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WO1998008818A1 - Inhibiteurs des enzymes phospholipases - Google Patents

Inhibiteurs des enzymes phospholipases Download PDF

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Publication number
WO1998008818A1
WO1998008818A1 PCT/US1997/014943 US9714943W WO9808818A1 WO 1998008818 A1 WO1998008818 A1 WO 1998008818A1 US 9714943 W US9714943 W US 9714943W WO 9808818 A1 WO9808818 A1 WO 9808818A1
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group
mmol
compound
independent
prepared
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PCT/US1997/014943
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English (en)
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Yibin Xiang
Jean Bemis
John Mckew
Neelu Kaila
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Genetics Institute, Inc.
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Priority to CA002264020A priority Critical patent/CA2264020A1/fr
Priority to JP10511798A priority patent/JP2000516958A/ja
Priority to EP97938589A priority patent/EP0922028A1/fr
Priority to AU40882/97A priority patent/AU717430B2/en
Publication of WO1998008818A1 publication Critical patent/WO1998008818A1/fr

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    • 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
    • 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • 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
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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

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. 227: 1 171-76 ( 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. Likewise arachidonic acid is not free in cells but is released from the sn-2 position of membrane phospholipids by phospholipase A : (hereinafter PLA 2 ). The reaction catalyzed by PLA 2 is believed to represent the rate-limiting step in the process of lipid mediated biosynthesis.
  • the lysophospholipid produced is the immediate precursor of platelet activating factor (hereafter called PAF), another potent mediator of inflammation [S.I. Wasserman, Hospital Practice, 15:49-58 ( 1988)]. Consequently the direct inhibition of the activity of PLA ; has been suggested as a useful mechanism for a therapeutic agent, i.e.. to interfere with the inflammatory response. [See, e.g., J. Chang et al, Biochem. Pharmacol.. 36:2429-2436 (1987)].
  • PAF platelet activating factor
  • 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,s have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLA,s are found in large quantities in mammalian pancreas, bee venom, and various snake venom. [See, e.g., references 13-15 in Chang et al, cited above; and E. A. Dennis, Drug Devel. Res.. 10:205-
  • pancreatic enzyme is believed to serve a digestive function and, as such, should not be important in the production of the inflammatory mediators whose production must be tightly regulated.
  • the primary structure of the first human non-pancreatic PLA has been determined.
  • This non-pancreatic PLA is found in platelets, synovial fluid, and spleen and is also a secreted enzyme
  • This enzyme is a member of the aforementioned family [See, J J Seilhamer et al. J Biol Chem . 264 5335-5338 (1989). R M Kramer et al. J Biol Chem . 264 5768-5775 (1989), and A Kando et al, Biochem Biophvs Res Comm .
  • a mu ⁇ ne PLA- has been identified in the mu ⁇ ne macrophage cell line, designated RAW 264 7
  • 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
  • this protein was not pu ⁇ fied to homogeneity [See, C C Leslie et al, Biochem Biophvs Acta .
  • 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 2 - and -CH 2 -CH 2 -;
  • R is independent of any other R group and is selected from the group consisting of -X-R 6 , -H. -OH, halogen, -CN, -N0 2 , C,-C, alkyl, alkenyl, alkinyl, aryl and substituted aryl;
  • R 2 is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR,, -CONR,R 6 , -(CH 2 ) n -W-(CH 2 ) m -Z-R réelle -(CH 2 ) deliberately-W-R discipline -Z-Rpractic C,-C, 0 alkyl, alkenyl and substituted aryl;
  • R is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR 5 , -CONR,R 6 , -(CH 2 ) n -W-(CH 2 ) m -Z-R s , (CH 2 ) n -W-Rlois -Z-R profession 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 6 , -SR 6 , -CN, -COR 6 , -NHR 6 , -COOH, -CONR 6 R 7 , -N0 2 , -CONHS0 2 R R , C,- C 5 alkyl, alkenyl and substituted aryl;
  • R is independent of any other R group and is selected from the group consisting of -H, -OH, -0(CH 2 ) n R 6 , -SR 6 , -CN, -COR 6 , -NHR 6 , -COOH, -N0 2 , -COOH, -CONR ⁇ R 7 , -CONHSO : R 8 , C r C, alkyl, alkenyl, alkinyl, aryl, substituted aryl, -CF essence -CF,CF, and
  • R 6 is independent of any other R group and is selected from the group consisting of -H, C,-C 3 alkyl, alkenyl, alkinyl, aryl and substituted aryl,
  • R 7 is independent of any other R group and is selected from the group consisting of -H, C,-C, alkyl, alkenyl, alkinyl, aryl and substituted aryl,
  • R 8 is independent of any other R group and is selected from the group consisting of C,-C 3 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 6 , -COOH, -CONR 6 R 7 , tetrazole, -CONHS0 2 R 8 , -COR ⁇ , -(CH 2 ) n CH(OH)R 6 and -(CH 2 ) n CHR 6 R flesh
  • R ⁇ 0 is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR 6 , -COOH, -CONR 6 R 7 , tetrazole, -CONHS0 2 R 8 , -COR 6 , -(CH 2 ) felicitCH(OH)R 6 and -(CH 2 ) n CHR 6 R 5 ,
  • X is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -O-, -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 2 -, -0-, -S-, -N(R 6 )-, - CO-, -CON(R 6 )- and -N(R lake)CO-, 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 preferrred embodiments include compounds having the following chemical formula
  • A is -CH 2 - and R 2 is
  • R ⁇ is selected froup the group consisting of alkyl, alkenyl, alkynyl, -(CH 2 ) p OH, and -0(CH 2 ) p CH 3 , and wherein p is an integer from 0 to 4.
  • R is selected from the group consisting of -H and -OCH 2 (C 6 H 6 ) and R, is -COR , R 5 is -OCH 2 R 6 and R 6 is a substituted aryl group.
  • said aryl group is substituted with one or more substituents selected from the group consisting of -CF 3 , -CF 2 CF 3 and -C(CH,) 2 CH 2 CH 3 .
  • 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 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.
  • Pharmaceutically acceptable salts of the compounds of the compounds desc ⁇ bed herein are also part of the present invention and may be used in practicing the compounds and methods disclosed herein.
  • Figs. 1 -13 depict schemes for synthesis of compounds of the present invention. The depicted schemes are desc ⁇ bed in further detail below.
  • halogen includes chlo ⁇ ne, fluorine, iodine and bromine; "alkyl”,
  • alkenyl and alkinyl include both straight chain and branched moieties; “aryl” includes single and multiple ⁇ ng moieties; and “substituted” denotes the presence of one or more similar ot dissimilar substituent groups of any character.
  • Tables I-VI also report data for the listed compounds in the "LysoPC” assay and the Coumarine assay (see Example 88 below).
  • 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 nume ⁇ cal 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
  • phospholipase enzyme activity means positive activity in an assay for metabolism of phospholipids (preferably one of the assays desc ⁇ bed in Example 88 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 desc ⁇ bed below in Example 88 or Example 89) for enzyme activity
  • a compound has ( 1 ) an IC S0 value of less than about 25 ⁇ M, preferably less than about 6 ⁇ M, in the LysoPC assay, (2) an IC S0 value of less than about 50 ⁇ M in the vesicle assay; (3) an IC ⁇ ;o value of less than about 1 ⁇ M in the PMN assay, (4) an IC 50 value of less than about 15 ⁇ M in the Couma ⁇ ne assay, and/or (5) measurable activity (preferably at least about 5% reduction in edema, more
  • Compounds of the present invention are useful for inhibiting phospholipase enzyme (preferably cPLA,) activity and, therefore, are useful in "treating” (I e., treating, preventing or ameliorating) inflammatory or inflammation-related conditions (e.g., rheumatoid arth ⁇ tis, pso ⁇ asis, asthma, inflammatory bowel disease, and other diseases mediated by prostaglandins, leukot ⁇ enes or PAF) and other conditions, such as 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
  • compositions when combined with a pharmaceutically acceptable earner
  • a pharmaceutically acceptable earner Such a composition may also contain (in addition to a compound or compounds of the present invention and a earner) diluents, fillers, salts, buffers, stabilizers, solubihzers, and other mate ⁇ als well known in the art
  • pharmaceutically acceptable means a non-toxic mate ⁇ al that does not interfere with the effectiveness of the biological activity of the active ⁇ ngred ⁇ ent(s) The characte ⁇ stics of the earner will depend on the route of administration.
  • the pharmaceutical composition may further contain other anti-inflammatory agents Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with compounds of the present invention, or to minimize side effects caused by the compound of the present invention
  • the pharmaceutical composition of the invention may be in the form of a liposome in which compounds of the present invention are combined, in addition to other pharmaceutically acceptable earners, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution
  • Suitable lipids for hposomal formulation include, without limitation, monoglyce ⁇ des, diglyce ⁇ des, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like
  • Preparation of such hposomal 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, l e , treatment, healing, prevention or amelioration of an inflammatory response or condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions
  • the term refers to that ingredient alone
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, se ⁇ ally or simultaneously
  • a therapeutically effective amount of a compound of the present invention is administered to a mammal having a condition to be treated
  • Compounds of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors
  • compounds of the present invention may be administered either simultaneously with the other anti-inflammatory agent(s), cytok ⁇ ne(s), lymphok ⁇ ne(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially If administered sequentially, the attending physician will decide on the approp ⁇ ate sequence of ad iniste ⁇ ng compounds of the present invention in combination with other anti- lnflammatory agent(s), cytokme(s), lymphok
  • 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 earner such as a gelatin or an adjuvant
  • a solid earner 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 earner 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 giycol.
  • the pharmaceutical composition When administered in liquid form, 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.
  • 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
  • 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.
  • the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.1 ⁇ g to about 100 mg of compound of the present invention per kg body weight.
  • the duration of intravenous therapy using the pharmaceutical composition of the present invention will vary, depending on the severity of the disease being treated and the condition and potential idiosyncratic response of each individual patient. It is contemplated that the duration of each application of the compounds of the present invention will be in the range of 12 to 24 hours of continuous intravenous administration. Ultimately the attending physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the present invention.
  • Indol-2-carboxylic acid ethyl ester I is converted to aldehyde II in two steps: reduction with lithium aluminum 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 aluminum hydride
  • THF tetrahydrofuran
  • an oxidizing reagent such as manganese dioxide in a solvent such as THF.
  • Deprotonation of aldehyde II with a strong base such as potassium hexamethyldisilyl amide (KHMDS) in THF followed by reaction with a chloroformate 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 converted to either trifluoromethyl ketone VII or to carboxylic acid IX in different procedures.
  • 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 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 substituted aniline in the presence of a carbodiimide such as dimethylaminopropyl ethylcarbodiimide hydrochlo ⁇ de (EDCI) in a suitable solvent such as dichloromethane affords amide XI XI is hydrolyzed to corresponding acid XII in a aqueous base such as sodium hydroxide
  • Indole I can be brominated on the 3-pos ⁇ t ⁇ on by reaction with a bromine or N- bromosucci ⁇ imide in a suitable solvent such ascarbon tetrachlo ⁇ de or dichloromethane to yield bromide XIII
  • 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 t ⁇ ethyl amine produces 3-subst ⁇ tuted indole XV
  • XV can be converted to amide XVII in two step reactions ( 1 ) hydrolysis with aqueous base such as NaOH and (2) coupling with an amine 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
  • Indole I can be converted to XXI in two steps ( 1 ) reduction with LAH in a solvent such as
  • Aldehyde II prepared by Method A, 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 hydnde or KHMDS in a solvent such as DMF to yield XXV
  • XXV can be converted to an unsaturated acid XXVI by two steps (1 ) Wittig reaction with a suitable reagent such as t ⁇ methyl phosphonoacetate in the presence of a base such as sodium hydnde in a solvent such as THF and (2) Hydrolysis by aqueous sodium hydroxide Coupling reaction of XXVI with an amine catalyzed by a dnmide such as EDCI (dimethylaminopropyl ethylcarbodnmide hydrochlo ⁇ de), followed by hydrolysis with aqueous base such as sodium hydroxide affords XX
  • Indole I is reduced with LAH in a solvent such as THF A second reduction with sodium cyanoborohyd ⁇ de in a solvent such as acetic acid to yield alcohol XXVIII Protection of the nitrogen of XXVIII with t-butoxycarbonyl (BOC) using di-t-butyldicarbonate ((BOC) 3 0) in the presence of a base such as tnethylamine affords carbamate XXIX The hydroxyl group in XXIX is mesylated using mesyl chlo ⁇ de and tnethylamine in a solvent such as dichloromethane, and then displaced by either a thiol or an alcohol as desc ⁇ bed in
  • XXXI is either acylated (acyl chlo ⁇ de, tnethylamine, dichloromethane) or alkylated (alkyl ha de, K 2 CO DMF) to afford XXXII, or XXXIII respectively
  • Carboxylic acid XXXIV is converted to aldehyde XXXV in two steps ( 1) reaction with N.O-dimethylhydroxy 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 phosphonoacetate in the presence of a strong base such as KHMDS in a solvent such as THF results in the formation of ester XXXVI.
  • Reduction of XXXVI with tin in hydrogen chloride, followed by cyclization in a heated inert solvent such as toluene gives XXXVII.
  • 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 NaHCO, 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 alkylated using alkyl halide in the presence of K- j CO, in a solvent such as DMF to produce alcohol XLIV.
  • a base such as triethyl amine or alkylated using alkyl halide in the presence of K- j CO
  • a solvent such as DMF
  • METHOD J illustrates the synthesis of alpha-substituted aminophenylacetic acid esters
  • Ester L can be deprotonated with a strong base such as lithium dnsobutylamide (LDA) in a solvent such as THF, and subsequently alkylated with an alkyl halide such as methyl iodide to give LI
  • 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 oxazindine 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 converted to amide LVI by the following steps' (1) reaction with oxalyl chlo ⁇ de in dichloromethane to form acid chlo ⁇ de 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 desc ⁇ bed 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 TBDMSCI in the presence of lmidazole and subsequently, reduction of the nitro group (H 2 / Pd-C) to the amine affords LIX LVIII can be converted to the secondary alcohol LX in two steps.
  • Alcohol LXrV prepared in METHOD I, can be debenzylated by hydrogenolysis catalyzed by palladium on carbon in a solvent such as ethanol
  • a solvent such as ethanol
  • the resulting alcohol is treated with p-methoxybenzyl chlo ⁇ de in the presence of K 2 C0 3 in a solvent such as THF to afford
  • LXV Alcohol LXV can be transformed into ether or sulfide LXVI by the procedures desc ⁇ bed 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 K-.CO, in a solvent such as THF affords LXVII
  • Step 3 Benzyl (l -(2-hvdroxymethyl-5-phenylmethoxy)indolyl)formate
  • Step 4 Benzyl ( 1 -(2-bromomethyl-5-phenylmethoxy)indolyl)formate
  • Step 5 Benzyl (l-(2-(2-formylphenoxy)methyl-5-phenylmethoxy)indolyl)formate
  • Step 1 Benzyl ( l -(2-(2-(l -hvdroxy-2.2.2-tnfluoroethyl)phenoxy)methyl-5- phenylmetho ⁇ y) ⁇ ndolyl)-formate
  • step 2 l -(3-d ⁇ methylam ⁇ nopropyl)-3- ethylcarbodiimide (EDCI) (0.32 g, 1.66 mmol), 4-d ⁇ methylam ⁇ nopy ⁇ dme (DMAP) (0.018 g, 0.15 mmol) and ethyl 3-am ⁇ nobenzoate (0.27 g, 1.66 mmol) were stirred in tetrahydrofuran (9 mL) at room temperature overnight The next day the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), d ⁇ ed over magnesium sulfate and concentrated.
  • EDCI l -(3-d ⁇ methylam ⁇ nopropyl)-3- ethylcarbodiimide
  • DMAP 4-d ⁇ methylam ⁇ nopy ⁇ dme
  • ethyl 3-am ⁇ nobenzoate 0.27 g, 1.66 mmol
  • Ethyl 5-methoxy-2- ⁇ ndolcarboxylate (30 g, 102 mmol) is dissolved in 250 mL of THF and cooled to 0° C and Lithium Aluminum Hydnde (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 dned over MgSOj and concentrated to yield 24 8 g of alcohol, which was used for the next reaction directly
  • Step 4 3-(2-tert-butvd ⁇ methyls ⁇ lyloxymethyl-5-methoxy- l -methyl) ⁇ ndolyl (2,4-b ⁇ s( l , l - dimethvpropyl)phenoxy)methyl ketone
  • Step 6 Methyl 3-(2-(3-(2.4-bis(l ,l -dimethvpropyl)phenoxy)acetyl-5-methoxy-l - methylindolyl)methylthioacetamido)-4-methoxybenzoate
  • the indole alcohol, prepared in step 5, (0.20 g, 0.43 mmol) was dissolved in dichloromethane (0.7 mL) and treated with tnethylamine (0.1 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.
  • T e reaction was stined for a further 2 hour at 0°C, it was then concentrated and used directly for the next reaction.
  • the above prepared mesylate was dissolved in DMF (0.8 mL). The solution was degassed by bubbling nitrogen through for ten min.
  • the carbamate, prepared in step 2 ( 15.25 g, 43 mmol) was dissolved in dichloromethane (180 mL) and treated with tnethylamine (9.0 mL, 64 4 mmol). The solution was cooled to -10° C at which time mesyl chlonde (4.3 mL. 56 mmol) was added over 5 minutes The reaction was stined for a further 2 hour at -10 °C, it was then concentrated and used directly for the next displacement reaction
  • Step 4 2-(5-Benzyloxy-l -tert-butoxycarbonyl) ⁇ ndol ⁇ nylmethylth ⁇ oacet ⁇ c acid
  • Step 7 Ethyl 3-f 2-f 5-benzyloxy- 1 -(2.4-bis( 1.1 - dimethyl)propyl)phenoxyacetyl)indolinv ⁇ methylthioacetamidobenzoate
  • step 7 The ester (0.231 g, 0.31 mmol) of step 7 was dissolved in THF (4.3 mL), methanol (4.3 L) and than IN NaOH (3.2 mL) was added.
  • N-tert-butoxycarbonyl indoline (3 0 g, 6 6 mmol), prepared in step 3 of Example 17, was added to a flask and cooled to 0 °C
  • t ⁇ fluoroacetic acid was added (35 mL) and the reaction was stired for 1 hour at 0 °C and then 1 hour at rt
  • the reaction was quenched by the addition of water, and the TFA was neutralized by the addition of solid sodium bicarbonate, the aqueous layer was extracted with ethyl acetate (4X) and dned over magnesium sulfate and concentrated to an orange oil (1.85 g, 79%) that was used directly for the next step
  • Step 2 Ethyl 2-(5-benzyloxy-l -(2.4-b ⁇ s(l , l -d ⁇ methv) ⁇ ropyl)phenoxyacetyl)- indolinylmethylthioacetate
  • Step 4 Methyl 3-(2-(5-benzyloxy- l -(2,4-b ⁇ s( 1.1- d ⁇ methv)propyl)phenoxyacetvh ⁇ ndol ⁇ nyl) methylth ⁇ oacetam ⁇ do-4-methylbenzoate
  • the titled compound was prepared from ester, prepared in step 4, according to the procedure desc ⁇ bed in step
  • Step 1 2-(5-Benzyloxy- 1 -(3.5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methanol
  • Step 2 Ethyl 2-(5-benzyloxy-l -(3.5-bis(trifluoromethyl)phenoxyacetyl)indolinyl) methylthioacetate
  • the titled compound was prepared according to the procedure desc ⁇ bed in step 2 of Example 38
  • Step 1 2-(5-Hvdroxy- 1 -(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methanol
  • Step 2 2-(5-(4-Methoxy)benzyloxy-l -(3.5- bis(trifluoromethyl)phenoxyacetv ⁇ indolinyl)methanol
  • Step 3 Methyl 5-(2-(-5-(4-methoxy)benzyloxy- l -(3.5-bis(trifluoromethyl)phenoxyacetyl) indolinyl)methylthioacetamido)benzene- 1.3-dicarboxylate
  • the reaction mixture was heated at 70 °C for 2 h.
  • the reaction mixture was partitioned between AcOEt (30 mL) and H 2 0 (20 mL)
  • the aqueous layer was extracted with AcOEt (3 x 30 mL).
  • the combined AcOEt extracts were washed with b ⁇ ne (50 mL), d ⁇ ed over Na 2 S0 and filtered.
  • the solvents were removed in vacuo. Punfication of the residue by column chromatography on silica gel using 15% EtOAc in dichloromethane afforded 0 20 g of the product (77%)
  • the titled compound was prepared from the ester, prepared in step 1 , according to the procedure desc ⁇ bed in step 5 of Example 44
  • Step 1 Methyl 3-(2-(5-benzyloxyindolinvPmethylthioacetamido)-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-(2-(5-benzyloxy-l -(2-naphthoxyacetvPindolinvPmethylthioacetarnido)- 4-methoxybenzoate
  • Step 1 Ethyl 3-(2-(5-benzyloxy- l -tert-butoxycarbonyl) ⁇ ndol ⁇ nyl)methylsulfonyl acetamidobenzoate
  • the titled compound was prepared according to the procedure desc ⁇ bed in step 3 of Example 59
  • Step 1 5-Benzyloxy- 1 -(2.4-b ⁇ s( 1 , 1 -d ⁇ methv)propy PphenoxyacetvP-2- hvdroxymethylindohne
  • Step 2 2-(5-Benzyloxy- 1 -(2.4-b ⁇ s( 1.1 -d ⁇ methv)propyPphenoxyacetvP ⁇ ndol ⁇ nylmethyl methylsulfonate
  • the titled compound was prepared according to the procedure desc ⁇ bed in step 3 of Example 59.
  • EXAMPLE 68 was prepared according to the procedures desc ⁇ bed in Example 67
  • reaction mixture was st ed at 25 °C for 1 5 h to afford a pale suspension.
  • Methyl iodide 161 mg, 1.14 mmol was added, and the reaction mixture was stined at 25 °C for 2 days. After chilling to 0 °C, water was added ( 10 mL), followed by 50 L of half saturated ammonium chlonde, 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 d ⁇ ed (sodium sulfate), filtered, and concentrated to afford 0 6 g of crude product as an orange oil.
  • EXAMPLE 71 was prepared according to the procedures desc ⁇ bed in Example 70. but using allyl bromide.
  • the titled compound was prepared according to the procedure descnbed in step 3 of Example 59.
  • Step 1 Ethyl 3-(2-(5-benzyloxy-l -(2- naphthvPmethv) ⁇ ndol ⁇ nyl)methylth ⁇ oacetam ⁇ dobenzoate
  • the titled compound was prepared according to the procedure described in step 3 of Example 59.
  • Step 1 2-(2-(-5-Benzyloxy- 1 -( 1.1 -dimethvPethoxycarbonvPindolinyl )methyl methylsulfonate
  • tert-Butyl l -(5-benzyloxy-2-hydroxymethy)lindolinylformate (6.72 g, 19 mmol), prepared in step 2 of Example 17, was dissolved in CH 2 C1 (80 mL, dried over MgS0 4 before use). The clear yellow solution was cooled in a dry-ice bath. Et,N (4.0 mL) was then added followed by methanesulfonyl chloride (2.0 mL). The reaction mixture was stined for 2 h at -40 °C then quenched with H 2 0. It was washed with satuarated NaHC0 3
  • Step 2 Methyl 2-(2-(5-Benzyloxy-l-(l .l-dimethyl)ethoxycarbonvPindolinvPmethylthio benzoate
  • Step 4 Methyl 2-(2-(5-Benzyloxy- l -(4-benzvPbenzvPindolinyl)methylthiobenzoate
  • ester ( 1 g), prepared in step 3 was dissolved in
  • Step 2 Methyl 4-( l -(5-Benzyloxy-2-(b ⁇ s-2,4-tnfluoromethyl)ben7yloxymethyl) ⁇ ndol ⁇ nyl) methylbenzoate
  • the titled compound was prepared according to the prodedure desc ⁇ bed in step 5 of Example 76
  • Step 1 2-(l -(2.4-Bis(trifluoromethvPbenzyl)indolinyl)carboxylic acid
  • N-Methylsulfonyl-2-(l -(2.4-bis(trifluoromethvPbenzvPindol ⁇ nyl)carboxamide The acid (0 13g, 0 32 mmol), prepared in step 1 of Example 83, EDCI (0 07 g, 0 39 mmol), DMAP (4 mg, 0.03 mmol) and methylsuifonanihde (004 g, 0 39 mmol) were dissolved THF (5 mL) and refluxed 16 hours which yielded after workup (0 16 g), punfication via Chromatography (98 2 dichloromethane methanol) yielded 0 04 g of the titled compound (29%)
  • the titled compound was prepared according to the prodedure desc ⁇ bed in Example 84, but using phenylsulfonylamide
  • Step 3 2-Trimethylsilylethyl l -(5-(4-methoxy)benzyloxy-2- hvdroxymethvPindolinylformate
  • Step 4 2-Trimethylsilylethyl l -(5-(4-methoxy)benzyloxy-2- bromomethvPindolinylformate
  • Step 6 2-Trimethylsilylethyl l -(5-(4-methoxy)benzyloxy-2- aminomethvDindolinylformate
  • Step 7 Methyl 5-(2-(5-Methoxybenzyloxy- l -(2- trimethylsilyloxy)ethoxycarbonv)lindolinyl) methylaminocarboxamido-1.3- benzenedicarboxylate
  • Step 9 Methyl 5-(2-(5-Methoxybenzyloxy- l -(b ⁇ s-2.4-tnfluoromethyl)benzvP ⁇ ndol ⁇ nvP eth ylaminocarboxamido- 1.3-benzened ⁇ carboxylate
  • EXAMPLE 87 was prepared according to the prodedure desc ⁇ bed in Example 86. but using 4-(3,5-b ⁇ s(tnfluoromethyl)phenoxymethyl)benzyl bromide.
  • Step 1 B ⁇ s(methyl 4-methoxy-3-d ⁇ th ⁇ oacetam ⁇ dobenzoate)
  • the titled compound was synthesized according to the procedures desc ⁇ bed in
  • the reaction mixture was cooled to -78°C again and added 4-methoxyphenylacet ⁇ c acid (50 g, 0.28 mol) dropwise via the dropping funnel After stirnng at -50 °C for 1 h., the reaction mixture was allowed to warm to -30 °C over 20 min and then cooled to -50 °C again The reaction mixture was quenched with H 2 0 (500 mL) at -50 °C and warmed up to room temperature and stmed for 0 5 h The reaction mixture was partitioned between CH 2 C1 2 (500 mL) and H,0 The aqueous layer was extracted with CH,CI, (3 x 500 mL) The combined CH 2 C1 2 extracts were concentrated in vacuo to give a yellow oil This was added slowly to a 2 M solution of NaOH (2 L) cooled at 0 °C and stined at room temperature overnight The reaction mixture was partitioned between CH 2 CL (500 mL) and H 2 0 The aqueous layer was
  • a 10-mL oven-dned round bottom flask fitted with a magnetic stimng bar was charged with alcohol (0.30 g, 1.24 mmol), prepared in step 2, Ag 2 0 (0 68 g, 3.0 mmol) and toluene (3 mL). To this was added CH,I (0.36 g, 5 75 mmol) dropwise. The reaction flask was capped tightly and placed into a sonication chamber. The reaction mixture was sonicated for 18 h while stirnng at room temperature.
  • reaction mixture was filtered through Celite and concentrated in vacuo to dryness
  • residue was pu ⁇ fied by column chromatography on silica gel (eluant: 30% AcOEt in hexane) to afford desired product Yield 0.26 g (82%).
  • reaction flask was placed under vacuum via the water aspirator and subsequently filled with H 2 This was repeated three times The reaction mixture was stmed for 18 hours under positive H 2 pressure until all starting matenal was reacted The reaction mixture was filtered through Cehte and concentrated in vacuo to dryness The residue was punfied by column chromatography on silica gel using 10% ethyl acetate in dichloromethane to afford the titled compound (0.57 g, 97%)
  • the titled compound was prepared from nitro compound, prepared in step 1 of Intermediate 3, according to the procedure desc ⁇ bed in step 4 of Intermediate 3 INTERMEDIATE 6
  • the reaction mixture was partitioned between CH 2 C1 2 (50 L) and H 2 0 (50 mL)
  • the aqueous layer was extracted with CH 2 C1, (3 x 50 mL).
  • the combined CH 2 C1 2 extracts were washed with b ⁇ ne (50 mL), d ⁇ ed over Na 2 S0 4 and filtered.
  • the solvents were removed in vacuo. Punfication by column chromatography on silica gel (eluant: 30% AcOEt in hexane) afforded 0 7 g of product (58%).
  • the titled compound was prepared from nitro compound, prepared in step 1 , according tothe procedure descnbed in step 4 of Intermediate 3.
  • This compound was synthesized form ester, prepared in step 1 of Intermediate 3, according to the procedure descnbed in step 1 of Intermediate 6, but using allyl bromide.
  • the titled compound was prepared from 4-benzylphenol according to the procedure descnbed in of Intermediate 8.
  • the titled compound was prepared from 2-naphthol according to the procedure desc ⁇ bed in of Intermediate 8.
  • the titled compound was prepared from 3,5-b ⁇ s(t ⁇ fluoromethyl)phenol according to the procedure desc ⁇ bed in of Intermediate 8.
  • Step 1 Methyl 5-n ⁇ tro-3-(N.N-d ⁇ methvPcarbamoylbenzoate
  • a 100-mL oven-dned round bottom flask fitted with a magnetic stimng bar was charged with 5-mtro-3-methoxycarbonylbenzo ⁇ c acid (3.15 g, 10 mmol), DMF ( 1 drop), anhydrous CH 2 C1 2 (70 L), and oxalyl chlonde (3.7 mL, 42.3 mmol).
  • the reaction mixture was stined at room temperature for 2 h.
  • the solvent was removed in vacuo to afford acid chlo ⁇ de as a white solid. This was used immediately in the next step without further punfication.
  • the titled compound was prepared from nitro compound, prepared in step 1 , according to the procedure desc ⁇ bed in step 4 of Intermediate 3.
  • the titled compound was prepared from nitro compound, prepared in step 1 , according to the procedure desc ⁇ bed 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 B ⁇ s-( methyl 4-methoxy-3-(2-dith ⁇ oethyl)am ⁇ nobenzoate
  • a typical assay consisted of the lipid mixture (85 ⁇ l) to which was added consecutively, the inhibitor (5 ⁇ l in DMSO) and cPLA 2 , 10 ng for an automated system or 1 ng for a manual assay, in lO ⁇ l of the BSA buffer. 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, 150 ⁇ l). A portion of the quench layer (50 ⁇ l) was passed through a Rainin Spheric-5 silica column
  • 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 scintillation proximity assay provided by
  • RBL-2H3 cells were routinely cultured as 37°C in a 5% C0 2 atmosphere in minimal essential medium containing nonessential amino acids and 12% fetal calf serum The day before the expenment, cells were seeded into spinner flasks at 3 x ⁇ 0 cells/ml and 100 ng/ml DNP specific-IgE was added After 20 hrs, the cells were harvested by centnfugation and washed once in serum-free minimal essential media, and resuspended to 2 x 10 6 ceils/ml in serum free media The cells were then premcubated 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 centnfugation, and the supernatant was assayed for PGD 2 content in accordance with known methods

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

Composés ayant une formule chimique sélectionnée dans le groupe composé de (I), (II) et de (III) ou leur sel pharmaceutiquement acceptable, où: A est indépendant de tout autre groupe et a été sélectionné dans le groupe composé de -CH2- et de -CH2-CH2-; B est indépendant de tout autre groupe et a été sélectionné dans le groupe constitué par -(CH2)n-, -(CH2O)n-, -(CH2S)n-, -(OCH2)n-, -(SCH2)n-, -(CH=CH)n-, -(C C)n-, -CON(R6)-, -N(R6)CO-, -O-, -S- et -N(R6)-; R2 est indépendant de tout autre groupe R et a été sélectionné dans le groupe constitué par -H, -COOH, COR5, -CONR5R6, -(CH2)n-W-(CH2)m-Z-R5-, -(CH2)n-W-R5-, -Z-R5-, alkyle C1-C10, alcényle et aryle substitué; R3 est indépendant de tout autre groupe R et a été sélectionné dans le groupe constitué par -H, -COOH, COR5, -CONR5R6, -(CH2)n-W-(CH2)m-Z-R5-, -(CH2)n-W-R5-, -Z-R5-, alkyle C1-C10, alcényle et aryle substitué. Lesdits composés inhibent l'activité des enzymes phospholipases, notamment de la phospholipase cytosolique A2. L'invention décrit également des compositions pharmaceutiques comprenant lesdits composants et des méthodes de traitement les utilisant.
PCT/US1997/014943 1996-08-26 1997-08-26 Inhibiteurs des enzymes phospholipases WO1998008818A1 (fr)

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JP10511798A JP2000516958A (ja) 1996-08-26 1997-08-26 ホスホリパーゼ酵素の阻害剤
EP97938589A EP0922028A1 (fr) 1996-08-26 1997-08-26 Inhibiteurs des enzymes phospholipases
AU40882/97A AU717430B2 (en) 1996-08-26 1997-08-26 Inhibitors of phospholipase enzymes

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EP0922028A1 (fr) 1999-06-16

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