CN101921303A - Benzisoselenazolone difluorocytidine compound as well as preparation method and application thereof - Google Patents
Benzisoselenazolone difluorocytidine compound as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN101921303A CN101921303A CN200910086559XA CN200910086559A CN101921303A CN 101921303 A CN101921303 A CN 101921303A CN 200910086559X A CN200910086559X A CN 200910086559XA CN 200910086559 A CN200910086559 A CN 200910086559A CN 101921303 A CN101921303 A CN 101921303A
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- CN
- China
- Prior art keywords
- compound
- deoxidation
- difluoro cytidine
- carcinoma
- ketone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 Benzisoselenazolone difluorocytidine compound Chemical class 0.000 title claims abstract description 43
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- LQICKZWUNRSEHI-BNHYGAARSA-N 4-amino-1-[(2r,3r,4s,5s)-5-[difluoro(hydroxy)methyl]-3,4-dihydroxyoxolan-2-yl]pyrimidin-2-one Chemical class O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](C(O)(F)F)O1 LQICKZWUNRSEHI-BNHYGAARSA-N 0.000 claims description 34
- 229910052760 oxygen Inorganic materials 0.000 claims description 34
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
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- 150000002367 halogens Chemical class 0.000 claims description 19
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a novel antitumor medicament, in particular a benzisoselenazolone difluorocytidine compound or a pharmaceutically acceptable salt or ester thereof as well as a preparation method and application thereof, wherein a benzisoselenazolone structure can identify selenocysteine residues in the activity center of thioredoxin reductase to generate the action of reversibly competitive inhibition and reserves the activity structure of 2'-deoxidization-2'2'-difluorocytidine. Therefore, the benzisoselenazolone difluorocytidine compound in the invention can selectively kill tumor cells, inhibit the growth of the tumor cells, and has the characteristics of high efficiency and low toxicity.
Description
Technical field
The present invention relates to a class new type antineoplastic medicine, relate in particular to a kind of Benzisoelenazolone difluoro cytidine compounds and preparation method thereof and its purposes.
Background technology
Nucleosides and analogue thereof have biologic activity widely, wherein, 2 '-deoxidation-2 ', 2 '-difluoro cytidine cytosine nucleoside analogs such as (Gemcitabine) has very strong anti-tumor activity, is the choice drug of present clinical prevention carcinoma of the pancreas.But the toxicity of such medicine is bigger, exists stronger bone marrow inhibition, thereby has influenced its popularity of using clinically.
Ribonucleotide reductase (RR) is as the synthetic indispensable enzyme of cell DNA, with the proper splitting and the abnormal division of cell confidential relation arranged all.Studies show that, RR unusually with the generation of tumour cell with shift closely relatedly, and in many tumour patients, exist than high expression level.And thioredoxin system provides needed electronics for the performance of Yeast Nucleic Acid reductase activity, therefore, the enzymic activity of RR has very important related with thioredoxin reductase, when showing as the thioredoxin reductase activity inhibited, the activity of Yeast Nucleic Acid reductase enzyme reduces (Ahmet Koc, Christopher K.Mathews.Thioredoxin is required forDeoxyribonucleotide pool maintenance during S phase.The Journal of BiologicalChemical, 2006,281 (22): 15058-15063), as shown in Figure 9.
2 '-deoxidation-2 ', 2 '-difluoro cytidine (Gemcitabine) is as the substrate analogue inhibitor of RR enzyme, its possible mechanism is after medicine enters human body, become activated diphosphate and triphosphate at endocellular metabolism, and in cell, build up, competitiveness is mixed the dna double chain, thereby synthetic (the Heinemann V that suppresses cell DNA, He stirs el LW, Grindey GB, Plunkett W.Comparison of thecellular pharmacokinetics and toxicity of 2,2-difluorodeoxycytidine and1-beta-d-arabino-furanosyl cytosine.Cancer Res, 1988; 48 (14): 4024-31).Wherein, the meta-bolites diphosphate can suppress the RR enzymic activity, makes the synthetic and necessary raw material deoxidation nucleoside triphosphate of reparation (dCTP) minimizing of DNA in the cell, thereby further suppresses the synthetic of DNA.2 '-deoxidation-2 ', the toxicity of 2 '-difluoro cytidine may be relevant with this mechanism of action, because diphosphate has not only suppressed the synthetic of tumour cell DNA, it is synthetic also can to influence quick value-added normal cell DNA simultaneously.Therefore, only strengthen or improve 2 '-deoxidation-2 ', 2 '-difluoro cytidine can not reduce its toxicity to the inhibition activity of ribonucleotide reductase.And, do not see 2 '-deoxidation-2 ', 2 '-difluoro cytidine modifier obviously reduces toxic report.
In addition, principle of pro-drug is applied to 2 '-deoxidation-2 ' widely, the transformation of 2 '-difluoro cytidine analogue, generate medicine with good pharmacokinetic property by preparation, reduce inactivation (the 2 '-deoxidation-2 ' in the drug transport process, 2 '-difluoro cytidine can be by the irreversible amine inactivation that takes off of the cytidine desaminase in the blood), thereby reduce dosage to reach the purpose (Robins that reduces toxic action, R.K.J.Med.Chem.1964,7,186, Darby, G.Antiviral Chem.Chemother.1995,6,54; Monnerjahn, C.; Konrad, M.ChemBiochem 2003,4, and 143; Townsend, L.B.Abstracts of Papers, 228th NationalMeeting of the American Chemical Society, Philadelphia, PA, USA, August 22-26,2004).Amidon is transformed into amino acid ester prodrug forms (Han, H.-K. with compound; Amidon, G.L.AAPS PharmSci 2000,2, E6; Denny, W.A.Eur.J.Med.Chem.2001,36,577), Wipf has reported that introducing polypeptide on the amino of compound has formed prodrug (Wipf, P.; Sekhar, V.Bioorg.Med.Chem.Lett.1991,1,745).Deyi Zhang etc. pass through primer aminoacyl etc. on the amino of compound.
Therefore, how by composition optimizes, reduce by 2 '-deoxidation-2 ', the toxicity of 2 '-difluoro cytidine analogue also keeps simultaneously even improves the problem that its antitumour activity becomes people's growing interest.
Summary of the invention
Because active performance of ribonucleotide reductase and thioredoxin reductase (TrxR) close association, and the generation of TrxR and tumour, development and apoptosis tight association, and in tumour high expression level, thereby, can be by suppressing the activity of the active inherent regulation reduction ribonucleotide reductase of thioredoxin reductase, to reach the purpose of attenuation synergistic.The present invention discovers, 1,2-two [1,2-benzisoxa selenazoles-3 (2H)-ketone] ethane (BBSKE) is thioredoxin reductase targeting type antitumor drug, wherein, the Benzisoelenazolone structure can be discerned the seleno-cysteine residue in thioredoxin reductase active centre, and produce a reversibly competitive inhibition, therefore, Benzisoelenazolone difluoro cytidine compounds provided by the present invention has fully utilized 2 '-deoxidation-2 ', and the antitumor agent structure of 2 '-difluoro cytidine and Benzisoelenazolone compounds are to the selectivity of TrxR, to realize that optionally the killing and wounding and restraining effect of tumour cell had characteristics of high efficiency and low toxicity.
The object of the present invention is to provide the novel Benzisoelenazolone difluoro cytidine compounds of a class or its pharmacy acceptable salt or its ester, described compound has the described structure of formula I-II:
Wherein, R
1Be selected from hydrogen, halogen, itrile group, C1-C6 alkyl, C1-C6 alkoxyl group, C1-C6 alkylthio, N (C1-C6 alkyl) 2, NH (C1-C6 alkyl), COOH ,-CORb, CONHRb, CONRcRd, SO3R, aryl, heteroaryl, cycloalkyl, heterocyclic radical, described group can be chosen wantonly by C1-C6 alkyl, C1-C6 alkoxyl group, halogen, itrile group, aryl, heteroaryl and replace, be preferably-H ,-CH3, halogen ,-OAc ,-OH, more preferably-H ,-CH3 ,-Cl ,-F ,-OAc ,-OH.
R
2Be selected from C
0-12Alkylidene group, phenylene, biphenylene, inferior triphenyl, inferior hexanaphthene, pentamethylene ,-RaSS Ra-,-(Ra O) n Ra-,-(CH2) (Ra O) 3Ra-,-Ra N (CH3) 2Ra-or-Ra NHRa-;
Ra is the C1-6 alkylidene group; Rb is H, C1-C6 alkyl, C1-C6 alkoxyl group; Rc, Rd independently are selected from H, C1-C6 alkyl or phenyl, or Rc, Rd form nitrogen heterocyclic ring or nitrogenous hetero-aromatic ring with the N that is connected;
R
3Be selected from-H,
N is 0-4;
Wherein, R
1' be selected from hydrogen, halogen, itrile group, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, N (C
1-C
6Alkyl)
2, NH (C
1-C
6Alkyl), COOH ,-COR
b, CONHR
b, CONR
cR
d, SO
3R, aryl, heteroaryl, cycloalkyl, heterocyclic radical, described group can be chosen wantonly by C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen, itrile group, aryl, heteroaryl replace, be preferably-H ,-CH3, halogen ,-OAc ,-OH, more preferably-H ,-CH3 ,-Cl ,-F ,-OAc ,-OH.
R
2' be selected from C
0-12Alkylidene group, phenylene, biphenylene, inferior triphenyl, inferior hexanaphthene, pentamethylene ,-R
aSS R
a-,-(R
aO)
nR
a-,-(CH
2) (R
aO)
3R
a-,-R
aN (CH
3)
2R
a-or-R
aNH R
a-;
R
aBe C
1-6Alkylidene group; R
bBe H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group; R
c, R
dIndependently be selected from H, C
1-C
6Alkyl or phenyl, or R
c, R
dForm nitrogen heterocyclic ring or nitrogenous hetero-aromatic ring with the N that is connected;
R
3' be selected from-H,
N is 0-4.
Further, the present invention preferably protects the Benzisoelenazolone difluoro cytidine compounds 1-22 of the described structure of table 1:
Title and the structural formula of table 1 compound 1-22
For clear statement protection scope of the present invention, the contriver is defined as follows following groups:
" C1-C6 alkyl " comprises the straight or branched low alkyl group with 1～6 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, tert-pentyl or hexyl etc.
" C1-C6 alkoxyl group " comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, uncle's pentyloxy or hexyloxy etc.
" C0-C12 alkylidene group " comprises the straight-chain alkyl-sub-with 0～12 carbon atom, is preferably the alkylidene group of 0-6 carbon atom, for example, and methylene radical, ethylidene, trimethylene, tetramethylene, pentamethylene or hexamethylene.
" phenylene, biphenylene, inferior triphenyl ", " inferior hexanaphthene, inferior pentamethylene " are meant the substituting group that contains two connecting keys, such as, phenylene comprises 1,2-phenylene, 1,3-phenylene, 1, the 4-phenylene, inferior hexanaphthene comprises 1,2-hexylidene, 1,3-hexylidene, 1, the 4-hexylidene, cyclopentylidene comprises 1,2-cyclopentyl or 1, the 3-cyclopentyl.
" aryl " comprises phenyl, naphthyl etc., and described aryl can have one or more (preferably 1～3) suitable substituents, for example halogen, itrile group, amino, C1-6 alkyl, C1-C6 alkoxyl group, list (or two or three) halos (rudimentary) alkyl etc.
Described " heteroaryl " be meant heteroatomic 5-unit's aromatic ring of comprising 1,2,3 or 4 such as nitrogen, oxygen or sulphur or 6 yuan of aromatic rings and with this class ring of aryl rings, cycloalkyl ring, heteroaryl ring or heterocycloalkyl ring condensed (for example benzothienyl, indyl), and comprise possible N-oxide compound.Described heteroaryl can be chosen wantonly and comprise that 1-4 substituting group, suitable substituents are selected from for example substituting groups such as halogen, itrile group, amino, C1-6 alkyl, C1-C6 alkoxyl group, list (or two or three) halos (rudimentary) alkyl;
" cycloalkyl " is meant 4-unit, 5-unit, the saturated or undersaturated carbocyclic ring of part of 6-unit or 7-unit, and described ring can be by for example replacements such as halogen, itrile group, amino, C1-6 alkyl, C1-C6 alkoxyl group, list (or two or three) halos (rudimentary) alkyl of suitable substituents.
" Heterocyclylalkyl " or " heterocycle " is meant 4-unit, 5-unit, the saturated or undersaturated ring of part of 6-unit or 7-unit, comprises 1-2 the heteroatoms such as nitrogen, oxygen and/or sulphur.Can have one or more (preferably 1～3) suitable substituents, for example, halogen, itrile group, amino, C1-6 alkyl, C1-C6 alkoxyl group, list (or two or three) halos (rudimentary) alkyl etc.
So-called " nitrogenous " heterocycle or hetero-aromatic ring refer to contain at least the ring of a N.
Of the present invention
The pharmaceutically acceptable salt of Benzisoelenazolone difluoro cytidine compounds of the present invention comprises its inorganic acid addition salt, any or its combination of organic acid adduct, for example, hydrochloride, hydrobromate, hydriodate, vitriol, nitrate, tosilate, mesylate, phosphoric acid salt, vitriol, perchlorate, acetate, trifluoroacetate, propionic salt, citrate, malonate, succinate, lactic acid salt, oxalate, tartrate, benzoate, magnesium salts or calcium salt, alkylbenzyldimethylasaltsum saltsum, piperidinium salt, the trialkyl amine salt, pyridinium salt, any or its combination of dimethylamine salt or diethyl amine salt.
The ester of Benzisoelenazolone difluoro cytidine compounds of the present invention is selected from any or its combination of amino acid ester, acetic ester, benzoic ether, dibenzoate, uncle's fourth oxygen manthanoate, two uncle's fourth oxygen manthanoate, polypeptide ester or amino acyl esters, is preferably any or its combination of amino acid ester, acetic ester, benzoic ether, dibenzoate, uncle's fourth oxygen manthanoate, two uncle's fourth oxygen manthanoate.
Another object of the present invention is to provide a kind of preparation method of Benzisoelenazolone difluoro cytidine compounds, comprise step 1-5, preparation technology as shown in Figure 1:
Wherein, R
1Be selected from hydrogen, halogen, itrile group, C1-C6 alkyl, C1-C6 alkoxyl group, C1-C6 alkylthio, N (C1-C6 alkyl) 2, NH (C1-C6 alkyl), COOH ,-CORb, CONHRb, CONRcRd, SO3R, aryl, heteroaryl, cycloalkyl, heterocyclic radical, described group can be chosen wantonly by C1-C6 alkyl, C1-C6 alkoxyl group, halogen, itrile group, aryl, heteroaryl and replace, be preferably-H ,-CH3, halogen ,-OAc ,-OH, more preferably-H ,-CH3 ,-Cl ,-F ,-OAc ,-OH;
R
2Be selected from C
0-12Alkylidene group, phenylene, biphenylene, inferior triphenyl, inferior hexanaphthene, pentamethylene ,-RaSS Ra-,-(Ra O) n Ra-,-(CH2) (Ra O) 3Ra-,-Ra N (CH3) 2Ra-or-Ra NHRa-;
Ra is the C1-6 alkylidene group; Rb is H, C1-C6 alkyl, C1-C6 alkoxyl group; Rc, Rd independently are selected from H, C1-C6 alkyl or phenyl, or Rc, Rd form nitrogen heterocyclic ring or nitrogenous hetero-aromatic ring with the N that is connected;
R
3Be selected from-H,
N is 0-4;
The reaction conditions of step 1-5 is:
Step 4 is that Fe is at rare CH
3In the COOH solution, stir;
Another object of the present invention is to provide a kind of pharmaceutical composition, described composition is made up of acceptable salt or its ester and pharmaceutically acceptable carrier on Benzisoelenazolone difluoro cytidine compounds or its pharmacology.
Further, acceptable salt or its ester on Benzisoelenazolone difluoro cytidine compounds of the present invention or its pharmacology in the composition: the weight ratio of auxiliary material is 0.001-99: 1-99, be preferably 0.001-90: 1-95, more preferably 0.001-80: 1-90 most preferably is 0.001-70: 1-85.
Further, in the composition on Benzisoelenazolone difluoro cytidine compounds of the present invention or its pharmacology weight percentage of acceptable salt or its ester be 1-99%, be preferably 5-95%, also be preferably 10-90%, more preferably 15-85% most preferably is 20-80%.
Composition of the present invention can be various formulation well known in the art.Be suitable for formulation of the present invention and can be oral preparations, external preparation or injection, be preferably oral preparations or injection.Described oral preparations is selected from inclusion preparation, dispersion agent, oral liquid, tablet, capsule, granule, dripping pill, pill, powder, syrup, mixture, distillate medicinal water, suspension agent, effervescent, paste, suspension, emulsion or medicinal tea; Be preferably inclusion preparation or dispersion agent; Preferred described suspension agent is selected from does outstanding agent or suspension; Described external preparation is selected from gelifying agent, paste, emplastrum, plaster, creme, ointment, liniment, lotion, suppository, basting agent or coagulates paste; Described injection is selected from injection (injection liquid), transfusion or freeze-dried powder etc.Can adopt preparation technique means well known in the art to prepare composition of the present invention.
Described pharmaceutically acceptable carrier is well known usual excipients or the auxiliary material that is used to prepare above-mentioned preparation, and vehicle that oral preparations or external preparation are commonly used or auxiliary material include but are not limited to weighting agent (claim not only thinner), lubricant (but also claiming glidant or antitack agent), dispersion agent, wetting agent, tackiness agent, conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent, correctives or reodorant etc.Tackiness agent, for example syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth, Mierocrystalline cellulose and derivative thereof, gelatine size, syrup, starch slurry or polyvinylpyrrolidone, preferred derivatived cellulose is Microcrystalline Cellulose, Xylo-Mucine, ethyl cellulose or HPMC; Weighting agent, for example lactose, Icing Sugar, dextrin, starch and derivative thereof, Mierocrystalline cellulose and derivative thereof, inorganic calcium salt, sorbyl alcohol or glycine, preferred inorganic calcium salt is calcium sulfate, calcium phosphate, secondary calcium phosphate or precipitated calcium carbonate; Lubricant, for example micropowder silica gel, Magnesium Stearate, talcum powder, aluminium hydroxide, boric acid, hydrogenated vegetable oil or polyoxyethylene glycol; Disintegrating agent, for example starch and derivative thereof, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone or Microcrystalline Cellulose, preferred starch derivative is sodium starch glycolate, Explotab, pregelatinized Starch, modified starch, hydroxypropylated starch or W-Gum; Wetting agent, for example sodium lauryl sulphate, water or alcohol etc.
Vehicle or auxiliary material that described injection is commonly used include but are not limited to: oxidation inhibitor, for example S-WAT, sodium bisulfite and Sodium Pyrosulfite; Fungistat, for example 0.5% phenol, 0.3% cresols, 0.5% trichloro-butyl alcohol; Acid-base modifier, for example hydrochloric acid, Citric Acid, potassium hydroxide, sodium hydroxide, Sodium Citrate and buffer reagent phosphoric acid salt and damping fluid thereof; Emulsifying agent, for example Tween-80, do not have that sour sorb is smooth, Pu Luonike F-68, lecithin, fabaceous lecithin; Solubilizing agent, for example tween-80, bile, glycerine etc.
In addition, also activeconstituents can be mixed by its preparation requirement with pharmaceutically acceptable slow controlled release carrier, again according to the preparation method of sustained-release preparation well known in the art, as adding the retarding agent dressing or with making micropill after the active principle microcapsulesization again, as sustained release pellet or controlled release micro pill; Described slow controlled release carrier includes but are not limited to oil agent, hydrophilic colloid or the dressing retarding agent etc. of mixing, described oil any or its combination that agent is selected from glyceryl monostearate, hydrogenated castor oil, Dormant oils, polysiloxane or dimethyl siloxane of mixing; Described hydrophilic colloid is selected from any or its combination of Xylo-Mucine, hydroxypropylcellulose, Vltra tears, PVP, gum arabic, tragcanth or carbopol; Described dressing retarding agent is selected from any or its combination of ethyl cellulose (EC), HPMC (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate-phthalate (CAP), acrylic resin.
Another object of the present invention is to provide acceptable salt on Benzisoelenazolone difluoro cytidine compounds of the present invention or its pharmacology or its ester or its composition to be used for the application of anti-tumor drug in preparation.
Antitumor action of the present invention is meant and is used for prevention or treatment abnormal cell growth, described abnormal cell growth can show as tumour, described tumour is selected from lung cancer, liver cancer, leukemia, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, cancer of the stomach, colorectal carcinoma, mammary cancer, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, carcinoma vulvae, esophagus cancer, carcinoma of small intestine, the endocrine system cancer, soft tissue sarcoma, urethral carcinoma, prostate cancer, lymphocytoma, bladder cancer, kidney, carcinoma of ureter, the vertebra tumour, the brain stem neurospongioma, any of pituitary adenoma or its combination are preferably carcinoma of the pancreas and lung cancer.
When acceptable salt or its ester are used to prevent and treat tumor disease on Benzisoelenazolone difluoro cytidine compounds of the present invention or its pharmacology, its dosage is about the 0.05-250mg/Kg body weight, be preferably the 0.5-200mg/Kg body weight, more preferably the 2-100mg/Kg body weight most preferably is the 5-80mg/Kg body weight.
Description of drawings
The synthetic route of Fig. 1 Benzisoelenazolone difluoro cytidine of the present invention compounds;
The synthetic route of the Benzisoelenazolone difluoro cytidine compounds 1-4 that Fig. 2 embodiment 1 is prepared;
The synthetic route of the Benzisoelenazolone difluoro cytidine compounds 5-6 that Fig. 3 embodiment 2 is prepared;
The synthetic route of the Benzisoelenazolone difluoro cytidine compounds 7-10 that Fig. 4 embodiment 3 is prepared;
The synthetic route of the Benzisoelenazolone difluoro cytidine compounds 11-14 that Fig. 5 embodiment 4 is prepared;
The synthetic route of the Benzisoelenazolone difluoro cytidine compounds 15-18 that Fig. 6 embodiment 5 is prepared;
The synthetic route of the Benzisoelenazolone difluoro cytidine compounds 19-22 that Fig. 7 embodiment 6 is prepared;
Fig. 82 '-deoxidation-2 ', 1 pair of influence that is tried the mouse body weight of 2 '-difluoro cytidine (Gemcitabine) and The compounds of this invention.
Fig. 9 is the synoptic diagram that concerns of RR and TrxR.
Embodiment
Specify the present invention below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
Embodiment 1The preparation of compound 1-4
The synthetic route of compound 1-4 as shown in Figure 2, wherein, R1 is selected from-H ,-Cl ,-F ,-CH3, preparation technology is:
1) get 4mmol 2-R14-nitrobenzoic acid (R1 is selected from-H ,-Cl ,-F ,-CH3) place the 25ml sulfur oxychloride 3h that refluxes, be spin-dried for excessive sulfur oxychloride, the residue oily liquids; Add an amount of methylene dichloride, dissolving is spin-dried for, and obtains faint yellow solid, promptly get 2-R1-4-nitrophenyl formyl chloride (R1 is selected from-H ,-Cl ,-F ,-CH3), it is dissolved in the 20ml methylene dichloride, standby;
2) take by weighing 0.132g (0.4mmol) bromination 4-butyl amine (TBAP) and be dissolved in the 10ml methylene dichloride, and slowly Dropwise 5 ml concentration is 20% NaOH solution, is cooled to-10 ℃, stirs; Slowly drip 1 again) go on foot the 2-R1-4-nitrophenyl formyl chloride dichloromethane solution that makes, reaction system keeps-10 ℃, continues to stir 2h; Add 30ml water, mixed solution is transferred in the separating funnel, separates and gets organic phase, and successively with after saturated aqueous sodium carbonate, water, the saturated sodium-chloride water solution washing, use anhydrous sodium sulfate drying again, is spin-dried for, and promptly gets 2,2 '-two R
14,4 '-dinitrobenzoic acid acid anhydride (R1 is selected from-H ,-Cl ,-F ,-CH3);
3) get 1mmol 2) 2,2 '-two R that make of step
1-4, the 2 '-deoxidation-2 ' of 4 '-dinitrobenzoic acid acid anhydride and equimolar amount, 2 '-difluoro cytidine is dissolved in it in dry DMF of 5ml stirring at normal temperature 24h; Be spin-dried for solvent, add the 30ml ether, be stirred to a large amount of white solids and separate out, collect solid, washing is moving phase with the chloroform again, through column chromatography, gets N-(4-nitro-2-R
1The phenyl acyl)-2 '-deoxidation-2 ', the pure product of 2 '-difluoro cytidine (R1 is selected from-H ,-Cl ,-F ,-CH3);
4) iron powder boils in the acetic acid dilute solution, and cool to room temperature is made reductive agent; Get 1mmol 3) N-(4-nitro-2-R of making of step
1The phenyl acyl)-2 '-deoxidation-2 ', the pure product of 2 '-difluoro cytidine are dissolved in the 5ml dry DMF, it slowly are added drop-wise in the iron powder dilute acetic acid solution stirring at normal temperature 20 minutes again; Suction filtration is removed iron powder, and standing over night is collected the white solid separate out, washing, dry crude product, be moving phase with the chloroform again, through column chromatography, N-(4-amino-2-R1 phenyl acyl)-2 '-deoxidation-2 ', the pure product of 2 '-difluoro cytidine;
5) take by weighing 4) N-(4-amino-2-R of making of step
1The phenyl acyl)-2 '-deoxidation-2 ', the pure product of 2 '-difluoro cytidine (R1 is selected from-H ,-Cl ,-F ,-CH3) with selenium chlorine, be placed in the DMF solution, stir, reaction 24h removes and desolvates, and is moving phase with the chloroform methanol, column chromatography, compound 1-4.
Embodiment 2The preparation of compound 5-6
The synthetic route of compound 5-6 as shown in Figure 3, the preparation condition of compound 5 is got compound 5 again and is placed the hydrogenation instrument with embodiment 1, adds the Ni of catalytic amount again, the reaction 20min, promptly get compound 6.
Embodiment 3The preparation of compound 7-10
The synthetic route of compound 7-10 as shown in Figure 4, wherein, R1 ' is selected from-H ,-Cl ,-F ,-CH3,2-R1-5-nitrophenyl acyl chlorides (R1 is selected from-H ,-Cl ,-F ,-CH3), 2,2 '-two R1-5,5 '-dinitrobenzoic acid acid anhydride, N-(5-nitro-2-R1 phenyl acyl)-2 '-deoxidation-2 ', 2 '-difluoro cytidine, N-(5-amino-2-R1 phenyl acyl)-2 '-deoxidation-2 ', the preparation condition of 2 '-difluoro cytidine and compound 7-10 is with embodiment 1.
Embodiment 4The preparation of compound 11-14
The synthetic route of compound 11-14 as shown in Figure 5, wherein, R1 ' is selected from-H ,-Cl ,-F ,-CH3,2-R1-4-nitrophenyl Acetyl Chloride 98Min. (R1 is selected from-H ,-Cl ,-F ,-CH3), 2,2 '-two R1-5,5 '-dinitrobenzene diacetyl oxide, N-(4-nitro-2-R1 phenyl acetyl)-2 '-deoxidation-2 ', 2 '-difluoro cytidine, N-(4-amino-2-R1 phenyl acyl)-2 '-deoxidation-2 ', the preparation condition of 2 '-difluoro cytidine and compound 11-14 is with embodiment 1.
Embodiment 5The preparation of compound 15-18
The synthetic route of compound 15-18 as shown in Figure 6; wherein; R1 ' is selected from-H ,-Cl ,-F ,-CH3; 2-R1-4-nitrophenyl acyl chlorides (R1 is selected from-H ,-Cl ,-F ,-CH3), 2; 2 '-two R1-5; 5 '-dinitrobenzoic acid acid anhydride synthetic route is with embodiment 1-2), O; O '-two uncle fourth oxygen formyl radical N-(4-nitro-2-R1 phenyl acetyl)-2 '-deoxidation-2 '; 2 '-difluoro cytidine, O; O '-two uncle fourth oxygen formyl radical N-(4-amino-2-R1 phenyl acetyl)-2 '-deoxidation-2 ', the preparation condition of 2 '-difluoro cytidine and compound 15-18 is with embodiment 1.
Embodiment 6The preparation of compound 19-22
The synthetic route of compound 19-22 as shown in Figure 6; wherein; R1 ' is selected from-H ,-Cl ,-F ,-CH3; 2-R1-4-nitrophenyl acyl chlorides (R1 is selected from-H ,-Cl ,-F ,-CH3), 2; 2 '-two R1-5; 5 '-dinitrobenzoic acid acid anhydride, O; O '-two uncle fourth oxygen formyl radical N-(4-nitro-2-R1 phenyl acetyl)-2 '-deoxidation-2 '; 2 '-difluoro cytidine, O; O '-two uncle fourth oxygen formyl radical N-(4-amino-2-R1 phenyl acetyl)-2 '-deoxidation-2 ', the preparation condition of 2 '-difluoro cytidine and compound 19-22 is with embodiment 1.
The nuclear magnetic data of table 2 compound 1-22 (
1H-NMR)
Embodiment 7Compound 1-10 is to the growth-inhibiting effect of human pancreatic cancer cell (Mia-paca-2)
With 2 '-deoxidation-2 ', the external growth-inhibiting effect to human pancreatic cancer cell (Mia-paca-2) of mtt assay research compound 1-10 is adopted in the positive contrast of 2 '-difluoro cytidine (Gemcitabine).
Get that to be in logarithmic phase concentration be 5 * 10
4The Mia-paca-2 cell of individual/ml, be inoculated in 96 orifice plates, 180 μ l/ holes treat that every hole, adherent back adds 20 μ l concentration and is respectively 0 μ M/ml, 5 μ M/ml, 10 μ M/ml, 20 μ M/ml, 50 μ M/ml, the compound 1-10 solution of 100 μ M/ml, behind the 48h, add the MTT (20 μ l/ hole) of 5mg/ml, put into CO
2After incubator was cultivated 3～4h, 3000r/min was centrifugal, abandons supernatant, treated that air-dry back adds the acidifying Virahol, surveys the OD value at microplate reader 570nm place.
Cell survival rate %=(the blank group of dosing cell OD-OD)/(the blank group of control cells OD-OD) * 100;
Cell killing rate %=1-cell survival rate %;
IC
50: the growth of tumour cell inhibiting rate is 50% o'clock a drug level.The growth inhibition ratio of tumour cell when now calculating different pharmaceutical concentration is X-coordinate again with the drug concentration, and the growth inhibition ratio of tumour cell is the ordinate zou mapping, promptly gets IC
50, the results are shown in Table 3.
Table 3 compound 1-10 is to the growth-inhibiting effect of human pancreatic cancer cell (Mia-paca-2)
Embodiment 8 compounds and gemcitabine (Gemcitabine) are to being tried the influence of mouse body weight
1, test method
Body weight is 192 of the kunming mices of 22 ± 3g, male and female half and half (Department Of Medicine, Peking University animal portion provides), be divided into 24 groups at random, be blank group, gemcitabine successive administration group and compound successive administration group, i.e. blank group, gemcitabine three days administration groups and compound three days administration groups at interval at interval.
Fasting 12h before the mouse administration.Gemcitabine abdominal injection (12.5mg/kg), compound of the present invention (20mg/Kg) gastric infusion.Divide cage to observe after the administration, feeding is fed water and is write down the diet amount of drinking water.Simultaneously, observe the body weight change of being tried mouse every day.
1) to being tried mouse peritoneal injection gemcitabine (12.5mg/kg), once a day, beginning in the 3rd day, it is all dead to be tried mouse; And given compound 1-compound 10 of the present invention (20mg/kg) to trying mouse, once a day, successive administration 7 days does not have dead;
2) to being tried mouse peritoneal injection gemcitabine (12.5mg/kg), every administration in 3 days 1 time, the body weight change of being tried mouse is referring to Fig. 1; And given compound 1-compound 10 of the present invention (20mg/kg) to trying mouse, and every 3 days once, successive administration 9 days, the body weight change of being tried mouse is referring to Fig. 1.
2, conclusion
1) given compound of the present invention (20mg/kg) to trying mouse, once a day, do not have dead in continuous 7 days; And given gemcitabine (12.5mg/kg) to trying mouse, and once a day, beginning in the 3rd day, it is all dead to be tried mouse;
2) given compound 1-compound 10 of the present invention (20mg/kg) to trying mouse, every 3 days 1 time, the body weight of being tried mouse do not had to be influenced.
Claims (10)
1. a Benzisoelenazolone difluoro cytidine compounds or its pharmacy acceptable salt or its ester, the structure of described compound is as follows:
Wherein, R
1Be selected from hydrogen, halogen, itrile group, C1-C6 alkyl, C1-C6 alkoxyl group, C1-C6 alkylthio, N (C1-C6 alkyl) 2, NH (C1-C6 alkyl), COOH ,-CORb, CONHRb, CONRcRd, SO3R, aryl, heteroaryl, cycloalkyl, heterocyclic radical, described group can be chosen wantonly by C1-C6 alkyl, C1-C6 alkoxyl group, halogen, itrile group, aryl, heteroaryl and replace, be preferably-H ,-CH3, halogen ,-OAc ,-OH, more preferably-H ,-CH3 ,-Cl ,-F ,-OAc ,-OH.
R
2Be selected from CO-12 alkylidene group, phenylene, biphenylene, inferior triphenyl, inferior hexanaphthene, pentamethylene ,-Ra SS Ra-,-(Ra O) n Ra-,-(CH2) (Ra O) 3Ra-,-Ra N (CH3) 2Ra-or-Ra NH Ra-;
Ra is the C1-6 alkylidene group; Rb is H, C1-C6 alkyl, C1-C6 alkoxyl group; Rc, Rd independently are selected from H, C1-C6 alkyl or phenyl, or Rc, Rd form nitrogen heterocyclic ring or nitrogenous hetero-aromatic ring with the N that is connected;
R
3Be selected from-H,
N is 0-4;
Wherein, R
1' be selected from hydrogen, halogen, itrile group, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, N (C
1-C
6Alkyl)
2, NH (C
1-C
6Alkyl), COOH ,-COR
b, CONHR
b, CONR
cR
d, SO
3R, aryl, heteroaryl, cycloalkyl, heterocyclic radical, described group can be chosen wantonly by C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen, itrile group, aryl, heteroaryl replace, be preferably-H ,-CH3, halogen ,-OAc ,-OH, more preferably-H ,-CH3 ,-Cl ,-F ,-OAc ,-OH.
R
2' be selected from C
0-12Alkylidene group, phenylene, biphenylene, inferior triphenyl, inferior hexanaphthene, pentamethylene ,-R
aSS R
a-,-(R
aO)
nR
a-,-(CH
2) (R
aO)
3R
a-,-R
aN (CH
3)
2R
a-or-R
aNH R
a-;
R
aBe C
1-6Alkylidene group; R
bBe H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group; R
c, R
dIndependently be selected from H, C
1-C
6Alkyl or phenyl, or R
c, R
dForm nitrogen heterocyclic ring or nitrogenous hetero-aromatic ring with the N that is connected;
R
3' be selected from-H,
N is 0-4.
2. Benzisoelenazolone difluoro cytidine compounds according to claim 1, described compound are selected from the Benzisoelenazolone difluoro cytidine compounds 1-22 of the described structure of table 1:
Compound 1:N-{4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 2:N-{2-methyl-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 3:N-{2-chloro-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 4:N-{2-fluoro-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 5:N-{3-acetoxyl group-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 6:N-{3-hydroxyl-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 7:N-{3-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 8:N-{2-methyl-5-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 9:N-{2-chloro-5-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 10:N-{2-fluoro-5-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 11:N-{4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] phenylacetyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 12:N-{3-methyl-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] phenylacetyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 13:N-{3-chloro-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] phenylacetyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 14:N-{3-fluoro-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] phenylacetyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 15:O, O '-two uncle fourth oxygen formyl radical-N-{4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 16:O, O '-two uncle fourth oxygen formyl radical-N-{2-methyl-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 17:O, O '-two uncle fourth oxygen formyl radical-N-{2-chloro-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 18:O, O '-two uncle fourth oxygen formyl radical-N-{2-fluoro-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 19:O, O '-dibenzoyl-N-{4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 20:O, O '-dibenzoyl-N-{2-methyl-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 21:O, O '-dibenzoyl-N-{2-chloro-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine;
Compound 22:O, O '-dibenzoyl-N-{2-fluoro-4-[1,2-benzisoxa selenazoles-3 (2H)-ketone] benzoyl }-2 '-deoxidation-2 ', 2 '-difluoro cytidine.
3. Benzisoelenazolone difluoro cytidine compounds according to claim 1, described pharmaceutically acceptable salt is selected from its inorganic acid addition salt, any or its combination of organic acid adduct, preferred described pharmaceutically acceptable salt is selected from hydrochloride, hydrobromate, hydriodate, vitriol, nitrate, tosilate, mesylate, phosphoric acid salt, vitriol, perchlorate, acetate, trifluoroacetate, propionic salt, citrate, malonate, succinate, lactic acid salt, oxalate, tartrate, benzoate, magnesium salts or calcium salt, alkylbenzyldimethylasaltsum saltsum, piperidinium salt, the trialkyl amine salt, pyridinium salt, any or its combination of dimethylamine salt or diethyl amine salt.
4. Benzisoelenazolone difluoro cytidine compounds according to claim 1; described ester is selected from any or its combination of amino acid ester, acetic ester, benzoic ether, dibenzoate, uncle's fourth oxygen manthanoate, two uncle's fourth oxygen manthanoate, polypeptide ester or amino acyl esters, is preferably any or its combination of amino acid ester, acetic ester, benzoic ether, dibenzoate, uncle's fourth oxygen manthanoate, two uncle's fourth oxygen manthanoate.
5. method for preparing each described Benzisoelenazolone difluoro cytidine compounds of claim 1-4, preparation technology sees Fig. 1.
6. pharmaceutical composition, described composition is made up of acceptable salt or its ester and pharmaceutically acceptable carrier on each described Benzisoelenazolone difluoro cytidine compounds of claim 1-4 or its pharmacology.
7. pharmaceutical composition according to claim 6, acceptable salt or its ester on Benzisoelenazolone difluoro cytidine compounds or its pharmacology in the pharmaceutical composition: the weight ratio of auxiliary material is 0.001-99: 1-99, be preferably 0.001-90: 1-95, more preferably 0.001-80: 1-90 most preferably is 0.001-70: 1-85.
The weight percentage of acceptable salt or its ester is 1-99% on Benzisoelenazolone difluoro cytidine compounds in the pharmaceutical composition or its pharmacology, is preferably 5-95%, also is preferably 10-90%, and more preferably 15-85% most preferably is 20-80%.
8. according to each described pharmaceutical composition of claim 6-7, the formulation of described pharmaceutical composition is selected from oral preparations, external preparation or injection, is preferably oral preparations or injection.
Described oral preparations is selected from inclusion preparation, dispersion agent, oral liquid, tablet, capsule, granule, dripping pill, pill, powder, syrup, mixture, distillate medicinal water, suspension agent, effervescent, paste, suspension, emulsion or medicinal tea, is preferably inclusion preparation or dispersion agent.
Described suspension agent is selected from does outstanding agent or suspension.
Described external preparation is selected from gelifying agent, paste, emplastrum, plaster, creme, ointment, liniment, lotion, suppository, basting agent or coagulates paste.
Described injection is selected from injection, transfusion or freeze-dried powder.
9. acceptable salt or its ester or each described pharmaceutical composition of claim 6-8 are used for the application of anti-tumor drug on each described Benzisoelenazolone difluoro cytidine compounds of claim 1-4 or its pharmacology in preparation.
10. application according to claim 14, described antitumor action is meant and is used for prevention or treatment abnormal cell growth, described abnormal cell growth can show as tumour, described tumour is selected from lung cancer, liver cancer, leukemia, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, cancer of the stomach, colorectal carcinoma, mammary cancer, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, carcinoma vulvae, esophagus cancer, carcinoma of small intestine, the endocrine system cancer, soft tissue sarcoma, urethral carcinoma, prostate cancer, lymphocytoma, bladder cancer, kidney, carcinoma of ureter, the vertebra tumour, the brain stem neurospongioma, any of pituitary adenoma or its combination are preferably carcinoma of the pancreas and lung cancer.
6, a kind of pharmaceutical composition, described composition is made up of acceptable salt or its ester and pharmaceutically acceptable carrier on each described Benzisoelenazolone difluoro cytidine compounds of claim 1-4 or its pharmacology.
7, pharmaceutical composition according to claim 6, acceptable salt or its ester on Benzisoelenazolone difluoro cytidine compounds or its pharmacology in the pharmaceutical composition: the weight ratio of auxiliary material is 0.001-99: 1-99, be preferably 0.001-90: 1-95, more preferably 0.001-80: 1-90 most preferably is 0.001-70: 1-85.
The weight percentage of acceptable salt or its ester is 1-99% on Benzisoelenazolone difluoro cytidine compounds in the pharmaceutical composition or its pharmacology, is preferably 5-95%, also is preferably 10-90%, and more preferably 15-85% most preferably is 20-80%.
8, according to each described pharmaceutical composition of claim 6-7, the formulation of described pharmaceutical composition is selected from oral preparations, external preparation or injection, is preferably oral preparations or injection.
Described oral preparations is selected from inclusion preparation, dispersion agent, oral liquid, tablet, capsule, granule, dripping pill, pill, powder, syrup, mixture, distillate medicinal water, suspension agent, effervescent, paste, suspension, emulsion or medicinal tea, is preferably inclusion preparation or dispersion agent.
Described suspension agent is selected from does outstanding agent or suspension.
Described external preparation is selected from gelifying agent, paste, emplastrum, plaster, creme, ointment, liniment, lotion, suppository, basting agent or coagulates paste.
Described injection is selected from injection, transfusion or freeze-dried powder.
9, acceptable salt or its ester or each described pharmaceutical composition of claim 6-8 are used for the application of anti-tumor drug on each described Benzisoelenazolone difluoro cytidine compounds of claim 1-4 or its pharmacology in preparation.
10, application according to claim 14, described antitumor action is meant and is used for prevention or treatment abnormal cell growth, described abnormal cell growth can show as tumour, described tumour is selected from lung cancer, liver cancer, leukemia, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, cancer of the stomach, colorectal carcinoma, mammary cancer, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, carcinoma vulvae, esophagus cancer, carcinoma of small intestine, the endocrine system cancer, soft tissue sarcoma, urethral carcinoma, prostate cancer, lymphocytoma, bladder cancer, kidney, carcinoma of ureter, the vertebra tumour, the brain stem neurospongioma, any of pituitary adenoma or its combination are preferably carcinoma of the pancreas and lung cancer.
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