CN108567768B

CN108567768B - Medical application of p- [ (dipropylamino) sulfonyl ] benzoic acid

Info

Publication number: CN108567768B
Application number: CN201710134891.3A
Authority: CN
Inventors: 徐迅迪
Original assignee: Second Xiangya Hospital of Central South University
Current assignee: Second Xiangya Hospital of Central South University
Priority date: 2017-03-07
Filing date: 2017-03-07
Publication date: 2020-04-14
Anticipated expiration: 2037-03-07
Also published as: CN108567768A

Abstract

The invention relates to application of p- [ (dipropylamino) sulfonyl ] benzoic acid in treating liver cancer. The p- [ (dipropylamino) sulfonyl ] benzoic acid can effectively inhibit the growth of liver cancer cells, and has a therapeutic effect on liver cancer.

Description

Medical application of p- [ (dipropylamino) sulfonyl ] benzoic acid

Technical Field

The invention relates to the field of pharmacy. In particular to application of p- [ (dipropylamino) sulfonyl ] benzoic acid in preparing a medicament for treating liver cancer.

Background

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies in the world, centered at position 3 in the cause of tumor-related death [1Lin S, Hoffmann K, Schemmer p. Liver Cancer 2012; 1: 144- & ltSUB & gt 158], mortality is second only to lung and colon cancer. Although there are many therapeutic approaches for liver cancer, the recurrence and metastasis problems are associated with improvement and improvement of therapeutic effects. The formation of HCC is a complex multi-step process. The causative factors of HCC can be divided into extrinsic factors and intrinsic factors. The exogenous factor is mainly Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. Endogenous factors include excessive alcohol consumption, metabolic disturbances, and environmental factors such as high aflatoxin exposure. When HCC is diagnosed at an early stage, surgical operation, liver transplantation, or the like can be used. In the middle and late stage liver cancer patients, namely patients with multiple lumps and/or people with vascular involvement, arterial liver chemoembolization or anti-angiogenesis drugs are usually clinically used for treatment, but the effect is very limited.

TRPV2 belongs to the TRPV family member and is a non-selective calcium channel. In 1999, Caterina et al discovered capsaicin-insensitive nociceptor TRPV2, also known as a vanilloid receptor-linked protein (VRL 1). TRPV2 is distributed primarily in the thermally nociceptive and mechanically stimulated class a nerves. The TRPV2 channel is highly expressed in medium and large cells of the Dorsal Root Ganglion (DRG), but it is also present in the brain, dorsal horn of the spinal cord, and spleen and lung. Its transcript is also found in many brain and non-neuronal tissues, suggesting that it may have other functions as well. At present, TRPV2 has been found to be involved in the regulation of temperature and pain sensation, and has important pathophysiological functions of regulating the circulation system, gastrointestinal tract movement, immune function, cell growth and death, inflammatory reaction and the like. In addition, TRPV2 is also involved in the process of canceration.

P- [ (dipropylamino) sulfonyl group]Benzoic acid (trade name: probenecid, molecular formula: C)₁₃H₁₉NO₄S)) has the following structural formula I, and as a fat-soluble benzoic acid derivative, it was originally thought to reduce the excretion of penicillin by the renal tubules and was used clinically to increase the plasma concentration of antibiotics. The U.S. FDA has approved it for the treatment of gout. Probenecid is also considered to have a competitive inhibitory effect in active transport in tissues such as brain, liver and eye. In addition, probenecid is also involved in the excretion process of uric acid. More recent studies have found that probenecid can enhance the motor-contractile ability of the heart muscle and the intestinal tract by selectively activating TRPV 2. Currently, probenecid is only clinically applied to the treatment of kidney diseases. The therapeutic effect of probenecid in tumors is gradually known, but no report is found on the treatment of liver cancer.

The application of probenecid in other aspects has not been reported yet, and further intensive research and observation are needed.

Disclosure of Invention

The inventor finds that p- [ (dipropylamino) sulfonyl ] benzoic acid has a therapeutic effect on liver cancer.

The invention aims to provide application of p- [ (dipropylamino) sulfonyl ] benzoic acid in preparing a medicament for treating liver cancer.

In a preferred embodiment of the present invention, the pharmaceutical composition of the present invention further comprises one or more pharmaceutical excipients.

The generation of the tumor is involved in the conduction of multiple factors, multiple stages, multiple genes and multiple signal paths, so the combined use of the anti-tumor drugs with different action mechanisms is expected to improve the treatment effect.

In a preferred embodiment of the invention, the medicament is used in combination with at least one further medicament for the treatment of liver cancer, wherein the further medicament is selected from e.g. sorafenib.

The medicine containing p- [ (dipropylamino) sulfonyl ] benzoic acid of the present invention is used for curing liver cancer. The medicine prepared from the compound of the formula I can adopt common administration modes such as oral administration, injection administration (such as intramuscular injection, intravenous injection and intraperitoneal injection), subcutaneous administration, inhalation administration, rectal administration and the like, and can be prepared into common dosage forms in the field of cost, such as tablets, capsules, suppositories, powder injections, aerosols and the like.

In a preferred embodiment of the present invention, the compound of the formula I is administered by injection, preferably at a dose of 2mg/kg, calculated on the body weight (kg) of human, by intraperitoneal injection, with a frequency of 1 administration per day. The administration dose of the animals is 2mg/kg, the administration mode is intraperitoneal injection, and the administration frequency is 1 time per day.

Drawings

FIG. 1 shows the Scid-HepG 2-subcutaneous tumor relative volumes of the control group and the treatment intervention group of example 1.

Detailed Description

The technical solution of the present invention is further described in detail with reference to the following specific examples. It is to be understood that these embodiments are provided to illustrate the basic principles, main features and advantages of the present invention, and that the specific implementation conditions adopted in the embodiments may be appropriately adjusted within the scope of the art, and the scope of the present invention is not limited by the embodiments.

In the examples of the present invention, the following raw materials were used:

four-week-old female non-obese diabetic/severe combined immunodeficiency (NOD/SCID) nude mice, purchased from beijing vintongli;

hepatoma cell line HepG2, purchased from cell bank of shanghai life science institute of china science;

probenecid (Probenecid) injection drug, purchased from Sigma Aldrich, having a product number of 1091108-100M, was dissolved in DMSO.

Example 1

5 × 10 of the liver cancer cell line HepG2 is adopted⁶The cells were injected into the right flank of each NOD/SCID nude mouse (6 in total) when tumors had formed to a volume of about 80mm³Mice were randomly divided into control and treatment intervention groups, 3 each.

Treatment intervention group:

probenecid was dissolved in DMSO to form an injectable drug, and a 2mg/kg dose (where 2mg is the mass of Probenecid) was injected intraperitoneally 1 time/day.

Control group:

the blank solvent DMSO was injected intraperitoneally at a dose of 2mg/kg, 1 time/day.

Tumor size in volume 1/2 × length × width²Detection, mice were sacrificed at week 6, comparing survival and tumor volume size. The experimental results of this example are as follows:

TABLE 1 Scid-HepG 2-subcutaneous tumor relative volumes of control group and treatment intervention group

In Table 1, DMSO represents the Scid-HepG 2-subcutaneous tumor relative volume of the blank solvent control group, and probenecid represents the Scid-HepG 2-subcutaneous tumor relative volume of the treatment intervention group. The tumor size on the first day of administration was 100%.

As can be seen from the results in table 1, the tumor volume changes significantly slower in mice injected with p- [ (dipropylamino) sulfonyl ] benzoic acid, indicating that p- [ (dipropylamino) sulfonyl ] benzoic acid has a therapeutic effect on HepG2 tumors.

Claims

1. The application of p- [ (dipropylamino) sulfonyl ] benzoic acid in preparing medicine for curing liver cancer.

2. The use according to claim 1, wherein the medicament further comprises one or more pharmaceutically acceptable excipients.

3. The use of claim 1, wherein the medicament is used in combination with at least one additional medicament for the treatment of liver cancer.

4. The use of claim 3, wherein the additional drug is sorafenib.

5. The use according to any one of claims 1 to 4, wherein the medicament is administered by a mode of administration comprising: oral administration, injection administration, subcutaneous administration, inhalation administration, rectal administration.

6. The use of claim 5, wherein the administration by injection is selected from intramuscular injection, intravenous injection, or intraperitoneal injection.

7. The use as claimed in any one of claims 1 to 4, wherein the medicament is formulated as a tablet, capsule, suppository, powder for injection, injection or aerosol.