPLE 65 (Scheme 2) 5-Acetyl-2-ethyl-6-phenyI-4-(pyrimidin-2-yIamino)pyridazin-3(2H)-one
To a stirred solution of 100 mg (0.343 mmol) of 5-acety!-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V etal, J. Med. Chem. 1997, 40, 1417) in 5 ml of ethanoi, 430 mg (4.524 mmol) of 2-aminopyrimidine was added. The resulting mixture was stirred at 50°C during five days and the final product was collected by filtration and washed with diethylether to yieid the title compound (42 mg, 35.6 % yield).
m.p. 197.1-198.3 °C.
5(DMSO-d,): 1.33 (m, 3H), 1.93 (s, 3H), 4.19 (q, 2H), 7.02 (m, 1H)t 7.37 (m, 2H) 7.49 (m7 3-H), 3.52 (m, 2H), 9.02 (s, 1H).
EXAMPLE 67 'Scheme 2)
5-Acetyl-2-ethyl-6-phenyl-4-(quinolin-8-yIamino)pyridazin-3(2H)-one
To a stirred solution of 100 ma ('0.343 mmol'" zf 5-acetvl-2-ethvl-4-niira-c-phenylpyridazin-3(2H}-one (Dal Piaz, V at ai. .. Med. Chem. 1597, 40, 1417) in 5 mi zf ethanoi, 75 mg (0.522 mmci) of 3-aminoquinciine was added. The resulting mixture was stirred at room temoeraiure for two hours and the final croduct was ccilected bv
* * >
filtration and washed with diethylether to yieic :he ntie compound (100 mg, 74.5 :/o
yield). .........
m.p. 179.2.1-130.3°C.
5(CDCU): 1.49 (m. 3h); 1.75 (s, 3H-), 4.34 (q, 2H). 7.25 ^m, 1H), 7.45 (m. 7K)
7.56 (m, 1H), 3.17 (dd, 1H). 3.92 (d,;TH)f9.55H's. 1H).
.EXAMPLE 63-'Scheme 2)
5-Acetyi-2-ethyl-4-[(5-nitropyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one
To a solution of 30 mg (0.273 mmol) of 5-acetyl-2-ethyl-4-nitro-6-pheny!pyridazin-3(2H)-one (Dal Piaz, V etal, J. Med. Chem. 1997, 40, 1417) in 4 mi of ethanoi, 77 mg (0.556 mmol) of 2-amino-5-nitropyridine;was added. The resulting mixture was irradiated in microwave oven for seven hours at 120dC. The final produc: was coliected by filtration and washed with diethylether to yield the title compound (36 mg, 34.3 °o yield).
m.p. 200.3-201.1°C.
5(DMSO-d5): 1.35 (m, 3H), 1.92 (s, 3H), 4.22 (q, 2H), 7.39 (mT 3h). 7.4S (m, 3H), 3.41-3.45 (dd, 1H), 3.92 (d,1H), 10.34 (s, 1H).
EXAMPLE 69 (Scheme 2)
5-Acetyl-2-ethyl-4-(1H-indol-4-ylamino)-6-phenyipyridazin-3(2H)-one
To a stirred solution of SO mg (0.273 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenyipyridazin-3(2H)-one (Dal Piaz, V etal, J. Med. Chem. 1997, 40, 1-17) in 4 ml of ethanoi, 55 mg (0.417 mmol) of 4-aminoindole was added. The resultinc mixture was
stirred at room temperature for one hcjr and the final produc: .vas collected by filtration and washed with diethylelher tc yield :?.e title compound (33 mg, 79.8 % yield).
m.p. 223.2-224.G°C.
3(CDC!3}: 1.27 (s, 3H), 1.36 'r. 3H), 4.19 (q, 2H), 6.33 (s. 1H), 6.66-6.67 (d.-1H) 5.95 (m, 1H), 7.25 (m, 3H\ 7.3'-*.37 (m. -H), 3.76 (s, :H), 11.20 (s, 1H).
EX,-MPL=3 70-73 (Scheme 2)
70. 5-Acetyl-4-(1)3-benzothiazol-6-y!amino)-2-ethyl-6-phenylpyridazin-3(2H)-cne
71. 5-Ac9tyl-2-ethyl-6-phenyl-4-(thian:hren-1-ylamino)pyridazin-3(2H)-one
72. Methyl 3-[(5-acetyl-2-ethyl-3-oxo-5-phenyl-2,3-dihydropyridazin-4-yl)amino]thiophene-2-carboxylate
73. 5-Acetyl-2-ethyl-4-[(4-methylpyridin-2-yl)amino]-.6-pn.enylpyridazin-3(2H)-one
74. 5-Acetyl-2-ethyl-6-phenyl-4-(1 H-1 ,2,4-triazoI-5-ylamino)pyridazin-3(2H)-one
75. 5-Acetyl-2-ethyl-4-[(6-methoxypyridin'-3-yi)amino]T6^ one
76. 5-Acetyl-2-ethyl-4-{2H-indazol-5-ylamino)-6-phenylpyridazin-3(2H)-one
77. Methyl 4-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]thiophene-3-carboxyiate
78. 5-Acetyl-2-ethyI-6-phenyl-4-{pyrldin-2-ylamino)pyridazin-3(2H)-one
The title compounds were synthesized from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piazt V et al, J. Med. Chem. 1997, 40,-1417) and the corresponding aniline or amine-pyridine following the procedure of Example 67. The ESI/MS data and HPLC retention times are summarized in Table 13.
EXAMFLz 79 (j-ivdrolisis: No scheme)
■ 3-[(5-acetyI-2-ethyl-3-oxo-S-phe^ carboxylic acid
The title compound was synthesized from the title compound of example ~2 following the experimental procedure described in example 41.
LRMS: m/Z333(M+1)+.
Retention Time: 3.5 min.
EXAMPLE 30 f Scheme 2)
5-Acetyi-2-ethyl-4-[(3-methyIcinnolin'5-yl)amino]-6-pheny(pyridazin-3(2H)-one
To a stirred solution of 30 mg (0.273 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et a/, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 66 mg (0.417 mmol) of 3-methylcinnolin-5-amine was added. The resulting mixture was stirred at room temperature for one day. The final product was collected by filtration and purified by column chromatography (silica gel, ethyl acetate,'hexane 2:1) to yield the title compound (65 mg, 53.6% yield).
m.p. 225.4-237.7°C.
5(DMSO-d9): 1.37 (mt 3H), 1.41 (s, 3H), 2.91 (s, 3H), 4.22 (q, 2H\ 7.25 (m, 2H) 7.35-7.40 (m, 3H), 7.53 (d, 1H), 7.57-7.72 (t, 1H), 8.10 (s, 1H), 8.24 (d, 1H), 9.19 (s, 1H).
.EXAMPLE 81 (Scheme 2)
5-Acetyl-2-ethyf-4-[(2-methyIquinoiin-3-yi)^^
To a stirred solution of SO mg (3.273 mmol) of 5-aceiyl-2-ethyf-4-niiro-5-phenyipyridazir-3(2/-/)-one (Dal Piaz. 7 etal, J. Med. Chem. 1997, 40, 1417) in 4 ml cf ethanol, 66 mg -0.417 mmol) cf 2-me:hylquinoiin-3-amine was added. The resulting .mixture' was stirred at rcom temperature for one hour and the final product was collected by filtration anc washed with diethylether to yield the title compound (97 mcT 93.3 % yield).
m.p. 172.2-172.S°C.
o(DMSC-d6): 1.22 (m, 3H), 1.32 (s, 3H), 2.54 (s, 3H). 4.07 (q, 2H),-7,02 (d. 1H), 7.21-7.30 (m, 6H), 7.35 (d, 1H)f 7.45 (d, 1H),8.13(d, 1H), 9.15 (s,-1H):;r ,;.,-
EXAMPLE 82 (Scheme 2)
5-Acetyl-2-ethyl-6-phenyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one
To a stirred solution of 80 mg (0.273 mmol) of 5-acetyl-2-ethyl-4-nitro-5- _■. phenyipyridazir-3(2H)-one (Dal Piaz, V etal, J. Med. Chem. 1997, 40, '1417) in 4 ml of ethanol, 60 mg '0.417 mmol) of 5-aninoquinoline was added. The resulting mixture was stirred at rcom temperature for four hours and the final product was collected by filtration and washed with diethylether to yieid the title compound (80 mg, 74.3 % yield).
m.p. 219.9-221.1°C.
5(DMSO-d«): 1.31 (s, 3H), 1.33 (m, 3H), 4.22 (q, 2H), 7.24 (m, 2H) 7.34-7.33 (m, 4H), 7.55-7.33 (m, 2H), 7.36 (d, 1H), 8.42 (d, 1H)f 8.92 (df 1H), 9.19 (s, 1H).
EXAMPLE 83 (Scheme 2) 5-Acetyi-2-ethyl-4-(1H-indoN5-ylamino)-6-phenylpyridazin-3(2H)-one
To a stirred solution of 30 mg (0.273 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dai Piaz, V etal, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 55 mg '0.417 mmol) of 5-arrinoindole was added. The resulting mixture was stirred at room Temperature for one hour and the final product was collected by filtration and washed wi:h diethylether to yieid the title compound (97 mg, 93.3 % yield).
m.p. 2-2.6-243.1°C.
5(DMSO-d5): 1.34 (m, 3H). 1.47 (s. 3H), 4.17 (q, 2H), 6.33 (bs, ;H\ 5.33 (d. 1H), 7.24-7.37 (m. SH), 3.77 (s. 1H). 11.09 (s. 1H).
EXAMPLE 34. Scheme 2)
5-Acetyl-2-ethyl-4-(isoquinoiin-5-ylamino)-6-phenyipyridazin-3(2H)-one
To a stirred section cf 30 rr.c '0.273 mmol) of 5-acstvl-2-ethv!-4-nitro-5-phenylpyridaz:n-3(2H--cne ;Dai F:az. 7 et a/. J. /Wee'. Crtem. 1997, 40, 1-17'. in 4 mi of ethanol, 60 mg .0.417 mmoi) of 5-iscquinolinamine was added. The resuming mixture was stirred at room temperature for ihree days. The final product was cc:!ected by - filtration and purified by coiumn chromatography (silica gel, ethyl acetate, hexare 7:3r to yield the title compound (20 mg, 12.4% yield).
o(DMSC-d^): 1.31 (s. 3H), 1.33 (m, 3H), 4.22 (q, 2H). 7.24 (m, 2H; 7.33 (m, ^ 3H), 7.53 (m. 2H), 7.35 (d, 1H), 7.97 (d. 1H), 3.53 (d; 1H), 9.13 (s, 1H). 5.32(3. 1H).
EXAMPLE 85 (Scheme 2)
5-Acetyl-2-ethyl-4-[(6-methoxyquinolin-8-yl)amino]-6-phenylpyridazin-3(2H)-one
To a stirred solution of 30 mg (0.273 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz. V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 73 mg (0.417 mmoi) of 3-amino-6-methoxyquinoline was added. The resulting mixture was stirred at room temperature for two hours and the final product was collected by nitration and washed with diethylether to yield the title compound (33 mg, 76.5 % yield).
m.p. 133.1-134.0°C.
5(DMSO-d9): 1.34 (m, 3H), 1.58 (s, 3H), 3.84 (s, 3H), 4.21 (q, 2K), 6.31 (s, 1H),
7.08 (s, 1H), 7.35-7.46 (m, 5H), 7.53-7.57 (m, 1H), 3.27 (d, 1H), 3.73 (d, Yd), 9.31 (s,
1H). - -
EXAMPLE 86 (Scheme 2) 5-Acatyl-4-[(5-bromoquinolin-3-yi)amino]-2-ethyl-6-phenyIpyridazin-3(2H}-one
To a stirred solution of-Omg -0.139 mmcl) of 5-acetyl-2-ethyl-4-nitro-5-phe^y!pyndaz;n-3(2H)-cne (Dai Piaz. V etal, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 3-aminc-5-brcmoquholine (47 mg, 0.209 mmol) was added. The resulting mixture was stirrad at room :emperature for five days and heated at 50 °C during four days. The solvent was evaporated and the residue purified by column chromatography (silica ce!, hexane.e:hyl acetate 4:1) to yield the title compound (16 mg, 25% yield).
m.p. 143.1-149.C3C.
5(DMSO-d6): 1.35 (m, 2H), 1.70 (s/3H), 4.20 (q, 2H). 7.13 (d, 1H), 7.39-7.45 . (m,5H) 7.76 (m, 1H)f7.34(d. 1H), 3.50(d, 1H), 8.99 (d, 1H), 9.41 (s, 1H).
EXAMPLE 37 (Scheme 2)
5-Acetyl-2-ethyl-4-[(4-methyfpyrimidin-2-yl)amino]-6-phenyipyridazin-3(2H)-one
To a stirred solution of 30 mg (0.273 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz. Vet a/, J. Med, Chem. 1997, 40, 1417) in ethanol (4 mL), 2-amino—-methylpynmidine (46 mg, 0.417 mmol) was added. The resulting mixture was stirred at 50 °C during five days. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/erhyi acetate 2:1) to yield the title compound (11 mg, 11.3% yield).
LRMS:m/Z350(M+ir.
Retention Time: 7.4 min.
EXAMPLE 83 (Scheme 2)
5-Acetyl-6-(3-chlorophenyl)-2-ethyl-4-(pyridin-3rylamino)- pyridazin-3(2H)-one
Dbtained from 5-acetyl-2-ethyl-^-nitro-5-(3-chlorophenyl)pyridazin-3(2H)-one (Dal Piaz, J etal, J. Med. Chem. 1997, 40, 1417; and pyridin-3-ylamine following the procedure Df Example 67. The product was purified by preparative HPLC/MS.
LRMS: n/Z369,M-1)\ Retention Time: 5.2 min. ■
EXAMPLE 3S f Scheme 21
5-AcetyI-6-(3-chlorophenyl)-2
Detained from re title compound of preparation 40 and pyncin-3-y!amire following the procedure of Example 57. The product was purified by preparative HPLC-MS.
LRMS:m,Z395 :\M)Retenticr Time: 9.; min.
EXAMPLE 90 f Scheme 2)
>-Acetyl-2-ethyl-6-(3-fluorophenyi)-4-(pyridin-3-ylamino)-pyridazin-3(2H)-one
)btained from the title compound of preparation 36 and pyridin-3-ylamine following the )rocedure of Example 67. The product was purified by preparative HPLC/MS.
LRMS: m/Z353(M+1)Retention Time: 1A min.
EXAMPLE 91 (Scheme 2)
-Acetyl-6-(3-ftuorophenyl)-2Hsopropyl-4-(pyridin-3-ylarnino)-pyridazin-3(2H)-one
)btained from the title compound of preparation 33 and pyridin-3-ylamine following the rocedure of Example 57. The product was purified by preparative HPLC/MS.
LRMS: m/Z367(M+1f.
Retention Time: 3.3 min.
EXAMPLE 92 (Scheme 2)
5-Acetyl-2-cyclopropy!methyl-6-(3-f!uorophenyl)-4-(pyridin-3-yIamino)-pyridazin-3(2H)-one
Ob;ained from :he title compound of preparation 37 and pyricin-3-ylamine following the procedure of Example 37. The prcduc: was purified by preparative HPLC, MS.
LRMS: m/2 379('.Kir.
Retention Time: 3.4 min.
EXAMPLE 93 ^Scheme 2)
5-Acetyi-6-{4-f!uorophenyl)-2-ethyl-4-(pyridin-3-ylamino)-pyridazin-3(2H)-one
- Obtained from :he title compound of preparation 30 and pyridin-3-ylamir.e following the procedure of Example 67. The product was purified by preparative HPLC/MS. LRMS: rn/Z353(W+ir. Retention Time: 7.4 min.
EXAMPLE 94
5-Acetyl-6-{1H-benzoimidazol-2-yl)-4-(3-chloro-phenyIamino)-2-ethyl-2H-pyridazin-3-one
To 10 mL of dry toluene under nitrogen, trimethylalumminium (1.05 mL of a 2M solution in toluene) was added and the solution was cooled down to 0°C. Then 1.2-diaminobenzene (68 mg, 0.63 mmol) was added in portions and the mixture was stirred at 0°C for 30 min and at 15°C for 1 hour. Then, the title product of preparation 45 (150 mg, 0.42 mmol) was added in one portion and the final mixture was refluxed for 1.5 hours. Then it was let to warm to room temperature and water and methanol were carefully added. The white precipitate thus formed was filtered and the mother liquor
was neutralized with HCI 2N and solvent was removed. Finally the residue was partitioned between water and dichicromethane and the organic layer was washed with brine. Dried and solvent -amoved to yieic a crude product that was purlfiec by column chromatography.
LRMS: rn/Z403(.\M.".
Retention Time: c.Z min.
OiCud:). i.4i it. orh;, O.01 (5. oH), s-.oo ',c. ih)f o.3o im. ^H), .'. . J-m. on;, 7.38 (s, 1H), '.73 ;s, -H;
EXAMPLES 95-95 ('Scheme 1)
95, 5-Acetyl-5-benzooxazoI-2-yl-4-(3-chIorophenylamino)-2-ethyl-pyr;dazin-3(2H)-
■one
96. 5-Acetyl-3-benzooxazol-2-yl-4-(3-fluorophenylamino)-2-ethyi-pyridazin-3(2H)-
one
The title compounds were synthesized from the title compound of Preparation -3 and the corresponcing boronic acid following the procedure of Example 1. The E5I/MS data and HPLC retention times are summarized in Table 14.
Table 1
ESI/MS m/e I Retention I EXAMPLE ' ! j
(M+H)* Time (min) ;
S5 408 9.7
:
1
96 392 j 9.4 i
[
EXAMPLES 97-98 fScheme 1)
97. 5-Acetyl-5-benzooxazoI-2-yi-4-[bis-(3-chlorophenyl)-amino]-2-ethyl-pyridazin-3(2H)-one
98. 5-Acetyl-6-benzooxazol-2^yi-4-[bis-{3-fIuorophenyl)-amino]-2-ethyl-pyridazin-3(2H)-one
The title compounds'were synthesized from the title compound of Preparation -3 and an excess of the corresponding an/boronic acid fcilowing the experimental procedure
described in example 1. The ESI/MS data and HPLC retention times are summarized in Table 15.
EXAMPLES 99-100
99. 5-Acetyl-6-(i;3-faenzoxazol-2-yl)-2-ethy!-4-[(3-methoxyphenyl)
amino]pyridazin-3(2H)-one
100. 5-Acetyi-5-{1,3-benzoxazol-2-y[)-2"ethyl-4-{[4-(hydroxyrnethyl)
phenyl]amino}pyridazin-3(2H)-one
The title compounds were synthesizes from the title compound of Preparation 43 and the corresponding boronic acid following the procedure of Example 1. The ESI/MS data and HPLC retention times are summarized in Table 16.
EXAMPLE 101 5-AcetyI-2-ethyl-4-(isoquinolin-4-ylamino)-6-phenyipyridazin-3(2H)-one
A mixture of the title corrcound of Preparation 49 (2.2 g, 3.33 mmci), 4-bromoisoquinoline (2.14 g, 10.2 mmci,. anhydrous cuprous iodide (170 mg, 0.39 mmci) mmol), N.N'-dimethyiethyleneciamine '0.185 ml, 0.39 mmo!) and potassium carbonate
(1.73 g, 12.5 mmol) in dry dioxane under argon was stirred in a sealed tube at 130°C for 24 h. The reaction was filtered and :he solvent removed under reduced pressure. The resulting residue was purified by :'!ash column cronathcgraohy ;5iO:; dichloromethane-ethyj acetate) to yieid the tii:e product (450 mg. 14% yield'.
0'CDC;2;: 1.43 (s, 3H), 1.-1-3 ,\ 3H). -.34 (q, 2H), 7.35 cm. 5H\ 7.73 -m, 1H\ 7.79 (m. 1H), 5.03 (m. 2H), 3.29 (m. 2H). 9.15 -s, 1H).
EXAMFLES ^02-103
102. 5-Acetyl-2-ethyi-4-(1?6-naphthyridin-3-ylamino)-6-phenylpyriciazin-3(2H)-one
103. 5-Acatyl-2-ethyl-4-[(5-methoxypyridin-3-yl)amino]-6-phenyipyridazin-3(2H)-one
The title compounds were synthesized from the title compound of Preparaticn 49 and he corresponding bromide following the procedure of Example 101. The ESS/MS data 3nd HPLC retention times-are summarized in-T3bie 17.
EXAMPLE 104 5-AcetyI-2-ethy!-6-pyndin-4-yl-4-(pyridin-3-ylamino)pyrida2in-3(2H)-one
Obtained as a yellow solid (69%) from the title compound of Preparation 15 and 3-bromopyridine following the procedure of Example 101. LRMS: m/Z336(M+1)7
unromstcgratic rr.e:ncd 3.
Retention Time: 6 min8(CDCUr 1.45 (t, 3H)f 1.79 .3. 3H), 4.30 (q, 2H)T 7.30 (m, 3H), 7.41 (m, 1H), 8.42 (m, 3H), 2.53 (m, 2H).
z'AMPLE 105
5-AcetyI-2-ethy[-4-[(4-methylpyridin-3-yO^
Obtained as a soiid (31 ^V) from the :;:le compound of Preparation 13 and 3-bromc-4-methylpyridine ""cilowing :he procedure of Example 101.
m.p. 207.3-208.9cC.
o(DMSC-d3): 1.33 (tf3H). 1.c! -;s,-3H). -2.21 (s7'3-H^4.15 (m, 2H)t 7.22 (m, 1H), 7.27 (m, 2H), 3.17 (m, 2H-. 3.57
EXAMPLES 106-4 07-
106. 5-Acetyl-2-ethyI-4-(isoquinolin-4-ylamino)-6-pyndin-4-ylpyridazin-3(2H}-one
107. 5-Acetyl-2-ethyI-6-pyridin-4-yi-4-[(3;4,5-trifIubrophenyl)aminoIpyridazin-' 3(2H)-one
The title compounds were synthesizes from the title compound of Preparation 16 and the corresponding bromide following tre procedure of Example 101. The ESI/MS data and HPLC retention times are summarized in Table 18.
EXAMPLE 103
5-Acetyl-2-ethyl-4-[(4-met^
Obtained as a-solid !2*%) "'rem [he title compound of Preparation 1~ arc 3-or:mo-4-methyipyricine fcilowirg the procedure of Exampie 101.
6(DMSO-d3): 1.35 -;t. 2h"). 1.52 (s. 3H). 2.22 (st or.}, 4.22 (q, 2h"\ ~2^ ;c. In). 7.40 (m, 1H,, 7.53 (m. 1H), 3.25 'm. 2H), 3.43 is. 1H), 3.53 (m, ;HJ. 3.3"" -.'s. 1H).
EXAMPLES 109-11Q.
109. 5-AcetyI-2-ethyl-4-(isoquinolin-4-ylamino)-6-pyridin-3rylpyridazin-3(2H)-one
110. 5-Acety[-2-ethyl-6-pyridin-3-yl-4-[(3,4,5-trifluorophenyi)amino]pyrida2in-3(2H)-one
The title compounds were synthesized from the title compound cf Preparation 14 and the corresponding bromide following the procedure of Example 101. The ESI/MS data and HPLC retention times are summarized in-Table-19:-
EXAMPLE 111 5-AcetyN2-ethyl-4-(quinolin-5-ylamino)-6-thien-2-ylpyridazin-3(2H)-one
Obtained as a sciid (50%) from the title compound of Preparation 25 and quinoline-5-boronic acid following the procedure of Example 1. m.p. 214.2-215.0°C.
.5(CDC;3): 1-43 (t. 2H), 1.51 (s. 3H), 4.32 (q, 2H), 6.35 (m, 1H), 5.90 (m. 1H). 7.36 (m, 2H), 7.52 (m, W\ 7.3- (m. 1H), 3.05 (m, 2H), 3.42 (m,1H), 9.00 (m, 1HEXAMPLES 112-114
112. 5-Acetyi-2-ethyl-4-{pyridin-3-y!amm^
113. 4-[(5-Acetyl-2-9thyI-3-oxo-6-thien-2-yl-2,3-dihydropyridazin-4-yl)amino]benzonitri!e
114. S-Acetyl^-ethyl-S-thien^-yi^-^S^^-trifluorophenylJaminolpyridazin^f^H)^ one
The title compounds were synthesized from the title compound of Preparationy26r3nd ' the corresponding boronic acid following the procedure oi Example" 1.-The ESI/MS'data and HPLC retention times are summarized in Table 20.
EXAMPLE 115
5-AcetyI-4-(bis (4-cyanophenyl)amino)- 2-ethyl-6-thien-2-ylpyridazin-3(2H)-one
Obtained as a solid from the title compound of Preparation 26 and an excess of 4-yanophenylboronic acid following the experimental procedure described in Example 1.
LRMS: m/Z466(M+1)~.
Retention Time: 9.9 min.
EXAMPLES 116-117
116. 5-Acetyi-2-(cyclopropylmethyl)-4-{quinolin-5-ylamino)-6-thien-2-ylpyrSdazin-3(2H)-one
117. 5-Acetyl-2-(cycIopropylmethyl)-4-(pyridin-3-yIamino)-6-thien-2-ylcyrid.^in-3(2H)-one
The title compounds were synihesized from the fee compound of P:epar3::cr 51 anc the correspcrcina borcric acid follcwina the orocedure of Exancie 1. The ESLMS data and HPLC re:e~:ion tires are summarized in Table 21.
EXAMPLE 113 5-Acetyl-2-ethyl-4-(quinolin-5-y[amino)-6-thien-3-ylpyridazin-3(2H)-one
Obtained as a solid (52%) from the title compound of Preparation 55 and quinoiine-5-boronic acid following the procedure of Example 1. m.p. 126.S-187.3°C.
8(CDC!3): 1.45 (s, 3H), 1.51 (t, 3H), 4,34 (q, 2H). 7.11 (mf 1H)f 7.30 (m, 3H), 7.52 (m, 1H), 7.35 (m, 1H), 3.08 (m, 2H), 8.43 (m,1H), 8.99 (m, 1H).
EXAMPLES 119-122
119. 5-Acetyl-4-[(3-chlorophenyI)amino]-2-ethyl-6-thien-3-ylpyridazin-3(2H)-one
120. 5-Acetyl-2-ethyl-4-(pyridin-3-ylarnirro)-6-thien-3-ylpyridazin-3(2H)-one
121. 4-[(5-Acetyl-2-ethy|.3-oxo-6-thien-3-y[-2,3-dihydropyridazin-4-y!)amino]benzonitrile
122. 5-Acetyl-2-ethyl-64hJen-3-yM-[(3A5-trifluorophenyl)amino]pyridazin-3(2H)-
one
The title compounds were synthesize: from :he title compound of Preparation 55 and the corresponding boronic acid following the procedure of Example 1. The E3i/MS data and HPLC retention times are summarized in Tabie 22.
EXAMPLE 123
2-EthyI-6-phenyl-5-(3-phenylpropanoyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one
Obtained as a solid (50%) from the title compound of Preparation 53 and quinoline-5-boronic acid following the procedure cf Example 1.
m.p. 164.0-165.3°C.
5(CDCU): 1.43 (t, 3H), 1.79 (t, 2H), 2.01 (t 2H), 4.35 (q, 2H), 6.42 (m, 2H), 7.05 (m, 3H), 7.32 (m, 6H)f 7.51 (m, 1H), 7.54 (m, 1H), 3.09 (m, 2H), 3.46 (m,1H), 9.00 (mf 1H).
EXAMPLES 124-125
124. 2-Ethyl-6-phenyl-5-(3-phenylpropanoyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one
125. 2-Ethyl-4-(isoquinolin-4-y[amino)-6-phenyl-5-(3-phenylpropanoyI)pyridazin-
3(2H)-one
The title ccmccurcs were synthesized from the ti;:e compound of ?r~zar2::c". z-l and ; the correspcrcing brormce fcilowirc :ne procedure of Example 101. The ESi.MS data end HPLC re:ene:on rimes are sumr~arlzed in Tac:e 23.
EXAMPLES 126-127
126. 2-Ethyl-6-phenyl-4-(quinolin-5-ylamino)-5-(3-thien-3-ylpropanoyI)pyridazin-
3(2H)-one
127. 2-Ethyl-5-phenyl-4-(pyridin-3-ylamino}-5--(3-thien-3-ylpropanoy!)pyridazin-
3(2H)-one
The title compounds were synthesized from the title compound of Preparation 53 and the corresponding boronic acid following the procedure of Example 1. The ESI/MS data and HPLC retention times are summarized in Table 24.
EXAMPLE 123
5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-(1H-imidazo[4,5-bIpyridin-2-yl)pyridazin-3(2H)-one
Obtained as a solid (7%) from the title compound of Preparaticn 45 arc 2.3-diaminopyridine acid following -he expenrnentai procedure described in example 94.
LRMS: rr\t'Z4Q2[V\+Vf.
Retention Time: 5.3 min.
- EXAMPLE 129
5-AcetyI-6-(1T3--benzothiazol-2-yf)-4-[^3-chiorophenyl)amino]-2-ethyipyridazin-3(2H)-one
Obtained as a solid (22%) from :he title compound of Preparation 45 arc 2-aminobenzeneihiol following the expe: mental procedure described in example 94.
-LRMS: m/Z425(I\,M)~.
Retention Time: 10.5 min.
EXAMPLE 130
5-Acetyl-6-(1-benzofuran-2-yl)-4-[(3
Obtained as a solid (31%) from the title compound of Preparation 63 arc 3-chlorophenyl boronic acid following the procedure of Example 1.
LRMS: m/Z40S(M+1)~.
Retention Time: 10.2 min.
EXAMPLE 131 5-Acetyl-2-ethyl-6-pyridin-3-yl-4-(pyridin-3-ylamino)pyrida2:n-3(2H)-one
Obtained as a soiia from :he title :cmpcunc :f Preparation 14 and 3-pyr:cineccronic acid following :he procedure of Example 1.
Retention Time; -.9 min.
4-[(5-Acetyl-2-ethyl-3-oxo-o-pyridin-3-yl-2.3-dihydropyridazin-4-yi)amino]benzoic acid " ~
Obtained as a solid from the title compound of Example 5 following the procedure of Example 41.
LRMS: m/Z379(M+ir.
Retention Time: 5.1 min.
EXAMPLE 133 5-AcetyI-2-ethyl-4-[(1-oxidopyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one
To a stirred solution of 50-55% m-chloroperbenzoic acid (130 mg, 0.33 mmol aprox.) in Jichloromethane (2 ml), a solution of the title product of example 63 (125 mg, 0.33 nmol) in dichlcromethane (2 ml) Y/as added dropwise and the resulting mixture was ;tirred at rt overnight. Then it was diluted with dichlcromethane and poured onto 10% iodium sulphite solution. The organic layer was further washed with saturated sodium n'carbonate sciution and brine. It was then dried and solvent removed to yield a crude iroduct that was purifiedd by preparative HPLC/MS.
LRMS: m/Z351 (M+1)V
Retention Time: 6.3 min.
EXAMPLE 134
Ethyl 3-(5-acetyl-2-9thyl-3-oxo-6-pyridin-4-yl-2T3-dihydro-pyridazin-4-
yiamino)benzoate
Obtained as a solid (67%) from the title compound of P-epararicn 15 arc 3-ethcxycarbonylphenylbcrcnic ac:d relieving the procedure of Exampie 1.
LRMS: ~VZ407(';H1)7
o(CDC.'::: 1.38 (t. 3H), 1.45 t. 3H), 1.53 (s. 3H), 4.35 (m. 4H.\ 7.23 (m. 2H), 7.at in, 1H), 7.70 (s, 1H'.. 7.33 [m, 1-.. 3.29 (s, 1H), 3.53 (m. 2H).
EXAMPLE 135
3-[(5-Acetyl-2-ethyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)amino] benzamide
To a 0°C precooled solution of saturated ammonia in THF (2 mi) under argon, trimethylaluminium (0.307 mlr, 0.515 m.mol) was added and the mixture was stirred for 30 min. Then, a solution of the title compound of Example 134 (50 mg, 0.123 mmel) in dry THF (1 mL) was added dropwise and the final mixture was stirred at rt overnight Some more trimethyialumminium (0.307 mLr 0.615 mmol) was added and the mixture was refluxed overnight. It was then let to cool down and water was added. The seiid thus formed was removed by filtration and the mother liquor was diluted with water, neutralized with 0.1 M HCI and extracted with dichloromethane. The organic layer was washed with water and brine and dried. Finally, solvent was removed to yield a crude product that was purified by preparative HPLC/MS (20% yield).
LRMS: m/Z78(M+1)+.
Retention Time: 5.1 min.
EXAMPLE 136 5-Acetyl-2-ethyl-6-phenyl-4-(thieno[2,3-b]pyridin-3-ylamino)pyriGa2in-3(2H)-one
Obtained (27%) from 5-aceb/l-2-ethyi-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz. V et al, J. Med. Chem. 1997, 40, 1417, and thieno[2,3-b]pyridin-3-ylamine (Klemm, L.H.,
Zell, R.. Banish, i.T., rCemm, RA, J. Het Chem. 1970, 273-3~"9; -'ollcwing the
procedure of Example 57. ■ ■
LRMS: ml 231 'M-1T Retenricn "ine: '- mir .
5-Acetyi-2-ethyl-4-[(6-f[ucropyridin-3-yi)arnino]-5-pheny!pyridazin-3(2H)-one
Obtained -55^- from 5-acs:y!-2-e:^vl-4-r;tro-5-pnenylpyridazin-2f2H:-■:■*e Dai Piaz, V ei a/T J. ;Ve£. Cne/77. 139". -2. 1-:^ arc o-fluoropyridin-S-ylamne ^Re.\:as:ie. G. VV.. Denny, 7-/A Winters, R.T, J. C~em Soc. Parkin Trans. 1, 1396. 12. 2221-2225; following :he procedure cf Example 57.
.m.p. ;33.1-13A2°C
oi'CCC!3): 1.43 ■:, 2H;. 1.53 (s,3H),-4.26 (q, 2H)f 6.92 (dc.lH:-. ~A2 :'mt 5H), 7.54 (m, 1H), 2.05 (d. 1H). 3.51 (5. 'H)-" - - -
EXAMPLE 133 5-Acetyl-2-ethyl-4-((2-methylpyridin-3-yl)amino]-6-phenyipyridazin-3(2H)-one
Obtained (17%) from 5-ac8tyl-2-e:ry!-4-nitro-6-phenylpyridazin-3(2H;-or:e Dai Piaz, V et al, J. Med. Chem. 1997, ^0, 1417; and 2-merhylpyridin-3-y!amine (Nanrka-Namirski, P., Kaczmarczyk, C, Tcba. L, Ac:a Poioniae Pharmaceutics. 1967, 2A3), 231-237) following the procedure of Example 63. The product was purified by coiumn cromatography ■ silica gel, rexane/ethyl acetate 1:1).
m.p. 157.9-158.6CC
o(CDCI3): 1.42 (t 3H). 1.5^ (s, 3H), 2.60 (s, 3H), 4.27 (q, 2H;, 7.13 (m,1H), '.26 (m, 1H), 7A2(m, 5H), 3.25 (s. 1H)f 8.39 (m, 1H)
EXAMPLE 139
5-Acetyi-4-{[2-(dimethyiamino) 3
Obtained (20°i>) from 5-3cety1-2-etr-;!-4-nitr:-G-phenylpyriciaz:n-3(2H)-one (Da! Piaz. V et alt J. Med. Chem. 199"". 40, 14:7} and 2-amiro-2-dimethylaminopyridine following
the orocedure of Exameie 63. Tr.e oroduc: was ourified bv column cromatccraohv
• > - >«i . «
(silica gel, hexane/ethyl acetate 5/..
m.p. 135.1-137.::'C
5(CDCI3): 1.42 ■:. 3H), 1.5-i 's, 3H). 2.93 (s, 6H)f-4.31 "(q, 2H), 5.38 (m,1H). 7.16 (m. 1H), 7.42 (m, 5H>. 3.05 (m. 1H), 8.19 (m, 1H) ' ~ ^-: ■
EXAMPLE "14Q
5-[(5-Acetyl-2-ethyl-3-oxo-5-phenyl-2,3-dihydropyridazin-4-yl)amino]pyridine-2-carboxylic acid
Obtained (43%) from 5-acer/[-2-ethyl-4-nitro-S-phenylpyridazin-3(2H)-one (Dal Piaz, V et al. J. Med. Chem. 1997. 4Q, 1417 and 5-amincpyridine-2-carboxylic acid (De Waal, A., Hartog, A. F., De Jong, L, Bicchimica et Biophysics Acta, 1988, 953(1), 20-25) following the procedure of Example 57.
m.p. 226.1-226.8°C • '
5(DMSO-d6): 1.33 (m, 3H), 1.92 (s, 3H), 4.18 (q, 2H), 7.38 (m, 1H), 7.42 (m,5H), 7.86 (d, 1H), 8.42 (s, 1H), 9.33 (s, 1H), 12.92 (1H, s).
EXAMPLE 141
5-Acetyl-2-ethyl-4-[(2-methoxypyridin-3-yl)amino]-6-phenyipyridazin-3(2H)-one
Obtained (43%) from 5-acet/l-2-ethyl-4-m'tro-6-phenylpyridazin-3(2H)-Qne (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and 2-methoxypyridin-3-ylamine (Hwu, J.R., Wong, F.F., Shiao, M.J., J. Org. Chem, 1992, 57(19), 5254-5255) following the procedure of Example 67.
m.p. 170.2-170.5'C
o(CDC!3): 1.-12 (t. 3H). 1.53 (s, 3H). 3.93 (s, 3H). 4.29 q, 2H>. 5.38 {m,1H). 7.26 (m, 1H), 7.39 (rr. 5H;. 7.93 »;m. 1H), 3.32 is. 1H)
EXAMPLE 1-2 5-Acetyl-2-ethyl-4-(1H-indazol-4-ylamino)-o-phenyipyrida2in-3
Obtained (33°; from 5-acety!-2-et~yl-4-n;tro-o-pnenyipyndazln-3
m.p. 217.3-219.0°C
o(CDC:3): 1.48 (t. 3H), 1.53 (3, 3H). 4.34 (a, 2H), 6.32 , 8.22 (s, 1H), 3.23 (sJH), 10.22(3. 1H)
EXAMPLE 143
5-Acetyl-4-[(2-chloropyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one
Obtained (30%; from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3f2H).-one-.Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and 2-chloropyridin-3-ylamine r'cilcwing :he procedure of Example 63. The product was purified by column cromatccraphy (siiica gel, hexane/ethyl acetate 2:1).
m.p. 153.0-153.5°C
5(CDCI3): 1.43 (t, 3H), 1.31 (s, 3H), 4.30 (q, 2H), 7.22 (m, 1 K), 7.39 (m, 6H), 8.45 (m, 1H), 3.2 (s. 1H)
EXAMPLE 144
5-Acetyl-4-[(5-chloropyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one
Obtained from 3-acer/l-2-ethyM-nitro-o-phenylpyridadn--3(2H)-one (Dai Piaz. V et al, J. Med. Chem. 1997, 40, 1417) and 5-chloropyridin-3-ylamine (Heindl, J.. Kessler, H.J., DE2607012) following the procedure of Example 33. The product was purified by preparative HPLC/MS.
LRMS: m/Z369(M+ir Retention Time: 15.0 min'.
EXAMPLE -45
5-[(5-Acetyl-2-ethyI-3-oxo-6-phenyl-2.3-dihydropyndazin-4-yi)aminc]nicotinarnide
Obtained (54%: ;'-:m 5-acer>'!-2-ethy>--nitro-5-phenyipyridazin-3(2H)-cne (Cai Piaz. V ei al. J. Med. Chem. 1997. 4QT 1417' and S-anir.o-nicotinamice (Uenc, Y. Chemics Scric:3 19S4, 24;4-5), 1 £5-7) foilcv;rc the procedure of Example 67.
m.p. 225.3-236.S°C
5(CDC;3';-: 1.43 (t, 3H), 1.32 "s. 3H), 4.30 (q, 2H), 5.64 (s,1H); 5.22 (s, 1H), 7.41 (m.5H), 7.73 (s, 1H)f 2.55 (d, 1H\3.69(s, 1H), 3.75 (d, 1H) ^
EXAMPLE 146
5-Acetyl-2-ethyi-4-{1,7-naphthyridin-3-ylamino)-6-phenylpyridazin-3(2H)-one
Obtained from 5-acetyl-2-ethyl-4-nitrc-5-phenylpyridazin-3(2H)-or.e (Da! Piaz.-:V:.eraL\ J. Med. Chem, 1997, 40, 1417) arc [1,7]naphthyridin-3-ylamine (Van den Haak, HJ. W.; Van der Plas, H.C.; Van Veldhuizen, B. Journal of Heterocyclic Chemistry- 1-931, -13(7), 1349-52.) following the procedure of Example 63. The product was purified by-preparative HPLC/MS.
LRMS: m/Z386(M+1)'
Retention Time: 10.0 min'.
EXAMPLE 147 2-Ethyl-5-gIycoloyl-4-[(2-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one
To a 0°C stirred solution of potassium hydroxide (510 mg, 9 mmol) in methanol (15 mL) a solution of the title compound of Example 133 (348 mgT 1 mmol) was added dropv/ise within 10 min. Then, diacetoxyiodobenzene (644 mg, 2 mmol) was added portionv/ise
Chromatografic method B.
and the final mixture was stirred at rt overnight. Solvent was removes under reduced pressure and the res.cue was suspended in ethyl acetate and washed with saturated NH4CI solution and :r;ne. The organic layer was dried and solvent .'.as removed to yield a crude product mat was purified by cciurnr. chromathcgraphy (11:: ..;e;c'LRMS: m/ZocvM+ir.
Retention Tjrre: i 3 minC./\
Methyl 5-[(5-aceryi-2-ethyl-3-oxo-5-phenyl-2,3-dihydropyricazin-4-yi)amino]
nicotinate
Obtained f'213V; '"rem 3-acetvl-2-ethvl-4-nitrQ-o-c-henylpvridazin-3'2H%,-cne .Dai P:az: V et al, J. /V/ecf. Chem. 1997, 40. 1417) and 5-aminonicotinic acid methyi es:her (Jensen, H. H.; Lyngbye. L; Jensen, A.; Bols, M. Chemisir/-A European Journa. 2C02. 3(5;. 1213-1225) fcilcwing the prccedure of Example 63. The product was punned by preparative HPLC/MS.
m.p. 144.S-145.3f)C
5(CDC13): 1.44 ft, 3H), 1.77 (s. 3H), 3.94 (s, 3H), 4.29 (q, 2H\ 7.43 (m? 5H), 7.92 (s. 1H), 3.54 (d, 1H), 3.35 (s, 1H), 9.05 (d, 1H)
EXAMPLE 149
5-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino(nicotinic acid
Obtained from 3-aceryi-2-ethyl-4-nitro-8-phenylpyridazin-3(2H)-one (Dai ?iazf V et al, J. Med. Chem. 1997, 40, 1417) and 5-aminonicotinic acid (Delarge, J. Phsrmacautica Acta Helvetiae (1969), 44(10), 637-43) following the procedure of Example 63. The product was purified by preparative HPLC/MS.
LRMS: m/Z379(M+1)~
Retention Time: 12.0 min*
EXAMPLE 150
5-Ac9tyl-2-ethyM-(1,5-naphthyridin-3-yIamino)-6-phenylpyridazin-3(2H)-one
Obtained from 5-3C8tyl-2-etnyi-4^itr:---;-pher.yipyridaz:n-3(2H)-one (Da! Piaz, 7 et ai, J. Med. Chem. 1997, 40, 1417) and ;:.5in5cr:hyridin-3-ylamine (Czuea W„ Akati. M.. Wroclaw, P., Rocniki Cherr.ii. 195". 41 (2\ 239-297) following the procecure cf Examole 63. The croduct was curried cv orecarative HPLC/MS.
LRMS: m/Z386 (M-1j~
Retention Time: 13.0 min*.
EXAMPLE 151
5-Acetyf-2-ethyl-4-[(8-hydroxy-1,7-naphthyridin-5-yi)amino]-6-phenylpyridazin-3(2H)-one
Obtained (43%) from 5-ac3tyl-2-ethyi-4-nitro-5-phenylpyridazin-3(2H)-cne (Dai Piaz, V et al, J. Med. Chem. 1997, 40, 1-17) and the title compound of Preparation 57 following the procedure of Example 67.
m.p. 269.5-271.3CC
5(DMSO-d6): 1.35 (m, 3H;, 1 A3 (s, 3H), 4.19 (q, 2H), 7.44 (m.5H), 8.59 (s, 1H), 8.75 (d, 1H)T 9.23 (sf 1H), 11.66 (s, 1H)
EXAMPLE 152 5-Acetyi-2-ethyl-6-phenyl-4-(thien-2-ylamino)pyridazin-3(2H)-one
To a solution of thiophen-2-yicarbamic acid tert-butyl ester (157 mgT 0.73 mmcl) (Binder, D., Habison, G„ Nee, C.R., Synthesis, 1977, 4, 255-256) in ethyl ether (6.5 ml), 12N chlorhidric acid (2.3 mL) was added. The mixture was stirred for 30 min. and the solvent was removed to yield the deprotected thiophen-2-yl-ammonium chloride. Then a solution of 5-acet/i-2-eth7l-4-r,itrc-6.-phenylpyridazin-3(2H)-ones(150 mg, 0.52 mmol) (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (9 ml) and triethylamine ( 0.25 ml, 3.5 mmol) were added. The resulting mixture was stirred at
room temperature for 3h. The final product '.vas collected by filtration and washed with diethyiether :o yield the title compound as a yellow solid (33%).
m.p. ^32.6-133.5
5( C.".;SO-d6): 1.33 :n. 3H). 1.62 ,s. 3H), 4.16 (q, 2H). c.73 (m.lH . 5.32 (m. 1H'. ~.27 (m. 3H). 7.-0 [r. 2H), 3,32 (s, 1H)
EXAMPLE 153
5-Acetyl-2-ethyl-5-phenyi-4-[(2-phenyipyridin-3-yl)amino]pyridazin-3(2H:-one
Obtained (-6:-. from 3-ace?yi-2-e'hyl-4-nitrc-6-phenylpyridazin-3;2H)-cne Za-. Piaz, V et al, J. Med. Chem. 1297, 40. 1417) and 2-pnenylpyridin-3-ylamine (Miller. -.A. Farell. R.P., Tetrahedron Lett., 1S23. 39(36), 6441-6444) following the procedure :f Example 67.
m.p. 131.3-132.4°C
o( CMSO-d6): 1.25 (m, 3H), 1.54 (s, 3H), 4.03 (q, 2H), 7.21 (m. 2h; 7.37 im, 7H), 7.67 (m. 2H), 3.43 (m, 1H), 3.95 (s, 1H)
EXAMPLE 154
Ethyl {5-((5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]
pyridin-2-yl}acetate
Obtained (3C0/;i from 5-ac9tyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dai Piaz, V et ai, J. Med. Chem. 1S97, 40. 1417) and 5-aminopyridine-2-carboxylic acid ethyl ester (Cooper, G. H.: Rickard, R. L, J. Chem. Soc, 1971, 19, 3257-3260.) fciicwing the procedure of Example 57.
LRMS: m/Z421 (M+1)" Retention Time: 14.0 min".
EXAMPLE 155
5-Acetyl-2-ethyl-4-[(6-methyfpyridin-3-yl)amino3-6-phenylpyridazin-3(2H)-one
To a stirred solution of the title compound of Example 154 (77 mg, 0.13 mrrtol) in 2 ml of ethanol, 1M NaOH sciuticn (0.5 ml) was added and the mixture was stirred at n for 1 hour and at 6C°C for 1 h. Then it was lei to cool down, acidified to pH 5 and refiuxed for 3 days, it was the basifed to c'ri 5 and extracted with dichioromethane. The organic layer was finally washed with wa:er arc brine, dried and solvent was removed to yield the title produc: (20%).
LRMS: m/Z349:M-i)7
Retention Time: 12 min'1.
EXAMPLE 156-162
156. 5-Acetyl-2-ethyI-4-{(6-hydroxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-
one
157. 5-Acetyl-2-ethyl-4-{(2-fIuoropyridin-3-yi)amino]-6-phenyipyrida2in-3(2H)-one
153. 5-Acetyl-4-[(6-ch!oro-4-methylpyridin-3-yl)amino]-2-ethyl-6-phenylpyridazin-
3(2H)-one
159. 5-Acetyl-2-ethyl-4-[(3-hydroxypyridin-2-yi)amino]-6-phenylpyridazin-3(2H)-one_rT ,
160. 5-Acetyl-2-ethyI-4-[(4-methoxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one
161. 5-Acetyl-2-ethyl-4-(isoquinoiin-3-yIamino)-6-phenyipyridazin-3(2H)-one
162. 5-Acety!-2-ethyl-6-phenyl-4-(quinoIin-7-ylamino)pyridazin-3(2H)-one
The title compounds were synthesized from 5-acetyl-2-ethyl-4-nitro-6-phenyipyridaz:n-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and the corresponding amines following the prcedure cf example 67. The ESI/MS data and HPLC retention :imes are summarized in Table 25.
Table 25
ESI/MS m/e EXAMPLE ;
| (M+H)+" Retention Time (min)
153 , ;. 351 6.9
■
157 ; 353 8.3
153 383 9.0
159 351 8.5
EXAMPLE 153
5-Acstyl-4-[;5-chlcrcpyr:din-2-y1)arinci-2-e^^
Ootamed as 5 solid '.54%) from the ::t!e compound of Preparation 36 an: 5-cnlcr: pyridin-3-ylamine 'Heincl. J.; Kessier, H.J. DE 2507012) following the procedure ;f Example 67.
m.p. :46.3-147.3°C.
o(DMSO-dV)f L33 ft. 2H), 1.90 (s, 3H), 4.17 (q, 2H), 7.13 -'m, 2H^, 7.23 :rr-, V-7.46 (m,"1H;.7"56:(rn. 1H), 3.27 (m, 2H), 9.25 (m, 1H).
EXAMPLE 164
5-Acetyl-2-ethyl-6-(4-fIuorophenyl)-4-[(2-methoxypyridin-3-yl)amino]pyrida2in-3(2H)-one
Obtained as a solid (90%) from the title compound of Preparation 30 and 2-methoxypyridin-3-ylamine (Hwu, JLR; Wong, F. F.; Shiao. M. J., J. Org. Chem., 19S2, 57, 5254-5 following the procedure of Example 67.
m.p. 158.3-169.7°C.
5(CDC!3): 1.44 (t, 3H), 1.71 (s, 3H), 3.97 (s, 3H), 4.29 (q, 2H), 6.37 (m, 1H) 7.10 (m, 2H), 7.27 (m, 1H), 7.39 (m, 2H), 3.00 (m, 1H), 8.22 (s, 1H).
EXAMPLES 165-168
165. 5-Acetyl-2-ethyl-6-(4-fIuorophenyi)-4-{(2-methylpyridin-3-yl)amino]pyridazin-
3(2H)-one
166. 5-Acetyl-4-[(2-chloropyridin-3-yi}amino]-2-ethyl-6-(4-fluorophenyI)pyrida2Sn-3(2H)-one
167. 5-Acetyl-2-ethy!-6-{4-fluorophenyl)-4-f{4-methylpyridin-3-yl)amino]pyrida2in-3(2H)-one
153. 5-Acetyl-2-ethyl-6-{4-fluorophenyl)-4-[(2-fIuoropyridin-3-yl)amino]pyrida2in-
3(2H)-one
The title compoundswere'synthesizec from the title compound of Preparation 30 and the corresponding pyridinylami.nes fc:!owing the procedure of Example 53. The ESI/MS data and HPLC retention times are summarized in Table 26.
EXAMPLE 169 .
5-Acetyl-4-[(2-chioropyridin-3-yi)aminc]-2-(cyclopropylmethyl)-6-(4-fIuorophenyl)pyridazin-3(2H}-one
Obtained as a solid (20%) from the title compound of Preparation 65 and 2-
chloropyridin-3-amine following the procedure of Example 67. - -
LRMS: m/Z413(M-Mr.
Retention Time: 16 min
o(CCCl.}: 0.47 .m, 2H). C.57 (m, 2H). 1.-12 (m, 1H). 1.S4 fs, 2H\ -.:•£ (d. 2H),
7.09 (m. 2H\ 7.22 (m. *H),7.4' (m. 3H). 2.21 ■.-.. 1H), 3.63(3. Yri).
EXA.VPLE -'70
5-Acetyi-2-(cyc!opropylmethyl)-o-{4-fluorophenyI)-4-[(2-methoxypyrid!n-3-yl)amino]pyridazin-3(2H)-one
Obtained as a sciid (66%) frorr. :he :::;e compound of Preparation -55 and I-methoxypyricip-Z-ylamire (Hwu. J.R; Wong. F. P.; Shiao, M. J.( J. On. Che-.. 1992. 57, 5254-5) "olicvving the procedure of Example 57.
m.p.
o(CDCh,: 0.46
4.10 (d, 2H>. 5.35 (m, 1H), 7.09 fm, 2H)V"7.27 (m. 1H), 7.33 (m, 2H), ".99 m. 'H). 2.22
(sf 1H).
EXAMPLE 171
5-Acetyl-2-(cycIopropylmethyl)-6-(4-fluorophenyl)-4-[(2-methylpyridin-3-
yl)amino]pyridazin-3(2H)-one -" " "
Obtained as a soiid (23%) from the title compound of Preparation 55 and 2-methylpyridin-3- yiamine (Nantka-Namirski, P.; Kaczmarczyk, C; Toba. L, Ac:a Poloniae Pharmacautica 1967, 2^, 231-7) following the procedure of Examole 37.
LRMS: n/Z393(M+1)*.
Retention Time: 14 mino(CCCI:;: 0.50 (m, 2H), 0.53 (m, 2H), 1.43 (mf 1H), 1.65 (s, 3H), 2.57 (s, 3H), 4.10 (d, 2H). 7.09 (m, 3H), 7.35 (m, 3H), 3.12 (s, 1H), 8.33 (m, 1H).
EXAMPLES 172-174
172. 5-Acetyl-2-(cyciopropylmethyl)-6-(4-fIuorophenyl)-4-[(2-fluoropyridin-3-yl)amino]pyridazin-3(2H)-one
173. 5-Acetyl-2-{cyclopropylmethyl)-8-{4-fIuorophenyl)-4-[(4-methyipyridin-3-yl)amino]pyridazin-3(2H)-one
174. 5-Acetyl-2-(cycIopropylmethyl}-6-{4-fluorophenyl)-4-[(pyridin-3-yl) amino]pyridazin-3(2H)-one
The "Jtle compounds were synthesized from the title compound of Preparation 55 and the corresponding pyridnylamines following the procedure_of,Example 93. The ESI/MS data and HPLC retention :imes are summarized in Table 27. - .-
EXAMPLES 175-177
175. 5-Acetyl-6-{3-chIorophenyl)-2-ethyi-4-[(2-methylpyridin-3-yl)amino]pyridazin-3(2H)-one
176. 5-Acetyl-6-(3-chlorophenyl)-4-[(2-chloropyridin-3-yl)amino]-2-ethylpyridazin-3(2H)-one
177. 5-Acetyl-6-(3-chlorophenyi)-2-ethyl-4-[(4-methylpyridin-3-yl)amino]pyridazin-
3(2H)-one
The title compounds were synthesized from 5-acetyl-2-ethyl-4-nitro-6-(3-'chlorophenyl)pyridazin-3(2H)-ons(Dal Piaz, V et a/, J. Med. Chem. 1997, 40, 1417)
and the corresponding ?yridiny!amines following the procedure c: Exarrcie 92.The ESI/MS date and HPLC retention times are summarized in Table 23.
EXAMPLE 173
Methyl 5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2J3-dihydropyndazin-4-yl)amino] quinoline-3-carboxylate
A mixture cf -150 -Tig, 0.556 mmol) of 5-ac3tyl-2-ethyl-4-nitro-o-phenylp>ridazin-3(2H}-one (Dal Piaz. V era/, J. Med. Cham. 1997, 40, 1417), 5-amincqunoiir.e-3-carboxiiic acid methy! ester (226 mg, 1.114 rr:mol) (Preparation 99)and ethanol (3 mL) was introduced in the microwave oven. The mixture was stirred at 120 °C during 45 minutes. The solvent was evaporated and the residue purified by column, chromatography (silica gel, dichlorcmethane/methanol 100:1) and preparative HPLC/MS to yield the title compound (7 mg, 3 % yield).
LRMS: rr,/Z443(M+1)+.
Retention time: 13min*.
EXAMPLE 179 5-Acety!-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one
A mixture of the title compound of Preparation 49 (2.0 g, 7.77 mrr.oi), 3-bromo-4-methylpyridine (1.3 ml, 15.5 mmci;, anhydrous cuprous iodide (100 mg, 0.52 mmoi) and potassium carbonate (1.60 gf 11.6 mmol) stirred at 145°C for 12 h. It was let lo
cool down and was partitioned bet.veen ethyl acetate and water. The organic layer was wshed with water and brine, dred and solvent.was removed in vacuo. Tne solid thus obtained was thoroughly washed with warm ethyl ether and recrystailized from methanol to yield the final product as a cream solid (0.97 g, 3-°o yield).
m.p. 215.9-216.3°C.
-3(DMSO
EXAMPLE 130
5-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-5-(4-methoxyphenyl)pyridazin-3(2H)-one -
Obtained as a solid (13%) from the tirle compound of preparation 71 and 4-_" bromoisoquinoline following the procedure of Example 101.
m.p. 210.3-212.7 °C:
o(DMSO-d6): 1.23 (s,3H), 1.37 (t, 3H), 3.7 (s, 3H), 4.2 (q, 2H). 5,9
EXAMPLE 181
5-Acetyl-2-ethyl-6-(4-methoxyphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one
Obtained as a solid (33%) from the title compound of Preparation 71 and 3-bromopyridine following the procedure of Example 101.
m.p. 175.0-175.7 °C.
5(DMSO-d9): 1.3 (t, 3H), 1.7 (s. 3H), 3.3 (s,"3H), 4.16 (q, 2H), 6.97 (d, 2H)T 7.23 (d, 2H), 7.27 (m, 1H), 7.43 (d, 1H), 3.27 (bs, 1H), 8.32 (s, 1H), 9.04 (s, 1H, NH).
CV A MCf IT 10O
5-Acetyl-2-ethyl-5-(4-methoxyphenyl)-4-{quinolin-5-ylamino)pyridazin-o-.2H)-on9
Obtained as a sciic (15°o) from the title ccmpcurc: of Preparation 71 ana 3-cuinolylborcr.ic acid following :he crcceci.~e cf Example 1.
m.p. _oo._-2o^.^ C.
o(DMSO~:5): 1.33 (s. 3H). -.37 it. In . 3.7- (s. 3H), 4.21 ..q, 2H\ c.;- d, 2H\ 7.16 (d, 2H). 7.35 (d. IrT. 7.35 (m .1H). ~5C m. >H), 7.36 (d, Irii, 3.4' d. '-', 3.52 fmf 1H), 9.12 (s. 1H, /VhEXAMPLE 133
5-AcetyI-2-ethyi-6-(4-methoxy-phenyi)-4-(1-oxy-quinoiin-5-yiamino)- -pyridazin-3(2H)-one
A solution ci m-chloroperbenzoic acid (36.4 mg, 0.16 mmol) in dry dichicfcn-.ethane (1 mL) was adced to a solution of the title compound of Example 132 (70 mg, 0/5 mmol), . in 2 mL of dichloromethane and the mixture was stirred at RT under argon overnight. The solvent was removed under reduced pressure and the residue was purified by column chromatography (C-13 reverse phase Biotage'5 cartridge (water (0.1M ammonium acetate)/acetonitriIe 99:1 to 1:99) to yield the title complour.d as a solid (43 mg, 62% yield).
m.p. 259.7-261.3 °C.
5(DMSO-dO: 1 -37 (t, 3H), 1.43 (s, 3H), 3.75 (s. 3H)7 4.20 (q, 2H), 6.94 /
EXAMPLE 184
5-Acetyl-2-ethyl-4-{isoquinolin-4-yIamino)-6-(3-methoxyphenyl)pyrfdazin-3(2H)-
one
Obtained as a sc!id (24%) from the title compound of Preparation 75 and 4-bromoisoquinoline following the procedure of Example 101.
m.p. 190.0-190.5 °C.
o(DMSO-d6): 1.28 (s, 3H). 1.33 (t, 3H), 3.70 (s, 3H), 4.22 (q, 2Hi. 5.77 (s, 1H), 6.79 ,d, 1H), 6.95 (d, 1H), 7.23 "t. 1H), 7.71 (t. 1H). 7.32 (t, lH'.7.97(d. 1H), 8.15 ■■:. 1H). 3.30 (s, 1H), 9.17 (s, 1H, NH), 9.13 (s, 1H).
EXAMPLE 135
5-Acatyl-2-ethyl-6-(3-methoxyphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one
Obtained as a solid (33%) from -.he titie compound of Preparation 75 and 3-bromopyridine following the procedure of Example 101. -
m.p. 152.7-153.8 °C.
3(DMSO-d6): 1.33 (t, 3H,, 1.73 ,;s. 3H), 3.75 (s, 3H), 4."i5 (q, 2H;. 3.35 (m, 2H), 6.93 (d, 1H), 7.2*7-731 (m. 2H), 7.42 (d. 1H), 8.27 (m, 1H), 8.32 (s, 1H). 9.03 (s, 1H. NH).
EXAMPLE 136
5-Acetyl-2-ethyl-6-(3-methoxyphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one
Obtained as a solid (28%) from tie title compound of Preparation 75 and 5-quinolylboronic acid following the procedure of Example 1.
m.p. 194.3-195.8 QC.
5(DMSO-d6): 1.32 (s, 3H), 1.37 (t, 3H), 3.70 (s, 3H), 4.21 (q, 2H), 6.77 (s, 1H), 6.78 (d, 1H), 6.95 (d, 1H), 7.30 (t, 1H), 7.34 (d, 1H), 7.54-7.63 (m ,2H), 7.86 (d, 1H), 8.42 (d, 1H), 8.92 (m, 1H), 9.13 (s, 1H, NH).
EXAMPLE 187
5-AcetyI-2-ethyl-6-(3-methoxyphenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one
Obtained as a yellow solid (53%; from the title compound of Example 136 following the procedure of Example 133. m.p. 215.5-216.1 °C.
o(DMSO-d6): 1.37 (t. 3H\ 1.43 (3. 3H\ 3.71 (s. 3H), 4.21 (q, 2r'. S.-2C (s, 1H) 6.31 (C. 1H), 5.55 (d, 1!-I). 7.30 (i. 1H), 7.43 m. 2H). 7.56 (1. 1H>. 7.95 2. 1H\ 3.37 : 1H), 3.51 (d. 1H). 9.24(3. 1H. /Vh",
5-Acetyl-2-e:hyl-4-(isoquino!in-4-ylarnino)-o-{4-rnethylphenyl)pyrica2in-3(2H)-on
Obtained as 5 s~iid (13%) :'r:n r.e :;r:e impound of Preparation 79 a~o 4-•bromoiscquinolire foiicwing the procedure of Example 101. m.p. 201.7-202.1 °C.
o(DMSO-d6): 1.27 (s. 2H). 1.37 ft. 2Hi. 2.29 (s, 3H), A21 ;q. 2H ■. 7.12 'd. 2H). 7.17 (d. 2H). 7.72 (t, 1H). 7.32 (t, 1H), 7.97 -t. 1H). 3.15 (d, 1H„ 3.30 =. 1H). 9.15 (s. 1H, AiH), 9.1^ (s. 1H).
EXAMPLE 139
5-Acetyl-2-ethyl-6-(4-methylphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one
Obtained as a solid (13%) from the ::tle compound of Preparation 79 aod 3-bromopyridine following the procedure of Example 101.
m.p. 137.3-139.1 °C.
5(DMSO-d6): 1.33 (t, 3H), 1.72 (s, 3H), 2.32 (s, 3H), 4.17 (q, 2H}. 7.20 (q, 4H), 7.27 (m, 1H), 7.-13 (d, 1H), 3.25 (d. 1H), 3.32 (s, 1H), 9.05 (s, 1H, NH).
EXAMPLE 190 5-Acetyl-2-ethyl-6-{4-methylphenyl)-4-(qutnolin-5-ylamino)pyridazin-3(2H)-one
Obtained as a sciid (40%) from the title compound of Preparation 79 and 5-quinolylboronic acid following the procedure of Exam-pie 1.
LRMS (rr:/z): 399 (M+1)".
Retention Time: 15 min
EXAMPLE 19 1
3-Acetyl-2-ethyl-6-(4-methyfphenyi;-4-[(1-oxidoquinoiin-5-yl)amino]pyridazin-J(2H)-one
Obtained as 2 solid (43°v r'rom the -j;!e compound of Exampie 190 following the :rcc3dure of Example 152.
m.p. 231.7-232.5 :C.
o(MeOH-d,): 1.4-1 :, 3H), 1.4" ..s. 3H), 2.35 (s, 3H), 4.29 (q, 2H), 7.20 (s. 4H,, \52
EXAMPLE 192
>-Acetyl-2-ethyI-6-(4-methyiphenyl)-4-[(4-methy!pyridin-3-yl)arnino]pyridazin-5(2H)-one
Dbtained as a solid (9%) from the title compound of Preparation 79 and 4-methyl-3-)romopyridine following the procedure of Example 101. m.p. 196.1-197.3 3C.
■5(DMSO-d6): 1.34 (5, 3H), 1.43 (s, 3H), 2.22 (s, 3H), 2.31 (s, 3H), 4.17 (q, 2H), M5 (d( 2H), 7.19 (d, 2H), 7.24 (d, 1H), 8.21 (s, 1H), 8.26 (d, 1H), 8.72 (s, 1H, NH).
EXAMPLE 193
i-Acetyl-2-ethyl-4-{isoquinoiin-4-ylamino)-6-{3-methylphenyl)pyridazin-3(2H)-o
Obtained as a solid (27%) from the title compound of Preparation 83 and 4-iromoisoquinciine following the procedure of Example 101. Retention Time: 15 min".
5(DMSC-d5): 1.25 (s. 3H), 1.37 (t, 3H>, 2.27 (s, 3K,, 4.22 (q, 2H\ 6.39 ;'d. 1H), 7.07 (s. 1H), 7.13-7.26 (m. 2HV 7.72(1 \~\ 7,32 (t, 1H), 7.97 (d, 1H), 3.15 -c. IK), 3.29 (s, 1H). 3.'-(s. 2H;.
£XAr.; = L= 194
5-Acety!-2-ethyl-o-{3-methylphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one
Obtained as a sc.rd (21°3) from the title ccnoound of Preparation 33 and 2-bromopyridire r'c'lowing the procedure of E/.ample 101.
m.p. "3-.9-136.I 3C.
o(DMSC-:,v 1.32 (t. 2H), 1.72 (s. 3H'), 2.32 (s, 3H), 4.17 (q, 2H). 7.05 d. 1H). 7.15 (s, 1H), 7.22-7.31 (m. 3h), 7.-3 Cdd, *K), 3.25 (dd, 1H), 3.32 (s. 1H). 9.13 's, 1H, NH).
EXAMPLE 195
- ■ r— — ii- " —' ■
5-A"cetyr-2-ethyl-5-(3-methylphe^
Obtained-as-a solid (25%) from the title comoound of Preparation 33 and 5-quinolylboronic acid following the procedure of Example 1.
LRMS (m/z):399(M+1)*.
Retention Time:-14 minm.p. 245.0-246.1 °C.
EXAMPLE 196
5-acetyl-2-ethyl-c-(3-methylph
Obtained as a solid (24%) from the title compound of Preparation 83 and 4-meihyl-3-
bromopyridine following the procedure of Example 1.
m.p. 171.1-172.0 °C. - -
5(DMSO-d6): 1.34 •:, 3H), 1.43 (s. 3H), 2.22 (s, 3H), 2.30 (s, 3H\ 4.13 (q, 2H), 7.02 (d, 1H), 7.10 («,, 1H). 7.20-7.23 (m. 3H). 3.21 (s, 1H), 3.25 (d, 1H). 3.75 (s, 1H, NH).
EXAMPLE 197
Methyl 4-[4-ac9ty!-1-ethyi-5-{isoquinoiin-4-y!amino)-6-oxo-1,5-dihydropyridazin-3 yljbenzoate
Obtained as a solid (13% from ire title compound of Preparation 33 arc 4-bromciscquircline following'the crccecLre of Example 101.
m.p. 1-S2.9-183.-6 ;G.~:7 ■■ -
8(DMSO-d,):-i.23(s73H\ 1.36 (t, 3H), 3.32 (s, 3H), 4.20 (q, 2h". 7.37 (d, 2H), 7.72 it, 1H), 7.30 (t, 1H), 7.91 (d. 2H), 7.97 (d. 1H), 3.12 (d, 1H>. 3.27 (5. 1H), 9.14 [s, 1H), 9.22 (s, :H,NH)-:-'
EXAMPLE 193
Methyl 4-[4-acetyl-1 -ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoate
Obtained as a solid (15%) from the title compound of Preparation 88 and 3-bromopyridine following the procedure of Example 101.
5(DMSO-d6): 1.3 (t, 3H), 1.7 (s, 3H), 3.82 (s, 3H), 4.20 (q, 2H), 7.27 (m, 1H), 7.44 (d, 3H), 7.97 (d, 2H), 3.27 (d, 1H), 8.32 (s, 1H), 9.18 (s, 1H, NH).
LRMS(m/z):393(M+1)*.
Retention Time: 13 min*.
EXAMPLE 1?9
4-{4-AcetyM-ethyl-6oxo-5-(pyridin-3-ylamino)-l,6-dihydropyndazin-3-yl]benzoic acid
Obtained as a sciid i-c%) from the ritie jcrrccur.:: of Example 1^3 "c-cwlrc tr.e procedure c: Example 41.
6.'Di\iSC-d5): 1.34 (t. 2H'.. 1.77 fs,2H .-.IS (q.2H), 7.27 m. '-■.7.44 z.3r.\ 7.95 (d, 2H). 3.27 f'd. 1H), 5.22 3. 1H . 3.1-5' s. '.'r.. NH), 13.09 3. 1r. :COr■ -EXAMPLE 200
Methyl 4-{4-acetyl-1 -ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-1.5-dihydropyridazin-3-yl}benzoate
Obtained as a sciid (32%) from the title compound of Preparation S3 a~d 4-methyl-3-bromopyridine following the procedure of-Exampie 101.
m.p. 195.5-197.0 °C.
o(DMSO-dg): 1.35 (t. 3H\ 1.43 (s, 3H). 2.22 (s, 3H), 3.86 (s, 2H •. 4.19 (c. 2H), 7.24 (d, 1H), 7.43 (d, 2H), 7.96 'd, 2H), 3.22 (s. 1H), 3.25 (d, 1H), 3,20 '3, 1H. NH).
EXAMPLE 201
4-{4-Acetyl-1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-1,6-dihydropyrida2in-3-yl}benzoic acid
Obtained as a solid (13%) from the title compound of Example 200 fc.lowing the procedure of Example 41.
m.p. 242.7-243.3 °C.
5(DMSO-d6): 1.35 (t, 3H), 1.43 (s, 3H), 2.22 (s, 3H), 4.19 (q, 2H:, 7.24 [d, 1H), 7.40 (d, 2H). 7.98 (d, 2H), 8.22 (s. 1H), 3.25 (d. 1H), 3.80 (s, 1K NH
EXAMPLE 202
Methyl 3-[4-acetyl-1-ethyl-6-oxo-5-(pyridin-3-yiamino)-1,5-dihydropyridazin-3-yljbenzoate
Obtained as a solid (20%
m.p. 143.3-150.2 SC.
5(MeCH-d.): 1.33 :t. 3H). '.53 (s. 3ri;. 3.32 (s, 3H), 4.19 (q, 2H), 7.27 (m, 1H), 7.44-7.52 (m. 3H), 7.93 (s. 1H), 7.97 (6. 1h". 3.20 (eld; 1..H.)/3.25 (s, 1H).
EXAMPLE 203.■■■T'-f'. .
3-[4-Acetyl-1-ethyl-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-yl]benzoic acid
Obtained as a solid (42%) from the title compound of Example 202 following the procedure of Example 41.
m.p. 259.1-270.3 3C.
5(DMSO-d6): 1.34
EXAMPLE 204
5-Acetyl-4-[(3-chloro-4-f!uorophenyl)amino]-2-ethy!-6-pyridin-4-ylpyridazin-3(2H)-one
Obtained as a solid (12%) from the title compound.of Preparation 16 and 3-chloro-4-fiuoro-boronic acid following the procedure of Example 1.
m.p. 168.6-169.6 aC.
5(DMSO-d6): 1.33 (t, 3H), 735 (s, 3H), 4.18 (q, 2H), 7.0S (m. 1H), 7.29-7.35 (m, 4H), 8.60 (d,2H), 9.19(3, IH./Vrr).
EXAMPLE 205
5-Acetyl-4-[bis(3-chioro-4-fluorophenyl)arT!ino]-2-ethyl-6-pyridin-4-ylpyrldazin-3(2H)-one
Obtained as 2 sciid (4%; "rem the title compound of Preparation "5 arc an e.;ces cf 2-chloro-4-flucro-borcnic acid relieving the procedure of Example *.
m.p. '55.7-156.2 "JC.
3(DUSO-d5): 1.25 *'t. 3H'. 2.13 3. 3H>. 4.15 (q/2H),7.06 rr,. 2H:. 7.3'-7.41 'm. 5H), 3.65 ids, 2H).
EXAMPLE 206
5-Acety!-4-[(3-chloro-4-fluoropnenyl)amino]-2-ethyl-6-pyridin-3-y[pyridazin-3(2H)-one
Obtained as a solid (10%) from the title compound of Preparation 14 a,nd-3-cnicro-4-
fluoro-boror.ic acid following the procedure of Example 1.
m.p. 159.3-160.3 °C. , -•■• •. . ■
5(DMSO-d5): 1.24 (t.3H), 1.32 (s, 3H), 4.18 (q, 2H), 7:08 im-, 1 f-i). 7.29-7.35 :m.
3H), 7.43 (is, 1H), 7.73 (d, 1H). 3.51 (bs, 1H), 9.13 (s, 1H, NH).
EXAMPLE 207
5-Acetyf-4-[bis(3-chloro-4-fluorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyrida2in-3(2H)-one
Obtained as a solid (11%) from the title compound of Preparation 14 and 3-chloro-4-fluoro-boronic acid following the procedure of Example 1.
o(DMSO-d6): 1.33 (t, 3H), 2.14 (s, 3H), 4.16 (q, 2H), 7.06 (m, 2HI 7.32-7.33 (m, 4H), 7.43 (bs. 1H), 7.30 (d, 1H), 3.-31-(bs, 2H).
LRMSfm/z):515(M+1)",
Retention Time: 13 min'.
EXAMPLE 208 Methyl [4-acetyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)pyridazin-1(6H)-yl]acetate
Obtained as a solid (44°^ from the title compound of Preparation 95 and quinoiire-5-boronic acid "blowing the procedure of Example 1.
m.p. J93.S-194.3°C.
5(CCC.:): 1.40 (s, 3H)T 3.30 -is. 3H), 4.S8 (s, 2H). 7.32 (m, 6H), 7.43 (m, 1H), 7.62 (m. 1H;. 5.06 (m. 1H), 3.41 (rn,2H'-. 3.93 (m, 1H).
EXAMPLE 209
[4-Acetyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)pyridazin-1(6H)-yl]acetic*acid ■
Obtained from the titie compound of Example 208 following the procedure of Example 41.
LRMS: m/Z415(M-ir.
Retention Time: 7.7 min
EXAMPLE 210 5-Acetyl-2-ethyl-4-[(3-methylpyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one
To a stirred solution cf 30 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridaz:n-3(2H)-one (Dal Piaz, V et a/, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 2-amino-3-methylpyricine (45 mg, 0.417 mmol) was added portionwise. The resulting mixture was stirred at room temperature for five days. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to yield the title compound (26 mg, 27% yield).
5(DMSO-d5): 1.35 (t, 3H), 1.30 (s, 3H), 2.32 (s, 3H), 4.22 (q, 2H), 6.95 (m, 1H), 7.35(m,2H), 7.47 (m,3H), 7.60 (df 1K),7.95(d, 1H), 8.50 (s, 1fl)/
EXAMPLE 211 5-Acetyl-2-sthyl-6-phenyl-4-{1H-pyra2ol-3-ylamino)pyridazin-3(2H'j-one
To a stirred solution of 30 mg 3.273 mmoi) of 5-3cet.---2-ethyi-4-ritro-5-phenylpyricarin-Sil.WVcne ;Dai ?:az. V e: ai. J. Med. Che:*:. 199T -C. 1417} in ethanci (4 mL) Lr.cer nitrogen a:mosphe~e. S-arrinopyrazoi (35 mg. 1.-17 mrncO was added. The resulting mixture was siirrec at room temperature curing 30 minutes anc the finai orccuct was collected ov nitration and washed with die:hvlethe~ to v:eid the title compound '30 mg. 55.7 % yield'.
3(Di\:SO-d3): 1-2S (t. 3H';T 1.55 (s. 3H), 475 (q, 2H\ 5.73 (s. *H}? 7.14 (s. 1H7 7.33-7.52 (m. 5H). 10.30 (s. 1H).
EXAMPLE 212
5-Acetyl-2-ethyl-6-phenyl-4-(9H-purin-6-yIamino)pyridazin-3(2H)-one
To a stirred solution of 250 mg (0.370 mmci) of 5-acetyl-2-ethyl-4-nitrc-o-phenylpyridazin-3(2H)-one (Dal Piaz, V er a/, J. Med. Chem. 19S7, 4G. T417) in ethanol (12 mL). adenine (235 mg. 1.740 mmoi) was added. The resuhmg mixture was stirred and refluxed during two days. The solvent was evaporated and :ne residue purified by column chromatography (silica gel, dichloromethane/metharol 95:5) and preparative HPLC/MS to yield the title compound (4.4 mg, 1.4"% yield).
LRMS: m/Z376(M+1)~.
Retention time: 7.5 min.
EXAMPLE 213 5-Acetyl-2-ethyl-4-[(3-methylisoxazol-5-yf)amino]-6-phenylpyridazin-3(2H)-one
To a stirred solution of 200 mg (0.596 mmoi) of 5-acetyl-2-ethyl-4-nitrc-5-phenylpyridazin-3(2H)-one (Dal Piaz, V eta/, J. Med. Chem. 1997, 40, 1417) in ethanol (10 mL), 5-amino-3-methyiisoxazc;e (204 mg, 2.083 mmoi) was added. The resulting mixture was stirred at 50 -C for four days. The solvent was evaporated and
the residue purified by column riv~Myography (silica gel, hexane/ethyl acetate 2:1) to yield :he title compound (35 mg, 1-.90-: yield).
m.p. 177.6-178.7 °C
o(DMSO-d6): i;33=t.3H). \Z2 s, 3HV 2.13'(s, 3H)T 4.1 9 (q, 2H). 5.71 (3l 1H)f 7.34 ■ m. 2H), ".47 (m, 3H;, 1.0.02 s. J - .
EXAMPLE 214
5-Ac8tyl-2-ethyl-4-[(8-hydroxyqL:inolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one
To a stirred solution of 30 ~g (0.273 rr.fnci) of 5-acetyl-2-ethyl-4-nitro-5-phenylpyridaz:n-3(2H)-one 'Dal F:sz. V at ai J- Med. Chem, 1997, 40, 1417) in ethanol (4 mL), 5-amino-3-quinci;rcl ,57 mc, 0.417 mmol) was added. The resuitir.c mixture was stirred at rocm temperaiure during 40 hours and the final crcduct was collected by filtration and washec .vi:h diethylether to yield the title compound (100 \ng, 90 % yield).
m.p. 261.9-262.6 °C.
5(DMSO-d6): 1.25 (s, 3H). 1.27 (t, 3H), 4.20 (q, 2H), 6.90 (d, 1H\ 7.22-7.26 (m, 6H), 7.50 (m, 1H), 3.30 (d. 1H). 3.EG (rn, 2H), 9.97 (s, 1H).
EXAMPLE 215 5-Acetyl-2-ethyl-4-(1H-indazol-7-yIamino)-6-phenylpyridazin-3(2H)-one
To a stirred solution of 80 mg (0.273 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenyipyridazin-3(2H)-one (Dal Fiaz, V era/, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 1H-indazcl-7-amine (56 mg, 0.417 mmol) was added. The resulting mixture was stirred at room temperature during one hour and the final product was collected by filtration and washed with diethylether to yield the title compound (SO mg, ' 86.5 % yield).
m.p. 252.6-263.8 °C.
5(DMSO-d6): 1.12 ^3. 3H). 1.37 (t, 3H), 4.20 (q, 2H), 7.03 (m, 2H), 7.25 (m, 2H), 7.33 (m, 3H), 7.57 (m, 1H), 3.06 .'s, 1H), 9.C4(s, 1H), 13.08(s, 1H).
EXAMPLE 216, 5-Ac9tyl-4-[(5-bromcquinoIin-3-vl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one
To a stirred solution cf SO mg 0.279 mmci) of 5-3C9tyl-2-ethyl-4-nitrc-o-
phenylpyridaz:n-3(2r/;--cne (Dai ?:az. 7 era/. J. Med. Chem. 1997. 4C. 4-i1' 'n ethancl (4 ~L\ S-amino-o-brcnccunciine (S3 mg, 0.417 mmcl) was accec. rhe resulting mixture was stirred ar rccm temperature or one day. The so/, en: v.s = evaporates end the resicue purifec cy :c;umn chromatography (silica zei. hexane/ethy acetate 3:1) to yield r.e :;■:= compound (110 mg, 35.3% .:eicm.p. 146.3-147.5 °C
3(Dt\;3C-dG): 1.35 , 3.93 (m, 1H), 9.36 (s. 1H-.
EXAMPLE 217
5-Acetyl-2-ethyl-4-[(5-methyiisoxazol-3-yl)amino]-6-phenylpyridazin-3(2H)-one
To a stirred solution of 30 mg (0.273 mmoi) of 5-acetyl-2-ethyl-4-nitro-c-phenylpyridaz:n-3(2H)-one (Dai Plaz. V era/, J. Med. Chem. 1997, 4C\ *417; in ethanol (4 mL), 3-amino-5-meihylisoxazol (96 mg, 0.973 mmoi) was acded. The resulting mixture was stirred at room temperature for four days and the final crccuct was collected by filtration and washed with diethylether to yield the title compound ;35 mg, 37.2% yield).
m.p. 170.1-170.8 °C.
5(DMSO-ds): 1.33 (t, 3H), 1.32 (s, 3H), 2.32 (s, 3H), 4.19 (q, 2H)f 3.12 (s, 1H)t 7.32 (m, 2H). 7.45 (m, 3H), 9.36 (s. 1H).
EXAMPLE 213
5-Acetyl-2-ethyl-4-(isoxazo(-3-ylamino)-6-phenylpyridazin-3(2H)-one. .
To a stirred solution of 80 mg (0.273 mmcl) of 5-acetyl-2-ethyl-4-nitro-5-phenylpyridazin-3(2H)-one (Dal P:az, V at a/, J. Med. Chem. 1997, 40, 1^17; In ethanol (4 mL), 3-aminoisoxazci (70 mg, 0.334 mmoi) was added. The resulting
mixture was stirred at room temperature for four days and the final product was collected by filtration and washed with diethyiether to yield the title compound (53 mg, 63.7 % yield).
m.p. 175.4-177.1 °C.
5(DMSO-d6): 1.34 (t. 3H». 1,3- 'a, 3H), 4.20 (q, 2H), 6.43 (s, 1H\ 7.32 (mt 2H), 7.46 fm, 3H). 3.57 (s. 1H), S.45 (s. 1HEXAMPLE 219
'5-Acetyl-2-{cyclopropylmethyl)-6-phenyl-4-{quinoIin-5-ylamino)pyrida2in-3(2H)-one
To a stirred solution of 100 mg (C.319 mmol) of Preparation 97 in ethanci (4 mL), 5-aminccuinoiine (69 mg, 0.479 mmol) was added. The resulting mixture was stirred at -room temperature during one day and the final product was collected by filtration arc washed with diethyiether to yield the title compound (53 mg, 40.4 % yield).
m.p. 203.9-205.1 °C.
o(DMSG-d6): 0.46 (m, 2H}. 0.55 (m, 2H), 1.33 (m, 4H)t 4.06 (q. 2H). 7.24 (m, 2H), 7.35 (m, 4H), 7.53 (m, 2H), 7.36 (d, 1H), 3.44 (d, 1H), 3.93 (m, 1H), 9.21 (s, 1H).
EXAMPLE 220
5-Acetyl-2-(cyclopropylmethyl)-6-phenyl-4-(quinoIin-8-y(amino)pyndazin-3(2H)-one
To a stirred solution of 100 mg (0.319 mmol) of the title compound of Preparation 97 in ethanol (4 mL), 8-aminoquinoline (59 mg, 0.479 mmol) was added. The resulting mixture was stirred at room temperature during 22 hours. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 3:1) to yield the title compound (110 mg, 84.6% yield). • - m.p. 123.1-124.7 °C.
5(DMSO-d6): 0.45 (m. 2H), 0.53 (m, 2H), 1.30 (m, 1H), 1.61 (s, 3H), 4.05 (a, 2H), 7.24 (d, 1H), 7.37-7.49 (m,5H), 7.31 (m, 1H), 7.71 (d, 1H)f8.40(d, 1H),8.S3(m, 1H), 9.35 (sf 1H).
EXAMPLE 221 5-Acetyl-2-ethyi-4-[(1-methyi-1H-pyrazoi-3-y!)amino]-6-phenyipyridazin-3(2H)-one
To a siirrec solution :f 30 mg (0.273 mmon ■:: 5-ac3iyi-2-ethyi---nitrc-3-phenylpyricazin-3(2r:>cne i.Cal P:azT V et a:. J. Med. Chem. 1597, 4>1. 1417'- in ethanol (4 mL';. S-arrinc-l-methyicyrazol (-2 mg. 0.417 mmoi; was added. The resulting m:\ture was stirred at rccm temperature during three hours and the nnai product was :ciiec:ed by filtration and washed with diethyiether :o yieid the title compound 55 mg. 59.5 % yield;. mfp 202.3-203.9 °C. ,3(D\iSC-d,): 1.32 (t. 3K-, 1.72 (s, 2H). 3.32 (s. 3H)?4.1o (q, 2H), 5.94 (rn. 1H). 7.29 (m,"2h ; 7.43 (m, 3H), 7.52 -s. 1H), 3.34 (3. 1H).
EXAMPLE 222
5-Acetyl-2-ethyl-4-[(1-oxidoquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one
A solution of the compound synthesized in Example 32 (210 mg, 0.546 mmcl) in 'dichiorcmethane (3 mL) was added dropwise to a cold solution of 3-chloroperoxybenzoic acid (11' mg, 0.545 mmol) in dichloromethane (7 mL). The mixture was stirred at room temperature for 27 hours and added to a solution of KHS04 in water (20 mL, 25%).The organic layer was washed with water, dried over sodium sulfate anhydride and evaporated.
The crude obtained was purified by-column chromatography (silica gel, dichloromethane/methanol 11 J:5) to yield 160 mg (0.399 mmol) cf the title compound (73%).
m.p. 254.0-264.3 °C.
0 (DMSO-d3): 1,37 (t, 3H), 1.41 (s, 3H), 4.?1 (q, 2H), 7.25 (bsT 2H), 7.39 (bsf 3H), 7.43 (m, 2H), 7.65 (m, 1H), 7.95 (d, 1H), 3.35 (d, 1H), 8.51 (m, 1H), 9.24 (s, 1H).
EXAMPLE 223
5-Acetyl-2-ethyl-4-[(2-oxidoi5oquinoiin-5-yl)amino]-6-phenylpyridazin-3(2H)-
one
Tee title impound was syniresized ~"rcm the title compound of Example 34 fcilowinc :re procec-fe of Example 222.The crude obtained was purified by preparative HPLC/MS to yieic re title compound (24 % yieid).
LRMS: m/Z40l -.M+ir.
Retention time.\-7.2 min.
EXAMPLE 22^ 5-Ac9tyl-6-(3-chlorophenyl)-2-ethyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one
To a stirred solution of 100 mg (CZI 1 mmol) of 5-acetyl-2-ethyi-4-nitro-o-(3-chlorophenyl'pyridazin-3'2H)-one Dai Piaz, V etal, J. Med. Cham. 1SS7, 40, 1417) in ethanol (5 mL), -5-aminccuinoiine 57 mg, 0.467 mmol) was-acded. Tha resulting mixture was stirred at room temperature during two hours and :he final product was collected by filtration-and washed .\::h diethylether to yield the title compound (67 mg, 51.5 % yield).
m.p. 136.2-186.9 :C.
5(DMSO-d6): 1.37 (m, 6H). -.22 (q, 2H), 7.17 (d, 1H), 7.33-7.45 (m, 4H), 7.60 (m, 2H), 7.37 (d, 1H), 8.4^ (d, 1H;, 3.93 (m, 1H), 9.28 (s, 1H)."
EXAMPLE 225 5-Acetyl-6-(3-chlorophenyl)-2-ethyi-4-(quinolin-8-ylamino)pyridazin-3(2H)-one
To a stirred solution of ICO mg (0.3: 1 mmcl) of 5-acstyl-2-ethyl-4-nitrc-S-(3-chlorophenyl)pyridazin-3.'2H)-or.e '3al Piaz, V etal, J. Med Chem. 1997, 40, 1417) in ethanol (4 mL), 8-aminocunoline ;5T mg-, 0.467 mmol) was added. The resulting mixture was stirred at room temperature for two hours. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyi acetate 2:1) to yield the title compound (55 mg, 50 % yield).
m.p. 127.0-127.7 °C
o(DMSC-d,): 1.26 (t, 3H). 1.55 fs. 3H-. 4.22 (q, 2H). 7.27 (m. 2H-. 7 -:-~.5' (m. 4H).7.52irn. 1H;. 7.72 (d, IHi, 3.42 (d. 1H). 3.S3 (m, 1H), 9.36 s. 1HEXAMPLE 225
5-Acetyl-2-ethyl-6-pyridin-4-yl-4-(quinolin-5-ylamino)pyn'dazin-3(2H)-one
The title ccmccund was synthesized from the title comcound of ?raza~a:icr,Jz arc the corresccncinc ccronic acid fcllcv/lr.c tre'orccedure of Example 1. Tr^.e resu::'n:: residue was purified by column chrcmatcgraphy-i'siiica gel, dichloromethane.-meihar.ci 95:-*) to yield the title compound (62.5 % yield). -~-
m.p. 214.0-215.5 °C
o(DMSO-d,): 1.33'(rh," 6H>. 4^23 (q7 2H), 7.26 (mT 2H), 7.34 (c.-n;. 7.53 (m. 2H), 7.36 (d, 1H). 3.50 (d, 1H), 3.56 (m,2"H)V 3.92 (m, 1H), 9.35 (s, 1HEXAMPLE 227
5-Acetyl-2-ethyl-6-pyridin-3-yI-4-(quinolin-5-ylarnino)pyrfdazin-3(2H)-one
The title compound was synthesized from the title compound of Preparation 14 and the corresponding bcronic acid following the procedure of Example 1. The resulting residue was purified by column chromatography (silica gel, dichloromethane.'methanol 97:3) to yield the title compound (32 % yield).
m.p. 130.7-181.6 °C
5(DMSO-d5): 1.33 (m, 6H), 4.23 (q, 2H), 7.33-7.41 (m, 2H), 7.56-7.57 [m, 3H), 7.87 (d, 1H), 3.45 (m, 2H), 3.55 (mf 1H), 8.93 (m, 1H), 9.32 (s, 1H).
EXAMPLE 223
5-Acetyl-2-ethyI-4-[(3-fIuoroquinoK^
To a stirred solution of 150 mg (0.522 mmol) of 5-acetyi-2-ethyl-4-nitr>5-phenylpyridazin-3(2H)-one (Dal P:az, V et a/, J. Med. Chem. 1997, 40. 1417) in ethanol (3 mL), 5-amino-S-fIuorccuinoline (127 mg, 0.733 mmcl) (Lee, Jae Keun et al.,
Bull. Kcrean Chem. Sec,
~:.p. 245.7-246-5 }C
■3.DMSO-C.V 1.35 :~. 5H'. -10 .;. ::- . ".22 im, 2H), 7.37-7.47 (m, 5H), 7.70 (m,1H}. 3.43 d. IH', 3.OS ~. 1H\ } 15 s. IH;..
5-Acetyl-2-(cyciopropylmetriyl)-6-4-fiucrophenyi)-4-{quinolin-3-ylamino) pyridazin-3(2.H)-one
To a stirred solution of 150 ~z [G.-zl mmci) cf the title-compound of Preparation 65 in ethanci [5 mLO S-amincquir.ciine I: mg. 0.630 mmoi) was added. The resulting mixture was stirred at room temperature during four hours and the finai product '//as collected by filtration and washed .vi-h diethylether to yield the title compound (115 mg, 59.3 % yield).
m.p. 149.7-150.5 °C.
5(DMSO-d5): 0'.44 (m. 2H, : 53 (m. 2H). 1.35 (m, 1H), 1.63 (s. 3H), 4.05 (q, 2H), 7.27 (m, 3H), 7.33 (m, 2Hi, 7.-5 fm, IH), 7.61 (m, 1H), 7.70 (d, IH), 3.40 (d, 1H), 3.93 (m. 1H), 9.35 (s, 1H).
EXAMPLE 230
5-Acety!-2-ethyl-5-(4-fluorophenyl}-4-(quirtolin-5-ylamino)pyridazin-3(2H)-one
To a stirred solution of 150 ~g (0.49' mmol) of the title compound of Preparation 30 in
ethanoi (3 mL), 5-aminoquirciine •'" 35 mg, 0.737 mmoi) was added. The resulting
mixture was stirred at room temperature during two hours and the final product was
collected by filtration and washed wth diethylether to yield the title compound (140 mg,
70.7 % yield). - -
m.p. 217.5-213.3 °C
5(DMSO-d»): 1.37 (r. 5K, 4.21 (q, 2H), 7.17-7.36 (m, 5H), 7.53 (m, 2H), 7.37 (d,1H), 3.43 (d, 1H), 3.92
EX^MP1
:— ^O H
5-Acetyl-2-ethyl-5-(4-fIuorcphenyl)-4-(quinolin-3-yiamino)pyridaz:n-3f2H)on^
To a stirrec soii/Jcn of "150 r~z 3.-51 rr~2\) c; :he title ccmpcur.c cf --~cara:;cn-3Q ;n ethane! ;3 rrL . 3-=ninocLr.c;ir.e -.'1Cc ~g, G.~37 mircli v;as acdez. "he 'esulting mixture was siired a: rcom temperature :ur:nc one hour and the -'rial :rccu:; ,vas coiiected bv filtration and wasnea with niethvlether to vielc the title cc~ court: :'13C ma, 65.6 % yield .
5(CMSC-d,): 1.36 (t. 3H,. 1.52 (s. 3H). 4.21 (a, 2H), 7:25 ~. 3H';. 7.33-7.51 (m, 3H), 7.61 (rr.. IK';. 7.70 (d, 1H), 340 (d. i'H), 3.92 (m, 1H). 9.25 ..s. ^nEXAMPLE 222--
5-Acetyl-2-(cyciopropylmethyl)-6-(4-fIuorophenyl)-4-(quinolin-5-yiamino) pyridazin-3(2H)-one
To a stirred solution of 150 n~g '7.-53 mrrol) of the title compound of Preparation 30 in ethanol (3 mL., S-aminccuinciine (93 rng, 0.630 mmol) was added. The solvent was evaporated and the residue purified by column chromatography /silica gel. hexane/ethyl acetate 1:1) to yield the title compound (174 mg, 39.7% yield).
m.p. 159.2-170.0 °C
5(DMSO-d9): 0.45 (m. 2H), 0.55 (m, 2H), 1.36 (m, 4H), 4.05 (q, 2H), 7.13-7.37 (m, 5H), 7.55-7.54 (m, 2H), 7.37 (d, 1H),8.43(d, 1H). .92 (m, 1H), 9.23 (s. 1H).
EXAMPLE 233
5-Acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one
The title compound was synthesized from the title compound of Example 224 '390 mg, 0.931 mmol) following the procedure of Example 222. The crude obtained was
purified by column chromatography (silica gel. dichloromethane/methano! 160:5' to yield the title compound (3C0 mg, 74.1 % yield), m.p. 244.0-244.9 °C
3(DMSO-d6): 1.37 (t. 3H). 1-43 (s. 3H), 4.21 (q, 2H), 7.19 (d, Vri), 7.35-7.52 m. 5H), 7.56 (t. 1H),7.96(df 1H), 3.25 (df IH',3.51 (d, 1H),9.32(s, 1H).
EXAMPLE 234
5-Acetyl-2-ethyl-4-[(2-methyiquinclin-5-yl)amino]-6-phenyIpyridazin-3(2H)-one
To a stirred solution of 100 mg (G.248 mmcl) of 5-acetyl-2-ethy!-4-nitro-6^,-, phenylpyridazin-3(2H)-one (Dai P:az, V era/, J. Med. Chem. 19Q7..4C. T417);in ethanol (5 mL), 5-amino-2-methyiquinolir>e (33 mg, 0.522 mmol) was added:The resulting mixture was stirred at room temperature during three hours and-the final product was collected by filtration 2nd washed with diethylether to yield .the title compound (30 mg, 57.6 % yield), m.p. 204.5-205.1 °C
o(DMSO-dg): 1.30 (sf 3H). 1.37 (t, 3H)^2.66 (s^H), 4.21 (q, 2H)>7.25"-(m, 3H), 7.36 (m, 3H), 7.45 (d, 1H), 7.54 (i. 1H), 7.76 (d, 1H), 3.30 (d, 1H), 9.15 (s, 1H).
EXAMPLE 235
5-Acetyl-6-(3-chlorophenyl)-2-ethyl-4-(isoquinolin-5-yIamino)pyridazin-3(2H)-one
To a stirred solution of 100 mg (0.311 mmol) of 5-acetyl-2-ethyl-4-nitrc-6-(3-chlorophenyl)pyridazin-3(2H)-one (Dal Piaz, V etal, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 5-amino-isocuinciine (67 mg? 0.467 mmol) was added. The resulting mixture was stirred at room temperature for two hours. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 1:2) to yield the title compound (23 mg, 21.5 % yield).
m.p. 139.2-190.6 °C
5(DMSO-d5): 1.37 (m, 6H)T 4.22 (q, 2H), 7.18 (d, 1H), 7.34-7.53 (m/5H), 7.35 (d, 1H), 7.99 (d, 1H), 8.54 (d, 1H), 3.25 (sf 1H), 9.33 (s, 1H).
EXAMPLE 236
5-Acetyi-2-ethyl-5-(4-fiuorophenyl)-4-[(1-oxidoquinoiin-5-yi)aminojpyridazin-3(2H)-one
The tide :cmpounc was synmesized r"rm :r.e ::tie compound of Examcie 230
3(DMSO-d6): 1.37 (t. 3H). 1.44 (5, 2'n). -.21 :q, 2H), 7.20-7.31 ,.m. 4H). 7.46-T 7.50 (m, 2H), T54 (m, 1H), 7.92 ."d, 1H), 3.36 id. 1H), 3.52 (d, 1H), 9.23 ($, Vr\EXAMPLE 237
5-Acetyl-2-ethyl-5-{3-fluorophenyI)-4-(quinoIin-5-ylamino)pyrida2in-3(2H)-one
To a stirred solution of 400 mg (1.31 mmol) of me title compound of Preparation 36 in . sthanol (20 mLi. 5-aminoquinoiine (283 mg, 1.965 mmol) was added. The resulting mixture was stirred at room temcerature durinc two hours and the finai crcduct was ~-;ollected by filtration and washed with diethvlether to yield the title compound (320 mg. 50.7 % yield).
m.p. 2C5.3-206.7°C
5(DMSC-dg): 1.33 (m, 6H), 4.20 (q, 2H). 7.10 (m, 2H), 7.22 (m. 1H). 7.35 (m, >H), 7.60 (m, 2H), 7.35 (d, 1H), 3.42 (d, 1H), 3.95 (m, 1H), 9.25 (s, 1H).
EXAMPLE 233
5-Acetyl-2-9thyl-6-(3-fluorophenyl)-4-[{1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-one
The title compound was synthesized from the title compound of Example 237 (200 mg, 0.497 mmol) following the procedure cf Example 222. The cruce obtained was purified by column chromatography (silica gel, dichloromethane/rr.ethanol 200:5) to
yield the title compound (150 mg, 72.1 % yield).
m.p. 249.4-250.6 °C
3(DMSO-d5): 1.23 (t, 2H), 1.33 (s. 3H), 4.07 (q, 2H), 6.92-7.00 (m. 2H), 7.11 (m, 1H). 7.25-7.33 (m, 3H), 7.51 (m, 1H),7.22;d, 1H), 8.22 (d, 1H), 3.43 (d, 1H),9.17 (s,
In);
EXAMPLE 239
5-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2t3-d[hydropyridazin-4-yl)amino]quinoline-
carboxyiic acid
A mixture of: 130 mgT 0.556 nrnci; of 5-ac3b/i-2-ethyl-4-nitro-6-pheny!pyridaz!n-3(2,h> one (Dal Piar. V era/, J. Med. Cham. 1997, 40, 1417), 5-amincquinoiine-3-carboxiiic. acid (210 mg. 1.114 mmol) (Ereckenridge, J. G. et al. Canadian J.of Research Seer. 3, 1947, 25, 49x> and ethanol (3 rnL) was introduced in the microwave. The mixture was stirred at 120 °C during 45 minutes. The solvent was evaporated and the residue purified by column chromatography (silica gel, dichlcromethane/methanol 300:1) to yield the title compound (50 mgT 4".7 % yield). LRMS: m/Z429(M+1)~. "Retention time: 14min*.
The following examples illustrate pharmaceutical compositions according to the present invention.
COMPOSITION EXAMPLES:
Using a mixer machine, 15 g of the compound of the present invention are mixed with 340.3 g of lactose anc 35.2 g cf microcrystaliine ceiluicse. The mixture is subjected to compression moulding using a roller compactor to give a fiake-iike ccnpressec material. The flake-like compressec material is pulverised using a hammer mi::, and the pulverised material is screened through a 20 mesh screen. A 4.5 g portion of .ignt silicic anhydride and -.5 g of magnesium stearate are added to the screened matenai and mixed. The mixed orocuct is subiected to a tablet makinc machine ecuioced with a die/punch system cf 7.5 mm in diameter, thereby obtaining 3.0C0 tablets each saving 150 mg in weignt.
COMPOSITION EXAMPLE 2 Preparation of coated tablets
Using a fluidised bed granulating machine, 15 g of the compound of the present invention are mixed with 235.6 g of lactose and 122.4 g of corn starch. Separately, 22.5 g of polyvinylpyrrolidone is dissolved in 127.5 g of water to prepare a binding solution. Using a fluidised bed granulating machine, the binding solution is sprayed on the above mixture to give granulates. A 4.5 g portion of magnesium stearate is acded to the obtained granulates and mixed. The obtained mixture is subjected to a tablet making machine equipped with a die/punch biconcave system of 6.5 mm in diameter, thereby obtaining 3,000 tablets, each having 150 mg in weight.
An oi|-in-water emulsion :cream is prepared with the ingredients listed above. -using conventions: methods
CLAIMS
1. A pyridazin-3(2H)-one derivative of formula (I):
wherein
R1 and R" represent independently from each other:
• a hydrogen atom;
10 • a group selected from acyl, hydroxycarbonyl, alkoxycarbonyl, ca-ro-amov. monoalkylcarbamoyl or diaikylcarbamoyl;
• an alkyi, aikenyl or alkynyl group, which is optionally substituted by one or more
substituents selected from halogen atoms and hydroxy, alkoxy. aryloxy. alkylthio,
oxo, amino, mono- or di-alkylamino, acyiamino, carbamoyl or mcnc- or c;-
..-*.. 15 alkylcarbamoyl groups an aryl or heteroaryl group which is optionally substituted by one or more
substituents selected from halogen atoms and hydroxy, hydroxyalkyl,
hydroxycarbonyl, alkoxy, alkylenedioxy, alkoxyacyl, aryloxy. acyl. acyloxy. alkylthio.
amino, nitro. cyano, mono- or di-alkylamino, acyiamino, carbamoyl or mcno- or di-
20 alkylcarbamoyl, difluoromethyl, trifluoromethyl, difluoromethoxy or triflucromethoxy
groups;
• a saturated or unsaturated neterocyclic group whtch is optionally substituted by one
or more substituents selected from halogen atoms and hydroxy, hydroxyalkyl,
hydroxycarbonyl, alkoxy, alkylenedioxy, alkoxyacyl, aryloxy, acyl, acyloxy, alkylthio,
25 oxo, amino, nitro, cyano, mono- or di-alkylamino, acyiamino, carbamoyl or mono- or
di-alkylcarbamoyl, difluoromethyl, trifluoromethyl, difluoromethoxy cr trifluoromethoxy groups;
• a group of formula
wherein n is an integer from 0 to 4 and R6 represents:
• a cycloalkyl or cycloalkenyl grouo;
• an aryl grouo. which is optionally substituted by one or mere substituents selected from halogen atoms arc aikyl, hydroxy, alkcxy. alkyleredicxy aikyithio. amino, mono-dr di-alkyammo, nitro. acyl. "ydrcxycarccnyi. aikcxycarbenyl, carbamoyl, more- or di-alkylcarbamoyl. cyarc. trifiucromethyi. difluorcmethcxy or trifluoromethoxy groups:
• or a 3- to 7-memberec ring comprising from 1 to 4 he:eroa:cms seiecreo from nitrogen, oxygen and suipr^r, which ring is optionally sucs::utec oy ore or more substituems selected from halogen atoms and alky, ^yorcxy. aikexy, aikylenedicxy. amino, mono- or di-alkylaminc. nitro. cya~c or tnfiuoromethyl groups;
RJ represents .a monocyclic or pciycyolic aryl or heteroaryl grouo. which is cotionaily substituted by one or more substituents selected from:
• halogen atoms;
• alkyl and alkylene groups, which are optionally substituted by one c~ more substituents selected from halogen atoms; and phenyl, hydroxy, hycroxyalkyl. alkoxy. afyte^ralkyrthror oxo, amino, mono-or di-alkylamino. acylamino. hydrcxycarbonyl, alkoxycarconyl, carbamoyl, mono- or di-alkylcarbamoyi groups
• phenyl, hydroxy, hydroxyaikyl, alkoxy, cycloalkoxy, nitro, aryloxy. aikyithio, alkylsuiphinyi, alkylsulphonyl, alkylsulfamoyl, acyl, amino, mono- or di-alkylamino, acylamino, hydrcxycarbonyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, ureido, N'-alkylureido, N'.N'-dialkylureido, alkylsulohamido, amincsuphonyl, mono- or di-alkylaminosulphonyl, cyano. difluoromethoxy or trifluoromethoxy groups;
R° represents a group -COOR7 or a monocyclic or polycyciic aryl or heteroaryl group, which is optionally substituted by one or more substituents selected from:
• halogen atoms;
• alkyl and alkenyi groups, which are optionally substituted by one or more substituents selected from halogen atoms and phenyl, hydroxy, hydroxyaikyl, alkoxy. an/loxy, aikyithio, o/o, amino, mono- or di-alkylamino. acylamino.
hydroxycarbonyl. alkoxycarbonyl. carbamoyl, mono- ordi-alkv-carbamoyl groups; and
• phenyl, hydroxy, alkyienecioxy, aikoxy. cycloalkyloxy, alkylthc. alkylsulphinyl,
alkvlsubhonvl. aikvlsuifamovl, amino, mono-ordi-alkylamir.c. acvlamino. nitro.
acyj. hydroxycarbonyl. alkcxycarconyl, carbamoyl, mono-or z -alkylcarbamoyi.
jreicc. N'-aikyiureido. N'.N'-diaikylureido. alkylsulphamico. a~ nosuchonyl,
more- or di-alkyiamincsuiphcnyi. cyano. difluoromethoxy or :-*;uorcmethoxy —«**i"> i * •■> ^ ■
yi -J O w O ,
wherein R represenis an alky! whicr, is optionally substituted by :~e or more sucstituems selected from halogen atoms and hydroxy, aikoxy. a*\!oxy, aikylthio, oxo. amino, mono-or di-alkylamino, acylamino, hydroxycarbony . alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamcyl groups or a group of form^a
-(CH2)n-R5
wherein n and R°are as defined above; and
R4 represents:
• a hydrogen atom;
• a hydroxy, aikoxy, amino, mono- or di-aikylamino group;
• an alkyl, alkenyl or alkynyi group which is optionally substituted by one or more substituents selected from halogen atoms and hydroxy, aikoxy. aryloxy, alkylthio, oxo, amino, mono- or di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- ordi-alkylcarbamoyl croups;
• or a group of formula
-(CH2)n-R5
wherein n and R°are as defined above.
as well as the N-oxides obtainable from the heteroaryl radicals preset in the structure when these heteroradicals compose N atoms and pharmaceutically acceptable salts thereof.
with the proviso that when Rz is neither an octionally substituted heteroary: group nor a group COOR , then R" :s an optionally substituted heteroaryl group.
2. A compound acceding to ciaim 1 wherein R: represents a hydrogen a::m or an aryl group /.rich \s optionally substituted by one or more substituents selected from halogen atoms and nitro. C--C- aiKoxy, C--C_ hydroxyaikyl and -CO:-
3. A compound according to ciaim 2, wherein R: is a hydroge~ atom or a zr,er-/\ group whicr. is unsubstitued or substituted with 1 or 2 unsubstituted 3ucst;t_ents selected from fluorine or chlorine atoms and nitro, d-d hydroxyaikyl and -CO:-'C--d alkyl) grouos.
4. A compound according to any preceding claim wherein R' represents a group selected from:
• a CC-.Ct) alkyl group which is optionally substituted by one or mere hydroxy
. . ^ groups; and
• crouos of formula
wherein n is an integer from 1 to 3 and R6 represents a (d-d) cycloaikyl group.
5. A compound according to claim 4, wherein R' is an unsubstituted d-d alkyl, an
unsubstituted d-d hydroxyaikyl or an unsubstituted cyclopropyl-(d-d alkyl)- group.
6. A compound according to any preceding claim wherein R3 represents a
monocyclic or polycyclic aryl or heteroaryl group, which is optionally substituted by one
or more substituents selected from:
• halogen atoms;
• alkyl and alkylene groups, which are optionally substituted by one or more substituents selected from halogen atoms
• phenyl, hydroxy, hydroxycarbonyl. hydrcxyalkyl, alkoxycarbcrv.!. alkoxy,
cycloalkoxy, nitro. aryloxy, alkylthic. alkylsuiphinyl. alkylsuiphc~yl.
alkylsuifamoyl. acyl. amino, mono- ordi-alkylamino. ac,. iamirc. hydroxycarbonyl, alkoxycarbonyl. carbamoyl, mono- or z'.-alky carbamoyl, ureido. Y-alkylureido. N'.N'-diaikyiureido. alkylsuiphamicc. am ■"osuchcnyl. mono- or di-aikyiaminosuipncryi, cyano. diflucromethcx;, or tr""^oromerhoxy groups:
7. A compound according to c:aim 6 wherein R° represents a crco selected from monocyclic or poiycyciic aryl or heteroaryl groups, which are c::icnai!y substituted by one or more suostituents selected from:
• halocen atoms:
• (C-.C^j alkyl groups, which are optionally substituted by one c more hydroxy groups:
• and (C-.Ci) alkoxy, nitro. hydroxy, hydroxycarbonyl, carbamc> . (C-.C: alkoxy/-carbonyl or cyano groups.
3. A comoound according to claim 7, wherein R3 represents a phenyl group, a ^^^^^napfTth^^hgroup or a 5- to 14-membered monocylic or poiycyciic heteroaryl
group containing 1, 2 or 3 heteroatoms selected from N. O arc 3, the phenyl, naphthyl and heteroaryl groups being unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from:
• halogen atoms;
• C--C4 alkyl and C--C4 hydroxyalkyl groups; and
• C:-C4 alkoxy, nitro, hydroxy, hydroxycarbonyl, carbamoyl, (C:-C4 a!koxy)-carbonyl and cyano groups.
9. A comcound according to claim 8 wherein R3 represents a phenyl group, a naphtyl group or a substituted or unsubtituted heteroaryl group selected from substituted or unsubstituted oxadiazolyl, oxazolyl, pyridyl, pyrclyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, ndoiyl, benzoxazolyl, naphthyridinyl, benzofuranyl, pyrazinyl/pyrimidryl and the various pyrrolopyridyl radicals.
10. A compound according to any preceding claim, wherein R" represents:
• an ^r.s-bstiti;ted'mcno-(Ci-C4 aikyHamino or di-(C-"C4 3:kyl)aminc group;
• a C--d alkyl group which is unsubstituted or substitute: by one or more SLC5t::-ents selected from hydroxy. C--C- alkcxy. amine. mcnc-(C--C^ ai-v.l-amno and di--;C--C^ alkyl'arnino groups:
• an _ns.cstituted pheny!-;C--C, aiky!)- group; or
• a g'O-: of formula
w~ere " n is 2 and R" recresents a radical selected from orer.vi. ovrdvl and thie^> optionally substituted by one or more substituents se acted from naiccen atoms and alkyl. hydroxy, alkoxy, alkylenedioxy. amino, mono- or di-alkyiaminc. nitre oano and trifluoromethyl groups.
1. A correct z according to claim 10 wherein R" represents an aikyi grouo having from 1 :o 5 carbon atoms and which is optionally substitutes by one or more substituents selected from halogen atoms and hydroxy grotos
2. A compound according to any precediftg-charinrwhisrem RD represents a group COOR or a monocyclic or polycyclic aryl or heteroaryl group, wr.ich is optionally substitutec oy one or more substituents selected from halogen atoms. C--C; alkyl groups. C'-Ci alkcxycarbonyl groups, a hydroxycarbonyl group and C--d alkoxy groups, wherein R' is as defined in claim 1.
3. A compound according to claim 12 wherein R° represents a group COOR' or a monocyclic or polycyclic an/I or heteroaryl group, which is optionally substituted by one or mere substituents selected from halogen atoms and C--C* alkoxy groups, wherein R is as defined in claim 1.
k A compound according to claims 12 or 13 , wherein R° represents -C02R7, wherein R7 represents an unsubstituted CrC- alkyl group, or R° represents a phenyl group or a 5- to '> membered monocyclic or polycyclic heteroan/l group containing 1 or 2 heteroato^s selected from N. 0 and S, the phenyl and heteroaryl groups being unsubstituted or substituted by 1 or 2 substituents selected from C--C^ alkoxy groups ar. - halogen atoms, for example chlorine and fluorine atoms.
15. A compound according to ciaim 14 -/herein R5 represents a pheryi group, or a substituted or unsubtituted heceroaryl group selected from substituted or unsubstituted oxadiazciyl, cxazoiyl, py-:dylt pyrrolyl. imidazolyl, thiazoly!. thiadiazolyl. thienyl. furanyl. ouinoiinyl. -soquinolinyl, indolyl. herzoxazcivl. naphthyridinyl, benzofuranyl. pyraziny. pyrimidinyl and the various pyrro'ccyridy! radicals
16. A compound according to any orececrg ciaim, wherein when R: represents a polycyciic hetercaryl group !: -epreser:s a group of formula (XXIii":
wherein Y represents an 0 atom , a S atom or an -NH- group, n '5 0, 1 or 2 and each R is the same or different and is a C«-C.i alkoxy group or a halogen atom.
17. A compound according to any preceding claim which is one of:
5-acetyl-2-9thyl-4-[(3-fluorophenyl)ami^no]-6-pyridin-3-ylpyridazin-3(2H)-one
5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyi-6-pyridin-3-yipyhdaz:n-3(2Hj-one
5-acetyl-4-[(315-dichloroph8nyi)amino]-2-ethyl-6-pyridin-3-ylpyrid3zin-3(2H)-one
5-acetyl-2-ethyl-4-(1-naphthy;amino)-6-pyridin-3-ylpyridazin-3(2H)-one
methyl 4-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2,3-dihydropyridaz:n-4-
yl)amino]benzoate
5-acetyl-2-ethyl-4-[(2-fluorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one
5-acetyl-4-[(2-chlorophenyl)amino]-2-ethyl-6-pyridin-3-ylpyridazin-3(2H)-one
5-acetyl-2-ethyi-4-{[4-(hydroxymethyl)phenyl]amino}-6-pyridin-3-ylpyridazin-3(2H)-
one
3-[(5-acetyl-2-ethyl-3-oxo-6-pyridin-3-yl-2(3-dihydropyridazin-4-yl)amino]benzonitrile
5-acetyl-4-[(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-pyridin-3-ylpyridazin-
3(2H)-one
5-acetyl-2-(cyclopropylmethy:;-4-[(3,5-dichlorophenyl)amino]-6-pyridir>-3-
ylpyridazin-3(2H)-one
5-acetyl-2-fcyclopropylmethy:;-4-[(2-fluorophenyl)amino]-5-pyricin-3-ylpyridazin-
3(2H)-one
5-acetV'---[(2-chlorophenyl)amino]-2-{cycldpropylmethyl)-6-pyric
3-{[5-ac5-yl-2-(cyc!opropylmethyl^
yl]aminc}benzor.itrile
methyl --{[5-3cer/l-2-(24iydroxy9thyi"'-3-cxo
yl]aminccenzcat9
5-acer. ---[(2-fiuoropnenyi)anino]-2-'2-nydroxyeLhyl)-6-py
one
5-acety'---[(2-chiorcphero^
one
5-acat\.---[(3-chloropheny!;amincJ-2-'2-hydroxyethyl)-6-pyndin-
one
5-acety:---[(3-chiorophenyl)amino]-2-ethyl-6-pyridin-2-ylpyridazin-3'7H--one
3-[(5-ac5:/l-2-ethyl-3-oxo-6-pyridin-2^
S-acety^-eihyM-f^hydroxymethyOphenylja
one
34[5-acer/l-2-(cyclopropylmethyl)-3-oxo-o-pyridin-2-yl-213-dihydrocyr;cazin
yl]aminc}benzonitrile
5-acety!-4-[(3-chIorophenyl)amiao}-2-(cyclopropylmethyl)-6-pyricin-2-y!oyrJG
3(2H)-one
5-acetyl-2-(cyclop^opylmethy^^-4-{[4-(hyd^oxymethyl)phenyl]amiro}-3-py^din-2-
ylpyridaz:n-3(2H)-one
5-acetyi-2-(cyclopropylmethyl)-4-[(3,5-dichlorophenyl)amino]-6-pyncin-2-
ylpyridazin-3(2H)-one
3-{[5-acer/l-2-(2-hydroxyethyl)-3-oxo-6-pyridin-2-yl-213-dihydropyrid3zin-4-
yl]amino}benzonitrile
5-acetyl^-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-2-ylpyridazin-3(2H)-
one
5-acetyl-"-[(3t5-dichiorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-2-ybyridazin-
3(2H)-one-
5-acetyl-2-(2-hydroxyethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-8-pyridin-2-
ylpyridazin-3(2H)-one - -
5-acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one
5-acetyl---[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3^2H)-one
5-acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-4-ylpyridazin-3(2H)-G,ne
5-acety!-2-ethyl-4-[(2-methyi^
methyl --[(5-acetyl-2-ethyi-3-oxo-5-pyridin-^-y!-2.3-dihydropyridaz;n-^-
yi)aminc]benzoate
5-acetyi-2-ethyl-4-[(2-~ethoxypheny^
5-acetyi-2-ethyl-4-[(3-methcxyph
5-ac8t\!-2-ethyl-4-[(2-nuoropte^
5-acety!-4-[(2-chloropheny!)arT!ino]-2-ethyi-c-pyriGin-4-ylpyridazir-3
3-[(5-acetyi-2-e:hyl-3-cxo-3-pyricin-4-y|-2.^^
5-acetyi-2-ethyl-4-{[4-(hydroxymethyi)pheryi]3mino}-6-pyridin-4-/
one
4-[(5-acetyl-2-ethyl-3-cxc-5vyridir-4^^
acid
5-acetyi-2-(cyc!opropylmethy:;-4-[(2-fluorcohenyl)amino]-6-pyridlr---ylpyn
3(2H)-cne
5-acety1-4-[(2-chIorophenyl)ar^^
3(2H)-one
3-{[5-acetyl-2-(cyciopropylrne:hy!)-3-oxo-6-pyridin-4-yl-2,3-dihydr3cyridaz:n-4-
yl]amino}benzonitrile _J>-acetyi-2-(cyclopropylrriethy^— =■ ylpyridazin-3(2H)-one
5-acety!-4-[(3-chlorophenyl)anino]-2-(cyclopropylmethyl)-5-pyriGin-4-ylpyridaz:n-3(2H)-one
5-acety!-4-[(2-fluorophenyl)anino]-2-(2-hydroxyethyl)-6-pyridin-4-y!pyridazin-3(2H)-one
5-acety!-4-[(2^hlorophenyl)anino]-2-(2-hydroxyethyl)-6-pyridin-4-ylpyridazin-3(2H one
3-{[5-acetyl-2-(2-hydroxyethyi}-3-oxo-6-pyridin-4-yl-2f3-dihydropyr;dazin-4-yl]amino}benzonitrile
5-acetyl-2-(2-hydroxyethyl)-4-{[4-(hydroxymethyl)phenyl]amino}-5-pyridin-4-ylpyridazin-3(2H)-one
5-acetyl-4-[(3-chlorophenyl)anino]-2-(2-hydrcxyethyl)-6-pyridin-4-ylpyridazin-3(2H)-one
5-acetyl-4-[(3-chloroph9nyl)ai'riino]-2-ethyl-6-thien-2-ylpyridazin-3(2H)-one 5-aceryl-4-ibis(3-fluoropheny^;arnino]-2-ethyl-3-pyridin-3-ylpyridazin-3(2H)-one
5-aceiyl-4-[bis-(4-me:hoxyc3rbonylphenyl)-aminc]-2-ethyl-6-pyridin-3-y
3(2H)-one
5-ac8:yW-{bis[4-(hycroxyrethyl)p^
3(2H)-one
5-ace:yM-[bis(3-nitrccher. aminc]-2-ethyl-6-pyriciin-4-ylpyridaz!n-3(2H'-cne
5-aceryl---[bis(3-fIucroph5:\/i)ami~o^ -one
5-ace:yl---rbis(3-chlcrophsryl)aminoj^^
3(2H--one
5-aceryi-4-[bis(3,5-Gichiorc:"enyl)amino]-2-(cyciopropylmeLhyl^5oyr:cir:-3-
ylpyricazir.-3(2H)-or;9
5-3C5:y!-4-[bis(4-mernoxy'ca.-zony!cheryl)amino]-2-(2-hydrcxye:hyl}-5^ pyicin-3-.
ylpyricazin-3(2H)-one
5-ac8tyl-4-[bis(3-chlcrophe"7l)amino]-2-(2-hydroxyethyl)-6-pyridin-2-yipyr:d3zin-
3(2H)-one 5-aceryl-4-[bis(3-chlcrophe"yl)amino]-2-(cyclopropylmethyl)-6-pyridin-4-yi
3(2H)-one
5-acsryl-2-ethyl-5-phenyl-4- pyridin-3-ylamino)pyridazin-3(2H)-one
5-ace!yl-4-[(3,5HJichlcropyr'cin-4-yl)amm^
5-aceryl-2-ethyl-6-pheny!---pyrazin-2-ylamino)pyridazin-3(2H)-aae^- --.
5-acetyl-2-9thyl-6-phenyl---'pyrimidin-2-ylamino)pyridazin-3(2H)-one
5-acetyl-2-ethyi-6-phenyl--- :uinoiin-3-ylamino)pyridazin-3(2H)-one
5-acetyl-2-ethyl-4-[(5-nitrocyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-one
5-acetyi-2-ethyl-4-(1h-indci-4-ylamino)-6-phenylpyridazin-3(2H)-one
5-acebyl-4-(1I3-benzothiazci-5-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one
5-acetyl-2-ethyl-6-phenyl--- thianthren-1-ylarnino)pyridazin-3(2H)-one
methyl 3-[(5-acetyl-2-ethy!-3-oxo-6-phenyl-2,3-dihydropyridazin-4-
yl)amino]thiophene-2-carbcxylate
5-acetyl-2-ethyl-4-[(4-methy!pyridin-2-yl)amino]-6-phenylpyridazin-3(2H)-on8
5-acetyl-2-ethyl-6-ph8nyl-4--1h-1t2,4-triazol-5-ylamino)pyridazin-3(2H)-one
5-acetyl-2-ethyl-4-[(6-methcxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one
5-acsbyl-2-ethyl-4-(2H-indazol-5-ylamino)-6-phenylpyridazin-3(2H)-on9
methyl 4-[(5-acetyl-2-ethyi-3-oxo-6-phenyl-2,3-dihydropyridazin-4-
yl)amino]thiophene-3-carbcxylate
5-acetyl-2-9thyl-6-phenyl-^-'pyridin-2-ylamino)pyridazin-3(2H)-one
3-[(5-acetyl-2-ethyl-3-oxo-5-pheny^
carboxylic acid
5-3C3tyl-2-ethyl-4-[(3-met^/lcinnciin-5-yl)amino]-5 -one
5-ac9tyl-2-ethyi-4-[(2-me^
5-acetvl-2-9thvl-5-ohenvl---«quirci:n-5-v!anino)cvridazin-3f2H.'-or5
5-ac5tyl-2-ethyl-4-(lh-incci-5-yl3r'nc>5-phenylpyridazin-3(2h -ore
5-ac9tyl-2-ethyl-4-(isoquiroiin-5-y!aminoi-5-phenylpyridazin-3f 2H '-one
5-3cetyl-2-ethy!-4-[(6-me:r.cxy^
5-ac3tyl-^-!(5-cromoquinciin-3-yi'3rrJno^
5-ac3tyl-2-9thy!-^-[(4-me;ryipyrirnidin-2-y])am
5-acetyl-5-(3-cnloropheny:>2-etry-4-i'pyridin-3-yiaiTiino)pyrid3z:n-3^2H;-cne
5-acetyl-5-(3-chloropheny!'--2-(cyc;opr^^
3(2H)-one
5-ac3tyl-2-ethyl-3-(34lucrcchenyiV4-(pyridin-3-ylamino)pyridaz:n-2i2Hl;-one
5-ac9tyl-5-(3-flucrophenylr24soprapyM^
5-acetyl-2-(cycIopropylme:hyi)-6-i.3-fi^
3(2H)-one
5-acstyl-2-ethyl-6-(4-fIuorcohenyi)-4-(pyridin-3-ylamino)pyridaz:n-3«2H}-Gne
5-acetyi-5-t1h-benziJT]^^
one
5-acetyl-6-(1,3-benzoxazcS-2-yir^-[(3-chlorophenyl)amm^
one
5-acetyl-3-(1,3-benzoxazol-2-yI)-2-ethyl-4-[(3-fluorophenyl)amino]pyridazin-3(2H)-
one
5-acetyl-6-benzooxazol-2-yi-4-[bis-(3-chlorophenyl)-amino]-2-ethyl-pyridazin-3(2H}-
one
5-acetyl-5-benzooxazoi-2-yl-4-[bis-(3-fluorophenyl)-amino]-2-eihy!-pyricazin-3(2H)-
one
3-[(5-acetyl-2-ethyl-3-oxo-5-pyridin-3-yl-2,3-dihydropyridazin-4-y!)annino]benzamide
5-ac8tyl-2-9thyl-4-(isoquinclin-1-ylamino)-6-phenylpyridazin-3(2H)-one
5-acetyl-4-[(2-butylquinazciin-4-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one
5-acetyl-4-(1t2-benzisothiazok3-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one
5-3cetyl-2-ethyI-6-phenyl---{pyridln-4-ylamino)pyridazin-3(2H)-one
5-acetyl-2-ethyl-4^(2-hydroxy-7h-purin-6-yl)amino]-6-phenyipyrid3Zin-3^2H)-one
5-acetyl-2-9thyl-6-phenyl-i^quin3Zolin-4-ylanino)pyridazin-3(2H)-on9
5-acetyl-^-[(4-chioro-1 H-i;:dazol-3-y!)arrnino]-2-ethyi-6-phenylpynciazin-3 2H)-one
5-acetyl---[(7-chloroquinc;;n-4-yl)^^^
5-acetyl-4-[(4,6HJichlorop>*;rcu^
5-acetyl-2-ethyi-4-i(5-nyGr:xy-2H-pyrazoio[34-d]pyrimidin-4-y:'an^;nci-c-
phenylpyr;c3zin-3i'2H)*-or5
5-3cetyl-2-eihyl-4-[(2-merylquir.ciin-4-y!)amino]-6-phenylpyr:c2zir-3i2r -one
5-3cety!-2-eihyi---(lH-irrc3Zoi-2-y!3rriir.o)-6-phenylpyridazJn-3i2H-CP.e
5-3cetyi-2-5ihyl-5-pheny!---/quinc1in-4-ylaminc)pyridazin-3(2H'-ore
5-acetyl---;c!nnciin-4-ylaw:no)-2-eihyi-5-phenylpyndazin-3(2h;-one
5-3C9tyl-2-ethy!-o-pheny:---nH-pyrazoio[3,4-d]pyrimidin-4-yi3nirc cyr::azln-3(2H -
one
S-acetyi^-ethyi-o-phenyi—-(thieno^^-dlpyrimidin^-ylaminc/pyricazin-S^HJ-one
5-3cetyl-2-5ihyi-4H;1H4nG3Zol-5-ylamino)-6-phenyipyridazin-2'.2H:-cn^
5-acetyl---[(3-chlorophery!)amino]-2-ethyl-6-(2-methoxypyrid;n-4-yi}py
3(2H)-one
5-acetyl-2-ethyl-4-{[4-(hysroxymethyl)ph^
yl)pyridazin-3(2H)-one
5-ac9tyl-2-ethyl-4-[(3-methoxyphenyl)amino]-6-thien-3-ylpyridazin-3(2Hi-one
5-acetyl-6-(1-benzofuran-5-yl)-2-ethyl-4-[(3-fl^
1-ethyl-5-[(3-methoxyphe^yI)amino]-n,n-dimethyl-6-oxo-3-pyridin-3-yl-1.5-
dihydropyridazine-4-carbcxamide
5-[(3-chlorophenyl)aminc]-1-ethyl-n-methyl-6-oxo-3-pyridin-4-yi-1.5-
dihydropyridazine-4-carbcxamide
2-ethyl-4-[(3-fluorophenyi;amino]-5-glycoloyl-6-pyridin-4-ylpyridazin-3(2H)-one
2-ethyl-4-[(3-fluorophenyi 3mino]-5-(methoxyacetyl)-6-pyridin-3-yipyridazin-3(2H)-
one
5-[(dimethylamino)acetyiV2-ethyl-4-[(3-methoxyphenyl)amino]-5-pyridin-3-
y!pyridazin-3(2H)-one
2-ethyl-4-[(3-fluorophenyr/amino^
3(2H)-one
3-{[2-ethyt-3-oxo-5-(3-pheTylpropanoyl)-6-pyridin-4-yl-2,3-dihydropyridazin-4-
yl]amino}benzarnide
ethyl 4-ac3tyl-5-[(3-chlorcohenyl)amino]-1-ethyl-6-bxo-1I6-dihydropyridazine-3-
carboxylate
ethyl 4-3cen/l-5-amino-1-e:hyl-6-oxo-1,6-dihydropyridazine-3-carbcxylate
5-acetyl-6-(1 J-benzoxazcJ-2-yl)-2-ethyl-4-[(3-methoxyphenyl)amino]pyr:cJazin-
3(2H)-one
5 acetyl-6-(1.3-benzoxaz2i-2-yl)-2-ethyl-4-{[4-
(hydroxymethyl)phenyl]arr;ino}pyridaz:n-3(2H)-one
5-acetyl-2-ethyI-4-(isoquir.olin-^-ylarr:Ho)-6-phenyipyridazJn-3'2H'-one
5-ac9tyl-2-ethy!-4-(1t5-nsohthyr;cin-S-y1aminc)-5-phenylpyrid3zin
5-acetyl-2-ethyl-4-[(5-me-hoxypyridin-3-yl)anino]-6-phenylpyridaz:r-3(2H^
5-ac6tyl-2-eLhy!-6-pyridin-^-yl-4-:pyriG:n-3-y!amino)pyridazin-3(2H'-one
5-3cetyI-2-eihyl-4-[(4-me:l?ylpyridin-3-yl)amino]-5-pyridin-4^
5-ac9tyl-2-ethyl-4-(isoquinolin-4-ylam:no)-5-pyridin-4-ylpyridazin-3'2H)-cr:9
5-ac9tyl-2-ethyl-6-pyridin-4-yl---; 3.4.5-trifluoroph9nyl)amino]pyrid3zin-3
5-3C9tyl-2-9thyl-4-[(4-me:hylpyridin-3^
5-ac9ty!-2-9thy!-4-(isoquinolin-4-ylarT,Iino)-6-pyridin-3-ylpyridazin-3>,2H)-on9
5-ac9ryl-2-9thyl-6-pyridin-3-yl-4-i(3,4,5-tnfluorophenyl)amino]pynG3zin-2';2H)-one
5-ac9tyl-2-9thyi-4-(quinolin-5-ylaminc)-6-thien-2-ylpyridazin-3(2H-one
5-ac9tyl-2-ethy[-4-(pyridin-3-ylamino)-3-thien-2-ylpyridazin-3(2H)-cn9
4-[(5-ac9tyl-2-ethyl-3-oxo-5-thi9n-2-yl-2t3-dihydropyridazin-4-yl)anino]b9nzonitrile
5-ac9tyl-2-9thyl-6-thi9n-2-yl-4-[(3.4,5-trifluorophenyl)amino]pyridazin-3(2H)-one
5-Acetyl-4-(bis (4-cyanophenyl)amino}- 2-ethyl-6-thien-2-ylpyridaz:n-3(2H)-one
5-acetyl-2-(cyclopropylmethyl)-^-(quinolin-5-ytamino)-6-thien-2-ylpyTidaz:n-3(2H)-
one
5-ac9tyl-2-(cyclopropylmethyl)-4-(pyri
5-ac9tyl-2-ethyl-4-(quinolin-5-ylamino)-6-thien-3-ylpyridazin-3(2H)-one
5-acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-thien-3-ylpyridazin-3(2H)-one
5-ac9tyl-2-ethyl-4-(pyridin-3-ylamino)-6-thien-3-ylpyridazin-3(2H)-one
4-[(5-acetyl-2-ethyl-3-oxo-S-thien-3-yl-2,3-dihydropyridazin-4-yl)amino]benzonitrile
5-acetyl-2-ethyl-6-thien-3-yW-[(3,4,5-trifluoroph9nyl)amino]pyridazin-3(2H
2-ethyi-6-phenyl-5-(3-phenylpropanoyl)-4-(quinolin-5-ylamino)pyricazin-3(2H)-one
2-9thyl-6-phenyl-5-(3-phenylpropanoy!)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one
2-ethyl-4-(isoquinolin-4-yIamino)-6-phenyl-5-(3-phenylpropanoyl)pyridazin-3(2H)-
one
2-ethyl-6-phenyl-4-(quinclin-5-ylamino)-5-(3-thien-3-ylpropanoyl)pyridazinr3(2H)-
one
2-ethy(-6-phenyl-4-(pyrid!n-3-ylamino)-5-(3-thien-3-ylpropanoyl)pyridazin-3(2H)-one
5-3cetyl-4-[(3-chlorophe™
yl)pyridaz:n-3(2H)-one
5-3C9tyi-5^1.3-benzothiaz:>2-yl)-4-[(3-^
one
5-3cetyl-5-{1-benzofuran-2-yl)-4-[(3-chiorophenyl)amino]-2-e^
ore
5-acetyl-2-ethyl-6-pyridin-2-yl-4-(pyridin-3-ylamino)pyridazin-2(2H"'-or;e 4-=[-5-3ce^/!-2-ethyl-3-oxc-5-pyridin-3-yi-213-dihydropyridazin-*i-yI)arnirc]csn2oic
ac;c!
5-3C9tyl-2-ethyl-4-[( i-oxic:oyridin-3-yramino]-6-phenyipyr!C3zin-3.2H '-zne
ethyl 3-(5-3C9iyl-2-ethyl-3-:xo-6-pyridir!-4-yl-2t3-dihydro-pyr!cazin-4-
ylaninojbenzoate
3-[!5-ace?/l-2-ethyl-3-oxc-5-pyridin-4-yl-2,3-dihydropyridaz;n-4-yl)arninc;benz3mide
5-3C9tyl-2-ethyl-6-phenyl-4-(thieno[2t3-b]pyridin-3-ylaming)c;/ridazin-3'2H)-one
5-3C9tyl-2-ethyl-4-[(6-flucrcpyridin-3-yl)amino]-6-phenytpyrid3zin-3i,2H'i-one
5-3C9tyl-2-ethyl-4-[(2-me:hylpyridin-3-yi)amino]-6-phenylpyridazin-3(2H'rone
5-ac9tyl-4-{[2-(dimethylarcino)pyridin-3-yfl
one
5-[(5-aceWI-2-ethyl-3-oxo-5-phenyl-2,3-dihydropyridazin-4-y!)arninc]pyr:dine-2-
carboxylicacid
5-3cetyl-2-ethyi-4-[(2-meLroxypyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one
5-acetyl-2-ethyl-4-(1H-incazol-4-ylamino)-6-phenylpyridazin-3(2H)-one
5-acetyl-4-[(2-chIoropyricin-3-yl)amino]-2-ethyl-6-phenylpyndazin-3(2H)-one
5-3cetyl-4-[(5-chloropyridin-3-yl)amino]-2-ethyl-6-phenyipyridazin-3(2H)-one
5-[(5-acer/l-2-ethyl-3-oxo-3-phenyl-2,3-dihydropyridazin-4-yl)amino]nicotinamide
5-acetyl-2-ethyl-4-(17-naphthyridin-8-ylamino)-6-phenylpyridazin-3(2H)-one
2-ethyl-5-glycoloyl-4-[(2-n3thylpyridin-3-yl)amino]-6-phenylpyridazin-3f2H)-one
methyl 5-[(5-acetyi-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-
yl)amino]nicotinate
5-[(5-ace^yl-2-9thyl-3-oxo-5-phenyl-2l3-dihydropy^idazin-4-yl)ami^o]nicotinicacid
5-acetyl-2-9thyl-4-(1,5-naphthyridin-3-ylamino)-6-phenylpyridazin-3(2H)-one
5-acetyl-2-9thyJ-4-[(3-hydrcxy-17-naphthyridin-5-yl)amino]-5-phenylpyridazin-
3(2H)-one
5-3cetyl-2-ethyl-6-phenyi-^-{thien-2-ylamino)pyridazin-3(2H;-one
5-3cetyl-2-ethyl-6-phenyl---;72-phenylpyridin-3-yl)amino]pyndazin-3(2H;-one
ethyi {5^(5-acetyl-2-ethyl-3-oxo-5-ph5^^
yljacetate
5-ac9tyl-2-ethyi-4^(6-methylpyrl^
5-acetyl-2-ethyl-4-[(6-hycroxypy';din-3-yi)amino]-5-phenylpyricaz!r-3(2H'-on
5-acetyl-2-ethyl-4-[(2-fiucropyric;--3-; 'amino]-6-phenylpyricaz;n-3:2H)-:ne
5-acetyl-4-[(5-chloro-4-rr9thylpy- :;n-3-yl)amino]-2-ethyI-6-pher.yicyr!caz:n-3(2H)-
one
5-acetyl-2-ethyl-4-[(3-hyc^
5-acatyl-2-9thyl-4-[(4-me:hoxypyr^^^
5-3C3ryl-2-ethyl-4-(isoqL;nolin-3-/3iT\no)-5-phenyipyridazin-3';2H'-one
5-ac3tyl-2-ethyl-6-pheny::4-(quir.o:;n-T-ylamino)pyridazin-3(2H\-or9
5-ac6tyl-4-[(5-chloropyric:n-3-yi;.aninc!-2-etpyl-6-(3-rluorophenyi)pyridaz:^
one
5;3cetyl-2-ethyl-6-(4-flucrophenyl)-4-[^ -
one
5-acetyl-2-ethyI-6-(4-flucropheny1)-4-[(2-methylpyridin-3-yl)aminc]pyridazin-3(2H)^
one
5-acetyl-4-[(2-chloropyric:n-3-yi}amino]-2-ethyl-6-(4-fluorophenyl)pyridazin-3(2H)-
one
5-acetyl-2-ethyl-6-(4-flucrophenyl)-4-[(4-methylpyridin-3-yl)amino]pyridazin-3(2H)-
one
5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(2-fluoropyridin-3-yl)amino]pyridazin-3(2H)-
one
5-acetyW-[(2-chloropyricin-3-yl)amino]-2-(cyclopropylmethyl)-6-(4-
fluorophenyl)pyridazin-3(2H)-one
5-acetyl-2-(cyclopropyimethyl)-6-(4-fluorophenyI)-4-[(2-methoxypyridin-3-
yi)amino]pyridazin-3(2H)-one
5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(2-methylpyridin-3-
yl)amino]pyridazin-3(2H)-one
5-acetyl-2-(cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(2-fluoropyrid;n-3-
yl)amino]pyridazin-3(2H)-one 5-acetyl-2-(cyclopropylmethyi)-6-(4-rluorophenyi)-4-[(4-methylpyridi
yl)amino]pyridazin-3(2H)-one 5-acety!-2-^cyclopropylmethyl)-6-(4-fluorophenyl)-4-[(pyridin-3-yl)arntno]pyri
3(2H)-one
t:-acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(2-methylpyridin-3-yl)amino]pyrica
one
5-acclyi-6-(3-chlorophenyl)-4^
one
5-acetyt-6-(3-chlorophenyi)-2-ethyl-4-[(4-methylpyridin-3-yl)amino]pyrica^
one
methyl 5-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyrida2in-4-
yl)amino]quinoline-8-carboxylate
5-acetyl-2-e:hyl-4-[(4-methyipyridin-3-yl)amino]-6-phenylpyridazin-3(2H-one
5-acetyI-2-e:hyl-4-(isoquinolin^
5-acetyl-2-eihyl-6-(4-me:hcxyphenyl)-4-(pyridin-3-ylarnino)pyrida2in-3(2H)-one
5-acetyl-2-ethyl-6-(4-meihoxyphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H
5-acetyl-2-ethyl-6-(4-methoxy-phenyl)-4-(1-oxy-quinoiin-5-ylamino)-2H-pyrida2in-3-
one
5-acetyl-2-e:hyl-4-(isoquinolin-4-ylamino)-6-(3-methoxyphenyl)pyridaz:n-3(2H)-one
5-acetyl-2-eLhyl-6-(3-methoxyphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one
5-acetyl-2-ethyl-6-(3-methoxyphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one
5-acetyl-2-eThyi-6-{3-methcxyphenylM4(1^ 3(2H)-one
5-acetyl-2-ethyM-(isoquinolin-4-ylarnino)-6-(4-rnethylphenyl)pyridazin-3(2H)-one
5-acetyl-2-ethyl-6-(4-methylphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H;-one
5-acetyi-2-ethyl-6-(4-methylphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one
5-acetyi-2-ethyt-6-(4-methylphenyl)-4-[(1-oxidoquinolin-5-yl)amino]pyridazin-3(2H)-
one
5-acetyl-2-ethyl-6-(4-methylphenyl)-4-[(4-methylpyridin-3-yi)amino]pyridazin-3(2H)-
one
5-acetyl-2-ethyl^-(isoquinolin^-ylamino)-6-(3-methylphenyl)pyridazin-3(2H)-one
5-acetyl-2-ethyl-6-(3-methylphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one
5-acetyl-2-ethyl-6-(3-methylphenyl)-4-(quinolin-5-ylamino)pyridazin-3(2H)-one
5-acetyl-2-ethyl-6-(3-methylphenyl)-4-[(4-methyipyridin-3-yl)amino]pyridazin-3(2H)-
one
methyl 4-[4-acetyl-1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-t,6-dihydropyrida2in-3-
yl]benzoate
methyl 4-[4-acetyl-1 -ethyl-5-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-
yljbenzoate
4-r4-acetyl-1-ethyi-S-oxo-5-(pyndin-3-y'amino)-1.5-dihydropyridazin-3-yi]benzoic
acid
methyl 4-{4-acatyl-1-ethyi-5-[(4-methybyridin-3-yi^amino]-6-oxo-1.G-
dihydropyridazin-3-yl}berzoate
4-{^-acetyi-1-ethyl-5-[(4-r3thylpyriGin-3-yl)aminc;-5-oxo-1.5^
yl}benzoic acid
rr.erhyi 3-[4-acetyl-1-eth\ -5-oxc-5-«'pyridin-3-ylanino)-1,6-dihydropyricaz!n-3-
yijbenzoate
3-[--aceiyl-1-ethyl-6-oxc-5-{pyricln-3-yiamino)-1.o-dihydropyridazin-3-yi]benzoic
acid
5-acetyl-4-[(3-chloro-4-TT-:ropheryl)aiTiino]-2-ethyl-6-pyridin-4-yipyridazin-3(2
one
5-3C3tyl-4-[b!S(3-chloro---'1uorcphenyi)amino]-2-ethyl-6-pyridin-4-yipyridazin-3(2H>
one
5-acetyl-4-[(3-chioro-4-flucrophenyl)arriino]-2-ethyl-6-pyridin-3-ylpyridazin-3^2H)-
one
5-acetyl-4-[bis(3-chloro-^-rluoFophenyl)amino]-2-9thyl-6-pyridin-3-ylpyridazin-3(2H.-
one
methyl [4-acetyl-6-oxo-3-cnenyl-5-(quinolin-5-ylamino)pyridazin-1(6H)-yl]acetate
[4-3cetyl-5-oxo-3-phenyl-5-(quinolin-5-ylamino)pyridazin-1(6H)-yl]acetic acid
5-acetyl-2-ethyl-4-[(3-me:hylpyridin-2-yl)amino]-5-phenylpyridazin-3(2H)-one
5-acetyl-2-ethyl-6-phenyl-4-(lH-pyrazol-3-ylamino)pyridazin-3(2H)-one
5-acetyl-2-ethyl-6-phenyl-4-(9H-purin-6-ylamino)pyridazin-3(2H)-one
5-acetyl-2-ethyl-4-[(3-meihylisoxazol-5-yl)amino]-6-phenylpyridazin-3(2H)-one
5-acetyl-2-ethyl-4-[(3-hydroxyquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one
5-acetyl-2-ethyl-4-(1H-indazol-7-ylamino)-6-phenylpyridazin-3(2H)-one
5-acetyl-4-[(6-bromoquinciin-8-yl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one
5-acetyl-2-ethyl-4-[(5-metbylisoxazol-3-yl)amino]-6-phenylpyridazin-3(2H)-one
5-acetyl-2-ethyl-4-(isoxazol-3-ylamino)-6-phenylpyridazin-3(2H)-one
5-acetyl-2-(cyclopropylme:hyl)-6-phenyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one
5-acetyl-2-(cydopropylmethyl)-6-phenyl-4-(quinolin-8-ylamino)pyridazin-3(2H)-^
-5-acetyi-2-ethyl-4-[(1-methyl-1H-pyrazol-3-yl)amino]-6-phenylpyridazin-3(2H
5-acetyl-2-ethyl-4-[(1-oxidcquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one
5-acetyl-2-ethyl-4-[(2-oxicoisoquinolin-5-yl)amino]-6-phenylpyridazin-3(2H)-one
5-aceiyl-5-(3-chlorophenyi;-2-ethyl-4-(quinolin-5-ylamino)pyridazin-3(2H)-one
5-acetyl-6-(3-chlorcpner.yi)-2-ethyl-4-(xquino!in-8-ylamino)pyridaz:n-3(2H;on^
5-acetyl-2-etnyi-5-pyridin---yl-4-(quinciin-5-ylamino)pyridazin-3(2H)-or5
5-ac9tyl-2-e*hyl-5-pyridin-3-yl-4-(quincitn-5-ylafTiino)pyridazin-3(2Hj-ore
5-ac9tyl-2-e:ryl-4-[(S-flucroquinoiin-5-yi)amino]-6-phenylpyridazir-3(2H,-cne
5-acetyl-2-(C;Ciopropylm5:hyl)-5-f'4-flucrophenyi)-4-(quinolin-3-y :yridazin-
3(2H)-one
5-3cetyl-2-e:ryl-5H.4-fluc^ohenyi)-4-.cuinolin-5-ylamino)pyridaz:r-3(2H -one
5-ac9tyl-2-etny1-6-(4-fluc^3^he^y!)-4-!q'Ji^oii^-3-ylamt^o)py^daz^^-3(2^ -one
5-acetyl-2-;cyc!cpropylme:hyl)-5-(4-r1ucrophenyl)-4-(quinolin-5-yl3niinc'cyndazin-
3(2H)-one
5-ac9tyl-6-(3-chloropheny:V2-ethyl^^^
one
5-ac8tyl-2-ethyi-4-[(2-meihylquinolin-5-yl)amino]-6-phenylpyridaz:r.-3(2H;-one
5-acetyl-6-(3-chlorophenyl)-2-ethyl-4-(isoquinolin-5-ylamino)pyric3zin-3(2H)-one
5-acetyl-2-ethyl-6-(4-fluorophenyl)-4-[(1-oxidoquinolin-5-yl)aminc]pyridaz:n-3(2H)-
one
5-acetyl-2-e:hyl-6-(3-fluorophenyl)-4-(quinniin-5-ylamino)pyridazln-3(2Hrone
5-acetyl-2-e:hyl-6-(3-flucrcphenyl)-4-[(1-oxidoquinolin-5-yl)aminc]pyridazin-3(2H)-
one
5-[(5-acetyl-2-ethy!-3-oxo-5-phenyl-2,3-dihydropyndazin-4-yl)amino]quinoline-3-
carboxylic acid
and pharmaceutical^ acceptable salts thereof.
3. A compound according to claim 17 which is one of: 5-Acetyl-2-5thyl-4-[(3-fIuorophenyl)amino]-6-pyridin-3-ylpyridazin-3(2H)-one 5-Acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-3-ylpyridazin-3(2H)-one 5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-pyridin-4-ylpyridazin-3(2H)-one . 5-Acetyl-2-ethyl-4-(1-naphthylamino)-6-pyridin-4-ylpyridazin-3(2H)-one 5-Acetyl-2-ethyl-4-[(2-methylphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one 5-Acetyl-2-ethyl-4-[(3-methoxyphenyl)amino]-6-pyridin-4-ylpyridazin-3(2H)-one 4-[(5-Acetyl-2-ethyl-3-oxo-5-pyridin-4-yl-2,3-dihydrof3yridazin-4-yi)amino]benzoic acid
5-Acetyl-4-[^3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-pyridin-4-y|pyridazin-3(2H)-one
5-AcetyI-4-[(3-chioropher7i)amincj-2-ethyl-5-thien-2-ylpyrida2in-3(2H)-cne
5-Ac8tyl-2-ethyl-5-phehy!-4-(pyricin-3-yl3mirio)pyrida2in-3(2H)-one
5-Ac8b/!-2-ethyl-5-phenyi-4-(quir.ciin-3-ylamino)pyridazin-3(2H)-one
5-Acetyl-2-ethyl-4-(1H-indol-4-ylaninc,--5-phenylpyridazin-3'2H)-one
5-Acetyi-2-ethyl-o-pheny:-4-(quirciin-5-ylamino)pyrida2in-3'2H'-one
5-Acetyl-5-{3-flucrophery';-2-iscc-ccy-4-(pyridin-3-ylaminc;pyr;daz:n-3!2H;-one
5-Ac8tyi-2-(cyc!opropylr5thyl)-6--3^
3('2H)-one
5-Ac8tyl-2-ethyl-o-(4-flLC*3pheny:)-4--pyridin-3-ylamino)pyr:d32:no
5-Acetyl-2-ethyl-4-(isoqLirolin-5-yi3r:po)-5-phenylpyrida2ir-3'2H l-cne
5-Acstyl-5-(1.3-benzoxaz3l-2-yi>2-ethyl-4-ft^^
one
5-Acetyl-2-ethyl-4-[(1-oxicoquinciin-5-yl)amino]-6-phenylpyricaz:n-3(2H)-ons
5-Acstyl-2-ethyl-4-(isoqijinolin-4-ylarr:ino)-6-phenylpyridazin-3«2H,)-cne - -
2-Ethyl-6-phsnyl-5-(3-phenylpropanoyl)-4-(pyridin-3-ylamino)pyrida2in-3(2H)-one
5-Acetyl-2-ethyl-4-(isoquinolin-4-ylamino)-6-(3-methylphenyl)pyridazin-3(2H)-one
5-Ac8tyl-2-ethyl-4-(isoqLinolin-4.ylarrlino)-6-pyridin-4-ylpyridaz:n-3(2H)s-one
5-Acetyl-2-ethyl-4-(isoqLinolin-4-ylamino)-6-(4-methylphenyl)pyrida2in-3(2H)-one
5-Acetyl-2-ethyl-6-(4-flucrophenyl)-4-[(4-methylpyridin-3-yl)arriino]pyridazin-3(2H
one
5-[(5-Acetyl-2-9thyl-3-oxc-5-phenyl-2.3-dihydropyridazin-4-yl)amino]quinolin9-8-
carboxylic acid
5-Acetyl-2-ethyl-4-[(4-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one
Methyl 3-[4-acetyl-1 -ethyl-5-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-3-
yljbenzoate
5-acetyi-2-ethyl-6-(3-methyiphenyi)-4-[(4-methylpyridin-3-yi)anino]pyn^
one
5-Ac8tyl-2-eLhyl-4-(pyridin-3-ylamino)-6-thien-3-ylpyridazin-3(2H)-one
5-Acetyl-2-ethyl-4-[(2-methylpyridin-3-yl)amino]-6-phenylpyridazin-3(2H)-one
3-(4-Acetyl-5-amino-1-e:hyi-6-oxo-1I6-dihydro-pyrida2in-3-yl)-ben2oic acid methyl
ester
5-Acetyl-2-ethyl-6-(3-methylphenyl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-ohe
5-Acetyl-2-ethyl-6-(3-flLJcrophenyl)-4-(pyridin-3-ylamino)-pyridazin-3(2H)-one
5-Acetyl-2-ethyl-4-[(4-me:hylpyridin-3-yl)amino]-6-pyridin-4-ylpyrid3zin-3(r2H)-one
5-Acetyl-2-9thyl-4-[(4-me:hylpyridin-3-yl)amino]-6-pyridin-3-ylpyrid3zin-3(2H)-one
5-Acetyl-4-[(2-chioropyricin-3-yl)aminc]-2-ethyl-6-phenylpyridazin-3(2H)-one
5-Ac8tyl-2-ethyi-5-pyridin-3-yl-4-(pyridin-3-ylamino)pyridazin-3(2H)-one 5-Ac3tyl-2-ethyi-5-(4-methylphenyl)---f(4-methylpyridin-3-yl)amino]pync2
one 5-Ac9tyl-2-e^yi-o-phenyl-4-(thierc[2.3-b]pyridin-3-ylarninc)py
19. A process ~cr the preparation of a compound of formula (XXiV):
wherein R1, R"1, R3, R^ have the meanings defined in-any of claims 1 to 14, wherein each G-, G2, G-, and d independently represent a nitrogen or carbon atom, Y represents an 0 atom, a S atom cr an -NH- group and the benzene ring may optionally be substituted by one or more substituents, which process comprises reacting a carboxylic acid ester of formula (VII)
D- rwherein R1, R*f R3 and R^are as defined in any one of claim 1 to 12. with an ortho-subtituted aniline of formula (VIII) in the presence of a dehydrating agent,
wherein each G1f G-, G3 anc 3* indspencently represent a nitrogen or carbon atom and Y represents an amino. .rercapio or hydroxy group.
20. A compound of formula ?XXV)
wherein M2 is either a hydrogen atom or a group R2 and M3 is either a hydrogen atom or a group R3 wherein R\ R\ R3, R4 and R7 are as defined in any of claims 1 to 15.
21. A compound according tc ciaim 20, which is ethyi 4-acetyl-5-amino-1-ethyl-S-oxo-1,6-dihydropyridazine-3-carboxylate.
22. A compound according tc any one of claims 1 to 18 for use in the treatment of the human or animal body.
23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 mixed with a pharmaceuticaily acceptable diluent or carrier.
24. Use of a compound according to any one of claims 1 to 18, in the manufacture of a medicament for the treatment or prevention of a pathological condition or disease -susceptible to amelioration by inhibition of phosphodiesterase 4.
25. Use according to claim 24, wherein tne medicament is for use in the treatment or prevention cf a disorder which is asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritable bowel disease.
25. A combination product comprising:
(i) a compounc accorcing to any one of claims 1 :o 13; and
(ii) another compound selected from (a) steroids, o) immunosuppressive agents, (c) T-cell receptor blockers and (d) ar.::inflammatcny drugs for simultaneous, separate or sequential use in the treatment of the human or aninai body-
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