CN105935361A - Application of composition of Virosaine A tetrahydropyrrole and morpholinyl derivatives in drugs for resisting low red blood cell anemia - Google Patents
Application of composition of Virosaine A tetrahydropyrrole and morpholinyl derivatives in drugs for resisting low red blood cell anemia Download PDFInfo
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- CN105935361A CN105935361A CN201610278640.8A CN201610278640A CN105935361A CN 105935361 A CN105935361 A CN 105935361A CN 201610278640 A CN201610278640 A CN 201610278640A CN 105935361 A CN105935361 A CN 105935361A
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- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, and in particular, relates to a composition, and a preparation method and an application thereof in preparation of drugs for resisting low red blood cell anemia. Disclosed are the composition and the preparation method thereof. Pharmacological experiments indicate that the composition has a low red blood cell anemia resisting effect and has the value of developing the drugs for resisting low red blood cell anemia.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions, preparation method and use thereof
On the way.
Background technology
Based on different clinical characters, anemia has different classification.As: divide acute and chronic by anemia tempo
Anemia；Divide hyperplastic anemia (as thin in hemolytic anemia, iron deficiency anemia, huge children by bone marrow red system proliferative conditions
Born of the same parents' anemia etc.) and Hypolasia anemia (such as aplastic anemia).
Clinically often from anemia pathogenesis and the classification of the cause of disease:
1. erythropoiesis minimizing property anemia
The anomalous effects erythropoiesis of hematopoietic cell, marrow stromal cell and hemopoietic raw material, can be formed red carefully
Born of the same parents generate 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, with primary and secondary
Hematopoietic stem/progenitor cells infringement relevant.The pathogenesis of parts whole blood cytopenia produces anti-bone with B cell
Myelocyte 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 is subject to
To infringement, and then cause anemia.According to the cause of disease, this disease can be divided into congenital and posteriority two class.Congenital
PRCA i.e. Diamond-Blackfan syndrome, is caused by heredity；Posteriority PRCA include primary, continue
Send out two classes.Having scholar to find in part constitutional PRCA patients serum has self EPO or normoblast antibody.
Secondary cases PRCA mainly has medicine relationship type, (antibacterial and virus, such as piconavirus B to infect relationship type19、
Hepatitis virus etc.), autoimmune disease relationship type, lymphoproliferative disease relationship type is (such as thymoma, pouring
Bar tumor, plasma cell dyscrasia and Lymphocytic leukemia etc.) and acute aplastic crisis etc..
3) to be that ancestral does in a red system of class heritability thin for congenital dyserythropoietic anemia (CDA) CDA
Born of the same parents' optimum clone 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's type.
4) these disease hematopoietic stem/progenitor cells of hemopoietic system malignant clone disease there occurs the exception of matter, including
Myelodysplastic syndrome and all kinds of hematopoietic system cancer disease such as leukemia etc..The former is because of DH,
High hypertrophy, high apoptosis, hemolysis in situ occurs；The latter's neoplastic hyperplasia, low apoptosis and low differentiation, hemopoietic regulates
Also be affected so that normal mature erythrocytopenia and there is anemia.
(2) hematopoieticmicroenviron-ment caused by abnormal anemia
Hematopoieticmicroenviron-ment includes bone marrow matrix, stromal cell and cytokine.
1) bone marrow matrix and stromal cell impaired Anemia BMN, myelofibrosis, myelosclerosis,
The bone marrow neoplasms of marble extramedullary tumor disease sick, various and various infection or non-infectious osteomyelitis, all
Can be 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), erythrocyte are raw
Cheng Su (EPO), thrombopoietin (TPO), PDGF (TGF), neoplasm necrosis
The factor (TNF) and interferon (IFN) etc. are respectively provided with positive negative regulation hemoposieis.Renal insufficiency, hepatopathy
Not enough with producing EPO when hypophysis or hypothyroidism etc.；Neoplastic disease or some virus infection can lure
Lead body and produce more hemopoietic negative regulatory factor such as TNF, IFN, inflammatory factor etc., all may result in chronic disease
Property anemia (ACD).
(3) hemopoietic insufficient raw material or Use barriers Anemia
Hemopoietic raw material refers to material necessary to hematopoietic cell proliferation, differentiation, 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 B12Lack or Use barriers Anemia is led due to various physiology or pathological factor
Cause body folic acid or absolute or that shortage or Use barriers can cause the relatively megaloblastic anemia of vitamin B12.
2) iron deficiency and ferrum Use barriers anemia this be the most modal anemia.Iron deficiency and ferrum Use barriers
Affecting haemachrome synthesis, having such anemia is called haemachrome resulting anomaly anemia.The erythrocyte shape of such anemia
State diminishes, and central authorities' olistherozone expands, and belongs to microcytic hypochromic anemia.
2. hemolytic anemia (HA)
I.e. hematoclasis too much property anemia.
3. hemorrhagic anemia
Dividing acute and chronic according to speed of losing blood, chronic blood loss anemia often merges iron deficiency anemia.Can be divided into
Go out disorders of blood coagulation (such as idiopathic thrombocytopenic purpura, hemophilia and severe liver disease etc.) make peace non-go out
Disorders of blood coagulation (such as wound, tumor, tuberculosis, bronchiectasis, peptic ulcer, hemorrhoid and gynaecopathia etc.)
Caused two classes.
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 most has important value.
The compound I that the present invention relates to be one within 2012, deliver (Bing-Xin Zhao et al., 2012.
Virosaines A and B,Two New Birdcage-Shaped Securinega Alkaloids with an
Unprecedented Skeleton from Flueggea virosa.Organic Letters 14(2012)3096–3099)
Compound, we have carried out structural modification to compound I, it is thus achieved that two i.e. compound III of new derivant
With compound IV, and it is prepared for compositions and to said composition anti-erythrocyte with compound III and compound IV
Low property anemia activity is evaluated, and it has anti-erythrocyte low property anemia activity.
Summary of the invention
The invention discloses a new compositions, said composition is made up of compound III and compound IV, should
In compositions, the mass percent of compound III and compound IV is respectively 30% and 70%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
It is an object of the invention to provide the present composition new application 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 had
Any restriction of body embodiment, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Virosaine A
The document that the preparation method of compound Virosaine A (I) is delivered with reference to Bing-Xin Zhao et al.
(Bing-Xin Zhao et al.,2012.Virosaines A and B,Two New Birdcage-Shaped
Securinega Alkaloids with an Unprecedented Skeleton from Flueggea virosa.Organic
Letters 14 (2012) 3,096 3099) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2 Virosaine A
Compound I (235mg, 1.00mmol) is dissolved in 20mL benzene, in solution, adds tetrabutyl phosphonium bromide
Ammonium (TBAB) (0.08g), glycol dibromide (3.760g, 20.00mmol) and 50% hydrogen of 5mL
Sodium hydroxide solution.Mixture stirs 8h at 35 degrees Celsius.After 8h, reactant liquor is poured in frozen water, immediately
It is extracted twice with dichloromethane, merges organic phase solution.Then to organic phase solution successively with water and saturated common salt
Water washs 3 times, then is dried with anhydrous sodium sulfate, and last concentrating under reduced pressure is removed solvent and obtained product crude product.Product
Crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), collects brown and concentrates
Elution band is also flung to solvent and is i.e. obtained the brown ceramic powder (261mg, 78%) of compound II.
1H NMR(500MHz,DMSO-d6)δ5.91(s,1H),4.07(s,1H),3.81(s,2H),3.59(s,1H),
3.43 (s, 2H), 3.33 (s, 1H), 2.26 (s, 1H), 1.58 (d, J=9.8Hz, 3H), 1.41 (s, 2H).
13C NMR(125MHz,DMSO-d6)δ171.81(s),106.71(s),79.95(s),74.33(s),69.81
(s),66.68(s),44.21(s),35.56(s),33.28(s),25.85(s),21.88(s).
HRMS(ESI)m/z[M+H]+calcd for C14H17BrNO4:342.0341；found 342.0343.
The synthesis of the O-(nafoxidine base) ethyl derivative (III) of embodiment 3 Virosaine A
Compound II (171mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and pyrrolidine (1420mg,
20mmol), mixture is heated to reflux 1h.Reactant liquor is poured in frozen water after terminating by reaction, uses equivalent dichloro
Methane extracts 2 times, merges organic facies.Organic facies after merging with water and saturated aqueous common salt washing successively, then
Being dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product silica gel column chromatography is pure
Change (flowing is mutually: petroleum ether/acetone=100:1.5, v/v), collect faint yellow concentration elution band and i.e. obtain Virosaine
The faint yellow colloidal solid (111.6mg, 67%) of the O-(nafoxidine base) ethyl derivative (III) of A.
1H NMR(500MHz,DMSO-d6)δ5.92(s,1H),4.11(s,1H),3.66(s,1H),3.53(s,
2H), 3.45 (d, J=66.9Hz, 1H), 2.64 (s, 2H), 2.52 (s, 4H), 2.29 (s, 1H), 1.71 (s, 4H),
1.64(s,2H),1.61(s,1H),1.50(s,2H).
13C NMR(125MHz,DMSO-d6)δ171.83(s),106.73(s),79.97(s),74.35(s),66.72
(d, J=9.2Hz), 54.42 (d, J=17.1Hz), 44.23 (s), 35.58 (s), 25.86 (s), and 25.23 (s), 21.90
(s).
HRMS(ESI):m/z[M+H]+calcd for C18H25N2O4:333.1814；found:333.1811.
The synthesis of O-(morpholinyl) ethyl derivative of embodiment 4 Virosaine A
Compound II (171mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and morpholine (1742mg, 20mmol),
Mixture is heated to reflux 1h.Reactant liquor is poured in 20mL frozen water after terminating by reaction, uses equivalent dichloromethane
Extract three times, merge organic facies.Organic facies after merging with water and saturated aqueous common salt washing successively, then use nothing
Aqueous sodium persulfate is dried, and concentrating under reduced pressure is removed solvent and obtained product crude product.Product crude product silica gel column chromatography purify (stream
Move and be mutually: petroleum ether/acetone=100:1.0, v/v), collect yellow and concentrate elution band i.e. to obtain Virosaine A's
The yellow solid (IV) (125.3mg, 72%) of O-(morpholinyl) ethyl derivative.
1H NMR(500MHz,DMSO-d6)δ5.95(s,1H),4.12(s,1H),3.68(s,1H),3.63(d,J
=8.4Hz, 1H), 3.61 (s, 4H), 3.57 3.26 (m, 3H), 2.61 (s, 2H), 2.56 (s, 2H), 2.51
2.03 (m, 5H), 1.70 (d, J=3.1Hz, 1H), 1.65 (d, J=25.6Hz, 1H), 1.52 (s, 2H).
13C NMR(125MHz,DMSO-d6)δ171.85(s),106.73(s),79.95(s),74.34(s),66.75
(t, J=4.6Hz), 54.46 (s), 52.93 (s), 44.22 (s), 35.55 (s), 25.88 (s), 21.89 (s).
HRMS(ESI):m/z[M+H]+calcd for C18H25N2O5:349.1763；found:349.1761.
Embodiment 5 compositions anti-erythrocyte low property anemia is tested
One, the compositions therapeutical effect to post hemorrhagic mice
ICR mice 30, ♀ ♂ half and half, it is divided into 5 groups (n=10).In addition to normal saline group, other group
Every mice, from orbital vein blood-letting 0.5ml, takes blood again and surveys whole index of respectively organizing, then continuous gavage after 24h
Blood-letting every day 0.5ml after being administered 1 week and being administered, after last is administered 1h, takes blood F-800 from orbital venous plexus
Full whole bliid platelet analyzer carries out red blood cell count(RBC) (1012/L)。
The preparation of compositions: powder and the grinding of the 30mg compound III of 200 mesh nets will be crossed after grinding
The powder of the 70mg compound IV of rear mistake 200 mesh net loads in tubule with cover and mixes with turbine stirring instrument
I.e. obtain 100mg compositions, during use, obtain the solution of compositions by the compositions of this 100mg of water dissolution.
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 shows
Write higher than model group, close to normal saline group.And compound III and compound IV acts on without this.
Two, compositions causes oligocythemic therapeutical effect to cyclophosphamide
Preventive and therapeutic effect ICR mice 50 to the damage of mouse bone marrow cells hemopoietic function, ♀ ♂ dual-purpose, it is divided into 5
Group (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.Within 0th, 5,10th, remove normal saline group
Outward, other respectively organizes mice lumbar injection cycli phosphate amine 80mg/kg respectively, then proceedes to be administered 3 days.In last
1h after administration, takes blood from orbital venous plexus, surveys RBC number (1012/L)。
The impact erythrocytic on caused by cyclophosphamide of table 2 compositions
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 thin
Born of the same parents decline, and compositions group compares with model group, can substantially resist cycli phosphate amine induced mice red blood cell decreased.And
Compound III and compound IV acts on without this.
Three, compositions is to therapeutical effect oligocythemic caused by benzene
Impact on Induced Aplastic Anemia Mice: Kunming mouse 50, ♀ ♂ dual-purpose, it is divided into 5 groups
(n=10), in addition to normal saline group, other organizes mouse subcutaneous injection benzene 0.5ml/kg, continuous 12 days, modeling
The same day, oral administration simultaneously, every day 1 time, totally 18 days, last be administered after 1h, orbital venous plexus takes blood,
Survey erythrocyte.
Table 3 compositions is to therapeutical effect oligocythemic caused by benzene
Compare with model group:**p<0.01
Result shows, compositions group compares with model group, can substantially resist Induced Aplastic Anemia Mice caused by benzene
Erythrocytic decline.And compound III and compound IV acts on without this.
Conclusion: compositions can significantly raise erythrocyte, can be used to the medicine of preparation treatment anemia.And chemical combination
Thing III and compound IV can not significantly raise erythrocyte, it is impossible to is used for preparing the medicine for the treatment of anemia.
The preparation of embodiment 6 composition tablet involved in the present invention
Taking 2 grams of compositionss, the customary adjuvant 18 grams of tablet is prepared in addition, and mixing, conventional tablet presses makes 100
Sheet.
The preparation of embodiment 7 composition capsule involved in the present invention
Taking 2 grams of compositionss, the customary adjuvant such as starch 18 grams of capsule is prepared in addition, mixing, encapsulated system
Become 100.
Claims (7)
1. a compositions, is characterized by that said composition is made up of, in said composition compound III and compound IV
The mass percent of compound III and compound IV is respectively 30% and 70%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: by powder and the change of compound III
The powder of compound IV is sufficiently mixed according to mass percent respectively 30% and 70%.
3. a compositions as claimed in claim 1 application in treatment erythrocyte low property anemia medicine.
4. the compositions as claimed in claim 3 application in treatment erythrocyte low property anemia medicine, its feature
For: described erythrocyte low property anemia is caused by losing blood.
5. the compositions as claimed in claim 3 application in treatment erythrocyte low property anemia medicine, its feature
For: described erythrocyte low property anemia is low by the erythrocyte caused by chemical substance.
6. the compositions as claimed in claim 5 application in treatment erythrocyte low property anemia medicine, its feature
For: described chemical substance is benzene, and described erythrocyte low property anemia is by the aplastic anemia caused by benzene.
7. the compositions as claimed in claim 5 application in treatment erythrocyte low property anemia medicine, its feature
For: described chemical substance is cycli phosphate amine, and described erythrocyte low property anemia is by erythrocyte caused by cycli phosphate amine
Decline.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610278640.8A CN105935361A (en) | 2016-04-28 | 2016-04-28 | Application of composition of Virosaine A tetrahydropyrrole and morpholinyl derivatives in drugs for resisting low red blood cell anemia |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610278640.8A CN105935361A (en) | 2016-04-28 | 2016-04-28 | Application of composition of Virosaine A tetrahydropyrrole and morpholinyl derivatives in drugs for resisting low red blood cell anemia |
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| CN105935361A true CN105935361A (en) | 2016-09-14 |
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| CN201610278640.8A Withdrawn CN105935361A (en) | 2016-04-28 | 2016-04-28 | Application of composition of Virosaine A tetrahydropyrrole and morpholinyl derivatives in drugs for resisting low red blood cell anemia |
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2016
- 2016-04-28 CN CN201610278640.8A patent/CN105935361A/en not_active Withdrawn
Non-Patent Citations (2)
| Title |
|---|
| BING-XIN ZHAO ET AL.: "Virosaines A and B, Two New Birdcage-Shaped Securinega Alkaloids with an unprecedented Skeleton from Flueggea virosa", 《ORGANIC LETTERS》 * |
| 赵冰心等: "白饭树属植物中一叶萩型生物碱类成分研究", 《中国化学会第9届天然有机化学学术会议论文集》 * |
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Application publication date: 20160914 |