CN105213377A - Compositions and the application in anti-anoxic medicine thereof - Google Patents
Compositions and the application in anti-anoxic medicine thereof Download PDFInfo
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- CN105213377A CN105213377A CN201510421026.8A CN201510421026A CN105213377A CN 105213377 A CN105213377 A CN 105213377A CN 201510421026 A CN201510421026 A CN 201510421026A CN 105213377 A CN105213377 A CN 105213377A
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Abstract
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions and the purposes on anti-anoxic medicine thereof.The invention discloses a kind of composition and method of making the same.Pharmacological experiment shows, compositions of the present invention has oxygen lack resistant function, has the value of exploitation anti-anoxic medicine.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions, preparation method and its usage.
Background technology
Oxygen is the essential condition that the mankind and many biologies are depended on for existence.Hypoxia (Hypoxia) refers to that the oxygen needed for body vital movement can not obtain sufficient supply.Oxygen and hypoxia are the most important key factors of vital movement, are the important topics of life sciences basic theories.The formation of hypoxia can be divided three classes: the first kind is that external environment oxygen content reduces, and makes normal physiological activity process can not absorb enough oxygen, as plateau and aviation anoxia; Equations of The Second Kind refers to because disease etc. causes extraneous normal oxygen amount fully not arrive in body, causes the anoxia of the heart, brain and respiratory system etc.; 3rd class is body activities requisite oxygen consumption, has exceeded the physiology ability of mobilization, causes relative oxygen supply not enough, is common in strenuous exercise and the amount of transfiniting work.Long-term hypoxia is the important hidden danger be detrimental to health, and severe patient can threat to life.Therefore, hypoxia causes the heart, brain and respiratory system equivalent damage to become one of 21 century medical circle subject matter anxious to be resolved.
From natural product, find compound or lead compound and carry out structural modification and obtain its derivant, thus the potential drug obtaining high-efficiency low-toxicity there is important value most.
The Compound I that the present invention relates to is one and delivers (AntonellaMaggioetal. in 2011, 2011.Artalbicacid, asesquiterpenewithanunusualskeletonfromArtemisiaalba (Asteraceae) fromSicily.TetrahedronLetters, 52 (2011) 4543 – 4545) compound, we have carried out structural modification to Compound I, obtain two new derivants and compound III and compound IV, and prepared compositions by compound III and compound IV and the Substituted phenyl-lactic acid of said composition is evaluated, it has Substituted phenyl-lactic acid.
Summary of the invention
The invention discloses a new compositions, said composition is made up of compound III and compound IV, and in said composition, the mass percent of compound III and compound IV is respectively 45% and 55%.
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, compositions of the present invention has good oxygen lack resistant function.Pharmaceutically acceptable salt of the present invention 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 any restriction of specific embodiment, but be limited by claim.
Detailed description of the invention
The preparation of embodiment 1 compd A rtalbicacid
Document (the AntonellaMaggioetal. that the people such as the preparation method reference AntonellaMaggio of compd A rtalbicacid (I) deliver, 2011.Artalbicacid, asesquiterpenewithanunusualskeletonfromArtemisiaalba (Asteraceae) fromSicily.TetrahedronLetters, 52 (2011) 4543 – 4545) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2Artalbicacid
By Compound I (266mg, 1.00mmol) be dissolved in 10mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.08g), 1,50% sodium hydroxide solution of 2-Bromofume (3.760g, 20.00mmol) and 6mL.Mixture stirs 16h at 40 degrees Celsius.After 16h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution.Then use water and saturated common salt water washing 5 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1.0, v/v), collects brown concentrated elution band and flings to the brown ceramic powder (272mg, 73%) that namely solvent obtains Compound II per.
1HNMR(500MHz,DMSO-d
6)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).
13CNMR(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]
+calcdforC
17H
26BrO
4:373.1014；found373.1017.
The synthesis of O-(diethylin) ethyl derivative (III) of embodiment 3Artalbicacid
Compound II per (187mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and diethylamine (1460mg, 20mmol), mixture reflux 12h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction 4 times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:0.5, v/v), collects brown concentrated elution band and flings to the brown ceramic powder (111.3mg, 61%) that namely solvent obtains compound III.
1HNMR(500MHz,DMSO-d6)δ11.52(s,1H),δ6.13(s,1H),5.81(s,1H),4.73(s,1H),4.62(d,J＝10.9Hz,2H),3.59(s,2H),2.92(s,4H),2.68(d,J＝10.5Hz,3H),2.56(s,2H),2.48(s,2H),2.22(s,1H),1.70(s,3H),1.54(d,J＝10.2Hz,3H),1.16(s,6H),1.00(s,3H).
13CNMR(125MHz,DMSO-d6)δ201.95(s),175.93(s),149.13(s),148.15(s),117.05(s),109.43(s),81.86(s),67.06(s),57.68(s),52.53(s),47.72(s),41.30(s),39.06(s),38.85(s),35.68(s),30.72(s),20.44(s),18.42(s),12.35(s).
HRMS(ESI):m/z[M+H]
+calcdforC
21H
36NO
4:366.2644；found:366.2640。
The synthesis of the O-(nafoxidine base) ethyl derivative (IV) of embodiment 4Artalbicacid
Compound II per (187mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and pyrrolidine (1420mg, 20mmol), mixture reflux 8h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction 3 times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1.0, v/v), collects brown concentrated elution band and flings to the brown ceramic powder (107.1mg, 59%) that namely solvent obtains compound IV.
1HNMR(500MHz,DMSO-d6)δ14.01(s,1H),6.15(s,1H),5.83(s,1H),4.75(s,1H),4.63(s,1H),3.96(s,1H),3.58(s,2H),2.70(d,J＝6.1Hz,3H),2.56–2.49(m,8H),2.09(s,1H),1.68(d,J＝10.0Hz,7H),1.58(s,2H),1.44(s,1H),1.02(s,3H).
13CNMR(125MHz,DMSO-d6)δ201.85(s),175.85(s),149.07(s),148.11(s),117.03(s),109.33(s),81.78(s),67.00(s),57.64(s),54.44(d,J＝17.1Hz),41.20(s),38.98(s),38.79(s),35.64(s),30.70(s),25.21(s),20.35(s),18.36(s).
HRMS(ESI):m/z[M+H]
+calcdforC
21H
34NO
4:364.2488；found:364.2491。
Embodiment 5 mice specificity myocardial ischemia is tested
1, method:
The preparation of compositions: the powder of the powder of 45mg compound III and 55mg compound IV is loaded
Mix in tubule with cover and with turbine stirring instrument and namely obtain 100mg compositions.
50 kunming mices, body weight (20 ± 2) g.Be divided into 5 groups at random, gastric infusion.First 2 groups give 0.3% sodium carboxymethyl cellulose (CMC-Na) solution, and rear 3 component shellfishes give compound III, compound IV and compositions, after 50min, except the 1st group, and equal lumbar injection isoproterenol (ISO) 15mgKg
-1, after 15min, mice is put into normobaric hypoxia device, record mouse diing time and oxygen consumption.
Result:
Isoproterenol, by excited heart beta receptor, makes myocardial oxygen consumption increase.This experiment shows, compared with Vehicle controls group, and compositions 0.010gKg
-1significantly can resist myocardial oxygen consumption increase (P<0.01) that isoproterenol (ISO) causes, extend the time-to-live (P<0.01) under anoxia in mice air-tight state simultaneously, the results are shown in Table 1.And compound III and compound IV all do not possess this effect.
Table 1 is waited to try thing causes specificity hypoxia mice impact (x, n=10) on isoproterenol
Note:
1)p<0.01, compares with matched group,
2)p<0.01, compares with isoproterenol group.
Embodiment 6 mice normal pressure asphyxia anoxia is tested
1, method:
40 kunming mices, body weight (20 ± 2) g.Be divided into 4 groups at random, gastric infusion.1st group gives 0.3% sodium carboxymethyl cellulose (CMC-Na) solution, and rear 3 groups of CMC-Na solution given respectively containing compositions, compound III and compound IV, concentration is 0.010gKg
-1.After administration 50min, be placed in wide mouthed bottle and cover tightly bottle stopper (placing 5g sodica calx in bottle).Take respiratory arrest as mark, the record mouse survival time.
2, result:
Compared with Vehicle controls group, the 0.010gKg of compositions
-1make the prolonged survival period of mice under atmospheric closed condition 47.26%, difference has significance (P<0.01), and compound III and compound IV all fail the time-to-live significant prolongation that makes mice under atmospheric closed condition.
Embodiment 7 mice hypobaric hypoxia is tested
1, method:
40 kunming mices, body weight (20 ± 2) g.Be divided into 4 groups at random, gastric infusion.Administration group gives compositions, compound III and compound IV respectively, and concentration is 0.010gKg
-1, matched group gives 0.3%CMC-Na solution, and gavage volume is 2mlKg
-1.After 50min, each administration group and matched group respectively get 5, put into decompressor, stop decompression when 26.7Kpa (be equivalent to height above sea level and be about 10000m), keep this pressure constant, until control animals dead 80% time, stop decompression immediately, slowly put into air, take out animal, record each group of dead and viable count, repetitive operation is to having tested.
2, result:
Compositions 0.010gKg
-1make the survival rate of mice under hypobaric hypoxia condition be increased to 60% by 20% of matched group, difference has significance (P<0.05); And compound III and compound IV are 20% to the survival rate of mice under hypobaric hypoxia condition, be not all improved.
Conclusion: compositions can significantly improve the time-to-live that isoproterenol causes specificity anoxia, the survival rate of asphyxia anoxia and acute decompression hypoxia mice, provides compositions and is preparing the purposes in anti-anoxic medicine.And compound III and compound IV all do not have above-mentioned activity.
The preparation of embodiment 8 composition tablet involved in the present invention
Get 2 grams of compositionss, add the customary adjuvant 18 grams preparing tablet, mixing, conventional tablet presses makes 100.
The preparation of embodiment 9 composition capsule involved in the present invention
Get 2 grams of compositionss, add prepare capsule customary adjuvant as starch 18 grams, mixing, encapsulatedly makes 100.
Claims (6)
1. a compositions, it is characterized by said composition and be made up of compound III and compound IV, in said composition, the mass percent of compound III and compound IV is respectively 45% and 55%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: the powder of compound III and the powder of compound IV are respectively 45% and 55% according to mass percent and fully mix.
3. the application of compositions as claimed in claim 1 in anti-anoxic medicine.
4. the application of compositions according to claim 3 in anti-anoxic medicine, is characterized in that: described anoxia is that isoproterenol causes specificity anoxia.
5. the application of compositions according to claim 3 in anti-anoxic medicine, is characterized in that: described anoxia is normal pressure asphyxia anoxia.
6. the application of compositions according to claim 3 in anti-anoxic medicine, is characterized in that: described anoxia is hypobaric hypoxia.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106074532A (en) * | 2016-05-24 | 2016-11-09 | 南京海澳斯生物医药科技有限公司 | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-anoxic medicine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102106890A (en) * | 2011-02-21 | 2011-06-29 | 贾正平 | Applications and preparation method of saussurea total sesquiterpene lactone |
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- 2015-07-16 CN CN201510421026.8A patent/CN105213377A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102106890A (en) * | 2011-02-21 | 2011-06-29 | 贾正平 | Applications and preparation method of saussurea total sesquiterpene lactone |
Non-Patent Citations (1)
| Title |
|---|
| ANTONELLA MAGGIO ET AL: "Artalbic acid, a sesquiterpene with an unusual skeleton from Artemisia alba (Asteraceae) from Sicily", 《TETRAHEDRON LETTERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106074532A (en) * | 2016-05-24 | 2016-11-09 | 南京海澳斯生物医药科技有限公司 | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-anoxic medicine |
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Application publication date: 20160106 |