CN106822105A - The imidazole radicals of Psiguadial A and two hydroxyethylamine derivative compositions are used for increasing leukocyte - Google Patents
The imidazole radicals of Psiguadial A and two hydroxyethylamine derivative compositions are used for increasing leukocyte Download PDFInfo
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- CN106822105A CN106822105A CN201611188003.8A CN201611188003A CN106822105A CN 106822105 A CN106822105 A CN 106822105A CN 201611188003 A CN201611188003 A CN 201611188003A CN 106822105 A CN106822105 A CN 106822105A
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- psiguadial
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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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
- A61K31/41—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
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
Imidazole radicals and two hydroxyethylamine derivative compositions the invention discloses Psiguadial A are used for increasing leukocyte, O (imidazole radicals) ethyls of i.e. a kind of Psiguadial A and application of the composition of O (two hydroxyethylamines) ethyl derivative in the medicine of increasing leukocyte, the present invention relates to organic synthesis and medicinal chemistry art, and in particular to the imidazole radicals of Psiguadial A and two hydroxyethylamine derivative compositions, preparation method and its purposes on increasing leukocyte medicine is prepared.Imidazole radicals and two hydroxyethylamine derivative compositions the invention discloses a kind of Psiguadial A and preparation method thereof.Pharmacological experiment shows, the imidazole radicals of Psiguadial A of the invention and two hydroxyethylamine derivative compositions have the effect of increasing leukocyte, the value with exploitation increasing leukocyte 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
Leukopenia is because reason is not clear and secondary to the disease caused after other diseases, is divided into primary
With the major class of Secondary cases two.Primary person's reason is failed to understand；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., acquired or reason
Not clear property granulocyte reduction etc..
Existing medicine has that toxicity is big, security is low at present for leukopenic treatment, from natural products
Find compound or lead compound and carry out structural modification and obtain its derivative, so as to the potential drug for obtaining high-efficiency low-toxicity 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 are carried out to compound I
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 said composition increasing leukocyte activity is evaluated, it has increasing leukocyte activity.
The 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 40% and 60%.
Composition disclosed by the invention can be made pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
It is an object of the invention to provide application of the composition in increasing leukocyte medicine is prepared.The present composition can be with
Significantly raise the leucocyte reduction lost blood and cause with chemical substance.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by specific real
Any limitation of example is applied, but is defined in the claims.
Specific embodiment
The preparation of the compound Psiguadial A of embodiment 1
Document (the Meng Shao that the preparation method of compound Psiguadial A (I) is delivered with reference to Meng Shao et al.
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.
The synthesis of O- bromoethyls derivative (II) of embodiment 2Psiguadial A
Compound I (474mg, 1.00mmol) is dissolved in 20mL benzene, to addition TBAB (TBAB) in 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 with dichloromethane immediately, merge organic phase solution.Then
To organic phase solution successively with water and saturated common salt water washing 3 times, then with anhydrous sodium sulfate drying, the removal that is finally concentrated under reduced pressure is molten
Agent obtains product crude product.(mobile phase is the purifying of product crude product 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.
The synthesis of O- (imidazole radicals) ethyl derivative (III) of embodiment 3Psiguadial A
Compound II (344mg, 0.5mmol) is dissolved in the middle of 25mL acetonitriles, be added thereto to Anhydrous potassium carbonate (690mg,
5.0mmol), KI (168mg, 1.0mmol) and imidazoles (3480mg, 40mmol), mixture is heated to reflux 2h.Reaction terminates
Reaction solution is poured into 25mL frozen water afterwards, is extracted 2 times with equivalent dichloromethane, merge organic phase.Water and saturated common salt are used successively
Water washing merge after organic phase, then with anhydrous sodium sulfate drying, removal solvent concentrated under reduced pressure obtains product crude product.Product is thick
(mobile phase is the purifying of product silica gel column chromatography：Petroleum ether/acetone=100:0.4, v/v) yellow, is collected to concentrate elution band and wave
Solvent is gone to obtain the yellow powder (235.0mg, 71%) of compound III.
1H NMR (500MHz, DMSO-d6) δ 10.38 (s, 2H), 7.80 (s, 2H), 7.17 (s, 2H), 7.11 (d, J=
10.0Hz,3H),7.07(s,2H),6.66(s,2H),4.47(s,4H),4.37(s,4H),3.91(s,1H),2.03(s,1H),
1.86-1.77 (m, 3H), 1.64 (s, 1H), 1.60 (s, 1H), 1.35 (d, J=4.6Hz, 3H), 1.15 (s, 1H), 0.89 (s,
3H),0.87–0.64(m,9H),0.43(s,1H),0.17(s,1H).
13C NMR(125MHz,DMSO-d6)δ188.52(s),170.35(s),165.17(s),163.13(s),142.49
(s),139.47(s),129.44(s),128.51(s),127.70(s),126.82(s),119.14(s),117.75(s),
116.59(s),114.54(s),69.29(s),43.78(s),39.96(s),34.50(s),34.09(s),30.66(s),
27.84(s),26.18(s),24.25(s),23.46(s),20.92(s),20.51(s),19.76(s),14.20(s).
HRMS(ESI):m/z[M+H]+calcd for C40H47N4O5:663.3546；found:663.3541.
The synthesis of the O- (two oxyethylamines) ethyl derivative (IV) of embodiment 4Psiguadial A
Compound II (344mg, 0.5mmol) is dissolved in 18mL acetonitriles, Anhydrous potassium carbonate (0.345g, 2.5mmol) is added,
KI (0.084g, 0.5mmol) and diethanol amine (2.103g, 20mmol), mixture is heated to reflux 2h.Reaction will after terminating
Reaction solution is poured into cold water, is extracted 2 times with dichloromethane, merges organic phase, successively with water and saturated common salt water washing, anhydrous sulphur
Sour sodium is dried, and be concentrated under reduced pressure removal solvent.Product silica gel column chromatography purifies (petroleum ether/acetone 100:0.7, v/v), changed
The Light brown solid (0.254g, 69%) of compound IV.
1H NMR (500MHz, DMSO-d6) δ 10.45 (s, 2H), 7.27 (t, J=15.0Hz, 2H), 7.21 (t, J=
15.0Hz,2H),7.21(s,1H),4.04(s,4H),3.97(s,1H),3.39(s,8H),2.68(s,4H),2.54(s,8H),
2.16(s,1H),2.01(s,1H),1.98–1.90(m,3H),1.68(s,1H),1.62(s,1H),1.45(s,2H),1.40
(s,1H),1.12(s,4H),1.00(s,3H),0.93(s,6H),0.89(s,3H),0.52(s,1H),0.27(s,1H).
13C NMR(125MHz,DMSO-d6)δ188.43(s),170.26(s),165.08(s),163.04(s),142.40
(s),129.34(s),127.61(s),126.73(s),117.67(s),116.49(s),114.46(s),69.16(s),
58.86(s),56.40(s),53.85(s),39.84(s),34.42(s),33.99(s),30.58(s),27.74(s),26.10
(s),24.15(s),23.38(s),20.82(s),20.43(s),19.66(s),14.02(s).
HRMS(ESI):m/z[M+H]+calcd for C42H61N2O9:737.4377；found:737.4374.
The composition increasing leukocyte of embodiment 5 activity
First, therapeutic action of the composition to post hemorrhagic mice
Influence ICR mouse 50 to post hemorrhagic mice, ♀ ♂ half and half are divided into 5 groups (n=10).In addition to physiological saline group,
Other every mouse of group take blood from orbital vein bloodletting 0.5ml, after 24h and survey whole each group leucocyte indexs again, then continuous to fill
Stomach is administered 1 week, after last dose 1h, takes the full whole bliid platelet analyzers of blood F-800 from orbital venous plexus and surveys leucocyte index.
The preparation of composition：The powder of the 40mg compounds III of 200 mesh nets will be crossed after grinding and 200 will be crossed after grinding
The powder of the 60mg compounds IV of mesh net is fitted into tubule with cover and obtains 100mg compositions with the mixing of turbine stirring instrument,
The solution of composition is obtained when using with the composition of water dissolves this 100mg.
The composition of table 1 is to because of caused leukopenic therapeutic action (10 of losing blood9/L)
Compare with model group：*p<0.05
Result shows that after taking composition treatment 7 days, composition administration group compares bloodletting mouse with model group, white thin
Born of the same parents are significantly higher than model group, close to physiological saline group.And compound III and compound IV is without this activity.
2nd, composition causes leukopenic therapeutic action to endoxan
The preventive and therapeutic effect ICR mouse 50 damaged to mouse bone marrow cells hematopoiesis function, ♀ ♂ 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, once a day.Other each group mouse distinguished intraperitoneal injection cycli phosphate amine in addition to physiological saline group on 0th, 5,10th
80mg/kg, then proceedes to administration 3 days.In 1h after last dose, blood is taken from orbital venous plexus, survey leucocyte.
The composition of table 2 is to the leukopenic therapeutic action (10 of caused by cyclophosphamide9/L)
Compare with model group：*p<0.05
Result shows, compares with physiological saline group that cycli phosphate amine can damage mouse bone marrow cells, under causing PBC
Drop, composition group compares with model group, can substantially resist the decline of cycli phosphate amine induced mice leucocyte.And compound III and
Compound IV is without this activity.
3rd, composition is to leukopenic therapeutic action 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 mouse subcutaneous injection benzene 0.5ml/kg, continuous 12 days, the same day of modeling, while be administered orally, often
It 1 time, totally 18 days, 1h after last dose, orbital venous plexus took blood, surveyed leucocyte.
The therapeutic action (10 that the composition of table 3 is reduced to haemocyte caused by benzene9/L)
Compare with model group：*p<0.05
Result shows that composition group compares with model group, and Induced Aplastic Anemia Mice caused by can substantially resisting benzene is thin in vain
The decline of born of the same parents.And compound III and compound IV is without this activity.
Conclusion：Composition can notable increasing leukocyte, can be used to prepare anti-leucocyte reduction medicine.And compound
Activity of the III and compound IV without notable increasing leukocyte, it is not possible to for preparing anti-leucocyte reduction medicine.
The preparation of the composition tablet involved in the present invention of embodiment 6
2 grams of compositions are taken, addition prepares 18 grams of the customary adjuvant of tablet, mixed, conventional tablet presses are made 100.
The preparation of the composition capsule involved in the present invention of embodiment 7
2 grams of compositions are taken, addition prepares customary adjuvant such as 18 grams of the starch of capsule, mixed, it is encapsulated to be made 100.
Claims (7)
1. a kind of composition, it is characterized by 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 40% and 60%,
2. the preparation method of composition as claimed in claim 1, it is characterized by：By the powder of compound III and compound IV
Powder be respectively 40% and 60% according to mass percent and be sufficiently mixed.
3. application of a kind of composition as claimed in claim 1 in increasing leukocyte medicine.
4. application of the composition as claimed in claim 3 in increasing leukocyte medicine, it is characterised in that the composition liter
Height is lost blood the reduction of caused leucocyte.
5. application of the composition as claimed in claim 3 in increasing leukocyte medicine, it is characterised in that the composition liter
The reduction of leucocyte caused by chemicals high.
6. application of the composition as claimed in claim 5 in increasing leukocyte medicine, it is characterised in that the chemicals is
Endoxan.
7. application of the composition as claimed in claim 5 in increasing leukocyte medicine, it is characterised in that the chemicals is
Benzene.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611188003.8A CN106822105A (en) | 2016-12-21 | 2016-12-21 | The imidazole radicals of Psiguadial A and two hydroxyethylamine derivative compositions are used for increasing leukocyte |
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| CN201611188003.8A CN106822105A (en) | 2016-12-21 | 2016-12-21 | The imidazole radicals of Psiguadial A and two hydroxyethylamine derivative compositions are used for increasing leukocyte |
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Application publication date: 20170613 |