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WO2017198196A1 - Dérivé de quinoléine ayant une activité antitumorale - Google Patents

Dérivé de quinoléine ayant une activité antitumorale Download PDF

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Publication number
WO2017198196A1
WO2017198196A1 PCT/CN2017/084929 CN2017084929W WO2017198196A1 WO 2017198196 A1 WO2017198196 A1 WO 2017198196A1 CN 2017084929 W CN2017084929 W CN 2017084929W WO 2017198196 A1 WO2017198196 A1 WO 2017198196A1
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arh
nmr
mmol
mhz
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Chinese (zh)
Inventor
王子厚
张晓东
曹日晖
荣祖元
陈西敬
王健
杨泽瀚
李忠野
徐�明
王忠奎
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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
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • 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
    • 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
    • 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
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • 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
    • C07D215/38—Nitrogen atoms
    • 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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms

Definitions

  • the present invention relates to a class of quinoline derivatives having antitumor activity, a process for the preparation of the quinoline derivatives, pharmaceutical compositions comprising the quinoline derivatives, and their use in the preparation of antitumor drugs.
  • Quinoline compounds are an important class of nitrogen-containing heterocyclic compounds whose backbone structure exists in the chemical structure of many clinical drugs, such as anti-malarial drugs (quinine, chloroquine, mefequolo, primaquine, etc.), antiviral Drugs (saquinavir), antibacterial drugs (quinolones ciprofloxacin, seroxacin, gatifloxacin, etc.).
  • camptothecin which opened the prelude to the application of quinoline derivatives in anti-tumor research, followed by camptothecin analogs topotecan, irinotecan, ezetacetin, etc.
  • the inventors have unexpectedly discovered that the compounds of the following formula I of the present invention have excellent antitumor activity, and the present invention has been completed based on this finding.
  • the invention provides a quinoline derivative which is a compound of formula I below:
  • R is one, two or three groups each independently selected from the group consisting of: optionally substituted hydrogen, halogen, hydroxy, amino, alkyl, alkoxy, alkanoyloxy, alkylthio, alkyl Amino, cyano, nitro, carboxy, sulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, acylamino, alkoxycarbonyl or alkyl acyl,
  • R 1 is an optionally substituted alkyl, alkenyl or alkynyl group
  • the optional substituents are each independently selected from the group consisting of aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl, alkane a heterocyclic group, an amino group, an alkylamino group, an amide group, an alkyl acylamino group, a hydroxy group, an alkoxy group, an alkyl acyl group, an alkyl acyloxy group, a decyl group, an alkylthio group, said optional substituent Further replaced; and
  • W is selected from NH, O or S.
  • At least one of said R is selected from the group consisting of: optionally substituted halogen, alkoxy, alkanoyloxy, alkylthio, alkylamino, cyano, nitro, carboxy, sulfonyl, alkane a sulfamoyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an acylamino group, an alkoxycarbonyl group or an alkyl acyl group, preferably at least one of said R is selected from the group consisting of an optionally substituted cyano group, a nitro group, a carboxyl group, Sulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, amido, alkoxycarbonyl or alkylacyl.
  • At least one of said R is nitro, methoxy, fluoro, chloro or bromo.
  • the R 1 is optionally substituted C 2 -C 12 alkyl, C 3 -C 12 alkenyl or C 3 -C 12 alkynyl, for example ethyl, propyl, butyl, pentyl, hexyl, Heptyl, octyl, decyl, decyl, allyl, enbutyl, propargyl, or alkynyl butyl.
  • said R 1 is optionally substituted arylalkyl or heteroarylalkyl, preferably arylmethyl, arylethyl, arylpropyl, for example benzyl, Phenylethyl, phenylpropyl, phenylbutyl; the arylalkyl or heteroarylalkyl group optionally being substituted by one or more halogens such as fluorine, chlorine or bromine, alkyl, alkoxy, Substituted by haloalkyl or haloalkoxy, for example, R 1 may be fluorobenzyl, fluorophenethyl or fluorophenyl.
  • the present invention provides a method of preparing the quinoline derivative of the present invention, which comprises:
  • the base is preferably NaH, and/or the acid is preferably concentrated hydrochloric acid.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned quinoline derivative of the present invention and a pharmaceutically acceptable carrier.
  • the invention also provides the use of the quinoline derivative for the manufacture of a medicament for the treatment of a proliferative disorder.
  • the proliferative disorder is a malignant tumor.
  • the proliferative disease may be selected from the group consisting of leukemia, colorectal cancer, liver cancer, non-small cell lung cancer, ovarian cancer, cervical cancer, and gastric cancer.
  • the present invention also provides a method of treating a proliferative disease comprising administering an effective amount of a quinoline derivative of the present invention to a subject in need thereof.
  • the inventors have unexpectedly found that the quinoline derivative of the present invention has excellent antitumor activity and can be used for effectively treating proliferative diseases, especially malignant tumors.
  • alkyl denotes a straight or branched saturated hydrocarbon group, usually the alkyl group has 1 or more carbon atoms, for example, a C1-C12 alkyl group means an alkane having 1 to 12 carbon atoms. base.
  • the alkyl group may also be a C2-C12 alkyl group, a C2-C11 alkyl group, a C2-C10 alkyl group, a C2-C9 alkyl group, a C2-C8 alkyl group, a C2-C7 alkyl group, a C2-C6 alkane.
  • C2-C5 alkyl, C2-C4 alkyl for example C2 alkyl (ie ethyl), C3 alkyl (including n-propyl, isopropyl), C4 alkyl (including n-butyl, isobutyl) , C5 alkyl (including n-pentyl, isopentyl, neopentyl), C6 alkyl (including n-hexyl, various branched hexyl), C7 alkyl (heptyl), C8 alkyl (octyl) ), C9 alkyl (fluorenyl), C10 alkyl (fluorenyl), C11 alkyl (undecyl), C12 alkyl (dodecyl).
  • C2 alkyl ie ethyl
  • C3 alkyl including n-propyl, isopropyl
  • C4 alkyl including n-butyl, isobut
  • alkyl group when mentioned in another group, for example, an alkoxy group, an alkanoyl group, an alkoxycarbonyl group, wherein the alkyl group has the definition of the alkyl group herein, but some groups (such as The alkanoyl group also includes a carbon atom on the structure other than the alkyl group when calculating the number of carbon atoms.
  • alkenyl denotes a straight or branched chain hydrocarbon radical having one or more carbon-carbon double bonds.
  • alkenyl denotes a straight or branched chain hydrocarbon radical having one or more carbon-carbon double bonds.
  • the alkenyl group may be a C3 alkenyl group (such as an allyl group), a C4 alkenyl group (such as a 1,3-butadienyl group), a C5 alkenyl group, a C6 alkenyl group, a C7 alkenyl group, a C8 alkenyl group, C9 alkenyl, C10 alkenyl, C11 alkenyl, C12 alkenyl.
  • a C3 alkenyl group such as an allyl group
  • a C4 alkenyl group such as a 1,3-butadienyl group
  • C5 alkenyl group such as an allyl group
  • a C6 alkenyl group such as a 1,3-butadienyl group
  • C7 alkenyl group such as a 1,3-butadienyl group
  • C8 alkenyl group such as a 1,3-butadienyl group
  • alkynyl denotes a straight or branched chain hydrocarbon radical having one or more carbon to carbon triple bonds.
  • alkynyl denotes a straight or branched chain hydrocarbon radical having one or more carbon to carbon triple bonds.
  • the alkynyl group may be a C3 alkynyl group (such as a propargyl group), a C4 alkynyl group (such as a 1,3-butadiynyl group), a C5 alkynyl group, a C6 alkynyl group, a C7 alkynyl group, a C8 alkynyl group, C9 alkynyl, C10 alkynyl, C11 alkynyl, C12 alkynyl.
  • a C3 alkynyl group such as a propargyl group
  • a C4 alkynyl group such as a 1,3-butadiynyl group
  • a C5 alkynyl group such as a propargyl group
  • a C6 alkynyl group such as a 1,3-butadiynyl group
  • C7 alkynyl group such as a C7 alkynyl group
  • aryl denotes a carbocyclic group having a cyclic conjugated structure.
  • the aryl group may have 6 or more carbon atoms, such as a C6-C14 aryl group, a C6-C12 aryl group, a C6-C10 aryl group.
  • the aryl group may be a phenyl group, a naphthyl group, an anthracenyl group or a phenanthryl group.
  • heteroaryl denotes a cyclic group having one or more heteroatoms selected from N, O and S in a cyclic conjugated structure.
  • the number of ring atoms in the heteroaryl group may be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more.
  • the heteroaryl group may be a pyridyl group, a thienyl group, a pyrazolyl group, a pyrimidinyl group, a fluorenyl group, a fluorenyl group, a thiazolyl group, or a morpholinyl group.
  • heterocyclyl denotes a cyclic group having one or more heteroatoms selected from N, O and S, for example piperidinyl, piperazinyl, pyrrolidinyl, pyranyl, Oxocyclopentyl, dioxane.
  • halogen denotes fluoro, chloro, bromo, iodo.
  • treatment denotes any treatment that allows the health condition of a subject to be treated to alleviate, ameliorate, restore, eliminate, and prevent the risk of disease and improve the prognosis of the disease.
  • treatments include, but are not limited to, medical treatment, radiation therapy, chemotherapy, surgery, and vaccination.
  • Table 1 below shows the correspondence between the compound 8-51 number of the present invention and the structural formula and basic parameters.
  • the quinoline derivative of the present invention is used as a pharmacological study for a medicament for treating cancer. All tested compounds were prepared as the hydrochloride salt prior to the test, using the commonly used anti-tumor drugs, cisplatin and besibutinib, as positive control drugs.
  • HCT116 Human rectal cancer cell line
  • HepG2 human hepatoma cell line
  • HepG2 human non-small cell lung cancer cell line
  • A549 and NCI-H1650 human ovarian cancer cell line
  • human cervical cancer cell line Hela
  • Human gastric cancer cell line BGC-823
  • other human tumor cell lines were tested by MTT assay.
  • the specific method is as follows: various cell lines are cultured according to standard culture methods, and cell lines in good growth state and in logarithmic growth phase are inoculated into 96-well plates at a concentration of 5 ⁇ 10 4 /ml, and 160 ⁇ l is inoculated per well, followed by The 96-well plate was incubated in an incubator containing 5% CO 2 at 37 ° C for 24 hours, the old solution was discarded, the fresh culture solution was replaced, the sterilized quinoline derivative was added, and the culture was continued for 48 hours, and then discarded.
  • the culture medium was added with 20 ul of RPMI-1640 medium containing 5 mg/ml MTT per well, and the culture was continued for 4 hours.
  • the cell survival rate was plotted against the logarithm of the drug concentration, and the IC 50 value of each sample was determined by the mapping method. The results are shown in Table 2 below.
  • reaction solution was cooled and transferred to a 500 mL beaker, and 150 mL of water was added thereto, and the mixture was extracted three times with ethyl acetate.
  • test examples all the tested compounds were prepared into the hydrochloride form before the test, and the commonly used antitumor drugs, cisplatin and besibutinib, were used as positive control drugs.
  • Human rectal cancer cell line (HCT116), human hepatoma cell line (HepG2), human non-small cell lung cancer cell line (A549), human ovarian cancer cell line (A2780), human gastric cancer cell line (BGC-823), etc. Human tumor cell lines were tested using the MTT method.
  • the specific method is as follows: various cell lines are cultured according to standard culture methods, and cell lines in good growth state and in logarithmic growth phase are inoculated into 96-well plates at a concentration of 5 ⁇ 10 4 /ml, and 160 ⁇ l is inoculated per well, followed by The 96-well plate was incubated in an incubator containing 5% CO 2 at 37 ° C for 24 hours, the old solution was discarded, the fresh culture solution was replaced, the sterilized quinoline derivative was added, and the culture was continued for 48 hours, and then discarded.
  • the culture medium was added with 20 ul of RPMI-1640 medium containing 5 mg/ml MTT per well, and the culture was continued for 4 hours.
  • the cell survival rate was plotted against the logarithm of the drug concentration, and the IC 50 value of each sample was determined by the mapping method. The results are shown in Table 3 below.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (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)

Abstract

La présente invention concerne un dérivé de quinoléine ayant une activité antitumorale, un procédé de préparation du dérivé de quinoléine, une composition pharmaceutique comprenant le dérivé de quinoléine, et des applications associées dans la préparation de médicaments antitumoraux.
PCT/CN2017/084929 2016-05-18 2017-05-18 Dérivé de quinoléine ayant une activité antitumorale Ceased WO2017198196A1 (fr)

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CN201610330810.2 2016-05-18

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020109039A1 (fr) 2018-11-28 2020-06-04 Basf Se Composés pesticides
US20200360365A1 (en) * 2018-01-05 2020-11-19 Instutut National de la Sante et de la Researche Medicale Substituted halo-quinoline derivates for use in the treatment of lymphomas and leukemia
WO2021219513A1 (fr) 2020-04-28 2021-11-04 Basf Se Composés pesticides
CN115260164A (zh) * 2021-05-01 2022-11-01 杭州星鳌生物科技有限公司 新型4(3h)-喹唑啉酮类似物的制备方法、结构组成及其在抗肿瘤药物中的应用
CN115466211A (zh) * 2022-06-09 2022-12-13 中国人民解放军空军军医大学 一种n-苯基喹啉-4-胺类化合物及其应用
CN116693452A (zh) * 2023-05-24 2023-09-05 中山大学 一种喹啉衍生物及其制备方法和应用

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200360365A1 (en) * 2018-01-05 2020-11-19 Instutut National de la Sante et de la Researche Medicale Substituted halo-quinoline derivates for use in the treatment of lymphomas and leukemia
US12048693B2 (en) 2018-01-05 2024-07-30 Centre National De La Recherche Scientifique Substituted halo-quinoline derivatives, method of preparation and applications thereof
WO2020109039A1 (fr) 2018-11-28 2020-06-04 Basf Se Composés pesticides
WO2021219513A1 (fr) 2020-04-28 2021-11-04 Basf Se Composés pesticides
CN115260164A (zh) * 2021-05-01 2022-11-01 杭州星鳌生物科技有限公司 新型4(3h)-喹唑啉酮类似物的制备方法、结构组成及其在抗肿瘤药物中的应用
CN115260164B (zh) * 2021-05-01 2024-03-26 杭州星鳌生物科技有限公司 新型4(3h)-喹唑啉酮类似物的制备方法、结构组成及其在抗肿瘤药物中的应用
CN115466211A (zh) * 2022-06-09 2022-12-13 中国人民解放军空军军医大学 一种n-苯基喹啉-4-胺类化合物及其应用
CN115466211B (zh) * 2022-06-09 2024-02-23 中国人民解放军空军军医大学 一种n-苯基喹啉-4-胺类化合物及其应用
CN116693452A (zh) * 2023-05-24 2023-09-05 中山大学 一种喹啉衍生物及其制备方法和应用
CN116693452B (zh) * 2023-05-24 2024-07-02 中山大学 一种喹啉衍生物及其制备方法和应用

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