WO2013039428A2 - Dérivés de quinoléine et notamment 1-(2-chloroquinoléin-3-yl)-4-diméthylamino-2-(naphthalén-1-yl)-1-phénylbutan-2-ols 5,6,7- substitués, procédés de leur production et d'utilisation - Google Patents

Dérivés de quinoléine et notamment 1-(2-chloroquinoléin-3-yl)-4-diméthylamino-2-(naphthalén-1-yl)-1-phénylbutan-2-ols 5,6,7- substitués, procédés de leur production et d'utilisation Download PDF

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Publication number
WO2013039428A2
WO2013039428A2 PCT/RU2012/000725 RU2012000725W WO2013039428A2 WO 2013039428 A2 WO2013039428 A2 WO 2013039428A2 RU 2012000725 W RU2012000725 W RU 2012000725W WO 2013039428 A2 WO2013039428 A2 WO 2013039428A2
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WO
WIPO (PCT)
Prior art keywords
compounds
substituted
methoxy
phenylbutan
chloroquinolin
Prior art date
Application number
PCT/RU2012/000725
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English (en)
Russian (ru)
Other versions
WO2013039428A3 (fr
Inventor
Анна Борисовна НАЗАРЕНКО
Владимир Егорович ФЕДОРОВ
Вадим Егоревич ИЛЬИН
Антон Владимирович ОМЕЛЬКОВ
Евсей Александрович РУЧКО
Original Assignee
Закрытое Акционерное Общество "Фарм-Синтез"
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Publication of WO2013039428A2 publication Critical patent/WO2013039428A2/fr
Publication of WO2013039428A3 publication Critical patent/WO2013039428A3/fr

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Classifications

    • 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
    • C07D215/18—Halogen atoms or nitro radicals
    • 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
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the invention relates to biologically active substances, in particular to derivatives of substituted quinolines having cytostatic and cytotoxic activity against mycobacteria, namely, substituted derivatives of 1 - (2-chloroquinolin-3-yl) -4-dimethylamino-2- (naphthalene-1 -yl) - 1 - phenylbutan-2-tins of the general formula (I), to the method for their preparation, and also to their use as antimycobacterial agents, in particular, substances of drugs (agents) for the treatment of tuberculosis and other infectious diseases mycobacterial th nature.
  • Ri is H, halogen, haloalkyl, cyano, hydroxy, aryl, hetaryl, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, aryl alkyl;
  • R 2 is H, hydroxy, thio, alkyloxy, alkyloxyalkyloxy, alkylthio, mono and dialkylamino;
  • R 3 is hydrogen, halogen, alkyl
  • R4 is naphthyl, halonaphthyl, phenyl, haloaryl, arylalkyl, pyridinyl, alkyl, thienyl;
  • R 5 is alkyl, H, benzyl, imidazolyl, hetaryl, alkylthio, pyrimidyl.
  • Quinoline derivatives of the general formula are known from RU 2404971, 27.1.
  • Ri means halogen
  • R 2 means halogen
  • R 3 means hydroxy
  • R ′′ means Ci-C3-alkyl
  • R6 means aryl
  • R 7 means aryl
  • Compounds of general formula (III), starting from patent N ° 2404971, 11/27/2010, can be obtained from intermediates (VI) and (IV) using a metalating reagent, for example, lithium disopropylamide, in particular obtained in situ from butyl lithium and disopropylamine in a suitable solvent, preferably an ether type, such as, for example, tetrahydrofuran (THF), diethyl ether, diisopropyl ether, methyl tert-butyl ether and mixtures thereof, as well as mixtures with other solvents or cosolvents (Scheme 1). All radicals have definitions as in formula (III).
  • the reaction can be easily carried out in the temperature range from -70 to + 20 ° C, preferably from -70 to -20 ° C.
  • the mixture of diastereomers formed during the reaction can be separated using known methods, such as chromatography or crystallization of diastereomeric salts.
  • the objective of the present invention is the introduction of arylquinoline into the quinoline core, instead of a halogen atom, of electron-donating substituents in order to increase the solubility of intermediates of the general formula (VI) in THF at temperatures below -50 ° C, and also to obtain new compounds of the formula (I) with improved and reproducible practical solution, as well as with improved antibacterial activity.
  • the technical task of the invention is to obtain new compounds - derivatives of quinoline [General formula (I)] with reproducible practical yield, with increased antibacterial activity, as well as their pharmaceutically acceptable salts with acids.
  • the technical result is achieved by obtaining substituted derivatives of 1- (2-chloroquinolin-3-yl) -4-dimethylamino-2- (naphthalene-1-yl) - 1-phenylbutan-2-ol having antimycobacterial activity, namely, such quinoline derivatives, as 5,6,7-protected 1- (2-chloroquinolin-3-yl) -4-dimethylamino-2- (naphthalen-1-yl) -1-phenylbutan-2-ol of general formula (I)
  • R 2 means H, methoxy, -0- (CH 2 ) p -0-;
  • R 3 means H, methoxy, -0- (CH 2 ) p -0-;
  • n 1-2, as well as their pharmaceutically acceptable salts with acids.
  • the invention also relates to a method for producing said new substituted derivatives of I - (2-chloroquinolin-3-yl) -4-dimethylamino-2- (naphthalen-1-yl) -1-phenylbutan-2-tins having antimycobacterial activity, by reacting substituted 2-arylmethylquinolines, for example, of general formula (VI):
  • Organic metal amides such as lithium diisopropylamide, lithium diethylamide, lithium 2,2,6,6-tetramethylpiperidide, etc., can be used as metalating agents in the method for producing said substituted quinolines of the general formula (I) according to the invention.
  • salts with acids of the indicated substituted quinoline derivatives of general formula (I) are characterized in that they contain therapeutically active non-toxic salt forms formed by the compounds of formula (I) with acids. These salts with acids can be obtained treating the free base materials represented by the formula (I) with suitable inorganic and organic acids.
  • Such acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid , tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid lot.
  • the compounds of the invention have antimycobacterial activity, and therefore can be used to treat infectious diseases caused by Mycobacterium tuberculosis, in particular, they can be used as a biologically active component (active principle) in the preparation of drugs (drugs) for treatment of tuberculosis, that is, to obtain anti-TB drugs.
  • the compounds of the invention of formula (I) can be prepared from an intermediate of formula (VI) and an intermediate of formula (IV) using a metalating reagent such as lithium diethylamide, in particular obtained from in situ from n-butyl lithium and diethylamine in a suitable solvent, such like THF, diethyl ether, diisopropyl ether, methyl tert-butyl ether and their mixtures, as well as in mixtures with other solvents and cosolvents (Scheme 2). All radicals have definitions as in formula (I).
  • the reaction is carried out in the temperature range from -70 to + 20 ° C, preferably at -70 ° C for 1-3 hours.
  • the resulting mixture of diastereomers (1-1 + 1-2) can be separated using known methods such as chromatography or crystallization of diastereomeric salts.
  • the starting compounds and intermediates of formulas (VI) and (IV) are compounds that are either commercially available or can be obtained by conventional methods known in the literature [D. Mature, et al., Med. Chem., 2005, 48, 2134-2153].
  • R.2 is H, methoxy, -0- (CH2) p -0-;
  • R 3 means H, methoxy, -0- (CH 2 ) p -0-;
  • the synthesis according to the presented scheme includes step (a), in which the substituted arylamine is reacted with 3-phenylpropionic acid in the presence of a suitable catalyst (strong Lewis acid) and an inert solvent such as benzene or toluene.
  • a suitable catalyst strong Lewis acid
  • an inert solvent such as benzene or toluene.
  • the process is carried out in the temperature range from 20 to 110 ° C, preferably by boiling the reaction mass.
  • step (b) the addition product obtained in step (a) is reacted with phosphorus oxychloride (POC1 3 ) in the presence of ⁇ , ⁇ -dimethylformamide (Vilsmeier-Haack formylation followed by cyclization).
  • the reaction can be carried out in the temperature range from 20 to 80 ° C, preferably at 75 ° C.
  • reaction (a) and (b) can be isolated individually and purified by extraction, crystallization or chromatography.
  • the products of reaction (I), existing as diastereomers, can be purified by chiral preparative high performance liquid chromatography.
  • Antimycobacterial action given in Table. 1 compounds were studied by the growth dynamics of M. tuberculosis H37Rv strain in Middlebrook 7H9 enriched liquid medium in the presence of various concentrations (0.312 ⁇ g / ml, 0.625 ⁇ g / ml, 1.25 ⁇ g / ml, 2.5 ⁇ g / ml, 5 ⁇ g / ml , 10 ⁇ g / ml, 20 ⁇ g / ml, 40 ⁇ g / ml) compared with the growth of these strains on a medium containing no compounds and a medium containing a first-line preparation of rifampicin in the same concentrations.
  • Mycobacterial suspension was seeded in an amount of 10 5 CFU / ml. Each of the concentrations, including control tubes without compound and tubes with rifampicin, was examined in triplicates.
  • Mycobacterium culture growth was detected using a Bactec MGIT 960 automated crop growth accounting system (Becton Dickenson, USA) in special MGIT tubes containing a bound fluorophore under a semipermeable membrane at the bottom of the tube. Mycobacterial culture growth was detected every hour using Epicenter software (Becton Dickenson, USA). The dynamics of the division of mycobacterial cells was expressed in relative fluorescence units (OEF).
  • OEF relative fluorescence units
  • the experiment lasted 42 days, according to the Becton Dickinson protocol. After that, all grown cultures were subjected to species specificity control (belonging to Mycobacterium tuberculosis).
  • each compound was tested as a diastereomeric pair and was not separated into individual enantiomers.
  • tubes were selected containing the test compounds (Ia-b) and rifampicin at concentrations at which no growth of the sensitive laboratory strain M. tuberculosis H37Rv was observed throughout the entire experiment to determine the bacteriostatic activity. Accordingly, the study included compounds (I-lb) (20 ⁇ g / ml and 40 ⁇ g / ml), (1-2a) (10 ⁇ g / ml, 20 ⁇ g / ml and 40 ⁇ g / ml) and (1-2b ) (5 ⁇ g / ml, 10 ⁇ g / ml, 20 ⁇ g / ml and 40 ⁇ g / ml).
  • the culture of the Office was seeded as a control; cultured without the drug, and the MBT culture exposed with rifampicin at concentrations of 0.625 ⁇ g / ml, 1, 25 ⁇ g / ml, 2.5 ⁇ g / ml, 5 ⁇ g / ml, 10 ⁇ g / ml, 20 ⁇ g / ml and 40 ⁇ g / ml, on which growth of culture was not recorded.
  • the compound (1-1 a) which did not lead to a suppression of the growth of the MBT culture at any of the tested concentrations, was not used to determine the bactericidal activity.
  • Figure 2 shows the growth curve of the M. tuberculosis H37Rv strain in fresh medium after exposure with the compound “R20Me” (I-2b) at a concentration of 5, 10, 20 and 40 ⁇ g / ml.

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

Abstract

La présente invention concerne de nouveaux dérivés de quinoléines tels que les 1-(2-chloroquinoléin-3-yl)-4-diméthylamino-2-(naphthalén-1-yl)-1-phénylbutan-2-ols substitués, un procédé de leur fabrication et aussi leur utilisation en tant que agents antimycobactériens, notamment des 1-(2-chloroquinoléin-3-yl)-4-diméthylamino-2-(naphthalén-1-yl)-1-phénylbutan-2-ols 5,6,7-substitués de la formule générale (I), dans laquelle R1 est Н ou méthoxy, R2 est Н, méthoxy ou -O-(CH2)n-O-, R3 est Н, méthoxy ou -O-(CH2)n-O-, n=1-2, et aussi leurs sels pharmaceutiquement acceptables avec des acides manifestant une activité par rapport aux mycobactéries. L'invention concerne aussi un procédé de fabrication des compositions de la formule (I) qui consiste en l'interaction des arylchinolines correspondantes avec un cétone aromatique et leur utilisation en tant que principe actif dans la création de préparations médicamenteuses dirigées contre la tuberculose.
PCT/RU2012/000725 2011-09-12 2012-09-04 Dérivés de quinoléine et notamment 1-(2-chloroquinoléin-3-yl)-4-diméthylamino-2-(naphthalén-1-yl)-1-phénylbutan-2-ols 5,6,7- substitués, procédés de leur production et d'utilisation WO2013039428A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2011137490 2011-09-12
RU2011137490/04A RU2486175C2 (ru) 2011-09-12 2011-09-12 Производные хинолина, в частности 5,6,7-замещенные 1-(2-хлорхинолин-3-ил)-4-диметиламино-2-(нафталин-1-ил)-1-фенилбутан-2-олы, способ получения и применение соединений

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WO2013039428A2 true WO2013039428A2 (fr) 2013-03-21
WO2013039428A3 WO2013039428A3 (fr) 2013-05-10

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RU (1) RU2486175C2 (fr)
WO (1) WO2013039428A2 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011436A1 (fr) * 2002-07-25 2004-02-05 Janssen Pharmaceutica N.V. Derives de quinoleine et leur utilisation en tant qu'inhibiteurs mycobacteriens
WO2006125769A1 (fr) * 2005-05-25 2006-11-30 Janssen Pharmaceutica N.V. Procede de preparation de (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphtalenyl-beta-phenyl-3-quinoline-ethanol
RU2006145336A (ru) * 2004-05-21 2008-06-27 Чирон Корпорейшн (Us) Замещенные производные хинолина, как ингибиторы митотического кинезина
RU2404971C2 (ru) * 2008-12-02 2010-11-27 ЗАО "Фарм-Синтез" Новые производные хинолина, способ их получения, их применение для лечения микобактериальных инфекций, фармацевтическая композиция на их основе

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP2321A (en) * 2004-01-29 2011-11-16 Janssen Pharmaceutica Nv Quinoline derivatives for use as mycobactrial inhibitor.
JO2725B1 (en) * 2006-12-06 2013-09-15 جانسين فارماسوتيكا ان. في Quinoline antibacterial derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011436A1 (fr) * 2002-07-25 2004-02-05 Janssen Pharmaceutica N.V. Derives de quinoleine et leur utilisation en tant qu'inhibiteurs mycobacteriens
RU2006145336A (ru) * 2004-05-21 2008-06-27 Чирон Корпорейшн (Us) Замещенные производные хинолина, как ингибиторы митотического кинезина
WO2006125769A1 (fr) * 2005-05-25 2006-11-30 Janssen Pharmaceutica N.V. Procede de preparation de (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphtalenyl-beta-phenyl-3-quinoline-ethanol
RU2404971C2 (ru) * 2008-12-02 2010-11-27 ЗАО "Фарм-Синтез" Новые производные хинолина, способ их получения, их применение для лечения микобактериальных инфекций, фармацевтическая композиция на их основе

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WO2013039428A3 (fr) 2013-05-10
RU2011137490A (ru) 2013-03-20
RU2486175C2 (ru) 2013-06-27

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