Patent Application: US-201013378385-A

Abstract:
the invention relates to compounds of formula , formula , formula and formula , and pharmaceutically acceptable salts thereof for the treatment of cancer , inflammation , auto - immune diseases , diabetes and diabetic complications , infection , cardiovascular disease and ischemia - reperfusion injuries .

Description:
the terms used to describe the present invention have the following meanings herein . the compounds and intermediates of the present invention may be named according to either the iupac ( international union for pure and applied chemistry ) or cas ( chemical abstracts service ) nomenclature systems . the carbon atom content of the various hydrocarbon - containing moieties herein may be indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety , for example , the prefix ( ca - cb ) alkyl indicate an alkyl moiety of the integer “ a ” to “ b ” carbon atoms , inclusive . thus , for example , ( c1 - c6 ) alkyl refers to an alkyl group of one to six carbon atoms inclusive . the term “ alkyl ” denotes a straight or branched chain of carbon atoms with only hydrogen atom substituents , wherein the carbon chain optionally contains one or more double or triple bonds , or a combination of double bonds and triple bonds . examples of alkyl groups include , but are not limited to , methyl , ethyl , propyl , isopropyl , propenyl , propynyl , hexadienyl , and the like . the term “ alkoxy ” refers to straight or branched , monovalent , saturated aliphatic chains of carbon atoms wherein one of the carbon atoms has been replaced with an oxygen atom . examples of alkoxy groups include , but are not limited to , methoxy , ethoxy and iso - propoxy . the term “ cycloalkyl ” refers to saturated and unsaturated nonaromatic monocyclic or bicyclic ring systems containing only carbon atoms as ring atoms . examples of cycloalkyl groups include , but are not limited to , cyclopropyl , cyclobutyl , cyclopentyl and cyclohexenyl . cycloalkyl groups may also be optionally fused to aryl rings such as , for example , but not limited to , benzene to form fused cycloalkyl groups , such as indanyl and the like . the term “ heteroalkyl ” refers to saturated and unsaturated nonaromatic monocyclic or bicyclic ring systems containing from 1 to 4 heteroatoms as ring atoms . examples of heteroalkyl groups include , but are not limited to , pyrrolidinyl , piperidinyl , piperazinyl , tetrahydrofuranyl , dioxanyl and morpholinyl . heteroalkyl groups may also be optionally fused to aryl rings such as , for example , but not limited to benzene to form fused heteroalkyl groups , such as dihydroindolyl and the like . the term “ aryl ” refers to aromatic monocyclic and bicyclic rings systems containing only carbon atoms as ring atoms . examples include , but are not limited to , phenyl and naphthyl . the term “ heteroaryl ” refers to aromatic monocyclic and bicyclic ring systems containing from 1 to 5 heteroatoms as ring atoms . examples include pyrrolyl , furanyl , thienyl , imidazolyl oxazolyl , isoxazolyl , thiazolyl , isothiazolyl , pyrazolyl , 1 , 2 , 3 - triazolyl , 1 , 2 , 5 - thiadiazolyl , 1 , 2 , 3 - thiadiazolyl , 1 , 2 , 3 - oxadiazolyl , 1 , 2 , 5 - oxadiazolyl , pyridinyl , pyrimidinyl , pyrazinyl , pyridazinyl , triazinyl , benzofuranyl , isobenzofuranyl , benzothienyl , isobenzothienyl , indolizinyl , indolyl , isoindolyl , benzoxazolyl , benzimidazolyl , indazolyl , benzisoxazolyl , benzisothiazolyl , benzopyrazolyl , benzoxadiazolyl , benzothiadiazolyl , benzotriazolyl , quinolinyl , isoquinolinyl , cinnolinyl , quinolizinyl , phthalazinyl , quinoxalinyl , quinazolinyl , naphthyridinyl , pteridinyl , pyrrolopyridinyl , thienopyridinyl , furanopyridinyl , isothiazolopyridinyl , thiazolopyridinyl , isoxazolopyridinyl , oxazolopyridinyl , pyrazolopyridinyl , imidazopyridinyl , pyrrolopyrazinyl , thienopyrazinyl , furanopyrazinyl , isothiazolopyrazinyl , thiazolopyrazinyl , isoxazolopyrazinyl , oxazolopyrazinyl , pyrazolopyrazinyl , imidazopyrazinyl , pyrrolopyrimidinyl , thienopyrimidinyl , furanopyrimidinyl , isothiazolopyrimidinyl , thiazolopyrimidinyl , isoxazolopyrimidinyl , oxazolopyrimidinyl , pyrazolopyrimidinyl , imidazopyrimidinyl , pyrrolopyridazinyl , thienopyridazinyl , furanopyridazinyl , isothiazolopyridazinyl , thiazolopyridazinyl , isoxazolopyridazinyl , oxazolopyridazinyl , pyrazolopyridazinyl , imidazopyridazinyl , oxadiazolopyridinyl , thiadiazolopyridinyl , triazolopyridinyl , oxadiazolopyrazinyl , thiadiazolopyrazinyl , triazolopyrazinyl , oxadiazolopyrimidinyl , thiadiazolopyrimidinyl , triazolopyrimidinyl , oxadiazolopyridazinyl , thiadiazolopyridazinyl , triazolopyridazinyl , isoxazolotriazinyl , isothiazolotriazinyl , pyrazolotriazinyl , oxazolotriazinyl , thiazolotriazinyl , imidazotriazinyl , oxadiazolotriazinyl , thiadiazolotriazinyl , triazolotriazinyl , carbazolyl and the like . the term “ alkylaryl ” refers to an alkyl group substituted by an aryl group . the term “ alkylheteroaryl ” refers to an alkyl group substituted by a heteroaryl group . the term “ substituted ” refers to a hydrogen atom on a molecule that has been replaced with a different atom or molecule . the atom or molecule replacing the hydrogen atom is denoted as a “ substituent .” the phrase “ therapeutically effective amount ” refers to an amount of a compound that ( i ) treats or prevents the particular disease , condition , or disorder , ( ii ) attenuates , ameliorates , or eliminates one or more symptoms of the particular disease , condition , or disorder , or ( iii ) prevents or delays the onset of one or more symptoms of the particular disease , condition . the phrase “ pharmaceutically acceptable ” indicates that the designated carrier , vehicle , diluent , excipient ( s ), and / or salt is generally chemically and / or physically compatible with the other ingredients comprising the formulation , and physiologically compatible with the recipient thereof . the term “ mammal ” relates to an individual animal that is a member of the taxonomic class mammalia . examples of mammals include , but are not limited to , humans , dogs , cats , horses and cattle . in the present invention , the preferred mammal is a human . in an exemplary embodiment , the compounds of the present invention have the structure shown in any one of formula ( v ), formula ( vi ), formula ( vii ) and formula ( viii ). the compounds of the invention may be resolved into their pure enantiomers by methods known to those skilled in the art , for example by formation of diastereoisomeric salts which may be separated , for example , by crystallization ; formation of diastereoisomeric derivatives or complexes which may be separated ( for example , by crystallization , gas - liquid or liquid chromatography ); selective reaction of one enantiomer with an enantiomer - specific reagent ( for example , enzymatic esterification ); or gas - liquid or liquid chromatography in a chiral environment , for example , on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent . it will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above , a further step is required to liberate the desired enantiomeric form . alternatively , the specific stereoisomers may be synthesized by using an optically active starting material , by asymmetric synthesis using optically active reagents , substrates , catalysts or solvents , or by converting one stereoisomer into the other by asymmetric transformation . wherein the compounds contain one or more additional stereogenic centers , those skilled in the art will appreciate that all diastereoisomers and diastereoisomeric mixtures of the compounds illustrated and discussed herein are within the scope of the present invention . these diastereoisomers may be isolated by methods known to those skilled in the art , for example , by crystallization , gas - liquid or liquid chromatography . alternatively , intermediates in the course of the synthesis may exist as racemic mixtures and be subjected to resolution by methods known to those skilled in the art , for example by formation of diastereoisomeric salts which may be separated , for example , by crystallization ; formation of diastereoisomeric derivatives or complexes which may be separated , for example , by crystallization , gas - liquid or liquid chromatography ; selective reaction of one enantiomer with an enantiomer - specific reagent , for example , enzymatic esterification ; or gas - liquid or liquid chromatography in a chiral environment , for example , on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent . it will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above , a further step is required to liberate the desired enantiomeric form . alternatively , the specific stereoisomers may be synthesized by using an optically active starting material , by asymmetric synthesis using optically active reagents , substrates , catalysts or solvents , or by converting one stereoisomer into the other by asymmetric transformation . these methods are described in more detail in texts such as “ chiral drugs ”, cynthia a . challener ( editor ), wiley , 2002 or “ chiral drug separation ” by bingyunh li and donald t . haynia in “ encyclopedia of chemical processing ” by sunggyu lee and lee lee ( editors ), crc press , 2005 . the compounds of the present invention , and the salts thereof , may exist in the unsolvated as well as the solvated forms with pharmaceutically acceptable solvents such as water , ethanol , and the like . selected compounds of formulas ( i )-( viii ) and their salts and solvates may exist in more than one crystal form . polymorphs of compounds represented by formulas ( i )-( viii ) form part of this invention and may be prepared by crystallization of a compound of formulas ( i )-( viii ) under different conditions . for example , using different solvents or solvent mixtures for recrystallization ; crystallization at different temperatures ; various modes of cooling , ranging from very fast to very slow cooling during crystallization . polymorphs may also be obtained by heating or melting a compound of formulas ( i )-( viii ) followed by gradual or fast cooling . the presence of polymorphs may be determined by solid state nmr spectroscopy , ir spectroscopy , differential scanning calorimetry , powder x - ray diffraction or other such techniques . this invention also includes isotopically - labeled compounds , which are identical to those described by formulas ( i )-( viii ), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature . examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen , carbon , nitrogen , oxygen , sulfur and fluorine , such as 2 h , 3 h , 13 c , 14 c , 15 n , 18 o , 17 o , 35 s , 36 cl , 125 i , 129 i and 18 f respectively . compounds of the present invention and pharmaceutically acceptable salts of the compounds which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention . certain isotopically - labeled compounds of the present invention , for example those into which an isotope such as 2 h ( deuterium ) are incorporated can afford certain therapeutic advantage resulting from greater metabolic stability , for example , increased in vivo half life or reduced dosage requirements and , hence , may be preferred in some circumstances . isotopically labeled compounds of formulas ( i )-( viii ) of this invention , salts and solvates thereof can generally be prepared by carrying out procedures disclosed in the schemes and / or in the examples below , by substituting a readily available isotopically labeled reagent for a non - isotopically labeled reagent . pharmaceutically acceptable salts , as used herein in relation to compounds of the present invention , include pharmaceutically acceptable inorganic and organic salts of said compounds . these salts can be prepared in situ during the final isolation and purification of a compound , or by separately reacting the compound with a suitable organic or inorganic acid and isolating the salt thus formed . representative salts include , but are not limited to , the hydrobromide , hydrochloride , hydroiodide , sulfate , bisulfate , nitrate , acetate , trifluoroacetate , oxalate , besylate , camsylate , palmitate , malonate , stearate , laurate , malate , borate , benzoate , lactate , phosphate , hexafluorophosphate , benzene sulfonate , tosylate , formate , citrate , maleate , fumarate , succinate , tartrate , naphthylate , mesylate , glucoheptonate , lactobionate , and laurylsulphonate salts , and the like . compounds of the present invention may also react to form salts with pharmaceutically acceptable metal and amine cations formed from organic and inorganic bases . the term “ pharmaceutically acceptable metal cation ” contemplates positively charged metal ions derived from sodium , potassium , calcium , magnesium , aluminum , iron , zinc and the like . the term “ pharmaceutically acceptable amine cation ” contemplates the positively charged ions derived from ammonia and organic nitrogenous bases strong enough to form such cations . bases useful for the formation of pharmaceutically acceptable nontoxic base addition salts of compounds of the present invention form a class whose limits are readily understood by those skilled in the art . ( see , for example , berge , et “ pharmaceutical salts ,” j . pharm . sci ., 66 : 1 - 19 ( 1977 )). the term “ prodrug ” is intended to refer to a compound that is transformed in vivo to yield a compound of formula ( i ) or a pharmaceutically acceptable salt or solvate of the compound . this transformation may occur by various mechanisms , such as , for example , through hydrolysis in blood . a prodrug of a compound of formulas ( i )-( viii ) may be formed , for example , in a conventional manner from functional groups such as with an amino , hydroxy or carboxy . a discussion of the use of prodrugs is provided by t . higuchi and w . stella , “ pro - drugs as novel delivery systems ,” vol . 14 of the a . c . s . symposium series , and in “ bioreversible carriers in drug design ”, ed . edward b . roche , american pharmaceutical association and pergamon press , 1987 . in an aspect of the invention , compounds ( i ) to ( viii ) are intended to serve as prodrugs for dhmeq . however , because each of these compounds also contains a “ nh ” moiety which may be further derivatized , the invention also includes prodrugs of the compounds of formulas ( i ) to ( viii ) resulting from such derivatization . in addition , compounds ( i ), ( iv ), ( v ) and ( viii ) contain a hydroxy ( oh ) moiety which may also be derivatized to create additional prodrugs . in general , compounds of the present invention may be prepared by the general synthetic methods outlined in reaction schemes 1 - 5 . these methods are simply illustrative of particular embodiments and are not intended to further limit the invention . compound 1 was prepared according to the method of umezawa ( suzuki , y . ; sugiyama , c . ; ohno , o . ; umezawa , k . : tetrahedron ( 2004 ), 60 , 7061 - 7066 . the reaction of compound ( 1 ) with an acid chloride ( r 1 cocl ) in a solvent such as , for example , but not limited to , acetone or tetrahydrofuran with a base such as , for example , but not limited to , potassium carbonate or pyridine gives the esters ( 2 ) or ( 3 ). the production of either compound ( 2 ) or ( 3 ) is dependent upon the stoichiometry of the acid chloride employed : one equivalent produces the mono - ester ( 2 ) while two equivalents produce the bis - esters ( 3 ) as shown in scheme 1 . the reaction of compound ( 1 ) with an acid chloride ( r 1 cocl ) in a solvent such as , but not limited to tetrahydrofuran with a base such as , for example , but not limited to , sodium hydride gives the ester ( 4 ). the reaction of compound ( 1 ) with chloroformates ( r 1 ococl ) in a solvent such as , for example , but not limited to , tetrahydrofuran with a base such as , for example , but not limited to , pyridine gives the carbonates ( 5 ) or ( 6 ). the production of either compound ( 5 ) or ( 6 ) is dependent upon the stoichiometry of the chloroformate employed : one equivalent produces the mono - carbonate ( 5 ) while two equivalents the bis - carbonates ( 6 ) as shown in scheme 2 . the reaction of compound ( 1 ) with a chloroformate ( r 1 ococl ) in a solvent such as , for example , but not limited to , tetrahydrofuran with a base such as , for example , but not limited to , potassium carbonate gives the carbonate ( 7 ). the reaction of compound ( 1 ) with isocyanates ( r 1 nco ) in a solvent such as , for example , but not limited to , dichloromethane with a catalytic amount of a base such as , for example , but not limited to , triethylamine gives the carbamates ( 8 ) or ( 9 ). the production of either compound ( 8 ) or ( 9 ) is dependent upon the stoichiometry of the isocyanate employed : one equivalent produces the mono - carbamate ( 8 ) while two equivalents produce the bis - carbamates ( 9 ) as shown in scheme 3 . the reaction of compound ( 1 ) with an isocyanate ( r 1 nco ) in a solvent such as , for example , but not limited to , tetrahydrofuran gives the carbamate ( 10 ). the reaction of compound ( 1 ) with a phosphorylating agent such as , for example , but not limited to , clp ( o )( och 3 ) 2 in a solvent such as , for example , but not limited to , tetrahydrofuran with a base such as , for example , but not limited to , triethylamine gives the phosphate ester ( 11 ) which can be further hydrolyzed to ( 12 ) using , for example , but not limited to , tms - br in a solvent such as , for example , but not limited to , dichloromethane as shown in scheme 4 . the reaction of compound ( 1 ) with , for example , but not limited to , an alkylcarbonyloxymethyl iodide r 1 c ( o ) och 2 i , ( generated from the corresponding chloride , r 1 c ( o ) och 2 cl in a modified finkelstein reaction using sodium iodide in a mixed solvent of acetonitrile and dimethylformamide ), in the presence of , for example , but not limited to , 1 , 8 - bis ( dimethylamino ) naphthalene in , for example , but not limited to , dry acetonitrile gave compound ( 13 ). the use of two equivalents of alkylcarbonyloxymethyl iodide r 1 c ( o ) och 2 i gave the compounds ( 14 ). the reaction of compound ( 1 ) with , for example , but not limited to , an alkylcarbonyloxymethyl iodide r 1 c ( o ) och 2 i in a solvent such as , for example , but not limited to , tetrahydrofuran with a base such as , for example , but not limited to , sodium hydride gives compound ( 15 ) as shown in scheme 5 . a pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of formulas ( i ) to ( iv ), or a pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable carrier , vehicle , diluent or excipient . an exemplary embodiment of a pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of formulas ( v ) to ( viii ), or a pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable carrier , vehicle , diluent or excipient . the pharmaceutical compositions formed by combining the compounds of this invention and the pharmaceutically acceptable carriers , vehicles or diluents are then readily administered in a variety of dosage forms such as tablets , powders , lozenges , syrups , injectable solutions and the like . these pharmaceutical compositions can , if desired , contain additional ingredients such as flavorings , binders , excipients and the like . thus , for purposes of oral administration , tablets containing various excipients such as sodium citrate , calcium carbonate and / or calcium phosphate , may be employed along with various disintegrants such as starch , alginic acid and / or certain complex silicates , together with binding agents such as polyvinylpyrrolidone , sucrose , gelatin and / or acacia . additionally , lubricating agents such as magnesium stearate , sodium lauryl sulfate and talc are often useful for tabletting purposes . solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules . preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols . when aqueous suspensions of elixirs are desired for oral administration , the active pharmaceutical agent therein may be combined with various sweetening of flavoring agents , coloring matter or dyes and , if desired , emulsifying or suspending agents , together with diluents such as water , ethanol , propylene glycol , glycerin and / or combinations thereof . for parenteral administration , solutions of the compounds or compositions of this invention in sesame or peanut oil , aqueous propylene glycol , or in sterile aqueous solutions may be employed . such aqueous solutions should be suitably buffered if necessary and the liquid diluents first rendered isotonic with sufficient saline or glucose . these particular aqueous solutions are especially suitable for intravenous , intramuscular , subcutaneous and intraperitoneal administration . in this connection , the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art . in an exemplary embodiment , the pharmaceutical preparation is in unit dosage form . in such form , the preparation is subdivided into unit doses containing appropriate quantities of the active component . the unit dosage form can be a packaged preparation , for example , packeted tablets , capsules , and powders in vial or ampoules . the unit dosage form can also be a capsule , cachet , or tablet itself or it can be the appropriate number of any of these packaged forms . methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known to those skilled in the art . for examples of methods of preparing pharmaceutical compositions , see remington : the science and practice of pharmacy , lippincott , williams & amp ; wilkins , 21 st ed . ( 2005 ), which is incorporated by reference in its entirety . compound 1 was prepared according to the method of umezawa ( suzuki , y . ; sugiyama , c . ; ohno , o . ; umezawa , k . : tetrahedron ( 2004 ), 60 , 7061 - 7066 . the 1 hnmr spectrum was consistent with that reported in the umezawa reference . in a 20 gram vial , compound 1 ( 100 mg , 0 . 383 mmol ) and potassium carbonate ( 117 mg , 0 . 843 mmol ) were suspended in acetone ( 5 ml ). the reaction mixture was cooled to 0 ° c . and then iso - valeryl chloride ( 0 . 050 ml , 0 . 421 mmol ) was added . the reaction mixture was stirred at 0 ° c . for 1 hour and then at 5 - 10 ° c . for 1 hour . the mixture was filtered and then concentrated and the residue was purified via silica gel chromatography ( 40 % ethyl acetate in heptanes ). the desired product was isolated as a white solid ( 39 mg , 30 %). the product structure was confirmed by 1 hnmr ( cdcl 3 ): δ 8 . 90 ( s , ih ), 7 . 85 ( m , 1h ), 7 . 55 ( m , ih ), 7 . 45 ( m , 1h ), 7 . 10 ( m , 1h ), 7 . 00 ( s , 1h ), 4 . 80 ( m , 1h ), 3 . 80 ( m , 1h ), 3 . 45 ( m , 1h ), 3 . 05 ( m , 1h ), 2 . 60 ( m , 2h ), 2 . 20 ( m , 1h ), 1 . 05 ( m , 6h ) ppm . in a 20 gram vial , compound ( 1 ) ( 100 mg , 0 . 383 mmol ) and potassium carbonate ( 127 mg , 0 . 919 mmol ) were suspended in acetone ( 4 ml ). the reaction mixture was cooled to 0 ° c . and then iso - propyl chloroformate ( 0 . 84 ml , 0 . 843 mmol ) was added . the reaction was stirred at 0 ° c . for 30 minutes and then at room temperature for 1 hour . the mixture was filtered , concentrated and the residue was purified via silica gel chromatography ( 15 - 40 % ethyl acetate in heptanes ). the fractions were allowed to sit at room temperature for 48 hours . the resulting crystals were filtered to yield the desired product ( 19 mg , 11 %). the product structure was confirmed by 1 hnmr ( cdcl 3 ): δ 8 . 10 ( m , 1h ), 7 . 65 ( m , ih ), 7 . 40 ( m , 1h ), 7 . 20 ( m , 1h ), 6 . 80 ( s , 1h ), 6 . 00 ( m , 1h ), 4 . 85 ( m , 1h ), 3 . 95 ( m , 1h ), 3 . 50 ( m , 1h ), 1 . 40 ( m , 6h ), 1 . 20 ( m , 6h ) ppm . in a 20 gram vial , compound 1 ( 78 mg , 0 . 299 mmol ) and potassium carbonate ( 62 mg , 0 . 448 mmol ) were suspended in acetone ( 5 ml ). the reaction was cooled to 0 ° c . and then cyclohexyl acetyl chloride ( 0 . 057 ml , 0 . 359 mmol ) was added . the reaction was stirred at 0 ° c . for 30 minutes and then at room temperature for 6 hours . the mixture was concentrated and the residue was purified via silica gel chromatography ( 2 % ethyl acetate in heptanes to 10 % ethyl acetate in heptanes ). the fractions containing the product were concentrated and then stored in the refrigerator in ethyl acetate / heptanes ( 1 : 2 ) for 72 h . the crystals were filtered and dried to yield the desired product as a white solid ( 29 mg , 25 %). the product structure was confirmed by 1 hnmr ( cdcl 3 ): δ 8 . 90 ( s , ih ), 7 . 85 ( m , 1h ), 7 . 55 ( m , ih ), 7 . 40 ( m , 1h ), 7 . 10 ( m , 1h ), 7 . 00 ( s , 1h ), 4 . 60 ( m , 1h ), 3 . 85 ( m , 1h ), 3 . 55 ( m , 1h ), 2 . 95 ( m , 1h ), 2 . 55 ( m , 2h ), 1 . 95 ( m , 1h ), 1 . 80 ( m , 5h ), 1 . 30 ( m , 5h ) ppm . in a 20 gram vial , compound 1 ( 325 mg , 1 . 25 mmol ) was suspended in tetrahydrofuran ( 12 ml ) to this mixture , pyridine ( 0 . 11 ml , 1 . 37 mmol ) and 2 - methyl valeryl chloride ( 0 . 19 ml , 1 . 37 mmol ) were added . the reaction was complete within 1 h . the reaction was filtered over a small pad of silica gel . the pad was washed with heptanes : ethyl acetate ( 1 : 1 ) and the eluant was concentrated . the crude solid was loaded onto a silica gel column . the final compound was isolated in three separate fractions ( 210 mg , 47 % yield , & gt ; 90 % pure ). the product structure was confirmed by 1 hnmr ( cdcl 3 ): δ 8 . 70 ( s , ih ), 7 . 85 ( 1h ), 7 . 55 ( m , ih ), 7 . 40 ( m , 1h ), 7 . 10 ( m , 1h ), 7 . 00 ( s , 1h ), 4 . 70 ( m , 1h ), 3 . 90 ( m , 1h ), 3 . 55 ( m , 1h ), 3 . 05 ( m , 1h ), 2 . 80 ( m , 1h ), 1 . 80 ( m , 1h ), 1 . 40 - 1 . 60 ( m , 4h ), 1 . 25 ( m , 3h ), 0 . 90 ( m , 3h ) ppm . the product structure was confirmed by 1 hnmr ( cdcl 3 ): δ 8 . 75 ( s , ih ), 7 . 80 ( m , 1h ), 7 . 60 ( m , ih ), 7 . 40 ( m , 1h ), 7 . 10 ( m , 1h ), 7 . 00 ( s , 1h ), 4 . 70 ( m , 1h ), 3 . 90 ( m , 1h ), 3 . 55 ( m , 1h ), 3 . 10 ( m , 1h ), 2 . 60 ( m , 1h ), 1 . 80 ( m , 1h ), 1 . 75 - 1 . 00 ( m , 11h ), 0 . 90 ( m , 3h ) ppm . the product structure was confirmed by 1 hnmr ( acetone - d6 ): δ7 . 90 ( m , 1h ), 7 . 60 ( m , ih ), 7 . 45 ( m , 1h ), 7 . 25 ( m , 1h ), 6 . 95 ( s , 1h ), 4 . 95 ( m , 2h ), 3 . 95 ( m , 1h ), 3 . 40 ( m , 1h ), 2 . 60 ( m , 2h ), 1 . 05 ( m , 9h ) ppm . the product structure was confirmed by 1 hnmr ( cdcl 3 ): δ 9 . 30 ( s , ih ), 7 . 90 ( m , 1h ), 7 . 60 ( m , ih ), 7 . 45 ( m , 1h ), 7 . 35 ( m , 1h ), 6 . 95 ( s , 1h ), 5 . 65 ( m , 1h ), 4 . 95 ( m , 2h ), 3 . 95 ( m , 1h ), 3 . 40 ( m , 1h ), 1 . 40 ( m , 6h ) ppm . in a 20 - gram vial , compound 1 ( 200 mg , 0 . 77 mmol ) was stirred in acetone ( 12 ml ). to this solution was added potassium carbonate ( 266 mg , 1 . 92 mmol ) and isopropyl chloroformate ( 0 . 54 ml , 0 . 54 mmol , 1 . 0m solution ). the reaction appeared to be complete by lc / ms after 30 minutes . the crude mixture was filtered over a silica gel plug and washed with 50 : 50 ethyl acetate : heptanes . the solvent was evaporated by rotary evaporation to yield pure product ( 150 mg , 80 %, & gt ; 90 % purity ). the product structure was confirmed by 1 hnmr ( cdcl 3 ): δ10 . 30 ( br . s , 1h ), 7 . 95 ( m , 1h ), 7 . 60 ( m , 1h ), 7 . 10 ( m , 1h ), 6 . 95 ( m , 1h ), 6 . 80 ( m , 1h ), 6 . 10 ( m , 1h ), 5 . 05 ( m , 1h ), 4 . 10 ( m , 1h ), 3 . 65 ( m , 1h ), 1 . 30 ( m , 6h ) ppm . in a 25 - ml round bottom flask , compound 1 ( 100 mg , 0 . 38 mmol ) was suspended in tetrahydrofuran ( 10 ml ) and cooled to − 78 ° c . to this mixture , lithium tert - butoxide ( 0 . 40 ml , 0 . 40 mmol , 1 . 0 m in tetrahydrofuran ) was added . after 30 minutes , tert - butyl acetyl chloride ( 49 mg , 0 . 363 mmol ) was added . the solution was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride . the organic layer was washed with brine , dried over anhydrous sodium sulfate , filtered , and concentrated . the crude material was purified by column chromatography ( eluting with pentanes : diethyl ether ). the bis - ester was obtained ( 22 mg , 12 . 5 %, & gt ; 90 % pure ) and the product structure was confirmed by 1 hnmr ( d 6 - acetone ): δ9 . 20 ( br . s , 1h ), 7 . 75 ( m , 1h ), 7 . 60 ( m , 1h ), 7 . 40 ( m , 1h ), 7 . 10 ( m , 1h ), 6 . 95 ( m , 1h ), 6 . 10 ( m , 1h ), 4 . 10 ( m , 1h ), 3 . 55 ( m , 1h ), 2 . 50 ( m , 4h ), 1 . 10 ( m , 18h ) ppm . in a 20 - gram vial , compound 1 ( 200 mg , 0 . 766 mmol ) was stirred with tetrahydrofuran ( 8 ml ). triethylamine ( 0 . 53 ml , 3 . 83 mmol ) and diethyl chlorophosphate ( 0 . 105 ml , 0 . 728 mmol ) were added . the reaction was complete after 10 minutes as determined by lc / ms . the crude mixture was filtered and then concentrated in vacuo . the crude oil was purified by column chromatography ( eluting with heptanes : ethyl acetate ). the phospho - ester was obtained ( 160 mg , 53 %, & gt ; 90 % pure ) and the product structure was confirmed by 1 hnmr ( d 6 - acetone ): δ9 . 40 ( br . s , 1h ), 7 . 90 ( m , 1h ), 7 . 60 ( m , 1h ), 7 . 50 ( m , 1h ), 7 . 40 ( m , 1h ), 6 . 95 ( m , 1h ), 4 . 90 ( m , 1h ), 4 . 25 ( m , 4h ), 3 . 90 ( m , 1h ), 3 . 40 ( m , 1h ), 1 . 30 ( m , 6h ) ppm . in a 20 - gram vial , compound 1 ( 250 mg , 0 . 958 mmol ) was stirred with tetrahydrofuran ( 10 ml ). to this mixture , phenyl isocyanate ( 0 . 10 ml , 0 . 956 mmol ) was added and the solution was stirred at room temperature overnight . the reaction mixture was filtered , concentrated in vacuo , and purified by column chromatography ( eluting with heptanes : ethyl acetate ). the carbamate was isolated ( 70 mg , 19 %, & gt ; 97 % pure ) and the product structure was confirmed by 1 hnmr ( d 6 - acetone ): δ9 . 20 ( br . s , 1h ), 7 . 90 ( m , 1h ), 7 . 60 ( m , 2h ), 7 . 40 ( m , 3h ), 7 . 10 ( m , 2h ), 6 . 95 ( m , 2h ), 6 . 10 ( m , 1h ), 4 . 10 ( m , 1h ), 3 . 50 ( m , 1h ) ppm . in a 20 - gram vial , compound 1 ( 300 mg , 1 . 15 mmol ) was stirred with tetrahydrofuran ( 12 ml ). triethylamine ( 0 . 80 ml , 5 . 75 mmol ) and dibenzyl chlorophosphate ( 3 . 23 ml , 1 . 09 mmol , 10 % w : v in benzene ) were added . the reaction was complete after 10 minutes as determined by lc / ms . the crude mixture was filtered and then concentrated in vacuo . the crude oil was purified by column chromatography ( eluting with heptanes : ethyl acetate ). the phospho - ester was obtained ( 450 mg , 75 %, & gt ; 90 % pure ) and the product structure was confirmed by 1 hnmr ( cdcl 3 ): δ9 . 40 ( br . s , 1h ), 7 . 30 ( m , 14h ), 6 . 95 ( m , 1h ), 5 . 10 ( m , 4h ), 4 . 60 ( m , 1h ), 3 . 80 ( m , 1h ), 3 . 40 ( m , 1h ) ppm . employing the general methods described in schemes 1 - 5 , the following compounds may be prepared : the compounds of examples 1 - 12 were observed to inhibit nf - κb signal transduction pathways in cells . two reporter cell assays were used to determine the ability of the compounds of examples 1 - 12 to inhibit nf - κb driven transcription . the first assay was a 293 - cell based assay with a stably integrated pnf - κb - luc reporter plasmid containing 3 nf - κb promoter elements . the second assay was a 293 - cell based assay with a stably integrated ptrh1 - nf - κb - dscgfp reporter containing 4 nf - κb promoter elements . cells were treated with 0 , 0 . 2 , 1 , 10 , 20 and 40 μm of the compounds of example 1 - 12 for 2 hours then were induced with 20 ng / ml tnf - α for 18 hours . following the induction , luminescence or fluorescence was quantified using a beckman - coulter 2300 plate reader . the compounds of example 1 - 12 were observed to inhibit the expression of the luciferase gene in a dose dependent manner . the compounds of examples 1 - 12 also inhibited the expression of the green fluorescent protein gene in a dose dependent manner . as a control , 0 . 5 % dmso treated and untreated cells were compared to verify that the compounds of examples 1 - 12 had no effect on the expression of luciferase or in the readout of the assay . there was a slight decrease in the output from the assay in the dmso treated population although it was not statistically significant . as a result of the controls , the decrease in activity in the drug treated samples was compared to the dmso control sample . the binding activity of nf - κb heterodimer or homodimer subunits from activated nuclear extracts or purified recombinant nf - κb proteins exposed to the drug compounds was evaluated using the transam nf - κb family binding elisa ( active motif ). approximately 3 - 5 μg of nuclear extracts from tnfα activated hela or raji cells ( active motif ) or 20 ng of purified recombinant proteins ( p65 and p50 from active motif , p52 from santa cruz ) were incubated for 1 hour at room temperature with 20 μl drug compounds diluted in complete lysis buffer without dtt . treated samples were then transferred to 30 μl complete binding buffer ( with dtt ) in microplate wells pre - coated with the nf - κb consensus oligonucleotide . controls included non - specific binding ( nsb ) wells containing lysis buffer without any extract or recombinant protein ( for background ), nuclear extract or recombinant protein treated with dmso only ( for maximal binding ), and wells containing the extract / protein plus 20 pmoles free wild - type nf - κb oligonucleotide as a competitor or 20 pmoles free mutant nf - κb oligonucleotide as a control to demonstrate specificity . the plate was incubated for 1 hour at room temperature with gentle shaking and then washed 3 times with 200 μl 1 × wash buffer . nf - κb p65 , p50 , p52 , relb , or c - rel subunits bound to the plate were detected with 100 μl of the primary antibody ( diluted 1 : 1000 in 1 × antibody buffer ) specific for that subunit . the plate was incubated for 1 hour at room temperature and then washed 3 times with 200 μl 1 × wash buffer . next , 100 μl of a hrp conjugated goat anti - rabbit antibody ( diluted 1 : 1 , 000 in 1 × antibody buffer ) was added to each well . the plate was incubated for 1 hour at room temperature and then washed 4 times with 200 μl 1 × wash buffer . 100 μl of room temperature developing solution was added to each well . the reaction was allowed to develop for 2 - 10 minutes until a medium dark blue color developed ( depending on the subunit activity in the lot of extract or lot of recombinant protein used ) and then the reaction was stopped with 100 μl stop solution yielding a yellow color . absorbance was recorded using a becton - dickinson dtx 880 multimode detector at 450 nm with a reference wavelength subtracted at 620 nm . raw 264 . 7 cells were seeded at 4 × 10 4 cells per well in complete growth medium in 96 well white tc plates with clear bottoms one day prior to the assay . the next day the cells were washed once and 100 μl fresh growth media was added . cells were pretreated with 0 . 5 μl from a 6 point 200 × dilution series of the test compounds in dmso for 2 hours . following pretreatment with the drugs , the inflammatory response was induced by adding 5 μl of a 20 μg / ml solution of lps ( sigma ). the cells were incubated in the presence of the drugs and 1 μg / ml lps for another 20 - 24 hours . typically after treatment the total dmso was 0 . 05 % of the culture volume and the final concentrations of the compounds were approximately : 40 , 20 , 10 , 1 , 0 . 2 and 0 μm depending on the mw of each compound . modified dilution series were prepared as needed to get adequate dose response curves without changing the % dmso . samples were run in duplicate or triplicate and included dmso treated control wells with and without lps stimulation . drugs with a known activity such as parthenolide or dhmeq were run as experimental controls . after 20 - 24 hours lps activation , the media supernatant was collected from the cells and replaced with fresh media . the supernatant samples were cleared by centrifugation at 1 , 000 × g for 5 minutes , transferred to fresh storage plates , and stored frozen at − 30 ° c . after determining the appropriate supernatant dilutions experimentally , mil - 6 levels in the supernatants were quantified using quantikine ™ mouse il - 6 immunoassay ( r & amp ; d systems ) according to the manufacturer &# 39 ; s protocol . approximately 50 μl of the supernatants diluted in calibrator diluent were added to 50 μl of assay diluent in microplate wells pre - coated with an anti - mouse il - 6 capture antibody . controls included a calibrated positive il - 6 control sample , non - specific binding ( nsb ) wells containing calibrator diluent but no il - 6 , and a recombinant mouse il - 6 standard dilution series ( 10 - 1000 pg / ml ). the plates were incubated at room temperature for 2 hours with shaking and then washed 5 times with 400 μl 1 × wash buffer . approximately 100 μl of an hrp - conjugated anti - mouse il - 6 antibody was added to each well to detect il - 6 captured on the plate . the plates were incubated at room temperature for 2 hours and then washed 5 times with 400 μl 1 × wash buffer . equal volumes of color reagents a and b were mixed and 100 μl of this hrp substrate solution was added to each well on the plate . the blue color was allowed to develop for 30 minutes and then the reaction was stopped using 100 μl of stop solution yielding a yellow color . absorbance at 450 nm with a reference wavelength subtracted at 595 nm was recorded using a becton - dickinson dtx 880 multimode detector . the concentration of mil - 6 in the unknown samples was determined from a curve - fit of the mil - 6 standard absorbance data and multiplying by the dilution factor . the maximum activity achieved in the absence of the inhibitor ( dmso + lps treated wells ) was arbitrarily given a value of 100 %; likewise the minimum activity in the absence of the stimulant ( no lps ) was assigned a value of 0 % inhibition of the amount of mil - 6 cytokine released in the drug treated wells was calculated relative to the maximum activation in the dmso + lps treated control wells ( i . e ., % inhibition = 100 −( drug + lps treated )/( dmso + lps treated )). dose response curves were used to determine the effective concentration to inhibit 50 % of the mil - 6 cytokine released ( ic 50 ) by means of a sigmaplot macro which fits a sigmoidal dose - response curve to the ( log 10 ) μm concentration versus % inhibition . in the case when compounds did not reach maximum inhibition at the concentrations tested , the curve fit was assisted with forced maximum ( 100 %) and minimum ( 0 %) values . this technique yields an objective value for the ic 50 provided that 50 % inhibition was approached at the concentrations tested . after determining the appropriate supernatant dilutions experimentally , pge2 levels in the supernatants were quantified using parameter ™ pge2 immunoassay ( r & amp ; d systems ) according to the manufacturer &# 39 ; s protocol . approximately 100 μl of the supernatants diluted in calibrator diluent and 50 μl of a primary monoclonal anti - pge2 antibody were added to the microplate wells pre - coated with a goat anti - mouse ig capture antibody . then 50 μl of an hrp conjugated pge2 competitor was added . controls included non - specific binding ( nsb ) wells containing calibrator diluent but no primary antibody and a recombinant pge2 standard dilution series ( 40 - 5000 pg / ml ). the plates were incubated at room temperature for 2 hours with shaking and then washed 5 times with 400 μl 1 × wash buffer . equal volumes of color reagents a and b were mixed and 200 μl of this hrp substrate solution was added to each well on the plate . the blue color was allowed to develop for 30 minutes and then the reaction was stopped using 50 μl of stop solution yielding a yellow color . absorbance at 450 nm with a reference at 595 nm was recorded using a becton - dickinson dtx 880 multimode detector . the concentration of pge2 in the unknown samples was determined from a curve - fit of the pge2 standard absorbance data and multiplying by the dilution factor . the maximum activity achieved in the absence of the inhibitor ( dmso + lps treated wells ) was arbitrarily given a value of 100 %; likewise the minimum activity in the absence of the stimulant ( no lps treated wells ) was assigned a value of 0 %. inhibition of the amount of pge2 released in the drug treated wells was calculated relative to the maximum activation in the dmso + lps treated control wells ( i . e ., % inhibition = 100 −( drug + lps treated )/( dmso + lps treated )). dose response curves were used to determine the effective concentration to inhibit 50 % of the pge2 released ( ic 50 ) by means of a sigmaplot macro which fits a sigmoidal dose - 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