Quinoline derivatives for the treatment of cholangiocarcinoma

Abstract

The present invention provides a quinoline derivative for use in the treatment of cholangiocarcinoma, and its use in the manufacture of a pharmaceutical composition for the treatment of tumors. In particular, the present invention relates to the use of quinoline derivative 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine in the treatment of cholangiocarcinoma:

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the use of quinoline derivatives in the preparation of drugs or pharmaceutical compositions for the treatment of cholangiocarcinoma. Background Technology

[0002] Cholangiocarcinoma is a type of malignant tumor originating from epithelial cells. Medically, cholangiocarcinoma is classified according to its anatomical location into: hilar cholangiocarcinoma (PHA), distal cholangiocarcinoma (DCCA), and intrahepatic cholangiocarcinoma (ICCA), with hilar cholangiocarcinoma being the most common.

[0003] Nataliya et al., in Lancet. Jun 21, 2014; 383(9935):2168–2179, noted that surgery is the preferred treatment for all subtypes of cholangiocarcinoma, but it is important to consider whether the tumor has invaded blood vessels and lymph nodes. The highly proliferative capacity of cholangiocarcinoma, its rich tumor microenvironment, and its profound genetic heterogeneity all contribute to its resistance to treatment. Although surgery and radical liver transplantation are the preferred treatments for patients with hilar cholangiocarcinoma, the 5-year survival rate remains very low. Chemotherapy regimens of gemcitabine and cisplatin are typically used for inoperable cases. Local treatment is used for intrahepatic cholangiocarcinoma, but conclusive evidence of its effectiveness is lacking.

[0004] In reality, due to the difficulty of early diagnosis, bile duct cancer is often diagnosed at an advanced stage, so less than 10% of patients can tolerate surgical treatment. Summary of the Invention

[0005] On one hand, the present invention provides a method for treating cholangiocarcinoma, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0006] The chemical name of the compound of formula (I) is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinoline-7-yl]oxy]methyl]cyclopropylamine, which has the following structural formula:

[0007]

[0008] On the other hand, the present invention provides the use of compound (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament or pharmaceutical composition for the treatment of cholangiocarcinoma.

[0009] In some specific embodiments of the invention, use of compound (I) or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament or pharmaceutical composition for the treatment of hilar cholangiocarcinoma, said use including administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0010] In some specific embodiments of the invention, use of compound (I) or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament or pharmaceutical composition for the treatment of distal bile duct cancer, said use including administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0011] In some specific embodiments of the invention, use of compound (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament or pharmaceutical composition for the treatment of intrahepatic cholangiocarcinoma is provided, said use including administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0012] In some specific embodiments of the invention, the use of compound (I) or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament or pharmaceutical composition for the prevention and / or treatment of moderately and / or poorly differentiated cholangiocarcinoma, said use including administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0013] In some specific embodiments of the present invention, the use of compound (I) or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament or pharmaceutical composition for the prevention and / or treatment of adenocarcinoma-type cholangiocarcinoma, said use including administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0014] In some specific embodiments of the present invention, use is provided of compound (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament or pharmaceutical composition for the treatment of advanced and / or metastatic cholangiocarcinoma, said use including administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0015] In some specific embodiments of the present invention, the use of compound (I) or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament or pharmaceutical composition for the prevention and / or treatment of recurrence of cholangiocarcinoma, said use including administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0016] In some specific embodiments of the present invention, the patients with cholangiocarcinoma have previously received chemotherapy, small molecule targeted therapy, and / or radiotherapy; in some preferred embodiments of the present invention, the patients with cholangiocarcinoma have experienced disease progression after previously receiving chemotherapy, small molecule targeted therapy, and / or radiotherapy; in some more preferred embodiments of the present invention, the chemotherapy agents previously received by the patients with cholangiocarcinoma include gemcitabine, oxaliplatin, cisplatin, 5-fluorouracil, paclitaxel, and / or tegafur; and the small molecule targeted therapy agent previously received by the patients with cholangiocarcinoma is sunitinib.

[0017] Compound (I) can be administered in its free base form, or in the form of its salt, hydrate, or prodrug, which is converted in vivo into the free base form of compound (I). For example, pharmaceutically acceptable salts of compound (I) within the scope of this invention can be produced from various organic and inorganic acids according to methods known in the art.

[0018] In some embodiments of the invention, the compound (I) is administered in the form of its hydrochloride salt. In some embodiments, the compound (I) is administered in the form of a monohydrochloride or dihydrochloride salt. In some embodiments, the compound (I) is administered in crystalline form of its hydrochloride salt. In some embodiments, the compound (I) is administered in crystalline form of its dihydrochloride salt.

[0019] Compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered via a variety of routes, including but not limited to: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, local, subcutaneous, intrafacial, intra-articular, and intrathecal administration. In some specific embodiments, oral administration is permitted, with specific dosage forms including but not limited to tablets, capsules, powders, granules, pellets, pastes, and powders, preferably tablets and capsules. Tablets may be ordinary tablets, dispersible tablets, effervescent tablets, sustained-release tablets, controlled-release tablets, or enteric-coated tablets, and capsules may be ordinary capsules, sustained-release capsules, controlled-release capsules, or enteric-coated capsules. The oral formulations may be prepared using pharmaceutically acceptable carriers known in the art through conventional methods. Pharmaceutically acceptable carriers include, but are not limited to, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants. Fillers include starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include, but are not limited to, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, etc.; binders include, but are not limited to, hydroxypropyl methylcellulose, povidone, microcrystalline cellulose, etc.; disintegrants include, but are not limited to, croscarmellose sodium, croscarmellose, surfactants, low-substituted hydroxypropyl cellulose, etc.; lubricants include, but are not limited to, magnesium stearate, talc, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talc, etc. Pharmaceutical excipients also include colorants, sweeteners, etc.

[0020] In some specific embodiments of the present invention, the daily dose given to the patient may be 2 mg to 20 mg; in some specific embodiments, the daily dose given to the patient may be 5 mg to 20 mg; in some specific embodiments, the daily dose given to the patient may be 10 mg to 16 mg; in some specific embodiments of the present invention, the daily dose given to the patient may be 10 mg to 14 mg; in some specific embodiments, the daily dose given to the patient may be 8 mg, 10 mg, 12 mg, 14 mg or 16 mg.

[0021] In the above-described treatment methods, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered once or multiple times daily in a single dose or multiple doses. In some specific embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily.

[0022] The amount of compound (I) or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the patient's age, and health status. Preferably, compound (I) or a pharmaceutically acceptable salt thereof is administered in an intermittent manner, the intermittent administration comprising a dosing period and a withdrawal period, during which compound (I) or a pharmaceutically acceptable salt thereof may be administered once or more daily. For example, compound (I) or a pharmaceutically acceptable salt thereof may be administered daily during the dosing period. Then, during the withdrawal period, administration is stopped for a period of time, followed by another dosing period, and then another withdrawal period, and this process can be repeated multiple times. The ratio of the dosing period to the withdrawal period in days is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, and more preferably 2:0.5-1.

[0023] In some specific implementation schemes, the drug is administered continuously for 2 weeks and then stopped for 2 weeks. In some specific implementation schemes, the drug is administered once daily for 14 days, then stopped for 14 days; then once daily for 14 days, then stopped for 14 days, and so on, with the interval between 14 days of continuous administration and 14 days of stoppage, which can be repeated multiple times.

[0024] In some specific implementation plans, the drug is administered continuously for 2 weeks and then stopped for 1 week. In some specific implementation plans, the drug is administered once daily for 14 days, then stopped for 7 days; then administered once daily for 14 days, then stopped for 7 days, and so on, with the interval between 14 days of continuous administration and 7 days of stoppage, which can be repeated multiple times.

[0025] In some specific implementation schemes, the drug is administered continuously for 5 days and then stopped for 2 days. In some specific implementation schemes, the drug is administered once daily for 5 days, then stopped for 2 days; then administered once daily for 5 days, then stopped for 2 days, and so on, with the interval between 5 days of continuous administration and 2 days of stopping, can be repeated multiple times.

[0026] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered alone as the sole active ingredient to patients with cholangiocarcinoma. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially to patients with cholangiocarcinoma along with other antitumor drugs. In some embodiments, the other antitumor drugs include, but are not limited to, alkylating agents, platinum complexes, fluoropyrimidine derivatives, camptothecin and its derivatives, anthraquinone antitumor antibiotics, taxane compounds, or monoclonal antibody anticancer drugs.

[0027] On the other hand, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for the treatment of cholangiocarcinoma.

[0028] In another aspect, the present invention provides a pharmaceutical composition for treating cholangiocarcinoma, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0029] In another aspect, the present invention provides a kit comprising (a) at least one unit dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) instructions for use in the treatment of cholangiocarcinoma.

[0030] Unless otherwise stated, the dosages and ranges provided herein are based on the molecular weight of the free base form of compound I.

[0031] In this document, the crystalline forms of the hydrochloride salt of compound I include, but are not limited to, the A, B, and C type crystals disclosed in Chinese patent application CN102344438A, wherein the A and B type crystals are essentially free of water of crystallization and other solvents, and the C type crystal is a crystal containing two molecules of water of crystallization. In some embodiments, the dihydrochloride salt of compound I is in the A type crystal form.

[0032] Unless otherwise stated, for the purposes of this application, the following terms used in this specification and claims shall have the following meanings.

[0033] "Patient" refers to a mammal, preferably a human.

[0034] "Pharmaceutical acceptable" means that it is used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes that it is acceptable for human pharmaceutical use.

[0035] "Pharmaceutical-acceptable salts" include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, etc.

[0036] "Therapeutic effective dose" refers to the amount of a compound that, when given to a person to treat a disease, is sufficient to control that disease.

[0037] "Treatment" means any application of a therapeutically effective amount of a compound, and includes:

[0038] (1) Inhibit the disease in a human body that is experiencing or exhibiting the pathology or symptomology of the disease (i.e., prevent the further development of the pathology and / or symptomology), or

[0039] (2) Improve the pathology or symptomology of the disease in a human body that is experiencing or exhibiting the pathology or symptomology of the disease (i.e., reverse the pathology and / or symptomology).

[0040] "CR" refers to complete remission, specifically meaning that the target lesion of the tumor is reduced, no new lesions appear, and tumor markers are normal, and this is maintained for at least 4 weeks.

[0041] "PR" refers to partial remission, specifically a reduction of more than 30% in the sum of the diameters of the target lesions of the tumor compared to the baseline level, which is maintained for at least 4 weeks.

[0042] "PD" refers to disease progression, specifically an increase of more than 20% in the sum of the diameters of the target lesions of the tumor compared to the baseline level.

[0043] "SD" refers to disease stability, specifically meaning that the reduction in tumor target lesions has not reached the PR level, nor has the increase reached the PD level, falling between the two.

[0044] "qd" means taking the medication once a day.

[0045] "bid" means taking the medication twice a day.

[0046] "Late stage" includes "local late stage". Brief description of the attached figures

[0047] Figure 1The displayed data shows the cell growth and proliferation curves measured by the CCK-8 assay in Example 3.

[0048] Figure 2 The graphs showing the average weight changes of the nude mice in each group as measured in Example 4 are as follows.

[0049] Figure 3 The image shown is a photograph of the tumor removed from a nude mouse after it was sacrificed in Example 4.

[0050] Figure 4 The graph shown is a bar chart displaying the average tumor weight of the tumors removed from each group of nude mice after sacrifice in Example 4. Detailed Implementation

[0051] Example 1

[0052] 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinoline-7-yl]oxy]methyl]cyclopropylamine dihydrochloride

[0053]

[0054] 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinoline-7-yl]oxy]methyl]cyclopropylamine was prepared according to the method of Example 24 in WO2008112407, and then the title compound was prepared according to the preparation method of the salt form in the specification.

[0055] Example 2

[0056] Preparation of capsules of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinoline-7-yl]oxy]methyl]cyclopropylamine dihydrochloride (compound of Example 1)

[0057]

[0058] The compound from Example 1 was pulverized and passed through an 80-mesh sieve; then it was mixed evenly with mannitol and hydroxypropyl cellulose; next, the prescribed amount of microcrystalline cellulose was added, mixed evenly, and passed through a 0.8 mm sieve; finally, the prescribed amount of magnesium stearate was added, mixed evenly, and then filled into capsules.

[0059] For capsules containing other amounts of the dihydrochloride of compound I, they can be prepared using the same proportions and formulation as described above.

[0060] Example 3

[0061] Cell experiments

[0062] Using the compound from Example 1 as the test drug, the inhibition of cell proliferation of the present invention against the human cholangiocarcinoma cell line huh28 was measured using the CKK-8 (Cell Counting Kit-8) method: 3000 cells per well were seeded with 100 μL of trypsin-digested cell suspension per well in a 96-well plate. The edges were wiped clean with sterile PBS. After 24 hours of adhesion, the culture medium (RMPI 1640 medium) was replaced, and 100 μL of culture medium with gradient concentrations of the drug was added to each well (6 concentrations: 0, 2, 4, 6, 8, and 10 μM). The plates were incubated at 37°C in a 5% CO2 incubator. Cell viability was measured every 24 hours after drug addition using the CCK-8 assay, i.e., 1:10 diluted CCK-8 was added, and the plates were incubated at 37°C for 2 hours. Finally, the optical density of each well was measured at 450 nm using an automated microplate reader. Based on the measured optical density, a cell growth and proliferation curve was constructed (see Appendix). Figure 1 ).

[0063] As can be seen from this example, compared with the 0 μM drug-free group, the drug-containing groups all showed a significant inhibitory effect on the cell proliferation of huh28, that is, the compound of Example 1 has a significant inhibitory effect on the cholangiocarcinoma cell line huh28.

[0064] Example 4

[0065] animal experiments

[0066] Under aseptic conditions, human cholangiocarcinoma cell line huh28 in logarithmic growth phase was subcutaneously inoculated into BALB / c nude mice at a dose of 1.5 x 10⁻⁶. 6 Cells / animal. On the third day after inoculation, animals were randomly divided into groups and administered the compound of Example 1 by gavage. The groups were divided into a solvent control group (control), a low-dose group (5 mg / kg), and a high-dose group (10 mg / kg), with 6 animals in each group. Administration was carried out Monday through Friday, and the mice were weighed (see Appendix). Figure 2 Measure the long and short diameters of the tumor and record the data (see Table 1 for details). On day 21 post-inoculation, sacrifice the mice and photograph them (see Appendix). Figure 3 ), remove the tumor, and weigh the tumor (see appendix). Figure 4 From this, we can know that...

[0067] Table 1 Animal Experiment Operation Record Sheet

[0068] 1 Weighing, measuring 2 Weighing, measuring 3 Weighing, measuring the tumor, and administering medication 6 Weighing, measuring the tumor, and administering medication 7 Weighing, measuring the tumor, and administering medication 8 Weighing, measuring the tumor, and administering medication 9 Weighing, measuring the tumor, and administering medication 10 Weighing, measuring the tumor, and administering medication 13 Weighing, measuring the tumor, and administering medication 14 Weighing, measuring the tumor, and administering medication 15 Weighing, measuring the tumor, and administering medication 16 Weighing, measuring the tumor, and administering medication 17 Weighing, measuring the tumor, and administering medication 20 Weighing, measuring the tumor, and administering medication 21 Weighing, measuring the tumor, and administering medication

[0069] This example demonstrates that, compared to the control group, tumor growth in nude mice treated with both the low-dose group (5 mg / kg) and the high-dose group (10 mg / kg) was significantly inhibited, exhibiting a marked inhibitory effect on huh28 cell proliferation. Furthermore, the body weight of the nude mice in both groups only slightly decreased after 21 days of administration, indicating good tolerance to the drug in the mice. Therefore, the compound in Example 1 exhibits a significant inhibitory effect on the huh28 cholangiocarcinoma cell line. This compound has low toxicity and shows promising clinical application potential in the treatment of cholangiocarcinoma.

[0070] Example 5

[0071] clinical trials

[0072] Inclusion criteria

[0073] 1) Patients with advanced malignant tumors diagnosed by pathology and / or cytology;

[0074] 2) Lack of conventional and effective treatment methods or failure or recurrence after conventional treatment;

[0075] 3) Ages 18–70; ECOG PS score: 0–1; expected survival time exceeding 3 months;

[0076] 4) Patients who have previously used other chemotherapy drugs must discontinue their medication for at least 30 days. If the chemotherapy drugs are nitrosoureas or mitomycin C, they must discontinue them for at least 6 weeks. Patients who have undergone major surgery must discontinue them at least 4 weeks after the surgery.

[0077] 5) Laboratory tests meet the following standards:

[0078] Complete blood count: Hb ≥ 90 g / L (no blood transfusion within 14 days); ANC ≥ 1.5 × 10⁹ / L; PLT ≥ 80 × 10⁹ / L

[0079] Biochemical tests: Serum creatinine (Cr) ≤ 1.5 upper limit of normal (ULN), bilirubin (BIL) ≤ 1.5 × ULN, ALT, AST ≤ 2.5 × ULN, ≤ 5 × ULN for patients with liver metastases; triglycerides ≤ 3.0 mmol / L, cholesterol ≤ 7.75 mmol / L;

[0080] Doppler ultrasound assessment: Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (50%).

[0081] 6) Women should agree to use contraception (such as an intrauterine device [IUD], birth control pills, or condoms) during the study and for 6 months after the study ends; have a negative serum or urine pregnancy test within 7 days prior to study enrollment; and must be a non-lactating patient. Men should agree to use contraception during the study and for 6 months after the study ends.

[0082] 7) Patients voluntarily joined this study, signed informed consent forms, and had good compliance.

[0083] A 55-year-old male patient presented with a mass in the porta hepatis compressing the bile duct, suspected to be malignant, revealed by an abdominal MRI. He underwent perihepatic resection, extended left hemihepatectomy, and portal vein reconstruction with choledochoenterostomy. Postoperative pathology revealed moderately to poorly differentiated adenocarcinoma of the porta hepatis bile duct with lymph node metastasis in 4 / 5 of the lymph nodes. More than a month later, he began systemic chemotherapy with gemcitabine and oxaliplatin for 6 cycles every 14 days. Post-treatment follow-up showed no significant abnormalities. He then received oral sunitinib for 2 months, followed by oral tegafur capsules 60mg twice daily for 2 months. 1-14 The treatment lasted 21 days x 3 cycles, and post-treatment follow-up examinations showed no obvious abnormalities. The patient was discharged and rested. Several months later, a follow-up examination revealed multiple nodules in the right abdominal cavity, the largest measuring 1.3 x 1.2 cm, and multiple small patchy shadows in the remaining abdominal cavity, suggesting peritoneal metastasis. Multiple peritoneal metastases were considered.

[0084] Treatment was then initiated with capsules of the compound from Example 1 administered orally once daily at a dose of 12 mg (two weeks of continuous use followed by one week of rest constitutes one treatment cycle).

[0085] In a CT scan prior to taking the capsule containing the compound of Example 1, the sum of the diameters of the target lesions was 15 mm (retinal metastases), and there were multiple metastases in the right lung and right supraclavicular lymph nodes (non-target lesions). During subsequent CT scans, after two cycles of treatment, the sum of the diameters of the metastatic lesions decreased to 12 mm (retinal metastases), and the non-target lesions remained stable. After four cycles of treatment, the sum of the diameters remained 12 mm (retinal metastases), and the non-target lesions remained stable, with a therapeutic evaluation of SD (stable disease). After six cycles of treatment, the sum of the diameters decreased to 10 mm (retinal metastases), and the non-target lesions remained stable, with a therapeutic evaluation of PR (partial response). After eight cycles of treatment, the sum of the diameters decreased to 11 mm (retinal metastases), and the non-target lesions remained stable, with a therapeutic evaluation of SD. After eleven cycles of treatment, the sum of the diameters decreased to 11 mm (retinal metastases), and the non-target lesions remained stable, with a therapeutic evaluation of SD. After fourteen cycles of treatment, the therapeutic evaluation remained SD, and the patient continued to receive capsule treatment with the compound from Example 1. During the fifteenth cycle of treatment, the patient experienced sudden syncope without any obvious cause, regained consciousness after one minute, and was diagnosed with acute myocardial infarction. Antithrombotic therapy was administered, and anlotinib was discontinued.

[0086] The patients generally tolerated the capsules containing the compound of Example 1 well. The main adverse reactions were grade II hypertension, grade I anemia, grade I bilirubin elevation, and grade I leukopenia.

Claims

1. Use of compound (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament or pharmaceutical composition for treating hilar cholangiocarcinoma in human patients, wherein said cholangiocarcinoma is moderately to poorly differentiated adenocarcinoma. Equation (I).

2. The use according to claim 1, wherein the cholangiocarcinoma is advanced or metastatic cholangiocarcinoma.

3. The use according to claim 1, wherein the cholangiocarcinoma is a recurrent cholangiocarcinoma.

4. The use according to claim 1, characterized in that... The drug is a preparation suitable for any of the following routes of administration: oral, parenteral, intraperitoneal, intravenous, intra-arterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, subcutaneous, intra-fat, intra-articular, or intrathecal.

5. The use according to claim 1, wherein the pharmaceutical composition is selected from tablets, capsules, powders, granules, pellets, pastes, and powders.

6. The use according to claim 1, characterized in that... The daily dose of the compound (I) or a pharmaceutically acceptable salt thereof is 5 mg to 14 mg.

7. The use according to claim 1, characterized in that... The daily dose of the compound (I) or a pharmaceutically acceptable salt thereof is 8 mg, 10 mg or 12 mg.

8. The use according to claim 1, characterized in that... The compound (I) or a pharmaceutically acceptable salt thereof is administered via a dosing and discontinuation interval; each treatment cycle consists of 3 weeks, with 2 weeks of continuous treatment followed by 1 week of discontinuation.

9. The use according to claim 1, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily in a single dose or multiple doses.

10. The use according to claim 1, further comprising one or more other antitumor drugs.

11. The use according to any one of claims 1-10, wherein the pharmaceutically acceptable salt is a salt formed by compound (I) and any of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid.

12. The use according to any one of claims 1-10, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

13. The use according to claim 12, wherein the pharmaceutically acceptable salt is a dihydrochloride.

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