BISPHOSPHONATE COMPOUNDS AND METHODS

BACKGROUND OF THE INVENTION

Earlier generation compounds of nitrogen-containing bisphosphonates such as pamidronate (Aredia®), alendronate (Fosamax®), risedronate (Actonel®), zoledronate (Zometa®), and ibandronate (Boniva) represent important 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. Certain bisphosphonates have also been found to have anti-parasitic activity and to stimulate human γδ T cells, and there is interest in cancer-related applications. There is continued interest, however, in the further development of alternative bisphosphonate compounds and methods of use such as therapeutic applications.

There have been reports regarding the significance of certain nitrogen-containing groups in the context of active bisphosphonate compounds. See US Publication 20060079487 and PCT Publication WO/2006/039721. The present invention discloses the fact that, remarkably, bisphosphonates lacking certain nitrogen-containing groups but containing instead aryl, substituted aryl, sulfonium and phosphonium groups have activity in killing cancer cells, in inhibiting the enzyme farnesyl diphosphate synthase from humans as well as from Trypanosoma brucei (the causative agent of African sleeping sickness), in stimulating gamma delta T cells in the human immune system, as well as acting as inhibitors of the enzyme undecaprenyl diphosphate synthase, essential for cell wall biosynthesis in many pathogenic bacteria such as Escherichia coli and Staphylococcus aureus. As such, these novel compounds are of interest in the context of the treatment of cancer, bone resorption diseases and infectious diseases caused by bacteria and protozoa.

SUMMARY OF THE INVENTION

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 (FPPS) 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.

Without wishing to be bound by any particular theory, there can be discussion herein of beliefs or understandings of underlying principles or mechanisms relating to the invention. It is recognized that regardless of the ultimate correctness of any mechanistic explanation or hypothesis, an embodiment of the invention can nonetheless be operative and useful.

In embodiments, bisphosphonate compounds of the invention can demonstrate activity in one or more contexts, including a farnesyl diphosphate synthase (FPPS) assay, a UPPS 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, and the treatment of bone pain.

The invention broadly provides bisphosphonate compounds and related methods of making and using. In embodiment, the invention specifically provides bisphosphonate compounds with either a sulfonium group, a phosphonium group, an arsonium group, a substituted aromatic group, in addition to a bisphosphonate group (and/or a pharmaceutically acceptable salt or ester group). In further embodiments, the invention specifically provides other variations of bisphosphonate compounds. In embodiments, functionally and/or therapeutically active bisphosphonates of this invention have general and specific structures as described herein.

In an embodiment, the invention provides a compound having the general structural formula BX1:

where:

Q=M or ⊖ (negative charge);

Z=cationic or neutral species

cationic Z are:

neutral Z are:

and salts, esters and hydrates thereof

wherein:

Q is M or a negative charge;

M, M₁, M₂or M₃, independently of one another are H, alkyl, —(CH₂)_p—O—CO—R or —(CH₂)_p—O—C—R where p is 1 to 6, R is H, optionally substituted alkyl or optionally substituted aryl; M₁, M₂or M₃which are hydrogen may also be in form of a salt (—O—A⁺, where A⁺ is a cation);

X is H, halogen, OH or methyl;

n is 1, 2, or 3;

R₆and R₇, independently of each other and other R₆and R₇in 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 where R₆and R₇can be linked together to form a 4-7 member ring;

U is H or OH;

R₁, R₂, R₃and R₄, independently of one another, are selected from the group consisting of an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, and an optionally substituted aryl group wherein any two R₁-R₃groups in the same molecule can be linked together to form a 4-7 member ring; and

Z₁-Z₅, independently of one another, 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, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —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, 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 wherein any two Z groups substituted on adjacent carbons of the ring can be linked together to form a 4-7 member ring which may contain one or more double bonds, be aromatic and/or contain one or more heteroatoms (e.g., S, O or N).

In an embodiment, the Z is cationic Z and comprises the sulfonium group CX1. In an embodiment, the Z is cationic Z and comprises the phosphonium group CX2. In an embodiment, the Z is cationic Z and comprises the arsonium group CX3. In an embodiment, X═H. In an embodiment, X═OH. In an embodiment, a compound of the invention excludes a compound described herein for a structure designated CX1A, CX2A, and/or CX3A; regardless of hydration state for such compounds. In an embodiment, the Z is neutral Z and comprises the CX4 group. In an embodiment, the Z is neutral Z and comprises the CX5 group. In an embodiment, the Z is neutral Z and comprises group CX6 or CX7.

In an embodiment, the invention provides a compound selected from the group consisting of: 491, 493, 494, 495, 496, 498, 608, 618, 621, 622, 623, 624, 625, 626, 628, 629, 640, 647,648; 527, 536, 540,541, 546, 547, 550, 564, 569, 572, 573, 574, 575, 576, 580, 581, 584, 585, 587, 589, 594, 560, 571; and for each respective said compound, a pharmaceutically acceptable salt or ester thereof. In an embodiment, said compound is also a compound of formula BX1.

In an embodiment, the invention provides a composition comprising a pharmaceutical formulation of a compound of the invention.

In an embodiment, 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.

In an embodiment, 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. In an embodiment, the cancer is breast cancer. In an embodiment, the breast cancer involves an actual or potential bone metastatic condition.

In an embodiment, 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.

In an embodiment, 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. In an embodiment, said infectious disease relates to an agent selected from the group consisting of: a virus, a fungus, a bacterium, and a protozoan parasite. In an embodiment, said virus is a retrovirus. In an embodiment, said retrovirus is human immunodeficiency virus (HIV). In an embodiment, said protozoan parasite is selected from the group consisting of: Leishmania, Toxoplasma, Cryptosporidium, Plasmodium, and Trypanosoma. In an embodiment, said protozoan parasite is Leishmania major. In an embodiment, said bacterium is Escherichia coli or Staphylococcus aureus.

In an embodiment, 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. In an embodiment, 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. In an embodiment, said T cell is a gammadelta T cell.

In an embodiment, the invention provides a method of synthesizing a compound of the invention or a pharmaceutical formulation thereof.

In an embodiment, 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.

In an embodiment, 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.

In specific embodiments, alkyl, alkenyl, alkynyl and aryl groups of the variables of the above formula are optionally substituted with one or more non-hydrogen substituent groups selected from halogens, —CN, —OR′, —COOR′, , —OCOOR′, —COR′, —CON(R′)₂, —OCON(R′)₂, —N(R′)₂, —NO₂, —SR′, —SO₂R′, —SO₂N(R′)₂or —SOR′ groups, or —R′, where each R′, independent of any other R′ in any listed group, is selected from H, an alkyl group, an alkenyl group, an alkynyl group or an aryl group, and an acyl group each of which alkyl, alkenyl, alkynyl, aryl or acyl groups is optionally substituted with a halogen, —OH, —CN, —NO₂, or —SH group and wherein any two R′ groups substituted on the same or adjacent atoms in a molecule can be linked together to form a 4-7 member ring. In specific embodiments, alkyl groups are substituted with optionally substituted aryl groups, particularly optionally substituted phenyl groups or optionally substituted biphenyl groups. In other specific embodiments, aryl groups, particularly phenyl groups, are optionally substituted with alkyl groups, particularly with alkyl groups having 1-3 carbon atoms or alkyl groups having 1-6 carbon atoms.

In specific embodiments for each definition for each of CX1-CX7above:

R₆and R₇are both H;

R₆and R₇are, independently, selected from H or alkyl having 1-3 carbon atoms;

n is 1;

n is 2;

X is H;

X is OH or any listed combination of R₆, R₇, n and X.

In specific embodiments for Z which is neutral:

Q is M and M, M₁-M₃are H; or

Q is H.

In specific embodiments for Z which are cationic:

Q is a negative charge;

Q is a negative charge and M₁-M₃are all H;

Q is a negative charge and M₁-M₃are all H; or

Q is a negative charge and one or more of M₁-M₃are —(CH₂)_p—O—CO—R or —(CH₂)_p—O—C—R groups.

In specific embodiments of compounds having structure CX5, any of Z₁-Z₅is an optionally substituted phenyl group, or an optionally substituted biphenyl group. In specific embodiments, Z₁-Z₅are phenyl groups substituted with one or more halogens. In specific embodiments, any two of Z₁-Z₅are halogens. In specific embodiments, any of Z₁-Z₅is a CN group. In specific embodiments, Z₁-Z₅are unsubstituted phenyl groups or unsubstituted biphenyl groups. In specific embodiments, any two Z on adjacent ring carbons can together form one or more rings which may contain one or more double bonds or which may be aromatic. In specific embodiments, Z₂and Z₃can together form one or more rings which may contain one or more double bonds or which may be aromatic. In a specific embodiments, Z₁or Z₂is a biphenyl group. In any of the specific embodiments listed for values of any of Z₁-Z₅,Q and M₁-M₃can be OH, —(CH₂)_p—O—CO—R, where p is 1 or 2 or —(CH₂)_p—O—C—R, where p is 1 or 2. In any embodiments having structure CX5, X can be H. In any embodiments having structure CX5, X can be OH. In any embodiments having structure CX5, n can be 1. In any embodiments having structure CX5, X can be OH. In any embodiments having structure CX5, n can be 2. Specific examples of embodiments having structure CX5 include among others compounds 491, 493, 494, 495, 496, 498, 608, 618, 621, 622, 623, 624, 625, 640, 647, and 648.

In specific embodiments, R₁-R₄groups which are alkyl, alkenyl, or alkynyl groups have 2, 3, 4, 5, 6 or more carbon atoms. In specific embodiments, at least one R₁-R₄group in a molecules which are alkyl, alkenyl, or alkynyl groups has 2, 3, 4, 5, 6 or more carbon atoms. In specific embodiments, R₁is an alkyl group substituted with an optionally substituted aryl group, and more specific is an alkyl group substituted with an optionally substituted phenyl group. In specific embodiments, R₁and R₂are alkyl or alkenyl groups which are linked together to form a 4-7 member and more preferably a 5 or 6 member ring.

Therapeutically and/or functionally compounds of this invention include those of formulas XX11-XX14:

and salts, esters and hydrates thereof.

In each of XX11-XX14, M₁-M₃, R₆, R₇, n, X, R₁and R₂are as defined above; Y₁to Y₅, independently of one another and other Y in the molecule, 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, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —SOR group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group and an optionally substituted aryl group which can be a heteroaryl 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 wherein any two Y groups substituted on adjacent carbons of the same ring or any two carbons substituted on adjacent rings can be linked together to form a 4-7 member ring which may contain one or more double bonds, be aromatic and/or contain one or more heteroatoms (e.g., S, O or N); R₁₁and R₁₂are selected from hydrogen, a halogen, a —CN, —OR, —COOR, , —OCOOR, —COR, —CON(R)₂, —OCON(R)₂, —N(R)₂, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —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, 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 is zero or an integer ranging from 1-10, or 1-6, and Ar is an optionally substituted aryl group which may be a heteroaromatic group, wherein one or more CR₁₁R₁₂moieties can be replaced with an O atom.

In specific embodiments of XX11, R₁is optionally substituted alkyl having 2-20 carbon atoms. In any specific embodiments of XX11, R₁is an alkyl ether group having 1-20 carbon atoms. In specific embodiments of XX11, R₁is an optionally substituted alkyl group having 1-10 carbon atoms. In specific embodiments of XX11, R₁is an optionally substituted alkenyl group having 1-20 carbon atoms. In specific embodiments of XX11, R₁is an optionally substituted dienyl group (alkenyl group with two double bonds) having 1-20 carbon atoms. In specific embodiments of XX11, R₁is an optionally substituted alkynyl group having 1-20 carbon atoms. In specific embodiments, R₁is an unsubstituted alkyl group having 1-6 carbon atoms. In specific embodiments of XX11, R₁is an alkyl group having 1-10 carbon atoms substituted with an aryl group. In specific embodiments of XX11, R₁is optionally substituted straight-chain alkyl having 2-20 carbon atoms. In specific embodiments of XX11, R₂is a group other than a methyl group. In specific embodiments of XX11, when n is 1, R₂is a group other than a methyl group. In specific embodiments of XX11, when n is 1, R₁and R₂are groups other than methyl groups. In specific embodiments of XX11, R₁and R₂are groups other than methyl groups. In specific embodiments of XX12 or XX13, all of Y₁-Y₅are hydrogens. In specific embodiments of XX12 or XX13, all of Y₁-Y₅are hydrogens or optionally substituted alkyl groups having 1-3 carbon atoms. In specific embodiments of XX12 or XX13, one or more of Y₁-Y₅are acyl groups. In specific embodiments of XX12 or XX13, one or more of Y₁-Y₅are alkoxy groups. In specific embodiments of XX12 or XX13, one of Y₁-Y₅are aryl groups. In specific embodiments of XX12 or XX13, all of Y₁-Y₅are optionally substituted phenyl groups. In specific embodiments of XX12 or XX13, one of Y₁-Y₅are optionally substituted biphenyl groups. In specific embodiments of XX12 or XX13, one of Y₁-Y₅is a heteroaromatic group. In specific embodiments of XX14 hydrogens, cyano groups, nitro groups, halogens or optionally substituted alkyl groups having 1-6 or 1-3 carbon atoms In specific embodiments of XX14, R₁₁and R₁₂are all hydrogens. In specific embodiments of XX14, Ar is an optionally substituted phenyl. In specific embodiments of XX14, Ar is optionally substituted with an alkyl or alkoxy group. In specific embodiments of XX14, Ar is optionally substituted with an alkyl or alkoxy group having 1-10 carbon atoms. In specific embodiments of XX14, Ar is optionally substituted with an alkyl or alkoxy group having 1-6 carbon atoms. In specific embodiments of XX14, Ar is an optionally substituted biphenyl. In specific embodiments of XX14, Ar is an optionally substituted naphthyl. In specific embodiments of XX14, Ar is an optionally substituted benzofuranyl. In specific embodiments of XX14, Ar is an optionally substituted dibenzofuranyl. In specific embodiments of XX14, Ar is an alkoxy-substituted phenyl group. In specific embodiments of XX14, r is 1-6. In specific embodiments of XX14, r is 2-4. In specific embodiments of XX14,—(CR₁₁CR₁₂)_r— is —O—(CR₁₁R₁₂)_r-1—. In specific embodiments of XX14,—(CR₁₁CR₁₂)_r— is —(R₁₁R₁₂)_t—O—(CR₁₁R₁₂)_swhere s+t=3-20 and more specifically where s and t, independently, are 2, 3 or 4. In specific embodiments, —(CR₁₁CR₁₂)_r— is —O—(CH₂)_r-1—. In specific embodiments of XX14,—(CR₁₁CR₁₂)_r— is —(CH₂)_t—O—(CH₂)_swhere s+t=3-20 and more specifically where s and t, independently, are 2, 3 or 4.

In any specific embodiments of XX11, XX12, XX13, or XX14, Q is M. In any specific embodiments of XX11, XX12 , XX13, or XX14, any one or more of M, M₁, M₂or M₃can be H or a salt or ester thereof. In specific embodiments of XX11, XX12, XX13, or XX14, all R₆and R₇are hydrogens. In any specific embodiments of XX11, XX12, XX13, or XX14, X can be H. In any specific embodiments of XX11, XX12, XX13, or XX14, X can be OH. In any specific embodiments of XX11, XX12, XX13, or XX14, n can be 1. In any specific embodiments of XX11, XX12, XX13, or XX14, n can be 2. In any specific embodiments XX11, XX12, XX13, or XX14 can be pharmaceutically acceptable salts. In any specific embodiments XX11, XX12, XX13, or XX14 can be pharmaceutically acceptable esters. In any specific embodiments XX11, XX12, XX13, or XX14 can be pharmaceutically acceptable hydrates. In any specific embodiments of XX11, XX12, XX13, or XX14, R₂is an alkyl groups having 1, 2 or 3 carbon atoms. In any specific embodiments of XX11, XX12, XX13, or XX14, R₂is a methyl group. In any specific embodiments of XX11, XX12, XX13, or XX14, R₂is an ethyl group. In any specific embodiments of XX11, XX12, XX13, or XX14, one or both of R₆and/or R₇are optionally substituted alkyl groups. . In any specific embodiments of XX11, XX12, XX13, or XX14, one or both of R₆and/or R₇are halogens.

Therapeutically and/or functionally active compounds of this invention include those of formulas XX21-XX22:

and salts, esters and hydrates thereof.

In each of XX21 or XX22, M₁-M₃, R₆, R₇, n, X, R₁and R₂are as defined above; R₁₁and R₁₂R₁₁and R₁₂are selected from hydrogen, a halogen, a —CN, —OR, —COOR, —OCOOR, —COR, —CON(R)₂, —OCON(R)₂, —N(R)₂, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —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, 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 is zero or an integer ranging from 1-10, or 1-6, and Ar is an optionally substituted aryl group which may be a heteroaromatic group, wherein one or more CR₁₁R₁₂moieties can be replaced with an O atom.

In specific embodiments of XX21, R₁is optionally substituted alkyl having 2-20 carbon atoms. In any specific embodiments of XX21, R₁is an alkyl ether group having 1-20 carbon atoms. In specific embodiments of XX21, R₁is an optionally substituted alkyl group having 1-10 carbon atoms. In specific embodiments of XX21, R₁is an optionally substituted alkenyl group having 1-20 carbon atoms. In specific embodiments of XX21, R₁is an optionally substituted dienyl group (alkenyl group with two double bonds) having 1-20 carbon atoms. In specific embodiments of XX21, R₁is an optionally substituted alkynyl group having 1-20 carbon atoms. In specific embodiments, R₁is an unsubstituted alkyl group having 1-6 carbon atoms. In specific embodiments of XX21, R₁is an alkyl group having 1-10 carbon atoms substituted with an aryl group. In specific embodiments of XX21, R₁is optionally substituted straight-chain alkyl having 2-20 carbon atoms. In specific embodiments of XX21, R₂is a group other than a methyl group. In specific embodiments of XX21, when n is 1, R₂is a group other than a methyl group. In specific embodiments of XX21, when n is 1, R₁and R₂are groups other than methyl groups. In specific embodiments of XX21, R₁and R₂are groups other than methyl groups. In specific embodiments of XX12 or XX13, all of Y₁-Y₅are hydrogens. In specific embodiments of XX22, R₁₁and R₁₂are selected from hydrogens, cyano groups, nitro groups, halogens or optionally substituted alkyl groups having 1-6 or 1-3 carbon atoms. In specific embodiments of XX22, R₁₁and R₁₂are all hydrogens. In specific embodiments of XX22, Ar is optionally substituted phenyl. In specific embodiments of XX22, Ar is optionally substituted biphenyl. In specific embodiments of XX22, Ar is optionally substituted naphthyl. In specific embodiments of XX22, Ar is optionally substituted benzofuranyl. In specific embodiments of XX22, Ar is optionally substituted dibenzofuranyl. In specific embodiments of XX22, Ar is substituted with an alkyl or alkoxy group. In specific embodiments of XX22, Ar is substituted with an alkyl or alkoxy group having 1-10 carbon atoms. In specific embodiments of XX22, Ar is substituted with an alkyl or alkoxy group having 1-6 carbon atoms. In specific embodiments of XX22, Ar is an alkoxy substituted phenyl group. In specific embodiments of XX22, r is 1-6. In specific embodiments of XX22, r is 2-4. In specific embodiments of XX22, —(CR₁₁CR₁₂)_r— is —O—(CR₁₁R₁₂)_r-1—. In specific embodiments of XX22,—(CR11CR₁₂)_r— is —(R₁₁R₁₂)_t—O—(CR₁₁R₁₂)_swhere s+t=3-20 and more specifically where s and t, independently, are 2, 3 or 4. In specific embodiments, —(CR₁₁CR₁₂)_r— is —O—(CH₂)_r-1—. In specific embodiments of XX22,—(CR₁₁CR₁₂)_r— is —(CH₂)_t—O—(CH₂)_swhere s+t=3-20 and more specifically where s and t, independently, are 2, 3 or 4.

In any specific embodiments of XX21 or XX22, any one or more of M, M₁, M₂or M₃can be H or a salt or ester thereof. In specific embodiments of XX21 or XX22, all R₆and R₇are hydrogens. In any specific embodiments of XX21 or XX22, X can be H. In any specific embodiments of XX21 or XX22, X can be OH. In any specific embodiments of XX21 or XX22, n can be 1. In any specific embodiments of XX21 or XX22, n can be 2. In any specific embodiments XX21 or XX22 can be pharmaceutically acceptable salts. In any specific embodiments XX21 or XX22 can be pharmaceutically acceptable esters. In any specific embodiments XX21 or XX22 can be pharmaceutically acceptable hydrates. In any specific embodiments XX21 or XX22, R₂is an alkyl groups having 1, 2 or 3 carbon atoms. In any specific embodiments of XX21 or XX22, R₂is a methyl group. In any specific embodiments of XX21 or XX22, R₂is an ethyl group. In any specific embodiments of XX21 or XX22, one or both of R₆and/or R₇are optionally substituted alkyl groups. In any specific embodiments of XX21 or XX22, one or both of R₆and/or R₇are halogens.

Therapeutically and/or functionally active compounds of this invention include those of formulas XX31 and XX32:

and salts, esters and hydrates thereof.

In each of XX31 or XX32, M₁-M₃, R₆, R₇, n, X, R₁, R₂and R₃are as defined above; R₁₁and R₁₂are selected from hydrogen, a halogen, a —CN, —OR, —COOR, —OCOOR, —COR, —CON(R)₂, —OCON(R)₂, —N(R)₂, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —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, 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 is zero or an integer ranging from 1-10, or 1-6, and Ar is an optionally substituted aryl group which may be a heteroaromatic group, wherein one or more CR₁₁R₁₂moieties can be replaced with an O atom.

In specific embodiments of XX31, R₁is optionally substituted alkyl having 2- 20 carbon atoms. In any specific embodiments of XX31, R₁is an alkyl ether group having 1-20 carbon atoms. In specific embodiments of XX31, R₁is an optionally substituted alkyl group having 1-10 carbon atoms. In specific embodiments of XX31, R₁is an optionally substituted alkenyl group having 1-20 carbon atoms. In specific embodiments of XX31, R₁is an optionally substituted dienyl group (alkenyl group with two double bonds) having 1-20 carbon atoms. In specific embodiments of XX31, R₁is an optionally substituted alkynyl group having 1-20 carbon atoms. In specific embodiments, R₁is an unsubstituted alkyl group having 1-6 carbon atoms. In specific embodiments of XX31, R₁is an alkyl group having 1-10 carbon atoms substituted with an aryl group. In specific embodiments of XX31, R₁is optionally substituted straight-chain alkyl having 2-20 carbon atoms. In specific embodiments of XX31 or XX32, R₂and R₃are optionally substituted alkyl groups having 1-10 carbon atoms. In specific embodiments of XX31 or XX32, R₂and R₃are optionally substituted alkyl groups having 1-6 carbon atoms. In specific embodiments of XX31 or XX32, R₃is an alkyl group substituted with an aryl group. In specific embodiments of XX31 or XX32, R₂is a group other than a methyl group. In specific embodiments of XX31 or XX32, when n is 1, R₂is a group other than a methyl group. In specific embodiments of XX31 or XX32, R₂and R₃the same groups. In specific embodiments of XX31 or XX32, R₂and R₃are different groups. In specific embodiments of XX31 or XX32, when n is 1, R₁and R₂are groups other than methyl groups. In specific embodiments of XX31 or XX32, R₁and R₂are groups other than methyl groups. In specific embodiments of XX31 or XX32, R₂and R₃are groups other than methyl groups. In specific embodiments of XX32, R₁₁and R₁₂are selected from hydrogens, cyano groups, nitro groups, halogens or optionally substituted alkyl groups having 1-6 or 1-3 carbon atoms. In specific embodiments of XX32, R₁₁and R₁₂are all hydrogens. In specific embodiments of XX32, Ar is an optionally substituted phenyl. In specific embodiments of XX32, Ar is optionally substituted with an alkyl or alkoxy group. In specific embodiments of XX32, Ar is optionally substituted with an alkyl or alkoxy group having 1-10 carbon atoms. In specific embodiments of XX32, Ar is optionally substituted with an alkyl or alkoxy group having 1-6 carbon atoms. In specific embodiments of XX32, Ar is optionally substituted biphenyl. In specific embodiments of XX32, Ar is optionally substituted naphthyl. In specific embodiments of XX32, Ar is optionally substituted benzofuranyl. In specific embodiments of XX32, Ar is optionally substituted dibenzofuranyl. In specific embodiments of XX32, Ar is an alkoxy substituted phenyl. In specific embodiments of XX32, r is 1-6. In specific embodiments of XX32, r is 2-4. In specific embodiments of XX32,—(CR₁₁CR₁₂)_r— is —O—(CR₁₁R₁₂)_r-1—. In specific embodiments of XX32,—(CR₁₁CR₁₂)_r— is —(R₁₁R₁₂)_t—O—(CR₁₁R₁₂)_swhere s+t=3-20 and more specifically where s and t, independently, are 2, 3 or 4. In specific embodiments, —(CR₁₁CR₁₂)_r— is —O—(CH₂)_r-1—. In specific embodiments of XX32, —(CR₁₁CR₁₂)_r— is —(CH₂)_t—O—(CH₂)_swhere s+t=3-20 and more specifically where s and t, independently, are 2, 3 or 4.

In any specific embodiments of XX31 or XX32, any one or more of M, M₁, M₂or M₃can be H or a salt or ester thereof. In specific embodiments of XX31 or XX32, all R₆and R₇are hydrogens. In any specific embodiments of XX31 or XX32, X can be H. In any specific embodiments of XX21 or XX22, X can be OH. In any specific embodiments of XX31 or XX32, n can be 1. In any specific embodiments of XX31 or XX32, n can be 2. In any specific embodiments XX31 or XX32 can be pharmaceutically acceptable salts. In any specific embodiments XX31 or XX32 can be pharmaceutically acceptable esters. In any specific embodiments XX31 or XX32 can be pharmaceutically acceptable hydrates. In any specific embodiments XX31 or XX32, R₂is an alkyl groups having 1, 2 or 3 carbon atoms. In any specific embodiments of XX31 or XX32, R₂is a methyl group. In any specific embodiments of XX31 or XX32, R₂is an ethyl group. In any specific embodiments of XX31 or XX32, one or both of R₆and/or R₇are optionally substituted alkyl groups. . In any specific embodiments of XX31 or XX32, one or both of R₆and/or R₇are halogens.

Therapeutically and/or functionally compounds of this invention include those of formulas XX41-XX42:

and salts, esters and hydrates thereof.

In each of XX41 or XX42, M, M₁-M₃, R₆, R₇, n, X, and R₁are as defined above; R₁₁and R₁₂are selected from hydrogen, a halogen, a —CN, —OR, —COOR, —OCOOR, —COR, —CON(R)₂, —OCON(R)₂, —N(R)₂, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —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, 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 is zero or an integer ranging from 1-10, or 1-6, and Ar is an optionally substituted aryl group which may be a heteroaromatic group, wherein one or more CR₁₁R₁₂moieties can be replaced with an O atom.

In specific embodiments of XX41, R₁is optionally substituted alkyl having 2-20 carbon atoms. In any specific embodiments of XX41, R₁is an alkyl ether group having 1-20 carbon atoms. In specific embodiments of XX41, R₁is an optionally substituted alkyl group having 1-10 carbon atoms. In specific embodiments of XX31, R₁is an optionally substituted alkenyl group having 1-20 carbon atoms. In specific embodiments of XX41, R₁is an optionally substituted dienyl group (alkenyl group with two double bonds) having 1-20 carbon atoms. In specific embodiments of XX41, R₁is an optionally substituted alkynyl group having 1-20 carbon atoms. In specific embodiments, R₁is an unsubstituted alkyl group having 1-6 carbon atoms. In specific embodiments of XX41, R₁is an alkyl group having 1-10 carbon atoms substituted with an aryl group. In specific embodiments of XX41, R₁is optionally substituted straight-chain alkyl having 2-20 carbon atoms. In specific embodiments of XX42, R₁₁and R₁₂are selected from hydrogens, cyano groups, nitro groups, halogens or optionally substituted alkyl groups having 1-6 or 1-3 carbon atoms. In specific embodiments of XX42, R₁₁and R₁₂are all hydrogens. In specific embodiments of XX42, Ar is an optionally substituted phenyl. In specific embodiments of XX42, Ar is optionally substituted biphenyl. In specific embodiments of XX42, Ar is optionally substituted naphthyl. In specific embodiments of XX42, Ar is optionally substituted benzofuranyl. In specific embodiments of XX42, Ar is optionally substituted dibenzofuranyl. In specific embodiments of XX42, Ar is an alkoxy substituted phenyl group. In specific embodiments of XX42, Ar is substituted with an alkoxy or alkyl group. In specific embodiments of XX42, Ar is substituted with an alkyl or alkoxy group having 1-10 carbon atoms. In specific embodiments of XX42, Ar is substituted with an alkyl or alkoxy group having 1-6 carbon atoms. In specific embodiments of XX42, r is 1-6. In specific embodiments of XX42, r is 2-4. In specific embodiments of XX42,—(CR₁₁CR₁₂)_r— is —O—(CR₁₁R₁₂)_r-1-. In specific embodiments of XX42,—(CR₁₁CR₁₂)_r— is —(R₁₁R₁₂)_t—O—(CR₁₁R₁₂)_swhere s+t=3-20 and more specifically where s and t, independently, are 2, 3 or 4. In specific embodiments, —(CR₁₁CR₁₂)_r— is —O—(CH₂)_r-1—. In specific embodiments of XX42,—(CR₁₁CR₁₂)_r— is —(CH₂)_t—O—(CH₂)_swhere s+t=3-20 and more specifically where s and t, independently, are 2, 3 or 4.

In any specific embodiments of XX41 or XX42, any one or more of M, M₁, M₂or M₃can be H or a salt or ester thereof. In specific embodiments of XX41 or XX42, all R₆and R₇are hydrogens. In any specific embodiments of XX41 or XX42, X can be H. In any specific embodiments of XX41 or XX42, X can be OH. In any specific embodiments of XX41 or XX42, n can be 1. In any specific embodiments of XX41 or XX42, n can be 2. In any specific embodiments XX41 or XX42 can be pharmaceutically acceptable salts. In any specific embodiments XX41 or XX42 can be pharmaceutically acceptable esters. In any specific embodiments XX41 or XX42 can be pharmaceutically acceptable hydrates. In any specific embodiments XX41 or XX42, R₂is an alkyl groups having 1, 2 or 3 carbon atoms. In any specific embodiments of XX41 or XX42, R₂is a methyl group. In any specific embodiments of XX41 or XX42, R₂is an ethyl group. In any specific embodiments of XX41 or XX42, one or both of R₆and/or R₇are optionally substituted alkyl groups. In any specific embodiments of XX41 or XX42, one or both of R₆and/or R₇are halogens.

Therapeutically and/or functionally compounds of this invention include those of formulas XX51-XX53:

In each of XX51-XX54, Q, M₁-M₃, R₆, R₇, n, Z₁-Z₅are as defined above and Z₆to Z₁₀, independently of one another and other Z in the molecule, 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, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —SOR group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group and an optionally substituted aryl group which can be a heteroaryl 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 wherein any two Z groups substituted on adjacent carbons of the same ring or any two carbons substituted on adjacent rings can be linked together to form a 4-7 member ring which may contain one or more double bonds, be aromatic and/or contain one or more heteroatoms (e.g., S, O or N).

In specific embodiments of XX51, XX52, XX53, or XX54, Z₁and Z₅are hydrogens. In specific embodiments of XX51, XX52, XX53, or XX54, Z₂and Z₅are hydrogen. In specific embodiments of XX51, XX52, XX53, or XX54, Z₆and Z₁₀are hydrogens. In specific embodiments of XX51, XX52, XX53, or XX54, Z₁, Z₅, Z₆and Z₁₀are all hydrogens. In specific embodiments of XX51, XX52, XX53, or XX54, all Zs are hydrogens or alkyl groups having 1-3 carbon atoms. In specific embodiments of XX52, Z₂, Z₅, Z₆and Z₁₀are all hydrogens. In specific embodiments of XX53, Z₁, Z₃, Z₆and Z₁₀are all hydrogens. In specific embodiments of XX54, Z₂, Z₄, Z₆and Z₁₀are all hydrogens. In specific embodiments of XX51, XX52, XX53, or XX54, one of Z₁-Z₁₀is an optionally substituted phenyl ring. In specific embodiments of XX51, XX52, XX53, or XX54, one of Z₁-Z₁₀is an unsubstituted phenyl ring. In specific embodiments of XX51, XX52, XX53, or XX54, one of Z₁-Z₁₀is a phenyl ring substituted with one cyano group. In specific embodiments of XX51, XX52, XX53, or XX54, one of Z₁-Z₁₀is a phenyl ring substituted with one or two halogens. In specific embodiments of XX51, XX52, XX53, or XX54, one of Z₁-Z₁₀is a phenyl ring substituted with one or two chlorines. In specific embodiments of XX51, XX52, XX53, or XX54, one of Z₁-Z₁₀is a phenyl ring substituted with one or two bromines. In specific embodiments of XX51, XX52, XX53, or XX54, one of Z₁-Z₁₀is a phenyl ring substituted with one or two fluorines. In specific embodiments of XX51, XX52, XX53, or XX54, one of Z₁-Z₁₀is a phenyl ring substituted with one or two iodines. In specific embodiments of XX51, XX52, XX53, or XX54, one of Z₁-Z₁₀is a phenyl ring substituted with one or two optionally substituted alkyl groups having 1-6 or 1-3 carbon atoms. In specific embodiments of XX51, one or both of Z₂or Z₃carry a non-hydrogen substituent. In specific embodiments of XX51, Z₂and Z₃together form an aromatic ring. In specific embodiments of XX51, one of Z₁-Z₅is a heterocyclic group which may be aromatic (e.g., a pyridinyl, pyrimidinyl, furanyl, benzofuranyl, dibenzofuranyl.). In specific embodiments of XX51, XX52, XX53, or XX54, one or two of Z₁-Z₁₀carry non-hydrogen substituents. In specific embodiments of XX52, XX53, or XX54, Z₁₀together with Z₂, Z₃or Z₄form a 5 or 6 member ring which may be aromatic and may contain one or more heteroatoms. In specific embodiments of XX52, XX53, or XX54, Z₁₀together with Z₂, Z₃or Z₄form a furan or benzofuranyl group.

In any specific embodiments of XX51, XX52, XX53, or XX54, Q is M. In any specific embodiments of XX51, XX52, XX53, or XX54, any one or more of M, M₁, M₂or M₃can be H or a salt or ester thereof. In any specific embodiments of XX51, XX52, XX53, or XX54, all R₆and R₇are hydrogens. In any specific embodiments of XX51, XX52, XX53, or XX54, X can be H. In any specific embodiments of XX51, XX52, XX53, or XX54, X can be OH. In any specific embodiments of XX51, XX52, XX53, or XX54, n can be 1. In any specific embodiments of XX51, XX52, XX53, or XX54, n can be 2. In any specific embodiments XX51, XX52, XX53, or XX54 can be pharmaceutically acceptable salts. In any specific embodiments XX51, XX52, XX53, or XX54 can be pharmaceutically acceptable esters. In any specific embodiments XX51, XX52, XX53, or XX54 can be pharmaceutically acceptable hydrates.

Therapeutically and/or functionally compounds of this invention include those of formulas XX61, XX62, XX71 and XX72:

and salts, esters and hydrates thereof.

In each of XX61, XX62, XX71 or XX72, M, M₁-M₃, R₆, R₇, n, X, and R₄are as defined above; R₁₁and R₁₂are selected from hydrogen, a halogen, a —CN, —OR, —COOR, —OCOOR, —COR, —CON(R)₂, —OCON(R)₂, —N(R)₂, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —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, 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 is zero or an integer ranging from 1-10, or 1-6, and Ar is an optionally substituted aryl group which may be a heteroaromatic group, wherein one or more CR₁₁R₁₂moieties can be replaced with an O atom.

In specific embodiments of XX61 or XX71, R₄is optionally substituted alkyl having 2-20 carbon atoms. In any specific embodiments of XX61 or XX71, R₄is an alkyl ether group having 1-20 carbon atoms. In specific embodiments of XX61 or XX71, R₄is an optionally substituted alkyl group having 1-1 0 carbon atoms. In specific embodiments of XX61 or XX71, R₄is an optionally substituted alkenyl group having 1-20 carbon atoms. In specific embodiments of XX61 or XX71, R₄is an optionally substituted dienyl group (alkenyl group with two double bonds) having 1-20 carbon atoms. In specific embodiments of XX61 or XX71, R₄is an optionally substituted alkynyl group having 1-20 carbon atoms. In specific embodiments of XX61 or XX71, R₄is an unsubstituted alkyl group having 1-6 carbon atoms. In specific embodiments of XX61 or XX71, R₄is an alkyl group having 1-10 carbon atoms substituted with an aryl group. In specific embodiments of XX61 or XX71, R₄is optionally substituted straight-chain alkyl having 2-20 carbon atoms. In specific embodiments of XX61 or XX71, R₄is an optionally substituted aryl group. In specific embodiments of XX61 or XX71, R₄is an optionally substituted phenyl group. In specific embodiments of XX61 or XX71, R₄is an optionally substituted heteroaromatic group. In specific embodiments of XX61 or XX71, R₄is an optionally substituted pyridine or pyrimidine group. In specific embodiments of XX61 or XX71, R₄is an optionally substituted nitrogen containing heteroaromatic group. In specific embodiments of XX61 or XX71, R₄is an optionally substituted carbazolyl group (carbazole ring). In specific embodiments of XX61 or XX71, R₁is an optionally substituted phenyl. In specific embodiments of XX61 or XX71, R₁is a halogen substituted phenyl or biphenyl. In specific embodiments of XX61 or XX71, R₁is optionally substituted biphenyl. In specific embodiments of XX61 or XX71, R₁is optionally substituted naphthyl. In specific embodiments of XX61 or XX71, R₁is optionally substituted benzofuranyl. In specific embodiments of XX61 or XX71, R₁is optionally substituted dibenzofuranyl. In specific embodiments of XX61 or XX71, R₁is an alkoxy substituted phenyl group. In specific embodiments of XX61 or XX71, R 1 is an aryl group substituted with an alkoxy or alkyl group. In specific embodiments of XX61 or XX71, R₁is an aryl group substituted with an alkyl or alkoxy group having 1-10 carbon atoms. In specific embodiments of XX61 or XX71, R₁is an aryl group substituted with an alkyl or alkoxy group having 1-6 carbon atoms. In specific embodiments of XX62 or XX72, R₁₁and R₁₂are selected from hydrogens, cyano groups, nitro groups, halogens or optionally substituted alkyl groups having 1-6 or 1-3 carbon atoms. In specific embodiments of XX62 or XX72, R₁₁and R₁₂are all hydrogens. In specific embodiments of XX62 or XX72, Ar is an optionally substituted phenyl. In specific embodiments of XX62 or XX72, Ar is optionally substituted biphenyl. In specific embodiments of XX62 or XX72, Ar is optionally substituted naphthyl. In specific embodiments of XX62 or XX72, Ar is optionally substituted benzofuranyl. In specific embodiments of XX62 or XX72, Ar is optionally substituted dibenzofuranyl. In specific embodiments of XX62 or XX72, Ar is an alkoxy substituted phenyl group. In specific embodiments of XX62 or XX72, Ar is substituted with an alkoxy or alkyl group. In specific embodiments of XX62 or XX72, Ar is substituted with an alkyl or alkoxy group having 1-10 carbon atoms. In specific embodiments of XX62 or XX72, Ar is substituted with an alkyl or alkoxy group having 1-6 carbon atoms. In specific embodiments of XX62 or XX72, r is 1-6. In specific embodiments of XX62 or XX72, r is 2-4. In specific embodiments of XX42, —(CR₁₁CR₁₂)_r— is —O—(CR₁₁R₁₂)_r-1—. In specific embodiments of XX62 or XX72, —(CR₁₁CR₁₂)_r—is —(R₁₁R₁₂)_t—O—(CR₁₁R₁₂)_swhere s+t=3-20 and more specifically where s and t, independently, are 2, 3 or 4. In specific embodiments, —(CR₁₁CR₁₂)_r— is —O—(CH₂)_r-1—. In specific embodiments of XX62 or XX72,—(CR₁₁CR₁₂)_r— is —(CH₂)_t—O—(CH₂)_swhere s+t=3-20 and more specifically where s and t, independently, are 2, 3 or 4.

In any specific embodiments of XX61, XX62, Xx71, or XX72, any one or more of M, M₁, M₂or M₃can be H or a salt or ester thereof. In specific embodiments of XX61, XX62, Xx71, or XX72, all R₆and R₇are hydrogens. In any specific embodiments of XX61, XX62, Xx71, or XX72, X can be H. In any specific embodiments of XX61, XX62, Xx71, or XX72, X can be OH. In any specific embodiments of XX61, XX62, Xx71, or XX72, n can be 1. In any specific embodiments of XX61, XX62, Xx71, or XX72, n can be 2. In any specific embodiments XX61, XX62, Xx71, or XX72 can be pharmaceutically acceptable salts. In any specific embodiments XX61, XX62, Xx71, or XX72 can be pharmaceutically acceptable esters. In any specific embodiments XX61, XX62, Xx71, or XX72 can be pharmaceutically acceptable hydrates. In any specific embodiments XX61, XX62, Xx71, or XX72, R₂is an alkyl groups having 1, 2 or 3 carbon atoms. In any specific embodiments of XX61, XX62, Xx71, or XX72, R₂is a methyl group. In any specific embodiments of XX61, XX62, Xx71, or XX72, R₂is an ethyl group. In any specific embodiments of XX61, XX62, Xx71, or XX72, one or both of R₆and/or R₇are optionally substituted alkyl groups. In any specific embodiments of XX61, XX62, Xx71, or XX72, one or both of R₆and/or R₇are halogens.

In certain embodiments, a compound of the invention includes compounds as described above in relation to compound BX1 but excepting the following compound structures (regardless of hydration state):

In claimed subject matter, the immediately foregoing arsonium, sulfonium, and phosphonium structures, regardless of hydration state, are optionally subject to disclaimer.

In an embodiment, the invention provides a composition comprising a compound. In embodiment, said composition comprises a therapeutically effective amount of the compound. In an embodiment, the invention provides a composition comprising a pharmaceutical formulation of a compound. In an embodiment, said pharmaceutical formulation comprises one or more excipients, carriers, and/or other components as would be understood in the art. In an embodiment, the invention provides a compound for use in the making of a medicament.

In an embodiment, 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. In an embodiment, the medical condition is a bone resorption disorder, a cancer, pain, an immune system disorder, and/or an infectious disease.

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., Ca²⁺, Mg²⁺), non-toxic heavy metal cations and ammonium (NH₄⁺) 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, trifluoroacetate), ascorbates, aspartates, benzoates, citrates, and lactate.

Compounds of the invention can have prodrug forms. 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. 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. (Academic Press, 1985); A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application of Prodrugs,” by H. Bundgaard, at pp. 113-191,1991); H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p. 1-38 (1992); H. Bundgaard, et al., Journal of Pharmaceutical Sciences, Vol. 77, p. 285 (1988); and Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates various bisphosphonate compounds (generally non-nitrogen containing) with compound designations that are aliases for certain compounds designated elsewhere with alternate compound numbers such as in the 500 and 600 series. Compound 55, for example, is an alias for Compound 647 and relates to synthesis Scheme 1. Compounds 56-63 relate to synthesis Scheme 2, and compounds 64-70 relate to synthetic Scheme 3.

FIG. 2 illustrates structures of certain bisphosphonate compounds, e.g., terphenyl and benzyl bisphosphonates.

FIG. 3 illustrates representative dose response curves from tumor cell growth inhibition tests (for compounds 8, 33, 55, 59, 64 and 67).

FIG. 4 illustrates structures of certain bisphosphonate compounds including sulfonium, phosphonium, arsonium, and ammonium analogs.

FIG. 5 illustrates structures of bisphosphonate compounds along with activity levels (micromolar IC50 values, μM) of non-nitrogen-containing benzyl bisphosphonates (upper group); and a sulfonium-bisphosphonate. Activity levels represent the capability to inhibit growth of three tumor cell lines: human breast cancer (MCF7), human lung cancer (NCIH460) and human CNS cancer (SF268). Values shown are the mean for the three cell lines.

FIG. 6 illustrates terphenyl containing bisphosphonates and anti-tumor cell activity levels (μM) as described above.

FIG. 7 illustrates bisphosphonate compounds with uncharged side-chains and activity levels for inhibiting a trypanosomal parasite enzyme, T. cruzi hexokinase.

FIG. 8 illustrates data relating to anti-parasite activity. An inverse correlation has been observed between compounds active in T. cruzi hexokinase and L. major FPPS (FIG. 8A). Two active hexokinase inhibitors also show activity in the clinically relevant amastigote form of the trypanosome (FIG. 8B).

FIG. 9 illustrates results of analyzing relative changes in E. coli gene expression levels upon treatment with fosmidomycin and a bisphosphonate compound.

DETAILED DESCRIPTION OF THE INVENTION

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); PIC₅₀/pEC₅₀, negative log of IC₅₀and EC₅₀, respectively, where IC₅₀and EC₅₀are 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 R¹-R⁵together 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 CH₂groups 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, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —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)₂where 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)₂where 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;

p13 N(R)₂where 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, —SO₂R, 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;

—OCOOR where R is an alkyl group or an aryl groups;

—SO₂N(R)₂where 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.

EXAMPLE 1
Bisphosphonate Compounds

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:

or a pharmaceutically acceptable salt or ester thereof;

wherein: Z comprises one of the structures shown above;

X is H, —OH, or a halogen;

n is 1, 2, or 3;

R¹-R³, 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, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —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 R¹-R⁵can together form one or more rings which may contain one or more double bonds or which may be aromatic; and

R¹, R², and R³, 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.

EXAMPLE 2
Terphenyl and Benzyl Bisphosphonate Compounds

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 FIG. 1 and FIG. 2.

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 FIG. 3 showing dose-response data.

TABLE 1Activity in Tumor Cell Growth Inhibition.MCF-7 cellNCI-H460 cellSF-268 cellCompoundIC₅₀(uM)IC₅₀(uM)IC₅₀(uM)6472.621.642.3862243.8746.8744.6662392.7486.0657.98608152.30139.70129.50621146.00133.40143.20618195.70132.20174.70640309.80285.30303.10625412.10413.10619.906241063.00328.70475.304930.220.620.654940.342.701.434951.974.854.7849615.2020.1028.3049858.6022.607.77491532.90445.60348.60

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.

TABLE 2UPPS inhibition by bisphosphonate compounds.compoundUPPS inhibition IC₅₀(uM)6290.336080.616280.886250.896401.866261.916222.396217.512949.0336410.0064612.0961812.4664212.6663319.2663232.7162036.7364147.8661485.63601112.65619153.57228411.29651279.38652500.63673399.50674522.60675629.40

Sunthetic methods are further described and elemental analysis results for zed are indicated in Table 3.

General method A )Suzuki coupling): An aryl boronic acid or its ester (6 mmol), a bromo substitued aromatic compound (5 mmol), K₂CO₃(15 mmol) and Pd(PPh₃)₄(50 mg) in toluene (10 mL) and H₂O (3 mL) were refluxed under N₂overnight. 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 NH₄Cl. 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 N₂in 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-H₂0 (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. (C₈H₁₀Br₂O₆P₂)C, H; ¹H NMR (400 MHz, D₂O): δ 2.78 (tt, J=20.8 Hz, 6.8 Hz, 1H, ArCH₂CH), 3.12 (td, J=17.2 Hz, 6.8 Hz, 2H, ArCH₂), 7.10 (d, J=8.4 Hz, 1H, aromatic), 7.43 (d, J=8.4 Hz, 1H, aromatic), 7.56 (s, 1H, aromatic); ³¹P NMR (162 MHz, CDCl₃):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. (C₃₂H₅₀Br₂O₁₄P₂)C, H; ¹H NMR (400 MHz, CDCl₃):δ1.21 (m, 36H, CH₃), 2.79 (tt, J=24.8 Hz, 6.8 Hz, 1H, ArCH₂CH), 3.08 (td, J=17.2 Hz, 6.8 Hz, 2H, ArCH₂), 5.62-5.69 (m, 8H, POCH₂), 7.10 (d, J=8.4 Hz, 1H, aromatic), 7.43 (d, J=8.4 Hz, 1H, aromatic), 7.56 (s, 1H, aromatic); ³¹P 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. (C₃₂H₅₀Cl₂O₁₄P₂) C, H; ¹H NMR (400 MHz, CDCl₃):δ1.21 (m, 36H, CH₃), 2.80 (tt, J=24.8 Hz, 6.8 Hz, 1H, ArCH₂CH), 3.15 (td, J=17.2 Hz, 6.8 Hz, 2H, ArCH₂), 5.62-5.69 (m, 8H, POCH₂), 7.10 (d, J=8.4 Hz, 1H, aromatic), 7.33-7.35 (m, 2H, aromatic); ³¹P 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. (C₂₈H₄₂Cl₂O₁₈P₂) C, H; ¹H NMR (500 MHz, CDCl₃):δ1.32 (d, J=6.4 Hz, 24H, CH₃), 2.75 (tt, J=24.4 Hz, 6.4 Hz, 1 H, ArCH₂CH), 3.47 (td, J=17.2 Hz, 6.8 Hz, 2H, ArCH₂), 4.89-4.95 (m, 4H, CHMe₂), 5.60-5.70 (m, 8H, OCH₂0), 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); ³¹P NMR (162 MHz, CDCl₃):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. (C₂₈H₄₂F₂O₁₈P₂) C, H; ¹H NMR (400 MHz, CDCl₃):δ1.33 (d, J=6.4 Hz, 24H, CH₃); 2.88 (tt, J=24.4 Hz, J=6.4 Hz, 1 H, ArCH₂CH), 3.40 (td, J=17.2 Hz, 6.8 Hz, 2H, ArCH₂), 4.89-4.95 (m, 4H, CHMe₂), 5.60-5.72 (m, 8H, OCH₂O), 6.99-7.13 (m, 3H, aromatic); ³¹P NMR (162 MHz, CDCl₃):δ21.94. ¹⁹F NMR (376 MHz, CDCl₃): −-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. (C₂₉H₄₃NO₁₈P₂) C, H, N; ¹H NMR (400 MHz, CDCl₃):δ1.31 (d, J=6.4 Hz, 24H, CH₃), 2.79 (tt, J=20.8 Hz, J=6.8 Hz, 1 H, ArCH₂CH), 3.40 (td, J=16.8 Hz, 6.8 Hz, 2H, ArCH₂), 4.89-4.96 (m, 4H, CHMe₂), 5.60-5.70 (m, 8H, OCH₂O), 7.36 (t, J=8 Hz, 1H, aromatic), 7.50-7.54 (m, 2H, aromatic), 7.57 (s, 1 H, aromatic); ³¹p NMR (162 MHz, CDCl₃):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. (C₂₀H₁₉NaO₇P₂.H₂O) C, H; ¹H NMR (400 MHz, D₂O):δ3.23 (t, J=12 Hz, 2H, CH₂), 7.20-7.80 (m, 13H, aromatic); ³¹P NMR (162 Hz, D₂O):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. (C₂₁H₂₀O₇P₂Na₂) C, H; ¹H NMR (400 MHz, D₂O): δ2.05-2.10 (m, 2H, CH₂), 2.80-2.85 (m, 2H, ArCH₂), 7.22-7.32 (m, 6H, aromatic), 7.35-7.64 (m, 7H, aromatic); ³¹P NMR (162 MHz, D₂O):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. (C₂₁H₁₉O₇P₂Na₃-H₂O) C, H; ¹H NMR (500 MHz, D₂O): 61.98-2.10 (m, 2H, CH₂), 2.69-2.72 (m, 2H, ArCH₂), 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). ³¹P NMR (202 MHz, D₂O):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. (C₂₁H₁₉O₇P₂Na₃.H₂O) C, H; ¹H NMR (400 Hz, D₂O):δ2.01-2.12 (m, 2H, CH₂), 2.80-2.85 (m, 2H, ArCH₂), 7.23-7.57 (m, 12H, aromatic), 7.77 (s,1 H, aromatic); ³¹P NMR (162 Hz, D₂O):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. (C₂₀H₁₈O₇P₂Na₂.H₂O) C, H; ¹H NMR (400 MHz, D₂O):δ3.10 (t, J=12 Hz, 2H, CH₂), 6.73-7.40 (m,13H, aromatic). ³¹P NMR (162 Hz, D₂O):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. (C₂₀H₁₈O₇P₂Na₂.2H₂O) C, H; ¹H NMR (400 MHz, D₂O)δ3.06 (t, J=12.4 Hz, CH₂), 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); ³¹P NMR (162 MHz, D₂O):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. (C₂₀H₁₉O₇P₂Na) C, H; ¹H NMR (400 MHz, D₂O)δ3.21 (t, J=12.4 Hz, CH₂), 7.27 (t, J=7.2 Hz, 1H, aromatic), 7.34-7.60 (m, 11H, aromatic), 7.80 (s, 1H, aromatic); ³¹p NMR (162 MHz, D₂O):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. (C₁₉H₁₇O₇P₂Na.0.25H₂O) C, H; ¹H NMR (400 MHz, D₂O):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); ³¹P NMR (162 MHz, D₂O):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), K₂CO₃(3.0 g, 21.7 mmol) and Pd(PPh₃)₄(100 mg) were refluxed in toluene-H₂O (50 mL, 5/1) overnight under N₂. 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 CCl₄(30 mL). After being washed successively with 5% HCl then 10% NaHCO₃, 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 ¹H NMR indicated 94% purity. ¹H NMR (400 MHz, CDCl₃):δ1.21 (m, 36H, CH₃), 2.80 (tt, J=24.8 Hz, 6.8 Hz, 1 H, ArCH₂CH), 3.15 (td, J=17.2 Hz, 6.8 Hz, 2H, ArCH₂), 5.62-5.69 (m, 8H, POCH₂), 7.23-7.85 (m, 13H, aromatic); ³¹P 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. (C₉H₈NNa₃O₆P₂.H₂O) C, H, N; ¹H NMR (400 MHz, D₂O):δ2.79 (tt, J=20.8 Hz, 6.8 Hz, 1H, ArCH₂CH), 3.40 (td, J=16.8 Hz, 6.8 Hz, 2H, ArCH₂), 4.89-4.96 (m,4H, CHMe₂), 5.60-5.70 (m, 8H, OCH₂O), 7.39 (t, J=8 Hz, 1H, aromatic); 7.45-7.52 (m, 2H, aromatic), 7.59 (s, 1H, aromatic); ³¹P NMR (162 MHz, D₂O):δ19.81.

TABLE 3Elemental analysis results for bisphosphonate compounds.CalculatedFoundCompoundFormulaC (%)H (%)N (%)C (%)H (%)N (%)9C₁₃H₁₃FNNaO₇P₃39.113.283.5139.163.653.5110C₁₄H₁₅F₃NNa₂O_8.5P₂33.753.032.8133.993.382.7611C₁₁H_19.5NO_7.25P₂38.445.724.0838.295.494.1114C₁₉H₃₉NO₆P₃54.424.573.3454.274.373.3015C₁₁H₃₀NO_6.5P₂39.776.074.2239.726.004.0016C₁₃H₃₅NO₆P₂45.494.414.0845.094.314.0819C₇H₁₁BrNNaO₃P₂20.912.763.4820.752.613.1720C₈H_14.5NO_6.75P₂32.614.964.7532.634.864.6221C₉H₂₄NNaO₆P₂34.084.454.4233.794.694.2828C₇H₁₃ClNO_6.5P₂27.073.574.5126.863.374.3429C₇H_21.5NO_6.25P₂30.954.275.1630.924.115.1130C₇H₂₃ClNO_6.5P₂27.073.574.5126.863.374.3431C₇H₁₀INO₆P₂21.392.563.5621.292.203.4332C₇H₁₀BrNO₆P₂24.302.914.0524.002.733.8033C₁₄H_26.25NNa_0.75O₆P₂44.994.383.7544.934.423.7934C₉H₁₀F₃NO₆P₂28.763.014.1828.412.923.9739C₁₉H₂₉NO₆P₂54.424.573.3454.244.473.3040C₁₂H₁₇NO₉P₂39.464.693.8439.334.503.8241C₁₉H_29.6NO_6.3P₃53.734.653.3053.384.473.3742C₁₂H₂₇NO₃P₂39.464.693.8439.034.314.0044C₁₃H₂₈NO_2.5P₂40.434.703.6340.344.493.2546C₃H₁₃NO₈P₂30.684.184.4730.324.054.3849C₁₂H₁₈N₃NaO_9.5P₂33.744.256.5633.934.126.1850C₁₁H₁₄NO_6.5P₂40.504.334.2940.644.114.3051C₃H₁₂P₃NO_6.5P₂27.923.224.0727.723.004.0452C₁₁H₁₉N₃O_8.5P₂S32.284.686.8432.134.386.6253C₁₉H₂₉NO₆P₂54.424.573.3454.194.003.2854C₁₉H₂₉NNaO_6.5P₂50.684.253.1150.434.133.1756C₂₁H₂₃Na₃O₈P₂47.383.9847.533.7557C₂₆H₂₀Na₃O₈P₂48.404.0648.614.2158C₂₆H₂₃NaO₈P₂50.644.4650.704.3559C₂₁H₂₃Na₂O_7.5P₂50.314.2250.023.9360C₂₁H₂₀Na₂O₇P₂51.234.0951.224.4761C₁₉H_17.5NaO_7.25P₂51.083.9550.923.6862C₂₆H₂₉NaO₇P₂52.6452.634.204.1463C₂₆H₂₂Na₂O₉P₂46.714.3146.634.4264C₃₂H₅₀Br₂O₁₄P₂43.655.7243.815.5265C₃₂H₅₀Cl₂O₁₄P₂48.556.3748.654.3766C₂₈H₄₂Cl₂O₁₈P₂42.075.3041.715.4167C₂₂H₄₂F₂O₁₂P₂43.875.5243.805.4368C₂₉H₄₃NO₁₅P₂46.105.7446.035.7969C₆H₁₉Br₂O₆P₂22.672.3822.782.4270C₉H₁₀NNa₃O₇P₂28.822.6928.832.76

EXAMPLE 3
Sulfonium and Phosphonium Bisphosphonates

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 FIG. 4 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.

TABLE 4Activity of bisphosphonate compounds in multiple functional tests.T. bruceiHumanGammadelta TCompoundFPPSD. discoideumFPPS Kicell stimulation,CompoundAliasIC50 (μm)IC50 (μm)(nM)EC₅₀ 1 (Pamidronate)167940 2 (alendronate)3252 3 (risedronate)0.12.81.236.2 4 (zoledronate)0.321.91.257.3 5 65270.44.7822.11 7536213.88.18127.2 85401.47.515.2423.68 954120722.631799105460.785.622.9226.02115470.255.953.5417.32125501019.84375.6135641.18.304.34260.9145697.9678.72155720.248.873.44217165734.235.201991757413.43.51199.6185750.596.583.4275.521957611.25.1451.972058014.63.3643.52215815.734.92308.7225842.05119235850.181.855.68245871.3415.74665255894.9412.4896.40265947.1513.94413.8

Synthesis of Bisphosphonates Including Sulfonium and Phosphonium Analogs

Scheme 4. Preparation of the Sulfonium diphosphonic acids (I)

4a) Preparation of sulfides

4b) Preparation of 1-hydroxy-2-(substituted sulfonium-1-yl)ethyl-1,1-diphosphonic acid.

4c) Preparation of 1-hydroxy-3-(substituted sulfonium-1-yl)propyl-1,1-diphosphonic acid

Scheme 5. Preparation of phosphonium diphosphonic acid

General procedure 1: A mixture of a carboxylic acid (3 mmol), H₃PO₃(15 mmol) and toluene (8 mL) were heated to 80° C. with stirring. After all solids were melted, POCl₃(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 H₂O/i-PrOH. In some cases, it can be neutralized with NaOH and crystallized as its sodium salt in H₂O/EtOH.

EXAMPLE A
1-hydroxy-2-(trimethylphosphoniumyl)ethylidene-1,1-bisphosphonic acid (536)

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 N₂overnight, 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. (C₅H₁₅O₇P₃) C, H.

EXAMPLE B
1-hydroxy-3-(trimethylphosphoniumyl)propylidene-1,1-bisphosphonic acid (541)

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 N₂overnight, 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. (C₆H₁₇O₇P₃.0.5 H₂O) C, H.

EXAMPLE C
1-hydroxy-2-(pentamethylenesulfoniumyl)ethylidene-1,1-bisphosphonic acid (527)

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 N₂overnight, 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. (C₇H₁₆O₇P₂S) C, H.

EXAMPLE D
1-hydroxy-2-(S-methyl-3-phenylpropylsulfoniumyl)ethylidene-1,1-bisphosphonic acid (585)

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 H₂O 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 N₂overnight, 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. (C₁₂H₁₉NaO₇P₂S.0.5 C₂H₅OH) C, H.

EXAMPLE E
1-hydroxy-3-(S-ethyl-3-phenoxypropylsulfoniumyl)propylidene-1,1-bisphosphonic acid (573)

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 H₂0 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 N₂at 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. (C₁₄H₂₂Na₂O₈P₂S.0.5 H₂O) C, H.

EXAMPLE 4
Further bisphosphonate Compounds

In embodiments, the invention provides compounds having the formula CA11:

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;

wherein:

X is H or —OH;

n is 1, 2, or 3;

R¹and R², 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, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —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;

R¹and R²can together form one or more rings which may contain one or more double bonds or which may be aromatic;

R³and R⁴, independently of each other and other R³and R⁴in 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 R³and R⁴can 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 R³and R⁴are hydrogens.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R³and R⁴are hydrogens.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R³and R⁴are hydrogens and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R³and R⁴are hydrogens, n is 1 and X is OH.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R³and R⁴are hydrogens and n is 2.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R³and R⁴are hydrogens, n is 2 and X is OH.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R³and R⁴are hydrogens and n is 3.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R³and R⁴are hydrogens, n is 3 and X is OH.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R³and R⁴are hydrogens, n is 1 and X is H.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R², independently of one another, are optionally substituted alkyl groups.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R², 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 R¹and R²are 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 R¹and R², independently of one another, are both optionally substituted alkyl groups.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R², 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 R¹and R²are 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 R¹and R²are both optionally substituted alkyl groups and one or more of R³or R⁴is a halogen.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R²are both optionally substituted alkyl groups, particularly wherein R¹is a small alkyl group and more particularly a methyl group, R³and R⁴are both hydrogens, X is OH and n is 1. Specific compounds of this invention are those as above in which R¹is a methyl group, R²is an optionally substituted alkyl group, R³and R⁴are both hydrogens, X is OH and n is 1. A specific compound of this invention is that as above in which R¹and R²are both methyl groups, R³and R⁴are both hydrogens, X is OH and n is 1. A specific compound of this invention is that as above in which R¹is a methyl group, R²is a propyl group, R³and R⁴are both hydrogens, X is OH and n is 1. A specific compound of this invention is that as above in which R¹is a methyl group, R²is a butyl group, R³and R⁴are both hydrogens, X is OH and n is 1. A specific compound of this invention is that as above in which R¹is a methyl group, R²is a pentyl group, R³and R⁴are both hydrogens, X is OH and n is 1. A specific compound of this invention is that as above in which R¹is a methyl group, R²is an octyl group, R³and R⁴are both hydrogens, X is OH and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R²are both optionally substituted alkyl groups, particularly wherein R¹is a small alkyl group and more particularly a methyl group, R³and R⁴are both hydrogens, X is OH and n is 2. Specific compounds of this invention are those as above in which R¹is a methyl group, R²is an optionally substituted alkyl group, R³and R⁴are both hydrogens, X is OH and n is 2. A specific compound of this invention is that as above in which R¹and R²are both methyl groups, R³and R⁴are both hydrogens, X is OH and n is 2. A specific compound of this invention is that as above in which R¹is a methyl group, R²is a propyl group, R³and R⁴are both hydrogens, X is OH and n is 2. A specific compound of this invention is that as above in which R¹is a methyl group, R²is a pentyl group, R³and R⁴are both hydrogens, X is OH and n is 2. A specific compound of this invention is that as above in which R¹is a methyl group, R²is an octyl group, R³and R⁴are both hydrogens, X is OH and n is 2.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹is a small alkyl group and more particularly a methyl group, R²is an optionally substituted arylalkyl group, R³and R⁴are both hydrogens, X is OH and n is 1. Specific compounds of the invention are those as above in which R¹is a methyl group, R²is an optionally substituted arylalkyl group, R³and R⁴are both hydrogens, X is OH and n is 1. A specific compound of the invention is that as above in which R¹is a methyl group, R²is a propylphenyl group, R³and R⁴are both hydrogens, X is OH and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹is a small alkyl group and more particularly a methyl group, R²is an optionally substituted arylalkyl group, R³and R⁴are both hydrogens, X is OH and n is 2. A specific compound of this invention is that as above in which R¹is a methyl group, R²is an ethylphenyl group, R³and R⁴are both hydrogens, X is OH and n is 2. A specific compound of this invention is that as above in which R¹is a methyl group, R²is a propylphenyl group, R³and R⁴are both hydrogens, X is OH and n is 2.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹is a small alkyl group and more particularly a methyl group, R²is an optionally substituted arylalkoxy group, R³and R⁴are both hydrogens, X is OH and n is 1. Specific compounds of the invention are those as above in which R¹is a methyl group, R²is an optionally substituted arylalkoxy group, R³and R⁴are both hydrogens, X is OH and n is 1. A specific compound of the invention is that as above in which R¹is a methyl group, R²is a propoxybenzyl group, R³and R⁴are both hydrogens, X is OH and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹is a small alkyl group and more particularly a methyl group, R²is an optionally substituted arylalkoxy group, R³and R⁴are both hydrogens, X is OH and n is 2. Specific compounds of the invention are those as above in which R¹is a methyl group, R²is an optionally substituted arylalkoxy group, R³and R⁴are both hydrogens, X is OH and n is 2. A specific compound of the invention is that as above in which R¹is a methyl group, R²is a propoxybenzyl group, R³and R⁴are both hydrogens, X is OH and n is 2.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹is a small alkyl group and more particularly an ethyl group, R²is an optionally substituted arylalkoxy group, R³and R⁴are both hydrogens, X is OH and n is 2. Specific compounds of the invention are those as above in which R¹is an ethyl group, R2 is an optionally substituted arylalkoxy group, R³and R⁴are both hydrogens, X is OH and n is 2. A specific compound of the invention is that as above in which R¹is an ethyl group, R²is a propoxybenzyl group, R³and R⁴are both hydrogens, X is OH and n is 2.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R²form an optionally substituted ring, R³and R⁴are both hydrogens, X is OH and n is 1. Specific compounds of the invention are those as above in which R¹and R²form an optionally substituted thiophenium group, R³and R⁴are both hydrogens, X is OH and n is 1. A specific compound of the invention is that as above in which R¹and R²form a thiophenium group, R³and R⁴are both hydrogens, X is OH and n is 1. A specific compound of the invention is that as above in which R¹and R²form a 3-phenylthiophenium group, R³and R⁴are both hydrogens, X is OH and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R²form an optionally substituted ring, R³and R⁴are both hydrogens, X is OH and n is 2. Specific compounds of the invention are those as above in which R¹and R²form an optionally substituted thiophenium group, R³and R⁴are both hydrogens, X is OH and n is 2. A specific compound of the invention is that as above in which R¹and R²form a thiophenium group, R³and R⁴are both hydrogens, X is OH and n is 2.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R²form an optionally substituted ring, R³and R⁴are both hydrogens, X is OH and n is 3. Specific compounds of the invention are those as above in which R¹and R²form an optionally substituted thiophenium group, R³and R⁴are both hydrogens, X is OH and n is 3. A specific compound of the invention is that as above in which R¹and R²form a thiophenium group, R³and R⁴are both hydrogens, X is OH and n is 3.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R²form an optionally substituted ring, R³and R⁴are both hydrogens, X is OH and n is 1. Specific compounds of the invention are those as above in which R¹and R²form an optionally substituted thiopyranium group, R³and R⁴are both hydrogens, X is OH and n is 1. A specific compound of the invention is that as above in which R¹and R²form a thiopyranium group, R³and R⁴are both hydrogens, X is OH and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R²form an optionally substituted ring, R³and R⁴are both hydrogens, X is OH and n is 2. Specific compounds of the invention are those as above in which R¹and R²form an optionally substituted thiopyranium group, R³and R⁴are both hydrogens, X is OH and n is 2. A specific compound of the invention is that as above in which R¹and R²form a thiopyranium group, R³and R⁴are both hydrogens, X is OH and n is 2.

In a particular embodiment of CA11, X is OH, n=1, R³and R⁴are hydrogens, and R¹and R²are 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 R¹is a methyl group and R²is 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, R³and R⁴are hydrogens, X is OH or H, and R¹and R²are 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 R¹is a methyl group and R²is 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, R³and R⁴are hydrogens, and R¹and R²are 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 R¹is a methyl group and R²is 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, R³and R⁴are hydrogens, X is OH or H, and R¹and R²are 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 R¹is a methyl group and R²is 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, R³and R⁴are hydrogens, and R¹and R²are 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 R¹is a methyl group and R²is 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, R³and R⁴are hydrogens, X is OH or H, and R¹and R²are 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 R¹is a methyl group and R²is 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, R³and R⁴are hydrogens, and R¹and R²are 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 R¹is an ethyl group and R²is 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, R³and R⁴are hydrogens, X is OH or H, and R¹and R²are 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 R¹is an ethyl group and R²is 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, R³and R⁴are hydrogens, X is OH or H, and R¹and R²form an optionally substituted thiophenium group. Of particular interest is that compound where R¹and R²form 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, R³and R⁴are hydrogens, X is OH or H, and R¹and R²form an optionally substituted thiophenium group. Of particular interest is that compound where R¹and R²form an unsubstituted thiophenium group.

In other specific embodiments, the invention includes compounds of formula CA11, wherein n is 3, R³and R⁴are hydrogens, X is OH or H, and R¹and R²form an optionally substituted thiophenium group. Of particular interest is that compound where R¹and R²form an unsubstituted thiophenium group.

In other specific embodiments, the invention includes compounds of formula CA11, wherein n is 1, R³and R⁴are hydrogens, X is OH or H, and R¹and R²form an optionally substituted thiopyranium group. Of particular interest is that compound where R¹and R²form an unsubstituted thiopyranium group.

In other specific embodiments, the invention includes compounds of formula CA11, wherein n is 2, R³and R⁴are hydrogens, X is OH or H, and R¹and R²form an optionally substituted thiopyranium group. Of particular interest is that compound where R¹and R²form an unsubstituted thiopyranium group.

In embodiments, the invention provides compounds having the formula CA12:

wherein:

X is H, —OH;

n is 1 or 2;

R¹-R³, 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, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —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 R⁴-R⁵can together form one or more rings which may contain one or more double bonds or which may be aromatic;

R⁴and R⁵, independently of each other and other R⁴and R⁵in 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 R⁴and R⁵can 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 R⁴and R⁵are hydrogens.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R⁴and R⁵are hydrogens.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R⁴and R⁵are hydrogens and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R⁴and R⁵are hydrogens, n is 1 and X is OH.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R⁴and R⁵are hydrogens, n is 1 and X is H.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹-R³are optionally substituted alkyl groups chosen independently of one another and R⁴-R⁵are both hydrogens.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁴and R⁵are both hydrogens, and R¹, R²and R³are 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 R⁴and R⁵are both hydrogens, R¹, R²and R³optionally 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 R⁴and R⁵are both hydrogens, R², R³and R⁴are methyl groups, X is OH and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁴and R⁵are both hydrogens, R¹, R²and R³are 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 R⁴and R⁵are both hydrogens, R², R³and R⁴are methyl groups, X is OH and n is 1.

In a particular embodiment of CA12, X is OH, n=1, R¹-R³are methyl groups and R⁴-R⁵are hydrogens.

In other specific embodiments, the invention includes compounds of formula CA12, wherein n is 1, R¹-R³are methyl groups and R⁴-R⁵are hydrogens, X is OH or H.

In other specific embodiments, the invention includes compounds of formula CA12, wherein n is 2, R¹-R³are methyl groups and R⁴-R⁵are hydrogens, X is OH or H.

In other specific embodiments, the invention includes compounds of formula CA12, wherein n is 1, R⁴-R⁵are hydrogens, X is OH and R¹-R³are 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.

In embodiments, the invention provides compounds having the formula CA13:

wherein:

X is H, —OH, a halogen, or a methyl group;

n is 1, 2, or 3;

R¹-R⁵, 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, —NO₂, —SR, —SO₂R, —SO₂N(R)₂or —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 R¹-R⁵can together form one or more rings which may contain one or more double bonds or which may be aromatic;

R⁶and R⁷, independently of each other and other R⁶and R⁷in 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 R⁶and R⁷can together form a ring which may contain one or more double bonds; and

wherein R⁸-R¹¹can 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 R⁶and R⁷are hydrogens.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R⁶and R⁷are hydrogens.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R⁶and R⁷are hydrogens and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R⁶and R⁷are hydrogens, n is 1 and X is H.

In other specific embodiments, the invention relates to compounds having the above formula wherein both of R⁶and R⁷are hydrogens, n is 1 and X is OH.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R⁵are both hydrogens.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R⁵are both hydrogen, X is H and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R⁵are both hydrogen, X is OH and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R⁵are both hydrogen, X is H and n is 2.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R⁵are both hydrogen, X is OH and n is 2.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R⁵are both hydrogen, X is H and n is 3.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R⁵are both hydrogen, X is OH and n is 3.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are hydrogens.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are hydrogens, X is H and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are hydrogens, X is OH and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are hydrogens, X is H and n is 2.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are hydrogens, X is OH and n is 2.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are hydrogens, X is H and n is 3.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are hydrogens, X is OH and n is 3.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are pivalolyl ester groups.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are pivalolyl ester groups, X is H and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are pivalolyl ester groups, X is H and n is 2.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are pivalolyl ester groups, X is H and n is 3.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are isopropyl carbonate groups.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are isopropyl carbonate groups, X is H and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are isopropyl carbonate groups, X is H and n is 2.

In other specific embodiments, the invention relates to compounds having the above formula wherein R⁸-R¹¹are isopropyl carbonate groups, X is H and n is 3.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R⁵are both hydrogen and one or more of R², R³or R⁴is a halogen.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R⁵are both hydrogens, one or more of R², R³or R⁴is a halogen, X is H and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R⁵are both hydrogens, one or more of R², R³or R⁴is a cyano group.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R⁵are both hydrogens, one or more of R², R³or R⁴is a cyano group, X is H and n is 1.

In other specific embodiments, the invention relates to compounds having the above formula wherein R¹and R⁵are both hydrogens, one or more of R², R³or R⁴is 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 R¹and R⁵are both hydrogens, one or more of R², R³or R⁴is 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 R¹and R⁵are both hydrogens, one or more of R², R³or R⁴is 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 R¹and R⁵are both hydrogens, one or more of R², R³or R⁴is 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 R¹and R⁵are both hydrogens, one or more of R², R³or R⁴is 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 R¹and R⁵are both hydrogens, one or more of R², R³or R⁴is 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, R¹and R⁵are both hydrogens, R⁶and R⁷are both hydrogens, R⁸-R¹¹are all hydrogens, X is H or OH, and one or more of R², R³or R⁴is 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, R¹and R⁵are both hydrogens, R⁶and R⁷are both hydrogens, R⁸-R¹¹are selected from the group consisting of hydrogen, pivalolyl ester groups, and isopropyl carbonate groups, X is H, and one or more of R², R³or R⁴is 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, R¹and R³-R⁷are hydrogens, X=OH, and R²=H, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted phenyl. In a more specific embodiment, the invention includes compounds where n=1, R¹and R³-R⁷═H, X═OH, and R²═H, alkyl, alkoxy, and phenyl. In a further specific embodiment, the invention includes compounds where n=1, R¹and R³-R⁷=H, X=OH, and R²=H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, or phenyl.

Therapeutic applications.

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.

Scheme 6

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 <0.4% error in C/H/N microanalysis; structures can be confirmed by ¹H and ³¹P NMR spectroscopy.

Scheme 7 (sulfonium bisphosphonates)

Scheme 8

Scheme 9 (including phosphonium, sulfoxide, and hydroxylamine analogs)

Scheme 10

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 CH₂spaces 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 13

Scheme 14

Scheme 15—General Scheme for Terphenyl PIV Synthesis. Compounds were generated and tested. Activity levels (μM) for certain compounds are shown in FIG. 6. 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.

EXAMPLE 5
Bisphosphonate Activity and Trypanosoma cruzi

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 FIG. 7 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 FIG. 8A. Two active hexokinase inhibitors also show in vitro activity in the clinically relevant amastigote form of the trypanosome. See FIG. 8B.

EXAMPLE 6
Bisphosphonate Compounds and Anti-Bacterial Activity

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. FIG. 9 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 FIG. 9, 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<2.54 E-8.

Statements Regarding Incorporation by Reference and Variations

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.

REFERENCES

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BISPHOSPHONATE COMPOUNDS AND METHODS

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