TW201141474A - Application of 5-substituted 4,7-dimethoxy-1,3-benzodioxoles in manufacturing pharmaceutical products for treating colorectal cancer - Google Patents

Abstract

The present invention provides an application of 5-substituted 4,7-dimethoxy-1,3-benzodioxoles in manufacturing pharmaceutical products for treatment of colorectal cancer, wherein 5-substituted 4,7-dimethoxy-1,3 -benzodioxoles has the following general formula I: where R is selected from the following substituted or nonsubstituted groups: C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl, cyano group, C1-C5 ester group, C1-C5 carboxylic group and isoxazole group, under the condition that R is non-methyl (other than -CH3). The invention also provides a pharmaceutical composition, cell cycle inhibitors, and colorectal cancer cytotoxic agents containing 5-substituted 4,7-dimethoxy-1,3-benzodioxoles.

Description

201141474 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to 5-substituted 4,7-dimethoxyoxyl,3-benzodioxanthene> (5-substituted 4, 7-dimethoxy-l,3-benzodi〇x〇ie) for the manufacture of a medicament for the treatment of colorectal cancer, wherein 5-substituted 4,7-dimethoxy-1,3. The 5-position substituent of the benzodioxan does not include a methyl group. The present invention also relates to a cell cycle inhibitor φ comprising a 5-substituted 4,7-dimethoxy-1,3-benzodioxolan and a colorectal cancer cell killing agent. [Prior Art] According to the cancer report published by the Department of Health in 2006, colorectal cancer ranks among the top five cancers in Taiwan. Current clinical treatments are limited to surgery, radiation therapy, general chemotherapy, and gene therapy (Asmis TR. and Saltz L., Gcmroewero/

North Am, 2008; 37:287-95, ix.; Durai R. et al., J

Gastrointest Liver Dis 2008; 17:59-67; Kuwai T. et al., Clin • Wuyi Ruchuan, 2008; 25:477-89). There is clearly a continuing need for novel therapeutic agents for the treatment of colorectal cancer. Antrodia camphorata (4«金〇山·α is used in traditional Chinese medicine to treat hypertension, pruritus, diarrhea, and liver cancer. The applicant's previous report pointed out that 4,7 _Dimethoxy-5-methyl-1,3-di- methoxy-S-methyl-U-benzodioxole (hereinafter referred to as SYu) is isolated from the extract of Antrodia camphorata SY-1 can effectively reduce the proliferative response of human c〇LO 205 cancer cells (COLO 205) (Lien ΗΜ·α/·, fresh

W W 201141474 and ί A/W. doi: l〇.l〇93/ecam/nep〇20 is published on March 17, 2009). However, the anti-tumor activities of 4,7-dimethoxy-M,3-benzodioxolane are still not fully understood, and SY1 has the effect of inhibiting tumor growth, but It still requires relatively high doses to achieve effective inhibition of colorectal cancer cells, and thus there is an urgent need in the art for novel drugs that can effectively treat colorectal cancer, thereby providing more drugs for the treatment of colorectal cancer. select. Therefore, in addition to the prior art SY-1, if (4) one step provides a variety of candidate drugs for the treatment of colorectal cancer, it will help to provide other options in advance to avoid when the individual's drug resistance is produced. There are no alternative medicines available for treatment and other issues. SUMMARY OF THE INVENTION In view of the foregoing various deficiencies and needs of the prior art, it is an object of the present invention to provide a compound derived from a natural product for the treatment of colorectal cancer, wherein the compound is a 5-substituted 4,7- Dimethoxy-oxime, 3_benzodioxolane, which can be a pharmaceutical composition containing 4,7-dimethoxy-oxime, 3-'benzodioxanane derivative The form is provided. In order to achieve the above object, the present invention provides a use of a 5-substituted diterpenoid $-1,3-stuplessdioxane for the manufacture of a medicament for treating colorectal cancer, wherein the 5_ Substituted 4,7-dimethoxy-i,3-benzodioxolane has the following formula ι : 201141474

Wherein R is selected from the group consisting of Ci to C6 alkyl group, C2 to C6 alkenyl group, c2-C6 alkyne

a group, a cyano group, a C丨 to C5 alkyl ester group, and a C to C5 carboxylic group, but conditionally (with the proviso that): R is not a thiol group ( Other than -CH3) The aforementioned group may be a substituted or nonsubstituted group, that is, preferably, the r is a substituted or unsubstituted ethyl group, C. Burning base, ethylene, propylene, butene, ethyl furnace, propynyl, cyano group, methyl ester group, ethyl aryl group and methyl carboxyl group, ethyl carboxyl group or propyl carboxyl group. Preferably, 'R' may be a substituted group such as, but not limited to, substituted c, to & alkyl, and the substituent may be hydroxy (-〇11), cyano, nitro (nitro Group), aromatic gr〇up or halogenyl; substituted Cz to alkenyl, and the substituents may be a trans group, a cyano group, a nitro group, an aryl group or a halogen group; The substituent to C6 may be a hydroxyl group, a cyano group, a nitro group, an aryl group or a dentate group. Preferably, R is selected from the group consisting of: _CN, _COOH, -CH2CH2OH, -COOCH3, -(CH, ΓΗ201141474 CH2CH(〇H)CH2CN^-ch2ch=ch2^

The foreskin has a half-inhibitory concentration (1C5) for human colorectal cancer cells to be no more than 375 μΜ, preferably no more than 200 μΜ, more preferably no more than 225 μΜ, and even more preferably no more than 35 μΜ. Still more preferred 'the 5-substituted 4,7-dimethoxy-1,3-benzodioxanthene apiole' is also 4,7-dimethoxy. 5-(2-Ace-1-yl)-1,3-benzo-dioxapentane. The present invention provides a pharmaceutical composition for treating colorectal cancer comprising: a therapeutically effective amount of any 5_substituted 4,7-dimethoxy-1,3-benzodioxane as described above Heteropentane and its enantiomers, diastereomers, pharmaceutically acceptable salts or combinations thereof; and their pharmaceutically acceptable carriers and/or excipients. The pharmaceutically acceptable salt means a salt which may be formed with the following pharmaceutically acceptable inorganic or organic acids, such as, but not limited to, hydrochloric acid, sulfuric acid, acidity acetic acid, propionic acid, butyl Diacid, malonic acid, holding acid, tartaric acid, sulphuric acid and p-toluene acid. According to the present invention, the "therapeutieally effective amount" means administration of a therapeutically effective dose of a compound to a subject, and wherein the evaluation of the therapeutic effect may be objectively utilized by some test or marker. Measured or subjectively based on the treatment given to the treatment of the 201141474 treatment effect and post-treatment feelings. The above 5-substituted 4,7-dimethoxy-1,3-benzodioxolane can be used in an effective dose ranging from about ο. mg/kg to about 500 mg/kg, or 1 mg / kg to about 50 mg / kg. The effective dose will also vary depending on the route of administration and the other agents that may be combined. The 5-substituted 4,7-dimethoxy-1,3-benzodioxanthene of the present invention is an active ingredient in a pharmaceutical composition, which can be administered orally or parenterally, including Intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration. For oral administration, the 5-substituted 4,7-dimethoxy-1,3-indolyl dioxagen of the present invention can be combined with existing anti-tumor agents and/or cells. Cell growth inhibitor - used and used, for example, by tablets or capsuie, powders (povvder), dispersible particles, cachets, aqueous solutions or suspensions Formal administration. In the case of oral administration in tablets, commonly used carriers include lactose, corn starch, magnesium carbonate, talc and sugar; lubricants' Such as magnesium stearate (magnesium stearate). Useful carriers for oral administration in the form of capsules include lactose, corn starch, magnesium carbonate, talc, and sugar. When the aqueous suspension is used as an oral administration, the carrier can be an emulsion and/or a suspension. In addition, oral administration may additionally include sweeteners and/or flavourings. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, the dosage form of 201141474 is often used as a sterile solution for the active ingredient. 〆pH value. It is adjusted by buffer solution to the total concentration of the solute of the intravenously administered, normal ingredient, and the obtained first-class sputum, control, and rectification are used for rectal administration, and the commonly used dosage form is a pick-up agent = first low-melting wax ( For example, a fatty acid, glycerol or a small form, which can be dissolved by mixing the active ingredient with, for example, a mixture of square dimer oil, in a wax, followed by dispersing the molten soil and the active ingredient in the low-melting model. And allowing it to cool and thereby solidify into a size. The pharmaceutical composition of the present invention can be used in combination with any of the other known methods or compositions that are particularly suitable for direct treatment. - The present invention also provides a cell cycle inhibitor, wherein the 5-substituted 4,7-dimethoxy 3 is ^^ +-open a-p-pentane. The present invention also provides a colorectal cancer cell poisoning reagent comprising ruthenium 5-substituted 4,7-di-octane oxane as described above. T-mercapto-1,3-benzodioxole The 5-substituted 47-field P (tetra) 4'7-methoxy-tri-3-benzodioxan t of the present invention has a cell type Specificity, which can kill colorectal cancer, does not poison normal human cells 'so it has an effective anti-colonial: proliferative effect of diseased cells' and thus can be applied to the treatment of colorectal cancer. The present invention: the monthly 5-substituted 4,7-dimethoxy], 3·benzodioxanthene and ', the pharmaceutical composition has a lower semi-inhibitory concentration on the proliferation of colorectal cancer cells 'It is shown that it can lower the effect of inhibiting the growth of cancer cells compared with the prior art, and can be used as a therapeutic reagent group for poisoning colorectal cancer, 'field cell or other colorectal cancer 201141474. In order to screen and optimize the novel active compounds with proliferation against colorectal cancer cells, Applicants are directed to having 4 4,7-dimethoxy-1,3-benzodioxolane A series of derivatives were evaluated for the in vitro inhibitory activity of human colorectal carcinoma cells (COLO 205), in which the derivatives were isolated as a lead compound from A. angustifolia (7) Melon...xian hook^丫-:^ is the basis ^The analysis of the structural activity relationship of the 10 compounds shows the importance of the chain length of the alkyl group at the 5_ position, and the acetyl-based celery brain Presenting the best inhibition The present invention demonstrates that the analog of SY-1, the parsley brain, can reduce the proliferation of COLO 205 cells (pr〇liferati〇n), but does not affect the proliferation of normal human colon epithelial cells (FHC). Month® (75~225 μΜ) induced G〇/G1 cell cycle arrest (G〇/Gi cycle arrest) with increased p53, p21 and p27 level 〇evei) and decreased levels of cyclosporin D1 Significant relationship. Regarding c〇L〇2〇5, 'cell death of the cell', the bud treatment (>15() state) significantly increased the cleaved cysteine protease _3, _8, The ratio of _9 and bax/bcl_2, and the analysis of the sub-G1 peak in the analysis of leg fragmentation and flow cytometry analysis, can induce the occurrence of job fragmentation. These results confirm SY] ' It will inhibit the growth of human colon cancer cells, especially in the brain. It has a remarkable effect. According to the invention, 5_substituted ^,. s ^ , fluorenyl-1,3·benzodioxole Hyun and its enantiomers, N. striata, this a ^ v , ^ diastereomers, pharmaceutically acceptable salts It can be made from burdock: ^ i • S.]. According to any known extraction technique, 10 201141474 can be taken as ' or 4/7 · - A s A 1, 1, a oxy -5_ mercapto-1,3-benzodioxanane is synthesized by a known chemical synthesis method. The present invention will be further illustrated by the following examples, but It is to be understood that the examples are for illustrative purposes only and are not to be considered as limiting. EXAMPLES Experimental Materials and Methods 1. Compounds and Reagents • 5-Substituted 4,7-dimethoxy-4-3-benzodioxole (5-Substituted 4,7) used in the following examples. -dimethoxyn benzodioxoles) (i.e., sy" derivatives (such as compounds 1 to 9 listed in the table below) were purchased from Aurora Fine Chmicah Ud (Austria), and the apiole was obtained from Uni-onward Company (Taiwan). The structures of these compounds were identified by NMR spectroscopy. 2. Cell culture Lu COLO 205 (p53-wild type) cell line was isolated from human colon adenocarcinoma (CCL-222, American Type Culture Collection, USA). The cell lines were cultured in RPMI-1640 medium (Invitrogen, Carsbad, CA) containing i 0% fetal bovine blood (FBS) and 1% penicillin-streptomycin (Invitrogen, Carlsbad, CA). FHC (CRL-1831, American

Type Culture Collection (USA) is a long-term epidermal cell culture derived from normal human embryonic colon mucosa (Siddiqui KM and Chopra DP, / « Fziro, 1984; 20: 859-68). The culture was cultured in a 37 ° C incubator with a humidified 5% c〇2 201141474. 3. Cell viability assay The anti-proliferative effect of the compound on cultured cells is analyzed by 3-4,5-dimethyl 0 sold by 0,2,5-di-tetradone desertification [3- (4,5-to 11161;11711;111&2〇1-2-yl)-2,5-diphenyltetrazolium bromide assay, MTT assay] 〇 cells are at a density of 2 x 104 cells per cell (cell s/we 11) The cells were cultured overnight in a 24-well culture plate and then treated with different concentrations of compound. After incubation at 24, 48, and 72 hours, 30 μΙ> of 2 mg of mL·1 MTT solution [with phosphate buffered saline (PBS), pH 7.4] was added to each well, and The plates were incubated for an additional 3 hours. Following incubation, the medium was removed from each well by slow pipetting and replaced with 200 pL of dimethyl hydrazine (DMSO). The absorbance of each well was measured by an enzyme-linked immunosorbent assay at a wavelength of 550 nm. 4. Flow cytometry analysis • COLO 205 cells were collected with trypsin-EDTA at various times after treatment with different concentrations of celery brain, filtered The PBS was washed twice and fixed in 70% alcohol at 4 ° C for more than 24 hours. The fixed cells were washed once with filtered PBS and treated with DNase-free RNase (2 U mL_1) for 30 minutes followed by propidium iodide reagent [3·8 mM sodium citrate] (sodium citrate), 0.1°/. Triton X-100 and 20 mg ml·1 propidium iodide; The DNA content was measured using a flow cell meter (Cytomics FC500, Beckman Coulter). The percentage of cells at each stage of the cell cycle at 12 201141474 was analyzed by the Multicycle 32bit version, Beckman Coulter. 5. Immunoblotting analysis COLO 205 cells were treated with different concentrations of parsley brain for different time courses and dissolved in lysis buffer [20 mM Tris-HCl, 1% NP-40, The cell lysate obtained in 137 mM NaCl, 50 mM EDTA 'protease inhibitor cocktail and 1 mM PMSF was used in immunoturbation analysis (Lin H <a7·, JC/zew) , 2007; 282: 2776-84). The protein extract obtained from the treated cells [each lane is 100 pg] was separated by SDS-PAGE and detected with a specific antibody, and the protein loading was corrected by the content of β-actin. Immunodetection was performed overnight at 4 °C using appropriately diluted specific antibodies. The primary antibody is diluted 1:100 and 1:1, and the primary antibody includes anti-cyclin D1 and anti-p27 (Santa Cruz, Inc., CA, USA), anti-actin (Chemicon Co., MA, USA), anti-cleaved cysteine protease-3, -8, -9 (anti-cleaved caspase-3) ,-8,-9) (Cell Signaling Technology, Inc., MA, USA), anti-p21 and anti-p53 (BD Bioscience, CA, USA) and anti-bax and anti-bcl-2 (Assay Designs, MI) , US A). Secondary antibodies include peroxidase-conjugated goat anti-mouse or anti-r abb it antibodies and amniotic fluid-conjugated goat anti-mouse antibodies (alkaline) The phosphatase-conjugated goat anti-mouse antibody (Jackson ImmunoResearch Laboratory, PA, USA) was diluted 1:500.13 201141474 for incubation at room temperature for 1 hour. ECL detection reagent and BCIP/NBT substrate solution (Perkin Elmer Co., MA, USA) were used to be used by Trans-Blot SD (Bio-Rad Co_, CA) , USA) Immunoactive proteins that are transferred to PVDF membranes are visualized. 6. Analysis of DNA fragmentation COLO 205 cells treated with different treatments, and cell apoptosis (apoptosis) was determined by analysis of DNA fragmentation (H〇YS α/., Mo / CWd/iog, 1996; 16:20-31). Genomic DNA was extracted and electrophoresed on a 2 aga/agarose gel. DNA 显 is visualized by ethidium bromide staining. 7. Statistics All values are presented as mean soil standard deviation (means, SE). Significant comparisons were performed using Dunnett's one-way ANOVA. Significantly defined as corpse <0.05. Example 1 Cytotoxic activity of substituted 4,7-dimethoxy-1,3-benzodioxanthene derivative for human colon cancer cells This example is directed to 10 SY- 1 The anti-proliferation effect of the derivative was analyzed, and the cells were treated with c〇L〇2〇5 cells at different concentrations of each compound (37·5 to 225 μΜ) through different sounds - 14 201141474 ( 24, 48 and 72 hours) and use 3-4,5-dimethylthio. The cytotoxic activity of each compound was determined by sitting on the _2 5_ _ phenol tetraterpene bromide by the "3 cell survival rate analysis" described in "Experiment #荇舆才法". The antiproliferative activity of each compound in COLO 205 cells is shown in Figures 1A to 1C. The results show that the functional group at the 5_ position carries an aliphatic substituents (compounds 4, 5 and the oceanic brain), which is higher than the polar alkyl functional group (compound 丨 to 3). Anti-proliferative effect. The IC5() values of compounds 1, 2, 3, 4, 5, and 6 (ic5.value:) were measured to be 59.4 μΜ, 152.3 μΜ, 148.5 μΜ, 72, 1 μΜ, 110.9 μΜ, and 66.7 μΜ, respectively. However, those with a 5-position of bulkier substituents (compounds 7, 8, and 9) showed a very weak inhibitory effect (>225 μΜ). The results are shown in Figures 1A to 1C. The most promising against COLO 205 cells is the api〇le '' IC5Q値 at 48 hours and 72 hours significantly <37·5 μΜ (Figures 1B and 1C) . The side chain of the SY-1 derivative can be divided into a 2-propenyl group (2_pr〇penyi gr0Up) (Citrus brain) with _ and n-pr〇pyl groups ( Compound 5), while the anti-proliferative activity of the buds on COLO 205 cells was more than three times that of those having a propyl group. In addition, 'in order to test the inhibitory effect of SY-1 derivatives on the proliferation of COLO 205 cancer cells, it is cell type-specific 'n〇rnlai human colonic epithelial cells (FHC) Different doses of the parsley brain (as indicated in Figure 2) were administered to treat the cytotoxic activity of each compound by the cell viability assay described in the "Essence of the Wool." 15 201141474 The results are shown in Figure 2. The cytotoxic activity of the celery brain was not observed in normal human cell lines. Therefore, in the following examples, the parsley brain will be taken as an example of the present invention. Table 1 Cytotoxic activity of S Y -1 derivatives OCH?

Och3 〇 R ΐε5〇(μΜ) -ch3 >375 -CN 59.4 -coon 152.3 .~ch,ch2oh 148.5 -COOCH^ 72.1 ~(CH2)2CH, J10.9 -CH2CH(OII)CH2CN 66.7 YVO >225

ο—N

Compound SY-1 0) (2) (3) (4) (5) (6) (7)

Example 2 SY-1 derivatives induce cell cycle arrest of human colon cancer cells according to previous studies (Lien HM. ei α/., 2009, supra;

Ho YS et al., Food Chem Toxicol, 2005; 43:1483-95) > 15 hours of COLO 205 cells after replacement in complete medium • ί S.1 16 201141474 (1 5h) The GO/G1 cell population of the compound treated group will have the greatest difference from the parent g group. Therefore, this time point (15 h) was selected for this example to investigate the dose-dependent effect of the celery brain on the induction of cell cycle arrest. In the present embodiment, cells of various stages of the cell cycle of COLO 205 cells treated with different doses of Chinese celery brain were analyzed by "4. Flow cytometry analysis" described in "Splashing Method". Percentage, and the performance of p21, p_27 and p53 and cyclin D1 in treated COLO 205 cells were ascertained by the "5. Immunoturbation analysis" described above. The φ result is shown in Figure 3. The celery brain has a dose-dependent G0/G1 stagnation.

A dose-dependent effect in which a significant G0/G1 arrest is induced in COLO 205 cells treated with celery brain (>75 μΜ), and the effect is Dose dependent. Previous studies have shown that Cycyn-dependent kinase inhibitors (CDKi), such as p21 and p27, are arrested in human colon cancer cells of G0/G1 by anti-cancer agents. Upregulated (Lien HM. ei α/·, # 2009, same as above; Ho YS e, α/·, 2005, same as above; Wu CH et al.,

Toxicol Appl Pharmacol, 2002; 180:22-35). In this example, the effect of the celery brain on the expression of cell cycle regulatory proteins was also analyzed. The results are shown in Figure 4, as described above, exposed to the parsley brain (<150 μΜ) COLO 205 cells over 15 hours were induced to express P21, p27 and p53 as well as cyclin D1. Example 3 SY-1 Derivatives Activate Caspase of Human Colon Cancer Cells This example further analyzes the exposure of COLO 205 cells to the foreign buds of the brain [S]. 17 201141474 'its: cells; In the case of the death of the week, it is carried out by "3. Flow cytometry analysis", "4 immunoturbation analysis" and "5. Fragmentation analysis" described in "仏". • First, the time-dependent dose-dependent effect of the bud brain on cell cycle regulation was measured by flow cytometry analysis with reference to the previous examples. The results are shown in Fig. 5 to 5D. The high dose of the oceanic brain (15 〇, 225 _ at 36 and 48 hours will significantly increase the sub (1) peak (sub Gi (four) population.

Second, since prior art techniques have shown that apoptosis occurs, it is required to activate cysteine protease (Thornberry NA and Lazebnik Y, Xinhua 匕 1998; 281:1312-6; el-Deiry WS w α/·, Ce//, 1993; 75:817_25); therefore, the applicant further determined the involvement of thiocysteine protease activation and bax/bci_2 ratio in COLO 205 cells treated with Western brain by immunoturbation analysis. Protein extracts of COLO 205 cells treated with different doses of Chinese celery brain [lanes 1 〇〇] were separated by SDS-PAGE and assayed with specific antibodies, and β_actin Correct the protein loading. The results are shown in Figure 5, which shows that 'C. chinensis (150 or 225 μM for 36 hours) induces COLO 205 cells > weekly death, which is accompanied by an increase in the bax/bcl-2 ratio and thiosinase-3, -8, - The cutting action of 9 occurs. Incidentally, the applicant evaluated the apoptosis of cox brain-treated COLO 205 cells by DNA fragmentation analysis. DNA fragmentation was observed only in COLO 205 cells treated with celery brain for 36 hours (>75 μΜ). DNA fragmentation was indeed induced by high doses of parsley brain (15 μ μΜ), as shown in Figure 6. .201141474 In summary, SY-1 derivatives such as celery brain do induce cell apoptosis in human colon cancer cells in a cell-like f-specific manner, and are available for chemotherapy in colorectal cancer. . [Simplified Schematic] Figures 1, 1B and 1C show that human colorectal adenocarcinoma cells (COLO 205) were treated with SY-1 for bioburdens for 24 hours and 48 hours after 72 hours of cell growth. Suppress the situation. Figure 2 shows the inhibition of cell growth by normal human cells (n〇rrnai human ceus) (FHC cells) after treatment with different concentrations of SY_丨 derivatives over time. Figure 3 shows the $dependent effect of the parsley brain on the G0/G1 phase arrest in COLO 205 cells, which was obtained by flow cytometry, with the sub-G1 'G0/G1, S and G2/M phases. The percentage of cells was determined by using the Multicycle analysis software, and each group of samples was three, and the values were expressed as mean ± SE, with respect to the control group * Ρ < 0.05. Figure 4 shows the effect of the parsley brain on the performance of cell cycle regulatory proteins. * Figures 5Α, 5Β, 5C, and 5d show the time- and dose-dependent effects of the celery brain on apoptosis of COLO 205 cells. After synchronized CHO205 cells were treated with 1% FCS for 15%, 48%, and 48 hours, The distribution of ethnic groups at various stages of the cell cycle. Figure 5E shows the effect of the treatment of the parsley brain on the ratio of thiosamine inferior protease and bax/bcl-2 in COLO 205 cells. Figure 6 shows the effect of parsley brain treatment on cells of COLO 205 cells with fc. ^ • 219 201141474. [Explanation of main component symbols] (None) [Simplified description of the schema] Annex 1 Schematic diagram of the information transmission path in which the celery brain induces cell cycle arrest in human COLO 205 cells.

[S.3 20

Claims (1)

201141474 VII. Patent Application Range·· 1. Use of a 5-substituted 4,7-dimethoxy-153-benzodioxolane for the manufacture of pharmaceuticals for the treatment of colorectal cancer, 5 _Substituted 4,7-dimethoxy-1,3-benzodioxolane has the following general formula: och3 • 〇CH3 (I); wherein R is a substituted or nonsubstituted group selected from the group consisting of: q to C6 alkyl group , C2 to C6 alkenyl group, C2-C6 alkynyl group, cyano group, C! to C5 alkyl ester group (ester group), C] to C5 carboxyl group (carboxylic group) and isoxazole Isoxaz〇ie group, but conditionally (with the proviso that): R is not methyl (other than -CH3). ® 2. The use of claim 2, wherein R is a substituted or unsubstituted ethane group, a propane group, an ethylene group, a propylene group, a butyl group, an ethynyl group, a propynyl group, a cyano group. , methyl ester group, ethyl ester group and methyl carboxyl group, ethyl carboxyl group or propyl carboxyl group. 3. The use of claim 1 wherein R is a substituted group wherein the substituent is hydroxy (-OH), cyano (-CN), nitro (nitr 〇 group) or dentate Halogenyl. 4. The use of claim 1 wherein R is selected from the group consisting of [S.1 21 201141474 in the group consisting of: _CN, -COOH COOCH3, -(CH2)2CH3, -CH2CH ( OH)CH2CN O-N Ch2ch2oh ch2ch=ch:s. and The use of any of the above-mentioned patents in the range of items 1 to 4, ^k-substituted 4'7-dimethoxy], % benzodioxanthene by 'f ( Intravenous, intramuscular, intraperitoneal. ^ T (subcutaneous) > £ (rectal) ^ ^ (topical) pathway administration. 6. For the application as described in any of the 1 to 4 items of the Gansu Gangudi, the 5-substituted 4,7-dimethyloxane into the milk thistle, 3·Benkai Dioxapentane is administered as a circumstance. (Approx. M mg/kg. Effective agent between the pen brother/the hall. 7. Kind of itch for the treatment of itching.) - v 縻, α A pharmaceutical composition for colorectal cancer comprising: a therapeutically effective dose of any 5-substituted 4,7-dimethoxy λ as described in the previous section of the ice... Τ rolling base · t M b ^ ^ f anamorphism, diastereomers, salts on the first sputum or its ΛΑ ^ ^ , ' and 〇, and their medical advice can be connected to A Carrier and / or excipient, potted ς & Emirates on j 殳 „ /, medium 5 · substituted 4,7-dimethoxy-i 3 floc, 曰 1 oxapentane Has the following general formula 1: soil, this open 22 201141474 OCH, OCH3 (1); wherein R is selected from the group consisting of: substituted (substituted) or non-substituted (non-substituted) 0, to C6 alkyl group, C2 to C6 alkenyl group 'C2-C6 block group, cyano group, C丨 to C5 Ester group, C丨 to C5 carboxylic group, and isoxazole group, but conditionally (with the proviso that) : R is not a sulfhydryl group (other Than -ch3). 8. The pharmaceutical composition according to claim 7, wherein R is substituted or unsubstituted ethane group, propane group, ethylene, propylene, butylene, ethynyl group, propynyl group, cyanide A group, a methyl ester group, an ethyl ester group, and a methyl thiol group, an ethyl sulfhydryl group or a propyl group. 9. The pharmaceutical composition according to claim 7, wherein R is selected from the group consisting of -匸1^, -(:0011, -CH2CH2OH, -COOCH3, -(CH2) 2CH3, -CH2CH(OH)CH2CN, 10. The pharmaceutical composition according to item 7 of the patent application, which is administered orally or parenterally [S 23 201141474. .U. The pharmaceutical composition of claim 7, wherein the carrier is a low melting wax. Electrocalyx = ^ Please patent (4) 7 to ig shot - the medicine described in the article - Bazhong 5 · Substituted 4,7_ dimethoxy", effective ratio range of 3 - benzodioxanane约1 mg, kg to about 5 mg, public 13. A cell cycle inhibitor, which contains one The 5-substituted 4,7-benzodioxolane described in any one of the above items. For example, if you apply for a patent, dimethoxy-1,3- 14 " 4 - a colorectal cancer cell, please contact any of the oxy-1,3-para-dioxane dioxane in the patent range 丨 to 4 . a poisoning agent comprising a 5-substituted 4,7-dimethyl group as described in the application 1 S.1 24