WO2014082230A1 - Dérivés de pyrrolo-triazine, leur procédé de préparation et leur application médicale - Google Patents

Dérivés de pyrrolo-triazine, leur procédé de préparation et leur application médicale Download PDF

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Publication number
WO2014082230A1
WO2014082230A1 PCT/CN2012/085469 CN2012085469W WO2014082230A1 WO 2014082230 A1 WO2014082230 A1 WO 2014082230A1 CN 2012085469 W CN2012085469 W CN 2012085469W WO 2014082230 A1 WO2014082230 A1 WO 2014082230A1
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group
methyl
substituted
unsubstituted
pyrrole
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PCT/CN2012/085469
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English (en)
Chinese (zh)
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安晓霞
别平彦
杨午立
刘俊
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上海希迈医药科技有限公司
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Priority to PCT/CN2012/085469 priority Critical patent/WO2014082230A1/fr
Publication of WO2014082230A1 publication Critical patent/WO2014082230A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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

Definitions

  • the invention belongs to the field of medicinal chemistry.
  • the present invention relates to pyrrolotriazine derivatives, processes for their preparation and their use in medicine. Background technique
  • Tumor is one of the most serious diseases that threaten human health. Its treatment mainly includes radiotherapy, chemotherapy and surgery. With the development of cell biology and oncology pharmacology in recent years, 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 (helix; the intracellular region includes the kinase region and has many tyrosines)
  • the carboxyl terminal tail of the phosphorylation site is provided.
  • Tyrosine kinase transports the gamma phosphate of ATP to a tyrosine residue.
  • EGFR After binding to the ligand, EGFR undergoes homologous or heterodimerization.
  • the TK region is tightly linked. 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). Intracellular signaling reactions begin. These signalings form distinct 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 related to tumor progression and poor prognosis.
  • Gefitinib ZD1839 or Iressa
  • erlotinib ; Erlotinib, OSI774 or Tarceva
  • NSCLC non-small cell lung cancer
  • the object of the present invention is to provide a novel pyrrotriazine derivative which exhibits strong activity as a tyrosinase inhibitor and has the advantages of high inhibitory activity, low effective amount and low drug resistance. It can be widely used in the preparation of a medicament for preventing or treating diseases associated with the epidermal growth factor receptor EGFR and/or the angiogenic factor receptor VEGFR.
  • the present invention also provides the pyrrolotriazine derivative or a pharmaceutically acceptable salt, solvate or isomer thereof (including tautomers, racemates, enantiomers, non-pairs Process for the preparation of the enantiomers.
  • a first aspect of the invention provides a pyrrolotriazine derivative of the formula I, or a pharmaceutically acceptable salt or solvate thereof,
  • an oxygen atom, a sulfur atom, a nitrogen atom, an unsubstituted methylene group (-CH 2 -) or a methylene group substituted by one or two C alkyl groups, a carbonyl group or 1 is absent;
  • X 2 is An oxygen atom, a sulfur atom, a nitrogen atom;
  • Y is a substituted or unsubstituted alkyl group;
  • m is 1 or 2;
  • n is 1 or 2;
  • R is hydrogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted d- 8 alkoxy, substituted or unsubstituted C 3 -8 cycloalkyl, substituted or unsubstituted C 3 -8 cycloalkoxy a substituted, unsubstituted or unsubstituted phenoxy group, a substituted or unsubstituted 3 to 8 membered nitrogen heterocyclic ring, a substituted or unsubstituted 3 to 11 membered azabicyclo, substituted or unsubstituted 3 to 8 Oxygen heterocycle, substituted or unsubstituted 3 to 11 membered oxabicyclic ring, substituted or unsubstituted 3 to 8 membered oxynitride, substituted or unsubstituted 3 to 11 membered oxynitride Heterobicyclic, substituted or unsubstituted 3 to 8 membered nitrogen sulfur
  • R 2 is hydrogen, substituted or unsubstituted d- 8 alkyl, substituted or unsubstituted C 3 -8 cycloalkyl, substituted or unsubstituted C 6 -12 aryl, alkylsulfonyl, d- 8 acyl or d_ 8 alkoxy acyl;
  • R 3 is a substituted or unsubstituted C 6 -12 aryl group, a substituted or unsubstituted aza heteroaryl group, a substituted or unsubstituted oxaheteroaryl group or a substituted or unsubstituted thiaheteroaryl group;
  • R 4 or R 5 are each independently hydrogen, halogen, d 3 alkyl, d 3 alkoxy, d 3 alkoxy, cyano (-CN), wherein the substituent is hydroxy, halogen, alkyl , halogenated d 6 alkyl, hydroxy d 6 alkyl, d 6 alkoxy, C 3 -6 epoxy acyl, d 6 alkoxy acyl, nitrile (-CN), nitro, amino, oxygen (or Oxo), d- 6 acyl, d- 6 amide, or d- 6 alkylsulfonyl.
  • Xi, m, Ri R 2 , R 3 , R4, and R 5 are as defined above.
  • the 3 to 8 is selected from the group consisting of
  • the 3- to 11-membered azabicyclo ring is selected from the group consisting of:
  • the 3- to 8-membered nitrogen-sulfur heterocycle is selected from the group consisting of
  • R 3 is a substituted or unsubstituted phenyl, thienyl, furyl, pyridine or pyrimidine, and the substituent is selected from one or more of the group consisting of: a hydroxyl group, a halogen, a cyano group, alkyl, d_ 3 halogenated alkyl group, an amino group, in
  • R is a d- 3- alkyl group.
  • the second aspect of the invention provides a process for producing a pyrrolotriazine derivative according to the first aspect of the invention, or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of:
  • Xi, X 2 , Y, m, ⁇ , Ri R 2 , R 3 , F , R 5 are as described in the first aspect of the invention;
  • L is a leaving group selected from the group consisting of fluorine, Chlorine, bromine, iodine or alkoxy.
  • the base is an organic base, an inorganic base, or a combination thereof; preferably, the organic base comprises trimethylamine, triethylamine, pyridine, piperidine, morpholine, or a combination thereof.
  • the inorganic base includes sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, or a combination thereof.
  • the preparation method comprises the steps of:
  • X 2 Y, m, n, and L are as defined above.
  • the preparation method comprises the steps of:
  • X 2 Y, n, R 2 R 3 R4 R 5 , L are as defined above, and R 7 is d- 8 alkyl, C 3 -8 cycloalkyl or substituted or unsubstituted phenyl, R 8 is a substituted or unsubstituted 3 to 8 membered nitrogen heterocyclic ring, substituted or unsubstituted 3 to 11 membered azabicyclo, substituted or unsubstituted 3 to 8 membered oxynitride, substituted or unsubstituted 3-11 yuan oxabicyclo nitrogen, substituted or unsubstituted 3- to 8-membered nitrogen heterocyclic sulfur, a substituted or unsubstituted amino; wherein the substituent is hydroxy, halo, d_ 6 Alkyl, halogenated d- 6 alkyl, hydroxy d- 6 alkyl, d- 6 alkoxy, C 3 -6 epoxy acyl,
  • the preparation method comprises the steps of:
  • X 2 Y, n, R 2 R 3 R 4 R 5 , L are as defined above;
  • R 7 is d- 8 alkyl, C 3 -8 cycloalkyl or unsubstituted or substituted phenyl;
  • R 9 is a substituted or unsubstituted d 8 alkoxy group; wherein the substituent is a hydroxyl group, a halogen, a C alkyl group, a halogenated d 6 alkyl group, a hydroxyl group d 6 alkyl group, a d 6 alkoxy group, C 3 -6 epoxy group, d- 6 alkoxy acyl group, nitrile group (-CN), nitro group, amino group, oxygen, d- 6 acyl group, d- 6 amide group, or d 6 alkylsulfonyl group.
  • the preparation method comprises the steps of:
  • X 2 Y, n, R 2 R 3 R 4 R 5 , L are as defined above, and R 7 is d- 8 alkyl, C 3 -8 cycloalkyl or unsubstituted or substituted phenyl, R 6 is d 8 alkyl, C 2 -6 alkenyl;
  • the third aspect of the invention provides the use of the pyrrolotriazine derivative, or a pharmaceutically acceptable salt or solvate thereof, according to the first aspect of the invention, which is used as a tyrosine kinase inhibitor; For the preparation of drugs for the treatment of tumors.
  • a fourth aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a safe and effective amount of the pyrrolotriazine derivative of the first aspect of the invention, or a pharmaceutically acceptable salt or solvate thereof; An acceptable carrier.
  • the fifth aspect of the invention provides the use of the pharmaceutical composition according to the fifth aspect of the invention as a tyrosine kinase inhibitor; or for the preparation of a medicament for treating a tumor.
  • the tumor comprises: skin cancer, esophageal cancer, gastric cancer, colon cancer, liver cancer, nasopharyngeal cancer, lung cancer, breast cancer, cervical cancer, blood cancer.
  • the pharmaceutical composition is used as an epidermal growth factor receptor (EGFR) inhibitor and/or an angiogenic growth factor receptor (VEGFR) inhibitor; or for the preparation of a prophylactic or therapeutic agent with epidermal growth factor Drugs for receptor (EGFR) and/or angiogenic factor receptor (VEGFR) related diseases.
  • EGFR epidermal growth factor receptor
  • VEGFR angiogenic growth factor receptor
  • the inventors have extensively and intensively studied to obtain a pyrrotriazine derivative of the formula I for the first time, which has a remarkable tyrosine kinase inhibitory activity and is a highly potent tyrosinase inhibitor. On this basis, the inventors completed the present invention.
  • d- 8 alkyl refers to a straight or branched alkyl group having from 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. , sec-butyl, tert-butyl, or the like.
  • alkyl refers to a straight or branched alkyl group having from 1 to 3 carbon atoms
  • d- 6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms.
  • C 2 -6 olefin means an olefin group having 2 to 6 carbon atoms, such as ethylene, propylene, 1,2-butene, 2,3-butene, butadiene, or the like.
  • d- 8 alkylamino refers to an amino group substituted with a d- 8 alkyl group, such as methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamine. Bases and the like.
  • d- 8 alkoxy refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutylene. An oxy group, a sec-butoxy group, a tert-butoxy group, or the like.
  • alkoxy refers to a straight or branched alkoxy group having from 1 to 6 carbon atoms; the term “d- 3 alkoxy” refers to a straight chain having from 1 to 3 carbon atoms. Or a branched alkoxy group.
  • C 3 -8 cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like.
  • C 3 -6 cycloalkyl refers to a cycloalkyl group having 3 to 6 carbon atoms.
  • d- 8 alkyl acyl refers to a d- 8 alkyl substituted acyl group such as formyl, acetyl, propionyl, isopropionyl, butanoyl, isobutyryl, sec-butyryl, t-butyryl, or the like.
  • d- 8 alkoxyl refers to a d- 8 alkoxy-substituted acyl group, such as methoxy, ethoxy, propanoyl, isopropoxy, butanoyl, isobutoxy, sec-butoxy, Tert-butoxycarbonyl, or a similar group.
  • CM alkoxyl refers to an acyl group substituted with d- 3 alkoxy
  • d- 6 alkanoyl refers to an acyl group substituted with d- 6 alkoxy.
  • d- 8 alkylamino acyl refers to an acyl group substituted with a d- 8 alkylamino group, such as carbamoyl, ethoxylyl, alanyl, isopropylamino, butyryl, isobutylyl, sec-butyryl , tert-butyryl, or the like.
  • C 3 -6 cycloalkyl acyl refers to a C 3 -6 cycloalkyl substituted acyl group, such as cyclopropyl acyl, cyclobutyl acyl, cyclopentyl acyl, cyclohexyl acyl, or the like.
  • C 2 -6 olefin acyl means an olefin acyl group having 2 to 6 carbon atoms, such as vinyl acyl, acryloyl, acryloyl, isoacryloyl, crotonyl, methacryloyl, sec-butenoyl, tert-butyl An enoyl group, or the like.
  • d- 8 acyloxy refers to an acyloxy group having from 1 to 8 carbon atoms, such as formyloxy, acetoxy, propionyloxy, isopropionyloxy, butyryloxy, isobutyryl. An oxy group, a sec-butyryloxy group, a tert-butyryloxy group, or the like.
  • d- 6 acyloxy refers to an acyloxy group having from 1 to 6 carbon atoms.
  • amido refers to an amide group having from 1 to 8 carbon atoms, such as formamide, acetamido, propionamido, isopropylamide, butanamide, isobutyramide, sec-butyramide, Tert-butylamide group, or a similar group.
  • C 6 -12 aryl acyl refers to an acyl group substituted with a C 6 -12 aryl group, such as a benzoyl group or the like.
  • alkylsulfonyl refers to. "!;
  • alkylsulfonyl refers d_ 8 alkyl substituted sulfonyl group; the "substituted C 6 _ 12 aryl group d_ 8
  • the alkylsulfonyl group “includes phenylacetyl, phenylpropionyl and the like.
  • acyl refers to a group having "z-,”.
  • acyloxy refers to a group having "one" - "
  • halogen means fluoro, chloro, bromo, iodo.
  • aryl preferably “C 6 -12 aryl” refers to a monocyclic or bicyclic aromatic group having 6 to 12 carbon atoms in the ring moiety, for example: phenyl, biphenyl, naphthalene A group, or a similar group, each of which may be optionally substituted.
  • azaaryl refers to an aromatic group containing one or more nitrogen atoms in the ring, preferably.
  • An azaaryl group is an aromatic group having 4 to 10 carbon atoms and having one or more nitrogen atoms in the ring, such as a pyridine, a pyrimidine, a pyrrole, or the like, each of which has a carbon atom Can be arbitrarily replaced.
  • oxaaryl refers to an aromatic group containing one or more oxygen atoms in the ring, preferably.
  • Oxyheteroaryl That is, an aromatic group having 4 to 10 carbon atoms and having one or more oxygen atoms in the ring, such as furan, benzofuran, or the like, each of which may be optionally substituted.
  • thiaheteroaryl refers to an aromatic group containing one or more sulfur atoms in the ring, preferably a "C 4 thiaheteroaryl group” having 4 to 10 carbon atoms and one or more rings in the ring.
  • azabicyclo refers to a 3-11 membered azabicyclic or spiro ring containing one or more nitrogen atoms; for example, an azabicyclo ring selected from the group consisting of:
  • oxabicyclo refers to a 3-11 membered oxabicyclic or spiro ring containing one or more oxygen atoms; for example, an oxabicyclic ring selected from the group consisting of:
  • nitrogenetero refers to a 3-8 membered azaoxamonocyclic ring containing one or more nitrogen and oxygen atoms; for example
  • nitrogen heterocycle refers to a 3-8 membered azathiomonocyclic ring containing one or more nitrogen and sulfur atoms
  • the nitrogen-sulfur heterocycle as described above is L N , , ⁇ , ⁇ .
  • condensation agent and “condensing agent” have the same meaning and refer to an agent capable of causing a condensation reaction.
  • a condensation reaction is a reaction in which two or more organic molecules interact to form a macromolecule by covalent bonding while losing water or other relatively simple inorganic or organic small molecules.
  • the small molecular substances are usually water, hydrogen chloride, and Alcohol or acetic acid, etc.
  • Table 1 The Chinese names corresponding to the abbreviations of the various condensing agents in the present invention are shown in Table 1.
  • the term "compound of the invention” refers to a compound of formula I.
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
  • the term "pharmaceutically acceptable salt” as used herein refers to a salt of the compound of the present invention which is formed with an acid or a base and which is suitable for use as a medicament.
  • the pharmaceutically acceptable salt includes a mineral acid salt or an organic acid salt; the inorganic acid is selected from one or more of the group consisting of: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid; One or more of the following groups: formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethylsulfonic acid, benzene Sulfonic acid, p-toluenesulfonic acid.
  • the compounds of the invention include the compounds shown in Table 2:
  • each reaction is usually carried out in an inert solvent at an ice bath temperature to reflux temperature (eg o °c ⁇
  • reaction time is determined by TLC monitoring (; usually from 0.1 hour to 60 hours, preferably from 0.5 to 48 hours).
  • the present invention provides a process for the preparation of a plurality of preferred compounds of formula I. E.g,
  • Method 1 The preparation method comprises the steps of: compounding a compound of formula IV or a salt thereof and a compound of formula V under basic conditions or
  • Xi, X 2 , Y, m, n, R, R 2 , R 3 , and R 5 are as defined above;
  • L is a leaving group selected from the group consisting of fluorine, chlorine, bromine, and iodine Or C ⁇ alkoxy.
  • the base is an organic base, an inorganic base, or a combination thereof; preferably, the organic base comprises trimethylamine, triethylamine, pyridine, piperidine, morpholine, or a combination thereof. And/or the inorganic base includes sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, or a combination thereof.
  • Method 2 the preparation method comprises the steps of:
  • X 2 Y, m, n, and L are as defined above.
  • the reducing agent is diisopropylaluminum hydride, lithium tetrahydrogenate, red aluminum or borane complex.
  • the base is an organic base, an inorganic base, or a combination thereof; preferably, the organic base comprises trimethylamine, triethylamine, pyridine, piperidine, Morpholine, or a combination thereof; and/or the inorganic base comprises sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, or a combination thereof.
  • Method 3 The preparation method includes the following steps:
  • X 2 Y, n, R 2 R 3 R 4 R 5 , L are as defined above, and R 7 is d- 8 alkyl, C 3 -8 cycloalkyl or substituted or unsubstituted phenyl, R 8 is a substituted or unsubstituted 3 to 8 membered nitrogen heterocyclic ring, substituted or unsubstituted 3 to 11 membered azabicyclo, substituted or unsubstituted 3 to 8 membered oxynitride, substituted Or an unsubstituted 3 to 11 membered azaoxabicyclic, substituted or unsubstituted 3 to 8 membered nitrogen sulfur heterocyclic ring, substituted or unsubstituted amino group; wherein the substituent is a hydroxyl group, a halogen, d_ 6 alkyl, halogenated d 6 alkyl, hydroxy d 6 alkyl, d 6 alkoxy, C 3 -6 epoxy
  • the base in the step (i), is an organic base, an inorganic base, or a combination thereof; preferably, the organic base comprises trimethylamine, triethylamine, pyridine, piperidine, Morpholine, or a combination thereof; and/or the inorganic base comprises sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, or a combination thereof.
  • the base in the step (ii), is sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof.
  • the condensing agent is selected from the group consisting of DIC, DCC, HOBt, EDC.HCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI, or a combination thereof .
  • the reducing agent is diisopropylaluminum hydride, lithium tetrahydrogenate, red aluminum or borane complex.
  • X 2 Y, n, R 2 R 3 R 4 R 5 , L are as defined above;
  • R 7 is d- 8 alkyl, C 3 -8 cycloalkyl or unsubstituted or substituted phenyl;
  • R 9 is a substituted or unsubstituted alkoxy acyl group; wherein the substituent is a hydroxyl group, a halogen, a d 6 alkyl group, a halogenated d 6 alkyl group, a hydroxyl group d 6 alkyl group, a d 6 alkoxy group, a C 3 group _ 6 epoxy acyl, d 6 alkoxy acyl, nitrile (-CN), nitro, amino, oxygen, d- 6 acyl, d- 6 amide, or d 6 alkylsulfonyl.
  • the base is an organic base, an inorganic base, or a combination thereof; preferably, the organic base comprises trimethylamine, triethylamine, pyridine, piperidine, Morpholine, or a combination thereof; and/or the inorganic base comprises sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, or a combination thereof.
  • the base in the step (b), the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof.
  • the azide reagent is sodium azide or diphenyl azide.
  • X 2 Y, n, R 2 R 3 R 4 R 5 , L are as defined above, and R 7 is d- 8 alkyl, C 3 -8 cycloalkyl or unsubstituted or substituted phenyl, R 6 is alkyl, C 2 -6 alkenyl;
  • the base is an organic base, an inorganic base, or a combination thereof; preferably, the organic base comprises trimethylamine, triethylamine, pyridine, piperidine, Morpholine, or a combination thereof; and/or the inorganic base comprises sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, or a combination thereof.
  • the format reagent comprises: a methyl format reagent, an ethyl format reagent, an isopropyl format reagent, and the like.
  • the oxidizing agent comprises: hydrogen peroxide, peroxybenzoic acid, m-chloroperoxybenzoic acid, peroxytert-butanol or the like.
  • the condensing agent comprises: an inorganic salt, an organic base, or a combination thereof; preferably, the inorganic salt comprises lithium chloride, sodium iodide, lithium carbonate Or a combination thereof; and/or the organic base comprises trimethylamine, triethylamine, pyridine, piperidine, or a combination thereof.
  • the compound of the present invention has excellent inhibitory activity against tyrosine kinases, particularly epidermal growth factor receptor (EGFR) and/or angiogenic growth factor receptor (VEGFR), the compounds of the present invention and various crystal forms thereof, Pharmaceutically acceptable
  • EGFR epidermal growth factor receptor
  • VEGFR angiogenic growth factor receptor
  • the inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the invention as the main active ingredient are useful for the treatment, prevention and alleviation of diseases mediated by tyrosine kinases.
  • the compounds of the present invention are useful for the treatment of epidermal growth factor receptor (EGFR) and/or vascular growth factor receptor (VEGFR)-related cell abnormal proliferation, morphological changes, hyperkinesia, angiogenesis, and tumor metastasis or growth. And other diseases.
  • EGFR epidermal growth factor receptor
  • VEGFR vascular growth factor receptor
  • the pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount, and a pharmaceutically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: The amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 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.
  • the "one dose" is a tablet.
  • “Pharmaceutically acceptable carrier” means: 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. By “compatibility” it is meant herein that the components of the composition are capable of blending with the compounds of the invention and with each other without significantly reducing the potency 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, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid;
  • binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia;
  • a humectant for example, glycerin
  • a disintegrant for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate
  • a slow solvent For example, paraffin wax
  • absorption accelerators for example, quaternary amine compounds
  • wetting agents such as cetyl alcohol and glyceryl monostearate
  • adsorbents for example, kaolin
  • lubricants For example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof.
  • the dosage form may also contain a buffer.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared from coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • 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, dimethyl Carbamide and oil, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar or a mixture of these and the like.
  • a suspending agent for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar or a mixture 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.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • 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.
  • 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 pyrrolotriazine derivative provided by the invention has novel structure, has obvious EGFR and VEGFR inhibitory activity, and can be used in tyrosine kinase EGFR or/and VEGFR inhibitor for preparing prevention or treatment and epidermal growth.
  • the medicinal tyrosine kinase inhibitor drug provides a new development direction and approach, and has broad application prospects and medicinal value.
  • the invention also provides a preparation method of the compound of the invention, which has the advantages of simple and easy raw materials, mild reaction conditions, simple operation, mature process, high efficiency and low cost, and is suitable for industrial production.
  • the invention will be further elucidated below in conjunction with specific implementations. 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.
  • the experimental methods in the following examples which do not specify the specific conditions are usually produced according to the conditions described in the conventional conditions, for example, Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturing conditions. The conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
  • NMR BrukerAVANCE-400 nuclear magnetic instrument
  • Mass spectrometry FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX); Determination of IC 5 Q value: NovoStar microplate reader (purchased from Germany National BMG); HPLC test equipment: Agilent 1200DAD high pressure liquid chromatograph CSunfire C 18 150 4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 4.6mm column).
  • Example S -4-(2-hydroxy-azine-6-carboxylic acid methyl ester
  • the preparation method of the starting compound (4-chloro-5-methyl-pyrrole [2, lf] [l, 2, 4] triazine-6-carboxylic acid methyl ester) is as follows:
  • Example 3 0(4-Methyl-piperazin-1-yl)-[4-(2-hydroxy-1-phenyl-ethylamine)-5-methyl-pyrrole [2, lf
  • Example 5 0-(4-Cyclopropylcarbonyl-piperazin-1-yl)-[4-(2-hydroxy-1-phenyl-ethylamine)-5-methyl-pyrrole [2, lf
  • Example 7 0(5-Methyl-hexahydro-pyrrole[3,4-c]pyrrol-2-yl)-[4-(2-hydroxy-1-phenyl-ethylamine)-5-methyl-pyrrole [2,1-11 [1,2,4]triazin-6-yl]-methanone 0-4-(2-hydroxy-1-phenyl-ethylamine)-5-methyl-pyrrole[2,lf][l,2,4]triazine-6-carboxylic acid (100 mg, 0.32 mmol) and 2-methyl-octahydropyrrole [3,4-C]pyrrole (61 mg, 0.48 mmol) were dissolved in N,N-dimethylformamide (8 ml), then 1-hydroxybenzotriene was added.
  • Example 9 0(3-Hydroxy-8-aza-bicyclo[3.2.1]octyl-8-yl)-[4-(2-hydroxy-1-phenyl-ethylamine)-5-methyl- Pyridine [2,lf
  • Triazin-6-yl]-methanone (190 mg, 0.45 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml), and then, in an ice bath, slowly added lithium tetrahydrogenate (190 mg, 5 mmol) After the addition is completed, the ice bath is removed, and the reaction is heated to 40 ° C until the reaction of the starting material is completely monitored by TLC.
  • DMSO-d 6 7.74 (s, 1H), 7.60 (s, 1H), 7.47 (d, 2H), 7.38 (t, 2H), 7.30 (d, 1H), 6.90 (d, 1H), 5.41 ( d, 1H), 5.31 (s, 1H), 4.41 (s, 2H), 3.87 (t, 2H), 3.63 (s, 2H), 3.42 (d, 4H), 3.04 - 2.78 (m, 4H), 2.62 (s, 3H), 1.21 (t, 3H).
  • the starting compound, phenyl-2-methoxyethylamine hydrochloride can be prepared according to the first to fifth steps of Example 4 of the patent CN102120724A (publication date 2011.07.13).
  • Example 28 (S)-4-(2-methoxy-1-phenyl-ethylamine)-5-methyl-pyrrole [2,lf
  • T-PBS PBS containing 0.1% Tween-20 in potassium free
  • Control group Two wells without ATP control wells (no enzyme control wells) were included in each experiment; and corresponding DMSO solvent control wells (negative control wells).
  • the inhibition rate of the sample is obtained by the following formula: 2.
  • the above preferred compounds are specifically obtained with EGFR or VEGFR inhibitory activity (inhibition rate of the compound of EGFR receptor tyrosine kinase or VEGFR> 50% 10- 5 M) formulated as a concentration gradient, for IC 5. (half the inhibitory concentration) evaluation.
  • the activity of the compounds of the present invention was tested as shown in Table 1.
  • the cytotoxicity inhibition IC 5Q value of the candidate compound against human squamous cell carcinoma cell line A431 was examined by CCK-8 detection kit.
  • CCK-8 test kit Cell Counting Kit-8, catalog number CK04-13, purchased from Dojindo
  • 96-well culture plate Cat. No. 3599, purchased from Coming Costar
  • fetal calf serum Cat#10099-141) , purchased from GIBCO
  • medium purchased from Invitrogen
  • the cells in the logarithmic growth phase were collected, counted, and the cells were resuspended in complete medium, and the cell concentration was adjusted to an appropriate concentration, and 96-well plates were seeded, and 100 ⁇ of the cell suspension was inoculated per well.
  • the cells were incubated for 24 hours at 37 ° C, 100% relative humidity, 5% C0 2 incubator.
  • 96-well plates were seeded, and each well was added with a ⁇ cell suspension.
  • the cells were incubated for 24 hours in a 37, 100% relative humidity, 5% C0 2 incubator.
  • test compound was diluted to 500 ⁇ M with a medium and then diluted 8 times with a gradient. Add cells to 25 ⁇ l/well.
  • the 34 test compounds (Compound 1-34) were applied at a final concentration ranging from 100 ⁇ to 0 ⁇ , with a 5-fold gradient dilution, for a total of 10 concentration points.
  • the cells were incubated for 72 hours at 37 ° C, 100% relative humidity, 5% C0 2 incubator.
  • the medium was aspirated, and the complete medium containing 10% CCK-8 was added and incubated in a 37 ° C incubator for 2-4 hours.
  • the absorbance at 450 nm was measured on a SpectraMax M5 Microplate Reader with gentle shaking, and the absorbance at 650 nm was used as a reference to calculate the inhibition rate.
  • the inhibition rate of the drug on tumor cell growth was calculated as follows:
  • Tumor cell growth inhibition rate % [(A e -A s ) / (A e -A b )] X 100%
  • a s sample OA (cell + CCK-8 + test compound); A c : negative control OA (cell + CCK-8 + DMSO); A b : positive control OA (medium + CCK- 8+ DMSO).
  • a represents an inhibitory activity of ⁇ 50 nanomolar (nM);
  • b represents an inhibitory activity of ⁇ 50 but ⁇ 250 nanomolar (nM);
  • c means ⁇ 250 but ⁇ 500 nanomolar ( The inhibitory activity of nM),
  • d represents the inhibitory activity of ⁇ 500 nanomolar (nM).
  • the compound of the present invention has a good tyrosine kinase EGFR inhibitory activity, wherein the tyrosine kinase EGFR activity inhibitory activity is preferably lower than that of the compounds 13, 16, 17, 18, 24, 33, 34. 50nM level.
  • the compounds of the invention have better A431 cell inhibitory activity, wherein compounds 13, 16

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Abstract

La présente invention se rapporte à des dérivés de pyrrolo-triazine, à leur procédé de préparation et à leur application médicale. En particulier, les dérivés de pyrrolo-triazine selon l'invention sont des inhibiteurs efficaces de la tyrosine kinase, ce qui ouvre de nouvelles perspectives de mise au point de nouveaux médicaments. Plus spécifiquement, l'invention propose des inhibiteurs qui interviennent prématurément en cas de résistance aux médicaments aussi faible soit-elle, ce qui confère avantageusement à l'invention une application médicale.
PCT/CN2012/085469 2012-11-28 2012-11-28 Dérivés de pyrrolo-triazine, leur procédé de préparation et leur application médicale WO2014082230A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000071129A1 (fr) * 1999-05-21 2000-11-30 Bristol-Myers Squibb Company Pyrrolotriazines inhibiteurs de kinases
WO2001014378A1 (fr) * 1999-08-23 2001-03-01 Shionogi & Co., Ltd. DERIVES DE PYRROLOTRIAZINE A ACTIVITES INHIBANT sPLA¿2?
WO2003090912A1 (fr) * 2002-04-23 2003-11-06 Bristol-Myers Squibb Company Composes pyrrolo-triazine aniline utiles en tant qu'inhibiteurs de kinase
WO2010088518A2 (fr) * 2009-01-31 2010-08-05 Kalypsys, Inc. Modulateurs hétérocycliques du gpr119 pour le traitement de maladies
WO2011025940A1 (fr) * 2009-08-28 2011-03-03 Array Biopharma Inc. Composés inhibiteurs de raf et leurs procédés d'utilisation
WO2012146666A1 (fr) * 2011-04-29 2012-11-01 Almirall, S.A. Dérivés de pyrrolotriazinone en tant qu'inhibiteurs de pi3k

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000071129A1 (fr) * 1999-05-21 2000-11-30 Bristol-Myers Squibb Company Pyrrolotriazines inhibiteurs de kinases
WO2001014378A1 (fr) * 1999-08-23 2001-03-01 Shionogi & Co., Ltd. DERIVES DE PYRROLOTRIAZINE A ACTIVITES INHIBANT sPLA¿2?
WO2003090912A1 (fr) * 2002-04-23 2003-11-06 Bristol-Myers Squibb Company Composes pyrrolo-triazine aniline utiles en tant qu'inhibiteurs de kinase
WO2010088518A2 (fr) * 2009-01-31 2010-08-05 Kalypsys, Inc. Modulateurs hétérocycliques du gpr119 pour le traitement de maladies
WO2011025940A1 (fr) * 2009-08-28 2011-03-03 Array Biopharma Inc. Composés inhibiteurs de raf et leurs procédés d'utilisation
WO2012146666A1 (fr) * 2011-04-29 2012-11-01 Almirall, S.A. Dérivés de pyrrolotriazinone en tant qu'inhibiteurs de pi3k

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