WO2013107278A1 - Composés anticancéreux d'un type nouveau synthétisés à partir de la réaction de dérivés de cétone et d'indole - Google Patents

Composés anticancéreux d'un type nouveau synthétisés à partir de la réaction de dérivés de cétone et d'indole Download PDF

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Publication number
WO2013107278A1
WO2013107278A1 PCT/CN2013/000002 CN2013000002W WO2013107278A1 WO 2013107278 A1 WO2013107278 A1 WO 2013107278A1 CN 2013000002 W CN2013000002 W CN 2013000002W WO 2013107278 A1 WO2013107278 A1 WO 2013107278A1
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WIPO (PCT)
Prior art keywords
group
ring
cancer
aryl
formula
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PCT/CN2013/000002
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English (en)
Chinese (zh)
Inventor
杨更亮
宋亚丽
刘晓明
杨春柳
马正月
刘玉欣
Original Assignee
Yang Gengliang
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Publication of WO2013107278A1 publication Critical patent/WO2013107278A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • Novel anticancer compounds synthesized by reaction of ketones with anthraquinone derivatives
  • the invention relates to the reaction of ketones and terpenoids under acid catalysis to form a novel class of terpenoids, in particular to the preparation and anticancer use of such novel compounds.
  • Cancer is mainly caused by chemical, physical, biological (mycotoxin, virus, etc.) and environmentally-changing carcinogenic factors. Cancer is divided into esophageal cancer, lung cancer, breast cancer, liver cancer, etc. due to different parts of the body.
  • anticancer drugs such as cisplatin, vinblastine, vincristine, camptothecin and its derivatives, paclitaxel, etc., but it has no activity and little or no toxicity.
  • a broad-spectrum or narrow-spectrum anticancer drug appears. Therefore, the development and exploration of a new compound with low-toxic, broad-spectrum and narrow-spectrum anticancer activity with dual efficacy and therapeutic and preventive effects has become an important research work.
  • One aspect of the present invention provides a novel anticancer compound represented by the general formulae (1) and (II).
  • Z is selected from the group consisting of 0, S, R ⁇ CRi;
  • Z 2 is selected from the group consisting of 0, S, NR 2 , CR 2 ;
  • Z 3 is selected from the group consisting of 0, S, NR 3 , CR 3 ;
  • Z 4 is selected from the group consisting of 0, S, NR
  • Ri, R 2 , and R 4 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, Cwo-hydrocarbyl, 2() -hydrocarbyloxy, C 2Q -hydrocarbylcarbonyl,
  • the hydrocarbyl moiety can be optionally substituted with one or more halogen atoms independently selected from the group consisting of fluorine, chlorine, bromine and iodine.
  • R 5 is each independently selected from the group consisting of hydrogen, d. 4 -hydrocarbyl, Cw-hydrocarbyloxy, Cw-hydrocarbylcarbonyl, Cw-hydrocarbylcarbonyloxy, phenyl ring or substituted benzene ring.
  • R 7 is selected from the group consisting of hydrogen, Cn' hydrocarbyl, hydrocarbyloxy, hydrocarbylcarbonyl, _ 2 . a hydrocarbylcarbonyloxy group, an aryl group, an arylalkyl group or a -CH 2 -NR U R 12 , wherein Ru, R 12 are each independently selected from a C ⁇ -hydrocarbyl group or both are bonded to each other by 0, N or CH 2 Or a six-membered ring.
  • R 9 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, nitro, -C 3 perfluoroalkyl, ⁇ -decyloxy, C 3 6 epoxyalkyl, -CH 2 -C 3 .C 6 epoxy fluorenyl, benzyloxy, saturated or unsaturated, linear or branched alkane a C 3 _C 1 () aromatic heterocyclic ring, a C 3 -C 1e heterocyclic ring-(C r C 4 ) alkylene group, wherein the heterocyclic ring contains at least one hetero atom N, 0 or 8, -NR 13 Ri4- Ri 3 and R 14 are the same or different and are selected from hydrogen, linear or branched CLC 4 fluorenyl, C 3 -C 6 cyclodecyl, dC 6 decanoyl, aryl, halogen, azide, nitro, cyanide base.
  • R 10 is selected from the group consisting of hydrogen, C ⁇ o-hydrocarbyl, d.-hydrocarbylcarbonyl, aryl, and aryl.
  • a t is selected from the group consisting of 0, S, S (0), S (O) 2 , and NR 1S .
  • R 15 is selected from the group consisting of hydrogen, Cwo-hydrocarbyl, C l-20 -hydrocarbyl, aryl, and aryl.
  • Another aspect of the present invention provides a method for producing a novel anticancer compound represented by the formula (1) and the formula (H), which is as follows:
  • a compound of the formula (I) or the formula (IV) is reacted with a compound of the formula (V) in the presence of a catalyst to obtain a compound of the formula (I) or the formula ( ⁇ ).
  • the catalyst in the method of preparing the compound of the formula (1), the formula (II), may be hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, sulfamic acid, silicotungstic acid, Phosphotungstic acid, phosphomolybdic acid, other Lewis acids or heteropolyacids.
  • Another aspect of the invention provides a method of reacting a ketone with an anthracene derivative to form a new compound.
  • the A ring may be selected from a five-membered or six-membered ring, and the five- or six-membered ring may be selected from an aromatic ring, an aromatic heterocyclic ring, a non-aromatic ring or a non-aromatic heterocyclic ring; and the B ring may be selected from an open ring and a five-membered ring.
  • a ring or a six-membered ring, which may be selected from a non-aromatic ring or a non-aromatic heterocyclic ring; and R 9 , R 1 () have the same meanings as defined above.
  • the compounds of formula (1), formula (II) may be prepared in crystalline or amorphous form, and if crystalline, they may optionally be solvates, for example as hydrates.
  • the present invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvents, such as water.
  • a compound of the formula (V) is added dropwise under reflux of an ethanol solution of the compound of the formula (III) or the formula (IV) and the catalyst.
  • the ethanol solution is kept at a temperature for 3 hours after the addition, and the solvent is evaporated to obtain a mixture containing the compound of the formula (I) or (II) and other side reaction products, which are separated and purified by a silica gel column to obtain the formula (I) or ( II) Compounds.
  • the compound of the formula (1) and the formula (II) of the present invention having anticancer activity can be administered to a variety of animals including mammals, particularly humans.
  • the dose may be administered by a medical practitioner according to the condition of the subject, including, for example, the severity of the disease of the patient, General health, weight, age, etc. are determined.
  • the biologically active pharmaceutical compounds of the present invention may be administered by various suitable routes including, for example, transdermal, transdermal and topical administration, and the like.
  • the compounds represented by the formulas (1) and (II) of the present invention can be formulated into pills, tablets, capsules, and the like, and can be administered to cancer cells by oral administration through the digestive tract for the treatment of cancer and the like.
  • the frequency of administration of the biologically active pharmaceutical compounds of the present invention represented by the general formulae (1), (II) can also be determined by various factors including, for example, the specific disease to be treated, the general health of the subject, and the like. Usually, 1-3 times a day for human subjects.
  • the present invention provides, in another aspect, the use of a novel anticancer compound or solvate of the formula (1), (II) for the treatment or prevention of cancer or the like, comprising topically administering the compound to a patient, or to the patient's whole body The compound is administered.
  • the cancer cell comprises gastric cancer, intestinal cancer, liver cancer, pancreatic cancer, esophageal cancer, chondrosarcoma, melanoma, Hodgkin's disease, leukemia, breast cancer, prostate cancer, thyroid cancer, skin cancer , bladder cancer, etc.
  • the reaction liquid recovers ethanol to obtain 4-(lH-indol-3-yl)-6-fluoro-2/-benzothiopyran or 4-(1H-indol-3-yl)thiophene [2, 3-b] a mixture of 2H-thiopyran and other side reaction products.
  • Purification by silica gel column chromatography to give 4-(lH-indol-3-yl)-6-fluoro-2H-benzothiopyran (a compound of formula (I) or 4-indol-3-yl) Thieno[2,3-b] 2H-thiopyran (a compound of formula (II)), yield 30-50%.
  • the measured physical and chemical constants are shown in Table 1 (Compound 1 or Compound 15).
  • novel anticancer compound series drugs of the present invention such as 4-(1-indol-3-yl)-6-fluoro-2H-benzothiopyran (Compound 1 of Table 1), 4-(lH- ⁇ -3- -8-fluoro-2H-benzothiopyran (Compound 2 of Table 1), 4-(1 ⁇ -indol-3-yl)-6-chloro-2H-benzothiopyran (Compound 3 of Table 1) , 4-(lH-indol-3-yl)-8-chloro-2H-benzothiopyran (Compound 4, Table 1), 4-(1-indol-3-yl)-6-methyl -2H-benzothiopyran (Compound 5 of Table 1), 4-(lH-indol-3-yl)-8-methyl-2H-benzothiopyran (Compound 6 of Table 1), 4-( lH-indodo
  • Cell cancer cells were purchased from the Chinese Academy of Military Medical Sciences]
  • Cell culture RPMI Medium 1640 cell culture medium, 10% (volume fraction) calf serum and 0.01% L-glutamine were formulated into culture medium. The cultured cells were routinely cultured at 37 ° C, 5% (volume fraction) CO, and saturated humidity, and the cells in the logarithmic growth phase were used for the experiments.
  • MTT assay Digest the cells with 0.25% trypsin and make a single cell suspension, inoculate 96-plates at 6000-7000 cells per well, 37'C, 5% (volume fraction) C0 2 overnight, add different concentrations For the samples, the culture medium and the non-drug-treated cells were used as the blank control and the negative control, respectively, and 8 replicate wells were set in each group, and the culture was continued for 48 or 72 hours.
  • Inhibition rate ( ⁇ negative control - ⁇ experimental sample) I ( ⁇ negative control - ⁇ blank control) xlOO% It can be seen from the experimental results that the new anti-cancer compound series compounds also have different degrees of inhibitory activity on cancer cells.
  • the medicaments of the present invention are synthesized by using various cyclic ketones as raw materials, and various chemical reagents used in the synthesis reaction process are common and simple and easy to obtain, and the reaction yield is also ideal.
  • pharmacological toxicology experiments it was shown that the series of compounds of the present invention have different degrees of inhibitory activity against cancer cells.
  • the compound of the invention is widely used in the field of anticancer, and has broad research value and application prospect.

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

Abstract

L'invention concerne des utilisations de composés anticancéreux d'un type nouveau représentés par la formule (I) et la formule (II), de leurs dérivés, de leurs stéréo-isomères ou de mélanges racémiques ou non racémiques de leurs stéréo-isomères ou de leurs sels ou solvates pharmaceutiquement acceptables, dans le traitement ou la prévention du cancer, et l'invention concerne en outre leur procédé de préparation et leur bioactivité.
PCT/CN2013/000002 2012-01-18 2013-01-04 Composés anticancéreux d'un type nouveau synthétisés à partir de la réaction de dérivés de cétone et d'indole WO2013107278A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2012100280770A CN103214470A (zh) 2012-01-18 2012-01-18 酮类与吲哚衍生物反应合成的新型抗癌化合物
CN201210028077.0 2012-01-18

Publications (1)

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WO2013107278A1 true WO2013107278A1 (fr) 2013-07-25

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007047646A2 (fr) * 2005-10-14 2007-04-26 Janssen Pharmaceutica, N.V. Dihydroisoindolones substituées pouvant être employées dans le traitement de troubles des kinases
WO2011045344A1 (fr) * 2009-10-13 2011-04-21 Pierre Fabre Medicament Dérivés de pyrazolopyridine comme agent anticancer

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2006257815A1 (en) * 2005-06-10 2006-12-21 Bipar Sciences, Inc. PARP modulators and treatment of cancer

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007047646A2 (fr) * 2005-10-14 2007-04-26 Janssen Pharmaceutica, N.V. Dihydroisoindolones substituées pouvant être employées dans le traitement de troubles des kinases
WO2011045344A1 (fr) * 2009-10-13 2011-04-21 Pierre Fabre Medicament Dérivés de pyrazolopyridine comme agent anticancer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
QUEIROZ, M.J.R.P. ET AL.: "Synthesis of new heteroaryl and heteroannulated indoles from dehydrophenylalanines: antitumor evaluation", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 16, no. 10, 2008, pages 5584 - 5589, XP022673140 *
ZHUNGIETU, G.I. ET AL.: "Reaction of some pyrylium salts with hydrazine", KHIMIYA GETEROTSIKLICHESKIKH SOEDINENII., no. 1, 1973, pages 38 - 40 *

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