KR102490547B1 - Methods and uses of quinoline derivatives in the treatment of thyroid cancer and pharmaceutical compositions for treatment of same - Google Patents

Abstract

Methods and uses for treating thyroid cancer with quinoline derivatives and pharmaceutical compositions for treating thyroid cancer are provided. Specifically, the present invention is a quinoline derivative, 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl] Methods and uses for treating thyroid cancer with cyclopropylamine and drug compositions for treating thyroid cancer.

Description

METHODS AND USES OF QUINOLINE DERIVATIVES IN THE TREATMENT OF THYROID CANCER AND PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF SAME}

The present invention belongs to the field of medicine and relates to methods and uses for treating tumors with quinoline derivatives and to pharmaceutical compositions for treating tumors. Specifically, the present invention relates to a method and use for treating thyroid cancer with a quinoline derivative and a pharmaceutical composition for treating thyroid cancer.

Thyroid cancer is a malignant tumor derived from thyroid epithelial cells, and is one of the most common tumors in the head and neck region, and is also a very common endocrine gland malignancy. Thyroid cancer accounts for about 1.3% to 1.5% of all malignant tumors in the body, and its incidence worldwide shows a clear upward trend in recent years, becoming one of the malignant tumors that are attracting attention.

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

Papillary thyroid carcinoma is a differentiated thyroid carcinoma, and is also the most common thyroid carcinoma, accounting for about 75% to 85% of the total; Lesions are usually solitary, and the size of the volume is different. The degree of malignancy of this type of tumor is relatively low, and the 10-year survival rate can reach 88%.

Thyroid follicular carcinoma accounts for 10% to 15% of the total thyroid cancer. Follicular thyroid carcinoma is most common in middle-aged women between the ages of 40 and 60, and the clinical presentation is similar to papillary carcinoma, but the cancer mass is relatively large and is less localized. It metastasizes to the lymph glands of people, often to distant places. A small number of thyroid follicular carcinomas infiltrate and damage nearby tissues, causing symptoms of respiratory tract obstruction.

Medullary thyroid carcinoma is a tumor arising from thyroid C cells or follicular cells, accounting for about 5% to 10% of thyroid malignancies, and its malignancy ranges between papillary carcinoma and undifferentiated carcinoma, and belongs to moderate malignancies. Hazard et al. described this disease for the first time in 1959. There are more women than men in medullary thyroid cancer patients, it is common in middle and young adults, and it is characterized by local infiltrative growth and early lymphatic metastases. there is. Medullary thyroid carcinoma is clinically divided into two types: hereditary MTC and sporadic MTC.

Undifferentiated thyroid cancer is a highly malignant tumor, relatively rare, accounting for about 1% to 2% of all thyroid cancers, and commonly occurring in the elderly. Undifferentiated carcinomas grow rapidly and often invade surrounding tissues in the early stages.

Common treatment methods for thyroid cancer include surgical treatment, chemotherapy, endocrine treatment, and radiation treatment. Here, although surgical treatment is an effective way to remove tumors, it tends to promote metastasis, and it is difficult to remove microscopic lesions; Most patients have already missed the optimal timing for surgery by the time they discover a tumor. Because differentiated thyroid carcinoma responds differently to chemotherapy, it is used only for patients who cannot excise some late stages or have metastasized to distant sites, optionally in combination with other treatment methods. Endocrine therapy has an inhibitory effect only on thyroid tissue proliferation and differentiated cancer cells, and is often used for treatment to prevent recurrence and metastasis. Different types of thyroid cancer have a very large difference in sensitivity to radiation, and since radiation lowers the body's immunity, it affects the patient's further treatment.

Vandetanib (ZD6474, trade name: Zactima, structural formula is as follows) was already approved by the US Food and Drug Administration (FDA) on April 6, 2011, and is used for the treatment of medullary thyroid carcinoma. The drug is researched and manufactured by AstraZeneca, and is an orally administered small-molecule multi-target tyrosine kinase inhibitor, mainly for rearranged during transfection (RET) tyrosine kinase, epidermal growth factor receptor (Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR-2).

Cabozantinib (COMETRIQ ^™ , cabozantinib, structural formula is as follows) is an orally administered small molecule kinase inhibitor for the treatment of medullary thyroid carcinoma, approved by the US Food and Drug Administration in November 2012.

To date, many small molecule tyrosinekinases (TKIs) are still further evaluated for their action in the treatment of thyroid cancer. Developing more drugs will bring substantial benefits to patients by reaching better therapeutic effects and improving survival rates.

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

In a second aspect, the present invention provides the use of Compound I or a pharmaceutically acceptable salt thereof in preparing a drug for treating thyroid cancer.

In a third aspect, the present invention provides a pharmaceutical composition for treating 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 carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma.

In a first aspect, the present invention provides a method for treating thyroid cancer comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment. The thyroid cancer includes, but is not limited to, papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma.

In some embodiments of the present invention, the present invention provides a method for treating papillary thyroid carcinoma comprising administering to a patient in need thereof a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof.

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

In some embodiments of the present invention, the present invention provides a method for treating late-stage medullary thyroid carcinoma comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

Compound I can be administered in its free base form, or in the form of salts, hydrates and prodrugs, which are converted into the free base form of Compound I in the body. For example, pharmaceutically acceptable salts of Compound I may be prepared with different organic and inorganic acids within the scope of the present invention by methods known in the art.

In some embodiments, Compound I is administered in the form of hydrochloride. In some embodiments, Compound I monohydrochloride is administered. In some embodiments, Compound I is administered in the form of dihydrochloride. In some embodiments, the drug is administered in crystalline form of Compound I hydrochloride. In certain embodiments, Compound I dihydrochloride is administered in crystalline form.

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

[Compound I]

Compound I or a pharmaceutically acceptable salt thereof can be administered through various routes, such as oral, extraintestinal, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, intracerebral, or nasal. routes selected from oral, inhalational, vaginal, intraocular, topical, subcutaneous, intrafacial, intraarticular, intraperitoneal and intrathecal. In one particular embodiment, via the oral route. dosing

The dosage of Compound I or a pharmaceutically acceptable salt thereof can be determined depending on the severity of the disease, the response of the disease, the toxicity related to any treatment, and the age and health condition of the patient. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg. In one specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In one particular embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In one particular embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 14 mg. In one specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 16 mg.

Compound I or a pharmaceutically acceptable salt thereof can be used once or several 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 be administered in single dose or multidose form. In one embodiment, administration is once daily. In one embodiment, a single dose is administered once daily. In one embodiment, a single dose oral solid formulation is administered once daily.

The administration method is comprehensively determined according to drug activity, toxicity, and patient tolerance. Preferably, Compound I or a pharmaceutically acceptable salt thereof is administered by administration at intervals.

Administration at such intervals includes an administration period and an administration suspension period, and Compound I or a pharmaceutically acceptable salt thereof may be administered once or several times daily during the administration period. For example, Compound I or a pharmaceutically acceptable salt thereof is administered every day during the administration period, administration is suspended for a certain period of time during the next administration period, and then the administration period, then the administration period is stopped, and so on repeatedly. can Here, the ratio calculated by the number of days between the administration period and the administration suspension period is 2:0.5 to 5, preferably 2:0.5 to 3, relatively preferably 2:0.5 to 2, and most preferably 2:0.5 is ~1.

In some embodiments, administration is continued for 2 weeks followed by discontinuation of administration for 2 weeks. In some embodiments, it is administered once daily, administered continuously for 14 days, and then stopped for 14 days; It can be continuously administered once daily, continuously administered for 14 days, and then stopped for 14 days, in this way, continuously administered for 2 weeks and administered at intervals of stopping administration for 2 weeks, and so on.

In some embodiments, administration is continued for 2 weeks followed by discontinuation of administration for 1 week. In some embodiments, it is administered once daily, administered continuously for 14 days, and then stopped for 7 days; It can be continuously administered once daily, administered continuously for 14 days, and then stopped for 7 days, but in this way, administration is continuously administered for 2 weeks and administration is stopped for 1 week, and the administration is repeated.

In some embodiments, administration is continuous for 5 days and administration is stopped for 2 days. In some embodiments, it is administered once daily, continuously administered for 5 days, and then stopped for 2 days; It is continuously administered once daily, continuously administered for 5 days, and then administration is stopped for 2 days, but in this way, administration is continuously administered for 5 days and administration is stopped for 2 days, and the administration can be repeated.

In one embodiment, Compound I or a pharmaceutically acceptable salt thereof is administered to the patient alone 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 preparing a drug for treating thyroid cancer. The thyroid cancer includes, but is not limited to, papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma.

In some embodiments, the present invention provides use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating papillary thyroid carcinoma.

In some embodiments, the present invention provides use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating follicular thyroid carcinoma.

In some embodiments, the present invention provides use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating medullary thyroid carcinoma. Here, the medullary thyroid cancer includes genetic medullary cancer and sporadic medullary cancer.

In some embodiments, the present invention provides use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating late stage medullary thyroid carcinoma.

Compound I may be in its free base form, or in the form of its salt, hydrate and prodrug, and the prodrug is converted into the free base form of Compound I in the body. For example, pharmaceutically acceptable salts of Compound I may be prepared with different organic and inorganic acids within the scope of the present invention by methods known in the art.

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

The amount of Compound I or a pharmaceutically acceptable salt thereof can be determined by the severity of the disease, the response of the disease, the toxicity related to any treatment, and the age and health condition of the patient. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg. In one specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In one particular embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In one particular embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 14 mg. In one specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 16 mg.

In a third aspect, the present invention provides a pharmaceutical composition for treating thyroid cancer comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The thyroid cancer includes, but is not limited to, papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma.

In some embodiments, the present invention provides a pharmaceutical composition for treating papillary thyroid carcinoma comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier thereof.

In some embodiments, the present invention provides a pharmaceutical composition for treating follicular thyroid carcinoma comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier thereof.

In some embodiments, the present invention provides a pharmaceutical composition for treating medullary thyroid carcinoma comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier thereof. The medullary thyroid cancer includes genetic medullary cancer and sporadic medullary cancer.

In some embodiments, the present invention provides a pharmaceutical composition for treating advanced medullary thyroid carcinoma comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier thereof. .

Compound I may be in its free base form, or in the form of its salt, hydrate and prodrug, and the prodrug is converted into the free base form of Compound I in the body. For example, pharmaceutically acceptable salts of Compound I may be prepared with different organic and inorganic acids within the scope of the present invention by methods known in the art.

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

The amount of Compound I or a pharmaceutically acceptable salt thereof can be determined by the severity of the disease, the response of the disease, the toxicity related to any treatment, and the age and health condition of the patient. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 16 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg. In one specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In one particular embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In one particular embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 14 mg. In one specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 16 mg.

In some embodiments of the present invention, the pharmaceutical composition is applied in an oral dosage form, which includes tablets, capsules, powders, granules, drop pills, pastes, and powders, preferably are tablets and capsules. Here, the tablets may be ordinary tablets, dispersed tablets, effervescent tablets, sustained-release tablets, controlled-release tablets, or enteric-coated tablets, and capsules may be ordinary capsules, sustained-release capsules, delayed-release capsules, or enteric-coated tablets. can be The oral formulation may be prepared through a conventional method using a pharmaceutically acceptable carrier known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, adhesives, disintegrants, lubricants and the like. fillers include starch, lactose, mannitol, microcrystalline cellulose, and the like; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate and the like; humectants include water, ethanol, and the like; adhesives include hydroxypropylmethyl cellulose, polyvinylpyrrolidone, microcrystalline cellulose, and the like; disintegrants include cross sodium carboxymethyl cellulose, cross polyvinylpyrrolidone, surfactants, low-substituted hydroxypropyl cellulose, and the like; Lubricants include magnesium stearate, talc powder, polyethylene glycol, sodium lauryl sulfate, fine powder silica, talc powder and the like. It also includes coloring agents, sweeteners, etc. as medicinal auxiliary materials.

In one embodiment, the pharmaceutical composition is applied to a solid preparation for oral administration. The composition may be in the form of tablets or capsules. In one particular embodiment, the composition is a capsule. In one particular embodiment of the present invention, the pharmaceutically acceptable carrier for the solid preparation for oral administration comprises mannitol, microcrystalline cellulose, hydroxypropylmethyl cellulose and magnesium stearate.

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

Preferably, the pharmaceutical composition is administered in a manner that is administered at intervals. Administration at such intervals includes an administration period and an administration suspension period, and Compound I or a pharmaceutically acceptable salt thereof may be administered once or several times daily during the administration period. For example, Compound I or a pharmaceutically acceptable salt thereof is administered every day during the administration period, administration is suspended for a certain period of time during the next administration period, and then the administration period, then the administration period is stopped, and so on repeatedly. can Here, the ratio calculated by the number of days between the administration period and the administration suspension period is 2:0.5 to 5, preferably 2:0.5 to 3, relatively preferably 2:0.5 to 2, and most preferably 2:0.5 is ~1.

In some embodiments, administration is continued for 2 weeks followed by discontinuation of administration for 2 weeks. In some embodiments, it is administered once daily, administered continuously for 14 days, and then stopped for 14 days; It can be continuously administered once daily, continuously administered for 14 days, and then stopped for 14 days, in this way, continuously administered for 2 weeks and administered at intervals of stopping administration for 2 weeks, and so on.

In some embodiments, administration is continued for 2 weeks followed by discontinuation of administration for 1 week. In some embodiments, it is administered once daily, administered continuously for 14 days, and then stopped for 7 days; It can be continuously administered once daily, administered continuously for 14 days, and then stopped for 7 days, but in this way, administration is continuously administered for 2 weeks and administration is stopped for 1 week, and the administration is repeated.

In some embodiments, administration is continuous for 5 days and administration is stopped for 2 days. In some embodiments, it is administered once daily, continuously administered for 5 days, and then stopped for 2 days; It is continuously administered once daily, continuously administered for 5 days, and then administration is stopped for 2 days, but in this way, administration is continuously administered for 5 days and administration is stopped for 2 days, and the administration can be repeated.

In some embodiments of the invention, the thyroid cancer is late stage thyroid cancer.

In this specification, unless otherwise stated, all dosage amounts and ranges provided herein are based on the molecular weight of the free base form of Compound I.

In this specification, unless stated otherwise, qd means once daily dosing.

In the present specification, the crystal form of the hydrochloride salt of Compound I includes, but is not limited to, crystals of Forms A, B and C disclosed in Chinese Patent Application CN102344438A, wherein the crystals of Forms A and B contain the number of crystals in the basic phase and It does not contain crystals of other solvents, and the crystals of form C contain crystals of two waters of crystallization. In some embodiments, the crystals of the dihydrochloride salt of Compound I are Form A crystals.

Unless otherwise specified, for the purposes of the present invention, the following terms used in this specification and claims should have the following meanings.

“Patient” means a mammal, preferably a human. In some embodiments, the patient has failed standard treatment or has failed standard treatment.

"Pharmaceutically acceptable thereof" means for preparing a pharmaceutical composition, which is generally safe, non-toxic, does not conflict with biological or other needs, and is acceptable for human use. includes being

"Pharmaceutically acceptable salts thereof" are acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or acetic acid, trifluoroacetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, propanedioxane, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, Methanesulfonic acid, ethanesulfonic acid, 1,2ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, pivalic acid, tert-butylacetic acid, lauryl sulfate , acid addition salts formed with organic acids such as gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, steriaric acid, and the like.

"Therapeutically effective amount" means an amount that achieves sufficient treatment for a disease when a compound is administered to a human for the treatment of the disease.

"Treatment" means any use of an effective amount of a compound in treatment, and also

(1) inhibiting the disease in a human body suffering from or displaying the disease pathologically or symptomatically (i.e., inhibiting further development of the pathology and/or symptomatically); or

(2) ameliorating (i.e., reversing the pathology and/or symptomatology) the disease in a human body suffering from or displaying the disease pathologically or symptomatically;

Example

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

.

.

Referring to the method of Example 24 in WO2008112407, 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl ] Cyclopropylamine was prepared and obtained, and then the title compound was prepared and obtained by referring to the preparation method of "Example of salt form" in the specification of WO2008112407.

or prepared by referring to a method disclosed in Chinese Patent Application CN102344438A.

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

Name of original auxiliary material Usage (1000 pills) Dihydrochloride of Compound I 14.16g (equivalent to 12g of Compound I) mannitol 89g microcrystalline cellulose 138.4g Hydroxypropyl Cellulose 5.9g Magnesium Stearate 0.99g

The dihydrochloride salt of Compound I was pulverized and subjected to 80 mesh screening; then uniformly mixed with mannitol and hydroxypropyl cellulose; Subsequently, a prescribed amount of microcrystalline cellulose was added, mixed uniformly, and filtered through a 0.8 mm filter net; Finally, add the prescribed amount of magnesium stearate, mix it evenly, and fill the capsule.

In capsules of other contents of dihydrochloride of compound I, it is prepared and obtained by referring to the same ratio and formulation as above.

Tolerance of compound I dihydrochloride capsule treatment and treatment effect on thyroid cancer

1) Resistance research results

If the diagnosis is confirmed including diagnosis, for patients with malignant tumors who fail standard treatment or lack standard treatment, the drug is used continuously for 2 weeks and administration is stopped for 1 week, that is, 3 weeks (21 days) as one treatment cycle. , At least 2 cycles (42 days) are maintained to observe resistance and at the same time, the therapeutic effect is also observed.

Administered once daily, administered 10mg each time, and side effects occurred in 3 patients, including 1 case of grade III and higher fat and diastase elevation, 1 case of grade II lethargy, and other grade I side effects. do. Other grade I side effects included hoarseness in 2 cases, diarrhea and abdominal pain in 1 case, and hypertension in 1 case.

Administered once daily, 16 mg each time, and in 3 cases, during the second week of drug use in 2 cycles, 1 case of grade III blood pressure rose and lethargy occurred.

Other side effects observed during the study of this group included 1 case of grade II hypertension, 2 cases of hypothyroidism, 1 case of elevation of alanine aminotransferase (ALT); Grade I included side effects such as elevated triglyceride in 2 cases, diarrhea and abdominal pain in 2 cases, limb syndrome in 1 case, and hoarseness in 1 case.

In the case of administration once daily and administration of 12 mg each time, a total of 18 cases (here, 5 cases are one group) of patients were observed in this group. In the process of using the drug, all of them showed different degrees of side effects. The severity was grade 1-2, and no side effects of grade 3 or higher occurred. In specific circumstances,

Blood lipids: elevated triglycerides in 8 cases, total cholesterol in 8 cases;

Liver function: total bilirubin elevation in 4 cases, ATL elevation in 4 cases, aspartate transaminase (AST) elevation in 5 cases; 1 case of elevated creatinine;

Skin Toxicity: 6 cases of limb skin reaction, 4 cases of dermatitis;

Endocrine system: hypothyroidism in 7 cases, hyperthyroidism in 2 cases, diastase elevation in 3 cases, and CK-MB elevation in 2 cases;

Symptoms: lethargy in 6 cases, hoarseness in 4 cases, diarrhea in 6 cases, dizziness in 2 cases, toothache in 3 cases, muscle aches in 3 cases; 3 cases of nausea and loss of appetite, 1 case each of tinnitus, fever, and sleepiness;

Others: including 5 cases of hypertension, 5 cases of hematuria, 5 cases of proteinuria, and 3 cases of decreased white blood cell (WBC).

2) Rudimentary treatment for medullary thyroid cancer

Medullary thyroid carcinoma (12 mg once daily): There are a total of 6 cases in subjects, 1 case not evaluable, 4 cases SD (stable disease) (small), 1 case PD (disease) degree of progress). Therefore, it can be seen that the benefit rate of medullary thyroid carcinoma is more than 80%.

All of the preparation amounts mentioned in the above examples were calculated by the calculation method of Compound I free base.

Compound I hydrochloride capsules were used at a dose of 12mg/day for 2 consecutive weeks and stopped for 1 week. The overall tolerance was very good, side effects were 1/2 degree, and other unexpected side effects were observed. did not; In terms of therapeutic effect, benefits have been obtained in the treatment of medullary thyroid carcinoma.

Therapeutic effect on medullary thyroid carcinoma

1) Patient's medical history

A 56-year-old male, in October 2005, a tumor was unknowingly discovered in the cervical region, and tumor removal was performed. During a physical examination in January 2007, a tumor was found in the left cervical spine. In January 2007, "cervical tumor removal + glandular surgery" was performed. The postoperative pathology was medullary thyroid carcinoma; Ten lymph nodes were detected in the "lymph gland under the left clavicle" tissue, all of which had metastasized to cancer, and two cancer nodules were also detected. Between February 2007 and April 2007, 49 cervical radiation treatments were performed. After surgery in May 2007, 2 cycles of drug treatment were performed, but no specific drug was identified. In a regular re-examination, in October 2012, an enlarged mediastinal lymph gland was found, and further treatment was given considering metastasis. Currently, 100ug qd of Yujale is orally administered.

From August 6, 2013, compound I dihydrochloride capsule 12mg qd was administered orally, and the drug was used continuously for 2 weeks and administration was stopped for 1 week.

The preparation amounts mentioned in the above examples were all calculated by the calculation method of Compound I free base.

2) CT result

In the imaging evaluation on August 3, 2013, the sum of the diameters of the target lesion area was 49 mm;

In the imaging evaluation on September 10, 2013, the sum of the diameters of the target lesion area was 44 mm;

In the imaging evaluation on October 26, 2013, the sum of the diameters of the target lesion area was 42 mm;

In the imaging evaluation on December 9, 2013, the sum of the diameters of the target lesion area was 41 mm;

In the imaging evaluation on January 20, 2014, the sum of the diameters of the target lesion area was 41 mm;

In the imaging evaluation on April 11, 2014, the sum of the diameters of the target lesion area was 41 mm;

In the imaging evaluation on July 9, 2014, the sum of the diameters of the target lesion area was 40 mm;

In the imaging evaluation on September 26, 2014, the sum of the diameters of the target lesion area was 38 mm.

3) Immunity

Overall tolerance is excellent. Occasionally seen Ⅰ° Diarrhea, I° Leukopenia, Ⅰ° Hand and foot skin reaction, Ⅰ° muscle soreness, Ⅰ° sore throat, Ⅰ° proteinuria, Ⅰ° elevated bilirubin, Ⅰ° hypertension, Ⅰ° decreased neutrophil cell count, Ⅰ° elevated low-density lipoprotein, Ⅰ Only ° stomach pain, I° appetite loss, I° diarrhea, I° toothache and II° leukopenia occurred, and the above reactions improved, recovered or abated within a short period of time.

Therapeutic effect on papillary thyroid carcinoma

1) Patient's medical history

A 56-year-old woman, who underwent bilateral thyroidectomy in 2010, had bilateral papillary thyroid carcinoma and right neck lymph node metastasis. In 2012, tumor removal surgery was performed again because of a tumor next to the bronchus on the right side. After surgery, it was diagnosed that papillary thyroid carcinoma had accumulated in the bronchial tube. Due to this difficult and difficult swallowing symptom, a fiber laryngoscopy was used to find pathology, and it was diagnosed that papillary thyroid carcinoma had metastasized into the bronchus. In May 2014, cervical and thoracic CT scans were reexamined, and some were new, and the progression of the disease was considered. I had high blood pressure and diabetes for nearly 5 years, so I took Irbesartan Hydrochlorothiazide 1 tablet/sheet, qd for a long term.

From June 3, 2014, compound I dihydrochloride capsule 12mg qd was administered orally, and the drug was used continuously for 2 weeks and administration was discontinued for 1 week.

All of the preparation amounts mentioned in the above examples were calculated by the calculation method of Compound I free base.

2) CT result

In the imaging evaluation on May 12, 2014, the sum of the diameters of the target lesion area was 10 mm;

In the imaging evaluation on July 14, 2014, the sum of the target lesion area diameters was 0 mm, and the target lesion area evaluation result was CR (all remission);

In the imaging evaluation on September 25, 2014, the sum of the target lesion area diameters was 0 mm, and the target lesions were reduced;

In the imaging evaluation on November 24, 2014, the sum of the diameters of the target lesion area was 0 mm;

In the imaging evaluation on January 20, 2015, the sum of the diameters of the target lesion area is 0 mm.

3) Immunity

Overall tolerance is excellent. Occasionally seen Ⅰ° Only muscle soreness, I° lethargy, I° back soreness, I° cough, I° toothache, I° hemoptysis, and I° limb skin reactions appeared, and these reactions improved, recovered, or abated within a short period of time.

Therapeutic effect on follicular thyroid carcinoma

1) Patient's medical history

She was a 67-year-old woman and underwent "left thyroidectomy + right thyroidectomy" in August 2007, and postoperative pathology showed follicular carcinoma of the left thyroid gland. In September 2007, PET-CT detected metastasis to the lungs and left iliac bones. In September 2007, "Raw thyroid lobe removal" was performed. In the postoperative pathology, swelling of the right nodular thyroid, fibrosis and swelling of the silk granular plaques were noted. Oral administration of thyroid medication continued after surgery instead of treatment. Between September 2007 and June 2011, I131 treatment was performed 11 times. From November 2007 to October 2009, 4 cycles of biological treatment and several cycles of chemotherapy with the THP+L-OHP+CF+FT-207 regimen (i.e. "pyrarubicin+oxaliplatin+calcium acid" regimen) were given. In November 2009, local radiotherapy was performed on the left iliac bone, and the amount used was 3000 Gy. A PET-CT re-examination in October 2011 suggested multiple metastases to the lungs and bones. From November 2011, disodium palmidronate (Pamidronate　Disodium) was applied and treated, and Vivatuxin was injected locally to metastasize to the cow scapula. In November 2011, bone tumor removal of the left fibula + polyvinylpyrrolidone filler + dynamic hip fixation was performed. In March 2012, partial removal of the right scapula was performed, and the postoperative pathology was metastatic follicular thyroid carcinoma. In June 2012, bone shearing of the left fibula tumor + artificial hip joint replacement was performed. In September 2012, palliative radiation therapy for bone metastases was performed. In January 2013, radiotherapy was performed on a metastatic lesion in the left chest wall, and in February 2013, radiotherapy was performed on a metastatic lesion in the lung. In April 2013, right axillary lymphadenectomy was performed. Between December 2012 and October 2013, sorafenib was administered orally. The patient has been diagnosed with hypertension for 1 year and is currently taking oral Telmisartan 40 mg qd.

From November 14, 2013, compound I dihydrochloride capsule 12mg qd was administered orally, and the drug was used continuously for 2 weeks and administration was discontinued for 1 week. On March 20, 2014, Compound I dihydrochloride capsule was reduced to 10 mg qd for treatment, and the drug was used continuously for 2 weeks and administration was stopped for 1 week; On July 3, 2014, the administration plan was changed to Compound I dihydrochloride capsule 10mg qd, and the drug was used continuously for 2 weeks and administration was stopped for 1 week.

All of the preparation amounts mentioned in the above examples were calculated by the calculation method of Compound I free base.

2) CT result

In the imaging evaluation on November 11, 2013, the sum of the diameters of the target lesion area was 33 mm;

In the imaging evaluation on December 23, 2013, the sum of the diameters of the target lesion area was 25 mm, a decrease of 24%;

In the imaging evaluation on January 28, 2014, the sum of the target lesion area diameters was 23 mm, a decrease of 30%;

In imaging evaluation on March 17, 2014, the sum of target lesion area diameters was 19 mm, a decrease of 42%;

In imaging evaluation on April 28, 2014, the sum of diameters of the target lesion area was 17 mm, a decrease of 49%;

In imaging evaluation on June 27, 2014, the sum of target lesion area diameters was 17 mm, a decrease of 49%;

In the imaging evaluation on October 16, 2014, the sum of the diameters of the target lesion area was 5 mm, which was reduced by 85%;

In imaging evaluation on February 3, 2015, the sum of the diameters of the target lesion area was 7 mm, which was reduced by 79%.

3) Immunity

Overall tolerance is excellent. Only occasional I° lethargy, I° sore throat, I° limb skin reaction, and II° elevated blood bilirubin were observed, and the above reactions improved, recovered, or abated within a short period of time.

Claims (17)

A pharmaceutical composition for treating thyroid cancer, comprising the following compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier:
[Compound I]

According to claim 1,
The thyroid cancer is differentiated thyroid cancer, poorly differentiated thyroid cancer or undifferentiated thyroid cancer, a pharmaceutical composition for treating thyroid cancer. According to claim 2,
The differentiated thyroid cancer is thyroid papillary or follicular thyroid cancer, a pharmaceutical composition for the treatment of thyroid cancer. According to claim 2,
The poorly differentiated thyroid cancer is medullary thyroid cancer, a pharmaceutical composition for treating thyroid cancer. According to claim 4,
The pharmaceutical composition for treating thyroid cancer, wherein the medullary thyroid cancer is hereditary medullary thyroid carcinoma or sporadic medullary thyroid carcinoma. According to claim 1,
The thyroid cancer is papillary thyroid cancer, thyroid follicular cancer or medullary thyroid cancer, a pharmaceutical composition for the treatment of thyroid cancer. According to claim 1,
The thyroid cancer is a terminal medullary thyroid cancer, a pharmaceutical composition for the treatment of thyroid cancer. According to any one of claims 1 to 7,
The Compound I or a pharmaceutically acceptable salt thereof is a dihydrochloride salt, a pharmaceutical composition for treating thyroid cancer. According to any one of claims 1 to 7,
The daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2mg to 20mg, 5mg to 20mg, 8mg to 20mg, 10mg to 16mg, 10mg to 14mg, 10mg, 12mg, 14mg and 16mg, which is one of the pharmaceuticals for treating thyroid cancer. enemy composition. According to any one of claims 1 to 7,
The Compound I or a pharmaceutically acceptable salt thereof is administered by a method of administration at intervals,
The administration at the interval is one of the following methods: administration for 2 weeks continuously and administration stopped for 2 weeks, administration for 2 weeks continuously and administration stopped for 1 week, and administration for 5 days and administration stopped for 2 days,
The administration at intervals that can be repeated several times, a pharmaceutical composition for treating thyroid cancer. delete delete delete delete delete delete delete