WO2019184866A1 - 磷酸盐类衍生物及其用途 - Google Patents

磷酸盐类衍生物及其用途 Download PDF

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WO2019184866A1
WO2019184866A1 PCT/CN2019/079492 CN2019079492W WO2019184866A1 WO 2019184866 A1 WO2019184866 A1 WO 2019184866A1 CN 2019079492 W CN2019079492 W CN 2019079492W WO 2019184866 A1 WO2019184866 A1 WO 2019184866A1
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aryl
alkyl
cycloalkyl
heteroaryl
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PCT/CN2019/079492
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French (fr)
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朱青
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朱青
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Priority to US17/044,173 priority Critical patent/US11918593B2/en
Priority to JP2021501068A priority patent/JP7345899B2/ja
Priority to EP19777124.9A priority patent/EP3778612A4/en
Publication of WO2019184866A1 publication Critical patent/WO2019184866A1/zh
Priority to AU2020102560A priority patent/AU2020102560A4/en
Priority to JP2023140006A priority patent/JP2023175716A/ja

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    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
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    • C07F9/3817—Acids containing the structure (RX)2P(=X)-alk-N...P (X = O, S, Se)
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Definitions

  • the invention relates to the technical field of medicine, in particular to a phosphate derivative which inhibits tumor proliferation and metastasis and uses thereof.
  • the microenvironmental characteristics of solid tumors include extracellular low pH, low oxygen concentration, and high glucose uptake rate.
  • the three are closely related and synergistic, which promotes the occurrence, proliferation, invasion and metastasis of tumors.
  • Normal cells are oxidatively phosphorylated by aerobic circulating mitochondria; cancer cells are metabolized by glycolysis (anaerobic and aerobic glycolysis).
  • PET positron emission tomography
  • Malignant tumors proliferate rapidly and consume a lot of glucose, so there are many radiopharmaceuticals that can be photographed.
  • LDH lactate dehydrogenase
  • the peripheral microenvironment of the malignant tumor has a pH (pHe) of 6.5-6.9, a core of 6.2, and a normal cell of 7.3-7.5. Normal people have saliva pH 6.5-7.4, while cancer patients can be as low as 4.5-5.7.
  • the peripheral acidic microenvironment of malignant tumors is mainly produced by the following aspects: the Wargurg effect leads to lactic acid aggregation, and the hypoxia drives the functions of carbonic anhydrase and proton transporter.
  • the combination of the two causes the pH of the external environment of the tumor cells to decrease; the tumor cells take up a large amount of After glucose, a large amount of lactic acid produced by high-efficiency glycolysis can be transported to the tumor microenvironment by a monocarboxylic acid transport pump (MCT); the intracellular CO2 is released to the extracellular space by diffusion, due to the hypoxia of the tumor tissue cells.
  • MCT monocarboxylic acid transport pump
  • hypoxia-inducible fac-tor 1 induces high expression of CA-IX in tumor cells, catalyzing the reaction of CO2 and H2O to form carbonic acid. Therefore, glycolysis and hypoxia are the main pathways for the acidic microenvironment of tumor cells (Modern Biomedical Progress 2014, Vol. 14 No. 19, 3775-3777).
  • lactic acid There are two types of lactic acid: L-lactic acid and D-lactic acid. Most of the lactic acid produced in cancer cells is D-lactic acid. Cancer is formed when the concentration of D-lactic acid in the cells is too high and the concentration of methylglyoxal is too low.
  • the intestinal mucosa has a barrier effect on D-lactic acid, and a large amount of D-lactic acid is excreted through the feces, so it generally does not cause cancer; only in the intestinal mucosa, intestinal surgery, enteritis
  • D-lactic acid will enter the bloodstream, and D-lactic acid entering the blood is the first step in cancer, so more than 90% of cancer patients have long been Gastrointestinal discomfort, long-term constipation, long-term enteritis; D-lactic acid entering the blood does not necessarily cause cancer, because the cell membrane also has a barrier effect on D-lactic acid. If the cell has inflammation, abscess, ulcer or surgery, trauma, etc.
  • the barrier function of the cell membrane disappears, and D-lactic acid enters the cell. This is the second step in cancer.
  • the amount of D-lactic acid entering the cell reaches a certain amount, insulin is activated and insulin is activated.
  • Dialdehyde, glyoxalase converts methylglyoxal to D-lactic acid, and cancer is formed. This is the trilogy of cancer.
  • There is a characteristic of the autocatalytic reaction as long as there is a supply of raw materials and continuously ingesting glucose, its reaction speed will be faster and faster, and it will never stop automatically. The result is: D-lactic acid concentration is very high, methylglyoxal concentration is very low, the imbalance between the two is the root cause of cancer.
  • the tumor cells themselves adapt to the acidic microenvironment, mainly through the mechanisms of autophagy and up-regulation of the transport system. Due to the continuous stimulation of various carcinogens and growth factors, the kinetics of hydrogen ions in tumor cells are seriously disturbed, and the pH balance of cells is abnormal. In order to avoid the toxicity of acidic microenvironment, tumor cells excrete hydrogen ions outward and eventually produce The extracellular acidic environment and the alkaline environment inside the cells.
  • Tumor cells regulate hydrogen ion-associated transport proteins of the plasma membrane such as sodium/hydrogen exchange protein (Na/H exchanger, NHE), Na/K ATPase, vesicle type H-ATPases (vacuolar-H ATPase, V-ATPase), H /C1 a total transporter and monocarboxylate transporter (MCT), etc., to achieve this mechanism.
  • Na/H exchanger sodium/hydrogen exchange protein
  • Na/K ATPase Na/K ATPase
  • vesicle type H-ATPases vacuum-H ATPase, V-ATPase
  • H /C1 a total transporter and monocarboxylate transporter (MCT), etc.
  • tumor cells There are other mechanisms for tumor cells to adapt to the acidic microenvironment, such as regulating the expression of VEGF and other genes, promoting tumor angiogenesis; releasing cathepsin B and other proteolytic enzymes, leading to degradation of extracellular matrix, leading to abnormal immune function, evading host immune response and Immunotherapy; promote tumor cells are not sensitive to radiotherapy, so that tumor cells produce drug resistance, evading chemotherapy drug damage.
  • the acidic microenvironment is a powerful weapon for tumor cells to achieve their invasiveness and metastasis.
  • Tumor cells themselves produce growth signals, which undergo apoptosis, immortalization, invasion, metastasis and immune evasion, and generate new blood vessels, while inducing an acidic environment. The mechanism is achieved.
  • the entire field of tumor research from pathogenesis to treatment is closely related to the acidic microenvironment of the tumor.
  • the acidic microenvironment of tumor affects the function of T cells.
  • acidic pH can reduce the secretion of IFN- ⁇ and TNF- ⁇ by T cells, indicating that the acidic microenvironment can block the production of pro-inflammatory cytokines; in addition, the specific acid receptor family can change the change of extracellular acidity. For the signal inside the cell.
  • the acidic microenvironment promotes the expression of G-protein, T cell inhibitory receptor and T cell death-associated gene-8, which mediates the translation and expression of c-myc in lymphocytes.
  • the acidic microenvironment affects the aggressiveness of tumors: the acidic microenvironment outside the tumor cells can stimulate cell proliferation, activate transcription factors, enhance target gene expression, and promote tumorigenesis; tumor cells can use lactic acid to maintain their acidic microenvironment to facilitate their Metastasis; induces extracellular matrix remodeling to increase tumor invasiveness and metastasis, delay cell metabolism of carcinogens, and inhibit cell damage caused by carcinogens.
  • tumor acidic microenvironment on tumor cells itself is: changing the biological activity of tumor cells; due to the strong growth of tumor cells, tumor tissues are prone to the accumulation of abnormal acidic metabolites due to insufficient blood perfusion, or by up-regulating VEGF and other genes.
  • Expression promotes the formation of tumor angiogenesis and provides a suitable environment for tumor metastasis; leading to abnormal immune function, including other components of the immune system, such as DC, MDSC or macrophage; cells evading host immune response and immunotherapy
  • lactic acidosis is a strong negative prognostic indicator of sepsis; it promotes tumor cells to be insensitive to radiotherapy, making tumor cells resistant and evading chemotherapy drug damage.
  • the damage of tumor acidic microenvironment products to normal tissues adjacent to the cancer is mainly caused by necrosis and apoptosis of peripheral normal cells; and by the release of cathepsin B and other proteolytic enzymes, the extracellular matrix is degraded.
  • the extracellular acidic environment within solid tumor tissue may reduce the therapeutic effect of mAbs because the microenvironment is too acidic to cause mAb degradation and ultimately reduce its activity.
  • PPI Proton pump inhibitors
  • PPI-sensitized tumor cell lines are more sensitive to chemotherapeutic drugs such as cisplatin, 5-fluorouracil and vinblastine, and omeprazole can induce susceptibility of human solid tumors inoculated to nude mice. Improve C30.
  • This mechanism of PPI may be mainly due to the inhibition of V-ATPase activity by drugs, the increase of pH in extracellular and lysosome organelles, the increase of drug concentration in cells, and the reversal of multidrug resistance (muhidrugresistance, MDR) gene high expression cells are sensitive to anti-tumor drugs.
  • MDR multidrug resistance
  • the ability of PPI to inhibit tumor cells is directly related to the acidity level of the medium; PPI can induce selective cytotoxicity of B cell tumors by activating a large number of reactive oxygen species (ROS) and destroying the lysosomal membrane. Structure that causes caspase-dependent apoptosis.
  • ROS reactive oxygen species
  • PPI can also increase the sensitivity of chemotherapy drugs, inhibit the growth of human transplanted tumors in animal models, and PPI does not cause systemic systemic reactions.
  • Down-regulation of NHE1 also significantly inhibited the invasion and metastasis of glioma cells.
  • Tumor metastasis is the underlying cause of clinical failure of malignant tumors. More than 80% of cancer deaths are caused by tumor metastasis. The accumulation of lactic acid in the tumor can not only reflect the degree of malignancy of the tumor, but also closely related to its distant metastasis. Tumor metastasis means that the tumor cells invade the lymphatic vessels, blood vessels, and body cavities from the primary site, migrate to other places and continue to grow, forming the same type of tumor as the primary tumor. This process is called metastasis. Benign tumors do not metastasize, only malignant tumors metastasize.
  • lymphatic metastasis malignant tumors of epithelial tissue are mostly lymphatic metastasis; hematogenous metastasis: all kinds of malignant tumors can occur, especially in meat. Cancer, kidney cancer, liver cancer, thyroid follicular carcinoma and choriocarcinoma; implantable metastasis: cancers commonly found in abdominal organs. Lactic acid can enter the endothelial cells through MCT1, causing the degradation and phosphorylation of I ⁇ B ⁇ , which in turn stimulates the migration of autoimmune nuclear factor kappa B/interleukin 8 pathway and the formation of blood vessels.
  • lactic acid released from tumor cells can be transported through MCT4, further stimulating interleukin-8-dependent tumor angiogenesis and tumor growth. Thereby achieving tumor metastasis. Lactic acid interferes with the body's immune response to cancer cells, helping cancer cells to spread. Studies have shown that lactic acid not only exists but also participates in every step of cancer development.
  • cTACE Conventional arterial intubation chemoembolization
  • the present invention is to solve the technical problem of currently lacking a small molecule compound which can effectively increase the pH value of the acidic microenvironment of the tumor, and provides a novel phosphate derivative having a monodentate or multidentate alkaline pH of >8.0.
  • the group can effectively inhibit the proliferation and metastasis of cancer cells by adjusting the acidity of the tumor microenvironment, so that clinical cancer treatment can achieve better results.
  • L is selected from C1-C10 alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl , alkylheteroaryl, alkenyl, alkynyl, straight or branched 3 to 15 carbon atoms containing N or O or S atoms, 1 to 15 carbon atoms containing N or O or S atoms, or a straight chain or a branched chain of a branched repeat unit, a tandem biaryl group, a tandem double heteroaryl group, a tandem aryl group and a heteroaryl group, through N or O or S or a linked diaryl and a biheteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is each independently selected from the group consisting of hydroxyl, halogen, alkyl,
  • Y and Z are independently selected from NR1, O, S, respectively. Or single button;
  • B is selected from Wherein B is preferably a trimethylolmethyl group; when D is selected from When K is selected as
  • F is CR 10 or a single bond
  • G is selected from
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycycloalkyl, cycloalkylalkyl, alkylcycloalkyl, Alkenyl, alkynyl, amino, hydroxy, decyl, carboxy, alkoxy, cycloalkoxy, haloalkyl, cyano, sulfanyl, sulfo, sulfone, sulfoxide, phosphate, alkylphosphonic acid a aryl group, an arylphosphino group, an arylphosphonic acid group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently selected from the group consisting of a hydroxyl group, a halogen group, an alkyl group, and an alkoxy group. Substituted by one
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroaryl Alkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenylalkyl, alkynylalkyl, said alkyl, cycloalkyl, cycloalkylalkyl , alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocycle Alkyl, alkenylalkyl, alkynylalkyl, optionally unsubstituted or substituted by one or more substituents, each independently selected
  • a 1 , A 2 are each independently selected from H, Li, Na, K, Cs and their corresponding cations, or A 1 , A 2 together form Ca, Mg, Al, Sc, Ti, Cr, Co, Fe, Ni , Cu, Zn, Cd, Hg and their respective corresponding cations;
  • E is selected from O atom or C(R 1 R 2 );
  • R 5 and R 6 are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxyalkyl group, a cycloalkyl group, an alkoxycycloalkyl group, a hydroxyalkyl group, a hydroxycycloalkyl group, a heterocyclic group, an aryl group. And a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently selected from the group consisting of a hydroxyl group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, and a heterocyclic group. Substituting one or more substituents in the aryl, aryl and heteroaryl groups; or R 5 , R 6 may form a 3 to 8 membered ring, which may contain 1 to 2 O, N, and/or S atom;
  • R 7 and R 8 are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, an alkoxyalkyl group, an alkoxycycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group.
  • the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups may each independently be selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl. Substituted by one or more substituents in the group;
  • R 9 is selected from the group consisting of a hydrogen atom, a halogen, an alkane group, an alkoxyalkyl group, a cycloalkyl group, an alkoxycycloalkyl group, a hydroxyalkyl group, a hydroxycycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, and an acyl group.
  • the alkane group, alkoxyalkyl group, cycloalkyl group, alkoxycycloalkyl group, hydroxyalkyl group, hydroxycycloalkyl group, heterocyclic group, aryl group, heteroaryl group and acyl group may each be independently selected Substituted from one or more substituents of a hydroxyl group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 10 is selected from a hydrogen atom, a halogen, an alkane group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, or an empty group, wherein the alkane group, cycloalkyl group, heterocyclic group, aryl group or hetero group
  • the aryl groups may each independently be substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 12 is selected from the group consisting of a hydrogen atom, an alkane group, an alkoxyalkyl group, a cycloalkyl group, an alkoxycycloalkyl group, a hydroxyalkyl group, a hydroxycycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a heterocyclic group.
  • alkyl group, an arylalkyl group, and a heteroarylalkyl group wherein the alkane group, alkoxyalkyl group, cycloalkyl group, alkoxycycloalkyl group, hydroxyalkyl group, hydroxycycloalkyl group, heterocyclic group,
  • the aryl, heteroaryl, heterocyclylalkyl, arylalkyl and heteroarylalkyl groups may each independently be selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aromatic Substituted with one or more substituents in the heteroaryl group;
  • N1 is selected from 1, 2, 3, 4, 5, 6, 7, 8;
  • N2 is selected from 1, 2, 3, 4, 5, 6;
  • N3 is selected from 1, 2, 3;
  • N4 is selected from 0, 1, 2, 3, 4;
  • N5 is selected from 0, 1, 2, 3;
  • N6 is selected from 1, 2, and 3.
  • the compound may be a compound of formula (II), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, or a prodrug molecule thereof,
  • L is selected from C1-C10 alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl , alkylheteroaryl, alkenyl, alkynyl, straight or branched 3 to 15 carbon atoms containing N or O or S atoms, 1 to 15 carbon atoms containing N or O or S atoms, or a straight chain or a branched chain of a branched repeat unit, a tandem biaryl group, a tandem double heteroaryl group, a tandem aryl group and a heteroaryl group, through N or O or S or a linked diaryl and a biheteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is each independently selected from the group consisting of hydroxyl, halogen, alkyl,
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycycloalkyl, cycloalkylalkyl, alkylcycloalkyl, Alkenyl, alkynyl, amino, hydroxy, decyl, carboxy, alkoxy, cycloalkoxy, haloalkyl, cyano, sulfanyl, sulfo, sulfone, sulfoxide, phosphate, alkylphosphonic acid a aryl group, an arylphosphino group, an arylphosphonic acid group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently selected from the group consisting of a hydroxyl group, a halogen group, an alkyl group, and an alkoxy group. Substituted by one
  • K is selected from:
  • B is selected from Among them, a trimethylolmethyl group and a dimethylolalkylmethyl group are preferred;
  • a 1 , A 2 are each independently selected from H, Li, Na, K, Cs and their corresponding cations, or A 1 , A 2 together form Ca, Mg, Al, Sc, Ti, Cr, Co, Fe, Ni , Cu, Zn, Cd, Hg and their respective corresponding cations;
  • E is selected from C(R 1 R 2 );
  • R 5 and R 6 are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxyalkyl group, a cycloalkyl group, an alkoxycycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein said The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups may each independently be selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl. Substituted by one or more substituents; or R 5 , R 6 may form a 3 to 8 membered ring, which ring may contain 1 to 2 O, N, and/or S heteroatoms;
  • R 7 and R 8 are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, an alkoxyalkyl group, an alkoxycycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group.
  • the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups may each independently be selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl. Substituted by one or more substituents in the group;
  • R 9 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group may be independently Substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R 10 is selected from a hydrogen atom, a halogen, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, or an empty group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the hetero
  • the aryl groups may each independently be substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • N1 is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8;
  • N2 is selected from 1, 2, 3, 4, 5, 6;
  • N3 is selected from 1, 2, 3;
  • N4 is selected from 0, 1, 2, 3, 4;
  • N5 is selected from 0, 1, 2, 3;
  • N6 is selected from 1, 2, and 3.
  • the compound may be a compound of formula (II), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, or a prodrug molecule thereof, wherein K is Or E is an O atom,
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroaryl Alkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenyl, alkynyl, said alkyl, cycloalkyl, cycloalkylalkyl, alkyl ring Alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenyl And alkynyl, optionally unsubstituted or substituted by one or more substituents, each independently selected from the group consisting of alkyl, cycloal
  • the compound may be a compound of formula (III), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, or a prodrug molecule thereof,
  • the R 11 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycycloalkyl, cycloalkylalkyl, alkylcycloalkane Alkyl, alkenyl, alkynyl, amino, hydroxy, alkoxy, cycloalkoxy, haloalkyl, cyano, sulfanyl, sulfo, sulfone, sulfoxide, aryl or heteroaryl,
  • the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups may each independently be selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl. Substituted by one or more substituents in the group.
  • the compound may be a compound of formula (IV), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, or a prodrug molecule thereof,
  • X 2 is selected from the group consisting of NR1, O, S, And a single bond, when X is a single bond, it means that the aryl group and the aryl group are directly connected;
  • R 11 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycycloalkyl, cycloalkylalkyl, alkylcycloalkyl, Alkenyl, alkynyl, amino, hydroxy, alkoxy, cycloalkoxy, haloalkyl, cyano, sulfanyl, sulfo, sulfone, sulfoxide, aryl or heteroaryl, wherein said The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups may each independently be selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl. Substituted by one or more substituents.
  • the compound of formula (I) comprises a compound of the following specific structure:
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the above formula (I) or a tautomer, a mesogen, a racemate thereof, Enantiomers, diastereomers, or mixtures thereof, pharmaceutically acceptable salts thereof or prodrug molecules thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the above acceptable carriers are non-toxic, can aid in administration and have no adverse effect on the therapeutic effect of the compound.
  • Such carriers can be any solid excipient, liquid excipient, semi-solid excipient or a gaseous excipient in an aerosol composition which is generally available to those skilled in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, stearyl glyceryl ester, sodium chloride , anhydrous skim milk, etc.
  • the liquid and semi-solid excipients may be selected from the group consisting of glycerin, propylene glycol, water, ethanol, and various oils, including those derived from petroleum, animal, vegetable, or synthetic oils, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like, preferably Liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycol. It is also possible to add other adjuvants such as flavoring agents, sweeteners and the like to the composition.
  • the compounds of the invention are administered in a therapeutically effective amount, which may be administered orally, systemically (e.g., through the skin, nasally, or with a suppository) or parenterally (e.g., intramuscularly, intravenously or subcutaneously). ).
  • the preferred mode of administration is oral or intravenous, which can be adjusted depending on the extent of the disease.
  • the actual amount of application (i.e., active ingredient) of a compound of the invention depends on a number of factors, such as the severity of the condition to be treated, the age and relative health of the subject being treated, the potency of the compound employed, the route and form of administration, and the like. factor.
  • the various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional methods in the pharmaceutical arts.
  • the compound is mixed with one or more carriers and then formulated into a desired dosage form such as a tablet, a pill, a capsule, a semisolid, a powder, a sustained release dosage form, a solution, a suspension, a formulation, a gas Aerosol and so on.
  • the disease includes various cancers as well as various cancer metastases.
  • the cancer includes breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tubes Tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small cells Lung cancer, head and neck cancer, uterine cancer, testicular cancer, fallopian tube cancer, endometrial cancer, vaginal cancer, vulvar cancer, rectal cancer, colon cancer, anal cancer, breast cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer , parathyroid carcinoma, adrenal cancer, urethral cancer, penile cancer, testicular cancer, lymphoma, transitional cell carcinoma, ureteral cancer,
  • a compound, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof or The use of a pharmaceutically acceptable salt thereof, or a prodrug molecule thereof, or a pharmaceutical composition as described above, for the manufacture of a medicament for inhibiting cancer metastasis.
  • the compounds of the present invention have remarkable antitumor activity, and it has been confirmed by experiments that these compounds have an inhibitory effect on proliferation of various cancer cells, and thus the compounds of the present invention are suitable for treating various cancers.
  • kidney cancer, liver cancer, prostate cancer, stomach cancer, ovarian cancer, colon cancer it has a good therapeutic effect, and has a very obvious inhibitory effect on cancer metastasis caused by orthotopic tumor.
  • the phosphate derivative of the invention as a modulator of the acidic microenvironment of the tumor, can be combined with a clinical anticancer drug, can effectively inhibit cell proliferation and metastasis, and has good therapeutic effects on various cancers, especially for kidney cancer, Liver cancer, prostate cancer, gastric cancer, ovarian cancer, colon cancer and the like have significant therapeutic effects, small toxic and side effects, and the application prospect is very broad.
  • Figure 1 is a graph showing the results of tumor suppression of a compound of Example 7 of Example 23 of the present invention on a Hepatoma cell Hep3B2.1-7-Luc orthotopic xenograft tumor model;
  • Figure 2 is a timing chart of the administration of the compound of Example 7 to the BALB ⁇ c nude mice of Example 23 of the present invention
  • Fig. 3 is a bar graph showing the distribution of drug concentration of tissues and organs after 24 hours of intraperitoneal administration of the compound of Example 7 in BALB ⁇ c nude mice of Example 23 of the present invention.
  • Step (1) Synthesis of diethyl 4-(bromomethyl)benzylphosphonate. Weigh 53.0 g (0.201 mol) of 1,4-bis(bromomethyl)benzene, and 33.4 g (0.201 mol) of triethyl phosphite was placed in a 250 ml single-neck round bottom flask and heated at 90 ° C in an oil bath. Magnetic stirring for 3 hours. The reaction solution was cooled and solidified, and 50 ml of dichloromethane was added to the solid. The well-dispersed suspension was poured into 100 ml of petroleum ether and stirred overnight.
  • Step (2) (4,4'-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylazanediyl)bis(methylene)bis(4,1-phenylene) Base)) Synthesis of ethyl bis(methylene)diphosphonate. 25.0 g (77.9 mmol) of diethyl 4-(bromomethyl)benzylphosphonate, 4.29 g (35.4 mmol) of trishydroxymethylaminomethane, 12.2 g (88.5 mmol) of anhydrous potassium carbonate, 150 ml of acetonitrile The mixture was stirred in an oil bath at 60 ° C for 24 hours in a single-neck round bottom flask having a volume of 500 ml.
  • Step (1) Synthesis of 2,2'-(5-(bromomethyl)-1,3-phenylene)bis(2,1-ethanediyl)phosphonic acid tetramethyl ester.
  • Step (2) 2,2'-(5-(((bis(2-hydroxyethyl)amino)methyl)-1,3-phenylene)bis(2,1-ethanediyl)di Synthesis of tetramethyl phosphonate.
  • 2,2'-(5-(((bis(2-hydroxyethyl)amino)methyl)-1,3-phenylene) bis(2,1-ethane two) 240 mg (0.513 mmol) of tetramethyl phosphonate, 5 ml of concentrated hydrochloric acid was placed in a 50 ml single-neck round bottom flask, and heated under reflux in an oil bath at 105 ° C for 24 hours. The reaction solution was cooled and rotary evaporated to give a solid.
  • Step (1) Synthesis of tert-butyl 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylcarbamate. Weighing 13.1 g (0.100 mol) of trimethylolamine methane (10000 ml) in tetrahydrofuran was placed in a 500 ml single-neck round bottom flask, and 21.8 g of di-tert-butyl dicarbonate was added dropwise thereto under magnetic stirring at 15 ° C for 30 minutes in a water bath. 0.100 mol) of a solution of 80 ml of tetrahydrofuran.
  • reaction solution was stirred at 15 ° C for 16 hours, and steamed to obtain 22.1 g of 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylcarbamic acid tert-butyl viscous liquid in a yield of 99%; C 9 H 19 NO 5 , MS (ES+) m/z: 244.0 (M+Na) + .
  • Step (2) Synthesis of tert-butyl 1,3-bis(benzyloxy)-2-(benzyloxymethyl)propan-2-ylcarbamate.
  • 12.1 g (0.100 mol) of 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylcarbamic acid tert-butyl ester was weighed, and 200 ml of dichloromethane was placed in a three-neck round bottom flask having a volume of 1000 ml. Ice water bath, 18.6 g (0.32 mol) of pulverized potassium hydroxide and 53.0 g (0.31 mol) of benzyl bromide were added under magnetic stirring at 0 °C.
  • reaction solution was stirred at 0-15 ° C for 16 hours.
  • the reaction solution was filtered to remove the inorganic salt, washed twice with 200 ml of water, dried over anhydrous sodium sulfate and then evaporated to give a crude silica gel column chromatography to give 1,3-bis(benzyloxy)-2-( benzyloxymethyl) propan-2-ylcarbamate viscous liquid 35.0g, yield 71.2%; C 30 H 37 NO 5, MS (ES +) m / z: 514.3 (m + Na) +.
  • Step (3) Synthesis of 1,3-bis(benzyloxy)-2-(benzyloxymethyl)propan-2-amine.
  • 26.0 g (52.9 mmol) of tert-butyl 1,3-bis(benzyloxy)-2-(benzyloxymethyl)propan-2-ylcarbamate was weighed, and 120 ml of dichloromethane was placed in a volume of 500 ml.
  • ice water bath was added to 40 ml of trifluoroacetic acid under magnetic stirring at 0 °C.
  • the reaction solution was stirred at 0-15 ° C for 16 hours.
  • the reaction liquid was evaporated to give a crude product.
  • Step (4) diethyl 4-(1,3-bis(benzyloxy)-2-(benzyloxymethyl)propan-2-ylamino)butylphosphonate and 4,4'-(1, Synthesis of 4-bis(benzyloxy)-2-(benzyloxymethyl)propan-2-ylazanediyl)bis(4,1-butanediyl)diphosphonic acid tetraethyl ester.
  • reaction mixture was evaporated to give a solid, which was then purified and purified by column chromatography.
  • the solid is dissolved in pure water, alkalized in 2N aqueous sodium hydroxide solution, and recrystallized from ethanol to give 4,4'-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylazanediyl) bis ( 4,1-butanediyl)diphosphonate crystals hydrated white solid 279 mg, yield 62.3%; C 12 H 25 NNa 4 O 9 P 2 ⁇ xH 2 O, MS (ES+) m/z: 394.1 (M +H) + .
  • Step (1) Synthesis of dimethyl 4-(bromomethyl)phenethylphosphonate. Weigh 12.4 g (0.100 mol) of dimethyl methylphosphonate, 200 ml of dry tetrahydrofuran in a three-neck round bottom flask with a volume of 1000 ml, and slowly add 40 ml of n-butyllithium at 78 ° C with magnetic stirring. A solution of n-hexane (0.10 mol, 2.5 M) was added dropwise for 30 min. Stirring was continued for 1 hour at this temperature.
  • Step (2) 2,2'-(4,4'-(2-hydroxyethylazanediyl)bis(methylene)bis(4,1-phenylene))di(ethane-2 Synthesis of tetramethyl dimethyl diphosphonate.
  • magnetic stirring was carried out in an oil bath at 60 ° C for 24 hours.
  • reaction solution was cooled, and the mixture was evaporated to give a solid.
  • the solid is dissolved in pure water, alkalized in 2N aqueous sodium hydroxide solution, and recrystallized from ethanol to give 2,2'-(4,4'-(2-hydroxyethylazanediyl)bis(methylene)di(4, 1-phenylene)) bis(ethane-2,1-diyl)diphosphonate crystals hydrated white solid 200 mg, yield 46.1%; C 20 H 25 NNa 4 O 7 P 2 ⁇ xH 2 O, MS (ES+) m/z: 458.1 (M+H) + .
  • Step (1) 2,2',2",2'"-(5,5'-(2-hydroxyethylazanediyl)bis(methylene)bis(phenylene-5,3,1 -Triyl)) Synthesis of octamethyltetrakis(ethane-2,1-diyl)tetraphosphonate.
  • Step (2) 2,2',2",2'"-(5,5'-(2-hydroxyethylazanediyl)bis(methylene)bis(phenylene-5,3,1 -Triyl)) Synthesis of tetrakis(ethane-2,1-diyl)tetraphosphonate.
  • Step (1) Synthesis of (5-(bromomethyl)-1,3-phenylene) bis(methylene)diphosphonic acid tetraethyl ester.
  • the magnetic stirring was carried out at ° C for 3 hours.
  • the reaction solution was cooled and solidified, and 30 ml of dichloromethane was added to the solid.
  • Step (2) (5,5'-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylazanediyl)bis(methylene)bis(phenylene-5,3) , 1-triyl)) Synthesis of tetrakis(methylene)tetraphosphonic acid octaethyl ester.
  • Step (3) (5,5'-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylazanediyl)bis(methylene)bis(phenylene-5,3) , 1-triyl)) Synthesis of tetrakis (methylene) tetraphosphonate.
  • Step (1) 2,2'-(5-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylamino)methyl)-1,2-phenylene) ru Synthesis of tetramethyl ethane-2,1-diyl)diphosphonate.
  • Step (2) 2,2'-(5-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylamino)methyl)-1,2-phenylene) ru Synthesis of sodium ethane-2,1-diyl)diphosphonate.
  • Step (1) 2,2'-(5-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylmethylamino)methyl)-1,2-phenylene) Synthesis of tetramethyl (ethane-2,1-diyl)diphosphonate.
  • Step (2) 2,2'-(5-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylmethylamino)methyl)-1,2-phenylene) Synthesis of sodium (ethane-2,1-diyl)diphosphonate.
  • Step (1) Synthesis of 2-butoxymethyl-2-nitro-1,3-propanediol.
  • 15.1 g (0.100 mol) of tris(hydroxymethyl)nitromethane was weighed into a one-neck round bottom flask having a volume of 250 ml, and 50 ml of a 50% potassium hydroxide aqueous solution was added dropwise with stirring at 0 ° C in an ice water bath. After magnetic stirring at 0 ° C for 30 minutes, 6.85 g (50 mmol) of bromobutane was added dropwise. Magnetic stirring at 0-15 ° C for 16 hours.
  • reaction solution was poured into 200 ml of a saturated aqueous solution of ammonium chloride under ice-cooled water, saturated with NaCl, and then extracted with dichloromethane-isopropanol (10:1).
  • the organic phase was combined and vortexed to give a viscous liquid, which was purified by column chromatography to give 4-butoxymethyl-2-nitro-1,3-propanediol pale yellow liquid 4.14 g, yield 40%; C 8 H 17 NO 5 , MS (ES+) m/z: 230.1 (M+Na) + .
  • Step (2) Synthesis of 2-amino-2-butoxymethyl-1,3-propanediol.
  • 2-butoxymethyl-2-nitro-1,3-propanediol 4.14g (40mmol)
  • Raney nickel 800mg 4ml concentrated ammonia water
  • 80ml methanol in a 250ml single-mouth round bottom flask, 30 ° C plus Hydrogen for 16 hours.
  • Filtration, filter residue 30 ml of methanol was washed twice, the organic phase was combined, and then evaporated to give 2-amino-2-butoxymethyl-1,3-propanediol white solid 3.3 g, yield 92%; C 8 H 19 NO 3 , MS (ES+) m/z: 178.1 (M+H) + .
  • Step (1) 2,2'-(5-((1-butoxy-3-hydroxy-2-(hydroxymethyl)propan-2-ylamino)methyl)-1,2-phenylene Synthesis of methyl bis(ethane-2,1-diyl)diphosphonate.
  • Step (2) 2,2'-(5-((1-Butoxy-3-hydroxy-2-(hydroxymethyl)propan-2-ylamino)methyl)-1,2-phenylene Synthesis of sodium bis(ethane-2,1-diyl)diphosphonate. Weigh 2,2'-(5-((1-butoxy-3-hydroxy-2-(hydroxymethyl)propan-2-ylamino)methyl)-1,2-phenylene) bis ( Methyl ethane-2,1-diyl)diphosphonate 220 mg (0.407 mmol), 10 ml of concentrated hydrochloric acid was placed in a 50 ml single-neck round bottom flask, and magnetically stirred at 105 ° C for 24 hours in an oil bath.
  • Step (1) Synthesis of methyl 5-(bromomethyl)pyridinecarboxylate.
  • the mixture was stirred by magnetic stirring at 90 ° C for 10 minutes in an oil bath, and 650 mg (2.5 mmol) of dibenzoyl peroxide was added.
  • the reaction solution was refluxed for 2 hours.
  • Step (2) Synthesis of methyl 5-((diethoxyphosphoryl)methyl)pyridinecarboxylate. Weigh 8.05 g (35.0 mol) of methyl 5-(bromomethyl)pyridinecarboxylate, 8.35 g (50 mmol) of triethyl phosphite, and place it in a single-neck round bottom flask with a volume of 100 ml, and heat the magnetic force at 90 ° C in an oil bath. Stir for 3 hours.
  • Step (3) Synthesis of diethyl (6-(hydroxymethyl)pyridin-3-yl)methylphosphonate. 3.75 g (13.1 mmol) of methyl 5-((diethoxyphosphoryl)methyl)pyridinecarboxylate was weighed, and 50 ml of anhydrous tetrahydrofuran was placed in a three-neck round bottom flask with a volume of 250 ml, and stirred under magnetic stirring in an ice water bath. 15.6 ml (15.6 mmol) of 1 M lithium aluminum hydride was added dropwise. The reaction solution was reacted at 0 ° C for 2 hours.
  • Step (4) Synthesis of diethyl (6-(bromomethyl)pyridin-3-yl)methylphosphonate.
  • 4.72 g (17.4 mmol) of phosphorus tribromide was added under magnetic stirring at 0 ° C, and the reaction mixture was stirred at 0 ° C for 3 hours.
  • Step (5) (6,6'-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylazanediyl)bis(methylene)bis(6,3-pyridinium) Base)) Synthesis of ethyl bis(methylene)diphosphonate.
  • Step (6) (6,6'-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylazanediyl)bis(methylene)bis(6,3-pyridinium) Base)) Synthesis of sodium bis(methylene)diphosphonate.
  • Step (1) Synthesis of diethyl 1-(4-(bromomethyl)phenyl)propan-2-ylphosphonate.
  • the solution (10.0 mmol, 2.5 M) was added dropwise for 2 minutes. Stirring was continued for 30 minutes at -45 °C.
  • Step (2) 1,1'-(4,4'-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylazanediyl)bis(methylene)di(4) , 1-phenylene)) Synthesis of ethyl bis(propane-2,1-diyl)diphosphonate.
  • Step (3) 1,1'-(4,4'-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylazanediyl)bis(methylene)di(4) , 1-phenylene)) Synthesis of sodium bis(propane-2,1-diyl)diphosphonate.
  • Step (1) 1,1'-(4,4'-(1,3-dihydroxy-2-methylpropan-2-ylazanediyl)bis(methylene)di(4,1- Synthesis of phenylene)) methyl bis(ethane-2,1-diyl)diphosphonate.
  • Step (2) 1,1'-(4,4'-(1,3-dihydroxy-2-methylpropan-2-ylazanediyl)bis(methylene)di(4,1- Synthesis of phenylene)) bis(ethane-2,1-diyl)diphosphonate.
  • Step (1) Synthesis of methyl 3-bromo-2-(bromomethyl)propionate.
  • Step (2) Synthesis of methyl 3-(diethoxyphosphoryl)-2-((diethoxyphosphoryl)methyl)propanoate.
  • 11.0 g (42.5 mol) of methyl 3-bromo-2-(bromomethyl)propanoate and 21.2 g (127 mmol) of triethyl phosphite were placed in a single-neck round bottom flask with a volume of 100 ml in an oil bath. The magnetic stirring was carried out at 120 ° C for 3 hours. The reaction solution is cooled, rotary-purified to obtain a viscous liquid, and purified by column chromatography to obtain a viscous liquid of methyl 3-(diethoxyphosphoryl)-2-((diethoxyphosphoryl)methyl)propanoate. 7.96 g, yield 50%; C 13 H 28 O 8 P 2 , MS (ES+) m/z: 375.1 (M+H) + .
  • Step (3) Synthesis of 4-(hydroxymethyl)propane-1,3-diyldiphosphonic acid tetraethyl ester.
  • 1 ml of lithium aluminum hydride 24 ml (24 mmol) was added dropwise under magnetic stirring in an ice water bath. The reaction solution was reacted at 0 ° C for 2 hours.
  • Step (4) Synthesis of 4-(bromomethyl)propane-1,3-diyldiphosphonic acid tetraethyl ester. Weigh 4.3 g (12.4 mmol) of 2-(hydroxymethyl)propane-1,3-diyldiphosphonic acid tetraethyl ester, and place 80 ml of dichloromethane in a 250 ml single-mouth round bottom flask in an ice water bath.
  • Step (5) Synthesis of 2-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylamino)methyl)propane-1,3-diyldiphosphonic acid tetraethyl ester. Weigh 614 mg (1.50 mmol) of 2-(bromomethyl)propane-1,3-diyldiphosphonic acid tetraethyl ester, 363 mg (3.00 mmol) of trishydroxymethylaminomethane, and 207 mg (1.5 mmol) of anhydrous potassium carbonate.
  • Step (6) Synthesis of 2-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylamino)methyl)propane-1,3-diyldiphosphonate.
  • Step (1) Synthesis of ethyl 1-(bromomethyl)methane-1,1,1-trimethylphosphonate. 7.76 g (20.0 mol) of tetrabromopentanol was weighed, and 13.3 g (80.0 mmol) of triethyl phosphite was placed in a one-neck round bottom flask having a volume of 100 ml, and magnetically stirred at 120 ° C for 4 hours in an oil bath.
  • reaction liquid was cooled, and the mixture was evaporated to give a viscous liquid, which was purified by column chromatography to obtain a viscous liquid of ethyl 5-(bromomethyl)methane-1,1,1-trimethylphosphonic acid 5.60 g, yield 50 %; C 17 H 38 BrO 9 P 3 , MS (ES+) m/z: 559.1 (M+H) + .
  • Step (2) Synthesis of 1-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylamino)methyl)methane-1,1,1-trimethylphosphonic acid ethyl ester .
  • Step (3) Synthesis of 1-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylamino)methyl)methane-1,1,1-trimethylphosphonate.
  • 1-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylamino)methyl)methane-1,1,1-trimethylphosphonic acid ethyl ester 500 mg (0.83 mmol) 10 ml of concentrated hydrochloric acid was placed in a 50 ml single-neck round bottom flask, and magnetically stirred at 105 ° C for 24 hours in an oil bath. The reaction solution was cooled, and the mixture was evaporated to give a solid.
  • Step (1) Synthesis of dimethyl 5-benzyloxyisophthalate. Weighing 21.02 g (100 mol) of dimethyl 5-hydroxyisophthalate, 100 ml of dry N,N-dimethylformamide was placed in a three-neck round bottom flask with a volume of 500 ml, and anhydrous potassium carbonate was added under magnetic stirring. 20.7 g (150 mmol) and 25.7 g (150 mmol) of benzyl bromide. Stir at room temperature overnight. The reaction solution was poured into 500 ml of ice water, and extracted with 200 ml of ethyl acetate.
  • Step (2) Synthesis of (5-(benzyloxy)-1,3-phenylene)dimethanol.
  • 27 g (90.0 mmol) of dimethyl 5-benzyloxyisophthalate 200 ml of anhydrous tetrahydrofuran was placed in a three-neck round bottom flask with a volume of 1000 ml, and 1 M lithium aluminum hydride tetrahydrofuran was slowly added dropwise at 0 ° C in an ice water bath.
  • the solution was 198 ml.
  • the reaction solution was magnetically stirred at 0-20 ° C for 2 hours.
  • the reaction solution was cooled in an ice water bath, and the reaction was quenched by carefully adding 50 g of sodium sulfate decahydrate.
  • Step (3) Synthesis of 1-(benzyloxy)-3,5-di(bromomethyl)benzene.
  • 67.2 g (248 mmol) of phosphorus tribromide was slowly added dropwise at 0 °C.
  • the reaction solution was magnetically stirred at 0-20 ° C for 2 hours.
  • reaction solution was poured into 500 g of ice, extracted twice with 200 ml of dichloromethane, and the organic phase was combined, washed with 200 ml of water, dried and evaporated to give a pale yellow solid of 1-(benzyloxy)-3,5-di(bromomethyl)benzene. 27.5g, yield 89%; C 15 H 14 Br 2 O, MS (ES +) m / z: 391.0 (m + Na) +.
  • Step (4) Synthesis of tetramethyl 2,2'-(5-(benzyloxy)-1,3-phenylene)bis(ethane-2,1-diyl)diphosphonate.
  • Step (5) Synthesis of 2,2'-(5-hydroxy-1,3-phenylene)bis(ethane-2,1-diyl)diphosphonic acid tetramethyl ester.
  • 10 1 g of palladium on carbon, 250 ml of ethanol was placed in a three-neck round bottom flask having a volume of 1000 ml, and subjected to H2 reaction at 20 ° C for 18 hours under magnetic stirring.
  • Step (6) 2,2'-(5-(2-(2-bromoethoxy)ethoxy)-1,3-phenylene)di(ethane-2,1-diyl)di Synthesis of tetramethyl phosphonate.
  • Step (7) 2,2'-(5-(2-(2-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylamino)ethoxy)ethoxy)- Synthesis of tetramethyl 1,3-phenylene bis(ethane-2,1-diyl)diphosphonate.
  • Step (8) 2,2'-(5-(2-(2-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylamino)ethoxy)ethoxy)- Synthesis of sodium 1,3-phenylene bis(ethane-2,1-diyl)diphosphonate.
  • the mixture was vortexed to give a viscous liquid, and 10 ml of dichloromethane and 5 ml of methanol were added thereto, and the mixture was stirred at 20 ° C for 30 minutes, dried, and purified by resin column chromatography.
  • Step (1) Synthesis of 2-methyl-4,4-dimethylol-4,5-dihydrooxazole. Weighed 5.0 g (41.3 mmol) of tris, N,N-dimethylformamide 50 ml, 9.1 ml of triethyl orthoacetate, and 7.2 ml of N,N-diisopropylethylamine in a volume of The mixture was stirred at 120 ° C for 8 hours in a 250 ml single-mouth round bottom flask.
  • Step (2) 2,2'-(5-((4-(hydroxymethyl)-2-methyl-4,5-dihydrooxazol-4-yl)methoxy)-1,3-Asia Synthesis of phenyl) bis(ethane-2,1-diyl)diphosphonic acid tetramethyl ester. 576 mg (2.2 mmol) of triphenylphosphine was weighed, and 40 m of dry toluene was placed in a three-neck round bottom flask having a volume of 250 ml, and 383 mg (2.2 mmol) of diethyl azodicarboxylate was slowly added dropwise at 0 ° C in an ice water bath.
  • Step (1) Synthesis of (3,5-bis(2-(dimethoxyphosphoryl)ethyl)phenyl)(2,4,6-trimethylphenyl)iodonium trifluoromethanesulfonate. 759 mg (4.4 mmol) of m-chloroperoxybenzoic acid was weighed, and 40 ml of anhydrous dichloromethane was placed in a dry single-mouth round bottom flask with a volume of 50 ml, and 2,2'-(5-iodine-1,3-ya was added.
  • Phenyl) dimethyl di(ethane-2,1-diyl)diphosphonic acid 1.90 g (4.0 mmol) and mesitylene 5.29 g (4.4 mmol).
  • 1.02 g (6.8 mmol) of trifluoromethanesulfonic acid was slowly added dropwise under ice-water bath. The reaction solution was stirred at 20 ° C for 2 hours. The dichloromethane was rotated at a low temperature, 100 ml of diethyl ether was added, and the solid was collected to obtain (3,5-bis(2-(dimethoxyphosphoryl)ethyl)phenyl) (2,4,6-trimethylphenyl). Iodine trifluoromethanesulfonate yellow solid 2.74g, yield 92%; C 24 H 34 F 3 IO 9 P 2 S, MS (ES+) m/z: 595.1 (M+) + .
  • Step (2) 2,2'-(5-(4-(hydroxymethyl)phenoxy)-1,3-phenylene)di(ethane-2,1-diyl)diphosphonic acid Synthesis of esters. Weighing (3,5-bis(2-(dimethoxyphosphoryl)ethyl)phenyl)(2,4,6-trimethylphenyl)iodonium trifluoromethanesulfonate yellow solid 1.30 g (1.75 Methyl), 20 m dry dichloromethane was placed in a three-neck round bottom flask with a volume of 100 ml, and 282 mg (2.27 mmol) of 4-(hydroxymethyl)phenol and 677 mg of N,N-diisopropylethylamine were added dropwise at 20 °C.
  • 10 ml of anhydrous dichloromethane was placed in a three-neck round bottom flask having a volume of 50 ml, and 710 mg (2.62 mmol) of phosphorus tribromide was slowly added dropwise at 0 ° C in an ice water bath.
  • reaction solution was magnetically stirred at 0-20 ° C for 3 hours.
  • the reaction solution was poured into 50 g of ice, extracted twice with 50 ml of dichloromethane, and the organic phase was combined, washed with 100 ml of water, dried and then evaporated to give a viscous liquid 2,2'-(5-(4-(bromomethyl)phenoxy) - 1,3-phenylene) bis(ethane-2,1-diyl)diphosphonic acid methyl ester 652 mg, yield 93%; C 21 H 29 BrO 7 P 2 , MS (ES+) m/ z: 535.1 (M+H) + .
  • the mixture was vortexed to give a viscous liquid, and 10 ml of dichloromethane and 5 ml of methanol were added thereto, and the mixture was stirred at 20 ° C for 30 minutes, dried, and purified by resin column chromatography.
  • Step (1) Synthesis of methyl 2,2'-(4'-hydroxyphenylene-3,5-diyl)bis(ethane-2,1-diyl)diphosphonate.
  • Step (2) 2,2'-(4'-((4-(hydroxymethyl)-2-methyl-4,5-dihydrooxazolyl-4-yl)methoxy)phenylene-3, Synthesis of methyl 5-(diyl)bis(ethane-2,1-diyl)diphosphonate. 369 mg (1.41 mmol) of triphenylphosphine was weighed, and 30 m of dry toluene was placed in a three-neck round bottom flask having a volume of 250 ml, and 245 mg (1.41 mmol) of diethyl azodicarboxylate was slowly added dropwise at 0 ° C in an ice water bath.
  • Step (3) 2,2'-(4'-(2-amino-3-hydroxy-2-(hydroxymethyl)propoxy)phenylene-3,5-diyl)di(ethane-2 Synthesis of sodium 1,1-diyl)bisphosphonate.
  • Step (1) Synthesis of methyl 4-(benzyloxy)-3,5-dibromobenzoate.
  • the reaction solution was stirred at 20 ° C for 16 hours.
  • the reaction solution was poured into 200 ml of ice water, and extracted with 100 ml of ethyl acetate.
  • Step (2) Synthesis of methyl 4-(benzyloxy)-3,5-bis(2-(diethoxyphosphoryl)vinyl)benzoate. Weigh 6.5 g (16.3 mmol) of methyl 4-(benzyloxy)-3,5-dibromobenzoate, 8.03 g (48.9 mmol) of diethyl vinylphosphonate, and 6.59 g (65.2 mmol) of triethylamine.
  • Step (3) Synthesis of methyl 4-hydroxy-3,5-bis(2-(diethoxyphosphoryl)ethyl)benzoate. Weighing 3.0 g (5.30 mmol) of 4-(benzyloxy)-3,5-bis(2-(diethoxyphosphoryl)vinyl)benzoate, 10% palladium on carbon 300 mg, 30 ml of ethanol was placed A single-neck round bottom flask having a volume of 100 ml was subjected to magnetic stirring at 20 ° C for 15 hours with H 2 reaction.
  • Step (4) Synthesis of 2,2'-(2-hydroxy-5-(hydroxymethyl)-1,3-phenylene)bis(ethane-2,1-diyl)diphosphonic acid ethyl ester .
  • 1 M tetrahydrogen aluminum 8.7 ml (8.7 mmol) was slowly added dropwise with magnetic stirring at 0 °C. The reaction was carried out at 0-20 ° C for 2 hours.
  • Step (5) 2,2'-(5-(2,6-bis(2-(bisethoxyphosphoryl)ethyl)-4-(hydroxymethyl)phenoxy)-1,3- Synthesis of phenylene) bis(ethane-2,1-diyl)diphosphonic acid methyl ester.
  • Step (6) 2,2'-(5-(2,6-bis(2-(bisethoxyphosphoryl)ethyl)-4-(bromomethyl)phenoxy)-1,3- Synthesis of phenylene) bis(ethane-2,1-diyl)diphosphonic acid methyl ester.
  • reaction solution was poured into 50 g of ice, extracted twice with 50 ml of dichloromethane, and the organic phase was combined, washed with 100 ml of water, dried, and evaporated to give a viscous liquid 2,2'-(5-(2,6-bis(2-(double) Ethoxyphosphoryl)ethyl)-4-(bromomethyl)phenoxy)-1,3-phenylene) bis(ethane-2,1-diyl)diphosphonic acid methyl ester 764mg The rate was 87%; C 33 H 55 BrO 13 P 4 , MS (ES+) m/z: 863.2 (M+H) + .
  • Step (7) 2,2'-(5-(2,6-bis(2-(bisethoxyphosphoryl)ethyl)-4-((1,3-dihydroxy-2-(hydroxyl)) Synthesis of methyl)propan-2-ylamino)methyl)phenoxy)-1,3-phenylene bis(ethane-2,1-diyl)diphosphonate.
  • Step (8) 2,2'-(5-(2,6-bis(2-(bishydroxyphosphoryl)ethyl)-4-((1,3-dihydroxy-2-(hydroxymethyl)) Synthesis of sodium propane-2-ylamino)methyl)phenoxy)-1,3-phenylene bis(ethane-2,1-diyl)diphosphonate.
  • the mixture was vortexed to give a viscous liquid, and 10 ml of dichloromethane and 5 ml of methanol were added thereto, and the mixture was stirred at 20 ° C for 30 minutes, dried, and purified by resin column chromatography.
  • Step (1) Synthesis of methyl 3-bromo-5-(2-(diethoxyphosphoryl)vinyl)benzoate. 6.82 g (20.0 mmol) of methyl 3-bromo-5-iodobenzoate, 3.28 g (20.0 mmol) of diethyl vinylphosphonate, 4.04 g (40.0 mmol) of triethylamine, tri(o-methyl) Phenyl)phosphine 608 mg (2.0 mmol), palladium acetate 223 mg (1.0 mmol), 100 ml of acetonitrile were placed in a 250 ml single-neck round bottom flask, and magnetically stirred under nitrogen at 80 ° C for 4 hours.
  • Step (2) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-(diethoxyphosphoryl)ethylene Synthesis of methyl benzoate.
  • methyl 3-bromo-5-(2-(diethoxyphosphoryl)vinyl)benzoate 2.22 g (8.75 mmol) of bis-pinacol borate, potassium acetate 1.72 g (17.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride 213 mg (0.29 mmol), 40 ml of dioxane in a single-mouth round bottom with a volume of 100 ml
  • the flask was magnetically stirred at 85 ° C for 6 hours with magnetic stirring.
  • Step (6) 2,2'-(5-(3-(bromomethyl)-5-(2-(bisethoxyphosphoryl)ethyl)benzyl)-1,3-phenylene) Synthesis of methyl bis(ethane-2,1-diyl)diphosphonate.
  • reaction solution was poured into 50 g of ice, extracted twice with 50 ml of dichloromethane, and the organic phase was combined, washed with 100 ml of water, dried and then evaporated to give a viscous liquid 2,2'-(5-(3-(bromomethyl)-5- Methyl 2-(diethoxyphosphoryl)ethyl)benzyl)-1,3-phenylene bis(ethane-2,1-diyl)diphosphonate 1.14 g, yield 85 %; C 28 H 44 BrO 9 P 3 , MS (ES+) m/z: 697.2 (M+H) + .
  • Step (7) 2,2'-(5-(3-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylamino)methyl)-5-(2-(double) Synthesis of methyl ethoxyphosphoryl)ethyl)benzyl)-1,3-phenylene bis(ethane-2,1-diyl)diphosphonate.
  • Step (8) 2,2'-(5-(3-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylamino)methyl)-5-(2-(double) Synthesis of sodium hydroxyphosphoryl)ethyl)benzyl)-1,3-phenylene bis(ethane-2,1-diyl)diphosphonate.
  • the mixture was vortexed to give a viscous liquid, and 10 ml of dichloromethane and 5 ml of methanol were added thereto, and the mixture was stirred at 20 ° C for 30 minutes, dried, and purified by resin column chromatography.
  • Example 23 Pharmacodynamic test of a compound of the present invention in a hepatocarcinoma cell Hep3B2.1-7-Luc orthotopic xenograft tumor model
  • Cell culture Hep3B2.1-7-Luc cells were cultured in vitro. The culture conditions were EMEM medium supplemented with 1.5 g/L sodium bicarbonate, 1.0 mM sodium pyruvate, 2 ug/ml puromycin, and 10% heat inactivated. Fetal bovine serum, 100 U/ml penicillin and 100 ⁇ g/ml streptomycin were incubated at 37 ° C 5% CO 2 . Passaged twice a week. When the cells are in the exponential growth phase, the cells are harvested, counted, and inoculated.
  • mice BALB/c nude mice, female, 6-8 weeks old, weighing 18-22 grams.
  • Tumor inoculation 25 uL of cell suspension of 1.25 x 10 6 Hep3B2.1-7-luc cells was inoculated into 50% Matrigel in situ into the left hepatic lobules of each mouse, sutured by suture. Seven days after cell seeding, mice were imaged with an IVIS Lumina XR small animal imager, and mice of appropriate signal intensity were selected for pharmacodynamic experiments, 10 in each group.
  • mice were placed in an imaging system cartridge with the abdomen facing up for detection of tumor cells.
  • the exposure time ranges from 1 minute to 1 second.
  • the imaging results are expressed by the imaging software in photons/second. The bioimaging will be performed once a week and the last imaging before the end of the experiment.
  • mice were imaged once a week through a small animal imager, IVIS Lumina XR, to monitor tumor growth. Tumor signals are judged by the number of exposure photons per second.
  • the drug compounds were mainly distributed in the liver, kidney, lung, intestine, spleen, prostate and other tissues and organs of the mouse, suggesting the present invention.
  • the compound is especially suitable for the treatment of cancers such as liver cancer, kidney cancer, prostate cancer, lung cancer, colon cancer and the like.

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Abstract

本发明公开了一种具有下述通式(I)的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，其中D选自：(II)。本发明还公开了上述化合物在制备预防和/或治疗癌症药物中的用途。本发明还公开了上述化合物在制备抑制癌症转移的药物中的用途。本发明的化合物，能通过调整肿瘤微环境的酸性，有效抑制癌细胞的增殖与转移，使临床癌症治疗取得更好效果，具有广阔的应用前景。

Description

磷酸盐类衍生物及其用途 技术领域
本发明涉及医药技术领域，具体涉及一种作为抑制肿瘤增殖和转移的磷酸盐类衍生物及其用途。
背景技术
实体肿瘤的微环境特征包括胞外低pH、低氧浓度、高葡萄糖吸收率。三者密切关联，相互协同，促使肿瘤的发生、增殖、侵袭与转移。糖代谢有2种途径，线粒体氧化磷酸化&糖酵解。正常细胞通过有氧循环线粒体氧化磷酸化；癌细胞代谢通过糖酵解(无氧和有氧糖酵解)。研究发现肿瘤细胞对葡萄糖的摄取量极高，PET(正电子发射断层显像)就是利用了这一原理，采用2- 18F-2-脱氧葡萄糖来显像。恶性肿瘤增殖迅速，消费葡萄糖同样很多，所以放射性药剂的聚集也多，因而能照出它。癌细胞生长很快，过快的生长使得细胞经常处于一种缺氧状态，于是癌细胞就关闭了需要线粒体的有氧氧化，能量则通过葡萄糖的无氧酵解提供。葡萄糖代谢至丙酮酸后不再通过线粒体的三羧酸循环进行有氧氧化，而是通过乳酸脱氢酶(LDH)，转变成乳酸排出细胞。缺氧也自然加剧了糖酵解，而糖酵解的终产物是乳酸。癌细胞的异常代谢造成肿瘤组织酸性环境。癌细胞在酸性环境里更能茁壮成长。糖酵解产生的乳酸极大地促进了癌细胞对正常细胞的侵略性，以及对癌细胞自身的适应性和调节性。缺氧酸性微环境介导肿瘤对常规化疗和放疗的耐药在免疫治疗耐药中也起到非常重要的作用。
恶性肿瘤的周边微环境的pH(pHe)在6.5-6.9，核心可到6.2，而正常细胞在7.3-7.5。正常人的唾液pH6.5-7.4，而癌症病人可低至4.5-5.7。
恶性肿瘤的周边酸性微环境主要通过以下几方面产生：Wargurg效应导致乳酸聚集,缺氧驱动碳酸酐酶和质子转运蛋白的功能,二者结合会引起肿瘤细胞外部环境pH降低；肿瘤细胞摄取大量的葡萄糖后，高效率的糖酵解生成的大量乳酸，可通过单羧酸转运泵(MCT)转运至肿瘤微环境中；胞内产生的CO2通过弥散作用排到胞外，由于肿瘤组织细胞缺氧，激活缺氧诱导因子1(hypoxia-inducible fac-tor 1，HIF-1)诱导肿瘤细胞高表达CA-Ⅸ，催化CO2和H2O反应生成碳酸。因此糖酵解和缺氧是肿瘤细胞酸性微环境的主要途径(现代生物医学进展2014，Vol.14NO.19，3775-3777)。
乳酸有两种：L-乳酸和D-乳酸。癌细胞中产生的乳酸大部份是D-乳酸。癌就是细胞内D-乳酸浓度过高，甲基乙二醛浓度过低而形成。有观点认为，正常情况下肠黏膜对D-乳酸有屏障作用，产生出的大量D-乳酸通过粪便被排出体外，所以一般情况下不会生癌；只有在肠黏膜受损、肠手术、肠炎的情况下，肠黏膜的通透性增加，D-乳酸就会进入到血液中，进入到 血液中的D-乳酸是患癌的第一步，所以90％以上的癌症患者先前都是长期的肠胃不适、长期便秘、长期肠炎；进入到血液中的D-乳酸还不一定会生癌，因为细胞膜对D-乳酸也有屏障作用，如果此时细胞出现炎症、脓肿、溃疡或者手术、创伤等，细胞膜的屏障作用消失了，D-乳酸就会进入到细胞内，这是患上癌的第二步；进入到细胞内的D-乳酸达到一定量时，就会激活胰岛素，胰岛素又会激活乙二醛酶，乙二醛酶又把甲基乙二醛转化为D-乳酸，这时癌症就形成了。这就是患癌三部曲。这里形成了一个恶性循环，在化学上叫做自动催化反应，谁也控制不了。自动催化反应有一个特性：就是只要有原料供应，不断摄入葡萄糖，它的反应速度就会越来越快，永远不会自动停止。其结果是：D-乳酸浓度很高，甲基乙二醛浓度很低，两者不平衡是癌症发生的根本原因。
肿瘤细胞本身适应酸性微环境，主要通过细胞自噬、上调转运系统等机制。由于各类致癌物和生长因子的持续刺激，肿瘤细胞内氢离子的动力学受到严重干扰，细胞pH动态平衡出现异常，为了躲避酸性微环境的毒性，肿瘤细胞遂向外排出氢离子，最终产生细胞外的酸性环境以及细胞内的碱性环境。肿瘤细胞通过上调细胞质膜的氢离子相关转运蛋白，如钠氢交换蛋白(Na/H exchanger，NHE)、Na/K ATPase、囊泡型H一ATPases(vacuolar—H ATPase，V—ATPase)、H/C1一共输送体和单羧酸转运蛋(monocarboxylate transporter，MCT)等，来实现这一机制。肿瘤细胞适应酸性微环境还有其他机制，如上调VEGF等基因表达,促进肿瘤新生血管生成；释放组织蛋白酶B和其他蛋白水解酶,导致细胞外基质降解，导致免疫功能异常,逃避宿主免疫应答以及免疫治疗；促使肿瘤细胞对放疗不敏感，使肿瘤细胞产生耐药性，逃避化疗药物损伤。
酸性微环境是肿瘤细胞实现其侵袭性和转移性的强大武器，肿瘤细胞自身产生生长信号，发生凋亡、无限增殖、侵袭、转移和免疫逃避，以及生成新生血管，而通过诱导产生酸性环境的机制得以实现。从发病机制到治疗各环节的整个肿瘤研究领域都与肿瘤酸性微环境密切相关。
肿瘤酸性微环境影响T细胞的功能，缺氧诱导的肿瘤酸性微环境是T细胞发挥功能的强大障碍,重度缺氧及乳酸强烈抑制T细胞的活化、增殖和细胞毒性；细胞外pH＝6.7时，由IL-2诱导的T细胞增殖会停止,而缺氧肿瘤细胞的胞外pH可以低至5.8-6.5,此时淋巴细胞实际上处于凋亡状态,而肿瘤细胞可以耐受并继续生长；在体外实验中,酸性pH可以降低T细胞分泌IFN-γ和TNF-α,表明酸性微环境可广泛阻断促炎细胞因子的产生；另外,特定酸感受体家族可以将细胞外酸度的变化转变为细胞内的信号。酸性微环境可以促进G-蛋白,T细胞抑制性受体及T细胞死亡相关基因-8的表达，后者在淋巴细胞中介导c-myc的翻译与表达。
酸性微环境影响肿瘤的攻击性：肿瘤细胞外的酸性微环境能够激发细胞增殖，活化转录因子，增强靶基因表达，促使肿瘤发生；肿瘤细胞能利用乳酸来维持自身的酸性微环境，以利于其转移；诱导细胞外基质重塑而增加肿瘤的侵袭性和转移性,延迟细胞对致癌物的代谢,抑制细胞对致癌物导致DNA损伤的修复。
肿瘤酸性微环境对肿瘤细胞本身的影响是：改变肿瘤细胞的生物活性；由于肿瘤细胞生长旺盛，肿瘤组织极易出现相对血流灌注不足而引起异常酸性代谢产物的蓄积，或通过上调VEGF等基因表达，促进了肿瘤新生血管的形成，也为肿瘤的转移提供了适宜的环境；导致免疫功能异常，包括免疫系统的其他组成部分,如DC、MDSC或巨噬；细胞逃避宿主免疫应答以及免疫治疗；例如，乳酸性酸中毒是败血症的强阴性预后指标；促使肿瘤细胞对放疗不敏感，使得肿瘤细胞产生耐药性，逃避化疗药物损伤。
肿瘤酸性微环境产物对暴露在癌旁正常组织的损害主要是：导致周边正常细胞的坏死和凋亡；通过释放组织蛋白酶B和其他蛋白水解酶，导致细胞外基质降解。
细胞内外pH差异所形成的pH梯度、组织液的高压和低氧压力阻碍了许多化疗药物的功能。弱酸环境(pH＝6-7)是mAb的最佳存在环境。实体肿瘤组织内细胞外的酸性环境可能会降低mAb的治疗效果,因为微环境过于偏酸会导致mAb降解最终降低其活性。
基于上述酸性微环境对肿瘤的重要作用，研究人员对肿瘤微环境与抗癌的关系进行了大量研究。磁共振波谱分析发现，给乳腺癌转移模型鼠口服或脾内注射NaHCO3可选择性提高肿瘤细胞外pH值，减少淋巴结和肝转移灶的形成。质子泵抑制剂(PPI)是治疗消化性溃疡的一线药物，主要有泮托拉唑、兰索拉唑、奥美拉唑等。它们能抑制H+/K+-ATP酶的活性来发挥抑制酸作用。近年来PPI的抗肿瘤效应逐渐被认识到并成为抗肿瘤治疗的一大热点。体内外实验发现，PPI致敏的肿瘤细胞系对顺铂、5-氟尿嘧啶和长春碱等化疗药物的敏感性提高，且奥美拉唑可诱导裸鼠接种的人实体瘤对顺铂的敏感性提高C30。PPI的这一机制可能主要是由于药物通过抑制V—ATPase的活性，增强了细胞外和溶酶体等细胞器内的pH值，增加了药物在细胞内的浓度，逆转多药耐药(muhidrugresistance，MDR)基因高表达细胞对抗肿瘤药物的敏感性。PPI抑制肿瘤细胞的能力与培养基酸度水平直接相关；PPI能诱导B细胞肿瘤的选择性细胞毒性，它是通过激活大量的活性氧分子(reactive oxygen species，ROS)，并破坏溶酶体膜的结构，引起依赖caspase的细胞凋亡。应用PPI还可以提高化疗药物的敏感性，抑制动物模型上人类移植瘤的生长，且PPI不会引起系统性全身反应。下调NHE1还可显著抑制脑胶质瘤细胞的侵袭和转移。这些都提示了靶向干预NHE1表达可以调节肿瘤细胞内外pH，改变肿瘤细胞生物学活性，从而干预肿瘤的生长转移。
肿瘤转移是恶性肿瘤的临床治疗失败的根本原因。80％以上癌症死亡由肿瘤转移所致。 肿瘤内乳酸的堆积不仅可以反应肿瘤的恶性程度，而且与其远处转移密切相关。肿瘤转移是指，瘤细胞从原发部位侵入淋巴管、血管、体腔，迁移到他处而继续生长，形成与原发瘤同样类型的肿瘤，这个过程称为转移。良性肿瘤不转移，只有恶性肿瘤才转移，常见的转移途径有以下几种：淋巴道转移：上皮组织的恶性肿瘤多经淋巴道转移；血道转移：各种恶性肿瘤均可发生，尤多见于肉癌、肾癌、肝癌、甲状腺滤泡性癌及绒毛膜癌；种植性转移：常见于腹腔器官的癌瘤。乳酸可以通过MCT1进入内皮细胞，引起IκBα的降解和磷酸化，进而刺激自分泌核转录因子κB/白细胞介素8通路引起细胞的迁移和血管的形成。研究指出，人类结直肠癌和乳腺癌小鼠移植瘤模型，发现肿瘤细胞释放的乳酸可以通过MCT4转运，进一步刺激白细胞介素8依赖性肿瘤血管生成和肿瘤生长。从而实现肿瘤的转移。乳酸会介入机体对癌细胞的免疫应答，从而帮助癌细胞扩散。研究显示，乳酸不仅存在于而且参与癌症发展的每一步。
哈尔滨医科大学孙学英教授指出,以免疫检查点阻断单克隆抗体和抗原受体T细胞免疫疗法细胞治疗为代表的免疫治疗取得重大突破,已经被应用于多种恶性肿瘤的临床治疗。然而,肿瘤特异微环境影响了免疫治疗的效果。深入了解肿瘤缺氧酸性微环境对免疫治疗的影响,研究癌细胞逃避免疫监视和攻击的机制，有助于探索新的思路和方法，提高肿瘤免疫治疗的疗效(世界华人消化杂志2017年7月28日；25(21):1934-1944)。
浙医大胡汛教授2017年提出饿死癌细胞。肿瘤中有大量的乳酸，乳酸解离成乳酸阴离子和氢离子，成为癌细胞的两位“帮手”，让其自身能够根据“食物”的多少决定“消耗”多少。在葡萄糖饥饿或缺乏的前提下，只要去除这两个因子中的任何一个，癌细胞就会快速死亡。他们发现用碱如碳酸氢钠(小苏打)去除肿瘤内的氢离子，就可破坏乳酸根和氢离子的协同作用，从而快速有效地杀死处于葡萄糖饥饿或缺乏的肿瘤细胞。“常规动脉插管化疗栓塞术(cTACE)切断了肿瘤的‘食物通道’，然后再用碳酸氢钠去除肿瘤内的氢离子，相当于不仅不给肿瘤‘吃饭’，还让它去健身房快速消耗，迅速‘饿死’。”令人欣喜的是，临床研究结果显示：用cTACE治疗了37例病人，18例有效；用TILA-TACE治疗了40例病人，40例有效。
美国弗罗里达州H.LEE MOFFITT癌症研究中心Robert Gillies用小苏打、咪唑及其衍生物、Tris、赖氨酸等具有缓冲能力的缓冲剂对肿瘤酸性微环境的作用做了大量研究，得出明确的结论，这种缓冲溶液能有效的抑制小鼠肿瘤的生长与转移。其中碳酸氢钠还被亚利桑那大学应用于临床试验。
目前大量研究表明增加肿瘤微环境的pH值能有效抑制肿瘤生长和转移。因此，实体瘤的酸性微环境是一个极具潜力的癌症治疗靶标，尤其是转移瘤。
因此，生物医疗技术领域急需能有效调整肿瘤酸性微环境的调节剂，尤其是具有较高pH值的新型小分子化合物。
发明内容
本发明要解决目前缺乏能有效增加肿瘤酸性微环境pH值的小分子化合物的技术问题，提供一种新型的磷酸盐类衍生物，该衍生物具有pH值>8.0的单齿或多齿碱性基团，能通过调整肿瘤微环境的酸性，有效抑制癌细胞的增殖与转移，使临床癌症治疗取得更好效果。
为了解决上述技术问题，本发明通过如下技术方案实现:
在本发明的一个方面，提供了一种具有通式(I)的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，
Figure PCTCN2019079492-appb-000001
其中：L选自C1-C10的烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、烯基、炔基、含有N或O或S原子的3-15个碳原子直链或支链、含有N或O或S原子的1-15个碳原子直链或支链重复单元的直链或支链、串联双芳基、串联双杂芳基、串联芳基与杂芳基、通过N或O或S或
Figure PCTCN2019079492-appb-000002
相连接的双芳基和双杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代，优选有一个或多个取代基的苯基、萘基；
Y、Z分别独立地选自NR1、O、S、
Figure PCTCN2019079492-appb-000003
Figure PCTCN2019079492-appb-000004
或单键；
D选自
Figure PCTCN2019079492-appb-000005
当D选为
Figure PCTCN2019079492-appb-000006
时，K选自：
Figure PCTCN2019079492-appb-000007
其中，B选自
Figure PCTCN2019079492-appb-000008
其中B优选三羟甲基甲基；当D选自
Figure PCTCN2019079492-appb-000009
时，K选为
Figure PCTCN2019079492-appb-000010
F为CR 10或单键；
G选自
Figure PCTCN2019079492-appb-000011
R 1和R 2各自独立地选自氢、卤素、烷基、环烷基、羟基烷烃基、烷氧基烷基、烷氧基环烷基、环烷基烷基、烷基环烷基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代烷基、氰基、硫烷基、磺基、砜基、亚砜基、磷酸基、烷基膦酸基、芳基磷酸基、芳基膦酸基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代，或为空；
R 3和R 4各自独立地选自氢、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基烷基、炔基烷基，所述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基烷基、炔基烷基，任选不取代或被一个或多个取代基所取代，所述取代基各自独立选自烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳香磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基、磷酸基、膦酸基、烷基磷酸基、烷基膦酸基、芳基磷酸基、芳基膦酸基；或者R 3和R 4连同二者所连接的N原子共同形成杂环基，所述杂环基为单环、双环或者三环，或者是稠环、桥环或螺环，所述杂环基包含至少一个N原子，或者包含1个或2个或3个任选于N、S和O的杂原子，所述杂环基 不取代或者任选被一个或多个取代基所取代，所述的取代基各自独立地选自于由烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳香磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基、磷酸基、膦酸基、烷基磷酸基、烷基膦酸基、芳基磷酸基、芳基膦酸基单独作为取代基或自由组合所形成的取代基；
A 1,A 2各自独立地选自H、Li、Na、K、Cs和其对应的阳离子，或者A 1,A 2共同形成Ca、Mg、Al、Sc、Ti、Cr、Co、Fe、Ni、Cu、Zn、Cd、Hg和其各自对应的阳离子；
E选自O原子或C(R 1R 2)；
R 5、R 6各自独立地选自氢原子、卤素、烷基、烷氧基烷基、环烷基、烷氧基环烷基、羟基烷基、羟基环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；或R 5、R 6可形成3至8元环，该环可含有1至2个O、N、和/或S杂原子；
R 7、R 8各自独立地选自氢原子、烷基、羟基烷基、环烷基、烷氧基烷基、烷氧基环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 9选自氢原子、卤素、烷烃基、烷氧基烷基、环烷基、烷氧基环烷基、羟基烷基、羟基环烷基、杂环基、芳基、杂芳基和酰基，所述烷烃基、烷氧基烷基、环烷基、烷氧基环烷基、羟基烷基、羟基环烷基、杂环基、芳基、杂芳基和酰基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 10选自氢原子、卤素、烷烃基、环烷基、杂环基、芳基、杂芳基，或为空，其中所述的烷烃基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 12选自氢原子、烷烃基、烷氧基烷基、环烷基、烷氧基环烷基、羟基烷基、羟基环烷基、杂环基、芳基、杂芳基、杂环基烷基、芳基烷基和杂芳基烷基，其中所述烷烃基、烷氧基烷基、环烷基、烷氧基环烷基、羟基烷基、羟基环烷基、杂环基、芳基、杂芳基、杂环基烷基、芳基烷基和杂芳基烷基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
n1选自1，2，3，4，5，6，7，8；
n2选自1，2，3，4，5，6；
n3选自1，2，3；
n4选自0，1，2，3，4；
n5选自0，1，2，3；
n6选自1，2，3。
优选的，所述化合物可以为式(II)所示化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，
Figure PCTCN2019079492-appb-000012
其中：L选自C1-C10的烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、烯基、炔基、含有N或O或S原子的3-15个碳原子直链或支链、含有N或O或S原子的1-15个碳原子直链或支链重复单元的直链或支链、串联双芳基、串联双杂芳基、串联芳基与杂芳基、通过N或O或S或
Figure PCTCN2019079492-appb-000013
相连接的双芳基和双杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代，其中优选有一个或多个取代基的苯基、萘基；
R 1和R 2各自独立地选自氢、卤素、烷基、环烷基、羟基烷烃基、烷氧基烷基、烷氧基环烷基、环烷基烷基、烷基环烷基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代烷基、氰基、硫烷基、磺基、砜基、亚砜基、磷酸基、烷基膦酸基、芳基磷酸基、芳基膦酸基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
K选自：
Figure PCTCN2019079492-appb-000014
B选自
Figure PCTCN2019079492-appb-000015
其中优选三羟甲基甲基和二羟甲基烷基甲基；
A 1,A 2各自独立地选自H、Li、Na、K、Cs和其对应的阳离子，或者A 1,A 2共同形成Ca、Mg、Al、Sc、Ti、Cr、Co、Fe、Ni、Cu、Zn、Cd、Hg和其各自对应的阳离子；
E选自C(R 1R 2)；
R 5、R 6各自独立地选自氢原子、卤素、烷基、烷氧基烷基、环烷基、烷氧基环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；或R 5、R 6可形成3至8元环，该环可含有1至2个O、N、和/或S杂原子；
R 7、R 8各自独立地选自氢原子、烷基、羟基烷基、环烷基、烷氧基烷基、烷氧基环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 9选自氢原子、烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 10选自氢原子、卤素、烷基、环烷基、杂环基、芳基、杂芳基，或为空，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
n1选自0，1，2，3，4，5，6，7，8；
n2选自1，2，3，4，5，6；
n3选自1，2，3；
n4选自0，1，2，3，4；
n5选自0，1，2，3；
n6选自1，2，3。
优选的，所述化合物可以为式(II)所示化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，其中，K为
Figure PCTCN2019079492-appb-000016
或E为O原子，
Figure PCTCN2019079492-appb-000017
R 3和R 4各自独立地选自氢、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，所述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，任选不取代或被一个或多个取代基所取代，所述取代基各自独立选自烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳香磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基、磷酸基、膦酸基、烷基磷酸基、烷基膦酸基、芳基磷酸基、芳基膦酸基；或者R 3和R 4连同二者所连接的N原子共同形成杂环基，所述杂环基为单环、双环或者三环，或者是稠环、桥环或螺环，所述杂环基包含至少一个N原子，或者包含1个或2个或3个任选于N、S和O的杂原子，所述杂环基不取代或者任选被一个或多个取代基所取代，所述的取代基各自独立地选自于由烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳香磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基、磷酸基、膦酸基、烷基磷酸基、烷基膦酸基、芳基磷酸基、芳基膦酸基单独作为取代基或自由组合所形成的取代基。
优选的，所述化合物可以为式(III)所示化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，
Figure PCTCN2019079492-appb-000018
所述R 11选自氢、卤素、C1-C6烷基、C3-C8环烷基、羟基烷烃基、烷氧基烷基、烷氧基环烷基、环烷基烷基、烷基环烷基、烯基、炔基、氨基、羟基、烷氧基、环烷氧基、卤代烷 基、氰基、硫烷基、磺基、砜基、亚砜基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。
优选的，所述化合物可以为式(IV)所示化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，
Figure PCTCN2019079492-appb-000019
其中，X 2选自NR1、O、S、
Figure PCTCN2019079492-appb-000020
和单键，当X为单键时表示芳基和芳基直接相连；
R 11选自氢、卤素、C1-C6烷基、C3-C8环烷基、羟基烷烃基、烷氧基烷基、烷氧基环烷基、环烷基烷基、烷基环烷基、烯基、炔基、氨基、羟基、烷氧基、环烷氧基、卤代烷基、氰基、硫烷基、磺基、砜基、亚砜基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。
优选的，所述通式(I)化合物包括下述具体结构的化合物：
Figure PCTCN2019079492-appb-000021
Figure PCTCN2019079492-appb-000022
Figure PCTCN2019079492-appb-000023
Figure PCTCN2019079492-appb-000024
Figure PCTCN2019079492-appb-000025
Figure PCTCN2019079492-appb-000026
Figure PCTCN2019079492-appb-000027
Figure PCTCN2019079492-appb-000028
在本发明的另一方面，还提供了一种药物组合物，其含有治疗有效量的上述通式(I)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其可药用盐或其前药分子，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
上述可接受的载体是无毒的、能辅助施用并且对化合物的治疗效果没有不利影响。此类载体可以是本领域的技术人员通常能得到的任何固体赋形剂、液体赋形剂、半固体赋形剂或者在气雾剂组合物中的气体赋形剂。固体药物赋形剂包括淀粉、纤维素、滑石、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻米、面粉、白垩、硅胶、硬脂酸镁、硬脂酸钠、甘油硬脂酰酯、氯化钠、无水脱脂乳等。液体和半固体赋形剂可以选自甘油、丙二醇、水、乙醇和各种油，包括那些源于石油、动物、植物或人工合成的油，例如，花生油、豆油、矿物油、芝麻油等、优选的液体载体，特别是用于可注射溶液的，包括水、盐水、葡萄糖水溶液和甘醇。另外还可以在组合物中加入其它辅剂如香味剂、甜味剂等。
本发明的化合物以治疗上的有效量施用，其施用方式可以是口服、全身施用(例如，透过皮肤的、鼻吸入的或者用栓剂)或肠胃外施用(例如，肌肉内、静脉内或皮下)。优选的施用方式是口服或静脉注射，它可根据疾病程度调节。
本发明的化合物的实际施用量(即活性组分)依赖于许多因素，如待治疗疾病的严重性、治疗对象的年龄和相对健康程度、所使用的化合物的效能、施用途径和形式，以及其他因素。
本发明药物组合物的各种剂型可以按照药学领域的常规方法制备。例如使该化合物与一种或者多种载体混合，然后将其制成所需的剂型，如片剂、药丸、胶囊、半固体、粉末、缓释剂型、溶液、混悬液、配剂、气雾剂等等。
在本发明的另一方面，还提供了上述通式(I)所示化合物或其互变异构体、内消旋体、 外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，或上述药物组合物在预防和/或治疗由酸性微环境引起和介导的疾病的药物中的用途。该疾病包括各种癌症以及各种癌症转移。
所述癌症包含乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌、头颈癌、子宫癌、睾丸癌、输卵管癌、子宫内膜癌、阴道癌、外阴癌、直肠癌、结肠癌、肛门区癌、乳腺癌、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、尿道癌、阴茎癌、睾丸癌、淋巴癌、移行细胞癌、输尿管癌、肾细胞癌、肾盂癌、霍奇金病、非霍奇金淋巴瘤、软组织肉瘤、儿童实体瘤、淋巴细胞性淋巴瘤、中枢神经系统(CNS)肿瘤、原发性中枢神经系统淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、黑色素瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、慢性或急性白血病、和/或所述各种癌的组合。
在本发明的另一方面，还提供了上述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，或上述的药物组合物在制备抑制癌症转移的药物中的用途。
在本发明的另一方面，还提供了上述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，或权利要求7所述的药物组合物在制备预防和/或治疗酸中毒引起的疾病的药物中的用途。
在本发明的另一方面，还提供了上述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，与至少一种另外的抗癌剂联用在制备治疗癌症或抑制癌症转移的药物中的用途。
本发明的化合物具有显著的抗肿瘤活性，通过实验证实这些化合物对各种癌细胞增殖具有抑制作用，因此本发明化合物适用于治疗各种癌症。尤其是对于肾癌、肝癌、前列腺癌、胃癌、卵巢癌、结肠癌具有较好的治疗效果，对原位瘤引起的癌转移有非常明显的抑制效果。
本发明的磷酸盐类衍生物，作为肿瘤酸性微环境的调控剂，与临床抗癌药物联合使用，能有效抑制细胞增殖与转移，对多种癌症具有良好的治疗效果，尤其是对于肾癌、肝癌、前列腺癌、胃癌、卵巢癌、结肠癌等具有显著的治疗效果，毒副作用小，应用前景非常广阔。
附图说明
下面结合附图和具体实施方式对本发明作进一步详细的说明。
图1是本发明实施例23的实施例7化合物对肝癌细胞Hep3B2.1-7-Luc原位异种移植肿 瘤模型的肿瘤抑制结果图；
图2是本发明实施例23的BALB\c nude小鼠腹腔给予实施例7化合物后的药-时曲线图；
图3是本发明实施例23的BALB\c nude小鼠腹腔给予实施例7化合物的24小时后各组织器官药物浓度分布柱状图。
具体实施方式
实施例1：(4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(亚甲基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000029
步骤(1)：4-(溴甲基)苄基膦酸二乙酯的合成。称量1,4-二(溴甲基)苯53.0g(0.201mol)，亚磷酸三乙酯33.4g(0.201mol)置于容积为250毫升的单口圆底烧瓶中，油浴中90℃加热磁力搅拌3小时。反应液冷却固化，向固体中加入50ml二氯甲烷，充分分散后的悬浊液倒入100ml石油醚中搅拌过夜，过滤，收集滤液，滤渣用100ml二氯甲烷：石油醚(1:10)混合物洗涤。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到无色液体4-(溴甲基)苄基膦酸二乙酯25.0g，产率为38.7％；C 12H 18BrO 3P，MS(ES+)m/z：321.0(M+H) +。
步骤(2)：(4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(亚甲基)二膦酸乙酯的合成。称量4-(溴甲基)苄基膦酸二乙酯25.0g(77.9mmol)，三羟甲基氨基甲烷4.29g(35.4mmol)，无水碳酸钾12.2g(88.5mmol)，150ml乙腈置于容积为500毫升的单口圆底烧瓶中，油浴中60℃加热磁力搅拌24小时。反应液冷却，过滤，收集滤液，滤渣用100ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到(4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(亚甲基)二膦酸乙酯无色液体16.1g，产率为75.6％；C 28H 45NO 9P 2，MS(ES+)m/z：602.2(M+H) +。
步骤(3)：(4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(亚甲基)二膦酸钠的合成。称量(4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(亚甲基)二膦酸乙酯16.1g(26.8mmol)，150ml浓盐酸置于容积为500毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌42小时。 反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干，固体溶解于纯水，加入2N氢氧化钠水溶液，乙醇重结晶得到(4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(亚甲基)二膦酸钠结晶水合白色固体16.0g，产率76.9％； 1H NMR(500MHz,D 2O)δ7.15(s,4H),3.90(s,2H),3.61(s,3H),2.72(d,J＝19.8Hz,2H)；C 20H 25NNa 4O 9P 2·xH 2O，MS(ES+)m/z：490.2(M+H) +。
实施例2：2，2’-(5-(((双(2-羟乙基)氨基)甲基)-1，3-亚苯基)双(2，1-乙烷二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000030
步骤(1)：2，2’-(5-(溴甲基)-1，3-亚苯基)双(2，1-乙烷二基)膦酸四甲酯的合成。称量甲基膦酸二甲酯24.8g(0.200mol)，400ml干燥四氢呋喃置于容积为2000毫升的三口圆底烧瓶中，磁力搅拌下干冰丙酮浴中缓慢滴加88ml正丁基锂正己烷溶液(0.22mol，2.5M)，滴加时间50分钟。在此温度下继续搅拌1小时。-78℃，半小时内滴加1,3,5-三(溴甲基)苯35.7g(0.100mol)的干燥四氢呋喃溶液200ml，继续搅拌1小时。LCMS检测产物占主要比例。立刻用磷酸二氢钾溶液(1M，100ml)淬灭反应并放置室温过夜。混合物分液，水相用50ml氯仿、异丙醇(3:1)混合物萃取4次。合并有机相，无水硫酸钠干燥，过滤，旋干。残余物柱层析纯化得到11.7g黄色油状2，2’-(5-(溴甲基)-1，3-亚苯基)双(2，1-乙烷二基)膦酸四甲酯，产率为26.4％；C 15H 25BrO 6P 2，MS(ES+)m/z：443.0(M+H) +。
步骤(2)：2，2’-(5-(((双(2-羟乙基)氨基)甲基)-1，3-亚苯基)双(2，1-乙烷二基)二膦酸四甲酯的合成。称量2，2’-(5-(溴甲基)-1，3-亚苯基)双(2，1-乙烷二基)膦酸四甲酯290mg(0.653mmol)，二乙醇胺137mg(1.31mmol)，无水碳酸钾90mg(0.653mmol)，10ml乙腈置于容积为50毫升的单口圆底烧瓶中，油浴中40℃加热16小时。反应液冷却，过滤，收集滤液，滤渣用10ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到无色液体2，2’-(5-(((双(2-羟乙基)氨基)甲基)-1，3-亚苯基)双(2，1-乙烷二基)二膦酸四甲酯240mg，产率为78.6％；C 19H 35NO 8P 2，MS(ES+)m/z： 468.2(M+H) +。
步骤(3)：2，2’-(5-(((双(2-羟乙基)氨基)甲基)-1，3-亚苯基)双(2，1-乙烷二基)二膦酸钠的合成。称量2，2’-(5-(((双(2-羟乙基)氨基)甲基)-1，3-亚苯基)双(2，1-乙烷二基)膦酸四甲酯240mg(0.513mmol)，5ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热回流24小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干得到固体溶解于纯水中，加入2N氢氧化钠水溶液，乙醇重结晶得到2，2’-(5-(((双(2-羟乙基)氨基)甲基)-1，3-亚苯基)双(2，1-乙烷二基)二膦酸钠结晶水合白色固体250mg，产率85.8％； 1H NMR(500MHz,D 2O)δ7.08(s,1H),7.01(s,2H),3.66(s,2H),3.59(t,J＝6.2Hz,4H),2.70–2.53(m,8H),1.60–1.43(m,4H)；C 15H 23NNa 4O 8P 2·xH 2O，MS(ES+)m/z：412.1(M+H) +。
实施例3：4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)双(4，1-丁烷二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000031
步骤(1)：1，3-二羟基-2-(羟甲基)丙烷-2-基氨基甲酸叔丁酯的合成。称量三羟甲基氨基甲烷12.1g(0.100mol)100ml四氢呋喃置于容积为500毫升的单口圆底烧瓶中，水浴中15℃磁力搅拌下30分钟内滴加二碳酸二叔丁酯21.8g(0.100mol)的80ml四氢呋喃溶液。反应液15℃搅拌16小时，旋蒸得到1，3-二羟基-2-(羟甲基)丙烷-2-基氨基甲酸叔丁酯粘稠液体22.1g，产率为99％；C 9H 19NO 5，MS(ES+)m/z：244.0(M+Na) +。
步骤(2)：1，3-二(苄氧基)-2-(苄氧甲基)丙烷-2-基氨基甲酸叔丁酯的合成。称量1，3-二羟基-2-(羟甲基)丙烷-2-基氨基甲酸叔丁酯22.1g(0.100mol)，200ml二氯甲烷置于容积为1000毫升的三口圆底烧瓶中，冰水浴0℃磁力搅拌下加入粉碎的氢氧化钾18.6g(0.32mol)和苄溴53.0g(0.31mol)。反应液0-15℃搅拌16小时.反应液滤去无机盐，200ml水洗三次，无水硫酸钠干燥，旋蒸得到粗品硅胶柱层析得到1，3-二(苄氧基)-2-(苄氧甲基)丙烷-2-基氨基甲酸叔丁酯粘稠液体35.0g，产率为71.2％；C 30H 37NO 5，MS(ES+)m/z：514.3(M+Na) +。
步骤(3)：1，3-二(苄氧基)-2-(苄氧甲基)丙烷-2-胺的合成。称量1，3-二(苄氧 基)-2-(苄氧甲基)丙烷-2-基氨基甲酸叔丁酯26.0g(52.9mmol)，120ml二氯甲烷置于容积为500毫升的三口圆底烧瓶中，冰水浴0℃磁力搅拌下加入40ml三氟乙酸。反应液0-15℃搅拌16小时。反应液旋蒸得到粗品，石油醚洗涤之后加入200ml水，5％碳酸氢钠调节pH至9，200ml二氯甲烷萃取二次，200ml水洗，200ml饱和食盐水洗，无水硫酸钠干燥，旋干得到1，3-二(苄氧基)-2-(苄氧甲基)丙烷-2-胺粘稠液体14.0g，产率为67.5％；C 30H 37NO 5，MS(ES+)m/z：392.2(M+H) +。
步骤(4)：4-(1，3-二(苄氧基)-2-(苄氧甲基)丙烷-2-基氨基)丁基膦酸二乙酯和4，4’-(1，3-二(苄氧基)-2-(苄氧甲基)丙烷-2-基氮烷二基)双(4，1-丁烷二基)二膦酸四乙酯的合成。称量1，3-二(苄氧基)-2-(苄氧甲基)丙烷-2-胺782mg(2.00mmol)，4-氯丁基膦酸二乙酯915mg(4.00mmol)，无水碳酸钾552mg(4.0mmol)20ml乙腈置于容积为100毫升的单口圆底烧瓶中，油浴80℃磁力搅拌30小时。反应液过滤，旋蒸得到粗品，柱层析得到4，4’-(1，3-二(苄氧基)-2-(苄氧甲基)丙烷-2-基氮烷二基)双(4，1-丁烷二基)二膦酸四乙酯粘稠液体608mg，产率为39.2％；C 41H 63NO 9P 2，MS(ES+)m/z：776.4(M+H) +和4-(1，3-二(苄氧基)-2-(苄氧甲基)丙烷-2-基氨基)丁基膦酸二乙酯粘稠液体249mg，产率为21.3％；C 33H 46NO 6P，MS(ES+)m/z：584.3(M+H) +。
步骤(5)：4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)双(4，1-丁烷二基)二膦酸钠的合成。称量4，4’-(1，3-二(苄氧基)-2-(苄氧甲基)丙烷-2-基氮烷二基)双(4，1-丁烷二基)二膦酸四乙酯608mg(0.784mmol)，10ml浓盐酸置于容积为100毫升的单口圆底烧瓶中，油浴105℃磁力搅拌回流18小时。反应液旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)双(4，1-丁烷二基)二膦酸钠结晶水合白色固体279mg，产率62.3％；C 12H 25NNa 4O 9P 2·xH 2O，MS(ES+)m/z：394.1(M+H) +。
实施例4：2，2’-(4，4’-(2-羟乙基氮烷二基)二(亚甲基)二(4，1-亚苯基))二(乙烷-2，1-二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000032
步骤(1)：4-(溴甲基)苯乙基膦酸二甲酯的合成。称量甲基膦酸二甲酯12.4g(0.100mol)， 200ml干燥四氢呋喃置于容积为1000毫升的三口圆底烧瓶中，磁力搅拌下干冰丙酮浴-78℃下缓慢滴加40ml正丁基锂正己烷溶液(0.10mol，2.5M)，滴加时间30分钟。在此温度下继续搅拌1小时。-78℃，半小时内滴加1，4-二(溴甲基)苯26.4g(0.100mol)的干燥四氢呋喃溶液100ml，继续搅拌1小时。LCMS检测产物占主要比例。立刻用磷酸二氢钾溶液(1M，50ml)淬灭反应并放置室温过夜。混合物分液，水相用50ml二氯甲烷萃取2次。合并有机相，无水硫酸钠干燥，过滤，旋干。残余物柱层析纯化得到11.8g黄色油状4-(溴甲基)苯乙基膦酸二甲酯，产率为38.4％；C 11H 16BrO 3P，MS(ES+)m/z：307.0(M+H) +。
步骤(2)：2，2’-(4，4’-(2-羟乙基氮烷二基)二(亚甲基)二(4，1-亚苯基))二(乙烷-2，1-二基)二膦酸四甲酯的合成。称量4-(溴甲基)苯乙基膦酸二甲酯675mg(2.2mmol)，乙醇胺61mg(1.0mmol)，无水碳酸钾304mg(2.2mmol)，10ml乙腈置于容积为50毫升的单口圆底烧瓶中，油浴中60℃加热磁力搅拌24小时。反应液冷却，过滤，收集滤液，滤渣用10ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到2，2’-(4，4’-(2-羟乙基氮烷二基)二(亚甲基)二(4，1-亚苯基))二(乙烷-2，1-二基)二膦酸四甲酯无色液体330mg，产率为64.0％；C 24H 37NO 7P 2，MS(ES+)m/z：514.2(M+H) +。
步骤(3)：2，2’-(4，4’-(2-羟乙基氮烷二基)二(亚甲基)二(4，1-亚苯基))二(乙烷-2，1-二基)二膦酸钠的合成。2，2’-(4，4’-(2-羟乙基氮烷二基)二(亚甲基)二(4，1-亚苯基))二(乙烷-2，1-二基)二膦酸四甲酯328mg(0.638mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌24小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2，2’-(4，4’-(2-羟乙基氮烷二基)二(亚甲基)二(4，1-亚苯基))二(乙烷-2，1-二基)二膦酸钠结晶水合白色固体200mg，产率46.1％；C 20H 25NNa 4O 7P 2·xH 2O，MS(ES+)m/z：458.1(M+H) +。
实施例5：2，2’，2”，2’”-(5，5’-(2-羟乙基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸钠的合成
Figure PCTCN2019079492-appb-000033
步骤(1)：2，2’，2”，2’”-(5，5’-(2-羟乙基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸八甲酯的合成。称量2，2’-(5-(溴甲基)-1，3-亚苯基)双(2，1-乙烷二基)膦酸四甲酯972mg(2.2mmol)，乙醇胺61mg(1.00mmol)，无水碳酸钾304mg(2.2mmol)，20ml乙腈置于容积为100毫升的单口圆底烧瓶中，油浴中60℃加热磁力搅拌24小时。反应液冷却，过滤，收集滤液，滤渣用20ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到2，2’，2”，2’”-(5，5’-(2-羟乙基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸八甲酯无色液体550mg，产率为70％；C 32H 55NO 13P 4，MS(ES+)m/z：786.3(M+H) +。
步骤(2)：2，2’，2”，2’”-(5，5’-(2-羟乙基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸钠的合成。称量2，2’，2”，2’”-(5，5’-(2-羟乙基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸八甲酯550mg(0.70mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌42小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2，2’，2”，2’”-(5，5’-(2-羟乙基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸钠结晶水合白色固体390mg，产率58％；C 24H 31NNa 8O 13P 4·xH 2O，MS(ES+)m/z：674.1(M+H) +。
实施例6：(5，5’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(亚甲基)四膦酸钠的合成
Figure PCTCN2019079492-appb-000034
步骤(1)：(5-(溴甲基)-1，3-亚苯基)双(亚甲基)二膦酸四乙酯的合成。称量1,3,5-三(溴甲基)苯7.14g(20.0mol)，亚磷酸三乙酯6.68g(40.2mol)置于容积为50毫升的单口圆底烧瓶中，油浴中90℃加热磁力搅拌3小时。反应液冷却固化，向固体中加入30ml二氯甲烷，充分分散后的悬浊液倒入30ml石油醚中搅拌过夜，过滤，收集滤液，滤渣用30ml二氯甲烷：石油醚(1:5)混合物洗涤。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到浅色液体(5-(溴甲基)-1，3-亚苯基)双(亚甲基)二膦酸四乙酯2.45g，产率为26％；C 17H 29BrO 6P 2，MS(ES+)m/z：493.0(M+Na) +。
步骤(2)：(5，5’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(亚甲基)四膦酸八乙酯的合成。称量(5-(溴甲基)-1，3-亚苯基)双(亚甲基)二膦酸四乙酯1.04g(2.2mmol)，三羟甲基氨基甲烷121mg(1.0mmol)，无水碳酸钾304mg(2.2mmol)，15ml乙腈置于容积为50毫升的单口圆底烧瓶中，油浴中60℃加热磁力搅拌24小时。反应液冷却，过滤，收集滤液，滤渣用10ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到(5，5’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(亚甲基)四膦酸八乙酯无色液体360mg，产率为40％；C 38H 67NO 15P 4，MS(ES+)m/z：902.4(M+H) +。
步骤(3)：(5，5’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(亚甲基)四膦酸钠的合成。称量(5，5’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(亚甲基)四膦酸八乙酯360mg(0.40mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌42小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到(5，5’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(亚甲基)四膦酸钠结晶水合白色固体210mg，产率57％；C 22H 27NNa 8O 15P 4·xH 2O，MS(ES+)m/z：678.1(M+H) +。
实施例7：2，2’，2”，2’”-(5，5’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二 基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸钠的合成
Figure PCTCN2019079492-appb-000035
步骤(1)：2，2’，2”，2’”-(5，5’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸八甲酯的合成。称量2，2’-(5-(溴甲基)-1，3-亚苯基)双(2，1-乙烷二基)膦酸四甲酯972mg(2.2mmol)，三羟甲基氨基甲烷121mg(1.0mmol)，无水碳酸钾304mg(2.2mmol)，10ml乙腈置于容积为50毫升的单口圆底烧瓶中，油浴中60℃加热磁力搅拌24小时。反应液冷却，过滤，收集滤液，滤渣用10ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到2，2’，2”，2’”-(5，5’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸八甲酯无色液体465mg，产率为55％；C 34H 59NO 15P 4，MS(ES+)m/z：846.3(M+H) +。
步骤(2)：2，2’，2”，2’”-(5，5’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸钠的合成。称量2，2’，2”，2’”-(5，5’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸八甲酯465mg(0.55mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌42小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2，2’，2”，2’”-(5，5’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸钠结晶水合白色固体360mg，产率65％；C 26H 35NNa 8O 15P 4·xH 2O，MS(ES+)m/z：606.2(M+H) +。
实施例8：2，2’-(5-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000036
步骤(1)：2，2’-(5-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸四甲酯的合成。称量2，2’-(5-(溴甲基)-1，3-亚 苯基)双(2，1-乙烷二基)膦酸四甲酯663mg(1.5mmol)，三羟甲基氨基甲烷363mg(3.0mmol)，无水碳酸钾207mg(1.5mmol)，10ml乙腈置于容积为50毫升的单口圆底烧瓶中，油浴中60℃加热磁力搅拌16小时。反应液冷却，过滤，收集滤液，滤渣用10ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到2，2’-(5-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸四甲酯无色液体493mg，产率为68％；C 19H 35NO 9P 2，MS(ES+)m/z：484.2(M+H) +。
步骤(2)：2，2’-(5-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸钠的合成。称量2，2’-(5-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸四甲酯493mg(1.02mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌24小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2，2’-(5-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸钠结晶水合白色固体349mg，产率60％；C 15H 23NNa 4O 9P 2·xH 2O，MS(ES+)m/z：428.1(M+H) +。
实施例9：2，2’-(5-((1，3-二羟基-2-(羟甲基)丙烷-2-基甲氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000037
步骤(1)：2，2’-(5-((1，3-二羟基-2-(羟甲基)丙烷-2-基甲氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸四甲酯的合成。称量2，2’-(5-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸四甲酯450mg(0.93mmol)，碘甲烷284mg(2.0mmol)，无水碳酸钾276mg(2.0mmol)，4ml乙腈置于容积为10毫升的微波管中，油浴中60℃加热磁力搅拌2小时。反应液冷却，过滤，收集滤液，滤渣用10ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到2，2’-(5-((1，3-二羟基-2-(羟甲基)丙烷-2-基甲氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸四甲酯无色液体300mg，产率为64％；C 20H 37NO 9P 2，MS(ES+)m/z：498.2(M+H) +。
步骤(2)：2，2’-(5-((1，3-二羟基-2-(羟甲基)丙烷-2-基甲氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸钠的合成。称量2，2’-(5-((1，3-二羟基-2-(羟 甲基)丙烷-2-基甲氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸四甲酯300mg(0.60mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌24小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2，2’-(5-((1，3-二羟基-2-(羟甲基)丙烷-2-基甲氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸钠结晶水合白色固体170mg，产率54％；C 16H 25NNa 4O 9P 2·xH 2O，MS(ES+)m/z：442.1(M+H) +。
实施例10：2，2’，2”，2’”-(5，5’-(1-丁氧基-3-羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸钠
Figure PCTCN2019079492-appb-000038
步骤(1)：2-丁氧甲基-2-硝基-1,3-丙二醇的合成。称量三(羟甲基)硝基甲烷15.1g(0.100mol)置于容积为250毫升的单口圆底烧瓶中，冰水浴中0℃磁力搅拌下滴加50％氢氧化钾水溶液50ml。0℃磁力搅拌30分钟之后滴加溴丁烷6.85g(50mmol)。0-15℃磁力搅拌16小时。冰水浴冷却下反应液倒入200ml饱和氯化铵水溶液中，NaCl饱和，二氯甲烷-异丙醇(10:1)连续萃取至产物大部分萃出。合并有机相，旋蒸得到粘稠液体，再经过柱层析纯化得到2-丁氧甲基-2-硝基-1,3-丙二醇淡黄色液体4.14g，产率为40％；C 8H 17NO 5，MS(ES+)m/z：230.1(M+Na) +。
步骤(2)：2-氨基-2-丁氧甲基-1,3-丙二醇的合成。2-丁氧甲基-2-硝基-1,3-丙二醇4.14g(40mmol)，雷尼镍800mg，4ml浓氨水，80ml甲醇置于容积为250毫升的单口圆底烧瓶中，30℃加氢16小时。过滤，滤渣30ml甲醇洗涤两次，合并有机相，旋蒸得到2-氨基-2-丁氧甲基-1,3-丙二醇白色固体3.3g，产率为92％；C 8H 19NO 3，MS(ES+)m/z：178.1(M+H) +。
步骤(3)：2，2’，2”，2’”-(5，5’-(1-丁氧基-3-羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸八甲酯的合成。称量2，2’-(5-(溴甲基)-1，3-亚苯基)双(2，1-乙烷二基)膦酸四甲酯972mg(2.2mmol)，2-氨基-2-丁氧甲基-1,3-丙二醇178mg(1.0mmol)，无水碳酸钾304mg(2.2mmol)， 10ml乙腈置于容积为50毫升的单口圆底烧瓶中，油浴中60℃加热磁力搅拌24小时。反应液冷却，过滤，收集滤液，滤渣用10ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到2，2’，2”，2’”-(5，5’-(1-丁氧基-3-羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸八甲酯无色液体380mg，产率为42％；C 38H 67NO 15P 4，MS(ES+)m/z：902.3(M+H) +。
步骤(4)：2，2’，2”，2’”-(5，5’-(1-丁氧基-3-羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸钠的合成。称量2，2’，2”，2’”-(5，5’-(1-丁氧基-3-羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸八甲酯380mg(0.42mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌24小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2，2’，2”，2’”-(5，5’-(1-丁氧基-3-羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(苯烷-5，3，1-三基))四(乙烷-2，1-二基)四膦酸钠结晶水合白色固体180mg，产率41％；C 30H 43NNa 8O 15P 4·xH 2O，MS(ES+)m/z：790.2(M+H) +。
实施例11：2，2’-(5-((1-丁氧基-3-羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000039
步骤(1)：2，2’-(5-((1-丁氧基-3-羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸甲酯的合成。称量2，2’-(5-(溴甲基)-1，3-亚苯基)双(2，1-乙烷二基)膦酸四甲酯662mg(1.5mmol)，2-氨基-2-丁氧甲基-1,3-丙二醇533mg(3.0mmol)，无水碳酸钾304mg(2.2mmol)，10ml乙腈置于容积为50毫升的单口圆底烧瓶中，油浴中60℃加热磁力搅拌24小时。反应液冷却，过滤，收集滤液，滤渣用10ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到2，2’-(5-((1-丁氧基-3-羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸甲酯无色液体567mg，产率为70％；C 23H 43NO 9P 2，MS(ES+)m/z：540.2(M+H) +。
步骤(2)：2，2’-(5-((1-丁氧基-3-羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸钠的合成。称量2，2’-(5-((1-丁氧基-3-羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸甲酯220mg (0.407mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌24小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2，2’-(5-((1-丁氧基-3-羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-1，2-亚苯基)二(乙烷-2，1-二基)二膦酸钠结晶水合白色固体160mg，产率62％；C 19H 31NNa 4O 9P 2·xH 2O，MS(ES+)m/z：484.2(M+H) +。
实施例12：(6，6’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(6,3-亚吡啶基))二(亚甲基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000040
步骤(1)：5-(溴甲基)吡啶甲酸甲酯的合成。称量5-(甲基)吡啶甲酸甲酯7.56g(50.0mmol)，N-溴代琥珀酰亚胺9.79g(55mmol)，100ml四氯化碳置于容积为500毫升的单口圆底烧瓶中，油浴中90℃加热磁力搅拌10分钟，加入过氧化二苯甲酰650mg(2.5mmol)。反应液继续回流2小时。冷却，加入100ml二氯甲烷，100ml水洗，5％碳酸氢钠100ml洗涤两次，100ml水洗，干燥，过滤，旋干，得到粗品。硅胶柱层析提纯得到5-(溴甲基)吡啶甲酸甲酯粘稠液体8.05g，产率为70％；C 8H 8BrNO 2，MS(ES+)m/z：252(M+Na) +。
步骤(2)：5-((二乙氧基磷酰基)甲基)吡啶甲酸甲酯的合成。称量5-(溴甲基)吡啶甲酸甲酯8.05g(35.0mol)，亚磷酸三乙酯8.35g(50mmol)置于容积为100毫升的单口圆底烧瓶中，油浴中90℃加热磁力搅拌3小时。反应液冷却，旋蒸得到粘稠液体，再经过柱层析纯化得到粘稠液体5-((二乙氧基磷酰基)甲基)吡啶甲酸甲酯4.02g，产率为40％；C 12H 18NO 5P，MS(ES+)m/z：288.1(M+H) +。
步骤(3)：(6-(羟甲基)吡啶-3-基)甲基膦酸二乙酯的合成。称量5-((二乙氧基磷酰基)甲基)吡啶甲酸甲酯3.75g(13.1mmol)，50ml无水四氢呋喃置于容积为250毫升的三口圆底烧瓶中，冰水浴中磁力搅拌下滴加1M氢化铝锂15.6ml(15.6mmol)。反应液0℃反应2小时。水冷却下加入十水合硫酸钠固体10g淬灭反应，过滤，滤渣50ml四氢呋喃洗涤两次，合并有机相，无水硫酸钠，过滤，旋干得到粗品。再经过柱层析纯化得到粘稠液体(6-(羟甲基)吡啶-3-基)甲基膦酸二乙酯2.59g，产率为76％；C 11H 18NO 4P，MS(ES+)m/z：260.1(M+H) +。
步骤(4)：(6-(溴甲基)吡啶-3-基)甲基膦酸二乙酯的合成。称量(6-(羟甲基)吡啶-3-基)甲基膦酸二乙酯2.25g(8.7mmol)，50ml二氯甲烷置于容积为250毫升的单口圆底烧瓶中，冰水浴中0℃磁力搅拌下加入三溴化磷4.72g(17.4mmol)，反应液0℃搅拌3小时。旋干，加入30g冰中，5％碳酸氢钠调节至中性，60ml二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，低温旋干得到粘稠液体。石油醚二氯甲烷混合液洗涤得到粘稠液体(6-(溴甲基)吡啶-3-基)甲基膦酸二乙酯1.6g，产率为57％；C 11H 17BrNO 3P，MS(ES+)m/z：322.0(M+H) +。
步骤(5)：(6，6’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(6,3-亚吡啶基))二(亚甲基)二膦酸乙酯的合成。称量(6-(溴甲基)吡啶-3-基)甲基膦酸二乙酯1.5g(4.66mmol)，三羟甲基氨基甲烷257mg(2.12mmol)，无水碳酸钾645mg(4.66mmol)，15ml乙腈置于容积为50毫升的单口圆底烧瓶中，油浴中40℃加热磁力搅拌16小时。反应液冷却，过滤，收集滤液，滤渣用30ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到(6，6’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(6,3-亚吡啶基))二(亚甲基)二膦酸乙酯无色液体320mg，产率为24％；C 26H 43N 3O 9P 2，MS(ES+)m/z：604.2(M+H) +。
步骤(6)：(6，6’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(6,3-亚吡啶基))二(亚甲基)二膦酸钠的合成。称量(6，6’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(6,3-亚吡啶基))二(亚甲基)二膦酸乙酯300mg(0.50mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌16小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到(6，6’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(6,3-亚吡啶基))二(亚甲基)二膦酸钠结晶水合白色固体50mg，产率15％；C 18H 23N 3Na 4O 9P 2·xH 2O，MS(ES+)m/z：492.1(M+H) +。
实施例13：1，1’-(4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(丙烷-2,1-二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000041
步骤(1)：1-(4-(溴甲基)苯基)丙烷-2-基膦酸二乙酯的合成。称量乙基膦酸二乙酯1.66g(10.0mol)，40ml干燥四氢呋喃置于容积为250毫升的三口圆底烧瓶中，磁力搅拌下干冰丙酮浴中缓慢滴加4.0ml正丁基锂正己烷溶液(10.0mmol，2.5M)，滴加时间2分钟。在-45℃继续搅拌30分钟。-78℃，滴加1,4-二(溴甲基)苯2.64g(10.0mol)的干燥四氢呋喃溶液10ml，-45℃继续搅拌1小时。立刻用磷酸二氢钾溶液(1M，40ml)淬灭反应并放置室温过夜。混合物分液，水相用40ml二氯甲烷萃取3次。合并有机相，无水硫酸钠干燥，过滤，旋干。残余物柱层析纯化得到1.2g黄色油状1-(4-(溴甲基)苯基)丙烷-2-基膦酸二乙酯，产率为34％；C 14H 22BrO 3P，MS(ES+)m/z：349.0(M+H) +。
步骤(2)：1，1’-(4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(丙烷-2,1-二基)二膦酸乙酯的合成。称量1-(4-(溴甲基)苯基)丙烷-2-基膦酸二乙酯1.2g(3.45mmol)，三羟甲基氨基甲烷190mg(1.57mmol)，无水碳酸钾476mg(3.45mmol)，10ml乙腈置于容积为50毫升的单口圆底烧瓶中，油浴中60℃加热磁力搅拌24小时。反应液冷却，过滤，收集滤液，滤渣用10ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到1，1’-(4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(丙烷-2,1-二基)二膦酸乙酯无色液体672mg，产率为65％；C 32H 53NO 9P 2，MS(ES+)m/z：658.3(M+H) +。
步骤(3)：1，1’-(4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(丙烷-2,1-二基)二膦酸钠的合成。称量1，1’-(4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(丙烷-2,1-二基)二膦酸乙酯672mg(1.02mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌24小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到1，1’-(4，4’-(1，3-二羟基-2-(羟甲基)丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(丙烷-2,1-二基)二膦酸钠结晶水合白色固体514mg，产率72％；C 24H 33NNa 4O 9P 2·xH 2O，MS(ES+)m/z：546.2(M+H) +。
实施例14：1，1’-(4，4’-(1，3-二羟基-2-甲基丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(乙烷-2,1-二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000042
步骤(1)：1，1’-(4，4’-(1，3-二羟基-2-甲基丙烷-2-基氮烷二基)二(亚甲基)二 (4,1-亚苯基))二(乙烷-2,1-二基)二膦酸甲酯的合成。称量4-(溴甲基)苯乙基膦酸二甲酯676mg(2.2mmol)，三羟甲基氨基甲烷121mg(1.00mmol)，无水碳酸钾304mg(2.2mmol)，10ml乙腈置于容积为50毫升的单口圆底烧瓶中，油浴中60℃加热磁力搅拌24小时。反应液冷却，过滤，收集滤液，滤渣用10ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到1，1’-(4，4’-(1，3-二羟基-2-甲基丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(乙烷-2,1-二基)二膦酸甲酯无色液体380mg，产率为68％；C 26H 41NO 8P 2，MS(ES+)m/z：558.2(M+H) +。
步骤(2)：1，1’-(4，4’-(1，3-二羟基-2-甲基丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(乙烷-2,1-二基)二膦酸钠的合成。称量1，1’-(4，4’-(1，3-二羟基-2-甲基丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(乙烷-2,1-二基)二膦酸甲酯380mg(0.68mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌24小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到1，1’-(4，4’-(1，3-二羟基-2-甲基丙烷-2-基氮烷二基)二(亚甲基)二(4,1-亚苯基))二(乙烷-2,1-二基)二膦酸钠结晶水合白色固体337mg，产率74％；C 22H 29NNa 4O 8P 2·xH 2O，MS(ES+)m/z：502.2(M+H) +。
实施例15：2-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)丙烷-1,3-二基二膦酸钠的合成
Figure PCTCN2019079492-appb-000043
步骤(1)：3-溴-2-(溴甲基)丙酸甲酯的合成。称量3-溴-2-(溴甲基)丙酸12.3g(50.0mol)，无水碳酸钾6.9g(50mmol)，100ml置于容积为250毫升的单口圆底烧瓶中，滴加碘甲烷10.65g(75mmol)，20℃磁力搅拌3小时。反应液过滤，滤渣50ml二氯甲烷洗涤，合并有机相，旋蒸得到粘稠液体3-溴-2-(溴甲基)丙酸甲酯11.7g，产率为90％；C 5H 8Br 2O 2，MS(ES+)m/z：281.0(M+Na) +。
步骤(2)：3-(二乙氧基磷酰基)-2-((二乙氧基磷酰基)甲基)丙酸甲酯的合成。称量3-溴-2-(溴甲基)丙酸甲酯11.0g(42.5mol)，亚磷酸三乙酯21.2g(127mmol)置于容积为100毫升的单口圆底烧瓶中，油浴中120℃加热磁力搅拌3小时。反应液冷却，旋蒸得 到粘稠液体，再经过柱层析纯化得到粘稠液体3-(二乙氧基磷酰基)-2-((二乙氧基磷酰基)甲基)丙酸甲酯7.96g，产率为50％；C 13H 28O 8P 2，MS(ES+)m/z：375.1(M+H) +。
步骤(3)：2-(羟甲基)丙烷-1,3-二基二膦酸四乙酯的合成。称量3-(二乙氧基磷酰基)-2-((二乙氧基磷酰基)甲基)丙酸甲酯7.5g(20.0mmol)，100ml无水四氢呋喃置于容积为500毫升的三口圆底烧瓶中，冰水浴中磁力搅拌下滴加1M氢化铝锂24ml(24mmol)。反应液0℃反应2小时。水冷却下加入十水合硫酸钠固体15g淬灭反应，过滤，滤渣50ml四氢呋喃洗涤两次，合并有机相，无水硫酸钠，过滤，旋干得到粗品。再经过柱层析纯化得到粘稠液体2-(羟甲基)丙烷-1,3-二基二膦酸四乙酯4.50g，产率为65％；C 12H 28O 7P 2，MS(ES+)m/z：347.1(M+H) +。
步骤(4)：2-(溴甲基)丙烷-1,3-二基二膦酸四乙酯的合成。称量2-(羟甲基)丙烷-1,3-二基二膦酸四乙酯4.3g(12.4mmol)，80ml二氯甲烷置于容积为250毫升的单口圆底烧瓶中，冰水浴中0℃磁力搅拌下加入三溴化磷5.04g(18.6mmol)，反应液0℃搅拌3小时。旋干，加入40g冰中，5％碳酸氢钠调节至中性，80ml二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，旋干得到粗品柱层析纯化得到粘稠液体2-(溴甲基)丙烷-1,3-二基二膦酸四乙酯3.1g，产率为61％；C 12H 27BrO 6P 2，MS(ES+)m/z：409.0(M+H) +。
步骤(5)：2-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)丙烷-1,3-二基二膦酸四乙酯的合成。称量2-(溴甲基)丙烷-1,3-二基二膦酸四乙酯614mg(1.50mmol)，三羟甲基氨基甲烷363mg(3.00mmol)，无水碳酸钾207mg(1.5mmol)，30ml乙腈置于容积为100毫升的单口圆底烧瓶中，油浴中80℃加热磁力搅拌16小时。反应液冷却，过滤，收集滤液，滤渣用30ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到2-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)丙烷-1,3-二基二膦酸四乙酯无色液体276mg，产率为41％；C 16H 37NO 9P 2，MS(ES+)m/z：450.2(M+H) +。
步骤(6)：2-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)丙烷-1,3-二基二膦酸钠的合成。称量2-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)丙烷-1,3-二基二膦酸四乙酯276mg(0.61mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌16小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)丙烷-1,3-二基二膦酸钠结晶水合白色固体220mg，产率72％；C 8H 17NNa 4O 9P 2·xH 2O，MS(ES+)m/z：338.1(M+H) +。
实施例16：1-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)甲烷-1,1,1-三甲基膦酸钠的合成
Figure PCTCN2019079492-appb-000044
步骤(1)：1-(溴甲基)甲烷-1，1，1-三甲基膦酸乙酯的合成。称量四溴季戊醇7.76g(20.0mol)，亚磷酸三乙酯13.3g(80.0mmol)置于容积为100毫升的单口圆底烧瓶中，油浴中120℃加热磁力搅拌4小时。反应液冷却，旋蒸得到粘稠液体，再经过柱层析纯化得到粘稠液体1-(溴甲基)甲烷-1，1，1-三甲基膦酸乙酯5.60g，产率为50％；C 17H 38BrO 9P 3，MS(ES+)m/z：559.1(M+H) +。
步骤(2)：1-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)甲烷-1,1,1-三甲基膦酸乙酯的合成。称量1-(溴甲基)甲烷-1，1，1-三甲基膦酸乙酯2.7g(4.83mmol)，三羟甲基氨基甲烷726mg(6.0mmol)，无水碳酸钾690mg(5.0mmol)，80ml乙腈置于容积为250毫升的单口圆底烧瓶中，油浴中80℃加热磁力搅拌16小时。反应液冷却，过滤，收集滤液，滤渣用60ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到1-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)甲烷-1,1,1-三甲基膦酸乙酯无色液体520mg，产率为18％；C 21H 48NO 12P 3，MS(ES+)m/z：600.2(M+H) +。
步骤(3)：1-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)甲烷-1,1,1-三甲基膦酸钠的合成。称量1-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)甲烷-1,1,1-三甲基膦酸乙酯500mg(0.83mmol)，10ml浓盐酸置于容积为50毫升的单口圆底烧瓶中，油浴中105℃加热磁力搅拌24小时。反应液冷却，旋蒸得到固体，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到1-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)甲烷-1,1,1-三甲基膦酸钠结晶水合白色固体210mg，产率39％；C 9H 18NNa 6O 12P 3·xH 2O，MS(ES+)m/z：432.1(M+H) +。
实施例17：2,2’-(5-(2-(2-(1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)乙氧基)乙氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000045
步骤(1)：5-苄氧基间苯二甲酸二甲酯的合成。称量5-羟基间苯二甲酸二甲酯21.02g(100mol)，100ml干燥N,N-二甲基甲酰胺置于容积为500毫升的三口圆底烧瓶中，磁力搅拌下加入无水碳酸钾20.7g(150mmol)和溴苄25.7g(150mmol)。室温搅拌过夜。反应液倒入500ml冰水中，200ml乙酸乙酯萃取2次，合并有机相，200ml水洗，200ml饱和食盐水洗，无水硫酸钠干燥，过滤，旋干得到粗品，柱层析纯化得到27g油状5-苄氧基间苯二甲酸二甲酯，产率为90％；C 17H 16O 5，MS(ES+)m/z：323.1(M+Na) +。
步骤(2)：(5-(苄氧基)-1，3-亚苯基)二甲醇的合成。称量5-苄氧基间苯二甲酸二甲酯27g(90.0mmol)，200ml无水四氢呋喃置于容积为1000毫升的三口圆底烧瓶中，冰水浴中0℃缓慢滴加1M氢化铝锂四氢呋喃溶液198ml。反应液0-20℃磁力搅拌2小时。反应液冰水浴冷却，小心分批加入50g十水硫酸钠淬灭反应。过滤，收集滤液，滤渣用200ml二氯甲烷洗涤两次。合并滤液，干燥，旋蒸得到粘稠液体(5-(苄氧基)-1，3-亚苯基)二甲醇20.2g，产率为92％；C 15H 16O 3，MS(ES+)m/z：267.1(M+Na) +。
步骤(3)：1-(苄氧基)-3，5-二(溴甲基)苯的合成。称量(5-(苄氧基)-1，3-亚苯基)二甲醇20.2g(82.7mmol)，200ml无水二氯甲烷置于容积为1000毫升的三口圆底烧瓶中，冰水浴中0℃缓慢滴加三溴化磷67.2g(248mmol)。反应液0-20℃磁力搅拌2小时。反应液倒入500g冰中，200ml二氯甲烷萃取两次，合并有机相，200ml水洗，干燥，旋蒸得到淡黄色固体1-(苄氧基)-3，5-二(溴甲基)苯27.5g，产率为89％；C 15H 14Br 2O，MS(ES+)m/z：391.0(M+Na) +。
步骤(4)：2,2’-(5-(苄氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯的合成。称量甲基膦酸二甲酯23.06g(186mol)，250ml干燥四氢呋喃置于容积为1000毫升的三口圆底烧瓶中，磁力搅拌下干冰丙酮浴中缓慢滴加74.4ml正丁基锂正己烷溶液(186mmol，2.5M)，滴加时间30分钟。在-78℃继续搅拌30分钟。-78℃，滴加1-(苄氧基)-3，5-二 (溴甲基)苯27.5g(74.3mol)的干燥四氢呋喃溶液100ml，-78℃继续搅拌2小时。立刻用磷酸二氢钾溶液(1M，100ml)淬灭反应并放置室温过夜。混合物分液，水相用200ml二氯甲烷萃取3次。合并有机相，无水硫酸钠干燥，过滤，旋干。残余物柱层析纯化得到25.4g无色油状2,2’-(5-(苄氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯，产率为75％；C 21H 30O 7P 2，MS(ES+)m/z：479.2(M+Na) +。
步骤(5)：2,2’-(5-羟基-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯的合成。称量2,2’-(5-(苄氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯25.4g(55.7mol)，10％钯碳1g，250ml乙醇置于容积为1000毫升的三口圆底烧瓶中，磁力搅拌下20℃加H2反应18小时。过滤，旋干得到19.4g黄色固体2,2’-(5-羟基-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯，产率为95％；C 14H 24O 7P 2，MS(ES+)m/z：389.1(M+Na) +。
步骤(6)：2,2’-(5-(2-(2-溴乙氧基)乙氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯的合成。称量2,2’-(5-羟基-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯1.83g(5.0mol)，1-溴-2-(2-乙氧基)乙烷2.32g(10.0mmol)，无水碳酸钾1.38g(10.0mmol)，20ml无水N,N-二甲基甲酰胺置于容积为100毫升的单口圆底烧瓶中，磁力搅拌下60℃反应18小时。反应液倒入120ml冰水中，120ml乙酸乙酯萃取两次，合并有机相，无水硫酸钠干燥过滤，旋干。粗品柱层析提纯得到1.47g粘稠液体2,2’-(5-(2-(2-溴乙氧基)乙氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯，产率为57％；C 18H 31BrO 8P 2，MS(ES+)m/z：517.1(M+H) +。
步骤(7)：2,2’-(5-(2-(2-(1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)乙氧基)乙氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯的合成。称量2,2’-(5-(2-(2-溴乙氧基)乙氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯1.35g(2.6mol)，三羟甲基氨基甲烷726mg(6.0mmol)，无水碳酸钾414mg(3.0mmol)，80ml乙腈置于容积为250毫升的单口圆底烧瓶中，油浴中80℃加热磁力搅拌16小时。反应液冷却，过滤，收集滤液，滤渣用60ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到2,2’-(5-(2-(2-(1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)乙氧基)乙氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯无色液体914mg，产率为63％；C 22H 41NO 11P 2，MS(ES+)m/z：558.2(M+H) +。
步骤(8)：2,2’-(5-(2-(2-(1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)乙氧基)乙氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠的合成。称量2,2’-(5-(2-(2-(1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)乙氧基)乙氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯860mg(1.54mmol)，10ml干燥二氯甲烷置于容积为50毫升的单口圆底 烧瓶中，冰水浴中0℃磁力搅拌氮气保护滴加3ml三甲基溴硅烷。1小时内反应液缓慢升温至20℃。继续搅拌6小时。旋蒸得到粘稠液体，加入10ml二氯甲烷和5ml甲醇，20℃搅拌30分钟，旋干，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2,2’-(5-(2-(2-(1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)乙氧基)乙氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠结晶水合白色固体236mg，产率24％；C 18H 29NNa 4O 11P 2·xH 2O，MS(ES+)m/z：502.2(M+H) +。
实施例18：2,2’-(5-(2-氨基-3-羟基-2-(羟甲基)丙氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000046
步骤(1)：2-甲基-4,4-二羟甲基-4,5-二氢噁唑的合成。称量三羟甲基氨基甲烷5.0g(41.3mmol)，N,N-二甲基甲酰胺50ml，9.1ml原乙酸三乙酯，N,N-二异丙基乙胺7.2ml置于容积为250毫升的单口圆底烧瓶中，120℃搅拌8小时。旋去溶剂，加入100ml石油醚，固体析出，收集固体得到2-甲基-4,4-二羟甲基-4,5-二氢噁唑淡黄色固体4.31g，产率为72％；C 6H 11NO 3，MS(ES+)m/z：146.1(M+H) +。
步骤(2)：2,2’-(5–((4-(羟甲基)-2-甲基-4,5-二氢噁唑4-基)甲氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯的合成。称量三苯基膦576mg(2.2mmol)，40m干燥甲苯置于容积为250毫升的三口圆底烧瓶中，冰水浴中0℃缓慢滴加偶氮二甲酸二乙酯383mg(2.2mmol)。冰水浴中继续搅拌30分钟后加入2,2’-(5–羟基-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯732mg(2.0mmol)和2-甲基-4,4-二羟甲基-4,5-二氢噁唑436mg(3.0mmol)。反应液加热回流16小时。旋去甲苯，粗品柱层析提纯得到2,2’-(5–((4-(羟甲基)-2-甲基-4,5-二氢噁唑4-基)甲氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯粘稠液体325mg，产率为33％；C 20H 33NO 9P 2，MS(ES+)m/z：494.2(M+H) +。
步骤(3)：2,2’-(5-(2-氨基-3-羟基-2-(羟甲基)丙氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠的合成。称量2,2’-(5–((4-(羟甲基)-2-甲基-4,5-二氢噁唑4-基)甲氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯325mg(0.67mmol)，10ml 干燥二氯甲烷置于容积为50毫升的单口圆底烧瓶中，冰水浴中0℃磁力搅拌氮气保护滴加3ml三甲基溴硅烷。1小时内反应液缓慢升温至20℃。继续搅拌6小时。旋蒸得到粘稠液体，加入2ml无水乙醇，6N盐酸水溶液2ml，油浴中70℃加热磁力搅拌1小时。反应液冷却，旋蒸得到粘稠液体，加入10ml二氯甲烷和5ml甲醇，20℃搅拌30分钟，旋干，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2,2’-(5-(2-氨基-3-羟基-2-(羟甲基)丙氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠结晶水合白色固体82mg，产率22％；C 14H 21NNa 4O 9P 2·xH 2O，MS(ES+)m/z：414.1(M+H) +。
实施例19：2,2’-(5-(4-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000047
步骤(1)：(3,5-二(2-(二甲氧基磷酰)乙基)苯基)(2,4,6-三甲苯基)碘鎓三氟甲磺酸盐的合成。称量间氯过氧苯甲酸759mg(4.4mmol)，40ml无水二氯甲烷置于容积为50毫升的干燥单口圆底烧瓶中，加入2,2’-(5–碘-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯1.90g(4.0mmol)和均三甲苯5.29g(4.4mmol)。冰水浴下缓慢滴加三氟甲磺酸1.02g(6.8mmol)。反应液20℃搅拌2小时。低温旋去二氯甲烷，加入100ml乙醚，过滤，收集固体，得到(3,5-二(2-(二甲氧基磷酰)乙基)苯基)(2,4,6-三甲苯基)碘鎓三氟甲磺酸盐黄色固体2.74g，产率为92％；C 24H 34F 3IO 9P 2S，MS(ES+)m/z：595.1(M+) +。
步骤(2)：2,2’-(5-(4-(羟甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯的合成。称量(3,5-二(2-(二甲氧基磷酰)乙基)苯基)(2,4,6-三甲苯基)碘鎓三氟甲磺酸盐黄色固体1.30g(1.75mmol)，20m干燥二氯甲烷置于容积为100毫升的三口圆底烧瓶中，20℃滴加4-(羟甲基)苯酚282mg(2.27mmol)和N,N-二异丙基乙胺677mg(5.25mmol)的10ml。反应液20℃搅拌16小时。旋去二氯甲烷，粗品柱层析提纯得到2,2’-(5-(4-(羟 甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯粘稠液体620mg，产率为75％；C 21H 30O 8P 2，MS(ES+)m/z：473.1(M+H) +。
步骤(3)：2,2’-(5-(4-(溴甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯的合成。称量2,2’-(5-(4-(羟甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯620mg(1.31mmol)，10ml无水二氯甲烷置于容积为50毫升的三口圆底烧瓶中，冰水浴中0℃缓慢滴加三溴化磷710mg(2.62mmol)。反应液0-20℃磁力搅拌3小时。反应液倒入50g冰中，50ml二氯甲烷萃取两次，合并有机相，100ml水洗，干燥，旋蒸得到粘稠液体2,2’-(5-(4-(溴甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯652mg，产率为93％；C 21H 29BrO 7P 2，MS(ES+)m/z：535.1(M+H) +。
步骤(4)：2,2’-(5-(4-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯的合成。称量2,2’-(5-(4-(溴甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯652mg(1.22mol)，三羟甲基氨基甲烷484mg(4.0mmol)，无水碳酸钾207mg(1.5mmol)，20mlN,N-二甲基甲酰胺置于容积为50毫升的单口圆底烧瓶中，20℃磁力搅拌16小时。反应液过滤，收集滤液，滤渣用60ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到2,2’-(5-(4-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯无色液体506mg，产率为72％；C 25H 39NO 10P 2，MS(ES+)m/z：576.2(M+H) +。
步骤(5)：2,2’-(5-(4-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠的合成。称量2,2’-(5-(4-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯506mg(0.878mmol)，10ml干燥二氯甲烷置于容积为50毫升的单口圆底烧瓶中，冰水浴中0℃磁力搅拌氮气保护滴加3ml三甲基溴硅烷。1小时内反应液缓慢升温至20℃。继续搅拌6小时。旋蒸得到粘稠液体，加入10ml二氯甲烷和5ml甲醇，20℃搅拌30分钟，旋干，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2,2’-(5-(4-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠结晶水合白色固体215mg，产率37％；C 21H 27NNa 4O 10P 2·xH 2O，MS(ES+)m/z：520.1(M+H) +。
实施例20：2,2’-(4’-(2-氨基-3-羟基-2-(羟甲基)丙氧基)连苯-3,5-二基)二(乙烷-2,1-二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000048
步骤(1)：2,2’-(4’-羟基连苯-3,5-二基)二(乙烷-2,1-二基)二膦酸甲酯的合成。称量2,2’-(5–碘-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸四甲酯954mg(2.0mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯146mg(0.20mmol)，无水碳酸钠424mg(4.0mmol)，10ml乙腈，1ml水置于容积为50毫升的单口圆底烧瓶中，20℃搅拌5分钟。加入N,N-二异丙基乙胺413mg(3.2mmol)，4-羟基苯硫酚404mg(3.2mmol)。反应液100℃搅拌8小时。旋去溶剂，粗品柱层析提纯得到2,2’-(4’-羟基连苯-3,5-二基)二(乙烷-2,1-二基)二膦酸甲酯粘稠液体567mg，产率为64％；C 20H 28O 7P 2S，MS(ES+)m/z：443.1(M+H) +。
步骤(2)：2,2’-(4’-((4-(羟甲基)-2-甲基-4,5-二氢噁唑4-基)甲氧基)连苯-3,5-二基)二(乙烷-2,1-二基)二膦酸甲酯的合成。称量三苯基膦369mg(1.41mmol)，30m干燥甲苯置于容积为250毫升的三口圆底烧瓶中，冰水浴中0℃缓慢滴加偶氮二甲酸二乙酯245mg(1.41mmol)。冰水浴中继续搅拌30分钟后加入2,2’-(4’-羟基连苯-3,5-二基)二(乙烷-2,1-二基)二膦酸甲酯567mg(1.28mmol)和2-甲基-4,4-二羟甲基-4,5-二氢噁唑279mg(1.92mmol)。反应液加热回流16小时。旋去甲苯，粗品柱层析提纯得到2,2’-(4’-((4-(羟甲基)-2-甲基-4,5-二氢噁唑4-基)甲氧基)连苯-3,5-二基)二(乙烷-2,1-二基)二膦酸甲酯粘稠液体299mg，产率为41％；C 26H 37NO 9P 2，MS(ES+)m/z：570.2(M+H) +。
步骤(3)：2,2’-(4’-(2-氨基-3-羟基-2-(羟甲基)丙氧基)连苯-3,5-二基)二(乙烷-2,1-二基)二膦酸钠的合成。称量2,2’-(4’-((4-(羟甲基)-2-甲基-4,5-二氢噁唑4-基)甲氧基)连苯-3,5-二基)二(乙烷-2,1-二基)二膦酸甲酯299mg(0.525mmol)，10ml干燥二氯甲烷置于容积为50毫升的单口圆底烧瓶中，冰水浴中0℃磁力搅拌氮气保护滴加3ml三甲基溴硅烷。1小时内反应液缓慢升温至20℃。继续搅拌6小时。旋蒸得到粘稠液体，加入2ml无水乙醇，6N盐酸水溶液2ml，油浴中70℃加热磁力搅拌1小时。反应液冷却，旋蒸得到粘稠液体，加入10ml二氯甲烷和5ml甲醇，20℃搅拌30分钟，旋干，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2,2’-(4’- (2-氨基-3-羟基-2-(羟甲基)丙氧基)连苯-3,5-二基)二(乙烷-2,1-二基)二膦酸钠结晶水合白色固体142mg，产率43％；C 20H 25NNa 4O 9P 2·xH 2O，MS(ES+)m/z：490.1(M+H) +。
实施例21：2,2’-(5-(2,6-二(2-(双羟基磷酰)乙基)-4-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000049
步骤(1)：4-(苄氧基)-3,5-二溴苯甲酸甲酯的合成。称量4-羟基-3,5-二溴苯甲酸甲酯6.2g(20.0mmol)，无水碳酸钾4.14g(30.0mmol)，30ml无水N,N-二甲基甲酰胺置于容积为100毫升的单口圆底烧瓶中。反应液20℃搅拌16小时。反应液倒入200ml冰水中，100ml乙酸乙酯萃取两次，合并有机相，200ml水洗，200ml饱和食盐水洗，无水硫酸钠干燥，旋去溶剂，粗品柱层析提纯得到4-(苄氧基)-3,5-二溴苯甲酸甲酯粘稠液体6.78g，产率为85％；C 15H 12Br 2O 3，MS(ES+)m/z：421.0(M+Na) +。
步骤(2)：4-(苄氧基)-3,5-二(2-(双乙氧基磷酰)乙烯基)苯甲酸甲酯的合成。称量4-(苄氧基)-3,5-二溴苯甲酸甲酯6.5g(16.3mmol)，乙烯基膦酸二乙酯8.03g(48.9mmol)，三乙胺6.59g(65.2mmol)，三(邻甲基苯基)膦496mg(1.63mmol)，醋酸钯183mg(0.82mmol)，100ml乙腈置于容积为250毫升的单口圆底烧瓶中，80℃氮气保护磁力搅拌16小时。旋蒸，粗品柱层析提纯得到4-(苄氧基)-3,5-二(2-(双乙氧基磷酰)乙烯基)苯甲酸甲酯粘稠液体6.18g，产率为67％；C 27H 36O 9P 2，MS(ES+)m/z：566.2(M+H) +。
步骤(3)：4-羟基-3,5-二(2-(双乙氧基磷酰)乙基)苯甲酸甲酯的合成。称量4-(苄氧基)-3,5-二(2-(双乙氧基磷酰)乙烯基)苯甲酸甲酯3.0g(5.30mmol)，10％钯碳300mg， 30ml乙醇置于容积为100毫升的单口圆底烧瓶中，20℃磁力搅拌加H 2反应16小时。过滤，旋蒸得到4-羟基-3,5-二(2-(双乙氧基磷酰)乙基)苯甲酸甲酯淡红色固体2.29g，产率为90％；C 20H 34O 9P 2，MS(ES+)m/z：481.2(M+H) +。
步骤(4)：2,2’-(2-羟基-5-(羟甲基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸乙酯的合成。称量4-羟基-3,5-二(2-(双乙氧基磷酰)乙基)苯甲酸甲酯2.7g(4.37mmol)，30ml无水四氢呋喃置于容积为100毫升的三口圆底烧瓶中，0℃磁力搅拌缓慢滴加1M四氢锂铝8.7ml(8.7mmol)。0-20℃反应2小时。加入5g十水硫酸钠淬灭反应，过滤，滤渣30ml二氯甲烷洗涤两次，合并有机相，旋蒸。粗品柱层析提纯得到2,2’-(2-羟基-5-(羟甲基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸乙酯淡红色固体1.34g，产率为68％；C 19H 34O 8P 2，MS(ES+)m/z：453.2(M+H) +。
步骤(5)：2,2’-(5-(2,6-二(2-(双乙氧基磷酰)乙基)-4-(羟甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯的合成。称量(3,5-二(2-(二甲氧基磷酰)乙基)苯基)(2,4,6-三甲苯基)碘鎓三氟甲磺酸盐黄色固体1.64g(2.21mmol)，20m干燥二氯甲烷置于容积为100毫升的三口圆底烧瓶中，20℃滴加2,2’-(2-羟基-5-(羟甲基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸乙酯1.20g(2.65mmol)和N,N-二异丙基乙胺685mg(5.3mmol)的10ml二氯甲烷溶液。反应液20℃搅拌16小时。旋去二氯甲烷，粗品柱层析提纯得到2,2’-(5-(2,6-二(2-(双乙氧基磷酰)乙基)-4-(羟甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯粘稠液体815mg，产率为46％；C 33H 56O 14P 4，MS(ES+)m/z：801.3(M+H) +。
步骤(6)：2,2’-(5-(2,6-二(2-(双乙氧基磷酰)乙基)-4-(溴甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯的合成。称量2,2’-(5-(2,6-二(2-(双乙氧基磷酰)乙基)-4-(羟甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯815mg(1.02mmol)，10ml无水二氯甲烷置于容积为50毫升的三口圆底烧瓶中，冰水浴中0℃缓慢滴加三溴化磷551mg(2.03mmol)。反应液0-20℃磁力搅拌3小时。反应液倒入50g冰中，50ml二氯甲烷萃取两次，合并有机相，100ml水洗，干燥，旋蒸得到粘稠液体2,2’-(5-(2,6-二(2-(双乙氧基磷酰)乙基)-4-(溴甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯764mg，产率为87％；C 33H 55BrO 13P 4，MS(ES+)m/z：863.2(M+H) +。
步骤(7)：2,2’-(5-(2,6-二(2-(双乙氧基磷酰)乙基)-4-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯的合成。称量2,2’-(5-(2,6-二(2-(双乙氧基磷酰)乙基)-4-(溴甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯764mg(0.884mol)，三羟甲基氨基甲烷424mg(3.5mmol)， 无水碳酸钾138mg(1.0mmol)，10mlN,N-二甲基甲酰胺置于容积为50毫升的单口圆底烧瓶中，20℃磁力搅拌16小时。反应液过滤，收集滤液，滤渣用60ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到2,2’-(5-(2,6-二(2-(双乙氧基磷酰)乙基)-4-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯无色液体543mg，产率为68％；C 37H 65NO 16P 4，MS(ES+)m/z：904.3(M+H) +。
步骤(8)：2,2’-(5-(2,6-二(2-(双羟基磷酰)乙基)-4-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠的合成。称量2,2’-(5-(2,6-二(2-(双乙氧基磷酰)乙基)-4-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯500mg(0.553mmol)，10ml干燥二氯甲烷置于容积为50毫升的单口圆底烧瓶中，冰水浴中0℃磁力搅拌氮气保护滴加3ml三甲基溴硅烷。1小时内反应液缓慢升温至20℃。继续搅拌16小时。旋蒸得到粘稠液体，加入10ml二氯甲烷和5ml甲醇，20℃搅拌30分钟，旋干，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2,2’-(5-(2,6-二(2-(双羟基磷酰)乙基)-4-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)苯氧基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠结晶水合白色固体97mg，产率18％；C 25H 33NNa 8O 16P 4·xH 2O，MS(ES+)m/z：736.1(M+H) +。
实施例22：2,2’-(5-(3-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-5-(2-(双羟基磷酰)乙基)苄基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠的合成
Figure PCTCN2019079492-appb-000050
步骤(1)：3-溴-5-(2-(双乙氧基磷酰)乙烯基)苯甲酸甲酯的合成。称量3-溴--5-碘苯甲酸甲酯6.82g(20.0mmol)，乙烯基膦酸二乙酯3.28g(20.0mmol)，三乙胺4.04g(40.0mmol)，三(邻甲基苯基)膦608mg(2.0mmol)，醋酸钯223mg(1.0mmol)，100ml乙腈置于容积为250毫升的单口圆底烧瓶中，80℃氮气保护磁力搅拌4小时。旋蒸，粗品柱层析提纯得到3-溴-5-(2-(双乙氧基磷酰)乙烯基)苯甲酸甲酯粘稠液体2.41g，产率为32％；C 14H 18BrO 5P，MS(ES+)m/z：399.0(M+Na) +。
步骤(2)：3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2基)-5-(2-(双乙氧基磷酰)乙烯基)苯甲酸甲酯的合成。称量3-溴-5-(2-(双乙氧基磷酰)乙烯基)苯甲酸甲酯2.2g(5.83mmol)，双联频哪醇硼酸酯2.22g(8.75mmol)，醋酸钾1.72g(17.5mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯213mg(0.29mmol)，40ml二氧六环置于容积为100毫升的单口圆底烧瓶中，85℃氮气保护磁力搅拌6小时。旋蒸，粗品柱层析提纯得到3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2基)-5-(2-(双乙氧基磷酰)乙烯基)苯甲酸甲酯1.86g，产率为75％；C 20H 30BO 7P，MS(ES+)m/z：447.2(M+Na) +。
步骤(3)：3-(3,5-二(2-(双甲氧基磷酰)乙基)苄基)-5-(2-(双乙氧基磷酰)乙烯基)苯甲酸甲酯的合成。称量3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2基)-5-(2-(双乙氧基磷酰)乙烯基)苯甲酸甲酯1.7g(4.01mmol)，2,2’-(5-(溴甲基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯1.95g(4.4mmol)，碳酸钾1.11g(8.02mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯293mg(0.40mmol)，30ml乙二醇二甲醚置于容积为100毫升的单口圆底烧瓶中，80℃氮气保护磁力搅拌18小时。旋蒸，粗品柱层析提纯得到3-(3,5-二(2-(双甲氧基磷酰)乙基)苄基)-5-(2-(双乙氧基磷酰)乙烯基)苯甲酸甲酯1.80g，产率为68％；C 29H 43O 11P 3，MS(ES+)m/z：683.2(M+Na) +。
步骤(4)：3-(3,5-二(2-(双甲氧基磷酰)乙基)苄基)-5-(2-(双乙氧基磷酰)乙基)苯甲酸甲酯的合成。称量3-(3,5-二(2-(双甲氧基磷酰)乙基)苄基)-5-(2-(双乙氧基磷酰)乙烯基)苯甲酸甲酯1.8g(2.72mmol)，10％钯碳180mg，30ml乙醇置于容积为100毫升的单口圆底烧瓶中，20℃磁力搅拌加H 2反应16小时。过滤，旋蒸得到3-(3,5-二(2-(双甲氧基磷酰)乙基)苄基)-5-(2-(双乙氧基磷酰)乙基)苯甲酸甲酯粘稠液体1.67g，产率为93％；C 29H 43O 11P 3，MS(ES+)m/z：685.2(M+H) +。
步骤(5)：2,2’-(5-(3-(羟甲基)-5-(2-(双乙氧基磷酰)乙基)苄基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯的合成。称量3-(3,5-二(2-(双甲氧基磷酰)乙基)苄基)-5-(2-(双乙氧基磷酰)乙基)苯甲酸甲酯1.67g(2.53mmol)，30ml无水四氢呋喃置于容积为100毫升的三口圆底烧瓶中，0℃磁力搅拌缓慢滴加1M四氢锂铝5.1ml(5.1mmol)。 0-20℃反应2小时。加入5g十水硫酸钠淬灭反应，过滤，滤渣30ml二氯甲烷洗涤两次，合并有机相，旋蒸。粗品柱层析提纯得到2,2’-(5-(3-(羟甲基)-5-(2-(双乙氧基磷酰)乙基)苄基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯粘稠液体1.22g，产率为76％；C 28H 45O 10P 3，MS(ES+)m/z：635.2(M+H) +。
步骤(6)：2,2’-(5-(3-(溴甲基)-5-(2-(双乙氧基磷酰)乙基)苄基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯的合成。称量2,2’-(5-(3-(羟甲基)-5-(2-(双乙氧基磷酰)乙基)苄基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯1.22(1.92mmol)，10ml无水二氯甲烷置于容积为50毫升的三口圆底烧瓶中，冰水浴中0℃缓慢滴加三溴化磷1.04g(3.84mmol)。反应液0-20℃磁力搅拌3小时。反应液倒入50g冰中，50ml二氯甲烷萃取两次，合并有机相，100ml水洗，干燥，旋蒸得到粘稠液体2,2’-(5-(3-(溴甲基)-5-(2-(双乙氧基磷酰)乙基)苄基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯1.14g，产率为85％；C 28H 44BrO 9P 3，MS(ES+)m/z：697.2(M+H) +。
步骤(7)：2,2’-(5-(3-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-5-(2-(双乙氧基磷酰)乙基)苄基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯的合成。称量2,2’-(5-(3-(溴甲基)-5-(2-(双乙氧基磷酰)乙基)苄基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯1.14g(1.63mol)，三羟甲基氨基甲烷594mg(4.90mmol)，无水碳酸钾225mg(1.63mmol)，15mlN,N-二甲基甲酰胺置于容积为50毫升的单口圆底烧瓶中，20℃磁力搅拌16小时。反应液过滤，收集滤液，滤渣用60ml二氯甲烷洗涤两次。合并滤液，旋蒸得到粘稠液体，再经过柱层析纯化得到2,2’-(5-(3-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-5-(2-(双乙氧基磷酰)乙基)苄基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯的合成无色液体842mg，产率为70％；C 32H 54NO 12P 3，MS(ES+)m/z：738.3(M+H) +。
步骤(8)：2,2’-(5-(3-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-5-(2-(双羟基磷酰)乙基)苄基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠的合成。称量2,2’-(5-(3-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-5-(2-(双乙氧基磷酰)乙基)苄基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸甲酯800mg(1.08mmol)，10ml干燥二氯甲烷置于容积为50毫升的单口圆底烧瓶中，冰水浴中0℃磁力搅拌氮气保护滴加3ml三甲基溴硅烷。1小时内反应液缓慢升温至20℃。继续搅拌16小时。旋蒸得到粘稠液体，加入10ml二氯甲烷和5ml甲醇，20℃搅拌30分钟，旋干，再经过树脂柱层析纯化冻干。固体溶解于纯水，2N氢氧化钠水溶液碱化，乙醇重结晶得到2,2’-(5-(3-((1，3-二羟基-2-(羟甲基)丙烷-2-基氨基)甲基)-5-(2-(双羟基磷酰)乙基)苄基)-1,3-亚苯基)二(乙烷-2,1-二基)二膦酸钠结晶水合白色固体221mg，产率25％；C 24H 32NNa 6O 12P 3·xH 2O，MS(ES+)m/z： 626.2(M+H) +。
实施例23 本发明化合物在肝癌细胞Hep3B2.1-7-Luc原位异种移植肿瘤模型中的药效学试验
1.细胞培养：Hep3B2.1-7-Luc细胞体外贴壁培养，培养条件为EMEM培养基加入1.5g/L碳酸氢钠，1.0mM丙酮酸钠，2ug/ml puromycin，加10％热灭活胎牛血清，100U/ml青霉素及100μg/ml链霉素37℃5％CO 2培养。一周两次传代处理。当细胞呈指数生长期时，收取细胞，计数，接种。
2.动物：BALB/c裸鼠小鼠，雌性，6－8周龄，体重18-22克。肿瘤接种:将1.25x10^6个Hep3B2.1-7-luc细胞的25uL细胞悬液加入50％Matrigel原位接种于每只小鼠的左肝小叶，缝合线缝合。细胞接种7天之后，小鼠用IVIS Lumina XR小动物成像仪进行成像，选取合适的信号强度的小鼠，用于药效实验，每组10只。
3.动物成像操作流程:
1)称取适量D-荧光素钾(luciferin)，用DPBS配制成15mg/ml的浓度，0.2um滤膜过滤除菌，避光-20℃保存。
2)用规格为25x 5/8”注射器，按小鼠体重10ul/g，单只小鼠注射150mg luciferin/kg.(如20g的小鼠，注射0.2ml)。
3)10-12分钟后，异氟烷麻醉。
4)将小鼠放置于成像系统盒中，腹部朝上，用于检测肿瘤细胞。
5)曝光时间范围在1分钟到1秒钟，成像结果通过成像软件，以光子数/秒表示，生物成像将于每周一次进行，并在实验结束前最后一次成像。
4.实验指标：实验指标是考察肿瘤生长是否可以被抑制、延缓或治愈。每周一次通过小动物成像仪IVIS Lumina XR，对小鼠进行成像，监测肿瘤生长情况。肿瘤信号以每秒的曝光光子数来判断。
5.数据分析：以实施例7化合物的数据为例，结果如图1所示，实施例7化合物有明显的抑制肿瘤生长作用。
实施例7化合物的药代实验结果如图2、3和下表1所示。
表1 BALB/c nude小鼠腹腔给予后各时间点血药浓度和参数
Figure PCTCN2019079492-appb-000051
Figure PCTCN2019079492-appb-000052
由图3可知，BALB/c nude小鼠腹腔给予本发明实施例7化合物的24小时后，药物化合物主要分布在小鼠的肝、肾、肺、肠、脾、前列腺等组织器官，提示本发明化合物尤其适用于肝癌、肾癌、前列腺癌、肺癌、结肠癌等癌症的治疗。
以上所述实施例仅表达了本发明的实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (12)

  1. 具有通式(I)的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，
    Figure PCTCN2019079492-appb-100001
    其中：L选自C1-C10的烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、烯基、炔基、含有N或O或S原子的3-15个碳原子直链或支链、含有N或O或S原子的1-15个碳原子直链或支链重复单元的直链或支链、串联双芳基、串联双杂芳基、串联芳基与杂芳基、通过N或O或S或
    Figure PCTCN2019079492-appb-100002
    相连接的双芳基和双杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    Y、Z分别独立地选自NR1、O、S、
    Figure PCTCN2019079492-appb-100003
    Figure PCTCN2019079492-appb-100004
    或为单键；
    D选自
    Figure PCTCN2019079492-appb-100005
    当D选为
    Figure PCTCN2019079492-appb-100006
    时，K选自：，
    Figure PCTCN2019079492-appb-100007
    其中，B选自
    Figure PCTCN2019079492-appb-100008
    当D选自
    Figure PCTCN2019079492-appb-100009
    时，K选为
    Figure PCTCN2019079492-appb-100010
    F为CR 10或单键；
    G选自
    Figure PCTCN2019079492-appb-100011
    R 1和R 2各自独立地选自氢、卤素、烷基、环烷基、羟基烷烃基、烷氧基烷基、烷氧基环烷基、环烷基烷基、烷基环烷基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代烷基、氰基、硫烷基、磺基、砜基、亚砜基、磷酸基、烷基膦酸基、芳基磷酸基、芳基膦酸基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代，或为空；
    R 3和R 4各自独立地选自氢、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基烷基、炔基烷基，所述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基烷基、炔基烷基，任选不取代或被一个或多个取代基所取代，所述取代基各自独立选自烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳香磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基、磷酸基、膦酸基、烷基磷酸基、烷基膦酸基、芳基磷酸基、芳基膦酸基；或者R 3和R 4连同二者所连接的N原子共同形成杂环基，所述杂环基为单环、双环或者三环，或者是稠环、桥环或螺环，所述杂环基包含至少一个N原子，或者包含1个或2个或3个任选于N、S和O的杂原子，所述杂环基不取代或者任选被一个或多个取代基所取代，所述的取代基各自独立地选自于由烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳香磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基、磷酸基、膦酸 基、烷基磷酸基、烷基膦酸基、芳基磷酸基、芳基膦酸基单独作为取代基或自由组合所形成的取代基；
    A 1,A 2各自独立地选自H、Li、Na、K、Cs和其对应的阳离子，或者A 1,A 2共同形成Ca、Mg、Al、Sc、Ti、Cr、Co、Fe、Ni、Cu、Zn、Cd、Hg和其各自对应的阳离子；
    E选自O原子或C(R 1R 2)；
    R 5、R 6各自独立地选自氢原子、卤素、烷基、烷氧基烷基、环烷基、烷氧基环烷基、羟基烷基、羟基环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；或R 5、R 6可形成3至8元环，该环可含有1至2个O、N、和/或S杂原子；
    R 7、R 8各自独立地选自氢原子、烷基、羟基烷基、环烷基、烷氧基烷基、烷氧基环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 9选自氢原子、卤素、烷烃基、烷氧基烷基、环烷基、烷氧基环烷基、羟基烷基、羟基环烷基、杂环基、芳基、杂芳基和酰基，所述烷烃基、烷氧基烷基、环烷基、烷氧基环烷基、羟基烷基、羟基环烷基、杂环基、芳基、杂芳基和酰基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 10选自氢原子、卤素、烷烃基、环烷基、杂环基、芳基、杂芳基，或为空，其中所述的烷烃基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 12选自氢原子、烷烃基、烷氧基烷基、环烷基、烷氧基环烷基、羟基烷基、羟基环烷基、杂环基、芳基、杂芳基、杂环基烷基、芳基烷基和杂芳基烷基，其中所述烷烃基、烷氧基烷基、环烷基、烷氧基环烷基、羟基烷基、羟基环烷基、杂环基、芳基、杂芳基、杂环基烷基、芳基烷基和杂芳基烷基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    n1选自0，1，2，3，4，5，6，7，8；
    n2选自1，2，3，4，5，6；
    n3选自1，2，3；
    n4选自0，1，2，3，4；
    n5选自0，1，2，3；
    n6选自1，2，3。
  2. 根据权利要求1所述的化合物，其特征在于，所述化合物为式(II)所示化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，
    Figure PCTCN2019079492-appb-100012
    其中：L选自C1-C10的烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、烯基、炔基、含有N或O或S原子的3-15个碳原子直链或支链、含有N或O或S原子的1-15个碳原子直链或支链重复单元的直链或支链、串联双芳基、串联双杂芳基、串联芳基与杂芳基、通过N或O或S或
    Figure PCTCN2019079492-appb-100013
    相连接的双芳基和双杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 1和R 2各自独立地选自氢、卤素、烷基、环烷基、羟基烷烃基、烷氧基烷基、烷氧基环烷基、环烷基烷基、烷基环烷基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代烷基、氰基、硫烷基、磺基、砜基、亚砜基、磷酸基、烷基膦酸基、芳基磷酸基、芳基膦酸基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    K选自：
    Figure PCTCN2019079492-appb-100014
    B选自
    Figure PCTCN2019079492-appb-100015
    A 1,A 2各自独立地选自H、Li、Na、K、Cs和其对应的阳离子，或者A1,A2共同形成Ca、Mg、Al、Sc、Ti、Cr、Co、Fe、Ni、Cu、Zn、Cd、H g和其各自对应的阳离子；
    E选自C(R 1R 2)；
    R 5、R 6各自独立地选自氢原子、卤素、烷基、烷氧基烷基、环烷基、烷氧基环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自 羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；或R 5、R 6可形成3至8元环，该环可含有1至2个O、N、和/或S杂原子；
    R 7、R 8各自独立地选自氢原子、烷基、羟基烷基、环烷基、烷氧基烷基、烷氧基环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 9选自氢原子、烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 10选自氢原子、卤素、烷基、环烷基、杂环基、芳基、杂芳基，或为空，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    n1选自0，1，2，3，4，5，6，7，8；
    n2选自1，2，3，4，5，6；
    n3选自1，2，3；
    n4选自0，1，2，3，4；
    n5选自0，1，2，3；
    n6选自1，2，3。
  3. 根据权利要求1所述的化合物，其特征在于，所述化合物为式(II)所示化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，其中，K为
    Figure PCTCN2019079492-appb-100016
    或E为O原子，
    Figure PCTCN2019079492-appb-100017
    R 3和R 4各自独立地选自氢、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，所述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，任选不取代或 被一个或多个取代基所取代，所述取代基各自独立选自烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳香磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基、磷酸基、膦酸基、烷基磷酸基、烷基膦酸基、芳基磷酸基、芳基膦酸基；或者R 3和R 4连同二者所连接的N原子共同形成杂环基，所述杂环基为单环、双环或者三环，或者是稠环、桥环或螺环，所述杂环基包含至少一个N原子，或者包含1个或2个或3个任选于N、S和O的杂原子，所述杂环基不取代或者任选被一个或多个取代基所取代，所述的取代基各自独立地选自于由烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳香磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基、磷酸基、膦酸基、烷基磷酸基、烷基膦酸基、芳基磷酸基、芳基膦酸基单独作为取代基或自由组合所形成的取代基。
  4. 根据权利要求1所述的化合物，其特征在于，所述化合物为式(III)所示化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，
    Figure PCTCN2019079492-appb-100018
    所述R 11选自氢、卤素、C1-C6烷基、C3-C8环烷基、羟基烷烃基、烷氧基烷基、烷氧基环烷基、环烷基烷基、烷基环烷基、烯基、炔基、氨基、羟基、烷氧基、环烷氧基、卤代烷基、氰基、硫烷基、磺基、砜基、亚砜基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。
  5. 根据权利要求1所述的化合物，其特征在于，所述化合物为式(IV)所示化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，
    Figure PCTCN2019079492-appb-100019
    其中，X 2选自NR1、O、S、
    Figure PCTCN2019079492-appb-100020
    和单键，当X为单键时表示芳基和芳基直接相连；
    R 11选自氢、卤素、C1-C6烷基、C3-C8环烷基、羟基烷烃基、烷氧基烷基、烷氧基环烷基、环烷基烷基、烷基环烷基、烯基、炔基、氨基、羟基、烷氧基、环烷氧基、卤代烷基、氰基、硫烷基、磺基、砜基、亚砜基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基可各自独立地被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。
  6. 根据权利要求1所述的化合物，其特征在于，所述通式(I)化合物包括：
    Figure PCTCN2019079492-appb-100021
    Figure PCTCN2019079492-appb-100022
    Figure PCTCN2019079492-appb-100023
    Figure PCTCN2019079492-appb-100024
    Figure PCTCN2019079492-appb-100025
    Figure PCTCN2019079492-appb-100026
    Figure PCTCN2019079492-appb-100027
    Figure PCTCN2019079492-appb-100028
  7. 一种药物组合物，其含有治疗有效量的权利要求1～6任意一项所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  8. 权利要求1～6任意一项所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，或权利要求7所述的药物组合物在制备预防和/或治疗癌症药物中的用途。
  9. 根据权利要求8所述的用途，其特征在于，所述癌症包含乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤、非小细胞肺癌、头颈癌、子宫癌、睾丸癌、输卵管癌、子宫内膜癌、阴道癌、外阴癌、直肠癌、结肠癌、肛门区癌、乳腺癌、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、尿道癌、阴茎癌、睾丸癌、淋巴癌、移行细胞癌、输尿管癌、肾细胞癌、肾盂癌、霍奇金病、非霍奇金淋巴瘤、软组织肉瘤、儿童实体瘤、淋巴细胞性淋巴瘤、中枢神经系统(CNS)肿瘤、原发性中枢神经系统淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、黑色素瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、慢性或急性白血病，和/或所述各种癌的组合。
  10. 权利要求1～6任意一项所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，或权利要求7所述的药物组合物在制备抑制癌症转移的药物中的用途。
  11. 权利要求1～6任意一项所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，或权利要求7所述的药物组合物在制备预防和/或治疗酸中毒引起的疾病的药物中的用途。
  12. 权利要求1～6任意一项所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐、或其前药分子，与至少一种另外的抗癌剂联用在制备治疗癌症或抑制癌症转移的药物中的用途。
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