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WO1999047497A2 - Acides carboxyliques et acylsulfonamides, compositions contenant ces composes et methodes de traitement - Google Patents

Acides carboxyliques et acylsulfonamides, compositions contenant ces composes et methodes de traitement Download PDF

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Publication number
WO1999047497A2
WO1999047497A2 PCT/CA1999/000212 CA9900212W WO9947497A2 WO 1999047497 A2 WO1999047497 A2 WO 1999047497A2 CA 9900212 W CA9900212 W CA 9900212W WO 9947497 A2 WO9947497 A2 WO 9947497A2
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Prior art keywords
lower alkyl
independently
compound
het
group
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PCT/CA1999/000212
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English (en)
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WO1999047497A3 (fr
Inventor
Yves Gareau
Marc Labelle
Helene Juteau
Michel Gallant
Nicolas Lachance
Michel Belley
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Merck Frosst Canada & Co.
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Priority claimed from GBGB9815856.1A external-priority patent/GB9815856D0/en
Application filed by Merck Frosst Canada & Co. filed Critical Merck Frosst Canada & Co.
Priority to EP99907214A priority Critical patent/EP1071648A2/fr
Priority to JP2000536694A priority patent/JP2002506851A/ja
Priority to AU27086/99A priority patent/AU756333B2/en
Priority to CA002322742A priority patent/CA2322742A1/fr
Publication of WO1999047497A2 publication Critical patent/WO1999047497A2/fr
Publication of WO1999047497A3 publication Critical patent/WO1999047497A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/18—Halogen atoms or nitro radicals
    • 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom 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
    • C07D307/64—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to compounds which are useful for treating or preventing prostaglandin mediated diseases, methods of treatment and pharmaceutical compositions containing such compounds.
  • the compounds are structurally different from conventional NSAIDs and opiates, and are antagonists of the pain and inflammatory effects of E-type prostaglandins.
  • PGE2 Prostaglandin E2
  • prostaglandin ligands, agonists or antagonists depending on which prostaglandin E receptor subtype is being considered, have anti-inflammatory, antipyretic and analgesic properties, and in addition inhibit hormone-induced uterine contractions. Moreover, the compounds have anti-cancer effects.
  • the compounds have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
  • the present invention relates to compounds represented by formula I:
  • HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from O, S(0)n and N(0) m wherein m is 0 or 1 and n is 0, 1 or 2;
  • Z is OH or NHSO 2 R 19 ;
  • R 1 R2 and R3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(R a )4_9 , -
  • each R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, S(0)n or N(0) m ; each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 , lower alkyl-HET, lower alkenyl-HET or -(C(R 18 ) 2
  • each R 12 is independently H, lower alkyl or benzyl; each R 13 is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, N(R b ) 2 , C0 2 R 12 , CN, CF 3 or NO 2 > R 14 and Rl5 are independently lower alkyl, halogen, CF 3 ,
  • each R 16 is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 .
  • each R 17 is independently H, lower alkyl or Bn;
  • each R 18 is independently H, F or lower alkyl, and when two
  • R 18 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from O, S(0) n or N; each R is lower alkyl, lower alkenyl, lower alkynyl, CF 3 '
  • each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 or Ph(R 13 ) 2 and each Ra is independently selected from the group consisting of:
  • a method of treating or preventing a prostaglandin mediated disease is also included which is comprised of administering to a mammalian patient in need thereof, a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease.
  • the present invention relates to carboxylic acids and acylsulfonamides, which are ligands at prostaglandin receptors, as well as a method for treating or preventing a prostaglandin mediated disease comprising administering to a patient in need of such a treatment of an amount of compound of Formula I which is effective for treating or preventing a prostaglandin mediated disease.
  • HET represents a 5-12 membered aromatic ring system containing 0-3 heteroatoms selected from O, S(O) n and N wherein n is 0,
  • HET may be substituted with up to three substituents on the aromatic ring system, Rl, R2 and R3.
  • "Aromatic ring systems" as used herein includes aryl and heteroaryl groups such as benzene, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, triazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole, 1,2-methylenedioxybenzene and pyrrole.
  • HET2 is a subset of HET and represents a member selected from the group consisting of: phenyl, thienyl, naphthyl, furanyl, thiazolyl, imidazolyl and indolyl.
  • Aryl refers to aromatic 6-10 membered groups having 1-2 rings and alternating (resonating) double bonds. Examples include phenyl, biphenyl and naphthyl.
  • Heteroaryl refers to aromatic 5-12 membered groups having alternating (resonating) double bonds and containing from 1-4 heteroatoms selected from O, S(0) n and N. Examples include the following: : quinoline, furan, benzofuran, thiophene, benzothiophene, thiazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, oxazole, indole, isoindole, pyridine, isoquinoline, imidazole, thiazole, triazole, 1,3- methylene dioxobenzene, pyrrole and naphthyridine,
  • Heterocyclyl refers to non- aromatic 5-12 membered cyclic groups having 1-4 heteroatoms selected from O, S(0) n and N.
  • heterocyclic groups are piperidine, piperazine, pyrrolidine, tetrahydrofuran, tetrahydropyran and morpholine.
  • X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from O, S(0) n and N(0) m , and optionally substituted with Rl4 and Rl5, and A and B are attached to the aryl or heteroaryl group X in positions which are ortho relative to each other.
  • Examples are selected from the group consisting of: phenyl, naphthyl, biphenyl, quinoline, furan, benzofuran, pyridyl, pyrrole, thiophene, benzothiophene, thiazole, benzothiazole, 1,2,5- thiadiazole, triazole, 1,2-methylenedioxybenzene, thienopyridine, oxazole and indole.
  • alkyl, alkenyl, and alkynyl mean linear, branched, and cyclic structures and combinations thereof.
  • “Lower alkyl” means alkyl groups of from 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, s- and t-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, and the like. When propyl and butyl are recited without the isomeric form being specified, these include all isomers thereof. "Lower alkenyl” means alkenyl groups of 2 to 7 carbon atoms.
  • lower alkenyl groups examples include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2- methyl-2-butenyl, cyclopropen-1-yl, cyclohexen-3-yl and the like. When cis or trans is not specified, both are intended in pure form as well as in the form of a mixture of isomers.
  • Lower alkynyl means alkynyl groups of 2 to 7 carbon atoms. Examples of lower alkynyl groups include ethynyl, propargyl, 3- methyl-1-pentynyl, 2-heptynyl, 2-(cyclopropyl)ethenyl, 3-(cyclobutyl)-l- propynyl and the like.
  • Halogen (halo) includes F, Cl, Br and I.
  • AIBN 2.2'-azobisisobutyronitrile
  • CC1 4 carbon tetrachloride
  • DIBAL diisobutyl aluminum hydride
  • LDA lithium diisopropylamide m-CPBA metachloroperbenzoic acid
  • NBS N-bromosuccinimide
  • NSAID non-steroidal anti-inflammatory drug
  • PCC pyridinium chlorochromate
  • Ph phenyl
  • c-Bu cyclobutyl
  • c-Pen cyclopentyl
  • c-Hex cyclohexyl
  • -N(R ) 2 represents -NHH, -NHCH , -
  • the invention relates to a compound represented by formula I:
  • HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from O, S(O) n and N(0)m wherein m is 0 or 1 and n is 0, 1 or 2;
  • X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from O, S(0) n and N(0)m , and optionally substituted with Rl4 and Rl5, and A and B are attached to the aryl or heteroaryl group ortho relative to each other;
  • Z is OH or NHS0 2 R 19 ;
  • R 1 R2 and R3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(R a )4_9 , - (C(R 4 )2)pSR5, -(C(R 4 ) 2 ) p OR 8 , -(C(R 4 ) 2 ) p N(R 6 ) 2 , CN, N0 2 , -(C(R 4 ) 2 ) p C(R 7 ) 3 , -
  • each R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, S(0)n or N(0) m ;
  • each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 , lower alkyl-HET, lower alkenyl-HET or -(C(R 18 ) 2 ) p Ph(R ⁇ ) ⁇ -
  • each R 6 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 , Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represents a ring of up to 6 atoms, optionally containing an additional heteroatom selected from O, S(0) n or N(O) m ;
  • each R 7 is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are presents, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from O, S(0) n and N(O) m ;
  • each R represents H or R5;
  • each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn;
  • each R 10 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 , Ph(R n ) ⁇ -3, CH 2 Ph(R
  • R 14 and Rl5 are independently lower alkyl, halogen, CF 3 , OR 16 , S(0) n R 16 or C(R 16 ) 2 OR 17 ; each R 16 is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 .
  • each R 17 is independently H, lower alkyl or Bn;
  • each R 18 is independently H, F or lower alkyl, and when two R 18 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from O, S(0) n or N; each R is lower alkyl, lower alkenyl, lower alkynyl, CF 3 >
  • each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 or Ph(R 13 ) 2 and each Ra is independently selected from the group consisting of: H, OH, halo, CN, NO2, amino, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, Ci-6alkylamino, di-Ci- 6alkylamino, CF3, C(0)Ci-6alkyl, C(0)C2-6alkenyl, C(O) Ct ⁇ - ⁇ alkynyl, CO2H, C ⁇ 2Ci-6alkyl, C ⁇ 2C2-6alkenyl, and C ⁇ 2C2-6alkynyl, said alkyl, al
  • HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from O, S(O) n and N(0) wherein m is 0 or 1 and n is 0, 1 or 2;
  • X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from O, S(0) n and N(0) m , and optionally substituted with Rl4 and Rl5, and A and B are attached to the aryl or heteroaryl group ortho relative to each other;
  • Z is OH or NHSO 2 R 19 ;
  • R 1 R and R3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(R a )4_9 .
  • each R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, S(0)n or N(0) m ; each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 , lower alkyl-HET, lower alkenyl-HET or -(C(R 18 ) 2
  • each R 12 is independently H, lower alkyl or benzyl; each R is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, N(R 6 ) 2 , CO 2 R 12 , CN, CF 3 or NO 2 >
  • R 14 and Rl5 are independently lower alkyl, halogen, CF 3 , OR 16 , S(0) n R 16 or C(R 16 ) 2 OR 17 ; each R 16 is independently H, lower alkyl, lower alkenyl, Ph, Bn, CHF2 or CF 3 .
  • each R 17 is independently H, lower alkyl or Bn; each R 18 is independently H, F or lower alkyl, and when two R 18 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from O, S(O)n or N; each R 19 is lower alkyl, lower alkenyl, lower alkynyl, CF 3 , HET2(Ra)4_ 9 , lower alkyl-HET2(Ra) 4 _ 9 0 r lower alkenyl-HET2(Ra) 4 _ 9 , wherein HET2 represents a member selected from the group consisting of: phenyl, thienyl, naphthyl, furanyl, thiazolyl, imidazolyl and indolyl; each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CHF 2 , CF 3 or Ph(R 13 ) 2
  • HET represents a member selected from the group consisting of: benzene, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, triazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole, 1,2-methylenedioxybenzene and pyrrole.
  • HET represents a member selected from the group consisting of: benzene, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, triazole, 1,2,5-thiadiazole, thienopyridine,
  • an embodiment of the present invention is represented by formula I wherein HET is selected from the group consisting of: benzene, biphenyl, naphthylene, indole, thiophene, benzofuran and quinoline.
  • HET is selected from the group consisting of: benzene, biphenyl, naphthylene, indole, thiophene, benzofuran and quinoline.
  • A represents a one or two atom moiety and is selected from the group consisting of: S, S(O), SO2, CH2, -C(O)- , -OCH2-, -CHOH- , -C(OH)(CH3)- and -CH 2 -0- .
  • A is selected from the group consisting of: : S, S(O), SO2, CH2, -C(O)-.
  • all other variables are as originally described with respect to formula I.
  • Another embodiment of the present invention that is of particular interest is represented by formula I wherein X represents phenyl optionally substituted with R 14 and R 15 .
  • X represents phenyl and R 14 and R 15 are absent or represent halo.
  • all other variables are as originally described with respect to formula I.
  • Another embodiment of the present invention that is of particular interest is represented by formula I wherein Z is NHS0 2 R 19 .
  • Z is NHS0 2 R 19 and R 19 represents a member selected from the group consisting of: lower alkyl and HET(Ra)3.
  • HET is selected from the group consisting of: phenyl, thienyl, naphthyl, furanyl, thiazolyl, imidazolyl and indolyl.
  • HET represents a member selected from the group consisting of: phenyl, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole and pyrrole;
  • A represents a one or two atom moiety and is selected from the group consisting of: S, S(O), SO2, CH2, -C(O)- , -OCH2- , -CHOH- , - C(OH)(CH3 )- and -CH2-O-;
  • X represents phenyl optionally substituted with R 14 and R 15 ;
  • Z is NHS0 2 R 19 and
  • R 19 represents a member selected from the group consisting of: lower alkyl and HET(Ra) 3 .
  • Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
  • compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain from about 1 mg to about 2 g of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
  • compound I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compound of the invention is effective in the treatment of humans.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, solutions, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water-miscible solvents such as propylene glycol, PEGs and ethanol
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally- occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • colouring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavouring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compound I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • a pharmaceutical carrier cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • prostaglandins This mimicking or antagonism of the actions of prostaglandins indicates that the compounds and pharmaceutical compositions thereof are useful to treat, prevent or ameliorate prostaglandin mediated diseases and conditions in mammals and especially in humans: Pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures as well as immune and autoimmune diseases.
  • Such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer.
  • Compound I may also be of use in the treatment and/or prevention prostaglandin-mediated proliferation disorders such as may occur in diabetic retinopathy and tumor angiogenesis.
  • Compound I will also inhibit prostanoid-induced smooth muscle contraction by antagonizing contractile prostanoids or mimicking relaxing prostanoids and hence may be use in the treatment of dysmenorrhea, premature labor, asthma and eosinophil related disorders.
  • compound I By virtue of its prostanoid or prostanoid antagonist activity, compound I will prove useful as an alternative to NSAID'S particularly where such non-steroidal anti-inflammatory drugs may be contraindicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems; kidney disease; thrombosis, occlusive vascular diseases; those prior to surgery or taking anti-coagulants.
  • Compound I will also be useful as a cytoprotective agent for patients under chemotherapy.
  • the invention encompasses pharmaceutical compositions for treating prostaglandin E 2 mediated diseases as defined above comprising a non-toxic therapeutically effective amount of the compound of Formula I as defined above and one or more ingredients such as another pain reliever including acetaminophen or phenacetin; a COX-2 selective NSAID; a conventional NSAID; a potentiator including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antiitussive including codeine, hydro
  • the invention encompasses a method of treating prostaglandin E 2 mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effective amount of the compound of Formula I, optionally co-administered with one or more of such ingredients as listed immediately above.
  • Compounds of the present invention can be prepared according to the following methods. Temperatures are in degrees Celsius.
  • Boronic acids and esters can be prepared from the corresponding halide according to literature procedure and reference cited therein (Charette, A.B.; Giroux, A. J. Org. Chem. 1996, 61, 8718; Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508; Miyaura, N.; Suzuki, A. Chem. Rev, 1995, 95, 2457; Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62, 6458; Watanabe, T. Miyaura, N.; Suzuki, A.
  • Cinnamic ester 1 is treated with a brominating agent such as NBS in a refluxing inert solvent such as CC1 4 , with the use of an initiator like benzoyl peroxide or light.
  • a brominating agent such as NBS
  • a refluxing inert solvent such as CC1 4
  • an initiator like benzoyl peroxide or light.
  • the resulting benzylic bromide is reacted in a Suzuki coupling reaction with the appropriate boronic acid or ester, a catalyst such as tetrakis(triphenylphosphine) palladium and cesium fluoride or Na 2 C0 3 or a base in an inert refluxing solvent such as DME at 80-90° C.
  • the new cinnamic ester 3 is hydrolyzed with aqueous sodium hydroxide to afford the acid 4 that is converted to the cinnamic sulfonamide 5 with a coupling reagent such as DCC or DCI in CH 2 C1 2 at r.t.
  • Cinnamic ester 2 is treated with an aryl or heteroaryl mercaptan, alcohol or amine, and with a base such as a hydride or an amine in benzene or THF at 0-23° C.
  • the cinnamic ester 8 is converted to 9 according to Method A.
  • the aldehyde 11 is prepared by an addition-elimination of a mercapto, hydroxy or amino aryl or heteroaryl with a base such as I ⁇ CO g in refluxing CHC1 3 . If needed a higher boiling point solvent can be used. This type of rection can also be performed with CuO in DMF.
  • An Emmons-Horner type reaction or Wittig in toluene at r.t. followed by Method A (or oxidation as described in Method B) results in the cinnamic sulfonamide 13.
  • Acetal 14 that came from an acetalization from a suitably substituted bromo benzaldehyde is converted to the Grignard reagent with magnesium in an etheral solvent at reflux and quenched with an aryl or heteroaryl ketone.
  • the alcohol 16 is reacted with an halide and a base (or protected as the o-nitrobenzyl, and removed at the end of the sequence) to furnish the compound 17.
  • Deprotection of the acetal under standard conditions followed by Method C gives 18.
  • Alcohol 16 is converted to an acetate with acetyl chloride (or acetic anhydride and an amine base) and coupled with a Grignard reagent and a copper salt at low temperature.
  • the alcohol 16 could also be converted to the bromide and treated in a similar way to yield 20.
  • Compound 20 is then converted to the cinnamic sulfonamide 21 according to Method D.
  • 22 can be treated with A1(R 7 ) 3 in toluene at 80 °C for 24h and 23 converted to the aldehyde with n-BuLi/DMF followed by an Emmons-Horner reaction and Method A to yield compound 21.
  • a suitably substituted bromo toluene 24 is treated with n- Buli at low temperature and quenched with an aryl or heteroaryl aldehyde.
  • the resulting alcohol is oxidized to the ketone with PDC, PCC, Mn0 2 or other typical oxidizing agent.
  • the carbonyl is treated with SF 4 , MoF 6 -BF 3 (or converted to a thioacetal and treated with nitrosonium BF 4 - pyridinium*HF) to yield the difluoride.
  • the appropriately substituted methyl bromo(or triflate) benzoate 27 is converted to compound 28 by a Suzuki coupling reaction followed by hydrogenation.
  • a Stille coupling reaction could also be used.
  • Benzylic bromination or benzylic oxidation followed by treatment with a brominating agent such as CBr 4 /triphenylphosphine gives compound 29 which can be treated with a boronic acid, or a tin compound (Stille) to furnish compound 30.
  • Reduction of the ester with DIBAL, oxidation with Mn0 2 and Method C gives compound 31.
  • the halide 29 can also be converted the Grignard reagent and added to the ketone. Dehydration under acidic conditions results in compound 32. Reduction of the double bond under standard conditions, followed by Methods G and C gives compound 33. From compound 32, cyclopropanation with diazomethane and palladium (0) followed by Methods G, C and A gives compound 34.
  • the (heterocyclic) vinylic bromide 35 is reacted in a Suzuki coupling reaction with an aryl or hetero aryl boronic acid and converted to a new borane by 9-BBN addition followed by a second Suzuki reaction with compound 14.
  • Compound 37 thus formed is reduced by hydrogenolysis ( H ⁇ metal or diimide) and deprotection followed by Method C gives cinnamic sulfonamide 39.
  • Ketone 40 which comes from oxidation of the corresponding alcohol is reacted with a phosphonium salt or phosphono ester with a base such as LDA to give the cinnamic ester 41.
  • Method A yields 42 and reduction of the double bond by the previously mentioned method gives the acyl sulfonamide 43.
  • Cinnamic ester 3 is reduced to 44 by the previously mentioned method, ⁇ Alkylation with a base such as LDA followed by an alkylating agent results in 45 after conversion to the acyl sulfonamide.
  • Cinnamic ester 3 is reduced to 46 with DIBAL and the double bond converted to a cyclopropane by a Simmons-Smith reaction, or similar reactions recently described in the literature.
  • Compound 47 is then oxidized and the cinnamic sulfonamide 48 is prepared according to Method A.
  • Ester 49 which can come from the homologation of the appropriately substituted methyl ortho-toluate, is treated with a base and with an alkylating agent to furnish compound 50. Benzylic bromination and Suzuki coupling gives an intermediate ester. Homologation according to J. Amer. Chem. Soc; 1985, 1429; J. Org. Chem. 1992, 7194, followed by alkylation with a base such as LDA and an alkylating agent furnishes acylsulfonamide 51 by Method A.
  • Compound 50 can also be converted to the benzylic bromide and to compound 52 by Method A.
  • Suitably substituted compound 53 is treated with a boronic acid to give compound 54 which is reduced with LDA to the alcohol 55.
  • Treatment with phosgene followed with the appropriate sulfonamide gives compound 56.
  • This can also be prepared by mixing phosgene and the sulfonamide at 140°C to generate the isocyanate.
  • Compound 54 is treated with a Grignard reagent to give the corresponding alcohol and as previously described, converted to compound 57.
  • Compound 55 is treated with NH 3 /Ph 3 P/DEAD (or treated with CBr 4 /Ph 3 P and the bromide converted to the amine 63 with ammonia).
  • Treatment with phosgene followed by sulfonamide yields 64, treatment of which with a base and an alkyl or benzylic halide gives compounds 65.
  • Aldehyde 10 is treated with a silylated source of hydroxyl or thiol at 80-130 °C, and the silyl group removed by fluoride treatment.
  • Compound 66 is then treated with an aryl or heteroaryl methylene bromide with a base such as a tertiary amine in CHC1 3 or benzene to yield aldehyde 67.
  • Emmons-Horner (or Wittig reaction) with LDA results in compound 68 via Method A.
  • a suitably substituted bromo toluene 24 is converted to the anion in an etheral solvent at low temperature and trapped with an aldehyde of an aryl or heteroaryl.
  • the resulting alcohol is oxidized with Mn0 2 , Jones' reagent, PDC, PCC or any other oxidant.
  • Benzylic bromination followed by oxidation with N-methyl morpholine N-oxide yields a ketoaldehyde.
  • Emmons-Horner and Method A gives the cinnamic sulfonamides 72.
  • Biological activity and thus utility for the compounds of formula I as modulators of prostaglandin mediated diseases can be demonstrated in accordance with the following assayswhich demonstrate prostanoid antagonist or agonist activity in vitro and in vivo and their selectivity.
  • the prostaglandin receptors investigated were DP, EP EP 2 , EP 3 , EP 4 , FP, IP and TP.
  • HEK 293(ebna) cell line Prostanoid receptor cDNAs corresponding to full length coding sequences were subcloned into the appropriate sites of mammalian expression vectors and transfected into HEK 293(ebna) cells.
  • HEK 293(ebna) cells expressing the individual cDNAs were grown under selection and individual colonies were isolated after 2-3 weeks of growth using the cloning ring method and subsequently expanded into clonal cell lines.
  • HEK 293(ebna) cells are maintained in culture, harvested and membranes are prepared by differential centrifugation, following lysis of the cells in the presence of protease inhibitors, for use in receptor binding assays.
  • Prostanoid receptor binding assays are performed in 10 mM MES/KOH (pH 6.0) (EPs, FP and TP) or 10 mM HEPES/KOH (pH 7.4) (DP and IP), containing 1 mM EDTA, 10 mM divalent cation and the appropriate radioligand.
  • the reaction is initiated by addition of membrane protein.
  • Ligands are added in dimethylsulfoxide which is kept constant at 1 % (v/v) in all incubations.
  • Non-specific binding is determined in the presence of 1 ⁇ M of the corresponding non-radioactive prostanoid. Incubations are conducted for 60 min at room temperature or 30 °C and terminated by rapid filtration. Specific binding is calculated by subtracting non specific binding from total binding. The residual specific binding at each ligand concentration is calculated and expressed as a function of ligand concentration in order to construct sigmoidal concentration-response curves for determination of ligand affinity.
  • Incubations contain 100 ⁇ M RO-20174 (phosphodiesterase type rV inhibitor, available from Biomol) and, in the case of the EP 3 inhibition assay only, 15 ⁇ M forskolin to stimulate cAMP production. Samples are incubated at 37°C for 10 min, the reaction is terminated and cAMP levels are then measured.
  • For calcium mobilization assays cells are charged with the co-factors reduced glutathione and coelenterazine, harvested and resuspended in Ham's F12 medium. Calcium mobilization is measured by monitoring luminescence provoked by calcium binding to the intracellular photoprotein aequorin. Ligands are added in dimethylsulfoxide which is kept constant at 1 % (v/v) in all incubations.
  • second messenger responses are expressed as a function of ligand concentration and both EC 50 values and the maximum response as compared to a prostanoid standard are calculated.
  • the ability of a ligand to inhibit an agonist response is determined by Schild analysis and both K B and slope values are calculated.
  • Female Lewis rats (body weight -146-170 g) were weighed, ear marked, and assigned to groups (a negative control group in which arthritis was not induced, a vehicle control group, a positive control group administered indomethacin at a total daily dose of 1 mg/kg and four groups administered with a test compound at total daily doses of 0.10-3.0 mg/kg) such that the body weights were equivalent within each group.
  • Six groups of 10 rats each were injected into a hind paw with 0.5 mg of Mycobacterium butyricum in 0.1 mL of light mineral oil (adjuvant), and a negative control group of 10 rats was not injected with adjuvant.
  • Body weights, contralateral paw volumes (determined by mercury displacement plethysmography) and lateral radiographs (obtained under Ketamine and Xylazine anesthesia) were determined before (day -1) and 21 days following adjuvant injection, and primary paw volumes were determined before (day -1) and on days 4 and 21 following adjuvant injection.
  • the rats were anesthetized with an intramuscular injection of 0.03 - 0.1 mL of a combination of Ketamine (87 mg/kg) and Xylazine (13 mg/kg) for radiographs and injection of adjuvant.
  • radiographs were made of both hind paws on day 0 and day 21 using the Faxitron (45 kVp, 30 seconds) and Kodak X-OMAT TL film, and were developed in an automatic processor. Radiographs were evaluated for changes in the soft and hard tissues by an investigator who was blinded to experimental treatment. The following radiographic changes were graded numerically according to severity: increased soft issue volume (0-4), narrowing or widening of joint spaces (0-5) subchondral erosion (0-3), periosteal reaction (0-4), osteolysis (0-4) subluxation (0-3), and degenerative joint changes (0-3). Specific criteria were used to establish the numerical grade of severity for each radiographic change. The maximum possible score per foot was 26.
  • test compound at total daily doses of 0.1, 0.3, 1, and 3 mg/kg/day, indomethacin at a total daily dose of 1 mg/kg/day, or vehicle (0.5% methocel in sterile water) were administered per os b.i.d. beginning post injection of adjuvant and continuing for 21 days.
  • the compounds were prepared weekly, refrigerated in the dark until used, and vortex mixed immediately prior to administration.
  • the ethyl ester can be prepared as well in the same way or from the 2-methyl benzaldehyde ( 5.00 g; 41.6 mmol) and triethyl phosphonoacetate (9.9 mL; 50.0 mmol) in 150 mL ot toluene at 0 C C, to which was added portionwise NaH (63.0 mmol). After 2 h of stirring the mixture was quenched with NH 4 OAc (25%) and extracted with EtOAc. The solvent was removed to give 7.1 g of the ethyl cinnamate. Step 2: Ethyl (E)-3-.2-(bromomethyl)phenyl1-2-propenoate
  • Step 3 Ethyl (E)-3-(2-.4-(methylthio)benzvHphenyl.-2-propenoate
  • Step 5 N-((E)-3-f2-.4-(methylthio)benzyllphenyl ⁇ -2-propenoyl)-2- thiophenesulfonamide (17)
  • 2-Thiophenesulfonamide was prepared from the corresponding sulfonyl chloride with 2.2 equivalent of NH 4 OH in THF at 0 °C. The solution was brought to r.t. and left 2 h. It was then quenched with NaHC0 3 and extracted with EtOAc. The organic phase was dried over Na 2 SO 4 and the solvent removed. The crude product was crystallized in toluene/EtOAc.
  • Step 2 (E)-3-.2-.(3-methyl-lH-l-indolyl)methyl1phenyl ⁇ -2-propenoic acid
  • Step 3 N2-((E)-3-f2-r ( 3-methyl-lH-l-indolyl)methvnphenyll-2-propenoyl)- 2-thiophenesulfonamide (3)
  • the coupling reaction of the previous acid (196 mg; 0.67 mmol) was done according to step 5 of example 1 to yield 134 mg of the title compound.
  • step 2 The benzyl bromide (500 mg) of example 1, step 2 was treated with 2-naphthylboronic acid according to the same procedure previously described to yield 360 mg of the title compound.
  • Step 1 Ethyl (E)-3-r2-(3.4-dichlorobenzyl)phenyl1-2-propenoate
  • the benzyl bromide (500 mg) of example 1 was treated with 3,4-dichlorobenzeneboronic acid according to the same procedure described in step 3 of example 1 to yield 410 mg of the title compound.
  • Step 3 N- ⁇ (E)-3-.2-(3.4-dichlorobenzyl)phenvn-2-propenoyl.-2- thiophenesulfonamide (8)
  • the coupling reaction of the previous acid (170 mg; 0.55 mmol) was done according to step 5 of example 1 to yield 110 mg of the title compound.
  • the acid was converted to the sodium salt with 1 equivalent of NaOH.
  • Step 1 Ethyl (E)-3- ⁇ 2-.naphthyloxy)methyriphenyl.-2-propenoate
  • Step 2 (E)-3-.2-.naphthyloxy)methyl1phenyl ⁇ -2-propenoic acid
  • Step 3 N-((E)-3-!2-.(2-naphthyloxy)methyllDhenyl)-2-propenoyl)-2- thiophenesulfonamide (20)
  • Step 3 Ethyl (E)-3-.2-(2-naphthylsulfinyl)phenyll-2-propenoate
  • the previous ester (3.00 g; 8.97 mmol) in 45 mL of dichloromethane was treated with 1.1 equivalent of mCPBA at 0 °C for 1 h.
  • the mixture was quenched with sodium thiosulf ⁇ te and extracted with EtOAc.
  • the organic phase was dry over Na 2 S0 4 and the crude purified by silica gel chromatography (30% EtOAc in hexane) to yield 2.35 g of the title compound.
  • Step 5 2-!(E)-3-r2-(2-naphthylsulfinyl)phenyl1-2-propenoyl.-2- thiophenesulfonamide (21)
  • the sodium salt was prepared with IN NaOH. Elemental analysis calcd. for C 23 H 16 NNa0 4 S 3 .l/2H 2 0: C, 55.36; H,3.40; N, 2.81; S,
  • Step 1 Ethyl ( E ) -3-.2- ( 2-naphthyloxy)phenyll-2-propenoate
  • Step 2 Ethyl (E)-3-r2-(2-naphthyloxy)phenyll-2-propenoate
  • the previous aldehyde (2.00 g; 8.0 mmol) was converted to the title compound according to step 1 of example 1 to yield 2.52 g .
  • Step 4 N-.(E)-3-.2-(2-naphthyloxy)phenyl.-2-propenoyl)-2- thiophenesulfonamide (28)
  • Step 1 [2-(2-naphthylthio)phenynmethanol To 2-(2-naphthylthio) benzaldehyde (7.24 g; 27.4 mmol from
  • Example 6 step 1) in 70 mL of methanol and 30 mL of THF at 0 °C was added NaBH 4 (54.8 mml) portionwise. After lh at 0 °C, the solution was brought to r.t. and quenched with water. After dilution with EtOAc, the solution was washed with water and brine. The organic phase was dry over Na 2 S0 4 , filtered and the crude purified by silica gel chromatography to yield 6.71 g of the title compound.
  • NaBH 4 54.8 mml
  • Step 2 .2-(2-Naphthylsulfonyl)phenyll methanol
  • step 2 To the alcohol of step 2 (250 mg; 0.84 mmol) in ether at 0 °C was added the previous isocyanate (2 equivalent) and let stirred lh at 0 °C. The solution was quenched with water and extracted with EtOAc. The organic phase dry over Na 2 S0 4 , filtered and the crude purified by silica gel chromatography (5% CH 3 OH in CH 2 C1 2 ) to yield 300 mg of the title compound.
  • Step 1 Ethyl 2-f2-(2-naphthylmethyl)phenyll-l-cyclopropanecarboxylate
  • the ethyl ester (300 mg; 0.95 mmol) of step 1 in example 3 and Pd(OAc) 2 (10 mg) were treated with diazomethane at 0° C for lh.
  • Step 2 2-.2-(2-naphthylmethyl)phenyl.-l-cyclopropanecarboxylic acid
  • the previous ester 300 mg; 0.91 mmol
  • Step 3 N-((2-.2-(2-naphthylmethyl)phenyllcyclopropyl.carbonyl-2- thiophenesulfonamide (45)
  • Step 6 N-((E)-3-(2-(6-benzyloxy-2-naphthyl)methyl)phenyl)-2-propenoyl)- 5-bromo-2-methoxybenzenesulfonamide (46)
  • step 5 To the acid from step 5 (190 mg, 0.482 mmol) in CH 2 C1 2 was added DMF (10 ⁇ L) and oxalyl chloride (60 ⁇ L) at 0°C and the mixture was warmed to r.t. for an hour and concentrated to dryness. The resulting acid chloride was redissolved in CH 2 C1 2 :THF 1:1 (10 mL) and 5- bromo-2-methoxybenzenesulfonamide (154 mg, 1.2 equiv., from step 6) and Et 3 N (135 ⁇ L, 2 equiv.) were added at 0°C. The mixture was then warmed to r.t.
  • Step 1 N- ( (E)-3-f 2-naphthylmethyl)phenyl )1 -2-propenoyl ⁇ -5-bromo-2- methoxy-l-benzenesulfonamide (301)
  • the carboxylic acid (400 mg; 1.22 mmol) of example 3 step 2 was coupled with 5-bromo-2-methoxy-l-benzenesulfonyl chloride according to the procedure of step 5 in example 1 to yield 284 mg of the title compound.
  • Step 3 Ethyl (E)-3-[2-(bromomethyl)-5-chlorophenyll-2-propenoate
  • the previous ester (16.66 g; 74.1 mmol) was converted to the benzylic bromide according to step 2 of example 1 to yield 9.0 g of the title compound.
  • Step 5 (E)-3-[5-chloro-2-(2-naphthylmethyl)phenyll-2-propenoic acid
  • the hydrolysis of the previous ester (1.14 g) was done according to Step 4 of example 1 to yield 0.99 g of the title compound.
  • Step 6 N-f(E)-3-l5-chloro-2-(2-naphthylmethyl)phenvn-2-propenoyl ⁇ -2- thiophenesulfonamide (303)
  • Step 1 Ethyl (E)-3-(5-chloro-2-methylphenyl)-2-propenoate To 2-bromo-4-chloro toluene (20.0g; 97.3 mmol) in 300 mL of THF at -78 oC was added n-BuLi 2.5 M (40.8 mL) dropwise. After 20 min. 1-formylpi ⁇ eridine (11.4 mL; 103.0 mmol) in 10 mL of THF was added dropwise. After 30 min the reaction mixture was brought to 0°C and quenched with HCl (10%) and diluted with EtOAc.
  • this procedure can be done in one reaction vessel.
  • the flask is brought to rt and the phosphonoacetate in THF is added.
  • Step 2 Ethyl(E)-3-.2-(bromomethyl)-5-chlorophenyll-2-propenoate The bromination was done according to step 2 of example 1 to provide the title compound in 45% yield.
  • Step 4 Ethyl (E)-3- ⁇ 4-chloro-2-[(6fluoro-2-naphthyl)methyllphenyl)-2- propenoate
  • Step 5 (E)-3- ⁇ 4-Chloro-2- (6-fluoro-2-naphthyl)methyllphenyll-2- propenoic acid, sodium salt
  • the title compound was prepared from 2-(4- fluorophenyl)acetyl chloride according to step 3 of example 13.
  • Step 2 Ethyl (E ) -3- ( 5-chloro-2-.(6-chloro-2-naphthyl)methyl1phenyl)-2- propenoate
  • Step 3 ( E ) -3- ( 5-Chloro-2-r ( 6-chloro-2-naphthyl)methyllphenyl ⁇ -2- propenoic acid, sodium salt
  • Step 1 5-Bromo -N-((E)-3-f5-chloro-2-_(6-chloro-2- naphthyl)methyl1phenyl ⁇ -2-propenoyl)-2-methoxybenzenesulfonamide
  • the coupling reaction of the acid of Example 15 Step 3 (500 mg; 1.4 mmol) was done according to step 5 of example 1 with 5-bromo- 2-methoxybenzesulfonamide to yield 662 mg (74%) of the title compound.
  • the sodium salt was prepared with IN NaOH.
  • Step 2 Ethyl (E)-3-(5-chloro-2-..6-difluoromethoxy)-2- naphthyl.methyl ⁇ phenyl)-2-propenoate
  • the corresponding boronic acid of the previous halide was coupled according to step 3 of example 1 of the title compound in 57% yield.
  • Step 3 (E)-3-(5-Chloro-2-( [6-difluoromethoxy)-2-naphthyllmethyl)phenyl)- 2-propenoic acid, sodium salt
  • Step 1 5-Bromo -N-.(E)-3-(5-chloro-2-U6-difluoromethoxy)-2- naphthyllmethyl)phenyl)-2-propenoyll-2-methoxybenzennesulfonamide
  • Step 1 Ethyl (E)-3-.2-(3.4-dichlorobenzyl)-5-chlorophenyl)-2-propenoate
  • the benzyl bromide of step 2 of example 13 was treated with
  • Step 2 (E)-3-r2-(3.4-Dichlorobenzyl)-5-chlorophenyl)-2-propenoic acid. sodium salt
  • Step 1 5-Bromo-N- ⁇ (E)-3-r5-chloro-2-)3.4-dichlorobenzyl)phenyll-2- propenoyll-2-methoxybenzenesulfonamide
  • Step 1 Ethyl (E)-3-f4-chloro-2-.(2-naphthylmethyl)phenyll-2-propenoate 2-Bromo-5-chloro toluene (20.0 g) was converted to the corresponding aldehyde and then to the cinnamate according to step 1 of example 13. This cinnamate was converted to the benzylic bromide according to step 2 of example 1 and coupled via a Suzuki coupling reaction according to step 3 of example 1 with naphthalene boronic acid to yield the title compound.
  • Step 2 (E)-3-.4-Chloro-2-[(2-naphthylmethyl)phenyl ⁇ -2-propenoic acid (530)
  • Step 3 5-Bromo-N-f .
  • the coupling reaction of the acid of Step 2 (0.296 g; 0.89 mmol) was done according to step 5 of example 1 with 5-bromo-2- methoxybenzesulfonamide to yield 213 mg (42%) of the title compound.
  • the sodium salt was prepared with IN NaOH.
  • Step 1 (2-Bromo-4-methoxyphenyl)(2-naphthyl)methanone AICI3 (17.48 g; 131.1 mmol) was added portionwise to a mixture of 3-bromocresol (16.04 g; 87.4 mmol) and 2-naphthoyl chloride (25.00 g; 131.1 mmol) in 50 mL of CHC13 gave 14.0 g (47%) of the title compound.
  • the naphthalene of Step 2 was converted to the corresponding aldehyde according to the step 1 of example 13 in 98% yield. This aldehyde was then converted to the cinnamate according to step 1 of example 13 in 90% yield.
  • Step 4 ( E ) -3-.5-Methoxy-2- ( 2-naphthmethyl)phenyl.-2-propenoic acid
  • the hydrolysis of the ester of Step 3 (2.83 g; 8.2 mmol) was done according to step 4 of example 1 to yield 2.16 g (83%) of the title compound.
  • the sodium salt was prepared with IN NaOH.
  • Step 1 5-Bromo-2-methoxy-N-!(E)-3-r5-methoxy-2-(2- naphthylmethyl)phenyll-2-propenoyl ⁇ benzenesulfonamide
  • Step 1 Ethyl(E)-3-r5-chloro-2-(4-chlorobenzyl)phenvn-2-propenoate
  • the benzyl bromide of step 2 of example 13 was coupled in a
  • Step 4 (E)-3- ⁇ 2-[(5-(Phenylmethoxy)indolyl)methyl]-5-fluorophenyl ⁇ -2- propenoic acid (493)
  • Step 5 (E)-3- ⁇ 2-[(5-(Phenylmethoxy)indolyl)methyl]-5-fluorophenyl ⁇ -N- ⁇ ( 5-bromo-2-methoxyphenyl)sulfonyll-2-propenamide
  • step 2 The ester (901 mg, 3.14 mmol) of example 13, step 2 was coupled with benzo[b]thiophene-2-boronic acid (from Lancaster).
  • Step 3 (E)-3-[2-(Benzo[b]thiophen-2-ylmethyl)-5-fluorophenyl]-N-[(5- bromo-2-methoxyphenyl)sulfonyl1-2-propenamide
  • the previous acid 264 mg; 0.85 mmol
  • 5- bromo-2-methoxybenzenesulfonamide of example 10 was coupled with 5- bromo-2-methoxybenzenesulfonamide of example 10, step 5 according to step 5 of example 1 to yield 287 mg of the title compound.
  • Step 1 Ethyl (E)-3-[5-fluoro-2-(indol-5-ylmethyl)phenyll-2-propenoate
  • step 2 was coupled with 5-indolyl boronic acid and NaHC0 3 in DME according to the procedure described in step 3 of example 10 to yield 1.08 g of the title compound.
  • ⁇ NMR (acetone-d 6 ) ⁇ 1.26 (3H, t), 4.17 (2H, q), 4.21 (2H, s),
  • Step 2 Ethyl (E)-3-(5-fluoro-2-( ⁇ l-benzylindol-5-yl1methyl ⁇ phenyl)-2- propenoate
  • Step 1 The indole of Step 1 (621 mg; 1.92 mmol) was coupled with benzyl bromide according to the procedure described in step 1 of example 2 to yield 678 mg of the title compound.
  • Step 3 (E)-3-(5-Fluoro-2-( [l-benzylindol-5-ynmethyllphenyl)-2-propenoic acid) (540)
  • the hydrolysis of the ester of Step 2 (678 mg) was done according to step 4 of example 1 to yield 276 mg of the title compound.
  • Step 4 N-(E)-[(5-Bromo-2-methoxyphenyl)sulfonyl]-3-(5-fluoro-2- ⁇ [l- benzylindol-5-yllmethyl ⁇ phenyl)-2-propenamide
  • the acid of Step 3 (219 mg; 0.57 mmol) was coupled with 5- bromo-2-methoxybenzenesulfonamide of example 10, step 5 according to step 5 of example 1 to yield 149 mg of the title compound.
  • Step 1 Ethyl (E)-3-(3-methyl-2-pyridyl)-2-propenoate To a solution of 2-bromo-3-methylpyridine (10.36 g; 60.2 mmol) in 120 mL of THF at -100 °C was added dropwise a 1.6 M solution of n-BuLi (65.6 mmol). After 20 min of stirring at that temperature, 1- formylpiperidine (7.65 g) in 10 mL of THF was added and the solution was warmed to r.t.. After 30 min of stirring at r.t., triethyl phosphonoacetate (13.7 mL; 69.1 mmol) was added dropwise below 30 °C .
  • Step 3 Ethyl ( E ) -3-.3-. ( 5-chloroindolyl ) methyl1-2-pyridyll-2-propenoate
  • the benzylic bromide of Step 2 (1.33 g; 4.91 mmol) was coupled with 5-chloroindole according to the procedure described in step 1 of example 2 to yield 1.22 g of the title compound.
  • Step 4 ( E ) -3-.3-. ( 5-Chloroindolyl)methyll-2-pyridyl ⁇ -2-propenoic acid
  • Step 5 N-(E)-r(2.4-Dimethyl(1.3-thiazol-5-yl))sulfonyl.-3-f3-.(5- chloroindolyl)methyll(2-pyridyl))-2-propenamide
  • the acid of Step 4 (283 mg; 0.90 mmol) was coupled with 2,4- dimethyl-l,3-thiazole-5-sulfonamide (from Maybridge Chemical) according to step 5 of example 1 to yield 315 mg of the title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des composés représentés par la formule (I), ainsi que des sels, des hydrates et des esters de ceux-ci qui sont acceptables d'un point de vue pharmaceutique. Les composés sont utiles pour traiter ou prévenir des maladies dans lesquelles intervient la prostaglandine. L'invention concerne également des compositions pharmaceutiques contenant ces composés et des méthodes de traitement.
PCT/CA1999/000212 1998-03-13 1999-03-12 Acides carboxyliques et acylsulfonamides, compositions contenant ces composes et methodes de traitement WO1999047497A2 (fr)

Priority Applications (4)

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EP99907214A EP1071648A2 (fr) 1998-03-13 1999-03-12 Acides carboxyliques et acylsulfonamides, compositions contenant ces composes et methodes de traitement
JP2000536694A JP2002506851A (ja) 1998-03-13 1999-03-12 カルボン酸類およびアシルスルホンアミド類、そのような化合物を含む組成物ならびに治療方法
AU27086/99A AU756333B2 (en) 1998-03-13 1999-03-12 Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment
CA002322742A CA2322742A1 (fr) 1998-03-13 1999-03-12 Acides carboxyliques et acylsulfonamides, compositions contenant ces composes et methodes de traitement

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GBGB9815856.1A GB9815856D0 (en) 1998-07-21 1998-07-21 Carboxylic acids and acylsulfonamides compositions containing such compounds and methods of treatment

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Publication number Priority date Publication date Assignee Title
WO2002002522A1 (fr) * 2000-06-29 2002-01-10 Abbott Laboratories Derives de sulfure d'aryle phenycyclopropyle et leur utilisation en tant que composes anti-inflammatoires inhibant l'adhesion cellulaire et agents immunosuppresseurs
WO2002018333A1 (fr) * 2000-08-31 2002-03-07 Pfizer Limited Derives de la phenoxybenzylamine inhibiteurs selectifs du recaptage de la serotonine
WO2002032422A3 (fr) * 2000-10-19 2002-07-25 Pfizer Pharma Inhibiteurs du recepteur ep4 destines au traitement de la polyarthrite rhumatoide
WO2001081312A3 (fr) * 2000-04-24 2002-08-08 Merck Frosst Canada Inc Methode de traitement se basant sur l'utilisation de derives de phenyle et de biaryle comme inhibiteurs de prostaglandine e
US6521619B2 (en) 2000-06-29 2003-02-18 Icos Corporation Aryl phenylcyclopropyl sulfide derivatives and their use as cell adhesion inhibiting anti-inflammatory and immune suppressive agents
WO2003024484A1 (fr) * 2001-09-14 2003-03-27 Ono Pharmaceutical Co., Ltd. Medicaments pour traiter le prurit
WO2003043655A1 (fr) * 2001-11-19 2003-05-30 Ono Pharmaceutical Co., Ltd. Remedes pour la frequence urinaire
US6610747B2 (en) 2000-08-31 2003-08-26 Pfizer Inc. Phenoxybenzylamine derivatives as SSRIs
WO2003087061A1 (fr) * 2002-04-12 2003-10-23 Pfizer Japan Inc. Composes de pyrazole en tant qu'agents anti-inflammatoires et analgesiques
US6956050B2 (en) 2002-04-12 2005-10-18 Pfizer, Inc. Imidazole compounds as anti-inflammatory and analgesic agents
US7074942B2 (en) 1999-08-04 2006-07-11 The Procter & Gamble Company 2-decarboxy-2-phosphinico prostaglandin derivatives and methods for their preparation and use
WO2007018314A3 (fr) * 2005-08-10 2007-07-05 Takeda Pharmaceutical Agent therapeutique pour le diabete
WO2007027630A3 (fr) * 2005-08-30 2007-07-12 Smithkline Beecham Corp Genes associes au diabete de type ii
US7279477B2 (en) 2001-01-26 2007-10-09 Chugai Seiyaku Kabushiki Kaisha Malonyl-CoA decarboxylase inhibitors useful as metabolic modulators
US7285562B2 (en) 2003-08-01 2007-10-23 Chugai Seiyaku Kabushiki Kaisha Cyanoamide compounds useful as malonyl-CoA decarboxylase inhibitors
US7335776B2 (en) 2001-03-14 2008-02-26 Ono Pharmaceutical Co., Ltd. Remedies for depression containing EP1 antagonist as the active ingredient
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WO2008099907A1 (fr) 2007-02-16 2008-08-21 Ono Pharmaceutical Co., Ltd. Agent thérapeutique pour trouble de la miction
US7449482B2 (en) 2003-08-01 2008-11-11 Chugai Seiyaku Kabushiki Kaisha Piperidine compounds useful as malonyl-CoA decarboxylase inhibitors
US7491748B2 (en) 2001-08-09 2009-02-17 Ono Pharmaceutical Co., Ltd. Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient
US7524969B2 (en) 2001-01-26 2009-04-28 Chugai Seiyaku Kabushiki Kaisha Malonyl-CoA decarboxylase inhibitors useful as metabolic modulators
US7696365B2 (en) 2003-08-01 2010-04-13 Chugai Seiyaku Kabushiki Kaisha Heterocyclic compounds useful as malonyl-CoA decarboxylase inhibitors
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US7786145B2 (en) 2003-08-01 2010-08-31 Chugai Seiyaku Kabushiki Kaisha Cyanoguanidine-based azole compounds useful as malonyl-CoA decarboxylase inhibitors
US7902354B2 (en) 2006-08-21 2011-03-08 Arqule, Inc. Lapachone compounds and methods of use thereof
US8143285B2 (en) 2005-09-06 2012-03-27 Shionogi & Co., Ltd. Indolecarboxylic acid derivative having PGD2 receptor antagonistic activity
US8242145B2 (en) 2008-02-14 2012-08-14 Panmira Pharmaceuticals, Llc Cyclic diaryl ether compounds as antagonists of prostaglandin D2 receptors
CN102838515A (zh) * 2011-06-23 2012-12-26 南京大学 肉桂酰磺酰胺类化合物的制备及其在抗癌治疗药物中的应用
US8383654B2 (en) 2008-11-17 2013-02-26 Panmira Pharmaceuticals, Llc Heterocyclic antagonists of prostaglandin D2 receptors
US8426449B2 (en) 2008-04-02 2013-04-23 Panmira Pharmaceuticals, Llc Aminoalkylphenyl antagonists of prostaglandin D2 receptors
US8513027B2 (en) 1997-09-25 2013-08-20 Asterand Uk Acquisition Limited Method of identifying an inhibitor of the prostanoid EP4 receptor
US9675539B2 (en) 2000-03-31 2017-06-13 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
KR20170102885A (ko) 2015-01-09 2017-09-12 오노 야꾸힝 고교 가부시키가이샤 삼환성 스피로 화합물
CN107628981A (zh) * 2017-10-31 2018-01-26 威海市妇女儿童医院 一种肉桂酰基吲哚啉化合物及其制备青光眼药物的应用
KR20190026736A (ko) 2016-07-07 2019-03-13 오노 야꾸힝 고교 가부시키가이샤 Ep4 길항약과 면역 체크 포인트 저해약을 포함하여 이루어진 조합
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Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1159266B1 (fr) 1999-03-05 2004-11-03 Duke University Analogues de prostaglandines c-16 fp selectives insaturees
US20020172693A1 (en) 2000-03-31 2002-11-21 Delong Michell Anthony Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US20020037914A1 (en) 2000-03-31 2002-03-28 Delong Mitchell Anthony Compositions and methods for treating hair loss using C16-C20 aromatic tetrahydro prostaglandins

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU543739B2 (en) * 1979-09-05 1985-05-02 Glaxo Group Limited Phenol derivatives
US4673684A (en) * 1984-04-04 1987-06-16 Terumo Corporation Amide derivatives and 5-lipoxygenase inhibitors containing the same as an active ingredient
GB8528398D0 (en) * 1985-11-19 1985-12-24 Glaxo Group Ltd Chemical compounds
DE4037003A1 (de) * 1990-05-30 1991-12-05 Bayer Ag Substituierte azine
US4996214A (en) * 1990-06-28 1991-02-26 Smithkline Beecham Corporation Quinolinyl substituted phenyl/thioalkanoic acid substituted propionic acids and leucotriene antagonist use thereof
DE4024347A1 (de) * 1990-07-27 1992-01-30 Schering Ag Cyclopentanderivate, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung
JP2986262B2 (ja) * 1991-09-18 1999-12-06 鐘紡株式会社 美白化粧料
US5827868A (en) * 1991-10-07 1998-10-27 E. R. Squibb & Sons, Inc. Prostaglandin analogs
US5346794A (en) * 1992-03-03 1994-09-13 Hodogaya Chemical Co., Ltd. Electrophotographic toner
GB9420557D0 (en) * 1994-10-12 1994-11-30 Zeneca Ltd Aromatic compounds
IL117797A0 (en) * 1995-04-07 1996-08-04 Pharmacopeia Inc Tricyclic compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
EP0833629A4 (fr) * 1995-06-19 1998-09-16 Ontogen Corp Derives d'acide aryl-acrylique convenant comme inhibiteurs de proteine-tyrosine-phosphatase
FR2738821B1 (fr) * 1995-09-15 1997-11-21 Rhone Poulenc Rorer Sa Indeno[1,2-e]pyrazin-4-ones, leur preparation et les medicaments les contenant
FR2743366B1 (fr) * 1996-01-10 1998-02-06 Rhone Poulenc Rorer Sa Derives de 5h,10h-imidazo(1,2-a)indeno(1,2-e)pyrazine-4-one, leur preparation, leurs intermediaires et les medicaments les contenant

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US7074942B2 (en) 1999-08-04 2006-07-11 The Procter & Gamble Company 2-decarboxy-2-phosphinico prostaglandin derivatives and methods for their preparation and use
US9675539B2 (en) 2000-03-31 2017-06-13 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
WO2001081312A3 (fr) * 2000-04-24 2002-08-08 Merck Frosst Canada Inc Methode de traitement se basant sur l'utilisation de derives de phenyle et de biaryle comme inhibiteurs de prostaglandine e
US6627656B2 (en) 2000-04-24 2003-09-30 Michel Gallant Method of treatment using phenyl and biaryl derivatives as prostaglandin E inhibitors and compounds useful therefore
US6521619B2 (en) 2000-06-29 2003-02-18 Icos Corporation Aryl phenylcyclopropyl sulfide derivatives and their use as cell adhesion inhibiting anti-inflammatory and immune suppressive agents
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WO2002018333A1 (fr) * 2000-08-31 2002-03-07 Pfizer Limited Derives de la phenoxybenzylamine inhibiteurs selectifs du recaptage de la serotonine
US6610747B2 (en) 2000-08-31 2003-08-26 Pfizer Inc. Phenoxybenzylamine derivatives as SSRIs
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US6710054B2 (en) 2000-10-19 2004-03-23 Pfizer Inc Aryl or heteroaryl fused imidazole compounds as anti-inflammatory and analgesic agents
US7479564B2 (en) 2000-10-19 2009-01-20 Raqualia Pharma Inc. Aryl or heteroaryl fused imidazole compounds as anti-inflammatory and analgesic agents
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EP1666480A1 (fr) * 2000-10-19 2006-06-07 Pfizer Pharmaceuticals Inc. Composés imidazoles condensés avec un groupement aryle ou hétéroaryle, intermédiaires d'agents analgésiques et anti-inflammatoires
US7141580B2 (en) 2000-10-19 2006-11-28 Pfizer Inc. Aryl or heteroaryl fused imidazole compounds as anti-inflammatory and analgesic agents
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US8110686B2 (en) 2001-02-20 2012-02-07 Chugai Seiyaki Kabushiki Kaisha Azoles as malonyl-CoA decarboxylase inhibitors useful as metabolic modulators
US7335776B2 (en) 2001-03-14 2008-02-26 Ono Pharmaceutical Co., Ltd. Remedies for depression containing EP1 antagonist as the active ingredient
US7491748B2 (en) 2001-08-09 2009-02-17 Ono Pharmaceutical Co., Ltd. Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient
US7786161B2 (en) 2001-08-09 2010-08-31 Ono Pharmaceutical Co., Ltd. Carboxylic acid derivatives and pharmaceutical agent comprising the same as active ingredient
WO2003024484A1 (fr) * 2001-09-14 2003-03-27 Ono Pharmaceutical Co., Ltd. Medicaments pour traiter le prurit
WO2003043655A1 (fr) * 2001-11-19 2003-05-30 Ono Pharmaceutical Co., Ltd. Remedes pour la frequence urinaire
WO2003087061A1 (fr) * 2002-04-12 2003-10-23 Pfizer Japan Inc. Composes de pyrazole en tant qu'agents anti-inflammatoires et analgesiques
US6956050B2 (en) 2002-04-12 2005-10-18 Pfizer, Inc. Imidazole compounds as anti-inflammatory and analgesic agents
US7001917B2 (en) 2002-04-12 2006-02-21 Warner Lambert Company Llc Pyrazole compounds as anti-inflammatory and analgesic agents
US7897615B2 (en) 2003-08-01 2011-03-01 Chugai Sciyaku Kabushiki Kaisha Cyanoamide compounds useful as malonyl-CoA decarboxylase inhibitors
US7786145B2 (en) 2003-08-01 2010-08-31 Chugai Seiyaku Kabushiki Kaisha Cyanoguanidine-based azole compounds useful as malonyl-CoA decarboxylase inhibitors
US7449482B2 (en) 2003-08-01 2008-11-11 Chugai Seiyaku Kabushiki Kaisha Piperidine compounds useful as malonyl-CoA decarboxylase inhibitors
US8080665B2 (en) 2003-08-01 2011-12-20 Chugai Seiyaku Kabushiki Kaisha Piperidine compounds useful as malonyl-CoA decarboxylase inhibitors
US7696365B2 (en) 2003-08-01 2010-04-13 Chugai Seiyaku Kabushiki Kaisha Heterocyclic compounds useful as malonyl-CoA decarboxylase inhibitors
US7285562B2 (en) 2003-08-01 2007-10-23 Chugai Seiyaku Kabushiki Kaisha Cyanoamide compounds useful as malonyl-CoA decarboxylase inhibitors
WO2007018314A3 (fr) * 2005-08-10 2007-07-05 Takeda Pharmaceutical Agent therapeutique pour le diabete
WO2007027630A3 (fr) * 2005-08-30 2007-07-12 Smithkline Beecham Corp Genes associes au diabete de type ii
US8623903B2 (en) 2005-09-06 2014-01-07 Shionogi & Co., Ltd. Indolecarboxylic acid derivative having PGD2 receptor antagonistic activity
US8143285B2 (en) 2005-09-06 2012-03-27 Shionogi & Co., Ltd. Indolecarboxylic acid derivative having PGD2 receptor antagonistic activity
US8039503B2 (en) 2006-08-21 2011-10-18 Arqule, Inc. Lapachone compounds and methods of use thereof
US7902354B2 (en) 2006-08-21 2011-03-08 Arqule, Inc. Lapachone compounds and methods of use thereof
WO2008099907A1 (fr) 2007-02-16 2008-08-21 Ono Pharmaceutical Co., Ltd. Agent thérapeutique pour trouble de la miction
US8242145B2 (en) 2008-02-14 2012-08-14 Panmira Pharmaceuticals, Llc Cyclic diaryl ether compounds as antagonists of prostaglandin D2 receptors
US8426449B2 (en) 2008-04-02 2013-04-23 Panmira Pharmaceuticals, Llc Aminoalkylphenyl antagonists of prostaglandin D2 receptors
US8383654B2 (en) 2008-11-17 2013-02-26 Panmira Pharmaceuticals, Llc Heterocyclic antagonists of prostaglandin D2 receptors
CN102838515A (zh) * 2011-06-23 2012-12-26 南京大学 肉桂酰磺酰胺类化合物的制备及其在抗癌治疗药物中的应用
KR20170102885A (ko) 2015-01-09 2017-09-12 오노 야꾸힝 고교 가부시키가이샤 삼환성 스피로 화합물
US10077247B2 (en) 2015-01-09 2018-09-18 Ono Pharmaceutical Co., Ltd. Tricyclic spiro compound
US10538502B2 (en) 2015-01-09 2020-01-21 Ono Pharmaceutical Co., Ltd. Tricyclic spiro compound
EP3778562A1 (fr) 2015-01-09 2021-02-17 ONO Pharmaceutical Co., Ltd. Composé spiro tricyclique
US11192876B2 (en) 2015-01-09 2021-12-07 Ono Pharmaceutical Co., Ltd. Tricyclic spiro compound
KR20220038804A (ko) 2015-01-09 2022-03-29 오노 야꾸힝 고교 가부시키가이샤 삼환성 스피로 화합물
KR20190026736A (ko) 2016-07-07 2019-03-13 오노 야꾸힝 고교 가부시키가이샤 Ep4 길항약과 면역 체크 포인트 저해약을 포함하여 이루어진 조합
US11065226B2 (en) 2016-07-07 2021-07-20 Ono Pharmaceutical Co., Ltd. Combination comprising EP4 antagonist and immune checkpoint inhibitor
CN107628981A (zh) * 2017-10-31 2018-01-26 威海市妇女儿童医院 一种肉桂酰基吲哚啉化合物及其制备青光眼药物的应用
CN117164462A (zh) * 2023-04-24 2023-12-05 江西师范大学 一种二芳基甲烷类化合物及其制备方法和应用

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