Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • 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
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
• • 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 present invention relates to Monocarbam compounds and their use as antibacterial agents in animais, including humans.
• the invention also relates to methods of preparing compounds, intermediates useful in preparing compounds, and pharmaceutical compositions containing compounds.
• the present invention further includes methods of treating disease, e.g., bacterial infections by administering compounds or compositions to subjects in need of such treatment.
• Disease e.g., bacterial infections by administering compounds or compositions to subjects in need of such treatment.
• Monocarbams are a class of synthetic monocyclic beta-lactam antibacterial agents which have as their salient feature, a substituted sulfonytaminocarbonyt activating group at the N-1 position. The early studies in this area were conducted by workers at the Squibb institute for Medical Research, Cimarusti, C. M. & R.B.
• the present invention relates to certain compounds of formula (!), their preparation and useful intermediates, pharmaceutical compositions thereof, and methods of treating and preventing bacterial infections therewith, in many embodiments, the compounds are active and effective against organisms that are resistant to other antibiotics.
• the present invention relates to a compound of formula (!):
• R 3 is hydrogen or methyl
• R 4 is hydrogen, deuterium, or methyl optionally substituted with 1 to 3 substituents independently selected from F or Cl;
• R 5 is hydrogen, deuterium or methyl optionally substituted with 1 to 3 substituents independently selected from F or Cl;
• X is C(H), C(F), C(CI), or N.
• the compound of formula (I) has the formula ⁇ iA):
• R 4 is methyl optionally substituted with 1 to 3 s ⁇ bstituents selected from F or Cl. in another embodiment R 4 is hydrogen.
• X is C(F). In another embodiment X is C(H).
• X is C(CI). !n another embodiment X is N.
• R 2 is hydrogen.
• R 2 is methyl
• R 3 is hydrogen.
• R 3 is methyl.
• R 1 is (C 1 -C 6 )alkyl substituted with 1 to 3 halo.
• R 1 is (C 1 -C 6 )alkyl substituted with 1 to 3 hydroxy.
• R 1 is (C 1 -C 6 )alkyl substituted with 1 to 3 NH 2 .
• R 1 is (C 1 -C 6 )alkyl substituted with -C(O)NH 2 .
• R 1 is a 3-7 membered heterocycle, wherein said heterocycie contains 1 to 3 heteroatoms independently selected from O, N, or S.
• the invention is:
• the invention is:
• the invention is:
• the invention is:
• the invention is:
• the compound of formula ! has the formuia (!B):
• R 1 is selected from the group consisting of;
• the invention is a compound of formula (IB) wherein R 1 is selected from the group consisting of:
• the invention is a compound of formula (IB) wherein R 1 is selected from the group consisting of:
• the invention is a compound of formula (IB) wherein R 1 is selected from the group consisting of:
• the invention is a compound of formula (IB) wherein R 1 is selected from the group consisting of:
• the pharmaceutically acceptable salt of compounds of the invention is a potassium or sodium salt. In one embodiment, the pharmaceutically acceptable salt of compounds of the invention is a bis-potassium or bis-sodium salt. In another embodiment, the invention is a pharmaceutical composition comprising the compounds described above, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the invention is a method for the treatment of a bacterial infection in a mammal comprising administering to said mammal an amount of a compound of formula (I) or pharmaceutically acceptable salt thereof that is effective in treating a bacterial infection.
• the bacterial infection is resistant or susceptible, in another particular embodiment, the bacterial infection is MDR (multi-drug resistant).
• the bacterial infection is selected from the group consisting of respiratory tract infections, lung infection in cystic fibrosis patients, complicated urinary tract infections, bum infections, wound infections, blood infections, complicated skin and soft tissue infections, nail infections, ear infections, infections caused from medical devices, infections caused from a catheter, noscomial pneumonia, ventilator-associated pneumonia (VAP), community- acquired pneumonia (CAP), bacteremia, hot-tub rash (dermatitis), and postoperative infection in radial keratotomy surgery in humans.
• the bacterial infection is selected from the group consisting of Nosocomial pneumonia, ventilator-associated pneumonia (VAP), complicated UTI (urinary tract infection), complicated skin and skin structure, and bacteremia.
• the bacterial infection is a burn infection.
• the bacterial infection is a lung infection in cystic fibrosis patients.
• the present invention aiso relates to a method of treating infection caused by Pseudomonas aeruginosa, Escherichia coli, a Klebsiella species, or an Acinetobact ⁇ r species, comprising administering a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof to a mammalian subject in need thereof.
• the infection is caused by Pseudomonas aeruginosa.
• the present invention also relates to a method of treating infection by
• Pseudomonas aeruginosa that is resistant to doripenem, meropenem or piperacil ⁇ n comprising administering a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof to a mammalian subject in need thereof.
• the present invention also relates to a composition
• a composition comprising a compound of formula (I), or pharmaceutically acceptable salt thereof, and an additional antibacterial agent selected from the group consisting of beta- iactams, aminoglycosides, polymyxins, penicillins, and lincosamides.
• the additional antibacterial agent is a beta-lactam selected from the group consisting of cephalosporins, carbapenems, and beta-lactamase inhibitors or beta-lactam/beta-lactamase inhibitor combinations
• the additional antibacterial agent is selected from the group consisting of clindamycin, metronidazole, imipenem, meropenem, doripenem, ertapenem, cefotetan, cefepime, and cefpirome, or a third generation cephalosporin.
• the additional antibacterial agent is cefepime.
• the addition antibacterial agent is meropenem
• the compound is:
• the compound is:
• the compound is:
• the compound in another embodiment of the composition, is:
• the compound is:
• composition is one of the specific compounds shown above and the additional anti-bacterial agent is cefepime.
• the composition is one of the specific compounds shown above and the additional anti-bacterial agent is meropenem.
• the present invention also relates to a complex or chelate comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as a ligand and an iron (+3) cation, wherein the ratio of ligand to iron cation is from about 1:1 to about 3:1, respectively. In one embodiment, the ratio is about 3:1.
• the present invention includes methods of treatment of the human or non-human animai body, e.g., to combat or treat (including prevention) bacterial infections, comprising administering to subjects a useful or effective amount of a compound of the invention, including a physioiogicaily acceptable salt or solvate thereof, and including compositions.
• the compounds of the invention can also be combined with other active ingredients as desired to attain combination therapy for more than one condition or biological target.
• the compounds of the invention can be combined with other anti-infectives, or agents that increase the efficacy or other properties of the anti-infective, e.g., efflux inhibitors.
• the compounds of formula (I) are useful for treating a patient suffering from a disorder such as, e.g., a bacterial infection.
• Bacterial infections amenable to treatment by compounds of formula (I), pharmaceutical compositions, and methods of the present invention include those caused by Acinetobacter baumannii, Acinetobacter spp., Bacteroides fragilis, Citobacter diversus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae ⁇ -lactamase negative, Haemophilus influenzae ⁇ -lactamase positive, Klebsiella oxytoca, Klebsiella pneumoniae (including those encoding extended-spectrum ⁇ - lactamases (hereinafter "ESBLs”), Legionella pneumophila, Moraxella catarrhalis ⁇ -iactamase-negative, Moraxella catarrhal ⁇ -positive, Morganefla morganii, Neisseria meningitidis, Prevotelia spp.
• Acinetobacter baumannii Acinetobacter s
• the compounds of formula (I) may, in one embodiment, be used to treat a variety of hospital and community acquired infections such as respiratory tract infections (including iung infection in cystic fibrosis patients), compiicated urinary tract infections, bum infections, wound infections, blood infections, complicated skin and soft tissue infections, naii and ear infections, infections caused from medicai devices ⁇ e.g., catheter, etc.), noscomial pneumonia (including ventilator-associated pneumonia (VAP)), community-acquired pneumonia (CAP), bacteremia, "hot-tub rash” (dermatitis), and post-operative infection in radial keratotomy surgery in humans (hereinafter "the infections”).
• the infection is selected from the group consisting of noscomial pneumonia, ventilator-associated pneumonia, complicated urinary tract infections, complicated skin & skin structure infections, and bacteremia.
• the composition of the invention comprises a therapeutically effective amount of a compound of formula (i) of the invention.
• the invention also relates to compositions of the invention which comprise any combination of one or more compounds of formula (I) and at least one additional ingredient (hereinafter "the compositions of the invention").
• Non-limiting examples of the at least one additional ingredient include impurities (e.g., intermediates present in the unrefined compounds of formula (I)), active or pharmaceutical agents as discussed below (e.g., another antibacterial agent), pharmaceutically acceptable excipients, or one or more solvents (e.g., a pharmaceutically acceptable carrier as discussed herein).
• impurities e.g., intermediates present in the unrefined compounds of formula (I)
• active or pharmaceutical agents as discussed below (e.g., another antibacterial agent)
• pharmaceutically acceptable excipients e.g., another antibacterial agent
• solvents e.g., a pharmaceutically acceptable carrier as discussed herein.
• compositions of the invention that are suitable for administration to a patient in need thereof (e.g., a human) are also referred to herein as "pharmaceutical compositions of the invention.”
• Administration of the compounds of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration. In one particular embodiment, the method of administration is intravenous.
• the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
• the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
• the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient, in addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
• Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
• Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
• the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
• tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, atginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia.
• lubricating agents such as magnesium stearate, sodium iauryi sulfate and talc are often useful for tableting purposes.
• Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols.
• the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
• compositions with a specific amount of active compound are known, or wiil be apparent, to those skilled in this art. For examples, see Remington's Pharmaceutical Sciences. Mack Publishing Company, Easter, Pa., 15th Edition (1975).
• the minimum amount of the compounds of formula ( ⁇ ) to be administered is a therapeuticaiiy effective amount.
• therapeutically effective amount means the amount of compound which prevents the onset of, alleviates the symptoms of, stops the progression of, and/or eliminates a bacterial infection in a mammal, e.g., a human.
• an effective dosing schedule of the compounds of formula (I) of the invention for adults is about 50 mg to about 3000 mg of a compound of formula (I) in a single dose; in another embodiment, an effective single dose is about 100 mg to about 2000 mg. In another embodiment, an effective single dose is about 800 mg to about 1000 mg. Typicaliy the dosages are given 1 to 4 times per day. In one embodiment, the dosages are given 3 times per day. In some cases, it may be necessary to use dosages outside these limits.
• the compounds of formula (I) of the invention may be administered in combination with one or more additional medicinal or pharmaceutical agents ("the additional active agent").
• the additional active agent Such use of the compounds of formula (i) in combination with an additional active agent may be for simultaneous, separate or sequential use.
• the additional active agent is an antibacterial agent.
• the antibacterial agent is a ⁇ iactam.
• ⁇ lactams include cephalosporins (e.g., cefepime, ceftazidime, cefpirome, cefditoren pivoxil (Spectracef®), cefoperazone, ceftazidime, cefdinir, cefotaxime, cefpodoxime, cephaiothin, cefaclor or cefixime), cephamycins (e.g., cefotetan), carbapenems (e.g., imipenem, meropenem, ertapenem, doripenem), beta- ⁇ actamase inhibitors and beta- ⁇ actam/beta-lactamase inhibitor combinations such as sulbactam, clavulanic acid, tazobactam and piperacillin in combination with tazobactam (Zosyn
• the antibacterial agent is may be selected from aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin, apramycin, etc.), polymyxins (e.g., polymyxin B, colistin), fluoroquinolones (norfloxacin, ciprofloxacin, ievofloxacin (Levaquin®), moxifloxacin (Aveiox®), or enoxacin), penicillins (e.g., amoxicillin, ampiciliin, etc.), and lincosamides (e.g., clindamycin, lincomycin, etc.).
• aminoglycosides e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin,
• the additional anti-bacterial agent is selected from metronidazole, glycopeptides (e.g., vancomycin, dalbavancin, telavancin, oritivancin), oxazolidinones (e.g., iinezoiid), lipeopetides (e.g., daptomycin), and tetracyclines including gyicylcyciines (e.g., tigecyciine).
• metronidazole glycopeptides
• glycopeptides e.g., vancomycin, dalbavancin, telavancin, oritivancin
• oxazolidinones e.g., iinezoiid
• lipeopetides e.g., daptomycin
• tetracyclines including gyicylcyciines (e.g., tigecyciine).
• additional antibacterial agents can be found in Walsh and Wright, Chemical Reviews 105(2):391-394 (2005); and Bush et al., Current Opinion in Microbiology 7:466-476 (2004).
• the additional antibacterial agent is used in combination with compounds or pharmaceutically acceptable salts of the invention to lower the frequency of resistance.
• examples include cefepime, cefpirome, imipenem, meropenem, ertapenem, doripenem, suiopenem, ceftazidime, piperacillin/tazobactam, ciprofloxacin, levofloxacin, moxifloxacin, polymyxin B, and tigecyciine.
• the additional antibacterial agent may be a standard anti-anaerobe drug used in combination with compounds or pharmaceutically acceptable saits of the invention to treat intra-abdominal infections.
• examples include clindamycin, metronidazole, imipenem, meropenem, doripenem, ertapenem, cefotetan, cefepime, cefpirome, and third generation cephalosporins.
• the additional antibacterial agent may be an acceptable anti-Gram positive agent used in combination with compounds or pharmaceutically acceptable salts of the invention for empiric therapy to treat P, aeruginosa and ail Enterobateriaceae.
• examples include vancomycin, Iinezoiid, daptomycin, dalbavancin, telavancin, and orittvancin.
• the one or more additional active agents, when used, are administered prior to administration of a compound of formula (I), in another embodiment, the one or more additional active agents, when used, are administered after administration of a compound of formula (!). in another embodiment, the one or more additionai active agents, when used, are administered at about the same time as administration of a compound of formula (i).
• the additional active agent may be administered by any route useful to administer said additional active agent.
• the one or more additional active agents are present in the pharmaceutical composition of the invention.
• the invention relates to a method of treating a patient with a pharmaceutical composition of the invention further comprising one or more additional active agents.
• (C 1 -C 6 )alkyl refers to linear or branched hydrocarbons (e.g., methyl, ethyl, n-propyl, isopropyl) of 1 to 6 carbon atoms in length.
• heterocycloalkyl refers to non-aromatic cyclic groups containing one or more heteroatoms, preferably from one to four heteroatoms, each preferably selected from oxygen, sulfur and nitrogen.
• the heterocycloalkyl groups of this invention can also include ring systems substituted with one or more oxo moieties.
• non-aromatic heterocycloalkyl groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1 ,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazoiidinyl, imidazoline, imidazolidinyl, 3- azabicyclo
• heteroaryl refers to an aromatic ring containing one or more heteroatoms (preferably oxygen, sulfur and nitrogen), preferably from one to four heteroatoms.
• heteroatoms preferably oxygen, sulfur and nitrogen
• Examples of 5 to 6 membered heteroaryls are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazoiyl, thiazolyl, oxazoiyl, isothiazolyl, pyrroiyi, triazinyl, purinyi, oxadiazolyl, thiadiazolyl, furazanyi.
• heterocycle includes heteroaryl and heter ⁇ cycloalkyl rings as weli as non-aromatic heterocyclic rings containing zero or more doubie bonds.
• compounds of the invention and term “compound” in the claims embraces any pharmaceutically acceptable salts or solvates, and any amorphous or crystal forms, or tautomers, whether or not specifically recited in context.
• a recitation is open to any material or composition containing the recited compound (e.g., a composition containing a sait of a racemic mixture of compounds, tautomers, epimers, stereoisomers, impure mixtures, etc.).
• the compounds of formula (i) may exist in unsolvated and solvated forms.
• the compounds of the invention also include hydrate and solvate forms as discussed below.
• the term "solvent" as it relates to the compositions of the invention includes organic solvents (e.g., methanol, ethanol, isopropanol, ethyl acetate, methylene chloride, and tetrahydrofuran) and water.
• the one or more solvents may be present in a non-stoichiometric amount, e.g., as a trace impurity, or in sufficient excess to dissolve the compound of the invention.
• the one or more solvents may be present in a stoichiometric amount, e.g., 0.5;1, 1 :1, or 2:1 molar ratio, based on the amount of compound of the invention.
• solvate is used herein to describe a noncovalent or easily reversible combination between solvent and solute, or dispersion means and disperse phase. It will be understood that the solvate can be in the form of a solid, slurry (e.g., a suspension or dispersion), or soiution.
• solvents include ethanol, methanol, propanol, acetonitrile, dimethyl ether, diethyl ether, tetrahydrofuran, methylene chloride, and water.
• 'hydrate' is employed when said solvent is water.
• a currently accepted classification system for organic hydrates is one that defines isolated site, or channel hydrates - see Polymorphism in Pharmaceutical Solids by K. R.
• Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules.
• the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions, In such cases, non-stoichiometry will be the norm.
• the term "pharmaceutically acceptable salt(s)" includes salts of acidic or basic groups which can be present in the compounds.
• Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• the acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts.
• the compounds can form, e.g., sulfates, phosphates, citrates, acetates, tosyiates, succinates, besyiates, mesylates, lactates, and hydrochlorides.
• Basic salts can be mono or dibasic. In one preferred embodiment, the salt is a fumarate.
• treat means reversing, alleviating, inhibiting the progress of one or more symptoms of such disorder or condition.
• the term "patient” refers to a mammal such as, e.g., a human, dog, cat, horse, pig, cow, and the like, in one embodiment, the patient is a human.
• pharmaceutical composition refers to an active compound in any form suitable for effective administration to a subject, e.g., a mixture of the compound and at ieast one pharmaceutically acceptable carrier.
• the term "pharmaceutically acceptable carrier” refers to a material that can be administered to a subject together with a compound in a pharmaceutical composition.
• the carrier should not destroy the pharmacological activity of the compound and should be non-toxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
• excipient means an inert material that is combined with the compounds of formula (I) to produce a pharmaceutical composition or oral drug dosage form.
• pharmaceutically acceptable excipienf means that the excipient must be compatible with other ingredients of the composition, and not deleterious to the recipient thereof.
• the pharmaceutically acceptable excipients are chosen on the basis of the intended dosage form.
• Compounds of the present invention have asymmetric centers and therefore can exist in different enantiomeric and diastereomeric forms.
• the invention includes all optical isomers and stereoisomers, and mixtures thereof in all ratios, and to all pharmaceutical compositions and methods of treatment that can employ or contain them.
• Compounds of this invention include pharmaceutically acceptable derivatives or prodrugs thereof.
• a "pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound that, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or a metabolite or residue thereof.
• Particularly favored derivatives and prodrugs of the invention are those that increase the bioavailability of the compounds when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more effectively absorbed into the blood), enhance delivery of the parent compound to a given biological compartment, increase solubility to allow administration by injection, alter metabolism or alter rate of excretion.
• the compounds of formula (i) may exhibit polymorphism.
• Polymorphic compounds of formula (I) may be prepared by crystallization of a compound of the present invention under various conditions. For example, there may be employed various solvents (including water) or different solvent mixtures for recrystaliization; crystallization at different temperatures; various modes of cooling ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting a compound of the present invention followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning caiorimetry, powder X-ray diffraction or other such techniques.
• the present invention includes compounds wherein one or more hydrogen, carbon or other atoms are replaced by different isotopes thereof. Such compounds can be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays. These isotopicaily-labeled compounds are identical to those compounds of formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and sulfur, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 O, and 35 S, respectively.
• the compounds of formula (I) of the invention containing the aforementioned isotopes and/or other isotopes of these atoms are within the scope of this invention.
• Certain isotopically-labeled compounds of formula (f), for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiatecl, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particular ⁇ y preferred for their ease of preparation and detectability.
• Isotopically-labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and described below, by substituting a readily available isotopicaliy- ⁇ abeied reagent for a non-isotopically-labeled reagent.
• protecting group refers to a suitable chemical group that can be attached to a functional group and removed at a later stage to reveal the intact functional group. Examples of suitable protecting groups for various functional groups are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons (1991 and later editions); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.
• hydroxy protecting group includes Ac, Bz, and various hydroxy protecting groups familiar to those skilled in the art, including the groups referred to in Greene.
• the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, as described above.
• the compounds of formula (i) are depicted structurally in the Summary of the Invention an elsewhere herein for the convenience of the reader.
• the compounds of the present invention may be prepared according to the descriptions, schemes, and examples herein, which are non-limiting, in combination with the knowledge of the skilled artisan.
• the compounds of the present invention can be prepared as outlined in schemes A through C.
• Compounds of the general formula I (Scheme A), prepared as described in Yamawaki, K., et al, Bioorganic & Medicinal Chem., (2007), 15, 6716 and Yamamoto, H., et aL, Bioorganic and Medicinal Chem., (2002), 10, 1535, can be reacted with hydroxylamines of the general formula Ii (prepared as described in WO 2007/065288, published June 14, 2007) in a solvent such as methanol at ambient temperature for approximately 2 hours to form carboxyiic acids of the formula IH.
• a solvent such as methanol
• Activated esters of the formula !V can be prepared by reaction of compounds of the formula Hi with N- hydroxysuccinamide in the presence of coupling reagent such as dicyclohexyicarbodiimide or diisopropylcarbodiimide in a solvent such as dichlonomethane at ambient temperature.
• a compound of formula V prepared as described by Waulte, S.R. et al. J. Org. Chem (1986), 51, 3133; Pai ⁇ ma, C, et al., J. Org. Chem. (1997), 62, 2070; LaIl, M.S., et al., J. Org. Chem.
• Triazolones of the formuia Xl can be prepared as outlined in Scheme B. Starting from commercia ⁇ y available Kojic acid (CAS number: 501-30-4), compound VH can be prepared in five steps as described in EP 0281289, published February 19, 1988. Reaction of Vl! with phosgene or a phosgene equivalent such as carbonyldiimidazole in a solvent such as dichloromethane or tetrahydrofuran at ambient temperature produces compound VIIi. Reaction of compound VlIi with a primary amine of formula IX in a solvent such as tetrahydrofuran at elevated temperature such as between 40°C and 60°C wii! produce compounds of the general formula X.
• the coupling of compounds Vl and Xl and the final construction of the compounds of the present invention can be accomplished as outlined in Scheme C.
• the coupling of Vl and Xl to generate compounds of the general formula XII can be accomplished by first reacting compounds of the formula Xl with excess MSTFA in tetrahydrofuran at approximately 40°C for one to two hours followed by removal of the tetrahydrofuran, excess MSTFA and byproducts under vacuum.
• compounds of the formula VI can be reacted with chlorosulfonylisocyanate (CSI) in dichloromethane at 0°C for approximately 45 minutes.
• CSI chlorosulfonylisocyanate
• the adduct of the compound of formula Xl can then be re-dissolved in tetrahydrofuran and to this mixture added the adduct from reaction of the compound of formula Vl with CSI. Stirring of these two components at 0°C for approximately two hours followed by stirring at ambient temperature for up to 18 hours produces the compounds of the general formula XiI.
• this coupling reaction can be accomplished as follows: the CSI adduct prepared as described above is mixed with the compound of formula Xi, which can be silylated by reaction with excess hexamethyldisilizide (HMDS) in the presence of a catalytic amount of trimethylsilylchliride (TMS-CI) at approximately 140°C.
• HMDS hexamethyldisilizide
• TMS-CI trimethylsilylchliride
• this material can be dissolved in a solvent such as dichloromethane and mixed the CSI adduct generating the compound of formula XII.
• a solvent such as dichloromethane
• Removal of the benzyl protecting groups from compounds of the formula XII can be accomplished by reaction with between two and four atmospheres of hydrogen gas in a binary solvent system consisting of tetrahydrofuran and acetic acid at ambient temperature and in the presence of a palladium catalyst such as palladium black.
• the crude material of the present invention (XIII) can then be purified by reverse-phase chromatography using a C18 resin with a gradient mobile phase consisting of acetonitrile and water, buffered with formic acid.
• the sodium salts with the general formula XIV can then be generated from the compounds of formula XiII by treatment with sodium bicarbonate in water followed by lyophilization. If a second acidic site is present within R 6 such as a carboxylic acid, the bis-sodium salts of the formula XIV can be produced following the same procedure, but adding a second equivalent of sodium bicarbonate prior to lyophilization.
• Step 3 Preparation of 5-(4,5-bis(benzyloxy)pyridin-2-yl)-4-ethyl-2H- 1 ,2,4-triazol-3(4H)-one (C8).
• A. Preparation of 1-(3,4-bis(benzyloxy)picolinoyl)-4-ethylsemicarbazide (C7).
• Step 4 Preparation of (3S)-3-aminoazetidin-2-one (C10).
• Benzyl [(3S)-2-oxoazetidin-3-yl]carbamate (C9, 13.37 g, 60.7 mmol) was mixed with degassed ethanol (500 mL) and toluene (125 mL).
• degassed ethanol 500 mL
• toluene 125 mL
• the reaction mixture was sonicated until all the solids dissolved, then purged with nitrogen.
• Step 5 Preparation of tert-butyl 2-( ⁇ t(1Z)-1- ⁇ 2-[(1-tert- butoxycarbonyl)amino]-1 ,3-thiazol-4-yl ⁇ -2-oxo-2- ⁇ [3S-2-oxoazetidin-3 - yl]amino ⁇ ethylidene]amino ⁇ oxy)-2-methylpropanoate (C13).
• C13 tert-butyl 2-( ⁇ t(1Z)-1- ⁇ 2-[(1-tert- butoxycarbonyl)amino]-1 ,3-thiazol-4-yl ⁇ -2-oxo-2- ⁇ [3S-2-oxoazetidin-3 - yl]amino ⁇ ethylidene]amino ⁇ oxy)-2-methylpropanoate (C13).
• Step 6 Preparation of Preparation of 2-( ⁇ [(1E)-1- ⁇ 2-amino-1 ,3-thiazol- 4-yl)-2- ⁇ [(3S)-1-( ⁇ [4-ethyl-3-(5-hydroxy-4-oxo-1 ,4-dihydropyridin-2-yl)-5-oxo- 4,5-dihydro-1 H-1 ,2,4-triazol-1 -yl]sulfonyl ⁇ carbamoyl)-2-oxoazetidin-3- yl]amino ⁇ -2-oxoethylidene]amino ⁇ oxy)-2-methylpropanoic acid (1 ).
• Step 1 Preparation of 2-( ⁇ [(1Z)-1-(2-amino-1 ,3-thiazol-4-yl)-2-( ⁇ (3S)-1- [( ⁇ 4-[2-(dimethylamino)ethyl]-3-(5-hydroxy-4-oxo-1 ,4-dihydropyridin-2-yl)-5- oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ⁇ sulfonyl)carbamoyl]-2-oxoazetidin-3- yi ⁇ amino)-2-oxoethylidene]amino ⁇ oxy)-2-methylpropanoic acid (2) and diasteriomeric diol mixture (Example 10).
• NMO N-methylmorpholine-N-oxide
• Step 1 Preparation of 5-[4,5-bis(benzyloxy)pyridin-2-yl]-4-[(2R)-2,3- dihydroxypropyl]-2,4-dihydro-3/"/-1 ,2,4-triazol-3-one (C20).
• Step 2 Preparation of tert-butyl 2-( ⁇ [(1Z)-1- ⁇ 2-[ ⁇ tert- butoxycarbonyl)amino]-1 ,3-thiazol-4-yl ⁇ -2-( ⁇ (3S)-1 -[ ⁇ 4-[ ⁇ 2R)-2,3- dihydroxypropyl]-3-(5-hydroxy-4-oxo-1 ,4-dihydropyndin-2-yl)-5-oxo-4,5-dihydro- 1H-1 ,2,4-triazol-1 -yl ⁇ sulfonyl)carbamoyl]-2-oxoazetidin-3-yl ⁇ amino)-2- oxoethylidene]amino ⁇ oxy)-2-methylpropanoate (C22).
• Step 3 Preparation of 2-( ⁇ [(1Z)-1-(2-amino-1 ,3-thiazol-4-yl)-2-( ⁇ (3S)-1- [( ⁇ 4-[(2f?)-2,3-dihydroxypropy1]-3-(5-hydroxy-4-oxo-1 ,4-dihydropyridin-2-yl)-5- oxo-4,5-dihydro-1 H-1 ,2,4-triazol-1 -yl ⁇ s ⁇ ifonyl)carbamoyi]-2-oxoazetidin-3- yi ⁇ amino)-2-oxoethylidene]amino ⁇ oxy)-2-methylpropanoic acid, disodi ⁇ m salt
• Step 2 Preparation of tert-butyl 2-( ⁇ [(12)-1- ⁇ 2-[( tert- butoxycarbonyl)amino]-1 ,3-thiazol-4-yl ⁇ -2- ⁇ [(3S)-1-( ⁇ [4-(cyanomethyl)-3-(5- hydroxy-4-oxo-1 ,4-dihydropyridin-2-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1- yl]s ⁇ lfonyl ⁇ carbarnoyl ⁇ -2-oxoazetidin-3-yl]amino ⁇ -2-oxoethylidene]amino ⁇ oxy)-2- methylpropanoate (C26).
• Compound C27 was prepared according to the general procedure for the synthesis of 3 in Example 3, except that C26 was used in place of C22. Also, the crude trifiuoroacetic acid sait of compound 4 was generated by evaporation of the trifiuoroacetic acid/dichloromethane solution as opposed to using the precipitation technique employed in example 3. The crude product was dissolved in dimethyl sulfoxide to a concentration of 100 mg/mL, filtered, and purified by preparative HPLC (column: Waters Symmetry CS, 5 ⁇ m, 30 x 50 mm; Solvent A: 0.1% aqueous formic acid; Solvent B: 0.1% formic acid in acetonitrile. Gradient: 3% to 22% B).
• Example 3 except that (2S)-3-aminopropane-1 ,2-dioi was used in place of (2R)-3-aminopropane-1,2-diol.
• Compound C28 was obtained as a yeilow solid. Additional product was obtained by removing the solvent from the fi ⁇ trate in vacuo to afford a yellow solid (8.58 g), which was slurried in tetrahydrofuran (50 mL), heated to reflux and then filtered to afford a second crop of C28. The combined yield for C28 was 16.73 g, 35.88 mmol, 90%. LCMS m/z 467.2 (M+1).
• Step 2 Preparation of tert-butyl 2-( ⁇ [(12)-1- ⁇ 2-[(te/t- butoxycarbonyl)amino]-1,3-thiazol-4-yl ⁇ -2-( ⁇ (3S)-1-[( ⁇ 4-[(2S)-2,3- dfhydroxypropyl]-3-(5-hydroxy ⁇ -oxo-1,4-dihydropyridin-2-yl)-5-oxo-4,5-dfhydro- 1 H- 1 ,2,4-triazoi-i -yl ⁇ s ⁇ ifonyi)carbamoyl]-2-oxoazetidin-3-yl ⁇ amino)-2- oxoethylidenejamino ⁇ oxy)-2-methylpropanoate (C31 ).
• Step 3 Preparation of 2- ⁇ [(1Z)-1-(2-amino-1 ,3-thiazol-4-yl)-2-( ⁇ (3S)-1- [( ⁇ SJ ⁇ dihydroxypropyl)-S-fS-hydroxy ⁇ -oxo-i ⁇ -dihyclropyridin ⁇ -yl ⁇ S- oxo-4,5-dihydro-1 H-1 ,2,4-triazoi-1 -yl>sulfonyl)carbamoyi]-2-oxoazetidin-3- yl>amino)-2-oxoethylidene]amfno ⁇ oxy)-2-methylpropanotc acid, disodium salt
• Compound C32 was prepared according to the general procedure for the synthesis of 3 in Example 3, except that C31 was used in place of C22.
• the crude product was dissolved in dimethyl sulfoxide to a concentration of 100 mg/mL, filtered, and purified by preparative HPLC (column: Waters Symmetry C8, 5 ⁇ m, 30 x 50 mm; Solvent A: 0.1% aqueous formic acid; Solvent B: 0.1% formic acid in acetonitrile. Gradient: 3% to 23% B).
• the fractions that pertained to the desired product were concentrated in vacuo, keeping the water bath ⁇ 30°C, to provide awardedd.
• HPLC analysis Hewlett Packard 1100; Column: Waters Symmetry C8, 5 ⁇ M, 4.6 x 50 mm; Fiow rate 1.2 mL/min; Solvent A: 0.1% aqueous formic acid; Sumble B: 0.1% formic acid in acetonitrile; Gradient: 5% to 100% B over 6 minutes; Injection volume: 15 uL; Detection: 254 nm; Retention time: 3.46 min.
• HPLC analysis Hewlett Packard 1100; Column: Waters Symmetry C8, 5 ⁇ M, 4.6 x 50 mm; Fiow rate 1.2 mL/min; Solvent A: 0.1% aqueous formic acid; Solvent 8: 0.1% formic acid in acetonitrile; Gradient; 5% to 100% B over 6 minutes; injection volume: 15 uL; Detection: 254 nm; Retention time: 3.44 min.
• Step 2 Preparation of te/t-b ⁇ tyl 2-( ⁇ [(1Z)-1- ⁇ 2-[(tert- butoxycarbonyl)amino]-1 ,3-thtazol-4-yl ⁇ -2-( ⁇ (3S)-1 -[( ⁇ 3-(5-hydroxy-4-oxo-1 ,4- dihydropyridin-2-yl)-4-[ ⁇ 2R)-2-hydroxypropy ⁇ ]-5-oxo-4,5-dihydro-1 HA ,2,4- triazol-1-yi ⁇ suifonyl)carbamoylJ-2-oxoazetidin-3-yl ⁇ amino>2 » oxoethylidene]amino ⁇ oxy)-2-methylpropanoate (C3 ⁇ ).
• Step 3 Preparation of 2- ⁇ [(1Z)-1-(2-amino-1 ,3-thiazol-4-yl)-2- ⁇ (3S)-1- [( ⁇ 3-(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)-4-[(2/?)-2-hydroxypropyl3-5-oxo- 4,5-dihydro-1H-1 l 2 ⁇ 4-triazol-1-yl>sulfonyl)carbamoyl3-2-oxoazetidin-3-yl ⁇ amino)- 2-oxoethylidene]amino ⁇ oxy)-2-methylpropanoic acid, disodium salt (6).
• Compound C37 was prepared according to the general procedure for the synthesis of 3 in Example 3, except that C36 was used in piace of C22.
• the crude product was dissolved in dimethyl sulfoxide to a concentration of 100 mg/mL, filtered, and purified by preparative HPLC (column: Waters Symmetry C8, 5 ⁇ m, 30 x 50 mm; Solvent A: 0.1% aqueous formic acid; Solvent B: 0.1% formic acid in acetonitrile; Gradient: 6% to 26% B).
• Step 2 Preparation of tert-butyl 2-( ⁇ [(1Z)-1- ⁇ 2-[(tert- butoxycarbonyl)amino3-1 ,3-thia2 ⁇ M-yl ⁇ -2-( ⁇ (3S) » 1 -[ «3-(5-hydroxy-4-oxo-1 ,4- dihydropyridin-2-yl)-4-[(2S ⁇ -2-hydroxypropyl]-5-oxo-4 ) 5-d!hydro-1 H-1 ,2,4-triazol- 1-yl ⁇ sulfonyt)carbamoyi3-2-oxoazetidin-3-yl ⁇ amino)-2-oxoethylidenejamino>oxy)- 2-methylpropanoate (C41).
• the prepared suifamoyl chloride solution (0.1 mL, 0.207 mmol) was then transferred via syringe to the complex prepared from C42 and the mixture stirred at -40°C for 30 minutes, warmed to room temperature over 1 hour and stirred for 2 hours at room temperature.
• the mixture was quenched by the addition of methanol (0.5 mL), the sumble was removed in vacuo and the crude material purified by column chromatography (silica-gel, 5% methanoi in dichloromethane) to give 0.050 g (22%) of C43.
• compounds of the invention exhibit a targeted and effective activity against bacteria.
• Compounds of the invention can therefore be used, e.g., for treating and/or preventing a variety of diseases caused by pathogenic bacteria in human beings and animals.
• C ⁇ iture collection strain 1045-06 is resistant to several classes of known antimicrobiai agents including carbapenems, aminoglycosides and fluoroquinolones, while strains 1000-02 and 3167 are resistant to cephalosporins.
• Strain PA0200 is a derivative of laboratory strain PAO1 that lacks a functional MexAB-oprM efflux pump. The compounds listed are highly active against ail three of these screening strains demonstrating their broad activity against gram- negative bacterial pathogens.
• Table 2 vitelloid a cephalosporin antibiotic indicated to treat bacterial infections caused from Pseudomonas aeruginosa), imipenem (a carbapenem antibiotic used to treat infections caused by R aeruginosa) and Comparative Example A (example 23 in EP 0281289, published September 7, 1988).
• cefipime a cephalosporin antibiotic indicated to treat bacterial infections caused from Pseudomonas aeruginosa
• imipenem a carbapenem antibiotic used to treat infections caused by R aeruginosa
• Comparative Example A example 23 in EP 0281289, published September 7, 1988.
• Tabie 2 In vitro and in Vivo Comparison Against R aeruginosa
• Table 2 shows the results for compounds of the invention which were evaluated for efficacy in the murine respiratory tract infection model against P. aeruginosa 1091-05.
• C3H/HeN mice were immunosuppressed with cyclophosphamide given orally at 150 mg/kg and 100 mg/kg on days -4 and - 85 -
• mice were anesthetized with isoflurane (5% in oxygen) and the bacterial inoculum was given to each mouse via intranasal instiliation in a 40 ⁇ L volume (-2.8 x 10 3 cfu per mouse).
• Mice were dosed with compound administered via subcutaneous injection beginning at four hours post- challenge, and continuing for two days of BID therapy. Lethalities were followed over ten days and the 50% protective doses (PD 50 S) were determined, include interpretative comment on The known monocarbam prototype Comparative Example A (example 23b in EP 0281289, published September 7, 1988) typically has a PDso of ⁇ 100 mg/kg in this model.
• Example 4 (25.0 mg/kg), Example 6 (32.7 mg/kg), Example 5 (18.6 mg/kg), Example 3 (20.6 mg/kg), and Example 7 (15.7 mg/kg).
• PD 5O is a measure of the ability of a compound to protect mice from a lethal infection. Hence, a lower value in this study is indicative of improved efficacy. Since the 95% confidence intervals (the range that predicts where the actual value will fie with 95% confidence) calculated for the compounds Example 3, Example 6, Example 4, Example 7 and Example 5 do not overlap with the PDso value determined for Comparative Example A, it can be concluded that these compounds are significantly more efficacious relative to Comparative Example A. This result was unexpected given the similar MICs against the pathogen used (P. aeruginosa 1091-05). Importantly, performance in these pre-clinical in vivo models is predictive of outcomes of clinical efficacy against these types of infections.

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