# US 7,745,422 B2 · Bisphosphonate compounds and methods for bone resorption diseases, cancer, bone pain, immune disorders, and infectious diseases

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- Number: US 7,745,422 B2
- Document ID: US7745422B2
- Status: Granted
- Kind: B2
- Application number: 12/103,551
- Filed: 2008-04-15
- Published: 2008-12-25
- Granted: 2010-06-29
- Earliest claimed: 2004-10-08
- Assignees: The Board of Trustees of the University of Illinois
- Inventors: John M. Sanders; Yongcheng Song; Julian M. W. Chan; Eric Oldfield; Yonghui Zhang
- Web page: https://patentgrep.com/patent/US7745422B2

## CPC

- C07F 9/3873: {containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)}
- A61P 19/00: Drugs for skeletal disorders
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 33/04: Amoebicides
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07F 9/58: Pyridine rings
- C07F 9/60: Quinoline or hydrogenated quinoline ring systems
- C07F 9/62: Isoquinoline or hydrogenated isoquinoline ring systems
- C07F 9/6506: having the nitrogen atoms in positions 1 and 3
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Bisphosphonate compounds and related methods of making and using are disclosed, including pyridinium-1-yl, quinolinium-1-yl, and related compounds. The activity of compounds is disclosed in the context of functional assays such as Leishmania major farnesyl diphosphate synthase (FPPS) inhibition, Dictyostelium discoideum growth inhibition, human gamma delta T cell activation, and bone resorption. The applicability of bisphosphonate compounds in the context of parasitic infections, for example against trypanosomes, is disclosed. Further potential applications of the invention are disclosed regarding the treatment of one or more conditions such as bone resorption disorders, cancer, bone pain, infectious diseases, and in immunotherapy.

## Claims

### Claim 1

A compound of formula CA1:
or a pharmaceutically acceptable salt thereof; wherein:
X is H
n is 1,2, or 3;
R1 and R5 are both hydrogens and R2, R3 and R4 are independently selected from the group consisting of hydrogen, halogen, an optionally substituted alkyl group having 4-20 carbon atoms, an optionally substituted alkenyl group having 2-20 carbon atoms, an —OR group, an optionally substituted aryl group and an optionally substituted arylalkyl group, where R is selected from an optionally substituted alkyl group having 1-20 carbon atoms; and
R6 and R7, independently, 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′, independently, is selected from H, an optionally substituted alkyl group and an optionally substituted aryl group,
wherein at least one of R2, R3 or R4 is selected from the group consisting of a halogen, an optionally substituted alkyl group having 4-20 carbon atoms, an optionally substituted alkenyl group having 2-20 carbon atoms, an —OR group;
and wherein R is selected from an optionally substituted alkyl group having 1-20 carbon atoms, an optionally substituted aryl group and an optionally substituted aryl alkyl group.

### Claim 2 (depends on 1)

The compound of claim 1, wherein n is 1.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R6 and R7 are both hydrogens.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1 and R5 are both hydrogens.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the alkyl, alkenyl or aryl groups are optionally substituted with one or more halogens, —CN, —COOR″, —OR″, —COR″, —OCOOR″, —CON(R″)2, —OCON(R″)2, —N(R″)2, —NO2, —SR″, —SO2R″, —SO2N(R″)2, —SOR″, alkyl, alkenyl, or aryl groups, where each R″, independently, is hydrogen, an alkyl group, alkenyl group or aryl group.

### Claim 6 (depends on 1)

The compound of claim 1, wherein at least one of R2, R3 or R4 is selected from the group consisting of an optionally substituted alkyl group having 4-20 carbon atoms, an optionally substituted alkenyl group having 2-20 carbon atoms, and an —OR group where R is selected from an optionally substituted alkyl group having 1-20 carbon atoms.

### Claim 7 (depends on 6)

The compound of claim 6, wherein n is 1 and R6 and R7 are both hydrogens.

### Claim 8 (depends on 1)

The compound of claim 1, wherein at least one of R2, R3 or R4 is selected from the group consisting of an optionally substituted alkyl group having 4-20 carbon atoms, and an —OR group where R is selected from an optionally substituted alkyl group having 4-20 carbon atoms.

### Claim 9 (depends on 1)

The compound of claim 1, wherein at least one of R2, R3 or R4 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted aryl alkyl group.

### Claim 10 (depends on 9)

The compound of claim 9, wherein the aryl groups are optionally substituted with one or more halogens, alkyl groups, alkoxy groups or hydroxy groups.

### Claim 11 (depends on 9)

The compound of claim 9, wherein at least one of R2, R3 or R4 is selected from the group consisting of an optionally substituted phenyl group and an optionally substituted phenylmethyl group.

### Claim 12 (depends on 11)

The compound of claim 11, wherein n is 1 and R6 and R7 are both hydrogen.

### Claim 13 (depends on 1)

The compound of claim 1, wherein at least one of R2, R3 or R4 is selected from the group consisting of an —OR group where R is selected from an optionally substituted alkyl group having 4-20 carbon atoms.

### Claim 14 (depends on 13)

The compound of claim 13, wherein n is 1 and R6 and R7 are both hydrogen.

### Claim 15 (depends on 1)

The compound of claim 1, wherein at least one of R2, R3 or R4 is selected from the group consisting of an —OR group where R is selected from an alkyl group having 4-20 carbon atoms.

### Claim 16 (depends on 15)

The compound of claim 15, wherein n is 1 and R6 and R7 are both hydrogen.

### Claim 17 (depends on 1)

The compound of claim 1, wherein n is 1, all of R1, R3-R7 are hydrogens, and R2 is selected from the group consisting of optionally substituted alkyl groups having 4-20 carbon atoms, optionally substituted alkoxy groups having 4-20 carbon atoms and optionally substituted phenyl groups.

### Claim 18 (depends on 17)

The compound of claim 17, wherein optional substitution is substitution by one or more halogens, alkyl groups, alkoxy groups or hydroxy groups.

### Claim 19 (depends on 1)

The compound of claim 1, wherein n is 1, all of R1, R3-R7 are hydrogens and R2 is an optionally substituted alkyl group having 4-20 carbon atoms.

### Claim 20 (depends on 1)

The compound of claim 1, wherein n is 1, all of R1, R3-R7 are hydrogens and R2 is an alkyl group having 4-20 carbon atoms.

### Claim 21 (depends on 1)

The compound of claim 1, wherein n is 1, all of R1, R3-R7 are hydrogens and R2 is an alkyl group having 4-10 carbon atoms.

### Claim 22 (depends on 1)

The compound of claim 1, wherein n is 1, all of R1, R3-R7 are hydrogens and R2 is an alkyl group having 10-20 carbon atoms.

### Claim 23 (depends on 1)

A therapeutic composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 24 (depends on 19)

A pharmaceutical composition comprising a compound of claim 19 and a pharmaceutically acceptable carrier.

### Claim 25 (depends on 1)

A method of treating a bone resorption disorder comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of claim 1.

### Claim 26 (depends on 1)

A method of treating an infectious disease comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of claim 1 wherein the infection is due to Trypanosoma or Leishmania parasites.

### Claim 27 (depends on 1)

A method for stimulating γδ T cells which comprises the step of contacting an effective amount of a compound of claim 1 with γδ T cells.