News Column

Patent Application Titled "Boronic Acid Derivatives and Therapeutic Uses Thereof" Published Online

August 1, 2014



By a News Reporter-Staff News Editor at Drug Week -- According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent application by the inventors Reddy, Raja (San Diego, CA); Glinka, Tomasz (Cupertino, CA); Totrov, Maxim (San Diego, CA); Hecker, Scott (Del Mar, CA), filed on March 14, 2013, was made available online on July 17, 2014 (see also Pharmaceutical Companies).

The assignee for this patent application is Rempex Pharmaceuticals, Inc.

Reporters obtained the following quote from the background information supplied by the inventors: "The present invention relates to the fields of chemistry and medicine. More particularly, the present invention relates to boronic acid antimicrobial compounds, compositions, their preparation, and their use as therapeutic agents.

"Antibiotics have been effective tools in the treatment of infectious diseases during the last half-century. From the development of antibiotic therapy to the late 1980s there was almost complete control over bacterial infections in developed countries. However, in response to the pressure of antibiotic usage, multiple resistance mechanisms have become widespread and are threatening the clinical utility of anti-bacterial therapy. The increase in antibiotic resistant strains has been particularly common in major hospitals and care centers. The consequences of the increase in resistant strains include higher morbidity and mortality, longer patient hospitalization, and an increase in treatment costs.

"Various bacteria have evolved .beta.-lactam deactivating enzymes, namely, .beta.-lactamases, that counter the efficacy of the various .beta.-lactam antibiotics. .beta.-lactamases can be grouped into 4 classes based on their amino acid sequences, namely, Ambler classes A, B, C, and D. Enzymes in classes A, C, and D include active-site serine .beta.-lactamases, and class B enzymes, which are encountered less frequently, are Zn-dependent. These enzymes catalyze the chemical degradation of .beta.-lactam antibiotics, rendering them inactive. Some .beta.-lactamases can be transferred within and between various bacterial strains and species. The rapid spread of bacterial resistance and the evolution of multi-resistant strains severely limits .beta.-lactam treatment options available.

"The increase of class D .beta.-lactamase-expressing bacterium strains such as Acinetobacter baumannii has become an emerging multidrug-resistant threat. A. baumannii strains express A, C, and D class .beta.-lactamases. The class D .beta.-lactamases such as the OXA families are particularly effective at destroying carbapenem type .beta.-lactam antibiotics, e.g., imipenem, the active carbapenems component of Merck's Primaxin.RTM. (Montefour, K.; et al. Crit. Care Nurse 2008, 28, 15; Perez, F. et al. Expert Rev. Anti Infect. Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J. Antimicrob. Agents Chemother. 2000, 40, 428. 2006, 50, 2280; Bou, G. et al, J. Antimicrob. Agents Chemother. 2000, 44, 1556). This has imposed a pressing threat to the effective use of drugs in that category to treat and prevent bacterial infections. Indeed the number of catalogued serine-based .beta.-lactamases has exploded from less than ten in the 1970s to over 300 variants. These issues fostered the development of five 'generations' of cephalosporins. When initially released into clinical practice, extended-spectrum cephalosporins resisted hydrolysis by the prevalent class A .beta.-lactamases, TEM-1 and SHV-1. However, the development of resistant strains by the evolution of single amino acid substitutions in TEM-1 and SHV-1 resulted in the emergence of the extended-spectrum .beta.-lactamase (ESBL) phenotype.

"New .beta.-lactamases have recently evolved that hydrolyze the carbapenem class of antimicrobials, including imipenem, biapenem, doripenem, meropenem, and ertapenem, as well as other .beta.-lactam antibiotics. These carbapenemases belong to molecular classes A, B, and D. Class A carbapenemases of the KPC-type predominantly in Klebsiella pneumoniae but now also reported in other Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. The KPC carbapenemase was first described in 1996 in North Carolina, but since then has disseminated widely in the US. It has been particularly problematic in the New York City area, where several reports of spread within major hospitals and patient morbidity have been reported. These enzymes have also been recently reported in France, Greece, Sweden, United Kingdom, and an outbreak in Germany has recently been reported. Treatment of resistant strains with carbapenems can be associated with poor outcomes.

"The zinc-dependent class B metallo-.beta.-lactamases are represented mainly by the VIM, IMP, and NDM types. IMP and VIM-producing K. pneumonia were first observed in 1990s in Japan and 2001 in Southern Europe, respectively. IMP-positive strains remain frequent in Japan and have also caused hospital outbreaks in China and Australia. However dissemination of IMP-producing Enterobacteriaceae in the rest of the word appears to be somewhat limited. VIM-producing enterobacteria can be frequently isolated in Mediterranean countries, reaching epidemic proportions in Greece. Isolation of VIM-producing strains remains low in Northern Europe and in the United States. In stark contrast, a characteristic of NDM-producing K. pneumonia isolates has been their rapid dissemination from their epicenter, the Indian subcontinent, to Western Europe, North America, Australia and Far East. Moreover, NDM genes have spread rapidly to various species other than K. pneumonia.

"The plasmid-expressed class D carbapenemases belong to OXA-48 type. OXA-48 producing K. pneumonia was first detected in Turkey, in 2001. The Middle East and North Africa remain the main centers of infection. However, recent isolation of OXA-48-type producing organisms in India, Senegal and Argentina suggest the possibility of a global expansion. Isolation of OXA-48 in bacteria other than K. pneumonia underlines the spreading potential of OXA-48.

"Treatment of strains producing any of these carbapenemases with carbapenems can be associated with poor outcomes.

"Another mechanism of .beta.-lactamase mediated resistance to carbapenems involves combination of permeability or efflux mechanisms combined with hyper production of beta-lactamases. One example is the loss of a porin combined in hyperproduction of ampC beta-lactamase results in resistance to imipenem in Pseudomonas aeruginosa. Efflux pump over expression combined with hyperproduction of the ampC .beta.-lactamase can also result in resistance to a carbapenem such as meropenem.

"Thus, there is a need for improved .beta.-lactamase inhibitors."

In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "Some embodiments disclosed herein include a compound having the structure of formula I:

"##STR00001##

"or pharmaceutically acceptable salt thereof, wherein: Y is selected from the group consisting of --S--, --O--, --CH.sub.2--, and --NH--; n is 0-3; G is selected from the group consisting of --C(O)NR.sup.1R.sup.2; --C(O)NR.sup.1OR.sup.2; --NR.sup.1C(O)R.sup.2; --NR.sup.1C(O)NR.sup.2R.sup.3; --NR.sup.1C(O)OR.sup.2; --NR.sup.1S(O).sub.2R.sup.2; --NR.sup.1S(O).sub.2NR.sup.2R.sup.3; --C(.dbd.NR.sup.1)R.sup.2; --C(.dbd.NR.sup.1)NR.sup.2R.sup.3; --NR.sup.1CR.sup.2(.dbd.NR.sup.3); --NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4; aryl optionally substituted with 0-2 substituents selected from the group consisting of C.sub.1-4 alkyl, --OR.sup.1, --NR.sup.1R.sup.2, halogen, --C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2; heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C.sub.1-4 alkyl, --OR.sup.1, --NR.sup.1R.sup.2, halogen, --C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2; and heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C.sub.1-4 alkyl, --OR.sup.1, --NR.sup.1R.sup.2, halogen, --C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2; J, L, and M are each independently selected from the group consisting of CR.sup.7 and N; R is selected from a group consisting of --H, --C.sub.1-9alkyl, --CR.sup.5R.sup.6OC(O)C.sub.1-9alkyl, --CR.sup.5R.sup.6OC(O)OC.sub.1-9alkyl, and

"##STR00002## R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently selected from --H and --C.sub.1-4alkyl; and R.sup.7 is selected from the group consisting of --H, --C.sub.1-4alkyl, --OH, --OC.sub.1-4alkyl, and halogen.

"Other embodiments disclosed herein include a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient.

"Other embodiments disclosed herein include a method of treating or preventing a bacterial infection, comprising administering to a subject in need thereof a compound disclosed herein.

DETAILED DESCRIPTION

"In some embodiments, compounds that contain a boronic acid moiety are provided that act as antimicrobial agents and/or as potentiators of antimicrobial agents Various embodiments of these compounds include compounds having the structures of Formula I as described above or pharmaceutically acceptable salts thereof.

"Some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts have the following stereochemistry as shown in the structure of formula (Ia):

"##STR00003##

"Some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts have the following stereochemistry as shown in the structure of formula (Ib):

"##STR00004##

"In some embodiments, n is 0 or 1.

"In some embodiments, Y is O or S; G is selected from the group consisting of phenyl, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, and pyrazine, each optionally substituted by 0-2 substituents selected from the group consisting of --OR.sup.1, --NR.sup.1R.sup.2, halogen, --C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2; and J, L and M are CR.sup.7.

"In some such embodiments, n is 0. In some such embodiments, G is thiadiazole. In other embodiments, G is thiadiazole optionally substituted with --NR.sup.1R.sup.2 or --NR.sup.1C(O)R.sup.2, wherein R.sup.1 and R.sup.2 are independently H or --C.sub.1-4alkyl. In other embodiments, G is triazole optionally substituted with NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are independently H or --C.sub.1-4alkyl. In other embodiments, G is tetrazole optionally substituted with methyl. In still other embodiments, G is pyridine, thiazole, or phenyl.

"In some embodiments, Y is S; n is 1 or 2; G is --C(O)NR.sup.1R.sup.2 or --C(.dbd.NR.sup.1)R.sup.2; and J, L, and M are CR.sup.7. In some such embodiments, R.sup.7 is H. In other embodiments, R.sup.1 is H and R.sup.2 is H.

"Some specific embodiments of the compounds described herein have the following structures:

"##STR00005## ##STR00006##

"Some embodiments of any of the compounds described above include prodrugs (e.g., prodrug esters), metabolites, stereoisomers, hydrates, solvates, polymorphs, and pharmaceutically acceptable salts of those compounds.

"Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.

"The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures may only represent a very small portion of a sample of such compound(s). Such compounds are considered within the scope of the structures depicted, though such resonance forms or tautomers are not represented herein.

"Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

"As shown below, the compounds disclosed herein may exist in cyclic form as cyclic boronate monoesters as formula I or in acyclic form as boronic acids as formula I.1 (Biochemistry, 2000, 39, 5312-21), or may exist as a mixture of the two forms depending on the medium. Such compounds or mixture of compounds are considered within the scope of the structures depicted, though such structural forms are not explicitly represented herein.

"##STR00007##"

For more information, see this patent application: Reddy, Raja; Glinka, Tomasz; Totrov, Maxim; Hecker, Scott. Boronic Acid Derivatives and Therapeutic Uses Thereof. Filed March 14, 2013 and posted July 17, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1806&p=37&f=G&l=50&d=PG01&S1=20140710.PD.&OS=PD/20140710&RS=PD/20140710

Keywords for this news article include: Acinetobacter baumannii, Asia, Boron Compounds, Boronic Acids, Carbapenems, Elements, Enzymes and Coenzymes, Gases, Gram-Negative Aerobic Bacteria, Gram-Negative Aerobic Rods and Cocci, Gram-Negative Bacteria, Hospital, Hydrogen, Inorganic Chemicals, Japan, Moraxellaceae, Noncarboxylic Acids, Pharmaceutical Companies, Pseudomonadaceae, Pseudomonas aeruginosa, Rempex Pharmaceuticals Inc., Sulfur Compounds, beta-Lactams.

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Source: Drug Week


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