Benzene 1,4-bis(bisphosphonic acid)-based metal complexes, method of synthesis and applications thereof

Patent metadata

Field	Value
Publication number	US-11713331-B2
Application number	US-202117228629-A
Country	US
Kind code	B2
Filing date	Apr 12, 2021
Priority date	Apr 12, 2020
Publication date	Aug 1, 2023
Grant date	Aug 1, 2023

Abstract

The invention provides extended bisphosphonate-based metal complexes using benzene1,4-bis(bisphosphonic acid) (BBPA), an analog of benzene 1,4-dicarboxylic acid (BDC). Hydrothermal synthesis of BBPA with the bioactive metals Ca2+, Zn2+, and Mg2+ leads to four crystals phases, namely, BBPA-Ca forms I and II, BBPA-Zn form I, and BBPA-Mg form I. Out of the three structures, BBPA-Ca form II presents large channels (8 Å×12 Å), potentiating the use of this framework to load drugs. Cytotoxicity effects of BBPA was elucidated in a human breast cancer MDA-MB-231 and a normal osteoblast hFOB 1.19 cell lines. The half-maximal inhibitory concentration (IC50) for BBPA used to treat both cell lines were >200 μM at 24, 48, and 72 h of treatment. The BBPA in the range of concentration employed (0-200 μM) was not cytotoxic against these cell lines.

First claim

The invention claimed is:

1. A bisphosphonate-based coordination complex comprising: a mixture of benzene 1,4-bis(bisphosphonic acid) (BBPA) and a bioactive metal selected from the group consisting of: Ca 2+ , Zn 2+ , and Mg 2+ .

2. The bisphosphonate-based coordination complex according to claim 1 , wherein said metal is Ca 2+ and a single crystal form is characterized by major x-ray powder diffraction peaks at 2.theta. angles of 8.42, 12.04, 14.79, 16.87, 18.68 and 27.70.

3. The bisphosphonate-based coordination complex according to claim 1 , wherein said metal is Ca 2+ and a single crystal form is characterized by major x-ray powder diffraction peaks at 2.theta. angles of 10.05, 10.98, 14.45, 15.18, 23.04 and 29.36.

4. The bisphosphonate-based coordination complex according to claim 1 , wherein said metal is Zn 2+ and a single crystal form is characterized by major x-ray powder diffraction peaks at 2.theta. angles of 9.25, 14.73, 14.77, 21.63, 26.42 and 32.75.

5. The bisphosphonate-based coordination complex according to claim 1 , wherein said metal is Mg 2+ and a single crystal form is characterized by major x-ray powder diffraction peaks at 2.theta. angles of 8.36, 10.69, 11.96, 12.89, 16.84 and 25.27.

6. The bisphosphonate-based coordination complex of claim 1 , having an empirical formula of: Ca 2 C 8 H 14 O 17 P 4 , 3(H 2 O).

7. The bisphosphonate-based coordination complex of claim 1 , having an empirical formula of: 2(CaC 4 H 9 O 9 P 2 ), 9(H 2 O).

8. The bisphosphonate-based coordination complex of claim 1 , having an empirical formula of: ZnC 4 H 5 O 8 P 2 , 2(H 2 O).

9. The bisphosphonate-based coordination complex of claim 1 , having an empirical formula of: Mg 3 C 8 H 22 O 11 P 4 , 8(H 2 O).

10. The bisphosphonate-based coordination complex of claim 2 , wherein the single crystal form is characterized by X-ray powder diffraction pattern of FIG. 16 .

11. The bisphosphonate-based coordination complex of claim 3 , wherein the single crystal form is characterized by X-ray powder diffraction pattern of FIG. 17 .

12. The bisphosphonate-based coordination complex of claim 4 , wherein the single crystal form is characterized by X-ray powder diffraction pattern of FIG. 18 .

13. The bisphosphonate-based coordination complex of claim 5 , wherein the single crystal form is characterized by X-ray powder diffraction pattern of FIG. 19 .

14. The bisphosphonate-based coordination complex of claim 2 , wherein the single crystal form has a monoclinic unit cell with cell parameters: a=11.65839 Å, b=12.35838 Å, c=21.9782 Å and β=138.112°.

15. The bisphosphonate-based coordination complex of claim 3 , wherein the single crystal form has a monoclinic unit cell with cell parameters: a=13.1217 Å, b=10.0502 Å, c=21.74.61 Å and β=95.844°.

16. The bisphosphonate-based coordination complex of claim 4 , wherein the single crystal form has a monoclinic unit cell with cell parameters: a=6.8687 Å, b=19.1708 Å, c=8.3853 Å and β=105.689°.

17. The bisphosphonate-based coordination complex of claim 5 , wherein the single crystal form has a monoclinic unit cell with cell parameters: a=10.60620 Å, b=10.39300 Å, c=13.9383 Å and β=97.8330°.

18. The bisphosphonate-based coordination complex of claim 2 , wherein the single crystal form has monoclinic space group of P2 1 /c.

19. The bisphosphonate-based coordination complex of claim 3 , wherein the single crystal form has monoclinic space group of I2/a.

20. The bisphosphonate-based coordination complex of claim 4 , wherein the single crystal form has monoclinic space group of P2 1 /n.

21. The bisphosphonate-based coordination complex of claim 5 , wherein the single crystal form has monoclinic space group of P2 1 /c.

Assignees

• Lopez Mejias Vilmali
• Carmona Sarabia Lesly Y
• Escalera Joy Andrea M
• Mojica Vazquez Darilys
• Univ Puerto Rico

Inventors

• Lopez-Mejias Vilmali
• Carmona-Sarabia Lesly Y
• Escalera Joy Andrea M
• Mojica Vazquez Darilys

Classifications

• C07F9/386 Primary

  containing hydroxy substituents in the hydrocarbon radicals · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07F9/3852 Primary

  Cycloaliphatic derivatives · CPC title

• C07F3/04

  Calcium compounds · CPC title

• C07F3/02

  Magnesium compounds · CPC title