WO2012130159A1 - Dérivés d'aminopyridine et leurs utilisations - Google Patents

Dérivés d'aminopyridine et leurs utilisations Download PDF

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Publication number
WO2012130159A1
WO2012130159A1 PCT/CN2012/073301 CN2012073301W WO2012130159A1 WO 2012130159 A1 WO2012130159 A1 WO 2012130159A1 CN 2012073301 W CN2012073301 W CN 2012073301W WO 2012130159 A1 WO2012130159 A1 WO 2012130159A1
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group
pyridyl
trifluoro
amino
indolyl
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Chinese (zh)
Inventor
李松
郑志兵
樊士勇
王莉莉
钟武
刘洪英
肖军海
谢云德
周辛波
陈伟
李行舟
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Institute of Pharmacology and Toxicology of AMMS
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Institute of Pharmacology and Toxicology of AMMS
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    • 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
    • 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
    • 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
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/12—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 linked by a chain containing hetero atoms as chain links
    • 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 aminopyridine derivative, and in particular to a compound of the formula I or formula II, a process for the preparation thereof and use thereof for the preparation of a medicament for inhibiting excessive proliferation of cells.
  • Cancer is a disease that poses a serious threat to human health. Since the advent of the first anticancer drug, the nitrogen mustard, in the 1940s, scientists have isolated and extracted several 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, there is a need to find small molecule antitumor drugs with structural cartridges. Summary of the invention
  • the present invention is directed to an aminopyridine derivative having an activity of inhibiting cell hyperproliferation.
  • a first aspect of the invention provides a compound of formula I, formula II, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof.
  • one represents an optional bond, provided that one and only one nitrogen atom in the ring is a double R 2 , R 3 , R 4 , R 5 , 11 7 or R 8 are each independently selected from hydrogen, hydroxy , halogen, Amino, nitro, nitrile, trifluoromethyl, -OR 9 , -C(0)R 9 , -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 10 R 9 , d-do alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 1Q cycloalkyl, C 3 -C 1Q cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocycloal
  • R 6 is independently 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 1 ⁇ ring
  • W is independently selected from -OR 9 , -NR 10 OR 9 , -NR 10 SO 2 R 9 and -NR 10 R 9 ;
  • R 9 Each is independently selected from the group consisting of hydrogen, hydroxy, halogen, trifluoromethyl, d-do alkane > 3 ⁇ 4 ⁇ , C - C 10 f ⁇ , C2 - C 10 > C - C 10 ⁇ 3 ⁇ 4 C - C 10 ⁇ 3 ⁇ 4
  • Preferred compounds have the structure of ⁇ , IV
  • Preferred compounds have the structure of V, VI
  • Ri RR 3 , R 4 , R 5 , R 6 , R 7 , R 8 , W, R 9 and R 10 are as defined above.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are independently selected from the group consisting of hydrogen, halogen, nitro, nitrile, trifluoromethyl, dC 6 alkyl, C 3 - C 6 cycloalkyl, C 3 -C 6 Cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl;
  • W is independently selected from -OR 9 , -NR 10 OR 9 or -NR 10 R 9 .
  • the compound is selected from the group consisting of:
  • the invention relates to a method of synthesizing a compound of formula I, II or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, which comprises the synthesis of the following key intermediates:
  • 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 A part of the water is removed to convert the amide bond to a cyano group; the substituted phenyl phthalocyanine containing the leaving group L is removed from the group by the action of a base such as a radical lithium. Carrying out a condensation reaction; hydrolyzing a cyano group to obtain a carboxyl group, and reacting a carboxyl group with a corresponding side chain to obtain a compound I;
  • L indicates the departure group, which can be a prime
  • 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, a few groups are thiolated; after the nitro group is reduced to an amino group, a ring-forming reaction is carried out to obtain a deoximation ester.
  • a key intermediate containing a carboxyl group the carboxyl group is reacted with a corresponding side chain moiety 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 compound of formula i, a hydrazine compound of the invention, or a pharmaceutically acceptable salt, solvate, optical isomer or N-oxide thereof, and a pharmaceutically acceptable carrier.
  • the -CH) alkyl group in the present invention means a straight or branched alkyl 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.
  • a preferred alkyl group is a d-alkyl group.
  • a more preferred alkyl group is dC 3 alkyl.
  • 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-hexyl- 5-alkenyl and the like. More preferred are lower alkenyl groups having 2 or 3-5 carbon atoms;
  • the C 2 -C 1Q alkynyl group means a hydrocarbon group having 2 to 10 carbon atoms and at least one hydrazone bond, and includes, for example, an ethyl group, a propynyl group, a butyl group, a pentyn-2-yl group and the like. More preferred are alkynyl groups having 3-5 carbon atoms; Halogen means fluorine, chlorine, bromine and iodine 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.
  • a carbocyclic ring, a carbocyclic group, a cycloalkyl group, a C 3 -C 1Q cycloalkyl group means 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 groups herein may be unsubstituted or substituted by various groups at one or more substitutable positions, as described in detail.
  • these cycloalkyl groups may be optionally substituted by the following groups: Cr alkyl group, d-Ce alkoxy group, nitrile group, halogen, hydroxy group, amino group, nitro group, mono(d-Ce)alkylamino group, two ( d-Ce)alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, d-Ce halo pit, d-Ce halo pit;
  • 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, tetrahydrothiophene, 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(-C6)alkylamino, two (d-)alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 haloalkyl, dC 6 haloalkoxy;
  • Arylalkyl means an alkyl group (as defined above) substituted by one or more (as defined above) aryl groups.
  • 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 heterocyclic group (as defined above).
  • a more preferred heterocyclylalkyl group is a 5- or 6-membered heterocyclyl-d-alkyl group. Examples include tetrahydropyranyl fluorenyl;
  • Cycloalkylalkyl refers to an alkyl group (as defined above) substituted by a cycloalkyl group (as defined above). More preferred heterocyclic groups are 5- or 6-membered cycloalkyl-d-alkyl groups. 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 compound of formula I or formula II include 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, toluenesulfonic acid, sulfonic acid, naphthalene 2-sulfonate Salts of acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroquinone, malic acid, steroi 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 invention also includes prodrugs of the compounds of the invention which, once administered, pass The metabolic process undergoes chemical conversion and then becomes an active drug.
  • 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 the selection and preparation of suitable prodrug derivatives are described, for example, in "Design Of Prodrugs", H 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, sheath Inside, intraventricular, intrasternal and intracranial injection or input or by means of an explant reservoir.
  • 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 includes 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 hair When applied topically, especially in the treatment of facial or organs easily accessible by topical application, such as eye, skin or lower intestinal neuropathy, the hair may be according to different affected faces or organs.
  • the compounds are prepared in different topical formulations, as specified below:
  • the compounds of the invention When applied topically to the eye, the compounds of the invention may be formulated in the form of a micronized suspension or solution in which the carrier is isotonic at a certain pH. Sterile saline, with or without preservatives such as benzyl chloride alkoxide.
  • the compound can also be formulated in the form of 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 may be used in ointment preparations include, but are not limited to, mineral oil, liquid petroleum jelly, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which may 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 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 for the treatment of 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 disease includes a tumor (benign or malignant) Tumors and/or diseases such as cancer, neuropathic pain, inflammation, etc.
  • 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, femoral stromal tumor, xenoderoma pigmentosum, squamous cell carcinoma and Kapos sarcoma.
  • the compounds of the present invention are effective for inhibiting excessive proliferation of cells and are useful for treating hyperproliferative diseases in mammals such as various tumors, cancer, neuropathic pain, inflammation and the like. 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 the excess trimethyl chlorosilane is obtained as a pale yellow liquid.
  • Dichloromethane 200 mL is added and washed with a 10% aqueous sodium hydroxide solution, and the aqueous layer is combined with dichloromethane. The organic layer was dried over anhydrous sodium sulfate overnight.
  • 2,3,4,5-tetrafluorobenzamide (5 g, 0.026 mol) was added to 20 mL of anhydrous acetonitrile, phosphorus oxychloride (16. 6 g, 0.11 mol) was added, and the temperature was raised to 70 ° C. 1.5 h.
  • the reaction solution was slowly added dropwise to a 200 mL water-water mixture, which was strongly exothermic, and the temperature was controlled to be not higher than 30 by controlling the dropping rate. After the completion of the dropwise addition, the mixture was stirred at room temperature for 0.5 h, extracted with ethyl acetate, and the organic layer was dried overnight.
  • 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.
  • Example 22 N-[2-(Acridin-1-yl)ethyl b 3,4,5-trifluoro-2-[(3-chloro-5-bromo-2-pyridyl)amino]phenyl hydrazide
  • the same procedure as in Example 4 gave a dark-yellow solid N-[2-(piperidin-1-yl)ethyl] -3,4,5-trifluoro ⁇ - ⁇ -chloro ⁇ -bromo ⁇ -pyr ⁇ ! ⁇ Benzanamide.
  • 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.
  • reaction solution was slowly added dropwise to a 2000 mL aqueous solution under stirring, stirred at room temperature for 2 h, allowed to stand overnight, and filtered to give a white solid 5-nitro-2,3,4-trifluorobenzoic acid (123.7 g, 90.3%) , ESI-MS m/z: 222.0 [M+1] + step 2, 5-nitro-3,4-difluoro-2-[(5-iodo-3-indolyl-2-pyridyl 1 ⁇ )amino 2-Amino-3-indolyl-5-indole pyridine (10.61 g, 0.045 mol) was dissolved in 70 mL of anhydrous tetrahydrofuran (THF) under a nitrogen-protected solvent, and then cooled to -70.
  • THF anhydrous tetrahydrofuran
  • Step 6 5-[(5- ⁇ -3-indolyl 2-pyridyl 1 ⁇ 4-fluoro-1H-benzimidazole-6-decanoic acid 5--((5- broken-3- ⁇ ) 2-Pyryl 2-pyridyl)amino-4-fluoro-1H-benzimidazole-6-decanoate ( 1.35 g 3.17 mmol) was suspended in methanol (30 mL), 20% NaOH (8 mL), 16 After h, the reaction mixture was cooled to 0 ° C, and 1 NHC1 solution was added dropwise until pH 2-3.
  • a preliminary activity test was carried out on some of the compounds in Examples 1-25 to evaluate the activity of the compounds in inhibiting the proliferation of myeloid leukemia cells (K562) and human colorectal cancer cells (HT-29) tumor cells in vitro.
  • K562 myeloid leukemia cells
  • HT-29 human colorectal cancer cells
  • 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.
  • each treatment is set to 3 repetitions, continue to culture for 72h at 37°C and 5 % C02, then aspirate the supernatant ⁇ per well, then add 5mg/mL thiazolyl blue (MTT) solution ⁇ , 37°C Incubation was continued for 4 h, and finally 10% SDS was added to each well, and incubated at 37 ° C for 5 h under C 2 2 to completely dissolve the MTT crystal.
  • the absorbance per well was measured by an enzyme-linked immunosorbent assay at a wavelength of 570 nm. According to the formula:
  • 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. Dose-response curve, and use the analysis software to find half of the cells Dosage value (IC 50 ).
  • the medium of K562 cells was 1640+10% FBS, and the medium of HT-29 was DMEM(Hg)+F12+5%FBS 0
  • 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.
  • Table 1 Inhibitory activity of some compounds on ⁇ 562 and ⁇ -29

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  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
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Abstract

L'invention concerne des dérivés d'aminopyridine, notamment représentés comme composés dans la formule I ou dans la formule II, leur procédé de préparation et leurs utilisations dans la préparation de médicaments visant à inhiber l'hyperprolifération cellulaire. L'invention concerne également des compositions pharmaceutiques comprenant lesdits composés. Ces composés sont utilisés dans le traitement de maladies hyperprolifératives telles que le cancer.
PCT/CN2012/073301 2011-03-31 2012-03-30 Dérivés d'aminopyridine et leurs utilisations Ceased WO2012130159A1 (fr)

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Publication number Priority date Publication date Assignee Title
KR101831553B1 (ko) 2017-01-23 2018-02-22 계명대학교 산학협력단 전이성 유방암의 유용한 신규 화합물 및 이의 의학적 용도
KR20210143803A (ko) * 2019-03-15 2021-11-29 더 제너럴 하스피탈 코포레이션 Tead 전사인자의 신규한 소분자 저해제

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WO2025007811A1 (fr) * 2023-07-06 2025-01-09 成都华健未来科技有限公司 Dérivé d'amide aromatique et son utilisation

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CN1538836A (zh) * 2001-01-12 2004-10-20 ��������ķ������ 取代的胺衍生物及使用方法
CN101065358A (zh) * 2004-10-20 2007-10-31 应用研究系统Ars股份公司 3－芳基氨基吡啶衍生物
WO2008041088A2 (fr) * 2006-10-03 2008-04-10 Eos (Ethical Oncology Science) S.P.A. N-hydroxybenzamides dotés d'une activité antitumorale

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CN1538836A (zh) * 2001-01-12 2004-10-20 ��������ķ������ 取代的胺衍生物及使用方法
CN101065358A (zh) * 2004-10-20 2007-10-31 应用研究系统Ars股份公司 3－芳基氨基吡啶衍生物
WO2008041088A2 (fr) * 2006-10-03 2008-04-10 Eos (Ethical Oncology Science) S.P.A. N-hydroxybenzamides dotés d'une activité antitumorale

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101831553B1 (ko) 2017-01-23 2018-02-22 계명대학교 산학협력단 전이성 유방암의 유용한 신규 화합물 및 이의 의학적 용도
KR20210143803A (ko) * 2019-03-15 2021-11-29 더 제너럴 하스피탈 코포레이션 Tead 전사인자의 신규한 소분자 저해제
US12187722B2 (en) 2019-03-15 2025-01-07 The General Hospital Corporation Small molecule inhibitors of TEAD transcription factors
KR102866499B1 (ko) * 2019-03-15 2025-10-02 더 제너럴 하스피탈 코포레이션 Tead 전사인자의 신규한 소분자 저해제

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