Patent Application: US-68757007-A

Abstract:
the invention provides , inter alia , novel bisphosphonate compounds and methods of making and using . in embodiments , the invention provides compounds and methods in connection with research and therapeutic applications , e . g ., for tumor cell growth inhibition , activation of gammadelta t cells , inhibition of farnesyldiphosphate and / or undecaprenyldiphosphate synthase enzymes , bone resorption diseases , cancer , immune disorders , immunotherapy , and infectious diseases . in regards to certain embodiments , a surprising advance has been the recognition that certain structural features can significantly enhance the activity of the compounds . for example , the presence of particular cationic species e . g ., phosphonium , sulfonium , and arsonium moieties can contribute to desirable functional activity when positioned near a bisphosphonate moiety . in other embodiments of non - nitrogen containing bisphosphonates , terphenyl and benzyl bisphosphonate compounds and methods are provided . further variations are also provided .

Description:
the invention may be further understood by the following non - limiting examples . the following abbreviations are applicable . fpps , farnesyl diphosphate synthase ; upps ( undecaprenyl pyrophosphate synthetase ; also known as undecaprenyl diphosphate synthase ); pic 50 / pec 50 , negative log of ic 50 and ec 50 , respectively , where ic 50 and ec 50 are the concentrations that produce half - maximal inhibition or activation , respectively ; t . brucei , trypanosoma brucei ; d . discoideum , dictyostelium discoideum ; γδ t cells , gamma delta t cells . bisphosphonate compounds are typically designated by a number . the following definitions are applicable . these definitions are intended to relate in particular to compounds having the general formula bx1 but can also apply to other compounds set forth herein . alkyl groups include straight - chain , branched and cyclic alkyl groups . alkyl groups include those having from 1 to 20 carbon atoms . alkyl groups include small alkyl groups having 1 to 3 carbon atoms . alkyl groups include medium length alkyl groups having from 4 - 10 carbon atoms . alkyl groups include long alkyl groups having more than 10 carbon atoms , particularly those having 10 - 20 carbon atoms . cyclic alkyl groups include those having one or more rings . cyclic alkyl groups include those having a 3 -, 4 -, 5 -, 6 -, 7 -, 8 -, 9 - or 1 0 - member carbon ring and particularly those having a 3 -, 4 -, 5 -, 6 -, or 7 - member ring . the carbon rings in cyclic alkyl groups can also carry alkyl groups . cyclic alkyl groups can include bicyclic and tricyclic alkyl groups . alkyl groups optionally include substituted alkyl groups . substituted alkyl groups include among others those which are substituted with aryl groups , which in turn can be optionally substituted . specific alkyl groups include methyl , ethyl , n - propyl , iso - propyl , cyclopropyl , n - butyl , s - butyl , t - butyl , cyclobutyl , n - pentyl , branched - pentyl , cyclopentyl , n - hexyl , branched hexyl , and cyclohexyl groups , all of which are optionally substituted . alkenyl groups include straight - chain , branched and cyclic alkenyl groups . alkenyl groups include those having 1 , 2 or more double bonds and those in which two or more of the double bonds are conjugated double bonds . alkenyl groups include those having from 2 to 20 carbon atoms . alkenyl groups include small alkyl groups having 2 to 3 carbon atoms . alkenyl groups include medium length alkenyl groups having from 4 - 10 carbon atoms . alkenyl groups include long alkenyl groups having more than 10 carbon atoms , particularly those having 10 - 20 carbon atoms . cyclic alkenyl groups include those having one or more rings . cyclic alkenyl groups include those in which a double bond is in the ring or in an alkenyl group attached to a ring . cyclic alkenyl groups include those having a 3 -, 4 -, 5 -, 6 -, 7 -, 8 -, 9 - or 10 - member carbon ring and particularly those having a 3 -, 4 -, 5 -, 6 - or 7 - member ring . the carbon rings in cyclic alkenyl groups can also carry alkyl groups . cyclic alkenyl groups can include bicyclic and tricyclic alkyl groups . alkenyl groups are optionally substituted . substituted alkenyl groups include among others those which are substituted with alkyl or aryl groups , which groups in turn can be optionally substituted . specific alkenyl groups include ethenyl , prop - 1 - enyl , prop - 2 - enyl , cycloprop - 1 - enyl , but - 1 - enyl , but - 2 - enyl , cyclobut - 1 - enyl , cyclobut - 2 - enyl , pent - 1 - enyl , pent - 2 - enyl , branched pentenyl , cyclopent - 1 - enyl , hex - 1 - enyl , branched hexenyl , cyclohexenyl , all of which are optionally substituted . aryl groups include groups having one or more 5 - or 6 - member aromatic or heteroaromatic rings . aryl groups can contain one or more fused aromatic rings . heteroaromatic rings can include one or more n , o or s atoms in the ring . heteroaromatic rings can include those with one , two or three n , those with one or two o , and those with one or two s . aryl groups are optionally substituted . substituted aryl groups include among others those which are substituted with alkyl or alkenyl groups , which groups in turn can be optionally substituted . specific aryl groups include phenyl groups , biphenyl groups , pyridinyl groups , and naphthyl groups , all of which are optionally substituted . arylalkyl groups are alkyl groups substituted with one or more aryl groups wherein the alkyl groups optionally carry additional substituents and the aryl groups are optionally substituted . specific alkylaryl groups are phenyl - substituted alkyl groups , e . g ., phenylmethyl groups . alkylaryl groups are aryl groups substituted with one or more alkyl groups wherein the alkyl groups optionally carry additional substituents and the aryl groups are optionally substituted . specific alkylaryl groups are alkyl - substituted phenyl groups such as methylphenyl . the rings that may be formed from two or more of r 1 - r 5 together can be optionally substituted cycloalkyl groups , optionally substituted cycloalkenyl groups or aromatic groups . the rings may contain 3 , 4 , 5 , 6 , 7 or more carbons . the rings may be heteroaromatic in which one , two or three carbons in the aromatic ring are replaced with n , o or s . the rings may be heteroalkyl or heteroalkenyl , in which one or more ch 2 groups in the ring are replaced with o , n , nh , or s . optional substitution of any alkyl , alkenyl and aryl groups includes substitution with one or more of the following substituents : halogens , — cn , — coor , — or , — cor , — ocoor , — con ( r ) 2 , — ocon ( r ) 2 , — n ( r ) 2 , — no 2 , — sr , — so 2 r , — so 2 n ( r ) 2 or — sor groups . optional substitution of alkyl groups includes substitution with one or more alkenyl groups , aryl groups or both , wherein the alkenyl groups or aryl groups are optionally substituted . optional substitution of alkenyl groups includes substitution with one or more alkyl groups , aryl groups , or both , wherein the alkyl groups or aryl groups are optionally substituted . optional substitution of aryl groups includes substitution of the aryl ring with one or more alkyl groups , alkenyl groups , or both , wherein the alkyl groups or alkenyl groups are optionally substituted . optional substituents for alkyl , alkenyl and aryl groups include among others : — coor where r is a hydrogen or an alkyl group or an aryl group and more specifically where r is methyl , ethyl , propyl , butyl , or phenyl groups all of which are optionally substituted ; — cor where r is a hydrogen , or an alkyl group or an aryl groups and more specifically where r is methyl , ethyl , propyl , butyl , or phenyl groups all of which groups are optionally substituted ; — con ( r ) 2 where each r , independently of each other r , is a hydrogen or an alkyl group or an aryl group and more specifically where r is methyl , ethyl , propyl , butyl , or phenyl groups all of which groups are optionally substituted ; r and r can form a ring which may contain one or more double bonds ; — ocon ( r ) 2 where each r , independently of each other r , is a hydrogen or an alkyl group or an aryl group and more specifically where r is methyl , ethyl , propyl , butyl , or phenyl groups all of which groups are optionally substituted ; r and r can form a ring which may contain one or more double bonds ; p 13 n ( r ) 2 where each r , independently of each other r , is a hydrogen , or an alkyl group , acyl group or an aryl group and more specifically where r is methyl , ethyl , propyl , butyl , or phenyl or acetyl groups all of which are optionally substituted ; or r and r can form a ring which may contain one or more double bonds . — sr , — so 2 r , or — sor where r is an alkyl group or an aryl groups and more specifically where r is methyl , ethyl , propyl , butyl , phenyl groups all of which are optionally substituted ; for — sr , r can be hydrogen ; — so 2 n ( r ) 2 where r is a hydrogen , an alkyl group , or an aryl group and r and r can form a ring ; — or where r ═ h , alkyl , aryl , or acyl ; for example , r can be an acyl yielding — ocor * where r * is a hydrogen or an alkyl group or an aryl group and more specifically where r * is methyl , ethyl , propyl , butyl , or phenyl groups all of which groups are optionally substituted ; specific substituted alkyl groups include haloalkyl groups , particularly trihalomethyl groups and specifically trifluoromethyl groups . specific substituted aryl groups include mono -, di -, tri , tetra - and pentahalo - substituted phenyl groups ; mono -, di -, tri -, tetra -, penta -, hexa -, and hepta - halo - substituted naphthalene groups ; 3 - or 4 - halo - substituted phenyl groups , 3 - or 4 - alkyl - substituted phenyl groups , 3 - or 4 - alkoxy - substituted phenyl groups , 3 - or 4 - rco - substituted phenyl , 5 - or 6 - halo - substituted naphthalene groups . more specifically , substituted aryl groups include acetylphenyl groups , particularly 4 - acetylphenyl groups ; fluorophenyl groups , particularly 3 - fluorophenyl and 4 - fluorophenyl groups ; chlorophenyl groups , particularly 3 - chlorophenyl and 4 - chlorophenyl groups ; methylphenyl groups , particularly 4 - methylphenyl groups , and methoxyphenyl groups , particularly 4 - methoxyphenyl groups . certain embodiments are exemplified by compounds of formula bx1 as disclosed herein . in embodiments , the invention provides compounds having the following general structural formula cxa ( which in many embodiments constitutes a subset of bx1 ). in embodiments , the invention specifically provides compounds with a charged sulfonium group , a charged phosphonium group , charged arsonium group , charged ammonium group , uncharged aromatic groups , taxane groups , and related bisphosphonate compounds . other compounds are also provided . see , e . g ., formula cxa : r 1 - r 3 , independently of one another and other r groups , are selected from the group consisting of a hydrogen , a halogen , a — cn , — or , — coor , — ocoor , — cor , — con ( r ) 2 , — ocon ( r ) 2 , — n ( r ) 2 , — no 2 , — sr , — so 2 r , — so 2 n ( r ) 2 or — sor group , an optionally substituted alkyl group , an optionally substituted alkenyl group , and an optionally substituted aryl group , where each r , independent of any other r in any listed group , is selected from h , an optionally substituted alkyl group and an optionally substituted aryl group , an optionally substituted acyl group ; two or more of r 1 - r 5 can together form one or more rings which may contain one or more double bonds or which may be aromatic ; and r 1 , r 2 , and r 3 , independently of each other , are selected from the group consisting of a hydrogen , an optionally substituted alkyl group , an optionally substituted alkenyl group , an optionally substituted alkoxy group , and an optionally substituted aryl group , where each r , independent of any other r in any listed group , is selected from h , an optionally substituted alkyl group and an optionally substituted aryl group . in an example of a salt , x can be a cation such as na +. for an ester , x can be , for example , pivaloyloxymethylene , isopropyloxycarbonyl , and / or other structure as would be understood in the art . in a specific embodiment , compounds 527 , 540 , 546 , 547 , 550 , 564 , 569 , 572 , 573 , 574 , 575 , 576 , 580 , 581 , 584 , 585 , 587 , 589 , and 594 ; and pharmaceutically acceptable salts , and esters thereof ; are useful for treatment of a bone resorption clinical disorder . in a specific embodiment , compounds 527 , 540 , 546 , 547 , 550 , 564 , 569 , 572 , 573 , 574 , 575 , 576 , 580 , 581 , 584 , 585 , 587 , 589 , and 594 ; and pharmaceutically acceptable salts , and esters thereof ; are useful in treatment of protozoan diseases , useful for treatment of a bone resorption clinical disorder , and for immunotherapy . in a specific embodiment , compounds , the des - hydroxy ( where x is h ) analogs of compounds 527 , 540 , 546 , 547 , 550 , 564 , 569 , 572 , 573 , 574 , 575 , 576 , 580 , 581 , 584 , 585 , 587 , 589 , and 594 ; and pharmaceutically acceptable salts , and esters thereof ; are useful in the treatment of a bone resorption clinical disorder . we report the synthesis and testing of a series of novel bisphosphonates . the most potent molecules have high activity and can represent useful compositions for a variety of applications such as in bone resorption disorders , parasitic diseases , bacterial diseases , immunomodulation , and cancer . the following general methods were used as shown in schemes 1 - 3 . this is a non - limiting embodiment and various a groups ( x ═ h , f , me ) may also be produced using methods well known in the art . scheme 1 ( top ), scheme 2 ( middle ), and scheme 3 ( bottom ). see also fig1 and fig2 . bisphosphonate compounds were tested regarding tumor cell growth inhibition . certain compounds were found to have potent activity in inhibiting tumor cell growth in breast ( mcf - 7 ), lung ( nih - h460 ) and central nervous system ( sf - 268 , glioblastoma ) cell lines . see table 1 and fig3 showing dose - response data . certain compounds were also tested regarding the ability to inhibit undecaprenyl diphosphate synthase ( upps ). see results in table 2 . the data demonstrated that compounds were able to inhibit upps with ic50 values at even the submicromolar level , which is important in bacterial peptidoglycan biosynthesis such as in escherichia coli . this indicates that the compounds can be useful in antimicrobial applications . for example , an antibacterial treatment can include contacting a bacterial cell with a compound of the invention . in an embodiment , a bacterial cell can be , e . g ., a gram negative organism such as e . coli or a gram positive organism such as staphylococcus aureus . general method a ) suzuki coupling ): an aryl boronic acid or its ester ( 6 mmol ), a bromo substitued aromatic compound ( 5 mmol ), k 2 co 3 ( 15 mmol ) and pd ( pph 3 ) 4 ( 50 mg ) in toluene ( 10 ml ) and h 2 o ( 3 ml ) were refluxed under n 2 overnight . upon extraction with diethyl ether , the product was purified by column chromatgraphy . general method c ( alkylation of tetramethyl methylenebisphosphonate ): tetramethyl methylenebisphosphonate ( 2 mmol ) in dry dmf ( 2 ml ) was treated with nah ( 2 . 2 mmol ) in ice bath . a benzyl bromide ( 2 mmol ) was added to the resulting solution . the reaction mixture was stirred at room temperature for 1 h before quenched with saturated nh 4 cl . the product was extracted with diethyl ether and purified by column chromatography . general method d ( transesterification ): the tetramethyl ester of a bisphosphonic acid ( 1 mmol ), nal ( 4 mmol ) and chloromethyl pivalate ( 5 mmol ) ( or chloromethyl isopropyl carbonate when making ipc esters ) were refluxed overnight under n 2 in dry acetonitrile ( 5 ml ). upon removal of solvent , the residue was partitioned between water and diethyl ether and the organic layer was washed with water and concentrated . the product was purified by using a flash column chromatography ( silica gel , hexane / ethyl acetate : 10 / 1 , then ethyl acetate ). general method e ( synthesis of terphenylbisphosphonate ): the methyl ester of a carboxylic acid ( 1 mmol ) was hydrolyzed with 3 n naoh ( 1 ml ) in methanol ( 5 ml ) at room temperature for 1 h . after acidification with 2 n hcl , methanol was removed and the resulting carboxylic acid filtered , then washed with water . the dried acid was dissolved in benzene ( 5 ml ) and oxalyl chloride ( 2 mmol ) added , followed by one drop of dmf . the reaction mixture was stirred for 1 h . upon removal of solvent , the crude acid chloride obtained was dissolved in dry thf ( 5 ml ) and p ( otms ) 3 ( 2 mmol ) added . after 3 h at room temperature , solvent was removed and methanol - h 2 0 ( 2ml , 1 : 1 ) was added and the mixture stirred for 30 minutes . concentrated aqueous naoh was then added to precipitate the target compound , which was washed thoroughly with methanol then ether and dried to afford the bisphosphonic acids as their sodium salts . 2 -( 3 , 4 - dibromophenyl ) ethylidene - 1 , 1 - bisphosphonic acid ( 491 ). compound 491 was prepared from 3 , 4 - dibromobenzyl bromide ( 1 mmol ) following general method c , followed by hydrolysis with bromotrimethylsilane as a white powder ( 275 mg , 65 % overall yield ). anal . ( c 8 h 10 br 2 o 6 p 2 ) c , h ; 1 h nmr ( 400 mhz , d 2 o ): δ 2 . 78 ( tt , j = 20 . 8 hz , 6 . 8 hz , 1h , arch 2 ch ), 3 . 12 ( td , j = 17 . 2 hz , 6 . 8 hz , 2h , arch 2 ), 7 . 10 ( d , j = 8 . 4 hz , 1h , aromatic ), 7 . 43 ( d , j = 8 . 4 hz , 1h , aromatic ), 7 . 56 ( s , 1h , aromatic ); 31 p nmr ( 162 mhz , cdcl 3 ): δ19 . 87 . tetrakis - pivaloyloxymethyl 2 -( 3 , 4 - dibromophenyl ) ethylidene - 1 , 1 - bisphosphonate ( 493 ). compound 493 was prepared from 3 , 4 - dibromobenzyl bromide ( 1 mmol ) following general method c , followed by general method d , as a pale yellow powder ( 159 mg , 18 % overall yield ). anal . ( c 32 h 50 br 2 o 14 p 2 ) c , h ; 1 h nmr ( 400 mhz , cdcl 3 ): δ1 . 21 ( m , 36h , ch 3 ), 2 . 79 ( tt , j = 24 . 8 hz , 6 . 8 hz , 1h , arch 2 ch ), 3 . 08 ( td , j = 17 . 2 hz , 6 . 8 hz , 2h , arch 2 ), 5 . 62 - 5 . 69 ( m , 8h , poch 2 ), 7 . 10 ( d , j = 8 . 4 hz , 1h , aromatic ), 7 . 43 ( d , j = 8 . 4 hz , 1h , aromatic ), 7 . 56 ( s , 1h , aromatic ); 31 p nmr ( 162 mhz , cdcl3 ): δ20 . 35 . tetrakis - pivaloyloxymethyl 2 -( 3 , 4 - dichlorophenyl ) ethylidene - 1 , 1 - bisphosphonate ( 494 ). compound 494 was prepared from 3 , 4 - dichlorobenzyl bromide ( 1 mmol ) following general method c , followed by general method d , as a pale yellow powder ( 153 mg , 21 %). anal . ( c 32 h 50 cl 2 o 14 p 2 ) c , h ; 1 h nmr ( 400 mhz , cdcl 3 ): δ1 . 21 ( m , 36h , ch 3 ), 2 . 80 ( tt , j = 24 . 8 hz , 6 . 8 hz , 1h , arch 2 ch ), 3 . 15 ( td , j = 17 . 2 hz , 6 . 8 hz , 2h , arch 2 ), 5 . 62 - 5 . 69 ( m , 8h , poch 2 ), 7 . 10 ( d , j = 8 . 4 hz , 1h , aromatic ), 7 . 33 - 7 . 35 ( m , 2h , aromatic ); 31 p nmr ( 162 mhz , cdcl3 ): δ20 . 41 . tetrakis - isopropoxycarboxymethyl 2 -( 3 , 4 - dichlorophenyl ) ethylidene - 1 , 1 - bisphosphonate ( 495 ). compound 495 was prepared from 3 , 4 - dichlorobenzyl bromide ( 1 mmol ) following general method c , followed by general method d , as a pale yellow powder ( 136 mg , 17 %). anal . ( c 28 h 42 cl 2 o 18 p 2 ) c , h ; 1 h nmr ( 500 mhz , cdcl 3 ): δ1 . 32 ( d , j = 6 . 4 hz , 24h , ch 3 ), 2 . 75 ( tt , j = 24 . 4 hz , 6 . 4 hz , 1 h , arch 2 ch ), 3 . 47 ( td , j = 17 . 2 hz , 6 . 8 hz , 2h , arch 2 ), 4 . 89 - 4 . 95 ( m , 4h , chme 2 ), 5 . 60 - 5 . 70 ( m , 8h , och 2 0 ), 7 . 13 ( d , j = 6 . 8 hz , 1h , aromatic ), 7 . 35 ( d , j = 6 . 8 hz , 1 h , aromatic ), 7 . 38 ( s , 1 h , aromatic ); 31 p nmr ( 162 mhz , cdcl 3 ): δ21 . 85 . tetrakis - isopropoxycarboxymethyl 2 -( 3 , 4 - difluorophenyl ) ethylidene - 1 , 1 - bisphosphonate ( 496 ). compound 496 was prepared from 3 , 4 - difluorobenzyl bromide ( 1 mmol ) following general method c , followed by general method d , as a pale yellow powder ( 107 mg , 14 %). anal . ( c 28 h 42 f 2 o 18 p 2 ) c , h ; 1 h nmr ( 400 mhz , cdcl 3 ): δ1 . 33 ( d , j = 6 . 4 hz , 24h , ch 3 ); 2 . 88 ( tt , j = 24 . 4 hz , j = 6 . 4 hz , 1 h , arch 2 ch ), 3 . 40 ( td , j = 17 . 2 hz , 6 . 8 hz , 2h , arch 2 ), 4 . 89 - 4 . 95 ( m , 4h , chme 2 ), 5 . 60 - 5 . 72 ( m , 8h , och 2 o ), 6 . 99 - 7 . 13 ( m , 3h , aromatic ); 31 p nmr ( 162 mhz , cdcl 3 ): δ21 . 94 . 19 f nmr ( 376 mhz , cdcl 3 ): −- 140 . 79 ˜− 140 . 67 ( m , 1f ), − 138 . 08 ˜− 137 . 97 ( m , 1f ). tetrakis - isopropoxycarboxymethyl 2 -( 3 - cyanophenyl ) ethylidene - 1 , 1 - bisphosphonate ( 498 ). compound 498 was prepared from 3 - cyanobenzyl bromide ( 1 mmol ) following general method c , followed by general method d , as a pale yellow powder ( 91 mg , 12 %). anal . ( c 29 h 43 no 18 p 2 ) c , h , n ; 1 h nmr ( 400 mhz , cdcl 3 ): δ1 . 31 ( d , j = 6 . 4 hz , 24h , ch 3 ), 2 . 79 ( tt , j = 20 . 8 hz , j = 6 . 8 hz , 1 h , arch 2 ch ), 3 . 40 ( td , j = 16 . 8 hz , 6 . 8 hz , 2h , arch 2 ), 4 . 89 - 4 . 96 ( m , 4h , chme 2 ), 5 . 60 - 5 . 70 ( m , 8h , och 2 o ), 7 . 36 ( t , j = 8 hz , 1h , aromatic ), 7 . 50 - 7 . 54 ( m , 2h , aromatic ), 7 . 57 ( s , 1 h , aromatic ); 31 p nmr ( 162 mhz , cdcl 3 ): δ21 . 70 . 1 - hydroxy - 2 -[ 3 -( 3 - phenylphenyl ) phenyl ] ethylidene - 1 , 1 - bisphsophonic acid ( 608 ). compound 608 was prepared from methyl 3 -( 3 - phenylphenyl ) phenylacetate ( 1 mmol ), following general method e as a white powder ( 265 mg , 56 %). anal . ( c 20 h 19 nao 7 p 2 . h 2 o ) c , h ; 1 h nmr ( 400 mhz , d 2 o ): δ3 . 23 ( t , j = 12 hz , 2h , ch 2 ), 7 . 20 - 7 . 80 ( m , 13h , aromatic ); 31 p nmr ( 162 hz , d 2 o ): δ19 . 20 . 1 - hydroxy - 3 -[ 3 -( 4 - phenylphenyl ) phenyl ] propylidene - 1 , 1 - bisphosphonic acid ( 618 ). compound 618 was prepared from methyl 3 -( 4 - phenylphenyl ) phenylpropionate ( 1 mmol ), following general method e as a white powder ( 270 mg , 55 %). anal . ( c 21 h 20 o 7 p 2 na 2 ) c , h ; 1 h nmr ( 400 mhz , d 2 o ): δ2 . 05 - 2 . 10 ( m , 2h , ch 2 ), 2 . 80 - 2 . 85 ( m , 2h , arch 2 ), 7 . 22 - 7 . 32 ( m , 6h , aromatic ), 7 . 35 - 7 . 64 ( m , 7h , aromatic ); 31 p nmr ( 162 mhz , d 2 o ): δ19 . 08 . 1 - hydroxy - 3 -[ 3 -( 2 - phenylphenyl ) phenyl ] propylidene - 1 , 1 - bisphosphonic acid ( 621 ). compound 621 was prepared from methyl 3 -( 2 - phenylphenyl ) phenylpropioate ( 1 mmol ), following general method e as a white powder ( 271 mg , 51 %). anal . ( c 21 h 19 o 7 p 2 na 3 - h 2 o ) c , h ; 1 h nmr ( 500 mhz , d 2 o ): 61 . 98 - 2 . 10 ( m , 2h , ch 2 ), 2 . 69 - 2 . 72 ( m , 2h , arch 2 ), 6 . 70 ( d , j = 6 . 5 hz , 1h , aromatic ), 6 . 97 ( t , j = 7 . 5 hz , 1h , aromatic ), 7 . 04 - 7 . 17 ( m , 7h , aromatic ), 7 . 32 - 7 . 45 ( m , 4h , aromatic ). 31 p nmr ( 202 mhz , d 2 o ): δ19 . 38 . 1 - hydroxy - 3 -[ 3 -( 3 - phenylphenyl ) phenyl ] propylidene - 1 , 1 - bisphsophonic acid ( 622 ). compound 622 was prepared from methyl 3 -( 3 - phenylphenyl ) phenylpropioate ( 1 mmol ), following general method e as a white powder ( 324 mg , 61 %). anal . ( c 21 h 19 o 7 p 2 na 3 . h 2 o ) c , h ; 1 h nmr ( 400 hz , d 2 o ): δ2 . 01 - 2 . 12 ( m , 2h , ch 2 ), 2 . 80 - 2 . 85 ( m , 2h , arch 2 ), 7 . 23 - 7 . 57 ( m , 12h , aromatic ), 7 . 77 ( s , 1 h , aromatic ); 31 p nmr ( 162 hz , d 2 o ): δ19 . 41 . 1 - hydroxy - 2 -[ 3 -( 2 - phenylphenyl ) phenyl ] ethylidene - 1 , 1 - bisphsophonic acid ( 623 ). compound 623 was prepared from methyl 3 -( 2 - phenylphenyl ) phenylacetate ( 1 mmol ), following general method e as a white powder ( 213 mg , 43 %). anal . ( c 20 h 18 o 7 p 2 na 2 . h 2 o ) c , h ; 1 h nmr ( 400 mhz , d 2 o ): δ3 . 10 ( t , j = 12 hz , 2h , ch 2 ), 6 . 73 - 7 . 40 ( m , 13h , aromatic ). 31 p nmr ( 162 hz , d 2 o ): δ19 . 23 . 1 - hydroxy - 2 -[ 4 -( 2 - phenylphenyl ) phenyl ] ethylidene - 1 , 1 - bisphosphonic acid ( 624 ). compound 624 was prepared from methyl 4 -( 2 - phenylphenyl ) phenylacetate ( 1 mmol ), following general method e as a white powder ( 232 mg , 45 %). anal . ( c 20 h 18 o 7 p 2 na 2 . 2h 2 o ) c , h ; 1 h nmr ( 400 mhz , d 2 o ) δ3 . 06 ( t , j = 12 . 4 hz , ch 2 ), 6 . 94 ( d , j = 8 hz , 2h , aromatic ), 7 . 01 - 7 . 07 ( m , 2h , aromatic ), 7 . 11 - 7 . 17 ( m , 4h , aromatic ), 7 . 30 - 7 . 39 ( m , 5h , aromatic ); 31 p nmr ( 162 mhz , d 2 o ): δ18 . 97 . 1 - hydroxy - 2 -[ 4 -( 3 - phenylphenyl ) phenyl ] ethylidene - 1 , 1 - bisphosphonic acid ( 625 ). compound 625 was prepared from methyl 4 -( 3 - phenylphenyl ) phenylacetate ( 1 mmol ), following general method e as a white powder ( 201 mg , 44 %). anal . ( c 20 h 19 o 7 p 2 na ) c , h ; 1 h nmr ( 400 mhz , d 2 o ) δ3 . 21 ( t , j = 12 . 4 hz , ch 2 ), 7 . 27 ( t , j = 7 . 2 hz , 1h , aromatic ), 7 . 34 - 7 . 60 ( m , 11h , aromatic ), 7 . 80 ( s , 1h , aromatic ); 31 p nmr ( 162 mhz , d 2 o ): δ19 . 11 . 1 - hydroxy -[ 3 -( 3 - phenylphenyl ) phenyl ] methylene - 1 , 1 - bisphsophonic acid ( 640 ). compound 640 was prepared from methyl 3 -( 3 - phenylphenyl ) benzoate ( 1 mmol ), following general method e as a white powder ( 174 mg , 40 %). anal . ( c 19 h 17 o 7 p 2 na . 0 . 25h 2 o ) c , h ; 1 h nmr ( 400 mhz , d 2 o ): δ7 . 17 - 7 . 25 ( m , 2h , aromatic ), 7 . 33 ( t , j h - h = 7 . 2 hz , 2h , aromatic ), 7 . 40 ( t , j = 8 hz , 1h , aromatic ), 7 . 47 ( d , j = 7 . 8 hz , 1h , aromatic ), 7 . 56 - 7 . 58 ( m , 4h , aromatic ), 7 . 65 ( d , j = 8 hz , 1 h , aromatic ), 7 . 83 ( s , 2h , aromatic ); 31 p nmr ( 162 mhz , d 2 o ): δ17 . 59 . tetrakis - pivaloyloxymethyl 2 -[ 3 -( 3 - phenylphenyl ) phenyl ] ethylidene - 1 , 1 - bisphosphonate ( 647 ). 3 - biphenyl boronic acid ( 2 . 0g , 10 mmol ), 3 - bromotoluene ( 1 . 7 g , 10 mmol ), k 2 co 3 ( 3 . 0 g , 21 . 7 mmol ) and pd ( pph 3 ) 4 ( 100 mg ) were refluxed in toluene - h 2 o ( 50 ml , 5 / 1 ) overnight under n 2 . upon extraction with diethyl ether , the crude product was then refluxed overnight with n - bromosuccimide ( 1 . 95 g , 11 mmol ) and aibn ( 100 mg ) in anhydrous ccl 4 ( 30 ml ). after being washed successively with 5 % hcl then 10 % nahco 3 , the organic layer was dried and concentrated to give crude 3 -( 3 - phenylphenyl ) benzyl bromide as a white powder . this was then reacted following general method c , followed by general method d , affording compound 647 as a pale yellow powder ( 472 mg , 27 % overall yield ). quantative 1 h nmr indicated 94 % purity . 1 h nmr ( 400 mhz , cdcl 3 ): δ1 . 21 ( m , 36h , ch 3 ), 2 . 80 ( tt , j = 24 . 8 hz , 6 . 8 hz , 1 h , arch 2 ch ), 3 . 15 ( td , j = 17 . 2 hz , 6 . 8 hz , 2h , arch 2 ), 5 . 62 - 5 . 69 ( m , 8h , poch 2 ), 7 . 23 - 7 . 85 ( m , 13h , aromatic ); 31 p nmr ( 162 mhz , cdcl3 ): 6 20 . 52 . 2 -( 3 - cyanophenyl ) ethylidene - 1 , 1 - bisphosphonic acid ( 648 ). compound 648 was prepared from 3 - cyanobenzyl bromide ( 1 mmol ) following general method c , followed by hydrolysis with bromotrimethylsilane as a white powder ( 29 %). anal . ( c 9 h 8 nna 3 o 6 p 2 . h 2 o ) c , h , n ; 1 h nmr ( 400 mhz , d 2 o ): δ2 . 79 ( tt , j = 20 . 8 hz , 6 . 8 hz , 1h , arch 2 ch ), 3 . 40 ( td , j = 16 . 8 hz , 6 . 8 hz , 2h , arch 2 ), 4 . 89 - 4 . 96 ( m , 4h , chme 2 ), 5 . 60 - 5 . 70 ( m , 8h , och 2 o ), 7 . 39 ( t , j = 8 hz , 1h , aromatic ); 7 . 45 - 7 . 52 ( m , 2h , aromatic ), 7 . 59 ( s , 1h , aromatic ); 31 p nmr ( 162 mhz , d 2 o ): δ19 . 81 . a series of novel sulfonium and phosphonium bisphosphonates were produced by using the following general schemes presented below . the synthesis of arsonium and ammonium compounds are able to be achieved as taught herein and by analogy as would be understood in the art . see fig4 illustrating structures of compounds including sulfonium , phosphonium , arsonium , and ammonium analogs . these bisphosphonates were found to have activity against trypanosoma brucei fpps ( anti - parasitic activity ), human fpps ( bone resorption assay ), d . dictyostelium ( bone resorption assay ) and in gamma delta t cell stimulation ( immunotherapy assay ), as shown in the following table 4 . general procedure 1 : a mixture of a carboxylic acid ( 3 mmol ), h 3 po 3 ( 15 mmol ) and toluene ( 8 ml ) were heated to 80 ° c . with stirring . after all solids were melted , pocl 3 ( 15 mmol ) was added slowly and the reaction mixture was vigorously stirred at 80 ° c . for 5 h . upon cooling , toluene was decanted and 6 n hcl ( 3 ml ) was added to the residue . the resulting solution was refluxed for 1 h and most of the solvents were removed in vacuo . isopropanol ( 25 ml ) was added to precipitate the bisphosphonate as a white powder , which was filtered , washed with isopropanol ( 5 × 5 ml ), dried and could be further purified by recrystallization in h 2 o / i - proh . in some cases , it can be neutralized with naoh and crystallized as its sodium salt in h 2 o / etoh . trimethyl phosphine ( 5 mmol , 0 . 52 ml ) was treated with bromoacetic acid ( 5 mmol , 0 . 7 g ) in acetonitrile ( 5 ml ) at room temperature under n 2 overnight , affording 2 - trimethylphosphoniumylacetic acid bromide as a white powder . it was then subjected to the general procedure 1 to give compound 536 as a white powder ( 0 . 65 g , 46 % overall yield ). anal . ( c 5 h 15 o 7 p 3 ) c , h . trimethyl phosphine ( 5 mmol , 0 . 52 ml ) was treated with bromopropionic acid ( 5 mmol , 0 . 77 g ) in acetonitrile ( 10 ml ) at 80 ° c . under n 2 overnight , affording 3 - trimethylphosphoniumylpropionic acid bromide as a white powder . it was then subjected to the general procedure 1 to give compound 541 as a white powder ( 0 . 46 g , 40 % overall yield ). anal . ( c 6 h 17 o 7 p 3 . 0 . 5 h 2 o ) c , h . dimethyl sulfide ( 5 mmol , 0 . 51 g ) was treated with bromoacetic acid ( 5 mmol , 0 . 7 g ) in acetone ( 5 ml ) at room temperature under n 2 overnight , affording 2 - pentamethylenesulfoniumylacetic acid bromide as a white powder . it was then subjected to the general procedure 1 to give compound 3 as a white powder ( 0 . 68 g , 38 % overall yield ). anal . ( c 7 h 16 o 7 p 2 s ) c , h . sodium methanethiolate ( 6 mmol , 0 . 42 g ) and 3 - phenylpropyl bromide ( 5 mmol , 1 g ) in methanol were refluxed overnight . after removal of solvent , diethyl ether was added , washed with h 2 o and evaporated to give 3 - phenylpropylmethyl sulfide . it was then reacted with equivalent amount of bromoacetic acid in acetonitrile ( 5 ml ) at room temperature under n 2 overnight , affording s - methyl - 3 - phenylpropylsulfoniumylacetic acid bromide as a white powder . it was then subjected to the general procedure 1 to give compound 585 as a white powder ( 0 . 75 g , 36 % overall yield ). anal . ( c 12 h 19 nao 7 p 2 s . 0 . 5 c 2 h 5 oh ) c , h . sodium ethanethiolate ( 6 mmol , 0 . 5 g ) and 3 - phenoxypropyl bromide ( 5 mmol , 1 . 1 g ) in ethanol were refluxed overnight . after removal of solvent , ether was added , washed with h 2 0 and evaporated to give 3 - phenoxypropylethyl sulfide . it was treated with 1 equivalent of acrylic acid in acetone in the presence of 4 equivalents of 12 n hcl under n 2 at room temperature overnight and then at 50 ° c . for 3 h , affording 3 -( s - ethyl - 3 - phenoxypropylsulfoniumyl ) propionic acid chloride as a white powder . it was then subjected to the general procedure 1 to give compound 573 as a white powder ( 0 . 58 g , 25 % overall yield ). anal . ( c 14 h 22 na 2 o 8 p 2 s . 0 . 5 h 2 o ) c , h . which can be in zwitterionic form ( e . g ., wherein one , and under certain circumstances more than one , of the oh groups of a phosphonate moiety can be depicted as an oxygen group with a negative charge ) and / or as a pharmaceutically acceptable salt , ester , or hydrate thereof , with variations as would be understood from the teaching herein for other general formulas presented ; r 1 and r 2 , independently of one another and other r groups , are selected from the group consisting of a hydrogen , a halogen , a — cn , — or , — coor , — ocoor , — cor , — con ( r ) 2 , — ocon ( r ) 2 , — n ( r ) 2 , — no 2 , — sr , — so 2 r , — so 2 n ( r ) 2 or — sor group , an optionally substituted alkyl group , an optionally substituted alkenyl group , and an optionally substituted aryl group , where each r , independent of any other r in any listed group , is selected from h , an optionally substituted alkyl group , an optionally substituted aryl group , and an optionally substituted acyl group ; r 1 and r 2 can together form one or more rings which may contain one or more double bonds or which may be aromatic ; r 3 and r 4 , independently of each other and other r 3 and r 4 in the compound , are selected from the group consisting of a hydrogen , a halogen , a — n ( r ) 2 , or — sr group , an optionally substituted alkyl group , an optionally substituted alkenyl group , an optionally substituted alkoxy group , and an optionally substituted aryl group , where each r , independent of any other r in any listed group , is selected from h , an optionally substituted alkyl group and an optionally substituted aryl group ; and wherein r 3 and r 4 can together form a ring which may contain one or more double bonds . in specific embodiments , the invention relates to compounds having the above formula where x is oh . in other specific embodiments , the invention relates to compounds having the above formula where x is h . in other specific embodiments , compounds of the invention are those of formula ca11 . in other specific embodiments , the invention relates to compounds having the above formula wherein n is 1 . in other specific embodiments , the invention relates to compounds having the above formula where x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein n is 2 . in other specific embodiments , the invention relates to compounds having the above formula where x is oh and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein n is 3 . in other specific embodiments , the invention relates to compounds having the above formula where x is oh and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula wherein one or both of r 3 and r 4 are hydrogens . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 3 and r 4 are hydrogens . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 3 and r 4 are hydrogens and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 3 and r 4 are hydrogens , n is 1 and x is oh . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 3 and r 4 are hydrogens and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 3 and r 4 are hydrogens , n is 2 and x is oh . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 3 and r 4 are hydrogens and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 3 and r 4 are hydrogens , n is 3 and x is oh . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 3 and r 4 are hydrogens , n is 1 and x is h . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 , independently of one another , are optionally substituted alkyl groups . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 , independently of one another , are optionally substituted alkyl groups , x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 , independently of one another , are optionally substituted alkyl groups , x is oh and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 , independently of one another , are optionally substituted alkyl groups , x is oh and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 are optionally substituted alkyl groups , x is h and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 , independently of one another , are both optionally substituted alkyl groups . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 , independently of one another , are both optionally substituted alkyl groups , x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 , independently of one another , are both optionally substituted alkyl groups , x is oh and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 , independently of one another , are both optionally substituted alkyl groups , x is oh and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 are both optionally substituted alkyl groups , x is h and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 are both optionally substituted alkyl groups and one or more of r 3 or r 4 is a halogen . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 are both optionally substituted alkyl groups , particularly wherein r 1 is a small alkyl group and more particularly a methyl group , and r 3 and r 4 are both hydrogens . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 are both optionally substituted alkyl groups , particularly wherein r 1 is a small alkyl group and more particularly a methyl group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . specific compounds of this invention are those as above in which r 1 is a methyl group , r 2 is an optionally substituted alkyl group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . a specific compound of this invention is that as above in which r 1 and r 2 are both methyl groups , r 3 and r 4 are both hydrogens , x is oh and n is 1 . a specific compound of this invention is that as above in which r 1 is a methyl group , r 2 is a propyl group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . a specific compound of this invention is that as above in which r 1 is a methyl group , r 2 is a butyl group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . a specific compound of this invention is that as above in which r 1 is a methyl group , r 2 is a pentyl group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . a specific compound of this invention is that as above in which r 1 is a methyl group , r 2 is an octyl group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 are both optionally substituted alkyl groups , particularly wherein r 1 is a small alkyl group and more particularly a methyl group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . specific compounds of this invention are those as above in which r 1 is a methyl group , r 2 is an optionally substituted alkyl group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . a specific compound of this invention is that as above in which r 1 and r 2 are both methyl groups , r 3 and r 4 are both hydrogens , x is oh and n is 2 . a specific compound of this invention is that as above in which r 1 is a methyl group , r 2 is a propyl group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . a specific compound of this invention is that as above in which r 1 is a methyl group , r 2 is a pentyl group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . a specific compound of this invention is that as above in which r 1 is a methyl group , r 2 is an octyl group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 is a small alkyl group and more particularly a methyl group , r 2 is an optionally substituted arylalkyl group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . specific compounds of the invention are those as above in which r 1 is a methyl group , r 2 is an optionally substituted arylalkyl group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . a specific compound of the invention is that as above in which r 1 is a methyl group , r 2 is a propylphenyl group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 is a small alkyl group and more particularly a methyl group , r 2 is an optionally substituted arylalkyl group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . a specific compound of this invention is that as above in which r 1 is a methyl group , r 2 is an ethylphenyl group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . a specific compound of this invention is that as above in which r 1 is a methyl group , r 2 is a propylphenyl group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 is a small alkyl group and more particularly a methyl group , r 2 is an optionally substituted arylalkoxy group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . specific compounds of the invention are those as above in which r 1 is a methyl group , r 2 is an optionally substituted arylalkoxy group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . a specific compound of the invention is that as above in which r 1 is a methyl group , r 2 is a propoxybenzyl group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 is a small alkyl group and more particularly a methyl group , r 2 is an optionally substituted arylalkoxy group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . specific compounds of the invention are those as above in which r 1 is a methyl group , r 2 is an optionally substituted arylalkoxy group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . a specific compound of the invention is that as above in which r 1 is a methyl group , r 2 is a propoxybenzyl group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 is a small alkyl group and more particularly an ethyl group , r 2 is an optionally substituted arylalkoxy group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . specific compounds of the invention are those as above in which r 1 is an ethyl group , r2 is an optionally substituted arylalkoxy group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . a specific compound of the invention is that as above in which r 1 is an ethyl group , r 2 is a propoxybenzyl group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 form an optionally substituted ring , r 3 and r 4 are both hydrogens , x is oh and n is 1 . specific compounds of the invention are those as above in which r 1 and r 2 form an optionally substituted thiophenium group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . a specific compound of the invention is that as above in which r 1 and r 2 form a thiophenium group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . a specific compound of the invention is that as above in which r 1 and r 2 form a 3 - phenylthiophenium group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 form an optionally substituted ring , r 3 and r 4 are both hydrogens , x is oh and n is 2 . specific compounds of the invention are those as above in which r 1 and r 2 form an optionally substituted thiophenium group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . a specific compound of the invention is that as above in which r 1 and r 2 form a thiophenium group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 form an optionally substituted ring , r 3 and r 4 are both hydrogens , x is oh and n is 3 . specific compounds of the invention are those as above in which r 1 and r 2 form an optionally substituted thiophenium group , r 3 and r 4 are both hydrogens , x is oh and n is 3 . a specific compound of the invention is that as above in which r 1 and r 2 form a thiophenium group , r 3 and r 4 are both hydrogens , x is oh and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 form an optionally substituted ring , r 3 and r 4 are both hydrogens , x is oh and n is 1 . specific compounds of the invention are those as above in which r 1 and r 2 form an optionally substituted thiopyranium group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . a specific compound of the invention is that as above in which r 1 and r 2 form a thiopyranium group , r 3 and r 4 are both hydrogens , x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 2 form an optionally substituted ring , r 3 and r 4 are both hydrogens , x is oh and n is 2 . specific compounds of the invention are those as above in which r 1 and r 2 form an optionally substituted thiopyranium group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . a specific compound of the invention is that as above in which r 1 and r 2 form a thiopyranium group , r 3 and r 4 are both hydrogens , x is oh and n is 2 . in a particular embodiment of ca11 , x is oh , n = 1 , r 3 and r 4 are hydrogens , and r 1 and r 2 are selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . of particular interest are those compounds in which r 1 is a methyl group and r 2 is selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . in other specific embodiments , the invention includes compounds of formula ca11 , wherein n is 1 , r 3 and r 4 are hydrogens , x is oh or h , and r 1 and r 2 are selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . of particular interest are those compounds in which r 1 is a methyl group and r 2 is selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . in other specific embodiments , the invention includes compounds of formula ca11 , wherein x is oh , n = 2 , r 3 and r 4 are hydrogens , and r 1 and r 2 are selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . of particular interest are those compounds in which r 1 is a methyl group and r 2 is selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . in other specific embodiments , the invention includes compounds of formula ca11 , wherein n is 2 , r 3 and r 4 are hydrogens , x is oh or h , and r 1 and r 2 are selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . of particular interest are those compounds in which r 1 is a methyl group and r 2 is selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . in other specific embodiments , the invention includes compounds of formula ca11 , wherein x is oh , n = 3 , r 3 and r 4 are hydrogens , and r 1 and r 2 are selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . of particular interest are those compounds in which r 1 is a methyl group and r 2 is selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . in other specific embodiments , the invention includes compounds of formula ca11 , wherein n is 3 , r 3 and r 4 are hydrogens , x is oh or h , and r 1 and r 2 are selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . of particular interest are those compounds in which r 1 is a methyl group and r 2 is selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . in other specific embodiments , the invention includes compounds of formula ca11 , wherein x is oh , n = 2 , r 3 and r 4 are hydrogens , and r 1 and r 2 are selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . of particular interest are those compounds in which r 1 is an ethyl group and r 2 is selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . in other specific embodiments , the invention includes compounds of formula ca11 , wherein n is 2 , r 3 and r 4 are hydrogens , x is oh or h , and r 1 and r 2 are selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . of particular interest are those compounds in which r 1 is an ethyl group and r 2 is selected from the group consisting of optionally substituted alkyl groups , optionally substituted arylalkyl groups and optionally substituted arylalkoxy groups . in other specific embodiments , the invention includes compounds of formula ca11 , wherein n is 1 , r 3 and r 4 are hydrogens , x is oh or h , and r 1 and r 2 form an optionally substituted thiophenium group . of particular interest is that compound where r 1 and r 2 form an unsubstituted thiophenium group or a 3 - phenyl thiophenium group . in other specific embodiments , the invention includes compounds of formula ca11 , wherein n is 2 , r 3 and r 4 are hydrogens , x is oh or h , and r 1 and r 2 form an optionally substituted thiophenium group . of particular interest is that compound where r 1 and r 2 form an unsubstituted thiophenium group . in other specific embodiments , the invention includes compounds of formula ca11 , wherein n is 3 , r 3 and r 4 are hydrogens , x is oh or h , and r 1 and r 2 form an optionally substituted thiophenium group . of particular interest is that compound where r 1 and r 2 form an unsubstituted thiophenium group . in other specific embodiments , the invention includes compounds of formula ca11 , wherein n is 1 , r 3 and r 4 are hydrogens , x is oh or h , and r 1 and r 2 form an optionally substituted thiopyranium group . of particular interest is that compound where r 1 and r 2 form an unsubstituted thiopyranium group . in other specific embodiments , the invention includes compounds of formula ca11 , wherein n is 2 , r 3 and r 4 are hydrogens , x is oh or h , and r 1 and r 2 form an optionally substituted thiopyranium group . of particular interest is that compound where r 1 and r 2 form an unsubstituted thiopyranium group . which can be in zwitterionic form ( e . g ., wherein one , and under certain circumstances more than one , of the oh groups of a phosphonate moiety can be depicted as an oxygen group with a negative charge ) and / or as a pharmaceutically acceptable salt , ester , or hydrate thereof , with variations as would be understood from the teaching herein for other general formulas presented ; r 1 - r 3 , independently of one another and other r groups , are selected from the group consisting of a hydrogen , a halogen , a — cn , — or , — coor , , — ocoor , — cor , — con ( r ) 2 , — ocon ( r ) 2 , — n ( r ) 2 , — no 2 , — sr , — so 2 r , — so 2 n ( r ) 2 or — sor group , an optionally substituted alkyl group , an optionally substituted alkenyl group , and an optionally substituted aryl group , where each r , independent of any other r in any listed group , is selected from h , an optionally substituted alkyl group , an optionally substituted aryl group , and an optionally substituted acyl group ; two or more of r 4 - r 5 can together form one or more rings which may contain one or more double bonds or which may be aromatic ; r 4 and r 5 , independently of each other and other r 4 and r 5 in the compound , are selected from the group consisting of a hydrogen , a halogen , a — n ( r ) 2 , or — sr group , an optionally substituted alkyl group , an optionally substituted alkenyl group , an optionally substituted alkoxy group , and an optionally substituted aryl group , where each r , independent of any other r in any listed group , is selected from h , an optionally substituted alkyl group and an optionally substituted aryl group ; and wherein r 4 and r 5 can together form a ring which may contain one or more double bonds . in specific embodiments , the invention relates to compounds having the above formula where x is oh . in other specific embodiments , the invention relates to compounds having the above formula where x is h . in other specific embodiments , compounds of the invention are those of formula ca12 . in other specific embodiments , the invention relates to compounds having the above formula wherein n is 1 . in other specific embodiments , the invention relates to compounds having the above formula where x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein one or both of r 4 and r 5 are hydrogens . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 4 and r 5 are hydrogens . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 4 and r 5 are hydrogens and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 4 and r 5 are hydrogens , n is 1 and x is oh . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 4 and r 5 are hydrogens , n is 1 and x is h . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 - r 3 are optionally substituted alkyl groups chosen independently of one another and r 4 - r 5 are both hydrogens . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 - r 3 are optionally substituted alkyl groups chosen independently of one another , r 4 - r 5 are both hydrogens , x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 - r 3 are optionally substituted alkyl groups chosen independently of one another , r 4 - r 5 are both hydrogens , x is h and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 4 and r 5 are both hydrogens , and r 1 , r 2 and r 3 are optionally substituted alkyl groups chosen independently of one another , particularly small alkyl groups and more particularly methyl groups . in other specific embodiments , the invention relates to compounds having the above formula wherein r 4 and r 5 are both hydrogens , r 1 , r 2 and r 3 optionally substituted alkyl groups chosen independently of one another , particularly small alkyl groups and more particularly methyl groups , x is oh and n is 1 . specific compounds of this invention are those as above in which r 4 and r 5 are both hydrogens , r 2 , r 3 and r 4 are methyl groups , x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 4 and r 5 are both hydrogens , r 1 , r 2 and r 3 are optionally substituted alkyl groups chosen independently of one another , particularly small alkyl groups and more particularly methyl groups , x is oh and n is 2 . specific compounds of this invention are those as above in which r 4 and r 5 are both hydrogens , r 2 , r 3 and r 4 are methyl groups , x is oh and n is 1 . in a particular embodiment of ca12 , x is oh , n = 1 , r 1 - r 3 are methyl groups and r 4 - r 5 are hydrogens . in other specific embodiments , the invention includes compounds of formula ca12 , wherein n is 1 , r 1 - r 3 are methyl groups and r 4 - r 5 are hydrogens , x is oh or h . in other specific embodiments , the invention includes compounds of formula ca12 , wherein n is 2 , r 1 - r 3 are methyl groups and r 4 - r 5 are hydrogens , x is oh or h . in other specific embodiments , the invention includes compounds of formula ca12 , wherein n is 1 , r 4 - r 5 are hydrogens , x is oh and r 1 - r 3 are selected from the group consisting of optionally substituted alkyl groups , optionally substituted alkoxy groups and optionally substituted phenyl groups . in a specific embodiment , compounds 536 and 541 ; and pharmaceutically acceptable salts , and esters thereof ; are useful for treatment of a bone resorption clinical disorder . in a specific embodiment , compounds 536 and 541 ; and pharmaceutically acceptable salts , and esters thereof ; are useful in treatment of protozoan diseases , useful for treatment of a bone resorption clinical disorder , and for immunotherapy . in a specific embodiment , compounds , the des - hydroxy ( where x is h ) analogs of compounds 536 and 541 ; and pharmaceutically acceptable salts , and esters thereof ; are useful in the treatment of a bone resorption clinical disorder . which can be in zwitterionic form ( e . g ., wherein one , and under certain circumstances more than one , of the oh groups of a phosphonate moiety can be depicted as an oxygen group with a negative charge ) and / or as a pharmaceutically acceptable salt , ester , or hydrate thereof , with variations as would be understood from the teaching herein for other general formulas presented ; r 1 - r 5 , independently of one another and other r groups , are selected from the group consisting of a hydrogen , a halogen , a — cn , — or , — coor , , — ocoor , — cor , — con ( r ) 2 , — ocon ( r ) 2 , — n ( r ) 2 , — no 2 , — sr , — so 2 r , — so 2 n ( r ) 2 or — sor group , an optionally substituted alkyl group , an optionally substituted alkenyl group , and an optionally substituted aryl group , where each r , independent of any other r in any listed group , is selected from h , an optionally substituted alkyl group , an optionally substituted aryl group , and an optionally substituted acyl group ; two or more of r 1 - r 5 can together form one or more rings which may contain one or more double bonds or which may be aromatic ; r 6 and r 7 , independently of each other and other r 6 and r 7 in the compound , are selected from the group consisting of a hydrogen , a halogen , a — n ( r ) 2 , or — sr group , an optionally substituted alkyl group , an optionally substituted alkenyl group , an optionally substituted alkoxy group , and an optionally substituted aryl group , where each r , independent of any other r in any listed group , is selected from h , an optionally substituted alkyl group and an optionally substituted aryl group ; and wherein r 6 and r 7 can together form a ring which may contain one or more double bonds ; and wherein r 8 - r 11 can be chosen from the group consisting of a hydrogen , a pivalolyl ester group , and an isopropyl carbonate group . in specific embodiments , the invention relates to compounds having the above formula where x is h . in other specific embodiments , the invention relates to compounds having the above formula where x is oh . in other specific embodiments , the invention relates to compounds having the above formula where x is a halogen . in other specific embodiments , the invention relates to compounds having the above formula where x is a methyl group . in other specific embodiments , the invention relates to compounds having the above formula wherein n is 1 . in other specific embodiments , the invention relates to compounds having the above formula where x is h and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula where x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula where x is a halogen and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula where x is a methyl group and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein n is 2 . in other specific embodiments , the invention relates to compounds having the above formula where x is h and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula where x is oh and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula where x is a halogen and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula where x is a methyl group and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein n is 3 . in other specific embodiments , the invention relates to compounds having the above formula where x is h and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula where x is oh and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula where x is a halogen and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula where x is a methyl group and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula wherein one or both of r 6 and r 7 are hydrogens . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 6 and r 7 are hydrogens . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 6 and r 7 are hydrogens and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 6 and r 7 are hydrogens , n is 1 and x is h . in other specific embodiments , the invention relates to compounds having the above formula wherein both of r 6 and r 7 are hydrogens , n is 1 and x is oh . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogens . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogen , x is h and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogen , x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogen , x is h and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogen , x is oh and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogen , x is h and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogen , x is oh and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are hydrogens . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are hydrogens , x is h and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are hydrogens , x is oh and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are hydrogens , x is h and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are hydrogens , x is oh and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are hydrogens , x is h and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are hydrogens , x is oh and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are pivalolyl ester groups . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are pivalolyl ester groups , x is h and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are pivalolyl ester groups , x is h and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are pivalolyl ester groups , x is h and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are isopropyl carbonate groups . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are isopropyl carbonate groups , x is h and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are isopropyl carbonate groups , x is h and n is 2 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 8 - r 11 are isopropyl carbonate groups , x is h and n is 3 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogen and one or more of r 2 , r 3 or r 4 is a halogen . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogens , one or more of r 2 , r 3 or r 4 is a halogen , x is h and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogens , one or more of r 2 , r 3 or r 4 is a cyano group . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogens , one or more of r 2 , r 3 or r 4 is a cyano group , x is h and n is 1 . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogens , one or more of r 2 , r 3 or r 4 is an optionally substituted aryl group . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogens , one or more of r 2 , r 3 or r 4 is an optionally substituted aryl group , x is h and n is 1 . specific aryl groups include but are not limited to the groups consisting of phenyl group , 2 - phenylbenzene , 3 - phenylbenzene , 4 - phenylbenzene , 2 - dibenzofuran , 3 - dibenzofuran , and 4 - dibenzofuran , all of which are optionally substituted . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogens , one or more of r 2 , r 3 or r 4 is an optionally substituted aryl group , x is oh and n is 1 . specific aryl groups include but are not limited to the groups consisting of phenyl group , 2 - phenylbenzene , 3 - phenylbenzene , 4 - phenylbenzene , 2 - dibenzofuran , 3 - dibenzofuran , and 4 - dibenzofuran , all of which are optionally substituted . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogens , one or more of r 2 , r 3 or r 4 is an optionally substituted aryl group , x is h and n is 2 . specific aryl groups include but are not limited to the groups consisting of phenyl group , 2 - phenylbenzene , 3 - phenylbenzene , 4 - phenylbenzene , 2 - dibenzofuran , 3 - dibenzofuran , and 4 - dibenzofuran , all of which are optionally substituted . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogens , one or more of r 2 , r 3 or r 4 is an optionally substituted aryl group , x is oh and n is 2 . specific aryl groups include but are not limited to the groups consisting of phenyl group , 2 - phenylbenzene , 3 - phenylbenzene , 4 - phenylbenzene , 2 - dibenzofuran , 3 - dibenzofuran , and 4 - dibenzofuran , all of which are optionally substituted . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogens , one or more of r 2 , r 3 or r 4 is an optionally substituted aryl group , x is h and n is 3 . specific aryl groups include but are not limited to the groups consisting of phenyl group , 2 - phenylbenzene , 3 - phenylbenzene , 4 - phenylbenzene , 2 - dibenzofuran , 3 - dibenzofuran , and 4 - dibenzofuran , all of which are optionally substituted . in other specific embodiments , the invention relates to compounds having the above formula wherein r 1 and r 5 are both hydrogens , one or more of r 2 , r 3 or r 4 is an optionally substituted aryl group , x is oh and n is 3 . specific aryl groups include but are not limited to the groups consisting of phenyl group , 2 - phenylbenzene , 3 - phenylbenzene , 4 - phenylbenzene , 2 - dibenzofuran , 3 - dibenzofuran , and 4 - dibenzofuran , all of which are optionally substituted . in other specific embodiments , the invention includes compounds of formula ca13 , wherein n is 1 , r 1 and r 5 are both hydrogens , r 6 and r 7 are both hydrogens , r 8 - r 11 are all hydrogens , x is h or oh , and one or more of r 2 , r 3 or r 4 is selected from the group consisting of h , a halogen , and aryl groups . in other specific embodiments , the invention includes compounds of formula ca13 , wherein n is 1 , r 1 and r 5 are both hydrogens , r 6 and r 7 are both hydrogens , r 8 - r 11 are selected from the group consisting of hydrogen , pivalolyl ester groups , and isopropyl carbonate groups , x is h , and one or more of r 2 , r 3 or r 4 is selected from the group consisting of h , a halogen , and aryl groups . in a specific embodiment , compounds 491 , 493 - 496 , 498 , 608 , 618 , 621 - 625 , 640 , 647 , 648 ; and pharmaceutically acceptable salts , and esters thereof ; are useful for treatment of cancer . in a specific embodiment , compounds 491 , 493 - 496 , 498 , 608 , 618 , 621 - 625 , 640 , 647 , 648 ; and pharmaceutically acceptable salts , and esters thereof ; are useful in treatment of protozoan diseases and useful for treatment of cancer . compounds of this invention and compounds useful in the methods of this invention include those of the above formulas and pharmaceutically - acceptable salts and esters of those compounds . salts include any salts derived from the acids of the formulas herein which acceptable for use in human or veterinary applications . the term esters refers to hydrolyzable esters of diphosphonate compounds of the formulas herein . salts and esters of the compounds of the formulas herein are those which have the same therapeutic or pharmaceutical ( human or veterinary ) properties as the diphosphonate compounds of the formulas herein . various combinations of salts are possible , with each phosphonate carrying a 2 -, 1 - or neutral charge . in principle there are multiple charge states possible , for example 9 charge states , for certain bisphosphonates of this invention . in a specific embodiment , the invention includes compounds of the above formula ca13 where n = 1 , r 1 and r 3 - r 7 are hydrogens , x = oh , and r 2 = h , optionally substituted alkyl , optionally substituted alkoxy , and optionally substituted phenyl . in a more specific embodiment , the invention includes compounds where n = 1 , r 1 and r 3 - r 7 ═ h , x ═ oh , and r 2 ═ h , alkyl , alkoxy , and phenyl . in a further specific embodiment , the invention includes compounds where n = 1 , r 1 and r 3 - r 7 = h , x = oh , and r 2 = h , methyl , ethyl , propyl , butyl , methoxy , ethoxy , propoxy , butoxy , or phenyl . in an embodiment , the invention provides various methods relating to the treatment of clinical disease . in an embodiment , the invention provides a method of treating a bone resorption disorder comprising administering to a patient in need a composition comprising a compound of the invention . in an embodiment , the invention provides a method of treating a cancer disorder comprising administering to a patient in need a composition comprising a compound of the invention . in a specific embodiment , the cancer is breast cancer . in a specific embodiment , the breast cancer involves an actual or potential bone metastatic condition . in a specific embodiment , the invention provides a method of treating myeloma , lymphoma , prostate cancer , an epidermoid cancer , or orthotopic tumors . in an embodiment , the invention provides compounds and methods for use in a combination therapy in the treatment of cancer . in a specific embodiment , a combination therapy utilizes a bisphosphonate compound of the invention and a different chemotherapeutic agent which can optionally be a distinct other bisphosphonate compound . in a particular embodiment the different chemotherapeutic agent is alendronate , zoledronate , risedronate , pamidronate , fas ligand ( fasl ), mevastatin , dexamethasone , paclitaxel , epirubicin , docetaxel , imatinib mesylate , tumor necrosis factor ( tnf )- related apoptosis inducing ligand ( trail ), uracil - tegafur , gemcitabine , melphalan , doxorubicin , vincristine , or r115777 farnesyl transferase inhibitor ( fti ) ( zarnestra ®). in a particular embodiment , the combination of the bisphosphonate compound of the invention and the different chemotherapeutic agent has a synergistic effect . in another particular embodiment the combination has an additive effect . in an embodiment , the invention provides a method of treating an infectious disease comprising administering to a patient in need a composition comprising a compound of the invention . in a specific embodiment , the infectious disease relates to an agent selected from the group consisting of : a virus , a bacterium , a fungus , and a protozoan parasite . in a specific embodiment , the virus is a retrovirus . in a more specific embodiment , the retrovirus is human immunodeficiency virus ( hiv ). in an embodiment , the protozoan parasite is leishmania major . in an embodiment , the protozoan parasite is selected from the group consisting of : leishmania , toxoplasma , cryptosporidium , plasmodium , and trypanosoma . in an embodiment , the infectious disease is selected from the group consisting of leishmaniasis , toxoplasmosis , cryptosporidiosis , sleeping sickness , and malaria . in an embodiment , the invention provides a method of immunotherapy comprising administering to a patient in need a composition comprising a compound of the invention . in a specific embodiment , the method stimulates t cells in the patient . in a more specific embodiment , the method stimulates gamma delta t cells . in an embodiment , the invention provides a method of screening a bisphosphonate test compound for a potential therapeutic activity , comprising : providing said bisphosphonate test compound , measuring a performance attribute of said test compound in at least three assays selected from the group consisting of : a t . brucei farnesyl diphosphate synthase ( fpps ) assay , a dictyostelium discoideum assay , a t cell activation assay , and a bone resorption assay , analyzing said performance attribute ; and selecting said bisphosphonate test compound based on said attribute ; thereby screening said bisphosphonate test compound . in a specific embodiment , the method further comprises providing a reference compound and comparing a performance attribute of said reference compound with said performance attribute of said test compound . in an embodiment , the invention provides a method of treating bone pain comprising administering to a patient in need a compound of the invention . in a particular embodiment , the treatment of bone pain is in the context of a bone disease . in a particular embodiment , the treatment of bone pain is in the context of a patient with a metastatic cancer . in a particular embodiment , the metastatic cancer has spread to a bone location or originated in a bone location . for example , the treatment of bone pain can be achieved in a breast cancer patient wherein a metastatic breast cancer can or has spread to a bone location . in an embodiment , the invention provides a method of synthesizing a bisphosphonate compound of the invention , for example of formulae bx1 , ca11 , ca12 , ca13 , and / or other general formulae , comprising : syntheses as shown and described herein , e . g . in schemes and as further would be understood in the art . for example , the synthesis of any of the functionally and / or therapeutically active compounds can be prepared according to techniques as disclosed herein and as would be routinely understood in the art . a general overview of methods for making bisphosphonates includes the following . the syntheses depicted in scheme 6 can be advantageous in that they are relatively short and in general give good yields ( 30 - 50 %) of pure products . purifications typically involve crystallization . purities are in accord with standards of & lt ; 0 . 4 % error in c / h / n microanalysis ; structures can be confirmed by 1 h and 31 p nmr spectroscopy . in connection with scheme 10 , the design of compounds can generate inhibitors that are specific for trypanosomes such as t . brucei and t . cruzi . in particular , inhibitors and selective inhibitors are generated , where a selective inhibitor can more specifically target a parasite enzyme such as fpps relative to a host cell enzyme such as human fpps . scheme 11 . in another approach , enzyme inhibition such as fpps inhibition is achieved by use of an alcohol functionality in a compound to form a hydrogen bond network with tyr94 and gln 167 in the t . cruzi enzyme ( where enhanced h - bonding may relate to activity ). in the scheme , the number of ch 2 spaces can be modified . scheme 12 . in an approach to generate fpps inhibitors , des - oxy analogs are generated , for example of risedronate . 1 - des - oxy sulfonium bisphosphonates are generated and fpps activity is measured ; compounds with enhanced activity are selected and used to inhibit fpps activity . scheme 15 — general scheme for terphenyl piv synthesis . compounds were generated and tested . activity levels ( μm ) for certain compounds are shown in fig6 . the non - nitrogen containing benzyl bisphosphonates show most potency with activity in the high nanomolar range . in order to improve cellular uptake , several of these new compounds include lipophilic pivaloyloxymethylene ( piv ) esters on the phosphonate groups . bisphosphonates are active against trypanosoma cruzi and can be directed to t . cruzi hexokinase . hexokinase is the first enzyme involved in glycolysis in most organisms , including the etiological agent of chagas disease ( trypanosoma cruzi ). unlike the human enzyme , the tchk enzyme can be regulated allosterically by inorganic diphosphate , and bisphosphonate analogues . certain bisphosphonates with high activity in tchk lack a positive charge in the side - chain , which can be a characteristic feature for fpps inhibition . we attempted to reduce activity of these compounds in fpps and have generated a new class of bisphosphonates which inhibit parasites . certain compounds are believed to be able to provide parasite - specific enzyme inhibition . a new class of bisphosphonates with uncharged side - chains has activity against t . cruzi hexokinase . these compounds are believed to act as allosteric regulators of the enzyme . see fig7 with activity levels for results of compounds which were tested ( shown as μm values ). an inverse correlation has been observed between those compounds active in t . cruzi hexokinase and l . major fpps . modeling suggests that positive charge in side - chain is unfavorable in hexokinase , but this charge is required for fpps activity . see fig8 a . two active hexokinase inhibitors also show in vitro activity in the clinically relevant amastigote form of the trypanosome . see fig8 b . we considered aspects of mevalonate and non - mevalonate pathway gene regulation . we determined that a bisphosphonate compound and fosmidomycin have anti - bacterial properties and are highly synergistic in e . coli . we generated a dendrogram showing the hierarchical cluster analysis of e . coli responses to compound 13 , fosmidomycin , carbenicillin , ciprofloxacin , and the combination 13 - fosmidomycin . we observed results for genes that significantly changed their expression relative to control . in particular , we tracked eleven genes from the isoprenoid biosynthesis pathway : dxs , ispg , isph , idi , ispb , ispa , dxr , upps , ispd , ispe , ispf . fig9 shows results of analysis for affymetrix genechip ® antisense e . coli genome results . we observed relative increases and decreases in e . coli gene expression levels upon treatment with fosmidomycin and compound 13 . in fig9 , each point represents the log2 expression ratio ( to control ) of one gene . the expression ratio is calculated for each gene from its estimated mean signal intensity determined for one treatment divided by the estimated mean signal intensity of that gene in untreated cells ( eleven isoprenoid biosynthesis pathway genes ); r2 = 0 . 972 , p & lt ; 2 . 54 e - 8 . all references throughout this application , for example patent documents including issued or granted patents or equivalents ; patent application publications ; and non - patent literature documents or other source material ; are hereby incorporated by reference herein in their entireties , as though individually incorporated by reference , to the extent each reference is at least partially not inconsistent with the disclosure in this application ( for example , a reference that is partially inconsistent is incorporated by reference except for the partially inconsistent portion of the reference ). when a group of substituents is disclosed herein , it is understood that all individual members of those groups and all subgroups , including any isomers and enantiomers of the group members , and classes of compounds that can be formed using the substituents are disclosed separately . when a markush group or other grouping is used herein , all individual members of the group and all combinations and subcombinations possible of the group are intended to be individually included in the disclosure . when a compound is described herein such that a particular isomer or enantiomer of the compound is not specified , for example , in a formula or in a chemical name , that description is intended to include each isomer and enantiomer of the compound described individually or in any combination . when an atom is described herein , including in a composition , any isotope of such atom is intended to be included . specific names of compounds are intended to be exemplary , as it is known that one of ordinary skill in the art can name the same compounds differently . every formulation or combination of components described or exemplified herein can be used to practice the invention , unless otherwise stated . whenever a range is given in the specification , for example , a temperature range , a time range , or a composition range , all intermediate ranges and subranges , as well as all individual values included in the ranges given are intended to be included in the disclosure . all patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains . references cited herein are incorporated by reference herein in their entirety to indicate the state of the art , in some cases as of their filing date , and it is intended that this information can be employed herein , if needed , to exclude ( for example , to disclaim ) specific embodiments that are in the prior art . for example , when a compound is claimed , it should be understood that compounds known in the prior art , including certain compounds disclosed in the references disclosed herein ( particularly in referenced patent documents ), are not intended to be included in the claim . where the terms “ comprise ”, “ comprises ”, “ comprised ”, or “ comprising ” are used herein , they are to be interpreted as specifying the presence of the stated features , integers , steps , or components referred to , but not to preclude the presence or addition of one or more other feature , integer , step , component , or group thereof . the invention has been described with reference to various specific and preferred embodiments and techniques . however , it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention . it will be apparent to one of ordinary skill in the art that methods , devices , device elements , materials , procedures and techniques other than those specifically described herein can be applied to the practice of the invention as broadly disclosed herein without resort to undue experimentation . all art - known functional equivalents of methods , devices , device elements , materials , procedures and techniques described herein are intended to be encompassed by this invention . whenever a range is disclosed , all subranges and individual values are intended to be encompassed . this invention is not to be limited by the embodiments disclosed , including any shown in the drawings or exemplified in the specification , which are given by way of example or illustration and not of limitation . u . s . application ser . no . 60783491 filed mar . 17 , 2006 ; u . s . application ser . no . 11 / 245 , 612 filed oct . 7 , 2005 ( see also us patent application publication no . 20060079487 published apr . 13 , 2006 ); u . s . application ser . no . 60 / 617 , 108 filed oct . 8 , 2004 ; pct international application no . pct / us05 / 036425 filed oct . 7 , 2005 ( see also international publication no . wo / 2006 / 039721 published apr . 13 , 2006 ); us patent application publication no . 20050113331 published may 26 , 2005 ; the foregoing in particular are incorporated by reference in entirety to the extent not inconsistent herewith . 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