CN105534985A - Composition and application thereof in leukocyte increasing medicines - Google Patents
Composition and application thereof in leukocyte increasing medicines Download PDFInfo
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- CN105534985A CN105534985A CN201511016776.3A CN201511016776A CN105534985A CN 105534985 A CN105534985 A CN 105534985A CN 201511016776 A CN201511016776 A CN 201511016776A CN 105534985 A CN105534985 A CN 105534985A
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- 239000000203 mixture Substances 0.000 title claims abstract description 48
- 210000000265 leukocyte Anatomy 0.000 title claims abstract description 22
- 230000001965 increasing effect Effects 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 229940079593 drug Drugs 0.000 title abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 14
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 14
- 210000004369 blood Anatomy 0.000 claims description 8
- 239000008280 blood Substances 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 3
- 229960004397 cyclophosphamide Drugs 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000000610 leukopenic effect Effects 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical class NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 3
- 208000035126 Facies Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- -1 phosphate amine Chemical class 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 208000032467 Aplastic anaemia Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 210000002798 bone marrow cell Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 230000002008 hemorrhagic effect Effects 0.000 description 2
- 201000002364 leukopenia Diseases 0.000 description 2
- 231100001022 leukopenia Toxicity 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- 206010018687 Granulocytopenia Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 206010033661 Pancytopenia Diseases 0.000 description 1
- 206010041660 Splenomegaly Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 208000024389 cytopenia Diseases 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000004976 peripheral blood cell Anatomy 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of organic synthesis and medicinal chemistry and particularly relates to a composition, a preparation method and an application thereof in preparation of leukocyte increasing medicines. The invention discloses a composition and a preparation method thereof. Pharmacological experiments indicate that the composition disclosed by the invention has a leukocyte increasing function and a value in developing leukocyte increasing medicines.
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 (Fan-YuMengetal. in 2011, 2011.SchiglautoneA, aNewTricyclicTriterpenoidwithaUnique6/7/9-FusedSkeletonf romtheStemsofSchisandraglaucescens.OrganicLetters13 (2011) 1502 – 1505) 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 15% and 85%.
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 chiglautoneA
Document (the Fan-YuMengetal. that the people such as the preparation method reference Fan-YuMeng of compound S chiglautoneA (I) deliver, 2011.SchiglautoneA, aNewTricyclicTriterpenoidwithaUnique6/7/9-FusedSkeletonf romtheStemsofSchisandraglaucescens.OrganicLetters13 (2011) 1502 – 1505) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2SchiglautoneA
By Compound I (502mg, 1.00mmol) be dissolved in 15mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.08g), 1,50% sodium hydroxide solution of 2-Bromofume (7.520g, 40.00mmol) and 6mL.Mixture stirs 8h at 35 degrees Celsius.After 8h, 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 3 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 (508mg, 71%) that namely solvent obtains Compound II per.
1HNMR(500MHz,DMSO-d
6)δ13.40(s,1H),6.10(s,1H),5.63(s,1H),5.53(s,1H),3.85(d,J＝11.2Hz,4H),3.52(d,J＝10.8Hz,4H),2.96(s,1H),2.20(s,1H),2.16(s,2H),2.00(s,1H),1.84(d,J＝13.9Hz,4H),1.69(s,1H),1.58(dd,J＝22.2,8.5Hz,4H),1.51(s,1H),1.47(s,1H),1.26(dd,J＝9.1,4.4Hz,4H),1.21(s,1H),1.08–0.98(m,4H),0.96-0.94(m,9H),0.94-0.85(m,6H).
13CNMR(125MHz,DMSO-d6)δ211.46(s),209.14(s),170.06(s),161.12(s),143.51(s),132.01(s),127.77(s),85.96(s),82.40(s),70.19(s),69.10(s),57.14(s),52.73(s),51.90(s),45.77(s),40.67(s),38.57(s),38.32(s),35.04(s),33.55(s),33.27(s),29.85(s),28.98(s),26.71(s),25.50(s),24.05(s),22.31(s),21.06(s),20.56(s),20.00(s),18.69(s),18.11(s),15.07(s).
HRMS(ESI)m/z[M-H]
-calcdforC
34H
51Br
2O
6:715.2032；found715.2027.
The synthesis of O-(morpholinyl) ethyl derivative (III) of embodiment 3SchiglautoneA
Compound II per (358mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (168mg, 1.0mmol) and morpholine (3484mg, 40mmol), mixture reflux 4h.After reaction terminates, reactant liquor is poured in 20mL 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 brown ceramic powder (247.5mg, 68%) that namely solvent obtains compound III.
1HNMR(500MHz,DMSO-d6)δ15.28(s,1H),6.10(s,1H),5.55(s,1H),5.30(s,1H),3.53(s,8H),3.46(d,J＝4.5Hz,4H),2.98(s,1H),2.52(d,J＝1.8Hz,4H),2.45(s,8H),2.28(s,2H),2.16(s,1H),1.87–1.77(m,5H),1.78(s,1H),1.67(s,1H),1.59(s,1H),1.57–1.50(m,3H),1.46(s,1H),1.31(s,1H),1.26(dd,J＝19.5,10.5Hz,4H),1.04–0.92(m,10H),0.89(s,3H),0.87(d,J＝20.0Hz,3H),0.82(s,3H).
13CNMR(125MHz,DMSO-d6)δ211.29(s),208.87(s),169.90(s),160.93(s),143.32(s),131.85(s),127.58(s),85.77(s),82.24(s),66.79(s),66.55(s),65.94(s),56.97(s),54.25(s),52.72(s),52.54(s),51.71(s),45.61(s),40.48(s),38.38(s),38.16(s),34.85(s),33.36(s),29.67(s),28.80(s),26.53(s),25.32(s),23.87(s),22.13(s),20.88(s),20.38(s),19.82(s),18.51(s),17.93(s),14.89(s).
HRMS(ESI):m/z[M+H]
+calcdforC
42H
69N
2O
8:729.5054；found:729.5051。
The synthesis of O-(two hydroxyethylamines) ethyl derivative of embodiment 4SchiglautoneA
Compound II per (358mg, 0.5mmol) is dissolved in 15mL acetonitrile, adds Anhydrous potassium carbonate (0.345g, 2.5mmol), potassium iodide (0.084g, 0.5mmol) and diethanolamine (1.0514g, 10mmol), mixture reflux 9h.Pour in cold water by reactant liquor after reaction terminates, with dichloromethane extraction three times, merge organic facies, use water and saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrating under reduced pressure removes solvent.Product, with purification by silica gel column chromatography (petroleum ether/acetone 100:1, v/v), obtains the faint yellow solid (0.199g, 52%) of O-(two hydroxyethylamines) ethyl derivative of SchiglautoneA.
1HNMR(500MHz,DMSO-d6)δ17.77(s,1H),6.00(s,1H),5.40(s,1H),5.20(s,1H),3.37(d,J＝17.8Hz,4H),3.28(s,8H),2.87(s,1H),2.51(d,J＝6.5Hz,4H),2.43(s,8H),2.24(s,2H),2.06(d,J＝12.7Hz,2H),1.76–1.68(m,5H),1.57(s,1H),1.53–1.39(m,8H),1.36(s,1H),1.24(s,1H),1.20–1.14(m,3H),1.11(s,1H),0.94–0.82(m,10H),0.80(s,3H),0.76(s,3H),0.72(d,J＝20.0Hz,3H).
13CNMR(125MHz,DMSO-d6)δ211.39(s),208.98(s),169.80(s),160.73(s),143.02(s),131.42(s),127.05(s),85.91(s),82.25(s),66.70(s),65.63(s),58.62(s),56.55(s),56.61(s),53.30(s),52.45(s),51.52(s),45.29(s),40.06(s),38.52(s),38.17(s),34.73(s),33.17(s),29.35(s),28.38(s),26.34(s),25.00(s),23.45(s),22.05(s),20.67(s),20.07(s),19.31(s),18.41(s),17.73(s),14.59(s).
HRMS(ESI):m/z[M+H]
+calcdforC
42H
73N
2O
10:765.5265；found:765.5261。
O-(two hydroxyethylamines) ethyl derivative of SchiglautoneA
The synthesis of the O-(bischloroethylamines base) ethyl derivative (IV) of embodiment 5SchiglautoneA
O-(two hydroxyethylamines) ethyl derivative (382mg, 0.5mmol) of SchiglautoneA embodiment 4 obtained is dissolved in 8mL chloroform, dropwise adds thionyl chloride (0.238g, 2mmol), reactant reflux 2h.Reactant is cooled to room temperature, drips the thionyl chloride that Methanol Decomposition is excessive, concentrating under reduced pressure is except desolventizing.Product, through purification by silica gel column chromatography (petroleum ether/acetone 100:1, v/v), obtains the faint yellow colloidal solid (0.297g, 71%) of compound IV.
1HNMR(500MHz,DMSO-d6)δ13.87(s,1H),6.01(s,1H),5.50(d,J＝8.4Hz,2H),3.61(s,4H),3.55(s,4H),3.45(s,2H),3.40(s,2H),2.98(s,1H),2.73(d,J＝17.4Hz,4H),2.67–2.57(m,6H),2.54(s,2H),2.40(s,1H),2.10(s,1H),1.99(s,2H),1.78(s,1H),1.73(d,J＝16.9Hz,4H),1.58(d,J＝3.0Hz,2H),1.46(d,J＝3.0Hz,2H),1.43(s,1H),1.37(s,1H),1.22(s,1H),1.17(dd,J＝18.9,11.1Hz,4H),0.95–0.83(m,10H),0.80(d,J＝20.0Hz,3H),0.78(d,J＝20.0Hz,3H),0.73(d,J＝20.0Hz,3H).
13CNMR(125MHz,DMSO-d6)δ211.19(s),208.87(s),169.79(s),160.85(s),143.24(s),131.74(s),127.50(s),85.69(s),82.13(s),66.71(s),65.84(s),56.87(s),55.80(s),53.19(s),52.44(s),51.64(s),45.51(s),40.38(s),39.22(s),38.30(s),38.05(s),34.77(s),33.28(s),29.56(s),28.72(s),26.45(s),25.21(s),23.79(s),22.05(s),20.77(s),20.30(s),19.76(s),18.41(s),17.85(s),14.81(s).
HRMS(ESI):m/z[M+H]
+calcdforC
42H
69C
l4N
2O
6:839.3880；found:839.3881。
Embodiment 6 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 85mg compound IV crossing 200 order nets after crossing the powder of the 15mg 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 7 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 8 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 15% and 85%,
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 15% and 85% 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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Non-Patent Citations (1)
| Title |
|---|
| FAN-YU MENG等: "Schiglautone A,a New Tricyclic Triterpenoid with a Unique 6/7/9-Fused Skeleton from the Stems of Schisandra glaucescens", 《ORGANIC LETTERS》 * |
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