CN107929288A - The miscellaneous source terpene piperazinyl of guava dialdehyde and tetrazole radical derivative composition are used to prepare anti-anemia action medicine - Google Patents
The miscellaneous source terpene piperazinyl of guava dialdehyde and tetrazole radical derivative composition are used to prepare anti-anemia action medicine Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the miscellaneous source terpene piperazinyl of guava dialdehyde and tetrazole radical derivative composition to be used to prepare anti-anemia action medicine, the present invention relates to organic synthesis and medicinal chemistry art, and in particular to the piperazinyl and 1H tetrazole radical derivatives composition of the miscellaneous source terpene of guava dialdehyde, the preparation method and its purposes on anti-anemia action medicine is prepared.The invention discloses a kind of piperazinyl of the miscellaneous source terpene of guava dialdehyde and 1H tetrazole radical derivative compositions and preparation method thereof.Pharmacological experiment shows that the piperazinyl and 1H tetrazole radical derivative compositions of the miscellaneous source terpene of guava dialdehyde of the invention have the function that anti-anemia action, has the value of exploitation anti-anemia action medicine.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, and in particular to composition, preparation method and its usage.
Background technology
Based on different clinical characters, anaemia has different classification.Such as：By the acute and chronic anaemia of anaemia tempo point；Press
The red system's proliferative conditions of marrow divide hyperplastic anemia (such as hemolytic anemia, hypoferric anemia, megaloblastic anemia) and hyperplasia low
Lower property anaemia (such as alpastic anemia).
Clinically often from the classification of anaemia pathogenesis and the cause of disease：
1. RBC acceptor garland rate reduction property anaemia
The anomalous effects RBC acceptor garland rate of hematopoietic cell, marrow stromal cell and hematopoiesis raw material, can form red blood cell life
Into reduction property anaemia.
(1) hematopoietic stem/progenitor cells caused by abnormal anaemia
1) alpastic anemia (AA) AA is a kind of marrow hematopoiesis function failure disease, with primary and secondary Hematopoietic Stem ancestral
Cell damage is related.The pathogenesis of parts whole blood cytopenia produces anti-bone marrow cell autoantibody with B cell, and then broken
Bad or suppression myeloid element is related.
2) pure red cell aplasia anaemia (PRCA) PRCA refers to that marrow erythroid hematopoiesis stem/progenitor cells are damaged, and then
Cause anaemia.According to the cause of disease, which can be divided into congenital and two class of posteriority.Congenital PRCA, that is, Diamond-Blackfan is comprehensive
Simulator sickness, caused by being heredity；Posteriority PRCA includes primary, secondary two class.There is scholar to find part primary PRCA patients serums
In have itself EPO or normoblast antibody.Secondary cases PRCA mainly have medicine relationship type, infection relationship type (bacterium and virus, such as
Piconavirus B19, hepatitis viruse etc.), autoimmunity disease relationship type, lymphoproliferative disease relationship type (such as thymoma, leaching
Bar knurl, plasma cell dyscrasias and lymphocytic leukemia etc.) and acute aplastic crisis etc..
3) congenital dyserythropoietic anemia (CDA) CDA is the red benign clone of system's stem/progenitor cells of a kind of heredity
Caused by abnormal, refractory anemia characterized by red system's ineffective hematopoiesis and paramophia.According to mode of inheritance, which can be divided into
The hidden flight of steps leading to a palace hall genotype of autosome and dominant inheritance type.
4) these disease hematopoietic stem/progenitor cells of hemopoietic system malignant clone disease there occurs matter exception, including marrow increase
Raw exception syndrome and all kinds of hematopoietic system cancer disease such as leukaemia etc..The former is because morbid hematopoiesis, high hyperplasia, and height withers
Die, hemolysis in situ occur；The latter's neoplastic hyperplasia, low apoptosis and low differentiation, hematopoiesis adjust also be affected so that normally into
Ripe red blood cell reduces and anaemia occurs.
(2) hematopoieticmicroenviron-ment caused by abnormal anaemia
Hematopoieticmicroenviron-ment includes bone marrow matrix, stroma cell and cell factor.
1) bone marrow matrix and stroma cell are damaged Anemia bone marrow necrosis, myelofibrosis, myelosclerosis, marble
The bone marrow neoplasms of sick, various extramedullary tumor diseases and various infection or non-infectious osteomyelitis, can be because damaging marrow base
Matter and stroma cell, hematopoieticmicroenviron-ment are abnormal and influence haemocyte generation.
2) hematopoietic regulators horizontal abnormality Anemia stem cell factor (SCF), interleukins (IL), grain-monosystem
Colony stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), erythropoietin(EPO) (EPO), thrombopoietin
(TPO), platelet growth factor (TGF), tumor necrosis factor (TNF) and interferon (IFN) etc. are respectively provided with positive negative regulation hematopoiesis
Effect.EPO deficiencies are produced when renal insufficiency, hepatopathy and hypophysis or hypothyroidism etc.；Tumor disease or some diseases
Poison infection can induce body to produce more hematopoiesis negative regulatory factor such as TNF, IFN, inflammatory factor etc., can cause chronic characteristic of disease
Anaemia (ACD).
(3) hematopoiesis insufficient raw material or Use barriers Anemia
Hematopoiesis raw material refers to material necessary to hematopoietic cell proliferation, differentiation, metabolism, such as protein, lipid, vitamin
(folic acid, vitamin B12 etc.), micro- (iron, copper, zinc etc.) etc..Any hematopoiesis insufficient raw material or Use barriers all may
RBC acceptor garland rate is caused to reduce.
1) folic acid or vitamin B12Lack or Use barriers Anemia is since various physiology or pathological factor cause body
Folic acid or vitamin B12 definitely or relatively lack or Use barriers can caused megaloblastic anemia.
2) iron deficiency and iron Use barriers anaemia this be clinically most common anaemia.Iron deficiency and iron Use barriers influence blood
Red pigment synthesizes, and it is referred to as ferroheme resulting anomaly anaemia to have such anaemia.The red cell morphology of such anaemia diminishes, the light dye in center
Area expands, and belongs to microcytic hypochromic anemia.
2. hemolytic anemia (HA)
That is the excessive property anaemia of hematoclasis.
3. blood loss anemia
According to losing blood, speed point is acute and chronic, and chronic blood loss anemia often merges hypoferric anemia.It can be divided into solidifying
Caused by courageous and upright disease (such as Idiopathic Thrombocytopenic Purpura, hemophilia and severe liver disease) and it is non-go out disorders of blood coagulation (such as
Wound, tumour, tuberculosis, bronchiectasis, peptic ulcer, hemorrhoid and gynecological disease etc.) caused by two classes.
Compound or lead compound are found from natural products and carries out structural modification and obtains its derivative, so as to obtain
The potential drug of high-efficiency low-toxicity most has important value.
Compound I of the present invention is one and delivers within 2011 (Meng Shao et al., 2010.Psiguadials
A and B,Two Novel Meroterpenoids with Unusual Skeletons from the Leaves of
Psidium guajava.Organic Letters 12 (2010) 5040-5043) compound, we to compound I carry out
Structural modification, obtains two new derivatives i.e. compound III and compound IV, and with compound III and compound IV
It is prepared for composition and the low property anaemia activity of said composition anti-erythrocyte is evaluated, it is with the low property of anti-erythrocyte
Anaemia activity.
The content of the invention
The invention discloses a new composition, said composition is made of compound III and compound IV, said composition
The mass fraction of middle compound III and compound IV are respectively 10 parts and 20 parts.
Pharmaceutically acceptable salt or pharmaceutically acceptable carrier can be made in composition disclosed by the invention.
It is an object of the invention to provide new application of the present composition in pharmaceutical field.
The present invention relates to composition as the application prepared in the treatment low property anaemia medicine of red blood cell.
The present invention is described in further detail by the following examples, but protection scope of the present invention is from specific reality
Any restrictions of example are applied, but are defined in the claims.
Embodiment
A kind of preparation of the miscellaneous source terpene of the guava dialdehyde of embodiment 1
Document (the Meng that a kind of preparation method of the miscellaneous source terpene (I) of guava dialdehyde is delivered with reference to Meng Shao et al.
Shao et al.,2010.Psiguadials A and B,Two Novel Meroterpenoids with Unusual
Skeletons from the Leaves of Psidium guajava.Organic Letters 12(2010)5040–
5043) method.
A kind of synthesis of the O- bromoethyls derivative (II) of the miscellaneous source terpene of the guava dialdehyde of embodiment 2
Compound I (474mg, 1.00mmol) is dissolved in 20mL benzene, tetrabutylammonium bromide (TBAB) is added into solution
50% sodium hydroxide solution of (0.16g), 1,2- Bromofume (7.520g, 40.00mmol) and 12mL.Mixture is Celsius 35
Degree stirring 8h.Reaction solution is poured into frozen water after 8h, is extracted twice immediately with dichloromethane, merges organic phase solution.Then
To organic phase solution successively with water and saturated common salt water washing 3 times, then dried with anhydrous sodium sulfate, being finally concentrated under reduced pressure, it is molten to remove
Agent obtains product crude product.Product crude product purifies that (mobile phase is with silica gel column chromatography：Petroleum ether/acetone=100:0.5, v/v), receive
Collection brown concentrates elution band and flings to the brown ceramic powder (502mg, 73%) that solvent obtains compound II.
1H NMR(500MHz,DMSO-d6) δ 10.44 (s, 2H), 7.24 (s, 2H), 7.20 (d, J=10.0Hz, 3H),
4.31(s,4H),3.89(s,1H),3.74(s,4H),2.30(s,1H),2.12(s,1H),2.02(s,1H),1.92(s,1H),
1.79 (s, 1H), 1.73 (s, 1H), 1.51 (d, J=19.8Hz, 3H), 0.99 (s, 3H), 0.95 (d, J=4.7Hz, 7H),
0.85(s,3H),0.53(s,1H),0.43(s,1H).
13C NMR(125MHz,DMSO-d6)δ188.69(s),170.54(s),165.42(s),163.38(s),142.72
(s),129.71(s),127.96(s),127.08(s),118.00(s),116.82(s),114.82(s),72.73(s),
40.19(s),34.75(s),34.32(s),31.75(s),30.93(s),28.09(s),26.43(s),24.48(s),23.74
(s),21.18(s),20.77(s),19.99(s),14.39(s).
HRMS(ESI)m/z[M+H]+calcd for C34H41Br2O5:689.1300；found 689.1303.
A kind of synthesis of O- (piperazinyl) ethyl derivative (III) of the miscellaneous source terpene of the guava dialdehyde of embodiment 3
Compound II (344mg, 0.5mmol) is dissolved among 25mL acetonitriles, thereto add Anhydrous potassium carbonate (690mg,
5.0mmol), potassium iodide (168mg, 1.0mmol) and Piperazine anhydrous (3446mg, 40mmol), mixture is heated to reflux 4h.Reaction
After reaction solution is poured into frozen water, with equivalent dichloromethane extract 3 times, merge organic phase.Water and saturated common salt are used successively
Organic phase after water washing merging, then dried with anhydrous sodium sulfate, the removal solvent that is concentrated under reduced pressure obtains product crude product.Product is thick
Product purify that (mobile phase is with silica gel column chromatography：Petroleum ether/acetone=100:1.0, v/v) yellow, is collected to concentrate elution band and wave
Solvent is gone to obtain the yellow powder (254.8mg, 73%) of compound III.
1H NMR (500MHz, DMSO-d6) δ 10.46 (s, 2H), 7.23 (s, 2H), 7.20 (d, J=10.0Hz, 3H),
4.02 (s, 4H), 3.96 (s, 1H), 2.62 (d, J=8.0Hz, 12H), 2.31 (s, 8H), 2.10 (s, 1H), 2.01-1.85 (m,
3H),1.79(s,1H),1.66(s,1H),1.44(s,2H),1.38(s,1H),1.27(s,1H),1.05(s,2H),1.03(d,
J=45.8Hz, 3H), 0.93-0.70 (m, 9H), 0.52 (s, 1H), 0.23 (s, 1H)13C NMR(125MHz,DMSO-d6)δ
188.62(s),170.44(s),165.27(s),163.22(s),142.59(s),129.52(s),127.80(s),126.91
(s),117.86(s),116.67(s),114.65(s),69.34(s),54.61(s),54.05(s),45.17(s),40.02
(s),34.61(s),34.17(s),30.77(s),27.92(s),26.29(s),24.33(s),23.57(s),21.00(s),
20.62(s),19.84(s),14.21(s).
HRMS(ESI):m/z[M+H]+calcd for C42H59N4O5:699.4485；found:699.4480.
A kind of synthesis of O- (1H- tetrazoles base) ethyl derivative (IV) of the miscellaneous source terpene of the guava dialdehyde of embodiment 4
Compound II (344mg, 0.5mmol) is dissolved among 20mL acetonitriles, thereto add Anhydrous potassium carbonate (690mg,
5.0mmol), potassium iodide (168mg, 1.0mmol) and 1H- tetrazoles (1401mg, 20mmol), mixture is heated to reflux 2h.Instead
Reaction solution is poured into 20mL frozen water after answering, is extracted 2 times with equivalent dichloromethane, merges organic phase.Water is used successively and is satisfied
Organic phase after merging with brine It, then dried with anhydrous sodium sulfate, the removal solvent that is concentrated under reduced pressure obtains product crude product.
Because tautomerization, two kinds of substitution products of 1H- tetrazoles base and 2H- tetrazoles base can be generated at reaction conditions.Product
Crude product purifies that (mobile phase is with silica gel column chromatography：Petroleum ether/acetone=100:1, v/v), collect yellow and concentrate elution band, then will
Elution band concentrates, and purifies that (mobile phase is with silica gel column chromatography：Petroleum ether/acetone=100:0.5, v/v), collection two is light successively
The elution band of yellow, 1 elution band obtains the faint yellow solid (89.9mg, 27%) of compound IV before concentration.
1H NMR(500MHz,DMSO-d6)δ10.47(s,2H),10.40(s,1H),10.26(s,1H),7.24(s,
2H), 7.21 (d, J=10.0Hz, 3H), 4.65 (s, 1H), 4.60 (s, 1H), 4.45 (d, J=2.6Hz, 5H), 4.42 (s,
1H),4.07(s,1H),2.20(s,1H),1.93–1.84(m,4H),1.72(s,1H),1.60–1.21(m,4H),0.99(s,
3H),0.92–0.71(m,9H),0.55(s,1H),0.25(s,1H).
13C NMR(125MHz,DMSO-d6)δ188.53(s),170.35(s),165.18(s),163.13(s),144.94
(s),142.48(s),129.45(s),127.69(s),126.84(s),117.75(s),116.60(s),114.54(s),
67.03(s),47.04(s),39.95(s),34.52(s),34.10(s),30.66(s),27.85(s),26.18(s),24.26
(s),23.46(s),20.93(s),20.51(s),19.77(s),14.10(s).
HRMS(ESI):m/z[M+H]+calcd for C36H43N8O5:667.3356；found:667.3352.
The low property anaemia experiment of 5 composition anti-erythrocyte of embodiment
Test therapeutic effect of 1 composition to post hemorrhagic mice
ICR mouse 30, ♀ ♂ are fifty-fifty, are divided into 5 groups (n=10).In addition to physiological saline group, other groups of every mouse from
Blood is taken to survey whole each group indexs after orbital vein bloodletting 0.5ml, 24h again, then continuous gavage is daily after being administered 1 week and being administered
After bloodletting 0.5ml, last dose 1h, blood is taken to carry out red blood cell count(RBC) with the full whole bliid platelet analyzers of F-800 from orbital venous plexus
(1012/L)。
The preparation of composition：The powder of the 10mg compounds III of 200 mesh nets is crossed after grinding and crosses 200 after grinding
The powder of the 20mg compounds IV of mesh net is fitted into tubule with cover and obtains 30mg compositions with the mixing of turbine stirring instrument, makes
The composition that used time dissolves this 30mg with water obtains the solution of composition.
1 composition of table is to the oligocythemic therapeutic effect caused by losing blood
Compared with model group：*p<0.05
The result shows that bloodletting mouse, after taking composition treatment 7 days, compared with model group, its red blood cell is significantly higher than
Model group, close to physiological saline group.And compound III and compound IV is acted on without this.
2nd, composition causes oligocythemic therapeutic effect to endoxan
To the preventive and therapeutic effect ICR mouse 50 of mouse bone marrow cells hematopoiesis function damage, ♀ ♂ dual-purposes, are divided into 5 groups (n=10),
That is physiological saline group, modeling group, composition 1.2mg/kg groups, compound III 1.2mg/kg groups and compound IV 1.2mg/kg
Group, is administered orally, 1 time a day.Cycli phosphate amine was injected intraperitoneally in other each group mouse respectively in addition to physiological saline group on 0th, 5,10
80mg/kg, then proceedes to administration 3 days.In 1h after the last administration, blood is taken from orbital venous plexus, surveys red blood cell number (1012/L)。
Influence of 2 composition of table to caused by cyclophosphamide red blood cell
Compared with model group：**p<0.01
The result shows that compared with physiological saline group, cycli phosphate amine can damage mouse bone marrow cells, cause under peripheral blood cells
Drop, composition group can substantially resist cycli phosphate amine induced mice red blood cell decreased compared with model group.And compound III and change
Compound IV is acted on without this.
3rd, composition is to oligocythemic therapeutic effect caused by benzene
Influence to Induced Aplastic Anemia Mice：Kunming mouse 50, ♀ ♂ dual-purposes, are divided into 5 groups (n=10), remove
Outside physiological saline group, other groups of mouse subcutaneous injection benzene 0.5ml/kg, continuous 12 days, on the same day of modeling, are administered orally, often at the same time
It 1 time, totally 18 days, 1h, orbital venous plexus took blood, survey red blood cell after the last administration.
3 composition of table is to oligocythemic therapeutic effect caused by benzene
Compared with model group：**p<0.01
The result shows that composition group, compared with model group, Induced Aplastic Anemia Mice caused by can substantially resisting benzene is red thin
The decline of born of the same parents.And compound III and compound IV is acted on without this.
Conclusion：Composition can significantly raise red blood cell, can be used for preparing the medicine for the treatment of anaemia.And compound III
Red blood cell can not be significantly raised with compound IV, it is impossible to for preparing the medicine for the treatment of anaemia.
The preparation of 6 composition tablet involved in the present invention of embodiment
2 grams of compositions are taken, addition prepares 18 grams of the customary adjuvant of tablet, mixes, and conventional tablet presses are made 100.
The preparation of 7 composition capsule involved in the present invention of embodiment
2 grams of compositions are taken, addition prepares customary adjuvant such as 18 grams of the starch of capsule, mixes, encapsulated to be made 100.
Claims (7)
1. a kind of composition, it is characterized in that said composition is made of compound III and compound IV, compound in said composition
The mass fraction of III and compound IV are 10 parts and 20 parts,
2. the preparation method of composition as claimed in claim 1, it is characterized in that：By the powder of compound III and compound IV
Powder be sufficiently mixed according to mass fraction for 10 parts and 20 parts.
A kind of 3. application of the composition in the low property anaemia medicine of red blood cell is treated as claimed in claim 1.
4. application of the composition as claimed in claim 3 in the low property anaemia medicine of red blood cell is treated, it is characterized in that：It is described
The low property anaemia of red blood cell is caused by losing blood.
5. application of the composition as claimed in claim 3 in the low property anaemia medicine of red blood cell is treated, it is characterized in that：It is described
The low property anaemia of red blood cell is low as the red blood cell caused by chemical substance.
6. application of the composition as claimed in claim 5 in the low property anaemia medicine of red blood cell is treated, it is characterized in that：It is described
Chemical substance is benzene, and the low property anaemia of red blood cell is the alpastic anemia caused by benzene.
7. application of the composition as claimed in claim 5 in the low property anaemia medicine of red blood cell is treated, it is characterized in that：It is described
Chemical substance is cycli phosphate amine, and the low property anaemia of red blood cell is the red blood cell decreased caused by cycli phosphate amine.
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| CN105250308A (en) * | 2015-11-06 | 2016-01-20 | 苏州贺澳德生物医药科技有限公司 | Composition and application thereof to medicines resistant to anemia due to low red cells |
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| CN105078985A (en) * | 2015-09-08 | 2015-11-25 | 苏州贺澳德生物医药科技有限公司 | Composition 53083001030571 and application of composition 53083001030571 to drug for resisting low-hematocrit anemia |
| CN105250308A (en) * | 2015-11-06 | 2016-01-20 | 苏州贺澳德生物医药科技有限公司 | Composition and application thereof to medicines resistant to anemia due to low red cells |
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