KR101374500B1 - Parmaceutical composition for preventing or treating cancer containing r(-)-propylnorapomorphine - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cancer containing R(-)-propylnorapomorphine or pharmaceutically acceptable salt thereof as an active ingredient. The composition of the present invention has excellent anticancer activity by inhibiting the proliferation of solid cancer cells, such as uterine cancer and fibrosarcoma, in a micromole concentration, thereby being practically used for preventing and treating cancer.

Description

Pharmaceutical Composition for Preventing or Treating Cancer Containing R (-)-propylnorapomorphine as an active ingredient

The present invention relates to a novel cancer prophylactic or therapeutic use of R (-)-propylnorapomorphine or a pharmaceutically acceptable salt thereof.

Cancer is the leading cause of death worldwide, and despite a number of efforts to find new approaches for cancer treatment, the choice of initial treatment is only a combination of surgery, chemotherapy and radiation therapy. However, surgery and radiation therapy are usually only useful for clearly identified types of cancer, and their use is limited to treating patients who have already spread.

Chemotherapy is an effective method for treating patients with metastatic cancer or diffuse cancer, such as leukemia. Although chemotherapy may provide a therapeutic effect, treatment often fails because the patient's cancer cells become resistant to chemotherapeutic agents. In part, it is common to provide these therapies in combination because of the resistance to chemotherapy around cancer cells.

Accordingly, there is a need for other chemotherapy and therapeutic agents for the treatment of cancer, and researchers, academia and companies are making constant efforts to find new and useful chemotherapeutic agents.

In particular, Protein Phospatase 2A (PP2A) is a serine / threonine protein phosphatase that is known to promote chemotherapy and inhibit cancer metastasis and development (Zhengping Zhuang et. al , Inhibition of serine / threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms, PNAS July 14, 2009 vol. 106 no. 28 11697-11702; Anna A Sablina et al , The Role of PP2A A Subunits in Tumor Suppression, Cell Adh Migr. 2007 Jul-Sep; 1 (3): 140-141). Therefore, there is a need for research on compounds having anticancer activity through a mechanism of activating Protein Phospatase 2A (PP2A).

Therefore, the present invention is to provide a compound having anticancer activity through a mechanism for activating Protein Phospatase 2A (PP2A), its use as an anticancer agent.

In order to solve the above problems, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer comprising R (-)-propylnorapomorphine (R (-)-propylnorapomorphine) or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.

The composition according to the present invention exhibits excellent anticancer activity by inhibiting the proliferation of cancer, especially solid cancer cells such as uterine cancer and fibrosarcoma at low micromolar concentrations, and thus can be usefully used for the prevention and treatment of cancer.

The present invention provides a pharmaceutical composition for preventing or treating cancer, comprising R (-)-propylnoramorphmorphine (R (-)-propylnorapomorphine) or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the structure of R (-)-propylnorapomorphine (R (-)-propylnorapomorphine) is represented by the following formula (1).

[Chemical Formula 1]

The R (-)-propylnorapomorphine may be used in the form of a pharmaceutically acceptable salt, and acid addition salts formed by pharmaceutically acceptable free acid are useful as salts. As the free acid, inorganic acid and organic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used. As the organic acid, citric acid, acetic acid, maleic acid, fumaric acid, , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and arpartic acid. Preferably, hydrochloric acid is used as the inorganic acid, and methanesulfonic acid is used as the organic acid. In addition, R (-)-propylnorapomorphine represented by Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods. .

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Chemical Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, etc., And then precipitating or crystallizing the acid solution. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.

R (-)-propylnorapomorphine or a pharmaceutically acceptable salt thereof according to the present invention may exhibit the effect of preventing or treating cancer through a mechanism of activating Protein Phosphatase 2A (PP2A). . The activation includes both the quantitative increase of PP2A, the increase in gene expression, the increase in enzyme activity, and the like. In addition, as can be seen in the following examples, the composition according to the present invention inhibits proliferation of HeLa, a cervical cancer cell line, HT-1080 cells, a fibrosarcoma cell line at low micromolar concentrations, and shows excellent anticancer activity. It can be used as an active ingredient of.

 Therefore, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer, comprising the R (-)-propylnorapomorphine (R (-)-propylnorapomorphine) or a pharmaceutically acceptable salt thereof as an active ingredient, for the manufacture of an anticancer agent It provides a method of treating cancer comprising the use of the R (-)-propylnorapomorphine, and administering the R (-)-propylnorapomorphine to the subject.

In one embodiment of the present invention, the pharmaceutical composition for preventing or treating cancer comprising the R (-)-propylnoramorphmorphine (R (-)-propylnorapomorphine) or a pharmaceutically acceptable salt thereof as an active ingredient is a pharmaceutical composition 0.01 to 90 parts by weight, 0.1 to 90 parts by weight, 1 to 90 parts by weight of the R (-)-propylnorapomorphine or a pharmaceutically acceptable salt thereof based on 100 parts by weight of the composition Or, but may include 10 to 90 parts by weight, but is not limited thereto, and may vary depending on the type and progression of the patient's condition and disease.

In another embodiment of the present invention, the pharmaceutical composition for preventing or treating cancer comprising the R (-)-propylnoramorphmorphine (R (-)-propylnorapomorphine) or a pharmaceutically acceptable salt thereof as an active ingredient is a carrier At least one auxiliary agent selected from the group consisting of excipients, disintegrants, sweeteners, coatings, swelling agents, lubricants, lubricants, flavoring agents, antioxidants, buffers, bacteriostatic agents, diluents, dispersants, surfactants, binders and lubricants. It may include.

Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.

In another embodiment of the present invention, the pharmaceutical composition for the prevention or treatment of cancer comprising the R (-)-propylnorapomorphine (R (-)-propylnorapomorphine) or a pharmaceutically acceptable salt thereof as an active ingredient The formulation may be selected from the group consisting of granules, powders, coated tablets, tablets, pills, capsules, suppositories, gels, syrups, juices, suspensions, emulsions, drops or solutions.

According to one embodiment of the present invention, the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.

Preferred dosage of the pharmaceutical composition for the prophylaxis or treatment of cancer comprising the R (-)-propylnorapomorphine (R (-)-propylnorapomorphine) or a pharmaceutically acceptable salt thereof as an active ingredient is a condition and weight of the patient Depending on the type and extent of the disease, drug form, route of administration and duration, it may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be 0.01 to 1,000 mg / kg, specifically 0.1 to 1,000 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto. The administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.

In the present invention, the 'subject' may be a mammal including a human, but is not limited thereto.

In one embodiment of the present invention, the cancer may be a solid cancer, more specifically R (-)-propyl noapomorphine according to the invention brain tumor (Brain tumor), fibrosarcoma, benign astrocytoma (Low) -Grade astrocytoma, High-grade astrocytoma, Pituitary adenoma, Meningioma, CNS lymphoma, Oligodendroglioma, Craniymoparyngioma (pendian cell) ), Brain stem tumor, head & neck tumor, larygeal cancer, oropharyngeal cancer, nasal cavity / PNS tumor, nasopharyngeal tumor , Salivary gland tumor, hypopopharyngeal cancer, thyroid cancer, thyroid cancer, oral cavity tumor, chest tumor, small cell lung cancer, non-small cell lung cancer Non small cell lung cancer, thymic cancer (Thy moma), mediastinal tumor, esophageal cancer, breast cancer, breast cancer, male breast cancer, abdomen-pelvis tumor, stomach cancer, liver cancer, hepatoma, Gall bladder cancer, biliary tract tumor, pancreatic cancer, small intestinal tumor, large intestinal tumor, anal cancer, bladder cancer cancer, Renal cell carcinoma, Male genital cancer, Penile cancer, Prostatic cancer, Female genital cancer, Cervical cancer (Cervix) cancer, Endometrial cancer, Ovarian cancer, Uterine sarcoma, Vaginal cancer, Vulva cancer, Urethral cancer or skin cancer ( It is preferably used for the treatment of skin cancer. Even more preferably, it may be used for the treatment of uterine cancer or breast cancer, but is not limited thereto.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

< Example  1> HeLa  For cell lines In vitro  Anticancer activity assay

The anticancer activity of R (-)-propylnorapomorphine hydrochloride against uterine cancer cell line was examined in HeLa cell line.

Human uterine cancer cell line HeLa cell line is Dulbecco's Modified Eagle's Medium containing 12 well plates, 10% fetal calf serum (FBS) (HyClone Laboratories, Logan, UT, USA) and 1% penicillin: streptomycin (Invitrogen, Carlsbad, CA, USA) Cultured in (DMEM) medium. Test Compound R (-)-propylnorapomorphine hydrochloride was dissolved in DMSO and 1 μl of standard solution was used to prepare 18.75 μM, 75 μM and 300 μM working concentrations per ml of culture. Each test included control wells. Cell supernatants were diluted to 1 × 10 ⁴ cells / mL by adding fresh medium, and 1 ml of the diluted supernatant was added to test and control wells. Plates were incubated for 24 hours at 37 ° C. under CO ₂ conditions. After incubation, the culture medium was replaced and cells were treated with 18.75 μM, 75 μM and 300 μM standard solutions. Cells were incubated at 37 ° C. for 24, 48, 72 hours under CO ₂ conditions. Cell growth was analyzed by low power microscopy, and cell viability was confirmed by MTT analysis. The results are expressed as the average of three measurements.

The results are shown in Table 1 below.

24 h 48 h 72 h 18.75 μM 95.97% 18.75 μM 74.68% 18.75 μM 48.85% 75 μM 34.14% 75 μM 5.63% 75 μM 3.66% 300 μM 24.85% 300 μM 15.03% 300 μM 7.42%

Referring to Table 1, HeLa cell viability was low in proportion to time due to the treatment of R (-)-propylnorapomorphine hydrochloride, and showed the best anticancer activity at the concentration of 75 μM. As time passed, the cell viability was maintained at 10% or less. As a result, the anticancer activity of the compound was excellent.

< Example  2> HT For -1080 cell line In vitro  Anticancer activity assay

The anticancer activity of R (-)-propylnorapomorphine hydrochloride was examined in human fibrosarcoma cell line (HT-1080).

Experiments were conducted in the same manner as in Example 1 except that the cell line using a HT-1080 cell line. The results are shown in Table 2.

24 h 48 h 72 h 18.75 μM 160.22% 18.75 μM 132.16% 18.75 μM 101.74% 75 μM 12.88% 75 μM 6.29% 75 μM 12.27% 300 μM 62.36% 300 μM 30.30% 300 μM 26.45%

Referring to Table 2, HT-1080 cell viability decreased in proportion to time due to the treatment of R (-)-propylnorapomorphine hydrochloride, but showed anticancer activity when treated at a concentration of 75 μM or more. And it was found.

Having described the specific parts of the present invention in detail, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (6)

A pharmaceutical composition for the prevention or treatment of cancer diseases selected from cervical cancer or fibrosarcoma, comprising R (-)-propylnorapomorphine (R (-)-propylnorapomorphine) or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 1,
The R (-)-propylnorapomorphine (R (-)-propylnorapomorphine) or a pharmaceutically acceptable salt thereof is to prevent or treat cancer disease that activates Protein Phosphatase 2A (PP2A) Pharmaceutical composition for. 3. The method according to claim 1 or 2,
Cancer disease further comprising one or more additives selected from the group consisting of carriers, excipients, disintegrants, sweeteners, coatings, swelling agents, lubricants, lubricants, flavoring agents, buffers, diluents, dispersants, surfactants, binders and lubricants Pharmaceutical composition for the prophylaxis or treatment of. 3. The method according to claim 1 or 2,
Formulation of the pharmaceutical composition for preventing or treating cancer is selected from the group consisting of granules, powders, coated tablets, tablets, pills, capsules, suppositories, gels, syrups, juices, suspensions, emulsions, drops or solutions. Pharmaceutical composition for the prevention or treatment of phosphorus cancer disease.
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