CN102068434B - Application of 4-(cyclohexyl)-aminoquinazoline compounds - Google Patents
Application of 4-(cyclohexyl)-aminoquinazoline compounds Download PDFInfo
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- CN102068434B CN102068434B CN2011100269599A CN201110026959A CN102068434B CN 102068434 B CN102068434 B CN 102068434B CN 2011100269599 A CN2011100269599 A CN 2011100269599A CN 201110026959 A CN201110026959 A CN 201110026959A CN 102068434 B CN102068434 B CN 102068434B
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Abstract
The invention relates to the field of medical immunology, and discloses application of a compound shown as a formula (I) in preparing a medicament used for inducing T cells to be differentiated into FoxP3+CD4+ regulatory T cells and inhibiting the T cells from proliferating, wherein the compound shown as the formula (I) belongs to 4-(cyclohexyl)-aminoquinazoline compounds. The compound shown as the formula (I) plays a remarkable role in inhibiting the T cells from proliferating and inducing the T cells to be differentiated into the FoxP3+CD4+ regulatory T cells, and the medicament which is prepared by the compound and is used for inducing the T cells to be differentiated into the FoxP3+CD4+ regulatory T cells and inhibiting the T cells from proliferating can be used for autoimmune diseases and transplantation rejection.
Description
Technical field
The present invention relates to the Medical Immunology field, be specifically related to 4-(cyclohexyl)-amido quinazoline compounds and be divided into FoxP3 at the preparation inducing T cell
+CD4
+Application in the medicine of regulatory T cells and suppressor T cell propagation.
Background technology
After immunne response was meant that body immune system is accepted antigenic stimulus, activation, propagation, differentiation or anergy, apoptosis took place in lymphocyte specific identification antigen, and then the overall process of performance biological effect.Immunne response is divided into cell-mediated cellular immunization of T and the cell-mediated humoral immunization of B.Though humoral immunization is cell-mediated by B, under the T cell is auxiliary, could produce.This shows that the T cell is the crucial quasi-lymphocyte of comparison in whole immunne response.
The most basic biological significance of immunne response is identification " oneself " and " non-own ", and removes " non-own " antigenicity substance, avoids the invasion and attack of antigen foreign body with the protection body.But under certain conditions, immunne response also possibly cause damage to body, like autoimmune disease and graft-rejection.Autoimmune disease refers to that body causes autologous tissue to damage caused disease to autoantigen generation immunoreation, and it is because the tolerance of body autoimmune is destroyed, the immunologic dysfunction that causes the activation of T cell transition, propagation to cause; And graft-rejection is meant in tissue transplantation or organ transplantation, after the receptor accepts the graft of donor, causes receptor's the immune system and the graft generation immunoreation of donor, the normal function of infringement receptor's body.
In order effectively to treat autoimmune disease and to avoid graft-rejection, generally use immunomodulator at present clinically, like CsA, FK506, MMF etc.But these materials have also suppressed regulatory T cells in suppressor T cell activation and propagation, and regulatory T cells is vital for inducing the autoimmune tolerance.Regulatory T cells is a subgroup of T cell, and it induces the autoimmune tolerance through depression effect property T cell and responsiveness B cell activity, and the protective tissue organ does not receive the autoimmune attack and sustains damage.Simultaneously, regulatory T cells also limits to the immunologic injury of pathogenicity antigen immune response due to excessively, has crucial effects to keeping immunity of organism dynamic equilibrium.
FoxP3
+CD4
+Regulatory T cells is a kind of in the regulatory T cells, has important function inducing of tolerating of autoimmune tolerance and transplantation immunity with in keeping.Wherein, FoxP3 is FoxP3
+CD4
+The significant molecule of regulatory T cells belongs to the foxhead family member, and the constructive expression is in FoxP3
+CD4
+Regulatory T cells, mediation FoxP3
+CD4
+Regulatory T cells is kept in growth, periphery expression and the function of thymus, and regulates immune response and immunologic tolerance through the function that influences the Th cell.FoxP3
+CD4
+The quantity of regulatory T cells descends, and will cause the immunoloregulation function defective, brings out serious autoimmune disease.
Therefore, a kind of can suppressor T cell propagation can induce FoxP3 again
+CD4
+The medicine of regulatory T cells differentiation is to treating autoimmune disease and avoiding graft-rejection significant.
Summary of the invention
The invention provides chemical compound shown in the formula I and be divided into FoxP3 at the preparation inducing T cell
+CD4
+Application in the medicine of regulatory T cells and suppressor T cell propagation.
Formula I chemical compound according to the invention is 4-(cyclohexyl)-amido quinazoline compounds, and structure is following:
Wherein, R is H, Cl, F, carboxyl, nitro, trifluoromethyl or C among the formula I
1-C
4Alkyl.At present; Pertinent literature has been reported the application of 4-(cyclohexyl)-amido quinazoline compounds aspect prevention and treatment of diseases such as inflammation, tumor and viral infection, but does not see that also 4-(cyclohexyl)-amido quinazoline compounds is divided into FoxP3 in suppressor T cell propagation and inducing T cell
+CD4
+The relevant report of regulatory T cells.
Formula I chemical compound according to the invention effect in people and mouse T cell propagation inhibition test is extremely remarkable; Simultaneously, at FoxP3
+CD4
+The streaming of regulatory T cells detects in the test also can significantly improve FoxP3
+CD4
+The quantity of regulatory T cells.Above result of the test fully show formula I chemical compound can suppressor T cell propagation can induce FoxP3 again
+CD4
+The regulatory T cells differentiation can be used for preparing inducing T cell and is divided into FoxP3
+CD4
+The medicine of regulatory T cells and suppressor T cell propagation.
Under normal circumstances, body immune system is identified as " oneself " with the antigenic component of autologous tissue, generally it is not produced immunne response, or only produces faint immunne response, and this is the autoimmune tolerance.But under the situation of immunologic dysfunction, the autoimmune tolerance is destroyed, and body immune system produces immunne response to autoantigen, and this is an autoimmune response.If autoimmune response is strong excessively, the persistent period is long; So that destroy self normal structure structure and cause corresponding clinical symptoms; Will cause autoimmune disease, for example type i diabetes, systemic lupus erythematosus (sle), multiple sclerosis, rheumatoid arthritis etc.Say from genesis mechanism, because regulatory T cells FoxP3 particularly
+CD4
+The quantity of regulatory T cells descends, and makes that the reaction-ive T cell of non-self tolerance is not suppressed, and gets into blood circulation in the thymus to meet with autoantigen, and immunne response also takes place for overactivity, propagation, causes autologous tissue to be damaged.According to above-mentioned result of the test, formula I chemical compound according to the invention can suppress the T cell of hyper-proliferative, and inducing T cell is divided into FoxP3 simultaneously
+CD4
+Regulatory T cells makes FoxP3
+CD4
+The ratio of regulatory T cells rises, and recovers the autoimmune tolerance, effectively treats autoimmune disease.
In graft-rejection, graft is the own antigen of right and wrong mostly, and receptor's immune system can't be set up the immunologic tolerance of graft antigenic component, and therefore can graft be regarded as " invador " and immunne response takes place with it, and then infringement receptor's body tissue.Though this phenomenon belongs to normal immunoreation, it is disadvantageous transplanting for organ or tissue.Formula I chemical compound according to the invention guarantees that through suppressing with graft immunoreactive T cell to take place housing construction is injury-free, induces FoxP3 simultaneously
+CD4
+Receptor's immune function is regulated in the regulatory T cells differentiation, sets up the immunologic tolerance between graft and the receptor's immune system, avoids the generation of graft-rejection.
In sum, formula I chemical compound according to the invention can the suppressor T cell activation and proliferation, thereby can suppress the immunne response of being brought out by non-oneself or autoantigen, and the protection body is injury-free; Simultaneously, formula I chemical compound can also be divided into FoxP3 by inducing T cell
+CD4
+Regulatory T cells, thus FoxP3 in the autoimmune disease patient body improved
+CD4
+The quantity of regulatory T cells makes the autoimmune tolerance recover normal.For graft-rejection, the FoxP3 that differentiates
+CD4
+Regulatory T cells suppresses the reaction-ive T cell with graft generation immunne response, makes reaction-ive T cell can not get into blood circulation, and then avoids and graft antigen generation immunne response, finally sets up new autoimmune tolerance.
Formula I chemical compound according to the invention is divided into FoxP3 in suppressor T cell propagation and inducing T cell
+CD4
+Effect in the regulatory T cells is remarkable, is divided into FoxP3 with the inducing T cell of its preparation
+CD4
+The medicine of regulatory T cells and suppressor T cell propagation can be used in autoimmune disease and graft-rejection.
Description of drawings
The β liquid scintillation instrument statistical result figure that is 4-according to the invention (cyclohexyl)-amido quinazoline to mouse T cell propagation inhibition test shown in Figure 1;
Wherein, cylindricality 1 is a matched group, does not promptly add 4-(cyclohexyl)-amido quinazoline after the stimulated in vitro; Cylindricality 2 is a test group, promptly adds 4-(cyclohexyl)-amido quinazoline behind the external stimulus; Cylindricality 3 is a blank control group, promptly without stimulated in vitro with do not add 4-(cyclohexyl)-amido quinazoline; Vertical coordinate is the CPM value, i.e. per minute radiocounting;
Shown in Figure 2ly the human T-cell is bred the β liquid scintillation instrument statistical result figure of inhibition test for 4-according to the invention (cyclohexyl)-amido quinazoline;
Wherein, cylindricality 1 is a matched group, does not promptly add 4-(cyclohexyl)-amido quinazoline after the stimulated in vitro; Cylindricality 2 is a test group, promptly adds 4-(cyclohexyl)-amido quinazoline behind the external stimulus; Cylindricality 3 is a blank control group, promptly without stimulated in vitro with do not add 4-(cyclohexyl)-amido quinazoline; Vertical coordinate is the CPM value, i.e. per minute radiocounting;
Shown in Figure 3ly be that streaming detects mouse boosting cell FoxP3
+CD4
+The matched group FoxP3 of regulatory T cells differentiation
+/ CD4
+Scatterplot, matched group are not add 4-(cyclohexyl)-amido quinazoline after the stimulated in vitro;
Wherein, upper right corner region representation many by the FoxP3 antibody labeling, by the many cells of CD4 antibody labeling; Upper left corner region representation is many by the FoxP3 antibody labeling, by the few cell of CD4 antibody labeling; Lower right corner region representation is few by the FoxP3 antibody labeling, by the many cells of CD4 antibody labeling; Lower left corner region representation is few by the FoxP3 antibody labeling, by the few cell of CD4 antibody labeling;
Shown in Figure 4ly be that streaming detects mouse boosting cell FoxP3
+CD4
+The test group FoxP3 of regulatory T cells differentiation
+/ CD4
+Scatterplot, test group are to add 4-(cyclohexyl)-amido quinazoline behind the external stimulus;
Wherein, upper right corner region representation many by the FoxP3 antibody labeling, by the many cells of CD4 antibody labeling; Upper left corner region representation is many by the FoxP3 antibody labeling, by the few cell of CD4 antibody labeling; Lower right corner region representation is few by the FoxP3 antibody labeling, by the many cells of CD4 antibody labeling; Lower left corner region representation is few by the FoxP3 antibody labeling, by the few cell of CD4 antibody labeling;
Shown in Figure 5ly be that streaming detects mouse boosting cell FoxP3
+CD4
+The blank control group FoxP3 of regulatory T cells differentiation
+/ CD4
+Scatterplot, blank control group are promptly without stimulated in vitro with do not add 4-(cyclohexyl)-amido quinazoline;
Wherein, upper right corner region representation many by the FoxP3 antibody labeling, by the many cells of CD4 antibody labeling; Upper left corner region representation is many by the FoxP3 antibody labeling, by the few cell of CD4 antibody labeling; Lower right corner region representation is few by the FoxP3 antibody labeling, by the many cells of CD4 antibody labeling; Lower left corner region representation is few by the FoxP3 antibody labeling, by the few cell of CD4 antibody labeling;
Shown in Figure 6ly be that streaming detects human peripheral blood cell FoxP3
+CD4
+The matched group FoxP3 of regulatory T cells differentiation
+/ CD4
+Scatterplot, matched group are not add 4-(cyclohexyl)-amido quinazoline after the stimulated in vitro;
Wherein, upper right corner region representation many by the FoxP3 antibody labeling, by the many cells of CD4 antibody labeling; Upper left corner region representation is many by the FoxP3 antibody labeling, by the few cell of CD4 antibody labeling; Lower right corner region representation is few by the FoxP3 antibody labeling, by the many cells of CD4 antibody labeling; Lower left corner region representation is few by the FoxP3 antibody labeling, by the few cell of CD4 antibody labeling;
Shown in Figure 7ly be that streaming detects human peripheral blood cell FoxP3
+CD4
+The test group FoxP3 of regulatory T cells differentiation
+/ CD4
+Scatterplot, test group are to add 4-(cyclohexyl)-amido quinazoline behind the external stimulus;
Wherein, upper right corner region representation many by the FoxP3 antibody labeling, by the many cells of CD4 antibody labeling; Upper left corner region representation is many by the FoxP3 antibody labeling, by the few cell of CD4 antibody labeling; Lower right corner region representation is few by the FoxP3 antibody labeling, by the many cells of CD4 antibody labeling; Lower left corner region representation is few by the FoxP3 antibody labeling, by the few cell of CD4 antibody labeling;
Shown in Figure 8ly be that streaming detects human peripheral blood cell FoxP3
+CD4
+The blank control group FoxP3 of regulatory T cells differentiation
+/ CD4
+Scatterplot, blank control group are promptly without stimulated in vitro with do not add 4-(cyclohexyl)-amido quinazoline;
Wherein, upper right corner region representation many by the FoxP3 antibody labeling, by the many cells of CD4 antibody labeling; Upper left corner region representation is many by the FoxP3 antibody labeling, by the few cell of CD4 antibody labeling; Lower right corner region representation is few by the FoxP3 antibody labeling, by the many cells of CD4 antibody labeling; Lower left corner region representation is few by the FoxP3 antibody labeling, by the few cell of CD4 antibody labeling.
The specific embodiment
The invention discloses chemical compound shown in the formula I and be divided into FoxP3 at the preparation inducing T cell
+CD4
+Application in the medicine of regulatory T cells and suppressor T cell propagation, those skilled in the art can use for reference this paper content, suitably improve technological parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as and are included in the present invention.Method of the present invention and application are described through preferred embodiment; The related personnel obviously can change or suitably change and combination methods and applications as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use technology of the present invention.
The invention provides chemical compound shown in the formula I and be divided into FoxP3 at the preparation inducing T cell
+CD4
+Application in the medicine of regulatory T cells and suppressor T cell propagation.
Wherein, said inducing T cell is divided into FoxP3
+CD4
+The medicine of regulatory T cells and suppressor T cell propagation is used for autoimmune disease and graft-rejection.Said autoimmune disease includes but not limited to type i diabetes, systemic lupus erythematosus (sle), multiple sclerosis, rheumatoid arthritis; Said graft-rejection is organ transplant rejection or tissue rejection reaction.
Formula I chemical compound according to the invention is 4-(cyclohexyl)-amido quinazoline compounds, and structure is following:
Wherein, R is H, Cl, F, carboxyl, nitro, trifluoromethyl or C among the formula I
1-C
4Alkyl.
The present invention uses through to mouse boosting cell and human peripheral blood cell's stimulated in vitro
3H-TdR detects mice and human T-cell's increment, and the result shows matched group CPM value apparently higher than test group CPM value (P＜0.001), and effect is extremely remarkable.Show the propagation that formula I chemical compound according to the invention can suppressor T cell.
Also to isolating mouse boosting cell and normal person's PBC stimulated in vitro, FACS detects FoxP3 in the present invention
+CD4
+The differentiation of regulatory T cells, the result shows, FoxP3 in the test group
+CD4
+Regulatory T cells ratio matched group has raise 12 and 25 times respectively.Show formula I chemical compound according to the invention effectively inducing T cell be divided into FoxP3
+CD4
+Regulatory T cells.
In order further to understand the present invention, formula I chemical compound according to the invention is divided into FoxP3 in suppressor T cell propagation and inducing T cell below in conjunction with embodiment
+CD4
+Application in the regulatory T cells is described in detail.
Embodiment 1: mouse T cell propagation inhibition test
Behind the splenocyte and splitting erythrocyte of aseptic separation mice, add in 96 well culture plates 1-2 * 10
5Cell/100 μ L/ holes.Add anti-CD3 (final concentration 1 μ g/mL), anti-CD28 monoclonal antibody (final concentration 1 μ g/mL), recombinant il-2 (final concentration 10Unit/mL) stimulated in vitro, 100 μ L/ holes, what establish adding 4-(cyclohexyl)-amido quinazoline is test group, 3 hole/groups; What do not add 4-(cyclohexyl)-amido quinazoline is matched group, 3 hole/groups.Simultaneously, establish without above-mentioned stimulated in vitro, what also do not add 4-(cyclohexyl)-amido quinazoline is blank control group, 3 hole/groups.
With three groups of samples, in 37 ℃, 5%CO
2Hatch 66h under the condition, every hole adds 0.5-1 μ ci3H-TdR 50 μ L, continues to cultivate 12h.Respectively organize sample on 9999 type glass fiber filter paper with the collection of DYQ-II type bull cell harvesting appearance, dry back β liquid scintillation instrument counting, the result is referring to Fig. 1.
The result shows; Matched group T cell proliferation is very fast, and its CPM value is about 22000, and the test group of adding 4-(cyclohexyl)-amido quinazoline; The propagation of T cell significantly is suppressed, and the blank control group through stimulated in vitro does not detect T cell proliferation (P＜0.001).Chemical compound shown in other formulas I such as 6-fluoro-4-(cyclohexyl)-amido quinazoline, 7-trifluoromethyl-4-(cyclohexyl)-amido quinazoline, 8-ethyl-4-(cyclohexyl)-amido quinazoline etc. have above-mentioned remarkable result equally.Show that formula I chemical compound according to the invention can significantly suppress the propagation of mouse T cell.
Embodiment 2: the human T-cell breeds inhibition test
Under the aseptic condition, from heparin anti-coagulating, separate PMNC (PBMC), the washing back uses 10%FCS RPMI1640 adjustment cell number to be 1-2 * 10
6/ mL adds in 96 well culture plates 1-2 * 10
5Cell/100 μ L/ holes.Add T cell mitogen PHA, 100 μ L/ holes, what establish adding 4-(cyclohexyl)-amido quinazoline is test group, 3 hole/groups; What do not add 4-(cyclohexyl)-amido quinazoline is matched group, 3 hole/groups.Simultaneously, establish without above-mentioned stimulated in vitro, what also do not add 4-(cyclohexyl)-amido quinazoline is blank control group, 3 hole/groups.
With three groups of samples, in 37 ℃, 5%CO
2Hatch 66h under the condition, every hole adds 0.5-1 μ ci
3H-TdR 50 μ L continue to cultivate 12h.Respectively organize sample on 9999 type glass fiber filter paper with the collection of DYQ-II type bull cell harvesting appearance, dry back β liquid scintillation instrument counting, the result is referring to Fig. 2.
The result shows; Matched group T cell proliferation is very fast, and its CPM value is about 60000, and the test group of adding 4-(cyclohexyl)-amido quinazoline; The propagation of T cell significantly is suppressed, and the blank control group through stimulated in vitro does not detect T cell proliferation (P＜0.001).Chemical compound shown in other formulas I such as 6-fluoro-4-(cyclohexyl)-amido quinazoline, 7-trifluoromethyl-4-(cyclohexyl)-amido quinazoline, 8-ethyl-4-(cyclohexyl)-amido quinazoline etc. have above-mentioned remarkable result equally.Show that formula I chemical compound according to the invention not only can significantly suppress the propagation of mouse T cell, also can significantly suppress human T-cell's propagation.
Embodiment 3: mice FoxP3
+CD4
+The regulatory T cells induction experiment
FoxP3
+CD4
+Regulatory T cells is one type of T cell with immunosuppressive action.Such cell is participated in the regulation and control of immunne response/immunologic tolerance with the mode of " initiatively ", not only participates in the autoimmune tolerance and regulates, and in transplantation immunity, also have important effect.In order to prove whether formula I chemical compound according to the invention can induce initial T cell differentiation is FoxP3
+CD4
+Regulatory T cells, after the present invention separated mouse boosting cell and stimulated in vitro, flow cytometer (FACS) had detected FoxP3
+CD4
+The differentiation of regulatory T cells.Concrete steps are following:
Method according to embodiment 1 is divided into matched group, test group and blank control group, cultivates 1-2 * 10 then with 24 orifice plates
6/ mL, the 2mL/ hole.In 37 ℃, 5%CO
2After hatching 66h under the condition, on each streaming, add the ready cell suspension of 100uL in the appearance pipe, cell number is about 1 * 10
6Individual.According to cell surface antigen colouring method labeled surface antigens c D4, CD25.PBS washed cell with pre-cooling.Fixing/rupture of membranes the working solution (Fixation/Permeabilization) that adds 1mL behind the vortex concussion re-suspended cell, and vortex mixing once more.Lucifuge, 4 ℃ are hatched 30-60min.Add 2mL Permeabilization Buffer (ebioscience Cat.No00-8333) working solution centrifuge washing cell and abandoning supernatant, repeat this step operated wash cell.Directly add good fluorescent labeling FoxP3 antibody (diluting with the Permeabilization Buffer working solution) 20ul of dilution, lucifuge, 4 ℃ are hatched 30min at least.Add 2mLPermeabilization Buffer (Cat.No 00-8333) working solution centrifuge washing cell and abandoning supernatant, repeat this step washed cell.With the Flow Cytometry Staining Buffer re-suspended cell of an amount of volume, the up flow type cell instrument detects and analyzes, and the result is referring to Fig. 3-5.
The result shows, FoxP3 in the test group
+CD4
+The ratio of regulatory T cells obviously rises, and is 12 times of matched group.FoxP3 in chemical compound shown in other formulas I such as 6-fluoro-4-(cyclohexyl)-amido quinazoline, 7-trifluoromethyl-4-(cyclohexyl)-amido quinazoline, 8-ethyl-4-(the cyclohexyl)-amido quinazoline etc.
+CD4
+The ratio of regulatory T cells also significantly rises.Show that formula I chemical compound according to the invention can inducing mouse T cell differentiation be FoxP3
+CD4
+Regulatory T cells.
Embodiment 4: people FoxP3
+CD4
+The regulatory T cells induction experiment
Formula I chemical compound according to the invention can inducing mouse T cell differentiation be FoxP3
+CD4
+Regulatory T cells can induce the human T-cell to be divided into FoxP3 in order to prove it equally
+CD4
+Regulatory T cells, the present invention is according to the method for embodiment 2 and 3, separates, the stimulated healthy PBC, and flow cytometer detects, and the result is referring to Fig. 6-8.
The result shows, FoxP3 in the test group
+CD4
+The ratio of regulatory T cells obviously rises, and is 25 times of matched group.FoxP3 in chemical compound shown in other formulas I such as 6-fluoro-4-(cyclohexyl)-amido quinazoline, 7-trifluoromethyl-4-(cyclohexyl)-amido quinazoline, 8-ethyl-4-(the cyclohexyl)-amido quinazoline etc.
+CD4
+The ratio of regulatory T cells also significantly rises.Show that formula I chemical compound according to the invention can induce the human T-cell to be divided into FoxP3
+CD4
+Regulatory T cells.
The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; Can also make some improvement and retouching, these improvement and retouching also should be regarded as protection scope of the present invention.
Claims (4)
1.4-(cyclohexyl)-amido quinazoline is divided into FoxP3 at the preparation inducing T cell
+CD4
+Application in the medicine of regulatory T cells and suppressor T cell propagation.
2. according to the said application of claim 1, it is characterized in that said inducing T cell is divided into FoxP3
+CD4
+The medicine of regulatory T cells and suppressor T cell propagation is used for autoimmune disease or graft-rejection.
3. according to the said application of claim 2, it is characterized in that said graft-rejection is tissue transplantation's rejection or organ transplant rejection.
4. according to the said application of claim 2, it is characterized in that said autoimmune disease is type i diabetes, systemic lupus erythematosus (sle), multiple sclerosis or rheumatoid arthritis.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1360582A (en) * | 1999-07-07 | 2002-07-24 | 阿斯特拉曾尼卡英国有限公司 | Quinazoline derivs. |
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| PE20030008A1 (en) * | 2001-06-19 | 2003-01-22 | Bristol Myers Squibb Co | DUAL INHIBITORS OF PDE 7 AND PDE 4 |
| GB0128108D0 (en) * | 2001-11-23 | 2002-01-16 | Astrazeneca Ab | Therapeutic use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1360582A (en) * | 1999-07-07 | 2002-07-24 | 阿斯特拉曾尼卡英国有限公司 | Quinazoline derivs. |
Non-Patent Citations (6)
| Title |
|---|
| Idit Sagiv-Barfi等.Design, synthesis, and evaluation of quinazoline T cell proliferation inhibitors.《Bioorganic & Medicinal Chemistry》.2010,第18卷(第17期),6404-6413. |
| Idit Sagiv-Barfi等.Design, synthesis, and evaluation of quinazoline T cell proliferation inhibitors.《Bioorganic & * |
| Medicinal Chemistry Letters》.2009,第19卷(第8期),2190-2194. * |
| Medicinal Chemistry》.2010,第18卷(第17期),6404-6413. * |
| Simon J. Mantell等.In vitro and in vivo SAR of pyrido[3,4-d]pyramid-4-ylamine based mGluR1 antagonists.《Bioorganic & * |
| SimonJ.Mantell等.InvitroandinvivoSARofpyrido[3 4-d]pyramid-4-ylamine based mGluR1 antagonists.《Bioorganic & Medicinal Chemistry Letters》.2009 |
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