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EP1062205A2 - Inhibitors of phospholipase enzymes - Google Patents

Inhibitors of phospholipase enzymes

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Publication number
EP1062205A2
EP1062205A2 EP99908378A EP99908378A EP1062205A2 EP 1062205 A2 EP1062205 A2 EP 1062205A2 EP 99908378 A EP99908378 A EP 99908378A EP 99908378 A EP99908378 A EP 99908378A EP 1062205 A2 EP1062205 A2 EP 1062205A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
cooh
indol
phenyl
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99908378A
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German (de)
English (en)
French (fr)
Inventor
Jasbir S. Seehra
John C. Mckew
Frank Lovering
Jean E. Bemis
Yibin Xiang
Lihren Chen
John L. Knopf
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Genetics Institute LLC
Original Assignee
Genetics Institute LLC
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Publication of EP1062205A2 publication Critical patent/EP1062205A2/en
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • 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
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A 2 enzymes.
  • Leukotrienes and prostaglandins are important mediators of inflammation, each of which classes contributes to the development of an inflammatory response in a different way.
  • Leukotrienes recruit inflammatory cells such as neutrophils to an inflamed site, promote the extravasation of these cells and stimulate release of superoxide and proteases which damage the tissue.
  • Leukotrienes also play a pathophysiological role in the hypersensitivity experienced by asthmatics [See, e.g. B. Samuelson et al., Science. 237:1171-76 (1987)].
  • Prostaglandins enhance inflammation by increasing blood flow and therefore infiltration of leukocytes to inflamed sites.
  • Prostaglandins also potentiate the pain response induced by stimuli.
  • Prostaglandins and leukotrienes are unstable and are not stored in cells, but are instead synthesized [W. L. Smith, Biochem. J.. 259:315-324 (1989)] from arachidonic acid in response to stimuli.
  • Prostaglandins are produced from arachidonic acid by the action of COX- 1 and COX- 2 enzymes.
  • Arachidonic acid is also the substrate for the distinct enzyme pathway leading to the production of leukotrienes.
  • PLA j phospholipase A, enzymes
  • the reaction catalyzed by PLA j is believed to represent the rate-limiting step in the process of lipid mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes.
  • PAF platelet activating factor
  • anti-inflammatory therapies have focussed on preventing production of either prostglandins or leukotrienes from these distinct pathways, but not on all of them.
  • ibuprofen, aspirin, and indomethacin are all NSAIDs which inhibit the production of prostaglandins by COX-l/COX-2, but have no effect on the inflammatory production of leukotrienes from arachidonic acid in the other pathways.
  • zileuton inhibits only the pathway of conversion of arachidonic acid to leukotriense, without affecting the production of prostaglandins. None of these widely-used anti-inflammatory agents affects the production of PAF.
  • a family of PLA enzymes characterized by the presence of a secretion signal sequenced and ultimately secreted from the cell have been sequenced and structurally defined. These secreted PLA 2 s have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLA,s are found in large quantities in mammalian pancreas, bee venom, and various snake venom. [See, e.g., references 13-15 in Chang et al, cited above; and E. A. Dennis, Drug Devel. Res.. 10:205-220 (1987).] However, the pancreatic enzyme is believed to serve a digestive function and, as such, should not be important in the production of the inflammatory mediators whose production must be tightly regulated.
  • the primary structure of the first human non-pancreatic PLA 2 has been determined.
  • This non-pancreatic PLA 2 is found in platelets, synovial fluid, and spleen and is also a secreted enzyme.
  • This enzyme is a member of the aforementioned family. [See, J. J. Seilhamer et al, J. Biol. Chem.. 264:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem.. 264:5768-5775 (1989); and A. Kando et al, Biochem. Biophvs. Res. Comm.. 163:42-48 (1989)].
  • PLA 2 is regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc. Nail. Acad. Sci. U.S.A.. 84:6374-6378 (1989)] which are cytosolic proteins which must act on intracellular proteins. It would be impossible for the non-pancreatic PLA 2 to function in the cytosol, since the high reduction potential would reduce the disulfide bonds and inactivate the enzyme.
  • a murine PLA 2 has been identified in the murine macrophage cell line, designated
  • cPLA j A cytosolic phospholipase A 2 (hereinafter "cPLA j ”) has also been identified and cloned. See, U.S. Patent Nos. 5,322,776 and 5,354,677, which are incorporated herein by reference as if fully set forth.
  • the enzyme of these patents is an intracellular PLA 2 enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli.
  • cPLA 2 is the only enzyme which is highly selective for phospholipids containing arachidonic acid in the sn-2 position (Clark et al., 1991, 1995; Hanel & Gelb, 1993); activation of cPLA 2 or its increased expression have been linked with increased leukotriene and prostaglandin synthesis (Lin et al., 1992a, 1992b, 1993); and following activation, cPLA 2 translocates to the nuclear membrane, where it is co-localized with the cyclooxygenase and lipoxygenase that metabolize arachidonate to prostaglandins and leukotrienes (Schievella et al., 1995; Glover et al., 1995).
  • mice made deficient in cPLA 2 through homologous recombination (Uozumi et al., 1997; Bonventre et al., 1997). Peritoneal macrophages derived from these animals failed to make leukotrienes, prostaglandins, or PAF.
  • the cPLA 2 deficient mice have also been informative of the role of cPLA 2 in disease, since these mice are resistant to bronchial hyperreactivity in an anaphylaxis model used to mimic asthma (Uozumi et al., 1997).
  • cPLA 2 is essential for prostaglandin, leukotriene, and PAF production.
  • a novel arachidonic acid-selective cytosolic PLA 2 contains a Ca 2+ -dependent translocation domain with homology to PKC and GAP. Cell 65, 1043-1051. Hanel, A. M., and Gelb, M. H. (1993). Processive interfacial catalysis by mammalian 85-kilodalton phospholipase A 2 enzymes on product-containing vesicles: application to the determination of substrate preferences. Biochemistry 32, 5949-5958.
  • R, and R r are independently selected from H, halogen, -CF,, -OH, -C,-C 10 alkyl, preferably -C,-C 6 alkyl, -S-C,-C 10 alkyl, preferably -S-C,-C 6 alkyl, C,-C 10 alkoxy, preferably
  • a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, - CF 3 or -OH; or
  • Z is O or S
  • R 6 is selected from the relevant members of the group H, -CF 3 , C,-C I0 alkyl, preferably C,-C 6 alkyl, C r C 10 alkoxy, preferably C,-C 6 alkoxy, phenyl, -O-phenyl, -S- phenyl, benzyl, -O-benzyl, or -S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C r C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, - CF 3 , or -OH;
  • R 7 is selected from the relevant members of the group -OH, -CF 3 , C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C I0 alkoxy, preferably C,-C 6 alkoxy, -NH 2 , -(CH 2 ) n -NH 2 , -NH- (C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , -(CH 2 ) n -NH-(C,-C 6 alkyl), -(CH 2 ) n -N-(C,-C 6 alkyl) 2 , phenyl, -O-phenyl, benzyl, or -O-benzyl; or
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C I0 alkyl, preferably C,-C 6 alkyl, C,-C ]0 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH;
  • n is an integer from 0 to 3;
  • R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C 10 alkyl, preferably C,-
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -,-(CH 2 ) ⁇ -S-(CH 2 ) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -,
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH 2 ) n -COOH, - (CH 2 ) n -C(O)-COOH, tetrazole,
  • R 10 is selected from the group of H, halogen, -CF 3 , -OH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -O-(C,-C 6 alkyl)-(OH) n , -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 , -N-C(O)-N-(C,-C 6 alkyl)-(OH) 2 ,
  • R Thallium is selected from H, C,-C 6 lower alkyl, C,-C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ) n - COOH, -(CH 2 ) n -C(O)-COOH,
  • R 3 , L 1 , M 1 , R 8 , R 9 , R 10 , and/or R n shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, -C,-C 6 alkyl-C 3 -C 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 :
  • L 2 indicates a linking or bridging group of the formulae -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) ⁇ -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -, or -(CH 2 ) n -S-(CH 2 ) n -, C(O)C(O)X; where X is O or N
  • M is selected from:
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C I0 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C C 6 alkoxy, -CHO, -NO,, -NH,, -CN, -CF 3 or -OH;
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH,) n -C 3 -C 10 cycloalkyl, -(CH 2 ) n -S-(CH 2 ) n -C 3 -C 10 cycloalkyl, -(CH 2 ) n -O-(CH 2 ) n -C 3 -C 10 cycloalkyl, or the groups of:
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2,
  • Y is C 3 -C 6 cycloalkyl, phenyl, biphenyl, each optionally substituted by from 1 to 3 groups selected from halogen, C,-C ]0 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -NO 2 , -NH 2 , -CN, or -CF 3 ; or
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C ⁇ C,,, alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH;
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -CF 3 or -(CH 2 ) n -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH, , -N(C,- C 6 ) 2 , -NH(C,-C 6 ), -N-C(O)-(C,-C 6 ), -NO 2 , or by a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S, such as, for example, morpholino; or a pharmaceutically acceptable salt thereof.
  • One group of compounds within this invention are those in which the indole or indoline 2-position (R 4 ) is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above.
  • R 3 is -L'-M 1 , wherein L ! is as defined above, more preferably wherein L 1 is a chemical bond, and M 1 is the moiety:
  • R g is as defined in the broad genus above.
  • Another group of this invention comprises compounds in which R 2 and R 4 are hydrogen and the groups at R,, R r , R 3 , and R 5 are as defined above. Within this group are two further preferred groups. In the first, R, is in the indole or indoline 5 position and in the second R ] is in the indole or indoline 6 position.
  • R is in the indole or indoline 5-position and is benzyloxy
  • R 2 and R 4 are hydrogen
  • R 3 and R 5 are as defined above.
  • R is selected from H, halogen, -CF 3 , -OH, -C,-C I0 alkyl, preferably -C,-C 6 alkyl, -S-
  • C,-C 10 alkyl preferably -S-C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CN, -NO 2 , -NH 2 , phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C ⁇ alkoxy, -NO 2 , -NH 2 , -CN, -CF 3 , or - OH;
  • R 7 is selected from -OH, -CF 3 , C r C 6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,- C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, -CN, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , -CF 3 , or -OH;
  • R is selected from H, halogen, -CF 3 , -OH, -C,-C ]0 alkyl, preferably -C,-C 6 alkyl, C,- C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 -C r C 6 alkyl, or -SO 2 -C,-C 6 alkyl;
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) ⁇ -C(O)-(CH 2 ) literal-, -(CH 2 ) n -O-(CH 2 ) n -,-(CH 2 ) n -S-(CH 2 ) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -, -C(Z)-NH-SO 2
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH 2 ) n -COOH, (CH 2 ) n -C(O)-COOH, tetrazole,
  • R is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C r C 6 alkyl), or -N(C,-C 6 alkyl) 2 ;
  • R 10 is selected from the group of H, halogen, -CF 3 , -OH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C r C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R Thallium is selected from H, C,-C 6 lower alkyl, C,-C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ) n - COOH, -(CH 2 ) n -C(O)-COOH,
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, -C,-C 6 alkyl-C 3 -C ]0 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 :
  • L 2 indicates a linking or bridging group of the formulae -(CH,) n -, -S-, -O-,
  • M 2 is selected from the group of C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -NO 2 , -NH 2 , -CN, or -CF 3 ; or
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C, 0 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH,, -CN, - CF 3 or -OH;
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -C 3 -C 10 cycloalkyl, -(CH 2 ) n -S-(CH 2 ) n -C 3 -C 10 cycloalkyl, -(CH 2 ) n -O-(CH 2 ) n -C 3 -C 10 cycloalkyl, or the groups of:
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2
  • Y is C 3 -C 5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole and pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C r C 6 alkyl, C r C 6 alkoxy, -CN, -NH 2 , - NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
  • D is H, C,-C 6 lower alkyl, C r C 6 lower alkoxy, -CF 3 or -(CH 2 ) n -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH, or -NO,; or a pharmaceutically acceptable salt thereof.
  • One group of compounds within this invention are those in which the indole or indoline 2-position (R 4 ) is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above.
  • R is in the indole or indoline 5 or 6 position and is cyclopentylcarboxamide or cyclopentyloxycarbonylamino
  • R ⁇ and R 4 are hydrogen
  • R 3 and R 5 are as defined above.
  • a further preferred group of this invention consists of R, and R,at the indole or indoline 5 and or 6 position and are each selected from the group consisting of C,-C 6 alkoxy, cyano, sulfonyl and halo
  • R 2 and R 4 are hydrogen
  • R 3 and R 5 are as defined above.
  • Another group of this invention comprises compounds in which R 2 and R 4 are hydrogen and the groups at R,, R 3 , and R 5 are as defined above.
  • R is in the indole or indoline 5 position and in the second R, is in the indole or indoline 6 position.
  • R is in the indole or indoline 5-position and is benzyloxy
  • R 2 and R 4 are hydrogen
  • R 3 and R 5 are as defined above.
  • R is selected form H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , CN, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl. benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NH,, -NO 2 , -CF 3 , or -OH;
  • R 7 is selected from -CF 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;
  • R is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C, 0 alkyl, preferably C,- C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH,, -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 -C r C 6 alkyl, or -SO 2 -C,-C 6 alkyl;
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -,-(CH 2 ) n -S-(CH,) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 5 )-, -C(O)-C(Z)-N(R 6 )-(CH,) n -, -C(Z)-NH-SO,-, or -C(Z)-NH-SO,-(CH 2 )
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH,) n -COOH, (CH 2 ) n -C(O)-COOH, tetrazole,
  • R g is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ;
  • R 10 is selected from the group of H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C r C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R Thallium is selected from H, C,-C 6 lower alkyl, C,-C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ) n - COOH, -(CH 2 ) n -C(O)-COOH,
  • R 3 , L 1 , M ⁇ R 8 , g , R I0 , and/or R u shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, -C r C 6 alkyl-C 3 -C 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 :
  • L 2 indicates a linking or bridging group of the formulae -(CH,) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -, or -(CH 2 ) n -S-(CH 2 ) ⁇ -;
  • M is selected from:
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH;
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -C 3 -C 5 cycloalkyl, -(CH 2 ) n -S-(CH 2 ) n -C 3 -C 5 cycloalkyl, -(CH 2 ) n -O-(CH 2 ) n -C 3 -C 5 cycloalkyl, or the groups of: a) -(CH 2 ) n -phenyl-O-phenyl, -(CH 2 ) n -phenyl-CH 2 -phenyl, -(CH,) n -O-phenyl-
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2
  • Y is C 3 -C 5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl benzothiazole or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
  • D is H, C,-C 6 lower alkyl, C r C 6 lower alkoxy, -(CH 2 ) n -CF 3 or -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C r C 6 alkoxy, -NH 2 or -NO 2 ; or a pharmaceutically acceptable salt thereof.
  • a preferred group among the compounds above are those in which the R, substitution is at the indole or indoline ring's 5-position and the other substituents are as defined above.
  • R is selected form H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO,, -NH 2 , phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -CF 3 , or -OH;
  • R 7 is selected from -CF 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C r C 6 alkyl, C,-C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;
  • R is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C 10 alkyl, preferably C,- C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO,-C,-C 6 alkyl, or -SO 2 -C,-C 6 alkyl;
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -,-(CH 2 ) n -S-(CH 2 ) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -,
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH 2 ) n -COOH, (CH 2 ) n -C(O)-COOH, tetrazole,
  • Rg is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ;
  • R, 0 is selected from the group of H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R ⁇ is selected from H, C,-C 6 lower alkyl, C,-C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ) n - COOH, -(CH 2 ) n -C(O)-COOH,
  • the complete moiety at the indole or indoline 3-position created by any combination of R 3 , L 1 , M 1 , R g , Rg, R 10 , and/or R ⁇ shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, -C,-C 6 alkyl-C 3 -C 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 :
  • L 2 indicates a linking or bridging group of the formulae -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -, or -(CH 2 ) n -S-(CH 2 ) n -;
  • M 2 is selected from:
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C j -C ⁇ alkoxy, preferably C r C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH;
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -C 3 -C 5 cycloalkyl or ⁇ (CH 2 ) n -A, -(CH 2 ) n -S-A, or -(CH 2 ) n -O-A wherein A is selected from :
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF 3
  • R ]2 is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF 3' or a pharmaceutically acceptable salt thereof.
  • R is selected form H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C r C 6 alkyl, C,-C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;
  • R 7 is selected from -CF 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -NH-(C r C 6 alkyl), -N-(C r C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, pyrazolyl, thiazolyl, -O-phenyl, benzyl or - O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;
  • R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C, 0 alkyl, preferably C,- C 6 alkyl, C,-C 10 alkoxy, preferably C r C 6 alkoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 -C,-C 6 alkyl, or -SO 2 -C,-C 6 alkyl;
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -,-(CH 2 ) n -S-(CH 2 ) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -,
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • L is a bridging or linking moiety selected from a chemical bond -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -, -(CH 2 ) n -S-(CH 2 ) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -, -C(Z)-NH-SO 2 -, or -C(Z)-
  • M is the moiety
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH 2 ) n -COOH, (CH 2 ) n -C(O)-COOH, tetrazole,
  • Rg is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ;
  • R 10 is selected from the group of H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R ⁇ is selected from H, C,-C 6 lower alkyl, C,-C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ) n -
  • R 3 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, -C,-C 6 alkyl-C 3 -C 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 3 -M 3 :
  • L 3 indicates a linking or bridging group of the formulae -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -, or -(CH 2 ) n -S-(CH 2 ) n -;
  • M 3 is selected from:
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicychc ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C ⁇ C ⁇ alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C r C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH;
  • R 5 is selected from C,-C 6 lower alkyl, C r C 6 lower alkoxy, -(CH 2 ) n -C 3 -C 5 cycloalkyl,
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2
  • Y is C 3 -C 5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole, or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 , - NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -CF 3 or -(CH 2 ) n -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 or -NO 2 ; or a pharmaceutically acceptable salt thereof.
  • Another preferred group of this invention are those of the formulae:
  • R j is selected form H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO,, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C r C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;
  • R 7 is selected from -CF 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , -CF 3 , or -OH;
  • R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C ]0 alkyl, preferably C,- C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 -C r C 6 alkyl, or -SO 2 -C r C 6 alkyl;
  • R 8 is selected from H, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH;
  • R 9 is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ;
  • R ]0 is selected from the group of H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C r C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R Thallium is selected from H, C,-C 6 lower alkyl, -CF 3 , -COOH, -(CH 2 ) n -COOH,
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, -C r C 6 alkyl-C 3 -C 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 :
  • L 2 indicates a linking or bridging group of the formulae -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -, or -(CH 2 ) n -S-(CH 2 ) n -;
  • M 2 is selected from:
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C ⁇ C,,, alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH;
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -C 3 -C 5 cycloalkyl or ⁇ (CH 2 ) n -A, -(CH 2 ) n -S-A, or -(CH 2 ) n -O-A wherein A is selected from:
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF 3 ;
  • R ]2 is H, C r C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF. 3'
  • R is selected form H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C ⁇ C g alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , -CF 3 , or -OH;
  • R 7 is selected from -CF 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, pyrazolyl, thiazolyl, -O-phenyl, benzyl or - O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C r C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , -CF 3 , or -OH;
  • R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C I0 alkyl, preferably C,-
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -,-(CH 2 ) n -S-(CH 2 ) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -,
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • R g in each appearance, is independently selected from H, -COOH, -(CH 2 ) n -COOH, (CH 2 ) n -C(O)-COOH, tetrazole,
  • R 9 is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH,
  • R 10 is selected from the group of H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) ⁇ -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C r C 6 alkyl, -NH(C r C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R u is selected from H, C,-C 6 lower alkyl, C r C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ) n - COOH, -(CH 2 ) n -C(O)-COOH,
  • R 3 , L 1 , M 1 , R 8 , R g , R 10 , and/or R ⁇ shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C ]0 cycloalkyl, -C,-C 6 alkyl-C 3 -C 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 :
  • L 2 indicates a linking or bridging group of the formulae -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) ⁇ -, or -(CH 2 ) n -S-(CH 2 ) n -, - C(O)C(O)X; where X is O or N,
  • M 2 is selected from:
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C ]0 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C r C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH; R 5 is selected from -(CH 2 ) n -S-(CH 2 ) n -C 3 -C 5 cycloalkyl, -(CH 2 ) n -O-(CH 2 )
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2
  • Y is C 3 -C 5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , - NH 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
  • n is an integer from 0 to 3 , preferably 1 to 3, more preferably 1 to 2
  • Y is napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl benzothiazole, or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C r C 6 alkoxy,
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -CF 3 or -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 or -NO 2 ; or a pharmaceutically acceptable salt thereof.
  • R is benzyloxy and R 4 , R 3 and R 5 are as defined above.
  • R is selected form H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C C 6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C r C 6 alkyl, C r C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;
  • R 7 is selected from -CF 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally
  • R 3 is selected from -COOH, -C(O)-COOH, -(CH 2 ) n -C(O)-COOH, -(CH 2 ) ⁇ -COOH,
  • -CH CH-COOH, -(CH 2 ) n C(O)NS(O)(O)(C r C 6 lower alkyl), -(CH 2 ) N C(O)NS(O)(O)(C,-C 6 lower haloalkyl),
  • R 8 and Rg are independently selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n - COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), or -N(C,-C 6 alkyl) 2 ;
  • R 10 is selected from the group of H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C r C 6 alkyl, -O-C r C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R Thallium is selected from H, C,-C 6 lower alkyl, -CF 3 , -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, or
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, or halogen;
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -C 3 -C 5 cycloalkyl or the groups of:
  • D is H, C,-C 6 lower alkyl, C r C 6 lower alkoxy, or -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 , or -NO 2 ; or a pharmaceutically acceptable salt thereof.
  • aryl and substituted aryl are understood to include monocyclic, particularly including five- and six-membered monocyclic, aromatic and heteroaromatic ring moieties and bicyclic aromatic and heteroaromatic ring moieties, particularly including those having from 9 to 10 ring atoms.
  • aryl groups are understood to be phenyl rings, including those found in phenoxy, benzyl, benzyloxy, biphenyl and other such moieties.
  • the aryl and heteroaryl groups of this invention also include the following:
  • a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine.
  • substituted aryl groups of this invention include such moieties being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -COOH or esters thereof, -NO 2 , -NH 2 , -CN, -CF 3 or -OH or combinations thereof, such as -CH 2 CF 3 , -NH(CH 3 ), etc.
  • substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -COOH or esters thereof, -NO 2 , -NH 2 , -CN, -CF 3 or -OH or combinations thereof, such as -CH 2 CF 3 , -NH(CH 3 ), etc.
  • a preferred subset of these groups include moieties formed from benzene, pyridine, napthylene or quinoline rings.
  • a further prefe ⁇ ed group includes those of furan, pyrrole, thiophene, pyrimidine, and mo ⁇ holine rings.
  • a prefe ⁇ ed group of bicyclic aromatic groups includes benzofuran, indole, napthalene, and quinoline rings.
  • alkyl, alkenyl and alkinyl groups refe ⁇ ed to herein indicate such groups having from 1 to 10, preferably 1 to 6 carbon atoms, and may be straight, branched or cyclic. Unless indicated otherwise, it is preferred that these groups be straight or branched.
  • Halogens herein are understood to include F, Cl, Br and I.
  • phospholipase enzyme activity means positive activity in an assay for metabolism of phospholipids (preferably one of the assays described in Example 116 below).
  • a compound has "phospholipase enzyme inhibiting activity" when it inhibits the activity of a phospholipase (preferably cPLA 2 ) in any available assay (preferably an assay described below in Example 116 or Example 117) for enzyme activity.
  • a compound has (1) an IC 50 value of less than about 25 ⁇ M, preferably less than about 6 ⁇ M, in the LysoPC assay; (2) an IC 50 value of less than about 50 ⁇ M in the vesicle assay; (3) an IC 50 value of less than about 1 ⁇ M in the PMN assay; (4) an IC 50 value of less than about 15 ⁇ M in the Coumarine assay; and/or (5) measurable activity (preferably at least about 5% reduction in edema, more preferably at least about 10% reduction, more preferably at least about 15%, most preferably 20-30%) in the rat ca ⁇ ageenan-induced footpad edema test.
  • Compounds of the present invention are useful for inhibiting phospholipase enzyme (preferably cPLA 2 ) activity and, therefore, are useful in "treating” (i.e., treating, preventing or ameliorating) inflammatory or inflammation-related responses or conditions (e.g., rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, and other diseases mediated by prostaglandins, leukotrienes or PAF) and other conditions, such as osteoporosis, colitis, myelogenous leukemia, diabetes, wasting and atherosclerosis.
  • inflammatory or inflammation-related responses or conditions e.g., rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, and other diseases mediated by prostaglandins, leukotrienes or PAF
  • the present invention encompasses both pharmaceutical compositions and therapeutic methods of treatment or use which employ compounds of the present invention.
  • Compounds of the present invention may be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may also contain (in addition to a compound or compounds of the present invention and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • pharmaceutically acceptable means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).
  • the characteristics of the carrier will depend on the route of administration.
  • the pharmaceutical composition may further contain other anti-inflammatory agents. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with compounds of the present invention, or to minimize side effects caused by the compound of the present invention.
  • the pharmaceutical composition of the invention may be in the form of a liposome in which compounds of the present invention are combined, in addition to other pharmaceutically acceptable earners, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution.
  • Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Patent No. 4,235,871; U.S. Patent No. 4,501,728; U.S. Patent No. 4,837,028; and U.S. Patent No. 4,737,323, all of which are inco ⁇ orated herein by reference.
  • the term "therapeutically effective amount” means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a meaningful patient benefit, i.e., treatment, healing, prevention or amelioration of an inflammatory response or condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
  • a meaningful patient benefit i.e., treatment, healing, prevention or amelioration of an inflammatory response or condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
  • the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • a therapeutically effective amount of a compound of the present invention is administered to a mammal having a condition to be treated.
  • Compounds of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors.
  • compounds of the present invention may be administered either simultaneously with the other anti-inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering compounds of the present invention in combination with other anti-inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.
  • compositions of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, or cutaneous, subcutaneous, or intravenous injection.
  • compounds of the present invention will be in the form of a tablet, capsule, powder, solution or elixir.
  • the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant.
  • the tablet, capsule, and powder contain from about 5 to 95% compound of the present invention, and preferably from about 25 to 90% compound of the present invention.
  • a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils
  • the liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol.
  • the pharmaceutical composition contains from about 0.5 to 90% by weight of compound of the present invention, and preferably from about 1 to 50% compound of the present invention.
  • compounds of the present invention When a therapeutically effective amount of compounds of the present invention is administered by intravenous, cutaneous or subcutaneous injection, compounds of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution.
  • a prefe ⁇ ed pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to compounds of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art.
  • the pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art.
  • the amount of compound(s) of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of compound of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of compound of the present invention and observe the patient's response. Larger doses of compounds of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further.
  • compositions used to practice the method of the present invention should contain about 0.1 ⁇ g to about 100 mg (preferably about .1 mg to about 50 mg, more preferably about 1 mg to about 2 mg) of compound of the present invention per kg body weight.
  • the duration of intravenous therapy using the pharmaceutical composition of the present invention will vary, depending on the severity of the disease being treated and the condition and potential idiosyncratic response of each individual patient. It is contemplated that the duration of each application of the compounds of the present invention will be in the range of 12 to 24 hours of continuous intravenous administration. Ultimately the attending physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the present invention.
  • the indole may be alkylated at the c-3 position with the appropriate alkyl bromide and treatment with a lewis acid such as silver(I)oxide or silver tetrafluoroborate in a solvent such as dioxane or THF at elevated temperatures of 50 °C - 100 °C.
  • a lewis acid such as silver(I)oxide or silver tetrafluoroborate in a solvent such as dioxane or THF at elevated temperatures of 50 °C - 100 °C.
  • it may be alkylated in a two step procedure by treatment of the indole with n-BuLi in a solvent such as THF or ether followed by ZnC12 and then concentrated and treated with the appropriate alkylating agent in a variety of solvents such as THF, ether, toluene or benzene.
  • the indole nitrogen may then be alkylated by treatment with a strong base such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride or potassium hydride in a solvent such as DMF, DMSO or THF followed by exposure to the appropriate alkyl halide.
  • a strong base such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride or potassium hydride in a solvent such as DMF, DMSO or THF followed by exposure to the appropriate alkyl halide.
  • the ester can be hydrolyzed under basic conditions with sodium hydroxide in water and methanol and THF.
  • it may be cleaved by treatment with sodium thiomethoxide in a solvent such as THF or DMF at elevated temperatures (50 °C - 100 °C).
  • the product acid by be coupled to a sulfonamide by the agency of a variety of coupling reagents such as DCC, EDCI or carbonyl diimidazole in a solvent such as THF, methylene chloride, dichloroethane or DMF in the presence of a base such as triethyl amine and/or N, N-dimethyl pyridine.
  • a solvent such as THF, methylene chloride, dichloroethane or DMF
  • a base such as triethyl amine and/or N, N-dimethyl pyridine.
  • Rl nitro the nitro group can be reduced by exposure to Pt/C in the presence of hydrogen in a solvent such as methanol, ethyl acetate or THF.
  • the resulting amine can be acylated or sulfonylated by exposure to the appropriate agent in the presence of a base such as triethyl amine, sodium bicarbonate or pyridine in a biphasic solvent system such as methylene chloride:water ( 1 : 1 ) or THF: water ( 1 : 1 ) or a monophasic organic solvent such as methylene chloride, THF or DMF with triethylamine.
  • a base such as triethyl amine, sodium bicarbonate or pyridine
  • a biphasic solvent system such as methylene chloride:water ( 1 : 1 ) or THF: water ( 1 : 1 ) or a monophasic organic solvent such as methylene chloride, THF or DMF with triethylamine.
  • Rl Br
  • it may be replaced with the copper salt of the desired nucleophile such as thiomethoxide, methoxide or sulphinic acid.
  • the indoleglyoxalyl chloride may be reacted with the desired amino ester in a biphasic system with methylene chloride and saturated sodium bicarbonate or in a monophasic system with a solvent such as methylene chloride, ethyl acetate or THF and a base such as triethylamine, Hunigs base or pyridine.
  • the indole nitrogen may then be alkylated with a variety of alkylatmg reagents in a solvent such as DMF, DMSO or THF and a base such as sodium hydride, n-BuLi or potassium bis(trimethylsilyl)amide.
  • the ester may then be hydrolyzed with sodium hydroxide or lithium hydroxide in a solvent system such as water:methanol:THF.
  • the 3-carboxyindole is elaborated via reductive amination by allowing the aldehyde to condense with an amino ester in a solvent such as methylene chloride or dichloromethane with or without acetic acid.
  • a solvent such as methylene chloride or dichloromethane with or without acetic acid.
  • the resulting imine is reduced in-situ with a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.
  • the acid is then prepared by hydrolysis of the resulting ester with sodium hydroxide or lithium hydroxide in a solvent system such as water:methanol:THF.
  • Rl alkyl
  • 5-benzyloxyindole may be treated with a base such at methyl or ethyl grignard and acylated at the 3-position with ethyloxychloride in a suitable solvent such at ether or THF.
  • the indole nitrogen may then be alkylated with a benzylbromide by the action of a base such as sodium hydride or n-butyllithium in a solvent such a THF or DMF.
  • the ester is then hydrolysed under basic conditions with sodium hydroxide or tetrabutylammonium hydroxide in a suitable solvent system such at wate ⁇ MeOHTHF.
  • Coupling of the appropriate aminoester may then be effected by the use of a coupling agent such as DCC or EDCI in a solvent such as methylenechloride, THF or DMF.
  • a coupling agent such as DCC or EDCI in a solvent such as methylenechloride, THF or DMF.
  • the target acid may the be revealed by hydrolysis of the ester under the same conditions discussed above.
  • Indole-3-acetic acid was alkylated with an appropriate alkyl bromide which was then subjected to Suzuki coupling conditions using Pd(PPh3)4 as a catalyst in a mixed solvent (ethanol- benzene- water) at elevated temperature to give the l-alkyl-5-substituted indole.
  • aldehyde ⁇ Alkylation of the nitrogen atom of I with a suitable base such a sodium hydride or potassium carbonate and an alkyl halide gave the aldehyde ⁇ .
  • the aldehyde could be transformed to the thiazolidinedione in using a base such as piperdine and isolated with an acid such as acetic acid.
  • Deprotonation with a suitable base such as sodium hydride and alkylation on the nitrogen atom of the thiazolidinedione with selected electrophiles such as alkyl or benzyl halides provided compounds such as IV.
  • nitro-indole I was converted to the unsaturated ester via a Homer- Wittig reaction with trimethoxyphosphonoacetate in a suitable solvent such as tetrahydrofuran. Reduction of the nitro group of II can be accomplished via hydrogenation with palladium on carbon in the presence of hydrogen and acylation of the resulting amine under Schotten-Bowmann conditions to give amides such as HI. Saponification of the ester function gave the acid-indole
  • 5-Chloro-2-methylindole could be reductively alkylated at the 3-position with a suitable aldehyde in the presence of an acid such as trifluoroacetic acid and a reducing agent such as triethylsilane in a suitable solvent such as methylene chloride to give the ester ⁇ .
  • the nitrogen atom could be alkylated by treatment with a suitable base such as sodium hydride and diphenyl bromo methane and the resulting compound in could be saponified to give IV.
  • the starting indole is C3 functionalized by either reaction of DMF/POC13 or by reacting the magnesium salt of the indole with methyl oxalyl chloride.
  • the resulting esters and aldehydes were then Nalkylated by treating the salt of the indole, generated by treating the indole with a strong base, with a variety of alkyl halides.
  • aldehydes when r' is a nitro group, the nitro is reduced to the amine using Pt/C and H2 or copper acetate/sodium borohydride and then acylated usind various acid chlorides, isocyanates, chloroformates or reductively alkylated using aldehydes and sodium triacetoxyborohydride.
  • These aldehydes could then be oxidised to the desired acid which could be coupled to an amino alkyl or aryl esters by an EDCI coupling method or by first transforming the acid into the acid chloride under the action of oxalyl chloride and the reacting this with an amino alkyl or aryl ester.
  • esters generated above could be treated in a similar fashion.
  • the ester could hydrolyzed and then coupled to an amino alkyl or aryl esters by an EDCI coupling method or by first transforming the acid into the acid chloride under the action of oxalyl chloride and the reacting this with an amino alkyl or aryl ester. These were then hydrolyzed to yield the final product.
  • Method 1(a)
  • the starting amine was treated with various sulfonyl chlorides in the presence of pyridiine and then the excess sulfonylchloride was scavenged by adding a polymer bound amine.
  • the desired products where then hydrolyzed using sodium hydroxide in THF MeOH and the reaction was aidified using IR-120 resin to yield the desired products.
  • the starting indole was bis alkylated by the addition of a strong base such as sodium hydride and then an alkylating agent such as an alkyl or aryl halide followed by the hydrolysis of the resulting ester with sodium hydroxide in THF MeOH.
  • the acid was then coupled with an alkyl or aryl amino ester and then hydrolyzed to yield the desired acid.
  • Step 1 To a solution of 5-nitro indole (21.24 g, 131 mmol) in dioxane (128 mL) in a reaction vessel wrapped in aluminum foil is added silver(I)oxide (30.34 g, 131 mmoL, 1.5 eq) and methyl 4-(bromomethyl)-3-methoxy-benzoate (34 g, 131 mmol) and the mixture is brought to 60 °C and stirred 20 h. The reaction is cooled, filtered through celite, taken up in ethyl acetate (500 mL), washed with brine (2 X 50 mL), dried (MgSO 4 ) and filtered.
  • Step 2 The C3-alkylated indole (1.5 g, 4.4 mmol) was dissolved with 15 mL THF. In a separate flask, NaH (185 g, 4.61 mmol) was suspended with 25 mL THF at 0 °C. The solution of starting material was cannulated into the NaH suspension, giving a deep red solution. This was then allowed to stir at room temperature for 10 minutes.
  • Step 3 The N-alkylated nitroindole (0.95 g) was dissolved with 40 mL anhydrous THF. The system was purged with argon. To the clear, yellow solution, Pt C (0.462 g) was added. The argon was then removed by evacuation and hydrogen was introduced to the system. The reaction was sti ⁇ ed 6.5 h. The hydrogen was evacuated and argon was then purged through the system. The reaction mixture was filtered through celite with THF. The solvent was removed by rotary evaporation to give the crude amine as a dark oil.
  • Step 4 The amine from above (0.7 g) was dissolved in 40 mL CH 2 C1 2 . 4- methylmo ⁇ holine (0.3 mL, 3.0 mmol) and cyclopentyl chloroformate (383 mg, 2.57 mmol) were then added to give a yellow/orange solution. The reaction was allowed to proceed at room temperature for 3 h. The reaction mixture was acidified with 1 N HCl and the mixture was extracted with 50 mL CH 2 C1 2 . The combined organic phases were washed with brine, dried over MgSO 4 , filtered and concentrated to give the crude carbamate.
  • Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
  • Step 3 The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
  • Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
  • Step 3 - The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 4 - The title compound is prepared as in Example 1, step 5, using the above intermediate.
  • Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
  • Step 3 The intermediate carbamate is prepared as in Example 1 , step 4, using the appropriate acylating agent.
  • Step 4 - The title compound is prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M-l) 547
  • Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • Step 3 - The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M-l) 461
  • Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
  • Step 3 - The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 4 - The title compound is prepared as in Example 1, step 5, using the above intermediate.
  • Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
  • Step 3 The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
  • Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • the intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
  • the intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
  • the intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent and the intermediate 5-amino indole is prepared as in Example 1, step 3, using the 5-nitro indole intermediate.
  • the intermediate urea is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • the title compound is prepared as in Example 1, step 5, using the urea intermediate.
  • the intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent followed by preparation of the intermediate 5-amino indole as in Example 1, step 3, using the 5-nitro indole.
  • the intermediate sulfonamide is next prepared as in Example 1, step 4, using the appropriate acylating agent.
  • the title compound is then prepared as in Example 1, step 5, using the sulfonamide intermediate.
  • Example 14 4-r(l-benzhydryl-5-fluoro-lH-indoI-3-yl)methyIl-3-methoxybenzoic acid
  • the intermediate 5-fluoro indole is prepared as in Example 1, step 1, using the appropriate indole and as in Example 1, step 2, using the appropriate alkylating agent.
  • the title compound is prepared as in Example 1, step 5, using the above intermediate.
  • Example 16 The intermediate 5-methyl indole is prepared as in Example 1, step 1, using the appropriate indole and as in Example 1, step 2, using the appropriate alkylating agent. The title compound is then prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M- 1) 460 Example 16
  • step 2 To the intermediate from Example 13, step 2 (0.25 g, 0.46 mmol), in DMF (1 mL) is added CuCN (0.05g, 1.2 eq) and the reaction mixture is stirred at 145 °C overnight and then cooled. To the cooled reaction mixture is added FeCl 3 (0.09 g, 1.2 eq). The reaction mixture is stirred 5 min, taken up in ethyl acetate (30 mL), washed with brine (3 X 10 mL), dried (MgSO 4 ), filtered and concentrated. The product was purified by silica chromatography (20% ethyl acetate/hexanes) to afford the intermediate ester (0.2 g, 89%) as a colorless oil. Step 2
  • step 3 (1 g, 1.9 mmol), in a solution of THF (2 mL) and methanol (2 mL) is added sodium hydroxide (0.41 mL, 4.63 M, 1 eq). The mixture is stirred for 20 min and then concentrated. The residual water is chased off by the addition of toluene and it's removal (3 X) a white powder (1 g, 100%).
  • step 4 (0.5 g, 0.87 mmol), in CH 2 C1 2 (4 mL) is added EDCI (0.2 g, 1.0 mmol, 1.2 eq), DMAP (0.011 g, 0.087 mmol, 0.1 eq) and ortho-toluene sulfonamide.
  • the reaction is stirred overnight at room temperature, taken up in ethyl acetate (50 mL), washed with sodium biphosphate (1 X 10 mL), brine (2 X 10 mL), dried (MgSO 4 ), filtered and concentrated.
  • Silica chromatography 1% acetic acid, 25% ethyl acetate/hexanes afforded the title compound (0.4 g, 63%) as a colorless solid.
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the product of Example 1, step 5, and the appropriate sulfonamide.
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
  • Example 28 cvclopentyl N-(l-benzhvdryl-3-F4-((F(2- chlorophenyl)sulfonyl1aminolcarbonyl)-2-methoxybenzvn-lH-indol-5- yllcarbamate
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
  • Example 3 step 4, and the appropriate sulfonamide.
  • Example 32 cvclopentyl N-f l-benzhydryl-3-F4-( ⁇ r(2.4-dimethvI-1.3-thiazol-5- yl)sulfonvIlamino)carbonyl)-2-methoxybenzyH-lH-indol-5-vI)carbamate
  • the title compound is prepared as illustrated in Example 19 starting with the product of
  • Example 3 step 4, and the appropriate sulfonamide.
  • Example 33 cvclopentyl N-ll-benzhvdryl-3-F4-( ⁇ F(3.5-dimethyl-4- isoxazolyl)sulfonyllaminolcarbonyl)-2-methoxybenzyll-lH-indoI-5- yllcarbamate
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
  • the intermediate 5-amino indole is prepared as in Example 1, step 3.
  • the intermediate sulfonamide is prepared as in Example 1, step 4, using the appropriate acylating agent. Step 3
  • the intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
  • the intermediate 5-amino indole is prepared as in Example 1, step 3.
  • the intermediate sulfonamide is prepared as in Example 1, step 4, using the appropriate acylating agent. Step 3
  • the intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
  • Step l The intermediate 5-amino indole is prepared as in Example 1, step 3.
  • the intermediate amide is prepared as in Example 1 , step 4, using the appropriate acylating agent.
  • Step 3 The intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the intermediate above and the appropriate sulfonamide.
  • Step l The intermediate 5-amino indole is prepared as in Example 1, step 3.
  • the intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 3 The intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the intermediate above and the appropriate sulfonamide.
  • the intermediate 3-alkylated 5-nitroindole is N-alkylated as illustrated in Example 3, step 1.
  • the intermediate 3-alkylated 5-bromoindole is prepared as illustrated in Example 13, step 1, using the appropriate alkylating agent.
  • the intermediate 3-alkylated 5-nitroindole is N-alkylated as illustrated in Example 13, step 2.
  • step 2 the desired intermediate is prepared as illustrated in Example 3, step 2.
  • the intermediate carbamate is prepared from the above intermediate as illustrated in Example 3, step 3.
  • Step 1 To a solution of methyl 3-aminobenzoate (2.4 g, 16.0 mmol) in CH 2 C1 2 (50 mL) and saturated sodium bicarbonate (50 mL) at 5 °C is added 3-indolylglyoxalyl chloride (3.0 g, 14.4 mmol). The reaction is stirred to room temperature over 2 h, taken up in ethyl acetate (200 mL), washed with brine (3 X 50 mL), dried (MgSO 4 ), filtered and concentrated. Crystallization of the crude material afforded the desired intermediate (2.7 g, 58%) as a colorless solid.
  • Step 2 To a solution of the above intermediate (0.3 g, 0.93 mmol) in DMF (1.5 mL) at 0 °C is added potassium bis(trimethylsilyl)amide (0.41 g, 2.06 mmol). After the reaction is stirred at room temperature 30 min 4-benzylbenzyl bromide (0.27 g, 1.03 mmol) is added. The reaction is sti ⁇ ed 3 h, taken up in ethyl acetate (10 mL), washed with brine (3 X 2 mL), dried (MgSO 4 ), filtered and concentrated. Radial silica chromatography (2 mm, 10% - 35% ethyl acetate/hexanes) afforded the desired intermediate (0.19 g, 41%) as a colorless oil.
  • Step 3 The ester obtained in step 2 was treated with sodium hydroxide (2 mL, 5 M) in THF (5 mL) and MeOH (2 mL). The reaction was stirred overnight, taken up in ethyl acetate (50 mL), washed with sodium biphosphate (1 X 10 mL), brine (2 X 10 mL), dried (MgSO 4 ), filtered and concentrated. Trituration of the material in ethyl acetate with hexanes afforded the title compound (0.105 g, 60%) as a colorless solid. MS: m/z (M-1) 487
  • Example 61 3- ⁇ F2-(l-benzhydryl-lH-indol-3-yl)-2-oxoacetyl1amino)benzoic acid
  • the intermediate prepared in Example 59, step 1 was N-l alkylated with the appropriate reagent using the procedure described in Example 59, step 2.
  • step 3 0.3 g, 0.7 mmol
  • dichloroethane (2 mL) and DMF (1 mL) is added methyl 3-amino benzoate (0.113 g, 0.735 mmol, 1.05 eq) and acetic acid (0.13 mL, 2.1 mmol, 3 eq).
  • Step 2 To the above indole in DMF at 0 °C was added sodium hydride (0.4 g, 60% dispersion in oil). After warming to room temperature, 4-benzylbenzylbromide (2.2 g) was added and the mixture was sti ⁇ ed overnight. As the reaction was not yet done (TLC) additional 4-benzylbenzylbromide (1.0 g) was added and the reaction stined for 2.5 h. The reaction was taken up in ethyl acetate and washed with water, dried (MgSO 4 ), filtered and concentrated. Chromatography (20% ethyl acetate/hexanes) afforded the desired compound (3.1 g 90%).
  • Step 3 The above ester was placed in a solution of NaOH (2N):THF:MeOH (1:2:1) and sti ⁇ ed overnight at room temperature. The reaction was acidified with 6 N HCl and the product extracted with ethyl acetate. The organic layers were dried (MgSO 4 ), filtered and concentrated. The solid was triturated with ethanol and sti ⁇ ed for 1 h. The solid was filtered and dried affording the title compound (1.85 g) as a yellow solid. MS: m/z (M-1) 474
  • Example 69 The indole prepared in Example 69, step 1, was alkylated with the appropriate alkyl bromide and hydrolyzed as described in Example 69, steps 2 and 3.
  • Step 1 To a solution of the acid from Example 69, step 3, (0.810 g) in THF (28 mL) was added CDI. The reaction was stined 30 min and then ethyl 3-aminobenzoate (0.330 g) was added and the reaction was sti ⁇ ed overnight. The reaction mixture was taken up in ethyl acetate and washed with water, dried (MgSO 4 ), filtered and concentrated. The crude material was triturated with ethanol and stined for 1 h, filtered and dried. The desired product (0.76 g, 75%) was isolated as a yellow solid. Step 2 - The above ester was dissolved in NaOH (2N):THF:MeOH (1:2: 1) and sti ⁇ ed
  • Example 69 The alkylated indole from Example 69 was coupled to the appropriate amino acid and hydrolyzed as illustrated in Example 71, steps 1 and 2.
  • Example 70 The alkylated indole from Example 70 was coupled to the appropriate amino acid and hydrolyzed as illustrated in Example 71, steps 1 and 2.
  • Example 77 To the acid obtained in Example 71 (0.1 g) in CH 2 C1 2 (10 mL) is added THF ( 5 mL) to help dissolve the compound. EDCI (0.045 g) and DMAP (0.02 g) was added and the mixmre was stined a room temperature of 1 h. p-Toluenesulfonamide (0.04 g) was added and the reaction was stined overnight. The reaction mixture was take up in ethyl acetate and washed with water, dried (MgSO 4 ), filtered and concentrated. Chromatography (7% MeOH/CH 2 Cl 2 ) afforded the title compound (0.045 g, 40%) as a yellow solid. MS: m/z (M-1) 746 Example 77
  • Example 82 The title compound was prepared according to the procedure described in Example 78 except that 2-[5-bromo-l-benzyl-lH-indol-3-yl]acetic acid and phenylboronic acid were used.
  • Example 82 A 2-[5-bromo-l-benzyl-lH-indol-3-yl]acetic acid and phenylboronic acid were used.
  • Example 22 The procedure in Example 22 was followed using 3-formyl indole (0.4g, 2.8mmol), sodium hydride (0.102g, 3.0mmol) and the iodide (0.97g, 2.8mmol) in DMF (10ml). Flash chromatography (Hex/EtOAc, 1/1) gave 0.86g (84%) of the desired intermediate.
  • step 1 The intermediate from step 1 (0.8 g, 2.2 mmol) and 2.4-thiazolidinedione (0.25, g, 2.2 mmol) was dissolved in toluene (5 mL). Piperidine (0.064 mL, 0.6 mmol) and acetic acid (0.012 mL) were added and the mixture was heated to reflux for 2h. The reaction was allowed to cool to rt, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine , dried (MgSO4), filtered and concentrated. Flash chromatography (hexane/ ethyl acetate , 3/2) afforded the title compound (0.345 g (33%) as an orange solid.
  • Example 83 3- ⁇ l-[3-(3-benzylphenoxy)propyl]-lH-indol-3-yl ⁇ propanoic acid The procedure in Example 22 step 1 was followed except 2 eq. of sodium hydride was used and 0.142g (65%) of the title compound was isolated as a white oily solid.
  • Example 84
  • stepl (l.Og, 2.8mmol) in toluene (20ml) was added carbomethoxyethyhdene triphenylphosphorane (0.98g, 2.9mmol). The mixture was heated overnight at reflux and then concentrated. The residue was dissolved in CH 2 C1 2 and silica gel was added. The mixture was concentrated and the resulting solid was purified by flash chromatography (Hex/EtOAc. 3/1). Compound 30 l.Olg (88%) was isolated as a yellow solid. Step 2
  • Stepl The same procedure as Example 84 step 2 was used to prepare the desired intermediate from the nitroindole (Example 114 step 1). Step 2 The procedures in Example 84, step 1 and 3 were used to prepare the title compound from the above intermediate.
  • Example 86A The acid from Example 86A was used to prepare the title compound according to the procedure in example 85.
  • Example 84 step 1 The ester from Example 84 step 1 was saponified according to the procedure in Example 84 step 3 and recrystallization from hot EtOAc afforded 0.155g (90%) of the title compound as a white solid.
  • Example 85 The procedure in Example 85 was used to prepare the title compound from the product of Example 87A.
  • Stepl - The intermediate from Example 3 step 2 (leq) (see scheme #) was weighed in to a flask along with the 4-trilflouromethylbenzene sulfonyl chloride (1.2 eq) and then they were flushed with nitrogen, taken up in dichloroethane (0.15 M) and then pyridine was added (1.2 eq) at which time the reaction was left to stir overnight and then worked up by the addition of the polymer bound amine ( Parlow, J.J, Mischke, D. A., Woodard, S.S.J Org. Chem.
  • Step 2 The crude material from stepl was dissolved THF/MeOH (2.5/1) and then 4N NaOH was added ( 3 eq) and the reaction was stined until complete hydrolysis was observed by TLC. At this point the reaction quenched with enough amberlite ir 120 to make the solution acidic and then the resin was filtered off and rinsed and the desired product was obtained in 94% yield by drying and concentrating the solution. MS: m/z (M-1) 669
  • Step 1 Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 76% of the title compound after chromatographic purification.
  • Step 2 An analogous proceedure to step 2 for Example 89 above yielded 83% of the desired product.
  • Step 1 Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
  • Step 2 An analogous proceedure to step 2 for Example 89 yielded 54% of the desired product after chromatographic purification. MS: m/z (M-1) 681
  • Step 2 An analogous proceedure to step 2 for Example 89 yielded 100% of the desired product.
  • Step 1 Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
  • Step 2 An analogous proceedure to step 2 for Example 89 yielded 100% of the desired product.
  • Step 1 Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 56% of the title compound after chromatographic purification.
  • Step 2 An analogous proceedure to step 2 for Example 89 yielded 82% of the desired product.
  • Example 95
  • Step 1 Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
  • Step 2 An analogous proceedure to step 2 for Example 89 yielded 96% of the desired product.
  • Step 1 Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
  • Step 2 An analogous proceedure to step 2 for Example 89 yielded 89% of the desired product.
  • Example 3 The compound of Example 3 (1.0 eq) was dissolved in THF (0.15M) and then carbonyl diimidizole (1.2 eq) was added and the reaction was stirred under N 2 for three hours at which time ammonium hydroxide was added (3ml g) and the reaction was stined overnight when TIC analysis showed it was complete. To the reaction was added water and ethyl acetate, the layers were separated and the aqueous layer was extracted three times, the combined organic extracts were dried concentrated and chromatographed to yield 64% of the desired primary amide.
  • Example 98 cvclopentyl N-(l-benzhvdryl-3-F2-methoxy-4-(lH-1.2.3.4-tetraazol-5- yl)benzyll-lH-indol-5-yllcarbamate Step 1 - To the compound of Example 97 (1.0 eq) under N 2 was added CH 2 C1 2
  • Step 2 To the nitrile (1.0 eq) isolated in step 1 was add sodium azide (3 eq) and triethyl amine hydrochloride (1.5 eq) and n-methyl-2-prynolidinone (0.05m) and then the reaction was heated to reflux under an inert atmosphere for 2.5 hours when it was poured into ice and water that was then acidified to pH 2 and the product was filtered off and then further purified by preparative chromatography to yield the desired compound in 22% yield. MS: m/z (M-1 ) 597
  • Step 2 The ester from the previous step was dissolved in THF/MeOH (3:1) and then IN NaOH (3.0eq) was added and the reaction was stined for until TLC analysis showed that the reaction was complete. The reaction was then concentrated, diluted with water, acidified to pH 2 with cone HCL, extracted with ethyl acetate 3X, the combined organics were dried over magnesium sulfate concentrated and purified via chromatography to yield the desired acid in 64% yield.
  • Step 1 The acid (see scheme #) was coupled with the appropriate amino ester following the procedure in Example 99, step one, except the reaction was run at room temperature and that the procedure yielded 80% of the desired product isolated by recrystalization.
  • Step 2 The nitro ester from step one (1.0 eq) was weighed into a flask along with 5% Platinum on Carbon (40 wt%) and the vessel was sealed with a septum and evacuated and flushed with argon 3X, then freshly distilled THF is added and the reaction is evacuated 2X and after the second evacuation a balloon of hydrogen inserted into the septum.
  • step 3 The amine (1.0 eq) was dissolved in dichloromethane (0.3M) and then an equivalent amount of saturated sodium bicarbonate was added and finally the acid chloride introduced.
  • the biphasic reaction mixture was vigorously sti ⁇ ed until TLC analysis indicated that the reaction was complete (generally a few hours) and then the reaction was diluted with dichloromethane and water, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried, concentrated and chromatographed to yield the desired amide in 41% yield.
  • Step 4 According to step 2, Example 99, the ester was hydrolyzed to the acid and yielded 71% of the final product. MS: m/z (M-1) 556
  • Step 2 To the acid chloride generated in step 1 was added dichloromethane (0.1M) and then a solution of alanine methyl ester (1.05eq, free base) in dichloromethane (1.0M) and then triethylamine (1.5eq)was added and the resulting mixture was stined overnight and worked up by the addition of 1/2 saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried and concentrated and purified via chromatography to yield the desired amide.
  • dichloromethane 0.1M
  • a solution of alanine methyl ester (1.05eq, free base)
  • triethylamine 1.5eq
  • Step 3 The ester from step 2 was hydrolyzed under the conditions outlined for step 2, Example 99, to yield the desired acid.
  • Step 1 The acid chloride (1.0 eq) synthesized in step 1, Example 101, was weighed into a flask along with o-tolylsulfonamide (1.5eq), DMAP (0.1 eq) and taken up in dichloromethane
  • Step 1 According to the general procedure in step 1, Example 101, using the product from Example 115 and the appropriate amino ester yielded the desired product in 100% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2, Example 99, to yield the desired acid.
  • Step 1 According to the general procedure in step 1, Example 99, using the product from Example 115 and the appropriate amino ester yielded the desired product in 100% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2, Example 99, to yield the desired acid.
  • step 2 To the acid from step 2 (1 eq) (see scheme- 1) was added methyl 3-aminobenzoate (1.05 eq), EDCI (1.37 eq) and DMAP (0.2 eq) followed by anhydrous DMF (0.086M), stined at 25°C, overnight. Workup with ethyl acetate/ IN HCl followed by chromatographic purification afforded the desired product in 80% yield. Step 4
  • Step 1 The 5-Hydroxy-2-Methylindole-3-Carboxylate (1 eq) was combined with benzyl bromide (1.3 eq) and K 2 CO 3 (325 mesh, 1.3 eq) in CH 3 CN (0.1 M). The resulting mixture was heated to reflux for 2 h. An additional amount of benzyl bromide (0.2 eq) and the heating was continued for 2 h. The reaction was worked up by addition of water and extraction with CH 2 C1 2 . The organic extracts were washed with water, dried and concentrated. Flash chromatography provided the desired benzyl ether (63 % yield), as well as the conesponding
  • Step 2 An ice cooled solution of the benzyl ether from step 1 (1 eq) in dry DMF (0.25 M) was treated with NaH (60 % in mineral oil, 1.1 eq). 2,4-Bis trifluoromethyl benzyl bromide (1.1 eq) was added after 1 h and the resulting mixture was sti ⁇ ed at 25°C for 2 h. Solvent was evaporated under vacuo, the residue was dissolved in EtOAc, washed with water, dried and concentrated. The desired product was obtained in 77 % yield after recrystallization from hexane/CHCl j .
  • Step 3 The product from step 2 (1 eq) in THF/MeOH (3/1) was heated to reflux with IN
  • Step 1 The acid prepared in step 3 (1 eq) of example 108 was reacted with EDCI (2 eq) and dimethyl 5-aminophthalate (5 eq) in THF (0.02 M) in the presence of DMAP (2 eq). The reaction was heated to reflux for 48 h. EtOAc/water work up, followed by flash chromatography produced the desired amide in 32 % yield.
  • Step 2 The material from step 1 (1 eq) was hydrolyzed by the action of LiOHH 2 O (2.2 eq) in THF/MeOH/water (3/1/1, 0.07 M). After stirring at 25°C overnight, the reaction mixture was quenched with AcOH and solvent was evaporated. EtOAc/water work up and trituration in hexane/CH,Cl 2 afforded the title compound in 82 % yield. MS: m/z (M-1) 669
  • Step 1 An analogous procedure to step 2 example 108 using the main product of step 1 above and the appropriate bromide yielded the desired N-substituted indole in 71 % yield after recrystallization.
  • Step 2 The ester from step 2 above (1 eq) in THF/MeOH (3/1) was heated to reflux with 4N KOH (2 eq). After 5 days solvent was evaporated and the residue partitioned between IN HCl and CHC1 3 . The organic extract was washed, dried and concentrated. The title compound was obtained in 92 % yield after chromatographic purification and crystallization. MS: m/z ( M - 1 ) 420 Example 110
  • Step 1 The acid in Example 109 was converted in the conesponding amide following an analogous procedure to step 1 of Example 108.
  • the product was contaminated with the aniline starting material which could only be partially removed by chromatography.
  • Step 2 Hydrolysis of the crude material following step 2
  • Example 108 provided the title compound after chromatographic purification (4 % yield in Example 109).
  • Step 1 The minor product of step 1 (1 eq) Example 107 was dissolved in THF (0.1 M). KOH (2 eq) and 18-crown-6 (2 eq) were added and the resulting mixture was heated to reflux for 1.5 days. Work up as on step 2 Example 108 above provided the title compound in 32 % yield. MS: m/z (M-1) 370
  • Step 1 The starting ethyl 5-benzyloxyindole-2-carboxylate (Scheme 21, step 1) was treated with LAH (1.3 eq) in THF (0.27 M) at 0 °C under nitrogen for 1 h. Workup with NaOH and water followed by concentration afforded crude product (100%).
  • Step 2 The crude alcohol from step 1 was dissolved in DMF (0.38 M), and treated with t- butyldimethylsilyl chloride (1.16 eq) and imidazole (1.26 eq) at 25 °C for 1 d. Workup and chromatographic purification afforded the pure product (93%).
  • Step 3 The silyl ether from step 2 was dissolved in methylene chloride (0.26 M), and treated with BOC anhydride (1.24 eq), triethylamine (1.53 eq) and DMAP (0.21 eq) at 25 °C for 3 d. Workup and chromatographic purification afforded the pure product (99%).
  • Step 4 The N-BOC silyl ether from step 3 was treated with acetic acid/ water/ THF (3:1:1) (0.04 M) at 25 °C for 1 d. Workup and chromatographic purification afforded the pure product (100%).
  • Steps 5 The alcohol from step 4 was dissolved in methylene chloride (0.2 M), and under nitrogen at -40°C treated with triethylamine (1.33 eq), and mesyl chloride (1.23 eq) for 1 h.
  • naphthalene-2-thiol (1.31 eq)
  • THF (1 M)
  • hthium hexamethyldisilazide 1 eq
  • Step 6 The purified BOC thioether from step 5 was heated under nitrogen at 160- 170°C for 1.25 h, and recrystalhzed from ethyl acetate and hexanes to afford the free indole thioether in 64% yield.
  • Step 7 The indole thioether from step 6 was dissolved in DMF (0.2 M), and treated with sodium hydride (1.1 eq) at 25°C for 45 min. 4-Chlorobenzyl chloride (1.3 eq) and KI (cat.) were added, and the mixture was sti ⁇ ed at 25°C for 3 d. Workup (ethyl acetate/water) and trituration (ethyl acetate/hexanes) afforded the pure product (52%).
  • Step 8 A solution of EtMgBr in ether (3 N, 2.17 eq) was cooled to - 70 °C.
  • methyl oxalyl chloride (3 eq) in ether 1.5 M
  • the reaction was sti ⁇ ed at - 40 °C for 2 h, allowed to warm to 25 °C. Quenched with sodium bicarbonate EtOAc/water work up and crystallization from hexane/EtOAc the desired ketone.
  • Step 9 The ester from step 8 was hydrolyzed using the general method in step 2 example 108 to yield the desired alpha keto acid.
  • Step 10 The indole thioether from step 9 was dissolved in dry methylene chloride (0.05 M), and treated with oxalyl chloride (2.05 eq) at 0°C for 1 h. In a separate dry flask were weighed 3-aminobenzoic acid (10 eq) and triethylamine (15 eq) in methylene chloride (0.5 M). The resulting solution was then added dropwise, at 0°C, and the mixture was allowed to warm to 25°C overnight. Workup (methylene chloride/aqueous HCl) and repeated purification by chromatography afforded the pure title compound product.
  • Step 11 The product from step 9 was hydrolyzed using the procedure from step 2 Example 108 to yield the desired compound in 28%. MS: m/z (M-1) 709
  • Step 1 Following step 4 of the above procedure using methyl iodide followed by trituration (ethyl acetate/hexanes) afforded the pure product (72%).
  • Step 2 An analogous procedure to step 5 through step 11 above yielded 58% of the title compound. MS: m/z (M-1) 599
  • Example 114 l-benzhvdryl-5-F(cvclopentylcarbonyl)aminol-lH-indole-3-carboxylic acid Step 1 5-nitroindole was alkylated as in Example 3 stepl with the appropriate bromide to yield the desired N-alkylated product.
  • Step 2 The indole from step 1 (l.Oeq) was dissolved in DMF (0.4M) and treated with phosporous oxychloride (6.9 eq) at room temperature and then the mixture was sti ⁇ ed for 1 day at 80 C at which time the reaction was poured onto ice and triturated with ethyl acetate/hexanes, followed by workup with sodium bicarbonate/chloroform yielded the C3 formylated product.
  • Step 3 The nitro indole from step 2 was reduced according to the procedure in
  • Example 100 step 2 to yield the amino aldehyde.
  • Step 4 The indole from step 3 was acylated according to the procedure from
  • Step 5 The indole from step 4 (1.0 eq), 2 methyl-2butene (45 eq), sodium dihydrogen phosphate (11.6 eq). were dissolved in t-BuOH (0.2M), water (0.2M) and then sodium chlorite (11.6q) was added and the reaction was heated to 65 C for 24 hours. The reaction was diluted with water, extracted 3 times with ethyl acetate, dried and concentrated and then purified by chromatography to yield the title compound.
  • Step 1 Following the procedure of Example 69, 5-niroindole was acylated in the 3-position with ethylmagnesiumbromide and ethyloxalylchloride. Step 2 The above intermediate was elaborated to the final product following steps 2-5 of Example 114 to afford the title compound.
  • Example 116
  • Table I reports data for the compounds described in the examples above in cPLA2 inhibition assays (described below). In the data columns of Tables I and ⁇ , assay results are reported as a percent inhibition at the concentration specified.
  • Each compound was suspended in 0.3ml absolute ethanol, 0.1 ml Tween-80 and 2.0 ml Dulbecco's PBS (without calcium or magnesium). To this mixture, 0.1ml IN NaOH was added. After solution was complete, additional amounts of PBS were added to adjust the concentration to 1 mg/ml. All compounds remained in solution.
  • Compounds were administered i.v. in a volume of 5 ml/kg to male Sprague Dawley rats at the same time that edema was induced by injection of 0.05ml of 1% Type TV canageenan into the hind footpad. Footpad volume was measured before dosing with compound and 3 hours after dosing with carageenan.
  • Step 1 To l-benzhydryl-6-chloro-lH-indole (1.0 eq) and methyl 2-(4-formy 1-2,6- dimethylphenoxy) acetate (0.6 eq) in CH 2 C1 2 (0.1M) at 0°C was added neat triethysilane (3eq) followed by triflouroacetic acid (3eq). After 10 minutes at 0°C the reaction was warmed to room temperature and stined until the initially formed spot by TLC yields a new spot.

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