CN1511834A - Immune regulation and biological therapeutic function of benzo-isoselenazole derivatives - Google Patents
Immune regulation and biological therapeutic function of benzo-isoselenazole derivatives Download PDFInfo
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Abstract
The present invention relates to benzo-isoselenazole derivative and its pharmaceutically acceptable salt. The derivative may be used in immunological regulation and biological therapy and as health composition with immunological regulation function.
Description
Invention field
The present invention relates to the application that a class can strengthen the benzisoxa selenazoles derivative of human inner cell's immunity system NK cell and LAK cytoactive.The invention still further relates to the pharmaceutical composition when comprising this benzisoxa selenazoles derivative and composition thereof as the technical scheme of the medicine of immunomodulatory and biotherapy, medicinal application, enforcement field and associated treatment; And this derivative has the formed technical scheme and methods for using them of health composition of immunomodulatory or biological regulatory function in preparation.
Background technology
Biotherapy technology or the biological therapy of regulating are the background technologies that important relationship is arranged with the related compound of the present patent application.The biotherapy technology is that development in recent years is swift and violent, with the corresponding biological medicine technology of chemotherapy and radiation.Main biotherapy technology has cytokine (element) therapy, immunocyte therapy and gene therapy.Be used for the material general designation biologically conditioning agent of biotherapy technology, comprise cell regulating factor or cytokine (Interferon, rabbit, interleukin-etc.), cell immunomodulator (biological response modifier) etc.
The biologically conditioning agent can be adjusted self potentiality of internal body to strengthen tumour, to infect the biologically of a class focus.For example interleukin II (IL-2) can promote B cell, natural killer (NK) cell, lymphokine activated to kill and wound the differentiation and proliferation of (LAK) cell, and is significant aspect the treatment of immunodeficient disease and autoimmune disorder and diagnosis and anti-malignant tumor.
Immunostimulant is a kind of brand-new biologically conditioning agent, is also referred to as immunomodulator, plays very important regulating and controlling effect in body immune system, can make too high or low excessively immunologic function is adjusted to normal level.Clinical learning with experiment immunization studies show that tumour, infection, allergic disorder, autoimmune disease and acquired immune deficiency syndrome (AIDS) (AIDS) etc. are all with immunologic injury.Immunomodulatory plays an important role in above-mentioned associated treatment, has boundless application prospect.Particularly tumor immunology develops rapidly in recent years, and oncobiology reaction control agent (Biological Rer Spense Modifier BRSM) therapy has entered a new stage.
In addition, the present other diseases of report as the high viral hepatitis of sickness rate, very harmful AIDS etc., uses or unites and use immunomodulator that the state of an illness is significantly improved.
The hepatic injury that has reported in literature viral hepatitis (HBV) to infect to cause and the immune response of body are closely related, sexually revise and to HBV cells infected and Normocellular cell toxicant immune response comprising virus replication, infected liver cell surface antigen.HBV can not the direct killing liver cell, and the infringement of liver is the immune response by the host mainly.Host's immune response has comprised specific immune response (antibody and cellular immunization) and nonspecific immune reaction (NK cell), and whether they are to causing chronic HBV infection to occupy an important position.
Patient AIDS shows immunologic function and lacks, being generally the IL-2 level descends, the medicine and the measure that strengthen patient's immunologic function have at present comprised that Interferon, rabbit and IL-2 utilize, IL-2 is produced by sophisticated T cell, one of important function is to improve NK cytoactive, promotion T cytodifferentiation propagation, promotion B cell proliferation etc., clinical report, external application IL-2 10U/ml, make patient's peripheral blood M Φ secretion of gamma-IFN and lymphocyte express IL-2 acceptor showed increased, patient's immunologic function is restored.The two second sulphur ammonia first diesteras of immune inducing agent are applied to clinically in addition, and 42% patient is taken a turn for the better, weight increase, and physique is recovered; And isoprinosine can make body IL-2 raise, and improves patient's the AIDS state of an illness.
With the related application of compound of the present patent application the immunocyte of important relationship being arranged is some nonspecific immune reaction cells, comprises NK cell and Lak cell, occupies critical role in the biotherapy technology.The NK cell is that (natural killer cell NK), is the important immune lymphocyte and the autarcetic main undertaker of body to natural killer cell.The NK cell do not rely on thymus gland, do not rely on antibody and complement, need not that antigen stimulates in advance can the secretory cell poison factor, under the situation that no antibody participates in, killing tumor cells one class cell is a kind of killer cell of wide spectrum in vivo and in vitro, plays crucial effect to stoping tumor growth.And antiviral, anti-infective, participate in immunomodulatory.Studies show that the NK cell occupies critical role in tumour immunity, is the antineoplastic the first line of defence of body.And the LAK cell is a kind of lymphokine IL-2 activated killer cell that needs, LAK cell and NK cell have complementarity, can kill and wound to the NK cell can not kill and wound tumour one class cell, have broad spectrum more widely than NK cell, it is the most important immunocyte of modern biotherapy equally.
The importance in immune biotherapy in view of NK cell and LAK cell, it is very important therefore to seek strong NK and LAK cytoactive toughener or inductor.
The compound related about the research of selenium and the present patent application all has direct relation on structure and function.Selenium is one of trace element of needed by human, and the blood selenium content is lower than 0.1ppm for a long time and might causes numerous diseases such as hepatic necrosis, myocardial damage, cancer and sacroiliitis in the questionnaire person of good sense body.Selenium is established the discovery to the Animal nutrition effect in nineteen fifty-seven K.Schwarz and C.M.Foltz as the teleorganic micro-status of Mammals (comprising the mankind).Recent two decades comes, the bioactivity research of selenium is obtained the development of advancing by leaps and bounds, scientists is found the intravital four kinds of selenium enzymes of Mammals continuously, comprise that cell Selenoperoxidase (GSH-Px), phospholipid hydroperoxide glutathione peroxidase (PHG-Px), blood plasma Selenoperoxidase (P GSH-Px) and I type iodine thyroxine 5 ' take off iodine enzyme (5 '-DI), in addition, also find with the selenium enzyme-Trx enzyme of some disease-related etc.
Selenium is to the importance of life science, makes to contain the selenium medicine and the nourishing function product become remarkable focus.Usually inorganic selenium is difficult for being absorbed, and biological activity is lower, and toxicity is big; And organoselenium is easily absorbed by human body, can be able to keep the long period in blood, easily be converted into activated metabolism intermediate in vivo, and bio-toxicity is less relatively.
In the state of the art, can obtain to have the chemical simulation thing 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, not only anti-oxidant activity height, 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.
There is article report R-bibenziisosehenazoleethane substitution compound to have anti-encephalomyocarditis virus (EMCV), stomatitis herpesvirus (VSV) and the active research of herpes simplex virus type 1 (HSV-1) recently (as Polish J Chem 75,823-830,2001), but except above-mentioned virus, other dna virus and RNA viruses, particularly hepatitis virus (HBV) and hiv virus (HIV) are not all reported.
Existing several pieces of Patent publish Ebselen derivatives are as medicinal research, and they are respectively the effect of Chinese patent 98124487.4 (application number) Benzisoelenazolone sulfamide derivative aspect inflammation-inhibiting and anaphylactic disease; Chinese patent 01118666.6 (application number) R-anti-inflammatory, antitumor action and PCT/CN02/00412 (application number) two or sugared benzisoxa selenazoles substitution compound have the benzisoxa selenazoles derivative and the application thereof of anti-inflammatory, antitumor and anti-thrombosis function; Aspect immunomodulatory research, although numerous research and utilization Ebselen parent nucleus is arranged, it is transformed into the immunostimulant compound, but successful medicament for immunity enhancement, particularly immunomodulatory research and the biotherapy application about the related compound of the present patent application do not appear in the newspapers as yet.
Summary of the invention
The objective of the invention is on the anti-oxidant mother nucleus structure of Ebselen (ebselen) basis, to locate and transform out novel organoselenium biological regulator and the immunostimulant agent medicine that immunoregulation effect is strong, adaptability is wider, toxicity is lower, be used for the treatment of various immunologic injury diseases and immunoloregulation function and rely on or promoted relative disease, as infection, viral hepatitis, allergic disorder, autoimmune disease, acquired immune deficiency syndrome (AIDS) (AIDS) and oncotherapy etc.
The medicine of the benzisoxa selenazoles derivative that the present invention relates to and nourishing function product mentality of designing are to take into full account on the basis that keeps the Ebselen active nucleus, increasing new functional group, a series of compounds of positioning design.Because the characteristics of structure have multiple biological activity in vivo, especially the characteristics that have " biological response modifier " (biologically conditioning agent), with the point of adjustment in the biological response device is target, directed generation effect, it is the novel active compound of a class with comprehensive adjusting body, multiaction target spot, especially to the activation of immunocytes such as NK cell and LAK cell, enhancing body's immunological function, show its anti-inflammatory, antitumor and other immunologic injury disease effects, have medicine application prospect preferably.
Content of the present invention comprises:
1, 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
1-6Alkylidene group, phenylene, biphenylene, inferior triphenyl or
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.
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
2, the invention provides and comprise above-mentioned general formula (I), (II) or benzisoxa selenazoles derivative (III), or acceptable vehicle and carrier on the pharmaceutical composition of acceptable salt and the pharmacology on its pharmacology, or acceptable vehicle and carrier on the nourishing function composition of acceptable salt and the hygiology on its hygiology
3, the invention provides above-mentioned general formula (I), (II) or benzisoxa selenazoles derivative (III), or acceptable salt is used for immunocytes such as NK cell and LAK cell are regulated the application of (enhancing) medicine on its pharmacology in preparation, or acceptable salt is used for having the application of the healthcare products of immunoloregulation function in preparation on its hygiology, shows its application prospect aspect biotherapy and biological health adjusting.
4, 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.
The form of medication that adopts 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, vehicle and as the binding substances of the present invention of activeconstituents (one or more), in addition, also can comprise other medicament and assistant agent etc.; Adopt the liquid form administration pharmaceutical composition can by means such as dissolving, dispersion with binding substances of the present invention (about 0.5 to about 20%) and optionally medicinal adjuvant dissolve, be scattered in the carrier, the example of carrier is water, salt solution, dextrose hydrate, glycerine, ethanol etc., thereby forms solution or suspensoid.
The administering mode that adopts, can select in the through port, nose, rectum, transdermal, drug administration by injection and liposome class target administration mode etc., 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;
Usually, according to required administering mode, pharmaceutically acceptable composition comprises the suitable pharmaceutical excipient of about 1 to 99 weight % of the binding substances that the present invention relates to 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.
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, with diagnosis, treatment and the anti-tumor aspect disease that is used for the treatment of corresponding immunodeficient disease and autoimmune disorder.
5, on derivative of the present invention or its hygiology acceptable salt can pure compound healthcare products form or suitable health composition carry out for oral usely, can adopt any acceptable mode of taking to carry out.
The form for oral use that adopts is solid, semisolid, lyophilized powder or liquid form, for example tablet, pill, soft hard-gelatin capsules, powder, solution, suspensoid etc., the preferred presented in unit dosage form that adopts the simple administration that is applicable to exact dosage desired; Composition can comprise the conventional carrier that uses, edible vehicle and as the binding substances of the present invention of activeconstituents (one or more), in addition, also can comprise the additive of other health-care components and needs and assistant agent etc.; Adopt composition that liquid form takes can by means such as dissolving, dispersion with binding substances of the present invention (about 0.5 to about 20%) and optionally assistant agent dissolve, be scattered in the carrier, the example of carrier is water, edible ethanol etc., thereby forms solution or suspensoid.
Usually, according to required form for oral use, acceptable composition will comprise suitable edible vehicle and the additive of about 1 to 99 weight % of the binding substances that the present invention relates to and 99 to 1 weight % on the hygiology.Preferred composition comprises the binding substances of the present invention of about 5 to 75 weight %, and all the other are suitable edible vehicle and additive.
The foodstuff additive that use in the present composition comprise emulsifying agent, antioxidant, sanitas etc.
The actual fabrication method of such formulation is that those skilled in the art is known or conspicuous.In any case according to technology of the present invention, employed composition will contain the binding substances of the present invention of the significant quantity that keeps healthy, to be used for the health care that human immunity is regulated.
6, the invention provides the corresponding various immunologic injury diseases of treatment and immunoloregulation function dependence or promoted relative disease in people and the Mammals, as the method for infection, viral hepatitis, allergic disorder, autoimmune disease, acquired immune deficiency syndrome (AIDS) (AIDS) and oncotherapy etc., comprise that patient to these treatments of needs gives on the above-mentioned general formula (I) of significant quantity or benzisoxa selenazoles derivative (II) or its pharmacology acceptable salt and unite to give other treatment medicine or immunoregulation druge.
7, when benzisoxa selenazoles derivative of the present invention and other treatment medicine or the medication combined use of immunocyte enhancing, 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 medicine or immunocyte of administration strengthens medicine, and other medicine or immunocyte of first administration strengthens medicine and then administration benzisoxa selenazoles of the present invention derivative.
8, benzisoxa selenazoles derivative of the present invention relies on or promoted relative disease in corresponding various immunologic injury diseases of treatment and immunoloregulation function, during as infection, viral hepatitis, allergic disorder, autoimmune disease, acquired immune deficiency syndrome (AIDS) (AIDS) and oncotherapy, its dosage is about 0.05-250mg/kg body weight.With other medicine or immunocyte when strengthening medication combined uses, 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 use.
Further described the present invention in the following embodiments, medicine is with 1, and 2-two { (1,2)-benzisoxa selenazoles-3 (2H)-ketone }-ethane (or butane) is example, and this does not limit the scope of the invention.
Embodiment
Embodiment 1: medicine is to the Study immune regulation of BALB/C normal mice
Animal grouping and administering mode:
The BALB/C mouse is divided into 4 groups at random, 20 animals of experiment medicine group, and the medicine of the fresh configuration of abdominal injection, 10 dosage are 25.0mg/kg, other 10 dosage are 12.5mg/kg, every day 1 time, successive administration 7 days; 10 animals of positive controls, abdominal injection positive control medicine ddp, dosage is 2.0mg/kg, be administered once every day, continuous 7 days.10 of control groups, abdominal injection solvent, volume are according to the body weight adjustment, and be identical with the medicine group.Inject continuous 7 days every day 1 time.
Below respectively organize mouse through successive administration, the execution of craning one in the 3rd day after drug withdrawal, the aseptic spleen of getting, claim weight in wet base, add the 2ml nutrient solution spleen is shredded, filter with 150 order cells sieve, add the 2ml nutrient solution, make single cell suspension, separate mononuclearcell, wherein be mainly lymphocyte with lymphocyte separation medium.Adjusting cell concn with RPMI-1640 is 2 * 10
6The effector cell that/ml measures as the NK cytoactive, the dyeing of 0.2% trypan blue, cell survival rate is greater than 95%.
Mtt assay is surveyed the splenocyte proliferation activity:
Separate mononuclearcell with lymphocyte separation medium, adjustment concentration is 3 * 106/ml.Get 96 porocyte culture plates, every hole adds cell suspension 100 μ l, and the ConA solution 100 μ l of 10mg/ml, each sample establish 6 multiple holes, and other establishes 3 blank holes, and every hole adds nutrient solution 200 μ l, jog mixing, 37.The C incubator was cultivated 72 hours, cultivated and finished preceding 4 hours every hole sucking-off culture supernatant, added the MTT20 μ l of people 5mg/ml, continued to cultivate; Cultivate the centrifugal 30min of 3000rpm when finishing,
(table)
NK activity, spleen weigh and splenocyte propagation result
| The medicine group | The medicine group | Positive drug group (DDP) | Blank (control) | |
| Dosage (mg/kg) | ????25 | ????12.5 | ????2 | |
| Splenocyte propagation (OD) | ????0.544 | ????0.465 | ????0.260 | ????0.121 |
| Spleen heavy (g) | ????0.410 | ????0.290 | ????0.120 | ????0.220 |
| The NK activity | ????0.429 | ????0.352 | ????0.026 | ????0.112 |
Abandon supernatant, every hole adds ethanol-DMSO solution dissolving of 200 μ l, and 595nm surveys the OD value.
Spleen heavy and splenocyte propagation result such as table one.As can be seen from Table I, experiment medicine group splenocyte proliferation activity is apparently higher than control group, and experiment medicine group mice spleen is heavy to increase with control group mice spleen heavy phase ratio, and positive drug group mice spleen is heavy minimum.
Embodiment 2: medicine is to the immunoregulation effect of common one-level small white mouse IC2
32 of IC2 mouse about 25 grams are divided into 4 groups at random, and 8 every group, the 1st group of intraperitoneal injection of drugs, dosage is 25mg/kg, successive administration 4 days; The 2nd group of intraperitoneal injection of drugs, dosage is 12.5mg/kg, successive administration 4 days; The 3rd group of abdominal injection DDP, dosage is 2mg/kg; The 4th group of abdominal injection equal-volume solvent, continuous 4 days.Spleen is got in the execution of craning one in the 5th day, and it is 2 * 10 that lymphocyte separation medium separates mononuclearcell adjustment cell concn
6/ ml is as the effector cell of NK cell.Get mononuclearcell suspension 3.6ml, add 10
4The IL of U/ml
20.4ml,, change the plastic culture bottle over to, cultivate after 48 hours, inhale and to remove nutrient solution and suspension cell, adds new nutrient solution, the concentration of keeping IL2 is 1000U/ml, continues cultivation, changes a not good liquor in two days.The 7th day results attached cell, adjusting cell concn is 10
6/ ml is as the effector cell of LAK cell.The concentration of adjusting YAC-1 and P815 cell is 10
5/ ml is standby
1. the mensuration of NK/LAK cytoactive
If experimental port, target cell control wells, effector cell's control wells and blank well, experimental port add effector cell and each 50 μ l of target cell; Cell control well adds target cell 50 μ l, nutrient solution 50 μ l; Effector cell's control wells adds effector cell 50 μ l, nutrient solution 50 μ l; The blank hole adds nutrient solution 100 μ l, and each sample is established 6 multiple holes, cultivates 4 hours, and the every hole of M adds MTT 20 μ l cultivated 2 hours again, and the centrifugal 30min of 3000rpm abandons supernatant, and every hole adds ethanol-DMSO solution dissolving of 200 μ l, and 595nm surveys the OD value.
NK/LAK cytoactive=(experimental port OD value-effector cell's control wells OD value)/target cell control wells OD value * 100%
2. each 100 μ l/ hole of the ConA of the mensuration mononuclearcell suspension of splenocyte proliferation activity and 10 μ g/ml add 96 well culture plates, cultivate after 72 hours and survey splenocyte propagation with mtt assay.
(table two)
The splenocyte proliferation activity
| Group | Dosage (mg/kg) | NK activity (%) | LAK activity (%) | Splenocyte propagation (OD value) |
| Medicine | ????25.0 | ????40.95 | ????89.02 | ????0.528 |
| Medicine | ????12.5 | ????34.34 | ????0.417 | |
| ????DDP | ????2.0 | ????2.65 | ??????- | ????0.284 |
| ????CONTROL | ????10.27 | ????67.06 | ????0.439 |
3. experimental result sees Table two.Experiment shows that the related benzisoxa selenazoles derivative of the present patent application can be induced the secretion of splenocyte to the NK cell, significantly improves the NK cytoactive.
Embodiment 3: medicine is to the research of the biological regulating effect of C57 tumor mouse
(1) C57 tumor mouse difference abdominal injection EB (25mg/kg), DDP and solvent, successive administration 7 days was with the execution of craning one in the 10th day, get Pi and claim spleen heavy, separate mononuclearcell, mtt assay is surveyed splenocyte proliferation activity and NK/LAK cytoactive, mtt assay is surveyed the NK cytoactive, and method is the same.Spleen heavy and splenocyte propagation result such as table three.
(table three)
Spleen heavy and splenocyte propagation result such as following table
| The medicine group | Positive drug group (DDP) | Blank | |
| Dosage (mg/kg) | 25 | ?2 | |
| Splenocyte propagation (OD) | 0.395 | ?0.025 | ?0.058 |
| Spleen heavy (g) | 0.428 | ?0.135 | ?0.305 |
| NK activity (%) | 20.06 | ?10.21 | ?10.32 |
Test medicine group splenocyte proliferation activity as can be seen from the table and compared evident difference with control group with positive controls, the former splenocyte proliferation activity is apparently higher than the latter; The spleen of ddp group mouse is heavy minimum, and experiment medicine group mice spleen is heavy the highest, and control group takes second place; Other two groups of height of experiment medicine group NK cells in mice specific activity
(2) medicine is to the influence of C57 mouse tumor
Behind the inoculated tumour 3 days, control group nape minister plays macroscopic lump, and growth is rapidly; Positive controls and experiment medicine group mouse the 4th, 5 day beginning behind inoculated tumour are seen nape portion lump, and poor growth.Put to death mouse in 10 days behind the inoculated tumour, peel off tumour, weigh, the results are shown in table four.
(table four)
Medicine is to the influence of Lewis lung cancer C57 mouse tumor
| Group | Dosage (mg/kg) | Administration time (my god) | The animal number of elements is front/rear | Knurl heavy (g) | Tumour inhibiting rate (%) | The P value |
| Control group | ?????- | ????7 | ????10 ????10 | ????2.36 ????±1.23 | ||
| The DDP group | ????2.0 | ????7 | ????10 ????10 | ????0.47 ????±0.231 | ????80.3 | ????＜0.0 ????1 |
| Experimental group | ????25.0 | ????7 | ????10 ????9 | ????0.61 ????±0.33 | ????74.3 | ????＜0.0 ????1 |
| Experimental group | ????12.5 | ????7 | ????6 ????6 | ????1.20 ????±0.38 | ????49.4 | ????0.017 |
As can be seen from the table, experiment medicine group and positive controls tumour knurl be heavy compares with control group that all there were significant differences, wherein the inhibiting rate of 25mg/kg dosage group and positive control medicine DDP2.0mg/kg dosage group difference are not remarkable, 12.5mg/kg the dosage group is compared with control group, and there were significant differences, but inhibiting rate is less than 25mg/kg dosage group.
(3) tumor tissue cell's morphologic observation
Tumor tissues is after specimens paraffin embedding slices, HE dyeing, 40 * light microscopic is observed down, cellular control unit nuclear is big, divides many mutually, heterogeneous strong, compare DDP group and the concentrated engrain of EB group nuclear with control group, nuclear morphology is various circle, Polygons, bar shaped, annular, lune etc., divide mutually less, as shown in Figure 2.Every group is selected 4 slice, thin pieces, every slice, thin piece 3 visuals field that count at random, and 120-150 cell, the numeration somatoblast, di=division phase cell count/total cell count, the calculating di is as follows:
As can be seen, DDP group and medicine group tumour cell division index are starkly lower than control group, and significant difference is arranged from table five.Di does not have significant difference between DDP group and the medicine group.
(table five)
. the painted cell division index of tumor tissues HE is observed in administration under the light microscopic after 7 days
| Group | Dosage (mg/kg) | Administration fate (day) | Di (X ± SD) | The p value |
| Contrast | ?????- | ????7 | ????0.71±0.065 | |
| The DDP group | ????2.0 | ????7 | ????0.19±0.004 | ＜0.01 |
| The medicine group | ????25.0 | ????7 | ????0.34±0.057 | ＜0.01 |
Embodiment 4: medicine is to the influence of macrophage phagocytic function
The healthy mice of body weight 18-22g is divided into administration group, feminine gender and positive controls at random.Test and gave 1 in preceding 4 days, 2-two { (1,2)-benzisoxa selenazoles-3 (2H)-ketone }-butane (medicine 1) is (25mg/kg), 1,2-two { (1,2)-benzisoxa selenazoles-3 (2H)-ketone }-(25mg/kg) administration after 4 days of ethane (medicine 2), every mouse abdominal injection 5% chicken red blood cell physiological saline suspension 0.5ml.10 hours at interval, mouse was put to death in the cervical vertebra dislocation, and abdominal skin is cut off in the center, inject physiological saline 2ml through peritonaeum, gently by rubbing the mouse belly 1 minute, sucking-off abdominal cavity washing lotion 1ml then, divide and drip on two slide glasss, put into the enamel box that is lined with wet gauze, 37 ℃ of incubator incubations of dislocation 30 minutes.With the physiological saline rinsing, to remove the not cell of bonding die.Dry, acetone one methanol solution was fixed 5 minutes in 1: 1.4% (V/V) Giemsa, one phosphoric acid buffer dyeing 3 minutes, with the flowing water flushing, dry in the air in.The oil mirror is the counting scavenger cell down, every 200 calculating:
1. scavenger cell number/200 scavenger cell (gulp down and do not gulp down) * 100% of the chicken red blood cell of phagocytic percentage=engulf
2. phagocytic index=quilt chicken red blood cell/200 scavenger cell * 2 of engulfing
When counting, observe the degree that chicken red blood cell is digested simultaneously, so as to judging macrophage phagocytic and digestive function, be divided into 4 grades usually:
I level: not digestion.The chicken red blood cell of being engulfed is complete, and the pale red or pale yellow band of kytoplasm is green, the karyon light violet magenta.
II level: slight digestion.The kytoplasm oyster, the karyon pyknosis is hyacinthine.
III level: severe digestion.Kytoplasm is light to be dyed, and karyon is ecru.
IV level: complete digestion.The cavity of the similar chicken red blood cell size of rarely seen form in the scavenger cell, neat in edge, karyon mays be seen indistinctly.
(table six). administration is the macrophage phagocytic function activity rating after 4 days
| Medicine 1 | Medicine 2 | Positive drug group (DDP) | Blank (control) | |
| Dosage (mg/kg) | ????25 | ????25 | ????2 | Physiological saline |
| Phagocytic percentage | ????73％ | ????68％ | ????18％ | ????22％ |
| The I level | ????11％ | ????9％ | ????14％ | ????14％ |
| The II level | ????38％ | ????32％ | ????82％ | ????78％ |
| The III level | ????36％ | ????37％ | ????4％ | ????8％ |
| The IV level | ????15％ | ????22％ | ????- | ????- |
Claims (18)
1, 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
1-6Alkylidene group, phenylene, biphenylene, inferior triphenyl or
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,
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, benzisoxa selenazoles derivative as claimed in claim 1 and application thereof, wherein R is the C1-4 alkylidene group.
3, benzisoxa selenazoles derivative as claimed in claim 2 and application thereof, wherein R is a butylidene.
4, benzisoxa selenazoles derivative as claimed in claim 1 and application thereof, wherein R is phenylene or biphenylene.
5, benzisoxa selenazoles derivative as claimed in claim 4 and application thereof, wherein R is a biphenylene.
6, benzisoxa selenazoles derivative as claimed in claim 1 and application thereof, wherein R ' is 1,3,4,
6-four-O-ethanoyl-2-deoxidation-D-glucopyranosyl.
7, benzisoxa selenazoles derivative as claimed in claim 1 and application thereof, wherein R and R " " respectively be independently-H ,-CH
3,-CH
2CH
3,-CH
2C
6H
5,-CH
2SH ,-CH
2CH
2SCH
3
8, a kind of pharmaceutical composition, it comprises acceptable vehicle or carrier on the pharmaceutical composition of acceptable salt on general formula as claimed in claim 1 (I), (II) or benzisoxa selenazoles derivative (III) or its pharmacology and the pharmacology.
9, a kind of nourishing function composition, it comprises acceptable vehicle or carrier on the nourishing function composition of acceptable salt on general formula as claimed in claim 1 (I), (II) or benzisoxa selenazoles derivative (III) or its hygiology and the hygiology.
10, pharmaceutical composition as claimed in claim 8, its medicine and cellular immunization that also comprises other strengthens medicine.
11, nourishing function composition as claimed in claim 9, it also comprises other nourishing function effective constituent.
12, acceptable salt is used for the treatment of various immunologic injury diseases and immunoloregulation function in preparation and relies on or promoted relative disease on general formula as claimed in claim 1 (I), (II) or benzisoxa selenazoles derivative (III) or its pharmacology, as the diagnosis of infection, viral hepatitis, allergic disorder, autoimmune disease, acquired immune deficiency syndrome (AIDS) (AIDS) and tumour, treatment etc.
13, being used for various immunologic injury diseases and immunoloregulation function in comprising people's Mammals relies on or promoted relative disease, as the diagnosis of aspect diseases such as infection, viral hepatitis, allergic disorder, autoimmune disease, acquired immune deficiency syndrome (AIDS) (AIDS) and tumour, the method for treatment, it comprises acceptable salt on the general formula as claimed in claim 1 (I) of patient's drug treatment significant quantity of these treatments of needs, (II) or benzisoxa selenazoles derivative (III) or its pharmacology.
14, being used for various immunologic injury diseases and immunoloregulation function in comprising people's Mammals relies on or promoted relative disease, as the diagnosis of aspect diseases such as infection, viral hepatitis, allergic disorder, autoimmune disease, acquired immune deficiency syndrome (AIDS) (AIDS) and tumour, the method for treatment, it comprises the medicine of on general formula as claimed in claim 1 (I), (II) or benzisoxa selenazoles derivative (III) or its pharmacology of patient's Combined Preparation of these treatments of needs treatment significant quantity acceptable salt and the above-mentioned disease of other treatment.
15, method as claimed in claim 14, acceptable salt is and other medicine administration simultaneously on general formula wherein as claimed in claim 1 (I), (II) or benzisoxa selenazoles derivative (III) or its pharmacology.
16, method as claimed in claim 14, acceptable salt on wherein first administration general formula as claimed in claim 1 (I), (II) or benzisoxa selenazoles derivative (III) or its pharmacology, and then the described other drug of administration.
17, method as claimed in claim 14, the described other drug of wherein first administration, and then acceptable salt on administration general formula as claimed in claim 1 (I), (II) or benzisoxa selenazoles derivative (III) or its pharmacology.
18, as the described method of one of claim 14-17, wherein the described other drug of administration is their combination.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02158916 CN1281593C (en) | 2002-12-27 | 2002-12-27 | Immune regulation and biological therapeutic function of benzo-isoselenazole derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1511834A true CN1511834A (en) | 2004-07-14 |
| CN1281593C CN1281593C (en) | 2006-10-25 |
Family
ID=34237232
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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| TWI852726B (en) * | 2022-11-21 | 2024-08-11 | 北京市神經外科研究所 | Application of benzoisoselenazole compounds in the preparation of drugs for treating spinal cord glioma |
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|---|---|
| CN1281593C (en) | 2006-10-25 |
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