CN112773797A - Application of pyrrolo six-membered heterocyclic compound in preparation of medicine for treating FLT3 mutant tumor - Google Patents
Application of pyrrolo six-membered heterocyclic compound in preparation of medicine for treating FLT3 mutant tumor Download PDFInfo
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- CN112773797A CN112773797A CN202011164008.3A CN202011164008A CN112773797A CN 112773797 A CN112773797 A CN 112773797A CN 202011164008 A CN202011164008 A CN 202011164008A CN 112773797 A CN112773797 A CN 112773797A
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- 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
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
The disclosure relates to application of a pyrrolo six-membered heterocyclic compound in preparation of a medicine for treating FLT3 mutant tumors. In particular, the disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of FLT3 mutated tumors, in particular for the preparation of a medicament for the treatment of Acute Myeloid Leukemia (AML).
Description
Technical Field
The disclosure relates to the field of medicinal chemistry, in particular to application of a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof in preparing a medicament for treating FLT3 mutant tumors.
Background
FMS-like tyrosine kinase 3(FLT3) is a protooncogene involved in key steps in hematopoiesis, such as proliferation, differentiation and survival. Diseases associated with FLT3 include leukemia, acute myeloid disease, and immature acute myelogenous leukemia, especially acute myeloid leukemia and acute lymphocytic leukemia. In recent years, FLT3 has become an important marker of different hematological malignancies, especially in acute myeloid leukemia, where the FLT3 mutation is associated with clinical prognosis, treatment and survival of the patient. The most common form of mutation in FLT3 is the internal tandem repeat (ITD), which promotes ligand-independent autophosphorylation and constitutive activation of the receptor. FLT3-ITD is closely associated with poor prognosis, leukocytosis, high primary cell count, increased risk of relapse, and shortened overall survival. The FLT3 tyrosine kinase domain mutation (FLT3-TKD) occurs in the second tyrosine kinase domain, mostly at the point mutation and deletion of codons 835 and 836 (D835/I836).
With the progress of molecular medicine, analysis and detection of leukemia oncogene variation also hold a place. The mutation of FLT3 gene was detected in about 20% of all patients with acute myelogenous leukemia. However, in up to 30% of patients with acute myelogenous leukemia with normal karyotype, mutations in FLT3 gene, mainly ITD and TKD (D835/I836), can be detected. According to the current report, the prognosis of the acute myelogenous leukemia patient with FLT3 gene mutation is poor.
Acute Myelogenous Leukemia (AML) is a hematological malignancy in which abnormal proliferation of myeloid hematopoietic blastocytes (rather than lymphoid blastocytes) occurs, and is a type of leukemia characterized by rapid proliferation of abnormal blastocysts in the bone marrow affecting the production of normal hematopoietic cells. AML is the most common acute leukemia in adults, with incidence increasing with age. AML can be primary (de novo), or can be caused by radiation exposure, carcinogenic chemical exposure, or have evolved into other hematological disorders such as myelodysplastic syndrome (myeloproliferative syndrome), myeloproliferative disorder (myeloproliferative disorder), which is called secondary AML. On the other hand, some patients have already developed AML that may be related to previous chemotherapy and radiotherapy, which is called therapy-related AML, years to decades after chemotherapy and radiotherapy are performed on other cancers, such as breast cancer and lymphoma.
Giltertinib is a new drug approved by FDA in 11 months in 2018 and used for treating acute leukemia in adults, and can inhibit FLT3 transmembrane internal tandem repeat (ITD) and FLT3 Tyrosine Kinase Domain (TKD). Phase III clinical trial results for Gilteritinib treatment of relapsed or refractory FLT3 mutant AML showed: the median overall survival for Gilteritinib was 9.3 months and rescue chemotherapy was 5.6 months (P ═ 007), and the percentage of patients with complete remission or partial hematological recovery of complete remission for Gilteritinib treatment turned almost double compared to rescue chemotherapy: 34% to 15%; the proportion of patients treated with Gilteritinib who were able to receive allogeneic stem cell transplantation (the only possible treatment) was higher (26% and 15%, respectively) compared to rescue chemotherapy.
CN101007815A discloses compounds of formula (I) and discloses that the compounds have VEGF, EGFR inhibitory activity. CN107137407A discloses that compounds of formula (I) are useful for the treatment of pancreatic cancer. CN106535896A discloses that compounds of formula (I) are useful for the treatment of fibrotic diseases, such as pulmonary fibrosis, liver cirrhosis, scleroderma or renal fibrosis.
Disclosure of Invention
The present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of FLT3 mutated tumours.
The FLT3 mutant tumor described in this disclosure is selected from the group consisting of leukemia, acute myelogenous disease, and immature acute myelogenous leukemia. In some embodiments, the leukemia is selected from chronic myelogenous leukemia, acute myelogenous leukemia, mutated chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, monocytic leukemia, leukemia-like response, aplastic anemia, preferably acute myelogenous leukemia, acute lymphocytic leukemia, or acute myelogenous leukemia, preferably acute myelogenous leukemia. In some embodiments, the FLT3 mutant tumor is a relapsed or refractory tumor.
The present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of acute myeloid leukemia. In some embodiments, the acute myeloid leukemia has the FLT3 mutation.
In some embodiments, the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia.
In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is the malate salt.
In some embodiments, the FLT3 mutation is selected from an internal tandem repeat of FLT 3(FLT 3-ITD), a FLT3 tyrosine kinase domain mutation (FLT3-TKD), or a FLT3-ITD/TKD double mutation.
In some embodiments, the FLT3 tyrosine kinase domain mutation (FLT3-TKD) may be selected from the group consisting of a point mutation and/or deletion of codons 835 and 836 (D835/I836), N676D/K, F691L, G697R, Y842C.
In an alternative embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a dosage selected from 0.1 to 1000mg, and the frequency of administration may be once a day, twice a day, three times a day, preferably once a day.
In alternative embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount selected from the group consisting of 0.1-100mg, specifically 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1.0mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 50mg, 51mg, 54mg, 62mg, 51mg, 63mg, 55mg, 62mg, 63mg, 55mg, 62mg, 23mg, 25mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, and the administration frequency may be once a day, twice a day, three times a day, preferably once a day.
In an alternative embodiment of the disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject in a dosage selected from 0.1 to 10.0mg/kg of body weight. In a regimen for administration by body weight, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.5 mg/kg, 5mg/kg, 4.5 mg/kg, 5mg/kg, 5.5 mg/kg, 2mg/kg, 2.4mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/kg, 7.2mg/kg, 7.4mg/kg, 7.6mg/kg, 7.8mg/kg, 8.0mg/kg, 8.2mg/kg, 8.4mg/kg, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0mg/kg, the frequency of administration may be once a day, twice a day, three times a day, preferably once a day.
In an alternative embodiment, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1 to 25mg, in particular 15mg, 20mg, 25mg, and the frequency of administration may be once a day, twice a day, three times a day, preferably once a day.
The present disclosure also provides a method of treating a FLT3 mutant neoplastic disease comprising administering to a patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the neoplastic disease is an FLT3 mutant acute myeloid leukemia.
An "effective amount" comprises an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: for example, the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.
Detailed Description
Example 1:
the in vitro proliferation inhibition effect of the compound malate shown in the formula (I) on MV-4-11, MOLM-13, Ba/F3-FLT3-D835V, Ba/F3-FLT3-ITD-D835V and Ba/F3 cells is detected by using CellTiter-Glo.
The test method comprises the following steps:
1. Ba/F3-FLT3-D835V, Ba/F3-FLT3-ITD-D835V, Ba/F3 cells
The compound malate of the formula (I) and a control positive compound Gilteritinib are respectively dissolved in DMSO, 1000X highest-concentration working solution with 9 concentration gradients in the following table is prepared according to a 3-fold dilution mode, stored in a 0.6mL transparent EP tube with 9 concentration gradients in total, and simultaneously, DMSO solvents with the same volume are used as blank controls, and the drug tube is stored at the temperature of-20 ℃.
TABLE 1 Malate concentration settings for Compounds of formula (I)
Sequentially diluting the prepared 9 concentration gradient 1000X highest concentration working solution medicines with RPMI 1640 cell culture medium to 20X working solution (adding 2 muL 1000X working solution into 98 muL cell culture medium), and taking logarithmic growth phase cell suspension (cell survival rate)>92%) 20 Xworking solution was diluted to 1 Xworking solution (20. mu.L of 20X compound was added to 380. mu.L of cell suspension), and then the 1 Xworking solution was seeded into 96-well white cell culture plates in a volume of 100. mu.L per well (3000 cells/well)) Each concentration gradient was 3 replicates/2 replicates, and the final assay concentrations of the different compounds are as follows, after plating was complete, 96-well plates were placed at 37 ℃ and 5% CO2Incubate in incubator for 72 hours.
The 96-well plate was loaded with 50. mu.L of CellTiter-Glo reagent per well, lysed by shaking for 2 minutes on a shaker, allowed to stand at room temperature for 10 minutes to stabilize the chemiluminescence readings using MD SpectraMax Paradigm.
The Cell Viability (CV) of the test compound was calculated using the following formula: CV (%) ═ RLU compound/RLU DMSO control (average) x 100%, RLU DMSO control refers to the reading of the solvent control wells (DMSO). Cell viability was calculated for compounds at different concentrations in Excel, followed by plotting the cell viability using GraphPad prism7.0 software and calculating IC50The value is obtained.
2. MV-4-11, MOLM-13 cells
100 μ L of cell suspension was added to each well of the 96-well plate, and the layout of the 96-well plate is shown in Table 2.
Table 296 Orifice plate layout
Remarks that Blank is not added with cells
Control＝0.2％DMSO
According to 96 hole plate layout will be added to the containing 100 u l medium cell plate hole 0.5 u l compound solution. With addition of medium and addition of fresh compound up to day 5 in culture at 5% CO2The plates were incubated at 37 ℃ for 72 hours. Add 100. mu.L CellTiter-Glo reagent to each well of 96-well plate, shake on shaker for 10 min to lyse cells, stand at room temperature for 10 min to stabilize the chemiluminescence reading, stick white back seal to transparent bottom, and record luminescence using Enspire, settings should be: luminescence, measurement time 0.1 ms.
The experimental results are as follows:
TABLE 3 inhibition of cells by malate of the compound of formula (I)
As can be seen from the results in Table 3, the activity of famitinib on FLT3 ITD cells is 3.9/4.7nM, which is equivalent to that of Giltertinib, and meanwhile, drug-resistant mutation and TKD mutation can be overcome.
Claims (11)
1. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a FLT3 mutant tumour,
2. the use of claim 1, wherein the FLT3 mutant tumor is selected from the group consisting of leukemia, acute myeloid disease, and immature acute myeloid leukemia.
3. Use according to claim 2, wherein the leukemia is selected from acute myeloid leukemia, acute lymphocytic leukemia or acute myelogenous leukemia, preferably acute myeloid leukemia.
4. The use of claim 1, wherein the FLT3 mutation is selected from the group consisting of FLT3-ITD, FLT3-TKD, and the FLT3-ITD/TKD double mutation.
5. The use according to claim 4, wherein the FLT3-TKD is selected from a point mutation and/or deletion of codons 835 and/or 836, N676D/K, F691L, G697R, Y842C.
6. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of acute myeloid leukaemia.
7. The use according to claim 1 or 6, wherein the pharmaceutically acceptable salt is the malate salt.
8. The use according to claim 6, wherein the acute myeloid leukemia has the FLT3 mutation.
9. The use according to claim 8, wherein the FLT3 mutation is selected from the group consisting of FLT3-ITD, FLT3-TKD and the FLT3-ITD/TKD double mutation.
10. The use according to claim 9, wherein the FLT3-TKD is selected from the group consisting of a point mutation and/or deletion of codon 835 and/or 836, N676D/K, F691L, G697R, Y842C.
11. The use according to claim 3 or 6, wherein the acute myeloid leukemia is relapsed or refractory acute myeloid leukemia.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116554167A (en) * | 2022-01-27 | 2023-08-08 | 成都百裕制药股份有限公司 | Deuterated indolone derivative and application thereof in medicine |
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| WO2014194242A2 (en) * | 2013-05-31 | 2014-12-04 | Nimbus Iris, Inc. | Flt3 inhibitors and uses thereof |
| CN109069410A (en) * | 2016-02-26 | 2018-12-21 | 安吉奥斯医药品有限公司 | For treating the IDH1 inhibitor of hematologic malignancies and solid tumor |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014194242A2 (en) * | 2013-05-31 | 2014-12-04 | Nimbus Iris, Inc. | Flt3 inhibitors and uses thereof |
| CN109069410A (en) * | 2016-02-26 | 2018-12-21 | 安吉奥斯医药品有限公司 | For treating the IDH1 inhibitor of hematologic malignancies and solid tumor |
Non-Patent Citations (2)
| Title |
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| 姚磊等: "FLT3 抑制剂的抗肿瘤研发现状", 《肿瘤药学》 * |
| 杨大俊: "聚焦抗肿瘤药物研究进展", 《药学进展》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116554167A (en) * | 2022-01-27 | 2023-08-08 | 成都百裕制药股份有限公司 | Deuterated indolone derivative and application thereof in medicine |
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