CN1360891A - Dithiolane amylene hepyrroleketone and its relative monoxide and dioxide using as antitumour agent - Google Patents
Dithiolane amylene hepyrroleketone and its relative monoxide and dioxide using as antitumour agent Download PDFInfo
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- CN1360891A CN1360891A CN01131401A CN01131401A CN1360891A CN 1360891 A CN1360891 A CN 1360891A CN 01131401 A CN01131401 A CN 01131401A CN 01131401 A CN01131401 A CN 01131401A CN 1360891 A CN1360891 A CN 1360891A
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
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- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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Abstract
Compounds, isolated from the bacteria Xenorhabdus bovienii, having formula (1), wherein R1 = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl group; R2 = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or group acyl; R3 = hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group, or (2), wherein R1 = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl group; R2 = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or group acyl; R3 = hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group, or (3), wherein R1 = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl group; R2 = hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or group acyl; R3 = hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclyl group or the salts thereof have antineoplastic activity. The invention provides pharmaceutical compositions containing the compounds and the methods for employing them as medicaments, particularly in the treatment of human and animal cancers.
Description
The field of the invention
The present invention relates to have dithia cyclopenta pyrrolidone (dithiolopyrrolone) derivant, its corresponding monoxide (xenomins) and the dioxide (xenorxides) of anti-tumor activity.The present invention also provides and has contained these chemical compounds, their anti-tumor compositions of salt, and The compounds of this invention is as the method for antitumor agent.
General introduction of the present invention
The present invention relates to have dithia cyclopenta 2-pyrrolidinone derivative, its corresponding monoxide (xenomins) and the dioxide (xenorxides) of anti-tumor activity.The present invention also provides and has contained these chemical compounds, their anti-tumor compositions of salt, and The compounds of this invention is as the method for antitumor agent.The chemical formula brief description
Following formula 1, formula 2 and formula 3 are represented the structural formula of dithia cyclopenta pyrrolidone, its corresponding monoxide (xenomins) and dioxide (xenorxides) respectively,
Formula 1 is R1=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical wherein; R2=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical, acyl group; R3=hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclic radical.
Or
Formula 2 is R1=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical wherein; R2=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical or acyl group; R
3=hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclic radical.
Or
Formula 3 is R1=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical wherein; R2=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclic radical or acyl group; R3=hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclic radical.
Cancer is one of underlying cause of death of humans and animals.Have every year the millions of people to be diagnosed as in the world and suffer from cancer, the major part of these philtrums is died from cancer subsequently.Although done very big effort, cancer still belongs to the disease that is difficult to treat.Urgent need to the effective antitumor medicine can not stop.
The soil organism is the tradition source that is used for the bioactive substance of pharmacy and soil chemistry industry.A nearest discovery is the commercialization that the assembly of the nematicide-antibacterial of soil existence is used as the biocontrol agent of harmful insect.A key character of this biocontrol agent is that the bacterial symbiont (Xenorhabdus kind or polished rod shape strain) of nematicide can produce the bioactive metabolites of wide range, and some chemical compounds in these special compounds have been separated, have defined, illustrated its structure (Fors and Nealson, 1996).In the chemical compound that these are defined, having several is dithia cyclopenta 2-pyrrolidinone derivatives.Dithia cyclopenta pyrrolidone is isolating in the streptomyces of the forties at first, and since then, also separates from other organism.These chemical compounds comprise aureothricin, thiolutin, 6-acetamido-1,2-dithiolo[4,3-b and xenorhabdins (Hamao etc., 1948; Eisenman etc., 1953; Celmer and Solomons, 1995; Von Daehne etc., 1969; Mclnerney etc., 1991).These chemical compounds have antimicrobial acivity to microorganism on a large scale.Recently, also from the bacterial cultures of Xenorhabdus kind, found to be called the new antimicrobial material (Webster etc., 1996) of xenorxides.To continually developing of the latent effect of the metabolite of these Xenorhabduses, found that xenorxides, xenomins and dithia cyclopenta pyrrolidone have very high activity to animal and human's cancerous cell, this also is a theme of the present invention.
When zooblast is subjected to the different chemical factor affecting, can stands various enzymatics variations and biochemistry usually and change.For example, when zooblast is subjected to the attack of carcinogen, can start many enzymatics and biochemical activity, the activity that some of them are activated can detect by experiment.In dithia cyclopenta pyrrolidone and derivant thereof, thiolutin is to have obtained one of broad research person.Thiolutin can suppress RNA polymerase synthetic (Jimenez etc., 1973 in the yeast; Tipper, 1973), have the film stabilizing active and can suppress the platelet aggregation (Yasuyuki etc., 1980) of rat.Report (Menta and Moon, 1991 are arranged; Sharma etc., 1994; What Arnold etc., 1995) thiolutin suppressed that the active startup of some these classes may be with the mammalian cell of contact carcinogen is carcinogenic relevant.This prompting thiolutin may participate in transcellular initial or pre-cancer cell to the development of malignant cancer cell.Yet this activity is not determined by experiment.Though the research of dithia cyclopenta pyrrolidone has constantly been carried out about 50 years, never relevant thiolutin and other dithia cyclopenta pyrrolidone has been estimated the active anticancer of mammalian cell so far and reported.Recently found Xenorxides and xenomins, and do not had report in the prior art about their active anticancer.
Though chemical compound of the present invention can obtain precursor compound by chemosynthesis from microorganism.Be used for organism of the present invention and comprise the Bai Shi Xenorhabdus, it is a kind of symbiotic bacteria relevant with the entomopathogenicity nematicide.From Britain, Colombia, Canadian soil, collected and be used for Bai Shi Xenorhabdus of the present invention and nematicide symbiont steinernema feltiae thereof.In brief, infect the last instar larvae Galleria mellonella of big wax moth with the speed of 25IJs/ larva with the infected children of guarantor (IJ) nematicide that has Bai Shi Xenorhabdus A21 strain.After 24-48 hour, the insect larvae of death is immersed in carries out surface sterilization in 95% ethanol, and calcination.Corpse is carried out aseptic dissection, hemolymph is carried out streak culture in agar culture medium, and cultivate in the room temperature lucifuge.In 1 liter of distilled water, this agar culture medium has following composition: beef extract 3g peptone 5g bromthymol blue 0.025g2,3,5-triphenyltetrazolium 0.04g agar 15g was 121 ℃ of sterilizations 15 minutes.
The rudimentary form that keeps resulting Bai Shi Xenorhabdus, and every 14 days to its cultivation of going down to posterity.For self-consistentency, the 14% sucrose freeze-dried powder that usually will be stored in-20 ℃ antibacterial is used as the initial substance of cultivating.The culture of Bai Shi Xenorhabdus A21 strain has the characteristic of tabulation 1 down and table 2, and culture can obtain chemical compound of the present invention thus:
The biochemical characteristic of table 1. Bai Shi Xenorhabdus A21 strain
*+ the positive;-feminine gender.
| The all hair cells of Gram-reaction cell size (μ m) mobility | - *5.3×2.2 + + |
| Chromogenesis catalase oxidase urase lecithinase lipase (Tween 80) | Yellow---++ |
The utilization of table 2. acid product and the carbon source that obtains by Bai Shi Xenorhabdus A21 strain
*+ the positive; +/-: the weak positive;-feminine gender.
| Acid product * | The utilization of carbon source |
| D-R+/-aesculin-D-Fructose+D-galactolipin-D-Glucose+inositol+/-synanthrin-D-lactose-D-Maltose+D-mannital-D-MANNOSE+D-raffinose-D-D-sorbite+/-L-sorbose-D-wood sugar- | Asparagine+cystine-glycine-tyrosine+nicotinic acid-ethanol-methyl alcohol-inositol+/-mannose+D-galactolipin-D-Glucose+D-lactose-D-mannital-D-D-sorbite-ribose+ |
These characteristics and Akhurst, R.J. and N.E.Boemare (1988) are consistent to the description of Bai Shi Xenorhabdus, thus, have determined the homogeneity of organism Bai Shi Xenorhabdus.According to budapest treaty therefrom this bacterial strain of isolated The compounds of this invention leave American type culture collection (ATCC) in, Rochville, MD, preserving number are ATCC55743.
The cultivation of microorganism Bai Shi Xenorhabdus can obtain bioactive substance xenomins, xenorxides and dithia cyclopenta pyrrolidone.For example, can be under about 25 ℃, deep layer aerobic conditions with the Bai Shi Xenorhabdus, in moisture Nutrient medium, cultivate (fermentation), this culture medium contains assimilable carbon (carbohydrate) source and nitrogenous source, thereby obtains xenomins, xenorxides and dithia cyclopenta pyrrolidone.This fermentation can reach about 48-96 hour, finally forms these chemical compounds, and can separate these chemical compounds, purification then from fermentation medium.
After fermentation is finished, the meat soup that is fermented can be filtered or centrifugal, the pH of filtrate be transferred to 7.0, perhaps maintain the original state by adding hydrochloric acid.Use then not and this filtrate of the blended organic solvent extraction of water, for example with ethyl acetate or this filtrate of chloroform extraction.Under vacuum (30 ℃ according to appointment), combined organic layer (as mixing ethyl acetate or chloroform extract) can be condensed into a kind of oily residue.This oily residue can be mixed with a small amount of organic solvent, and on silicagel column, carry out chromatography.After the sampling, chloroform or other organic solvent can be used for this biologically-active moiety of eluting.By high performance liquid chroma-tography (HPLC), can be further purified this biologically-active moiety with organic and/or aqueous solution.
In the conventional cultivation, the main compound that is produced by the Bai Shi Xenorhabdus is a dithia cyclopenta pyrrolidone, and the formation amount of xenorxides and xenomins is relative less.Perhaps, can from other microorganism, prepare dithia cyclopenta pyrrolidone by the combination of chemical method and/or two kinds of methods.
By the biological or chemical method can be respectively be that xenorxides and xenomins transform from its corresponding dithia cyclopenta 2-pyrrolidinone derivative with the monoxide and the dioxide of corresponding dithia cyclopenta pyrrolidone, and corresponding dithia cyclopenta pyrrolidone is isolating from the Bai Shi Xenorhabdus.Adopt biological method, the culture broth of Bai Shi Xenorhabdus can be filtered or centrifugal, this meat soup has corresponding dithia cyclopenta 2-pyrrolidinone derivative.Cell-free filtrate and air Long contact time one thoughtful one month can be stirred under room temperature or other temperature simultaneously or do not stir.This method can make the corresponding dithia cyclopenta of all or part 2-pyrrolidinone derivative be oxidized to xenomins and xenorxides.Can obtain xenorxides and xenomins with the corresponding dithia cyclopenta of chemical method oxidation 2-pyrrolidinone derivative.Can in mixture, add oxidant such as permonosulphuric acid potassium and potassium bicarbonate then with pure dithia cyclopenta 2-pyrrolidinone derivative or the dissolving of its mixture in the mixture of acetone and water.Make more than this mixture reaction a few minutes to 1 hour.Reactant mixture is mixed with water, and use organic solvent extraction.With extract merging, drying, and by column chromatography or high performance liquid chroma-tography purification, thereby respective x enorxides and xenomins obtained.From different microorganisms, can obtain the other monoxide and the dioxide of dithia cyclopenta pyrrolidone, and can prepare by chemosynthesis and/or the combination by biological method and chemical method, and have several examples disclose (Takahashi, etc., 1995; Fujimoto, etc., 1996).
Chemical compound of the present invention comprises dithia cyclopenta pyrrolidone, its corresponding monoxide such as xenomins, its corresponding dioxide such as xenorxides and salt thereof.Term used herein " salt " is meant acidity and/or basic salt, it is formed by inorganic and/or organic bronsted lowry acids and bases bronsted lowry, the acid that is fit to comprises example hydrochloric acid, sulphuric acid, nitric acid, benzenesulfonic acid, acetic acid, maleic acid, tartaric acid etc., and these acid all are pharmaceutically acceptable.To those skilled in the art, be to select the salt that is fit to as everyone knows according to physics and chemical stability, flowable, hygroscopicity and dissolubility.Preferred pharmaceutically acceptable salt, especially when The compounds of this invention is used as medicine, other salt that can be used for processing these chemical compounds or non-medicine type purposes also can be considered.Antitumor agent and uses thereof.
The present invention relates to contain the pharmaceutical preparation of active component or its pharmaceutically acceptable salt of these chemical compounds.Those skilled in the art can select dosage form, administering mode and dosage.Adult's typical daily dose is about 2 for about 2.5mg-, 000mg/ days.Can for example oral, non-intestinal or topical to the mammal people.
When these compound or its salts are used for treating, can they are individually dosed, perhaps dosage form administration to be fit on the medicine, said preparation also contains one or more common vectors except that containing active component.According to the character and/or the route of administration of disease, the present composition can be prepared by known method.
The example of pharmaceutical composition comprises any solid (tablet, pill, capsule, granule, powder etc.) or liquid (solution, suspension or Emulsion) compositions that is suitable for oral, part or parenterai administration, and they can contain pure compound or its salt or combine with any carrier or other medicines reactive compound.These compositionss should be aseptic when parenterai administration.
The therapeutic combination of the present invention that the drug substance that uses the present technique field to obtain can be easy to be used as the antitumor agent of the disease for the treatment of the animal and human is prepared into this unit dosage forms, also can prepare by conventional method.Can select the solid or liquid excipient or the diluent that are fit to, prepare this compositions with method known to those skilled in the art.Use the generally acknowledged scheme of national cancer research meeting (NCI), what give that any The compounds of this invention and/or its have a pharmacologically active goes up compatible derivant with the physiology, all can be used for the animal or human who suffers from tumor disease is treated, these diseases are colon cancer, cervix uteri (cevercal) cancer, breast carcinoma, leukemia, pulmonary carcinoma, ovarian cancer, central nervous system's cancer, renal carcinoma, carcinoma of prostate etc. for example.Dosage is the characteristic according to tumor disease, related patient's type, and treatment type of comprise age, health and body weight, carrying out simultaneously and treatment number of times and treatment rate are determined.For instance, the dosage of the active component that is given is: by the every kg weighing machine of patient, and the about 200mg/kg of intravenous 0.1-; The about 500mg/kg of intramuscular 1-; With the about 1000mg/kg of oral 5-.Represent that with concentration the concentration content of active component is in the present composition: during local the use, active component accounts for the about 50%w/w of about 0.01-of compositions, the about 20%w/w of preferably about 1-; During parenterai administration, active component accounts for the about 50%w/v of about 0.05-of compositions, the about 20%w/v of preferably about 5-.The drug substance that uses the present technique field to obtain can be easy to the active component of the present invention as antitumor agent is prepared into this unit dosage forms, also can prepare by conventional method.
The preparation of the preparation A. selectivity dithia cyclopenta pyrrolidone of embodiment 1.xenorxides, xenomins and dithia cyclopenta pyrrolidone.
Up to now, report several dithia cyclopenta pyrrolidone, comprised aureothricin, thiolutin, 6-acetamido-1,2-dithiolo[4,3-b xenorhabdins and thiomarinol.Aureothricin is at first by report such as Umezawa (1948), by Celmer and Solomons (1955) with its structure full disclosure.Thiolutin is made by several strains, and these strains comprise grey yellowish pink streptoverticillium, and it can be from the bent type culture collection center (ATCC) of the U.S., Rockville, and MD obtains, and preserving number is ATCC33049.Thiolutin by chemosynthesis and 6-acetamido-1,2-dithiolo[4,3-b be by Schmidt and Geiger (1962), Hagio, and K. and Yoneda, N. (1974) and Stachel, H.D. etc. (1992) announce.The preparation of xenorhabdins has had report, and Mclnerney etc. (1991) and Li etc. (1995) have done comprehensive report.Other have dithia cyclopenta pyrrolidone ring other different chemical compounds preparation recently by Baggaley etc. (1994a, b) and Takahashi etc. (1994) open.Method described in can list of references by reference prepares and is used for dithia cyclopenta pyrrolidone of the present invention, and determines the structure of every kind of dithia cyclopenta 2-pyrrolidinone derivative according to NMR spectrum.Skilled pharmacists can use method as herein described, in addition, can obtain these dithia cyclopenta pyrrolidone from available existing material.When realizing these operations, those skilled in the art can adopt any suitable filtration, chromatography and other purification technique.For these technical staff of this area, realize that obviously the material of these operations and reagent can buy from chemical company, therefore relevant details is not described.B. prepare corresponding dioxide by microbial fermentation by dithia cyclopenta pyrrolidone.
Xenorxides: on the Eberbach gyratory shaker, shook 24 hours with 180rpm at 25 ℃ of cultures with the Bai Shi Xenorhabdus.2, in the 000ml flask, this bacterial cultures of 100ml is added in the 900ml trypticase soya broth beginning bacterial fermentation.At 25 ℃ this flask placed and to carry out lucifuge on the gyratory shaker and cultivate.After 96 hours, immediately with culture centrifugal (12,000g, 20 minutes, 4 ℃) with the preparation bacterial cell.Then with this acellular meat soup of ethyl acetate extraction 4 times.With these mixed extracts of anhydrous sodium sulfate drying, pass through filter paper filtering again.Below 30 ℃, in the vacuum filtrate is concentrated, obtain brown oil on rotary evaporator.After repeating above-mentioned experiment 10 times, obtain about 3g grease.Then crude extract is installed on silica gel (200g silica gel 60,40cm * 5cm, EM Sinence, Darmstadt, the Germany) chromatographic column.Go out xanchromatic biologically-active moiety with ether or eluent ethyl acetate.Then with this biologically-active moiety at C18 preparative column (Spherisorb 10 (ODS (1)), 250 * 10mm, 10 micro, Phenomenex, Torrance, CA) upward (the medium degree of 10% acetonitrile in water 5 minutes increased to 85% acetonitrile then gradually in 35 minutes with 2.5ml/ branch, follow procedure, Deng degree 5 minutes, in 2 minutes, subtract again and get back to 10%) carry out HPLC.In 254nm monitoring eluate.33.6 minute the time eluting go out XENORXIDE 1 (about 0.3mg/l culture broth), after this eluting goes out XENORXIDE 2 (about 0.2mg/l) in the time of 35.2 minutes.C. prepare corresponding monoxide by microbial fermentation by dithia cyclopenta pyrrolidone.
Xenomins; For purification xenomins, cultivate identical with xenorxides with the condition of extracting.After the extraction, as eluent, handle the crude extract that is concentrated by silica gel column chromatography with ethyl acetate.After eluting goes out the less bioactive substance of polarity, can obtain the bigger biologically-active moiety of polarity with methanol-eluted fractions.Concentrate the bigger biologically-active moiety of this polarity under vacuum, separate by the C18 chromatographic column, at first water is used aqueous 25% methanol, 50% methanol, 75% methanol then as eluent, uses pure methanol at last.Most of biologically-active moieties are with aqueous 75% methanol-eluted fractions.Then this biologically-active moiety is concentrated, and at C18 preparative column (Spherisorb 10 (ODS (1)), 250 * 10mm, 10 micro, Phenomenex, Torrance CA) goes up with 2.0ml/ branch, follow procedure (the medium degree of the 30%MeCN in water 1 minute, in 24 minutes, increase to 70%MeCN then gradually, degree of grade 5 minutes) carry out HPLC.In 254nm monitoring eluate.Collect active peak 1 (25.4 minutes) and peak 2 (25.8 minutes).Concentrate active peak 1, and with 60% ethyl acetate in the dichloromethane as eluent, further separate by preparing silica gel tlc, thereby obtain xenomin 1 (Rf=0.32).Concentrate active peak 2, and with 60% ethyl acetate in the dichloromethane as eluent, further separate by preparing silica gel tlc, thereby obtain xenomin 2 (Rf=0.31).D. prepare xenorxides by biotransformation by its corresponding dithia cyclopenta 2-pyrrolidinone derivative.
Obtain acellular meat soup with above-mentioned same method, to room temperature, store 3-6 week at 4 ℃ then.This moisture meat soup of reuse ethyl acetate extraction separates mixed extract with above-mentioned same method.Eluting goes out XENORXIDE 1 (2mg/l) in the time of 33.6 minutes, and eluting goes out XENORXIDE 2 (1.5mg/l) in the time of 35.2 minutes.E. prepare corresponding dioxide by chemical oxidation by dithia cyclopenta pyrrolidone.
With 152mg 6-(hexanamido)-4-methyl-4,5-dihydro-1,2-dithia cyclopenta (dithiolo) [4,3-b] pyrroles-5-ketone (XN1) is dissolved in the mixture of 20ml acetone and 15ml water, with ice it is cooled to 0 ℃ then.In the time of 0 ℃, permonosulphuric acid potassium (510mg) is added in this solution.Reactant mixture was stirred 1 hour at 0 ℃.Under 0 ℃, the saturated solution of 5ml potassium bicarbonate is added in the reactant mixture then, simultaneously continuous stirring half an hour.After adding entry, with this reactant mixture of ethyl acetate extraction 3 times.Merge these extracts, dry on Na2SO4, evaporation obtains crude product, uses hexane then: ethyl acetate (2: 1), be further purified through silica gel column chromatography, thereby obtain pure xenorxide 1 (78mg, 51% productive rate).Similarly, by 6-(5 '-methyl hexanamido)-4,5-dihydro-1,2-dithia cyclopenta [4,3 ,-b] pyrroles-5-ketone can prepare xenorxide 3, and productive rate is 50%.The evaluation of embodiment 2. active component
On Bruker WM400 spectrometer, in CDCl3, write down NMR spectrum, use remaining CDCl3 (～7.25) as interior mark.In the Hewlett-Packrad 5985B GC/MS system with the 70eV operation, using in the same way, probe obtains Low Resolution Mass Spectra.On Kratos MS80 instrument, write down high resolution mass spectrum.With Perkin-Elmer 599B spectrometer infrared spectrum is recorded as clean film on Nacl.(employed abbreviation is as follows: the EI=electron collision, and the M=molecular ion, the t=triplet, the J=coupling constant, the Hz=hertz, d=is bimodal, m=multiplet, bs=broad peak).
6-(acetylamino)-4-methyl-4,5-dihydro-1,2-dithia cyclopenta [4,3 ,-b] pyrroles-5-ketone (thiolutin) be (XN0):
1HNMR (DMSO-d
6) δ 2.05 (3H, s), 3.92 (3H, s), 7.19 (1H, s) and 9.85 (1H, broad peaks); EIMS m/e228 (M
+), 186.
6-(hexanamido)-4-methyl-4,5-dihydro-1,2-dithia cyclopenta [4,3 ,-b] pyrroles-5-ketone (XN1):
1HNMR (CDCl
3) δ 0.90 (3H, t, J=6.9Hz), 1.35 (4H, m), 1.70 (2H, m), 2.35 (2H, t, J=7.4Hz), 3.35 (3H, s), 6.63 (1H, s) and 7.43 (1H, broad peaks); EIMS m/e 284 (M
+), 186.
6-(5 '-methyl hexanamido)-4,5-dihydro-1,2-dithia cyclopenta [4,3 ,-b] pyrroles-5-ketone (XN3):
1HNMR (CDCl
3) δ 0.89 (6H, d, J=6.6Hz), 1.24 (3H, m), 1.70 (2H, m), 2.32 (2H, t, J=7.6Hz), 6.74 (1H, s), 7.44 (1H, broad peaks) and 7.94 (1H, broad peaks); EIMS m/e 284 (M
+), 172.
XENORXIDE 1 (XO1): EIMS:317 (2), 316 (M
+, 13), 220 (9), 219 (9), 218 (100), 186 (23), 154 (16), 99 (40), 71 (39); HRMS:316.0555 (C
12H
16N
2O
4S
2Value of calculation: 316.0551,20), 217.9824 (C
6H
6N
2O
3S
2Value of calculation: 217.9820,100), 154.0197 (C
6H
6N
2The value of calculation of OS: 154.0201,16); IR (KBr): 3448,3298,3275,1720,1686,1654,1637,1560,1522,1310,1139,551 cm
-1 1HNMR (CDCl
3) δ: 7.56 (1H, bs, CO-NH), 6.35 (1H, s, H-3), 3.20 (3H, s, N-Me), 2.38 (2H, t, CO-CH
2, J=7.4Hz), 1.67 (2H, m, CH
2), 1.32 (4H, m, CH
2CH
2), 0.89 (3H, t, J=7.0Hz);
13CNMR (CDCl
3) δ: 171.6 (s, CON), 164.7 (s, CO), 145.4 (s, C
7), 121.3 (s, C
6), 116.2 (s, C8), 109.2 (d, C
3), 36.4,31.2,27.8,24.6,22.3,13.8.
XENORXIDE?2(XO2)：EIMS：330(M
+，10)，218(100)；HRMS：330.0707(C
13H
18N
2O
4S
2
Value of calculation: 330.0708,18), 217.9829 (C
6H
6N
2O
3S
2Value of calculation: 217.9820,100), 154.0213 (C
6H
6N
2The value of calculation of OS: 154.0201,16); IR (KBr): 3438,3298,1719,1686,1654,1637,1560,1522,1400,1310,1142,551 cm
-1 1HNMR (CDCl
3) δ: 7.56 (1H, bs, CO-NH), 6.35 (1H, s, H-3), 3.20 (3H, s, N-Me), 2.36 (2H, t, CO-CH
2, J=7.4Hz), 1.67 (2H, m, CH
2), 1.2-1.6 (1H, m, CH), 1.22 (2H, m, CH
2), 0.89 (6H, d, J=6.6Hz); Different NOE tests the NOE effect between the peak value that has shown 6.35ppm and 3.20ppm;
13CNMR (CDCl
3) δ: 171.6 (s, CON), 164.7 (s, CO), 145.4 (s, C
7), 121.3 (s, C
6), 116.2 (s, C
8), 109.2 (d, C
3), 38.2 (t, CH
2), 36.7 (t, CH
2), 28.0 (q, CH
3), 27.8 (d, CH), 22.8 (t, CH
2), 22.4 (q, CH
3).
XENORXIDE?3(XO3)：EIMS：316(M
+，7.5)，218(9)，204(65)185(7)，172(15)，105(25)，95(95)，69(100)，43(70)；
1HNMR(CDCl
3)δ：10.10(1H，bs)，9.32(1H，bs)，6.85(1H，s，H-3)，2.53(2H，t，CO-CH
2，J＝7.5Hz)，1.66(2H，m，CH
2)，1.58(1H，m)，1.21(2H，m，)，0.87(6H，d，J＝6.6Hz).
Xenomin 1 (XM1): EIMS:300 (M
+, 13), 202 (36), 186 (44), 185 (41), 85 (62), 69 (100); HRMS:300.0605 (C
12H
16N
2O
3S
2Value of calculation: 300.0602,12), 201.9871 (C
6H
6N
2O
2S
2Value of calculation: 201.9871,30);
1HNMR (CDCl
3) d:7.52 (1H, bs.CO-NH), 6 46 (
1H, s, H-3) .3.30 (3H, s.N-Me), 2.49 (2H, t, CO-CH
2, J=7.4Hz), 1.79 (2H, m.CH
2), 1.41 (4H.m, CH
2-CH
2), 0.90 (3H, t, J=6.9).
Xenomin 2 (XM2): EIMS:314 (M
+, 21), 218 (15), 202 (59), 187 (18), 186 (98), 185 (73), 69 (100); HRMS:314.0759 (C
13H
18N
2O
3S
2Value of calculation: 314.0759,12), 201.9871 (C
6H
6N
2O
2S
2Value of calculation: 201.9871,45);
1HNMR (CDCl
3) d:7.43 (1H, bs, CO-NH), 6.46 (
1H, s, H-3), 3.30 (3H, s, N-Me), 2.48 (2H, t, CO-CH
2, J=7.6Hz), 1.71 (2H, m, CH
2), 1.29 (3H, m, CH and CH
2), 0.88 (6H, d, J=7.0). embodiment 3. is as the dithia cyclopenta pyrrolidone of antitumor agent, corresponding monoxide and dioxide.
Can confirm a kind of active anticancer of special compound by the standard test method.American National cancer research meeting (NCI) is normally used, be used to prove that a kind of method of effect of chemical compound is according to LC50.LC50 is meant that this chemical compound kills the concentration of half cancerous cell population.Those skilled in the art use this algoscopy usually, and can be illustrated in the active anticancer in the mammal.The cancerous cell of experimental animal can obtain from ATCC, NCI and other tissue.Use the standard NCI method make an amendment slightly, in the cell culture of various people's cancerous cell, measured the active anticancer (seeing the following form) of The compounds of this invention.Skehan etc. (1990) are illustrated this method.In brief, cancerous cell is grown in the RPMI-1640 culture medium that contains glutamine and 10% hyclone, and keep from exponential phase and to gather in the crops cancerous cell the culture medium.The cell of being gathered in the crops is counted, and it is dispersed in the copy type 96 hole culture plates that volume is 180 μ l, wherein the cell density in each hole reaches 2,500 cells/well.At 37 ℃ with about 4 hours of these cell settlements.The culture medium that then 20 μ l is contained this test compound adds in each hole the concentration of the final test compound that obtains being fit to.Then with this test board 37 ℃ of cultivations.In each hole, join in 50 μ l, the 50% cold trichloroacetic acid cultivate after, stop this test.Cell is fixed 1 hour at 4 ℃, then with tap water flushing 5 times.The air-dry dish that is rinsed, and with being dissolved in (wt/ volume) the sulforhodamine B of 0.4% in 1% acetic acid (SRB) dyeing 30 minutes.When dyeing finishes, remove SRB, will coil quick rinsing 5 times with 1% acetic acid.After the rinsing, will coil air-dryly, in each hole, add 100 μ l, 10 mM, three alkali (tris base) (pH 10.5) with dissolving and the bonded dyestuff of cell.Place dish on the gyratory shaker and shook (100 rpm) 10 minutes.At last, will coil at 570nm and carry out reading with the microtitration plate reader.The chemical compound of all tests all has very strong anti-tumor activity (seeing the following form) to these cancerous cell.
Anti-tumor activity:
| ??????????????????????????????????LC50(1 ??????????????????????????????????0-6M) | |||||||
| Cancerous cell | ??XN0 | ??XN1 | ?XN3 | ??XO1 | ?XO2 | ?XM1 | XM2 |
| HT29 | ??0.13 | ??0.11 | ??0.11 | ??0.22 | ?0.85 | ?0.47 | ?0.11 |
| MCF-7 | ??0.35 | ??0.56 | ??0.39 | ??0.89 | ?0.95 | ?0.47 | ?0.55 |
| Hela | ??0.31 | ??0.46 | ??0.32 | ??0.16 | ?0.13 | ?0.80 | ?0.21 |
| P388 | ??- * | ??- | ??- | ??0.66 | ?0.28 | ?- | ?- |
| NC1-H460 | ??- | ??- | ??0.03 | ??0.28 | ?0.22 | ?- | ?- |
| Sk-Mel-28 | ??- | ??- | ??0.24 | ??0.19 | ?0.73 | ?- | ?- |
| LNCap | ??- | ??- | ??- | ??0.54 | ?0.19 | ?- | ?- |
| DU-145 (prostate) | ??- | ??- | ??0.14 | ??1.80 | ?1.60 | ?- | ?- |
| UO-31 (renal carcinoma) | ??- | ??- | ??0.18 | ??1.85 | ?6.0 | ?- | ?- |
| SF-295 (CNS cancer) | ??- | ??- | ??0.04 | ??1.58 | ?2.12 | ?- | ?- |
*Not test (N.T.).
From the embodiment of front and embodiment obviously as can be seen this paper invention is described and illustrates.Though top explanation comprises many particularitys, should not regard these as limiting the scope of the invention, and should be considered as embodiment preferred.Therefore, we should not determine protection scope of the present invention according to the embodiment that is exemplified, and should decide according to appending claims and the legal requirement that is equal to thereof.
The list of references 1.Akhyrst that quotes, R.J. and N.E.Boemare, 1988. " gene microorganism magazine " 134 volumes, 1835-1845.2.Amold, J.T. etc., 1995. " cancer research " 55:537-543.3 Baggaley, K.H. etc., 1994a.WO 94/26750.4 Baggaley, K.H. etc., 1994b.WO 94/28001.5.Celmer, W.D. and I.A.Solomons 1995. " American Chemical Society's magazine " 77:2861-2865.6.Eisenman, W. etc., 1953. " antibiotic and chemotherapy " 3:385-392.7.Forst, S. and K.Nealson, 1996. " microbe research " 60:21-43.8 Fujimoto, K. etc., 1996.WO 96/23795.9.Hagio, K. and Yoneda, N.1974. " Japanization association communique " 47:1484-1489.10.Jimenez, A. etc., 1973. " antimicrobial chemotherapy " 729-738.11.Li, etc., 1995. " environmental microorganism application " 61:4329-4333.12.Li, J. etc., 1995. " natural product magazine " 58:1081-1085.13.Mclnerney, B.V. etc., 1991. " natural product magazine " 54:774-784.14.Menta R.G. and R.C.Moon, 1991. " anticancer research " 11:593-596.15.Monks etc., 1991. " national cancer research meeting magazine " 83:757-766.16.Ninomiya, Y.T. etc., 1980. " chemicals communique " 28:3157-3162.17.Sharma, S. etc., 1994. " cancer research " 54:5848-5855.18.Shroeder etc., 1981. " medical chemistry magazine " 24:1078-1083.19.Shehan, P. etc., 1990. " national cancer research meeting magazine " 82:1107-1118.20.Stachel, H.D. etc., 1992. " Liebigs chemistry annual " 473-480.21.Takahashi S. etc., 1994. United States Patent (USP)s 5,292,892.22.Takahashi S. etc., 1995. United States Patent (USP)s 5,399,711.23.Tipper D.J.1973. " bacteriology's magazine " 116:245-156.24.Umezawa, H. etc., 1948. " Japan medical science magazine " 1:512-517.25 Webster etc., WO:96/32396.26.von Daehne, W. etc., 1969. " antibiotic magazine " 22:233-235.
Claims (18)
1. pharmaceutical composition that is used for the treatment of tumor disease, it comprises chemical compound or its pharmaceutically acceptable salt with following structural, and pharmaceutical carrier or diluent,
Wherein R1=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical; R2=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical, acyl group; R3=hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclic radical.
2. pharmaceutical composition that is used for the treatment of tumor disease, it comprises chemical compound or its pharmaceutically acceptable salt with following structural, and pharmaceutical carrier or diluent,
Or
R wherein
1=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical; R
2=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical, acyl group; R
3=hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclic radical.
3. pharmaceutical composition that is used for the treatment of tumor disease, it comprises chemical compound or its pharmaceutically acceptable salt with following structural, and pharmaceutical carrier or diluent,
Or
R wherein
1=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical; R
2=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical, acyl group; R
3=hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclic radical.
4. pharmaceutical composition that is used for the treatment of tumor disease, it comprises the described chemical compound of claim 1 or its pharmaceutically acceptable salt, and pharmaceutical carrier or diluent, wherein R
1=hydrogen; R
2=acyl group; R
3=hydrogen, methyl.
5. pharmaceutical composition that is used for the treatment of tumor disease, it comprises the described chemical compound of claim 2 or its pharmaceutically acceptable salt, and pharmaceutical carrier or diluent, wherein R
1=hydrogen; R
2=acyl group; R
3=hydrogen, methyl.
6. pharmaceutical composition that is used for the treatment of tumor disease, it comprises the described chemical compound of claim 3 or its pharmaceutically acceptable salt, and pharmaceutical carrier or diluent, wherein R
1=hydrogen; R
2=acyl group; R
3=hydrogen, methyl.
7. pharmaceutical composition that is used for the treatment of tumor disease, it comprises the described chemical compound of claim 1 or its pharmaceutically acceptable salt, and pharmaceutical carrier or diluent, wherein R
1=hydrogen; R
2=have an acyl group of 1-10 carbochain of straight or branched; R
3=hydrogen or methyl.
8. pharmaceutical composition that is used for the treatment of tumor disease, it comprises the described chemical compound of claim 2 or its pharmaceutically acceptable salt, and pharmaceutical carrier or diluent, wherein R
1=hydrogen; R
2=have an acyl group of 1-10 carbochain of straight or branched; R
3=hydrogen or methyl.
9. pharmaceutical composition that is used for the treatment of tumor disease, it comprises the described chemical compound of claim 3 or its pharmaceutically acceptable salt, and pharmaceutical carrier or diluent, wherein R
1=hydrogen; R
2=have an acyl group of 1-10 carbochain of straight or branched; R
3=hydrogen or methyl.
10. method that suppresses mammal tumor growth, it comprises that patient to this treatment of needs uses chemical compound or its pharmaceutically acceptable salt of structural formula shown in effective antitumor amount following, and pharmaceutical carrier or diluent,
R wherein
1=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical; R
2=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical, acyl group; R
3=hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclic radical.
11. a method that suppresses mammal tumor growth, it comprises that patient to this treatment of needs uses chemical compound or its pharmaceutically acceptable salt of structural formula shown in effective antitumor amount following, and pharmaceutical carrier or diluent,
Or
R wherein
1=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical; R
2=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical, acyl group; R
3=hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclic radical.
12. a method that suppresses mammal tumor growth, it comprises that patient to this treatment of needs uses chemical compound or its pharmaceutically acceptable salt of structural formula shown in effective antitumor amount following, and pharmaceutical carrier or diluent,
Or
R wherein
1=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical; R
2=hydrogen, replacement or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclic radical, acyl group; R
3=hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclic radical.
13. a method that suppresses the mammal tumor growth, it comprises that the patient to this treatment of needs uses the described chemical compound of claim 10 or its pharmaceutically acceptable salt of effective antitumor amount, and pharmaceutical carrier or diluent, wherein R
1=hydrogen; R
2=acyl group; R
3=hydrogen, methyl.
14. a method that suppresses the mammal tumor growth, it comprises that the patient to this treatment of needs uses the described chemical compound of claim 11 or its pharmaceutically acceptable salt of effective antitumor amount, and pharmaceutical carrier or diluent, wherein R
1=hydrogen; R
2=acyl group; R
3=hydrogen, methyl.
15. a method that suppresses the mammal tumor growth, it comprises that the patient to this treatment of needs uses the described chemical compound of claim 12 or its pharmaceutically acceptable salt of effective antitumor amount, and pharmaceutical carrier or diluent, wherein R
1=hydrogen; R
2=acyl group; R
3=hydrogen, methyl.
16. a method that suppresses the mammal tumor growth, it comprises that the patient to this treatment of needs uses the described chemical compound of claim 10 or its pharmaceutically acceptable salt of effective antitumor amount, and pharmaceutical carrier or diluent, wherein R
1=hydrogen; R
2=have an acyl group of 1-10 carbochain of straight or branched; R
3=hydrogen or methyl.
17. a method that suppresses the mammal tumor growth, it comprises that the patient to this treatment of needs uses the described chemical compound of claim 11 or its pharmaceutically acceptable salt of effective antitumor amount, and pharmaceutical carrier or diluent, wherein R
1=hydrogen; R
2=have an acyl group of 1-10 carbochain of straight or branched; R
3=hydrogen or methyl.
18. a method that suppresses the mammal tumor growth, it comprises that the patient to this treatment of needs uses the described chemical compound of claim 12 or its pharmaceutically acceptable salt of effective antitumor amount, and pharmaceutical carrier or diluent, wherein R
1=hydrogen; R
2=have an acyl group of 1-10 carbochain of straight or branched; R
3=hydrogen or methyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002212237A CA2212237A1 (en) | 1997-09-05 | 1997-09-05 | Novel antineoplastic agents |
| CA2,212,237 | 1997-09-05 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98810328A Division CN1276723A (en) | 1997-09-05 | 1998-09-03 | Dithiolopyrrolones and their corresponding monoxides and dioxides as antineoplastic agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1360891A true CN1360891A (en) | 2002-07-31 |
Family
ID=4161181
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98810328A Pending CN1276723A (en) | 1997-09-05 | 1998-09-03 | Dithiolopyrrolones and their corresponding monoxides and dioxides as antineoplastic agent |
| CN01131401A Pending CN1360891A (en) | 1997-09-05 | 2001-09-06 | Dithiolane amylene hepyrroleketone and its relative monoxide and dioxide using as antitumour agent |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98810328A Pending CN1276723A (en) | 1997-09-05 | 1998-09-03 | Dithiolopyrrolones and their corresponding monoxides and dioxides as antineoplastic agent |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1009401A1 (en) |
| JP (1) | JP2001515861A (en) |
| CN (2) | CN1276723A (en) |
| AU (1) | AU759990B2 (en) |
| CA (1) | CA2212237A1 (en) |
| HK (1) | HK1046373A1 (en) |
| WO (1) | WO1999012543A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1238668A1 (en) * | 2001-03-09 | 2002-09-11 | Aventis Pharma Deutschland GmbH | Use of thiolutin dioxide and its derivatives in the manufacture of a medicament for the treatment of CNS disorders and a process for the preparation thereof |
| JP4530667B2 (en) * | 2002-03-26 | 2010-08-25 | ウェリケム バイオテック インコーポレーテッド | Novel dithiolopyrrolones with therapeutic activity |
| KR101377358B1 (en) * | 2006-09-29 | 2014-03-27 | 웰리켐 바이오 테크 인크. | Dithiolopyrrolones compounds and their therapeutical applications |
| CN101381371B (en) | 2007-09-05 | 2011-05-18 | 上海医药工业研究院 | Dithiolopyrrolones compounds and preparation method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1214130A (en) * | 1982-10-26 | 1986-11-18 | Stuart H. Rhodes | Xenorhabdin antibiotics |
| DE19513040A1 (en) * | 1995-03-29 | 1996-10-02 | Schering Ag | New borne esters, processes for their preparation and their pharmaceutical use |
| WO1996032396A1 (en) * | 1995-04-11 | 1996-10-17 | John Malcolm Webster | Xenorxides with antibacterial and antimycotic properties |
-
1997
- 1997-09-05 CA CA002212237A patent/CA2212237A1/en not_active Abandoned
-
1998
- 1998-09-03 AU AU90570/98A patent/AU759990B2/en not_active Ceased
- 1998-09-03 EP EP98942414A patent/EP1009401A1/en not_active Withdrawn
- 1998-09-03 CN CN98810328A patent/CN1276723A/en active Pending
- 1998-09-03 WO PCT/CA1998/000841 patent/WO1999012543A1/en active IP Right Grant
- 1998-09-03 JP JP2000510440A patent/JP2001515861A/en active Pending
-
2001
- 2001-09-06 CN CN01131401A patent/CN1360891A/en active Pending
-
2002
- 2002-11-02 HK HK02107990.3A patent/HK1046373A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN1276723A (en) | 2000-12-13 |
| JP2001515861A (en) | 2001-09-25 |
| AU759990B2 (en) | 2003-05-01 |
| CA2212237A1 (en) | 1999-03-05 |
| WO1999012543A1 (en) | 1999-03-18 |
| AU9057098A (en) | 1999-03-29 |
| HK1046373A1 (en) | 2003-01-10 |
| EP1009401A1 (en) | 2000-06-21 |
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