CN106074528A - The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-erythrocyte low property anaemia medicine - Google Patents
The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-erythrocyte low property anaemia medicine Download PDFInfo
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- CN106074528A CN106074528A CN201610347281.7A CN201610347281A CN106074528A CN 106074528 A CN106074528 A CN 106074528A CN 201610347281 A CN201610347281 A CN 201610347281A CN 106074528 A CN106074528 A CN 106074528A
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- 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
- A61K31/4192—1,2,3-Triazoles
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- 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
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Abstract
The invention discloses the application in anti-erythrocyte low property anaemia medicine of the composition of O (triazolyl) ethyl of a kind of Ah draw'sing Bick acid i.e. Artalbic acid and O (1H tetrazole base) ethyl derivative, the present invention relates to organic synthesis and medicinal chemistry art, be specifically related to O (triazolyl) ethyl of Ah draw'sing Bick acid i.e. Artalbic acid and the composition of O (1H tetrazole base) ethyl derivative, preparation method and in the purposes prepared on anti-erythrocyte low property anaemia medicine.The invention discloses O (triazolyl) ethyl of a kind of Ah draw'sing Bick acid i.e. Artalbic acid and composition of O (1H tetrazole base) ethyl derivative and preparation method thereof.Pharmacological experiment shows, the composition of O (triazolyl) ethyl of Ah draw'sing Bick acid i.e. Artalbic acid of the present invention and O (1H tetrazole base) ethyl derivative has the effect of anti-erythrocyte low property anaemia, has the value of exploitation anti-erythrocyte low property anaemia medicine.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to composition, preparation method and its usage.
Background technology
Based on different clinical characters, anaemia has different classification.As: divide acute and chronic anaemia by anaemia tempo；Press
Marrow red system proliferative conditions divides hyperplastic anemia (such as hemolytic anemia, hypoferric anemia, megaloblastic anemia etc.) and hyperplasia low
Lower property anaemia (such as alpastic anemia).
The normal classification from anaemia pathogenesis and the cause of disease clinically:
1. RBC acceptor garland rate minimizing property anaemia
The anomalous effects RBC acceptor garland rate of hematopoietic cell, marrow stromal cell and hematopoiesis raw material, can form red blood cell raw
Become minimizing 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
Primary cellular defect is relevant.The pathogenesis of parts whole blood cytopenia and B cell produce anti-bone marrow cell autoantibody, and then broken
Go bad or suppression myeloid element is relevant.
2) pure red cell aplasia anaemia (PRCA) PRCA refers to that marrow erythroid hematopoiesis stem/progenitor cells suffers damage, and then
Cause anaemia.According to the cause of disease, this disease can be divided into congenital and posteriority two class.Congenital PRCA i.e. Diamond-Blackfan combines
Simulator sickness, caused by being heredity；Posteriority PRCA includes primary, secondary two class.Scholar is had to find part primary PRCA patients serum
In have self EPO or normoblast antibody.Secondary cases PRCA mainly have medicine relationship type, infect relationship type (bacterium and virus, as
Piconavirus B19, hepatitis viruse etc.), autoimmunity disease relationship type, lymphoproliferative disease relationship type is (such as thymoma, pouring
Bar knurl, plasma cell dyscrasias and lymphocytic leukemia etc.) and acute aplastic crisis etc..
3) congenital dyserythropoietic anemia (CDA) CDA is an optimum clone of class heredity red system stem/progenitor cells
Caused by abnormal, the refractory anemia that is characterized with red system ineffective hematopoiesis and paramophia.According to mode of inheritance, this disease can be divided into
Autosome hidden flight of steps leading to a palace hall genotype and dominant inheritance type.
4) these disease hematopoietic stem/progenitor cells of hemopoietic system malignant clone disease there occurs the exception of matter, including marrow increases
Raw abnormal syndrome and all kinds of hematopoietic system cancer disease such as leukaemia etc..The former is because DH, and high hyperplasia, height withers
Die, hemolysis in situ occurs；The latter's neoplastic hyperplasia, low apoptosis and low differentiation, hematopoiesis regulation is also affected, so that normally becoming
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 impaired Anemia BMN, myelofibrosis, myelosclerosis, marble
The bone marrow neoplasms of extramedullary tumor diseases sick, various and various infection or non-infectious osteomyelitis, all can be because of damage marrow base
Matter and stroma cell, hematopoieticmicroenviron-ment occurs abnormal and affects haemocyte and generate.
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), TPO
(TPO), PDGF (TGF), TNF (TNF) and interferon (IFN) etc. are respectively provided with positive negative regulation hematopoiesis
Effect.EPO is produced not enough when renal insufficiency, hepatopathy and hypophysis or hypothyroidism etc.；ND or some disease
Poison infection can induce body to produce more hematopoiesis negative regulatory factor such as TNF, IFN, inflammatory factor etc., all may result in 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.), trace element (iron, copper, zinc etc.) etc..Any one hematopoiesis insufficient raw material or Use barriers all may
RBC acceptor garland rate is caused to reduce.
1) folic acid or Cobastab12Lack or Use barriers Anemia causes body due to various physiology or pathological factor
The megaloblastic anemia that folic acid or vitamin B12 definitely or relatively lack or Use barriers can cause.
2) iron deficiency and iron Use barriers anaemia this be modal anaemia clinically.Iron deficiency and iron Use barriers affect blood
Red pigment synthesizes, and has such anaemia to be called ferroheme resulting anomaly anaemia.The red cell morphology of such anaemia diminishes, central light dye
District expands, and belongs to microcytic hypochromic anemia.
2. hemolytic anemia (HA)
I.e. hematoclasis too much property anaemia.
3. blood loss anemia
Dividing acute and chronic according to speed of losing blood, chronic blood loss anemia often merges hypoferric anemia.Can be divided into solidifying
Courageous and upright disease (such as ITP, hemophilia and severe liver disease etc.) make peace non-go out disorders of blood coagulation (as
Wound, tumour, tuberculosis, bronchiectasis, peptic ulcer, hemorrhoid and gynecological disease etc.) caused by two classes.
Find compound or lead compound and carry out structural modification and obtain its derivative from natural products, thus obtaining
The potential drug of high-efficiency low-toxicity has important value most.
The compound I that the present invention relates to be one within 2011, deliver (Antonella Maggio et al.,
2011.Artalbic acid,a sesquiterpene with an unusual skeleton from Artemisia
Alba (Asteraceae) from Sicily.Tetrahedron Letters, 52 (2011) 4,543 4545) compound, I
Structural modification has been carried out to compound I, it is thus achieved that two new derivative i.e. compound III and compound IV, and use chemical combination
Thing III and compound IV is prepared for composition and is evaluated said composition anti-erythrocyte low property anaemia activity, its tool
There is anti-erythrocyte low property anaemia activity.
Content of the invention
The invention discloses a new composition, said composition is made up of compound III and compound IV, said composition
The mass percent of middle compound III and compound IV is respectively 35% and 65%.
Composition disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
It is an object of the invention to provide new application in pharmaceutical field for the present composition.
The present invention relates to composition as the application in preparation treatment red blood cell low property anaemia medicine.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by specifically in fact
Execute any restriction of example, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Artalbic acid
The document that the preparation method of compound Artalbic acid (I) is delivered with reference to Antonella Maggio et al.
(Antonella Maggio et al.,2011.Artalbic acid,a sesquiterpene with an unusual
skeleton from Artemisia alba(Asteraceae)from Sicily.Tetrahedron Letters,52
(2011) 4,543 4545) method.
The synthesis of O-bromoethyl derivative (II) of embodiment 2 Artalbic acid
Compound I (266mg, 1.00mmol) is dissolved in 10mL benzene, in solution, adds TBAB (TBAB)
(0.08g), 1,2-Bromofume (3.760g, 20.00mmol) and 50% sodium hydroxide solution of 6mL.Mixture is Celsius 40
Degree stirring 16h.After 16h, reactant liquor is poured in frozen water, be extracted twice with dichloromethane immediately, merge organic phase solution.So
Washing organic phase solution 5 times with water and saturated aqueous common salt successively afterwards, then being dried with anhydrous sodium sulfate, last reduced pressure concentration is removed
Solvent obtains product crude product.Product crude product silica gel column chromatography purifies (flowing is mutually: petroleum ether/acetone=100:1.0, v/v),
Collect brown concentrate elution band and fling to the brown ceramic powder (272mg, 73%) that solvent i.e. obtains compound II.
1H NMR(500MHz,DMSO-d6)δ11.41(s,1H),6.06(s,1H),5.76(s,1H),4.99(s,1H),
4.71(s,1H),4.56(s,1H),3.86(s,2H),3.54(s,2H),2.65(s,1H),2.43(s,2H),2.33(s,2H),
2.10(s,1H),1.64(s,3H),1.54(s,1H),1.44(s,2H),0.95(s,3H).
13C NMR(125MHz,DMSO-d6)δ201.95(s),175.93(s),149.13(s),148.15(s),117.05
(s),109.43(s),81.86(s),70.27(s),57.68(s),41.26(s),39.07(s),38.86(s),35.69(s),
33.36(s),30.72(s),20.44(s),18.42(s).
HRMS(ESI)m/z[M+H]+calcd for C17H26BrO4:373.1014；found 373.1017.
The synthesis of O-(triazolyl) ethyl derivative (III) of embodiment 3 Artalbic acid
Be dissolved in compound II (187mg, 0.5mmol) in the middle of 25mL acetonitrile, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), KI (84mg, 0.5mmol) and 1,2,3-triazoles (2760mg, 40mmol), mixture is heated to reflux 3h.
Reaction after terminating is poured reactant liquor in frozen water into, extracts three times with equivalent dichloromethane, merges organic phase.Use water and saturated successively
Organic phase after brine It merging, then be dried with anhydrous sodium sulfate, reduced pressure concentration is removed solvent and is obtained product crude product.Produce
Thing crude product silica gel column chromatography purifies (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), collects faint yellow concentration and elutes
Band i.e. obtains the faint yellow colloidal solid (124.5mg, 69%) of compound III.
1H NMR (500MHz, DMSO-d6) δ 16.23 (s, 1H), 7.99 (d, J=29.4Hz, 2H), 6.11 (s, 1H),
5.82 (s, 1H), 4.76 (d, J=17.3Hz, 2H), 4.62 (s, 1H), 4.24 (s, 1H), 4.18 (s, 1H), 3.84 (s, 2H),
(2.70 s, 1H), 2.52 (d, J=16.3Hz, 4H), 2.02 (s, 1H), 1.69 (s, 3H), 1.62 (s, 2H), 1.51 (s, 1H),
1.02(s,3H).
13C NMR(125MHz,DMSO-d6)δ201.95(s),175.95(s),149.17(s),148.18(s),136.99
(s),120.76(s),117.09(s),109.44(s),81.89(s),65.54(s),57.72(s),46.43(s),41.30
(s),39.08(s),38.89(s),35.71(s),30.77(s),20.46(s),18.43(s).
HRMS(ESI):m/z[M+H]+calcd for C19H28N3O4:362.2080；found:362.2085.
The synthesis of O-(the 1H-tetrazole base) ethyl derivative of embodiment 4 Artalbic acid
Be dissolved in compound II (187mg, 0.5mmol) in the middle of 20mL acetonitrile, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), KI (84mg, 0.5mmol) and 1H-tetrazole (1401mg, 20mmol), mixture is heated to reflux 5h.Reaction
After end pour reactant liquor in frozen water into, extract three times with equivalent dichloromethane, merge organic phase.Use water and saturated common salt successively
Organic phase after water washing merging, then be dried with anhydrous sodium sulfate, reduced pressure concentration is removed solvent and is obtained product crude product.Because mutually
Become isomerization, 1H-tetrazole base and two kinds of substitution products of 2H-tetrazole base can be generated at reaction conditions.Product crude product is used
Silica gel column chromatography purifies (flowing is mutually: petroleum ether/acetone=100:1.5, v/v), collects yellow and concentrates elution band, then will wash-out
Band concentrates, and is purified (flowing is mutually: petroleum ether/acetone=100:0.5, v/v) by silica gel column chromatography, and collection two is faint yellow successively
Elution band, concentrate front 1 elution band and i.e. obtain the faint yellow solid (41.6mg, 23%) of compound IV.
1H NMR(500MHz,DMSO-d6)δ11.50(s,1H),10.04(s,1H),6.07(s,1H),5.78(s,1H),
4.69 (d, J=11.0Hz, 2H), 4.58 (s, 1H), 4.22 (s, 1H), 4.15 (s, 1H), 3.84 (s, 2H), 2.66 (s, 1H),
2.52 (s, 2H), 2.45 (s, 2H), 2.20 (s, 1H), 1.65 (d, J=8.0Hz, 5H), 1.44 (s, 1H), 0.98 (s, 3H).
13C NMR(125MHz,DMSO-d6)δ201.92(s),175.93(s),149.14(s),148.15(s),145.18
(s),117.08(s),109.40(s),81.85(s),65.53(s),57.68(s),46.71(s),41.29(s),39.04
(s),38.85(s),35.70(s),30.73(s),20.42(s),18.42(s).
HRMS(ESI):m/z[M+H]+calcd for C18H27N4O4:363.2032；found:363.2029.
Embodiment 5 composition anti-erythrocyte low property anaemia is tested
First, the therapeutic action to post hemorrhagic mice for the composition
ICR mouse 30, ♀ ♂ half and half, it is divided into 5 groups (n=10).In addition to physiological saline group, other every mouse of group from
Orbital vein bloodletting 0.5ml, takes blood again and surveys all each group indexs after 24h, then every day after continuous gastric infusion 1 week and administration
Bloodletting 0.5ml, after last is administered 1h, takes the full whole bliid platelet analyzer of blood F-800 from orbital venous plexus and carries out red blood cell count(RBC)
(1012/L)。
The preparation of composition: the powder of the 35mg compound III that will cross 200 mesh nets after grinding crosses 200 after grinding
The powder of the 65mg compound IV of mesh net loads in tubule with cover and i.e. obtains 100mg composition with the mixing of turbine stirring instrument,
Dissolve, with water, the solution that the composition of this 100mg obtains composition during use.
Table 1 composition is to because of caused oligocythemic therapeutic action of losing blood
Compare with model group: * p < 0.05
Result shows, bloodletting mouse, after taking composition and treating 7 days, is compared with model group, and its red blood cell is significantly higher than
Model group, close to physiological saline group.And compound III and compound IV acts on without this.
2nd, composition causes oligocythemic therapeutic action to endoxan
Preventive and therapeutic effect ICR mouse 50 to the damage of mouse bone marrow cells hematopoiesis function, ♀ ♂ dual-purpose, it is divided into 5 groups (n=10),
I.e. physiological saline group, modeling group, composition 1.2mg/kg group, compound III 1.2mg/kg group and compound IV 1.2mg/kg
Group, oral administration, every day 1 time.The the 0th, the 5th, in addition to physiological saline group, other respectively organized mouse lumbar injection cycli phosphate amine respectively on 10th
80mg/kg, then proceedes to be administered 3 days.1h after last is administered, takes blood from orbital venous plexus, surveys red blood cell number (1012/L)。
The erythrocytic impact on caused by cyclophosphamide of table 2 composition
Compare with model group: * * p < 0.01
Result shows, compares with physiological saline group, and cycli phosphate amine can make mouse bone marrow cells damage, and causes under PBC
Fall, composition group compares with model group, can substantially resist cycli phosphate amine induced mice red blood cell decreased.And compound III and change
Compound IV acts on without this.
3rd, composition is to therapeutic action oligocythemic caused by benzene
Impact on Induced Aplastic Anemia Mice: Kunming mouse 50, ♀ ♂ dual-purpose, it is divided into 5 groups (n=10), remove
Outside physiological saline group, other organize mouse subcutaneous injection benzene 0.5ml/kg, continuous 12 days, the same day of modeling, simultaneously oral administration, often
It 1 time, totally 18 days, 1h after last administration, orbital venous plexus took blood, surveys red blood cell.
Table 3 composition is to therapeutic action oligocythemic caused by benzene
Compare with model group: * * p < 0.01
Result shows, composition group compares with model group, and caused by can substantially resisting benzene, Induced Aplastic Anemia Mice is red carefully
The decline of born of the same parents.And compound III and compound IV acts on without this.
Conclusion: composition can significantly raise red blood cell, can be used to the medicine of preparation treatment anaemia.And compound III
Can not significantly raise red blood cell with compound IV, it is impossible to be used for preparing the medicine for the treatment of anaemia.
The preparation of embodiment 6 composition tablet involved in the present invention
Taking 2 grams of compositions, the customary adjuvant 18 grams of tablet is prepared in addition, mixes, and conventional tablet presses makes 100.
The preparation of embodiment 7 composition capsule involved in the present invention
Taking 2 grams of compositions, the customary adjuvant such as starch 18 grams of capsule is prepared in addition, mixes, encapsulated makes 100.
Claims (7)
1. a composition, is characterized by that said composition is made up of compound III and compound IV, compound in said composition
The mass percent of III and compound IV is respectively 35% and 65%,
2. the preparation method of composition as claimed in claim 1, is characterized by: by powder and the compound IV of compound III
Powder be respectively 35% and 65% according to mass percent and be sufficiently mixed.
3. a composition as claimed in claim 1 application in treatment red blood cell low property anaemia medicine.
4. application in treatment red blood cell low property anaemia medicine for the composition as claimed in claim 3, is characterized by: described
Red blood cell low property anaemia is caused by losing blood.
5. application in treatment red blood cell low property anaemia medicine for the composition as claimed in claim 3, is characterized by: described
Red blood cell low property anaemia is low by the red blood cell caused by chemical substance.
6. application in treatment red blood cell low property anaemia medicine for the composition as claimed in claim 5, is characterized by: described
Chemical substance is benzene, described red blood cell low property anaemia be by benzene caused by alpastic anemia.
7. application in treatment red blood cell low property anaemia medicine for the composition as claimed in claim 5, is characterized by: described
Chemical substance is cycli phosphate amine, and described red blood cell low property anaemia is by red blood cell decreased caused by cycli phosphate amine.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104127421A (en) * | 2014-07-31 | 2014-11-05 | 南京广康协生物医药技术有限公司 | Application of O-(piperidyl)ethyl derivative of Cleistanone in preparation of anti-low erythrocyte anemia drugs |
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2016
- 2016-05-24 CN CN201610347281.7A patent/CN106074528A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104127421A (en) * | 2014-07-31 | 2014-11-05 | 南京广康协生物医药技术有限公司 | Application of O-(piperidyl)ethyl derivative of Cleistanone in preparation of anti-low erythrocyte anemia drugs |
Non-Patent Citations (3)
| Title |
|---|
| ANTONELLA MAGGIO等: "Artalbic acid, a sesquiterpene with an unusual skeleton from Artemisia alba (Asteraceae) from Sicily", 《TETRAHEDRON LETTERS》 * |
| 林果为等: "《现代临床血液病学》", 31 August 2013 * |
| 邓家栋等: "《邓家栋临床血液学》", 31 July 2001 * |
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Application publication date: 20161109 |