CN111012785B

CN111012785B - Methods and uses of quinoline derivatives for treating thyroid cancer

Info

Publication number: CN111012785B
Application number: CN201910645272.XA
Authority: CN
Inventors: 张喜全; 王训强; 湛筱乐; 于鼎; 田心; 杨玲
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2014-06-06
Filing date: 2015-06-05
Publication date: 2024-01-30
Anticipated expiration: 2035-06-05
Also published as: WO2015185011A1; CN111012785A; CN105213394A; KR102490547B1; CN106413712A; CN111035640B; KR20170007789A; CN106413712B; CN111035640A; CN105213394B

Abstract

The present invention relates to methods and uses of quinoline derivatives for the treatment of thyroid cancer and pharmaceutical compositions for the treatment of thyroid cancer. In particular, the invention relates to methods and uses of quinoline derivative 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine for treating thyroid cancer and pharmaceutical compositions for treating thyroid cancer.

Description

Methods and uses of quinoline derivatives for treating thyroid cancer

The invention relates to a Chinese application (the name of the invention: a method and application of quinoline derivatives for treating thyroid cancer and a pharmaceutical composition for treating thyroid cancer; the application is divided into 2015, 6, 5 and 201580026812.6).

The present invention claims priority to chinese application number 201410249544.1 filed on 6/2014, 6, and incorporated herein by reference in its entirety.

Technical Field

The invention belongs to the field of medicines, and relates to a method and application of quinoline derivatives in treating tumors and a pharmaceutical composition for treating tumors. In particular, the invention relates to methods and uses of quinoline derivatives for the treatment of thyroid cancer and pharmaceutical compositions for the treatment of thyroid cancer.

Background

Thyroid cancer is a malignant tumor derived from thyroid epithelial cells, is one of the most common cancer tumors of the head and neck, and is also a very common endocrine gland malignant tumor. Thyroid cancer accounts for about 1.3% -1.5% of the malignant tumors of the whole body, and has a remarkable rising trend in recent years in global morbidity, and is one of the malignant tumors of great concern.

Thyroid cancer is generally classified into differentiated thyroid cancer (including papillary thyroid cancer and follicular thyroid cancer), poorly differentiated thyroid cancer (such as medullary thyroid cancer (medullary thyroid carcinoma, MTC)) and undifferentiated thyroid cancer.

Papillary thyroid carcinoma is a differentiated thyroid carcinoma, and is also the most common thyroid carcinoma, accounting for about 75% -85% of the total number; lesions are generally single shot and vary in size. The cancer has low malignant degree, and the survival rate of 10 years can reach 88%.

Thyroid follicular cancer accounts for 10% -15% of the total number of thyroid cancers, which are mostly seen in middle-aged and elderly women aged 40-60 years, and has clinical manifestations similar to papillary carcinoma, but the cancer mass is generally larger, fewer regional lymph node metastases, and more distant metastases. Few follicular thyroid cancers infiltrate and destroy adjacent tissues, and may present symptoms such as airway obstruction.

Medullary thyroid carcinoma is a tumor originating in thyroid C cells or perifollicular cells, accounting for about 5% -10% of thyroid malignant tumors, and is a moderate malignancy with a malignancy between papillary carcinoma and undifferentiated carcinoma. Hazard et al in 1959 described the disease for the first time, and MTC patients were more female than male, frequently seen in middle-aged and young patients, and had localized infiltration growth and early appearance of lymphatic metastasis in the blood tract. MTC is clinically divided into two types, hereditary myeloid cancer (MTC) and sporadic myeloid cancer (sporadic MTC).

The thyroid undifferentiated carcinoma is highly malignant, is less frequently about 1% -2% of all thyroid carcinomas, and is good for the elderly. Undifferentiated carcinoma grows rapidly, often early invading surrounding tissue.

Common treatment methods for thyroid cancer include surgical treatment, chemotherapy, endocrine treatment, radiation treatment, and the like. Among them, surgical treatment is an effective means for eliminating tumors, but tends to promote metastasis, and it is difficult to eliminate microscopic lesions; most patients have missed the best opportunity for surgery when they find a tumor. Differentiated thyroid cancer responds poorly to chemotherapy and is used only selectively in combination with other therapies in some patients with advanced local unresectable or distant metastasis. Endocrine therapy has only inhibitory effect on thyroid tissue hyperplasia and differentiated cancers, and is often used for treatment of preventing recurrence and metastasis. Various types of thyroid cancer have very different sensitivity to radiation, and radiation can reduce the immunity of the organism, affecting the further treatment of patients.

Vandetanib (Vandetanib, ZD6474, trade name Zactima, structural formula below) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of Medullary Thyroid Carcinoma (MTC) on month 4 and 6 of 2011. The drug is developed by the company of Aspirin, is an oral small molecule multi-target tyrosine kinase inhibitor, and mainly acts on transfection Rearrangement (RET) tyrosine kinase, epidermal Growth Factor Receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2).

Cabozitinib (COMETRIQ) ^TM Cabozantinib, structural formula below) is an FDA approved oral small molecule kinase inhibitor for the treatment of thyroid medullary carcinoma (MTC) at 11, 2012.

The role of many small molecule Tyrosine Kinase Inhibitors (TKIs) in the treatment of thyroid cancer has been further evaluated to date. More medicines are to be developed in order to achieve better therapeutic effects, improve survival rate and bring substantial benefits to patients.

Disclosure of Invention

In a first aspect, the present invention provides a method of treating thyroid cancer comprising administering to a patient in need thereof a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof.

In a second aspect, the present invention provides the use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of thyroid cancer.

In a third aspect, the present invention provides a pharmaceutical composition for the treatment of thyroid cancer comprising compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In the present invention, the "thyroid cancer" includes, but is not limited to, papillary thyroid cancer, follicular thyroid cancer, and medullary thyroid cancer.

Detailed Description

In a first aspect, the present invention provides a method of treating thyroid cancer comprising administering to a patient in need thereof a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof. Such thyroid cancers include, but are not limited to, papillary thyroid cancers, follicular thyroid cancers, and medullary thyroid cancers.

In some embodiments of the invention, there is provided a method of treating papillary thyroid cancer comprising administering to a patient in need of treatment a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, there is provided a method of treating thyroid follicular cancer, the method comprising administering to a patient in need of treatment a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, there is provided a method of treating thyroid medullary cancer, the method comprising administering to a patient in need of treatment a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof. The medullary thyroid carcinoma includes hereditary medullary carcinoma and sporadic medullary carcinoma.

In some embodiments of the invention, there is provided a method of treating advanced medullary thyroid cancer, the method comprising administering to a patient in need of treatment a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof.

Compound I may be administered in its free base form, or in the form of its salts, hydrates and prodrugs which are converted in vivo to the free base form of compound I. For example, pharmaceutically acceptable salts of compound I are within the scope of the invention, which salts can be produced from different organic and inorganic acids according to methods well known in the art.

In some embodiments, the compound I hydrochloride salt is administered. In some embodiments, the compound I monohydrochloride is administered. In some embodiments, the compound I dihydrochloride is administered. In some embodiments, the compound I hydrochloride salt is administered in crystalline form. In a particular embodiment, the compound I dihydrochloride is administered in crystalline form.

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

compound I or a pharmaceutically acceptable salt thereof may be administered by a variety of routes including, but not limited to, those selected from the group consisting of: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhaled, vaginal, intraocular, topical, subcutaneous, intraadipose, intra-articular, intraperitoneal and intrathecal. In a particular embodiment, the administration is by oral administration.

The amount of compound I or a pharmaceutically acceptable salt thereof administered may be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered in the range of 2mg to 20 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered in the range of 5 mg to 20 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered in the range of 8 mg to 20 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered is from 10mg to 16 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered is from 10mg to 14 mg. In a particular embodiment, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered at 10 mg. In a particular embodiment, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered at 12 mg. In a particular embodiment, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered at 14 mg. In a particular embodiment, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered at 16 mg.

Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered once daily. Compound I or a pharmaceutically acceptable salt thereof may also be administered in single or multiple dose form. In one embodiment, the administration is 1 time per day. In one embodiment, the administration is 1 time per day in a single dose. In one embodiment, the oral solid formulation is administered once daily in a single dose.

The method of administration can be determined comprehensively based on the activity, toxicity, tolerance of the patient, etc. Preferably, compound I or a pharmaceutically acceptable salt thereof is administered in a divided dosing regimen.

The interval administration includes administration period and withdrawal period, and the compound I or a pharmaceutically acceptable salt thereof may be administered once or more times daily during the administration period. For example, compound I or a pharmaceutically acceptable salt thereof may be administered daily during the administration period, followed by discontinuation of administration for a period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which may be repeated a number of times. Wherein the ratio of the administration period to the withdrawal period in days is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, more preferably 2:0.5-1.

In some embodiments, administration is stopped for 2 weeks following 2 weeks of administration. In some embodiments, administration is 1 time per day for 14 days, followed by 14 days of discontinuation; the administration is then continued for 14 days and then for 14 days, 1 time per day, and the administration is repeated at intervals of 2 weeks for 2 weeks.

In some embodiments, administration is stopped for 1 week for 2 weeks. In some embodiments, administration is 1 time per day for 14 days, followed by 7 days of discontinuation; the administration is then continued for 14 days and then for 7 days 1 time per day, and the administration is repeated at intervals of 1 week for 2 weeks.

In some embodiments, administration is stopped for 2 days 5 days continuously. In some embodiments, administration is 1 time per day for 5 days, followed by 2 days of discontinuation; the administration is then continued 1 time per day for 5 days and then stopped for 2 days, so that the administration mode of stopping for 2 days at intervals of 5 days in succession can be repeated for a plurality of times.

In one embodiment, compound I or a pharmaceutically acceptable salt thereof is administered alone to a patient as the sole active ingredient.

In a second aspect, the present invention provides the use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of thyroid cancer. Such thyroid cancers include, but are not limited to, papillary thyroid cancers, follicular thyroid cancers, and medullary thyroid cancers.

In some embodiments of the invention, there is provided the use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of papillary thyroid cancer.

In some embodiments of the invention, there is provided the use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of thyroid follicular cancer.

In some embodiments of the invention, there is provided the use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of medullary thyroid cancer. Wherein, the thyroid medullary cancer comprises hereditary medullary cancer and sporadic medullary cancer.

In some embodiments of the invention, there is provided the use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of advanced medullary thyroid cancer.

Compound I may be in its free base form, or in the form of its salts, hydrates and prodrugs which are converted in vivo to the free base form of compound I. For example, pharmaceutically acceptable salts of compound I are within the scope of the invention, and salts may be produced from various organic and inorganic acids according to methods well known in the art.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof is the hydrochloride salt form of compound I. In some embodiments, in the form of compound I monohydrochloride. In some embodiments, in the form of compound I dihydrochloride. In some embodiments, is a crystalline form of compound I hydrochloride. In a particular embodiment, is a crystalline form of compound I dihydrochloride.

The amount of compound I or a pharmaceutically acceptable salt thereof may be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered in the range of 2mg to 20 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered in the range of 5 mg to 20 mg. In some embodiments, the amount of compound I or a pharmaceutically acceptable salt thereof is from 8 mg to 20 mg. In some embodiments, the amount of compound I or a pharmaceutically acceptable salt thereof is from 10mg to 16 mg. In some embodiments, the amount of compound I or a pharmaceutically acceptable salt thereof is from 10mg to 14 mg. In a particular embodiment, the amount of compound I or a pharmaceutically acceptable salt thereof is 10 mg. In a particular embodiment, the amount of compound I or a pharmaceutically acceptable salt thereof is 12 mg. In a particular embodiment, the amount of compound I or a pharmaceutically acceptable salt thereof is 14 mg. In a particular embodiment, the amount of compound I or a pharmaceutically acceptable salt thereof is 16 mg.

In a third aspect, the present invention provides a pharmaceutical composition for the treatment of thyroid cancer comprising compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. Such thyroid cancers include, but are not limited to, papillary thyroid cancers, follicular thyroid cancers, and medullary thyroid cancers.

In some embodiments of the present invention, there is provided a pharmaceutical composition for treating papillary thyroid cancer comprising compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments of the present invention, there is provided a pharmaceutical composition for treating thyroid follicular cancer comprising compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments of the present invention, there is provided a pharmaceutical composition for treating thyroid medullary cancer comprising compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The medullary thyroid carcinoma includes hereditary medullary carcinoma and sporadic medullary carcinoma.

In some embodiments of the present invention, there is provided a pharmaceutical composition for treating advanced medullary thyroid cancer comprising compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

Compound I may be in its free base form, or in the form of a salt, hydrate or prodrug which is converted in vivo to the free base form of compound I. For example, pharmaceutically acceptable salts of compound I are within the scope of the invention, and salts may be produced from various organic and inorganic acids according to methods well known in the art.

The amount of compound I or a pharmaceutically acceptable salt thereof administered may be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered in the range of 2mg to 20 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is administered in the range of 5 mg to 20 mg. In some embodiments, the amount of compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is from 8 mg to 20 mg. In some embodiments, the amount of compound I or a pharmaceutically acceptable salt thereof is from 10mg to 16 mg. In some embodiments, the amount of compound I or a pharmaceutically acceptable salt thereof is from 10mg to 14 mg. In a particular embodiment, the amount of compound I or a pharmaceutically acceptable salt thereof is 10 mg. In a particular embodiment, the amount of compound I or a pharmaceutically acceptable salt thereof is 12 mg. In a particular embodiment, the amount of compound I or a pharmaceutically acceptable salt thereof is 14 mg. In a particular embodiment, the amount of compound I or a pharmaceutically acceptable salt thereof is 16 mg.

In some embodiments of the invention, the pharmaceutical composition is a formulation suitable for oral administration, including tablets, capsules, powders, granules, drops, pastes, powders, and the like, preferably tablets and capsules. Wherein the tablet can be common tablet, dispersible tablet, effervescent tablet, sustained release tablet, controlled release tablet or enteric-coated tablet, and the capsule can be common capsule, sustained release capsule, controlled release capsule or enteric-coated capsule. The oral formulations may be prepared by conventional methods using pharmaceutically acceptable carriers well known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like. Fillers include starch, lactose, mannitol, microcrystalline cellulose, and the like; the absorbent comprises calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, and the like; the binder comprises hypromellose, povidone, microcrystalline cellulose, etc.; the disintegrating agent comprises croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose and the like; the lubricant comprises magnesium stearate, talcum powder, polyethylene glycol, sodium dodecyl sulfate, micro silica gel, talcum powder and the like. The pharmaceutical excipients also comprise coloring agents, sweeteners, etc.

In one embodiment, the pharmaceutical composition is a solid formulation suitable for oral administration. The composition may be in the form of a tablet or capsule, for example. In a particular embodiment, the pharmaceutical composition is a capsule. In a particular embodiment of the invention, the pharmaceutically acceptable carrier of the oral solid formulation comprises mannitol, microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate.

In one embodiment, a pharmaceutical composition formulated in a single dose form for treating thyroid cancer is provided. In one embodiment, the single dosage form contains 2mg to 20 mg of compound I or a pharmaceutically acceptable salt thereof. In one embodiment, the single dosage form contains 5 mg to 20 mg of compound I or a pharmaceutically acceptable salt thereof. In one embodiment, the single dosage form contains 8 mg to 20 mg of compound I or a pharmaceutically acceptable salt thereof, preferably 10mg to 16mg of compound I or a pharmaceutically acceptable salt thereof, more preferably 10mg to 14 mg of compound I or a pharmaceutically acceptable salt thereof. In a particular embodiment, the pharmaceutical composition contains 10mg of compound I or a pharmaceutically acceptable salt thereof. In a particular embodiment, the pharmaceutical composition contains 12mg of compound I or a pharmaceutically acceptable salt thereof. In a particular embodiment, the pharmaceutical composition contains 14 mg of compound I or a pharmaceutically acceptable salt thereof. In a particular embodiment, the pharmaceutical composition contains 16mg of compound I or a pharmaceutically acceptable salt thereof.

Preferably, the above pharmaceutical compositions are administered in a spaced-apart administration. The interval administration includes administration period and withdrawal period, and the above pharmaceutical composition may be administered once or more times daily during the administration period. For example, the pharmaceutical composition may be administered daily during the administration period, followed by a period of discontinuance during the withdrawal period, followed by a period of administration, and then a withdrawal period, which may be repeated a number of times. Wherein the ratio of the administration period to the withdrawal period in days is from 2:0.5 to 5, preferably from 2:0.5 to 3, more preferably from 2:0.5 to 2, more preferably from 2:0.5 to 1.

In some embodiments of the invention, the thyroid cancer is advanced thyroid cancer.

The dosages and ranges provided herein are based on the molecular weight of the free base form of compound I, unless otherwise indicated.

Herein, qd refers to once daily administration unless otherwise indicated.

The crystal forms of the hydrochloride of the compound I described herein include, but are not limited to, A, B and form C crystals disclosed in chinese patent application CN102344438A, wherein the forms a and B crystals are crystals substantially free of water of crystallization and other solvents, and the form C crystals are crystals containing two water of crystallization. In some embodiments, the crystalline form of the dihydrochloride salt of compound I is form a crystals.

For the purposes of this application, the following terms, as used in the specification and claims, shall have the following meanings, unless otherwise indicated.

"patient" means a mammal, preferably a human. In some embodiments, the patient is a patient who has failed standard therapy or lacks standard therapy.

By "pharmaceutically acceptable" is meant 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.

"pharmaceutically acceptable salts" include, but are not limited to, acid addition salts with mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like; or with an organic acid such as acetic acid, trifluoroacetic acid, propionic acid, caproic 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, t-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and the like.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a human being for treating a disease, is sufficient to effect treatment of the disease.

"treatment" means any administration of a therapeutically effective amount of a compound and includes:

(1) Inhibiting the disease in a human experiencing or exhibiting the pathology or symptomology of the disease (i.e., inhibiting further development of the pathology and/or symptomology), or

(2) Improving the disease in a human experiencing or exhibiting the pathology or symptomology of the disease (i.e., reversing the pathology and/or symptomology).

Examples

Example 1 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine dihydrochloride (dihydrochloride of Compound I)

The title compound was prepared by the method of example 24 in WO2008112407 to give 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine and then by the method of "example in salt form" in the specification of WO 2008112407.

Or by reference to the method disclosed in chinese patent application CN 102344438A.

Example 2 capsules containing 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine dihydrochloride (dihydrochloride of Compound I)

Crushing the dihydrochloride of the compound I, and sieving the crushed dihydrochloride with a 80-mesh sieve; then evenly mixing with mannitol and hydroxypropyl cellulose; then adding microcrystalline cellulose with the prescription amount, uniformly mixing, and sieving with a 0.8mm sieve; and finally adding the magnesium stearate with the prescription amount, uniformly mixing, and filling the capsule.

For capsules with other contents of dihydrochloride of compound I, reference can be made to the same proportions and formulations described above.

EXAMPLE 3 tolerance of Compound I dihydrochloride Capsule treatment and efficacy study on medullary thyroid carcinoma

1) Results of tolerability studies

It is clear from the diagnosis that the patients with malignant tumors failed or lacking the standard treatment continue to observe the tolerance and efficacy by taking continuous administration for 2 weeks and 1 week, that is, 3 weeks (21 days) as one treatment period, and maintaining at least 2 periods (42 days).

The administration is carried out 1 time a day, 10mg of each administration is carried out, adverse reactions of 3 patients comprise 1 case of rise of III degree and above fat and amylase, 1 case of II degree hypodynamia, and other adverse reactions of I degree comprise 2 cases of hoarseness, diarrhea, 1 case of abdominal pain, 1 case of hypertension and the like.

The administration was carried out 1 time a day, 16mg each time, and 1 case of III-degree blood pressure elevation and debilitation occurred when 3 patients were administered 2 times during 2 nd cycle and 2 nd week.

Other adverse reactions occurring during the study in this group included 1 case of II degree hypertension, 2 cases of reduced thyroid function, 1 case of ALT elevation; increased level of triglyceride is 2, diarrhea, abdominal pain is 2, hand syndrome is 1, hoarseness is 1, etc.

The group was observed for a total of 18 patients (5 of which were given) at 12mg each given 1 dose per day. Adverse reactions of different degrees appear in the process of medication. The severity is 1-2 degrees, and no adverse reaction of 3 degrees or more occurs yet. The specific cases include:

blood lipid: triglyceride increased by 8 cases, total cholesterol increased by 7 cases;

liver function: total bilirubin increases by 4, ALT increases by 4, AST increases by 5; creatinine elevation 1 case;

skin toxicity: 6 cases of skin reaction of hands and feet and 4 cases of rash;

endocrine system: low cases of nail, 2 cases of hyperthyroidism, 3 cases of amylase rise, and 2 cases of CK-MB rise;

symptoms: 6 cases of hypodynamia, 4 cases of hoarseness, 6 cases of diarrhea, 2 cases of dizziness and headache, 3 cases of toothache and 3 cases of muscular soreness; nausea, 3 cases of appetite decrease, 1 case of tinnitus, fever and insomnia;

other: hypertension 5, haematuria 5, proteinuria 5, WBC drop 3.

2) Preliminary curative effect on medullary thyroid carcinoma

Medullary thyroid carcinoma (12 mg once daily): a total of 6 subjects, 1 failed to evaluate, 4 were SD (disease stable) (small), and 1 were PD (disease progression). The thyroid medullary cancer benefit rate is more than 80%.

The dosages referred to in this example are all calculated as compound I free base.

The compound I hydrochloride capsule adopts a dosage regimen of 12 mg/day, wherein the dosage regimen is continuously used for two weeks and stopped for one week, the overall tolerance is very good, the adverse reaction is 1/2 ℃, and other unexpected adverse reactions are not observed; in terms of curative effect, the composition has the benefit of treating medullary thyroid cancer.

EXAMPLE 4 efficacy against medullary thyroid carcinoma

1) Medical history of patient

A 56 year old male, 10 2005, unintentionally found cervical tumor, and underwent a tumor resection. Left cervical tumor was found in 1 month physical examination in 2007, 1 month in 2007, "cervical tumor resection+lymphadenectomy", postoperative pathology: medullary thyroid carcinoma; 10 lymph nodes were detected in the tissue of "left subclavian lymph node", and cancer metastasis was observed, and 2 cancer nodules were detected. Neck radiotherapy is carried out 49 times from 2 months in 2007 to 4 months in 2007. The specific drugs are not detailed in the postoperative chemotherapy 2 cycles of 5 months 2007. Periodic review, 10 months 2012, found an enlargement of the mediastinal lymph nodes, considering metastasis for further treatment. At present, you Jia le 100ug qd is orally taken.

Oral compound I dihydrochloride capsule 12mg qd treatment was started on 8 and 6 2013, and was discontinued for two weeks and one week continuously.

2) CT results

Imaging evaluation at 8.3.2013: target lesion diameter and 49mm;

imaging evaluation of 2013, 9 and 10: target lesion diameter and 44mm;

imaging evaluation at 10.2013, 26 days: target lesion diameter and 42mm;

imaging evaluation of 12/9/2013: target lesion diameter and 41mm;

imaging evaluation of 2014, 1 month, 20 days: target lesion diameter and 41mm;

imaging evaluation of 2014, 4, 11: target lesion diameter and 41mm;

imaging evaluation of 2014, 7 and 9: target lesion diameter and 40mm;

imaging evaluation at 2014, 9, 26: target lesion diameter and 38mm.

3) Tolerance to

The overall tolerability was good. Only occasional i°diarrhea, i°leukopenia, i°hand-foot skin reactions, i°muscle soreness, i°pharyngalgia, i°proteinuria, i°bilirubin elevation, i°hypertension, i°neutrophil count reduction, i°low density lipoprotein elevation, i°gastralgia, i°cholesterol elevation, i°appetite reduction, i°diarrhea, i°toothache, and ii°leukopenia occur, and the above reactions are ameliorated, restored, or alleviated in a short period of time.

EXAMPLE 5 efficacy against papillary thyroid carcinoma

1) Medical history of patient

56 year old female, 2010 line bilateral thyroidectomy, postoperative pathology: bilateral papillary thyroid carcinoma, metastasis of right cervical lymph node. The right tracheal side tumor is treated by the tumor resection again in 2012, the thyroid papillary carcinoma affects the trachea after the operation, the disease is not treated, the dyspnea is caused in 10 months in 2013, the dysphagia is free from dysphagia symptoms, the pathological diagnosis is the tracheal transfer of the thyroid papillary carcinoma by the fiber laryngoscope, the recurrence focus expansion resection is carried out in 11 months in 2013, and the tracheostomy is carried out. The CT of neck chest in 2014, 5 months, reviews the two lung nodules, and considers the disease progress. Hypertension and diabetes mellitus are 5 years old, and irbesartan hydrochlorothiazide 1 granule/tablet and qd are taken for a long time.

Oral compound I dihydrochloride capsule 12mg qd treatment was started on 6 and 3 months 2014, and was discontinued for two weeks and one week continuously.

2) CT results

Imaging evaluation at 2014, 5 and 12 days: target lesion diameter and 10mm;

imaging evaluation of 2014, 7, 14: target lesion diameter and 0mm, target lesion evaluation results were CR (complete remission);

imaging evaluation at 2014, 09, 25: target lesion diameter and 0mm, non-target lesions are reduced;

11.24-day imaging evaluation 2014: target lesion diameter and 0mm;

imaging evaluation of 2015, 01, 20 days: target lesion diameter and 0mm.

3) Tolerance to

The overall tolerability was good. Only occasional I muscle soreness, I weakness, I waist soreness, I cough, I toothache, I hemoptysis, I finger skin reactions which turn well or return to normal within a short period of time appear.

EXAMPLE 6 therapeutic Effect on follicular thyroid carcinoma

1) Medical history of patient

67 year old female, "left thyroidectomy+right thyroidectomy", 8 months of 2007, postoperative pathology: follicular carcinoma of the left thyroid gland. The 2007 9-month PET-CT examination showed double lung and left ilium metastasis. Right thyroidectomy was performed at 9 months 2007. Postoperative pathology shows: right nodular goiter with fibrosis and granuloma on silk. Thyroxine tablet replacement therapy has been orally administered after surgery. Treatment with month 9 2007 to month 6 2011 was 11 times. The thp+l-ohp+cf+ft-207 regimen (i.e. "pirarubicin+oxaliplatin+calcium folinate+pyranfludine" regimen) was treated with biotherapy 4 times from 11 months 2007 to 10 months 2009) multiple times. Left ilium local radiotherapy is performed in 2009 for 11 months, and the dosage is 3000Gy. Review of PET-CT 10 months 2011 suggests multiple metastasis in both lungs and multiple bone metastases. Treatment with pamidronate disodium was applied since 2011, with local injection of only metaplasia treatment for right scapular metastasis. Left femur bone tumor resection, bone cement filling and dynamic hip internal fixation at 11 months 2011. Right scapula segmental resection at 3 months 2012, postoperative pathology: metastatic follicular thyroid carcinoma. Left femoral osteoma segment osteotomy in 6 months 2012 + artificial hip arthroplasty. And (3) performing bone metastasis palliative radiotherapy in 2012 and 9 months. Regional radiation therapy of chest wall metastasis in 2013 month 1 and regional radiation therapy of lung metastasis in 2013 month 2. Right axillary lymph node dissection performed in row 4 of 2013. Intermittent oral sorafenib treatment from 12 months 2012 to 10 months 2013. Patients find hypertension for 1 year, and currently take telmisartan 40mg qd orally.

Oral compound I dihydrochloride capsule 12mg qd treatment was started on 11.14.2013, and was discontinued for two weeks and one week continuously. The dosage of the compound I dihydrochloride capsule is reduced to 10mg qd treatment in 3 and 20 days of 2014, and the dosage is stopped for one week after two weeks; the dosing regimen of 7.3.2014 was changed to compound I dihydrochloride capsule 10mg qd treatment, and the administration was stopped for two weeks and two weeks continuously.

2) CT results

Imaging evaluation of 11.11.2013: target lesion diameter and 33mm;

imaging evaluation of 12/23/2013: target lesion diameter and 25mm, 24% reduction;

imaging evaluation at 2014, 1, 28 days: target lesion diameter and 23mm, 30% decrease;

imaging evaluation at 3 months and 17 days 2014: target lesion diameter and 19mm, 42% reduction;

imaging evaluation at 2014, 4, 28: target lesion diameter and 17mm, 49% decrease;

imaging evaluation of 2014, 6, 27: target lesion diameter and 17mm, 49% decrease;

imaging evaluation of 10 months and 16 days in 2014: target focus diameter and 5mm, reduced by 85%;

2 nd month 3 rd day imaging evaluation 2015: target lesion diameter and 7mm, 79% reduction.

3) Tolerance to

The overall tolerability was good. Only occasional I degree hypodynamia, I degree pharyngalgia, I degree hand-foot skin reaction and II degree blood bilirubin rise appear, and the reaction can be well turned or recovered to be normal in a short period of time.

Claims

1. Use of compound I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of differentiated thyroid cancer, wherein compound I or a pharmaceutically acceptable salt thereof is administered orally,

a compound I.

2. The use of claim 1, wherein the thyroid cancer is advanced or metastatic thyroid cancer.

3. The use according to claim 1 or 2, wherein the thyroid cancer is papillary thyroid cancer, follicular thyroid cancer.

4. The use according to claim 1 or 2, wherein the pharmaceutically acceptable salt is the hydrochloride salt.

5. The use according to claim 4, wherein the pharmaceutically acceptable salt is a dihydrochloride salt.

6. The use according to claim 4, wherein the hydrochloride salt of compound I is in crystalline form.

7. The use of claim 6, wherein the thyroid cancer is advanced or metastatic thyroid cancer.

8. The use according to any one of claims 1,2, 6, 7, wherein the daily dose of compound I or a pharmaceutically acceptable salt thereof is one of the following daily doses: 2mg to 20 mg, 5 mg to 20 mg, 8 mg to 20 mg, 10mg to 16mg, 10mg to 14 mg, 10mg, 12mg, 14 mg or 16 mg.

9. The use according to any one of claims 1,2, 6, 7, wherein compound I or a pharmaceutically acceptable salt thereof is administered by means of intermittent administration; the interval administration comprises an administration period and a withdrawal period, wherein the ratio of the administration period to the withdrawal period in terms of days is 2:0.5-5.

10. The use according to claim 9, wherein the ratio of the administration period to the withdrawal period in days is 2:0.5-3.

11. The use according to claim 9, wherein the ratio of the administration period to the withdrawal period in days is 2:0.5-2.

12. The use according to claim 9, wherein the ratio of the administration period to the withdrawal period in days is 2:0.5-1.

13. Use according to claim 9, characterized in that compound I or a pharmaceutically acceptable salt thereof is administered in a regimen of 2 weeks of continuous administration.

14. Use according to claim 9, characterized in that compound I or a pharmaceutically acceptable salt thereof is administered in a regimen of 2 weeks off for 1 week on a continuous administration.

15. Use according to claim 9, characterized in that compound I or a pharmaceutically acceptable salt thereof is administered in a regimen of 5 days of continuous administration with 2 days of withdrawal.