CN106074529A - The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing preventing and treating pancreatic fibrosis medicine - Google Patents
The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing preventing and treating pancreatic fibrosis medicine Download PDFInfo
- Publication number
- CN106074529A CN106074529A CN201610347322.2A CN201610347322A CN106074529A CN 106074529 A CN106074529 A CN 106074529A CN 201610347322 A CN201610347322 A CN 201610347322A CN 106074529 A CN106074529 A CN 106074529A
- Authority
- CN
- China
- Prior art keywords
- composition
- pancreatic fibrosis
- acid
- compound
- triazolyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- A61K31/4192—1,2,3-Triazoles
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses O (triazolyl) ethyl of a kind of Ah draw'sing Bick acid i.e. Artalbic acid with the composition of O (1H tetrazole base) ethyl derivative in prevention or the application treating in pancreatic fibrosis medicine, 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 the purposes in preparation prevention or treatment pancreatic fibrosis medicine thereof.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, O (triazolyl) ethyl of Ah draw'sing Bick acid i.e. Artalbic acid of the present invention has prevention or the effect for the treatment of pancreatic fibrosis with the composition of O (1H tetrazole base) ethyl derivative, has exploitation prevention or the value for the treatment of pancreatic fibrosis 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
Pancreatic fibrosis is the common trait of chronic pancreatitis caused by a variety of causes, is also that the tissue adjoint with it is sick simultaneously
Feature of science, shows as a large amount of fibroblast proliferation and rich in the extracellular matrix connecting tissue.It is that many reasons causes pancreas
The result of gland injury repair, discovery pancreatic stellate cells and cytokine profiles are relevant with pancreatic fibrosis in the recent period, pancreas fiber
Change the current incidence of disease more and more high, be badly in need of the anti-pancreatic fibrosis medicine of research and development high-efficiency low-toxicity.
There is the problem that toxicity is big, security is low, from natural products in the current existing medicine for the treatment of of pancreatic fibrosis
Find compound or lead compound and carry out structural modification and obtain its derivative, thus obtaining the potential drug of high-efficiency low-toxicity
There is important value.
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,
We have carried out structural modification to compound I, it is thus achieved that two new derivative i.e. compound III and compound IV, and with change
Compound III and compound IV is prepared for composition and is evaluated said composition anti-pancreatic fibrosis activity, and it has anti-
Pancreatic fibrosis 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 80% and 20%.
Composition disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, the composition of the present invention has preferable anti-pancreatic fibrosis effect.The pharmacy of the present invention
Upper 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 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-pancreatic fibrosis activity
1 material
1.1 animal Wistar rats, male, body weight 180-200g.
1.2 composition dosage: 0.9mg/kg.
The preparation of composition: the powder of the 80mg compound III that will cross 200 mesh nets after grinding crosses 200 after grinding
The powder of the 20mg 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.
2 experimental techniques
2.1 modeling methods: Wistar rat, with lumbar injection dl-ethionine 250mg/ days, continuous 2 months, may occur in which
Pancreas gland cell reduces, the adipocellular hyperplasia of interstitial.
2.2 packets and medication
Rat model is randomly divided into model group, composition 0.9mg/kg group, compound III 0.9mg/kg group and compound
IV 0.9mg/kg group, separately sets blank group.Administration group is administered after modeling starts, oral continuous 30 days；Dissect dynamic when 60 days
Thing.
2.3 Testing index
2.3.1 take pancreas at the end of testing to weigh.
2.3.2 pancreas hydroxyproline content measures and takes 100mg sample and be homogenized in water, and in 110 DEG C of 10N HCl, hydrolysis 20 is little
When.HCl nitrogen volatilizees, and hydrolysate filters after distilled water dissolving.Take 0.5ml liquid and 3ml citric acid phosphate buffer
(0.15M citric acid adds 0.6M disodium hydrogen phosphate) and 0.5ml are dissolved in the 1M periodic acid mixing of 9M phosphoric acid.Add 1.75ml and extract buffering
Liquid (5 parts of toluene: 5 parts of 2-methyl isophthalic acid-propyl alcohol: 2 parts of 1-propyl alcohol), shakes 30min, centrifugal.Tissue phase (0.6ml) and Ehrlich,
15min is placed in the mixing of s reagent.Measure trap at 565nm, make calibration curve with 4-hydroxyl-1-proline and calculate concentration, content
Represent with ug/g tissue.
2.3.3 histological examination pancreatic tissues is fixed by 10% formalin, FFPE, microscopy after dyeing.To fiber
Change situation marks (0-3 divides).
3 results
The impact on rat pancreas organ coefficient for 3.1 compositions
At the end of experiment, rat is put to death, dissects, weigh in and weigh and calculate the ratio (pancreas of itself and body weight with pancreas
Organ coefficient), the results are shown in Table 1.The impact on pancreas organ coefficient for the composition, comparing with model group has significant difference.Chemical combination
Thing III and the impact on pancreas organ coefficient for the compound IV, compare with model group that there was no significant difference.
Table 1
* represent p < 0.05, compare with model group
3.2 pancreas hydroxyproline contents measure
At the end of experiment, lung's hydroxyproline content mensuration is carried out to each group of rat, result such as table 2.Composition is to hydroxyl dried meat
The impact of histidine content, comparing with model group has significant difference.Compound III and the shadow to hydroxyproline content for the compound IV
Ring, compare with model group that there was no significant difference.
Table 2
* represent p < 0.05, compare with model group
3.3 histological examination
At the end of experiment, rat is put to death, dissects；The conventional embedding of sample, fixing, HE dyeing, microscopy.
Result: model group visible pancreas surrounding catheter extensive inflammation reaction in the 60th day；Addicted to middle granulocyte karyolymph cellular infiltration,
Interstitial edema, bleeding and accidental pancreas cystencyte are downright bad；Between pancreas cystencyte disappearance position and pancreas bubble, fibrillatable occurs.
Composition can reduce inflammatory reaction and fibrillatable.Appraisal result is shown in Table 3.The impact on scoring for the composition, with model
Group compares significant difference.
Table 3
* represent p < 0.05, compare with model group；The inflammatory cell infiltration of blank group and Fibrosis score are all 0.
Conclusion: the present invention is affected it was confirmed composition has anti-pancreas fibre on pancreas in rat is Fibrotic by composition
The effect of dimensionization.Therefore, composition can be as active component for preparing the medicine of anti-pancreatic fibrosis.And compound III and
Compound IV is without this activity, it is impossible to for preparing the medicine of anti-pancreatic fibrosis.
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 (6)
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 80% and 20%,
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 80% and 20% according to mass percent and be sufficiently mixed.
3. a composition as claimed in claim 1 application in treatment pancreatic fibrosis medicine.
4. application in treatment pancreatic fibrosis medicine for the composition as claimed in claim 3, is characterized by: described composition
Reverse the pancreas organ coefficient caused by pancreatic fibrosis to decline.
5. application in treatment pancreatic fibrosis medicine for the composition as claimed in claim 3, is characterized by: described composition
Reverse the hydroxyproline content caused by pancreatic fibrosis to raise.
6. application in treatment pancreatic fibrosis medicine for the composition as claimed in claim 3, is characterized by: described composition
Reverse the inflammatory cell infiltration caused by pancreatic fibrosis to raise.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610347322.2A CN106074529A (en) | 2016-05-24 | 2016-05-24 | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing preventing and treating pancreatic fibrosis medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610347322.2A CN106074529A (en) | 2016-05-24 | 2016-05-24 | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing preventing and treating pancreatic fibrosis medicine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106074529A true CN106074529A (en) | 2016-11-09 |
Family
ID=57229305
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610347322.2A Pending CN106074529A (en) | 2016-05-24 | 2016-05-24 | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing preventing and treating pancreatic fibrosis medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106074529A (en) |
-
2016
- 2016-05-24 CN CN201610347322.2A patent/CN106074529A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| 《BRITISH JOURNAL OF PHARMACOLOGY》 * |
| 《TETRAHEDRON LETTERS》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104147019B (en) | The application in preparation prevention or treatment pancreatic gland fibrosis medicine of O-(nafoxidine base) ethyl derivative of Cleistanone | |
| CN106928274A (en) | A kind of dihydroartemisinine dliploid derivative, its pharmaceutical composition and application | |
| CN104825466A (en) | Applications of cleistanone O-(benzimidazolyl) ethyl derivative in preparation of drugs for preventing or treating pancreatic fibrosis | |
| CN106074529A (en) | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing preventing and treating pancreatic fibrosis medicine | |
| CN105232508A (en) | Composition and application thereof to drugs for preventing or treating pancreas fibrosis | |
| CN106038553A (en) | Application of composition of Schiglautone A derivatives in preparation of pancreatic fibrosis control drugs | |
| CN105193791A (en) | Composition and application thereof in medicine for preventing or treating pancreatic fibrosis | |
| CN106074516A (en) | The compositions of Ah draw'sing Bick acid benzimidazolyl and two hydroxyethylamine derivants prevents and treats pancreatic gland fibrosis medicine for preparation | |
| CN106619620A (en) | Application of benzimidazolyl derivative and morpholino derivative composition of Atropurpuran in prevention and treatment of pancreatic fibrosis | |
| CN105853427A (en) | Application of composition of piperazine and imidazole based derivatives of Virosaine A in preparation of drugs for preventing or treating pancreatic fibrosis | |
| CN105998003A (en) | Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in drugs for preventing or treating pancreas fibrosis | |
| CN104739846A (en) | Application of O-(1H-tetrazole) ethyl derivative of cleistanone to preparing drug for preventing or treating pancreatic fibrosis | |
| CN105878252A (en) | Application of pyrrolidyl and morpholino derivative composition of virosaine A in drugs for preventing or treating pancreatic fibrosis | |
| CN106420719A (en) | Applications of composition of Atropurpuran derivatives in preparing medicines for preventing or treating pancreatic fibrosis | |
| CN106420750A (en) | Application of composition of O-(diethylamino)ethyl derivative and O-(piperazinyl)ethyl derivative of Harrisotone A in pancreatic fibrosis preventing or treating drugs | |
| CN106176733A (en) | The application in prevention or treatment pancreatic gland fibrosis medicine of the derivative composition of Schiglautone A | |
| CN106074480A (en) | The compositions of the derivant of Artalbic acid prevents and treats pancreatic gland fibrosis medicine for preparation | |
| CN106727522A (en) | The imidazole radicals and bischloroethylamines radical derivative composition of Atropurpuran are used to prevent and treat pancreatic fibrosis | |
| CN106822111A (en) | Harrisotone A imidazole radicals and benzimidazolyl derivatives composition are used to prevent and treat pancreatic fibrosis | |
| CN106727465A (en) | The derivative composition of Atropurpuran is used to prevent and treat pancreatic fibrosis | |
| CN105343089A (en) | Composition and application thereof in drugs for preventing or treating pancreatic fibrosis | |
| CN106727509A (en) | Application of the composition of Harrisotone A derivatives in preventing or treating pancreatic fibrosis medicine | |
| CN106822132A (en) | The piperazinyl of Atropurpuran and two hydroxyethylamine derivative compositions are used to prevent and treat pancreatic fibrosis | |
| CN105343081A (en) | Composition and application of composition in medicines for preventing or treating pancreas fibrosis | |
| CN105267190A (en) | Composition and application thereof to drugs for preventing or treating pancreatic fibrosis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20161109 |