CN106074512A - The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-rhinitis medicament thing - Google Patents
The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-rhinitis medicament thing Download PDFInfo
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- CN106074512A CN106074512A CN201610349743.9A CN201610349743A CN106074512A CN 106074512 A CN106074512 A CN 106074512A CN 201610349743 A CN201610349743 A CN 201610349743A CN 106074512 A CN106074512 A CN 106074512A
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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
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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
- A61K31/4192—1,2,3-Triazoles
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- 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
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- 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
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Abstract
The invention discloses the application in anti-rhinitis medicament thing of the composition of O (triazolyl) ethyl of a kind of Ah draw'sing Bick acid i.e. Artalbic acid and O (1H tetrazole base) ethyl derivative, 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 and in the purposes prepared on anti-rhinitis medicament thing.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 anti-rhinitis effect with the composition of O (1H tetrazole base) ethyl derivative, has the value of exploitation anti-rhinitis medicament thing.
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
Rhinitis is common clinical and frequently-occurring disease, and the generation of rhinitis is mainly relevant with allergic reaction, belongs to immune inflammation
Category.At present, treat rhinitis and mainly use the antihistamine drug such as teldane or the antiallergic such as tranilast, Ketotifen
Thing, these medicines are poor or invalid to chronicity and the recurrent exerbation curative effect of rhinitis.Therefore, definite ingredients, quality controllable and peace
Complete efficient micromolecular compound, in terms of developing treatment of rhinitis medicine, has potential value.
Find compound or lead compound and carry out structural modification and obtain its derivative from natural products, thus obtaining
The potential drug of high-efficiency low-toxicity has important value most.
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, I
Structural modification has been carried out to compound I, it is thus achieved that two new derivative i.e. compound III and compound IV, and use chemical combination
Thing III and compound IV is prepared for composition, and is evaluated said composition anti-rhinitis activity, and it has anti-rhinitis and lives
Property.
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 10% and 90%.
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-rhinitis effect.The present invention pharmaceutically can connect
The salt being subject to has same drug effect.
Composition 10mg/kg oral administration, nose that rat caused by antigen (ovalbumin) and histamine is scratched, sneeze anti-
Answer and nasal cavity vasopermeability raises inhibited, therefore, can be used for the medicine of preparation treatment rhinitis.
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 2Artalbic 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 3Artalbic 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 4Artalbic 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 present composition causes the impact of rat allergic rhinitis to ovalbumin
Male SD rat, body weight 180～220g, lumbar injection ovalbumin 1mg and gel aluminum hydroxide 10mg, thereafter every
Day injection 1 time, totally 7 times.Began from the 14th day, in the nasal cavity of rat both sides, instill 1mg/ml ovalbumin normal saline solution every day
10ul, totally 7 times.In last is observed 30 minutes after instiling at once, rat is sneezed and wipes the number of times of nose, and trial drug is in white of an egg egg
White last instils and is orally administered to for first 1 hour.
The preparation of composition: the powder of the 10mg compound III that will cross 200 mesh nets after grinding crosses 200 after grinding
The powder of the 90mg 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.
From table 1, the sneeze of allergic rhinitis rat and scratching caused by composition (10mg/kg) substantially suppression ovalbumin
Grab nose reaction.Compound III and compound IV acts on without this.
Table 1 present composition causes the impact of rat allergic rhinitis to ovalbumin
* p < 0.05, compares with control group
The impact of the rat rhinitis that histamine is caused by embodiment 6 present composition
Male SD rat, body weight 180～220g, it is orally administered to after trial drug 1 hour, in the nasal cavity of both sides, instill 1M histamine
Normal saline solution 10ul, in observing 30 minutes, rat is sneezed and wipes the number of times of nose.
From table 2, the present composition (10mg/kg) significantly reduces the sneeze number of times of rhinitis rat caused by histamine, right
Nose of scratching reacts in suppression trend.Compound III and compound IV acts on without this.
Table 2 present composition causes the impact of rat rhinitis to histamine
* p < 0.05, compares with control group
Embodiment 7 present composition causes the impact that rat nasal cavity vasopermeability raises to ovalbumin, histamine
Male SD rat, body weight 180～220g, observes ovalbumin and group with active sensitization rat and normal rat respectively
Nasal cavity vasopermeability that amine causes raises, and the method for sensitization of rat is tested with allergic rhinitis, after initial immunity the 14th day,
This, from tracheae to nasal intubation after anesthesia, is intubated and constant flow pump phase after fixing by rats by intraperitoneal injection yellow Jackets 40mg/kg
Even (0.25ml/min0, with 37 DEG C of normal saline flushing nasal cavities 10 minutes, the blue physiology of the 1%Evans of rat tail vein injection thereafter
Saline solution 5ml/kg, collected perfusate 10 minutes after 3 minutes.At sensitized rats and normal rat, perfusate contains ovum respectively
Albumin 1mg/ml and histamine 40ug/ml, the perfusate collected from nasal cavity centrifuges 10 minutes through 1200 × g, and at 620nm, colorimetric is surveyed
Determine the blue concentration of the Evans in supernatant, test medicine and antigen or first 1 hour oral administration of histamine perfusion.
From table 3, the nose of allergic rhinitis rat caused by the present composition (10mg/kg) substantially suppression ovalbumin
Chamber vasopermeability.Compound III and compound IV acts on without this.
Table 3 present composition causes the impact that rat nasal cavity vasopermeability raises to ovalbumin
* p < 0.01, compares with control group
From table 4, present composition 10mg/kg substantially reduces the nasal cavity vasopermeability of rat caused by histamine.Change
Compound III and compound IV acts on without this.
Table 4 present composition causes the impact that rat nasal cavity blood flow permeability raises to histamine
* p < 0.01, compares with control group
Conclusion: composition oral is administered, scratch rat caused by antigen (ovalbumin) and histamine nose, reaction of sneezing
And nasal cavity vasopermeability raises and has the effect of significantly inhibiting, therefore, can be used for the medicine of preparation treatment rhinitis.Compound III
Rat caused by antigen (ovalbumin) and histamine scratched nose, sneeze reaction and nasal cavity vasopermeability liter with compound IV
Height does not significantly inhibit effect, therefore, is not useable for the medicine of preparation treatment rhinitis.
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 (10)
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 10% and 90%,
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 10% and 90% according to mass percent and be sufficiently mixed.
3. a composition as claimed in claim 1 application in anti-rhinitis medicament thing.
4. application in anti-rhinitis medicament thing for the composition according to claim 3, is characterized by: described rhinitis is antigen institute
The rhinitis causing.
5. application in anti-rhinitis medicament thing for the composition according to claim 4, is characterized by: described antigen is white of an egg egg
In vain.
6. application in anti-rhinitis medicament thing for the composition according to claim 5, is characterized by: described composition can press down
Scratch caused by ovalbumin processed nose number of times and reaction of sneezing.
7. application in anti-rhinitis medicament thing for the composition according to claim 5, is characterized by: described composition can press down
The rising of nasal cavity vasopermeability caused by ovalbumin processed.
8. application in anti-rhinitis medicament thing for the composition according to claim 3, is characterized by: described rhinitis is histamine institute
The rhinitis causing.
9. application in anti-rhinitis medicament thing for the composition according to claim 8, is characterized by: described composition can press down
Scratch caused by histamine processed nose number of times and reaction of sneezing.
10. application in anti-rhinitis medicament thing for the composition according to claim 8, is characterized by: described composition is permissible
The rising of nasal cavity vasopermeability caused by suppression histamine.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610349743.9A CN106074512A (en) | 2016-05-24 | 2016-05-24 | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-rhinitis medicament thing |
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|---|---|---|---|
| CN201610349743.9A CN106074512A (en) | 2016-05-24 | 2016-05-24 | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-rhinitis medicament thing |
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| CN106074512A true CN106074512A (en) | 2016-11-09 |
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| CN201610349743.9A Pending CN106074512A (en) | 2016-05-24 | 2016-05-24 | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-rhinitis medicament thing |
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2016
- 2016-05-24 CN CN201610349743.9A patent/CN106074512A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| ANTONELLA MAGGIO等: "Artalbic acid，a sesquiterpene with an unusual skeleton from Artemisia alba (Asteraceae) from Sicily", 《TETRAHEDRON LETTERS》 * |
| JIN-BIN WU等: "Biologically Active Constituents of Centipeda minima: Sesquiterpenes of Potential Anti-allergy Activity", 《CHEM. PHARM. BULL.》 * |
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Application publication date: 20161109 |