WO2013064068A1 - Dérivés de thiénopyrimidine et de furopyrimidine, leur procédé de fabrication et leur utilisation médicale - Google Patents

Dérivés de thiénopyrimidine et de furopyrimidine, leur procédé de fabrication et leur utilisation médicale Download PDF

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Publication number
WO2013064068A1
WO2013064068A1 PCT/CN2012/083830 CN2012083830W WO2013064068A1 WO 2013064068 A1 WO2013064068 A1 WO 2013064068A1 CN 2012083830 W CN2012083830 W CN 2012083830W WO 2013064068 A1 WO2013064068 A1 WO 2013064068A1
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Prior art keywords
phenyl
pyrimidin
group
substituted
hydroxy
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PCT/CN2012/083830
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English (en)
Chinese (zh)
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安晓霞
别平彦
刘俊
杨午立
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上海希迈医药科技有限公司
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Publication of WO2013064068A1 publication Critical patent/WO2013064068A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to a pyrimidine derivative, a preparation method and application thereof, and more particularly to a thienopyrimidine and furanopyrimidine derivative having an epidermal growth factor receptor EGFR and/or an angiogenic factor receptor VEGFR inhibitory activity.
  • the invention, the preparation method thereof and the application thereof in medicine belong to the technical field of medicinal chemistry. Background technique
  • Tumor is one of the most serious diseases that threaten human health. Its treatment mainly includes radiotherapy, chemotherapy and surgery. In recent years, with the development of cell biology and oncology, the chemical treatment of tumors has undergone tremendous changes. Conventional chemotherapeutic drugs are gradually rejected due to non-specific blockade of cell division, which also causes normal cell death while killing tumor cells. At the same time, key node proteins in abnormally activated signaling pathways in tumor cells are targeted. It has been found that high-efficiency, low-toxicity and specific small-molecule inhibitors have become an important direction for the research and development of anti-tumor drugs. Receptor tyrosine kinase (RTK), which is aberrantly expressed in tumors, has become a hot spot in anti-tumor drug research because it plays a key role in tumor development, invasion and metastasis, and chemotherapy resistance.
  • RTK Receptor tyrosine kinase
  • Epidermal growth factor receptor also known as HER1 or cerbBl
  • HER1 or cerbBl is a member of the HER family, the most widely expressed tyrosine kinase in human cancers.
  • the EGFR structure consists of three regions: the extracellular region, the transmembrane region, and the intracellular region.
  • the amino terminal of the extracellular domain consists of 622 amino acids, with two cysteine-rich segments forming a ligand binding region; the transmembrane region is single (X-helix; the intracellular region includes the kinase region and has many tyrosine The terminal end of the carboxyl group of the acid phosphorylation site.
  • Tyrosine kinase transports the gamma phosphate of ATP to the tyrosine residue. After binding to the ligand, homologous or heterodimerization of EGFR occurs. The ⁇ region is tightly linked.
  • the phosphorylation of the tyrosine phosphorylation site at the carboxyl terminal tail RTK creates a binding site for the enzyme and the linker protein (Y992, Y1068, Y1086, Y1148 and Y11730). It can initiate intracellular signaling reactions. These signals form different cellular responses, including proliferation, differentiation, adhesion and angiogenesis, metastasis, and inhibition of apoptosis.
  • EGFR is expressed in non-small cell lung cancer, prostate cancer, breast cancer, colorectal cancer, head and neck cancer, gastric cancer, ovarian cancer, and pancreatic cancer.
  • EGFR activation triggers complex signaling reactions.
  • EGFR proliferates and overexpresses, leading to the loss of control of downstream signaling leading to the formation of various tumors.
  • Mutations in the ATP-binding site in EGFR affect the RTK activity of the receptor and interfere with the formation of tumorigenic signals.
  • EGFR is also closely associated with tumor progression and poor prognosis.
  • Gefitinib also known as ZD1839 or Iressa
  • Erlotinib is a standard regimen for the treatment of ineffective second- or third-line treatments for advanced NSCLC.
  • an object of the present invention is to provide a thienopyrimidine and furan pyrimidine derivative having epidermal growth factor receptor EGFR and/or angiogenic factor receptor VEGFR inhibitory activity, and preparation thereof Method and its application in medicine.
  • a compound of formula V, or a tautomer, racemate, enantiomer, diastereomer, pharmaceutically acceptable salt thereof or pharmaceutically acceptable Accepted solvate is provided.
  • R is selected from: hydrogen, d- alkyl or substituted alkyl of 6, d- 6 alkyl group (preferably an alkyl group of 3 ⁇ 4- 6), C 3 - 6 cycloalkyl group (preferably C 4 - 6 cycloalkyl group), C 2 - 6 alkene group (preferably C 3 - 6 alkene group) or a substituted alkene group, an aryl group an acyl group or a substituted aryl group, a sulfonyl group, an amide group or a substituted amide group, a reverse amide group or a substituted reverse amide group, an alkoxy group of - 8 ;
  • R 3 is hydrogen, C 6 alkyl or substituted -6 alkyl
  • Z is nitrogen or CH
  • Ar is selected from the group consisting of: C 6 _ 2 .
  • Q is , X is oxygen or sulfur, R 2 is hydrogen or d- 6 alkyl or substituted
  • Ar 2 is selected from the group consisting of: an aryl group of C 6 -20 or a substituted C 6 _ 2 . Aryl, or C 4 _ 2 . Heteroaryl or substituted C 4 _ 2 . Miscellaneous Base.
  • the compound of formula V is a compound of formula I, formula II, formula III or formula IV:
  • X is oxygen or sulfur;
  • Z is nitrogen or carbon;
  • R is hydrogen, an alkyl group having 1 to 6 carbon atoms or a substituted alkyl group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, and 2 to 6 Any one of an olefin acyl group or a substituted olefin acyl group of a carbon atom, an aryl acyl group or a substituted aryl acyl group, a sulfonyl group, an amide group or a substituted amide group, a reverse amide group or a substituted reverse amide group;
  • Ar 1 is phenyl, 2 or 3-fluoro substituted phenyl, 2 or 3-trifluoromethyl substituted phenyl, 2 or 3-chloro substituted phenyl, 2 or 3-nitryl substituted phenyl, 2- or 3 a -C 3 alkyl substituted phenyl, thienyl, 3-C 3 alkyl substituted thienyl, furyl, 3-C 3 alkyl substituted furanyl, 2 or 3-pyridyl;
  • R is hydrogen, an alkyl group having 1 to 6 carbon atoms or a substituted alkyl group, an alkyl group having 1 to 6 carbon atoms, and a cycloalkyl group having 3 to 6 carbon atoms.
  • Ar is phenyl, 2 or 3-fluoro substituted phenyl, 2 or 3-trifluoromethyl substituted phenyl, 2 or 3-chloro substituted phenyl, 2 or 3-nitryl substituted phenyl, 2- or 3- Any one of d- 3 alkyl substituted phenyl groups; Any one of a phenyl group, a halogen-substituted phenyl group, a d- 6 alkyl-substituted phenyl group, a biphenyl group, a halogen-substituted biphenyl group, and a naphthyl group.
  • the substituted alkyl group is a substituted d- 6 alkyl group
  • the substituted olefin acyl group is a substituted C 3 -6 olefin acyl group
  • the aryl acyl group is C 6 - 2 .
  • An aryl acyl group, the substituted aryl acyl group is a substituted C 6 -20 aryl acyl group
  • the sulfonyl group is a sulfonyl group of d- 15
  • the amide group is an amide group of d- 15
  • the substituted amide group is the substituted amide group of C i5 .
  • the substituted alkyl group, substituted olefin acyl group, substituted aryl acyl group, substituted amide group or substituted reverse amide group, substituted aryl group, or substituted heteroaryl group means substituents selected from the group consisting of: fluoro, chloro, bromo, iodo, cyano, hydroxy, d- 6 alkyl, C 3 - 6 cycloalkyl, d- 6 alkoxy, amino, d_ 6 alkoxycarbonyl group , nitro, amino, acyl, amide, sulfonyl, d- 6 haloalkyl.
  • the substituted amide group or substituted reverse amide group refers to a substituent-substituted amide group or a substituted reverse amide group selected from the group consisting of: the substituent is bonded to N in the amide group to form Morpholine, pyrrole, piperazine or piperidine, optionally substituted with a substituent selected from the group consisting of d- 6 alkyl, d- 6 alkoxy.
  • the compound of the formula V is any one of the compounds listed in Table 1.
  • the pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, and the like; organic acid salts such as formate, acetic acid Salt, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, etc.; alkyl sulfonate, such as methyl sulfonate, ethyl sulfonate Salts and the like; aryl sulfonates such as besylate, p-toluenesulfonate and the like.
  • inorganic acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, and the like
  • organic acid salts such as formate, acetic acid Salt, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, etc.
  • the pharmaceutically acceptable solvate includes, without limitation, a solvate of the compound with water, ethanol, isopropanol, diethyl ether, acetone or the like.
  • R 5 -Q- is Or, R 5 is F, Cl, Br, I;
  • R, Z, R 3 , RX, R 2 , Ar and Ar 2 are as described in the first aspect.
  • the invention provides a method for preparing a thienopyrimidine and a furanopyrimidine derivative represented by the formula I, which comprises the following step 3 or steps 1 and 3 or steps 2 and 3 or steps 1 to 3:
  • the preparation method of the thienopyrimidine and furanopyrimidine derivatives represented by the formula of the present invention includes the following Step 5 or Steps 2 and 5 or Steps 4 and 5 or Steps 2 and 4 and 5:
  • the present invention provides a process for the preparation of a thienopyrimidine and a furanopyrimidine derivative represented by the general formula III, which comprises the following step 7 or steps 1 and 7 or steps 6 and 7 or steps 1 and 6 and 7:
  • the method for preparing a thienopyrimidine and a furanopyrimidine derivative represented by the formula IV provided by the present invention comprises the following Step 8 or Steps 4 and 8 or Steps 6 and 8 or Steps 4 and 6 and 8:
  • the thienopyrimidine and the furanopyrimidine derivative represented by the above formula ⁇ can also be obtained by hydrogenating a thienopyrimidine represented by the formula I and a furand pyrimidine derivative.
  • thienopyrimidine and the furanopyrimidine derivative represented by the above formula IV can also be obtained by hydrogenating a thienopyrimidine represented by the formula III and a furanopyrimidine derivative.
  • a compound of formula V, or a tautomer, racemate, enantiomer, diastereomer, pharmaceutically acceptable salt thereof or pharmaceutically acceptable The use of solvates.
  • the thienopyrimidine and furanopyrimidine derivatives of the present invention have inhibitory activities against epidermal growth factor receptor (EGFR) and/or angiogenic factor receptor (VEGFR), and thus, the thiophene of the present invention
  • EGFR epidermal growth factor receptor
  • VEGFR angiogenic factor receptor
  • Any one or a mixture of solvates may be used to prepare tyrosine kinase inhibitors, particularly for the preparation of EGFR and/or VEGFR inhibitors.
  • the inhibitor may be applied to the preparation of a medicament for preventing or treating a disease associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR, and in particular, for the preparation of a prophylactic or therapeutic agent with epidermal growth factor Receptor EGFR and/or angiogenic factor receptor VEGFR-associated cells with abnormal proliferation, morphological changes, hyperkinesia, angiogenesis, and tumor metastasis.
  • the inhibitors are useful for the preparation of a medicament for the treatment or prevention of tumor growth and metastasis associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR.
  • the active ingredient of the inhibitor is preferably a compound shown in Table 1 or a tautomer, a racemate, an enantiomer, a diastereomer, or a pharmaceutically acceptable compound of the indicated compound. Any one or a mixture of the accepted salts, pharmaceutically acceptable solvates.
  • a tyrosine kinase inhibitor the compound of the formula V according to the first aspect, or a tautomer thereof, a racemate, an enantiomer, a diastereomer
  • a mixture of any one or a mixture of an isomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate is prepared.
  • the tyrosine kinase inhibitor refers to an EGFR and/or VEGFR inhibitor.
  • the use of the tyrosine kinase inhibitor of the fourth aspect for the preparation of:
  • a drug that prevents or treats abnormal cell proliferation, morphological changes, hyperkinesia, angiogenesis, and metastatic disease associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR;
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a compound of the formula V according to the first aspect, or a tautomer thereof, a racemate, an enantiomer A diastereomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate.
  • the pharmaceutically acceptable salt includes, without limitation, a mineral acid salt such as a hydrochloride, a hydrobromide salt, a nitrate salt, a sulfate salt, a phosphate salt or the like; an organic acid salt such as formic acid.
  • a mineral acid salt such as a hydrochloride, a hydrobromide salt, a nitrate salt, a sulfate salt, a phosphate salt or the like
  • an organic acid salt such as formic acid.
  • a salt an acetate, a propionate, a benzoate, a maleate, a fumarate, a succinate, a tartrate, a citrate, etc.
  • an alkylsulfonate such as a methylsulfonate, Ethyl sulfonate or the like
  • aryl sulfonate such as benzenesulfonate, p-toluenesulfonate and the like.
  • the pharmaceutically acceptable solvate includes, without limitation, a solvate of the compound with water, ethanol, isopropanol, diethyl ether, acetone or the like.
  • the thienopyrimidine and furanopyrimidine derivatives provided by the present invention have novel structures, have obvious EGFR inhibitory activity, and some compounds have significant inhibitory activity against VEGFR, and are expected to be developed as tyrosine.
  • Kinase EGFR or/and VEGFR inhibitors for the prevention or treatment of abnormal cell proliferation, morphological changes, hyperkinesia, and angiogenesis associated with epidermal growth factor receptor EGFR and/or angiogenic factor receptor VEGFR Or a drug for tumor metastasis-related diseases, especially for the preparation of a drug for treating or preventing tumor growth and metastasis associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR, for the development of novel low drug resistance Or tyrosine kinase inhibitor drugs that can alleviate the resistance of early inhibitors provide new development directions and approaches, and have broad application prospects and medicinal value. detailed description
  • d- 6 means having 1 to 6 carbon atoms
  • C 3 - 6 means having 3 to 6 carbon atoms
  • C 2 - 6 Means having 2 to 6 carbon atoms
  • C 2 - 8 means having 2 to 8 carbon atoms.
  • Alkyl means a chain-saturated organic functional group containing only carbon and hydrogen atoms, including branched and linear alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, and iso- Butyl, sec-butyl, tert-butyl and the like.
  • Cycloalkyl means a cyclic organic functional group containing two atoms of carbon and hydrogen, such as cyclopropyl, cyclobutane and the like.
  • Aryl means a hydrocarbyl moiety containing one or more aromatic rings.
  • the aryl group in the invention preferably has 6 to 20 carbon atoms, and examples of the aryl moiety include a phenyl group, a phenylene group, a naphthyl group, a naphthylene group, an anthracenyl group, an anthracenyl group and a phenanthryl group.
  • Heteroaryl means a moiety which contains one or more aromatic rings having at least one hetero atom (e.g., N, 0 or S).
  • the heteroaryl group in the present invention preferably has 4 to 20 carbon atoms, and examples of the heteroaryl group include furyl, furanyl, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, Pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl and fluorenyl.
  • Amido means a functional group having an amide bond -CONH-.
  • Reverse amide group means a functional group having a reverse amide bond -NHCO-.
  • alkoxy means a group formed by linking an alkyl group to an oxygen atom, such as a methoxy group, Ethoxylate and the like.
  • Amino means NH 2 -.
  • Amine refers to one or more Cw.
  • a hydrocarbyl-substituted amino group such as (CH 3 ) 2 N -, (CH 3 CH 2 ) 2 N- (CH 3 )(CH 3 CH 2 )N-CH 3 NH -, CH 3 CH 2 NH-, and the like.
  • an alkyl group, a cycloalkyl group, an olefin acyl group, an aryl group, a heteroaryl group, an aryl acyl group, an amide group or a reverse amide group includes both substituted and unsubstituted moieties.
  • Possible substituents on an alkyl, cycloalkyl, olefin acyl, aryl, heteroaryl, aryl acyl, amide or reverse amide group include, but are not limited to: fluorine, chlorine, bromine, iodine, nitrile, hydroxy , d- 6 alkyl, C 3 -6 cycloalkyl, d- 6 alkoxy, amino, d- 6 alkoxy, nitro, amino, acyl, Amido group, sulfonyl group.
  • the compound of the formula V of the present invention can be produced by the following method, however, the conditions of the method, such as the reactant, the solvent, the base, the amount of the compound used, the reaction temperature, the time required for the reaction, and the like are not limited to the following explanations.
  • the compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
  • the process comprises the step of a condensation reaction of a compound of formula VI with a compound of formula VII to obtain a compound of formula V.
  • R 4 , R 5 -Q -, R, Z, R 3 , RX, R 2 , Ar and Ar 2 are as defined above.
  • the reaction is carried out in an inert solvent at a temperature of from 10 ° C to a reflux temperature (e.g., 100 ° C) for 0.1 to 72 hours.
  • solvents include, but are not limited to: acetone, methanol, ethanol, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, diethyl ether, acetonitrile or a mixture of two or more .
  • compositions of the present invention comprise a safe and effective amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • Compound of the invention means a compound of formula V (including a compound of formula I, formula ⁇ , formula m or formula IV), or a tautomer thereof, a racemate, an enantiomer, a diastereomer A pharmaceutically acceptable salt or a pharmaceutically acceptable solvate.
  • the compound of the present invention has an inhibitory activity against epidermal growth factor receptor (EGFR) and/or vascular growth factor receptor (VEGFR)
  • the compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the preparation of prophylaxis or A medicament for treating a disease associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR.
  • a safe and effective amount of a compound of the invention is included in the pharmaceutical compositions of the invention, wherein "safe and effective amount” means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or a tablet.
  • a “pharmaceutically acceptable carrier” can be one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • composition capable of intermixing with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), moist Wet agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween®
  • moist Wet agents such as sodium lauryl sulfate
  • colorants such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen®
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, nasal inhalation, rectal, and parenteral (intravenous, intramuscular, or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and sterile powder for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds such as cisplatin.
  • a pharmaceutical composition When a pharmaceutical composition is used, a safe and effective amount of a compound of the invention is applied to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight,
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the structures of the compounds prepared in the following examples were determined by nuclear magnetic resonance (HNMR) and mass spectrometry (MS).
  • the 1H NMR shift ( ⁇ ) is given in parts per million (ppm).
  • the 1H NMR measurement was performed on a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), internal standard was tetramethylsilane (TMS), and the chemical shift was to give 10-6 as a unit.
  • DMSO-d 6 dimethyl sulfoxide
  • CDC1 3 deuterated chloroform
  • TMS tetramethylsilane
  • the MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • IC 5 The value was determined using a NovoStar plate reader (BMG, Germany).
  • the thin layer of silica gel is made of Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • Silica gel column chromatography was carried out using Yantai Huanghai silica gel 200 ⁇ 300 mesh silica gel as a carrier.
  • the HPLC test was performed using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150 x 4.6 mm column).
  • the microwave reaction was performed using a CEM Discover-S Model 908860 microwave reactor.
  • the argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 liter.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the solution in the reaction means an aqueous solution.
  • the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. Various modifications and alterations of the present invention will be apparent to those skilled in the ⁇ RTIgt; The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight and parts by weight. -1 and compound II -1
  • the first step is a first step:
  • P-carboxyphenyl boronic acid pinacol ester (lg, 4.03 mmol) was dissolved in dichloromethane (10 ml, 0.16 mol) at room temperature N-ethylpiperazine (0.6 ml, 4.8 mmol) was added to N,N-dimethylformamide (1 ml, 13.0 mmol), and 1-ethyl-(3-dimethylaminopropyl group was added sequentially.
  • Carbodiimide hydrochloride (0.93 g, 4.8 mmol), N-hydroxybenzotriazole (0.66 g, 4.8 mmol), triethylamine (0.84 ml, 6.04 mmol), stirred at room temperature until TLC The reaction was completed, and 10 ml of water was added to the reaction mixture, and the mixture was stirred for 30 minutes, extracted with dichloromethane (50 ml*3), and washed with saturated sodium chloride (50 ml*2).
  • 6-bromo-4-chlorothiophene [2,3-d]pyrimidine was prepared according to the method described in WO 2007/059257.
  • Lithium tetrahydroaluminum (27.3 mg, 0.718 mmol) and anhydrous tetrahydrofuran (8 ml, 98.63 mmol) were stirred and stirred at room temperature, and the compound I-I (140 mg, 0.287 mmol) of tetrahydrofuran (10 ml, 0.123mol), the reaction was stirred at room temperature for 1 hour, and the temperature was raised to 50 ° C until the reaction was completed by TLC. The reaction was cooled to room temperature. 20 ml of water was added to the reaction mixture, and extracted with ethyl acetate (100 ml*3). The mixture was washed with a saturated aqueous solution of sodium chloride (100 ml?).
  • the first step is a first step:
  • Lithium tetrahydrogenate (100 mg, 2.640 mmol) and anhydrous tetrahydrofuran (10 ml, 0.123 mol) were stirred and stirred at room temperature, and the compound I-2 (500 mg, 1.056 mmol) of tetrahydrofuran (10 ml, 0.123 mol) was added dropwise to the reaction mixture.
  • the solution was stirred at room temperature for 1 hour, and the temperature was raised to 50 ° C until the reaction was completed by TLC.
  • the first step is a first step:
  • the p-carboxyphenylboronic acid pinacol ester (3 g, 12.10 mmol) was dissolved in dichloromethane (27 ml, at room temperature).
  • Lithium tetrahydrogenate (90 mg, 2.369 mmol) and anhydrous tetrahydrofuran (10 ml, 0.123 mol) were stirred and stirred at room temperature, and the compound 1-3 (250 mg, 0.474 mmol) of tetrahydrofuran (10 ml, 0.123 mol) was added dropwise to the reaction mixture.
  • the solution was stirred at room temperature for 1 hour, and the temperature was raised to 50 ° C until the reaction was completed by TLC.
  • the first step is a first step:
  • the p-carboxyphenyl boronic acid pinacol ester (3 g, 12.10 mmol) was dissolved in dichloromethane (27 ml, 0.422 mol) and N,N-dimethylformamide (9 ml, 0.116 mol) at room temperature, and N-hydroxyl was added.
  • Lithium tetrahydroaluminum (90 mg, 2.369 mmol) and anhydrous tetrahydrofuran (10 ml) were stirred and stirred at room temperature, and a solution of compound 1-4 (250 mg, 0.496 mmol) in tetrahydrofuran (10 ml, 0.123 mol) was added dropwise at room temperature.
  • the reaction was stirred for 1 hour, and the temperature was raised to 50 ° C until the reaction was completed by TLC.
  • the first step is a first step:
  • P-carboxyphenyl boronic acid pinacol ester (0.894 g, 4.8 mmol) was dissolved in dichloromethane (10 ml, at room temperature).
  • N-Boc piperazine (lg, 4.03 mmol) was added to N,N-dimethylformamide (1 ml, 17.78 mmol), and 1-ethyl-(3-dimethylaminopropyl) was added sequentially.
  • Carboxylideneimide hydrochloride (0.93 g, 4.8 mmol), N-hydroxybenzotriazole (0.66 g, 4.8 mmol), triethylamine (0.84 ml, 6.04 mmol), stirred at room temperature until TLC The reaction of the starting material was monitored.
  • Lithium tetrahydroaluminum (51.5 mg, 1.355 mmol) and anhydrous tetrahydrofuran (25, 0.308 mol) were stirred and stirred at room temperature, and the compound 1-5 (500 mg, 0.451 mmol) of tetrahydrofuran (25 ml, 0.308 mol) was added dropwise to the reaction mixture.
  • the solution was stirred at room temperature for 1 hour, and the temperature was raised to 50 ° C until the reaction of the starting material was completely monitored by TLC.
  • the mixture was cooled to room temperature, and 20 ml of water was added to the reaction mixture, and ethyl acetate (50 ml*3) was used for extraction.
  • the morpholine (5 ml, 57.405 mmol) was dissolved in dichloromethane (40 ml), and N,N-diisopropylethylamine (9.5 ml, 57.405 mmol)
  • the triphosgene (6g, 20.69mmol) in 30ml) was slowly added dropwise. The temperature of the addition process was kept at 0 ⁇ 3 °C for 1 hour.
  • Tetrahydropyrrole 600 mg, 8.436 mmol was dissolved in 15 ml of dichloromethane, and N,N-diisopropylethylamine (1.4 ml, 8.436 mmol) was added in an ice bath at 0 ° C and dissolved in dichloromethane.
  • the triphosgene 801mg, 2.70mmol) in (5ml) was slowly added dropwise. The temperature of the addition process was kept at 0 ⁇ 3°C for 1 hour.
  • N-Boc piperazine (1.57g, was added to the ice bath at 0°C.
  • Tetrahydropyrrolyl piperazinyl urea (370 mg, 2.022 mmol) and 4-formylbenzeneboronic acid (334 mg, 2.224 mmol) were dissolved in 10 ml of tetrahydrofuran and 10 ml of methanol, and acetic acid solution (0.5 ml, 8.75 mmol) was added and stirred at room temperature. After reacting for 1 hour, sodium triacetoxyborohydride (1. lg, 5.055 mmol) was added, and the mixture was heated to 60 ° C. The reaction was stirred until the reaction was completed by TLC. Yield: (4-Benzyl-piperazin-1-yl)-tetrahydropyrrole-1-yl-methanone-boronic acid (210 mg), Yield: 33%.
  • Tetramethoxypiperidine 500 mg, 4.314 mmol was dissolved in 10 ml of dichloromethane.
  • N,N-diisopropylethylamine (0.72 ml, 4.314 mmol)
  • the triphosgene (412mg, 1.389mmol) in dichloromethane (5ml) was slowly added dropwise.
  • the temperature of the addition process was kept at 0 ⁇ 3 °C for 1 hour.
  • N-Boc piperazine was added to the ice bath at 0 °C. 809 mg, 4.341 mmol) and N,N-diisopropylethylamine (0.72 ml, 4.341 mmol).
  • the compound ⁇ -5 (100 mg, 0.225 mmol) was dissolved in N,N-dimethylformamide (5 ml) at room temperature, and 4-bromocrotonic acid (37.2 mg, 0.225 mmol) and N-(3-di) were added.
  • Methylaminopropyl)-3-ethylcarbodiimide hydrochloride (43.0 mg, 0.225 mmol). The reaction was stirred at room temperature until the reaction was completed by TLC, and concentrated under reduced pressure.
  • the first step is a first step:
  • the first step is a first step:
  • N-Ethylpiperazine (1 g, 8.77 mmol) was dissolved in 15 ml of dichloromethane, and N,N-diisopropylethylamine (1.5 ml, 8.77 mmol) was added in an ice bath at 0 ° C, dissolved in The triphosgene (833mg, 2.81mmol) in dichloromethane (10ml) was slowly added dropwise, the temperature of the addition process was kept at 0 ⁇ 3 °C, the reaction was carried out for 1 hour, and the mixture was added at 0 °C in an ice bath.
  • N-Boc piperazine (1.63 g, 8.77 mmol), EtOAc, EtOAc (EtOAc:EtOAc.
  • N-Ethyl piperazinyl piperazine urea (1 g, 4.40 mmol) and 4-formylbenzeneboronic acid (729 mg, 4.86 mmol) were dissolved in 10 ml of tetrahydrofuran and 10 ml of methanol, and acetic acid solution (0.7 ml, 12.67 mmol) was added.
  • the reaction was stirred at room temperature for 1.5 hours, sodium triacetoxyborohydride (2.33 g, l l mmol) was added, and the mixture was warmed to 60 ° C. The reaction was stirred until the reaction was completed by TLC, and concentrated under reduced pressure.
  • 6-bromo-4-chlorothiophene [ 3,2-d] pyrimidine was prepared according to the method described in WO 2009/007421.
  • Lithium tetrahydroaluminum (75 mg, 1.95 mmol) and anhydrous tetrahydrofuran (5 ml, 61.27 mmol) were stirred and stirred at room temperature, and (4-ethyl-piperazin-1-yl)- ⁇ 4-[ 4-(2-Hydroxy-1-phenyl-ethylamino)-thieno[3,2,d]pyrimidin-6-yl]-phenylmethanone (370 mg, 0.78 mmol) in tetrahydrofuran (10 ml, 0.123 mol
  • the solution was stirred at room temperature for 1 hour, and the temperature was raised to 55 ° C until the reaction of the starting material was completely monitored by TLC.
  • Lithium tetrahydroaluminum (20.14 mg, 0.53 mmol) and anhydrous tetrahydrofuran (5 ml, 61.27 mmol) were stirred and stirred at room temperature, and a solution of the compound ⁇ -2 in tetrahydrofuran (10 ml, 0.123 mol) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature. After 1 hour, the temperature was raised to 55 °C until the reaction of the starting material was completely monitored by TLC.
  • Lithium tetrahydroaluminum (54 mg, 1.423 mmol) and anhydrous tetrahydrofuran (10 ml, 0.123 mol) were stirred and stirred at room temperature, and a solution of the compound ⁇ -3 OOO mg, 0.57 mmol) in tetrahydrofuran (10 ml, 0.123 mol) was added dropwise to the reaction mixture.
  • the reaction was stirred at room temperature for 1 hour, and the temperature was raised to 55 ° C until the reaction of the starting material was completely monitored by TLC.
  • Lithium tetrahydroaluminum (41.8 mg, 1.1 mmol) and anhydrous tetrahydrofuran (10 ml, 0.123 mol) were stirred and stirred at room temperature, and the compound III-4 (220 mg, 0.44 mmol) of tetrahydrofuran (10 ml, 0.123) was added dropwise to the reaction mixture.
  • the first step is a first step:
  • 6-bromo-4-chlorofuran [ 3,2-d ] pyrimidine is based on the preparation of 6-bromo-4-chlorothiophene [ 3,2-d ] pyrimidine and WO 2008/073785.
  • Lithium tetrahydrogen aluminum (75 mg, 1.95 mmol) and 5 mL of anhydrous tetrahydrofuran were mixed and stirred at room temperature to the reaction.
  • a solution of compound III-5 (355 mg, 0.75 mmol) in tetrahydrofuran (10 mL, 0.123 mol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, and then warmed to 55 ° C until the reaction was completed by TLC. 20 ml of water was added to the reaction mixture, which was extracted with ethyl acetate (50 ml*2), and then washed with saturated sodium chloride (50 ml*3) and dried over anhydrous sodium sulfate.
  • the first step is a first step:
  • Lithium tetrahydroaluminum (20.14 mg, 0.53 mmol) and anhydrous tetrahydrofuran (5 ml, 61.27 mmol) were stirred and stirred at room temperature, and the compound III-6 (90 mg, 0.19 mmol) of tetrahydrofuran (10 ml, 0.123 mol) was added dropwise to the reaction mixture.
  • the solution was stirred at room temperature for 1 hour, and the temperature was raised to 55 ° C until the reaction of the starting material was completely monitored by TLC. 20 ml of water was added to the reaction mixture under ice bath at 0 ° C, extracted with ethyl acetate (40 ml * 2 ), and then saturated.
  • the first step is a first step:
  • Lithium tetrahydrogenate 60 mg, 1.578 mmol
  • 10 mL of anhydrous tetrahydrofuran 10 mL
  • a solution of compound III-7 290 mg, 0.567 mmol
  • the reaction was carried out at 55 ° C until the reaction of the starting material was completely monitored by TLC.
  • the p-carboxyphenylboronic acid pinacol ester (2.8 g, 11.3 mmol) was dissolved in dichloromethane (27 ml, 0.422 mol), hydrazine, dimethyl-dimethylformamide (9 ml, 0.116 mol), and added -Boc-3-methylpiperazine (2.9 g, 14.52 mmol), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 2.79 g, 14.55 mmol).
  • N-hydroxybenzotriazole (1.98 g, 14.66 mmol), triethylamine (2.5 ml, 17.99 mmol), stirred at room temperature until the reaction was completed by TLC, 30 ml of water was added to the reaction mixture, and stirred for 30 minutes.
  • Dichloromethane (100 ml * 3 ) was extracted and washed with a saturated sodium chloride solution (100 ml * 2 ). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give: g, white solid), yield 85.4%.
  • Lithium tetrahydroaluminum (132 mg, 3.479 mmol) and anhydrous tetrahydrofuran (30 ml, 0.369 mol) were stirred and stirred at room temperature, and -(4-(4-(2-hydroxy-1-phenylethylamine)) was added dropwise to the reaction mixture.
  • the first step is a first step:
  • the hydrazine-methylpiperazine (1.5 g, 10 mmol) was dissolved in 15 ml of dichloromethane, and N,N-diisopropylethylamine (1.65 ml, 10 mmol) was added to the ice bath at 0 ° C, which was dissolved in two The triphosgene (950mg, 3.2mmol) in methyl chloride (10ml) was slowly added dropwise. The temperature of the addition process was kept at 0 ⁇ 3 °C for 1 hour. N-Boc piperazine was added to the ice bath at 0 °C (1.9).
  • N-methylpiperazinylpiperazine urea (2.3 g, 10.85 mmol) and 4-formylbenzeneboronic acid (1.9 g, 11.93 mmol) were dissolved in 20 ml of tetrahydrofuran and 10 ml of methanol, and a solution of acetic acid (1.2 ml, 21.72 mmol) was added.
  • the reaction was stirred at room temperature for 1.5 hours, sodium triacetoxyborohydride (5.8 g, 27.12 mmol) was added, and the mixture was warmed to 60 ° C. The reaction was stirred until the reaction was completed by TLC, concentrated under reduced pressure and purified by silica gel column chromatography.
  • the first step is a first step:
  • the first step is a first step:
  • 6-bromo-4-chloro-2-methyl-thiophene [3,2-d]pyrimidine can be produced by the methods described in WO 2009/007421 and WO2008/058285.
  • 6-Bromo-4-chloro-2-methyl-thiophene [3,2-d]pyrimidine (830 mg, 3.15 mmol) and L-phenylglycinol (648 mg, 4.725 mmol) were dissolved in N, N at room temperature - dimethylformamide (10 ml), triethylamine (1.1 ml, 7.875 mol) was added dropwise, heated to 55 ° C, reacted for 24 hours, allowed to cool, added 40 ml of ice water, filtered under reduced pressure, filter cake The mixture was slurried with 10 ml of water, filtered under reduced pressure, and then filtered with 10 ml of n-hexane and filtered under reduced pressure to give: 2-(6-bromo-2-methyl-thiophene[3,2-d]pyrimidine-4-amino 2 -Phenyl-ethanol (780 mg, pale yellow solid), Yield: 71%.
  • T-PBS PBS containing 0.1% Tween-20 in potassium free
  • reaction buffer 50 mmol/L HEPES H 7.4, 50 mmol/L MgCl 2 , 0.5 mmol/L MnCl 2 , 0.2 mmol/L Na 3 V0 4 , 1 mmol/L DTT.
  • the ATP solution was 50 ⁇ M, and the final concentration was 5 mol/L.
  • the above screening compound obtained was confirmed to have inhibitory activity EGFR or VEGFR (compound 10 "5 M for inhibition of EGFR receptor tyrosine kinase or VEGFR 50%>) formulated as a concentration gradient, for IC 5. Evaluation The ic 5 value of the inhibitory protein tyrosine kinase at the molecular level of each compound was calculated by a four-parameter method, and the results are shown in Table 1.
  • the receptor VEGFR has a good inhibitory effect, and some compounds have a good inhibitory effect on the epidermal growth factor receptor EGFR and the angiogenesis factor receptor VEGFR; and the compound activity of the [3,2-d]pyrimidine skeleton It is obviously superior to the activity of the compound having a [2,3-d]pyrimidine skeleton; the order of the substituent activity on the piperazine ring can be roughly arranged as follows: cyclopropyl>methyl>2-hydroxyethyl>ethyl>Urea; EGFR inhibitory activity of most compounds with a [3,2-d]pyrimidine skeleton is comparable to or better than the control drug Gefitinib Gefitinib, especially compounds III-9 and IV-3, the half-inhibitory concentration IC 5 .

Abstract

L'invention concerne des dérivés de thiénopyrimidine et de furopyrimidine, leur procédé de fabrication et leur utilisation médicale. La structure de ces dérivés est telle que représentée dans la formule V. Les dérivés de thiénopyrimidine et de furopyrimidine de l'invention ont une activité dominante d'inhibition de EGFR à laquelle s'ajoute, chez certains de ces composés, une activité dominante d'inhibition de VEGFR ; on peut donc escompter que ces dérivés puissent être développés en tant qu'inhibiteurs de la tyrosine kinase EGFR et/ou VRGFR et soient utilisés pour la préparation de médicaments destinés à la prévention ou au traitement de maladies en rapport avec le récepteur du facteur de croissance épidermique EGFR et/ou le récepteur du facteur de croissance endothéliale vasculaire VEGFR. Cette invention fournit un axe pour de nouveaux développement et une méthode pour la mise au point de nouveaux médicaments inhibiteurs de la tyrosine kinase à faible pharmaco-résistance ou qui soient capables d'atténuer précocement la pharmaco-résistance par rapport à l'inhibiteur, ce qui ouvrirait de vastes perspectives d'application et présenterait une grande valeur médicale.
PCT/CN2012/083830 2011-11-03 2012-10-31 Dérivés de thiénopyrimidine et de furopyrimidine, leur procédé de fabrication et leur utilisation médicale WO2013064068A1 (fr)

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