KR20170007789A - Methods and uses of quinoline derivatives in the treatment of thyroid cancer and pharmaceutical compositions for treatment of same - Google Patents

Abstract

 A method and an application for treating thyroid cancer with quinoline derivatives, and a drug composition for treating thyroid cancer. Specifically, the present invention relates to a process for producing a quinoline derivative, which comprises reacting a quinoline derivative such as 1 - [[[4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin- Methods and uses for treating thyroid cancer with cyclopropylamine and drug compositions for treating thyroid cancer.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a method for treating cancer of the thyroid with quinoline derivatives, and a pharmaceutical composition for the treatment of thyroid cancer. ≪ Desc / Clms Page number 1 >

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

Thyroid cancer is a malignant tumor originating from the thyroid epithelium. It is one of the most common tumors in the head and neck, and it is also a very common endocrine malignancy. Thyroid cancer accounts for approximately 1.3% to 1.5% of malignant tumors of the whole body. Recently, worldwide incidence has markedly increased, and it is becoming one of the most notable malignant tumors.

Thyroid cancer is generally divided into differentiated thyroid carcinoma (including thyroid papillary carcinoma and thyroid follicular carcinoma) and low-grade thyroid carcinoma (for example, medullary thyroid carcinoma (MTC)) and undifferentiated thyroid carcinoma.

Thyroid papillary carcinoma is a differentiated thyroid cancer, and it is also the most common thyroid cancer, accounting for 75% to 85% of the total number of patients; Lesions are usually single-footed, and the size of the volume is different. The degree of malignancy of the above type tumors is relatively low, and the survival rate of 10 years may reach 88%.

Thyroid folliculogenesis accounts for 10% to 15% of the total number of thyroid cancer. Thyroid follicular carcinoma is present in middle-aged women aged 40 to 60 years. Clinical expression is similar to papillary carcinoma, but cancerous mass is relatively large, To the lymphatic system, and to a greater extent, to the distant metastasis. A small number of thyroid follicular carcinomas may infiltrate and damage nearby tissues, resulting in symptoms of obstruction of the respiratory tract.

Thyroid carcinoma is a tumor that occurs in thyroid C cells or follicular cells. It accounts for 5% ~ 10% of thyroid malignancies. The degree of malignancy is between papillary carcinoma and undifferentiated carcinoma. It belongs to middle malignant tumor. In 1959, Hazard et al. Described this disease for the first time. Patients with thyroid cancers are more common in women than males, and are characterized by premature local invasion growth and hemolytic lymphoma have. There are two types of thyroid carcinoma: hereditary MTC and sporadic MTC.

Undifferentiated thyroid carcinoma is a highly malignant tumor, relatively rare, accounting for 1% to 2% of total thyroid cancer, and is common in older patients. Undifferentiated carcinomas grow at a high rate and often infiltrate the surrounding tissues early on.

Common methods of treating thyroid cancer include surgical treatment, chemotherapy, endocrine therapy, and radiation therapy. Here, although surgical treatment is an effective way to remove the tumor, it has a tendency to promote metastasis, and it is difficult to remove fine lesions; When most patients find a tumor, they have already missed the optimal timing of surgery. Differentiated thyroid carcinomas have different responses to chemotherapy, so they are used exclusively for patients who have not been able to cut some of their terminal parts or transfer to distant sites, along with other treatment options. Endocrine therapy has inhibitory action on thyroid tissue proliferation and differentiated cancer cells, and is often used to prevent recurrence and metastasis. Since the sensitivity of various types of thyroid cancer to radiation is very large and the radiation reduces the immunity of the organism, the patient is given an additional treatment effect.

Vandetanib (ZD6474, trade name: Zactima, as below) has been approved by the US Food and Drug Administration (FDA) on April 6, 2011 for the treatment of thyroid cancer. The drug is studied and manufactured by the Astrazeneca company, which is an orally administered small molecule multi-target point tyrosine kinase inhibitor and is mainly used for Rearranged During Transfection (RET) tyrosine kinase, epidermal growth factor receptor growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR-2).

Carbozantinib (COMETRIQ ^™ , cabozantinib, structural formula is shown below) is an oral small molecule kinase inhibitor for the treatment of thyroid carcinoma of the thyroid, licensed by the US Food and Drug Administration in November 2012.

So far, many small molecule tyrosine kinases (TKI) have been further evaluated for their role in thyroid cancer treatment. By developing more drugs, reaching better therapeutic effects and improving survival rates, they will bring real benefits to the patient.

In a first aspect, the present invention provides a method of treating adenocarcinoma comprising administering to a patient in need of treatment 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 invention provides a pharmaceutical composition for treating a 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, thyroid papillary carcinoma, thyroid follicular carcinoma, and thyroid carcinoma.

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

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

In some embodiments of the present invention, the present invention provides a method of treating thyroid carcinoma comprising administering to a patient in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof. The thyroid gland carcinoma comprises a genotypic watery rock and a sporadic watery rock.

In some embodiments of the present invention, the present invention provides a method of treating end-stage thyroid cancer which comprises 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 and may be administered in the form of a 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 formed within the scope of the present invention with the different organic and inorganic acids in a manner known in the art.

In some embodiments, administration is in the form of a Compound I hydrochloride. In some embodiments, the compound is administered in the form of a mono hydrochloride salt. In some embodiments, the compound is administered in the form of its hydrochloride salt. In some embodiments, the drug is administered in the crystalline form of Compound I hydrochloride. In a particular embodiment, it is administered in crystalline form of the hydrochloride salt in Compound I.

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 Methyl-1H-indol-5-yl) oxy-6-methoxy-quinoline-7-yl] oxy] methyl] cyclopropylamine) .

[Compound I]

Compound I or a pharmaceutically acceptable salt thereof may be administered through various routes including oral, intestinal, intraperitoneal, intra-arterial, intra-arterial, transdermal, sublingual, intramuscular, rectal, But are not limited to, intravenous, intramuscular, intravenous, inhalation, vaginal, intra-ocular, topical, subcutaneous, intra-articular, intraperitoneal and intraperitoneal routes. In one particular embodiment, .

The dose of Compound I or a pharmaceutically acceptable salt thereof may be determined by the severity of the disease, the response of the disease, the toxicity with respect to any treatment, the age and health condition of the patient. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 5 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 8 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 10 mg to 16 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 10 mg to 14 mg. In one particular 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 particular 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 a single dose or in a multiple dose form. In one embodiment, it is administered once daily. In one embodiment, a single dose is administered once daily. In one embodiment, a single daily dose of the solid preparation is administered once daily.

The method of administration is comprehensively determined according to the activity of the drug, toxicity and tolerance of the patient. The compound I or a pharmaceutically acceptable salt thereof is administered in such a manner that it is administered in an apportioned, spaced-apart manner.

The above-mentioned interval administration includes the administration period and the suspension period, and the compound I or a pharmaceutically acceptable salt thereof may be administered once or several times daily during the administration period. For example, the compound I or its pharmaceutically acceptable salt is administered daily during the administration period, the administration is stopped for a certain period of time in the next administration suspension period, and the administration period and then the administration suspension period are repeated many times . The ratio calculated by the number of days between the administration period and the suspension period is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, and most preferably 2: 0.5 ~ 1.

In some embodiments, administration is continued for two weeks and stopped for two weeks. In some embodiments, once daily, continuously for 14 days, then stop for 14 days; Followed by administration once a day, followed by continuous administration for 14 days, followed by stopping the administration for 14 days, followed by continuous administration for 2 weeks and administration for 2 weeks.

In some embodiments, administration is continued for two weeks and stopped for one week. In some embodiments, once daily, continuously for 14 days, then stopping for 7 days; The administration is continued once a day, followed by continuous administration for 14 days, followed by stopping the administration for 7 days, followed by continuous administration for 2 weeks and administration for 1 week.

In some embodiments, administration is continued for 5 days and stopped for 2 days. In some embodiments, once daily, continuously for 5 days, then stop for 2 days; Followed by continuous administration once a day, followed by continuous administration for 5 days, followed by stopping the administration for 2 days, followed by continuous administration for 5 days and suspension for 2 days.

In one embodiment, Compound I or a pharmaceutically acceptable salt thereof is administered to a 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 the manufacture of a medicament for the treatment of thyroid cancer. The thyroid cancer includes, but is not limited to, thyroid papillary carcinoma, thyroid follicular carcinoma, thyroid carcinoma.

In some embodiments of the present invention, 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 papillary carcinoma.

In some embodiments of the present invention, 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 follicular carcinoma.

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

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

Compound I may be in its free base form, in the form of its salts, hydrates and prodrugs, and the prodrugs are converted into the free base form of Compound I in the body. For example, pharmaceutically acceptable salts of Compound I can produce salts 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 in the hydrochloride form of Compound < RTI ID = 0.0 > I. < / RTI > In some embodiments, it is in the form of a Compound I monohydrochloride salt. In some embodiments, it is in the hydrochloride form of Compound I. In some embodiments, it is in the form of a Compound I hydrochloride crystal. In a particular embodiment, it is in the form of the hydrochloride salt in Compound I.

The amount of Compound I or a pharmaceutically acceptable salt thereof may be determined by the severity of the disease, the response of the disease, the toxicity with respect 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 from 2 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 5 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 8 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 10 mg to 16 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 10 mg to 14 mg. In one particular 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 particular embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 16 mg.

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

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

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

In some embodiments of the present invention, the present invention provides a pharmaceutical composition for treating a thyroid cancer, comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier thereof. The thyroid gland carcinoma comprises a genotypic watery rock and a sporadic watery rock.

In some embodiments of the present invention, the present invention provides a pharmaceutical composition for treating end-stage thyroid cancer 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, in the form of its salts, hydrates and prodrugs, and the prodrugs are converted into the free base form of Compound I in the body. For example, pharmaceutically acceptable salts of Compound I can produce salts 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 in the hydrochloride form of Compound < RTI ID = 0.0 > I. < / RTI > In some embodiments, it is in the form of a Compound I monohydrochloride salt. In some embodiments, it is in the hydrochloride form of Compound I. In some embodiments, it is in the form of a Compound I hydrochloride crystal. In a particular embodiment, it is in the form of the hydrochloride salt in Compound I.

The amount of Compound I or a pharmaceutically acceptable salt thereof may be determined by the severity of the disease, the response of the disease, the toxicity with respect 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 from 2 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 5 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 8 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 10 mg to 16 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 10 mg to 14 mg. In one particular 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 particular embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 16 mg.

In some embodiments of the invention, the pharmaceutical composition is applied to an oral dosage form, which includes tablets, capsules, powders, granules, drop pills, pastes, powders, Are tablets and capsules. Herein, the tablet may be a normal tablet, a dispersion tablet, a foam tablet, a sustained release tablet, a controlled release tablet or an enteric-coated tablet, and the capsule may be a normal capsule, a sustained capsule, Lt; / RTI > The oral preparation can be prepared by 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; The absorbent includes calcium sulfate, calcium hydrogen phosphate, calcium carbonate and the like; Wetting agents include water, ethanol, and the like; The adhesive includes hydroxypropylmethylcellulose, polyvinylpyrrolidone, microcrystalline cellulose and the like; Disintegrants include cross sodium carboxymethylcellulose, cross polyvinyl pyrrolidone, surfactants, low substituted hydroxypropyl cellulose, and the like; The lubricant includes magnesium stearate, talc powder, polyethylene glycol, sodium lauryl sulfate, fine powder silica, talc powder and the like. Medicinal auxiliary materials include coloring agents and sweeteners.

In one embodiment, the pharmaceutical composition is applied to a solid oral preparation. 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 invention, the pharmaceutically acceptable carrier of the oral solid preparation comprises mannitol, microcrystalline cellulose, hydroxypropyl methylcellulose, magnesium stearate.

In one embodiment, there is provided a pharmaceutical composition prepared in a unit dosage form, wherein the thyroid cancer is treated. In one embodiment, the unit dosage form contains 2 mg to 20 mg of Compound I or a pharmaceutically acceptable salt thereof. In one embodiment, the unit dosage form contains from 5 mg to 20 mg of Compound I or a pharmaceutically acceptable salt thereof. In one embodiment, the unit dosage form contains from 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 preferred are 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 such a manner that it is administered at intervals. The above-mentioned interval administration includes the administration period and the suspension period, and the compound I or a pharmaceutically acceptable salt thereof may be administered once or several times daily during the administration period. For example, the compound I or its pharmaceutically acceptable salt is administered daily during the administration period, the administration is stopped for a certain period of time in the next administration suspension period, and the administration period and then the administration suspension period are repeated many times . Here, the ratio calculated as the number of days between the administration period and the suspension period is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, and most preferably 2: 0.5 ~ 1.

In some embodiments, administration is continued for two weeks and stopped for two weeks. In some embodiments, once daily, continuously for 14 days, then stop for 14 days; Followed by administration once a day, followed by continuous administration for 14 days, followed by stopping the administration for 14 days, followed by continuous administration for 2 weeks and administration for 2 weeks.

In some embodiments, administration is continued for two weeks and stopped for one week. In some embodiments, once daily, continuously for 14 days, then stopping for 7 days; The administration is continued once a day, followed by continuous administration for 14 days, followed by stopping the administration for 7 days, followed by continuous administration for 2 weeks and administration for 1 week.

In some embodiments, administration is continued for 5 days and stopped for 2 days. In some embodiments, once daily, continuously for 5 days, then stop for 2 days; Followed by continuous administration once a day, followed by continuous administration for 5 days, followed by stopping the administration for 2 days, followed by continuous administration for 5 days and suspension for 2 days.

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

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

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

In this specification, the crystal form of the hydrochloride salt of Compound I includes, but is not limited to crystals of type A, B and C disclosed in Chinese patent application CN 102344438A, wherein A and B crystals have a basic crystal number And does not contain any crystals of other solvents, and the C-type crystal contains crystals of two crystals. In some embodiments, the crystals of the heavy hydrochloride salt of Compound I are Form A crystals.

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

"Patient" means a mammal, preferably a human. In some embodiments, the patient is a patient who fails standard therapy or fails standard therapy.

"Pharmaceutically acceptable, " " pharmaceutically acceptable" means for preparing a pharmaceutical composition, which is generally safe, non-toxic, compatible with the needs of biology or otherwise, .

"Pharmaceutically acceptable salts thereof" include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; Or an organic acid such as acetic acid, trifluoroacetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, propanedioic acid, succinic acid, malic acid, maleic acid, fumaric acid, Examples of the organic acid include methanesulfonic acid, ethanesulfonic acid, 1,2 ethane disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, pivalic acid, , Acid addition salts formed with organic acids such as gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and the like.

"Therapeutically effective amount" means an amount which, when administered to a human for the treatment of a disease, results in sufficient treatment for the disease.

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

(1) inhibit the disease (i. E., Inhibit the pathology and / or symptomatically progressive development) in the human being suffering from or manifesting the disease pathologically or symptomatically; or

(2) ameliorating (i. E., Pathologically and / or symptomatically reversing) the disease in a human suffering or exhibiting the pathology or symptomatology of the disease.

Example

Methyl] cyclopropylamine hydrochloride (compound of formula (I) in the form of a salt of the compound Hydrochloride)

.

.

7-yl] oxy] methyl] -2-methyl-1H-indol-5-yl) ] Cyclopropylamine, and then the title compound is prepared by referring to the preparation method of "salt form example" in the specification of WO2008112407.

Or by referring to the method disclosed in Chinese patent application CN102344438A.

Methyl] cyclopropylamine hydrochloride (compound of formula (I) in the form of a salt of the compound ≪ / RTI > hydrochloride)

Circular auxiliary material designation Amount used (1000 eggs) The hydrochloride salt of Compound I 14.16 g (corresponding to 12 g of Compound I) Mannitol 89g Microcrystalline cellulose 138.4 g Hydroxypropyl cellulose 5.9 g Magnesium stearate 0.99g

Pulverization of the hydrochloride salt of Compound I to 80 mesh screening; Then homogeneously mixed with mannitol and hydroxypropyl cellulose; Subsequently, the prescribed amount of microcrystalline cellulose was added, uniformly mixed, and filtered through a filter net of 0.8 mm; Finally, the prescribed amount of magnesium stearate is added and mixed uniformly to fill the capsules.

In capsules of other contents of the dihydrochloride salt of Compound I, with reference to the same ratios and formulations mentioned above.

Study on the tolerance of the treatment of dihydrochloride capsule of Compound I and the therapeutic effect on thyroid cancer

1) Results of resistance study

If diagnosed, including diagnosis, patients with malignant tumors failing standard therapy or lacking standard therapy will be treated with a two-week continuous dose of drug and a one-week suspension, ie three weeks (21 days) in one treatment cycle , And at least two cycles (42 days) are observed to observe tolerance, and the therapeutic effect is also observed.

Daily dosing once, every 10 mg dose, 3 cases of side effects, 1 case of elevation of Ⅲ and more fat, 1 case of diastase, 1 case of helplessness, 1 case of other Ⅰ. do. Miscellaneous I also includes side effects such as 2 cases of diarrhea, 1 case of diarrhea, 1 case of abdominal pain, 1 case of hypertension.

Each day, one dose of 16 mg is administered each time. In three cases, one Ⅲ in the second week of drug use of the second cycle also has a rise in blood pressure and a lethargy phenomenon.

Other adverse events in the study group were Ⅱ hypertension 1 case, thyroid dysfunction case 2, alanine aminotransferase (ALT) elevation case 1 case, Ⅰ also includes side effects such as 2 cases of elevated triglycerides, 2 cases of diarrhea, abdominal pain, 1 case of limb symptom, 1 case of neck relaxation.

Patients were observed in a total of 18 cases (here, 5 cases were one case) in this group when they were administered once every day and 12mg each time. There were different side effects in the drug use process. The degree of severity was 1 to 2 degrees, and no side effects of 3 degrees or more occurred. Specifically,

Blood lipid: 8 cases of elevated triglycerides, 8 cases of elevated total cholesterol;

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

Skin Toxicity: 6 cases of skin reaction, 4 cases of pidgin;

Endocrine system: 7 cases of thyroid function decline, 2 cases of hyperthyroidism, 3 cases of diastasis, 2 cases of CK-MB increase;

Symptoms: 6 helpless cases, 4 neck swelling cases, 6 diarrhea cases, 2 dizzy and sore cases, 3 sore cases, 3 muscle sore cases; 3 cases of discomfort, loss of appetite, 1 case of tinnitus, fever,

Others include 5 cases of hypertension, 5 cases of hematuria, 5 cases of proteinuria and 3 cases of reduction of white blood cell (WBC).

2) Initial treatment of thyroid carcinoma

Thyroid carcinoma of the thyroid (once daily dose of 12 mg): There were 6 subjects in total, one case was unevaluated, 4 cases were SD (stable disease) (small), 1 case was PD . Therefore, we can see that the rate of gain of thyroid cancer is more than 80%.

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

Compound I hydrochloride capsules were used 12 mg / day for 2 weeks continuously for 1 week. The overall tolerance was very good, the side effects were 1/2 degree, and other unexpected side effects were observed Not; In terms of therapeutic efficacy, we have benefited from the treatment of thyroid cancer.

Therapeutic effect of thyroid medullary carcinoma

1) History of patient

A 56-year-old male was diagnosed as having a tumor in the neck in October 2005 and had a tumor removal operation. In January 2007, a tumor was found in the left side of the body during the physical examination. In January 2007, "Neoplastic tumor removal + preoperative" was performed. Postoperative pathology was thyroid carcinoma; Ten lymphatic vessels were detected in the "left subclavian lymphatic" tissue from which the test was sent, all were metastasized to the cancer, and two other cancer nodules were detected. Between February 2007 and April 2007, radiotherapy was performed 49 times. In May 2007, two cycles of drug treatment were performed after surgery, but no specific drug was identified. In the periodic retest, we found that the mediastinal lymph nodes enlarged in October 2012, and further treatment was considered considering the metastasis. At present, Yuugaru (甲) 100ug qd is orally administered.

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

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

2) CT results

In the Aug. 3, 2013 imaging evaluation, the target lesion site diameter sum is 49 mm;

In the September 10, 2013 imaging evaluation, the target lesion site diameter sum is 44 mm;

In the October 26, 2013 imaging evaluation, the target lesion site diameter sum is 42 mm;

On December 9, 2013 imaging evaluation, the target lesion site diameter sum is 41 mm;

In the January 20, 2014 imaging evaluation, the target lesion site diameter sum is 41 mm;

On the April 11, 2014 imaging evaluation, the target lesion site diameter sum is 41 mm;

In the July 9, 2014 imaging evaluation, the target lesion site diameter sum was 40 mm;

In the September 26, 2014 imaging evaluation, the target lesion site diameter sum is 38 mm.

3) Immunity

Overall tolerance is excellent. Sometimes seen Ⅰ ° Diarrhea, Ⅰ ° Leukocyte reduction, Ⅰ ° skin reaction, Ⅰ ° muscular tingling, Ⅰ ° human pain, Ⅰ ° proteinuria, Ⅰ ° bilirubin elevation, Ⅰ ° hypertension, Ⅰ ° neutrophil cell count reduction, Ⅰ ° low density lipoprotein elevation, Ⅰ ° Stomach pain, Ⅰ ° loss of appetite, Ⅰ ° diarrhea, Ⅰ ° toothache and Ⅱ ° leukocytosis, and the response is improved, recovered or alleviated in the short term.

Therapeutic effect on thyroid papillary carcinoma

1) History of patient

A 56-year-old woman underwent bilateral thyroidectomy in 2010. Postoperative pathology is bilateral thyroid papillary carcinoma and metastatic lymph node metastasis. In 2012, we performed tumor removal surgery for the right bronchial tumor and diagnosed that the thyroid papillary adenocarcinoma was accumulated in the bronchus after surgery. After that, we did not treat it and after that, the voice was cracked in October, 2013, The patient was diagnosed as having difficulty in swallowing, and the pathologic examination revealed a fibroid of the thyroid papillary adenocarcinoma. She was diagnosed as having metastasis to the bronchus in November, 2013 and performed bronchoscopy and bronchoscopy. In May 2014, a double necked nodule was reexamined by neck and chest CT, and a part of the nodule was newly appeared. Hypertension, and diabetes mellitus for about five years, and in the long term, one dose of Irbesartan Hydrochlorothiazide / qd was taken.

From June 3, 2014, 12 mg qd of the hydrochloride salt in Compound I was orally administered, followed by 2 weeks of continuous use of the drug, and the administration was stopped for 1 week.

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

2) CT results

In the May 12, 2014 imaging evaluation, the target lesion site diameter sum is 10 mm;

In the July 14, 2014 imaging evaluation, the target lesion site diameter sum is 0 mm and the target lesion site evaluation result is CR (all mitigation);

On September 25, 2014 imaging evaluation, the target lesion site diameter sum was 0 mm and the target lesion was reduced;

On November 24, 2014 imaging evaluation, the target lesion site diameter sum is 0 mm;

On January 20, 2015, in the imaging evaluation, the sum of the diameter of the target lesion site is 0 mm.

3) Immunity

Overall tolerance is excellent. Sometimes seen Ⅰ ° Muscular tongue, Ⅰ ° helplessness, Ⅰ ° waist squeeze, Ⅰ ° cough, Ⅰ ° toothache, Ⅰ ° hemorrhage, Ⅰ ° skin reaction, and the response is improved, recovered or alleviated in the short term.

Therapeutic effect on thyroid follicular carcinoma

1) History of patient

A 67-year-old woman was treated with "left thyroidectomy + right thyroid gland resection" in August 2007, and postoperative pathology was left thyroid follicular carcinoma. In September 2007, PET-CT detected metastasis to lung and left iliac bone. In September 2007, he performed "Right thyroid lobectomy". In the postoperative pathology, the right nodular thyroid swelled, fibrosis and silk uptake swelled. After the operation, the thyroid gland was administered orally to replace the treatment. From September 2007 to June 2011, 11 treatments were performed. Chemotherapy was repeated several times between November 2007 and October 2009 with 4 cycles of biotherapy, THP + L-OHP + CF + FT-207 (ie, "Pirarubicin + Oxaliplatin + Calcium Calcium" In November 2009, local iliac bone localization was performed and the dose was 3000 Gy. In October 2011, recurrence of multiple pulmonary metastases and multiple metastases of the lungs were suggested by PET-CT. From November 2011, treatment with Pamidronate Disodium was applied, and Vivatuxin was injected into the localization of the right scapular metastasis. In November 2011, a left fibular bone tumor removal + polyvinylpyrrolidone filler + dynamic hip fixation was performed. In March 2012, the right scapular part was removed and the postoperative pathology was metastatic thyroid follicular carcinoma. In June 2012, left lateral fibrillary tibial bone shear + total hip arthroplasty was performed. In September, 2012, conventional radiotherapy for bone metastases was performed. Radiotherapy was performed on the left chest wall metastatic lesion site in January 2013, and radiotherapy was performed in the localization of the metastatic lesion in February 2013. In April 2013, the right axillary lymph node was removed. Between December 2012 and October 2013, sorafenib was orally administered. One year after the patient found hypertension, he is currently orally administering Telmisartan 40 mg qd.

From November 14, 2013, 12 mg qd of the hydrochloride capsule of Compound I was orally administered, and the drug was continuously used for 2 weeks and stopped for 1 week. On March 20, 2014, a dose of 10 mg qd of hydrochloride capsules of Compound I was treated, followed by two consecutive weeks of drug use and stopped for 1 week; On July 3, 2014, the dose was changed to 10 mg qd of the hydrochloride salt in Compound I, and the drug was continuously used for 2 weeks and stopped for 1 week.

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

2) CT results

In the November 11, 2013 imaging evaluation, the target lesion site diameter sum is 33 mm;

In the December 23, 2013 imaging evaluation, the target lesion site diameter sum was reduced by 25 mm to 24%;

In the January 28, 2014 imaging evaluation, the target lesion site diameter sum is 23 mm, reduced by 30%;

On the March 17, 2014 imaging evaluation, the target lesion site diameter sum was reduced by 19 mm to 42%;

On the 28 April 2014 imaging evaluation, the target lesion site diameter sum is 17 mm, reduced by 49%;

In the June 27, 2014 imaging evaluation, the target lesion site diameter sum was 17 mm, a 49% reduction;

On the October 16, 2014 imaging evaluation, the target lesion site diameter sum is reduced by 5 mm to 85%;

On February 3, 2015, in the imaging evaluation, the target lesion site diameter sum was reduced by 7 mm to 79%.

3) Immunity

Overall tolerance is excellent. Only occasional Ⅰ ° helplessness, Ⅰ ° tenderness, Ⅰ ° skin reactions, Ⅱ ° blood bilirubin elevations were observed, and the response improved, recovered or alleviated in the short term.

Claims (17)

A method of treating adenocarcinoma comprising administering to a patient in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof.
[Compound I]

The method according to claim 1,
Wherein said thyroid cancer is a thyroid papillary carcinoma, thyroid follicular carcinoma, thyroid carcinoma, thyroid cancer. The method according to claim 1,
Wherein said thyroid cancer is end stage thyroid carcinoma. 4. The method according to any one of claims 1 to 3,
The method for treating thyroid cancer, wherein the compound I or a pharmaceutically acceptable salt thereof is a hydrochloride salt, and is preferably a dihydrochloride salt. 5. The method according to any one of claims 1 to 4,
The daily dose of Compound I or a pharmaceutically acceptable salt thereof may be in the range of 2 mg to 20 mg, 5 mg to 20 mg, 8 mg to 20 mg, 10 mg to 16 mg, 10 mg to 14 mg, 10 mg, 12 mg, ≪ / RTI > 6. The method of claim 5,
The compound I or a pharmaceutically acceptable salt thereof is administered by a method of administering the compound at intervals, and administration of the compound I at the above intervals includes the period of administration and the period of suspension, and the ratio of the administration period to the period Is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, most preferably 2: 0.5 to 1, For 2 weeks, stopping the administration for 2 weeks, stopping the administration for 2 weeks continuously, stopping the administration for 1 week, and continuously stopping the administration for 5 days, and stopping the administration for 2 days. Wherein the method comprises the steps of: Use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of thyroid cancer.
[Compound I]

8. The method of claim 7,
Wherein the thyroid cancer is thyroid papillary carcinoma, thyroid follicular carcinoma, thyroid carcinoma, thyroid cancer, or a pharmaceutically acceptable salt thereof. 8. The method of claim 7,
The use of thyroid cancer in the preparation of a medicament for the treatment of thyroid cancer of Compound I or a pharmaceutically acceptable salt thereof, which is an end stage thyroid carcinoma. 10. The method according to any one of claims 7 to 9,
The use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of thyroid cancer of Compound I or a pharmaceutically acceptable salt thereof, wherein the compound is a hydrochloride salt, preferably a dihydrochloride salt. A pharmaceutical composition for treating thyroid cancer, comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
[Compound I]

12. The method of claim 11,
Wherein said thyroid cancer is thyroid papillary carcinoma, thyroid follicular carcinoma, thyroid carcinoma, thyroid carcinoma. 12. The method of claim 11,
Wherein said thyroid cancer is endometrial thyroid carcinoma. 14. The method according to any one of claims 11 to 13,
Wherein the compound I or a pharmaceutically acceptable salt thereof is a hydrochloride salt, preferably a dehydrochloride salt. 15. The method according to any one of claims 11 to 14,
The amount of the compound I or a pharmaceutically acceptable salt thereof administered per day is in the range of 2 mg to 20 mg, 5 mg to 20 mg, 8 mg to 20 mg, 10 mg to 16 mg, 10 mg to 14 mg, 10 mg, 12 mg, 14 mg and 16 mg, Gt; 16. The method according to any one of claims 11 to 15,
Preferably the single dose form is formulated as a single dose form of the pharmaceutical composition wherein the dosage form comprises from 2 mg to 20 mg, 5 mg to 20 mg, 8 mg to 20 mg, 10 mg to 16 mg, 10 mg to 14 mg, 10 mg, 12 mg, ≪ / RTI > or a pharmaceutically acceptable salt thereof. 17. The method according to any one of claims 11 to 16,
The compound I or a pharmaceutically acceptable salt thereof is administered by a method of administering the compound at intervals, and administration of the compound I at the above intervals includes the period of administration and the period of suspension, and the ratio of the administration period to the period Is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, most preferably 2: 0.5 to 1, For 2 weeks, stopping the administration for 2 weeks, stopping the administration for 2 weeks continuously, stopping the administration for 1 week, and continuously stopping the administration for 5 days, and stopping the administration for 2 days. Or a pharmaceutically acceptable salt thereof.