WO2013053372A1 - Inhibiteurs de type acide boronique de bêta-lactamases - Google Patents

Inhibiteurs de type acide boronique de bêta-lactamases Download PDF

Info

Publication number
WO2013053372A1
WO2013053372A1 PCT/EP2011/005142 EP2011005142W WO2013053372A1 WO 2013053372 A1 WO2013053372 A1 WO 2013053372A1 EP 2011005142 W EP2011005142 W EP 2011005142W WO 2013053372 A1 WO2013053372 A1 WO 2013053372A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituents
substituted
alkyl
heteroaryl
Prior art date
Application number
PCT/EP2011/005142
Other languages
English (en)
Inventor
Fabio Prati
Emilia Caselli
Original Assignee
Therabor Pharmaceuticals
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Therabor Pharmaceuticals filed Critical Therabor Pharmaceuticals
Priority to PCT/EP2011/005142 priority Critical patent/WO2013053372A1/fr
Publication of WO2013053372A1 publication Critical patent/WO2013053372A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to novel boronic acid compounds, a method for the preparation of such compounds, intermediate compounds for the preparation of such compounds, intermediate compounds for the use in a method for preparation of such compounds, a pharmaceutical composition, the use of one or more compounds discussed above or of a pharmaceutical composition in the manufacture of a medicament for the treatment of a bacterial infection, and a screening method.
  • the present disclosure relates to boronic acids containing at least one heterocyle. These compounds act as beta-lactamase enzyme inhibitors.
  • Multidrug resistant pathogens are now characterized by their heterogeneity, increasing virulence, rsistance even to reserve agents and spread within and between hospitals and the community. Examples are the meticillin-resistance Staphylococcus aureus (MRSA) and enterococci, extended spectrum ⁇ -lactamases (ESBL) and carbapenemase- producing coliform, and toxin-hyperproducing Clostridium difficile.
  • MRSA meticillin-resistance Staphylococcus aureus
  • ESBL extended spectrum ⁇ -lactamases
  • carbapenemase- producing coliform and toxin-hyperproducing Clostridium difficile.
  • Resistance to ⁇ -lactams in Staphylococcus aureus is mainly caused by acquisition of a low affinity penicillin-binding protein, PBP 2a, but is accompained by other resistance factors that provide resistance to most of clinically used antibiotics.
  • PBP 2a penicillin-binding protein
  • a number of relatevly new drugs such as linezolid, daptomycin and tigecycline are now available to treat infections caused by ⁇ -lactam-resistant Gram positive cocci.
  • Boronic acids have been known since the late '80 to inhibit ⁇ -lactamases (Crompton, I. E., Cuthbert, B. K., Lowe, G., Waley, S. G., Biochem. J., 1988, 251, 453-9.). They are compounds that replace the ⁇ -lactam ring with boronic acid.
  • the boron atom forms of a reversible, dative covalent bond with the active site serine of class A and C and D ⁇ -lactamases, assuming a geometry that resembles the tetrahedral transition state of the ⁇ -lactamase hydrolytic reaction.
  • Ness et al. discloses ⁇ -lactamase inhibitors that target TEM-1 (a non-ESBL TEM variant from class A; one of approximately 140 known TEM-type betalactamase variants). More recently patent WO2010/130708 disclosed a-aminoacyl-p-boron (3-carboxyphenyl) as broad spectrum ⁇ -lactamases inhibitors.
  • the object of the invention Taking respect to the rapidly evolving ⁇ -lactamase capability of bacteria, it is the object of the invention to provide novel compounds for inhibition of ⁇ -lactamase activity.
  • the invention provides compounds featuring a boronic acid structure bearing a heterocycle.
  • ⁇ is a bond or a C1-C8 saturated or unsaturated linear or branched aliphatic chain, optionally substituted with one or more groups chosen from hydroxyl, alkyl, cycloalkyi, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidine, halogen, heteroaryl, heterocyclyl, sulfide, sulfonyl, sulfoxido, sulfonic acid, sulfate and thiol; is chosen from hydrogen, linear or branched C1-C12 alkyl, linear or branched C1-C12 alkenyl, or C3-C8 cycloalkyi; said linear or branched C1-C12 alkyl, linear or branched C1-C12 alkenyl, or C3- C8 cycl
  • R2, R3, R4, R5 are independently selected from the group consisting of:
  • substituents of Ri, R 2 , R3, R4 and R 5 being independently selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, C(0)R6, C(0)NR 6 R7, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyi, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino group wherein any of the C1-C10 carbons of (b), any of the carbons of the cycloalkyi group of (c) other than the one attached to the rest of
  • the heterocyclic or heteroaromatic ring system Z is a stable 3- to 8-membered monocyclic or stable 7- to 14-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of N, O, and S, preferably N.
  • heterocyclic or heteroaromatic ring system Z is a bicyclic group in which a heterocyclic ring is fused to a benzene ring.
  • the heterocyclic or heteroaromatic ring system Z is selected from the group comprising azetidinyl, oxetanyl, oxazolyl, pirazolyl, thiazolyl, triazolyl, tetrazolyl, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1 ,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indo
  • the heterocyclic or heteroaromatic ring system Z is a heteroaryl group, preferably a group having 5 to 14 ring atoms, more preferably a group having 5, 6, 9, or 10 ring atoms; said heteroaryl group preferably having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having 1 , 2 or 3 heteroatoms independently selected from the group consisting of N, O, and S, even more preferably the heterocyclic or heteroaromatic ring system of Z is a heteroaryl group selected from the group comprising thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, is
  • the heterocyclic or heteroaromatic ring system Z is fused to an aryl or heteroaryl group, preferably the heterocyclic or heteroaromatic ring system Z is selected from the group comprising tetrahydroquinolinyl, dihydrobenzofuranyl, benzoxazinyl, 1 ,2,3,4-tetrahydro- quinoxalinyl, benzoimidazolyl, benzothiazolyl, benzotriazolyl.
  • the heterocyclic or heteroaromatic ring system Z is substituted with 0, 1 , 2 or 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, C(0)R6, C(O)NR 6 R7, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, wherein
  • R6 and R 7 are independently selected from hydrogen, or from the group consisting of
  • R6 and R 7 being selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino group wherein any of the C1-C6 carbons of (a), any of the carbons of the cycloalkyl group of (b) other than the one attached to the rest of the molecule, or any of the carbons of the heterocyclic group of (e)
  • L is a bond or a C1-C8 saturated or unsaturated linear or branched aliphatic chain, preferably a bond, (CH 2 ) or (CH 2 )2, more preferably (Chfe).
  • Z is an triazol optionally substituted with 1 or more substituents selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidine, halogen, heteroaryl, heterocyclyl, sulfide, sulfonyl, sulfoxido, sulfonic acid, sulfate and thiol, preferably from
  • Y is a heteroaryl group substituted with from 0 to 3 substituents, said substituents being independently selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, C(O)R , C(0)NR 4 R 5 , thiol, sulfonic acid, sulfate, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido; preferably Y is selected from the group comprising thienyl, benzothien
  • coumpound according to the invention is having the general formula (II), (V), (VI) or (VII)
  • Re, R9, R10, R11 and R12 are independently selected from the group consisting of
  • R 8 , Rg, Rio, R and R12 are selected independently from either hydrogen or a compound according to one of the following formulas a., b., c, d., or e. ther preferred that the compound is
  • the compound according to the invention is an inhibitor for ⁇ -lactamase, preferably for a class A, C or D ⁇ -lactamase, even more preferably for a ⁇ -lactamase selected from SHV-1 , TEM-1 , PDC-3 or KPC-2.
  • the invention further provides a compound according to the above said for use in the prevention or treatment of bacterial infections, preferably for the treatment of an bacterial infection caused by bacteria of the genus Staphylococcus, preferably Staphylococcus aureus or Staphylococcus epidermidis, Streptococcus, preferably Streptococcus agalactiae, Streptococcus pneumoniae or Streptococcus faecalis, Micrococcus, preferably Micrococcus luteus, Bacillus, preferably Bacillus subtilis, Listerella, preferably Listerella monocytogene, Escherichia, preferably Escherichia coli, Klebsiella, preferably Klebsiella pneumoniae, Proteus, preferably Proteus mirabilis or Proteus vulgaris, Salmonella, preferably Salmonella typhosa, Shigella, preferably Shigella sonnef, Enterobacter, preferably Enterobacter aerogenes or Entero
  • the invention also provides a method for the preparation of a compound according to the above said wherein the heterocyclic or heteroaromatic ring system Z is synthesized by click chemistry, preferably by cycloaddition, more preferably by 1 ,3-dipolar cycloaddition, 2,4 cycloaddition or 2+2-cycloaddition, even more preferably by Huisgen 1 ,3-dipolar cycloaddition or strained- cycloaddtion.
  • the method according to the invention comprises the steps a. providing an alkylboronate, preferably providing an azido- alkylboronate, more preferably a compound of the formula (III)
  • Y, R, m, L, ⁇ , X 2 are defined as above, wherein are preferably a protectiongroup, more preferably X1 , X2 are pinanediol; b. sythesis of Z by cycloaddtion, preferably by Cu/C-catalyzed click reaction, even more preferably by Huisgen 1 ,3-dipolar cycloaddtion, providing a compound of the formula IV wherein Y, m, R, L, Xi, X 2l R8, R9 are defined in step a., c. optionally purification of the product; d. optionally deprotection of the protected boronate-group.
  • the click reaction is a Cu/C-catalyzed click reaction comprising at least the steps
  • step b adding Cu(0)/C to the provided solution of step a); c. optionally providing inert gas-influx, preferably Argon-influx, into sealed reaction vessel;
  • reaction mixture optionally exposure of the reaction mixture to irradiation, preferably microwave irradiation under stirring at 150°C.
  • the invention further provides a compound according to one of the formulas (III), (IV), (VIII), (IX).or (X)
  • Y is chosen from hydrogen or from the group consisting of aryl group substituted with from 0 to 3 substituents, heteroaryl group substituted with from 0 to 3 substituents and heterocyclic group substituted with from 0 to 3 substituents, said substituents being independently selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, C(0)R 4 , C(0)NR 4 R 5 , thiol, sulfonic acid, sulfate, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sul
  • R ⁇ R 2 are as defined above; preferably Xi and X 2 are protection groups or do form together one protection group, wherein preferably the protection group is pinanediol; is a bond or a C1-C8 saturated or unsaturated linear or branched aliphatic chain, optionally substituted with one or more groups chosen from hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidine, halogen, heteroaryl, heterocyclyl, sulfide, sulfonyl, sulfoxido, sulfonic acid, sulfate and thiol; R is chosen from hydrogen, linear or branched C1-C12 alkyl, linear or
  • Re, Rg are independently selected from the group consisting of
  • the substituents being selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyi, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino group wherein any of the C1-C6 carbons of (a), any of the carbons of the cycloalkyl group of (b) other than the one attached to the rest of the molecule, or any of the carbons of the heterocyclic group of (e) other than the one attached
  • this compound is an inhibitor for ⁇ -lactamase, preferably for a class A, C or D ⁇ -lactamase, even more preferably for a ⁇ - lactamase selected from SHV-1 , TEM-1 , PDC-3 or KPC-2.
  • the invention provides said compound for use in preparation of a compound according to formula I as said above. It is preferred that the compound is for use in a method according to the invention.
  • the invention provides a compound according to the above said for use in manufacturing a medicament for the prevention or treatment of bacterial infections, preferably for the treatment of an bacterial infection caused by bacteria of the genus Staphylococcus, preferably Staphylococcus aureus or Staphylococcus epidermidis, Streptococcus, preferably Streptococcus agalactiae, Streptococcus pneumoniae or Streptococcus faecalis, Micrococcus, preferably Micrococcus luteus, Bacillus, preferably Bacillus subtilis, Listerella, preferably Listerella monocytogene, Escherichia, preferably Escherichia coli, Klebsiella, preferably Klebsiella pneumoniae, Proteus, preferably Proteus mirabilis or Proteus vulgaris, Salmonella, preferably Salmonella typhosa, Shigella, preferably Shigella sonnef, Enterobacter, preferably Entero
  • the invention provides a pharmaceutical composition comprising a compound according to the invention or a salt thereof.
  • the pharmaceutical composition comprises a ⁇ -lactam antibiotic, preferably a ⁇ -lactam antibiotic selected from the group comprising penicillins, cephalosporins, penems, carbapenems, and monobactams.
  • a ⁇ -lactam antibiotic selected from the group comprising penicillins, cephalosporins, penems, carbapenems, and monobactams.
  • composition further comprises a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is for use in the prevention or treatment of bacterial infection caused by gram-positive or gram- negative bacteria, preferably for the treatment of an infection caused by bacteria of the genus Staphylococcus, preferably Staphylococcus aureus or Staphylococcus epidermidis, Streptococcus, preferably Streptococcus agalactiae, Streptococcus pneumoniae or Streptococcus faecalis, Micrococcus, preferably Micrococcus luteus, Bacillus, preferably Bacillus subtilis, Listerella, preferably Listerella monocytogene, Escherichia, preferably Escherichia coli, Klebsiella, preferably Klebsiella pneumoniae, Proteus, preferably Proteus mirabilis or Proteus vulgaris, Salmonella, preferably Salmonella typhosa, Shigella, preferably Shigella sonnef, Enterobacter, preferably Enterobacter aerogene
  • Z is an heterocylce comprising preferably at least one heteroatom selected from N, O and S, more preferably seleceted from N.
  • Another aspect of the invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) one or more compounds discussed above; (b) one or more ⁇ - lactam antibiotics; and (c) one or more pharmaceutically acceptable carriers
  • a further aspect of the invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) one or more compounds discussed above; and (b) one or more pharmaceutically acceptable carriers.
  • An additional aspect of the invention is related to a method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof: (a) one or more of the compounds discussed above and (b) and effective amount of ⁇ -lactam antibiotic.
  • Another aspect is for a method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof an effective amount of a compound discussed above.
  • An additional aspect of the invention is related to the use of one or more compounds discussed above in the manufacture of a medicament for the treatment of a bacterial infection.
  • the present invention relates generally to novel boronic acids and their derivatives which act as broad-spectrum inhibitors of betalactamase enzymes, ⁇ - Lactamases hydrolyze ⁇ -lactam antibiotics, and are therefore an important cause of ⁇ -lactam antibiotic resistance.
  • the present invention also relates to pharmaceutical compositions comprising a compound of the present invention, or salt thereof, an optional ⁇ -lactam antibiotic, and a pharmaceutically acceptable excipient.
  • the present invention also relates to a method for treating a bacterial infection in a mammal by administration of a therapeutically acceptable amount of the aforementioned pharmaceutical compositions.
  • the present invention also relates to a method for increasing the effectiveness of a ⁇ -lactam antibiotic in mammals by administering an effective amount of a compound of the present invention in combination with an effective amount of such ⁇ -lactam antibiotic.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • cow, pig, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
  • mammal refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal.
  • a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.
  • treat are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • prevent are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1 ,2,3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0.5%, or 0.05% of a given value or range.
  • active ingredient and active substance refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
  • active ingredient and active substance may be an optically active isomer, a diasteromeric mixture in any isomeric ratio, or an isotopic variant of a compound described herein.
  • antibiotic is used herein to describe a compound or composition which decreases the viability of a microorganism, or which inhibits the growth or reproduction of a microorganism. "Inhibits the growth or reproduction” means increasing the generation cycle time by at least 2-fold, preferably at least 10-fold, more preferably at least 100-fold, and most preferably indefinitely, as in total cell death.
  • an antibiotic is further intended to include an antimicrobial, bacteriostatic, or bactericidal agent.
  • Non-limiting examples of antibiotics useful according to this aspect of the invention include penicillins, cephalosporins, aminoglycosides, sulfonamides, macrolides, tetracyclins, lincosides, quinolones, chloramphenicol, vancomycin, metronidazole, rifampin, isoniazid, spectinomycin, trimethoprim, sulfamethoxazole, and others.
  • ⁇ -lactam antibiotic is used to designate compounds with antibiotic properties containing a ⁇ -lactam functionality.
  • Non-limiting examples of ⁇ -lactam antibiotics useful according to this aspect of the invention include penicillins, cephalosporins, penems, carbapenems, and monobactams.
  • ⁇ -Lactam antibiotics are effective (in the absence of resistance) against a wide range of bacterial infections.
  • bacteria of the genus Staphylococcus such as Staphylococcus aureus and Staphylococcus epidermidis
  • Streptococcus such as Streptococcus agalactiae, Streptococcus pneumoniae and Streptococcus faecalis
  • Micrococcus such as Micrococcus luteus
  • Bacillus such as Bacillus subtilis
  • Listerella such as Listerella monocytogenes
  • Escherichia such as Escherichia coli
  • Klebsiella such as Klebsiella pneumoniae
  • Proteus such as Proteus mirabilis and Proteus vulgaris
  • Salmonella such as Salmonella typhosa
  • Shigella such as Shigella sonne
  • Enterobacter such as Enterobacter aerogenes and Enterobacter cloacae
  • Serratia such as Serratia
  • ⁇ -lactamase means an enzyme produced by a bacterium that has the ability to hydrolyze the ⁇ -lactam ring of ⁇ -lactam antibiotics. Such enzymes are often classified into 4 major classes (Classes A, B, C, and D) according to the so- called Ambler classification scheme, based principally on protein homology.
  • ⁇ -lactamase inhibitors with broad-spectrum functionality refers to the ability of an inhibitor to inhibit a broad range of ⁇ -lactamase enzymes, spanning multiple subtypes from multiple classes (for example numerous enzyme subtypes from both Ambler Class A and Ambler Class C).
  • ⁇ -lactamase enzyme(s) from at least two classes of ⁇ - lactamase enzymes are inhibited by a compound disclosed herein, with preferred embodiments being those where ⁇ -lactamase enzyme(s) from more than two classes of ⁇ -lactamase enzymes are inhibited by a compound disclosed herein.
  • the term “consisting essentially of is intended to include embodiments encompassed by the term “consisting of.
  • the terms "effective amount”, “therapeutically effective amount”, and “therapeutically effective period of time” are used to denote known treatments at dosages and for periods of time effective to show a meaningful patient benefit, i.e., healing of conditions associated with bacterial infection, and/or bacterial drug resistance.
  • such administration should be parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
  • the therapeutic composition When administered systemically, the therapeutic composition is preferably administered at a sufficient dosage to attain a blood level of inhibitor of at least about lOC ⁇ g/mL, more preferably about 1 mg/mL, and still more preferably about 10mg/mL.
  • a blood level of inhibitor of at least about lOC ⁇ g/mL, more preferably about 1 mg/mL, and still more preferably about 10mg/mL.
  • alkyl means both straight and branched saturated hydrocarbon chain of 1-12 carbons, preferably of 1-8 carbon atoms, which may be optionally substituted.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).
  • alkenyl means both straight and branched chain containing at least a carbon-carbon double bond, of 1-12 carbon atoms, optionally substituted.
  • the alkenyl moiety has 2-8 carbons and one or two double bonds.
  • alkenyl moieties may exist in the E or Z conformations; the compounds of this invention include both conformations.
  • alkenyl groups include, but are not limited to, methlenyl, ethelenyl, propenyl (including all isomeric forms), n- propenyl, isopropenyl, butenyl (including all isomeric forms), n-butenyl, isobutenyl, pentenyl (including all isomeric forms), and hexenyl (including all isomeric forms).
  • alkynyl includes both straight chain and branched chain, optionally substituted, containing 2-12 carbon atoms and at least one triple bond, preferably the alkynyl moiety has 2-6 carbons and one or two triple bonds.
  • alkynyl groups include, but are not limited to, ethynyl (-CECH), propynyl (including all isomeric forms, e.g., 1 -propynyl (-CECCH3) and propargyl (-CH2CECH)), butynyl (including all isomeric forms, e.g., 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl).
  • cycloalkyl means an alicyclic hydrocarbon group having 3-14 carbon atoms, optionally substituted, preferably the cycloalkyl moiety contain 3-8 carbon atoms.
  • cycloalkyl groups may be saturated or unsaturated but non-aromatic, and/or bridged, and/or non-bridged, and/or fused bicyclic groups.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.
  • aryl means a monovalent monocyclic aromatic group and/or monovalent multicyclic aromatic group that contain at least one aromatic carbon ring.
  • aryl groups include, but are not limited to, phenyl, ⁇ -naphthyl, ⁇ - naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may be optionally substituted.
  • Heteroaryl is defined as an aromatic heterocyclic ring system (monocyclic or bicyclic) where the heteroaryl moieties are selected from, but not limited to,: (1) furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N- methylpyrrole, pyrazole, N-methyl pyrazole, 1 ,3,4-oxadiazole, ,2,4-triazole, 1- methyl-1 ,2,4-triazole, 1 H-tetrazole, 1 -methyltetrazole, 1 ,2,4-thiadiazole, 1 ,3,4- thiadiazole, 1 ,2,3-thiadiazole, 1 ,2,3-triazole, 1 -methyl-1 ,2,3-triazole,
  • Arylalkyl is defined as aryl-C1-C12alkyl ⁇ .
  • Arylalkyl moieties include benzyl, 1- phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
  • arylakyl are optionally substituted with one or more substituents.
  • Arylalkenyl is defined as aryl-C2-C12alkenyl-.
  • Arylalkenyl moieties include, 1- phenylethenyl, 2-phenylethenyl, 1-phenylpropenyl, 2-phenylpropenyl and the like. Such arylalkenyl moieties may exist in the E or Z conformations and be optionally substituted with one or more substituents.
  • Arylalkynyl is defined as aryl-C2-C12alkynyl ⁇ .
  • Arylalkynyl moieties include, phenylethynyl, phenylpropynyl, and the like.
  • Alkylaryl is defined as C1-C12alkyl-aryk
  • Alkenylaryl is defined as C2-C12 alkenylaryl-.
  • Alkynylaryl is defined as C2-C12alkynylaryl-.
  • Heteroarylalkyl is defined as heteroaryl-C 1-C12alkyl— .
  • Alkylheteroaryl is defined as C1-C12alkyl-heteroaryl ⁇ .
  • Heteroaryl is defined as a monovalent monocyclic aromatic group or monovalent multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from 0, S, and N in the ring. Heteroaryl groups are bonded to the rest of a molecule through the aromatic ring.
  • monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimi
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • heteroaryl may also be optionally substituted.
  • Heterocyclyl is defined as a monovalent monocyclic non-aromatic ring system or monovalent multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from 0, S, and N; and the remaining ring atoms are carbon atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, hexahydroazepinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1 ,4-dioxanyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, -carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenz
  • halogen is defined as CI, Br, F, and I.
  • Alkoxy is defined as C1-C6alkyl-O ⁇ .
  • Cycloalkoxy is defined as C3-C7cycloalkyl-O-.
  • Aryloxy is defined as aryl-O-.
  • Heteroaryloxy is defined as heteroaryl-O-.
  • Heterocyclyloxy is defined as C3-C7heterocyclyl-0-.
  • Sulfonic acid is defined as -S03H.
  • Sulfate is defined as -OS03H.
  • Amino is defined as -NH2.
  • Hydroxyl is defined as -OH
  • Carboxyl is defined as -CO2H.
  • Oxo is defined as double bonded oxygen.
  • Trialkylammonium is defined as (A1 )(A2)(A3)N+- where A 1 , A2 and A3 are independently alkyl, cycloalkyl, heterocyclyl and the nitrogen is positively charged.
  • Carbonyl is defined as -C(O)- where the carbon is optionally substituted and also attached to the rest of the molecule.
  • Aminocarbonyl is defined as -C(0)-N--, where the carbon is optionally substituted and the nitrogen is attached to the rest of the molecule.
  • Oxycarbonyl is defined as ⁇ C(0)-0 ⁇ , where the carbon is optionally substituted and the oxygen is attached to the rest of the molecule.
  • Aminosulfonyl is defined as— S(0)2-N- where the sulfur is optionally substituted and the nitrogen is attached to the rest of the molecule.
  • Sulfonyl is defined as -S(0)2- where the sulfur is bonded to an optional substituent and also to the rest of the molecule.
  • Guanidino is defined as ⁇ N1 (H)-C(NH)-N2(H) ⁇ where N1 is optionally substituted and N2 is attached to the rest of the molecule.
  • Oxyimino is defined as (N-O-A) where the nitrogen is double bonded to a carbon which is attached to the rest of the molecule and A can be hydrogen, optionally substituted: alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl.
  • Sulfido is defined as -S- where sulfur is bound to an optional substituent and also to the rest of the molecule.
  • Sulfoxido is defined as ⁇ S ⁇ O) ⁇ where sulfur is bound to an optional substituent and also to the rest of the molecule.
  • Optional substituents may be attached to the group or atom which they substitute in a variety of ways, either directly or through a connecting group of which the following are examples: alkyl, amine, amide, ester, ether, thioether, sulfonamide, sulfamide, sulfoxide, urea.
  • an optional substituent may itself be further substituted by another substituent, the latter being connected directly to the former or through a connecting group such as those exemplified above.
  • optically active and “enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91 %, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
  • the compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the compound.
  • R and S are used to denote the absolute configuration of the molecule about its chiral center( s).
  • the (+) and ( -) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • isotopic variant refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such compounds.
  • an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen 1 H), deuterium 2 Hj, tritium 3 H), carbon-1 1 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 Cj, nitrogen-13 ( 13 N), nitrogen-14 ( 14 N , nitrogen-15 ( 15 N), oxygen-14 ( 14 0), oxygen-15 ( 15 0), oxygen-16 ( 16 0), oxygen-17 ( 17 0), oxygen- 18 ( 18 0), fluorine-17 ( 17 F), fluorine-18 ( 18 Fj, phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( ⁇ S), sulfur- 35 ( 35 S), sulfur-36 ( 36 S),
  • an "isotopic variant" of a compound is in a stable form, that is, non-radioactive.
  • an "isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 3 C), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 0j, oxygen-17 ( 17 0), oxygen-18 ( 18 0), fluorine-17 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( ⁇ S), sulfur-36 ( 36 S), chlorine-35 ( 35 CI), chlorine-37 ( 37 CI), bromine-79 ( 79 Br), bromine-81 ( 81 Br), and iodine-127 ( 127 l).
  • an "isotopic variant" of a compound is in an unstable form, that is, radioactive.
  • an "isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon-11 ( 1 C), carbon-14 ( 1 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 0), oxygen-15 ( 15 0), fluorine-18 ( 18 Fj, phosphorus- 32 ( 32 P), phosphorus-33 ( 33 P), sulfur-35 ( 35 S), chlorine-36 ( 36 CI), iodine-123 ( 123 l), iodine-125 ( 125 l), iodine-129 ( 129 l), and iodine-131 ( 131 l).
  • any hydrogen can be 2 H, for example, or any carbon can be 13 C, as example, or any nitrogen can be 15 N, as example, and any oxygen can be 18 0 , where feasible according to the judgment of one of skill.
  • an "isotopic variant" of a compound contains unnatural proportions of deuterium.
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which present in stoichiometric or non-stoichiometric amount.
  • Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid.
  • the solvent is pharmaceutically acceptable.
  • the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate.
  • FIG. 1 scheme of synthesis of a first compound according to the invention
  • a preferred embodiment relates to compounds of general formula II. Such a compound can be obtained by the synthesis shown in Fig. 1 and described as a retro-synthesis hereinafter.
  • R8 and R9 are selected from the group consisting of hydrogen; C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituent; C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents; aryl group substituted with from 0 to 3 substituents; heteroaryl group substituted with from 0 to 3 substituents and heterocyclic group substituted with from 0 to 3 substituents, the substituents being selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl,
  • the reaction can be carried out at a temperature ranging from room to boiling temperatures, using a base such as N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), lutidine, pyridine etc., a suitable ligand like Tris[(1-benzyl-1H-1 ,2,3-triazol-4-yl)methyl] amine (TBTA), proline, lutidine etc.... and a large choice of Cu(l) source such as copper halides (Cul, CuBr), copper sulfate (CuS0 4 ) and sodium ascorbate (NaAsc), Cu(0) with or without addition of CuS0 4 .(Hein J.
  • DIPEA N,N-diisopropylethylamine
  • TEA triethylamine
  • TBTA Tris[(1-benzyl-1H-1 ,2,3-triazol-4-yl)methyl] amine
  • TBTA
  • compound XIII can be obtained from compound XIV by conversion to the bis(trimethylsilyl)amine intermediate using conditions as described in Morandi F. et al., J. Amer. Chem. Soc, 2003, 125, 685-695, followed by coupling reaction with a suitable acid chloride or with an active ester such as that derived from the reaction of a carboxylic acid and isobutyl chloroformate or from the reaction of a carboxylic acid with a tetramethyluronium agent such as 0-(7-Azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).
  • a suitable acid chloride or with an active ester such as that derived from the reaction of a carboxylic acid and isobutyl chloroformate or from the reaction of a carboxylic acid with a tetramethyluronium agent such as 0-(7-Azabenzotri
  • Compound XIV can be obtained from compound XV by treatment with chloromethyllithium at -100 °C according to the well known Matteson protocol (Sadhu, K. M., Matteson, D. S., Organometallics, 1985, 4, 1687-1689) whereas the a-azidomethane boronic ester XV can be obtained by nuleophilic substitution of the a-halogenated derivative XVI as described in Matteson D. S. et al, J. Org. Chem., 2008, 693, 2258-2262.
  • a protection group particularly (+)-pinanediol
  • HAL is a halogen.
  • the present invention relates to compounds of general formula I that can be prepared according but not limited to the procedures shown schematically in Fig. 1 and described herein as an example or obtained by any method known to a person skilled in the art.
  • Certain compounds of Formula (I) include compounds of Formula (II)
  • Y is chosen from hydrogen, optionally substituted linear or branched C1- C12 alkyl, optionally substituted linear or branched C1-C12 alkenyl, NR1 R2, OR 3 , SR3, or from the group consisting of aryl group substituted with from 0 to 3 substituents, heteroaryl group substituted with from 0 to 3 substituents and heterocyclic group substituted with from 0 to 3 substituents, said substituents being independently selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, C(0)R4, C(0)NR 4 R5, thiol, sulfonic acid, sulfate, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy,
  • substituents of Ri, R2, R3, 4 and R5 being independently selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, C(0)R 6 , C(0)NR 6 R 7 , thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyi, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino group wherein any of the C1-C10 carbons of (b), any of the carbons of the cycloalkyi group of (c) other than the one attached to the rest of
  • the substituents of F*6 and R 7 being selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino group wherein any of the C1-C6 carbons of (a), any of the carbons of the cycloalkyl group of (b) other than the one attached to the rest of the molecule, or any of the carbons of the heterocyclic group of (
  • Re Rg are selected from the group consisting of hydrogen; C1 -C6 alkyl any carbon of which can be substituted with from 0 to 3 substituent; C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents; aryl group substituted with from 0 to 3 substituents; heteroaryl group substituted with from 0 to 3 substituents and heterocyclic group substituted with from 0 to 3 substituents, the substituents being selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroary
  • Xi and X 2 are OH.
  • the compound provided herein can be prepared, isolated, or obtained by any method known to one of skill in the art.
  • a particularly preferred embodiment of the invention is related to compounds 7a-e
  • Most preferred compounds are compounds 7d-e.
  • the compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt. See, Berge et al., 1. Pharm. Sci. 1977,66, 1-19; and Handbook of Pharmaceutical Salts, Properties, and Use; Stahl and Wermuth, Ed.; Wiley-VCR and VRCA: Zurich, Switzerland, 2002.
  • Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzene sulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+ )-camphoric acid, camphorsulfonic acid, (+ HiS camphor-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1 ,2-disulfonic acid, ethane sulfonic acid, 2-hydroxy- ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-( diethylamino )-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1 H- imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethy
  • the compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound itself and is readily convertible into the parent compound in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not.
  • the prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound.
  • a prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
  • ⁇ -Lactamase inhibitors can be administered to subjects in a biologically compatible form suitable for pharmaceutical administration in vivo to, e.g., increase antibacterial activity of ⁇ -lactam antibiotics.
  • Administration of a ⁇ - lactamase inhibitor as described herein can be in any pharmacological form including a therapeutically active amount of a ⁇ -lactamase inhibitor alone or in combination with a pharmaceutically acceptable carrier.
  • a therapeutically active amount of a ⁇ -lactamase inhibitor may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the betalactamase inhibitor to elicit a desired response in the subject. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • the therapeutic or pharmaceutical compositions can be administered by any suitable route known in the art including, for example, intravenous, subcutaneous, intramuscular, oral, buccal, intranasal, suppository, transdermal, intrathecal, or intracerebral or administration to cells in ex vivo treatment protocols. Administration can be either rapid as by injection or over a period of time as by slow infusion or administration of slow release formulation.
  • compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • modified release dosage forms including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al, Eds.; Marcel Dekker, Inc.: New York, NY, 2008).
  • a ⁇ -lactamase inhibitor can also be linked or conjugated with agents that provide desirable pharmaceutical or pharmacodynamic properties.
  • a ⁇ - lactamase inhibitor can be coupled to any substance known in the art to promote penetration or transport across the blood-brain barrier such as an antibody to the transferrin receptor, and administered by intravenous injection (see, e.g., Friden PM et al, Science 259:373-77 (1993».
  • a ⁇ -lactamase inhibitor can be stably linked to a polymer such as polyethylene glycol to obtain desirable properties of solubility, stability, half-life, and other 5 pharmaceutically advantageous properties (see, e.g., Davis et al., Enzyme Eng.
  • a ⁇ -lactamase inhibitor can be in a composition which aids in delivery into the cytosol of a cell.
  • the ⁇ -lactamase inhibitor may be conjugated with a carrier moiety such as a liposome that is capable of delivering the ⁇ -lactamase inhibitor into the cytosol of a cell.
  • a carrier moiety such as a liposome that is capable of delivering the ⁇ -lactamase inhibitor into the cytosol of a cell.
  • a ⁇ -lactamase inhibitor can be modified to include specific transit peptides or fused to such transit peptides which are capable of delivering their ⁇ - lactamase inhibitor into a cell.
  • the ⁇ -lactamase inhibitor can be delivered directly into a cell by microinjection.
  • the compositions are usually employed in the form of pharmaceutical preparations. Such preparations are made in a manner well known in the pharmaceutical art. One preferred preparation utilizes a vehicle of physiological saline solution, but it is contemplated that other pharmaceutically acceptable carriers such as physiological concentrations of other non-toxic salts, five percent aqueous glucose solution, sterile water, or the like may also be used.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any standard media or agent is incompatible with the active compound, use thereof in the therapeutic compositions is contemplated.
  • Supplementary active compounds can also be incorporated into the compositions. It may also be desirable that a suitable buffer be present in the composition.
  • Such solutions can, if desired, be lyophilized and stored in a sterile ampoule ready for reconstitution by the addition of sterile water for ready injection.
  • the primary solvent can be aqueous or alternatively non-aqueous.
  • a ⁇ -lactamase inhibitor can also be incorporated into a solid or semi-solid biologically compatible matrix which can be implanted into tissues.
  • the carrier can contain other pharmaceutically-acceptable excipients for modifying or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, rate of dissolution, or odor of the formulation.
  • excipients are those substances usually and customarily employed to formulate dosages for parenteral administration in either unit dosage or multi-dose form or for direct infusion by continuous or periodic infusion.
  • the pharmaceutical compositions further comprise an effective amount of a ⁇ -lactam antibiotic.
  • ⁇ -lactam antibiotics include penicillins, cephalosporins, penem, carbapenems, monobactams, bridged monobactams, or a combination thereof.
  • Pencillins include, but are not limited to, benzathine penicillin, benzylpenicillin, phenoxymethylpenicillin, procaine penicillin, oxacillin, methicillin, dicloxaciliin, flucloxacillin, temociilin, amoxicillin, ampicillin, co-amoxiclav, azlocillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, apalcillin, hetacillin, bacampiciliin, sulbenicillin, mecicilam, pevmecillinam, ciclacillin, talapiciliin, aspoxicillin, cloxacillin, nafcillin, pivampicillin, or a combination thereof.
  • Cephalosporins include, but are not limited to, cephalothin, cephaloridin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrll, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefinenoxime, cefinetazole, cepha[oglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepim, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil
  • Penem include but are not limited to faropenem.
  • Carbapenems include, but are not limited to, imipenem, meropenem, ertapenem, doripenem, biapenem, panipenem, anti-MRSA carbapenems (e.g., razupenem (PZ-601) or ME1 036, see Expert Rev. Anti-lnfect Ther. (2008) 6:39-49), or a combination thereof.
  • Monobactams include, but are not limited to, aztreonam, carumonam, BAL30072 or a combination thereof. See Figure 2 for structures of razupenem (PZ-601), ME1036, and BAL30072.
  • the ⁇ -lactamase inhibitors or their pharmaceutically acceptable salts may be administered at the same time as the dose of betalactam antibiotics or separately. This may be carried out in the form of a mixture of the two active ingredients or in the form of a pharmaceutical combination of the two separate active ingredients.
  • the dosage of the ⁇ -lactamase inhibitors and of their pharmaceutically acceptable salts may vary within wide limits and should naturally be adjusted, in each particular case, to the individual conditions and to the pathogenic agent to be controlled.
  • the daily dose may be between 0.10 g and 10 g per day, by the oral route in humans, or else between 0.10 g and 10 g per day by the intramuscular or intravenous route.
  • the ratio of the ⁇ -lactamase inhibitor or of the pharmaceutically acceptable salt thereof to the ⁇ -lactam antibiotic may also vary within wide limits and should be adjusted, in each particular case, to the individual conditions. In general, a ratio ranging from about 1 :20 to about 4: 1 is recommended.
  • Dose administration can be repeated depending upon the pharmacokinetic parameters of the dosage formulation and the route of administration used.
  • formulations containing a ⁇ -lactamase inhibitor are to be administered orally.
  • Such formulations are preferably encapsulated and formulated with suitable carriers in solid dosage forms.
  • suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, gelatin, syrup, methyl cellulose, methyl- and propylhydroxybenzoates, talc, magnesium, stearate, water, mineral oil, and the like.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • the compositions may be formulated so as to provide rapid, sustained, or delayed release of the active ingredients after administration to the patient by employing procedures well known in the art.
  • the formulations can also contain substances that diminish proteolytic degradation and/or substances which promote absorption such as, for example, surface active agents. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage 5 unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • the specific dose can be readily calculated by one of ordinary skill in the art, e.g., according to the approximate body weight or body surface area of the patient or the volume of body space to be occupied. The dose will also be calculated dependent upon the particular route of administration selected.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for determining the LD 50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 5 o/ED 50 .
  • Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
  • levels In plasma may be measured, for example, by high performance liquid chromatography.
  • the present disclosure also provides methods for inhibiting bacterial growth, by e.g. reducing bacterial resistance to a ⁇ -lactam antibiotic, such methods comprising contacting a bacterial cell culture, or a bacterially infected cell culture, tissue, or organism, with a ⁇ -lactamase inhibitor described herein.
  • the bacteria to be inhibited by administration of a ⁇ -lactamase inhibitor of the invention are bacteria that are resistant to ⁇ -iactam antibiotics. More preferably, the bacteria to be inhibited are ⁇ -lactamase positive strains that are highly resistant to ⁇ -lactam antibiotics.
  • resistant and highly resistant are well-understood by those of ordinary skill in the art (see, e.g., Payne et al., Antimicrobial Agents and Chemotherapy 38:767-772 (1994); Hanaki et al., Antimicrobial Agents and Chemotherapy 30:1120-1126 (1995).
  • highly resistant bacterial strains are those against which the MIC of methicillin is >100 ⁇ g/mL
  • slightly resistant bacterial strains are those against which the MIC of methicillin is >25 ⁇ g/mL.
  • the compound of the invention is administered to an experimental cell culture in vitro to prevent the growth of ⁇ -lactam resistant bacteria.
  • the compound of the invention is administered to a mammal, including a human, to prevent the growth of betalactam resistant bacteria in vivo.
  • the method according to this embodiment of the invention comprises administering a therapeutically effective amount of a betalactamase inhibitor for a therapeutically effective period of timeto a mammal, including a human.
  • the betalactamase inhibitor is administered in the form of a pharmaceutical composition as described above.
  • a betalactam antibiotic is co-administered with the ⁇ -lactamase inhibitor as described above.
  • Assays for the inhibition of ⁇ -lactamase activity are well known in the art. For instance, the ability of a compound to inhibit betalactamase activity in a standard enzyme inhibition assay may be used (see, e.g., Page, Biochem J. 295:295-304 (1993)).
  • ⁇ -Lactamases for use in such assays may be purified from bacterial sources or, preferably, are produced by recombinant DNA techniques, since genes and cDNA clones coding for many ⁇ -lactamases are known (see, e.g., Cartwright & Waley, Biochem J. 221 :505-12 (1984)).
  • a ⁇ -lactamase can be inhibited by contacting the beta-lactamase enzyme with an effective amount of an inventive compound or by contacting bacteria that produce the ⁇ -lactamase enzymes with an effective amount of such a compound so that the ⁇ -lactamase in the bacteria is contacted with the inhibitor.
  • the contacting may take place in vitro or in vivo.
  • Contacting means that the betalactamase and the inhibitor are brought together so that the inhibitor can bind to the ⁇ -lactamase. Amounts of a compound effective to inhibit a betalactamase may be determined empirically, and making such determinations is within the skill in the art. Inhibition includes both reduction and elimination of ⁇ -lactamase activity.
  • Mass spectra were determined on a gas chromatography HP 5890 associated with mass spectrometer detector HP 5972 (El, 70 eV) or on an Agilent Technologies LC-MS (n) Ion Trap 631 OA (ESI, 70 eV).
  • (+)-pinanediol a-bromomethaneboronate 1 was synthesized according to the literature (Matteson et al., Organometallics, 1996, 15(1), 152).
  • (+)-pinanediol azidomethaneboronate 2 A solution of 1 (3g, 11 mmol) in EtOAc (18 ml_) was stirred with a solution of sodium azide (7.15 g, 110 mmol) and tetrabutylammonium bromide (2.03 g, 5.5 mmol) in water under argon at rt for 18 hrs.
  • (+)-pinanediol 1-chloro-2-azidoethaneboronate 3 (Dichloromethyl)lithium was prepared by addition of n-butyllithium (3.3 ml of a 2.5 M solution) to dichloromethane (0.92 mL, 14.4 mmol) in anhydrous THF (30 mL) at -100 °C under argon.
  • (+)-pinanediol 1-bis-trimethylsilylamino-2-azidoethaneboronate 4 lithium hexamethyldisilazane (8.0 mL of a 1 M solution in THF) was added dropwise to a solution of 3 (2.27 g, 8.0 mmol) in anhydrous THF (20 mL) at -100°C under argon. The mixture was allowed to warm to rt overnight. Petroleum Ether (500 mL) was added and the abundant precipitate was filtered on a MgS0 4 pad. The solution was concentrated under vacuum to afford the title compound 4 as a pale yellow oil (2.25 g, 69%).[oc] D +4.2 (c, 1.6 , CDCI 3 ).
  • the title compound was prepared according to the general procedure but decreasing the temperature to 120 °C.
  • the pinanediol esters were dissolved in CH 3 CN (3 mL) and HCI (3 equivalent of a 1 M solution in degassed H 2 0), phenylboronic acid (1 equivalent) and n-exane (3 mL) were sequentially added and the resulting biphasic solution was vigourously stirred. After 30 min the n-hexane solution (containing the pinanediol phenylboronate) was removed and n-hexane (3 mL) was added. This last procedure was repeated several times until a TLC analysis revealed no more presence of 6a-e. The acetonitrile phase was concentrated affording the desired compounds 7a-e.
  • Fig. 2, 3 and 4 do show the synthesis of further compounds according to the invention, comprising further embodiments of the heterocylce Z.
  • the />/asHv-i coding sequence and natural promoter were cloned into a pBC SK (-) vector and transformed into E. coli DH10B cells.
  • 10 ml of an overnight culture grown in lysogeny broth (LB) were used to inoculate 500 ml of super optimal broth (SOB) and grown overnight.
  • Cells were harvested by centrifugation at 4 °C and frozen at -20 °C. After thawing, ⁇ -lactamase was liberated using stringent periplasmic fractionation with 0.04 mg/mL lysozyme (Sigma) and 1 mM EDTA, pH 7.8.
  • Preparative isoelectric focusing was performed with the lysate in a Sephadex G-100 (GE Healthcare) using ampholines in the pH range 3.5-10 (Bio-Rad) and running the gel overnight at a constant power of 8 W on a Multiphor II isoelectric focusing apparatus (GE Healthcare). Purity was assessed by 5% stacking, 12% resolving sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS- PAGE). ⁇ -Lactamase concentration was determined using Bio-Rad Bradford protein assay with bovine serum albumin standards.
  • the b/apDc-3 coding sequence (minus the leader sequence) was cloned into a pET24a(+) vector and transformed into E. coli BL21 (DE3) RP CodonPlus cells. 12 ml of an overnight culture grown in LB were used to inoculate 500 ml of SOB and grown at 37 °C for 2 hr. Isopropyl ⁇ -D-thiogalactopyranoside (IPTG) was added to a final concentration of 1 mM, and the cells grown for an additional 2.5 hr. The cells were harvested, frozen, resuspended in 50 mM Tris (pH 7.4), and ⁇ - lactamase liberated with lysozyme.
  • IPTG Isopropyl ⁇ -D-thiogalactopyranoside
  • PDC-3 enzyme was purified by preparative isoelectric focusing (PIEF) followed by fast protein liquid chromatography (FPLC) with a Sephadex Hi Load 16/60 column and a HiTrap High Performance sulfopropyl strong cation exchanger (GE Healthcare).
  • PIEF preparative isoelectric focusing
  • FPLC fast protein liquid chromatography
  • the protein was quantified by the Bradford protein assay and purity was assessed by 5% stacking, 12% resolving SDS-PAGE.
  • TEM-1 enzyme was purified by PIEF and FPLC with a Sephadex Hi Load 16/60 column. The protein was quantified by the Bradford protein assay and purity was assessed by 5% stacking, 12% resolving SDS-PAGE.
  • KPC-2 enzyme was purified by PIEF followed by FPLC with a Sephadex Hi Load 16/60 column.
  • the protein was quantified by the Bradford protein assay and purity was assessed by 5% stacking, 12% resolving SDS- PAGE.
  • ⁇ -lactamase inhibition was assessed by 5% stacking, 12% resolving SDS- PAGE.

Abstract

La présente invention porte sur de nouveaux composés d'acide boronique, un procédé de préparation de tels composés, des composés intermédiaires dans la préparation de tels composés, des composés intermédiaires destinés à être utilisés dans un procédé de préparation de tels composés, une composition pharmaceutique, l'utilisation d'un ou de plusieurs des composés ci-dessus ou d'une composition pharmaceutique dans la fabrication d'un médicament pour le traitement d'une infection bactérienne, et un procédé de criblage.
PCT/EP2011/005142 2011-10-13 2011-10-13 Inhibiteurs de type acide boronique de bêta-lactamases WO2013053372A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2011/005142 WO2013053372A1 (fr) 2011-10-13 2011-10-13 Inhibiteurs de type acide boronique de bêta-lactamases

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2011/005142 WO2013053372A1 (fr) 2011-10-13 2011-10-13 Inhibiteurs de type acide boronique de bêta-lactamases

Publications (1)

Publication Number Publication Date
WO2013053372A1 true WO2013053372A1 (fr) 2013-04-18

Family

ID=44910160

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2011/005142 WO2013053372A1 (fr) 2011-10-13 2011-10-13 Inhibiteurs de type acide boronique de bêta-lactamases

Country Status (1)

Country Link
WO (1) WO2013053372A1 (fr)

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8912169B2 (en) 2012-12-07 2014-12-16 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9012491B2 (en) 2011-08-31 2015-04-21 Rempex Pharmaceuticals, Inc. Heterocyclic boronic acid ester derivatives and therapeutic uses thereof
US9040504B2 (en) 2013-01-10 2015-05-26 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9101638B2 (en) 2013-01-04 2015-08-11 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9132140B2 (en) 2013-01-04 2015-09-15 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9156858B2 (en) 2012-05-23 2015-10-13 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
WO2016003929A1 (fr) * 2014-07-01 2016-01-07 Rempex Pharmaceuticals, Inc. Dérivés d'acide boronique et leurs utilisations thérapeutiques
US9241947B2 (en) 2013-01-04 2016-01-26 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9296763B2 (en) 2010-08-10 2016-03-29 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US9511142B2 (en) 2014-06-11 2016-12-06 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US20170065626A1 (en) * 2015-09-04 2017-03-09 Case Western Reserve University Compositions and methods of treating of bacterial infections with beta-lactamase inhibitors
US9637504B2 (en) 2014-06-11 2017-05-02 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9642869B2 (en) 2013-01-04 2017-05-09 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9687497B1 (en) 2014-05-05 2017-06-27 Rempex Pharmaceuticals, Inc. Salts and polymorphs of cyclic boronic acid ester derivatives and therapeutic uses thereof
US9944658B2 (en) 2013-03-14 2018-04-17 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9963467B2 (en) 2014-05-19 2018-05-08 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US10294249B2 (en) 2016-06-30 2019-05-21 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
US10364257B2 (en) 2014-12-19 2019-07-30 Rempex Pharmaceuticals, Inc. Apparatus and continuous flow process for production of boronic acid derivatives
US10385074B2 (en) 2014-05-05 2019-08-20 Rempex Pharmaceuticals, Inc. Synthesis of boronate salts and uses thereof
CN110156820A (zh) * 2019-04-25 2019-08-23 四川大学 一类巯基酰胺硼酸类衍生物及其作为mbl和/或sbl抑制剂的用途
US10399996B2 (en) 2015-09-11 2019-09-03 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US10464952B2 (en) 2015-12-10 2019-11-05 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US10561675B2 (en) 2012-06-06 2020-02-18 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US10618918B2 (en) 2015-03-17 2020-04-14 Qpex Biopharma, Inc. Substituted boronic acids as antimicrobials
US10662205B2 (en) 2014-11-18 2020-05-26 Qpex Biopharma, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US10730832B2 (en) 2016-06-21 2020-08-04 Orion Ophthalmology LLC Aliphatic prolinamide derivatives
US10889600B2 (en) 2016-08-04 2021-01-12 VenatoRx Pharmaceuticals, Inc. Boron-containing compounds
US11091505B2 (en) 2017-03-06 2021-08-17 VenatoRx Pharmaceuticals, Inc. Solid forms and combination compositions comprising a beta-lactamase inhibitor and uses thereof
US11267826B2 (en) 2017-05-26 2022-03-08 VenatoRx Pharmaceuticals, Inc. Penicillin-binding protein inhibitors
US11286270B2 (en) 2017-10-11 2022-03-29 Qpex Biopharma, Inc. Boronic acid derivatives and synthesis thereof
US11332485B2 (en) 2017-05-26 2022-05-17 VenatoRx Pharmaceuticals, Inc. Penicillin-binding protein inhibitors
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5731439A (en) * 1995-03-24 1998-03-24 The Dupont Merck Pharmaceutical Company Piperidine containing aminobornic acids
FR2758329A1 (fr) * 1997-01-16 1998-07-17 Synthelabo Derives d'imidazole-4-butane boronique, leur preparation et leur utilisation en therapeutique
US7271186B1 (en) 2002-12-09 2007-09-18 Northwestern University Nanomolar β-lactamase inhibitors
WO2010130708A1 (fr) 2009-05-12 2010-11-18 Novartis International Pharmaceutical Ltd. Inhibiteurs de béta-lactamases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5731439A (en) * 1995-03-24 1998-03-24 The Dupont Merck Pharmaceutical Company Piperidine containing aminobornic acids
FR2758329A1 (fr) * 1997-01-16 1998-07-17 Synthelabo Derives d'imidazole-4-butane boronique, leur preparation et leur utilisation en therapeutique
US7271186B1 (en) 2002-12-09 2007-09-18 Northwestern University Nanomolar β-lactamase inhibitors
WO2010130708A1 (fr) 2009-05-12 2010-11-18 Novartis International Pharmaceutical Ltd. Inhibiteurs de béta-lactamases

Non-Patent Citations (32)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Additives", 2007, GOWER PUBLISHING COMPANY
"Handbook of Pharmaceutical Excipients", 2009, THE PHARMACEUTICAL PRESS AND THE AMERICAN PHARMACEUTICAL ASSOCIATION
"Handbook of Pharmaceutical Salts, Properties, and Use", 2002, WILEY-VCR AND VRCA
"Modified-Release Drug Delivery Technology", 2008, MARCEL DEKKER, INC.
"Pharmaceutical Preformulation and Formulation", 2009, CRC PRESS
"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS
AMSELEM S ET AL., CHEM. PHYS. LIPIDS, vol. 64, 1993, pages 219 - 37
BERGE ET AL., PHARM. SCI., vol. 66, 1977, pages 1 - 19
BOREN, B. C., NARAYAN, S., RASMUSSEN, L. K., ZHANG, L., ZHAO, H., LIN, Z., JIA, G., FOKIN, V. V., J. AMER. CHEM. SOC., vol. 130, 2008, pages 8923 - 8930
BURNHAM NL, AM. J. HOSP. PHARM., vol. 51, 1994, pages 210 - 18
BUSH, K., CURR. OP. MICROBIOL., vol. 13, 2010, pages 558 - 564
CARTWRIGHT, WALEY, BIOCHEM J., vol. 221, 1984, pages 505 - 12
COUTTS, S. J., ADAMS, J., KROLIKOWSKI, D., SNOW, R. J, TETRAHEDRON LETT., vol. 35, 1994, pages 5109 - 5112
CROMPTON, I. E., CUTHBERT, B. K., LOWE, G., WALEY, S. G., BIOCHEM. J., vol. 251, 1988, pages 453 - 9
DAVIS ET AL., ENZYME ENG., vol. 4, 1978, pages 169 - 73
EXPERT REV. ANTI-INFECT THER., vol. 6, 2008, pages 39 - 49
FRIDEN PM ET AL., SCIENCE, vol. 259, 1993, pages 373 - 77
HANAKI ET AL., ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 30, 1995, pages 1120 - 1126
HEIN J. E., FOKIN, V.V., CHEM. SOC. REV., vol. 39, 2010, pages 1302 - 1315
INGLIS, S. R., WOON, E. C., THOMPSON, A. L., SCHOFIELD, C. J., J. ORG. CHEM., vol. 75, 2010, pages 468 - 471
JIN, S., ZHU, C. Y., CHENG Y. F., LI M. Y., WANG, B. H., BIORG. MED. CHEM., vol. 18, 2010, pages 1449 - 1455
MARTIN, R., BRYAN JONE, J., TETRAHEDRON LETT., vol. 36, 1995, pages 8399 - 8402
MATTESON D. S. ET AL., J. ORG. CHEM., vol. 693, 2008, pages 2258 - 2262
MATTESON ET AL., ORGANOMETALLICS, vol. 15, no. 1, 1996, pages 152
MORANDI F. ET AL., J. AMER. CHEM. SOC., vol. 125, 2003, pages 685 - 695
NESS ET AL., BIOCHEMISTRY, vol. 39, 2000, pages 5312 - 21
PAGE, BIOCHEM J., vol. 295, 1993, pages 295 - 304
PAYNE ET AL., ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 38, 1994, pages 767 - 772
SADHU, K. M., MATTESON, D. S., ORGANOMETALLICS, vol. 4, 1985, pages 1687 - 1689
TAKEDA ET AL., ANTIMICROB. AGENTS CHEMOTHER., vol. 51, 2007, pages 826 - 30
TRAUB, LEONHARD, CHEMOTHERAPY, vol. 43, 1997, pages 159 - 67
ZHU, Y., ZHU, X., WU, Y., MA, Y., LI, Y., ZHAO, X., YUAN, Y., YANG, J., YU, S., SHAO, F., J. MED CHEM., vol. 53, 2010, pages 1990 - 1999

Cited By (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9694025B2 (en) 2010-08-10 2017-07-04 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US11684629B2 (en) 2010-08-10 2023-06-27 Melinta Subsidiary Corp. Therapeutic uses of pharmaceutical compositions comprising cyclic boronic acid ester derivatives
US11090319B2 (en) 2010-08-10 2021-08-17 Melinta Subsidiary Corp. Therapeutic uses of pharmaceutical compositions comprising cyclic boronic acid ester derivatives
US10639318B2 (en) 2010-08-10 2020-05-05 Rempex Pharmaceuticals, Inc. Therapeutic uses of pharmaceutical compositions comprising cyclic boronic acid ester derivatives
US9296763B2 (en) 2010-08-10 2016-03-29 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US10183034B2 (en) 2010-08-10 2019-01-22 Rempex Pharmaceuticals, Inc. Therapeutic uses of pharmaceutical compositions comprising cyclic boronic acid ester derivatives
US10172874B2 (en) 2010-08-10 2019-01-08 Rempex Pharmaceuticals, Inc. Pharmaceutical compositions comprising cyclic boronic acid ester derivatives
US10004758B2 (en) 2010-08-10 2018-06-26 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and methods of making the same
US9012491B2 (en) 2011-08-31 2015-04-21 Rempex Pharmaceuticals, Inc. Heterocyclic boronic acid ester derivatives and therapeutic uses thereof
US9156858B2 (en) 2012-05-23 2015-10-13 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US11007206B2 (en) 2012-06-06 2021-05-18 Melinta Subsidiary Corp. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US10561675B2 (en) 2012-06-06 2020-02-18 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US10669290B2 (en) 2012-12-07 2020-06-02 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US10214547B2 (en) 2012-12-07 2019-02-26 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9828391B2 (en) 2012-12-07 2017-11-28 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US8912169B2 (en) 2012-12-07 2014-12-16 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9422314B2 (en) 2012-12-07 2016-08-23 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9642869B2 (en) 2013-01-04 2017-05-09 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9101638B2 (en) 2013-01-04 2015-08-11 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9132140B2 (en) 2013-01-04 2015-09-15 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9241947B2 (en) 2013-01-04 2016-01-26 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9771382B2 (en) 2013-01-10 2017-09-26 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9376454B2 (en) 2013-01-10 2016-06-28 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9403850B2 (en) 2013-01-10 2016-08-02 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US10125152B2 (en) 2013-01-10 2018-11-13 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US11414435B2 (en) 2013-01-10 2022-08-16 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9040504B2 (en) 2013-01-10 2015-05-26 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US10294248B2 (en) 2013-03-14 2019-05-21 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9944658B2 (en) 2013-03-14 2018-04-17 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9687497B1 (en) 2014-05-05 2017-06-27 Rempex Pharmaceuticals, Inc. Salts and polymorphs of cyclic boronic acid ester derivatives and therapeutic uses thereof
US10669292B2 (en) 2014-05-05 2020-06-02 Rempex Pharmaceuticals, Inc. Synthesis of boronate salts and uses thereof
US10385074B2 (en) 2014-05-05 2019-08-20 Rempex Pharmaceuticals, Inc. Synthesis of boronate salts and uses thereof
US9963467B2 (en) 2014-05-19 2018-05-08 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9783555B2 (en) 2014-06-11 2017-10-10 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9511142B2 (en) 2014-06-11 2016-12-06 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US10294247B2 (en) 2014-06-11 2019-05-21 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US11008346B2 (en) 2014-06-11 2021-05-18 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9802966B2 (en) 2014-06-11 2017-10-31 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US9926336B2 (en) 2014-06-11 2018-03-27 Venatorx Pharmaceuticals Beta-lactamase inhibitors
US9637504B2 (en) 2014-06-11 2017-05-02 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
JP2017526636A (ja) * 2014-07-01 2017-09-14 レンペックス・ファーマシューティカルズ・インコーポレイテッド ボロン酸誘導体およびその治療的使用
WO2016003929A1 (fr) * 2014-07-01 2016-01-07 Rempex Pharmaceuticals, Inc. Dérivés d'acide boronique et leurs utilisations thérapeutiques
US10206937B2 (en) 2014-07-01 2019-02-19 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
CN106536529A (zh) * 2014-07-01 2017-03-22 莱姆派克斯制药公司 硼酸衍生物及其治疗用途
US10662205B2 (en) 2014-11-18 2020-05-26 Qpex Biopharma, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US10364257B2 (en) 2014-12-19 2019-07-30 Rempex Pharmaceuticals, Inc. Apparatus and continuous flow process for production of boronic acid derivatives
US10618918B2 (en) 2015-03-17 2020-04-14 Qpex Biopharma, Inc. Substituted boronic acids as antimicrobials
US20170065626A1 (en) * 2015-09-04 2017-03-09 Case Western Reserve University Compositions and methods of treating of bacterial infections with beta-lactamase inhibitors
US20180256614A1 (en) * 2015-09-04 2018-09-13 Case Western Reserve University Compositions and methods of treating of bacterial infections with beta-lactamase inhibitors
US10335425B2 (en) 2015-09-04 2019-07-02 Case Western Reserve University Compositions and methods of treating of bacterial infections with β-lactamase inhibitors
US9949995B2 (en) * 2015-09-04 2018-04-24 Case Western Reserve University Compositions and methods of treating of bacterial infections with β-lactamase inhibitors
US11046716B2 (en) 2015-09-11 2021-06-29 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US10399996B2 (en) 2015-09-11 2019-09-03 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US10464952B2 (en) 2015-12-10 2019-11-05 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US10730832B2 (en) 2016-06-21 2020-08-04 Orion Ophthalmology LLC Aliphatic prolinamide derivatives
US10570159B2 (en) 2016-06-30 2020-02-25 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
US10294249B2 (en) 2016-06-30 2019-05-21 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
US11180512B2 (en) 2016-06-30 2021-11-23 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
US10889600B2 (en) 2016-08-04 2021-01-12 VenatoRx Pharmaceuticals, Inc. Boron-containing compounds
US11560392B2 (en) 2016-08-04 2023-01-24 VenatoRx Pharmaceuticals, Inc. Boron-containing compounds
US11091505B2 (en) 2017-03-06 2021-08-17 VenatoRx Pharmaceuticals, Inc. Solid forms and combination compositions comprising a beta-lactamase inhibitor and uses thereof
US11820784B2 (en) 2017-03-06 2023-11-21 VenatoRx Pharmaceuticals, Inc. Solid forms and combination compositions comprising a beta-lactamase inhibitor and uses thereof
US11332485B2 (en) 2017-05-26 2022-05-17 VenatoRx Pharmaceuticals, Inc. Penicillin-binding protein inhibitors
US11267826B2 (en) 2017-05-26 2022-03-08 VenatoRx Pharmaceuticals, Inc. Penicillin-binding protein inhibitors
US11286270B2 (en) 2017-10-11 2022-03-29 Qpex Biopharma, Inc. Boronic acid derivatives and synthesis thereof
CN110156820A (zh) * 2019-04-25 2019-08-23 四川大学 一类巯基酰胺硼酸类衍生物及其作为mbl和/或sbl抑制剂的用途
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

Similar Documents

Publication Publication Date Title
WO2013053372A1 (fr) Inhibiteurs de type acide boronique de bêta-lactamases
EP2220097A1 (fr) Inhibiteurs de bêta-lactamases
US20100120715A1 (en) Beta-lactamase inhibitors
US9132140B2 (en) Boronic acid derivatives and therapeutic uses thereof
WO2010130708A9 (fr) Inhibiteurs de béta-lactamases
US7271186B1 (en) Nanomolar β-lactamase inhibitors
TW201431866A (zh) 硼酸衍生物及其治療用途
US20110136763A1 (en) Trisubstituted boron-containing molecules
WO2018218190A1 (fr) Inhibiteurs de protéines de liaison à la pénicilline
JP2017517508A (ja) ボロン酸誘導体およびその治療的使用
CA2721060A1 (fr) Inhibiteurs d'hydrolase d'amide d'acide gras
BR112014026057B1 (pt) composto inibidor da arginase, composição farmacêutica e uso do composto
WO2013056163A1 (fr) Inhibiteurs de bêta-lactamase
US8541581B2 (en) Inhibitors of fatty acid amide hydrolase
US8802064B2 (en) Inhibitors of fatty acid amide hydrolase
TW202128718A (zh) 青黴素結合蛋白抑制劑
US20100137248A1 (en) Boron-containing compounds, uses and preparation thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11773399

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11773399

Country of ref document: EP

Kind code of ref document: A1