WO1999043672A9 - Inhibiteurs de la phospholipase a2 - Google Patents

Inhibiteurs de la phospholipase a2

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Publication number
WO1999043672A9
WO1999043672A9 PCT/US1999/003388 US9903388W WO9943672A9 WO 1999043672 A9 WO1999043672 A9 WO 1999043672A9 US 9903388 W US9903388 W US 9903388W WO 9943672 A9 WO9943672 A9 WO 9943672A9
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cooh
compound
alkoxy
phenyl
Prior art date
Application number
PCT/US1999/003388
Other languages
English (en)
Other versions
WO1999043672A1 (fr
Inventor
Jasbir S Seehra
Yibin Xiang
Jean Bemis
John Mckew
Neelu Kaila
Lihren Chen
Original Assignee
Genetics Inst
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to KR1020007009459A priority Critical patent/KR20010041346A/ko
Priority to CA002322163A priority patent/CA2322163A1/fr
Priority to EP99936073A priority patent/EP1062216A1/fr
Priority to AU32970/99A priority patent/AU3297099A/en
Application filed by Genetics Inst filed Critical Genetics Inst
Priority to SK1278-2000A priority patent/SK12782000A3/sk
Priority to JP2000533428A priority patent/JP2002504551A/ja
Priority to EEP200000522A priority patent/EE200000522A/xx
Priority to EA200000873A priority patent/EA200000873A1/ru
Priority to HU0100156A priority patent/HUP0100156A3/hu
Priority to IL13754099A priority patent/IL137540A0/xx
Publication of WO1999043672A1 publication Critical patent/WO1999043672A1/fr
Publication of WO1999043672A9 publication Critical patent/WO1999043672A9/fr
Priority to HR20000513A priority patent/HRP20000513A2/hr
Priority to NO20004217A priority patent/NO20004217L/no
Priority to BG104781A priority patent/BG104781A/xx

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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • 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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Definitions

  • the present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A enzymes.
  • Leukotrienes and prostaglandins are important mediators of inflammation. 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 produciton of leukotrienes.
  • PLA phospholipase A
  • PAF platelet activating factor
  • 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 have an approximately 14 kD molecular weight and contain seven disulf ⁇ de 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 . JO 205-220 ( 1987) ] However the pancreatic enzyme is believed to serve a digestiv e function and as such, should not be impo ⁇ ant in the production of the inflammatory mediators whose production must be tightly regulated
  • the primary structure of the first human ncn-pancreatic PLA has been determined This non- pancreat PLA, is found in platelets synovial fluic 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 B ol Chem .
  • a murme PLA has been identified in the murine macrophage ce'l line designated R AW 264 7
  • a specific activity of 2 ⁇ mols, m ⁇ n/mg, resistant to reducing conditions was reported to be associated with the approximately 60 kD molecule
  • this protein was not purified to homogene-ty [See, C C Leslie et al Biochem Biophvs Ac * -a . 963 476-492 (1988)]
  • the references cited above are incorporated by reference herein for information pertaining to the function of the phospholipase enzymes, particularly PLA,.
  • cytosolic phospholipase A (hereinafter "cPLA,") 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 enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli.
  • the present invention provides compounds having a chemical formula selected from the group consisting of
  • A is independent of any other group and is selected from the group consisting of -CH,- and -CH,-CH,-,
  • R is independent of any other R group and is selected from the group consisting of -X-R. -H - OH, halogen -CN , -NO,, C -C_ alky l, alkenyl, alkin l. aryl and substituted aryl,
  • R is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR,, -CONR,R,, -(CH ⁇ -W- CH ⁇ -Z-R,, -(CHJ Collector-W-R «, -Z-R 5 , C C lQ alkyl. alkenyl and substituted aryl.
  • R j is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR,, -CONR.R,, -(CH,).-W-(CH,) m -Z-R réelle -(CH,) n -W-R ⁇ , -Z-R 3 , C r C l0 alkyl, alkenyl and substituted aryl,
  • R 4 is independent of any other R group and is selected from the group consisting of -H, -OH, - OR «, -SR., -CN . -COR,, -NHR, -COOH, -CONR.R-, -NO,, -CONHSO,R 3 , C r C_ alkyl, alkenyl and substituted arvl.
  • R 5 is independent of any other R group and is selected from the group consisting of -H, -OH, 0(CH,) contendR,, -SR,, -CN, -CORterrorism, -NHR,, -COOH, -NO.. -COOH, -CONR ⁇ , -CONHSO : R 3 , C,-C, alkyl, alkenyl, alkinyl, aryl, substituted aryl, -C ⁇ , -CF,CF 3 and
  • R. is independent of any other R group and is selected from the group consisting of -H, C-C 5 alkyl, alkenyl, alkinyl, aryl and substituted aryl,
  • R- is independent of any other R group and is selected from the group consisting of -H, C-C 5 alkyl, alkeny l. alkinyl, aryl and substituted aryl,
  • Rj is independent of any other R group and is selected from the group consisting of C-C_ alkyl. aryl and substituted aryl,
  • R is independent of any other R group and is selected from the group consisting of -H. -OH. a halogen, -CN. -OR,, -COOH. -CONR-R-. tetrazole. -CONHSO-R,. -COR,, -(CH,) interceptCH(OH)R, and -(CH .CHR.R,.
  • Rrust is independent of any other R group and is selected from the group consisting of -H. -OH, a halogen. -CN . -OR,, -COOH, -CONR.R-. tetrazole. -CON " HSO,R 3 , -COR ⁇ , -(CH ; ) complicatCH(OH R, and -(CH ; ),CHR,R..
  • X is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -0-, -S- and -N(R6)-,
  • Z is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -CH-, -0-, -S-, -N ⁇ R -, -CO-, -CON(R,)- and - NWCO-, m is independently each time used including within the same compound, an integer from 0 to 4, and n is independent of m and is, independently each time used including within the same compound, an integer from 0 to 4
  • the compounds of the invention have phospholipase enzyme inhibiting activity
  • Other preferred embodiments include compounds having the following chemical formula:
  • A is -CH- and R, is -(CH i ) n -W-(CH 2 ) ra -ZR 5
  • R is -(CH i ) n -W-(CH 2 ) ra -ZR 5
  • W is -S- and Z is -CO-; those wherein R j is - HR J ; those wherein R, is a substituted aryl group and those wherein said aryl group is substituted with one or more substituents independently selected from the group consisting of a halogen, -C ⁇ _,
  • R, is selected froup the group consisting of alkyl, alkenyl, alkynyl, -(CHJ.OH, and O(CW> ? CE_, and wherein p is an integer from 0 to 4.
  • R is selected from the group consisting of -H and -OCH(C 6 H 6 ) and R 3 is -COR 5 , R 5 is -OCH,R ⁇ , and j is a substimted aryl group.
  • said aryl group is substimted with one or more substiments selected from the group consisting of -CF, -
  • R [ and R,. are independently selected from C,-C 6 alkyl, -Z-C,-C 6 alkyl, phenyl. -(CH,) compassion- Z-(CH : ) n -phenyl, benzyl, -(CH,) n -Z-(CH,) r ⁇ -benzyl, napthyl, -(CH,).-Z-(CH,) ⁇ -napthyl, pyrimidinyl, -(CH : ) 11 -Z-(CH ; ) deliberately-pyrimidinyl.
  • alkyl, phenyl, benzyl, napthyl and pyrimidinyl groups being optionally substituted by from 1 to 3 substiments selected from halogen, C,-C 6 alkyl, C,- alkoxy, -NO,, -NH,. -CN, -CF 3 , or -OH;
  • Z is 0 or S
  • n is an integer from 0 to 3;
  • R is selected from H. halogen. -CF,. -OH. -C,-C 10 alkyl, C,-C 10 alkoxy. -CHO. -CN, - NO,, -NH,. -NH-C,-C 6 alkyl, -N(C.-C 6 alkyl),, -N-SO,-C,-C 6 alkyl. or -SO,-C.-C 6 alkyl;
  • R 3 is selected from H. halogen, -CF 3 , -OH. -C
  • n in each appearance is independently selected as an integer selected from 0-3; 672
  • R 3 and R 9 are independently selected in each appearance from H, -COOH, -(CH,) n -C00H, -(CH,) deliberately-C(0)-COOH, -CF 3 , -OH, -(CH,) admir-C(0)-COOH, -C,-C 6 alkyl, -0-C r C 6 alkyl, -NH(C r C 6 alkyl). or -N(C,-C 6 alkyl)-;
  • R ! is selected from H, -CF 3 , C,-C 6 alkyl. -(CH,) I1 -C,-C S cycloalkyl, phenyl. or benzyl, the cycloalkyl. phenyl or benzyi groups being optionally substimted by from 1 to 3 groups selected from halogen, -CF 3 , -OH, -COOH, -(CH,) a -COOH. -(CH,) n -C(0)-COOH. -C,-C 3 alkyl. -O-C.- C 6 alkyl. -NH(C r C s alkyl), or -N(C,-C 6 alkyl),;
  • L 1 is selected from -(CH,) precaution-0-, -(CH,) n -S-, -(CH,) n -0-(CH,) n -, -(CH,) n -S-(CH,) n -, -C(0)-0-, -C(0)-(CH,) ⁇ -0-, -C(0)-N-, or -(CH,),-S-(CHJ Container-C(0)-N-;
  • M 1 is -COOH or a moiety selected from;
  • R 10 is selected from H, -COOH, -(CH,) n -COOH, -(CH 2 ) hinder-C(0)-COOH, -CF 3 , -OH, (CH j ) B -C(O)-COOH. -C,-C 6 alkyl, -0-C.-Q alkyl,
  • R j is selected from:
  • L 2 is selected from a chemical bond or a bridging group selected from -(CH,).-Z-, -(CH 2 ) B -Z-(CH 2 ) B -, -C(0)-0-, -C(0)-(CH 2 ) lake-0-, -C(0)-N-, or -(CH 2 ) hinder-S-(CH 2 ) ⁇ -C(0)-N-
  • M 2 is selected from -C C 6 alkyl, -0-C,-C ⁇ alkyl,
  • R 3 and R 9 are as defined above and can be substituted anywhere on the cyclic or bicyclic ring; or
  • M 3 is selected from -(CH,).-C 3 -C 3 cycloalkyl, furanyl, thienyl, pyrrolyl,
  • a preferred subset include those in which the core molecule is an indole.
  • R 1 and R" are hydrogen, and the moieties R , R", R ; , R 3 , R 3 and R 10 , n. L 1 , L ⁇ M 1 and M : are as defined above.
  • R : is in the indole 5-position.
  • R is selected from -O-C.- alkyl. -S-C-C 3 alkyl. -O-phenyl. -S-phenyl. -O-benzyl. -S- benzyl. the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.-C aikvl, C,-C alko.xv, -NO,, -NH,. -CN. -CF., or -OH; /43672
  • R. is selected from H, halogen, -CF 3 , -OH, -C,-C 10 alkyl, preferably -C -C_ alkyl, C,-C I0 alkoxy, preferably C x -C_ alkoxy, -CHO, -CN, -NO,, -NH,, -NH-C,-C 5 alkyl. -N(C,- alkyl),, - N-SO,-C.-C 3 alkyl, or -SO : -C,-C 6 alkyl;
  • R 3 is selected from H, halogen, -CF 3 , -OH. -C C lQ alkyl, preferably -C,-C 6 alkyl, C,-C !0 alkoxy, preferably C r C s alkoxy, -CHO, -CN, -NO : , -NH : , -NH-C,-C a alkyl, -N(C,-C 6 alkyl),, - N-SO--C- alkyl. -SO : -C,-C 5 alkyl, or a moiety of the formula:
  • n in each appearance is independently selected as an integer selected from 0-3;
  • R 11 and R 9 are independently selected in each appearance from K. -COOH. -(CK ; ) a -COOH. -(CH,) B -C(0)-COOK. -CF,, -OH, -(CHJ.-C(O)-COOH. -C ; -C 5 alkyl. -0-C.-C 5 alkyl. -NHfC,- C s alkyl). or -N(C.-C 5 alkyl),;
  • R. is ⁇ e oietv -L'-M' or
  • L 1 is selected from a chemical bond or a bridging group selected from -(CH,) B -0-, -(CH,).-S-, -(CH .-C CH,),-. -(CH,),-S-(CHJ.-, -C(0 -0-, -C(0)-(CK-) a -0-. -C(0)-N-, or -(CH , ) B -S-(CH,) a -C(0)-N-; 672
  • M 1 is the moiety:
  • R 10 is selected from H, -COOH, -(CH,) ⁇ -COOH, -(CH : ) B -C(0)-COOH, -CF , -OH, - (CH 2 )_-C(0)-C00H, -C C 6 alkyl, -O-C,-C 6 alkyl,
  • R 5 is a structure of the formula -L : -M : ;
  • L 2 is selected from a chemical bond or a bridging group selected from -(CH 2 ) B -0-, -(CH,) a -S-, -(CH,) B -0-(CH,) a -, -(CH : ).-S-(CH : ).-. -C(0)-0-, -C(0)-(CH,) n -0-, -C(0)-N- or -(CHJ n -S-(CH 2 ) ⁇ -C(0)-N-;
  • M 2 is selected from -C,-C 6 alkyl. -0-C,-C 6 alkyl.
  • R 3 . R° and R 10 are as defined above; or a pharmaceutically acceptable salt thereof.
  • R is selected from -0-C C 6 alkyl, -S-C C s alkyl, -O-phenyl, -O-benzyl, -S-benzyl, the alkyl, phenyl or benzyl groups being optionally substimted by from 1 to 3 substiments selected from halogen, C,-C 6 alkyl, C,-C ⁇ alkoxy, -NO,, -NH,, -CN, -CF 3 , or -OH;
  • R 3 is selected from H, halogen, -CF., -OH, - ⁇ C ⁇ alkyl, preferably -C,-C 10 alkyl, C r C l0 alkoxy, preferably C,-C 10 alkoxy.
  • R R " , R , R and R are as defined above, or a pharmaceutically acceptable salt thereof.
  • R, and R are independently selected from H, halogen, -CF 3 , -OH. -C,-C, 0 alkyl, preferably -C,-C 6 alkyl, -S-C,-C I0 alkyl, preferably -S-C,-C 6 alkyl, C r C [Q alkoxy, preferably C,- C 6 alkoxy, -CN, -NO,, -NH,, phenyl, -O-phenyl. -S-phenyl, benzyl, -O-benzyl. -S-benzyl; or a ring moiety of the groups a), b) or c).
  • a six-me bered heterocyclic ring containing one, two or three ⁇ ng heteroatoms selected from N, S or 0 including, but not limited to. pyran, pyridine. pyrazine. pyrimidine. pyridazine, piperidine. piperazine. tetrazine. thiazi ⁇ e. thiadizine. o azine. or morpholine.
  • the six- membered heterocyclic ring being optionally substituted by from 1 to 3 substiments selected from halogen, C.-C 10 alkyl. preferably C,-C 6 alkyl. C,-C :0 alkoxy, preferably C,-C ⁇ alkoxy, -CHO. - NO,, -NH,, -CN, -CF. or -OH; or
  • a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 including, but not limited to benzo uran. chromene. indole. isoi dole. indoline, isoindoline, napthalene. purine, indolizine, indazole, quinoline, isoquinoline.
  • quinolizine quinazoline, cinnoline, phthalazine, or napthyridine
  • the bicyclic ring moiety being optionally substimted 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,, -NH 2 , -CN, -CF 3 or -OH; or
  • Z is 0 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.
  • R 7 is selected from the relevant members of the group -OH, -CF 3 , C ⁇ -C w alkyl, preferably C,-C 6 alkyl.
  • a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or 0 including, but not limited to, pyran. pyridine, pyrazine, pyrimidine, pyridazine. piperidine, piperazine, tetrazine, thiazine, thiadizine. o azine. or morpholine.
  • the six- membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C C alkyl. preferably C ⁇ C ⁇ alkyl. C -C, Q alkoxy, preferably C,-C 6 alkoxy, -CHO, - NO,, -NH,, -CN. -CF 3 or -OH; 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 0 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 substimted by from 1 to 3 substituents selected from halogen, C ⁇ C ⁇ alkyl, preferably C,-C 5 alkyl. C-C 10 alkoxy. preferably C.-C 3 alkoxy. -CHO. -NO,. - NH,. -CN. -CF, or -OH;
  • n is an integer from 0 to 3. preferably 1 to 3. more preferably 1 to 2;
  • R is selected from H, halogen, -CN, -CHO, -CF 3 , -OH.
  • C.-C I0 alkyl preferably C,-C alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy.
  • -CHO, -CN, -NO, -NH,. -NH-C,-C 6 alkyl. -N(C,-C 6 alkyl),, -N-SO : -C,-C 6 alkyl, or -SO,-C,-C 5 alkyl;
  • R 3 is selected from H, halogen, -CF , -OH, -C,-C 10 alkyl, C,-C l0 alkoxy, -CHO, - C(0)CH,, -C(0)-(CH,)n-CF 3 , -CN, -NO,, -NH,, -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl),, -N-S0 2 - C,-C 3 alkyl, -SO,-C,-C 6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(0)-phenyl, -C(O)- benzyl, -CH,-(C 3 -C 6 cycloalkyl).
  • n in each appearance is an integer independently selected from 0-3:
  • R 3 and R 9 are independently selected in each appearance from H. -COOH, -(CH,) a -COOH, -(CHJ.-C(O)-COOH, -CF.. -OH. -(CH,) admir-C(0)-COOH. -C,-C 6 alkyl. -0-C,-C 6 alkyl. -NH(C,- C 6 alkyl), or -N(C,-C 6 alkyl),;
  • R ⁇ is selected from H, -CF 3 , C,-C 6 alkyl, -(CH 2 ) compassion-C,-C 6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substimted by from 1 to 3 groups selected from halogen, -CF 3 , -OH, -COOH, -(CH,) admir-COOH. -(CH 2 ) n -C(0)-COOH, -C C 6 alkyl, -O-C,- C 6 alkyl, -NH(C,-C 6 alkyl), or -N(C,-C 6 alkyl),;
  • L 1 is selected from -(CH 2 ) ⁇ -, -S-, -0-, -C(O)-, -C(0)-0-,-(CH,) n -0-, -(CH 2 ) n -S-, -(CH 2 ) n -0-(CH,) n -, -(CH,).-S-(CH,) B -, -(CH,) n -C(0)-(CH,) n -, -(CH,) B -0-(CH,) n -, -(CH,) n -S-(CH 2 ) B -,-C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH,) B -, -C(0)-C(Z)-N(R 6 )-(CH,) B -, -C(0)-C(Z)-N(R 6 )-(CH,) B -, -
  • M 1 is -COOH or a moierv selected from:
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH,) a -COOH, (CH 2 ) B -C(0)-COOH, tetrazole,
  • R in each appearance is independently selected from H. halogen. -CF 3 , -OH, -COOH. (CH 2 ) B -COOH, -(CH 2 ) B -C(0)-COOH, -C,-C 6 alkyl, -0-C,-C 6 alkyl. -NH(C,-C 6 alkyl), or -N(C,-C 6 alkyl),;
  • R'° is selected from H, -COOH, -(CH,).-COOH, -(CH,) n -C(0)-COOH, -CF 3 , -OH, (CH,) B -C(0)-COOH. -C,-C 6 alkyl, -O-C,-C 6 alkyl.
  • R is selected from H. C,-C 5 lower alkyl. C,-C 6 cycloalkyl, -CF 3 , -COOH, -(CH,) B COOH, -(CH : meticulous-C(0)-COOH,
  • moieties comprising R 4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae:
  • R 3 is selected from C,-C 6 lower alkyl, C [ -C 6 lower alkoxy, -(CH,) a -C 3 -C 10 cycloalkyl, -(CH,) n -S-(CH 2 ) n -C 3 -C I0 cycloalkyl. -(CH,) B -O-(CH,) B -C 3 -C I0 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 3 cycloalkyl
  • a bicyclic ring oiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 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 substimted by from 1 to 3 substituents selected from halogen.
  • C r C w alkoxy preferably C.-C 6 alkoxy. -CHO, -NO,, - NH,, -CN, -CF, or -OH;
  • D is H. C,-C 6 lower alkyl, C [ -C 1 lower alkoxy, -CF. or -(CH,) B -CF 3 ;
  • B and C are independently selected from phenyl, pyridi ⁇ yl, 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 , -OH. -C,-C 6 alkyl, C,-C 6 alkoxy, -NH, or -NO,; 2
  • Preferred compounds include those having the formula:
  • R is selected from H. halogen, -CF 3 , -OH, -C,-C 10 alkyl. preferably -C,-C 5 alkyl. -S-C,- C 10 alkyl, preferably -S-C,-C 6 alkyl, C,-C 10 alkoxy. preferably C,-C 6 alkoxy, -CN, -NO,. -NH,, phenyl, -O-phenyl, -S-phenyl.
  • furan. pyrrole, or thiophene being optionally substimted by from 1 to 3 substituents selected from halogen.
  • C x -C ]0 alkyl preferably C,-C 3 alkyl, C,-C l0 alkoxy. preferably C,-C 6 alkoxy, -CHO, -NO,, -NH heap -CN, -CF or -OH; or
  • benzofuran, indole, napthalene, purine, or quinoline each being optionally substimted by from 1 to 3 substiments selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C C l0 alkoxy, preferably C,-C 6 alkoxy.
  • halogen C,-C 10 alkyl, preferably C,-C 6 alkyl, C C l0 alkoxy, preferably C,-C 6 alkoxy.
  • Z is O or S
  • R s is selected from the relevant members of the group H, -CF,, C,-C 10 alkyl, preferably C,-C ⁇ alkyl, C,-C 10 alkoxy, preferably C,-C ⁇ alkoxy, phenyl, -O-phenyl, -S-phenyl, benzyl, -0- benzyl, or -S-benzyl, the phenyl and benzyl rings of these groups being optionally substimted by from 1 to 3 substiments selected from halogen.
  • R- is selected from the relevant members of the group -OH. -CF 3 , C,-C 10 alkyl, preferably C,-C ⁇ alkyl, C,-C I0 alkoxy, preferably C,-C 6 alkoxy.
  • -NH,. -(CH,) often-NH,, -NH-(C,-C 6 alkyl), - N-(C,-C 6 alkyl),.
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2;
  • R is selected from H. halogen, -CN, -CHO, -CF 3 , -OH, C C l0 alkyl, preferably C,-C 6 alkyl, C r C x0 alkoxy, preferably C C 6 alkoxy, -CHO, -CN, -NO,, -NH,, -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl),, -N-SO,-C,-C 6 alkyl, or -SO,-C,-C 6 alkyl;
  • R is selected from H, halogen, -CF 3 , -OH, -C,-C 10 alkyl, C,-C 10 alkoxy, -CHO, -C(0)CH 3 , -C(OMCH,)n-CF 3- -CN, -N0 2 , -NH,, -NH-C,-C 6 alkyl, -N(C,-C S alkyl),, -N-SO,- C,-C 6 alkyl, -SO,-C,-C 6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(0)-phenyl, -C(O)- benzyl, -CH,-(C 3 -C 5 cycloalky), -C(0)-OH, C(0)-C,-C 6 alkyl, -C(0)-0-C,-C 6 alkyl, -C(0)-CF 3 , or -(CH,) n -S-CH,
  • n in each appearance is independently selected as an integer selected from 0-3;
  • R 3 and R 9 are independently selected in each appearance from H. -COOH. -(CH,) a -COOH, -(CH,) B -C(0)-COOH. -CF,, -OH. -(CH,) n -C(0)-COOH. -C,-C ⁇ alkyl, -0-C,-C 6 alkyl. -NH(C,- C 6 alkyl), or -N(C.-C S alkyl),;
  • R !2 is selected from H, -CF., C C 6 alkyl, -(CH 2 ) compassion-C 3 -C S cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substimted by from 1 to 3 groups selected from halogen, -CF 3 , -OH, -COOH, -(CH,) n -COOH, -(CH,) n -C(0)-COOH, -C,-C 6 alkyl, -O-C,- C 6 alkyl, -NH(C,-C 6 alkyl), or -N(C,-C 0 alkyl),;
  • L' is selected from -(CH,) protest-, -S-, -0-, -C(O)-, -C(0)-0-,-(CH,) B -0-, -(CH,) B -S-, -(CH,) B -O-(CH ) B -.
  • M' is -COOH or a moierv selected from:
  • R 3 . in each appearance, is independently selected from H. -COOH, -(CH,),,-COOH. (CH , ) n -C ( 0)-C0OH, tetrazole,
  • Ro in each appearance is independently selected from H. halogen, -CF 3 , -OH, -COOH, (CH,) deliberately-COOH. -(CH,) a -C(0)-COOH. -C,-C 5 alkyl. -0-C,-C 6 alkyl. -NH(C,-C 6 alkyl), or -N(C t -C, alkyl),;
  • R ' ° is selected from H. -COOH, -(CH,) B -COOH. -(CH,) n -C(0)-COOH. -CF 3 . -OH. (CH,) B -QO)-COOH. -C,-C 3 alkyl. -0-C,-C 6 alkyl,
  • the moiety or combination of moieties comprising R 4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae:
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH,) B -C 3 -C 10 cycloalkyl, /43672
  • D is H, C x -C 6 lower alkyl, C x -C 6 lower alkoxy, -CF or -(CH 2 ) n -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substimted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF 3 , -OH. -C ⁇ alkyl, C C_ alkoxy, -NH, or -NO,; or a pharmaceutically acceptable salt thereof.
  • R is selected from H, halogen, -CF 3 , -OH. -C x -C. 0 alkyl. preferably -C 1 -C 1 alkyl, -S-C,- C 10 alkyl, preferably -S-C,-C 6 alkyl, C C l0 alkoxy, preferably C C 6 alkoxy, -CN, -NO,, -NH,, phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl; or furan, pyrrole, or thiophene, bonded to the indole ring by a chemical bond or a -S-, -0- or -(CH,) a - bridge, the phenyl, benzyl, furan, pyrrole, or thiophene rings being optionally substimted by from 1 to 3 substituents selected from halogen, C
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2;
  • R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C 10 alkyl, preferably C,-C 6 alkyl, C C l0 alkoxy, preferably C x -C 6 alkoxy, -CHO, -CN, -NO,, -NH,, -NH-C,-C 6 alkyl, -N(C,-C alkyl),, -N-SO,-C,-C 6 alkyl, or -SO,-C,-C 6 alkyl;
  • R 3 is selected from H, halogen, -CF 3 , -OH, -C,-C 10 alkyl, C,-C ]0 alkoxy, -CHO, -C(0)CH 3 , -C(0)-(CH 2 )n-CF 3 , -CN, -NO., -NH,, -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl),, -N-S0 2 - C x -C 6 alkyl, -SO,-C,-C 6 alkyl, phenyl, phenyloxy.
  • benzyl benzyloxy-C(0)-phenyl, -C(O)- benzyl, -CH,-(C 3 -C 5 cycloalky), -C(O)-OH, C(O)-C,-C 5 alkyl. -C(0)-0-C,-C 6 alkyl, -C(0)-CF 3 , or -(CH,) a -S-CH,-(C 3 -C 5 cycloalky).
  • the rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen.
  • n in each appearance is independently selected as an integer selected from 0-3:
  • R 3 and R 9 are independently selected in each appearance from H, -COOH, -(CH,) B -COOH, -(CH,) deliberately-C(0)-COOH. -CF., -OH, -(CH,) a -C(0)-COOH. -C,-C 5 alkyl, -0-C,-C 5 alkyl, -NH(C,- C 6 alkyl), or -N(C,-C 6 alkyl),;
  • R 12 is selected from H, -CF., C x -C 6 alkyl. -(CH,).-C 3 -C 6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen. -CF 3 , -OH, -COOH, -(CH,) B -COOH. -(CH,) compassion-C(O)-COOH. -C.-Q alkyl, -O-C- C 6 alkyl, -NH(C,-C 6 alkyl), or -N(C,-C 6 alkyl),;
  • M 1 is -COOH or a moiety selected from:
  • R 3 . in each appearance, is independently selected from H. -COOH, -(CH-).-COOH, (CH,) a -C(O)-COOH. tetrazole,
  • R 9 in each appearance is independently selected from H, halogen, -CF 3 , -OH, -COOH. (CH,) a -COOH. -(CH,) compassion-C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), or -N(C,-C 6 alkyl),;
  • R 10 is selected from H, -COOH, -(CH,) deliberately-COOH, -(CH,) n -C(O)-COOH, -CF 3 , -OH, (CH,) deliberately-C(O)-COOH, -C -C 6 alkyl, -0-C,-C 6 alkyl.
  • moiedes compnsing R 4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae:
  • R 5 is selected from C x -C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) B -C 3 -C I0 cycloalkyl, -(CH,) n -S-(CH,) n -C 3 -C 10 cycloalkyl, -(CH 2 ).-O-(CH,) B -C 3 -C I0 cycloalkyl, -(CH,) B -phenyl-O- phenyl, -(CH,)_-phenyl-CH,-phenyl, -(CH,) n -0-phenvl-CH,-phenyl, -(CH,) n -phenyl-(0-CH 2 - phenyl) 2 , -CH,-phenyl-C(0)-benzotniazole or a moiety of the formulae -(CH 2 ) n -A, -(CH 2 ) a
  • D is H. C x -C 6 lower alkyl, C,-C 6 lower alkoxy, -CF 3 or -(CH,) ⁇ -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl. pyrimidinyl, fury I. 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 x -C 6 alkyl. C,-C 6 alkoxy, -NH, or -NO,: or a pharmaceutically acceptable salt thereof.
  • the present invention also provides for a method of inhibiting the phospholipase enzyme activity of an enzyme, comprising administering to a mammalian subject a therapeutically effective amount of a compound of the present invention.
  • Methods of treating an inflammatory response or condition comprising administering to a mammalian subject a therapeutically effective amount of a compound of the present invention are also provided.
  • Pharmaceutical compositions comprising compounds of the present invention and a pharmaceutically acceptable carrier are also provided.
  • Figs. 1-13 depict schemes for synthesis of compounds of the present invention. The depicted schemes are described in further detail below.
  • aryl and “substimted aryl” are understood to include monocyclic, pa ⁇ icularly- including five- and six-membered monocyclic. aromatic and heteroaromatic ring moieties and bicyclic aromatic and heteroaromatic ring moieties, pa ⁇ icularly including those having from 9 to 10 ring atoms.
  • aryl groups are understood to be phenyl rings, including those found in pheno.xy. benzyl, benzyloxy, biphenyl and other such moieties.
  • the aryl and heteroary! groups of this invention also include the following:
  • N selected from N, S or 0 including, but not limited to benzofuran, chromene, indole, isoindole, indohne, isoindolme. napthalene, pu ⁇ ne, lndolizi ⁇ e, mdazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine
  • the 'substimted aryl" groups of this invention include such moieties being optionally substimted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl. preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, -CHO, -COOH or esters thereof, -N02, -NH2, -CN, -CF3 or -OH or combinations thereof, such as -CH2CF3, -NH(CH3), 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 morpho ne rings
  • a preferred group of bicyclic aromatic groups includes benzofuran, indole. napthalene, and quinoline rings
  • alkyl, alkeny l and alkiny l 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 Unless indicated otherwise, it is preferred that these groups be straight or oranched Halogens herein are understood to include F, Cl, Br and I
  • Taoles I- VI also report data for the listed compounds in the "LysoPC assay and the Couma ⁇ ne assay (see Example 88 below)
  • assay results are repo ⁇ ed as an ' ⁇ G_ ' value
  • whica is the concentration of a compound which mhioits 50 * ⁇ of the activity of the pnospholipase enzyme in such assay Where no numerical IC 0 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
  • pnospholipase enzyme activity means positive activity in an assay for metabolism of phosphohpids (preferably one of the assays described in Example 88 below;
  • a compound has "phospholipase enzyme inhibiting activity” when it inhibits the activity of a phospholipase (preferably cPLA in any available assay (preferably an assay described below m Example 88 or Example 89) for enzyme activity
  • a compound has (1) an IC 0 value of less than about 25 ⁇ M. preferably less than about 6 ⁇ M.
  • IC 0 value of less than about 50 ⁇ M in the vesicle assay (2) an IC 0 value of less than about 50 ⁇ M in the vesicle assay, (3) an IC 0 value of less than about 1 ⁇ M in the PMN assay, (4) an IG 0 value of less than about 15 ⁇ M in the Couma ⁇ ne assay, and/or (5) measurable activity (preferably at least about 5 % reduction m edema, more preferably at least about 10% reduction, more preferaoly at least about 15 % , most preferably aDout 20-30% ) in the rat carrageenan-induced footpad edema test
  • Compounds of the present invention are useful for innibiting p ⁇ ospnohpase enzyme (preferaoly cPLA activity and. therefore, are useful in 'treating ' (I e , treating prev enting or ameliorating* inflammatory or mflammation-related responses or conations (e g . rheumatoid arthritis, psoriasis, astnma. inflammatory bowel disease, and other diseases mediatec oy prostaglandins. leukct ⁇ enes or P ⁇ F) and other conditions sucn as osteoporosis, colitis, my elogenous leukemia, oiaoetes wasting and atherosclerosis
  • the present invention encomoasses ooth pharmaceutical compositions and therapeutic memoes of treatment or use whicn employ compounds of tne present in ention
  • Compour.cs of the present invention av oe used in a pharmaceutical composition w nen ememe ⁇ w ith a pnarmaceuticaily acceptable earner Sucn ⁇ composition mav aiso contain i .n addition to a compound or compounds of the present invention and a carrier) diluents fillers, salts, buffers, stabilizers soluoihzers.
  • 'pnarmaceutically acceptaoie ' means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active mgre ⁇ ent(s)
  • the cnaracteristics of tne carrier will depend on the route of administration
  • the pharmaceutical composition may further contain other anti- flammatory agents Such additional factors and/or agents may be included in the pnarmac ⁇ utical composition to produce a synergistic effect wth 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 m the form of a liposome in whicn 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.
  • Suitable lipids for liposomal formulation include, without limitation, monogiycerides. diglycerides, sulfatides. lysolecithin. phospholipids, saponin. bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the an, 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 mat is sufficient to show a meaningful patient benefit, I e . treatment, healing, prevention or amelioration of an inflammatory response or condition, or an xcrease in rate of treatment, heai g, 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 xcrease in rate of treatment, heai g, prevention or amelioration of such conditions
  • the term refers to that ingredient alone
  • the term refers to combined amounts c: the active ingredients that result in the therapeutic effect, whether administered ccmoi ⁇ at-.cn. serially or simultaneously
  • a therapeutically effective amount of a compound of tne present invention is administered to a mammal ha ing a condition :o be treated
  • Compounds of the present m ention may be administered in accordance vv itn tne metr.cc c ⁇ the inv ention either aione or in comDina ⁇ on with ether therapies such as treatments emplo ing other anti-inflammatory agents, cy tokines.
  • lymphokmes or other he atopoietic factors When co-administered w.tn one or more other anti-inflammatory agents, cvtokmes, ly mphokmes or other hematopoietic factors, compounds of the present invention may be administered either simultaneously with the other anti- mflammatory agent(s). cytokme(s).
  • lymphck ⁇ ne(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 , cytok ⁇ ne(s ) , lymphckme(s ), other hematopoietic facto ⁇ s), thrombolytic or anti-thrombotic factors
  • Administration of compounds of the present invention used in the pharmaceutical composition or :o practice the method of the present invention can be earned 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 tabiet, 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 sucn as peanut oil, mineral oil. soyoean oii, or sesame oil.
  • Tne liquid form of the pharmaceutical composition may fu ⁇ her contain ph siological saline solution, dextrose or other saccha ⁇ de solution, or giy cols such as ethy iene giycol. propylene glycol or polyethy lene giycol When administered in liquid form.
  • tne pharmaceutical composition contains from about 0.5 to 90% by weignt of compound of tne present invention, and preferably from about 1 to 50% compound of the present inv ention.
  • compounds of the present invention When a tnerapeutically effective amount of compounds of the present inv ention is administered by intravenous, cutaneous or subcutaneous injection, compounds of the present invention will be .n tne form of a py rogen-fre ⁇ . parenterally acceptable aqueous solution
  • a preferred pnarmaceutical composition for intravenous, cutaneous, or suocutaneous injection should contain, in addition to compounds of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer s Injection. Dextrose Injection.
  • the pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants. or other additives known to those of skill m the an.
  • the amount of compound(s) of the present invention in the pnarm ⁇ ceu ⁇ cai composition of the present invention will depend upon the nature and sev enty 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 funher. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.1 ⁇ g to about 100 mg (preferably about J mg to about 50 mg. more preferably about Img 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 van', 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 2- 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.
  • Indol-2-carboxylic acid ethyl ester I is convened to aldehyde II in two steps: reduction with lithium aiuminum hydride (LAH) or other hydride in a suitable solvent such as tetrahydrofuran (THF) at 0 °C. and then oxidation with an oxidizing reagent such as manganese dioxide in a solvent such as THF.
  • LAH lithium aiuminum hydride
  • THF tetrahydrofuran
  • an oxidizing reagent such as manganese dioxide
  • THF tetrahydrofuran
  • Deprotonation of aldehyde II with a strong base such as potassium hexamethyldisilyl amide (KHMDS) in THF followed by reaction with a chloro formate in the presence of a base, such as triethyl amine. produces carbamate III.
  • KHMDS potassium hexamethyldisilyl amide
  • Ill is transformed into bromide IV in two steps: (1) reduction with sodium borohydride in an alcoholic solution and (2) reaction withcarbon tetrabromide in the presence of a phosphine reagent such as bis(diphenylphosphino)propane in dichloromethane.
  • a phosphine reagent such as bis(diphenylphosphino)propane in dichloromethane.
  • Displacement of the bromine in IV with potassium phenoxide, prepared by reaction of a phenol with KHMDS, in a suitable solvent such as THF or DMF affords ether V.
  • V can be convened to either trifluoromethyl ketone VII or to carboxylic acid IX in different procedures.
  • 2-Indoiyl carboxylic acid ethyl ester I is deprotonated with a strong base such as sodium hydride (NaH) in THF. and then reacted with a suitable alkyl bromide to give X.
  • a strong base such as sodium hydride (NaH) in THF.
  • a suitable alkyl bromide to give X.
  • Hydrolysis of X with a aqueous base such as sodium hydroxide and reaction with aniline or a substimted aniline in the presence of a carbodiimide such as dimethylaminopropyl ethylcarbcdiimide hydrochloride (EDCI) in a suitable solvent such as dichloromethane affords amide XI.
  • XI is hvcrolvzed to corresponding acid XII in a aoueous base such as sodium hvdroxide.
  • Indole I can be brominated on the 3-position by reaction with a bromine or N- bromosuccinimide in a suitable solvent such ascarbon tetrachloride or dichloromethane to yield bromide XIII.
  • a suitable solvent such ascarbon tetrachloride or dichloromethane
  • Reaction of XIII with a suitable alkyl bromide in the presence of a strong base such as NaH in THF or DMF affords indole XIV.
  • Palladium mediated coupling of XIV with a suitable alkene in the presence of phosphine and a base such as triethyl amine produces 3-substiruted indole XV.
  • XV can be convened to amide XVII in two step reactions: ( 1) hydrolysis with aqueous base such as NaOH and (2) coupling with an a ine in the presence of carbodiimide such as EDCI.
  • Ester XIV can be transformed to lithium salt XVIII by hydrolysis with aqueous base and then reaction with lithium hydroxide in a suitable solvent such as ether. Lithiation with n-butyl lithium in a suitable solvent such as THF, and then acylation with an acyl chloride in THF affords ketone XIX.
  • Carbodiimide (EDCI) catalyzed coupling of XIX and a suitable amine gives amide XX.
  • Indole I can be convened to XXI 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.
  • TBDMSC1 t-butyldimethylsilyl chloride
  • a base such as imidazole.
  • Grignard reagent such as ethyl magnesium bromide in a solvent such as THF at -6GC.
  • a strong base such as NaH in DMF
  • ketone XXII The silyl group on XXII is removed using tetrabutylammcnium fluoride in a solvent such THF, the resulting alcohol is then convened to bromide using carbon tetrabromide and bis(diphenylphosphino)ethane in a solvent such as dichloromethane to yield bromide XXIII.
  • Aldehyde II prepared by Method A. can be alkvlated by a suitable alkyl bromide (or iodide), such as benzyl bromide or ethyl iodide in the presence of a strong base such as sodium hydride or KHMDS in a solvent such as DMF to yield XXV.
  • XXV can be convened to an unsaturated acid XXVI by two steps: ( 1) Wittig reaction with a suitable reagent such as trimethyl phosphonoacetate in the presence of a base such as sodium hydride in a solvent such as THF and (2) Hydrolysis by aqueous sodium hydroxide.
  • Indole I is reduced with LAH in a solvent such as THF.
  • BOC t-butoxycarbonyl
  • (BOGO) di-t-buryldicarbonate
  • a base such as triethvlamine
  • the hydroxyl group in XXIX is mesylated using mesyl chloride and triethylamine in a solvent such as dichloromethane, and then displaced by either a thiol or an alcohol as described in METHOD D to produce indoiine XXX.
  • XXXI Deprotection of XXX using trifluoroaceiic acid affords XXXI. which is either acylated (acyl chloride, triethylamine, dichloromethane) or alkvlated (alkyl halide. K 2 CO 3 , DMF) to afford XXXII. or XXXIII respectively.
  • Carboxylic acid XXXIV is convened to aldehyde XXXV in two steps: ( 1 ) reaction with N.O- dimeihylhydroxy amine in the presence of EDCI in a solvent such as dichloromethane. and ( 2) reduction with diisobutyl aluminum hydride (DIBAL) in a solvent such as THF.
  • DIBAL diisobutyl aluminum hydride
  • Treatment of XXXV with trimethyl phosphcnoacetate in the presence of ⁇ strong base such as KHMDS in a solvent such as THF results in the formation of ester XXXVI.
  • XXXVII Reduction of XXXVI with tin in hydrogen chloride, followed by cyclization in a heated inen solvent such as toluene gives XXXVII. All viation on nitrogen of XXXVII under conditions described in METHOD F, and then hydrolysis of the ester with aqueous base such as NaOH affords acid XXXVIII.
  • XXXVIII can be convened to an amide XXXIX by coupling with a suitable ⁇ mine such as benzylamine in the presence of EDCI.
  • METHOD H Aldehyde XXXV prepared in METHOD G, is subjected to a Wittig reaction using methyl triphenylphosphonium iodide in the presence of a strong base such as KHMDS or NaH in a solvent such as THF to afford alkene XL.
  • a strong base such as KHMDS or NaH in a solvent such as THF
  • Reduction of the nitro group of XL with iron powder in an ammonium chloride solution, followed by treatment with benzyl chloroformate in the presence of a base such as triethyl amine produces carbamate XLI.
  • XLI is treated with iodine in a basic solution such as aqueous NaHCQ in THF to yield iodide XLII.
  • Displacement of the iodine on XLII with lithium benzoate in a solvent such as DMF, followed by hydrolysis with NaOH affords alcohol XLIII.
  • Indoline XXVIII prepared in METHOD F or METHOD H. can be either acylated by reaction with an acyl chloride in the presence of a base such as triethyl amine or alkvlated using alkyl halide in the presence of KC0 3 in a solvent such as DMF to produce alcohol XLIV.
  • a base such as triethyl amine or alkvlated using alkyl halide in the presence of KC0 3 in a solvent such as DMF
  • KC0 3 in a solvent such as DMF
  • XLVI Hydrolysis of XLV with an aqueous base such as NaOH gives acid XLVI, which can be coupled with an amine catalyzed by a diimide such as EDCI in a solvent such as dichloromethane to afford amide XLVII.
  • XLVTI can be alkylated on the amide nitrogen by treatment with alkyl halide and strong base such as NaH in DMF.
  • Hydrolysis of the resulting amide with aqueous base such as NaOH gives acid XLIX.
  • XLIV can also be directly hydrolyzed with NaOH to a carboxylic acid XLVIII.
  • Ester L can be deprotonated with a strong base such as lithium diisobutylamide (LDA) in a solvent such as THF, and subsequently alkylated with an alkyl halide such as methyl iodide to give LI.
  • LDA lithium diisobutylamide
  • Reduction of LI to amine LIII can be accomplished using hydrogenation catalyzed by palladium in a solvent such as ethanol.
  • L can be oxidized to alcohol LII using LDA and oxaziridine in a solvent such as THF.
  • Alkylation of LII with a alkylating reagent such as methyl iodide in the presence of a strong base such as NaH in DMF, followed by catalytic hydrogenation in the presence of palladium produces amine LIV.
  • METHOD K illustrates the synthesis of substituted aminobenzoic acid esters.
  • Mono-acid LV can be convened to amide LVI by the following steps: (1) reaction with oxalyl chloride in dichloromethane to form acid chloride and (2) treatment with a suitable amine such as dimethyl amine. Reduction of the nitro group to the amine is accomplished with hydrogenation catalyzed by palladium as described in METHOD J. LV can be reduced to alcohol LVIII with hydroborane-THF complex in THF. Protection of the hydroxy group as a silyl ether using TBDMSC1 in the presence of imidazole and subsequently, reduction of the nitro group (H 2 / Pd-C) to the amine affords LIX.
  • LVIII can be convened to the secondary alcohol LX in two steps: (1) oxidation with a suitable reagent such as manganese dioxide (MnO : ) in ethyl acetate and (2) addition of a desired Grignard reagent such as methyl magnesium bromide in THF. Oxidation of LX with MnO in THF and reduction of the nitro group (H : / Pd-C) produces ketone LXIII. Reduction of LVII (H / Pd-C) yields LXI.
  • a suitable reagent such as manganese dioxide (MnO : ) in ethyl acetate
  • Grignard reagent such as methyl magnesium bromide
  • Alcohol LXIV prepared in METHOD I, can be debenzylated by hydrogenolysis catalyzed by palladium on carbon in a solvent such as ethanol. The resulting alcohol is treated with p- methoxybenzyl chloride in the presence of C0 in a solvent such as THF to afford LXV. Alcohol LXV can be transformed into ether or sulfide LXVI by the procedures described in METHOD D. Deprotection of the p-methoxybenzyl group with TFA in a solvent such as dichloromethane, and subsequent alkylation on oxygen with a suitable reagent such as 4- benzylbenzyl bromide in the presence of C0 3 in a solvent such as THF affords LXVII. EXPERIMENTAL SECTION
  • Step 1 2- ( 5-Phenylmethoxy ' )indolyl aldehvde
  • Step 3 Benzyl (l-(2-hvdroxymethyl-5-phenylmetho ⁇ v)indolyl)formate
  • Step 4 Benzyl ⁇ -(2-bromomethyl-5-phenylmethoxy')indolyDformate
  • Step 6 120 mg (0J4 mmol) of the aldehyde of step 5 was dissolved in 11 mL of 5: 1 :5 THF- acetonitrile-2J-dimethylethanol. To this solution was added a solution of 56 mg (0.5 mmol) of sodium chlorite in 0.5 mL water and 1 drop of aqueoues hydrogen peroxide solution. After 4 hours, another 56 mg (0.5 mmol) of sodium chlorite was added. The mixture was stirred at room temperature for three days. Aqueous work up and flash chromatography using 2.5: 1:0.05 hexane:ethyl acetate-acteic acid afforded 110 mg of the title compound.
  • Step 1 Benzyl (l-(2-(2-(l -hydro ⁇ v-2J J-trifluoroethyl)phenoxy nethyl-5- phenylmethoxy ⁇ ndolyP-formate
  • Step 1 Ethyl 2-(l-benzyl-5-benzyloxy)indolecarboxylate
  • Step 3 Ethyl 3-(2-(l-benzyl-5-benzylo ⁇ v ndolecarboxamido ' )benzoate
  • step 2 l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDCI) (0J2 g, 1.66 mmol), 4-dimethylaminopyridine (DMAP) (0.018 g, 0J5 mmol) and ethyl 3-aminobenzoate (0J7 g, 1.66 mmol) were stirred in tetrahydrofuran (9 mL) at room temperamre overnight. The next day the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated.
  • EDCI l-(3-dimethylaminopropyl)-3- ethylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • ethyl 3-aminobenzoate 0.018 g, 0J5 mmol
  • Ethyl 5-methoxy-2-indolcarboxylate (30 g. 102 mmol) is dissolved in 250 mL of THF and cooled to 0 3 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 MgS0 and concentrated to yield 24.8 g of alcohol, which was used for the next reaction directly.
  • LAH Lithium Aluminum Hydride
  • Step 2 2-(5-methoxy)indolylmethoxy-tert-buthyldimethylsilane
  • DMF dimethyl methoxy-buthyldimethylsilane
  • imidazole 5.5g, 81.5 mmol
  • t- butyldimethylsilyl chloride 5.4g, 35.8 mmol
  • the reaction was poured into water and extracted with ethyl acetate (3X). Organic layers were dried over magnesium sulfate and concentrated.
  • Step 4- 3-(2-te ⁇ -butvdimethylsilylo ⁇ vmethyl-5-metho ⁇ v-l-methyl)indolyl (2.4-bis(l J- dimethypropyPphenoxylmethyl ketone
  • Step 5 3-(2-Hydroxymethyl-5-methoxy-l-methyl)indolyl (bis-2.4- ( 1 J . dimethylpropyPphen ⁇ xylmethyl ketone
  • the crude material was purified on silica gel using hexane:ethyl acetate 2: 1 to yield pure alcohol (0.82 g, 60 % , TLC: 0J Rf in 2: 1 hexane:ethyl acetate).
  • the indole alcohol, prepared in step 5, (0J0 g, 0.43 mmol) was dissolved in dichloromethane (0J mL) and treated with triethylamine (0J mL, 0.64 mmol) and cooled to 0° C at which time mesyl chloride (0.04 mL 0.52 mmol) was added over 5 minutes, followed by addition of two drops of DMF. Tne reaction was stirred for a further 2 hour at 0C, it was then concentrated and used directly for the next reaction.
  • EXAMPLES 13. 14. 15 andj ⁇ in Table I were prepared by the procedures of Example 12 using Ethyl 2-(5-benzyloxy)indolecarboxylate, acetyl chlorides and suitable alkyl halides.
  • Ethyl 5-benzyloxy-2-indolecarboxyIate (30 g, 102 mmol) was dissolved in 250 mL of THF and cooled to 0° C. to which Lithium Aluminum Hydride (LAH) (255 mL of a 1.0 M solution in THF) was added via addition funnel over 40 minutes. The reaction was stirred a for 2 hours at 0 °C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts were filtered and washed with ethyl acetate (3X400 mL), the filtrates were combined, dried over MgS0 and concentrated to yield 24.8 g.
  • LAH Lithium Aluminum Hydride
  • Step 2 te ⁇ -Butyl l-(5-benzyloxy-2-hvdroxymethv indolinylformate 25 g (85 mmol) of crude alcohol, prepared in step 1 , and 4-dimethylamino pyridine (DMAP) (1 J9 g, 9.78 mmol) were dissolved in dichloromethane (180 mL). The solution was cooled to (f C and then triethylamine (13.6 mL, 98 mmol) was added to it. After 10 minutes of stirring a solution of di-tert-butyl dicarbonate (21.3 mL, 98mmol) dissolved in dichloromethane (20 mL) was added via syringe pump over 2 hours.
  • DMAP 4-dimethylamino pyridine
  • the carbamate, prepared in step 2 (15.25 g, 43 mmol) was dissolved in dichloromethane (180 mL) and treated with triethylamine (9.0 mL, 64.4 mmol). The solution was cooled to -1CP C at which time mesyl chloride (4.3 mL. 56 mmol) was added over 5 minutes. The reaction was stirred for a further 2 hour at -10 C C, it was then concentrated and used directly for the next displacement reaction.
  • Step 7 Ethyl 3-(2-(5-benzyloxy-l-(2J-bis(l J-dimethvPpropyPphenoxyacetyPindolinyl) methylthioacetamidobenzoate
  • Step 2 Ethyl 2-(5-benzyloxy-l -(2.4-bisf I . l -dimethv)propyl)phenoxyacetyl)- indolinylmethylthioacetate
  • Step 3 2-(5-Benzyloxy-l-(2.4-bis(l J- dimethy propyPphenoxyacetvPindoli ⁇ ylmethylthioacetic acid
  • the ester (2.5 g. 3.9 mmol), prepared in step 2. was dissolved in THF (20 mL), methanol (6 mL) and then IN sodium hydroxide (12 mL) was added. The resulting mixmre was stirred 24 hours at which time it was concentrated, diluted with water, acidified to pH 4 with concentrated HC1 and extracted with ethyl acetate (4X), the organic extracts were dried over magnesium sulfate, concentrated, and purified via chromatography (3: 1 hexane:ethyl acetate with 1 % acetic acid) to yield 1.17 g ( 50%) of the product as white solid.
  • Step 4 Methyl 3-(2-(5-benzyloxy-l-(2J-bis( l . l -dimethv')propyl)phenoxyacetyPindolinyl) methylthioacetamido-4-rnethylbenzoate
  • the titled compound was prepared from ester, prepared in step 4, according to the procedure described in step 3.
  • Step 1 2-(5-Benzyloxy- 1 -(3 J-bis(trifluoromethvPphenoxyacetyPindolinvPmethanol
  • Step 2 Ethyl 2-C5-benzyloxy-l-J J-bis(trifluoromethyl)phenoxyacetyl ' )indolinyl) methylthioacetate
  • Step 1 5-(2-(-5-Benzyloxy-l-( J-bis(trifluoromethyl)phenoxyacetyl)indolinyl) methylthioacetamido)benzene- 1.3-dicarboxylate
  • Step 1 Methyl 5-(2-(-5-benzyloxy-l-GJ-bis(trifluoromethvPphenoxyaceryl)indolinyl) methylthioacetamidoV3-ten-butyldimethylsilyloxymethylbenzoate
  • This compound was prepared according to the procedure described in step 1 of Example 38.
  • the titled compound was prepared according to the procedure described in step 2 of Example 38.
  • EXAMPLE 42 in table 3 was prepared according to the procedures described in Example 41.
  • Step I 2-(5-Hydroxy-l-(3J-bis(trifluoromethvPphenoxyacetyl)indolinyl)methanoI
  • Step 2 2- ( 5- ( 4-Methoxy1benzv1oxy-l- J- bisftrifluoromethyPphenoxyacervPindolinv methanol
  • Step 3 Methyl 5-f2-(-5-(4-methoxy benzylo ⁇ v-l-C -bis(trifluoromethvPpheno ⁇ vacetyl) indolinyPmethylthioacetamidolbenzene-l J-dicarboxylate
  • Stepl Methyl 5-(2-(5-GJ-Dibromo benzyloxy-I-( J-bis(trifluoromethv ⁇ pheno ⁇ vacetyl) indolinvPmethylthioacetamidolbenzene-l J-dicarboxylate
  • the titled compound was prepared from the ester, prepared in step 1 , according to the procedure described in step 5 of Example 44.
  • EXAMPLES 46 to 50 in table 4 were prepared according to the procedures described in Example 44. but using corresponding alkylating reagent.
  • Step 1 Methyl 3-(2-(5-benzyloxyindolinyl)methylthioacetamido -4-methoxybenzoate
  • This compound was prepared according to the procedures described in step 6 of Example 17. but with methyl 4-methoxybenzoate.
  • Step 2 Methyl 3-f2-(5-benzyloxy-l-(2- ⁇ aphthoxyaceryl)indolinyl)methylthioacetamido)-4- methoxybenzoate
  • EXAMPLES 60 to 63 in Table 5 were prepared according to the procedures described either in Example 59 or in Examples 51 and _52.
  • Step 1 Ethyl 3-J-(5-benzylo ⁇ v-l-tert-buto ⁇ vcarbonvPindolinvPmethylsulfonyl acetamidobenzoate
  • the titled compound was prepared according to the procedure described in step 3 of Example 59.
  • Step 1 5-Be ⁇ zylo ⁇ v-l-(2.4-bis(l J-dimethv propyPpheno ⁇ vacetvP-2-hydroxymethylindoline
  • Step 2 2- ⁇ f 5-Benzyloxy-l-(2.4-bis(l J-dimethv propyPphenoxyacetvPindolinylmethyl _ methylsulfonate
  • Step 3 Methyl 2-(2-(-5-be ⁇ zyloxy-l-(2.4-bis(l J-dimethv)propyl)phe ⁇ oxyacetyl) indoliny ⁇ methylthiobenzoate
  • the titled compound was prepared according to the procedure described in step 3 of Example 59.
  • EXAMPLE 68 was prepared according to the procedures described in Example 67.
  • Methyl iodide (161 mg, 1 J4 mmol) was added, and the reaction mixmre was stirred at 25 °C for 2 days. After chilling to 0 °C, water was added (10 mL), followed by 50 mL of half samrated ammonium chloride, and 100 mL of EtOAc. The layers were separated, and the aqueous phase was extracted once with EtOAc (50 mL). The combined organic phases were dried (sodium sulfate), filtered, and concentrated to afford 0.6 g of crude product as an orange oil. This material was dissolved in 15 mL of THF and 10 mL of methanol, and 7 mL of IN NaOH solution was added, under nitrogen.
  • EXAMPLE 71 was prepared according to the procedures described in Example 70. but using allvl bromide.
  • Step l Ethyl 3-(2-(5-benzyloxyJ-(J-(4- pyridinvDethvPindoHnvPmethylthioacetamidobenzoate
  • the titled compound was prepared according to the procedure described in step 3 of Example 59.
  • Step 1 Ethyl 3- ⁇ '2-(5-benzyloxy-l -(2-naphthyPmethv')indolinvPmethylthioacetamidobenzoate
  • the titled compound was prepared according to the procedure described in step 3 of Example 59.
  • Step 1 2-(2- ( -5-Benzyloxy- 1 -( 1 J -dimethyPethoxycarbonyPindolinvPmethyl methylsulfonate
  • ester (1 g), prepared in step 3 was dissolved in DMF (6 mL).
  • p-Benzylbenzyl bromide was added (1 eq) followed by KC0 (1 eq).
  • the reaction mixmre was stirred overnight at room temperature.
  • additional p-benzylbenzyl bromide (0.5 eq) was added and the reaction was stirred for another 2 hours.
  • the reaction was diluted with HO and extracted with EtOAc (2 x). The organic layers were combined and dried over MgSQ. The MgSQ, was filtered and the solvent was evaporated to give an oily material which was dried overnight on high vacuum to give the product (1.59 g, 109 % yield).
  • Step 1 Methyl l-(5-Benzylo ⁇ v-2-(hvdroxymethyPindolinvPmethylbenzoate
  • the titled compound was prepared according to the prodedure described in step 5 of Example 76.
  • Step 1 2-(l-(2.4-Bis(trifluoromethyl)benzyl)indolinyl)carboxylic acid
  • 2-IndoIinylcarboxylic acid (0.43 g, 2.6 mmol) was dissolved in DMF (5 mL), placed under N 2 , and cooled to CP C, the sodium hydride (0J6 g of a 60 % dispersion, 6.5 mmol) was added and stirring was continued for 1 hour at this temperamre.
  • 2,4- Bis(trifluoromethyl)benzyl bromide (1.22 mL. 6.5 mmol) was next added and the reaction was warmed to room temperamre overnight.
  • the titled compound was prepared according to the prodedure described in Example 84, but using phenylsulfonylamide.
  • Step 1 2-Trimethylsilylethyl I-G-benzylo ⁇ v-2-hydroxymethyPi ⁇ dolinylfo ⁇ ate
  • Step 2 2-Trimethylsilylethyl l-(5-hvdro ⁇ v-2-hvdroxymethyl)i ⁇ dolinylforrnate
  • Step 5 2-Trimethylsilylethyl l-(5-f4-methoxy benzyloxy-2-azidomethyl)indolinylformate
  • Step 6 2-Trimethv silylethyl l- 5-(- ⁇ -methoxy benzyloxy-2-aminomethyl)indolinylformate
  • Step 7 Methyl 5-J-G-Methoxybenzylo ⁇ v- ! -f2-trimethylsilyloxy ethoxycarbony indolinyl) methylaminocarboxamido-l J-benzenedicarboxylate
  • the product was extracted with ethyl acetate, and the combined organic layers were washed with water, samrated aqueous NaHCQ, brine and dried over MgS0 4 .
  • the crude product was purified by flash chromatography using 10% MeOH/CHC , to afford 0.78 g of the product.
  • Step 8 Methyl 5-(2-(5-Methoxybenzylo ⁇ v)indolinyl)methylaminocarboxamido-l J- benzenedicarboxylate
  • EXAMPLE 87 was prepared according to the prodedure described in Example 86. but using 4-(3 ,5-bis(trifluoromethyI)phenoxymethyl)benzyl bromide.
  • Step 1 BisOnethyl 4-methoxy-3-dithioacetamidobenzoate
  • reaction mixmre After stirring at -50 °C for 1 h. , the reaction mixmre was allowed to warm to -30°C over 20 min. and then cooled to -50 °C again. The reaction mixmre was quenched with HO (500 mL) at -50 °C and warmed up to room temperamre and stirred for 0.5 h. The reaction mixmre was partitioned between CH 2 C1 2 (500 mL) and H 2 0. The aqueous layer was extracted with CHC1 2 (3 x 500 672
  • the deep purple solution was added dropwise a solution of racemic camphor sulfonyloxaziridine (3.4 g, 15 mmol), prepared by mixing the commercially available (lS)-( ⁇ )-(10- camphorsulfonyOoxaziridine (1.7 g) and (lR)-(-)-(10-camphorsulfonyl)oxaziridine (1.7 g) in 50 mL THF. After stirring at -78 °C for 30 min., the reaction mixmre was quenched with sat. NHjCl solution (45 mL) at -78 °C and then allowed to warm to room temperamre.
  • racemic camphor sulfonyloxaziridine 3.4 g, 15 mmol
  • reaction mixmre was partitioned between ether (250 mL) and HO (50 mL). The aqueous layer was extracted with ether(3 x 250 mL). The combined ether extracts were washed with brine (250 mL), dried over NaS0 4 and filtered. The solvents were removed in vacuo. Purification by column chromatography on silica gel (eluant: 50% AcOEt in he ane) afforded desired product. Yield 2J g (88%).
  • the titled compound was prepared from nitro compound of step 1 according to the procedure described in step 4 of Intermediate 3.
  • the titled compound was prepared from nitro compound, prepared in step 1 of Intermediate 3, according to the procedure described in step 4 of Intermediate 3.
  • the titled compound was prepared from nitro compound, prepared in step 1, according tothe procedure described in step 4 of Intermediate 3.
  • Step 1 Methyl 2-(3-nitro-4-methoxyphenyl)-2-allylacetate
  • This compound was synthesized form ester, prepared in step 1 of Intermediate 3, according to the procedure described in step 1 of Intermediate 6, but using allyl bromide.
  • the titled compound was prepared from 2-naphthol according to the procedure described in of Intermediate 8.
  • the titled compound was prepared from 3,5-bis(trifiuoromethyl)phenol according to the procedure described in of Intermediate 8.
  • the titled compound was prepared from nitro compound, prepared in step 1 , according to the procedure described in step 4 of Intermediate 3.
  • the titled compound was prepared from nitro compound, prepared in step 1, according to the procedure described in step 4 of Intermediate 3.
  • the titled compound was prepared from nitro compound, prepared in step 2, according to the procedure described in step 4 of Intermediate 3.
  • Step 2 Bis-(methyl 4-methoxy-3-(2-dithioethyl)aminobenzoate Bromide (0J9 mg, 1J87 mmol), prepared in step 1 , and methyl 3-amino-4-methoxy benzoate (1.00 g, 5.51 mmol) were added into a flask, flush with nitrogen and take up in DMF (5 mL) and then heat to 60° C for 24 hours at which time the reaction was diluted with ethyl acetate and quenched into water, extracted with ethyl acetate (3X), the combined organic layers were washed with water (3X), dried and concentrated to yield 1.27 g of a product that was purified by chromatography (hexane:ethyl acetate 5: 1 to 3: 1) to yield 0J5 g of the desired product.
  • the aldehyde is reacted with the alpha-carbon of a heterocycle such at 2,4-thiazolidinedione or rhodanine or 2-thiohydantoin in the presence of a base such a potassium carbonate or potassium hydroxide in a solvent system such a wate ⁇ ethanol or ethanol.
  • a base such as potassium carbonate or potassium hydroxide
  • a solvent system such as a wate ⁇ ethanol or ethanol.
  • the final acid may then be realized by cleavage of the ester with hydrogen fluoride in a solvent such as acetonitrile.
  • Indole-2-carboxylic acid was alkylated with an appropriate alkyl bromide which was then subjected to Suzuki coupling conditions using Pd(PPh,) 4 as a catalyst in a mixed solvent (ethanol-benzene- water) at elevated temperamre to give the l-alkyl-5-substimted indole.
  • Acid isosteres such as tetrazole were prepared from the carboxylic acids I via the nitriles III . Conversion to the nitriles was accomplished through primary amide formation of the acid functionality via the acid chloride with a suitable reagent such as oxalyl chloride and reaction with ammonia followed by a dehydration sequence using a suitable reagent such as oxalyl chloride and a base such as pyridine.
  • the nitriles such as III could be converted to the tetrazoles by reaction with an azide source such as sodium azide in an appropriate high boiling point solvent such as N-methyl pyrrolidinone to give compounds such as IV.
  • a Homer- Wittig reaction with trimethoxyphospho ⁇ oacetate in a suitable solvent such as tetrahydrofuran gave the unsamrated ester III, which was converted to the aldehyde FV under the conditions described for II.
  • the aldehyde could then be transformed to the thiazolidinedione V using a base such as piperdine and isolated with an acid such as acetic acid.
  • 2-Indolyl carboxylic acid ethyl ester I is deprotonated with a strong base such as sodium hydride (NaH) in THF, and then reacted with a suitable alkyl bromide to give VI.
  • a strong base such as sodium hydride (NaH) in THF
  • a suitable alkyl bromide to give VI.
  • Hydrolysis of VI witha aqueous base such as sodium hydroxide and reaction with aniline or a substituted aniline in the presence of a carbodiimide such as dimethylaminopropylethyl carbodiimide hydrochloride (EDCI) in a suitable solvent such as dichloromethane affords amide VII.
  • Amide VII is hydrolyzed to corresponding acid VH1 in a aqueous base such as sodium hydroxide.
  • Aldehyde LX is prepared from Indol-2-carboxylic acid ethyl ester I in two steps: (1) Reduction with lithium aluminium hydride or other hydride in a suitable solvent such as THF at 0°C and (2) oxidation with an oxidizing reagent such as manganese dioxide in a solvent such as THF.
  • Aldehyde EX can be alkylated by a suitable alkyl bromide (or iodide), such as benzyl bromide or ethyl iodide in the presence of a strong base such as sodium hydride or KHMDS in a solvent such as DMF to yield indole X .
  • Indole X can be convened to an unsa rated acid XI in two steps: (1) Wittig reaction with a suitable reagent such as trimethyl phosphonoacetate in the presence of a base such as sodium hydride in a solvent such as THF and (2) Hydrolysis by aqueous sodium hydroxide.
  • 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 HI 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.
  • R" halogen, CN, alkyl, alkoxy, alkoxycarbonyl, amido, acyl, H, OH
  • R alkoxy, benzyloxy, phenoxy, halogen, CN, N0 2 , alkyl or aryl
  • R' alkyl, aryl
  • Step 1 The aldehyde from Example 124, (5.2 g) was suspended in ethanol (150 mL). To the thick slurry was added 2,4-thiazolidinedione (1.28g) and potassium carbonate (6Jg). The mixture was heated in a bath at 60 °C (later dropped to 45 °C). After 1 h TLC showed no reaction. Sodium hydroxide (2.1 g) was added and the mixture was heated at 58 °C. After 45 minutes the TLC showed reaction progress. Additional 2,4-thiazolidinedione (OJ g) was added. The mixture was stirred overnight at room temperamre.
  • Step 2 To the material prepared in step 1 (1J g) in DMF (15 mL) at 0 °C was added sodium hydride (0.08 g. 60% dispersion in mineral oil). The suspension was stirred for 30 minutes. To the reaction mixture was added the benzyl bromide (0.54 g) and the reaction was stirred overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were concentrated. Column chromatography (1:6 ethyl acetate:hexane to 1:4 ethyl acetate:hexane) afforded the desired product (1J8 g, 75%) as a yellow solid.
  • Step 3 To the material prepared in step 2 (0J4 g) in acetonitrile (15 mL) was added HF (48% aqueous, 3.1 mL) via syringe. The reaction was stirred overnight. The reaction was not complete by TLC therefore THF was added to dissolve the starting material and additional HF (0.6 mL) was added. The reaction was stirred for 2 h after which the TLC showed reaction completion. Water was added which resulted in the formation of a yellow solid. The yellow solid was dissolved in ethyl acetate, washed with brine, dried over MgS0 4 and concentrated. The resulting crude solid was suspended in ethanol and stirred for 30 min. filtered and dried to afford the title compound (140 mg, 48%) as a yellow solid.
  • Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
  • Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
  • Step 3 The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
  • Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
  • Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent. .
  • Step 3 The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
  • Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
  • Step 3 The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
  • Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
  • Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2. using the appropriate alkylating agent.
  • Step 3 The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
  • Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
  • Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2. using the appropriate alkylating agent.
  • Step 3 The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
  • the compounds of the following Examples 101-106 were prepared as illustrated in Example 88, step 1, starting with the appropriate indole and rhodanine.
  • Step 1 The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole and rhodanine.
  • Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
  • Step 3 The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
  • Example 117A To a suspension of the acid prepared in Example 117A (1.5g, 3.0mmol) in CH 2 C1 2 (20ml) was added oxalyl chloride (0.8ml, 9Jmmol) and three drops of DMF. The mixture became homogeneous and was stirred for Ih at rt. The reaction was concentrated and redissolved in CH CI : (5ml) and NH 4 OH (2.0ml) was added. The bipha ⁇ ic mixture was stirred for 24h and concentrated. The remaining aqueous residue was extracted with CH 2 C1 2 and the combined organic layers washed with brine, dried and concentrated to give 1.4g (95%) of the desired intermediate as a yellow powder.
  • EXAMPLE 1 19 benzyl l-(4- ⁇ [3J-bis(trifluoromethyl)phenoxy]methyl ⁇ benzyl)-2-(lH-lJJ,4-tetraazol-5-yl)-lH- indol-5-yl ether acid was prepared in an analogous manner to Example 1 18 according to steps 1-3 starting from the acid prepared in EXAMPLE 117C.
  • Example 101 The thiasolidinedione prepared in Example 101 (OJg, OJmmol), was alkylated by treatment with sodium hydride (0.006g, 0J2mmol), and the bromomethyl SEM ester (0.058g, OJmmol) in
  • Step 1 To ethyl 5-benzyloxy-2-indolcarboxylate ( 1 g, 3.4 mmol) in 12 ml of DMF, sodium hydride (0J63g, 60% oil dispersion, 4.07 mmol) is added at room temperature. The reaction is stirred for 30 minutes. a-Bromo-a'-[3,5-bis(trifluoromethyl)phenoxyl]-p-xylene (1.54 g, 3.73 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 2 The ester ( 2J g. 3J9 mmol) is dissolved in 40 mL of 1/1 THF/ methanol and then IN sodium hydroxide (15 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 (1J3 g, 85%) of solid.
  • EXAMPLE 123 5- (ri-benzyl-5-(benzvIoxy)-lH-indoI-2-vncarbonyl ⁇ amino)isophthalic acid
  • Step 1 This intermediate was prepared according to the procedure described in Example 122, but using benzyl bromide.
  • Step 2 The acid (0.27 g, 0.75 mmol) prepared in step 1, EDCI (0.18 g, 0.97 mmol), DMAP (3 mg, 0.02 mmol) and dimethyI-5 aminoisophthalate (0J8g, 0.75 mmol) were dissolved in THF
  • 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 MgS0 4 and concentrated to yield 24.8 g (96%).
  • LAH Lithium Aluminum Hydride
  • Step 2 Indole alcohol (26J g. 103 mmol) from step 1 is dissolved in THF (900 ml). Manganese dioxide ( 106.6 g) is added and the mixmre is stirred for 2h at room temperature. After the reaction is complete the mixmre is filtered through celite and washed with ethyl acetate. The filtrate is concentrated under reduced pressure, dried to give the desired aldehyde (22.9 g, 89%).
  • Step 3 This intermediate was prepared from indole, prepared in step 2 above and 2- (bromomethyl)naphthalene, according to the procedure described in step 1, Example 122.
  • Step 4 To sodium hydride (0.025 g. 60% oil dispersion. 0.63 mmol) in 7.5 mL of THF is added trimethyl phosphonoacetate (0.1 mL. 0.62 mmol) in 2.5 mL of THF at room temperamre. The reaction is stirred for 10 minutes. Next the aldehyde (0J4 g, 0.62 mmol) prepared in step 3 above in 2.5 mL THF is added dropwise at room temperamre. Reaction is stirred for another 30 minutes EXAMPLE 133
  • Step 1 p-Toluoyl chloride (0.8 M) was added to triethylamine (2.44 eq) and methoxymethyl amine HCl (1J 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 3 The tolyl ketone from step 2 was dissolved in carbon tetrachloride (0J9M), and
  • Step 4 The intermediate from step 3, Example 131 was dissolved in dry DMF (0.1 M). followed by NaH (1.2 eq). After 1.5 h at 25°C. added the bromobenzyl ketone from step 3 and stirred for 1 d at 25°C. Workup (ethyl acetate/hexanes) and trituration (ethyl acetate hexanes) afforded the product in 46% yield.
  • Step 5 The product from step 4 was dissolved in methylene chloride and 1 N HCl (ca. 0.04 M) and stirred at 25'C for 1 h. Workup (sodium bicarbonate), and trituration with ether afforded the product alcohol (89%).
  • Step 6 The alcohol from step 5 was dissolved in dry methylene chloride (0.014 M). treated with thionyl chloride (1.2 eq) and stirred at 25°C for 1 d. Concentration and trituration with ethyl acetate/hexanes afforded the product chloride (100%).
  • Vesicle Assav l-palmitoyl-2-[- 4 C] arachidonyl phosphotidylcholine (58 mCi/mmol) (final concentration 6 ⁇ M) and 1 J-dioleyolglycerol (final concentration 3 ⁇ M) were mixed and dried under a stream of nitrogen.
  • To the lipids was added 50 mM Hepes pH 7.5 (2x final concentration of lipids) and the suspension was sonicated for 3 min. at 4?C.
  • a typical assay consisted of the lipid mixmre (85 ⁇ l) to which was added consecutively, the inhibitor (5 ⁇ l in DMSO) and cPLA, 10 ng for an automated system or 1 ng for a manual assay, in 10 ⁇ l of the BSA buffer. This assay was conducted by either the manual assay or automated assay protocol described below.
  • Soluble Substrate Assav ('LvsoPO l-[ M C]-palmitoyl-2-hydroxyphosphotidyl-choline (57 mCi/mmol) (final concentration 4.4 ⁇ M) was dried under a stream of nitrogen.
  • the lipid was resuspended by vo ⁇ exing 80 M Hepes pH 7.5, 1 mM EDTA (1 J x final concentration).
  • a typical assay consisted of lipid suspension (85 ⁇ l) to which was added consecutively the inhibitor (5 ⁇ l in DMSO) and cPLA. 200 ng in 80 mM Hepes pH 1.5, 2 M DTT and 1 M EDTA. This assay was conducted by either the manual assay or automated assay protocol described below.
  • RBL-2H3 cells were routinely cultured as 37C in a 5% CO; 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 1(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 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 37C followed by stimulation with DNP-BSA (300 ng/ml). After 6 min, the cells were removed by centrifugation, and the supernatant was assayed for PGI ⁇ 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, Analytical Biochemistry 222, 110-115). Inhibitors were mixed with 200 ⁇ L assay buffer (80mM Hepes, 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-hydroxycoumarinyl 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 increasein emission at 460 nm per minute. In the presence of a cPLA2 inhibitor, the rate of increase is less.

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Abstract

L'invention porte sur des inhibiteurs de l'activité de la cPLA2 présentant une formule chimique sélectionnée parmi les formules suivantes (I), (II) et (III), (IV), (V) ou (VI).
PCT/US1999/003388 1998-02-25 1999-02-17 Inhibiteurs de la phospholipase a2 WO1999043672A1 (fr)

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JP2000533428A JP2002504551A (ja) 1998-02-25 1999-02-17 ホスホリパーゼａ２の阻害剤
EP99936073A EP1062216A1 (fr) 1998-02-25 1999-02-17 Inhibiteurs de la phospholipase a2
AU32970/99A AU3297099A (en) 1998-02-25 1999-02-17 Inhibitors of phospholipase a2
EA200000873A EA200000873A1 (ru) 1998-02-25 1999-02-17 Ингибиторы фосфолипазы a
SK1278-2000A SK12782000A3 (sk) 1998-02-25 1999-02-17 Inhibítory fosfolipázových enzýmov, farmaceutický prostriedok s ich obsahom a ich použitie
CA002322163A CA2322163A1 (fr) 1998-02-25 1999-02-17 Inhibiteurs de la phospholipase a2
EEP200000522A EE200000522A (et) 1998-02-25 1999-02-17 Fosfolipaas A2 ensüümi inhibiitor, seda sisaldav farmatseutiline kompositsioon ning meetod fosfolipaasensüümi toime pärssimiseks
KR1020007009459A KR20010041346A (ko) 1998-02-25 1999-02-17 포스포리파제 ａ2 억제제
HU0100156A HUP0100156A3 (en) 1998-02-25 1999-02-17 Indole derivatives as inhibitors of phospholipase a2 and use of them for producing pharmaceutical compositions
IL13754099A IL137540A0 (en) 1998-02-25 1999-02-17 Inhibitors of phospholipase a2
HR20000513A HRP20000513A2 (en) 1998-02-25 2000-07-31 Inhibitors of phospholipase a2
NO20004217A NO20004217L (no) 1998-02-25 2000-08-23 Inhibitorer av fosfolipase A2
BG104781A BG104781A (en) 1998-02-25 2000-09-19 Inhibitors of phospholipase a2

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IL137540A0 (en) 2001-07-24
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PL342516A1 (en) 2001-06-18
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ID26123A (id) 2000-11-23
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CA2322163A1 (fr) 1999-09-02
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