CN105832742A - Application of composition of Virosaine A pyrrolidine derivative and morpholinyl derivative to medicine for increasing leucocyte - Google Patents
Application of composition of Virosaine A pyrrolidine derivative and morpholinyl derivative to medicine for increasing leucocyte Download PDFInfo
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- CN105832742A CN105832742A CN201610277881.0A CN201610277881A CN105832742A CN 105832742 A CN105832742 A CN 105832742A CN 201610277881 A CN201610277881 A CN 201610277881A CN 105832742 A CN105832742 A CN 105832742A
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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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Abstract
The invention discloses application of a composition of a Virosaine A pyrrolidine derivative and a morpholinyl derivative to medicine for increasing leucocyte and relates to the fields of organic synthesis and medicinal chemistry, in particular to the composition, a preparation method and application of the composition to preparation of the medicine for increasing leucocyte .The invention discloses the composition and the preparation method thereof .Pharmacological tests show that the composition has the function of increasing leucocyte and has the value of developing the medicine for increasing leucocyte.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to composition, preparation method and use thereof
On the way.
Background technology
Leukopenia is due to disease that is agnogenio and that cause after being secondary to other diseases, is divided into former
The property sent out and the big class of Secondary cases two.Primary person is agnogenio；Secondary cases person think its cause of disease can by acute infection,
Physics, chemical factor, disease in the blood system, the disease of companion's splenomegaly, connective tissue disease, anaphylactia,
Genetic disease etc., it is thus achieved that property or unexplained granulocyte minimizing etc..
There is the problem that toxicity is big, security is low, from natural product in the current existing medicine of leukopenic treatment
Thing found compound or lead compound and carries out structural modification and obtain its derivative, thus obtaining high-efficiency low-toxicity
Potential drug have 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 derivative
With compound IV, and it is prepared for composition with compound III and compound IV and said composition is raised white thin
Cytoactive is evaluated, and it has increasing leukocyte activity.
Summary of the invention
The invention discloses a new composition, said composition is made up of compound III and compound IV, should
In composition, the mass percent of compound III and compound IV is respectively 70% and 30%.
Composition disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
It is an object of the invention to provide composition application in preparing increasing leukocyte medicine.The present composition
The leucocyte that can significantly raise loses blood causes with chemical substance reduces.
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 derivative (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), 1,2-Bromofume (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 reduced pressure concentration is removed solvent and obtained product crude product.Product
Crude product silica gel column chromatography purifies (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), KI (84mg, 0.5mmol) and pyrrolidines (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 phase.Organic phase after merging with water and saturated aqueous common salt washing successively, then
Being dried with anhydrous sodium sulfate, reduced pressure concentration 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), KI (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 phase.Organic phase after merging with water and saturated aqueous common salt washing successively, then use nothing
Aqueous sodium persulfate is dried, and reduced pressure concentration 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 composition increasing leukocyte activity
One, the composition therapeutic action to post hemorrhagic mice
Post hemorrhagic mice affected ICR mouse 50, ♀ ♂ half and half, is divided into 5 groups (n=10).Except raw
Outside reason salt solution group, other every mouse of group, from orbital vein bloodletting 0.5ml, takes blood again and surveys whole each group after 24h
Leucocyte index, then continuous gastric infusion 1 week, after last is administered 1h, takes blood F-800 from orbital venous plexus
Full whole bliid platelet analyzer surveys leucocyte index.
The preparation of composition: powder and the grinding of the 70mg compound III of 200 mesh nets will be crossed after grinding
The powder of the 30mg compound IV of rear mistake 200 mesh net loads in tubule with cover and mixes with turbine stirring instrument
I.e. obtaining 100mg composition, during use, use water dissolves the composition of this 100mg and obtains the solution of composition.
Table 1 composition is to because of caused leukopenic therapeutic action (10 of losing blood9/L)
Compare with model group: * p < 0.05
Result shows, bloodletting mouse is after taking composition and treating 7 days, and composition administration group compares with model group,
Leucocyte is significantly higher than model group, close to physiological saline group.And compound III and compound IV does not have this and lives
Property.
Two, composition causes leukopenic 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
Group (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.Within 0th, 5,10th, remove physiological saline group
Outward, other respectively organizes mouse 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 leucocyte.
Table 2 composition therapeutic action leukopenic to caused by cyclophosphamide (109/L)
Compare with model group: * p < 0.05
Result shows, compares with physiological 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 composition group compares with model group, all can substantially resist cycli phosphate amine induced mice leucocyte and decline.
And compound III and compound IV does not have this activity.
Three, composition is to therapeutic action leukopenic 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 physiological 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 leucocyte.
The therapeutic action (10 that haemocyte caused by benzene is reduced by table 3 composition9/L)
Compare with model group: * p < 0.05
Result shows, composition group compares with model group, can substantially resist Induced Aplastic Anemia Mice caused by benzene
The decline of leucocyte.And compound III and compound IV does not have this activity.
Conclusion: composition can notable increasing leukocyte, can be used to prepare anti-leucocyte and reduce medicine.And change
Compound III and compound IV does not have the activity of notable increasing leukocyte, it is not possible to be used for preparing anti-leucocyte fall
Low medicine.
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, and mixing, conventional tablet presses makes 100
Sheet.
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, mixing, encapsulated makes
100.
Claims (7)
1. a composition, 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 70% and 30%,
2. the preparation method of composition 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 70% and 30%.
3. a composition as claimed in claim 1 application in increasing leukocyte medicine.
4. composition application in increasing leukocyte medicine as claimed in claim 3, it is characterised in that described group
Compound raises the reduction of caused leucocyte of losing blood.
5. composition application in increasing leukocyte medicine as claimed in claim 3, it is characterised in that described group
Compound raises the reduction of leucocyte caused by chemicals.
6. composition application in increasing leukocyte medicine as claimed in claim 5, it is characterised in that describedization
Product are endoxan.
7. composition application in increasing leukocyte medicine as claimed in claim 5, it is characterised in that describedization
Product are benzene.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610277881.0A CN105832742A (en) | 2016-04-28 | 2016-04-28 | Application of composition of Virosaine A pyrrolidine derivative and morpholinyl derivative to medicine for increasing leucocyte |
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| CN201610277881.0A CN105832742A (en) | 2016-04-28 | 2016-04-28 | Application of composition of Virosaine A pyrrolidine derivative and morpholinyl derivative to medicine for increasing leucocyte |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104193756A (en) * | 2014-09-04 | 2014-12-10 | 南京标科生物科技有限公司 | Method for extracting securinine from securinega |
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2016
- 2016-04-28 CN CN201610277881.0A patent/CN105832742A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104193756A (en) * | 2014-09-04 | 2014-12-10 | 南京标科生物科技有限公司 | Method for extracting securinine from securinega |
Non-Patent Citations (1)
| Title |
|---|
| BING-XIN ZHAO等: "《Virosaines A and B,Two New Birdcage-Shaped Securinega Alkaloids with an Unprecedented Skeleton from Flueggea virosa》", 《ORGANIC LETTERS》 * |
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