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US-12624057-B2 - Bisphosphonate quinolone conjugates and uses thereof

US12624057B2US 12624057 B2US12624057 B2US 12624057B2US-12624057-B2

Abstract

Described herein are bisphosphonate quinolone compounds, conjugates and pharmaceutical formulations thereof that can include a bisphosphonate and a quinolone, where the quinolone can be releasably coupled to the bisphosphonate. Also provided herein are methods of making and methods of using the bisphosphonate quinolone compounds, conjugates and pharmaceutical formulations thereof.

Inventors

  • Frank H. Ebetino
  • Shuting Sun
  • Philip T. Cherian

Assignees

  • BIOVINC, LLC

Dates

Publication Date
20260512
Application Date
20231211

Claims (20)

  1. 1 . A compound comprising a bisphosphonate (BP) and a quinolone moiety, wherein the BP has an alpha carbon substituent (X) and wherein the quinolone moiety is directly or indirectly conjugated to the BP at the geminal bisphosphonate alpha carbon substituent (X) of the BP, the compound having the following structure: wherein R can be H, substituted and unsubstituted alkyl, alkyl amino, alkyl-aryl, aryl, alkylheteroaryl, or heteroaryl, wherein the quinolone moiety is releasably conjugated to the bisphosphonate by a linkage incorporating X, wherein the linkage incorporating X includes a carbonate linker, a carbamate linker, a thio carbamate linker, or a urea linker, wherein the carbonate linker, carbamate linker, thio carbamate linker or urea linker is directly coupled to the geminal carbon of the BP; and wherein the quinolone moiety is conjugated to the bisphosphonate via the linkage in which the linkage is directly or indirectly coupled to a substituent on position 7 on the bicyclic core ring of the quinolone moiety, using accepted quinolone bicyclic ring position numbering where position 1 on the bicyclic ring of the quinolone moiety is the location of the nitrogen (N) on the bicyclic ring of the quinolone moiety, position 3 on the bicyclic ring of the quinolone moiety is the location of the carboxylate on the bicyclic ring of the quinolone moiety and position 6 on the bicyclic ring of the quinolone moiety is the carbon bearing the Fluorine group in a fluorinated quinolone moiety.
  2. 2 . The compound of claim 1 , wherein the alpha substituent (X) prior to conjugation of the quinolone moiety to the bisphosphonate is a hydroxy, amino or thiol group.
  3. 3 . The compound of claim 1 , wherein the bisphosphonate, prior to conjugation of the quinolone to the bisphosphonate, is selected from the group consisting of: etidronate, methylenehydroxybisphosphonate (MHBP), risedronate, zoledronate, minodronate, neridronate, pamidronate, and alendronate, modified or unmodified.
  4. 4 . The compound of claim 1 , wherein the BP is an alpha-OH containing BP and wherein the quinolone moiety is directly or indirectly conjugated to the BP at the geminal O of the BP OH moiety.
  5. 5 . The compound of claim 1 , wherein the quinolone moiety is selected from the group consisting of alatrofloxacin, amifloxacin, balofloxacin, besifloxacin, cadazolid, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, difloxacin, enoxacin, enrofloxacin, finafloxacin, flerofloxacin, flumequine, gatifloxacin, gemifloxacin, grepafloxacin, ibafloxacin, JNJ-Q2, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, ofloxacin, orbifloxacin, pazufloxacin, pefloxacin, pradofloxacin, prulifloxacin, rufloxacin, sarafloxacin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin, zabofloxacin, and nemonoxacin.
  6. 6 . The compound of claim 1 , according to Formula (41), Formula (43), Formula (44) or Formula (45)
  7. 7 . The compound of claim 1 , according to the following formula
  8. 8 . The compound of claim 1 , wherein the quinolone moiety of the BP quinolone compound is comprised of a quinolone antibiotic analog or substituent according to Formula (A), wherein R 1 is either and wherein R 2 is and wherein R 3 is either H or OCH3, and where R 4 is H, and wherein R 5 is H or F.
  9. 9 . The compound of claim 8 , wherein the bisphosphonate is selected from the group consisting of: etidronate, methylenehydroxybisphosphonate (MHBP), risedronate, zoledronate, minodronate, neridronate, pamidronate, and alendronate, modified or unmodified.
  10. 10 . The compound of claim 9 , wherein the quinolone moiety is selected from the group consisting of: amifloxacin, balofloxacin, ciprofloxacin, danofloxacin, delafloxacin, difloxacin, enrofloxacin, finafloxacin, flerofloxacin, gatifloxacin, grepafloxacin, ibafloxacin, JNJ-Q2, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, ofloxacin, orbifloxacin, pazufloxacin, pefloxacin, pradofloxacin, prulifloxacin, rufloxacin, sarafloxacin, sparfloxacin, and temafloxacin.
  11. 11 . The compound of claim 9 , wherein the quinolone moiety is ciprofloxacin or moxifloxacin.
  12. 12 . The compound of claim 8 , wherein the linker is a selected from the group consisting of carbamate linker, thiocarbamate linker, an O-thiocarbamate linker, and an S-thiocarbamate linker.
  13. 13 . A pharmaceutical formulation comprising: an amount of a compound as set forth in claim 1 ; and a pharmaceutically acceptable carrier.
  14. 14 . The pharmaceutical formulation of claim 13 , wherein the amount of the compound is an amount effective to kill or inhibit bacteria.
  15. 15 . The pharmaceutical formulation of claim 13 , wherein the amount of the compound is an amount effective to treat or prevent bone diseases with abnormal bone resorption, osteoporosis, bone infections, osteomyelitis, osteonecrosis, peri-implantitis, and/or periodontitis.
  16. 16 . A bone graft composition comprising: a bone graft material and a compound as in claim 1 or a pharmaceutical formulation thereof, wherein the compound or pharmaceutical formulation is attached to, integrated with, chemisorbed to, or mixed with the bone graft material.
  17. 17 . The bone graft composition of claim 16 , wherein the bone graft material is autograft bone material, allograft bone material, xenograft bone material, a synthetic bone graft material, or any combination thereof.
  18. 18 . A method comprising: implanting the bone graft composition of claim 16 into a subject in need thereof.
  19. 19 . A method of treating a bone infection, osteomyelitis, peri-implantitis, periodontitis, diabetic foot disease, and/or biofilm infection at an osseous or implant surgical site or at a surgical site where bone grafting is performed, where the method comprises: administering a compound claim 1 , or a pharmaceutical formulation comprising a compound of claim 1 and a pharmaceutically acceptable carrier, to a subject in need thereof.
  20. 20 . The compound of claim 1 , wherein the linkage incorporating X is coupled to the quinolone moiety via a carbamate, an S-thiocarbamate or an O-thiocarbamate, and wherein an oxygen or a sulfur of the carbamate, the S-thiocarbamate or the O-thiocarbamate is directly coupled to an aryl group and where the aryl group is directly or indirectly coupled to the linkage incorporating X such that the coupling of the oxygen or the sulfur to the aryl group creates an aryl carbamate, an S-thioarylcarbamate or an O-thioarylcarbamate coupling to the quinolone moiety, and wherein a nitrogen of the aryl carbamate, S-thioarylcarbamate or O-thioarylcarbamate is directly or indirectly coupled to, or a component of, a substituent coupled to position 7 on the bicyclic ring structure of the quinolone moiety, wherein position 1 on the bicyclic ring structure of the quinolone moiety is the location of the nitrogen (N) on the carbonyl bearing ring of the bicyclic ring structure of the quinolone moiety, and position 3 on the bicyclic ring structure of the quinolone moiety is the location of the carboxylate on the bicyclic ring structure of the quinolone moiety.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 17/118,795, filed Dec. 11, 2020, which is a continuation of U.S. patent application Ser. No. 16/207,465, filed Dec. 3, 2018, entitled “Bisphosphonate Quinolone Conjugates and Uses Thereof”, now U.S. Pat. No. 10,865,220, issued Dec. 15, 2020, which claims the benefit of and priority to U.S. Provisional Patent Application No. 62/695,583, filed Jul. 9, 2018, entitled “BISPHOSPHONATE QUINOLONE CONJUGATES AND USES THEREOF” and which is a continuation-in-part of PCT/US2017/035764, filed Jun. 2, 2017, that claims the benefit of and priority to: U.S. Provisional Patent Application No. 62/345,370, filed on Jun. 3, 2016, entitled “BONE TARGETED THERAPEUTICS AND DIAGNOSTICS;” U.S. Provisional Patent Application No. 62/357,727, filed on Jul. 1, 2016, entitled “BISPHOSPHONATE QUINOLONE BIOCONJUGATES AND USES THEREOF;” and U.S. Provisional Patent Application No. 62/448,060, filed on Jan. 19, 2017, entitled “BISPHOSPHONATE QUINOLONE BIOCONJUGATES AND USES THEREOF;” the contents of all of which are incorporated by reference herein in their entirety. This application also claims the benefit of and priority to U.S. Provisional Patent Application No. 62/695,583, filed Jul. 9, 2018, entitled “BISPHOSPHONATE QUINOLONE CONJUGATES AND USES THEREOF,” the contents of which are incorporated by reference herein in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made in part with government support under grant number 1R41DE025789-01 & R42DE025789-02, awarded by the NIH/NIDCR. The government has certain rights in the invention. BACKGROUND Infectious bone disease, also referred to as osteomyelitis, jawbone infections, and other bone infections, is a significant problem in human and animal health and can have devastating consequences from limb loss to fatality. Due to the inherent difficulties bone presents, treatment of osteomyelitis and other bone infections is typically long and difficult and often requires surgical intervention. Therefore, there exists a long-felt and unmet need for improved treatments for osteomyelitis in all its forms or clinical subtypes and other bone infections. SUMMARY Provided herein, in some aspects, are BP quinolone compounds and conjugates that can contain a bisphosphonate (BP) that can be releasably conjugated to a quinolone, such as ciprofloxacin or moxifloxacin. In embodiments, the BP quinolone conjugate can selectively deliver a quinolone to bone, bone grafts, and or bone graft substitutes (i.e. can target bone, bone grafts, or bone graft substitutes) in a subject. In some embodiments, the BP quinolone conjugate can release the quinolone. Also provided herein are methods of synthesizing BP quinolone conjugates and methods of killing or inhibiting bacteria growth and of treating or preventing bone diseases with abnormal bone resorption, osteoporosis, osteomyelitis, osteonecrosis, peri-implantitis, periodontis, and/or other bone infections with one or more of the BP quinolone compounds and conjugates provided herein. In some aspects, the conjugate can be a compound according to Formula (6) Also provided herein are pharmaceutical compositions containing a compound according to Formula (6) and a pharmaceutically acceptable carrier. Also provided herein are methods of treating a bone infection in a subject in need thereof that can include the step of administering an amount of the compound according to Formula (6) or a pharmaceutical formulation containing a compound according to Formula (6) to a subject in need thereof. Also provided herein are compounds and conjugates containing a bisphosphonate (BP) and a quinolone compound, wherein the quinolone compound is releasably coupled to the bisphosphonate via a linker. The BP can be selected from the group of: hydroxyl phenyl alkyl or aryl bisphosphonates, hydroxyl phenyl (or aryl) alkyl hydroxyl bisphosphonates, amino phenyl(or aryl) alkyl bisphosphonates, amino phenyl(or aryl) alkyl hydroxyl bisphosphonates, hydroxyl alkyl bisphosphonates, hydroxyl alkyl hydroxyl bisphosphonates, hydroxyl alkyl phenyl(or aryl) alkyl bisphosphonates, hydroxyl phenyl(or aryl) alkyl hydroxyl bisphosphonates, amino phenyl(or aryl) alkyl bisphosphonates, amino phenyl(or aryl) alkyl hydroxyl bisphosphonates, hydroxyl alkyl bisphosphonates, hydroxyl alkyl hydroxyl bisphosphonates, hydroxypyridyl alkyl bisphosphonates, pyridyl alkyl bisphosphonates, hydroxyl imadazoyl alkyl bisphosphonates, imidazoyl alkyl bisphosphonates, etidronate, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, zoledronate, minodronate and combinations thereof, wherein all the compounds can be optionally further substituted or are unsubsituted. The quinolone compound can be a fluoroquinolone. The quinolone compound can be selected from the group of: alatrofloxacin, amifloxacin, balofloxacin, besifloxacin, cadazolid, ciprofloxac