EP2203460A1 - Biphosphonat-verbindungen und verfahren mit erhöhter potenz für mehrere ziele, darunter fpps, ggpps und dpps - Google Patents

Biphosphonat-verbindungen und verfahren mit erhöhter potenz für mehrere ziele, darunter fpps, ggpps und dpps

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Publication number
EP2203460A1
EP2203460A1 EP08780519A EP08780519A EP2203460A1 EP 2203460 A1 EP2203460 A1 EP 2203460A1 EP 08780519 A EP08780519 A EP 08780519A EP 08780519 A EP08780519 A EP 08780519A EP 2203460 A1 EP2203460 A1 EP 2203460A1
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Prior art keywords
compound
carbon atoms
group
groups
alkyl
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EP08780519A
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English (en)
French (fr)
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EP2203460A4 (de
Inventor
Eric Oldfield
Yonghui Zhang
Fenglin Yin
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University of Illinois
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University of Illinois
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Priority claimed from PCT/US2008/060051 external-priority patent/WO2008128056A1/en
Publication of EP2203460A1 publication Critical patent/EP2203460A1/de
Publication of EP2203460A4 publication Critical patent/EP2203460A4/de
Withdrawn legal-status Critical Current

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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3878—Polyphosphonic acids containing substituents selected from B, Si, P (other than -PO3H2 groups) or a metal
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
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    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
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    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/5532—Seven-(or more) membered rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
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    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/9116—Transferases (2.) transferring alkyl or aryl groups other than methyl groups (2.5)
    • G01N2333/91165—Transferases (2.) transferring alkyl or aryl groups other than methyl groups (2.5) general (2.5.1)
    • G01N2333/91171—Transferases (2.) transferring alkyl or aryl groups other than methyl groups (2.5) general (2.5.1) with definite EC number (2.5.1.-)

Definitions

  • Earlier generation compounds of nitrogen-containing bisphosphonates such as pamidronate (Aredia ® ), alendronate (Fosamax ® ), risedronate (Actonel ® ), zoledronate (Zometa ® ), and ibandronate (Boniva) represent drugs currently used to treat conditions such as osteoporosis, Paget's disease and hypercalcemia due to malignancy. These compounds function primarily by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), resulting in decreased levels of protein prenylation in osteoclasts.
  • FPPS farnesyl diphosphate synthase
  • the mevalonate pathway also referred to as the HMG-CoA reductase pathway, or mevalonate-dependent (MAD) route, is an important cellular metabolic pathway present in higher eukaryotes and many bacteria. This pathway contributes to the production of dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP) that serve as the basis for the biosynthesis of molecules used in processes as diverse as protein prenylation, cell membrane maintenance, hormones, protein anchoring and N-glycosylation.
  • DMAPP dimethylallyl pyrophosphate
  • IPP isopentenyl pyrophosphate
  • the ability to inhibit a single molecule in such a pathway can provide an option for the modification of function and one or more outputs of the pathway.
  • the ability to interact with multiple molecular targets of such a fundamentally important pathway can provide opportunities for greater levels of modification. For example, the ability to simultaneously knock out a pipeline at several points can dramatically diminish the impact of the pipeline's flow and/
  • compounds of the invention include bisphosphonates that are capable of selectively inhibiting one or more of FPPS, GGPPS, and DPPS.
  • compounds of the invention are capable of selectively inhibiting two or more of FPPS, GGPPS, and DPPS.
  • compounds and methods of the invention demonstrate superior activity levels, such as in the anti-cancer context, which in several cases exceed the activity levels of previous generation bisphosphonate drugs by orders of magnitude. The invention disclosed herein thus represents a major advance in the development of useful agents which in certain embodiments are compounds capable of demonstrating high potency levels.
  • the invention provides, inter alia, novel bisphosphonate compounds and methods of making and using the compounds.
  • 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 (FPPS), GGPPS, and/or DPPS enzymes, and for treatment of bone resorption diseases, cancer, immune disorders, immunotherapy, and infectious diseases.
  • FPPS farnesyldiphosphate
  • GGPPS farnesyldiphosphate
  • DPPS farnesyldiphosphate
  • certain structural features significantly enhance the activity of the compounds.
  • Certain compounds are disclosed with structural features that correlate with useful and in certain embodiments high activity levels in functionally relevant contexts. For example, in specific embodiments the presence of particular alkoxy substituents on a ring component in an organic bisphosphonate compound contribute to desirable functional activity. Further variations are also provided.
  • Structural features of compounds have been identified which correlate with functional properties and activities.
  • compounds of the invention are capable of demonstrating profound activity levels, for example in inhibiting tumor cell growth inhibition and immunostimulation.
  • Compounds having such features have been synthesized and tested. This testing has allowed the further identification and development, for example, of a first class of compounds with significant anti-cancer and immunostimulatory ability and a second class of compounds with anti-cancer ability, but without substantial immunostimulatory capability.
  • compounds of the invention can provide advantages such as desirable activity, improved activity and/or therapeutic effect, reduced toxic effect, and/or such therapeutic and/or toxic effect with a more advantageous administration profile.
  • the more advantageous administration profile can invole one or more of lowered individual and/or total dosage amount; less frequent dosing regime; etc.
  • one or more of such advantages or qualities is capable of being determine in relation to another bisphosphonate compound, for example by comparison with a previous generation compound such as an approved drug.
  • bisphosphonate compounds of the invention can demonstrate activity in one or more contexts, including a farnesyl diphosphate synthase (FPPS) assay, a GGPPS assay, a DPPS assay, a D. discoideum growth inhibition assay, a T cell activation assay, a bone resorption assay, the treatment of infectious disease, the treatment of a bone resorption clinical disorder, an immunotherapeutic treatment, the treatment of cancer, the treatment of bone pain, stimulation of an immune cell and/or system, and inhibition of growth of a cancer cell or tumor.
  • FPPS farnesyl diphosphate synthase
  • the invention broadly provides bisphosphonate compounds and related methods of making and using.
  • the invention specifically provides organic bisphosphonate compounds and/or pharmaceutically acceptable salts or esters thereof.
  • the invention specifically provides other variations of bisphosphonate compounds.
  • functionally and/or therapeutically active bisphosphonates of this invention have general and specific structures as described herein.
  • the present invention provides compounds of bisphosphonates and pharmaceutical compositions comprising one or more bisphosphonates.
  • the bisphosphonates are high potency bisphosphonates in one or more functional contexts.
  • the invention provides compounds of formula XA1 :
  • X is hydrogen, hydroxyl group, or a halogen
  • M independently of other M in the compound, are a negative charge, a hydrogen, alkyl group, -(CH 2 ) P -O-CO-R or -(CH 2 ) P -O-CO-O-R, where p is 1 to 6, and R is hydrogen, optionally substituted alkyl or optionally substituted aryl;
  • -OM can also be a salt of form -O " A + , where A + is a cation;
  • n 1 , 2, or 3:
  • each R 1 and R 2 are selected from the group consisting of a hydrogen, a halogen, -N(R') 2 , -SR', OR', an optionally substituted alkyl, an optionally substituted alkenyl, 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 one of Ri and one of R 2 together form a 3-10 member carbocyclic or hetrocyclic ring containing one to three heteroatoms, particularly N, S, and O;
  • R 3 -R 7 if present, independently of one another, are selected from the group consisting of a hydrogen, a halogen, a -CN, -OR'", -COOR”', -OCOOR”', -COR”', - CON(FT) 2 , -OCON(FT) 2 , -N(FT) 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, an optionally substituted alkynyl group and an optionally substituted aryl group, where each R or R"', is independently selected from H, an optionally substituted alkyl group, an optionally substituted aryl group, and an optionally substituted acyl group; [00021] wherein at least one of R3-R7, if present is RL and when Z is Z6, R 4 , is
  • R N is an optionally substituted alkyl group having 1 -3 carbon atoms
  • Rs, R10 and R13 are groups selected from alkyl groups having 6- 20 carbon atoms; alkenyl or alkynyl groups having 6 to 20 carbon atoms; alkyl ether groups which are alkyl groups having 6-20 carbon atoms in which one or more non- adjacent carbon atoms are replaced with an O; or 3-R M or 4-R M substituted phenyl groups, where R M is selected from alkyl, alkenyl, alkynyl, alkoxy, alkenyoxy, alkynoxy or alkyl ether groups having 3-15 carbon atoms, where the other ring positions of the phenyl ring are optionally substituted with one or more halogens, or one or more optionally substituted alkyl groups having 1 -3 carbon atoms;
  • R 9 , Rn and R12 are groups selected from alkyl, alkenyl or alkynyl groups having 1 -6 carbon atoms; alkyl ether groups which are alkyl groups having 1 -6 carbon atoms in which one or more non-adjacent carbon atoms are replaced with an O; or optionally substituted phenyl groups;
  • Ri 4 , R-15, R16 are independently selected from hydrogen or optionally substituted alkyl having 1 -6 carbon atoms or optionally substituted aryl groups; wherein Rg can be linked to the first carbon of Rs to form a 5-8 member carbon ring which may be saturated or carry one or two double bonds;
  • optional substitution most generally means substitution of one or more carbons of the listed optionally substituted groups with non-hydrogen substituents selected from the groups consisting of one or more halogens, one or more cyano, one or more alkyl, haloalkyl, or hydroxyalkyl groups having 1 -3 carbon atoms, one or more alkenyl, haloalkenyl or hydroxyalkenyl groups having 1 -4 carbon atoms; one or more alkynyl groups having 1 -4 carbon atoms, one or more acyl or haloacyl groups; or one or more groups selected from a -ORs, -COORs, -OCOORs, -CORs, -CON(Rs) 2 , -OCON(Rs) 2 , -N(Rs) 2 , -NO 2 , -SRs, -SO 2 Rs, -SO 2 N(Rs) 2 or - SORs group, where Rs is hydrogen, an halogens,
  • Z is any one of Z1 -Z5; Z is Z6; Z is Z7; Z is Z9; Z is Z8 or Z10; Z is Z11 or Z is Z12.
  • R 4 is RL; when Z is Z1 , R 5 is RL; when Z is Z1 , R 6 is RL; when Z is Z2, R 4 is RL; when Z is Z2, R 5 is RL; when Z is Z2, R 6 is RL; when Z is Z3, R 5 is RL; when Z is Z3, R 6 is RL; when Z is Z4, R 4 is RL; when Z is Z4, R 6 is RL; when Z is Z5, R 3 is RL; when Z is Z5, R 4 is RL; when Z is Z12, R 4 is RL; or when Z is Z12, R 5 is RL.
  • RL is a group selected from alkyl, alkenyl or alkynyl groups having 7-20 carbon atoms or alkoxy groups having 7-20 carbon atoms.
  • RL is a group selected from alkyl or alkynyl groups having 7-20 carbon atoms or alkoxy groups having 7-20 carbon atoms. In other embodiments, RL is a group selected from alkyl, or alkynyl groups having 7-14 carbon atoms or 8-12 carbon atoms. In other embodiments, RL is an alkoxy group having 7-14 carbon atoms or 8-12 carbon atoms.
  • RL is a straight-chain alkyl or alkoxy group having from 7 to 20 carbons atoms or 7 to 12 carbon atoms.
  • Z is Z1 -Z5
  • RL is a straight-chain alkyl or alkoxy group having from 7 to 20 carbons atoms.
  • Z is Z1 -Z5
  • RL is a straight-chain alkyl or alkoxy group having from 7 to 10 carbons atoms.
  • Z is Z1 -Z4
  • RL is a straight-chain alkyl or alkoxy group having from 7 to 10 carbons atoms.
  • R 4 is RL and RL is a straight-chain alkyl or alkoxy group having from 6 to 10 carbons atoms or 7-10 carbon atoms.
  • R 4 is RL and RL is a straight-chain alkyl or alkoxy group having from 7 to 10 carbon atoms.
  • Z is Z1 , R 4 is RL and RL is a straight-chain alkoxy group having from 6 to 20 carbon atoms.
  • Z is Z1 , R 4 is RL and RL is a straight-chain alkoxy group having from 7 to 10 carbon atoms.
  • Z is Z8 or Z10 and R 8 or R 10 , respectively, is an alkyl group having 8-20 carbon atoms.
  • Rs or Ri 0 is an alkyl group having 9-17 carbon atoms.
  • Z is Z8 or Z10, R 8 or R 10 , respectively, is a straight- chain alkyl group having 8-20 carbon atoms or a straight-chain alkyl group having 9- 17 carbon atoms.
  • Z is Z8 and Rs is an alkyl group having 8-20 carbon atoms.
  • Z is Z8 and Rs is a straight-chain alkyl group having 8-20 carbon atoms.
  • Z is Z8 and R 8 is a straight-chain alkyl group having 9-17 carbon atoms.
  • Z is Z1 -Z5 and RL is an alkynyl group -C ⁇ C-R A ⁇ where R AK is a straight-chain alkyl group having 4-20 carbon atoms or 5-10 carbon atoms.
  • Z is Z1 -Z4 and RL is an alkynyl group -C ⁇ C-R A ⁇ where R AK is a straight-chain alkyl group having 4-20 carbon atoms or 5-10 carbon atoms.
  • Z is Z1 -Z2 or Z4, R 4 is RL and RL is an alkynyl group -C ⁇ C-R AK where R AK is a straight-chain alkyl group having 4-20 carbon atoms or 5-10 carbon atoms.
  • Z is Z1 , R 4 is RL and RL is an alkynyl group -C ⁇ C-R AK where R AK is a straight-chain alkyl group having 4-20 carbon atoms or 5-10 carbon atoms.
  • RL are alkyl ether groups which are alkyl groups having 7-20 carbon atoms or 7-14 carbon atoms n which one or more non-adjacent carbon atoms are replaced with an O.
  • RL is a 3-R M or 4-R M substituted phenyl group, where R M is selected from alkyl, alkenyl, alkynyl, alkoxy, alkenyoxy, alkynoxy or alkyl ether groups having 3-15 carbon atoms or 6-12 carbon atoms, where the other ring positions of the phenyl ring are optionally substituted with one or more halogens, or one or more optionally substituted alkyl groups having 1 -3 carbon atoms.
  • one or more alkyl groups herein are optionally substituted with one or more halogens.
  • aryl groups herein are phenyl groups optionally substituted with one or more halogens, or one or more alkyl groups having 1 -3 carbon atoms.
  • Ri 3 is a group selected from alkyl, or alkynyl groups having 7-20 carbon atoms; or an alkyl ether groups which are alkyl groups having 7-20 carbon atoms in which one or more non-adjacent carbon atoms are replaced with an O;
  • Ri 3 is a group selected from alkyl, or alkynyl groups having 7-20 carbon atoms or 9-17 carbon atoms;
  • RL when Z is Z12, RL is R 4 or R 5 and RL is an optionally substituted alkyl, or alkoxy group having 7-20 carbon atoms or an alkynyl group having 6 to 20 carbon atoms. In other embodiments, when Z is Z12, RL is an unsubstituted alkyl or alkoxy group having 7-20 carbon atoms. In additional embodiments, the alkyl group is a straight-chain alkyl group or the alkyl of the alkoxy group is a straight -chain alkyl group. In other specific embodiments, R 4 is RL. In other embodiments, the alkyl or alkoxyl group has 7-17 carbon atoms.
  • the alkyl or alkoxy group has 8-12 carbon atoms.
  • Z is Z12
  • RL is an alkynyl group -C ⁇ C-R AK where R AK is a straight-chain alkyl group having 4-20 carbon atoms or 5-10 carbon atoms.
  • RL is a substituted aryl, preferably phenyl; and more particularly RL is a sulfonamide substituted phenyl or is a naphthyl sulfonamide substituted phenyl.
  • the cation A + is a pharmaceutically acceptable cation.
  • R3-R7 if present, which are not RL are selected from the group consisting of a hydrogen, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted alkoxy group, and an optionally substituted aryl group;
  • R3-R7 if present, which are not RL are hydrogens, halogens or unsubstituted alkyl groups having 1 -3 carbon atoms;
  • R 3 -R 7 if present, which are not RL are hydrogens
  • each R 9 is an alkyl group having 1 -6 carbon atoms
  • each R 9 is an alkyl group having 1 -4 carbon atoms
  • each R 9 is an alkyl group having 1 -3 carbon atoms
  • each R 9 if present is a methyl group
  • Rn or R12 are the same groups
  • Rn or R12 are different groups
  • Rn or R 12 are alkyl groups having 1 -6 carbon atoms
  • R 11 or R 12 are alkyl groups having 1 -4 carbon atoms;
  • R 11 or R 12 are alkyl groups having 1 -3 carbon atoms;
  • R 11 or R 12 if present, are methyl groups
  • R 14 and R 15 are hydrogens
  • R 15 and R 16 are hydrogens
  • R 15 and R 16 are hydrogens and R 14 is hydrogen or an alkyl group having 1 -3 carbon atoms;
  • R N is a methyl group; or [00059] R 4 is a straight-chain alkyl group having from 6-20 carbon atoms or 7-17 carbon atoms or 8-15 carbon atoms.
  • high potency bisphosphonates include those of formula XA1 wherein Z is Z1A, Z2A, Z2B, Z3A, Z4A, Z5A, Z12A or Z12B:
  • R 3 -R 7 are not RL, but take all other values as listed above and RL is as defined above including various specific embodiments set forth herein.
  • R3-R7 are selected from hydrogens, halogens or alkyl groups having 1 -3 carbon atoms; or all of R3-R7 are hydrogens.
  • RL are alkyl or alkoxy groups having 7-20 carbon atoms or 7 to 17 carbon atoms.
  • RL are straight-chain alkyl or alkoxy groups having 6-20 carbon atoms or 7 to 17 carbon atoms.
  • RL are alkynyl groups having from 8- 20 carbon atoms or 9 to 17 carbon atoms.
  • Ri and R 2 are all hydrogens
  • n 1 ;
  • n 2;
  • X is hydrogen
  • X is a hydroxyl group
  • X is fluorine
  • X is chlorine
  • At least one M is a negative charge and the remaining M are hydrogens
  • At least one M is , -(CH 2 ) P -O-CO-R or -(CH 2 ) P -CO-R, where p is 1 to 6, and R is hydrogen, optionally substituted alkyl or optionally substituted aryl; or
  • One, or two of -OM are -O " A + , where A + is a cation and the remaining M are hydrogens;
  • Z is one of Z as set forth herein.
  • the invention provides a compound selected from the group consisting of: 637, 638, 677, 687, 688, 693, 694, 695, 696, 714, 715, 716, 717, 722, 754, 675, 678, and 728; and for each respective said compound, a pharmaceutically acceptable salt or ester thereof.
  • said compound is also a compound of formula XA1.
  • the invention provides a composition comprising a pharmaceutical formulation of a compound of the invention of any formula herein.
  • the invention provides a medicament which comprises a therapeutically effective amount of one or more compositions of the invention.
  • the invention provides a method for making a medicament for treatment of a condition described herein.
  • the invention provides a method of inhibiting growth of a cancer cell comprising contacting said cancer cell with an effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the invention provides a method of treating a cancer comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the cancer is a breast cancer.
  • the breast cancer involves an actual or potential bone metastatic condition.
  • the cancer is a cancer known in the art.
  • the invention provides a method of stimulating a T cell, comprising contacting the T cell with a compound of the invention or a pharmaceutical formulation thereof.
  • said T cell is a gammadelta T cell.
  • the invention provides a method of immunotherapeutic treatment comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the invention provides a method of treating a bone resorption disorder comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the invention provides a method of treating a bone pain condition comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the invention provides a method of inhibiting growth of an infectious disease agent comprising contacting said infectious disease agent with an effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the invention provides a a method of treating an infectious disease comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the infectious disease relates to an agent selected from the group consisting of: a virus, a fungus, a bacterium, and a protozoan parasite.
  • said virus is a retrovirus.
  • said retrovirus is human immunodeficiency virus (HIV).
  • said protozoan parasite is selected from the group consisting of: Leishmania, Toxoplasma, Cryptosporidium, Plasmodium, and Trypanosoma.
  • said protozoan parasite is Leishmania major.
  • said bacterium is Escherichia coli or Staphylococcus aureus.
  • the invention provides a method of synthesizing a compound of the invention or a pharmaceutical formulation thereof.
  • a synthetic scheme is used or adapted from such of US Application Serial 11687570 filed March 17, 2006; PCT International Application Serial PCT/US07/64239 filed March 17, 2006; US Application Serial 60783491 filed March 17, 2006; US Application Serial 11/245,612 filed October 7, 2005 (see also US Patent Application Publication No. 20060079487 published April 13, 2006); US Application Serial 60/617,108 filed October 8, 2004; PCT International Application No. PCT/US05/036425 filed October 7, 2005 (see also International Publication No. WO/2006/039721 published April 13, 2006); US Patent Application Publication No. 20050113331 published May 26, 2005; and as would be understood in the art.
  • the invention provides a method of selectively inhibiting one or more of an FPPS, GGPPS, DDPPS, and a DHDDS enzyme. In an embodiment, the invention provides a method of selectively inhibiting two or more of an FPPS, GGPPS, and a DPPS enzyme, comprising contacting said enzymes or a cell containing said enzymes with an organic compound.
  • said organic compound is a bisphosphonate compound.
  • said compound is a compound of formula XA1 or other compound as described herein.
  • said compound has a plC50 value of at least 4 in a cancer cell or tumor growth inhibition assay and/or an immunostimulation assay. In an embodiment, said compound has a plC50 value of at least 5. In an embodiment, said compound has a plC50 value of at least 6. In an embodiment, said compound has a plC50 value of at least 7.
  • the invention provides a method of selectively inhibiting an FPPS enzyme, a GGPPS enzyme, and a DPPS enzyme comprising contacting said enzymes or a cell containing said enzymes with an organic compound, wherein said compound is capable of selectively inhibiting said FPPS, GGPPS, and DPPS enzymes.
  • the invention provides a method of selectively inhibiting a GGPPS enzyme and a DPPS enzyme comprising contacting said enzymes or a cell containing said enzymes with an organic compound, wherein said compound is capable of selectively inhibiting said GGPPS enzyme and said DPPS enzyme.
  • said compound is compound 715.
  • the invention provides a method of selectively inhibiting a GGPPS enzyme without substantially inhibiting a DPPS enzyme comprising contacting said enzymes or a cell containing said enzymes with an organic compound, wherein said compound is capable of selectively inhibiting said GGPPS enzyme without substantially inhibiting said DPPS enzyme.
  • said compound is compound 754.
  • the invention provides a method of one or more of immunostimulation and inhibition of tumor or cancer cell growth, comprising contacting a mammalian cell with an organic bisphosphonate compound capable of substantially inhibiting a GGPPS enzyme and a DPPS enzyme.
  • the invention provides a method of inhibition of cancer cell growth, comprising contacting a mammalian cell with an organic bisphosphonate compound capable of substantially inhibiting a GGPPS enzyme without substantially inhibiting a DPPS enzyme.
  • said compound has a structure of formula XA1.
  • the invention provides a method of screening an organic bisphosphonate test compound for one or more properties, comprising: providing said test compound, measuring a performance attribute of said test compound in at least two enzyme assays selected from the group consisting of: an FPPS enzyme assay; a GGPPS enzyme assay; a DPPS enzyme assay; and measuring an activity level of said test compound in at least two activity assays selected from the group consisting of: a cancer cell or tumor growth inhibition assay; a T cell activation assay; a bone resorption assay; a bone binding assay; analyzing said performance attributes and said activity levels; and selecting said test compound based on said attributes and activity levels; thereby screening said test compound for said one or more properties.
  • 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.
  • the invention provides a method of inhibiting a dehydrodolichyl diphosphate synthase (DHDDS) enzyme.
  • the invention provides a method of selectively inhibiting a DHDDS enzyme comprising contacting said enzyme or a cell containing said enzyme with an organic compound or composition of the invention.
  • a method is described as inhibiting a target selectively, there can be specific inhibition of one or more other targets.
  • the invention provides a method of treating a cancer comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the cancer is breast cancer.
  • the breast cancer involves an actual or potential bone metastatic condition.
  • the invention provides a method of treating a bone resorption disorder comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the invention provides a method of treating a bone pain condition comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the invention provides a method of treating an infectious disease comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • said infectious disease relates to an agent selected from the group consisting of: a virus, a fungus, a bacterium, and a protozoan parasite.
  • said virus is a retrovirus.
  • said retrovirus is human immunodeficiency virus (HIV).
  • said protozoan parasite is selected from the group consisting of: Leishmania, Toxoplasma, Cryptosporidium, Plasmodium, and Trypanosoma.
  • said protozoan parasite is Leishmania major.
  • said bacterium is Escherichia coli or Staphylococcus aureus.
  • the invention provides a method of immunotherapeutic treatment comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the invention provides a method of stimulating a T cell, comprising contacting the T cell with a compound of the invention or a pharmaceutical formulation thereof.
  • said T cell is a gammadelta T cell.
  • the invention provides a method of synthesizing a compound of the invention or a pharmaceutical formulation thereof.
  • the invention provides a method of inhibiting growth of an infectious disease agent comprising contacting said infectious disease agent with an effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the invention provides a method of inhibiting growth of a tumor or cancer cell comprising contacting said tumor or cancer cell with an effective amount of a compound of the invention or a pharmaceutical formulation thereof.
  • the invention provides a compound having anti- angiogenic activity.
  • the invention provides a method of inhibiting angiogenesis comprising administering to a subject in need thereof an effective amount of a compound or composition of the invention.
  • the invention provides a composition comprising a compound.
  • said composition comprises a therapeutically effective amount of the compound.
  • the invention provides a composition comprising a pharmaceutical formulation of a compound.
  • said pharmaceutical formulation comprises one or more excipients, carriers, and/or other components as would be understood in the art.
  • an effective amount of a composition of the invention can be a therapeutically effective amount.
  • a composition of the invention is used as a medicament.
  • a composition is used in the preparation or manufacture of a medicament.
  • the medicament is for treatment of one or more conditions as described herein and as would be understood in the art.
  • the invention provides a method for treating a medical condition comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention.
  • the medical condition is a bone resorption disorder, a cancer, pain, an immune system disorder, and/or an infectious disease.
  • composition of the invention is isolated or purified.
  • a purified FPPS, GGPPS, DPPS, or other enzyme can be employed in addition to cellular and animal-based assays.
  • Pharmaceutically acceptable salts comprise pharmaceutically-acceptable anions and/or cations.
  • Pharmaceutically-acceptable cations include among others, alkali metal cations (e.g., Li + , Na + , K + ), alkaline earth metal cations (e.g., Ca 2+ , Mg 2+ ), non-toxic heavy metal cations and ammonium (NH 4 + ) and substituted ammonium (N(R') 4 + , where R' is hydrogen, alkyl, or substituted alkyl, i.e., including, methyl, ethyl, or hydroxyethyl, specifically, trimethyl ammonium, triethyl ammonium, and triethanol ammonium cations).
  • Pharmaceutically-acceptable anions include among other halides (e.g., Cl “ , Br “ ), sulfate, acetates (e.g., acetate, thfluoroacetate), ascorbates, aspartates, benzoates, citrates, and lactate.
  • Certain molecules disclosed herein contain one or more ionizable groups [groups from which a proton can be removed (e.g., -COOH) or added (e.g., amines) or which can be quaternized (e.g., amines)]. All possible ionic forms of such molecules and salts thereof are intended to be included individually in the disclosure herein. With regard to salts of the compounds herein, one of ordinary skill in the art can select from among a wide variety of available countehons those that are appropriate for preparation of salts of this invention for a given application. In specific applications, the selection of a given anion or cation for preparation of a salt may result in increased or decreased solubility of that salt.
  • Prodrugs of the compounds of the invention are useful in the methods of this invention. Any compound that will be converted in vivo to provide a biologically, pharmaceutically or therapeutically active form of a compound of the invention is a prodrug.
  • prodrugs Various examples and forms of prodrugs are well known in the art. Examples of prodrugs are found, inter alia, in Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985), Methods in Enzymology, Vol. 42, at pp. 309-396, edited by K. Widder, et. al.
  • Figure 1 illustrates aspects of relevant chemistry.
  • A Structures of common nitrogen-containing bisphosphonates
  • B schematic illustration of several pathways involved in bisphosphonate activity in tumor cells, v ⁇ T cells, osteoclasts, and macrophages.
  • C FPP, GGPP biosynthesis and protein prenylation showing carbocation transition state/reactive intermediates and bisphosphonate analog (enclosed in red circle);
  • E cationic bisphosphonates;
  • F structures of selected GGPPS inhibitors.
  • Figures 2A-2I illustrates extensive results of assays for activity of compounds including data for tumor cell growth inhibition and v ⁇ T cell activation.
  • A MCF-7 cell growth inhibition by bisphosphonates
  • B FOH, GGOH rescue of zoledronate cell growth inhibition
  • C FOH, GGOH rescue of BPH-675 cell growth inhibition
  • D correlation matrix for enzyme, cell growth inhibition and SlogP
  • E CoMSIA predictions with FPPS and GGPS descriptors
  • F gammadelta T cell activation by bisphosphonates
  • G HQSAR predictions for v ⁇ T cell activation
  • H percent proliferation response
  • I percent of total CD3+ cells.
  • Figures 3A-3E illustrates results from X-ray and NMR experiments.
  • A B: x-ray structures of BPH-527 and BPH-461 bound to human FPPS shown superimposed on risedronate (from PDB File # 1YV5);
  • C D 31 P magic-angle sample spinning NMR spectra (600 MHz 1 H resonance frequency) of bisphosphonates, IPP bound to T. brucei FPPS;
  • E x-ray structure of BPH-675 bound to GGPPS (from Saccharomyces cerevisae) shown superimposed on GGPP bound to human GGPPS (PDB File 2FVI); see also Table 8.
  • Figure 4 is a schematic illustration of bisphosphonate targets.
  • Figure 5 provides structures of inhibitors investigated in MCF-7 cell growth inhibition, FPPS inhibition and GGPPS inhibition ( Figures 2D-G).
  • Figure 6 is a graph of plCso values for MCF-7 growth inhibition by bisphosphonates plotted versus the pED 50 values for ⁇ . ⁇ T cell activation. The structures of the compounds investigated are shown in Figure 5.
  • Figure 7 provides structures of compounds investigated in assays including MCF-7 cell growth inhibition and ⁇ T cell activation.
  • Figure 8 provides structures of compounds investigated in assays including MCF-7 cell growth inhibition and ⁇ T cell activation.
  • Figure 9 is a graph of MCF-7 cell growth inhibition plC 50 values versus bone resorption (pEDso results, from Widler et al.). The structures of the compounds investigated are shown in Figure 8.
  • Figure 10 provides structures of bone resorption drugs tested in MCF-7 cell growth inhibition.
  • Figures 11A-D are exemplary 31 P NMR spectra of bisphosphonate/IPP/FPPS complexes. The structures of the compounds are shown above the spectra.
  • Figures 12A and B indicate X-ray structures of exemplary bisphosphonates bound to Trypanosoma cruzi FPPS. A, BPH-527 and B, BPH-461. Risedronate is shown superimposed on each.
  • Figures 13A and B provide representative ITC results for a sulfonium bisphosphonate (BPH-527) bound to T. brucei FPPS and ⁇ H, ⁇ S correlation (novel cationic compounds in red with arrows, others from references).
  • Figure 14 is a graph of predicted cell growth inhibition based on FPPS, GGPPS enzyme inhibition in addition to SlogP descriptor.
  • Figure 15 is a graph of predicted cell growth inhibition based on FPPS and GGPPS enzyme inhibition data.
  • Figure 16 provides structures of several compounds discussed herein.
  • the invention relates at least in part to the discovery that certain compounds including bisphosphonates, particularly those having at least one substitutent carrying a long hydrocarbon chain, particularly a straight chain alkyl or alkoxy group having 7 or more carbon atoms, exhibit useful or enhanced activity including in the context of inhibition of cell growth and/or inhibition of certain ezymes.
  • FPPS farnesyl diphosphate synthase
  • GGPPS geranylgeranyl diphosphate synthase (also known as geranylgeranyl pyrophosphate synthetase)
  • DPPS decaprenyl pyrophosphate synthase
  • UPPS undecaprenyl pyrophosphate synthetase; also known as undecaprenyl diphosphate synthase
  • DHDDS or DDPPS dehydrodolichyl diphosphate synthase
  • pICso/pECso negative log of IC 50 and EC50, respectively, where IC50 and EC50
  • brucei Trypanosoma brucei
  • D. discoideum Dictyostelium discoideum
  • ⁇ T cells gamma delta T cells
  • ITC isothermal calorimetry.
  • Compounds/structures are typically designated by a number for convenience.
  • 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 10-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.
  • 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.
  • 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 any R (e.g., R1 and R2) groups herein 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:
  • 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;
  • 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;
  • 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;
  • 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;
  • 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.
  • 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;
  • R H, alkyl, aryl, or acyl
  • 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 thhalomethyl 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.
  • 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.
  • EXAMPLE 1 Bisphosphonate compounds including structures with high potency for anti-cancer and/or immunostimulatory function.
  • Bisphosphonates such as Fosamax, Actonel and Zometa are potent inhibitors of the enzyme farnesyl diphosphate synthase (FPPS) and are used to treat osteoporosis and bone cancers. They have direct activity against osteoclasts and tumor cells and also activate gammadelta T cells of the innate immune system to kill tumor cells.
  • FPPS farnesyl diphosphate synthase
  • bisphosphonates can act as polypharmaceuticals, inhibiting not only FPPS but geranylgeranyl diphosphate and decaprenyl diphosphate synthases as well, in addition to describing the development of novel compounds having activities approximately 100-1000x greater than current bisphosphonates in y ⁇ T cell activation and tumor cell killing.
  • Bisphosphonates such as Fosamax, Boniva and Zometa are drug molecules used to treat bone resorption diseases such as osteoporosis, Paget's disease and hypercalcemia due to malignancy(7, 2).
  • they activate ⁇ T cells (containing the V ⁇ 2V ⁇ T cell receptor) to kill tumor cells(3-5), plus, they have direct activity against tumor cells (6-9) and many parasitic PrOtOZOa(YO, 77). While used clinically for two decades, their mode of action has been unclear.
  • bisphosphonates were thought to act simply by coating bone surfaces, but more recently, the enzyme farnesyl diphosphate synthase (FPPS, EC 2.5.1.10) has been implicated(72).
  • FPPS farnesyl diphosphate synthase
  • Inhibition of FPPS results in decreased prenylation of small GTPases (such as Ras, Rho, Rap, Rac) which is expected to caused deranged patterns of cell signaling ( Figure 1 B) and in some protozoa, inhibition of ergosterol biosynthesis(70). More recently, it has been shown that this inhibition of FPPS results in increased levels of the substrate, isopentenyl diphosphate (IPP)(73, 14). This increase in IPP levels can activate ⁇ T cells (75).
  • small GTPases such as Ras, Rho, Rap, Rac
  • IPP isopentenyl diphosphate
  • IPP is converted to the isopentenyl ester of ATP, Apppl, which can inhibit the mitochondrial adenine nucleotide translocase (ANT), a component of the mitochondrial permeability transition pore ( Figure 1 B) (76).
  • ANT mitochondrial adenine nucleotide translocase
  • Proteins are prenylated by either farnesyl diphosphate (FPP) or geranylgeranyl diphosphate (GGPP), which are synthesized from IPP and dimethylallyl diphosphate (DMAPP) as shown in Figure 1 C.
  • FPP farnesyl diphosphate
  • GGPP geranylgeranyl diphosphate
  • DMAPP dimethylallyl diphosphate
  • the reactions are believed to proceed via carbocationic transition state/reactive intermediates ⁇ 7) such as that circled in red in Figure 2C, with the bisphosphonate sidechains (of e.g. Boniva, red, Figure 1A) mimicking the charge center and the bisphosphonate providing a hydrolytically stable analog of diphosphate(77).
  • DPPS decaprenyl diphosphate synthase
  • DPPS is a heterodimehc prenyl- transferase used in coenzyme Qi 0 PrOdUCtJOn(YS).
  • DPPS decap
  • bisphosphonates could be "polypharmaceuticals” capable of inhibiting multiple targets.
  • the bisphosphonate Boniva can be a potent inhibitor of squalene synthase(20), used in cholesterol biosynthesis, and numerous bisphosphonates are potent, low nM inhibitors of another heterodimeric prenyltransferase, geranyl diphosphate synthase, found in plants(27). The ability to determine the potential significance of other relevant target enzymes and to develop inhibitors, however, involved further exploration.
  • cationic bisphosphonate species such as BPH-715 ( Figure 1 F, left) are indeed far more active in MCF-7 tumor cell growth inhibition than are bisphosphonates such as zoledronate and pamidronate, with IC50 values of approximately 50 nM, to be compared with values on the order of around 15 ⁇ M (zoledronate) or around 300 ⁇ M (pamidronate).
  • IC50 values approximately 50 nM
  • the large hydrophobic bisphosphonate BPH-675 has an IC 50 of 5 ⁇ M, but its growth inhibitory effect is essentially fully rescued by addition of 20 ⁇ M geranyl geraniol, Figure 2C.
  • BPH-675 is a selective GGPPS inhibitor
  • BPH-715 has multiple targets, including GGPPS.
  • plCso (cell) a'plCso (FPPS) + b « plC 50 (GGPPS) + CpIC 50 (DPPS) + d'SlogP + e
  • plCso -log-m (IC50 M) and a,b...n are regression coefficients.
  • a potential drawback to the use of bisphosphonates in treating non-bone resorption diseases is expected to be that they would be rapidly adsorbed onto bone.
  • the highly hydrophobic species BPH-675 and BPH-715 are only very weakly adsorbed onto bone in vivo (Sl), resulting in only modest IC 50 values in bone resorption (e.g. -800 nM for BPH-715 versus -70 nM for zoledronate, Sl), but weak bone binding is desirable in the context of certain conditions, e.g., immunotherapy, treating infectious diseases, and various cancers.
  • the compound 754 and certain compounds with related structural features can represent a genus of compounds which potently inhibits GGPPS while not substantially inhibiting DPPS or FPPS. In certain instances it can be advantageous to retain properties such as anti-cancer activity while not having a pro-immunostimulatory effect. There are circumstances where immunostimulation can lead to immune system overreaction such as in a variety of inflammatory disorders.
  • the structural features of interest can include the lack of positive charge for the ring moiety adjoining the bisphosphonate component in addition to an alkoxy tail substituent on the ring.
  • compounds which share other structural features can exhibit accompanying functional properties such as inhibition of multiple targets (for example, GGPPS and DPPS in the case of compound 715) and can demonstrate combinations of activities such as anti-cancer and immunostimulation; there are circumstances where such combinations can be advantageous.
  • ternary bisphosphonate-IPP-FPPS complexes form (31-34). This has been demonstrated crystallographically as well as by using solid state 31 P NMR spectroscopy, where individual 31 P NMR resonances are seen for both sets of bisphosphonate and IPP 31 P nuclei(35).
  • the pyridinium bisphosphonate BPH-461 forms the same type of complex, containing 3 Mg 2+ plus IPP, shown in Figure 3C.
  • ternary complexes with IPP, Mg 2+ can also be deduced by using solid-state 31 P NMR and results for the pyridinium and sulfonium bisphosphonate are shown in Figure 2C,D (and Figure 11 ) and indicate that the pyridinium, sulfonium, phosphonium, arsonium and guanidinium bisphosphonates all form ternary complexes with, on average, a 1 :1 ( ⁇ 0.2) bisphosphonate :IPP stoichiometry.
  • GGPPS inhibitor site binding site motif is also seen with BPH-675 (PDB 2E95) and may be common with long chain GGPPS inhibitors, such as those described earlier(25), as proposed by Kavanagh et al. ⁇ 37). Since this is a product (or inhibitor) binding site, we determine that there is no requirment for a positive charge feature, and both cationic and neutral side-chain containing species can bind, but only the cationic species inhibit DPPS (and FPPS).
  • GGPPS is the major target for the most potent species, but in ⁇ 5 T cell activation, GGPPS inhibition has no effect on T cell activation, which relies on IPP formation.
  • suitable chemical modification we have obtained several novel species having activities about 100-100Ox greater than existing bisphosphonates in both tumor cell growth inhibition as well as ⁇ 5 T cell activation, suggesting new routes to the use of bisphosphonates in immuno- and chemotherapy using a polypharmaceutical approach.
  • compositions including salts and ester forms of compounds 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.
  • esters refers to hydrolyzable esters of compounds including diphosphonate compounds of the formulas herein.
  • salts and esters of the compounds of the formulas herein can include those which have the same therapeutic or pharmaceutical (human or veterinary) general properties as the 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 compounds including bisphosphonate compounds of this invention.
  • the invention provides compounds represented by structure XA2:
  • variable group options can be as described elsewhere herein.
  • RL is an alkoxy having 7-12 carbons.
  • a compound having structural formula XA2 can be used to selectively inhibit GGPPS without substantially inhibiting DPPS. In an embodiment, such a compound is used to inhibit a tumor or cancer cell growth.
  • Compound 754 was synthesized and tested for activity. It was found to have in IC50 value as follows (micromolar): 0.50 for inhibition of cancer call growth (average); 0.401 for inhibition of human breast cancer cell line MCF7; 0.524 for inhibition of human CNS cancer SF268; 0.672 for inhibition of human lung cancer NCIH460; 0.5918 for inhibition of purified GGPPS.
  • EXAMPLE 3 Results of testing compounds for activities.
  • Table 1 plC 50 values for FPPS, GGPPS, and DPPS enzyme inhibition, cell growth inhibition, and QSAR predicted cell activity.
  • Table 4 Data collection and refinement statistics for BPH-527 3 bound to human FPPS.
  • BPH-527 is (2-Hydroxy-2,2-bis-phosphono-ethyl)-dimethyl-sulfonium
  • b Brookhaven National Laboratory Table 5: Data collection and refinement statistics for BPH-461 a bound to human FPPS.
  • BPH-461 is 3-fluoro-1 -(2-hydroxy-2,2-bisphosphonoethyl)-pyhdinium
  • b Brookhaven National Laboratory Table 6: Data collection and refinement statistics for BPH-527 3 bound to T. brucei FPPS.
  • BPH-527 is (2-Hydroxy-2,2-bis-phosphono-ethyl)-dimethyl-sulfonium
  • BPH-461 Brookhaven National Laboratory Table 7: Data collection and refinement statistics for BPH-461 a bound to T. brucei FPPS.
  • Unit cell dimension (A) ⁇ (°) 112.364 a b, c 135.565, 118.520, 63.186
  • BPH-461 is 3-fluoro-1 -(2-hydroxy-2,2-bisphosphonoethyl)-pyhdinium
  • b Brookhaven National Laboratory Table 8: Data collection and refinement statistics for BPH-675 3 bound to S. cerevisiae GGPPS.
  • BPH-675 is 1 -Hydroxy-2-[3'-(Naphthalene-2-sulfonylamino)-biphenyl-3- yl]ethylidene-1 ,1 -bisphosphonic acid
  • the human tumor cell lines MCF-7 (breast adenocarcinoma), NCI-H460 (lung large cell) and SF-268 (central nervous system glioblastoma) were obtained from the National Cancer Institute. All lines were cultured in RPMI-1640 medium supplemented with 10 % fetal bovine serum and 2 mM L-glutamine at 37°C in a 5% CO 2 atmosphere with 100% humidity. A broth microdilution method was used to determine IC50 values for growth inhibition by each bisphosphonate.
  • NBPs were typically initially dissolved in H 2 O (0.01 M) while NNBPs were typically dissolved in DMSO (0.01 M).
  • V ⁇ 2V ⁇ 2 T cell TNF- ⁇ release and proliferation were performed basically as described previously 1 . Briefly, to measure bioactivity for V ⁇ 2V ⁇ 2 T cells, the CD4 + JN.24, CD4 + HF.2, CD8 ⁇ + 12G12, or the CD4 " 8 " HD.108 V ⁇ 2V ⁇ 2 T cell clones were stimulated with phosphoantigens in the presence of CP. EBV (an EBV transformed B cell line) for CD4 + clones or Va-2 (a transformed fibroblast) for CD8 ⁇ + and CD4 " 8 " clones. CP.
  • EBV an EBV transformed B cell line
  • Va-2 a transformed fibroblast
  • NMR spectroscopy Spectra were obtained by using the magic-angle sample spinning technique on a 600 MHz ( 1 H resonance frequency) Infinity Plus spectrometer equipped with a 14.1 T, 2 inch bore Oxford magnet and Vahan/Chemagnetics 3.2 mm T3 HXY probe. Spectra were referenced to an external standard of 85% orthophosphoric acid. 1 H transverse magnetization was created by a 3.5 ⁇ s pulse (75 kHz field) and cross polarization was used for signal enhancement, followed by TPPM decoupling (80 kHz 1 H field) during data acquisition. 1 H- 31 P cross polarization pulse shapes and decoupling were optimized on risedronate (Actonel) prior to data acquisition on the protein samples.
  • Data were acquired using a dwell time of 10 ⁇ s (a 100 kHz spectral width), 2048 points, a 2 sec recycle delay and a spinning speed of 13.333 kHz. All spectra were processed by using zero-filling to 4096 points, 50Hz exponential multiplication, and a polynomial correction for baseline correction prior to peak integration. The number of scans varied between 32 k and 86 k.
  • the reactions were started by adding 5 ⁇ l_ of a 250 ⁇ M solution of [ 14 C] IPP and incubated at 37 °C for 20 min. The reaction was terminated by the addition of 75 ⁇ l_ of HCI/MeOH. Following a second 20 min incubation at 37 °C to effectively hydrolyze the allylic pyrophosphates, the reaction mixtures were neutralized by the addition of 75 ⁇ l_ of 6 N NaOH and extracted with 500 ⁇ l_ of hexane. 200 ⁇ l_ of the organic phase was transferred to a scintillation vial for counting. The IC 50 values were obtained by fitting the data to the dose-response curve in Origin 6.1 (OriginLab Corp., Northampton, MA, www.OriginLab.com).
  • the human FPPS structure (1 YV5) 3 minus the hsedronate ligand was used as a search model using the molecular replacement method. Rigid body refinement was applied to the model obtained using AMoRe 5 . The crystal structure was then further refined by using Shelxl-97 6 . Rebuilding and fitting the ligand was carried out by using the program O 7 in the 2Fo-Fc electron density map. Certain refinement statistics are included in Tables 4 and 5.
  • T.brucei FPPS-Bisphosphonate Complexes The crystal structures of the T.brucei FPPS bisphoshponate complexes were determined by using the molecular replacement method using the program AMoRe 5 . The previously solved T.brucei FPPS structure (2EWG) 8 minus the minodronate ligand was used as a starting model. The structure has been further refined using CNS 9 . After iterative rounds of refinement using CNS and rebuilding using Coot, the structures had the final refinement statistics shown in Tables 6 and 7.
  • 2D QSAR Molecular Descriptors. Structures of inhibitors were imported into the Molecular Operating Environment (MOE) 2006.08 10 . In order to compute certain molecular descriptors, a three-dimensional structure was required. The three-dimensional models were built by minimizing all molecules using a 0.05 kcal/mol gradient and MMFF94 11 force field. In addition to computed 2D molecular descriptors, GGPPS and FPPS enzyme plC 50 values were also used. The AutoQuaSAR module 12 , an expert system for QSAR in MOE, was used.
  • This iteratively builds a series of models by evaluating the importance of each of the descriptors available, removing less important ones in a step-wise fashion in order to produce a trajectory of r 2 and q 2 (leave-one-out cross-validated r 2 ) as a function of the number of descriptors.
  • the final model computer output is shown in Table 10.
  • 3D-QSAR CoMSIA Descriptors and Analysis. Conformers of all compounds were generated in MOE 2006.08 10 using the conformation import utility. In order to avoid potential bias in the alignment, the pharmacophore perception algorithm (in MOE) was used to generate alignments of the molecules, based on overlap of perceived features, specifically: hydrophobic, aromatic, cation, donor and acceptor. The ranked list of putative pharmacophores then served as the basis for initial alignment 13 . Alignment of molecules in the top pharmacophore (containing a cationic feature) was selected and refined sequentially using the flexible alignment module in MOE with TAFF (Tripos) and MMFF94 force fields.
  • TAFF Tripos
  • a scrambling stability test as implemented in Sybyl 7.3 14 , was then performed on the data to ensure that the model was not obtained due to chance and, additionally, to verify the optimum number of components.
  • the scrambling method applies small, random perturbations to the dataset while monitoring the predictivity of the resulting models.
  • the predictivity of unstable models typically falls off disproportionately rapidly from even small perturbations, while robust models exhibit more predictive stability 16 .
  • the output results, confirming stability at three components, are shown in Table 11.
  • Hologram HQSAR Hologram QSAR
  • Sybyl 7.3 14 uses an extended molecular fingerprint (molecular hologram) to correlate structural features and biological activity. Structures of the 64 molecules were imported into Sybyl 7.3 and three dimensional coordinates generated for ease of structure inspection and verification using up to 10,000 steps at 0.01 kcal/mol gradient using the BFGS 18 energy minimization method. Structures were then automatically fragmented into pre-defined fragment sizes.
  • a molecular hologram (fingerprint) was then generated for each molecule using these fragments, retaining information about the fragment, possible overlap and constituent sub- fragments, implicitly encoding three-dimensional structure information.
  • EXAMPLE 4 Anti-cancer activity including such against tumors in vivo.
  • Isotopic variants including those carrying radioisotopes, may also be useful in diagnostic assays and in therapeutics. Methods for making such isotopic variants are known in the art. 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.
  • Widler L et al., Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa), J Med Chem. 2002 Aug 15;45(17):3721 -38.

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