SK286972B6 - Arylpyridazinones as prostaglandin endoperoxide H synthase biosynthesis inhibitors, use thereof and pharmaceutical composition containing them - Google Patents

Abstract

Described are pyridazinone compounds of formula (I) which are cyclooxygenase inhibitors, and in particular, are selective inhibitors of cyclooxygenase-2 (COX-2), which is the inducible isoform associated with inflammation, as opposed to the constitutive isoform, cyclooxygenase-1 (COX-1) which is an important "housekeeping" enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys. The selectively of these compounds for COX-2 minimizes the unwanted GI and renal side-effects seen with currently marketed non-steroidal anti-inflammatory drugs (NSAIDs).

Description

Technical field

The present invention includes novel pyridazinone compounds which are useful in the treatment of cyclooxygenase-2 diseases. More particularly, the present invention relates to a method of inhibiting prostaglandin biosynthesis, in particular induced prostaglandin endoperoxide H synthase protein (PGHS-2, cyclooxygenase-2, COX-2).

BACKGROUND OF THE INVENTION

Prostaglandins are potent substances that produce a variety of biological effects, often from nanomolar to picomolar concentrations. The discovery of two forms of prostaglandin endoperoxide H synthase, the PGHS-1 and PGHS-2 isoenzymes, which catalyze the oxidation of arachidonic acid, leading to the biosynthesis of prostaglandins, results in renewed research to clarify the role of these two isozymes in physiology and pathophysiology. These isozymes have been shown to have different gene regulations and to represent different prostaglandin biosynthesis pathways. The PGHS-1 biosynthesis pathway constitutively occurs in most cell types. This corresponds to the production of prostaglandins, which regulate acute cases in vascular homeostasis, and also plays a role in maintaining gastric and renal function in a normal state. The PGHS-2 biosynthesis pathway relates to the induction of mechanisms that have been associated with inflammation, mitogenesis and ovulation phenomena.

Prostaglandin inhibitors provide therapies for pain, fever and inflammation and also serve as useful therapies, e.g. in the treatment of rheumatoid arthritis and osteoarthritis. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and phenamates inhibit both isozymes. Inhibition of the constitutive enzyme PGHS-1 results in gastrointestinal side effects including ulcers, bleeding and the occurrence of renal problems with chronic therapy. Inhibitors of induced isozyme PGHS-2 may have anti-inflammatory activity without the side effects of PGHS-1 inhibitors.

The problem of NSAID-related side effects has never been solved in the past. Enteric-coated tablets and co-administration with mizoprostol, a prostaglandin derivative, have been tested in attempts to minimize toxic effect in the stomach. It is clear that the discovery of compounds that are selective inhibitors of induced PGHS-2 isozyme will be very advantageous.

The present invention discloses novel compounds that are selective inhibitors of PGHS-2.

All patents, patent applications, and references cited in the specification are incorporated herein by reference in their entirety. In cases where inconsistencies occur, the submitted material, including definitions, will be decisive.

SUMMARY OF THE INVENTION

The present invention provides pyridazinone compounds which are cyclooxygenase (COX) inhibitors and are also selective cyclooxygenase-2 (COX-2) inhibitors. COX-2 is an inducible isoform associated with inflammation as opposed to the constitutive cyclooxygenase-1 (COX-1) isoform, which is an important "maintenance" enzyme in many tissues, including the gastrointestinal tract (GI) and kidney.

The compounds of the present invention have the general formula (I):

wherein X is O;

R is a 6-membered carbon aromatic ring substituted with one or two fluorine atoms, R ¹ is hydroxyC 1 -C ₁₅ alkoxy R is hydrogen and R ² is

SK 286972 Β6

wherein X ¹ is -SO 2, R ⁹ is selected from the group consisting of C Ci5alkylu and amino, the substituent X ² is selected from the group consisting of hydrogen and halogen, or a pharmaceutically acceptable salt, ester, or an ester with a C _r C ₆ aliphatic carboxylic acid.

According to a preferred embodiment, the compounds of the invention have the general formula (I) wherein X ¹ is -SO 2 -, R ⁹ is selected from the group consisting of -CH 3 and -NH ₂ , X ² is hydrogen, X is O, substituent R is selected from the group consisting of 3,4-difluorophenyl and 4-fluorophenyl, R ¹ is selected from the group consisting of 2-hydroxy-2-methyl-1-propoxy, 3-hydroxy-3-methyl-1-butoxy and 3-hydroxy-2-methyl-l-propoxy group, R ³ is H, or a pharmaceutically acceptable salt, ester, or an ester with a C _r C ₆ aliphatic carboxylic acid.

Definitions of terms

The following terms used in this specification and the appended claims are defined as follows:

The term "protecting groups" includes "carboxy protecting groups" and "N-protecting groups". The term "carboxy-position-protecting group" as used herein refers to an ester group that protects the carboxylic acid used to block or protect the carboxyl group, whereas the reaction itself concerns only other functional groups of the compound. Protecting groups at the carboxy position are published in Greene, "Protective Groups in Organic Synthesis", 152-186 (1981), incorporated herein by reference. In addition, a carboxy-protecting group can be used as a prodrug, whereby the carboxy-protecting group can be readily cleaved in vivo, for example by enzymatic hydrolysis, to release the biologically active parent. T. Higuchi and V. Stella provide a complete view of drug precursors in the book "Pre-drugs as Novel Delivery Systems", Vol 14 of the ACS Symposium Serie, American Chemical Society (1975), incorporated herein by reference. Such carboxy protecting groups are well known to those of skill in the art since they have been widely used in the protection of carboxyl groups in the penicillin and cephalosporin regions as disclosed in U.S. Patent Nos. 3,840,556 and 3,719,667, incorporated herein by reference. Examples of esters useful as prodrugs for carboxylic acid containing compounds can be found on pages 14-21 of the book "Bioreversiblc Carriers in Drug Design: Theory and Application", published by EB Roche, Pergamon Press, New York (1987), incorporated herein by reference. . Representative protecting groups at the carboxy position are C 1 -C ₈ alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkylalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl and the like; cycloalkyl and substituted derivatives thereof, such as cyclohexylmethyl, cyclopentylmethyl and the like; arylalkyl e.g. phenethyl or benzyl and substituted derivatives thereof, such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl e.g. phenyletenyl and the like; aryl and substituted derivatives thereof e.g. 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1- (propionyloxy) -1-ethyl, 1- (pivaloyloxy) -1-ethyl, 1-methyl-1- (propionyloxy) -1-ethyl, pivaloyloxymethyl , propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-1-ethyl and the like; alkoxycarbonyloxyalkyl such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and the like; alkoxycarbonylaminoalkyl such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl such as acetylaminomethyl and the like; heterocyclic carbonyloxyalkyl such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5- (lower alkyl) -2-oxo-1,3-dioxolen-4-yl) alkyl such as (5-t-butyl-2-oxo-1,3-dioxolen-4-yl) methyl and the like .; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl) alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl and the like.

The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesired reactions during synthesis procedures. Commonly used N-protecting groups are published in Greene's book "Protective Groups in Organic Synthesis", (John Wiley & Sons, New York (1981)), incorporated herein by reference. N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl,

4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, α; α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and cyclohexyloxycarbonyl; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (t-Boc) and benzyloxycarbonyl (Cbz).

The term "alkanoyl" as used herein refers to a defined alkyl group attached to the parent molecular moiety through a carbonyl (-C (O) -) group. Examples of alkanoyl include acetyl, propionyl and the like.

The term "alkanoylamino" as used herein refers to a defined alkanoyl group attached to an amino group. Examples of the alkanoylamino group include acetamido, propionylamido and the like.

The term "alkenyl" as used herein refers to a branched or unbranched chain of hydrocarbon radicals containing 2-15 carbon atoms, as well as at least one double bond between carbon atoms. Alkenyl groups include e.g. vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.

The term "alkenylene" denotes a divalent group obtained from a branched or unbranched chain of hydrocarbon radicals containing 2-15 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenylene include -CH = CH-, -CH 2 CH = CH-, -C (CH ₃ ) = CH-, -CH 2 CH = CHCH ₂ and the like.

The term "alkenyloxy" as used herein refers to a defined alkenyl group attached to the parent molecular moiety through an oxygen (-O-) bond. Examples of the alkenyloxy group include isopropenoxy, butenyloxy and the like.

The term "alkoxy" as used herein refers to R 41 -O-, wherein R 41 is defined as a lower alkyl group. Examples of the alkoxy group include, but are not limited to, an ethoxy group, an isobutyloxy group, an isopentyloxy group, a tert-butoxy group, and the like.

The term "alkoxyalkylamino" as used herein refers to a defined alkoxy group attached to the parent molecular moiety through a defined alkylamino group. Examples of the alkoxyalkylamino group include, but are not limited to, ethoxymethylamino, isobutyloxyethylamino, and the like.

The term "alkoxyalkoxy" as used herein refers to R ₈₀ or _ion-8, wherein R ₈₀ is as defined lower alkyl and R ₈ and R is alkylene. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.

The term "alkoxycarbonyl" as used herein refers to a defined alkoxy group attached to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.

The term "alkoxycarbonylalkenyl," as used herein, refers to a defined alkoxycarbonyl group attached to an alkenyl radical. Examples of alkoxycarbonylalkenyl include methoxycarbonyletenylene, ethoxycarbonylpropenylene and the like.

The term "alkoxyalkoxyalkyl," as used herein, refers to a defined alkoxyalkoxy group attached to an alkyl radical. Examples of alkoxyalkoxyalkyl include methoxyethoxyethyl, methoxymethoxymethyl and the like.

The term "alkoxyalkoxyalkenyl," as used herein, refers to a defined alkoxyalkoxy group attached to an alkenyl radical. Examples of alkoxyalkoxyalkenyl include methoxyethoxyethenyl, methoxymethoxymetenyl and the like.

The term "alkoxyalkyl," as used herein, refers to a defined alkoxy group attached to a defined alkyl radical. Examples of alkoxyalkyl groups include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

The term "(alkoxycarbonyl) thioalkoxy" as used herein refers to a defined alkoxycarbonyl group attached to a thioalkoxy radical. Examples of (alkoxycarbonyl) thioalkoxy groups include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.

The term "alkyl" and "lower alkyl" as used herein refers to a branched or unbranched chain of alkyl radicals containing from 1 to 15 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

The term "alkylamino" as used herein refers to R ₅₁ NH, wherein R ₅₁ is a lower alkyl group e.g. ethylamino, butylamino and the like.

The term "alkylaminoalkyl," as used herein, refers to a lower alkyl radical to which an alkylamino group is attached.

The term "alkylaminocarbonyl" as used herein refers to a defined alkylamino group attached to the parent molecular moiety through a carbonyl (-C (O) -) bond. Examples of alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like.

The term "alkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which an alkylaminocarbonyl group is attached.

The term "alkylcarbonylalkyl," as used herein, refers to R 40 -C (O) -R 11 -, wherein R 40 is an alkyl group and R 41 is an alkylene group.

The term "alkylene" refers to a divalent group obtained from a branched or unbranched chain of a saturated hydrocarbon having 1-15 carbon atoms by removing two hydrogen atoms e.g. -CH ₂ -, -CH ₂ CH ₂ -, -CH (CH ₃ ) -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ C (CH ₃ ) ₂ CH ₂ - and the like.

The term "alkylsulfonyl," as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group (-S (O) ₂ -). Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like.

The term "alkylsulfonylalkyl" as used herein refers to a defined alkyl group attached to the parent molecular moiety through a sulfonylalkyl group (-S (O) ₂ -R-). Examples of alkylsulfonylalkyl include methylsulfonylmethyl, ethylsulfonylmethyl, isopropylsulfonylethyl and the like.

The term "alkylsulfonylamino" as used herein refers to a defined alkyl group attached to the parent molecular moiety through a sulfonylamino (-S (O) ₂ NH-) group. Examples of the alkylsulfonylamino group include a methylsulfonylamino group, an ethylsulfonylamino group, an isopropylsulfonylamino group, and the like.

The term "alkylsulfonylarylalkyl, as used herein, refers to an alkyl group as defined appended to the parent molecular moiety through a sulfonylalkyl group (-S (O ₂₎ -R 4 ₅ R ₃₃₎ wherein R 45 is aryl and R ₃₃ is alkylene. Examples of alkylsulfonylarylalkyl include methylsulfonylphenylmethyl, ethylsulfonylphenylmethyl, isopropylsulfonylphenylethyl and the like.

The term "alkylthio" as used herein refers to R ₅₃ S-, wherein R ₅₃ is alkyl.

The term "alkylthioalkyl", as used herein, refers to a defined alkylthio group attached to the parent molecular moiety through an alkylene group.

The term "alkylthioalkoxy" as used herein refers to a defined alkylthio group attached to the parent molecular moiety through a defined alkoxy group.

The term "alkynyl" as used herein refers to a branched or unbranched chain of hydrocarbon radicals containing 2-15 carbon atoms, as well as at least one triple bond between carbon atoms. Examples of alkynyl include -C =CH, H-OC-CH ₂ -, HC = C-CH (CH ₃ ) - and the like.

The term "amido" as used herein refers to R ₅₄ -C (O) -NH-, wherein R ₅₄ is alkyl.

The term "amidoalkyl" as used herein refers to R ₃₄ -C (O) -NHR ₃₅ -, wherein R ₃₄ is alkyl and R _{35 is} alkylene.

The term "amino" as used herein refers to H ₂ N-.

The term "aminoalkoxy" as used herein refers to an amino group attached to the parent molecular moiety through an alkoxy group.

The term "aminocarbonyl," as used herein, refers to H ₂ NC (O) -.

The term "aminocarbonylalkyl" as used herein refers to said aminocarbonyl group attached to the parent molecular moiety through alkylene.

The term "aminocarbonylalkenyl", as used herein, refers to an alkenyl radical to which an aminocarbonyl (H ₂ NC (O) -) group is attached.

The term "aminocarbonylalkoxy" as used herein refers to H ₂ NC (O) - attached to a defined alkoxy group. Examples of the aminocarbonylalkoxy group include an aminocarbonylmethoxy group, an aminocarbonylethoxy group, and the like.

The term "aroyloxyalkyl" as used herein refers to R ₃₂ -C (O) -OR ₃₃ - wherein R ₃₂ is an aryl group and R ₃₃ is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.

The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups may be unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of lower alkyl, halo, haloalkyl, haloalkoxy, hydroxy, oxo (= O), hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl , alkoxycarbonylalkenyl, (alkoxycarbonyl) thioalkoxy groups, thioalkoxy groups, alkylimino (R * N = wherein R * is lower alkyl), amino groups, alkylamino groups, alkylsulfonyl, dialkylamino groups, aminocarbonyl, aminocarbonylalkoxy groups, alkanoylamino groups, aryl, arylalkyl groups, arylalkyl groups , aryloxy groups, mercapto groups, cyano groups, nitro groups, carboxaldehyde, carboxy groups, carboxamide, cycloalkyl, carboxyalkenyl, carboxyalkoxy groups, alkylsulfonylamino groups, cyanoalkoxy groups, heterocyclic alkoxy groups, -SO ₃ H, hydroxyalkoxy groups, phenyl and tetrazolylalkoxy groups. In the case of halogen, ar The yl may have 5 halogen substituents. Examples of substituted aryl include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-methylsulfonylphenyl, pentafluorophenyl and the like.

The term "arylalkenyl, as used herein," refers to an alkenyl radical to which an aryl group, e.g. phenyletenyl and the like.

The term "arylalkinyl" as used herein refers to an alkynyl radical to which an aryl group, e.g. phenyletinyl and the like.

The term "arylalkoxy" as used herein refers to R 42 O-, wherein R < ₂ is an arylalkyl group e.g. benzyloxy group and the like.

The term "arylalkoxyalkyl," as used herein, refers to a lower alkyl radical to which an arylalkoxy group, e.g. benzyloxymethyl and the like.

The term "arylalkyl" as used herein refers to a defined aryl group attached to a lower alkyl radical e.g. benzyl and the like.

The term "arylalkylamino" as used herein refers to a defined arylalkyl group attached to the parent molecular moiety through an amino group.

The term "arylalkylthio" as used herein refers to a defined arylalkyl group attached to the parent molecular moiety through a thiol group.

The term "arylamino" as used herein refers to R 45 NH 2 -, wherein R 45 is aryl.

The term "arylcarbonylalkyl," as used herein, refers to R ₄ C (O) R ₃₃ - wherein R 45 is an aryl group and R ₃₃ is an alkylene group.

The term "arylhaloalkyl" as used herein refers to a defined aryl group attached to the parent molecular moiety through a defined haloalkyl. Examples of arylhaloalkyl include phenyl-2-fluoropropyl and the like.

The term "arylhydroxyalkyl" as used herein refers to a defined aryl group attached to the parent molecular moiety through a defined hydroxyalkyl. Examples of hydroxyalkyl include phenyl-2-hydroxypropyl and the like.

The term "aryloxy" as used herein refers to R 45 O-, wherein R 45 is an aryl group e.g. a phenoxy group and the like.

The term "aryloxyalkyl," as used herein, refers to a defined aryloxy group attached to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like.

The term "aryloxyhaloalkyl," as used herein, refers to a defined aryloxy group attached to the parent molecular moiety through a defined haloalkyl. Examples of aryloxyhaloalkyl include phenyloxy-2-fluoropropyl and the like.

The term "aryloxyhydroxyalkyl" as used herein refers to a defined aryloxy group attached to the parent molecular moiety through a defined hydroxyalkyl. Examples of aryloxyhydroxyalkyl include phenoxy-2-hydroxypropyl and the like.

The term "carboxaldehyde" as used herein refers to the formaldehyde radical, -C (O) H.

The term "carboxamide," as used herein, refers to NH ₂ -C (O) -.

The term "carboxy," as used herein, refers to a carboxylic acid radical, -C (O) OH.

The term "carboxyalkyl," as used herein, refers to a defined carboxy group attached to a defined alkyl radical. Examples of carboxyalkyl include 2-carboxyethyl, 3-carboxy-1-propyl and the like.

The term "carboxyalkenyl," as used herein, refers to a defined carboxy group attached to a defined alkenyl radical. Examples of carboxyalkenyl include 2-carboxyethenyl, 3-carboxy-1-ethenyl and the like.

The term "carboxyalkoxy" as used herein refers to a defined carboxy group attached to a defined alkoxy radical. Examples of the carboxyalkoxy group include a carboxymethoxy group, a carboxyethoxy group, and the like.

The term "cyano" as used herein refers to a cyano group (-CN).

The term "cyanoalkyl" as used herein refers to a defined alkyl radical to which a cyano (-CN) group is attached. Examples of cyanoalkyl include 3-cyanopropyl, 4-cyanobutyl and the like.

The term "cyanoalkoxy" as used herein refers to a cyano group (-CN) attached to the parent moiety through an alkoxy radical. Examples of the cyanoalkoxy group include a 3-cyanopropoxy group, a 4-cyanobutoxy group, and the like.

The term "cycloalkanoyloxyalkyl," as used herein, refers to a lower alkyl radical to which a cycloalkanoyloxy group is attached (namely, R 10 -Q 10 -O-, wherein R 10 is cycloalkyl).

The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3-10 carbon atoms and 1-3 rings, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl groups may be unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of hydroxy, halogen, oxo (= O), alkylimino (R * N = wherein R * is lower alkyl), amino groups , alkylamino groups, dialkylamino groups, alkoxy groups, alkoxyalkoxy groups, alkoxycarbonyl, thioalkoxy groups, haloalkyl, mercapto groups, carboxy groups, carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl, -SO ₃ H, nitro groups, cyano groups and lower alkyl.

The term "cycloalkenyl" as used herein refers to an aliphatic ring system having 3-10 carbon atoms and 1-3 rings containing at least one double bond in the ring structure. Cycloalkenyl groups may be unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of hydroxy, halogen, oxo (= O), alkylimino (R * N = wherein R * is lower alkyl), amino groups , alkylamino groups, dialkylamino groups, alkoxy groups, alkoxyalkoxy groups, alkoxycarbonyl, thioalkoxy groups, haloalkyl, mercapto groups, carboxy groups, carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl, -SO ₃ H, nitro groups, cyano groups and lower alkyl.

The term "cycloalkylalkyl," as used herein, refers to a cycloalkyl group attached to a lower alkyl radical, including but not limited to cyclohexylmethyl.

The term "cycloalkoxy," as used herein, refers to a cycloalkyl group attached to a defined alkoxy group including, but not limited to, cyclohexylmethyloxy.

The term "cycloalkylamino" as used herein refers to a cycloalkyl group attached to the parent molecular moiety through a defined amino group including, but not limited to, cyclohexylamino groups and the like.

The term "cycloalkylalkylamino" as used herein refers to a cycloalkyl group attached to the parent molecular moiety through a defined alkylamino group including, but not limited to, cyclohexylmethylamino groups and the like.

The term "cycloalkylidenalkyl" as used herein refers to a cycloalkyl group attached to the parent molecular moiety through a double bond that attaches alkylene (= (CH ₂ ) _n ) -. Examples include cyclopropylidenemethyl, cyclobutylidenenopropyl and the like.

The term "cycloalkyloxy" as used herein refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom, including, but not limited to, cyclohexyloxy groups and the like.

The term "cycloalkenylalkyl," as used herein, refers to a cycloalkenyl group attached to a lower alkyl radical, including, but not limited to, cyclohexenylmethyl.

The term "cycloalkenylalkoxy" as used herein refers to a cycloalkenyl group attached to a defined alkoxy group including, but not limited to, cyclohexenylmethyloxy groups and the like.

The term "dialkylamino" as used herein refers to (R _{5 S)} (R ₅ 7) N-, wherein the substituents R ₅₆ and R ₅₇ are independently selected from the group consisting of lower alkyl, e.g. diethylamino groups, methylpropylamino groups and the like.

The term "dialkylaminoaryloxy" as used herein refers to a defined dialkylamino group attached to the parent molecular moiety through said aryloxy group.

The term "diarylamino" as used herein, refers to (R 1, X R 1, N-, wherein R 45a are independently aryl such as diphenylamino and the like.

The term "dialkylaminoalkyl" as used herein refers to a lower alkyl radical to which a dialkylamino group is attached.

The term "dialkylaminocarbonyl" as used herein refers to a defined dialkylamino group attached to the parent molecular moiety through a carbonyl (-C (O) -) bond. Examples of dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.

The term "dialkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which a dialkylaminocarbonyl group is attached.

The term "dialkylaminocarbonylalkyl," as used herein, refers to R ₅₀ -C (O) -R _{5 '} - wherein R ₅₀ is a dialkylamino group and R 51 is alkylene.

The term "halo" or "halogen" as used herein refers to iodine, bromine, chlorine or fluorine.

The term "haloalkyl" as used herein refers to a defined alkyl radical having at least one halogen substituent e.g. chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl, 2,3-difluoropentenyl and the like.

The term "haloalkenyl" as used herein refers to an alkenyl radical having at least one halogen substituent e.g. chlorometenyl, fluoroethenyl, trifluorometenyl or pentafluoroethenyl, 2,3-difluoropentenyl and the like.

The term "haloalkenyloxy" as used herein refers to a defined haloalkenyl group attached to the parent molecular moiety through an oxygen atom.

The term "haloalkynyl" as used herein refers to an alkynyl radical having at least one halo substituent e.g. chloromethynyl, fluoroethynyl, trifluoromethynyl or pentafluoroethynyl, 2,3-difluoropentinyl and the like.

The term "haloalkoxy" as used herein refers to a defined alkoxy radical having at least one halogen substituent e.g. 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3, pentafluoropropoxy and the like.

The term "haloalkoxyalkyl". as used herein refers to a lower alkyl radical to which a haloalkoxy group is attached.

The term "haloalkoxyhydroxyalkyl" as used herein refers to a defined haloalkoxy group attached to the parent molecular moiety through a defined hydroxyalkyl.

The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein refers to any 3-membered or 4-membered ring containing a heteroatom selected from oxygen, sulfur or nitrogen; or a 5-membered, 6-membered or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen atom and one sulfur atom; one nitrogen atom and one oxygen atom; two oxygen atoms that are not in an adjacent position; one oxygen atom and one sulfur atom not in an adjacent position; or two sulfur atoms that are not in an adjacent position. Examples of heterocycles include, but are not limited to, thiophene, pyrrole and furans. The 5-membered ring has 0-2 double bonds and the 6-membered and 7-membered rings have 0-3 double bonds. Nitrogen heteroatoms may optionally be quatized. The terms "heterocyclic" include bicyclic groups in which any of said heterocyclic rings is fused to a benzene ring or a cycloalkane ring, or another heterocyclic ring (e.g., indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroisoquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroquinolyl, decahydroisoquinolyl, decahydroisoquinolyl, decahydroisoquinolyl, decahydroisoquinolyl) or benzothienyl and the like). Heterocycles include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazinyl, oxazinyl, oxazinyl, oxazinyl, oxazinyl, oxazinyl, oxazinyl, oxazinyl, oxazinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxolyl, isoxolyl, isoxolyl, isoxolyl, isoxolyl, isoxolyl, isoxolyl,

Heterocyclic rings also include compounds of formula wherein X * is -CH ₂ - or -O- and Y * is -C (O) - or [-C (R ") ₂ ] v, wherein R" is an atom H or C _r C 4 -alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like.

Heterocycles also include bicyclic rings such as quinuclidinyl and the like.

Heterocycles may be unsubstituted or substituted with substituents independently selected from the group consisting of hydroxy, halogen, oxo (= O), alkylimino (R * N = wherein R * is lower alkyl), amino, alkylamino, dialkylamino , alkoxy groups, alkoxyalkoxy groups, alkoxycarbonyl, thioalkoxy groups, haloalkyl, mercapto groups, carboxy groups, carboxyaldehyde, carboxyamide, cycloalkyl, aryl, arylalkyl, -SO ₃ H, nitro groups, cyano groups and lower alkyl. In addition, heterocycles containing a nitrogen atom may be N-protected.

The term "(heterocyclic group) alkoxy" as used herein refers to a defined heterocyclic group attached to a defined alkoxy radical. Examples (heterocyclic groups and alkoxy groups include

A 4-pyridylmethoxy group, a 2-pyridylmethoxy group, and the like.

The term "(heterocyclic groupamino), as used herein, refers to a defined heterocyclic group attached to a defined amino group. Examples of (heterocyclic group) amino groups include

A 4-pyridylamino group, a 2-pyridylamino group, and the like.

The term "(heterocyclic group) oxy" as used herein refers to a defined heterocyclic group attached to the parent molecular moiety through a molecule atom. Examples of the (heterocyclic group) oxy group include a 4-pyridyloxy group, a 2-pyridyloxy group, and the like.

The term "(heterocyclic-alkyl)" as used herein refers to a defined heterocyclic group attached to a defined lower alkyl radical.

The term "(heterocyclic group jalkylamino)" as used herein refers to a defined heterocyclic group attached to a defined alkylamino group.

The term "(heterocyclic) carbonyloxyalkyl" as used herein refers to R ₁₆ -C (O) -O-R 47 -, wherein R ₁₆ is a heterocyclic group and R 47 is an alkylene group.

The term "(heterocyclicthio), as used herein, refers to a defined heterocyclic group attached to the parent moiety through a thiol group. Examples (heterocyclicthio groups include 4-pyridylthio, 2-pyridylthio, and the like).

The term "hydroxy" as used herein refers to -OH.

The term "hydroxyalkenyl," as used herein, refers to an alkenyl radical to which a hydroxy group is attached. Examples of the hydroxyalkenyl group include a 3-hydroxypropenyl group, a 3,4-dihydroxybutenyl group, and the like.

The term "hydroxyalkoxy" as used herein refers to a defined alkoxy radical to which a hydroxy group (-OH) is attached.

Examples of the hydroxyalkoxy group include a 3-hydroxypropoxy group, a 4-hydroxybutoxy group, and the like.

The term "hydroxyalkyl" as used herein refers to a lower alkyl radical to which a hydroxy group is attached. Examples of the hydroxyalkyl group include 1-hydroxypropyl, 4-hydroxybutyl, 1,3-dihydroxyisopentyl and the like.

The term "hydroxyalkylamino" as used herein refers to a hydroxyalkyl group attached to the parent molecular moiety through an amino group. Examples of the hydroxyalkylamino group include 1-hydroxypropylamino, 4-hydroxybutylamino, 1,3-dihydroxyisopentylamino, and the like.

The term "hydroxyalkylthio" as used herein refers to a hydroxyalkyl group attached to the parent molecular moiety through a thiol group. Examples of the hydroxyalkylamino group include 1-hydroxypropylthio, 4-hydroxybutylthio, 1,3-dihydroxyisopentylthio, and the like.

The term "mercapto" or "thiol" as used herein refers to -SH.

The term "nitro" as used herein refers to -NO ₂ .

The term "oxoalkoxy" refers to a carbonyl group attached to the parent molecular moiety through an alkoxy group.

The term "mercaptoalkoxy" or "thioalkoxy" as used herein refers to R ₇₀ S-, wherein R ₇₀ is an alkoxy group. Examples of the thioalkoxy group include, but are not limited to, methylthio, ethylthio, and the like.

The term "tetrazolyl," as used herein, refers to a radical of the formula or its tautomeric form.

N-N

The term "tetrazolylalkoxy," as used herein, refers to a defined tetrazolyl radical attached to a defined alkoxy group. Examples of the tetrazolylalkoxy group include a tetrazolylmethoxy group, a tetrazolylethoxy group, and the like.

The term "thioalkoxyalkoxy" as used herein refers to R ₈₀ SR ₈₁ O-, wherein R ₈₀ is defined as lower alkyl and R ₅₁ is alkylene. Representative examples of alkoxyalkoxy groups include CH ₃ SCH ₂ O-, CH ₃ CH ₂ SCH ₂ O-, t-BuSCH ₂ P- and the like.

The term "thioalkoxyalkoxyalkyl" as used herein refers to a thioalkoxyalkoxy group attached to an alkyl radical. Representative examples of the thioalkoxyalkoxyalkyl group include CH ₃ SCH ₂ CH ₂ OCH ₂ CH ₂ -, CH ₃ SCH ₂ OCH ₂ - and the like.

The compounds of the present invention may be used in the form of salts derived from inorganic or organic acids. These salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphate, camphrosulfonate, digluconate, cyclopentane propionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glucoheptanoate, glucoheptanoate, glucoheptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, pirate, pivalucate, propionate, propionate, propionate, propionate, propionate, propionate thiocyanate, p-toluenesulfonate and undecanoate. Also, basic nitrogen-containing groups can be quatified by such agents as lower alkyl halides such as methyl chloride, ethyl chloride, propyl chloride and butyl chloride, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl chloride, lauryl chloride, myristyl chloride and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl bromide and phenethyl bromide and others. As a result, water-soluble or oil-soluble or dispersible products are obtained.

Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and such organic acids as oxalic acid, maleic acid, succinic acid, and citric acid. Base addition salts may be prepared in situ during the final isolation and purification of the compounds of formula (I) or separately by reacting the carboxylic acid with a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or ammonia, or with an organic primary, secondary or a tertiary amine. Such pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, aluminum and the like, as well as non-toxic cations of ammonium, quaternary ammonium, amine including, but not limited to, ammonia, tetramethyl ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Other representative organic amines useful for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

The term "pharmaceutically acceptable ester" as used herein refers to esters that hydrolyze in vivo and include those esters that readily tear off in the human body and leave the parent compound or salt thereof. Suitable ester groups include e.g. those groups obtained from pharmaceutically acceptable aliphatic carboxylic acids, in particular alkanoic, alkene, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety preferably has no more than 6 carbon atoms. Examples of individual esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates.

The term "pharmaceutically acceptable prodrug" as used herein refers to prodrugs of the compounds of the present invention, to the extent of sound medical judgment suitable for use in contact with human and lower animal tissues without toxicity, irritation, allergic reactions and the like. proportional to the reasonable benefit / risk ratio and effective for their intended use, as well as possible forms of zwitterion, where possible, of the compounds of the invention.

The term "prodrug" as used herein refers to a compound that rapidly transforms in vivo to the parent compound of the formula e.g. hydrolysis in the blood. A thorough discussion of this can be found in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of te A.C.

S. Symposium Šerieš, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

The term "metabolic cleavable moiety" refers to a moiety that is readily cleaved from the parent compound in vivo, whereby said compound remains or becomes pharmacologically active upon cleavage. Metabolic cleavable groups form a kind of carboxyl group reactive groups of the compounds of this invention, as is known in the art. Examples include, but are not limited to, groups such as e.g. alkanoyl, e.g. acetyl, propionyl, butyryl and the like; unsubstituted and substituted aroyls such as e.g. benzoyl and substituted benzoyl; alkoxycarbonyl such as e.g. ethoxycarbonyl; trilakylsilyl such as e.g. trimethyl- and triethylsilyl; monoesters formed with dicarboxylic acids such as e.g. succinyl and the like. To mitigate with which the metabolic cleavable groups of the invention are cleaved in vivo, the compounds have those groups that react as prodrugs of other prostaglandin biosynthesis inhibitors. Compounds bearing metabolic cleavable groups have the advantage that they may have improved bioavailability as a result of increased solubility and / or absorption rates of the parent compound by the preferential presence of a metabolic cleavable group.

The compounds of the present invention may have appropriate asymmetric centers. The present invention relates to their various stereoisomers and mixtures thereof. The individual stereoisomers of the compounds of the present invention are formed in the synthesis from starting materials having chiral centers or by preparing a mixture of enantiomeric products followed by separation such as e.g. conversion to a mixture of diastereoisomers followed by separation by recrystallization or chromatographic techniques or by direct separation of optical enantiomers on chiral chromatography columns. The starting compounds in a single stereochemistry are either commercially available and / or are prepared by the above methods and resolved into enantiomers by techniques well known in the art of organic chemistry.

Preferred embodiments of the compounds of the present invention include, but are not limited to, the following: 2- (2,2,2-trifluoroethyl) -4- (4-chlorophenyl) -5- [4- (ammosulfonyl) phenyl) -3 (2H) - -pyridazinoneThe; 2- (4-fluorophenyl) -4- (3-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3-chlorophenyl) -4- (3-methyl-3-butenoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (2.2.2-trifhióretyl) -4- (4-chloro-3-fluorophenyl) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (4-fluorophenyl) -4- (4-fluorophenyl) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-Difluorophenyl) -4- (3-fluorophenyl) -5- [4- (methylsulfonyl) phenyl) -3 (2H) -pyridaziiión; 2- (3,4-difluorophenyl) -4- (2-hydroxy-2-methyl-l-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (4-fluorophenyl) -4- (3-hydroxy-3-methyl-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (t-butyl) -4- (3-methyl-butoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone;

2- (t-butyl) -4- (3-methyl-butoxy) -5- [4- (methylsulfonyl) phenyl) -3 (2H) -pyridazinone; 2- (2,2,2-trifluoroethyl) -4- (2,2-Dimethyl-propoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (2,2,2-trifluoroethyl) -4- (2-methyl-propoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-Difluorophenyl) -4- (3-methyl-butoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (4-fluorophenyl) -4- (3-methylbutyl) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3-chlorophenyl) -4- (3-methyl-butoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (4-fluorophenyl) -4- (3-methyl-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3-chlórenyl) -4- (3-methyl-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-difluorophenyl) -4- (2-methyl-propoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3-chlorophenyl) -4- (2-methyl-propoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (4-fluorophenyl) -4- (3-methyl-butoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (4-fluorophenyl) -4- (2-methyl-propoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (4-fluorophenyl) -4- (2-methyl-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-difluorophenyl) -4- (2-methyl-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-Difluorophenyl) -4- (4-fluorophenoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-Difluorophenyl) -4- (3-methyl-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (4-fluorophenyl) -4- (4-fluorophenoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (2,2,2-trifluoroethyl) -4- (2,2-Dimethyl-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (4-chloro-3-fluorophenyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-difluorophenyl) -4- (4-fluorophenoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-Difluorophenyl) -4- (4-fluorophenyl) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-difluorophenyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (4-fluorophenyl) -4- (3-methyl-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone;

2,4-bis (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone;

2- (4-fluorophenyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-difluorophenyl) -4- (2-hydroxy-2-methyl-propoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-difluorophenyl) -4- (2-oxopropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-difluorophenyl) -4- (2-methoxy-imino-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone;

(R) -2- (3,4-difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone;

(S) -2- (3,4-difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3- (2H) -pyridazinone;

(R) -2- (3,4-difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone;

(S) -2- (3,4-difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-Difluorophenyl) -4- (3-oxo-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone;

2- (4-fluorophenyl) -4- (3-oxo-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone;

2,4-Bis (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone or pharmaceutically acceptable salts, esters or prodrugs thereof.

More preferred embodiments of the compounds of the present invention include, but are not limited to, the following:

2-phenyl-4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone; 2- (2,2,2-trifluoroethyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone; 2- (2,2,2-trifluoroethyl) -4- (4-chlorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone; 2- (4-fluorophenyl) -4- (3-methyl-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; 2- (3,4-difluorophenyl) -4- (2-methyl-propoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone;

2,4-Bis (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone or pharmaceutically acceptable salts, esters or prodrugs thereof.

Preparation of the compounds of the invention

The compounds of the invention may be prepared by a variety of synthetic procedures. Representative procedures are outlined in Schemes 1-3.

A general process for the preparation of compounds of formula (III) wherein the aryl group at the 5-position in the pyridazinone ring is substituted with a sulfonyl group is described in Scheme 1. Dichloro-3 (2H) -pyridazinone is reacted with benzyl chloride and potassium carbonate in methanol. Then, 2-benzyl-4-chloro-5-methoxy-3 (2H) -pyridazinone is reacted with boric acid such as 4-fluorobenzeneboronic acid (mentioned) and palladium catalyst. The methoxy group is hydrolyzed with 48% hydrobromic acid to provide the 5-hydroxypyridazinone compound. This product is reacted with trifliic anhydride followed by substitution on the pyridazinone ring using 4-methylthiobenzeneboronic acid. There was thus obtained a methylthioether compound which was then reacted with peracetic acid in acetic acid and methylene chloride to give methylsulfone. The benzyl group is removed using AlBr ₃ or other

A suitable Lewis acid. The substituent group R can be added via substitution using the appropriate alkylating agent and base.

Scheme 1

K2CQ3. RX anhyd. DMF

Another method for preparing compounds of the invention having formula (III) is described in Scheme 2. 4-Bromothioanisole or another suitable thioether is reacted with a trialkoxyborate such as trimethoxyborate or triisopropylborate to convert to 4- (methylthio) benzeneboronic acid. Boric acid is reacted with 2-benzyl-4,5-dibromo-3 (2H) -pyridazinone with tetrakis (triphenylphosphine) palladium in dimethoxyethane. The product is then coupled with a second boric acid such as 4-fluorobenzeneboronic acid (mentioned) and palladium catalyst to yield the thioether. There was thus obtained a methylthioether compound which was reacted with meta-chloroperoxybenzoic acid (MCPBA) in methylene chloride to give methylsulfone. The benzyl group is removed with AlBr ₃ or another suitable Lewis acid. The substituent group R can be added via substitution using the appropriate alkylating agent and base.

Scheme 2

B (OH) ₂

1) n-BuLi, (MeO) ₃ B, THF, -78 · C

2) 10% NaOH, water, THF, RT

SK 286972 Β6

A third process for preparing compounds of the invention having formula (ΠΙ) is described in Scheme 3. Mono-S-oxide - [(4-thiomethylphenyl) dimethylthioketeneacetal is prepared by reacting 4-thiomethylbenzaldehyde (Y is CH ₃ S) with methyl (methylsulfmethylmethyl) sulfide and sodium hydroxide. Thioketeneacetal and methyl (4-fluorophenylacetate) or a suitable ester (substituent X is fluoro) are reacted with a strong base such as sodium hexamethyldisilazide 5 in THF to give the butyrate ester. The dithioacetalketene is directly cyclized to unsubstituted pyridazinone using hydrazine and salt. Pyridazinone is oxidized with peroxyacetic acid to give sulfonylpyridazone. Alternatively, Scheme 3-A may be followed by reacting the thioacetalketene with perchloric acid to provide the aldehyde ester as a mixture of diastereomers. The oxidation products are reacted with hydrazine and then oxidized with peracetic acid to give the sulfonyldihydropyridazinone. Dihydro10 pyridazinone can be dehydrogenated to pyridazinone by treatment with agents such as bromine in acetic acid. The R group can be added by substitution with a suitable alkylating agent and a base.

Scheme 3

O ₂ CH ₃

NaHMDS, 0 ° C THF

Scheme 3

K ₂ CO ₃ RX DMF RT

SK 286972 Β6

K ₂ CO ₃ RX

DMF, RT

The preparation of 5-hydroxy-2 (5H) -furanones can be achieved by applying a published methodology, including:

J. Med. Chem., 1987, 30, 239-249 and WO 96/36623, both incorporated herein by reference, and is shown in Scheme 4.

Scheme 4

Method IV

about R ABOUT NH 3 NH 3 .H 2 O 1 1 J. A * Na ₂ CO ₃ , RX ¹ LA Ti NR n-BuOH DMF MeO ₂ S ?. U R ³ Μθθ2θ lj R ³

A general way to prepare compounds of the invention having formula (III) wherein the aryl group at the 5-position in the pyridazinone ring is substituted with a sulfonyl group having a ring structure is described in Scheme 5. Mucohaloic acid such as e.g. mucobromic acid or mucochloride acid 15 is reacted with hydrazine having the desired R group to give the dihalopyridazinone compound 5A. Reaction of dihalogen with an alcohol in the presence of a base such as e.g. sodium hydride or potassium hydride yields alkoxide 5B. (When the alkoxy group is removed later, methanol is more preferred.) Reaction of the alkoxy halide with methylthiophenylboronic acid provides the alkoxypyridazinone 5C. The alkoxy group can be converted to a hydrocarbyl group by reaction with a Grignard reagent to give the thioether 5D. The thioether can be oxidized with an oxidizing agent such as 5 e.g. peracetic acid, meta-chloroperoxybenzoic acid and the like. for forming the sulfinyl compound 5G or the methylsulfone compound 5E. Rearrangement and hydrolysis of the sulfinyl compound 5G affords thiophenol. The thiophenol is then oxidized, activated and aminated to convert to the amino-sulfonyl compound 5H. Alternatively, methylsulfonyl 5E can be converted to aminosulfonyl 5H by reacting methylsulfonyl with a diazodicarboxylate such as e.g. DBAD, D1 AD, DEAD and the like. and a disilazane anion 10 such as e.g. lithium HMDS and the like. followed by treatment with sodium acetate and hydroxylamine-O-sulfonic acid in water to give the aminosulfonyl 5H.

Scheme 5

'1. DBAD / HMDS í 2. NaOH N _____________

3. NaOAc / hydroxylamine O-sulfonic acid / h ₂ o

Alternatively, as shown in Scheme 5A, the alkoxypyridazinone 5C can be oxidized. In a first step, an oxidizing agent such as e.g. peracetic acid, metachloroperoxybenzoic acid and the like. for forming a sulfinyl compound 5G 'or a methylsulfone compound 5E'. Rearrangement and hydrolysis of the sulfinyl compound yields thiophenol. The thiophenol is then oxidized, activated and aminated to convert to the amino-sulfinyl compound 5H '. Finally, the methylsulfonyl compound can be converted to the aminosulfonyl compound 5H 'by reacting the methylsulfonyl compound 5E' with a diazodicarboxylate such as e.g. DBAD, DIAD, DEAD etc. and a disilazane anion such as e.g. lithium HMDS and the like. followed by the reaction of sodium acetate and hydroxylamine-O-sulfonic acid in water to obtain the aminosulfonyl compound of 10 H 5.

Scheme 5A

1. DBAD / HMDS

2. NaOH

3. NaOAc / hydroxylamine O-sulfonic acid / b ^ O

5E '

5H '

The preparation of compounds of the invention having formula (III) wherein the group at the 4-position in the pyridazinone ring is substituted with alkyl or alkenyl is described in Scheme 6A. Thioether 5E wherein R ⁹⁶ is alkyl e.g. methyl (mentioned) is halogenated with a halogenating agent such as e.g. NBS and peroxide to obtain the bromo compound 6A. The bromo compound can be reacted with an alcohol with a weak base such as e.g. sodium carbonate or potassium carbonate to give the 4-alkyl ether 6B. The bromo compound can be reacted with a thi compound in the presence of a base such as e.g. silver carbonate to give 4-alkylthioether 6C. The bromo compound can be reacted with an amine and a weak base such as e.g. sodium carbonate or potassium carbonate to give the 4-alkylamine 6D.

Scheme 6

NBS r ⁹⁵ oh base

R ⁹⁴ SH / base r ⁹³ nh ₂ base

5A

5D

A general process for preparing compounds of the invention having formula (III) wherein the group at the 4-position in the pyridazinone ring can be easily substituted is shown in Scheme 6. The synthesis begins with alkoxide 5E 'where R ⁹⁷ is methyl. The methoxy compound is reacted with a base such as e.g. sodium hydroxide or potassium hydroxide to give 4-hydroxy-pyradisinone 6A. The alcohol is then reacted with p-toluenesulfonyl chloride to provide the tosyloxy compound 6B. The tosyloxy compound can be easily substituted with 10 by the compound R ⁹² Z ', which proceeds through the substitution mechanism S _N 2. Examples of such compounds are e.g. alcohols, thiols, amines or anions of hydrocarbyl.

The following abbreviations used in these descriptions and the appended claims are: ACD for dextrose acid citrate, CAP for prostaglandin-induced carrageenan-induced air sacs, CIP for rat carrageenan-induced pleural inflammation model, COX-2 for cyclooxygenase-2, CPE for carrageenan-induced paw edema in rats, DBAD for di-t-butyl azodicarboxylate, D AD for diethyl azodicarboxylate, DIAD for disopropylazodicarboxylate, DMAP for 4- (dimethylamino) pyridine, DME for 1,2-dimethoxyethane, DMF for Ν, Ν-dimethylformamide, DMSF for dimethylsulfoxide, DMSO for dimethylsulfoxide, EDTA for ethylenediaminetetraacetic acid, EIA for immunochemical enzyme determination, FAB for fast blasting method, GI for gastrointestinal, HMDS, lithium or Li HMDS for lithium 1,1,1,3,3,3-hexamido , HWPX for whole Cyclooxygenase-1 human plate, MCPBA for metachloroperoxybenzoic acid, NSAID for nonstero Identical anti-inflammatory drugs, PEG 400 for polyethylene glycol, PGE ₂ for prostaglandin E ₂ , PGHS for prostaglandin endoperoxide H synthase, RHUCX1 for recombinant human cyclooxygenase-1, RHUCX2 for recombinant human cyclooxygenase -2, rhu Coxl for recombinant human TxX1 for triethylamine, TFA for trifluoroacetic acid and TF for tetrahydrofuran and WISH for human amnionic whole cell cyclooxygenase-2. The following examples illustrate procedures of the invention without any limitation.

The compounds of the present invention include, but are not limited to, the following examples.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention include, but are not limited to, the following examples:

Example 1 2- (4-Fluorophenyl) -4- (2-ethyl-1-hexyloxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazmone

To a solution of 2-ethyl-1-hexanol (65 mg, 0.5 mmol) in THF (15 mL) at room temperature was added NaH (60% oil suspension) (20 mg, 0.5 mmol) and after 10 min. 2- (4-fluorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (277) -pyridazinone (193 mg, 0.5 mmol) was added. The resulting mixture was stirred at room temperature for a further 2 hours. Quench the mixture with 10% citric acid and extract with ethyl acetate. The extract was washed with water, brine, dried over MgSO ₄ and chromatographed on a silica gel column (2: 1 hexanes-ethyl acetate) to afford the desired product (yield: 140 mg, 60%). 1.1. 120-122 ° C, 11 NMR (300 MHz, DMSO-d 6) δ 0.75 (m, 6H), 1.1 (m, 6H), 1.20 (quintet, J = 7 Hz, 2H) 1.44 (m, 1H), 3.27 (s, 3H), 4.30 (d, J = 6Hz, 2H), 7.37 (t, J = 9Hz, 2H), 7 65 (m, 2H), 7.89 (d, J = 9Hz, 2H), 8.06 (d, J = 9Hz, 2H), 8.18 (s, 1H). MS (APCI +) m / z 473 (M + H) ⁺ ; (APCl -) m / z 507 (M + Cl) -. Analysis calculated for C 5 H ₂₉ FN ₂ O ₄ S ₂ * 0.5 H ₂ O: C, 62.35; H, 6.27; N, 5.87. Found: C, 62.22; H, 6.14; N, 6.22,

Example 2 2- (4-Fluorophenyl) -4- (3-hydroxy-3-methyl-1-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound was prepared according to the method for EXAMPLE 1, substituting 3-methyl-1,3-butanediol for 2-ethyl-1-hexanol (yield: 110 mg, 61%). 1.1. 133-134 ° C, 1 H NMR (300 MHz, DMSO-d 6) δ 1.04 (s, 6H), 1.72 (t, J = 7 Hz, 2H), 3.29 (s, 3H) 4.32 (s, 1H), 4.53 (t, J = 7Hz, 2H), 7.37 (t, J = 9Hz, 2H), 7.66 (m, 2H), 90 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.19 (s, 1H). MS (APCl +) m / z 447 (M + H) ⁺ , (APCl ⁺ ) m / z 481

SK 286972-6 (M + Cl) -. Calculated for C ₂₂ H ₂₃ FN ₂ O ₅ S * 0.25 H ₂ O: C, 58.59; H, 5.25; N, 6.21. Found: C, 58.42;

H, 5.00; N, 6.02.

Example 3 2- (3,4-Difluorophenyl) -4- (2-hydroxy-2-methyl-1-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound was prepared according to the method for EXAMPLE 1, starting from 2- (3,4-difluorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone in place of m.p. 2- (4-fluorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and replace 2-methyl-1,2-propanediol with 2-ethyl-1- hexanol (yield: 55 mg, 31%). 1 H NMR (300 MHz, DMSO-d 6) δ 0.97 (s, 6H), 3.30 (s 3H), 4.20 (s, 2H), 4.54 (s, 1H), 7 52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.98 (d, J = 9Hz, 2H), 8.05 (d, J) = 9 Hz, 2H), 8.21 (s, 1H). MS (APCI +) m / z 451 (M + H) ⁺ ; (APCl) m / z 485 (M + Cl) +. Analysis calculated for C ₂ H ₂₀ F ₂ N ₂ O ₅ S: C, 55.99; H, 4.47; N,

6.21. Found: C, 56.00; H, 4.48; N, 5.87.

Example 4 2- (3,4-Difluorophenyl) -4- (2-hydroxy-2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone

2- (3,4-Difluorophenyl) -4- (2-hydroxy-2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 3) is converted to the desired sulfonamide according to the method of Example 4A.

Example 20A

2-Benzyl-4- (4-fluorobenzyl) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone

To a solution of 2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (130 mg, 0.3 mmol) and di-t-butyl azodicarboxylate (DBAD) ( 69 mg, 0.3 mmol) in THF (30 mL) at -78 ° C was added dropwise a 1 N solution of 1,1,1,3,3,3-hexamethyldisilazide lithium (0.9 mL, 0.9 mmol) in THF. After the addition, the reaction was stirred for an additional 45 minutes at -78 ° C (or until all starting material was detected by TLC). Quench the reaction with saturated NH ₄ Cl solution and extract with ethyl acetate. The ethyl acetate extract was dried over MgSO ₄ and concentrated in vacuo to give 220 mg of crude adduct.

The prepared adduct was dissolved in THF (30 mL) and treated at room temperature with 1 N NaOH (3 mL) for 5 hours. Add sodium acetate (NaOAc * 3H ₂ 0.1.38 g, 10 mmol) and H ₂ O (30 mL). The resulting mixture was stirred at room temperature for 18 hours and then extracted with ethyl acetate. The extract was washed with water, brine, dried over MgSO ₄ and concentrated in vacuo. The residue is chromatographed on a silica gel column (1: 1 hexanes-ethyl acetate) to give the desired product (yield: 70 mg, 54%). T, t. 185-189 ° C, 1 H NMR (DMSO- d 6, 300 MHz) δ 5.33 (s, 2H), 7.11 (m, 2H), 7.22 (m, 2H), 7.40 ( m, 7H), 7.83 (d, J = 9Hz, 2H), 8.10 (s, 1H). MS _(DCI-NH3) m / z 436 (M + H) ^+. Calcd for C ₂₃ H ₁₈ FN ₃ O ₃ S * 0.75 H ₂ O: C, 61.65; H, 4.26; N, 9.04. Found: C, 61.67; H, 4.61; N, 8.66.

Example 20 (S) -2- (3,4-Difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

5A. (R) -3- t -Butoxy-2-methyl-1-propanol

A solution of (S) - (+) - methyl [3-hydroxy-2-methylpropionate] (1.18 g, 10 mmol) in t-butyl acetate (30 mL) was treated with 70% HCl ₄ (0.1 mL) The reaction mixture was allowed to stand at room temperature in a sealed flask for 24 hours, then poured into saturated sodium bicarbonate solution and extracted with diethyl ether. The ether was removed in vacuo and the residue was dissolved in THF (50 mL). To the resulting solution was added sodium borohydride (925 mg, 25 mmol), and methanol (10 mL) was added dropwise at 55 ° C. The reaction was continued at 55 ° C for an additional 1 hour and then cooled to room temperature, acidified to pH 5 with 10% citric acid, and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried over MgSO ₄ and concentrated in vacuo. The residue was chromatographed on a silica gel column (2: 1 hexanes-ethyl acetate) to give (R) -3-t-butoxy-2-methyl-1-propanol (yield: 1 g, 68%). 1 H NMR (300 MHz, CDCl ₃ ) δ 0.85 (d, J = 7 Hz, 3H),

I, 20 (s, 9H), 2.03 (m, 1H), 3.30 (t, J = 12Hz, 1H), 3.53 (dd, J = 12Hz, 4.5Hz, 1H) 3.70 (m, 2H). MS _(DCI-NH3) m / z 164 (M + NH ₄₎ ^+.

5B. (5) -2- (3,4-Difluorophenyl) -4- (3-tert-hydroxy-2-methyl-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2/7) -pyridazinone

To a solution of 2- (3,4-difluorophenyl) -4-hydroxy-5- [4- (methylsulfonyl) phenyl] -3 (2/7) -pyridazinone (378 mg, 1 mmol), Ph ₃ P (524 mg, 2 mmol) and the prepared alcohol (R) -3-t-butoxy-2-methyl-1-propanol (146 mg, 1 mmol) in THF (25 mL) at room temperature are added dropwise a solution of DIAD (0.4 mL, 2 mmol) in THF (5 mL). The mixture was then stirred at room temperature for 6 hours and concentrated in vacuo. The residue was purified on a silica gel column (hexanes-ethyl acetate) to give 550 mg of crude purified (S) -2- (3,4-difluorophenyl) -4- (3-t-butoxy-2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2/7) -pyridazinone contaminated with reduced DIAD. MS (APCI +) m / z 507 (M + H) ⁺ ; (APCl-1) m / z 541 (M + Cl) +

SK 286972 Β6

5C. (S) -2- (3,4-Difluorophenyl) -4- (3-hydroxy-2-methyl-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

A mixture of the prepared product (100 mg, 0.2 mmol) in TFA (5 mL) was stirred at room temperature for 24 hours and then concentrated in vacuo. The residue was neutralized with saturated NaHCO ₃ and extracted with ethyl acetate. Purification by silica gel column chromatography (1: 2 hexanes-ethyl acetate) to afford the desired compound (yield: 51 mg, 56%). 1 H NMR (300 MHz, DMSO-d 6) δ 0.75 (d, J = 7Hz, 3H), 1.81 (septet, J = 7Hz, 1H), 3.21 (d, J = 6) Hz, 2H), 3.30 (s, 3H), 4.29 (dd, J = 12Hz, 6Hz, 1H), 4.40 (dd, J = 12Hz, 6Hz, 1H), 4.48 (br s, 1H), 7.52 (m, 1H), 7.61 (m, 1H), 7.80 (m, 1H), 7.91 (d, J = 9) Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.20 (s, 1H). MS (APCI +) m / z 451 (M + H) ⁺ ; (APCl +) m / z 485 (M + Cl) +. Calcd for C 21 H ₂₀ F ₂ N ₂ O ₅ S: C, 55.99; H, 4.47; N, 6.21. Found: C, 55.65; H, 4.65; N, 5.92.

Example 6 (R) -2- (3,4-Difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound was prepared according to the procedure for EXAMPLE 5, starting from (R) - (-) - methyl [3-hydroxy-2-methylpropionate] instead of from (S) - (-) methyl- [3-hydroxy Of 2-methylpropionate] (yield: 65 mg, 61%). 1 H NMR (300 MHz, DMSO-d 6) δ 0.75 (d, J = 7 Hz, 3H), 1.81 (septet, J = 7 Hz, 1H), 3.21 (t, J = 6) Hz, 2H), 3.30 (s, 3H), 4.29 (dd, J = 6 Hz and 12 Hz, 1H), 4.40 (dd, J = 6 Hz and 12 Hz, 1H), 4.49 (t, J = 6 Hz, 1H), 7.52 (m, 1H), 7.61 (m, 1H), 7.80 (m, 1H), 7.91 (d) J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.20 (s, 1H). MS (APCI +) m / z 451 (M + H) ⁺ ; (APCI-) m / z 485 (M + Cl); Calcd for C21H20F2N2O5S: C, 55.99; H, 4.47; N,

6.21. Found: C, 55.62; H, 4.52; N, 6.06.

Example 21 (S) -2- (3,4-Difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone

To a solution of (S) -2- (3,4-difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone from Example 462 (450 mg, 0.9 mmol) and DBAD (207 mg, 0.9 mmol) in THF (25 mL) at -78 ° C was added dropwise a solution of 1M lithium bis (trimethylsilyl) amide in THF (3 mL, 3 mmol). The resulting mixture was stirred at -78 ° C for 2 hours. The mixture was warmed to room temperature and 1N NaOH (5 mL, 5 mmol) was added. After 12 hours at room temperature, sodium acetate trihydrate (2.76 g, 20 mmol) and H ₂ O (10 mL) and hydroxylamine-O-sulfonic acid (2 g, 15 mmol) were added. The mixture was stirred at room temperature for 5 hours. The product was extracted with ethyl acetate and purified by silica gel column chromatography (1: 2 hexanes-ethyl acetate) to obtain the desired intermediate (yield: 160 mg, 35%). MS (APCI +) m / z 508 (M + H) ⁺ ; (APCI-) m / z 542 (M + Cl);

To the prepared intermediate was added TFA (5 mL) and the resulting solution was stirred at room temperature for 24 hours. TFA was removed in vacuo and the residue was neutralized with saturated NaHCO ₃ and extracted with ethyl acetate. The organic extract was dried over MgSO ₄ and filtered. The filtrate was concentrated in vacuo and chromatographed on a silica gel column (1: 2 hexanes-ethyl acetate) to afford the desired compound (yield: 50 mg, 33%). 1 H NMR (300 MHz, DMSO- d 6) δ 0.76 (d, J = 7 Hz, 3H), 1.81 (sextet, J = 7 Hz, 1 H), 3.22 (t, J = 6) Hz, 2H), 4.28 (dd, J = 12 Hz, 6 Hz, 1H), 4.40 (dd, J = 12 Hz, 6 Hz, 1H), 4.50 (t, J = 6 Hz, 1H), 7.51 (m, 3H), 7.61 (m, 1H), 7.80 (m, 1H), 7.84 (d, J = 9 Hz, 2H), 7 95 (d, J = 9Hz, 2H), 8.20 (s, 1H). MS (APCI +) m / z 452 (M + H) ⁺ ; (APCl-) m / z 486 (M + Cl);

Example 21 (R) -2- (3,4-Difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound is prepared according to the method for Preparation 7, starting from (R) -2- (3,4-difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4 (methylsulfonyl) phenyl] ] -3 (2H) -pyridazinone instead of (S) -2- (3,4-difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2 H) -pyridazinone (yield: 30 mg, 20%). 1 H NMR (300 MHz, DMSO-d 6) δ 0.76 (d, J = 7Hz, 3H), 1.81 (sextet (J = 7Hz, 1H), 3.22 (t, J = 6) Hz, 2H), 4.28 (dd, J = 6 Hz and 12 Hz, 1H), 4.40 (dd, J = 6 Hz and 12 Hz, 1H); 4.50 (t, J = 6 Hz, 1H), 7.51 (m, 3H), 7.61 (m, 1H), 7.80 (m, 1H), 7.84 (d, J = 9 Hz, 2H), 95 (d, J = 9Hz, 2H), 8.20 (s, 1H): MS (APCl +) m / z 452 (M + H) ⁺ ; (APCl ⁺ ) m / z 486 (M + Cl) ; calculated for C ₂ oH ₁₉ F ₂ N ₃ 0 ₅ S: C, 53.21; H, 4.24; N, 9.30. Found: C, 53.45; H, 5.53; N, 9.50.

Determination of prostaglandin inhibition Application and preparation of compounds

For oral administration, test compounds were suspended on the day of use in 100% polyethylene glycol (PEG 400) using a motorized homogenizer equipped with a Teflon-coated pistol (TRI-R Instrument, Jamaica, NY).

Variation analysis was applied to compare the mean response of the reacting groups. The percent inhibition values reported in percent were determined by comparing the individual mean response values with the mean of the control group. Calculation of IC ₅ o / E ₅ in appropriate assays was performed by the linear regression method.

Determination of prostaglandins using the EIA method

EIA prostaglandin assay agents were purchased from Perseptive Diagnosis (Cambridge, MA). The levels of prostaglandin E ₂ (PGE ₂ ) in the elution fluid were determined after the samples were dried under nitrogen and reconstituted with assay buffer. PGE ₂ levels in enzyme assays or cell culture medium were measured against standards prepared in the same medium. Immunochemical determinations were performed according to the manufacturer's recommendations. EIA was performed in 96-well microtiter plates (Nunc Roskilde, Denmark) and optical density was measured using a microplate reader (Vmax, Molecular Devices Corp., Menol Park, CA).

Determination of human recombinant PGHS-1 and PGHS-2 enzymes

In vitro inhibition of prostaglandin biosynthesis was evaluated using the human recombinant Cox-1 (r-hu Cox-1) and Cox-2 (r-hu Cox2) assays. Representative compounds dissolved in DMSO (3.3% v / v) were preincubated with microsomes from human recombinant PGHS-1 or PGHS-2 expressed in the baculovirus / Sf9 cell system (Gierse, JK, Hauser, SD, Creely, DP, Koboldt, C). Rangwala, S., H., Isakson, P.C, and Seibert, K. Expression and Selective Inhibition of the Constituitive and Inducible Forms of Cyclooxygenase, Biochem J., 1995, 305: 479.), together with phenol cofactors ( 2 mM) and hematin (1 μΜ) for 60 minutes prior to the addition of 10 μΜ of arachidonic acid. The reaction was carried out for 2.5 minutes at room temperature before quenching with HCl and neutralization with NaOH. Production of PGE ₂ in the presence and absence of drug was determined by EIA analysis. EIA was performed in 96 well microtiter plates (Nunc Roskilde, Denmark) and optical density was measured using a microplate reader (Vmax, Molecular Devices Corp., Menol Park, CA). EIA prostaglandin assay reagents were purchased from Perseptive Diagnostics (cambridge, MA). PGE ₂ levels were measured against standards prepared in the same environment. Immunochemical determinations were performed according to the manufacturer's recommendations.

Data illustrating the in vitro inhibition of prostaglandin biosynthesis by the compounds of the present invention are shown in Table 1. The compounds are numbered according to the example number. Column 2 shows the percent inhibition of Cox-1 at each micromolar dose level and Column 3 shows the percent inhibition of Cox-2 at individual nanomolar dose levels. Values for inhibition of Cox-2, which are parental, indicate IC ₅₀ values.

Table 1

Example number Inhibition of RHUCX1 (%) at dose (μΜ) Inhibition of RHUCX1 (%) at dose (μΜ) 1 6 at 100 92 at 1,000 34 at 10 2 10 at 100 43 at 1 22 at 0.1 3 14 at 100 15 at 1

IL-1β induced PGE ₂ production in WISH cells

Human WISH amnionic cells were cultured to 80% coilence in 48 well plates. Then, the growth medium was removed and washed twice with Glys Balanced Salt solution, added to cells with 5 ng II-1 / S / ml (UBI, Lake Placid, NY) with or without test compound in DMSO (0.01% v / v). ) in Neuman-Tytell Serumless Medium (GIBCO, Grand Island, NY). Following 18 hours of incubation to achieve maximal induction of PGHS-2, the conditioned medium was removed and the described PGE content determination _from EIA analysis was performed.

U937 monocyte cells (ATCC, Rockville, MD) were cultured at a similar time to WISH cells. After incubation, the maintenance medium was removed and the Cox-1 assay as described by EIA analysis was performed.

Data illustrating the in vitro inhibition of prostaglandin biosynthesis by the compounds of the invention are shown in Table 2. U937 values indicate percent inhibition of Cox-1 at single micromolar doses, while partentethical values indicate IC ₅₀ values. WISH cell values indicate percent inhibition at single micromolar doses, while parental values indicate IC ₅₀ values of whole human platelet cyclooxygenase-1 (HWCX).

Blood from normal healthy donors was collected in tubes containing ACD (acid citrate dextrose) as an anticoagulant. This blood was centrifuged at 175 x g to prepare platelet-rich plasma. This plasma was then centrifuged again at 100 x g to round white blood cells that leave platelets in the supernatant. The supernatant was layered on a pincushion-shaped structure of 0.7 ml of 10% bovine serum albumin in Tyrodes solution (Gibco; Grand Island, NY) and then centrifuged at 1,000 x g. The resulting supernatant from this centrifugation was then removed and 11 ml of Tyrodes solution was added to the remaining well of the plate. Plates were aliquoted at 120 μΐ into 96 well plates. Compounds were added to the experiment and allowed to pre-incubate for 10 minutes. At the end of this incubation, calcium ionophore A23187 was added to a final concentration of 8.8 / 3M and incubated for a further 10 minutes. The reaction was stopped by the addition of cold 6 mM EDTA, the incubation mixture was centrifuged at 220 x g, and the supernatants were then analyzed for troboxane using a commercial kit from Cayman Chemical (Ann Arbor, MI).

Table 2

Example number U937 Inhibition (%) at Dose (μΜ) Inhibition of HWPX (%) at dose (μΜ) Inhibition of WISH (%) at dose (μΜ) 2 (25.6) (0.15) 3 56 at 1 L at 0.1

Carrageenan-induced paw edema (CPE) in rats

Hind paw edema is induced in male rats as described in Winter et al, Proc. Soc. Exp. Biol. Med., 1962, 111, 544. Male Sprague-Dawley rats weighing 170-190 g are dosed orally 1 hour prior to subplant injection of 0.1 ml of 1% sodium carrageenan (lambda carrageenan, Sigam Chemickal Co., St. Louis). , MO) to the right hind paw. Volumes (ml) of right hind paw are measured immediately after carrageenan injection, using a plethysmograph (Buxco Electronics, Inc. Troy, NY) to measure baseline volumes. After 3 hours of the injection of carrageenan, the right paw is measured and paw edema is calculated for each rat by subtracting zero reading time from 3 hours. Data are given as percent of mean inhibition +/- SEM. The statistical significance of the results is analyzed by Dunnetts multiple comparison test, where p <0.05 is considered statistically significant.

Model of rat pleural inflammation induced by carrageenan

Pleural inflammation was induced in male Sprague-Dawley rats adrenalectomized according to the method of Vinegar et al., Fed. Proc. 1976, 35, 2447-2456. Animals were administered test compounds orally, 30 minutes prior to intrapleural injection of 2% lambda carrageenan (Sigma Chemical Co., St. Louix MO). After 4 hours, the animals were euthanized and pleural cavity rinsed with ice cold saline. The rinse fluid was then added to two volumes of ice cold methanol (66% final methanol concentration) to lyse the cells and precipitate the protein. Eicosanoids were determined by the described EIA analysis.

Data illustrating the inhibition of prostaglandin biosynthesis by the compounds of the present invention are shown in Table 3. The values shown are percent inhibition at 10 milligrams per kilogram body weight.

Model of carrageenan-induced air sacs (CAP) in which prostaglandin biosynthesis occurs

Air bags are formed on the back of male Sprague-Dawley rats by injecting 20 mL of sterile air on day 0. After 3 days, the bags are inflated again with a further dose of 10 mL of sterile air. On day 7, 1 ml of saline containing 0.2% lambda carrageenan (Sigma Chemical Co.) is injected into the pouches to induce an inflammatory response, which is characterized by the release of prostaglandin. Test compounds are dosed from 0.1 to 10 mg / kg 30 minutes prior to carrageenan. After 4 hours, the carrageenan injected pouch was eluted and prostaglandin levels were determined by the enzyme immunoassay method using cormently available kits. Percent inhibitions were calculated by comparing the response in vehicle-treated animals versus compound-treated animals. Values for Cox-2 inhibition that are parenthetical indicate ED values _50th

Data illustrating the inhibition of prostaglandin biosynthesis in vivo by the compounds of the present invention are shown in Table 3. The values are percent inhibition at 10 milligrams per kilogram body weight for CIP and CPE assays and at 3 milligrams per kilogram body weight for CAP assays.

Table 3

Example number Inhibition of CIP (%) at 10 mpk CPE inhibition (%) at 10 mpk Inhibition of CAP (%) at 3 mpk 2 80.5 ED50 ⁼ 1 3 71

Pharmaceutical preparations

The present invention also provides pharmaceutical compositions comprising the compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" as used herein means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulated material or excipient of any type. At

The pros of the substances which can be administered as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and derivatives thereof such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppositories of wax; oils such as peanut oil, cottonseed oil; saffron oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solutions as well as other non-toxic, compatible lubricants such as sodium lauryl sulphate and magnesium stearate, as well as coloring agents, disintegrants, coating agents, sweeteners, flavorants and fragrance release agents, preservatives, in preparations antioxidants may also be present, according to judgments and procedures well known in the art. The pharmaceutical compositions of this invention may be administered to humans and other animals orally, rectally, parenterally, intracisterially, intravaginally, intraperitoneally, topically (by dusting, ointments, drops), buccally, or as oral or nasal sprays.

The compounds of the present invention can be very useful in the treatment of various diseases or disease states such as inflammatory diseases, dysmenorrhoea, asthma, premature labor, adhesion and certain pelvic adhesion, osteoporosis and spondylitis of joint stiffness. Current Medicines Ltd, ID Patent Fast Alert, AG16, May 9, 1997.

The compounds of the present invention can be very useful in the treatment of cancers, and in particular colon cancer. Proc. Natl. Acad. Sci., 94, 3336-3340, 1997.

The compounds of the present invention may be very useful in providing pharmaceutical compositions for inhibiting prostaglandin biosynthesis comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester or prodrug thereof, and a pharmaceutically acceptable carrier.

In addition, the compounds of the present invention may be very useful in the manufacture of a medicament for inhibiting prostaglandin biosynthesis.

In addition, the compounds of the present invention may be very useful in the manufacture of a medicament for the treatment of pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesion and cancer comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I).

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, groundnuts, corn, germ, olive, castor and sesame oils and the like), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. Compared to inert diluents, oral preparations may also include adjuvants such as detergents, emulsifiers and suspending agents, sweeteners, flavorants, and fragrance release agents.

Injectable preparations such as e.g. sterile injectable aqueous or oleaginous suspensions may be formulated according to techniques known in the art using suitable dispersing and suspending detergents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent such as e.g. solution in 1,3-butanediol. Suitable vehicles and solvents that may be used include water, Ringer's solution, isotonic sodium chloride solution and the like. In addition, sterile, solid oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable formulations may be sterilized by any method known in the art, e.g. by filtration through a bacterial-retention filter or by inserting a sterilizing agent in the form of sterile solid preparations which can be dissolved or dispersed in sterile water or other sterile, injectable preparation prior to use.

In order to prolong the effect of the drug, it is often desirable to delay the absorption of the drug upon subcutaneous and intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous substances with poor water solubility. The rate of absorption of a drug then depends on its dissolution rate, which may depend on crystalline size and crystalline form. Alternatively, slower absorption of the parenterally administered form of the drug is accomplished by dissolving or suspending the drug in an oily vehicle. Injectable depot forms are made by forming microencapsulated drug matrices in biodegradable polymers such as polyactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the origin of the individual polymers used. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by retaining the drug in liposomes or microemulsions that are compatible with body tissues.

Formulations for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or wax suppositories that are solid at room temperature but liquid at body temperature and therefore they melt in the rectum or vaginal cavity to release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is usually admixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and orthosilicic acid , b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gelatin, c) wetting agents such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginate certain silicates and calcium carbonate, e) solution inhibitors such as paraffin, i) absorption accelerators such as quaternary ammonium compounds, g) detergents such as ethyl alcohol and glycerol monostearate, h) adsorbents such as for example kaolin and bentonite kaolin and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also contain a buffering agent.

Solid compositions of a similar type may also be used as fillers for lightly filled and densely filled gelatin capsules using such excipients as lactose or milk sugar as well as polyethylene glycols having a high relative molecular weight.

The active compounds may also be in microencapsulated form with one or more of the foregoing carriers. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the art of pharmaceutical formulations. In such dosage forms, the active compound may be admixed with at least one inert diluent such as starch, lactose or sucrose. Such dosage forms may also contain, as is normal practice, other substances other than inert diluents, e.g. tableting lubricants and other tableting entities such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain a buffering agent or an opacifying agent and may also be free of such agents that release only or preferably the active ingredients in a certain part of the intestinal tract, optionally to some extent delayed. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of the invention further include ointments, pastes, creams, liquid forms for external use, gels, dusts, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer as desired. Ophthalmic formulations, ear drops, eye ointments, dusting powders and solutions are also within the scope of the present invention.

Ointments, pastes, creams and gels may contain, in addition to the active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, orthosilicic acid, talc, zinc oxide or mixtures thereof.

Powders and sprays may contain, in addition to the active compound of the invention, excipients such as lactose, talc, orthosilicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures thereof. Sprays may further contain customary propellants such as chlorofluorocarbons.

In addition, transdermal patches have the advantage of providing accurate delivery of the compound to the body. Also, dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Those entities that enhance absorption can be used to increase the flow of the compound through the skin. The rate of increase can be controlled by either controlling the membrane and / or dispersing the compound in a polymer matrix or gel.

According to the methods of treatment of the present invention, patients or mammals are treated by administering a therapeutically effective amount of a compound of the invention in such amounts and at such time as is necessary to achieve the desired result. By "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of a compound of the invention to achieve the desired amelioration of the negative state in a reasonable benefit / risk ratio applicable to any medical treatment. It is more or less obvious that the total daily use of the compounds and compositions of the present invention depends on the judgment of the attending physician (careful medical judgment). The specific therapeutically effective dose level for any individual patient will depend on various factors including the disorder being treated and the severity of the disorder; the activity of the specific compound used; use of a specific preparation; the patient's age, body weight, general health, sex and lifestyle; the time of administration, the method of administration and the rate of excretion of the specific compound used; duration of treatment; drugs used in combination or in accordance with the specific compound used; and similar factors well known in medical practice.

SK 286972 Β6

The total daily dose of the compounds of the present invention administered to a human or other mammal in a single or at different doses may be in amounts e.g. from 0.001 to about 1,000 mg / kg body weight per day or more preferably from 0.1 to about 100 mg / kg body weight for oral administration 0.01 to about 10 mg / kg for parenteral administration daily. Single dose formulations may contain an amount or part of that amount to form a daily dose.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

The agents required for the synthesis of a compound of the present invention are readily commercially available in e.g. Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St. Louis, MO, USA); and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alpha Aesar (Ward Hill, MA 01835-9953); Eastman Chemical Company (Rochester, New York, 14652-3512); Lancaster Syntesis Inc. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901); Pfaltz and Bauar (Waterbury, CT. 06708). Compounds that are not commercially available can be prepared using known methods in the chemical literature.

Claims (6)

PATENT CLAIMS 1. Arylpyridazinone of formula (I): wherein X is O; R is a 6-membered carbon aromatic ring substituted with one or two fluorine atoms, R ¹ is hydroxyC 1 -C ₁₅ alkoxy, R ³ is hydrogen and R ² is X ² wherein X ¹ is -SO 2 -, R 1 is selected from the group consisting of C 1 -C 15 alkyl and amino, X ² is selected from the group consisting of hydrogen and halogen, or a pharmaceutically acceptable salt, ester or ester thereof; CrC ₆ aliphatic carboxylic acid. The compound of claim 1, wherein X ¹ is -SO 2 -, R ⁹ is selected from the group consisting of -CH 3 and -NH ₂ , X is hydrogen, X is O, R is selected from the group consisting of 3,4-difluorophenyl and 4-fluorophenyl, R ¹ is selected from the group consisting of 2-hydroxy-2-methyl-1-propoxy, 3-hydroxy-3-methyl-1-butoxy and 3-hydroxy-2 methyl-l-propoxy group, R ³ is H, or a pharmaceutically acceptable salt, ester, or an ester with a C _r C ₆ aliphatic carboxylic acid. A compound according to claim 1 selected from the group consisting of: 2- (3,4-difluorophenyl) -4- (2-hydroxy-2-methyl-1-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2 //) - pyridazinone; 2- (4-fluorophenyl) -4- (3-hydroxy-3-methyl-l-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2 //) - pyridazinone; 2- (3,4-difluorophenyl) -4- (2-hydroxy-2-methyl-l-propoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2/7) -pyridazinone; (R) -2- (3,4-Difluorophenyl) -4- (3-hydroxy-2-methyl-l-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2 //) - pyridazinone ; (OJ-2- (3,4-Difluorophenyl) -4- (3-hydroxy-2-methyl-l-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2/7) -pyridazinone; (R) -2- (3,4-Difluorophenyl) -4- (3-hydroxy-2-methyl-1-propoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone; ( 5) 2- (3,4-difluorophenyl) -4- (3-hydroxy-2-methyl-l-propoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2Z /) - pyridazinone Or a pharmaceutically acceptable salt, ester or ester thereof with a C 1 -C ₆ aliphatic carboxylic acid. A pharmaceutical composition for inhibiting prostaglandin biosynthesis comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. Use of a compound according to claim 1 for the manufacture of a medicament for inhibiting prostaglandin biosynthesis. Use of a compound according to claim 5 for the manufacture of a medicament for the treatment of pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesion and cancer.