CN104887667A - Application of Daphmalenine A ramification to preparing medicine for resisting low red blood cell anemia - Google Patents
Application of Daphmalenine A ramification to preparing medicine for resisting low red blood cell anemia Download PDFInfo
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- CN104887667A CN104887667A CN201510240553.9A CN201510240553A CN104887667A CN 104887667 A CN104887667 A CN 104887667A CN 201510240553 A CN201510240553 A CN 201510240553A CN 104887667 A CN104887667 A CN 104887667A
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Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, and in particular to a Daphmalenine A ramification, a preparing method and application of the Daphmalenine A ramification to preparing a medicine for resisting low red blood cell anemia. The new Daphmalenine A ramification is synthesized, and the preparing method of the new Daphmalenine A ramification is disclosed. Pharmacological tests show that the Daphmalenine A ramification has the effect on resisting the low red blood cell anemia, and the Daphmalenine A ramification has the value for developing the low red blood cell anemia.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Daphmalenine A derivant, 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 D aphmalenine A that the present invention relates to is one and within 2011, delivers (Yu Zhang et al., 2011.Daphmalenines A and B:Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense.Eur.J.Org.Chem.2011, 4103 – 4107) compound, we have carried out structural modification to Compound D aphmalenine A, obtain a new Daphmalenine A derivant, and its 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 Daphmalenine A derivant, its structure is:
Daphmalenine A derivant (III) of the present invention is by method preparation below:
(1) Daphmalenine A (I) and glycol dibromide are obtained by reacting the O-bromoethyl derivant (II) of Daphmalenine A;
(2) O-bromoethyl derivant (II) and the pyrrolidine generation substitution reaction of Daphmalenine A obtain O-(nafoxidine base) ethyl derivative (III) of Daphmalenine A.
The preparation method of the O-(nafoxidine base) ethyl derivative (III) of further Daphmalenine A is:
(1) 419mg Compound D aphmalenine A (I) is dissolved in 10mL benzene, in solution, adds the tetrabutyl ammonium bromide of 0.08g, the glycol dibromide of 7.520g and 50% sodium hydroxide solution of 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 the yellow yellow solid concentrating elution band namely to obtain the O-bromoethyl derivant (II) of Daphmalenine A.
(2) the O-bromoethyl derivant (II) of the Daphmalenine A of 263mg is dissolved in the middle of 20mL acetonitrile, adds the Anhydrous potassium carbonate of 345mg wherein, the potassium iodide of 84mg and the pyrrolidine of 2840mg, mixture reflux 12h; After reaction terminates, reactant liquor is poured in 20mL frozen water, with equivalent dichloromethane extraction four 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=100:1.5, v/v, collects the brown gummy solid 183.2mg that namely brown concentrated elution band obtains the O-(nafoxidine base) ethyl derivative (III) of Daphmalenine A.
Compound 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 compounds of this invention in pharmaceutical field.
The present invention relates to the compounds of this invention 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 D aphmalenine A
Document (the Yu Zhang et al. that the people such as the preparation method reference Yu Zhang of Compound D aphmalenine A (I) deliver, 2011.Daphmalenines A and B:Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense.Eur.J.Org.Chem.2011,4103 – 4107) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2 Daphmalenine A
By Compound I (419mg, 1.00mmol) be dissolved in 10mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.08g), 1,50% sodium hydroxide solution of 2-Bromofume (7.520g, 40.00mmol) 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 the yellow yellow solid (320mg, 61%) concentrating elution band namely to obtain Compound II per.
1H NMR(500MHz,DMSO-d
6)δ3.84(d,J＝1.6Hz,2H),3.76–3.50(m,5H),3.42(s,2H),3.09(s,1H),2.99(s,1H),2.88(s,1H),2.70(s,1H),2.64(d,J＝19.1Hz,3H),2.45(d,J＝5.6Hz,3H),2.33(s,1H),2.19–2.12(m,5H),2.07(s,1H),1.97(d,J＝9.2Hz,3H),1.84–1.76(m,3H),1.69(s,1H),1.15(s,1H),1.04(s,3H)。
13C NMR(125MHz,DMSO-d6)δ219.71(s),211.07(s),176.65(s),66.24(s),65.38(s),63.59(s),59.42(s),54.79(s),52.18(s),46.22(s),46.01(s),45.50(s),45.27(s),40.33(s),37.86(s),37.61(s),36.27(s),34.26(s),30.89(s),28.52(s),26.04(s),25.24(s),8.50(s)。
HRMS(ESI)m/z[M+H]
+calcd for C
25H
37BrNO
6:526.1804；found 526.1801.
The synthesis of the O-(nafoxidine base) ethyl derivative (III) of embodiment 3 Daphmalenine A
Compound II per (263mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and pyrrolidine (2840mg, 40mmol), mixture reflux 12h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction four 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.(mobile phase is product crude product purification by silica gel column chromatography: petroleum ether/acetone=100:1.5, v/v), collect the brown gummy solid (183.2mg, 71%) that namely brown concentrated elution band obtains the O-(nafoxidine base) ethyl derivative (III) of Daphmalenine A.
1H NMR(500MHz,DMSO-d6)δ3.80(s,1H),3.71(s,3H),3.50(s,2H),3.14(s,1H),3.06(s,1H),2.86(s,1H),2.73(d,J＝2.7Hz,2H),2.67(d,J＝5.3Hz,4H),2.55(s,4H),2.53–2.36(m,4H),2.21–2.15(m,5H),2.16–1.86(m,4H),1.85(d,J＝7.5Hz,2H),1.78(s,1H),1.72(d,J＝10.7Hz,5H),1.14(s,1H),1.08(s,3H)。
13C NMR(125MHz,DMSO-d6)δ219.76(s),211.10(s),176.66(s),66.23(s),63.55(s),61.51(s),59.41(s),54.83(s),54.50(s),53.87(s),52.18(s),46.20(s),46.04(s),45.53(s),45.24(s),40.32(s),37.87(s),37.64(s),36.26(s),30.85(s),28.50(s),25.95(s),25.18(d,J＝8.8Hz),8.42(s)。
HRMS(ESI):m/z[M+H]
+calcd for C
29H
45N
2O
6:517.3278；found:517.3271。
Embodiment 4 compound III anti-erythrocyte low property anemia is tested
Test the therapeutical effect of 1 compound III 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).1-ethyl pyrrolidine (compound IV) is commercially available analytical pure.
Table 1 compound III 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 compound III 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 I and 1-ethyl pyrrolidine act on without this.
Two, compound III 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, be divided into 5 groups (n=10), i.e. normal saline group, modeling group, compound III 1.2mg/kg group, Compound I 1.2mg/kg group and 1-ethyl pyrrolidine 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 compound III 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 compound III group compares with model group, obviously can resist cycli phosphate amine induced mice red blood cell decreased.And Compound I and 1-ethyl pyrrolidine act on without this.
Three, compound III 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 compound III is to oligocythemic therapeutical effect caused by benzene
Compare with model group: * * p<0.01
Result shows, administration group compares with model group, obviously can resist the erythrocytic decline of Induced Aplastic Anemia Mice caused by benzene.And Compound I and 1-ethyl pyrrolidine act on without this.
Conclusion: compound III significantly can raise erythrocyte, can be used for preparing the medicine for the treatment of anemia.And Compound I and 1-ethyl pyrrolidine significantly can not raise erythrocyte, can not be used for preparing the medicine for the treatment of anemia.
The preparation of embodiment 5 compound III tablet involved in the present invention
Get the one in the middle of 20 g of compound III or its pharmaceutically acceptable salt, add the customary adjuvant 180 grams preparing tablet, mixing, conventional tablet presses makes 1000.
The preparation of embodiment 6 compound III capsule involved in the present invention
Get the one in the middle of 20 g of compound III or its pharmaceutically acceptable salt, add prepare capsule customary adjuvant as starch 180 grams, mixing, encapsulatedly makes 1000.
Claims (5)
1. one kind has Daphmalenine A derivant (III) and the application of pharmaceutically acceptable salt in treatment erythrocyte low property anemia medicine thereof of structure shown in formula III:
2. a kind of Daphmalenine A derivant (III) and the application of pharmaceutically acceptable salt in treatment erythrocyte low property anemia medicine thereof with structure shown in formula III as claimed in claim 1, is characterized by: described erythrocyte low property anemia is caused by losing blood.
3. a kind of Daphmalenine A derivant (III) and the application of pharmaceutically acceptable salt in treatment erythrocyte low property anemia medicine thereof with structure shown in formula III as claimed in claim 1, is characterized by: described erythrocyte low property anemia is that the erythrocyte caused by chemical substance is low.
4. a kind of Daphmalenine A derivant (III) and the application of pharmaceutically acceptable salt in treatment erythrocyte low property anemia medicine thereof with structure shown in formula III as claimed in claim 3, it is characterized by: described chemical substance is benzene, described erythrocyte low property anemia is the aplastic anemia caused by benzene.
5. a kind of Daphmalenine A derivant (III) and the application of pharmaceutically acceptable salt in treatment erythrocyte low property anemia medicine thereof with structure shown in formula III as claimed in claim 3, 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 |
|---|---|---|---|---|
| CN105616403A (en) * | 2015-07-16 | 2016-06-01 | 南京海澳斯生物医药科技有限公司 | Composition and application thereof to low red blood cell anemia resisting medicine |
-
2015
- 2015-05-12 CN CN201510240553.9A patent/CN104887667A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| YU ZHANG等: ""Daphmalenines A and B: Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense"", 《EUR.J.ORG.CHEM》 * |
| 李震宇 等: "虎皮楠生物碱研究进展", 《有机化学》 * |
| 穆淑珍 等: "两种黔产药用植物虎皮楠中生物碱成分的区域性差异", 《广东化工》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105616403A (en) * | 2015-07-16 | 2016-06-01 | 南京海澳斯生物医药科技有限公司 | Composition and application thereof to low red blood cell anemia resisting medicine |
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Application publication date: 20150909 |