WO2022038645A1 - Nouveaux dérivés de quinolones substitués, leurs procédés de préparation, et leur utilisation pour traiter des infections microbiennes - Google Patents

Nouveaux dérivés de quinolones substitués, leurs procédés de préparation, et leur utilisation pour traiter des infections microbiennes Download PDF

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Publication number
WO2022038645A1
WO2022038645A1 PCT/JO2020/050006 JO2020050006W WO2022038645A1 WO 2022038645 A1 WO2022038645 A1 WO 2022038645A1 JO 2020050006 W JO2020050006 W JO 2020050006W WO 2022038645 A1 WO2022038645 A1 WO 2022038645A1
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WO
WIPO (PCT)
Prior art keywords
reaction mixture
och
obu
ome
pharmaceutical composition
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Application number
PCT/JO2020/050006
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English (en)
Inventor
Rula Madhat Khalil DARWISH
Yusuf Mohammad Ali ALHIARI
Somaia M Abdalla ELSHEIHKI
Violet Najeeb Awad KASABRI
Original Assignee
The University Of Jordan
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by The University Of Jordan filed Critical The University Of Jordan
Priority to PCT/JO2020/050006 priority Critical patent/WO2022038645A1/fr
Publication of WO2022038645A1 publication Critical patent/WO2022038645A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present disclosure relates to quinolone derivatives in general, and more particularly to novel substituted quinolone derivatives, methods of preparing, and their use in treating bacterial infections.
  • BACKGROUND [02] Infection is considered as a common abnormal issue for patients either who are subjected to inpatient or outpatient care. Infection is accompanied with considerable costs, morbidity and mortality.
  • Fluoroquinolones is considered as a new class of highly potential orally absorbed antimicrobial drugs.
  • Nalidixic acid was the first analog in these synthetic drugs, while non- fluorinated analogues that were released in 1962for the treatment of urinary tract infections.
  • new fluoroquinolone derivatives which were named as quinolones, carboxyquinolones, 4-quinolones or quinolone carboxylic acids, were developed including ciprofloxacin, norfloxacin pefloxacin, ofloxacin, fleroxacin, lomefloxacin, enoxacin, temafloxacin, tosufloxacin, difloxacin, and others.
  • These drugs are significantly different from the earlier ones through modifying their potency, wide spectrum of antimicrobial activity, and reduction of bacterial resistance.
  • the objective of the present invention is to provide novel substituted quinolone derivatives of the general Formula (I), or salts thereof: Formula (I) wherein R 1 is selected from a group containing OH, OEt, OMe, OPr-n, OPr-i, OBu-n, OBu-i, OBu-s, or OBu-t; R 2 is selected from a group containing (C 2 – C 6 ) alkyl, (C 4 – C 8 ) cycloalkyl, heteroaryl or heterocycle unsubstituted or substituted; R 3 is selected from a group containing NH 2 , NO 2 , OH, SH, CN, OSO 3 H, F, Cl, or Br; R 4 is OMe; R 5 is selected from a group containing H, or OMe; R 6 is OMe; and X is a halogen.
  • R 1 is selected from a group containing OH, OEt, OMe, OPr-n,
  • X is fluorine.
  • salt is selected from alkali metal, alkaline earth metal, ammonium or an amine salt.
  • Other aspects of the present disclosure provide a method for preparing the compound of the general formula (I) or salts thereof, the method may include the steps of: - Adding excess of substituted-anisidine into a solution of Ethyl 7-chloro-1-butyl-6- fluoro-8-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylate, dimethylsulfoxide, and pyridine to produce a first reaction mixture; - Refluxing the first reaction mixture under anhydrous conditions; - Monitoring the first reaction mixture by TLC until no starting material remained then leaving the first reaction mixture to crystallize; - Filtering and washing formed crystals, and leaving it to dry in dark place; - Heating a vigorously stirred suspension of the formed crystals in HCl and ethanol under reflux
  • the method may further include the steps of: - Stirring a mixture of the resulting product in HCl in an ice bath for about 15 minutes; - Removing the ice bath and adding stannous chloride portion wise to produce a third reaction mixture, leaving the reaction mixture stirring overnight and monitoring it by TLC until completion; and - Pouring the third reaction mixture on crushed ice to precipitate, and collecting formed precipitate by filtration and leaving it to dry.
  • Other aspects of the present disclosure provide a pharmaceutical composition including a compound of the general Formula (I) and/or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier/excipient.
  • the pharmaceutical composition in aspects of the present disclosure may be for use in treating a microbial infection.
  • the infection may be an infection caused by Gram positive and/or Gram negative bacteria.
  • the infection may be caused by S. aureus (ATCC6538), S. aureus (ATCC33591) MRSA, E.coli (ATCC4157), S. oralis (ATCC35037), S. epidermidus (ATCC22105), and/or B. subtilis (ATCC6634).
  • the pharmaceutical composition may be in oral dosage form.
  • the oral dosage form may include liquid oral dosage form.
  • the liquid oral dosage form may include a solution, syrup, emulsion and suspension.
  • the oral dosage form may include solid oral dosage form.
  • the solid oral dosage form may include a capsule, caplet, tablet, pill, and powder.
  • the pharmaceutical composition may be for parenteral injection.
  • the pharmaceutical composition may be for vaginal or rectal administrations.
  • the pharmaceutical composition may be formulated in immediate release formulation.
  • the pharmaceutical composition may be formulated in sustained release formulation.
  • the pharmaceutical composition may be formulated in targeted release formulation.
  • FIG. 1 illustrates a flow chart of a method of preparing substituted quinolone derivatives, prepared in accordance with embodiments of the present disclosure.
  • FIG. 2 illustrates a flow chart of a method of preparing substituted quinolone derivatives, prepared in accordance with embodiments of the present disclosure.
  • FIG. 3 illustrates a flow chart of a method of preparing substituted quinolone derivatives, prepared in accordance with embodiments of the present disclosure.
  • Embodiments of the present disclosure to provide substituted quinolone derivatives of the general Formula (I), or a salt thereof: Formula (I) wherein R 1 is selected from a group containing OH, OEt, OMe, OPr-n, OPr-i, OBu-n, OBu- i,OBu-s, or OBu-t; R 2 is selected from a group containing (C 2 – C 6 ) alkyl, (C 4 – C 8 ) cycloalkyl, heteroaryl or heterocycle unsubstituted or substituted; R 3 is selected from a group containing NH 2 , NO 2 , OH, SH, CN, OSO 3 H, F, Cl, or Br; R 4 is OMe; R 5 may be selected from a group containing H, or OMe; R 6 is OMe; and X is a halogen.
  • R 1 is selected from a group containing OH, OEt, OMe, OPr
  • X is fluorine.
  • salt is selected from alkali metal, alkaline earth metal, ammonium or an amine salt.
  • Embodiments of the present disclosure further provide a pharmaceutical composition including a compound of general formula (I) and/or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier/excipient.
  • pharmaceutical composition is intended to include a compound of general formula (I) and/or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition can be, for example, in a liquid form, e.g.
  • composition in embodiments of the present disclosure can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • the pharmaceutical composition can be administered to humans and other mammals orally, sublingually, rectally, parenterally, intracisternally, intraurethrally, intraperitoneally, topically (as powder, ointment or drop), as buccal or as an oral or nasal spray.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, subcutaneous, intra-articular injection and infusion.
  • the pharmaceutical composition of the present disclosure for parenteral injection may include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and non-aqueous carriers, diluents, solvents or vehicles may include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants for example, by the use of surfactants.
  • pharmaceutically acceptable carrier/excipient means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; binding agents such as hypromellose; disintegrating agents such as crosscarmellose; water; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil; cottonseed oil; safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar
  • the pharmaceutical composition may be for use in the treatment of microbial infections.
  • the pharmaceutical composition is for use in the treatment of infections caused by Gram positive and/or Gram negative bacteria.
  • the Gram positive and/or Gram negative bacteria may include S. aureus (ATCC6538), S.
  • FIGS.1-3 illustrate flow charts of a method of preparing substituted quinolone derivative compounds, in accordance with embodiments of the present disclosure.
  • compound 2 For the preparation of compound 2, add excess of substituted- anisidine (3M excess, about 16.24 mmol) into a solution of Ethyl 7-chloro-1-butyl-6- fluoro-8-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylate (about 5.40 mmol) and about 20 ml of dimethylsulfoxide (“DMSO”) as a solvent, and few drops of pyridine as a catalyst (process block 1-1).
  • DMSO dimethylsulfoxide
  • Example 3 In vitro antimicrobial activity [048] Antimicrobial activities of the synthesized compounds were investigated in vitro against S.aureus (ATCC6538), methicillin resistant S.aureus (ATCC33591), E.coli (ATCC4157), S.oralis (ATCC35037), S.epidermidus (ATCC22105), and B.subtilis (ATCC6634), which were provided by American Type Culture Collection, U.S.A. All media were prepared according to manufacturer instructions under sterilized conditions. Bacterial broth cultures stocks were cultivated in the appropriate medium at about 37 °C for 24 hours prior to testing.0.5 McFarland standards were used to visually approximate the concentration of cells in a suspension.
  • MICs minimal inhibitory concentrations
  • DMSO dimethyl sulfoxide
  • a numerical range of approximately 1 to approximately 4.5 should be interpreted to include not only the explicitly recited limits of 1 to approximately 4.5, but also to include individual numerals such as 2, 3, 4, and sub- ranges such as 1 to 3, 2 to 4, etc.
  • the same principle applies to ranges reciting only one numerical value, such as “less than approximately 4.5,” which should be interpreted to include all of the above-recited values and ranges. Further, such an interpretation should apply regardless of the breadth of the range or the characteristic being described. [057] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently disclosed subject matter belongs.
  • the term “about”, when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.
  • the term “and/or” when used in the context of a listing of entities refers to the entities being present singly or in combination.
  • the phrase “A, B, C, and/or D” includes A, B, C, and D individually, but also includes any and all combinations and sub-combinations of A, B, C, and D.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés de quinolones substitués de formule générale (I) ou un sel de ces derniers : Formule (I) dans laquelle R1 peut être choisi dans un groupe contenant OH, OEt, OMe, OPr-n, OPr-i, OBu-n, OBu-i, OBu-s ou OBu-t ; R2 peut être choisi dans un groupe contenant alkyle en C2-C6, cycloalkyle en C4-C8), hétéroaryle ou hétérocycle non substitué ou substitué ; R3 peut être choisi dans un groupe contenant ΝH2, NO2, OH, SH, CN, OSO3H, F, Cl, ou Br ; R4 peut être OMe ; R5 peut être choisi dans un groupe contenant H, ou OMe ; R6 peut être OMe ; et X peut être un halogène.
PCT/JO2020/050006 2020-08-17 2020-08-17 Nouveaux dérivés de quinolones substitués, leurs procédés de préparation, et leur utilisation pour traiter des infections microbiennes WO2022038645A1 (fr)

Priority Applications (1)

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PCT/JO2020/050006 WO2022038645A1 (fr) 2020-08-17 2020-08-17 Nouveaux dérivés de quinolones substitués, leurs procédés de préparation, et leur utilisation pour traiter des infections microbiennes

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PCT/JO2020/050006 WO2022038645A1 (fr) 2020-08-17 2020-08-17 Nouveaux dérivés de quinolones substitués, leurs procédés de préparation, et leur utilisation pour traiter des infections microbiennes

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3542781A (en) * 1968-12-23 1970-11-24 Merck & Co Inc 7-alkylamino 7-hydroxy quinoline 3-carboxylates
US20160052892A1 (en) * 2010-08-10 2016-02-25 Shionogi & Co., Ltd. Novel heterocyclic derivative and pharmaceutical composition comprising the same (as amended)
WO2020163816A1 (fr) * 2019-02-08 2020-08-13 Frequency Therapeutics, Inc. Composés de quinolin-4-one et de 4(1h)-cinnolinone et procédés d'utilisation associés

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3542781A (en) * 1968-12-23 1970-11-24 Merck & Co Inc 7-alkylamino 7-hydroxy quinoline 3-carboxylates
US20160052892A1 (en) * 2010-08-10 2016-02-25 Shionogi & Co., Ltd. Novel heterocyclic derivative and pharmaceutical composition comprising the same (as amended)
WO2020163816A1 (fr) * 2019-02-08 2020-08-13 Frequency Therapeutics, Inc. Composés de quinolin-4-one et de 4(1h)-cinnolinone et procédés d'utilisation associés

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