Patent Abstract:
retinoic acid metabolism blocking agents . the rambas may be used for treatment of cancer , including breast and prostate cancers . methods for preparing novel retinamide rambas . the methods include reacting rambas with terminal polar carboxylic acid group with a variety of amines in the presence of suitable coupling reagents . the retinamide rambas are potent inhibitors of the growth of prostate and breast cancer cells and may be useful for the treatment of these diseases in humans .

Detailed Description:
scheme 1 and scheme 2 below are examples of the syntheses of the anilineamide rambas . the examples involves the coupling of the imidazolyl carboxylic acid ( vn / 14 - 1 ) with various anilines using 1 , 3 - dicyclohexylcarbodiimide ( dcc ) and 1 - hydroxybenzotriazole ( hobt ) in dimethylformamide ( dmf ) to yield the corresponding amides . this synthesis has been used for synthesis of vnlg / 145 , vnlg / 146 , vnlg / 147 , vnlg / 148 , vnlg / 152 , and vnlg / 153 and vn / 66 - 1 . scheme 3 below shows an example of the synthesis of compounds 34 and 35 . vn / 66 - 1 may be sulfamoylated under standard conditions liv lv , with sulfomoyl chloride in dimethyl acetamide to give compound 34 . the carbamate ( 35 ) may be synthesized in two steps from vn / 66 - 1 , first reacted with trichloroacetyl isocyanate to give the n - trichloroacetyl carbamate , followed by hydrolysis with k 2 co 3 in meoh / thf / h 2 o ) to give compound 35 . n , n - dialkyl derivatives of 34 and 35 may be synthesized by reaction with appropriate alkyl halides under basic conditions . lvi the heterocyclic and amide rambas of the present invention may be synthesized as outlined in scheme 4 below . some reactions will involve the coupling of the imidazolyl carboxylic acid ( vn / 14 - 1 ) with various anilines using 1 , 3 - dicyclohexylcarbodiimide ( dcc ) and 1 - hydroxybenzotriazole ( hobt ) in dimethylformamide ( dmf ) to yield the corresponding amides . while other compounds will involve formation ( i . e ., reactions with carbonyldiimidazole ( cdi )) of imidazolide intermediates followed by coupling with appropriate amino heterocyles . ivii for synthesis of compounds 42 , 44 , 46 and 48 , the primary amino groups will first be protected with di - tent - butyl dicarbonate ( boc ) 2 o lviii prior to use for coupling reactions . the boc groups will then be readily deprotected to give the desired compounds . with the recent availability of simple procedures for the synthesis of large numbers of substituted purines lix , purine related compounds may be synthesized . the compounds of general formulae 5 may be made with synthesis methods similar to those for making vn / 66 - 1 . in the above synthesis methods , the starting ramba may be a racemate or a (+) or (−) enantiomer to obtain an enantiomer of the rambas of the present invention . the synthesized compounds ( intermediates and final products ) may be purified by chromatographic procedures ( flash column chromatography , tlc or hplc ) and / or crystallization . the compounds may be fully characterized by spectroscopic methods ( ir , uv , nmr and ms ) and elemental analyses . the melting points of all compounds may be determined with a fisher - johns melting point apparatus . synthesis of vn / 66 - 1 enantiomers : one synthesis of enatiopure ( 4s )-(+)- vn / 66 - 1 and ( 4r )-(−)- vn / 66 - 1 is outlined in scheme 1 below , starting from racemic ( 45 , r )-(±)- 4 - hydroxymethylretinoate which will be readily synthesized from commercially available all - trans - retinoic acid ( atra ) as previously described . 1x lxi next the recent efficient and high yielding procedure reported by learmonth lxii will be used to resolve the racemic allylic alcohol ( 1 ) to give the enantiopure alcohols 2 and 3 . the procedure involves use of diacetyl - l - tartaric acid anhydride to precipitate the diastereoisomeric precursor ( 1a ) of ( 4s )-(+)- 1 and diacetyl - d - tartaric acid anhydride to precipitate the diastereoisomeric precursor ( 1b ) of ( r )-(−)- 1 followed by mild hydrolysis to give eantiopure alcohols ( scheme 1 ). based on previous studies , it is expected that the terminal methyl ester group will be stable under the mild hydrolysis of the diastereoisomers . lxiii lxiv these two alcohols are expected to have optical purity in the range 92 to 99 %, which will be purified to 100 % ee either by several recrystallizations or by hplc using a chiralcel oj semipreparative column . lxv the enantiopure alcohols 2 and 3 will each be used to synthesize enatiopure ( 4s )-(+)- vn / 66 - 1 and ( 4r )-(−)- vn / 66 - 1 as previously described lxvi lxvii and will be characterized by hplc , 1 h - nmr and optical rotation . it has been previously reported that conversion of the allylic alcohol to the corresponding imidazole via reaction with carbonyl diimidazole proceeds via sn i mechanism with retention of configuration lxviii corroborated by earlier studies . lxix several alternative procedures to enantiopure vn / 66 - 1 and analogs are described below . there are several other methods to prepare chiral allylic alcohols such as asymmetric reductions lxx lxxi lxxii and enzymatic lxxiii , as well as non - enzymatic lxxiv kinetic resolutions . compounds ( s )- 2 and ( r )- 3 may be synthesized via enantioselective reduction of precursor 4 - ketone using ( r )- or ( s )- 2 - methyl - cbs - oxazaborolidine and bh 3 . se 2 as recently reported for closely related retinoids lxxv ( scheme 4a ). another alternative method will be formation of amine salts lxxvii of (±)- vn / 12 - 1 to form two diastereoisomers and subsequent separation by crystallization . another alternative method will be formation of amine salts lxxvii of (±)- vn / 66 - 1 to form two diastereoisomers and subsequent separation by crystallization . the coupling of some amines may be difficult . applicants propose to use alternative strategies of amide syntheses as outlined in scheme 4b below . these procedures involve either key pyridylthioester intermediate lxxviii or solid phase synthesis that involves reaction of the carboxylic acid with an activating chlorinating reagent . lxxix the new compounds synthesized may be screened at 1 and 10 μm concentrations for their ability to inhibit atra metabolizing enzymes using established procedure . lxxx lxxxi lxxxii lxxxiii lxxxiv compounds may also be evaluated to determine their concentrations that will cause 50 % enzyme inhibition ( ic 50 values ). potent rambas from u . s . pat . no . 7 , 265 , 143 vn / 14 - 1 and vn / 66 - 1 and liarozole can be used to determine the relative potencies of the new compounds . the ramba activities of the pure enantiomers , racemic vn / 66 - 1 and 4 - hpr ( standard ) and also their growth inhibitory effects on four pca cell lines ( lncap , lapc4 , c 4 - 2b and lapc4 - br may be tested . the ramba activities of (+)- vn / 66 - 1 and (−)- vn / 66 - 1 may also be tested to check for differential anti - neoplastic activities against the four prostate cancer cell lines . applicants also consider that the enantiopure (+)- and (−)- vn / 66 - 1 may be more stable in in vitro and more importantly , in vivo . in vitro stability of entiopure (+)- or (−)- vn / 66 - 1 and the derivatives of vn / 66 - 1 may be assessed by treating pca cells with their ic 50 and ic 90 concentrations . cells and media may be extracted at specific time intervals over the usual mtt assay conditions , and than analyzed by chiral hplc column . to further evaluate their stabilities in vivo , animals may be dosed with 10 mg / kg of pure (+)- or (−)- vn / 66 - 1 . blood will be drawn at specified times , processed and than analyzed as described above . applicants synthesized novel retinamides of the present invention with reactions that involve coupling of our imidazolyl carboxylic acid ( vn / 14 - 1 ) with appropriate amines / anilines using 1 , 3 - dicyclohexylcarbodiiimide ( dcc ) and 1 - hydroxybenzotriazole ( hobt ) in dimethylformamide ( dmf ) as outlined in scheme 1 below . compounds vnlg / 145 , vnlg / 146 , vnlg / 147 , vnlg / 148 , vnlg / 152 and vnlg / 153 were tested and evaluated for their ability to inhibit the growth ( proliferation ) of pc - 3 prostate cancer cells using the mtt [ 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide ] assay ( gediyal et al . 2005 ). vn / 66 - 1 of u . s . pat . no . 7 , 265 , 143 was tested side by side for comparison . the gi 50 values ( concentrations that cause 50 % growth inhibition ) were determined from dose - response curves . see in fig1 for vnlg / 145 . the growth inhibitory experiments with the other compounds gave plots that were similar to fig1 . the structures of the six compounds of the present invention and the parent vn / 66 - 1 and their gi 50 values are presented in table 1 below . as used herein in the specification , “ a ” or “ an ” may mean one or more . as used herein in the claims , when used in conjunction with the word “ comprising ,” the words “ a ” or “ an ” may mean one or more than one . as used herein “ another ” may mean at least a second or more . furthermore , unless otherwise required by context , singular terms shall include pluralities and plural terms shall include the singular . it is believed that the present invention and many of its attendant advantages will be understood by the forgoing description . it is also believed that it will be apparent that various changes may be made in the form , construction and arrangement of the components thereof without departing from the scope and spirit of the invention or without sacrificing all of its material advantages . the form herein before described being merely an explanatory embodiment thereof . i sonneveld et al , human retinoic acid ( ra ) 4 - 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