EP0825989A1 - Oxazoles substitues utilises dans le traitement d'inflammations - Google Patents

Oxazoles substitues utilises dans le traitement d'inflammations

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Publication number
EP0825989A1
EP0825989A1 EP96920231A EP96920231A EP0825989A1 EP 0825989 A1 EP0825989 A1 EP 0825989A1 EP 96920231 A EP96920231 A EP 96920231A EP 96920231 A EP96920231 A EP 96920231A EP 0825989 A1 EP0825989 A1 EP 0825989A1
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EP
European Patent Office
Prior art keywords
phenyl
oxazolyl
benzenesulfonamide
methyl
aminosulfonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP96920231A
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German (de)
English (en)
Inventor
John J. Talley
Stephen Bertenshaw
Donald J. Rogier, Jr.
Matthew Graneto
David L. Brown
Balekudru Devadas
Lu Hwang-Fun
James A. Sikorski
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GD Searle LLC
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GD Searle LLC
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Publication date
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Publication of EP0825989A1 publication Critical patent/EP0825989A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/38—One oxygen atom attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/46—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/653—Five-membered rings

Definitions

  • This invention is in the field of anti-inflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating inflammation and inflammation-associated disorders, such as arthritis.
  • NSAIDs common non-steroidal antiinflammatory drugs
  • An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
  • the novel oxazoles disclosed herein are such safe and also effective antiinflammatory agents furthering such efforts.
  • the invention compounds are found to show usefulness in vivo as antiinflammatory agents with minimal side effects.
  • the substituted oxazoles disclosed herein preferably selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
  • 2,3-Diaryl-5-halo thiophenes are described in U.S. Patent No. 4,590,205 as analgesic or antiinflammatory agents. More particularly, 2,3-diaryl-5-bromo thiophenes are described in U.S. Patent No. 4,820,827 as having antiinflammatory and prostaglandin synthetase inhibitory activity for use in the treatment of inflammation and dys enorrhea.
  • PCT publication 094/15932 describes 4,5- substitutedphenyl-thiophenes/furans and pyrroles as having antiinflammatory activity.
  • U.S. Patent No. 3,578,671, to K. Brown describes antiinflammatory 4,5-diphenyloxazoles substituted in the 2- position by a saturated or unsaturated aliphatic acid.
  • U.S. Patent No. 4,051,250, to J. Dahm et al describes oxazole, imidazole and thiazole compounds, including 2- mercapto-4- (4-methylmercaptophenyl) -5-(4- chlorophenyDoxazole, as having antiphlogistic, analgesic and antipyretic activity.
  • Other related diphenyloxazole disclosures include U.S. Patent No. 4,001,228, to G. Mattalia, for antiaggregating activity and U.S. Patent No. 3,895,024, to R.
  • U.S. Potent No. 4,632,930 to Carini et al, describes antihypertensive alkyl and aryl substituted imidazole, thiazole and oxazole derivatives. Specifically, 5-phenyl- 4- (4-methylsulfonylphenyl) - ⁇ , ⁇ - bis (trifluoromethyl) thiazole-2-methanol is described.
  • R. Cremylin et al describe the synthesis of heterocyclic sulfonyl derivatives and specifically, 4',4"- (2-methyl-4, 5-oxazoldiyl) -bis-benzenesulfonamide (J. Heterocycl . Chem. , 22, 1211 (1985)) . T.
  • a class of substituted oxazolyl compounds useful in treating inflammation-related disorders is defined by Formula I:
  • R is selected from hydrido, halo, mercapto, hydroxyl, carboxyalkylthio, carboxyalkylthioalkyl, carboxyalkoxy, carboxyalkoxyalkyl, haloalkoxy, alkylthio, alkylsulfmyl, alkylsulfonyl, alkoxy, aryloxy, aralkoxy, alkylamino, aminocarbonyl, alkoxyalkyl, carboxy(haloalkyl) , alkyl, hydroxyalkyl, haloalkyl, alkenyl, hydroxyalkenyl, alkynyl, hydroxyalkynyl, cycloalkyl, cycloalkylalkyl, aminoalkyl, hydroxyalkoxyalkyl, alkylcarbonyl, phosphonylalkyl, amino acid residue, heterocyclylalkyl, cyanoalkyl, alkoxycarbonyl, alkoxycarbony
  • compositions of Formula I would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other inflammation-associated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever.
  • compounds of the invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthopathies, 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, tendinitis, ' jrursitis, and skin-related conditions such as psoriasis, eczema, burns and dermatitis.
  • 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, and for the prevention or treatment of cancer, such as colorectal cancer.
  • Compounds of the invention would be useful in treating inflammation in such diseases as vascular diseases, migraine headaches, 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.
  • diseases as vascular diseases, migraine headaches, 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
  • the compounds would also be useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis, conjunctivitis, 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 Alzheimers disease.
  • the compounds of the invention are useful as anti-inflammatory 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, atrerosclerosis and central nervous system damage resulting from stroke, ischemia and trauma.
  • these compounds are also useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to, horses, dogs, cats, cows, -sheep and pigs.
  • the present compounds may also be used in co- therapies, partially or completely, in place of other conventional antiinflammatories, such as together with steroids, NSAIDs, 5-lipoxygenase inhibitors, LTB 4 receptor antagonists and LTA 4 hydrolase inhibitors .
  • Suitable LTB 4 receptor antagonists 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, Teru o 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-104493.
  • the LTB 4 receptor antagonists 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.
  • phrase "combination therapy" in 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.
  • Suitable 5-LO inhibitors include, among others, masoprocol, tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadrem phosphate, and bunaprolast.
  • the present invention preferably includes compounds which selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
  • the compounds have a cyclooxygenase-2 IC 50 of less than about 0.5 ⁇ M, 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.
  • the compounds have a cyclooxygenase-1 IC 50 of greater than about 1 ⁇ M, and more preferably of greater than 20 ⁇ M. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
  • a preferred class of compounds consists of those compounds of Formula I wherein R is selected from hydrido, halo, mercapto, hydroxyl, lower carboxyalkylthio, lower carboxyalkylthioalkyl, lower carboxyalkoxy, lower carboxyalkoxyalkyl, lower haloalkoxy, lower alkylthio, lower alkylsulfmyl, lower alkylsulfonyl, lower alkoxy, aryloxy, lower aralkoxy, lower alkylamino, aminocarbonyl, lower alkoxyalkyl, lower carboxy(haloalkyl) , lower alkyl, lower hydroxyalkyl, lower haloalkyl, lower alkenyl, lower hydroxyalkenyl, lower alkynyl, lower hydroxyalkynyl, lower cycloalkyl, ' .lower cycloalkylalkyl, lower aminoalkyl, lower hydroxyalkoxyalkyl, lower alky
  • R ⁇ is selected from lower cycloalkyl, lower cycloalkenyl, aryl and heteroaryl, wherein R ⁇ is optionally substituted at a substitutable position by lower alkyl, lower alkylamino, lower alkoxy and halo; wherein R 2 is selected from lower alkyl and amino; and wherein R ⁇ is selected from hydrido and lower alkyl; or a pharmaceutically-acceptable salt thereof.
  • a class of compounds of particular interest consists of those compounds of Formula I wherein R is selected from hydrido, chloro, fluoro, bromo, iodo, mercapto, hydroxyl, carboxymethylthio, carboxyethylthio, trifluoromethoxy, ethylthio, ethylthio, methylsulfinyl, methylsulfonyl, methoxy, ethoxy, propoxy, butoxy, phenyloxy, benzyloxy, N- methylamino, N,N-dimethylamino, N,N-diethylamino, aminocarbonyl, methoxymethyl, ⁇ -bromo-carboxymethyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dich
  • R 2 is selected from lower alkyl and amino; wherein R ⁇ is selected from hydrido, alkyl, alkylamino, alkoxy and halo; and wherein R 5 is selected from halo, mercapto, ca-.boxyalkylthio, carboxyalkylthioalkyl, carboxyalkoxy, carboxyalkoxyalkyl, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, aryloxy, alkylamino, aminocarbonyl, alkoxyalkyl, carboxy(haloalkyl) , aminoalkyl, hydroxyalkoxyalkyl, alkylcarbonyl, phosphonylalkyl, alkylcarbonylammoalkyl, aralkoxycarbonylaminoalkyl, amino acid residue, heterocyclylalkyl, and cyanoalkyl; or a pharmaceutically-acceptable salt
  • a preferred class of compounds consists of those compounds of Formula II wherein R 2 is selected from lower alkyl and amino; wherein R ⁇ is selected from hydrido, lower alkyl, lower alkylamino, lower alkoxy and halo; and wherein R 5 is selected from halo, mercapto, lower carboxyalkylthio, lower carboxyalkylthioalkyl, lower haloalkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy, aryl.'xy, lower alkylamino, aminocarbonyl, lower alkoxyalkyl, lower carboxy(haloalkyl) , lower aminoalkyl, lower hydroxyalkoxyalkyl, lower alkylcarbonyl, lower phosphonylalkyl, lower alkylcarbonylammoalkyl, lower aralkoxycarbonylaminoalkyl, amino acid residue, lower heterocyclylalky
  • a class of compounds of particular interest consists of those compounds of Formula II wherein R 2 is selected from methyl and amino; wherein R ⁇ is selected from hydrido, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, amino, methoxy, ethoxy, propoxy, butoxy, N-methylamino, N,N-dimethylamino, fluoro, chloro, bromo and iodo; and wherein R 5 is selected from chloro, fluoro, bromo, iodo, mercapto, carboxymethylthio, carboxyethylthio, carboxyethylthiomethyl, trifluoro ethoxy, methylthio, ethylthio, methylsulfinyl, methylsulfonyl, methoxy, ethoxy, propoxy, butoxy, phenyloxy, benzyloxy,
  • R 2 is selected from lower alkyl and amino; wherein R ⁇ is selected from hydrido, lower alkyl, lower alkylamino, lower alkoxy and halo; wherein R 6 is -Y-Q; wherein Y is selected from aryl, heterocyclyl, alkoxyalkyl, aryloxyalkyl, alkylaryloxyalkyl, aralkoxyalkyl, alkylaralkoxyalkyl, aminoalkyl, heterocyclylalkyl, alkylheterocyclyl, alkylheterocyclylalkyl, alkylaralkyl, aralkyl, alkynylaralkyl, alkyl, alkylsulfonylalkyl, alkylthioalkyl, and alkylsulfonylaminoalkyl; and wherein Q is an acidic moiety selected from carboxylic acid, tetrazole, phosphorous-containing acids, sulfur- containing acids, and
  • a preferred class of compounds consists of those compounds of Formula III wherein R 2 is selected from lower alkyl and amino; wherein R 4 is selected from hydrido, lower alkyl, lower alkoxy and halo; wherein Y is selected from phenyl, five and six membered heterocyclyl, lower alkoxyalkyl, lower aminoalkyl, lower heterocyclylalkyl, lower alkylheterocyclyl, lower alkylheterocyclylalkyl, lower aryloxyalkyl, lower alkylaryloxyalkyl, lower aralkoxyalkyl, lower alkylaralkoxyalkyl, lower alkylaralkyl, lower alkynylaralkyl, lower aralkyl, lower alkylsulfonylalkyl, lower alkylthioalkyl, alkyl, and lower alkylsulfonylaminoalkyl; wherein Q is selected from carboxyl, lower alkoxycarbonyl, lower
  • each of R 7 and R8 s independently selected from hydrido, lower alkyl, lower cycloalkyl, phenyl and lower aralkyl; or a pharmaceutically-acceptable salt thereof.
  • a class of compounds of particular interest consists of those compounds of Formula III wherein R 2 is selected from methyl and amino; wherein R ⁇ is selected from hydrido, methyl, methoxy, fluoro, chloro and bromo; wherein Y is selected from phenyl, pyridyl, pyrrolyl, pyrrolidinyl, imidazolyl, piperidinyl, methoxymethyl, 3-aminopropyl, pyrrolylmethyl, pyrrolidinylmethyl, pyrrolylpropyl, methylpyrrolyl, ethylphenylmethyl, methylphenylethyl, phenoxymethyl, methylphenoxymethyl, benzyl, ethylsulfonylmethyl, ethylthiomethyl, methylthiomethyl, methylthioethyl, methyl, ethyl, propyl, pentyl, 2,2- dimethylpropyl, 2,2-dimethylbutyl
  • R 7 and RS is independently selected from hydrido, methyl, and ethyl; or a pharmaceutically- acceptable salt thereof.
  • a family of specific compounds of particular interest within Formulas I-III consists of compounds and pharmaceutically-acceptable salts thereof as follows :
  • 5-phenyloxazole 4- [2- (ethyl) -5-phenyl-4-oxazolyl]benzenesulfonamide; 4- [2- (trifluoromethyl) -5-phenyl-4- oxazolyl]benzenesulfonamide; 4- [2- (difluoromethyl) -5-phenyl-4- oxazolyl]benzenesulfonamide; 4- [2- (hydroxymethyl) -5-phenyl-4- oxazolyl]benzenesulfonamide;
  • hydro denotes a single hydrogen atom (H) .
  • 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 (-CH2-) radical.
  • alkyl is used, either alont, or within other terms such as “haloalkyl”, “alkoxyalkyl” and “hydroxyalkyl” 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.
  • 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.
  • 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, provided that the double bond does not directly bond to the oxazole ring. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms.
  • radicals examples include ethenyl, n-propenyl, butenyl, and the like.
  • alkynyl embraces linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms, and containing a carbon-carbon triple bond.
  • the more preferred "lower alkynyl” are radicals having two to ten carbons.
  • examples of such radicals include ethynyl, 1- or 2- propynyl, 1-, 2- or 3-butynyl and the like and isomers thereof.
  • halo means halogens such as fluorine, chlorine, bromine or iodine.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have either n 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 1-6 carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl .
  • 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 .
  • hydroxyalkenyl embraces linear or branched alkenyl radicals having three to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals.
  • hydroxyalkynyl embraces linear or branched alkynyl radicals having three to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals.
  • alkoxy and alkoxyalkyl embrace linear or branched oxy-containing radicals each having alkyl portions of one to about twelve carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having one l. six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and ter -butoxy.
  • alkoxyalkyl embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
  • alkoxy or “alkoxyalkyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyalkyl radicals.
  • halo atoms such as fluoro, chloro or bromo
  • aryl embraces aromatic radicals such as phenyl, naphthyl and biphenyl .
  • Preferred aryl radicals are those consisting of one, two, or three benzene rings.
  • 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, amino, halo, nitro, alkylamino, alkylcarbonylamino, alkylsulfonyl, arylsulfonyl, alkynyl, hydroxyalkynyl, aminoalkynyl, heteroarylalkynyl, heteroaralkyl, alkenyl, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and alkylthio.
  • heterocyclyl or “heterocyclic” embrace saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • saturated heterocyclic radicals include saturated 5 to 7-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, tropanyl, homotropanyl, etc.]; saturated 5 to 7-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • morpholinyl etc.
  • saturated 5 to 7-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., thiazolidinyl, etc.
  • partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, oxazolinyl, dihydrofuran and dihydrothiazole.
  • heteroaryl radicals examples include unsaturated 5 to 7 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, azepinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H- 1,2, 4-triazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, etc.] tetrazolyl [e.g.
  • unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolofl, 5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 5 to 7-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 5 to 7-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example
  • benzoxazolyl, benzoxadiazolyl, etc.] unsaturated 5 to 7-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2, 5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like.
  • the term also embraces radicals where heterocyclic radicals are fused with aryl radicals .
  • fused bicyclic radicals examples include benzofuryl, benzothienyl, and the like.
  • the heterocyclyl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, amino, halo, nitro, alkylamino, alkylcarbonylamino, alkylsulfonyl, alkynyl, alkenyl, arylsulfonyl, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and alkylthio.
  • aralkyl embraces aryl-substituted alkyl radicals.
  • Preferable aralkyl radicals are "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl .
  • benzyl and phenylmethyl are interchangeable.
  • heterocyclylalkyl embraces saturated and partially unsaturated heterocyclyl-substituted alkyl radicals, such as pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals, such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl.
  • aryloxy embrace oxy-containing aryl radicals attached through an oxygen atom to other radicals . More preferred aryloxy radicals are "lower aryloxy" radicals having a phenyl radical. An example of such radicals is phenoxy.
  • aryloxyalkyl embraces alkyl radicals having one or more aryloxy radicals attached to the alkyl radical, that is, to form monoaryloxyalkyl and diaryloxyalkyl radicals.
  • the "aryloxy” or “aryloxyalkyl” radicals may be further substituted on the aryl rings as defined above.
  • the term “aralkyloxy” embrace oxy-containing aralkyl radicals attached through an oxygen atom to other radicals.
  • the “aralkoxy” radicals may be further substituted on the aryl ring portion of the radical as described above.
  • aralkyloxyalkyl embraces alkyl radicals having one or more aralkyloxy radicals attached to the alkyl radical, that is, to form monoaralkyloxyalkyl and diaralkyloxyalkyl radicals.
  • the "aralkyloxy” or “aralkyloxyalkyl” radicals may be further substituted on the aryl ring portion of the radical.
  • heteroaryloxyalkyl embraces alkyl radicals having one or more heteroaryloxy radicals attached to the alkyl radical, that is, to form monoheteroaryloxyalkyl and diheteroaryloxyalkyl radicals.
  • heteroaryloxy radicals may be further substituted on the heteroaryl ring portion of the radical.
  • arylthio embraces radicals containing an aryl radical, as described above, attached to a divalent sulfur atom, such as a phenylthio radical.
  • arylthioalkyl embraces alkyl radicals substituted with one or more arylthio radicals, as described above.
  • cycloalkyl embraces radicals having three to ten carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl” radicals having three to seven carbon atoms.
  • Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl .
  • cycloalkylalkyl embraces alkyl radicals substituted with cycloalkyl radicals having three to ten carbon atoms, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, eyelohexyIpropy1 and cycloheptylmethyl.
  • cycloalkenyl embraces unsaturated radicals having three to ten carbon atoms, such as cylopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl .
  • sulfonyl whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -S ⁇ 2 ⁇ .
  • Alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above.
  • alkylsulfonyl radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals.
  • halo atoms such as fluoro, chloro or bromo
  • alkylsulfinyl embraces alkyl radicals attached to a sulfinyl (-S(O)-) radical, where alkyl is defined as above. More preferred alkylsulfinyl radicals are "lower alkylsulfinyl" radicals having one to six carbon atoms.
  • alkylsulfinyl radicals examples include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.
  • alkylthio embraces alkyl radicals attached to a divalent sulfur radical, where alkyl is defined as above. More preferred alkylthio radicals are "lower alkylthio" radicals having alkyi radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.
  • sulfamyl denote a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO2NH2) .
  • alkylcarbonyl , “arylcarbonyl” and “aralkylcarbonyl” include radicals having alkyl, hydroxylalkyl, aryl, arylalkyl and aryl- hydroxylalkyl radicals, as defined herein, attached to a carbonyl radical.
  • radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, phenylcarbonyl, benzylcarbonyl, and phenyl (hydroxymethyl) carbonyl.
  • carboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes -CO2H.
  • carboxyalkyl embrace radicals having a carboxy radical as defined above, attached to an alkyl radical, which may be substituted, such as with halo radicals, or unsubstituted. 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, carboxybutyl, carboxypentyl, carboxyhexyl and carboxypropyl.
  • acyl denotes a radical provided by the residue after removal of hydroxyl from an organic acid.
  • acyl radicals include alkanoyl and aroyl radicals.
  • alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, j . :ivaloyl, hexanoyl, and radicals formed from succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, mandelic, pantothenic, ⁇ -hydroxybutyric, galactaric and galacturonic acids.
  • aroyl embraces aryl radicals with a carbonyl radical as defined below.
  • aroyl examples include benzoyl, naphthoyl, phenylacetyl, and the like, and the aryl in said aroyl may be additionally substituted, such as in p-hydroxybenzoyl, and salicylyl.
  • carboxyalkylthio embraces carboxyalkyl radicals as defined above, connected to a divalent sulfur atom.
  • alkoxycarbonyl ester radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl .
  • alkoxycarbonylalkyl embraces alkyl radicals having one or more alkoxycarbonyl radicals attached to the alkyl radical.
  • phosphonylalkyl describes alkyl radicals substituted with phosphonic acid residues or esters thereof.
  • aminoalkyl embraces alkyl radicals substituted with amino radicals. More preferred are “lower aminoalkyl” radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like.
  • aminocarbonyl embraces radicals having an amino radical radicals attached to a carbonyl radical forming -C(0)NH2.
  • aminocarbonylalkyl embraces alkyl radicals having one or more aminocarbonyl radicals attached to the alkyl radical.
  • alkylaminoce.rbonylalkyl embraces alkyl radicals having aminocarbonyl radicals substituted with one or two alkyl radicals. Examples of such include N- alkylaminocarbonylalkyl and N,N-dialkylaminocarbonylalkyl radicals such as N-methylaminocarbonylmethyl and N,N- dimethylaminocarbonylmethyl.
  • alkylamino denotes amino groups which have been substituted with one or two alkyl radicals. More preferred alkylamino radicals are "lower alkylamino" having alkyl radicals of one to six carbon atoms attached to the nitrogen atom of an amine. Suitable “lower alkylamino” may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.
  • amino acid residue means any of the naturally occurring alpha-, beta- and gamma- amino 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 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, ⁇ -alanine, and ⁇ -aminobutyric acid.
  • the present invention comprises a pharmaceutical composition for the treatment of inflammation and inflammation-associated disorders, such as arthritis, comprising a therapeutically-effective amount of a compound of Formula I in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
  • the present invention also comprises a therapeutic method of treating inflammation or inflammation-associated disorders in a subject, the method comprising treating the subject havi::g such inflammation or disorder a therapeutically-effective amount of a compound of Formula I.
  • the method of the present invention also includes prophylactic treatment.
  • a preferred method of the invention is the administration of water soluble compounds of Formulas III via injection.
  • pharmaceutically-acceptable salts are also included in the family of compounds of Formula I.
  • pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases .
  • the nature of the salt is not 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 h drochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, 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, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, ⁇ -hydroxybutyric, salicylic,
  • Suitable pharmaceutically-acceptable base addition salts of com ounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, diastereoisomeric salts by treatment with an optically active acid or base.
  • 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 synthesis 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.
  • 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.
  • optically sodium and zinc or organic salts made from N,N'- dibenzylethylenediamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N- methylglucamme) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.
  • stereoisomers thereof are also included in the family of compounds of Formula I.
  • 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 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 active compounds of Formula I-III 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.
  • Synthetic Scheme I shows the four step procedure which can be used to prepare the substituted ketone compounds 4 from the substituted benzaldehyde 1 and acid 2, where R 2 is alkyl.
  • step one benzaldehyde 1 and substituted acetic acid 2 are first heated in acetic anhydride and triethylamine via a Perkin condensation.
  • step two hydrolysis produces the corresponding 2,3- disubstituted acrylic acids 3.
  • step three the acrylic acids 3 are reacted with diphenylphosphorylazide (DPPA) and triethylamine in toluene at 0°C and then warmed to room temperature to form acylazides .
  • DPPA diphenylphosphorylazide
  • step four the crude acylazides are heated to form an isocyanate via a Curtius rearrangement .
  • the isocyanate is trapped as the N-t-butyloxycarbonyl enamine derivative via the addition of tert-butanol .
  • Acidic hydrolysis such as by using concentrated HC1, provides the substituted ketone 4 intermediates.
  • Synthetic Scheme II shows an alternative approach which can be used to prepare substituted ketone intermediates 7, isomers of 4 where R 2 is alkyl, via the use of Friedel-Crafts acylation.
  • An acylating agent 5, such as an acid chloride is treated with aluminum chloride in an inert solvent, such as methylene chloride, chloroform, nitrobenzene, dichlorobenzene or chlorobenzene, and reacted with alkylthiobenzene 6 to form ketone 7.
  • an inert solvent such as methylene chloride, chloroform, nitrobenzene, dichlorobenzene or chlorobenzene
  • alkylthiobenzene 6 alkylthiobenzene
  • Scheme III shows the five step synthesis, as described in U.S. Patent No. 3,647,858, which can be used to prepare the 5- (4-alkylsulfonylphenyl)oxazoles 12 of Formula I from ketone 4 (prepared in Scheme I) .
  • Preparation of the silyl enol ether 8 (where TBSCl is ter -butyl-dimethylsilyl chloride) is followed by oxidation, such as with m-chloroperoxybenzoic acid MCPBA), to give the appropriate silylated benzoin 9.
  • Desilylation of this silylated benzoin 9 is achieved using aqueous acid, such as trifluoroacetic acid, to give the desired benzoin 10.
  • Scheme IV shows the five step synthesis, similar to that described above in Scheme III, which can be used to prepare the 4- (4-alkylsulfonylphenyl) oxazoles 17 of Formula I from ketone 7 (prepared in Scheme II) .
  • Preparation of the silyl enol ether 13 is followed by oxidation, such as with m-chloroperbenzoic acid, to give the appropriate silylated benzoin 14.
  • Desilylation of this silylated benzoin 14 is achieved using aqueous acid, such as trifluoroacetic acid to give the desired benzoin 15.
  • Scheme V shows the four step synthesis which can be used to prepare oxazoles 20 from ketones 4 (prepared in Synthetic Scheme I) .
  • ketones 4 are readily brominated via the addition of bromine in acetic acid to form the 2-bromoethanone intermediates.
  • reaction of the bromoethanone with aqueous acetone yields the benzoin 18.
  • reaction of the benzoin 18 with the appropriate acid chloride in the presence of base, such as pyridine gives the benzoin esters 19.
  • benzoin esters 19 are converted to the oxazoles 20 upon treatment with ammonium acetate in acetic acid at reflux.
  • Scheme VI shows the four step synthesis which can be used to prepare oxazoles 23 from ketones 7 (prepared in Synthetic Scheme II) .
  • ketones 7 are readily brominated via the addition of bromine in acetic acid to form the 2-bromoethanone intermediates.
  • reaction of the bromoethanone with aqueous acetone yields the benzoin 21.
  • reaction of the benzoin 21 with the appropriate acid chloride in the presence of base, such as pyridine gives the benzoin esters 22.
  • step four benzoin esters 22 are converted to the oxazoles 23 upon treatment with ammonium acetate in acetic acid at reflux.
  • Scheme VIII shows a method for preparing oxazoles 28 where Ar ⁇ - represents an aromatic or heteroaryl radical without a sulfur substituent.
  • a solution of aldehyde 24 and zinc iodide in an organic solvent such as dichloromethane (100 mL) is treated with trimethylsilylcyanide to give the trimethylsilyl cyanohydrin.
  • the trimethylsilyl cyanohydrin is added to a solution of Ar ⁇ -magnesium bromide in diethyl ether while maintaining the temperature between 25-35 °C to give the benzoin 25.
  • the benzoin 25, pyridine, and acid chloride are reacted at room temperature to yield the benzoin ester 26.
  • Synthetic Scheme VIII shows the three step procedure used to prepare sulfonamide antiinflammatory agents 30 from their corresponding methyl sulfones 29.
  • a THF solution of the methyl sulfones 29 at about -78°C is treated with an alkyllithium reagent, e.g., methyllithium, n-butyllithium, etc.
  • an organoborane e.g., triethylborane, tributylborane, etc.
  • an aqueous solution of sodium acetate and hydroxyamine-O-sulfonic acid is added to provide the corresponding sulfonamide antiinflammatory agents 30 of this invention.
  • Scheme X shows another method of preparing oxazolylbenzenesulfonamides 33 of the present invention.
  • the oxazole 31 is stirred with chlorosulfonic acid at about 5 °C to give the sulfonyl chlorides 32.
  • the sulfonyl chloride 32 is reacted at about 5 °C with ammonium hydroxide to give the sulfonamides 33 of the current invention.
  • disulfonamides can be formed by substitution on Rl where R 1 is aryl or heteroaryl.
  • Synthetic Scheme XI shows the five step procedure which can be used to prepare the substituted oxazolebenzenesulf onamide compounds 39 , from the substituted ketone 34 .
  • the benzenesulfonamide 36 is formed, such as by adding the ketone 34 to chlorosulfonic acid at about -78 °C, then warming to room temperature to form the sulfonyl chloride 35 .
  • the sulfonyl chloride 35 is reacted with aqueous ammonium hydroxide in a solvent, such as acetone, at about 5 °C, and then at room temperature to form the sulfonamide 36.
  • step 3 the sulfonamide 36 is selectively brominated, such as with a solution of 30% HBr in acetic acid, acetic acid and bromine to form the bromoketone 37.
  • Step 4 the bromoketone 37 is added to an acid and potassium carbonate in dimethylacetamide to give the desired crude ⁇ -acyloxy ketone 38.
  • step 5 acetic acid and ammonium acetate are added to the acyloxy ketone 38, and heated, such as at about 100 °C to give the oxazole 39.
  • Step 1 Preparation of 1- (4-f luorophenyl) -2-hvdroxy-2- (irtethylsulfonyl )phenyl) ethanone
  • the benzoin silyl ether was dissolved in 100 mL of 90% aqueous trifluoroacetic acid and stirred at 25'C for 18 hours. The reaction was quenched by slowly pouring into saturated aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate.
  • Step 2 Preparation of 4- (4-fluorophenyl) -2- (2- phenylethyl) -5- (4- (methylsulfonyl)phenyl) oxazole.
  • a solution containing 5.00 g of 1- (4-fluorophenyl) - 2-hydroxy-2- (4- (methylsulfonyl)phenyl) ethanone in 100 mL methylene chloride (CH 2 CI 2 ) was stirred at 25'C as 6.60 mL of pyridine was added, followed by 3.61 mL of hydrocinnamoyl chloride.
  • Methyl 3- [4- (4-f luorophenyl) -5- [4- methylsulf onylphenyl] oxazol-2-yl]propanate was prepared in a manner analogous to Example 1.
  • Example 13 4- [4- (4 -Fluorophenyl) -5- [4- (methylsulfonyl) phenyl] ] -2 -oxazolebutanoic acid was prepared from Example 13 in a manner analogous to Example 17. Melting point: 140-141°C. The m / z 404 (M+H) + was consistent with the assigned structure.
  • Step 1 Preparation of 5- (fluorophenyl) -4- ⁇ 4- (methylthio)phenyl1 -2-phenyloxazole A solution containing 560 mg (2.03 mmol) of 2- (4- fluorophenyl) -2-hydroxy-l- [4- (methylthio)phenyl] ethanone in 50 mL of methylene chloride was stirred at 25°C as 0.82 mL (10.15 mmol) of pyridine was added, followed by 0.28 mL (2.44 mmol) of benzoyl chloride.
  • Step 2 Preparation of 5- (4-fluorophenyl) -4- ⁇ 4- (methylsulfinyl)phenyll -2-phenyloxazole.
  • the reaction was poured into a solution of aqueous sodium metabisulfite.
  • the aqueous solution was extracted using ethyl acetate and the organic layer was washed with saturated sodium metabisulfite, saturated sodium bicarbonate and brine.
  • the resulting clear solution was dried over sodium sulfate and concentrated in vacuo to give a white solid which was purified by flash chromatography on a silica gel column using 50% ethyl acetate/hexane as the eluent.
  • Step 3 Preparation of 5- (4-fluorophenyl) -4- f4- (methylsulfonyl)phenyll -2-phenyloxazole.
  • Step 1 Preparation of the benzoin ester A solution containing 2.07 g (6.71 mmol) of l-(4- fluorophenyl) -2-hydroxy-2- [4-
  • Step 2 Preparation of 2-benzyloxymethyl-4- (4- fluorophenyl) -5- T4- (methylsulfonyl)phenylloxazole.
  • Step 1 Preparation of 1- (cvclohexyl) -2-hvdroxy-2- F4- (methylthiophenyl) ethanone
  • a 250 mL round bottomed flask was equipped with a mechanical stirrer and reflux condenser and charged with 30 mL of absolute ethanol, 3 , 4-dimethyl-5- (2- hydroxyethyl)thiazolium iodide (2.00 g, 7.0 mmol), 4- methylthiobenzaldehyde (10.66 g, 70.0 mmol), and freshly distilled cyclohexanecarboxaldehyde (7.68 g, 70.1 mmol) .
  • the solution was stirred vigorously, treated with triethylamine (4.27 g, 42.2 mmol) and heated to reflux for 24 hours.
  • the solution was treated with additional portions of 3 ,4-dimethyl-5- (2-hydroxyethyl) thiazolium iodide (2.05 g , 7.01 mmol), triethylamine (4.84 g, 48.0 mmol), and cyclohexanecarboxaldehyde (7.01 g, 62.5 mmol), and heated to reflux for an additional 42 hours.
  • Step 3 Preparation of 4-cvclohexyl-5- [4- (methythio)phenyll -2-phenyloxazole
  • Step 4 Preparation of 4- (cvclohexyl) -5- f4- (methylsulfonyl)phenyll -2-phenyloxazole
  • aqueous solution was extracted using ethyl acetate and the organic layer was washed with saturated sodium metabisulfite, saturated sodium bicarbonate and brine.
  • the resulting clear solution was dried over sodium sulfate and concentrated in vacuo to give a white solid which was purified by flash chromatography on a silica gel column using 50% ethyl acetate/hexane as the eluent.
  • Step 1 Preparation of 2- (4-fluorophenyl) -3- (4- methylthiophenyl)propenoic acid
  • Acetic anhydride 500 mL
  • 4- (methylthio)benzaldehyde 100.2 g, 0.66 mol
  • 4- fluorophenylacetic acid 101.6 g, 0.66 mol
  • triethylamine 68.1 g, 0.67 mol
  • Step 2 Preparation of 1- (4-fluorophenyl) -2- (4- methylthiophenyl) ethanone
  • the di ry1 acrylic acid (226.5 g, 0.78 mol) was placed in a 2 L round bottom flask with anhydrous toluene (800 mL) and triethylamine (81.2 g, 0.80 mol) . After cooling to 0°C, diphenylphosphoryl azide (217.4 g, 0.79 mol) was added, the solution was stirred at 0°C for 20 minutes and at room temperature for 2.50 hours. The reaction was poured into water, extracted with ether, dried over magnesium sulfate, and concentrated in vacuo to remove the ether. The remaining toluene solution was heated to reflux and a vigorous evolution of gas occurred.
  • Step 3 Preparation of 1- (4-fluorophenyl) -2- (4- methylthiophenyl) -2-hvdroxy-ethanone
  • a I L three necked round bottomed flask equipped with reflux condenser, magnetic stir bar, thermometer adapter, and constant pressure addition funnel was charged with the intermediate from Step 2, (55.5 g, 0.21 mol) , acetic acid (250 mL) and 33% HBr in acetic acid (120 mL) .
  • the solution was stirred and treated with bromine (11.1 mL, 0.21 mol) from the addition funnel at such a rate that the bromine color was discharged rapidly, ca . 15 minutes.
  • Step 4 Preparation of ethyl 2- r4- (4-fluorophenyl) -5- r4-methylthio)phenyll 1 -2-oxazoleacetate
  • the crude solid was purified via flash chromatography on a silica gel column using 10% ethyl acetate/hexane as the eluent. This provided 7.31 g (64%) of a white foam, which was used directly without further purification.
  • the product from above (7.31 g, 18.7 mmol) and 7.2 g of ammonium acetate (93.5 mmol, 5 equivalents) in 50 mL of glacial acetic were heated to reflux for 2 hours. The reaction mixture was cooled to 25°C and poured into 100 mL of water.
  • the aqueous solution was extracted with ethyl acetate and the combined organic extracts were washed with water and sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo .
  • the crude solid was purified by flash chromatography using a silica gel column and 20% ethyl acetate/hexane as the eluent to give a white solid which was recrystallized from 50% ethyl acetate/isooctane to give 5.55 g (80%) of a white solid whose structure was assigned as ethyl 2-[4-(4- fluorophenyl)-5- [4-methylthio)phenyl]oxazol-2-yl]acetate and was judged suitable for taking onto the next step.
  • Step 5 Preparation of ethyl 2- T4- (4-fluorophenyl) -5- f4-methylsulfonyl)phenyl1 -2-oxazolyl1 -2-benzyl-acetate
  • the trimethylsilyl-cyanohydrin was dissolved in diethyl ether (50 mL) and added dropwise to a solution of phenyImagnesium bromide (174 mmol) in diethyl ether (658 mL) while maintaining the temperature between 25-35 °C with an ice water bath.
  • the reaction was stirred for 0.4 hours at room temperature then quenched by adding 3N HCl.
  • the reaction mixture was extracted with ethyl acetate, washed with saturated NaHC03 and brine, dried over MgS04, and concentrated in vacuo to give an orange oil (39.57 g) .
  • Step 3 Preparation of ethyl r4-phenyl-5- (3-fluoro-4 methoxyphenyl) 1 -2-oxazoleacetate.
  • the ketone from the Step 2 (1.83 g, 4.9 mmol) was dissolved in acetic acid (25 mL) , treated with ammonium acetate (3.86 g, 50.0 mmol), and heated to reflux for 2.0 hours.
  • the reaction mixture was diluted with ethyl acetate, washed with water, saturated NaHC03, and brine, dried over MgS04, concentrated in vacuo, and passed through a column of silica gel eluting with 16% ethyl acetate/hexane to give a yellow solid (0.67 g, 39%): mp 85-86 °C.
  • the trimethylsilyl cyanohydrin was dissolved in diethyl ether (50 mL) and added dropwise to a solution of phenyImagnesium bromide (54 mmol) in diethyl ether (268 mL) while maintaining the temperature between 25-35 °C with an ice water bath.
  • the reaction was stirred for 0.67 hours at room temperature then quenched by adding 3N HCl (60 mL) .
  • the organic layer was collected, washed with saturated NaHC03 and brine, dried over MgS04, and concentrated in vacuo to give a white solid (12.96 g) .
  • Step 4 Preparation of ⁇ A -(4-ammosulfonylphenyl)-5- cvclohexyll -2-oxazoleacetic acid
  • the compound from Step 3 (0.47 g, 1.6 mmol) was stirred with chlorosulfonic acid (2.5 mL) for 1.25 hours at 5 °C.
  • Step 3 Preparation of 14- (4-chlorophenyl) -5-phenyll -2- oxazoleacetic acid
  • the ester from Step 2 (4.69 g, 14.1 mmol) was dissolved in ethanol (20 mL) , treated with ammonium acetate (10.87 g, 141.0 mmol), and heated to reflux for 4.75 hours.
  • the ethanol was removed in vacuo and the residue was dissolved in water, acidified with 3N HCl, precipitated with diethyl ether and hexane and filtered to give an orange solid (2.71 g,
  • Step 4 Preparation of ⁇ 5- (4-aminosulfonylphenyl)-4- (4- chlorophenyl) 1-2-oxazoleacetic acid
  • the compound from Step 3 (1.71g, 5.4 mmol) was stirred with chlorosulfonic acid (7 mL) for 1.25 hours at 5 °C.
  • the reaction mixture was added to ice water, and extracted with dichloromethane.
  • the dichloromethane was stirred with ammonium hydroxide (30 mL) for 1.2 hours at room temperature.
  • the trimethylsilyl cyanohydrin was dissolved in diethyl ether (50 mL) and added dropwise to a solution of phenyImagnesium bromide (69 mmol) in diethyl ether (269 mL) while maintaining the temperature between 15-28 °C with an ice water bath.
  • the reaction was stirred for 0.75 hours at room temperature then quenched by adding 3N HCl (50 mL) .
  • the organic layer was collected, washed with saturated NaHC03 and brine, dried over MgS04, and concentrated in vacuo to give a yellow solid (13.06 g) .
  • the yellow solid was dissolved in 9:1 trifluoroacetic acid/water (30 mL) and stirred for 1.6 hours at room temperature.
  • the reaction was neutralized with solid sodium carbonate, extracted with ethyl acetate, washed with 10% Na2C03 and brine, dried over MgS04, concentrated in vacuo to give a yellow solid (9.43 g) and used in the next step without further purification.
  • Step 3 Preparation of ⁇ 5 - (4-chlorophenyl) -4-phenyll -2- oxazoleacetic acid
  • the ester from Step 2 (2.88 g, 12.4 mmol) was dissolved in ethanol (20 mL) , treated with ammonium acetate (6.74 g, 87.4 mmol), and heated to reflux for 4.1 hours.
  • the reaction mixture was concentrated in vacuo, and the residue was partitioned between water and diethyl ether.
  • the aqueous layer was acidified with 3N HCl, allowed stand at room temperature then filtered to give a white solid (0.75 g, 28%) : mp 21. " '.5-219 °C.
  • Mass spectrum: M+ 313.
  • Step 1 Esterification of benzoin Benzoin (33.32 g, 157 mmol) was dissolved in THF (65 mL) , 2,2-dimethyl-l,3-dioxane-4, 6-dione (22.85 g, 159 mmol) was added and the reaction heated to reflux for 22.6 hours. The reaction mixture was partitioned between saturated NaHC03 and ethyl acetate. The aqueous layer was acidified with concentrated HCl, extracted with diethyl ether, dried over MgS04, and concentrated in vacuo to give a yellow oil (35.08 g) which was used in the next step without further purification.
  • Step 2 Preparation of ethyl r4-hydroxy-4,5-diphenyl-2- oxazolinyllacetate.
  • Step 3 Preparation of ethyl f5- ( -aminosulfonylphenyl) -4- phenyll-2-oxazoleacetate.
  • the compound from Step 2 (1.32 g, 4.2 mmol) was stirred with chlorosulfonic acid (13 mL) for 1.25 hours at 5 °C.
  • the reaction mixture was slowly added to ice water, and extracted with dichloromethane.
  • the dichloromethane was stirred with ammonium hydroxide (40 mL) for 1.9 hours at 5 °C.
  • Step 4 Preparation of 5- (4-aminosulfonylphenyl)-4-phenyll - 2-oxazoleacetic acid
  • methanol 10 mL
  • NaOH 0.09 g dissolved in 5 mL water, 2.2 mmol
  • additional NaOH 0.10 g, 2.5 mmol
  • Water was added and the reaction mixture was extracted with ethyl acetate.
  • the aqueous layer was acidified with concentrated HCl and extracted with ethyl acetate.
  • Step 1 Preparation of 2-hvdroxy-2- (3-chloro-4- fluorophenyl)-1-phenylethanone.
  • a solution of 3-chloro-4-fluorobenzaldehyde (14.00 g, 89 mmol) and zinc iodide (0.16 g) in dichloromethane (50 mL) was treated with a solution of trimethylsilylcyanide (12 mL, 90 mmol) in dichloromethane (15 mL) .
  • the solution was stirred for 0.5 hours at room temperature, washed with saturated NaHC03 and brine, dried over MgS04, and concentrated in vacuo to give the trimethylsilyl cyanohydrin as an orange oil (20.18 g) .
  • the trimethylsilyl cyanohydrin was dissolved in diethyl ether (20 mL) and added dropwise to a solution of phenyImagnesium bromide (90 mmol) in diethyl ether (200 mL) while maintaining the temperature between 25-33 °C with an ice water bath.
  • the reaction was stirred for 0.6 hours at room temperacure then quenched by adding 3N HCl (90 mL) .
  • the organic layer was collected, washed with saturated NaHC03 and brine, dried over MgS04, and concentrated in vacuo to give the an orange oil (24.13 g) .
  • Step 2 Esterification of 2-hvdroxy-2- (3-chloro-4- fluorophenyl)ethanone
  • the ketone from Step 1 (5.54 g, 20.9 mmol) was dissolved in THF (5 mL) , 2,2 dimethyl-1,3-dioxane-4,6-dione (4.65 g, 32.2 mmol) was added and the reaction heated to reflux for 17.2 hours.
  • the reaction mixture was partitioned between saturated NaHC03 and diethyl ether.
  • Step 1 Preparation of 2-hvdroxy-2- (3 , 4-dichlorophenyl) -1- phenylethanone.
  • a solution of 3 , 4-dichlorobenzaldehyde (25.35 g, 145 mmol) and zinc iodide (0.42 g) in dichloromethane (100 mL) was treated with a solution of trimethylsilylcyanide (20 mL, 150 mmol) in dichloromethane (25 mL) .
  • the solution was stirred for 0.33 hours at room temperature, washed with saturated NaHC03 and brine, dried over MgS04, and concentrated ⁇ n vacuo to give the trimethylsilyl cyanohydrin as an orange oil (36.79 g) .
  • the trimethylsilyl cyanohydrin was dissolved in diethyl ether (50 mL) and added dropwise to a solution of phenyImagnesium bromide (144 mmol) in diethyl ether (500 mL) while maintaining the temperature between 25- 33 °C with an ice water bath. The reaction was allowed to stir for 1.8 hours at room temperature then quenched by adding 3N HCl (160 mL) .
  • Step 2 Esterification of 2-hvdroxy-2- (3 ,4-dichlorophenyl) - 1-phenylethanone
  • the ketone from Step 1 (7.43 g, 26.4 mmol) was dissolved in THF (8 mL) , 2,2-dimethyl-l,3 dioxane-4, 6-dione (5.92 g, 41.1 mmol) was added and the reaction heated to reflux for 19.9 hours.
  • the reaction mixture was partitioned between saturated NaHC03 and diethyl ether.
  • the ester from Step 2 (6.67 g, 18.2 mmol) was dissolved in methanol (10 mL) , treated with ammonium acetate (2.90 g, 37.6 mmol), and heated to reflux. After 2.0 hours, the reaction was cooled, additional methanol (50 mL) was added, and the reaction mixture was acidified by adding concentrated ⁇ ulfuric acid and heated to reflux for an additional 0.6 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate, washed with water, saturated NaHC03, and brine, dried over MgS04, and concentrated in vacuo to give an orange oil (4.38 g) which was used in the next step without further purification.
  • Step 4 Preparation of methyl " 4- (4-aminosulfonylphenyl) -5- (3 , 4-dichlorophenyl) 1 -2-oxazoleacetate.
  • the compound from Step 3 (4.32 g,11.4 mmol) was stirred with chlorosulfonic acid (13 mL) for 0.4 hours at room temperature and then for 0.6 hours at 75 °C.
  • the reaction was cooled, slowly added to ice water, and extracted with dichloromethane.
  • the dichloromethane was stirred with ammonium hydroxide (20 mL) for 1.1 hours at room temperature.
  • Step 5 Preparation of * 4- ( -aminosulfonylphenyl) -5- (3 , 4- dichlorophenyl) 1 -2-oxazoleacetic acid.
  • the oxazole ester from Step 4 (0.35 g, 0.8 mmol) was dissolved in methanol (10 mL) , treated with NaOH (0.07 g dissolved in 5 mL water, 1.8 mmol), and stirred at room temperature. After 1.1 hours, additional NaOH (0.10 g, 2.5 mmol) was added and stirring continued for 1.4 hours. Water was added and the reaction mixture was extracted with ethyl acetate. The aqueous layer was then acidified with concentrated HCl and extracted with ethyl acetate.
  • Step 1 Preparation of 2 -hvdroxy-2 - ( 3 , 4-dif luorophenyl ) -1- phenyl ethane.: e .
  • the trimethylsilyl cyanohydrin was dissolved in diethyl ether (50 mL) and added dropwise to a solution of phenyImagnesium bromide (186 mmol) in diethyl ether (560 mL) while maintaining the temperature between 25- 33 °C with an ice water bath. The reaction was stirred for
  • Step 3 Preparation of methyl " 5-(3 ,4-difluorophenyl) -4- hvdroxy-4-phenyl-2-oxazolinyl1acetate
  • the ester from Step 2 (6.03 g, 18.0 mmol) was dissolved in methanol (10 mL) , treated with ammonium acetate (3.07 g, 39.8 mmol), and heated to reflux. After 2.4 hours, the reaction was cooled, additional methanol (60 mL) was added, and the reaction mixture was acidified by adding concentrated sulfuric acid and heated to reflux for an additional 1.9 hours.
  • the oxazoline from Step 3 (3.34 g, 9.6 mmol) was stirred with chlorosulfonic acid (13 mL) for 0.4 hours at room temperature and then for 0.75 hours at 75 ⁇ C.
  • the reaction was cooled, slowly added to ice water, and extracted with dichloromethane.
  • the dichloromethane was stirred at room temperature with ammonium hydroxide (20 mL) for 1.1 hours.
  • the oxazole ester from Step 4 (0.64 g, 1.3 mmol) was dissolved in methanol (10 mL) , treated with NaOH (0.07 g dissolved in 5 L water, 1.8 mmol), and stirred at room temperature. After one hour, additional NaOH (0.11 g, 2.8 mmol) was added and stirring continued for 1.4 hours. Water was added and the reaction mixture was extracted with ethyl acetate. The aqueous layer was acidified with concentrated
  • Step 1 Preparation of 3-trifluoromethyl-4-phenyl-5- (3 , 4- difluorophenyl) oxazole.
  • reaction mixture was diluted with ethyl acetate, washed with 3N HCl, saturated NaHC0 , brine, dried over
  • Step 2 Preparation of 4- [5- (3 , 4-difluorophenyl) -2- trifluoromethyl-4-oxazolyllbenzenesulfonamide 3-Trifluoromethyl-4-phenyl-5- (3,4-difluorophenyl)oxazole from Step 1 (1.02 g, 3.14 mmol) was stirred with chlorosulfor.ic acid (9.5 mL) for 0.9 hours at room o temperature and then for 2.5 hours at 75 C. The reaction was cooled, slowly added to ice water, and extracted with dichloromethane. The dichloromethane was stirred with ammonium hydroxide (100 mL) for 14.7 hours at room temperature.
  • 4,5-Diphenyl-2-oxazolepropionic acid (1.0 g, 34 mmol), prepared as in U.S. Patent # 3,578,671, was added to chlorosulfonic acid cooled to 0 °C (25 mL) , and the stirred solution was warmed to room temperature for 1.0 hour. The mixture was added dropwise to ice and dichloromethane (50 mL) with stirring. The resultant layers were separated, and the organic layer was washed once with water and added to a 0 °C stirred solution of ammonium hydroxide (10 mL) . The mix was stirred for 1.0 hour and extracted with dichloromethane (3 X 50 mL) .
  • Step 1 Preparation of 4 , 5-diphenyloxazole.
  • Benzoin (4.25 g, 20 mmol) was stirred at 0 °C in dichloromethane (150 mL) with triethylamine (2.23 g, 22 mmol) .
  • Methanesulfonyl chloride (2.52 g, 22 mmol) was added dropwise. The solution was warmed to room temperature for
  • Benzom (31.8 g, 0.15 mol) and urethane (42.79 g, 0.45 mol) were heated to reflux for 3.0 hours.
  • the hot mixture was poured into water (150 mL) .
  • Acetone (150 mL) was added and heat was applied until the mixture dissolved.
  • the solution was cooled and filtered yielding a white solid which
  • Example 45 (1.67 g , 5 mmol), dimethylsulfoxide (50 mL) , and sodium thiomethoxide (0.70 g, 10 mmol) were stirred at room temperature for 16.0 hours. The mixture was diluted with ethyl acetate (100 mL) washed with 1 N HCl, brine, water, dried over MgS ⁇ and concentrated. Recrystallization from ethyl acetate/hexanes gave the product as a brown solid (0.8 g, 48 %) : mp 247-249 °C.
  • Example 45 (1.67 g, 5 mmol), DMF (20 mL) , potassium carbonate (1.38 g, 10 mmol), and 3-chlorophenol (0.64 g, 5 mmol) were stirred at room temperature for 16.0 hours, diluted with ethyl acetate (100 mL) , washed with 1 N HCl, brine and water, dried over MgS0 and concentrated. The residue was dissolved in ethyl acetate/hexanes (1:1) and filtered through silica.
  • Example 45 (1.67 g, 5 mmol), DMF (20 mL) , potassium carbonate (].38 g, 10 mmol), and 2,2,2-trifluoroethanol (0.75 g, 7.5 mmol) were stirred at room temperature for 16.0 hours.
  • This reaction mixture was heated at 100 °C for 3 h, cooled to room temperature, and water (100 mL) was added to the cooled reaction mixture.
  • the aqueous solution was extracted with ethyl acetate (1 x 150 mL) .
  • the organic phase was separated and washed with water (2 x 100 mL) , saturated sodium bicarbonate (2 x 100 mL) , brine (2 x 100 mL) and dried over magnesium sulfate, filtered and concentrated.
  • Step 2 Preparation of 2- ⁇ 5- ( -aminosulfonyl)phenv!1-4- phenyloxazol-2-yllethan-2-one
  • Example 50 (0.5 g, 1.44 mmol), ethanol (100 mL) , water (50 mL) , and Oxone (potassium peroxymonosulfate, 0.88 g, 1.44 mmol) were stirred at room temperature for 16.0 hours.
  • Sodium metabisulfite (5 g) and water (50 mL) were added and the resulting mixture stirred for 0.25 hours before the addition of ethyl acetate (200 mL) .
  • the organic layer was separated and washed with brine and water, dried over MgS0 and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate:hexanes (1:3).
  • Example 45 (1.0 g, 3 mmol), DMF (20 mL) , potassium carbonate (0.83 g, 6 mmol), and pentafluorophenol (0.55 g, 3 mmol) were stirred at room temperature for 16.0 hours. The solution was diluted with ethyl acetate (100 mL) , washed with 1 N HCl, brine and water, dried over MgS0 and concentrated.
  • Example 45 (1.0 g, 3 mmol) , DMF (20 mL) , potassium carbonate (0.46 g, 3.3 mmol) , and ethyl ⁇ alicylate (0.55 g,
  • Step 1 Preparation of 2-hydroxy-2- (4-chlorophenyl) -1- phenylethanone.
  • a solution of 4-chlorobenzaldehyde (9.86 g, 70 mmol) and zinc iodide (0.18 g) in dichloromethane (40 mL) was treated with a solution of trimethylsilylcyanide (9 mL, 71 mmol) in dichloromethane (20 mL) .
  • the solution was stirred for 0.33 hours at room temperature, washed with water and saturated NaHC ⁇ 3 , dried over MgS ⁇ 4 and concentrated in vacuo to give the trimethylsilyl cyanohydrin as an orange oil (13.90 g) .
  • Trifluoroacetonitrile (1.5 g, 15.8 mmol) was bubbled into DMF (100 mL) . This solution was cooled to 0 °C and 4'- chlorobenzoin (Example 37, Step 1) (2.5 g, 10 mmol) was added. DBU (1.83 g, 12 mmol) was added and the solution was warmed to room temperature for 4 hours. The reaction was heated to approximately 100 °C for an additional 4 hours. The solution was cooled to room temperature, poured into 400 mL IN HCl and extracted with 500 mL ethyl acetate. The organics were wa ⁇ hed consecutively with IN HCl (400 mL) , NaHC ⁇ 3 (saturated) (400 mL) and brine (400 mL) , dried over
  • Step 2 (0.9 g, 2.8 mmol) was added to chlorosulfonic acid, cooled to 0 °C (25 mL) , and the reaction was warmed to room temperature for 5 hours. The solution was carefully poured into ice water and extracted with three 75 mL portions of dichloromethane. The combined organics were washed once with brine (75 mL) and stirred over ice cold NH4OH (125 mL) for 2 hours. The dichloromethane layer was separated, washed consecutively with IN HCl (2 x 75 mL) , NaHC0 3 (saturated) (75 mL) and brine (75 mL) , dried over Na 2 S ⁇ and concentrated.
  • reaction (which now contained a gummy precipitate) was stirred an additional 15 minutes at which time IN HCl (400 mL) was added and the reaction stirred until all solids were dis ⁇ olved.
  • the reaction wa ⁇ poured into a IL separatory funnel and the layers separated. The organics were washed with NaHC ⁇ 3 (saturated) (400 mL) and brine (400 mL) , dried over Na S ⁇ and concentrated to yield a mixture of benzoin and silyl benzoin.
  • the crude product was dissolved in 90% TFA (75 mL) and stirred for 15 minutes. The TFA solution was poured into saturated NaHC ⁇ 3(aq.) .
  • Trifluoroacetonitrile 0.92 g (9.7 mmol) was added to a solution of DMF (100 ml) . This solution was cooled to 0 °C and 3 '-fluoro-4' -methoxy benzoin from Step 2 (2.08 g, 8 mmol) was added. DBU (1.45 g, 9.7 mmol) was added and the solution was warmed to room temperature for 4 hours. The reaction was heated to approximately 100 °C for an additional 4 hours. The solution was cooled to room temperature, poured into 400 mL IN HCl and extracted with 500 mL ethyl acetate.
  • Step 4 Preparation of 4- " 5- (3-fluoro-4-methoxyphenyl) -2- trifluoromethyl-4-oxazolyl1benzenesulfonamide 2-Trifluoromethyl-4-phenyl-5- (3-fluoro-4-methoxy phenyl)oxazole from Step 3 (337 mg, 1 mmol) was added to chlorosulfonic acid cooled to 0 °C (10 mL) and the reaction was warmed to room temperature for 3 hours. The solution was carefully poured into ice water and extracted with three 75 mL portions of dichloromethane. The combined organics were washed once with brine (75 mL) and stirred over ice cold NH4OH (125 mL) for 2 hours.
  • the dichloromethane layer was separated and washed consecutively with IN HCl (2 x 75 mL) , NaHC03 (saturated) (75 mL) and brine (75 mL) , dried over Na 2 S ⁇ and concentrated.
  • the crude material was chromatographed over Si0 2 eluting with a gradient from 10% -
  • Step 1 Preparation of 2-hvdroxy-2-phenyl-l- (4- methylphenyl ) ethanone .
  • Trifluoroacetonitrile (0.84 g, 8.84 mmol) was added to DMF (100 ml) . This solution was cooled to 0 °C and 4- methylbenzoin from Step 1 (1.36 g, 6 mmol) was added. DBU (1.35 g, 8.84 mmol) was added and the solution was warmed to room temperature for 4 hours . The reaction was then heated to approximately 100 °C for an additional 4 hours. The solution was cooled to room temperature, poured into 400 mL
  • the dichloromethane layer was separated and washed consecutively with IN HCl (2 x 75 mL) , NaHC0 3 (saturated) (75 mL) and brine (75 mL) , dried over Na 2 S0 4 and concentrated.
  • Trifluoroacetonitrile (1.57 g (16.5 mmol) was added to DMF (100 mL) . This ⁇ olution was cooled to 0 °C and 4'- methylbenzoin from Step 1 (3.05 g, 13.5 mmol) was added.
  • DBU (2.51 g, 16.5 mmol) was added and the solution was warmed to room temperature for 4 hours. The reaction was heated to approximately 100 °C for an additional 4 hours. The solution was cooled to room temperature and poured into 400 mL IN HCl and extracted with 500 mL ethyl acetate.
  • Step 3 Preparation of 5- (3-aminosulfonyl-4-methylphenyl) -4- phenyl-2-trifluoromethyloxazole.
  • the dichloromethane layer was separated, washed consecutively with IN HCl (2 x 75 mL) , NaHC0 3 (saturated) (75 mL) and brine (75 mL) , dried over Na 2 S0 4 and concentrated.
  • Trifluoroacetonitrile (1.58 g, 16.5 mmol) wa ⁇ added to DMF (100 ml) . This solution was cooled to 0 °C and benzoin (2.87 g, 13.5 mmol) was added. DBU (2.51 g, 16.5 mmol) was added and the solution was warmed to room temperature for 4 hours. The reaction was heated to approximately 100 °C for an additional 4 hours. The solution was cooled to room temperature and poured into 400 mL IN HCl and extracted with
  • Step 1 Preparation of 2-trif luoromethyl -4- (4- dimethylaminophenyl) -5-phenyloxazole.
  • Example 33 was prepared from the oxazole of Step 1 as described in Example 32, Step 2 (0.38 g, 62%) : mp 159-160 °C.
  • the trimethylsilyl cyanohydrin (5.0 g, 20 mmol) was dissolved in diethyl ether (50 mL) and added dropwise to a solution of p-tolylmagnesium bromide (24 mmol) in diethyl ether (175 mL) while maintaining the temperature at less than 30 °C with an ice water bath.
  • the reaction was stirred for 0.25 hours at room temperature and then quenched by adding IN HCl (250 mL) .
  • the organic layer was collected, washed with saturated NaHCU3 and brine, dried over MgS04, and concentrated in vacuo to give a yellow solid.
  • the yellow solid was dissolved in 9:1 trifluoroacetic acid/water (30 mL) and stirred for 0.25 hours at room temperature.
  • the reaction was neutralized with saturated NaHC ⁇ 3 solution, extracted with ethyl acetate, washed with saturated NaHC03 solution and brine, dried over MgS04, and concentrated in vacuo to give a yellow oil.
  • the oil was purified by Si0 2 chromatography eluting with a gradient from 20-30% ethyl acetate in hexane to yield 2- hydroxy-2- (4-methylthiophenyl) -1- (4-methylphenyl) ethanone
  • Step 2 Preparation of 4- (4-methylphenyl) -5- (4- methylthiophenyl) 2-trifluoro ethyl-oxazole.
  • Step 3 2-trifluoromethyl-4- (4-methylphenyl) -5- (4- methy1sulfonylphenyl) oxazole.
  • 4- (4-Methylphenyl) -5- (4-methylthiophenyl) -2- trifluoromethyloxazole from Step 2 (350 mg, 1.0 mmol) was dissolved in THF (20 mL) , ethanol (20 mL) and water (20 mL) .
  • Step 1 Preparation of 4-methylthio-3 ' -fluoro-4 '-methoxy benzoin.
  • Magnesium (1.34 g, 55 mmol) was suspended in THF (300 mL) and a solution of 4-bromothioanisole (10.16 g, 50 mmol) in THF (50 mL) was added dropwise over 0.5 hour maintaining the temperature at less than 30 °C. The reaction was stirred an additional 0.5 hour once the addition was complete.
  • the crude product was dis ⁇ olved in TFA/H 0 (9:1) (75 mL) and stirred for 15 minutes.
  • the TFA solution was poured into saturated NaHC ⁇ 3 (aq.) .
  • the benzoin was extracted with ethyl acetate (350 mL) and washed with NaHC0 3 (saturated) (300 mL) and brine (300 mL) .
  • Step 3 Preparation of 5- (3-fluoro-4-methoxyphenyl-4- (4- methylsulfonylphenyl)2-trifluoromethyloxazole.
  • the trimethylsilyl cyanohydrin was dissolved in diethyl ether (15 mL) and added dropwise to a solution of phenylmagnesium bromide (13.8 mmol) in diethyl ether (90 mL) while maintaining the temperature below 25 ⁇ C with an ice water bath. The reaction was stirred for 1.2 hours at room temperature then quenched by adding 3N HCl. The organic layer was collected, washed with saturated NaHC ⁇ 3 and brine, dried over MgS ⁇ , and concentrated in vacuo to give a yellow oil (3.99 g) . The yellow oil was dissolved in 9:1 trifluoroacetic acid/water (20 mL) and stirred for 0.33 hours at room temperature.
  • Step 5 Preparation of 4- " 5- (3-bromo-4-methoxy-5- fluorophenyl) -2-trifluoromethyl-4-oxazolyllbenzenesulfonamide The oxazole of Step 4 wa ⁇ reacted as described in
  • Example 64 Step 2.
  • the crude material wa ⁇ chromatographed over Si0 2 eluting with a gradient from 10% - 50% ethyl acetate in hexane to yield 4-[5- (3-bromo-4-methoxy-5- fluorophenyl)-2-trifluoromethyl-4-oxazolyl]benzenesulfonamide (0.25 g, 15%):
  • X H NMR (CDCI3) 300 MHz ⁇ 4.05 (s, 3H) , 5.18
  • Step 2 Preparation of 4- * 2-methoxymethyl-4-pheny1- oxazolyllbenzenesulfonamide. 2-Methoxymethyl-4,5-diphenyloxazole from Step 1 (500 mg,
  • the dichloromethane layer was separated, washed consecutively with IN HCl (2 x 75 mL) , NaHC0 3 (saturated) (75 mL) and brine (75 mL) , dried over Na 2 S0 4 and concentrated.
  • Deoxybenzoin (10 g, 51 mmol) was added to chlorosulfonic acid cooled to 0 °C (25 mL) and the reaction was warmed to room temperature for 4 hours. The solution was carefully poured into ice water, filtered and the aqueous layer was extracted with three 250 mL portions of dichloromethane. The combined organics were washed once with brine (75 mL) and stirred over ice-cold NH4OH (125 mL) for 16 hours. The dichloromethane layer was separated and washed consecutively with IN HCl (2 x 75 mL) , NaHC0 3 (saturated) (75 mL) and brine
  • Step 1 Preparation of 2- F (4-chlorosulfonyl)phenyl1 -1- phenylethanone
  • Deoxybenzoin (10 g, 0.051 mol) was added in portions to neat chlorosulfonic acid (50 mL) at -78 °C .
  • the reaction mixture was stirred at -78 °C for 2 h, then warmed to room temperature and stirred at room temperature for 1.5 h.
  • the reaction mixture was cooled to -78 °C and was carefully poured onto crushed ice.
  • the resulting solid was collected by filtration, washed with water, and dried to give 10.3 g (68.5%) of the desired sulfonyl chloride as a yellow solid.
  • This crude material was used for the next reaction without further purification:
  • HRMS (calcd for C 14 H 11 O 3 SCI 295.0196) 295.0205.
  • Step 2 Preparation of 2- ⁇ (4-aminosulfonyl)phenv ⁇ -1- phenylethanone
  • Step 3 Preparation of 2-bromo-2- I (4-amino ⁇ ulfonyl) phenyll -1-phenyl-ethanone
  • the sulfonamide from Step 2 (5.0 g, 0.018 mol) was suspended in dichloroethane (50 mL) , then a solution of 30% HBr in acetic acid (20 mL) , acetic acid (70 mL) and bromine (1 mL) was added at room temperature. The reaction mixture was stirred for 40 minutes at room temperature and then was concentrated in vacuo . Water (200 mL) was added to the resulting concentrated residue, and the mixture was extracted with ethyl acetate (2 x 250 mL) .

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Abstract

L'invention se rapporte à une classe d'oxazoles substitués destinés à être utilisés dans le traitement d'inflammations ou de troubles liés à des inflammations. Des composés d'intérêt particulier sont définis par la formule (I) dans laquelle R est sélectionné parmi hydrido, halo, mercapto, hydroxyle, carboxyalkylthio, carboxyalkylthioalkyle, carboxyalcoxy, carboxyalcoxyalkyle, haloalcoxy, alkylthio, alkylsulfinyle, alkylsulfonyle, alcoxy, aryloxy, aralcoxy, alkylamino, aminocarbonyle, alcoxyalkyle, carboxy(haloalkyle), alkyle, hydroxyalkyle, haloalkyle, alcényle, hydroxyalcényle, alkynyle, hydroxyalkynyle, cycloalkyle, cycloalkylalkyle, aminoalkyle, hydroxyalcoxyalkyle, alkylcarbonyle, phosphonylalkyle, un résidu aminoacide, hétérocyclylalkyle, cyanoalkyle, alcoxycarbonyle, alcoxycarbonylalkyle, carboxy, carboxyalkyle, arylthioalkyle, aminocarbonylalkyle, alkylcarbonylaminoalkyle, alcoxycarbonylaminoalkyle, aralcoxycarbonylaminoalkyle, aryle, hétéroaryle, aralkyle, aryloxyalkyle, aralcoxyalkyle, hétéroaryloxyalkyle et hétéroarylalcoxyalkyle; où R1 est sélectionné parmi cycloalkyle, cycloalcényle, aryle et hétérocyclyle, R1 étant éventuellement substitué à une position substituable par alkyle, alkylamino, alcoxy et halo; où R2 est sélectionné parmi alkyle et amino; et où R3 est sélectionné parmi hydrido et alkyle.
EP96920231A 1995-05-19 1996-05-16 Oxazoles substitues utilises dans le traitement d'inflammations Withdrawn EP0825989A1 (fr)

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JPH11509835A (ja) 1999-08-31
AU5860396A (en) 1996-11-29
WO1996036617A1 (fr) 1996-11-21

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