EP1056719A2 - Inhibitoren von phospholipasen enzymen - Google Patents

Inhibitoren von phospholipasen enzymen

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Publication number
EP1056719A2
EP1056719A2 EP99908379A EP99908379A EP1056719A2 EP 1056719 A2 EP1056719 A2 EP 1056719A2 EP 99908379 A EP99908379 A EP 99908379A EP 99908379 A EP99908379 A EP 99908379A EP 1056719 A2 EP1056719 A2 EP 1056719A2
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EP
European Patent Office
Prior art keywords
alkyl
methyl
phenyl
pharmaceutically acceptable
compound
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EP99908379A
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English (en)
French (fr)
Inventor
Jasbir S. Seehra
Neelu Kaila
John C. Mckew
Frank Lovering
Jean E. Bemis
Yibin Xiang
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Genetics Institute LLC
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Genetics Institute LLC
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Publication of EP1056719A2 publication Critical patent/EP1056719A2/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/12—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • 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
    • C07D405/12—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 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

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.
  • 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.
  • Arachidonic acid which is fed into these two distinct inflammatory pathways is released from the sn-2 position of membrane phospholipids by phospholipase A 2 enzymes
  • PLA 2 The reaction catalyzed by PLA 2 is believed to represent the rate- limiting step in the process of lipid mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes.
  • the phospholipid substrate of PLA 2 is of the phosphotidyl choline class with an ether linkage in the sn-1 position, the lysophospholipid produced is the immediate precursor of platelet activating factor
  • PAF PAF
  • 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.
  • PLA 2 is regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc. Natl. 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 RAW 264.7. A specific activity of 2 mols/min/mg, resistant to reducing conditions, was reported to be associated with the approximately 60 kD molecule. However, this protein was not purified to homogeneity. [See, C. C. Leslie et al, Biochem. Biophys. Acta.. 963:476-492 (1988)]. The references cited above are inco ⁇ orated by reference herein for information pertaining to the function of the phospholipase enzymes, particularly PLA 2 .
  • cPLA 2 A cytosolic phospholipase A 2 (hereinafter "cPLA 2 ”) 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.
  • R, and R are independently selected from H, halogen, -CF 3 , -OH, -C,-C I0 alkyl, preferably -C,-C 6 alkyl, -S-C,-C, 0 alkyl, preferably -S-C,-C 6 alkyl, C,-C 10 alkoxy, preferably C r C 6 alkoxy, -CN, -NO 2 , -NH 2 , -HN(C,-C 6 ), -N(C,-C 6 ) 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 r 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 , -NH 2 , -CN, - CF 3 , or -OH;
  • R 7 is selected from -OH, -CF 3 , C,-C 6 alkyl, C r C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C r C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, 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 2 is selected from H, halogen, -CF 3 , -OH, -C,-C l0 alkyl, preferably -C,-C 6 alkyl, C,- C I0 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,-C 6 alkyl, or -SO 2 -C,-C 6 alkyl;
  • R 3 is selected from H, -CF 3 , C r 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 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 JQ 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 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -
  • n is an integer from 0 to 3;
  • R 4 is selected from the group of C r C 6 lower alkyl, C r C 6 lower alkoxy, -(CH 2 ) n -C 3 -
  • CT Y wherein 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 or pyrrolyl; 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, 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, or -NO 2 ; or
  • Z is O or S and the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, -CF 3 , - OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 , or -NO 2 ;
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-,
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • R 8 , RQ or R ]0 can be attatched anywhere in the cyclic or bicyclic system
  • R 8 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, -(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, -(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,
  • R 5 , 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; or a pharmaceutically acceptable salt thereof. It will be understood in the group above that substituents R 3 and R 4 are bound to the indole or indoline ring's 2- or 3 -position and the R,, R,, and R 2 groups are bound to one of the indole or indoline ring's 4-, 5-, 6- or 7-position carbon atoms.
  • One group of compounds within this invention are those in which the R,, and R 3 groups are hydrogen and the substituents at the other indole or indoline positions are as described above.
  • Another group of this invention comprises compounds in which the R r and R 3 groups are hydrogen and the groups at R,, R 4 , and R 5 are as defined above.
  • R is in the indole or indoline 5-position and in the second R j 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 in the indole or indoline 5 or 6 position and is cyclopentylcarboxamide or cyclopentyloxycarbonylamino
  • R 2 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 j 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, and R 3 and R 5 are as defined above.
  • Preferred compounds of this invention include those of the following formulae:
  • R t is selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , - HN(C,-C 6 ), -N(C,-C 6 ) 2 , phenyl, -O-phenyl, benzyl, -O-benzyl, or a moiety of the formulae:
  • R 6 is selected from H, C r 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 2 , -NO 2 , -CF 3 , or -OH;
  • R 7 is selected from -(CH 2 ) n -COOH, -(CH 2 ) n -N-(C,-C 6 alkyl) 2 , -(CH 2 ) n -NH-(C,-C 6 alkyl), -CF 3 , C,-C 6 alkyl, C 3 -C 5 cycloalkyl, 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, adamantyl, or morpholinyl, 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 , -
  • R 2 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 ,
  • R 3 is selected from the group of C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -C 3 - C 6 cycloalkyl, -(CH 2 ) n -S-(CH 2 ) n -C 3 -C 6 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, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; 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, -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, 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, or -NO 2 ; or
  • phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, -CF 3 , -OH, -C,-C 6 alkyl, C r C 6 alkoxy, or -NO 2 ;
  • the phenyl and benzyl rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -CF 3 , -C(O)-OH, or -OH;
  • n is an integer from 0 to 3;
  • R 8 is 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, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C.- alkyl, -NH(C r C 6 alkyl), -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 r 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
  • R 5 , 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:
  • 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 6 alkyl, C,-C 6 alkoxy, -NO 2 , -CF 3 , or -OH;
  • R 7 is selected from -(CH 2 ) n -COOH, -(CH 2 ) n -N-(C,-C 6 alkyl) 2 , -(CH 2 ) n -NH-(C r C 6 alkyl), -CF 3 , C r C 6 alkyl, C 3 -C 5 cycloalkyl, 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, adamantyl, or morpholinyl, the pyridinyl, 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 alk
  • R 2 is selected from H, halogen, -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 2 -C,-C 6 alkyl, or -SO 2 -C,-C 6 alkyl;
  • the phenyl and benzyl rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -CF 3 , -C(O)-OH, or -OH;
  • n is an integer from 0 to 3;
  • R 4 is selected from the group of 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 :
  • 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, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; 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 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, 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, or -NO 2 ; or
  • Z is O or S and the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, -CF 3 , - OH, -C,-C 6 alkyl, C,-C 6 alkoxy, or -NO 2 ;
  • R 8 is 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, -(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, -(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 ,
  • Rcliff is selected from H, C,-C 6 lower alkyl, -CF 3 , -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, or
  • the complete moiety at the indole or indoline 1 -position created by any combination of R 5 , R 8 , R 9 , 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:
  • One group of compounds within this invention are those in which the indole or indoline 3-position (R 3 ) is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above.
  • Another group of this invention comprises compounds in which R 2 is 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 j 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 r C 6 alkoxy, -NO 2 , -NH 2 , phenyl, -O-phenyl, benzyl, -O-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 -(CH 2 ) n -COOH, -(CH 2 ) n -N-(C,-C 6 alkyl) 2 , -(CH 2 ) n -NH-(C,-C 6 alkyl), -CF 3 , C,-C 6 alkyl, C 3 -C 5 cycloalkyl, 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, adamantyl, or morpholinyl, the pyridinyl, 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 alk
  • R 3 is selected from the group of C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -C 3 -
  • 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 or pyrrolyl; 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 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
  • D is H, C r C 6 lower alkyl, C,-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 r C 6 alkyl, C,-C 6 alkoxy, -NH 2 or -NO 2 ; or c) a moiety of the formulae:
  • Z is O or S and the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, -CF 3 , - OH, -C r C 6 alkyl, C,-C 6 alkoxy, or -NO 2 , -NH 2 ;
  • the phenyl and benzyl rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -CF 3 , -C(O)-OH, or -OH;
  • n is an integer from 0 to 3;
  • R 8 is 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, -(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 ]0 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, -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
  • R is selected form -NH 2 , -O-phenyl, benzyl, -O-benzyl, -N-benzyl, -N-benzyl-O- phenyl, -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 -(CH 2 ) n -COOH, -(CH 2 ) n -N-(C,-C 6 alkyl) 2 , -(CH 2 ) n -NH-(C r C 6 alkyl), -CF 3 , C,-C 6 alkyl, C 3 -C 5 cycloalkyl, 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, adamantyl, or morpholinyl, 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 , -CF 3 , or
  • n is an integer from 0 to 3;
  • R 4 is selected from the group of -(CH 2 ) n -C 3 -C 6 cycloalkyl, -(CH 2 ) n -S-(CH 2 ) n -C 3 -C 6 cycloalkyl, -(CH 2 ) n -O-(CH 2 ) n -C 3 -C 6 cycloalkyl, -(CH 2 ) n -S-C,-C 6 alkyl, the groups of:
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF 3 ;
  • R 8 is 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, -(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, -(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, -CF 3 , -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, or
  • R 5 , R 8 , R 9 , R ]0 , 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:
  • 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, 0 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, 0 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 preferred group includes those of furan, pyrrole, thiophene, pyrimidine, and morpholine rings.
  • a preferred group of bicyclic aromatic groups includes benzofuran, indole, napthalene, and quinoline rings.
  • alkyl, alkenyl and alkinyl groups referred to herein indicate such groups having from 1 to 10, preferably 1 to 6 carbon atoms, and may be straight, branched or cyclic.
  • 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 86 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 86 or Example 87) 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 carrageenan-induced footpad edema test.
  • Compounds of the present invention are useful for inhibiting phospholipase enzyme
  • 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
  • osteoporosis colitis, myelogenous leukemia, diabetes, wasting and atherosclerosis.
  • 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 carriers, 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 incorporated 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 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.
  • 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.
  • Administration of compounds 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 When a therapeutically effective amount of compounds of the present invention is administered orally, 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 may be added.
  • 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.
  • the preparation of such parenterally acceptable protein solutions having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.
  • a preferred 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.
  • 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.
  • Ethyl 5-nitro-2-carboxylate indole is chlorinated in the 3-position by the agency of N- chlorosuccinamide in a solvent such as DMF or DMSO at an elevated temperature of 40 °C - 80 °C.
  • the ester is then reduced in a three step procedure. First the ester is hydrolysed under basic conditions with a base such as sodium hydroxide or potassium hydroxide in a solvent system such as water:methanol:THF.
  • the acid is then activated by he addition of carbonyl diimidizole in THF and reduced with a reducing agent such as sodium borohydride or sodium triacetoxyborohydride in an alcoholic solvent system such as methanol or ethanol.
  • the resulting alcohol is protected as the TBDMS ether with TBDMSC1 in a solvent such as DMF, methylene chloride or THF with a base such a triethylamine or imidazole.
  • a solvent such as DMF, methylene chloride or THF with a base such a triethylamine or imidazole.
  • the indole nitrogen is then alkylated with methyl 4- bromomethlybenzoate in a solvent such as THF, acetonitrile or DMF with a base such as sodium hydride, n-BuLi or potassium bis(trimethylsilyl)amide.
  • the 5-nitro group is then reduced by exposure to H 2 in the presence of a catalyst such as Pt C or Pd C in a solvent such as ethyl acetate, methanol or THF or a mixture of two or all of the three.
  • the amine is then acylated with cyclopentylcarbonyl chloride in a biphasic system of saturated sodium bicarbonate and methylene chloride.
  • Rl is then introduced in a two step procedure wherein the TBDMS ether is converted to a bromide by exposure to dibromotriphenylphosphorane in methylene chloride and then the crude bromide is displaced by a variety of thiols or phenols in a solvent such as THF, methylene chloride or DMF in the presence of a base such as potassium carbonate or cesium carbonate.
  • the product esters are then prepared by the hydrolysis of the ester under basic conditions with sodium hydroxide in a solvent system such as water:MeOH:THF.
  • Acylation at the 3-position of indole I with an acylating agent such as naphthoyl chloride could be accomplished using ethylmagnesium bromide in a solvent such as THF to give II.
  • Alkylation of the indole nitrogen could be accomplished by exposure to a suitable base such as sodium hydride followed by treatment with the appropriate. Deprotection of the hydroxy protecting group with tetrabutylammonium fluoride and oxidation with a suitable oxidizing agent provided IV.
  • Indole I can be converted to II in two steps: (1) reduction with LAH in a solvent such as THF and (2) silylation with t-butyldimethylsilyl chloride (TBDMSC1) in a solvent such as dichloromethane or DMF in the presence of a base such as imidazole.
  • a solvent such as THF
  • TBDMSC1 t-butyldimethylsilyl chloride
  • the silyl group on III is removed using tetrabutylammonium fluoride in a solvent such as THF, the resulting alcohol is then converted to bromide using carbon tetrabromide and bis(diphenylphosphino)ethane in a solvent such as dichloromethane to yield bromide IV.
  • Method D The protected alcohol was deprotected in a suitable solvent such as THF and the resulting alcohol was functionalized to a halide using carbon tetrabromide or methanesulfonyl chloride and then reacted with an oxygen nucleophile, coupled with prior deprotonation with a strong base such as sodium hydride, or a sulfur nucleophile in the presence of cesium carbonate in DMF or THF.
  • a strong base such as sodium hydride, or a sulfur nucleophile in the presence of cesium carbonate in DMF or THF.
  • the nitro group could then be reduced to an amine via a Pt/carbon hydrogenation protocol or copper acetate sodium borohydride procedure.
  • the resulting amine could be hydrolyzed,using a standard procedure of sodium hydroxide in THF MeOH or coupled to a variety of acylating reagents, such as acid chlorides, chloroformates and isocyanates where the reactions are generally performed in the presence of a base in a solvent such as THF or dichloromethane.
  • the amine could also be acylated via an EDCI coupling procedure with a variety of acids.
  • the starting amine could also be alkylated by a reductive amination procedure using a varity of aldehydes and sodium triacetoxyborohydride as the reducing agent.
  • These functionalized amines could be hydrolyzed to yield the desired acids which could also be converted to the acylsulfonamide by EDCI coupling with an sulfonamide.
  • the functionalized amines could be alkylated further by reaction with a strong base and an alkyl halide and then hydrolyzed under the standard conditions to yield the requisite product.
  • These products where then N-alkylated by the action of a strong base and a variety of alkyl or aryl halo esters.
  • R' is a nitro group
  • the nitro was reduced with Pt/C and H2 or copper acetate and sodium borohydride to the amine which was then acylated with a variety of acid chlorides, isocyantes, chloroformates, reductively alkylated with amines or coupled with acids.
  • the resulting esters were hydrolyzed to the desired acids which could further be transformed to the acylsulfonamide.
  • Step 1 Ethyl 5-nitroindole-2-carboxylate (21.1 g) was dissolved in DMF (500 mL). To this dark brow solution, a solution of N-chlorosuccinamide was added (12 g in 125 mL DMF) over a period of 5 minutes. The reaction mixture was heated to 50 °C for 1.5 h. Reaction completion was determined by TLC. The reaction was cooled to room temperature, diluted with water (2 L), and extracted with ethyl acetate (3 X 1 L). The organic layers were combined , dried over MgSO 4 , filtered and concentrated. The result was the desired ethyl ester (96 g wet with DMF) which was carried on to the next step without further purification.
  • Step 2 The ethyl ester was dissolved in methanol (400 mL) and THF (800mL). To this clear, brown solution 2 N NaOH was added (450 mL). The black mixture was stirred at room temperature overnight. The reaction was not quite complete (TLC) therefore an additional 7.2 g of NaOH pellets were added. After 7 h the reaction was complete. Approximately 1 L of solvent was removed by rotary evaporation. The residue was dissolved with ethyl acetate and water and acidified with 2 N HC1 to pH 2. The mixture was then extracted with ethyl acetate (3 X 1 L). The combined organic layers were dried over MgSO 4 , filtered and concentrated to give the acid (24.3 g, 100%) as a brown solid.
  • Step 3 The carboxylic acid (24 g) was dissolved in THF (700 mL). CDI (16.2 g) was added to this clear, amber-colored solution. The mixture was stirred at room temperature for 1.5 h, during which time it became a light brown suspension. The reaction was cooled in an ice bath. Sodium borohydride (10.8 g) was added slowly. Ethanol was then added
  • Step 4 The alcohol prepared above (25.4 g), imidazole (18.6 g), and tert- butyldimethylsilyl chloride (13.3 g) were dissolved in DMF (350 mL). The reaction was stirred overnight and found not to be complete. Therefore imidazole (18.7 g) and t- butyldimethylsilyl chloride (18.6 g) were added. After 1 h, the reaction was complete. Water ( 1.5 L) was added and the mixture was extracted with ethyl acetate (3 X 500 mL).
  • Step 5 The tert-Butyldimethylsilyl-protected alcohol (1.0 g) was dissolved in DMF
  • Step 6 N-alkylated indole (3.8 g) was dissolved in THF (50 mL) and 5% Pt/C (1.6 g) was added. Hydrogen was purged in and the reaction was stirred at room temperature overnight. The reaction was filtered (celite) and concentrated. Column chromatography (35% ethyl acetate in hexane) gave the desired amine (1.7 g) as an off-white solid.
  • Step 7 To a solution of the above amine (1.6 g, 3.5 mmol) in CH 2 C1 2 (10 mL) and saturated sodium bicarbonate (10 mL) was added cyclopentyl carbonyl chloride (0.467 ml, 1.1 eq). The reaction was stirred 45 min, taken up in ethyl acetate (100 mL), washed with brine (3 X 20 mL), dried (MgSO 4 ), filtered and concentrated. Chromatography (20% ethyl acetate/hexanes) afforded the desired product (1.55 g, 82%) as a pale yellow oil.
  • Step 8 To a solution of the above amide (0.6 g, 1.1 mmol) in dichloroethane (3 mL) at 0 °C is added dibromotriphenylphosphorane (0.5 g, 1.1 eq). The reaction is stirred to room temperature over 2h, taken up in ethyl acetate ( 50 mL), washed with brine (3 X 10 mL), dried (MgSO 4 ) and concentrated and carried immediately to the next step.
  • Step 9 To a solution of the crude bromide prepared above (0.54 mmol) in DMF (2 mL, degassed) is added phenethyl mercaptan (0.08 g, 1.1 eq) followed by cesium carbonate (0.21 g, 1.2 eq). The reaction is stirred lh, taken up in ethyl acetate (20 mL), washed with brine (3 X 5 mL), dried (MgSO 4 ), filtered and concentrated. Chromatography (25% ethyl acetate/hexanes) afforded the desired compound (0.17 g,
  • Step 10 To a solution of the above ester in THF (1 mL) and MeOH (0.5 mL) is added NaOH (0.28 mL, 5 M, 5 eq). The reaction is stirred 4 h, acidified with sodium biphosphate, poured into ethyl acetate, washed with brine and dried (MgSO 4 ). The title compound (0.157, 98%) was triturated from ethyl acetate with hexanes.
  • Example 1 Each of the compounds of the following Examples 2 through 11 was prepared by a first step as illustrated in Example 1, step 9, using the appropriate thiol, followed by a second step as described in Example 1, step 10.
  • Example 8 4-( ⁇ 2-U4-(tert-butvnphenoxy1methyl)-3-chloro-5- r(cyclopentylcarbonyl)aminol-lH-indol-l-yllmethyl)benzoic acid
  • Example 9 4-( ⁇ 2-U4-(tert-butvnphenoxy1methyl)-3-chloro-5- r(cyclopentylcarbonyl)aminol-lH-indol-l-yllmethyl)benzoic acid
  • Step 1 - The material prepared in Example 1, step 6, was acylated at the 5-amino position using the protocol of Example 1 , step 7, with the appropriate acylating reagent.
  • Step 2 The title compound was prepared from the intermediate of Step 1 following the procedure described in Example 1, steps 8 through 10, using the appropriate thiol.
  • Example 17 4-((3-chloro-5- ⁇ r3-(diethylamino)propanoyllaminol-2-r(2- naphthylsulfanyl)methyll-lH-indol-l-yllmethyl benzoic acid
  • step 5 4- ⁇ [5-(benzyloxy)-2-[(E)-2-carboxyethenyl]-3-(2-naphthoyl)-lH-indol-l- yl]methyl ⁇ benzoic acid
  • Step 1 Ethyl 5-benzyloxy-2-indolcarboxylate (30 g, 102 mmol) is dissolved in 250 mL of THF and cooled to 0° C and Lithium Aluminum Hydride (LAH) (255 mL of a 1.0 M solution in THF) is added via addition funnel over 40 minutes. The reaction was stirred a further 2 hours at 0° C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts are filtered and washed with ethyl acetate (3X400 mL), the filtrates are combined and dried over MgSO 4 and concentrated to yield 24.8 g.
  • LAH Lithium Aluminum Hydride
  • Step 2 The crude indole alcohol prepared in step 1 (8.3 g, 32.6 mmol) is dissolved in DMF (10.5 mL). To this solution is added imidazole (5.5g, 81.5 mmol) and t- butyldimethylsilyl chloride (5.4g, 35.8 mmol). The mixture is stirred at room temperature overnight. The reaction is poured into water and extracted with ethyl acetate (3X). Organic layers are dried over magnesium sulfate and concentrated. The crude material is purified on a silica gel column using 19:1 Hexane. ⁇ thyl acetate to give pure product (11.9g, 31 mmol, 94 % yield, TLC . 0.8 Rf in Toluene:Ethyl acetate 2:1)
  • Step 3 A solution of the silyl protected indole prepared in step 2 (2 g, 6.56 mmol) in ether (20 mL) was added dropwise to ethyl magnesium bromide (2.4 mL of a 3M solution in ether, 7.2 mmol) in ether (10 ml), the latter maintained at -78°C. The reaction was stirred at -60°C for 2 hr. Next acetylchloride (0.51 mL, 7.2 mmol) in ether (4 mL) was added slowly. The reaction maintained between -50°C and -60°C for another 2 hrs. The reaction was then quenched with saturated sodium bicarbonate. Extracted with ethyl acetate (3X). Organic layers were dried over magnesium sulfate and concentrated. The crude material was purified on a silica gel column using 19: 1 Hexane:Ethyl acetate to give pure product (1.2 g, 50%).
  • Step 4 To the indole (1.2 g, 2.9 mmol, prepared in step 3 above) in 10.5 ml of DMF, sodium hydride (0.13g, 60% oil dispersion, 3.23 mmol) is added at room temperature. The reaction is stirred for 30 minutes. Methyl (4-bromomethyl) benzoate (0.81 g, 3.53 mmol) is added at this time and the reaction stirred overnight. On completion of the reaction (monitored by TLC) it is quenched with water, extracted with ethyl acetate (3X). Organic layers are dried over magnesium sulfate, concentrated and used for the next step.
  • Step 5 A mixture of silyl protected indole prepared in step 4 above (0.65 g, 1.2 mmol) and tetra-butyl ammoniumfluoride (2.9 mL of a 1M solution in tetrahydrofuran, 2.9 mmol) in tetrahydrofuran (6 mL) were stirred at room temperature for one hour. At this time the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 1 : 1 Hexane:Ethyl acetate to yield pure alcohol (0.47 g, 91 %).
  • Step 6 The indole alcohol (0.3 g, 0.68 mmol), carbon tetrabromide (0.27 g, 0.81 mmol) and l,3-bis(diphenylphosphino)propane (0.21 g, 0.51 mmol) were taken up in dichloromethane (8.4 mL) and stirred for 16 hours at which time the reaction was diluted with dichloromethane and half saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (3X) dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using2: 1 Hexane:Ethyl acetate to yield pure alcohol (0.27 g, 78 %).
  • Step 7 The indole bromide prepared in step 6 (0.1 g, 0.2 mmol) was dissolved in dimethylformamide (0.4 mL, degassing the solvent is strongly recommended) cesium carbonate (0.2 g, 0.6 mmol) was added and then ethyl 2 naphthalenethiol (0.034g, 0.22 mmol) was added and the mixture was stirred for 1 day, then the reaction was poured into 1/2 saturated ammonium chloride and extracted with ethyl acetate (3X), dried, concentrated and chromatographed (Hexane:Ethyl acetate 3: 1) to yield 0.05 g (57%) of pure product.
  • Step 8 The ester ( 0.2 g, 0.34 mmol) prepared in step 7 above is dissolved in 4.0 mL of 1/1 THF/ methanol and then IN sodium hydroxide (2.5 mL) is added and the resulting mixture is stirred for 16 hours at RT, workup gave crude product that is purified via chromatography (1:1 Hexane:Ethyl acetate with 1 % acetic acid) to yield (0.17 g, 85%) of solid.
  • Step 1 This intermediate was prepared from the indole, prepared in step 2 of Example 23 and trifluoroacetic anhydride, according to the procedure described in step 3 of Example 23.
  • Step 2 This intermediate was prepared according to the procedure described in step 4 of Example 23, but using the indole derivative prepared in step 1 above and methyl (4- bromomethyl) benzoate.
  • Step 3 To a solution of the indole alcohol prepared in step 2 (0.1 g, 0.2 mmol) and triethylamine (0.04 mL, 0.3 mmol) in dichloromethane (0.4 mL), methanesulphonyl chloride (0.02 mL, 0.24 mmol) is added dropwise at 0°C. The reaction is stirred for 1.5h and then the dichloromethane removed. To the residue in 0.4 mL of DMF at 0°C 2- naphthalene thiol (0.034 g, 0.22 mmol) is added.
  • Step 4 The title compound was prepared from ester, prepared in step 3 above, according to the procedure described in step 8 of Example 23.
  • step 1 The t-butylsilyl protected alcohol (25g) from step 6 of Example 1, was dissolved in THF(200mL) and then tetrabutylammonium flouride ( 125mL of a 1.0 M solution) was added and the mixture was stirred for 10 minutes at room temperature and then the reaction was diluted with water and the THF was concentrated, ethyl acetate was added and the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated to yield the desired alcohol (21.5 g).
  • Step2 The alcohol (13. lg) from step 1 was suspended in dichloromethane (450 mL), cooled to 0°C and triethylamine(10 mL) and methanesulfonyl chloride (4.0 mL) were added and the resulting mixture was left to warm to room temperature overnight at which time it was diluted with saturated sodium bicarbonate was added and the reaction was diluted with dichloromethane, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried, concentrated to yield the desired chloride (13.5g).
  • Step 3 To the chloride (13.5g) generated in step 2 was added DMF (150 mL), cesium carbonate (33.5 g) and then the solution was degassed by bubbling argon through the solution for 20 minutes and then 2-naphthalene thiol was added and the reaction was stirred for 20 minutes at room temperature, then water was added as was ethyl acetate, the layers were separated and the combined organic layers were concentrated to a slurry which was stirred overnight and then the slurry was filtered and the solid was triturated with 40% ethyl acetate in hexane to deliver the desired disulfide (12.2 g) in 69% yield.
  • Step 4 The product from step three (11.25 g) was dissolved in THF (500 mL), methanol (500mL) and then copper II acetate (19.2 g) suspended in water (300 mL) was added as was more THF (lOOmL) and then sodium borohydride (11.2 g) was added portionwise. After 2.5 hours of stirring at room temperature the foamy black solution was diluted with saturated sodium bicarbonate and the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated and chromatographed to yield the desired amine (9.0 g) in 85% yield.
  • step 5 The amine from step 4 above was coupled to fmoc protected 4-aminobutyric acid following the procedure outlined in step 1, Example 43, followed by trituration with dichloromethane delivered the amide in 43% yield.
  • Step 6 The amide (1.0 eq) from step 5 was dissolved in methanol (5 mg/ml) and piperidine (0.024 ml/mg) and then the reaction was stirred at room temperature for two hours, concentrated and chromatographed to yield the desired product in quantitative yield.
  • Step 7 The amino ester from step 6 was hydrolyzed using the conditions outlined for step 2 of Example 43 to deliver the title compound in 54%.
  • Example 26 The amino ester from step 6 was hydrolyzed using the conditions outlined for step 2 of Example 43 to deliver the title compound in 54%.
  • the biphasic reaction mixture was vigorously stirred 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, or used crude, to yield the desired amide in 50% yield.
  • 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 stirred 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 69% yield.
  • Stepl The amine from step 4 of Example 25 was treated with the appropriate acid chloride according to the general procedure for Example 71, step 1, to deliver the amide in 76% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 53% yield.
  • Stepl The amine from step 4 of Example 25 was treated with the appropriate acid chloride according to the general procedure for Example 71, step 1, to deliver the amide in 100% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 79% yield.
  • Example 29 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 79% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of
  • Stepl The amine from step 4 of Example 25 was treated with acetic anhydride according to the general procedure for Example 71 , step 1 , to deliver the amide in 92% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid.
  • Stepl The amine from step 4 of Example 25 was treated with acetic anhydride according to the general procedure for Example 71, step 1, to deliver the amide in 77% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 29%.
  • Stepl THF (0.12M) was added to the amine (1.0 eq) generated in step 4, the reaction mixture was cooled to 0°C and then butylisocyanate (1.1 eq) was added and the mixture was warmed to room temperature overnight and the reaction was diluted with 1/2 saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated and purified via chromatography to yield the desired urea in 57% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 41 % .
  • Step 1 According to the procedure for Example 32, step 1 , the amine was treated with benzyl isocyanate to deliver the title compound in 16% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 100%.
  • Step 1 The amine (1.0 eq) generated above in step 4 was weighed into a flask along with 4-dimethyaminopyridine (1.5eq) and then they were taken up in dichloroethane (0.08
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 79%.
  • Step 1 The amine (l.Oeq) from step 1 was dissolved in dichloroethane and then benzaldehyde ( 1.0 eq) was added followed by acetic acid (1.0 mL/ 1 mmol) and the reaction was stirred for 20 minutes and then the sodium triacetoxyborohydride (1.3 eq) was added and the reaction was stirred overnight at room temperature, quenched by the addition of aqueous diethanolamine and dichloromethane 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 urea in 74% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 49%.
  • Example 36 4-( ⁇ 3-chloro-2-r ( 2-naphthylsulfanyl)methy ⁇ -5-[Y3-phenoxybenzyl)amino1- lH-indol-l-yl)methyl)benzoic acid
  • Step 1 According to the procedure for step 1 of Example 35 the amine from step 4 of Example 25 was treated with the appropriate aldehyde to yield the desired secondary amine in 38% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 87%.
  • Step 1 To the ester generated in step 1 of the synthesis of Example 27 was added DMF (0.05M), the reaction was cooled to 0°C and then sodium hydride (10 eq) was added and the mixture was stirred for 30 minutes, methyl iodide (lOeq) was then added and the resulting mixture was stirred overnight at room temperature and then diluted with ethyl acetate and 1/2 saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated and purified via chromatography to yield the desired methylated amide in 56% yield.
  • DMF 0.05M
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 57%.
  • Example 38 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 57%.
  • Stepl The amide synthesized in step 1 of Example 31 was benzylated according to the procedure in step 1 for Example 37 to yield the tertiary amide in 90% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 41%.
  • Step 1 To the indole amine (1.0 eq) was added the acid (1.2 eq) the dimethylaminopyridine (10 mol %), l-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq) and then DMF(0.3M) and the reaction was stirred under nitrogen for 24 hours at room temperature at which time it was poured into 1/2 saturated ammonium chloride solution and ethyl acetate and then the layers were separated and the aqueous layer was extracted 3 times, the combined organic layers were washed with water 2X, dried, concentrated and chromatographed to yield 55% of the title compound.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 55%.
  • step 1 According to the procedure for step 1 of Example 39 the amine from step 4 of Example 25 was treated with the requisite acid to yield the amide in 100% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 21%.
  • Step 1 According to the procedure for step 1 of Example 39 the amine from step 4 of
  • Example 25 was treated with the requisite acid to yield the amide in 100% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 35%.
  • Step 1 According to the procedure for step 1 of Example 39 the amine from step 4 of Example 25 was treated with the requisite acid to yield the amide in 100% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 20%.
  • Step 1 According to the procedure for step 1 of Example 39 the amine from step 4 of Example 25 was treated with the requisite acid to yield the amide in 100% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 32%.
  • step 1 4-( ⁇ 5-amino-3-chloro-2-r(2-naphthylsulfanyl)methyll-lH-indol-l- yllmethyPbenzoic acid step 1: The amine generated in step 4 was hydrolyzed according to the procedure for step 2 of Example 26 to yield 79% yield.
  • Step 1 To Example 26 (1.0 eq), EDCI (1.5 eq), DMAP (1.0 eq), methane sulfonamide (1.0 eq) in a flask under nitrogen was added DMF (0.08M) and the reaction was stirred overnight at room temperature and then worked up by the addition of 1/2 saturated ammonium chloride solution and ethyl acetate and then the layers were separated and the aqueous layer was extracted 3 times, the combined organic layers were washed with water
  • Step 1 To Example 26 was added the appropriate sulfonamide under the conditions outlined for step 1, Example 45, to yield the desired acylsulfonamide in 43% yield.
  • Step 1 To Example 26 was added the appropriate sulfonamide under the conditions outlined for step 1, Example 45, to yield the desired acylsulfonamide in 40% yield.
  • Step 1 To Example 26 was added the appropriate sulfonamide under the conditions outlined for step 1, Example 45, to yield the desired acylsulfonamide in 40% yield.
  • Step 3 In an oven dried flask was added the crude indole alcohol (1 eq) from step 2 followed by anhydrous DMF (0.135 M). To this was then added imidazole (1.3 eq) and TBSC1 (1.2 eq), stirred at 25°C for 1 h. Workup with ethyl acetate/water followed by chromatographic purification afforded the desired product in 70% yield.
  • step 9 The indole from step 9 (1 eq) was weighed into a flask along with NaH 2 PO 4 (12 eq), t- butyl alcohol (0.13 M), water (0.13 M), 2-mefhyl-2-butene (46 eq) and to this mixture was added NaO 2 Cl (12 eq) at 25°C. Reaction mixture was then heated at 65°C, overnight.
  • Example 53 Following step 1 above (Example 52) and using the corresponding acid Example 51 (step 4, scheme-4) afforded the desired product in 96% yield.
  • Example 53 A Following step 1 above (Example 52) and using the corresponding acid Example 51 (step 4, scheme-4) afforded the desired product in 96% yield.
  • Example 53 A
  • Step 1 The product of Step 1, Example 53B (1 eq) was weighed into a flask along with
  • Example 50 The compound of Example 50 (1 eq) was weighed into a flask and to this was added EDCI (3 eq), DMAP (1.2eq), methyl 3-aminobenzoate (1.2 eq) followed by anhydrous
  • Step 2 of Example 55 and using the corresponding morpholino from step 1 afforded the desired product in 91% yield.
  • Step 1 A solution of MeMgBr in butyl ether (1 M, 1.2 eq) was ice cooled. 4- Benzyloxy indole (1 eq) in CH 2 C1 2 (0.5 M) was added and the reaction mixture was allowed to warm to 25 °C. After the addition of 1-naphthoyl chloride (1 eq) in CH 2 C1 2 (1
  • Step 2 An ice cooled solution of the ketone (1 eq) from step lin DMF (0.2 M) was treated with NaH (60 % in mineral oil, 2.5 eq). 4-bromophenyl acetic acid (1.1 eq) in DMF (0.4 M) was added after 15 minutes and the resulting mixture was stirred overnight at 25°C. The reaction was quenched with IN HCl and extracted with EtOAc. The organic extracts were dried and concentrated. The desired product was obtained in 68 % yield after purification by chromatography and recrystallization from hexane/EtOAc.
  • Step 2 An analogous procedure to step 2 of Example 59 yielded 35 % of the title compound after chromatographic purification and recrystallization from acetone/pentane.
  • Example 61
  • Step 1 Following step 1 of Example 59 using the appropriate acyl chloride yielded 30 % of the desired ketone after recrystallization hexane/CH 2 Cl 2 /EtOAc.
  • Step 2 An analogous procedure to step 2 of Example 59 yielded 73 % of the title compound after chromatographic purification and recrystallization from CHCl 3 /MeOH.
  • 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. In a separate dry flask was weighed naphthalene-2-thiol (1.31 eq), and THF (1
  • Step 7 The product of step 6 (1 eq) in CH 2 C1 2 (0.125 M) was ice cooled. A solution of MeMgBr (1.2 eq) in butyl ether (1 M) was added and the resulting mixture was stirred for 30 minutes. After warming up to 25 °C, benzoyl chloride was added dropwise. The reaction was heated to reflux for 3 h, then stirred at 25 °C overnight. After quenching with NH 4 C1, the mixture was extracted with CH 2 C1 2 . Organic extracts were washed with brine, dried and concentrated. The desired ketone was obtained in 55 % yield after chromatographic purification.
  • Step 8 A solution of the product from step 1 (1 eq) in dry DMF (0.1 M) was treated with NaH (60 % in mineral oil, 1.05 eq). Methyl 4-bromomethylbenzoate (1.2 eq) was added after 1 h at 25 °C and the resulting mixture was stirred overnight. EtO Ac/water work up produced the desired crude material which was purified by chromatography (56).
  • Step 9 The material from step 2 (1 eq) was hydrolyzed by the action of
  • Step 1 Following step 7 of Example 62 using isopropyl chloride yielded the desired ketone after chromatography.
  • Step 2 An analogous procedure to step 8 of example 62 yielded 50 % of the N- alkylated material after chromatographic purification.
  • Step 3 Following step 9 of example 62 the methyl ester was hydrolyzed to the title compound in 67 % yield after chromatography.
  • Example 64 2-(3-acetyl-5-fbenzyloxy -2-r(2-naphthylsulfanvPmethyll-lH-indol-l- vUacetic acid
  • Step 2 The product of step 1 of Example 80 was alkylated with methyl bromoacetate following an analogous procedure to step 8 of example 62 to yield 65 % of the desired compound after recrystallization from EtOAc.
  • Step 3 Following step 9 of example 62 above the methyl ester was hydrolyzed to the title compound in 84 % yield after chromatography.
  • Step 2 An analogous procedure to step 2 of Example 63 started from methyl bromo acetate and the isopropyl ketone described in step 1 of Example 63 (step 1, see above).
  • Step 3 Following step 3 of Example 63 the methyl ester was hydrolyzed to the title compound in 50 % yield after chromatography.
  • Step 1 A solution of EtMgBr in ether (3 N, 2.17 eq) was cooled to - 70°C.
  • the product of step 2 in Example 62 (1 eq) in ether (0.55 M) was added and the reaction mixture was stirred at - 70°C for 2 h.
  • EtOAc/water work up and crystallization from hexane/EtOAc the desired ketone in 89 % yield.
  • Step 2 The material from step 1 (1 eq) in CH 2 C1 2 (0.25 M) was treated with NEt 3 (2 eq), followed by BOC anhydride (1.24 eq) and DMAP (0.21 eq). After stirring for 20 minutes at 25 °C the reaction mixture was worked up with CH 2 C1 2 and water. Pure desired material was obtained in 97 % yield by trituration with hexane.
  • Step 3 The above material (1 eq) in THF (0.3 M) was combined with pyridine (excess) and HFpyridine (excess) at 0°C. The reaction was stirred at 25°C for 1.5 h. EtOAc/water work up followed by chromatographic purification afforded the desired alcohol in 86 % yield.
  • Step 4 The alcohol from step 3 (1 eq) in CH 2 C1 2 (0.4 M) was treated with 2,6-lutidine
  • Step 5 A mixture of the above material (1 eq), 325 mesh K 2 CO 3 (2.4 eq), b-naphthol (1.2 eq) and KI (1.2 eq) in CH 3 CN (0.3 M) was heated to reflux for 2 h. EtOAc/water work up, followed by trituration in hexane/EtOAc and chromatography of the mother liquor yielded 70 % of the expected ether.
  • Step 6 A NaOMe solution in MeOH was prepared by dissolving Na (3 eq) in MeOH (0.2 M). The product of step 5 (1 eq) in THF (0.04 M) was added and the reaction mixture was stirred at 25 °C for 3 h. EtOAC/water work up followed by trituration with hexane/EtOAc afforded the indole compound in 93 %.
  • Step 7 A solution of the product from step 6 (1 eq) in dry DMF (0.1 M) was treated with NaH (60 % in mineral oil, 1.1 eq). Methyl 4-bromobutyrate (1.2 eq) and KI (1.2 eq) were added after 1 h and the reaction mixture was stirred at 75°C for 3 h. EtOAc/water work up followed by chromatographic purification yielded 96 % of the required ester.
  • Step 8 The material from step 7 (1 eq) was hydrolyzed by the action of LiOHH 2 O (1.2 eq) in THF/MeOH/water (3/1/1, 0.2 M). After stirring at 25°C for 2 h, the reaction mixture was quenched with IN HCl and extracted with EtOAc and CH 2 C1 2 . The organic extracts were combined, washed, dried and concentrated. The crude material was purified by trituration in hexane/EtOAc to afford the title compound in 86 % yield.
  • Step 1 The product of Example 66 (1 eq) was reacted with EDCI (1.37 eq) and methyl 3- amino benzoate (1.05 eq) in DMF (0.09 M) in the presence of DMAP (0.2 eq). The reaction was stirred at 25°C for 1.5 h. EtOAc/water work up, followed by flash chromatography produced the desired amide in 81 % yield.
  • Step 2 An analogous procedure to step 2 of Example 66 yielded 98 % of the title compound after purification by trituration in hexane/EtOAc.
  • Step 1 Following step 1 of Example 67 and using the acid of Example 67 and the appropriate sulfonamide provided after overnight reaction and analogous work up the desired product. Trituration with hexane/EtOAc yielded 100 % of the title compound.
  • Step 1 Following step 1 of Example 67 above using acid of Example 66 and the appropriate aniline yielded 76 % of the expected amide.
  • Step 2 An analogous procedure to step 2 of Example 67 yielded 78 % of the title compound after purification by trituration in hexane/EtOAc.
  • Step 1 Following step 1 of Example 67 using acid of Example 66 and the appropriate aniline yielded 36 % of the expected amide after chromatography.
  • Step 2 An analogous procedure to step 2 of Example 67 yielded 67 % of the title compound after purification by trituration in hexane/EtOAc.
  • Step 1 Following step 1 of Example 67 using acid of Example 66 and the appropriate aniline yielded 96 % of the expected amide after chromatography.
  • Step 2 An analogous procedure to step 2 of Example 67 yielded 90 % of the title compound after purification by trituration in hexane/EtOAc.
  • Step 1 A solution of the product from step 6 of Example 66 (1 eq) in dry DMF (0.1 M) was treated with NaH (60 % in mineral oil, 1.1 eq). Ethyl 4-bromopentanoate (1.2 eq) and KI (1.2 eq) were added after 1 h and the reaction mixture was stirred at 75°C for 2 h. EtOAc/water work up followed by chromatographic purification yielded 92 % of the required ester.
  • Step 2 The material from step 1 (1 eq) was hydrolyzed by the action of LiOHH 2 O (1.3 eq) in THF/MeOH/water (3/1/1, 0.2 M). After stirring at 25°C for 3.5 h, the reaction mixture was quenched with IN HCl and extracted with EtOAc and CH 2 C1 2 . The organic extracts were combined, washed, dried and concentrated. The crude material was purified by trituration in hexane/EtOAc to afford the title compound in 95 % yield.
  • Step 2 An analogous procedure to step 2 of Example 74 yielded 83 % of the title compound after purification by trituration in hexane/EtOAc.
  • Example 76
  • Step 1 Following step 1 of Example 68 using acid of Example 75 and the appropriate sulfonamide yielded 83 % of the title compound after overnight reaction and analogous work up.
  • Step 2 An analogous procedure to step 2 of Example 74 yielded 90 % of the title compound after trituration in hexane/EtOAc.
  • Step 1 Following step 1 of Example 74 using the appropriate bromide yielded 33 % of the expected amide after chromatography.
  • Step 2 An analogous procedure to step 2 of Example 74 yielded 70 % of the title compound after trituration in hexane/EtOAc.
  • Step 1 Following step 1 of Example 74 using the appropriate bromide yielded 75 % of the expected amide after chromatography.
  • Step 2 An analogous procedure to step 2 of Example 74 yielded 92 % of the title compound after trituration in hexane/EtOAc.
  • Example 80 l-il-r4-(1.3-benzothiazol-2-ylcarbonyl)benzyll-5-(benzylsulfanvP-2-r(2- naphthylsulfanyPmethyll-lH-indol-3-yl)-l-ethanone
  • Step 1 The thioether from step 6, Example 62 was dissolved in methylene chloride (0.12 M), and under nitrogen at 0°C treated with methylmagnesium bromide (1.1 eq), and stirred at 0 to 25°C for 1 h. The mixture was recooled to 0°C and acetyl chloride
  • Step 2 Following the procedure for Example 81 step 1 and using p-Toluoyl chloride yielded the corresponding para amide.
  • Step 3 Following the procedure for Example 81 step 2 and using the product from step 1 above, the desired product was obtained.
  • Step 4 Following the procedure for step 3, Example 81 and using the material from step 3 yielded the desired benzyl bromide.
  • Step 5 Following the procedure for Example 81 step 4, the material from step 4 was coupled to the material from step 1 to yield the titled compound.
  • Example 81 l-ll-r3-(1.3-benzothiazoI-2-ylcarbonyPbenzyll-5-(benzylsulfanyP-2-r(2- naphthylsulfanyPmethyP-lH-indol-3-yll-l-ethanone Step 1 m-Toluoyl chloride (0.8 M) was added to triethylamine (2.44 eq) and methoxymethyl amine HCl (1.1 eq) dissolved in methylene chloride at 0°C over 20 min. The reaction was allowed to warm to 25°C. After stirring at 25°C for 1 day, workup with methylene chloride and water afforded crude product in ca. 100% yield.
  • Step 4 The indole from step 1 of Example 80 was dissolved in dry DMF (0.04
  • Stepl Ethyl 4-aminobenzoate was dissolved in 95% v/v HO Ac/water (0.4 M) and at 25 °C treated with sodium thiocyanate (4.1 eq), and stirred at 25°C for 20 min.
  • Step 3 The thiophenol from step 2 was dissolved in 90% v/v HCOOH water
  • Step 4 Benzothiazole ester (step 3) was dissolved in THF/methanol/water
  • Step 5 Under anhydrous conditions the benzothiazole acid (step 4) was dissolved in THF (0.052 M). At -78°C added BuLi (2.2 eq). After 1 h at -78°C to 0°C, added the amide (1.28 eq) from step 1 of Example 81, in THF, at -78°C, over 5 min. After 0.5 h at -78°C, the reaction was allowed to warm to 25°C. After stirring at 25°C for
  • Step 6 The tolyl ketone acid from step 5 was suspended in (1:1) THF/ethanol , (0.075 M), and cone, sulfuric acid (excess) was added. After reflux for 1 d, workup
  • Step 7 The tolyl ketone ester from step 6 was dissolved in carbon tetrachloride (0.05M), and NBS (1.2 eq) and AIBN (0.15 eq) were added. After 1.25 h at reflux, another portion of NBS (0.3 eq) and AIBN (0.07 eq) were added. Filtration and recrystallization from ethyl acetate afforded pure bromobenzyl ketone product (22%).
  • Step 8 The indole from step 1 of Example 80 was dissolved in dry DMF (0.06 M), followed by NaH (1.11 eq). After 45 min at 25°C, added the bromobenzyl ketone from step 7 above (1.25 eq), and stirred for 1 h at 25°C. Workup afforded the crude ester, used in the next step.
  • Step 9 The crude ester from step 8 was dissolved in THF/methanol/water (8:2:2), (0.013 M), lithium hydroxide (4.3 eq) was added in portions, as the mixture was stirred for a total of 3-4 d at 25°C. Workup (ethyl acetate/ aqueous HCl) and purification by chromatography afforded pure benzothiazole acid (31%).
  • Step 1 The indole from step 6 of Example 66 was dissolved in dry DMF (0.17
  • Step 2 The alkyl chloride from step 1 was dissolved in methyl ethyl ketone
  • Step 3 NaH (1.0 eq) was weighed into a dry flask under nitrogen, and dry benzene (0.14 M) was added. At 0°C, added dry DMF (0.4 M), ethyl 2-carboxy-l,3- dithiane (1.0 eq), and the iodide from step 2 (1.0 eq) into a separate dry flask.
  • Step 4 Silver nitrate (4.5 eq) and NCS (4.0 eq) were dissolved in 4: 1 v/v acetonitrile/water (ca. 0.04 M), and a solution of the dithianyl ester from step 3 (1 eq) in acetonitrile (0.03 M) was added at 25°C. After stirring for 5 min at 25°C, added a sodium sulfite solution, followed in one minute by a sodium carbonate solution. Workup (ethyl acetate/water) and chromatography afforded the product ketoester in 17% yield.
  • Step 5 The ketoester from step 4 was dissolved in THF/water (8:1), (0.03 M), lithium hydroxide (1.5 eq) was added, and the mixture was stirred for 2 h at 25°C. Workup (ethyl acetate/ aqueous HCl) and purification by chromatography afforded pure ketoacid (64%).
  • Step 1 The dithianyl ester from step 3 Example 83 was dissolved in
  • Step 2 The dithianyl acid from step 1 was dissolved in dry methylene chloride
  • Step 4 Silver nitrate (4.6 eq) and NCS (4.0 eq) were dissolved in 4: 1 v/v acetonitrile/water (ca. 0.03 M), and a solution of the dithianyl acid from step 3 (1 eq) in acetonitrile (0.009 M) was added at 25°C. After stirring for 10 min at 25°C, there was added a sodium sulfite solution, followed in one minute by a sodium carbonate solution. Workup (ethyl acetate/aqueous acid) and chromatography afforded the title compound in 82% yield.
  • Step 2 The dithianyl ester from step 1 was treated as described for step 3 of
  • Step 3 The dithianyl from step 6 was treated as described for step 4 of Example
  • Table I reports data for the compounds described in the examples above in cPLA2 inhibition assays (described below). In the data columns of the tables, assay results are reported as an "IC 50 " value, which is the concentration of a compound which inhibits 50% of the activity of the phospholipase enzyme in such assay. Where no numerical IC 50 value appears, "NA” denotes that inhibitory activity was not detected from such compound in the corresponding assay and a blank box denotes that the compound was not tested in such assay as of the time of filing of the present application.
  • IC 50 is the concentration of a compound which inhibits 50% of the activity of the phospholipase enzyme in such assay.
  • a typical assay consisted of the lipid mixture (85 1) to which was added consecutively, the inhibitor (5 1 in DMSO) and cPLA 2 , 10 ng for an automated system or 1 ng for a manual assay, in 101 of the BSA buffer. This assay was conducted by either the manual assay or automated assay protocol described below.
  • lipid suspension 85 1 to which was added consecutively the inhibitor (51 in DMSO) and cPLA 2 , 200 ng in 80 mM Hepes pH 7.5, 2 mM DTT and 1 M EDTA. This assay was conducted by either the manual assay or automated assay protocol described below.
  • the lipid suspension and inhibitor were pre-incubated for 7 min. at 37°C. Enzyme was added and the incubation was continued for a further 30 mins. The reaction was then quenched by the addition of decane: isopropanol: trifluoroacetic acid (192:8: 1 w/v, 1501). A portion of the quench layer (50 1) was passed through a Rainin Spheric-5 silica column (5, 30 x 2.1 mm) eluting with heptane:methanol:TFA (97:3:0.1 v/v). The level of [ 14 C]- arachidonic acid was analyzed by an in-line Radiomatic Flo-One/Beta counter (Packard).
  • the lipid, inhibitor and enzyme mixture were incubated at 37°C for 30 min. The reaction was quenched by the addition of heptane:isopropanol:0.5M sulfuric acid
  • PMNs were isolated using Ficoll-Hypaque according to the manufacturers directions. Red blood cells contaminating the PMNs were removed by hypotonic lysis, and the PMN pellet was washed once, and resuspended in Hanks buffered saline at a concentration of 2 x 10 6 cells/ml. The cells were preincubated with inhibitors for 15 min at 37%C and then stimulated with 2 uM A23187. When monitoring LTB 4 production as a measure of cPLA 2 inhibition, the reaction was quenched with an equal volume of ice cold phosphate buffered saline. Cells were removed by centrifugation, and the LTB 4 present in the cell supernatant was measured using the LTB 4 scintillation proximity assay provided by Amersham according to the manufacturers directions. In the assays reported in the Tables above,
  • LTB 4 was measured.
  • the reaction was quenched with methanol containing D8-arachidonic acid as an internal reference.
  • the lipids were extracted by the method of Bligh et al. ((1959) Can. J. Biochem. Physiol., 37, 911-917), and the fatty acid was converted to the pentafluorobenzyl ester and analyzed by GC-MS in a manner similar to that reported by Ramesha and Taylor (( 1991 ) Anal.
  • RBL-2H3 cells were routinely cultured as 37°C in a 5% CO 2 atmosphere in minimal essential medium containing nonessential amino acids and 12% fetal calf serum. The day before the experiment, cells were seeded into spinner flasks at 3 x 10 5 cells/ml and 100 ng/ml DNP specific-IgE was added. After 20 hrs, the cells were harvested by centrifugation and washed once in serum-free minimal essential media, and resuspended to 2 x 10 6 cells/ml in serum free media.
  • the cells were then preincubated with either inhibitor in DMSO (1% v/v) or DMSO (1% v/v) for 15 min at 37°C followed by stimulation with DNP-BSA (300 ng/ml). After 6 min, the cells were removed by centrifugation, and the supernatant was assayed for PGD 2 content in accordance with known methods.
  • 7-hydroxycoumarinyl 6-heptenoate was used as a monomeric substrate for cPLA2 as reported previously (Huang, Z. et al., 1994, Nalytical Biochemistry 222, 110-115). Inhibitors were mixed with 200 ⁇ L assay buffer (80 mM Heped, pH 7.5, 1 mM EDTA) containing 60 ⁇ M 7-hydroxycoumarinyl 6-heptenoate. The reaction was initiated by adding 4 ⁇ g cPLA2 in 50 ⁇ L assay buffer. Hydrolysis of the 7-hydroxycounarimyl 6- heptenoate ester was monitored in a fluorometer by exciting at 360 nm and monitoring emission at 460 nm. Enzyme activity is proportional to the increase in emission at 460 nm per minute. In the presence of a cPLA2 inhibitor, the rate of increase is less.
EP99908379A 1998-02-25 1999-02-24 Inhibitoren von phospholipasen enzymen Withdrawn EP1056719A2 (de)

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US3006298A 1998-02-25 1998-02-25
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