WO1996036617A1 - Substituted oxazoles for the treatment of inflammation - Google Patents

Substituted oxazoles for the treatment of inflammation Download PDF

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Publication number
WO1996036617A1
WO1996036617A1 PCT/US1996/006992 US9606992W WO9636617A1 WO 1996036617 A1 WO1996036617 A1 WO 1996036617A1 US 9606992 W US9606992 W US 9606992W WO 9636617 A1 WO9636617 A1 WO 9636617A1
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Prior art keywords
phenyl
oxazolyl
benzenesulfonamide
methyl
aminosulfonyl
Prior art date
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PCT/US1996/006992
Other languages
French (fr)
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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G.D. Searle & Co.
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Publication date
Application filed by G.D. Searle & Co. filed Critical G.D. Searle & Co.
Priority to JP8535029A priority Critical patent/JPH11509835A/en
Priority to EP96920231A priority patent/EP0825989A1/en
Priority to AU58603/96A priority patent/AU5860396A/en
Publication of WO1996036617A1 publication Critical patent/WO1996036617A1/en

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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

  • inflammation and inflammation-associated disorders such as arthritis.
  • NSAIDs common non-steroidal antiinflammatory drugs
  • corticosteroids An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is
  • cyclooxygenase-2 (COX-2)
  • prostaglandin G/H synthase II provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
  • 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.
  • 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 dysmenorrhea.
  • PCT publication W094/15932 describes 4,5- substitutedphenyl-thiophenes/furans and pyrroles as having antiinflammatory activity.
  • 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- chlorophenyl) oxazole, as having antiphlogistic, analgesic and antipyretic activity.
  • Other related diphenyloxazole disclosures include U.S. Patent No. 4,001,228, to G.
  • 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.
  • heterocyclic sulfonyl derivatives and specifically, 4',4"- (2-methyl-4,5-oxazoldiyl)-bis-benzenesulfonamide (J.
  • a class of substituted oxazolyl compounds useful in treating inflammation-related disorders is defined by
  • R is selected from hydrido, halo, mercapto, hydroxyl, carboxyalkylthio, carboxyalkylthioalkyl,
  • phosphonylalkyl amino acid residue, heterocyclylalkyl, cyanoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, arylthioalkyl, aminocarbonylalkyl,
  • alkylcarbonylaminoalkyl alkoxycarbonylaminoalkyl
  • aralkoxycarbonylaminoalkyl aryl, heteroaryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, heteroaryloxyalkyl and
  • R 1 is selected from cycloalkyl, cycloalkenyl, aryl and heterocyclyl, wherein R 1 is optionally substituted at a substitutable position by alkyl, alkylamino, alkoxy and halo;
  • R 2 is selected from alkyl and amino; and wherein R 3 is selected from hydrido and alkyl; or a pharmaceutically-acceptable salt thereof;
  • R is not methyl when R 2 is amino and when R 1 is phenyl or 4-halophenyl; further provided R is haloalkyl when R 3 is alkyl; and further provided that R 1 is not phenyl when R 2 is methyl and R is isopropyl or tert-butyl.
  • Compounds 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, kursitis, 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.
  • 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.
  • ophthalmic diseases such as retinitis, retinopathies, uveitis, conjunctivitis, and of acute injury to the eye tissue.
  • the compounds would also be useful in the
  • 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, 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-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
  • the compounds have a
  • 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 alkylcarbonyl, lower
  • phosphonylalkyl amino acid residue, lower cyanoalkyl, lower alkoxycarbonyl, lower alkoxycarbonylalkyl, carboxy, lower carboxyalkyl, lower arylthioalkyl, lower
  • heteroaryloxyalkyl optionally substituted at a
  • R 1 is selected from lower cycloalkyl, lower cycloalkenyl, aryl and heteroaryl, wherein R 1 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 3 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, methylthio, ethylthio, methylsulfinyl, methylsulfonyl, methoxy, ethoxy, propoxy, butoxy, phenyloxy, benzyloxy, N- methylamino, N,N-dimethylamino, N,N-diethylamino,
  • cyclohexylmethyl cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, aminoethyl, aminopropyl,
  • R 1 is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1- cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,
  • R 1 is optionally substituted at a substitutable position by methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, amino, methoxy, ethoxy, propoxy, butoxy, N-methylamino, N,N-dimethylamino, fluoro, chloro, bromo and iodo; wherein R 2 is selected from methyl, and amino; wherein R 3 is selected from hydrido, and methyl.
  • R 2 is selected from lower alkyl and amino; wherein R 4 is selected from hydrido, alkyl, alkylamino, alkoxy and halo; and wherein R 5 is selected from halo, mercapto, carbbxyalkylthio, carboxyalkylthioalkyl,
  • a preferred class of compounds consists of those compounds of Formula II wherein R 2 is selected from lower alkyl and amino; wherein R 4 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, aryloxy, lower alkylamino, aminocarbonyl, loweralkoxyalkyl, lower carboxy(haloalkyl), lower aminoalkyl, lower hydroxyalkoxyalkyl, lower alkylcarbonyl, lower phosphonylalkyl, lower alkylcarbonylammoalkyl, lower aralkoxycarbonylaminoalkyl, amino acid residue, lower heterocyclylalkyl, and lower
  • 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 4 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,
  • carboxyethylthiomethyl trifluoromethoxy, methylthio, ethylthio, methylsulfinyl, methylsulfonyl, methoxy, ethoxy, propoxy, butoxy, phenyloxy, benzyloxy, N- methylamino, N,N-dimethylamino, N,N-diethylamino, aminocarbonyl, methoxymethyl, ⁇ -bromo-carboxymethyl, aminoethyl, bis (hydroxymethyl)methoxymethyl,
  • R 2 is selected from lower alkyl and amino; wherein R 4 is selected from hydrido, lower alkyl, lower alkylamino, lower alkoxy and halo; wherein R 6 is -Y-Q;
  • Y is selected from aryl, heterocyclyl,
  • alkoxyalkyl aryloxyalkyl, alkylaryloxyalkyl
  • heterocyclylalkyl alkylheterocyclyl
  • alkylheterocyclylalkyl alkylaralkyl, aralkyl
  • alkynylaralkyl alkyl, alkylsulfonylalkyl,
  • alkylthioalkyl and alkylsulfonylaminoalkyl
  • Q is an acidic moiety selected from carboxylic acid, tetrazole, phosphorous-containing acids, sulfur- containing acids, and the amide, ester and salt
  • 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
  • alkylaralkyl lower alkynylaralkyl, lower aralkyl, lower alkylsulfonylalkyl, lower alkylthioalkyl, alkyl, and lower alkylsulfonylaminoalkyl; wherein Q is selected from carboxyl, lower alkoxycarbonyl, lower aralkoxycarbonyl, tetrazolyl,
  • each of R 7 and R 8 is 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 4 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, 3,3 -dimethylbutyl, 2- methylpropyl, butyl, and methylsulfonylammopropyl; wherein Q is selected from carboxyl, methoxycarbonyl,
  • R 7 and R 8 are 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
  • hydrido 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
  • alkyl methylene (-CH 2 -) radical.
  • alkyl haloalkyl
  • alkoxyalkyl alkoxyalkyl
  • 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. Most preferred are lower alkyl radicals having one to about six carbon atoms.
  • 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 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
  • haloalkyl embraces radicals having 1-6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,
  • 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 to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-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.
  • 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
  • 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.
  • 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.
  • unsaturated heterocyclic radicals also termed "heteroaryl" radicals include unsaturated 5 to 7 membered heteromonocyclic group
  • 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.
  • 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. Examples of such fused bicyclic radicals 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,
  • 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,
  • 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.
  • 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
  • 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,
  • cycloalkylalkyl embraces alkyl radicals substituted with cycloalkyl radicals having three to ten carbon atoms, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, eyelohexyIpropyl and cycloheptylmethyl.
  • cycloalkenyl embraces unsaturated radicals having three to ten carbon atoms, such as cylopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • alkylsulfonyl denotes respectively divalent radicals -SO 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
  • 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. Examples of such lower alkylsulfinyl radicals include methylsulfinyl,
  • 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 alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.
  • sulfamyl denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO 2 NH 2 ).
  • alkylcarbonyl denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO 2 NH 2 ).
  • 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,
  • carboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes -CO 2 H.
  • 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
  • lower carboxyalkyl which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo.
  • 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. Examples of such acyl radicals include alkanoyl and aroyl radicals.
  • alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pi valoyl, 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
  • aroyl examples include benzoyl, naphthoyl, phenylacetyl, and the like, and the aryl in said aroyl may be
  • alkoxycarbonyl ester radicals include substituted or unsubstituted methoxycarbonyl,
  • 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(O)NH 2 .
  • 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
  • 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 having such inflammation or disorder a
  • the method of the present invention also relates to the method of the present invention.
  • a preferred method includes prophylactic treatment.
  • 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 hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and
  • sulfonic classes of organic acids examples 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,
  • Suitable pharmaceutically-acceptable base addition salts of compounds 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,
  • 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.
  • the optically sodium and zinc or organic salts made from N,N'- dibenzylethylenediamine, choline, chloroprocaine,
  • 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.
  • step four the crude acylazides are heated to form an acylazides.
  • isocyanate via a Curtius rearrangement.
  • the isocyanate is trapped as the N-t-butyloxycarbonyl enamine
  • 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).
  • Desilylation of this silylated benzoin 9 is achieved using aqueous acid, such as trifluoroacetic acid, to give the desired benzoin 10.
  • aqueous acid such as trifluoroacetic acid
  • 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).
  • silyl enol ether 13 is followed by oxidation, such as with m-chloroperbenzoic acid, to give the appropriate silylated benzoin 14.
  • oxidation such as with m-chloroperbenzoic acid
  • 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.
  • alkylsulfonylphenyloxazoles 12 and 17 is accomplished as shown in Synthetic Scheme VII from oxazoles 20 and 23 (prepared in Schemes V and VI).
  • Oxazoles 20 and 23, where R 2 is an alkyl radical are oxidized, such as with MCPBA (2 equivalents) in methylene chloride to form the
  • suitable oxidizing agents include Oxone®, hydrogen
  • Scheme VIII shows a method for preparing oxazoles 28 where Ar 1 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 1 -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.
  • step one a THF solution of the methyl sulfones 29 at about -78°C is treated with an alkyllithium reagent, e.g., methyllithium, n-butyllithium, etc.
  • step two the anions generated in step one are treated with an organoborane, e.g.,
  • step three 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 are stirred with chlorosulfonic acid at about 5 °C to give the sulfonyl chlorides 32.
  • sulfonyl chloride 32 is reacted at about 5 °C with
  • disulfonamides can be formed by substitution on R 1 where R 1 is aryl or
  • 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.
  • 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-fluorophenyl)-2-hydroxy-2- (metethylsulfonyl)phenyl)ethanone
  • the benzoin silyl ether was dissolved in 100 mL of 90% aqueous trifluoroacetic acid and stirred at 25oC 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
  • Step 2 Preparation of 4-(4-fluorophenyl)-2-(2- phenylethyl)-5-(4-(methylsulfonyl)phenyl)oxazole.
  • 2-phenyloxazole 4-(4-Fluorophenyl)-5-[4-(methylsulfonyl) phenyl]-2- phenyloxazole was prepared in a manner analogous to Example 1. Melting point: 204-205oC.
  • Methyl 3-[4-(4-fluorophenyl)-5-[4- methylsulfonylphenyl]oxazol-2-yl]propanate was prepared in a manner analogous to Example 1.
  • Example 12 3-[4-(4-Fluorophenyl)-5-[4-(methylsulfonyl) phenyl]]-2-oxazolepropanoic acid was prepared from Example 12 in a manner analogous to Example 17. Melting point: 197-198°C. The m / z 390 (M+H) + was consistent with the assigned structure.
  • 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.
  • Example 15 in a manner analogous to Example 17.
  • tetrahydrofuran was cooled to 0°C with stirring under a nitrogen atmosphere as 0.53 mL of diisobutylaluminum hydride (1M in toluene, 0.523 mmol) was added dropwise over 5 minutes. The reaction was allowed to warm to 25°C and poured into 100 mL of a saturated solution of sodium potassium tartarate. Ethyl acetate (100 mL) was added and the mixture was stirred until the layers separated (approx. 1 hour). The organic layer was separated and dried over sodium sulfate.
  • phenyl]]-2-oxazolepropanamide was prepared by treating methyl 3-[4-(4-fluorophenyl)-5-(4-
  • Step 2 Preparation of 5-(4-fluorophenyl)-4-[ 4- (methylsulfinyl)phenyl]-2-phenyloxazole.
  • Step 3 Preparation of 5-(4-fluorophenyl)-4-[4- (methylsulfonyl)phenyl]-2-phenyloxazole.
  • reaction mixture consisted of mostly sulfone.
  • 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
  • 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.
  • reaction mixture consisted of mostly sulfone.
  • 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
  • reaction mixture consisted of mostly sulfone.
  • 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 1 Preparation of 2-(4-fluorophenyl)-3-(4- methylthiophenyl)propenoic acid
  • Step 2 Preparation of 1-(4-fluorophenyl)-2-(4- methylthiophenyl)ethanone
  • the diaryl 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
  • Step 3 Preparation of 1-(4-fluorophenyl)-2-(4- methylthiophenyl)-2-hydroxy-ethanone
  • the crude bromoketone was dissolved in dichloromethane and washed with 1N NaHSO 3 , dried over anhydrous MgSO 4 , filtered and concentrated in vacuo to give 68.8 g of 1-(4-fluorophenyl)-2-(4- methylthiophenyl)-2-bromoethanone as a yellow solid which was used directly without further purification.
  • the crude bromoketone was dissolved in 300 mL acetone and 150 mL of water and heated to reflux for 2.5 hours.
  • Step 4 Preparation of ethyl 2-[4-(4-fluorophenyl)-5- [4-methylthio)phenyl]]-2-oxazoleacetate
  • Step 5 Preparation of ethyl 2-[4-(4-fluorophenyl)-5- [4-methylsulfonyl)phenyl]-2-oxazolyl]-2-benzyl-acetate
  • the resulting clear solution was dried over sodium sulfate and concentrated in vacuo to give a transparent oil which was purified by flash chromatography on a silica gel cr lumn using 30% ethyl acetate/hexane as the eluent.
  • the purified material was an oil whose

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Abstract

A class of substituted oxazoles is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by formula (I), wherein R is selected from hydrido, halo, mercapto, hydroxyl, carboxyalkylthio, carboxyalkylthioalkyl, carboxyalkoxy, carboxyalkoxyalkyl, haloalkoxy, alkylthio, alkylsulfinyl, 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, alkoxycarbonylalkyl, carboxy, carboxyalkyl, arylthioalkyl, aminocarbonylalkyl, alkylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aralkoxycarbonylaminoalkyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, heteroaryloxyalkyl and heteroarylalkoxyalkyl; wherein R1 is selected from cycloalkyl, cycloalkenyl, aryl and heterocyclyl, wherein R1 is optionally substituted at a substitutable position by alkyl, alkylamino, alkoxy and halo; wherein R2 is selected from alkyl and amino; and wherein R3 is selected from hydrido and alkyl.

Description

SUBSTITUTED OXAZOLES FOR THE TREATMENT OF
INFLAMMATION
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG2, PGH2 and PGE2, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is
involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named
"cyclooxygenase-2 (COX-2)" or "prostaglandin G/H synthase II") provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
The references below that disclose antiinflammatory activity, si.vw continuing efforts to find a safe and effective antiinflammatory agent. 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 dysmenorrhea. PCT publication W094/15932 describes 4,5- substitutedphenyl-thiophenes/furans and pyrroles as having antiinflammatory activity.
Pyrazole derivatives having antiinflammatory activity are described in U.S. Patent No. 5, 134,142, to Matsuo et al.
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- chlorophenyl) oxazole, 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. Hafeli, for intermediates in the
production of antiinflammatory agents. U. S. Patent No. 4,489,084, to F. Haviv and F.Kerdesky, describes
diphenyloxazolyl hydrazinoalkyl nitrile compounds for use as antiinflammatory agents. U.S. Patent No. 4,143,047, to R. Harrison, describes oxazole compounds as reactants to make 2-acylamino oxazole derivatives having anti-allergy activity. U.S. Patent No. 4,791,124, to Lutomski et al,
describes the pesticide activity of substituted bis (4- halophenyl)oxazoles. U.S. Patent No. 4,775,687, to Meguro et al describes the possible use of 4,5-phenyl oxazoles as starting materials for antidiabetic compounds. WO
publication Ko. W092/21665, published December 9, 1992, describes bis (halophenyl)oxazole derivatives as starting materials for the preparation of antiinflammatory agents.
N. Meanwell et al [J.Med. Chem ., 35, 3498 (1992)] describe bis (substitutedphenyl) oxazoles as having ADP- induced platelet aggregation inhibition activity.
U.S. Patent No. 4,812,470, to N. Rogers et al, describes phenyl substituted oxazoles as having
antibacterial activity.
U.S. Patent No. 3.901,908, to K. Fitzi and R. Pfister, describes 2-alkyl and 2-cycloalkyl-4,5-phenyloxazoles as intermediates in the synthesis of imidazoles having
analgesic and antipyretic activity. Specifically, 2-tert- butyl-4-(4-methylsulfonylphenyl)-5-phenyloxazole is
described.
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)-α,α- 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. van Es and O.G.Backeberg [J. Chem. Soc . , 1363 (1963)] describe the synthesis of 2-methyl-4,5- substitutedphenyloxazoles, and specifically, 4-[5-(4- chlorophenyl)-2-methyl-4-oxazolyl]benzenesulfonamide.
U.S. Patent No. 5,380,738, to Norman et al, describes 4-methylsulfonylphenyloxazoles for the treatment of
inflammation. WO94//27980, published Dec. 8, 1994, describes substituted oxazoles for the treatment of inflammation. WO95/00501, published Jan 5, 1995, describes substituted oxazoles for the treatment of inflammation.
DESCRIPTION OF THE INVENTION
A class of substituted oxazolyl compounds useful in treating inflammation-related disorders is defined by
Formula I:
Figure imgf000006_0001
wherein 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, alkoxycarbonylalkyl, carboxy, carboxyalkyl, arylthioalkyl, aminocarbonylalkyl,
alkylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl,
aralkoxycarbonylaminoalkyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, heteroaryloxyalkyl and
heteroarylalkoxyalkyl;
wherein R1 is selected from cycloalkyl, cycloalkenyl, aryl and heterocyclyl, wherein R1 is optionally substituted at a substitutable position by alkyl, alkylamino, alkoxy and halo;
wherein R2 is selected from alkyl and amino; and wherein R3 is selected from hydrido and alkyl; or a pharmaceutically-acceptable salt thereof;
provided R is not methyl when R2 is amino and when R1 is phenyl or 4-halophenyl; further provided R is haloalkyl when R3 is alkyl; and further provided that R1 is not phenyl when R2 is methyl and R is isopropyl or tert-butyl.
The pherse "further provided", as used in the above description, is intended to mean that the denoted proviso is not to be considered conjunctive with the other
provisos.
Compounds 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. For example, 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, kursitis, 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. 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.
Besides being useful for human treatment, 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, LTB4 receptor antagonists and LTA4 hydrolase inhibitors.
Suitable LTB4 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, 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-104493. Preferably, the LTB4 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.
The phrase "combination therapy" (or "co-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. Preferably, the compounds have a
cyclooxygenase-2 IC50 of less than about 0.5 μM, 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 IC50 of greater than about 1 μM, and more preferably of greater than 20 μM.
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 alkylcarbonyl, lower
phosphonylalkyl, amino acid residue, lower cyanoalkyl, lower alkoxycarbonyl, lower alkoxycarbonylalkyl, carboxy, lower carboxyalkyl, lower arylthioalkyl, lower
aminocarbonylalkyl, lower alkylcarbonylaminoalkyl, lower alkoxycarbonylaminoalkyl, lower aralkoxycarbonylaminoalkyl, aryl optionally substituted at a substitutable position by carboxy, lower carboxyalkyl, lower alkyl, lower alkoxy and halo, heteroaryl optionally substituted at a substitutable position by carboxy, lower carboxyalkyl, lower alkyl, lower alkoxy and halo, lower aralkyl optionally substituted at a substitutable position on the aryl radical by carboxy, lower carboxyalkyl, lower alkyl, lower alkoxy and halo, lower heterocyclylalkyl optionally substituted at a
substitutable position on the heterocyclyl radical by carboxy, lower carboxyalkyl, lower alkyl, lower alkoxy and halo, lower aryloxyalkyl optionally substituted at a substitutable position with halo, carboxy, lower
carboxyalkyl, lower alkyl and lower alkoxy, aralkoxyalkyl optionally substituted at a substitutable position with halo, carboxy, lower carboxyalkyl, lower alkyl and lower alkoxy, heteroarylalkoxyalkyl optionally substituted at a substitutable position with halo, carboxy, lower
carboxyalkyl, lower alkyl and lower alkoxy, and
heteroaryloxyalkyl optionally substituted at a
substitutable position with halo, carboxy, lower
carboxyalkyl, lower alkyl and lower alkoxy; wherein R1 is selected from lower cycloalkyl, lower cycloalkenyl, aryl and heteroaryl, wherein R1 is optionally substituted at a substitutable position by lower alkyl, lower alkylamino, lower alkoxy and halo; wherein R2 is selected from lower alkyl and amino; and wherein R3 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, methylthio, ethylthio, methylsulfinyl, methylsulfonyl, methoxy, ethoxy, propoxy, butoxy, phenyloxy, benzyloxy, N- methylamino, N,N-dimethylamino, N,N-diethylamino,
aminocarbonyl, methoxymethyl, α-bromo-carboxymethyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, 1- propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, hydroxyethenyl, hydroxypropenyl, ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, hydroxyethynyl, hydroxypropynyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, aminoethyl, aminopropyl,
bis(hydroxymethyl)methoxymethyl, methylcarbonyl, N- benzyloxycarbonylaminomethyl, N-methoxycarbonylaminomethyl, N-methoxycarbonylaminomethyl, cyanopentyl, phenyl
optionally substituted at a substitutable position by fluoro, chloro, bromo, iodo, carboxy, carboxymethyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, methoxy, ethoxy, propoxy and butoxy, heteroaryl selected from pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, pyrrolyl, furyl and quinolyl, optionally substituted at a substitutable position by fluoro, chloro, bromo, iodo, carboxy, carboxymethyl, methyl, ethyl, n- propyl, isopropyl, butyl, tert-butyl, isobutyl, methoxy, ethoxy, propoxy and butoxy, lower aralkyl selected from benzyl, phenethyl, diphenylmethyl and phenylpropyl, optionally substituted at a substitutable position on the phenyl radical by fluoro, chloro, bromo, iodo, carboxy, carboxymethyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, methoxy, ethoxy, propoxy and butoxy, lower heterocyclylalkyl selected from pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylpropyl, pyrrolylethyl, (2- methylimidazolyl)propynylphenylmethyl, piperidinylethyl, and tetrazolylpentyl, optionally substituted at a
substitutable position by fluoro, chloro, bromo, iodo, carboxy, carboxymethyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, methoxy, ethoxy, propoxy and butoxy, phenoxymethyl optionally substituted at a
substitutable position on the phenyl radical with fluoro, chloro, bromo, iodo, carboxy, carboxymethyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, methoxy, ethoxy, propoxy and butoxy, benzyloxymethyl optionally substituted at a substitutable position on the phenyl radical with fluoro, chloro, bromo, iodo, carboxy,
carboxymethyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, methoxy, ethoxy, propoxy and butoxy, heteroaryloxyalkyl selected from pyridyloxymethyl and quinolyloxymethyl, optionally substituted at a
substitutable position with fluoro, chloro, bromo, iodo, carboxy, carboxymethyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, methoxy, ethoxy, propoxy and butoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, methoxycarbonylmethyl,
ethoxycarbonylmethyl, methoxycarbonylethyl,
ethoxycarbonylethyl, carboxy, carboxymethyl, carboxyethyl, carboxypropyl, carboxypentyl, carboxybutyl,
phenylthiomethyl, aminocarbonylmethyl, N- methylaminocarbonylmethyl and N,N- dimethylaminocarbonylmethyl; wherein R1 is selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1- cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,
cyclopentenyl, cycloheptenyl, phenyl, naphthyl, pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, furyl, quinolyl, benzothiazolyl, 2,3-thianaphthalenyl, 2,3- dihydrothianaphthalenyl, 2,3-benzofuryl, and 2,3- dihydrobenzofuryl, wherein R1 is optionally substituted at a substitutable position by methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, amino, methoxy, ethoxy, propoxy, butoxy, N-methylamino, N,N-dimethylamino, fluoro, chloro, bromo and iodo; wherein R2 is selected from methyl, and amino; wherein R3 is selected from hydrido, and methyl.
Within Formula I there is a subclass of compounds of high interest represented by Formula II:
Figure imgf000013_0001
wherein R2 is selected from lower alkyl and amino; wherein R4 is selected from hydrido, alkyl, alkylamino, alkoxy and halo; and wherein R5 is selected from halo, mercapto, carbbxyalkylthio, 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 thereof.
A preferred class of compounds consists of those compounds of Formula II wherein R2 is selected from lower alkyl and amino; wherein R4 is selected from hydrido, lower alkyl, lower alkylamino, lower alkoxy and halo; and wherein R5 is selected from halo, mercapto, lower carboxyalkylthio, lower carboxyalkylthioalkyl, lower haloalkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy, aryloxy, lower alkylamino, aminocarbonyl, loweralkoxyalkyl, lower carboxy(haloalkyl), lower aminoalkyl, lower hydroxyalkoxyalkyl, lower alkylcarbonyl, lower phosphonylalkyl, lower alkylcarbonylammoalkyl, lower aralkoxycarbonylaminoalkyl, amino acid residue, lower heterocyclylalkyl, and lower cyanoalkyl; or a
pharmaceutically-acceptable salt thereof.
A class of compounds of particular interest consists of those compounds of Formula II wherein R2 is selected from methyl and amino; wherein R4 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 R5 is selected from chloro, fluoro, bromo, iodo, mercapto,
carboxymethylthio, carboxyethylthio,
carboxyethylthiomethyl, trifluoromethoxy, methylthio, ethylthio, methylsulfinyl, methylsulfonyl, methoxy, ethoxy, propoxy, butoxy, phenyloxy, benzyloxy, N- methylamino, N,N-dimethylamino, N,N-diethylamino, aminocarbonyl, methoxymethyl, α-bromo-carboxymethyl, aminoethyl, bis (hydroxymethyl)methoxymethyl,
methylcarbonyl, N-methylcarbonylaminomethyl,
aminopropyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylpropyl, pyrrolylethyl,
methylcarbonylaminomethyl, N- (benzyloxycarbonyl)aminomethyl, N- (benzyloxycarbonyl)aminoethyl, N-
(benzyloxycarbonyl)aminopropyl, N-methyl-N- (benzyloxycarbonyl)aminoethyl, [N-
(phenylmethoxycarbonyl)amino]methoxycarbonylpropyl, [N- (phenylmethoxycarbonyl)amino]carboxypropyl,
piperidinylethyl, tetrazolylpentyl, and cyanopentyl; or a pharmaceutically-acceptable salt thereof.
Within Formula I there is a subclass of
compounds of high interest represented by Formula III
Figure imgf000015_0001
wherein R2 is selected from lower alkyl and amino; wherein R4 is selected from hydrido, lower alkyl, lower alkylamino, lower alkoxy and halo; wherein R6 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 the amide, ester and salt
derivatives of said acids; provided Y is not methyl when Q is -P(O) (OH)2; and further provided Y is not
methyl or ethyl when Q is carboxyl; or a
pharmaceutically-acceptable salt thereof.
A preferred class of compounds consists of those compounds of Formula III wherein R2 is selected from lower alkyl and amino; wherein R4 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 aralkoxycarbonyl, tetrazolyl,
Figure imgf000016_0001
and wherein each of R7 and R8 is 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 R2 is selected from methyl and amino; wherein R4 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, 3,3 -dimethylbutyl, 2- methylpropyl, butyl, and methylsulfonylammopropyl; wherein Q is selected from carboxyl, methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, tetrazolyl,
Figure imgf000016_0002
and wherein each of R7 and R8 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: 4-[2-[[4-[3-(hydroxy)-1-propynyl]phenyl]methyl]-4- phenyloxazol-5-yl]benzenesulfonamide;
4-[2-[[4-[3-(N,N-dimethylamino)-1-propynyl]phenyl]
methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;
4-[2-[[4-[3-(N,N-dimethylamino)propyl]phenyl]methyl]-4- phenyloxazol-5-yl]benzenesulfonamide;
4-[2-[[4-[3-(hydroxy)-1-propynyl]phenyl]methyl]-4- phenyloxazol-5-yl]benzenesulfonamide;
1,1-dimethylethyl [3-[4-[[5-[4-(ammosulfonyl)phenyl]-4- phenyloxazol-2-yl]methyl]phenyl]-2-propynyl]carbamate; 4-[2-[[4-[3-(2-methyl-1H-imidazol-1-yl)-1-propyl]phenyl] methyl]-4-phenyloxazol-5-yl]benzenesulfonamide;
4-[2-[[4-[3-(amino)-1-propynyl]phenyl]methyl]-4- phenyloxazol-5-yl]benzenesulfonamide;
4-[2-[[4-[3-(tert-butylamino)-1-propynyl]phenyl]methyl]- 4-phenyloxazol-5-yl]benzenesulfonamide
phenylmethyl [2-[5-[4-(ammosulfonyl)phenyl]-4- phenyloxazol-2-yl]methyl]carbamate;
phenylmethyl [2-[5-[4-(ammosulfonyl)phenyl]-4- phenyloxazol-2-yl]ethyl]carbamate;
phenylmethyl [2-[5-[4-(aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]ethyl]methylcarbamate;
phenylmethyl [2-[5-[4-(aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]propyl]carbamate;
methyl 5-[4-(aminosulfonyl)phenyl]-αR- [ [(phenylmethoxy)carbonyl]aminno]-4-phenyloxazole-2- butanoate;
5-[4-(aminosulfonyl)phenyl]-αR-
[ (phenylmethoxy)carbonyl]aminno]-4-phenyloxazole-2- butanoic acid;
4-[4-(3-chloro-4-methoxyphenyl)-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide; 4-phenyl-2-(benzyloxymethyl)-5-(4- methylsulfonylphenyl)oxazole;
5-phenyl-2-(benzyloxymethyl)-4-(4- methylsulfonylphenyl)oxazole;
[4-(3-fluoro-4-methoxyphenyl)-5-(aminosulfonylphenyl)-2- oxazolyl]methanol;
4-[5-phenyl-2-methyl-4-oxazolyl]benzenesulfonamide;
4-[5-(4-brortcphenyl)-2-methyl-4- oxazolyl]benzenesulfonamide;
4-[5-(4-bromophenyl)-2-methoxymethyl-4- oxazolyl]benzenesulfonamide;
4-[2-methoxymethyl-5-phenyl-4- oxazolyl]benzenesulfonamide;
[5-(aminosulfonylphenyl)-4-phenyl-2-oxazolyl]-2-ethanol;
[5-(aminosulfonylphenyl)-4-phenyl-2-oxazolyl]-1-ethanol; 4-[4-(3-fluorophenyl)-2-methyl-5- oxazolyl]benzenesulfonamide;
4-[4-(4-chlorophenyl)-2-methoxymethyl-5- oxazolyl]benzenesulfonamide;
4-[4-(4-chlorophenyl)-2-methyl-5- oxazolyl]benzenesulfonamide;
[4-(phenyl)-5-(aminosulfonyllhenyl)-2-oxazolyl]-α,α- dimethylmezhanol;
4-[4-(4-fluorophenyl)-2-methyl-5- oxazolyl]benzenesulfonamide;
4-[4-(3-chlorophenyl)-2-methoxymethyl-5- oxazolyl]benzenesulfonamide;
4-[4-(3-chlorophenyl)-2-ethyl-5- oxazolyl]benzenesulfonamide;
[4-(3-chlorophenyl)-5-(ammosulfonylphenyl)-2-oxazolyl]-
2-methanol;
[4-(4-chlorophenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]-
2-methanol;
4-[5-(4-chlorophenyl)-2-methoxymethyl-4- oxazolyl]benzenesulfonamide;
4-[5-(3-chlorophenyl)-2-methoxymethyl-4- oxazolyl]benzenesulfonamide; 4-[5-(3-chlorophenyl)-2-ethyl-4- oxazolyl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-2-methoxymethyl-4- oxazolyl]benzenesulfonamide;
4-[4-phenyl-2-(1-methyl-2-pyrrolyl)-5- oxazolyl]benzenesulfonamide;
4-[4-phenyl-2-(methylcarbonylaminomethyl)-5- oxazolyl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-methyl-4- oxazolyl]benzenesulfonamide;
4-[4-(3,4-dichlorophenyl)-2-ethyl-5- oxazolyl]benzenesulfonamide;
[4-(3-chlorophenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]- α,α-dimethylmethanol;
[5-(3-chlororhenyl)-4-(aminosulfonylphenyl)-2-oxazolyl]- α,α-dimethylmethanol;
[4-(phenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]-2- propanol;
(R) 4-[4-phenyl-2-[2-(1-pyrrolyl)ethyl]-5- oxazolyl]benzenesulfonamide;
(S) 4-[4-phenyl-2-[2-(1-pyrrolyl)ethyl]-5- oxazolyl]benzenesulfonamide;
4-[4-phenyl-2-(2-pyrrolyl)-5- oxazolyl]benzenesulfonamide;
5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-pentanoic acid;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- butanoate;
5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-butanoic acid;
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]oxy]acetic acid;
5-[(4-aminosulfonyl)phenyl]-4-phenyl-β,β-dimethyloxazole- 2-butanoic acid;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- hexanoate; 5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-hexanoic acid;
diethyl [[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- yl]propyl]phosphonate;
[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- yl]propyl]phosphonic acid;
diethyl [[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- yl]methyl]phosphonate;
ethyl [[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- yl]methyl]phosphonate;
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]sulfonyl]propanoic acid;
methyl 3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]ethyl]thio]acetate;
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]ethyl]thio]acetic acid;
tert-butyl 3-[[[5-[4-aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]methyl]thio] acetate;
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyllthio]acetic acid;
5-[(4-aminosulfonyl)phenyl]-4-phenyl-β-methyloxazole-2- butanoic acid;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyl-β- methyloxazole-2-butanoate;
4-[2-cyanopentyl-4-phenyloxazol-5-yl]benzenesulfonamide;
4-[(2-tetrazolyl)pentyl-4-phenyloxazol-5- yl]benzenesulfonamide;
[[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]-1-pyrrol-2-yl]carboxylic acid;
methyl [[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]-1-pyrrol-2-yl]carboxylate;
[[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]-2- pyrrol-1-yl]acetic acid;
ethyl [[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]-2-pyrrol-1-yl]acetate;
methyl [[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]-1-pyrrolidin-2-yl] carboxylate; methyl [[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]propyl]aminosulfonyl]acetate;
5-[(4-aminosulfonyl)phenyl]-4-phenyl-βS-amino-oxazole-2- butanoic acid;
[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol-2- yl]ethyne;
4-[2-propargyl-4-phenyloxazol-5-yl]benzenesulfonamide;
[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol-2- yl]ethanamine;
4-[(1-piperidinyl)ethyl-4-phenyloxazol-5- yl]benzenesulfonamide;
4-[2-(1-pyrrolidinyl)methyl-4-phenyloxazol-5- yl]benzenesulfonamide;
4-[2-[bis(hydroxymethyl)methoxy]ethyl-4-phenyloxazol-5- yl]benzenesulfonamide;
methyl [5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)oxazole]-2-propanoate;
5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)oxazole-2-propanoic acid;
methyl [5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)oxazole]-2-butanoate;
5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)oxazole-2-butanoic acid;
methyl [5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)oxazole]-2-pentanoate;
5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)oxazole-2-pentanoic acid;
4-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)oxazole-2- pentanoic acid;
5-[(4-aminosulfonyl)phenyl]-4-(3,4-dichlorophenyl)-β,β- dimethyloxazole-2-butanoic acid;
4-[(4-methylsulfonyl)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoic acid;
4-[(4-aminosulfonyl)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoic acid;
5-[(4-aminosulfonyl)phenyl]-4-phenyl-αS-(1H-pyrrol-1- yl)oxazole-2-butanoic acid; 2-[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]ethan-2-one;
4-(2-ethenyl)-4-phenyl-oxazol-5-yl]benzenesulfonamide; 3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]thio]propanoic acid;
3-[[[4-[4-aminosulfonyl)phenyl]-5-phenyloxazol-2- yl]methyl]thio]propanoic acid;
4-[2-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol-2- yl]methyl]benzenepropanoic acid;
methyl 4-[2-[5-[(4-aminosulfonyl)phenyl]-4-phenyl- oxazol-2-yl]methyl]benzenepropynoic acid;
5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)oxazole-2- pentanoic acid;
-[2-ethyl-4-(3-fluorophenyl)oxazol-5- yl]benzenesulfonamide;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- pentanoate;
methyl 4-[(4-aminosulfonyl)phenyl]-5-(4- fluorophenyl)oxazole-2-pentanoate;
methyl 5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)-β,β-dimethyloxazole-2-butanoate;
methyl 4-[(4-methylsulfonyl)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoate;
methyl 4-[(4-aminosulfonyl)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoate;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyl-αS-(1H- pyrrol-1-yl)oxazole-2-butanoate;
tert butyl 3-[[[5-[4-aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]methyl]thio]propanoate;
tert butyl 3-[[[4-[4-aminosulfonyl)phenyl]-5- phenyloxazol-2-yl]methyl]thio]propanoate;
methyl 5-[(4-aminosulfonyl)phenyl]-4-(4- fluorophenyl)oxazole-2-pentanoate;
ethyl [4-(4-aminosulfonylphenyl)-5-(3-fluoro-4- methoxyphenyl)]-2-oxazoleacetate;
[4-(4-aminosulfonylphenyl)-5-cyclohexyl]-2-oxazoleacetic acid; [5-(4-aminosulfonylphenyl)-4-(4-chlorophenyl)]-2- oxazoleacetic acid;
[4-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)]-2- oxazoleacetic acid;
[4-(4-aminosulfonylphenyl)-5-(3-chloro-4-fluorophenyl)]-
2-oxazoleacetic acid;
[4-(4-aminosulfonylphenyl)-5-(3,4-dichlorophenyl)]-2 - oxazoleacetic acid;
[4-(4-aminosulfonylphenyl-5-(3,4-difluorophenyl)]-2- oxazoleacetic acid;
[5-(3,4-difluorophenyl)-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide;
[5-(4-aminosulfonylphenyl)-4-phenyl]-2-oxazolepropanoic acid;
4-[4-phenyl-5-oxazolyl]benzenesulfonamide;
4-[2-chloro-4-phenyl-5-oxazolyl]benzenesulfonamide;
4-[2-mercapto-4-phenyl-5-oxazolyl]benzenesulfonamide; 4-[2-(3-chlorophenoxy)-4-phenyl-5-
(oxazolyl]benzenesulfonamide;
5-(4-aminosulfonylphenyl)-4-phenyl-2- oxazolemercaptoacetic acid;
4-[4-phenyl-2-(2,2,2-trifluoroethoxy-5- oxazolyl]benzenesulfonamide;
4-[2-(methylthio)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide;
4-[2-methylsulfinyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-(methylsulfonyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-(2,3,4,5,6-pentafluorophenoxy)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-methoxy-4-phenyl-5-oxazolyl]benzenesulfonamide; ethyl 2-[[5-(4-aminosulfonylphenyl)-4-phenyl-2- oxazolyl]oxy]benzoate;
ethyl 3-[[5-(4-aminosulfonylphenyl)-4-phenyl-2- oxazolyl]oxy]benzoate; 4-[2-(N,N-dimethylamino)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide;
4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4- oxazolyl]benzenesulfonamide;
4-methyl-3-[5-phenyl-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide;
4-[4-(3-aminosulfonyl-4-methylphenyl)-2-trifluoromethyl- 5-oxazolyl]benzenesulfonamide;
4-methyl-3-[4-phenyl-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide;
4-[4-(N,N-dimethylamino)phenyl-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide;
[4-(4-aminosulfonylphenyl)-5-(3-fluoro-4- methoxyphenyl)]-2-oxazoleacetic acid;
4-[4-aminosulfonylphenyl)-5-(3-fluoro-4-methoxyphenyl)-
2-oxazolyi]α-bromoacetic acid;
4-(4-methylpnenyl)-5-(4-methylsulfonylphenyl)-2- trifluoromethyloxazole;
4-[5-(3-fluoro-4-methoxyphenyl)-2-methyl-4- oxazolyl]benzenesulfonamide;
5-(3-fluoro-4-methoxyphenyl)-4-(4-methylsulfonylphenyl)-
2-trifluoromethyloxazole;
4-[5-(3-bromo-4-methoxy-5-fluorophenyl)-2- trifluoromethyl-4-oxazolyl]benzenesulfonamide;
[5-(4-aminosulfonylphenyl)-4-phenyl]-2- oxazolecarboxamide;
4-[2-methoxymethyl-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(phenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-fluorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-fluorophenyl)-4- oxazolyl]benzenesulfonamide; 4-[2-benzyl-5-(4-fluorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,4-difluorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,5-difluorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,6-difluorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,4-difluorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,5-difluorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-chlorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-chlorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-chlorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,4-dichlorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,5-dichlorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,6-dichlorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,4-dichlorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl--5-(3,5-dichlorophenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,4-dimethoxyphenyl)-4- oxazolyl]benzenesulfonamide; 4-[2-benzyl-5-(2,5-dimethoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,6-dimethoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,4-dimethoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,5-dimethoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,4-dimethylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,5-dimethylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2,6-dimethylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,4-dimethylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,5-dimethylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-chloro-4-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-chloro-4-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-chloro-2-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-chloro-6-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-chloro-2-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-chloro-3-methylphenyl)-4- oxazolyl]benzenesulfonamide; 4-[2-benzyl-5-(2-chloro-4-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-chloro-4-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-chloro-2-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-chloro-6-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-chloro-2-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-3-(4-chloro-3-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3,5-dichloro-4-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-fluoro-4-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-fluoro-4-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-fluoro-2-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-fluoro-6-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-fluoro-2-methyl3henyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-fluoro-3-methylphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-fluoro-4-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-fluoro-4-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-fluoro-2-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-fluoro-6-methoxyphenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(4-fluoro-2-methoxyphenyl)-4- oxazolyl]benzenesulfonamide; 4- [2 -benzyl-5- ( 2 -thienyl ) -4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(5-chloro-2-thienyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(yl)-4-oxazolyl]benzenesulfonamide; 4-[2-benzyl-5-(1-cyclohexenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(2-cyclohexenyl)-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-5-(3-cyclohexenyl)-4- oxazolyl]benzenesulfonamide;
2-benzyl-4-(4-methylsulfonylphenyl)-5-phenyloxazole; 2-benzyl-4-(4-methylsulfonylphenyl)-5-(2- fluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3- fluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,4- difluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,5- difluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,6- difluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3,4- difluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3,5- difluorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2- chlorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3- chlorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(4- chlorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,4- dichlorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2,5- dichlorophenyl)oxazole; 2-benzyl-4-(4-methylsulfonylphenyl)-5- (2,6- dichlorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (3,4- dichlorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl -5- 3,5- dichlorophenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (2- methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl
methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- 4- methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl -5- 2,4- dimethoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (2,5- dimethoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (2,6- dimethoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylpheny)-5- (3 ,4- dimethoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (3,5- dimethoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- 4- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (2,4- dimethylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (2,5- dimethylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (2,6- dimethylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (3,4- dimethylphenyl)oxazole; 2-benzyl-4-(4-methylsulfonylphenyl)-5- (3,5- dimethylpnenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (2-chloro-4- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (3 chloro-4- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (3-chloro-2- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (2-chloro-6- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (4-chloro-2- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (4-chloro-3- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (2-chloro-4- methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (3-chloro-4- methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (3-chloro-2- methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (2-chloro-6- methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (4-chloro-2- methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (4-chloro-3- methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (3,5-dichloro-
4-methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (2-fluoro-4- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (3-fluoro-4- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- 3-fluoro-2- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (2-fluoro-6- methylphenyl)oxazole; 2-benzyl-4-(4-methylsulfonylphenyl)-5-(4-fluoro-2- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(4-fluoro-3- methylphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-fluoro-4- methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-fluoro-4- methoxyphenyl )oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3-fluoro-2- methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2-fluoro-6- methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(4-fluoro-2- methoxyphenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2- thienyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(5-chloro-2- thienyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5- (cyclohexyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(1- cyclohexenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(2- cyclohexenyl)oxazole;
2-benzyl-4-(4-methylsulfonylphenyl)-5-(3- cyclohexenyl)oxazole;
2-(ethyl)-4-(4-methylsulfonylphenyl)-5- phenyloxazole;
2-(trifluoromethyl)-4-(4-methylsulfonylphenyl)-5- phenyloxazole;
2-(difluoromethyl)-4-(4-methylsulfonylphenyl)-5- phenyloxazo;e;
2-(hydroxymethyl)-4-(4-methylsulfonylphenyl)-5- phenyloxazole;
[4-(4-methylsulfonylphenyl)-5-phenyl]-2- oxazolecarboxylic acid; methyl [4-( 4 -methylsulfonylphenyl)-5-phenyl]-2- oxazolecarboxylate;
ethyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2- oxazolecarboxylate;
2-(propyl)-4-(4-methylsulfonylphenyl)-5- phenyloxazole;
2-(benzyl)-4-(4-methylsulfonylphenyl)-5- phenyloxazole;
2-(phenylthiomethyl)-4-(4-methylsulfonylphenyl)-5- phenyloxazole;
2-(phenoxymethyl)-4-(4-methylsulfonylphenyl)-5- phenyloxazole;
2-((4-chlorqphenoxy)methyl)-4-(4- methylsulfonylphenyl)-5-phenyloxazole;
2-((3-chlorophenoxy)methyl)-4-(4- methylsulfonylphenyl)-5-phenyloxazole;
2-((2-chlorophenoxy)methyl)-4-(4- methylsulfonylphenyl)-5-phenyloxazole;
2-((4-fluorophenoxy)methyl)-4-(4- methylsulfonylphenyl)-5-phenyloxazole;
2-((3-fluorophenoxy)methyl)-4-(4- methylsulfonylphenyl)-5-phenyloxazole;
2-((2-fluorophenoxy)methyl)-4-(4- methylsulfonylphenyl)-5-phenyloxazole;
2-((4-carboxyphenoxy)methyl)-4-(4- methylsulfonylphenyl)-5-phenyloxazole;
2-((3-carboxyphenoxy)methyl)-4-(4- methylsulfonylphenyl)-5-phenyloxazole;
2-((2-carboxyphenoxy)methyl)-4-(4- methylsulfonylphenyl)-5-phenyloxazole;
2-(2-phenethyl)-4-(4-methylsulfonylphenyl)-5- phenyloxazole;
2-(3-phenyIpropyl)-4-(4-methylsulfonylphenyl)-5- phenyloxazole;
[4-(4-methylsulfonylphenyl)-5-phenyl]-2- oxazoleacetic acid; ethyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2- oxazoleacetate;
methyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2- oxazoleacetate;
[4-(4-methylsulfonylphenyl)-5-phenyl]-2- oxazolepropanoic acid;
ethyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2- oxazolepropanoate;
methyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2- oxazolepropanoate;
[4-(4-methylsulfonylphenyl)-5-phenyl]-2- oxazolebutanoic acid;
ethyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2- oxazolebutanoate;
methyl [4-(4-methylsulfonylphenyl)-5-phenyl]-2- oxazolebutanoate;
2-(2-quinolyloxymethyl)-4-(4-methylsulfonylphenyl)-
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;
[4-(4-aminosulfonylphenyl)-5-phenyl]-2- oxazolecarboxylic acid;
methyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2 - oxazolecarboxylate;
ethyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2- oxazolecarboxylate;
4-[2-(propyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-(benzyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-(phenythiomethyl )-5-phenyl-4- oxazolyl]benzenesulfonamide; 4-[2-(phenoxymethyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-((4-chlorophenoxy)methyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-((3-chlorophenoxy)methyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-((2-chlorophenoxy)methyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-((4-fluorophenoxy)methyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-((3-fluorophenoxy)methyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-((2-fluorophenoxy)methyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-((4-carboxyphenoxy)methyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-((3-carboxyphenoxy)methyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-((2-carboxyphenoxy)methyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-(2-phenylethyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-(3-phenyIpropyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
[4-(4-aminosulfonylphenyl)-5-phenyl]-2-oxazoleacetic acid;
methyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2- oxazoleacetate;
ethyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2- oxazoleacetate;
[4-(4-aminosulfonylphenyl)-5-phenyl]-2- oxazolepropanoic acid;
methyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2- oxazolepropanoate;
ethyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2- oxazolepropanoate; [4-(4-aminosulfonylphenyl)-5-phenyl]-2- oxazolebutanoic acid;
methyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2- oxazolebutanoate;
ethyl [4-(4-aminosulfonylphenyl)-5-phenyl]-2- oxazolebutanoate;
4-[2-(2-quinolyloxymethyl)-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-phenyl-5-oxazolyl]benzenesulfonamide; 4-[2-benzyl-4-(2-fluorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-fluorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-fluorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,4-difluorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,5-difluorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,6-difluorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,4-difluorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,5-difluorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-chlorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-chlorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-chlorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,4-dichlorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,5-dichlorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,6-dichlorophenyl)-5- oxazolyl]benzenesulfonamide; 4-[2-benzyl-4-(3,4-dichlorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,5-dichlorophenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,4-dimethoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,5-dimethoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,6-dimethoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,4-dimethoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,5-dimethoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-1-(2,4-dimethylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,5-dimethylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2,6-dimethylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,4-dimethylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,5-dimethylphenyl)-5- oxazolyl]benzenesulfonamide; 4-[2-benzyl-4-(2-chloro-4-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-chloro-4-methylphenyl)-5- oxazolyl]be nzenesulfonamide;
4-[2-benzyl-4-(3-chloro-2-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-bebzyl-4-(2-chloro-6-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-chloro-2-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-chloro-3-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-chloro-4-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-chloro-4-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-chloro-2-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-chloro-6-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-chloro-2-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-chloro-3-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3,5-dichloro-4-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-fluoro-4-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-fluoro-4-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-fluoro-2-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-fluoro-6-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(4-fluoro-2-methylphenyl)-5- oxazolyl]benzenesulfonamide; 4-[2-benzyl-4-(4-fluoro-3-methylphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-fluoro-4-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-fluoro-4-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-fluoro-2-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-fluoro-6-methoxyphenyl)-5- oxazolyl]be nzenesulfonamide;
4-[2-benzyl-4-(4-fluoro-2-methoxyphenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-thienyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(5-chloro-2-thienyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(cyclohexyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(1-cyclohexenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(2-cyclohexenyl)-5- oxazolyl]benzenesulfonamide;
4-[2-benzyl-4-(3-cyclohexenyl)-5- oxazolyl]benzenesulfonamide;
2-benzyl-5-(4-methylsulfonylphenyl)-4-phenyloxazole; 2-benzyl-5-(4-methylsulfonylphenyl)-4-(2- fluorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3- fluorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,4- difluorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,5- difluorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,6- difluorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,4- difluorophenyl)oxazole; 2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,5- difluorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2- chlorophenyl)-4-oxazolyl]benzenesulfonamide; 2-benzyl-5-(4-methylsulfonylphenyl)-4-(3- chlorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4- chlorophenyl)-4-oxazolyl]benzenesulfonamide; 2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,4- dichlorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,5- dichlorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,6- dichlorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,4- dichlorop'isnyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,5- dichlorophenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2- methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3- methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4- methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,4- dimethoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,5- dimethoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,6- dimethoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,4- dimethoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,5- dimethoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2- methylphenyl)oxazole; 2-benzyl-5-(4-methylsulfonylphenyl)-4-(3- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,4- dimethylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,5- dimethylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2,6- dimethylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,4- dimethylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,5- dimethylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-chloro-4- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-chloro-4- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-chloro-2- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-chloro-6- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-chloro-2- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-chloro-3- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-chloro-4- methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-chloro-4- methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-chloro-2- methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-chloro-6- methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-chloro-2- methoxyphenyl)oxazole; 2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-chloro-3- methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3,5-dichloro- 4-methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-fluoro-4- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-fluoro-4- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-fluoro-2- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-fluoro-6- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-fluoro-2- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-fluoro-3- methylphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-fluoro-4- methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-fluoro-4- methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(3-fluoro-2- methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2-fluoro-6- methoxyphenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(4-fluoro-2- methoxyphenyl)oxazole;
2-benzyl-5-(1-methylsulfonylphenyl)-4-(2- thienyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(5-chloro-2- thienyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-
(cyclohexyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(1- cyclohexenyl)oxazole;
2-benzyl-5-(4-methylsulfonylphenyl)-4-(2- cyclohexenyl)oxazole; 2-benzyl-5-(4-methylsulfonylphenyl)-4-(3- cyclohexenyl)oxazole;
2-(ethyl)-5-(4-methylsulfonylphenyl)-4- phenyloxazole;
2-(trifluoromethyl)-5-(4-methylsulfonylphenyl)-4- phenyloxazole;
2-(difluoromethyl)-5-(4-methylsulfonylphenyl)-4- phenyloxazole;
2-(hydroxymethyl)-5-(4-methylsulfonylphenyl)-4- phenyloxazole;
[5-(4-methylsulfonylphenyl)-4-phenyl]-2- oxazolecarboxylic acid;
methyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2 - oxazolecarboxylate;
ethyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2- oxazolecarboxylate;
2-(propyl)-5-(4-methylsulfonylphenyl)-4- phenyloxazole;
2-(benzyl)-5-(4-methylsulfonylphenyl)-4- phenyloxazole;
2-(phenylthiomethyl)-5-(4-methylsulfonylphenyl)-4- phenyloxazole;
2-(phenoxymethyl)-5-(4-methylsulfonylphenyl)-4- phenyloxazole;
2-((4-chlorophenoxy)methyl)-5-(4- methylsulfonylphenyl)-4-phenyloxazole;
2-((3-chlorophenoxy)methyl)-5-(4- methylsulfonylphenyl)-4-phenyloxazole;
2-((2-chlorophenoxy)methyl)-5-(4- methylsulfonylphenyl)-4-phenyloxazole;
2-((4-fluorophenoxy)methyl)-5-(4- methylsulfonylphenyl)-4-phenyloxazole;
2-((3-fluorophenoxy)methyl)-5-(4- methylsulfonylphenyl)-4-phenyloxazole;
2-((2-fluorophenoxy)methyl)-5-(4- methylsulfonylphenyl)-4-phenyloxazole; 2-((4-carboxyphenoxy)methyl)-5-(4- methylsulfonylphenyl)-4-phenyloxazole;
2-((3-carboxyphenoxy)methyl)-5-(4- methylsulfonylphenyl)-4-phenyloxazole;
2-((2-carboxyphenoxy)methyl)-5-(4- methylsulfonylphenyl)-4-phenyloxazole;
2-(2-phenethyl)-5-(4-methylsulfonylphenyl)-4- phenyloxazole;
2-(3-phenylpropyl)-5-(4-methylsulfonylphenyl)-4- phenyloxazole;
[5-(4-methylsulfonylphenyl)-4-phenyl]-2- oxazoleaceoxic acid;
ethyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2- oxazoleacetate;
methyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2- oxazoleacetate;
[5-(4-methylsulfonylphenyl)-4-phenyl]-2- oxazolepropanoic acid;
ethyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2 - oxazolepropanoate;
methyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2- oxazolepropanoate;
[5-(4-methylsulfonylphenyl)-4-phenyl]-2- oxazolebutanoic acid;
ethyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2- oxazolebutanoate;
methyl [5-(4-methylsulfonylphenyl)-4-phenyl]-2- oxazolebutanoate;
2-(2-quinolyloxymethyl)-5-(4-methylsulfonylphenyl)- 4-phenyloxazole;
4-[2-(ethyl)-4-phenyl-5-oxazolyl]benzenesulfonamide; 4-[2-(trifluoromethyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-(difluoromethyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-(hydroxymethyl)-4-phenyl-5- oxazolyl]benzenesulfonamide; [5-(4-aminosulfonylphenyl)-4-phenyl]-2- oxazolecarboxylic acid;
methyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2- oxazolecarboxylate;
ethyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2- oxazolecarboxylate;
4-[2 -(propyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-(benzyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-(phenylthiomethyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-(phenoxymethyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-((4-chlorophenoxy)methyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-((3-chlorophenory)methyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-((2-chlorophenoxy)methyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-((4-fluorophenoxy)methyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-((3-fluorophenoxy)methyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-((2-fluorophenoxy)methyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-((4-carboxyphenoxy)methyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-((3-carboxyphenoxy)methyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-((2-carboxyphenoxy)methyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-(2-phenethyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-(3-phenyIpropyl)-4-phenyl-5- oxazolyl]benzenesulfonamide; [5-(4-aminosulfonylphenyl)-4-phenyl]-2-oxazoleacetic acid;
methyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2- oxazoleacetate;
ethyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2- oxazoleacetate;
[5-(4-aminosulfonylphenyl)-4-phenyl]-2- oxazolepropanoic acid;
methyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2- oxazolepropanoate;
ethyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2- oxazolepropanoate;
[5-(4-aminosulfonylphenyl)-4-phenyl]-2- oxazolebutanoic acid;
methyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2- oxazolebutanoate;
ethyl [5-(4-aminosulfonylphenyl)-4-phenyl]-2- oxazolebutanoate;
4-[2-(2-quinolyloxymethyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
5-(4-fluorophenyl)-2-methyl-4-[4-
(methylsulfonyl)phenyl]oxazole;
3-[5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]]-
2-oxazolepropanoic acid;
methyl 3-[5-(4-fluorophenyl)-4-[4-
(methylsulfonyl)phenyl]]-2-oxazolepropanoate;
4-(4-fluorophenyl)-2-(2-phenylethyl)-5-(4-
(methylsulfonyl)phenyl)oxazole;
4-(4-fluorophenyl)-2-methyl-5-[4- (methylsulfonyl)phenyl]oxazole;
4-(4-flzorophenyl)-5-[4-(methylsulfonyl)phenyl]-2- phenyloxazole;
2-benzyl-4-(4-fluorophenyl)-5-(4-
(methylsulfonyl)phenyl)oxazole;
4-(4-fluorophenyl)-5-[4-methylsulfonylphenyl]-2-(3- phenylpropyl)oxazole; 4-(4-fluorophenyl)-5-[4-methylsulfonylphenyl]-2- propyloxazole;
2-(tert-butyl)-4-(4-fluorophenyl)-5-[4- methylsulfonylphenyl]oxazole;
4-(4-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-5-[4- methylsulfonylphenyl]oxazole
4-(4-fluorophenyl)-2-[(3-methoxyphenyl)methyl]-5-[4- methylsulfonylphenyl]oxazole;
2-(diphenylmethyl)-4-(4-fluorophenyl)-5-[4- methylsulfonylphenyl]oxazole;
2-[4-(4-fluorophenyl)-5-[4-methylsulfonylphenyl]]-2- oxazoleacetic acid;
ethyl 2-[4-(4-fluorophenyl)-5-[4- methylsulfonylphenyl]]-2-oxazoleacetate;
3-[4-(4-fluorophenyl)-5-[4-methylsulfonylphenyl]]-2- oxazolepropanoic acid;
methyl 3-[4-(4-fluorophenyl)-5-[4- methylsulfonylphenyl]]-2-oxazolepropanoate;
4-[4-(4-fluorophenyl)-5-[4-methylsulfonylphenyl]]-2- oxazolebutanoic acid;
methyl 4-[4-(4-fluorophenyl)-5-[4- methylsulfonylphenyl]]-2-oxazolebutanoate;
3-[4-(4-fluorophenyl)-5-[4-methylsulfonylphenyl]]-2- oxazolepropanamide;
4-(4-fluorophenyl)-2-(cyclohexylethyl)-5-[4-
(methylsulfonyl)phenyl]oxazole;
4-(4-fluorophenyl)-2-(3-fluorophenoxymethyl)-5-[4-
(methylsuifonyl)phenyl]oxazole;
4-(4-fluorophenyl)-2-(3-chlorophenoxymethyl)-5-[4- (methylsulfonyl)phenyl]oxazole;
4-(4-fluorophenyl)-2-(pyridyloxymethyl)-5-[4-
(methylsulfonyl)phenyl]oxazole;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2- phenoxymethyloxazole;
4-(4-fluorophenyl)-2-(2-hydroxyethyl)-5-[4-
(methylsulfonyl)phenyl]oxazole; 4-(4-fluorophenyl)-2-(hydroxymethyl)-5-[4-
(methylsulfonyl)phenyl]oxazole;
4-(cyclohexyl)-2-phenyl-5-[4-
(methylsulf onyl)phenyl]oxazole;
4-(4-fluorophenyl)-2-benzyloxymethyl-5-[4-
(methylsulfonyl)phenyl]oxazole;
4-(4-fluorophenyl)-2-cyclohexyl-5-[4-
(methylsulfonyl)phenyl]oxazole;
5-(4-fluorophenyl)-2-phenyl-4-[4- (methylsulfonyl)phenyl]oxazole;
[5-(3,4-dichlorophenyl)-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide;
4-[4-(3-aminosulfonyl-5-fluoro-4-methoxyphenyl)-2- trifluoromethyl-5-oxazolyl]benzenesulfonamide;
4-(3-fluoro-4-methoxyphenyl)-5-(4-methylsulfonylphenyl)-
2-trifluoromethyloxazole;
4-[4-(4-bromophenyl)-2-methyl-5- oxazolyl]oenzenesulfonamide;
5-fluoro-4-methoxy-3-[5-phenyl-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide;
4-[4-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide;
ethyl 4-[[5-(4-aminosulfonylphenyl)-4-phenyl-2- oxazolyl]oxy]benzoate; and
4-[5-(3-chloro-4-fluorophenyl)-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide.
The term "hydrido" 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. Where the term "alkyl" is used, either alone 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. 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 "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. Examples of such radicals include ethenyl, n-propenyl, butenyl, and the like. The term "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. 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. 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 1-6 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 term "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. The term "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. The terms "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 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 dialkoxyalkyl radicals.
The "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. The term "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. The terms "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. Examples of 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.]. Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, oxazolinyl, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed "heteroaryl" radicals 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. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; 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, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. 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. Examples of such fused bicyclic radicals 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. The term "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. The terms benzyl and phenylmethyl are interchangeable. The term "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. The term "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. The term "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. The term "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. The term "heteroaryloxyalkyl" embraces alkyl radicals having one or more heteroaryloxy radicals attached to the alkyl radical, that is, to form
monoheteroaryloxyalkyl and diheteroaryloxyalkyl radicals. The "heteroaryloxy" radicals may be further substituted on the heteroaryl ring portion of the radical. The term
"arylthio" embraces radicals containing an aryl radical, as described above, attached to a divalent sulfur atom, such as a phenylthio radical. The term "arylthioalkyl" embraces alkyl radicals substituted with one or more arylthio radicals, as described above. The term "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. The term
"cycloalkylalkyl" embraces alkyl radicals substituted with cycloalkyl radicals having three to ten carbon atoms, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, eyelohexyIpropyl and cycloheptylmethyl. The term "cycloalkenyl" embraces unsaturated radicals having three to ten carbon atoms, such as cylopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO2-. "Alkylsulfonyl" embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. The "alkylsulfonyl" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide
haloalkylsulfonyl radicals. The term "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. Examples of such lower alkylsulfinyl radicals include methylsulfinyl,
ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term "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 alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The terms "sulfamyl", "aminosulfonyl" and "sulfonamidyl" denote a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO2NH2). 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 terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -CO2H. The term "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. 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, pi valoyl, hexanoyl, and radicals formed from succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, mandelic, pantothenic, β-hydroxybutyric, galactaric and galacturonic acids. The term "aroyl" embraces aryl
radicals with a carbonyl radical as defined below.
Examples of aroyl include benzoyl, naphthoyl, phenylacetyl, and the like, and the aryl in said aroyl may be
additionally substituted, such as in p-hydroxybenzoyl, and salicylyl. The term "carboxyalkylthio" embraces
carboxyalkyl radicals as defined above, connected to a divalent sulfur atom. The term "alkoxycarbonyl" means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a "carbonyl" (-C=O) radical. Examples of such "alkoxycarbonyl" ester radicals include substituted or unsubstituted methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and
hexyloxycarbonyl. The term "alkoxycarbonylalkyl" embraces alkyl radicals having one or more alkoxycarbonyl radicals attached to the alkyl radical. The term "phosphonylalkyl" describes alkyl radicals substituted with phosphonic acid residues or esters thereof. The term "aminoalkyl" embraces alkyl radicals substituted with amino radicals. More preferred are "lower aminoalkyl" radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like. The term "aminocarbonyl" embraces radicals having an amino radical radicals attached to a carbonyl radical forming -C(O)NH2. The term "aminocarbonylalkyl" embraces alkyl radicals having one or more aminocarbonyl radicals attached to the alkyl radical. The term
"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. The term "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, β-alanine, and γ-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 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 having 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.
Also included in the family of compounds of Formula I are the pharmaceutically-acceptable salts thereof. The term "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 hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate 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, β
-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, 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 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.
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 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.
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 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.
Additional methods for resolving optical isomers, known to those skilled in the art may be used, for example, those discussed by J. Jaques et al in Enantiomers,
Racemates, and Resolutions, John Wiley and Sons, New York (1981).
GENERAL SYNTHETIC PROCEDURES
The compounds of the invention can be synthesized according to the following procedures of Schemes I-XI, wherein the R-R8 substituents are as defined for Formula I-III, above, except where further noted.
Figure imgf000058_0001
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 R2 is alkyl. In step one, benzaldehyde 1 and substituted acetic acid 2 are first heated in acetic anhydride and triethylamine via a Perkin condensation. In step two, hydrolysis produces the corresponding 2,3- disubstituted acrylic acids 3. In 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. In 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 HCl , provides the substituted ketone 4 intermediates.
Figure imgf000059_0001
Synthetic Scheme II shows an alternative approach which can be used to prepare substituted ketone
intermediates 7, isomers of 4 where R2 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.
Other synthetic approaches are possible to form the desired ketones. These alternatives include reacting appropriate Grignard or lithium reagents with
substituted acetic acids or corresponding esters.
Figure imgf000060_0001
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 tert-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. Reaction of the benzoin 10 with the appropriate acid chloride in the presence of base, such as pyridine, gives the benzoin esters 11 which may be converted to the antiinflammatory oxazoles 12 of the present invention upon treatment with ammonium acetate in acetic acid at reflux.
Figure imgf000061_0001
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. Reaction of the benzoin 15 with the appropriate acid chloride in the presence of base, such as pyridine, gives the benzoin esters 16 which may be converted to the antiinflammatory oxazoles 17 of the present invention upon treatment with ammonium acetate in acetic acid at reflux.
Figure imgf000062_0001
Scheme V shows the four step synthesis which can be used to prepare oxazoles 20 from ketones 4 (prepared in Synthetic Scheme I). In step one, ketones 4 are readily brominated via the addition of bromine in acetic acid to form the 2-bromoethanone intermediates. In step two, reaction of the bromoethanone with aqueous acetone yields the benzoin 18. In step three, reaction of the benzoin 18 with the appropriate acid chloride in the presence of base, such as pyridine, gives the benzoin esters 19. In step four, benzoin esters 19 are converted to the oxazoles 20 upon treatment with ammonium acetate in acetic acid at reflux.
Figure imgf000063_0001
Similarly, Scheme VI shows the four step synthesis which can be used to prepare oxazoles 23 from ketones 7 (prepared in Synthetic Scheme II). In step one, ketones 7 are readily brominated via the addition of bromine in acetic acid to form the 2-bromoethanone intermediates. In step two, reaction of the bromoethanone with aqueous acetone yields the benzoin 21. In step three, reaction of the benzoin 21 with the appropriate acid chloride in the presence of base, such as pyridine, gives the benzoin esters 22. In step four, benzoin esters 22 are converted to the oxazoles 23 upon treatment with ammonium acetate in acetic acid at reflux.
Figure imgf000064_0001
An alternative synthesis of the
alkylsulfonylphenyloxazoles 12 and 17 is accomplished as shown in Synthetic Scheme VII from oxazoles 20 and 23 (prepared in Schemes V and VI). Oxazoles 20 and 23, where R2 is an alkyl radical, are oxidized, such as with MCPBA (2 equivalents) in methylene chloride to form the
antiinflammatory alkylsulfonyl oxazoles 12 and 17. Other suitable oxidizing agents include Oxone®, hydrogen
peroxide, periodate, peracetic acid and the like.
Figure imgf000065_0001
In a method similar to that shown in Scheme IV, Scheme VIII shows a method for preparing oxazoles 28 where Ar1 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 Ar1-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. Addition of ammonium acetate to the benzoin ester 26 yields the oxazole 28. Alternatively, the hydroxy-oxazoline 27 is isolated. Dehydration of the hydroxy-oxazoline 27 yields the oxazoles 28. By reversing the positions of R1 and Ar1 in the keto-enol 25, oxazoles can be prepared with R1 is at position 4.
Figure imgf000066_0001
Synthetic Scheme VIII shows the three step procedure used to prepare sulfonamide antiinflammatory agents 30 from their corresponding methyl sulfones 29. In step one, a THF solution of the methyl sulfones 29 at about -78°C is treated with an alkyllithium reagent, e.g., methyllithium, n-butyllithium, etc. In step two, the anions generated in step one are treated with an organoborane, e.g.,
triethylborane, tributylborane, etc., at about -78°C then allowed to warm to ambient temperature prior to stirring at reflux. In step three, an aqueous solution of sodium acetate and hydroxyamine-O-sulfonic acid is added to provide the corresponding sulfonamide antiinflammatory agents 30 of this invention.
Figure imgf000066_0002
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. In addition, disulfonamides can be formed by substitution on R1 where R1 is aryl or
heteroaryl.
Figure imgf000067_0001
Synthetic Scheme XI shows the five step procedure which can be used to prepare the substituted
oxazolebenzenesulfonamide 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. In 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. In Step 4, the bromoketone 37 is added to an acid and potassium carbonate in dimethylacetamide to give the desired crude α-acyloxy ketone 38. In 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.
The following examples contain detailed descriptions of the methods of preparation of compounds of Formula 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.
The following abbreviations are used:
EtOAc - ethyl acetate
NaOAc - sodium acetate
NaH - sodium hydride
NH4OAC - ammoniuum acetate
HCl - hydrochloric acid
DMSO - dimethylsulfoxide
DMSOd6 - deuterated dimethylsulfoxide
CHCl3 - chloroform
CD3OD - deuterated methanol
MgSO4 - magnesium sulfate
NaHCO3 - sodium bicarbonate
Na2SO4 - sodium sulfate
DMF - dimethylformamide
CH3CN - acetonitrile
Cul - copper iodide
NaOH - sodium hydroxide Pd/C - palladium on carbon
HBr - hydrobromic acid
K2CO3 - potassium carbonate
MeOH - methanol
EtOH - ethanol
LiOH - lithium hydroxide
CH2Cl2 - methylene chloride/dichloromethane
DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene
h - hour
min - minutes
THF - tetrahydrofuran
HRMS - high resolution mass spectrum
Figure imgf000069_0001
4-(4-Fluorophenyl)-2-(2-phenylethyl)-5-(4- (methylsulfonyl)phenyl)oxazole
Step 1: Preparation of 1-(4-fluorophenyl)-2-hydroxy-2- (metethylsulfonyl)phenyl)ethanone
A suspension of 2.03 g sodium hydride in 125 mL tetrahydrofuran (THF) was stirred at 0°C under a
nitrogen atmosphere as a solution containing 20.0 g of 1-(4-fluorophenyl)-2-[4-(methylthio)phenyl]ethanone, as prepared in U.S. Patent No. 3,647,858, in 100 mL of THF was added dropwise over 30 minutes. The reaction was allowed to warm to 25ºC for 18 hours. A solution containing 12.7 g (84.5 mmol) of tert-butyl- dimethylsilyl chloride (DBSCL) in 20 mL THF was added over 5 minutes and the resulting solution stirred at 25°C for 18 hours. The reaction was quenched by pouring into aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the combined organic extracts dried over sodium sulfate. Concentration in vacuo provides a yellow oil, which solidified on standing to give 27.9 g of the silyl enol ether. NMR spectra was consistent with the assigned structure. The silyl enol ether was used without further purification.
A solution containing 27.9 g of the silyl enol ether in 500 mL methylene chloride (CH2Cl2) was cooled to 0°C under a nitrogen atmosphere while being stirred mechanically. 77.1g of m-chloroperoxybenzoic acid (technical grade, 50-60%) was added and the reaction was stirred at 0°C for 2 hours and allowed to warm to 25ºC over 1 hour. The reaction mixture was washed with an aqueous solution of sodium metabisulfite, followed by aqueous sodium bicarbonate. The organic solution was dried over sodium sulfate and concentrated in vacuo to give 24.5 g of 1-(4-fluorophenyl)-2-tert- butyldimethylsilyloxy-2-[4-
(methylsulfonyl)phenyl]ethanone. NMR spectra were consistent with the assigned structure. This material was used without further purification.
The benzoin silyl ether was dissolved in 100 mL of 90% aqueous trifluoroacetic acid and stirred at 25ºC 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. Concentration in vacuo provided an oily solid, which was recrystallized from 50% ethyl
acetate/isooctane to give 15.5 g of a crystalline white solid (mp 122-123ºC) whose structure was assigned as 1- (4-fluorophenyl)-2-hydroxy-2- (methylsulfonyl)phenyl)ethanone on the basis of its spectral properties.
The isomeric benzoin, 2-(4-fluorophenyl)-2-hydroxy- 1-(4-(methylsulfonyl)phenyl)ethanone, was prepared analogously from 2-(4-fluorophenyl)-1-[4- (methylthio)phenyl ethanone.
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 (CH2CI2) was stirred at 25ºC as 6.60 mL of pyridine was added, followed by 3.61 mL of hydrocinnamoyl chloride.
The reaction was stirred at 25ºC for 48 hours, after which the organic solution was washed with 1N HCl, dried over sodium sulfate and concentrated in vacuo to give an oily solid. This material was recrystallized from 50% ethyl acetate/isooctane to give 4.40 g of a beige crystalline solid (mp 152-153.5ºC). NMR spectra were consistent with the assigned structure of 1-(4- fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-2-(2- phenyl)propionyloxy ethanone. This material was dissolved in 100 mL of glacial acetic acid and 7.70 g of ammonium acetate was added. The reaction was heated to reflux with stirring for 1.5 hours, after which it was cooled to room temperature and poured into 100 mL of water. The product was extracted with ethyl acetate and the combined organic extracts washed with aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo to give an oily solid which was recrystallized from 50% ethyl acetate/isooctane to give 3.55 g of 4-(4- fluorophenyl)-2-(2-phenylethyl)-5-(4-(methylsulfonyl) phenyl) oxazole as a white crystalline solid (mp 117- 118ºC). NMR spectra was consistent with the assigned structure.
Figure imgf000072_0001
4-(4-Fluorophenyl)-2-methyl-5-[4- (methylsulfonyl)phenyl]oxazole
4-(4-Fluorophenyl)-2-methyl-5-[4- (methylsulfonyl)phenyl]oxazole was prepared in an analogous manner to that shown in Example 1. Melting point: 158-159 °C.
Figure imgf000072_0002
4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
2-phenyloxazole 4-(4-Fluorophenyl)-5-[4-(methylsulfonyl) phenyl]-2- phenyloxazole was prepared in a manner analogous to Example 1. Melting point: 204-205ºC.
Figure imgf000073_0001
2-Benzyl-4-(4-fluorophenyl)-5-(4- (methylsulfonyl)phenyloxazole
2-Benzyl-4-(4-fluorophenyl)-5-(4- (methylsulfonyl)phenyloxazole was prepared in a manner analogous to Example 1. The m/z 408 (M+H)+ was
consistent with the assigned structure.
Figure imgf000073_0002
4-(4-Fluorophenyl)-5-[4-methylsulfonylphenyl]-2- (3-phenylpropyl)oxazole 4-(4-Fluorophenyl)-5-[4-methylsulfonyl phenyl]-2- (3-phenylpropyl)oxazole was prepared in a manner analogous to Example 1. The m/z 436 (M+H)+ was
consistent with the assigned structure.
Figure imgf000074_0001
4-(4-Fluorophenyl)-5-[4-methylsulfonylphenyl]-2- propyloxazole
4-(4-Fluorophenyl)-5-[4-methylsulfonyl phenyl]-2- propyloxazole was prepared in a manner analogous to Example 1. The m/z 360 (M+H)+ was consistent with the assigned structure.
Figure imgf000074_0002
2-(tert-Butyl)-4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]oxazole
2-(Tert-butyl)-4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]oxazole was prepared in a manner analogous to Example 1. Melting point: 130-131ºC.
Figure imgf000075_0002
4-(4-Fluorophenyl)-2-(4-methoxyphenyl)methyl-5-
[4-methylsulfonylphenyl]oxazole
4-(4-Fluorophenyl)-2-(4-methoxyphenyl)methyl-5-[4- methylsulfonylphenyl]oxazole was prepared in a manner analogous to Example 1. Melting point: 123-124ºC.
Figure imgf000075_0001
4 -(4-Fluorophenyl)-2-(3-methoxyphenyl)methyl-5- [4-methylsulfonylphenyl]oxazole
4-(4-Fluorophenyl)-2-(3-methoxyphenyl)methyl-5-[4- methylsulfonylphenyl]oxazole was prepared in a manner analogous to Example 1. The m/z 437 (M+H)+ was
consistent with the assigned structure.
Figure imgf000076_0001
2-Diphenylmethyl-4-(4-fluorophenyl)-5-[4- methylsulfonylphenyl]oxazole
2-Diphenylmethyl-4-(4-fluorophenyl)-5-[4- methylsulfonylphenyl]oxazole was prepared in a manner analogous to Example 1. Melting point: 155-156ºC.
Figure imgf000076_0002
Ethyl 2-[4-(4-fluorophenyl)-5-(4- methylsulfonylphenyl)]-2-oxazoleacetate
Ethyl 2-[4-(4-fluorophenyl)-5-(4- methylsulfonylphenyl)-2-oxazoleacetate was prepared in a manner analogous to Example 1. Melting point: 123-124ºC.
Figure imgf000077_0001
Methyl 3-[4-(4-fluorophenyl)-5-(4- methylsulfonylphenyl)]-2-oxazolepropanate
Methyl 3-[4-(4-fluorophenyl)-5-[4- methylsulfonylphenyl]oxazol-2-yl]propanate was prepared in a manner analogous to Example 1. The m/z 404 (M+H)+ was consistent with the assigned structure.
Figure imgf000077_0003
Figure imgf000077_0002
Methyl 4-[4-(4-fluorophenyl)-5-(4- methylsulfonyl)phenyl]]-2-oxazolebutanate Methyl 4-[4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]]-2-oxazolebutanate was prepared in a manner analogous to Example 1. Melting point: 89- 91ºC.
Figure imgf000078_0001
5-(4-Fluorophenyl)-2-methyl-4-[4-
(methylsulfonyl)phenyl]oxazole
5-(4-Fluorophenyl)-2-methyl-4-[4-(methylsulfonyl) phenyl]oxazole was prepared in a manner analogous to Example 1 but with 2-(4-fluorophenyl)-1-[4-
(methylthio) phenyl] ethanone as the starting material. The m/z 332 (M+H)+ was consistent with the assigned structure.
Figure imgf000078_0002
Methyl 3-[5-(4-fluorophenyl)-4-[4- (methylsulfonyl)phenyl]]-2-oxazolepropanoate
Methyl 3-[5-(4-fluorophenyl)-4-[4- (methylsulfonyl)phenyl]]-2-oxazolepropanoate was prepared in a manner analogous to Example 14. The m/z
404 (M+H)+ was consistent with the assigned structure.
Figure imgf000079_0001
2-[4-(4-Fluorophenyl)-5-[4- (methylsulfonyl)phenyl]]-2-oxazoleacetic acid
2-[4-(4-Fluorophenyl)-5-[4-(methylsulfonyl) phenyl]oxazol-2-yl]acetic acid was prepared from Example 11 via alkaline hydrolysis using 1 N sodium hydroxide in methanol and appropriate reaction conditions. Melting point: 118-120ºC.
Figure imgf000079_0002
3-[4-(4-Fluorophenyl)-5-[4- (methylsulfonyl)phenyl]]-2-oxazolepropanoic acid
3-[4-(4-Fluorophenyl)-5-[4-(methylsulfonyl) phenyl]]-2-oxazolepropanoic acid was prepared from Example 12 in a manner analogous to Example 17. Melting point: 197-198°C. The m/z 390 (M+H)+ was consistent with the assigned structure.
Figure imgf000080_0001
4-[4-(4-Fluorophenyl)-5-[4- (methylsulfonyl)phenyl]]-2-oxazolebutanoic acid
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.
Figure imgf000080_0002
3-[5-(4-Fluorophenyl)-4-[4- (methylsulfonyl)phenyl]]-2-oxazolepropanoic acid 3-[5-(4-Fluorophenyl)-4-[4-(methylsulfonyl) phenyl]]-2-oxazolpropanoic acid was prepared from
Example 15 in a manner analogous to Example 17. The m/z
390 (M+H)+ was consistent with the assigned structure.
Figure imgf000081_0001
4-(4-Fluorophenyl)-2-(3-hydroxypropyl)-5-[4-
(methylsulfonyl)phenyl]oxazole
A solution containing 100 mg (0.239 mmol) of 3-[4- (4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2- yl] propanoic acid, methyl ester in 10 mL of
tetrahydrofuran was cooled to 0°C with stirring under a nitrogen atmosphere as 0.53 mL of diisobutylaluminum hydride (1M in toluene, 0.523 mmol) was added dropwise over 5 minutes. The reaction was allowed to warm to 25°C and poured into 100 mL of a saturated solution of sodium potassium tartarate. Ethyl acetate (100 mL) was added and the mixture was stirred until the layers separated (approx. 1 hour). The organic layer was separated and dried over sodium sulfate. Concentration in vacuo gave an oily solid, which was recrystallized from 50 % ethyl acetate-isooctane to give 75 mg of a white crystalline solid (mp 123-124°C) which was characterized on the basis of its spectral characteristics: 1H-NMR (CDCI3, 300 MHz) δ 2.10 (m, 2H), 2.56 (bs, 1H), 3.01 (t, 2H, J=7.0 Hz), 3.07 (s, 3H), 3.80 (t, 2H, J=5.9 Hz), 7.09 (t, 2H, J=8.5 Hz), 7.57 (dd, 2H, J=8.5 and 5.5 Hz), 7.73 (d, 2H, J=8.5 Hz) and 7.89 (d, 2H, J=8.5 Hz). 19F-NMR (CDCI3, 280 MHz) δ
-111.97. LRMS m/z 376 (M + H)+. HRMS calc. for
C19H18NO4FS: 376.1019. Observed: 376.1026. Analysis calc. for C19H18NO4FS-C: 60.79, H: 4.83, N: 3.73.
Observed-C: 60.53, H: 4.85, N: 3.66.
Figure imgf000082_0001
3-[4-(4-Fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]]-2-oxazolepropanamide
3-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)
phenyl]]-2-oxazolepropanamide was prepared by treating methyl 3-[4-(4-fluorophenyl)-5-(4-
(methylsulfonyl)phenyl)-2-oxazolepropanoic acid,
(Example 12) with excess ammonia in methanol for 5 days. Melting point: 193-195°C.
Figure imgf000083_0001
5-(4-Fluorophenyl)-2-phenyl-4-[4- (methylsulfonyl)phenyl]oxazole
Step 1: Preparation of 5-(fluorophenyl)-4-[4- (methylthio)phenyl]-2-phenyloxazole
A solution containing 560 mg (2.03 mmol) of 2-(4- fluorophenyl)-2-hydroxy-1-[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.
The reaction was stirred at 25°C for 2 days, after which it was washed with 1N HCl, dried over sodium sulfate and concentrated in vacuo to give a crude oil which was characterized as the benzoin ester on the basis of its spectral characteristics: 1H-NMR (CDCI3, 300 MHz) δ 2.53 (s, 3H), 7.08 (s, 1H), 7.12 (t, 2H, J=8.7 Hz), 7.27 (d, 2H, J=8.7 Hz), 7.49 (t, 2H, J=7.7 Hz), 7.60 (m, 3H), 7.94 (d, 2H, J=8.7 Hz) and 8.14 (d, 2H, J=8.7 Hz). This material was dissolved in 50 mL of glacial acetic acid and 1.56 g (20.3 mmol) of ammonium acetate was added. The reaction was heated at reflux for 2 hours, 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 50% ethyl acetate/hexane as the eluent to give a white solid which was recrystallized from 50% ethyl
acetate/isooctane to give 450 mg (61%) of a white crystalline solid (mp 118-119°C) whose structure was assigned as 5-(4-fluorophenyl)-4-[4-(methylthio)
phenyl]-2-phenyl oxazole on the basis of its spectral characteristics: 1H-NMR (CDCI3, 300 MHz) δ 2.52 (s, 3H),
7.10 (t, 2H, J=8.8 Hz), 7.28 (d, 2H, J=8.5 Hz), 7.47 (m, 3H), 7.62 (m, 4H) and 8.13 (m, 2H). 19F-NMR (CDCI3, 280 MHz) δ -111.96. LRMS m/ z 361 (M) + . HRMS Calc ' d . for C22H16NOFS : 361 .0937. Observed: 361.0970. Analysis Calc'd. for C22H16NOFS: C, 71.51; H, 6.55; N, 3.79.
Observed: C, 72.85; H, 4.52; N, 3.84.
Step 2: Preparation of 5-(4-fluorophenyl)-4-[ 4- (methylsulfinyl)phenyl]-2-phenyloxazole.
A solution containing 64 mg (0.173 mmol) of 5-(4- fluoropheny.')-4-[4-(methylthio)phenyl]-2-phenyloxazole in 10 mL of methylene chloride was stirred at -78°C as 60 mg (0.173 mmol based on 50% purity) of m- chloroperoxybenzoic acid was added all at once. The reaction was stirred at -78°C for 1 hour. Thin-layer chromatography (TLC) (silica, 50% hexane-ethyl acetate) indicated that the reaction mixture consisted of mostly sulfoxide, with a minor amount of sulfide and sulfone. 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. Recrystallization from 50% ethyl acetate/isooctane gave 48 mg (74%) of a white crystalline solid (mp 164-165°C) whose structure was assigned as 5-(4-fluorophenyl)-4-[4- (methylsulfinyl)phenyl]-2-phenyl oxazole on the basis of its spectral characteristics: 1H-NMR (CDCI3, 300 MHz) δ 2.80 (s, 3H), 7.16 (t, 2H, J=8.5 Hz), 7.54 (m, 3H), 7.66-7.75 (m, 4H), 7.93 (d, 2H, J=8.5 Hz) and 8.19 (m, 2H). LRMS m/z 377 (M) + . HRMS Calc'd. for C22H16NO2FS: 377.0886. Observed: 377.0868. Analysis Calc'd. for C22H16NO2FS: C,70.01; H, 4.27; N, 3.71. Observed: C, 68.18; H, 4.19; N, 3.58.
Step 3: Preparation of 5-(4-fluorophenyl)-4-[4- (methylsulfonyl)phenyl]-2-phenyloxazole.
A solution containing 64 mg (0.173 mmol) of 5- (4- fluorophenyl)-4-[4-(methylthio)phenyl]-2-phenyloxazole in 10 mL of methylene chloride was stirred at -78 °C as 120 mg (0.346 mmol based on 50% purity) of m- chloroperoxybenzoic acid was added all at once. The reaction was stirred at -78 °C for 1 hour and TLC
(silica, 50% hexane-ethyl acetate) indicated that the reaction mixture consisted of mostly sulfone. 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. Recrystallization from 50% dichloromethane/isooctane gave 62 mg (91%) of a white crystalline solid (mp 175-176°C) whose structure was assigned as 5-(4-fluorophenyl)-4-[4-
(methylsulfonyl)phenyl]-2-phenyl oxazole on the basis of its spectral characteristics: 1H -NMR (CDCI3, 300 MHz) δ
3.13 (s, 3H), 7.19 (t, 2H, J=8.6 Hz), 7.55 (m, 3H), 7.69 (m, 2H), 8.00 (m, 2H), 8.17 (m, 2H). LRMS m/z 393 (M)+. HRMS Calc'd. for C22H16NO3FS: 393.0835. Observed:
393.0865.
Figure imgf000086_0001
2-Cyclohexyl-4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]oxazole
2-Cyclohexyl-4-(4-fluorophenyl)-5-[4- (methylsulforyl)phenyl]oxazole was prepared in a manner analogous to Example 1. Melting point: 127-128°C.
Figure imgf000086_0002
2-Benzyloxymethyl-4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]oxazole
Step 1: Preparation of the benzoin ester
A solution containing 2.07 g (6.71 mmol) of 1-(4- fluorophenyl)-2-hydroxy-2-[4-
(methylsulfonylphenyl)ethanone in 100 mL of methylene chloride was stirred at 25°C as 2.71 mL (33.55 mmol) of pyridine was added, followed by the addition of 1.27 mL (8.05 mmol) of benzyloxyacetyl chloride. The reaction was stirred at 25°C for 48 hours, after which the resulting yellow solution was washed with 1N HCl, dried over sodium sulfate and concentrated in vacuo . The oily yellow solid was purified via flash chromatography on a silica gel column using 20 % ethyl acetate/hexane as the eluent. This provided 2.22 g (73 %) of a white foam, which was characterized as the benzoin ester on the basis of its NMR spectra: 1H-NMR (CDCI3, 300 MHz) δ 3.03 (s, 3H), 4.23 (d, 1H, J=17.0 Hz), 4.33 (d, 1H, J=17.0
Hz), 4.67 (s, 2H), 6.95 (s, 1H), 7.13 (t, 2H, J=8.5 Hz), 7.35 (m, 5H), 7.66 (d, 2H, J=8.1 Hz) and 7 . 98 (m, 4H) . 19F-NMR (CDCI3 , 280 MHz ) δ -102 . 5 . Step 2: Preparation of 2-benzyloxymethyl-4-(4- fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazole.
A solution containing 2.22 g (4.86 mmol) of the benzoin ester and 3.74 g (48.6 mmol) of ammonium acetate in 100 mL of acetic acid was heated to 80°C for 2 hours. The reaction was cooled to 25°C and poured into water. The product was extracted into ethyl acetate and the combined organic extracts washed with an aqueous solution of sodium bicarbonate. The solution was dried over sodium sulfate and concentrated in vacuo to give a yellow oil. This crude material was purified by flash chromatography on a silica gel column using 25 % ethyl acetate/hexane as the eluent to give 1.92 g (90%) of a clear oil, which was characterized as 2- benzyloxymethyl-4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]oxazole on the basis of its spectral properties: 1H-NMR (CDCI3, 300 MHz) δ 3.07 (s,
3H), 4.70 (s, 2H), 4.72 (s, 2H), 7.11 (t, 2H, J=8.8 Hz), 7.22-7.40 (m, 5H), 7.58 (m, 2H), 7.76 (d, 2H, J=8.8 Hz) and 7.91 (d, 2H, J=8.8 Hz). 19F-NMR (CDCI3, 280 MHz) δ -111.88.
Figure imgf000088_0001
4-(Cyclohexyl)-5-[4-(methylsulfonyl)phenyl]-2- phenyloxazole
Step 1: Preparation of 1-(cyclohexyl)-2-hydroxy-2-[4- (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. The solution was concentrated in vacuo, the residue dissolved in chloroform, washed with 3 N HCl, saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 18.75 g, (>100%) of a yellow oil that solidified upon standing. The crude solid was purified by
trituration with ether providing the desired compound in pure form 15.80 g, (86%, mp 110-111.5°C) which wascharacterized as 1-(cyclohexyl)-2-hydroxy-2-[4-
(methylthiophenyl)ethanone on the basis of its NMR spectra. 1H-NMR (CDCI3, 300 MHz) δ 1.00-1.47 (m, 6H), 1.60-1.95 (m, 4H), 2.45 (m, 1H), 2.52 (s, 3H), 4.38(d, J=3.9 Hz, 1H), 7.55 (d, J=3.9 Hz, 1H), 7.25 (m, 4H). HRMS Calc'd. for C15H20NO2S: 264.1184. Observed:
264.1207.
Step 2: Preparation of benzoin ester
A solution containing 162 mg (0.62 mmol) of 1- (cyclohexyl)-2-hydroxy-2-[4-(methylthiophenyl) ethanone in 10 mL of methylene chloride was stirred at 25°C as 251 μL (31 mmol) of pyridine was added, followed by the addition of 86 μL (1.24 mmol) of benzoyl chloride. The reaction was stirred at 25°C for 48 hours, after which the resulting yellow solution was washed with 1N HCl, dried over sodium sulfate and concentrated in vacuo . The crude solid was purified via flash chromatography on a silica gel column using 10 % ethyl acetate/hexane as the eluent. This provided 131 mg (57 %) of a white foam, which was characterized as the benzoin ester on the basis of its NMR spectra: 1H-NMR (CDCI3, 300 MHz) δ 1.03-1.48 (m, 6H), 1.56-1.88 (m, 3H), 2.03-2.14 (m, 1H), 2.48 (s, 3H), 2.53 (m, 1H), 6.28 (s, 1H), 7.20-7.70 (m, 5H), 8.05-8.17 (m, 4H).
Step 3: Preparation of 4-cyclohexyl-5-[4- (methythio)phenyl]-2-phenyloxazole
A solution containing 131 mg (0.355 mmol) of the benzoin ester and 273 mg (35 mmol) of ammonium acetate in 10 mL of acetic acid was heated to 80°C for 2 hours. The reaction was cooled to 25°C and poured into water. The product was extracted into ethyl acetate and the combined organic extracts washed with an aqueous solution of sodium bicarbonate. The solution was dried over sodium sulfate and concentrated in vacuo to give the crude oxazole. This crude material was purified crystallization from a mixture of dichloromethane and isooctane to give 89 mg, (72%, mp 151-151.5°C) of material, which was characterized as 4-(cyclohexyl)-5- [4-(methythio)phenyl]-2-phenyloxazole on the basis of its spectral properties: 1H-NMR (CDCI3, 300 MHz) δ 1.30-
1.45 (m, 3H), 1.70-1.94 (m, 7H), 2.54 (s, 3H), 2.80-2.90 (m, 1H), 7.34 (d, J=8.5Hz, 2H), 7.42 (m, 3H), 7.55 (d, J=8.5Hz, 2H), 8.08 (d, J=7.7Hz, 2H). HRMS Calc'd. for C22H23NOS (M+H) : 350.1579. Observed: 350.1597. The material from this experiment was used directly in the next step without further purification. Step 4: Preparation of 4-(cyclohexyl)-5-[4- (methylsulfonyl)phenyl]-2-phenyloxazole
A solution of 38 mg (0.11 mmol) of 2-phenyl-4- (cyclohexyl)-5-[4-(methythio)phenyl]oxazole in 4 mL of methylene chloride was stirred at -78°C as 75 mg (0.22 mmol based on 50% purity) of m-chloroperoxybenzoic acid was added all at once. The reaction was stirred at -78°C for 1 hour. Thin-layer chromatography (TLC)
(silica, 50% hexane/ethyl acetate) indicated the
reaction mixture consisted of mostly sulfone. 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 crystallization from 50% dichloromethane/isooctane gave 26 mg (62%) of pure product, whose structure was assigned as 4- (cyclohexyl)-5-[4-(methylsulfonyl)phenyl]-2- phenyloxazole on the basis of its spectral
characteristics: mp 231°C. 1H-NMR (CDCI3, 300 MHz) δ
1.34-1.43 (m, 3H), 1.72-1.95 (m, 7H), 2.84 (m, 1H), 3.10 (s, 3H), 7.47 (m, 3H), 7.82 (d, J=8Hz, 2H), 8.03 (d, J=8Hz, 2H), 8.10 (m, 2H). . LRMS m/z 382 (M)+. HRMS Calc'd. for C22H23NO3S: 382.1477. Observed: 382.1436. Analysis Calc'd. for C22H23NO3S: C, 69.27; H, 6.08; N, 3.67. Observed: C, 68.99; H, 6.07; N, 3.63.
Figure imgf000091_0001
4-(4-Fluorophenyl)-2-(hydroxymethyl)-5-[4- (methylsulfonyl)phenyl]oxazole
To a solution containing 5.0 g (11.4 mmol) of 2- benzyloxymethyl-4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]oxazole (prepared in Example 24) in 20 mL of 50 % THF-methanol, was added 100 mg of 10% Pd on charcoal in a Fisher-Porter bottle. The reaction vessel was evacuated and then charged with hydrogen at 50 psi for 24 hours. The Pd on carbon was removed by filtration through diatomaceous earth and the filtrate concentrated in vacuo to give 3.8 g (97 %) of a white crystalline solid (mp 156-157°C) (recrystallized from 50% ethyl acetate/isooctane) whose structure was
assigned as 4-(4-fluorophenyl)-2-hydroxymethyl-5-[4- (methylsulfonyl)phenyl]oxazole on the basis of its spectral characteristics: 1H-NMR (CDCl3, 300 MHz) δ 3.07
(s, 3H), 3.21 (bs, 1H), 4.81 (s, 2H), 7.10 (t, 2H, J=8.5 Hz), 7.56 (m, 2H), 7.72 (d, 2H, J=8.8 Hz) and 7.90 (d, 2H, J=8.8 Hz). 19F-NMR (CDCI3, 280 MHz) δ -111.5. LRMS m/z 348 (M + H) + . HRMS Calc'd. for C17H14NO4FS:
348.0706. Observed: 348.0681. Analysis Calc'd. for C17H14NO4FS: C:, 58.78; H, 4.06; N, 4.03. Observed: C, 58.67; H, 4.02; N, 4.01.
Figure imgf000092_0001
4-(4-Fluorophenyl)-2-(2-hydroxyethyl)-5-[4- (methylsulfonyl)phenyl]oxazole
4-(4-Fluorophenyl)-2-(2-hydroxyethyl)-5-[4- (methylsulfonyl)phenyl]oxazole was prepared in a manner consistent with that described in Example 20. The m/z
362 (M+H) + was consistent with the assigned structure.
Figure imgf000092_0002
4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]- 2-phenoxymethyloxazole
A solution containing 1.69 g (4.87 mmol) of 4- (4- fluorophenyl)-2-hydroxymethyl-5-[4- (methylsulfonyl)phenyl]oxazole (Example 26) in 100 mL of methylene cMoride was stirred at 25°C as 1.36 mL (9.74 mmol) of triethylamine was added dropwise, followed by the addition of 560 uL (7.30 mmol) of methanesulfonyl chloride. The reaction was stirred for 20 minutes, after which the organic solution was washed with 1N HCl, dried over sodium sulfate and concentrated in vacuo to give methyl [4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]oxazol-2-yl]methanesulfonate as a yellow oil which was characterized as the expected mesylate by its NMR spectrum: 1H-NMR (CDCI3, 400 MHz) δ
3.08 (s, 3H), 3.17 (s, 3H), 5.37 (s, 2H), 7.12 (t, 2H, J=8.8 Hz), 7.58 (m, 2H), 7.78 (d, 2H, J=8.8 Hz) and 7.94 (d, 2H, J=8.8 Hz). This material was used without further purification. A solution containing 544 mg (1.28 mmol) of methyl [4-(4-fluorophenyl)-5-[4- (methylsulfonyl) phenyl]oxazol-2-yl]methanesulfonate in 20 mL of DMF was stirred at 25°C as 353 mg (2.56 mmol) of potassium carbonate and 240 mg (2.56 mmol) of phenol were added. The reaction was stirred for 2 days at 25°C and poured into 100 mL of water. To this mixture was added 100 mL of ethyl acetate and the layers separated. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo to give a crude beige solid which was purified by flash chromatography on a silica gel column using 25% ethyl acetate/hexane as the eluent to give 475 mg (88%) of a white solid which was recrystallized from 50% ethyl acetate/isooctane to give a white crystalline solid (mp 168-169°C) whose structure was assigned as 4-(4-fluorophenyl)-5-[4- (methylsulfonyl)-phenyl]-2-phenoxymethyloxazole on the basis of its spectral characteristics: 1H-NMR (CDCI3, 300 MHz) δ 3.07 (s, 3H), 5.23 (s, 2H), 6.98 (m, 5H),
7.33 (t, 2H, J=8.2 Hz) , 7.60 (m, 2H), 7.77 (d, 2H, J=8.5 Hz) and 7.92 (d, 2H, J=8.5 Hz) . 19F-NMR (CDCI3, 280 MHz) δ -111.9. Analysis calc. for C23H18NO4FS- C: 65.24, H:
4.28, 3.31. Observed- C: 65.10, H: 4.29, N: 3.28.
Figure imgf000094_0001
4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]
2-(pyridyloxymethyl)oxazole
4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2- (pyridyloxymethyl)oxazole was prepared in a manner consistent with Example 28. Melting point: 276-278°C.
E
Figure imgf000094_0002
2-(3-Chlorophenoxymethyl)-4-(4-fluorophenyl)-5- [4-(methylsulfonyl)phenyl]oxazole
A solution containing 612 mg (1.44 mmol) of methyl [4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-
2-yl]methanesulfonate (as prepared in Example 28) in 20 mL of DMF was stirred at 25°C as 397 mg (2.88 mmol) of potassium carbonate and 0.3 mL (2.88 mmol) of 3- chlorophenol were added. The reaction was stirred for 2 days at 25°C and poured into 100 mL of water. To this mixture was added 100 mL of ethyl acetate and the layers separated. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo to give the crude solid which was purified by flash
chromatography on a silica gel column using 50% ethyl acetate/hexane as the eluent to give 528 mg (80%) of a white solid which was recrystallized from 50%
dichloromethane/isooctane to give a white crystalline solid (mp 112-114°C) whose structure was assigned as 4- (4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-(3- chlorophenoxy) methyloxazole on the basis of its spectral characteristics: 1H-NMR (CDCI3, 300 MHz) δ 3.08 (s, 3H),
5.22 (s, 2H), 7.08 (m, 2H), 7.13 (m, 3H), 7.26 (m, 1H), 7.59 (dd, 2H, J=8.8, 5.4 Hz), 7.62 (dd, 2H, J=8.8, 5.4 Hz), 7.78 (d, 2H, J=8.8 Hz), 7.93 (d, 2H, J=8.8 Hz).
19F-NMR (CDCI3, 280 MHz) δ -111.8. Analysis Calc'd. for
C23H17NO4FSCI: C, 60.33; H, 3.74; N, 3.06. Observed: C, 60.19; H, 3.80; N, 3.03.
Figure imgf000095_0001
4-(4-Fluorophenyl)-2-(4-fluorophenoxymethyl)-5- [4-(methylsulfonyl)phenyl]oxazole A solution containing 585 mg (1.37 mmol) of methyl [4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol- 2-yl]methanesulfonate (as prepared in Example 28) in 15 mL of DMF was stirred at 25°C as 380 mg (2.74 mmol) of potassium carbonate and 308 mg (2.74 mmol) of 4- fluorophenol are added. The reaction was stirred for 2 days at 25°C and poured into 100 mL of water. To this mixture was added 100- mL of ethyl acetate and the layers separated. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo to give the crude solid which was purified by flash
chromatography on a silica gel column using 50% ethyl acetate/hexane as the eluent to give 528 mg (80%) of a white solid which was recrystallized from 50%
dichloromethane/isooctane to give a white crystalline solid (mp 133-134°C) whose structure was assigned as 4- (4-fluorophenyl)-5-[4-(methylsulfonyl)-phenyl]-2-[(4- fluorophenoxy) methyl] oxazole on the basis of its
spectral characteristics: 1H-NMR (CDCI3, 300 MHz) δ 3.08
(s, 3H), 5.19 (s, 2H), 7.00 (m, 4H), 7.13 (m, 2H), 7.58 (dd, 2H, J=8.8, 5.2 Hz), 7.61 (dd, 2H, J=8.8, 5.2 Hz), 7.77 (d, 2H, J=8.7 Hz), 7.93 (d, 2H, J=8.7 Hz). 19F-NMR (CDCI3, 280 MHz) δ -111.8, -122.5. Analysis Calc'd. for C23H17NO4F2S: C, 62.58; H, 3.88; N, 3.17. Observed: C, 62.44; H, 4.04; N, 3.11.
E
Figure imgf000097_0001
2-(Cyclohexylethyl)-4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]oxazole
A solution containing 2.02 g (7.24 mmol) of l-(4- fluorophenyl)-2-hydroxy-2-[4-(methylthiophenyl)ethanone in 100 mL of methylene chloride was stirred at 25°C as 1.76 mL (21.72 mmol) of pyridine was added, followed by the addition of 1.52 g (8.69 mmol) of 2- cyclohexylpropionyl chloride. The reaction was stirred at 25°C for 48 hours, after which the resulting yellow solution was washed with 1N HCl, dried over sodium sulfate and concentrated in vacuo . The crude solid was purified via flash chromatography on a silica gel column using 10 % ethyl acetate/hexane as the eluent. This provided 2.87 g (96 %) of a white foam, which was characterized as the benzoin ester on the basis of its NMR spectra: 1H-NMR (CDCI3, 300 MHz) δ 0.80-0.96 (m,
2H), 1.10-1.25 (m, 4H), 1.45-1.78 (m, 7H), 2.40 (m, 2H), 2.43 (s, 3H), 6.75 (s, 1H), 7.05 (m, 2H), 7.23 (d, 2H, J=8 Hz), 7.35 (d, 2H, J=8 Hz) and 7.95 (m, 2H). 19F-NMR (CDCI3, 280 MHz) δ -104.4.
A solution containing 2.87 g (6.92 mmol) of the benzoin ester and 5.3 g (69 mmol) of ammonium acetate in 100 mL of acetic acid was heated to 80°C for 2 hours. The reaction was cooled to 25°C and poured into water. The product was extracted into ethyl acetate and the combined organic extracts washed with an aqueous solution of sodium bicarbonate. The solution was dried over sodium sulfate and concentrated in vacuo to give the crude oxazole. This crude material was purified by flash chromatography on a silica gel column using 25% ethyl acetate/hexane as the eluent to give 1.87 g (68%) of a clear oil, which was characterized as 2-(2- cyclohexylethyl)-4-(4-fluorophenyl)-5-[4- (methythio ) phenyl ] oxazole on the basis of its spectral properties: 1H-NMR (CDCI3, 400 MHz) δ 0.90-1.02 (m,
2H), 1.10-1.40 (m, 4H), 1.62-1.82 (m, 7H), 2.49 (s, 3H), 2.84 (t, J=8.0 Hz, 2H), 7.03 (d, J=8.7Hz, 1H), 7.06 (d, J=8.7Hz, 1H), 7.22 (d, J=8.6Hz, 2H), 7.45 (d, J=8.6Hz, 2H), 7.58 (d, J=5.4Hz, 1H), 7.61 (d, J=5.4Hz, 1H). The material from this experiment was used directly in the next step without further purification.
A solution of 1.87g (4.73 mmol) of 2-(2- cyclohexylethyl)-4-(4-fluorophenyl)-5-[4- (methythio) phenyl] oxazole in 100 mL of methylene chloride was stirred at -78°C as 3.26 g (9.46 mmol based on 50% purity) of m-chloroperoxybenzoic acid was added all at once. The reaction was stirred at -78°C for 1 hour and TLC (silica, 50% hexane/ethyl acetate)
indicated that the reaction mixture consisted of mostly sulfone. 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. Recrystallization from 50% ethyl acetate/isooctane gave 1.76 g (87%) of a low melting semi-solid whose structure was assigned as 2-(2-cyclohexylethyl)-4-(4-fluorophenyl)-5-[4- (methylsulfonyl) phenyl] oxazole on the basis of its spectral characteristics: 1H-NMR (CDCI3, 300 MHz) δ
0.90-1.06 (m, 2H), 1.11-1.40 (m, 7H), 2.87 (apparent t, J=8.1Hz, 2H), 3.07 (s, 3H), 7.10 (t, J=8.7Hz, 2H), 7.59(m, 2H), 7.74 (d, J=8.7Hz, 2H), 7.90 (d, J=8.7Hz, 2H). 19F-NMR (CDCI3, 280 MHz) δ -112.49. LRMS m/z 427 (M)+.
HRMS Calc'd. for C24H26NO3FS: 421.1617. Observed:
421.1611. Analysis Calc'd. for C24H26NO3FS: C, 67.43; H, 6.13; N, 3.28. Observed: C, 67.27; H, 6.15; N, 3.24.
Figure imgf000099_0001
Ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyl]-2-oxazolyl]-2-benzyl-acetate
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), and
triethylamine (68.1 g, 0.67 mol) were placed in a 3 L round bottom flask and heated to reflux for 1.75 hours. The reaction was cooled to 110°C, and water (500 mL) was added cautiously through an addition funnel. This caused the solution to reflux vigorously and the
temperature to rise to 135°C. A yellow precipitate formed, and after cooling to room temperature, was collected by filtration, washed with water, and
recrystallized from ethyl acetate/isooctane to provide the diarylacrylic acid as yellow needles (135.2 g, 71%): mp 172-176°C. 1H NMR (acetone d6) 300 MHz 7.84 (s, 1H), 7.03-7.28 (m, 10H), 2.46 (s, 3H). 19F NMR (acetone d6) -116.11 (m). Mass spectrum M+ 288.
Step 2: Preparation of 1-(4-fluorophenyl)-2-(4- methylthiophenyl)ethanone
The diaryl 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. After 1.25 hours, tert-butyl alcohol (80 mL, 0.84 mol) was added to the reaction. After an
additional 20 minutes, concentrated hydrochloric acid (41 mL) was added slowly causing the reaction to foam. The reaction was heated at 90°C overnight (14 hours) and a white precipitate formed after cooling. The
precipitate was isolated by filtration, washed with cold ether, and air dried to yield the desired intermediate (182.7 g, 89%): mp 134.5-138°C. % NMR (acetone d6) 300 MHz 8.16 (m, 2H), 7.24 (m, 6H), 4.34 (s, 2H), 2.46 (s, 3H). 19F NMR (acetone d6) -107.88 (m).
Step 3: Preparation of 1-(4-fluorophenyl)-2-(4- methylthiophenyl)-2-hydroxy-ethanone
A 1 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. After an additional 10 minutes at room temperature, the solution was filtered through a Buchner funnel and the filtrate concentrated in vacuo to give an orange solid. The crude bromoketone was dissolved in dichloromethane and washed with 1N NaHSO3, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 68.8 g of 1-(4-fluorophenyl)-2-(4- methylthiophenyl)-2-bromoethanone as a yellow solid which was used directly without further purification. The crude bromoketone was dissolved in 300 mL acetone and 150 mL of water and heated to reflux for 2.5 hours. The solution was concentrated in vacuo and the residue taken up in dichloromethane, washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and reconcentrated in vacuo to give a light yellow solid that was crystallized from a mixture of dichloromethane and isooctane to provide 37.8 g (65%) of pure 1-(4-fluorophenyl)-2-(4- methylthiophenyl)-2-hydroxy-ethanone: mp 90-92 °C.
Step 4: Preparation of ethyl 2-[4-(4-fluorophenyl)-5- [4-methylthio)phenyl]]-2-oxazoleacetate
A solution containing 8.00 g (29 mmol) of 1-(4- fluorophenyl)-2-hydroxy-2-[4-(methylthiophenyl)ethanone in 100 mL of methylene chloride was stirred at 25°C as 7.0 mL (31 mmol) of pyridine was added, followed by the addition of 4.5 mL (35 mmol) of ethyl malonyl chloride. The reaction was stirred at 25°C for 48 hours, after which the resuiting yellow solution was washed with 1N HCl, dried over sodium sulfate and concentrated in vacuo . 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-[4-(4-fluorophenyl)-5- [4-methylsulfonyl)phenyl]-2-oxazolyl]-2-benzyl-acetate
A solution of 755 mg (2.03 mmol) of ethyl 2-[4-(4- fluorophenyl)-5-[4-methylthio)phenyl]oxazol-2-yl]acetate (from Step 4) was dissolved in 20 mL of anhydrous tetrahydrofuran (THF) and cooled to -78°C and treated with a solution of potassium bid (trimethylsilyl) amide (2.44 mL. 1.2 equivalents, 1M in THF via syringe. The solution was maintained at -78°C for 15 minutes and treated with a solution of 290 uL (2.44 mmol) of benzyl bromide. The solution was warmed to room temperature and poured into a saturated aqueous solution of ammonium chloride. The aqueous solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give an oil that was purified by flash chromatography on silica gel eluting with 10% ethyl acetate/hexane to provide 396 mg of the dia lkylated product and 182 mg (19%) of ethyl 2-[4- ( 4-fluorophenyl ) -5- [ 4-methylthio ) phenyl ] oxazol-2 - yl ]-1-benzyl-acetate that was used directly in the next step. A solution of 182 mg (0.344 mmol) of ethyl 2-[4- (4-fluorophenyl)-5-[4-methylthio)phenyl]oxazol-2-yl]-1- benzyl-acetate in 5 mL of dichloromethane was cooled to -78°C and treated with 272 mg (2 equivalents) of m- chloroperoxybenzoic acid for 2 hours. 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 transparent oil which was purified by flash chromatography on a silica gel cr lumn using 30% ethyl acetate/hexane as the eluent. The purified material was an oil whose
structure was assigned as ethyl 2-[4-(4-fluorophenyl)-5- [4-methylsulfonyl)phenyl]oxazol-2-yl]-2-benzyl-acetate on the basis of its spectral characteristics: 1H-NMR (CDCI3, 300 MHz) δ 1.20 (t, J= 7.0Hz, 3H), 3.07 (s, 3H), 3.53 (m, 2H), 4.19 (q, J= 7.0Hz, 2H), 4.23 (m, 1H), 7.10
(d, J= 8.7Hz, 2H), 7.25 (m, 5H), 7.57 (m, 2H), 7.70 (d, J= 8.7Hz, 2H), 7.90 (d, J= 8.7Hz, 2H). 19F-NMR (CDCI3, 280 MHz) δ -112.15. LRMS m/z 493 (M)+. HRMS Calc'd. for
C27H24NO5FS: 493.1359. Observed: 493.1371.
Figure imgf000104_0001
Ethyl [4-(4-aminosulfonylphenyl)-5-(3-fluoro-4- methoxyphenyl)]-2-oxazole]acetate Step 1. Preparation of 2-hydroxy-2-(3-fluoro-4- methoxyphenyl)-1-phenylethanone
A solution of 3-fluoro-para-anisaldehyde (25.00 g, 162 mmol) and zinc iodide (0.27 g) in dichloromethane (100 mL) was treated with a solution of trimethylsilylcyanide (22 mL, 165 mmol) in dichloromethane (20 mL). The solution was stirred for 0.4 hours at room temperature, washed with saturated NaHCO3, dried over MgSO4, and concentrated in vacuo to give the trimethylsilyl cyanohydrin as an orange oil (37.83 g). 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 NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to give an orange oil (39.57 g). The orange oil was dissolved in 9:1 trifluoroacetic acid/water (80 mL) and stirred for 1.4 hours at room temperature. The reaction was neutralized with solid sodium carbonate, extracted with ethyl acetate, washed with 10% Na2CO3 and brine, dried over MgSO4, and concentrated in vacuo to give a brown solid which was recrystallized from diethyl
ether/hexane to give the benzoin (13.87 g, 33%): mp 76-79 °C. 1H NMR (CDCI3) 300 MHz δ 7.89 (d, J=7.3 Hz, 2H) 7.55 (m, 1H)
7.42 (m, 2H) 7.05 (m, 2H) 6.90 (m, 1H) 5.88 (br d, J=3.0 Hz, 1H) 4.50 (br d, 1H). 19F NMR (CDCI3) 282 MHz -134.05 (m). Step 2. Esterification of 2-hydroxy-2-(3-fluoro-4- methoxyphenyl)-1-phenylethanone
A solution of benzoin from Step 1 (3.25 g, 12.5 mmol), pyridine (4.94 g, 62.5 mmol), and ethyl malonyl chloride (2.38 g, 15.8 mmol) in dichloromethane (20 mL) was stirred for 94 hours at room temperature. The reaction mixture was washed with 3N HCl, saturated NaHCO3 and water, dried over MgSO4, concentrated in vacuo and passed through a column of silica gel eluting with 25% ethyl acetate/hexane to give a yellow oil (1.93 g, 41%): 1H NMR (CDCI3) 300 MHz δ 7.89 (d, J=7.7 Hz, 2H) 7.53 (m, 1H) 7.41 (m, 2H) 7.16 (m, 2H) 6.92 (m, 1H) 6.84 (s, 1H) 4.50 (q, J=7.0 Hz, 2H) 3.85 (d, J=1.0 Hz, 3H) 3.52 (s, 2H) 1.25 (t, J=7.0 Hz, 3H). 19F NMR (CDCI3) 282 MHz -133.67 (m). Mass spectrum: M+Li=381. Step 3. Preparation of ethyl [4-phenyl-5-(3-fluoro-4 methoxyphenyl)]-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 NaHCO3, and brine, dried over MgSO4, 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. 1H NMR (CDCI3) 300 MHz δ 7.61 (d, J=7.5 Hz, 2H) 7.35 (m, 5H) 6.93 (m, 1H) 4.24 (q, J=7.1 Hz, 2H) 3.93 (s, 2H) 3.91 (s, 3H) 1.30 (t, J=7.1 Hz, 3H). 19F NMR (CDCI3) 282 MHz δ 134.77 (m). High
resolution mass spectrum Calc'd. for C20H18FNO4: 356.1298. Found: 356.1303.
Step 4. Preparation of ethyl [4-(4-aminosulfonylphenyl)-5- (3-fluoro-4-methoxyphenyl)]-2-oxazoleacetate
The compound from Step 3 (0.63 g, 1.8 mmol) was stirred with chlorosulfonic acid (15 mL) for 1.1 hours at 5 °C. The reaction mixture was slowly added to ice water, and extracted with dichloromethane. The dichloromethane solution was stirred at 5 °C with ammonium hydroxide for 3.0 hours. The organic layer was collected, washed with 3N HCl, dried over MgSO4, concentrated in vacuo, and the residue recrystallized from ethyl acetate/hexane to give a white solid (0.02 g,
2.6%): mp 127-130 °C. 1H NMR (acetone-d6) 300 MHz δ 7.90 (d, J=8.7 Hz, 2H) 7.84 (d, J=8.7 Hz, 2H) 7.38 (m, 2H) 7.26 (m, 1H) 6.64 (br s, 1H) 4.20 (q, J=7.0 Hz, 2H) 4.01 (s, 2H) 3.95 (s, 3H) 1.27 (t, J=7.0 Hz, 3H). 19F NMR (acetone-d6) 282 MHz -135.76 (m). High resolution mass spectrum Calc'd. for C20H20F1N2O6S1: 435.1026. Found: 435.1036.
Figure imgf000107_0001
[4-(4-Aminosulfonylphenyl)-5-cyclohexyl]-2- oxazoleacetic acid
Step 1. Preparation of 2-hydroxy-2-cyclohexyl-1- phenylethanone
A solution of cyclohexanecarboxaldehyde (8.5 g, 76 mmol) and zinc iodide (0.11 g) in dichloromethane (40 mL) was treated with a solution of trimethylsilylcyanide (10 mL, 76 mmol) in dichloromethane (20 mL). The solution was stirred for 0.33 hours at room temperature, washed with water and saturated NaHCO3, dried over MgSO4, and concentrated in vacuo to give the trimethylsilyl cyanohydrin as an orange oil
(13.02 g). 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 NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to give a white solid (12.96 g). The white solid was dissolved in 9:1 trifluoroacetic acid/water (50 mL) and stirred for 2.0 hours at room temperature. The reaction was neutralized with solid sodium carbonate, extracted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over MgSO4, concentrated in vacuo and recrystallized from diethyl ether/hexane to give the benzoin (2.55 g, 25%): mp 87-92 °C. 1H NMR (CDCI3) 300 MHz δ 7.88 (d, J=7.1 Hz, 2H) 7.62 (m, 1H) 7.50 (m, 2H) 4.93 (d, J=2.2 Hz 1H) 3.60 (br s, 1H) 1.52-1.82 (m, 6H) 1.02 1.24 (m, 5H). Mass spectrum: M+Li=225.
Step 2. Esterification of 2-hydroxy-2-cyclohexyl-1- phenylethanone
The ethanone of Step 1 (2.55 g, 11.7 mmol) was dissolved in THF (10 mL), 2,2-dimethyl-1,3-dioxane-4,6-dione (1.73 g, 12.0 mmol) was added and the reaction was heated to reflux for 17.3 hours. The reaction mixture was partitioned between saturated NaHCO3 and diethyl ether. The aqueous layer was acidified with concentrated HCl, extracted with diethyl ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil (2.26 g) which was used in the next step without further purification.
Step 3. Preparation of 2-carboxymethyl-4-hydroxy-4-phenyl-5-cyclohexyloxazoline
The ethanone from the Step 2 (1.87 g, 6.1 mmol) was dissolved in ethanol (20 mL), treated with ammonium acetate (4.94 g,16.3 mmol), and heated to reflux for 4.3 hours. The reaction mixture was concentrated in vacuo, and the residue was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was acidified with 3N HCl, extracted with diethyl ether, washed with brine, dried over MgSO4, and concentrated in vacuo dissolved in ethyl acetate, washed with water, saturated NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo to give a white solid (0.75 g, 43%) : mp 151-155 °C dec. Mass spectrum: M+Li=310.
Step 4. Preparation of [4-(4-ammosulfonylphenyl)-5- cyclohexyl]-2-oxazo-eacetic 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.
The reaction mixture was slowly added to ice water, and extracted with dichloromethane. The dichloromethane was stirred at room temperature with ammonium hydroxide (20 mL) for 23.1 hours. The aqueous layer was collected, acidified with concentrated HCl, and filtered to give a white solid (0.17 g, 28%): mp 223-230 °C. 1H NMR (acetone-d6) 300 MHz δ
7.95 (d, 2H) 7.85 (d, 2H) 6.60 (br s, 2H) 3.90 (s, 2H) 3.20
(m, 1H) 1.20-1.95 (m, 10H). High resolution mass spectrum Calc'd. for C17H21N2O5S: 365.1171. Found: 365.1187.
Figure imgf000109_0001
[5-(4-Aminosulfonylphenyl)-4-(4-chlorophenyl)]-2- oxazoleacetic acid Step 1. Preparation of 2-hydroxy-2-phenyl-1-(4- chlorophenyl)ethanone
The trimethylsilyl cyanohydrin of benzaldehyde, prepared similar to that described in Example 34, Step 1, (10.18 g, 50 mmol) was dissolved in diethyl ether (10 mL) and added dropwise to a solution of 4-chlorophenyImagnesium bromide (59 mmol) in diethyl ether (319 mL) while maintaining the
temperature between 23-35 °C with an ice water bath. The reaction was stirred for 1.2 hours at room temperature then quenched by adding 3N HCl (50 mL). The organic layer was collected, washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil (15.57 g). The yellow oil was dissolved in 9:1 trifluoroacetic acid/water (30 mL) and stirred for 1.75 hours at room temperature. The reaction was neutralized with solid sodium carbonate, extracted with ethyl acetate, washed with 10% Na2CO3 and brine, dried over MgSO4, concentrated in vacuo and recrystallized from diethyl ether/hexane to give the benzoin (5.76 g, 47%) : mp 87-92 °C. Step 2. Esterification of 2-hydroxy-2-phenyl-1-(4- chlorophenyl)ethanone
The ethanone from Step 1 (4.28 g,17.3 mmol) was
dissolved in THF (15 mL), 2,2 dimethyl-1,3-dioxane-4,6-dione (2.52 g, 17.5 mmol) was added and the reaction heated to reflux for 15.7 hours. The reaction mixture was partitioned between saturated NaHCO3 and diethyl ether. The aqueous layer was acidified with concentrated HCl, extracted with diethyl ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil (4.55 g) which was used in the next step without further purification: Mass spectrum: M+Li=339.
Step 3. Preparation of [4-(4-chlorophenyl)-5-phenyl]-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,
61%): mp 158-160 °C. 1H NMR (DMSO-d6) 300 MHz δ 14.8 (br s, 1H) 7.48 (m, 9H) 4.19 (s, 2H).
Step 4. Preparation of [5-(4-aminosulfonylphenyl)-4-(4- chlorophenyl)]-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 aqueous layer was collected and acidified with
concentrated HCl, extracted with ethyl acetate, dried over MgSO4, and concentrated in vacuo to give a white solid (0.11 g, 5%) : 1H NMR (DMSO-d6) 300 MHz δ 13.5 (br s, 1H) 7.81 (d,
J=8.5 Hz, 2H) 7.62 (d, J=8.3 Hz, 2H) 7.47 (m, 6H) 3.90 (s, 2H).
Figure imgf000111_0001
[4-(4-Aminosulfonylphenyl)-5-(4-chlorophenyl)]-2 oxazoleacetic acid 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 NaHCO3, dried over MgSO4, and concentrated in vacuo to give the trimethylsilyl cyanohydrin as an orange oil (13.90 g). 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 NaHCO3 and brine, dried over MgSO4, 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% Na2CO3 and brine, dried over MgSO4, concentrated in vacuo to give a yellow solid (9.43 g) and used in the next step without further purification. Step 2. Esterification of 2-hydroxy-2-(4-chlorophenyl)-1- phenylethanone
The ethanone from Step 1 (4.34 g,17.6 mmol) was
dissolved in THF (40 mL), 2,2 dimethyl-1,3-dioxane-4,6-dione (2.56 g, 17.8 mmol) was added and the reaction heated to reflux for 18.3 hours. The reaction mixture was partitioned between saturated NaHCO3 and diethyl ether. The aqueous layer was acidified with concentrated HCl, extracted with diethyl ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil (4.66 g, 68%): 1H NMR (CDCI3) 300 MHz δ 7.89 (d, J=8.5 Hz, 2H) 7.54 (m, 1H) 7.35 (m, 6H) 6.90 (s, 1H) 3.59 (s, 2H). Mass spectrum M+Li=339.
Step 3. Preparation of [ 5 -(4-chlorophenyl)-4-phenyl]-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 212.5-219 °C. Mass spectrum: M+=313.
Step 4. Preparation of [ 4-(4-aminosulfonylphenyl)-5-(4- chlorophenyl)]-2-oxazoleacetic acid
The compound from Step 3 (0.71 g, 2.3 mmol) was stirred with chlorosulfonic acid (7 mL) at 5 °C for 1.0 hour. The reaction mixture was added to ice water, and extracted with dichloromethane. The dichloromethane was stirred with ammonium hydroxide for 1.3 hours at room temperature. The aqueous layer was collected and acidified with concentrated HCl, extracted with ethyl acetate, dried over MgSO4, and concentrated in vacuo to give a white solid (0.18 g, 20%): mp 118-120 °C (dec). 1H NMR (DMSO-d6) 300 MHz δ 7.86 (d, J=8.3
Hz, 2H) 7.66 (d, J=8.5 Hz, 2H) 7.56 (m, 4H) 4.15 (s, 2H).
EXAMPLE 38
Figure imgf000113_0001
[5-(4-Aminosulfonylphenyl)-4-phenyl]-2-oxazoleacetic acid
Step 1. Esterification of benzoin
Benzoin (33.32 g, 157 mmol) was dissolved in THF (65 mL), 2,2-dimethyl-1,3-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 NaHCO3 and ethyl acetate. The aqueous layer was acidified with concentrated HCl, extracted with diethyl ether, dried over MgSO4, 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 [4-hydroxy-4,5-diphenyl-2- oxazolinyl]acetate.
The compound from Step 1 (2.26 g, 7.6 mmol) was
dissolved in methanol (25 mL), treated with ammonium acetate (1.26 g,16.3 mmol), and heated to reflux. After 1.8 hours, the reaction was cooled, acidified by adding concentrated sulfuric acid and heated to reflux for an additional 2.0 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate, washed with water, saturated NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo to give an orange oil (1.50 g) which was used in the next step without further purification.
Step 3. Preparation of ethyl [5-(4-aminosulfonylphenyl)-4- phenyl]-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. The organic layer was collected, washed with 3N HCl, dried over MgSO4, concentrated in vacuo, and passed through a column of silica gel eluting with 40% ethyl acetate/hexane to give a white solid (0.30 g, 19%): mp 84-88 °C. 1H NMR (acetone-d6) 300 MHz δ 7.92 (d, J=8.5 Hz, 2H) 7.77 (d, J=8.5 Hz, 2H) 7.63 (m, 2H) 7.41 (m, 3H) 6.71 (br s, 2H) 4.06 (s, 2H) 3.74 (s,
3H). High resolution mass spectrum Calc'd. for C18H17N2O5S: 373.0858. Found: 373.0833.
Step 4. Preparation of [5-(4-aminosulfonylphenyl)-4-phenyl]- 2-oxazoleacetic acid The oxazole ester from Step 3 (0.65 g, 1.7 mmol) was dissolved in methanol (10 mL), treated with NaOH (0.09 g dissolved in 5 mL water, 2.2 mmol), and stirred at room temperature. After 0.33 hours, additional NaOH (0.10 g, 2.5 mmol) was added and stirring continued for 0.4 hours. 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. The ethyl acetate was washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow solid (0.43 g, 69%): mp 134-137 °C (dec). 1H NMR (acetone-d6) 300 MHz δ 7.92 (d, J=8.5 Hz, 2H) 7.78 (d, J=8.7 Hz, 2H) 7.64 (m, 2H) 7.42 (m, 3H) 6.68 (br s,
1H) 4.03 (s, 2H). High resolution mass spectrum Calc'd. for C17H15N2O5S: 359.0702. Found: 359.0722.
Figure imgf000115_0001
[4-(4-Aminosulfonylphenyl)-5-(3-chloro-4 fluorophenyl)]-2-oxazoleacetic acid
Step 1. Preparation of 2-hydroxy-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 NaHCO3 and brine, dried over MgSO4, 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 NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to give the an orange oil (24.13 g). The orange oil was dissolved in 9:1 trifluoroacetic acid/water (100 mL) and stirred for 1.5 hours at room temperature. The reaction was neutralized with solid sodium carbonate, extracted with diethyl ether, washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to give a brown solid which was
recrystallized from diethyl ether/hexane to give the benzoin (9.78 g, 41%): mp 58-63 °C. 1H NMR (CDCI3) 300 MHz δ 7.88 (d, J=7.0 Hz, 2H) 7.57 (m, 1H) 7.44 (m, 3H) 7.20 (m, 1H) 7.08 (t, J=8.7 Hz, 1H) 5.92 (s, 1H) 4.60 (br s, 1H). 19F NMR (CDCI3) 282 MHz -115.88 (m).
Step 2. Esterification of 2-hydroxy-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 NaHCO3 and diethyl ether. The aqueous layer was acidified with concentrated HCl, extracted with diethyl ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (6.94 g) which was used in the next step without further purification. Step 3. Preparation of methyl [5-(3-chloro-4-fluorophenyl)- 4-hydroxy-4-phenyl-2-oxazolinyl]acetate.
A solution of the ester from Step 2 (6.86 g, 19.6 mmol) dissolved in methanol (11 mL) was treated with ammonium acetate (3.17 g, 41.1 mmol), and heated to reflux. After 1.9 hours, the reaction was cooled, additional methanol (65 mL) was added, and the reaction mixture was acidified by adding concentrated sulfuric acid and heated to reflux for an additional 1.4 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate, washed with water, saturated NaHCO3, and brine, dried over MgSO4, concentrated in vacuo, and passed through a column of silica gel eluting with 50% ethyl acetate/hexane to give a yellow oil (2.10 g, 29%): 1H NMR (acetone-d6) 300 MHz δ 8.30 (br s, 1H) 8.18 (dd, J=7.3 Hz 2.2 Hz, 1H) 8.12 (m, 1H) 7.30- 7.50 (m, 6H) 6.60 (d, J= 6.8 Hz, 1H) 3.65 (s, 3H) 3.41 (s, 2H). 19F NMR (acetone-d6) 282 MHz -109.78 (m). Mass spectrum: M+Li=370. Step 4. Preparation of methyl [4-(4-aminosulfonylphenyl)-5- (3-chloro-4-fluorophenyl)]-2-oxazoleacetate
The compound from Step 3 (2.05 g, 5.6 mmol) was stirred with chlorosulfonic acid (10 mL) for 0.33 hours at room temperature and then for 0.25 hours at 75 °C. The reaction was cooled, slowly added to ice water, and extracted with dichloromethane. The dichloromethane layer was stirred with ammonium hydroxide for one hour at room temperature. The organic layer was concentrated in vacuo , dissolved in ethyl acetate, washed with 3N HCl, brine, dried over MgSO4, concentrated in vacuo and recrystallized from ethyl
acetate/hexane to give a white solid (0.58 g, 24%): mp 142- 144 °C. 1H NMR (acetone-d6) 300 MHz δ 7.92 (d, J=8.5 Hz, 2H) 7.85 (d, J=8.7 Hz, 2H) 7.78 (dd, J=7.1 Hz 2.2 Hz, 1H) 7.62 (m, 1H) 7.44 (t, J=8.8 Hz, 1H) 6.66 (br s, 1H) 4.06 (s, 2H) 3.75 (s, 3H). 19F NMR (acetone-d6) 282 MHz -115.94 (m). High resolution mass spectrum Calc'd. for C18H15CIFN2O5S: 425.0374. Found: 425.0379.
Step 5. Preparation of [4-(4-aminosulfonylphenyl)-5-(3- chloro-4-fluorophenyl)]-2-oxazoleacetic acid
The ester from Step 4 (0.55 g, 1.3 mmol) was dissolved in methanol (10 mL), treated with NaOH (0.09 g dissolved in 5 mL water, 2.2 mmol), and stirred at room temperature. After 1 hour, additional NaOH (0.10 g, 2.5 mmol) was added and stirring was 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. The ethyl acetate was washed with brine, dried over MgSO4, and concentrated in vacuo to give a white solid (0.39 g, 74%): mp 222-223 °C. 1H NMR
(acetone-d6) 300 MHz δ 7.92 (d, J=8.5 Hz, 2H) 7.85 (d, J=8.6 Hz, 2H) 7.79 (dd, J=7.0 Hz 2.2 Hz, 1H) 7.62 (m, 1H) 7.44 (t, J=8.9 Hz, 1H) 6.67 (br s, 1H) 4.04 (s, 2H). 19F NMR
(acetone-d6) 282 MHz -116.41 (m).
Figure imgf000119_0001
[4-(4-Aminosulfonylphenyl)-5-(3,4-dichlorophenyl)] - 2 - oxazoleacetic acid
Step 1. Preparation of 2-hydroxy-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 NaHCO3 and brine, dried over MgSO4, and
concentrated in 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). The organic layer was collected, washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to give an orange oil (49.07g). The orange oil was dissolved in 9:1 trifluoroacetic acid/water (100 mL) and stirred for 1.5 hours at room temperature. The reaction was neutralized with solid sodium carbonate, extracted with diethyl ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow solid which was recrystallized from ethyl acetate/iso-octane to give the benzoin (16.35 g, 37%): mp 68-71 °C. 1H NMR (CDCI3) 300 MHz δ 7.88 (d, J=7.5 Hz, 2H) 7.57 (m, 1H) 7.44 (m, 3H) 7.37 (d, J=8.3 Hz, 1H) 7.07 (dd, J=8.3 Hz 2.0 Hz, 1H) 5.92 (s, 1H) 4.60 (br s, 1H).
Step 2. Esterification of 2-hydroxy-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-1,3 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 NaHCO3 and diethyl ether. The aqueous layer was acidified with concentrated HCl, extracted with diethyl ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (6.67 g) which was used in the next step without further purification. Step 3. Preparation of methyl [5-(3,4-dichlorophenyl)-4- hydroxy-4-phenyl-2-oxazolinyl]acetate
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 sulfuric 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 NaHCO3, and brine, dried over MgSO4, 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)]-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. The organic layer was concentrated in vacuo, dissolved in ethyl acetate, washed with 3N HCl, brine, dried over MgSO4, concentrated in vacuo, passed through a column of silica gel eluting with 50% ethyl acetate/hexane, and recrystallized from ethyl acetate/hexane to give a tan solid (1.20g, 24%): mp 144-153 °C. 1H NMR (acetone-d6) 300 MHz 7.94 (d, J=8.5 Hz, 2H) 7.86 (d, J=8.3 Hz, 2H) 7.80 (d, J=1.8 Hz, 1H) 7.67 (d, J=8.3 Hz, 1H) 7.60 (dd, J=8.5 Hz 2.0 Hz, 1H) 6.67 (br s, 1H) 4.07 (s, 2H) 3.75 (s, 3H). High resolution mass spectrum Calc'd. for C18H15C12N2O5S: 441.0079. Found: 441.0088.
Step 5. Preparation of [4-(4-aminosulfonylphenyl)-5-(3,4- dichlorophenyl)]-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. The ethyl acetate was washed with brine, dried over MgSO4, and
concentrated in vacuo to give a yellow solid (0.33 g, 97%): mp 204-209 °C. 1H NMR (acetone-d6) 300 MHz δ 7.94 (d, J=8.9 Hz, 2H) 7.87 (d, J=8.7 Hz, 2H) 7.82 (d, J=2.0 Hz, 1H) 7.67 (d, J=8.3 Hz, 1H) 7.60 (dd, J=8.5 Hz 2.2 Hz, 1H) 6.68 (br s, 1H) 4.05 (s, 2H). EXAMPLE 41
Figure imgf000122_0001
[4-(4-Aminosulfonylphenyl-5-(3,4-difluorophenyl)]-2 oxazoleacetic acid
Step 1. Preparation of 2-hydroxy-2-(3,4-difluorophenyl)-1- phenylethanone.
A solution of 3,4-difluorobenzaldehyde (25.33 g, 178 mmol) and zinc iodide (0.13 g) in dichloromethane (100 mL) was treated with a solution of trimethylsilylcyanide (24.5 mL, 184 mmol) in dichloromethane (20 mL). The solution was stirred for 0.25 hours at room temperature, washed with saturated NaHCO3 and brine, dried over MgSO4 and
concentrated in vacuo to give the trimethylsilyl cyanohydrin as a yellow oil (41.03 g). 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
0.5 hours at room temperature then quenched by adding 3N HCl
(150 mL). The organic layer was collected, washed with saturated NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo to give an orange oil (49.71g). The orange oil was dissolved in 9 : 1 trifluoroacetic acid/water
(100 mL) and stirred for 0.5 hours at room temperature. The reaction was neutralized with solid sodium carbonate, extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown solid which was recrystallized from diethyl ether/hexane to give the benzoin (16.35 g, 37%): mp 68-71 °C. 1H NMR (CDCl3) 300 MHz δ
7.87 (d, J=7.1 Hz, 2H) 7.56 (m, 1H) 7.42 (m, 2H) 7.07 (m, 3H) 5.92 (s, 1H) 4.40 (br s, 1H). 19F NMR (CDCI3) 282 MHz
-136.37 (m) -137.70 (m). Mass spectrum: M+Li=255.
Step 2. Esterification of 2-hydroxy-2-(3,4-difluorophenyl)-
1-phenylethanone
The ethanone from Step 1 (5.93 g, 23.9 mmol) was
dissolved in THF (6 mL), 2, 2-dimethyl-1,3-dioxane-4,6-dione
(3.70 g, 25.7 mmol) was added and the reaction heated to reflux for 23.7 hours. Additional 2, 2-dimethyl-1,3-dioxane-
4,6-dione (1.46 g, 10.1 mmol) was added and the reaction was stirred at reflux an additional 19.7 hours. The reaction mixture was partitioned between saturated NaHCO3 and diethyl ether. The aqueous layer was acidified with concentrated
HCl, extracted with diethyl ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil (6.05 g) which was used in the next step without further purification.
Step 3. Preparation of methyl [5-(3,4-difluorophenyl)-4- hydroxy-4-phenyl-2-oxazolinyl]acetate
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 reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate, washed with water, saturated NaHCO3, and brine, dried over MgSO4 , and concentrated in vacuo to give an orange oil (4.64 g, 74%) which was used in the next step without further purification. Step 4. Preparation of methyl-[4-(4-aminosulfonylphenyl)-5-
(3,4-difluorophenyl)]-2-oxazoleacetate.
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 organic layer was concentrated in vacuo, dissolved in ethyl acetate, washed with 3N HCl, brine, dried over MgSO4, concentrated in vacuo, passed through a column of silica gel eluting with 45% ethyl acetate/hexane, and recrystallized from ethyl acetate/hexane to give a yellow solid (0.71 g, 27%): mp 144-149 °C. 1H NMR (acetone-d6) 300 MHz δ 7.92 (d,
J=8.7 Hz, 2H 7.84 (d, J=8.5 Hz, 2H) 7.58 (m, 1H) 7.47 (m,
2H) 6.67 (br s, 1H) 4.06 (s, 2H) 3.75 (s, 3H). 19F NMR
(acetone-d6) 282 MHz -138.46 (m) -138.79 (m). High
resolution mass spectrum Calc'd. for C18 H15F2N2O5S:
409.0670. Found: 409.0686.
Step 5. Preparation of [ 4-(4-aminosulfonylphenyl-5-(3,4- difluorophenyl)]-2-oxazoleacetate.
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 mL 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
HCl and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over MgSO4, and concentrated in vacuo to give a white solid (0.49 g, 80%): mp 223-227 °C. 1H NMR (acetone-d6) 300 MHz δ 7.92 (d, J=8.7 Hz, 2H) 7.85 (d, J=8.7 Hz, 2H) 7.58 (m, 1H) 7.48 (m, 2H) 6.66 (br s, 1H) 4.04 (s, 2H) 19F NMR (acetone-d6) 282 MHz -138.97 (m) -139.24 (m).
Figure imgf000125_0001
[2-Trifluoromethyl-5-(3,4-difluorophenyl)-4- oxazolyl]benzenesulfonamide
Step 1. Preparation of 3-trifluoromethyl-4-phenyl-5-(3,4- difluorophenyl)oxazole.
A solution of 2-hydroxy-2-(3,4-difluorophenyl)-1- phenylethanone (Example 41, Step 1) (3.48 g, 14.0 mmol) in dimethylformamide (DMF) (15 mL) was added to a solution of trifluoroacetonitrile (1.85 g, 19.5 mmol) in DMF (150 mL).
The reaction was cooled to 5 °C, treated with 1,8- diazabicyclo[5.4.0]undecane (DBU) (2.31 g , 15.2 mmol), and stirred for ι5.3 hours at room temperature and 3.5 hours at
90 °C. The reaction mixture was diluted with ethyl acetate, washed with 3N HCl, saturated NaHCO3, brine, dried over
MgSO4, concentrated in vacuo, and passed through a column of silica gel eluting with 10% diethyl ether/hexane to give a clear oil (2.35 g, 52%): 1H NMR (acetone-d6) 300 MHz δ 7.66
(m, 3H) 7.47 (m, 5H). 19F NMR (acetone-d6) 282 MHz -67.02 (s) -137.15 (m) -138.58 (m).
Step 2. Preparation of 4-[5-(3,4-difluorophenyl)-2- trifluoromethyl-4-oxazolyl]benzenesulfonamide 3-Trifluoromethyl-4-phenyl-5-(3,4-difluorophenyl)oxazole from Step 1 (1.02 g, 3.14 mmol) was stirred with
chlorosulfonic acid (9.5 mL) for 0.9 hours at room
temperature and then for 2.5 hours at 75º 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. The organic layer was concentrated in vacuo, dissolved in ethyl acetate, washed with 3N HCl, brine, dried over MgSO4, concentrated in vacuo, and recrystallized from ethyl acetate/hexane to give a tan solid (0.87 g, 69%): mp 146-148 °C. 1H NMR (acetone-d6) 300 MHz δ 7.97 (d, J=8.5 Hz,
2H) 7.88 (d, J=8.7 Hz, 2H) 7.71 (m, 1H) 7.58 (m, 2H) 6.70 (br s, 1H). 19F NMR (acetone-d6) 282 MHz -67.04 (s) -136.52 (m) -138.30 (m). High resolution mass spectrum Calc'd. for
C16H10F5N2O3S: 405.0332. Found: 405.0323.
Figure imgf000126_0001
β-[5-(4-Aminosulfonylphenyl)-4-phenyl]-2- oxazolepropionic acid 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). The combined organic layers were washed with 1 N HCl followed by brine and water, dried over MgSO4 and
concentrated. The crude product was purified by
recrystallization from ethyl acetate/hexane to afford a white solid (0.6 g, 47.4%): mp 236-239 °C. 1H NMR (DMSO-d6) 300 MHz δ 12.15 (bs, 1H) 7.84 (d, J=8.5 Hz, 2H) 7.68 (d, J=8.5 Hz,
2H) 7.4-7.5 (m, 7H) 3.07 (t, J=7.1 Hz, 2H) 2.78 (t, J=7.1 Hz, 2H). Anal. Calc'd. for C18H16N2O5S: C, 58.06; C, 58.22; H,
4.33; H, 4.52; N, 7.52; N, 7.30.
Figure imgf000127_0001
4-[4-Phenyl-5-oxazolyl]benzenesulfonamide
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
1.0 hour. Formamide (10 mL) was added and the mixture was concentrated to remove dichloromethane. The residue was heated to 50 °C overnight, cooled, diluted with ether, washed with 1 N HCl, brine, water dried over MgSO4, concentrated in vacuo, and passed through a column of silica gel eluting with (1:16) ethyl acetate/hexane to give a clear oil (3.1 g, 70 %): 1H NMR (CDCl3) 300 MHz 7.96 (s, 1H) 7.60-7.70 (m, 4H)
7.31-7.41 (m, 6H). Anal. Calc'd. for C15H11NO·1.5 H2O: C,
80.20; H, 5.10; N, 6.24. Found: C, 80.20; H, 5.07; N, 6.25.
Step 2. Preparation of 4-[4-phenyl-5- oxazolyl]benzenesulfonamide
4, 5-Diphenyloxazole from Step 1 (0.5 g, 2.3 mmol) was added to chlorosulfonic acid cooled to 0 °C (5 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) and stirred for 1.0 hour and extracted with dichloromethane (3 X
50 mL). The combined organic layers were washed with 1 N HCl followed by brine and water, dried over MgSO4 and
concentrated. The residue was purified by recrystallization from ether/hexanes to give a white solid (0.3 g, 4.4 %) : mp 122-125 °C. 1H NMR (acetone-d6) 300 MHz δ 8.35 (s, 1H) 7.88
(d, J=8.7 Hz, 2H) 7.79 (d, J=8.7 Hz, 2H) 7.64-7.70 (m, 2H) 7.40-7.5 (m, 3H) 6.68 (bs, 2H). Anal. Calc'd. for
C15H12N2O3S: C, 59.9;9 H, 4.03; N, 9.33. Found: C, 60.09; H, 4.05; N, 9.27.
Figure imgf000129_0001
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
Step 1. Preparation of 4,5-diphenyloxazolone.
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 was used in the next step without further purification: 1H NMR (DMSO-d6) 300 MHz δ 7.2-7.5 (m, 11H).
Step 2. Preparation of 2-chloro-4,5-diphenyl-oxazole.
4,5-Diphenyloxazolone from Step 1 (30 g, 0.126 mol), triethylamine (12.8 g , 0.126 mol), and phosphorous
oxychloride (96.6 g , 0.63 mol) were stirred at reflux for 4.0 hours. The mixture was concentrated in vacuo and dissolved in ether (250 mL), washed with 1 N HCl, brine, water, dried over MgSO4 and concentrated to a light yellow oil which was used in the rext step without further purification or characterization.
Step 3 . Preparation of 4- [ 2 -chloro-4-phenyl-5- oxazolyl]benzenesulfonamide.
2-Chloro-4,5-diphenyl-oxazole from Step 2 (1.53 g, 6 mmol) was added to chlorosulfonic acid cooled to 0 °C (20 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 mixture was stirred for 1.0 hour and extracted wich dichloromethane (3 X 50 mL). The combined organic layers were washed with 1 N HCl followed by brine and water, dried over MgSO4 and concentrated. Recrystallization from ethyl acetate/hexanes gave a white solid (1.5 g, 75 %): mp 158-159 °C. 1H NMR (acetone-d6) 300 MHz δ 7.98 (d, J=8.7
Hz, 2H) 7.78 (d, J=8.7 Hz, 2H) 7.64-7.70 (m, 2H) 7.42-7.5 (m, 3H) 6.72 (bs, 2H). Anal. Calc'd. for C15H11N2O3SCl: C,
53.82; H, 3.31; N, 8.37. Found: C, 53.92; H, 3.32; N, 8.33.
Figure imgf000130_0001
4-[2-Mercapto-4-phenyl-5-oxazolyl]benzenesulfonamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(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 MgSO4 and concentrated. Recrystallization from ethyl acetate/hexanes gave the product as a brown solid (0.8 g, 48 %) : mp 247-249 °C. 1H NMR (acetone-d6) 300 MHz δ 12.1 (bs, 1H) 7.89 (d, J=8.7 Hz, 2H) 7.62-7.68 (m, 4H) 7.54-7.59 (m, 3H) 6.7 (bs, 2H). Anal. Calc'd. for C15H12N2O3S2: C, 54.20; H, 3.64; N, 8.43. Found: C, 54.27; H, 3.68; N, 8.41.
Figure imgf000131_0001
4-[2-(3-Chlorophenoxy)-4-phenyl-5- oxazolyl]benzenesulfonamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(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 MgSO4 and concentrated. The residue was dissolved in ethyl acetate/hexanes (1:1) and filtered through silica. The eluant was concentrated and the residue recrystallized from ethyl acetate/hexanes to afford the product as a light yellow solid (1.4 g, 66 %): mp 138-140 °C. 1H NMR (acetone-d6) 300 MHz δ 7.92 (d, J=8.9 Hz, 2H) 7.75
(d, J=8.9 Hz, 2H) 7.7 (m, 1H) 7.60-7.65 (m, 2H) 7.54-7.56 (m,
2H) 7.38-7.46 (m, 4H) 6.90 (bs, 2H) . Anal. Calc'd. for C21H15N2O4SCl: C, 59.09; H, 3.54; N, 6.56. Found: C,
59.02; H, 3.55; N, 6.61.
EXAMPLE 48
Figure imgf000132_0001
5-(4-Aminosulfonylphenyl)-4-phenyl-2- oxazolemercaptoacetic acid
4- [2-Chloro-4-phenyl-5-oxazolyl] benzenesulfonamide
(Example 45) (1.67 g, 5 mmol), DMF (20 mL), sodium hydride
(1.32 g, 5.5 mmol), and mercaptoacetic acid, sodium salt
(0.63 g, 5.5 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 MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate:methanol:water
(20:10:1) to provide the product as a light yellow solid (0.8 g, 41 %): mp 235-238 °C. 1H NMR (D2O) 300 MHz δ 7.62 (d,
J=8.7 Hz, 2H) 7.43 (d, J=8.7 Hz, 2H) 7.32 (m, 5H) 3.76 (s,
2H). High resolution mass spectrum Calc'd. for
C17H15N2O5S2: 391.0422. Found: 391.0423.
Figure imgf000133_0001
4-[4-Phenyl-2-(2,2,2-trifluoroethoxy-5- oxazolyl]benzenesulfonamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.67 g, 5 mmol), DMF (20 mL), potassium
carbonate (1.38 g, 10 mmol), and 2,2,2-trifluoroethanol (0.75 g, 7.5 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 MgSO4 and
concentrated. The residue was dissolved in ethyl
acetate/hexanes (1:1) and filtered through silica. The eluant was concentrated and recrystallized from ethyl
acetate/hexanes to provide the product was a white solid (1.4 g, 70 %): mp 180-182 °C. 1H NMR (CDCl3) 300 MHz δ 7.85 (d,
J=8.5 Hz, 2H) 7.65 (d, J=8.5 Hz, 2H) 7.6 (m, 2H) 7.4 (m, 3H) 4.9 (dd, J=8.1 Hz, 2H) 4.85 (bs, 2H). Anal. Calc'd. for
C17H13N2O4S1F3 : C, 51-26; H, 3.29; N, 7.03. Found: C, 51.32; H, 3.30; N, 7.01.
Figure imgf000134_0001
4-[2-(Methylthio)-4-phenyl-5- oxazolyl]benzenesulfonamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.67 g, 5 mmol), methanol (50 mL), and sodium thiomethoxide (0.39 g, 5.5 mmol) were stirred at room
temperature for 16.0 hours. The solution was concentrated and dissolved in ethyl acetate (100 mL), washed with 1 N HCl, brine and water, dried over MgSO4 and concentrated. The residue was recrystallized from ethyl acetate/hexanes to give the product was a light yellow solid (1.4 g, 81 %) : mp 162- 164 °C. 1H NMR (CDCl3) 300 MHz δ 7.85 (d, J=8.9 Hz, 2H) 7.68
(d, J=8.9 Hz, 2H) 7.6 (m, 2H) 7.4 (m, 3H) 4.85 (bs, 2H) 2.75 (s, 3H). Anal. Calc'd. for C16H14N2O3S2: C, 55.48; H,
4.07; N, 8.09. Found: C, 55.56; H, 4.10; N, 8.15.
Figure imgf000134_0002
4-[2-Methyl-4-phenyl-5-oxazolyl]benzenesulfonamide Chlorosulfonic acid (25 mL) was cooled to -78 °C with stirring and 2-methyl-4,5-diphenyloxazole (Aldrich) (2.0 g,
8.5 mmol) was added, and the stirred solution was warmed to room temperature for 4.0 hours. The mixture was then added dropwise to ice and dichloromethane (100 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 (20 mL). The solution was stirred for 1.0 hour and extracted with dichloromethane (3 X
50 mL). The combined organic layers were washed with 1 N HCl followed by brine and water, dried over MgSO4 and
concentrated. The residue was purified by recrystallization from ethanol water to give the product as a white solid (1.6 g, 60 %): mp 176-178 °C. 1H NMR (acetone-d6) 300 MHz δ 7.92
(d, J=8.7 Hz, 2H) 7.74 (d, J=8.7 Hz, 2H) 7.61-7.66 (m, 2H)
7.40-7.48 (m, 3H) 6.68 (bs, 2H) 2.53 (s, 3H). Anal. Calc'd. for C16H14N2O3S: C, 61.13; H, 4.49; N, 8.91. Found: C,
60.89; H, 4.53; N, 8.85.
Figure imgf000135_0001
2-[5-[(4-Aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]ethan-2-one Step 1: Preparation of 2-[5-[(4-Aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]- (2-hydroxy)ethane
A solution of 2-bromo-2-[(4-aminosulfonyl)phenyl]-1- phenylethanone (0.5 g, 1.41 mmol) in 3 mL of anhydrous DMF was added to a suspension of lactic acid sodium salt (0.16 g, 1.41 mmol) in 2 mL of anhydrous DMF, and the reaction mixture was stirred for 18 h at room temperature. The DMF was then removed under vacuum. Ethyl acetate (50 mL) was added to the concentrated residue, and the mixture was filtered. The filtrate was concentrated and dried under vacuum. Acetic acid (5 mL) and ammonium acetate (0.33 g, 4.28 mmol) were added to this concentrated residue. 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. The concentrated residue was purified by flash chromatography on silica gel eluting with 45% ethyl acetate in hexane to give 0.26 g (57%) of 2-[5-[(4- aminosulfonyl)-phenyl]-4-phenyl-oxazol-2-yl]-(2- hydroxy) ethane as a yellow solid. 1H NMR (CDCI3/300 MHz) 1.72 (d, 3H, J = 6.60 Hz), 2.69 (d, 1H, J = 5.50 Hz), 4.87
(bs, 2H), 5.05-5.13 (m, 1H), 7.41-7.43 (m, 3H), 7.56-7.60 (m, 2H), 7.72 (d, 2H, J = 8.40 Hz), 7.89 (d, 2H, J = 8.70 Hz). HRMS (calcd for C17H16N2O4S1 345.0909) 345.0896. Step 2: Preparation of 2-[5-[(4-aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]ethan-2-one
e
The 2-[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl](2-hydroxy)ethane (0.3 g, 0.87 mmol) from Step 1 was suspended in 15 mL of methylene chloride. Pyridinium chlorochromate (0.3 g, 1.4 mmol) and molecular sieves (0.4 g) were added, and the resulting mixture was stirred for 10 minutes at room temperature. Acetone (5 mL) was added, and the reaction mixture was stirred for 48 h at room
temperature. The reaction mixture was filtered, and the filtrate was concentrated. The concentrated residue was crystalized from ethyl acetate and hexane to give 0.11 g (30%) of 2-[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl ] ethan-2 -one as a white solid, m. p . 208 . 5-210 . 2 °C . 1H NMR(DMSO-d6/300 MHz) 2.65 (s, 3H), 7.45-7.52 (m, 5H), 7.59- 7.62 (m, 2H), 7.78 (d, 2H, J = 8.40 Hz), 7.90 (d, 2H, J = 8.40 Hz). HRMS (calcd. for C17H14N2O4S1 343.0753) 343.0728.
Figure imgf000137_0001
4- [2-Methylsulfinyl)-4-phenyl-5- oxazolyl]benzenesulfonamide
4-[2-Methylthio-4-phenyl-5-oxazolyl]benzenesulfonamide
(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 MgSO4 and concentrated. The residue was purified by flash
chromatography eluting with ethyl acetate:hexanes (1:3). The first material collected was concentrated and recrystallized to yield 4-[2-methylsulfonyl)-4-phenyl-5- oxazolyl]benzenesulfonamide as a white solid (0.3 g, 55 %): mp 186-188 °C. 1H NMR (DMSO-d6) 300 MHz δ 7.92 (d, J=8.5 Hz,
2H) 7.81 (d, J=8.5 Hz, 2H) 7.6 (m, 2H) 7.48 (m, 5H) 3.3 (s, 3H). Anal. Calc'd. for C16H14N2O5S2: C, 50.78; H, 3.73; N,
7.40. Found: C, 50.79; H, 3.72; N, 7.38. The second material collected was concentrated and recrystallized to yield 4-[2-methylsulfinyl)-4-phenyl-5- oxazolyl] benzenesulfonamide as a white solid (0.16 g, 31 %) : mp 174-176 °C. 1H NMR (DMSO-d6) 300 MHz δ 7.9 (d, J=8.5 Hz,
2H) 7.8 (d, J=8.5 Hz, 2H) 7.6 (m, 2H) 7.48 (m, 5H) 3.2 (s, 3H). Anal. Calc'd. for C16H14N2O4S2: C, 53.03; H, 3.89; N,
7.73. Found: C, 53.08; H, 3.85; N, 7.66.
Figure imgf000138_0001
4-[2-(2,3,4,5,6-Pentafluorophenoxy)-4-phenyl-5- oxazolyl]benzenesulfonamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(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 MgSO4 and concentrated.
The residue was dissolved in ethyl acetate/hexanes (1:1) and filtered through silica and the eluant concentrated and recrystallized from ethyl acetate/hexanes to afford the product was a white solid (0.4 g, 28 %) : mp 146-148 °C. 1H NMR (DMSO-d6) 300 MHz δ 7.88 (d, J=8.5 Hz, 2H) 7.71 (d, J=8.5
Hz, 2H) 7.56 (m, 2H) 7.42-7.48 (m, 5H).
Figure imgf000139_0001
4-[2-Methoxy-4-phenyl-5-oxazolyl]benzenesulfonamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.0 g, 3 mmol), methanol (15 mL), and sodium methoxide (25 % in methanol) (0.65 g, 6 mmol) were stirred at room temperature for 16.0 hours. Water was added until crystals appeared that were isolated by filtration to afford the desired product as a white solid (0.6 g, 61 %) : mp 180- 182 °C. 1H NMR (DMSO-d6) 300 MHz δ 7.81 (d, J=8.5 Hz, 2H)
7.62 (d, J=8.5 Hz, 2H) 7.57 (m, 2H) 7.38-7.46 (m, 5H) 4.12 (s, 3H). Anal. Calc'd. for C16H14N2O4S: C, 58.17; H, 4.27;
N, 8.48. Found: C, 58.12; H, 4.31; N, 8.44.
Figure imgf000140_0001
Ethyl 2-[[5-(4-aminosulfonylphenyl)-4-phenyl-2
oxazolyl]oxy]benzoate
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.0 g, 3 mmol), DMF (20 mL), potassium
carbonate (0.46 g, 3.3 mmol), and ethyl salicylate (0.55 g,
3.3 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 MgSO4 and concentrated. The residue was dissolved in ethyl acetate/hexanes (1:1) and filtered through silica. The eluant was concentrated and recrystallized from ethyl acetate/hexanes to give the product was a white solid (0.7 g, 50 %) : mp 183-184 °C. 1H NMR
(CDCI3/CD3OD) 300 MHz 8.12 (dd, J=1.8 Hz and J=7.8 Hz, 1H)
7.86 (d, J=8.5 Hz, 2H) 7.62-7.72 (m, 3H) 7.38-7.54 (m, 7H) 4.35 (dd, J=7.2 Hz, 2H) 1.3 (t, J=7.2 Hz, 3H). Anal.
Calc'd. for C24H20N2O6S: C, 62.06; H, 4.34; N, 6.03. Found:
C, 61.85; H, 4.37; N, 5.91.
Figure imgf000141_0001
Ethyl 3-[[5-(4-aminosulfonylphenyl)-4-phenyl-2- oxazolyl]oxy]benzoate
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.0 g, 3 mmol), DMF (20 mL), potassium
carbonate (0.46 g, 3.3 mmol), and ethyl 3-hydroxybenzoate
(0.55 g, 3.3 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 MgSO4 and concentrated. The residue was dissolved in ethyl
acetate/hexanes (1:1), filtered through silica and the eluant was concentrated and recrystallized from ethyl
acetate/hexanes to give the product as a white solid (0.6 g, 43 %): mp 157-158 °C. 1H NMR (CDCl3/CF3CO2H) 300 MHz δ 8.12
(dd, J=1.6 Hz and J=0.6 Hz, 1H) 7.94-8.0 (dt, J=1.0 Hz and J=7.8 Hz, 1H) 7.89 (d, J=8.7 Hz, 2H) 7.72 (d, J=8.7 Hz, 2H)
7.67 (m, 1H) 7.60 (m, 2H) 7.52 (m, 1H) 7.4 (m, 3H) 4.56 (s,
2H) 4.4 (q, J=7.1 Hz, 2H) 1.4 (t, J=7.1 Hz, 3H). Anal.
Calc'd. for C24H20N2O6S: C, 62.06; H, 4.34; N, 6.03. Found:
C, 62.00; H, 4.36; N, 5.95.
Figure imgf000142_0001
4-[2-(N,N-Dimethylamino)-4-phenyl-5- oxazolyl]benzenesulfonamide
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide
(Example 45) (1.0 g, 3 mmol) and 40 % aqueous dimethylamine (25 mL) were stirred at room temperature for 16.0 hours, diluted with ethyl acetate (100 mL), washed with brine and water, dried over MgSO4 and concentrated. The residue was recrystallized from ethyl acetate/hexanes to afford the product as a light yellow/green solid (0.6 g, 58 %): mp 254- 256°C. 1H NMR (DMSO-d6) 300 MHz 7.74 (d, J=8.7 Hz, 2H) 7.56
(m, 4H) 7.38-7.46 (m, 3H) 7.33 (bs, 2H) 3.08 (s, 6H). Anal. Calc'd. for C17H17N3O3S: C, 57.31; H, 5.21; N, 11.79.
Found: C, 57.32; H, 5.23; N, 11.73.
Figure imgf000143_0001
4-[5-(4-Chlorophenyl)-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide
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 NaHCO3, dried over MgSO4 and concentrated in vacuo to give the trimethylsilyl cyanohydrin as an orange oil (13.90 g).
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 NaHCO3 and brine, dried over
MgSO4, 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% Na2CO3 and brine, dried over MgSO4, concentrated in vacuo to give a yellow solid (9.43 g) and used in the next step without further purification.
Step 2. Preparation of 2-trifluoromethyl-4-phenyl-5-(4- chlorophenyl)oxazole.
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 1N HCl and extracted with 500 mL ethyl acetate. The organics were washed consecutively with 1N HCl (400 mL), NaHCO3 (saturated) (400 mL) and brine (400 mL), dried over
Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluting with 10% ether in hexane to give a white solid (2.2 g, 67%): mp 53-53 °C. Anal. Calc'd. for C16H9NOClF3: C, 59.37; H, 2.80; N, 4.33. Found: C, 59.35;
H, 2.76; N, 4.25. Step 3. Preparation of 4-[2-trifluoromethyl-5-(4- chlorophenyl)-4-oxazolyl]benzenesulfonamide.
2-Trifluoromethyl-4-phenyl-5-(4-chlorophenyl)oxazole
(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 1N HCl (2 x 75 mL), NaHCO3 (saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated.
The crude material was crystallized from ethyl acetate/hexane to yield 4-[5-(4-chlorophenyl)-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide (0.84 g, 75%): mp 167-168 °C. Anal. Calc'd. for C16 H10 N2O3 SClF3 : C, 47.71; H, 2.50; N,
6.96. Found: C, 47.62; H, 2.44; N, 6.88.
Figure imgf000145_0001
4-[5-(3-Fluoro-4-methoxyphenyl-2-trifluoromethyl)-4- oxazolyl]benzenesulfonamide Step 1. Preparation of 3-fluoro-p-anisaldehyde silyl cyanohydrin.
3-Fluoro-p-anisaldehyde (14.68 g, 95.2 mmol) was dissolved in anhydrous methylene chloride (300 mL) and Znl2
(0.4 g) was added. Trimethylsilyl cyanide (12.7 g, 95.2 mmol) and methylene chloride (75 mL) were added dropwise over
10 minutes. The reaction was stirred an additional 20 minutes and separated. The organics were washed
consecutively with water (350 mL), NaHCO3 (saturated) (300 mL) and brine (300 mL). The methylene chloride was dried over Na2SO4 and concentrated to yield silyl cyanohydrin
(24.52 g, 100%) which was used without further purification. Step 2. Preparation of 3'-fluoro-4'-methoxy benzoin.
3-Fluoro-p-anisaldehyde silyl cyanohydrin (from Step 1)
(24.52 g, 96.8 mmol) and diethyl ether (75 mL) added dropwise to the solution of diethyl ether (250 mL) and phenyl
magnesium bromide (3M in ether, 34 mL) were added at such a rate that the reaction temperature did not rise above 30 °C.
Upon complete addition, the reaction (which now contained a gummy precipitate) was stirred an additional 15 minutes at which time 1N HCl (400 mL) was added and the reaction stirred until all solids were dissolved. The reaction was poured into a IL separatory funnel and the layers separated. The organics were washed with NaHCO3 (saturated) (400 mL) and brine (400 mL), dried over Na2SO4 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 NaHCO3(aq.). The benzoin was extracted with ethyl acetate (350 mL) and washed with NaHCO3 (saturated) (300 mL) and brine (300 mL).
Crystallization of crude benzoin from ether and hexane yielded a first crop of crystals which were >99% pure (14.9 g) : mp 84-85 °C. Anal. Calc'd. for C15H13 O3F: C, 69.22;
H, 5.03. Found: C, 69.13; H, 5.07. Step 3. Preparation of 2-trifluoromethyl-4-phenyl-5-(3- fluoro-4-methoxyphenyl)oxazole.
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 1N HCl and extracted with 500 mL ethyl acetate. The organics were washed consecutively with 1N HCl (400 mL), NaHCO3 (saturated) (400 mL) and brine (400 mL) dried over Na2SO4 and concentrated. The crystalline solid residue was recrystallized from ether and hexane to yield analytically pure oxazole (2.32 g, 86%): mp 75-76 °C. Anal. Calc ' d . for C17H11NO2F4 : C , 60 . 54 ; H, 3 .29 ; N, 4 . 15 . Found: C, 60.62;
H, 3.30; N, 4.18.
Step 4. Preparation of 4-[5-(3-fluoro-4-methoxyphenyl)-2- trifluoromethyl-4-oxazolyl]benzenesulfonamide
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 1N HCl (2 x 75 mL), NaHCO3 (saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated. The crude material was
chromatographed over Si02 eluting with a gradient from 10% -
35% ethyl acetate in hexane to yield 4-[5-(3-fluoro-4- methoxyphenyl)-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide (20 mg, 5%): mp 150-151 °C. 1H NMR (acetone-d6), 300 MHz δ 3.99 (s, 3H), 6.69 (s, 2H), 7.32 (t, 1H), 7.51 (m, 2H), 7.85 (d, J=8.3 Hz, 2H), 7.97 (d, J=8.3 Hz, 2H).
Figure imgf000148_0001
4-Methyl-3-[5-phenyl-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide
Figure imgf000148_0002
4-[4-(3-Aminosulfonyl-4-methylphenyl)-2- trifluoromethyl-5-oxazolyl]benzenesulfonamide Step 1. Preparation of 2-hydroxy-2-phenyl-1-(4- methylphenyl)ethanone.
The trimethylsilyl cyanohydrin of benzaldehyde Example 34, Step 1 (5.0 g, 24.4 mmol) was dissolved in diethyl ether (50 mL) and added dropwise to a solution of 4- methylphenyImagnesium bromide (29.3 mmol) in diethyl ether (130 mL) while maintaining the temperature between 23-35 °C with an ice water bath. The reaction was stirred for 0.5 hours at room temperature. At this time 1N HCl (100 mL) and ether (150 mL) were added and the layers separated. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo to give a yellow oil. The yellow oil was dissolved in 9:1 trifluoroacetic acid/water (30 mL) and stirred for 0.5 hours at room
temperature. The reaction was neutralized with solid sodium bicarbonate, extracted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over Na2SO4, concentrated in vacuo and recrystallized from diethyl ether/hexane to give the benzoin (2.54 g, 46%): 1H NMR (CDCl3) 300 MHz, δ 2.35 (s,
3H), 4.45 (broad s, 1H), 5.92 (s, 1H), 7.19 (m, 2H), 7.32 (m, 3H), 7.82 (m, 2H).
Step 2. Preparation of 2-trifluoromethyl-4-(4-methyl phenyl)-5-phenyloxazole.
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 1N HCl and extracted with 500 mL ethyl acetate. The organics were washed consecutively with 1N HCl (400 mL), NaHCO3
(saturated) (400 mL) and brine (400 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluting with 1% ether in hexane to give a white solid (0.72 g, 40%): mp 49-50 °C. Anal. Calc'd. for C17H12NOF3: C, 67.33; H, 3.99; N, 4.62. Found: C, 67.27;
H, 3.99; N, 4.58. Step 3. Preparation of 2-trifluoromethyl-4-(4-methyl phenyl)-5-phenyloxazole.
2-Trifluoromethyl-4-(4-methylphenyl)-5-phenyloxazole from Step 2 (0.4 g) was added to chlorosulfonic acid (10 mL) cooled to 0 °C and the reaction was warmed to room
temperature for 2 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 1N HCl (2 x 75 mL), NaHCO3 (saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated.
The crude material was chromatographed, eluting with a gradient from 10-60% ethyl acetate in hexane to yield 4- methyl-3-[5-phenyl-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide (141 mg, 28%) : mp 150-151 °C;
Anal. Calc'd. for C17H13N2O3SF3 : C, 53.40; H, 3.43; N,
7.27. Found: C, 53.33; H, 3.48; N, 7.27; and 4-[4-(3- aminosulfonyl-4-methylphenyl)-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide (150 mg, 25%) : mp 241-242 °C;
Anal. Calc'd. for C17H14N3O5S2F3: C, 44.25; H, 3.06; N,
9.11; Found: C, 44.34; H, 3.07; N, 9.05.]
Figure imgf000151_0001
4-Methyl-3-[4-phenyl-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide
Step 1. Preparation of 2-hydroxy-2-(4-methylphenyl)-1- phenylethanone.
A solution of p-tolulylaldehyde (33.55 g, 279 mmol) and trimethylsilylcyanide (38 mL, 285 mmol) in dichloromethane
(160 mL) was treated with zinc iodide (0.34 g). The solution was stirred for 0.33 hours at room temperature, washed with water and saturated NaHCO3, dried over MgSO4 and
concentrated in vacuo to give the trimethylsilyl cyanohydrin as a yellow oil (59.76 g). The trimethylsilyl cyanohydrin was dissolved in diethyl ether (200 mL) and added dropwise to a solution of phenyImagnesium bromide (285 mmol) in diethyl ether (1095 mL) while maintaining the temperature between 25- 30 °C with an ice water bath. The reaction was stirred for
0.5 hours at room temperature then quenched by adding 3N HCl
(220 mL). The organic layer was collected, washed with saturated NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo to give an orange oil (48.22 g). The orange oil was dissolved in 9:1 trifluoroacetic acid/water
(100 mL) and stirred for 0.67 hours at room temperature. The reaction was extracted with ethyl acetate, washed with 10% Na2CO3 and brine, dried over MgSO4, and concentrated in vacuo to give a brown solid which was recrystallized from diethyl ether/hexane to give the benzoin (32.90 g, 52%): mp 118-123 °C. 1H NMR (CDCl3) 300 MHz δ7.90 (d, J=7.1 Hz, 2H) 7.57 (m,
1H) 7.39 (m, 2H) 7.21 (d, J=8.1 Hz, 2H) 7.14 (d, J=7.9 Hz, 2H) 5.93 (s, 1H) 4.50 (br s, 1H) 2.29 (s, 3H).
Step 2. Preparation of 2-trifluoromethyl-4-phenyl-5-(4- methylphenyl)oxazole.
Trifluoroacetonitrile (1.57 g (16.5 mmol) was added to DMF (100 mL). This solution 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 1N HCl and extracted with 500 mL ethyl acetate. The organics were washed consecutively with 1N HCl (400 mL), NaHCO3 (saturated) (400 mL) and brine (400 mL), dried over Na2S)4 and
concentrated. The residue was purified by silica gel
chromatography eluting with 5% ether in hexane to give a white solid (1.28 g, 31%): mp 54-55 °C. Anal. Calc'd. for C17H12NOF3: C, 67.33; H, 3.99; N, 4.62. Found: C, 67.22; H, 3.94; N, 4.55.
Step 3. Preparation of 5-(3-aminosulfonyl-4-methylphenyl)-4- phenyl-2-trifluoromethyloxazole.
2-Trifluoromethyl-4-phenyl-5-(4-methylphenyl)oxazole from Step 2 (0.34 g) was added to chlorosulfonic acid cooled to 0 °C (12 mL) and the reaction was warmed to room
temperature for 1.25 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 1N HCl (2 x 75 mL), NaHCO3 (saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated.
The crude material was crystallized from ethyl acetate and hexane to yield 2-trifluoromethyl-4-phenyl-5-(3- aminosulfonyl-4-methylphenyl) oxazole (184 mg, 54 %) : mp 156- 157 °C. Anal. Calc'd. for C17H13N2O3SF3: C, 53.40; H,
3.43; N, 7.33. Found: C, 53.23; H, 3.44; N, 7.31.
Figure imgf000153_0001
4-[4-Phenyl-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide
Step 1. Preparation of 2-trifluoromethyl-4,5-diphenyl oxazole.
Trifluoroacetonitrile (1.58 g, 16.5 mmol) was 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 1N HCl and extracted with
500 mL ethyl acetate. The organics were washed consecutively with 1N HCl (400 mL), NaHCO3 (saturated) (400 mL) and brine
(400 mL), dried over Na2SO4 and concentrated. The residue was purifieft by silica gel chromatography eluting with 5% ether in hexane to give a white solid (1.75 g, 45%): mp 70-71 °C. Anal. Calc'd. for C16H10NOF3: C, 66.44; H, 3.48; N,
4.84. Found: C, 67.33; H, 3.52; N, 4.92.
Step 2. Preparation of 4-[4-phenyl-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide.
2-Trifluoromethyl-4,5-diphenyloxazole from Step 1
(0.77g, 2.8 mmol) was added to chlorosulfonic acid (25 mL) (cooled to 0 °C) and the reaction was stirred from 0 °C 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 and washed consecutively with 1N HCl (2 x 75 mL), NaHCO3
(saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated. The crude material was crystallized from ethyl acetate and hexane to yield 4-[4-phenyl-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide (0.56 g, 57%): mp 137-138 °C.
Anal. Calc'd. for C16H11N2O3SF3: C, 52.18; H, 3.01; N,
7.61. Found: C, 52.15; H, 2.98; N, 7.52.
Figure imgf000155_0001
4-[4-Dimethylaminophenyl-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide
Step 1. Preparation of 2-trifluoromethyl-4-(4- dimethylaminophenyl)-5-phenyloxazole.
The oxazole was prepared as described in Example 32 with the substitution of 4-dimethylaminobenzoin (3.06 g, 12 mmol) to give a yellow solid (1.84 g, 46%): mp 120-121 °C. Anal. Calc'd. for C18H15N2OF3: C, 65.06; H, 4.55; N, 8.43. Found:
C, 65.96; H, 4.52; N, 8.42.
Step 2. Preparation of 4-[4-Dimethylaminophenyl-2- trifluoromethyl-5-oxazolyl]benzenesulfonamide
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.
Anal. Calc'd. for C18H16N3O3SF3 :3 C, 52.55; H, 3.92; N,
10.21. Found: C, 52.29; H, 3.98; N, 10.05.
Figure imgf000156_0001
4-(4-Aminosulfonylphenyl)-5-(3-fluoro-4- methoxyphenyl)-2-oxazoleacetic acid
Ethyl [4-(4-aminosulfonylphenyl)-5-(3-fluoro-4- methoxyphenyl)]-2-oxazoleacetate (8.7 mg 0.021 mmol) (Example 34, Step 4) was dissolved in ethanol (1 mL), and a NaOH solution (2.5 N, 18 ml) was added. The reaction was stirred for 0.25 hours at room temperature at which time HCl (aq., concentrated) was added to acidify the reaction. The aqueous solution was extracted with ethyl acetate (dried over MgSO4) and concentrated to yield [4-(4-aminosulfonylphenyl)-5-(3- fluoro-4-methoxyphenyl)]-2-oxazoleacetic acid (6.0 mg, 70%): 1H NMR (CD3OD) 300 MHz δ 3.91 (s, 3H), 3.97 (s, 2H), 7.19 (t,
1H), 7.31 (m, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.91 (d, J=8.7 Hz,
2H). 19F NMR (CD3OD) 282 MHz d -132.8 (multiplet).
Figure imgf000157_0001
4-[4-Aminosulfonylphenyl)-5-(3-fluoro-4- methoxyphenyl)-2-oxazolyl]α-bromoacetic acid
[4-(4-Aminosulfonylphenyl)-5-(4-chlorophenyl)-2- oxazolyl]acetic acid (Example 66) (65 mg, 0.165 mmol) was dissolved in chloroform (5 mL) and acetic acid (3 mL).
Bromine in acetic acid solution (1.1 M, 0.2 mL) was added and the reaction was stirred for 16 hours. Sodium sulfite was added until the orange color dissipated. 1N HCl (10 mL) was added and the reaction concentrated to dryness. The residue was suspended in acetone (2 mL), filtered through Celite® and concentrated to yield 4-[4-aminosulfonylphenyl)-5-(3-fluoro- 4-methoxyphenyl)-2-oxazolyl]α-bromoacetic acid (73 mg, 94%): 1H NMR (acetone-d6), 300 MHz δ 4.57 (s, 1H), 6.81 (s, 2H), 7.51 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.79 (d, J=8.3 Hz, 2H), 7.94 (d, J=8.3 Hz, 2H).
Figure imgf000158_0001
4-(4-Methylphenyl)-5-(4-methylsulfonylphenyl)-2- trifluoromethyloxazole
Step 1. Preparation of 2-hydroxy-2-(4-methylthiophenyl)-1-
(4-methylphenyl)ethanone.
A solution of p-thioanisaldehyde (15.22 g, 100 mmol) and zinc iodide (1 g) in dichloromethane (100 mL) was treated with a solution of trimethylsilylcyanide (13.3 mL, 100 mmol) in dichloromethane (50 mL). The solution was stirred for 0.5 hours at room temperature, washed with water and saturated NaHCO3, dried over MgSO4 and concentrated in vacuo to give the trimethylsilyl cyanohydrin as an orange oil (24.9 g).
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 1N HCl (250 mL). The organic layer was collected, washed with saturated NaHCO3 and brine, dried over MgSO4, 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 NaHCO3 solution, extracted with ethyl acetate, washed with saturated NaHCO3 solution and brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil. The oil was purified by Si02 chromatography eluting with a gradient from 20-30% ethyl acetate in hexane to yield 2- hydroxy-2-(4-methylthiophenyl)-1-(4-methylphenyl)ethanone
(2.8 g, 51%): 1H NMR (CDCI3) 300 MHz δ 2.36 (s, 3H), 2.43 (s,
3H), 4.54 (d, J=6.0 Hz, 1H), 5.89 (d, J=6.0 Hz, 1H), 7.20 (m, 6H) 7.80 (d, J=8.3 Hz, 2H). Step 2. Preparation of 4-(4-methylphenyl)-5-(4- methylthiophenyl)2-trifluoromethyl-oxazole.
The oxazole was prepared as in Example 64, Step 1, with the substitution of 2-hydroxy-2-(4-methylthiophenyl)-1-(4- methylphenyl)ethanone to give a white solid (0.6 g, 46%): mp 129 -130 °C . Anal . Calc ' d . for C18H14NOSF3 : C , 61 . 88 ; H,
4.04; N, 4.01. Found: C, 61.81; H, 4.09; N, 3.92.
Step 3. 2-trifluoromethyl-4-(4-methylphenyl)-5-(4- methylsulfonylphenyl) 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).
Oxone® (1.2 g, 2 mmol) was added and the reaction stirred for
3 hours. The reaction mixture was filtered and concentrated to dryness. The residue was dissolved in ethyl acetate (200 mL), washed with water, NaHCO3 and brine, dried and
concentrated to yield a white crystalline product (350 mg) which was recrystallized from ethanol and water to yield 4-
(4-methylphenyl)-5-(4-methylsulfonylphenyl)-2- trifluoromethyl-oxazole (300 mg, 79%): mp 141-142 °C. Anal. Calc'd. for C18H14NO3SF3 : C, 56.69; H, 3.70; N, 3.67.
Found : C , 56 . 47 ; H , 3 . 79 ; N, 3 . 57 .
EXAMPLE 69
Figure imgf000160_0001
4-[5-(3-Fluoro-4-methoxyphenyl)-2-methyl-4- oxazolyl]benzenesulfonamide
Step 1. Preparation of 5-(3-fluoro-4-methoxyphenyl)2-methyl-
4-phenyloxazole.
3-Fluoro-4-methoxybenzoin (Example 34, Step 1) (2.6 g,
10 mmol) and acetic anhydride (1.63 g, 16 mmol) were added to THF (150 mL) and cooled to 0 °C. DBU (1.83 g, 12 mmol) was added and the solution was warmed to room temperature for 16 hours. The reaction was poured into 300 mL 1N HCl and extracted with 500 mL ethyl acetate. The organics were washed consecutively with, NaHCO3 (saturated) (400 mL) and brine (400 mL) dried over Na2SO4 and concentrated. Ammonium acetate (6 g) and acetic acid (100 mL) were added to the acetylated benzoin and the solution was heated to reflux for
2.5 hours. The reaction was concentrated to dryness and the residue dissolved in ethyl acetate (250 mL), washed with 1N HCl, NaHCO3 and brine, dried and concentrated to yield a crystalline solid (2.37 g, 65%) which was used without further purification.
Step 2. Preparation of 5-(3-fluoro-4-methoxyphenyl-2-methyl- 4-oxazolyl]benzenesulfonamide
The oxazole of Step 1 was converted to the sulfonamide by the method of Example 64, Step 2 to yield 4-[5-(3-fluoro- 4-methoxyphenyl-2-methyl-4-oxazolyl]benzenesulfonamide (173mg, 55%): 1H NMR (acetone d6), 300 MHz δ 2.52 (s, 3H), 3.96
(s, 3H), 6.61 (s, 2H), 7.24 (m, 1H), 7.37 (m, 2H), 7.81 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H).
Figure imgf000161_0001
5-(3-Fluoro-4-methoxyphenyl)-4-(4- methylsulfonylphenyl)-2-trifluoromethyloxazole
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. 3- Fluoro-p-anisaldehyde silyl cyanohydrin (Example 34, Step 1) (12.7 g, 50 mmol) and diethyl ether (50 mL) were added dropwise to the solution of Grignard at such a rate that the reaction temperature did not rise above 30 °C. Upon complete addition, the reaction was stirred an additional 15 minutes at which time 1N HCl (400 mL) was added and the reaction stirred until all solids were dissolved. The organics were washed with NaHCO3 (saturated) (400 mL) and brine (400 mL), dried over Na2SO4 and concentrated to yield a mixture of benzoin and silyl benzoin. The crude product was dissolved in TFA/H2O (9:1) (75 mL) and stirred for 15 minutes. The TFA solution was poured into saturated NaHCO3 (aq.). The benzoin was extracted with ethyl acetate (350 mL) and washed with NaHC03 (saturated) (300 mL) and brine (300 mL). The crude benzoin was crystallized from ethyl acetate and hexane to yield crystals of 4-methylthio-3'-fluoro-4'-methoxybenzoin (4.9 g, 32%): 1H NMR (CDCI3) 300 MHz δ 2.45 (s, 3H), 3.81 (s, 3H), 5.8 (s, 1H), 6.86 (m, 1H), 7.01 (m, 2H), 7.17 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H); 19F NMR (CDCI3) 282 MHz δ
-134.0 (multiplet).
Step 2. Preparation of 2-trifluoromethyl-4-(4- methylthiophenyl)-5-(3-fluoro-4-methoxyphenyl)oxazole.
5-(3-Fluoro-4-methoxyphenyl)-4-(4-methylthiophenyl)-2- trifluoromethyloxazole was prepared from the benzoin of Step
1 by the method of Example 64, Step 1. The residue was crystallized from ethanol and water to give a white solid (0.26 g, 50%): 1H NMR (CDCI3) 300 MHz δ 2.52 (s, 3H), 3.94
(s, 3H), 6.98 (t, J=8.7 Hz, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.36 (m, 2H), 7.55 (d, J=8.5 Hz, 2H); 19F NMR (CDCI3) 282 MHz δ
-66.6 (s), -134.2 (s). Step 3. Preparation of 5-(3-fluoro-4-methoxyphenyl-4-(4- methylsulfonylphenyl)2-trifluoromethyloxazole.
2-Trifluoromethyl-4-(4-methylthiophenyl)-5-(3-fluoro-4- methoxyphenyl) oxazole from Step 2 (38 mg, 0.1 mmol) was converted by the method of Example 68, Step 3 to yield a white crystalline product which was recrystallized from ethanol and water to yield 5-(3-fluoro-4-methoxyphenyl)-4-(4- methylsulfonylphenyl)-2-trifluoromethyloxazole (39 mg, 94%): 1H NMR (CDCI3) 300 MHz 8 3.1 (s, 3H), 3.96 (s, 3H), 6.98 (t,
J=8.5 Hz, 1H), 7.36 (m, 2H), 7.88 (d, J=8.5 Hz, 2H), 7.98 (d, J=8.5 Hz, 2H); 19F NMR (CDCI3) 282 MHz δ -66.6 (s), -133.5 (s). FAB Mass spec. M + H 416.
Figure imgf000163_0001
4-[5-(3-Bromo-4-methoxy-5-fluorophenyl)-2- trifluoromethyl-4-oxazolyl]benzenesulfonamide
Step 1. Preparation of 3-bromo-5-fluoro-4- hydroxybenzaldehyde.
A solution of 3-fluoro-p-anisaldehyde (10.40 g, 67.5 mmol) in 1,2-dichloroethane (80 mL) was treated with bromine
(3.9 mL, 75.6 mmol) then cooled in ice while adding aluminum chloride (11.87 g, 89.0 mmol). The reaction was stirred for
1.75 hours at room temperature and 1.3 hours at 60 °C: The excess bromine was quenched by adding 10% sodium bisulfite solution. The reaction mixture was extracted with ethyl acetate, washed with 3N HCl, brine, dried over MgSO4, and concentrated in vacuo to give a white solid (14.84 g, 100%): mp 136-138 °C. 1H NMR (acetone-d6) 300 MHz δ 10.30 (br s, 1H)
9.86 (d, J=2.0 Hz, 1H) 7.95 (t, J=1.6 Hz, 1H) 7.70 (dd,
J=10.3 Hz 1.8 Hz, 1H); 19F NMR ( acetone-d6) 282 MHz -133.27
(m). Mass spectrum: M+H=219/221 Step 2. Preparation of 3-bromo-5-fluoro-4- methoxybenzaldehyde.
A solution of 3-bromo-5-fluoro-4-hydroxybenzaldehyde from Step 1 (6.01 g, 27.3 mmol) was treated with methyl iodide (8.89 g, 62.6 mmol) and potassium carbonate (5.79 g,
41.9 mmol). The reaction was stirred for 15.1 hours at 50
°C, filtered and concentrated in vacuo . The residue was dissolved in ethyl acetate, washed with water, 10% sodium hydroxide, and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give a brown oil which was crystallized from diethyl ether/hexane to give a white solid (2.63 g, 41%): mp 47-49 °C. 1H NMR (CDCl3) 300 MHz δ 9.82 (d,
J=2.0 Hz, 1H) 7.85 (t, J=1.6 Hz, 1H) 7.58 (dd, J=11.1 Hz 2.0 Hz, 1H) 4.09 (d, J=3.0 Hz, 3H); 19F NMR (CDCI3) 282 MHz
125.92 (m) . Mass spectrum: M+H=233/235.
Step 3. Preparation of 3'-bromo-4'-methoxy-5'-fluorobenzoin.
A solution of 3-bromo-5-fluoro-4-hydroxybenzaldehyde from Step 2 (2.63 g, 11.2 mmol) and zinc iodide (0.44 g) in methylene chloride (10 mL) was treated with trimethylsilyl cyanide (1.7 mL, 12.7 mmol). The solution was stirred for 0.6 hours at room temperature, washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to give the trimethylsilyl cyanohydrin as a yellow oil (3.04 g). 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 NaHCO3 and brine, dried over MgSO4, 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. The reaction was neutralized with solid potassium carbonate, extracted with ethyl acetate, washed with 10% Na2CO3 and brine, dried over MgSO4, and concentrated in vacuo to give the benzoin (3.15 g) as a yellow oil which was used in the next step without further purification.
Step 4. Preparation of 5-(3-bromo-4-methoxy-5-fluorophenyl-
4-phenyl)-2-trifluoromethyl-oxazole.
5-(3-Bromo-4-methoxy-5-fluorophenyl-4-phenyl)-2- trifluoromethyloxazole was prepared by the method described in Example 64, Step 1, substituting 3'-bromo-4'-methoxy-5'- fluorobenzoin from Step 3. The crystalline solid residue was recrystallized from ether and hexane to yield analytically pure oxazole (1.9 g, 49%): 1H NMR (CDCI3) 300 MHz δ 4.03 (s, 3H), 7.32 (m, 1H), 7.44 (m, 3H), 7.63 (m, 3H); 19F NMR
(CDCI3) 282 MHz d -66.6 (s), -126.4 (s).
Step 5. Preparation of 4-[5-(3-bromo-4-methoxy-5- fluorophenyl)-2-trifluoromethyl-4-oxazolyl]benzenesulfonamide The oxazole of Step 4 was reacted as described in
Example 64, Step 2. The crude material was chromatographed over SiO2 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%): 1H NMR (CDCI3) 300 MHz δ 4.05 (s, 3H), 5.18
(s, 2H), 7.28 (m, 1H), 7.61 (m, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.98 (d, J=8.5 Hz, 2H); 19F NMR (CDCI3) 282 MHz δ -66.6 (s),
-125.7 (s).
EXAMPLE 72
Figure imgf000166_0001
5-(4-Aminosulfonylphenyl)-4-phenyloxazole-2- carboxamide
Step 1. Preparation of 4,5-diphenyloxazole-2-acetic acid methyl ester.
Benzoin (2.12 g, 10 mmol) was dissolved in THF (100 mL) and the solution cooled to 0 °C. Methyl oxalylchloride (1.47 g, 12 mmol) and triethylamine (1.67 mL, 12 mmol) were added and the rearcion was warmed to room temperature for 2 hours.
Ether (150 mL) was added and the reaction mixture was filtered and concentrated. Ammonium acetate (1.5 g) and acetic acid (150 mL) were added to the acylated benzoin and the solution was heated to reflux for 2.5 hours. The reaction was concentrated to dryness, the residue was dissolved in ethyl acetate (250 mL), washed with water, NaHCO3 and brine, dried and concentrated to yield a crystalline solid which was chromatographed over Si02 eluting with a gradient from 5% - 10% ethyl acetate in hexane to yield the methyl ester (0.79 g, 28%): 1H NMR (CDCI3) 300 MHz δ 4.02 (s, 3H), 7.36 (m,
6H), 7.67 (m, 4H).
Step 2. Preparation of 5-(4-aminosulfonylphenyl)-4-phenyl- oxazole-2-carboxamide.
4, 5-Diphenyloxazole-2-acetic acid methyl ester from Step 1 (790 mg, 2.8 mmol) was added to chlorosulfonic acid cooled to 0 °C (25 mL) and the reaction was warmed to room temperature for 2 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 2.5 hours. The dichloromethane layer was separated and washed consecutively with 1N HCl (2 x 75 mL), NaHCO3
(saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated. The crude material was crystallized from a minimum amount of boiling ethyl acetate to yield 5-(4- aminosulfonylphenyl)-4-phenyl-oxazole-2-carboxamide (0.45 g,46%): 1H NMR (acetone-d6) 300 MHz δ 6.73 (broad s, 2H), 7.22 (broad s, 2H), 7.48 (m, 3H), 7.68 (m, 2H), 7.84 (d, J=8.5 Hz, 2H), 7.98 (d, J=8.5 Hz, 2H). FAB Mass spec. M + H 344.
Figure imgf000167_0001
4-[2-Methoxymethyl-4-phenyl- oxazolyl]benzenesulfonamide
Step 1. Preparation of 2-methoxymethyl-4,5-diphenyloxazole.
Benzoin (2.12 g, 10 mmol) was dissolved in THF (50 mL) and the solution cooled to 0 °C. Methoxy acetylchloride
(2.28 g, 21 mmol) and triethylamine (2.12 mL, 21 mmol) were added and the reaction was warmed to room temperature for 32 hours. Ether (150 mL) was added and the reaction was filtered. The organics were washed with 1N HCl, NaHCO3 and brine, dried over Na2SO4 and concentrated. Ammonium acetate
(1.32 g, 17.1 mmol) and acetic acid (50 mL) were added to the acylated benzoin and the solution was heated to reflux for 3 hours. The reaction was concentrated to dryness, residue was dissolved in ethyl acetate (250 mL), washed with water,
NaHCO3 and brine, dried and concentrated to yield a
crystalline solid (2.1 g) which was recrystallized from ethyl acetate and hexane to yield 2-methoxymethyl-4,5- diphenyloxazole (0.82 g, 36%): 1H NMR (CDCI3) 300 MHz d 3.53
(s, 3H), 4.62 (s, 2H), 7.35 (m, 6H), 7.62 (m, 4H).
Step 2. Preparation of 4-[2-methoxymethyl-4-phenyl- oxazolyl]benzenesulfonamide.
2-Methoxymethyl-4,5-diphenyloxazole from Step 1 (500 mg,
1.9 mmol) was added to chlorosulfonic acid cooled to 0 °C (25 mL) and the reaction allowed 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
2.5 hours. The dichloromethane layer was separated, washed consecutively with 1N HCl (2 x 75 mL), NaHCO3 (saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated. The crude material was chromatographed over SiO2 eluting with a gradient from 50% - 75% ethyl acetate in hexane to yield 4- [2-methoxymethyl-4-phenyl-oxazolyl]benzenesulfonamide (0.22 g, 34%): 1H NMR (acetone-d6) 300 MHz δ 3.47 (s, 3H), 4.62 (s, 2H), 6.69 (s, 2H), 7.44 (m, 3H), 7.65 (m, 2H), 7.77 (d, J=8.7 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H). FAB Mass spec. M + H 345.
EXAMPLE 74
Figure imgf000169_0001
4-[2-Difluoromethyl-4-phenyl-5- oxazolyl]benzenesulfonamide
Step 1. Preparation of 2-difluoromethyl-4,5-diphenyloxazole.
Difluoroacetic acid was dissolved in ethanol containing
NaOH (4 mL, 2.5 N), and concentrated to dryness. The solid was re-dissolved in EtOH (50 mL) and re-concentrated to dryness. The salt was suspended in DMF (30 mL) and
desylbromide (2.75 g, 10 mmol) was added. The reaction was stirred for 16 hours and concentrated. The residue was dissolved in ethyl acetate (250 mL), washed with 0.1N HCl (75 mL), NaHCO3 (saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated to yield 3.09 g of a colorless oil.
Ammonium acetate (2.31 g, 30 mmol) and acetic acid (25 mL) were added to the acylated benzoin and the solution was heated to reflux for 3 hours. The reaction was concentrated to dryness, the residue was dissolved in ethyl acetate (250 mL), washed with water, NaHCO3 and brine, dried and
concentrated. The crude product was chromatographed over SiO2, eluting with a gradient from 1% - 10% ether in hexane, to yield 2-difluoromethyl-4,5-diphenyloxazole (0.35 g, 12%): 1H NMR (CDCI3) 300 MHz δ 6.74 (t, J 52.6 Hz, 1H), 7.39 (m, 6H), 7.64 (m, 4H). 19F NMR (CDCI3) 282 MHz δ -118.6 (d, J
52.9 Hz). FAB Mass spec. M + H 272. Step 2. Preparation of 4-[2-difluoromethyl-4-phenyl-5- oxazolyl]benzenesulfonamide
2-Difluoromethyl-4,5-diphenyloxazole from Step 1 (320 mg, 1.18 mmol) was added to chlorosulfonic acid cooled to 0 °C (10 mL) and the reaction was warmed to room temperature for 2 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 2.5 hours. The dichloromethane layer was separated, washed consecutively with 1N HCl (2 x 75 mL), NaHCO3 (saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated.
The crude material was chromatographed over Si02, eluting with a gradient from 20%-50% ethyl acetate in hexane, to yield 4-[2-difluoromethyl-4-phenyl-5- oxazolyl]benzenesulfonamide (0.26 g, 63%): 1H NMR (CD3OD)
300 MHz δ 6.99 (t, J 52.2 Hz, 1H), 7.43 (m, 3H), 7.61 (m, 2H), 7.75 (d, J=6.8 Hz, 2H), 7.93 (d, J=6.8 Hz, 2H) . 19F
NMR (CD3OD) 282 MHz δ -121.6 (d, J 52.2 Hz).
Figure imgf000171_0001
4-[2-Hydroxymethyl-4-phenyl-5- oxazolyl]benzenesulfonamide
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 1N HCl (2 x 75 mL), NaHC03 (saturated) (75 mL) and brine
(75 mL), dried over Na2SO4 and concentrated. The crude material (4.23 g) was suspended in acetic acid (75 mL) and HBr/HOAc solution (33 u/V% HBr in HOAc, 25 mL) and Br2 (0.79 mL, 15.4 mmol) was added. After 0.25 hours at room
temperature the reaction was complete by TLC, and the
reaction was concentrated to remove the acetic acid. The residue was dissolved in ethyl acetate (250 mL) and NaHSO3
(10%, 250 mL). The organics were washed with NaHCO3
(saturated) (75 mL) and brine (75 mL), dried over Na2SO4 and concentrated yielding a crude 4-sulfonamido-desylbromide which was used without purification. Glycolic acid mono sodium salt (1.55 g, 15.8 mmol) and the 4-sulfonamido- desylbromide were suspended in DMF (350 mL) and stirred at room temperature for 16 hours. The reaction was concentrated and the residue, along with ammonium acetate (2.31 g, 30 mmol) and acetic acid (25 mL), were heated to reflux for 3 hours. The reaction was concentrated to dryness. The residue was dissolved in ethyl acetate (250 mL), washed with water, NaHCO3 and brine, dried and concentrated. The crude product was chromatographed over SiO2, eluting with a gradient from
50%-75% ethyl acetate in hexane, to yield 4-[2-hydroxymethyl- 4-phenyl-5-oxazolyl]benzenesulfonamide: 1H NMR (acetone-d6)
300 MHz δ 4.76 (m, 2H), 6.68 (s, 2H), 7.45 (m, 3H) , 7 . 65 (m, 2H) , 7 . 77 ( d, J=6 . 8 Hz , 2H) , 7 . 94 ( d, J=8 . 7 Hz , 2H).
Figure imgf000172_0001
5-[(4-Aminosulfonyl)phenyl]-4-phenyloxazole-
2-pentanoic acid, sodium salt.
Step 1: Preparation of 2-[(4-chlorosulfonyl)phenyl]-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 C14H11O3SCI 295.0196) 295.0205. Step 2: Preparation of 2-[(4-aminosulfonyl)phenyl]-1- phenylethanone
A solution of the sulfonyl chloride from Step 1 (9 g, 0.03 mol) in tetrahydrofuran (100 mL) was slowly added to ammonium hydroxide (100 mL) at 5 °C. The reaction mixture was stirred first for 1.5 h at 5 °C and then for 30 minutes at room temperature. The resulting solid was collected by filtration, washed with excess water and hexane, and vacuum dried to give 3.47 g (41.3%) of the desired sulfonamide as a white solid: m.p. 259-261.5 °C. 1H-NMR (DMSO-d6/300 MHz) δ 4.52 (s, 2H), 7.30 (s, 2H), 7.43 (bd, 2H, J = 8.26 Hz), 7.54
(dd, 2H, J = 7.56 Hz), 7.65 (dd, 1H, J = 7.35 Hz), 7.75 (d,
2H, J = 8.26 Hz), 8.04 (d, 2H, J = 7.45 Hz). HRMS (calcd for C14H13NO3S 276.0694) 276.0709. Step 3: Preparation of 2-bromo-2-[(4-aminosulfonyl)
phenyl]-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). The combined ethyl acetate extracts were washed with 5% sodium bicarbonate (2 x 250 mL), and brine (2 x 250 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. Methylene chloride (50 mL) was added to the concentrated residue, and a solid precipitated. This solid was collected by filtration, washed with cold methylene chloride and air-dried to give 3.5 g (54.9%) of 2-bromo-2-[(4-aminosulfonyl)phenyl]-1- phenylethanone as a yellow solid: m.p. 153.6-155 °C. 1H-NMR (DMSO-d6/300 MHz) δ7.25 (s, 1H), 7.38 (s, 2H), 7.54 (dd, 2H,
J = 7.55 Hz), 7.62-7.74 (m, 3H), 7.82 (d, 2H, J = 8.46 Hz), 8.07 (d, 2H, J = 8.66 Hz). HRMS (calcd for C14H12NO3SBr 353.9800) 353.9824.
Step 4: Preparation of methyl 5-[(4-aminosulfonyl)phenyl]- 4-phenyloxazole-2-pentanoate
An aqueous solution of 2.5N NaOH (2.3 mL, 5.65 mmol) was added to adipic acid monomethyl ester (0.9 g, 5.65 mmol) in ethanol (10 mL), and the mixture was stirred for 15 min at room temperature. The solvents were removed at reduced pressure. Several mL of absolute ethanol were added to the concentrated residue, and the mixture was again concentrated at reduced pressure. This procedure was repeated three times until a white 3θlid formed, which was dried under high vacuum. The resulting carboxylic acid sodium salt was suspended in 10 mL of anhydrous DMF. The bromoketone (2 g, 5.65 mmol) from Step 3 was dissolved in 10 mL of anhydrous DMF and added at room temperature to the DMF solution of the sodium carboxylate. The reaction mixture was stirred for 18 h at room temperature, and then the DMF was removed at reduced pressure. Ethyl acetate (100 mL) was added to the concentrated residue, and the mixture was filtered. The filtrate was concentrated and dried to give the desired crude α-acyloxy ketone. Acetic acid (10 mL) and ammonium acetate (1.32 g, 17.1 mmol) were added to this concentrated residue, and this mixture was heated at 100 °C for 3 h. The reaction mixture was cooled to room temperature, and the excess acetic acid was removed under vacuum. The resulting residue was partitioned becween water (100 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (2 x 100 mL), saturated brine (1 x 100 mL), dried over magnesium sulfate, filtered and
concentrated. The concentrated residue was purified by flash chromatography on silica gel (eluting with 4:1 ethyl
acetate:hexane) to give 0.73 g of a white solid which was recrystallized from methylene chloride and hexane to give 0.48 g (21%) of methyl 5-[(4-aminosulfonyl)phenyl]-4- phenyloxazole-2-pentanoate as a white solid: m.p. 165.8-167.3 °C. 1H -NMR (CDCl3/300 MHz) 1.78-1.89 (m, 4H), 2.40 (t, 2H, J = 7.25 Hz), 2.90 (t, 2H, 7.35 Hz), 3.68 (s, 3H), 4.85 (s, 2H), 7.37-7.42 (m, 3H), 7.58-7.61 (m, 2H), 7.71 (d, 2H, J = 8.66 Hz), 7.88 ( d, 2H, J = 8.66 Hz). HRMS (calcd for
C21H22N2O5S 414.1249) 414.1259.
Step 5: Preparation of 5-[(4-aminosulfonyl)phe(yl]-4- phenyloxazole-2-pentanoic acid
Methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- pentanoate (1.48 g, 3.57 mmol) (Step 4) and LiOH (0.45 g, 0.011 mmol) were dissolved in 1:1 tetrahydrofuran/methanol (90 mL) containing 3 mL of water. The resulting mixture was stirred for 48 h at room temperature. The solvents were removed at reduced pressure, and the concentrated residue was partitioned between ethyl acetate (150 mL) and 1 N HCl (150 mL) in a separatory funnel and shaken vigorously. The organic layer was separated and washed with saturated brine (1 x 150 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was vacuum dried to give 1.03 g (72%) of 5-[(4-aminosulfonyl)phenyl]-4- phenyloxazole-2-pentanoic acid as a white solid: mp. 157.2- 159.0 °C. 1H-NMR (CD3OD/300 MHz) 1.70-1.80 (m, 2H), 1.86-1.94 (m, 2H), 2.38 (t, 2H, J = 7.25 Hz), 2.93 (t, 2H, J = 7.35
Hz), 7.42-7.45 (m, 3H), 7.55-7.58 (m, 2H), 7.69 (d, 2H, J = 8.66 Hz), 7.87 (d, 2H, J = 8.66 Hz). HRMS (calcd for
C20H20N2O5S 400.1093) 400.1087. Step 6: Preparation of 5-[(4-aminosulfonyl)phenyl]-4- phenyloxazole-2-pentanoic acid, sodium salt
5-[(4-aminosulfonyl)phenyl)-4-phenyloxazole-2-pentanoic acid (Step 5) (0.19 g, 0.47 mmol) was dissolved in 3 mL of ethanol. 2.5 N Sodium hydroxide (2.4 mL, 0.47 mmol) was added, and the solution was stirred for 5 min. at room temperature. The solvents were removed, several mL of absolute ethanol were added to the concentrated residue, and the mixture was again concentrated at reduced pressure. This procedure was repeated twice until a white solid formed, which was dried under high vacuum to give 0.19 g (96%) of 5- [(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-pentanoic acid, sodium salt as a white solid: m.p. >250 °C. 1H NMR(CD3OD/300 MHz) 1.70-1.80 (m, 2H), 1.86-1.93 (m, 2H), 2.25 (t, 2H, J = 7.35 Hz), 2.93 (t, 2H, J = 7.45 Hz), 7.41-7.44 (m, 3H), 7.55-7.58 (m, 2H), 7.70 ( d, 2H, J = 8.86 Hz), 7.88 (d, 2H, J = 8.66 Hz). HRMS (calcd for C20H19N2O5SNa 423.0991) 423.0991.
Other representative examples prepared by similar methods from 2-bromo-2-[(4-aminosulfonyl)phenyl]-1-phenyl- ethanone are summarized in Table 1.
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
4-[(4-Aminosulfonyl)phenyl]-5-(4-fluorophenyl)oxazole-
2-pentanoic acid
Step 1: Preparation of 2-(4-fluorophenyl)-2-hydroxy-1- phenylethanone
4-Fluorobenzaldehyde (25 g, 0.2 mol) and zinc iodide (0.14 g, 0.4 mmol) were mixed with 100 mL of methylene chloride. Trimethylsilyl cyanide (20.6 g, 0.21 mol) was dissolved in 30 mL of methylene chloride and added over 30 minutes. The reaction mixture was stirred at room
temperature for 1 h. The reaction mixture was diluted with 200 mL of methylene chloride, and the organic phase was washed with saturated aqueous sodium bicarbonate (1 x 150 mL), saturated brine (1 x 150 mL), dried over magnesium sulfate, filtered, concentrated and vacuum dried to give 47.3 g of the desired trimethylsilyl cyanohydrin as a yellow liquid.
The trimethylsilyl cyanohydrin (45 g, 0.2 mol) was diluted with 100 mL of ether and added to a solution of phenyImagnesium bromide (72 mL of 3.0 M solution in ether, 0.215 mol) in 600 mL of diethyl ether over 1.5 h at room temperature. The reaction mixture was stirred for 3 h at room temperature and slowly quenched with 3 N HCl (300 mL). The organic layer was separated and washed with saturated sodium bicarbonate (1 x 300 mL), saturated brine (1 x 300 mL), dried over magnesium sulfate, filtered, concentrated, and vacuum dried to give 43.2 g of a brown oil. This oil was treated with 150 mL of 9:1 trifluoroacetic acid in water for 3 h at room temperature. Excess saturated aqueous sodium carbonate was slowly added to the reaction mixture, followed by water (200 mL). The aqueous solution was extracted with ether (2 x 200 mL). The combined organic layers were washed with saturated sodium bicarbonate (1 x 200 mL), saturated brine (1 x 200 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was crystallized from ethyl acetate and hexane to give 17.4 g (38%) of 2-(4- fluorophenyl)-2-hydroxy-1-phenylethanone as a yellow solid: m.p. 91-94 °C. HRMS (calcd for C14H11FO2 231.0831) 231.0835.
Step 2 Preparation of methyl 4-[(4-aminosulfonyl)phenyl]-
5-(4-fluorophenyl)oxazole-2-pentanoate
5- (Methoxycarbonyl)pentanoyl chloride (6.5 g, 0.036 mol) in 10 mL of methylene chloride and triethylamine (7.1 g, 0.07 mol) was added to 2-(4-fluorophenyl)-2-hydroxy-1- phenylethanone (Step 1) (8 g, 0.035 mol) in 100 mL of
methylene chloride. The resulting mixture was stirred for 2 h at room temperature, diluted with 200 mL of methylene chloride, washed with water (1 x 100 mL), and saturated brine (1 x 100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was dried under vacuum to give 12.2 g of crude ester intermediate. Acetic acid (50 mL) and ammonium acetate (10.2 g, 0.132 mol) were added to this ester intermediate (12.2 g, 0.033 mol). The resulting mixture was heated for 3 h at 100 °C. The reaction mixture was cooled to room temperature, and the excess acetic acid was removed under vacuum. The resulting residue was partitioned between water (150 mL) and ethyl acetate (300 mL). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (2 x 150 mL), saturated brine (2 x 150 mL), dried over magnesium sulfate, filtered and
concentrated. The concentrated residue was purified by flash chromatography on silica gel (eluting with 1: 9 ethyl
acetate: hexane) to give 7 g (60%) of pure methyl 4-(phenyl)- 5-(4-fluorophenyl)oxazole-2-pentanoate as a yellow oil. Chlorosulfonic acid (38.6 g, 0.33 mol) was slowly added to methyl 4-(phenyl)-5-(4-fluorophenyl)oxazole-2-pentanoate (4.7 g, 0.013 mol) at 5 °C. The ice bath was removed, and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was diluted with methylene chloride (200 mL) and poured slowly into ice. The organic layer was separated and added to ammonium hydroxide (50 mL) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature. The organic layer was separated and washed with water (1 x 200 mL), brine (1 x 200 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash chromatography on silica gel (eluting with 9:11 ethyl acetate:hexane) to give 0.74 g (13%) of methyl 4-[(4-aminosulfonyl)phenyl]-5-(4- fluorophenyl)-oxazole-2-pentanoate as a pale yellow solid: m.p. 82.4-87.4 °C. 1H NMR (CDCl3/300 MHz) 1.74-1.95 (m, 4H), 2.40 (t, 2H, J = 7.25 Hz), 2.88 (t, 2H, J = 7.35 Hz), 3.67 (s, 3H), 4.93 (bs, 2H), 7.07-7.13 (m, 2H), 7.50-7.55 (m, 2H), 7.75 (d, 2H, J = 8.66 Hz), 7.89 (d, 2H, J = 8.66 Hz). 19F NMR (CDCl3/300 MHz) -111.22 to -111.127 ppm. HRMS (calcd for C21FH21N2O5S 433.1233) 433.1209.
Step 3: Preparation of 4-[(4-aminosulfonyl)phenyl]-5-(4- fluorophenyl)-oxazole-2-pentanoic acid
Methyl 4-[(4-aminosulfonyl)phenyl]-5-(4- fluorophenyl)oxazole-2-pentanoate (Step 2) (0.51 g, 1.2 mmol) was dissolved in 30 mL of 1:1 THF/methanol. Lithium
hydroxide (0.2 g, 4.7 mmol) and 1 mL of water were added.
The reaction mixture was stirred for four days at room temperature, then the solvents were removed at reduced pressure. The concentrated residue was partitioned between ethyl acetate (100 mL) and 3 N HCl (100 mL) in a separatory funnel and shaken vigorously. The organic layer was
separated and washed with saturated brine (1 x 100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was crystallized from ethyl acetate and hexane to give 0.4 g (81%) of 4-[(4-aminosulfonyl)phenyl]-5- ( 4-fluorophenyl)oxazole-2-pentanoic acid as a white solid: m.p. 153-154.5 °C. 1H NMR (CD3OD/300 MHz) 1.69-1.79 (m, 2H), 1.85-1.95 (m, 2H), 2.38 (t, 2H, J = 7.15 Hz), 2.91 (t, 2H, = 7.35 Hz), 7.14-7.20 (m, 2H), 7.55-7.60 (m, 2H), 7.73 (d, 2H, J = 8.66 Hz), 7.90 (d, 2H, J = 8.46 Hz). 19F NMR
(CD3COD/300 MHz) -113.73 to -113.63 ppm. HRMS (calcd for C20H19N2O5FS 419.1077) 419.1083.
Figure imgf000185_0001
5-[(4-Aminosulfonyl)phenyl]-4-(3,4-dichlorophenyl)- β,β-dimethyloxazole-2-butanoic acid
Step 1: Preparation of methyl 5-(phenyl)-4-(3,4- dichlorophenyl)-β,β-dimethyloxazole-2-butanoate
2-Bromo-2-(phenyl)-1-(3,4-dichlorophenyl)ethanone (3.00 g, 8.72 mmol), monomethyl 3,3-dimethylglutarate (3.0 g, 17.22 mmol), and powdered anhydrous potassium carbonate (1.79 g, 12.97 mmol) were mixed at room temperature in
dimethylformamide (40 mL) for 15 min. The dimethyl-formamide solution was poured into ethyl acetate (200 mL). This solution was extracted with water (2 x 100 mL), 10% aqueous hydrochloric acid (2 x 100 mL), and finally extensively extracted with saturated aqueous ammonium chloride (6 x 100 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was removed at reduced pressure. The resulting residue was purified by preparative silica gel chromatography to give 2.78 g (73%) of the desired α- acyloxyketone as a light yellow oil: 1H NMR (CDCI3/300 MHz) 1.16 (s, 6H), 2.48 (s, 2H), 2.58 (AB, 2H, Jab = 15.0 Hz, Δv = 26.0 Hz,), 3.61 (s, 3H), 6.70 (s, 1H), 7.38-7.42 (m, 5H), 7.47 (d, 1H, J = 8.1 Hz), 7.73 (dd, 1H, J = 8.1 Hz, J = 2.0 Hz), 8.01 (d, 1H, J = 2.0 Hz). FABMS m/z = 437 (m+H+). HRMS (calcd for C22H22O5CI2 437.0923) 437.0905.
The α-acyloxyketone (2.53 g, 5.78 mmol) and ammonium acetate (2.53 g, 32.8 mmol) were heated to reflux in acetic acid (40 mL) for 8 h. The solution was poured into ethyl acetate (200 mL) and extracted with water (2 x 200 mL), saturated sodium bicarbonate (2 x 200 mL), and finally saturated aqueous ammonium chloride (1 x 200 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was removed at reduced pressure. The resulting residue was purified by preparative silica gel chromatography to give 1.57 g (65%) of methyl 5-(phenyl)-4-(3,4-dichloro- phenyl)-β,β-dimethyloxazole-2-butanoate as a yellow oil: 1H
NMR (CDCI3/300 MHz) 1.10 (s, 6H), 2.44 (s, 2H), 2.95 (s, 2H), 3.67 (s, 3H), 7.37-7.56 (m, 7H), 7.79 (d, 1H, J = 1.8 Hz). FABMS m/z = 418 (m+H+). HRMS (calcd for C22H22Cl2NO3 418.0977) 418.0969.
Step 2: Preparation of methyl 5-[(4-aminosulfonyl)phenyl]- 4-(3,4-dichlorophenyl)-β,β-dimethyloxazole-2-butanoate
Methyl 5-(phenyl)-4-(3,4-dichlorophenyl)-β,β- dimethyloxazole-2-butanoate (Step 1) (980.0 mg, 2.34 mmol) was cooled to -25 °C in a dry ice/methanol bath.
Chlorosulfonic acid (15.0 mL) was added, and the solution was warmed to room temperature over 1 h. The solution was stirred for 6 h and slowly poured directly into ice (300 mL in a 500 mL Erlenmeyer flask). The resulting heterogeneous aqueous solution was poured into ethyl acetate (200 mL). The ethyl acetate layer was collected, extracted with water (1 x 100 mL) and mixed with ammonium hydroxide solution (50 mL) for 30 min. The ethyl acetate was collected, extracted with saturated aqueous ammonium chloride (2 x 100 mL), dried over sodium sulfate and concentrated in vacuo to give 924 mg (79%) of methyl 5-[(4-aminosulfonyl)-phenyl]-4-(3,4- dichlorophenyl)-β,β-dimethyloxazole-2-butanoate as a foam: m.p. 54-57 °C. 1H NMR (CDCI3/300 MHz) 1.19 (s, 6H), 2.45 (s, 2H), 2.99 ( s, 2H), 3.68 (s, 3H), 4.89 (bs, 2H), 7.42-7.48 (m, 2H), 7.69 (d, 2H, J = 8.5 Hz), 7.76 (d, 1H, J = 1.7 Hz), 7.92 (d, 2H, J = 8.5 Hz). FABMS m/z = 497 (m+H+). HRMS
(calcd for C22H22CI2N2O5S 497.0705) 497.0681.
Step 3: Preparation of 5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)-β,β-dimethyloxazole-2-butanoic acid
Methyl 5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)-β,β-dimethyloxazole-2-butanoate (Step 2) (165.0 mg, 0.33 mmol) and lithium hydroxide mono hydrate (15.0 mg, 0.36 mmol) were mixed in tetrahydrofuran-methanol- water (5.0 mL, 7:2:1) and stirred at room temperature for 16 h. The solution was acidified with 10% aqueous hydrochloric acid (pH = 1) and poured into ethyl acetate (50 mL). The organic layer was extracted with brine (2 x 25 mL), dried over sodium sulfate and concentrated at reduced pressure to give 140 mg (87%) of 5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)-β,β-dimethyloxazole-2-butanoic acid as a foam: m.p. 82-85 °C. 1H NMR (CD3OD/300 MHz) 1.20 (s, 6H), 2.41 (s, 2H), 3.02 (s, 2H), 7.53 (dd, 1H, J = 8.4 Hz, J = 2.1 Hz), 7.57 (d, 1H, J = 8.4 Hz), 7.72 (d, 2H, J = 8.7 Hz), 7.78 (d, 1H, J = 2.1 Hz), 7.94 (d, 2H, J = 8.7 Hz). FABMS m/z = 483 (m+H+). HRMS (calcd for C21H20Cl2N2O5S 483.0548) 483.0522.
Other representative examples prepared by similar methods from 2-bromo-2-(phenyl)-1-(3,4-dichlorophenyl)-ethanone are summarized in Table 2.
Figure imgf000188_0001
Figure imgf000189_0001
4-[(4-Methylsulfonyl)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoic acid
Step 1: Preparation of 2-(3,4-dichlorophenyl)-2- hydroxy-1-[(4-methylthio)-phenyl]ethanone
Trimethylsilyl cyanide (14.6 g, 0.147 mol) was diluted with 30 mL of methylene chloride and added to a solution of 3,4-dichlorobenzaldehyde (25 g, 0.143 mol) in 100 mL of methylene chloride over 20 minutes. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with 200 mL of methylene chloride, and the organic solution was washed with saturated sodium bicarbonate (2 x 150 mL),
saturated brine (2 x 150 mL), dried over magnesium sulfate, filtered and concentrated to give 39 g of a brown oil, which was used in the next reaction without further purification.
Magnesium (1.8 g, 0.073 mol) was suspended in ether (20 mL), and iodomethane (0.1 mL) was added. 4- Bromothioanisole (14.8 g, 0.073 mol), dissolved in 100 mL of ether, was added over 50 min., and the reaction mixture was stirred overnight at room temperature. The cyanohydrin (10 g, 0.036 mol) was diluted with 100 mL of ether and added to the pre-formed Grignard reagent over a 1 h period. The reaction mixture was stirred for 3 h at room temperature. The reaction was slowly quenched with 50 mL of 3 N HCl and the aqueous layer was removed by separation. The organic layer was washed with water (2 x 100 mL), saturated sodium bicarbonate (1 x 100 mL), saturated brine (1 x 100 mL), dried over magnesium sulfate, filtered and concentrated. A solution of 9:1 trifluoroacetic acid:water (50 mL) was added to the concentrated residue, and the mixture was stirred for 1.5 h at room temperature. The reaction mixture was neutralized by adding solid sodium carbonate. Water (300 mL) and ether (300 mL) were added. The ether layer was separated and washed with saturated sodium
bicarbonate (2 x 150 mL), saturated brine (2 x 150 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel eluting with 1:9 ethyl acetate:hexane to give 3.3 g (28%) of the desired benzoin as a yellow oil. This yellow oil was crystallized from hexane and ethyl acetate to give 0.46 g of 2- (3 , 4-dichlorophenyl) -2- hydroxy-1-[(4-methylthio)phenyl]ethanone as a white solid: m.p. 54-58 °C. HRMS (calcd for C15H12O2SCI2
327.0013) 327.0024.
Step 2: Preparation of methyl 4-[(4- methylthio)phenyl]-5-(3,4-dichlorophenyl)oxazole-2- butanoate
5-(Methoxycarbonyl)pentanoyl chloride (1.63 g, 9.9 mmol) was diluted with 20 mL of methylene chloride and was added to a solution of 2-(3,4-dichloro-phenyl)-2- hydroxy-1-[(4-methylthio)phenyl]ethanone (Step 1) (3.24 g, 9.9 mol) in 60 mL of methylene chloride containing triethylamine (2 g, 0.02 mmol). The reaction mixture was stirred for 1.5 h at room temperature. The reaction mixture was diluted with 100 mL of methylene chloride and washed with water (1 x 100 mL), saturated brine (1 x 100 mL), dried over magnesium sulfate, filtered, concentrated and dried under high vacuum. Acetic acid (10 mL) and ammonium acetate (3.05 g, 0.04 mol) were added to this concentrated residue, and the mixture was heated at 100 °C for 3 h. The reaction mixture was cooled to room temperature, and the excess acetic acid was removed under vacuum. The resulting residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (2 x 100 mL), saturated brine (1 x 100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash chromatography on silica gel (eluting with 1:4 ethyl acetate:hexane) to give 2.14 g (50%) of methyl 4-[(4-methylthio)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoate as a yellow oil.
Step 3: Preparation of methyl 4-[(4- methylsulfonyl)phenyl]-5-(3,4-dichlorophenyl)oxazole-2- butanoate
Methyl 4-[(4-methylthio)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoate (1.7 g, 3.89 mmol) from Step 2 was dissolved in 60 mL of methanol:water (9:1), then Oxone® (8.38 g, 0.014 mol) was added. The reaction mixture was stirred for 3 h at room
temperature, and the solvents were removed under reduced pressure. The resulting residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (2 x 100 mL), saturated brine (2 x 100 mL), dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (eluting with 3:7 ethyl acetate:hexane) to give 0.6 g (33%) of methyl 4-[(4- methylsulfonyl)phenyl]-5-(3,4-dichlorophenyl)oxazole-2- butanoate as a clear oil: 1H NMR (CDCI3/300 MHz) 2.15- 2.25 (m, 2H), 2.52 (t, 2H, J = 7.35 Hz), 2.94 (t, 2H, J = 7.35 Hz), 3.09 (s, 3H), 3.70 (s, 3H), 7.36 (dd, 1H, J = 2.01 Hz), 7.46 (d, 1H, J = 8.46 Hz), 7.69 (d, 1H, J = 2.01 Hz), 7.85 ( d, 2H, J = 8.66 Hz), 7.96 (d, 2H, J = 8.46 Hz). HRMS (calcd for C21H19NO5SCI2 468.0439)
468.0435.
Step 4: Preparation of 4-[(4-methylsulfonyl)phenyl]-5- (3,4-dichlorophenyl)oxazole-2-butanoic acid
The methyl ester (0.5 g, 1.07 mmol) from Step 3 was mixed with 15 mL of methanol, lithium hydroxide (0.18 g, 4.27 mmol) and 1 mL of water. The reaction mixture was stirred for 1 h at room temperature and quenched with 15 mL of 1N HCl. The solvents were removed, and the resulting residue was partitioned between 1 N HCl (100 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with 1 N HCl (1 x 100 mL), saturated brine (1 x 100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was crystallized from methylene chloride and hexane to give 0.26 g (54%) of 4-[(4-methylsulfonyl)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoic acid as white
crystals: m.p. 181.7-182.9 °C. 1H NMR (CD3OD/300 MHz) 2.10-2.20 (m, 2H), 2.48 (t, 2H, J = 7.15 Hz), 2.97 (t, 2H, J = 7.45 Hz), 3.16 (s, 3H), 7.46 (dd, 1H, J = 2.11 Hz), 7.58 (d, 1H, J = 8.46 Hz), 7.74 (d, 1H, J = 2.01 Hz), 7.85 ( d, 2H, J = 8.66 Hz), 8.00 (d, 2H, J = 8.66 Hz). HRMS (calcd for C20H17NO5SCI2 454.0283) 454.0277.
Figure imgf000192_0001
4-[(4-Aminosulfonyl)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoic acid Step 1: Preparation of 2-(3,4-dichlorophenyl)-2- hydroxy-1-phenylethanone
Trimethylsilyl cyanide (14.6 g, 0.147 mol) was dissolved in 30 mL of methylene chloride and added over 20 minutes to a solution of 3,4-dichloro-benzaldehyde (25 g, 0.143 mol) and zinc iodide (0.41 g, 1.28 mmol) in 100 mL of methylene chloride. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with 200 mL of methylene chloride and the organic layer was washed with saturated sodium bicarbonate (2 x 150 mL), saturated brine (2 x 150 mL), dried over magnesium sulfate, filtered and concentrated to give 38.4 g (98%) of a brown oil, which was used in the next reaction without further purification.
This trimethylsilyl cyanohydrin (15 g, 0.0547 mol) was dissolved in 20 mL of diethyl ether and added to phenyImagnesium bromide (19.5 mL of 3.0 M in ether solution, 0.0585 mol) in 250 mL of ether over 15
minutes. The reaction mixture was stirred for 1.5 h at room temperature, then slowly quenched with 100 mL of 3 N HCl. The organic layer was separated and washed with saturated sodium bicarbonate (1 x 150 mL), saturated brine (1 x 150 mL), dried over magnesium sulfate, filtered and concentrated to give 13.0 g of a brown oil. A solution of 9:1 trifluoroacetic acid in water (50 mL) was added to the concentrated residue, and the mixture was stirred for 1.5 h at room temperature. The reaction mixture was neutralized by adding solid sodium
carbonate. The resulting residue was partitioned between water (200 mL) and ethyl acetate (300 mL). The organic layer was separated, washed with saturated sodium bicarbonate (1 x 150 mL), saturated brine (1 x 150 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was crystallized from ethyl acetate and hexane to give 7.37 g (48%) of 2- (3,4-dichlorophenyl)-2-hydroxy-1-(phenyl)ethanone as a yellow solid: HRMS (calcd. for C14H10O2CI2 281.0136) 281.0112.
Step 2: Preparation of methyl [(4-phenyl)-5-(3,4- dichlorophenyl)oxazole]-2-butanoate
5-(Methoxycarbonyl)pentanoyl chloride (2.82 g,
0.017 mol) and triethylamine (3.47 g, 0.034 mol) were added to a solution of 2-(3,4-dichlorophenyl)-2-hydroxy- 1-[phenyl]ethanone (Step 1) (4.77 g, 0.017 mmol) in 40 mL of methylene chloride. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with 100 mL of methylene chloride. The organic solution was washed with water (1 x 100 mL), saturated brine (1 x 100 mL), dried over magnesium sulfate, filtered, concentrated and dried under high vacuum. Ammonium acetate (4.6 g, 0.06 mol) and 30 mL of acetic acid were added. The reaction mixture was heated at 100 °C for 2.5 h. The reaction mixture was cooled to room temperature, and the excess acetic acid was removed under vacuum. The resulting residue was
partitioned between water (100 mL) and ethyl acetate
(200 mL). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (2 x 100 mL), saturated brine (1 x 100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash chromatography on silica gel (eluting wjth 1:9 ethyl acetate: hexane) to give 2.82 g (42.6%) of methyl [(4-phenyl)-5-(3,4- dichlorophenyl)oxazole]-2-butanoate as a yellow oil: HRMS (calcd. for C20H17NO3CI2 390.0664) 390.0648. Step 3: Preparation of methyl 4-[(4- aminosulfonyl)phenyl]-5-(3.4-dichlorophenyl)oxazole-2- butanoate
Chlorosulfonic acid (28 g, 0.24 mol) was added to methyl [(4-phenyl)-5-(3,4-dichlorophenyl)oxazole]-2- butanoate (Step 2) (3.74 g, 9.58 mmol) at 5 °C. The ice bath was removed, and the reaction was stirred for 3 h at room temperature. The reaction mixture was diluted with 100 mL of methylene chloride and slowly poured into ice. The organic layer was separated and washed with saturated brine (1 x 100 mL). The organic layer was separated, poured into 50 mL of concentrated ammonium hydroxide and stirred for 30 minutes at room
temperature. The organic layer was separated, washed with water (1 x 100 mL), saturated brine (1 x 100 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was crystallized from methanol and water to give 1.7 g (38%) of methyl 4-[(4- aminosulfonyl)phenyl]-5-(3,4-dichlorophenyl)oxazole-2- butanoate as a yellow solid: m.p. 130.7-131.8 °C. HRMS (calcd. for C20H18N2O5Cl2 469.0392) 469.0413.
Step 4: Preparation of 4-[(4-aminosulfonyl)phenyl]-5- (3,4-dichlorophenyl)oxazole-2-butanoic acid
Methyl 4-[(4-aminosulfonyl)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoate (Step 3) (0.6 g, 1.28 mmol) was dissolved in 30 mL of 1:1 methanol/THF.
Lithium hydroxide (0.21 g, 5.11 mmol) and 3 mL of water were added. The reaction mixture was stirred for 18 h at room temperature. The solvents were removed, and the resulting residue was partitioned between 1 N HCl (100 mL) and ethyl acetate (100 mL). The organic layer was separated and washed with saturated sodium bicarbonate (1 x 100 mL). The aqueous layer was acidified by adding excess 3N HCl and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated brino (1 x 100 mL), dried over magnesium sulfate, filtered and concentrated to give 0.27 g (46%) of 4-[(4-aminosulfonyl)phenyl]-5-(3,4-dichlorophenyl)- oxazole-2-butanoic acid as a yellow solid: m.p. 168-171 °C. HRMS (calcd for C19H16N2O5SCl2 455.0235) 455.0197.
Figure imgf000196_0001
5-[4-[(Aminosulfonyl)phenyl]-4-phenyl-αS-(1H- pyrrol-1-yl)oxazole-2-butanoic acid
Step 1: Preparation of methyl 5-1[(4- aminosulfonyl)phenyl]-αS-
[[(phenylmethoxy)carbonyl]amino]-4-phenyloxazole-2-
Fbutanoate
A solution of 2-bromo-2-[(4-aminosulfonyl)phenyl]-
1-phenylethanone (1.0 g, 2.8 mmol) and N-Cbz-glutamic acid α-methyl ester (0.92 g, 3.1 mmol) in
dimethylacetamide (5.0 mL) was treated with K2CO3 (0.27 g, 1.96 mmol) and 18-crown-6 (0.05 g), and stirred at room temperature for 3.5 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 25 mL). The combined organic phase was washed with water (2 x 25 mL), dried (Na2SO4), filtered, and concentrated to give an amorphous pale yellow substance. This material was dried in vacuo for 3 h, then dissolved in glacial acetic acid (10 mL). After adding NH4OAC (0.7 g, 9.1 mmol), the resulting mixture was heated at 100 °C for 2.5 h under a nitrogen atmosphere. The acetic acid was removed in vacuo, and the residue was partitioned between water (50 mL) and EtOAc (50 mL). The organic phase was washed with water, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with 40% EtOAc in hexane) to give 0.9 g (58%) of methyl 5-[(4-aminosulfonyl)phenyl]-αS-
[[(phenylmethoxy)carbonyl]amino]-4-phenyloxazole-2- [butanoate as a white amorphous substance: 1H-NMR
(CD3OD/300 MHz) 7.86 (d, 2H, J = 8.4 Hz), 7.66 (d, 2H, J
= 8.4 Hz), 7.54 (m, 2H), 7.4 (m, 3H), 7.3 (s, 5H), 5.05 (s, 2H), 4.4 (m, 1H), 3.72 (s, 3H), 3.01 (t, 2H, J = 7.2 Hz), 2.42 (m 1H), 2.21 (m, 1H) ; FABMS: m/z = 550 (M+H+) HRMS (calcd for C28H28N307S 550.1648) 550.1616.
Step 2: Preparation of methyl 5-[4-(aminosulfonyl) phenyl]-4-phenyl-αS-(1H-pyrrol-1-yl)oxazole-2-butanoate
A solution of methyl 5-[(4-aminosulfonyl)phenyl]- αS-[[(phenylmethoxy)carbonyl]amino]-4-phenyloxazole-2- [butanoate (Step 1) (1.0 g, 1.82 mmol) in EtOAc (20 mL) was treated with 10% Pd/C (0.5 g) and hydrogenated at 50 psi for 3 h at room temperature. The catalyst was removed by filtration, and the filtrate was
concentrated. The residue was dissolved in glacial acetic acid (10 mL), then NaOAc (0.9 g) and 2,5- dimethoxytetrahydrofuran (0.26 g, 2.0 mmol) were added, and the mixture was heated at 100 °C for 15 min under a nitrogen atmosphere. The acetic acid was removed in vacuo, and the residue was partitioned between water (25 mL) and EtOAc (30 mL). The organic phase was washed with water, dried (Na2SO4), filtered, and concentrated. The resulting material was purified by silica gel flash chromatography eluting with 45% EtOAc in hexane, to give 0.35 g (41%) of methyl 5-[4-(aminosulfonyl)
phenyl]-4-phenyl-αS-(1H-pyrrol-1-yl)oxazole-2-butanoate as a white amorphous material: 1H-NMR (CD3OD/300 MHz) 7.87 (d, 2H, J = 8.7 Hz), 7.66 (d, 2H, J = 8.7 Hz), 7.54 (m, 2H), 7.42 (m, 3H), 6.79 (t, 2H, J = 2.1 Hz), 6.09 (t, 2H, J = 2.1 Hz), 4.95 (m, 1H), 3.72 (s, 3H), 2.86-2.45 (m, 4H) FABMS m/z = 466 (M+H+). HRMS (calcd for C24H24N3O5S 466.1437) 466.1458.
Step 3: Preparation of 5-[ 4-[(Aminosulfonyl)phenyl]-4- phenyl-αS-(1H-pyrrol-1-yl)oxazole-2-butanoic acid
A solution of methyl 5-[4-(aminosulfonyl)
phenyl]-4-phenyl-αS-(1H-pyrrol-1-yl)oxazol-2-butanoate (Step 2) (0.2 g, 0.43 mmol) in MeOH (0.3 mL) and water (0.3 mL) was treated with NaOH (0.026 g) and stirred at room temperature for 1.5 h. The reaction mixture was diluted with 5% citric acid (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water, dried (Na2SO4), filtered, and
concentrated under reduced pressure. The resulting substance was purified by reverse-phase HPLC (using 10- 90% CH3CN in water (30 min gradient)). The appropriate fractions were combined and freeze-dried to give 0.15 g (78%) of 5-[4-[(aminosulfonyl)phenyl]-4-phenyl-αS-(1H- pyrrol-1-yl)oxazole-2-butanoic acid as a light brown powder: m.p. 74-78 °C. 1H-NMR (CD3OD/300 MHz) 7.87 (d, 2H, J = 8.7 Hz), 7.66 (d, 2H, J = 8.7 Hz), 7.55 (m, 2H), 7.44 (m, 3H), 6.79 (t, 2H, J = 2.1 Hz), 6.08 (t, 2H, J = 2.1 Hz), 4.91 (m, 1H), 2.85-2.45 (m, 4H) FABMS m/z = 452 (M+H+) HRMS (calcd for C23H22N3O5S 452.1280) 452.1291.
Other representative examples prepared by similar methods are summarized in Table 3.
Figure imgf000199_0001
Figure imgf000200_0001
4-(2-Ethenyl-4-phenyloxazol-5- yl]benzenesulfonamide
Step 1: Preparation of 2-[5-[(4- aminosulfonyl)phenyl]-4-phenyl-oxazol-2-yl]-1- hydroxyethane
Lithium aluminum hydride (0.33 g, 8.6 mmol) was suspended in 5 mL of anhydrous THF and cooled to -78 °C. Methyl 5-[(4-aminosulfonyl)phenyl]-4- phenyloxazole-2-acetate (1.6 g, 4.3 mmol) (prepared similar to that described in Example 38, step 3) was dissolved in 15 mL of anhydrous THF and added at -78 °C. The reaction mixture was stirred at -78 °C for 2 h, stirred at room temperature overnight, and quenched with 50 mL of 1 N HCl. The aqueous solution was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (1 x 100 mL), saturated brine (1 x 100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash chromatography on silica gel (eluting with 3:2 ethyl acetate:hexane to 4:1 ethyl acetate: hexane) to give 0.2 g (14%) of 2-[5-[(4- aminosulfonyl)phenyl]-4-phenyl-oxazol-2-yl]-1- hydroxyethane as a white solid: 1H NMR(DMSO-d6/300 MHz) 2.98 (t, 2H, J = 6.45 Hz), 3.81-3.87 (m, 2H), 4.91 (t, 1H, J = 5.4 Hz), 7.35-7.46 (m, 5H), 7.56 (dd, 2H, J = 1.65 Hz), 7.68 (d, 2H, J = 8.7 Hz), 7.84 (d, 2H, J = 8.7 Hz). HRMS (calcd for
C17H16N2O4S 345.0909) 345.0902. Step 2: Preparation of 4-(2-ethenyl-4- phenyloxazol-5-yl]benzenesulfonamide
2-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol- 2-yl]-1-hydroxyethane (Step 1) (0.2 g, 0.58 mmol) in 4 mL of dimethylacetamide (DMA) was added to NaH suspended in 1 mL of DMA at 5 °C. The reaction mixture was stirred at 5 °C for 30 minutes. 4- [4- Bromomethylphenyl]-4-methoxytetrahydropyran (0.2 g, 0.70 mmol) was dissolved in 3 mL of DMA and added to the reaction at 5 °C. The reaction mixture was stirred at 5 °C for 1.5 h and at room temperature overnight. The DMA was removed at reduced pressure, and the concentrated residue was dissolved in 150 mL of ethyl acetate. The organic solution was washed with 1 N HCl (2 x 100 mL), saturated sodium
bicarbonate (2 x 100 mL), saturated brine (2 x 100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was filtered through silica gel (eluting with 4:1 ethyl
acetate:hexane). The material recovered from this column was purified by reverse phase HPLC (eluting with a gradient from 10% to 90% acetonitrile in water with 0.1% TFA) to give 15 mg (8%) of 4-(2- ethenyl-4-phenyloxazol-5-yl]benzenesulfonamide as a white solid: 1H NMR (CD3OD/300 MHz) 5.82 (d, 1 H, J = 11.70 Hz), 6.38 (d, 1H, J = 17.40 Hz), 6.71 (dd, 1H, J = 11.10 Hz), 7.43-7.45 (m, 3H), 7.57-7.60 (m, 2H), 7.74 (d, 2H, J = 8.70 Hz), 7.89 (d, 2H, J = 8.40 Hz). HRMS (calcd for C17H14N2O3S 327.0803) 327.0800.
Figure imgf000202_0001
3-[[[5-[4-Aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]methyl]thio]propanoic acid
Figure imgf000202_0002
3-[[[4-[4-Aminosulfonyl)phenyl]-5- phenyloxazol-2-yl]methyl]thio]propanoic acid Step 1: Preparation of tert-butyl 3-[(2-methoxy-2- oxoethyl)thio]propanoate
A solution of tert-butyl acrylate (3.7 g, 0.03 mol) and methyl thioglycolate (3.3 g, 0.31 mol ) in CH2Cl2 (10 mL) was treated with DBU (0.3 g, 0.002 mol), and stirred at 10 °C for 2 h. The reaction mixture was diluted with CH2Cl2 (100 mL), washed sequentially with 5% citric acid (2 x 50 mL), brine (2 x 50 ml), and dried (Na2SO4). After the removal of the solvent, the resulting liquid was purified by silica gel flash chromatography (eluting with 30% EtOAc in hexane) to give 6.0 g (90%) of tert-butyl 3-[(2-methoxy-2-oxoethyl)-thio]propanoate as a colorless liquid: 1H-NMR (CDCl3/300 MHz) 3.75 (s, 3H), 3.26 (s, 2H), 2.87 (t, 2H, J = 6.9 Hz), 2.55 (t, 2H, J = 6.9 Hz), 1.46 (s, 9H).
Step 2: Preparation of tert-butyl 3- [(carboxymethyl)
thio]propanoate
A solution of tert-butyl 3-[(2-methoxy-2- oxoethyl)thio]propanoate (Step 1) (2.0 g, 8.5 mmol) in MeOH (6.00 mL) and water (4.0 mL) was treated with LiOH (0.45 g, 10.8 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with water (15 mL) and washed with EtOAc (2 x 10 mL). The aqueous phase was acidified with 5% citric acid and extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 1.1 g (59%) of tert-butyl 3- [(carboxymethyl) thio] propanoate as a colorless liquid which was used in the next step without further purification: 1H-NMR (CDCI3/300 MHz) 3.31 (S, 2H), 2.85 (t, 2H, J = 6.9 Hz), 2.58 (t, 2H, J = 6.9 Hz), 1.47 (s, 9H).
Step 3: Preparation of tert-butyl 3-[[[5-[4- aminosulfonyl)phenyl]-4-phenyl-oxazol-2-yl]methyl]- thiol propanoate and tert-butyl 3-[[[4-[4- aminosulfonyl)-phenyl]-5-phenyloxazol-2- yl]methyl]thio]propanoate
A mixture of 2-bromo-2-[(4- aminosulfonyl)phenyl]-1-phenylethanone (1.3 g, 3.7 mmol), tert-butyl 3-[(carboxymethyl)thio]propanoate (Step 2) (1.0 g, 4.5 mmol), and K2CO3 (0.40 g, 2.9 mmol) in dimethylacetamide (5.0 mL) was stirred at 10 °C for 2 h, and at room temperature for 1 h. The reaction mixture was diluted with water (50 mL), and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with water (2 x 25 mL), dried (Na2SO4), filtered, and concentrated to give the desired α-acyloxy ketone. The resulting viscous liquid (1.5 g) was used in the following reaction without further purification.
This α-acyloxy ketone (1.3 g) was dissolved in acetic acid (20 mL), NH4OAC (0.8 g, 10.4 mmol) was added, and the resulting mixture was heated at 100 °C for 2.5 h under a nitrogen atmosphere. The acetic acid was distilled in vacuo, and the residue was partitioned between water (25 mL) and EtOAc (30 mL). The organic phase was washed with water, dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (eluting with 40% EtOAc in hexane) to give 0.45 g (36%) of a mixture of tert-butyl 3-[[[5-[4-aminosulfonyl)phenyl]-4- phenyl-oxazol-2-yl]methyl]thiolpropanoate and tert- butyl 3-[[[4-[4-amino-sulfonyl)phenyl]-5- phenyloxazol-2-yl]methyl]-thiolpropanoate oxazole esters, as a light brown amorphous substance: m.p. 49-54 °C. 1H-NMR (CDCI3/300 MHz) 7.81 (d, 2H, J = 7.8 Hz), 7.66 (d, 2H, J = 7.8 Hz), 7.52 (m, 2H),
7.33 (m, 3H), 4.84 (s, 2H), 3.83 (s, 2H), 2.87 (t, 2H, J = 6.9 Hz), 2.53 (t, 2H, J = 6.9 Hz), 1.37 (s, 9H) . HRMS (calcd for C23H27N2O5S2 475.1361) 475.1326. Step 4: Preparation of 3-[[[5-[4- aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]methyl]- thio]propanoic acid and 3-[[[4-[4- aminosulfonyl)phenyl]-5-phenyloxazol-2- yl]methyl]thio]propanoic acid
A mixture of the oxazole esters (0.25 g, 5.2 mmol) Step 3, and p-toluenesulfonic acid (0.06 g 0.3 mmol) in acetonitrile (5.0 mL) was heated to reflux for 1.5 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was partioned between water (10 mL) and EtOAc (20 mL). The organic phase was washed with water, dried (Na2SO4), filtered, concentrated, and the resulting substance was purified by reverse- phase HPLC (10-90% CH3CN/H2O) to give two isomeric products: 3-[[[5-[4-aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]methyl]thio]propionic acid as a white powder; (0.16 g (73%)) m.p. 170-173 °C 1H-NMR (CD3OD/300 MHz) 7.9 (d, 2H, J = 8.7 Hz), 7.71 (d, 2H, J = 8.7 Hz), 7.57 (m, 2H), 7.42 (m, 3H), 3.98 (s, 2H), 2.95 (t, 2H, J = 7.2 Hz), 2.67 (t, 2H, J = 7.2 Hz); HRMS ( calcd for C19H19N2O5S2 419.0735) found 419.0700;
3-[[[4-[4-aminosulfonyl)phenyl]-5-phenyl-oxazol-2- yl]methyl]thio]propionic acid as a light brown powder: (0.03 g (14%)) m.p. 171-175 °C; 1H-NMR
(CD3OD/300 MHz) 7.91 (d, 2H, J = 8.4 Hz), 7.76 (d, 2H, J = 8.4 Hz), 7.56 (m, 2H), 7.43 (m, 3H), 3.97 (s, 2H), 2.94 (t, 2H, J = 6.9 Hz), 2.67 (t, 2H, J = 6.9 Hz); HRMS (calcd for C19H19N2O5S2 419.0735) 419.0708.
Figure imgf000205_0001
4-[[5-[(4-Aminosulfonyl)phenyl]-4-phenyl- oxazol-2-yl]methyl]benzenepropanoic acid Step 1: Preparation of 5-[(4- aminosulfonyl)phenyl]-4-phenyl-2-[(4-iodo- phenyl)methyl]oxazole
A mixture of 2-bromo-2-[(4- aminosulfonyl)phenyl]-1-phenylethanone (2.0 g, 5.65 mmol) and 4-iodophenylacetic acid (1.8 g, 6.9 mmol) in dimethylacetamide (6.0 mL) was treated with potassium carbonate (0.57 g, 4.13 mmol) and 18- crown-6 (0.06 g) and stirred at room temperature for 4 h. The reaction mixture was diluted with cold water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with water (2 x 25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting material was purified by flash
chromatography on silica gel (eluting with 40% EtOAc in hexane) to give the desired α-acyloxy ketone as an amorphous substance, which was used in the next reaction without further purification: 1H-NMR
(CDCl3/300 MHz) 7.86 (m, 4H), 7.63 (d, 2H, J = 8.4 Hz), 7.59 (m, 3H), 7.41 (t, 2H, J = 7.8 Hz), 7.03 (d, 2H, J = 8.4 Hz), 6.89 (s, 1H), 4.82 (s, 2H), 3.73 (q, 2H, J = 5.1 Hz). FABMS m/z = 536 (M+H+) HRMS (calcd for C22H19NO5SI 536.0029) 536.0023.
A mixture of this α-acyloxy ketone (2.2 g, 4.1 mmol), and ammonium acetate (1.3 g, 16.9 mmol) in acetic acid (15.0 mL) was heated at 100 °C under a nitrogen atmosphere for 2.5 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water (50 mL) and EtOAc (50 mL). The organic: phase was washed with water (2 x 30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting solid was
triturated with methanol, cooled and filtered to give 1.1 g (52%) of 5-[(4-aminosulfonyl)phenyl]-4- phenyl-2-[(4-iodophenyl)
methyl] oxazole as a pale yellow powder: m.p. 198-201 °C. 1H-NMR (CDCl3/ 300 MHz) 7.86 (d, 2H, J = 8.7 Hz), 7.7 (dd, 4H), 7.59 (m, 2H), 7.41 (m, 3H), 7.15 (d, 2H, J = 8.1 Hz), 4.81 (s, 2H), 4.16 (s, 2H). FABMS m/z = 517 (M+H+) HRMS (calcd for C22H18N2O3SI 517.0083) 517.0063. Step 2: Preparation of methyl 4-[[5-[(4- aminosulfonyl)phenyl]-4-phenyl-oxazol-2- yl]methyl]benzenepropynoate
To a solution of 5-[(4-aminosulfonyl)phenyl]-4-phenyl-2-[(4-iodophenyl)methyl]oxazole (Step 1) (0.3 g, 0.58 mmol) in dimethylacetamide (5.00 mL) was added K2CO3 (0.05 g, 0.3 mmol), 18-crown-6 (0.05 g), PdCl2. (PPh3)2, methyl propiolate (0.32 g, 3.8 mmol) and Cul (0.005 g), and the resulting mixture was stirred at room temperature for 16 h under an argon atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. This residue was purified by silica gel flash chromatography (25% EtOAc in hexane) to afford 0.11 g (40%) of methyl 4-[[5-[(4- amino-sulfonyl)phenyl]-4-phenyl-oxazol-2- yl]methyl]benzenepropynoate as a brown amorphous powder: 1H-NMR (CDCl3/300 MHz) 7.87 (d, 2H, J = 8.7 Hz), 7.68 (d, 2H, J = 8.7 Hz), 7.59 (m, 4H), 7.43 (m, 5H), 4.78 (s, 2H), 4.25 (s, 2H), 3.84 (s, 3H) FABMS m/z = 473 (M+H+) HRMS (calcd for C26H21N2O5S 473.1171) 473.1181. Step 3: Preparation of 4-[[5-[(4- aminosulfonyl)phenyl] -4-phenyl-oxazol-2-yl]methyl]benzenepropanoic acid
A mixture of methyl 4-[[5-[(4- aminosulfonyl)phenyl]
-4-phenyl-oxazol-2-yl]methyl]benzenepropynoate (Step 2) (0.12 g, 0.25 mmol) in MeOH (5 mL) was
hydrogenated in the presence of 10% Pd/C (0.13 g) at 50 psi for 3 h at room temperature. The catalyst was removed by filtration, the filtrate was
concentrated, and the residue was stirred with IM LiOH (1 mL) in MeOH (0.7 mL) and water (0.3 mL) for 1 h. The reaction mixture was diluted with 5% citric acid (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 0.08 g (69%) of 4- [[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol-2- yl]methyl]benzenepropanoic acid as a light brown amorphous powder : 1H-NMR (CDCI3 /300 MHz ) 7 . 83 ( d, 2H, J = 8.7 Hz), 7.66 (d, 2H, J = 8.7 Hz), 7.58 (m, 2H), 7.39 (m, 3H), 7.31 (d, 2H, J = 8.1 Hz), 7.19
(d, 2H, J = 8.1 Hz), 4.9 (s, 2H), 4.18 (s, 2H), 2.95 (t, 2H, J = 7.0 Hz), 2.68 (t, 2H, J = 7.0 Hz) FABMS m/z = 463 (M+H+). HRMS (calcd for C25H23N2O5S
463.1328) 463.1324.
Other representative examples prepared by similar methods from 5-[(4-aminosulfonyl)phenyl]-4- phenyl-2-[(4-iodophenyl)methyl]oxazole are
summarized in Tables 3 and 4.
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
5 - [ ( 4 -Aminosul fonyl ) phenyl ] - 4 - ( 4 - f luorophenyl ) oxazole-2 -pentanoic acid
Step 1. Preparation of 2-[(4-aminosulfonyl)phenyl]-1-(p- fluorophenyl)-ethanone.
Neat 2-(phenyl)-1-(p-fluorophenyl)ethanone (6.10 g, 28.54 mmol) was cooled to -78 °C in a dry ice methanol bath. Chlorosulfonic acid (15.0 mL) was added, and the solution was warmed to room temperature over 1 h. The solution was stirred for 2 h and poured directly into ice. The resulting heterogenous aqueous solution was extracted with ethyl acetate (2 x 300 mL). The ethyl acetate layers were combined, extracted with water (1 x 100 mL) and mixed with ammounium hydroxide solution (50 mL) for 1 h. The ethyl acetate was collected, extracted with 1N HCl (2 x 200 mL), brine (1 x 200 mL), and dried over sodium sulfate. The solvent was removed to a volume of 50 mL and crystals formed. The crystals were kept at room temperature for 4 h and collected by vaccuum filtration to give 3.1 g (37%) of 2-[(4- aminosulfonyl)phenyl]-1-(p-fluorophenyl)ethanone: m.p. 198-204 °C. 1H NMR (CD3OD/300 MHz) 4.46 (s, 2H), 7.23 (t, 2H, J = 8.8 Hz), 7.43 (d, 2H, J = 8.5 Hz), 7.85 (d, 2H, J = 8.5 Hz). 8.10-8.20 (m, 2H). FABMS m/z = 294 (m+H+) HRMS (calcd for Ci4H13FNO3S 294.0600) 294.0583. Step 2: Preparation of 2-[(4-aminosulfonyl)phenyl]-2- bromo-1-(p-fluoro-phenyl)ethanone
To a solution of 2-[(4-aminosulfonyl)phenyl]-1-(p- fluorophenyl)ethanone (Step 1) (2.93 g, 10.00 mmol) in acetic acid (25 mL) at room temperature was added 33% HBr in acetic acid (5.0 mL), followed by bromine (1.59 g, 10.00 mmol), and the solution was stirred at room
temperature for 1 h. The acetic acid was removed at reduced pressure, and the resulting yellow liquid was poured into ethyl acetate (100 mL). This solution was washed with saturated sodium bicarbonate (2 x 100 mL), and brine (100 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed at reduced pressure to give 3.21 g (86%) of 2-[(4-aminosulfonyl)phenyl]-2-bromo-1-(p- fluorophenyl)ethanone as a gummy foam: 1H NMR (CDCI3/300 MHz) 5.05 (bs, 2H), 6.30 (s, 1H), 7.16 (t, 2H, J = 8.6 Hz), 7.67 (d, 2H, J = 8.5 Hz), 7.92 (d, 2H, J = 8.5 Hz), 8.02-8.07 (m, 2H). FABMS m/z = 389 (m+NH3 +). HRMS (calcd for Ci4Hι2BrFNO3S 371.9705) 371.9721.
Step 3: Preparation of methyl 5-[(4- aminosulfonyl)phenyl]-4-(4-fluoro-phenyl)oxazole-2- pentanoate
A mixture of 2-[(4-aminosulfonyl)phenyl]-2-bromo-1- (p-fluorophenyl)ethanone (Step 2) (760 mg, 2.56 mmol) and the sodium salt of adipic acid monomethyl ester (550 mg, 2.91 mmol) were combined in dimethylformamide (5.0 mL) and stirred at room temperature for 1 h. The solvent was removed at reduced pressure, and the residue was taken up in ethyl acetate (35 mL). This solution was washed with saturated aqueous ammonium chloride (2 x 25 mL), dried over anhydrous sodium sulfate, and the solvent removed at reduced pressure to give 924 mg (80%) of the desired α- acyloxy ketone intermediate as a thick yellow oil: 1H NMR (CDCI3/300 MHz) 1.70-1.95 (m, 4H), 2.31 ( t, 2H, J = 6.9 Hz), 2.43-2.57 (m, 2H), 4.95 (bs, 2H), 6.85 (s, 1H), 7.11 (t, 2H, J = 8.6 Hz), 7.60 (d, 2H, J = 8.3 Hz), 7.91 (d, 2H, J = 8.3 Hz), 7.95-8.00 (m, 2H). FABMS m/z = 452
(m+H+). HRMS (calcd for C21H23FNO7S 452.1179) 452.1209.
This α-acyloxy ketone intermediate (861 mg, 1.90 mmol) and ammonium acetate (1014 mg, 13.1 mmol) were refluxed in acetic acid (5 mL) for 2 h. The solution was poured into water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The ethyl acetate extracts were combined and washed with saturated sodium bicarbonate (3 x 50 mL), and saturated aqueous sodium chloride (1 x 50 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed at reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 371 mg (45%) of methyl 5-[(4-amino-sulfonyl)phenyl]-4-(4-fluorophenyl)- oxazole-2-pentanoate as a gummy yellow semi-solid: 1H NMR (CD3OD/300 Mhz) 1.64-1.99 (m, 4H), 2.41 (t, 2H, J = 7.2 Hz), 2.91 (t, 2H, J = 7.3 Hz), 3.65 (s, 3H), 7.17 (t, 2H, J = 8.9 Hz), 7.57-7.61 (m, 2H), 7.67 (d, 2H, J = 8.6 Hz), 7.88 (d, 2H, J = 8.6 Hz). FABMS m/z = 433 (m+H+). HRMS (calcd for C21H22FN2O5S 433.1233) 433.1213.
Step 4: Preparation of 5-[(4-aminosulfonyl)phenyl]-4- (4-fluorophenyl)-oxazole-2-pentanoic acid
Methyl 5-[(4-aminosulfonyl)phenyl]-4-(4- fluorophenyl)oxazole-2-pentanoate (Step 3) (264.0 mg, 0.61 mmol) and lithium hydroxide monohydrate (100.0 mg, 2.40 mmol) were mixed in tetrahydrofuran/methanol/water (10.0 mL, 7:2:1) at room temperature for 16 h. The solution was acidified with 10% aqueous hydrochloric acid (pH = 1) and poured into ethyl acetate (30 mL). The solution was extracted with 10% aqueous hydrochloric acid (10 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and the solvent was removed at reduced pressure to give 251 mg (99%) of the desired product 5- [(4-aminosulfonyl)-phenyl]-4-(4-fluorophenyl)-oxazole-2- pentanoic acid as a white solid: m.p. 164.0-165.6 °C. 1H NMR (CD3OD/300 MHz) 1.69-1.99 (m, 4H), 2.38 (t, 2H, J = 7.2 Hz), 2.92 (t, 2H, J = 7.3 Hz), 7.17 (t, 2H, J = 8.8 Hz), 7.57-7.61 (m, 2H), 7.68 (d, 2H, J = 8.6 Hz), 7.88 (d, 2H, J = 8.6 Hz). FABMS m/z = 419 (m+H+). HRMS (calcd for C20H20FN2O5S 419.1077) 419.1082.
Figure imgf000214_0001
4-[2-Ethyl-4-(3-fluorophenyl)-oxazol-5- yl]benzenesulfonamide
Step 1: Preparation of 1-(3-fluorophenyl)-2-phenyl- ethan-1-one
3-Fluorobenzaldehyde (10.0 g, 81 mmol),
dichloromethane (100 mL), and zinc iodide (5 mg) were stirred at 0 °C under nitrogen. Trimethylsilylcyanide (8.83 g, 89 mmol) was added dropwise with a slight exotherm. The cooling bath was removed and the reaction proceeded for 2 hours when water (5 mL) was added
dropwise. The mixture was washed with brine (2 X 30 mL), dried over magnesium sulfate, and concentrated under high vacuum. The resulting oily residue was dissolved in tetrahydrofuran (150 mL) and cooled to -78 °C under nitrogen. Lithium diisopropylamine (2.0 M solution in heptane/tetrahydrofuran/ethylbenzene, 45 mL, 90 mmol) was added dropwise maintaining the temperature below -60 °C. The reaction was stirred for 1/2 hour and benzyl bromide was added (15.4 g, 90 mmol) all at once. The cooling bath was removed and the mixture was stirred until the temperature reached -15 °C and poured into a stirred solution of 1N hydrochloric acid (150 mL) and
trifluoroacetic acid (10 mL). After one hour, the mixture was extracted with ethyl acetate (2 X 50 mL), combined, washed with brine (2 X 50 mL), and
concentrated. The resulting dark oily residue was treated with 2.5 N sodium hydroxide, and a solid was collected by filtration. Recrystallization from
ethanol/water resulted in 11.4 g of a light yellow solid: mp 54.6-57.0 °C. This material was used in the next step without further purification or characterization.
Step 2. Preparation of 1-(3-fluorophenyl)-2-bromo-2- phenyl-ethan-1-one
1-(3-Fluorophenyl)-2-phenyl-ethan-1-one (Step 1) (4.28 g, 20 mmol), acetic acid (50 mL), 33% hydrobromic acid in acetic acid (10 mL), and bromine (3.2 g, 20 mmol) were stirred at room temperature for 2 hours. The mixture was concentrated and ethyl acetate (150 mL) was added. After washing with brine, drying over magnesium sulfate, and concentrating, 5.3 g of a brown oil was obtained. This material was used in the next step without further purification or characterization.
Step 3. Preparation of 2-ethyl-4-(3-fluorophenyl)-5- phenyloxazole.
1-(3-Fluorophenyl)-2-bromo-2-phenyl-ethan-1-one
(Step 2) (1.5 g, 5.15 mmol), N',N'-dimethylformamide (25 mL), sodium hydroxide (60%, 0.23 mL, 5.67 mmol), and propionic acid (0.33 g, 5.67 mmol) were stirred at room temperature overnight. After the addition of ethyl acetate (100 mL), the mixture was washed successively with 1N hydrochloric acid, brine, and water. The organic solution was dried over magnesium sulfate and
concentrated. The resulting oily residue was dissolved in acetic acid (50 mL) and ammonium acetate (6.0 g) was added. After refluxing for 12 hours, the mixture was concentrated, dissolved in ethyl acetate (100 mL), washed with brine, dried and concentrated. Purification by flash column chromatography (eluting with hexanes : ethyl acetate (20:1)) yielded 0.6 g of a light yellow oil which formed an oily solid upon standing: 1H NMR
(CDCl3/300 MHz) 7.57 (m, 2H), 7.5-7.25 (m, 5H), 7.02 (m,
1H), 2.88 (q, J = 8.7 Hz, 2H), 1.42 (t, J= 8.7 Hz, 3H). This material was used in the next step without further purification or characterization. Step 4: Preparation of 4-[2-ethyl-4-(3-fluorophenyl)- oxazol-5-yl]benzenesulfonamide
Chlorosulfonic acid (10 mL) was cooled to -78 °C. 2-Ethyl-4-(3-fluorophenyl)-5-phenyloxazole (Step 3) (0.6 g, 22 mmol) was dissolved in a minimum amount of
dichloromethane and added dropwise. The mixture was stirred and warmed to room temperature over 5 hours, when it was added dropwise to ice (500 mL). Ammonium
hydroxide (100 mL) and ethyl acetate (100 mL) were added and the mixture was stirred overnight. The layers were separated and the organic phase was washed with 1 N hydrochloric acid, and brine. After drying over
magnesium sulfate and concentrating, 0.4 g of a light yellow solid was recrystallized from ethanol water: mp 133.5-135.1 °C. 1H NMR (acetone-d6/300 MHz) 7.96 (d, J = 9.3 Hz, 2H), 7.78 (d, J = 9.3 Hz, 2H), 7.5-7.3 (m, 3H), 7.18 (m, 1H), 6.70 (bs, 2H), 2.90 (q, J = 8.3 Hz, 2H), 1.40 (t, J = 8.3 Hz, 3H). FABHRMS m/z 347.0848. (M+H, C17H15FN2O3S calcd 347.0866). 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 determined (Otterness and Bliven, Laboratory Models for Testing NSAIDs, in Non-steroidal Anti- Inflammatory Drugs, (J. 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 6.
Rat Carrageenan-induced Analgesia Test
The analgesia test using rat carrageenan 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 6.
Figure imgf000218_0001
Evaluation of COX I and COX II activity in vitro
The compounds of this invention exhibited inhibition in vitro of COX-2. The COX-2 inhibition activity of the compounds of this invention illustrated in the Examples was determined by the following methods. a. Preparation of recombinant COX baculoviruses
Recombinant COX-1 and COX-2 were prepared as described by Gierse et al, [J. Biochem., 305, 479-84 (1995)]. A 2.0 kb fragment containing the coding region of either human or murine COX-1 or human or murine COX-2 was cloned into a BamHl site of the baculovirus transfer vector pVL1393 (Invitrogen) to generate the baculovirus transfer vectors for COX-1 and COX-2 in a manner similar to the method of D.R. O'Reilly et al (Baculovirus
Expression Vectors: A Laboratory Manual (1992)).
Recombinant baculoviruses were isolated by transfecting 4 μg of baculovirus transfer vector DNA into SF9 insect cells (2x108) along with 200 ng of linearized baculovirus plasmid DNA by the calcium phosphate method. See M.D. Summers and G.E. Smith, A Manual of Methods for
Baculovirus Vectors and Insect Cell Culture Procedures, Texas Agric. Exp. Station Bull. 1555 (1987). Recombinant viruses were purified by three rounds of plaque
purification and high titer (107 - 108 pfu/ml) stocks of virus were prepared. For large scale production, SF9 insect cells were infected in 10 liter fermentors (0.5 x 106/ml) with the recombinant baculovirus stock such that the multiplicity of infection was 0.1. After 72 hours the cells were centrifuged and the cell pellet
homogenized in Tris/Sucrose (50 mM: 25%, pH 8.0)
containing 1% 3-[(3-cholamidopropyl)dimethylammonio]-1- propanesulfonate (CHAPS). The homogenate was centrifuged at 10,000xG for 30 minutes, and the resultant supernatant was stored at -80°C before being assayed for COX
activity. b. Assay for COX-1 and COX-2 activity COX activity was assayed as PGE2 formed/μg
protein/time using an ELISA to detect the prostaglandin released. CHAPS-solubilized insect cell membranes containing the appropriate COX enzyme were incubated in a potassium phosphate buffer (50 mM, pH 8.0) containing epinephrine, phenol, and heme with the addition of arachidonic acid (10 μM). Compounds were pre-incubated with the enzyme for 10-20 minutes prior to the addition of arachidonic acid. Any reaction between the
arachidonic acid and the enzyme was stopped after ten minutes at 37°C/room temperature by transferring 40 μl of reaction mix into 160 μl ELISA buffer and 25 μM
indomethacin. The PGE2 formed was measured by standard ELISA technology (Cayman Chemical). Results are shown in Table 7.
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
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 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, e.g., 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 15% 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- 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 so- called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the
formulation of the present invention include Tween 60, 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 esters such as di-isoadipate, isocetyl 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 10% 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, 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 administration 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 or diluents mentioned for use in the formulations for oral
administration. The compounds may be dissolved in 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.

Claims

What is claimed is:
1. A compound of Formula II
Figure imgf000227_0001
wherein R2 is selected from lower alkyl and amino; wherein R4 is selected from hydrido, alkyl, alkylamino, alkoxy and halo; and wherein R5 is selected from halo, mercapto, carboxyalkylthio,
carboxyalkylthioalkyl, carboxyalkoxy,
carboxyalkoxyalkyl, haloalkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkoxy, aryloxy,
alkylamino, aminocarbonyl, alkoxyalkyl,
carboxy(haloalkyl), aminoalkyl, hydroxyalkoxyalkyl, alkylcarbonyl, phosphonylalkyl, alkylcarbonylaminoalkyl, aralkoxycarbonylaminoalkyl, amino acid residue,
heterocyclylalkyl, and cyanoalkyl; or a
pharmaceutically-acceptable salt thereof.
2. Compound of Claim 1 wherein R2 is selected from lower alkyl and amino; wherein R4 is selected from hydrido, lower alkyl, lower alkylamino, lower alkoxy and halo; and wherein R5 is selected from halo, mercapto, lower carboxyalkylthio, lower carboxyalkylthioalkyl, lower haloalkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy, aryloxy, lower alkylamino, aminocarbonyl, lower alkoxyalkyl, lower carboxy(haloalkyl), lower aminoalkyl, lower
hydroxyalkoxyalkyl, lower alkylcarbonyl, lower phosphonylalkyl, lower alkylcarbonylaminoalkyl, lower aralkoxycarbonylaminoalkyl, amino acid residue, lower heterocyclylalkyl, and lower cyanoalkyl; or a
pharmaceutically-acceptable salt thereof.
3. Compound of Claim 2 wherein R2 is selected from methyl and amino; wherein R4 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 R5 is selected from chloro, fluoro, bromo, iodo, mercapto, carboxymethylthio, carboxyethylthio, carboxyethylthiomethyl,
trifluoromethoxy, methylthio, ethylthio, methylsulfinyl, methylsulfonyl, methoxy, ethoxy, propoxy, butoxy, phenyloxy, benzyloxy, N-methylamino, N,N-dimethylamino, N,N-diethylamino, aminocarbonyl, methoxymethyl, α-bromo- carboxymethyl, aminoethyl,
bis(hydroxymethyl)methoxymethyl, methylcarbonyl, N- methylcarbonylaminomethyl, aminopropyl,
pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylpropyl, pyrrolylethyl, methylcarbonylaminomethyl, N- (benzyloxycarbonyl)aminomethyl, N- (benzyloxycarbonyl)aminoethyl, N- (benzyloxycarbonyl)aminopropyl, N-methyl-N- (benzyloxycarbonyl)aminoethyl, [N-
(phenylmethoxycarbonyl)amino]methoxycarbonylpropyl, [N- (phenylmethoxycarbonyl)amino]carboxypropyl,
piperidinylethyl, tetrazolylpentyl, and cyanopentyl; or a pharmaceutically-acceptable salt thereof.
4. Compound of Claim 3 selected from compounds and their pharmaceutically-acceptable salts, of the group consisting of phenylmethyl [2-[5-[4-(aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]methyl]carbamate; phenylmethyl [2-[5-[4-(aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]ethyl]carbamate;
phenylmethyl [2-[5-[4-(aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]ethyl]methylcarbamate;
phenylmethyl [2-[5-[4-(aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]propyl]carbamate;
methyl 5-[4-(aminosulfonyl)phenyl]-αR-
[[(phenylmethoxy)carbonyl]aminno]-4-phenyloxazole-2- butanoate;
5-[4-(aminosulfonyl)phenyl]-αR-
[[(phenylmethoxy)carbonyl]aminno]-4-phenyloxazole-2- butanoic acid;
4-[2-cyanopentyl-4-phenyloxazol-5-yl]benzenesulfonamide; 4-[2-methoxymethyl-4-phenyl-5- oxazolyl]benzenesulfonamide;
[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol-2- yl]propanamine;
4-[2-(1-pyrrolyl)propyl-4-phenyloxazol-5- yl]benzenesulfonamide;
[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol-2- yl]ethanamine;
4-[2-(1-piperidinyl)ethyl-4-phenyloxazol-5- yl]benzenesulfonamide;
4-[2-(1-pyrrolidinyl)methyl-4-phenyloxazol-5- yl]benzenesulfonamide;
4-[2-[bis(hydroxymethyl)methoxy]methyl-4-phenyloxazol-5- yl]benzenesulfonamide;
2-[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]ethan-2-one;
4-[2-chloro-4-phenyl-5-oxazolyl]benzenesulfonamide;
4-[2-mercapto-4-phenyl-5-oxazolyl]benzenesulfonamide; 4-[2-(3-chlorophenoxy)-4-phenyl-5- (oxazolyl]benzenesulfonamide;
5-(4-aminosulfonylphenyl)-4-phenyl-2- oxazolyl)mercaptoacetic acid;
4-[4-phenyl-2-(2,2,2-trifluoroethoxy-5- oxazolyl]benzenesulfonamide; 4-[2-(methylthio)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-methylsulfinyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-(methylsulfonyl)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-(2,3,4,5,6-pentafluorophenoxy)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-[2-methoxy-4-phenyl-5-oxazolyl]benzenesulfonamide; ethyl 2-[[5-(4-aminosulfonylphenyl)-4-phenyl-2- oxazolyl]oxy]benzoate;
ethyl 3-[[5-(4-aminosulfonylphenyl)-4-phenyl-2- oxazolyl]oxy]benzoate;
4-[2-(N,N-dimethylamino)-4-phenyl-5- oxazolyl]benzenesulfonamide;
4-methyl-3-[5-phenyl-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide;
4-[4-(3-aminosulionyl-4-methylphenyl)-2-trifluoromethyl- 5-oxazolyl]benzenesulfonamide;
4-methyl-3-[4-phenyl-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide;
4-[4-aminosulfonylphenyl)-5-(3-fluoro-4-methoxyphenyl)-
2-oxazolyl]α-bromoacetic acid;
4-[4-(3-aminosulfonyl-5-fluoro-4-methoxyphenyl)-2- trifluoromethyl-5-oxazolyl]benzenesulfonamide;
5-fluoro-4-methoxy-3-[5-phenyl-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide;
ethyl 4-[[5-(4-aminosulfonylphenyl)-4-phenyl-2- oxazolyl]oxy]benzoate;
4-[5-(4-bromophenyl)-2-methoxymethyl-4- oxazolyl]benzenesulfonamide;
4-[2-methoxymethyl-5-phenyl-4- oxazolyl]benzenesulfonamide;
4-[4-(4-chlorophenyl)-2-methoxymethyl-5- oxazolyl]benzenesulfonamide;
4-[4-(3-chlorophenyl)-2-methoxymethyl-5- oxazolyl]benzenesulfonamide; 4-[5-(4-chlorophenyl)-2-methoxymethyl-4- oxazolyl]benzenesulfonamide;
4-[5-(3-chlorophenyl)-2-methoxymethyl-4- oxazolyl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-2-methoxymethyl-4- oxazolyl]benzenesulfonamide;
4-[4-phenyl-2-(methylcarbonylaminomethyl)-5- oxazolyl]benzenesulfonamide;
(R) 4-[4-phenyl-2-[2-(1-pyrrolyl)ethyl]-5- oxazolyl]benzenesulfonamide; and
(S) 4-[4-phenyl-2-[2-(1-pyrrolyl)ethyl]-5- oxazolyl]benzenesulfonamide.
Figure imgf000231_0001
wherein R2 is selected from lower alkyl and amino; wherein R4 is selected from hydrido, lower alkyl, lower alkylamino, lower alkoxy and halo; wherein R6 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 the amide, ester and salt derivatives of said acids; provided Y is not methyl when Q is -P(O) (OH)2; and further provided Y is not
methyl or ethyl when Q is carboxyl; or a
pharmaceutically-acceptable salt thereof.
6. Compound of Claim 5 wherein R4 is selected from lower alkyl and amino; wherein R4 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 aralkoxycarbonyl, tetrazolyl,
Figure imgf000232_0001
and wherein each of R 7 and R8 is independently selected from hydrido, lower alkyl, lower cycloalkyl, phenyl and lower aralkyl; or a pharmaceutically-acceptable salt thereof.
7. Compound of Claim 6 wherein R2 is selected from methyl and amino; wherein R4 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, 3,3-dimethylbutyl, 2- methylpropyl, butyl, and methylsulfonylaminopropyl; wherein Q is selected from carboxyl, methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, tetrazolyl,
Figure imgf000233_0001
and wherein each of R7 and R8 is independently selected from hydride, methyl, and ethyl; or a pharmaceutically- acceptable salt thereof.
8. Compound of Claim 7 selected from compounds and their pharmaceutically-acceptable salts, of the group consisting of
5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-pentanoic acid;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- pentanoate;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- butanoate;
5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-butanoic
acid;
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]oxy]acetic acid;
5-[(4-aminosulfonyl)phenyl]-4-phenyl-β,β-dimethyloxazole- 2-butanoic acid;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- hexanoate;
5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2-hexanoic
acid;
diethyl [[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- yllpropyl]phosphonate; [[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- yl]propyl]phosphonic acid;
diethyl [[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- yl]methyl]phosphonate;
ethyl [[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazole-2- yl]methyl]phosphonate;
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]sulfonyl]propanoic acid;
methyl 3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]ethyl]thio]acetate;
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]ethyl]thio]acetic acid;
tert-butyl 3-[[[5-[4-aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]methyl]thio]acetate;
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]thio]acetic acid;
5-[(4-aminosulfonyl)phenyl]-4-phenyl-β-methyloxazole-2- butanoic acid;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyl-β- methyloxazole-2-butanoate;
4-[(2-tetrazolyl)pentyl-4-phenyloxazol-5- yl]benzenesulfonamide;
[[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]-1-pyrrol-2-yl]carboxylic acid;
methyl [[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]-1-pyrrol-2-yl]carboxylate;
[[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2-yl]-2- pyrrol-1-yl]acetic acid;
ethyl [ [[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]-2-pyrrol-1-yl]acetate;
methyl [[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]-1-pyrrolidin-2-yl]carboxylate;
methyl [[[5-[(4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]propyl]aminosulfonyl] acetate;
5-[(4-aminosulfonyl)phenyl]-4-phenyl-βS-amino-oxazole-2- butanoic acid;
methyl [5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)oxazole]-2-propanoate; 5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)oxazole-2-propanoic acid;
methyl [5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)oxazole]-2-butanoate;
5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)oxazole-2-butanoic acid;
methyl [5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)oxazole]-2-pentanoate;
5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)oxazole-2-pentanoic acid;
4-[(4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)oxazole-2- pentanoic acid;
methyl 4-[(4-aminosulfonyl)phenyl]-5-(4- fluorophenyl)oxazole-2-pentanoate;
5-[(4-aminosulfonyl)phenyl]-4-(3,4-dichlorophenyl)-β,β- dimethyloxazole-2-butanoic acid;
methyl 5-[(4-aminosulfonyl)phenyl]-4-(3,4- dichlorophenyl)-β,β-dimethyloxazole-2-butanoate;
4-[(4-methylsulfonyl)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoic acid;
methyl 4-[(4-methylsulfonyl)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoate;
4-[(4-aminosulfonyl)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoic acid;
methyl 4-[(4-aminosulfonyl)phenyl]-5-(3,4- dichlorophenyl)oxazole-2-butanoate;
5-[(4-aminosulfonyl)phenyl]-4-phenyl-αS-(1H-pyrrol-1-- yl)oxazole-2-butanoic acid;
methyl 5-[(4-aminosulfonyl)phenyl]-4-phenyl-αS-(1H- pyrrol-1-yl)oxazole-2-butanoate;
3-[[[5-[4-aminosulfonyl)phenyl]-4-phenyloxazol-2- yl]methyl]thio]propanoic acid;
3-[[[4-[4-aminosulfonyl)phenyl]-5-phenyloxazol-2- yl]methyl]thio]propanoic acid;
tert butyl 3-[[[5-[4-aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]methyl]thio]propanoate; tert butyl 3- [[[4-[4-aminosulfonyl)phenyl]-5- phenyloxazol-2-yl]methyl]thio]propanoate;
4-[2-[5-[(4-aminosulfonyl)phenyl]-4-phenyl-oxazol-2- yl]methyl]phenylpropanoic acid;
methyl 4-[2-[5-[(4-aminosulfonyl)phenyl]-4-phenyl- oxazol-2-yl]methyl]phenylpropynoic acid;
methyl 5-[(4-aminosulfonyl)phenyl]-4-(4- fluorophenyl)oxazole-2-pentanoate; and
5-[(4-aminosulfonyl)phenyl]-4-(4-fluorophenyl)oxazole-2- pentanoic acid.
9. A Compound selected from compounds and their pharmaceutically-acceptable salts, of the group
consisting of
4-[2-[[4-[3-(hydroxy)-1-propynyl]phenyl]methyl]-4- phenyloxazol-5-yl]benzenesulfonamide;
4-[2-[[4-[3-(N,N-dimethylamino)-1- propynyl]phenyl]methyl]-4-phenyloxazol-5- yl]benzenesulfonamide;
4-[2-[[4-[3-(N,N-dimethylamino)propyl]phenyl]methyl]-4- phenyloxazol-5-yl]benzenesulfonamide;
4-[2-[[4-[3-(2-methyl-1H-imidazol-1-yl)-1- propynyl]phenyl]methyl]-4-phenyloxazol-5- yl]benzenesulfonamide;
1,1-dimethylethyl [3-[4-[[5-[4-(aminosulfonyl)phenyl]-4- phenyloxazol-2-yl]methyl]phenyl]-2- propynyl]carbamate;
4-[2-[[4-[3-(2-methyl-1H-imidazol-1-yl)-1- propyl]phenyl]methyl]-4-phenyloxazol-5- yl]benzenesulfonamide;
4-[2-[[4-[3-(amino)-1-propynyl]phenyl]methyl]-4- phenyloxazol-5-yl]benzenesulfonamide;
4-[2-[[4-[3-(tert-butylamino)-1-propynyl]phenyl]methyl]- 4-phenyloxazol-5-yl]benzenesulfonamide;
4-phenyl-2-(benzyloxymethyl)-5-(4- methylsulfonylphenyl)oxazole; 5-phenyl-2-(benzyloxymethyl)-4-(4- methylsulfonylphenyl)oxazole;
4-[4-phenyl-2-(2-pyrrolyl)-5- oxazolyl]benzenesulfonamide;
4-[2-ethyl-4-(3-fluorophenyl)oxazol-5- yl]benzenesulfonamide;
[5-[(4-aminesulfonyl)phenyl]-4-phenyl-oxazol-2- yl]ethyne;
4-[2-propargyl-4-phenyloxazol-5-yl]benzenesulfonamide; 4-(2-ethenyl)-4-phenyl-oxazol-5-yl]benzenesulfonamide; ethyl [4-(4-aminosulfonylphenyl)-5-(3-fluoro-4- methoxyphenyl)]-2-oxazoleacetate;
[4-(4-aminosulfonylphenyl)-5-cyclohexyl]-2-oxazoleacetic acid;
[5-(4-aminosulfonylphenyl)-4-(4-chlorophenyl)]-2- oxazoleacetic acid;
[4-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)]-2- oxazoleacetic acid;
[4-(4-aminosulfonylphenyl)-5-(3-chloro-4-fluorophenyl)]- 2-oxazoleacetic acid;
[4-(4-aminosulfonylphenyl)-5-(3,4-dichlorophenyl)]-2- oxazoleacetic acid;
[4-(4-aminosulfonylphenyl-5-(3,4-difluorophenyl)]-2- oxazoleacetic acid;
[5-(3,4-difluorophenyl)-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide;
[5-(4-aminosulfonylphenyl)-4-phenyl]-2-oxazolepropionic acid;
4-[4-phenyl-5-oxazolyl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide;
4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4- oxazolyl]benzenesulfonamide;
4-[4-(N,N-dimethylamino)phenyl-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide;
[4-(4-aminosulfonylphenyl)-5-(3-fluoro-4- methoxyphenyl)]-2-oxazoleacetic acid; 4-(4-methylphenyl)-5-(4-methylsulfonylphenyl)-2- trifluoromethyloxazole;
4-[5-(3-fluoro-4-methoxyphenyl)-2-methyl-4- oxazolyl]benzenesulfonamide;
5-(3-fluoro-4-methoxyphenyl)-4-(4-methylsulfonylphenyl)- 2-trifluoromethyloxazole;
4-[5-(3-bromo-4-methoxy-5-fluorophenyl)-2- trifluoromethyl-4-oxazolyl]benzenesulfonamide;
4-(4-fluorophenyl)-2-cyclohexyl-5-[4- (methylsulfonyl)phenyl]oxazole;
5-(4-fluorophenyl)-2-phenyl-4-[4-
(methylsulfonyl)phenyl]oxazole;
[5-(3,4-dichlorophenyl)-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide;
4-(3-fluoro-4-methoxyphenyl)-5-(4-methylsulfonylphenyl)- 2-trifluoromethyloxazole;
4-[4-(4-bromophenyl)-2-methyl-5- oxazolyl]benzenesulfonamide;
4-[4-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-5- oxazolyl]benzenesulfonamide;
4-[5-(3-chloro-4-fluorophenyl)-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide;
4-[5-(3-chloro-4-methoxyphenyl)-2-trifluoromethyl-4- oxazolyl]benzenesulfonamide;
4-[4-phenyl-2-(2-pyrrolyl)-5- oxazolyl]benzenesulfonamide;
4-[5-phenyl-2-difluoromethyl-4- oxazolyl]benzenesulfonamide;
[5-phenyl-4-(aminosulfonylphenyl)-2-oxazolyl]methanol;
[4-phenyl-5-(aminosulfonylphenyl)-2-oxazolyl]methanol;
[5-phenyl-4-(methylsulfonylphenyl)-2-oxazolyl]methanol;
[4-phenyl-5-(methylsulfonylphenyl)-2-oxazolyl]methanol;
[4-(3-fluoro-4-methoxyphenyl)-5-(aminosulfonylphenyl)-2- oxazolyl]methanol;
4-[5-phenyl-2-methyl-4-oxazolyl]benzenesulfonamide;
4-[5-(4-bromophenyl)-2-methyl-4- oxazolyl]benzenesulfonamide;
[5-(aminosulfonylphenyl)-4-phenyl-2-oxazolyl]-2-ethanol; [5-(aminosulfonylphenyl)-4-phenyl-2-oxazolyl]-1-ethanol; 4-[4-(3-fluorophenyl)-2-methyl-5- oxazolyl]benzenesulfonamide;
4-[4-(4-chlorophenyl)-2-methyl-5- oxazolyl]benzenesulfonamide;
[4-(phenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]-α,α- dimethylmechanol ;
4-[4-(4-fluorophenyl)-2-methyl-5- oxazolyl]benzenesulfonamide;
4-[4-(3-chlorophenyl)-2-ethyl-5- oxazolyl]benzenesulfonamide;
[4-(3-chlorophenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]-
2-methanol;
[4-(4-chlorophenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]- 2-methanol;
4-[5-(3-chlorophenyl)-2-ethyl-4- oxazolyl]benzenesulfonamide;
4-[4-phenyl-2-(1-methyl-2-pyrrolyl)-5- oxazolyl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-methyl-4- oxazolyl]benzenesulfonamide;
4-[4-(3,4-dichlorophenyl)-2-ethyl-5- oxazolyl]benzenesulfonamide;
[4-(3-chlorophenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]- α,α-dimethylmethanol;
[5-(3-chlorophenyl)-4-(aminosulfonylphenyl)-2-oxazolyl]- α,α-dimethylmethanol; and
[4-(phenyl)-5-(aminosulfonylphenyl)-2-oxazolyl]-2- propanol.
10. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from a family of compounds of Claim 1, 2, 3, 4, 5, 6, 7, 8 or 9; or a pharmaceutically- acceptable salt thereof.
11. A method of treating inflammation or an inflammation-associated disorder in a subject, said method comprising treating the subject having or susceptible to said disorder with a therapeutically- effective amount of a compound of Claim 1, 2, 3, 4, 5, 6, 7, 8 or 9; or a pharmaceutically-acceptable salt thereof.
12. The method of Claim 11 for use in treatment of inflammation.
13. The method of Claim 11 for use in treatment of an inflammation-associated disorder.
14. The method of Claim 13 wherein the
inflammation-associated disorder is arthritis.
15. The method of Claim 13 wherein the
inflammation-associated disorder is pain.
16. The method of Claim 13 wherein the
inflammation-associated disorder is fever.
PCT/US1996/006992 1995-05-19 1996-05-16 Substituted oxazoles for the treatment of inflammation WO1996036617A1 (en)

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AU58603/96A AU5860396A (en) 1995-05-19 1996-05-16 Substituted oxazoles for the treatment of inflammation

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US11439625B2 (en) 2016-03-14 2022-09-13 Avexxin As Combination therapy for proliferative diseases
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