CN105287525A - Composition and application of composition in medicine for resisting low red blood cell type anemia - Google Patents
Composition and application of composition in medicine for resisting low red blood cell type anemia Download PDFInfo
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- CN105287525A CN105287525A CN201510759770.9A CN201510759770A CN105287525A CN 105287525 A CN105287525 A CN 105287525A CN 201510759770 A CN201510759770 A CN 201510759770A CN 105287525 A CN105287525 A CN 105287525A
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Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, in particular to a composition, a preparation method and an application of the composition in medicine for resisting low red blood cell type anemia, and discloses a composition and a preparation method thereof. Pharmacological experiments indicate that the composition has the function of resisting low red blood cell type anemia, and has the value of developing the medicine for resisting low red blood cell type anemia.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions, preparation method and its usage.
Background technology
Based on different clinical characters, anemia has different classification.As: divide acute and chronic anemia by anemia tempo; Hyperplastic anemia (as hemolytic anemia, iron deficiency anemia, megaloblastic anemia etc.) and Hypolasia anemia (as aplastic anemia) is divided by bone marrow red system proliferative conditions.
The normal classification from anemia pathogenesis and the cause of disease clinically:
1. erythropoiesis minimizing property anemia
The anomalous effects erythropoiesis of hematopoietic cell, marrow stromal cell and hemopoietic raw material, can form erythropoiesis minimizing property anemia.
(1) hematopoietic stem/progenitor cells caused by abnormal anemia
1) aplastic anemia (AA) AA is a kind of marrow hematopoiesis function failure disease, damages relevant with the hematopoietic stem/progenitor cells of former and secondary.The pathogenesis of parts whole blood cytopenia and B cell produce anti-medullary cell autoantibody, and then destroy or suppress myeloid element relevant.
2) pure red cell aplasia anemia (PRCA) PRCA refers to that bone marrow erythroid hematopoiesis stem/progenitor cells suffers damage, and then causes anemia.According to the cause of disease, this disease can be divided into congenital and posteriority two class.Congenital PRCA and Diamond-Blackfan syndrome is caused by heredity; Posteriority PRCA comprises former, secondary two class.Scholar is had to find have self EPO or normoblast antibody in part constitutional PRCA patients serum.Secondary cases PRCA mainly contains medicine relationship type, (antibacterial and virus, as piconavirus B to infect relationship type
19, hepatitis virus etc.), autoimmune disease relationship type, lymphoproliferative disease relationship type (as thymoma, lymphoma, plasma cell dyscrasia and Lymphocytic leukemia etc.) and acute aplastic crisis etc.
3) congenital dyserythropoietic anemia (CDA) CDA be a class heritability red system stem/progenitor cells optimum clone caused by abnormal, the refractory anemia that is feature with red system ineffective hematopoiesis and paramophia.According to mode of inheritance, this disease can be divided into the hidden flight of steps leading to a palace hall genotype of autosome and dominant inheritance's type.
4) these disease hematopoietic stem/progenitor cells of hemopoietic system malignant clone disease there occurs the exception of matter, comprise myelodysplastic syndrome and all kinds of hematopoietic system cancer disease as leukemia etc.The former is because DH, high hypertrophy, and hemolysis in situ, appears in high apoptosis; The latter's neoplastic hyperplasia, low apoptosis and low differentiation, hemopoietic regulates and is also affected, thus makes normal mature erythrocytopenia and anemia occurs.
(2) hematopoieticmicroenviron-ment caused by abnormal anemia
Hematopoieticmicroenviron-ment comprises bone marrow matrix, stromal cell and cytokine.
1) bone marrow neoplasms of sick, the various extramedullary tumor disease of bone marrow matrix and stromal cell impaired Anemia BMN, myelofibrosis, myelosclerosis, marble and various infection or non-infectious osteomyelitis, all can because of damage bone marrow matrix and stromal cell, hematopoieticmicroenviron-ment occurs abnormal and affects hemopoietic.
2) hematopoietic regulators horizontal abnormality Anemia stem cell factor (SCF), interleukin (IL), grain-monosystem colony stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), erythropoietin (EPO), thrombopoietin (TPO), PDGF (TGF), tumor necrosis factor (TNF) and interferon (IFN) etc. all have positive negative regulation hemoposieis.Renal insufficiency, hepatopathy and hypophysis or hypothyroidism etc. time to produce EPO not enough; Neoplastic disease or some viral infection can induce body to produce more hemopoietic negative regulatory factor as TNF, IFN, inflammatory factor etc., all can cause ACD (ACD).
(3) hemopoietic insufficient raw material or Use barriers Anemia
Hemopoietic raw material refers to hematopoietic cell proliferation, differentiation, the necessary material of metabolism, as protein, lipid, vitamin (folic acid, vitamin B12 etc.), trace element (ferrum, copper, zinc etc.) etc.Any one hemopoietic insufficient raw material or Use barriers all may cause erythropoiesis to reduce.
1) folic acid or vitamin B
12to lack or Use barriers Anemia causes the megaloblastic anemia that body folic acid or vitamin B12 definitely or relatively lack or Use barriers can cause due to various physiology or pathological factor.
2) iron deficiency and ferrum Use barriers anemia this be modal anemia clinically.Iron deficiency and ferrum Use barriers affect haemachrome synthesis, have and claim such anemia to be haemachrome resulting anomaly anemia.The red cell morphology of such anemia diminishes, and central olistherozone expands, and belongs to microcytic hypochromic anemia.
2. hemolytic anemia (HA)
I.e. hematoclasis too much property anemia.
3. hemorrhagic anemia
Divide acute and chronic according to the speed of losing blood, chronic blood loss anemia often merges iron deficiency anemia.Can be divided into disorders of blood coagulation (as idiopathic thrombocytopenic purpura, hemophilia and severe liver disease etc.) make peace non-go out caused two classes of disorders of blood coagulation (as wound, tumor, tuberculosis, bronchiectasis, peptic ulcer, hemorrhoid and gynaecopathia etc.).
From natural product, find compound or lead compound and carry out structural modification and obtain its derivant, thus the potential drug obtaining high-efficiency low-toxicity there is important value most.
The Compound I that the present invention relates to is one and delivers (AyumiOhsakietal. in 2011, 2011.SalviskinoneA, aditerpenewithanewskeletonfromSalviaprzewalskii.Tetrahed ronLetters52 (2011) 1375 – 1377) compound, we have carried out structural modification to Compound I, obtain two new derivants and compound III and compound IV, and prepared compositions by compound III and compound IV and said composition anti-erythrocyte low property anemia activity is evaluated, it is active that it has anti-erythrocyte low property anemia.
Summary of the invention
The invention discloses a new compositions, said composition is made up of compound III and compound IV, and in said composition, the mass percent of compound III and compound IV is respectively 40% and 60%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
The object of the present invention is to provide the new application of the present composition in pharmaceutical field.
The present invention relates to compositions as the application in preparation treatment erythrocyte low property anemia medicine.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by any restriction of specific embodiment, but be limited by claim.
Detailed description of the invention
The preparation of embodiment 1 compound S alviskinoneA
Document (the AyumiOhsakietal. that the people such as the preparation method reference AyumiOhsaki of compound S alviskinoneA (I) deliver, 2011.SalviskinoneA, aditerpenewithanewskeletonfromSalviaprzewalskii.Tetrahed ronLetters52 (2011) 1375 – 1377) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2SalviskinoneA
By Compound I (312mg, 1.00mmol) be dissolved in 15mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.08g), 1,50% sodium hydroxide solution of 2-Bromofume (3.760g, 20.00mmol) and 6mL.Mixture stirs 12h at 35 degrees Celsius.After 12h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution.Then use water and saturated common salt water washing 4 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1.5, v/v), collects brown concentrated elution band and flings to the brown ceramic powder (327mg, 78%) that namely solvent obtains Compound II per.
1HNMR(500MHz,DMSO-d
6)δ6.63(s,1H),6.37(s,1H),5.81(s,1H),4.51(s,2H),3.84(s,1H),3.79(s,2H),2.15(s,1H),2.04(s,1H),1.91(s,1H),1.65(s,1H),1.39(s,3H),1.08(s,6H),0.99(s,6H).
13CNMR(125MHz,DMSO-d6)δ188.07(s),183.70(s),154.38(s),147.57(s),140.21(s),136.40(s),134.71(s),131.25(s),128.40(s),118.83(s),72.12(s),45.49(s),37.54(s),33.58(s),31.78(s),26.17(s),25.12(s),24.66(s),23.51(s),23.17(s),22.65(s).
HRMS(ESI)m/z[M+H]
+calcdforC
22H
28BrO
3:419.1222；found419.1220.
The synthesis of O-(imidazole radicals) ethyl derivative (III) of embodiment 3SalviskinoneA
Compound II per (209mg, 0.5mmol) is dissolved in the middle of 30mL acetonitrile, adds Anhydrous potassium carbonate (690mg wherein, 5.0mmol), potassium iodide (252mg, 1.5mmol) and imidazoles (870mg, 10mmol), mixture reflux 4h.After reaction terminates, reactant liquor is poured in 45mL frozen water, with equivalent dichloromethane extraction 3 times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:0.2, v/v), collects brown concentrated elution band and flings to the Light brown solid (144.1mg, 71%) that namely solvent obtains compound III.
1HNMR(500MHz,DMSO-d6)δ7.91(s,1H),7.16(s,1H),6.65(d,J＝103.6Hz,2H),6.41(s,1H),5.76(s,1H),4.50(s,2H),4.39(s,2H),3.82(s,1H),2.05(s,1H),1.94(s,1H),1.87(s,1H),1.61(s,1H),1.30(s,3H),0.99(s,6H),0.90(s,6H).
13CNMR(125MHz,DMSO-d6)δ187.81(s),183.33(s),153.90(s),147.28(s),139.81(s),139.19(s),136.14(s),134.34(s),130.77(s),128.43(s),128.01(s),118.85(s),118.53(s),69.03(s),45.02(s),43.70(s),37.46(s),33.09(s),25.87(s),25.06(s),24.29(s),23.03(s),23.05(s),22.41(s).
HRMS(ESI):m/z[M+H]
+calcdforC
25H
31N
2O
3:407.2335；found:407.2331。
The synthesis of O-(triazolyl) ethyl derivative (IV) of embodiment 4SalviskinoneA
By Compound II per (209mg, 0.5mmol) be dissolved in the middle of 20mL acetonitrile, add Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and 1,2,3-triazole (2760mg, 40mmol), mixture reflux 4h.After reaction terminates, reactant liquor is poured in 20mL frozen water, with equivalent dichloromethane extraction 3 times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:0.5, v/v), collects the yellow yellow powder (134.3mg, 66%) concentrating elution band namely to obtain compound IV.
1HNMR(500MHz,Chloroform-d1)δ8.37(s,1H),7.95(s,1H),6.35(s,1H),6.14(s,1H),5.35(s,1H),4.13(s,1H),4.42(d,J＝16.4Hz,3H),3.71(s,1H),2.13(s,1H),2.05(s,1H),1.81(s,1H),1.63(s,1H),1.30(s,3H),1.08(s,6H),0.97(s,6H).
13CNMR(125MHz,DMSO-d6)δ188.09(s),183.61(s),154.18(s),147.26(s),139.72(s),136.40(s),136.32(s),134.52(s),130.95(s),127.99(s),120.16(s),118.62(s),67.14(s),46.27(s),45.18(s),37.69(s),33.32(s),26.14(s),25.01(s),24.41(s),23.23(s),23.06(s),22.47(s).
HRMS(ESI):m/z[M+H]
+calcdforC
24H
30N
3O
3:408.2287；found:408.2282。
Embodiment 5 compositions anti-erythrocyte low property anemia is tested
Test the therapeutical effect of 1 compositions to post hemorrhagic mice
ICR mice 30, ♀ ♂ half and half, is divided into 5 groups (n=10).Except normal saline group, other group every mice is from orbital vein blood-letting 0.5ml, get blood survey after 24h again and all respectively organize index, then continuously gastric infusion 1 week and blood-letting every day 0.5ml after administration, after last administration 1h, get the full whole bliid platelet analyzer of blood F-800 from orbital venous plexus and carry out red blood cell count(RBC) (10
12/ L).
The preparation of compositions: loaded by the powder of 60mg compound IV crossing 200 order nets after crossing the powder of the 40mg compound III of 200 order nets and grinding after grinding to mix in tubule with cover and with turbine stirring instrument and namely obtain 100mg compositions, obtains the solution of compositions by the compositions of this 100mg of water dissolution during use.
Table 1 compositions is to because of caused oligocythemic therapeutical effect of losing blood
Compare with model group: * p<0.05
Result shows, blood-letting mice, after taking compositions and treating 7 days, is compared with model group, and its erythrocyte is significantly higher than model group, close to normal saline group.And compound III and compound IV act on without this.
Two, compositions causes oligocythemic therapeutical effect to cyclophosphamide
To the preventive and therapeutic effect ICR mice 50 of mouse bone marrow cells hemopoietic function damage, ♀ ♂ dual-purpose, is divided into 5 groups (n=10), i.e. normal saline group, modeling group, compositions 1.2mg/kg group, compound III 1.2mg/kg group and compound IV 1.2mg/kg group, oral administration, every day 1 time.0th, except normal saline group, other respectively organized mice lumbar injection cycli phosphate amine 80mg/kg respectively, then continued administration 3 days on 5th, 10.1h after last administration, gets blood from orbital venous plexus, surveys RBC number (10
12/ L).
Table 2 compositions is on the erythrocytic impact of caused by cyclophosphamide
Compare with model group: * * p<0.01
Result shows, compares with normal saline group, and cycli phosphate amine can make mouse bone marrow cells damage, and causes peripheral blood cells to decline, and compositions group compares with model group, obviously can resist cycli phosphate amine induced mice red blood cell decreased.And compound III and compound IV act on without this.
Three, compositions is to oligocythemic therapeutical effect caused by benzene
Impact on Induced Aplastic Anemia Mice: Kunming mouse 50, ♀ ♂ dual-purpose, is divided into 5 groups (n=10), except normal saline group, other group mouse subcutaneous injection benzene 0.5ml/kg, continuous 12 days, the same day of modeling, oral administration simultaneously, every day 1 time, totally 18 days, 1h after last administration, orbital venous plexus gets blood, surveys erythrocyte.
Table 3 compositions is to oligocythemic therapeutical effect caused by benzene
Compare with model group: * * p<0.01
Result shows, compositions group compares with model group, obviously can resist the erythrocytic decline of Induced Aplastic Anemia Mice caused by benzene.And compound III and compound IV act on without this.
Conclusion: compositions significantly can raise erythrocyte, can be used for preparing the medicine for the treatment of anemia.And compound III and compound IV significantly can not raise erythrocyte, can not be used for preparing the medicine for the treatment of anemia.
The preparation of embodiment 6 composition tablet involved in the present invention
Get 2 grams of compositionss, add the customary adjuvant 18 grams preparing tablet, mixing, conventional tablet presses makes 100.
The preparation of embodiment 7 composition capsule involved in the present invention
Get 2 grams of compositionss, add prepare capsule customary adjuvant as starch 18 grams, mixing, encapsulatedly makes 100.
Claims (7)
1. a compositions, it is characterized by said composition and be made up of compound III and compound IV, in said composition, the mass percent of compound III and compound IV is respectively 40% and 60%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: the powder of compound III and the powder of compound IV are respectively 40% and 60% according to mass percent and fully mix.
3. the application of compositions as claimed in claim 1 in treatment erythrocyte low property anemia medicine.
4. the application of compositions as claimed in claim 3 in treatment erythrocyte low property anemia medicine, is characterized by: described erythrocyte low property anemia is caused by losing blood.
5. the application of compositions as claimed in claim 3 in treatment erythrocyte low property anemia medicine, is characterized by: described erythrocyte low property anemia is that the erythrocyte caused by chemical substance is low.
6. the application of compositions as claimed in claim 5 in treatment erythrocyte low property anemia medicine, it is characterized by: described chemical substance is benzene, described erythrocyte low property anemia is the aplastic anemia caused by benzene.
7. the application of compositions as claimed in claim 5 in treatment erythrocyte low property anemia medicine, it is characterized by: described chemical substance is cycli phosphate amine, described erythrocyte low property anemia is red blood cell decreased caused by cycli phosphate amine.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105998010A (en) * | 2016-04-22 | 2016-10-12 | 南京赋海澳赛医药科技有限公司 | Application of composition of Salviskinone A derivatives in anti-low red blood cell anemia drugs |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5929124A (en) * | 1997-08-22 | 1999-07-27 | Hostettmann; Kurt | Antimicrobial diterpenes |
-
2015
- 2015-11-10 CN CN201510759770.9A patent/CN105287525A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5929124A (en) * | 1997-08-22 | 1999-07-27 | Hostettmann; Kurt | Antimicrobial diterpenes |
Non-Patent Citations (2)
| Title |
|---|
| AYUMI OHSAKI等: "Salviskinone A, a diterpene with a new skeleton from Salvia przewalskii", 《TETRAHEDRON LETTERS》 * |
| 程纬民等: "丹参酮注射液治疗难治性贫血20例", 《广西中医药》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105998010A (en) * | 2016-04-22 | 2016-10-12 | 南京赋海澳赛医药科技有限公司 | Application of composition of Salviskinone A derivatives in anti-low red blood cell anemia drugs |
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