WO2017206948A1 - Nouveau diazabicyclo b-lactamase inhibiteurs - Google Patents

Nouveau diazabicyclo b-lactamase inhibiteurs Download PDF

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WO2017206948A1
WO2017206948A1 PCT/CN2017/087004 CN2017087004W WO2017206948A1 WO 2017206948 A1 WO2017206948 A1 WO 2017206948A1 CN 2017087004 W CN2017087004 W CN 2017087004W WO 2017206948 A1 WO2017206948 A1 WO 2017206948A1
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compound
acid
group
mmol
reaction
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PCT/CN2017/087004
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Chinese (zh)
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胡伯羽
丁照中
黄志刚
来巍
林锐彬
肖敏亮
雷鸽娟
谢金生
胡国平
黎健
陈曙辉
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南京明德新药研发股份有限公司
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • 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

Definitions

  • the present invention relates to a series of novel diazabicyclo ⁇ -lactamase inhibitors, in particular to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Beta-lactam antibiotics have been used for more than 70 years and are the main varieties of clinical treatment of various infections.
  • bacterial resistance is also rapidly increasing.
  • the situation facing physicians has become worse and worse, that is, the incidence and mortality of bacterial infections are rising rapidly in both communities and hospitals.
  • MDR multidrug-resistant strains
  • XDR extremely drug-resistant strains
  • ESKAPE includes Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and intestines. 6 pathogenic bacteria such as Enterobacterspecies. These six strains cover most MDR and XDR strains, greatly limiting the choice of treatment options for physicians.
  • bacteria can be resistant to ⁇ -lactam antibiotics. The most important thing is that bacteria can produce enzymes that hydrolyze the ⁇ -lactam ring, causing antibiotics to lose their antibacterial activity. Bacteria can also selectively alter the target of antibiotic action. For example, multi-drug resistance of methicillin-resistant Staphylococcus aureus is associated with the production of new PBP 2a , increased synthesis of PBPs, and decreased drug affinity. The ⁇ -lactamase can rapidly bind to certain enzyme-resistant ⁇ -lactam antibiotics, allowing the drug to stay in the extracellular space of the cytoplasm, failing to reach the target site to exert an antibacterial effect.
  • the outer membrane of G-bacteria is not easily permeable to certain ⁇ -lactam antibiotics, resulting in non-specific low-level resistance.
  • Bacteria can produce various types of ⁇ -lactamases, which can be classified into four categories A, B, C, and D according to their amino acid and nucleotide sequences. Class A, B, and D enzymes catalyze hydrolysis with serine as the active site, and class B enzymes cleave the ring by one or more metal atoms at its active site.
  • the first well-known high-activity beta-lactamase inhibitor is potassium clavulanate, and its combination with amoxicillin has so far been popular in the market.
  • Two other important beta-lactamase inhibitors on the market are sulbactam and tazobactam. What these three drugs have in common is that the structure has a highly active ⁇ -lactam ring, which is the active site of the inhibitor. Although the three drugs are hot in the market, their antibacterial spectrum is very narrow. They have only an effect on the A- and D-class ⁇ -lactamases, but are completely ineffective against the K-type enzymes of the C-type enzymes and the A-class.
  • the drug contains a novel diazabicyclo ring structure that has a broader spectrum of antibacterial activity than the three older generation beta-lactamase inhibitors described above.
  • a large number of new compounds of the diazabicyclo ring are disclosed in the patents of the ⁇ -lactamase inhibitors, including: WO2009133442, WO2009091856, WO2010126820, WO2012086241, WO2013030733, WO2013030735, WO2013149121, WO2013149136, WO2013180197, WO20140191268, WO2014141132, WO2014135931, WO2015063653 , WO2015110885, US20140296526.
  • two new drugs, MK-7655 and OP-0595 have entered the clinical stage.
  • MK-7655 has entered phase III clinical trial
  • OP-0595 has entered phase I clinical.
  • OP-0595 is extremely active in vitro and is owned by Roche Pharmaceuticals. Wockhardt, Inc. of India is also conducting research on diazonium heterocyclic inhibitors, in which the compound REF-1 is disclosed in the company's two patents US20150203503A1 and WO2014033560A1, which have certain biological activity. Therefore, diazabicyclic inhibitors will be a new direction in the development of ⁇ -lactamase inhibitors.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • n 1 or 2;
  • n 1 or 2;
  • i 1, 2 or 3.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the above claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of a ⁇ -lactamase inhibitor for treating a bacterial infection.
  • a base addition salt refers to a salt of a compound of the invention, a compound having a particular substituent found by the present invention and relatively free Preparation of toxic acids or bases.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted at most by two R, and each In this case, R has separate options.
  • substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price.
  • Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Figure 1 is a comparison of the efficacy of Compound 1 and the reference compound OP-0595 in a mouse thigh muscle infection model.
  • Figure 2 is a comparison of the dose-effect relationship between the compound 1-H2 and the reference compound OP-0595 in a mouse thigh muscle infection model.
  • step 1
  • step 1
  • the activated zinc powder (12.41 g, 189.87 mmol) was suspended in 150 ml of tetrahydrofuran, trimethylchlorosilane (317.31 mg, 2.92 mmol, 0.369 ml) was added at 35 ° C, and then slowly cooled at 66 ° C under nitrogen atmosphere. Ethyl bromoacetate (9.27 g, 55.5 mmol, 6.14 ml) was added dropwise. During the reaction, the suspension gradually turned into a clear orange solution. After the zinc powder was completely dissolved, it was cooled to 20 ° C and transferred to a dropping funnel.
  • reaction was quenched with 10 mL of saturated sodium hydrogen sulfate and the pH of the reaction mixture was adjusted to about 5, then ethyl acetate / petroleum ether (1:1)
  • the mixed solution was washed twice with 15 ml each time, and tetrabutylammonium hydrogen sulfate (271.33 mg, 0.8 mmol) was added to the aqueous phase and stirred at 15 ° C for 10 minutes, then extracted twice with ethyl acetate.
  • the organic phase was combined and washed once with 10 ml of brine, dried over anhydrous sodium sulfate and filtered to afford compound 4-H (260 mg, yield 90%).
  • step 1
  • reaction temperature was slowly raised to 20 ° C, stirred for 1 hour, thin layer chromatography analysis showed that the raw material 7-B consumption was complete, at this time the reaction was re-cooled to 0 ° C, slowly added 3 mol / liter of sodium hydroxide solution 9.38 ml, tight Then, hydrogen peroxide (3.19 g, 28.14 mmol, 30%) was added, then the reaction temperature was raised to 20 ° C and stirred for 2 hours. The thin layer chromatography showed that the reaction intermediate was consumed completely, and the reaction solution was poured into 10 ml of water with ethyl acetate.
  • the synergistic inhibition concentration test was established based on the Clinical Laboratory Standardization Association (CLSI) method M7, with a combined initial concentration of antibiotics of 128 ⁇ g/ml for continuous dilution, for a total of 11 serial dilutions, active ⁇ -lactam
  • CLSI Clinical Laboratory Standardization Association
  • the enzyme inhibitor test concentration was fixed at 4 ⁇ g/ml.
  • test compound is dissolved (if it is not dissolved, it can be suspended) diluted in dimethyl sulfoxide to a concentration of 12.8 mg/ml as a stock solution, and ceftazidime (CAZ) is dissolved in water and diluted to 25.6 mg/ml, erectem ( ETP) was diluted in phosphate buffered saline (PBS) to 25.6 mg/ml.
  • CAZ ceftazidime
  • ETP erectem
  • PBS phosphate buffered saline
  • test compound After diluting the test compound at a concentration of 12.8 mg/ml with DMSO to 0.8 mg/ml, 30 ⁇ L was added to one column of the mother plate. Mix the liquid in the mother board with a lance.
  • 96-U type plate as a test plate.
  • the experimental plate was incubated at 37 ° C for 20 hours.
  • the minimum inhibitory concentration of ceftazidime is the lowest concentration that can completely or significantly inhibit bacterial growth.
  • Table 1 is the specific information of the ⁇ -lactamase-producing bacterial strain used in the experiment:
  • the compound 1-H2 also showed antibacterial activity against Enterobacter cloacae, and the inhibitory concentration was below 8 ⁇ g/ml, which was equivalent to OP-0595. Therefore, the isomer 1-H2 after compound 1 resolution is superior to the reference compound OP-0595.
  • the in vitro activity of Compound 4 was also slightly better than that of reference compound OP-0595.
  • This test was designed to evaluate the advantages of the compounds in the examples compared to the inhibitory activity of OP-0595 on ⁇ -lactamase.
  • the microplate reader can give a curve of OD490 growth over time.
  • the slopes of the curves (Abs2-Abs1)/(T2-T1) were calculated by taking two data points Abs1 and Abs2 within the linear range of the curve.
  • Slope (EC) is the slope in the absence of inhibitor and Slop (S) is the slope at a certain inhibitor concentration.
  • PBS refers to phosphate buffer solution
  • BSA bovine serum albumin
  • mice Female CD-1 mice of about 7 weeks old, weighing 26-28 grams; 150 mg/kg 4 days before cyclophosphamide infection, 100 mg/kg 1 day before; the infected bacteria is Enterobacter cloacae 1143 ( AmpC).
  • Compound 1,1-H2, reference compound OP-0595 All have laboratory synthesis.
  • Each female CD-1 mouse was infected with Klebsiella pneumoniae by injecting 100 microliters of bacterial solution into the right leg muscle.
  • the infection dose was greater than 5.00E+05 CFU per mouse, and 2 hours after infection, each group of mice passed the tail vein.
  • the corresponding compound or combination of compounds is administered, and after the first treatment interval of 8 hours, a second round of treatment is given.
  • mice were euthanized 24 hours after infection, and the right leg thigh muscles were placed in a 50 ml centrifuge tube containing 10 ml of sterile physiological saline, placed on wet ice and transferred to a BSL-2 laboratory for CFU counting.
  • the muscle tissue was ground using an IKA T10 homogenizer (maximum rotation speed 20S, repeated once).
  • the homogenate was diluted in a gradient and placed on a tryptone soy agar plate.
  • the bacteria were cultured in a 37 ° C incubator. After 24 hours, the plate was removed and the plate was counted. The number of single colonies grown on each of the diluted gradient homogenates was calculated, and the amount of bacteria in the leg muscles of each mouse was calculated therefrom.
  • the compound 1 group was reduced by 0.59 log more than the reference compound OP-0595, and its efficacy was improved by 3.9 times.
  • Compound 1 was significantly more potent than the reference compound OP-0595.
  • Compound 1-H2 showed superior efficacy against the reference compound OP-0595 at different doses in the model.

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Abstract

La présente invention concerne une série de nouveaux inhibiteurs de diazabicyclo β-lactamase et spécifiquement destinée à un composé représenté par la formule (I) ou un sel pharmaceutique accepté de celui-ci.
PCT/CN2017/087004 2016-06-03 2017-06-02 Nouveau diazabicyclo b-lactamase inhibiteurs WO2017206948A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014091268A1 (fr) * 2012-12-11 2014-06-19 Naeja Pharmaceutical Inc. Nouveaux composés bicycliques et leur utilisation en tant qu'agents antibactériens et inhibiteurs de β-lactamase
US20140288051A1 (en) * 2011-12-02 2014-09-25 Naeja Pharmaceutical Inc. Bicyclic compounds and their use as antibacterial agents and beta-lactamase inhibitors
CN104768951A (zh) * 2012-08-25 2015-07-08 沃克哈特有限公司 1,6-二氮杂双环[3,2,1]辛-7-酮衍生物及其在治疗细菌感染中的用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140288051A1 (en) * 2011-12-02 2014-09-25 Naeja Pharmaceutical Inc. Bicyclic compounds and their use as antibacterial agents and beta-lactamase inhibitors
CN104768951A (zh) * 2012-08-25 2015-07-08 沃克哈特有限公司 1,6-二氮杂双环[3,2,1]辛-7-酮衍生物及其在治疗细菌感染中的用途
WO2014091268A1 (fr) * 2012-12-11 2014-06-19 Naeja Pharmaceutical Inc. Nouveaux composés bicycliques et leur utilisation en tant qu'agents antibactériens et inhibiteurs de β-lactamase

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