CN104083385B - The application in the medicine preparing leukocyte increasing of O-(piperidyl) ethyl derivative of Cleistanone Cleistanone - Google Patents
The application in the medicine preparing leukocyte increasing of O-(piperidyl) ethyl derivative of Cleistanone Cleistanone Download PDFInfo
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- CN104083385B CN104083385B CN201410374733.1A CN201410374733A CN104083385B CN 104083385 B CN104083385 B CN 104083385B CN 201410374733 A CN201410374733 A CN 201410374733A CN 104083385 B CN104083385 B CN 104083385B
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- ethyl derivative
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- XURLTFUKDPZAPN-QFIPXVFZSA-N Cleistanone Natural products O(C)[C@H]1OC(=O)c2c(-c3cc4OCOc4cc3)c3c(c(O)c12)cc(OC)c(OC)c3 XURLTFUKDPZAPN-QFIPXVFZSA-N 0.000 title claims abstract description 75
- GEIFQLXIDUDMNZ-PCJVTFPHSA-N (4aR,4bR,6aR,8S,10aR,10bR,12R,12aR)-12-hydroxy-1,1,1',1',4a,10a,10b-heptamethyl-3'-methylidenespiro[3,4,4b,5,6,6a,7,9,10,11,12,12a-dodecahydrochrysene-8,2'-cyclopentane]-2-one Chemical compound CC1(C)CCC(=C)[C@@]11C[C@@H](CC[C@H]2[C@]3(C[C@@H](O)[C@H]4C(C)(C)C(=O)CC[C@@]42C)C)[C@@]3(C)CC1 GEIFQLXIDUDMNZ-PCJVTFPHSA-N 0.000 title claims abstract description 74
- 210000000265 leukocyte Anatomy 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 230000001965 increasing effect Effects 0.000 title claims abstract description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title claims description 31
- -1 (piperidyl) ethyl Chemical class 0.000 claims abstract description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 21
- 210000004369 blood Anatomy 0.000 claims description 8
- 239000008280 blood Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 2
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 241001597008 Nomeidae Species 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 230000000610 leukopenic effect Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 208000035126 Facies Diseases 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XBZYWSMVVKYHQN-MYPRUECHSA-N (4as,6as,6br,8ar,9r,10s,12ar,12br,14bs)-10-hydroxy-2,2,6a,6b,9,12a-hexamethyl-9-[(sulfooxy)methyl]-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4a-carboxylic acid Chemical compound C1C[C@H](O)[C@@](C)(COS(O)(=O)=O)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C XBZYWSMVVKYHQN-MYPRUECHSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 208000032467 Aplastic anaemia Diseases 0.000 description 2
- 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 2
- 241000785597 Cleistanthus Species 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000002798 bone marrow cell Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000000284 extract Substances 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
- 238000000034 method Methods 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
- 239000010452 phosphate Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010992 reflux Methods 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
- 210000003462 vein Anatomy 0.000 description 2
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- 206010018687 Granulocytopenia Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 206010033661 Pancytopenia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 206010041660 Splenomegaly Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- ODJZWVFLHZHURI-UHFFFAOYSA-M [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] Chemical compound [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] ODJZWVFLHZHURI-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- SISAYUDTHCIGLM-UHFFFAOYSA-N bromine dioxide Inorganic materials O=Br=O SISAYUDTHCIGLM-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 208000024389 cytopenia Diseases 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- 229940056582 human hair preparation Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 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
- 229930014626 natural product Natural products 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 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
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to O (piperidyl) ethyl derivative of Cleistanone Cleistanone, preparation method and in the purposes preparing on anti-inflammatory drug.The present invention has synthesized O (piperidyl) ethyl derivative of a new Cleistanone Cleistanone, and discloses its preparation method.Pharmacological experiment shows, O (piperidyl) ethyl derivative of the Cleistanone Cleistanone of the present invention has the effect of leukocyte increasing, has the value of exploitation leukocyte increasing medicine.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Cleistanone Cleistanone's
O-(piperidyl) ethyl derivative, 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 former
The property sent out and the big class of Secondary cases two.Constitutional person is agnogenio；Secondary cases person think 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., it is thus achieved that property or unexplained granulocytopenia etc..
There is the problem that toxicity is big, safety is low, from natural product in the current existing medicine of leukopenic treatment
Thing found compound or lead compound and carries out structural modification and obtain its derivant, thus obtaining high-efficiency low-toxicity
Potential drug have important value.
The compound Cleistanone Cleistanone that the present invention relates to is one and within 2011, delivers (Van Trinh Thi
Thanh et al.,2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis with
a New Carbon Skeleton.Volume 2011,Issue22,Pages4108 4111, August2011)
Compound, we have carried out structural modification to compound Cleistanone Cleistanone, it is thus achieved that one new
O-(piperidyl) ethyl derivative of Cleistanone Cleistanone, and its leukocyte increasing activity is carried out
Evaluating, it has leukocyte increasing activity.
Summary of the invention
The invention discloses O-(piperidyl) ethyl derivative of a Cleistanone Cleistanone, its structure
For:
O-(piperidyl) ethyl derivative (III) of Cleistanone Cleistanone of the present invention can pass through following side
Prepared by method:
(1) Cleistanone Cleistanone (I) reacts with glycol dibromide and obtains Cleistanone Cleistanone
O-bromoethyl derivant (II)；
(2) O-bromoethyl derivant (II) of Cleistanone Cleistanone and piperidines generation substitution reaction system
Obtain O-(piperidyl) ethyl derivative (III) of Cleistanone Cleistanone.
The further preparation method of O-(piperidyl) ethyl derivative (III) of Cleistanone Cleistanone
For:
(1) 440mg compound Cleistanone Cleistanone (I) is dissolved in 10mL benzene, adds in solution
The tetrabutyl ammonium bromide of 0.04g, the glycol dibromide of 3.760g and 50% sodium hydroxide solution of 6mL；
Mixture stirs 24h at 25 degrees Celsius；After 24h, reactant liquor is poured in frozen water, use dichloromethane immediately
It is extracted twice, merges organic phase solution；Then to organic phase solution successively with water and saturated aqueous common salt washing 3
Secondary, then be dried with anhydrous sodium sulfate, last concentrating under reduced pressure is removed solvent and is obtained product crude product；Product crude product silicon
Gel column chromatography eluting, flowing is mutually: petroleum ether/acetone=100:1, v/v, collects yellow and concentrates elution band and get final product
Yellow solid to O-bromoethyl derivant (II) of Cleistanone Cleistanone.
(2) O-bromoethyl derivant (II) of the Cleistanone Cleistanone of 273mg is dissolved in 20mL
In the middle of acetonitrile, it is added thereto to the Anhydrous potassium carbonate of 345mg, the potassium iodide of 84mg and the piperidines of 852mg,
Mixture is heated to reflux 16h；Reactant liquor is poured in 20mL frozen water after terminating by reaction, uses equivalent dichloromethane
Alkane extracts three times, merges organic facies；Organic facies after merging with water and saturated aqueous common salt washing successively, then use
Anhydrous sodium sulfate is dried, and concentrating under reduced pressure is removed solvent and obtained product crude product；Product crude product silica gel column chromatography is purified,
Flowing is mutually: petroleum ether/acetone=100:0.5, v/v, collects yellow and concentrates elution band i.e. to obtain Cleistanone
The yellow gummy solid 157.0mg of O-(piperidyl) ethyl derivative (III) of Cleistanone.
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
O-(piperidyl) ethyl derivative (III) that it is an object of the invention to provide Cleistanone Cleistanone exists
Prepare the application in leukocyte increasing medicine.O-(piperidyl) ethyl derivative of Cleistanone Cleistanone
(III) can significantly raise the leukocyte caused with chemical substance of losing blood to reduce.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not had
Any restriction of body embodiment, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Cleistanone Cleistanone
The preparation method of compound Cleistanone Cleistanone (I) is with reference to Crinis Carbonisatus such as Van Trinh Thi Thanh
Document (Van Trinh Thi Thanh et al., the 2011.Cleistanone:A Triterpenoid from of table
Cleistanthus indochinensis with a New Carbon Skeleton.Volume2011,Issue22,
Pages4108 4111, August2011) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2 Cleistanone Cleistanone
Compound I (440mg, 1.00mmol) is dissolved in 10mL benzene, in solution, adds tetrabutyl phosphonium bromide
Ammonium (TBAB) (0.04g), glycol dibromide (3.760g, 20.00mmol) and 50% hydrogen of 6mL
Sodium hydroxide solution.Mixture stirs 24h at 25 degrees Celsius.After 24h, reactant liquor is poured in frozen water, vertical
I.e. it is extracted twice with dichloromethane, merges organic phase solution.Then to organic phase solution successively with water and saturated food
Saline washs 3 times, then is dried with anhydrous sodium sulfate, and last concentrating under reduced pressure is removed solvent and obtained product crude product.Produce
Thing crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1, v/v), collects yellow and concentrates
Elution band i.e. obtains the yellow solid (344mg, 63%) of compound II.
1H NMR (500MHz, DMSO-d6) δ 5.04 (s, 1H), 4.82 (s, 1H), 3.94 (d, J=26.5Hz,
1H), 3.87 (d, J=26.5Hz, 2H), 3.57 (s, 2H), 2.40 (d, J=14.0Hz, 1H), 2.39 (d, J=
14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H),1.82(s,1H),1.62(s,2H),1.57
(d, J=3.3Hz, 1H), 1.54 (d, J=3.3Hz, 1H), 1.50 (d, J=1.2Hz, 1H), 1.47 (d, J=1.2
Hz, 1H), 1.39 (d, J=15.3Hz, 2H), 1.34 (d, J=15.3Hz, 1H), 1.26 (dd, J=32.6,13.7
Hz, 4H), 1.13 (d, J=18.0Hz, 2H), 1.05 (s, 6H), 0.98 (s, 1H), 0.88 (s, 12H), 0.78 (s,
3H),0.74(s,1H)。
13C NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.63(s),
69.85(s),59.71(s),52.55(s),51.21(s),47.92(s),44.10(s),42.25(s),41.73(s),
40.64 (s), 40.16 (s), 38.88 (s), 38.65 (s), 37.21 (s), 36.23 (s), 33.34 (d, J=1.1Hz),
32.96(s),29.91(s),27.18(s),26.03(s),24.23(s),23.96(s),20.77(s),18.48(s),
17.98(s),16.93(s)。
HRMS(ESI)m/z[M+H]+calcd for C32H52BrO2:547.3151；found547.3159.
The synthesis of O-(piperidyl) ethyl derivative (III) of embodiment 3 Cleistanone Cleistanone
Compound II (273mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and piperidines (852mg, 10mmol),
Mixture is heated to reflux 16h.Reactant liquor is poured in 20mL frozen water after terminating by reaction, uses equivalent dichloromethane
Alkane extracts three times, merges organic facies.Organic facies after merging with water and saturated aqueous common salt washing successively, then use
Anhydrous sodium sulfate is dried, and concentrating under reduced pressure is removed solvent and obtained product crude product.Product crude product silica gel column chromatography is purified
(flowing is mutually: petroleum ether/acetone=100:0.5, v/v), collects yellow and concentrates elution band i.e. to obtain Cleistanone
The yellow gummy solid (157.0mg, 57%) of O-(piperidyl) ethyl derivative.
1H NMR(500MHz,DMSO-d6)δ5.04(s,1H),4.85(s,1H),4.37(s,1H),3.54(s,2H),
2.57 (s, 2H), 2.47 (dd, J=44.3,41.4Hz, 6H), 2.29 (s, 1H), 2.22 (s, 1H), 2.19 (s, 1H),
1.82 (s, 1H), 1.65 (s, 2H), 1.58 (d, J=8.0Hz, 2H), 1.53 1.46 (m, 6H), 1.39 (t, J=
7.8Hz, 5H), 1.30 (dd, J=21.8,9.9Hz, 4H), 1.16 (d, J=0.4Hz, 2H), 1.06 (s, 6H),
0.91(s,1H),0.88(s,12H),0.85–0.57(m,4H).
13C NMR(125MHz,DMSO-d6)δ216.69(s),154.70(s),105.53(s),74.75(s),67.02
(s), 59.85 (s), 55.00 (d, J=14.4Hz), 52.87 (s), 51.30 (s), 48.09 (s), 44.44 (s), 42.38
(s),41.98(s),40.93(s),40.25(s),39.07(s),38.99(s),37.34(s),36.48(s),33.66(s),
33.05(s),30.10(s),27.52(s),26.16(s),24.80(s),24.59(s),24.06(s),23.65(s),
21.05(s),18.56(s),18.21(s),17.28(s).
HRMS(ESI):m/z[M+H]+calcd for C37H62NO2:552.4781；found:552.4787.
O-(piperidyl) the ethyl derivative leukocyte increasing activity of embodiment 4Cleistanone
One, O-(piperidyl) ethyl derivative of the Cleistanone therapeutical effect to post hemorrhagic mice
Post hemorrhagic mice affected ICR mice 30, ♀ ♂ half and half, is divided into 3 groups (n=10).Except raw
Outside reason saline group, other every mice of group, from orbital vein blood-letting 0.5ml, takes blood again and surveys whole each group after 24h
Leukocyte index, then continuous gastric infusion 1 week, after last is administered 1h, takes blood F-800 from orbital venous plexus
Full whole bliid platelet analyzer surveys leukocyte index.
O-(piperidyl) ethyl derivative of table 1Cleistanone is made because of caused leukopenic treatment of losing blood
With (109/L)
Compare with model group: * * p < 0.01
Result shows, blood-letting mice is treated after 7 days through O-(piperidyl) ethyl derivative taking Cleistanone,
O-(piperidyl) the ethyl derivative administration group of Cleistanone compares with model group, and leukocyte is significantly higher than model
Group, close to normal saline group.
Two, O-(piperidyl) ethyl derivative of Cleistanone causes leukopenic treatment work to cyclophosphamide
With
Preventive and therapeutic effect ICR mice 30 to the damage of mouse bone marrow cells hemopoietic function, ♀ ♂ dual-purpose, it is divided into 3
Group (n=10), i.e. O-(piperidyl) the ethyl derivative 1.2mg/kg of normal saline group, modeling group, Cleistanone
Group, oral administration, every day 1 time.In addition to normal saline group, other respectively organized mice respectively on 0th, 5,10th
Lumbar injection cycli phosphate amine 80mg/kg, then proceedes to be administered 3 days.1h after last is administered, quiet from eye socket
Arteries and veins clump takes blood, surveys leukocyte.
O-(piperidyl) the ethyl derivative treatment leukopenic to caused by cyclophosphamide of table 2Cleistanone
Effect (109/L)
Compare with model group: * * p < 0.01
Result shows, compares with normal saline group, and cycli phosphate amine can make mouse bone marrow cells damage, and causes peripheral blood thin
Born of the same parents decline, and O-(piperidyl) the ethyl derivative group of Cleistanone compares with model group, all can substantially resist ring
Phosphamide induced mice leukopenia.
Three, O-(piperidyl) ethyl derivative of Cleistanone is to therapeutical effect leukopenic caused by benzene
Impact on Induced Aplastic Anemia Mice: Kunming mouse 30, ♀ ♂ dual-purpose, it is divided into 3 groups
(n=10), in addition to normal saline group, other organizes mouse subcutaneous injection benzene 0.5ml/kg, continuous 12 days, modeling
The same day, oral administration simultaneously, every day 1 time, totally 18 days, last be administered after 1h, orbital venous plexus takes blood,
Survey leukocyte.
O-(piperidyl) ethyl derivative of the table 3Cleistanone therapeutical effect to cytopenia caused by benzene
(109/L)
Compare with model group: * * p < 0.01
Result shows, administration group compares with model group, can substantially resist Induced Aplastic Anemia Mice caused by benzene white
The decline of cell.
O-(piperidyl) ethyl derivative of conclusion: Cleistanone can notable leukocyte increasing, can be used to
Prepare anti-leukocyte and reduce medicine.
Embodiment 5 compound involved in the present invention II and the preparation of III tablet
Take in the middle of O-(piperidyl) ethyl derivative or its pharmaceutically acceptable salt of 20 grams of Cleistanone
One, addition prepares the customary adjuvant 180 grams of tablet, and mixing, conventional tablet presses makes 1000.
Embodiment 6 compound involved in the present invention II and the preparation of III capsule
Take in the middle of O-(piperidyl) ethyl derivative or its pharmaceutically acceptable salt of 20 grams of Cleistanone
One, addition prepares the customary adjuvant such as starch 180 grams of capsule, mixing, encapsulated makes 1000.
Claims (4)
1. O-(piperidyl) ethyl derivative (III) and the pharmaceutically acceptable salt thereof of Cleistanone Cleistanone is being made
Application in standby leukocyte increasing medicine, it is characterised in that the O-(piperidyl) of described Cleistanone Cleistanone
Ethyl derivative raises the reduction of caused leukocyte of losing blood,
2. O-(piperidyl) ethyl derivative (III) and the pharmaceutically acceptable salt thereof of Cleistanone Cleistanone is being made
Application in standby leukocyte increasing medicine, it is characterised in that the O-(piperidyl) of described Cleistanone Cleistanone
Ethyl derivative raises the reduction of leukocyte caused by chemicals,
3. O-(piperidyl) ethyl derivative (III) of Cleistanone Cleistanone as claimed in claim 2 and medicine thereof
Acceptable salt application in preparing leukocyte increasing medicine on, it is characterised in that described chemicals is ring phosphorus
Amide.
4. O-(piperidyl) ethyl derivative (III) of Cleistanone Cleistanone as claimed in claim 2 and medicine thereof
Acceptable salt application in preparing leukocyte increasing medicine on, it is characterised in that described chemicals is benzene.
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| CN104447938B (en) * | 2014-11-05 | 2016-11-30 | 南京大学 | O-(piperazinyl) ethyl derivative of Cleistanone, preparation method and its usage |
| CN104706642A (en) * | 2015-03-10 | 2015-06-17 | 南京大学 | Application of O-(triazolyl) ethyl derivative of cleistanone to preparation drug for rising white blood cells |
| CN104758297A (en) * | 2015-04-15 | 2015-07-08 | 南京大学 | Application of O-(1H-tetrazolyl) ethyl derivative of cleistanone in preparation of anti-osteoporosis medicines |
| CN104825469A (en) * | 2015-04-29 | 2015-08-12 | 南京广康协生物医药技术有限公司 | Application of cleistanone O-(benzimidazolyl) ethyl derivative in preparation of drugs for increasing leukocyte |
| CN104784175A (en) * | 2015-05-12 | 2015-07-22 | 南京大学 | Application of derivative of Daphmalenine A in preparation of drugs for increasing white blood cells |
| CN104873508A (en) * | 2015-05-27 | 2015-09-02 | 南京大学 | Application of O-(diethylamino) ethyl derivative of Daphmalenine A in preparation of anti-inflammatory drug |
| CN104922121A (en) * | 2015-05-27 | 2015-09-23 | 南京广康协生物医药技术有限公司 | Application of O-(diethylin) ethyl derivative of Daphmalenine A to preparation of drug for increasing white blood cells |
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