CN106822109A - The benzimidazolyl and bischloroethylamines radical derivative composition of Psiguadial A are used to prevent and treat hepar damnification - Google Patents
The benzimidazolyl and bischloroethylamines radical derivative composition of Psiguadial A are used to prevent and treat hepar damnification Download PDFInfo
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- CN106822109A CN106822109A CN201611196517.8A CN201611196517A CN106822109A CN 106822109 A CN106822109 A CN 106822109A CN 201611196517 A CN201611196517 A CN 201611196517A CN 106822109 A CN106822109 A CN 106822109A
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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
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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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
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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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Abstract
Benzimidazolyl and bischloroethylamines radical derivative composition the invention discloses Psiguadial A are used to prevent and treat hepar damnification, that is application of O (benzimidazolyl) ethyls of Psiguadial A with the composition of O (bischloroethylamines base) ethyl derivative in hepar damnification medicine is prevented and treated, the present invention relates to organic synthesis and medicinal chemistry art, and in particular to the benzimidazolyl and bischloroethylamines radical derivative composition of Psiguadial A, preparation method and its purposes on preventing and treating hepar damnification medicine is prepared.Benzimidazolyl and bischloroethylamines radical derivative composition the invention discloses a kind of Psiguadial A and preparation method thereof.Pharmacological experiment shows that the benzimidazolyl and bischloroethylamines radical derivative composition of Psiguadial A of the invention have the effect of preventing and treating hepar damnification, the value with exploitation preventing and treating hepar damnification 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
There is multiple the reason for causing hepatic injury：1st, virus infection：Caused by various hepatitis viruses, it is strong with infectiousness, pass
Broadcast approach complicated, it is popular wide general, the features such as the incidence of disease is high.2nd, medicine or chemical toxicant：Many medicines and chemical toxicant all may be used
Cause hepar damnification, drug hepatitis or toxic hepatitis occur.3rd, indulge in excessive drinking：Infringement of the alcohol to liver is very serious, is damaged
Harmful consequence includes alcoholic hepatitis, alcoholic fatty liver, alcoholic cirrhosis, mainly due to alcohol (ethanol) and its metabolism
The toxicity of product acetaldehyde is direct to liver cell to damage what is caused.4th, other reasonses：Primary and secondary liver neoplasm, heart function is not
Cause liver extravasated blood, some congenital hepatic diseases, vein high price nutrition etc. entirely, different degrees of hepatic lesion can be caused,
The Early manifestation of these hepatic lesions is often the rising of ALT (transaminase) or bilirubin, does not dispel the cause of disease, and the infringement of liver can enter
One step is aggravated.At present China for these reasons every year occur hepatic injury number it is numerous, situation allows of no optimist.It is badly in need of research and development
The preventing and treating hepar damnification medicine of high-efficiency low-toxicity.
Existing medicine has that toxicity is big, security is low at present for the treatment of hepar damnification, is sought from natural products
Look for 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 the anti-hepar damnification activity of said composition is evaluated, it has anti-hepar damnification 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.
Pharmacodynamic experiment shows that composition of the invention has preferably anti-hepar damnification effect.It is of the invention pharmaceutically
Acceptable salt has same drug effect.
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 the Psiguadial A of embodiment 2
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- (benzimidazolyl) ethyl derivative (III) of the Psiguadial A of embodiment 3
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 benzimidazole (4720mg, 40mmol), mixture is heated to reflux 3h.Reaction
Reaction solution is poured into 20mL frozen water after end, is extracted 3 times with equivalent dichloromethane, merge organic phase.Water and saturation are used successively
Brine It merge after organic phase, then with anhydrous sodium sulfate drying, removal solvent concentrated under reduced pressure obtains product crude product.Produce
(mobile phase is the purifying of thing crude product silica gel column chromatography：Petroleum ether/acetone=100:0.5, v/v), collect yellow and concentrate elution band
And fling to the yellow powder (289.6mg, 76%) that solvent obtains compound III.
1H NMR (500MHz, DMSO-d6) δ 10.45 (s, 2H), 8.21 (s, 2H), 7.62 (d, J=25.0Hz, 4H),
7.23(s,4H),7.22–7.14(m,5H),4.66(s,4H),4.45(s,4H),3.88(s,1H),2.11(s,1H),1.93
(s, 1H), 1.89 (s, 1H), 1.82 (s, 1H), 1.71 (d, J=4.2Hz, 1H), 1.62 (d, J=26.0Hz, 1H), 1.54 (s,
1H),1.47(s,2H),1.18(s,1H),0.96(s,3H),0.95–0.71(m,9H),0.50(s,1H),0.25(s,1H).
13C NMR(125MHz,Common NMR Solvents)δ188.43(s),170.27(s),165.08(s),
163.05(s),147.11(s),146.19(s),142.40(s),132.81(s),129.35(s),127.61(s),126.74
(s),123.84(s),123.27(s),120.67(s),117.67(s),116.50(s),114.46(s),112.79(s),
68.49(s),44.65(s),39.85(s),34.42(s),34.00(s),30.58(s),27.75(s),26.10(s),24.16
(s),23.38(s),20.83(s),20.43(s),19.67(s),14.02(s).
HRMS(ESI):m/z[M+H]+calcd for C48H51N4O5:763.3859；found:763.3857.
The synthesis of the O- (bischloroethylamines base) ethyl derivative (IV) of the Psiguadial A of embodiment 4
1st, the synthesis of O- (two oxyethylamines) ethyl derivative of Psiguadial 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), obtain
The Light brown solid (0.254g, 69%) of O- (two oxyethylamines) ethyl derivative of Psiguadial A.
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.
O- (two oxyethylamines) ethyl derivative of Psiguadial A
2nd, the synthesis of the O- (bischloroethylamines base) ethyl derivative (IV) of Psiguadial A
O- (two hydroxyethylamines) ethyl derivative of the enough Psiguadial A of synthesis, by the O- of Psiguadial A
(two hydroxyethylamines) ethyl derivative (0.368g, 0.5mmol) is dissolved in 4mL chloroforms, be added dropwise over thionyl chloride (2.38g,
20mmol), reactant is heated to reflux 2h.Reactant is cooled to room temperature, the excessive thionyl chloride of Methanol Decomposition is added dropwise, depressurized dense
Contracting removes solvent.Product purifies (petroleum ether/acetone 100 through silica gel column chromatography:0.5, v/v) the faint yellow of compound IV, is obtained
Solid (271.4mg, 67%).
1H NMR (500MHz, DMSO-d6) δ 10.33 (s, 2H), 7.09 (t, J=15.0Hz, 5H), 3.97 (s, 1H),
3.92 (s, 4H), 3.60 (s, 8H), 2.74 (s, 2H), 2.68 (s, 2H), 2.61 (d, J=17.2Hz, 4H), 2.51 (s, 4H),
2.08 (s, 1H), 1.77 (dd, J=13.8,8.4Hz, 4H), 1.54 (s, 1H), 1.30 (d, J=12.7Hz, 3H), 1.13 (s,
1H),0.86(s,3H),0.81(s,6H),0.75(s,3H),0.39(s,1H),0.11(s,1H).
13C NMR(125MHz,DMSO-d6)δ205.87(s),197.63(s),194.85(s),189.66(s),134.68
(s),119.48(s),114.43(s),83.84(s),75.99(s),66.29(s),62.15(s),59.77(s),59.54
(s), 55.66 (s), 53.29 (s), 52.49 (s), 50.35 (s), 44.63 (s), 39.08 (d, J=0.9Hz), 36.02 (s),
30.20 (d, J=8.9Hz), 28.18 (s), 24.69 (s), 23.50 (d, J=19.2Hz), 22.16 (s), 17.61 (s)
HRMS(ESI):m/z[M+H]+calcd for C42H57Cl4N2O5:811.2992；found:811.2988.
The effect of the composition for preventing and controlling hepatic injury of embodiment 5
(1) the chmice acute liver that composition is induced D-Gal amine (D-galactosamine, D-GalN) damages
The protective action of wound
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.
5 groups of mouse point.Control group is with physiological saline gavage (0.3mLd-1), continuous 7d；And also want intraperitoneal injection in 7d
Physiological saline (0.15mL10g-1), blood is taken after intraperitoneal injection 16h, survey AST and ALT vigor.D-GalN groups, composition
3.0mg·kg-1Group, compound III groups and compound IV groups are respectively with physiological saline, composition, compound III and compound IV
Gavage (0.3mLd-1), continuous 7d；And also want intraperitoneal injection D-GalN (800mgkg in 7d-1, 0.15mL10g-1),
Blood is taken after intraperitoneal injection 16h, AST and ALT vigor is surveyed.
The protective action of the acute liver damage that the composition of table 1 is induced D-GalN
Note：1)p<0.01vs control groups,2)p<0.01vs D-GalN groups
As shown in Table 1, composition can effectively suppress the notable rising of mouse AST and the ALT activity that D-GalN causes.Chemical combination
Thing III and compound IV is acted on without this.
(2) composition is to CCl4The protective action of the acute liver of induction
5 groups of mouse point, control group is with physiological saline gavage (0.3mLd-1), continuous 5d, 6d intraperitoneal injection vegetable oil is every
0.1mL10g-1；CCl4Group and composition, compound III and compound IV administration groups (3.0mgkg-1) respectively with physiology
Salt solution and composition, compound III and compound IV gavages (0.3mLd-1), continuous 5d, in 6d intraperitoneal injections 0.1%
CCl4 0.1mL·10g-1.Animal is put to death after 24h, serum is taken and is surveyed AST and ALT vigor.
The composition of table 2 is to CCl4The protective action of the acute liver damage of induction
Note：1)p<0.01vs control groups,2)p<0.01vs CCl4Group
As shown in Table 2, composition can suppress CCl4The notable rising of mouse AST and the ALT activity for causing.Compound III
Acted on without this with compound IV.
Conclusion：Composition can effectively protect the mouse liver injury that D-GalN causes, composition effectively to protect CCl4Cause
Mouse liver injury, can be used to prepare anti-liver injury medicament.Compound III and compound IV can not effectively protect D-GalN to draw
The mouse liver injury for rising, it is impossible to effectively protect CCl4The mouse liver injury for causing, it is not possible to for preparing anti-liver injury medicament.
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 (6)
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 hepar damnification medicine is prevented and treated.
4. application of the composition as claimed in claim 3 in hepar damnification medicine is prevented and treated, it is characterized by：The hepar damnification
It is the hepar damnification caused by chemical substance induction.
5. application of the composition as claimed in claim 4 in hepar damnification medicine is prevented and treated, it is characterized by：The chemical substance
It is D-Gal amine.
6. application of the composition as claimed in claim 4 in hepar damnification medicine is prevented and treated, it is characterized by：The chemical substance
It is carbon tetrachloride.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112300110A (en) * | 2020-10-30 | 2021-02-02 | 李艳 | Preparation method and application of gallinaceous tea sesquiterpene dialdehyde |
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2016
- 2016-12-22 CN CN201611196517.8A patent/CN106822109A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112300110A (en) * | 2020-10-30 | 2021-02-02 | 李艳 | Preparation method and application of gallinaceous tea sesquiterpene dialdehyde |
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