WO2003004458A1 - New compounds - Google Patents

New compounds Download PDF

Info

Publication number
WO2003004458A1
WO2003004458A1 PCT/SE2002/001323 SE0201323W WO03004458A1 WO 2003004458 A1 WO2003004458 A1 WO 2003004458A1 SE 0201323 W SE0201323 W SE 0201323W WO 03004458 A1 WO03004458 A1 WO 03004458A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
dichlorobenzoyl
benzoate
ethoxy
biphenyl
Prior art date
Application number
PCT/SE2002/001323
Other languages
French (fr)
Inventor
Anna-Lena Gustavsson
Lena Jendeberg
Patrick Roussel
Martin Slater
Markus Thor
Original Assignee
Biovitrum Ab
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 claimed from SE0102384A external-priority patent/SE0102384D0/en
Application filed by Biovitrum Ab filed Critical Biovitrum Ab
Publication of WO2003004458A1 publication Critical patent/WO2003004458A1/en

Links

Classifications

    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • 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
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed 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
    • 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
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • 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
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • 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
    • 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
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen 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
    • C07D233/66—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 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
    • C07D233/84—Sulfur 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
    • C07D233/66—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 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
    • C07D233/91—Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
    • C07D241/18—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C07D277/22—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen 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
    • C07D307/38—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen 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
    • C07D307/38—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—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
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—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
    • 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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen 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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/18—Radicals substituted by singly bound hetero atoms other than halogen by 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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—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
    • 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
    • C07D333/28—Halogen 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2299/00—Coordinates from 3D structures of peptides, e.g. proteins or enzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the present invention relates to novel compounds which are 2- (benzoylamino)benzoic acids and which modulate the activity of peroxisome proliferator- activated receptors (PPAR) ⁇ and/or ⁇ .
  • PPAR peroxisome proliferator- activated receptors
  • the said compounds are predicted to be useful in the treatment of metabolic diseases, e.g. type II diabetes.
  • PPARs peroxisome proliferator-activated receptors
  • PPARs were first cloned as the nuclear receptors that mediate the effects of synthetic compounds called peroxisome proliferators on gene transcription. It soon became clear that eicosanoids and fatty acids can also regulate gene transcription through PPARs.
  • PPARs act in a similar manner to other nuclear hormone receptors. First, they bind a specific element in the promoter region of target genes. PPAR and some other nuclear hormone receptors bind the promoter only as a heterodimer with the receptor for 9- cis retinoic acid, RXR (retinoid X receptor). Second, they activate transcription in response to binding ofthe hormone (ligand).
  • PPAR:RXR heterodimer binding ofthe ligand of either receptor can activate the complex, but binding of both ligands simultaneously is more potent.
  • Three PPAR isotypes have been identified: ⁇ , ⁇ (also called ⁇ and NUC1) and ⁇ .
  • PPAR ⁇ (GenBank Accession No. NM_005036) is expressed most in brown adipose tissue and liver, then kidney, heart and skeletal muscle.
  • PPAR ⁇ GenBank Accession No. NM_005037
  • PPAR ⁇ is mainly expressed in adipose tissue, and to a lesser extent in colon, the immune system and the retina.
  • PPAR ⁇ is found in many tissues but the highest expression is in the gut, kidney and heart.
  • PPARs are ligand-dependent transcription factors: activation of target gene transcription depends on the binding ofthe ligand to the receptor. Some ligands are shared by the three isotypes, such as polyunsaturated fatty acids and probably oxidized fatty acids.
  • Type I insulin-dependent diabetes mellitus
  • IDDM insulin-dependent diabetes mellitus
  • Type II non-insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • NTDDM is linked to heredity and obesity.
  • NIDDM is almost invariably accompanied by dyslipidemia, characterized by elevated triglycerides (TGs), VLDL-C and increased small dense LDL-C in combination with decreased levels of HDL-C and prolonged postprandial hyperlipidemia.
  • This form of dyslipidemia is highly atherogenic and thus represents a major risk factor for the development of premature atherosclerosis and coronary artery disease (CAD), which is the major cause of mortality in diabetic patients.
  • CAD coronary artery disease
  • a direct correlation between low HDL levels and incidence of CAD has been identified.
  • this pathological lipid profile or "lipotoxicity" is suggested to contribute to ⁇ - cell failure and as a consequence impaired glucose stimulated insulin release.
  • PPAR ⁇ and PPAR ⁇ are key sensors and transcriptional modulators of lipid and glucose homeostasis, respectively. Accordingly, a selective "dual action drug" that selectively binds and activates PPAR ⁇ and ⁇ is hypothesized to mechanistically target the two major metabolic abnormalities observed in type II diabetic patients and thus therapeutically intervene with insulin resistance, CAD and possibly also impaired insulin secretion or ⁇ -cell failure.
  • Murakami et al. discloses a thiazolidinedione derivative which activated both PPAR ⁇ and PPAR ⁇ , and restored reduced lipid oxidation, when administered to obese rats. It was suggested that PPAR ⁇ agonism has a protective effect against abnormal lipid metabolism in liver of obese rats. Agents modulating both PPAR ⁇ and PPAR ⁇ are also disclosed in Shibata, T. et al. (1999) Eur. J. Pharmacol. 364: 211-219; and in WO 99/19313.
  • Figure 1 shows the structure ofthe ligand-binding domain of human PPAR ⁇ , in complex with the compound according to Example 1 ofthe invention.
  • PPAR modulator is intended to mean a PPAR ligand that is capable of acting as an activator (agonist), or alternatively as an inhibitor (antagonist), in PPAR mediated transcriptional responses. Consequently, in a first aspect this invention provides a compound ofthe formula I
  • Ar is aryl, which is optionally substituted in one or more positions by halogen, cyano, nitro,
  • X is a bond, or a heteroalkyl chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms, or a formula wherein m is 0, 1, or 2, n is O, 1, 2, or 3, and
  • R is a CrC ⁇ -alkyl or an optionally substituted aryl or heteroaryl group
  • R is an optionally substituted aryl or heteroaryl group; and when X is a heteroalkyl chain comprising from 1 to 4 carbon atoms and from
  • R is a C ⁇ -C 6 -alkyl or an optionally substituted aryl or heteroaryl group, with the proviso that when X is a bond, then R is not a C ⁇ -C 6 -alkyl; or said compound is not a dibenzoyl-bisanthranilic acid, or
  • Preferred compounds ofthe formula I include those wherein:
  • Ar is phenyl or naphthyl, optionally substituted in one or more positions independently by halogen, nitro, cyano, methoxy, or trifluoromethyl.
  • X is a bond
  • O-(CH 2 ) n wherein n is an integer 0 to 3, e.g. O, O-CH 2 , or O-(CH 2 )2; O-(CH 2 ) n -Y, wherein n is an integer 0 to 3, and Y is an atom selected from O, N and S, e.g. O-(CH 2 ) 2 -O, or O-(CH 2 ) 2 -S;
  • R is methyl or selected from the group consisting of, optionally substituted, phenyl, naphthyl, thienyl, pyridinyl, quinoxalinyl, benzoylphenyl, thiazolyl, furyl, imidazolyl, oxazolyl, pyrazinyl, quinolinyl, indolyl, benzofuran, benzothiophenyl (benzothienyl), pyrimidinyl, benzodioxolyl, with the proviso that when X is a bond then R is not methyl
  • R is an aryl or heteroaryl, it is independently substituted in one or more positions with
  • R can be independently substituted in one or more positions with methyl, ethyl, isopropyl, methoxy, thiomethoxy ethoxy, methylsulfonyl, formyl, acetyl, nitro, cyano, methylhydroxy, methylamino, carboxy, trifluoromethyl, trifluoromethoxy, chloro, fluoro, bromo, iodo, benzyloxy, amino, dimethylamino, acetylamino, phenyl, phenoxy, or benzoyl.
  • the following compounds are especially preferred:
  • C ⁇ g alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms.
  • Examples of said C _ alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
  • C j .g alkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms.
  • Examples of said C g alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • aryl denotes aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms. Examples of said aryl include phenyl, indenyl and naphthyl.
  • heteroaryl denotes a mono- or bicyclic ring system (only one ring need to be aromatic, and substitution may be in any ring) having from 5 to 10 ring atoms (which are carbon atoms), in which one or more ofthe carbon ring atoms are other than carbon, such as nitrogen, oxygen, selenium, and sulfur.
  • heteroaryl examples include pyrrole, thiazole, imidazole, thiophene, furan, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, quinazolineindole, indole, isoindole, isoindoline, indoline, benzothiophene, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2, 1 ,3 -benzothiadiazole, 2,1 ,3-benzoselenadiazole, benzimidazole, ind
  • heteroalkyl chain denotes a straight or branched, saturated or unsaturated, chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of O, N, and S.
  • the heteroatom(s) may be placed at any position ofthe heteroalkyl group.
  • the end products ofthe Formula I are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope ofthe invention group (e.g., lithium, sodium, potassium salts, hydrochloride, hydrobromide, and the like). All diastereomeric forms possible (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope ofthe invention.
  • Therapeutic or prophylactic treatment of mammals for conditions where modulation of either PPAR ⁇ or PPAR ⁇ activity, or the combination of both PPAR ⁇ and PPAR ⁇ activities, is of therapeutic benefit.
  • Such conditions could be e.g. diabetes, diabetes mellitus type 2, insulin resistance, impaired glucose tolerance and / or in combinations with dyslipidemias, obesity, atherosclerosis, coronary artery disease, PCOS, gestational diabetes, inflammation.
  • the compounds according to the invention are particularly useful for the treatment of type II diabetes, in combination(s) with dyslipidemias, obesity, atherosclerosis and coronary artery disease.
  • the compounds according to the invention can be used alone or in combinations) with sulfonylureas, metformin, alpha-glycosidase inhibitors, insulin or other anti-diabetic treatments/agents.
  • Reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
  • the compounds ofthe invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
  • Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients.
  • the formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc.
  • the formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections.
  • Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.
  • the typical daily dose ofthe active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient and the route of administration.
  • the compounds according to the invention may also be administered as prodrugs that may be converted to the active ingredient in question after metabolic transformation in vivo. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985.
  • This invention also relates to a method of treatment or prevention of diabetes.
  • the method includes administering to a subject (e.g., a human, a mammal, a horse, a dog, or a cat) in need thereof an effective amount of one or more compounds ofthe formula I :
  • Ar is aryl, which is optionally substituted in one or more positions by halogen, cyano, nitro,
  • X is a bond, or a heteroalkyl chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms, or a formula
  • R is C ⁇ -C 6 -alkyl or an optionally substituted aryl or heteroaryl group.
  • the methods delineated herein can also include the step of identifying that the subj ect is in need of treatment of diabetes.
  • Also within the scope of this invention is a method for modulating (e.g., stimulating or inhibiting) peroxisome proliferator-activated receptors activities.
  • the method includes contacting the receptors with an effective stimulatory or inhibitory amount of a compound ofthe formula I.
  • “An effective amount” refers to an amount of a compound which confers a therapeutic effect on the treated subject.
  • the therapeutic effect maybe objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • the dose level and frequency of dosage ofthe specific compound will vary depending on a variety of factors including the potency ofthe specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity ofthe condition to be treated, and the patient undergoing therapy.
  • the daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
  • the invention provides a process for the preparation of a compound as defined above.
  • the compounds according to the invention can be prepared by, or in analogy with, standard synthetic methods, and especially according to, or in analogy with, the following methods.
  • the chemicals used in the above-described synthetic routes may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents.
  • the methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis ofthe compounds of Formula (I).
  • various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2 n Ed., John Wiley and Sons (1991); L. Fieser and M.
  • the structures ofthe prepared compounds were confirmed by standard spectroscopical methods.
  • the NMR data was obtained on a Jeol JNM-EX 270 or a Bruker DRX 500 spectrometer.
  • Electrospray MS data was obtained on a Micromass platform LCMS spectrometer. Melting points, when given, were obtained on a Electrothermal IA9000 melting point apparatus, and are uncorrected.
  • TMAD 183 mg, 1.06 mmol
  • TMAD 183 mg, 1.06 mmol
  • a suspension of methyl 2-[(2,4- dichlorobenzoyl)amino]-5-hydroxybenzoate 240 mg, 0.71 mmol; prepared in Example XX
  • polymer bound triphenylphosphine 480 mg, 1.4 mmol
  • thiophene-2 -methanol 73 ⁇ l, 0.78 mmol
  • the suspension was shaken at room temperature over night and filtered through a plug of Celite.
  • Step 4 Lithium 2-f(2,4-dichlorobenzoyl)aminoJ-5-(2-thienylmethoxy)benzoate General procedure B
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(3-pyridinylmethoxy)benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate
  • 2-(3-thienyl)ethanol afforded the title compound (370 mg, 93%) as an oil by the application ofthe general procedure A described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate afforded the title compound (260 mg, 95%) as a white solid by the application ofthe general procedure B described above.
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)aminoJ-5-[(4-ethoxybenzyl)oxyJbenzoate
  • 4-ethoxybenzyl alcohol afforded the title compound (206 mg, 37%) as an yellow solid by the application ofthe general procedure A described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(4-ethoxybenzyl)oxy]benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [3- (dimethylamino)benzyl]oxy ⁇ benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [3- (dimethylaminojbenzyljoxyjbenzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methylphenyl)ethoxy]benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3- methylphenyl)ethoxy]benzoate afforded the title compound (119 mg, 94%) as a solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(l-naphthyl)ethoxy]benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyridinylmethoxy)benzoate
  • Step 1 Methyl 2- [(2, 4-dichlorobenzoyl)amino]-5-(2- ⁇ [2-(methylsulfanyl)-3- pyridinyl] oxy ⁇ ethoxy) benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2- ⁇ [2-(methylsulfanyl)-3- pyridinyl] oxy ⁇ ethoxy)benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2- ⁇ [2-(methylsulfanyl)-3- pyridinyl]oxy ⁇ ethoxy)benzoate afforded the title compound (98 mg, 100%) as a beige solid by the application ofthe general procedure B described above.
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-pyridinyloxy)ethoxy]benzoate
  • 2-(3-pyridinyloxy)ethanol (disclosed in WO 00/76984) afforded, the title compound (50 mg, 22%), as a white solid, by the application ofthe general procedure A described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-pyridinyloxy)ethoxy]benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3- pyridinyloxy)ethoxy]benzoate afforded the title compound (35 mg, 96%) as a white solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-quinoxalinyloxy)ethoxy]benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[2-(methylsulfanyl)phenoxy] ethoxyjbenzoate
  • 2-[2-(methylsulfanyl)phenoxy]ethanol afforded the title compound (6 mg, 2%), as a white solid, by the application ofthe general procedure A described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[2-(methylsulfanyl)phenoxy] ethoxyjbenzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[2-
  • Step 1 Methyl 5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)ammo]benzoate
  • 2-(2-aminophenoxy)ethanol (disclosed in EP 0881488 and EP 0881225) afforded the title compound (25 mg, 11%), as a white solid, by the application ofthe general procedure A described above.
  • Step 2 Lithium 5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of methyl 5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate afforded the title compound (22 mg, 99%) as a beige solid by the application ofthe general procedure B described above.
  • Step 1 Methyl 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate
  • Step 2 Lithium 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of methyl 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate afforded the title compound (30 mg, 80%) as a white solid by the application ofthe general procedure B described above.
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2,3,6- trifluorophenoxyjethoxyjbenzoate
  • Step 2 Lithium 2- [(2, 4-dichlorobenzoyl)amino]-5-[2-(2, 3, 6- trifluorophenoxyjethoxyjbenzoate
  • Step 1 Methyl 5-[2-([l ,l'-biphenyl] -3-yloxy)ethoxy] -2-[(2,4- dichlor Tavernzoyl) amino] benzoate
  • Step 2 Lithium 5-[2-([l, 1 '-biphenyl] -3-yloxy)ethoxy]-2-[(2, 4- dichlorobenzoy I) amino] benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(phenylsulfanyl)ethoxy]benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2- (phenylsulfanyl)ethoxy]benzoate afforded the title compound (25 mg, 88%) as a white solid by the application ofthe general procedure B described above.
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[(4-methyl-l,3-thiazol-5-yl)oxy] ethoxyjbenzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[(4-methyl-l,3-thiazol-5- yljoxyj ' ethoxyjbenzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(3-furylmethoxy)benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(3-furylmethoxy)benzoate afforded the title compound (31 mg, 86%) as a yellow solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-thienyl)ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH-imidazol-l- yl)ethoxy] benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH-imidazol-l- yl)ethoxy] benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH- imidazol-l-yl)ethoxy]benzoate afforded the title compound (50 mg, 96%) as a brown-red solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2, 4-dichlorobenzoyl) amino] -5-(3-thienylmethoxy)benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(3-thienylmethoxy)benzoate afforded the title compound (28 mg, 95%) as a white solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- pyridinylsulfany I) ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-thiazol-4- y I) ethoxy] benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5 ⁇ [2-(5-methyl-2-phenyl-l,3-thiazol-4- yl) ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4- yl) ethoxy] benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4- yl) ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-ethyl-2-pyridinyl)ethoxy]benzoate
  • 2-(5-ethyl-2-pyridinyl)ethanol afforded the title compound (90 mg, 38%) by the application ofthe general procedure A described above.
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methoxyphenoxy)ethoxy]benzoate Use of 2-(2-methoxyphenoxy)ethanol (previously described in J. Chem. Soc.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- methoxyphenoxy) ethoxy] benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- methoxyphenoxy)ethoxy]benzoate afforded the title compound (163 mg, 98%) as a solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(4-pyridinylmethoxy)benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[3-(3-pyridinyl)propoxy]benzoate
  • Step 2 Lithium 2- [(2, 4-dichlorobenzoyl)amino]-5-[2-(2-pyridinyl) ethoxy] benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methoxyphenyl)ethoxy]benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3- methoxyphenyl)ethoxy]benzoate afforded the title compound (quantitative yield) as a pink solid by the application ofthe general procedure B described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(6-nitro-2-pyridinyl)oxy]benzoate
  • Use of methyl 2-[(2,4-dicMorobenzoyl)amino]-5-[(6-nitro-2- pyridinyl)oxy]benzoate afforded the title compound (88 mg, 94%) as a yellow solid by the application ofthe general procedure B described in Example 1.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(5-nitro-2-pyridinyl)oxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [5-(trifluoromethyl)-2- pyridinyl] oxy ⁇ benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [5-(trifiuoromethyl)-2- pyridinyl] oxy ⁇ benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [5-(trifluoromethyl)-2- pyridinyl]oxy ⁇ benzoate afforded the title compound (41 mg, 95%) as a yellow solid by the application ofthe general procedure B described above.
  • Step 1 Methyl 5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate
  • Step 2 Lithium 5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate
  • Use of methyl 5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate afforded the title compound (84 mg, 83%) as a white solid by the application ofthe general procedure B described above.
  • 1H NMR (DMSO) £ 15.19 (s, IH), 8.68-8.44 (m, 3H), 7.80-7.51 (m, 4H), 7.23 (dd, J 8.70, 2.91 Hz IH); MS m/z 436 (M-l).
  • Step 2 Lithium 2-[(2, 4-dichlorobenzoyl) amino] -5-(2-pyrimidinyloxy)benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [(2E)-3-phenyl-2- propenyl] oxy ⁇ benzoate
  • D Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ [(2E)-3-phenyl-2- propenyl] oxy ⁇ benzoate
  • Cinnamyl bromide 131 ⁇ l, 0.88 mmol was added to a stirred mixture of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-hydroxybenzoate (300 mg, 0.88 mmol) and potassium carbonate (185 mg, 1.3 mmol) in DMF (10 ml). After heating at 65°C for 4 hours the mixture was allowed to cool and then chloroform was added. Filtration and concentration ofthe filtrate in vacuo gave a residue which subsequently was purified by chromatography on silica gel eluting with CHCI 3 to give the title compound (196 mg, 50%) as a white solid.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(3-methoxybenzyl)oxy] benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[(3- methoxybenzyl)oxy]benzoate afforded the title compound (110 mg, 76%) as a white solid by the application ofthe general procedure B described above.
  • the crude isatoic anhydride (9.5 g, 27 mmol) was dissolved in dry methanol (670 ml) to which was added powdered anhydrous potassium carbonate (4.4 g, 31 mmol). The solution was allowed to stir at ambient overnight before being evaporated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and water (200 ml) and the aqueous layer adjusted to pH 7.0 with concentrated hydrochloric acid before separating.
  • Step 3 Methyl 2-[(2, 4-dichlorobenzoyl)amino]-5-(3-thienyl)benzoate
  • General procedure F To a stirred mixture of methyl 2-[(2, 4-dichlorobenzoyl)amino]-5-iodobenzoate
  • Step 4 Lithium 2-[(2, 4-dichlorobenzoyl)amino]-5-(3-thienyl)benzoate General procedure G
  • Step 1 Methyl 2- [(2, 4-dichlorobenzoyl)amino]-5-(2, 4-dichloropheny i) benzoate
  • Step 2 Lithium 2-[(2, 4-dichlorobenzoyl)amino] -5-(2, 4-dichlorophenyl) benzoate
  • Step 1 2-(2,4-dichlorophenyl)-6-(4-ethylphenyl)-l,3-benzoxazin-4-one
  • Step 2 2-[(2, 4-dichlorobenzoyl)amino]-5-(4-ethylphenyl)benzoic acid
  • Step 1 Methyl 5-(l,3-benzodioxol-5-yl)-2-[(2,4-dichlorobenzoyl)amino] benzoate
  • Step 2 2-[(2,4-Dichlorobenzoyl)amino]-5-(8-quinolinyl)benzoic acid
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2,4-dimethoxy-5-pyrimidinyl)benzoate
  • (2,4-dimethoxy)pyrimidine-5-boronic acid 41 mg, 0.22 mmol
  • the crude product was used in the next step without further purification.
  • Step 2 2-[(2,4-Dichlofobenzoyl)amino]-5-(2,4-dimethoxy-5-pyrimidinyl)benzoic acid Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (17 mg, 21%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M+1) 448.
  • Step 1 Methyl 3'-(acetylamino)-4-[(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl] -3- carboxylate
  • 3-(acetamido)phenylboronic acid 40 mg, 0.22 mmol
  • Step 2 3'-(Acetylamino)-4-[(2,4-dichlorobenzoyl)amino] [1 , 1 '-biphenyl] -3-carboxylic acid
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino] -3 '-(trifluoromethoxy) [1,1 '-biphenyl] -3- carboxylate
  • Step 2 4-[(2,4-Dichlorobenzoyl)amino] -3'-(trifluoromethoxy) [1 ,l'-biphenyl] -3- carboxylic acid
  • Step 1 Methyl 4-[(2, 4-dichlorobenzoyl) amino) '-3 '-ethoxy [1, 1 '-biphenyl] -3-carboxylate
  • 3-(ethoxy)phenylboronic acid afforded a crude mixture ofthe title compound and the corresponding cyclized benzoxazine by the application ofthe general procedure F described above. The crude product was used in the next step without further purification.
  • Step 2 4-[(2,4-Dichlorobenzoyl)amino] -3'-ethoxy[l ,1 '-biphenyl] -3-carboxylic acid
  • MS m/z (M-l) 428 Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (35 mg, 45%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 428.
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino) '-3 '-(hydroxymethyl) [1,1 '-biphenyl) -3- carboxylate
  • 3-(hydroxymethyl)phenylboronic acid 34 mg, 0.22 mmol
  • Step 2 4- [(2, 4-Dichlorobenzoyl)amino]-3 '-(hydroxymethyl) [1, 1 '-biphenyl] -3-carboxylic acid
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino] -3' -formyl[l,V -biphenyl] -3-carboxylate
  • Step 1 2-(2, 4-Dichlorophenyl)-6-(naphth-2-yl)-l, 3-benzoxazin-4-one
  • Step 2 2-[(2,4-Dichlorobenzoyl)amino]-5-(2-naphthyl)benzoic acid
  • Step 1 Methyl 4-[(2,4-Dichlorobenzoyl)amino]-3'-isopropyl-6'-methoxy[l,l'-bipheny ⁇ ]- 3-carboxylate
  • Step 2 4-[(2,4-Dichlorobenzoyl)amino) '-3'-isopropyl-6'-methoxy[l ,V -biphenyl) '-3- carboxylic acid
  • Step 1 Methyl 4-[(2, 4-dichlorobenzoyl) amino) '-4 '-fiuorofl, 1 '-biphenyl] -3-carboxylate
  • 4-fluorophenylboronic acid 31 mg, 0.22 mmol
  • Step 2 4-[(2,4-Dichlorobenzoyl)amino] -4'-fluoro[l ,l'-biphenyl] -3-carboxylic acid Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (27 mg, 37%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 402. EXAMPLE 55
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-furyl)benzoate
  • Step 2 Lithium 5-(l-benzothien-3-yl)-2-[(2,4-dichlorobenzoyl)amino) 'benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-formyl-3-thienyl)benzoate
  • Step 2 Lithium 5-(5-acetyl-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of methyl 5-(5-acetyl-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate afforded the title compound (13 mg, 100%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 432.
  • Step 2 2-[(2,4-Dichlorobenzoyl)amino]-5-(lH-indol-5-yl)benzoic acid trifluoroacetate
  • Step 1 Methyl 5-(3-carboxyphenyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate
  • 3-(carboxy)phenylboronic acid 47 mg, 0.28 mmol
  • the crude product was used in the next step without further purification.
  • Step 1 Methyl 2'-(benzyloxy)-4-[(2,4-dichlorobenzoyl)amino][l,l'-biphenyl]-3- carboxylate
  • Step 2 2 '-(benzyloxy)-4-[(2, 4-dichlorobenzoyl) amino] [1, 1 ' -biphenyl] -3-benzoic acid
  • Use of methyl 2'-(benzyloxy)-4-[(2,4-dichlorobenzoyl)amino] [1 , 1 '-biphenyl]-3- carboxylate afforded the title compound (10 mg, 30%) as a colorless solid by the application ofthe general procedure G described above.
  • MS m/z (M-l) 490 2 '-(benzyloxy)-4-[(2, 4-dichlorobenzoyl) amino] [1, 1 ' -biphenyl] -3-benzoic acid
  • Step 1 Methyl 4- [(2, 4-dichlorobenzoyl)amino] [1, 1 '-biphenyl] -3 -carboxylate
  • Step 2 Lithium 4-[(2,4-dichlorobenzoyl)amino] [1 ,1' -biphenyl] ' -3-carboxylate
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l,r-biphenyl] -3-carboxylate
  • Step 2 Lithium 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l,l -biphenyl) '-3-carboxylate
  • Use of methyl 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l, -biphenyl]-3- carboxylate afforded the title compound (38 mg, 99%) as a colorless solid by the application ofthe general procedure G described above.
  • MS m/z (M-l) 460 Lithium 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l,l -biphenyl) '-3-carboxylate
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino) -3 '-(trifluoromethyl) [1,1 '-biphenyl] -3- carboxylate
  • Step 2 Lithium methyl 4-[(2,4-dichlorobenzoyl)amino] -3 '-(trifluoromethyl) [1,1 '- biphenyl] -3-carboxylate Use of methyl 4-[(2,4-dichlorobenzoyl)amino]-3 , -(trifluoromethyl)[l,r-biphenyl]-
  • Step 1 Methyl 5-(5-chloro-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate
  • 5-(chloro)thiophene-2-boronic acid 36 mg, 0.28 mmol
  • afforded the title compound 75 mg, 96%) as an yellow solid by the application ofthe general procedure F described above.
  • Step 2 Lithium 5-(5-chloro-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino] benzoate
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino] -4'-phenoxy[l ,1 '-biphenyl] -3-carboxylate
  • Step 2 Lithium 4-[(2,4-dichlorobenzoyl)amino]-4'-phenoxy[l,l '-biphenyl] -3-carboxylate
  • Use of methyl 4-[(2,4-dichlorobenzoyl)amino]-4'-phenoxy[l,r-biphenyl]-3- carboxylate afforded the title compound (40 mg, 98%) as an yellow solid by the application ofthe general procedure G described above.
  • MS m/z (M-l) 476 MS m/z (M-l) 476.
  • Step 1 Methyl 4-[(2,4-dichlorobenzoyl)amino]-2',5'-dimethoxy[l,l '-biphenyl]-3- carboxylate
  • Step 2 Lithium 4-[(2,4-dichlorobenzoyl)amino] -2', 5'-dimethoxy[l , 1 '-biphenyl] -3- carboxylate
  • Use of methyl 4-[(2,4-dichlorobenzoyl)amino]-2',5'-dimethoxy[ 1 , 1 '-biphenyl] -3- carboxylate afforded the title compound (38 mg, 99%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 444.
  • EXAMPLE 68 Lithium 4-[(2,4-dichlorobenzoyl)amino] -2', 5'-dimethoxy[l , 1 '-biphenyl] -3- carboxylate
  • Step 1 6-(3-Aminomethylphenyl)-2-(2, 4-dichlorophenyl)-l , 3-benzoxazin-4-one
  • Step 2 3'-(Aminomethyl)-4-[(2,4-dichlorobenzoyl)amino][l,l '-biphenyl] -3-carboxylic acid
  • 6-(3 -aminomethylphenyl)-2-(2,4-dichlorophenyl)- 1 ,3 -benzoxazin-4-one afforded the title compound (4 mg, 18%) as a solid by the application ofthe general procedure G described above.
  • Step 1 Methyl 2-[(2-naphtoyl)amino]-5-iodobenzoate
  • General procedure I To a sti ⁇ ed solution of methyl 2-amino-5-iodobenzoate (500 mg, 1.8 mmol) in dry THF (10 ml) in a STEMBLOCK chiller at 0°C under an atmosphere of nitrogen, diisopropylethylamine (0.53 ml, 3.0 mmol) was added.
  • Step 2 Methyl 2-(2-naphthoylamino)-5-(3-thienyl)benzoate
  • General B2 To a sti ⁇ ed mixture of methyl 2-[(2-naphtoyl)amino]-5-iodobenzoate (100 mg,
  • Step 3 Lithium 2-(2-naphthoylamino)-5-(3-thienyl)benzoate
  • Step 1 Methyl 3'-(acetylamino)-4-(2-naphthoylamino)[l,l'-biphenyl] -3-carboxylate
  • 3-acetamidophenylboronic acid 51 mg, 0.29 mmol
  • afforded the title compound 47 mg, 46%>) as a beige solid by the application ofthe general procedure J described above.
  • Step 2 Lithium 3 '-(acetylamino)-4-(2-naphthoylamino) [1 , 1 '-biphenyl] -3-carboxylate
  • Use of methyl 3 '-(acetylamino)-4-(2-naphthoylamino) [1,1 '-biphenyl] -3 - carboxylate afforded the title compound (39 mg, 100%) as a yellow solid by the application ofthe general procedure G described above.
  • MS m/z (M-l) 423 MS m/z (M-l) 423.
  • Step 1 Methyl 3 '-(ltydroxymethyl)-4-(2-naphthoylamino)[l, 1 '-biphenyl] -3-carboxylate
  • 3-(hydroxymethyl)phenylboronic acid 44 mg, 0.29 mmol
  • afforded the title compound 39 mg, 41%) as a beige solid by the application ofthe general procedure
  • Step 1 6-(3-Acetamideophenyl)-2-[4-(trifl oromethyl)phenyl] -1 , 3-benzoxazine-4-one
  • Step 2 Lithium 3'-(acetylamino)-4-[[4-(trifluoromethyl)benzoyl]amino ⁇ [l,l '-biphenyl]-3- carboxylate
  • Step 1 6-[3-Hydroxymethyl)phenyl] -2-[4-(trifluoromethyl)phenyl] -1 , 3-benzoxazin-4-one
  • Use of methyl 5-iodo-2-[(4-(trifluoromethyl)benzoyl)amino]benzoate (100 mg, 0.22 mmol) and 3-(hydroxymethyl)phenylboronic acid (42 mg, 0.28 mmol) afforded the title compound (86 mg, 98%) as a white solid by the application ofthe general procedure Jdescribed above.
  • Step 2 Lithium 3'-(hydroxymeihyl)-4- ⁇ [4-(trifluoromethyl)benzoyl]amino ⁇ [l,l'- biphenyl] -3 -carboxylate
  • Step 3 Lithium 2- ⁇ [3,5-bis(trifluoromethyl)benzoyl]amino ⁇ -5-(8-quinolinyl)benzoate
  • Step 1 Methyl 2- ⁇ [3,5-bis(trifluoromethyl)benzoyl]amino ⁇ -5-(3-formylphenyl)benzoate
  • MS m/z (M-l) 494 MS m/z (M-l) 494.
  • Step 2 Lithium 2- ⁇ [3,5-bis(trifluoromethyl)benzoyl]amino ⁇ -5-(3-formylphenyl)benzoate Use of methyl 2- ⁇ [3,5-bis(trifluoromethyl)benzoyl]amino ⁇ -5-(3-formylphenyl)benzoate afforded the title compound (7 mg, 100%) as a white solid by the application ofthe general procedure G described above. MS m/z (M-l) 480.
  • Step 3 Lithium 2-[(4-methoxybenzoyl)amino]-5-(8-quinolinyl)benzoate
  • Step 2 Methyl 4-[(3, 5-dichlorobenzoyl) amino] [l,l'-biphenyl] -3-carboxylate
  • phenylboronic acid 38 mg, 0.31 mmol
  • afforded the title compound as a colorless solid 28 mg, 28%) by the application ofthe general procedure F described above.
  • Step 3 Lithium 4- [(3, 5-dichlorobenzoyl) amino] [1,1 '-biphenyl) '-3-carboxylate
  • Step 5 Lithium 2-[(4-cyanobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
  • Step 2 Lithium 2-[(2,4-difluorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
  • Step 2 Methyl 2-[(2-chlorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate
  • Step 1 Methyl 2-amino-5-(2-thienylmethoxy)benzoate hydrochloride A solution of tert-butylazodicarboxylate (TMAD) (4.21g, 18.3 mmol) in dry THF
  • Step 3 Lithium 2-[(2-chloro-5-nitrobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
  • Step 2 Methyl 5-[2-(2-aminoethoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate trifluoroacetate
  • Step 4 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [l-methyl-lH-imidazol-4- yl)sulfonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Y Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [l-methyl-lH-imidazol-4- yl)sulfonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[2-(2-pyridinylamino)ethoxy] ethoxy ⁇ benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5- ⁇ 2-[2-(2- pyridinylamino) ethoxy] ethoxy ⁇ benzoate
  • Step 1 Methyl 5-[2-(2- ⁇ [(3-chloro-4-methylphenyl)sulfonyl]amino ⁇ ethoxy)ethoxy]-2-
  • Step 2 Lithium 5-[2-(2- ⁇ [(3-chloro-4-methylphenyl)sulfonyl) ' amino ⁇ ethoxy) ethoxy) '-2- [(2, 4-dichlorobenzoyl) amino] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2- ⁇ 2-[(3- pyridinylsulfonyl)amino]ethoxy ⁇ ethoxy)benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2- ⁇ 2-[(3-pyridinylsulfonyl)amino] ethoxy ⁇ ethoxy)benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [(2,4- difluoroanilino)carbonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [(2,4- difluoroanilino)carbonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [(4- fluoroanilino)carbonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Step 2 Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [(4 ⁇ fluoroanilino)carbonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Step 1 Methyl 2-[(2,4-dichlorobenzoyl)amino] -5-[2-(2- ⁇ [(4- isopropylanilino)carbonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • 4-isopropylphenyl isocyanate 34 mg, 0.21 mmol afforded the title compound (24 mg, 20%) by the application ofthe general procedure X described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- ⁇ [(4- isopropylanilino)carbonyl] amino ⁇ ethoxy) ethoxy] benzoate
  • Step 1 Methyl 2- [(2, 4-dichlorobenzoyl) amino] -5 -[2-(methylsulfanyl)ethoxy] benzoate
  • 2-(methylsulfanyl)ethanol afforded the title compound (8 mg, 4%), as a white solid, by the application ofthe general procedure A described above.
  • Step 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(methylsulfanyl)ethoxy] benzoate
  • Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2- (methylsulfanyl)ethoxy]benzoate afforded the title compound (4.4 mg, 100%) as a white solid by the application ofthe general procedure B described above.
  • the compounds of formula I exhibit EC50 values on PPAR ⁇ and PPAR ⁇ in the range of 1-35 ⁇ M and 0.3-50 ⁇ M, respectively.
  • Crude extracts were prepared from E. coli (BL21(DE3)pLysS, Novagen) producing GST-PPAR ⁇ LBD or GST-PPAR ⁇ LBD fusion proteins by freeze thawing in buffer containing 50 mM Tris-HCl pH 7.9, 250 mM KC1, 10% glycerol, 1% Triton X-100, 10 mM DTT, lmM PMSF, 10 ⁇ g/mL DNase and 10 mM MgCl.
  • Competitive ligand binding assays were performed on immobilized GST-PPAR ⁇ LBD or GST-PPAR ⁇ LBD fusion proteins from crude extracts incubated with glutathione-Sepharose 4B (Amersham Pharmacia Biotech).
  • the slu ⁇ y was washed three times in binding buffer containing 50 mM Tris-HCL, pH7.9, 50 mM KC1, 0.1% Triton-XlOO, 10 mM DTT, 2 mM EDTA, dispensed in 96-well filter plates (MHVB N45, Millipore) and incubated with a fixed amount tritiated ligand and different concentrations of cold competing ligands. Equilibrium binding was reached after incubation for 2 hours at room temperature on a plate shaker.
  • the compounds of formula I exhibit K j values on PPAR ⁇ and PPAR ⁇ in the range of 1-70 ⁇ M and 0.3-35 ⁇ M, respectively.
  • Selected compounds of formula I were tested in animal models of relevance for measuring PPAR ⁇ efficacy.
  • the animal model used was ob/ob mouse and as a reference compound the known PPAR ⁇ ligand, rosiglitazone.
  • the animals were orally treated during 7 days and parameters as food intake, body weight, plasma glucose, insulin, cholesterol, triglycerides and free fatty acids were monitored.
  • Compounds of formula I were shown to give dose related pharmacological effects.
  • PPAR ⁇ ligand binding domain (LBD) has previously been described in literature (Nolte, R. T. et al. (1998) Nature 395: 137-143; Uppenberg, J. et al. (1998) J. Biol. Chem. 273: 31108-31112).
  • the present inventors have determined the structure of human PPAR ⁇ LBD in complex with one ofthe compounds (Example 1) according to the invention. As indicated in Fig. 1, the compound according to Example 1 was shown to be located in the ligand binding pocket of human PPAR ⁇ .
  • the compound was found in an elongated conformation and occupied a region in proximity with, and approximately parallel to, helix 3 (the numbering of helices and strands follow the convention of Uppenberg et al. supra) and in proximity to beta-strand 3 and helices 5 and 2b.
  • the interactions between the compound (ligand) according to the invention and human PPAR ⁇ can be separated into four categories: (1) Interaction between the dibromo-phenyl moiety ofthe ligand and the predominantly hydrophobic pocket of human PPAR ⁇ , in particular the side chains of Ile326, Met329, Leu330, Leu333, Ala292 and Arg288.
  • the compounds according to the invention bind in a novel binding mode. These compounds modulate the activity of PPARs in a range of agonistic effects determined in a cell based reporter assay.

Abstract

The present invention relates to 2-(benzoylamino)benzoic acid derivatives of the formula (I), wherein the variants Ar, X and R are described in the specification. The said compounds modulate the activity of peroxisome proliferator-activated receptors (PPAR) α and/or γ, and are predicted to be useful in the treatment of metabolic diseases, e.g. type II diabetes.

Description

NEW COMPOUNDS
TECHNICAL FIELD
The present invention relates to novel compounds which are 2- (benzoylamino)benzoic acids and which modulate the activity of peroxisome proliferator- activated receptors (PPAR) α and/or γ. The said compounds are predicted to be useful in the treatment of metabolic diseases, e.g. type II diabetes.
BACKGROUND ART
In developed societies, chronic diseases such as diabetes, obesity, atherosclerosis and cancer are responsible for most deaths. These ailments have complex causes involving genetic, environmental and nutritional factors. There is evidence that a group of closely related nuclear receptors, called peroxisome proliferator-activated receptors (PPARs), may be involved in these diseases. This, together with the fact that PPAR activity can be modulated by drugs such as thiazolidinediones and fibrates, has instigated a huge research effort into PPARs. For reviews on PPARs and their medical significance, see e.g. Kersten, S. et al. (2000) Nature 405:421-424; Willson, T.M. et al. (2000) J. Med. Chem. 43:527-550; Vamecq, J. et al. (1999) Lancet 354:141-148.
The PPARs were first cloned as the nuclear receptors that mediate the effects of synthetic compounds called peroxisome proliferators on gene transcription. It soon became clear that eicosanoids and fatty acids can also regulate gene transcription through PPARs. At the molecular level, PPARs act in a similar manner to other nuclear hormone receptors. First, they bind a specific element in the promoter region of target genes. PPAR and some other nuclear hormone receptors bind the promoter only as a heterodimer with the receptor for 9- cis retinoic acid, RXR (retinoid X receptor). Second, they activate transcription in response to binding ofthe hormone (ligand). For the PPAR:RXR heterodimer, binding ofthe ligand of either receptor can activate the complex, but binding of both ligands simultaneously is more potent. Three PPAR isotypes have been identified: α, β (also called δ and NUC1) and γ. PPARα (GenBank Accession No. NM_005036) is expressed most in brown adipose tissue and liver, then kidney, heart and skeletal muscle. PPARγ (GenBank Accession No. NM_005037) is mainly expressed in adipose tissue, and to a lesser extent in colon, the immune system and the retina. PPARβ is found in many tissues but the highest expression is in the gut, kidney and heart.
PPARs are ligand-dependent transcription factors: activation of target gene transcription depends on the binding ofthe ligand to the receptor. Some ligands are shared by the three isotypes, such as polyunsaturated fatty acids and probably oxidized fatty acids.
There are two varieties of diabetes. Type I is insulin-dependent diabetes mellitus (IDDM), for which insulin injection is required; it was formerly referred to as juvenile onset diabetes, i this type, insulin is not secreted by the pancreas and hence must be taken by injection. Type II, non-insulin-dependent diabetes mellitus (NIDDM) may be controlled by dietary restriction. It derives from insufficient pancreatic insulin secretion and tissue resistance to secreted insulin, which is complicated by subtle changes in the secretion of insulin by the beta cells. Despite their former classifications as juvenile or adult, either type can occur at any age; NIDDM, however, is the most common type, accounting for 90 percent of all diabetes.
While the exact causes of diabetes remain obscure, it is evident that NTDDM is linked to heredity and obesity. NIDDM is almost invariably accompanied by dyslipidemia, characterized by elevated triglycerides (TGs), VLDL-C and increased small dense LDL-C in combination with decreased levels of HDL-C and prolonged postprandial hyperlipidemia. This form of dyslipidemia is highly atherogenic and thus represents a major risk factor for the development of premature atherosclerosis and coronary artery disease (CAD), which is the major cause of mortality in diabetic patients. A direct correlation between low HDL levels and incidence of CAD has been identified. In addition, this pathological lipid profile or "lipotoxicity" is suggested to contribute to β- cell failure and as a consequence impaired glucose stimulated insulin release. Pharmacological, genetic and biochemical studies have unequivocally established that PPARα and PPARγ are key sensors and transcriptional modulators of lipid and glucose homeostasis, respectively. Accordingly, a selective "dual action drug" that selectively binds and activates PPARα and γ is hypothesized to mechanistically target the two major metabolic abnormalities observed in type II diabetic patients and thus therapeutically intervene with insulin resistance, CAD and possibly also impaired insulin secretion or β-cell failure.
Murakami et al. (1998) Diabetes 47: 1841-1847, discloses a thiazolidinedione derivative which activated both PPARα and PPARγ, and restored reduced lipid oxidation, when administered to obese rats. It was suggested that PPARα agonism has a protective effect against abnormal lipid metabolism in liver of obese rats. Agents modulating both PPARα and PPARγ are also disclosed in Shibata, T. et al. (1999) Eur. J. Pharmacol. 364: 211-219; and in WO 99/19313.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 shows the structure ofthe ligand-binding domain of human PPARγ, in complex with the compound according to Example 1 ofthe invention.
DISCLOSURE OF THE INVENTION
It has surprisingly been found that compounds ofthe general formula I, which are substituted derivatives of 2-(benzoylamino)benzoic acid, exhibits activity as modulators of peroxisome proliferator-activated receptors (PPAR) α and γ (PPAR modulators). The term "PPAR modulator" is intended to mean a PPAR ligand that is capable of acting as an activator (agonist), or alternatively as an inhibitor (antagonist), in PPAR mediated transcriptional responses. Consequently, in a first aspect this invention provides a compound ofthe formula I
Figure imgf000005_0001
harmaceutically acceptable salt or a prodrug form thereof, wherein
Ar is aryl, which is optionally substituted in one or more positions by halogen, cyano, nitro,
Ci-6 alkyl, , {
Cj.6 alkoxy,
Cι_6 alkylthio fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, allyloxy, aryloxy, or arylthio;
X is a bond, or a heteroalkyl chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms, or a formula
Figure imgf000006_0001
wherein m is 0, 1, or 2, n is O, 1, 2, or 3, and
Y is a bond, O, S, NH, NHSO2, NHC(O)NH, or CH=CH; and
R is a CrCβ-alkyl or an optionally substituted aryl or heteroaryl group,
provided that
when X is a bond, or the formula
Figure imgf000006_0002
, then R is an optionally substituted aryl or heteroaryl group; and when X is a heteroalkyl chain comprising from 1 to 4 carbon atoms and from
1 to 4 heteroatoms, then R is a Cι-C6-alkyl or an optionally substituted aryl or heteroaryl group, with the proviso that when X is a bond, then R is not a Cι-C6-alkyl; or said compound is not a dibenzoyl-bisanthranilic acid, or
(4,4'-bis [( 1 -naphthalenylcarbonyl) amino] -[1,1 '-Biphenyl] -3 ,3 '-dicarboxylic acid.
Preferred compounds ofthe formula I include those wherein:
Ar is phenyl or naphthyl, optionally substituted in one or more positions independently by halogen, nitro, cyano, methoxy, or trifluoromethyl.
X is a bond;
O-(CH2)n wherein n is an integer 0 to 3, e.g. O, O-CH2, or O-(CH2)2; O-(CH2)n-Y, wherein n is an integer 0 to 3, and Y is an atom selected from O, N and S, e.g. O-(CH2)2-O, or O-(CH2)2-S;
0-(CH2)2-O-(CH2)2-NH; O-(CH2)2-O-(CH2)2-NHSO2; or O-(CH2)2-O-(CH2)2-NHCONH.
R is methyl or selected from the group consisting of, optionally substituted, phenyl, naphthyl, thienyl, pyridinyl, quinoxalinyl, benzoylphenyl, thiazolyl, furyl, imidazolyl, oxazolyl, pyrazinyl, quinolinyl, indolyl, benzofuran, benzothiophenyl (benzothienyl), pyrimidinyl, benzodioxolyl, with the proviso that when X is a bond then R is not methyl
When R is an aryl or heteroaryl, it is independently substituted in one or more positions with
Cι_6-alkyl,
Cι_6-alkoxy,
C^.g-alkylthio, Cι_6-acyl, cyano, nitro, hydroxy, methylhydroxy, carboxy, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, halogen, formyl, amino,
Cι_6-alkylamino, di(Cι_6-alkyl)amino or C^-acylamino, aryl, aryloxy, arylthio,
C i .6-alkylsulphonyl, C _6-allyloxy, benzyloxy, benzoyl.
ticular, R can be independently substituted in one or more positions with methyl, ethyl, isopropyl, methoxy, thiomethoxy ethoxy, methylsulfonyl, formyl, acetyl, nitro, cyano, methylhydroxy, methylamino, carboxy, trifluoromethyl, trifluoromethoxy, chloro, fluoro, bromo, iodo, benzyloxy, amino, dimethylamino, acetylamino, phenyl, phenoxy, or benzoyl. The following compounds are especially preferred:
2-[(2,4-dichlorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(3-pyridinylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate,
5-[2-(3-chlorophenyl)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[(4-ethoxybenzyl)oxy]benzoate, 2-[(2,4-dichlorobenzoyl)arnino]-5-{[3-(dimethylamino)benzyl] oxyjbenzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methylphenyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(l-naphthyl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyridinylmethoxy)benzoate, 2- [(2,4-dichlorobenzoyl)amino] -5 -(2- { [2-(methylsulfanyl)-3 - pyridinyl]oxy} ethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-pyridinyloxy)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-quinoxalinyloxy)ethoxy]benzoate,
2- [(2,4-dichlorobenzoyl)amino] -5 - {2- [2-(methylsulfanyl)phenoxy] ethoxy}benzoate,
5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2,3,6-trifluorophenoxy)ethoxy]benzoate,
5-[2-([l, -biphenyl]-3-yloxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(phenylsulfanyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(4-methyl-l,3-thiazol-5-yl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(3-furylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-thienyl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH-imidazol-l- yl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-(3-thienylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-pyridinylsulfanyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-thiazol-4- yl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4- yl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-ethyl-2-pyridinyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methoxyphenoxy)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(4-pyridinylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[3-(3-pyridinyl)propoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-pyridinyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methoxyphenyl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[(5-nitro-2-pyridinyl)oxy]benzoate, 2-[(2,4-dichloroberιzoyl)amino]-5-{[5-(trifluoromethyl)-2-pyridinyl]oxy}benzoate, 5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyrimidinyloxy)benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-{[(2E)-3-phenyl-2-propenyl]oxy}benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[(3-methoxybenzyl)oxy]benzoate,
2-[(2, 4-dichlorobenzoyl)amino]-5-(3-thienyl)benzoate,
2-[(2, 4-dichlorobenzoyl)amino]-5-(2, 4-dichlorophenyl)benzoate, 2-[(2, 4-dichlorobenzoyl)amino]-5-(4-ethylphenyl)benzoic acid,
2-[(2,4-dichlorobenzoyl)amino]-5-(8-quinolinyl)benzoic acid, 5-(l,3-benzodioxol-5-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid, 2-[(2,4-dichlorobenzoyl)amino]-5-(2,4-dimethoxy-5-pyrimidinyl)benzoic acid, 3'-(acetylamino)-4-[(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl]-3-carboxylic acid, 4- [(2,4-dichlorobenzoyl)amino] -3 '-(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxylic acid,
4-[(2,4-dichlorobenzoyl)amino]-3'-ethoxy[l,r-biphenyl]-3-carboxylic acid, 5-(l -benzofuran-2-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid, 4-[(2,4-dichlorobenzoyl)amino]-3'-(hydroxymethyl)[l, -biphenyl]-3-carboxylic acid,
4-[(2,4-dichlorobenzoyl)amino]-3'-formyl[l,r-biphenyl]-3-carboxylic acid, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-naphthyl)benzoic acid, 4-[(2,4-dichlorobenzoyl)amino]-3'-isopropyl-6'-methoxy[l , 1 '-biphenyl]-3- carboxylic acid, 4-[(2,4-dichlorobenzoyl)amino]-4'-fluoro[l,r-biphenyl]-3-carboxylic acid,
2-[(2,4-dichlorobenzoyl)arnino]-5-(2-furyl)benzoate, 5-(l-benzothien-3-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-formyl-3-thienyl)benzoate, 5-(5-acetyl-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(lH-indol-5-yl)benzoic acid, 5-(3-carboxyphenyl)-2-[(2,4-dichlorobenzoyl)aniino]benzoic acid, 2'-(benzyloxy)-4-[(2,4-dichlorobenzoyl)amino][l,r-biphenyl]-3-carboxylate, 4-[(2,4-dichlorobenzoyl)amino] [1 , 1 '-biphenyl] -3 -carboxylate, 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l,r-biphenyl]-3-carboxylate,
4-[(2,4-dichlorobenzoyl)amino]-3'-(trifluoromethyl)[l, -biphenyl]-3-carboxylate, 5-(5-chloro-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate, 4-[(2,4-dichlorobenzoyl)amino]-4'-phenoxy[l, -biphenyl]-3-carboxylate, 4-[(2,4-dichlorobenzoyl)amino]-2',5'-dimethoxy[l,r-biphenyl]-3-carboxylate, 3'-(ammomethyl)-4-[(2,4-dichlorobenzoyl)amino][l,r-biphenyl]-3-carboxylic acid,
2-(2-naphthoylamino)-5-(3-thienyl)benzoate, 3 '-(acetylamino)-4-(2-naphthoylamino) [1,1 '-biphenyl] -3 -carboxylate 3 '-(hydroxymethyl)-4-(2-naphthoylamino) [1,1 '-biphenyl] -3 -carboxylate, 5-(3-thienyl)-2-{[4-(trifluoromethyl)benzoyl]amino}benzoate, 3 '-(acetylamino)-4- { [4-(trifluoromethyl)benzoyl] amino } [ 1 , 1 '-biphenyl] -3 - carboxylate,
3 '-(hydroxymethyl)-4- { [4-(trifluoromethyl)benzoyl] amino } [ 1 , 1 '-biphenyl] -3 - carboxylate, 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-5-(8-quinolinyl)benzoate, 4- { [3 , 5 -bis(trifluoromethyl)benzoyl] amino } -3 '-formyl[ 1 , 1 '-biphenyl] -3 -carboxylate,
2-[(4-methoxybenzoyl)amino]-5-(8-quinolinyl)benzoate, 4-[(3,5-dichlorobenzoyl)amino] [1,1 '-biphenyl] -3 -carboxylate, 2-[(4-cyanobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, 2-[(2,4-difluorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, 2-[(2-chlorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate,
2-[(2-chloro-5-nitrobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, or 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(methylsulfanyl)ethoxy]benzoate.
Definitions
The term "C^g alkyl" denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said C _ alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl. The term "Cj.g alkoxy" denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms. Examples of said C g alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
The term "halogen" shall mean fluorine, chlorine, bromine or iodine.
The term "aryl" denotes aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms. Examples of said aryl include phenyl, indenyl and naphthyl.
The term "heteroaryl" denotes a mono- or bicyclic ring system (only one ring need to be aromatic, and substitution may be in any ring) having from 5 to 10 ring atoms (which are carbon atoms), in which one or more ofthe carbon ring atoms are other than carbon, such as nitrogen, oxygen, selenium, and sulfur. Examples of said heteroaryl include pyrrole, thiazole, imidazole, thiophene, furan, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, quinazolineindole, indole, isoindole, isoindoline, indoline, benzothiophene, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2, 1 ,3 -benzothiadiazole, 2,1 ,3-benzoselenadiazole, benzimidazole, indazole, 2,3-dihydro-l,4-benzodioxine, indane, 1,3-benzodioxole, 3,4-dihydro-2H-l,4- benzoxazine, 1,5-naphtyridine, 1,8-naphtyridine, 1,5-naphthyridine, and 1,8- naphthyridine.
The term "heteroalkyl chain" denotes a straight or branched, saturated or unsaturated, chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of O, N, and S. The heteroatom(s) may be placed at any position ofthe heteroalkyl group.
Depending on the process conditions the end products ofthe Formula I are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope ofthe invention group (e.g., lithium, sodium, potassium salts, hydrochloride, hydrobromide, and the like). All diastereomeric forms possible (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope ofthe invention.
Therapeutic or prophylactic treatment of mammals, including man, for conditions where modulation of either PPARα or PPARγ activity, or the combination of both PPARα and PPARγ activities, is of therapeutic benefit. Such conditions could be e.g. diabetes, diabetes mellitus type 2, insulin resistance, impaired glucose tolerance and / or in combinations with dyslipidemias, obesity, atherosclerosis, coronary artery disease, PCOS, gestational diabetes, inflammation.
The compounds according to the invention are particularly useful for the treatment of type II diabetes, in combination(s) with dyslipidemias, obesity, atherosclerosis and coronary artery disease. For this purpose the compounds according to the invention can be used alone or in combinations) with sulfonylureas, metformin, alpha-glycosidase inhibitors, insulin or other anti-diabetic treatments/agents. Reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
For clinical use, the compounds ofthe invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients. The formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc.
The formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner. The typical daily dose ofthe active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient and the route of administration. The compounds according to the invention may also be administered as prodrugs that may be converted to the active ingredient in question after metabolic transformation in vivo. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985.
This invention also relates to a method of treatment or prevention of diabetes. The method includes administering to a subject (e.g., a human, a mammal, a horse, a dog, or a cat) in need thereof an effective amount of one or more compounds ofthe formula I :
Figure imgf000014_0001
or a pharmaceutically acceptable salt or a prodrug form thereof, wherein
Ar is aryl, which is optionally substituted in one or more positions by halogen, cyano, nitro,
Cι_6 alkyl, Cι_6 alkoxy,
Cι_6 alkylthio fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio , allyloxy, aryloxy, or arylthio;
X is a bond, or a heteroalkyl chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms, or a formula
■0-(CH2)n— Y—
Jm wherein m is 0, 1, or 2, n is 0, 1, 2, or 3, and
Y is a bond, O, S, NH, NHSO2, NHC(O)NH, or CH=CH; and
R is Cι-C6-alkyl or an optionally substituted aryl or heteroaryl group.
The methods delineated herein can also include the step of identifying that the subj ect is in need of treatment of diabetes.
Also within the scope of this invention is a method for modulating (e.g., stimulating or inhibiting) peroxisome proliferator-activated receptors activities. The method includes contacting the receptors with an effective stimulatory or inhibitory amount of a compound ofthe formula I.
"An effective amount" refers to an amount of a compound which confers a therapeutic effect on the treated subject. The therapeutic effect maybe objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). The dose level and frequency of dosage ofthe specific compound will vary depending on a variety of factors including the potency ofthe specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity ofthe condition to be treated, and the patient undergoing therapy. The daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
Processes for preparation
In a further aspect the invention provides a process for the preparation of a compound as defined above. The compounds according to the invention can be prepared by, or in analogy with, standard synthetic methods, and especially according to, or in analogy with, the following methods.
Method 1
Compounds of formula (I) in which X is oxygen can be prepared beginning with commercially available 2-amino-5-hydroxybenzoic acid (i) as shown in Scheme 1. The corresponding methyl ester (ii) is formed by treatment with sulfuric acid and methanol and is subsequently coupled with a benzoyl chloride or a heteroarylcarbonyl chloride
(commercially available or prepared from the corresponding carboxylic acid using thionyl chloride or oxalyl chloride) to provide the amide (iii). Reaction of (iii) with an alcohol in the presence of diethyl azodicarboxylate (DEAD) or l,l'-azobis(NN- dimethylformamide) (TMAD; cf. Tetrahedron Lett.1995, vol. 36: 3789-3792) and triphenylphosphine or polymer supported triphenylphosphine in a solvent such as dichloromethane and/or tetrahydrofuran (Mitsunobu reaction; see Org. React. 1992, vol. 42: 335-656) gives the adduct (iv). Ester hydrolysis, using IM lithium hydroxide, affords the target compounds (v) as lithium salts.
Scheme 1
Figure imgf000017_0001
(iv) (v)
Method 2
Other compounds ofthe present invention can be prepared as shown in Scheme 2. The Mitsunobu reaction can also be performed on the intermediate (ii), i.e. before the amide coupling, to form the adduct (vi). Subsequent amide coupling and ester hydrolysis afford the target compounds (v).
Scheme 2
Figure imgf000017_0002
(v)
Method 3 Compounds of formula (I) in which X = C0 and R is an aryl or heteroaryl substituent can be prepared as outlined in Scheme 3. Treatment ofthe commercially available 2-amino-5-iodobenzoic acid (vii) with trichloromethyl chloroformate in solvents such as dioxane gives the isatoic anhydride (viii) which can be further reacted with methanol and a base such as potassium carbonate to form the methyl ester (ix). Subsequent coupling with a benzoyl chloride or a heteroarylcarbonyl chloride (commercially available or prepared from the corresponding carboxylic acid using thionyl chloride or oxalyl chloride) provides amide (x). Palladium-catalyzed cross-coupling of (x) with an aryl or heteroaryl boronic acid (Suzuki coupling; see Chem. Rev. 1995, 95, 2457- 2483) gives biaryl (xii) or a mixture of (xii) and the bicycle (xi). Subsequent ester hydrolysis using IM lithium hydroxide solution affords the target compounds (xiii).
Scheme 3
CLCOCOCI
Figure imgf000018_0002
Dioxane
Figure imgf000018_0001
(vii) (viϋ) (ix)
Figure imgf000018_0003
(xii)
Method 4 Other compounds ofthe present invention can be prepared as shown in Scheme 4.
The intermediate (iii) can be reacted with nitrogen containing heterocycles to form diaryl ethers (xiv), which can be hydrolyzed as described earlier to afford compounds (xv). Scheme 4
Figure imgf000019_0001
(iii) (xiv) (XV)
Method 5
Other compounds ofthe present invention can be prepared as shown in Scheme 5. Intermediate (iii) can be reacted with benzylic (or aliphatic) bromides to form compounds (xvi), which can be hydrolyzed as described earlier to afford compounds (xvii).
Scheme 5
Figure imgf000019_0002
(iϋ) (xvi) (xvii)
The chemicals used in the above-described synthetic routes may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents. The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis ofthe compounds of Formula (I). In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2n Ed., John Wiley and Sons (1991); L. Fieser and M.
Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
The invention will now be further illustrated by the following non-limiting examples. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety.
EXAMPLES
The structures ofthe prepared compounds were confirmed by standard spectroscopical methods. The NMR data was obtained on a Jeol JNM-EX 270 or a Bruker DRX 500 spectrometer. Electrospray MS data was obtained on a Micromass platform LCMS spectrometer. Melting points, when given, were obtained on a Electrothermal IA9000 melting point apparatus, and are uncorrected.
EXAMPLE 1
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
Step 1: Methyl 2-amino-5-hydroxybenzoate
Figure imgf000020_0001
To a stirred suspension of 2-amino-5-hydroxybenzoic acid (15 g, 98 mmol) in methanol (100 ml) was added sulfuric acid (95%, 15 ml) at room temperature. The solution was stirred at 90°C for 3.5 hours after which it was allowed to reach room temperature and carefully poured into saturated sodium bicarbonate. Subsequent extraction with chloroform (3 x 300 ml), drying ofthe organic phase using magnesium sulfate and concentration in vacuo gave the title compound (15 g, 80%) as a dark solid. mp: 154-155°C; 1H NMR (DMSO) δ 8.66 (s, IH), 7.09 (d, J = 2.72 Hz IH), 6.82-6.76 (m, IH), 6.66-6.60 (m, IH), 6.07 (br s, 2H), 3.75 (s, 3H); 13C NMR (DMSO) δ 167.7, 146.6, 144.8, 123.6, 117.9, 114.4, 108.8, 51,4; MS m/z 168 (M+1). Step 2: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-hydroxybenzoate
Figure imgf000021_0001
To a stirred mixture of methyl 2-amino-5-hydroxybenzoate (10 g, 60 mmol) pyridine (80 ml) and molecular sieves (4A), 2,4-dichlorobenzoyl chloride (7.6 ml, 54 mmol) in pyridine (3 ml) was added slowly at 0°C. The mixture was allowed to reach room temperature and then stirred over night. After addition of chloroform, the mixture was filtered and the filtrate washed with IM hydrochloric acid (3 x 150 ml) and brine, dried with magnesium sulfate and concentrated in vacuo. The residue was re-crystallized from chloroform to give the title compound (4 g, 20%) as a grey solid, mp: 181-182°C; 1H NMR (DMSO) δ 10.64 (s, IH), 9.81 (s, IH), 7.92-7.55 (m, 4H), 7.29 (d, J = 2.73 Hz IH), 7.08-7.02 (m, IH), 3.79 (m, 3H); MS m/z 338 (M-l).
Step 3: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate General procedure A
Figure imgf000021_0002
TMAD (183 mg, 1.06 mmol) was added to a suspension of methyl 2-[(2,4- dichlorobenzoyl)amino]-5-hydroxybenzoate (240 mg, 0.71 mmol; prepared in Example XX), polymer bound triphenylphosphine (480 mg, 1.4 mmol) and thiophene-2 -methanol (73 μl, 0.78 mmol) in anhydrous THF (3 ml) and DCM (3 ml). The suspension was shaken at room temperature over night and filtered through a plug of Celite. The filtrate was concentrated in vacuo and the residue purified by chromatography on silica gel eluting with CHCI3 to give the title compound (130 mg, 42%) as an yellow oil. 1H NMR (CDCI3) δ 11.31 (s, IH), 8.79 (d, J= 9.40 Hz IH), 7.67-7.57 (m, 2H), 7.47 (d, J= 1.98 Hz IH), 7.35-7.30 (m, 2H), 7.27-7.21 (m, IH), 7.12-7.09 (m, IH), 7.02-6.97 (m, IH), 5.23 (s, IH), 3.89 (s, 3H); 13C NMR (CDCI3) δ 168.3, 164.1, 153.7, 138.7, 136.9, 135.2, 134.7, 132.3, 130.5, 130.4, 127.6, 127.2, 127.0, 126.6, 122.2, 122.0, 116.6, 166.6, 65.5, 52.7
Step 4: Lithium 2-f(2,4-dichlorobenzoyl)aminoJ-5-(2-thienylmethoxy)benzoate General procedure B
Figure imgf000022_0001
Lithium hydroxide (1 M solution, 298 μl) was added at room temperature to a stirred solution of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate (130 mg, 0.30 mmol) in THF (2 ml). The mixture was stirred over night and then concentrated in vacuo, re-dissolved in methanol and concentrated again. The residue was washed with diethyl ether to give the title compound (120 mg, 94%) as an yellow solid, mp: 165-168°C; 1H NMR (CD3OD) δ 8.56 (d, J = 8.91 Hz IH), 7.75 (d, J = 2.97 Hz IH), 7.66-7.56 (m, 2H), 7.47-7.37 (m, 2H), 7.17-7.13 (m, IH), 7.08 (dd, J = 9.16, 3.22 Hz IH), 7.02-6.97 (m, IH), 5.27 (s, 2H); ,3C NMR (CD3OD) δ 172.5, 164.4, 154.1,
139.6, 136.2, 135.6, 133.6, 132.1, 129.9, 127.4, 126.7, 126.3, 125.9, 125.6, 120.6, 118.0, 116.9, 64.9; MS m/z 420 (M-l).
EXAMPLE 2 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(3-pyridinyImethoxy)benzoate
Figure imgf000023_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(3-pyridinylmethoxy)benzoate
Use of pyridine-3 -methanol afforded the title compound (227 mg, 75%) as a white solid by the application ofthe general procedure A described above. 1H NMR (CDCI3) δ 11.27 (s, IH), 8.75 (d, J = 9.40 Hz IH), 8.65 (d, J = 1.73 Hz IH), 8.55 (dd, J = 1.73, 4.70 Hz IH), 7.76-7.70 (m, IH), 7.61-7.53 (m, 2H), 7.42-7.40 (m, IH), 7.31-7.16 (m, 3H), 5.05 (s, 2H), 3.85 (s, 3H); 13C NMR (CDCI3) δ 168.1, 164.1, 153.7, 149.7, 149.1, 136.9, 135.4, 135.2, 134.6, 132.3, 132.1, 130.5, 127.6, 123.6, 122.3, 121.7, 116.7, 116.1, 68.1, 52.7.
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(3-pyridinylmethoxy)benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(3-pyridinylmethoxy)benzoate afforded the title compound (227 mg, 75%) as a solid by the application ofthe general procedure B described in Example 1. 1H NMR (CD3OD) δ 8.66-8.46 (m, 3H), 7.98-7.92 (m, IH), 7.77 (d, J = 2.97 Hz IH), 7.65-7.55 (m, 2H), 7.49-7.40 (m, 2H), 7.11 (dd, J = 9.16, 3.21 Hz IH), 5.17 (s, 2H); 13C NMR (CD3OD) δ 172.4, 164.4, 154.1, 148.2, 148.0, 136.4, 136.2, 135.6, 134.0, 133.8, 132.1, 129.9, 129.8, 127.4, 125.7, 124.0, 120.7, 117.8, 116.7, 67.3; MS m/z 415 (M-l).
EXAMPLE 3
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate
Figure imgf000023_0002
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate Use of 2-(3-thienyl)ethanol afforded the title compound (370 mg, 93%) as an oil by the application ofthe general procedure A described above. 1H NMR (CDC13) δ 11.31 (s, IH), 8.78 (d, J = 9.15 Hz IH), 7.62-7.53 (m, 2H), 7.45 (d, J = 1.98 Hz IH), 7.34-7.25 (m, 2H), 7.19-7.13 (dd, J= 9.16, 3.21 Hz IH), 7.10-7.07 (m, IH), 7.05-7.01 (m, IH), 4.17 (t, J = 6.92 Hz 2H), 3.87 (s, 3H), 3.12 (t, J = 6.93 Hz); 13C NMR (CDCI3) δ 168.3, 164.1, 154.3, 138.3, 136.9, 134.8, 132.4, 130.5, 130.4, 128.5, 127.6, 125.8, 122.3, 121.8, 121.6, 116.6, 115.7, 68.6, 52.7, 30.3.
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate afforded the title compound (260 mg, 95%) as a white solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) δ 8.55 (d, J = 8.91 Hz IH), 7.69-7.55 (m, 3H), 7.43 (dd, j = 8.16, 1.97 Hz IH), 7.34-7.29 (m, IH), 7.18-7.15 (m, IH), 7.09-6.98 (m, 2H), 4.20 (t, j = 6.68 Hz 2H), 3.09 (t, J = 6.68 Hz 2H); 13C NMR (CD3OD) δ 172.7, 164.3, 154.6, 138.8, 136.1, 135.7, 133.2, 132.1, 129.8, 128.2, 127.4, 125.6, 125.0, 121.1, 120.6, 117.5, 116.3, 68.2, 29.9; MS m/z 434 (M-l).
EXAMPLE 4
Lithium 5-[2-(3-chlorophenyI)ethoxy]-2-[(2,4-dichlorobenzoyI)amino]benzoate
Figure imgf000024_0001
Step 1: Methyl 5-[2-(3-chlorophenyl)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate
Use of 3-chlorophenethyl alcohol afforded the title compound (342 mg, 60%) as a white solid by the application ofthe general procedure A described above. 1H NMR
(CDCI3) δ 11.30 (s, IH), 8.77 (d, J= 9.15 Hz IH), 7.61-7.45 (m, 3H), 7.35-7.12 (m, 7H), 4.17 (t, J= 6.93 Hz 2H), 3.88 (s, 3H), 3.06 (t, J= 6.68 Hz 2H); 13C NMR (CDC13) δ 168..3, 164.1, 154.1, 140.2, 136.9, 134.9, 134.7, 134.3, 132.3, 130.5, 130.4, 129.9, 129.2, 127.6, 127.3, 126.9, 122.3, 121.6, 116.6, 115.7, 68.8, 52.7, 35.5; MS m/z 480 (M+1). Step 2: Lithium 5-[2-(3-chlorophenyl)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate
Use of methyl 5-[2-(3-chlorophenyl)ethoxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate afforded the title compound (100 mg, 91%) as a white solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) δ 8.54 (d, J= 8.91 Hz IH), 7.66-7.55 (m, 3H), 7.46-7.41 (m, IH), 7.35 (br s, IH), 7.29- 7.17 (m, 3H), 7.00 (dd, J= 9.16, 3.22 Hz IH), 4.22 (t, J- 6.68 Hz 2H), 3.07 (t, J= 6.68 Hz 2H); MS m/z 462 (M-l); Anal. (C2 Hι5Cl3LiNO4) C, H, N.
EXAMPLE 5 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(4-ethoxybenzyI)oxy]benzoate
Figure imgf000025_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)aminoJ-5-[(4-ethoxybenzyl)oxyJbenzoate Use of 4-ethoxybenzyl alcohol afforded the title compound (206 mg, 37%) as an yellow solid by the application ofthe general procedure A described above. 1H NMR (CDCI3) ^ 11.30 (s, IH), 8.78 (d, J= 9.15 Hz IH), 7.65-7.57 (m, 2H), 7.47 (d, J= 1.98 Hz IH), 7.37-7.30 (m, 3H), 7.25-7.20 (m, IH), 6.93-6.87 (m, 2H), 4.99 (s, 2H), 4.03 (q, J = 6.93 Hz 2H), 3.89 (s, 3H), 1.41 (t, J= 7.05 Hz 3H); 13C NMR (CDC13) δ 168.4, 164.1, 159.0, 154.3, 136.9, 134.8, 132.3, 130.5, 130.4, 129.4, 128.3, 127.6, 122.2, 121.9, 116.6, 116.3, 114.7, 70.4, 63.6, 52.7, 14.9; MS m/z 474 (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(4-ethoxybenzyl)oxy]benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[(4-ethoxybenzyl)oxy]benzoate afforded the title compound (110 mg, 92%) as an yellow solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) δ 8.54 (d, J= 8.90 Hz IH), 7.74 (d, J= 2.97 Hz IH), 7.66-7.55 (m, 2H), 7.47-7.31 (m, 3H), 7.06 (dd, J= 9.16, 3.22 Hz IH), 6.93-6.86 (m, 2H), 5.01 (s, 2H), 4.06-3.95 (m, 2H), 1.37 (t, J= 6.93 Hz 3H); MS m/z 458 (M-l); Anal. (C23H18Cl2LiNO5) C, H, N. EXAMPLE 6
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-{[3-(dimethyIamino)benzyl] oxy}benzoate
Figure imgf000026_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-{[3- (dimethylamino)benzyl]oxy}benzoate
Use of 3-dimethylbenzyl alcohol afforded the title compound (385 mg, 69%) as an yellow oil by the application ofthe general procedure A described above. 1H NMR (CDC13) 11.31 (s, IH), 8.79 (d, J= 9.16 Hz IH), 7.69-7.58 (m, 2H), 7.48 (d, J= 1.98 Hz IH), 7.37-7.22 (m, 3H), 6.81-6.67 (m, 3H), 5.05 (s, 2H), 3.89 (s, 3H), 2.96 (s, 3H); 13C NMR (CDC13) δ 168.4, 164.1, 154.4, 150.9, 137.3, 136.9, 134.8, 132.3, 130.5, 129.5, 127.6, 122.2, 121.9, 116.6, 116.3, 115.8, 112.4, 111.6, 71.1, 52.7, 40.7; MS m/z All (M- 1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-{[3- (dimethylaminojbenzyljoxyjbenzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-{[3- (dimethylamino)benzyl]oxy}benzoate afforded the title compound (100 mg, 65%) as an yellow solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) δ 8.54 (d, J= 8.90 Hz IH), 7.75 (d, J= 3.21 Hz IH), 7.67-7.56 (m, 2H), 7.47- 7.41 (m, IH), 7.19 (t, J= 7.92 Hz IH), 7.07 (dd, J= 9.15, 3.21 Hz IH), 6.89-6.69 (m, 3H), 5.05 (s, 2H), 2.92 (s, 6H); MS m/z 457 (M-l); Anal. (C23H19Cl2LiN2O4) C, H, N. EXAMPLE 7
Lithium 2-[(2,4-dichIorobenzoyl)amino]-5-[2-(3-methylphenyl)ethoxy]benzoate
Figure imgf000027_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)aminoJ-5-[2-(3-methylphenyl)ethoxy]benzoate
Use of 3-methylphenethyl alcohol afforded the title compound (362 mg, 67%) as an oil by the application ofthe general procedure A described above. 1H NMR (CDCI3) δ 11.32 (s, IH), 8.79 (d, J= 9.15 Hz IH), 7.63-7.54 (m, 2H), 7.48 (d, J= 1.98 Hz IH), 7.36-7.32 (m, IH), 7.27-7.05 (m, 5H), 4.18 (t, J= 7.18 Hz 2H), 3.89 (s, 3H), 3.08 (t, J= 7.18 Hz 2H), 2.36 (s, 3H); 13C NMR (CDCI3) δ 168.4, 164.1, 154.4, 138.3, 137.9, 136.9, 134.7, 132.4, 130.5, 130.4, 129.9, 128.6, 127.6, 127.5, 126.1, 122.2, 121.7, 116.6, 115.6, 69.4, 52.6, 35.8, 21.5; MS m/z 458 (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methylphenyl)ethoxy]benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3- methylphenyl)ethoxy]benzoate afforded the title compound (119 mg, 94%) as a solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) δ 8.53 (d, J= 9.16 Hz IH), 7.67-7.56 (m, 3H), 7.46-7.41 (m, IH), 7.20-6.96 (m, 5H), 4.19 (t, J= 6.93 Hz 2H), 3.03 (t, J= 6.93 Hz 2H), 2.31 (s, 3H); 13C NMR (CD3OD) δ 164.3, 154.7, 138.4, 137.7, 136.1, 135.7, 133.2, 132.1, 129.9, 129.8, 129.4, 128.0, 127.4, 126.7, 125.8, 125.6, 120.6, 117.5, 68.9, 35.4, 20.2; MS m/z 448 (M-l).
EXAMPLE 8
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(l-naphthyl)ethoxy]benzoate
Figure imgf000028_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(l-naphthyl)ethoxy]benzoate
Use of 2-(l-naphthyl)ethanol afforded the title compound (417 mg, 71%) as an yellow oil by the application ofthe general procedure A described above. H NMR (CDC13) δ 11.32 (s, IH), 8.80 (d, J= 9.15 Hz IH), 8.14-8.09 (m, IH), 1.92-1.16 (m, 2H), 7.63-7.43 (m, 7H), 7.36-7.31 (m, IH), 7.21-7.15 (m, IH), 4.32 (t, J= 7.42 Hz 2H), 3.87 (s, 3H), 3.60 (t, J- 7.42 Hz 2H); 13C NMR (CDCI3) δ 168.3, 164.1, 154.3, 136.9, 134.8, 134.0, 130.5, 130.4, 129.0, 127.6, 127.3, 126.3, 125.8, 125.7, 123.6, 122.3, 121.8, 116.6, 115.4, 68.6, 52.6, 32.9; MS m/z 494 (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(l-naphthyl)ethoxy]benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(l-naphthyl)ethoxy]benzoate afforded the title compound (140 mg, 79%) as a white solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) δ 8.53 (d, J= 8.91 Hz IH), 8.16 (d, J= 8.66 Hz IH), 7.89-7.36 (m, 10H), 6.99 (dd, J= 9.15, 3.21 Hz IH), 4.34 (t, J= 6.93 Hz 2H), 3.57 (t, J= 6.93 Hz 2H); MS m/z 478 (M-l).
EXAMPLE 9
Lithium 2-[(2,4-dichIorobenzoyl)amino]-5-(2~pyridinylmethoxy)benzoate
Figure imgf000028_0002
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyridinylmethoxy)benzoate
Use of pyridine-2-methanol afforded the title compound (58 mg, 27%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDCI3) δ 11.31 (s, IH), 8.81 (d, J= 9.42 Hz IH), 8.66-8.60 (m, IH), 7.78-7.68 (m, 2H), 7.62 (d, J = 8.16 Hz IH), 7.55-7.48 (m, 2H), 7.37 (d, J= 8.17 Hz IH), 7.32-7.23 (m, 2H), 5.25 (s, 2H), 3.91 (s, 3H); MS m/z 431 (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyridinylmethoxy)benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyridinylmethoxy)benzoate afforded the title compound (31 mg, 93%) as a white solid by the application ofthe general procedure B described above. 1H NMR (DMSO) δ 14.95 (s, IH), 8.78-6.88 (m, 10H), 5.15 (s, 2H); MS m/z 415 (M-l).
EXAMPLE 10 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-{[2-(methylsulfanyl)-3- pyridinyl] oxy } ethoxy)benzoate
Figure imgf000029_0001
Step 1 : Methyl 2- [(2, 4-dichlorobenzoyl)amino]-5-(2-{[2-(methylsulfanyl)-3- pyridinyl] oxy} ethoxy) benzoate
Use of 2- {[2-(methylsulfanyl)-3-pyridinyl]oxy} ethanol (disclosed in WO
00/76984) afforded the title compound (104 mg, 41%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDCI3) δ 11.29 (s, IH), 8.80 (d, J= 9.42 Hz IH), 8.13 (d, J= 4.71 Hz IH), 7.67-7.61 (m, 2H), 7.52-7.50 (m,
IH), 7.39-7.36 (m, IH), 7.29-7.26 (m, IH), 7.10-7.06 (m, IH), 7.02-6.98 (m, IH), 4.43-
4.36 (m, 4H), 3.90 (s, 3H), 2.53 (s, 3H); MS m/z 507 (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-{[2-(methylsulfanyl)-3- pyridinyl] oxy}ethoxy)benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2- {[2-(methylsulfanyl)-3- pyridinyl]oxy}ethoxy)benzoate afforded the title compound (98 mg, 100%) as a beige solid by the application ofthe general procedure B described above. 1H NMR (DMSO) δ 14.86 (s, IH), 8.50 (d, J= 8.71 Hz IH), 8.08 (d, J= 4.48 Hz IH), 7.76-7.49 (m, 4H), 7.35 (d, J= 7.65 Hz IH), 7.14-6.94 (m, 2H), 4.49-4.22 (m, 4H), 2.41 (s, 3H); MS m/z 491 (M- 1).
EXAMPLE 11
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-pyridinyloxy)ethoxy]benzoate
Figure imgf000030_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-pyridinyloxy)ethoxy]benzoate Use of 2-(3-pyridinyloxy)ethanol (disclosed in WO 00/76984) afforded, the title compound (50 mg, 22%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDC13) δ 11.31 (s, IH), 8.81 (d, J= 9.24 Hz IH), 8.43-8.22 (m, 2H), 7.65-7.58 (m, 2H), 7.48 (d, J= 1.84 Hz IH), 7.37-7.32 (m, IH), 7.29-7.20 (m, 3H), 4.38 (br s, 4H), 3.90 (s, 3H); MS m/z 461 (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-pyridinyloxy)ethoxy]benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3- pyridinyloxy)ethoxy]benzoate afforded the title compound (35 mg, 96%) as a white solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) δ 15.06 (s, IH), 8.48 (d, J= 8.97 Hz IH), 8.35 (d, J= 2.91 Hz IH), 8.18 (dd, J= 4.49, 1.32 Hz IH), 7.72 (d, J= 1.85 Hz IH), 7.64-7.30 (m, 5H), 6.95 (dd, J= 8.98, 3.17 Hz IH), 4.43-4.25 (m, 4H).
EXAMPLE 12
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-quinoxaIinyloxy)ethoxy]benzoate
Figure imgf000031_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-quinoxalinyloxy)ethoxy]benzoate
Use of 2-(2-quinoxalinyloxy)ethanol (previously described in JP 06009622) afforded the title compound (65 mg, 25%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDC13) ^ 11.29 (s, IH), 8.74 (d, J= 9.50 Hz IH), 8.33 (s, IH), 7.93-7.88 (m, IH), 7.68-7.54 (m, 3H), 7.49-7.31 (m, 4H), 7.11- 7.05 (m, IH), 4.68 (t, J- 5.67 Hz 2H), 4.38 (t, J= 5.67 Hz 2H), 3.88 (s, 3H); MS m/z 512 (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-quinoxalinyloxy)ethoxy]benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- quinoxalinyloxy)ethoxy]benzoate afforded the title compound (46 mg, 80%) as a white solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) δ 8.50 (d, J= 8.97 Hz IH), 8.23 (s, IH), 7.91-7.37 (m, 8H), 6.97-6.87 (m, IH), 4.78-4.70 (m, 2H), 4.44-4.37 (m, 2H); MS m/z 498 (M+1).
EXAMPLE 13
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-{2-[2~(methylsulfanyI)phenoxy] ethoxy}benzoate
Figure imgf000031_0002
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-{2-[2-(methylsulfanyl)phenoxy] ethoxyjbenzoate Use of 2-[2-(methylsulfanyl)phenoxy]ethanol (disclosed in WO 00/76984) afforded the title compound (6 mg, 2%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDC13) δ 11.31 (s, IH), 8.79 (d, J= 9.24 Hz IH), 7.65-7.58 (m, 2H), 7.48 (d, J= 1.85 Hz IH), 7.35 (dd, J= 8.18, 2.11 Hz IH), 7.29- 7.22 (m, IH), 7.20-7.10 (m, 2H), 7.03-6.95 (m, IH), 6.93-6.88 (m, IH), 4.40 (s, 4H), 3.90 (s, 3H), 2.42 (s, 3H); MS m/z 506 (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-{2-[2-(methylsulfanyl)phenoxy] ethoxyjbenzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-{2-[2-
(methylsulfanyl)phenoxy]ethoxy} benzoate afforded the title compound (5 mg, 85%) as a white solid by the application ofthe general procedure B described above. MS m/z 490 (M-l).
EXAMPLE 14
Lithium 5-[2-(2-ammophenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate
Figure imgf000032_0001
Step 1: Methyl 5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)ammo]benzoate Use of 2-(2-aminophenoxy)ethanol (disclosed in EP 0881488 and EP 0881225) afforded the title compound (25 mg, 11%), as a white solid, by the application ofthe general procedure A described above. H NMR (CDCI3) δ 11.31 (s, IH), 8.80 (d, J= 9.23 Hz IH), 7.63-7.58 (m, 2H), 7.49 (d, J= 1.85 Hz IH), 7.35 (dd, J= 8.18, 2.11 Hz IH), 7.26-7.20 (m, IH), 6.88-6.68 (m, 4H), 4.36 (s, 4H), 3.90 (s, 3H), 2.83 (br s, 2H); MS m/z 475 (M+1).
Step 2: Lithium 5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of methyl 5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate afforded the title compound (22 mg, 99%) as a beige solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) δ 8.57 (d, J= 8.97 Hz IH), 7.74 (d, J= 3.17 Hz IH), 7.66-7.57 (m, 2H), 7.45 (dd, J= 8.18, 2.11 Hz IH), 7.09 (dd, J= 8.98, 3.17 Hz IH), 6.94-6.88 (m, IH), 6.79-6.65 (m, 3H), 4.41-4.31 (m, 4H); MS m/z 459 (M-l).
EXAMPLE 15
Lithium 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate
Figure imgf000033_0001
Step 1: Methyl 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of [4-(2-hydroxyethoxy)phenyl](phenyl)methanone afforded the title compound (38 mg, 13%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDCI3) δ 11.31 (s, IH), 8.80 (d, J= 9.24 Hz IH), 7.83-7.78 (m, 2H), 7.65-7.55 (m, 3H), 7.52-7.32 (m, 7H), 7.27-7.16 (m, 2H), 4.38 (br s, 4H), 3.89
(s, 3H); MS m/z 564 (M+1).
Step 2: Lithium 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of methyl 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate afforded the title compound (30 mg, 80%) as a white solid by the application ofthe general procedure B described above. 1H NMR (DMSO) δ 15.07 (s, IH), 8.48 (d, J= 8.70 Hz IH), 7.80-7.44 (m, 10H), 7.38-7.25 (m, 3H), 6.94 (dd, J= 8.70, 2.90 Hz IH), 4.42-4.23 (m, 4H); MS m/z 548 (M-l). EXAMPLE 16
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2,3,6- trifluorophenoxy)ethoxy]benzoate
Figure imgf000034_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2,3,6- trifluorophenoxyjethoxyjbenzoate
Use of 2-(2,3,6-trifluorophenoxy)ethanol afforded the title compound (67 mg, 26%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDC13) δ 11.31 (s, IH), 8.80 (d, J= 9.24 Hz IH), 7.63-7.58 (m, 2H), 7.48 (d, J= 2.11 Hz IH), 7.35 (dd, J= 8.31, 1.98 Hz IH), 7.21 (dd, J= 9.24, 3.17 Hz IH), 7.04-6.86 (m, 2H), 4.35 (s, 4H), 3.90 (s, 3H); MS m/z 514 (M+1).
Step 2: Lithium 2- [(2, 4-dichlorobenzoyl)amino]-5-[2-(2, 3, 6- trifluorophenoxyjethoxyjbenzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2,3,6- trifluorophenoxy)ethoxy]benzoate afforded the title compound (55 mg, 83%) as a beige solid by the application ofthe general procedure B described above. 1H NMR (DMSO) δ 15.03 (s, IH), 8.49 (d, J= 8.97 Hz IH), 7.73 (d, J= 2.11 Hz IH), 7.67-7.44 (m, 5H), 6.94
(dd, J= 8.71, 3.17 Hz IH), 4.44-4.23 (m, 4H); MS m/z 498 (M-l).
EXAMPLE 17
Lithium 5-[2-([l,l'-biphenyl]-3-yloxy)ethoxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate
Figure imgf000035_0001
Step 1: Methyl 5-[2-([l ,l'-biphenyl] -3-yloxy)ethoxy] -2-[(2,4- dichlor obenzoyl) amino] benzoate
Use of 2-(3-ρhenylphenoxy)ethanol (disclosed in WO 00/76984) afforded the title compound (55 mg, 21%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDC13) δ 11.32 (s, IH), 8.81 (d, J= 9.24 Hz IH), 7.66-7.55 ( , 4H), 7.49-7.31 (m, 6H), 7.28-7.17 (m,.3H), 6.97-6.91 ( , IH), 4.39 (s, 4H), 3.89 (s, 3H); MS m/z 536 (M+1).
Step 2: Lithium 5-[2-([l, 1 '-biphenyl] -3-yloxy)ethoxy]-2-[(2, 4- dichlorobenzoy I) amino] benzoate
Use of methyl 5-[2-([l,l'-biphenyl]-3-yloxy)ethoxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate afforded the title compound (52 mg, 96%) as a white solid by the application ofthe general procedure B described above. 1H NMR (DMSO) δ 15.04 (s, IH), 8.50 (d, J= 8.97 Hz IH), 7.74-7.22 (m, 12H), 7.03-6.94 (m, 2H), 4.43-4.28
(m, 4H); MS m/z 520 (M-l).
EXAMPLE 18
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(phenylsulfanyl)ethoxy]benzoate
Figure imgf000035_0002
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(phenylsulfanyl)ethoxy]benzoate
Use of 2-(phenylsulfanyl)ethanol afforded the title compound (29 mg, 12%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDC13) δ 11.29 (s, IH), 8.76 (d, J= 9.24 Hz IH), 7.61-7.57 (m, IH), 7.52 (d, J= 3.16 Hz IH), 7.48 (d, J= 1.85 Hz IH), 7.44-7.38 (m, 2H), 7.36-7.27 (m, 3H), 7.25-7.18 (m, IH), 7.12 (dd, J= 9.24, 2.90 Hz IH), 4.16 (t, J= 6.86 Hz 2H), 3.88 (s, 3H), 3.29 (t, J= 6.86 Hz 2H); MS m/z 476 (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(phenylsulfanyl)ethoxy]benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2- (phenylsulfanyl)ethoxy]benzoate afforded the title compound (25 mg, 88%) as a white solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) δ 8.53 (d, J= 8.97 Hz IH), 7.65-7.56 (m, 3H), 7.47-7.40 (m, 3H), 7.34-7.16 (m, 3H), 6.96 (dd, J= 8.97, 3.17 Hz IH), 4.17 (t, J- 6.60 Hz 2H), 3.32-3.28 (m, 2H); MS m/z 460 (M-l).
EXAMPLE 19
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(4-methyl-l,3-thiazoI-5- yl)ethoxy] benzoate
Figure imgf000036_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-{2-[(4-methyl-l,3-thiazol-5-yl)oxy] ethoxyjbenzoate
Use of 2-(4-methyl-l,3-thiazol-5-yl)ethanol afforded the title compound (21 mg, 9%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDCI3) δ 11.29 (s, IH), 8.78 (d, J= 9.23 Hz IH), 8.60 (s, IH), 7.62-7.56 (m, IH), 7.53 (d, J= 2.90 Hz IH), 7.47 (d, J- 1.85 Hz IH), 7.34 (dd, J= 8.19, 2.12 Hz IH), 7.16 (dd, J- 9.23, 3.17 Hz IH), 4.15 (t, J= 6.47 Hz 2H), 3.89 (s, 3H), 3.25 (t, J= 6.47 Hz 2H), 2.45 (s, 3H); MS 465 m/z (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-{2-[(4-methyl-l,3-thiazol-5- yljoxyj ' ethoxyjbenzoate
Use of methyl 2- [(2,4-dichlorobenzoyl)amino] -5 - {2- [(4-methyl- 1 ,3 -thiazol-5 - yl)oxy]ethoxy}benzoate afforded the title compound (18 mg, 90%) as a white solid by the application ofthe general procedure B described above. 1H NMR (DMSO) δ 15.09 (s, IH), 8.82 (s, IH), 8.46 (d, J= 8.97 Hz IH), 7.72 (d, J= 1.85 Hz IH), 7.63-7.50 (m, 3H), 6.89 (dd, J= 8.97, 3.17 Hz IH), 4.10 (t, J= 6.07 Hz 2H), 3.20 (t, J= 3.20 Hz 2H), 2.35 (s, 3H); MS m/z 449 (M-l).
EXAMPLE 20
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(3-furylmethoxy)benzoate
Figure imgf000037_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(3-furylmethoxy)benzoate
Use of 3-furylalcohol afforded the title compound (37 mg, 18%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDC13) δ 11.30 (s, IH), 8.78 (d, J= 9.23 Hz IH), 7.68-7.30 (m, 7H), 7.25-7.19 (m, IH), 6.48 (s, IH), 4.96 (s, 2H), 3.89 (s, 3H); MS 420 m/z (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(3-furylmethoxy)benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(3-furylmethoxy)benzoate afforded the title compound (31 mg, 86%) as a yellow solid by the application ofthe general procedure B described above. 1H NMR (DMSO) δ 15.06 (s, IH), 8.47 (d, J= 8.97 Hz IH), 7.78-7.49 (m, 7H), 6.96 (dd, J= 8.97, 3.17 Hz IH), 6.58-6.56 (m, IH), 4.92 (s, 2H); MS m/z 404 (M-l). EXAMPLE 21
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-thienyl)ethoxy]benzoate
Figure imgf000038_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-thienyl)ethoxy] benzoate
Use of 2-(2-thienyl)ethanol afforded the title compound (38 mg, 17%>), as an oil, by the application ofthe general procedure A described above. 1H NMR (CDCI3) δ 11.30 (s, IH), 8.78 (d, J= 9.24 Hz IH), 7.62-7.55 (m, 2H), 7.47 (d, J= 1.85 Hz IH), 7.34 (dd, J= 8.18, 2.11 Hz IH), 7.21-7.16 (m, 2H), 6.98-6.91 (m, 2H), 4.21 (t, J= 6.73 Hz 2H), 3.89 (s, 3H), 3.31 (t, J= 6.60 Hz 2H); MS 450 m/z (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-thienyl)ethoxy] benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-thienyl)ethoxy]benzoate afforded the title compound (32 mg, 86%) as a white solid by the application ofthe general procedure B described above. 1H NMR (DMSO) δ 14.96 (s, IH), 8.48 (d, J= 8.71 Hz IH), 7.72 (d, J= 1.85 Hz IH), 7.64-7.50 (m, 3H), 7.37-7.32 (m, IH), 7.00-7.68 (m, 3H), 4.15 (t, J= 6.33 Hz 2H), 3.23 (t, J= 6.33 Hz 2H); MS m/z 434 (M-l).
EXAMPLE 22
Lithium 2-[(2,4-dichIorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH-imidazol-l- yl)ethoxy]benzoate
Figure imgf000038_0002
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH-imidazol-l- yl)ethoxy] benzoate
2>1 Use of l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole afforded the title compound (53 mg, 21%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDC13) δ 11.28 (s, IH), 8.75 (d, J- 9.24 Hz IH), 7.95 (s, IH), 7.57 (d, J= 8.18 Hz IH), 7.45 (d, J= 1.85 Hz IH), 7.41 (d, J- 3.17 Hz IH), 7.32 (dd, J= 8.18, 2.11 Hz IH), 7.06 (dd, J= 9.24, 3.17 Hz IH), 4.71 (t, J= 4.88 Hz 2H), 4.33 (t, J= 4.75 Hz 2H), 3.88 (s, 3H), 2.61 (s, 3H); MS 493 m/z (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH-imidazol-l- yl)ethoxy] benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH- imidazol-l-yl)ethoxy]benzoate afforded the title compound (50 mg, 96%) as a brown-red solid by the application ofthe general procedure B described above. 1H NMR (DMSO) δ 14.98 (s, IH), 8.45 (d, J= 8.97 Hz IH), 8.03 (s, IH), 7.72 (d, J= 1.84 Hz IH), 7.64-7.47 (m, 3H), 6.86 (dd, J= 8.97, 3.16 Hz IH), 4.70 (t, J= 5.01 Hz 2H), 4.29 (t, J= 5.01 Hz 2H), 2.53 (s, 3H); MS m/z All (M-l).
EXAMPLE 23
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(3-thienylmethoxy)benzoate
Figure imgf000039_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(3-thienylmethoxy)benzoate
Use of thiophene-3 -methanol afforded the title compound (30 mg, 14%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDCI3) δ 11.30 (s, IH), 8.78 (d, J= 9.24 Hz IH), 7.65-7.58 (m, 2H), 7.48 (d, J= 2.11 Hz IH), 7.37-7.32 (m, 3H), 7.23 (dd, J= 9.24, 3.17 Hz IH), 7.15 (dd, J= 4.75, 1.59 Hz IH), 5.09 (s, 2H), 3.89 (s, 3H); MS 436 m/z (M+1).
Step 2: Lithium 2-[(2, 4-dichlorobenzoyl) amino] -5-(3-thienylmethoxy)benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(3-thienylmethoxy)benzoate afforded the title compound (28 mg, 95%) as a white solid by the application ofthe general procedure B described above. 1H NMR (DMSO) δ 15.03 (s, IH), 8.47 (d, J= 8.98 Hz IH), 7.73 (d, J= 1.85 Hz IH), 7.66-7.50 (m, 5H), 7.20-7.15 (m, IH), 6.97 (dd, J = 8.97, 3.17 Hz IH), 5.05 (s, 2H); MS m/z 420 (M-l).
EXAMPLE 24
Lithium 2-[(2,4-dichlorobenzoyI)amino]-5-[2-(2-pyridinylsuIfanyl)ethoxy]benzoate
Figure imgf000040_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-pyridinylsulfanyl)ethoxy]benzoate
Use of 2-(2-pyridylthio)ethanol afforded the title compound (1.7 mg, 1%), as an oil, by the application ofthe general procedure A described above. 1H NMR (CDCI3) δ 11.29 (s, IH), 8.78 (d, J= 8.98 Hz IH), 8.46-8.43 (m, IH), 7.63-7.57 (m, 2H), 7.51-7.45 (m, 2H), 7.37-7.32 (m, IH), 7.29-7.19 (m, 2H), 7.03-6.98 (m, IH), 4.27 (t, J= 6.86 Hz 2H), 3189 (s, 3H), 3.57 (t, J= 6.86 Hz 2H); MS 477 m/z (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- pyridinylsulfany I) ethoxy] benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- pyridinylsulfanyl)ethoxy]benzoate afforded the title compound (1.7 mg, 100%) as a white solid by the application ofthe general procedure B described above. MS m/z 469 (M+1). EXAMPLE 25
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-thiazol-4- yI)ethoxy]benzoate
Figure imgf000041_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-thiazol-4- y I) ethoxy] benzoate
Use of 2-(5-methyl-2-phenyl-l,3-thiazol-4-yl)ethanol afforded the title compound (170 mg, 63%>) by the application ofthe general procedure A described above. 1H NMR (DMSO) £ 10.72 (s, 1 H), 8.05-7.25 (aromatic signal, 11 H), 4.35 (triplet-like, 2 H), 3.76 (s, 3 H), 3.15 (triplet-like, 2 H), 2.44 (s, 3 H).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5~[2-(5-methyl-2-phenyl-l,3-thiazol-4- yl) ethoxy] benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3- thiazol-4-yl)ethoxy]benzoate afforded the title compound (165 mg, 97%) as a solid by the application ofthe general procedure B described above. 1H NMR (DMSO) £8.46 (d, J= 8.9 Hz 1 H), 7.90-7.40 (aromatic signals, 9 H), 6.92 (dd, J= 8.9, 3 Hz 1 H), 4.26 (t, J= 7.2, 6.7 Hz 2 H), 3.12 (t, J= 6.5, 6.7 Hz 2 H), 2.49 (s, 3 H); MS m/z (M+1) 527.
EXAMPLE 26
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-oxazoI-4~ yl)ethoxy]benzoate
Figure imgf000041_0002
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4- yl) ethoxy] benzoate
Use of 2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethanol afforded the title compound (145 mg, 55%) by the application ofthe general procedure A described above. 1H NMR (DMSO) £8.47 (d, J= 8.91 Hz IH), 7.95-7.89 (m, 2H), 7.72 (d, J= 1.98 Hz IH), 7.64- 7.45 (m, 6H), 6.96-6.89 (m, IH), 4.18 (t, J= 6.68 Hz 2H), 2.92 (t, J= 6.68 Hz 2H), 2.36 (s, 3H); MS m/z (M+l) 511.
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4- yl) ethoxy] benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3- oxazol-4-yl)ethoxy]benzoate afforded the title compound (134 mg, 92%) by the application ofthe general procedure B described above. 1H NMR (DMSO-d6) £8.50 (d, J = 8.9 Hz 1 H), 7.99-7.36 (aromatic signals, 9 H), 6.90 (dd, J= 8.9, 3.1 Hz 1 H), 4.20 (t, J
= 6.5 Hz 2 H), 2.90(t, J= 6.5 Hz 2 H), 2.49 (s, 3 H); MS m/z (M+1) 511.
EXAMPLE 27
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-ethyl-2-pyridinyl)ethoxy]benzoate
Figure imgf000042_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-ethyl-2-pyridinyl)ethoxy]benzoate Use of 2-(5-ethyl-2-pyridinyl)ethanol afforded the title compound (90 mg, 38%) by the application ofthe general procedure A described above. 1H NMR (CDCI3) £ 11.28 (s, 1 H), 8.74 (d, J= 10.5 Hz 1 H), 8.39 (s, 1 H), 7.70-7.05 (aromatic signals, 7 H), 4.35 (t, J= 6.6 Hz 2 H), 3.87 (s, 3 H), 3.25 (t, J= 6.6 Hz 2 H), 2.65 (dd, J- 15.2, 7.5 Hz 2 H), 1.24 (t, J= 7.5 Hz 3 H); MS m/z (M+1) 473. Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-ethyl-2- pyridinyl) ethoxy] benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-ethyl-2- pyridinyl)ethoxy]benzoate afforded the title compound (70 mg, 85%) by the application ofthe general procedure B described above. 1H NMR (DMSO-d6) £ 14.98 (s, 1 H), 8.45 (d, J= 8.1 Hz 1 H), 8.38 (s, 1 H), 7.85-6.80 (aromatic signals, 7 H), 4.28 (t, J= 6.6, 6.6 Hz 2 H), 3.12 (t, J= 6.6, 6.6 Hz 2 H), 2.56 (dd, J= 15.2, 7.5 Hz 2 H), 1.17 (t, J= 7.5, 7.5 Hz 3 H); MS m/z (M+1) 459.
EXAMPLE 28
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methoxyphenoxy)ethoxy]benzoate
Figure imgf000043_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methoxyphenoxy)ethoxy]benzoate Use of 2-(2-methoxyphenoxy)ethanol (previously described in J. Chem. Soc.
Dalton Trans. 1997, 449-462 and Org. Mass Spectrom. 1992, 995-999) afforded the title compound (167 mg, 68%) by the application ofthe general procedure A described above.
1H NMR (CDC13) £ 11.31 (s, 1 H), 8.78 (d, J= 8.1 Hz 1 H), 7.65-6.80 (aromatic signals, 9 H), 4.45-4.25 (overlapping signals, 4 H), 3.89 (s, 3 H), 3.85 (s, 3 H); MS m/z (M+1)
490.
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- methoxyphenoxy) ethoxy] benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2- methoxyphenoxy)ethoxy]benzoate afforded the title compound (163 mg, 98%) as a solid by the application ofthe general procedure B described above. 1H NMR (DMSO-d6) £ 14.91 (s, 1 H), 8.48 (s, 1 H), 7.80-7.40 (aromatic signals, 4 H), 7.10-6.80 (overlapping signals, 5 H), 4.26 (s, 3 H), 3.85 (s, 4 H), 3.74 (s, 3 H); MS m/z (M-l) 475. EXAMPLE 29
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(4-pyridinylmethoxy)benzoate
Figure imgf000044_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(4-pyridinyhnethoxy)benzoate
Use of 4-pyridinylmethanol afforded the title compound (38 mg, 16%) by the application ofthe general procedure A described above. 1H NMR (CDCI3) £ 11.31 (s, IH), 8.81 (d, J= 9.2 Hz IH), 8.63 (br s, 2H), 7.63-7.58 (m, 2H), 7.48 (d, J= 2.1 Hz IH), 7.38-7.33 (m, 3H), 7.22-7.21 (m, IH), 5.12 (s, 2H), 3.9 (s, 3H).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(4-pyridinylmethoxy)benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(4-pyridinylmethoxy)benzoate afforded the title compound (quantitative yield) as a white solid by the application ofthe general procedure B described above. 1H NMR (DMSO-d6) £ 15.13 (s, IH), 8.57-8.55 (m, 2H), 8.47 (d, J= 9.0 Hz IH), 7.72 (d, J= 1.8 Hz IH), 7.64-7.59 (m, 2H), 7.54-7.51 (m, IH), 7.45-7.42 (m, 2H), 6.99 (dd, J= 9.0, 3.2 Hz IH), 5.16 (s, 2H); HRMS m/z calc. for C20H14C12N2O4 (M)+ 416.0335, found 416.0331.
EXAMPLE 30
Lithium 2-[(2,4-dichlorobenzoyl)ammo]-5-[3-(3-pyridinyI)propoxy]benzoate
Figure imgf000044_0002
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[3-(3-pyridinyl)propoxy]benzoate
Use of 3-(3-pyridinyl)-l-propanol afforded the title compound (144 mg, 57%) by the application ofthe general procedure A described above. 1H NMR (CDCI3) £ 11.29 (s, IH), 8.78 (d, J= 9.2 Hz IH), 8.49-8.45 (m, 2H), 7.61-7.47 (m, 4H), 7.36-7.32 (m, IH), 7.24-7.14 (m, 2H), 3.99 (t, 2H), 3.89 (s, 3H), 2.86-2.81 (m, 2H), 2.17-2.07 (m, 2H).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[3-(3-pyridinyl)propoxy]benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[3-(3- pyridinyl)propoxy]benzoate afforded the title compound (quantitative yield) as a white solid by the application ofthe general procedure B described above. 1H NMR (DMSO- d6) £ 15.03 (s, IH), 8.48-8.45 (m, 2H), 8.40 (dd, J= 4.8, 1.6 Hz IH), 7.72 (d, J= 1.8 Hz IH), 7.69-7.64 (m, IH), 7.62-7.59 (m, IH), 7.57-7.50 (m, 2H), 3.93 (t, J= 6.3 Hz 2H), 3.61-3.56 (m, 2H), 2.79-2.74 (m, 2H), 2.07-1.97 (m, 2H), 1.77-1.72 (m, 2H); HRMS m/z calc. for C22H18Cl2N2O4 (M)+ 444.0644, found 444.0641
EXAMPLE 31
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-pyridinyl)ethoxy]benzoate
Figure imgf000045_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-pyridinyl)ethoxy]benzoate
Use of 2-(2-pyridinyl)ethanol afforded the title compound (47 mg, 19%) by the application ofthe general procedure A described above. 1H NMR (CDCI3) £ 11.28 (s, IH), 8.75 (d, J= 9.2 Hz IH), 8.57-8.55 (m, IH), 7.66-7.55 (m, 3H), 7.47 (d, J= 1.8 Hz IH), 7.35-7.32 (m, IH), 7.28 (br s, IH), 7.18-7.14 (m, 2H), 4.39 (t, J= 6.A Hz 2H), 3.88 (s, 3H), 3.27 (t, J= 6.4 Hz 2H).
Step 2: Lithium 2- [(2, 4-dichlorobenzoyl)amino]-5-[2-(2-pyridinyl) ethoxy] benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-pyridinyl)ethoxy]benzoate afforded the title compound (quantitative yield) as a white solid by the application ofthe general procedure B described above. !H NMR (DMSO-d6) £ 15.05 (s, IH), 8.52-8.49 (m, IH), 8.44 (d, J= 9.0 Hz IH), 7.77-7.69 (m, 2H), 7.62-7.50 (m, 3H), 7.37-7.35 (m, IH), 7.26-7.21 (m, IH), 6.88 (dd, J= 9.0, 3.2 Hz IH), 4.31 (t, J= 6.6 Hz 2H), 3.61-3.56 (m, IH), 3.17 (t, J= 6.6 Hz 2H), 1.77-1.72 (m, IH); HRMS m/z calc. for C21H16Cl2N2O4 (M)+ 430.0487, found 430.0489
EXAMPLE 32
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methoxyphenyl)ethoxy]benzoate
Figure imgf000046_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methoxyphenyl)ethoxy]benzoate
Use of 2-(3-methoxyphenyl)ethanol afforded the title compound (48 mg, 18%) by the application ofthe general procedure A described above. 1H NMR (CDCI3) £ 11.29 (s, IH), 8.77 (d, J= 9.2 Hz IH), 7.61-7.58 (m, IH), 7.53 (d, J= 2.9 Hz IH), 7.48 (d, J= 1.8 Hz IH), 7.36-7.32 (m, IH), 7.28-7.14 (m, 2H), 6.89-6.78 (m, 3H), 4.18 (t, J= 7.1 Hz 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.08 (t, J= 7.1 Hz 2H).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methoxyphenyl)ethoxy]benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3- methoxyphenyl)ethoxy]benzoate afforded the title compound (quantitative yield) as a pink solid by the application ofthe general procedure B described above. 1H NMR (DMSO-d6) £ 15.07 (s, IH), 8.46 (d, J= 9.0 Hz IH), 7.62-7.50 (m, 3H), 7.24-7.18 (m, IH), 6.91-6.87 (m, 3H), 6.80-6.76 (m, IH), 4.14 (t, J= 6.9 Hz 2H), 3.73 (s, 3H), 3.61- 3.56 (m, 2H), 2.99 (t, J= 6.6 Hz 2H), 1.77-1.72 (m, 2H). EXAMPLE 33
Lithium 2-[(2,4-dichIorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate
Figure imgf000047_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[(6-nitro-2-pyridinyl)oxy]benzoate General procedure C
Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-hydroxybenzoate (200 mg, 0.59 mmol) was added to a mixture of 2-chloro-3-nitropyridine (187 mg, 1.18 mmol) and potassium carbonate (244 mg, 1.8 mmol) in anhydrous dimethylformamide (6ml) and the suspension was stirred at 80°C over night. After addition of chloroform, the reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was treated with acetonitrile and the title compound (170 mg, 63%) could be filtered of as a white solid. !H NMR (CDC13) £ 11.55 (s, IH), 8.99 (d, J= 9.24 Hz IH), 8.39 (dd, J= 7.92, 1.85 Hz IH), 8.33 (dd, J= 4.75, 1.84 Hz IH), 7.91 (d, J= 2.64 Hz IH), 7.61 (d, J= 8.44 Hz IH), 7.50 (d, J = 2.11 Hz IH), 7.46 (dd, J= 9.24, 2.90 Hz IH), 7.37 (dd, J= 8.44, 2.11 Hz IH), 7.19 (dd, J= 7.92, 4.75 Hz IH), 3.89 (s, 3H); MS 462 m/z (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(6-nitro-2-pyridinyl)oxy]benzoate Use of methyl 2-[(2,4-dicMorobenzoyl)amino]-5-[(6-nitro-2- pyridinyl)oxy]benzoate afforded the title compound (88 mg, 94%) as a yellow solid by the application ofthe general procedure B described in Example 1. 1H NMR (DMSO) £ 15.31 (s, IH), 8.63-8.53 (m, 2H), 8.41 (dd, J= 4.75, 1.84 Hz IH), 7.94 (s, IH), 7.75 (d, J = 1.85 Hz IH), 7.72 (d, J= 2.91 Hz IH), 7.66 (d, J= 8.18 Hz IH), 7.56 (dd, J= 8.18, 1.85 Hz IH), 7.36 (dd, J= 7.91, 4.75 Hz IH), 7.18 (dd, J= 8.71, 2.90 Hz IH); MS m/z 446 (M-l). EXAMPLE 34
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(5-nitro-2-pyridinyl)oxy]benzoate
Figure imgf000048_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[(5-nitro-2-pyridinyl)oxy]benzoate
Use of 2-chloro-5-nitropyridine afforded the title compound (89 mg, 33%), as a yellow solid, by the application ofthe general procedure C described above, with the exception that after filtration ofthe reaction mixture and evaporation, the residue was extracted between chloroform and brine. The organic phase was dried with magnesium sulphate and concentrated in vacuo. The crystalline residue was washed with diethyl ether to give the title compound. 1H NMR (CDC13) £ 11.54 (s, IH), 9.02-8.96 (m, 2H), 8.50 (dd, J= 8.98, 2.91 Hz IH), 7.88 (d, J= 2.91 Hz IH), 7.61 (d, J= 8.18 Hz IH), 7.50 (d, J = 1.85 Hz IH), 7.42 (dd, J= 9.24, 2.90 Hz IH), 7.36 (dd, J= 8.44, 2.11 Hz IH), 7.09 (d, J= 8.71 Hz IH), 3.89 (s, 3H); MS 462 m/z (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(5-nitro-2-pyridinyl)oxy] benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[(5-nitro-2- pyridinyl)oxy]benzoate afforded the title compound (58 mg, 98%) as a yellow solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) £ 9.00 (d, J= 2.91 Hz IH), 8.74 (d J= 8.97 Hz IH), 8.58 (dd, J= 9.24, 2.90 Hz IH), 7.88 (d, J= 2.91 Hz IH), 7.68 (d, J= 8.44 Hz IH), 7.60 (d, J= 1.85 Hz IH), 7.47 (dd, J= 8.44, 2.11 Hz IH), 7.28 (dd, J= 8.97, 2.90 Hz IH), 7.16 (d, J= 9.24 Hz IH); MS m/z 446 (M-l). EXAMPLE 35
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-{[5-(trifluoromethyl)-2- pyridinyl] oxy}benzoate
Figure imgf000049_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-{[5-(trifluoromethyl)-2- pyridinyl] oxy}benzoate
Use of 2-chloro-5-trifluoromethylpyridine afforded the title compound (44 mg, 15%), as a white solid, by the application ofthe general procedure C described above, with the exception that the crude product was purified by column chromatography on silica gel (eluting with chloroform) and re-crystallized from diethyl ether. 1H NMR (CDC13) £ 11.53 (s, IH), 8.97 (d, J= 8.97 Hz IH), 8.42 (s, IH), 7.93 (dd, J= 8.44, 2.11 Hz IH), 7.87 (d, J= 2.90 Hz IH), 7.61 (d, J= 8.18 Hz IH), 7.50 (d, J= 1.84 Hz IH), 7.42 (dd, J= 9.24, 2.90 Hz IH), 7.37 (dd, J= 8.45, 2.11 Hz IH), 7.07 (d, J= 8.71 Hz IH), 3.89 (s, 3H); MS 485 m/z (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-{[5-(trifiuoromethyl)-2- pyridinyl] oxy} benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-{[5-(trifluoromethyl)-2- pyridinyl]oxy}benzoate afforded the title compound (41 mg, 95%) as a yellow solid by the application ofthe general procedure B described above. 1H NMR (DMSO) £ 15.17 (s, IH), 8.70-8.50 (m, 2H), 8.25-8.17 (m, IH), 7.79-7.51 (m, 4H), 7.25-7.13 (m, 2H); MS m/z A69 (M-l). EXAMPLE 36
Lithium 5-[(6-chloro-2-pyrazinyI)oxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate
Figure imgf000050_0001
Step 1: Methyl 5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate
Use of 2-4-dichloropyrazine afforded the title compound (112 mg, 42%), as a white solid, by the application ofthe general procedure C described above. 1H NMR (CDC13) £ 11.52 (s, IH), 8.95 (d, J= 9.23 Hz IH), 8.32 (s, IH), 8.29 (s, IH), 7.86 (d, J= 2.90 Hz IH), 7.61 (d, J= 8.44 Hz IH), 7.49 (d, J= 1.84 Hz IH), 7.42 (dd, J= 9.23, 2.90 Hz IH), 7.36 (dd, J= 8.19, 2.11 Hz IH), 3.89 (s, 3H); MS 452 m/z (M+1).
Step 2: Lithium 5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of methyl 5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate afforded the title compound (84 mg, 83%) as a white solid by the application ofthe general procedure B described above. 1H NMR (DMSO) £ 15.19 (s, IH), 8.68-8.44 (m, 3H), 7.80-7.51 (m, 4H), 7.23 (dd, J= 8.70, 2.91 Hz IH); MS m/z 436 (M-l).
EXAMPLE 37
Lithium 2-[(2,4-dichlorobenzoyI)amino]-5-(2-pyrimidinyloxy)benzoate
Figure imgf000050_0002
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyrimidinyloxy)benzoate
Use of 2-chloropyrimidine afforded the title compound (78 mg, 24%), as a white solid, by the application ofthe general procedure C described above. 1H NMR (CDCI3) £ 11.52 (s, IH), 8.96 (d, J= 9.23 Hz IH), 8.56 (d, J= 5.02 Hz 2H), 7.91 (d, J= 2.90 Hz IH), 7.60 (d, J= 8.45 Hz IH), 7.50-7.42 (m, 2H), 7.35 (dd, J= 8.18, 1.85 Hz IH), 7.06 (t, J= 4.75 Hz IH), 3.87 (s, 3H); MS 418 m/z (M+1).
Step 2: Lithium 2-[(2, 4-dichlorobenzoyl) amino] -5-(2-pyrimidinyloxy)benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyrimidinyloxy)benzoate afforded the title compound (64 mg, 90%) as a solid by the application ofthe general procedure B described above. 1H NMR (DMSO) £ 15.11 (s, IH), 8.70-8.55 (m, 3H), 7.80-7.52 (m, 4H), 7.29-7.12 (m, 2H); MS m/z 402 (M-l).
EXAMPLE 38
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-{[(2E)-3-phenyl-2-propenyl]oxy}benzoate
Figure imgf000051_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-{[(2E)-3-phenyl-2- propenyl] oxy}benzoate General procedure D
Cinnamyl bromide (131 μl, 0.88 mmol) was added to a stirred mixture of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-hydroxybenzoate (300 mg, 0.88 mmol) and potassium carbonate (185 mg, 1.3 mmol) in DMF (10 ml). After heating at 65°C for 4 hours the mixture was allowed to cool and then chloroform was added. Filtration and concentration ofthe filtrate in vacuo gave a residue which subsequently was purified by chromatography on silica gel eluting with CHCI3 to give the title compound (196 mg, 50%) as a white solid. 1H NMR (CHCI3) £ 11.30 (s, IH), 8.80 (d, J= 9.15 Hz IH), 7.64- 7.20 (m, 11H), 6.75 (d, J= 16.08 Hz IH), 6.46-6.34 (m, IH), 4.72 (dd, J= 5.69, 1.49 Hz 2H), 3.90 (s, 3H); ); 13C NMR (CHC13) £ 168.3, 164.2, 154.1, 136.9, 136.3, 134.9, 134.8, 133.6, 132.3, 130.5, 130.4, 128.7, 128.1, 127.6, 126.7, 123.9, 122.3, 121.8, 116.7, 116.2, 100.0, 69.2, 52.7; MS m/z 456 (M+1). Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-{[(2E)-3-phenyl-2- propenyl] oxy}benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-{[(2E)-3-phenyl-2- propenyl]oxy}benzoate afforded the title compound (160 mg, 96%) as a solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) £ 8.57 (d, J = 8.90 Hz IH), 7.76-7.18 (m, 10H), 7.08 (dd, J= 8.90, 2.96 Hz IH), 6.81-6.72 (m, IH), 6.53-6.41 (m, IH), 4.72 (dd, J= 5.69, 1.24 Hz 2H); MS m/z 440 (M-l).
EXAMPLE 39
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(3-methoxybenzyl)oxy]benzoate
Figure imgf000052_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[(3-methoxybenzyl)oxy]benzoate
Use of 3-methoxybenzyl bromide afforded the title compound (148 mg, 45%) as an oil by the application ofthe general procedure D described above. 1H NMR (CD3OD) £ 11.30 (s, IH), 8.78 (d, J= 9.15 Hz IH), 7.66-7.57 (m, 2H), 7.47 (d, J= 1.98 Hz IH), 7.35-7.20 (m, 3H), 7.03-6.97 (m, 2H), 6.89-6.84 (m, IH), 5.05 (s, 2H), 3.89 (s, 3H), 3.81 (s, 3H); 13C NMR (CHCI3) £ 168.3, 164.1, 160.0, 154.2, 138.1, 136.9, 134.9, 134.7, 132.3, 130.5, 130.4, 129.8, 127.6, 122.2, 121.8, 119.7, 116.7, 116.3, 113.7, 113.1, 70.4, 55.3, 52.7; MS m/z 460 (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[(3-methoxybenzyl)oxy] benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[(3- methoxybenzyl)oxy]benzoate afforded the title compound (110 mg, 76%) as a white solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) £ 8.55 (d, J= 8.91 Hz IH), 7.75 (d, J= 2.97 Hz IH), 7.66-7.56 (m, 2H), 7.47-7.41 (m, IH), 7.31-7.22 (m, IH), 7.08 (dd, J= 8.90, 2.96 Hz IH), 7.04-6.98 (m, 2H), 6.89-6.82 (m, IH), 5.07 (s, 2H), 3.79 (s, 3H); 13C NMR (CD3OD) £ 172.6, 164.4, 160.0, 154.5, 138.9, 136.1, 133.4, 132.1, 129.9, 129.2, 127.4, 125.6, 120.6, 119.4, 117.7, 116.7, 113.1, 112.6, 100.0, 69.8, 54.3; MS m/z AAA (M-l).
EXAMPLE 40 Lithium 2-[(2, 4-dichlorobenzoyl)amino]-5-(3-thienyl)benzoate
Figure imgf000053_0001
Step 1: Methyl 2-amino-5-iodobenzoate To a solution of 2-amino-5-iodobenzoic acid (10 g, 38 mmol) in dry dioxane (280 ml) was added dropwise with stirring trichloromethylchloroformate (4.6 ml, 38 mmol). The vessel was allowed to stir for 1 hour at ambient temperature after which the solvent was removed at 50°C by rotary evaporation. The residue was suspended in water (100 ml) and filtered and dried in a vacuum desiccator overnight to give the crude isatoic anhydride (13 g) IR; C=O stretch; 1795, cm"1 and NH stretch; 3184-3088 cm"1.
The crude isatoic anhydride (9.5 g, 27 mmol) was dissolved in dry methanol (670 ml) to which was added powdered anhydrous potassium carbonate (4.4 g, 31 mmol). The solution was allowed to stir at ambient overnight before being evaporated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and water (200 ml) and the aqueous layer adjusted to pH 7.0 with concentrated hydrochloric acid before separating. The aqueous phase was extracted with two further portions of ethyl acetate (2 x 100 ml) and the combined f actions were dried (MgSO4) and evaporated under reduced pressure to give a pale brown oil which solidified on standing (6.8g, 91%); JH NMR (CDC13) £8.12 (d, J= 2.6Hz IH), 7.46 (dd, J= 8.7, 2.4Hz IH), 6.45 (d, J= 8.8Hz IH), 3.86 (s, 3H). Step 2: Methyl 2-[(2, 4-dichlorobenzoyl)amino]-5-iodobenzoate General procedure E
To a stirred solution of methyl 2-amino-5-iodobenzoate (1.5 g, 5.4 mmol) in dry THF (30ml) cooled by an ice- water bath and under an atmosphere of nitrogen diisopropylethylamine (1.2 ml, 9.2 mmol) was added. A solution of 2,4- dichlorobenzoylchloride (0.84 ml, 6.0 mmol in 5 ml of THF) was added dropwise over ten minutes and the vessel was allowed to warm to ambient temperature slowly overnight after which the flask contents were filtered, the solid washed with ethyl acetate (20 ml) and the combined filtrate evaporated under reduced pressure. The residue was taken up in dichloromethane (50 ml) washed with an equal volume of IM hydrochloric acid, water and brine. The organic phase was then dried (MgSO4) and evaporated under reduced pressure to give an off-white solid (2.25 g) which was re-crystallized from 1:1 hexane: dichloromethane to give colorless needles (1.88 g, 77%). 1H NMR (CDC13) £ 11.49 (br s, IH), 8.66 (d, J- 9.0 Hz IH), 8.38 (d, J= 2.2Hz IH), 7.89 (dd, J= 8.8, 2.2 Hz IH), 7.61 (d, J= 8.3 Hz IH), 7.50 (d, J = 2.0 Hz IH), 7.37 (dd, J= 8.3, 2.0 Hz IH), 3.92 (s, 3H); MS m/z (M-l) 448.
Step 3: Methyl 2-[(2, 4-dichlorobenzoyl)amino]-5-(3-thienyl)benzoate General procedure F To a stirred mixture of methyl 2-[(2, 4-dichlorobenzoyl)amino]-5-iodobenzoate
(100 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium(0) (13.5 mg, 5 mol%) and 3-thiopheneboronic acid (36 mg, 0.28 mmol) in degassed 1,2-dimethoxyethane (1.7 ml) was added sodium carbonate solution (0.25 ml, 2 N) before heating to reflux for 2.5 hours under an atmosphere of nitrogen. The solvent was removed under reduced pressure and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The organic phase was separated, washed with brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure to give the crude product. Purification by flash chromatography on a short column, eluting with a gradient from 100% hexane to 20%ι ethyl acetate in hexane, gave pale yellow needles (74 mg, 82%); 1H NMR (CDCI3) £ 11.56 (br s, IH), 8.90 (d, J= 8.8 Hz IH), 8.30 (d, J- 2.4 Hz IH), 7.83 (dd, J= 8.7, 2.3 Hz IH), 7.63 (d, J= 8.3 Hz IH), 7.49 (br s, 2H), 7.41-7.34 (m, 3H) and 3.93 (s, 3H).
Step 4: Lithium 2-[(2, 4-dichlorobenzoyl)amino]-5-(3-thienyl)benzoate General procedure G
To a stirred solution of methyl 2-[(2, 4-dichlorobenzoyl)amino]-5-(3- thienyl)benzoate (37 mg, 0.091 mmol) in dioxane (1.1 ml) was added a solution of aqueous lithium hydroxide (2.46 mg in 1.1 ml). The reaction mixture was strrred overnight under an atmosphere of nitrogen and then freeze dried to give the pure lithium salt (25 mg, 70%) as a pale yellow solid; MS m/z 390 (M-l).
EXAMPLE 41
Lithium 2-[(2, 4-dichIorobenzoyl)amino]-5~(2, 4-dichlorophenyl)benzoate
Figure imgf000055_0001
Step 1: Methyl 2- [(2, 4-dichlorobenzoyl)amino]-5-(2, 4-dichloropheny i) benzoate
Use of 2,4-dichlorophenylboronic acid (42 mg, 0.22 mmol) afforded a 4:1 mixture of the title compound with characteristic NMR signals; 1H NMR (CDC13) £ 11.38 (br s, IH), 8.77 (d, J= 9.0 Hz IH), 8.24 (d, J=2.0 Hz IH) 7.90 (dd, J= 9.0, 2.0 Hz IH), 3.81 (s, 3H) and the corresponding 2-aryl-l,3-benzoxazin-4-one with characteristic NMR signals; 1H NMR (CDCI3) £8.68 (d, J= 9.0 Hz IH), 8.36 (d, J= 2.0 Hz IH) by the application ofthe general procedure F described above.
Step 2: Lithium 2-[(2, 4-dichlorobenzoyl)amino] -5-(2, 4-dichlorophenyl) benzoate
To the crude mixture fro step 1, dissolved in dioxane (3.3 ml) was added a solution of aqueous lithium hydroxide (7.2 mg in 3.3 ml). The reaction mixture was stirred overnight under an atmosphere of nitrogen and monitored by HPLC. A second aliquot of base (0.5 eq) was added followed by another 16 hours stirring at ambient temperature. The reaction mixture was then adjusted to pH 7.0 with concentrated hydrochloric acid, purified by prep HPLC and freeze dried to give the title compound (7.4 mg, 9%) as a colorless solid; MS m/z (M+1) 456. EXAMPLE 42
2-[(2, 4-Dichlorobenzoyl)amino]-5-(4-ethylphenyI)benzoic acid
Figure imgf000056_0001
Step 1: 2-(2,4-dichlorophenyl)-6-(4-ethylphenyl)-l,3-benzoxazin-4-one
Use of 4-ethyl phenylboronic acid (33 mg, 0.22 mmol) afforded the crude title compound by the application ofthe general procedure F described above. This was used in step 2 without further purification.
Step 2: 2-[(2, 4-dichlorobenzoyl)amino]-5-(4-ethylphenyl)benzoic acid
Use ofthe crude 2-(2,4-dichlorophenyl)-6-(4-ethylphenyl)-l,3-benzoxazin-4-one (ca 0.18 mmol) afforded, after purification by HPLC, the title compound (23 mg, 32%) by the application ofthe general procedure G described above. MS m/z (M-l) 412.
EXAMPLE 43
2- [(2,4-Dichlorobenzoyl)amino] -5-(8-quinolinyl)benzoic acid
Figure imgf000056_0002
Step 1: 2-(2,4-Dichlorophenyl)-6-(quinolin-8-yl)-l,3-benzoxazin-4-one
Use of quinoline-8-boronic acid (38 mg, 0.28 mmol) afforded the crude title compound by the application ofthe general procedure F described above. The crude product was used in the next step without further purification. Step 2: 2-[(2,4-Dichlorobenzoyl)amino]-5-(8-quinolinyl)benzoic acid
Use ofthe crude 2-(2,4-dichlorophenyl)-6-(quinolin-8-yl)-l,3-benzoxazin-4-one afforded, after purification by HPLC, the title compound (12 mg, 15%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M+1) 437.
EXAMPLE 44
5-(l ,3-Benzodioxol-5-yl)-2- [(2,4-dichlorobenzoyl)amino] benzoic acid
Figure imgf000057_0001
Step 1: Methyl 5-(l,3-benzodioxol-5-yl)-2-[(2,4-dichlorobenzoyl)amino] benzoate
Use of l,3-benzodioxole-5-boronic acid (37 mg, 0.22 mmol) afforded the crude title compound by the application ofthe general procedure F described above. The crude product was used in the next step without further purification.
Step 2: 2-[(2,4-Dichlorobenzoyl)amino]-5-(8-quinolinyl)benzoic acid
Use ofthe crude methyl 5-(l,3-benzodioxol-5-yl)-2-[(2,4- dichlorobenzoyl)amino]benzoate afforded, after purification by HPLC, the title compound (16 mg, 21%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 428.
EXAMPLE 45 2-[(2,4-Dichlorobenzoyl)amino]-5-(2,4-dimethoxy-5-pyrimidinyl)benzoic acid
Figure imgf000057_0002
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2,4-dimethoxy-5-pyrimidinyl)benzoate Use of (2,4-dimethoxy)pyrimidine-5-boronic acid (41 mg, 0.22 mmol) afforded a crude mixture of title compound and the corresponding cyclized benzoxazine by the application ofthe general procedure F described above. The crude product was used in the next step without further purification.
Step 2: 2-[(2,4-Dichlofobenzoyl)amino]-5-(2,4-dimethoxy-5-pyrimidinyl)benzoic acid Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (17 mg, 21%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M+1) 448.
EXAMPLE 46
3'-(Acetylamino)-4-[(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyIJ-3-carboxylic acid
Figure imgf000058_0001
Step 1: Methyl 3'-(acetylamino)-4-[(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl] -3- carboxylate Use of 3-(acetamido)phenylboronic acid (40 mg, 0.22 mmol) afforded a crude mixture ofthe title compound and the corresponding cyclized benzoxazine by the application ofthe general procedure F described above. The crude product was used in the next step without further purification.
Step 2: 3'-(Acetylamino)-4-[(2,4-dichlorobenzoyl)amino] [1 , 1 '-biphenyl] -3-carboxylic acid
Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (19 mg, 25%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 441. EXAMPLE 47
4-[(2,4-Dichlorobenzoyl)amino]-3'-(trifluoromethoxy)[l,l'-biphenyI]-3-carboxylic acid
Figure imgf000059_0001
Step 1: Methyl 4-[(2,4-dichlorobenzoyl)amino] -3 '-(trifluoromethoxy) [1,1 '-biphenyl] -3- carboxylate
Use of 3-(trifluoromethoxy)phenylboronic acid (46 mg, 0.22 mmol) afforded a crude mixture ofthe title compound and the corresponding cyclized benzoxazine by the application ofthe general procedure F described above. The crude product was used in the next step without further purification.
Step 2: 4-[(2,4-Dichlorobenzoyl)amino] -3'-(trifluoromethoxy) [1 ,l'-biphenyl] -3- carboxylic acid
Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (13 mg, 16%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 468.
EXAMPLE 48
4-[(2,4-Dichlorobenzoyl)amino]-3'-ethoxy[l,l'-biphenyl]-3-carboxylic acid
Figure imgf000059_0002
Step 1 : Methyl 4-[(2, 4-dichlorobenzoyl) amino) '-3 '-ethoxy [1, 1 '-biphenyl] -3-carboxylate Use of 3-(ethoxy)phenylboronic acid (37 mg, 0.22 mmol) afforded a crude mixture ofthe title compound and the corresponding cyclized benzoxazine by the application ofthe general procedure F described above. The crude product was used in the next step without further purification.
Step 2: 4-[(2,4-Dichlorobenzoyl)amino] -3'-ethoxy[l ,1 '-biphenyl] -3-carboxylic acid Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (35 mg, 45%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 428.
EXAMPLE 49 5-(l-Benzofuran-2-yI)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid
Figure imgf000060_0001
Step 1: Methyl 5-(l-benzofuran-2-yl)-2-[(2,4-dichlorobenzoyl)amino] benzoate
Use of benzofuran-2 -boronic acid (23 mg, 0.14 mmol) afforded a crude mixture of the title compound and the corresponding cyclized benzoxazine by the application ofthe general procedure F described above. The crude product was used in the next step without further purification.
Step 2: 5-(l-Benzofuran-2-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid
Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (4 mg, 9%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 424.
EXAMPLE 50
4- [(2,4-DichIorobenzoyl)amino] -3 '-(hydroxymethyl) [1 ,1 '-biphenyl]-3-carboxylic acid
Figure imgf000061_0001
Step 1: Methyl 4-[(2,4-dichlorobenzoyl)amino) '-3 '-(hydroxymethyl) [1,1 '-biphenyl) -3- carboxylate Use of 3-(hydroxymethyl)phenylboronic acid (34 mg, 0.22 mmol) afforded a crude mixture ofthe title compound and the coπesponding cyclized benzoxazine by the application ofthe general procedure F described above. The crude product was used in the next step without further purification.
Step 2: 4- [(2, 4-Dichlorobenzoyl)amino]-3 '-(hydroxymethyl) [1, 1 '-biphenyl] -3-carboxylic acid
Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (20 mg, 27%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 414.
EXAMPLE 51 4-[(2,4-Dichlorobenzoyl)amino]-3'-formyl[l,l'-biphenyl]-3-carboxyIic acid
Figure imgf000061_0002
Step 1: Methyl 4-[(2,4-dichlorobenzoyl)amino] -3' -formyl[l,V -biphenyl] -3-carboxylate
Use of 3-(foπnyl)phenylboronic acid (33 mg, 0.22 mmol) afforded a crude mixture ofthe title compound and the conesponding cyclized benzoxazine by the application ofthe general procedure F described above. The crude product was used in the next step without further purification. Step 2: 4-[(2,4-Dichlorobenzoyl)amino]-3'-formyl[l,l' -biphenyl] -3-carboxylic acid Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (6 mg, 8%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 412.
EXAMPLE 52 2-[(2,4-DichIorobenzoyl)amino]-5-(2-naphthyl)benzoic acid
Figure imgf000062_0001
Step 1 : 2-(2, 4-Dichlorophenyl)-6-(naphth-2-yl)-l, 3-benzoxazin-4-one
Use of naphthyl-2-boronic acid (38 mg, 0.22 mmol) afforded the crude title compound by the application ofthe general procedure F described above. The crude product was used in the next step without further purification.
Step 2: 2-[(2,4-Dichlorobenzoyl)amino]-5-(2-naphthyl)benzoic acid
Use ofthe crude 2-(2,4-dichlorophenyl)-6-(naphth-2-yl)-l,3-benzoxazin-4-one from step 1 afforded, after purification by HPLC, the title compound (8 mg, 10%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 434.
EXAMPLE 53
4-[(2,4-Dichlorobenzoyl)amino]-3'-isopropyI-6'-methoxy[l,l'-biphenyl]-3-carboxylic acid
Figure imgf000062_0002
Step 1: Methyl 4-[(2,4-Dichlorobenzoyl)amino]-3'-isopropyl-6'-methoxy[l,l'-biphenyϊ]- 3-carboxylate
Use of 2-methoxy-5-isopropylphenylboronic acid (43 mg, 0.22 mmol) afforded a crude mixture ofthe title compound and the conesponding cyclized benzoxazine by the application ofthe general procedure F described above. The crude product was used in the next step without further purification.
Step 2: 4-[(2,4-Dichlorobenzoyl)amino) '-3'-isopropyl-6'-methoxy[l ,V -biphenyl) '-3- carboxylic acid
Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (9 mg, 11%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 456.
EXAMPLE 54
4-[(2,4-Dichlorobenzoyl)amino]-4'-fluoro[l,l'-biphenyl]-3-carboxy lie acid
Figure imgf000063_0001
Step 1 : Methyl 4-[(2, 4-dichlorobenzoyl) amino) '-4 '-fiuorofl, 1 '-biphenyl] -3-carboxylate Use of 4-fluorophenylboronic acid (31 mg, 0.22 mmol) afforded a crude mixture ofthe title compound and the corresponding cyclized benzoxazine by the application of the general procedure F described above. The crude product was used in the next step without further purification.
Step 2: 4-[(2,4-Dichlorobenzoyl)amino] -4'-fluoro[l ,l'-biphenyl] -3-carboxylic acid Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (27 mg, 37%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 402. EXAMPLE 55
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-furyl)benzoate
Figure imgf000064_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2-furyl)benzoate General procedure J
To a stined mixture of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-iodobenzoate (100 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium (13 mg, 5 mol%) and furan- 2-boronic acid (31 mg, 0.27 mmol) in degassed 1,2-dimethoxyethane (1.7 ml) was added 2N sodium carbonate solution (0.25 ml) before heating for 5 hours at 80°C under an atmosphere of nitrogen. The reaction mixture was washed with brine, dried (MgSO4) and evaporated under reduced pressure to give the crude product. Purification by flash chromatography on a short silica column, eluting with a mixture of hexane and ethyl acetate (2:1), gave a bright yellow solid (55 mg, 64%). 1H NMR (CDC13) £ 11.56 (br s, IH), 8.90 (d, J= 8.8 Hz IH), 8.37 (d, J= 2.2 Hz IH), 7.89 (dd, J= 8.8, 2.2 Hz IH), 7.63 (d, J= 8.3 Hz IH), 7.50 (s, 2H), 7.37 (dd, J= 8.3, 1.9 Hz IH), 6.68 (s, IH), 6.51 (s, IH), 3.95 (s, 3H).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-furyl)benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2-furyl)benzoate afforded the title compound (53 mg, 100%) as a beige solid by the application ofthe general procedure G described above. MS m/z (M-l) 374. EXAMPLE 56
Lithium 5-(l-benzothien-3-yl)-2-[(2,4-dichIorobenzoyl)amino]benzoate
Figure imgf000065_0001
Step 1: Methyl 5-(l-benzothien-3-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoate
Use of benzothiophene-3 -boronic acid (49 mg, 0.27 mmol) afforded the title compound (54 mg, 74%) as a white solid by the application ofthe general procedure J described above. 1H NMR (CDC13) £ 11.61 (br s, IH), 8.99 (d, J= 8.8 Hz IH), 8.31 (s, IH), 7.96-7.83 (m, 3H), 7.65 (d, J= 8.3 Hz IH), 7.52 (s, IH), 7.44-7.36 (m, 4H), 3.92 (s, 3H).
Step 2: Lithium 5-(l-benzothien-3-yl)-2-[(2,4-dichlorobenzoyl)amino) 'benzoate
Use of methyl 5-(l-benzothien-3-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoate afforded the title compound (51 mg, 96%) as a white solid by the application of the general procedure G described above. MS m/z (M-l) 440.
EXAMPLE 57
Lithium 2-[(2,4-dichIorobenzoyl)amino]-5-(2-formyl-3-thienyl)benzoate
Figure imgf000065_0002
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2-formyl-3-thienyl)benzoate
Use of 2-formylthiophene-3 -boronic acid (43 mg, 0.27 mmol) afforded, after purification by HPLC, the title compound (31 mg, 32%) as a white solid by the application ofthe general procedure J described above. 1H NMR (CDCI3) £ 11.65 (br s, IH), 9.89 (s, IH), 9.01 (d, J= 8.5 Hz IH), 8.20 (d, J= 1.9 Hz IH), 7.79-7.72 (m, 2H), 7.65 (d, J= 8.3 Hz IH), 7.52 (d, J= 1.9 Hz IH), 7.39 (dd, J= 8.3, 1.9 Hz IH), 7.24 (s, IH), 3.94 (s, 3H). Also isolated was the coπesponding cyclized benzoxazine. 1H NMR (CD3OD) £9.90 (s, IH), 8.79 (d, J= 8.5 Hz IH), 8.28 (d, J- 2.2 Hz IH), 7.96 (dd, J= 5.1, 1.2 Hz IH), 7.69-7.59 (m, 3H), 7.47 (dd, J= 8.3, 1.9 Hz IH), 7.37 (d, J= 5.1 Hz IH).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-formyl-3-thienyl)benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2-formyl-3-thienyl)benzoate afforded the title compound (31 mg, 84%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 418.
EXAMPLE 58
Lithium 5-(5-acetyl-2-thienyl)-2-[(2,4-dichIorobenzoyl)amino]benzoate
Figure imgf000066_0001
Step 1: Methyl 5-(5-acetyl-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate
Use of 5-acetylthiophene-2-boronic acid (47 mg, 0.27 mmol) afforded the title compound (16 mg, 16%) as a white solid by the application ofthe general procedure J described above. 1H NMR (CDCI3) £ 11.63 (br s, IH), 8.95 (d, J- 8.8 Hz IH), 8.37 (d, J = 2.4 Hz IH), 7.88 (dd, J= 8.8, 2.2 Hz IH), 7.68-7.62 (m, 2H), 7.51 (d, J= 1.9 Hz IH), 7.40-7.34 (m, 2H), 3.96 (s, 3H), 2.58 (s, 3H).
Step 2: Lithium 5-(5-acetyl-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of methyl 5-(5-acetyl-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate afforded the title compound (13 mg, 100%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 432.
EXAMPLE 59 2- [(2,4-Dichlorobenzoyl)amino] -5-(l H-indol-5-yl)benzoic acid trifluoroacetate
Figure imgf000067_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(lH-indol-5-yl)benzoate
Use of 5-indolylboronic acid afforded the title compound (68 mg, 70%) as a beige solid by the application ofthe general procedure J described above. 1H NMR (CDCI3) £ 11.56 (br s, IH), 8.91 (d, J= 8.5 Hz IH), 8.36 (s, 2H), 7.91-7.86 (m, 2H), 7.61 (d, J= 8.3 Hz IH), 7.48 (s, IH), 7.43 (s, 2H), 7.33 (d, J= 8.3 Hz IH), 6.61 (s, IH), 3.93 (s, 3H).
Step 2: 2-[(2,4-Dichlorobenzoyl)amino]-5-(lH-indol-5-yl)benzoic acid trifluoroacetate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(lH-indol-5-yl)benzoate, 8 days reaction time and purification by HPLC afforded the title compound (31 mg, 37%) as a purple solid by the application ofthe general procedure G described above. H NMR (CD3COCD3) £ 11.76 (br s, IH), 10.38 (br s, IH), 8.92 (d, J= 8.5 Hz IH), 8.46 (d, J= 2.0 Hz IH), 8.03 (dd, J= 8.5, 2.0 Hz IH), 7.92 (s, IH), 7.80 (d, J= 8.3 Hz IH), 7.68 (s, IH), 7.60-6.39 (m, 4H), 6.58 (s, IH); MS m/z (M-l) 423.
EXAMPLE 60
5-(3-Carboxyphenyl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid
Figure imgf000067_0002
Step 1: Methyl 5-(3-carboxyphenyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of 3-(carboxy)phenylboronic acid (47 mg, 0.28 mmol) afforded a crude mixture ofthe title compound and the conesponding cyclized benzoxazine by the application ofthe general procedure F described above. The crude product was used in the next step without further purification.
Step 2: 5-(3-Carboxyphenyl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid
Use ofthe mixture from step 1 afforded, after purification by HPLC, the title compound (24 mg, 72%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 428.
EXAMPLE 61
Lithium 2'-(benzyloxy)-4-[(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl] -3-carboxylate
Figure imgf000068_0001
Step 1: Methyl 2'-(benzyloxy)-4-[(2,4-dichlorobenzoyl)amino][l,l'-biphenyl]-3- carboxylate
Use of 2-(benzyloxy)phenylboronic acid (63 mg, 0.28 mmol) afforded the title compound as a colorless solid (91 mg, 82%) by the application ofthe general procedure F described above.
1H NMR (CDC13) £ 11.59 (br s, IH), 8.89 (d, J= 8.8 Hz IH), 8.37 (d, J=2.2 Hz 2H), 7.85 (dd, J= 8.8, 2.2 Hz IH), 7.63 (d, J= 8.3 Hz IH), 7.50 (d, J= 1.7 Hz IH), 7.39-7.26 (m, 8H) 7.10-7.04 (m, 2H), 5.10 (s, IH) and 3.87 (s, 3H); MS m/z (M+Na) 528.
Step 2: 2 '-(benzyloxy)-4-[(2, 4-dichlorobenzoyl) amino] [1, 1 ' -biphenyl] -3-benzoic acid Use of methyl 2'-(benzyloxy)-4-[(2,4-dichlorobenzoyl)amino] [1 , 1 '-biphenyl]-3- carboxylate afforded the title compound (10 mg, 30%) as a colorless solid by the application ofthe general procedure G described above. MS m/z (M-l) 490.
EXAMPLE 62 Lithium 4-[(2,4-dichIorobenzoyl)amino] [1,1 '-biphenyl] -3-carboxylate
Figure imgf000069_0001
Step 1 : Methyl 4- [(2, 4-dichlorobenzoyl)amino] [1, 1 '-biphenyl] -3 -carboxylate
Use of phenylboronic acid (34 mg, 0.28 mmol) afforded the title compound, after heating at reflux for 16 h, as a colorless solid (25 mg, 28%) by the application ofthe general procedure F described above. 1H NMR (CDC13) £ 11.50 (br s, IH), 8.87 (d, J= 8.8 Hz IH), 8.25 (d, J=2.4 Hz IH), 7.79 (dd, J= 8.8, 2.2 Hz IH), 7.58-7.52 (m, 3H), 7.44-7.39 (m, 3H), 7.36-7.31 (m, 2H), 3.87 (s, 3H); MS m/z (M+1) 400.
Step 2: Lithium 4-[(2,4-dichlorobenzoyl)amino] [1 ,1' -biphenyl] ' -3-carboxylate
Use of methyl 4-[(2,4-dichlorobenzoyl)amino][l, -biphenyl]-3-carboxylate ) afforded the title compound (22 mg, 79%) as a colorless solid by the application ofthe general procedure G described above. MS m/z 384 (M-l).
EXAMPLE 63
Lithium 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l,l'-biphenyl]-3-carboxylate
Figure imgf000069_0002
Step 1: Methyl 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l,r-biphenyl] -3-carboxylate
Use of 3-(phenyl)phenylboronic acid (55 mg, 0.28 mmol) afforded the title compound as a colorless solid (8 mg, 74%) by the application ofthe general procedure F described above. 1H NMR (CDCI3) £ 11.59 (br s, IH) 8.89 (d, J= 8.8 Hz IH), 8.37 (d, J=2.2 Hz IH), 7.85 (dd, J= 8.8, 2.2 Hz IH), 7.63 (d, J= 8.3 Hz IH), 7.50 (d, J= 1.7 Hz IH), 7.39-7.26 (m, 8H), 7.10-7.04 (m, 2H), 5.10 (s, IH), 3.87 (s, 3H); MS m/z (M+Na) 528.
Step 2: Lithium 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l,l -biphenyl) '-3-carboxylate Use of methyl 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l, -biphenyl]-3- carboxylate afforded the title compound (38 mg, 99%) as a colorless solid by the application ofthe general procedure G described above. MS m/z (M-l) 460.
EXAMPLE 64
Lithium 4-[(2,4-dichlorobenzoyl)amino]-3'-(trifmoromethyl)[l,l'-biphenyl]-3- carboxylate
Figure imgf000070_0001
Step 1: Methyl 4-[(2,4-dichlorobenzoyl)amino) -3 '-(trifluoromethyl) [1,1 '-biphenyl] -3- carboxylate
Use of 3-(trifluoromethyl)phenylboronic acid (42 mg, 0.28 mmol) afforded the title compound (61 mg, 73%) as a solid by the application ofthe general procedure F described above. 1H NMR (CDCI3) £ 11.60 (br s, IH), 9.0 (d, J= 8.8 Hz IH), 8.35 (d, J= 2.2 Hz IH), 7.90-7.41 (m, 8H), 3.99 (s, 3H).
Step 2: Lithium methyl 4-[(2,4-dichlorobenzoyl)amino] -3 '-(trifluoromethyl) [1,1 '- biphenyl] -3-carboxylate Use of methyl 4-[(2,4-dichlorobenzoyl)amino]-3,-(trifluoromethyl)[l,r-biphenyl]-
3-carboxylate afforded the title compound (24 mg, 79%) as a solid by the application of the general procedure G described above. MS m/z (M-l) 452.
EXAMPLE 65 Lithium 5-(5-chloro-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate
Figure imgf000071_0001
Step 1: Methyl 5-(5-chloro-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate Use of 5-(chloro)thiophene-2-boronic acid (36 mg, 0.28 mmol) afforded the title compound (75 mg, 96%) as an yellow solid by the application ofthe general procedure F described above.
1H NMR (CDC13) £ 11.56 (br s, IH), 8.90 (d, J= 8.8 Hz IH), 8.19 (d, J=2.4 Hz IH),
7.74 (dd, J= 8.8,2.4 Hz IH), 7.63 (d, J= 8.3 Hz IH), 7.50 (d, J=2.0 Hz IH), 7.37 (dd, J = 8.3, 2.0 Hz IH), 7.10 (d, J= 3.9 Hz IH), 6.91 (d, J= 3.9 Hz IH), 3.95 (s, 3H).
Step 2: Lithium 5-(5-chloro-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino] benzoate
Use of methyl 5-(5-chloro-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate afforded the title compound (21 mg, 57%) as a brown solid by the application ofthe general procedure G described above. MS m/z (M-l) 426.
EXAMPLE 66
Lithium 4-[(2,4-dichlorobenzoyl)amino]-4'-phenoxy[l,l'-biphenyl]-3-carboxylate
Figure imgf000071_0002
Step 1: Methyl 4-[(2,4-dichlorobenzoyl)amino] -4'-phenoxy[l ,1 '-biphenyl] -3-carboxylate
Use of 4-phenoxyphenylbororhc acid (48 mg, 0.28 mmol) afforded the title compound (83 mg, 95%) as an yellow solid by the application ofthe general procedure F described above. 1H NMR (CDC13) £ 11.56 (br s, IH), 8.93 (d, J= 8.8 Hz IH), 8.28 (d, J = 2.2 Hz IH), 7.82 (dd, J= 8.8, 2.4 Hz IH), 7.72-7.32 (m 7H), 7.16-7.03 (m, 5H), 3.93 (s, 3H).
Step 2: Lithium 4-[(2,4-dichlorobenzoyl)amino]-4'-phenoxy[l,l '-biphenyl] -3-carboxylate Use of methyl 4-[(2,4-dichlorobenzoyl)amino]-4'-phenoxy[l,r-biphenyl]-3- carboxylate afforded the title compound (40 mg, 98%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 476.
EXAMPLE 67 Lithium 4-[(2,4-dichlorobenzoyl)amino]-2',5'-dimethoxy[l,l'-biphenyl]-3- carboxylate
Figure imgf000072_0001
Step 1: Methyl 4-[(2,4-dichlorobenzoyl)amino]-2',5'-dimethoxy[l,l '-biphenyl]-3- carboxylate
Use of 2,5-(dimethoxy)phenylboronic acid (40 mg, 0.28 mmol) afforded the title compound (79 mg, 97%) as a solid by the application ofthe general procedure F described above. 1H NMR (CDCI3) £ 11.59 (br s, IH), 8.90 (d, J= 8.8 Hz IH), 8.24 (d, J = 2.2 Hz IH), 7.82 (dd, J= 8.8, 2.2 Hz IH), 7.63 (d, J= 8.3 Hz IH), 7.50 (d, J= 1.7 Hz IH), 7.36 (dd, J= 8.3, 2.0 Hz IH), 7.00-6.83 (m, 3H), 3.91 (s, 3H) 3.82 (s, 3H), 3.76 (s, 3H).
Step 2: Lithium 4-[(2,4-dichlorobenzoyl)amino] -2', 5'-dimethoxy[l , 1 '-biphenyl] -3- carboxylate Use of methyl 4-[(2,4-dichlorobenzoyl)amino]-2',5'-dimethoxy[ 1 , 1 '-biphenyl] -3- carboxylate afforded the title compound (38 mg, 99%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 444. EXAMPLE 68
3 '-(Aminomethyl)-4- [(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl] -3-carboxylic acid
Figure imgf000073_0001
Step 1 : 6-(3-Aminomethylphenyl)-2-(2, 4-dichlorophenyl)-l , 3-benzoxazin-4-one
Use of 3-ammomethylphenylboronic acid (38 mg, 0.14 mmol) afforded the title compound (23 mg, 50%) as a solid by the application ofthe general procedure F described above. 1H NMR (CD3COCD3) £8.84 (d, J= 8.3 Hz IH), 8.44 (d, J=2.2 Hz IH), 7.97 (dd, J= 8.3, 1.7 Hz IH), 7.90 (d, J=0.7 Hz IH), 7.76 (d, J= 8.1 Hz IH), 7.74- 7.65 (m, IH), 7.65 (d, J=2.0 Hz IH), 7.64-7.48 (m, 3H), 4.41 (s, 2H);
Step 2: 3'-(Aminomethyl)-4-[(2,4-dichlorobenzoyl)amino][l,l '-biphenyl] -3-carboxylic acid Use of 6-(3 -aminomethylphenyl)-2-(2,4-dichlorophenyl)- 1 ,3 -benzoxazin-4-one afforded the title compound (4 mg, 18%) as a solid by the application ofthe general procedure G described above. MS m/z (M-l) 413.
EXAMPLE 69 Lithium 2-(2-naphthoylamino)-5-(3-thienyl)benzoate
Figure imgf000073_0002
Step 1: Methyl 2-[(2-naphtoyl)amino]-5-iodobenzoate General procedure I To a stiπed solution of methyl 2-amino-5-iodobenzoate (500 mg, 1.8 mmol) in dry THF (10 ml) in a STEMBLOCK chiller at 0°C under an atmosphere of nitrogen, diisopropylethylamine (0.53 ml, 3.0 mmol) was added. A solution of 2-naphthoyl chloride (0.44 ml, 2.3 mmol) was added dropwise and the reaction mixture allowed to reach ambient temperature stirring overnight after which the flask contents were filtered, the solid washed with THF and the residue taken up in dichloromethane. The organic phase was washed with a solution of citric acid (5 %) and a solution of saturated sodium bicarbonate. The organic phase was then dried (MgSO4) and concentrated in vacuo to give the title compound (0.4 g, 51%) as a white solid. 1H NMR (CDC13) £ 12.12 (br s, IH), 8.79 (d, J= 9.0 Hz IH), 8.56 (s, IH), 8.41 (s, IH), 8.10-7.87 (m, 5H), 7.64-7.54 (m, 2H), 4.00 (s, 3H). MS m/z (M+1) 432.
Step 2: Methyl 2-(2-naphthoylamino)-5-(3-thienyl)benzoate General B2 To a stiπed mixture of methyl 2-[(2-naphtoyl)amino]-5-iodobenzoate (100 mg,
0.23 mmol), tetrakis(triphenylphosphine)palladium (13 mg, 5mol%>) and thiophene-3- boronic acid (37 mg, 0.29 mmol) in degassed 1,2-dimethoxyethane (1.7 ml) and degassed toluene (0.5 ml) was added 2N sodium carbonate solution (0.26 ml) before heating for 32 hours at 80°C under an atmosphere of nitrogen. The reaction mixture was washed with brine, dried (MgSO4) and evaporated under reduced pressure to give the crude product. Purification by flash chromatography on a short column, eluting with a mixture of hexane and ethyl acetate (2:1), gave the title compound as a white solid (17 mg, 19%). 1H NMR (CDCI3) £ 12.20 (br s, IH), 9.03 (d, J= 8.8 Hz IH), 8.60 (s, IH), 8.34 (s, IH), 8.13-7.84 (m, 5H), 7.60-7.57 (m, 2H), 7.50 (s, IH), 7.43 (s, 2H), 4.02 (s, 3H). MS m/z (M+1) 388.
Step 3: Lithium 2-(2-naphthoylamino)-5-(3-thienyl)benzoate
Use of methyl 2-(2-naphthoylamino)-5-(3-thienyl)benzoate afforded the title compound (18 mg, 100%) as a yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 372.
EXAMPLE 70
Lithium 3 '-(acetylamino)-4-(2-naphthoylamino) [1,1 '-biphenyl] -3-carboxylate
Figure imgf000075_0001
Step 1: Methyl 3'-(acetylamino)-4-(2-naphthoylamino)[l,l'-biphenyl] -3-carboxylate Use of 3-acetamidophenylboronic acid (51 mg, 0.29 mmol) afforded the title compound (47 mg, 46%>) as a beige solid by the application ofthe general procedure J described above. 1H NMR (CDC13) £ 12.22 (br s, IH), 9.03 (d, J= 8.8 Hz IH), 8.59 (s, IH), 8.31 (s, IH), 8.13-7.75 (m, 6H), 7.61-7.37 (m, 6H), 4.00 (s, 3H), 2.22 (s, 3H). MS m/z (M+1) 439.
Step 2: Lithium 3 '-(acetylamino)-4-(2-naphthoylamino) [1 , 1 '-biphenyl] -3-carboxylate Use of methyl 3 '-(acetylamino)-4-(2-naphthoylamino) [1,1 '-biphenyl] -3 - carboxylate afforded the title compound (39 mg, 100%) as a yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 423.
EXAMPLE 71
Lithium 3'-(hydroxymethyl)-4-(2-naphthoylamino)[l,l'-biphenyl]-3-carboxylate
Figure imgf000075_0002
Step 1 : Methyl 3 '-(ltydroxymethyl)-4-(2-naphthoylamino)[l, 1 '-biphenyl] -3-carboxylate Use of 3-(hydroxymethyl)phenylboronic acid (44 mg, 0.29 mmol) afforded the title compound (39 mg, 41%) as a beige solid by the application ofthe general procedure
J described above.
1H NMR (DMSO-d6) £11.73 (br s, IH), 8.68 (d, J= 8.8 Hz IH), 8.62 (s, IH), 8.28 (s, IH), 8.17-8.02 (m, 5H), 7.70-7.36 (m, 6H), 4.59 (s, 2H), 3.96 (s, 3H). MS m/z (M+1) 412. Step 2: Lithium 3'-(hydroxymethyl)-4-(2-naphthoylammo)[l,l'-bipheτιyl] -3-carboxylate
Use of methyl 3'-(hydroxymethyl)-4-(2-naphthoylamino)[l, -biphenyl]-3- carboxylate afforded the title compound (21 mg, 91%) as a yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 396.
EXAMPLE 72
Lithium 5-(3-thienyl)-2-{[4-(trifluoromethyl)benzoyl]amino}benzoate
Figure imgf000076_0001
Step 1: Methyl 5-iodo-2-[(4-(trifluoromethyl)benzoyl)amino] benzoate
Methyl 2-amino-5-iodobenzoate (500 mg, 1.8 mmol) in dry THF (lOmL), diisopropylethylamme (0.53 ml, 3.0 mmol) and 4-(trifluoromethyl)benzoyl chloride (0.35 ml, 2.3 mmol) were reacted following the general procedure I. Purification by chromatography eluting with dichloromethane, followed by re-crystallization in a mixture of dichloromethane and hexane gave the title compound as a white solid (660 mg, 82%).
1H NMR (CDC13) £ 12.10 (br s, IH), 8.71 (d, J= 9.0 Hz IH), 8.41 (s, IH), 8.14 (d, J=
8.5 Hz 2H), 7.90 (d, J= 9.0 Hz IH), 7.80 (d, J= 8.5 Hz 2H), 3.99 (s, 3H); MS m/z (M-l)
448.
Step 2: 6-(Thiophen3-yl)-2-[4-(trifluoromethyl)phenyl]-l, 3-benzoxazine-4-one
Use of methyl 5-iodo-2-[(4-(trifluoromethyl)benzoyl)amino]benzoate (100 mg,
0.22 mmol), tetrakis(triρhenylphosphine)palladium (13 mg, 5 mol%), thiophene-3- boronic acid (35 mg, 0.28 mmol) and 2N sodium carbonate (0.26 ml), in 1,2- dimethoxyethane (1.7 ml) at 80°C for 32 hours afforded the title compound (66 mg, 80%) as a beige solid by the application ofthe general procedure J described above. 1H NMR
(DMSO-d6) £8.69 (d, J= 8.5 Hz IH), 8.36 (s, IH), 8.23 (d, J= 8.1 Hz 2H), 7.93 (d, J=
8.3 Hz 2H), 7.78-7.51 (m, 4H). MS m/z (M-l, +H2O) 390. Step 3: Lithium 5-(3-thienyl)-2-{[4-(trifluoromethyl)benzoyl]amino}benzoate
Use of 6-(thiophen3-yl)-2-[4-(trifluoromethyl)phenyl]-l,3-benzoxazine-4-one afforded the title compound (22 mg, 63%) as a gray solid by the application ofthe general procedure G described above. MS m/z (M-l) 390.
EXAMPLE 73
Lithium 3'-(acetylamino)-4-{[4-(trifluoromethyl)benzoyl]amino} [1,1 '-biphenyI]-3- carboxylate
Figure imgf000077_0001
Step 1 : 6-(3-Acetamideophenyl)-2-[4-(trifl oromethyl)phenyl] -1 , 3-benzoxazine-4-one Use of methyl 5-iodo-2-[(4-(trifluoromethyl)benzoyl)amino]benzoate (100 mg, 0.22 mmol) and 3-acetamidophenylboronic acid (50 mg, 0.28 mmol) afforded the title compound (35 mg, 37%) as a solid by the application ofthe general procedure J described above. MS m/z (M-l, +H2O) 441.
Step 2: Lithium 3'-(acetylamino)-4-[[4-(trifluoromethyl)benzoyl]amino}[l,l '-biphenyl]-3- carboxylate Use of 6-(3-acetamideophenyl)-2-[4-(trifluoromethyl)phenyl]-l ,3-benzoxazine-4- one afforded the title compound (22 mg, 63%) as a gray solid by the application ofthe general procedure G described above. MS m/z (M-l) 441.
EXAMPLE 74 Lithium 3'-(hydroxymethyl)-4-{[4-(trifluoromethyl)benzoyl]amino} [l,l'-biphenyl]-3- carboxylate
Figure imgf000078_0001
Step 1 : 6-[3-Hydroxymethyl)phenyl] -2-[4-(trifluoromethyl)phenyl] -1 , 3-benzoxazin-4-one Use of methyl 5-iodo-2-[(4-(trifluoromethyl)benzoyl)amino]benzoate (100 mg, 0.22 mmol) and 3-(hydroxymethyl)phenylboronic acid (42 mg, 0.28 mmol) afforded the title compound (86 mg, 98%) as a white solid by the application ofthe general procedure Jdescribed above. MS m/z (M-l, +H2O) 414.
Step 2: Lithium 3'-(hydroxymeihyl)-4-{[4-(trifluoromethyl)benzoyl]amino}[l,l'- biphenyl] -3 -carboxylate
Use of 6-[3-hydroxymethyl)phenyl]-2-[4-(trifluoromethyl)phenyl]-l,3- benzoxazin-4-one afforded the title compound (50 mg, 73%) as an yellow solid by the application ofthe general procedure G described above. MS m/z (M-l) 414.
EXAMPLE 75
Lithium 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-5-(8-quinolinyϊ)benzoate
Figure imgf000078_0002
Step 1: Methyl 2-[(3,5-bis(trifluoromethyl)benzoyl)amino]-5-iodobenzoate
Use of 3,5-bis(trifluoromethyl)benzoyl chloride (0.42 ml, 2.3 mmol) and afforded the title compound (200 mg, 21%) as a white solid by the application ofthe general procedure I described above. 1H NMR (CDC13) £ 12.27 (br s, IH), 8.67 (d, J= 9.0 Hz IH), 8.48 (s, 2H), 8.43 (d, J= 2.2 Hz IH), 8.08 (s, IH), 7.92 (dd, J= 9.0, 2.2 Hz IH), 4.00 (s, 3H). MS m/z (M-l) 516. Step 2: Methyl 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-5-(8-quinolinyl)benzoate
Use of methyl 2-[(3,5-bis(trifluoromethyl)benzoyl)amino]-5-iodobenzoate (100 mg, 0.19 mmol) and 8-quinolineboronic acid (42 mg, 0.24 mmol) afforded the title compound (50 mg, 51%) as a white solid by the application ofthe general procedure J described above. 1H NMR (CDC13) £12.45 (br s, IH), 9.03-8.95 (m, 2H), 8.55 (s, 2H), 8.49 (d, J= 2.2 Hz IH), 8.23 (dd, J= 8.3, 2.0 Hz IH), 8.09 (s, IH), 8.02 (dd, J= 8.5, 2.2 Hz IH), 7.84 (dd, J= 8.1, 1.5 Hz IH), 7.78-7.60 (m, 2H), 7.45 (dd, J= 8.3, 4.1 Hz IH), 3.99 (s, 3H).
Step 3: Lithium 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-5-(8-quinolinyl)benzoate
Use of methyl 2-{[3,5-bis(trifluoromethyl)benzoyι]amino}-5-(8- quinolinyl)benzoate afforded the title compound (47 mg, 100%) as solid by the application ofthe general procedure G described above. MS m/z (M-l) 503.
EXAMPLE 76
Lithium 4- {[3,5-bis(trifluoromethyl)benzoyl]amino}-3'-formyl[l,l'-biphenyl]-3- carboxylate
Figure imgf000079_0001
Step 1: Methyl 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-5-(3-formylphenyl)benzoate Use of methyl 2-[(3,5-bis(trifluoromethyl)benzoyl)amino]-5-iodobenzoate (100 mg, 0.19 mmol) and 3-formylphenylboronic acid (36 mg, 0.24 mmol) afforded the title compound (6 mg, 6%) as a white solid by the application ofthe general procedure J described above. MS m/z (M-l) 494.
Step 2: Lithium 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-5-(3-formylphenyl)benzoate Use of methyl 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-5-(3-formylphenyl)benzoate afforded the title compound (7 mg, 100%) as a white solid by the application ofthe general procedure G described above. MS m/z (M-l) 480.
EXAMPLE 77
Lithium 2-[(4-methoxybenzoyl)amino]-5-(8-quinolinyl)benzoate
Figure imgf000080_0001
Step 1: Methyl 5-iodo-2-[(4-methoxybenzoyl) amino] benzoate
Use of 4-methoxybenzoyl chloride (0.58 ml, 3.4 mmol) and catalytic DMAP afforded the title compound (300 mg, 40%) as a beige solid by the application ofthe general procedure I described above. 1H NMR (CDC13) £ 11.88 (br s, IH), 8.73 (d, J= 8.8 Hz IH), 8.37 (d, J= 2.2 Hz IH), 8.00 (d, J= 8.8 Hz 2H), 7.85 (dd, J= 9.0, 2.2 Hz IH), 7.01 (d, J= 9.0 Hz 2H), 3.97 (s, 3H), 3.88 (s, 3H).
Step 2: Methyl 2-[(4-methoxybenzoyl)amino]-5-(8-quinolinyl)benzoate
Use of methyl 5-iodo-2-[(4-methoxybenzoyl)amino]benzoate (100 mg, 0.24 mmol) and 8-quinolineboronic acid (52 mg, 0.30 mmol) afforded the title compound (8 mg, 8%) as a beige solid by the application ofthe general procedure J described above. 1H NMR (CDCI3) £ 12.05 (br s, IH), 9.07 (d, J= 8.8 Hz IH), 8.97-8.95 (m, IH), 8.46 (s, IH), 8.23 (d, J= 8.3 Hz IH), 8.07 (d, J= 8.8 Hz 2H), 7.96 (d, J= 8.6 Hz IH), 7.85 (d, J= 8.1 Hz IH), 7.76 (d, J= 7.2 Hz IH), 7.65-7.59 (m, IH), 7.46-7.41 (m, IH), 7.04 (d, J= 9.0 Hz 2H), 3.96 (s, 3H), 3.90 (s, 3H); MS m/z (M+1) 413.
Step 3: Lithium 2-[(4-methoxybenzoyl)amino]-5-(8-quinolinyl)benzoate
Use of methyl 2-[(4-methoxybenzoyl)amino]-5-(8-quinolinyl)benzoate afforded the title compound (6 mg, 100%) as a brown solid by the application ofthe general procedure G described above. MS m/z (M-l) 397. EXAMPLE 78
Lithium 4-[(3,5-dichlorobenzoyl)amino] [1,1 '-biphenyl] -3-carboxylate
Figure imgf000081_0001
Step 1: Methyl 2-[(3,5-dichlorobenzoyl)amino]-5-bromobenzoate
Use of methyl-2-amino-5-bromobenzoate (1.0 g, 4.9 mmol) and 3,5- dichlorobenzoyl chloride (1.1 g, 5.4 mmol) afforded the title compound as a white solid (1.9 g, 86%) by the application ofthe general procedure E described above. 1H NMR (CDC13) £ 12.01 (br s, IH), 8.78 (d, J= 9.0 Hz IH), 8.23 (d, J=2.2 Hz IH), 7.87 (s, 2H), 7.71 (dd, J= 8.9, 2.3 Hz IH), 7.56 (d, J= 1.5 Hz IH), 4.00 (s, 3H); MS m/z (M) 402.
Step 2: Methyl 4-[(3, 5-dichlorobenzoyl) amino] [l,l'-biphenyl] -3-carboxylate Use of phenylboronic acid (38 mg, 0.31 mmol) afforded the title compound as a colorless solid (28 mg, 28%) by the application ofthe general procedure F described above. 1H NMR (CDC13) £12.07 (br s, IH), 8.89 (d, J= 8.8 Hz IH), 8.32 (d, J= 2.4 Hz IH), 7.90 (d, J=2.0 Hz IH), 7.84 (dd, J= 8.8, 2.2 Hz IH), 7.60 (d, J= 7.1 Hz 2H), 7.53 (s, IH), 7.48-7.36 (m, 3H), 4.00 (s, 3H); MS m/z (M+1) 400.
Step 3: Lithium 4- [(3, 5-dichlorobenzoyl) amino] [1,1 '-biphenyl) '-3-carboxylate
Use of methyl 4-[(3,5-dichlorobenzoyl)amino][l, -biphenyl]-3-carboxylate afforded the title compound (16 mg, 87%) as a colorless solid by the application ofthe general procedure G described above. MS m/z (M-l) 384.
EXAMPLE 79
Lithium 2-[(4-cyanobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
Figure imgf000082_0001
Step 1: Methyl 5-hydroxy-2-nitrobenzoate
To a stined suspension of 5-hydroxy-2-nitrobenzoic acid (5.1 g, 28 mmol) in methanol (20 ml) was added sulfuric acid (95%, 8 ml) at room temperature. The solution was stiπed at 90°C for 1 hour after which it was allowed to reach room temperature and carefully poured into saturated sodium bicarbonate. Subsequent extraction with dichloromethane, drying ofthe organic phase using magnesium sulfate and concentration in vacuo gave the title compound (2.8 g, 52%) as a yellow solid. 1H NMR (DMSO) £ 11.40 (br s, IH), 8.04 (d, J= 8.97 Hz IH), 7.05-6.98 (m, 2H), 3.82 (s, 3H); MS m/z (M-l) 196.
Step 2: Methyl 2-nitro-5-(2-thienylmethoxy)benzoate
DEAD (4.0 ml, 25 mmol) was added to a solution of methyl 5-hydroxy-2- nitrobenzoate (3.3 g, 17 mmol), triphenylphosphine (6.6 g, 25 mmol) and thiophene-2- methanol (1.8 ml, 18 mmol) in anhydrous THF (40 ml) and the solution was stiπed at room temperature over night. After being concentrated in vacuo the residue was purified by chromatography on silica gel, eluting with toluene, to give the title compound (700 mg, 14%). 1H NMR (CDC13) £ 8.03 (d, J= 8.98 Hz IH), 7.37 (dd, J= 5.01, 1.32 Hz IH), 7.16-7.00 (m, 4H), 5.31 (s, 2H), 3.92 (s, 3H); MS m/z (M-l) 292.
Step 3: Methyl 2-amino-5-(2-thienylmethoxy)benzoate
To a vigorously stiπed solution of methyl-2-nitro-5-(2-thienylmethoxy)benzoate (4.7 g, 16 mmol) in ethanol (180 ml) and THF (10 ml) was added Raney Nickel (in ethanol solution) and then immediately hydrazine hydrate (3.1 ml, 80 mmol). The mixture was stiπed at room temperature for 1 hour, filtered through a pad of Celite (pretreated with water) and the filtrate was concentrated in vacuo to give an yellow oil. Purification by chromatography on silica gel, eluting with 10% methanol in dichloromethane, afforded the title compound (400 mg, 10%). MS m/z (M+1) 264. Step 4: Methyl 2-[(4-cyanobenzoyl)amino]-5-(2-thienylmethoxy)benzoate General procedure H.
A mixture of 4-cyanobenzoic acid (56 mg, 0.38 mmol) and thionyl chloride (1.5 ml) was heated at 70°C in a sealed glass vial for 2.5 hours and then concentrated in vacuo. To the residue was added polymer-supported N-methyl morpholine (380 mg, 0.76 mmol) and methyl 2-amino-5-(2-thienylmethoxy)benzoate (50 mg, 0.19 mmol) in anhydrous dichloromethane (4 ml) and the mixture was shaken at room temperature over night. Filtration ofthe reaction mixture and concentration ofthe filtrate in vacuo gave a solid which subsequently was re-crystallized in acetonitrile to afford the title compound as a white solid (35 mg, 47%). 1H NMR (CDC13) £ 11.97 (s, IH), 8.82 (d, J= 9.24 Hz IH), 8.14-8.08 (m, 2H), 7.83-7.77 (m, 2H), 7.68 (d, J= 3.17 Hz IH), 7.34 (dd, J= 5.02, 1.06 Hz IH), 7.25 (dd, J= 9.23, 3.17 Hz IH), 7.13-7.10 (m, IH), 7.03-6.98 (m, IH), 5.24 (s, 2H), 3.96 (s, 3H); MS m/z (M+1) 393.
Step 5: Lithium 2-[(4-cyanobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
Use of 2-[(4-cyanobenzoyl)amino]-5-(2-thienylmethoxy)benzoate afforded the title compound (30 mg, 93%) as an yellow solid by the application ofthe general procedure B described above. 1H NMR (DMSO) £ 8.58 (d, J= 8.97 Hz IH), 8.19-7.97 (m, 4H), 7.70 (d, J= 2.90 Hz IH), 7.54 (d, J= 5.02 Hz IH), 7.19 (d, J= 2.90 Hz IH), 7.06-6.97 (m, 2H), 5.26 (s, 2H); MS m/z (M-l) 377.
EXAMPLE 80
Lithium 2-[(2,4-difluorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
Figure imgf000083_0001
Step 1: Methyl 2-[(2,4-difluorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
Use of 2,4-difluorobenzoic acid (60 mg, 0.38 mmol) afforded the title compound (32 mg, 42%o) as a white solid by the application ofthe general procedure H described above. 1H NMR (CDC13) £ 11.60 (d, J= 8.45 Hz IH), 8.79 (d, J= 9.23 Hz IH), 8.16- 8.06 (m, IH), 7.67 (d, J= 2.91 Hz IH), 7.33 (dd, J= 5.01, 1.32 Hz IH), 7.23 (dd, J= 9.50, 3.16 Hz IH), 7.13-7.10 (m, IH), 7.05-6.88 (m, 3H), 5.24 (s, 2H), 3.94 (s, 3H); ); MS m/z (M+1) 404.
Step 2: Lithium 2-[(2,4-difluorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
Use of methyl 2-[(2,4-difluorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate afforded the title compound (10 mg, 57%) as a white solid by the application ofthe general procedure B described above. 1H NMR (CD3OD) £ 8.55 (d, J= 9.23 Hz IH), 8.00-7.87 (m, IH), 7.74 (d, J= 3.17 Hz IH), 7.39 (dd, J= 5.01, 1.05 Hz IH), 7.18-6.96 (m, 5H), 5.27 (s, 2H); MS m/z (M-l) 388.
EXAMPLE 81
Lithium 2-[(2-chIorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate
Figure imgf000084_0001
Step 1: Methyl 2-[(2-chlorobenzoyl)amino]-5-hydroxybenzoate
Use of 2-chlorobenzoic acid (580 mg, 2.4 mmol) afforded the title compound (460 mg, 63%) as a beige solid by the application ofthe general procedure H described above. 1H NMR (CDCI3) £ 11.25 (s, IH), 8.72 (d, J= 9.23 Hz IH), 7.67-7.62 (m, IH), 7.53 (d, J = 2.90 Hz IH), 7.48-7.31 (m, 3H), 7.12 (dd, J= 9.23, 2.91 Hz IH), 3.87 (s, 3H); MS m/z (M-l) 306.
Step 2: Methyl 2-[(2-chlorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate Use of methyl 2-[(2-chlorobenzoyl)amino]-5-hydroxybenzoate (150 mg, 0.49 mmol) afforded the title compound (44 mg, 21%) as an yellow oil by the application of the general procedure C described above. 1H NMR (CDC13) £ 11.49 (s, IH), 9.02 (d, J= 8.97 Hz IH), 8.40-8.30 (m, 2H), 7.90 (d, J= 2.90 Hz IH), 7.67-7.62 (m, IH), 7.49-7.35 (m, 4H), 7.21-7.15 (m, IH), 3.88 (s, 3H); MS m/z (M+1) 428. Step 3: Lithium 2-[(2-chlorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate
Use of methyl 2-[(2-chlorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate afforded tlie title compound (40 mg, 93%) as an yellow solid by the application ofthe general procedure B described above. 1H NMR (DMSO) £ 15.03 (s, IH), 8.68-8.53 (m, 2H), 8.44-8.38 (m, IH), 7.74 (d, J= 2.64 Hz IH), 7.65-7.31 (m, 5H), 7.19 (dd, J= 8.97, 2.90 Hz IH); MS m/z (M-l) 412.
EXAMPLE 82 Lithium 2-[(2-chloro-5-nitrobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
Figure imgf000085_0001
Step 1: Methyl 2-amino-5-(2-thienylmethoxy)benzoate hydrochloride A solution of tert-butylazodicarboxylate (TMAD) (4.21g, 18.3 mmol) in dry THF
(10 ml) was added dropwise to a solution of methyl-(2-amino-5-hydroxy)benzoate (2.03 g, 12.2 mmol; see Example 1), triphenylphosphine (6.40 g, 24.4 mmol) and thiophene-2- methanol (1.53 g, 13.4 mmol) in dry THF (90 ml) at 0°C, turning the solution from purple to green. After 15 minutes, the solution was warmed to ambient temperature and left to stir overnight. Concentration in vacuo followed by purification using flash chromatography on SiO2 (gradient system 100% heptane-4%ethylacetate/heptane) gave a total of 1.68g ofthe free base. This was then dissolved in ether followed by addition of hydrochloric acid/ether, to give, after filtration and drying, (1.2 g, 33%) ofthe title compound as a white solid. 1H NMR (CD3OH): δ 7.75 (d, IH), 7.40 (m, 3H), 7.20 (d, IH), 7.00 (m, IH), 5.35 (s, 2H), 3.95 (s, 3H); MS m/z (M) 263.
Step 2: Methyl 2-[(2-chloro-5-nitrobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
Use of methyl 2-amino-5-(2-thienylmethoxy)benzoate hydrochloride (200 mg, 0.67 mmol) and 2-chloro-5-nitrobenzoic acid (135 mg, 0.67 mmol) afforded the title compound (70 mg, 23%) as an yellow solid by the application ofthe general procedure H described above. 1H NMR (CDC13) £ 11.47 (s, IH), 8.79 (d, J- 8.97 Hz IH), 8.52 (d, J = 2.64 Hz IH), 8.25 (dd, J= 8.71, 2.64 Hz IH), 7.70-7.62 (m, 2H), 7.35 (dd, J= 5.02, 1.06 Hz IH), 7.30-7.24 (dd, J= 9.24, 3.17 Hz IH), 7.14-7.11 (m, IH), 7.04-6.99 (m, IH), 5.26 (s, 2H), 3.91 (s, 3H); MS m/z (M+1) 447.
Step 3: Lithium 2-[(2-chloro-5-nitrobenzoyl)amino]-5-(2-thienylmethoxy)benzoate
Use of methyl 2-[(2-chloro-5-nitrobenzoyl)amino]-5-(2-thienylmethoxy)benzoate afforded the title compound (30 mg, 88%) as an yellow solid by the application ofthe general procedure B described above. 1H NMR (DMSO) £ 15.40 (s, IH), 8.48 (d, J= 8.98 Hz IH), 8.38 (d, J= 2.64 Hz IH), 8.31 (dd, J= 8.70, 2.63 Hz IH), 7.87 (d, J= 8.71
Hz IH), 7.66 (d, J= 3.17 Hz IH), 7.54 (dd, J= 5.01, 1.05 Hz IH), 7.21-7.17 (m, IH),
7.06-6.98 (m, 2H), 5.26 (s, 2H); MS m/z (M-l) 431.
EXAMPLE 83 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[l-methyl-lH-imidazol-4- yl)sulfonyl]amino}ethoxy)ethoxy]benzoate
Figure imgf000086_0001
Step 1: 2-(2-N-Boc-aminoethoxy)ethanol
To a solution of 2-(2-aminoethoxy)ethanol (5.3 g, 50 mmol) and diisopropylethylamme (13 ml, 75 mmol) in DCM (10 ml) at 0°C was added dropwise a solution of di-tert-butyl dicarbonate (12 g, 55 mmol) in DCM (20 ml). The reaction was agitated for 4 hours, extracted with DCM and purified by flash chromatography (EtOAc/PE) (75/25) to give the title compound (5.9 g, 60%). 1H NMR (CDC13) £3.65 (dd, J= 8.6, 3.8 Hz 2H), 3.47 (m, 5H), 2.23 (dd, J= 8.6, 3.8 Hz 2H), 1.35 (s, 9H); 13C NMR (CDC13) d 156.1, 79.1, 72.1, 70.1, 61.3, 40.3, 28.2.
Step 2: Methyl 5-[2-(2-aminoethoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate trifluoroacetate
To methyl 2-[(2,4-dichlorobenzoyl)amino]-5-hydroxybenzoate (1.19 g, 3.50 mmol, from Example 1, Step 2) in dry THF (20 ml) were added 2-(2-N-Boc- aminoethoxy)-ethanol (0.9 g, 4.40 mmol) in dry THF and resin-bound PI13P. The suspension was cooled down to 0°C before the addition of a dry THF (10 ml) solution of TMAD (0.9 g, 5.25 mmol). The reaction was then agitated for 12 hours before complete conversion was assessed to have taken place by TLC analysis. After extraction in DCM and flash chromatography purification (Et Ac / PE) (40 / 60), the compound was agitated in (TFA / DCM) (50 / 50) (10 ml) for 4 hours. Conversion was complete as assessed by TLC analysis and the title product was isolated (1.7 g, 90%) as a solid. MS m/z (M+1) 427.
Step 3: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(l-methyl-lH-imidazol-4- yl)sulfonyl] amino} ethoxy) ethoxy] benzoate General procedure X
A solution of methyl 5-[2-(2-aminoethoxy)ethoxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate trifluoroacetate (0.20 mmol), 1 -methyl- lH-imidazole-4- sulfonyl chloride (0.21 mmol) and resin-bound DIPEA (0.70 mmol) in
(acetonitrile/dichloroethane) (1/1) (3.5 ml) was agitated at room temperature for 20 hours and then at 75°C for 5 hours. After filtration, the solvents were evaporated. The crude material was purified by preparative LC-MS yielding the title product (14 mg, 12%). MS /z (M+l)571.
Step 4: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[l-methyl-lH-imidazol-4- yl)sulfonyl] amino} ethoxy) ethoxy] benzoate General procedure Y
To a solution of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(l-methyl-lH- imidazol-4-yl)sulfonyl] amino} ethoxy)ethoxy]benzoate in THF (2 ml) was added 2 eq of IM LiOH. The reaction was stiπed for as long as need for the hydrolysis to be shown to be complete by TLC assessment. Evaporation ofthe solvents gave the title compound (12 mg, 89%); MS m/z (M-l) 555.
EXAMPLE 84
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-{2-[2-(2-pyridinylamino)ethoxy]ethoxy} benzoate
Figure imgf000088_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-{2-[2-(2-pyridinylamino)ethoxy] ethoxy} benzoate
A solution of methyl 5-[2-(2-aminoethoxy)ethoxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate trifluoroacetate (0.42 mmol, prepared in Example 83, Step 2), 2-fluoropyridine (4.20 mmol) and TEA (6.30 mmol) in acetonitrile (10 ml) was heated at reflux for 4 days. The reaction was quenched with water, the products were extracted, and the solvent was concentrated. The crude material was purified by preparative LC-MS yielding the title compound (28 mg, 14%). 1H NMR (CDC13) £ 11.30 (s, 1 H), 8.75 (dd, J= 9.1, 6.6 Hz 1 H), 7.75-6.65 (m, 9 H), 4.15 (m, 2 H), 3.90 (s, 3 H), 3.80 (m, 4 H), 3.55 (m, 2 H); MS m/z (M+l)506.
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-{2-[2-(2- pyridinylamino) ethoxy] ethoxy} benzoate
To a solution of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-{2-[2-(2- pyridinylamino) ethoxy] ethoxy} benzoate (27 mg) in THF (2 ml) was added 2 eq of IM LiOH. The reaction was stined for as long as need for the hydrolysis to be shown to be complete by TLC assessment. After evaporation ofthe solvents, the title compound was isolated in a quantitative yield. MS m/z (M-l) 488.
EXAMPLE 85
Lithium 5-[2-(2~{[(3-chloro-4-methylphenyl)sulfonyl] amino}ethoxy)ethoxy]-2-[(2,4- dichlorobenzoyl)amino] benzoate
Figure imgf000089_0001
Step 1: Methyl 5-[2-(2-{[(3-chloro-4-methylphenyl)sulfonyl]amino}ethoxy)ethoxy]-2-
[(2, 4-dichlorobenzoyl) amino) 'benzoate
Use of 3-chloro-4-methylbenzene-l-sulfonyl chloride (47 mg, 0.21 mmol) afforded the title compound (14 mg, 11%) by the application ofthe general procedure X described above. MS m/z (M+1) 617.
Step 2: Lithium 5-[2-(2-{ [(3-chloro-4-methylphenyl)sulfonyl) ' amino} ethoxy) ethoxy) '-2- [(2, 4-dichlorobenzoyl) amino] benzoate
Use of methyl 5-[2-(2-{[(3-chloro-4- methylphenyl)sulfonyl]amino}ethoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate (14 mg, 0.22 mmol) afforded the title compound (14 mg, 82%) by the application ofthe general procedure Y described above. MS m/z (M-l) 601.
EXAMPLE 86 Lithium 2-[(2,4-dichIorobenzoyl)amino]-5-(2-{2-[(3-pyridinylsulfonyl)amino] ethoxy}ethoxy)benzoate
Figure imgf000090_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2-{2-[(3- pyridinylsulfonyl)amino]ethoxy}ethoxy)benzoate
Use of pyridine-3-sulfonyl chloride (37 mg, 0.21 mmol; Corey, E. J. et al.; J.Org.Chem.; EN; 54; 2; 1989; 389-393) afforded the title compound (8 mg, 6%) by the application ofthe general procedure X described above. MS m/z (M+1) 568.
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-(2-{2-[(3-pyridinylsulfonyl)amino] ethoxy}ethoxy)benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-(2-{2-[(3- pyridinylsulfonyl)amino] ethoxy} ethoxy)benzoate (7.2 mg, 0.13 mmol) afforded the title compound (7.7 mg, 84%) by the application ofthe general procedure Y described above. MS m/z (M-l) 553.
EXAMPLE 87
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(2,4- difluoroanilino)carbonyl] amino} ethoxy)ethoxy]benzoate
Figure imgf000091_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(2,4- difluoroanilino)carbonyl] amino} ethoxy) ethoxy] benzoate
A suspension of methyl 5-[2-(2-aminoethoxy)ethoxy]-2-[(2,4- dichlorobenzoyl)amino]benzoate trifluoroacetate (90 mg, 0.16 mmol), 2,4-difluorophenyl isocyanate (40 mg, 0.26 mmol) and resin-bound diisopropylethylamme (0.40 mmol) in acetonitrile:DCM (1:1) (6 ml) was agitated at room temperature for 20 hours. After filtration and evaporation the residue was purified by preparative LC-MS to give the title compound (16 mg, 17%). MS m/z (m+1) 582.
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(2,4- difluoroanilino)carbonyl] amino} ethoxy) ethoxy] benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(2,4- difluoroanilino)carbonyl] amino} ethoxy)ethoxy]benzoate (16 mg, 0.027 mmol) afforded the title compound (17 mg, 97%) by the application ofthe general procedure Y described above. MS m/z (M-l) 566.
EXAMPLE 88 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(4-fluoroanilino)carbonyI]amino} ethoxy)ethoxy]benzoate
Figure imgf000092_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(4- fluoroanilino)carbonyl] amino} ethoxy) ethoxy] benzoate
Use of 4-fluorophenyl isocyanate (29 mg, 0.21 mmol) afforded the title compound (2.1 mg, 2%) by the application ofthe general procedure X described above. MS m/z (M+1) 564.
Step 2: Methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(4~ fluoroanilino)carbonyl] amino} ethoxy) ethoxy] benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(4- fluoroanilino)carbonyl]amino} ethoxy)ethoxy]benzoate (2.1 mg, 0.0037 mmol) afforded the title compound (3.3 mg, 81%) by the application ofthe general procedure Y described above. MS m/z (M-l) 548.
EXAMPLE 89 Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(4- isopropylanilino)carbonyl] amino} ethoxy)ethoxy]benzoate
Figure imgf000093_0001
Step 1: Methyl 2-[(2,4-dichlorobenzoyl)amino] -5-[2-(2-{ [(4- isopropylanilino)carbonyl] amino} ethoxy) ethoxy] benzoate Use of 4-isopropylphenyl isocyanate (34 mg, 0.21 mmol) afforded the title compound (24 mg, 20%) by the application ofthe general procedure X described above. MS m/z (M+1) 588.
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(4- isopropylanilino)carbonyl] amino} ethoxy) ethoxy] benzoate
Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-{[(4- isopropylanilino)carbonyl]amino}ethoxy)ethoxy]benzoate (24 mg, 0.041 mmol) afforded the title compound (25 mg, 95%) by the application ofthe general procedure Y described above. MS m/z (M-l) 572.
EXAMPLE 90
Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(methylsulfanyl)ethoxy]benzoate
Figure imgf000094_0001
Step 1: Methyl 2- [(2, 4-dichlorobenzoyl) amino] -5 -[2-(methylsulfanyl)ethoxy] benzoate Use of 2-(methylsulfanyl)ethanol afforded the title compound (8 mg, 4%), as a white solid, by the application ofthe general procedure A described above. 1H NMR (CDC13) £ 11.30 (s, IH), 8.78 (d, J = 9.23 Hz IH), 7.62-7.55 (m, 2H), 7.48 (d, J = 2.12 Hz IH), 7.35 (dd, I = 8.31, 1.98 Hz IH), 4.17 (t, J = 6.86 Hz 2H), 3.90 (s, 3H), 2.89 (t, J = 6.86 Hz 2H), 2.22 (s, 3H); MS 414 mlz (M+1).
Step 2: Lithium 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(methylsulfanyl)ethoxy] benzoate Use of methyl 2-[(2,4-dichlorobenzoyl)amino]-5-[2- (methylsulfanyl)ethoxy]benzoate afforded the title compound (4.4 mg, 100%) as a white solid by the application ofthe general procedure B described above. MS mlz 398 (M-l).
BIOLOGICAL METHODS
(I) Cell-based reporter assays
The effect of compounds according to the invention on activation of PPARα and PPARγ were determined. Reporter gene assays were performed essentially as described in Bertilsson et al., 1998 (Proc. Natl. Acad. Sci. U.S.A. 95:12208-12213), by transient co-transfections of CaCo2/TC cells with a GAL- 4-LBD (Ligand Binding Domain) fusion constructs, containing the nucleotide sequence coπesponding to human PPARαLBD (i.e. amino acid residuesl67- 468) or human PPARγLBD (i.e. amino acid residues 204-477), together with a 4xUAS-luciferase reporter gene construct, using the FuGENE-6 transfection reagent (Roche) according to the manufacturers recommendations. After 24 hours, the cells were treated with trypsin, transfeπed to 96-well microplates and allowed to settle. Induction was performed for 24 hours by applying different concentrations of compounds diluted in DMSO or DMSO alone (vehicle).
Subsequently, the cells were lysed and luciferase activity measured, according to standard procedures. Experiments were performed in quadruplicate on at least three occasions.
The compounds of formula I exhibit EC50 values on PPARα and PPARγ in the range of 1-35 μM and 0.3-50 μM, respectively.
(II) Ligand binding assays
Crude extracts were prepared from E. coli (BL21(DE3)pLysS, Novagen) producing GST-PPARαLBD or GST-PPARγLBD fusion proteins by freeze thawing in buffer containing 50 mM Tris-HCl pH 7.9, 250 mM KC1, 10% glycerol, 1% Triton X-100, 10 mM DTT, lmM PMSF, 10 μg/mL DNase and 10 mM MgCl. Competitive ligand binding assays were performed on immobilized GST-PPARαLBD or GST-PPARγLBD fusion proteins from crude extracts incubated with glutathione-Sepharose 4B (Amersham Pharmacia Biotech). Following immobilization, the sluπy was washed three times in binding buffer containing 50 mM Tris-HCL, pH7.9, 50 mM KC1, 0.1% Triton-XlOO, 10 mM DTT, 2 mM EDTA, dispensed in 96-well filter plates (MHVB N45, Millipore) and incubated with a fixed amount tritiated ligand and different concentrations of cold competing ligands. Equilibrium binding was reached after incubation for 2 hours at room temperature on a plate shaker. The plates were then washed 3 times in binding buffer, dried overnight at room temperature followed by scintillation counting after the addition of 25 μl of scintillant (Optiscint Hisafe, Wallac) per well. Each experiment was performed in duplicate and repeated independently at least three times. 3H-BRL49653 (ART-605; American Radiolabeled Chemicals, USA) was used as the tracer in PPARγ competitive ligand binding experiments at a concentration of 30 nM (10). 3H-GW2331 (70 nM) was synthesized at Pharmacia Corporation and used as the tracer in PPARα competitive ligand binding experiments (Kliewer, S.A. et al. (1997) Proc. Natl. Acad. Sci. U.S.A. 94: 4318-4323).
The compounds of formula I exhibit Kj values on PPARα and PPARγ in the range of 1-70 μM and 0.3-35 μM, respectively.
(Ill) In vivo experiment
Selected compounds of formula I were tested in animal models of relevance for measuring PPARγ efficacy. The animal model used was ob/ob mouse and as a reference compound the known PPARγ ligand, rosiglitazone. The animals were orally treated during 7 days and parameters as food intake, body weight, plasma glucose, insulin, cholesterol, triglycerides and free fatty acids were monitored. Compounds of formula I were shown to give dose related pharmacological effects.
STRUCTURAL STUDIES OF A REPRESENTATIVE FROM THE COMPOUND SERIES
The structure of PPARγ ligand binding domain (LBD) has previously been described in literature (Nolte, R. T. et al. (1998) Nature 395: 137-143; Uppenberg, J. et al. (1998) J. Biol. Chem. 273: 31108-31112). The present inventors have determined the structure of human PPARγ LBD in complex with one ofthe compounds (Example 1) according to the invention. As indicated in Fig. 1, the compound according to Example 1 was shown to be located in the ligand binding pocket of human PPARγ. The compound was found in an elongated conformation and occupied a region in proximity with, and approximately parallel to, helix 3 (the numbering of helices and strands follow the convention of Uppenberg et al. supra) and in proximity to beta-strand 3 and helices 5 and 2b.
The interactions between the compound (ligand) according to the invention and human PPARγ can be separated into four categories: (1) Interaction between the dibromo-phenyl moiety ofthe ligand and the predominantly hydrophobic pocket of human PPARγ, in particular the side chains of Ile326, Met329, Leu330, Leu333, Ala292 and Arg288.
(2) Interaction between the carbonyl oxygen on the peptide linker ofthe ligand and the side chain sulfur, as well as the backbone carbonyl oxygen, of Cys285 in human
PPARγ.
(3) Interaction between the central benzoic acid moiety ofthe ligand and human PPARγ. The central benzoic acid moiety is located in a narrow groove in the protein made up by the side chains of Met364, Ile341, Cys285 and Arg288, but also the backbone atoms of Cys285, Ala284 and Ser342. The interactions are hydrophobic in nature, with the exception of a distinct hydrogen bond formed between the backbone nitrogen of Ser342 and one ofthe carboxylate oxygens ofthe ligand.
(4) Interaction between the thiophene tail ofthe ligand and human PPARγ. This interaction is predominantly hydrophobic in nature. The protein atoms involved belong to the side chains and backbone of Leu255, Ile281 and Arg280.
It has been argued that the activation of nuclear receptors, including PPARγ, follows a common mechanism where a ligand binds in the ligand binding pocket and thereby stabilizes helix 12, which in turn allows for the recruitment of coactivator proteins and subsequent activation ofthe transcriptional machinery. Furthermore it has been reported (Elbrecht, A. et al. (1999) J. Biol. Chem. 274: 7913-7922) that Cys 285 on helix 3 is also important for the induction of conformational changes mediating this mechanism. Ligands, binding in different parts ofthe binding pocket, have been reported to show varying and tissue specific agonistic effects from full to partial agonism, as illustrated by the estrogen receptor (McDonnell, D. P. et al. (1995) Mol. Endocrinol. 9: 659-669; Mueller-Fahrnow, A. and Egner, U. (1999) Current opinion in Biotechnology 10: 550- 556). Compared with previously disclosed PPAR ligands, the compounds according to the invention bind in a novel binding mode. These compounds modulate the activity of PPARs in a range of agonistic effects determined in a cell based reporter assay.

Claims

1. A compound of the formula I
Figure imgf000098_0001
or a pharmaceutically acceptable salt or a prodrug form thereof, wherein
Ar is aryl, which is optionally substituted in one or more positions by halogen, cyano, nitro,
Cx.6 alkyl,
Ci_g alkoxy,
Cι_6 alkylthio fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, allyloxy, aryloxy, or arylthio;
X is a bond, a heteroalkyl chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms, or a formula
-O— (CH2)n— Y—
wherein m is 0, 1, or 2, n is O, 1, 2, or 3, and Y is a bond, O, S, NH, NHSO2, NHC(O)NH, or CH=CH;; and
R is a Ci-Ce-alkyl or an optionally substituted aryl or heteroaryl group, with the proviso that when X is a bond or O, then R is not a Ci-Cό-alkyl; or that said compound is not a dibenzoyl-bisanthranilic acid, or
(4,4'-bis [( 1 -naphthalenylcarbonyl) amino] -[1,1 '-Biphenyl] -3,3'- dicarboxylic acid.
2. The compound according to claim 1 wherein Ar is an, optionally substituted, phenyl or naphthyl.
3. The compound according to claim 2 wherein Ar is phenyl, substituted in one or more positions independently by halogen, nitro, cyano, methoxy, or trifluoromethyl.
4. The compound according to claim 3 wherein the said phenyl group is substituted in one or more positions by halogen.
5. The compound according to claim 4 wherein Ar is 2,4-dichlorophenyl.
6. The compound according to any one of claims 1 to 5 wherein X is O-(CH2)n,
O-(CH2)n-Y - and Y is an atom selected from O, N and S, O-(CH2)2-O-(CH2)2-NH,
O-(CH2)2-O-(CH2)2-NHSO2, or O-(CH2)2-O-(CH2)2-NHCONH.
7. The compound according to claim 6 wherein X is O,
O-CH2, O-(CH2)2,
O-(CH2)2-O, or O-(CH2)2-S.
8. The compound according to any one of claims 1 to 5 wherein X is a bond.
9. The compound according to any one of claims 1 to 8 wherein R is an optionally substituted aryl or heteroaryl group.
10. The compound according to any one of claims 1 to 9 wherein R is selected from the group consisting of, optionally substituted, phenyl, naphthyl, thienyl, pyridinyl, quinoxalinyl, benzoylphenyl, thiazolyl, furyl, imidazolyl, oxazolyl, pyrazinyl, quinolinyl, indolyl, benzofuran, benzothiophenyl (benzothienyl), pyrimidinyl, benzodioxolyl.
11. The compound according to claim 10 wherein the group R is independently substituted in one or more positions with
C1-6-alkyl,
Figure imgf000100_0001
Ci.g-alkylthio, Ci.g-acyl, cyano, nitro, hydroxy, methylhydroxy, carboxy, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, halogen, formyl, amino,
C^.g-alkylamino, di(Cι_6-alkyl)amino or Cι_6-acylamino, aryl, aryloxy, arylthio,
C j .6-alkylsulphonyl,
C2.6.allyloxy, benzyloxy, benzoyl.
12. The compound according to claim 11 wherein R is independently substituted in one or more positions with methyl, ethyl, isopropyl, methoxy, thiomethoxy ethoxy, methylsulfonyl, formyl, acetyl, nitro, cyano, methylhydroxy, methylamino, carboxy, trifluoromethyl, trifluoromethoxy, chloro, fluoro, bromo, iodo, benzyloxy, amino, dimethylamino, acetylamino, phenyl, or phenoxy, benzoyl.
13. The compound according to any one of claims 1 to 7 wherein R is methyl.
14. The compound according to claim 1 which is the compound
2-[(2,4-dichlorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(3-pyridinylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate, 5-[2-(3-chlorophenyl)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[(4-ethoxybenzyl)oxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-{[3-(dimethylamino)benzyl] oxy}benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methylphenyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(l-naphthyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyridinylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2- {[2-(methylsulfanyl)-3- pyridinyl]oxy} ethoxy)benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-pyridinyloxy)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-quinoxalinyloxy)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-{2-[2-(methylsulfanyl)phenoxy] ethoxy}benzoate,
5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2,3,6-trifluorophenoxy)ethoxy]benzoate, 5-[2-([l,l'-biphenyl]-3-yloxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(phenylsulfanyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(4-methyl-l,3-thiazol-5-yl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(3-furylmethoxy)berιzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-thienyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH-imidazol-l- yl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-(3-thienylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-pyridinylsulfanyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-thiazol-4- yl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4- yl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-ethyl-2-pyridinyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methoxyphenoxy)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(4-pyridinylmethoxy)benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[3-(3-pyridinyl)propoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-pyridinyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methoxyphenyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[(3-nitro-2-pyridmyl)oxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[(5-nitro-2-pyridinyl)oxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-{[5-(trifluoromethyl)-2-pyridinyl]oxy}benzoate, 5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyrimidinyloxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-{[(2E)-3-phenyl-2-propenyl]oxy}benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[(3-methoxybenzyl)oxy]benzoate,
2- [(2, 4-dichlorobenzoyl) amino] -5 -(3 -thienyl)benzoate, 2-[(2, 4-dichloroberιzoyl)amino]-5-(2, 4-dichlorophenyl)benzoate, 2-[(2, 4-dichlorobenzoyl)amino]-5-(4-ethylphenyl)benzoic acid, 2-[(2,4-dichlorobenzoyl)amino]-5-(8-quinolinyl)benzoic acid, 5-(l ,3-benzodioxol-5-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid,
2-[(2,4-dichlorobenzoyl)amino]-5-(2,4-dimethoxy-5-pyrimidinyl)benzoic acid, 3'-(acetylamino)-4-[(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl] -3 -carboxylic acid, 4-[(2,4-dichlorobenzoyl)amino]-3'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxylic acid, 4-[(2,4-dichlorobenzoyl)amino]-3'-ethoxy[l, -biphenyl]-3-carboxylic acid, 5-(l-benzofuran-2-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid, 4-[(2,4-dichlorobenzoyl)amino]-3'-(hydroxymethyl)[ 1 , 1 '-biphenyl]-3-carboxylic acid, 4- [(2,4-dichlorobenzoyl) amino] -3 '-formyl[ 1 , 1 '-biphenyl] -3 -carboxylic acid,
2-[(2,4-dichlorobenzoyl)amino]-5-(2-naphthyl)benzoic acid, 4-[(2,4-dichlorobenzoyl)amino]-3'-isopropyl-6'-methoxy[l , 1 '-biphenyl] -3- carboxylic acid, 4-[(2,4-dichlorobenzoyl)amino]-4'-fluoro[l, -biphenyl]-3-carboxylic acid, 2-[(2,4-dichloroberιzoyl)amino]-5-(2-furyl)benzoate,
5-(l-benzotlιien-3-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-formyl-3-thienyl)benzoate, 5-(5-acetyl-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(lH-indol-5-yl)benzoic acid, 5-(3-carboxyphenyl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid,
2'-(benzyloxy)-4-[(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl] -3 -carboxylate,
4-[(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl]-3 -carboxylate,
4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l,r-biphenyl]-3-carboxylate,
4- [(2,4-dichlorobenzoyl) amino] -3 '-(trifluoromethyl) [1,1 '-biphenyl] -3 -carboxylate, 5-(5-chloro-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate,
4-[(2,4-dichlorobenzoyl)amino]-4'-phenoxy[ 1 , 1 '-biphenyl]-3-carboxylate,
4-[(2,4-dichlorobenzoyl)amino]-2',5'-dimethoxy[l,r-biphenyl]-3-carboxylate,
3 '-(aminomethyl)-4- [(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl]-3 -carboxylic acid,
2-(2-naphthoylamino)-5-(3-thienyl)benzoate, 3'-(acetylamino)-4-(2-naphthoylamino)[l, -biphenyl]-3-carboxylate
3 '-(hydroxymethyl)-4-(2-naphthoylamino) [1,1 '-biphenyl] -3 -carboxylate, 5-(3-thienyl)-2-{[4-(trifluoromethyl)benzoyl]amino}benzoate, 3'-(acetylamino)-4- { [4-(trifluoromethyl)benzoyl]amino} [1,1 '-biphenyl] -3- carboxylate, 3 '-(hydroxymethyl)-4- { [4-(trifluoromethyl)benzoyl] amino } [ 1 , 1 '-biphenyl] -3 - carboxylate,
2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-5-(8-quinolinyl)benzoate, 4- { [3 ,5 -bis(trifluoromethyl)benzoyl] amino } -3 '-formyl[ 1 , 1 '-biphenyl] -3 -carboxylate, 2-[(4-methoxybenzoyl)amino]-5-(8-quinolinyl)benzoate, 4-[(3,5-dichlorobenzoyl)amino] [1 , 1 '-biphenyl]-3-carboxylate, 2-[(4-cyanobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, 2-[(2,4-difluorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, 2-[(2-chlorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate, 2-[(2-chloro-5-nitrobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, or
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(methylsulfanyl)ethoxy]benzoate.
15. A compound according to any one of claims 1 to 14 for use in therapy.
16. A pharmaceutical formulation containing a compound according to any one of claims 1 to 14 as an active ingredient in combination with a pharmaceutically acceptable diluent or earner.
17. Use of a compound according to the fonnula I
Figure imgf000105_0001
or a pharmaceutically acceptable salt or a prodrug form thereof, wherein
Ar is aryl, which is optionally substituted in one or more positions by halogen, cyano, nitro,
C1-6 alkyl, Cj.g alkoxy,
C g alkylthio fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, allyloxy, aryloxy, or arylthio;
X is a bond, or a heteroalkyl chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms, or a formula
- — (CH2)n- -Y- m wherein m is 0, 1, or 2, n is 0, 1, 2, or 3, and
Y is a bond, O, S, NH, NHSO2, NHC(O)NH, or CH=CH;; and
R is C;ι-C6-alkyl or an optionally substituted aryl or heteroaryl group,
for the manufacture of a medicament for use in the treatment or prevention of diabetes.
18. The use according to claim 17, wherein the said compound is 2-[(2,4-dichlorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(3-pyridinylmethoxy)benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate, 5-[2-(3-chlorophenyl)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[(4-ethoxybenzyl)oxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-{[3-(dimethylamino)benzyl] oxy}benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methylphenyl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(l-naphthyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyridinylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-{[2-(methylsulfanyl)-3- pyridmyljoxy} ethoxy)benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-pyridinyloxy)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-quinoxalinyloxy)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5- {2-[2-(methylsulfanyl)phenoxy] ethoxy}benzoate,
5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)arnino]-5-[2-(2,3,6-trifluorophenoxy)ethoxy]benzoate, 5-[2-([l, -biphenyl]-3-yloxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(phenylsulfanyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(4-methyl-l,3-thiazol-5-yl)ethoxy]benzoate, 2-[(2,4-dichlorobeιιzoyl)amino]-5-(3-furylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-thienyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH-imidazol-l- yl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-(3-thienylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-pyridinylsulfanyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-thiazol-4- yl)ethoxy]benzoate,
2- [(2,4-dichlorobenzoyl)amino] -5 - [2-(5 -methyl-2-phenyl- 1 ,3 -oxazol-4- yl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-ethyl-2-pyridinyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methoxyphenoxy)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(4-pyridinylmethoxy)benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[3-(3-pyridinyl)propoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-pyridinyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methoxyphenyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[(5-nitro-2-pvridinyl)oxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-{[5-(trifluoromethyl)-2-pyridinyl]oxy}benzoate, 5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyrimidinyloxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-{[(2E)-3-phenyl-2-propenyl]oxy}benzoate, 2-[(2,4-dichlorobenzoyl)amino] -5-[(3 -methoxybenzyl)oxy]benzoate, 2-[(2, 4-dichlorobenzoyl)amino]-5-(3-thienyl)benzoate, 2-[(2, 4-dichlorobenzoyl)amino]-5-(2, 4-dichlorophenyl)benzoate, 2-[(2, 4-dichlorobenzoyl)amino]-5-(4-ethylphenyl)benzoic acid, 2-[(2,4-dichlorobenzoyl)amino]-5-(8-quinolinyl)benzoic acid,
5-(l,3-benzodioxol-5-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid, 2-[(2,4-dichlorobenzoyl)amino]-5-(2,4-dimethoxy-5-pyrimidinyl)benzoic acid, 3'-(acetylamino)-4-[(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl]-3-carboxylic acid, 4-[(2,4-dichlorobenzoyl)amino] -3 '-(trifluoromethoxy) [ 1 , 1 '-biphenyl]-3 -carboxylic acid,
4-[(2,4-dichlorobenzoyl)amino]-3'-ethoxy[l, -biphenyl]-3-carboxylic acid, 5-(l-benzo fur an-2-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid, 4-[(2,4-dichlorobenzoyl)amino]-3'-(hydroxymethyl)[l,r-biphenyl]-3-carboxylic acid, 4-[(2,4-dichlorobenzoyl)amino]-3'-formyl[l, -biphenyl]-3-carboxylic acid,
2-[(2,4-dichlorobenzoyl)amino]-5-(2-naphthyl)benzoic acid, 4-[(2,4-dichlorobenzoyl)amino]-3'-isopropyl-6'-methoxy[l,l'-biphenyl]-3- carboxylic acid, 4-[(2,4-dichlorobenzoyl)amino]-4'-fluoro[l ,1 '-biphenyl]-3-carboxylic acid, 2-[(2,4-dichlorobeιιzoyl)arnino]-5-(2-furyl)benzoate,
5-(l-benzothien-3-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dicMorobenzoyl)amino]-5-(2-formyl-3-thienyl)benzoate, 5-(5-acetyl-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(lH-indol-5-yl)benzoic acid, 5-(3-carboxyphenyl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid,
2'-(benzyloxy)-4-[(2,4-dichlorobenzoyl)amino][l,r-biphenyl]-3-carboxylate, 4-[(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl]-3 -carboxylate, 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l, -biphenyl]-3-carboxylate, 4-[(2,4-dichlorobenzoyl)amino]-3'-(trifluoromethyl)[l, -biphenyl]-3-carboxylate, 5-(5-chloro-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate,
4-[(2,4-dichlorobenzoyl)amino]-4'-phenoxy[l, -biphenyl]-3-carboxylate, 4-[(2,4-dichlorobenzoyl)amino]-2',5'-dimethoxy[l, -biphenyl]-3-carboxylate, 3'-(aminomethyl)-4-[(2,4-dichlorobenzoyl)amino][l,r-biphenyl]-3-carboxylic acid, 2-(2-naphthoylamino)-5-(3-thienyl)benzoate, 3'-(acetylamino)-4-(2-naphthoylamino)[l, -biphenyl]-3-carboxylate 3'-(hydroxymethyl)-4-(2-naphthoylamino)[l, -biphenyl]-3-carboxylate, 5-(3-thienyl)-2-{[4-(trifluoromethyl)benzoyl]amino}benzoate, 3'-(acetylamino)-4-{[4-(trifluoromethyl)benzoyl]amino}[l,r-biphenyl]-3- carboxylate,
3 '-(hydroxymethyl)-4- { [4-(trifluoromethyl)benzoyl] amino } [ 1 , 1 '-biphenyl] -3 - carboxylate,
2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-5-(8-quinolinyl)benzoate,
4- { [3 , 5 -bis(trifluoromethyl)benzoyl] amino } -3 '-formyl[ 1 , 1 '-biphenyl] -3 -carboxylate, 2-[(4-methoxybenzoyl)amino]-5-(8-quinolinyl)benzoate,
4-[(3 ,5-dichlorobenzoyl)amino] [1,1 '-biphenyl]-3-carboxylate, 2-[(4-cyanobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, 2-[(2,4-difluorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, 2-[(2-chlorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate, 2-[(2-chloro-5-nitrobenzoyl)amino]-5-(2-thienylmethoxy)benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(methylsulfanyl)ethoxy]benzoate, or 2-[(2,4-dichlorobenzoyl)amino]-m-toluate
19. A pharmaceutical formulation containing a compound according to any one of claims 1 to 14 as an active ingredient in combination with a pharmaceutically acceptable diluent or carrier.
20. A method for treatment or prevention of diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to the formula I
Figure imgf000109_0001
or a pharmaceutically acceptable salt or a prodrug form thereof, wherein Ar is aryl, which is optionally substituted in one or more positions by halogen, cyano, nitro, C1-6 alkyl,
Cj.β alkoxy,
Cι_6 alkylthio fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, allyloxy, aryloxy, or arylthio;
X is a bond, or a heteroalkyl chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms, or a formula
-+0-(CH2)n- -Y-
wherein m is 0, 1, or 2, n is O, 1, 2, or 3, and Y is a bond, O, S, NH, NHSO2, NHC(O)NH, or CH=CH;; and
R is d-Cό-alkyl or an optionally substituted aryl or heteroaryl group.
21. The method according to claim 20, wherein the said compound is 2-[(2,4-dichlorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(3-pyridinylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-thienyl)ethoxy]benzoate, 5-[2-(3-chlorophenyl)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[(4-ethoxybenzyl)oxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5- {[3-(dimethylamino)benzyl] oxy}benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methylphenyl)ethoxy]benzoate, 2- [(2,4-dichlorobenzoyl) amino] -5 - [2-( 1 -naphthyl)ethoxy]b enzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pyridinylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-{[2-(methylsulfanyl)-3- pyridinyl]oxy}ethoxy)benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-pyridinyloxy)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-quinoxalinyloxy)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-{2-[2-(methylsulfanyl)phenoxy] ethoxy}benzoate, 5-[2-(2-aminophenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate,
5-[2-(4-benzoylphenoxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2,3,6-trifluorophenoxy)ethoxy]benzoate, 5-[2-([l,l'-biphenyl]-3-yloxy)ethoxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(phenylsulfanyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(4-methyl-l,3-thiazol-5-yl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-(3-furylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-thienyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methyl-5-nitro-lH-imidazol-l- yl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(3-thienylmethoxy)benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-pyridinylsulfanyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-thiazol-4- yl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-methyl-2-phenyl-l,3-oxazol-4- yl)ethoxy]benzoate,
2-[(2,4-dichlorobenzoyl)amino]-5-[2-(5-ethyl-2-pyridinyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-methoxyphenoxy)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(4-pyridinylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[3-(3-pyridinyl)propoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(2-pyridinyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(3-methoxyphenyl)ethoxy]benzoate, 2-[(2,4-dichlorobenzoyl)aιιιino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate, 2-[(2,4-dichlorobenzoyl)arnino]-5-[(5-nitro-2-pyridinyl)oxy]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-{[5-(trifluoromethyl)-2-pyridinyl]oxy}benzoate,
5-[(6-chloro-2-pyrazinyl)oxy]-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-pvrimidinyloxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-{[(2E)-3-phenyl-2-propenyl]oxy}benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[(3-methoxybenzyl)oxy]benzoate, 2-[(2, 4-dichlorobenzoyl)amino]-5-(3-thienyl)benzoate,
2-[(2, 4-dichlorobenzoyl)amino]-5-(2, 4-dichlorophenyl)benzoate, 2-[(2, 4-dichlorobenzoyl)amino]-5-(4-ethylphenyl)benzoic acid, 2-[(2,4-dichlorobenzoyl)amino]-5-(8-quinolinyl)benzoic acid, 5-(l,3-benzodioxol-5-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid, 2-[(2,4-dichloroberzoyl)amino]-5-(2,4-dimethoxy-5-pyrirnidinyl)benzoic acid,
3 '-(acetylamino)-4-[(2,4-dichlorobenzoyl)amino] [1,1 '-biphenyl]-3 -carboxylic acid, 4- [(2,4-dichlorobenzoyl)amino] -3 '-(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxylic acid, 4-[(2,4-dichlorobenzoyl)amino]-3'-ethoxy[l,r-biphenyl]-3-carboxylic acid, 5-(l-benzofuran-2-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid,
4- [(2,4-dichlorobenzoyl)amino] -3 '-(hydroxymethyl) [1,1 '-biphenyl] -3 -carboxylic acid,
4-[(2,4-dichlorobenzoyl)amino] -3 '-formylf 1 , 1 '-biphenyl]-3 -carboxylic acid,
2-[(2,4-dichlorobenzoyl)amino]-5-(2-naphthyl)benzoic acid, 4-[(2,4-dichlorobenzoyl)amino]-3'-isopropyl-6'-methoxy[l,l'-biphenyl]-3- carboxylic acid,
4-[(2,4-dichlorobenzoyl)amino]-4'-fluoro[l, -biphenyl]-3-carboxylic acid, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-furyl)benzoate, 5-(l-benzothien-3-yl)-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(2-formyl-3-thienyl)benzoate,
5-(5-acetyl-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-(lH-indol-5-yl)benzoic acid, 5-(3-carboxyphenyl)-2-[(2,4-dichlorobenzoyl)amino]benzoic acid, 2'-(benzyloxy)-4-[(2,4-dichlorobenzoyl)amino][l,r-biphenyl]-3-carboxylate, 4-[(2,4-dichlorobenzoyl)amino][l,r-biphenyl]-3-carboxylate, 4-[(2,4-dichlorobenzoyl)amino]-3'-phenyl[l,r-biphenyl]-3-carboxylate, 4-[(2,4-dichlorobenzoyl)amino]-3'-(trifluoromethyl)[l,r-biphenyl]-3-carboxylate, 5-(5-chloro-2-thienyl)-2-[(2,4-dichlorobenzoyl)amino]benzoate, 4-[(2,4-dichlorobenzoyl)amino]-4'-phenoxy[l,r-biphenyl]-3-carboxylate,
4-[(2,4-dichlorobenzoyl)amino]-2',5'-dimethoxy[l,r-biphenyl]-3-carboxylate,
3'-(aminomethyl)-4-[(2,4-dichlorobenzoyl)amino][l,r-biphenyl]-3-carboxylic acid,
2-(2-naphthoylamino)-5-(3-thienyl)benzoate,
3 '-(acetylamino)-4-(2-naphthoylamino)[ 1 , 1 '-biphenyl]-3-carboxylate 3'-(hydroxymethyl)-4-(2-naphthoylamino)[l,r-biphenyl]-3-carboxylate,
5-(3-thienyl)-2-{[4-(trifluoromethyl)benzoyl]amino}benzoate, 3 '-(acetylamino)-4- { [4-(trifluoromethyl)benzoyl] amino } [ 1 , 1 '-biphenyl]-3 - carboxylate, 3 '-(hydroxymethyl)-4- {[4-(trifluoromethyl)benzoyl] amino} [1,1 '-biphenyl]-3- carboxylate,
2- { [3 , 5 -bis(trifluoromethyl)benzoyl] amino } -5 -(8-quinolinyl)benzo ate,
4- { [3 , 5 -bis(trifluoromethyl)benzoyl] amino } -3 '-formyl[ 1 , 1 '-biphenyl] -3-carboxylate,
2-[(4-methoxybenzoyl)amino]-5-(8-quinolinyl)benzoate,
4- [(3 ,5 -dichlorobenzoyl) amino] [1,1 '-biphenyl] -3 -carboxylate, 2-[(4-cyanobenzoyl)amino]-5-(2-thienylmethoxy)benzoate,
2-[(2,4-difluorobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, 2-[(2-chlorobenzoyl)amino]-5-[(3-nitro-2-pyridinyl)oxy]benzoate, 2-[(2-chloro-5-nitrobenzoyl)amino]-5-(2-thienylmethoxy)benzoate, 2-[(2,4-dichlorobenzoyl)amino]-5-[2-(methylsulfanyl)ethoxy]benzoate, or 2-[(2,4-dichlorobenzoyl)amino]- -toluate
22. A method for modulating peroxisome proliferator-activated receptor activity, comprising contacting the receptor with an effective stimulatory or inhibitory amount of a compound ofthe formula I:
Figure imgf000114_0001
or a pharmaceutically acceptable salt or a prodrug form thereof, wherein
Ar is aryl, which is optionally substituted in one or more positions by halogen, cyano, nitro,
Ci.6 alkyl, Cj.6 alkoxy,
Cι_6 alkylthio fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, allyloxy, aryloxy, or arylthio;
X is a bond, or a heteroalkyl chain comprising from 1 to 4 carbon atoms and from 1 to 4 heteroatoms, or a formula
Figure imgf000114_0002
wherein m is 0, 1, or 2, n is O, 1, 2, or 3, and
Y is a bond, O, S, NH, NHSO2, NHC(O)NH, or CH=CH; and
R is CrCβ-alky! or an optionally substituted aryl or heteroaryl group.
PCT/SE2002/001323 2001-07-03 2002-07-03 New compounds WO2003004458A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE0102384A SE0102384D0 (en) 2001-07-03 2001-07-03 New compounds
SE0102384-5 2001-07-03
US30470601P 2001-07-11 2001-07-11
US60/304,706 2001-07-11

Publications (1)

Publication Number Publication Date
WO2003004458A1 true WO2003004458A1 (en) 2003-01-16

Family

ID=26655510

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/SE2002/001322 WO2003005025A1 (en) 2001-07-03 2002-07-03 Methods for identifying compounds modulating the activity of ppar-gamma
PCT/SE2002/001323 WO2003004458A1 (en) 2001-07-03 2002-07-03 New compounds

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/SE2002/001322 WO2003005025A1 (en) 2001-07-03 2002-07-03 Methods for identifying compounds modulating the activity of ppar-gamma

Country Status (1)

Country Link
WO (2) WO2003005025A1 (en)

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004018414A2 (en) * 2002-08-23 2004-03-04 Pharmacia & Upjohn Company Llc Antibacterial agents
WO2003075907A3 (en) * 2002-03-11 2004-03-04 Tibotec Pharm Ltd Small molecule entry inhibitors
WO2004076402A1 (en) * 2003-02-27 2004-09-10 Aventis Pharma Deutschland Gmbh Arylcycloalkyl derivatives with branched side chains as ppar receptor modulators, method for their production and their use as medicaments
US6890947B2 (en) 2002-09-12 2005-05-10 Hoffmann-La Roche Inc. Indolyl derivatives
US7098228B2 (en) 2002-11-25 2006-08-29 Hoffmann-La Roche Inc. Indolyl derivatives
US7148246B2 (en) 2003-02-27 2006-12-12 Sanofi-Aventis Deutschland Gmbh Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals
WO2006034402A3 (en) * 2004-09-21 2007-08-09 Synta Pharmaceutical Corp Compounds for inflammation and immune-related uses
WO2008019477A1 (en) * 2006-08-17 2008-02-21 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7335671B2 (en) 2003-02-27 2008-02-26 Sanofi-Aventis Deutschland Gmbh Arylcycloalkyl-substituted alkanoic acid derivatives, processes for their preparation and their use as pharmaceuticals
WO2009076747A1 (en) * 2007-12-19 2009-06-25 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
JP2009525287A (en) * 2006-02-03 2009-07-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Viral polymerase inhibitor
US7645881B2 (en) 2004-07-22 2010-01-12 Ptc Therapeutics, Inc. Methods for treating hepatitis C
WO2010087430A1 (en) * 2009-01-30 2010-08-05 富山化学工業株式会社 N-acyl anthranilic acid derivative or salt thereof
US7772271B2 (en) 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7868037B2 (en) 2004-07-14 2011-01-11 Ptc Therapeutics, Inc. Methods for treating hepatitis C
EP2305352A1 (en) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
US8013006B2 (en) 2004-07-14 2011-09-06 Ptc Therapeutics, Inc. Methods for treating hepatitis C
WO2012027331A1 (en) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8242140B2 (en) 2007-08-03 2012-08-14 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
WO2013082106A1 (en) 2011-12-02 2013-06-06 The General Hospital Corporation Differentiation into brown adipocytes
JP2013525448A (en) * 2010-04-27 2013-06-20 カルシメディカ，インク． Compounds that regulate intracellular calcium
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
EP2810951A2 (en) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US20140364421A1 (en) * 2013-06-06 2014-12-11 Astellas Pharma Inc. Benzothiophene compound
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
JP2015511224A (en) * 2012-01-26 2015-04-16 ピーティーシー セラピューティクス， インコーポレイテッド Compounds for treating spinal muscular atrophy
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1303218C (en) * 2003-12-19 2007-03-07 中国科学院上海药物研究所 Method of screening peroxisome proliferator-activated receptor antagon and agonist

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3444136A (en) * 1967-11-01 1969-05-13 Celanese Corp Process for the preparation of polyquinazolones
US3636094A (en) * 1969-07-25 1972-01-18 Searle & Co Norbornanecarboxylic acid amides of anthranilic acid
WO1999038845A1 (en) * 1998-01-29 1999-08-05 Tularik Inc. Ppar-gamma modulators
WO2001000579A1 (en) * 1999-06-30 2001-01-04 Tularik Inc. COMPOUNDS FOR THE MODULATION OF PPARη ACTIVITY

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010042373A (en) * 1998-03-30 2001-05-25 린다 에스. 스티븐슨 Methods and compounds for modulating nuclear receptor activity

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3444136A (en) * 1967-11-01 1969-05-13 Celanese Corp Process for the preparation of polyquinazolones
US3636094A (en) * 1969-07-25 1972-01-18 Searle & Co Norbornanecarboxylic acid amides of anthranilic acid
WO1999038845A1 (en) * 1998-01-29 1999-08-05 Tularik Inc. Ppar-gamma modulators
WO2001000579A1 (en) * 1999-06-30 2001-01-04 Tularik Inc. COMPOUNDS FOR THE MODULATION OF PPARη ACTIVITY

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
ARCHIV. DER PHARMAZIE, vol. 333, no. 10, 2000, WEINHEIM, GERMANY, pages 323 - 328 *
DATABASE CAPLUS [online] EL-SHERBENY MAGDA A.: "Synthesis, antitumor activity and anti-HIV-1 testing of certain heterocyclic systems containing an adamantane nucleus", XP002954998, accession no. STN Database accession no. 2000:785234 *
DATABASE CAPLUS [online] FENTON GARRY ET AL.: "Hipolipidemic 2-(4-(1,1-dimethylethyl)phenyl)-4H-3,1-benzoxazin-4-ones", XP002958301, accession no. STN Database accession no. 1989:38944 *
DATABASE CAPLUS [online] PONOMAREV I.I. ET AL.: "Synthesis, structure and properties of ladder-typepolyquinazolones", XP002954999, accession no. STN Database accession no. 1992:634645 *
DATABASE CAPLUS [online] STASKUN BENJAMIN ET AL.: "Production of 3-benzoyl-2,1-benzisoxazoles, 2-phenyl-4H-3,1-benzoxazin-4-ones and novel quinolinone derivatives from 2-phenylquinolin-4(1H)-ones and sodium dichloroisocyanurate", XP002955000, accession no. STN Database accession no. 1993:603359 *
DATABASE CHEMCATS [online] 7 July 2001 (2001-07-07), XP002958306, accession no. STN Database accession no. 2002:664205 *
DATABASE CHEMCATS [online] XP002958307, accession no. STN Database accession no. 2001:2075558 *
DATABASE CHEMCATS [online] XP002958308, accession no. STN Database accession no. 2001:552210 *
DATABASE CHEMCATS [online] XP002958309, accession no. STN Database accession no. 2001:83794 *
DATABASE CHEMCATS [online] XP002958310, accession no. STN Database accession no. 2001:107851 *
DATABASE CHEMCATS [online] XP002958311, accession no. STN Database accession no. 2000:999231 *
DATABASE CHEMCATS [online] XP002958312, accession no. STN Database accession no. 2000:922148 *
DATABASE CHEMCATS [online] XP002958313, accession no. STN Database accession no. 2000:931318 *
JOURNAL OF MEDICINAL CHEMISTRY, vol. 32, no. 1, 1989, pages 265 - 272 *
JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1: ORGANIC AND BIO-ORGANIC CHEMISTRY (1972-1999), no. 4, 1993, pages 511 - 516 *
VYSOKOMOL., SOEDIN, SER. A, vol. 34, no. 4, 1992, pages 20 - 28 *

Cited By (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7429677B2 (en) 2002-03-11 2008-09-30 Tibotec Pharmaceuticals Ltd. Small molecule entry inhibitors
WO2003075907A3 (en) * 2002-03-11 2004-03-04 Tibotec Pharm Ltd Small molecule entry inhibitors
JP2005526062A (en) * 2002-03-11 2005-09-02 テイボテク・フアーマシユーチカルズ・リミテツド Small molecule penetration inhibitor
CN101519368A (en) * 2002-03-11 2009-09-02 泰博特克药品有限公司 Small molecule entry inhibitors
WO2004018414A3 (en) * 2002-08-23 2004-06-17 Upjohn Co Antibacterial agents
WO2004018414A2 (en) * 2002-08-23 2004-03-04 Pharmacia & Upjohn Company Llc Antibacterial agents
US6890947B2 (en) 2002-09-12 2005-05-10 Hoffmann-La Roche Inc. Indolyl derivatives
US7098228B2 (en) 2002-11-25 2006-08-29 Hoffmann-La Roche Inc. Indolyl derivatives
JP2006519196A (en) * 2003-02-27 2006-08-24 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Arylcycloalkyl derivatives having branched side chains as PPAR receptor modulators, processes for their preparation and their use as medicaments
WO2004076402A1 (en) * 2003-02-27 2004-09-10 Aventis Pharma Deutschland Gmbh Arylcycloalkyl derivatives with branched side chains as ppar receptor modulators, method for their production and their use as medicaments
US7148246B2 (en) 2003-02-27 2006-12-12 Sanofi-Aventis Deutschland Gmbh Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals
US7872034B2 (en) 2003-02-27 2011-01-18 Sanofi-Aventis Deutschland Gmbh Arylcycloalkyl-substituted alkanoic acid derivatives, processes for their preparation and their use as pharmaceuticals
US7335671B2 (en) 2003-02-27 2008-02-26 Sanofi-Aventis Deutschland Gmbh Arylcycloalkyl-substituted alkanoic acid derivatives, processes for their preparation and their use as pharmaceuticals
CN100417641C (en) * 2003-02-27 2008-09-10 塞诺菲-安万特德国有限公司 Arylcycloalkyl derivatives having branched side chains used as ppar receptor regulator, processes for their preparation and their use as pharmaceuticals
US7220876B2 (en) 2003-02-27 2007-05-22 Sanofi-Aventis Deutschland Gmbh Arylcycloalkyl derivatives having branched side chains, processes for their preparation and their use as pharmaceuticals
EP2305352A1 (en) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders
US7772271B2 (en) 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7868037B2 (en) 2004-07-14 2011-01-11 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US8013006B2 (en) 2004-07-14 2011-09-06 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7645881B2 (en) 2004-07-22 2010-01-12 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US8314134B2 (en) 2004-09-21 2012-11-20 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US7709518B2 (en) 2004-09-21 2010-05-04 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8524756B2 (en) 2004-09-21 2013-09-03 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
WO2006034402A3 (en) * 2004-09-21 2007-08-09 Synta Pharmaceutical Corp Compounds for inflammation and immune-related uses
US8592486B2 (en) 2005-01-07 2013-11-26 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
JP2009525287A (en) * 2006-02-03 2009-07-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Viral polymerase inhibitor
US7816348B2 (en) 2006-02-03 2010-10-19 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7897622B2 (en) 2006-08-17 2011-03-01 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
EP2054388A1 (en) * 2006-08-17 2009-05-06 Boehringer Ingelheim International GmbH Viral polymerase inhibitors
JP2010500978A (en) * 2006-08-17 2010-01-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Viral polymerase inhibitor
WO2008019477A1 (en) * 2006-08-17 2008-02-21 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
EP2054388A4 (en) * 2006-08-17 2009-10-28 Boehringer Ingelheim Int Viral polymerase inhibitors
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8242140B2 (en) 2007-08-03 2012-08-14 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US8912182B2 (en) 2007-12-19 2014-12-16 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US8541402B2 (en) 2007-12-19 2013-09-24 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US8476257B2 (en) 2007-12-19 2013-07-02 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
WO2009076747A1 (en) * 2007-12-19 2009-06-25 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
EP2810951A2 (en) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
US8492582B2 (en) 2009-01-30 2013-07-23 Toyama Chemical Co., Ltd. N-acyl anthranilic acid derivative or salt thereof
WO2010087430A1 (en) * 2009-01-30 2010-08-05 富山化学工業株式会社 N-acyl anthranilic acid derivative or salt thereof
JP5602641B2 (en) * 2009-01-30 2014-10-08 富山化学工業株式会社 N-acyl anthranilic acid derivative or salt thereof
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
EP2923706A1 (en) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia
JP2013525448A (en) * 2010-04-27 2013-06-20 カルシメディカ，インク． Compounds that regulate intracellular calcium
WO2012027331A1 (en) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
WO2013082106A1 (en) 2011-12-02 2013-06-06 The General Hospital Corporation Differentiation into brown adipocytes
JP2015511224A (en) * 2012-01-26 2015-04-16 ピーティーシー セラピューティクス， インコーポレイテッド Compounds for treating spinal muscular atrophy
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
EP3708179A1 (en) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
EP4309673A2 (en) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
US8981119B2 (en) * 2013-06-06 2015-03-17 Astellas Pharma Inc. Benzothiophene compound
US20140364421A1 (en) * 2013-06-06 2014-12-11 Astellas Pharma Inc. Benzothiophene compound

Also Published As

Publication number Publication date
WO2003005025A1 (en) 2003-01-16

Similar Documents

Publication Publication Date Title
WO2003004458A1 (en) New compounds
CA2558585C (en) Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
US11447453B2 (en) Metabotropic glutamate receptor negative allosteric modulators (NAMs) and uses thereof
US6613942B1 (en) Glucagon antagonists/inverse agonists
KR100620337B1 (en) Carboxylic acid derivatives and drugs containing the same as the active ingredient
KR101507173B1 (en) ACTIVATING AGENT FOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR δ
JP4395076B2 (en) Tricyclic steroid hormone nuclear receptor modulator
CA2397018C (en) Compounds exhibiting thrombopoietin receptor agonism
JP4988128B2 (en) β3 adrenergic agonist
WO2005058883A1 (en) 2, 6 bisheteroaryl-4-aminopyrimidines as adenosine receptor antagonists
WO2005051890A1 (en) Aminophenylcyclopropyl carboxylic acids and derivatives as agonists to gpr40
JP2006516254A (en) Fused heterocyclic derivatives as PPAR modulators
JPWO2002046176A1 (en) Activator of peroxisome proliferator-activated receptor
US20030073862A1 (en) Compounds
EP1706386A1 (en) Bicyclic derivatives as ppar modulators
CZ20014637A3 (en) Substituted phenoxyacetic acids
WO2009147121A1 (en) Carboxyl substituted indoles for use as ppar alpha modulators
Li et al. Discovery of HWL-088: a highly potent FFA1/GPR40 agonist bearing a phenoxyacetic acid scaffold
JP2000001431A (en) Uricosuric agent
WO2014123203A1 (en) Therapeutic agent for diabetes
WO2003053976A1 (en) PIPAZOLO [1,5-a] PYRIMIDINE DERIVATIVES AS MODULATORS OF PPAR
US20150018411A1 (en) Compounds as ppar beta/delta inhibitors for treating ppar beta/delta-mediated diseases
JP2002322163A (en) Piperazine derivative
JPH03193746A (en) Substituted alkylamine derivative
JPH03173865A (en) Substituted allylamine derivative, preparation thereof and use thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG UZ VN YU ZA ZM ZW GH

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP