CN110903246A

CN110903246A - Compound for treating thyroid cancer and composition and medical application thereof

Info

Publication number: CN110903246A
Application number: CN201911317420.1A
Authority: CN
Inventors: 李霞; 张先娟; 李莉; 孙苗苗; 赵洁
Original assignee: Individual
Current assignee: Individual
Priority date: 2019-12-19
Filing date: 2019-12-19
Publication date: 2020-03-24

Abstract

The invention provides a compound for treating thyroid cancer, and a composition and medical application thereof. The compound and the composition thereof have certain inhibitory activity on thyroid cancer, and in vitro tests show that the compound has good inhibitory effect on proliferation of human medullary thyroid carcinoma cell lines (TT), so the compound and the composition thereof have certain clinical application prospect.

Description

Compound for treating thyroid cancer and composition and medical application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a compound for treating thyroid cancer, a composition thereof and medical application thereof.

Background

Thyroid cancer (thyroid carcinoma) is one of the most common diseases of the endocrine system of the human body, and is a tumor of low malignancy. It is divided into four distinct pathological types, Papillary Thyroid Carcinoma (PTC), Follicular Thyroid Carcinoma (FTC), Medullary Thyroid Carcinoma (MTC) and undifferentiated carcinoma (anaplastic thyroid carcinoma). In recent years, the incidence of thyroid cancer has increased year by year. According to the statistics data of 2018 national cancer center, thyroid cancer becomes a malignant tumor with the seventh national malignant tumor incidence rate, the female incidence rate is far higher than that of the male, the age tends to be younger, and the thyroid cancer becomes one of killers threatening the life health of human beings, particularly women.

At present, the main treatment means of thyroid cancer mainly comprises surgical treatment and radioactive I¹³¹Treatment, Thyroid Stimulating Hormone (TSH) inhibition therapy, and the like. Currently, surgery and administration of TSH-inhibiting, radioactive I¹³¹The cooperative treatment is a more conventional and effective treatment means, firstly, the pathological part is removed by operation, but because thyroid cancer focuses are tiny and numerous and are easy to leave, the postoperative patient needs to be matched with radioactivity I¹³¹In treatment, the principle that thyroid cells take up iodine is utilized to remove residual focus. In addition, thyroid cancer is highly susceptible to metastasis of peripheral lymph node tissue, and lymph node clearing is also required during the operation. However, radioactivity I¹³¹The dose of treatment varies from person to person, and if too low a dose may cause recurrence of the tumor due to incomplete removal, and if too high a dose may cause irreversible damage to normal tissues in the patient. The TSH inhibition treatment is mainly realized by administering levothyroxine sodium tablets, and excessive administration can cause hyperthyroidism of patients, and bring clinical symptoms such as palpitation, sweating, emotional agitation and the like, which are not favorable for postoperative recovery of the patients. Therefore, the search for effective molecular targeted drugs, which reduce the probability of postoperative recurrence and postoperative side effects, is the future direction of thyroid cancer treatment.

The targeted therapy is a therapeutic means for accurately killing tumor cells by taking specific gene mutation, histone modification, DNA methylation and the like in tumors as targets on the basis of molecular biology. It has the advantages of high accuracy, less side effect, high curative effect, etc. The BRAF gene mutation is a more thorough gene mutation type in the current thyroid cancer research, and a target drug of BRAF inhibitor Sorafenib is approved by the United states food and drug administration in 2014 to be marketed and used for treating certain refractory thyroid cancers, so that the BRAF gene mutation can block RAS/RAF/MEK/ERK signal pathways and inhibit the activity of vascular endothelial growth factor receptors and platelet-derived growth factor receptors, thereby achieving the treatment effect of reducing the proliferation rate of tumor cells and the angiogenesis capacity. However, since sorafenib has side effects, can cause adverse reactions such as hypertension, cardiac discomfort and the like of a patient, and is not beneficial to prolonging the overall life of the patient, it is often used in combination with glucocorticoid to reduce the side effects. In addition, the existing thyroid cancer also has an RAS targeted therapeutic drug, namely tipifarnib, which can play a certain role in inhibiting proliferation of RAS mutant tumor cells. In summary, the position of molecular targeted therapy in thyroid cancer treatment is very important, and finding a new target drug through scientific research becomes a significant research direction.

Disclosure of Invention

The invention aims to provide a compound for treating thyroid cancer, a composition thereof and medical application thereof.

The technical scheme for realizing the above purpose of the invention is as follows:

a compound of formula (I) or a pharmaceutically acceptable salt thereof

Wherein, X is selected from C or N, R1 is selected from C or N, R2 is selected from NH or O, R3 and R4 are selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, nitro, hydroxyl and amino, and R5 is selected from H, halogen and C1-C4 alkyl.

Preferably, X is selected from C, R1 is selected from C, R2 is selected from NH, R3 and R4 are selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl, and R5 is selected from H.

Further preferably, X is selected from N, R1 is selected from C, R2 is selected from O, R3 and R4 are selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl, and R5 is selected from H and halogen.

Most preferably, the compounds provided by the present invention having antithyroid activity have the following structure:

the present invention also includes pharmaceutically acceptable salts of the above compounds, including organic or inorganic acid salts, representative salts including, but not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) above, together with one or more pharmaceutically acceptable carriers.

The acceptable carriers described above are non-toxic, can be adjunctive to administration, and do not adversely affect the therapeutic benefits of the compounds of formula (I). Such carriers can be any solid excipient, liquid excipient, semi-solid excipient, or in aerosol compositions, gaseous excipient, commonly available to those skilled in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl stearyl ester, sodium chloride, anhydrous skim milk, and the like. The liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil and the like, preferably liquid carriers, particularly for injectable solutions, including water, saline, aqueous dextrose and glycols.

The compounds of the invention are administered in pharmaceutical compositions by the following routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). The preferred method of administration is oral using a convenient daily dosage regimen which may be adjusted depending on the extent of the disease.

Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional methods in the pharmaceutical field. For example, the compound (active ingredient) can be combined with one or more carriers and then formulated into a desired dosage form, e.g., tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, formulations, aerosols, and the like.

The amount of the compound in the dosage form may vary within the full range used by those skilled in the art. Typically, the dosage form contains about 1-99 wt% of the compound of formula (I) based on the total dosage form, in weight percent (wt%), and one or more suitable pharmaceutical excipients as a balance. Preferably, the compound is present in a proportion of about 20 to 70 wt%.

The invention also provides application of the compound in preparing a medicament for treating thyroid cancer.

Detailed Description

The present invention will be described in further detail with reference to examples.

Example 1

Dissolving 3, 5-bis-trifluoromethyl-benzoic acid (2.6g) and 2-chloro-5-hydroxy-benzimidazole (1.7g) in a solvent DMF, adding 10ml of sulfuric acid, heating to 100 ℃ for reaction for 3 hours, washing with a saturated sodium carbonate solution and a saturated common salt solution for 3 times, and drying to obtain an intermediate 1(3.0g), mixing the intermediate 1 with 3, 5-diiodoaniline (3.4g), adding triethylamine into DMF, heating to 105 ℃, reacting for 6 hours, cooling, removing the solvent, extracting with dichloromethane, combining organic layers, washing with brine, and drying to obtain a compound A.

1H NMR(400MHz，CDCl₃)δ：7.18(d，1H)，7.77(d，1H)，7.62(d，1H)，5.1(s，1H)，4.0(s，1H)，6.83(d，1H)，7.39(d，1H)，8.32(d，1H)，7.90(d，1H)，8.34(d，1H)；

MS(ESI)m/z：717.13(M+1)。

Examples 2 to 5

Based on a similar method, compound B-compound E can be synthesized.

Compound B

1H NMR(400MHz，CDCl₃)δ：7.16(d，1H)，7.77(d，1H)，7.62(d，1H)，5.0(s，1H)，4.0(s，1H)，6.82(d，1H)，8.02(d，1H)，7.55(d，1H)，8.03(d，1H)；

MS(ESI)m/z：650.13(M+1)。

Compound C

1H NMR(400MHz，CDCl₃)δ：7.16(d，1H)，7.75(d，1H)，7.62(d，1H)，5.0(s，1H)，4.1(s，1H)，6.82(d，1H)，7.55(d，1H)，8.53(d，1H)，8.33(d，1H)；

MS(ESI)m/z：832.88(M+1)。

Compound D

1H NMR(400MHz，CDCl₃)δ：7.16(d，1H)，7.77(d，1H)，7.62(d，1H)，5.1(s，1H)，4.1(s，1H)，6.82(d，1H)，7.55(d，1H)，6.84(d，1H)，7.75(d，1H)，7.11(d，1H)；

MS(ESI)m/z：1364.72(M+1)。

Compound E

1HNMR(400MHz，CDCl₃)δ：7.16(d，1H)，7.76(d，1H)，7.62(d，1H)，5.1(s，1H)，4.1(s，1H)，6.08(d，1H)，6.09(d，1H)，7.75(d，1H)，7.75(d，1H)，7.11(d，1H)；

MS(ESI)m/z：1896.55(M+1)。

Example 6

Human medullary thyroid carcinoma cell line (TT, obtained from the cell bank of the China academy of sciences' typical culture Collection) was suspended in RPMI1640 medium (obtained from Sigma) containing 15% fetal bovine serum. The cell suspension (3X 104 cells/mL) was added to a 96-well plate for cell culture at 0.1 mL/well in 5% CO₂The cells were incubated overnight in an incubator (37 ℃). After the culture, 0.1mL each of the test substance A-Compound E diluted in RPMI1640 medium containing 15% fetal bovine serum was added to each well, followed by 5% CO₂The culture was carried out in an incubator (37 ℃) for 10 days. After culturing, Cell Counting Kit-1 (purchased from DOJINDO Co.) was added to each well) mu.L of the resulting mixture was developed in a 5% CO2 incubator (37 ℃ C.), and then the absorbance of each well was measured at 435nm as a measurement wavelength and 620nm as a control wavelength using a plate reader MTP-500. The ratio (%) of the absorbance in each well to which the test substance was added to the absorbance in the wells to which the test substance was not added was determined, and the concentration of the test substance necessary for inhibiting cell growth by 50% (IC50) was calculated from the ratio.

As a result: the compounds A-E have certain inhibitory activity on the proliferation of human medullary thyroid carcinoma cell line (TT), and the results are shown in the table.

Compound (I)	IC50(nM)
		Compound A	21.5
Compound B	35.0
		Compound C	43.3
Compound D	40.2
		Compound E	18.5

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the structure:

2. The compound of claim 1, wherein: x is selected from C, R1 is selected from C, R2 is selected from NH, R3, R4 is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, and R5 is selected from H.

3. The compound of claim 1, wherein: x is selected from N, R1 is selected from C, R2 is selected from O, R3, R4 is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, and R5 is selected from H and halogen.

4. The compound of claim 1, in particular of the structure:

5. a pharmaceutical composition characterized by: comprising a therapeutically effective amount of a compound of the preceding claims, together with one or more pharmaceutically acceptable carriers.

6. The pharmaceutical composition of claim 5, wherein: the composition comprises clinically common dosage forms, such as tablets, pills, capsules, semi-solids, powders, sustained release dosage forms, solutions, suspensions, formulations, aerosols and the like.

7. The pharmaceutical composition of claim 5, wherein: methods of use of the compositions include oral, systemic administration (e.g., transdermal, intranasal, or by suppository), or parenteral administration (e.g., intramuscular, intravenous, or subcutaneous).

8. Use of a compound according to claim 1 or a pharmaceutical composition according to claims 5-7 for the manufacture of a medicament for the treatment of thyroid cancer.