CN105287556A - Composition and application thereof to medicines capable of increasing leukocytes - Google Patents
Composition and application thereof to medicines capable of increasing leukocytes Download PDFInfo
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- CN105287556A CN105287556A CN201510742199.XA CN201510742199A CN105287556A CN 105287556 A CN105287556 A CN 105287556A CN 201510742199 A CN201510742199 A CN 201510742199A CN 105287556 A CN105287556 A CN 105287556A
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Abstract
The invention relates to the field of organic synthesis and medicinal chemistry and in particular relates to a composition, a preparation method and an application of the composition to preparation of medicines capable of increasing leukocytes. The invention discloses the composition and the preparation method thereof. Pharmacological experiments show that the composition has the function of increasing leukocytes and has the value in developing the medicines capable of increasing leukocytes.
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
Leukopenia is due to disease that is agnogenio and that cause after being secondary to other diseases, is divided into constitutional and the large class of Secondary cases two.Constitutional person is agnogenio; Secondary cases person thinks that its cause of disease can by actute infection, physics, chemical factor, disease in the blood system, the disease of companion's splenomegaly, connective tissue disease, anaphylactic disease, hereditary etc., acquired or agnogenio property granulocytopenia etc.
There is the problem that toxicity is large, safety is low in the current existing medicine of leukopenic treatment, finds compound or lead compound and carry out structural modification to obtain its derivant from natural product, thus the potential drug obtaining high-efficiency low-toxicity has important value.
The Compound I that the present invention relates to is one and delivers (AyumiOhsakietal. in 2011,2011.SalviskinoneA, aditerpenewithanewskeletonfromSalviaprzewalskii.Tetrahed ronLetters52 (2011) 1375 – 1377) 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 said composition leukocyte increasing activity is evaluated, it has leukocyte increasing activity.
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 5% and 95%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
The object of this invention is to provide compositions and prepare the application in leukocyte increasing medicine.The present composition significantly can raise the leukocyte caused with chemical substance of losing blood to be reduced.
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 compound S alviskinoneA
Document (the AyumiOhsakietal. that the people such as the preparation method reference AyumiOhsaki of compound S alviskinoneA (I) deliver, 2011.SalviskinoneA, aditerpenewithanewskeletonfromSalviaprzewalskii.Tetrahed ronLetters52 (2011) 1375 – 1377) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2SalviskinoneA
By Compound I (312mg, 1.00mmol) be dissolved in 15mL 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 12h at 35 degrees Celsius.After 12h, 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 4 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=100:1.5, v/v), collects brown concentrated elution band and flings to the brown ceramic powder (327mg, 78%) that namely solvent obtains Compound II per.
1HNMR(500MHz,DMSO-d
6)δ6.63(s,1H),6.37(s,1H),5.81(s,1H),4.51(s,2H),3.84(s,1H),3.79(s,2H),2.15(s,1H),2.04(s,1H),1.91(s,1H),1.65(s,1H),1.39(s,3H),1.08(s,6H),0.99(s,6H).
13CNMR(125MHz,DMSO-d6)δ188.07(s),183.70(s),154.38(s),147.57(s),140.21(s),136.40(s),134.71(s),131.25(s),128.40(s),118.83(s),72.12(s),45.49(s),37.54(s),33.58(s),31.78(s),26.17(s),25.12(s),24.66(s),23.51(s),23.17(s),22.65(s).
HRMS(ESI)m/z[M+H]
+calcdforC
22H
28BrO
3:419.1222；found419.1220.
The synthesis of the O-(nafoxidine base) ethyl derivative (III) of embodiment 3SalviskinoneA
Compound II per (209mg, 0.5mmol) is dissolved in the middle of 20mL 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 yellow powder (131.6mg, 65%) that namely solvent obtains compound III.
1HNMR(500MHz,DMSO-d6)δ6.57(s,1H),6.29(s,1H),5.82(s,1H),4.25(s,2H),3.86(s,1H),3.10(s,2H),2.55(s,4H),2.16(s,1H),2.07(s,1H),1.893(s,1H),1.73(s,4H),1.70(s,1H),1.38(s,3H),1.09(s,6H),1.02(s,6H).
13CNMR(125MHz,DMSO-d6)δ188.10(s),183.71(s),154.37(s),147.57(s),140.19(s),136.41(s),134.73(s),131.25(s),128.38(s),118.82(s),69.23(s),54.54(d,J＝16.6Hz),45.51(s),37.54(s),33.56(s),26.16(s),25.19(d,J＝10.3Hz),24.73(s),23.58(s),23.24(s),22.69(s).
HRMS(ESI):m/z[M+H]
+calcdforC
26H
36NO
3:410.2695；found:410.2693。
The synthesis of O-(piperidyl) ethyl derivative (IV) of embodiment 4SalviskinoneA
Compound II per (209mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and piperidines (852mg, 10mmol), mixture reflux 10h.After reaction terminates, reactant liquor is poured in 25mL frozen water, with equivalent dichloromethane extraction 2 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 yellow concentrated elution band and flings to the yellow powder (116.3mg, 55%) that namely solvent obtains compound IV.
1HNMR(500MHz,Chloroform-d1)δ6.44(d,J＝95.3Hz,1H),6.31(s,1H),5.73(s,1H),4.20(s,2H),3.74(s,1H),3.01(s,2H),2.39(s,4H),2.07(s,1H),1.96(s,1H),1.86(s,1H),1.60(s,1H),1.44(s,4H),1.33(d,J＝15.0Hz,5H),1.00(s,6H),0.91(s,6H).
13CNMR(125MHz,DMSO-d6)δ188.16(s),183.79(s),154.48(s),147.63(s),140.27(s),136.51(s),134.79(s),131.33(s),128.47(s),118.88(s),69.31(s),54.69(d,J＝16.2Hz),45.56(s),37.61(s),33.62(s),26.21(s),25.21(s),24.65(d,J＝19.1Hz),23.50(d,J＝17.2Hz),23.23(s),22.68(s).
HRMS(ESI):m/z[M+H]
+calcdforC
27H
38NO
3:424.2852；found:424.2856。
Embodiment 5 compositions leukocyte increasing is active
One, compositions is to the therapeutical effect of post hemorrhagic mice
ICR mice 50 is affected, ♀ ♂ half and half to post hemorrhagic mice, is divided into 5 groups (n=10).Except normal saline group, other organizes every mice from orbital vein blood-letting 0.5ml, gets blood again and survey all each group leukocyte index, then continuous gastric infusion 1 week after 24h, after last administration 1h, get the full whole bliid platelet analyzer of blood F-800 from orbital venous plexus and survey leukocyte index.
The preparation of compositions: loaded by the powder of 95mg compound IV crossing 200 order nets after crossing the powder of the 5mg compound III of 200 order nets and grinding after grinding to mix in tubule with cover and with turbine stirring instrument and namely obtain 100mg compositions, obtains the solution of compositions by the compositions of this 100mg of water dissolution during use.
Table 1 compositions is to because of caused leukopenic therapeutical effect (10 of losing blood
9/ L)
Compare with model group: * p<0.05
Result shows, blood-letting mice is after taking compositions and treating 7 days, and compositions administration group compares with model group, and leukocyte is significantly higher than model group, close to normal saline group.And compound III and compound IV do not have this activity.
Two, compositions causes leukopenic therapeutical effect to cyclophosphamide
To the preventive and therapeutic effect ICR mice 50 of mouse bone marrow cells hemopoietic function damage, ♀ ♂ dual-purpose, is divided into 5 groups (n=10), i.e. normal saline group, modeling group, compositions 1.2mg/kg group, compound III 1.2mg/kg group and compound IV 1.2mg/kg group, oral administration, every day 1 time.0th, except normal saline group, other respectively organized mice lumbar injection cycli phosphate amine 80mg/kg respectively, then continued administration 3 days on 5th, 10.1h after last administration, gets blood from orbital venous plexus, surveys leukocyte.
Table 2 compositions is to the leukopenic therapeutical effect (10 of caused by cyclophosphamide
9/ L)
Compare with model group: * p<0.05
Result shows, compares with normal saline group, and cycli phosphate amine can make mouse bone marrow cells damage, and causes peripheral blood cells to decline, and compositions group compares with model group, all obviously can resist cycli phosphate amine induced mice leukopenia.And compound III and compound IV do not have this activity.
Three, compositions is to leukopenic therapeutical effect caused by benzene
Impact on Induced Aplastic Anemia Mice: Kunming mouse 50, ♀ ♂ dual-purpose, is divided into 5 groups (n=10), except normal saline group, other group mouse subcutaneous injection benzene 0.5ml/kg, continuous 12 days, the same day of modeling, oral administration simultaneously, every day 1 time, totally 18 days, 1h after last administration, orbital venous plexus gets blood, surveys leukocyte.
Table 3 compositions is to the therapeutical effect (10 of cytopenia caused by benzene
9/ L)
Compare with model group: * p<0.05
Result shows, compositions group compares with model group, obviously can resist the leukocytic decline of Induced Aplastic Anemia Mice caused by benzene.And compound III and compound IV do not have this activity.
Conclusion: compositions can remarkable leukocyte increasing, can be used for preparing anti-leukocyte and reduce medicine.And compound III and compound IV do not have the activity of remarkable leukocyte increasing, be not available to prepare anti-leukocyte and reduce medicine.
The preparation of embodiment 6 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 7 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 (7)
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 5% and 95%,
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 5% and 95% according to mass percent and fully mix.
3. the application of compositions as claimed in claim 1 in leukocyte increasing medicine.
4. the application of compositions in leukocyte increasing medicine as claimed in claim 3, is characterized in that described compositions raises caused leukocytic reduction of losing blood.
5. the application of compositions in leukocyte increasing medicine as claimed in claim 3, is characterized in that described compositions raises leukocytic reduction caused by chemicals.
6. the application of compositions in leukocyte increasing medicine as claimed in claim 5, is characterized in that described chemicals is cyclophosphamide.
7. the application of compositions in leukocyte increasing medicine as claimed in claim 5, is characterized in that described chemicals is benzene.
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| CN201510742199.XA CN105287556A (en) | 2015-11-04 | 2015-11-04 | Composition and application thereof to medicines capable of increasing leukocytes |
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| CN201510742199.XA CN105287556A (en) | 2015-11-04 | 2015-11-04 | Composition and application thereof to medicines capable of increasing leukocytes |
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| CN105287556A true CN105287556A (en) | 2016-02-03 |
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2015
- 2015-11-04 CN CN201510742199.XA patent/CN105287556A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| AYUMI OHSAKI,ET AL.: "Salviskinone A, a diterpene with a new skeleton from Salvia przewalskii", 《TETRAHEDRON LETTERS》 * |
| 王羽伦等: "丹参酮ⅡA的临床应用与配伍禁忌", 《医药导报》 * |
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