Boronic acid esters and pharmaceutical formulations thereof

• US 10,167,311 B2
• Filed: 02/03/2015
• Issued: 01/01/2019
• Est. Priority Date: 02/03/2014
• Status: Active Grant

• Current Assignee: Ohio State Innovation Foundation (Ohio State University)
• Original Assignee: Ohio State Innovation Foundation (Ohio State University)
• Inventors: Caligiuri, Michael, Lee, Robert, Marcucci, Guido
• Primary Examiner(s): Carcanague, Daniel R
• Application Number:
  US15/116,312
• Publication Number:
  US 20160347791A1
• Time in Patent Office: 1,428 Days
• Field of Search: 549213
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 47/543 Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• CPC Class Codes: A61K 47/544 Phospholipids
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N

Abstract

Provided herein are boronic acid esters of boronic acid therapeutic agents, such as bortezomib. The boronic acid esters can be used to prepare liposomal formulations of boronic acid therapeutic agents with improved properties, such as enhanced stability. This disclosure, in one aspect, relates to compositions and methods of making and using the compositions.

Claims

1. A compound defined by Formula IA

2. The compound of claim 1, wherein the polyol comprises a monosaccharide.

3. The compound of claim 1, wherein the polyol comprises a reduced sugar.

4. The compound of claim 1, wherein the polyol comprises an amino sugar.

5. The compound of claim 1, wherein the polyol is meglumine, glucamine, mannitol, sorbitol, or fructose.

6. The compound of claim 1, wherein A is a C₈-C₄₀ alkyl group, a C₈-C₄₀ alkenyl group, a C₈-C₄₀ alkoxy group, a C₈-C₄₀ alkylthio group, a C₈-C₄₀ alkylsulfinyl group, a C₈-C₄₀ alkylsulfonyl group, a C₈-C₄₀ alkylamino group, a C₈-C₄₀ dialkylamino group, a C₈-C₄₀ alkylcarbonyl group, a C₈-C₄₀ alkoxycarbonyl group, a C₈-C₄₀ alkylaminocarbonyl group, a C₈-C₄₀ dialkylaminocarbonyl group, or a moiety defined by the formula below

7. The compound of claim 1, wherein the compound is defined by Formula IIA

8. The compound of claim 7, wherein X is —

NH—

or —

N(CH₃)—

.

9. The compound of claim 1, wherein the compound is

10. A pharmaceutical formulation comprising

(i) liposomes formed from a vesicle-forming lipid;

and

(ii) a compound of claim 1 entrapped in the liposomes.

11. The formulation of claim 10, wherein the formulation is lyophilized.

12. The formulation of claim 10, wherein the formulation further comprises a lyoprotectant.

13. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound defined by claim 1.