Method for making and prescribing sphaelactone derivate and its composites

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to micheliolide derivatives of formula , a based pharmaceutical composition and using them for treating cancer. In formula (I) R₁ represents H, -C(O)R₄, wherein R₄ represents C_1-8alkyl; R₂=R₃ represents a double bond, or R₃ represents H, and R₂ represents substituted alkyl having from 1 to 8 carbon atoms, wherein a substitute represents -NR₇R₈; or its pharmaceutically acceptable salts; and wherein R₇ and R₈ can be identical or different, and represent C_1-8alkyl; X represents oxygen; Y represents a single bond.

EFFECT: preparing the pharmaceutical composition for treating cancer.

6 cl, 1 tbl, 8 ex

The technical field to which the invention relates.

The present invention relates to the field of pharmaceutical technology. More specifically, the present invention relates to a derivative miliolid and their salts, pharmaceutical compositions containing these compounds as active ingredient, for the treatment of cancer, the way they are received and used to produce anti-cancer tools or auxiliary anti-cancer tool.

Prior art

The tumor has a greater threat to human health at the present time, the number of cancer patients around 200 million, and each year the number of new cancer patients is 1.6 million. Currently, anticancer research is very important and is of great importance in science. At present, the commonly used clinical anticancer drugs are cytotoxic drugs. These drugs have poor selectivity, strong side effects, resistance to the drug, and so on, They are typical dualistic drugs and hard to destroy cancer, which leads to a high percentage of cancer recurrence. The high rate of cancer recurrence is a problem for doctors, and more and more studies confirm that there are a small number of the trunk is o cancer cells in a population of cancer cells, which can increase cell cancer group. Stem cancer cells are usually found in slow cyclic status and have low sensitivity to chemotherapeutic drugs. They are a source of cancer recurrence. Found stem tumor cell makes a new target for cancer treatment and research of drug is focused on tumor stem cell, can lead to complete cure of cancer.

In recent years, research on anti-cancer compounds from natural products have become very popular in the field of research and development of anticancer drugs. In the past 20 years, 61% of the drug in the form of new small molecules could be obtained from natural products. Natural products are very common in some therapeutic areas: 78% antibacterial compounds and 74% of anticancer compounds are natural products or derived from natural products. Practice has proved that the unique role of natural products in the discovery of anticancer drugs again attracted a lot of attention.

Traditional anticancer chemotherapeutic drug has the problem of sustainability, in particular low sensitivity to tumor stem cell. Traditional Chinese medicine (TCM) is about novelny in the cancer field, has high efficiency and low toxicity. Accordingly, there is a high chance to detect drugs that destroy cancer stem cells for the treatment of malignant tumors in SCI.

Parthenolide (Parthenolide), sesquiterpene lactone extracted from Tanacetum Parthenium, has traditionally been used to treat skin infections, rheumatism and migraine. Recent studies have shown that parthenolide can inhibit the growth of cancer cells, such as prostate cancer, breast cancer, stomach cancer, leukemia, kidney cancer, lung cancer, colon glandular cancer, medulloblastoma. Moreover, parthenolide is effective in the treatment of skin cancer caused by UV-rays at animal model. The study of its mechanism found that parthenolide can inhibit activation of the transcription factor NF-KB. Activity mainly was obtained from a thiol on the subunit p65/NF-KB, which is accompanied by a Michael reaction with parthenolide. NF-KB is a key gene in the regulation of tumor development, metastasis and resistance genes to drugs, and therefore, inhibition of activation of NF-KB may increase the sensitivity of apoptosis of the tumor to the inhibitor of the tumor. Recently, Professor Jordan ARTICLE. and his colleagues at the medical Institute found that parthenolide can selectively eliminate cancer stem cells without the destruction n is malinich stem cells, which you can suppress recurrence of acute myeloid leukemia (AML). This unique mechanism parthenolide attracted wide attention.

Miliolid refers to the sesquiterpene lactone from guaiac type. As indicated in the literature [J. Nat. Prod. 1993, 56, 90-98; Bioorg. Med. Chem. Lett. 2003, 11, 1503-1510]. Based on these results, the present invention refers to the use of derivatives miliolid and their salts for the treatment of cancer.

The invention

Option of implementing the present invention relates to a derivative miliolid, anticancer pharmaceutical composition containing an effective amount of a derivative miliolid formula (I) or its salt, its preparation and the use of derivative miliolid formula (I) or its salts, or pharmaceutical compositions to obtain anti-cancer tool.

The embodiment of the present invention provide the above objects of the invention are:

Features compound of formula (I) or its salt:

where

R₁represents R, -C(O)R₄or-C(O)NR₅R₆where R₅and R₆may be the same or different, R₄, R₅and R₆represent hydrogen, alkyl, cycloalkyl, alkenyl, quinil, aryl, alkylaryl, arylalkyl, arylalkyl, arylalkyl and heterocycle;

R₂=R 3represents a double bond, or

R₃is a R, a R₂represents alkyl having from 1 to 8 carbon atoms and containing a Deputy where the Deputy is chosen from cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, a fragment of the amino acid or-NR₇R₈and its pharmaceutically acceptable salts formed with inorganic and/or organic acid and Quaternary ammonium salts formed with R₉Z preferably Deputy is a fragment of the amino acid and methylene substituted by-NR₇R₈;

where R₇and R₈may be the same or different and represent hydrogen, alkyl, cycloalkyl, alkyl, substituted by hydroxyl, alkenyl, quinil, aryl, alkylaryl, arylalkyl, arylalkyl, arylalkyl, heterocycle, trifluoromethyl, perfluoroalkyl, cyano, cyanomethyl, carboxyl, carbamate, sulfonyl, sulfonamide or aryloxyalkyl; or R₇and R₈taken together with the N atom, form a ring, preferably 3 to 9-membered ring, where the ring may contain one or more substituents selected from hydrogen, alkyl, cycloalkyl, alkenyl, quinil, aryl, alkylaryl, arylalkyl, arylalkyl, arylalkyl or heterocycle, preferably R₇and R₈selected from hydrogen, alkyl having from 1 to 8 carbon atoms or a cyclo is Lila;

Z represents fluorine, chlorine, bromine, iodine, tosylate, methanesulfonate, bansilalpet, triftorbyenzola; R₉represents alkyl, cycloalkyl, alkyl, substituted by hydroxyl, alkenyl, quinil, aryl, heterocycle, arylalkyl, arylalkyl, arylalkyl, cyanomethyl, alkoxy or aryloxyalkyl; inorganic or organic acid is a hydrofluoric acid, hydrochloric acid, Hydrobromic acid, idiscovered acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, se acid, phosphoric acid, phosphoric acid, sulfurous acid, citric acid, maleic acid, D-malic acid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid, DL-lactic acid, oxalic acid, methanesulfonate, valeric acid, oleic acid, laurinova acid, n-methyl benzosulfimide, 1-naphthalenesulfonate, 2-naphthalenesulfonate, phthalic acid, tartaric acid, malonic acid, succinic acid, fumaric acid, glycolic acid, thiol acid, glycine, Sarkozy, acid, nicotinic acid, Pikalyovo acid, isonicotinoyl acid, benzoic acid or substituted benzoic acids;

X represents oxygen or R₁₀N, where R₁₀pre whom represents a hydrogen, alkyl, cycloalkyl, alkenyl, quinil, aryl, alkylaryl, arylalkyl, arylalkyl, arylalkyl or heterocycle;

Y represents a single bond, O, R₁₁N, R₁₂R₁₃C, where R₁₁represents hydrogen, alkyl, cycloalkyl, alkenyl, quinil, aryl, alkylaryl, arylalkyl, arylalkyl, arylalkyl or heterocycle; R₁₂and R₁₃may be the same or different and represent hydrogen, fluorine, chlorine, bromine, iodine, alkyl, cycloalkyl, alkyl, substituted by hydroxyl, alkenyl, quinil, aryl, heterocycle, arylalkyl, arylalkyl, arylalkyl, cyanomethyl, alkoxy or aryloxyalkyl.

Preferably, if R₁represents H, Y is a single bond, R₂=R₃is not a double bond.

Preferably, R₂represents a methylene, substituted NR₇R₈or a fragment of the amino acids, where R₇and R₈may be the same or different and represent hydrogen, alkyl, cycloalkyl, alkyl, substituted by hydroxyl, alkenyl, quinil, aryl, alkylaryl, arylalkyl, arylalkyl, arylalkyl, heterocycle, trifluoromethyl, perfluoroalkyl, cyano, cyanomethyl, carboxyl, carbamate, sulfonyl, sulfonamide or aryloxyalkyl; or R₇and R₈taken together with the N atom, form a ring, preferably 3 to 9-membered ring, where the ring may contain one who does several deputies, selected from hydrogen, alkyl, cycloalkyl, alkenyl, quinil, aryl, alkylaryl, arylalkyl, arylalkyl, arylalkyl or heterocycle, preferably R₇and R₈selected from hydrogen, alkyl having from 1 to 8 carbon atoms, or cycloalkyl.

The present invention also relates to a method for obtaining compounds of formula (I) or its salts, including the provision of michailidou as source material, adding a catalyst in an organic solvent, and the interaction of the organic solvent with the catalyst and the starting material to obtain the desired connection.

Preferably, the compound of formula (I) or its salt can be represented by the formula (II), formula (III), formula (IV) or formula (V):

In particular, the invention concerns a method of deriving miliolid formula (II), including the interaction of the parent compounds with obtaining the target compound, where the parent compounds are miliolid and dimethenamid.

Also the invention concerns a method of deriving miliolid formula (III), including the interaction of the starting compounds, solvent and catalyst to obtain the target compound, where the original soy is inanami are miliolid and propionitrile, the catalyst is triethylamine, the solvent is CH₂C1₂.

Also the invention concerns a method of deriving miliolid formula (IV), including the interaction of the parent compounds and solvent to obtain the target compound, where the parent compounds are miliolid and 3-chloroperbenzoic acid, the solvent is CH₂Cl₂.

In particular, the present invention relates to a method for obtaining compounds of formula (V), including the dissolution of the source material in CH₂Cl₂where the starting compound is a compound of formula (V) to bring the pH to a value of 4-5 with hydrochloric acid and lyophilization of an aqueous solution to obtain the target compounds.

The present invention also concerns the use of compounds of formula (I) or its salts for the treatment of cancer where the cancer includes leukemia, breast cancer, prostate cancer, nasopharynx cancer, colon cancer, lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, pancreatic cancer, colorectal cancer and colon cancer, cervical cancer, lymphoma non-Hodgkin's lymphoma, glioma, melanomas, cystosarcoma, ovarian cancer, thyroid cancer or Kaposi's sarcoma.

The present invention also concerns the use of compounds of formula (I) or it is possible for the auxiliary treatment of cancer, where cancer includes leukemia, breast cancer, prostate cancer, nasopharynx cancer, colon cancer, lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, pancreatic cancer, colorectal cancer and colon cancer, cervical cancer, lymphoma non-Hodgkin's lymphoma, glioma, melanomas, cystosarcoma, ovarian cancer, thyroid cancer or Kaposi's sarcoma.

The present invention also concerns the use of compounds of formula (I) or its salts as a drug, where the specified drug used for the treatment of cancer where the cancer includes leukemia, breast cancer, prostate cancer, nasopharynx cancer, colon cancer, lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, pancreatic cancer, colorectal cancer and colon cancer, cervical cancer, lymphoma non-Hodgkin's lymphoma, glioma, melanomas, cystosarcoma, ovarian cancer, thyroid cancer or Kaposi's sarcoma.

The present invention also concerns the use of compounds of formula (I) or its salts as a drug, where the specified drug is used for the auxiliary treatment of cancer where the cancer includes leukemia, breast cancer, prostate cancer, nasopharynx cancer, colon cancer, cancer of the Le is fir, liver cancer, esophageal cancer, stomach cancer, colon cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, pancreatic cancer, colorectal cancer and colon cancer, cervical cancer, lymphoma non-Hodgkin's lymphoma, glioma, melanomas, cystosarcoma, ovarian cancer, thyroid cancer or Kaposi's sarcoma.

The present invention also relates to pharmaceutical compositions for treating cancer containing an effective amount of a derivative miliolid formula (I) or salts thereof, in combination with a pharmaceutically acceptable carrier or another anticancer drug.

The present invention also concerns the use of compounds of formula (II), (III), (IV), (V) or its salts for the treatment of cancer where the cancer includes leukemia, breast cancer, prostate cancer, nasopharynx cancer, colon cancer, lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, pancreatic cancer, colorectal cancer and colon cancer, cervical cancer, lymphoma non-Hodgkin's lymphoma, glioma, melanomas, cystosarcoma, ovarian cancer, thyroid cancer or Kaposi's sarcoma.

The present invention also concerns the use of compounds of formula (II), (III), (IV), (V) or salts thereof for adjunctive treatment of cancer where the cancer includes leukemia, breast cancer, prostate cancer, nasopharynx cancer, cancer of the colon Kish and, lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, pancreatic cancer, colorectal cancer and colon cancer, cervical cancer, lymphoma non-Hodgkin's lymphoma, glioma, melanomas, cystosarcoma, ovarian cancer, thyroid cancer or Kaposi's sarcoma.

The present invention also concerns the use of compounds of formula (II), (III), (IV), (V) or its salts for the treatment of cancer where the cancer includes leukemia, breast cancer, prostate cancer, nasopharynx cancer, colon cancer, lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, pancreatic cancer, colorectal cancer and colon cancer, cervical cancer, lymphoma non-Hodgkin's lymphoma, glioma, melanomas, cystosarcoma, ovarian cancer, thyroid cancer or Kaposi's sarcoma.

The present invention also concerns the use of compounds of formula (II), (III), (IV), (V) or salts thereof as a drug, where the drug is used to treat cancer, where the cancer includes leukemia, breast cancer, prostate cancer, nasopharynx cancer, colon cancer, lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, pancreatic cancer, colorectal cancer and colon cancer, cervical cancer, lymphoma non-Hodgkin's lymphoma, glioma, chalk is nomates, cystosarcoma, ovarian cancer, thyroid cancer or Kaposi's sarcoma.

The present invention also concerns the use of compounds of formula (II), (III), (IV), (V) or salts thereof as a drug, where the drug is used for the auxiliary treatment of cancer where the cancer includes leukemia, breast cancer, prostate cancer, nasopharynx cancer, colon cancer, lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, pancreatic cancer, colorectal cancer and colon cancer, cervical cancer, lymphoma non-Hodgkin's lymphoma, glioma, melanomas, cystosarcoma, ovarian cancer, thyroid cancer or Kaposi's sarcoma.

The present invention also relates to pharmaceutical compositions for treating cancer containing an effective amount of a derivative miliolid formula (II), (III), (IV), (V) or salts thereof, in combination with a pharmaceutically acceptable carrier or another anticancer drug.

Compounds of the present invention can be directly or in the form of a pharmaceutical composition used as a drug. The pharmaceutical compositions contain 0.1 to 99%, preferably 0.5 to 90%, of compounds of the present invention, and pharmaceutically acceptable carriers and/or excipients, which are not dangerous for the LM is now and man, or in combination with other anticancer drugs. The composition can be obtained in the form of injections, tablets and capsules.

Pharmaceutically acceptable carriers and eccipienti are solid, semi-solid and liquid. The dose of the pharmaceutical composition of the present invention depends on the unit weight. The pharmaceutical compositions may be introduced in the form of injections and oral form. Injections include injection for intravenous and intramuscular injection and oral form is a tablet and a capsule.

Derivatives miliolid and their salts show good effect in the treatment of cancer and do not show obvious inhibition of normal cells.

Examples

The present invention is hereinafter described with reference to examples, which do not limit the present invention.

Example 1

Getting 11βH, 13-hydro,13-dimethylaminopyridine (compound II):

Miliolid (106 mg, 0.40 mmol), triethylamine (2.0 ml), Me₂NH-HCl (41 mg, 0.5 mmol) and methanol (30 ml) is added to 100-ml round bottom flask. The resulting mixture is heated and refluxed for 3 hours, and then concentrated under reduced pressure to obtain a crude residue, which was purified on a column of silica gel (petroleum ether:ethyl acetate:triethylamine=50:50:0.5) with with the rucenim to 107.4 mg solid white, with the release of 86%.

Formula: C₁₇H₂₇NO₃

Molecular weight: 293

Description: White amorphous powder

Spectral data:

¹H-NMR (CDCl₃, 400 MHz) δ 3,76 (t, J=10.0 Hz, 1H), 2,96 (s, 1H), 2,49-to 2.67 (m, 3H), 2,28-of 2.34 (m, 1H), 2,30-of 2.34 (m, 2H), 2,18 (s, 6H), 2,09 (user.s, 2H), 1,96 (d, J=11.2 Hz, 1H), 1,67-of 1.73(m, 2H), 1,60 (s, 3H) 1,22 (user.s, 3H), 1,18 (user.s, 2H);

¹³C-NMR (CDCl₃, 100 MHz) δ 177,0, 131,8, 131,3, 84,0, 80,2, 58,3, 58,1, 50,9, 46,0, 44,6, 38,4, 35,3, 30,0, 27,2, 23,7, 22,8.

Example 2

Getting 4-propionylthiocholine (compound III):

Miliolid (106 mg, 0.40 mmol), triethylamine (2.0 ml), propionate (0.2 ml) and CH₂Cl₂(5 ml) is added to 20-ml round bottom flask. The resulting mixture is stirred for 24 hours at room temperature, and then concentrated under reduced pressure, and purified on a column of silica gel (petroleum ether:ethyl acetate=90:10), to obtain 87 mg of a solid substance of white color, yield: 72%.

Formula: C₁₈H24NO₄

Molecular weight: 304

Description: White amorphous powder

Spectral data:

¹H-NMR (CDCl₃, 400 MHz) δ 6,14 (s, 1H), 5,42 (s, 1H), 3,74 (t, J=10.0 Hz, J=10.0 Hz, 1H), 1,80-to 2.74 (m, N), to 1.67 (s, 3H), 1,50 (s, 3H), of 1.07 (t, J=4.0 Hz, 3H);

¹³C-NMR (CDCl₃, 100 MHz) δ 173,8, 170,1, 139,5, 131,5, 130,4, 118,6, 88,4, 83,0, 56,6, 50,1, 36,5, 34,9, 30,4, 28,7, 25,9, 24,1, 18,8, 9.1.

Example 3

Getting 1,10-aproximaciones (Obedinenie IV):

Miliolid (106 mg, 0.40 mmol), m-chloroperbenzoic acid (0.45 mmol) and methylene chloride (5 ml) was added a 20-millilitrovyh round bottom flask. The resulting mixture is stirred for 6 hours at room temperature, and then concentrated under reduced pressure, and purified on a column of silica gel (petroleum ether:ethyl acetate=80:20) to obtain 96 mg of a solid substance of white color, yield: 91%.

Formula: C₁₅H₂₀NO₄

Molecular weight: 264

Description: White amorphous powder

Spectral data:

¹H-NMR (CDCl₃, 400 MHz) δ 6,13 (d, J=3.2 Hz, 1H), 5,44 (d, J=2,8 Hz, 1H), of 3.73 (t, J=10.4 Hz, 1H), 1.30 and the 2.46 (m, 11N), of 1.29 (s, 3H), 1.28 (in s, 3H);

¹³C-NMR (CDCl₃, 100 MHz) δ 168,7, 137,8, 118,6, 79,2, 77,3, 74,2, 66,7, 52,6, 48,4, 37,1, 33,8, 29,0, 24,6, 22,5, 21,3.

Example 4

Getting hydrochloride 11βH,13-hydro,13-dimethylaminopyridine (compound V):

The compound (II) (293 mg, 1 mmol) dissolved in methylene chloride (2 ml) and stirred at room temperature, then add hydrochloric acid to bring pH=4-5. The resulting mixture was extracted with dichloromethane (2×10 ml). The resulting aqueous layer lyophilizer with obtaining a solid white color, yield: 82%.

Formula: C₁₇H₂₈ClNO₃

Molecular weight: 328.5

Description: White amorphous powder/p>

Spectral data:

[a]_D²⁰=-42, O (C=10, H₂O);

IR (cm^-1): 3334,25, 2927,18, 2856,17, 1767,94, 1467,25, 992,801, 967,371, 874,796, 831,311, 719,915, 669,783, 626,854, 5 04,24;

¹H-NMR (D₂O, 400 MHz) δ 4,14 (t, J=10.3 Hz, 1H), 3,51 (kV, J=12,6 Hz, 1H), 3,40 (DD, J=13.3-inch, 2.9 Hz, 1H), 3,18 totaling 3.04 (m, 1H), 2,96 (d, J=10,6 Hz, 6N), to 2.67 (d, J=10,2 Hz, 1H), 2,37 (DD, J=16,2, 8,1 Hz, 1H), 2,27-2,05 (m, 4H), of 1.87 (d, J=12.9 Hz, 1H), 1,73 (DD, J=19,5, 11.7 Hz, 2H), of 1.66 (s, 3H), 1,46 to 1.31 (m, 2H), 1.26 in (s, 3H);

¹³C-NMR (CDCl₃, 100 MHz) δ 178,4, 132,6, 131,4, 85,1, 80,7, 56,9, 55,6, 49,9, 45,1, 42,3, 41,5, 39,2, 34,4, 29,5, 25,9, 23,2, 21,4.

Example 5

Pharmacological activity of derivatives miliolid

Cancer cells are suspended in 2x10⁵/ml, and then add in a 24-well plate with round-bottom wells for tissue culture. Then add miliolid and its derivatives, where one test with a single density is 5 holes. The resulting suspension is incubated (at 37°C, 5% CO₂for 18 hours to allow the connection has entered into cooperation. The value of absorption coefficient (A) was measured using the MTT-test (used to assess the cytotoxicity of potentially antitumor compounds) and enzyme-linked detector at a wavelength of 570 nm and measure the inhibitory activity of the compounds. The results of inhibitory activity are presented in Table 1.

In Table 1, HL-60, C, MCF-7, CNE-1, CNE-2, SW620, A, HepG-2, Es, SGC7901, SW1116, A, ASPC-1, HT-29, HeLa, GL15, B16F1, T24, SKOV3, SW579, RS-3 is a cell line acute leukemia cell line chronic leukemia cell lines breast cancer cell line highly differentiated nasopharyngeal carcinoma, cell line benedettiintravenous nasopharyngeal carcinoma, a cancer cell line abadon the th and rectum, cell line lung cancer cell line hepatocellular carcinoma, cell line cancer of the esophagus, cancer cell line gastric cancer cell line colon cell line renal kletochnogo cancer cell line cancer of the pancreas cancer cell line colon cell line cervical cancer cell line Horny human neuroblastoma, cell lines melanoma cell line bladder cancer cell line of ovarian cancer cell line thyroid cell line prostate cancer.

The results obtained demonstrate that the compounds of the present invention possess strong activity against the tested cells, but also have obvious inhibition on cells at 50 μm.

Example 6

Injection

Compounds II, III, IV, V, obtained in Examples 1-4, dissolved in a small quantity of DMSO. Then water for injection added to the resulting mixture, filtered and then poured and sterilized with getting the injection.

Example 7

Tablet

Compounds II, III, IV, V, obtained in Examples 1-4, mixed with excipients in accordance with the weight ratio of 5:1, and then tabletirujut with reception of tablets.

Example 8

Capsule

Compounds II, III, IV, V, obtained in Examples 1-4, mixed with excipients in accordance with the weight ratio of 5:1, to obtain capsules.

Connection is altoadige of the invention, the use and methods have been described using specific embodiments of the invention. To a person skilled in the art it is obvious that the appropriate changes to the source materials, process conditions, etc. will lead to the achievement of the relevant objectives. Any modifications, equivalent replacements and improvements are the contents of the present invention.

1. The compound of formula (I):

where
R₁represents H, -C(O)R₄where R₄represents a C_1-8alkyl;
R₂=R₃represents a double bond, or
R₃represents N, and R₂represents a substituted alkyl having from 1 to 8 carbon atoms, where the Deputy represents-NR₇R₈;
and its pharmaceutically acceptable salts;
where R₇and R₈may be the same or different and represents a C_1-8alkyl;
X represents oxygen;
Y represents a single bond About;
if R₁represents N, Y is a single bond, R₂=R₃is not a double bond.

2. Connection on p. 1, where R₂represents methylene substituted by-NR₇R₈where R₇and R₈may be the same or different and represent a_1-8alkyl.

3. Connection on p. 1, where FD is the mule (I) is the formula selected from formula (II), formula (III), formula (IV), formula (V):

4. The use of compounds according to any one of paragraphs.1-3 or its salt to obtain drugs for the treatment of cancer, where the cancer is a leukemia, breast cancer, prostate cancer, nasopharynx cancer, colon cancer, lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, cancer of the pancreas, cancer of the rectum and colon, cervical cancer, lymphoma non-Hodgkin's lymphoma, glioma, melanoma, bladder cancer, ovarian cancer, thyroid cancer or Kaposi's sarcoma.

5. The use of compounds according to any one of paragraphs.1-3 or its salt to obtain a secondary drug for the treatment of cancer, where the cancer is a leukemia, breast cancer, prostate cancer, nasopharynx cancer, colon cancer, lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, cancer of the pancreas, cancer of the rectum and colon, cervical cancer, lymphoma non-Hodgkin's lymphoma, glioma, melanoma, bladder cancer, ovarian cancer, thyroid cancer or Kaposi's sarcoma.

6. Pharmaceutical composition for treating cancer containing an effective amount of a compound according to any one of paragraphs.1-3, or it is salt and a pharmaceutically acceptable carrier.