WO1997038986A1 - Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors - Google Patents

Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors Download PDF

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Publication number
WO1997038986A1
WO1997038986A1 PCT/US1997/005497 US9705497W WO9738986A1 WO 1997038986 A1 WO1997038986 A1 WO 1997038986A1 US 9705497 W US9705497 W US 9705497W WO 9738986 A1 WO9738986 A1 WO 9738986A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
sulfonyl
methyl
phenylisoxazol
acetamide
Prior art date
Application number
PCT/US1997/005497
Other languages
English (en)
French (fr)
Inventor
John J. Talley
James W. Malecha
Stephen Bertenshaw
Matthew J. Graneto
Jeffery S. Carter
Jinglin Li
Srinivasan Nagarajan
David L. Brown
Donald J. Rogier, Jr.
Thomas D. Penning
Ish K. Khanna
Xiangdong Xu
Richard M. Weier
Original Assignee
G.D. Searle & Co.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP53713997A priority Critical patent/JP3382624B2/ja
Priority to HU9901807A priority patent/HU225473B1/hu
Priority to DK02025005T priority patent/DK1288206T3/da
Priority to AT97921092T priority patent/ATE233743T1/de
Priority to IL12584997A priority patent/IL125849A/xx
Priority to EA199800919A priority patent/EA003319B1/ru
Priority to CA002249009A priority patent/CA2249009C/en
Priority to DK97921092T priority patent/DK0892791T3/da
Priority to AU27227/97A priority patent/AU734275C/en
Priority to EE9800351A priority patent/EE03685B1/xx
Priority to BR9708574A priority patent/BR9708574A/pt
Priority to RO98-01469A priority patent/RO121338B1/ro
Priority to NZ331542A priority patent/NZ331542A/xx
Priority to SI9720035A priority patent/SI9720035B/sl
Application filed by G.D. Searle & Co. filed Critical G.D. Searle & Co.
Priority to DE69719496T priority patent/DE69719496T2/de
Priority to EP97921092A priority patent/EP0892791B1/en
Priority to SI9720101A priority patent/SI22713B/sl
Priority to MEP-1998-443A priority patent/ME00768B/me
Priority to PL97329276A priority patent/PL195955B1/pl
Priority to APAP/P/1998/001355A priority patent/AP1009A/en
Priority to SK1242-98A priority patent/SK285353B6/sk
Publication of WO1997038986A1 publication Critical patent/WO1997038986A1/en
Priority to UA98115994A priority patent/UA47475C2/uk
Priority to IS4863A priority patent/IS2156B/is
Priority to NO19984727A priority patent/NO314184B1/no
Priority to LVP-98-215A priority patent/LV12239B/en
Priority to HK99104900A priority patent/HK1019741A1/xx
Priority to IS7292A priority patent/IS7292A/is
Priority to US10/939,852 priority patent/US7420061B2/en

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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/16—Amides, e.g. hydroxamic acids
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated

Definitions

  • cyclooxygenase-2 (COX-2) provides a viable target of
  • prodrugs of antiinflammatory compounds are advantageous, especially where the prodrugs have increased water solubility or delayed onset of action.
  • JP 5,323,522 describes the use of heterocyclic compounds in black and white photographic material.
  • U.S. Patent No. 5,389,635 describes substituted imidazoles as angiotensin II antagonists.
  • U.S. Patent No. 5,387,592 describes substituted benzimidazole derivatives as angiotensin II antagonists.
  • G. Dorofeenko et al [Khim . Farm. Zh . , 16, 920 (1982)] describe pyridinium salts as antiviral agents.
  • U.S. Patent No. 5,338,749 describes diaryl- substituted heterocyclyl compounds as antiarthritis agents.
  • W094/26731 describes thiophene compounds which selectively inhibit cyclooxygenase-2.
  • WO95/00501 describes compounds which selectively inhibit
  • a class of substituted sulfonamide compounds useful as prodrugs is defined by Formula I :
  • A is a ring substituent selected from partially unsaturated heterocyclyl, heteroaryl, cycloalkenyl and aryl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalky, carboxyalkoxyalkyl,
  • cycloalkylalkyl alkenyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl,
  • alkylthioalkyl arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, N- arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, N-arylamino, N- aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N- arylamino, aminoalkyl, alkylaminoalkyl, N- arylaminoalkyl, N-aralkylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N- arylamin
  • R 1 is selected from heterocyclyl
  • radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,
  • R 2 is selected from hydrido and
  • R 3 is selected from alkyl, carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl,
  • alkoxycarbonylalkylcarbonyl alkoxycarbonylcarbonyl, amino acid residue, and
  • A is not tetrazolium, or pyridinium; and further provided A is not indanone when R 3 is alkyl or carboxyalkyl;
  • Compounds of Formula I would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other cyclooxygenase-2 mediated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the
  • compounds of the invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis,
  • spondyloarthropathies gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.
  • Such compounds of the invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, skin-related conditions such as psoriasis, eczema, burns and
  • 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
  • Compounds of the invention would be useful for the prevention or treatment of cancer, such as colorectal cancer, and cancer of the breast, lung, prostate, bladder, cervix and skin.
  • Compounds of the invention would be useful in treating inflammation m such diseases as vascular diseases, migraine headacnes, periarteritis nodosa, thyroiditis, aplastic anemia,
  • sarcoidosis multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensltivity, swelling occurring after injury, myocardial ischemia, and the like.
  • the compounds would also be useful in the treatment of ophthalmic diseases, such as retmitis, retmopathies, uveitis, ocular
  • the compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis.
  • the compounds would also be useful for the treatment of certain central nervous system disorders, such as cortical dementias including Alzheimer's disease, and central nervous system damage resulting from stroke, ischemia and trauma.
  • the compounds of the invention are useful as anti- mflammatory agents, such as for the treatment of arthritis, with the additional benefit of having
  • These compounds would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, and atherosclerosis.
  • the compounds would also be useful in the treatment of pam, but not limited to postoperative pain, dental pam, muscular pam, and pam resulting from cancer.
  • the compounds would be useful for the prevention of dementias, such as Alzheimer's disease.
  • these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • the present compounds may also be used in co- therapies, partially or completely, in place of other conventional antimflammatories, such as together with steroids, NSAIDs, 5-lipoxygenase inhibitors, LTB 4 antagonists and LTA 4 hydrolase inhibitors .
  • Suitable LTB 4 inhibitors include, among others, ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS- 25019C, Leo Denmark compound ETH-615, Lilly compound LY- 293111, Ono compound ONO-4057, Terumo compound TMK-688, Lilly compounds LY-213024, 264086 and 292728, ONO compound ONO-LB457 , Searle compound SC-53228,
  • the LTB 4 inhibitors are selected from ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS- 25019C, Leo Denmark compound ETH-615, Lilly compound LY- 293111, Ono compound ONO-4057, and Terumo compound TMK- 688.
  • Suitable 5-LO inhibitors include, among others, masoprocol, tenidap, zileuton, pranlukast, tepoxalm, ⁇ lopirox, flezelastine hydrochloride, enazadrem
  • the present compounds may also be used in any combination.
  • combination therapies with opioids and other analgesics such as morphine, meperidine or codeine.
  • cyclooxygenase-2 inhibitor embraces compounds which selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
  • the compounds have a cyclooxygenase-2 IC 50 of less than about 0.5 ⁇ M, and also have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and more preferably of at least 100.
  • the compounds have a cyclooxygenase-1 IC 50 of greater than about 1 ⁇ M, and more preferably of greater than 20 ⁇ M.
  • Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-mduced side
  • 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 multnple, separate capsules for each agent.
  • prodrug refers to compounds which are drug precursors which, following administration to a subject and subsequent absorption, is converted to an active species m vivo via some process, such as a metabolic process. Other products from the conversion process are easily disposed of by the body. More preferred prodrugs produce products from the conversion process which are generally accepted as safe.
  • cyclooxygenase-2 consists of compounds of Formula I wherein A is selected from partially unsaturated heterocyclyl, 5- or 6-membered heteroaryl, lower cycloalkenyl and phenyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from formyl, lower alkylcarbonyl, halo, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, lower haloalkylsulfonyloxy, lower alkoxyalkyloxyalkyl, lower carboxyalkoxyalkyl, lower cycloalkylalkyl, lower alkenyl, lower alkynyl,
  • heterocyclyloxy lower alkylthio, lower cycloalkyl, phenyl, 5-6 membered heterocyclyl, lower cycloalkenyl, lower phenylalkyl, 5-6 membered heterocyclylalkyl, lower
  • alkylthioalkyl phenylcarbonyl, lower phenylalkylcarbonyl, lower phenylalkenyl, lower alkoxyalkyl, lower
  • alkoxyalkylcarbonyl (5-6-membered heteroaryl) carbonyl, lower alkoxycarbonylalkylcarbonyl, lower
  • a more preferred class of compounds whicn inhibit cyclooxygenase-2 consists of compounds of Formula I wherein A is a radical selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, pyrazolyl,
  • R 1 is selected from thienyl, oxazolyl, isoxazolyl, furyl, thiazolyl, pyridyl, and phenyl, where R 1 is optionally substituted at a substitutable position with one or more radicals selected from methyl, trifluoromethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, nitro, methoxymethyl, fluoro, chloro, bromo, methoxy and methylthio; wherein R 2 is hydrido, or ethoxycarbonylmethyl; and wherein R 1 is selected from methyl, carboxymethyl, formyl,
  • methoxycarbonylmethylcarbonyl aminomethylcarbonyl, methoxycarbonylethylcarbonyl, methoxycarbonylcarbonyl, tert-butoxycarbonylaminomethylcarbonyl, and
  • A is a ring substituent selected from partially unsaturated heterocyclyl, 5- or 6-membered heteroaryl, lower cycloalkenyl and phenyl; wherein A is optionally substituted at a substitutable position with one or more radicals selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro,
  • alkoxycarbonyl lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, lower alkylcarbonyloxyalkyl, and phenyl;
  • R 4 is selected from heterocyclyl
  • R 4 is optionally substituted at a substitutable position with one or more radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; and
  • R 5 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower
  • alkoxycarbonyl lower aminoalkyl
  • alkoxycarbonylaminoalkyl and lower
  • a preferred class of compounds consists of those compounds of Formula II wherein A is a ring substituent selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, mdenyl, benzothienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyciopentadienyl, benzindazolyl, benzopyranopyrazolyl, phenyl, and pyridyl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower alkylcarbonyloxyalkyl, phenyl and
  • alkylsulfinyl halo, lower alkoxy and lower alkylthio; and wherein R 5 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower
  • alkoxycarbonylalkyl lower alkoxycarbonyl, lower aminoalkyl, lower alkoxycarbonylaminoalkyl, and lower alkylcarbonylaminoalkyl; or a pharmaceutically- acceptable salt thereof.
  • a class of compounds of particular interest consists of those compounds of Formula II wherein A is a ring substituent selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl,
  • R 4 is selected from thienyl, pyridyl and phenyl, wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from methyl, trifluoromethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, nitro, methoxymethyl, fluoro, chloro, bromo, methoxy and methylthio; and wherein R 5 is selected from hydrido, methyl, ethyl, isopropyl, propyl, tert-butyl, butyl, pentyl, methoxy, tert-butoxy, methoxyethyl, ethoxymethyl, methoxymethyl, phenyl, carboxyethyl, methoxycarbonylmethyl,
  • R 1 is selected from hydroxyl, lower alkyl, carboxyl, halo, lower carboxyalkyl, lower
  • alkoxycarbonylalkyl lower aralkyl, lower alkoxyalkyl, lower alkoxyalkyloxyalkyl, lower aralkoxyalkyl, lower haloalkyl, lower hydroxylalkyl, lower
  • R 7 is one or more radicals selected from hydrido, lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; and
  • R 8 is selected from hydrido, lower alkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower
  • alkoxycarbonyl lower aminoalkyl
  • alkoxycarbonylaminoalkyl and lower
  • a preferred class of compounds consists of those compounds of Formula III wherein R 6 is selected from lower alkyl, lower haloalkyl, and lower hydroxylalkyl; wherein R 7 is one or more radicals selected from hydrido, lower alkyl, halo, and lower alkoxy; and wherein R 8 is selected from lower alkyl, phenyl, and lower aminoalkyl; or a pharmaceutically-acceptable salt thereof.
  • a more preferred class of compounds consists of those compounds of Formula III wherein R 6 is selected from methyl, difluoromethyl and hydroxymethyl; wherein R 7 is one or more radicals selected from hydrido, methyl, fluoro, chloro, bromo, and methoxy; and wherein R 8 is selected from methyl, ethyl, isopropyl, propyl, tert-butyl, butyl, pentyl, phenyl, and aminomethyl; or a pharmaceutically-acceptable salt thereof.
  • a family of specific compounds of particular interest within Formulas I-III consists of compounds and pharmaceutically-acceptable salts thereof as follows:
  • Formulas I-III consists of compounds as follows: N-[[4-[2-(2-methylpyridin-6-yl)-4-(trifluoromethyl)-1H- imidazol-1-yl]phenyl]sulfonyl]acetamide, sodium salt;
  • hydro denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH 2 -) radical. Where used, either alone or withm other terms such as "haloalkyl",
  • alkylsulfonyl "alkoxyalkyl” and “hydroxyalkyl”
  • alkyl embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals havmg 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 “alkyl” embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals havmg one to about
  • alkenyl embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl” radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl .
  • alkynyl denotes linear or branched radicals having at least one carbon-carbon triple bond, and having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms.
  • alkynyl radicals are "lower alkynyl” radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
  • alkenyl and “lower alkenyl” embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations.
  • cycloalkyl is cycloalkyl
  • cycloalkyl radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and
  • cyclohexyl embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkenyl radicals are "lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include
  • 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.
  • a monohaloalkyl radical for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl,
  • 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
  • alkoxy and alkyloxy embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms . Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
  • 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” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals. More preferred haloalkoxy radicals are "lower
  • haloalkoxy radicals having one to six carbon atoms and one or more halo radicals.
  • examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
  • aryl alone or in combination, means a
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
  • Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl.
  • substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl.
  • heterocyclyl embraces saturated,
  • saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidmyl, piperidino, piperazinyl, etc.);
  • heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
  • Heterocyclyl radiclas may include a pentavalent nitrogen, such as in tetrazolium and
  • heteroaryl embraces unsaturated heterocyclyl radicals.
  • heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolmyl, imidazolyl,
  • pyrazolyl pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.
  • unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms for example, mdolyl, isoindolyl, mdolizinyl, benzimidazolyl, qumolyl, isoquinolyl, mdazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,
  • unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom for example, thienyl, etc.
  • unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl, etc.) etc.
  • heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. benzoxazolyl, benzoxadiazolyl, etc.
  • unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms for example, thiazolyl, thiadiazolyl (e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazoiyl, 1,2,5- thiadiazolyl, etc.) etc.
  • heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., benzothiazolyl
  • heteroaryl also embraces radicals where heterocyclyl radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran,
  • heterocyclyl group may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred 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.
  • alkylthioalkyl embraces radicals containing an
  • alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkyl radicals are
  • lower alkylthioalkyl radicals having alkyl radicals of one to six carbon atoms.
  • lower alkylthioalkyl radicals include methylthiomethyl.
  • sulfonyl whether used alone or linked to other terms such as “alkylsulfonyl”, denotes a divalent radical, -SO 2 -.
  • Alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
  • the "alkylsulfonyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals.
  • sulfamyl denotes NH 2 O 2 S-.
  • 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 examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and radicals formed from succinic, glycolic, gluconic, lactic, malic, tartarie, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, mandelic, pantothenic, ⁇ -hydroxybutyric, galactaric and galacturonic acids.
  • aroyl embraces aryl radicals with a carbonyl radical as defined below.
  • aroyl examples include benzoyl, naphthoyl, phenylacetyl, and the like, and the aryl in said aroyl may be additionally substituted, such as in p-hydroxybenzoyl, and salicylyl.
  • carbonyl whether used alone or with other terms, such as
  • carboxyalkyl denotes -CO 2 H.
  • Carboxyalkyl embraces alkyl radicals substituted with a carboxy radical. More preferred are "lower
  • carboxyalkyl which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo.
  • lower carboxyalkyl radicals include carboxymethyl
  • alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are “lower alkoxycarbonyl” radicals with alkyl portions having one to six carbons. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.
  • alkylcarbonyl examples 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,
  • Carboxyalkylcarbonyl embraces alkylcarbonyl radicals substituted with a carboxy radical. More preferred are “lower carboxyalkylcarbonyl” which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with hydroxyl.
  • Examples of such lower carboxyalkylcarbonyl radicals include carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, HO 2 C(CHOH) 4 C(O)-, HO 2 C(CHOH) 2 C(O) - , HO 2 C(CH 2 )(CHOH)C(O)-, and HO 2 CCH 2 C(OH)(CO 2 H)C(O)-.
  • the term "carboxyalkenylcarbonyl” embraces derivatives of maleic and fumaric acids. Examples of such
  • carboxyalkenylcarbonyl radicals include (Z)- carboxyethenylcarbonyl and (E)-carboxyethenylcarbonyl.
  • aralkyl embraces aryl-s bstituted alkyl radicals such as benzyl, diphenylmethyl,
  • triphenylmethyl, phenylethyl, and diphenylethyl triphenylmethyl, phenylethyl, and diphenylethyl.
  • the aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • 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
  • the heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • aryloxy embraces aryl radicals attached through an oxygen atom to other radicals.
  • arylthio embraces aryl radicals attached to a sulfur atom.
  • aralkoxy embraces aralkyl radicals attached through an oxygen atom to other radicals.
  • heterocyclyloxy embraces heterocyclyl radicals attached through an oxygen atom to other radicals.
  • aralkoxyalkyl embraces aralkoxy radicals attached through an oxygen atom to an alkyl radical.
  • aralkylthio embraces aralkyl radicals attached to a sulfur atom.
  • aralkylthioalkyl embraces aralkylthio radicals
  • aminoalkyl embraces alkyl radicals substituted with amino radicals. More preferred are "lower
  • aminoalkyl radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like.
  • alkylamino denotes amino groups which are substituted with one or two alkyl radicals. Preferred are “lower alkylamino" radicals having alkyl porions having one to six carbon atoms. Suitable lower alkylamino may be monosubstituted N-alkylamino or disubstituted N,N- alkylamino, such as N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-diethylamino or the like.
  • arylamino denotes amino groups which are substituted with one or two aryl radicals, such as N-phenylamino. The "arylamino" radicals may be further substituted on the aryl ring portion of the radical.
  • aminoalkylamino embraces amino groups which are
  • N-arylaminoalkyl and “N-aryl-N-alkyl-aminoalkyl” denote aminoalkyl groups which are substituted with one aryl radical or one aryl and one alkyl radical,
  • Examples of such radicals include N- phenylaminomethyl and N-phenyl-N-methylaminomethyl .
  • the term “alkylaminocarbonyl” denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals on the amino nitrogen atom. Preferred are “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” radicals. More preferred are “lower N-alkylaminocarbonyl” and “lower N,N- dialkylaminocarbonyl” radicals with lower alkyl portions as defined above.
  • alkylaminoalkyl embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical.
  • aryloxyalkyl embraces radicals having an aryl radicals attached to an alkyl radical through a divalent oxygen atom.
  • arylthioalkyl embraces radicals having an aryl
  • 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, alanme, arginine, asparagme, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidme, isoleucine, leucme, lysine, methionme, ornithine, phenylalanme, proline, serine, threonine, cyclohexylalanme, tryptophan, tyrosine, valme, ⁇ -alanme, and ⁇ -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,
  • the present invention comprises a pharmaceutical composition
  • a pharmaceutical composition 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 method of
  • A is a ring substituent selected from partially unsaturated heterocyclyl, heteroaryl, cycloalkenyl and aryl, wherein A is optionally substituted at a substitutable position with one or more radicals selected from
  • alkylcarbonyl formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, aryl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, arylthioalkyl, arylcarbonyl,
  • alkylaminosulfonyl N-arylaminosulfonyl, arylsulfonyl, and N- alkyl-N-arylaminosulfonyl; wherein R 1 is selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R 1 is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl,
  • alkylcarbonylaminoalkylcarbonyl or a pharmaceutically- acceptable salt thereof.
  • 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 I-III via injection.
  • 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
  • optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of
  • diastereoisomeric salts by treatment with an optically active acid or base.
  • appropriate acids are tartarie, diacetyltartaric, dibenzoyltarta ⁇ c, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting an amine functionality of precursors to compounds of Formula I with an optically pure acid in an activated form or an optically pure isocyanate.
  • diastereomeric derivatives can be prepared by reacting a carboxyl functionality of precursors to compounds of Formula I with an optically pure amine base.
  • synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the
  • compounds of Formula I can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
  • 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, heterocyclyl, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic,
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts and organic salts. More preferrred metallic salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group Ila) salts and other
  • Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Preferred organic salts can be made from tertiary amines and quanternary ammonium salts, including in part, trometamine, diethylamine, N,N'-dibenzylethylenediamme, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the
  • cyclooxygenase-2 inhibitor prodrugs of the invention can be synthesized according to the following procedures of Schemes I-XVII, wherein the R 1 -R 8 substituents are as defined for Formulas I-III, above, except where further noted.
  • step 1 ketone 1 is treated with a base, preferably NaOMe or NaH, and an ester, or ester equivalent, to form the intermediate diketone 2 (in the enol form) which is used without further purification.
  • step 2 diketone 2 in an anhydrous protic solvent, such as absolute ethanol or acetic acid, is treated with the hydrochloride salt or the free base of a substituted hydrazine at reflux to afford a mixture of pyrazoles 3 and 4. Recrystallization or chromatography affords 3 usually as a solid. Similar pyrazoles can be prepared by methods
  • Scheme II shows the four step procedure for forming cyclooxygenase-2 inhibitor pyrazoles 8 as described in U.S. patent No. 5,486,534 (where R a is hydrido or alkyl) from ketones 5.
  • ketone 5 is reacted with a base, such as lithium bis (trimethylsilyl) amide or lithium
  • step 2 the anion is reacted with an acetylatmg reagent to provide diketone 6.
  • step 3 the reaction of diketone 6 with hydrazine or a substituted hydrazine, gives pyrazole 7.
  • step 4 the pyrazole 7 is oxidized with an oxidizing reagent, such as Oxone ® (potassium peroxymonosulfate), 3- chloroperbenzoic acid (MCPBA) or hydrogen peroxide, to give a mixture of the desired 3-(alkylsulfonyl)phenyl-pyrazole 8 and the 5-(alkylsulfonyl)phenyl-pyrazole isomer.
  • Oxone ® potassium peroxymonosulfate
  • MCPBA 3- chloroperbenzoic acid
  • Sulfonamides 9 can be prepared such as by the Huang method [Tet. Lett., 35, 7201-04 (1994)] .
  • diketone 6 can be formed from ketone 5 by treatment with a base, such as sodium hydride, in a solvent, such as dimethylformamide, and further reacting with a nitrile to form an aminoketone. Treatment of the aminoketone with acid forms the diketone 6.
  • a base such as sodium hydride
  • a solvent such as dimethylformamide
  • Treatment of the aminoketone with acid forms the diketone 6.
  • Similar pyrazoles can be prepared by methods described in U.S. Pat. No. 3,984,431 which is incorporated by reference.
  • thiophenes (where T is S, and R b is alkyl) can be prepared by the methods described in U.S. Patent Nos. 4,427,693, 4,302,461, 4,381,311, 4,590,205, and 4,820,827, and PCT documents WO 95/00501 and W094/15932, which are
  • Cyclooxygenase-2 inhibitor diaryl/heteroaryl oxazoles can be prepared by the methods described in U.S. Patent Nos. 5,380,738, 3,743,656, 3,644,499 and 3,647,858, and PCT documents WO 95/00501 and WO94/27980, which are
  • isoxazoles can be prepared by the methods described in PCT application Serial No. US96/01869, PCT documents
  • Sulfonamides 27 can be formed from the hydrated isoxazole 26 in a two step procedure. First, hydrated isoxazole 26 is treated at about 0 °C with two or three equivalents of chlorosulfonic acid to form the corresponding sulfonyl chloride. In step two, the sulfonyl chloride thus formed is treated with concentrated ammonia to provide the sulfonamide derivative 27.
  • Scheme VI shows a three step preparation of the cyclooxygenase-2 inhibitor imidazoles 33.
  • step 1 the reaction of substituted nitriles (R 1 CN) 28 with primary phenylamines 29 in the presence of alkylaluminum reagents such as trimethylaluminum, triethylaluminum,
  • step 2 the reaction of amidine 30 with 2-haloketones (where X is Br or Cl) in the presence of bases, such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate or hindered tertiary amines such as N, N' - dnsopropylethylamine, gives the 4 , 5-dihydroimidazoles 31 (where R" is alkyl).
  • bases such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate or hindered tertiary amines such as N, N' - dnsopropylethylamine.
  • step 3 the 4, 5-dihydroimidazoles 31 may be dehydrated in the presence of an acid catalyst such as 4-toluenesulfonic acid or mineral acids to form the 1,2- disubstituted imidazoles 32 of the invention.
  • an acid catalyst such as 4-toluenesulfonic acid or mineral acids
  • Suitable solvents for this dehydration step are e.g., toluene, xylene and benzene.
  • Trifluoroacetic acid can be used as solvent and catalyst for this dehydration step.
  • Sulfonamides 33 can be prepared such as by the Huang method [Tet. Lett., 35, 7201-04 (1994)].
  • the intermediate 31 may not be readily isolable.
  • the reaction proceeds to give the targeted imidazoles directly.
  • imidazoles can be prepared having the sulfonylphenyl moiety attached at position 2 and R 1 attached at the nitrogen atom at position 1.
  • Diaryl/heteroaryl imidazoles can be prepared by the methods described in U.S. Patent ⁇ os. 4,822,805 and PCT documents WO 93/14082 and WO96/03388, which are incorporated by reference.
  • Imidazole cyclooxygenase-2 inhibitor compounds 41 may be synthesized according to the sequence outlined in Scheme VII. Aldehyde 34 may be converted to the protected
  • cyanohydrin 35 by reaction with a trialkylsilyl cyanide, such as trimethylsilyl cyanide (TMSCN) in the presence of a catalyst such as zinc iodide (Znl 2 ) or potassium cyanide (KCN).
  • TMSCN trimethylsilyl cyanide
  • Znl 2 zinc iodide
  • KCN potassium cyanide
  • Reaction of cyanohydrin 35 with a strong base followed by treatment with benzaldehyde 36 and using both acid and base treatments, in that order, on workup gives benzoin 37.
  • strong bases suitable for this reaction are lithium diisopropylamide (LDA) and lithium hexamethyldisilazane.
  • Benzoin 37 may be converted to benzil 38 by reaction with a suitable oxidizing agent, such as bismuth oxide or manganese dioxide, or by a Swern oxidation using dimethyl sulfoxide (DMSO) and
  • Benzil 38 may be obtained directly by reaction of the anion of cyanohydrin 35 with a substituted benzoic acid halide. Any of compounds 37 and 38 may be used as intermediates for conversion to
  • oxidation of the sulfide to the sulfone may be carried out at any point along the way beginning with compounds 36, and including oxidation of imidazoles 39, using, for examples, reagents such as hydrogen peroxide in acetic acid, m-chloroperoxybenzoic acid (MCPBA) and potassium peroxymonosulfate (OXONE ® ).
  • Sulfonamides 41 can be prepared such as by the Huang method [Tet. Lett., 35, 7201-04 (1994)].
  • Diaryl/heteroaryl imidazoles can be prepared by the methods described in U.S. Patent Nos.
  • Diaryl/heteroaryl cyclopentene cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Patent No. 5,344,991, and PCT document WO 95/00501, which are incorporated by reference.
  • Synthetic Scheme IX shows the procedure for the preparation of 1, 2-diarylbenzene cyclooxygenase-2 inhibitor agents 51 from 2-bromo-biphenyl intermediates 49 (prepared similar to that described in Synthetic Scheme VIII) and the appropriate substituted phenylboromc acids. Using a coupling procedure similar to the one developed by Suzuki et al. [Synth. Commun . , 11, 513 (1981)],
  • intermediates 49 are reacted with the boronic acids in toluene/ethanol at reflux in the presence of a Pd°
  • Sulfonamides 51 can be prepared such as by the Huang method [Tet. Lett . , 35, 7201-04 (1994)].
  • Such terphenyl compounds can be prepared by the methods described in U.S. application Serial No. 08/346,433, which is incorporated by reference.
  • Diaryl/heteroaryl thiazole cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Patent No. 4,051,250, 4,632,930, European document EP 592,664, and PCT documents WO96/03392, and WO 95/00501, which are
  • Isothiazoles can be prepared as described in PCT document WO 95/00501.
  • Diaryl/heteroaryl pyridine cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Patent Nos. 5,169,857, 4,011,328, 4,533,666, PCT application Serial No. US96/01110 and PCT application Serial No.
  • Synthetic Scheme XI illustrates a method for the preparation of acylated sulfonamides 57.
  • the method involves treatment of an unsubstituted sulfonamide 56 with a suitable acylating agent such as an anhydride, acid chloride, acyl imidazole, or active ester, in the presence of base and a suitable solvent, such as tetrahydrofuran (THF), to afford the acylated
  • the product 57 can then be isolated by chromatography or by crystallization.
  • Synthetic Scheme XII shows the method for the preparation of the corresponding salt form of 57.
  • a suitable strong base such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like produces the corresponding salt form 58.
  • a suitable strong base such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.
  • solvents such solvents as ethanol and tetrahydrofuran are preferred.
  • Synthetic Scheme XIII shows the method used for the preparation of substituted sulfonamides 60.
  • the step involves treatment of a suitable sulfonyl chloride 59 with an amine to produce the substituted sulfonamide 59.
  • the amine may be either a primary amine (R 1 NH 2 ) or a secondary amine (R 3 R 2 NH).
  • the reaction is generally conducted in the presence of added base.
  • the reaction may also be conducted in the presence of excess amine. Under the conditions of excess amine, the amine functions as both nucleophile and base.
  • Synthetic Scheme XIV shows the method used for the synthesis of N-substituted acyl sulfonamides 61, The procedure involves treatment of the salt of an acylated sulfonamide 58 with an alkyl halide (R 2 -X) to produce the corresponding N-alkylated acyl
  • This process may be conducted in a
  • Synthetic Scheme XV illustrates the method used for the synthesis of certain N-acylated sulfonamides 57.
  • the procedure involves treatment of the sulfonamide 56 with an excess of an anhydride, acid chloride or carbamyl chloride in the presence of a tertiary amine base to provide the
  • Oxidation with pyridinium chlorochromate produces the ketones 68.
  • Condensation with a [(N- substituted amino)sulfonyl]benzeneamine in the presence of p-toluenesulfonic acid (produces the substituted pyrrole sulfonamide 69.
  • Synthetic Scheme XVII illustrates the method for the preparation of acylated isoxazole sulfonamides 71.
  • the step involves treatment of an unsubstituted sulfonamide 70 with a suitable acylating agent such as an anhydride, acid chloride, acyl imidazole, or active ester to afford the acylated sulfonamide 71.
  • a suitable acylating agent such as an anhydride, acid chloride, acyl imidazole, or active ester to afford the acylated sulfonamide 71.
  • the product 71 can be isolated by chromatography or by crystallization.
  • Acetic anhydride (1.01 g, 9.39 mmol) and triethylamine (0.401 g, 3.97 mmol) were added to a solution of 4-[5-methyl- 3-(3-fluorophenyl)isoxazol-4-yl]benzenesulfonamide (1.10 g, 3.31 mmol) and N,N-dimethylpyridine (0.202 g) in dry
  • 1 H NMR (D 2 O/300 MHz) 7.62 (d, 2H, J 8.4 Hz), 7.2 (m, 7H), 2.27 (s, 3H), 1.77 (s, 3H).
  • Example 73 (0.867 g, 2.09 mmol) in methanol was treated with sodium hydroxide. The reaction was concentrated in vacuo , dissolved in water and slowly acidified with 1 N HCl to yield a solid.
  • Step 2 Preparation of N-[[4-(5-hydroxymethyl-3- phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide
  • Step 1 4-yl]phenyl]sulfonyl]propanamide (Step 1) was dissolved in methanol and NaOH solution (0.89 mL of 2.5 N, 2.24 mmol) added with stirring. After
  • Step 3 Preparation of N-[[4-(5-hydroxymethyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide, sodium salt
  • the 5,5-dimethyl-1,3-dioxane-2-propanol was synthesized by following the literature procedure (J. Org. Chem . 57, 2195,1992).
  • Step 3 Preparation of C: ⁇ -(4-fluorophenyl) -5,5- dimethyl-1,3-dioxane-2-propanol
  • Step 4 Preparation of 3-(5,5-dimethyl-1,3-dioxan-2- yl)-1-(4-fluorophenyl)propan-1-one
  • Step 3 To a solution of ⁇ -(4-fluorophenyl)-5,5-dimethyl- 1,3-dioxane-2-propanol (Step 3) (2.6 g, 10.7 mmol) in methylene chloride (100 ml), pyridinium chlorochromate (3.5 g, 16.05 mmol) was added. After stirring at room temperature for 3 hr, the reaction mixture was diluted with ether and filtered through a short silica gel column.
  • Step 5 N-methyl-4- nitrobenzenesulfonamide (Step 5) (4.8 g, 22.2 mmol) in methanol (100 ml) in a Parr bottle was added Raney- nickel in methanol. The reaction mixture was flushed with nitrogen and hydrogen several times and maintained under hydrogen at delivery pressure of 5 psi. After stirring at 25 °C for approximately 20 hr, the reaction was vented and purged with nitrogen. The contents of the reaction were filtered and concentrated to remove the solvent. The 4-[(N-methylamino)sulfonyl]aniline obtained as a white solid (4.1 g, 100%) was used in the next step without further purification: mp (DSC) 138 °C.
  • Step 4 A mixture of 3-(5,5-dimethyl-1,3-dioxan-2-yl)-1- (4-fluorophenyl)propan-1-one (Step 4) (400 mg, 1.5 mmol), 4-[(N-methylamino)sulfonyl]aniline (Step 6) (308 mg, 1.65 mmol) and p-toluenesulfonic acid (40 mg) in toluene (80 ml) was heated to reflux for 48 hr. The reaction mixture was cooled, filtered and concentrated.
  • Step 1 Preparation of N-acetyl-N-[[4-(5-methyl-3- phenylisoxazol-4-vl)phenyl]sulfonvn ⁇ rvcine, ethyl ester
  • Step 1 (0.24 g, 0.54 mmol) in methanol was added
  • Step 1 To 20 mL of stirring chlorosulfonic acid cooled to -5 °C was added 3 ,4-diphenyl-2-( 5H ) - furanone (Step 1) (3.160 g, 13.4 mmol) portion- wise over 30 minutes. The solution was warmed to room temperature and maintained at that
  • a composition is prepared having the following components: N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl] sulfonyl]propanamide, sodium salt 40 mg phosphate buffer, pH 7.5 (10 mM) 2 ml mannitol 40 mg
  • Mannitol (40 mg) is added to phosphate buffer solution (2 ml).
  • phosphate buffer solution (2 ml).
  • the N-[[4-(5-methyl-3- phenylisoxazol-4- yl)phenyl]sulfonyl]propanamide, sodium salt is added and the resulting solution is lyophilized.
  • the carrageenan foot edema test was performed with materials, reagents and procedures essentially as described by Winter, et al., (Proc. Soc . Exp . Biol . Med. , Ill, 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
  • the conversion of the prodrugs by S9 liver fractions was determined by the following method.
  • the S9 liver fraction suspension (HAM) was thawed and the suspension was stirred by vortex.
  • the suspension was mixed with 12M urea at 1:7, v:v, (yielding 10.5 M urea final concentration) and further stirred by vortex.
  • the S9 suspension solution was partially purified by solid phase extraction (Vac-Elut apparatus:C 18 columns (Varian #1210- 2001)) eluting with acetonitrile.
  • the fractions were mixed by vortex and concentrated to dryness under nitrogen (no heat).
  • the fractions were resuspended in 100 ⁇ l acetonitrile: phosphate buffer (8.3 mM, pH 7.2) (20:80).
  • the compounds were dissolved in water (0.2 ml, 10 ug/ml) and incubated at 37 °C (pH 7.2, 90
  • compositions comprising the active
  • carrier materials
  • 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.
  • carrier materials
  • active compounds of the present invention may be administered by any suitable route, preferably in the form of a
  • 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, mtravascularly (IV),
  • IM intramuscularly
  • the pharmaceutically acceptable salt 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.
  • IV injection
  • IM subcutaneous or jet
  • 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.
  • 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
  • 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.
  • the daily dose can be administered in one to four doses per day.
  • 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,
  • the active When formulated in an ointment, the active
  • ingredients may be employed with either paraffmic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in- water cream base.
  • 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.
  • 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.
  • 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.
  • 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.
  • formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
  • the cream should preferably be a non-greasy, non-stainmg 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 orin 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.
  • suitable carrier especially an aqueous solvent for the active ingredients.
  • the antimflammatory active ingredients are preferably present in such formulations in a
  • the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the
  • 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 algmate,
  • 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 lsotonic 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.

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PCT/US1997/005497 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors WO1997038986A1 (en)

Priority Applications (28)

Application Number Priority Date Filing Date Title
DE69719496T DE69719496T2 (de) 1996-04-12 1997-04-11 N-[[4-(5-METHYL-3-PHENYLISOXAZOL-4-YL]PHENYL]SULPHONYLPROPYLAMID und sein NATRIUMSALZ ALS PRO-PHARMAKON VON COX-2 INHIBITOREN
HU9901807A HU225473B1 (en) 1996-04-12 1997-04-11 Heterocycle substituted n-acyl benzenesulfonamide derivatives, process for their preparation and their use as prodrug for the preparation of pharmaceutical compositions treating inflammation or inflammation-associated disorders
AT97921092T ATE233743T1 (de) 1996-04-12 1997-04-11 N-((4-(5-methyl-3-phenylisoxazol-4- yl)phenyl)sulphonylpropylamid und sein natriumsalz als pro-pharmakon von cox-2 inhibitoren
IL12584997A IL125849A (en) 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives, their preparation and pharmaceutical compositions comprising them
EA199800919A EA003319B1 (ru) 1996-04-12 1997-04-11 Производные замещенного бензолсульфонамида - пролекарства ингибиторов cox-2
CA002249009A CA2249009C (en) 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors
DK97921092T DK0892791T3 (da) 1996-04-12 1997-04-11 N-[[4-(5-methyl-3-phenylisoxazol-4-yl]-phenyl]-sulfonylpropylamid og dets natriumsalt som prodrugs for COX-2-inhibitorer
AU27227/97A AU734275C (en) 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives as prodrugs of COX-2 inhibitors
EE9800351A EE03685B1 (et) 1996-04-12 1997-04-11 Asendatud benseensulfoonamiidi derivaadid kui COX-2 inhibiitorite eelravimid
BR9708574A BR9708574A (pt) 1996-04-12 1997-04-11 Derivados benzeno sulfonamida substituídos como pródrogas de inibidores cox-2
RO98-01469A RO121338B1 (ro) 1996-04-12 1997-04-11 Derivaţi de benzensulfonamidă, procedeu de preparare a acestora, compoziţie farmaceutică şi utilizarea ca inhibitori de cox-2
NZ331542A NZ331542A (en) 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors and salts thereof that are useful in treating inflammation and inflammation-related disorders
SI9720035A SI9720035B (sl) 1996-04-12 1997-04-11 Substituirani benzensulfonamidni derivati kot predzdravila COX-2 inhibitorjev
JP53713997A JP3382624B2 (ja) 1996-04-12 1997-04-11 Ｃｏｘ―２阻害剤のプロドラッグとしての置換ベンゼンスルホンアミド誘導体
DK02025005T DK1288206T3 (da) 1996-04-12 1997-04-11 Substituerede benzensulfonamidderivater som prolægemidler af COX-2-inhibitorer
EP97921092A EP0892791B1 (en) 1996-04-12 1997-04-11 N-[[4-(5-METHYL-3-PHENYLISOXAZOL-4-YL]PHENYL]SULFONYLPROPYLAMIDE and its SODIUMSALT AS PRODRUGS OF COX-2 INHIBITORS
SI9720101A SI22713B (sl) 1996-04-12 1997-04-11 Substituirani benzensulfonamidni derivati kot predzdravila COX-2 inhibitorjev
MEP-1998-443A ME00768B (me) 1996-04-12 1997-04-11 Derivati supstituisanih benzol sulfonamida kao pro-lekovi cox-2 inhibitora
PL97329276A PL195955B1 (pl) 1996-04-12 1997-04-11 Związek, pochodna benzenosulfonamidu, sposób jegowytwarzania, kompozycja farmaceutyczna zawierająca go oraz jego zastosowanie
APAP/P/1998/001355A AP1009A (en) 1996-04-12 1997-04-11 Substituted benzenesulfonamide derivatives as products of COX-2 inhibitors.
SK1242-98A SK285353B6 (sk) 1996-04-12 1997-04-11 Substituované benzénsulfónamidy ako proliečivá COX-2 inhibítorov, farmaceutická kompozícia a spôsobich prípravy a použitia
UA98115994A UA47475C2 (uk) 1996-04-12 1997-11-04 Похідні заміщеного бензолсульфонаміду, спосіб їх одержання та фармацевтична композиція
IS4863A IS2156B (is) 1996-04-12 1998-10-09 Settar bensensúlfonamíðafleiður sem forlyf fyrir COX-2 tálma, aðferð til þess að búa þær til, lyfjasamsetningar sem innihalda þær og notkun þeirra við framleiðslu lyfja
NO19984727A NO314184B1 (no) 1996-04-12 1998-10-09 Substituert benzensulfonamid derivater, fremgangsmåte for fremstilling av samme, farmasöytisk sammensetning innbefattende samme og anvendelseav samme forfremstilling av medikament
LVP-98-215A LV12239B (en) 1996-04-12 1998-10-12 BENZOLSULFONAMIDE DERIVATIVES AS COX-2 INHIBITORS
HK99104900A HK1019741A1 (en) 1996-04-12 1999-11-01 Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors
IS7292A IS7292A (is) 1996-04-12 2004-06-02 Staðgengnar bensensúlfonamíðafleiður sem forlyf fyrir COX-2 tálma
US10/939,852 US7420061B2 (en) 1996-04-12 2004-09-13 Process for preparing prodrugs of benzenesulfonamide-containing COX-2 inhibitors

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