WO2011137758A1 - Nouveaux dérivés de kétolides, procédés d'élaboration et compositions pharmaceutiques correspondants - Google Patents

Nouveaux dérivés de kétolides, procédés d'élaboration et compositions pharmaceutiques correspondants Download PDF

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WO2011137758A1
WO2011137758A1 PCT/CN2011/073762 CN2011073762W WO2011137758A1 WO 2011137758 A1 WO2011137758 A1 WO 2011137758A1 CN 2011073762 W CN2011073762 W CN 2011073762W WO 2011137758 A1 WO2011137758 A1 WO 2011137758A1
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梁建华
安堃
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北京理工大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • 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

  • Novel ketone lactone derivative, preparation method and pharmaceutical composition thereof Novel ketone lactone derivative, preparation method and pharmaceutical composition thereof
  • the invention belongs to the field of chemical synthesis and pharmacy, and relates to a novel ketone lactone (9-0-arylpropynyl ketolide derivative) and a preparation method thereof, and the use of the compound as an anti-infective drug and a corresponding drug combination.
  • Background technique 9-0-arylpropynyl ketolide derivative
  • the fourteen-membered macrolide antibiotic-erythromycin has been widely used in clinical practice for more than 50 years, especially for those who are allergic to penicillin.
  • the second generation of erythromycin such as clarithromycin, azithromycin, roxithromycin, etc., overcomes the problem of erythromycin resistance to acid.
  • clinically isolated strains of respiratory tract bacteria are increasingly showing resistance, such as Streptococcus pneumoniae, S. pneumoniae, S. aureus, and S. pyogenes. Wait.
  • a survey conducted by the previous world from 1997 to 1999 Hoban, DJ et al., Clin. Infect. Dis. 2001, 32, S81-S93.
  • 29.5% of the strains were resistant to penicillin, 19.3% to erythromycin, and 13.2% to tetracycline. Therefore, the task of developing novel antibiotics with novel structures and resistance to drug-resistant bacteria is imminent.
  • the third-generation erythromycin derivative-ketolide has activity against multi-type resistant bacteria (Agouridas, C. et al., J. Med. Chem. 1998, 41: 4080-4100). Its structure-activity relationship indicates that the introduction of 3-carbonyl avoids the resistance-induced resistance of 3-carragedan in the original macrolide, and also proves that 3-clad sugar is not a necessary group. However, the introduction of 3-carbonyl alone could not increase the activity of resistant bacteria. The newly introduced aromatic side chain on the macrocycle produced a new binding target for the resistant bacteria, thus obtaining anti-resistant bacteria activity. Therefore, 3-carbonyl and aromatic side chains constitute important structural features of ketolactone antibiotics.
  • the binding position of the aromatic side chain on the ketolide and its side chain length directly affect the strength of its anti-resistant bacteria.
  • the aromatic side chain of Telithromycin is attached to 11,12-amino phthalate and has a length of 4 atoms (Denis A. et al., / oor. Med. Chem. Lett. 1999, 9'. 3075- 3080. );
  • the aromatic side chain of Cethromycin is attached to 6-0H and has a length of 3 atoms (Or YS et al, J. Med. Chem. 2000, 43: 1045-1049).
  • 9-decanoic acid formed by linking with various sulfhydryl groups or aromatic hydrocarbon groups is an important modification direction (Gasc JC et al., J. Antibiot. 1991, 44: 313-330; Kawashima Y. et al., Chem. Pharm. Bull. 1994, 42: 1088-1095; Kato H. et al., WO00/61593; Pandey, D. et al., Bioorg. Med. Chem. 2004, 12, 3807-3813.
  • the technical problem to be solved by the present invention is to provide a novel ketolide compound (9-arylpropynyl ketolide derivative) and a synthesis method thereof, and the use of the compound as an anti-infective drug and a corresponding drug combination Things.
  • the compound and the preparation method thereof can be better adapted to industrial production, and the compound has good anti-sensitive bacteria and anti-resistant bacteria activity against respiratory diseases and the like.
  • the present invention discloses a compound having the following formula (I) or (II) or a pharmaceutically acceptable salt or ester thereof formed with an inorganic or organic acid:
  • Ar represents an aromatic heterocyclic hydrocarbon group or a substituted aromatic heterocyclic hydrocarbon group; and X is hydrogen or fluorine.
  • the Ar is a nitrogen-containing, sulfur-containing or oxygen-containing aromatic heterocycloalkyl group; or Ar is a substituted nitrogen-containing, sulfur-containing or oxygen-containing aromatic heterocycloalkyl group.
  • the Ar is imidazolyl, pyridyl, pyrimidinyl, benzopyrazinyl, benzoxazinyl, quinolinyl, isoquinolyl, imidazolylphenyl, thienylphenyl, fluorenyl Or thiophenyl; or, Ar is substituted imidazolyl, substituted pyridyl, substituted pyrimidinyl, substituted benzopyrazinyl, substituted benzoxazinyl, substituted quinolyl, substituted isoquinolyl, substituted imidazolylphenyl And a substituted thienylphenyl group, a substituted indenyl group, a substituted thienyl group.
  • the Ar is 2-pyridyl, 3-pyridyl, 5-pyrimidinyl, 3-quino-p-linyl, 4-iso-p-quinolinyl, 4-p-quino-p-linyl, 5-iso-quinionyl " 1 ⁇ , 5- ⁇ 1 ⁇ , 6- ⁇ 1 ⁇ , 4-(1-imisyl)phenyl, 4-(2-thienyl)phenyl, 5-nonyl, 2 -Thienyl, 2-[5-(2-pyridyl)]thienyl, or 2-(5-benzoyl)thienyl.
  • the inorganic acid is selected from the group consisting of hydrochloric acid, acid, hydrobromic acid or phosphoric acid; the organic acid is selected from the group consisting of acetic acid, malonic acid, sulfonic acid, succinic acid, p-benzoic acid, citric acid, maleic acid. , fumaric acid or stearic acid.
  • R group corresponds to an acetyl group, a benzoyl group or a trimethylsilyl group; the protecting reagent is used to achieve an R protecting group;
  • the acetyl group on the 9-fluorenyl hydroxyl group of the compound of the step (1) is selectively substituted by the combination of a propargylating agent and a strong base.
  • a benzoyl or trimethylsilyl group then, a ring closure reagent is used to ring 11, 12-0H, and then an oxidizing reagent is used to oxidize 3-0H to a 3-carbonyl group to obtain a formula (V).
  • R group corresponds to an acetyl group, a benzoyl group or a trimethylsilyl group; (3) Substituting a heteroaromatic hydrocarbon (for example, a halo (for example, a brominated or iodo) heteroaromatic hydrocarbon) with a 9-fluorene hydroxyl group in the acetonitrile, THF or DMF solvent, catalyzed by a palladium salt and a copper salt.
  • a heteroaromatic hydrocarbon for example, a halo (for example, a brominated or iodo) heteroaromatic hydrocarbon
  • the propargyl group acts to form a heteroaromatic side chain, and the 2-0-R protecting group is removed to obtain a compound having the following formula (I) or (II);
  • substituted heteroaromatic hydrocarbons for example, halo (for example, brominated or iodo) heteroaromatic hydrocarbons
  • propargylpropane on 9-fluorene hydroxyl groups.
  • the base acts to form a heteroaromatic side chain; further introduces a fluorine atom at the 2-position and removes 2 -0-R
  • Ar represents an aromatic heterocyclic hydrocarbon group or a substituted aromatic heterocyclic hydrocarbon group
  • X is hydrogen or fluorine.
  • the protective reagent is selected from the group consisting of acetic anhydride, benzoic anhydride, tridecylchlorosilane or hexamethylenedisilylamine;
  • the propargylating agent is selected from the group consisting of propargyl bromide or propargyl iodide;
  • the strong base is selected from potassium t-butoxide, potassium hydroxide, sodium hydride, or hexamethyldisilazide;
  • the ring-closing agent is selected from the group consisting of triphosgene, phosgene, or trichlorodecyl chlorodecanoate;
  • the oxidizing agent is selected from the group consisting of N-chlorosuccinimide/disulfonium sulfide, or an oxidizing combination reagent containing disulfoxide;
  • the palladium salt is selected from dichlorobis(triphenylphosphine)palladium, or
  • Ar represents an aromatic heterocyclic hydrocarbon group or a substituted aromatic heterocyclic hydrocarbon group
  • X is hydrogen or fluorine.
  • the present invention also provides a compound of the above formula (I) or (II) or a pharmaceutically acceptable salt or ester thereof for use in the preparation of a medicament for the treatment of antibacterial microbial infections.
  • the present invention also claims the use of a compound of the formula (I) or (II) or a pharmaceutically acceptable salt or ester thereof as described above as an antibacterial microbial infection drug.
  • the invention also claims a method of treating a bacterial microbial infection, the method comprising administering to a patient a therapeutically effective amount of at least one compound of formula (I) or (II) as hereinbefore described Or a pharmaceutically acceptable salt or ester thereof.
  • aromatic heterocycloalkyl denotes a heteroaryl group which includes a monocyclic heteroaryl group such as a 5-membered or 6-membered heteroaryl group such as furyl, pyrrolyl, thienyl, imidazole.
  • aryl as used herein means an aromatic carbocyclic group having one single ring or two or more fused rings.
  • the aryl group preferably has 5 - 18, 5 - 14, 5 - 10, 5 - 8, 5 - 6 or 6 carbon atoms.
  • Typical examples of the "aryl group” include, but are not limited to, a phenyl group, a naphthyl group, an anthryl group, and the like.
  • the "aryl group” is most preferably a phenyl group.
  • heteroaryl denotes an aryl group, as defined herein, wherein one or two or more carbon atoms are one or two or more heteroatoms independently selected from 0, S or N.
  • the heteroaryl group is preferably 5 - 18 members, 5 - 14 members, 5 - 10 members, 5 - 8 members, 5 - 6 members or 5 members or 6-membered heteroaryl groups.
  • heteroaryl examples include, but are not limited to, furyl, pyrrolyl, p-septyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazole A pyridyl group (e.g., 3-pyridyl), pyrazinyl, pyrimidinyl (e.g., 5-pyrimidinyl), pyridazinyl, triazinyl, benzofuranyl, isobenzofuranyl, fluorenyl (e.g.
  • 5-indenyl isodecyl, benzo[b]thienyl, benzo[c]thienyl, benzimidazolyl, fluorenyl, carbazolyl, benzoxazolyl, benzoisomeric Azolyl, benzothiazolyl, quinolyl (eg 3-quinolyl, 4-quinolyl, 5-quinolinyl, 6-quinolinyl, 8-quinolinyl), isoquinolyl (eg eg 4-iso-p-quino-l-based, 5-iso-quino-p-linyl, 6-iso-quino-p-l-yl), quinazolyl, benzopyrazine.
  • quinolyl eg 3-quinolyl, 4-quinolyl, 5-quinolinyl, 6-quinolinyl, 8-quinolinyl
  • isoquinolyl eg eg 4-iso-p-quino-l-based, 5-iso-quino-p-linyl,
  • heteroaryl group is preferably a sulfur atom-containing heteroaryl group or a nitrogen atom-containing heteroaryl group, more preferably a thienyl group, a pyridyl group, a pyrimidinyl group, a benzopyrazinyl group, a benzoxazinyl group, a quinolyl group.
  • substituted heteroaryl means that "heteroaryl” as defined herein is substituted by one or two or more substituents independently selected from the group consisting of aryl (eg phenyl), heteroaryl (e.g., furyl, pyrrolyl, p p plug points, imidazolyl, triazolyl, tetrazolyl, pyrazolyl group 1 ⁇ , 1 ⁇ pyrimidinyl group, pyrazolyl group 13 Qin, da p group Qin, Qin three 13-yl , quinolinyl, isoquinolinyl, p-quinazolyl, fluorenyl), 5- or 6-membered cycloalkyl, 5- or 6-membered heterocycloalkyl, C1-C4 alkyl, C2- C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, nitro, cyano, hydroxy, flavo
  • C2-C4 alkynyl refers to an acetylenically unsaturated straight or branched chain hydrocarbon radical containing at least one carbon-carbon triple bond (_C ⁇ C-) having from 2 to 4 carbon atoms.
  • C1-C4 alkoxy refers to the group -ORa, wherein Ra is C1-C4 alkyl as defined herein.
  • 5- or 6-membered cycloalkyl as used herein means a saturated cyclic hydrocarbon group having 5 or 6 carbon atoms.
  • 5- or 6-membered heterocycloalkyl as used herein, is intended to mean a 5- or 6-membered cycloalkyl group, as defined herein, containing one or more heteroatoms independently selected from N, 0 and S. .
  • halogen as used herein means fluoro, chloro, bromo or iodo.
  • the compound of the formula (I) or (II) of the present invention has a novel structure, and an aroheterocyclic hydrocarbon group is bonded to the 9-fluorenylhydroxy group of the ketolide via a propargyl side chain, and is synthesized into a tube, which is suitable for industrial production.
  • the aromatic side chain of ketolide acts as an important pharmacophore for anti-resistant bacteria, and its attachment position on the ketolide and its side chain length and structure directly affect the activity of its anti-resistant bacteria.
  • the propargyl-linked aroheterocycloalkyl group has been selected as the aromatic side chain of the ketone lactone, and the activity of the anti-sensitive bacteria and the anti-resistant bacteria can be obtained.
  • the compound of the formula (I) or (II) of the invention has outstanding antibacterial activity against common clinical sensitive bacteria and resistant bacteria, such as Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus epidermidis, Haemophilus influenzae, etc., can be used alone or as one of the active ingredients in combination with other drugs in various dosage forms or routes of administration for the treatment of infections such as bacteria.
  • the present invention provides a compound having the following structural formula (I) or ( ⁇ ),
  • Ar represents an aromatic heterocyclic hydrocarbon group or a substituted aromatic heterocyclic hydrocarbon group
  • X is a hydrogen atom or a fluorine atom
  • Ar may be 2-pyridyl, 3-pyridyl, 5-pyrimidinyl, 3-quinolinyl, 4-quinolinyl, 4-isoquinolinyl, 5-quinolinyl, 5- Isoquinolyl, 6-quinolyl, 6-isoquinolyl, 8-quinolinyl, 4-(1-imidazolyl)phenyl, 4-(2-thienyl)phenyl, 5-nonyl, 2-Thienyl, 3-thienyl, 2-[5-(2-pyridyl)]thienyl, or 2-(5-benzoyl)thienyl, and the like.
  • Ar may also further substitute the derivatized group on the basis of the above groups.
  • the compound of the present invention having the above formula (I) or (?) may form a salt or ester with various pharmaceutically acceptable inorganic or organic acids.
  • the inorganic acid may be selected from hydrochloric acid, sulfuric acid, hydrobromic acid or phosphoric acid;
  • the organic acid may be selected from the group consisting of acetic acid, malonic acid, sulfonic acid, succinic acid, p-toluenesulfonic acid, citric acid, maleic acid, and rich Horse acid, stearic acid.
  • the invention is not limited to the above examples.
  • the preparation method of the compound having the above formula (I) or (II) will be described below by way of example.
  • the preparation process of the invention is as follows:
  • compound 1 is 2, 4" -6>-bis(trimethylsilylsulfonyl)-6-fluorenylerythromycin
  • a 9-0-( 1-isopropoxy Cyclohexyl) hydrazine can be replaced by 2, 4" - bis(trimethylsilyl) _6_ ⁇ thioerythromycin A9_ ⁇ (1-ethoxycyclohexyl) fluorene.
  • Compound 1 can also be replaced by 2, 4" _ 6> - bis (trimethylsilyl) _6_ fluorenylerythromycin A 9 - (1-decyloxy_1 - fluorenyl B
  • Compound 1 can also be replaced by 2/ , 4 " -OH (trimethylsilyl) - 6 - ⁇ -based erythromycin A 9-0- (1-ethoxyl-yl) Ethyl) hydrazine, or 2 4"_6> - bis (trimethylsilyl fluorenyl) _6_ fluorenyl erythromycin A 9-0- (di-tert-butyl fluorenyl silicon) hydrazine.
  • the reagent as the step 3 protecting reagent can also be replaced.
  • acetic anhydride can be replaced with benzoic anhydride, or a silicon sulfonating reagent such as trimethyl chlorosilane, hexamethylene disilazane or the like to obtain an analog of compound 3, that is, the acetyl group on compound 3 is replaced with benzene.
  • Decanoyl, tridecylsilyl, this analog can be used in the subsequent reaction without changing the reaction history.
  • THF tetrahydrofuran
  • DMF dimercaptophthalamide
  • a palladium salt such as dichlorobis(triphenylphosphine)palladium
  • a copper salt such as cuprous iodide
  • the aromatic hydrocarbon interacts with the propargyl group on the 9-fluorenyl hydroxyl group to form a heteroaromatic side chain, further in the THF (tetrahydrofuran) or DMF (dimercaptophthalamide) solvent, sodium hydride and hydrazine-fluorobenzoimide
  • a fluorine atom is introduced at the lower 2-position, and 2 _Ac is removed from the decyl alcohol to obtain a target compound 6 which is fluorinated at the 2-position.
  • Fluorination at the 2-position of the ketolide can increase the antibacterial activity. Since the technical process of fluorination at the 2-position of ketolide is relatively mature, it will not be described herein. For example, see, Deni s, A. et al, Drug. Future. 2001, 26, 975; Phan, LT, et al, Org. Le t t.
  • propargyl bromide as a propargylating agent can be replaced with propargyl iodide or the like;
  • Potassium tert-butoxide as a strong base can be replaced by potassium hydroxide, sodium hydride, hexamethyldisilazide potassium or the like; as a ring-closing reagent, triphosgene can be replaced by phosgene, trichlorodecyl chloroantimonate or the like;
  • the Corey-Kim Oxidation Reagent (N-chlorosuccinimide/diterpene ether) as an oxidizing agent can be replaced with various oxidizing combination reagents containing disulfoxide, such as disulfoxide/oxalyl chloride, diterpene Sulfone/acetic anhydride, disulfoxide/trifluoroacetic anhydride, disulfoxide/dicyclohexylcarbodiimide, or disulfoxide/phosphorus pentoxide;
  • a fluorinating reagent for the fluorination of the keto lactone at the 2-position, N-fluorophenyl amide can be replaced with a commercial reagent Se l ec t i f luorTM;
  • the palladium salt dichlorobis(triphenylphosphine)palladium may be replaced by tetrakis(triphenylphosphine)palladium; the copper salt cuprous iodide may be replaced with cuprous bromide.
  • Reagents and conditions (a) HC1, EtOH. (b) Ac 2 0, CH 2 C1 2 . (c) KO tu, propargyl bromide, THF. (d) bis(trichloroindenyl) carbonate, Pyridine, CH 2 C1 2 . (e) Me 2 S, N-chlorosuccinimide, Et 3 N, CH 2 C1 2 . (f) ArBr, (PPh 3 ) 2 PdCl 2 , Cul, Et 3 N , CH 3 CN. (g) MeOH.
  • This compound was dissolved in 25 ml of decyl alcohol, and refluxed at 65 ° C for 3 hours to remove the acetyl group to obtain a crude compound.
  • the present invention can also provide a pharmaceutical composition for antibacterial treatment, which composition can include an antibacterial effective amount of a compound having the above formula, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.
  • PU-27 0.064 1 wherein, the reference substance is: 3_carbonyl-6-mercaptoerythromycin 9_[3_(6_quinoline)_2_propenyl]fluorene-11, 12-cyclic carbonate.
  • the target compounds showed more prominent anti-sensitive and anti-resistant bacteria activities than the current clinical main drugs, clarithromycin and azithromycin.
  • the target compound of Example 13 is 3-carbonyl-6-oxime-based erythromycin A 9_6 3_(6-quinolinyl) 2 -propynyl]fluorene-11, 12-cyclocarbonate and analog (reference) 3
  • the compounds of the formulae (I) and (II) of the present invention can be used in various drugs for the treatment of microbial infections such as bacteria, including chlamydia or mycoplasma infection and the like.
  • the principles and embodiments of the present invention have been described herein with reference to specific examples. The foregoing description of the embodiments is merely to aid in understanding the method of the present invention and its core concepts. The present invention is not limited by the scope of the present invention.

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Abstract

La présente invention concerne des dérivés de kétolides représentés par les formules générales (I) ou (II), ou certains de leurs sels ou esters pharmaceutiquement admis, réalisés avec des acides inorganiques ou organiques. Dans ces formules, Ar est alkyle aromatique hétérocyclique éventuellement substitué, et X est hydrogène ou fluor. L'invention concerne également des procédés d'élaboration des composés représentés par les formules générales (I) ou (II), des compositions pharmaceutiques contenant ces composés, et leurs utilisations comme médicaments anti-infectieux.
PCT/CN2011/073762 2010-05-07 2011-05-06 Nouveaux dérivés de kétolides, procédés d'élaboration et compositions pharmaceutiques correspondants WO2011137758A1 (fr)

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CN104961785B (zh) * 2015-06-19 2019-01-11 北京理工大学 一种新型酰内酯衍生物及其制备方法
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Publication number Priority date Publication date Assignee Title
US20020019355A1 (en) * 2000-02-24 2002-02-14 Zhenkun Ma Anti-infective agents useful against multidrug-resistant strains of bacteria
WO2002032919A2 (fr) * 2000-10-16 2002-04-25 Abbott Laboratories Derives d'erythromycine substitue en 6-o possedant une tolerance gastro-intestinale amelioree

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US20020019355A1 (en) * 2000-02-24 2002-02-14 Zhenkun Ma Anti-infective agents useful against multidrug-resistant strains of bacteria
WO2002032919A2 (fr) * 2000-10-16 2002-04-25 Abbott Laboratories Derives d'erythromycine substitue en 6-o possedant une tolerance gastro-intestinale amelioree

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LIANG, JIAN-HUA ET AL.: "Synthesis and antibacterial activities of 6-O-methylerythromycin A 9-O-(3-aryl-2-propenyl) oxime ketolide, 2,3-enol ether, and alkylide analogs", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 45, no. 9, 12 May 2010 (2010-05-12), pages 3627 - 3635, XP027458784, DOI: doi:10.1016/j.ejmech.2010.05.008 *
NAM, GHILSOO ET AL.: "Synthesis and antibacterial activity of new 9-O-arylpropenyloxime ketolides", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 20, no. 8, 15 April 2010 (2010-04-15), pages 2671 - 2674 *

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