CN115894385A - Tirapazamine derivative and preparation method and application thereof - Google Patents

Tirapazamine derivative and preparation method and application thereof Download PDF

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CN115894385A
CN115894385A CN202310026036.6A CN202310026036A CN115894385A CN 115894385 A CN115894385 A CN 115894385A CN 202310026036 A CN202310026036 A CN 202310026036A CN 115894385 A CN115894385 A CN 115894385A
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cancer
substituted
unsubstituted
tirapazamine
derivative
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汤朝晖
徐亚军
沈娜
吕鉴霖
陈学思
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Changchun Institute of Applied Chemistry of CAS
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides a tirapazamine derivative with a structure shown in a formula (I). The derivative provided by the invention has more excellent hypoxic activation capability, maintains the hypoxic selective toxicity, shows strong cytotoxicity even in tumor cells with lower hypoxic degree, obviously reduces the toxicity in the normoxic environment, and hopefully solves the problem of poor curative effect of tirapazamine caused by insufficient hypoxic degree of tumor of patients.

Description

Tirapazamine derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a tirapazamine derivative and a preparation method and application thereof.
Background
Tumor hypoxia is a common feature of solid tumors in humans and animals, is a powerful negative clinical biomarker, and is considered to be one of the best validated therapeutic targets in cancer therapy. On the one hand, tumor hypoxia is a major factor that leads to the failure of many anticancer therapies. On the other hand, tumor hypoxia may be an attractive therapeutic target because it is the basis for major differences between tumor and normal tissues. The hypoxia activated prodrug has high selectivity toxicity on hypoxic cells, and has low toxicity in areas with high oxygen tension such as normal tissues. Thus, hypoxia activated prodrugs have the potential to selectively kill hypoxic cells, thereby converting tumor hypoxia from a problem to a selective therapeutic advantage.
Tirapazamine (TPZ for short) is a representative hypoxia activated prodrug that is selectively cytotoxic to hypoxic cells in solid tumors and inhibits tumor growth by inducing single and double strand breaks in DNA, base damage and cell death. Although the results of phase II clinical trials are encouraging, most phase III clinical trials fail to show the added benefit of TPZ. However, a further sub-study of phase II clinical trial data indicates that TPZ significantly improves clinical efficacy if selecting patients with tumor hypoxia, indicating that the failure of TPZ in clinical trials is mainly due to insufficient hypoxia in the tumor, which is insufficient to effectively activate TPZ and achieve potent killing of tumor cells. At present, most of researches are combined with other treatment means to improve the hypoxic degree of a tumor part and the activation degree of TPZ (thermoplastic vulcanizate) at the tumor part so as to realize the inhibition of tumor growth. The hypoxic level of a tumor is often enhanced by oxygen depletion or vascular occlusion in the tumor. For example, consumption of oxygen is achieved by photodynamic therapy or sonodynamic therapy; hepatic artery ligation and vascular blocking agents are used to induce tumor vascular occlusion and increase tumor hypoxia. Clinical phase ii trials of TPZ in combination with TAE embolization (trans-atrial embolization) are now underway. TAE embolism can only be used for treating liver cancer, and photodynamic therapy, sonodynamic therapy and TAE embolism can only be used for local treatment, can not well improve the treatment effect of the medicine on patients, and no effective blood vessel blocking agent is on the market at present.
Therefore, it is very necessary to develop a TPZ derivative having more sensitive selectivity to hypoxic oxygen.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a tirapazamine derivative, which has a better hypoxic activation ability, retains hypoxic selective toxicity, and shows strong cytotoxicity even in tumor cells with a low hypoxic degree.
The invention provides a tirapazamine derivative with a structure shown in a formula (I),
Figure BDA0004044983330000021
/>
wherein n is-CH in parentheses 2 -a number of repeating units, n is 0. Ltoreq. N.ltoreq.10;
and R is H, substituted C1-C6 alkyl, unsubstituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, unsubstituted C3-C7 cycloalkyl, substituted C2-C8 heterocycloalkyl, unsubstituted C2-C8 heterocycloalkyl, substituted C6-C12 aryl, unsubstituted C6-C12 aryl, substituted C2-C9 heteroaryl, unsubstituted C2-C9 heteroaryl, hydroxyl, C1-C5 alkylamine, carboxyl, trifluoromethyl, C2-C4 alkynyl, C2-C4 alkenyl and acylamino.
Preferably, the substituent of the substituted alkyl is F, cl, br or I.
Preferably, R is hydrogen or a structure of formula (a-1) to formula (a-17):
Figure BDA0004044983330000022
Figure BDA0004044983330000031
preferably, the tirapazamine derivative with the structure of the formula (I) has the following structure:
Figure BDA0004044983330000032
the invention provides a preparation method of a tirapazamine derivative with a structure shown in formula (I) in any one of the technical schemes, which comprises the following steps:
a) Reacting tirapazamine with p-nitrophenyl chloroformate in a solvent of an alkaline substance to obtain an intermediate product TPZ-NPC;
b) TPZ-NPC reacts with an amino compound shown as a formula (II) in a solvent to obtain the compound;
Figure BDA0004044983330000033
and R is H, substituted C1-C6 alkyl, unsubstituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, unsubstituted C3-C7 cycloalkyl, substituted C2-C8 heterocycloalkyl, unsubstituted C2-C8 heterocycloalkyl, substituted C6-C12 aryl, unsubstituted C6-C12 aryl, substituted C2-C9 heteroaryl, unsubstituted C2-C9 heteroaryl, hydroxyl, C1-C5 alkylamine, carboxyl, trifluoromethyl, C2-C4 alkynyl, C2-C4 alkenyl and acylamino.
Preferably, the basic substance is triethylamine, pyridine, lutidine, diisopropylethylamine; the solvent is tetrahydrofuran, acetonitrile, chloroform, dichloromethane, carbon tetrachloride, benzene, toluene, dimethyl sulfoxide and dimethylformamide.
Preferably, the reaction temperature of the step A) is 25 ℃, and the reaction time is 24h.
Preferably, the reaction temperature of the step B) is 25 ℃, and the reaction time is 24h. The invention provides an application of a tirapazamine derivative with a structure shown in the formula (I) in any one of the technical schemes and pharmaceutically acceptable salt thereof in preparing an anti-cancer medicament.
Preferably, the cancer comprises one or more of nasal cavity and sinus malignant tumor, nasopharyngeal carcinoma, oral cancer, laryngeal carcinoma, intracranial tumor, thyroid cancer, tongue cancer, lung cancer, esophageal cancer, breast cancer, stomach cancer, colorectal cancer, sigmoid colon and rectal cancer, liver cancer, pancreatic cancer and periampulla cancer, biliary tract cancer, kidney cancer, prostate cancer, bladder cancer, testicular malignant tumor, penis cancer, cervical cancer, endometrial cancer, ovarian cancer, fibrohistiocyte cancer, rhabdomyocarcinoma, synovial sarcoma, melanoma, osteosarcoma, ewing's sarcoma, leukemia, lymphoma and multiple myeloma.
The invention provides an anti-cancer drug, which comprises a tirapazamine derivative with a structure shown in the formula (I) in any one of the technical schemes or a tirapazamine derivative with a structure shown in the formula (I) prepared by the preparation method in any one of the technical schemes.
Compared with the prior art, the invention provides a tirapazamine derivative with a structure shown in a formula (I). The derivative provided by the invention has more excellent hypoxic activation capability, and shows strong cytotoxicity even in tumor cells with lower hypoxic degree while retaining hypoxic selective toxicity, while the toxicity in normal cells is obviously reduced, so that the problem of poor curative effect of tirapazamine caused by insufficient hypoxic degree of tumor of a patient is hopefully solved.
Drawings
FIG. 1 shows the synthesis route and nuclear magnetic hydrogen spectrum characterization of the intermediate compound (TPZ-NPC) of the present invention;
FIG. 2 is a nuclear magnetic hydrogen spectrum characterization of compound TPZ-His;
FIG. 3 is a nuclear magnetic hydrogen spectrum characterization of compound TPZ-BZA;
FIG. 4 is a nuclear magnetic hydrogen spectrum characterization of compound TPZ-Hex;
FIG. 5 is a nuclear magnetic hydrogen spectrum characterization of compound TPZ-Acp;
Detailed Description
The invention provides a tirapazamine derivative and a preparation method and application thereof, and a person skilled in the art can realize the tirapazamine derivative by properly improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The invention provides a tirapazamine derivative with a structure shown in a formula (I),
Figure BDA0004044983330000051
wherein n is-CH in parentheses 2 -a number of repeating units, 0. Ltoreq. N.ltoreq.10; preferably, 2. Ltoreq. N.ltoreq.8;
r is H, substituted C1-C6 alkyl, unsubstituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, unsubstituted C3-C7 cycloalkyl, substituted C2-C8 heterocycloalkyl, unsubstituted C2-C8 heterocycloalkyl, substituted C6-C12 aryl, unsubstituted C6-C12 aryl, substituted C2-C9 heteroaryl, unsubstituted C2-C9 heteroaryl, hydroxyl, C1-C5 alkylamine, carboxyl, trifluoromethyl, C2-C4 alkynyl, C2-C4 alkenyl and acylamino;
preferably, R is H, substituted C2-C6 alkyl, unsubstituted C2-C6 alkyl, substituted C3-C7 cycloalkyl, unsubstituted C3-C7 cycloalkyl, substituted C3-C8 heterocycloalkyl, unsubstituted C3-C8 heterocycloalkyl, substituted C6-C10 aryl, unsubstituted C6-C10 aryl, substituted C2-C9 heteroaryl, unsubstituted C2-C9 heteroaryl, hydroxyl, C1-C5 alkylamine, carboxyl, trifluoromethyl, C2-C3 alkynyl, C2-C3 alkenyl, or amido;
specifically, the substituent of the substituted alkyl is F, cl, br and I;
the substituent of the substituted aryl is nitro;
in a preferred embodiment of the present invention, R is hydrogen or a structure of formula (a-1) to formula (a-15):
Figure BDA0004044983330000052
Figure BDA0004044983330000061
according to the invention, the tirapazamine derivative with the structure of formula (I) is specifically as follows:
Figure BDA0004044983330000062
/>
the invention provides a preparation method of a tirapazamine derivative with a structure in a formula (I) in any one of the technical schemes, which comprises the following steps:
a) Reacting tirapazamine with p-nitrophenyl chloroformate in a solvent of an alkaline substance to obtain an intermediate product TPZ-NPC;
b) TPZ-NPC reacts with an amino compound shown as a formula (II) in a solvent to obtain the compound;
Figure BDA0004044983330000071
and R is H, substituted C1-C6 alkyl, unsubstituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, unsubstituted C3-C7 cycloalkyl, substituted C2-C8 heterocycloalkyl, unsubstituted C2-C8 heterocycloalkyl, substituted C6-C12 aryl, unsubstituted C6-C12 aryl, substituted C2-C9 heteroaryl, unsubstituted C2-C9 heteroaryl, hydroxyl, C1-C5 alkylamine, carboxyl, trifluoromethyl, C2-C4 alkynyl, C2-C4 alkenyl and acylamino.
Preferably, R is H, substituted C2-C6 alkyl, unsubstituted C2-C6 alkyl, substituted C3-C7 cycloalkyl, unsubstituted C3-C7 cycloalkyl, substituted C3-C8 heterocycloalkyl, unsubstituted C3-C8 heterocycloalkyl, substituted C6-C10 aryl, unsubstituted C6-C10 aryl, substituted C2-C9 heteroaryl, unsubstituted C2-C9 heteroaryl, hydroxyl, C1-C5 alkylamine, carboxyl, trifluoromethyl, C2-C3 alkynyl, C2-C3 alkenyl, or amido;
specifically, the substituent of the substituted alkyl is F, cl, br and I;
the substituent of the substituted aryl is nitro;
the preparation method of the tirapazamine derivative with the structure of the formula (I) provided by the invention comprises the following step of reacting tirapazamine with p-nitrophenyl chloroformate in a solvent of an alkaline substance to obtain an intermediate product TPZ-NPC.
The preferable concrete is as follows: dissolving tirapazamine in a solvent, and performing ice bath; dissolving p-nitrophenyl chloroformate by using a solvent, slowly dropwise adding for reaction, after the reaction is finished, spin-drying the solvent, washing the solvent by using an ethyl acetate/n-hexane mixed solution until the solvent is clear and colorless, centrifuging, collecting precipitate, and drying to obtain the target product TPZ-NPC.
The reaction formula is as follows:
Figure BDA0004044983330000072
the alkaline substance is triethylamine, pyridine, lutidine and diisopropylethylamine;
the solvent is tetrahydrofuran, acetonitrile, chloroform, dichloromethane, carbon tetrachloride, benzene, toluene, dimethyl sulfoxide and dimethylformamide.
Specifically, the reaction temperature in the step A) is 25 ℃, and the reaction time is 24h.
TPZ-NPC and an amino compound shown in a formula (II) react in a solvent to obtain the compound.
The reaction of the invention preferably further comprises the steps of draining the solvent, washing for 1-3 times by using a washing solvent, centrifuging, taking the precipitate and drying to obtain a crude product. After dichloromethane is dissolved, column chromatography is carried out, eluent is dichloromethane and methanol, and the target compound is collected. The washing solvent is ethyl acetate/normal hexane mixed solution.
Figure BDA0004044983330000081
And R is H, substituted C1-C6 alkyl, unsubstituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, unsubstituted C3-C7 cycloalkyl, substituted C2-C8 heterocycloalkyl, unsubstituted C2-C8 heterocycloalkyl, substituted C6-C12 aryl, unsubstituted C6-C12 aryl, substituted C2-C9 heteroaryl, unsubstituted C2-C9 heteroaryl, hydroxyl, C1-C5 alkylamine, carboxyl, trifluoromethyl, C2-C4 alkynyl, C2-C4 alkenyl and acylamino.
The amino compound of the invention includes, but is not limited to histamine, benzylamine, n-hexylamine, cyclopropylmethylamine.
The reaction temperature is 25 ℃, and the reaction time is 24 hours. The reaction formula is as follows:
Figure BDA0004044983330000082
the invention provides an application of a tirapazamine derivative with a structure shown in the formula (I) in any one of the technical schemes and pharmaceutically acceptable salt thereof in preparing an anti-cancer medicament.
The cancer of the invention comprises one or more of malignant tumors of nasal cavity and nasal sinuses, nasopharyngeal carcinoma, oral cancer, laryngeal carcinoma, intracranial tumor, thyroid cancer, tongue cancer, lung cancer, esophageal cancer, breast cancer, stomach cancer, colorectal cancer, sigmoid colon and rectal cancer, liver cancer, pancreatic cancer and periampulla cancer, biliary tract cancer, kidney cancer, prostate cancer, bladder cancer, testicular malignant tumor, penis cancer, cervical cancer, endometrial cancer, ovarian cancer, fiber histiocyte cancer, rhabdomyocarcinoma, synovial sarcoma, melanoma, osteosarcoma, ewing's sarcoma, leukemia, lymphoma and multiple myeloma.
The invention provides an anti-cancer drug which comprises a tirapazamine derivative with a structure shown in the formula (I) in any one of the technical schemes or a tirapazamine derivative with a structure shown in the formula (I) prepared by the preparation method in any one of the technical schemes.
The present invention has been described in detail with respect to the above specific structures and preparation methods, and will not be described herein again.
The tirapazamine ureido derivative designed by the invention can improve the sensitivity to hypoxic on the basis of retaining the selectivity of the hypoxic, and shows higher cytotoxicity under the hypoxic condition.
The invention provides and develops the ureido derivative of TPZ for the first time, which is more sensitive to hypoxic tumor microenvironment, can effectively realize high-toxicity killing on tumor cells under the condition of lower hypoxic degree, shows lower toxicity at the level of normoxic cells, has more excellent tumor hypoxic sensitivity selectivity, hopefully realizes killing on tumor cells with lower hypoxic degree, inhibits tumor growth and widens the applicability of patients with different hypoxic levels.
In order to further illustrate the present invention, the following will describe in detail a tirapazamine derivative provided by the present invention, and a preparation method and application thereof, with reference to examples.
Example 1:
700.0mg of tirapazamine (3.93 mmol) was weighed, and the resulting solution was put into a 100mL eggplant type flask, dissolved in 20mL of ultra-dry acetonitrile, and then cooled in ice for 5 minutes. 1188.3mg p-nitrophenyl chloroformate (NPC, 5.90 mmol) was weighed, dissolved in 10mL of an ultra-dry solvent, slowly added dropwise to the reaction system, and reacted at 30 ℃ in the dark for 24 hours. After the reaction is finished, the solvent is dried in a spinning mode, the mixture is washed by ethyl acetate/normal hexane until the mixture is clear and colorless, and the precipitate is collected by centrifugation and dried to obtain the target product TPZ-NPC with the yield of 1.2g and the yield of 90 percent. The synthetic route (FIG. 1,a) and nuclear magnetic hydrogen spectrum characterization (FIG. 1,b).
Example 2:
weighing 100.0mg of TPZ-NPC, dissolving in 20mL of ultra-dry acetonitrile, then weighing 64.8mg of amino compound histamine (0.3 mmol), dissolving in 20mL of ultra-dry acetonitrile, slowly adding into a reaction system, reacting at 30 ℃ in a dark place for 48 hours, draining the solvent, washing with an ethyl acetate/n-hexane mixed solution for three times, centrifuging, taking the precipitate, and drying to obtain a crude product. After dichloromethane is dissolved, column chromatography is carried out, eluent is dichloromethane and methanol, and the target compound tirapazamine ureido derivative TPZ-His is collected. Nuclear magnetic hydrogen spectrum characterization (fig. 2).
Example 3:
referring to the procedure of example 2, tirapazamine ureido derivative TPZ-Bza was prepared using benzylamine instead of histamine. Nuclear magnetic hydrogen spectrum characterization (fig. 3).
Example 4:
with reference to the procedure of example 2, tirapazamine ureido derivative TPZ-Hex was prepared using n-hexylamine instead of histamine. Nuclear magnetic hydrogen spectrum characterization (fig. 4).
Example 5:
referring to the procedure of example 2, tirapazamine ureido derivative TPZ-Acp was prepared using cyclopropylmethylamine instead of histamine. Nuclear magnetic hydrogen spectroscopy characterization (fig. 5).
Example 6:
preparing 4T1 cells in logarithmic growth phase into 2.6 × 10 cells 3 The cell suspension is inoculated in a 96-well plate at 190 mu L per well; after 12h of culture, adding a drug-containing culture medium with the corresponding concentration of the corresponding drug, setting 3 multiple wells for each concentration, setting the final volume of each well to be 200 mu L, after 24h of culture, adding CCK-820 mu L/well, after 1h of culture, shaking for 120s, and detecting the absorbance at 450nm by using an enzyme-labeling instrument. Cell survival rate = (drug absorbance/control absorbance) × 100%, and IC was calculated by plotting cell survival rate against drug concentration 50 The value is obtained. Table 1 shows the IC50 values of some compounds on 4T1 cells.
Compound Normoxia IC50 (μM) Hypoxia IC50 (μM)
TPZ 22.98 9.72
TPZ-His 1.65 0.58
TPZ-Bza 2.06 0.87
TPZ-Hex 1.57 0.79
TPZ-Acp 1.66 0.60
TABLE 1
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (10)

1. A tirapazamine derivative with a structure shown in a formula (I),
Figure FDA0004044983320000011
wherein n is-CH in parentheses 2 -a number of repeating units, 0. Ltoreq. N.ltoreq.10;
and R is H, substituted C1-C6 alkyl, unsubstituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, unsubstituted C3-C7 cycloalkyl, substituted C2-C8 heterocycloalkyl, unsubstituted C2-C8 heterocycloalkyl, substituted C6-C12 aryl, unsubstituted C6-C12 aryl, substituted C2-C9 heteroaryl, unsubstituted C2-C9 heteroaryl, hydroxyl, C1-C5 alkylamine, carboxyl, trifluoromethyl, C2-C4 alkynyl, C2-C4 alkenyl and acylamino.
2. The derivative of claim 1, wherein the substituent of the substituted alkyl is F, cl, br, I.
3. The derivative of claim 1, wherein R is hydrogen or a structure of formula (a-1) to (a-17):
Figure FDA0004044983320000012
Figure FDA0004044983320000021
4. the derivative according to claim 1, wherein the tirapazamine derivative of formula (I) is specifically of the following structure:
Figure FDA0004044983320000022
5. a process for the preparation of a tirapazamine derivative of formula (I) according to any one of claims 1 to 4, comprising the steps of:
a) Reacting tirapazamine with p-nitrophenyl chloroformate in a solvent of an alkaline substance to obtain an intermediate product TPZ-NPC;
b) TPZ-NPC reacts with an amino compound shown as a formula (II) in a solvent to obtain the compound;
Figure FDA0004044983320000023
and R is H, substituted C1-C6 alkyl, unsubstituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, unsubstituted C3-C7 cycloalkyl, substituted C2-C8 heterocycloalkyl, unsubstituted C2-C8 heterocycloalkyl, substituted C6-C12 aryl, unsubstituted C6-C12 aryl, substituted C2-C9 heteroaryl, unsubstituted C2-C9 heteroaryl, hydroxyl, C1-C5 alkylamine, carboxyl, trifluoromethyl, C2-C4 alkynyl, C2-C4 alkenyl and acylamino.
6. The method according to claim 5, wherein the basic substance is triethylamine, pyridine, lutidine, diisopropylethylamine; the solvent is tetrahydrofuran, acetonitrile, chloroform, dichloromethane, carbon tetrachloride, benzene, toluene, dimethyl sulfoxide and dimethylformamide.
7. The preparation method according to claim 5, wherein the reaction temperature of the step A) is 20-40 ℃, preferably 25 ℃; the reaction time is 12-48 h, preferably 24h;
the reaction temperature of the step B) is 20-40 ℃, and the optimal temperature is 25 ℃; the reaction time is 12-48 h, preferably 24h.
8. Use of tirapazamine derivatives of formula (I) as defined in any one of claims 1 to 4 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of cancer.
9. The use of claim 8, wherein said cancer comprises one or more of nasal and sinus malignancies, nasopharyngeal cancer, oral cancer, laryngeal cancer, intracranial cancer, thyroid cancer, tongue cancer, lung cancer, esophageal cancer, breast cancer, stomach cancer, large intestine cancer, sigmoid and rectal cancer, liver cancer, pancreatic and peri-ampullate cancer, biliary tract cancer, kidney cancer, prostate cancer, bladder cancer, testicular malignancy, penile cancer, cervical cancer, endometrial cancer, ovarian cancer, fibrocyte cancer, rhabdomyosarcoma, synovial sarcoma, melanoma, osteosarcoma, ewing's sarcoma, leukemia, lymphoma, and multiple myeloma.
10. An anticancer drug comprising the tirapazamine derivative having the structure of formula (I) according to any one of claims 1 to 4 or the tirapazamine derivative having the structure of formula (I) prepared by the preparation method according to any one of claims 5 to 7.
CN202310026036.6A 2023-01-09 2023-01-09 Tirapazamine derivative and preparation method and application thereof Pending CN115894385A (en)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2255947A1 (en) * 1972-11-15 1974-05-22 Bayer Ag SUBSTITUTED 3-AMINO-BENZO-1,2,4TRIAZINE-DI-N-OXIDES (1,4), METHOD FOR MANUFACTURING AND USING THEM AS ANTIMICROBIAL AGENTS
GB1438179A (en) * 1972-11-15 1976-06-03 Bayer Ag Microbicidal use of 3-aminobenzo-1,2,4-triazine-1,4-di-n-oxide derivatives
GB1438180A (en) * 1972-11-15 1976-06-03 Bayer Ag 1,2,4-benzotriazine derivatives their production and their pharmaceutical and veterinary use
US4160833A (en) * 1973-02-02 1979-07-10 Ciba-Geigy Corporation 1,2,4-Benzotriazine-1,4-di-N-oxide derivatives
WO2008059259A2 (en) * 2006-11-16 2008-05-22 Sentinel Oncology Limited Anticancer compounds with a benzo ( 1, 2, 4 ) triazin-3yl-amine core
US20080234276A1 (en) * 2005-02-01 2008-09-25 Sentinel Oncology Limited Heterocyclic Triazines as Hypoxic Selective Protein Kinase Inhibitors
WO2016089208A2 (en) * 2014-12-04 2016-06-09 Stichting Maastricht Radiation Oncology "Maastro-Clinic" Sulfonamide, sulfamate and sulfamide derivatives of anti-cancer agents
CN109675039A (en) * 2018-12-21 2019-04-26 中国科学院长春应用化学研究所 Pharmaceutical composition, anti-tumor drug and application
US20190282701A1 (en) * 2016-07-25 2019-09-19 The University Of Manchester Conjugates of hyaluronic acid and anticancer compounds

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2255947A1 (en) * 1972-11-15 1974-05-22 Bayer Ag SUBSTITUTED 3-AMINO-BENZO-1,2,4TRIAZINE-DI-N-OXIDES (1,4), METHOD FOR MANUFACTURING AND USING THEM AS ANTIMICROBIAL AGENTS
GB1438179A (en) * 1972-11-15 1976-06-03 Bayer Ag Microbicidal use of 3-aminobenzo-1,2,4-triazine-1,4-di-n-oxide derivatives
GB1438180A (en) * 1972-11-15 1976-06-03 Bayer Ag 1,2,4-benzotriazine derivatives their production and their pharmaceutical and veterinary use
US4160833A (en) * 1973-02-02 1979-07-10 Ciba-Geigy Corporation 1,2,4-Benzotriazine-1,4-di-N-oxide derivatives
US20080234276A1 (en) * 2005-02-01 2008-09-25 Sentinel Oncology Limited Heterocyclic Triazines as Hypoxic Selective Protein Kinase Inhibitors
WO2008059259A2 (en) * 2006-11-16 2008-05-22 Sentinel Oncology Limited Anticancer compounds with a benzo ( 1, 2, 4 ) triazin-3yl-amine core
WO2016089208A2 (en) * 2014-12-04 2016-06-09 Stichting Maastricht Radiation Oncology "Maastro-Clinic" Sulfonamide, sulfamate and sulfamide derivatives of anti-cancer agents
US20190282701A1 (en) * 2016-07-25 2019-09-19 The University Of Manchester Conjugates of hyaluronic acid and anticancer compounds
CN109675039A (en) * 2018-12-21 2019-04-26 中国科学院长春应用化学研究所 Pharmaceutical composition, anti-tumor drug and application

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