WO2012130160A1 - Dérivés d'aminopyridine contenant un cycle acridine et leur utilisation - Google Patents

Dérivés d'aminopyridine contenant un cycle acridine et leur utilisation Download PDF

Info

Publication number
WO2012130160A1
WO2012130160A1 PCT/CN2012/073303 CN2012073303W WO2012130160A1 WO 2012130160 A1 WO2012130160 A1 WO 2012130160A1 CN 2012073303 W CN2012073303 W CN 2012073303W WO 2012130160 A1 WO2012130160 A1 WO 2012130160A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
acridine
amino
pyridyl
trifluoro
Prior art date
Application number
PCT/CN2012/073303
Other languages
English (en)
Chinese (zh)
Inventor
李松
郑志兵
樊士勇
***
钟武
刘洪英
肖军海
谢云德
周辛波
陈伟
李行舟
Original Assignee
中国人民解放军军事医学科学院毒物药物研究所
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
Application filed by 中国人民解放军军事医学科学院毒物药物研究所 filed Critical 中国人民解放军军事医学科学院毒物药物研究所
Publication of WO2012130160A1 publication Critical patent/WO2012130160A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to an acridine ring-containing aminopyridine derivative, and more particularly to a compound represented by Formula I or Formula II, a process for the preparation thereof, and use thereof for the preparation of a medicament for inhibiting cell hyperproliferation. Background technique
  • Cancer is a disease that poses a serious threat to human health. Since the advent of the first anticancer drug in the 1940s, scientists have isolated and extracted a number of natural products with potential cytotoxic activity from plants. Based on this, a variety of clear anti-tumor have been obtained through structural modification. Active compounds in which vinblastine, etoposide, paclitaxel, etc. are successively approved for clinical treatment of cancer. However, these natural product drugs have limited resources, their molecular structures are complex, chemical synthesis is difficult, and it is difficult to scale production. Therefore, it is necessary to find a small molecule antitumor drug with a simple structure. Summary of the invention
  • the present invention is directed to an acridine ring-containing aminopyridine derivative having an activity of inhibiting cell hyperproliferation.
  • the first aspect of the invention provides a compound of formula I, hydrazine or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof.
  • R 2 , R 3 , R 4 , R 5 , R 7 or R 8 are each independently selected from hydrogen , hydroxyl, halogen, Amino, nitro, nitrile, trifluoromethyl, -OR 9 , -C(O)R 10 , -C(0)OR 9 , -NR 10 C(O)OR 9 , -OC(0)R 9 -NR 10 SO 2 R 9 , -SO 2 NR 10 R 9 , -NR 10 C(O)R 9 NR oR C - C o J3 ⁇ 4 ⁇ 3 ⁇ 4 ⁇ , C2 - C 10 Women ⁇ , C - C o Block ⁇ , C3-C10 ring ⁇ 3 ⁇ 4 > 3 ⁇ 4 ⁇ , C 3 -C 1Q cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero
  • R 6 is selected from the group consisting of hydrogen, trifluoromethyl, d-do alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 1Q cycloalkyl, C 3 -C 1Q cycloalkyl An alkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group and a heterocyclic alkyl group;
  • W selects ll -OR 9 , - NR 10 OR 9 , - NR 10 SO 2 R 9 , - NR 10 R 9 ;
  • R 9 Each is independently selected from the group consisting of hydrogen, hydroxy, halogen, trifluoromethyl, d-do alkyl, C 2 -C 10 alkenyl, C 2 -C 10 block, C 3 -C 10 cycloalkyl, C 3 - C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkane
  • the aryl, aryl, heteroaryl and heterocyclyl are optionally substituted by one to five (e.g., 1, 2, 3, 4, 5) groups independently selected from the group consisting of: hydroxy, hydroxy , amino, nitro and trifluoromethyl;
  • Preferred compounds have the structure of formulae IV, IV:
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , 11 8 are selected from the group consisting of hydrogen, halogen, nitro, nitrile, trifluoromethyl;
  • W is -NR 1() OR 9 or -NR 10 R 9 .
  • the compound is selected from the group consisting of:
  • the invention relates to a compound of formula I, II or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide synthesis thereof.
  • the substituted benzoic acid containing the leaving group L is used as a starting material, and the carboxyl group is thiolated by reacting with a thiolation reagent; and the oxime ester is converted into an amide group by reacting with ammonia water; under the action of P0C1 3 Removing a portion of water to convert the ugly amine bond to a cyano group; the substituted phenyl phthalocyanine containing the leaving group L is subjected to a base (for example, lithium amide) to remove the group-derived and substituted aminopyridine compound. Condensation reaction; hydrolysis of a cyano group to give a carboxyl group. Reacting with a 3-carboxy acridine ring, the carboxyl group on the acridine ring is reacted with the corresponding side chain to give a compound of formula I; L represents the leaving group and can be halogen;
  • the substituted benzoic acid containing the leaving group L is used as a starting material, and after the nitration reaction, a nitro group is introduced on the benzene ring; under the action of a base (for example, lithium), the group is removed and the substituted amino group is removed.
  • the pyridine compound undergoes a condensation reaction; under the action of ammonia water, an amino group is introduced into the benzene ring; after reacting with a thiolation reagent, the carboxyl group is thiolated; after the nitro group is reduced to an amino group, a ring-forming reaction is carried out, and the decarboxylated ester is obtained.
  • a key intermediate of a carboxy group which is then reacted with a 3-carboxy acridine ring to give a compound of formula II;
  • L represents the leaving group and can be halogen
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , W, R 9 and R 10 are as defined in the first aspect of the invention.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a Formula I of the invention, a guanidine compound, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, and a pharmaceutically acceptable carrier.
  • the invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament for inhibiting cell hyperproliferation.
  • the cell hyperproliferation includes diseases such as leukemia, glioblastoma, lymphoma, melanoma, cancer, neuropathic pain, inflammation, and the like.
  • the inhibiting cell hyperproliferation means inhibiting tumor cell proliferation.
  • the invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament against tumors and/or cancer.
  • the invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, for the manufacture of a medicament for the prevention and/or treatment of a cell hyperproliferative disorder.
  • the invention also relates to a method of preventing and/or treating a tumor and/or cancer comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate thereof, Optical isomer or N-oxide.
  • the invention also relates to a method of preventing and/or treating a cell hyperproliferative disorder comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate thereof, Optical isomer or N-oxide.
  • the cell hyperproliferative diseases include tumors (benign or malignant tumors) and/or diseases such as cancer, neuropathic pain, inflammation, and the like.
  • the tumor and/or cancer described therein may be any tumor and/or cancer known in medicine.
  • the tumor and/or cancer includes but is not limited to:
  • Malignant tumors including but not limited to bladder cancer, breast cancer, colon cancer, kidney cancer, lung cancer (including small cell lung, non-small cell carcinoma), head and neck cancer, esophageal cancer, biliary cancer, stomach cancer, cervical cancer, Sickle adenocarcinoma, prostate cancer and skin cancer (including squamous cell carcinoma);
  • Hematopoietic tumors of the lymphatic system including but not limited to leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair Cellular lymphoma, mantle cell lymphoma, myeloma, and Burketfs' lymphoma;
  • Hematopoietic tumors of the myeloid system including but not limited to acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia;
  • Tumors of interstitial origin including but not limited to fibrosarcoma and rhabdomyosarcoma;
  • Centrally occurring tumors including but not limited to fibrosarcoma and rhabdomyosarcoma;
  • Tumors of the central and peripheral nervous system including astrocytoma, fibrosarcoma, neuroglioma, and schwannomas;
  • tumors including but not limited to melanoma, seminoma, teratocarcinoma, osteosarcoma, Shielded cell tumor, xenoderoma pigmentosum, squamous cell carcinoma and Kaposi's sarcoma.
  • the -CH) alkyl group in the present invention means an alkyl or branched fluorenyl group having 1 to 10 carbon atoms, such as an anthracenyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group or a sec-butyl group.
  • Base tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-decylpentyl, heptyl, octyl and the like.
  • Preferred alkyl groups are d-alkyl groups. More preferred alkyl groups are - alkyl groups;
  • C 2 -C 1Q alkenyl means an alkenyl group having 2 to 10 carbon atoms and at least one double bond, and includes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl , 1-hex-5-alkenyl, and the like. More preferred are lower alkenyl groups having 2 or 3-5 carbon atoms;
  • the C 2 -C 1Q block group means a hydrocarbon group having 2 to 10 carbon atoms and at least one triple bond, and includes, for example, an ethynyl group, a propynyl group, a butynyl group, a pentyn-2-yl group and the like. More preferred is a block group having 3-5 carbon atoms;
  • Halogen means fluorine, chlorine, bromine and germanium atoms
  • An aryl group means a fused ring having a single ring (such as a phenyl group), a polycyclic ring (such as a biphenyl group), or at least one of which is aromatic (for example, 1, 2, 3, 4-tetrahydronaphthyl,
  • An anthranyl carbocyclyl group optionally substituted by, for example, a sulfonyl group, a lower alkyl group (for example, an alkyl group), a lower alkoxy group (for example, an alkoxy group), a trifluoromethyl group, or an aryl group.
  • Heteroaryl refers to one or more aromatic ring systems of a 5, 6 or 7 membered ring comprising a 5-10 atom fused ring system (wherein at least one ring is aromatic), said ring system containing At least one and up to four heteroatoms selected from nitrogen, oxygen or sulfur.
  • heteroaryl groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, iso Thiazolyl, pyrrole ring, quinoline ring, isoquinoline ring, anthracene ring, benzimidazole, benzofuran ring, benzothiophene ring, benzothiazole ring, pyridazine ring and the like.
  • a pharmaceutically acceptable group for example, a lower alkyl group (for example, a d-alkyl group), a lower alkoxy group (for example, an alkoxy group), a trifluoromethyl group, an aryl group, a heteroaryl group, and a hydroxy group.
  • a pharmaceutically acceptable group for example, a lower alkyl group (for example, a d-alkyl group), a lower alkoxy group (for example, an alkoxy group), a trifluoromethyl group, an aryl group, a heteroaryl group, and a hydroxy group.
  • Carbocyclic, carbocyclic, cycloalkyl, C 3 -C IE cycloalkyl refers to a saturated carbocyclic group having 3 to 10 carbon atoms.
  • the cycloalkyl group can be a monocyclic or polycyclic fused system and can be fused to the aromatic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the cycloalkyl group herein may be unsubstituted or as detailed, in one Or a plurality of substitutable positions are substituted by various groups.
  • these cycloalkyl groups may be optionally substituted by the following groups: d-alkyl, d-Ce alkoxy, nitrile, halogen, hydroxy, amino, nitro, mono(d-Ce)alkylamino, di (d-)alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, dC 6 haloalkyl, dC 6 halo alkoxy;
  • Heterocyclic or heterocyclic group means one or more carbocyclic ring systems of a 5, 6 or 7 membered ring comprising a fused ring system of 4 to 10 atoms, said ring system containing at least one and up to four selected A hetero atom from nitrogen, oxygen or sulfur, provided that the ring of the group does not contain two adjacent O or S atoms.
  • the fused ring system may be a heterocyclic ring fused to an aromatic group.
  • Preferred heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholine, cyclohexyl, pyrazine ring, dioxolane (eg 1, 3) - Dioxolane) and the like, which may be substituted by the following groups: d-Ce alkyl, d-Ce alkoxy, nitrile, halogen, hydroxy, amino, nitro, mono(d-Ce)alkyl Amino group, di(d-)alkylamino group, C 2 -C 6 fluorenyl group, C 2 -C 6 alkynyl group, d-Ce halogenated pit group, d-Ce halogenated pit oxy group;
  • Arylalkyl means an alkyl group (as defined above) substituted by one or more aryl groups (as defined above).
  • a more preferred arylalkyl group is an aryl-d-alkyl group. Examples include benzyl, phenylethyl and the like;
  • Heteroarylalkyl means an alkyl group (as defined above) substituted by a heteroaryl group (as defined above). More preferred heteroarylalkyl groups are 5- or 6-membered heteroaryl-d-alkyl groups. Examples include pyridylethyl and the like;
  • Heterocyclylalkyl means an alkyl group (as defined above) substituted by a heterocyclyl group (as defined above). More preferred heterocyclylalkyl is a 5 or 6-membered heterocyclic group -C rC 3 - alkyl group. Examples include tetrahydropyranyl fluorenyl;
  • Cycloalkylalkyl refers to an alkyl group (as defined above) substituted by a cycloalkyl group (as defined above).
  • a more preferred heterocyclic group is a 5- or 6-membered cycloalkyl-Cr-alkyl group. Examples include cyclopropyl fluorenyl;
  • the compounds of the invention may also be used in the form of their pharmaceutically acceptable salts or solvates.
  • Physiologically acceptable salts of the compounds of Formula I or Formula II include the conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and quaternary ammonium acid addition salts.
  • Suitable acid salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, citric acid, lactic acid, maleic acid, Tartaric acid, citric acid, citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, terephthalic acid, sulfonate Salts of acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroquinone, malic acid, steroic, citric acid and the like.
  • acids such as oxalic
  • suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, N-decyl glucosamine and procaine salt.
  • Some of the compounds in the present invention may be crystallized or recrystallized with water or various organic solvents, in which case various solvates may be formed.
  • the present invention includes those stoichiometric solvates, such as hydrates, as well as compounds containing variable amounts of water formed upon preparation by low pressure sublimation drying.
  • the present invention also encompasses prodrugs of the compounds of the invention which, upon administration, are chemically converted by metabolic processes and thereafter become active drugs.
  • prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula I or formula II.
  • Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design Of Prodrugs", ⁇ Bund Saard, Elsevier, ed., 1985.
  • the invention also includes active metabolites of the compounds of the invention.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a racemate or an optical isomer of a compound of the invention and at least one pharmaceutically acceptable carrier which is useful for in vivo treatment and is biocompatible.
  • the pharmaceutical composition can be prepared in various forms depending on the route of administration.
  • the compounds mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts.
  • compositions of the present invention comprise an effective amount of a compound of formula I or formula II of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated plants.
  • composition of the compound of the present invention can be administered in any of the following ways: Oral, Spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or input or by means of a Explant storage.
  • parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or input or by means of a Explant storage.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier used for the tablet generally comprises lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsule preparation generally comprises lactose and dried corn starch.
  • Aqueous suspension formulations are usually those in which the active ingredient is admix If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.
  • the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs.
  • the form is as follows:
  • the compound of the present invention When applied topically to the eye, the compound of the present invention can be formulated into a micronized suspension or solution preparation, the carrier used is an isotonic pH of sterile saline, with or without preservatives such as chlorination. Benzyl alkoxide.
  • the compound can also be formulated into a cream such as a vaseline cream.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be formulated in a suitable cartilage, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers which can be used for cartilage preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which can be used include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspension or sterile injectable solutions.
  • a sterile injectable preparation including sterile injectable aqueous or oily suspension or sterile injectable solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the compounds of the present invention are effective for inhibiting excessive proliferation of cells, and are useful for treating hyperproliferative diseases such as various tumors, cancers, neuropathic pain, inflammation, and the like in mammals. detailed description
  • 2,3,4,5-Tetrafluorobenzoic acid (48.5 g, 0.25 mol) was dissolved in 130 mL of anhydrous decyl alcohol, and trimethyl chlorosilane (63 mL, 0.50 mol) was slowly added dropwise. After the addition was completed, reflux was carried out for 12 h. The pump is distilled off under reduced pressure and excess trimethyl chlorosilane to obtain a pale yellow liquid. Dichloromethane (200 mL) is added and washed with 10% aqueous sodium hydroxide solution, and the aqueous layer is combined with the organic layer. The organic layer was dried over anhydrous sodium sulfate overnight.
  • Step 3 2,3,4,5-tetrafluorobenzonitrile
  • 2,3,4,5-tetrafluorobenzamide 5 g, 0.026 mol
  • 20 mL of anhydrous acetonitrile add phosphorus oxychloride (16.6 g, 0.11 mol), and warm to 70 °C. 1.5 h.
  • the reaction solution was slowly added dropwise to a 200 mL water-water mixture. The process was strongly exothermic. The temperature was controlled to 30 ° C by controlling the dropping rate. After the completion of the dropwise addition, the mixture was stirred at room temperature for 0.5 h, and extracted with ethyl acetate.
  • the system was naturally cooled to room temperature, and a 10% aqueous solution of Na 2 S 2 4 4 (150 mL) was added thereto, and the mixture was stirred for 30 min, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with 10% aqueous sodium hydroxide. The organic layer was dried overnight without sodium sulfate.
  • 2-J ⁇ -3-chloro-5-bromopyridine (10.30 g, 0.050 mol) and lithium amide (4.58 g, 0.20 mol) were added to 150 mL of diphenylbenzene under nitrogen atmosphere and heated to 100 °C. , stir the reaction for 2 h. Naturally, the temperature was lowered to room temperature, 2,3,4,5-tetrafluorobenzonitrile (7.33 g, 0.042 mol) was added, and the mixture was heated to 126 ° C for 3.5 h. The reaction solution was added to 100 mL of ethyl acetate and stirred for 10 min to yield a large white solid.
  • the product was sandwiched between black solids, washed in small portions with ethyl acetate, and sonicated for 5 min.
  • the obtained ethyl acetate layer and the reaction mixture were washed with 1N aqueous hydrochloric acid, and the organic layer was combined, and the organic layer was dried overnight.
  • the solvent was evaporated under reduced pressure.
  • the fuming nitric acid (37 mL, 0.78 mol) was slowly added dropwise to concentrated sulfuric acid (200 mL) in a water bath.
  • 2,3,4-trifluorobenzoic acid (109.4 g, 0.62) was added. Mol) and 330 mL of concentrated sulfuric acid.
  • a concentrated sulfuric acid solution of fuming nitric acid was slowly added dropwise to the concentrated sulfuric acid solution of the reaction raw material under water bath conditions. The water bath was removed, and the temperature was naturally raised to room temperature, and the reaction was stirred for 5 hours.
  • Step 6 5-[(5- ⁇ -3-indolyl-2-pyridyl)J ⁇ ]-4-fluoro-1H-benzimidazole-6-decanoic acid 5-[(5- ⁇ -3 - mercapto 2-pyridyl)amino-4-fluoro-1H-benzimidazole-6-decanoate ( 1.35 g 3.17 mmol) was suspended in methanol (30 mL) and 20% NaOH (8 mL) was added. After 16 h, the reaction mixture was cooled to 0 ° C, and 1 NHC1 solution was added dropwise until pH 2-3. The reaction mixture was diluted with ethyl acetate and water, and the layers were separated.
  • Step 7 l- ⁇ 5-[(5-broken -3-indolyl 2-pyridyl)) J ⁇ ]-4-fluoro-1H-benzimidazole-6-decanoyl-3-carboxylic acid acridine
  • a preliminary activity test was performed on some of the compounds of Examples 1-18 to evaluate the activity of the compounds in tumor cell proliferation of myeloid leukemia cells (K562) and human colorectal cancer cells (HT-29) in vitro.
  • the adherent cells are digested with 0.25% trypsin for 2-5 min, and the suspension cells are centrifuged (1000 rpm/min), and the single cell suspension is prepared by using the corresponding culture medium to adjust the cell concentration to corresponding Density (lxlO 5 / mL), inoculated in 96-well culture plate, 100 ⁇ well, cultured at 37 ° C, 5 % C0 2 for 24 h, then added the whole medium of the corresponding cells of 80 ⁇ pupil, and then added different concentrations of the affected medium.
  • Test compounds 20 ⁇ each treatment set 3 replicates, continue to culture for 72h at 37°C, 5% C02, then aspirate the supernatant ⁇ per well, then add 5mg/mL thiazolyl blue (MTT) solution lO L, 37 Incubate for 4 h at °C, finally add ⁇ 10% SDS per well, incubate for 24 h at 37 °C 5 % C0 2 to completely dissolve the MTT crystals.
  • MTT thiazolyl blue
  • Inhibition rate (%) (1—the OD value of the test well/the average OD value of the solvent control well) ⁇ 100% Calculate the inhibition rate, and take the logarithm of the concentration of the test compound as the abscissa, and the average value of the cell inhibition rate as the ordinate.
  • the dose-response curve was used and the half-cell inhibitor (IC 50 ) was determined using the Origin analysis software.
  • the medium of K562 cells is 1640+10% FBS, and the medium of HT-29 is
  • the drug was dosed to the mother liquor concentration with DMSO (Sigma) before the test and diluted to the desired application concentration with whole medium without factor.
  • DMSO DMSO
  • Preliminary evaluation of compounds for tumor cell growth inhibition For the treatment, three dose groups of compound concentration of 3, 30, 300 ⁇ , blank control group (no tumor cells and test compound, only culture medium), solvent control group (only solvent added without test compound) were used; Further, when half of the cytostatic amount (IC 5Q ) was obtained, six dose groups with a compound concentration of 1, 3, 10, 30, 100, 200, 300 ⁇ , a blank control group (the same as before), and a solvent were selected according to the preliminary screening results. Control group (same as before). The specific results are shown in Table 1. Table 1 shows the inhibitory activity of some compounds on ⁇ 562 and ⁇ -29
  • Example 3 119.81 117.48
  • Example 12 233.33 >300
  • Example 4 107.76 105.86
  • Example 13 119.50 131.79
  • Example 5 136.13 120.11
  • Example 14 113.04 155.14
  • Example 6 135.91 136.27
  • Example 17 56.32 72.36
  • Pdl98306 is a positive photo, and its structural formula is as follows:

Abstract

L'invention concerne des dérivés d'aminopyridine contenant un cycle acridine, notamment des composés représentés par la formule I ou la formule II, leur procédé de préparation et leur utilisation dans la préparation d'un médicament visant à inhiber une prolifération cellulaire excessive. L'invention concerne également des compositions comprenant les composés de la présente invention. Ces composés peuvent être utilisés dans le traitement de maladies hyperprolifératives telles que le cancer, la douleur neuropathique, les inflammations et analogue.
PCT/CN2012/073303 2011-03-31 2012-03-30 Dérivés d'aminopyridine contenant un cycle acridine et leur utilisation WO2012130160A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110079345.7A CN102718750B (zh) 2011-03-31 2011-03-31 含吖啶环的氨基吡啶类衍生物及其用途
CN201110079345.7 2011-03-31

Publications (1)

Publication Number Publication Date
WO2012130160A1 true WO2012130160A1 (fr) 2012-10-04

Family

ID=46929479

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2012/073303 WO2012130160A1 (fr) 2011-03-31 2012-03-30 Dérivés d'aminopyridine contenant un cycle acridine et leur utilisation

Country Status (2)

Country Link
CN (1) CN102718750B (fr)
WO (1) WO2012130160A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008124085A2 (fr) * 2007-04-03 2008-10-16 Exelixis, Inc. Méthodes d'utilisation de combinaisons d'inhibiteurs de mek et de jak-2
CN101365676A (zh) * 2005-10-07 2009-02-11 埃克塞利希斯股份有限公司 作为用于治疗增生性疾病的mek抑制剂的吖丁啶
CN101528231A (zh) * 2006-08-16 2009-09-09 埃克塞利希斯股份有限公司 在癌症的治疗中使用pi3k和mek调控剂
CN101605540A (zh) * 2006-12-14 2009-12-16 埃克塞利希斯股份有限公司 使用mek抑制剂的方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101365676A (zh) * 2005-10-07 2009-02-11 埃克塞利希斯股份有限公司 作为用于治疗增生性疾病的mek抑制剂的吖丁啶
CN101528231A (zh) * 2006-08-16 2009-09-09 埃克塞利希斯股份有限公司 在癌症的治疗中使用pi3k和mek调控剂
CN101605540A (zh) * 2006-12-14 2009-12-16 埃克塞利希斯股份有限公司 使用mek抑制剂的方法
WO2008124085A2 (fr) * 2007-04-03 2008-10-16 Exelixis, Inc. Méthodes d'utilisation de combinaisons d'inhibiteurs de mek et de jak-2

Also Published As

Publication number Publication date
CN102718750A (zh) 2012-10-10
CN102718750B (zh) 2015-03-11

Similar Documents

Publication Publication Date Title
EP2565191B1 (fr) Dérivés d'acide 4-(indol-7-ylcarbonylaminométhyl)cyclohexanecarboxylique comme antagonistes du récepteur EP4 utilisables pour le traitement de l'insuffisance rénale chronique ou de la néphropathie diabétique
EP2903968B1 (fr) Inhibiteurs d'histone déméthylases
KR102093608B1 (ko) 이미다조피리딘 화합물
DK2455381T5 (en) Triazolopyridinforbindelse and its effect as an inhibitor of prolyl hydroxylase and induce erythropoietin production by
EP2368887B1 (fr) Dérivés de 1,2,3-triazole destinés à être utilisés comme inhibiteurs de la stéaroyl-coa désaturase
KR102212981B1 (ko) 4-알키닐이미다졸 유도체 및 그것을 유효 성분으로서 함유하는 의약
WO1999038829A1 (fr) Nouveau compose tricyclique
JP6692354B2 (ja) １，４−ジ置換イミダゾール誘導体
KR20080039348A (ko) 불포화되거나 사이클릭 링커 그룹을 포함하는 헤테로아릴치환된 아미드 및 약제로서의 이들의 용도
JP6511450B2 (ja) Ｗｎｔ経路のモジュレーターとしてのマレイミド誘導体
EP1389460A1 (fr) Medicaments antagonistes de cxcr4 comprenant un compose contenant de l'azote
JP2000063363A (ja) 新規なトリアゾール誘導体
JP6127056B2 (ja) スルホンアミド化合物
AU2001248753B2 (en) Nitrogenous compounds and antiviral drugs containing the same
WO2012130160A1 (fr) Dérivés d'aminopyridine contenant un cycle acridine et leur utilisation
JP2023552655A (ja) ボロン酸化合物
WO2012122891A1 (fr) Dérivé amino contenant une oxime, composition pharmaceutique le contenant, son procédé de préparation et son utilisation
JP2023545677A (ja) Ｆｘｒ小分子アゴニストとその調製方法および用途
WO2012130159A1 (fr) Dérivés d'aminopyridine et leurs utilisations
JP2003128548A (ja) 縮合イミダゾリウム誘導体を含む医薬組成物
TWI624466B (zh) 苯并噻吩化合物
CN104370885B (zh) 氨基吡啶类衍生物及其用途
WO2010001990A1 (fr) Composé tétracyclique
JP2018100270A (ja) １，４−ジ置換イミダゾール誘導体からなる医薬
TW202300486A (zh) Ｌｐａ受體拮抗劑及其用途

Legal Events

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

Ref document number: 12764231

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12764231

Country of ref document: EP

Kind code of ref document: A1