TW201124134A - Ethacrynic acid derivatives of cancer treatment - Google Patents

Abstract

The present invention relates to derivatives of ethacrynic acid, wherein the derivatives are derived from lactamization of ethacrynic acid. The derivatives of ethacrynic acid have cytotoxicity to cancer cells, including lung cancer, breast cancer, colon cancer or prostate cancer cells.

Description

201124134 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to the synthesis of a diuretic derivative and its use for treating cancer. [Prior Art] Cancer 'also known as malignant tumor' is a disease caused by abnormal cell proliferation. In addition to uncontrolled growth of cancer cells, cancer cells also locally invade surrounding normal tissues and even transfer to other parts of the body via the internal circulatory system or lymphatic system. There are many types of cancer, and the severity of the condition depends on where the cancer is located and the extent of malignant growth and whether metastasis occurs. The doctor can make a series based on the __(4) of the examinee or the content of the Nade, or even the biomarker. Recording is based on its _, Weng _ position and development _ segment & treatment and even cure sores. Once diagnosed, cancer is usually treated in combination with surgery, chemotherapy, and radiation therapy. With the advancement of scientific research, the production of music for certain types of cancer has also improved the therapeutic effect. If the cancer is left untreated, usually the end result will result in death. Cancer is now the leading cause of death worldwide. According to the statistics of the World Health Organization, there are about 丨, _ 10,000 people suffering from cancer every year in the world. It is estimated that the number of new cases in the world will reach 2,700,000 a year, and the death toll will reach 10,000 people. It will become more serious as the world's population increases, and thus the cancer medical market is the biggest. Glutathione s_t deletease (gst) is an enzyme that can help to get rid of poison. Usually they are all in the liver. All the eukaryotic Js are in possession. It will have different catalytic effects in the _f _, and also in the cell membrane of the mother cell, and the GST in the cytoplasm will be at least 5 (4) genes (alpha) (GsTA) ), bili (GSTP) sigma(GSTS) ^ theta(GSTT) ) »

GST is the microsome (4) Cros〇mai) GST and white leucovorin c4 (ieuk〇triene c4 ah (4), which are translated from the same gene family. The most common GST in mammalian movement 201124134 The family is GSTA, GSTM and GSTP. There is a lot of evidence that the amount of GST in the cell can determine whether the cell is susceptible to external toxic substances such as carcinogenic substances, anti-tumor drugs, environmental pollutants and oxidative free radicals. Therefore, many scientists are constantly studying the transcription and post-transcriptional modification of GST, trying to find out how GST regulates resistance to external toxic substances. Many scientists have tried to use GX's drugs to regulate GST so that cancer cells can be made into cells. Apoptosis. = Urine, (ethacrynic acid) was originally used as a diuretic, but recent studies have found that ^ a drug has the potential to fight cancer, and its egg is self-quality is GSTPW, and recently even researched nine found 'right Use butylgr〇up to modify the formation of uric acid. (4) Tinghua coffee can strengthen the ability to kill cancer cells. fr version 2007, 67(16), =6 7864) 'Another Also use dynamic combinatorial chemistry concept (iv) Wenxing ^ c〇mbinat〇rial be in the GST ㈣W H 128 (26), 8459-8467) Summary of the Invention square diuretic utility of disease. Η disclosed by the present invention

NR (i-i) wherein NR represents a stilbene-based molecule, and the hananoic acid molecule may be selected from a carboxylic acid or a halogen chain carboxylic acid which loses a hydroxyl group in a hydrazine-like carboxylic acid. ', anthracene carboxylic acid, functional cyclic carboxylic acid, long chain carboxylic acid 201124134 The benzene ring carboxylic acid molecule of the present invention is selected from the following molecules (A1-A23):

A21 A22 A23 The heterocyclic carboxylic acid molecule of the present invention is selected from the group consisting of the following molecules (B1-B20):

201124134

The halocyclic carboxylic acid molecule of the present invention is selected from the group consisting of the following molecules (C1-C26):

C5

C8

CQ C10 F. F HO f=\ 0 0 Ό -S-F 0 H0> C11 F F C12

0

C13

HO F

C14

HO

C17 C18

6 201124134

The long chain carboxylic acid molecule of the present invention is selected from the group consisting of the following molecules (D1-D18):

Nh2 0 D9

Ο D13

HO

Ο Ο

D12 D16 D17 D18 201124134 The chain carboxylic acid molecule of the present invention is selected from the following molecules (ei_ei5)

E13 E14 6e15 The preferred Lewis acid derivative of the present invention is the following molecule (I 2).

The invention of the bribery creature Na is poisonous. Shuming cancer cell line refers to epithelial cell type cancer cells, including lung cancer, breast cancer, rectal cancer and prostate cancer cells. The invention also provides a method for poisoning cancer cells by uric acid derivatives, the steps of which are as follows: (1) manufacturing grade derivatives: (1) 丨) urinary amination; (4) uridine tails after amiodalation On the side of the weaving side, the two sides of the Wei-Amine bribe are taken; (2) The _ type: the product is smashed into appropriate _ to the patient with the disease, the appropriate dosage form referred to here may be ·, π, drug rotation, syrup, Age, injection or any pharmaceutical dosage form suitable for use in 201124134. In the above method for poisoning cancer cells by using a diuretic derivative, the preferred steps for preparing the diuretic acid are as follows: (1) preparing a linking molecule having an amine group at both ends (or an amine group and an azide group, respectively); (2) urinating the diuretic acid by using the linking molecule; (3) re-actuating the amine group of the urethral acid end of the guanidinated acid with other tickic acid molecules to carry out the guanidation to bind the two molecules. [Embodiment] Synthesis of a diuretic derivative

The preparation process of the diuretic acid derivative is shown in Fig. 1, and is summarized as follows: First, a 4-azidobutan-l-amine (4-azidobutan-l-amine) (compound 1) having an amine group at both ends is prepared. ), reacting it with TfNKtrifluoromethanesulfonyl azide) to oxidize the amine group at one end to an azide group (Compound 2); and further preparing diuretic acid (Compound 3) to react with Compound 2' at HBTU (O-benzotriazole-WAWM) -teframethyl-uronium-hexafluorophosphate), DIEA (Λ^-diisopropylethylamine) and dimethyl sulfoxide DMSCKdimethyl sulfoximeide are subjected to guanidation to form compound 4; compound 4 is azide in hydrogen (3⁄4) Reduction to an amine group by the action of a palladium carbon catalyst (Pd/C) to form compound 5; finally 'the compound 5 is further subjected to a guanidine reaction with another carboxylic acid molecule (RCOOH) to synthesize the final product compound 6' and Purification. Compound 6 is a diuretic derivative of the present invention. In the synthesis reaction, the purpose of using the linking molecule is to make the diuretic acid connect to other molecules by using its hydroxyl group. Therefore, in practical applications, as long as the compound having such a function can be used as a linking molecule, it is not limited to the present example. 4-azido-1.butylamine; in other words, diuretic acid itself has a slow acid property' so it can also play the role of RCOOH in Figure 1 and react directly with other compounds 'in this case' Use the steps to connect the molecules. The carboxylic acid molecules linked to the diuretic acid in Figure 1 can be roughly classified into the following five categories: benzene ring carboxylic acids (Fig. 2, A1-A23), heterocyclic carboxylic acids (Fig. 3, B1-B20), and functional rings. Carboxylic acid (Fig. 4, C1-C26), long chain carboxylic acid (Fig. 5, D1-D18) and halogen chain carboxylic acid (Fig. 6, E1_E15). 201124134 There are 102 kinds of products of diuretic acid derivatives after synthesis. Cancer cell toxicity test

When 102 kinds of diuretic derivatives are synthesized, the cancer cell toxicity test can be performed. The cancer cell lines used in the experiment were human lung cancer cells A549 (No. 60074, Food Industry Development Research Institute), human breast cancer cells MCF7 (No. 60436, Food Industry Development Research Institute), mouse prostate cancer cells Tramp-Cl (National Tsinghua University, Jiang Qixun Laboratory) and mouse rectal cancer C26 (Atomic Energy Commission, Institute of Nuclear Energy). The test method was the MTT (3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) test. The control drugs used in the toxicity test were Cisplatin (positive control group) and benzoic acid Benzoid acid (negative control group). The test procedure is summarized as follows: the cells are cultured in a 96-well plate, and the MTT reagent and the drug to be tested at a final concentration of 100 μM are added, and then the cells are cultured for a period of time, and the absorbance value can be determined to determine whether the drug to be tested has cells. Poisoning effect. Fig. 7 to Fig. 11 show the results of preliminary toxicity test of 1 〇 2 kinds of diuretic acid derivatives, and the vertical axis represents cell survival rate (%). It can be seen from the figure that many diuretic derivatives have toxic acaricidal activity on these cells, and when diuretic acid couples different kinds of carboxylic acids, it will cause different degrees of cytotoxicity. In addition, cell lines of different origins will also be the same. Compounds have varying degrees of sensitivity. Further analysis of the carboxylic acid species revealed that the poisoning characteristics of the cyclic acid were weak, the sensitivity of AM9 to monocyclic acid was poor, and Tramp_ci was weak to the tolerance of toluene acid, but the ring was found. Acid and polycyclic acid have strong poisoning ability for C26. In addition, for the linear acid and the chain acid, the toxicity of the halogen acid is relatively strong, especially for A549 and MCF7, the difference in the toxic ability is very large. In addition, the light-toothed, acid-rich uric acid derivative has a __ poisoning effect on C26 and MCF7, and I makes the sensitivity of A549 strong, and the poisoning effect is high. 201124134 This test also found a compound with particularly strong poisoning effect, as shown in Figure 12, which is the B17 coupled product (1-2). The IQ of this derivative for different cell lines was further determined. The value can be obtained as follows (B17 itself is fenbufen, so this experiment uses fenbufen as a control group, fcnbufen is not particularly toxic to cancer cells): Cell line ICs〇values (mM) Cisplatin 1-2 Fenbufen A549 15 19 >100 MCF7 55 5 10 Tramp C-1 22 >100 > 100 C26 17 35 >100 In addition to the above compounds, there are also many diuretic derivatives which can be used in 1〇〇#Μ or The lower concentration achieves the effect of IC5〇' and the 1-2 compound is only provided as an experimental reference here. [Simplified illustration] Figure 1. Synthesis of diuretic derivatives Figure 2. Phenyl ring-like acid Figure 3. Heterocyclic Carboxylic Acids Figure 4. Tooth Rings Retinoids Figure 5. Long Chain Carboxylic Acids Figure 6. Halogen Chains of Oremic Acids Figure 7. Toxicity Test of Diuretic Acid Coupled Phenylcyclocarboxylic Acids for Different Cell Lines Figure 8. Toxicity test of diuretic acid-coupled heterocyclic carboxylic acid for different cell lines. Figure 9. Toxicity of uric acid coupling _ cyclic carboxylic acid to different cell lines. Figure 1 利, diuretic acid coupled long-chain carboxylic acid for different Toxicity test of cell lines Figure 11. Diuretic acid-coupled halogen chain carboxylic acid Toxicity testing in different cell lines of FIG. 12, with the preferred cancer cells to ethacrynic acid derivatives The main element SIGNS LIST None

Claims (1)

201124134 VII. Patent application scope: 1. A composition for treating cancer, which comprises an ethacrynic acid skeleton and a compound selected from the group of compounds represented by the following chemical formula (1-1) as an active ingredient; It is an amidino group. 2. The composition of claim 1, wherein the R is selected from the group consisting of the following carboxylic acid molecules and loses its hydroxyl group by amidoximation reaction: 201124134 Br CQ 0 C10 HO 0 0 -〇 C11 -S-F 0 H〇> F F C12 13 201124134 Ο C13 ΗΟ F C14 C16 Ο C17 C18 C20 Η0, /0Ϊ II _α CI ONa C22 Cl Cl C23 C24 C21 c 〇</ 1 ,αΛ: D2 D3 D4 HO D5 0 X D6 D7 D8 NH2 OH 〇 HCT "V NH2 D10 H2N OH 0 D12 D9 D11 v> ^0H 013 D14 0: 0 D15 OHO D16 HSN , NH2 〇 0 HO D17 D18 14 =0 201124134 3. The composition of claim 1, wherein the preferred compound is i-2: 4. According to _ please look at @第丨项职植, riding the skin of the skin of the fine-faced cancer cells have the ability to kill. 5. The composition of claim 1, which is toxic to lung cancer, breast cancer, rectal cancer or prostate cancer cells. 6. A method for killing cancer cells by using diuretic acid, the steps of which are as follows: 〇) preparation of a diuretic acid derivative. (1-1) first amination of the diuretic acid; (1·2) the benefit of the amidation The amine group at the tail of the uric acid is again reacted with other carboxylic acid molecules to carry out guanidation to link the two molecules; (2) Formulation dosage form: 15 201124134 This product is suitable for use in cancer patients, as indicated herein. The dosage form may be a spray, a medicinal tablet, a syrup, an ointment, an injection or any medicinally applicable pharmaceutical dosage form. According to the method of the patent application, the preferred steps of preparing the thorns are as follows: (1) Preparing a broken chain with an amine group (or an amine group and an azide group, respectively) at both ends; (2) amidating the diuretic acid by using the linked carbon chain; (3) amidating the guanidinium The amine-based re-human end of the diuretic acid is melamined with the side of the lysole-acid molecule to link the two molecules.