JP2001515861A - Dithiolopyrrolones and their corresponding monooxides and dioxides as antitumor agents - Google Patents

Abstract

(57) Abstract: Formula (1) wherein R ₁ = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl group; R ₂ = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl , Aralkyl, heterocyclyl or group acyl; R ₃ = hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group], or (2) wherein R ₁ = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, An aralkyl or heterocyclyl group; R ₂ = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or group acyl; R ₃ = hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group], or (3) wherein, R ₁ = hydrogen, a substituted or unsubstituted A Kill, cycloalkyl, aryl, aralkyl or heterocyclyl group; R ₂ = hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or acyl; R ₃ = hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl The compound isolated from the bacterium Xenorhabdus bovienii or a salt thereof has antitumor activity. The present invention provides pharmaceutical compositions containing the compounds and methods of using them as medicaments, especially for treating cancer in humans and animals. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to dithiolopyrrolone derivatives having antitumor activity, their corresponding monooxides (zenomines) and dioxides (zenoloxides). The invention also provides antitumor compositions comprising these compounds, salts thereof, and methods of using the compounds of the invention as antitumor agents.

SUMMARY OF THE INVENTION The present invention provides dithiolopyrrololone derivatives having antitumor activity, their corresponding monooxides (zenomines) and dioxides (zenoloxides). The invention also provides antitumor compositions comprising these compounds, salts thereof, and methods of using the compounds of the invention as antitumor agents.

BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1, 2 and 3 below show the structural formulas of dithiolopyrrolone, its corresponding monooxide (zenomine) and dioxide (zenoloxide), respectively.

Embedded image Wherein R ₁ = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl group; R ₂ = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or group acyl; R ₃ = Hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group].

[0004]

Embedded image Wherein R ₁ = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl group; R ₂ = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or group acyl; R ₃ = Hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group].

Embedded image Wherein R ₁ = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl group; R ₂ = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or group acyl; R ₃ = Hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group].

Background Art Cancer is one of the leading causes of human and animal death. Millions of people worldwide are diagnosed with cancer each year, and most of these people subsequently die of cancer. Despite great efforts, cancer remains a difficult disease to treat. The urgent need for effective anticancer drugs continues.

[0006] Soil organisms are a traditional source of bioactive substances in the pharmaceutical and agrochemical industries. One recent development has commercialized a soil-living nematode-bacteria combination as a biocontrol agent for entomopathogens. A critical property of this ecological control agent is its nematode bacterial symbiosis.
(Xenorhabdus spp. Or Photorhabdus spp.) Produce a wide range of bioactive metabolites, and some of these specific compounds have been isolated, identified, and their structures elucidated (Forst and Nealson, 1996). ) That is. Of these identified compounds, some are dithiolopyrrolones. Dithiolopyrrolone is initially 4
It was isolated from Streptomyces in the 0's and has since been isolated from other organisms.
These compounds include aureoslysin, thiorutin, holomycin and xenolabudine (Hamao et al., 1948; Eisenman et al., 1953; Celmer and Sol
omons, 1955; von Daehne et al., 1969; McInerney et al., 1991). These compounds have antimicrobial activity against a wide range of microorganisms. Recently, a new antimicrobial substance, xenoxide (Webster et al., 1996), has also been discovered from bacterial cultures of Xenorhabdus spp. Some results from an ongoing investigation of the potential utility of these metabolites of Xenorhabdus have shown that xenoxide, zenomine and dithiolopyrrololone are highly active against animal and human cancer cells, It is the subject of the invention.

[0007] Animal cells typically undergo various enzymatic and biochemical changes when affected by various chemical factors. For example, when animal cells are challenged with a carcinogen, many enzymatic and biochemical activities are enhanced, and some of the enhanced activity can be detected experimentally. Among dithiolopyrrolones and their derivatives, thiorutin is one of the most studied. Thiortin inhibits RNA polymerase synthesis in yeast (Jimenez et al., 1973; Tipper, 1973), has membrane stabilizing activity, and inhibits platelet aggregation in rats (Yasuyuki et al., 1980). Thiorutin has been reported to inhibit the promotion of some of these activities, possibly related to carcinogenesis in mammalian cells exposed to carcinogens (Menta and Moon, 1991; Sharma et al., 1994).
Arnold et al., 1995). This suggests that thiorutin may be involved in the initiation or progression of precancerous cell transformation of cells that become malignant cells. However, this activity has not been experimentally established. Although research on dithithiolopyrrolones has been ongoing for about 50 years, the anticancer activity of thiorutin and other dithiolopyrrolones on mammalian cells has not been evaluated and reported to date. Xenoloxide and xenomin were discovered very recently and there are no prior reports on their anticancer activity.

DETAILED DESCRIPTION OF THE INVENTION Although the compounds of the present invention can be chemically synthesized, the first compounds were obtained from microorganisms. The organism used in the present invention is Xeno, a symbiotic bacterium associated with entomopathogenic nematodes.
Including rhabdus bovienii. X. bovienii and its nematode symbion S used in the present invention
teinernema feltiae was collected from soil in British Columbia, Canada. Briefly, the last instar larva of the honeybee, Galleria mellonella, was infected with infectious juvenile (IJ) larvae carrying the X. bovienni A21 strain at a rate of 25 IJ / larva. 24 to 48
After hours, dead insect larvae were surface disinfected by dipping in 95% EtOH and igniting. The carcass was aseptically dissected and hemolymph was linearly plated on agar culture medium and incubated at room temperature in the dark. The agar medium had the following composition per liter of distilled water:

[Table 1] Sterilize at 121 ° C for 15 minutes.

[0009] The resulting primary from X. bovienii was maintained and passaged at 14 day intervals. For consistency, lyophilized 14% sucrose powder of bacteria stored at -20 ° C was often used as starting material for the culture. X. bovienii from which the compounds of the invention are obtained
Cultures of strain A21 exhibit the properties shown in Tables 1 and 2:

[Table 2] ^* + Positive; -negative

[0010]

[Table 3] ^* + Positive; +/- weak positive;-negative

[0011] These properties are described by X. bovieni by Akhurst, RJ and NE Boemare (1988).
i, thus confirming the identity of the organism as X. bovienii. The bacterial strain from which the compounds of the present invention were isolated was isolated and subjected to American T
Deposited with the ype Culture Collection (ATCC), Rochville, MD under the accession number ATCC55743.

[0012] The culture of the microorganism X. bovienii produces the biologically active substances xenomin, xenoxide and dithiolopyrrololone. X. bovienii can be cultured (fermented) in an aqueous, nutrient medium containing assimilable carbon (carbohydrate) and nitrogen sources under submerged aerobic conditions, for example, at about 25 ° C. obtain. The fermentation can be carried out for a time such as about 48 to 96 hours, at the end of which time these compounds have been formed and can be isolated and purified from the fermentation medium.

After the fermentation is over, the fermentation broth can be filtered or centrifuged and the pH of the filtrate can be adjusted to about 7.0 by adding hydrochloric acid or kept there. The filtrate can then be extracted with a water-immiscible, organic solvent such as ethyl acetate or chloroform. The combined organic phases (eg, pooled ethyl acetate or chloroform extracts) can be concentrated under vacuum (eg, at about 30 ° C.) to an oily residue. The oily residue can be mixed with a small amount of organic solvent and chromatographed on a silica gel column. After introduction of the sample, chloroform or other organic solvent may be applied to elute the bioactive fraction. The biologically active fraction can be further purified by high performance liquid chromatography (HPLC) with organic and / or aqueous solutions.

[0014] In conventional cultures, the dominant compound produced by X. bovienii is dithiolopyrolone, while xenoxide and xenomin are present in relatively small amounts.
Alternatively, dithiolopyrrolone may be produced from other microorganisms, from chemical methods and / or a combination of both approaches.

[0015] The isolated corresponding dithiolopyrrolone monooxide and dioxide from X. bovienii, ie, zenoloxide and zeminine, respectively, can be converted from their corresponding dithiolopyrrolone derivatives by biological or chemical means. By biological means, culture broths of X. bovienii in which the corresponding dithiolopyrrololone derivative is present can be filtered or centrifuged. The cell-free filtrate can be exposed to air with or without agitation at room or other temperatures for a period of one week to one month. This method can oxidize all or part of the corresponding dithiolopyrrololone derivative to zenomine and xenoxide. Xenoloxide and xenomin can be obtained by oxidation of the corresponding dithiolopyrrolone derivative by chemical means. The pure dithiolopyrrolone derivative or a mixture thereof can be dissolved in a mixture of acetone and water, and then an oxidizing reagent such as potassium peroxomonosulfate and potassium bicarbonate can be added to the mixture. The mixture can be reacted for a few minutes to an hour or more. The reaction mixture can be mixed with water and extracted with an organic solvent. Combine extracts, dry, column chromatography or HPLC
To give the corresponding xenoxide and / or xenomin. Further monooxides and dioxides of dithiolopyrrolone can be obtained from different microorganisms, synthesized chemically and / or produced by a combination of biological and chemical methods, and several examples have been described (Takahashi , et al., 1995; Fujimoto,
et al., 1996).

The compounds of the present invention include the corresponding monooxides, such as dithiolopyrrololone, zenomine, the corresponding dioxides, such as xenoxide, and salts thereof. The term "salt" as used herein refers to acidic and / or basic salts formed from inorganic and / or organic acids and bases. Suitable acids include, for example, pharmaceutically acceptable hydrochloric, sulfuric, nitric, benzenesulfonic, acetic, maleic, tartaric, and the like. It is known to those skilled in the art that a suitable salt is selected based on physical and chemical stability, flowability, hygroscopicity and solubility. Pharmaceutically acceptable salts are preferred, especially when the compounds of the present invention are used as medicaments, but the use of other salts is seen, for example, in the processing of the compounds or when non-pharmaceutical use is intended. .

[0017] Antineoplastic agents and uses thereof. The present invention relates to pharmaceutical formulations comprising the active ingredient of these compounds or a pharmaceutically acceptable salt thereof. Dosage forms and dosage forms, and dosages may be selected by one skilled in the art. An exemplary daily dosage for an adult is from about 2.5 mg to about 2,000 mg.
/ Day range. Administration to a mammalian host can be, for example, oral, parenteral or topical.

When these compounds or their salts are used as therapeutic agents, they alone
Alternatively, they can be administered as a pharmaceutically suitable formulation containing, in addition to the active ingredient, one or more conventional carriers. Depending on the nature of the disease and / or the route of administration, the compositions of the present invention can be formulated by known means.

Examples of pharmaceutical compositions include solid (tablets, pills, capsules, granules, powders, etc.) or liquid (solutions, suspensions or emulsions) compositions suitable for oral, topical or parenteral administration. , They may consist of pure compounds or their salts, or may be in combination with carriers or pharmaceutically active compounds. These compositions may need to be sterilized when administered parenterally.

[0020] Therapeutic compositions of the present invention for use as anti-tumor agents in the treatment of animal and human diseases are available in the art per se, and are based on the use of pharmaceutical substances that can be manufactured by established methods. It can be easily manufactured into unit dosage forms. Appropriate solid or liquid media or diluents are chosen, and the compositions can be prepared in a manner known to those skilled in the art.
Administration of a compound of the present invention and / or a pharmaceutically active and physiologically equivalent derivative thereof can be performed using an approved protocol of the National Cancer Institute (NCI), using a neoplastic disease such as colorectal cancer. , Cervical cancer, breast cancer, leukemia, lung cancer, ovarian cancer, CNS cancer, renal cancer, prostate cancer and the like. The dosage to be administered depends on the type of host involved, including the identity, age, health and weight of the tumor disease, the type of concurrent treatment, if any, and the frequency and therapeutic index of the treatment. Illustratively, the dosage level of active ingredient administered is 0.1 to about 200 mg / kg of host body weight intravenously; 1 to about 500 mg / kg of host body weight intramuscularly and 5 to about 100 mg orally.
0 mg / kg of host body weight. Expressed in terms of concentration, the active ingredient may comprise from about 0.01 to about 50% w / w of the composition, preferably from about 1 to about 20% w / w of the composition in a composition of the invention for topical use. w, and for parenteral use, may be present at about 0.05 to about 50% w / v, and preferably about 5 to about 20% w / v of the composition. The active ingredient used as an antitumor agent can be readily prepared in such unit dosage form by the use of pharmaceutical substances which are themselves available in the art and can be prepared in an established manner.

Examples Example 1 Preparation of Xenoloxide, Zenomine and Dithiolopyrrolone Preparation of Selected Dithiopyrrolones Several dithiolopyrrolones have been described to date, including aureolysin, thiortin, holomycin, xenolabudine and thiomarinol. Aureoslysin is described in detail by Umezawa et al. (1948) and the structure is Celmer
and Solomons (1955). Thiortin is American Ty
Produced from several bacterial species, including the Streptoverticillium album, available from the Pe Culture Collection (ATCC), Rockville, MD, under ATCC number 33049. The production of thiortin and holomycin by chemical synthesis is described in Schmidt and Geiger (1962), Hag
Published by io, K. and Yoneda, N. (1974) and Stachel, HD, et al. (1992). Xenolabudine production was determined by McInerney et al. (1991) and Li et al.
(1995) and detailed. The preparation of yet another compound having a dithiolopyrrolone ring has recently been described in Baggaley et al. (1994a, b) and Takahasi et al.
(1994). The dithiolopyrrololone used in the present invention was produced by the method described in the cited reference, and the structure of each dithiolopyrrololone derivative was confirmed by its NMR spectrum. Chemical technicians can obtain these dithiolopyrrolones from available storage materials using the methods described herein and others. In performing such operations, appropriate filtration, chromatography, and other purification methods should be used by those skilled in the art. It is clear to a person skilled in the art that the substances and reagents for carrying out such operations are commercially available from chemical companies, and no details regarding them are given.

B. Production of the corresponding dioxides from dithiolopyrrolones by microbial fermentation Cultures of xenoxide: X. bovienii are shaken in an Eberbach gyro rotary shaker at 180 rpm for 24 hours at 25 ° C. Bacterial fermentation was initiated by adding 100 ml of this bacterial culture to 900 ml of trypsin soil broth in a 2,000 ml flask. The flask was incubated in a gyro rotary shaker at 25 ° C. in the dark. After 96 hours, the culture was immediately centrifuged (12,000
0 g, 20 minutes, 4 ° C.). The cell-free broth was then extracted four times with ethyl acetate. The combined extracts were extracted with anhydrous sodium sulfate and then filtered on filter paper. The filtrate is concentrated under vacuum on a rotary evaporator at 30 ° C. or lower,
A brown oil was obtained. After repeating the above experiment 10 times, about 3 g of oil was obtained. The crude extract was then purified on silica gel (200 g silica gel 60, 40 cm × 5 cm, EM Sc
ience, Darmstadt, Germany). A yellow bioactive fraction eluted with ether or ethyl acetate. This biologically active fraction was applied to a C ₁₈ preparative column (Spherisorb 10 (ODS (1)), 250 × 10 mm, 10 micro, Phenomen
ex, Torrance, CA) HPLC (10% acetonitrile in water, 5 min isocratic, then gradually rise to 85% acetonitrile in 35 min, 5 min isocratic, then decrease to 10% in 2 min) And returned at 2.5 ml / min. The eluate was monitored at 254 nm. Xenoroxide 1 (about 0.3 mg in 1 liter of crude broth) eluted at 33.6 minutes, and then at 35.2 minutes Zenoroxide 2 (0.2 mg).
mg / l).

C. Production of the corresponding monooxide from dithiolopyrrololone by microbial fermentation Xenomine: For purification of xenomin, the culture and extraction conditions were the same as for xenoxide. After extraction, the concentrated crude extract was passed through a silica gel chromatography column using ethyl acetate as an eluent. After elution of the less polar bioactive material, a more active bioactive fraction was obtained by elution with methanol.
The more polar bioactive fractions were concentrated under vacuum and separated on a _C18 chromatography column, firstly water, then 25% methanol, 50% methanol, 75% methanol in water and finally pure methanol as eluent. The most bioactive fraction eluted at 75% methanol in water. Next, the bioactive fraction was concentrated, and a C ₁₈ preparative column (Spherisorb 10 (ODS (1)), 250 × 10 mm, 10 micro, Ph)
enomenex, Torrance, the HPLC of CA), the program (gradually increased in 24 minutes to 1 minute and H ₂ O in 70% MeCN in 30% MeCN in H ₂ O, 5 minutes isocratic)
And applied at 2.0 ml / min. The eluate was monitored at 254 nm. Activity peak 1 (
25.4 min) and peak 2 (25.8 min) were collected. Activity peak 1 was concentrated and further purified by preparative silica gel TL using 60% ethyl acetate in dichloromethane as eluent.
Separation with C gave xenomin 1 (R _f = 0.32). Activity peak 2 was concentrated and further separated by preparative silica gel TLC using 60% ethyl acetate in dichloromethane as eluent to give xenomin 2 (R _f = 0.31).

D. Production of Xenoloxide from the Corresponding Dithiolopyrrololone Derivative by Biological Transformation Cell-free broth was obtained in the same way as described above and then stored at 4 ° C. to room temperature for 3 to 6 weeks. The aqueous broth was then extracted with ethyl acetate and the combined extracts were separated in the same manner as above. Xenoloxide 1 eluted at 33.6 minutes (2 mg / l), and zenoxide 2 eluted at 35.2 minutes (1.5 mg / l).

E. Preparation of the corresponding dioxide from dithiolopyrrolones by chemical oxidation 152 mg of 6- (hexaneamido) -4-methyl-4,5-dihydro-1,2-dithiolo [4,3-b] pyrrol-5-one (XN1 ) Was dissolved in a mixture of 20 ml of acetone and 15 ml of water and then cooled to 0 ° C. with ice. Potassium peroxomonosulfate (510 mg) was added to the solution at 0 ° C. The reaction mixture was stirred for 1 hour at 0 ° C. Then 5 ml of a saturated solution of potassium bicarbonate were added for 0.5 hours at 0 ° C. with continuous stirring. The reaction mixture was extracted three times with ethyl acetate after adding water.
The extracts were combined, dried over Na ₂ SO ₄ and evaporated to give a crude product, which was then purified by column chromatography on silica gel using hexane: ethyl acetate (2: 1) to give pure xenoxide 1 ( 78 mg, yield 51%). Similarly, xenoxide 3 was obtained from 6- (5'-methylhexanamide) -4,5-dihydro-1,2-dithio [4,3-b] pyrrol-5-one in 50% yield.

[0026] Identification NMR spectra of Examples 2 active ingredients Bruker WM400 spectrometer, the residual CDCl ₃ (~7.25) was used as internal standard, were recorded in CDCl _3. Hewlett for low-resolution mass spectra
-Obtained on a Packard 5985B GC / MS system operating at 70 eV using a direct probe. High resolution MS spectra were recorded on a Kratos MS80 instrument. P IR spectrum
Recorded as neat film on NaCl using an erkin-Elmer 599B spectrometer. (The abbreviations used are as follows: EI = electron impact, M = molecular ion, t = triplet, J = coupling constant, Hz = Hertz, d = doublet, m
= Multiplet, bs = broad singlet).

6- (acetamido) -4-methyl-4,5-dihydro-1,2-dithiolo [4,3
-B] pyrrol-5-one (thiorutin) (XN0):

[Table 4]

6- (hexaneamido) -4-methyl-4,5-dihydro-1,2-dithiolo [4,
3-b] pyrrol-5-one (XN1):

[Table 5]

6- (5′-Methylhexaneamide) -4,5-dihydro-1,2-dithiolo [4,3-b] pyrrol-5-one (XN 3):

[Table 6]

[0030]

[Table 7]

[0031]

[Table 8] Different NOE experiments showed a NOE effect between the 6.35 ppm and 3.20 ppm peaks;

[Table 9]

[0032]

[Table 10]

[0033]

[Table 11]

[0034]

[Table 12]

Example 3 Dithiolopyrrolones, Corresponding Monooxides and Dioxides as Antineoplastic Agents The anticancer activity of certain compounds can be demonstrated by standard assays. The normal American National Cancer Institute (NCI), the method being used for the efficacy of the compounds is based on the LC _{5 0.} LC ₅₀ is the concentration of compound at which half of the population of cancer cells are killed. This assay is commonly used by those skilled in the art and has been recognized as an indicator of mammalian anti-cancer activity. Test animal cancer cells are available from the ATCC, NCI and other tissues. The anti-cancer activity of the compounds of the present invention has been demonstrated in cell cultures of various human cancer cells (see table below) using slightly modified standard NCI methods. Details of the method are described in Skehan et al.
(1990). Briefly, cancer cells were grown in RPMI-1640 medium supplemented with glutamine and 10% fetal bovine serum and harvested from exponential phase maintenance cultures. The harvested cells were counted and placed in duplicate 96-well culture plates in a volume of 180 μl per well for 2,2.
The cells were distributed at a cell density of 500 cells / well. The cells were left at 37 ° C. for about 4 hours. Then, 20 μl of medium containing the test compound was added to each well to give the appropriate final test compound concentration. The test plate was then incubated at 37 ° C. The test was terminated after incubation by adding 50 μl of cold 50% trichloroacetic acid to each well. Cells were fixed for 4 hours and then washed 5 times with tap water. The wash plate was air-dried and dried for 30 minutes in 0.4% (wt / vol) dissolved in 1% acetic acid.
) Stained with sulforhodamine B (SRB). At the end of the staining time, the SRB was removed and the plate was quickly rinsed five times with 1% acetic acid. After rinsing, air dry the plate,
100 μl of 10 mM Tris base (pH 10.5) was added to each well to dissociate the dye binding to the cells. The plate was placed in a rotating shaker and shaken (100 rpm) for 10 minutes. Finally, the plates were read at 570 nm in a microtiter plate reader. All tested compounds have very strong anticancer activity in these cancer cells (see table below)
Shown against

Antitumor activity:

[Table 13] ^* Not tested

From the above aspects and examples, it is apparent that the present invention has been described and illustrated herein. Although our above description contains many limitations, these should not be construed as limiting the scope of the invention, but as examples of preferred embodiments.
Therefore, the scope of the specification should not be determined by the embodiments presented, but by the claims and their legal homologs.

[0038]

[Brief description of the drawings]

FIG. 1 is a diagram showing the structural formula of dithiolopyrrolone.

FIG. 2 is a diagram showing the structural formula of the corresponding monooxide (zenomine).

FIG. 3 is a view showing a structural formula of dioxide (zenoloxide).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 339: 02 C07D 339: 02 207: 44) 207: 44) (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ) , MD, RU, TJ, TM), AU, BG, BR, CH, CN, CZ, DE, ES, GB, HR, HU, ID, IL, JP, KP, KR, LU, MX, NO NZ, PL, PT, RU, SE, SG, TR, UA, US, UZ, VN, YU, ZW (72) Inventor Giantion Li Canada, Buoy 3ti 2ti 4, British Columbia, Port Moody, Buckingham Drive 117 (72) Inventor Genhuy Chen Canada, Buoy 5A 1S 6, British Columbia, Burnaby, Louis Riel 725, Simon Fraser University F-term (reference) 4B064 AE55 BA03 BA04 BH04 BH05 BH07 BH08 CA02 DA05 4C071 AA01 BB01 CC01 CC22 DD40 EE12 FF03 GG01 HH08 HH17 LL01 4C086 AA01 AA02 AA03 CB27 MA01 MA04 MA14 NA14 ZB26 ZB27 Has tumor activity. The present invention provides pharmaceutical compositions containing the compounds and methods of using them as medicaments, particularly for treating human and animal cancer. Embedded image

Claims (18)

[Claims] 1. The following structural formula:[Wherein, R₁= Hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl group; R_Two= Hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl, acyl group; _Three = Hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group) or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier or diluent.
A pharmaceutical composition for treating a tumor disease. 2. The following structural formula:[Wherein, R₁= Hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl group; R_Two= Hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl, acyl group; _Three = Hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group) or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier or diluent.
A pharmaceutical composition for treating a tumor disease. 3. The following structural formula:[Wherein, R₁= Hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl group; R_Two= Hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl, acyl group; _Three = Hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group) or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier or diluent.
A pharmaceutical composition for treating a tumor disease. 4. A tumor comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier or diluent, wherein R ₁ = hydrogen; R ₂ = acyl; R ₃ = hydrogen, methyl. A pharmaceutical composition for the treatment of a disease. 5. A tumor comprising a compound according to claim _2, wherein R ₁ = hydrogen; R ₂ = acyl; R ₃ = hydrogen, methyl, or a pharmaceutically acceptable salt thereof, together with a pharmaceutical carrier or diluent. A pharmaceutical composition for the treatment of a disease. 6. A tumor comprising a compound according to claim 3 or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier or diluent, wherein R ₁ = hydrogen; R ₂ = acyl; R ₃ = hydrogen, methyl. A pharmaceutical composition for the treatment of a disease. 7. The compound according to claim 1, wherein R ₁ = hydrogen, R ₂ = an acyl group having a linear or branched 1 to 10 carbon atom chain; R ₃ = hydrogen or methyl. A pharmaceutical composition for the treatment of a tumor disease, comprising a salt thereof together with a pharmaceutical carrier or diluent. 8. The compound according to claim ₂ , wherein R ₁ = hydrogen, R ₂ = an acyl group having a linear or branched 1 to 10 carbon atom chain; R ₃ = hydrogen or methyl. A pharmaceutical composition for the treatment of a tumor disease, comprising a salt thereof together with a pharmaceutical carrier or diluent. 9. The compound according to claim 3, wherein R ₁ = hydrogen, R ₂ = an acyl group having a linear or branched 1 to 10 carbon atom chain; R ₃ = hydrogen or methyl. A pharmaceutical composition for the treatment of a tumor disease, comprising a salt thereof together with a pharmaceutical carrier or diluent. 10. In a subject in need of treatment, an effective antitumor amount of the following structural formula:[Wherein, R₁= Hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl group; R_Two= Hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl, acyl group; _Three = Hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group) or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier or diluent.
A method of inhibiting the growth of a mammalian tumor, comprising administering to the subject. 11. In a subject in need of treatment, an effective antitumor amount of the following structural formula:[Wherein, R₁= Hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl group; R_Two= Hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl, acyl group; _Three = Hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group) or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier or diluent.
A method of inhibiting the growth of a mammalian tumor, comprising administering to the subject. 12. In a subject in need of treatment, an effective antitumor amount of the following structural formula:[Wherein, R₁= Hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl group; R_Two= Hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl, acyl group; _Three = Hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group) or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier or diluent.
A method of inhibiting the growth of a mammalian tumor, comprising administering to the subject. 13. The compound of claim 10, wherein R ₁ = hydrogen; R ₂ = acyl; R ₃ = hydrogen, methyl, or a pharmaceutically acceptable salt thereof, as an antitumor effective amount. A method of inhibiting the growth of a mammalian tumor, comprising administering to a subject in need thereof a treatment with a diluent. 14. An antitumor effective amount of R ₁ = hydrogen; R ₂ = acyl; R ₃ = hydrogen, methyl, or a pharmaceutically acceptable salt thereof, as a pharmaceutical carrier or a pharmaceutically acceptable salt thereof. A method of inhibiting the growth of a mammalian tumor, comprising administering to a subject in need thereof a treatment with a diluent. 15. The compound according to claim 12, wherein R ₁ = hydrogen; R ₂ = acyl; R ₃ = hydrogen, methyl, or a pharmaceutically acceptable salt thereof, in an antitumor effective amount. A method of inhibiting the growth of a mammalian tumor, comprising administering to a subject in need thereof a treatment with a diluent. 16. An antitumor effective amount of R ₁ = hydrogen, R ₂ = straight or branched chain 1-1.
An acyl group having a chain of 0 carbon atoms; R ₃ = hydrogen or methyl; administering the compound or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier or diluent to a subject in need of treatment. A method of inhibiting the growth of a mammalian tumor, comprising: 17. An antitumor effective amount of R ₁ = hydrogen, R ₂ = straight or branched chain 1-1.
An acyl group having a chain of 0 carbon atoms; R ₃ = hydrogen or methyl; administering the compound or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier or diluent to a subject in need of treatment. A method of inhibiting the growth of a mammalian tumor, comprising: 18. An antitumor effective amount of R ₁ = hydrogen, R ₂ = straight or branched chain 1-1.
An acyl group having a chain of 0 carbon atoms; R ₃ = hydrogen or methyl; administering the compound or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier or diluent to a subject in need of treatment. A method of inhibiting the growth of a mammalian tumor, comprising: