CN1242999C - Benzo-isoselenazole derivatives having anti inflammation, anti-tumor and anti-thrumbosis function and its use - Google Patents
Benzo-isoselenazole derivatives having anti inflammation, anti-tumor and anti-thrumbosis function and its use Download PDFInfo
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Abstract
The present invention relates to a benzo-isoselenazole derivative of a general formula (I), (II) or (II) and salts thereof which can be accepted in the pharmacology. The derivative can be used for resisting inflammation, resisting viruses and resisting thrombosis.
Description
Invention field
The present invention relates to a kind of benzisoxa selenazoles derivative and application thereof with anti-inflammatory, antitumor and anti-thrombosis function.The invention still further relates to the pharmaceutical composition and application and treatment inflammation, tumour or the antithrombotic method of this derivative in the preparation medicine that comprise this benzisoxa selenazoles derivative.
Background technology
Selenium is one of important trace element, and epidemiology survey shows that the blood selenium content is lower than 0.1ppm for a long time in the human body, might cause numerous diseases such as hepatic necrosis, myocardial damage, cancer and sacroiliitis.Selenium comes from the discovery of the selenium of nineteen fifty-seven K.Schwarz and C.M.Foltz to the trophism of animal as the establishment of the status of the life essential trace element of Mammals (comprising the mankind).Recent two decades comes, selenium has been obtained the development of advancing by leaps and bounds at life science, scientists has been found the intravital four kinds of selenium enzymes of Mammals continuously:: cell Selenoperoxidase (GSH-Px), phospholipid hydroperoxide glutathione peroxidase (PHG-Px), blood plasma Selenoperoxidase (P GSH-Px) and I type iodine thyroxine 5 ' take off the iodine enzyme (5 '-DI), and with selenium enzyme Trx enzyme of some disease-related etc.
Selenium is to the importance of life science, makes to contain the selenium medicine or the nourishing function product become remarkable focus.Usually inorganic selenium is difficult for being absorbed, and biological activity is lower, and toxicity is big; Organoselenium is easily absorbed by human body, and it is longer to hold time in blood, easily is converted into activated metabolic intermediate in vivo, and biological activity is longer, and toxicity is less relatively.
In the state of the art, can obtain to have the stand-in of glutathione peroxidase GSHPx sample active function by the artificial method.Experimental results show that (Benzisoselenazolones BISA) can suppress external foundation of microsomal Lipid Peroxidation effect to the Benzisoelenazolone compounds, has the damage function that the protection body is avoided peroxidation.The 2-phenyl-1 that wherein has following chemical formula, 2-benzisoxa selenazoles-3 (2)-ketone (ebselen, Ebselen), be the stand-in of the most promising GSH-Px that generally acknowledges at present, anti-oxidant activity height not only, and toxicity extremely low (LD50＞6810mg/kg mice), be the best representative of organoselenium class antioxidant up to now, Japanese first drugmaker has finished the three phases clinical study of Ebselen.
Though numerous researchs are arranged aspect the active compound for anti tumor utilizing this parent nucleus that it is transformed into, successful active compound for anti tumor is found not appear in the newspapers as yet.Therefore, the objective of the invention is on the ebselen basis, to transform out novel organoselenium anti-inflammatory drug and the antithrombotic reagent that anti-inflammatory is higher, adaptability is wider, toxicity is lower; Also utilize simultaneously the anti-oxidant mother nucleus structure of ebselen location to transform out the organic selenium compounds of anti-tumor activity with " biological response modifier " characteristics.
Summary of the invention
According to an aspect, The compounds of this invention provides acceptable salt on following general formula (I), (II) or benzisoxa selenazoles derivative (III) and the pharmacology thereof:
Wherein:
R is C
1-12Alkylidene group, phenylene, biphenylene, inferior triphenyl or
-(CH
2)SS(CH
2)-
-(CH
2)CH(CH
3)-
-(R
aO)2R
a-
-(CH
2)(R
aO)3R
a-
-R
aN(CH
3)
2 a-
-R
aNHR
a-
R
aSSR
a-wherein: R
aBe C
1-6Alkylidene group;
Wherein M is Pt, Pd or Rh,
R ' be saccharide residue or
Wherein: R " be Cl, H
2O, OH, Br or I,
R is-H ,-CH
2C
6H
5OH ,-CH
2OH ,-CH
2CONH
2,-CH
2CH
2COOH-CH
2(CH
2)
4NH
2,-CH
2COOH ,-CH
2CH
2CONH
2,-(CH
2)
3CH ,-(CH
2)
3NHC (NH) NH
2,-(CH
2)
3CHCH
2,-CH
3,-CH
2CH
3,-CH
2C
6H
5,-CH
2SH or-CH
2CH
2SCH
3, and
R " " is-H ,-CH
2C
6H
5OH ,-CH
2OH ,-CH
2CONH
2,-CH
2CH
2COOH-CH
2(CH
2)
4NH
2,-CH
2COOH ,-CH
2CH
2CONH
2,-(CH
2)
3CH ,-(CH
2)
3NHC (NH) NH
2,-(CH
2)
3CHCH
2,-CH
3,-CH
2CH
3,-CH
2C
6H
5,-CH
2SH or-CH
2CH
2SCH
3
According to another aspect, the invention provides acceptable vehicle or carrier on the pharmaceutical composition that comprises acceptable salt on above-mentioned general formula (I), (II) or benzisoxa selenazoles derivative (III) or its pharmacology and the pharmacology.
According to another aspect, the invention provides acceptable salt on above-mentioned general formula (I), (II) or benzisoxa selenazoles derivative (III) or its pharmacology is used for anti-inflammatory, antitumor or antithrombotic medicine in preparation application.
According to another aspect, the invention provides the method for the treatment of inflammation, tumour or thrombotic disease in comprising people's Mammals, it comprises acceptable salt on the above-mentioned general formula (I) of patient's drug treatment significant quantity of these treatments of needs, (II) or benzisoxa selenazoles derivative (III) or its pharmacology.
According to another aspect, the invention provides the method for the treatment of inflammation, tumour or thrombotic disease in comprising people's Mammals, it comprises acceptable salt and other antiphlogiston or antitumor drug on above-mentioned general formula (I), (II) or benzisoxa selenazoles derivative (III) or its pharmacology of patient's Combined Preparation treatment significant quantity of these treatments of needs.
Embodiment
Benzisoxa selenazoles derivative of the present invention is at the active parent nucleus of considering fully to keep ebselen, under the medicinal design thinking of enhancement function group, and a series of compounds of positioning design.Because the characteristics of structure thereby have the multiaction target spot in vivo, thereby has multiple biological activity.Because this compound is to be the directed main antitumor drug of target with the point of adjustment in the biological response device, thereby has the antitumor characteristics of " biological response modifier " as antitumor drug the time.It is the novel active compound for anti tumor of a class with comprehensive adjusting body, multiaction target spot.
According to one embodiment of the invention, it provides acceptable salt on following general formula (I), (II) or benzisoxa selenazoles derivative (III) and the pharmacology thereof:
Wherein:
R is C
1-12Alkylidene group, phenylene, biphenylene, inferior triphenyl or
-(CH
2)SS(CH
2)-
-(CH
2)CH(CH
3)-
-(R
aO)2R
a-
-(CH
2)(R
aO)3R
a-
-R
aN(CH
3)
2R
a-
-R
aNHR
a-
R
aSSR
a-wherein: R
aBe C
1-6Alkylidene group;
Wherein M is Pt, Pd or Rh;
R ' be saccharide residue or
Wherein: R " be Cl, H
2O, OH, Br or I,
R is-H ,-CH
2C
6H
5OH ,-CH
2OH ,-CH
2CONH
2,-CH
2CH
2COOH-CH
2(CH
2)
4NH
2,-CH
2COOH ,-CH
2CH
2CONH
2,-(CH
2)
3CH ,-(CH
2)
3NHC (NH) NH
2,-(CH
2)
3CHCH
2,-CH
3,-CH
2CH
3,-CH
2C
6H
5,-CH
2SH or-CH
2CH
2SCH
3, and
R is-H ,-CH
2C
6H
5OH ,-CH
2OH ,-CH
2CONH
2,-CH
2CH
2COOH-CH
2(CH
2)
4NH
2,-CH
2COOH ,-CH
2CH
2CONH
2,-(CH
2)
3CH ,-(CH
2)
3NHC (NH) NH
2,-(CH
2)
3CHCH
2,-CH
3,-CH
2CH
3,-CH
2C
6H
5,-CH
2SH or-CH
2CH
2SCH
3
In the present embodiment, R is preferably C
1-4Alkylidene group, phenylene, biphenylene, more preferably butylidene and biphenylene.
R ' is preferably 1,3,4,6-four-O-ethanoyl-2-deoxidation-D-glucopyranosyl.
R and R " " are preferred to be respectively independently-H ,-CH
3,-CH
2CH
3,-CH
2C
6H
5,-CH
2SH or-CH
2CH
2SCH
3
Benzisoxa selenazoles derivative of the present invention can synthesize according to the method for method known to those skilled in the art or record in this manual.For example, under cooling and atmosphere of inert gases, 2-selenium chloro-benzoyl chloride and corresponding diamine compounds or aminosugar are reacted in appropriate organic solvent.Available then standard technique well known by persons skilled in the art is separated, and obtains target compound.
For wherein R or R ' is the benzisoxa selenazoles derivative of the present invention of metal complexes, and available organometallic compound such as cis-platinum synthesizes according to the known method of those skilled in the art as initiator.
Cis-platinum
On derivative of the present invention or its pharmacology acceptable salt can the pure compound form or the appropriate drug composition carry out administration, the reagent that can adopt any acceptable administering mode or be used for similar applications carries out.Therefore, another aspect of the present invention provides acceptable vehicle or carrier on the pharmaceutical composition that comprises acceptable salt on above-mentioned general formula (I) or benzisoxa selenazoles derivative (II) or its pharmacology and the pharmacology, and it can be used for anti-inflammatory, antitumor and prevent thrombotic treatment.
The administering mode that adopts can be selected in through port, the nose, rectum, transdermal or drug administration by injection mode, its form is solid, semisolid, lyophilized powder or liquid preparation form administration, for example, tablet, suppository, pill, soft hard-gelatin capsules, powder, solution, suspensoid or aerosol etc., the preferred presented in unit dosage form that adopts the simple administration that is applicable to exact dosage desired.Composition can comprise conventional pharmaceutical carrier or vehicle and as the binding substances of the present invention of activeconstituents (one or more), in addition, also can comprise other medicament, carrier, assistant agent etc.
Usually, according to required administering mode, pharmaceutically acceptable composition will comprise the suitable pharmaceutical excipient of about 1 to about 99 weight % binding substances of the present invention and 99 to 1 weight %.Preferred composition comprises the binding substances of the present invention of about 5 to 75 weight %, and all the other are suitable pharmaceutical excipient.
Preferred route of administration is a drug administration by injection, adopts conventional per daily dose scheme, and this scheme can be adjusted according to the severity of disease.Binding substances of the present invention or its pharmacy acceptable salt also can be mixed with the injection agent, for example use about 0.5 to about 50% activeconstituents to be scattered in the medicinal adjuvant that can adopt the liquid form administration, example is water, salt solution, dextrose hydrate, glycerine, ethanol etc., thereby forms solution or suspensoid.
Can adopt the pharmaceutical composition of liquid form administration for example can dissolve, be scattered in the carrier by the medicinal adjuvant of means such as dissolving, dispersion with binding substances of the present invention (about 0.5 to about 20%) and selectivity existence, the example of carrier is water, salt solution, dextrose hydrate, glycerine, ethanol etc., thereby forms solution or suspensoid.
If necessary, pharmaceutical composition of the present invention also can comprise a spot of auxiliary substance, as wetting agent or emulsifying agent, pH buffer reagent, antioxidant etc., for example: citric acid, Arlacel-20, Emulphor FM, Yoshinox BHT etc.
The actual fabrication method of such formulation is that those skilled in the art is known or conspicuous, for example can be referring to Remington ' s Pharmaceutical Sciences, the 18th edition, (MackPublishing Company, Easton, Pennsylvania, 1990).In any case according to technology of the present invention, employed composition will contain the binding substances of the present invention for the treatment of significant quantity, to be used for the treatment of corresponding disease.
According to another aspect, the invention provides the method for the treatment of inflammation and tumor disease in comprising people's Mammals, it comprises acceptable salt on the above-mentioned general formula (I) of patient's drug treatment significant quantity of these treatments of needs or benzisoxa selenazoles derivative (II) or its pharmacology.
According to another aspect, the invention provides the method for the treatment of inflammation, tumour or thrombotic disease in comprising people's Mammals, it comprises acceptable salt and other antiphlogiston or antitumor drug on the benzisoxa selenazoles derivative of the above-mentioned general formula (I) of patient's Combined Preparation treatment significant quantity of these treatments of needs or (II) or its pharmacology.
Unite when using at benzisoxa selenazoles derivative of the present invention and other antiphlogistons, antitumour drug or anti-thrombosis drug, can be simultaneously or these two kinds of medicines of administration sequentially, comprise first administration benzisoxa selenazoles of the present invention derivative, and then other antiphlogiston, antitumour drug or anti-thrombosis drug of administration, and other antiphlogiston, antitumour drug or anti-thrombosis drug of first administration, and then administration benzisoxa selenazoles of the present invention derivative.
In preferred embodiments, described other antitumor drug is Zorubicin, cis-platinum, taxol, carboplatin, Ro 2-9757, endoxan, ifosfamide, ranomustine, fotemustine, mitomycin, daunorubicin, pidorubicin, Rheumatrex, Zhengguangmycin A5 etc., or their combination.
In preferred embodiments, described other anti-inflammatory drugs are acetylsalicylic acid, INDOMETHACIN, cephalosporins and macrolide antibiotics etc., or their combination.
In preferred embodiments, described other anti-thrombosis drugs are acetylsalicylic acid.
Benzisoxa selenazoles derivative of the present invention is when the treatment tumor disease, and its dosage is about 0.05-250mg/kg body weight; When the treatment inflammation, dosage is about 1-100mg/kg body weight; And when antithrombotic formed, dosage was about 1-100mg/kg body weight.
When uniting use with other antiphlogiston, antitumour drug or anti-thrombosis drug, the dosage of derivative of the present invention and corresponding other drug all can significantly reduce, 1/10th to 1/2nd when being about independent the use.
Below will the present invention be described in more detail by embodiment.
Embodiment 1
Preparation 1,2-two { (1,2)-benzisoxa selenazoles-3 (2H)-ketone }-ethane (E003)
Ice bath, N
2Protection drips the solution of 2-selenium chloro-benzoyl chloride in tetrahydrofuran (THF) of 1g down in the tetrahydrofuran (THF) that comprises 0.14ml quadrol, 1.29ml triethylamine, white precipitate occurs, stirs and gets faint yellow emulsion after 3 hours; The pressure reducing and steaming solvent, washing, suction filtration, the DMSO recrystallization gets O.1g faint yellow solid, and productive rate is 11%, m.p＞320 ℃.
EI-MS：(m/z)(m
+)424；
1HNMR(DMSO-d
6)，7.37-7.98(8H，m，ArH)，4.02(4H，S，-CH
2CH
2-)。
Embodiment 2
Preparation 4,4 '-two { (1,2)-benzisoxa selenazoles-3 (2H)-ketone }-biphenyl (E002)
In the ice bath, N
2Protection down; in the tetrahydrofuran (THF) that comprises 0.182g p-diaminodiphenyl and 0.62ml triethylamine, drip the tetrahydrofuran solution of 0.5g 2-selenium chloro-benzoyl chloride; stirred 3 hours, and produced a large amount of white solids, suction filtration; use tetrahydrofuran (THF); washing with alcohol, the DMSO recrystallization gets shallow look solid 0.1g; productive rate is 18.2%, m.p＞320 ℃.
EI-MS：(m/z)(m
+)550；
1HNMR(DMSO-d
6)，7.48-8.12(m，16H，ArH)。
Embodiment 3
Preparation { 2-(1,3,4,6-four-O-ethanoyl)-2-deoxidation-D-glucopyranosyl }-1,2 benzisoxa selenazoles-3 (2H)-ketone (E001)
At N
2Under the protection, in the ice bath, with { 1 of 730mg; 3,4,6-is tetra-acetylated-and D-glucosamine is dissolved in the chloroform; add 0.64ml ethamine, under the induction stirring, slowly drip the chloroformic solution of the 2-selenium chloro-benzoyl chloride of people 0.551g; stirred 2 hours; reaction solution is with silica gel mixed sample, through silica gel column chromatography, sherwood oil: ethyl acetate=separate at 3: 1 faint yellow solid 200mg; productive rate is 18%, m.p 73-75 ℃.
IR1745 (CO); UV (CHCl
3) 320nm, 260nm (showing different selenazoles ring);
FAB-MS(m/z)566.3(M+K)；
1HNMR: δ H (ppm) 7.24-8.12 (4H, m, ArH), 6.20 (IH, d, sugared end group H), 3.97-5.64 (m, 6H, sugar ring H), 1.82-2,16 (12H, m ,-COCH
3);
13C NMR: δ (ppm) 166.77,168.66,169.29,169.61,170.44 (CO), 124.22,126.28,128.81,132.37,138.30 (aromatic ring carbon), 91.43, (sugared end group carbon, C-I), 60.15,61.35,68.35,71.91,72.35, (sugar ring carbon, C-2,3,4,5,6), 20.34,20.48,20.55,20.78, (COCH
3).
Embodiment 4
Cyclohexanediamine closes the synthetic of platinum Ebselen glycine
1) KPtCl
4Synthetic
0.7g K
2PtCl
6(1.44mmol) be dissolved in the 7ml water, careful 10% the hydrazine hydrate solution of slowly dripping in 80 water-baths is noted stirring and is reacted fully, treat the solution becomes laking after, remove by filter unreacted KPtCl
6And the by product platinum black, concentrated filtrate gets KPtCl
4Red needle-like crystal 0.5g, productive rate is about 84%.
2) cyclohexanediamine closes the synthetic of platinum
0.2g K
2PtCl
4(0.48mmol) be dissolved in the 2ml water.0.8g KI be dissolved in the 0.6g water, with KPtCl
4Solution lucifuge in the boiling water-bath is mixed, and is warming up to 80 rapidly, in the dark leaves standstill half an hour then.Add about 0.05g cyclohexanediamine solid in solution, generate yellow mercury oxide, filtering-depositing is with a small amount of frozen water, and ethanol and ether wash, and being weighed as the 0.21g productive rate after the drying is 78%.
3) glycine ebselen cyclohexanediamine closes the synthetic of platinum:
The glycine ethyl ester ebselen woods of getting 0.020g is dissolved in the 0.5ml chloroform, adds the sodium hydroxide solution 15ml of 1M again, 50-60 ℃ of following incubation 10 hours, will become the sucking-off of xanchromatic water layer, and other adds the sodium hydroxide solution 15ml of 1M, makes the hydrolysis of ester abundant.Combining water layer, the hydrochloric acid that adds 1M makes it acidifying and separates out, and filtration drying gets glycine ebselen woods 0.025g.
Take by weighing the 0.015g cyclohexanediamine and be dissolved in 0.15ml water and get yellow mashed prod, the AgNO that takes by weighing 0.009g is dissolved in the 0.5ml water, joins in the yellow mashed prod, and lucifuge stirred 4 hours.Remove by filter the yellow AgI precipitation of generation,, get a filtrate and mix with the KCl solution of a 1M and should can't see white casse with a small amount of frozen water washing leaching cake.
Get the glycine ebselen woods of 0.015g, add the KOH of 0.0036g and the water of about 2ml, make it fully to dissolve yellow suspension, join in the solution of platinum, lucifuge stirred 90 minutes, filtered, must the about 25mg of yellow crystals after the filtrate decompression drying.Productive rate is 50%.FAB:m/z (M+1) 566, far infrared IR340cm
-1(being shown with Pt-O), IR420cm
-1(being shown with Pt-N).
Embodiment 5
Medicine is to the growth-inhibiting experiment of tumour cell
Be to adopt srb assay to study the growth-inhibiting effect of medicine in the present embodiment to tumour cell (attached cell).Particularly, the cell of taking the logarithm vegetative period (3-5 * 10
4Cells/ml), be inoculated in respectively in (180 μ l/ hole) in 96 well culture plates, place 37 ℃, 5%CO
2, saturated humidity incubator in cultivate after 24 hours, add the test-compound of 20 μ l different concns, place 37 ℃, 5%CO
2, saturated humidity incubator in continue to cultivate required time more respectively.Cell discards nutrient solution after end is cultivated in dosing, add 10% Tricholroacetic Acid (TCA), 100 μ l and place 4 ℃ of refrigerators, fixed cell 1 hour.Abandon liquid, deionized water rinsing.After drying water, every hole adds 0.4% SRB solution (with the preparation of 1%HAC solution) 50 μ l, and room temperature was placed 10 minutes.After discarding unnecessary SRB, the acetum with 1% washes 96 orifice plates 5 times, removes not and protein bound SRB.After the drying of 96 orifice plates, place dry air.Every hole adds 10mmol/L non-buffering Tris alkali lye (pH10.5) 150 μ l, fully dissolved cell bonded SRB.After dull and stereotyped shaking table shakes up,, measure the OD value of each aperture at the 540nm place of TECANSUNRISE Magellan 96Well microplate reader (USA).Wherein, used test hole OD value=test hole OD value-background OD value (being that perfect medium adds MTT, SRB, acellular).The OD value of repeating hole is mean value ± SD.Calculate the survival rate of cell and the inhibiting rate of medicine on cell proliferation according to following formula then.
Cell survival rate %=(the OD value of the OD value/control cells of dosing cell) * 100
Cell proliferation inhibition rate %=[1-(the OD value of the OD value/control cells of dosing cell)] * 100
According to above srb assay, the anti tumor activity in vitro of compd E 003 of the present invention has been carried out primary dcreening operation, result's (as shown in table 1) shows, it is to Bel-7402 people's liver cancer, have antitumour activity to KB human nasopharyngeal carcinoma and human cervical carcinoma (HeLa).
Table 1
| The compound title | Test purpose and model | Observation index | The test effect | Dosage or concentration |
| E003 | Ble-7402 people's liver cancer | Inhibiting rate % | 2.05 | 1μM |
| 7.28 | 5μM | |||
| 58.72 | 10μM | |||
| 82.46 | 50μM | |||
| 89.57 | 100μM |
| E003 | The KB human nasopharyngeal carcinoma | Inhibiting rate % | 2.94 | 1μM |
| 4.61 | 5μM | |||
| 25.71 | 10μM | |||
| 92.49 | 50μM | |||
| 97.46 | 100μM | |||
| E003 | The HeLa human cervical carcinoma | Inhibiting rate % | 4.89 | 1μM |
| 12.16 | 5μM | |||
| 64.12 | 10μM | |||
| 86.18 | 50μM | |||
| 88.12 | 100μM |
In addition, also according to identical method measured E003 to nine kinds of human tumor cells of vitro culture at the inhibiting IC of different time cell growth
50Value is estimated the growth-inhibiting effect of E003 to tumour cell thus.Gained the results are shown in Table 2.
Table 2:E003 is to the growth-inhibiting effect IC of nine kinds of human tumor cells of vitro culture
50Value
| The cell title | IC 50Value (μ mol/L) | ||
| 24h | 48h | 72h | |
| HL-60 K562 A549 Calu-3 BGC-823 Bel-7402 Hela MCF-7 KB | 33.03 - 3.920 45.41 31.92 35.23 16.78 ** ** | 3.773 8.507 3.600 16.77 19.07 12.06 10.31 39.88 2.067 | 0.1467 4.24 2.904 14.18 12.97 7.867 9.845 27.49 ** |
*The growth-inhibiting IC that represents this time period of this cell
50Value is not done; This cell strain of-expression does not obtain IC in this time period
50Value.
Embodiment 6
Medicine is to the influence of tumor weight
Lewis lung cancer flesh tissue piece, frozen after wide seam mill grinds.After the cryopreserved tissue recovery, go down to posterity, get the tumor tissues that grows up to after inoculation is gone down to posterity then, grind, make concentration 10 with physiological saline through wide seam mill at the C57 mouse hypodermic inoculation
6The cell suspension of individual/ml is at the back inoculation 0.2-0.3ml of every C57 mouse.
The C57 mouse of inoculated tumour tissue is divided into three groups, ten every group at random; First group is the administration group, and to being tried mouse peritoneal injection E003, dosage is 50mg/Kg; Second group of positive control group, to being tried mouse peritoneal injection cis-platinum (DDp), dosage is 2mg/Kg.The 3rd group of negative control group (group of solvents), abdominal injection 0.5%CMC-Na, the administration volume is identical with the administration group.
Tried behind the mouse inoculation tumor line second day, intraperitoneal injection, successive administration are after three days, and the vertebra dislocation is put to death.Tried mouse behind 70% alcohol disinfecting, earlier the tumour profile of mouse is taken pictures, carefully separate tumor tissues, weigh after taking pictures, the tumor tissues with gained places formaldehyde fixed again, does other and analyzes usefulness.DDP and E003 the results are shown in Table 3 to what the animal tumor volume influenced to the effect of Lewis lung cancer mouse in the time of three days.
Table 3
| Numbering | E003 | Control group | The cis-platinum group |
| Average (mm 3) | 284.2 | 748.1 | 473 |
| Inhibiting rate | 0.62 | 0.367 |
By the result of table 3 as can be seen, compound of the present invention is compared with cis-platinum has remarkable antitumor effect more.
Embodiment 7
The synergistic function of benzisoxa selenazoles derivative of the present invention and other antitumor drugs
Use in the present embodiment compd E 003 that the method measurement identical with embodiment 4 make in embodiment 1 respectively with other antitumor drugs---the synergy when taxol, adriamycin and Platinol cisplatin Combined Preparation.The Combined Preparation mode of E003 and other cancer therapy drugs has three kinds: the two administration simultaneously; The two administration successively, the dosing interval of this moment is 4.0 hours.
Concrete the results are shown in shown in the following table 4-6.
Table 4:E003 and purple triol Combined Preparation are to the Growth Inhibition influence of tumour cell
| Numbering | The knurl strain | Action time (hour) | Combined Preparation mode and concentration | Inhibiting rate | Activity influence |
| Control group 1 | HL-60 | 24 | T0.01-E5.0 T0.01+E5.0 T0.001-E5 T0.001+E5.0 E5.0-T0.01 E5.0-T0.001 | 0.47±0.046 0.57±0.022 0.46±0.003 0.60±0.016 0.55±0.005 0.55±0.020 | Synergy synergy synergy synergy synergy synergy- |
| T0.01 T0.001 E5 | 0.27±0.079 0.02±0.010 0.33±0.624 |
Table 5:E003 and Zorubicin Combined Preparation are to the Growth Inhibition influence of tumour cell
| Numbering | The knurl strain | Action time (hour) | Combined Preparation mode and concentration | Inhibiting rate | Activity influence |
| Control group 1 | HL-60 | 24 | A0.1-E5.0 A0.1+E5.0 E5.0-A0.1 A0.1 E5.0 | 0.55±0.002 0.55±0.003 0.52±0.017 -0.07±0.007 0.33±0.062 | Synergy synergy synergy |
Table 6:E003 and cisplatin combined administration are to the Growth Inhibition influence of tumour cell
| Numbering | The knurl strain | Action time (hour) | Medicine and drug level | Inhibiting rate | Activity influence |
| According to group 1 | HL-60 | 24 | DDP0.5-E5.0 | 0.44±0.014 | Synergy synergy synergy |
| DDP0.5+E5.0 | 0.55±0.016 | ||||
| E5.0-DDP0.5 | 0.51±0.004 | ||||
| E5-DDP5 | 0.51±0.007 | Synergy | |||
| DDP5+E5 | 0.56±0.007 | Synergy | |||
| DDP0.5-E5 | 0.44±0.014 | Synergy | |||
| DDP0.5+E5 | 0.55±0.016 | Synergy | |||
| E5-DDP0.5 | 0.51±0.003 | Synergy | |||
| DDP0.5 | 0.067±0.014 | ||||
| DDP5 | 0.12±0.032 | ||||
| E0.05 | -0.08±0.031 | ||||
| E0.5 | 0.05±0.0167 | ||||
| E5.0 | 0.33±0.062 |
Illustrate:
(1) medicine code name and concentration thereof
E represents E003, and concentration unit is μ mol/L
A represents Zorubicin, and concentration unit is mg/L
DDP represents cis-platinum, and concentration unit is μ mol/L
T represents taxol, and concentration unit is mg/L
(2) administering mode
With E and A is the symbolic representation that example is explained the Combined Preparation mode, and E+A represents the two administration simultaneously; E-A represents to give 4h behind the E, gives A again; A-E represents to give 4h behind the A, gives E again.E and DDP, T Combined Preparation and expression mode thereof are by that analogy.
Embodiment 8
The anti-inflammatory action of The compounds of this invention
The following mice caused by dimethylbenzene xylene ear swelling that carries out is tested: with the kunming mice random packet, 10 every group, gastric infusion, positive control drug are acetylsalicylic acid and INDOMETHACIN, and feminine gender is an isometric(al) physiological saline.After 1 hour, dimethylbenzene 0.05ml is dripped in mouse right ear; After 2 hours the mouse dislocation is caused death, strike bottom left auris dextra sheet, diameter (8 millimeters) is weighed.Calculate the restraining effect of compd E 001-E003 p-Xylol induced mice ear swelling of the present invention then according to the ear weight of gained.The result is as shown in table 7.
Table 7
| The compound title | The anti-inflammatory model | Swelling degree % | Inhibiting rate (%) | Dosage or concentration |
| Physiological saline | Ear swelling | 14.66 | ||
| INDOMETHACIN | Ear swelling | 19.89 | 22mg/kg | |
| Acetylsalicylic acid | Ear swelling | 10.63 | 200mg/kg | |
| Ebselen | Ear swelling | 6.22 | (68.72 with the INDOMETHACIN ratio) 41.48 (with the acetylsalicylic acid ratio) | 50mg/kg |
| E001 | Ear swelling | 4.81 | (75.81 with the INDOMETHACIN ratio) 54.75 (with the acetylsalicylic acid ratio) | 50mg/kg |
| E002 | Ear swelling | 9.85 | (50.47 with the INDOMETHACIN ratio) 7.33 (with the acetylsalicylic acid ratio) | 50mg/kg |
| E003 | Ear swelling | 7.91 | (60.20 with the INDOMETHACIN ratio) 25.58 (with the acetylsalicylic acid ratio) | 50mg/kg |
Above presentation of results, compound of the present invention has the anti-inflammatory activity that is better than INDOMETHACIN and acetylsalicylic acid.
Embodiment 9
The compounds of this invention is to thrombotic influence
Male SD rat (300-400g), fasting is divided into PX group, solvent control group (0.25% CMC), ASA positive controls (0.25% CMC at random after 12 hours, and add a spot of tween 80) and administration group (administration derivative E001-003 of the present invention respectively), every group of 5 animals.All medicines or solvent all are by gastric infusion, and dosage is 30mg/kg.After the administration 1 hour, with urethane anesthesia, operation separates arteria carotis communis, and mensuration OT value (incentive condition: electric current 3mA, the time is 180 seconds).The results are shown in following table 8.
Table 8
| Medicine | Average OT value (second) | Variance | P |
| CMC | 457.8 | ||
| E001 * | 561.2 | 70.9 | 0.0270 |
| E002 | 481.4 | 73.4 | 0.5309 |
| E003 ** | 539.4 | 40.1 | 0.0057 |
| PX | 626 | 172.0 | 0.0936 |
| ASA | 588.2 | 83.8 | 0.0220 |
Compare with the solvent control group,
*P＜0.05,
*P＜0.05.
Claims (9)
1, have acceptable salt on following general formula (I), (II) or benzisoxa selenazoles derivative (III) or its pharmacology:
Wherein:
R is-(CH
2) SS (CH
2)-
-(R
aO)2R
a-
-(CH
2)(R
aO)3R
a-
-R
aN(CH
3)2R
a-
-R
aNHR
a-or
-R
aSSR
a-, wherein: R
aBe C
1-6Alkylidene group;
R ' is
Wherein: R " be Cl, H
2O, OH, Br or I,
R is-H ,-CH
2C
6H
5OH ,-CH
2OH ,-CH
2CONH
2,-CH
2CH
2COOH-CH
2(CH
2)
4NH
2,-CH
2COOH ,-CH
2CH
2CONH
2,-(CH
2)
3CH ,-(CH
2)
3NHC (NH) NH
2,-(CH
2)
3CHCH
2,-CH
3,-CH
2CH
3,-CH
2C
6H
5,-CH
2SH or-CH
2CH
2SCH
3, and
R " " is-H ,-CH
2C
6H
5OH ,-CH
2OH ,-CH
2CONH
2,-CH
2CH
2COOH-CH
2(CH
2)
4NH
2,-CH
2COOH ,-CH
2CH
2CONH
2,-(CH
2)
3CH ,-(CH
2)
3NHC (NH) NH
2,-(CH
2)
3CHCH
2,-CH
3,-CH
2CH
3,-CH
2C
6H
5,-CH
2SH or-CH
2CH
2SCH
3
2, compound as claimed in claim 1, wherein R and R " " respectively be independently-H ,-CH
3,-CH
2CH
3,-CH
2C
6H
5,-CH
2SH ,-CH
2CH
2SCH
3
3, a kind of pharmaceutical composition with anti-inflammatory, antitumor or anti-thrombosis function, it comprises as acceptable salt on any described general formula of claim 1-2 (I), (II) or benzisoxa selenazoles derivative (III) or its pharmacology, and acceptable vehicle or carrier on the pharmacology.
4, pharmaceutical composition as claimed in claim 3, it also comprises other antitumor drug.
5, pharmaceutical composition as claimed in claim 4, wherein said other antitumor drugs are Zorubicin, cis-platinum, taxol or its combination.
6, acceptable salt is used for the application of anti-inflammatory, antitumor or antithrombotic medicine in preparation on following general formula (I), (II) or benzisoxa selenazoles derivative (III) or its pharmacology, and its formula of (I), (II) or structure (III) are:
Wherein:
R is-(CH
2) SS (CH
2)-
-(R
aO)2R
a-
-(CH
2)(R
aO)3R
a-
-R
aN(CH
3)2R
a-
-R
aNHR
a-or
R
aSSR
a-, wherein: R
aBe C
1-6Alkylidene group;
R ' is
Wherein: R " be Cl, H
2O, OH, Br or I,
R is-H ,-CH
2C
6H
5OH ,-CH
2OH ,-CH
2CONH
2,-CH
2CH
2COOH-CH
2(CH
2)
4NH
2,-CH
2COOH ,-CH
2CH
2CONH
2,-(CH
2)
3CH ,-(CH
2)
3NHC (NH) NH
2,-(CH
2)
3CHCH
2,-CH
3,-CH
2CH
3,-CH
2C
6H
5,-CH
2SH or-CH
2CH
2SCH
3, and
R " " is-H ,-CH
2C
6H
5OH ,-CH
2OH ,-CH
2CONH
2,-CH
2CH
2COOH-CH
2(CH
2)
4NH
2,-CH
2COOH ,-CH
2CH
2CONH
2,-(CH
2)
3CH ,-(CH
2)
3NHC (NH) NH
2,-(CH
2)
3CHCH
2,-CH
3,-CH
2CH
3,-CH
2C
6H
5,-CH
2SH or-CH
2CH
2SCH
3
7. application as claimed in claim 6, R wherein and R " " be respectively independently-H ,-CH
3,-CH
2CH
3,-CH
2C
6H
5,-CH
2SH or-CH
2CH
2SCH
3
8. application as claimed in claim 6, this medicine can be united use with other antitumor drug simultaneously or sequentially.
9, application as claimed in claim 8, described other antitumor drugs are Zorubicin, cis-platinum, taxol or its combination.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02158917 CN1242999C (en) | 2002-12-27 | 2002-12-27 | Benzo-isoselenazole derivatives having anti inflammation, anti-tumor and anti-thrumbosis function and its use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02158917 CN1242999C (en) | 2002-12-27 | 2002-12-27 | Benzo-isoselenazole derivatives having anti inflammation, anti-tumor and anti-thrumbosis function and its use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1511835A CN1511835A (en) | 2004-07-14 |
| CN1242999C true CN1242999C (en) | 2006-02-22 |
Family
ID=34237233
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02158917 Expired - Fee Related CN1242999C (en) | 2002-12-27 | 2002-12-27 | Benzo-isoselenazole derivatives having anti inflammation, anti-tumor and anti-thrumbosis function and its use |
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| Country | Link |
|---|---|
| CN (1) | CN1242999C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021223780A2 (en) | 2020-05-06 | 2021-11-11 | 上海元熙医药科技有限公司 | Use of benzisoselazole derivative for anti-coronavirus and control of interstitial lung disease (ild) related to coronavirus |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1990475B (en) * | 2005-12-29 | 2011-09-07 | 曾慧慧 | Substituted benzisoselenazolone compounds and use thereof |
| CN101016319B (en) * | 2007-02-13 | 2010-08-04 | 中国海洋大学 | Benzoisoselenothiazolidone aminosugar derivative, preparing method and application therheof |
| CN101921303A (en) * | 2009-06-09 | 2010-12-22 | 曾慧慧 | Benzisoselenazolone difluorocytidine compound as well as preparation method and application thereof |
| CN102898402B (en) * | 2011-04-26 | 2016-01-20 | 北京大学 | The indole ketone compound that the minaline ester that a kind of Benzisoelenazolone is modified replaces and application thereof |
| CN105277699B (en) * | 2014-07-21 | 2017-05-03 | 武汉尚宜康健科技有限公司 | Application of detection reagent in preparation of drugs for evaluation of clinical tumor patient clinical treatment monitoring |
| CN104098627B (en) * | 2014-07-31 | 2017-04-12 | 大连大学 | Seleno derivative of N-trifluoroacetyl epidaunorubicin as well as preparation method and application thereof |
-
2002
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021223780A2 (en) | 2020-05-06 | 2021-11-11 | 上海元熙医药科技有限公司 | Use of benzisoselazole derivative for anti-coronavirus and control of interstitial lung disease (ild) related to coronavirus |
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| Publication number | Publication date |
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| CN1511835A (en) | 2004-07-14 |
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