CN107137407B - Application of VEGFR inhibitor in preparation of medicine for treating pancreatic cancer - Google Patents
Application of VEGFR inhibitor in preparation of medicine for treating pancreatic cancer Download PDFInfo
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- CN107137407B CN107137407B CN201710110730.0A CN201710110730A CN107137407B CN 107137407 B CN107137407 B CN 107137407B CN 201710110730 A CN201710110730 A CN 201710110730A CN 107137407 B CN107137407 B CN 107137407B
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- pancreatic cancer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
Abstract
The invention relates to application of a VEGFR inhibitor in preparation of a medicine for treating pancreatic cancer. The VEGFR inhibitor can be used in combination with a Hedgehog inhibitor. The invention also relates to a pharmaceutical composition containing the two inhibitors.
Description
Technical Field
The invention relates to application of a VEGFR inhibitor in preparation of a medicine for treating pancreatic cancer.
Background
Pancreatic cancer is a malignant tumor of the digestive tract that is highly malignant and difficult to diagnose and treat, and about 90% of pancreatic cancers are ductal adenocarcinomas originating from the epithelium of the glandular duct. Its morbidity and mortality has increased dramatically in recent years. Survival rate < 1% for 5 years is one of the worst-prognosis malignancies. The early diagnosis rate of pancreatic cancer is low, the operative mortality rate is high, and the cure rate is low. The incidence rate of the disease is higher for men than for women, the ratio of men to women is 1.5-2: 1, male patients are far more common than women before menopause, and the incidence rate of postmenopausal women is similar to that of men. Pancreatic cancer has a high malignancy, a low surgical resection rate, and a poor prognosis. Although surgery remains the primary treatment, combined treatment of pancreatic cancer is required because pancreatic cancer is often found late and the chance of radical cure is lost. To date, as with most tumors, there is no comprehensive treatment regimen that is highly effective and fully applicable. The existing comprehensive treatment still takes surgical treatment as the main part and radiotherapy and chemotherapy as the auxiliary part, and a new method combining biological treatment of immunity, molecules and the like is discussed. Pancreatic cancer progression, local infiltration and metastasis are all dependent on the formation of new blood vessels. Therefore, molecular targeted therapeutic drugs against Vascular Endothelial Growth Factor Receptor (VEGFR) or its ligand have become the focus of clinical research for drug therapy of advanced pancreatic cancer at present.
CN101007815A discloses a class of multi-target protein kinase inhibitors having strong inhibitory effect on VEGFR, especially VEGFR-2, including compounds represented by the following formula (I) with chemical name 5- (2-diethylamino-ethyl) -2- (5-fluoro-2-oxo-1, 2-dihydro-indol-3-ylidene-methyl) -3-methyl-1, 5,6, 7-tetrahydro-pyrrolo [3,2-c ] pyridin-4-one, and also indicates that the concentration of VEGF is related to breast, lung, prostate and colon cancers, suggesting that these protein kinase inhibitors may be useful for treating the above tumors, but not pancreatic cancer.
CN103261198A discloses a class of Hedgehog signaling pathway inhibitors, which includes compounds of the following formula (II) with the chemical name N- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -1-methylcyclopropylformamide, and discloses that the Hedgehog signaling pathway may be associated with glioblastoma, basal cell carcinoma and pancreatic cancer.
Disclosure of Invention
The present invention surprisingly found that VEGFR inhibitors, particularly VEGFR-2 inhibitors, have a good therapeutic effect on pancreatic cancer. In a preferred embodiment of the present invention, the VEGFR inhibitor is a compound represented by formula (I) below or a pharmaceutically acceptable salt thereof. In the present invention, the VEGFR inhibitor may be used in an amount of 0.1-1000 mg/kg, preferably 1-100mg/kg, more preferably 5-20 mg/kg, said amount being measured as compound (I).
In a preferred embodiment of the present invention, the VEGFR inhibitor is used in combination with a Hedgehog signaling pathway inhibitor, which is more effective for pancreatic cancer, and particularly preferably, the Hedgehog signaling pathway inhibitor is a compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof. In the present invention, the amount of said Hedgehog signaling pathway inhibitor may be in the range of 1-1000 mg/kg, preferably 5-500 mg/kg, more preferably 10-200 mg/kg, most preferably 20-100 mg/kg, said amount being measured as compound (II). In the present invention, the combined use means that two or more drugs are administered to a subject in the same administration cycle, but whether they are administered simultaneously or not is not limited, and may be preceded and followed by a certain time interval.
The pharmaceutically acceptable salts of the compounds of formula (I) in the present invention are selected from a wide variety, such as inorganic or organic acid salts, preferably malate salts.
The compounds of formula (I) and (II) or their pharmaceutically acceptable salts can also be formulated with pharmaceutically acceptable carriers into compositions well known in the art, such as tablets, capsules, granules, injections, etc. The invention also relates to the use of a composition containing a compound selected from formula (I) and formula (II) or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of pancreatic cancer as described above.
Drawings
FIG. 1 shows the therapeutic effect of compounds (I), (II) alone or in combination on human pancreatic cancer PANC05.04 nude mouse transplantable tumors.
FIG. 2 shows the therapeutic effect of compounds (I), (II) alone or in combination on transplantation tumors of human pancreatic cancer PANC05.04 nude mice (tumor photographs).
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Example 1: evaluating the curative effect of the compound (I) and the compound (II) on the transplantation tumor of the human pancreatic cancer PANC05.04 nude mouse singly or in combination.
1 test drugs
The test compound (I) and the compound (II) were synthesized in accordance with the disclosures of CN101007815A and CN103261198A, respectively. The preparation method comprises the following steps: compound (I) was formulated with distilled water and compound (II) was formulated with 30% PEG 400.
2 laboratory animals
BALB/cA-nude mice, 6-7 weeks old, purchased from Shanghai Spiker laboratory animals, Inc. Certificate number: SCXK (Shanghai) 2012-0002. A breeding environment: SPF grade.
3 Experimental procedures
Nude mice are inoculated with human pancreatic cancer PANC05.04 cells subcutaneously until the tumor grows to 100-3Thereafter, the animals were randomly assigned (D0). The dosage and schedule of administration are shown in table 1. Tumor volumes were measured 2-3 times a week, mice weighed, and data recorded. Tumor volume (V) was calculated as:
V＝1/2×a×b2wherein a and b represent length and width, respectively.
T/C(％)＝(T-T0)/(C-C0) X 100 where T, C is the tumor volume at the end of the experiment; t is0、C0Tumor volume at the beginning of the experiment.
4 results
The compound (I) (10mg/kg, PO, QD multiplied by 14) can obviously inhibit the growth of subcutaneous transplantation tumor of a nude mouse with human pancreatic cancer PANC05.04 by using the compound (I) alone, and the tumor inhibition rate is 74 percent; the compound (II) (50mg/kg, PO, QD multiplied by 14) has no obvious curative effect on PANC05.04 by singly using, and the tumor inhibition rate is 24 percent; the tumor-bearing mice can better tolerate the two medicines and have no symptoms such as obvious weight loss and the like. When the two drugs are used together, the tumor inhibition rate is obviously enhanced to 95 percent, and 2/8 mice are caused to partially regress (P <0.01 compared with the single drug).
TABLE 1 curative effects of Compound (I), Compound (II) alone or in combination on human pancreatic cancer PANC05.04 nude mouse transplantable tumor
D0 time to first dose. P-value refers to Student's t' test compared to control; p <0.01vs compound (I)10mg/kg group. Control group n is 10 and treatment group n is 8.
5 conclusion
Compound (I) (10mg/kg, PO, QD × 14) alone significantly inhibited the growth of subcutaneous transplantable tumors in nude mice with human pancreatic cancer PANC 05.04; compound (II) (50mg/kg PO, QD × 14) alone had no significant effect on PANC 05.04; the combination of the two has obviously enhanced tumor inhibition rate, which shows that the compound (II) has obvious synergistic effect on the compound (I) to treat subcutaneous transplantation tumor of PANC05.04 nude mice.
Claims (11)
1. The application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof and the compound shown in the formula (II) or the pharmaceutically acceptable salt thereof in preparing the medicament for treating pancreatic cancer,
2. the use according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in an amount of 0.1-1000 mg/kg.
3. The use according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in an amount of 1-100 mg/kg.
4. The use according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in an amount of 5-20 mg/kg.
5. The use according to claim 1, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is used in an amount of 1-1000 mg/kg.
6. The use according to claim 1, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is used in an amount of 5-500 mg/kg.
7. The use according to claim 1, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is present in an amount of 10-200 mg/kg.
8. The use according to claim 1, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is used in an amount of 20-100 mg/kg.
9. The use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula (I) is the malate salt.
10. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier.
11. Use of the pharmaceutical composition of claim 10 in the manufacture of a medicament for the treatment of pancreatic cancer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610115261 | 2016-03-01 | ||
| CN2016101152617 | 2016-03-01 |
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| CN107137407A CN107137407A (en) | 2017-09-08 |
| CN107137407B true CN107137407B (en) | 2021-07-27 |
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| CN201710110730.0A Active CN107137407B (en) | 2016-03-01 | 2017-02-28 | Application of VEGFR inhibitor in preparation of medicine for treating pancreatic cancer |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116283940A (en) * | 2017-12-07 | 2023-06-23 | 哈尔滨珍宝制药有限公司 | Salt form and crystal form used as FGFR and VEGFR inhibitor compound and preparation method thereof |
| WO2020177678A1 (en) * | 2019-03-04 | 2020-09-10 | 江苏恒瑞医药股份有限公司 | Use of multi-target tyrosine kinase inhibitor in combination with egfr inhibitor in preparing drug for treating tumor |
| CN113491693B (en) * | 2020-03-19 | 2023-11-14 | 江苏恒瑞医药股份有限公司 | Application of famotidine or pharmaceutically acceptable salt thereof in preparing medicament for treating Ras mutation disease |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103261198A (en) * | 2010-12-22 | 2013-08-21 | 江苏恒瑞医药股份有限公司 | 2-arylimidazo[1,2-]pyridazine, 2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives |
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2017
- 2017-02-28 CN CN201710110730.0A patent/CN107137407B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103261198A (en) * | 2010-12-22 | 2013-08-21 | 江苏恒瑞医药股份有限公司 | 2-arylimidazo[1,2-]pyridazine, 2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives |
Non-Patent Citations (3)
| Title |
|---|
| Cen Xie等.Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients.《British Journal of Pharmacology》.2013,第168卷(第7期),1687-1706. * |
| Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients;Cen Xie等;《British Journal of Pharmacology》;20131231;第168卷(第7期);1687-1706 * |
| Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib;Aiping Zhou等;《Cancer Chemother Pharmacol》;20130917;第72卷(第5期);1043-1053 * |
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