KR20140105988A - Pharmaceutical compositions comprising 8-Hydroxy-7-iodo-5-quinolinesulfonic acid or 1-(2,4,6-trihydroxyphenyl)propan-1-one for treating or preventing cancer - Google Patents

Abstract

The present invention provides a pharmaceutical composition comprising at least one selected from a group consisting of 8-hydroxy-7-iodo-5-quinoline sulfonic acid, 1-(2,4,6-trihydroxyphenyl)propan-1-one, and pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating cancer. The composition can be valuably used for preventing or treating cancer.

Description

A pharmaceutical composition for the treatment or prevention of cancer comprising 8-hydroxy-7-iodo-5-quinoline sulfonic acid or 1- (2,4,6-trihydroxyphenyl) propan- Pharmaceutical compositions comprising 8-Hydroxy-7-iodo-5-quinolinesulfonic acid or 1- (2,4,6-trihydroxyphenyl) propan-

The present invention relates to 8-hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propane- (1, 2, 4, 6-trihydroxyphenyl) propan-1-one, and pharmaceutically acceptable salts thereof as an active ingredient. ≪ / RTI >

The most important feature of cancer cells is unlimited cell division. Normal cells divide according to the needs of cells and normally stop cell division, but cancer cells continue to divide unlimitedly, causing cells to grow more than necessary, resulting in the loss of life due to the side effects . So the most direct way to treat cancer is to prevent this unlimited cell division. Several proteins have been identified for cell division. Among them, Plk1 is known to be one of the most important proteins in cell division. Plk1 is a kinase that phosphorylates several proteins necessary for cell division and helps them divide completely. In a cell experiment, knockdown of Plk1 causes all cells to stop in mitosis, which shows how important Plk1 is in cell division. Cancer treatment through Plk1 inhibition is currently being tried by several famous pharmaceutical companies. However, most of them are trying to inhibit the activity of Plk1 by inhibiting the ATP pocket of Plk1. The problem with this approach is that the structure of the ATP pocket can have serious adverse effects, even if a good Plk1 inhibitor is developed because all the kinases have similarity.

In order to avoid such side effects, the present invention utilizes Plk1 activity inhibitor through inhibition of the Polo box domain (PBD), another domain of Plk1, as a cancer treatment agent. Through the polo box domain, Plk1 moves to the desired location. Plk1 is located centrally in the cytoplasm of the kinetochocyte. The PBD domain is a necessary domain to be located here. In the case of a mutation in the PBD domain, Plk1 fails to migrate to the kinetochocyte and centrosome, resulting in a cell divider problem causing the mitosis to stop and the cancer cells to die. The way in which Plk1 moves through the PBD domain into the kinetochore and centrosomes is through the binding of these proteins to these proteins. In particular, in the case of the kinetics core, Plk1 is able to bind to PBIP1 through the PBD domain and thus to be located in the kinetochore. In particular, Plk1 is located in the kinetochore by the strong binding of the threonine of PBIP1 to the phosphorylated PLHSpT amino acid. Therefore, if Plk1 interferes with PLHSpT of PBIP1, Plk1 will not be located in the kinetics core, and cells will stop in mitosis while cell division is not done properly, and cancer cells will die.

Accordingly, the inventors of the present invention found that 8-hydroxy-7-iodo-5-quinoline sulfonic acid, which is currently used as anti-protozoal, and antispasmodic, 1- (2,4,6-trihydroxyphenyl) propan-1-one, which is used in the present invention, effectively inhibits the binding thereof.

Polo-like kinase 1 (PLK1) inhibition suppresses cell growth and enhances radiation sensitivity in medulloblastoma cells (BMC Cancer 2012, 12:80) Sensitivity of cancer cells to Plk1 inhibitor GSK461364A is associated with loss of p53 function and chromosome instability. 9Mol Cancer Ther. 2010 Jul; 9 (7): 2079-89)

The present invention provides a composition comprising a compound useful for the prevention or treatment of cancer.

In order to solve the above-mentioned object, the present invention provides a process for producing 8-hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-tri (2,4,6-trihydroxyphenyl) propan-1-one, and pharmaceutically acceptable salts thereof as an active ingredient. Or a pharmaceutically acceptable salt thereof.

8-Hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-tri 1- (2,4,6-trihydroxyphenyl) propan-1-one, or a pharmaceutically acceptable salt thereof, is characterized by inhibiting the binding of Plk1 to PBIP1.

In the present invention, the cancer may be a cancer selected from the group consisting of gastric cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, Endometrioid cancer, thyroid cancer, pituitary cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, endometrial carcinoma, endometrial carcinoma, endometrial carcinoma, cervical cancer, vulvar carcinoma, vulvar carcinoma, Hodgkin's disease, (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, or pituitary gland, or a pituitary gland, or a pituitary gland, Adenoma, < / RTI >

The composition may further comprise a pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutically acceptable salt may be an alkali metal salt by reaction with an alkali metal such as lithium, sodium or potassium; Alkaline earth metal salts by reaction with alkaline earth metals such as calcium or magnesium salts; Or an ammonium salt composed of an organic ligand such as a tetravalent ammonium salt.

The present invention relates to a pharmaceutical composition comprising 8-hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan-1-one, , And an oral tablet obtained by tabletting a mixture containing at least one selected from the group consisting of 8-hydroxy-7-iodo-5-quinoline sulfonic acid, 1- (2,4,6-trihydroxyphenyl) propane -1-one, and a pharmaceutically acceptable salt thereof. The present invention also provides an injectable formulation comprising at least one compound selected from the group consisting of:

The 8- hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan-1-one, or a salt thereof, It is possible to inhibit the binding of PBIP1, in particular, to effectively inhibit the binding of PBIP1 to PLHSpT. Therefore, a pharmaceutical composition containing these as an active ingredient can prevent cell division and inhibit the growth of cancer cells, and thus can be usefully used for prevention or treatment of various cancers.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the binding inhibition effect of 8-hydroxy-7-iodo-5-quinolinic sulfonic acid with PBD and PLHSpT through ELISA assay.
FIG. 2 is a graph showing ELISA assay experiments for inhibiting the binding of 1- (2,4,6-trihydroxyphenyl) propan-1-one to PBD and PLHSpT.

The terms, techniques, and the like used in the present specification are used in the meaning commonly used in the technical field to which the present invention belongs, unless otherwise specified. The term "preventive or therapeutic ", as used herein, refers to: 1) preventing the disease or disorder from occurring in an animal, preferably a mammal, more preferably a human, having cancer cells; 2) Inhibiting, i.e., suppressing development, and 3) alleviating cancer cells.

Hereinafter, the present invention will be described in detail.

The present invention relates to a pharmaceutical composition comprising 8-hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan-1-one, The present invention relates to a pharmaceutical composition for treating or preventing cancer comprising as an active ingredient at least one selected from the group consisting of

The 8-hydroxy-7-iodo-5-quinoline sulfonic acid has a structure represented by the following formula (1), and has a compound name of 'Chiniofon'. The 8-hydroxy-7-iodo-5-quinolinesulfonic acid is one of the drugs used as anti-protozoal.

≪ Formula 1 >

The 1- (2,4,6-trihydroxyphenyl) propan-1-one has a structure represented by the following formula (2) and has a chemical name of 'Flopropione'. The 1- (2,4,6-trihydroxyphenyl) propan-1-one is currently used as an antispasmodic.

(2)

The 8-hydroxy-7-iodo-5-quinolinesulfonic acid of Formula 1 and the 1- (2,4,6-trihydroxyphenyl) propan-1- Can be used in the form of an acceptable salt. For example, pharmaceutically acceptable salts include alkali metal salts by reaction with alkali metals such as lithium, sodium and potassium; Alkaline earth metal salts by reaction with alkaline earth metals such as calcium or magnesium salts; Or an ammonium salt composed of a suitable organic ligand such as a tetravalent ammonium salt, and the like.

The 8-hydroxy-7-iodo-5-quinolinesulfonic acid and 1- (2,4,6-trihydroxyphenyl) propan-1-one of the present invention can be used by purchasing commercially available compounds, The synthesis can also be carried out by conventional synthesis and fractionation of substituents. In addition, the compounds of the present invention may be prepared into pharmaceutically acceptable salts and solvates by methods conventional in the art.

The 8-hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan-1-one or a salt thereof, contained in the composition of the present invention, , Inhibits the growth of cancer cells by inhibiting the binding of PBIP1 to PBIP1, in particular, the binding of threonine of PBIP1 to phosphorylated PLHSpT, and has cancer prevention or therapeutic uses for mammals, preferably humans (see Figures 1 and 2) 2).

 The cancer is selected from the group consisting of gastric cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, , Cancer of the uterine cervix, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute From a group consisting of leukemia, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, or pituitary adenoma And preferably selected from the group consisting of brain cancer, stomach cancer, breast cancer, colon cancer, pancreatic cancer and liver cancer, but is not limited thereto.

In addition to their use in human therapy, the compounds of this invention are also useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs and cats.

Hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan-1-one, and their pharmaceutically acceptable salts The pharmaceutical composition comprising at least one selected from the group consisting of the active ingredient may further comprise suitable carriers, excipients or diluents according to conventional methods. Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The pharmaceutical composition of the present invention may be formulated into a unit dosage form suitable for intra-body administration of a patient according to conventional methods in the pharmaceutical field. Formulations suitable for this purpose include injectable preparations such as injectable solutions or suspensions for parenteral administration, or ready-to-use injectable dry powders which can be used as distilled water for injections at the time of injection; Or a preparation for topical administration such as an ointment. At this time, a commonly used diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, or an excipient may be used together. In addition, the pharmaceutical compositions of the present invention may be formulated into tablets, aqueous or oily suspensions, powders or granules, emulsions, hard or soft capsules, syrups, or elixirs, suitable for administration. The preparation of such compositions can be prepared by any method known to those skilled in the art.

The pharmaceutical composition of the present invention may further comprise at least one selected from the group consisting of an antibiotic, an alkylating agent, an antimetabolite, a hormone, an immunological agent, an interferon agent and other anticancer agents to a patient in need of treatment for cancer . However, the pharmaceutical use and therapeutic composition of the present invention are not limited to those described above, and other drugs that can be used in combination are not limited to those described above.

The daily dosage of the 8-hydroxy-7-iodo-5-quinoline sulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan-1-one or its salt is 1 to 1000 mg / kg Body weight, preferably 10 to 100 mg / kg body weight, preferably one or several divided doses. In the composition of the present invention, the chrysopone, fluroprofen or its salt may be present in an amount of 0.001 to 50% by weight, preferably 0.01 to 50% by weight, based on the total weight of the total composition, or 0.1 to 100 μM, But it is not limited thereto. The actual dosage of the active ingredient may be determined taking into account various relevant factors such as the amount of cancer cells, the route of administration, the body weight of the patient, age and sex, and thus the dose limits the scope of the invention in any form no.

One aspect of the present invention also relates to the aforementioned 8-hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan-1-one, Or an acceptable salt thereof. The tablet may be an oral tablet obtained by tableting a mixture containing at least one member selected from the group consisting of acceptable salts. Wherein the mixture comprises at least one disintegrant selected from the group consisting of crospovidone, sodium starch glycolate, sodium carboxymethylcellulose, and alginic acid; One or more excipients selected from the group consisting of lactose, microcrystalline cellulose, and corn starch; And at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, talc, and silicon dioxide.

Another aspect of the present invention is the use of 8-hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan- Acceptable salts containing at least one member selected from the group consisting of possible salts. The injectable preparation may be in the form of a sterile injectable aqueous solution. Suitable vehicles and solvents that may be used include water, Ringer's solution and isotonic sodium chloride solution. Aseptic injectable preparations may also be sterile injectable water-in-oil microemulsions in which the active ingredient is dissolved in the oily phase. For example, the active ingredient may first be dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into a mixture of water and glycerol and processed to form a microemulsion. The injectable solution or microemulsion may be introduced into the patient ' s blood stream by local bolus injection. Such injectable solutions or microemulsions may be formulated according to known techniques using the above-described suitable dispersing or wetting agents and suspending agents.

Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for illustrating the present invention specifically, and the scope of the present invention is not limited by these embodiments. Here, unless otherwise defined in the technical terms and the scientific terms used, those having ordinary skill in the art to which the present invention belongs have a common meaning.

< Experimental Example  1> Plk1  and PLHSpT  Screening of compounds with binding inhibition activity

Among 2,000,000 kinds of compounds in the Korea Research Institute of Chemical Technology, about 2,000 compounds which can be used for drug repositioning were screened and tested on these compounds.

< Experimental Example  2> Plk1  and PLHSpT  Confirmation of binding inhibition

In order to confirm the inhibitory effect of the compounds of the present invention on the binding of Plk1 to PLHSpT, an ELISA assay method was used. A 384 well plate coated with streptavidin (purchased from Thermoscientific) was washed three times with 100 μl of PBS (PBS-T) containing 0.05% tween-20. PLHSpT peptide (made from peptone) with biotin was dissolved in the coating solution to make 0.3 μM. 50 μl of 0.3 μM PLHSpT peptide was added to each well and left at room temperature for 2 hours to allow biotin and streptavidin to attach, resulting in fixing the peptide to each well. After 2 hours, the wells were washed 3 times with 100 μl of PBS-T for 5 minutes, and 50 μl of PBS containing 1% Bovine Serum Albumin (BSA) was added to the wells for 30 minutes. In the meantime, 293T (purchased from ATCC) cells in which the GFP-Plk1 was transfected were cultured in TBS-N (20 mM Tris-Cl (pH 8.0), 150 mM NaCl, 0.5% NP-40, 5 mM EGTA, 1.5 Cell proteins were obtained with mM EDTA, 0.5 mM Na ₃ VO ₄ , 20 mM p-nitrophenyl phosphate, and protease inhibitor cocktail. Each well was washed three times with PBS-T, The cells were incubated at 25 ° C. for 1 hour, washed with PBS-T 4 times, and plk1 antibody 0.1 was added to each well. After washing each well 4 times with PBS-T, wait for 1 hour with the secondary antibody with Horseradish Peroxidase (HRP), wash each well 4 times with PBS-T, 50 [mu] l of 3,3 ', 5,5'-Tetramethylbenzidine (TMB) purchased from Sigma Chemical Co. was added to each well, Waited not. The color is somewhat changes measured at 450nM wavelength stop the reaction put 50㎕ a 1N H ₂ SO _4, exhibited a combination results in inhibition IC ₅₀ values, are shown in Table 1 to this.

As a result, as shown in Table 1, it was confirmed that the compound of the present invention, 8-hydroxy-7-iodo-5-quinoline sulfonic acid (Example 1), 1- (2,4,6-trihydroxy Phenyl) propan-1-one (Example 2), respectively, inhibited the binding of PBD and PLHSpT. In contrast, Comparative Examples 1 to 3 did not inhibit the binding of PBD to PLHSpT, as can be seen in the table below. In addition, other compounds that were carried out in this experiment were also compared with Comparative Examples 1 to 3 Were similar to each other, it was found that the compounds of the present invention inhibited the binding of PBD and PLHSpT to excellent (see FIGS. 1 and 2).

The binding inhibition concentration (IC 50) measurement results of PBD and PLHSpT of the compounds compound IC 50 ([mu] M) Example 1 8-hydroxy-7-iodo-5-quinoline sulfonic acid 42 Example 2 1- (2,4,6-trihydroxyphenyl) propan-1-one 1.3 Comparative Example 1 Medrysone > 100 Comparative Example 2 Vinolelbine > 100 Comparative Example 3 Capecitabine > 100

Examples of formulations for the composition of the present invention are illustrated below. The compounds of the present invention are hereinafter referred to as 8-hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan- &Lt; RTI ID = 0.0 &gt; possible salts. &Lt; / RTI &gt;

< Formulation example  1> Sanje  Produce

20 mg of the compound of the present invention

Lactose 100 mg

10 mg of talc

The above components are mixed and filled in airtight bags to prepare powders.

< Formulation example  2> Preparation of tablets

10 mg of the compound of the present invention

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

< Formulation example  3> Preparation of capsules

10 mg of the compound of the present invention

3 mg of crystalline cellulose

Lactose 14.8 mg

0.2 mg of magnesium stearate

The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.

< Formulation example  4> Preparation of injection

10 mg of the compound of the present invention

180 mg mannitol

2974 mg of sterile distilled water for injection

_{Na 2 HPO 4 · 12H 2 O} 26 ㎎

(2 ml) per ampoule in accordance with the usual injection method.

Claims (10)

8-hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan-1-one, and pharmaceutically acceptable salts thereof. Or a pharmaceutically acceptable salt thereof, as an active ingredient. The method of claim 1, wherein said 8-hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan- Wherein the salt inhibits the binding of Plk1 to PBIP1. The method of claim 1, wherein the cancer is selected from the group consisting of gastric cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, Endometrioid cancer, thyroid cancer, pituitary cancer, adenocarcinoma, soft tissue sarcoma, urethral cancer, penile cancer, endometrial cancer, endometrial carcinoma, endometrial carcinoma, endometrial carcinoma, cervical cancer, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, (CNS) tumors, primary CNS lymphoma, spinal cord tumors, brain stem glioma, or other neoplasms, such as prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, kidney cell carcinoma, renal pelvic carcinoma, central nervous system Pituitary adenoma. &Lt; RTI ID = 0.0 &gt; 8. &lt; / RTI &gt; The pharmaceutical composition of claim 1, wherein the composition comprises a pharmaceutically acceptable carrier, diluent, or excipient. The method of claim 4, wherein the carrier, diluent or excipient is selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil. The pharmaceutical composition according to claim 1, wherein the effective ingredient is contained in an amount of 0.001 to 50% by weight based on the total weight of the composition. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of an alkali metal salt by reaction with an alkali metal such as lithium, sodium, potassium and the like; Alkaline earth metal salts by reaction with alkaline earth metals such as calcium or magnesium salts; Or an ammonium salt of an organic ligand such as a tetravalent ammonium salt. The method of claim 1, wherein the 8-hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan- Wherein the tablet is obtained by tableting a mixture containing at least one member selected from the group consisting of possible salts. 8. The composition of claim 7, wherein the mixture comprises at least one disintegrant selected from the group consisting of crospovidone, sodium starch glycolate, sodium carboxymethylcellulose, and alginic acid; One or more excipients selected from the group consisting of lactose, microcrystalline cellulose, and corn starch; And at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, talc, and silicon dioxide. The method of claim 1, wherein the 8-hydroxy-7-iodo-5-quinolinesulfonic acid, 1- (2,4,6-trihydroxyphenyl) propan- Acceptable salts thereof. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt;

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