[go: up one dir, main page]

WO2011095027A1 - Dérivés pyridyl cyanoguanidines - Google Patents

Dérivés pyridyl cyanoguanidines Download PDF

Info

Publication number
WO2011095027A1
WO2011095027A1 PCT/CN2010/078868 CN2010078868W WO2011095027A1 WO 2011095027 A1 WO2011095027 A1 WO 2011095027A1 CN 2010078868 W CN2010078868 W CN 2010078868W WO 2011095027 A1 WO2011095027 A1 WO 2011095027A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyano
hexyl
pharmaceutically acceptable
compound
pyridyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2010/078868
Other languages
English (en)
Chinese (zh)
Inventor
张和胜
陈鑫
陈英伟
从俊杰
李幸稳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tianjin Michele Sci Tech Development Co Ltd
Tianjin Hemay Biotechnology Co Ltd
Original Assignee
Tianjin Michele Sci Tech Development Co Ltd
Tianjin Hemay Biotechnology Co Ltd
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.)
Filing date
Publication date
Priority claimed from PCT/CN2010/000156 external-priority patent/WO2010088842A1/fr
Application filed by Tianjin Michele Sci Tech Development Co Ltd, Tianjin Hemay Biotechnology Co Ltd filed Critical Tianjin Michele Sci Tech Development Co Ltd
Priority to US13/577,218 priority Critical patent/US8604065B2/en
Priority to CN201080063137.1A priority patent/CN102740850B/zh
Publication of WO2011095027A1 publication Critical patent/WO2011095027A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • This application relates to terpenoids and their use, and in particular to pyridyl-containing cyanoguanidine derivatives and their use. Background technique
  • the present invention is a compound of the following formula (I) or a pharmaceutically acceptable salt thereof,
  • X is N or CH
  • n is an integer from 3 to 10;
  • Y is -0-, -S-, -N; -OC(O)- or -NR 3 C(O)-, wherein R 3 is H or C alkyl;
  • R! is a decyloxy group substituted by one or more F or C1, preferably a decyloxy group substituted by at least two F or C1 at the 2- or 3-position of the phenyl ring;
  • R 2 is H, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, nitro, decanoylamino, aminosulfonyl, halogen, any alkyl substituted by halogen or optionally substituted by halogen Alkoxy group.
  • the present application is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the above formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.
  • the present application relates to a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, including, preferably, a compound of formula (II) in the presence of a base
  • R is a C 1-6 alkyl or aryl group or an aryl group substituted by a halogen, a C 1-6 alkyl group, X, Y, ⁇ , and
  • R 2 is defined as before, and
  • the resulting compound of formula (I) is formulated into a pharmaceutically acceptable salt thereof.
  • the present application relates to a method of inhibiting tumor cell growth comprising administering an inhibitory effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, to said tumor cell.
  • the present application is also directed to a method of treating a tumor in an individual comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.
  • the inventors have found through research that, for the compound of the formula (I), if the terminal benzene ring has at least one decyloxy group substituted by at least one F or C1, it is preferably at the 2- or 3-position thereof, particularly At the 2-position, these compounds have unexpectedly high cell viability compared to other substituted compounds.
  • the compounds of the formula of the present application have improved hydrophilicity and are advantageous in forming corresponding formulations.
  • d- 6 pit group means a straight or branched saturated hydrocarbon group having one to six carbon atoms, preferably a C M alkyl group having one to four carbon atoms.
  • Examples of the Ci- 6 alkyl group specifically include But not limited to: mercapto, ethyl, propyl, isopropyl, butyl, isobutyl, 1-mercaptopropyl, tert-butyl, pentyl, isopentyl, 1,2-dimercaptopropyl Base, 2,2-dimercaptopropyl, hexyl, isohexyl, and the like.
  • d- 6 alkoxy means a straight or branched saturated alkoxy group having one to six carbon atoms, preferably a CM alkoxy group having one to four carbon atoms. Specifically, but not limited to: decyloxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 1-mercaptopropoxy, tert-butoxy, pentyloxy, iso Pentyloxy, 1,2-dimercaptopropoxy, 2,2-dimercaptopropoxy, hexyloxy, isohexyloxy and the like.
  • aryl means a monocyclic or fused aromatic ring containing from 6 to 20 carbon atoms.
  • Non-limiting examples include benzene Base, naphthyl.
  • halogen means fluoro, chloro, bromo or iodo.
  • pharmaceutical composition refers to a formulation of a compound of the present application and a medium which is generally accepted in the art for delivery of a biologically active compound to a mammal such as a human.
  • Such media include all pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, excipient, or helper that has been approved by the U.S. Food and Drug Administration (FDA) for use in humans or animals.
  • Agents, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, disintegrating agents, solvents or Emulsifiers and the like have various forms of carriers which do not have side effects in constituting the pharmaceutical composition.
  • inhibitory effective amount and “therapeutically effective amount” are used interchangeably, meaning that the compound of the present application is sufficient to effectively inhibit tumor cells or treatment when administered to a human, preferably a mammal, more preferably to a human.
  • the amount of tumor The amount of the compound of the present application which constitutes an "inhibitory effective amount, or a therapeutically effective amount” will vary depending on the state of the selected compound or the subject to be administered, but those skilled in the art will, based on their own knowledge and the disclosure of the present application. An effective amount of a compound of the present application can be determined according to common knowledge in the art.
  • treating means administering a compound or formulation of the invention to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • “Pharmaceutically acceptable salts” include “pharmaceutically acceptable acid addition salts” and “pharmaceutically acceptable base additions”
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and which are formed using inorganic or organic acids.
  • the inorganic acid is, for example but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • the organic acid is, for example but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, Aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexyl Alkyl sulfamic acid, dodecyl sulphate, ethan
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic base or an organic base to the free acid. In the present application, salts derived from inorganic bases are preferred, including but not limited to sodium, potassium, A compound of the invention I) or a pharmaceutically acceptable salt thereof
  • X is N or CH
  • n is an integer from 3 to 10;
  • Y is -0-, -S-, -NR 3 -, -OC(O)- or -NR 3 C(O)-, wherein R 3 is H or C 1-6 ;
  • Ri is a decyloxy group substituted by one or more F or C1, preferably a decyloxy group substituted by at least two F or C1 at the 2- or 3-position of the phenyl ring;
  • R 2 is H, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, nitro, decanoylamino, aminosulfonyl, halogen, any d- 6 alkyl substituted by halogen or optionally Halogen substituted d- 6 alkoxy.
  • the compounds of formula (I) in relation to various aspects of the present application are methoxy groups substituted with at least two F or C1, preferably a decyloxy group substituted by two F, most preferably It is a trifluoromethoxy group.
  • the 2-position of the phenyl ring is 2-position of the phenyl ring.
  • X is N, more preferably, N is in the para position of the thiol group.
  • Y is -0-, -S -, -NR 3 - , -OC (O) - or -NR 3 C (O) -, wherein R 3 is H or Yue group; preferably, Y is -O-, -NR 3 -, -OC(O)- or -NR 3 C(O)-, wherein R 3 is H or a fluorenyl group; more preferably, Y is -0-, -NH- or -OC(O)-; Most preferably, Y is -0-.
  • n is an integer from 4-8.
  • X is N
  • n is an integer of 4-8;
  • Y is -O-, -S -, -NR 3 -, -OC(O)- or -NR 3 C(O)-, wherein R 3 is H or C 1-6 alkyl;
  • i is a decyloxy group substituted by at least two F, preferably a methoxy group substituted by at least two F at the 2-position of the phenyl ring;
  • n is an integer of 4-8;
  • ⁇ is -0-, -NH- or -OC(O)-;
  • i is a methoxy group substituted by at least two F, preferably a decyloxy group substituted by at least two F at the 2-position of the phenyl ring;
  • X is N
  • n is an integer of 4-8;
  • Y is -0-, -NH- or -OC(O)-;
  • Ri is OCF 3 or OCHF 2, preferably located at the 2-position of the phenyl ring OCF 3 or OCHF 2; 1 2 to 11, C 1-4 alkyl, F, C1 or Br.
  • X is N
  • n is an integer of 4-8;
  • Y is -O-
  • Ri is OCF 3 or OCHF 2, preferably located at the 2-position of the phenyl ring OCF 3 or OCHF 2; 1 2 to 11, C 1-4 alkyl, F, C1 or Br.
  • the application provides the following compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • the present application also provides a pharmaceutical composition comprising A therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present application, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is for use in treating cancer.
  • the compound of the formula (I) or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of the present application can inhibit mammalian, preferably human, tumor cells.
  • tumors include, but are not limited to, pancreatic cancer, acute lymphocytic leukemia, lung cancer such as lung adenocarcinoma, pharyngeal squamous cell carcinoma, lymphoma, gastric cancer, breast cancer, melanoma, neuroendocrine tumor, intestinal cancer, multiple myeloma, fibrosarcoma , prostate cancer or liver cancer. Therefore, the compound of the formula (I) of the present application or a pharmaceutically acceptable salt thereof can be expected as a drug for treating the above tumor (cancer).
  • the pharmaceutical composition contains a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable fatty acid, stearoyl sulfate, stearoyl sulfate, stearoyl sulfate, stearoyl sulfate, stearoyl sulfate, a pharmaceutically acceptable carrier.
  • the effective amount may range from 0.01 to 99.99%, preferably from 0.1 to 75%, more preferably from 0.5 to 50% by weight of the composition.
  • compositions referred to in the present application can be formulated into various preparations for various routes of administration for therapeutic administration.
  • it is prepared in a form suitable for topical administration, a form for oral administration, a form for intravenous administration, and a form for intramuscular administration.
  • the preparation may be administered to an individual or a patient in need of the drug by various routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal, and the like.
  • the topical preparation may be in the form of a transdermal patch, a suppository, a paste, a lotion, a paste, a gel, or the like.
  • Topical formulations may include one or more penetrants, thickeners, diluents, emulsifiers, dispersing agents or binding agents.
  • the composition can be used with or with the penetration enhancer.
  • the penetration enhancer includes a chemical penetration enhancer and a physical penetration enhancer that facilitates transport of the composition through the skin.
  • the permeation enhancer is selected from the group that is compatible with the compound and is present to promote delivery of the compound through the skin of the individual, for example, for the compound The transmission of the individual's systemic circulation.
  • the compounds may be prepared alone or in combination with suitable additives to prepare tablets, powders, granules and capsules, for example, with conventional additives such as lactose, mannitol, corn starch or potato starch; , such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; with disintegrants such as corn starch, potato starch or sodium carboxymethyl cellulose; and lubricants such as talc or magnesium stearate; If necessary, combine with diluents, buffers, wetting agents, preservatives and flavoring agents. It is especially advantageous that the combination of the compound and buffer provides the protection of the compound against the low pH gastric acid environment.
  • an enteric coating may also be preferred to provide an enteric coating to avoid precipitation of the compound when passed through the stomach.
  • a similar oil, synthetic fatty acid glyceride, higher fatty acid ester or propylene glycol) is dissolved, suspended or emulsified into the injection formulation. If desired, it can be combined with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • Particularly beneficial solubilizers include Vitamin E TPGS (da-tocopherol polyethylene glycol 1000 succinate), cyclodextrin, and the like.
  • the present application relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (II)
  • R is a C 1-6 alkyl or aryl group or an aryl group substituted by a halogen, a C 1-6 alkyl group, X, Y, ⁇ , and
  • R 2 is defined as before, and
  • the resulting compound of formula (I) is formulated into a pharmaceutically acceptable salt thereof.
  • the compound of the formula (II) and the formula (III) may be used in a molar ratio of 1:1, but it is understood that one of the excess will favor the yield of the final product.
  • the molar ratio of the compound of the formula (II) to the compound of the formula (III) may be from 1.2 to 1.5:1.
  • the reaction is carried out in the presence of a base.
  • the base may be an organic base, preferably a tertiary amine such as triethylamine or pyridine.
  • the molar ratio of the amount to the reference reactant may be from 1.5 to 2.5:1.
  • the reaction can be carried out in a polar organic solvent which is inert to the reaction, preferably in a solvent having a relatively high polarity.
  • a polar organic solvent which is inert to the reaction
  • the reaction temperature of the above reaction is not limited, and it can be generally carried out at normal temperature. It is preferred to place the reaction system under inert gas protection.
  • the present application relates to a method of inhibiting tumor cell growth comprising administering an inhibitory effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, to said tumor cell.
  • the present application is also directed to a method of treating a tumor in an individual comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.
  • sodium chlorodifluoroacetate 723 mg (5.0 mmol), sodium hydroxide 220 mg (5.5 mmol) and 4-chlorocatechol 838 mg (5.5 mmol) were added to N, N.
  • dimethylformamide 7.0 mL and water 0.1 mL the temperature was slowly raised to 125 ° C for 1.0 hour. Stop the reaction and drop to room temperature. 10 mL of 1.0 mol/L hydrochloric acid was added to the reaction solution, and the solution was adjusted to be acidic, and then 50 mL of water and 20 mL of ethyl acetate were added.
  • the lb compound (5-tert-butyl-2-difluoromethoxyphenol) and the lc compound (5-mercapto-2-difluoromethoxyphenol) were prepared in a similar manner to the preparation of la.
  • the temperature of the external bath was controlled to 0 ⁇ 5 °C, and sodium nitrite 33 mg (0.48 mmol) was added to the solution of 4-amino-2-trifluoromethoxyphenol 77 mg (0.4 mmol). % (w/w) pyridine fluoride solution in 0.8 mL.
  • the bath was raised to 5 ⁇ 10 °C, and it was shed for 30 min. The solution was brownish red.
  • stannous chloride dihydrate 90 mg (0.4 mmol) and tetrabutylammonium fluoride trihydrate 105 mg (0.4 mmol) were successively added, and the temperature was slowly raised to 100.
  • the compound of 2b (6-(tert-butoxycarbonylamino)hexyl 2-(trifluorophosphonio)benzoate) was synthesized in a similar manner to the preparation of 2a.
  • 5-Chloro-2-difluoromethoxyphenol 189 mg (0.97 mmol) and sodium hydride 47 mg (1.94 mmol) were added to N,N-dimercaptoamide 3.0 mL with argon protection and ice-bath stirring. Medium, stirring for 1.0 h.
  • a solution of 721 mg (1.94 mmol) of 6-aminodecanoic acid-tert-butylbenzenesulfonate in N,N-dimercaptoamide (3.0 mL) was added dropwise to the above solution. After the dropwise addition, the mixture was stirred at room temperature overnight.
  • the compound of 3b (t-butyl 6-(2-(trifluorodecyloxy)phenylamino)hexyl decanoate) was synthesized in a similar manner to the preparation of 3a.
  • diphenyl-N-cyanocarbonate 10.0 g (0.042 mol) and 4-aminopyridine 2.44 g (0.026 mol) were sequentially added to tetrahydrofuran (re-distilled) 10 mL, and the temperature was slowly raised to At 50 ° C, the reaction was carried out for 2.5 h, and the solid was completely dissolved. Stir at room temperature overnight. The reaction was stopped and the reaction solution was placed in a water tank for 20 min. After suction filtration, a solid of 4.7 g was obtained, and the yield was 75.9 %.
  • O-methoxyphenol 745 mg, dissolved in 10 mL DMF, 144 mg sodium hydride, stirred for 20 min, 7-(1,3-dioxoisoindol-2-yl)heptyl 4-methyl 1.25 g of benzoic acid ester was added to the reaction system. Stir the reaction overnight. After 16 h, 50 mL of water and 50 mL of ethyl acetate were added to the system, and the mixture was shaken well, and then separated. The aqueous layer was extracted with 50 mL of ethyl acetate and then combined with organic layer.
  • the 9b compound (8-(2-(trifluoromethoxy)phenoxy)octyl-1-amine) was synthesized in a similar manner to the compound 9a.
  • Triethylamine 0.17 mL (1.2 mmol) and 1-cyano-2-phenyl-3-(pyridin-4-yl)-isourea 140 mg (0.59 mmol) were sequentially added to 6 under argon atmosphere with stirring.
  • Example 14 N-Cyano-N,-(6-(2-trifluoromethoxy-4-nitrophenoxy)hexyl)-N,,-(4-pyridyl)indole
  • Example 15 N- ⁇ J ⁇ -N,-(6-(2-Trifluoromethoxy-4-fluorophenyliLi hexyl)-N"-(4-pyridinium)
  • Control compound 2 N- ⁇ LN,-(6-(4-chlorophenylfl ⁇ )hexyl)-1 ⁇ "-(4-pyridyl)3 ⁇ 4_3 ⁇ 4 ⁇ Control compound 3. N-cyano-N,-(6-(2-chlorophenyl)hexyl)-N,,-(4-' is 3 ⁇ 4J ⁇
  • Control compound 4 ⁇ - ⁇ -(6-(2-indolyloxy)hexyl)- ⁇ -(4-pyridinium)
  • Human pancreatic cancer AsPC-1 Human acute lymphoblastic leukemia cell line CCRF-CEM/T; human lung adenocarcinoma NCI-H1975; human squamous cell carcinoma Fadu; human B lymphoma BA25; human B lymphoma BA91; Human B lymphoma BA127; human gastric cancer NCI-N87; human non-small cell lung cancer A549; human liver cancer SK-Hep-1; human lung cancer NCI-H460; human prostate cancer PC-3.
  • AsPC-1 90% RPMI1640, 10% FBS;
  • NCI-N87 90% RPMI1640, 10% FBS;
  • the cells were trypsinized, and a single cell suspension was prepared in complete medium.
  • 96 well microplates were seeded with appropriate concentrations of cells (AsPC-1: 8000 cells/well; CI-H1975: 5000 cells/well; Fadu: 6000 cells/well; CI-N87: 15000 cells/well). The cells are attached.
  • test compound was dissolved in DMSO to make a 2 mM stock solution, diluted to 20 ⁇ or 2 ⁇ of 10 ⁇ working solution in basal medium (without serum), and diluted in 1/3 gradient to maintain the DMSO concentration during the dilution. No change, a total of 8 dose groups. 20 ⁇ M of lOx compound working solution was added to the experimental wells, and finally the volume per well was 200 ⁇ , and the DMSO concentration was 1%. ; also set a solvent-free control group (PC) without compound and no A solvent control group (NC) containing cells and compounds. Continue to culture the cells for 72 h.
  • PC solvent-free control group
  • NC solvent control group
  • the activity of the cells was measured by a tetrazolium salt reduction method (MTT method).
  • MTT method tetrazolium salt reduction method
  • the specific method was to aspirate the medium in the well, and add a basal medium containing 0.5 mg/ml MTT, 100 ⁇ /well, and continue to culture 3 h, then remove the medium containing MTT, add DMSO 100 ⁇ /well, dissolve the ⁇ crystal, and measure the OD 490 nm value by enzyme microplate.
  • the cells were cultured under the following conditions:
  • Complete medium 90% RPMI 1640, 10% FBS; C, 5% C0 2 , cultured in saturated humidity. After the cells are cultured to the end of logarithmic growth, the cells are diluted with the complete medium to the desired concentration.
  • 96-well microtiter plates were seeded with appropriate concentrations of cells (CCRF-CEM/T: 20000 cells/well; BA25: 20000 cells/well; BA91: 60000 cells/well; BA127: 60000 cells/well).
  • test compound was dissolved in DMSO to make a 2 mM stock solution, diluted to 20 ⁇ or 2 ⁇ of 10 ⁇ working solution in basal medium (without serum), and diluted in 1/3 gradient to maintain the DMSO concentration during the dilution. No change, a total of 8 dose groups.
  • a solvent control group (PC) containing no compound and a solvent control group (NC) containing no cells and compounds were also provided. Continue to culture the cells for 72 h.
  • the activity of the cells was measured by the tetrazolium salt reduction method (MTT method) by adding 30 ⁇ l/well of PBS containing 2.5 mg/ml MTT, continuing to culture for 3 hours, and then adding triple lysate (10% SDS, 5%). Isobutanol, 0.012 M HC1) 100 ⁇ /well, dissolved in ⁇ crystal at room temperature, and measured by OD 570 nm.
  • MTT method tetrazolium salt reduction method
  • Table 1 shows the in vitro growth inhibitory activity of some compounds against Aspc-1.
  • Table 1 In vitro growth inhibitory activity of some compounds on Aspc-1 Compound number IC 50 (nM) Compound number IC 50 (nM) Control 2 19 Control 3 7.2 Control 4 7.3 Control 1 135 Example 11 2.1 Example 12 2.3 Example 16 0.9 As can be seen from Table 1, Examples 11 and 12 The in vitro growth inhibitory activity against 16 human pancreatic cancer AsPC-1 was significantly better than that of controls 1-4, indicating a significant effect of these compounds on pancreatic cancer.
  • Table 2 shows the in vitro growth inhibitory activity of some compounds on CCRF-CEM-T. Table 2. In vitro growth inhibitory activity of some compounds on CCRF-CEM-T
  • Table 5 shows the in vitro growth inhibitory activity of some compounds against BA127.
  • Example 11 shows the in vitro growth inhibitory activity of Example 11 against six tumor cell models compared to Control 2 and 4 is much better.

Landscapes

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

Abstract

L'invention concerne des composés de formule (I) ou leurs sels pharmaceutiquement acceptables, et leur utilisation pour le traitement du cancer, les définitions de X, Y, R1, R2 et n étant décrites dans la description.
PCT/CN2010/078868 2010-02-04 2010-11-18 Dérivés pyridyl cyanoguanidines Ceased WO2011095027A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US13/577,218 US8604065B2 (en) 2010-02-04 2010-11-18 Pyridyl cyanoguanidine derivatives
CN201080063137.1A CN102740850B (zh) 2010-02-04 2010-11-18 吡啶基氰基胍衍生物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/CN2010/000156 WO2010088842A1 (fr) 2009-02-06 2010-02-04 Compositions pharmaceutiques contenant des pyridyl-cyanoguanidines, leurs méthodes de préparation et utilisations
CNPCT/CN2010/000156 2010-02-04

Publications (1)

Publication Number Publication Date
WO2011095027A1 true WO2011095027A1 (fr) 2011-08-11

Family

ID=44355655

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2010/078868 Ceased WO2011095027A1 (fr) 2010-02-04 2010-11-18 Dérivés pyridyl cyanoguanidines

Country Status (1)

Country Link
WO (1) WO2011095027A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1258278A (zh) * 1997-05-29 2000-06-28 里奥药物制品有限公司 作为细胞增殖抑制剂的氰基胍
CN1509283A (zh) * 2001-05-24 2004-06-30 ������ҩ�����޹�˾ 新的吡啶基氰基胍化合物
WO2010088842A1 (fr) * 2009-02-06 2010-08-12 天津和美生物技术有限公司 Compositions pharmaceutiques contenant des pyridyl-cyanoguanidines, leurs méthodes de préparation et utilisations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1258278A (zh) * 1997-05-29 2000-06-28 里奥药物制品有限公司 作为细胞增殖抑制剂的氰基胍
CN1509283A (zh) * 2001-05-24 2004-06-30 ������ҩ�����޹�˾ 新的吡啶基氰基胍化合物
WO2010088842A1 (fr) * 2009-02-06 2010-08-12 天津和美生物技术有限公司 Compositions pharmaceutiques contenant des pyridyl-cyanoguanidines, leurs méthodes de préparation et utilisations

Similar Documents

Publication Publication Date Title
CN116323616B (zh) 用作shp2抑制剂的化合物及其应用
EP2120578B1 (fr) Composés inhibiteurs de kinase
CN112661745A (zh) 用作cdk7激酶抑制剂的化合物及其应用
RU2600928C2 (ru) Цианохинолиновые производные
JP5670325B2 (ja) キナーゼ阻害化合物としての置換されたピリダジンカルボキサミド化合物
JP2022509534A (ja) Ｂｅｔ阻害剤としてのヘテロ環式化合物
CA3011254A1 (fr) Derive de quinazolinone, son procede de preparation, composition pharmaceutique, et applications associees
JP2017534657A (ja) 新型シチジン誘導体およびその適用
AU2019218187A1 (en) Dioxinoquinoline compounds, preparation method and uses thereof
RU2129546C1 (ru) 6,9-бис(аминозамещенные)-бензо(g)изохинолин-5,10-дионы, способ их получения, фармацевтическая композиция на их основе и способ ингибирования опухолей у млекопитающих
AU2016262642A1 (en) Substituted pyridazine carboxamide compounds as kinase inhibitor compounds
CN111825700A (zh) 一种吡嗪并噻唑类化合物、其应用及含其的药物组合物
KR20100132553A (ko) 신규한 ｎ-(2-아미노-페닐)-아크릴아미드
KR100364205B1 (ko) 나프탈이미도벤즈아미드 유도체 또는 그의 염
KR20140044790A (ko) 피페라진디온 화합물
CN115772170B (zh) 一种吡唑并[1,5-a]吡啶衍生物及其制备方法和应用
WO2011095027A1 (fr) Dérivés pyridyl cyanoguanidines
CN121127472A (zh) 蛋白质精氨酸酶甲基转移酶-5抑制剂及其医药用途
EP3750893A1 (fr) Composé de dioxazoline, son procédé de préparation et ses applications
US6034092A (en) 2-[2-[(2-hydroxyethyl)amino]ethy [l]-5-[[2-methylamino)ethyl]amino]indazolo4,3-gh]isoquinolin-6(2H)-one as antitumor agent
CN102740850B (zh) 吡啶基氰基胍衍生物
JP2004509897A (ja) シクロヘキシルアミン誘導体の立体選択的製造方法
CN118206507A (zh) 一种含硒化合物及其制备方法与用途
JP4328873B2 (ja) 放射線増感剤
CN116987073A (zh) 一种PI3Kα/HDAC6亚型选择性双重抑制剂及其应用

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201080063137.1

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10845110

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 13577218

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 07-01-2013)

122 Ep: pct application non-entry in european phase

Ref document number: 10845110

Country of ref document: EP

Kind code of ref document: A1