AU3509901A - Substituted benzenesulfonamide derivatives as prodrugs of COX -2 inhibitors - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 REGULATION 3.2 0.0* .0 0 Name of Applicant: Actual Inventor/s: G. D. SEARLE CO.

JOHN J. TALLEY, JAMES W. MALECHA, STEPHEN BERTENSHAW, MATTHEW J.

GRANETO, JEFFERY CARTER, JINGLIN LI, SRINIVASAN NAGARAJAN, DAVID L. BROWN, DONALD J. ROGIER, JR., THOMAS D.

PENNING, ISH K. KHANNA, XIANGDONG XU and RICHARD M. WEIER.

E.F. WELLINGTON CO., Patent and Trade Mark Attorneys, 312 St. Kilda Road, Melbourne, Southbank, Victoria, 3006.

Address for Service: Invention Title: "SUBSTITUTED BENZENESULFONAMIDE DERIVATIVES AS PRODRUGS OF COX-2 INHIBITORS" Details of Associated Provisional Applications Nos: The following statement is a full description of this invention including the best method of performing it known to us.

SUBSTITUTED BENZENESULFONAMIDE DERIVATIVES AS PRODRUGS OF COX-2 INHIBITORS FIELD OF THE INVENTION This invention is in the field of antiinflammatory pharmaceutical agents and specifically relates to prodrugs of compounds which selectively inhibit cyclooxygenase-2.

S 10 BACKGROUND OF THE INVENTION The use of non-steroidal antiinflamatory drugs (NSAIDs) in treating pain and the swelling associated with inflammation also produce severe side effects, including life threatening ulcers. The recent e. discovery of an inducible enzyme associated with inflammation ("prostaglandin G/H synthase II" or "cyclooxygenase-2 provides a viable target of inhibition which more effectively reduces inflammation S 20 and produces fewer and less drastic side effects.

Compounds which selectively inhibit cyclooxygenase-2 have been described. U.S. patent 5,380,738 describes oxazoles which selectively inhibit cyclooxygenase-2. U.S. patent 5,344,991 describes cyclopentenes which selectively inhibit cyclooxygenase- 2. U.S. patent 5,393,790 describes spiro compounds which selectively inhibit cyclooxygenase-2. W094/15932 describes thiophene and furan derivatives which selectively inhibit cyclooxygenase-2. W094/27980 describes oxazoles which selectively inhibit cyclooxygenase-2. W094/13635 describes compounds which selectively inhibit cyclooxygenase-2. W094/20480 describes compounds which selectively inhibit cyclooxygenase-2. W095/15316 describes pyrazolyl sulfonamide derivatives which selectively inhibit cyclooxygenase-2. However, in some circumstances, prodrugs of antiinflammatory compounds are advantageous, especially where the prodrugs have increased water solubility or delayed onset of action.

Substituted sulfonamides have been described.

Pyrazolyl-sulfonylureas have been described as having possible hypoglycemic activity Faid-Allah and H.

Mokhtar, Ind. J. Chem, 27, 245 (1988)]. JP 1,045,374 describes water soluble tetrazolium compounds useful in assays for determining reducing substances. D.

Mukerjee et al [Acta. Pharma. Jugosl., 31, 151 (1981)] S 10 describe tetrazolium sulfonamides as antiviral agents.

"JP 4,277,724 describes triphenyl pyrazolines as nonlinear optical material. JP 5,323,522 describes the use of heterocyclic compounds in black and white photographic material. U.S. Patent No. 5,389,635 describes substituted imidazoles as angiotensin II S" antagonists. U.S. Patent No. 5,387,592 describes oo substituted benzimidazole derivatives as angiotensin II antagonists. G. Dorofeenko et al [Khim. Farm. Zh., 16, 920 (1982)] describe pyridinium salts as antiviral 20 agents. U.S. Patent No. 5,338,749 describes diarylsubstituted heterocyclyl compounds as antiarthritis agents. W094/26731 describes thiophene compounds which selectively inhibit cyclooxygenase-2. W095/00501 describes compounds which selectively inhibit cyclooxygenase-2, and specifically, 3-(4- (trifluoroacetylaminosulfonyl)phenyl)-2-(4fluorophenyl)thiophene is described. T. Ivanov [Mh.

Chem., 97, 1499 (1966)] describes the preparation of diarylindone derivatives as possible indicators, and 2- (4-(N-methylaminosulfonyl)phenyl)-3-phenylindone is specifically described.

J. Larsen and H. Bundgaard [Int. J. Pharmaceutics, 37, 87 (1987)] describe the evaluation of Nacylsulfonamides as potential prodrug derivatives. J.

Larsen et al [Int. J. Pharmaceutics, 47, 103 (1988)] describe the evaluation of N-methylsulfonamides as potential prodrug derivatives.

There currently exists a need for compounds suitable for injectable antiinflarmaccory compositions.

The compounds of the present invention are found to show usefulness as prodrugs.

DESCRIPTION OF THE INVENTION A class of substituted sulfonamide compounds useful as prodrugs is defined by Formula I: 2 *0 0 patal unatrae heerccl heerarl *morewhereinlA islacringfsumstituentrselectedofrom halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, 20 cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxycarbonylalkyl, artinocarbonylalkyl, alkylarrinocarbonyl,

N-

arylaminocarbonyl, N-alkyl -N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, N-arylamino,

N-

aralkylanino, N-alkyl -N-aralkylamino, N-alkyl-Nar-ylamino, aminoalkyl, alkvlaminoalkyl,

N-

arylarninoalkyl, N-aralkylaxninoalkyl, N-alkvl-Naralkylarninoalkyl, N-alkvl -N-arylaxinoalk-yl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylarninosulfonyl,

N-

arylaminosulfonyl, arylsulfonyl, and N-alkyl-Narylaminosulfonyl; wherein R 1 is selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R 1 is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and 10 alkylthio; wherein R 2 is selected from hydrido and alkoxycarbonylalkyl; and wherein R 3 is selected from alkyl, carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, amino acid residue, and alkylcarbonylaminoalkylcarbonyl; provided A is not tetrazolium, or pyridinium; and further provided A is not indanone when R 3 is alkyl or 20 carboxyalkyl; or a pharmaceutically-acceptable salt thereof.

Compounds of Formula I would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other cyclooxygenase-2 mediated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, compounds of the invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such compounds of the invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, skin-related conditions such as psoriasis, eczema, burns and dermatitis, and from post-operative inflammation including from ophthalmic surgery such as cataract surgery and refractive surgery. Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. Compounds of the invention would be useful for the prevention or treatment of cancer, such as colorectal cancer, and cancer of the breast, lung, prostate, bladder, cervix and skin. Compounds of the invention would be useful in treating inflammation in such diseases as vascular diseases, migraine headaches, 10 periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like. The compounds would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, uveitis, ocular 20 photophobia, and of acute injury to the eye tissue. The compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. The compounds would also be useful for the treatment of certain central nervous system disorders, such as cortical dementias including Alzheimer's disease, and central nervous system damage resulting from stroke, ischemia and trauma. The compounds of the invention are useful as antiinflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. These compounds would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, and atherosclerosis. The compounds would also be useful in the treatment of pain, but not limited to postoperative pain, dental pain, muscular pain, and pain resulting from cancer. The compounds would be useful for the prevention of dementias, such as Alzheimer's disease.

Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including .mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

The present compounds may also be used in cotherapies, partially or completely, in place of other conventional antiinflammatories, such as together with steroids, NSAIDs, 5-lipoxygenase inhibitors,

LTB

4 10 antagonists and LTA 4 hydrolase inhibitors.

Suitable LTB 4 inhibitors include, among others, ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS- 25019C, Leo Denmark compound ETH-615, Lilly compound LY- 293111, Ono compound ONO-4057, Terumo compound TMK-688, Lilly compounds LY-213024, 264086 and 292728, ONO compound ONO-LB457, Searle compound SC-53228, calcitrol, Lilly compounds LY-210073, LY223982, LY233469, and LY255283, ONO compound ONO-LB-448, Searle compounds SC-41930, SC-50605 and SC-51146, and SK&F compound SKF- 20 104493. Preferably, the LTB 4 inhibitors are selected from ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS- 25019C, Leo Denmark compound ETH-615, Lilly compound LY- 293111, Ono compound ONO-4057, and Terumo compound TMK- 688.

Suitable 5-LO inhibitors include, among others, masoprocol, tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadrem phosphate, and bunaprolast.

The present compounds may also be used in combination therapies with opioids and other analgesics, such as morphine, meperidine or codeine.

The term "cyclooxygenase-2 inhibitor" embraces compounds which selectively inhibit cyclooxygenase-2 over cyclooxygenase-l. Preferably, the compounds have a cyclooxygenase-2 ICSo of less than about 0.5 PM, and also have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and more preferably of at least 100. Even more preferably, the compounds have a cyclooxygenase-1

IC

50 of greater than about 1 M, and more preferably of greater than pM. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.

The phrase "therapeutically-effective" is intended to qualify the amount of each agent for use in the combination therapy which will achieve the goal of improvement in severity and the frequency of incidence 1 0 over treatment of each agent by itself, while avoiding "adverse side effects typically associated with alternative therapies.

The phrase "combination therapy" (or "co-therapy"), in S"defining use of a cyclooxygenase-2 inhibitor agent and another agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.

~The term "prodrug" refers to compounds which are drug precursors which, following administration to a subject and subsequent absorption, is converted to an active species in vivo via some process, such as a metabolic process. Other products from the conversion process are easily disposed of by the body. More preferred prodrugs produce products from the conversion process which are generally accepted as safe.

A preferred class of compounds which inhibit cyclooxygenase-2 consists of compounds of Formula I wherein A is selected from partially unsaturated heterocyclyl, or 6-membered heteroaryl, lower cycloalkenyl and phenyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from formyl, lower alkylcarbonyl, halo, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, lower haloalkylsulfonyloxy, lower alkoxyalkyloxyalkyl, lower carboxyalkoxyalkvl, lower cycloalkyvlalkyl, lower alkenyl, lower alkynyl, heterocyclyloxy, lower alkylthio, lower cycloalkyl, phenyl, 5-6 memnbered heterocyclyl, lower cycloalkenyl, lower phenylalkyl, 5-6 mnembered heteroc-vclylalk-vl, lower alkylthioalkyl, phenylcarbonyl, lower phenylalkylcarbonvl, lower phenylalkenyl, lower alkoxyalkyl, lower phenylthioalkyl, lower phenyloxyalkyl, lower phenylalkylthioalkyl, lower phenylalkoxyalkyl, lower alkoxycarbonylalkyl, lower atinocarbonylalkyl, lower alkylaminocarboriyl, N -phenyl amino carbonyl1, lower N-alkyl-Nphenylaminocarbonyl, lower alkylaminocarbonylalkyl, .lower alkvlanino, N-pheriylamino, lower N-phenylalkylanino, lower N-alkyl-N-phenalkylamino, lower N-alkyl-N-phenylamino, lower arinoalkyl, lower alkylaninoalkvl, lower Nphenylarinoalkyl, lower N-phenalkylaminoalkyl, ,lower Nalkyl -N-phenalkylaminoalkyl, lower N-alkyl -Nphenylaminoalkyl, phenyloxy, lower phenylalkoxy, lower phenylthio, lower phenalkylthio, lower alkylsulfinyl, lower 20 alkylsulfonyl, aiinosulfonyl, lower alkvlaminosulfonyl, Nphenylaminosulfonyl, phenylsulfonyl, and lower N-alkyl-Nphenylarninosulfonyl; wherein R1 is selected from 5- or 6memibered heterocyclyl, lower cycloalkyl, lower cycloalkenyl arnd phenyl, where Rl is optionally substituted at a substitutable oosition with one or more radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkvlamnino, phenylanino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; wherein R 2 is selected from hydrido, arid lower alkoxvcarbonylalkyl; and wherein R 3 is selected from lower alkyl, lower carboxyalkvl, alkanoyl, aroyl, amino acid residue, lower alkoxycarbonyl, lower alkoxyalkylcarbonyl, (5-6-mernbered heteroaryl)carbonyl, lower alkoxycarbonylalkylcarbonyl, lower alkoxycarbonylcarbonyl, and lower alkylcarbonylaininoalkvlcarbonyl; or a pharmaceuticallyacceptable salt thereof.

A more preferred class of compountds which inhibit cyclooxygenase-2 consists of compounds of Formula I wherein A is a radical selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, D indenyl, benzothienyl, isoxazolyl, pyrazolvl, cyclopentenyl, cyclopentadienyl, benzindazolyl, benzopyranopyrazolyl, phenyl, and pyridyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from formyl, methylcarbonyl, fluoro, chloro, bromo, methyl, trifluoromethyl, difluoromethyl, oxo, cyano, carboxyl, methoxy, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, hydroxymethyl, cyanomethyl, phenyl, phenylmethyl, methoxycarbonyl, phenylcarbonyl, methoxymethyl, phenyloxyrnethyl, aminocarbonylmethyl, carboxymethyl, and phenyloxy; wherein R 1 is selected from thienyl, oxazolyl, isoxazolyl, furyl, thiazolyl, pyridyl, and phenyl, where R1 is optionally substituted at a substitutable position with one or more radicals selected from methyl, trifluorornethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, nitro, methoxymethyl, 00.0.

0000 fluoro, chioro, bromo, methoxy and methylthio; wherein 0 R 2 is hydrido, or ethoxvcarbonylmethyl; and wherein R 3 is selected from methyl, carboxymethyl, forrryl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hydroxyethylcarbonyl, benzylcarbonyl, phenyl (hydroxyl) methylcarbonyl, methoxycarbonyl, tertbutoxycarbonyl, methoxyethylcarbonyl, phenylcarbonyl, ethoxvmethylcarbonyl, rethoxyrethylcarbonyl, carboxyethylcarbonyl, carboxyrnethylcarbonyl, carboxy 2 bis (hydroxy) ethyl) carbonyl, methoxycarbonylmethylcarbonyl, aininomethylcarbonyl, methoxvcarbonylethylcarbonyl, methoxycarbonylcarbonyl, tert-butoxycarbonylaminomethylcarbonyl, and methylcarbonylaminomethylcarbonyl; or a pharmaceutically-acceptable salt thereof.

Within Formula I there is a subclass of compounds of high interest represented by Formula II: H N A R4

R

5 N II o S0 0 wherein A is a ring substituent selected from partially unsaturated heterocyclyl, 5- or 6-membered heteroaryl, lower cycloalkenyl and phenyl; wherein A is optionally substituted at a substitutable position with 10 one or more radicals selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, lower alkylcarbonyloxyalkyl, and phenyl; wherein R 4 is selected from heterocyclyl, cycloalkyl, cycloalkenyl and phenyl, wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from lower alkyl, lower 20 haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; and wherein R 5 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower alkoxycarbonyl, lower aminoalkyl, lower alkoxycarbonylaminoalkyl, and lower alkylcarbonylaminoalkyl; or a pharmaceutically-acceptable salt thereof.

A preferred class of compounds consists of those compounds of Formula II wherein A is a ring substituent selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, indenyl, 11 benzothienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, benzindazolyl, benzopyranopyrazolyl, phenyl, and pyridyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower alkylcarbonyloxyalkyl, phenyl and lower hydroxyalkyl; wherein R 4 is selected from 5-6 ,0 10 membered heteroaryl and phenyl, wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; and wherein R 5 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower alkoxycarbonylalkyl, lower alkoxycarbonyl, lower

CCC.

aminoalkyl, lower alkoxycarbonylaminoalkyl, and lower alkylcarbonylaminoalkyl; or a pharmaceuticallyacceptable salt thereof.

A class of compounds of particular interest consists of those compounds of Formula II wherein A is a ring substituent selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, benzindazolyl, benzopyranopyrazolyl, phenyl, and pyridyl; wherein A is optionally substituted at a substitutable position with one or more radicals selected from formyl, fluoro, chloro, bromo, methyl, trifluoromethyl, oxo, cyano, carboxyl, methoxy, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, carboxymethyl, carboxypropyl, methylcarbonyloxymethyl, and hydroxymethyl; wherein R 4 is selected from thienyl, pyridyl and phenyl, wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from methyl, trifluoromethyl, hydroxyl, 12 hydroxymethyl, trifluorornethoxy, nitro, methoxymethyl, fluoro, chioro, bromo, me-thoxy and rnethylthio; and wherein R 5 is selected from hydrido, methyl, ethyl, isopropyl, propyl, tert-butyl, butyl, pentyl, methoxy, tert-butoxy, rethoxyethyl, ethoxymethyl, rnethoxyrnethyl, phenyl, carboxyethyl, methoxycarbonylmethyl, methoxycarbonylethyl, Ctert -but oxycarbonylaminomet hyl, methoxycarbonyl, aminomethyl, and methylcarbonylaainomethyl; or a pharmaceuticallyacceptable salt thereof.

Within Formula I there is a subclass of compounds of high interest represented by Formula III: *R 7 Y 0 0 0 whri R6** isslceIrmhdoylwrakl carboxyl haoNoer.%oylkl oe whrenR 6 i slctdfrmhydroxylakl, lower hlalkylufnlxy oe arboxyal, hloyl, lower carb yloxyalkyl, lower acyloyarbylalkyln lower arclalkyl oe lkxakl 2 yrlower kxakoalky, lower araoxalkyl, lcrower, oharoalkl owrbnl hydroxlyl, lower yrxakl aowry (hydroxalkylai, lower oalkylsulfnoxy, enlowero aitkoylloealkyl lwe cawroxalkoxyalkyinl, hloe cloaralklyl and lower ylo;anyl werein R is n rmr aias selected from yrdlwrak lower oalkoxy, n, lower alk ylaminol phenyl aminor carboxyalkyl, lower alkoxycarbonylalkyl, lower alkoxycarbonyl, lower aminoalkyl, lower alkoxycarbonylaminoalkyl, and lower alkylcarbonylaminoalkyl; or a pharraceutically-acceptable salt thereof.

A preferred class of compounds consists of those compounds of Formula III wherein R 6 is selected from lower alkyl, lower haloalkyl, and lower hydroxylalkyl; wherein R 7 is one or more radicals selected from hydrido, lower alkyl, halo, and lower alkoxy; and wherein R 8 is selected from lower alkyl, phenyl, and lower aminoalkyl; or a pharmaceutically-acceptable salt thereof.

A more preferred class of compounds consists of those compounds of Formula III wherein R 6 is selected from methyl, difluoromethyl and hydroxymethyl; wherein

R

7 is one or more radicals selected from hydrido, methyl, fluoro, chloro, broro, and methoxy; and wherein

R

8 is selected from methyl, ethyl, isopropyl, propyl, tert-butyl, butyl, pentyl, phenyl, and aminomethyl; or a pharmaceutically-acceptable salt thereof.

A family of specific compounds of particular interest within Formulas I-III consists of compounds and pharmaceutically-accepcable salts thereof as follows: 4 -f 2 -(2-methylpyridin-6-yl)-4-(trifluoromethyl)-lHimidazol-l-yl]phenyl]sulfonyl]acetamide; N-f 4 2 -(2-methylpyridin-Gyl)-4-(trifluororethyl)-lHimidazol-l-yl]phenyl]sulfonyl]propanamide; 4-[ 2 2 -methylthiazol-4-yl)-4-(trifluoromethyl)-lHimidazol-l-yl]phenyl]sulfonyl]acetamide; 4 2 2 -methylthiazol-4-yl)- 4 -(trifluoromethyl)-lHimidazol-lyl]phenyllsulfonyl]propanamide; 4 -rethylthiazol-2-yl)-4-(trifluoromethyl) 1H irmdazol-1yljphenylsulfonylacetamide; N- [14- (4-methylthiazol-2-yl) (trifluoromethyl) -lHimidazol-l-yljphenyllsulfonylpropanamide; N- ff4- (2-methylpyridin-3-yl) (trifluoromethyl) -1Himidazol-1-yl]phenyl] sulfonyl]acetamjde; N- (2-methylpyridin-3-yl) (trifluoromethyl) -1Kirnidazol-1-yllpheiyl] sulftonyl]acetanmjde; (3-pyridinyl) -4(rfurmty)-Hindzll yllphenyl] sulfonyl] acetarnide; [4-[2-(5-methylpyridin-3-yl)-4- (trifluoromethyl)-lHirnidazol-1-yl Iphenyl]I sulfonyl]acetamide; N- (2-rethylpyridin-3-yl) (trifluoromethyl) -1Himidazol-1-yl]phenyl]sulfonyl]acetamide; 2 -(5-rnethylpyridin-3-yl) (trifluoromethyl)-lHiinidazol-1-yl Iphenyl]I sulf onyl]butanamide; N-f [4-[2-(2-rnethylpyridin-3-yl) (trifluoromethyl) -lHilidazol-1-yllphenyl] sulfonvl]butanamide; N-f 4 2

-C

3 -chloro-5-methylphenyl) -4-(trifluoromethyl)-lHiridazol-1-yl]phenyl] sulfonyl]acetamide; N-f f 4 3 -(difluoromethy)-5(3fuoro4methoxypenyl) -lHpyrazol-1-yl~phenyl] sulfonyl Ipropanarnide; N-f 4 -f 3 -(difluoromethy)-5-(3fuoro4methoxphenyl)lHpyrazol-l-yl]phenyl]sulfony1]butanamide; N-f [f 4 -dimethyl) -3-phenyl-H-pyrazo..4yl]pheiyl] sulfonyl] acetarnide; 2-hydroxy-3-[ f[ 4 -(5-xehy-3-phenylisoxazo1-4yl)phenyl] sulfonyllanino] -3-oxopropanoic acid; 2-hydroxy-N-f 4 -(5-methyl-3-phenyisoxazola.yl)phenyl] sulfonyl] propoananide a-hydroxy-N-[f 4 -(S-methyl-3-phenylisoxazo-4yl) phenyl] sulfonyl] benzeneethanamide; N- (5-methyl-3-phenylisoxazol-4yl)phenyl] sulfonyl]benzeneethanamide; N- 3- (3-fluorophenyl) -5-mrethylsoxazol-4yllphenyl] sulfonyl] acectaride; 2-methvl-N-(f[ 4 -(5-methyl-3-pohenylisoxazo14yl)phenyl] sulfonyl] propanamnide; [4-(5-methyl-3-phenylisoxazo14yl] phenyl] sulfonyl] propanamide; (5-methy1-3-phenylisoxazol-4yl) phenyl] sulfonvi] benza-mide; 2, 2-dimethyl-N- (5-mehyP3-phenlisoxatol- 4 ylJ phenyl I sulfoly I] propanainide; N-ili 4 (-mehy13-pheflisoxazol- 4 yl) phenlyl] sulfonyl IbutalamJde; N- (S-methyl-3-phenlisoxazol1 4 yl) phenyl] sulfony- pentanaxnide; N- (5-methy13-phenylisoxazol- 4 yl) phenyll sulfonlhexanamitde; 3-methoxy-N- (5-rethyJ-3phenylisoxazol- 4 yl) pheiy-I 5 lfonyllpropalamide; 2 -ethoyN- [4-(5-mehy13phenyisoxazol-4 yl1) phenyl1] s u Ifony I I ac e tami de; 0: N-il [5-methyl-3-pheflisoxazol- 4 yl] phenyl] 5 u1follacetaide; 0. 15 N- l4 (5 (4 chlQrohenyl) -3 (trif uoromehyl) -1H-pyrazol 1 yi Iphenyl] sulfonyl] propanaxrnide N- (4-chiorophelyl) (trifluoromethYl) -lH-pyrazol-lyllphenyll sulfonyllbutanan-Lde; N- 5- (4 -chiorophelYl) -3 (trif lUOromfethyl) -1H-pyrazol

I

yl~pheiy1Isulfonyllacetami~de; N- [4 3- (di fluo rOtethy 1) 6- fluoro 1, 5 -dihydro -7 -mfet hoxy [21benz othi opyralo 4 3- c ]pyrazQo 1 l 0. y 1 phenyl1 sul fonylI] ac etamri de; 2 1 b fz othi opyrano 4, -cI pyraz o 1 yllphellsulfonyll]acetamtride; N 3- (d f luoromethJ1) 5- 3 -f luoro -4 -me thoxypheny 1) -IH pyra zo I I-y Iphely I sul f oy11 a cet amide; N-i[ 4 (2-me-hyl4-phenyloxazolS5 yl)phenlYJIsulfonyllIaceta-mide; methyl (5-methyl3-pheTnylisoxazol- 4 yl) phenyll sul f orl I amino I oxoacetate; 2 -me thoxW-N i4 5 -me thy phely Ii s oxa zo I- 4 y 1) phenylI s ulIf oly II a c e t anide; N-il 4 (5-(dif luoromethyl) 3-phenylisoxazol4 yl] phenyl I sulf oyll propanaide; N-l (dif luoromethYl) -3-phenylisoxazol- 4 yllpheny1l sulf onlY) butanamfide; CS-methyl-3-phenylisoxazol-4yl)phenyl} sulfonyl]arnino} -4-oxobutanoic acid; N- (5-methyl-3-phenylisoxazol-4 yl) phenyl] sulfonyl] forrnaride; 1,1-dimethy-lethyl N-([4-(5-methyl-3-phenylisoxazol.4yl) ohenvl] sulfonyl] carbamate; N- (5-methyl-3-phenylisoxazol-4yl) phenyl] sulfonyl] glvcine; 2-ami'no-N-l( 4 -(5-methyl-3-phenylisoxazol-4.

yl)phenyl] sulfonyllacetamide; 2- Cacetylamino) (5-methyl-3-phenylisoxazol.4yl) phenyl] sulfonyl] acetainide; methyl 4 -(5-rnethyl-3-phenylisoxazol-4yl)phenyl] sulfonyllamino] -4-oxobutanoate; 4 -(5-methyl-3-phenylisoxazol-4.

yl) phenyl] sulfonyl] carbanate; N-acetyl-N- 4 -(5-methyl-3-phenylisoxazol-4yl) phenyl] sulfonyllglycine, ethyl ester; (5-rethyl-3-phenylisoxazol -4yl)phenyl] sulfonyl]aminol -4-oxobutanoic acid; N- (4-methyiphenyl) (trifluoromethyl) -lH-pyrazol-lyl] phenyl] sul fonyl] acetanide; methyl 3 4 -(5-rnethyl-3-phenylisoxazo-4 yl) phenyl] sulfonyllarnino] -3-oxopropanoate; 4 5-( 3 broo 5- f 1uo ro- 4 -me thoxpheny) 2 (trifluoromethyl) oxazol-4-yl] -N-methylbenzenesulfonamide; 1-dimethylethyl) (5-methyl-3-phenylisoxazol-4yl) benzenesulfonanide; 4 fl1uo rophe ny1) 3- (t ri1f 1u orome thyl1) -l1H -pyraz ol1-l1-y N methylbenzenesulfonamide; N-methyl-4- (5-methyl-3-phenylisoxazol-4 yl) benzenesul fonaniide; N- C(4- (hydroxynethyl) -3-phenylisoxazol-4yl] chenyl] sulfonyl] acetLamide; N- 4 [5-(acetoxynethyl) -3-phenylisoxazol-4yl] phenyl] sulfonvi] acetanide; 1, 1-dimethyl ethyl 4 (5-methyl-3-phenylisoxazol-4yl) phenyl] sulfonyll amino] -2-oxoethyl] carbamate; (3-chloro-4-fluorophenyl) cyclopenten-lyl] phenyl] sulfonyl] acetamide; 4- (4-f luorophenyl) -'iH-pyrrol-l-yl] -Nrethylbenzenesulfonamide; (4-fluorophenyl)cvclopenten-l-yl]I -Nmethylbenzenesulfonamide; (4-fluorophenyl) -2,3-dihydro-2-oxofuran-4yllpheny] sulfonyl] acetarnide; [4-(3-phenyl-2,3-dihydro-2-oxofuran-4yl)pheny] sulfonyl] acetainide; N- 3, 4 -dimethyl -l1-phenyl H-pyrazo1- 5 yllphenyl] sulfonyl] propanamide; N- (2-rethylpyridin-3-yl) -4tri fluoromethyl imidazol -1yl ]phenyl]I sul fonyl Ipropananide; N N- [4 3- (4 -fl1uo ro phenyl1) 2, 3- d ihydro 2-oxo fu ran -4 yllpheny] sulfonyllpropananide; and N- (3-phenyl-2, 3-dihydro-2-oxofuran-4yl) pheny] sulfonyl] propanamide.

A preferred family of specific compounds of particular interest within FormulaS I-III consists of compounds as follows: 25 [4-[2-(2-methylpoyridin-6-yl)-4- (trifluoromethyl)-lHimidazol-l-yllphenyllsulfonyl)acetanide, sodium salt; N-f (2-methylpyridin-6-yl) (trifluoromethyl) -lHimidazol-l-yl~phenyllsulfonyllpropanamide, sodium salt; N- (2-methylthiazol-4-yl) (trifluoromethyl) -lHimidazol-l-yllphenyllsulfonyllacetamide, sodium salt; N-Il (2-methylthiazol-4-yl) (trifluoromethyl) -IIiridazol-l-yljphenyl] sulfonvllproTanamide, sodium salt; N- (4-rethylthiazol-2-yl) -4--(trifluoromethyl) -liiimidazol-1-yl]Dhenyllsulfonyllacetamjde, sodium salt; 4 -[2-(4-rnethvlthiazol-2-yl)-4-(trifluoromethyl)-lHimidazol-l-yllphenyl] sulfonyllpropanamide, sodium salt; [4 -pyridinyl) -4 -(tri fluoromer-hyl) -lH- imridazol -1yllphenyl] sulfonyllacetamide, sodium salt; N-f (5-rethy1pyridin-3-y1l -4-(trifluorbomethyl) -lHimidazol-1-yl]phenyl]sulfony1]acetamide, sodium salt; N-f[4- 2 -methylpyridin-3-yl) -4-(trif1uoromethyl) -lHimidazol-1-yl]phenyllsulfonyl]acetamide, sodium salt; f 4 -[2-(5-methylpyridin-3-yl) 4 -(trifluoromethyl)-lHimidazol-1-yllphenvllsulfonyllbutanamide sodium salt; N-Il 4- (2-methylpyridin-3-yl) -4-(trifluoromethyl) -lHimidazol-1-yl]phenylsufonybutanmde, sodium salt; N- 4 2 3clr--ehlpey)4 tiLlooehi -1Himidazol-1-yl]phenyl]sulfonyl]acetamide, sodium salt; N-f f4-[3-C(difluoromethyl) 3 -fluoro-4-mrethoxyphenyl) -lH- *pyrazol-l-yllphenyllsulfonyllpropanarmide, sodium salt; *006 N-f 4 3 -(difluoromethyl)5(3fluoro4methoxyhenyl) -18- 0 oo: opyrazol-l--yllphenyl] sulfonyl] butanarnide, sodium salt; 15 N-f 4 -[1,5-dimethyl)-3-phenyl-lH-pyrazo14- 0 yl] phenyl] sulfonyl] acetamide, sodium salt; 2-hydroxy-3- (5-methyl-3-phenylisoxazol-4o o..:yl)phenyl) sulfonyl] amino] -3-oxopropanoatLe, sodium salt; o'2-hydroxy-N-f f 4 -(5-rnethyl-3-pherlylisoxazol-4yl)phenyl] sulfonyllpropanainide, sodium salt; 0:00a-hydroxy-N- C5-methyl-3-phenylisoxazol-4- 00o~ooyl)phenyl] sulfonyllbenzeneethanam-ide, sodium salt; N- (5-methvl-3-phenylisoxazol-4 yl)phenyl] sulfonyllbenzeneethanami*de, sodium salt; 25 N-[f 4 -f 3

-C

3 -fluorophenyl)-5methylisoxazol-4 yllphenyl] sulfonyllacetamide, sodium salt; 2-methyl-N-f f 4 (5-methyl-3-ph-enyl-isoxazol-dyl)phenyl] sulfonyllpropananide, sodium salt; N- (-methyl-3-phenylisoxazol-4yllphenyllsulfonyllpropanainide, sodium salt; N- 5-methyl-3-phenylisoxazol-4 yl)phenyl] sulfonyljbenzamide, sodium salt; 2,2-dimethyl-N-f 4 -(5-methyl-3-phenylisoxazol-4yl)phenyl] sulfonyllpropanamjde, sodium salt; N-f f4-(5-methyvl-3-phenylisoxazoy4yl)phenyl] sulfonyllbutanamide, sodium salt; N-f[(4-(5-methyl-3-phenyvlisoxazol4 yl)phenyl) sulfonyl~peritanamide, sodium salt; (5-rethyl-3-phenylisoxazol-4yl)iohenyl] sulfonyllhexanamide, sodium salt; 3-met-hoxy-N- 4 (5-ethyl-3-phenylisoxazol.4yl)phenyl] Sulfonyllpropanamide, sodium salt; 2-ethoxy-N- 4 -(5-ethyl-3-phenylisoxazol-4yl)phenyl] sulfonyl] acetamide, sodium salt; N-Il[4- lS-methyl-3-phenylisoxazol-4yl] phenyl] sulforiyl] acetarnide, potassium salt; 5- (4 -chiorophenyl) 3- (tri fluoromethyl) 1Hpyrazol-l-yl]phenyl] sulfonyllpropanamnide, sodium salt; N-f 4 [5 -(4-chlorophenyl) 3 -(tri fluoromethyl) 1pyrazol-1-yllphenyl] sulfonyl] butanarnide, sodium salt; N- 4 (4-chlorophenyl) (trifJluoromethyl) -1Hpyrazol-l-yllphenyll sulfonyl] acetarnide, sodium salt; N- (difluoromethyl) -6-fluoro-1, 5-dihydro-7met-hoxy- [2]benzothiopyrano[4, 3-c] pyrazol-lyl]phenyl] sulfonyl] acetamide, sodium salt; [4-[6-fluoro-1, 5-dihydro-7-methox~y-3- (trifluororecthyl) -[2]benzothiopyrano 3-clpyrazol- 1-vi ]phenyllsulfonyllacetamide, sodium salt; N-f f3-(difluoromethyl) -5-(3-fluoro-4methoxyphenyl) -lH-pyrazol-l- 25 yllphenyllsulfonylacetamide, sodium salt; N-f [4-(2-methyl-4-phenyloxazol-5 yl)phenyl] sulfonyllacetamide, sodium salt; methyl (5-methyl-3-phenylisoxazol-4yl)phenyllsulfonlaninoloxacetate, sodium salt; 2-methoxy-N- 4- (5-methyl-3-phenylisoxazol.4yl) phenyl] sulfonyltacetaide, sodium salt; N- (difluoromethyl) -3-Phenylisoxazol-4yl]phenyl] sulfonyllpropanamide, sodium salt; N-f [4-f5-(difluoromethyl) -3-phenylisoxazol-4yllphenyllsulfonyllbutanamide, sodium salt; 4-f[[(4-(5-methvl-3-phenylisoxazol-4.

yl)phenyl] sulfonyl] amino] -4-oxobutanoic acid, sodium salt; N- [14-(5-methyl-3-phenylisoxazol-4 yl)phenyl] sulforiyl] forrnamide, sodium salt; 1, l-dimethv-lethyl 4 -(5-methyl-3-phenylisoxazol.4.

yl) phenvi] sulfonyl] carbainate, sodium salt; CS-methyl-3-phenylisoxazol.4yl) phenyl] sulfonyl Iglycine, sodium salt; 2-amino-N-[ 4 -(5-methyl-3-phenylisoxazol-4yl) phenyl] sulfonyl] acetanide, sodium salt; 2- (acetylamino) (5-rethyl-3-phenylisoxazolp4.

yl)phenyllsulfonyllacetamide, sodium salt; methyl 4 -(5-methyl-3-phenylisoxazol.4yl)phenyl] sulfonyl] amino] 4 -oxobutanoate, sodium *...salt; N- (5-methyl-3-phenylisoxazol-4 15 yl)phenyllsulfonyllcarbamate, sodium salt; 9 4- (5-methyl-3-phenylisoxazol-4yl)phenyl] sulfonyl] amino] -4-oxobutanoic acid, sodium salt; 4 -[S-(4-methylphenyl) 3 -(trifluorornethyl)-lHpyrazol-l-yllphenyllsulfonyllacetande, sodium salt; *Soo methyl 4 -(5-methyl-3-phenylisoxazol-4 yl)phenyl] sulfonyl] amino] 3 -oxopropanoate, sodium salt; 4 -[5-(hydroxymethyl) -3-phenylisoxazol-ayl]phenyl]sulfonyl]acetamide, sodium salt; (acetoxyrnethyl) -3-phenylisoxazol-4yl] phenyl] sulfonyl] acetainide, sodium salt; pfenylisoxazol-4-yl)phenyl] sulfonvllanino] -2oxoethyllcarbante, sodium salt; N- (3-chloro-4-fluorophenvl) cyclopenten-lyl]phenyllsulfonyllacetamide, sodium salt; and 4

K[

3 -(4-fluorophenyl) 2 ,3-dihydro-2-oxofuran-4yl] pheny] sulfonyl] acetaride, sodium salt; (3-ohenyl-2,3-dihdro2oxofuran-4 yl)pheny] sulfonyl] acetamide, sodium salt; N- 4 -dimethyl-1-phenyl-l~Hpyrazolyl]phenyl] sulfonyllpropanamide, sodiumn salt; 4 -[2-(2-methylpyridin-3-yl)-4trifluoromethylimidazol-1yl]phenyl] sulfonyl]propanamide, sodium salt; N-[[4-[3-(4-fluorophenyl)-2,3-dihydro-2-oxofuran-4yl]pheny]sulfonyl]propanamide, sodium salt; and N- [4-(3-phenyl-2,3-dihydro-2-oxofuran-4yl)pheny] sulfonyl]propanamide, sodium salt.

The term "hydrido" denotes a single hydrogen atom This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene radical. Where used, either alone or within other terms such as "haloalkyl", "alkylsulfonyl", "alkoxyalkyl" and "hydroxyalkyl", the term "alkyl" embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. The term 25 "alkenyl" embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms.

Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term "alkynyl" denotes linear or branched radicals having at least one carbon-carbon triple bond, and having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, bucynyl, and the like. The terms "alkenyl" and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, and orientations. The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkenyl" embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having four to about eight carbon atoms. Examples of such radicals include 15 cyclobutenyl, cyclopentenyl and cyclohexenyl. The term "halo" means halogens such as fluorine, chlorine, bromine or iodine. The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above.

20 Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.

"Lower haloalkyl" embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms "alkoxy" and "alkyloxy" embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms.

More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term "alkoxyalkyl" embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkvl radicals. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as e"0 fluoro, chloro or bromo, to provide haloalkoxy radicals.

15 More preferred haloalkoxy radicals are "lower haloalkoxy" radicals having one to six carbon atoms and one or more halo radicals. Examples of such radicals '.eo include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces aromatic radicals such as phenyi, naphthyl, 25 tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl. The term "heterocyclyl" embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms thiazolidinyl, etc.).

Examples of partially unsaturated heterocyclyi radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radiclas may include a pentavalent nitrogen, such as in tetrazolium and pyridinium radicals. The term "heteroaryl" embraces unsaturated heterocyclyl radicals. Examples of .6heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl 4 H-1,2,4-triazolyl, 1H-1, 2 ,3-triazolyl, 2 H-1,2 3-triazolyl, etc.) tetrazolyl 1H- 0* tetrazolyl, 2 H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, las benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl tetrazolo(1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 0:00 25 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl 1,2, 4 -oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5oxadiazolyl, etc.) etc.; unsaturated condensed heterocvclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term "heteroaryl"also embraces radicals where heterocyclyl radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heterocyclyl group" may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino. The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred 15 alkylthio radicals are "lower alkylthio" radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term "alkylthioalkyl" embraces radicals containing an 20 alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkyl radicals are "lower alkylthioalkyl" radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkyl radicals include methylthiomethyl. The term "alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms, attached to a divalent radical.

More preferred alkylsulfinyl radicals are "lower alkylsulfinyl" radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include mechylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term "sulfonyl", whether used alone or linked to other terms such as "alkylsulfonyl", denotes a divalent radical,

-SO

2 "Alkylsulfonyl" embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having one to six carbon atoms.

Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The "alkylsulfonyl" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals. The terms "sulfaryl", "aminosulfonyl" and "sulfonamidyl" denote

NH

2 0 2 The term "acyl" denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and radicals formed from succinic, glycolic, gluconic, lactic, malic, 15 tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, mandelic, pantothenic, -hydroxybutyric, galactaric and galacturonic acids. The term "aroyl" embraces aryl radicals with a carbonyl radical as defined below. Examples of aroyl include benzoyl, 20 naphthoyl, phenylacetyl, and the like, and the aryl in said aroyl may be additionally substituted, such as in p-hydroxybenzoyl, and salicylyl. The term "carbonyl", whether used alone or with other terms, such as "alkoxycarbonyl", denotes The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -C02H. The term "carboxyalkyl" embraces alkyl radicals substituted with a carboxy radical. More preferred are "lower carboxyalkyl" which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term "alkoxycarbonyl" means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are "lower alkoxycarbonyl" radicals with alkyl portions having one to six carbons. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The terms "alkylcarbonyl", "arylcarbonyl" and "aralkylcarbonyl" include radicals having alkyl, hydroxylalkyl, aryl, arylalkyl and aryl-hydroxylalkyl radicals, as defined herein, attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, phenylcarbonyl, benzylcarbonyl, and phenyl(hydroxymethyl)carbonyl. The term "carboxyalkylcarbonyl" embraces alkylcarbonyl radicals substituted with a carboxy radical. More preferred are 15 "lower carboxyalkylcarbonyl" which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with hydroxyl.

Examples of such lower carboxyalkylcarbonyl radicals include carboxymethylcarbonyl, carboxyethylcarbonyl, 20 carboxypropylcarbonyl,

HO

2 C(CHOH) 4 HO2C(CHOH) 2 C(0)- SH0 2

C(CH

2 (CHOH)C(O)-, and HO2CCH 2 C(OH) (CO 2 The term "carboxyalkenylcarbonyl" embraces derivatives of maleic and fumaric acids. Examples of such carboxyalkenylcarbonyl radicals include carboxyethenylcarbonyl and (E)-carboxyethenylcarbonyl.

The term "aralkyl" embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The terms benzyl and phenylmethyl are interchangeable.

The term "heterocyclylalkyl" embraces saturated and partially unsaturated heterocyclyl-substituted alkyl radicals, such as pyrrolidinylmethyl, and heteroarylsubstituted alkyl radicals, such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "aryloxy" embraces aryl radicals attached through an oxygen atom to other radicals. The term "arylthio" embraces aryl radicals attached to a sulfur atom. The term "aralkoxy" embraces aralkyl radicals attached through an oxygen atom to other radicals. The term "heterocyclyloxy" embraces heterocyclyl radicals attached through an oxygen atom to other radicals. The term "aralkoxyalkyl" embraces aralkoxy radicals attached through an oxygen atom'to an alkyl radical. The term "aralkylthio" embraces aralkyl radicals attached to a sulfur atom. The term "aralkylthioalkyl" embraces aralkvlthio radicals attached through a sulfur atom to an alkyl radical. The term "aminoalkyl" embraces alkyl radicals substituted 15 with amino radicals. More preferred are "lower aminoalkyl" radicals. Examples of such radicals include o* aminomethyl, aminoethyl, and the like. The term "alkylamino" denotes amino groups which are substituted with one or two alkyl radicals. Preferred are "lower 20 alkylamino" radicals having alkyl porions having one to six carbon atoms. Suitable lower alkylamino may be monosubstituted N-alkylamino or disubstituted

N,N-

alkylamino, such as N-methylamino, N-ethylamino,

N,N-

dimethylamino, N,N-diethylamino or the like. The term "arylamino" denotes amino groups which are substituted with one or two aryl radicals, such as N-phenylamino.

The "arylamino" radicals may be further substituted on the aryl ring portion of the radical. The term "aralkylamino" embraces amino groups which are substituted with one or two aralkyl radicals. The terms "N-arylaminoalkyl" and "N-aryl-N-alkyl-aminoalkyl" denote aminoalkyl groups which are substituted with one aryl radical or one aryl and one alkyl radical, respectively. Examples of such radicals include Nphenylaminomethyl and N-phenyl-N-methylaminomethyl. The term "aminocarbonyl" denotes an amide group of the formula -C(=O)NH2. The term "alkylaminocarbonyl" denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals'on the amino nitrogen atom. Preferred are "N-alkylaminocarbonyl" and "N,N-dialkylaminocarbonyl" radicals. More preferred are "lower N-alkylaminocarbonyl" and "lower N,Ndialkylaminccarbonyl" radicals with lower alkyl portions as defined above. The term "alkylaminoalkyl" embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical. The term "aryloxyalkyl" embraces radicals having an aryl radicals attached to an alkyl radical through a divalent oxygen atom. The term "arylthioalkyl" embraces radicals having an aryl radicals attached to an alkyl radical through a divalent sulfur atom. "Amino acid residue" means any of the naturally occurring alpha-, beta- and gamma-amino 15 carboxylic acids, including their D and L optical isomers and racemic mixtures thereof, synthetic amino acids, and derivatives of these natural and synthetic amino acids. The amino acid residue is bonded either through an amino or an acid functional group of the 20 amino acid. The naturally occurring amino acids which can be incorporated in the present invention include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, cyclohexylalanine, tryptophan, tyrosine, valine, P-alanine, and y-aminobutyric acid. Derivatives of amino acids which can be incorporated in the present invention include, but are not limited to amino acids having protected and modified carboxylic acids, including acid esters and amides, protected amines, and substituted phenyl rings, including but not limited to alkyl, alkoxy and halo substituted tyrosine and phenylalanine.

The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formula I in association with at least one pharmaceutically-accepcable carrier, adjuvant or diluent.

The present invention also comprises a method of treating inflamm~ation or inflammation-related disorder in a subject, the method comp~rising treating the subject having or susceptible to such inflammuation or inflammnation-relate d disorder with a compound of Formula I' R2 A-..R1 10 0 0 wherein A is a ring substituent selected from partially unsaturated heterocyclyl, heteroaryl, cycloalkenyl and aryl, wherein A is optionally substituted at a substitutable 15 position with one or more radicals selected from alkylcarbonyl, formryl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, amninocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl, cydloalkenyl, aralkyl, heterocyclylalkyl, alkvlthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxycarbonylalkyl, aininocarbonylalkyl, alkylaininocarbonyl, N-aryla-ninocarbonyl, N-alkyl-Narylaminocarbonyl, alkylalninocarbonylalkyl, alkylanino, Narylainino, N-aralkylamino, N-alkvl-N-aralkylainino, N-alkyl-Narylamino. aminoalkyl, alkylaminoalkyl, N-arylaxninoalkyl,

N-

aralkylaminoalkyl, N-alkyl -N-aralkylaminoalkyl, N-alkyl -Narylarninoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylarninosulfonyl, arylsulfonyl, and Nalkyl-N-arylaminosulfonyl; wherein R 1 is selected from heterocyclyl, cycloalkyl, .cycloalkenyl and aryl, wherein R 1 is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; wherein R 2 is selected from hydrido and alkoxycarbonylalkyl; and wherein R 3 is selected from alkyl, carboxvalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, amino acid residue, and alkylcarbonylaminoalkylcarbonyl; or a pharmaceuticallyacceptable salt thereof.

The method of the present invention also includes o prophylactic treatment. A preferred method of the invention is the administration of water soluble compounds of Formulas I-III via injection.

15 Also included in the family of compounds of Formula I are the stereoisomers thereof. Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures 20 thereof. Accordingly, some of the compounds of this invention may be present in racemic mixtures which are also included in this invention. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synchesis of covalent diastereoisomeric molecules by reacting an amine functionality of precursors to compounds of Formula I with an optically pure acid in an activated form or an optically pure isocyanate.

Alternatively, diastereomeric derivatives can be prepared by reacting a carboxyl functionality of precursors to compounds of Formula I with an optically pure amine base. .The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of Formula I can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.

Also included in the family of compounds of Formula I are the pharmaceutically-acceptable salts thereof. The term "pharmaceutically-acceptable salts" embraces salts commonly o used to form alkali metal salts and to form addition salts of o free acids or free bases. The nature of the salt is not S 15 critical, provided that it is pharmaceutically-acceptable.

Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, 20 sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, 33 algenic, P-hydroxybutyric, gaiactaric and galacturonic acid.

Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts and organic salts. More preferrred metallic salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts and other physiological acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quanternary ammonium salts, including in part, trometamine, diethylamine, N,N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, •meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the 15 corresponding compound of Formulas I-III by reacting, for example, the appropriate acid or base with the compound of Formulas I-III.

GENERAL SYNTHETIC PROCEDURES The cyclooxygenase-2 inhibitor prodrugs of the invention can be synthesized according to the following procedures of Schemes I-XVII, wherein the R 1

-R

8 substituents are as defined for Formulas I-III, above, except where further noted.

Scheme I

R!

o Base 11 R- CCH3 R 1 CO2CH- R- 0 2 0 EtOH, A -NHNH o S NH2N

N

R1 R1 3 4 Synthetic Scheme I shows the preparation of cyclooxygenase-2 inhibitor compounds, as described in WO95/15316, which is incorporated by reference. In step 1, ketone 1 is treated with a base, preferably NaOMe or NaH, and an ester, or ester equivalent, to form the intermediate diketone 2 (in the enol form) which is used without further purification. In step 2, diketone 2 in an anhydrous protic solvent, such as absolute ethanol or acetic acid, is treaced with the hydrochloride salt or the free base of a substituted hydrazine at reflux to afford a mixture of pyrazoles 3 and 4.

Recrystallization or chromatography affords 3 usually as a solid. Similar pyrazoles can be prepared by methods described in U.S. Pat. Nos. 5,401,765, 5,434,178, 4,146,721, 5,051,518, 5,134,142 and 4,914,121 which also are incorporated by reference.

Scheme II Cw 1) Base R SCH3 R 2) RCO-X Ri S C 6 RaNHNH-, Ri Oxidize R

,N

R

8 Scheme II shows the four step procedure for forming cyclooxygenase-2 inhibitor pyrazoles 8 as described in U.S.

patent No. 5,486,534 (where Ra is hydrido or alkyl) from ketones 5. In step 1, ketone 5 is reacted with a base, such as lithium bis(trimethylsilyl)amide or lithium diisopropylamide (LDA) to form the anion. In step 2, the anion is reacted with an acetylating reagent to provide diketone 6. In step 3, the reaction of diketone 6 with hydrazine or a substituted hydrazine, gives pyrazole 7. In step 4, the pyrazole 7 is oxidized with an.oxidizing reagent, such as Oxone® (potassium peroxymonosulfate), 3chloroperbenzoic acid (MCPBA) or hydrogen peroxide, to give a mixture of the desired 3 -(alkylsulfonyl)phenyl-pyrazole 8 and the 5-(alkylsulfonyl)phenyl-pyrazole isomer. Sulfonamides 9 can be prepared such as by the Huang method [Tet. Lett., 7201-04 (1994)].

Alternatively, diketone 6 can be formed from ketone by treatment with a base, such as sodium hydride, in a solvent, such as dimethylformanide, and further reacting with a nitrile to form an aminoketone. Treatment of the aminoketone with acid forms the diketone 6. Similar pyrazoles can be prepared by methods described in U.S. Pat.

No. 3,984,431 which is incorporated by reference.

*°oO* *ooo **ooo Scheme III Z~pl S02CH +Base HO

R

01 0 Rb Ir ORb 0 0 12 Iaq. NaOH, a ,SO 2

CH

1 s0 2 cH 3 00 5

SO

2

NH,

T

Cu, a

SOCH

3 SOCH, R- ~P.1 16 Cyclooxygenase-2 inhibitor diaryl/heteroaryl bthiohenes (where T is S, and Rb is alkyl) can be prepared by the mnethods described in U.S. Patent Nos. 4,427,693, 4,302,461, 4,381,311, 4,590,205, and 4,820,827, and PCT documents WO 95/00501 and W094/15932, which are incorporated by reference. Similar pyrroles (where T is furanones and furans (where T is 0) can be prepared by 4, C, 38 methods described in POT documents WO'95/O50. and W094/15 932.

Scheme

IV

CH

3 S 0 NaH TBS,-i

OTBS

cH 3

S

0* es 9*

S

0 MC

PBA

0 It

H

3

CS

It 0 H 0

H

3

CS

11 0 IRCOC1 Base 0 N Rl H-aS 0 0 N~HdOAc HOAc *000

S

S

0000.0

S

N

0 0 11 0 Cyclooxygenase-2 inhibitor diaryl/heteroaryl oxazoles can be prepared by the methods described in U.S. Patent Nos. 5,380,738, 3,743,656, 3,644,499 and 3,647,858, and PCT documents WO 95/00501 and.W094/27980, which are incorporated by reference.

Scheme V NOH

N-O

R1 1) 2 eq. n-BuLi RI OH 2) (R 3 CO) 2 0 25 26 1) ClS03H 2) NH40H N-0 2) NHi 4

OH

27 Cyclooxygenase-2 inhibitor diaryl/heteroaryl isoxazoles can be prepared by the methods described in PCT application Serial No. US96/01869, PCT documents WO92/05162, and WO92/19604, and European Publication EP 26928, which are incorporated by reference. Sulfonamides 27 can be formed from the hydrated isoxazole 26 in a two step procedure. First, hydrated isoxazole 26 is treated at about 0 °C with two or three equivalents of chlorosulfonic acid to form the corresponding sulfonyl chloride. In step two, the sulfonyl chloride thus formed is treated with concentrated ammonia to provide the sulfonamide derivative 27.

Schemre

VI

R

1 CN ck,,/ 28 29 A.kylalunjnum Reagent Solvent

NH

R kNH 30 SO2)CH-z Rb X, R Alkylation; 0 base Dehydration

R

R1 N SO0 2 CHi

SO

2

NE-,

SO2 CH 3 Scheme VI shows a three step preparation of the cyclooxygenase-2 inhibitor imidazoles 33. In step 1, the reaction of substituted nitriles (R'CN) 28 with primary phenylamines 29 'in the presence of alkylaluminum reagents such as trimethylaluminum, r-riethlaluminum, dimethylaluminum chloride, diethylaluminum chloride in the presence of inert solvents such as toluene, benzene, and xylene, gives amidines 30. In step 2, the reaction of amidine 30 with 2-haloketones (where X is Br or Cl) in the presence of bases, such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate or hindered tertiary amines such as N,N'diisopropylethylamine, gives che 4 ,5-dihydroimidazoles 31 (where Rb is alkyl). Some of the suitable solvents for this reaction are isopropanol, acecone and dimethylformamide.

The reaction may be carried out at temperatures of about 0 C to about 90 0 C. In step 3, the 4 ,5-dihydroimidazoles 31 may be dehydrated in the presence of an acid catalyst such as 4-toluenesulfonic acid or mineral acids to form the 1,2disubstituted imidazoles 32 of the invention. Suitable solvents for this dehydration step are toluene, xylene and benzene. Trifluoroacetic acid can be used as solvent and catalyst for this dehydration step.

Sulfonamides 33 can be prepared such as by the Huang method 15 [Tet. Lett., 35, 7201-04 (1994)].

In some cases where R methyl or phenyl) the intermediate 31 may not be readily isolable. The reaction, under the conditions described above, proceeds to give the targeted imidazoles directly.

Similarly, imidazoles can be prepared having the sulfonylphenyl moiety attached at position 2 and R 1 attached at the nitrogen atom at position 1.

Diaryl/heteroaryl imidazoles can be prepared by the methods described in U.S. Patent Nos. 4,822,805 and PCT documents 25 WO 93/14082 and W096/03388, which are incorporated by reference.

42 Scheme

VII

0 OTMS RI',H TMSCN R I CN catalyst

H

1) Ba, 2) se

SR

2

SCH

3 1) Base 2) L H~CH- 36 Oxidi zing agent

SCH

3

R

NTI

4 OAc, HOAc

RCHO/

N.

S0 2

CH

3

N

Oxidat ion £02NH2

N

H

Imidazole cyclooxygenase-2 inhibitor compounds 41 may be synthesized according to the sequence outlined in Scheme VII. Aldehyde 34 may be converted to the protected cyanohydrin 35 by reaction with a trialkylsilyl cyanide, such as trimethylsilyl cyanide (TMSCN) in the presence of a catalyst such as zinc iodide (Znl2) or potassium cyanide (KCN). Reaction of cyanohydrin 35 with a strong base followed by treatment with benzaldehyde 36 and using both acid and base treatments, in that order, on workup gives benzoin 37. Examples of strong bases suitable for this reaction are lithium diisopropylamide (LDA) and lithium hexamethyldisilazane. Benzoin 37 may be converted to benzil 38 by reaction with a suitable oxidizing agent, such as bismuth oxide or manganese dioxide, or by a Swern 15 oxidation using dimethyl sulfoxide (DMSO) and trifluoroacetic anhydride. Benzil 38 may be obtained directly by reaction of the anion of cyanohydrin 35 with a substituted benzoic acid halide. Any of compounds 37 and 38 may be used as intermediates for conversion to imidazoles 39 according to chemical procedures known by those skilled in the art and described by M. R. Grimmett, "Advances in Imidazole Chemistry" in Advances in Heterocyclic Chemistry, 12, 104 (1970). The conversion of 38 to imidazoles 39 is carried out by reaction with ammonium acetate and an appropriate aldehyde (RCHO) in acetic acid. Benzoin 37 may be converted to imidazoles 39 by reaction with formamide. In addition, benzoin 37 may be converted to imidazoles by first acylating with an appropriate acyl group (RCO-) and then treating with ammonium hydroxide. Those skilled in the art will recognize that the oxidation of the sulfide to the sulfone may be carried out at any point along the way beginning with compounds 36, and including oxidation of imidazoles 39, using, for examples, reagents such as hydrogen peroxide in acetic acid, m-chloroperoxybenzoic acid.(MCPBA) and potassium peroxymonosulfate (OXONE®) Sulfonamides 41 can be prepared such as by the Huang method [Tet. Lett., 7201-04 (1994)].

IDiaryl/htteroaryl imidazoles can be prepared by the methods described in U.S. Patent Nos. 3,707,475, 4,686,231, 4,503,065, 4,472,422, 4,372,964, 4,576,958, 3,901,908,

POT

application Serial No. US95/09505, European publication

EP

372,445, and POT document WO 95/00501, which are incorporated by reference.

Scheme

VIII

0 CH3S Br 1. n-BuLi, TI-F, -78 -C- 0o' 2. Znc1 2 42 0 cH 3 Znc1 0, Br Br

)I

44 0

SCH

3 clzn- R R 0

SCH

3 1. n-BuLj., THF, -78 OC Br 2. Zncl,j Pd'j RI Br 0 SCH3 R R R R 48 Diaryl/heteroaryl cyclopentene cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S.

Patent No. 5,344,991, and PCT document WO 95/00501, which are incorporated by reference.

Scheme. IX

SO

2

CH

3

SO

2

CH

3 Pd°, PhCH 3

R'

C

2 Br RB H Na 2

CO

3

A

R-B (OH) R R R R 49

SO

2N H2

R

1 R R 51 Similarly, Synthetic Scheme IX shows the procedure for Sthe preparation of 1, 2 -diarylbenzene cyclooxygenase-2 inhibitor agents 51 from 2-bromo-biphenyl intermediates 49 (prepared similar to that described in Synthetic Scheme VIII) and the appropriate substituted phenylboronic acids.

Using a coupling procedure similar to the one developed by Suzuki et al. [Synth. Commun., 11, 513 (1981)], intermediates 49 are reacted with the boronic acids in toluene/ethanol at reflux in the presence of a Pdo catalyst, tetrakis(triphenylphosphine)palladium(0), and 2M sodium carbonate to give the corresponding 1,2diarylbenzene antiinflammatory agents 50 of this invention.

Sulfonamides 51 can be prepared such as by the Huang method [Tet. Lett., 35, 7201-04 (1994)]. Such terphenyl compounds can be prepared by the methods described in U.S.

application Serial No. 08/346,433, which is incorporated by reference.

Scheme

X

0 II 0 N~R C-i-CN, EtOH C/ I 0N

R'

*52 53 54 Di rlh t r ay *h a o ec c oxge a e2 ih b t r ca be pr p rdb.h eh d es rb d i .P t n o 4, 5 ,5 ,4 6 2 90*u o e nd c m n P 5 2 6 4 n C Nos 5,6,87 4,1,2,45366 7C p lcto Seral o. S9/0110 ndPCT app icaio SeialNo US96/01111, ~N Shc r noprae yrfrne Scheme XI

R

H

2

N,

0 0 56 Et 3 N DMAP THF R O RS1 R 0 H R 57 Synthetic Scheme XI illustrates a method for the preparation of acylated sulfonamides 57. The method involves treatment of an unsubstituted sulfonamide 56 with a suitable acylating agent such as an anhydride, acid chloride, acyl imidazole, or active ester, in the 10 presence of base and a suitable solvent, such as tetrahydrofuran (THF), to afford the acylated sulfonamide 57. The product 57 can then be isolated by chromatography or by crystallization.

Scheme XII R I RS

NR

O O0 NaOH EtOH

H

2 0 Na' N /A.R T 0 o 0 0 Synthetic Scheme XII shows the method for the preparation of the corresponding salt form of 57.

Treatment of 57 with a suitable strong base such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like produces the corresponding salt form 58. A wide variety of solvents can be used so long as they do not react with the added strong base, 48 such solvents as ethanol and tetrahydrofuran are preferred.

Scheme

XIII

R

3

R

2 NH base A..i N*1N O O

R

3

O

59 Synthetic Scheme XIII shows the method used for 10 the preparation of substituted sulfonamides 60. The step involves treatment of a suitable sulfonyl chloride 59 with an amine to produce the substituted sulfonamide 59. The amine may be either a primary e amine (R3NH 2 or a secondary amine (R 3

R

2 NH). The 15 reaction is generally conducted in the presence of added base. The reaction may also be conducted in the presence of excess amine. Under the conditions of excess amine, the amine functions as both nucleophile and base.

Scheme XIV Na* A R1 R 2 X

A-R~R

1 R N C

R

5

N

So 0o 0 0 58 61 Synthetic Scheme XIV shows the method used for the synthesis of N-substituted acyl sulfonamides 61.

The procedure involves treatment of the salt of an acylated sulfonamide 58 with an alkyl halide (R 2

-X)

I 49 to produce the corresponding N-alkylated acyl sulfonamide 61. This process may be conducted in a wide variety of solvents with a wide array of electrophiles.

Scheme XV excess R 5

COCI

Et 3 N DMAP THF 2 eq. NaOH Synthetic Scheme XV illustrates the method used for the synthesis of certain N-acylated sulfonamides 57. The procedure involves treatment of the sulfonamide 56 with an excess of an anhydride, acid chloride or carbamyl chloride ir the presence of a tertiary amine base to provide the corresponding bis(N-acylated)sulfonamide 62. The bis(Nacylated) sulfonamide 62 is then treated with two equivalents of a strong base such as sodium hydroxide to provide the sodium salt 58.

Scheme

XVI

HO OH Aq. HCI, H 0± 63 oxidation

OH

S S

S.

S 5555 *5 *5

S

R

1 MgBr 70 0

C

0 ox idat ion 0 R 1

SO-,NHR

3 TSOH, Toluene N

R

555555

S

69 5 Synthetic Scheme XVI illustrates the method used for the synthesis of certain N-alkylated pyrrole sulfonamides.

Alcohol 65 is synthesized by following the literature procedure Or-g. Chemi. 57, 2195, 1992) The alcohol 65 is oxidized such as by treatment with oxalyl chloride in an appropriate solvent, such as methylene chloride or DMSO.

Addition, such as by Grignard reagents, produces the alcohol 67. Oxidation with pyridinium chlorochromate produces the ketones 68. .Condensation with a (Nsubstituted amino) sulfonlbenzenamin in the presence of p-toluenesulfonic acid (produces the substituted pyrrole sulfonamide 69.

I 1 1.

51 Scheme XVII Et 3 N DMAP THF 0

R

H2N 0 a 99*. *be.

5 Synthetic Scheme XVII illustrates the method for the preparation of acylated isoxazole sulfonamides 71. The step involves treatment of an unsubstituted sulfonamide 70 with a suitable acylating agent such as an anhydride, acid chloride, acyl ilnidazole, or active ester to afford the acylated sulfonamide 71.

The product 71 can be isolated by chromatography or by crystallization.

0555 S S

S

SOS SSS

S

The following examples contain detailed descriptions of the methods of preparation of compounds of Formulas I-III.

These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures.

The following abbreviations are used: "HC1 hydrochloric acid DMSO dimethylsulfoxide DMSOd6 deuterated dimethylsulfoxide SCDC1 3 deuterated chloroform MgSO 4 magnesium sulfate 5 •NaHCO 3 sodium bicarbonate 0

KHSO

4 potassium hydrogen sulfate DMF dimethylformamide NaOH sodium hydroxide BOC tert-butyloxycarbonyl CD30D deuterated methanol 0. EtOH ethanol LiOH lithium hydroxide

CH

2 C1 2 methylene chloride h hour hr hour min minutes THF tetrahydrofuran TLC thin layer chromatography Et 3 N triethylamine DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DMAP 4 -dimethylaminopyridine EXAMPLE 1 NFs

N-

N N o 3 i,'

H

N-[[4-[2-(3-Pyridinyl)-4-(trifluoromethyl)-lH-imidazol-lyllphenyllsulfonyllacetamide A mixture of 4-[2-(pyridin-3-yl)-4-(trifluoromethyl)- 1H-imidazol-l-yl]benzenesulfonamide (0.5 g, 1.36 mmol), acetic anhydride (0.42 g, 4.1 mmol), 4-dimethylaminopyridine (DMAP) (0.083 g, 0.68 mmol) and triethylamine (0.17 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and filtered.

The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford o g of N-[[4-[2-(3-pyridinyl)-4-(trifluoromethyl)-1Himidazol-l-yl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC): 244-246 Anal. Calc'd. for C 1 7

H

13

F

3

N

4 0 3 S: C, 49.76; H, 3.19; N, 13.65; S, 7.81. Found: C, 49.66; H, 3.06; N, 13.53; S, 8.11.

EXAMPLE 2 N

CF

3

N

N

Na+ N-C 4 2 3 -Pyridinyl)-4-(trifuoromethyl)-1H.imidazo11.

yl]phenyl] sulfonyl)acetamide, sodium salt To a suspension of. N-{[4-[2-(3-pyridinyl)-4- (trifluoromethyl) -lH-imidazol-1-yl phenvljsulfonyl]acetamjde (Example 1) (0.41 g, 1.0 mmol) in 10 rL of absolute ethanol was added a solution of sodium hydroxide (0.04 g, 1.0 rmol) in 0.4 nL of ethanol. The mixture was stirred at room temperature for 10 min. Solvent was evaporated in vacuo and the residue was dried at high vacuum to give 0.33 g of 4 2 3 -pyridinyl)-4-(trifluoromethyl) -lH-imidazol-lyl]phenyllsulfonyllacetamide, sodium salt as a white powder: mp (DSC): 291 'C (dec). Anal. Calc'd. for C 1 7H 1 2

F

3

N

4

O

3

H

2 0: C, 46.26; H, 2.97; N, 12.69; S, 7.26. Found: C, 45.88; H, 3.02; N, 11.69; S, 7.13.

EXAMPLE 3 N-

CF

3 N

N

N

0

'TL

0

H

N- C C2- (5-Methylpyridin-3-yl) (trifluoromethyl) -1Himidazol-1-yllphenyl]Bulfonyl) acetamide A mixture of 4-[2-(5-methylpyridin-3-yl)-4- (trifluoromethyl)-1H-imidazol-l-yl]benzenesulfonamide (0.5 g, 1.3 mmol), acetic anhydride (0.40 g, 3.9 mmol), DMAP (0.09 g, 0.7 mmol) and triethylamine (0.16 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate.

The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.4 g of [2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-IH-imidazol-lyl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC) 268-270 Anal. Calc'd. for Ci 8

H

15

F

3

N

4 0 3 S: C, 50.94; H, 3.56; N, 13.20; S, 7.56. Found: C, 50.68; H, 3.47; N, 12.53; S. S, 7.43.

S EXAMPLE 4

NCF

3

N-

o*

N

O.N

0 -Na 2-(5-Methylpyridin-3-yl)-4-(trifluoromethyl)-1Himidazol-l-yl]phenyl]sulfonyl]acetamide, sodium salt To a suspension of N-[[4-[2-(5-methylpyridin-3-yl)-4- (trifluoromethyl)-1H-imidazol-l-yl]phenyl]sulfonyl]acetamide (Example 3) (0.25 g, 0.6 mmol) in 5 mL of absolute ethanol was added a solution of sodium hydroxide (0.024 g, 0.6 mmol) in 0.4 mL of ethanol. The mixture was stirred at room temperature for 10 min. Solvent was evaporated in vacuo and the residue was dried at high vacuum to give 0.25 g of N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1Himidazol-l-yl]phenyl]sulfonyl]acetamide, sodium salt as a 56 white powder: mp(DSC) 278-281 Anal. Calc'd. for C18H14F3N 4 03SNa-1.0

H

2 0: C, 46.55; H, 3.47; N, 12.06; S, 6.90.

Found: C, 46.35; H, 3.19; N, 11.79; S, 6.52.

EXAMPLE N

CF

3 I I

N

N- 2- (2-Methylpyridin-3-yl) (trifluoromethyl)

-H-

imidazol-1-yl]phenyl]sulfonyllacetamide A mixture of 4-[2-(2-methylpyridin-3-yl)-4- (trifluoromethyl)-lH-imidazol-l-yl]benzenesulfonamide (0.5 g, 1.3 mmol), acetic anhydride (0.40 g, 3.9 mmol), DMAP (0.09 g, 0.7 mmol) and triethylamine (0.16 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate.

•The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.55 g of N- [[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1Himidazol-l-yl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC) 243-245 Anal. Calc'd. for C 1 8

H

15

F

3

N

4 0 3 S: C, 50.94; H, 3.56; N, 13.20; S, 7.56. Found: C, 50.64; H, 3.43; N, 12.64; S, 7.37.

EXAMPLE 6 N CF 3

NN

01=' 0 -Na+ N- [4-[2-(2-Methylpyridin-3-yl)-4-(trifluoromethyl)-lHimidazol-1-yl phenyl sulfonylJ acetamide, sodium salt To a susoension of N-f 4-[2-(2-methylpyridin-3-yl)-4- (trifluoromethyl) -lH-imidazol-l-yl]phenyl] sulfonyllacetamide (Example 5) (0.35 g, 0.83 nunol) in 7.5 rL of absolute ethanol was added a solution of sodium hydroxide (0.033 g, 0.83 rmol) in 0.83 mL of ethanol. The mixture was stirred at room temperature for 10 min. Solvent was evaporated in vacuo and the residue was dried at high vacuum to give 0.37 g of N-f[ 4 -f 2 2 -methylpyridin-3-yl)-4-(trifluoromethyl)-lHimidazol-1-yl]phenyljsulfonyl]acetamide, sodium salt as a white powder: mp(DSC) 313 *C (dec). Aknal. Calc'd. for C18H1 4

F

3

N

4 03SNa-0.75 H 2 0: C, 47.01; H, 3.40; N, 12.18; S, 6.97.

Found: C, 47.51; H, 3.71; N, 11.70; S, 6.51.

EXAMPLE 7 N CF 3 N J,

NI

0 H 4 2 -(5-Methylpyridin-3-yl)-4-(trifluoromethyl)1H imidazol-1-yllphenylJsulfonylibutanamide A mixture of 4-[2-(5-methylpyridin-3-yl)-4- (trifluoromethyl)-1H-imidazol--yl]benzenesulfonamie (0.5 g, 1.3 mmol), butyric anhydride (0.62 g, 3.9 mmol), DMAP (0.09 g, 0.7 mmolr and triethylamine (0.16 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate.

The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.50 g of N- 4 2 -(5-methylpyridin-3-yl)-4-(trifluoromethyl)-lH- S. ~imidazol-l-yliphenyl]sulfonyl]butanamide as a colorless solid: mp (DSC) 203-204 Anal. Calc'd. for C20H 1 9

F

3

N

4 0 3

S:

C, 53.09; H, 4.23; N, 12.38; S, 7.09. Found: C, 52.73; H, 4.21; N, 11.79; S, 7.00.

EXAMPLE 8

CF

3

NI

N

N

o Nal N-[[4-[2-(5-Methylpyridin-3-yl)-4-(trifluoromethyl)-lHimidazol-1-yl]phenyl]sulfonyl]butanamide, sodium salt To a suspension of N-[4-(2-(5-methylpyridin-3-yl)-4- (trifluoromethyl)-H-imidazol-1-yl]phenyl]sulfonyl]butanamide (Example 7) (0.31 g, 0.68 mmol) in 5 mL of absolute ethanol was added a solution of sodium hydroxide (0.028 g, 0.68 mmol) in 0.68 mL of ethanol. The mixture was stirred at room temperature for 10 min. Solvent was evaporated in vacuo and the residue was dried at high vacuum to give 0.28 g of

N-[

4 2 -(5-methylpyridin-3-yl)-4-(trifluoromethyl)-lHimidazol-1-yl}phenyl]sulfonyl]butanamide, sodium salt as a white powder: mp(DSC) 303 'C (dec) Anal. Calc'd. for C20H18F3N 4 03SNa-1.0 H 2 0: C, 48.78; H, 4.09; N, 11.38; S, 6.51.

Found: C, 47.90; H, 3.67; N, 11.38; S, 6.06.

EXAMPLE 9 N CF 3 N O N N-[[4-[2-(2-Methylpyridin-3-yl)-4-(trifluoromethyl)-1Himidazol-1-yl]phenyl] sulfonyl]butanamide A mixture of 4-[2-(2-methylpyridin-3-yl)-4- (trifluoromethyl)-lH-imidazol-1-yl]benzenesulfonamide (0.5 g, 1.3 mmol), butyric anhydride (0.62 g, 3.9 mmol), DMAP (0.09 g, 0.7 mmol) and triethylamine (0.16 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate.

The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recryscallized from ethyl acetate and hexane to afford 0.49 g of N- 4 -(2-(2-methylpyridin-3-yl) -4-(trifluoromethyl)-1Himidazol-l-yl]phenyl]sulfonyl]butanamide as a colorless solid: mp (DSC) 250-252 Anal. Calc'd. for C 2 0

H

19

F

3

N

4 0 3

S:

C, 53.09; H, 4.23; N, 12.38; S, 7.09. Found: C, 52.97; H, 4.21; N, 11.07; S, 7.11.

L It EXAMPLE N

CF

3 NA N

N

OaS N

N'

Na+ N- E[4- (2-Methylyridin-3 .yl) (trifluoromethyl) -lHimidazol-l-yl]phenylj sulfonyl butanamide, sodium salt To a suspension of N-[[4-[2-(2-methylpyridin-3-yl)-4- (trifluoromethyl) -lH-imidazol-1-yl]phenyl] sulfonyl]butanamide (Example 9) (0.3 g, 0.66 mmol) in 5 mL of absolute ethanol was added a solution of sodium hydroxide (0.027 g, 0.66 mmol) in 0.66 rL of ethanol. The mixture was stirred at room temperature for 10 min. Solvent was evaporated in vacuo and the residue was dried at high vacuum to give 0.26 g of 4

-C

2 -C2-methylpyridin-3-yl)-4-(trifluoromethyl)-lHimidazol-l-yllphenyllsulfonyl]butanamide sodium salt as a white powder: mp(DSC) 320 .0 (dec). Anal. Calc'd. for C2OHl 8

F

3

N

4 0 3 SNa: C, 50.63; H, 3.82; N, 11.81; S, 6.76. Found: C, 49.85; H, 3.78; N, 11.51; S, 6.32.

EXAMPLE 11

CF

3

N

0 H 2 -(3-Chloro-5-methylhenyl)4-(trifluoromethyl)-1H imidazol-1-yl phenylJsulfonyl]acetamide To a suspension of 4-[2-(3-chloro-5-methylphenyl)-4- (trifluoromethyl)-1H-imidazol-l-yl]benzenesulfonamide (0.30 g, 0.72 mmol) in 1.5 mL of acetic acid was added 1.5 mL of acetyl chloride at room temperature. The mixture was heated at reflux for 5 hours. After cooling, the reaction mixture was concentrated under vacuum and the residue was treated with ether to give 0.23 g of N-[[4-[2-(3-chloro-5methylphenyl)-4-(trifluoromethyl)-IH-imidazol-lyllphenyl]sulfonyl]acetamide as a white solid: mp (DSC) 232- 235 Anal. Calc'd. for C19gHsClF3N303S: C, 49.84; H, 3.30; N, 9.18; S, 7.00. Found: C, 49.72; H, 3.48; N, 8.81; S, 7.18.

EXAMPLE 12

CF

3 SNa 2 3 -Chloro-5-methylphenyl)-4-(trifluoromethyl)-1Ha imidazol-1-yl]phenyl]sulfonyl]acetamide, sodium salt To a suspension of N-[[4-[2-(3-chloro-5-methylphenyl)-4- (trifluoromethyl)-1H-imidazol-l-yl]phenyl]sulfonyl]acetamide (Example 11) (0.1 g, 0.22 mol) in 3 mL of absolute ethanol was added a solution of sodium hydroxide (0.0088 g, 0.22 mmol) in 2 mL of ethanol. The mixture was stirred at room temperature for 10 min. Solvent was evaporated in vacuo and the residue was dried at high vacuum to give 0.09 g of N-[[4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)-1Himidazol-l-yl]phenyllsulfonyl]acetamide, sodium salt as a white powder: mp(DSC) 320 'C (dec). Anal. Calc'd. for C19H14C1F3N303SNa: C, 47.56; H, 2.94; N, 8.76; S, 6.68.

Found: C, 46.89; H, 3.02; N, 8.27; S, 6.03.

EXAMPLE 13

F

H

I

CH

3

H

3 Cy N, t o SN-[[4-[3-(3-Fluorophenyl)-5-methylisoxazol-4yl]phenyl]sulfonyl]acetamide Acetic anhydride (1.01 g, 9.39 mmol) and triethylamine (0.401 g, 3.97 mmol) were added to a solution of 3-( 3 -fluorophenyl)isoxazol- 4 -yl]benzenesulfonamide (1.10 g, .3.31 mmol) and N,N-dimethylpyridine (0.202 g) in dry tetrahydrofuran. After stirring for 18 hours at room temperature, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed successively with IN hydrochloric acid and brine, dried over anhydrous MgSO 4 and concentrated to afford 1.0 g of the desired product as a crystalline product: mp 144-145 1H NMR (CDC1 3 8.00 2H, J 7.3 Hz), 7.30-7.27 4H), 7.10- 7.06 3H), 2.46 3H), 1.99 3H). Anal. Calc'd for

C

18

H

15

FN

2 04S: C, 57.75; H, 4.04; N, 7.48. Found: C, 57.84; H, 4.06; N, 7.49.

63 EXAMPLE 14

F

N

-i Na' C H 3 000 N- [3-(3-Fluorophenyl) -5-methyJlisoxazol-4yllphenylj sujlfonyl] acetamide, sodium salt A mixture of [4-[3-(3-fluorophenyl) 4-yllphenyl]sulfonyllacetamide (Example 13) (0.312 g, 0.83 inmol) and sodium hydroxide (0.33 niL, 2.5 N) in ethanol was concentrated to dryness. The residue was diluted with ethanol and was concentrated again. The residue was dried in vacuc to afford 0.32 g of the crystalline product: mp 112-3 HC ~I NMvR (D 2 0/300 M{z) 7.64 2H, J 8.3 Hz), 7.21-6.91 (mn, 6H), 2.27 3H), 1.78 3H). Anal. Calc'd for C 1 8H 14

FN

2

O

4 SNa -0.5H 2 0: C, 53.28; H, 3.73; N, 6.80.

Found: C, 53.57; H, 3.73; N, 6.80.

The following compounds (Examples 15-67) were obtained according to procedures similar to that exemplified in Examples 13-14, with the substitution of the appropriate sulfonamide and anhydride.

EXAMPLE

H

I OH 3 ,4 2-Methyl-N- (5-methyl-3-phenylisoxazol-4yl )phenyl] sulfonyljpropanamide 64 rp 115.0-115.6 1 H NMR CCDC1 3 /300'MHz) 8.43 (brs, 1H), 8.04 2H, J 8.4 Hz), 7.40-7.31 Cm, 7H), 2.50 (s, 3H), 2.45 (sept, 1H, J 6.9 Hz), 1.12 6H, J 6.9 Hz).

FABLRMS m/z 385 FABHRMS m/z 385.1222

(M+H,

C

20

H

2 1

N

2 0 4 S Calc'd 385.1245). Anal. Calc'd for C 2 0

H

2 0 N0jS: C, 62.48; H, 5.24; N, 7.29. Found: C, 62.55; H, 5.24; N, 7.21.

EXAMPLE 16 o N Na+

CH

3 0 0 2-Methyl-N-[[4-( 5 -methyl-3-phenylisoxazo 4- 0 yl)pheny±] sulfonyllp ropanamide, sodium salt mp >300 1 H NMR (DMSO-d 6 /300 MHz) 7.71 Cd, 2H, J 8.1 Hz), 7.43-7.24 Cm, 5H), 7.19 2H, J 8.1 Hz), 2.44 Cs, 3H), 2.15 (sept, 1H, J 6.9 Hz), 0.89 6H, J 6.9 Hz). FABLRMS m/z 407 (MtH). FABHRMS m/z 407.1053 (M+H,

C

2 0

H

2 1N 2

O

4 SNa Calc'd 407.1041). Anal. Calc'd for

C

2 0

H

1 9

N

2 0 4 SNa: C, 59.10; H, 4.71; N, 6.89. Found: C, 58.98; H, 4.68; N, 6.94.

EXAMPLE 17

H

1 1CH 3 N l 4 -(5-Methy-3-.phenylisoxazol.4yl]phenyl sulfony ]propanamide mp 148.9-151.0 0 C. 1H NMR (CDC1 3 /300 MHz) 8.60 (brs, 1H), 8.04 2H, J 8.7 Hz), 7.38-7.31 7H), 2.50 3H), 2.32 2H, J 7.2 Hz), 1.10 3H, J 7.2 Hz). FABLRMS m/z 371 (MPH). FABHRMS m/z 371.1049 Calc'd 371.1066. Anal. Calc'd for

C

1 9 H1 8

N

2 0 4 S: C, 61.61; H, 4.90; N, 7.56. Found: C, 61.52; H, 4.92; N, 7.53.

:i EXAMPLE 18

_N

Na

CH

3

S

0 00 N-[[4-(5-Methy-3-henylisoxazol-4yllphenyi]suifonyllpropanamide, sodium salt mp 271.5-272.7 1 H NMR (D 2 0/300 MHz) 7.57 (d, 2H, J 8.4 Hz), 7.30-6.90 7H), 2.12 3H), 2.00 2H, J 7.8 Hz), 0.83 3H, J 7.8 Hz). FABLRMS r/z 393 (MPH). Anal. Calc'd for C 1 9

H

1 7

N

2

O

4 SNa: C, 1 1. 1, 66 58.61; H, 4.37; N, 7.14. Found: C, 57.92; 4.53; N, 0.95.

EXAMPLE 19

SO

S

*5

C

S

N- 5 -Methyl-3-phenylisoxazol-4 yl )phenyl] sulfonyl] benzamide mrp 208.8-210.2 0 C. 1H NI'R (CDC1 3 /300 Miz) 9.05 (brs, 1H) 8.14 2H, J =8.5 Hz) 7.82 2H, J Hz), 7.59 (dd, 1H, J 7.5 Hz), 7.49-7.30 (mn, 9K), 2.50 3H) FABLRMS zn/z 419 FABHI'S m/z 419.1083 CM+H, Calc'd 419.1066). Anal. Calc'd for

C

23

H

18

N

2 0 4 S: C, 66.02; H, 4.34; N, 6.69. Found: C, 65.95; H, 4.40; N, 6.69.

**CC

S

55 0 EXAMPLE N- (5-Methyl-3-phenyisoxazo.4yl)phenylJ sulfonylJbenzmiae, sodium salt mp 288.2-291.2 OC. 1H NMR (DMSO-6/30'0 MHz) 7.90 2H, J 8.1 Hz) 7.83 2H, j 8.4 Hz) 7.44- 7 .23 8H) 7 .22 2H, J 8 .4 Hz) 2. 44 3H).

FABLRMS m/z 441 FABHRMS m/z 441.0898 (M+H, Calc'd 441.0885). A4nal. Calc'd for C2H17N204SNa:

C,

62.72; H, 3.89; N, 6.36. Found: C, 62-53; H, 4.06; N, 6.17.

EXAMPLE 21 1 CH3 0 ON 22-Dimethyl-N- 4-(5-methyl-3-henylisoxzl4 yl) phenyl Isulf onyl I ropanamide :i mp 190.5-191.1 OC. 1HNR(D182 H NR (DC3/300 MHz) 82 (brs, 1H) 8. 04 2H, J 8. 5 Hz) 7.39-7.30 7H), sees 2.51 3H), 1.10 9H) FABLRMS ml'z 399 (MH).

FABHRMS m/z 399.1388 Calc'd 399.1379) Anal.

Calc'd for C21H22N204S: C, 63.30; H, 5.56; N, 7.03.

Found: C, 63.45;. H, 5.53; N, 7.08.

EXAMPLE 22

N

N+ CH 0 0 0 2, 2 -Dimethyl 4 -methyl 3 -heyl isox o yl)phenyllsulfo~yllroanamide, sodium salt mp >300 00. 1H NMR (DMSO-d 6 /300 Miz) 7.68 2H, J 8.1 Hz), 7.42-7.31 Cm, 5H), 7.18 2H, J 8.1 Hz), 2.44 3H), 0.96 Cs, 9H). FABLRMS m/z 421 (MPH) FABHRMS m/z 421.1196 Calc'd 421.1198) Anal. Calc'd for C 2 lH 2 1

N

2

O

4 SNa: C, 59.99; H, 5.03; N, 6.66. Found: C, 59.83; H, 5.08; N, 6.58.

EXAMPLE 23 o 0* 0 Methyl 4- 5 -methyl-3-phenylisoxazol4yllphenyl] sulf onyll amino] -4-oxobutanoate mfp 114.9-117.7 'C. 1HNM CCDC1 3 /300 M~flz) 8.70.

0 0000*0 Cbrs, 1H) 8.04 Cd, 2H, J 8.4 Hz) 7.38-7.26 Cm, 7H) 3.-66 3H) 2.67-2. 57 (mn, 4H) 2.50 3H) 1.10 Cs, 9H) .FABLRMS m/z 429 (MPH) FABHRMS m/lz 429.1102 Calc'd 429.1120). A-nal. Calc'd for C 2 1

H

2 0

N

2 0 6

S:

C, 58.87; H, 4.70; N, 6.54. Found: C, 58.61; H, 4.77; N, 6.44.

EXAMPLE 24 N- C (5-methy1-3-phenyisoxazol4yl phenyl) Isulf onyl]I but anamiae 69 mp 173.2 0 C. 1 H NMR (CDC1 3 /300 MHz) 8.55 (brs, 1H), 8.05 2H, J 8.7 Hz), 7.40-7.29 Cm, 7H), 2.50 Cs, 3H), 2.86 Ct, 2H, i 7.2 Hz), 1.61 (sext, 2H, J 7.2 Hz), 0.88 3H J 7.2 Hz). FABLRMS m/z 391 FABHRMS m/z 385.1224 Calc'd 385.1222).

Anal. Calc'd for C 20

H

20

N

2

O

4 S: C, 62.48; H, 5.24; N, 7.29. Found: C, 62.37; H, 5.28; N, 7.22.

EXAMPLE i.*

N

0 Na+ CH 3 N

S

0I/

\\O

N-[(4-(5-Methyl-3-phenylisoxazol-4yl)phenyl)sulfonyllbutanamide, sodium salt rp 273.5-277.7 1 H NNR (D 2 0/300 MHz) 7.54 Cd, 2H, J 8.4 Hz), 7.13-6.73 Cm, 7H), 2.06 Cs, 3H), 1.94 Ct, 2H, J 7.2 Hz), 1.27 (sext, 2H, J 7.2 Hz), 0.55 Ct, 3H, J 7.2 Hz). FABLRMS m/z 407 FABHRMS m/z 407.1065 Calcd 407.1041). Anal. Calc'd. for

C

20

H

1 9

N

2 0 4 SNa: C, 59.10; H, 4.71; N, 6.89. Found: C, 58.91; H, 4.77; N, 6.80.

EXAMPLE 26

H

OH

3

N,

N-[[4-(5-Methyl-3-phenylisoxazol-4yl)phenyl]sulfonyl)pentanamide mp 134.1-136.5 0 C. 1H NMR (CDC1 3 /300 M~z) 8.58 Cbrs, 1H), 8.04 2H, J =8.6 Hz), 7.40-7.31 Cm, 7H), 2.50 Cs, 3H), 2.28 2H, J =7.5 Hz), 1.56 (pent, 2H, J 7.5 Hz), 1.27 (sext, 2H, J 7.5 Hz), 0.85 Ct, 3H, J =7.5 Hz) FABLRNS m/z 399 FABHRMS mz 399.1286 Calc'd 399.1300). Anal. Calc'd for

C

21

H

2 1 2

N

2 0 4 S: C, 63.30; H, 5.56; N, 7.03. Found: C, 63.25; H, 5.63; N, 9.69.

EXAMPLE 27 fN0 0 0 0 e h l- -h ny i o az l 4 yl p ey*uf nl p n a a e so iu sal mp 2 4. C. 1 N R (D S -d 00 M z) 7 71 H 8 .1 .43 .32 5H 7 .1 (d 2 H z 2 4 *N N N- N[ 4 5 -Methyl-3-phenylisoxazol4yl~pheyl] sunl lonlpetan a, sdiu sl 1 H NMR (CDC1 3 /300 M~iz) 8.50 Cbrs, 1W), 8.04 (d, 2H, J 8.4 Hz), 7.40-7.30 (mn, 7H), 2.50 Cs, 3H), 2.27 2H, T 7.2 Hz), 1.58 (pen., 2H, J 7.2 Hz), 1.27- 1.19 4H), 0.84 3H, J 7.2 Hz). FABLRMS m/z 413 FABHRMS m/z 413.1517 (MPH, Calc'd 413.1535). Anal. Calcd for C 22

H

24

N

2

O

4 S: C, 64.06; H, 5.86; N, 6.79. Found: C, 54.04; H, 5.85; N, 6.70.

EXAMPLE 29 3-Methoxy-N- 4 -(5-metyl-3-phenylisoxazol4yl )phenyl] suJlfonyl] propanamide mp 139.7-140.9 1 H NMR~ CCDC1 3 /300 Mflz) 9.34 Cbrs, 1H), 8.05 Cd, 2H, J 8.5 Hz), 7.37 (mn, 7H), 3.62 Ct, 2H, J 5.5 Hz), 3.43 Cs, 3H), 2.54 Ct, 2H, J Hz), 2.51 3H) FABHRMS m/z 400.1071

C

20

H

20

N

2 0 5 S Calc'd 400.1093).

EXAMPLE

N

0 Na'

CH

3 3-Methoxy-N-[[4- CS-methyl-3-phenylisoxazol.4yl)phenyl] aulfonyl]propanamide, sodium salt mp 240.7-243.2 OC. 1 H N4R CD 2 0/300 MHz) 7.63 Cd, 2H, J Hz), 7.33 1H), 7.20 4H), 7.16 2H, J Hz), 3.49 2H, J 6.2 Hz), 3.11 3H), 2.29 (s and t overlapped, 5H, J 6.2 Hz) FABHRMS m/z 429.1074 (M+Li),

C

2 0

H

1 9

N

2

O

5 SNaLi Calc'd 429.1072).

EXAMPLE 31

H

CH

3 ~01(oN, 2-Ethoxy-N- (5-methyl-3-phenylisoxazol-4yl)phenyl Isulfonyl ]acetamide mp 131.3-132.2 1 H NNR (CDC1 3 /300 MHz) 8.98 (brs, 1H), 8.08 2H, J 8.7 Hz), 7.37 7H), 3.95 2H), 3.58 2H, J 7.0 Hz), 2.51 Cs, 3H), 1.26 3H, J 7.0 Hz). FABHRMS m/z 400.1093

C

2 0

H

20

N

2 0 5 S Calc'd 400.1072).

EXAMPLE 32 Na j CH 3

-N,

0 00 2-Ethoxy-N-[[4-( 5-methyl-3-phenylisoxazol-4 yl)phenyl]sufonylacetamide, sodium salt rnp 207.2-210.0 00. 'H NMR (D 2 0/300 MHz) 7 .67 2H, J 8 Hz) 7 .3 3 (mn, 1H) 7 .2 6-7 .19 Cm, 6H1), 3 .8 0 2H) 3 .3 6 2H, T 7 .1 Hz) 2 .3 3 Cs, 3 H) 1.-0 0 3 H, J 7 1 Hz) FABH-RMS m/z 423.0992

C

2 0

H

2 0

N

2

O

5 SNa Calc~d 423 .0991).- EXAMPLE 33 N- [4 5- (4 -Chiorophenyl) 3- Ctr if luorometh2yl) 1H pyra zo 1- 1-yl phenyl]I sul fonyl]I propanamide mp 77.9-85.1 OC. Anal. Calc'd for Cl 9 Hl 5 ClF3N 3

O

3 S: C, 49.84; H 3.30; N, 9.18. Found: C, 49.83; H, 3.36; N, 9.10.

EXAMPLE 34 Na"' Is N

CF

3

C

N- (4-Chloropbhenyl) -3-C trifluoromethyl) -1Wpyrazol-1-yl]phenyl] sulfonyl~propanamide, sodium salt rnp >300 Anal. Calc'd for ClqH 1 4ClF 3

I

3

O

3 SNa: C, 47.56; H 2.94; N, 8.76. Found: C, 47.51; H, 3.02; N, 8.72.

EXAMPLE (4-Chiorophenyl) (trifluoromethyl) -1Hpyrazol-1-yl] phenylJ sulfonyllbutanamide 1HNM (CDC1 3 /300 MA~z) 8.1 2H, T 8.7 Hz), 7.94 Cbrs, 1H), 7.5 2H, J 8.7 Hz), 7.37 Cd, 2H, J 8.4 Hz), 7.17 Cd, 2H, J 8.4 Hz) 6.79 CS, 1H) 2.24 2H, J =7.5 Hz), 1.62 Cm, 2H), 0.9 Ct., 3H, J Hz) FABLRYS m/z 494 (MPH).

EXAMPLE 36 0 Na~

U-ZN

o /I N- (4-Chiorophenyl) Ctrifluoromethyl) -lHpyrazol-1-yl]phenylj sulfonyllbutanamide' sodium salt mp 285.4-286.5 0 C. 1 H NM?. (CD 3 OD/30-0 MHz) 7.95 2H, J 8. 7 Hz) 7. 37 Cm, 4H) 7. 27 Cd, 2 H, J 9 .0 Hz) 6. 96 (S, 1H) 2. 1 2H, 6. 9 Hz) 1. 55 (in, 2H) 0 .84 3H, J 2 Hz).

EXAMPLE 37

N-U

4 -5-(4-Choropheny)-3(trifuoromethyl)..H.

pyrazol -1 -ylJ phenyl] sulfonyll3acetamide mo) 161.9-162.7 0 C. 1 H NM?. (CDC1 3 /300 MHz) 8.6 (brs, 1H), 8.07 2H, J 6.9Hz), 7.5 2H, J 6.9 Hz), 7.38 2H, J 6.9 Hz), 7.18 2H, J 6.9 Hz), 6.79 Cs, IH), 2.07 Cs, 3H).

EXAMPLE 38

I,

0 N- 4- (5-(4-Chiorophenyl) (trif2.uoromethyl) -lHpy'razol-l-yllphenyl] sulfonyllacetamide, sodium salt mp 269.8-272 0 C. 'H NMR (D 2 0/300 M4H'z) 7.73 2H, J 8.7 Hz) 7.3 Cd, 2H, J 8.7 Hz) 7.23 2H, J 8.4 Hz), 7.06 2H, T 8.4 Hz) 6.87 1H), 1.8 Cs, 3H) EXAMPLE 39

CH

3 [5-Methyl-3-phenylisoxazol-4- 10 ylI phenyl ]sulf onylI acetamide mp) 169.3-170.6 0 c. Anal. Calc'd for Cj 8

H

1 6

N

2 0 4

S:

C, 60.66; H 4.53; N, 7.86. Found C, 60 .57; H 4.59; N, 7 .81.

EXAMPLE

N

Na+

CH

N-f £5-Methyi-3-phenylisoxazol-4.

yllphenyi] Bulfonyll acetamide, sodium Bait rnp 245.6-247 0 C. Anal. Calc'd for Cj 8

H

1 5

N

2 0 4 SNa.H 2 0: C, 54.54; H, 4.32; N, 7.07. Found C, 54.47; H 4.34; N, 7.07.

a 4 '77 EXAMPLE 41

N

0 CH3 0 N- C (5-Methyl-3-phenylisoxazol-4yllphenyl] sulfonyl] acetamide, potassium salt nip 279.7-283.7 1H NI'sR (D 2 0/300 MHz) 7.62 (d, J =8.4 Hz), 7.2 (in, 7H) 2.27 3H), 1.77 Cs, 10 3H).

EXAMPLE 42

HQ<

0

N-N

N N CF 2

H

MeO N-f (Difluoromethyl) -6-fluoro-1, 5-dihydro-7me thoxy- 2 benz ot hi opyrano 3- c ]pyra z o1-1 yllphenyl] sulfonyl] acetamide 1 H NMR (300 MHz/OD1 3 8 .1 2H, J 6 .9 Hz), 7.61 Cd, 2H, J 6.9 Hz), 6.69 (mn, 3H) 4.0 Cs, 2H), 3.82 Cs, 3H) 1.96 Cs, 3H) FABLRI4S rn/z'484 (MPH).

I 78 EXAMPLE 43 MeO' a 5 N-C[ 4 3 -(Difluoromethyl)-6.fluoro-1,5-dihydro-7methoxy- [2Jbenzothiopyrano (4,3-c~pyrazol-1yllphenylJ sulfonyl~acetamide, sodium salt mp >300 1 H NMR~ (CD 3 OD/300 Mflz) 8.04 2H, J 10 6.6 Hz), 7.6 2H, J 6.6 Hz), 6.82 (mn, 4.08 2H), 3.85 3H), 1. 90 3H).

EXAMPLE 44 0 H 1N 0 a a N- E6-Fluoro-1, 5-dihydro-7 -methoxy-3- (trifluoromethyl) 2 Jbenzothiopyrano 3-c~pyrazol-1yl Iphenyl I sulf onylJ] acetamide IH NMR (CDC1 3 /300 MHz) 8.06 2H, J 8.4 Hz), 7 .6 2H, J 8.4 Hz) 6 .68 2H, J 8 .7 Hz) 79 6.50 2H, J 8.7 Hz), 3.97 Cs, 2H), 3.79 Cs, 3H), 1.92 3H). FABLRMS m/z 502 EXAMPLE NaL 0

N-N

N CF 3 **MeO

F

N- [6-Fluoro-1, 5-dihydcro-7-methoxy-3trifluoromethyl) [21benzothiopyrano 3-cjpyrazol-1yljphenylJsulfonyl)acetamide, sodium salt 10 mp 183-191.1 00 1 H NMR (CD 3 D/300 MHz) 8.06 Cd, 2H, j 8.7 Hz), 7.62 2H, J 8.7 Hz), 6.9 2H, J 8.7 Hz), 6.6 Cd, 2H, J 8.7 Hz), 4.11 2H), 3.85 3K) 1.90 Cs, 3H).

EXAMPLE 46

H

3 C N N.

HIN

SCF

2

H

H3- N- E[4- [3-(Difluoromethyl) -5-(3-fluoro-4-ethoxyphenyl)lH-pyrazol-1-yl]phenyl]sulfonyl)acetamide rnp 173-175 OC. 1H NMR (acetone-d 6 /3O0 MHz) 8.1 Cd, 2H, J 8.9 Hz), 7.6 Cd, 2H, J 8.9 Hz), 7.2-6.8 Cm, 6H), 3.9 3H). Anal. Calc'd for C 19

H

16

N

3

F

3 0 4

S:

C, 51.94; H, 3.67; N, 9.56. Found: C, 51.30; H, 3 .72; N, 9.47.

EXAMPLE 47 0 0 0* N- 3 (Difluormethy) 5(3-f uoro-4.methoxyphenyl) lH-pyrazo1l-yllphenyl)aulffonyllacetamide, sodium salt mp 140.1-146.0 0 C. 1 H NMR (D 2 0/300 M~flz). 7.7 (d, 2H, J 8.4 Hz) 7.2 Cd, 2H, T 8. 4 Hz) 6.-9-6.6 (mn, 3.7 3H), 1.8 Cs, 3H) Anal. Calc'd for

C

19 H1 5

N

3

F

3

O

4 SNa 3.06% H 2 0: C, 47.95; H, 3.52; N, 8.83. Found: C, 47.94; H, 3.42; N, 8.73.

EXAMPLE 48 2UN-[E 4 (2-Methyl4-phenyoxazol5yl )phenyl) sulfony. 3acetamide rup 220 .7 -221 .0 0 C. 1H NMR (acetcone-d 6 /300 M4Hz) Cd, 2H, J 8.7 Hz), 7.8 Cd, 2H, J =9.0 Hz), 7.6 2H) 7.4 Cm, 3H) 2.5 3H) 2 .0 Cs, 3H). A-nal 81 Calc'd, for C18H1 6

N

2

O

4 S: C, 60.66; H, 4.53; N, 7.86.

Found: C, 60.54; H, 4.56; N, 7.90.

EXAMPLE 49

N

-N N H 3CyNN, 00 N- (2-Methyl-4-henloxazol-5yl)phenylJ sulfonyl]acetamide, sodium salt np 259.9-260.0 0 C. 1 H NMR (D 2 0/300 MHz) 7.6 (d, 2H, J 8.4 Hz), 7.4 2H, J= 8.4 Hz), 7.3 2.3 3H), 1.8 3H). Anal. Calc'd for C18H1 5

N

2 04SNa 5.94% H 2 0: C, 53.74; H, 4.42; N, 6.96.

Found: C, 53.73; H, 4.28; N, 6.94.

EXAMPLE

N

*N

00

H

3 C~

H

3 0 S/ Methyl [C[4-C5-methyl-3-phenylsoxazol-4yl)phenyl] sulfony. Jamino) oxoacetate mp 171.1-172.3 CC. 1 H NMR (CDC1 3 /300 Mfz) 9.4 (bs, 1H) 8.1 2H, J 8.7 Hz), 7.4-7.2 7H), 7.6 2H), 3.9 3H), 2.5 3H). Anal. Calc'd for 82

C

1 9 Hl 6

N

2 0 6 S: C, 56.99; H, 4.03; N, 7.00. Found: C, 56.74; H, 3.96; N, 6.94.

EXAMPLE 51 I NaN 0 Na~ j H 3 H3CoLN, 0 H3C S 14 CH3 .M .DS-d/0 00z 0.

11 \\O 0. Methyl 5 -methyl-3-henylioxaz 4.

yl)phenyl sulfonyl]amino]oxoacetate, sodium salt np 146.0-151.8 1 H NMR (DMSO-d 6 /300 MHz) 7.8- *7.7 2H), 7.5-7.2 7H), 3.5 3H), 2.5 3H).

Anal. Calc'd for C 19

H

1 5

N

2 0 6 SNa 3.22% H 2 0: C, 52.29; H, 3.82; N, 6.42. Found: C, 52.28; H, 3.77; N, 6.44.

EXAMPLE 52 C N

H

3 C.,O H f

H

3 0 e 0 2-Methoxcy-N-[£[ 4 -(5-methy-3-phenyioxazol4yl)phenyl] sulfonyl] acetamide mp 123 .9-125 .3 0 C. 1 H NMR (acetone-d 6 /300 M~z) 2H, J 8.7 Hz), 7.5 Cd, 2H, J =8.7 Hz), 7.4 (in, 5H), 4.0 2H), 3.4 3H), 2.5 Cs, 3H).

Anal. Calc'd for C 19

H

18

N

2 0 5 S: C, 59.06; H, 4.70; N, 7.25. Found: C, 59.14; H, 4.73; N, 725.

83 EXAMPLE- 53

N

0 Na'

CH

3 2-Methoxy-N- (5-methyl-3-phenylisoxazol.4.

yl)phenyl] sulfonyl] acetamide, sodium salt mp 276.9-277.9 0 C. 1 H NNP. (DMSO-d6/300 M.flz) 7.7 Cd, 2H-, T 8.4 Hz), 7.5-7.3 (mn, 5H) 7.2 J =8.4 Hz, 2H), 3.6 Cs, 2H), 3.2 3H), 2.4 Cs, 3H).

FABHRMS m/z 409.0848 Calc'd 409.0851).

84 EXAMPLE 54

-N

0 H -1

CF

2

H

00 4 -yl Iphenyl sulf onyl Ipropanamjde rp 136.9-141.0 1 H NimR (acetone-d 6 /300 IMz) 10.7 (bs, 1H) 8. 1 2H, T 8. 4 Hz) 7. 6 2H, J 4 7. 6 -7.4 (in, 5 7. 2 1H, J 5 2. 2 Hz), 2. 4 2 H, J 7. 5 H z) 1. 0 3KH, J 7.5 Hz). Anal. Calcd for C 19

H

16

F

2 N0S:C 56.15; H, 3.97; N, 6.89. Found: C, 56.10;- H, 3.93; o: N, 6.81.

EXAMPLE

N

0 00 Na' F2

H

3 C -NC1 00 yllphenyllsulfonyl]propanamide, sodium salt mp 287.8-293.6 1 H NM2. (DMSO-d 6 /300 M"Hiz) 7.7 (d, 2H, J 8.1 Hz), 7.5-7.1 (mn, 8 H) 1. 9 (dd, 2KH, J 7. Hz), 0.8 3H, J 7.5 Hz). Anal. Calc'd for

C

1 9 H 1 5

N

2

F

2 Na0 4 S 2.04% H-20: C, 52.17; H, 3.63; N, 6.45.

Found: C, 52.18; H, 3.69; N, 6.41.

EXAMPLE 56

N

0 H

CF

2

H

00 N- 4 5 (Dif luoromethy)3 -phenylisoxazo-4yljp h e ny 1 sulf o nyl1] b u tanam id e tr154.9-155.9 1 H NMR Caceetone-d /300 MHz) 10.7 6 Cbs, 1H) 8. 1 2H, j 8.4 Hz) 7. 6 Cd, 2H, J 8. 4 Hz) 7.6-7.4 Cm, 5H) 7.2 Ct, 1H, J 51.9 Hz) 2.3 Cdd, 2H, J 7. 2 Hz) 1. 6 (mi, 2H) 0. 8 Ct, 3H, J 2 Hz).

**Anal. Calcd for C 2 0 Hl 8

F

2

N

2 0 4 S: C, 57 .14; H, 4.32; N, 6.66. Found: C, 57.18; H, 4.37; N, 6.65.

EXAMPLE 57

N

0 Na:+CC

H

3 C NCF 2

H

N~f-C(Difuromety)-3phenyisoxazo.4yllpheny1]sulfonyl)butanamide, sodium salt mp 281.7-286.3 1 H NM?. CDMSO-d 6 /300 MHz) 7.7 Cd, 2H, T 8.1 Hz), 7.6-7.1 Cm, 8H), 1.9 Cdd, 2H, J 7. 2 Hz) 1. 4 Cm, 2H) 0. 7 -3H, T 7. Hz) Anal. Calc'd for C 2 0 Hl 7

N

2

F

2 Na0 4 S 2.25% H 2 0: 86 C, 53.07; H, 3.96; N, 6.17. Found: C, 53.08; H, 4.04; N, 6.19.

EXAMPLE 5 8

NN

0

H

H) I C H 3 0 A 4

-EEE

4 -(5-Methyl-3-phenylisoxazol.4- Yl)phenyl) sulfonyllaminoj -4-oxobutanoic acid mp 158.4-165.4 00 1H NMvR (CDC1 3 /300 MHz) 8.04 (in, 2H, J 8.7 Hz), 7.45-7.25 (mn 7H) 2.75-2.65 (mn, 2H), 2.65-2.53 (mn, 2H) 2.51 3H) FABLRNS m/z 415 FABHPJAS m/z 415.0958 Calc'd 415.0964). Anal.

Calc'd for C 2 0

H

1 8

N

2 0 6 S: C, 57.96; H, 4.38; N, 6.76.

Found: C, '57.71; H, 4.81; N, 6.67.

EXAMPLE 59

N\

NN

0~ 0 4- -etol 3-h Nyl -5x zo-4 yl)phenyl] sulfonyl)amino)-4-oxobutanoic acid, disodium salt 4, 4, 87 mp 300 1H NMR (D 2 0/300 MHz) 7. 68 Cd, 2H, T Hz), 7.39-7.20 C m, 7H), 2.34 3H), 2.33-2.15 (m, 4 Anal. Calc'd for C 2 0 Hl 6

N

2 0 6 SNa 2 -0.95 H 2 0: C, 53 H,,3-79; N, 5.89. Found: C, 50.52; H, 3.82; N, .89.

EXAMPLE

H

H

I

-e 0 Nl 0 4 -(5-Methyl3..penyisoxazol4yl)phenyl] sulfonyl) formamide mp 111-122 0 C. 1 H N1M. (CDC1 3 /300 Mflz) 8.69 (br s, 1K), 7.92 Cd, 2H, T 8.5 Hz) 7.48-7.31 (in, 7H) 2.52 Cs, 3H) FABLRMS rn/z 343 FABHRMS m/lz 343 .0753

(M

4 H, Calc'd 343.0753). Anial. Calc'd for C 17 H1 4

N

2 0 4 S: C, 59.64; H, 4.12; N, 8.18; Found C, 59 .59; H, 4. 17; N, 8 .07.

EXAMPLE

61

CH

3 N-EE4-(5-Methyl-3-phenylisoxazo14y1)plienylJ sulfonyl] formamide, sodium salt mp 198-204 'C.

mp~~~1 19-0NC Mp. (D 2 0/300 Miz) 8.57 1H) 7. 64 -2H, J 8. 3 Hz) 7 .3 8-7.-13 Cm, 7H) 2. 31 (s, 3H) FABLRMS m/z 365 EABHRMS m/z 365.0565

(M+H,

Calc'd 3 65. 0572) Anal. Calc -d f or C 1 7

H

1 3N 2

O

4 SNa 0. 73 EtOH '0.51 H 2 0: C, 54.46; H, 4.55; N, 6.88; Found C, 54.46; H, 4.44; N, 6.74.

EXAMPLE

62 a 0.

1,1-Dimethylethyl N- C(4- (5-methyl-3phenylisoxazo1-4-yl)phenyl1sulfonylJcarbamate mp 168-171 0 C. 1NMR (CDCJ.

3 /300 Mz 8.01(d, 2H, ,T 8.7 Hz) 7 .51 Cs, 1H) 7 .46-7 .30 7H) 2. 50 (s, 3H) 1.40 9H) FABLRMS m/z 415 FABHRMS m,'z 415.1337 Calc'd 415.1328). Anal. Calcd for

C

21

H

22

N

2 0 5 S: C, 60.86; H, 5.35; N, 6.76; Found C, 60.79; H, 5.40; N, 6.75.

EXAMPLE

63 l,1-Dimethylethyl N-E[4-(5-methyl-3phenylisoxazo1-4.yl)phenyl]sulfonylJcarbamate, sodium salt mp 241-243 00. 1H NMR (D 2 O/300 MHz) 7.67 2H, J =8.3 Hz), 7.42-7.17 Cm, 7H) 2.35 Cs, 3H) 1.11 9H) FABLRMS m/z 437. FABHRMS m/z 4 3 7 .1l71(M'H, Calc'd 437.1147) .Anal. Calc'd for C-)lH 2 lN 2

O

5 SNa 0.96 H 2 0: C, 55.52; H, 5.10; N, 6.17; Found C, 55.50; H, 5.06; N, 6.29 EXAMPLE 64 F

SO

2

NHCH

3 4 o o h n l y l p n e 1 y N .nzneufaamd mp 12*2 C HNR(D1)520 p z 2H) 2 *7 3 2 1 I z H 4 r s 1H) 6. 92 ,9 H 2 7 7 .1 m H 7 2 d 9* Hz H .6 d z, 2 F B 3

N[

4 2 -(3-ho--luorophenyl)cyclopenten-..w mlpehylenzensl fonamide .4.

rnp 127-129 0 C. 1 1i NMR (CDC1 3 5 2.03-2.14 Cm, 2.84-2.95 Cm, 4H) 6.92-7.00 Cm, 2H) 7.18 (dd, i 2, 8 Hz, 1H) 7.29 J 9 Hz, 2H) 7.88 I. 9 Hz, 2H) 8.20 (br s, 1H) MS (FAB) m/z 394 HRMS Calc'd for CM+H) 394.0680. Found 3 9 4 .0 630. Anal. Calc'd for Cl9Hl7NClFO 3 S 0. 49 H 2 0) C, 5 6.68; H, 4 .50; N, 3.-48.

Found: C, 56.65; H, 4.39; N, 3.74.

EXAMPLE 6 6 Na c 1 F C).SO2)NCOCH 3

F

I-Clr--lorpey~ycoetnl ylpey*sloy*aeaie soimsl mp 8 C H N R (2 )5 .7 ,3 1 9 P 8 H z. 2 m 4H .94 J 8 Hz, 2H 7 13 1 J 8 H 2 7 d z 2H) Anl.a cd f r (lH 6~l OS a& 0 1 H 0 8 52.28 H, 2.67- 2 Cm .94CJ=8H,2) EXAMPLE 67

N

0

H

CH

3 0 0 00 Methyl 3 -[E[4-(5-methyl-3-phenylisoxazol-4yl)phenyllsulfonyllamino]-3-oxopropanoate 1 NMR (acetone-d 6 /300 MHz) 8.04 J 8.5 Hz, 2H), 7.49 Cd, T 8.5 Hz, 2H), 7.40-7.39 Cm, 5H), 3.64 3H), 3.47 Cs, 2H), 2.53 3H). FABLRMS m/z 415 EXAMPLE 68

NN

CH

3 H CH3 N 'H 3 0 s \\O 000

N-E(

4 -[3,4-Dimethyl-l-phenyl-1Hpyrazol-5yllphenyl)sulfonyl]propanamide np 187.4-188.7 1H NMR Cacerone d6/300 Miz) 8.0 Cd, 2H, J 8.5 Hz), 7.43 Cd, 2H, j 8.5 Hz), 7.23 Cm, 2.27 3H), 2.05 Cs, 3H). Anal. Calcd for C 2 0

H

21 N303S: C, 62.64; H, 5.52; N, 10.96. Found C, 62.83; H 5.61; N, 10.90.

EXAMPLE

Na

G-

000yN*1SJ

C

C

C*

C

N-fC 4 -Dimethyl-l-pheny1lH-pyrazolyllphenyl) sulfonyllpropanamide, sodium salt mp 264.0-267.6 0 C. 1H NMR CDMSO d6/300 M{z) 7.68 2H, J 8.4 Hz), 7.25 (in, 3H), 7.11 (mn, 4H), 2.19 3H), 1.94 Cs, 3H) EXAMPLE 7 0

C

C CFi N- ff4-[f5-(C 4 -Methylphenyl) -3- (trifluoromethyl)1lH-pyrazol-l ylJ]phenyl) sulfonylj acetamide 4m~ypey)-3 tilooeh! lH-pyrazol-i-y1]benzenesulfonanide (0.60 g, 1.57 rnmol) was heated in 2 mi acetyl chloride and 2 mL acetic acid at reflux for 2 h. An addicional 2 mL acetyl chloride was added and the mixture was heated to reflux for an additional 5 h. The mixture was cooled and concentrated.

Recrystallization from echer/hexane furnished the product as a white solid: Anal. Calc'd for Cl 9 Hl 6

N

3 0 3

SF

3 C, 53 .90; H, 3.81; N, 9.92; s, 7.57. Found: C, 54.04; H, 3.80; N, 9.93; S, 7.66.

EXAM4PLE 7 1 0 0

**H

3 C N

CF

3 N-ri luro4-yl rS(4MeHypeya y P ph e ny11s ulf o ny 1] a c 'tami de, sodium salt To 3 00 mg 71 mmol) of N-t 14 [5 -methylphenyl) 3- (trif luoromethyl) -lH-pyrazol-1yllphenyllsulfonyllacetamide (Example 70) in 4 rnL EtOH was added 40 LL of 50% NaOH (0.76 minol) and the mixture was stirred at room temperature for 1 h. Concentration provided the sodium sale. as a white solid.

EXAMPLE 72

N

T0 O -Na CH 3 Methyl N- 4 5 -methyl-3-phenylisoxazol-4yl)phenyl]sulfonyl]carbamate, sodium salt A solution of 4-[5-methyl-3- (phenyl)isoxazol-4-yl]benzenesulfonamide (1.920 g, 6.11 mmol) in 40 mL of THF was treated with methyl chloroformate (1.16 mL, 1.38 g, 14.60 mmol) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.80 mL, 2.79 g, 18.33 mmol) at room temperature. After 48 hours, the resulting mixture was partitioned between ethyl acetate and

KHSO

4 solution. The organic phase was washed with brine, dried over MgSO 4 filtered and concentrated in vacuo yielding a pale yellow clear oil. This oil was purified by running two flash chromatographic columns (1st eluant 1:1; hexane: ethyl acetate; 2nd eluant CH 2 C1 2 with THF) yielding the crude compound which was suitable for use without further purification.

The crude compound was dissolved in 8 mL of chloroform and treated with 2 mL of saturated aqueous NaHCO 3 The product separated as a crystalline solid and was collected by filtration to afford pure salt as white needles (0.607 g, mp 267.4-275.0 C. 1H NMR (D 2 0/300 MHz) 7.68 2H, J 8.5 Hz), 7.39-7.12 7H), 3.37 3H), 2.34 3H). FABLRMS m/z 401 (M+Li) 1 FABHRMS m/z 395.0675 Calc'd 395.0673).

Anal. Calc'd for C18H1 5

N

2

O

5 SNa 3.66 H 2 0: C, 46.96; H, 4.89, N, 6.09; Found: C, 46.91, H, 4.40, N, 6.00.

EXAMPLE 73

N

0 HO 0

NNC

00 0 0 0H 3

C

00= 4 -f5-Acetoxymethyl3-phenylisoxaxzol 4yllphenyl]sulfonyl~acetamide A suspension of 4-[5-hydroxymethyl-3- (phenyl)isoxazol-4-yl]benzenesulfonamide (1.51 g, 4.56 mmol) in 60 rL of dichlororethane was see treated with acetic anhydride (1.30 rL, 1.40 g, 13.69 mmol), triethylamine (1.90 mL, 1.40 g, 0 13.70 mmol) and direthylarinopyridine (0.056 g, 0.46 mrol). Within 5 minutes the mixture became homogeneous and stirring was continued for hours. The reaction mixture was diluted with ethyl acetate and washed with 1N KHSO 4 brine, dried over MgSO 4 filtered and concentrated in vacuo to afford 4 -[5-acetoxymethyl-3phenylisoxaxzol-4-yl]phenyl]sulfonyl]acetamide (1.67 g, mp 137-139 OC. 1H NIR (CDC1 3 /300 MHz) 8.58 (brs, 1H), 8.06 2H, J 8.47 Hz), 7.47-7.34 7H), 5.17 2H), 2.12 3H), 2.10 3H). FABLRMS m/z 421

FABHRMS

m/z 415.0953 (M+H C 20

H

19

N

2 0 6 S Calc'd 415.0964).

EXAMPLE 74 0 0 0 Nf[[ 4 5 -Hydroxymethyl3-phenyhenylisol- 4 y 1p h enyl1) s ulf o ny11ac e tam i de A solution of N-[[4-[5-acetoxyrnethyl-3 pheny1i s oxaxzol1- 4 -yl11phenyl1] sul f onyl]1 ac e tami de (Example 73) (0.867 g, 2.09 mmol) in methanol was treated with sodium hydroxide. The reaction was concentrated in vacua, dissolved in water and slowly acidified with 1 N HC]. to yield a solid.

The solid was 'dissolved in ethyl acetate, washed with brine, dried over MgSO 4 filtered and concentrated in vacua to afford hydroxymethyl-3 -phenylisoxaxzol-4 yllphenyllsulfonyl]acetamide as a yellow foam, (0.513 g, 66%) of suitable purity for use without further purification: mo 94-103 0 C. 1 H NMR (CDCl 3 /300 M'flz) 8.18 (brs, 1H), 7.09 2H, J .08 Hz) 7. 47-7 .3 5 (in, 7H) 4. 78 (Cs, 2H) 2. 23 (brs, 1H) 2. 11 3H) FARBLRMS m/lz 373 FABHRMS rn/z 373.0876 Calc'd 373.0858).

Anal. Calcd for Cl 8 Hl 6

N

2 0 5

S

1 C, 58.06; H, 4.33, N, 7.52. Found: C, 57.73, H, 4.70, N, 7.07.

97 EXAMPLE

N

0 Na-

O

[4 5 -Hydroxymethyl 3 -henyli s xa 4 0 yllphenyl lsulfonyllacetamide, sodium salt o e.

A solution of N-((4-[5-hydroxymethyl-3i' phenylisoxaxzol-4-yllphenyl sulfonyl acetamide (Example 74) (0.468 g, 1.26 mrol) in methanol was treated with NaOH solution (0.50 rL, 2.50 N solution, 1.26 mmol). After 5 minutes, the solution was concentrated in vacuo to afford No: o. (5-hydroxymethyl-3-phenylisoxaxzol-4- 0 yl phenyl] sulfonyl acetamide, sodium salt (0.462 g, 93%) as a tan foam: 1 NR (D 2 0/300 mHz) 7.68 .0000 2H, J 8.46 Hz), 7.39-7.23 7H), 4.60 (s, OV 0 2H), 1.79 3H). FABLRMS m/z 395 (M+Na) EXAMPLE 76

NN

0

OH

0 S0 N-f[ 4 -(5-Hydroxymethyl-3-phenylisoxazol-4yl]phenyl) sulfonyllpropanamide, sodium salt Stec 1: Preiparation of, N-f f4-(5-ioroipoxvmethyi-3- D~henvlisoxazol-4-vllDhe~nv11sulfonv11proDanamide A suspension of 4 -15-hydroxymethyl-3- (phenyl)isoxazol-4-yllbenzenesulforiamide (0.314 g, 0.947 mxnol) in TI-F was treated with propionic anhydride (0.36 mL, 0.37 9, 2.846 rnmol), triethylamine (0.40 mL, 0.29 g 2.85 rnmol),) and dimethylarninopyridine (0.025 g, 0.205 mmol). The resulting solution was stirred for 24 hours. The crude reaction was diluted with ethyl acetate and washed with KH-S0 4 brine, dried over MgSO 4 filtered and concentrated in vacua. The resulting product was purified by flash chromatography using as eluant hexane/ethyl acetate Concentration of the appropriate fractions gave N- f 4- (5-propoxymethyl-3- ~phenylisoxazol-4 -ylj phenyl] sulforiyl] propanamide (0.33 g, 79%) as a clear brown oil of suitable purity to use in the next step.

SteDp 2: Prenaration of N- Fr4 -(5-hvdroxvmethyl-3 Dph envli s ax a z o I vl11Dh env11 s u 1fony 11r)roiDa nam id e The (5-propoxymethyl-3-phenylisoxazol.

4 -yllphenyllsulfonyllpropanamide (Step 1) was dissolved in methanol and NaOH solution (0.89 mL of 2.5 N, 2.24 mmol) added with stirring. After 12 hours, the reaction was acidified with 1 N HCl solution and extracted with a mixture of dichloromethane and ethyl acetate. The combined organic phases were dried over MgSO 4 filtered and concentrated in vacuo yielding hvdroxymethyl-3 -phenylisoxazol-4yllohenyllsulfonyl]propanamide (0.238 g, 83%) of sufficient purity to use in the next step.

Steo 3: Prevaration of N-r14- (5-hvdroxymethvl-3phenvlisoxazol-4 -vllrhenllsulfonvll ropanamide, sodium salt N-[(4-(5-Hydroxymethyl-3-phenylisoxazol4 yl]phenyllsulfonvl]propanamide (Step 2) was dissolved in methanol and treated with NaOH solution (1.23 mL of 0.50 N,.0.62 mnol). The resulting solution was concentrated in vacuo.

The resulting oil was diluted with water and concentrated on high vacuum yielding hydroxymethyl-3 -phenylisoxazol-4yllphenyll sulfonyl]propanamide, sodium salt (0.195 mg, 64%) as a tan foam: mo 153.5-157.1 0

C.

1 H NMR (D 2 0/300 MHz) 7.68 2H, J 8.46 Hz), 7.39-7.15 7H), 4.59 2 2.04 2H, J 7.66 Hz), 0.86 3H, J 7.66 Hz).

EXAMPLE 77 //0 *H3c\ ,*s

N

CFS

4-[5-(4-Fluorophenyl)-3-trifluoromethyl-lH pyrazol--yl]-N-met hylbenzenesulfon amide To a solution of 4-[5-(4-fuoropheny)-3trifluoromethyl-lH-pyrazol-1-yllbenzenesufnmd (100 mg, 0.26 mmol) in DMSO (2 mL) was added sodium hydride (6 mg, 0.26 mmol). The reaction mixture was strred at ambient temperature for 1.5 h. To this mixture was added methyl iodide (0.025 mL,, 0.4 mmol).

The mixture was stirred at room temperature for 16 h- 100 The mixture was diluted with ethyl acetate (15 rn.) and washed with water (3 X 10 rnL) .The organic solution was collected, dried (NaISO 4 and concentrated. The residue was chromatographed (3:1 hexane:ethyl acetate) to give the monomethyl sulfonamide (22 mg, 21%) as a gum. Exact mass Calc~d for C 17 Hj 3

F

4 NiO.S: 399.0664. Found 399.0662.

EXAMPLE 7 8

N

SO

2

NHCH

3 methylbenzene suif onamide Stec 1: Preparation of 9S-dinethvl-1,3-dioxane-2prolpano 1 The 5, S-dimethyl-l,3-dioxane-2-propanol was synthesized by following the literature procedure

(J.

Org. Chem. 57, 2195,1992).

Steip 2n: reoaration of ,5-dimethv1-1.3-dioxpne-2roroopanal DMSO (10.2 ml, 0.14 mol) was added to a solution of oxalyl chloride (5.5 ml, 63.2 rnmol) in methylene chloride (25 ml) at -78 OC. After stirring for 15 min, a solution of 5,5-dimet-hyl-l,3-dioxane-2-propanoI (Step 1) (10 g, 57.5 mmol) in met-hylene chloride (100 ml) was added over 10 min. The reaction was stirred for 1 hr and triethylamine (40 ml, 0.2 mol) was added. After stirring at -70 OC for 1 hr, the reaction mixture was warmed to room temperature and stirred for 2 hr. The (I I 101 reaction was quenched with water and extracted with methylene chloride. The organic fractions were washed with aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration, the crude compound was chromatographed (silica gel, hexane/ethyl acetate 7/3) to give 5,5-dimethyl-l,3-dioxane-2propanal (6.1 g, 61%) as a colorless liquid: Anal Calc'd. for C9H 16 0 3 0.2H20: C, 61.48; H, 9.40. Found: C, 61.46; H, 9.24.

Step 3: Preparation of C: a -(4-fluoroDhenvl) dimethvl-1,3-dioxane-2-proanol 4-Fluorophenyl magnesium bromide (8.7 ml, 2M solution in ether, 17.44 mmol) was added to a solution of 5,5-dimethyl-l,3-dioxane-2-propanal (2 g, 11.62 mmol) (Step 2) in THF (50 ml) at -70 OC. After stirring at -70 OC for 2 hr, the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic fractions were combined and washed successively with water and brine. After drying (MgSO4), filtration and concentration, the crude compound (3.5 g) was chromatographed to give a-(4fluorophenyl) -5,5-dimethyl-l,3-dioxane-2-propanol (2.73 g) as a white solid: mp (DSC) 84 OC. Anal Calc'd. for C15H2 1 F0 3 C, 67.14; H, 7.89. Found: C, 67.18; H, 7.98.

Step 4: Preparation of 3-(5,5-dimethvl-l,3-dioxan-2vl)-1-( 4 -fluoroohenvl)propan-l-one To a solution of a-(4-fluorophenyl)-5,5-dimethyl- 1,3-dioxane-2-propanol (Step 3) (2.6 g, 10.7 mmol) in methylene chloride (100 ml), pyridinium chlorochromate g, 16.05 mmol) was added. After stirring at room temperature for 3 hr, the reaction mixture was diluted with ether and filtered through a short silica gel column. The column was eluted with ether and the fractions containing 3 -(5,5-dimethyl-l,3-dioxan-2-yl)l-( 4 -fluorophenyl)propan-l-one were combined and concentrated (2.2 g, mp (DSC) 65 OC. Anal Calc'd.

for C15H 19

FO

3 C, 67.65; H, 7.19. Found: C, 67.21; H, 7.43.

Step 5: PreDaration of N-methvl-4nitrobenzenesulfonamide To a suspension of 4 -nitrobenzenesulfonyl chloride (5 g, 22.56 mmol) in ether (250 ml), methylamine (5 ml, 40% aq. solution, 56.4 mmol) was added, and the mixture was stirred at room temperature.

After 16 hr, the reaction mixture was concentrated to remove the solvent and the residue was resuspended in methylene chloride. After washing with 2N HCl and brine, the organic fractions were dried (MgSO4), filtered and concentrated to give N-methyl-4e..t bnitrobenzenesulfonamide (4.8 g, mp (DSC) 109 oC.

Anal Calc'd. for C7H8N204S: C, 38.89; H, 3.73; N, 12.96. Found: C, 38.83; H, 3.72; N, 12.96.

Step 6: Preparation of methvlamino)sulfonvllaniline To a solution of N-methyi-4nitrobenzenesulfonamide (Step 5) (4.8 g, 22.2 mmol) in methanol (100 ml) in a Parr bottle was added Raneynickel in methanol. The reaction mixture was flushed with nitrogen and hydrogen several times and maintained under hydrogen at delivery pressure of 5 psi. After stirring at 25 OC for approximately 20 hr, the reaction was vented and purged with nitrogen. The contents of the reaction were filtered and concentrated to remove the solvent. The 4-[(N-methylamino)sulfonyllaniline obtained as a white solid (4.1 g, 100%) was used in the next step without further purification: mp (DSC) 138 OC. Anal Calc'd. for C7H0oN 2 02S 0.25 H20: C, 44.08; H, 5.55; N, 14.69. Found: C, 43.83; H, 5.39; N, 14.81.

Ste ~:Prpar~jn o 4f2- 4 -fluoronthenyl1-I1H-prrol- 1-vi 1 mthvI eze-sufonamide A mixture of 3 -dimethyl-1, 3-dioxan-2.yl)l1 4 -fluorophenyl)propan-l-one (Step 4) (400 mg, mmol) 4- (N-methylaiino) sulf onyl Ianiline (Step 6) (308 mg, 1.65 rnmol) and p-toluenesulfonic acid (40 mg) in toluene (80 ml) was heated to reflux for 48 hr. The reaction mixture was cooled, filtered and concentrated.

The crude yellowish solid (760 mg) was chromatographed (silica gel, hexane/ethyl acetate 7/3) to give fluorophenyl) -lH-pyrrol-l-yl]

-N-

*methylbenzenesulfonamide (198 mg, 40%) as a white *solid: mp (DSC) 174 0 C. Anal Calc'd. for C17H1 5 N2F0 2

S

.0.25 H20: C, 60.97; H, 4.67; N, 8.37. Found: C, 60.86; 4.56; N, 8.01.

EXAMPLE 7 9

N,

H ICH 3 N-Cf 4 -(5-Methyl-3-phenylisoxazol- 4 yl)pheny1. sulfony1jglycjne Stec 1- Preparftion of N-ae-t-V1-N-FL4-(5methvp3phnlaxzl4v~hnvlslo1Lrvie ethyl ester To a stirred solution of N-((4-(5-methyl-3phenylisoxazol-4-yl)phenyllsulfonyllacetamide (Example 39) (0.612 g, 1.72 mmol) in dichloromethane was treated with ethyl bromoacetce (0.20 mL, 0.29 g, 1.72 rnmol) and Et 3 N (0.26 mL, 0.19 g, 1.89 mmol) After 7 days the reaction was still incomplete by TLC. Additional ethyl bromoacetate (0.20 m.L, 0.29 g, 1.72 mrnol) and Et3N (0.26 m.L, 0.19 g, 1.89 rnmol) were added and the reaction was stirred for an additional 6 days. The reaction was diluted with dichioromethane and washed with KHS0 4 solution, NaHCO 3 solution, and brine, dried over MgSO 4 filtered and concentrated in vacuo yielding a clear oil.

This oil was purified by flash chromatography yielding

N-

acetyl-N-1 4 -(5-methyl-3-phenyisoxazol..4yl)phenyllsulfonyllglycine, ethyl ester (0.243 g, 32%) as a clear colorless oil of suitable purity for use in the next step: 1 H NMR~ (CDCl 3 /300 MHz) 8.03 2H, J 8.7 Hz) 7. 47-7.27 9H) 4.61 Cs, 2H) 4.21 2H, J= 7. 1 Hz) 2.51 3H) 2.33 3H) 1. 28 3H, j= 7. 1 00 Hz) FABLRMS m/z 443 FABHRMS m/z 442.1201

C

22

H

22

N

2 0 6 S Calc'd 442.1199).

Step) 2: Preparation of N-rf 4 -(5-methl-3-ohenvlisoxazol- S4 -vl ohenyvisul fonvli lycine To a stirred solution of N-acetyl-N-[[4-(5-methyl-3phnlsxzl4y~heylufnlgyie ethyl ester (Step 1) (0.24 g, 0.54 mmol) in methanol was added LiOH-H 2 O (0.06 g, 1.36 mmol) in water. After 5 days the reaction was complete and the solvents were removed in vacua. The resulting semi-solid was partitioned between ethyl acetate and 1N KHS0 4 solution. The ethyl acetate phase was dried over MgSO 4 filtered and concentrated in vacua yielding 4 -CS-methyl-3-phenylisoxazol-4 yl)phenyl]sulfonyl~glycine (0.139 g, 69%) as a white powder: mp 242-248 18 NMR~ (CDCl 3 /300 MHz with DMSOd 6 7.76 Cd, 2H, j 8.5 Hz), 7.33-7.22 5H), 7.19 (d, 2H, J =8.5 Hz) 6.35 1H, J =5.4 Hz) 3.63 Cd, 2H, J 5 .4 Hz) 2 .3 9 FABLRMS m/lz 373 FABHRMS m/z 372.0786 CM+, Calc'd 372.0780) Anal. Calc'd for C 18

H

16 2 0 5 S: C, 58.06;'H, 4.33; N, 7.52; Found C, 58.09; H, 4.44; N, 7.45.

105 EXAMPLE :*ooo o oee o 4 -C5-Methyl-3-phenyisoxazol-4yl)phenyl]sulfonyl]glycine, sodium salt To a solution of 4-(5-methyl-3-phenylisoxazol-4yl)phenyllsulfonyllglycine (Example 79) (0.095 g, 0.255 mmol) in EtOH was added 0.5022N NaOH (0.58' mL, 0.29 rmol). The solution was concentrated in vacuo to afford the desired salt (0.100 g, 100%) as a white powder: mp 216 'C (dec). 1 H NMR (D 2 0/300 MHz) 7.66 2H, J 8.1 Hz), 7.42-7.15 7H), 3.36 2H), 2.32 3H).

FABLRMS m/z 395 FABH.MS n/z 395.0707 (MPH, Calc'd 395.0678). Anal. Calc'd for C 1 8H 1 5

N

2

O

5 SNa 1.55 H 2 0: C, 51.19; H, 4.32; N, 6.63. Found C, 51.18; H, 4.20; N, 6.56.

EXAMPLE 81

H

CH3 H2N 0 00 2 -Amino-N-4-(5-methyl -3 -phenylisoxazol -4 yl)phenyl)sulfonyl acetamide 106 Ste-p 1. Preparatijon_ of 1, 1-dirnethvlethvl N-F2- F fr4- methvl- 3 -ohenisoxazo14.v-hev y lsulfonl l 2 oxoethvllcarbamate A mixture of 4 -[S-methv1-3-(phenyl)isoxazol.4yl~benzenesulfonamide (15.0 g, 47.7 rniol), N-.t-bocglycine N-hydroxysuccinimide ester (13.0 g, 47.7 mmol) and l,8-diazobicyclof4.30]lundec-7ene (14.5 g, 95.4 rnmol) were mixed together in tetrahydrofuran for 1 hour at room temperature. Additional N-t-boc-glycine

N-

hydroxysuccinimide ester (1.3 g, 4.7 mmol) was added and the solution was stirred an additional 2 hours. The solvent was removed at reduced pressure and residue was taken up in ethyl acetate. The ethyl acetate was washed *with 10% aqueous HC1, sat. aq. NaHCO 3 dried over anhydrous Na 2

SO

4 filtered and concentrated in vacuo to afford the desired amide as a clear glassy solid (6.5 g, mp 160.2-2. HC 1 NMR CCDCI 3 /300 M'flz) 8.04 (d, 2H, J 8.4 Hz), 7.44-7.33 5H), 7.28 2K, J 8.4 Hz), 5.24 (brs, 1K), 3.85 Cm, 2H), 2.50 3H), 1.43 Cs, 9H). FABLRMS m/z 472 Anal. Calc'd for

C

2 3

H

2 5

N

3

O

5 S 0.18 H 2 0: C, 58.19; H, 5.38; N, 8.85.

Found: C, 58.22; K, 5.73; N, 8.92.

Steo 2. Prearation of 2 -amino-N-f[4-(5-methl-3ophenvlisoxazol-4-vl).ohenvllsulfonv11acet-amide The amide from Step 1 (16.2 g, 34.3 mmol) was dissolved in dichioromethane. Anhydrous KCl was bubbled through the solution for 30 minutes at room temperature.

The solution was mixed for 1 hour and solvent was removed at reduced pressure. The resulting residue was dissolved in water and crystals began to form. The solution was stirred for 3 hours and crystals collected by vacuum filtration. The product, was dried to a constant weight under vacuum (25 'C at 15 mm Kg, 4 days) (9.4 g, 73%) mp 230. 7-23 4 .7 1H NMR (DMSO-d 6 /300 MHz) 7.84 2H, J 8.4 Hz), 7.70-7.60 (brs, 3H) 7.45-7.30 (in, 5H), 7.23 107 2H, J 8.4 Hz), 3.24 2H), 2.43 3H). FABLRMS m/z 372 Anal. Calc'd for C 1 8

HI

7

N

3 0 4 S 0.30 H 2 0: C, 57.37; H. 4.71; N, 11.15. Found: C, 57.37; H, 4.70; N, 11.12.

EXAMPLE 82 0 H

|CH

3 H 3 N

O

N

2- (Acetylamino)-N- (5-methyl-3-phenylisoxazol- 4-yl)phenyl]sulfonyl]acetamide The 2-amino-N-[ 4 -(5-methyl-3-phenylisoxazol-4yl)phenyl]sulfonyl]acetamide (Example 81) (4.08 g, 10.9 mmol) was mixed in acetonitrile at room temperature.

Triethylamine (3.03 g, 30.0 mmol) and acetic anhydride (1.23 g, 12.1 mmol) were added and the heterogeneous solution was stirred for 2 hours. The solution was vacuum filtered through a pad of diatomaceous earth and solvent was removed at reduced pressure. Water was added and the solution was stirred for 30 minutes. White crystals formed, were collected by vacuum filtration and dried to afford the desired product as a white solid (3.25 g, mp 218.2-219.3 C. 1H NMR (CD 3 OD/300 MHz) 8.01 2H, J 8.2 Hz), 7.42-7.36 7H), 3.85 (s, 2H), 2.50 3H), 1.95 3H). FABLRMS m/z 414 Anal. Calc'd for C 2 0

H

1 9

N

3 0 5 S: C, 58.10; H, 4.63; N,10.16.

Found: C, 58.18; H, 4.66; N, 10.14.

108 EXAMPLE 83 0 0/ N- 4 3 -Phenyl-2,3-dihydro-2-.oxofuran-4 yl) pheny) sul fonyl I prop anamide Step 1. -Preparation of 34-dilphenvl-2-(5H furanone.

A solution of phenacyl bromide (16.540 g, 83.1 mrnol) and phenylacetic acid (11.612 g, 85.3 mmol) in acetonitrile was treated with triethylamine (9.23 g, 91.4 rnmol) arnd the solution was stirred at room cemperature for 1 hour. The solution was treated with 1,8diazabicyclo(5.4.0]undec-7-ene CDBU) (30 mL, 0.234 mol) and the solution was stirred at room temperature for 1 hour. The solution was diluted with 3 N HCl and extracted with ethyl acetate.

The combined extract was washed with 3 N HCl, brine, dried over anhydrous MgSO 4 filtered and concentrated in vacuo t.o afford a solid. The solid was crystallized from hexanies/ethyl acetate 1:1 to afford the furanone (11.627 g, mp 103.8-104.9 0 C. 1H NI"R (CDCl 3 /300 MHz) 7.45-7.25 Cm, 10H) 5.18 Cs, 2H) FABLRMS rn/z 237 Anal. Calc'd for C 1 6

H

1 2 0 2 0.83% H 2 0: C, 80.66; H, 5.17. Found: C, 80.67; H, 5.29.

2.09 Steo 2. Prenaration of 3-f(4aminosulfonvl)Dhenvl) 1-A-oherivl-2- (5H )-furanone.

To 20 rnL of stirring chiorosulfonic acid cooled to -5 00 was added 3,4-diphenyl-2-(SHi furanone (Step 1) (3.160 g, 13 .4 mmol) portionwise over 30 minutes. The solution was warmed to room temnperature and maintained at, that temperature for 16 hours. 'The reaction mixture was diluted with dichioromethane arnd quenched into ice water. The phases were separated and the aqueous phase extracted with dichioromethane, the combined dichloromethane extract was dried over anhydrous MgSO 4 filtered and concentrated :in vacuo. The residue was diluted with dichloromethane and added to excess concentrated

NH

4 OH. The mixture was stirred for I hour. The phases were separated and the aqueous phase was extracted with dichloromethane. The organic extract was dried over anhydrous MgSO 4 filtered and concentrated in vacuo to give a white solid a that was crystallized from aqueous ethanol to afford pure 3-E (4-aminosulfonyl)phenyl) 1-4- )-furanone (2.110 g, mp 225.5a:..:226.5 0 C. 1H NI4R (CDCl 3 /300 MHz) 7.79 2H, J 8.4 Hz), 7.41 2H, i 8.4 Hz), 6.38 (brs, 2H), 5.09 2H). FABLRMS m/z 3 16 Anal.

Calc'd for Cl 6

H

13 N0 4 S: C, 60.94; H, 4.16; N, 4.44. Found: C, 60.86; H, 4.18; N, 4.40.

Ste-p 3. Preoaration of N-f f4-(3-nhenvl-2,3dihvdro-2 -oxofuran-4 vi) ohenv 1sul fonvi 1 rooanamide- A solution of 3 4 -aminosulfonyl)phenyl1)-4- )-furanone (Step 2)(209 mg, 0.663 mmol) trimzhylamine (13 4 mg, 1. 33 mmnol) N, Ndime thy lam inopyr idine (58 mg, 0.475 mmcl) in THE was treated with propionic anhydride (129 mg, 0.994 110 mmol) at room temperature for 45 minutes. The solution was diluted with 3N HC1 and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried over anhydrous MgSO 4 filtered and concentrated to give an oil that was crystallized from ethyl acetate/hexanes to afford the acylated sulfonamide as a white solid (179 mg, mp 182.3-183.4 C. 1 H NMR (CDC13/300 MHz) 8.56 1H), 8.06 2H, J 8.7 Hz), 7.62 (d, 2H, J 8.7 Hz), 7.44-7.22 5H), 5.23 2H), 2.30 2H, &J 7.5 Hz), 1.08 3H, J 7.5 Hz) FABLRMS m/z 372 Anal. Calc'd for C 1 9

H

1 7 C, 61.44; H, 4.61; N, 3.77. Found: C, 61.26; H, 4.64; N, 3.71.

EXAMPLE 84 N. CH 3

N

N -CF 3

N

H

N"Sia 0 0 \0 N- i4-flu2-2-Methylpyridin-3-y -4trifluoromethylimidazol-1yl] phenyl sul fonyl] propanamide A mixture of of 4 2 -(2-methylpyridin-3-yl)-4- (trifluoromethyl)-lH-imidazol--yl]benzenesulfonamide g, 5.2 mmol), propionic anhydride (2.03 g, 15.6 mmol), DMAP (0.38 g, 2.6 mmol) and triethylamine (0.65 g, 6.4 mmol) in 80 mL of THF was stirred at room temperature for 16 hours. The reaction mixture was diluted with 200 mL of water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4 and filtered. The filtrate was concentrated under ill vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 1.95 g of the desired product as a colorless solid mp(DSC) :217-218 0

C.

Anal. Calc'd for Cj9H 1 7F 3

N

4 0 3 S: C, 52.05; H, 3.91; N, 12.98; S, 7.31. Found: C, 51.87; H, 3.84; N, 12.67; S, 7.63.

EXAMPLE 8 N CH 3

N

0D

CF

3

N/

N

N

0 N 4. y1p 0jh~liidzo-l e y ls l o y l ro a a e so iu*s l To N a sus4-io (2 4(-Mehyprii-3-yl) -4di-3y) 4--rflotmr-yimluorometlidzo 1 yllphenyllsulfonyllpropanamide (Example 84) (1.1 g, mmol) in 20 mL of absolute ethanol was added a solution of sodium hydroxide (0.1 g, 2.5 rnxol) in 1.0 mL of ethanol. The mixture was stirred at room temperature for minutes. Solvent was evaporated in vacuc and the residue was dried at high vacuum to give 1. 15 g of compound as a white powder mpC(DSC) 298 0 C (dec) Anal. Calc'd. for C19H17F3N 4

O

3 SNa.l.0 H20: C, 47.70;. H, 3.79; N, 11.71; S, 6.70. Found: C, 47.37; H, 4.03; N, 11.32; S, 6.32.

EXAMPLE 87 A composition is prepared having the following components: j 112 4 -(5-methyl-3-phenylisoxazol-4- yl)phenyl] sulfonyl]propanamide, sodium salt 40 mg phosphate buffer, pH 7.5 (10 mM) 2 ml mannitol 40 mg Mannitol (40 mg) is added to phosphate buffer solution (2 ml). The N-[[4-(5-methyl-3phenylisoxazol-4- yl)phenyl]sulfonyl]propanamide, sodium salt is added and the resulting solution is lyophilized.

BIOLOGICAL EVALUATION Rat Carrageenan Foot Pad Edema Test The carrageenan foot edema test was performed with materials, reagents and procedures essentially as described by Winter, et al., (Proc. Soc. Exp.

Biol. Med., 111, 544 (1962)). Male Sprague-Dawley rats were selected in each group so that the average body weight was as close as possible. Rats were fasted with free access to water for over sixteen hours prior to the test. The rats were dosed orally (1 mL) with compounds suspended in vehicle containing 0.5% methylcellulose and 0.025% surfactant, or with vehicle alone. One hour later a subplantar injection of 0.1 mL of 1% solution of carrageenan/sterile 0.9% saline was administered and the volume of the injected foot was measured with a displacement plethysmometer connected to a pressure transducer with a digital indicator. Three hours after the injection of the carrageenan, the volume of the foot was again measured. The average foot swelling in a group of drug-treated animals was compared with that of a group of placebo-treated animals and the percentage inhibition of edema was 113 determined (Otterness and Bliven, Laboratory Models for Testing NSAIDs, in Non-steroidal Anti- Inflammatory Drugs, Lombardino, ed. 1985)). The inhibition shows the decrease from control paw volume determined in this procedure and the data for selected compounds in this invention are summarized in Table I.

Rat Carrageenan-induced Analgesia Test The rat carrageenan analgesia test was performed with materials, reagents and procedures essentially as described by Hargreaves, et al., (Pain, 32, 77 (1988)). Male Sprague-Dawley rats were treated as previously described for the Carrageenan Foot Pad Edema test. Three hours after the injection of the carrageenan, the rats were placed in a special plexiglass container with a transparent floor having a high intensity lamp as a radiant heat source, positionable under the floor.

After an initial twenty minute period, thermal stimulation was begun on either the injected foot or on the contralateral uninjected foot. A photoelectric cell turned off the lamp and timer when light was interrupted by paw withdrawal. The time until the rat withdraws its foot was then measured. The withdrawal latency in seconds was determined for the control and drug-treated groups, and percent inhibition of the hyperalgesic foot withdrawal determined. Results are shown in Table 114 TABLE I.

RAT PAW EDEMA

ANALGESIA

Inhibition Inhibition 30ma/kq body weiahr 1OmQ/ka body weight Example 13 58 61.5 14 65 41 60 33 In Vitro Conversion of prodrugs The conversion of the prodrugs by S9 liver fractions S.was determined by the following method. The S9 liver fraction suspension (IIAM) was thawed and the suspension was stirred by vortex. The suspension was mixed with 12M urea at 1:7, v:v, (yielding 10.5 M urea final concentration) and further stirred by vortex. The S9 suspension solution was partially purified by solid phase extraction (Vac-Elut apparatus:C 18 columns (Varian #1210- 2001)) eluting with acetonitrile. The fractions were mixed by vortex and concentrated to dryness under nitrogen (no heat). The fractions were resuspended in 00 Ll acetonitrile:phosphate buffer (8.3 mM, pH 7.2) (20:80).

The compounds were dissolved in water (0.2 ml, ug/ml) and incubated at 37 oC (pH 7.2, minutes) with purified S9 fractions (0.2 ml, 3 mg/ml). Conversion of the prodrug to the active COX-2 inhibitor was followed by HPLC (Beckmann System Gold, Novapak C 18 column (3.9xl50mm), acetonitrile:phosphate buffer (8.3 mM, pH 7.2) (20:80 40:60), UV detection 240nm). Quantitation of the conversion of the prodrug was determined by measurement of integrated HPLC peak area. The results of the analysis are included in Table II: 115 TABLE II Metabolism of Prodrugs Example Parent remaining) 14 63.4 18 3.3 0.8 Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of this combination therapy in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly

(IV),

intraperitoneally, subcutaneously, intramuscularly

(IM)

or topically.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, hard or soft capsule, lozenges, dispensable powders, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules.

The active ingredient may also be administered by injection (IV, IM, subcutaneous or jet) as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier. The pH of the composition may be adjusted, if necessary, with suitable acid, base, or buffer. Suitable bulking, dispersing, wetting or suspending agents, including mannitol and PEG 400, may 116 also be included in the composition. A suitable parenteral composition can also include a compound formulated as a sterile solid substance, including lyophilized powder, in injection vials. Aqueous solution can be added to dissolve the compound prior to injection.

The amount of therapeutically active compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and. medical condition of the subject, the severity of the inflammation or inflammation related disorder, the route and frequency of administration, and the particular compound employed, and thus may vary widely. The prodrug compositions should include similar dosages as for the parent compounds. The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 1000 mg, preferably in the range of about 0.5 to 250 mg and most preferably between about 1 and 60 mg. A daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.05 and about 20 mg/kg body weight and most preferably between about 0.1 to 10 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.

In the case of skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day.

For disorders of the eye or other external tissues, mouth and skin, the formulations are preferably applied as a topical gel, spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in- 117 water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane- 1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. The transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch.

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the socalled emulsifying ointment base which forms the oily 118 dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage-from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl escers such as di-isoadipate, socetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The antiinflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to and particularly about 1.5% w/w.

For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, 119 magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral admihistration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers oo or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved Sin water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.

With reference to the use of the word(s) "comprise" or "comprises" or "comprising" in the foregoing description and/or in the following claims, we note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that we intend each of those words to be so interpreted in construing the foregoing description and/or the following claims.

Claims (35)

1. A compound of Formula I 500 wherein A i~s a ring substituent- selected from partially unsaturated heterocyclyl, heteroaryl, cycloalkenyl and aryl, wherein A is optionally substituted at a substit~utable posit~ion with one or more radicals selected from alkylcarbonyl, formyl, .o halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, 15 alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyc2-yl, 6000 cycloalkenyl, aralkyl, heterocyclylalkyl, alkylt-hioalkyl, arylcarbonyl, aralkylcarbonyl, 20 aralkeriyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, 0000 aralkylthioalkyl., aralkoxyalkyl, alkoxycarbonylalkyl, 0000 aminocarbonylalkyl, alkylaminocarbonyl. N- arylaminocarbonyl, N-aklNayafioabnl alkylaminocarbonylalkyl, alkylarnino, N-arylamino, N- aralkvlamino, N-alkyl-N-aralkylamino, N-alkyl-N- ar-ylamino, aminoalkyl, alkylaminoalkyl, Mr- arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N- aralkylaminoalkyl, N-alkyl-N-arylaminoa-kyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylamrinosulfonyl, N- arylaminosulfonyl, arylsulfonyl, and N-alky 1-N- arylaminosulfonyl; wherein RI is selected from heterocyclyl, cycloalkcyl, cyc.loalkenyl and ar-yl, wherein RI is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; wherein R 2 is selected from hydrido and alkoxycarbonylalkyl; and wherein R 3 is selected from alkyl, carboxyalkyl, acyl, alkoxycarbonyl, hetero- arylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, amino acid residue, and alkylcarbonylaminoalkylcarbonyl; provided A is not tetrazolium, or pyridinium; and further provided A is not indanone when R 3 is alkyl or carboxyalkyl; further provided A is not thienyl when R 4 is

4-fluorophenyl, when R 2 is hydrido, when R 3 is methyl or acetyl; or a pharmaceutically-acceptable salt thereof. 2. Compound of Claim 1 wherein A is selected from partially unsaturated heterocyclyl, 5- or 6-membered heteroaryl, C 3 -C8-cycloalkenyl and phenyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from formyl, Cl-Clo-alkylcarbonyl, halo, Cl-Cl 0 -alkyl, Cl-C 6 -haloalkyl, oxo, cyano, nitro, carboxyl, Cl-C 6 -alkoxy, aminocarbonyl, 0 1 -C 6 -alkoxycarbonyl, Cl-Clo-carboxyalkyl, Cl-Cl 0 -cyanoalkyl, Cl-C 6 -hydroxyalkyl, C 1 -0 6 -haloalkylsulfonyioxy, Cl-C 10 alkoxyalkyloxyalkyl, carboxy-C 1 o-alkoxyalkyl, C 3 -C 8 -cycloalkylalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heterocyclyloxy, Cl-C 6 -alkylthio, C 3 -C8-cycloalkyl, phenyl, 5-6 membered heterocyclyl, C 4 -C8-cycloalkenyl, phenyl-C 1 -C 10 -alkyl, 5-6 membered heterocyclylalkyl, Cl-C 6 -alkylthioalkyl, phenylcarbonyl, phenyl-Cl-Ci 0 alkylcarbonyl, phenyl-C 2 -C 6 alkenyl, Cl-C 10 -alkoxyalkyl, phenylthio-Cl-Cl 0 -alkyl, phenyloxy-Cl-Clo-alkyl, phenyl-C 1 -C6-alkylthioalkyl, phenyl-Cl-C 6 -alkoxyalkyl, C 1 -C 6 alkoxycarbonylalkyl, aminocarbonyl-Cl-Cl 0 -alkyl, Cl-C 6 -alkylaminocarbonyl, N- phenylaminocarbonyl, N-Cl-C6-alkyl-N-phenylaminocarbonyl, C 1 -Cr.- alkylaminocarbonylalkyl, C 1 -C 6 122 alkylamino, N-phenylamino, N-phenyl-Cl-Cr-alkylamino, N-Cl-C 6 -alkyl-N-phenylalkyl- amino, N-Cl-C 6 -alkyl-N-phenylamino, Cl-Clo-aminoalkyl, Cl-C 6 -alkylaminoalkyl, N- phenylamino-Cl-Clo-alkyl, N-phenyl-C 1 -C 6 -alkylaminoalkyl, N-C 1 -C6-alkyl-N-phenyl- alkylaminoalkyl, N-Cl-C 6 -alkyl-N-phenylaminoalkyl, phenyloxy, phenyl-0 1 -C 6 -alkoxy, phenylthio, phenyl-Cl-Cl 0 -alkylthio, Cl-C 6 -alkylsulflnyl, Cl-C 6 ,-alkylsulfonyl, amino- sulfonyl, C 1 -C 6 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N- Cl-C 6 -alkyl-N-phenylaminosulfonyl; wherein R 1 is selected from 5- or 6-membered hetercyclyl, 03-C8-cycloalkyl, C 4 -C8-CYCloalkenyl and phenyl, wherein R 1 is optionally substituted at a substitutable position with one or more radicals selected from C 1 -Cl 0 alkyl, Cl-C 6 haloalkyl, cyano, carboxyl, Cl-C6-alkoxycarbonyl, hydroxyl, Cl-C 6 -hydroxy- alkyl, Cl-C 6 -haloalkoxy, amino, Cl-C 6 -alkylamino, phenylamino, nitro, Cl-Cla-alkoxy- alkyl, C 1 -C 6 -alkylsulfinyl, halo, Cl-C 6 -alkoxy and Cl-C 6 -alkylthio; wherein R 2 is selected from hydrido and Cl-C6-alkoxy(carbonylalkyl; and wherein R 3 is selected from C 1 -Clo-alkyl, carboxy-Cl-Cl 0 -alkyl, alkanoyl, aroyl, amino acid residue, Cl-C 6 alkoxycarbonyl, Cl-C 1 -alkoxyalkylcarbonyl, (5-6-membered heteroaryl)carbonyl, C, -C 6 -alkoxycarbonylalkylcarbonyl, C, -C 6 -alkoxycarbonylcarbonyl, and Cl-Clo- alkylcarbonylaminoalkylcarbonyl; or a pharmaceutically-acceptable salt thereof. 3. Compound of Claim 2 wherein A is a radical selected Lrom thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopencadienyl, benzindazolyl, benzopyranopyrazolyl, phenyl, and pyridyl, wherein A is opt~ionally substituted at a substitutable position with one or more radicals selected from formyl, methylcarbonyl, fluoro, chioro, bromo, methyl, trifluoromethyl, difluoromethyl, oxo, cyano, carboxyl, methoxy, arninocarbonyl, mechoxycarbonyl, ethoxvcarbonyl, 123 carboxypropyl, hydroxymethyl, cyartomethyl, ohenyl, phenylmethyl, met-hoxycarboiyl, phenylcarbonyl, methoxymethyl, phenyloxymethyl, aminocarbonylmechyl, carboxymethyl, and phenyloxy; wherein RI is selected from thienyl, oxazolyl, isoxazolyl, furyl, thiazolyl, pyridyl, and phenyl, where RI is optionally substituted at a substitutable position with one or more radicals selected from methyl, trifluoromethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, nitro, methoxymethyl, fluoro, chioro, bromo, methoxy and methylthio; wherein R 2 is hydrido, or echoxycarbonylmethyl; and wherein R 3 is selected from methyl, carboxymethyl, formyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hydroxyethylcarbonyl, benzylcarbonyl, phenyl (hydroxyl) methylcarbonyl, methoxycarbonyl, cert- butoxycarbonyl, methoxyethylcarbonyl, ethoxymethylcarbonyl, mechoxymethlcarbolyl, phenylcarbonyl, carboxye thylIcarbonyl1, carboxymethylcarbonyl, carboxy(l,2- bis (hydroxy) ethyl) carbonyl, methoxycarbonylmethyicarbonyl, methoxycarbonylethylcarboflYl, methoxcycarbonylcarbonyl, aminornethylcarbonyl, ceL-c- butoxycarbonylaminorehylcarbonvl, and methylcarbonylaminomethylcarbolYl; or a pharmaceutically- acceptable salt thereof. 4. Compound of Claim 3 selected from compounds and their pharmaceutically-acceptable salts, of the group consisting of N-(-3(ilooehl--3-loo4mtoyhnl-H pyrazol-l-yllphenyl~sulfonylpropanamide; N-i -3(ilormrhl--3-loo4mrhovhnl-H pyrazol-l-yvllphenyll sulfonylibut-anamide; N-(4-(,5-dimethyl)-3-phenyl-lE-pyrazol-4- yliphenyl] sulfonyllacetamide; 124 yl) pheriyli sulfonyll acer-amide; imidazol- I-y I!phely I I suIf onyl) ace ramide; imidazo I-1-ylIphenyl] sufonyl Iace amide; iridazo I-1-y I Iphenyl I sulfonyl Ibut ananide; N-C (4-(2-(2-methylpyridin-3-yl) -4-(trifluorometiy I) -lH- imidazo I-1-yl IphenlIsulfofylI butaflamide; (4(-3clr--ehlhnl--(rfurmrhl -11-- imidazol-1-y I phenyl I sulfonyl Iace tamide; (3-fluorophenvi) -5-methylisQxazol1- 4 ylLphenyl] sulforiyllacet-amide; 2-me thylI-N-C (C4- (5-methy I-3-phenyl is oxazo 1 4 yl) phenyl) sulfonylipropanamide; N-C (4-(5-methyl-3-phenylisoxazol-4- yl] phenyl] sulfonyl] propanamide; N-C C4-(5-methyl-3-phenylisoxazol-4- yl) phenyl] sulfonyllbenzamide; 2, 2-dimethy-N-C4-(5-methyl-3-phenvY1.1soxazol- 4 yl) pheriyll sulfonyljpropanamide; N-C( (5-methyl-3-phenylisoxazol-4- yl) phenyl] sulfonyllibutanamide; N-C (4-(5-methyl-3-phenylisoxazol-4- yl) phenyl] sulfonylipentanarnide; N-Cehx- (5-methyl-3-phenylisoxazol-4- pheriyl sul fonyl] hexanamide; 2-ethoxy-N-C (4-(5-mehy-3-phenylisoxazol-4- yl)phenyl] sulfonyllraaride; 2-ethox--etC4-(5-methyli-3-PhenliS4 aO1 yl) phenyl Isulfonyl] acetamide; N-C C 4-[5-(4ethlo-phefl) 3-tiSOZl 4 ehl)-Hprao- yl] phenyl] sulfonylipropananide; 125 y II phenyl]I sul fonyl Ibuctanamide; yllphenyil sulfonyl] acetamide; iq[(-3 dfurmrh )--looL -iyr 7-etoy benzothiopyrano 14, 3-clpyrazoi-I- yI] phenyl] sulfonyl] acetaride; benzothiopyralo(4, 3-clpyrazoi-I- yllphenyl] sulfonyllacetamide; 0 OV. py ra z o I- 1- y 1ph e y 1 s ulf o nylla c:e tam ide; -((4-(2-methy-4-heyloxazol-5- 0 yl) phenyillsulfonyl] acetamide; methyl (([4-(5-met-hyl-3-pheflylisoxazol-4- ~yl) phenyl] sulfonyl] amino] oxoacetate; 2 -me choxy (4 -me thy I- 3 -phely 1i so xaz Ol1- 4 yl) phenyll sulfonyl] acetamide; N if luo rome chy 1) 3- phenyl1i s oxaz o1- 4 yllphenyl] sulfonyllpropananide; N 4 5 -(di f uo rome thy 1) 3 -phefy Ii soxa zo I- 4 000.yl]phenyll sulfonylibutananide; oo4- (5-methyl-3-pherlylisoxazoi-4- 0, vl) phenyl suIEorIyIlaminlo] -4-oxobucanoic acid; N-((4-(5-methyl-3-pheflylisoxazol-4- yl)phenyllsulfofl]formamide; 1,1-dimethylethyl N-I:(4-(5-methyli-3-phenylisoxazol- 4 yl) phenyll sulfonyl] carbamate; N-(:(4-(5-methyl-3-pheflylisoxazol-4- yl)pheiyl] sulfonyl] glycine; 2 -amino (4 mehy I3 phely Iisoxazo 1-4 yl)phenyl] sulfonyllacetamide; 2 (acety lamilo) (C (5 -methyl 3 -henyl1isoxazol1-4 yl)phelyl] sulfonyllacetamide; methyl 4- (5-met-hy-3phelylisoxazol-4 yl) pheny IIsul fonyl I minlo] 4-oxobu canoace; 126 meechyl ',I-((4-(5-methy1-3-phieflY1isoxazo1-4- yl) pheny1I sulfonylcarbamace; Nl-acecy1-Nq-( f4-(5-methyl-3-phenlisoxazo- 4 y1)ph1enyilsufollgYCinfe, er-hyi escer; ylphenyl) sulfonyl] acetamide; mechyl (4-(5-mechy1-3-pheli-soxazo- 4 yI) phenyl] sulfonyll amino] -3 -oxopropaloate; 4-[5-(3-bromo-5-1uoro-4-TeCthoxyphefli)- 2 Ctrifluoromethyl)oxazol- 4 -yll -N-met-hylbenzenesulfonamfide; yl) benzenesulfOflamride; methylbenzenesufolatide; N-methyl-4-(5-methyl13-phelylisoxazoI- 4 yL) benzenesulfolamfide; N- C 4- (hydroxymethyl) -3-phenylisoxazol- 4 ~yl Iphenyl) sul fonyl) acetamide; N- (acetoxymethyl) -3-phenylisoxazol- 4 20 yllphenyl] sulfonyllacetanide; 1,1dmcyehlN 2 4 5mty--hnlsxzl4 yl)phenyl] sulfonyl]amino)-2-oxoehyl]carbamate; N o-4-fiuor yI)c yl] phenyLl sulfonyll acer-amide; 4-t2-(4-fluoropheny1)-VH-pyrrol-1-y1V-N- methylbenzenesufoflamide; (4-(3,4-dimethy1-l-pheny1-lH-P~yrazol-5- v 11I p h eny L1 sulI f ony I p ropanarnide; N-f f4-f2-(2-rnethylpyridifl-3-yl)-4- r-rifluoromer-hylitnidazol-l yI Iphenyl] sulfonyl Ipropanarnide; 4- 2 4 -f 1uoro phe ny1)cy c1 openlt e n yIN methylbenzenesulfolamtide; and N (C4 p he ny 1- 2, 3- d ihydro -2 oxof uranf- 4 yI)pheny] sulfonllpropalamtide. 127 A compound of Formula I! H A- wherein A is a ring substituent selected from partially unsaturated heterocyclyl, 10 5- or 6-membered heteroaryl, C 4 -C8-CYCloalkenyl and phenyl; wherein A is optionally substituted at a substitutable position with one or more radicals selected from acyl, halo, hydroxy, Cl-Clo-alkyl, Cl-C6-haloalkyl, oxo, cyano, nitro, carboxyl, Cl-C 6 -alkoxy, oo*::aminocarbonyl, Cl-C 6 -alkoxycarbonyl, carboxy-Cl-Clo-alkyl, Cl-Cl 0 -cyanoalkyl, 01-06- 0 hydroxy(alkyl, Cl-Clo-alkylcarbonyloxyalkyl, and phenyl; wherein R 4 is selected from heterocyclyl, cycloalkyl, cycloalkenyl and phenyl, wherein R 4 is optionally substituted at a substitutable position with one or more o radicals selected from Cl-Clo-alkyl, C 1 -C6-haloalkyl, cyano, carboxyl, 01-06- o~o. alkoxycarbonyl, hydroxyl, C 1 -C 6 -hydroxyalkyl, Cl-C6-haloalkoxy, amino, 01-06- *lyaio pnyaiontrC-Cl 0 -alkoxyalkyl, C-C6-alkylsulfinyl, halo, C-C 6 alkoxy and Cl-C 6 -alkylthio; and 0...'wherein R 5 is selected from hydrido, C 1 -Clo-alkyl, Cl-C 10 -alkoxy, Cl-CI 0 -alkoxy- 0* alkyl, phenyl, aryl-Cl-Clo-alkyl, carboxy-Cl-Cl 0 -alkyl, Cl-C 6 -alkoxycarbonylalkyl, 01-06- alkoxycarbonyl, amino-Cl-Clo-alkyl, Cl-C 6 -alkoxycarbonylaminoalkyl, and C,-CjO- alkyicarbonylaminoalkyl; provided A is not tetrazolium or pyridinium; further provided A is not thienyl when R 1 is 4-fluorophenyl, when R 2 is hydrido and when R 5 is methyl; or a pharmaceutically-acceptable salt thereof.

6. Compound of Claim 5 wherein A is a ring substituent selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxa- zolyl, pyrazolyl, cyclopentenyl, 128 cyctopentadienyl, benzindazolyl, benzopyranopyrazolyl, phenyl, and pyridyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from acyl, halo, hydroxy, Cl-Clo-alkyl, Cl-Ce-haloalkyl, oxo, cyano, nitro, carboxyl, Cl-C 6 -alkoxy, aminocarbonyl, Cl-C 6 -alkoxycarbonyl, cairboxy-C-Clo-alkyl, 01-010- cyanoalkyl, Cl-C io-alkylcarbonyloxyalkyl, phenyl and Cl -C6-hydroxyalkyl; wherein R 4 is selected from 5-6 membered heteroaryl and phenyl, wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected 10 from C 1 -Cl 0 -alkyl, 01-06-haloalkyl, cyano, carbonyl, Ci-Ce-alkoxycarbonyl, hydroxyl, l-0 6 -hydroxyalkyl, Cl-Ce-haloalkoxy, amino, Cl-C6-alkylamino, phenylamino, nitro, Cl-Clo-alkoxyalkyl, Ci-Ce-alkylsulfinyl, halo, Cl-Ca-alkoxy and Cl-Cs-alkylthio; and **:wherein R 5 is selected from hydrido, Cl-Clo-alkyl, Cl-C6-alkoxy, Cl-Cl 0 -alkoxy- alkyl, phenyl, Cl-Ce-aikoxycarbonylalkyl, Ci-Ca-alkoxycarbonyl, amino-Cl-Clo-alkyl, C1-C6-alkoxycarbonylaminoalkyl, and Cl-Clo-alkylcarbonylaminoalkyl; or a pharmaceutically-acceptable salt thereof.

7. Compound of claim 6 wherein A is a ring subs tituent -ectdfrom theyoxazolyl, frl pyrrolyl, thiazolyl, imidazolyl, isor-hiazolyi, isoxazolyl, pyrazolyl, cYclopentenyl, c'v-clopentadjenvl, benzindazolyl, benzopyranopyrazolyl, phenyl, and pyridyl; wherein A is optionally substituted at a substi~tutable position with one or more radicals selected from Eormyl, fluoro, chioro, bromo, methyl, trifluoromethyl, oxo, cyano, carboxyl, methoxy, arinocarbonyl, methoxycarbonyl, ethoxycarbonyl, carboxymethyl, carboxypropyl, me thy lcarbonyloxymethyl, and hydroxyrnethyl; 129 wherein R 4 is selected from thienyl, pyridyl and phenyl, wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from methyl, z.-rifluoromethyl, hydroxyl, hydroxymet-hyl, trifluoromer-hoxy, nitro, met-hoxymer-hyl, fluoro, chioro, bromo, met-hoxy and methylthio; and wherein R5 is selected from hydrido, methyl, ethyl, isopropyl, propyl, tert-butyl, butvl, pentyl, methoxv, cert-butoxy, methoxyethyl, ethoxymethyl, methoxymethyl, phenyl, carboxyethyl, methoxycarbonyirnethyl, me thoxycarbonyl ethyl, tert-butoxycarbonylaminomethyl, methoxycarbonyl, aminomethyl, and methylcarbonylaminomethyl; or a pharmaceutically'-acceptable salt thereof.

8. Compound of Claim 7 selected from compounds and their pharmaceutically -acceptable salts, of the groulp consisting of (4-(3-(difluoromethyl) (3-fluoro-4-methoxypheflyl) -IH pyrazol-l-yllphenyllsulfonyl]propalamide; (4-(3-(difluoromethy-l) (3-fluoro-4-methoxyphenyl) pyrazol-1-yllphenyll sulfonylibur-ananide; (4(,5-dimehyl) -3-phenyl-lH-pyrazol-4- yilphenyll sulfonyllacetamide; (3-pyridinyl) (trifluoromethyl) -1H-imidazol-1- yllphenyl] sulfonyllacetamide; [2-(C5-methylpyridin-3 -yl) (trifluoromethyl) -lH- imidazol-l-ylphenyil sulfonyll acetamide; N- 4(-2mtyprdn3yl 4(rfurmtv)-H imidazol-1-yllphenylI sulfonyllacecamide; N- 4(-5mtyprdn3yl 4(rfurmty)-H imidazol-1-yllphenylsulfonyllbutanamide; (2-methylpyridin-3-yi) -4-(trjifLuoromethyl) -!H imidazol-l-yllphenyl] sulfonylibutanamide; (4-(2-(3-chloro-5-mechylphenyl)-4- (trifluoromethyl) -2-H- imidazol-1-yllphenyll sulfonyllacecamide; 130 ylI phenyl sulfaflyll acecamide; 2-mechvl-N- (5-methyl-3-ohefvlYisQxazoL- 4 4i) ohenylsuifonyllprapananide; N-il(4-(5-mer-hy1-3-phenlisoxazol- 4 yI) phenyillsulfonyl) prouaiatnide; N-il(4-(5-methyi-3-pheflylisoxazoi- 4 yl) phenyl3 sulfonyl) benzamide; 2, 2-dime thy L-N C (4(5methy -3pheny Iisoxazo I- yl)phenyl1sulfonylipropanamide; N-il i4-(5-methyl-3-phefliisoxazol- 4 yl)phenyl] sulfonyilbutalamide; 4l) henyl] sul foryl] pentanamide; N-il(4-(5-methvl-3-phelisoxazo 2 4 yI) phenyl] sulfonylihexaflamide; 3 -me thoxy-N-( [4-(5-ethv.3-phely I isoxazo 1- 4 yl)phenyi] sulfonyllpropanamide 2-ethoxy-N-l(4 (5-methy-3-phenylisoxazol- 4 yl)phenyl] sulfonyllacecanide; N-il i4-(5-methyl-3-pheflylisoxazol- 4 4] phenyll suifonyll acectamide; N-il(4-(5-(4-chlorophelyl) -3-(trifluoromer.hy1)-1-H-oyrazoI-l- y~llohenylIsuifonyl ipropanamide; l(4(-4clrpey)3(rfurmrhl-Hprzll ylI phenyllIsuifonyll bucanarnide; N-il(4- (4-chlorophelYl) rifluoromechy1) -1H-pyrazol-1- yI] phenyil sulfonyllacetamide; N-(il4-i3-(difluoromechy1)-6-fIluoro-l. 5-dihydro-7-methoxy- i2]benzothiopyrafloi43-cIpyrazol- yl] phenyl Isuifonyll acetarnide; N-(-6fur-,-iyr--ehx--tilooehv) i2Ibenzothiopyraloi 4 3-clpyrazol-1- yllphenyi) sulfonyl] acetarnide; N-(-3(ilooehl--3-loo4mtoyhnl-H pyrazol-1-yi]phelyi)sulfonllaceta-mide; 131 N-f f4-(2-mechyl-4-phenvloxazol-5- yl) phenyll sulfonylacer-amide; mechyl (ff4- (5-methyl-3-ohenylisoxazol-4- yl) phenyl Isulfonyl]amino] oxoacetac-e; 2-mer-hoxy-N-ff4-(5-mechyl-3)-phenylisoxazol-4- yl)phenyll sulifonyllacecamide; N-f f4-I5-(difluoromethyl)-3-phenylisoxazol-4- yl] phenyl] sulfonyl] propanamide; N-f f4-[5-(difluoromethyl)-3-phenylisoxazol-4- yllphenyllsulfonyllbutanamide; 4-f f4-C5-met-hyl-3-phenylisoxazoi-4- yI)phenyl] suifonyllamino] -4-oxobutanoic acid; NT-f 4-(5-methyl-3-phenylisoxazol-4- yl)phenyl] sulfonyl] formamide; 15 1, 1-dimethylethyl N-f (4-(5-methyl-3-phenylisoxazol-4- yl) phenyll sulfonyl] carbamate; N-f (4-(5-methyl-3-phenylisoxazol-4- yI) phenyll sulfonyl] glycine; 2-amino-N-f f4-(5-methyl-3-phenylisoxazol-4- yl)phenyll suifonyllacer-amide; 2-(acecylamino) -N-f f4-(5-methyl-3-phenvlisoxazo1-4- yl)phenyll sulfonyllacetamide; mechyl 4-fff4-C5-methyi-3-pheny.Lisoxazol-4- N/i) phenyll sulfonyll amino] -4-oxobutanoarte; mechyl N-f(f4- (5-mechyl-3 -ohenylisoxazol-4- yl) phenyl] sulforiyl] carbamate; N-f f4-f5-(4-methylphenyl)-3-(trifluoromer-hyl)-1H-pyrazol-l- yl] phenyll sulfonyl]acetamide; methyl 3-(((4-(5-methyl-3-phenylisoxazoi-4- vI) phenyll sulfonyll amino] -3 -oxoprcopanoate; N-f f4-(5-(hydroxymethyl)-3-phenylisoxazol-4- yl Iphenyl] sulfonyl] acetarnide; N-f f4-f5-(acetoxymethyl)-3-phenylisoxazol-4- yl] phenyl Isulfonyl] acetamide; 1,1-dimethylethyl-N-f2-fff4-(5-methvl-3-ph-enylisoxazol-4- yl)phenyllsulfonyllamino] -2-oxoethylicarbamate; 132 4 -dime c-hyl-Il-pfefly-LH-pyrazol ylphenyll sulfonvllpropaflamide; N-C C4-(2- (2-methylpyridinf-3-yi) -4- tri fluoromethylimidazol -1- yllphenyl] sulfonyllpropanamide; yllphenyllsulfofllacetamide; and [4-(3-phenyl-2,3-d3hydro-2-oxofuran- 4 yl) pheny Isul fonyl] propanamide.

9. Compound of any one of Claims 5 to 8 wherein the pharmaceutically -acceptable salts are metal salts. Compound of Claim 9 wherein the pharmaceutically -acceptable salts are selected from alkali metal salts and alkaline earth metal salts.

11. Compound of Claim 10 wherein -the pharmaceut ical ly -acceptable salts are selected from sodium and potassium salts.

12. Compound of Claim 11 selected from compounds .9...and their pharmaceut icallyIv-acceptable salts, of the group consist~ing of pyrazol-l-yl]pherIyllsulfofllIpropanamide, sodium salt; 4 -(3-(difluoromethyl)5(3fluoro4mer-hoxyphenyl)iH pyrazol-l-yl1phenylIsulfonyl~butanamide, sodium salt; N-f(4-(l,5-dimethyl)-3-phenyl-lH-pyrazol- 4 yllphenyll sulfonyll acetamide, sodium salt; N-[-2(-yiiy)--tifurmty)I-mdzll yl]phenyllsulEfnllacetamide, sodium salt; N-(-2(-ehlyii--y)4(rfurmrhl-H imidazol-1-yllphernyl]5ulfoflyllacer-amide, sodium salt; N-C (4-112- (2-methylpyridin-3-yl) trifluoromer-hYl) -18- imidazol-1-yllphenllIulfonllaceamide, sodium salt; 133 N-(L (5-mechlpyridin-3-yI) -4-kcrifluoromer-hyl) -!H imidazol-l-yllphenyll sulfonyibur-anamide, sodium salt; N-IL(4-I2-(2-methylpyridin-3-yl) ifluoromethivl) -lH- imidazol-l-yllphenyvlsulfonyilbucanamide, sodium salt; N-IL I4-I2-(3-chloro-5-mechylphenvl)-4- (trifluoromet-hyl) imidazol-l-yllphenyllsulfon.lacecamide, sodium salt; N-ILI4-I3-(3-fluorophenyl)-5-mer-ylisoxazol-4- yl Iphenyll sulfonyl] acetamide, sodium salt; 2-methyl-N-L I4-(5-methyl-3-phenylisoxazol-4- yl)phenyl] sulfonyllpropanamide, sodium salt; N-IL I4-(5-mectyl-3-phenylisoxazol-4- yllphenyll sulfonylipropaiamide, sodium salt; N-IL I4-(5-methyl-3-phenylisoxazol-4- yl)phenylsulfonyllbenzamide, sodium salt; 2,2-dimet-hyl-N-ILI4-(5-methyl-3-phenylisoxazol-4- yl) phenyl] sulfonylipropanamide, sodium salt; N-L I4-(5-methyl-3-phenylisoxazol-4- yl)phenyll sulfonylibutaiamide, sodium salt; N-L 4-C5-methyl-3-phenylisoxazol-4- yl)phenyll sulfonyllpentanamide, sodium salt; N-IL I4-(5-methyl-3-phenylisoxazol-4- yl)phenyl] sulfonylihexanamide, sodium salt; 3-methoxy-N-L I4- (5-methyl-3-phenvlisoxazol-4- yl)phenyll sulfonylipropanamide, sodium salt; 2-echoxy-N-L I4-(5-methyl-3-phenylisoxazol-4- yl)phenyll sulfonyllacecamide, sodium salt; N-IL I4-I5-methyl-3-phenylisoxazol-4- yl]phenyllsulfonyllacetamide, sodium salt; N-L I4-I5-methy-3-phenylisoxazol-4- yllphenyllsulfonyllacetamide, potassium salt; N-IL I4-IS- (4-chloroorhenyl) (trifluoromer-hyl) -1H- pyrazol-l-yllphenyllsulfonyllpropanamide, sodium salt; N-IL I4-I5-(4-chlorophenyl)-3-(trifluoromethyl)-lH- pyrazol-l-yllphenyl] sulfonyllbutanamide, sodium salt; 134 pyrazol-l-yllphenlsuifolYIlacetamide, sodium salt; me th-oxy- (2 1 benzothiopoyrano 4, 3 -c)pyrazoI -I yllphenylsulfonyl]aceamide, sodium salt; N4-((4-[6-fluoro-1,5-dihydro-7-mechoxy-3- (trifluoromethyl) -(2lbenzothiopyrano( 4 ,3-clpyrazol- 1-yllphenyllsulfonyllacetamide, sodium salt; N-((4-(3-Cdifluoromethyl)-5-(3-fluoro-4- mechoxyphenyl) -lH-pyrazol-l- yilphenyllsulfonyllacecamide, sodium salt; yl)phenyllsulfonyllacetamide, sodium salt; methyl (((4-(5-methyl-3-pheflYlioxazol-4 yl)phenyl]sulfonyllaminloxoacetate, sodium salt; 2-methoxy-NI-( (4-(5-methyl-3--pheflylisoxazol-4- yl) phenyll sulfony-l]acetamide, sodium salt; N 4- (5 (d ifl1uo rome thyl1) 3- ph enyli s c)xaz olI-4 vll phenyll sulfonyllpropaaride, sodium salt; N -4 5 ifl1uo rome t hy1)- 3-ph eflyIi sc)xa z o1- 4 yllphenyll sulfonylbutanamide, sodium salt; ((4-(5-met-hyl--phenylisoxazol-4 yl)phenyllsulfofllamil]-4-oxobucanoic acid, sodium salt; N\I-f (4-(5-mechvl-3-phenylisoxazol-4- vl)phenyllsulfonyl] formamide, sodium salt; 1,1-dimethylechyl N-((4-(5-methyl-3-pherlyliSOXazol-4 yl) phenyl sulfonyl Icarbamate, sodium salt; NI-f(4-(5-methyl-3-phenylisoxazol-4- y.L)phenyllsulfonyllglYCile, sodium salt; 2 -am ino -N 4 -C(5 me thylI- 3 p h efyIi so xaz oI- 4 yl)phenyllsulfonyllacer-amide, sodium salt; 2-(acetylamino)-N-(f4-(5-methyl-3phelylisoxazol- 4 yi)phenyll sulfonyllacer-amide, sodium salt; methyl 4-(((4-(5-methyl-3-pherLylisoxazol-4- yl) phenyll si.-fonyl] amino] -4-oxobur-anoate, sodium salt; 135 methyl N-((4-(5-methyl-3-pheflylisoxazol-4- yl)phenyl] sulfonyllcarbamate, sodium salt; N-fj(4-(5-hydroxymec.hvl-3-phernylisoxazol-4- yllphenyllsufony1iacecanide, sodium salt; N-((4-(5-(4-methylphenyl)-3)-(trifl:uoromechy1)-LH- pyrazol-l-yllphenyllsulfonyllacecamide, sodium salt; methyl 3-(((4-(5-methyl-3-phenylisoxazol-4- yl) phenyll sulfonyl] amino] -3 -oxopropanoate, sodium salt; (4-(5-(hydroxcymethyl) -3-phenylisoxazol-4- yl)phenyllsulfonyllacetamide, sodium salt; N (ac e t:oxyme t.hy1) 3 -phefly 1i soxa zolI-4 yllphenyll sulfonyllacetamide, sodium salt; N-((4-(3,4-dimethyl-l-pheflyl-1H-pyrazol-5- yllphenyllsulfony1]propanamide, sodium salt; trifluoromethylimidazol -1- yllphenyl] sulfonyllpropanamide, sodium salt; (4-(2-(3-chloro-4-Eluorophelyl)cycopeltel- yl]phenylllsulfonyllacetamide, sodium salt; and (4-(3-phenyl-2,3-dihydro-2-oxofuran-4- yl)pheny] sulfonyllpropanamide, sodium salt. *13. A compound of Formula II N..N, 00 alkyl, 0 1 -Clo-alkoxyalkyl, 136 Cl-Clo-alkoxyalkyloxyalkyl, aryl-Cl-Clo-alkoxyaikyl, C 1 -C 6 -haloalkyl, CI-C 6 hydroxyalkyl, aryl-C 1 -C 6 (hydroxyalkyl), Cl -C6-haloalkylsulfonyloxy, carboxy-C 1 -Clo- alkoxyalkyl, C3-C8-cycloalkylalkyl and C 3 -C 8 -CYClO- alkyl; wherein R 7 is one or more radical selected from hydrido, Cl-Clo-alkyl, 01-06- haloalkyl, cyano, carboxyl, Cl-C 6 -alkoxycarbonyI, hydroxyl, Cl-Ce-hydroxyalkyl, Cl-C 6 -haloalkoxy, amino, Cl-C 6 -alkylamino, phenylamino, nitro, Cl-Clo-alkoxyalkyl, Cl-C 6 -alkylsulfinyl, halo, Cl-C 6 -alkoxy and Cl-C6-alkylthio; and wherein R 8 is selected from hydrido, Cl-Clo-alkyl, Cl-C 6 -alkoxy, Cj-Cj 0 C. alkoxyalkyl, phenyl, carboxy-Cl-Cl 0 -alkyl, Cl-C 6 -alkoxycarbonylalkyl, Cl-C 6 -alkoxy- carbonyl, amino-C 1 -Clo-alkyl, C1-C6-alkoxycarbonylaminoalkyl, and Cl-Cl 0 -alkyl- carbonylaminoalkyl; or a pharmaceutically-acceptable salt thereof.

14. Compound o f Claim 13 wherein R 6 is selected from Cl-Clo-alkyl, C 1 -C 6 haloalkyl, and Cl-C 6 -hydroxyalkyl; wherein R 7 is one or more radicals selected from hydrido, Cl-Cl 0 -alkyl, halo, and CI-Cr 6 -alkoxy; and wherein R 8 is selected from Cj-Cj 0 alkyl, phenyl, and amino-Cl-Clo-alkyl; or a pharmaceutically-acceptable salt thereof. Compound of Claim 14 wherein RO' is selected from methyl, difluoromethyl and hydroxynethyl; wherein R 7 is one or more radicals selected from hydrido, methyl, Eluoro, chioro, bromo, and metchoxy; and wherein R 8 is selected from methyl, ethyl, isopropyl, propyl, tez-c-butyl, bucyl, penrtyl, phenyl, and aminomethyl; or a phar-maceutically-acceptable salt thereof.

16. Compound of Claim 15 selected from compounds and '"eir pharmaceutically-accepcable salts, of the group, consisting of 4 3 (3-fluoropheny I) 5-mer-hylisoxazo 1 4- ylI phenyl] sulfonyl] acetamide; 2-mechyl-N-f 4 -(5-methyl-3-phenylisoxazol-4- yl) phenyl Isulfonyl Ipropanamide; M-.f f 4 -(5-methyl-3-phenylisoxazol-4- yllphenyl] sulfonyllpropanamide; 4 -(5-methyl-3-phenylisoxazol-4- yl) phenyl] sulfonyl] benzamide; 2,2-dimethyl-N-( [4-(5-methyl-3-phenylisoxazol-4- yl) phenyl] sulfonyllpropanamide; N-f 4 -(5-methyl-3-phenylisoxazol-4- yl) phenyl] sulfonyl] butanamide; *S N-f -5mtyl3peyisxzl4 yl) phenyl Isulfonyl] pentanamide; N-f f4-(5-methyl-3-.phenylisoxazol-4- yl) phenyl] sulfonyl] hexanamide; N-f f4-(5-methyl-3-phenylisoxazol-4- ylI phenyl iisulfonyl] acetamide; (5-hvdroxvmethyl-3-phenylisoxazol4.- 5 yl Iphenvl] sulfonyllIpropanamide; N- C 4- [5-Cdif luoromerthyl) -3-pheny I -soxazold.. yllIphenyl sulfonyl Ipropanamide; N-f f4-(5-Cdifluoromechyl) -3-phenylisoxazol-4- yllphenyl] sulfonyllbucananide; N-f f4-(5-mechyl-3-phenylisoxazol-4- yl)phenyl] suifonyllglycine; and N-f 4 -fS-(hydroxymethyl)-3-phenylisoxazol-4 yl] phenyl IsulfonyllIacecamide.

17. Compound of any one of Claims 13 to 16 wherein the oharmaceutically-acceptabie salts are selected from alkali metal salts and alkaline earth metal salts. 1.38

18. Compound of Claim 17 wherein the pharmaceutically -acceptable salts are selected from sodium and potassium salts.

19. Compound of Claim 18 selected from compounds and their pharmaceutically-acceptable salts, of the group consisting of N-f (4-f 5-methyl-3-phenylisoxazol-4- yilphenyl] sulfonyllacetamide, potassium salt; N-f f4-f3-(3-fluorophenyl) -5-met-hylisoxazol-4- yllphenyl] sulfonyllacetamide, sodium salt; 2-methyl-N- (5-methyl-3Y-phenylisoxazol-4- yl) phenyl] sulfonyllpropanamide, sodium salt; N-f f4-(5-methyl-3-phenylisoxazol-4- yllphenyll sulfonylpropnzamide, sodium salt; et-L-(4-(5-methyl-3-phenylisoxazol-4- yl)phenyllsulfonyllpropanamide, sodium salt; *6:6 (5-methyl-3-phenylisoxazol-4- yl)phenyl] sulfonyllbutanamide, sodium salt; 6066rrf4(-ehl3-hnlsxzl4. ea0 (-5mehl3peylsxzl4 Yl)phenyl] sulfonyllpent-anamide, sodium salt,; MN-ff4-(5-mec-hvl-3-phenylisoxazol-4- yl) phenyl] sulfonyl] hexanamide, sodium salt; N-f f4-(2-methyl-4-phenyloxazol-- yl)phenyl] sulfonyllacetamide, sodium salt; N-f f4-(5-(difluoromethyl) -]-phenylisoxazol-4- yllphenvl] sulforiyllpropanamide, sodium salt; N-f f 4 -(5-(difluoromethyl)-3-phenylisoxazol.4- yllphenyl] sulfoniylibutanamide, sodium sal-t; N-f f4-(5-hydroxymethyl-3-phenylisoxazol.4- yllphenyl) sulfonylipropanamide, sodium salt; N\-f f4-(5-meth-vl-3-phenylisoxazol-4- yl)phenyl] sulfonyljglycine, sodium salt; and 139 N-[[4-(5-(hydroxymethyl)-3-phenylisoxazol-4-yl]phenyl] sulfonyljacetamide, sodium salt. A pharmaceutical composition comprising a therapeutically- effective amount of a compound, said compound selected from a family of compounds according to claim 1, including those wherein A is tetrazolium or A is indane when R 3 is alkyl or cycloalkyl; or according to any one of Claims 2-19.

21. A method of preparing a compound of Formula 11 H wherein A is a ring substituent selected from partially unsaturated heterocyclyl, 5- or 6-membered heteroaryl, C 3 -C8-cycloalkenyl and phenyl; wherein A is optionally substituted at a substitutable position with one or more radicals selected from acyl, halo, hydroxy, Cl-Clo-alkyl, Cl-C 6 -haloalkyl, oxo, cyano, nitro, carboxyl, 01-06- alkoxy, aminocarbonyl, 0 1 -0 6 -alkoxycarbonyl, carboxy-Cl-C 10 -alkyl, Cl-0 1 0 -cyanoalkyl, Cl-0 6 -hydroxyalkyl, 0 1 -Cl 0 -alkylcarbonyloxyalkyl, and phenyl; wherein R 4 is selected from heterocyclyl, cycloalkyl, cyanoalkyl and phenyl, wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from Cl-CI 0 -alkyl, Cl-C6-haloalkyl, cyano, carboxyl, Cl-C 6 alkoxycarbonyl, hydroxyl, 0 1 -C 6 -hydroxyalkyl, Cl-C6-haloalkoxy, amino, Cl-0 6 -alkyl- amino, phenylamino, nitro, 0 1 -Clo-alkoxyalkyl, 0 1 -0 6 -alkylsulfinyl, halo, 0 1 -0 6 -alkoxy and Cl-C 6 -alkylthio; and wherein R 5 is selected from hydrido, CI-Cl 0 -alkyl,tiC0-alkoxy, 0 1 -Clo-alkoxy- alkyl, phenyl, aryi-0 1 -Clo-alkyl, carboxy-Cl-Cl 0 -alkyl, Cl-C 6 -alkoxycarbonylalkyl, Cl-C 6 alkoxycarbonyl, amino-0 1 -C 10 -alkyl, Cl-C 8 5-alkoxycarbonylaminoalkyl, and Cl-Clo- 140 alkylcarbonylaminoalkyl; further provided A is not thienyl when R 4 is 4-fluorophenyl and when R' is methyl; or a pharmaceutically-acceptable salt thereof, the method comprising treatment of an unsubstituted sulfonamidle with an acylating agent in the presence of base and a solvent.

22. The method of Claim 21 wherein the acylating agent is selected from anhydrides, acid chlorides, acyl, imidazoles and active esters.

23. The method of Claim 22, wherein the acylating agent is selected from acetic anhydride, propionic anhydride and butyric anyrie

24. The method of any one of Caimn 21 to 23 wherein the solvent is tetrahydrofuran. A method of preparing a compound of Formula Ill R6I H R 8 N Y 0 wherein Rr 6 is selected from hydroxyl, Cl-Clo-alkyl, carboxyl, halo, carboxy- Cl-Clo-alkyl, Cl-Ce-alkoxycarbonylalkyl, aryl-Cl-Cl 0 -alkyl, Cl-Cl 0 -alkoxyalkyl, Cl-Cl 0 alkoxyalkyloxyalkyl, aryl-Cl-Clo-alkoxyalkyl, halo-Cl-Clo-alkyl, Cl-C 6 -hydroxyalkyl, aryl- Ci-Cr,-(hydroxylalkyl), Ci-Ce-haloalkylsulfonyloxy, carboxy-C 1 -Clo-alkoxyalkyl, 03-05- cycloalkylalkyl and 03-08-cycloalkyl; wherein R 7 is one or more radicals selected from hydrido, Cl-Cl 0 -alkyl, 01-06,- haloalkyl, cyano, carboxyl, Cl-C6-alkoxycarboiyl, hydroxyl, Cl-Ce-hydroxyalkyl, 0l-Cr,- haloalkoxy, amino, Ci-C6-alkylamino, phenylamino, nitro, 0,-Clo-alkoxyalkyl, 01-06- 141 alkylsulfinyl, halo, Cl-C 8 -alkoxy and C 1 -C 6 -alkylthio; and wherein R 8 is selected from hydrido, C 1 -C 10 -alkyl, Cl-C 6 -alkoxy, C, -C 10 -alkoxyalkyl, phenyl, carboxy-C 1 -Cl o-alkyl, Cl,-Ce-alkoxycarbonylalkyl, Cl-C 8 -alkoxycarbonyl, amino-Cl-Clo-alkyl, CI-C6-alkoxycarbonylaminoalkyl, and Cl-Clo-alkylcarbonylaminoalkyl; or a pharmaceutically-acceptable salt thereof, the method comprising treatment of an unsubstituted isoxazolyl benzene- sulfonamide with an acylating agent in the presence of base and a solvent.

26. A method of preparing a pharmaceutically-acceptable salt of a compound of Formula 11 *A R4* RS N R 5 a N11.I wherein A is a ring substituent selected from partially unsaturated heterocyclyl, 5- or 6-membered heteroaryl, C4-C 8 -cycloalkenyl and phenyl; wherein A is optionally 0 substituted at a substitutable position with one or more radicals selected from acyl, 0: halo, hydroxy, C,-Clo-alkyl, Ci-C 8 -haloalkyl, oxo, cyano, nitro, carboxyl, C 1 -C 6 -alkoxy, aminocarbonyl, Cl-C6-alkoxycarbonyl, carboxy-Cl-0 1 0 -alkyl, Cl-Clo-cyanoalkyl, Cl-C 6 -hydroxyalkyl, Cl-Cla-alkylcarbonyloxyalkyl, and phenyl; wherein R 4 is selected from heterocyclyl, cycloalkyl, cycloalkenyl and phenyl, wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from Cl-C 10 -alkyl, Cl-C8-haloalkyl, cyano, carboxyl, Cl-C 6 -alkoxy- carbonyl, hydroxyl, Cl-Ce-hydroxyalkyl, Cl-C 6 -haloalkoxy, amino, C 1 -C 6 -alkylamino, phenylamino, nitro, Cl-C 10 -alkoxyalkyl, Cl-C 6 -alkylsulfinyl, halo, Cl-C 6 -alkoxy and Cl-C6-alkylthio; and wherein R 5 is selected from hydrido, Cl-C 10 -alkyl, C 1 -C 6 -alkoxy, Ci-Cia-alkoxy- alkyl, phenyl, aryl-Cl-Clo-alkyl, carboxy-Cl-C 0 alkyl, Cl-C 6 -alkoxycarbonylalkyl, CI-C 6 -alkoxycarbonyl, amino-C 1 -Clo-alkyl, Cl-C6-alkoxycarbonylaminoalkyl, and Cj- Cl 0 -alkylcarbonylaminoalkyl; the method comprising forming a bis(N-acylated)sulfonamide by treatment of an unsubstituted sulfonamide with an excess of an anhydride, acid chloride or carbamyl chloride, in the presence of a tertiary amine base, and treating said bis(N-acylated)- sulfonamide with about two equivalents of a strong base to provide the salt.

27. A method of preparing a compound of Formula rA-R R N%..i1Ilj~ I, 0 0 0 whri.*sarn usiuetslce rmprily nauae eeoyl A is a igsttetselected from partiyllcylalyclyey nau ated henocyl, weenR4iopinlysubstituted at a substitutable position with one or more rdcl eetdfo cl hadiaslote ydoxm C 1 -C 1 -alkyl, Cl-C 6 -haloalkyl cyanno, carboxyl, 0-6-loy lkxy incarbonyl, hyrxyC alkroxyarbon l c-arbaoxy-,aino, 0-C-a-yamnol, i 6 heydrmioyaitro, Cl-Clo-alkycoyoxyalkyl, afn l phnlo, -6akx n wlC-a heind sslce rmhtrccyccolyccoley n hnl s selected from 1 -C 10 ClCl-alkyl, Cl-C 6 -haoiycao aoxy, C-Cl-alkoxy- alkyl, phenyl, aryl-0 1 -Clo-alkyl, carboxy-Cl-0 10 -alkyl, Cl-C 6 -alkoxycarbonylalkyl, 01-C6- alkoxycarbonyl, amino-Cl-Clo-alkyl, Cl-CB-alkoxycarbonylaminoalkyl and Cl-0lo- alkylcarbonylaminoalkyl; further provided A is not thienyl when R 4 is 4-fluorophenyl and when R 5 is methyl; or a pharmaceutically-acceptable salt thereof, 143 the method comprising treatment of an unsubstituted sulfonamide with an acylating agent in the presence of acid.

28. The method of Claim 27 wherein the acylating agent is selected from anhydrides and acid chlorides.

29. The method of Claim 28 wherein the acylating agent is selected from acetyl chloride, acetic anhydride, propionic anhydride and butyric anhydride.

30. The method of Claim 27 wherein A is selected from oxazolyl, furyl, thiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, benzindazolyl, benzopyranopyrazolyl, phenyl, and pyridyl.

31. The method of Claim 30 wherein A is selected from imidazolyl, isoxazolyl, and pyrazolyl.

32. Use of a compound according to Claim 1 including those wherein A is tetrazolium or pyridinium; or indanone when R 3 is alkyl or carboxyalkyl; or according to any one of claims 1-19 for prepairng a medicament for treating inflammation or inflammation-associated disorder.

33. Use according to Claim 32 wherein the condition is an inflammation.

34. Use according to Claim 32 wherein the condition is an inflammation- associated disorder. Use according to Claim 34 wherein the inflammation-associated disorder is pain.

36. Use according to Claim 35 wherein the pain is associated with cancer.

37. Use according to Claim 35 wherein the pain is dental pain. 144

38. Use according to Claim 35 wherein the compound is administered intravenously.

39. Use according to Claim 35 wherein the compound is administered intramuscularly. A method of treating inflammation, said method comprising administering to the subject having or susceptible to such inflammation or inflammation-associated disorder, a therapeutically-effective amount of: a compound or salt according to Claim 1 including those wherein A is tetrazolium or pyridinium, or indanone where R 3 is alkyl or carboxyalkyl; or a compoundor salt according to any one of claims 1 to 19; or a composition of Claim

41. The method of claim 40 wherein the condition is inflammation. 15 42. The method of claim 40 wherein the condition is an inflammation-associated disorder.

43. The method of claim 42 wherein the inflammation-associated disorder is pain.

44. The method of claim 43 wherein the pain is associated with cancer. The method of Claim 43 wherein the pain is dental pain.

46. The method of claim 43 wherein the compound is administered intravenously.

47. The method of claim 43 wherein the compound is administered intramuscularly. DATED this 1( day of April 2001 G. D. SEARLE CO., By its Patent Attorneys, E. F. WELLINGTON CO., (Bruce Wellington) BA/2591a