Patent Application: US-57811809-A

Abstract:
the present invention relates to the field of non - specific anti inflammatory drugs . in particular , the invention relates to bismuth tris - carboxylate complexes having the formula l 3 ] n including its pharmaceutically acceptable salts and solvates , wherein , l is chosen from the group comprising carboxylato - nsaids , their derivatives , prodrugs or metabolytes , and n is ≧ 1 . the bismuth tris - carboxylate complexes of the invention may be formulated for use in treatments for a wide range of ailments , particularly those where an anti - microbial activity is advantageous . in a particularly preferred embodiment the bismuth tris - carboxylate complexes of the present invention exhibit activity against bacteria found in the gastrointestinal tract such as helicobacter pylori , escherichia coli , klebsiella pneumoniae , bacillus pumilus , staphylococcus aureus and staphylococcus epidermidis .

Description:
to compare the efficacy of the synthetic strategies and to allow for a comparison of their efficiency , reactions to form the fully substituted bismuth ( iii ) tris - carboxylate complexes derived from the free acids of the nsaids were conducted on a 1 : 3 stoichiometric ratio under solvent free conditions ( general procedure 2 , gp2 ) and under reflux in toluene ( general procedure 1 , gp1 ). the general synthetic procedures are shown in scheme 1 and described in the examples . the data summarised in table 1 indicates that the isolated yields obtained for complexes 2 , 4 , 5 and 6 were similar using both synthetic approaches . in the case of 1 , however , the isolated yield obtained by the solvent free method is lower . this is mostly due to the fact that the product of the reaction by this method is an oily liquid . after testing a range of solvents and solvent mixtures it was found that the best medium for extracting a solid product was a 1 : 1 mixture of ch 2 cl 2 and hexane . the reverse was observed for 3 . both methods produce a product which resembles a thick oil or paste . gentle heating under high vacuum for 2 h leaves a slightly sticky white solid which is soluble in toluene . the higher solubility of 3 in toluene in comparison with the five other compounds accounts for the lower isolated yield from the solvent based reaction since precipitation using methanol is required to obtain a purified solid product . all the solids 1 - 11 were assessed for their solubility in common solvents and their hydrolytic stability , and were analysed by nmr , ft - ir , elemental analysis and mass spectrometry . unfortunately , attempts at obtaining single crystal x - ray structural data proved unsuccessful , mostly due to the small size of the crystals which were obtained . the thermochemical profiles of the solvent free reactions were studied by dsc - tga . compounds 2 - 6 are sparingly soluble in toluene ( 3 has the greatest solubility ) and acetone and all show greater solubility in dmso . compound 1 is soluble in dmso and chcl 3 . compounds 7 - 11 also show greater solubility in dmso . compound 9 and 10 is sparingly soluble in toluene as well . 1 h - nmr and 13 c - nmr spectra for compounds 1 - 11 were obtained in d 6 - dmso . all the complexes show a general downfield shift for the h and c resonances in comparison to the free acids . this , coupled with the lack of signals corresponding to either the co 2 h proton or residual ph groups , is good initial evidence for the formation of tris - substituted bismuth ( iii ) carboxylate complexes . hydrolysis of bismuth carboxylates leads to the formation of ligand encapsulated oxo - clusters of varying nuclearity , and this can occur either during formation or through subsequent decomposition of the bil 3 complex . 11 if the oxo - cluster species is / are soluble , this is not easily detectable by nmr except through the appearance of signals attributable to the release of free acid . the nmr spectral data on solutions of 1 - 6 gave no indication of facile hydrolysis and the composition of the solid products as pure [ bil 3 ] n ( or [ bil 3 . h 2 o ] n in the case of 1 ) was confirmed by elemental analysis . ir data on 1 - 6 show a relative shift in the absorbances of the bismuth complexes in comparison to the nsaid free acids . the acids show the stretch corresponding to the carboxyl group in the range 1670 - 1700 cm − 1 . all the complexes showed a decrease in wavenumber for the symmetric and asymmetric carboxylate stretches of 35 - 50 cm − 1 , indicating deprotonation of the co 2 h group and formation of the carboxylate bound complex . the spectrum of 1 also showed an absorbance band corresponding to oh ( h 2 o ) stretching at 3300 cm − 1 . in terms of structural information it is interesting to note that for bismuth complexes 1 - 11 the value of δv { δv = vco 2 -( asymm )- vco 2 -( symm )} is less than 200 cm − 1 , as shown in table 2 . according to deacon and phillips since δv & lt ; 200 cm − 1 then the ligands adopt the bidentate chelating mode . 21 this is perhaps not unexpected given previous solid state structures of bismuth carboxylates , 13 , 14 , 22 - 24 the lack of other donor molecules and the high coordination demands of the bi 3 + ion . the present invention will be further described with reference to the following non - limiting examples describing the synthesis and characterisation of the compounds of the present invention . biph 3 was purchased as a white microcrystalline solid from strem chemicals inc . ketoprofen , mefenamic acid , diflunisal and 5 - sulfosalicylic acid ( 99 %) were purchased from aldrich chemical co . naproxen was extracted from commercially available naprogesic ( bayer ) tablets . 30 the purity was checked by nmr spectroscopy and by melting point analysis . all other reagents and solvents were purchased from aldrich and used without further purification . horse blood agar ( hba ) and brain heart infusion broth ( bhi ) were obtained from oxoid australia pty . fetal calf serum ( fcs ) was purchased from invitrogen . polymyxin b , vancomycin , trimethoprim and amphotericin b were purchased from sigma , mo ., usa . infrared spectra were obtained on a perkin elmer 1600 ft - ir . nmr spectra were obtained with bruker av - 200 and dpx - 300 spectrometers with chemical shifts referenced to the appropriate deuterated solvent . mass spectrometry ( esi ) was performed on a micromass platform electrospray mass spectrometer . elemental analysis was carried out by cmas , melbourne , australia and the campbell microanalytical laboratory , new zealand . h . pylori strains 251 , b128 and 26695 31 were routinely cultured on hba or in bhi , supplemented with either 7 . 5 % ( v / v ) fresh horse blood or 10 % ( v / v ) fcs , respectively . 32 culture media were further supplemented with 155 μg / l polymyxin b , 6 . 25 mg / l vancomycin , 3 . 125 mg / l trimethoprim , 1 . 25 mg / l amphotericin b . the minimum inhibitory concentration ( mic ) of the bismuth complexes was determined by the agar dilution technique . for this , h . pylori cultures were incubated in bhi for 18 hours shaking at 140 rpm at 37 ° c . under microaerobic conditions . bacteria were pelleted , washed in phosphate - buffered saline , then resuspended in bhi . 31 each suspension was adjusted to give an approximate density of 10 6 bacteria / ml . aliquots ( 10 μl ) of these suspensions were then streaked onto hba plates containing doubling dilutions of the different concentrations of bismuth compounds , ranging in concentration from 25 μg / ml to 6 . 25 μg / ml . each compound was tested alongside bss and the nsaids , in comparable concentrations . the mics of the different compounds were determined by examination of the plates after incubation under microaerobic conditions for 3 - 5 days at 37 ° c . for solvent based reactions the reagents were placed in a round bottom flask with toluene ( 15 ml ) and heated to reflux for 10 - 12 hours . the reaction mixture was allowed to cool to room temperature and the precipitate collected by filtration and washed with a small amount of toluene to remove excess biph 3 then dried in air . for the solvent - free reactions biph 3 and the carboxylic acid were ground together and placed in a small pear shaped flask which was heated in an oven at 120 ° c . for 4 hours . occasionally the liquid or solid mixture was stirred to assist mixing . after 4 hours the flask was removed from the oven and allowed to cool to room temperature . the solid product was collected and washed with a small amount of toluene to remove excess biph 3 then dried in air . the reaction of biph 3 ( 1 . 0 mmol , 0 . 44 g ) with ketoprofen ( 3 . 0 mmol , 0 . 77 g ) was performed according to gp1 . the reaction mixture was homogeneous . on completion of the reaction all volatiles were removed under reduced pressure . a crude solid , which precipitated on removal of the solvent , was taken up in chloroform ( 5 ml ). addition of hexane ( 5 ml ) precipitated a white solid which was identified as bismuth ( iii ) tris -{ 2 -( 3 - benzoylphenyl )- propionoate } monohydrate , 1 . yield : 0 . 68 g , 70 %. melting point : 52 - 55 ° c . 1 h nmr ( 200 mhz , d 6 - dmso ) δ = 7 . 40 ( 27h , m , ar ), 3 . 86 ( 3h , q , j = 7 ) 13 c nmr ( 50 mhz , d 6 - dmso ) δ = 194 . 8 ( arc ═ oar ) 136 . 1 ( ch ), 131 . 8 ( ar ), 131 . 1 ( ch ), 128 . 7 ( ar ), 127 . 7 ( ar ), 11 . 9 ( ch 3 ). m / z ( esi +) 507 [ l 2 h ] + , 529 [ l 2 na ] + , 761 [ bil 2 ( etoh )] + ( esi −) 785 [ bil 2 cl 2 ] − ( where l = c 16 h 13 oco 2 − ). ν max ( cm − 1 ) ( kbr ): 3300 b , 2727 w , 1706 w , 1655 m , 1596 w , 1576 w , 1348 m , 1283 m , 1178 w , 1075 m , 998 w , 953 w , 898 m , 835 m , 774 w , 719 m , 668 m , 667w . anal . found : c 58 . 2 , h 4 . 3 , bi 20 . 8 %; bic 48 h 41 o 10 requires c 58 . 4 , h 4 . 1 , bi 21 . 2 %. the same reaction was conducted using gp2 . an oily liquid was obtained on completion of the reaction , which on cooling to room temperature solidified . this solid was taken up in a 1 : 1 mixture of dcm and hexane ( 10 ml ) and the solution cooled to − 20 ° c . overnight . this produced a microcrystalline precipitate that was collected by filtration and washed with cold ethanol leaving a colourless solid . this was identified as 1 ( 0 . 48 g , 50 %). the reaction of biph 3 ( 1 . 0 mmol , 0 . 44 g ) with naproxen ( 3 . 0 mmol , 0 . 69 g ) was performed and purified according to gp1 and gp2 producing a white solid in both cases . the solid was identified as bismuth ( iii ) tris -{( s )- 2 -( 6 - methoxynaphthalen - 2 - yl ) propanote }, 2 . yield : 0 . 72 g , 80 %. melting point : 193 - 194 ° c . 1 h nmr ( 200 mhz , d 6 - dmso ) δ = 7 . 13 - 7 . 70 ( 18h , m , ar ), 3 . 86 ( 9h , s , och 3 ), 3 . 65 ( 3h , s , chch 3 ), 1 . 40 ( 9h , s , ch 3 ). 13 c nmr ( 50 mhz , d 6 - dmso ) δ = 156 . 5 ( coch 3 ), 136 . 5 ( ar ), 132 . 6 ( ar ), 128 . 5 ( ar ), 127 . 8 ( ar ), 126 . 2 ( ar ), 125 . 9 ( ar ), 125 . 1 ( ar ), 117 . 9 ( ar ), 105 . 2 ( ar ), 54 . 6 ( och 3 ), 18 . 3 ( ch 3 ). m / z ( esi +) 745 . 2 [ bil 2 ( dmso )] + , 823 [ bil 2 ( dmso ) 2 ] + ; ( esi −) 229 [ l ] − , 459 [ l 2 ] − ( where l = c 13 h 13 oco 2 − ). ν max ( cm − 1 ) ( kbr ): 3447 m , 2930 w , 1636 s , 1606 s , 1560 w , 1522 w , 1507 s , 1485 m , 1458 m , 1393 vs , 1273 vs , 1230 s , 1215 s , 1160 m , 1073 w , 1031 s , 928 w , 853 s , 809 m , 751 w , 713 m , 670 w , 473 s . anal . found ; c 56 . 1 , h 4 . 4 , bi 22 . 9 %; bic 42 h 39 o 9 requires c 56 . 3 , h 4 . 4 , bi 23 . 3 %. the reaction of biph 3 ( 1 . 0 mmol , 0 . 44 g ) with ibuprofen ( 3 . 0 mmol , 0 . 62 g ) was performed according to gp1 . on cooling to room temperature the final reaction mixture is a homogeneous toluene solution . all volatiles were removed under reduced pressure leaving a thick oily colourless liquid . addition of methanol ( 10 ml ) precipitated a white solid which was identified as bismuth ( iii ) tris -{ 2 -( 4 - isobutylphenyl )- propionoate }, 3 . yield : 0 . 50 g , 60 . 6 %. melting point : 123 - 125 ° c . 1 h nmr ( 300 mhz , d 6 - dmso ) δ = 7 . 18 ( 6h , d , j = 7 . 7 hz , ar ), 7 . 05 ( 6h , d , j = 7 . 7 hz , ar ), 3 . 49 ( 3h , q , ch ), 2 . 40 ( 6h , d , j = 7 . 0 hz , ch 2 ), 1 . 80 ( 3h , m , ch 2 ch ), 1 . 15 ( 18h , d , j = 6 . 9 hz , ch 3 ), 0 . 84 ( 9h , d , j = 6 . 6 hz , ch 3 ). 13 c nmr ( 75 mhz , d 6 - dmso ) δ = 170 . 6 ( coobi ), 138 . 6 ( cch 2 ), 128 . 1 ( ar ), 126 . 7 ( ar ), 43 . 7 ( ch 2 ), 29 . 0 ( c ( h ) me ), 28 . 4 ( ch ( ch 3 ) 2 ), 21 . 6 ( ch 3 ), 18 . 4 ( ch 3 ). m / z ( esi +) 229 [ lhna ] + , 847 [ bil 3 na ] + ; ( esi −) 205 [ l ] − , 773 [ bil 2 {( dmso )- h } 2 ] − ( where l = c 12 h 17 co 2 − ). ν max ( cm − 1 ) ( kbr ): 2955 m , 2868 w , 1546 m , 1512 m , 1460 m , 1384 s , 1358 w , 1261 m , 1168 m , 1067 w , 1022 w , 893 w , 800 w . anal . found ; c 55 . 1 , h 6 . 3 %; bic 39 h 51 o 6 requires c 56 . 8 , h 6 . 2 %. in a variation to gp2 the reaction mixture was heated to 85 ° c . for 2 h . on cooling a thick colourless gel was obtained . the sample was then dried under high vacuum for 2 h leaving a sticky white solid . this solid , which is soluble in toluene , analysed as compound 3 . yield : 0 . 74 g , 90 %. reaction of biph 3 ( 1 . 0 mmol , 0 . 44 g ) with mefenamic acid ( 3 . 0 mmol , 0 . 72 g ) was performed and purified according to gp1 and gp2 , producing a yellow solid . this was identified as bismuth ( iii ) tris -{ 2 -( 2 , 3 - dimethylphenyl ) aminobenzoate }, 4 . yield : 0 . 76 g , 82 % ( gp1 ); 0 . 80 g , 86 % ( gp2 ). melting point : 255 - 256 ° c . 1 h nmr ( 200 mhz , d 6 - dmso ) δ = 9 . 47 ( 3h , s , nh ), 7 . 85 ( 3h , d , j = 6 . 94 hz , ar ), 7 . 25 ( 3h , m , ar ), 7 . 03 ( 6h , m , ar ), 6 . 80 ( 9h , m , ar ), 2 . 15 ( 9h , s , ch 3 ), 1 . 93 ( s , 9h , ch 3 ). 13 c nmr ( 50 mhz , d 6 - dmso ) δ = 142 . 1 ( coobi ), 133 . 3 ( c — ch 3 ), 132 . 1 ( c — nh ), 128 . 0 ( ar ), 126 . 5 ( c — ch 3 ), 124 . 6 ( ar ), 123 . 4 ( ar ), 122 . 7 ( ar ), 120 . 1 ( ar ), 115 . 1 ( ar ), 110 . 8 ( ar ), 107 . 8 ( c — coo — bi ), 14 . 7 ( ch 3 ), 7 . 85 ( ch 3 ). m / z ( esi +) 604 [ bil ( dmso ) 2 ] + ; ( esi −) 985 . 5 [ bil 3 cl ( h 2 o )] − ( where lh ═ c 14 h 14 nco 2 − , l = c 14 h 13 nco 2 2 − ). ν max ( cm − 1 ) ( kbr ): 2361 m , 1652 s , 1614 m , 1580 vs , 1506 s , 1472 w , 1454 w , 1372 m , 1262 s , 1161 w , 1096 w , 866 w , 778 w , 752 w , 681 vw . anal . found ; c , 58 . 3 ; h , 4 . 6 ; n , 4 . 5 , bi 22 . 5 %; bic 45 h 42 n 3 o 6 requires c , 58 . 1 ; h , 4 . 6 ; n , 4 . 5 , bi 22 . 5 %. the reaction of biph 3 ( 1 . 0 mmol , 0 . 44 g ) with diflunisal ( 3 . 0 mmol , 0 . 75 g ) was performed and purified according to gp1 and gp2 . this produced a yellow solid which was identified as bismuth ( iii ) tris -{ 2 ′, 4 ′- difluoro - 4 - hydroxybiphenyl - 3 - carboxylate }, 5 . yield : 0 . 77 g , 81 % ( gp1 ), 0 . 78 g , 82 % ( gp2 ). melting point : decomposes above 250 ° c . 1 h nmr ( 200 mhz , d 6 - dmso ) δ = 7 . 88 ( 3h , s , ar ), 7 . 55 - 6 . 78 ( 15h , m , ar ). 13 c nmr ( 50 mhz , d 6 - dmso ) δ = 156 . 8 ( c — f ), 130 . 8 ( ar ), 128 . 9 ( ar ), 127 . 7 ( ar ), 125 . 5 ( ar ), 123 . 7 ( c — oh ), 111 . 3 ( ar ), 103 . 8 ( ar ). m / z ( esi +) 785 [ bil 2 ( dmso )] + , 863 [ bil 2 ( dmso ) 2 ] + ; ( esi −) 249 [ l ] − . ν max ( cm − 1 ) ( kbr ): 3154 w , 2925 w , 1654 s , 1618 w , 1592 w , 1512 w , 1486 m , 1453 m , 1268 w , 1239 w , 1214 w , 1144 m , 1106 w , 1096 m , 1039 w , 967 m , 852 vw , 837 s , 812 w , 792 vw , 727 vw , 661 s . anal . found ; c 48 . 9 , h 2 . 2 , f 11 . 6 , bi 21 . 5 %; bic 39 h 21 f 6 o 9 requires c 48 . 9 , h 2 . 3 , f 11 . 9 , bi 21 . 9 % the reaction of biph 3 ( 1 . 0 mmol , 0 . 44 g ) with 5 - chlorosalicylic acid ( 3 . 0 mmol , 0 . 52 g ) was performed and purified according to gp1 and gp2 . this produced a yellow solid which was identified as bismuth ( iii ) tris -{ 5 - chlorosalicylate }, 6 . yield : 0 . 55 g , 76 % ( gp1 ); 0 . 54 g , 75 % ( gp2 ). melting point : 245 - 246 ° c . 1 h nmr ( 300 mhz , d 6 - dmso ) δ =□ 7 . 70 ( s , 3h , ar ), 6 . 83 ( d , 3h , j = 8 . 1 hz , ar ), 6 . 79 ( s , 3h , ar ). 13 c nmr ( 75 mhz , d 6 - dmso ) δ = 159 . 3 ( c — oh ), 132 . 2 ( ar ), 128 . 6 ( ar ) 127 . 9 ( c — cl ), 127 . 2 ( ar ), 115 . 8 ( c — coo ). ν max ( cm − 1 ) ( kbr ): 1665 m , 1621 w , 1580 w , 1567 m , 1524 m , 1471 m , 1413 m , 1369 w , 1287 m , 1234 w , 1211m , 1107 w , 1074 w , 892 m , 827 m , 794 w , 722 s , 694 vw , 650 m . h 1 . 67 %, bi 28 . 8 %. m / z ( esi +) 535 [ bi ( l )] + , 629 [ bi ( lh ) 2 ( dmso )] + , 707 [ bi ( lh ) 2 ( dmso ) 2 ] + ; ( esi −) 549 [ bi ( l ) 2 ] − , 723 [ bi ( lh ) 2 {( dmso )- h } 2 h 2 o ] − . anal . found : c 34 . 1 , h 1 . 9 , bi 27 . 9 %; bic 21 h 12 cl 3 o 9 requires c 34 . 8 , h 1 . 7 , bi 28 . 8 %. reaction of biph 3 ( 1 . 0 mmol , 0 . 44 g ) with fenbufen ( 3 . 0 mmol , 0 . 76 g ) was performed and purified according to gp1 and gp2 , producing a white solid . this was identified as bismuth ( iii ) tris -{ γ - oxo -( 1 , 1 ′- biphenyl )- 4 - butanoate }, 7 . yield : 0 . 97 g , 83 % ( gp1 ); 0 . 66 g , 68 % ( gp2 ). melting point : 206 - 207 ° c . 1 h nmr ( 200 mhz , d 6 - dmso ) δ = 8 . 04 ( 6h , d , j = 8 . 0 hz , ar ), 7 . 80 ( 6h , d , j = 8 . 0 hz , ar ), 7 . 72 ( 6h , d , j = 8 . 0 hz , ar ), 7 . 44 ( 9h , m , ar ), 3 . 36 ( 6h , t , ch 2 ), 2 . 58 ( 6h , t , ch 2 ). 13 c nmr ( 50 mhz , d 6 - dmso ) δ = 197 . 7 ( arcoch 2 ), 173 . 6 ( coobi ), 144 . 1 ( ar ), 138 . 5 ( ar ), 134 . 9 ( ar ), 128 . 6 ( ar ), 128 . 0 ( ar ), 126 . 5 ( ar ), 32 . 8 ( arcoch 2 ch 2 ), 27 . 7 ( arcoch 2 ch 2 ). ν max ( cm − 1 ) ( kbr ): 1678 s , 1603 m , 1560 w , 1485 w , 1401 m , 1354 m , 1249 w , 1196 m , 982 m , 838 m , 765 s , 720 w , 690 s , 627 w . anal . found ; c 60 . 6 , h 4 . 3 %; bic 48 h 3 o 9 requires c 59 . 5 , h 4 . 1 %. the reaction of biph 3 ( 0 . 3 mmol , 0 . 14 g ) with sulindac ( 1 mmol , 0 . 36 g ) was performed in ethanol ( heated to reflux for 6 - 7 hours ). on cooling to room temperature the final reaction mixture was a homogeneous ethanol solution . all volatiles were removed under reduced pressure leaving a thick oily yellow liquid . addition of methanol ( 5 ml ) precipitated a white solid which was identified as bismuth ( iii ) tris -{( z )- 2 -( 5 - fluoro - 2 - methyl - 1 -( 4 -( methylsulfinyl ) benzylidene )- 1h - inden - 3 - yl ) acetate } monohydrate , 8 . yield : 0 . 22 g , 54 % ( gp1 ). melting point : 226 - 227 ° c . 1 h nmr ( 200 mhz , d 6 - dmso ) δ = 7 . 78 ( 6h , d , j = 8 . 4 hz , ar ), 7 . 70 ( 6h , s , j = 8 . 2 hz , ar ), 7 . 30 ( 3h , s , arch = cp ), 7 . 15 ( 3h , dd , j = 8 . 3 hz , ar ), 7 . 00 ( 3h , dd , j = 8 . 0 hz , ar ), 6 . 68 ( 3h , m , ar ), 3 . 50 ( 6h , s , ch 2 ), 2 . 81 ( 9h , s , soch 3 ), 2 . 14 ( 9h , s , ch 3 ). 13 c nmr ( 50 mhz , d 6 - dmso ) δ = 165 . 4 ( coobi ), 160 . 6 ( cf ), 147 . 6 ( cp ), 146 . 7 ( csoch 3 ), 140 . 9 ( cp ), 139 . 0 ( ar ), 138 . 2 ( c — ch 3 ), 130 . 4 ( cp ), 129 . 9 ( cp ), 129 . 8 ( cp ) 124 . 4 ( ar ), 123 . 7 ( ar ), 123 . 5 ( ar ), 110 . 8 ( ar ), 106 . 6 ( ar ), 43 . 6 ( soch 3 ) 19 . 0 ( ch 2 ), 10 . 7 ( ch 3 ). m / z ( esi +) 377 [ lna ] + , 1275 [ bil 3 h ] + ( where l = c 19 h 16 fosco 2 − ). ν max ( cm − 1 ) ( kbr ): 3448 b , 1654 w , 1603 m , 1560 m , 1466 s , 1368 m , 1262 w , 1195 w , 1166 m , 1086 m , 997 w , 915 m , 891 m , 856 m , 811 m , 728 m , 680 m , 657 w . anal . found ; c 55 . 3 , h 3 . 8 %; bic 60 h 50 f 3 o 10 s 3 requires c 55 . 7 , h 3 . 9 %. reaction of biph 3 ( 1 . 0 mmol , 0 . 44 g ) with tolfenamic acid ( 3 . 0 mmol , 0 . 78 g ) was performed and purified according to gp2 , producing a yellow solid . this was identified as bismuth ( iii ) tris -{ 2 -( 3 - chloro - 2 - methylphenyl ) aminobenzoate }, 9 . yield : 0 . 64 g , 65 %. melting point : 225 - 229 ° c . 1 h nmr ( 400 mhz , d 6 - dmso ) δ = 9 . 70 ( 3h , s , nh ), 7 . 87 ( 3h , d , j = 7 . 2 hz , ar ), 7 . 34 - 7 . 17 ( 12h , br , ar ), 6 . 95 ( 3h , br , ar ) 6 . 81 ( 3h , br , ar ), 2 . 07 ( 9h , s , ch 3 ). 13 c nmr ( 100 mhz , d 6 - dmso ) δ = 146 . 1 ( c — nh ), 141 . 0 ( c — nh ), 137 . 0 ( c — cl ), 136 . 9 ( ar ), 134 . 2 ( ar ) 132 . 5 ( c — ch 3 ), 131 . 9 ( ar ), 128 . 1 ( ar ), 123 . 6 ( ar ), 119 . 7 ( ar ), 117 . 5 ( ar ), 113 . 9 ( c — coobi ), 14 . 7 ( ch 3 ). m / z ( esi −) 604 [ bil 2 cl 2 ] − , 1081 . 6 [ bil 3 cl ( h 2 o ) 3 ] − ( where l = c 13 h 11 clnco 2 − ). ν max ( cm − 1 ) ( kbr ): 1656 s , 1612 m , 1582 vs , 1499 s , 1453 m , 1372 m , 1262 s , 1276 s , 1162 w , 1011 m , 854 m , 778 s , 751 s , 669 m . anal . found ; c , 51 . 4 ; h , 3 . 6 ; n , 4 . 1 %; bic 42 h 33 cl 3 n 3 o 6 requires c , 50 . 9 ; h , 3 . 4 ; n , 4 . 2 %. reaction of biph 3 ( 1 . 0 mmol , 0 . 44 g ) with flufenamic acid ( 3 . 0 mmol , 0 . 84 g ) was performed and purified according to gp1 and gp2 , producing a yellow solid . this was identified as bismuth ( iii ) tris -{ 2 -( 3 -( trisfluoromethyl ) phenyl ) aminobenzoate }, 10 . yield : 0 . 71 g , 70 % ( gp1 ); 0 . 69 g , 68 % ( gp2 ). melting point : 208 - 210 ° c . 1 h nmr ( 400 mhz , d 6 - dmso ) δ = 10 . 0 ( 3h , s , nh ), 7 . 99 ( 3h , d , j = 6 . 4 hz , ar ), 7 . 31 ( 18h , m , ar ), 6 . 92 ( 3h , m , ar ). 13 c nmr ( 100 mhz , d 6 - dmso ) δ = 173 . 4 ( coobi ), 145 . 2 ( c — nh ), 142 . 9 ( c — nh ), 137 . 8 ( ar ), 133 . 9 ( ar ), 132 . 7 ( ar ), 131 . 2 ( ar ) 130 . 6 ( c — cf 3 ), 126 . 5 ( cf 3 ), 123 . 5 ( ar ), 122 . 8 ( ccoobi ), 119 . 4 ( ar ), 118 . 6 ( ar ), 116 . 2 ( ar ) 115 . 5 ( ar ). m / z ( esi +) 847 [ bil 2 ( dmso )] + , 925 [ bil 2 ( dmso ) 2 ] + , 1150 [ bil 3 na ( dmso )] + ( where l = c 13 h 9 f 3 nco 2 − ). ν max ( cm − 1 ) ( kbr ): 1584 m , 1508 m , 1465 m , 1399 m , 1333 s , 1275 m , 1162 m , 1122 m , 1069 w , 930 m , 865 m , 791 m , 747 s 696 s , 664 m . anal . found ; c , 48 . 1 ; h , 2 . 5 ; n , 3 . 9 %; bic 42 h 27 f 9 n 3 o 6 requires c , 48 . 1 ; h , 2 . 6 ; n , 4 . 0 %. reaction of biph 3 ( 1 . 0 mmol , 0 . 44 g ) with probenecid acid ( 3 . 0 mmol , 0 . 86 g ) was performed in ethanol ( heated to reflux for 6 - 7 hours ). the reaction mixture was allowed to cool to room temperature and the precipitate collected by filtration and washed with a small amount of ethanol to remove excess biph 3 then dried in air . the product was identified as bismuth ( iii ) tris -{ 4 -( dipropylsulfamoyl ) benzoate }, 11 . yield : 0 . 85 g , 80 %. melting point : 225 - 226 ° c . 1 h nmr ( 200 mhz , d 6 - dmso ) δ = 8 . 13 ( 6h , d , j = 6 . 8 hz , ar ). 7 . 87 ( 6h , d , j = 6 . 8 hz , ar ), 3 . 05 ( 12h , t , ch 2 ), 1 . 44 ( 12h , q , ch 2 ), 0 . 79 ( 18h , t , ch 3 ). 13 c nmr ( 50 mhz , d 6 - dmso ) δ = 168 . 7 ( coobi ), 145 . 0 ( cso 2 ), 132 . 0 ( c — coobi ), 132 . 0 ( ar ), 128 . 8 ( ar ), 51 . 4 ( ch 2 ), 23 . 4 ( ch 2 ), 12 . 7 ( ch 3 ). m / z ( esi +) 1163 [ bil 3 na ( dmso )] + ; ( esi −) 1138 [ bil 3 {( dmso )— h }] − ( where l = c 13 h 18 no 2 sco 2 − ). ν max ( cm − 1 ) ( kbr ): 2966 m , 1602 m , 1574 m , 1522 m , 1469 m , 1427 m , 1346 s , 1288 s , 1158 s , 1084 s , 997 m , 985 m , 930 m , 866 s , 797 s , 778 m , 765 m , 737 s , 711 w , 688 m . anal . found ; c , 44 . 1 ; h , 5 . 4 ; n , 3 . 8 %; bic 39 h 54 n 3 o 12 s 3 requires c , 44 . 1 ; h , 5 . 1 ; n , 3 . 9 %. all the solvent free reactions were studied using differential scanning calorimetry ( dsc ) and thermogravimetric analysis ( tga ). the success of the solvent free reactions can be observed in the dsc profiles of the reaction mixtures . the energy changes relating to the temperature and phase dependent reaction of the acid with biph 3 observed in the dsc can be correlated directly with the loss of phh observed in the tga trace . final and rapid decomposition of the bil 3 compounds derived from naproxen , mefenamic acid and diflunisal are observed at 292 , 260 and 250 ° c . respectively . the product from the reaction with ibuprofen undergoes two distinct exothermic decomposition processes at 270 and 300 ° c . while the product from 5 - chlorosalicylic acid does not appear to decompose below 350 ° c . in general , this is in agreement with reports on the thermal decomposition of bismuth medicinals , corresponding closely to a ‘ stage iii ’ decomposition process involving decarboxylation and combustion of organic components . 25 as an illustrative example , fig2 shows the dsc trace for the reaction of naproxen with biph 3 in a 3 : 1 stoichiometric ratio . the endotherm at 76 . 2 ° c . corresponds to the melting of biph 3 . as is now typical for these systems , at the onset of melting the reaction begins and an exotherm is observed ( ca 85 ° c .). from the tga this corresponds to the loss of 3 phh . the beginning of the endotherm at 193 ° c . and centred at 196 ° c . corresponds with the melting point of the tris - substituted product , consistent with that found experimentally ( 193 - 194 ° c .). the final large exotherm at 292 ° c . indicates rapid decomposition of bil 3 . the dsc profile for the reaction of diflunisal with biph 3 displays a distinct and unusual feature in comparison with the other reactions performed herein . as can be seen in fig3 , the exotherm at 65 . 5 ° c . suggests that the onset of the reaction occurs before biph 3 is expected to begin melting at ca 78 ° c . ( diflunisal melts at 211 - 213 ° c .). this exotherm corresponds in the tga to a loss of three equivalents of phh , indicative of a complete reaction . one plausible reason for the unusual observation of the reaction occurring prior to generation of a partial melt phase could be the fact that the presence of fluorine in the ligand , an electron withdrawing group , stabilises the carboxylate anion and increases the acidity of the molecule , making it more reactive . this pattern of reactivity can be observed experimentally on a larger scale . when the solvent - free reaction of diflunisal with biph 3 was conducted in an oil bath maintained at 70 ° c . a gradual colour change from colourless to yellow was observed as the reaction proceeded . the formation of a ‘ reactive ’ liquid phase was not visible by the naked eye . analysis of the final product 4 is consistent with that obtained from the solvent free reaction conducted at 120 ° c ., and that obtained by reflux in toluene . the low melting point of pure ibuprofen ( 76 ° c .) means the reactive melt phase with biph 3 occurs at the relatively low temperature of 65 ° c . this depressed melting point for the mixture is lower than that of both reactants . the dsc trace , fig4 , indicates that the reaction to form the tris - substituted product occurs rapidly thereafter . therefore the solvent free reaction was conducted at 85 ° c . for only 2 h , leading to near quantitative formation of 3 . if the standard gp2 conditions are employed ( ie 4 h ) there is clear evidence of partial decomposition as the liquid phase blackens and an impure solid is obtained on cooling and extraction . to assess the compounds for stability to atmospheric moisture , microanalytical data was collected on a regular basis over a period of six months . during this time there was no appreciable change in the mass % of c , h and n indicating that the compounds are air stable over that time , or hydrolyse only very slowly . the compounds were also suspended in deionised water and stirred overnight before being collected by filtration and dried . melting point analyses indicted little or no decomposition . the compounds also appear to be stable in solution . nmr spectra on the compounds were recorded in c 6 d 6 before and after the addition of two drops of d 2 o . there were no observable changes in the chemical shift patterns . the underlying premise of generating the bismuth derivatives of nsaids is that on oral administration the complexes decompose in the acidic environment of the stomach , thereby producing bismuth salts capable of assisting gi protection and healing , and killing h . pylori . this would be accompanied by liberation of the nsaid , predominantly in its free acid form ( lh ), which on absorption would provide their typical and expected therapeutic effects . to assess this , compounds 1 - 6 were added to a 1m solution of hcl . after 10 - 15 mins any free organic acid generated was extracted into diethyl ether , dried and analysed by nmr , and purity confirmed by melting point analysis . it was found that for all complexes the nsaids in their free acid form were gradually released , and could ultimately be extracted from hcl solution in near quantitative amounts while bi 3 + remained soluble ( presumably as a solution of biocl in hcl ( aq )). dependent on ph and the contents of the stomach , in vivo bismuth can remain bound to ionised carboxylate , form complexes with other intestinal anions ( ci , citrate ) and also bind with sulfur rich proteins . 26 an assessment of the antibacterial activity of complexes 1 - 6 , bismuth tris - salicylate [ bi ( hsal ) 3 ] n bismuth subsalicylate ( bss ), and the nsaids in their free acid form ( lh ) was carried out against three standard laboratory strains of h . pylori : b128 , 251 and 26695 , using compound concentrations ranging from 2 to 0 . 0625 mg ml − 1 . the minimum inhibitory concentration ( mic ) of each was determined by the agar diffusion method ( as described above ). the activity of all complexes was found to be ≧ 6 . 25 μg / ml ; below this confluent growth of the bacteria was observed . these activities compare favourably with those of the control compounds : bismuth salicylate , as prepared in a laboratory , and the commercial sample of bss were active at ≧ 12 . 5 μg / ml , while the nsaids in their free acid form were inactive (& gt ; 25 μg / ml ). the mic value of these complexes is lower than for rbc ( 8 μg / ml ) and for cbs (≧ 12 . 5 μg / ml ) indicating they display better in - vitro anti - bacterial activity . they also compare well with the activity of other bismuth compounds previously reported in the literature ( 4 - 64 μg / ml ). 27 - 29 these data suggest that bismuth complexes 1 - 11 are more effective than current standard bismuth preparations at killing h . pylori strains . one contributing factor to this may be the lack of prior hydrolysis and decomposition meaning the bismuth compounds are applied in their pure bil 3 form rather than in an oxidised ‘ sub ’ form . while this invention has been described in connection with specific embodiments thereof , it will be understood that it is capable of further modification ( s ). this application is intended to cover any variations uses or adaptations of the invention following in general , the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth . as the present invention may be embodied in several forms without departing from the spirit of the essential characteristics of the invention , it should be understood that the above described embodiments are not to limit the present invention unless otherwise specified , but rather should be construed broadly within the spirit and scope of the invention as defined in the appended claims . the described embodiments are to be considered in all respects as illustrative only and not restrictive . various modifications and equivalent arrangements are intended to be included within the spirit and scope of the invention and appended claims . therefore , the specific embodiments are to be understood to be illustrative of the many ways in which the principles of the present invention may be practiced . in the following claims , means - plus - function clauses are intended to cover structures as performing the defined function and not only structural equivalents , but also equivalent structures . “ comprises / comprising ” and “ includes / including ” when used in this specification is taken to specify the presence of stated features , integers , steps or components but does not preclude the presence or addition of one or more other features , integers , steps , components or groups thereof . thus , unless the context clearly requires otherwise , throughout the description and the claims , the words ‘ comprise ’, ‘ comprising ’, ‘ includes ’, ‘ including ’ and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense ; 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