WO2018129008A1 - Composés et procédés pour le traitement d'infections bactériennes - Google Patents

Composés et procédés pour le traitement d'infections bactériennes Download PDF

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WO2018129008A1
WO2018129008A1 PCT/US2018/012137 US2018012137W WO2018129008A1 WO 2018129008 A1 WO2018129008 A1 WO 2018129008A1 US 2018012137 W US2018012137 W US 2018012137W WO 2018129008 A1 WO2018129008 A1 WO 2018129008A1
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alkyl
alkylnh
compound
heteroaryl
optionally substituted
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PCT/US2018/012137
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English (en)
Inventor
Thomas Francois DURAND-REVILLE
Satering GULER
Mark Sylvester
Ruben Tommasi
Camilo VELEZ-VEGA
Frank Wu
Xiaoyun Wu
Jing Zhang
Hoan Huynh
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Entasis Therapeutics Inc.
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Publication of WO2018129008A1 publication Critical patent/WO2018129008A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • 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

  • antibacterial compounds which are useful for, among other uses, the treatment of bacterial infections.
  • Such com ounds are represented by Formula I,
  • compositions comprising the compounds of Formula I.
  • the disclosed compounds are designed to act as PBP3 inhibitors and show substantial in vitro and in vivo improvement over PBP2 inhibitor counterparts. See e.g., Table 2, which shows a direct comparison between a known PBP2 inhibitor and an exemplary compound of Formula I where the amino methyl group was replaced with a dimethyl amide group. Treatment of a murine model of P.
  • FIG. 1 shows in vivo profiling for two P. aeruginosa PBP inhibitors, where panel a) is Example 6 and panel b) is a comparator compound.
  • R 1 and FT 2 are each independently (C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl;
  • R 3 and R 4 are each independently hydrogen, (C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl;
  • R 6 is -OR A or -NR A R B ;
  • R 7 is -OR C , -SR C , -NR D R E , -OCONR A R F , -OCOR G , -S(O)R H -S(O) 2 R H ,
  • the (C 1 -C 6 )alkyl represented by R is optionally substituted with one or more groups selected from NH 2 , -NHCOO(C 1 -C 6 )alkyl, -N((C 1 -C 6 )alkyl) 3 , phenyl, monocyclic heteroaryl, monocyclic heterocyclyl,
  • each R A is independently hydrogen or (C 1 -C 6 )alkyl;
  • each R D is independently hydrogen, (C 1 -C 6 )alkyl, or -COO(C 1 -C 6 )alkyl;
  • R B , R C , R E , R F , R G and R H are each independently hydrogen, (C 1 -C 6 )alkyl, phenyl, monocyclic heteroaryl, bicyclic fused heteroaryl, or monocyclic heterocyclyl, wherein:
  • -(C 1 -C 6 )alkylNH(C NH)NH 2 , COOH, -(C 1 -C 6 )alkylN((C 1 -C 6 )alkyl) 3 , -CONR A R I -SO 2 NR A R A , -COO(C 1 -C 6 )alkyl, or -(C 1 -C 6 )alkylCONR A R I ;
  • the (C 1 -C 6 )alkyl represented by R B , R C , R E , R F , R G and R H is optionally substituted with one or more groups selected from NH 2 ,
  • -(C 1 -C 6 )alkylNH(C NH)NH 2, COOH, -(C 1 -C 6 )alkylN((C 1 -C 6 )alkyl) 3 , -CONR A R I -SO 2 NR A R A , -COO(C 1 -C 6 )alkyl, and -(C 1 -C 6 )alkylCONR A R I ; and R 1 is hydrogen, (C 1 -C 6 )alkyl, or -(C 1 -C 6 )alkylNH 2 .
  • a hyphen designates the point of attachment of that group to the variable to which it is defined.
  • -(C 1 -C 6 )alkylCONR A R I means that the point of attachment for this group occurs on the (C 1 -C 6 )alkyl.
  • alkyl used alone or as part of a larger moiety, such as “alkoxy”, “haloalkyl”, and the like, means saturated straight-chain or branched monovalent
  • an alkyl group typically has 1-6 carbon atoms, i.e., (C 1 -C 6 )alkyl.
  • a "(C 1 -C 6 )alkyl” group means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement.
  • haloalkyl includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.
  • Alkoxy means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl.
  • (C 1 -C 4 )alkoxy includes methoxy, ethoxy, proproxy, and butoxy.
  • aralkoxy or “aryloxy alkyl” refers to an aromatic carbocyclic ring system having, unless otherwise specified, a total of 6 to 10 ring members.
  • aryl may be used
  • aryl ring refers to an aromatic ring system which includes, but is not limited to, phenyl (abbreviated as “Ph”), naphthyl and the like. It will be understood that when specified, optional substituents on an aryl group may be present on any substitutable position and, include, e.g., the position at which the aryl is attached.
  • heteroaryl used alone or as part of a larger moiety as in
  • heteroarylalkyl refers to a 5- to 12- membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. Nitrogen atoms in an heteraryl may be quaternized e.g., as in 1-methylpyridin- l-ium (see e.g., compounds 32, 48, and the like).
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic".
  • a heteroaryl group may be mono- or bi-cyclic.
  • Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc.
  • Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings.
  • Nonlimiting examples include indolyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl,
  • pyrrolopyridinyl pyrrolopyrimidinyl
  • pyrrolopyridinyl pyrrolopyrimidinyl
  • thienopyridinyl thienopyrimidinyl
  • indolizinyl purinyl, naphthyridinyl, and pteridinyl.
  • optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached.
  • heterocyclyl means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
  • heterocycle means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
  • heterocycle means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
  • heterocycle means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
  • heterocycle means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
  • heterocycle means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
  • monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and
  • Bi-cyclic heterocyclyl groups include, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as for example, benzodioxolyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, and the like. It will be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached.
  • Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.
  • Enantiomer means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that contain two or more
  • a hyphen ("-") at the beginning or end of a recited group designates the point at which a recited group is attached to a defined group.
  • -SO 2 -(C 1 -C3)alkyl-(C 2 -C6)cycloalkyl means that the group is attached via the sulfonyl.
  • Racemate or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity, i.e., they do not rotate the plane of polarized light.
  • Gaometric isomer means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z
  • the compounds of the herein may be prepared as individual enantiomers by either enantio-specific synthesis or resolved from an enantiomerically enriched mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an enantiomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each enantiomer of an enantiomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the enantiomers of an enantiomeric pair using an optically pure acid, amine or alcohol (followed by
  • the stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers.
  • Percent by weight pure relative to all of the other stereoisomers is the ratio of the weight of one stereoisomer over the weight of the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure.
  • Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
  • a disclosed compound is named or depicted by structure without indicating the stereochemistry and e.g. , the compound has more than one chiral center (e.g., at least two chiral centers), it is to be understood that the name or structure encompasses one stereoisomer free of other stereoisomers, mixtures of stereoisomers, or mixtures of stereoisomers in which one or more stereoisomers is enriched relative to the other stereoisomer(s).
  • the name or structure may encompass one stereoisomer free of other diastereomers, mixtures of stereoisomers, or mixtures of stereoisomers in which one or more diastereomers is enriched relative to the other diastereomer(s).
  • the compounds of the herein may be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • subject and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • companion animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, pigs, horses, sheep, goats and the like
  • laboratory animals e.g., rats, mice, guinea pigs and the like.
  • the subject is a human in need of treatment.
  • inhibitor includes a decrease in the baseline activity of a biological activity or process.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • the term "effective amount” or “therapeutically effective amount” includes an amount of the compound of Formula I that will elicit a biological or medical response of a subject, for example, the reduction or inhibition of enzyme or protein activity related to a bacterial DNA gyrase or a bacterial infection, amelioration of symptoms of a bacterial infection, or the slowing or delaying of progression of a bacterial infection.
  • the language "effective amount” includes the amount of a compound of Formula I, that when administered to a subject, is effective to at least partially alleviate, inhibit, and/or ameliorate a bacterial infection or inhibit bacterial DNA gyrase, and/or reduce or inhibit the bacterial growth, replication or bacterial load of a bacteria in a subject.
  • compositions of this disclosure refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, organic or inorganic carriers, excipients or diluents suitable for pharmaceutical applications.
  • R 1 and R 2 in Formula I are each independently (C 1 - C 6 )alkyl; and R is (C 1 -C 6 )alkyl, wherein the remaining variables are as described above for Formula I.
  • each R C in Formula I is independently phenyl, monocyclic heterocyclyl, monocyclic heteroaryl, or (C 1 -C 6 )alkyl, wherein:
  • R is hydrogen or (C 1 -C 6 )alkyl optionally substituted with one or more groups selected from NH 2 , -NHCOO(C 1 -C 6 )alkyl, -N((C 1 -C 6 )alkyl) 3 , phenyl,
  • the compound of Formula I is of the Formula Ila or Ilb:
  • the compound of Formula I is of the Formula IIla or Illb:
  • the compound of Formula I is of the Formula IVa or IVb:
  • the compound of Formula I is of the Formula Va or Vb:
  • the compound of Formula I is of the Formula VI:
  • R D in Formula I, Ila, Ilb, IIla, Illb, IVa, IVb, Va, Vb or VI is hydrogen or -COO(C 1 -C 6 )alkyl;
  • R E is -(C 1 -C 6 )alkylNH 2 or
  • R F is -(C 1 -C 6 )alkylNH 2 ;
  • Vb or VI is selected from
  • the compound of Formula I is of the Formula Vila or Vllb:
  • the compound of Formula I is of the Formula Villa or VIIIb:
  • the compound of Formula I is of the Formula IXa or IXb:
  • the compound of Formula I is of the Formula Xa or Xb:
  • R in the compound of Formula I, Vila, Vllb, Villa, Vlllb, IXa, IXb, Xa, or Xb is phenyl or a monocyclic nitrogen containing heteroaryl optionally substituted with (C 1 -C 6 )alkyl, wherein the remaining variables are as described above for Formula I or the second embodiment.
  • R in the compound of Formula I, Vila, Vllb, Villa, Vlllb, IXa, IXb, Xa, or Xb is phenyl or pyridinyl optionally substituted with (C 1 -C 6 )alkyl, wherein the remaining variables are as described above for Formula I or the second embodiment.
  • R in the compound of Formula I, Vila, Vllb, Villa, Vlllb, IXa, IXb, Xa, or Xb is hydrogen, a 5- or 6- membered monocyclic nitrogen containing heteroaryl, a 9-membered fused bicyclic nitrogen containing heteroaryl, -(C 1 - C 6 )alkylNH 2 , -(C 1 -C 6 )alkylN((C 1 -C 6 )alkyl) 3 , or (C 1 -C 6 )alkyl substituted with a 5- or 6- membered nitrogen containing heteroaryl, wherein each of said heteroaryl are optionally substituted with one or more -NH 2 , (C 1 -C 6 )alkyl, or -(C 1 -C 6 )alkylN((C 1 -C 6 )alkyl) 3 , wherein the remaining variables are as described above for Formula I or the second or eight
  • IXa, IXb, Xa, or Xb is hydrogen, pyridinyl, pyrazolyl, indazolyl, -(C 1 -C 6 )alkylNH 2 , or (C 1 - C 6 )alkyl substituted with pyridinyl or pyrazolyl, wherein each of said pyridinyl and pyrazolyl are optionally substituted with one or more -NH 2 , (C 1 -C 6 )alkyl, or -(C 1 -C 6 )alkylN((C 1 - C 6 )alkyl)3, wherein the remaining variables are as described above for Formula I or the second or eighteenth embodiment.
  • R 6 in the compound of Formula I, Vila, Vllb, Villa, Vlllb, IXa, IXb, Xa, or Xb is selected from
  • Gram-negative bacteria include, but are not limited, to Haemophilus influenzae, Acinetobacter baumannii,
  • Burkholderia spp. Citrobacter spp., Escherichia coli, Enterobacter spp., Pseudomonas aeruginosa, Klebsiella spp., Stenotrophomonas maltophila, Francisella tularensis, Yersinia spp., Salmonella spp., Shigella spp., Legionella spp. and Neisseria gonorrhoeae.
  • Atypical bacteria include, but are not limited to, Mycoplasma pneumoniae, Chlamydophila
  • the bacteria are resistant to one or more antibacterials other than the compounds of Formula I described herein.
  • the language “resistance” and “antibacterial resistance” refers to bacteria that are able to survive exposure to one or more antibacterials.
  • the compounds described herein can be used to treat bacterial infections caused by Gram-negative bacteria or resistant Gram-negative bacteria.
  • the compounds described herein can be used to treat bacterial infections caused by Pseudomonas Aeruginosa, Acinetobacter Baumannii, or Enter obacteriaceae, as well as antibacterial- resistant forms.
  • the compounds described herein can be used to treat bacterial infections caused by Pseudomonas Aeruginosa, as well as antibacterial-resistant forms.
  • resistance mechanisms in Gram- negative bacteria include, but are not limited to, extended- spectrum ⁇ -lactamase expression, metallo- ⁇ -lactamase expression, carbapenemase expression, DNA gyrase mutation, porin mutation, efflux system
  • the bacterial infection treated by the present compounds is caused by a Gram-negative bacteria.
  • the bacterial infection treated by the present compounds is caused by P. aeruginosa, A. baumannii, E. coli, or K. pneumoniae and other Enterobacteriaceae.
  • the bacterial infection treated by the present compounds is caused by P. aeruginosa.
  • the bacterial infection treated by the present compounds is caused by an antibacterial-resistant Gram-negative bacteria.
  • the bacterial infection treated by the present compounds is caused by an antibacterial-resistant strain of P. aeruginosa.
  • Bacterial infections treated by the present compounds include, but are not limited to, respiratory (e.g., pneumonia), blood stream (e.g., bacteremia), heart (e.g., endocarditis), CNS (e.g., meningitis, brain abscess), ear (e.g., otitis externa), eye (e.g., bacterial keratitis, endophthalmitis), GI tract (diarrhea, enteritis, enterocolitis), urinary tract, skin,
  • respiratory e.g., pneumonia
  • blood stream e.g., bacteremia
  • CNS e.g., meningitis, brain abscess
  • ear e.g., otitis externa
  • eye e.g., bacterial keratitis, endophthalmitis
  • GI tract diarrhea, enteritis, enterocolitis
  • the compounds described herein inhibit penicillin binding protein 3 (PBP3).
  • PBP3 penicillin binding protein 3
  • the present disclosure provides a method of inhibiting PBP3, comprising administering to a subject in need thereof one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof.
  • the compounds described herein inhibit penicillin binding protein 1 (e.g., PBPla and/or PBPlb).
  • PBPla penicillin binding protein 1
  • PBPlb penicillin binding protein 1
  • the present disclosure provides a method of inhibiting PBP1, comprising administering to a subject in need thereof one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof.
  • the compounds described herein are not specific inhibitors of penicillin binding protein 2 (PBP2).
  • compositions comprising a compound described herein; and a pharmaceutically acceptable carrier. These compositions can be used to treat one or more of the bacterial infections described above, as well as inhibit PBP3.
  • compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms, injectable preparations, solid dispersion forms, and dosage forms for topical or transdermal administration of a compound are included herein.
  • the amount of provided compounds that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient to be treated and the particular mode of administration. [0062] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a provided compound in the composition will also depend upon the particular compound in the composition.
  • Tert-butyl 3,5-dioxopiperidine-l-carboxylate can be purchased from commercial sources (for example PharmaBlock) or synthesized following the procedure described in Blake, James F. et al., WO2012118850.
  • nBuli (285.87mL, 457.38mmol) was added to an ice bath cooled solution of diisopropylamine (64.11mL, 457.38mmol) in THF (466.74mL) and stirred for 20 minutes then further cooled to -78°C and this was added (via cannula) to a solution of tert- butyl 3-(benzyloxymethyl)-l-methyl-4-oxo-5,7-dihydropyrazolo[3,4-c]pyridine-6- carboxylate (48.54g, 130.68mmol) and PMDTA (95.49mL, 457.38mmol) in THF
  • 2,2,2- trifluoroacetaldehyde (44 mL, 20.00 equiv) was then slowly added. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting oil was re-dissolved in DCM and washed with saturated solution of sodium bicarbonate. The resulting mixture was washed with brine. The mixture was dried over sodium sulfate. The solids were filtered out and the filtrate was concentrated under vacuum.
  • DIPEA 10-allyloxy-3- (benzyloxymethyl)-5-methyl-9-oxo-4,5,8, 10-tetrazatricyclo ]undeca-2(6),3-diene- 7-carboxylic acid (5.61g, 14.08mmol), dimethylamine hydrochloride (2296.32mg,
  • DIPEA (0.07mL, 0.4000mmol) was added to a solution of 10-allyloxy-7- (dimethylcarbamoyl)-5-methyl-9-oxo-4,5,8,10-tetrazatricyclo undeca-2(6),3- diene-3 -carboxylic acid (70. mg, 0.2000mmol), l-Methyl-lH-pyrazol-4-amine (38.92mg, 0.4000mmol) and HATU (83.81mg, 0.2200mmol) in DMF (lmL) and the reaction was stirred for 20min. LCMS shows reaction is complete.
  • Tubes that had the desired product mass were combined and lyophilized together to give 77mg beige solid which was purified on Sepabeads SP20SS (0-10%ACN/Water), then lyophilized to give [7- (dimethylcarbamoyl)-5-methyl-3-[(l-methylpyrazol-4-yl)carbamoyl]-9-oxo-4,5,8,10- tetrazatricyclo undeca-2(6),3-dien-10-yl] hydrogen sulfate (47mg, O. lOmmol,
  • TEA (2.07mL, 14.88mmol) was added to a mixture of Ethyl 4- hydroxybenzenecarboximidoate hydrochloride (1.5g, 7.44mmol) and Tert-butyl-N- 2(aminoethyl)carbamate (1.43g, 8.93mmol) in DMF (lOmL) and the reaction stirred at RT. After 2 hours the reaction was complete and used as is in next step assuming 100% yield. (ES, m/z): 297 [M+1] .
  • Peak A the first to elute, retention time 5.6 minutes, in the chiral preparative separation conditions described for Int-30, was pooled and solvent removed under reduced pressure to give the chiral product Int-32 (4S,8R)-5-(benzyloxy)-N,N, l-trimethyl-6-oxo- 4,5,6,8-tetrahydro- lH-4,7-methanopyrazolo[3,4-e] [l,3]diazepine-8-carboxamide (525mg, 32%) with an as a white solid.
  • the %ee was checked using the analytical SCF described for Int-30 and the chiral purity of Int-32, retention time 1.98 minutes, was >99.9%.
  • mice Female CD-I mice from Charles River Laboratories and were allowed to acclimate for 5 days prior to start of study. Animals were housed 5 per cage with free access to food and water. To induce a transcient state of neutropenia mice received two doses of cyclophosphamide on days -4 and -1 with 150 mg/kg and 100 mg/kg delivered
  • P. aeruginosa strain ARC 6347 (AmpC+, PoxB+) was prepared for infection from an overnight plate culture. A portion of the plate was resuspended in sterile saline and adjusted to an OD of 0.1 at 625 nm. The adjusted bacterial suspension was further diluted to target an infecting inoculum of 5.0xl0 5 CFU/mouse. Plate counts of the inoculum was performed to confirm inoculum concentration. Mice were infected with 100 uL of the prepared bacterial inoculum into both the left and right thigh muscles.
  • mice were dosed with either test article, positive control antibiotic (levofloxacin), or vehicle.
  • Mice receiving Example 6 and Comparator 1 or vehicle were dosed subcutaneous at 10 mL/kg for 8 doses spaced 3 hours apart.
  • Animals receiving levofloxacin were dosed with a single dose of 160 mg/kg at two hours post infection.
  • mice Three animals were dosed per group / concentration. One group of three mice were euthanized at initiation of therapy (T-Rx) and CFUs determined. All remaining mice were euthanized at 26 hours post infection. Both thighs were aseptically removed, weighed, homogenized to a uniform consistency, serially diluted and plated on bacterial growth media. The CFUs were enumerated after overnight incubation.
  • aeruginosa were measured using the BOCILLIN FL penicillin fluorescence anisotropy assay method ⁇ Anal. Biochem. 463, 15-22 (2014)).
  • the BOCILLIN FL (Thermo-Fisher Scientific, Waltham, MA) concentration was 30 nM in each case.
  • the PBP concentrations were 60 nM for P. aeruginosa PBPla and PBP3, and 300 nM for P. aeruginosa PBP2.
  • the assay buffer was 0.1 M sodium phosphate with 0.01% Triton X-100.
  • the pH was 7.0 for all the PBPs with the exception of P. aeruginosa PBP2, for which the pH was 6.2. Serial 2-fold dilutions of compounds were employed, with concentrations ranging from 328 to 0.02 ⁇ for the P. aeruginosa PBPs.
  • MIC minimal inhibitory concentration

Abstract

La présente invention concerne des composés de formule (I) ou des sels pharmaceutiquement acceptables de ceux-ci. Dans la formule, R1, R2, R3, R4 et R5 sont tels que définis dans la description. La présente invention concerne également des compositions pharmaceutiques comprenant les composés de formule I.
PCT/US2018/012137 2017-01-04 2018-01-03 Composés et procédés pour le traitement d'infections bactériennes WO2018129008A1 (fr)

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