CN106074508A - The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-inflammatory drug - Google Patents
The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-inflammatory drug Download PDFInfo
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- CN106074508A CN106074508A CN201610347675.2A CN201610347675A CN106074508A CN 106074508 A CN106074508 A CN 106074508A CN 201610347675 A CN201610347675 A CN 201610347675A CN 106074508 A CN106074508 A CN 106074508A
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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-inflammatory drug 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, preparation method and in the purposes preparing on anti-inflammatory drug.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 the effect of anti-inflammatory with the composition of O (1H tetrazole base) ethyl derivative, has the value of exploitation anti-inflammatory drug.
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
Inflammation occurs, in local, also to affect whole body simultaneously.Local clinical feature is red, hot, swollen, pain and dysfunction.
Red, hot is owing to inflammation local vessel expansion, blood flow are accelerated.Swollen is owing to local inflammation is congested, flow components oozes out
Cause.Research and development have the medicine of antiinflammatory action for alleviate checking, palliate the agonizing sufferings significant.
There is the problem that toxicity is big, security is low, searchingization from natural products in the current existing medicine for the treatment of of inflammation
Compound or lead compound simultaneously carry out structural modification and obtain its derivative, thus the potential drug obtaining high-efficiency low-toxicity has important valency
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, 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-inflammatory activity, and it has anti-inflammatory 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 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 application in preparing anti-inflammatory drug for the composition.Described inflammation is that aseptic is scorching
Disease.
What the present composition was applied in preparing anti-inflammatory drug has the beneficial effect that:
First demonstrate the present composition and there is effective antiinflammatory effect.Have employed classics dimethylbenzene caused by mouse ear
Swelling model and rat agar foot swelling model, observe the present composition anti-inflammatory to animal used as test within a certain period of time
Effect.Research shows:
1st, the mice ear caused by present composition paraxylene has obvious inhibiting effect.
2nd, the present composition has obvious inhibiting effect to rat agar foot swelling.
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-inflammatory pharmacodynamic study
Test material
1. Kunming (KM) plants mouse: male, 6 weeks, and 18.5-22.5g is provided by Jiangsu Province's Experimental Animal Center.
2. rat (Wistar): male, weight 140～160g, provided by Jiangsu Province's Experimental Animal Center.
3. the preparation of composition: will grind after cross 200 mesh nets 70mg compound III powder and grinding after mistake
The powder of the 30mg compound IV of 200 mesh nets loads in tubule with cover and i.e. obtains 100mg combination with the mixing of turbine stirring instrument
Thing, dissolves, with water, the solution that the composition of this 100mg obtains composition during use.
Test method
1. the effect to mouse ear inflammation for the gavage composition: take weight 18.5～22.5g healthy male mice 50,
It is randomly divided into 5 groups, often organize 10.It is grouped into: composition 2.5mg kg-1, compound III 2.5mg kg-1, compound IV
2.5mg·kg-1, aspirin group (200mg kg-1), blank group (physiological saline).Each group gastric infusion respectively, continuously
7d, 1h after the 7th day gavage, 3 groups of mouse all uniformly apply dimethylbenzene 0.02mL in the forward and backward face of mouse right ear, prepare auricle inflammation mould
Type.Mouse is put to death in collare dislocation after 1h, cuts two ears along auricle baseline, with diameter 8mm card punch respectively in the same portion of two ears
Round auricle is laid in position, weighs and is accurate to 0.0001g.Claim quality immediately respectively with electronic balance, using left and right two ear of poor quality as
Swelling, and calculate its swelling.
Swelling=auris dextra tablet weight left auricle weight
2. the effect to rat agar foot swelling for the gavage composition: take the healthy male Wistar of weight 140～160g
Rat 40, is randomly divided into 5 groups.Composition 2.5mg kg-1, compound III 2.5mg kg-1, compound IV 2.5mg
kg-1, aspirin group (200mg kg-1), blank group (physiological saline).Gastric infusion respectively, continuous 7d, within the 7th day, fill
1h after stomach, the right metapedes of rat is wasted time the swollen acute inflammation model of hypodermic injection 10g/L agar 0.1mL preparation foot, with rat foot capacity
Its right metapedes normal volume surveyed by measuring instrument.After causing inflammation, the 1st, the 5th, 8h measures each mouse right metapedes volume respectively, and calculates swelling.
Swelling=left back sufficient volume of right metapedes volume
Result of the test
1st, the impact on mouse ear inflammation for the composition
After causing inflammation, each group mouse right ear occurs highly red and swollen phenomenon at once.Aspirin group and composition group paraxylene
Caused mice ear all significantly inhibits effect, the mouse ear caused by compound III and compound IV then paraxylene
Swelling does not significantly inhibit effect, the results are shown in Table 1.
The impact of table 1 composition paraxylene induced mice auricle edema
Compare * P < 0.01 with model group
2nd, the impact on rat agar foot swelling for the composition
After injection agar, each group rat foot claw all has a certain degree of swelling phenomenon.Under visually observing, model group swelling
Rubescent the most obvious, the slightly swelling of aspirin group is without obvious redness phenomenon, and composition group has swelling without obvious redness phenomenon.Combination
Thing significantly inhibits effect to rat foot is swollen, and compound III and compound IV is then swollen without significantly inhibiting effect to rat foot,
It is shown in Table 2.
The impact on rat agar toes swelling for table 2 composition
Compare * P < 0.05 with model group
Conclusion: the mice ear caused by composition paraxylene has obvious inhibiting effect；Composition is to rat agar
Foot swelling has obvious inhibiting effect.Mice ear caused by compound III and compound IV then paraxylene is without substantially pressing down
Make and use；Compound III and compound IV then to rat agar foot swelling without obvious inhibiting effect.Composition may be used for system
Standby anti-inflammatory drug, compound III and compound IV cannot be used for preparing anti-inflammatory drug.
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 (7)
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 70% and 30%,
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 70% and 30% according to mass percent and be sufficiently mixed.
3. application in anti-inflammatory medicaments for the composition as claimed in claim 1.
4. application in anti-inflammatory medicaments for the composition as claimed in claim 3, is characterized by: described inflammation is that aseptic is scorching
Disease.
5. application in anti-inflammatory medicaments for the composition as claimed in claim 4, is characterized by: described aseptic inflammation is for changing
Product stimulation causes.
6. application in anti-inflammatory medicaments for the composition as claimed in claim 5, is characterized by: described chemicals is diformazan
Benzene.
7. application in anti-inflammatory medicaments for the composition as claimed in claim 5, is characterized by: described chemicals is agar.
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| CN201610347675.2A CN106074508A (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-inflammatory drug |
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| CN201610347675.2A CN106074508A (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-inflammatory drug |
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| CN201610347675.2A Pending CN106074508A (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-inflammatory drug |
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2016
- 2016-05-24 CN CN201610347675.2A patent/CN106074508A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| ANTONELLA MAGGIO: "《Artalbic acid，a sesquiterpene with an unusual skeleton from Artemisia alba (Asteraceae) from Sicily》", 《TETRAHEDRON LETTERS》 * |
| 赵爱华: "《倍半萜类化合物生理活性研究进展》", 《天然产物研究与开发》 * |
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Application publication date: 20161109 |