Cyclic boronic acid ester derivatives and methods of making the same

• US 10,004,758 B2
• Filed: 06/15/2017
• Issued: 06/26/2018
• Est. Priority Date: 08/10/2010
• Status: Active Grant

• Current Assignee: Melinta Therapeutics, Inc.
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Hirst, Gavin, Reddy, Raja, Hecker, Scott, Totrov, Maxim, Griffith, David C., Rodny, Olga, Dudley, Michael N., Boyer, Serge
• Primary Examiner(s): Shameem, Golam M
• Application Number:
  US15/624,473
• Publication Number:
  US 20180071325A1
• Time in Patent Office: 376 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/546 containing further heterocyclic rings, e.g. cephalothin
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to cyclic boronic acid ester derivatives and their use as therapeutic agents.

Claims

1. A method of preparing a compound of formula (I):

2. The method of claim 1, wherein the pinanediol boronic ester comprises a hydroxyl protecting group selected from the group consisting of trityl, t-butyldimethylsilyl, and benzyl.

3. The method of claim 1, wherein the deprotection and cyclization comprises contacting the pinanediol boronic ester with a reagent selected from the group consisting of HCl, BCl₃, BBr₃, and CF₃COOH.

4. The method of claim 1, wherein the pinanediol boronic ester comprises a tert-butyldimethylsilyloxy (TBS) group and a tert-butyl ester group.

5. The method of claim 1, wherein the pinanediol boronic ester derivative has the structure of formula (XII):

6. The method of claim 5, wherein the pinanediol boronic ester derivative is obtained by a step selected from coupling a bis-trimethylsilyl (TMS)₂ amine derivative with R^aCOOH, or reacting a bis-trimethylsilyl (TMS)₂ amine derivative with R^aCOCl.

7. The method of claim 6, wherein the bis-trimethylsilyl amine derivative has the structure of formula (XI):

8. The method of claim 7, wherein the bis-trimethylsilyl (TMS)₂ amine derivative is obtained by displacing a chloro group of a compound of formula (X):

9. The method of claim 8, wherein displacing a chloro group is achieved in the presence of lithium bis(trimethylsilyl)amide.

10. The method of claim 8, wherein the compound of formula (X) is obtained by homologation of a compound of formula (IX):

11. The method of claim 10, wherein the homologation is achieved in the presence of dichloromethane and n-butyllithium.

12. The method of claim 1, wherein the pinanediol boronic ester has the structure of formula (XLII):

13. The method of claim 12, wherein the pinanediol boronic ester is obtained by reacting a bis-trimethylsilyl (TMS)₂ amine derivative having the following structure:

14. The method of claim 13, wherein the bis-trimethylsilyl (TMS)₂ amine derivative is obtained by displacing a chloro group of a compound of formula (XL):

15. The method of claim 14, wherein the compound of formula (XL) is obtained by homologation of a compound of formula (XXXIX):

16. The method of claim 1, wherein the pinanediol boronic ester has the structure of formula (XV):

17. The method of claim 16, wherein the pinanediol boronic ester is obtained by displacing a bromo group of a bromo-compound of formula (XIV):

18. The method of claim 17, wherein displacing a bromo group is achieved using an agent selected from the group consisting of an α

-alkoxy substituted alkyllithium agent, an organomagnesium reagent, a sodium salt of an alkyl derivative, and a sodium salt of an aryl carbamate derivative.

19. The method of claim 1, wherein the pinanediol boronic ester has the structure of formula (XXV):

20. The method of claim 19, wherein the pinanediol boronic ester is obtained by Matteson homologation of a formula (XXIV):

21. The method of claim 1, wherein the pinanediol boronic ester has the structure of formula (XXXIV):

22. The method of claim 21, wherein the pinanediol boronic ester is obtained by trans-esterification of a pinacol boronate of formula (XXXIII):

23. The method of claim 22, wherein the trans-esterification is achieved by reacting the pinacol boronate with a pinane diol in the presence of tetrahydrofuran.

24. The method of claim 22, wherein the pinacol boronate is obtained using iridium catalysis with a tert-butyldimethylsilyl compound of formula (XXXII):

25. The method of claim 1, wherein the compound of formula (I) has the structure of formula (II):

26. The method of claim 25, wherein:

R¹ is selected from a group consisting of —

C_1-9alkyl, —

C_2-9alkenyl, —

C_2-9alkynyl, —

NR⁹R¹⁰, —

C_1-9alkylR¹¹, —

C_2-9alkenylR¹¹, —

C_2-9alkynylR¹¹, —

CH(OH)C_1-9alkylR⁹, —

CH(OH)C_2-9alkenylR⁹, —

CH(OH)C_2-9alkynylR⁹, —

C(═

O)R⁹, —

C(═

O)C_1-9alkylR⁹, —

C(═

O)C_2-9alkenylR⁹, —

C(═

O)C_2-9alkynylR⁹, —

C(═

O)NR⁹R¹⁰, —

N(R⁹)C(═

O)R⁹, —

N(R⁹)C(═

O)NR⁹R¹⁰, —

N(R⁹)C(═

O)OR⁹, —

N(R⁹)C(═

O)C(═

NR¹⁰)R⁹, —

N(R⁹)C(═

O)C_1-4alkylN(R⁹)C(═

O)R⁹, —

N(R⁹)C(═

NR¹⁰)R⁹, —

C(═

NR¹⁰)NR⁹R¹⁰, —

N═

C(R⁹)NR⁹R¹⁰, —

N(R⁹)SO₂R⁹, —

N(R⁹)SO₂NR⁹R¹⁰, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;

R⁶ is selected from a group consisting of H, —

C_1-9alkyl, C_2-9alkenyl, —

C_2-9alkynyl, —

C_1-9alkylR¹¹, —

C_2-9alkenylR¹¹, —

C_2-9alkynylR¹¹, —

C(═

O)OR⁹, and —

C_1-9alkylCO₂R⁹, —

C_2-9alkenylCO₂R⁹, and —

C_2-9alkynylCO₂R⁹, or alternatively R⁶ and an R⁷ are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R⁷ is independently selected from a group consisting of H, —

NR⁹R¹⁰, —

OR⁹, and —

C_1-9alkylCO₂R⁹, —

C_2-9alkenylCO₂R⁹, and —

C_2-9alkynylCO₂R⁹, or independently, R⁶ and an R⁷ or independently an R⁷ and an R⁸ are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R⁸ is independently selected from a group consisting of H, —

NR⁹R¹⁰, —

OR⁹, and —

C_1-9alkylCO₂R⁹, —

C_2-9alkenylCO₂R⁹, and —

C_2-9alkynylCO₂R⁹, or independently, an R⁷ and an R⁸ are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R⁹ is independently selected from a group consisting of H, —

C_1-9alkyl, C_2-9alkenyl, —

C_2-9alkynyl, —

C_1-9alkylR¹¹, —

C_2-9alkenylR¹¹, —

C_2-9alkynylR¹¹, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted —

(CH₂)_0-3carbocyclyl, and substituted or unsubstituted heterocyclyl;

each R¹⁰ is independently selected from a group consisting of H, —

C_1-9alkyl, —

OR⁹, —

CH(═

NH), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; and

X is selected from a group consisting of —

CO₂H and a carboxylic acid isostere.

27. The method of claim 1, wherein the compound of formula (I) has a structure of formula (IIIa) or (IIIb):

28. The method of claim 1, wherein the compound of formula (I) has the structure of formula (Iva), (IVb), or (IVc):

29. The method of claim 1, wherein the compound of formula (I) has a structure selected from the group consisting of:

30. The method of claim 1, wherein the compound of formula (I) has a structure: