WO2014029251A1 - Composé benazépine et son application - Google Patents

Composé benazépine et son application Download PDF

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Publication number
WO2014029251A1
WO2014029251A1 PCT/CN2013/079885 CN2013079885W WO2014029251A1 WO 2014029251 A1 WO2014029251 A1 WO 2014029251A1 CN 2013079885 W CN2013079885 W CN 2013079885W WO 2014029251 A1 WO2014029251 A1 WO 2014029251A1
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WO
WIPO (PCT)
Prior art keywords
group
chloro
benzopyridine
diazepine
methyl
Prior art date
Application number
PCT/CN2013/079885
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English (en)
Chinese (zh)
Inventor
李建其
王文雅
黄道伟
杜振新
卢秀莲
王佳静
黄美花
Original Assignee
辰欣药业股份有限公司
上海医药工业研究院
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Application filed by 辰欣药业股份有限公司, 上海医药工业研究院 filed Critical 辰欣药业股份有限公司
Publication of WO2014029251A1 publication Critical patent/WO2014029251A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to benzopyridinium azide compounds and the use of such compounds in the preparation of antitumor compounds.
  • Hepatocyte growth factor also known as Scatter Factor (SF)
  • SF Scatter Factor
  • the c-Met transmembrane protein is a protein product encoded by the c-met proto-oncogene and is a high affinity receptor for HGF.
  • HGF binds to its receptor c-Met, it leads to autophosphorylation of c-Met tyrosine kinase, which activates c-Met tyrosine kinase activity, further activates many different downstream signaling molecules in cells, induces cell development.
  • a range of biological effects such as cell dispersion, movement, proliferation, invasion, migration, and ultimately metastasis and angiogenesis (Bottaro et al, Science, 1991, 251, 802-804).
  • HGF/c-Met signaling plays an important role in the development, progression and secondary metastasis of malignant tumors, and is closely related to the poor prognosis of patients (Sattler et al, Curr Oncol Rep, 2007, 9). , 102-108; Mazzone et al, FASEB J, 2006, 20, 1611-1621; Trusolino et al, Nature Rev, Cancer 2002, 2, 289-300).
  • the continuous activation of c-Met will destroy the adhesion between tumor cells, promote cell movement and tumor angiogenesis, and make tumor cells easy to enter the blood circulation and obtain the ability to invade and metastasize.
  • c-Met and HGF are overexpressed relative to surrounding tissues, such as thyroid cancer, breast cancer, lung cancer, stomach cancer, colon cancer, pancreatic cancer, prostate cancer, kidney cancer, liver cancer, ovarian cancer, and brain glue.
  • Qualitative tumors, etc. Borchmeier et al, Nat Rev Mol Cell Biol, 2003, 4, 915-925; Otsuka et al, Cancer Res, 1998, 58, 5157-5167; Parr et al, Clin Cancer Res, 2004, 10, 202-211) .
  • MET gene amplification is closely associated with acquired resistance to 20% of epidermal growth factor inhibitors (EGFR-TKIs) (Engelman et al, Science, 2007, 316, 1039-1043). Therefore, small molecule kinase inhibitors targeting c-Met have important research significance for the treatment of the aforementioned cancers.
  • EGFR-TKIs epidermal growth factor inhibitors
  • c-Met small molecule inhibitors have been in preclinical and clinical research.
  • Crizotinib developed by Pfizer has been approved by the FDA in August 2011 for the treatment of patients with advanced non-small cell lung cancer (NSCLC) expressing abnormal anaplastic lymphoma kinase (ALK) gene, showing good results. treatment effect.
  • NSCLC non-small cell lung cancer
  • ALK abnormal anaplastic lymphoma kinase
  • C-Met inhibitors that are clinically studied differ in their binding patterns to the c-Met kinase domain and can be divided into two broad categories: (1) U-type small molecule inhibitors: such as Crizotinib and MK-2461;
  • Linear small molecule inhibitors such as Cabozantinib (XL184) and Foretinib (XL880).
  • the first type of U-type small molecule inhibitor acts on the ATP-binding site at the beginning of the c-Met kinase pocket, surrounding the amino acid residue Metl211, mainly as a highly selective inhibitor of c-Met;
  • the second type of linear type Small molecule inhibitors are novel c-Met inhibitors developed in recent years, acting through a stretched conformation on deep Ilel l45 hydrophobic pockets from the ATP-binding site, the kinase junction chain to the C-terminal helix region, mainly Target inhibitor.
  • the linear small molecule c-Met inhibitor consists of an aromatic ring, an aromatic ring linking region and a three-membered carbocyclic diamide side chain, which act on the ATP-binding site, the linking region and the C-terminal helix of the c-Met enzyme, respectively.
  • Deep Ilel l45 hydrophobic pocket near the area.
  • the two carbonyl oxygen atoms in the side chain of the ternary carbocyclic diamide can form two hydrogen bonds with the amino acid residues in the hydrophobic pocket, and are the basic pharmacological groups of such compounds having c-Met inhibitory activity.
  • the aromatic ring acting on the ATP-binding site has the function of regulating the physicochemical properties of the molecule, regulating the affinity and specificity of the inhibitor molecule and the c-Met target enzyme, and finally improving its inhibitory activity. Therefore, it is important to find and discover aromatic structures of different structures as synthons for the synthesis of novel high-activity linear small molecule c-Met inhibitors.
  • the object of the present invention is to disclose a benzopyridinium azide compound and its use in the preparation of an antitumor compound.
  • the benzopyridinium azide compound of the present invention is a compound having the formula (I) or a pharmaceutically acceptable salt thereof:
  • X is selected from halogen
  • Y is selected from NH, NHBn, NCH 3 , 0 or S;
  • Ri is selected from H or methyl
  • R 2 is selected from H, CN, methyl, methoxy or fluoro
  • R 3 and each independently selected from hydrazine, 03 ⁇ 4 d- 5 alkyl, amino, NH, halogen, cyano, nitro, substituted amino, phenyl, heterocyclyl, substituted phenyl or substituted heterocyclic;
  • the Cw alkyl group is preferably a methyl group, an ethyl group or an isopropyl group
  • the substituted amino group is preferably d- 5 alkylamino, morpholine-N-propylamino, piperidin-4-methylamino or piperidin-1-propyl; heterocyclic group is preferably morpholine-1-yl, piperidine- ⁇ Or a piperidin-1-yl group;
  • the substituted phenyl or substituted heterocyclic group is a phenyl or heterocyclic group having 1 to 4 substituents, and the substituent is preferably a hydroxyl group, a methoxy group, a methyl group or an amino group;
  • R 6 is selected from hydrogen, d- 5 straight or branched alkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl, substituted Cw alkyl, substituted aryl, substituted aralkyl, Substituted heterocyclic or substituted heterocycloalkyl;
  • the Cw branched or branched alkyl group is preferably methyl, ethyl or isopropyl
  • the aryl group is preferably a phenyl group
  • the aralkyl group is preferably a benzyl group, a 3,4-dimethoxybenzyl group or a 3-(3,4-dimethoxyphenoloxy)propyl group;
  • the heterocyclic group is preferably an imidazolyl group, a thiazolyl group or Pyridyl group;
  • the heterocycloalkyl group is preferably morphinolylpropyl, piperidine-4-methyl, piperidin-1-propyl, N-methylpiperidin-1-propyl or pyrrolidinyl;
  • the substituted d- 5 alkyl group is preferably a methylol group, an aminomethyl group, a 3-(hydroxy)propyl group or a 3-(dimethylamino)propyl group;
  • the substituted aryl group is preferably a 3,4-dimethoxy group.
  • the substituted heterocyclic group or substituted heterocycloalkyl group is a heterocyclic group or a heterocycloalkyl group having 1 to 4 a substituent, preferably a hydroxyl group, a methoxy group, a methyl group or an amino group;
  • R 5 is divided into two cases:
  • R 5 is selected from H, Cw alkyl or Cw acyl, wherein: the Cw alkyl group is preferably a methyl group, and the C 1-4 acyl group is preferably an acetyl group;
  • the compound of the formula (I) or the salt of any one of 1-1 to 1-28 which is a hydrochloride, a hydrobromide, a sulfate, an acetate, a lactate, a tartrate, a citrate, Citrate, trifluoroacetate, malate, maleate, Succinate, p-toluenesulfonic acid or methanesulfonate.
  • the structural formula of the above compounds is shown in Table 1.
  • Raw material 1 and raw material 2 were reacted with K 2 C0 3 as a base, and stirred in a DMF solution at room temperature for 12 h to obtain Intermediate 3.
  • the intermediate is catalytically reduced by iron powder and ammonium chloride in a mixed solvent of ethanol and water under reflux to obtain Intermediate 4.
  • the compound of the present invention can be used for preparing a benzopyridinium azalea antitumor compound, for example, when the compound of the present invention 1- 17 is used as a raw material, an antitumor compound V can be prepared (N- ⁇ 4-[( 8,9-Dimethoxy-11H-benzopyridine [3,2-6][1,4]diazepine- ⁇ -yloxy]phenyl ⁇ -N-(4-fluorophenyl) ring Propane-1,1-diamide), when using 1-18 as a raw material, an antitumor compound VKN-(4-fluorophenyl)-N- ⁇ 4-[8-methoxy-9-(3) can be prepared.
  • the above preparation method may further comprise reacting a compound of the formula I with a mineral acid or an organic acid in a solvent to cool a salt of the compound of the formula I.
  • R 2 , R 3 , R 4 , R 5 , Y are as described above;
  • the in vitro inhibition assay showed that the compound V and the compound VI synthesized by the compound of the present invention as an intermediate inhibited the activity of c-Met aC 5 Q : V, 15.0 nM ; VI, 18.4 nM) compared with the positive control drug Cabozantinib.
  • the compound of the present invention is used as a synthon for preparing a novel antitumor active compound, and the obtained compound has an improved inhibitory activity in vitro, and exhibits multi-target inhibition effect, and has significant scientific progress and in-depth research. Development value. difficult
  • the base product target compound 1- 1 was a pale yellow solid, 0.08 g, yield 66.7%.
  • the target compound can be prepared according to Example 7.
  • the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, followed by implementation.
  • Example 7 the target compound 1-7 can be prepared, yield
  • the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, and then the target compound 1 was prepared according to Example 7. -9, yield 48.9%.
  • Example 1 Using 4,6-dichloro-5-methylpyridin-3-amine and aniline as raw materials, followed by Example 1, Example 2 and Examples
  • the formamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, and then according to Example 7, The target compound 1-13 was prepared in a yield of 58.3 %.
  • Example 2 Starting from 4,6-dichloropyridin-3-amine and N-benzylaniline, according to Example 1, Example 2 and Example 4, 11-benzyl-4-chloro-6,11 can be prepared. -Dihydro 5H-benzopyridine [3,2-6][1,4]diazepine.
  • the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, followed by In Example 7, the target compound 1-16 was obtained in a yield of 53.1%.
  • Formamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3 using 2,4-dichloro-3-nitropyridine and N-benzyl-3,4-dimethoxyaniline as starting materials. Then, according to Example 7, the title compound 1-17 was obtained in a yield of 50.2%.
  • Example 1 Using 2,4-dichloro-3-nitropyridine and N-benzyl-4-methoxy-3-(3-morpholinepropoxy)aniline as raw materials, followed by Example 1, Example 2 and Example 3 Preparation of Formamide Intermediate 5, followed by the preparation of the title compound 1- 18 in a yield of 47.6 %.
  • the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, followed by implementation.
  • Example 7 the target compound 1-19 can be prepared, the yield
  • the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, followed by the examples. 7, the target compound 1-20 was prepared in a yield of 64.7%.
  • Example 24 Synthesis of 4-chloro-11H-benzopyr[3,2-indolyl][1,4]diazepine-9-carbonitrile (target compound 1-21) as 2,4-dichloro-3-nitro Starting from pyridine and N-benzyl-3-cyanoaniline, the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, and then the target compound 1-21 was prepared according to Example 7. Yield
  • target compound 1-22 4-Chloro-8-nitro-11H-benzopyrazole [3,2- ⁇ ][1,4]diazepine (target compound 1-22) was used as the starting material, according to Example 2, by Fe/NH 4 C1 was reduced to prepare the target compound 1-23 in a yield of 87.4%.
  • Example 1 Using 2,4-dichloro-3-nitropyridine and N-benzyl-3-[(3-dimethylamino)propoxy]-4-methoxyaniline as raw materials, followed by Example 1, Example 2 and Example 3 were prepared as the carboxamide intermediate 5, followed by the preparation of the title compound 1-24 in a yield of 50.4%.
  • Example 1 Using 2,4-dichloro-3-nitropyridine and 4-methoxy-3-(3-morpholinepropoxy)aniline as raw materials, followed by Example 1, Example 2 and Example 4, The title compound 1-28 was obtained in a yield of 58.2%.
  • the compound of the invention 1- 17 (0.29 g, 1 mmol) and ⁇ 4-fluorophenyl)-indole 4-hydroxyphenyl)cyclopropane-1,1-diamide (intermediate 6) (0.47 g, 1.5 mmol)
  • Cu powder (6.1 mg, 0.1 mmol) and B C3 ⁇ 4C0 3 (0.98 g, 3 mmol) were added to DMF 3 mL, placed in a microwave reactor, power set at 60 W, and stirred at 100 ° C for 10 Min.
  • the mixture is filtered, and the solvent is evaporated to dryness, and 10 mL of water is slowly added dropwise with stirring, and the solid is precipitated and purified by column chromatography.
  • the solvent is petroleum ether: ethyl acetate (V/V, 1:1), and the target compound V is white.
  • the solid was 0.23 g, and the yield was 40.5%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne un composé benazépine et une application de celui-ci. Le composé benazépine, comme synthon pour préparer un nouveau composé possédant une activité antitumorale, donne un composé qui possède une activité inhibitrice d'enzyme ex vivo considérablement améliorée et présente un effet d'inhibition à cibles multiples, représentant ainsi une avancée scientifique notable et une valeur de recherche et de développement approfondies. Le composé benazépine est un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2013/079885 2012-08-24 2013-07-23 Composé benazépine et son application WO2014029251A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201210307549.6 2012-08-24
CN201210307549.6A CN103626762B (zh) 2012-08-24 2012-08-24 苯并吡啶氮杂卓类化合物及其应用

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WO2014029251A1 true WO2014029251A1 (fr) 2014-02-27

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110015993B (zh) * 2019-04-08 2022-07-08 汕头大学 一种可见光催化制备氮杂七元环苯并吖庚因类化合物的方法
CN114835716B (zh) * 2022-05-06 2023-05-12 徐州医科大学 一种苯并二氮卓并吡咯类化合物及其制备方法和应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030140A2 (fr) * 2003-09-26 2005-04-07 Exelixis, Inc. Modulateurs de c-met et procede d'utilisation
CN101203495A (zh) * 2005-06-23 2008-06-18 默克公司 作为受体酪氨酸激酶met抑制剂的苯并环庚烷并吡啶化合物
US20090131423A1 (en) * 2005-10-21 2009-05-21 Merck & Co., Inc. Tyrosine Kinase Inhibitors
WO2009124024A1 (fr) * 2008-04-01 2009-10-08 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Compositions et procédés d'inhibition de la signalisation de récepteur c-met de facteur de croissance d'hépatocyte
CN101801969A (zh) * 2007-06-22 2010-08-11 艾科尔公司 治疗癌症的吲哚基吡咯烷
CN101857594A (zh) * 2010-06-18 2010-10-13 南方医科大学 一种四氢吡啶并吲哚类化合物及其制备方法和应用
WO2012006960A1 (fr) * 2010-07-14 2012-01-19 Zhejiang Beta Pharma Inc. Nouveaux dérivés hétérocycliques fusionnés convenant comme inhibiteurs de c-met tyrosine kinase

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030140A2 (fr) * 2003-09-26 2005-04-07 Exelixis, Inc. Modulateurs de c-met et procede d'utilisation
CN101203495A (zh) * 2005-06-23 2008-06-18 默克公司 作为受体酪氨酸激酶met抑制剂的苯并环庚烷并吡啶化合物
US20090131423A1 (en) * 2005-10-21 2009-05-21 Merck & Co., Inc. Tyrosine Kinase Inhibitors
CN101801969A (zh) * 2007-06-22 2010-08-11 艾科尔公司 治疗癌症的吲哚基吡咯烷
WO2009124024A1 (fr) * 2008-04-01 2009-10-08 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Compositions et procédés d'inhibition de la signalisation de récepteur c-met de facteur de croissance d'hépatocyte
CN101857594A (zh) * 2010-06-18 2010-10-13 南方医科大学 一种四氢吡啶并吲哚类化合物及其制备方法和应用
WO2012006960A1 (fr) * 2010-07-14 2012-01-19 Zhejiang Beta Pharma Inc. Nouveaux dérivés hétérocycliques fusionnés convenant comme inhibiteurs de c-met tyrosine kinase

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CN103626762B (zh) 2015-07-29

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