CN113968867A - Camptothecin prodrug and application thereof - Google Patents
Camptothecin prodrug and application thereof Download PDFInfo
- Publication number
- CN113968867A CN113968867A CN202111327069.1A CN202111327069A CN113968867A CN 113968867 A CN113968867 A CN 113968867A CN 202111327069 A CN202111327069 A CN 202111327069A CN 113968867 A CN113968867 A CN 113968867A
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- CN
- China
- Prior art keywords
- cancer
- ring
- ethyl
- hydroxy
- heterocycle
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims abstract description 43
- 229940127093 camptothecin Drugs 0.000 title claims abstract description 39
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 title claims abstract description 38
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 229940002612 prodrug Drugs 0.000 title claims abstract description 30
- 239000000651 prodrug Substances 0.000 title claims abstract description 30
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 10
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 10
- -1 methoxy, ethoxy, propoxy, isopropoxy Chemical group 0.000 claims description 64
- 125000000623 heterocyclic group Chemical group 0.000 claims description 49
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 30
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 16
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 229910052805 deuterium Inorganic materials 0.000 claims description 15
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 14
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- 150000001555 benzenes Chemical group 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 10
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 8
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
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- 238000002360 preparation method Methods 0.000 claims description 7
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- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
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- JWZMLPVLGNVRKQ-UHFFFAOYSA-N (4-nitrophenyl)methyl hydrogen carbonate Chemical compound OC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 JWZMLPVLGNVRKQ-UHFFFAOYSA-N 0.000 claims description 4
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine group Chemical group NO AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 208000021309 Germ cell tumor Diseases 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
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- 229910019142 PO4 Inorganic materials 0.000 claims description 2
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
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- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
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- 102000004459 Nitroreductase Human genes 0.000 abstract description 15
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
Provides a camptothecin prodrug and application thereof in preparing antitumor drugs, and the camptothecin prodrug has the following general formula (I): MTT experiments show that the camptothecin prodrug has cytotoxicity only under the condition of nitroreductase and has low cytotoxicity in a culture solution without nitroreductase. Because the nitroreductase concentration in the tumor tissue is higher, the antitumor drug prepared from the camptothecin prodrug has the characteristic of lower toxicity
Description
Technical Field
The invention provides a novel camptothecin prodrug and application of the prodrug in preparation of antitumor drugs.
Technical Field
Malignant tumors are one of the common diseases threatening human health, and the tumor death rate is in the front of various diseases. The toxic and side effects of the existing clinical antitumor drugs are the outstanding problems which plague tumor chemotherapy. Improving the tumor treatment effect and simultaneously reducing the drug toxicity are important research subjects of the current tumor treatment drugs.
Camptothecin (CPT) and hydroxycamptothecin (hydroxycamptothecin) are alkaloids separated from camptotheca acuminata (camptotheca acuminata) of davidiaceae, which is a unique Chinese herb. The camptothecin is synthesized by merging A, B, C, D, E pentacyclic rings, wherein ring A, B is quinoline ring, ring C is pyrrole ring, ring D is pyridone, ring E is hexatomic alpha-hydroxy lactone ring, and the carbon atom at the 20-position of the hydroxyl is in S-configuration.
Camptothecin has strong cytotoxicity, and has good therapeutic effect on malignant tumors such as digestive tract tumor (such as gastric cancer, colon cancer, and rectal cancer), hepatocarcinoma, bladder cancer, leukemia, etc. But has high toxicity and poor water solubility. In order to solve the problem of water solubility, the lactone ring of the sodium salt is opened to prepare water-soluble hydroxy acid sodium salt for clinical application, but the activity of the sodium salt is only 1/10 of camptothecin, and the toxicity is greatly increased. The toxicity and water solubility problems of camptothecin have hindered its clinical use. Hydroxycamptothecin has lower toxicity than camptothecin, rarely causes hematuria and liver and kidney function injury, and is mainly used for treating intestinal cancer, liver cancer and leukemia clinically. However, hydroxycamptothecin, like camptothecin, has poor water solubility and is difficult to apply.
The action mechanism of camptothecin, namely acting on DNA topoisomerase I, is discovered in the late 80 s of the 20 th century, so that DNA replication, transcription and the like are hindered, and finally, DNA breakage is caused. The target of action of camptothecin is Topo I. However, camptothecin does not kill tumor cells by inhibiting the catalytic activity of Topo I, but reversibly binds to a DNA-TopoI cleavable complex formed by DNA and TopoI to form a DNA-TopoI I-CPT ternary complex, stabilizes the cleavable complex, prolongs the lifetime of the cleavable complex, and forms a "roadblock" (rad blocker). Thus, the single strand of DNA "encapsulated" by Topo I interferes with the replication of the growing DNA, and the result is a break in the DNA strand, eventually leading to apoptosis of the cell. The interaction of camptothecin compounds and DNA-Topo I covalent complexes is mainly hydrogen bond and hydrophobic accumulation, for example, two oxygen atoms on an E lactone ring of camptothecin and an amino group of Arg364 of Topo I have hydrogen bond interaction, and a ketone carbonyl oxygen of D-ring pyridone and cytosine of which a single strand is not cut off DNA form hydrogen bond. The 20S-hydroxyl group is hydrogen bonded to the carboxyl oxygen of Asp533, and in the case of camptothecin in the 20R-configuration, the steric hindrance of the ethyl group affects this interaction and is therefore less active.
Camptothecin derivatives currently being developed are irinotecan (CPT-11), topotecan (topotecan), and the like. Irinotecan is metabolized in the body (mainly in the liver) to generate SN-38, and belongs to a prodrug. Is mainly used for treating small cell and non-small cell lung cancer, colon cancer, ovarian cancer, cancer of sense organs, malignant lymphoma, etc. Topotecan is a semi-synthetic water-soluble camptothecin derivative. Is mainly used for treating metastatic ovarian cancer. Has good curative effect on small cell lung cancer, breast cancer, colon cancer and rectal cancer. However, the existing camptothecin derivatives lack the targeting of tumor tissues, and have large toxic and side effects.
The tumor microenvironment is the complex environment in which tumor cells survive and develop and is composed of cellular and non-cellular components. Wherein the cell components comprise tumor cells, inflammatory cells, immune cells, mesenchymal stem cells, endothelial cells, fibroblasts related to tumors and the like; the acellular component mainly comprises cytokines, chemokines and the like. The cellular and non-cellular components together act as a support for tumor growth. Tumor cells cause tumor tissues to show physiological characteristics which are obviously different from those of normal tissues due to uncontrolled growth, abnormal gene expression and the like, such as low pH, increased concentration of reducing substances and enzymes, increased content of Reactive Oxygen Species (ROS) and Adenosine Triphosphate (ATP) and the like. The targeted antitumor drug can improve the selectivity of the drug and reduce the toxic and side effects based on the research of the tumor microenvironment.
Latent design of the drug based on the specific microenvironment of the tumor yields an inactive prodrug. The prodrug keeps relatively stable in normal human blood circulation, can be rapidly metabolized to generate original drugs with anti-tumor activity in a specific microenvironment of tumor tissues after being conveyed to tumor parts, realizes the targeting of the drugs, and reduces the toxic and side effects caused by poor selectivity.
Hypoxia is a ubiquitous phenomenon in the process of generation and development of malignant tumors, and is mainly related to unlimited growth of tumor cells, increase of oxygen consumption, insufficient blood oxygen supply, tumor tissue blood vessel dysplasia and the like. Tumor cells under hypoxic environment are prone to metastasis and can increase resistance to radiotherapy and chemotherapy, thereby reducing treatment effects. Hypoxia of tumor cells can often lead to an increase in intracellular Nitroreductase (Nitroreductase). Based on high-level nitroreductase in tumor tissues, nitro is introduced into the antitumor drug to reduce the antitumor drug into amino at a tumor part, and the amino is rearranged to release a raw drug to exert antitumor activity.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel camptothecin prodrug and application of the prodrug in preparing antitumor drugs.
The technical scheme of the invention is as follows: a novel camptothecin prodrug has the following general formula (I):
wherein, the A ring and the B ring exist simultaneously or not simultaneously, are same or different and are respectively a benzene ring, a substituted benzene ring, a heterocycle, a substituted heterocycle, a fused heterocycle and a substituted fused heterocycle; the substituted benzene ring is independently substituted by one or two or three or four of deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano and hydroxyl; the heterocycle is imidazole, pyridine, furan, thiophene, thiazole, piperazine or piperidine; the substituted heterocycle is independently substituted on the heterocycle by one or two deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano or hydroxyl; the fused heterocycle is quinoline or indole; the substituted fused heterocycle is independently substituted by one or two or three of deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano and hydroxyl on the fused heterocycle;
R1and R2The two or more of the amino groups are simultaneously or non-simultaneously, are same or different and are respectively nitro, nitroso, amino and hydroxylamine groups;
R3and R4Identical or different and are each hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano, nitro, amino, N-dimethylaminomethyl, N-diethylaminomethyl, N-dimethylaminoethyl, N-diethylaminoethyl, hydroxy, trifluoromethyl-substituted or C3-C10A carbocyclic ring;
R5is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, trifluoromethyl or C3-C10A carbocyclic ring;
x is absent, or is CH2、CHD、CD2、
X1 is an a ring;
y is none, or CH2、CHD、CD2、
Y1 is a B ring.
Preferred camptothecin prodrugs are those of the general formula (II):
wherein, the A ring and the B ring exist simultaneously or not simultaneously, are same or different and are respectively a benzene ring, a substituted benzene ring, a heterocycle and a substituted heterocycle; the substituted benzene ring is independently substituted by one or two or three or four of deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano and hydroxyl; the heterocycle is imidazole, pyridine, furan, thiophene, thiazole, piperazine or piperidine; the substituted heterocycle is independently substituted on the heterocycle by one or two deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano or hydroxyl;
R1and R2Are simultaneously or non-simultaneously present, are the same or different and are each nitro;
R3and R4The same or different and each is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano, nitro, amino, hydroxy, trifluoromethyl substituted or C3-C10A carbocyclic ring;
R5is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, trifluoromethyl or C3-C10A carbocyclic ring;
x is absent, or is CH2、CD2、
X1 is an a ring;
y is none, or CH2、CD2、
Y1 is a B ring.
Preferred are fluorouracil derivatives represented by the general formula (III):
wherein, the A ring and the B ring exist simultaneously or not, are same or different and are respectively a benzene ring and a heterocycle; the heterocyclic ring is pyridine, furan, thiophene or thiazole;
R1and R2Are simultaneously or non-simultaneously present, are the same or different and are each nitro;
R3and R4The same or different and each is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano, nitro, amino, hydroxy, trifluoromethyl substituted or C3-C10A carbocyclic ring;
x is CH2、CD2、
X1 is an a ring;
y is CH2、CD2、
Y1 is a B ring.
Preferred compounds are selected from, but not limited to, the following compounds:
4-ethyl-4-hydroxy-9- ((4-nitrobenzyl) oxy) -1, 12-dihydro-14H-pyran [3',4':6,7] benzazole [1,2-b ] quinoline-3, 14(4H) -dione;
4-ethyl-4-hydroxy-9- ((5-nitrofuran-2-yl) methoxy) -1, 12-dihydro-14H-pyran [3',4':6,7] indolizine [1,2-b ] quinoline-3, 14(4H) -dione;
4-Ethyl-4-hydroxy-9- ((5-nitrothiophen-2-yl) methoxy) -1, 12-dihydro-14H-pyran [3',4':6,7] benzazole [1,2-b ] quinoline-3, 14(4H) -dione
4-ethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyran [3',4':6,7] indolizine [1,2-b ] quinolin-9-yl (4-nitrobenzyl) carbonate;
4-ethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyran [3',4':6,7] indolizine [1,2-b ] quinolin-9-yl ((5-nitrofuran-2-yl) methyl) carbonate;
4-ethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyran [3',4':6,7] indolizine [1,2-b ] quinolin-9-yl ((5-nitrothiophen-2-yl) methyl) carbonate;
4, 11-diethyl-4-hydroxy-9- ((4-nitrobenzyl) oxy) -1, 12-dihydro-14H-pyran [3',4':6,7] benzazole [1,2-b ] quinoline-3, 14(4H) -dione;
4, 11-diethyl-4-hydroxy-9- ((5-nitrofuran-2-yl) methoxy) -1, 12-dihydro-14H-pyran [3',4':6,7] indolizine [1,2-b ] quinoline-3, 14(4H) -dione;
4, 11-diethyl-4-hydroxy-9- ((5-nitrothiophen-2-yl) methoxy) -1, 12-dihydro-14H-pyran [3',4':6,7] indolizine [1,2-b ] quinoline-3, 14(4H) -dione
4, 11-diethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyran [3',4':6,7] indolizine [1,2-b ] quinolin-9-yl (4-nitrobenzyl) carbonate;
4, 11-diethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyran [3',4':6,7] indolizine [1,2-b ] quinolin-9-yl ((5-nitrofuran-2-yl) methyl) carbonate;
4, 11-diethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyran [3',4':6,7] indolizine [1,2-b ] quinolin-9-yl ((5-nitrothiophen-2-yl) methyl) carbonate.
The application of the compound or the salt thereof in preparing the medicine for treating the tumor.
The salt is hydrochloride, phosphate, sulfate, carbonate, nitrate, citrate, tartrate, maleate, succinate, sulfonate, p-toluenesulfonate, methanesulfonate, benzoate and fumarate.
The tumor is a hematological tumor or a malignant solid tumor. Specifically, the tumor includes chorioepithelial cancer, malignant hydatidiform mole, rectal cancer, lung cancer, head and neck cancer, prostate cancer, breast cancer, colon cancer, stomach cancer, pancreatic cancer, liver cancer, esophageal cancer, brain cancer, ovarian cancer, uterine cancer, kidney cancer, head and neck cancer, skin cancer, bladder cancer, vulvar cancer, testicular cancer, rectal cancer, germ cell tumor, malignant lymphoma, leukemia, and multiple myeloma, and even more preferred tumors may include chorioepithelial cancer, malignant hydatidiform mole, colon cancer, rectal cancer, stomach cancer, breast cancer, and head and neck cancer.
A pharmaceutical composition comprises camptothecin prodrug represented by general formula (I) or pharmaceutically acceptable salt thereof as active ingredient, and one or more pharmaceutically acceptable carriers or excipients.
The composition is in the form of injection or oral preparation, wherein the injection is solution injection, suspension injection, emulsion injection or sterile powder for injection, and the oral preparation is tablet, powder, granule, capsule, pellet preparation, solution, suspension, emulsion, syrup or elixir.
Unless otherwise indicated, the terms in the specification and claims have the following meanings.
"pharmaceutical composition" means a mixture comprising one or more compounds of the general formula (I) of the present invention or a pharmaceutically acceptable salt, ester, or prodrug thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the absorption of the active ingredients by organisms and to facilitate the active ingredients to exert biological activity in organisms.
The synthetic schemes for the compounds of the present invention are shown in scheme one and scheme two:
the first scheme is as follows: preparing a compound of formula (I):
the compound (VI) can be prepared by reacting a compound represented by the general formula (II) with a compound represented by the general formula (VII) (each of which is simply referred to as compound II and compound VII) in the presence of a base, and the obtained compound VI is further reacted with a compound represented by the general formula (VIII) in the presence of a base to obtain the compound (I).
Wherein, the A ring and the B ring exist simultaneously or not simultaneously, are same or different and are respectively a benzene ring, a substituted benzene ring, a heterocycle, a substituted heterocycle, a fused heterocycle and a substituted fused heterocycle; the substituted benzene ring is independently substituted by one or two or three or four of deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano and hydroxyl; the heterocycle is imidazole, pyridine, furan, thiophene, thiazole, piperazine or piperidine; the substituted heterocycle is independently substituted on the heterocycle by one or two deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano or hydroxyl; the fused heterocycle is quinoline or indole; the substituted fused heterocycle is independently substituted by one or two or three of deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano and hydroxyl on the fused heterocycle;
R1and R2The two or more of the amino groups are simultaneously or non-simultaneously, are same or different and are respectively nitro, nitroso, amino and hydroxylamine groups;
R3and R4Identical or different and are each hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano, nitro, amino, N-dimethylaminomethyl, N-diethylaminomethyl, N-dimethylaminoethyl, N-diethylaminoethyl, hydroxy, trifluoromethyl-substituted or C3-C10A carbocyclic ring;
R5is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, trifluoromethyl or C3-C10A carbocyclic ring;
x is absent, or is CH2、CHD、CD2X1 is the A ring;
y is none, or CH2、CHD、CD2And Y1 is a B ring.
W represents a leaving group, and there may be mentioned, for example, Cl, Br, I, an optionally halogenated C1-C6 alkylsulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy), an optionally substituted C6-C10 arylsulfonyloxy group (e.g., phenylsulfonyloxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy, etc.), etc.;
as the base, inorganic bases and organic bases are included, and as the inorganic bases, there can be mentioned, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as potassium bicarbonate, sodium bicarbonate, and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; as the organic base, for example, triethylamine, pyridine, 1, 8-diazabicycloundecen-7-ene, diisopropylethylamine, N-dimethylaminopyridine, N-butyllithium, tert-butylpotassium and the like can be mentioned.
Scheme II: preparing a compound of formula (I):
the compound (VI) can be prepared by reacting a compound represented by the general formula (II) with a compound represented by the general formula (VII) (each of which is simply referred to as compound II and compound VII) in the presence of a base, and the obtained compound VI is further reacted with a compound represented by the general formula (VIII) in the presence of a base to obtain the compound (I).
Wherein, the A ring and the B ring exist simultaneously or not simultaneously, are same or different and are respectively a benzene ring, a substituted benzene ring, a heterocycle and a substituted heterocycle; the substituted benzene ring is independently substituted by one or two or three or four of deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano and hydroxyl; the heterocycle is imidazole, pyridine, furan, thiophene, thiazole, piperazine or piperidine; the substituted heterocycle is independently substituted on the heterocycle by one or two deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano or hydroxyl;
R1and R2Are simultaneously or non-simultaneously present, are the same or different and are each nitro;
R3and R4The same or different and each is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano, nitro, amino, hydroxy, trifluoromethyl substituted or C3-C10A carbocyclic ring;
R5is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl,Propargyl, trifluoromethyl or C3-C10A carbocyclic ring;
x is absent, or is
X1 is an a ring;
y is none, or,
Y1 is a B ring.
W represents a leaving group, and there may be mentioned, for example, Cl, Br, I, an optionally halogenated C1-C6 alkylsulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy), an optionally substituted C6-C10 arylsulfonyloxy group (e.g., phenylsulfonyloxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy, etc.), etc.;
as the base, inorganic bases and organic bases are included, and as the inorganic bases, there can be mentioned, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal hydrogencarbonates such as potassium hydrogencarbonate, sodium hydrogencarbonate, and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; as the organic base, for example, triethylamine, pyridine, 1, 8-diazabicycloundecen-7-ene, diisopropylethylamine, N-dimethylaminopyridine, N-butyllithium, tert-butylpotassium and the like can be mentioned.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of the teachings of the present invention may be made by those skilled in the art without departing from the scope of the claims of the present application.
Example 1
The camptothecin prodrug 4-ethyl-4-hydroxy-9- ((4-nitrobenzyl) oxy) -1, 12-dihydro-14H-pyran [3',4':6,7] indolizine [1,2-b ] quinoline-3, 14(4H) -dione (number I-1) of this example was synthesized in 1 step with the following reaction formula:
0.5g (1.37mmol) of camptothecin was dissolved in 20ml of N, N-dimethylformamide, 0.38g (2.74mmol) of potassium carbonate was added, cooled to 0 ℃ and protected with nitrogen. 0.30g (1.37mmol) of p-nitrobenzyl bromide dissolved in 5mL of N, N-dimethylformamide was slowly dropped by a syringe. After the addition, the temperature is slowly raised to the room temperature, and the reaction is carried out for 12 hours at the room temperature. After the reaction is finished, filtering to remove potassium carbonate, concentrating the filtrate to obtain a crude product, and separating by silica gel column chromatography, wherein dichloromethane: methanol (20: 1) was eluted to give 0.57g of (I-1) as a white solid in 83.2% yield.
Nuclear magnetic resonance characterization of I-1:
1H NMR(500MHz,DMSO-d6)δ8.51(d,J＝1.1Hz,1H),8.29(d,J＝8.8Hz,2H),8.10(d,J＝10.4Hz,1H),7.81(d,J＝8.8Hz,2H),7.67–7.58(m,2H),7.28(s,1H),6.51(s,1H),5.46(s,2H),5.41(s,2H),5.24(s,2H),1.93–1.80(m,2H),0.88(t,J＝7.3Hz,3H)；
13C NMR(125MHz,DMSO-d6)δ172.98,157.24,150.92,150.51,147.61,146.13,144.84,144.60,131.18,130.80,130.56,129.68,128.93,124.15,123.54,118.93,108.18,96.61,72.87,69.01,65.71,50.69,30.73,8.23。
example 2
The camptothecin prodrug 4, 11-diethyl-4-hydroxy-9- ((4-nitrobenzyl) oxy) -1, 12-dihydro-14H-pyran [3',4':6,7] benzazole [1,2-b ] quinoline-3, 14(4H) -dione (code I-2) of this example was synthesized by the following reaction:
0.5g (1.27mmol) hydroxycamptothecin is dissolved in 20ml N, N-dimethylformamide, 0.35g (2.57mmol) potassium carbonate is added, cooled to 0 ℃ and protected with nitrogen. 0.28g (1.27mmol) of p-nitrobenzyl bromide dissolved in 5mL of N, N-dimethylformamide was slowly dropped by a syringe. After the addition, the temperature was slowly raised to 80 ℃ and the mixture was refluxed for 12 hours. After the reaction is finished, filtering to remove potassium carbonate, concentrating the filtrate under reduced pressure to obtain a crude product, and separating by silica gel column chromatography, wherein dichloromethane: methanol (2: 1) was eluted to give 0.51g of (I-2) as a white solid in 75.9% yield.
Nuclear magnetic resonance characterization of I-2:
1H NMR(500MHz,DMSO-d6)δ8.30(d,J＝8.7Hz,2H),8.12(d,J＝9.1Hz,1H),7.84(d,J＝8.7Hz,2H),7.66–7.60(m,2H),7.28(s,1H),6.50(s,1H),5.55(s,2H),5.43(s,2H),5.30(s,2H),3.18(q,J＝7.6Hz,2H),1.94–1.78(m,2H),1.26–1.23(m,3H),0.88(t,J＝7.3Hz,3H)；
13C NMR(125MHz,DMSO)δ173.03,157.35,157.22,150.56,149.35,146.94,145.08,144.14,143.25,132.06,128.97,128.69,128.51,124.16,122.87,118.49,105.27,96.26,72.88,65.73,49.95,30.72,22.76,13.90,13.83,8.23。
example 3
Study of tumor microenvironment (nitroreductase) -mediated degradation of camptothecin prodrugs: dissolving I-1 or I-2 in 15mL of 10mmol/L Tris buffer, adding appropriate amount of nitroreductase and nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate, diluting to 20mL with 10mmol/L Tris buffer, and measuring the concentration of camptothecin and I-1 or hydroxycamptothecin and I-2 after adding nitroreductase buffer for 100s, 200s, 300s, 400s, 500s and 600s … … by using HPLC to determine whether the target compound can be degraded in the presence of nitroreductase. The results show that the compounds I-1 and I-2 can be degraded more rapidly under the nitroreductase condition.
Example 4
Cytotoxicity experiments: collecting HepG2 cell line logarithmic phase cells, adjusting the concentration of cell suspension, adding 100uL into each hole, and plating to adjust the density of the cells to be detected to 1000-10000 holes (the edge holes are filled with sterile PBS); 5% CO2Incubating at 37 ℃ until the cell monolayer is fully paved on the bottom of the well (96-well flat bottom plate), adding a drug with a concentration gradient, and setting 5-7 concentration gradients and 5 multiple wells with 100uL per well; 5% CO2Incubating for 24h at 37 ℃, and observing under an inverted microscope; 20uL of MTT solution (5mg/ml, i.e., 0.5% MTT) was added to each well and incubation was continued for 4 h. If the drug reacts with MTT, the culture medium can be discarded after centrifugation, and the MTT-containing culture medium can be added after 2-3 times of washing with PBS carefully. Final (a Chinese character of 'gan')Stopping culturing, and carefully sucking out culture solution in the holes; 150uL of dimethyl sulfoxide is added into each hole, and the mixture is placed on a shaking bed to be shaken at low speed for 10min, so that the crystals are fully dissolved. The absorbance of each well was measured at OD 490nm of an ELISA and the cell viability was calculated. The experimental groups included camptothecin group (group 1), hydroxycamptothecin group (group 2), group I-1 (group 3), group I-2 (group 4), group I-1+ nitroreductase (group 5), and group I-2+ nitroreductase (group 6). The results are shown in Table 1.
TABLE 1
The results show that the cytotoxicity of the camptothecin prodrug I-1 and I-2 is reduced, and the camptothecin prodrug shows obvious cytotoxicity only in the presence of nitroreductase. Because the concentration of nitroreductase in tumor tissues is higher, the camptothecin prodrug shown in the general formula (I) can reduce the toxic and side effects of the camptothecin antitumor drug.
Claims (9)
1. The novel camptothecin prodrug of claim, having the following general formula (I):
wherein, the A ring and the B ring exist simultaneously or not simultaneously, are same or different and are respectively a benzene ring, a substituted benzene ring, a heterocycle, a substituted heterocycle, a fused heterocycle and a substituted fused heterocycle; the substituted benzene ring is independently substituted by one or two or three or four of deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano and hydroxyl; the heterocycle is imidazole, pyridine, furan, thiophene, thiazole, piperazine or piperidine; the substituted heterocycle is independently substituted on the heterocycle by one or two deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano or hydroxyl; the fused heterocycle is quinoline or indole; the substituted fused heterocycle is independently substituted by one or two or three of deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano and hydroxyl on the fused heterocycle;
R1and R2The two or more of the amino groups are simultaneously or non-simultaneously, are same or different and are respectively nitro, nitroso, amino and hydroxylamine groups;
R3and R4Identical or different and are each hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano, nitro, amino, N-dimethylaminomethyl, N-diethylaminomethyl, N-dimethylaminoethyl, N-diethylaminoethyl, hydroxy, trifluoromethyl-substituted or C3-C10A carbocyclic ring;
R5is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, trifluoromethyl or C3-C10A carbocyclic ring;
x is absent, or is CH2、CHD、CD2、
X1 is an a ring;
y is none, or CH2、CHD、CD2、
Y1 is a B ring.
2. Camptothecin prodrug of general formula (I) according to claim 1, which is preferably a camptothecin prodrug of general formula (II):
wherein, the A ring and the B ring exist simultaneously or not simultaneously, are same or different and are respectively a benzene ring, a substituted benzene ring, a heterocycle and a substituted heterocycle; the substituted benzene ring is independently substituted by one or two or three or four of deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano and hydroxyl; the heterocycle is imidazole, pyridine, furan, thiophene, thiazole, piperazine or piperidine; the substituted heterocycle is independently substituted on the heterocycle by one or two deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano or hydroxyl;
R1and R2Are simultaneously or non-simultaneously present, are the same or different and are each nitro;
R3and R4The same or different and each is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano, nitro, amino, hydroxy, trifluoromethyl substituted or C3-C10A carbocyclic ring;
R5is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, trifluoromethyl or C3-C10A carbocyclic ring;
x is absent, or is CH2、CD2、
X1 is an a ring;
y is none, or CH2、CD2、
Y1 is a B ring.
3. Camptothecin prodrug of general formula (II) according to claim 2, which is preferably a camptothecin prodrug of general formula (III):
wherein, the A ring and the B ring exist simultaneously or not, are same or different and are respectively a benzene ring and a heterocycle; the heterocyclic ring is pyridine, furan, thiophene or thiazole;
R1and R2Are simultaneously or non-simultaneously present, are the same or different and are each nitro;
R3and R4The same or different and each is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, allyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, halogen, cyano, nitro, amino, hydroxy, trifluoromethyl substituted or C3-C10A carbocyclic ring;
x is CH2、CD2、
X1 is an a ring;
y is CH2、CD2、
Y1 is a B ring.
4. A camptothecin prodrug of general formula (I) as defined in claims 1 to 3, selected from but not limited to the following compounds:
4-ethyl-4-hydroxy-9- ((4-nitrobenzyl) oxy) -1, 12-dihydro-14H-pyran [3',4':6,7] benzazole [1,2-b ] quinoline-3, 14(4H) -dione;
4-ethyl-4-hydroxy-9- ((5-nitrofuran-2-yl) methoxy) -1, 12-dihydro-14H-pyran [3',4':6,7] indolizine [1,2-b ] quinoline-3, 14(4H) -dione;
4-Ethyl-4-hydroxy-9- ((5-nitrothiophen-2-yl) methoxy) -1, 12-dihydro-14H-pyran [3',4':6,7] benzazole [1,2-b ] quinoline-3, 14(4H) -dione
4-ethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyran [3',4':6,7] indolizine [1,2-b ] quinolin-9-yl (4-nitrobenzyl) carbonate;
4-ethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-2 pyran [3',4':6,7] indolizine [1,2-b ] quinolin-9-yl ((5-nitrofuran-2-yl) methyl) carbonate;
4-ethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyran [3',4':6,7] indolizine [1,2-b ] quinolin-9-yl ((5-nitrothiophen-2-yl) methyl) carbonate;
4, 11-diethyl-4-hydroxy-9- ((4-nitrobenzyl) oxy) -1, 12-dihydro-14H-pyran [3',4':6,7] benzazole [1,2-b ] quinoline-3, 14(4H) -dione;
4, 11-diethyl-4-hydroxy-9- ((5-nitrofuran-2-yl) methoxy) -1, 12-dihydro-14H-pyran [3',4':6,7] indolizine [1,2-b ] quinoline-3, 14(4H) -dione;
4, 11-diethyl-4-hydroxy-9- ((5-nitrothiophen-2-yl) methoxy) -1, 12-dihydro-14H-pyran [3',4':6,7] indolizine [1,2-b ] quinoline-3, 14(4H) -dione
4, 11-diethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyran [3',4':6,7] indolizine [1,2-b ] quinolin-9-yl (4-nitrobenzyl) carbonate;
4, 11-diethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyran [3',4':6,7] indolizine [1,2-b ] quinolin-9-yl ((5-nitrofuran-2-yl) methyl) carbonate;
4, 11-diethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyran [3',4':6,7] indolizine [1,2-b ] quinolin-9-yl ((5-nitrothiophen-2-yl) methyl) carbonate.
5. Use of the compound or the salt thereof according to claims 1 to 4 for the preparation of an antitumor drug.
6. The salt of claim 5, wherein the salt is selected from the group consisting of hydrochloride, phosphate, sulfate, carbonate, nitrate, citrate, tartrate, maleate, succinate, sulfonate, p-toluenesulfonate, methanesulfonate, benzoate and fumarate.
7. The tumor of claim 5 is a hematological tumor or a malignant solid tumor, specifically, the tumor includes chorioepithelial cancer, hydatidiform mole, rectal cancer, lung cancer, head and neck cancer, prostate cancer, breast cancer, colon cancer, stomach cancer, pancreatic cancer, liver cancer, esophageal cancer, brain tumor, ovarian cancer, uterine cancer, kidney cancer, head and neck cancer, skin cancer, bladder cancer, vulval cancer, testicular tumor, rectal cancer, germ cell tumor, malignant lymphoma, leukemia, and multiple myeloma, and even more preferably the tumor may include chorioepithelial cancer, hydatidiform mole, colon cancer, rectal cancer, stomach cancer, breast cancer, and head and neck cancer.
8. A pharmaceutical composition comprises camptothecin prodrug represented by general formula (I) or pharmaceutically acceptable salt thereof as active ingredient, and one or more pharmaceutically acceptable carriers or excipients.
9. The composition of claim 8, which is in the form of injection or oral preparation, wherein the injection is in the form of solution injection, suspension injection, emulsion injection, or sterile powder for injection, and the oral preparation is in the form of tablet, powder, granule, capsule, pellet, solution, suspension, emulsion, syrup, or elixir.
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