CN1210864A - New medicine for curing presenile dementia and cerebral apoplexy sequelae - Google Patents
New medicine for curing presenile dementia and cerebral apoplexy sequelae Download PDFInfo
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Abstract
The present invention discloses a triterpene saponin medicine, which has the function of elongating axon and may be used for curing presenile dementia and cerebral apoplexy sequelae.
Description
The invention belongs to a kind of novel triterpenoid saponin compounds and be effective constituent and medicine with nervous process elongation effect with them.
The sickness rate of presenile dementia is in rising trend always in recent years, all can find the dead and disappearance of major part domination choline active nervous process of the neurocyte Mai Neiteshi nuclear (meynert nuclear) of memory charge and thinking in the case of majority.Nerve growth factor (to call NGF in the following text) is these neurocyte existence and breaks up necessary material [Pharmasia, 22,147 (1986)].Can see that NGF can promote the differentiation of neurocyte in the experiment in vitro, impel the nervous process elongation, and keep the existence of neurocyte.There is reported in literature NGF can suppress the domination vagusstoff active neurodegeneration that causes because of fibre breakage and come off [S.Korsching etc., Neuroscience Lett.The 66th volume, the 175th page, 1986] improve aged cavy the maze learning obstacle, suppress the atrophy (progress of luxuriant wild Zhuo etc., medical science, the 145th volume, the 579th page, 1986 years) of domination vagusstoff active neurocyte.This shows that NGF might become the medicine of treatment presenile dementia.In addition, NGF also is proved coming off of the hippocampal neurons that can prevent the cerebral ischemia mouse, so it also might become the medicine of treatment apoplexy sequela.
Also there are a variety of neurocyte projection elongations to promote material in the non-protein compound.Such as: the spy opens disclosed Sphingolipids,sialo (ganglioside) compound that can be used as nerve growth factor in flat 5-271081 number, disclosedly in Te Kaiping 6-9396 number can be used as the oxazole pyrrole of nerve growth factor and cough up quinoline (Oxazopyrroloquinoline) compounds, disclosed NGF effect enhancement factor in Te Kaiping 6-128264 number, the disclosed diacetyl type glycerol phosphate that can be used as nerve growth factor production promotor in Te Kaiping 6-157338 number, disclosed physiologically active substance in Te Kaiping 6-157419 number with neurite-outgrowth effect, and the special disclosed thiophenes that can be used as nerve growth factor production promotor etc. of opening in flat 6-157512 number.
Vegetarian rattan, dregs of rice paddy [Japan J.Pharmacol, 27,114 (Supplement) (1977); Same magazine, 27,445 (1977)] studied saponin class NGF growth-promoting effect to the nerve fiber aixs cylinder in the organ culture of chicken embryo spinal cord posterior root ganglion and sympathetic ganglion, found that Ginsenoside Rb l (ginsenoside Rbl) and the ginsenoside Rd (ginsenoside Rd) in the ginsenoside has significant promoter action.Also find chikusetsu saponin III (chikusetsusaponin III) in addition, jujuboside B (jujuboside B), periploca spium saponin K, H1, (H2) grade also has significant NGF enhancement to H2 for glycoside K, H1.These saponins all are steroid oside compounds.
Up to the present, though various non-peptide matters was studied, also there is not a kind of gratifying medicine that becomes.
The object of the present invention is to provide new physiologically active substance, promptly treat the medicine of presenile dementia and apoplexy sequela with NGF nervous process elongation effect.
In order to reach aforesaid purpose, the chemical ingredients of multiple Chinese medicinal plant is extracted, rough segmentation and purifying, and the activity rating that carries out nervous process elongation effect respectively, find to contain new physiologically active substance in the certain plants, thereby finished this invention with nervous process elongation effect.
The formula I according to the present invention
[R is the sugar chain of oleanolic acid glucoside unit]
Can provide by Ara, Rha, Xyl form the novel triterpenoid saponin compounds of oleanolic acid glucoside unit sugar chain.
The compound that is comprised among the present invention mainly is contained in the two ginsengs of plant (Dipsacaceae Triplostegia grandifora Gagnep.) that are grown in Chinese Sichuan Province.After the herb drying with two ginsengs, the extraction using alcohol with 95% removes and to desolvate, and utilizes suitable for separation such as column chromatography that the gained crude extract is separated, and purifying promptly obtains the represented compound of formula I.The structures of the two ginseng of physiologically active substance among resulting as stated above the present invention glucoside (Triplostegia) A～E are identified according to the analysis result of nucleus magnetic resonance (NMR) spectrum, mass spectrum, glycan analysis etc.Such as, the structure of two ginseng glucosides (Triplostegia) E is as follows:
The structure of contained sugar chain is as follows among Triplostegia A～D:
Triplostegia A：Ara-Rha-Xyl
Triplostegia B：Ara-Rha-Xyl-Rha
Triplostegia C：Ara-Rha-Xyl-Rha-Xyl
Triplostegia D：Ara-Rha-Xyl-Rha-Xyl-Xyl
Compound among the present invention can be with compound of the present invention directly or add the additive that allows in the medicine to add and make pharmaceutical preparation and carry out administration when making pharmaceuticals and use; Perhaps with the mixture of these compounds, or contain two conopsea extractions of these compounds or medicinal extract (medicinal extract is meant and removes the extract that extracts behind the solvent) and carry out administration.The administering mode of this pharmaceuticals, promptly oral, but the also oral mode of right and wrong.Under oral situation, can make capsule commonly used, tablet, pulvis etc.Under non-oral situation, can make formulations such as injection liquid, liquid preparation, also can make sustained release dosage, can also together use with other medicament.The method of preparation can adopt method commonly used.Compound among the present invention, for grownup patient can every day medicine for several times, administration total amount 0.01～500mg.Dosage can be according to the kind of disease, the state of an illness such as patient's age, body weight, symptom plus-minus.
Be specifically described below in conjunction with the pharmacological action of example the preparation of the represented triterpenoid saponin compounds of the formula I compound relevant with the present invention.The present invention is not limited only in following the specifying.
Embodiment 1: the preparation of triterpenoid saponin compounds:
After the herb of the two ginsengs of the Dipsacaceae plant that Chinese Sichuan Province is wild (Triplostegia grandiforaGagnep) carried out drying, the ethanol with 95% extracted, and obtains the solid of chocolate.3.5 gram extracts are carried out centrifugate liquid distribution chromatography (CPC) with the solvent of chloroform/methanol/isopropanol (4/3/1/2) formation, obtain 8 components, find that wherein B component (201mg) and C (305mg) have activity.Then B component is gone up at Lobar RP-18 post (A type) successively and separate with methanol (3/7 → 8/2), isopropanol (3/2), methanol (6/4 → 7/3).Obtained the 104mg active part, (chloroform/methanol/water (4: 1: 0.1) elutriant carries out column chromatography for separation for 70～230 orders, 1.2 * 18.0cm) posts, and obtained component B is activeconstituents Triplostegia A (3.4mg) with silica gel 60 with this part then.Component D～F (44mg) is carried out column chromatography for separation once more, obtained the pure product (35.5mg) of activeconstituents Triplostegia B, component H～I (34.2mg) is carried out having obtained activeconstituents Triplostegia C (8.8mg) and D (3.0mg) after the column chromatography for separation once more.After obtained component C (305mg) carries out same Lobar post and silica gel column chromatography separation after the initial CPC rough segmentation, obtained activeconstituents Triplostegia E (20.4mg).The structure composition utilization of Triplostegia A～E
13C-NMR,
1H-NMR, mass spectrum, glycan analysis is identified.The glucoside unit of each compound all is the represented Oleanolic Acid (C of formula III
30H
48O
3), sugar moieties has nothing in common with each other.The numbering of carbon atom is carried out according to the formula III in the NMR spectrum.(1) the NMR data of each compound: the part 1 chemical shift δ (ppm) of glucoside unit] [table 1] Triplostegia A
Carbon
13C-NMR
1H-NMR
1 38.98
2 26.55 1.82,2.06
3 88.97 3.298(11.6,4.3)
4 39.57 -
5 56.07 0.827(11.3)
6 18.59
7 33.20
8 39.83 -
9 48.13
10 37.10 -
11 23.71
12 122.60 5.471(3.5)
13 144.79 -
14 42.23 -
15 28.33
16 23.83
17 46.76 -
18 42.03 3.26(11,4)
19 48.55 1.80,1.29
20 30.91 -
21 34.25
22 33.20
23 28.29 1.265
24 17.05 1.076
25 15.54 0.859
26 17.44 0.981
27 26.18 1.310
28 180.32 -
29 33.28 0.982
30 23.79
(table 2) Triplostegia B
Carbon
13C-NMR
1H-NMR
1 38.92 0.95,1.50
2 20.55 1.83,1.98
3 88.87 3.288(11.8,4.3)
4 39.53 -
5 56.01 0.822(12.0)
6 18.53 1.32,1.55
7 33.16 1.81,1.28
8 39.76 -
9 48.07 1.86(9.2,8.8)
0 37.04 -
1 23.85 1.93,2.10
2 122.54 5.477(4.0,3.3)
3 144.77 -
4 42.16 -
5 28.28 1.22,2.13
6 23.78 1.92
7 46.71 -
8 41.96 3.263(11.0,3.7)
9 46.49 1.28,1.82
20 30.90 -
21 34.19 11.44(13.5,3.0)
22 33.16 1.99,1.47
23 28.20 1.268(s)
24 17.05 1.085(s)
25 15.52 0.854(s)
26 17.39 0.982(s)
27 26.17 1.318(s)
28 180.41 -
29 33.26 0.968(s)
30 23.77 1.013(s)
[table 3] Triplostegia C
Carbon
13C-NMR
1H-NMR
1 38.95
2 26.53
3 88.96 3:288(11,6.4)
4 39.53 -
5 56.03 0.824(d,11.6)
6 18.54
7 33?20
8 39.77
9 48.09
10 37.05
11 23.67
12 122.55 5.479(4.0,3.4)
13 144.80 -
14 42.19 -
15 28.29
16 23.79
17 48.77 -
18 41.99 3.28(11,4.0)
19 46.54
20 30.89
21 34.20
22 33.20
23 28.23 1.264
24 17.03 1.077
25 15.53 0.856
26 17.41 0.980
27 26.17 1.314
28 180.57 -
29 33.24 0.967
30 23.78 1.013
[table 4] Triplostegia D
Carbon
13C-NMR
1H-NMR
1 39.01
2 26.57
3 88.95 3.283(11.6,4.4)
4 39.58 -
5 56.09 0.823(d,11.6)
6 18.61
7 33.29
8 39.88
9 48.17
10 37.13
11 23.84
12 122.52 5.472(4.0,3.4)
13 144.95 -
14 42.27 -
15 28.39
16 23.84
17 46.82 -
18 42.11 3.28
19 46.65
20 30.98 -
21 34.35 1.251
25 15.57 0.062
26 17.47 0.992
27 28.21 1.313
28 do not find out-
29 33.29 0.960
30 23.84 1.017
[table 5] Triplostegia E
Carbon
13C-NMR
1H-NMR
1 38.97
2 26.55
3 88.93 3.286(11.6,4.3)
4 39.54 -
5 56.06 0.824(d,11.6)
6 18.56
7 33.26
8 39.81
9 48.12
10 37.08
11 23.70
12 127.55 5.479(4.0,3.4)
13 144.83 -
14 42.22
15 28.33
16 23.82
17 46.76 -
18 42.02 3.27(12,4.3)
19 46.57
20 30.91
21 34.?25
22 33.23
23 28.25 1.261
24 17.05 1.076
25 15.53 0.857
26 17.44 0.982
27 26.18 1.314
28 180.50 -
29 33.28 0.985
30 23.79 1.012
(2) the NMR data of each compound: sugar moieties [the upright δ (ppm) that moves of chemistry]
[table 6] Triplostegia A
Carbon
13C-NMR
1H-NMR Ara 1 104.73 4.875 (J1.2=5.5)
2 75.77 4.469(J2.3=7.3)
3 73.49 4.24
4 68.51 4.275
5 86.84 3.803(J5.5=11.3,J4.5=
1.7)
4.298(J4.5=4.9) Rha 1 101.35 6.016(J1.2=1.5)
2 71.62 4.817(J2.3=3.4)
3 82.39 4.631(J3.4=9.5)
4 72.57 4.398(J4.5=9.5)
5 69.7 4.538(J5.6=6.1)
6 18.36 1.561
1 106.71 5.232(J1.2=7.5)
2 75.22 4.030(J2.3=8.5)
3 77.82 4.092(J3.4=8.5)
4 70.82 4.128(J4.5=5.2,9.5)
5 67.05 3.613,4.24(J6.6=11.3)
[table 7] Triplostegia B
Carbon
13C-NMR
1H-NMR Ara 1 104.83 4.850 (5.6)
2 75.65 4.480(7.5,5.6)
3 73.85 4.24
4 68.66 4.28
5 64.86 3.808(11.3,1.9)
44.31(11.3,4.8) Rha-1 1 101.27 6.048(1.7)
2 71.54 4.813(3.4,1.7)
3 81.98 4.638(9.5,3.4)
4 72.53 4.399(t,9.5)
5 69.72 4.545
6 18.31 1.546(6.1) Xyl 1 108.39 5.205(7.7)
2 75.43 3.993(8.9,7.7)
3 83.02 4.194(t,8.9)
4 69.27 44.039(5.5,8.9,10.2)
5 66.96 3.592(11.6,10.2)
4.22 Rha-2 1 102.39 6.070?(1.7)
2 72.11 4.898?(3.4,1.7)
3 72.29 4.5366(9.5,3.4)
4 73.80 4.261(t,9.6)
5 69.76 4.83
6 18.42 1.622(8,1)
[table 8] Triplostegia C
Carbon
13C-NMR
1H-NMR
Ara 1 104.74 4.857(J1,2=5.7)
2 75.84 4.461(J2,3=7.5)
3 73.52 4.23
4 68.55 4.29
5 64.70 3.812(J5,5=11)
4.31 Rha-1 1 101.38 6.011(J1,2=1.6)
2 71.60 4.807(J2,3=3.2)
3 82.20 4.629(J3,4=9.2)
4 72.63 4.386(J4,5=9.6)
5 69.75 4.528(J5,6=6.1)
6 18.33 1.554 Rha-2 1 102.07 6.039(J1,2=1.6)
2 71.90 4.656(J2,3=3.2)
3 72.37 4.610(J3,4=9.2)
4 83.85 4.317(J4,5=9.6)
5 67.93 4.815(J5,6=6.1)
6 18.26 1.67
Xyl-1 1 106.47 5.191(J1,2=7.7)
2 75.55 3.983(J2,3=8.9)
3 82.89 4.178(J3,4=8.9)
4 69.31 4.03
5 67.08 3.602(J4,5=10.3)
4.23(J5,5=11.6) Xyl-2 1 105.94 5.103(J1,2=7.7)
2 74.75 3.947(J2,3=8.9)
3 87.15 4.003(J3,4=8.9)
4 88.98 4.11
5 66.56 3.492(J5,5=11.4)
4.185(J4,5=10.0,J4,5=4)
[table 9] Triplostegia D
Carbon
13C-NMR
1H-NMR
Ara 1 104.74 4.861(J1,2=5.5)
2 75.84 4.455(J2,3=7.3)
3 73.52 4.22
4 68.55 4.25
5 84.70 3.789(J5,5=11.5,J4,5=2.
4)
4.285(J4,5=4.9)
Rha-1 1 101.36 6.003(J1,2=1.5)
2 71.60 4.780(J2,3=3.3)
3 82.20 4.611(J3,4=9.5)
4 72.63 4.359(J4,5=9.5)
5 69.75 4.517(J5,6=6.1)
6 18.33 1.537
Rha-2 1 102.07 6.039(J1,2=1.6)
2 71.90 4.634(J2,3=3.3)
3 72.37 4.573(J3,4=9.5)
4 83.05 4.311(J4,5=9.5)
5 67.93 4.192(J5,6=6.1)
6 14.26 1.635
Xyl-1 1 100.47 5.176(J1,2=7.6)
2 75.55 3.962(J2,3=8.8)
3 82.89 4.162(J3,4=8.8)
4 69.31 4.02
5 67.08 3.577(J4,5=10.4)
4.21(J5,5=11.6)
Xyl-2 1 105.94 5.127(J1,2=7.3)
2 74.75 3.95
3 87.15 3.97
4 68.95 3.99
5 66.56 3.448(J4,5=10.1)
4.17(J5,5=11.0)
Xyl-3 1 105.62 5.115(J1,2=7.3)
2 75.02 3.98(J2,3=8.8)
3 77.84 4.083(J3,4=8.8)
4 70.89 4.11
5 67.08 3.637(J4,5=9.8)
4.20(J5,5=11.6)
[table 10] Triplostegia E
Carbon
13C-NMR
1H-NMR Ara 1 104.75 4.858 (J1,2=5.7)
2 75.77 4.466(J2,3=7.4)
3 73.52 4.23
4 88.56 4.27
5 84.73 3.803(J5,5=11.3,J4,5=2)
4.30?Rha-1 1 101.31 8.021(J1,2=1.8)
2 71.55 4.81(J2,3=3.3)
3 82.05 4.626(J3,4=9.5)
4 72.55 4.384(J4,5=9.5)
5 89.75 4.531(J5,5=5.1)
6 18.31 1.546?Rha-2 1 102.02 6.048(J1,2=1.6)
2 71.84 4.650(J2,3=3.3)
3 72.31 4.584(J3,4=9.5)
4 83.69 4.319(J4,5=9.5)
5 67.90 4.80(J5,5=8.1)
6 18.22 1.840?Xyl-1 1 106.38 5.190(J1,3=1.7)
2 75.53 3.975(J2,3=8.8)
3 82.78 4.175(J3,4=8.8)
4 89.25 4.03
5 67.03 3.593(J4,5=9.8)
4.22(J1,2=7.7)?Xyl-2 1 105.81 5.129(J1.2=7.1)
2 74.76 3.98
3 86.88 3.97
4 68.89 3.99
5 68.50 3.453(J4,5=9.8)?Xyl-3 4.17(J3,5=11.6)
1 105.19 5.108(J1,2=7.7)
2 74.82 3.98(J2,3=8.8)
3 71.50 4.101(J3,4=8.8)
4 70.47 4.12
5 67.03 3.645(J4,5=9.8)
4.28(J5,5=11.6)?Xyl-4 1 103.59 4.815(J1,2=7.7)
2 73.75 3.036(J2,3=8.8)
3 15.40 4.101(J3,4=8.8)
4 76.89 4.15
5 84.52 3.632(J4,5=9.8)
4.303(J5,5=11.6)
(3) specific rotation of each compound [α]
D
The specific rotation of [table 11] each compound [α]
D
Triplostegia?A:[α]
D R2-3.63(MeOH?C=0.11)
The same B:[α]
D R2-25.45 (MeOH C=0.495)
The same C:[α]
D R2-29.64 (MeOH C=0.425)
The same D:[α]
D R2-8.42 (MeOH C=0.095)
The same E:[α]
D R2-30.14 (MeOH C=0.94)
(4) mass spectrum of each compound (FAB-MS method/positive ion detects)
[table 12] Triplostegia A:m/z=867 (M+1)
+
C46H74O15?MW866
The same B:m/z=1013 (M+1)
+
C52H84O19?MW1012
The same C:m/z=1145 (M+1)
+
C57H92O23?MW1144
The same D:m/z=1278 (M+2)
+
1299(M+1+Na)
+
C62H100O27?MW1278
The same E:m/z=1409 (M+1)
+
1431(M+1+Na)
+
C87H108O31?MW1408
Embodiment 2: the nervous process extensional process of compound among the present invention
With the cavy adrenal gland medullary substance brown cell big Japanese pharmacy of PC12[(strain)] carry out cell cultures after the cell mass sterilization that obtains after the cloning to the NGF sensitivity, go up at the flat board that is coated with collagen [Sumitomo Bakelite (strain) system] in 96 holes and press every hole 5 * 10
3The individual sowing is to have added RDM11640[Nissui (strain) system of 10% horse serum and 5% fetal bovine serum] as substratum,, contain 5%CO at 37 ℃
2Incubator in cultivate 2～3 hours after, add be dissolved in contain in the PVP water by the experiment material, every hole 200ul cultivated four days in incubator.Viewed nervous process elongation activity was used respectively when the concentration of measured matter was respectively 5ug/ml, 10ug/ml ++ ,+expression.NGF has as a comparison observed nervous process and has stretched active under the concentration of 5ng/ml.Experimental result is as shown in table 1.The nervous process of allied compound stretching, extension activity is observed under the condition that does not have NGF to exist among the present invention.
The elongation of cavy adrenal gland medullary substance brown cell PC12 projection is active
Being tested the material projection stretches active
Triplostegia A +
The same B ++
The same C ++
The same D ++
The same E ++
The compound that has nervous process elongation effect among the present invention can be used as the medicine of dementias such as treating presenile dementia and apoplexy sequela.
Claims (5)
1. medicine for the treatment of presenile dementia, it is characterized in that: effective constituent is triterpenoid saponin, structural formula is
(R is the sugar chain of oleanolic acid glucoside unit).
2. medicine according to claim 1 is characterized in that: the sugar chain of oleanolic acid glucoside unit is made of Ara (pectinose), Rha (rhamnosyl), Xyl (wood sugar).
3. medicine according to claim 2 is characterized in that: the sugar chain that is made of Ara, Rha, Xyl is respectively Ara-Rha-Xyl, Ara-Rha-Xyl-Rha, Ara-Rha-Xyl-Rha-Xyl, Ara-Rha-Xyl-Rha-Xyl-Xyl, Ara-Rha-Xyl-Rha-Xyl-Xyl-Xyl.
4. according to claim 1,2 and 3 described medicines, it is characterized in that: with the novel triterpenoid saponin compounds is the medicine of effective constituent as nervous process elongation effect.
5. medicine according to claim 4 is characterized in that: the medicine with nervous process elongation effect that is used for the treatment of presenile dementia and apoplexy sequela.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96117572A CN1100062C (en) | 1996-06-03 | 1996-06-03 | New medicine for curing presenile dementia and cerebral apoplexy sequelae |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96117572A CN1100062C (en) | 1996-06-03 | 1996-06-03 | New medicine for curing presenile dementia and cerebral apoplexy sequelae |
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| CN1210864A true CN1210864A (en) | 1999-03-17 |
| CN1100062C CN1100062C (en) | 2003-01-29 |
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| WO2008086739A1 (en) * | 2007-01-16 | 2008-07-24 | Chengdu Di'ao Jiuhong Pharmaceutical Factory | Use of ursolic acid saponin, oleanolic acid saponin in preparation of increasing leucocyte and/or platelet medicine |
| CN107875157A (en) * | 2017-11-10 | 2018-04-06 | 中国药科大学 | The application of hederagenin and its glucosides in the medicine for preparing preventing and treating cerebral apoplexy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101235070B (en) * | 2004-12-29 | 2011-01-19 | 浙江大学 | Oleanane triterpene with A ring containing double bond and C ring containing conjugated ketenes, and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3359774B2 (en) * | 1994-07-07 | 2002-12-24 | 株式会社資生堂 | External preparation for skin |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1303097C (en) * | 2004-12-09 | 2007-03-07 | 中国人民解放军第二军医大学 | Japanese polygala saponin kind compound and aglucon, total saponin and total aglucon and its application in medicine |
| WO2008086739A1 (en) * | 2007-01-16 | 2008-07-24 | Chengdu Di'ao Jiuhong Pharmaceutical Factory | Use of ursolic acid saponin, oleanolic acid saponin in preparation of increasing leucocyte and/or platelet medicine |
| US8394776B2 (en) | 2007-01-16 | 2013-03-12 | Chengdu Di'ao Jiuhong Pharmaceutical Factor | Use of ursolic acid saponin,oleanolic acid saponin in preparation of increasing leucocytes and/or platelet medicine |
| CN107875157A (en) * | 2017-11-10 | 2018-04-06 | 中国药科大学 | The application of hederagenin and its glucosides in the medicine for preparing preventing and treating cerebral apoplexy |
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| CN1100062C (en) | 2003-01-29 |
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