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WO2016041201A1 - Dérivés de thiénopyrimidine, leur méthode de préparation et leur application médicale - Google Patents

Dérivés de thiénopyrimidine, leur méthode de préparation et leur application médicale Download PDF

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Publication number
WO2016041201A1
WO2016041201A1 PCT/CN2014/086951 CN2014086951W WO2016041201A1 WO 2016041201 A1 WO2016041201 A1 WO 2016041201A1 CN 2014086951 W CN2014086951 W CN 2014086951W WO 2016041201 A1 WO2016041201 A1 WO 2016041201A1
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group
substituted
carbon atoms
unsubstituted
compound
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Chinese (zh)
Inventor
安晓霞
别平彦
刘俊
庄戈诗
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SHANGHAI ACEBRIGHT PHARMACEUTICALS GROUP Co Ltd
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SHANGHAI ACEBRIGHT PHARMACEUTICALS GROUP Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular, the present invention provides a thienopyrimidine derivative, a preparation method and application thereof.
  • 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 by killing tumor cells while causing normal cell death by non-specifically blocking cell division, and targeting key node proteins in abnormally activated signaling pathways in tumor cells. It has been found that high-efficiency, low-toxicity and specificity of small molecule inhibitors have become an important direction for the research and development of anti-tumor drugs. Receptor tyrosine kinase (RTK), which is abnormally 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 cerbB1
  • HER1 or cerbB1 is a member of the HER family, the most widely expressed tyrosine kinase in human cancers.
  • the EGFR structure includes 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 a single alpha helix; the intracellular region includes the kinase region and has many tyrosines The carboxyl terminal tail of the phosphorylation site.
  • Tyrosine kinase transports the gamma phosphate of ATP to a tyrosine residue.
  • EGFR Upon binding to the ligand, EGFR undergoes homologous or heterodimerization to form a tight junction in the TK region.
  • RTK-mediated tyrosine phosphorylation site phosphorylation at the carboxyl terminal tail creates a binding site for the enzyme and linker proteins (Y992, Y1068, Y1086, Y1148, and Y11730) to initiate intracellular signaling reactions. These signalings 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 related to 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.
  • the use of multiple targets in cancer therapy is also advantageous, especially for cancer patients who develop resistance to single-target inhibitors.
  • the occurrence and development of tumors is a complex process involving multi-step, multi-stage, in vitro and in vivo interactions involving multiple genes, and most tumors have 4 to 7 independent mutation sites, so multi-target therapy is needed. Ensure the effectiveness and persistence of the anti-tumor effect of the drug.
  • the FDA has approved the launch of several multi-target tyrosine kinase inhibitors, including sorafenib approved in 2005, dasatinib approved in 2006, and obtained in 2007. Batch of sunitinib and lapatinib.
  • the target of lapatinib is epidermal growth factor receptor (EFGR) and human epidermal growth factor receptor 2 (HER-2), which can target these two targets. Produces dual inhibition.
  • EFGR epidermal growth factor receptor
  • HER-2 human epidermal growth factor receptor 2
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl having 1 to 6 carbon atoms, substituted or unsubstituted alkyl acyl group having 1 to 6 carbon atoms, substituted or Unsubstituted cycloalkyl acyl group having 3 to 6 carbon atoms, substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, substituted or unsubstituted aryl acyl group having 6 to 10 carbon atoms, a sulfonyl group, a substituted or unsubstituted amide group having 2 to 6 carbon atoms -CONH, a substituted or unsubstituted amino-acyl NHCO having 1 to 6 carbon atoms;
  • R 1 and R 2 together with the nitrogen atom to which they are bonded form a substituted or unsubstituted monocyclic or polycyclic nitrogen-containing heterocyclic group having 3 to 10 carbon atoms, or a nitrogen atom or an oxygen atom at any position.
  • R 1 , R 2 together with the attached nitrogen atom and the ortho carbon atom of the nitrogen atom constitute a 5-7-membered nitrogen-containing heteroaryl group
  • R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted 1 to 1 6-carbon atom amide group, substituted or unsubstituted cycloalkyl acyl group having 3 to 6 carbon atoms, substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, substituted or unsubstituted 5 An aryl acyl group of 6 carbon atoms, a substituted or unsubstituted alkyl phosphate group having 1 to 6 carbon atoms;
  • R is a substituted aromatic ring or a heteroaromatic ring
  • substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, alkoxy, hydroxy, amino, cyano, hydroxy-C1-C4 alkyl, a C2-C10 heterocycloalkyl group, a C2-C10 heterocycloalkyl-oxy group, a carboxyl group, or a C2-C6 carboxylate group;
  • Ar 2 is selected from the group consisting of phenyl, halogen substituted phenyl, C 1 -C 6 alkyl substituted phenyl, biphenyl, halogen substituted biphenyl, naphthyl, pyridyl, thienyl, halogen substituted Thienyl, C 1 -C 3 alkyl substituted thienyl, furyl, halogen substituted furanyl, or C 1 -C 3 alkyl substituted furan;
  • A, B, and D are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom, or none; and at most one of A, B, and D is none;
  • n 0, 1 or 2;
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, hydroxy, oxo, nitro, C1-C6 haloalkyl, C1 ⁇ .
  • C6 alkyl group C1-C6 alkenyl group, C1-C6 alkynyl group, C3-C12 aryl group, C3-C12 arylalkyl group, C1-C6 alkoxy group, C3-C12 aryl oxygen Amino group, amino group, C1-C6 acylamino group, C1-C6 alkylcarbamoyl group, C3-C12 arylcarbamoyl group, C1-C6 aminoalkyl group, C1-C6 acyl group, carboxyl group, C1-C6 Hydroxyalkyl, C1-C6 alkylsulfonyl, C5-C12 arylsulfonyl, C1-C6 alkylsulfonylamino, C5-C12 arylsulfonylamino, C3-C12 aralkyl a sulfonylamino group, a C1-C6
  • the dotted line is a chemical bond or none.
  • the heterocyclic ring is a saturated ring or an unsaturated ring.
  • any one of R 1 , R 2 , R 3 , R, Ar 2 , A, B, and D is a group corresponding to the specific compound described in Table 1, respectively.
  • A, B, and D are each independently selected from the group consisting of a carbon atom and a nitrogen atom; and one of A, B, and D is a nitrogen atom.
  • only one of A, B, and D is a nitrogen atom.
  • A, B, and D are all carbon atoms
  • Ar 2 is an unsubstituted or halogen substituted phenyl
  • R 1 and R 2 are each independently selected from the group consisting of 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 3 to 6 carbon atoms.
  • R 1 and R 2 together with the nitrogen atom to which they are bonded form a substituted or unsubstituted C 3 -C 10 heterocyclic group, wherein the heterocyclic group has 1 to 3 hetero atoms selected from the group consisting of O: , S or N;
  • R 1 and R 2 together with the attached nitrogen atom and the ortho carbon atom of the nitrogen atom constitute a 5- to 7-membered nitrogen-containing heteroaryl group.
  • the compound of formula I is a specific compound shown in Table 1.
  • the compound of formula I is selected from the group consisting of:
  • each group is as defined in the first aspect of the invention.
  • the palladium catalyst is selected from the group consisting of dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphine). Ferrocene] palladium dichloride, or a combination thereof.
  • the method further comprises the step of reacting a compound of formula (3) with R 3 X to provide a compound of formula I:
  • X is selected from the group consisting of Cl and OTs.
  • a tyrosine kinase inhibitor comprising an inhibitory effective amount of a compound of formula I as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof , tautomers, optical isomers, pharmaceutically acceptable solvates.
  • the tyrosine kinase inhibitor is a dual inhibitor of EGFR/HER2.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, tautomerous Isomers, optical isomers, pharmaceutically acceptable solvates.
  • the pharmaceutical composition is for treating a disease associated with tyrosine kinase overexpression and/or tyrosine kinase activity, or the pharmaceutical composition is used for treatment and epidermal growth Factor receptor related diseases.
  • the epidermal growth factor receptor-associated disease is selected from the group consisting of abnormal cell proliferation, morphological changes, hyperkinesia, angiogenic diseases, tumor growth, tumor metastasis, or a combination thereof.
  • the disease associated with epidermal growth factor receptor activity is selected from the group consisting of abnormal cell proliferation, morphological changes, hyperkinesia, angiogenic diseases, tumor growth, tumor metastasis, or a combination thereof.
  • the tumor cell is an A431 cell.
  • the tyrosine kinase inhibitor is a multi-target tyrosine kinase inhibitor.
  • the epidermal growth factor receptor is selected from the group consisting of EGFR and/or HER2.
  • the inhibition has an IC50 value of ⁇ 50 nM.
  • the pharmaceutically acceptable salt is a salt of the compound of formula I selected from the group consisting of inorganic acid salts, organic acid salts, alkyl sulfonic acids a salt, an aryl sulfonate, or a combination thereof; preferably, the salt is selected from the group consisting of the hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, Propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, methanesulfonate, ethylsulfonate, besylate, p-toluene Acid salt, or a combination thereof;
  • the pharmaceutically acceptable solvate refers to a solvate of a compound of formula I with a solvent selected from the group consisting of water, ethanol, isopropanol, diethyl ether, acetone, or a combination thereof.
  • the present inventors After long-term and intensive research, the present inventors have unexpectedly prepared a class of compounds having the structure shown in formula (I), and the compounds are a class of effective tyrosine kinase inhibitors, and are particularly suitable for use as EGFR. And / or HER2 inhibitors. Based on the above findings, the inventors completed the present invention.
  • the alkyl group includes a linear or branched alkyl group
  • the alkenyl group includes a linear or branched alkenyl group
  • the alkynyl group includes a linear or branched chain.
  • An alkynyl group, said halogen being F, Cl, Br or I, preferably F or Br.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4.
  • the referenced atoms include all isotopic forms thereof, for example, when referring to "hydrogen atom", it refers to a hydrogen atom, a deuterium atom, a deuterium atom, or a combination thereof.
  • hydrogen atom it refers to a hydrogen atom, a deuterium atom, a deuterium atom, or a combination thereof.
  • the abundance of various isotopic atoms of an element may be a state in which the element naturally exists in nature, or may be a state in which an isotopic is enriched.
  • C1-C4 alkyl refers to a straight or branched alkyl group having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Tert-butyl, or a similar group.
  • the number of carbon atoms of the group when the number of carbon atoms of the group is not limited, it means a group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms.
  • substituted or unsubstituted monocyclic or polycyclic nitrogen-containing heterocyclic group having 3 to 10 carbon atoms means a nitrogen-containing cyclic group having 3 to 10 carbon atoms, including a monocyclic ring (for example, piperazine, piperazine).
  • the piperazinyl group, piperidinyl group, morpholinyl group and the like, the above polycyclic nitrogen-containing heterocyclic group includes, but is not limited to, azabicyclo[3.2.1]octyl group, or a group shown below:
  • 5-7 membered heteroaryl refers to a heteroaryl group having 5 to 7 carbon atoms or a hetero atom (selected from N, O, S), such as pyrrolyl, pyridyl, furyl, or the like.
  • the heterocyclic ring is a saturated ring or an unsaturated ring.
  • C1-C4 alkoxy refers to a straight or branched alkoxy group having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, sec-butoxy, tert-butoxy, or the like.
  • alkyl acyl refers to a group having the structure "-CO-alkyl", such as methyl acyl, ethyl acyl, propyl acyl, isopropyl acyl, butyl acyl, isobutyl acyl, sec-butyl An acyl group, a t-butyl acyl group, or the like.
  • amido group having 2 to 6 carbon atoms means a group having a structure as shown by "C1-C5 alkyl-CONH-".
  • amino-acyl group having 1 to 6 carbon atoms or “aminoacyl group having 1 to 6 carbon atoms” means having, for example, “NH 2 CO-” or “C1-C5 alkyl-NHCO-”
  • the group of the structure is shown, in particular, when the group is “NH 2 CO-", "amino-acyl” is written as “amino-acyl”.
  • oxo refers to two or more hydrogen atoms on the group is substituted with one or more oxygen atoms, e.g., -CH 2 - oxo after being formed -C (O) -Structure.
  • pharmaceutically acceptable solvate refers to a solvate of the corresponding compound with water, ethanol, isopropanol, diethyl ether, acetone.
  • the present invention provides a compound of formula I:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl having 1 to 6 carbon atoms, substituted or unsubstituted alkyl acyl group having 1 to 6 carbon atoms, substituted or Unsubstituted cycloalkyl acyl group having 3 to 6 carbon atoms, substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, substituted or unsubstituted aryl acyl group having 6 to 10 carbon atoms, a sulfonyl group, a substituted or unsubstituted amide group having 2 to 6 carbon atoms, a substituted or unsubstituted aminoacyl group having 1 to 6 carbon atoms;
  • R 1 and R 2 together with the nitrogen atom to which they are bonded form a substituted or unsubstituted monocyclic or bicyclic nitrogen-containing heterocyclic group having 3 to 10 carbon atoms, or a nitrogen atom or an oxygen atom at any position.
  • R 1 , R 2 together with the attached nitrogen atom and the ortho carbon atom of the nitrogen atom constitute a 5-7-membered nitrogen-containing heteroaryl group
  • R 3 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted 1 to 1 6-carbon atom amide group, substituted or unsubstituted cycloalkyl acyl group having 3 to 6 carbon atoms, substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, substituted or unsubstituted 5
  • R is a substituted aromatic ring or a heteroaromatic ring
  • substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, alkoxy, hydroxy, amino, cyano, hydroxy-C1-C4 alkyl, a C2-C10 heterocycloalkyl group, a C2-C10 heterocycloalkyl-oxy group, a carboxyl group, or a C2-C6 carboxylate group;
  • Ar 2 is selected from the group consisting of phenyl, halogen substituted phenyl, C 1 -C 6 alkyl substituted phenyl, biphenyl, halogen substituted biphenyl, naphthyl, pyridyl, thienyl, halogen substituted Any one of a thienyl group, a C 1 -C 3 alkyl-substituted thienyl group, a furyl group, a halogen-substituted furyl group, a C 1 -C 3 alkyl-substituted furyl group;
  • A, B, and D are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom, or none; and at most one of A, B, and D is none;
  • n 0, 1 or 2;
  • said one or more hydrogen atoms on the substituent group are substituted with a substituent selected from the group consisting of halogen, Hydroxy, oxo, nitro, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C12 aryl, C3-C12 aryl alkane a group, a C1-C6 alkoxy group, a C3-C12 aryloxy group, an amino group, a C1-C6 acylamino group, a C1-C6 alkylcarbamoyl group, a C3-C12 arylcarbamoyl group, C1 ⁇ An aminoalkyl group of C6, an acyl group of C1 to C6, a carboxyl group, a C1-C6 hydroxyalkyl group, a C1-C6 alkylsulfonyl group, a C1
  • the dotted line is a chemical bond or none.
  • A, B, and D are all carbon atoms
  • Ar 2 is a phenyl group
  • R 1 and R 2 are each independently selected from the group consisting of 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 3 to 6 carbon atoms.
  • R 1 and R 2 together with the nitrogen atom to which they are bonded form a substituted or unsubstituted C 3 -C 10 heterocyclic group, wherein the heterocyclic group has 1 to 3 hetero atoms selected from the group consisting of O: , S or N;
  • R 1 and R 2 together with the attached nitrogen atom and the ortho carbon atom of the nitrogen atom constitute a 5- to 7-membered nitrogen-containing heteroaryl group (that is, in the case of the compound 3 in Table 1).
  • the compound of formula I is as shown in Table 1.
  • the invention also provides a process for the preparation of a compound of formula I, the process comprising the steps of:
  • a compound of formula (1) i.e., 2-(6-bromo-thiophene[3,2-d]pyrimidin-4-amino)-2-phenyl-ethanol protected with different substituents
  • the compound of formula (1a) (different substituted phenylborate or phenylboronic acid) is subjected to a coupling reaction to give a compound of formula I:
  • the coupling reaction is a Suzuki coupling.
  • the palladium catalyst is selected from the group consisting of dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphine). Ferrocene] palladium dichloride, or a combination thereof.
  • the process for the preparation of a compound of formula I comprises the step of reacting a compound of formula (3) with R 3 X to give a compound of formula I:
  • X is selected from the group consisting of Cl and OTs.
  • the pharmaceutical forms of the compounds of the invention may include the compounds themselves, as well as other pharmaceutically acceptable modifications, such as optical isomers, cis and trans isomers, or the like, or pharmaceutically acceptable salts or solvates.
  • the pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, etc.; organic acid salts such as Acid salt, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, etc.; alkyl sulfonate, such as methyl sulfonate An ethyl sulfonate or the like; an aryl sulfonate such as a benzenesulfonate or a p-toluenesulfonate.
  • inorganic acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, etc.
  • organic acid salts such as Acid salt, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, etc.
  • the pharmaceutically acceptable solvate includes, but is not limited to, a solvate of the compound with water, ethanol, isopropanol, diethyl ether, acetone, and the like.
  • the thienopyrimidine derivative of the present invention has an inhibitory activity against epidermal growth factor receptor (EGFR) and/or human epidermal growth factor receptor 2 (HER2), and therefore, Thienopyrimidine derivatives of the invention or tautomers, racemates, enantiomers, diastereomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable Any one or a mixture of the accepted solvates can be used to prepare tyrosine kinase inhibitors, and is particularly useful for the preparation of EGFR and/or HER2 inhibitors.
  • EGFR epidermal growth factor receptor
  • HER2 human epidermal growth factor receptor 2
  • the inhibitor can be applied to the preparation of a medicament for preventing or treating a disease associated with the epidermal growth factor receptor EGFR and/or HER2. Specifically, it can be applied to the preparation of a medicament for preventing or treating abnormal cell proliferation, morphological changes, hyperkinesia, angiogenesis, and tumor metastasis diseases associated with the epidermal growth factor receptor EGFR and/or HER2.
  • the inhibitors are useful in the manufacture of a medicament for the treatment or prevention of tumor growth and metastasis associated with the epidermal growth factor receptor EGFR and/or HER2.
  • the active ingredient of the inhibitor of the present invention 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.
  • the thienopyrimidine derivatives provided by the present invention have novel structures, have obvious EGFR inhibitory activities, and some compounds have significant inhibitory activity against VEGFR, and are expected to be developed as tyrosine kinases EGFR or / And VEGFR inhibitors for the prevention or treatment of cell abnormal proliferation, morphological changes, and hyperkinesia associated with epidermal growth factor receptor EGFR and/or angiogenic factor receptor VEGFR and associated with angiogenesis or tumor metastasis Drugs for disease, especially for the preparation of drugs 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, for the development of novel drugs with low drug resistance or can alleviate early
  • the inhibitor-resistant tyrosine kinase inhibitor drug provides a new development direction and approach, and has broad application prospects and medicinal value.
  • the 1 H NMR shift ( ⁇ ) is given in parts per million (ppm).
  • the 1 H NMR measurement was performed on a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), internal standard tetramethylsilane (TMS), chemical shift. It is given in units of 10 -6 .
  • the MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the IC 50 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 C18 150 x 4.6 mm column).
  • the microwave reaction was performed using a CEM Discover-S Model 908860 microwave reactor.
  • reaction was carried out under a nitrogen atmosphere.
  • the argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 L.
  • 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.
  • 6-Bromo-4-chlorothieno[3,2-d]pyrimidine (40 g, 0.16 mol) and 2-methoxy-1-phenyl-ethylamine (29 g, 0.19 mol) were dissolved in N,N- In dimethylformamide (250 ml), N,N-diisopropylethylamine (40 ml) was then added, and the ice bath was removed, and the mixture was warmed to 55 ° C. The reaction was completed until the reaction was completed by TLC, and water was added, ethyl acetate was evaporated. The organic phase was dried over anhydrous sodium sulfate and evaporated. Bromo-thieno[3,2-d]pyrimidin-4-yl)-(2-methoxy-1-phenyl-ethyl)amine (32 g, white solid), yield: 55%.
  • Hydroxylamine hydrochloride (7.2 g, 86 mmol) was dissolved in methanol (30 ml) and water (20 ml), then magnesium oxide (5.1 g, 129 mmol) was added and stirred for 10 minutes, then p-toluenesulfonyl chloride (8 g, 43 mmol) of tetrahydrofuran was added. (300 ml) solution, stir vigorously at room temperature, and react to TLC to monitor the completion of the reaction. After suction filtration with celite, dried over anhydrous magnesium sulfate, and evaporated.
  • N-Hydroxy-4-methyl-benzenesulfonamide (2.8 g, 15 mmol) was dissolved in methanol (12 ml) and water (2 ml), and then potassium carbonate (3.33 g, 24 mmol) and 4-(4-bromo- A solution of phenyl)-but-3-en-2-one (450 mg, 2 mmol) in MeOH (6 mL) was taken to the TLC. The mixture was combined with EtOAc. EtOAc (EtOAc m. (220 mg, yellow solid), yield: 46%.
  • the HTRF kinEASE TK kit (Cat.62TK0PEB, Cisbio) kit of CISBIO was used to test the inhibitory effect of candidate compounds on EGFR enzyme activity.
  • the test method was carried out according to the standard method provided by the manufacturer.
  • the approximate experimental procedure is as follows: In the 10 ⁇ L enzyme reaction system, the enzyme reaction substrate TK-biotin, ATP, EGFR enzyme (Cat. PV3872, Invitrogen) and a certain concentration of compound in 50 mM Hepes/NaOH pH 7.5, 10 mM MgCl 2 were added. , 1 mM EGTA, 0.01% BRIJ-35 enzyme reaction buffer solution was reacted at room temperature for 30 minutes.
  • Each screening concentration of the test compound was determined by a re-pore test, and each experiment was performed with a negative control well without EGFR kinase and a positive control well without compound. After the reaction was completed, 10 ⁇ l of Streptavidin-XL665 and TK antibody europium cryptate (1:100) mixed test solution diluted with 50 mM Hepes/NaOH pH 7.0, 0.1% BSA, 0.8 M KF, 20 mM EDTA were added to all wells, and reacted at room temperature. After 1h, use 2104 Fluorescence signals (320 nm stimulation, 665 nm, 615 nm emission) were detected by a Multilabel Reader (Perkinelmer) instrument.
  • the inhibition rate of each well was calculated from the fully active wells and the background signal wells, and the duplicate wells were averaged, and the half-inhibitory activity (IC50) of each test compound was fitted using a professional drawing analysis software GraphPad PRISM 5.0.
  • the HTRF kinEASE TK kit (Cat.62TK0PEB, Cisbio) kit of CISBIO was used to test the inhibitory effect of candidate compounds on HER2 enzyme activity.
  • the test method was carried out according to the standard method provided by the manufacturer.
  • the approximate experimental procedure is as follows: In the 10 ⁇ L enzyme reaction system, the enzyme reaction substrate TK-biotin, ATP, HER2 enzyme (Cat: PV3366, Invitrogen) and a certain concentration of compound in 50 mM Hepes/NaOH pH 7.5, 5 mM MgCl 2 were added. , 1 mM DTT, 50 nM SEB, 1 mM MnCl 2 in an enzyme reaction buffer solution for 30 minutes at room temperature.
  • Each screening concentration of the test compound was determined by a re-pore test, and each experiment was performed with a negative control well without the HER2 enzyme and a positive control well without the compound. After the reaction was completed, 10 ⁇ l of Streptavidin-XL665 and TK antibody europium cryptate (1:100) mixed test solution diluted with 50 mM Hepes/NaOH pH 7.0, 0.1% BSA, 0.8 M KF, 20 mM EDTA were added to all wells, and reacted at room temperature. After 1h, use 2104 Fluorescence signals (320 nm stimulation, 665 nm, 615 nm emission) were detected by a Multilabel Reader (Perkinelmer) instrument.
  • the inhibition rate of each well was calculated from the fully active wells and the background signal wells, and the duplicate wells were averaged, and the half-inhibitory activity (IC50) of each test compound was fitted using a professional drawing analysis software GraphPad PRISM 5.0.
  • Fetal bovine serum (Cat#10099-141, GIBCO)
  • test compound was diluted to 500 ⁇ M with medium and diluted 8 times. The cells were added at 25 ⁇ l/well. The final concentration of the compound was diluted from 100 ⁇ M to 0 ⁇ M in 5 fold gradients for a total of 10 concentration points.
  • tumor cell growth inhibition rate % [(A c - A s ) / (A c - A b )] ⁇ 100%
  • a c negative control OA (cell + CCK-8 + DMSO)
  • a b positive control OA (medium + CCK-8 + DMSO)
  • Table 2 Some examples of compounds inhibited tyrosine kinase EGFR, HER2 enzyme activity and A431 cell test results
  • Example 1 Pharmacokinetics of Example 1 (code CDDD-000261) and Example 21 (code CDDD-000257) in rats were administered intravenously or orally.
  • the purpose of this experiment was to administer an effective amount of the compound of Example 21 and the compound of Example 1 to a SD rat test sample by single intravenous (IV) and oral (PO), and blood samples were taken at different time points, and LC/MS/MS was administered.
  • the concentration of the test sample in the rat plasma after the test sample was calculated and the relevant parameters and bioavailability were calculated.
  • Example 21 the compound of Example 21 and the compound of Example 1 were dissolved in water for injection to obtain a solution having a concentration of 5 mg/mL for intravenous and intragastric administration.
  • mice Twenty male SD rats (male weight 130-150 g) of approximately 6-8 weeks old were purchased from Shanghai Sippur-Beikai Experimental Animal Co., Ltd., and 12 animals were used for the test. All groups of animals were fasted overnight (10-14 hours) prior to intravenous and oral administration and fed 4 hours after dosing.
  • Example 21 The compound of Example 21 and the compound of Example 1 were administered by intravenous or oral administration. Drug administration information is shown in the table below.
  • the time points of blood collection in groups 1-8 were: before administration, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h. Each animal received approximately 0.25 mL of blood per heart puncture and K2EDTA was anticoagulated. Blood samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C). The collected plasma was stored at –80 °C prior to analysis. In addition, there were no excess animals left for experimental studies for the collection of blank blood. The blank plasma after centrifugation was used for bioanalytical method development and biological sample analysis of the test article throughout the study.
  • the mean clearance was 2.60 L/hr/kg.
  • the average half-life (T1/2) was 1.67 hr.
  • the mean value of Cmax after administration was 3218.39 ⁇ g/L, and the average value of Tmax was 0.083 hr.
  • the AUC (0-t) value was 1903.30 hr* ⁇ g/L.
  • the average apparent volume of the final phase distribution was 6.22 L/kg.
  • the average Cmax was 1528.74 ⁇ g/L
  • the average Tmax was 0.50 hr
  • the average AUC (0-t) was 3736.13 hr* ⁇ g/L, half-life (T1). /2)
  • the average is 2.51 hr.
  • the average bioavailability of the compound of Example 21 was 33.01%.
  • the mean clearance was 3.74 L/hr/kg.
  • the average half-life (T1/2) was 5.11 hr.
  • the mean value of Cmax after administration was 616.65 ⁇ g/L, and the average value of Tmax was 0.083 hr.
  • the AUC (0-t) value was 1309.41 hr* ⁇ g/L.
  • the average apparent volume of the final phase distribution was 27.66 L/kg.
  • the average Cmax was 296.20 ⁇ g/L
  • the average Tmax was 5.33 hr
  • the average AUC (0-t) was 3593.95 hr* ⁇ g/L, half-life (T1). /2)
  • the average value is 5.67 hr.
  • the average bioavailability of the compound of Example 1 was 47.71%.
  • CDDD-000257 ie, the compound of Example 21
  • CDDD-000261 ie, the compound of Example 1
  • positive control CDDD-000275 i.e., positive control gefitinib
  • Preparation method all were prepared with 20% PEG400 distilled water.
  • the nude mice were subcutaneously inoculated with human epidermoid carcinoma A431 cells, and after the tumors were grown to 100-200 mm 3 , the animals were randomly grouped (D0).
  • the dosage and administration schedule are shown in Table 1.
  • the tumor volume was measured 2-3 times a week, the rats were weighed, and the data were recorded.
  • the tumor volume (V) is calculated as:
  • V 1/2 ⁇ a ⁇ b 2
  • a and b represent length and width, respectively.
  • T/C(%) (T-T0)/(C-C0) 100 wherein T and C are the tumor volumes at the end of the experiment; T0 and C0 are the tumor volumes at the beginning of the experiment.

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Abstract

L'invention concerne des dérivés de thiénopyrimidine, une méthode de préparation et une application médicale de celle-ci. En particulier, chaque groupe des composés, tels que représentés par la formule I dans la présente invention, est défini comme indiqué dans la description. Les composés de l'invention sont des inhibiteurs effectifs de la tyrosine kinase, et sont particulièrement adapté à l'emploi comme inhibiteurs de l'EGFR et/ou du HER2.
PCT/CN2014/086951 2014-09-19 2014-09-19 Dérivés de thiénopyrimidine, leur méthode de préparation et leur application médicale Ceased WO2016041201A1 (fr)

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WO2016205590A1 (fr) * 2015-06-18 2016-12-22 Cephalon, Inc. Dérivés de 4-benzyl et 4-benzoyl-pipéridine substitués
US10851057B2 (en) 2015-06-18 2020-12-01 89Bio Ltd 1,4-substituted piperidine derivatives

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CN103360407A (zh) * 2012-04-10 2013-10-23 上海希迈医药科技有限公司 一种噻吩并嘧啶类衍生物、其制备方法及其在医药上的应用

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CN103360407A (zh) * 2012-04-10 2013-10-23 上海希迈医药科技有限公司 一种噻吩并嘧啶类衍生物、其制备方法及其在医药上的应用

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016205590A1 (fr) * 2015-06-18 2016-12-22 Cephalon, Inc. Dérivés de 4-benzyl et 4-benzoyl-pipéridine substitués
JP2018524318A (ja) * 2015-06-18 2018-08-30 セファロン、インク． 置換４−ベンジル及び４−ベンゾイルピペリジン誘導体
US10851057B2 (en) 2015-06-18 2020-12-01 89Bio Ltd 1,4-substituted piperidine derivatives
US10919875B2 (en) 2015-06-18 2021-02-16 89Bio Ltd Substituted 4-benzyl and 4-benzoyl piperidine derivatives
JP2021121612A (ja) * 2015-06-18 2021-08-26 エイティナイン バイオ リミテッド 置換４−ベンジル及び４−ベンゾイルピペリジン誘導体
US11702388B2 (en) 2015-06-18 2023-07-18 89Bio Ltd 1,4-substituted piperidine derivatives
JP7334211B2 (ja) 2015-06-18 2023-08-28 エイティナイン バイオ リミテッド 置換４－ベンジル及び４－ベンゾイルピペリジン誘導体
US11878966B2 (en) 2015-06-18 2024-01-23 89Bio Ltd Substituted 4-benzyl and 4-benzoyl piperidine derivates
US12098130B2 (en) 2015-06-18 2024-09-24 89Bio Ltd 1,4-substituted piperidine derivatives
US12441702B2 (en) 2015-06-18 2025-10-14 Cephalon Llc Substituted 4-benzyl and 4-benzoyl piperidine derivates

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