WO2015080396A1 - Anticancer composition for oral administration, containing pegylated botulin derivative - Google Patents

Abstract

The present invention relates to an anticancer composition for oral administration, containing a pegylated botulin derivative.

Description

Anticancer composition for oral administration comprising pegylated betulin derivatives

The present invention relates to an anticancer drug composition for oral administration comprising a PEGylated betulin derivative. More specifically, the present invention relates to an anticancer composition for oral administration comprising a pegylated betulin derivative which has excellent anticancer effect against various carcinomas and is particularly useful for the treatment of cancer as a drug with significantly improved oral absorption.

Betulin and betulinic acid are known to have apoptosis potency. Apoptosis refers to the destruction or suicide of cells in eukaryotic cells, and is a basic intracellular process for maintaining homeostasis of an individual, including controlling the normal development of an animal, or removing unnecessary or abnormal cells. Apoptosis occurs in response to various external and internal stimuli, with the progression of apoptosis, such as cytoplasmic breakdown, blebbing of cell membranes, changes in the cytoskeleton, cell contraction, chromosome condensation and DNA fragmentation. Distinctive changes occur and, if not activated, cells divide indefinitely and form tumors.

Betulin represented by the following formula (2) is a lupine-based natural 5-ring triterpene alcohol, betulinol and loop-20 (29) -ene-3β, 28-diol (lup). -20 (29) -ene-3β, 28-diol). Betulin is present in many bark of tree species, especially in the bark of Betula sp., And methods for separating betulin by extraction from birch bark are known.

[Formula 2]

On the other hand, betulinic acid (betulinic acid) represented by the following formula (3) is isolated by extraction from the cork of the birch ( Betula sp.) Bark or Quercus suber L., or to the direct oxidation of It is known that it can be prepared by the methods. For example, as shown in Scheme 1, betulin (2) was oxidized in the presence of a chromium (VI) catalyst according to the Jones oxidation method disclosed in US Pat. No. 6,280,778 to obtain betunic acid. It is then reported that betulinic acid (3) can be obtained by selective reduction of the obtained beturonic acid with sodium borohydride.

Scheme 1

U. S. Patent No. 5,804, 575 also discloses another method for preparing betulinic acid comprising protecting the 3-β-hydroxy group of betulin by acetylation and then oxidizing.

These betulin derivatives are a kind of natural biosynthesis produced by plants having a pentacyclic triterpenoid structure, first isolated from evergreen (Ziziphus mauritiana), and are known to be particularly abundant in the bark of white birch. It is known to have an effect of selectively acting on melanoma or neuroectoderm-derived cancer cells to kill cancer cells. These anticancer actions of betulin derivatives are known to be through various mechanisms, such as reducing the permeability of mitochondria or deactivating mitochondria, such as cytochrome-C release into the cytoplasm, active oxygen formation, or caspase activation. In addition, betulin derivatives have been shown to block the activity of HIV-1, showing the possibility of being used as an antiviral agent, and has been reported to be effective in other infectious diseases such as bacteria and malaria. In addition, since these betulin derivatives have been reported to have NO production inhibitory activity by interferon-γ, interest in the anti-inflammatory action of betulin is also increasing.

Betulin derivatives have been studied in addition to the various physiological activities mentioned above, but researches on anticancer agents using them are particularly active due to their excellent anticancer effects based on cell death.

Especially in case of betulinic acid, it was confirmed that KB cell, which is a cervical cancer cell line, reduced cell proliferation and induced apoptosis. References: J. Fd Hyg. , 26, No. 2, pp. 150-153 (2011)), and Bax / Bcl-2 through NFkB inhibition in PC-3 cell line, a hormone-resistant prostate carcinoma There have also been reports of studies showing significant reductions ( Mol carcinog , 47, No. 12, pp. 964-973 (2008)).

EP 1309605 and 1124842 disclose that betulin derivatives have inhibitory effects against various malignant tumor cell lines such as sarcomas, oral cancers, breast cancers, lung cancers, colon cancers and the like.

However, betulin and its derivatives known to date have problems in the development and commercialization of oral anticancer drugs due to solubility in water and absorption into the body.

The present inventors have tried to solve the problems of the oral absorption rate of the betulin and its derivatives, as a result, the pegylated betulin derivatives of the general formula (1) is found that the oral absorption is significantly improved and has an excellent anticancer effect and the present invention It was completed.

[Formula 1]

In the above formula, X, X ', Y, R ₁ and n are as defined in the specification.

Accordingly, an object of the present invention relates to an anticancer composition for oral administration comprising a pegylated betulin derivative of Formula 1 or a pharmaceutically acceptable salt thereof having an excellent anticancer effect and particularly having improved oral absorption.

The present invention relates to an anticancer composition for oral administration comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

Where

X is CH ₂ or CO,

X 'is H, CH ₂ R ₂ or COR ₂ ,

Y is NR ₃ , NH, O, S or -OCO,

R ₁ , R ₂ and R ₃ are each independently an alkyl group of C ₁ -C ₆ ,

n is an integer of 0-800, Preferably it is 10-400, More preferably, it is 40-200.

In the compound of the present invention, the C ₁ -C ₆ alkyl group means a straight or branched hydrocarbon having 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i- Butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

Pegylated betulin derivatives of the present invention include compounds represented by the following Formulas 1a and 1b.

[Formula 1a]

X ', Y, R ₁ and n in Formula 1a are as defined in Formula 1.

[Formula 1b]

In Formula 1b, X ', Y, R ₁ and n are as defined in Formula 1.

Methods for preparing the compounds of the present invention are shown in Schemes 2-5. The methods described in the following reaction schemes are merely illustrative of the methods used, and the order of unit operations, reaction reagents, reaction conditions, and the like may be changed as much as the case may be.

Scheme 2

The polyethylene glycol derivative (5) disclosed in Scheme 2 is an intermediate for single pegylation, and is commercially available or known methods [Ref. Sandler and Karo, Polymer Synthesis , Academic Press, New York, Vol. 3, PP 138-161] may be prepared by ring-opening polymerization of ethylene glycol.

Scheme 3

As shown in Scheme 3, the PEGylated betulin derivative (6) of the present invention can be prepared by reacting the betulin (2) and methoxy polyethylene glycol propionic acid.

Scheme 4

As disclosed in Scheme 4, the PEGylated betulinic acid derivative (8) of the present invention is acetylated betulinic acid (3) to obtain 3-β-acetoxybutulinic acid (7), and then the polyethylene of Scheme 2 It can be prepared by reacting with a glycol derivative (5). In addition, the pegylated betulinic acid derivative (8) may be deacetylated to prepare another pegylated betulinic acid derivative (9).

The anticancer agent compositions of the present invention are not limited thereto, but may be useful for treating various cancers such as prostate cancer, lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer or glioblastoma. It is preferably useful for the inhibition or treatment of prostate cancer.

An anticancer composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is administered orally (dose or inhalation). That is, the anticancer composition of the present invention may be administered by formulating in oral form of tablets, capsules, dragees or film coating tablets, solutions or suspensions.

When the anticancer composition of the present invention is formulated as an oral solid, a diluent (for example, lactose, dextrose, sucrose, cellulose, corn starch or potato starch) with an active ingredient, a suspending agent (for example, Silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol), binders (e.g. starch, arabic gum, gelatin methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone), disintegrants (e.g. Starch, alginic acid, alginate or sodium starch glycolate), formal mixtures, dyes, sweeteners, humectants (e.g. lecithin, polysorbates, laurylsulfate) and pharmacologically inert substances generally used in pharmaceuticals It may contain. These agents can be prepared by known methods, for example by means of mixing, granulating, tableting, dragging or film-coating processes.

In addition, when formulated in liquid dispersions for oral administration such as syrups, emulsions and suspensions, the active ingredient may contain natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. .

The content of a compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of the medicament depends on the form of the medicament, but is preferably in a concentration of 0.01 to 100% by weight.

The dosage of the anticancer agent of the present invention varies in a wide range depending on the type of mammal including the person to be treated, the extent of the disease and the judgment of the doctor. In general, however, in the case of oral administration, 0.01 to 50 mg of the active ingredient may be administered per 1 kg of body weight per day. The daily dosages described above can be used one at a time or dividedly, and can be arbitrarily changed depending on the extent of the disease and the judgment of the physician.

Pegylated betulin derivatives according to the present invention can be effectively used as a novel anticancer agent, maximize the efficacy by improving solubility and oral absorption through pegylation can be an effective treatment for various carcinomas. In addition, it has excellent stability and has both water-soluble and fat-soluble properties, so it can be easily used for various formulation development and complex development. In particular, the betulin derivatives can be easily used in the formulation development to maximize the convenience of medication by significantly improving oral absorption through pegylation.

1 is a graph showing changes in tumor size for 21 days upon repeated oral administration of betulinic acid and BA-mPEG samples to PC-3 xenograft mice of Test Example 3 according to the present invention.

Figure 2 is a graph showing the tumor weight of the last day of 21 days when repeated oral administration of betulinic acid, BA-mPEG samples to PC-3 xenograft mice of Test Example 3 according to the present invention.

Figure 3 is a photograph showing the tumor size of the last day 21 days after repeated oral administration of betulinic acid, BA-mPEG samples to PC-3 xenograft mice of Test Example 3 according to the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it is apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1 Preparation of Polyethylene Glycol Derivatives

Example 1-1 Preparation of Methoxypoly (ethyleneglycol) tosylate (MeO-PEG (2K) -OTs) (4)

p-toluenesulfonylchloride (p-toluenesulfonyl) in a solution of 10 g (4.975 mmol) of α-methoxy-ω-hydroxypoly (ethylene glycol) (MeO-PEG (2K) -OH) dissolved in 300 ml of dry dichloromethane. chloride) 2.46 g (13 mmol), 2 ml (15 mmol) of triethylamine, and 0.18 g (15 mmol) of 4-dimethylaminopyridine were added thereto and stirred at room temperature for 5 hours. The reaction solution was diluted with 1 L of dichloromethane, washed sequentially with 800 ml of 1N aqueous hydrochloric acid solution, saturated sodium bicarbonate and saturated sodium chloride aqueous solution, and the organic layer was dried over anhydrous magnesium sulfate and filtered and concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography with methanol and dichloromethane (1:30) to give 10.5 g (4.976 mmol) of the title compound (4) as a white solid.

¹ H NMR 400 MHz (CDCl ₃ ): δ 7.93 (d, 2H), 7.41 (d, 2H), 3.82-3.46 (m, 175H), 3.38 (s, 3H), 2.49 (s, 3H)

Example 1-2: α-methoxy-ω-aminopoly (ethylene glycol) (MeO-PEG (2K) -NH ₂ Manufacture of 5

10.5 g (4.976 mmol) of MeO-PEG (2K) -OTs (4) was added to 800 ml of 30% aqueous ammonia and stirred at room temperature for 12 hours. The reaction solution was extracted with 500 ml of dichloromethane and washed with 500 ml of saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was precipitated in dimethyl ether to give 10 g (4.96 mmol) of the title compound (5) as a white solid.

¹ H NMR 400 MHz (CDCl ₃ ): δ 3.82-3.46 (m, 175H), 3.38 (s, 3H), 2.92 (t, 3H)

Example 2: Preparation of Pegylated Betulin Derivatives

Example 2-1 Preparation of Pegylated Bettulin Derivatives of Formula 6 (BET-mPEG)

1.7 g (3.8 mmol) of betulin (2) and 19.2 g (3.8 mmol) of methoxypolyethylene glycol propionic acid were dissolved in 200 mL of dry dichloromethane, and 0.47 g (0.38 mmol) of 4-dimethylaminopyridine was added. It was. Then, the reaction solution N- (3- dimethylaminopropyl) -N- (ethylcarbodiimide) hydrochloride (N - (3-dimethylaminopropyl) - N -ethylcarbodiimide hydrochloride) 0.95 g (4.6 mmol) was added and stirred at room temperature for 12 hours. The reaction solution was diluted with 100 ml of dichloromethane, washed with 300 mL of 0.1 N aqueous hydrochloric acid solution, and then the separated organic layer was washed with 300 mL of saturated aqueous sodium hydrogen carbonate solution. Then, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was precipitated by adding 400 ml of diethyl ether. The precipitate was filtered while washing sufficiently with diethyl ether to give 20.3 g of the title compound (6) as a white solid.

¹ H NMR 400 MHz (CDCl ₃ ): δ 4.69 (ds, 29-1H), 4.59 (s, 29-1H), 4.29 (d, 28-1Ha), 3.88 (d, 28-1Hb), 3.82-3.46 (m, PEG back-bone), 3.38 (s, CH ₃ O-PEG, 3H), 3.19 (t, 3-1 H), 2.62 (t, -CH ₂ COO-, 2H), 2.44 (m, 19- 1H), 1.68 (s, 30-3H), 1.03 (s, 26-3H), 0.97 (s, 23-3H), 0.96 (s, 24-3H), 0.82 (s, 25-3H), 0.76 ( s, 27-3H), 2.02-0.65 (m, betulin-24H)

Example 3: Preparation of PEGylated Betulinic Acid Derivatives

Example 3-1 Preparation of 3β-Acetoxyvetulinic Acid (3-Ac-BA) (7)

21 g (0.046 mol) of betulinic acid (3) was added to 15.2 ml (0.189 mol) of pyridine and 186.6 ml (1.98 mol) of acetic anhydride, and stirred at room temperature for 12 hours. The reaction solution was poured into 300 ml of ice water, stirred for 30 minutes, and the resulting solid was filtered through silica gel column chromatography with ethyl acetate: hexane (1: 1) to give 15.6 g of the title compound (7) as a white solid.

¹ H NMR 400 MHz (CDCl ₃ ): δ 4.74 (ds, 29-1H), 4.61 (s, 29-1H), 4.47 (dt, 3-1H), 2.99 (m, 19-1H), 2.30-2.16 (m, 2-2H), 2.04 (s, CH ₃ CO-3H), 2.01-1.93 (m, 21-2H), 1.69 (s, 30-3H), 0.97 (s, 26-3H), 0.94 ( s, 23-3H), 0.85 (s, 24-3H), 0.84 (s, 25-3H), 0.83 (s, 27-3H), 1.74-0.77 (m, 20H)

Example 3-2 Preparation of Pegylated Betulinic Acid Derivatives (Ac-BA-mPEG) of Formula 8

2.1 g (4.211 mmol) of 3-Ac-BA (7) obtained in Example 3-1 was dissolved in 40 ml of benzene, and 2.2 ml (25.263 mmol) of oxalyl chloride were added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to remove the remaining oxalyl chloride. After obtaining the compound in the form of a yellow solid, dissolved in 80 ml of dry dichloromethane, 7.03 g (3.79 mmol) of PEG2000-mono NH ₂ (5) obtained in Example 1-2 was added and stirred at room temperature for 3 hours. The reaction solution was diluted with 500 ml of dichloromethane, washed sequentially with 5000 ml of 1N aqueous hydrochloric acid solution, saturated sodium bicarbonate and saturated sodium chloride aqueous solution, and the organic layer was dried over anhydrous magnesium sulfate and filtered and concentrated under reduced pressure. The resulting mixture was subjected to silica gel column chromatography with methanol and dichloromethane (1:30) to give 2.4 g (0.968 mmol) of the title compound (8) as a white solid.

¹ H NMR 400 MHz (CDCl ₃ ): δ 6.13 (t, 1H), 4.75 (s, 1H), 4.60 (s, 1H), 3.83 (t, 2H), 3.82-3.4 (m, 175H), 3.40 ( s, 3H), 3.18 (t, 2H), 2.43 (bs, 3H), 2.02 (s, 3H), 2.0-1.2 (m, 25H), 1.67 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H), 0.84 (m, 9H)

Example 3-3 Preparation of Pegylated Betulinic Acid Derivatives of Formula 9 (BA-mPEG)

5.0 g (2.02 mmol) of 3β-acetyl-28-methoxypolyethylene glycol betulinic acid amide (8) obtained in Example 3-2 was dissolved in a solution of 0.5 g (11.5 mmol) of sodium hydroxide in 2.5 ml of water. Was added to a solution dissolved in 10 ml of tetrahydrofuran and stirred at room temperature for 12 hours. A 1.0 N aqueous hydrochloric acid solution was slowly added to the reaction solution until the pH was 2, and extracted with 100 ml of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and precipitated by adding 100 ml of diethyl ether. The precipitate was filtered off with sufficient washing with diethyl ether to give 4.3 g of the title compound (9) as a white solid.

_{^{1 H NMR 400 MHz (CDCl 3}} ): δ 6.07 (t, - NH CO-, 1H), 4.70 (ds, 29-1H), 4.56 (s, 29-1H), 3.79 (t, -NHCH 2 CH 2 O-), 3.72-3.39 (m, PEG back-bone), 3.38 (s, CH ₃ O-PEG, 3H), 3.20-3.05 (m, 3, 19-2H), 2.41 (dt, 2-1H) , 1.67 (s, 30-3H), 0.99 (s, 26,23-6H), 0.93 (s, 24-3H), 0.79 (s, 25-3H), 0.72 (s, 27-3H), 1.93- 0.63 (m, Betulinic acid-22H)

Test Example 1 Test of Cell-Based Inhibitory Effect on Eight Human Cancer Cell Lines

Test Example 1-1: Cell Culture

SNU354 was distributed by the Korea Cell Line Bank, and the remaining cell lines used in the experiment were purchased from ATCC. All cell lines were used within 10 passages. Cell lines were cultured containing RPMI1640 and 10% calf serum.

Test Example 1-2: Human-derived Cancer Cell Line

Prostate cancer: PC-3, LN Cap

Lung cancer: NCI-H23

Breast cancer: MDA-MB-231

Colon cancer: HCT-15

Renal cancer: ACHN

Liver cancer: SNU354

Glioblastoma cancer: U87MG

Test Example 1-3: Preparation of Sample

Samples were dissolved 30 mM using DMSO and diluted again 30, 10, 3, 1, 0.3, 0.1, 0.03 mM. The diluted stock solution was diluted 1000-fold at each dose using RPMI-1640 culture media, and then each sample was treated with final 30, 10, 3, 1, 0.3, 0.1, and 0.03 uM.

Test Example 1-4: Measurement method and result of cell growth inhibition activity

The loading of cancer cell lines was applied differently depending on the growth rate of the cell line. After loading each cell line into a 96-well plate, the working solution was treated to a final concentration of 30, 10, 3, 1, 0.3, 0.1, 0.03 (uM). After 48 hours of incubation, the drug-treated plate was fixed by adding 50 μl / well in 50% TCA. The plate was fixed for 60 minutes at 4 ℃ and then washed 4 to 5 times with tap water (tap water). After washing, the plate was dried, and 100 μl / well of SRB solution (0.4% sulforhodamine B in 1% acetic acid) was added and left for 30 minutes. Unbound dyeing reagent was washed by adding 0.1% acetic acid, and after drying, the dyeing reagent was dissolved by adding 100 μl / well of 10 mM Tris Base (pH 10.5). Absorbance was measured at 540 nm using a Versa max microplate reader (Molecular Devices), and the measured absorbance was calculated as a percentage of the solvent treated group. The GI ₅₀ value of the test material was calculated using Graphpad prism v4.0 software.

Table 1 shows the GI ₅₀ values of the two betulin derivatives and the comparative substances for eight human-derived cancer cell lines.

TABLE 1

GI ₅₀ Values of Two Betulin Derivatives and Comparative Substances on Eight Human-derived Cancer Cell Lines

In the case of compounds 6 and 9, the activity was reduced as a precursor, and the active forms of betulin and betulinic acid showed activity of several uM levels, which showed a significant result.

Test Example 2: Evaluation of anticancer drug efficacy by repeated oral administration in PC-3 xenograft model of human-derived prostate cancer

Test Example 2-1: Cancer Cell Types

Human prostate cancer cell line PC-3 (prostate cancer)

Test Example 2-2: Cancer Cell Culture

The cells were thawed and thawed in the liquid nitrogen and then cultured. Culture of the cells was incubated for a suitable period of time in a CO ₂ incubator (Forma, USA) at a temperature of 37 ℃ and 5% CO ₂ concentration.

Test Example 2-3: Test Animal

Specific pathogen free (SPF) nude mouse of BALB / C strain, 5w, female (Source: Nara Biotech Co.)

Test Example 2-4: Cancer Cell Transplantation

All cancer cells were harvested and counted on the last day of culture and the cell concentration was adjusted to 3 × 10 ⁷ cells / ml using serum free media. The cell cultures thus adjusted were injected subcutaneously between the scapula and the chest wall at 0.3 ml (9 x 10 ⁶ cells / mouse) per mouse.

Test Example 2-5: Test Substance

(1) Name: Betulinic acid, BA-mPEG

(2) Appearance color and appearance: white, pale yellow (betulinic acid) and crystalline powder

(3) Storage condition: refrigerated

Test Example 2-6: Positive Control

(1) Name: Doxorubicin hydrochloride

(2) Appearance color and appearance: cerise and crystalline powder

(3) Model number: D1515

Lot number: Lot # SLBF1340V

(5) Storage conditions: Refrigerated storage

(6) Supplier: SIGMA-ALDRICH ^®

Test Example 2-7: Preparation and Administration Method of Sample

Betulinic acid was dissolved at concentrations of 0.5, 2 mg / ml and 3.13, 12.52 mg / ml (molecular weight considerations) using EtOH 10% + [20% HPBCD (in distilled water) 90% solvent, respectively. mPEG was used after dissolving at a concentration of 2.925, 11.7 mg / ml and 4.285, 17.14 mg / ml (considering molecular weight) using sterile distilled water, respectively.

The prepared samples were orally administered to the mice five times a week at 0.2 ml per 20 g (days 0-4, 7-11, 14-18). Positive control substance (Dox.hcl) was dissolved in physiological saline at the concentration of 0.2 mg / ml, and then in mice every 10 days with 10 ml / kg fluid ( days 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20) repeated intraperitoneal administration.

Test Example 2-8: Observation and Inspection Items

Test Example 2-8-1: General Symptoms and Weight Change

All animals were observed for general symptoms and weighed at the start of administration and immediately prior to administration.

Test Example 2-8-2: Change in tumor size

After cancer cell transplantation, the average tumor size of each group from 56.6 mm ³ to 21 days was measured in three directions using a vernier caliper, and then expressed as a formula of length X width X height / 2.

Test Example 2-8-3: Last Day Autopsy (Tumor Weighing, Photography, Fixation)

On day 21 after the start of drug administration, mice were killed by CO ₂ gas, and tumors were separated and weighed on a chemical balance. After taking pictures, the tumors were fixed in formalin.

Test Example 2-8-4: Statistical Test Method

The values of all measurement items were tested for statistical significance by comparing the experimental control group and the drug administration group using the t-TEST statistical method.

Test Example 2-9: Results of Anticancer Drug Evaluation by Repeated Oral Administration

Test Example 2-9-1: General Symptoms and Weight Change

The general symptoms and body weight of the animals were observed during the administration period to determine the toxicity of repeated doses of betulinic acid and BA-mPEG samples at 5 and 20 mg / kg doses in PC-3 transplanted nude mice, respectively. As a result, there were no general symptoms during the trial period, and no statistically significant weight loss was observed during the administration period. The positive control (Dox.hcl) showed extraordinary symptoms and statistically significant weight loss of 33.3% (p <0.001) at the last day.

Test Example 2-9-2: Tumor Size Change

Day 21 results showed 4.0% and 5.4% for betulinic acid and BA- mPEG 5 and 20 mg / kg, respectively; Tumor growth inhibition of 4.6% and 45.2% (p <0.001) was observed. Positive control (Dox.hcl) had a tumor growth inhibition of 62.2% (p <0.001) (Table 2 and Figure 1).

Test Example 2-9-3: Last Day Tumor Weight

PC-3 tumors were excised and weighed 21 days after the initiation of drug administration and showed 2.2% and 6.3% for betulinic acid and BA-mPEG 20 mg / kg, respectively; Tumor weight reductions of 1.2% and 42.0% (p <0.001) were noted. Positive control (Dox.hcl) had a tumor weight reduction of 60.8% (p <0.001) (Table 2, Figure 2).

TABLE 2

Tumor size change and last day (day 21) tumor weight

significant figures (t-TEST): * p <0.05, ** p <0.01, *** p <0.001 (vs Vehicle Control)

^† Δt = Vt-Vo, Measurement of the tumor volume (Vt), Initial tumor volume (Vo)

^‡ Inhibition Rate (vs Vehicle Control)

The new oral anticancer drugs containing pegylated betulin derivatives according to the present invention have confirmed excellent efficacy with a PC-3 xenograft model, a hormone refractory prostate cell line. In addition, in the present invention, the efficacy of cell-based analysis was confirmed through experiments on various representative carcinomas including prostate cancer, and can be widely used as a novel oral anticancer agent related to apoptosis.

Claims (13)

1. An anticancer composition for oral administration comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof:

   [Formula 1]

   

   Where

   X is CH ₂ or CO,

   X 'is H, CH ₂ R ₂ or COR ₂ ,

   Y is NR ₃ , NH, O, S or -OCO,

   R ₁ , R ₂ and R ₃ are each independently an alkyl group of C ₁ -C ₆ ,

   n is an integer of 0 to 800.
2. [Claim 2] The anticancer composition for oral administration according to claim 1, wherein the compound of Formula 1 is a compound represented by the following Formula 1a:

   [Formula 1a]

   

   In Formula 1a, X ', Y, R ₁ and n are as defined for Formula 1 of claim 1.
3. According to claim 1, wherein the compound of Formula 1 is an oral anticancer composition, characterized in that the compound represented by the formula (1b):

   [Formula 1b]

   

   In Formula 1b, X ', Y, R ₁ and n are as defined for Formula 1 of claim 1.
4. The compound of claim 1, wherein R ₁ is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl and n-hexyl Anticancer composition for oral administration, characterized in that.
5. The anticancer composition for oral administration according to claim 4, wherein R ₁ is methyl.
6. The anticancer composition for oral administration according to claim 2, wherein X 'is H and Y is -OCO.
7. The anticancer composition for oral administration according to claim 3, wherein X 'is H or CH ₃ CO, and Y is NH.
8. 8. The anticancer composition for oral administration according to claim 6 or 7, wherein R ₁ is methyl.
9. The anticancer composition for oral administration according to claim 1, wherein n is an integer of 10 to 400.
10. The anticancer composition for oral administration according to claim 1, wherein n is an integer of 40 to 200.
11. The anticancer composition for oral administration according to claim 1, which is applied to prostate cancer, lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer or glioblastoma.
12. The anticancer composition for oral administration according to claim 11, which is applied to prostate cancer.
13. The anticancer composition for oral administration according to claim 1, which is formulated as an oral solid or oral liquid dispersion.

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