Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
  • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present disclosure relates to orally administered combinations of amoxicillin and avibactam derivatives.
• the pharmaceutical compositions can be used to treat mycobacterial infections.
• Resistance to commonly used ⁇ -lactam anti-infectives is related to expression of ⁇ -lactamases by the targeted bacteria.
• ⁇ -Lactamase enzymes can hydrolyze the ⁇ -lactam ring of ⁇ -lactam antibiotics, thus rendering the ⁇ -lactam antibiotics ineffective against the ⁇ -lactamase-producing bacteria.
• Inhibition of ⁇ -lactamases by a suitable substrate can prevent degradation of the ⁇ -lactam antibiotic, thereby increasing the effectiveness of the administered ⁇ -lactam antibiotic and mitigating the emergence of resistance.
• Avibactam is a ⁇ -lactamase inhibitor approved for intravenous use in combination with ceftazidime, a cephalosporin antibiotic, to treat intraabdominal infections, urinary tract infections and pneumonia.
• Avibactam derivatives that provide therapeutically effective plasma concentrations of avibactam when administered orally have been developed. When co- administered with amoxicillin, the avibactam derivatives provide the opportunity to treat bacterial infections caused by bacteria producing ⁇ -lactamase enzymes with oral administration.
• Mycobacteria are naturally resistant to most ⁇ -lactams because the presence of ⁇ - lactamases and the permeability barrier of the cell wall. Story-Roller, et al., Front Microbiol. 2018 9:2273. A limited number of IV ⁇ -lactams are used for therapy of non-tuberculous mycobacteria NTM). Floto, et al., Thorax. 2016 71 :88-90. For example, cefoxitin or imipenem are used for the treatment of infections caused by M. abscessus because these antibiotics are stable to hydrolysis by mycobacterial ⁇ -lactamases.
• ⁇ -lactam antibiotics are lengthy, with a recommended initial treatment phase of up to 12 weeks and requires an intravenous (IV) infusion several times per day.
• IV intravenous
• a maintenance phase of treatment can extend to one year or longer.
• ⁇ -lactam antibiotics available to treat NTM because none of the orally available ⁇ -lactam antibiotics are sufficiently potent.
• the minimal inhibitory concentration (MIC) of NTM to amoxicillin, an IV oral antibiotic is often well above the concentrations reached at the site of the infection after oral administration, which precludes clearing the infection.
• An effective oral treatment could be used not only during the initial treatment phase for NTM infections, but also during the maintenance phase (approximately 12 months), where only oral or inhaled antibiotics are more conveniently used.
• compositions comprise: amoxicillin or a pharmaceutically acceptable salt thereof; and an avibactam derivative of Formula (1): or a pharmaceutically acceptable salt thereof, wherein, each R 1 is independently selected from C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded forms a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a substituted C 3-6 cycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;
• R 2 is selected from a single bond, C 1-6 alkanediyl, C 1-6 heteroalkanediyl, C 5-6 cycloalkanediyl, C 5-6 heterocycloalkanediyl, C 6 arenediyl, C 5-6 heteroarenediyl, substituted C 1-6 alkanediyl, substituted C 1-6 heteroalkanediyl, substituted C 5-6 cycloalkanediyl, substituted C 5-6 heterocycloalkanediyl, substituted C 6 arenediyl, and substituted C 5-6 heteroarenediyl;
• R 3 is selected from C 1-6 alkyl, -O-C(O)-R 4 , -S-C(O)-R 4 , -NH-C(O)-R 4 , -O- C(O)-O-R 4 , -S-C(O)-O-R 4 , -NH-C(O)-O-R 4 , -C(O)-O-R 4 , -C(O)-S-R 4 , -C(O)-NH- R 4 , -O-C(O)-O-R 4 , -O-C(O)-S-R 4 , -O-C(O)-NH-R 4 , -S-S-R 4 , -S-R 4 , -NH-R 4 , - CH(-NH 2 )(-R 4 ), C 5-6 heterocycloalkyl, C 5-6 heteroaryl, substituted C 5-6 cycloalkyl, substituted C 5
• R 4 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl;
• R 5 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl; and
• R 6 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl.
• oral dosage forms comprise the pharmaceutical composition according to the present invention.
• kits comprise a pharmaceutical composition according to the present invention.
• kits comprise: a first pharmaceutical composition comprising amoxicillin or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising an avibactam derivative of Formula (1): or a pharmaceutically acceptable salt thereof, wherein, each R 1 is independently selected from C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded forms a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a substituted C 3-6 cycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;
• R 2 is selected from a single bond, C 1-6 alkanediyl, C 1-6 heteroalkanediyl, C 5-6 cycloalkanediyl, C 5-6 heterocycloalkanediyl, C 6 arenediyl, C 5-6 heteroarenediyl, substituted C 1-6 alkanediyl, substituted C 1-6 heteroalkanediyl, substituted C 5-6 cycloalkanediyl, substituted C 5-6 heterocycloalkanediyl, substituted C 6 arenediyl, and substituted C 5-6 heteroarenediyl;
• R 3 is selected from C 1-6 alkyl, -O-C(O)-R 4 , -S-C(O)-R 4 , -NH-C(O)-R 4 , -O- C(O)-O-R 4 , -S-C(O)-O-R 4 , -NH-C(O)-O-R 4 , -C(O)-O-R 4 , -C(O)-S-R 4 , -C(O)-NH- R 4 , -O-C(O)-O-R 4 , -O-C(O)-S-R 4 , -O-C(O)-NH-R 4 , -S-S-R 4 , -S-R 4 , -NH-R 4 , - CH(-NH 2 )(-R 4 ), C 5-6 heterocycloalkyl, C 5-6 heteroaryl, substituted C 5-6 cycloalkyl, substituted C 5
• R 4 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl;
• R 5 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl; and R 6 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroal
• methods of treating a bacterial infection in a patient in need of such treatment comprise orally administering to the patient: a therapeutically effective amount of amoxicillin or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of an avibactam derivative of Formula (1): or a pharmaceutically acceptable salt thereof, wherein, each R 1 is independently selected from C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded forms a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a substituted C 3-6 cycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;
• R 2 is selected from a single bond, C 1-6 alkanediyl, C 1-6 heteroalkanediyl, C 5-6 cycloalkanediyl, C 5-6 heterocycloalkanediyl, C 6 arenediyl, C 5-6 heteroarenediyl, substituted C 1-6 alkanediyl, substituted C 1-6 heteroalkanediyl, substituted C 5-6 cycloalkanediyl, substituted C 5-6 heterocycloalkanediyl, substituted C 6 arenediyl, and substituted C 5-6 heteroarenediyl;
• R 3 is selected from C 1-6 alkyl, -O-C(O)-R 4 , -S-C(O)-R 4 , -NH-C(O)-R 4 , -O-C(O)-O-R 4 , -S-C(O)-O-R 4 , -N H-C (O)-O-R 4 , -C(O)-O-R 4 , -C(O)-S-R 4 , -C(O)-NH-R 4 , -O-C(O)-O-R 4 , -O-C(O)-S-R 4 , -O-C(O)-NH-R 4 , -S-S-R 4 , - S-R 4 , -NH-R 4 , -CH(-NH 2 )(-R 4 ), C 5-6 heterocycloalkyl, C 5-6 heteroaryl, substituted C 5-6 cycloalkyl, substituted C
• R 4 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl;
• R 5 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6- 12 heterocycloalkylalkyl; and
• methods of treating a bacterial infection in a patient in need of such treatment comprise orally administering to the patient a therapeutically effective amount of a pharmaceutical composition according to the present invention
• a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a moiety or substituent.
• -CONH 2 is attached through the carbon atom.
• Alkyl refers to a saturated, branched, or straight-chain, monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne.
• An alkyl group can be, for example, C 1-10 alkyl, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, or C 1-3 alkyl.
• An alkyl can be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl or iso-butyl.
• Alkoxy refers to a radical -OR where R is alkyl as defined herein. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. An alkoxy group can be C 1-6 alkoxy, C 1-5 alkoxy, C 1-4 alkoxy, C 1-3 alkoxy, ethoxy, or methoxy.
• Aryl by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
• Aryl encompasses 5- and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
• aryl groups include groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.
• An aryl group can be C 6-10 aryl, C 6-9 aryl,
• Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group.
• arylalkyl groups include benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, and 2-naphthophenylethan-1-yl. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl, or arylalkynyl is used.
• An arylalkyl group can be C 7-16 arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is C 1-6 and the aryl moiety is C 6-10
• An arylalkyl group can be C 7-16 arylalkyl, such as the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is C 1-6 and the aryl moiety is C 6-10 .
• An arylalkyl group can be C 7-9 arylalkyl, wherein the alkyl moiety can be C 1 -3 alkyl and the aryl moiety can be phenyl.
• An arylalkyl group can be C 7-16 arylalkyl, C 7-14 arylalkyl, C 7-12 arylalkyl, C 7- 10 arylalkyl, C 7-8 arylalkyl, or benzyl.
• Avibactam derivative refers to an avibactam derivative of Formula (1), a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a combination of any of the forgoing.
• An avibactam derivative of Formula (1) includes sub-genuses and specific compounds within the scope of Formula (1). When orally administered, an avibactam derivative provides avibactam in the plasma of a patient.
• “Avibactam equivalents” refers to the amount of avibactam in an avibactam derivative provided the by the present disclosure.
• Avibactam derivatives provided by the present disclosure are absorbed within the gastrointestinal tract and release avibactam in the systemic circulation.
• the avibactam derivatives comprise a promoiety that enhances absorption of avibactam from the gastrointestinal tract.
• Avibactam has a molecular weight of 265.25 Da, and the corresponding avibactam derivative will have a greater molecular weight due to the promoiety.
• the avibactam derivative ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo- 1 ,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate has a molecular weight of 393.41 Da.
• this avibactam derivative comprises 0.674 avibactam equivalents.
• 1 mg of the avibactam derivative will provide 0.674 mg avibactam in the systemic circulation of a patient.
• the avibactam equivalents provided by a particular avibactam derivative will depend, at least in part, on factors affecting the oral bioavailability of the particular avibactam derivative such as, for example, the stability of the avibactam derivative in the gastrointestinal tract, the extent of absorption into the systemic circulation, and the conversion efficiency of the avibactam derivative to avibactam in the systemic circulation.
• the percent oral bioavailability accounts for these multiple factors.
• Avibactam derivatives provided by the present disclosure can exhibit an oral bioavailability in a patient such as a human, for example, greater than 20%F, greater than 30%, greater than 40%F, greater than 50%F, or greater than 60%F.
• a 1 mg dose of the avibactam derivative ethyl 3-(((((1R,2S,5R)-2- carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate having an oral bioavailability, for example, of 25% can provide 0.25 mg avibactam in the systemic circulation of a patient.
• Bioavailability refers to the rate and amount of a drug that reaches the systemic circulation of a patient following administration of the drug or prodrug thereof to the patient and can be determined by evaluating, for example, the plasma concentration-versus-time profile for a drug.
• Parameters useful in characterizing a plasma or blood concentration-versus-time curve include the area under the curve (AUC), the time to maximum concentration (T max ), and the maximum drug concentration ( C max ), where C max is the maximum concentration of a drug in the plasma of a patient following administration of a dose of the drug or form of drug to the patient, and T max is the time to the maximum concentration (C max ) of a drug in the plasma of a patient following administration of a dose of the drug or form of drug to the patient.
• Oral bioavailability refers to the fraction of an orally administered drug that reaches systemic circulation compared to a comparable dose delivered intravenously.
• Compounds and moieties provided by the present disclosure include any specific compounds within these formulae.
• Compounds may be identified either by their chemical structure and/or chemical name.
• Compounds are named using the ChemBioDraw Professional Version 17.1.0.105 (19) (CambridgeSoft, Cambridge, MA) nomenclature/structure program. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
• the compounds described herein may comprise one or more stereogenic centers and/or double bonds and therefore may exist as stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers, diastereomers, or atropisomers.
• any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
• Enantiomeric and stereoisomeric mixtures may be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
• Compounds and moieties provided by the present disclosure include optical isomers of compounds and moieties, racemates thereof, and other mixtures thereof.
• the single enantiomers or diastereomers may be obtained by asymmetric synthesis or by resolution of the racemates.
• Resolution of the racemates may be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column with chiral stationary phases.
• compounds include (Z)- and (E)-forms (or cis- and trans-forms) of compounds with double bonds either as single geometric isomers or mixtures thereof.
• Compounds and moieties may also exist in several tautomeric forms including the enol form, the keto form, and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds may exist in multiple crystalline, co-crystalline, or amorphous forms. Compounds include pharmaceutically acceptable salts thereof, or a pharmaceutically acceptable solvates of the free acid form of any of the foregoing, as well as crystalline forms of any of the foregoing
• Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl radical.
• a cycloalkyl group can be C 3-6 cycloalkyl, C 3-5 cycloalkyl, C 5-6 cycloalkyl, cyclopropyl, cyclopentyl, or cyclohexyl.
• a cycloalkyl can be selected from, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• Cycloalkylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced with a cycloalkyl group as defined herein.
• a cycloalkylalkyl group can be C 4-30 cycloalkylalkyl, for example, the alkyl moiety of the cycloalkylalkyl group is C 1-10 and the cycloalkyl moiety of the cycloalkylalkyl moiety is C 3-20 .
• a cycloalkylalkyl group can be C 4-20 cycloalkylalkyl for example, the alkanyl, alkenyl, or alkynyl moiety of the cycloalkylalkyl group is C 1-8 and the cycloalkyl moiety of the cycloalkylalkyl group is C 3-12 .
• a cycloalkylalkyl can be C 4-9 cycloalkylalkyl, wherein the alkyl moiety of the cycloalkylalkyl group is C 1-3 alkyl, and the cycloalkyl moiety of the cycloalkylalkyl group is C 3-6 cycloalkyl.
• a cycloalkylalkyl group can be C 4-12 cycloalkylalkyl, C 4-10 cycloalkylalkyl, C 4-8 cycloalkylalkyl, and C 4-6 cycloalkylalkyl.
• a cycloalkylalkyl group can be cyclopropylmethyl (- CH 2 -cyclo-C 3 H 5 ), cyclopentylmethyl (-CH 2 -cyclo-C 5 H 9 ), or cyclohexylmethyl (-CH 2 -cyclo- C 6 H 11 ).
• “Cycloalkylheteroalkyl” by itself or as part of another substituent refers to a heteroalkyl group in which one or more of the carbon atoms (and certain associated hydrogen atoms) of an alkyl group are independently replaced with the same or different heteroatomic group or groups and in which one of the hydrogen atoms bonded to a carbon atom is replaced with a cycloalkyl group.
• the heteroatomic group in a cycloalkylheteroalkyl, can be selected from -O-, -S-, - NH-, — N (—CH 3 ) — , -SO-, and -SO 2 -, or the heteroatomic group can be selected from -O-and - NH-, or the heteroatomic group is -O- or -NH-.
• Cycloalkyloxy refers to a radical -OR where R is cycloalkyl as defined herein.
• cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.
• a cycloalkyloxy group can be C 3-6 cycloalkyloxy, C 3-5 cycloalkyloxy, C 5-6 cycloalkyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.
• “Disease” refers to a disease, disorder, condition, or symptom of any of the foregoing.
• Heteroalkoxy refers to an alkoxy group in which one or more of the carbon atoms are replaced with a heteroatom.
• a heteroalkoxy group can be, for example, C 1-6 heteroalkoxy, C 1-5 heteroalkoxy, C 1-4 heteroalkoxy, or C 1-3 heteroalkoxy.
• the heteroatomic group in a heteroalkoxy, can be selected from -O-, -S-, -NH-, -NR-, -SO 2 -, and -SO 2 -, or the heteroatomic group can be selected from -O- and -NH-, or the heteroatomic group is -O- and -NH-.
• a heteroalkoxy group can be C 1-6 heteroalkoxy, C 1-5 heteroalkoxy, C 1-4 heteroalkoxy, or C 1-3 heteroalkoxy.
• Heteroalkyl by itself or as part of another substituent refer to an alkyl group in which one or more of the carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatomic group or groups.
• Each R in a heteroatomic group can be independently selected from hydrogen and C 1-3 alkyl.
• Reference to, for example, a C 1-6 heteroalkyl means a C 1-6 alkyl group in which at least one of the carbon atoms (and certain associated hydrogen atoms) is replaced with a heteroatom.
• C 1-6 heteroalkyl includes groups having five carbon atoms and one heteroatom, groups having four carbon atoms and two heteroatoms, and so forth.
• the heteroatomic group in a heteroalkyl, can be selected from -O-, -S-, -NH-, -N(-CH 3 )-, -SO-, and — SO 2 — , or the heteroatomic group can be selected from -O- and -NH-, or the heteroatomic group can be -O- or -NH-
• a heteroalkyl group can be C 1-6 heteroalkyl, C 1-5 heteroalkyl, or C 1-4 heteroalkyl, or C 1-3 heteroalkyl.
• Heteroaryl by itself or as part of another substituent refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
• Heteroaryl encompasses multiple ring systems having at least one heteroaromatic ring fused to at least one other ring, which may be aromatic or non- aromatic.
• heteroaryl encompasses bicyclic rings in which one ring is heteroaromatic and the second ring is a heterocycloalkyl ring.
• the radical carbon may be at the aromatic ring or at the heterocycloalkyl ring.
• the heteroatoms may or may not be adjacent to one another.
• the total number of heteroatoms in the heteroaryl group is not more than two.
• the heteroatomic group can be selected from -O-, -S-, - NH-, — N (—CH 3 ) — , — S(O) — , and -SO 2 -, or the heteroatomic group can be selected from -O- and -NH-, or the heteroatomic group can be -O- or-NH-.
• a heteroaryl group can be selected from, for example, C 5-10 heteroaryl, C 5-9 heteroaryl, C 5-8 heteroaryl, C 5-7 heteroaryl, C 5-6 heteroaryl, C 5 heteroaryl, or C 6 heteroaryl.
• heteroaryl groups include groups derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadia
• a heteroaryl group can be derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, or pyrazine.
• a heteroaryl can be C 5 heteroaryl and can be selected from furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, or isoxazolyl.
• a heteroaryl can be C 6 heteroaryl, and can be selected from pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl.
• the heteroatomic group in a heteroarylalkyl, can be selected from, for example, -O-, -S-, -NH-, - N( — CH 3 ) — , -SO-, and -SO 2 -, or the heteroatomic group can be selected from -O-and -NH-, or the heteroatomic group can be -O- or -NH-.
• Heterocycloalkyl by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatom; or to a parent aromatic ring system in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatom such that the ring system violates the Hückel-rule.
• heteroatoms to replace the carbon atom(s) include N, P, O, S, and Si.
• a heterocycloalkylalkyl can be, for example, C 4-12 heterocycloalkylalkyl, C 4-10 heterocycloalkylalkyl, C 4-8 heterocycloalkylalkyl, C 4-6 heterocycloalkylalkyl, C 6-7 heterocycloalkylalkyl, or C 6 heterocycloalkylalkyl or C 7 heterocycloalkylalkyl.
• Parent aromatic ring system refers to an unsaturated cyclic or polycyclic ring system having a cyclic conjugated p (pi) electron system with 4n+2 electrons ( Hückel rule). Included within the definition of “parent aromatic ring system” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, or phenalene.
• parent aromatic ring systems include aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
• Neopentyl refers to a radical in which a methylene carbon is bonded to a carbon atom, which is bonded to three non-hydrogen substituents.
• non-hydrogen substituents include carbon, oxygen, nitrogen, and sulfur.
• Each of the three non-hydrogen substituents can be carbon.
• Two of the three non-hydrogen substituents can be carbon, and the third non- hydrogen substituent can be selected from oxygen and nitrogen.
• a neopentyl group can have the structure: where each R 1 and R can be defined as for Formula (1).
• parent heteroaromatic ring systems include fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindole, benzodioxan, benzofuran, chromane, chromene, indole, indoline, and xanthene.
• parent heteroaromatic ring systems include arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole
• Patient refers to a mammal, for example, a human.
• “Pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
• a salt can be formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
• organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
• 3-(4-hydroxybenzoyl) benzoic acid cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1 -carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.
• a salt can be formed when one or more acidic protons present in the parent compound are replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or combinations thereof; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, and N-methylglucamine.
• a pharmaceutically acceptable salt can be a hydrochloride salt.
• a pharmaceutically acceptable salt can be a sodium salt.
• a pharmaceutically acceptable salt can comprise one or more counterions, such as a bi-salt, for example, a dihydrochloride salt.
• pharmaceutically acceptable salt includes hydrates and other solvates, as well as salts in crystalline or non-crystalline form. Where a particular pharmaceutically acceptable salt is disclosed, it is understood that the particular salt such as a hydrochloride salt, is an example of a salt, and that other salts may be formed using techniques known to one of skill in the art. Additionally, one of skill in the art would be able to convert the pharmaceutically acceptable salt to the corresponding compound, free base and/or free acid, using techniques generally known in the art.
• a pharmaceutically acceptable salt can include pharmaceutically acceptable esters.
• “Pharmaceutically acceptable vehicle” refers to a pharmaceutically acceptable diluent, a pharmaceutically acceptable adjuvant, a pharmaceutically acceptable excipient, a pharmaceutically acceptable carrier, or a combination of any of the foregoing with which a compound provided by the present disclosure may be administered to a patient and which does not destroy the pharmacological activity thereof and which is non-toxic when administered in doses sufficient to provide a therapeutically effective amount of the compound.
• “Pharmaceutical composition” refers to amoxicillin or a pharmaceutically acceptable salt thereof and/or an avibactam derivative of Formula (1) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable vehicle, with which amoxicillin or a pharmaceutically acceptable salt thereof and/or an avibactam derivative of Formula (1) or a pharmaceutically acceptable salt thereof is administered to a patient.
• Preventing refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease “Preventing” or “prevention” refers to reducing symptoms of the disease by taking the compound in a preventative fashion.
• the application of a therapeutic for preventing or prevention of a disease of disorder is known as prophylaxis.
• Prodrug refers to a derivative of a drug molecule that requires a transformation within the body to release the active drug. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the parent drug. Avibactam derivatives of Formula (1) are prodrugs of avibactam.
• “Promoiety” refers to a group bonded to a drug, typically to a functional group of the drug, via bond(s) that are cleavable under specified conditions of use.
• the bond(s) between the drug and promoiety may be cleaved by enzymatic or non-enzymatic means. Under the conditions of use, for example, following administration to a patient, the bond(s) between the drug and promoiety may be cleaved to release the parent drug.
• the cleavage of the promoiety may proceed spontaneously, such as via a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature or pH.
• the agent may be endogenous to the conditions of use, such as an enzyme present in the systemic circulation of a patient to which the prodrug is administered or the acidic conditions of the stomach or the agent may be supplied exogenously.
• the promoiety can have the structure: where R 1 , R 2 , and R 3 are defined as for Formula (1).
• Single bond as in the expression “R 2 is selected from a single bond” refers to a moiety in which R 2 is a single bond (-).
• R 2 is a single bond
• -R 2 - corresponds to a single bond
• the moiety has the structure -C(R 1 ) 2 -R 3 .
• solvent molecules refers to a molecular complex of a compound with one or more solvent molecules in a stoichiometric or non-stoichiometric amount.
• solvent molecules are those commonly used in the pharmaceutical arts, which are known to be innocuous to a patient, such as water, ethanol, and the like.
• a molecular complex of a compound or moiety of a compound and a solvent can be stabilized by non-covalent intra-molecular forces such as, for example, electrostatic forces, van der Waals forces, or hydrogen bonds.
• hydrate refers to a solvate in which the one or more solvent molecules is water.
• Methods of making solvates include, for example, storage in an atmosphere containing a solvent, dosage forms that include the solvent, or routine pharmaceutical processing steps such as, for example, crystallization (i.e., from solvent or mixed solvents) vapor diffusion. Solvates may also be formed, under certain circumstances, from other crystalline solvates or hydrates upon exposure to the solvent or upon suspension material in solvent. Solvates may crystallize in more than one form resulting in solvate polymorphism.
• “Substituted” refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituent(s).
• Each substituent can be independently selected from deuterio, halogen, -NH 2 , -OH, C 1-3 alkoxy, and C 1-3 alkyl, trifluoromethoxy, and trifluoromethyl.
• Each substituent can be independently selected from, for example, deuterio, -OH, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy.
• Each substituent can be selected from, for example, deuterio, -OH, -NH 2 , C 1-3 alkyl, and C 1-3 alkoxy.
• Treating” or “treatment” of a disease refers to arresting or ameliorating a disease or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease or at least one of the clinical symptoms of a disease, reducing the development of a disease or at least one of the clinical symptoms of the disease or reducing the risk of developing a disease or at least one of the clinical symptoms of a disease.
• Treating” or “treatment” also refers to alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease such as preventing or delaying the worsening of the disease, preventing or delaying the spread of the disease, preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, providing a remission, either partial or total, of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
• Treating” or “treatment” also refers to inhibiting the disease, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, and to inhibiting at least one physical parameter or manifestation that may or may not be discernible to the patient. “Treating” or “treatment” also refers to delaying the onset of the disease or at least one or more symptoms thereof in a patient who may be exposed to or predisposed to a disease or disorder even though that patient does not yet experience or display symptoms of the disease.
• “Therapeutically effective amount” refers to the amount of a compound that, when administered to a patient for treating a disease, or at least one of the clinical symptoms of a disease, is sufficient to affect such treatment of the disease or symptom thereof.
• a “therapeutically effective amount” may vary depending, for example, on the compound, the disease and/or symptoms of the disease, severity of the disease and/or symptoms of the disease or disorder, the age, weight, and/or health of the patient to be treated, and the judgment of the prescribing physician. An appropriate amount in any given instance may be ascertained by those skilled in the art or capable of determination by routine experimentation.
• “Therapeutically effective dose” refers to a dose that provides effective treatment of a disease or disorder in a patient.
• a therapeutically effective dose may vary from compound to compound, and from patient to patient, and may depend upon factors such as the condition of the patient and the route of delivery.
• a therapeutically effective dose may be determined in accordance with routine pharmacological procedures known to those skilled in the art.
• “Therapeutically effective amount” means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to treat the disease.
• the “therapeutically effective amount” will vary depending, for example, on the compound, the disease and its severity and the age, weight, adsorption, distribution, metabolism and excretion, of the patient to be treated.
• a therapeutica!iy effective amount can comprise an amount sufficient to cause the total number of bacteria present in a patient to diminish and/or to slow the growth rate of the bacteria,
• a therapeutically effective amount can be an amount sufficient to prevent or delay recurrence of the bacterial infection.
• a therapeutically effective amount can reduce the number of bacterial cells: inhibit, retard, slow to some extent and preferably stop bacterial cell proliferation; prevent or delay occurrence and/or recurrence of the bacterial infection; and/or relieve to some extent one or more of the symptoms associated with the bacterial infection.
• “Simultaneous administration,” means that a first administration and a second administration in a combination therapy are done within a time separation of less than 30 minutes, such as less than 15 minutes, less than 10 minutes, less than 5 minutes, or less than 1 minute.
• two therapeutically active compounds can be simultaneously administered in a single dosage form or in two separate dosage forms.
• “Sequential administration” means that a first administration and a second administration are administered within a time separation, for example, of greater than 30 minutes, greater than 60 minutes or greater than 120 minutes.
• two therapeutically active compounds can be sequentially administered in two separate dosage forms.
• Vehicle refers to a diluent, excipient or carrier with which a compound is administered to a patient.
• the vehicle is pharmaceutically acceptable.
• MIC refers to the minimum inhibitory concentration of an antimicrobial agent that will inhibit the growth, such as the visible growth, of a microorganism after a certain time of incubation, for example, after overnight incubation.
• MIC 90 and MIC 50 are metrics used to assess the in vitro susceptibility of a cohort of bacterial isolates to a specific antimicrobial agents or combination of antimicrobial agents using the testing method.
• MIC 90 and MIC 50 values refer to the lowest concentration of the antibiotic at which 90% and 50% of the isolates are inhibited, respectively.
• a MIC 90 can be defined as the lowest concentration of an antibiotic at which the growth of 90% of microorganism isolates are inhibited after overnight incubation.
• a MIC 50 can be defined as the lowest concentration of an antibiotic at which the growth of 50% of microorganism isolates are inhibited after overnight, such as after a 12 hour, incubation.
• PK Pharmacokinetics
• PD Pharmacodynamics
• the PK/PD Index for an antimicrobial agent is a parameter of pharmacodynamics expressed as bacteriostasis, 1-log kill or 2-log kill, and is associated with the pharmacokinetics to constitute an exposure-response relationship (PK/PD) that is adjusted for the MIC of a given bacterial isolate.
• the most common PK/PD measures associated with efficacy are the area under the concentration-time curve (AUC) to MIC ratio (AUC:MIC), peak concentration (C max ) to MIC ratio (C max :MIC), the percentage of time that drug concentrations exceed the MIC over the dosing interval (T>MIC), and the percentage of time that drug concentrations exceed a concentration threshold (T>Cf).
• the PK/PD indices can be corrected for plasma protein binding and expressed as fAUC:MIC, fC max -MIC, fT>MIC and fT>C t .
• compositions provided by the disclosure comprise amoxicillin and an avibactam derivative that when orally administered provide a therapeutically effective amount of amoxicillin and avibactam in the plasma of a patient for treating a bacterial infection such as a mycobacterial infection.
• Methods provided by the present disclosure include methods of treating a mycobacterial infection in a patient comprising orally administering to a patient in need of such treatment a therapeutically effective amount of amoxicillin or a pharmaceutically acceptable salt thereof and an avibactam derivative or a pharmaceutically acceptable salt thereof.
• This range of MICs is similar to that used for cefoxitin or imipenem when treating mycobacterial infections and suggests that if the MICs of amoxicillin are similar, it should be possible to design an oral amoxicillin treatment regimen that in combination with oral delivery of avibactam with a prodrug can be effective in treating mycobacterial infections.
• % free concentration that is associated with efficacy is not known for mycobacterial infections and amoxicillin, one can predict that for MICs that are in the range of from 8 ⁇ g/mL to 16 ⁇ g/mL or lower, a dosing regimen of amoxicillin at 500 mg, 875 mg, or 1000 mg, administered q6h, q8h or q12h, could lead to efficacy and clear an infection. Because the MICs of amoxicillin in mycobacteria can be much higher (Dubee et al., J Antimicrob Chemother. 2015 70:1051-8), the oral delivery of avibactam should effectively increase the potency of orally administered amoxicillin. Amoxicillin is well-suited for long term therapy based on the safety of the drug.
• Amoxicillin is in the class of ⁇ -lactam antibiotics.
• Amoxicillin, (1S,4S,7S)-7-((R)-2-amino- 2-(4-hydroxyphenyl)acetamido)-3,3-dimethyl-2-thia-6-azabicyclo[3.2.0]heptane-4-carboxylic acid has the structure: ⁇ -lactams act by binding to penicillin-binding proteins that inhibit a process called transpeptidation, leading to activation of autolytic enzymes in the bacterial cell wall. This process leads to lysis of the cell wall, and thus, the destruction of the bacterial cell. This type of activity is referred to as bactericidal killing.
• Amoxicillin is used to treat infections caused by Gram-positive bacteria and Gram- negative bacteria including most Streptococus species including Listeria monocytogenes, Enterococcus, Haemophilus influenzae, some Escherichia coli, Actinomyces, Clostridial species, Salmonella, Shigella, and Corynebacteria.
• Amoxicillin is FDA approved for the treatment of genitourinary tract infections, ear, nose, and throat infections, lower respiratory tract infections, Helicobacter pylori infections, pharyngitis, tonsillitis, and skin and skin structure infections. Amoxicillin is recommended as the first-line treatment by the Infectious Disease Society of America (IDSA), for acute bacterial rhinosinusitis and as one of the treatments for community-acquired pneumonia.
• IDSA Infectious Disease Society of America
• Amoxicillin can be administered in combination with a ⁇ -lactamase inhibitor such as clavulanic acid and sulbactam.
• ⁇ -lactamase inhibitors work by binding irreversibly to the catalytic site of an organism’s penicillinase enzyme, which causes resistance to the original beta-lactam ring.
• These drugs when combined with amoxicillin, ⁇ -lactamase inhibitors can broaden spectrum amoxicillin to organisms that produce the penicillinase enzyme.
• Avibactam derivatives provided by the present disclosure are sulfonate ester prodrugs of the hoh- ⁇ -lactam ⁇ -lactamase inhibitor, avibactam ([2S,5R]-2-carbamoyl-7-oxo-1 ,6- diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate; (1R,2R,5R)-2-carbamoyl-7-oxo-1 ,6- diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (ChemDraw Professional 17.1.0.105 (19)), which has the structure:
• avibactam prodrugs a nucleophilic moiety is positioned proximate to the hydrogen sulfate group. In vivo, the nucleophilic moiety reacts to release avibactam.
• Avibactam is an inhibitor of class A, class C, and certain Class D ⁇ -lactamases and can be useful in the treatment of bacterial infections when used in combination with amoxicillin.
• Avibactam derivatives can have the structure of Formula (1): or a pharmaceutically acceptable salt thereof, wherein, each R 1 is independently selected from C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded forms a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a substituted C 3-6 cycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;
• R 2 is selected from a single bond, C 1-6 alkanediyl, C 1-6 heteroalkanediyl, C 5-6 cycloalkanediyl, C 5-6 heterocycloalkanediyl, C 6 arenediyl, C 5-6 heteroarenediyl, substituted C 1-6 alkanediyl, substituted C 1-6 heteroalkanediyl, substituted C 5-6 cycloalkanediyl, substituted C 5-6 heterocycloalkanediyl, substituted C 6 arenediyl, and substituted C 5-6 heteroarenediyl;
• R 3 is selected from C 1-6 alkyl, -O-C(O)-R 4 , -S-C(O)-R 4 , -NH-C(O)-R 4 , -O- C(O)-O-R 4 , -S-C(O)-O-R 4 , -NH-C(O)-O-R 4 , -C(O)-O-R 4 , -C(O)-S-R 4 , -C(O)-NH- R 4 , -O-C(O)-O-R 4 , -O-C(O)-S-R 4 , -O-C(O)-NH-R 4 , -S-S-R 4 , -S-R 4 , -NH-R 4 , - CH(-NH 2 )(-R 4 ), C 5-6 heterocycloalkyl, C 5-6 heteroaryl, substituted C 5-6 cycloalkyl, substituted C 5
• R 4 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl;
• R 5 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl; and
• R 6 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl.
• Compounds of Formula (1) can have the stereochemistry of Formula (1a):
• each R 1 can independently be C 1-6 alkyl.
• each R 1 can independently be methyl, ethyl, or n-propyl. In compounds of Formula (1), each R 1 can be same and is methyl, ethyl, or n-propyl.
• each R 1 is methyl.
• each R 1 together with the geminal carbon atom to which they are bonded can form a C 3-6 cycloalkyl ring or a substituted C 3-6 cycloalkyl ring.
• each R 1 together with the geminal carbon atom to which they are bonded can form a C 3-6 cycloalkyl ring.
• each R 1 together with the geminal carbon atom to which they are bonded can form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring.
• each R 1 each R 1 together with the geminal carbon atom to which they are bonded can form a C 3-6 heterocycloalkyl ring or a substituted C 3-6 heterocycloalkyl ring.
• R 2 can be selected from a single bond, C 1-2 alkanediyl, and substituted C 1-2 alkanediyl.
• R 2 can be a single bond.
• R 2 can be a single bond; and R 3 can be C 1-8 alkyl.
• R 2 can be selected from C 1-2 alkanediyl and substituted Ci-2 alkanediyl.
• R 2 can be methanediyl, ethanediyl, substituted methanediyl, or substituted ethanediyl.
• R 2 can be substituted C 1-2 alkanediyl where the substituent group can be a nucleophilic group.
• R 2 can be substituted C 1-2 alkanediyl where the substituent group can be selected from -OH, -CF 3 , -O-CF 3 , -NO 2 ,-O- C(O)-R 4 , -S-C(O)-R 4 , -NH-C(O)-R 4 , -O-C(O)-O-R 4 , -S-C(O)-O-R 4 , -NH-C(O)-O-R 4 , - C(O)-O-R 4 , -C(O)-S-R 4 , -C(O)-NH-R 4 , -O-C(O)-O-R 4 , -O-C(O)-S-R 4 , -O-C(O)-NH-R 4 , -O-C
• R 2 can be substituted C 1-2 alkanediyl where the substituent group is selected from -OH, -O-C(O)-R 4 , -S-C(O)-R 4 , -NH-C(O)-R 4 ,-C(O)-O- R 4 , -C(O)-S-R 4 , -C(O)-NH-R 4 , -S-S-R 4 , -S-R 4 , -NH-R 4 , -CH(-NH 2 )(-R 4 ), substituted C 5-6 aryl, -NHR 4 , -CH(-NH 2 )(-R 4 ); and R 4 is defined as for Formula (1), or each R 4 is selected from hydrogen and C 1-8 alkyl.
• R 2 is selected from C 5-6 cycloalkanediyl, C 5-6 heterocycloalkanediyl, C 5-6 arenediyl, and C 5-6 heterocycloalkanediyl.
• R 2 can be cyclopenta-1 ,3-diene-diyl, substituted cyclopenta-1 ,3-diene-diyl, benzene-diyl or substituted benzene-diyl.
• R 2 can be 1 ,2-benzene-diyl or substituted 1 ,2-benzene-diyl.
• R 3 can be selected from -O-C(O)-R 4 , -S-C(O)-R 4 , - NH-C(O)-R 4 , -O-C(O)-O-R 4 , -S-C(O)-O-R 4 , -NH-C(O)-O-R 4 , -C(O)-O-R 4 , -C(O)-S-R 4 , -C(O)-NH-R 4 , -O-C(O)-O-R 4 , -O-C(O)-S-R 4 , -O-C(O)-NH-R 4 , -S-S-R 4 , -S-R 4 , -NH-R 4 , -CH(-NH 2 )(-R 4 ); where R 4 is defined as for Formula (1), or each R 4 is selected from hydrogen and C 1-8 alkyl.
• R 3 can be selected from -O-C(O)-R 4 , -C(O)-O-R 4 , -S- C(O)-R 4 , -C(O)-S-R 4 , -S-S-R 4 , -NH-R 4 , and -CH(-NH 2 )(-R 4 ); where R 4 is defined as for Formula (1), or each R 4 is selected from hydrogen and C 1-8 alkyl.
• R 3 is -C(O)-O-R 4 ); where R 4 is defined as for Formula (1), or each R 4 is selected from hydrogen and C 1-8 alkyl.
• R 4 can be selected from hydrogen, C 1-3 alkyl, C 5-6 cycloalkyl, C 5-6 heterocycloalkyl, C 5-6 aryl, substituted C 1-3 alkyl, substituted C 5-6 cycloalkyl, substituted C 5-6 heterocycloalkyl, and substituted C 5-6 aryl.
• R 4 can be selected from methyl, ethyl, phenyl, and benzyl.
• R 4 can be selected from hydrogen and C 1-8 alkyl.
• R 4 can be selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 7-9 arylalkyl, C 5-7 heterocycloalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 7- 9 arylalkyl, and substituted C 5-7 heterocycloalkyl.
• R 4 can be selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 7-9 arylalkyl, and C 5-7 heterocycloalkyl.
• R 4 can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl, cyclopentyl, cyclohexyl, and 2-pyrrolidinyl.
• R 3 can be -C(O)-O-R 4 ; and R 4 can be selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 5-7 cycloalkyl, C 5-7 heterocycloalkyl, C 6 aryl, C 7-9 arylalkyl, substituted Ci_ 8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-6 cycloalkyl, substituted C 5-6 heterocycloalkyl, substituted C 6 aryl, and C 7-9 arylalkyl.
• R 3 can be -C(O)-O-R 4 ; and R 4 can be selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 7-9 arylalkyl, C 5-7 heterocycloalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 7-9 arylalkyl, and substituted C 5-7 heterocycloalkyl.
• R 3 can be -C(O)-O-R 4 ; and R 4 can be selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 7-9 arylalkyl, and C 5-7 heterocycloalkyl.
• R 3 can be selected from -O-C(O)-CH 3 , -O-C(O)-CH 2 - CH 3 , -O-C(O)-phenyl, -O-C(O)-CH 2 -phenyl, -S-C(O)-CH 3 , -S-C(O)-CH 2 -CH 3 , -S-C(O)- phenyl, -S-C(O)-CH 2 -phenyl, -NH-C(O)-CH 3 , -NH-C(O)-CH 2 -CH 3 , -NH-C(O)-phenyl, - NH-C(O)-CH 2 -phenyl, -O-C(O)-O-CH 3 , -O-C(O)-O-CH 2 -CH 3 , -O-C(O)-O-phenyl, -O- C(O)-O-CH 3 , -
• R 3 can be selected from C 5-6 cycloalkyl, C 5-6 heterocycloalkyl, C 5-6 aryl, C 5-6 heteroaryl, substituted C 5-6 cycloalkyl, substituted C 5-6 heterocycloalkyl, substituted C 5-6 aryl, and substituted C 5-6 heteroaryl, comprising at least one nucleophilic group.
• R 3 can have the structure of Formula (2a) or Formula (2b):
• R 4 can be selected from C 1-3 alkyl, C 5-6 cycloalkyl, C 5-6 heterocycloalkyl, C 5-6 aryl, substituted C 1-3 alkyl, substituted C 5-6 cycloalkyl, substituted C 5-6 heterocycloalkyl, and substituted C 5-6 aryl.
• R 2 can be a bond;
• the promoiety -CH 2 -C(R 1 ) 2 -R 3 -R 4 can have any of the following structures, where R 3 can be C 1-6 alkyl, such as C 1-4 alkyl, such as methyl or ethyl:
• R 2 can be a single bond;
• R 3 can be C 1-3 alkyl; and each R 1 together with the carbon atom to which they are bonded can form a C 4-6 heterocycloalkyl ring or a substituted C 4-6 heterocycloalkyl ring.
• R 2 can be a single bond;
• R 2 can be a single bond;
• R 3 can be C 1-3 alkyl; and each R 1 together with the carbon atom to which they are bonded can form a 1 ,2-dithiolane, 1 ,2-dithane ring, thietan-2-one ring, dihydrothiophen-2(3H)-one ring, tetrahydro-2H-thipyran-2-one ring, oxetan-2-one ring dihydrofuran-2(3H)-one ring, or tetrahydro-2H-pyran-2-one ring.
• each R 1 can be methyl
• R 2 can be selected from a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-O- C(O)-CH 2 CH 3 )-, and 1 ,2-benzene-diyl;
• R 3 can be selected from -O-C(O)-R 4 , -C(O)-O-R 4 , -S-C(O)-R 4 , -C(O)-S-R 4 , -S-S- R 4 , -NHR 4 , and -CH(-NH 2 )(-R 4 ), where R 4 can be selected from hydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and 2-pyrrolidinyl.
• each R 1 and the geminal carbon to which they are bonded can form a C 3-6 cycloalkyl ring;
• R 2 can be selected from a bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-O-C(O)- CH 2 CH 3 )-, and 1 ,2-benzene-diyl;
• R 3 can be selected from -O-C(O)-R 4 , -C(O)-O-R 4 , -S-C(O)-R 4 , -C(O)-S-R 4 , -S-S- R 4 , -NHR 4 , and -CH(-NH 2 )(-R 4 ), where R 4 can be selected from hydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and 2-pyrrolidinyl.
• R 2 can be a bond
• R 3 be C 1-3 alkyl; and each R 1 together with the carbon atom to which they are bonded can form a 1 ,2- dithiolante, 1 ,2-dithane ring, thietan-2-one ring, dihydrothiophen-2(3H)-one ring, tetra hydro-2 H- thipyran-2-one ring, oxetan-2-one ring dihydrofuran-2(3H)-one ring, ortetrahydro-2H-pyran-2- one ring.
• each R 1 can be methyl
• R 2 can be selected from a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-O- C(O)-CH 2 CH 3 )-, and 1 ,2-benzene-diyl;
• R 3 can be selected from -O-C(O)-R 4 , -C(O)-O-R 4 , -S-C(O)-R 4 , -C(O)-S-R 4 , -S-S- R 4 , -NHR 4 , and -CH(-NH 2 )(-R 4 ); wherein R 4 can be selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 7-9 arylalkyl, and C 5-7 heterocycloalkyl.
• each R 1 can be methyl
• R 2 can be selected from a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-O- C(O)-CH 2 CH 3 )-, and 1 ,2-benzene-diyl; and R 3 can be-C(O)-O-R 4 ; wherein R 4 can be selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 7-9 arylalkyl, and C 5-7 heterocycloalkyl.
• each R 1 can be methyl;
• R 2 can be selected from a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-O - C(O )-CH 2 CH 3 )-, and 1 ,2-benzene-diyl;
• R 3 can be selected from -O -C(O )-R 4 , -C(O )-O -R 4 , -S-C(O )-R 4 , -C(O )-S-R 4 , -S-S- R 4 , -NHR 4 , and -CH(-NH 2 )(-R 4 ); wherein R 4 can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl, cyclopentyl, cyclohexyl, and 2-pyrrolidinyl.
• each R 1 can be methyl
• R 2 can be selected from a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-O - C(O )-CH 2 CH 3 )-, and 1 ,2-benzene-diyl; and R 3 can be-C(O )-O -R 4 ; wherein R 4 can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl, cyclopentyl, cyclohexyl, and 2-pyrrolidinyl.
• each R 1 can be methyl
• R 2 can be a single bond; and R 3 can be-C(O )-O -R 4 ; wherein R 4 can be selected from C 1-10 alkyl, C 1-10 heteroalkyl, C 7-10 alkylarene, and C 5-10 heterocycloalkylalkyl.
• each R 1 can be methyl
• R 2 can be a single bond
• R 3 can be-C(O )-O -R 4 , wherein R 4 can be selected from C 1-10 alkyl, C 1-10 heteroalkyl, C 7- 10 alkylarene, and C 5-10 heterocycloalkylalkyl; and each of R 5 , R 6 , and R 7 can be hydrogen.
• the compound can be selected from:
• the compound can be selected from: ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (3); benzyl 3-((((1R,2S,5R)-2-carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (4); methyl 3-((((1R,2S,5R)-2-carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (10); iso
• the compound can be selected from: ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (3); benzyl 3-((((1R,2S,5R)-2-carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (4); methyl 3-((((1R,2S,5R)-2-carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (10); iso
• the compound can be selected from: hexyl 5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate (36); heptyl 5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6- yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate (37);
• each R 1 can be independently selected from C 1-3 alkyl, or each R 1 together with the geminal carbon atom to which they are bonded form a C 3-6 cycloalkyl ring, a substituted C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;
• R 2 can be a single bond
• R 3 can be -C(O)-O-R 4 ;
• R 4 can be selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 7-9 arylalkyl, C 5-7 heterocycloalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 7-9 arylalkyl, and substituted C 5-7 heterocycloalkyl.
• each R 1 can be independently selected from C 1-3 alkyl, or each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring;
• R 2 can be selected from single bond, methane-diyl, and ethane-diyl
• R 3 can be selected from -C(O)-O-R 4 and -S-C(O)-R 4 , wherein R 4 can be selected from C 1-10 alkyl, C 1-10 heteroalkyl, C 5-10 arylalkyl, C 3-6 heterocycloalkyl, and substituted C 4-10 heterocycloalkylalkyl.
• each R 1 can be independently selected from C 1-3 alkyl, or each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring;
• R 2 can be a single bond
• R 3 can be -C(O)-O-R 4 , where R 4 can be selected from C 1-10 alkyl, C 1-10 heteroalkyl, C 5 - 10 arylalkyl, C 3-6 heterocycloalkyl, and substituted C 4-10 heterocycloalkylalkyl.
• each R 1 can be independently selected from C 1-3 alkyl, or each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring;
• R 2 can be -(CH 2 ) 2 -;
• R 3 can be -C(O)-O-R 4 wherein R 4 can be selected from C 1-10 alkyl, C 1-10 heteroalkyl, C 5 - 10 arylalkyl, C 3-6 heterocycloalkyl, and substituted C 4-10 heterocycloalkylalkyl.
• each R 1 can be selected from C 1-3 alkyl, or each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring;
• R 2 can be -CH 2 -; and R 3 can be -S-C(O)-R 4 , wherein R 4 can be selected from C 1-10 alkyl, C 1-10 heteroalkyl, C 5-10 arylalkyl, C 3-6 heterocycloalkyl, substituted C 4-10 heterocycloalkylalkyl.
• each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a C 3-6 cycloalkyl ring, or a C 3-6 heterocycloalkyl ring;
• R 2 can be a single bond; and R 3 can be C 1-3 alkyl.
• each R 1 can be independently selected from C 1-3 alkyl
• each R 1 can be independently selected from C 1-3 alkyl
• R 2 can be a single bond
• each R 1 can be independently selected from C 1-3 alkyl
• R 2 can be selected from a single bond and methanediyl; and R 3 can be substituted phenyl, wherein the one or more substituents can be independently selected from -CH 2 -O-C(O)-R 4 and -O-C(O)-R 4 , wherein R 4 can be selected from C 1-10 alkyl and phenyl.
• each R 1 can be independently selected from C 1-3 alkyl
• R 2 can be selected from -C(R 8 ) 2 - and -CH 2 -C(R 8 ) 2 -, wherein each R 8 can be independently selected from C 1-3 alkyl;
• R 3 can be selected from -C(O)-O-R 4 and -O-C(O)-R 4 , wherein R 4 can be selected from C 1-10 alkyl, C 1-10 heteroalkyl, substituted C 1-10 alkyl, substituted C 1-10 heteroalkyl, and 4(yl- methyl)-5-methyl-1 ,3-dioxol-2-one.
• each R 1 together with the carbon atom to which they are bonded form a substituted C 5-6 heterocyclic ring;
• R 2 can be a single bond; and R 3 can be C 1-3 alkyl.
• a compound of Formula (1) can be a compound of sub-genus (1A), or a pharmaceutically acceptable salt thereof, wherein, each R 1 can be independently selected from C 1-3 alkyl, or each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring;
• R 2 can be selected from single bond, methane-diyl, and ethane-diyl
• R 3 can be selected from -C(O )-O -R 4 and -S-C(O )-R 4 , wherein R 4 can be selected from C 1-10 alkyl, C 1-10 heteroalkyl, C 5-10 arylalkyl, C 3-6 heterocycloalkyl, and substituted C 4-10 heterocycloalkylalkyl.
• each R 1 can be independently selected from C 1-3 alkyl.
• each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring.
• R 2 can be methane-diyl.
• R 2 can be ethane-diyl.
• R 3 can be -C(O)-O-R 4 .
• R 3 can be -S-C(O)-R 4 .
• R 4 can be C 1-10 alkyl.
• R 4 can be C 1-10 heteroalkyl.
• R 4 can be C 5-10 arylalkyl.
• R 4 can be C 3-6 heterocycloalkyl.
• R 4 can be substituted C 4-10 heterocycloalkylalkyl.
• a compound of Formula (1) can be a compound of sub-genus (1 B), or a pharmaceutically acceptable salt thereof, wherein, each R 1 can be independently selected from C 1-3 alkyl, or each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring;
• R 2 can be a single bond
• R 3 can be -C(O)-O-R 4 , where R 4 can be selected from C 1-10 alkyl, C 1-10 heteroalkyl, C 5 - 10 arylalkyl, C 3-6 heterocycloalkyl, and substituted C 4-10 heterocycloalkylalkyl.
• each R 1 can be independently selected from C 1-3 alkyl.
• each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring.
• each R 1 can be methyl, or each R 1 together with the carbon atom to which they are bonded form a cyclohexyl ring or a cyclopentyl ring.
• R 4 can be selected from methyl, ethyl, n-propyl, iso propyl, n-butyl, n-hexyl, n-heptyl, -CH 2 -CH 2 -O-CH 3 , benzyl, 3-oxetanyl, and methyl-5-methyl- 1 ,3-dioxol-2-one.
• each R 1 can be methyl, or each R 1 together with the carbon atom to which they are bonded form a cyclohexyl ring or a cyclopentyl ring;
• R 2 can be a single bond
• R 3 can be -C(O)-O-R 4 , wherein R 4 can be selected from methyl, ethyl, n-propyl, iso propyl, n-butyl, n-hexyl, n-heptyl, -CH 2 -CH 2 -O-CH 3 , -CH 2 -phenyl (benzyl), 3-oxetanyl, and methyl-5-methyl-1 ,3-dioxol-2-one.
• R 4 can be selected from methyl, ethyl, n-propyl, iso propyl, n-butyl, n-hexyl, n-heptyl, -CH 2 -CH 2 -O-CH 3 , -CH 2 -phenyl (benzyl), 3-oxetanyl, and methyl-5-methyl-1 ,3-dioxol-2-one.
• each R 1 can be independently selected from C 1-3 alkyl.
• each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring.
• each R 1 can be methyl
• R 2 can be -(CH 2 ) 2 -;
• R 3 can be -C(O)-O-R 4 wherein R 4 can be selected from n-hexyl and n-heptyl.
• a compound of Formula (1) can be a compound of sub-genus (1 D), or a pharmaceutically acceptable salt thereof, wherein, each R 1 can be selected from C 1-3 alkyl, or each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring;
• R 2 can be -CH 2 -; and R 3 can be -S-C(O)-R 4 , wherein R 4 can be selected from C 1-10 alkyl, C 1-10 heteroalkyl, C 5-10 arylalkyl, C 3-6 heterocycloalkyl, and substituted C 4-10 heterocycloalkylalkyl.
• each R 1 can be independently selected from C 1-3 alkyl. In compounds of subgenus (1 D), each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring.
• each R 1 can be methyl
• R 2 can be -CH 2 -
• R 3 can be -S-C(O)-R 4 , wherein R 4 can be methyl.
• a compound of Formula (1) can be a compound of sub-genus (1 E), or a pharmaceutically acceptable salt thereof, wherein, each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a C 3-6 cycloalkyl ring, or a C 3-6 heterocycloalkyl ring;
• each R 1 together with the carbon atom to which they are bonded form a C 3-6 heterocycloalkyl ring or a C 3-6 heterocycloalkyl ring.
• R 2 can be a single bond; and R 3 can be methyl.
• a compound of Formula (1) can be a compound of sub-genus (1 F), or a pharmaceutically acceptable salt thereof, wherein, each R 1 can be independently selected from C 1-3 alkyl;
• R 2 can be selected from a single bond and methanediyl; and R 3 can be selected from -O-C(O)-R 4 and -C(O)-O-R 4 , wherein R 4 can be selected from C 1-10 alkyl and substituted phenyl.
• R 2 can be a single bond.
• R 2 can be methanediyl; and R 3 can be -O-C(O)-R 4 .
• R 3 can be -C(O)-O-R 4 .
• R 2 can be a single bond; and R 3 can be -C(O)-O-R 4 .
• R 4 can be C 1 -4 alkyl.
• R 4 can be substituted phenyl.
• R 2 can be methanediyl; R 3 can be -O-C(O)-R 4 ; and R 4 can be substituted phenyl.
• the one or more substituents can be independently selected from halogen, C 1-3 alkyl, and C 1-3 alkoxy.
• each of the substituents can be selected from C 1-3 alkyl and C 1-3 alkoxy.
• a compound of Formula (1) can be a compound of sub-genus (1 G), or a pharmaceutically acceptable salt thereof, wherein, each R 1 can be independently selected from C 1-3 alkyl;
• R 2 can be a single bond
• each R 4 can be -C(O)-O-R 8 .
• each R 4 can be -C(O)-O-R 8 , or each R 4 together with the carbon atom to which they are bonded from a substituted heterocyclohexyl ring.
• the one or more heteroatoms in the substituted heterocyclohexyl ring, can be oxygen.
• the substituted heterocycloalkyl ring can be 2,2- dimethyl-5-yl-1 ,3-dioxane-4,6-dione.
• a compound of Formula (1) can be a compound of sub-genus (1H), or a pharmaceutically acceptable salt thereof, wherein, each R 1 can be independently selected from C 1-3 alkyl;
• R 2 can be selected from a single bond and methanediyl; and R 3 can be substituted phenyl, wherein the one or more substituents can be independently selected from -CH 2 -O-C(O)-R 4 and -O-C(O)-R 4 , wherein R 4 can be selected from C 1-10 alkyl and phenyl.
• R 2 can be a single bond.
• R 2 can be 2-substituted phenyl.
• the one or more substituents can be -CH 2 -O-C(O)- R 4 .
• a compound of Formula (1) can be a compound of sub-genus (11), or a pharmaceutically acceptable salt thereof, wherein, each R 1 can be independently selected from C 1-3 alkyl;
• each R 1 can be methyl.
• each R 1 can be methyl; and each R 8 can be methyl.
• R 3 can be -C(O)-O-R 4 .
• R 3 can be -O-C(O)-R 4 .
• R 3 can have the structure of Formula (3): wherein R 9 can be selected from hydrogen, C 1-6 alkyl, C 4-6 cycloalkyl, C 1-6 heteroalkyl, C 4-6 heterocycloalkyl, substituted C 1-6 alkyl, substituted C 4-6 cycloalkyl, substituted C 1-6 heteroalkyl, and substituted C 4-6 heterocycloalkyl.
• R 9 can be selected from hydrogen and C 1-6 alkyl such as C 1-4 alkyl such as methyl or ethyl.
• An avibactam derivative can be avibactam derivative (10), methyl 3-(((((1R,2S,5R)-2- carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (10), having the structure:
• a compound of Formula (1), (1a), or (1b) can be a pharmaceutically acceptable salt of a compound of Formula (1), a hydrate thereof, or a solvate of any of the foregoing.
• Avibactam derivatives when orally administered, provide an enhanced oral bioavailability of the ⁇ -lactamase inhibitor compared to the oral bioavailability of the parent ⁇ - lactamase inhibitor.
• avibactam derivatives of Formula (1) can exhibit an avibactam oral bioavailability (%F) of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%.
• the oral bioavailability of avibactam in a human is about 7%.
• Oral dosage forms containing a fractional therapeutically effective amount of amoxicillin and/or an avibactam derivative can be intended to be administered simultaneously as multiple dosage forms that in total provide a therapeutically effective amount or can be intended to be administered over a period of time such as, for example, from 1 to 6 times daily to provide a therapeutically effective amount of amoxicillin and avibactam in the plasma of a patient.
• Amoxicillin and an avibactam derivative can be provided in separate dosage forms or can be combined in a single dosage form.
• Doses and dosing regimens of amoxicillin and an avibactam derivative can be any suitable dose and dosing regimen that achieves a therapeutic effect.
• a combination of amoxicillin and an avibactam derivative of Formula (1) can be administered, for example, from 1 to 6 times per day, from 2 to 4 times per day, or from 2 to 3 times per day.
• amoxicillin and an avibactam derivative can independently be administered 1 , 2, 3, 4, 5, or 6 times per day.
• amoxicillin and an avibactam derivative can each be administered 1 , 2, 3, 4, 5, or 6 times per day.
• amoxicillin and an avibactam derivative can be administered three times per day (TID) such as every 8 hours, q8h.
• TID three times per day
• a pediatric dose of amoxicillin can be from 20 mg/kg to 40 mg/kg TID, or up to 90 mg
• a combination of amoxicillin and an avibactam derivative can be administered for a sufficient period of time to treat the bacterial infection.
• Treatment can continue over a several days or over several weeks.
• a pharmaceutical composition can be administered once, twice, or less than 5 times.
• pharmaceutical compositions provided by the present disclosure can be administered for from 3 days to 30 days, for from 7 days to 21 days, or from 7 days to 14 days.
• Treatment can continue for prescribed number of days or to a specified endpoint.
• pharmaceutical compositions provided by the present disclosure can be administered for from 1 week to 15 weeks, from 2 weeks to 12 weeks, or from 3 weeks to 9 weeks.
• Treatment can continue for prescribed number of days or to a specified endpoint. Treatment can continue until the symptoms of the bacterial infection have been reduced and/or there are no detectable signs of the bacterial infection.
• Methods of treating a bacterial infection include multiple phase treatment regimens. For example, in an initial treatment phase a combination of amoxicillin and an avibactam derivative can be administered to a patient in a first dose and/or first regimen to treat a bacterial infection, and in a second treatment phase a combination of amoxicillin and an avibactam derivative can be administered to a patient in a second dose and/or second regimen, where the first and second dose and/or regimen can be different.
• the target plasma concentration of amoxicillin and/or avibactam during the first phase can be greater than during the second phase; the amount of amoxicillin and/or avibactam derivative administered during the first phase can be greater than during the second phase; and/or the frequency of dosing can be more frequent during the first phase compared to during the second phase.
• the second phase can be referred to as a maintenance phase.
• the first phase can last, for example, less than 4 weeks, less than 6 weeks, less than 8 weeks, or less than 12 weeks.
• the second or maintenance phase can have a duration, for example, of less than 12 months, less than 8 months, or less than 6 months.
• Methods of treating a bacterial infection can comprise administering amoxicillin and an avibactam derivative of Formula (1).
• Amoxicillin can be administered to provide, for example, greater than 40% fT>MIC, greater than 45% fT>MIC, or greater than 50% fT>MIC, in the systemic circulation of a patient.
• amoxicillin can be administered at a total daily dose of 1200 mg fractionated into 400 mg administered q8h.
• a therapeutically effective amount of avibactam can be an avibactam concentration can be, for example, greater than 40% fT>C t , greater than 50% fT>C t , or greater than 60% fT>C t .
• the mean C max was about 2,740 ng/mL
• the T max was about 1 .75 hours
• the AUC inf was about 8,505 ng ⁇ h/mL
• the T 1/2 was about 1.51 hours.
• a MIC of amoxicillin for an ⁇ -lactamase-producing Mycobacteria can be, for example, equal to or greater than 10 mg/L, greater than 20 mg/L, greater than 40 mg/L, or greater than 60 mg/L.
• the MBC of amoxicillinwhen used in combination with an avibactam derivative can be equal to or greater than the MIC of amoxicillin when used in combination with an avibactam derivative.
• the genus Actinomycetes includes A. israelii, A. meyeri, A. naeslundii, A. odontolyticus, and A. viscosus.
• the genus Nocardia includes several pathogenic species including N. asteroids, N. abscessus, N. brasiliensis, N. cyriacigeorgica, N. farcinica, N. nova, N. otitidiscaviarum, and N. veterana.
• a daily dose of 1 ,200 mg amoxicillin can be provided as three doses of 400 mg amoxicillin to be administered three times a day
• a daily dose of 1 ,200 mg of an avibactam derivative can be provided as three doses of 400 mg of the avibactam derivative to be administered three times a day.
• Other doses and other ⁇ -lactam antibiotics can be provided within a kit.
• compositions provided by the present disclosure can be administered in combination with an antibiotic such as a ⁇ -lactam antibiotic in addition to amoxicillin.
• Suitable antibiotics can include, for example, aminoglycosides such as amikacin, gentamicin, neomycin, plazomycin, streptomycin, and tobramycin; ⁇ -lactams (cephalosporins, first generation) such as cefadroxil, cefazolin, cephalexin; ⁇ -lactams (cephalosporins, second generation) such as cefaclor, cefotetan, cefoxitin, cefprozil, and cefuroxime; ⁇ -lactams (cephalosporins, third generation) such as cefotaxime, cefpodoxime, ceftazidime, ceftibuten, cefixime, and ceftriaxone; ⁇ -lactams (cephalosporins, sixth generation) such as cefepime; ⁇ - lactams (cephalosporins, fifth generation) such as ceftaroline; ⁇ -lact
• Suitable ⁇ -lactam antibiotics include penams such as ⁇ -lactamase-sensitive penams such as benzathine penicillin, benzylpenicillin, phenoxymethyl penicillin, and procain penicillin; ⁇ -lactamase-resistant penams such as cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxacillin, and temocillin; broad spectrum penams such as amoxicillin and ampicillin; extended-spectrum penams such as mecillinam; carboxypenicillins such as carbenicillin and ticarcillin, and ureidopenicillins such as azlocillin, mezlocillin, and peperacillin.
• penams such as ⁇ -lactamase-sensitive penams such as benzathine penicillin, benzylpenicillin, phenoxymethyl penicillin, and procain penicillin
• R 3 is selected from C 1-6 alkyl, -O-C(O)-R 4 , -S-C(O)-R 4 , -NH-C(O)-R 4 , -O- C(O)-O-R 4 , -S-C(O)-O-R 4 , -NH-C(O)-O-R 4 , -C(O)-O-R 4 , -C(O)-S-R 4 , -C(O)-NH- R 4 , -O-C(O)-O-R 4 , -O-C(O)-S-R 4 , -O-C(O)-NH-R 4 , -S-S-R 4 , -S-R 4 , -NH-R 4 , - CH(-NH 2 )(-R 4 ), C 5-6 heterocycloalkyl, C 5-6 heteroaryl, substituted C 5-6 cycloalkyl, substituted C 5
• R 5 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl; and
• Aspect 18 The pharmaceutical composition of any one of aspects 1 to 16, wherein the pharmaceutical composition comprises from 300 mg to 1 ,000 mg of the avibactam derivative.
• a method of treating a bacterial infection in a patient in need of such treatment comprising orally administering to the patient: a therapeutically effective amount of amoxicillin or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of an avibactam derivative of Formula (1): or a pharmaceutically acceptable salt thereof, wherein, each R 1 is independently selected from C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded forms a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a substituted C 3-6 cycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;
• R 6 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6- 12 heterocycloalkylalkyl.
• Aspect 43 The method of any one of aspects 32 to 36, wherein the bacterial infection comprises a non-tuberculous mycobacterial infection.
• Aspect 47 The method of any one of aspects 32 to 45, wherein the method comprises orally administering to the patient: a total daily dose from 600 mg to 1 ,500 mg of amoxicillin or a pharmaceutically acceptable salt thereof; and a total daily dose from 900 mg to 1 ,800 mg of the avibactam derivative or a pharmaceutically acceptable salt thereof.
• Aspect 48 The method of any one of aspects 32 to 47, wherein the method comprises administering an amount of amoxicillin or a pharmaceutically acceptable salt thereof to achieve a sustained plasma concentration of amoxicillin over MIC of greater than 8 ⁇ g/mL.
• Aspect 59 The method of any one of aspects 53 to 57, wherein the second treatment phase has a duration of less than 6 months.

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• 2020
  • 2020-12-16 US US17/123,858 patent/US20210186983A1/en not_active Abandoned
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