CN100360129C - Dehydro eleagnine derivative, its synthesizing method and use - Google Patents
Dehydro eleagnine derivative, its synthesizing method and use Download PDFInfo
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- CN100360129C CN100360129C CNB2004100742031A CN200410074203A CN100360129C CN 100360129 C CN100360129 C CN 100360129C CN B2004100742031 A CNB2004100742031 A CN B2004100742031A CN 200410074203 A CN200410074203 A CN 200410074203A CN 100360129 C CN100360129 C CN 100360129C
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Abstract
The present invention discloses a novel dehydro-eleagnine derivative, a preparing method and the purpose thereof. A compound of the present invention is prepared by connecting a side chain carboxyl of dehydro- eleagnine with diazanyl, amido ethylamino, dehydro- eleagnine-3-formamido ethylamino or amino-acid remnants. Experiments indicate that the compound of the present invention has stronger smooth muscle relaxing activity and antihistamine activity.
Description
Technical field
The present invention relates to alcaloid-derivatives, relate in particular to the new dehydro eleagnine derivative of a class, its preparation method and application thereof.
Background technology
The leaf energy antiasthmatic-antitussive of climing Fructus Elaeagni and corner piece Fructus Elaeagni, fruit energy astringing to arrest diarrhea, root can stop blooding.Main effective ingredient in climing Fructus Elaeagni and the corner piece Fructus Elaeagni is eleagnine (Lin Qishou, medicinal herb components chemistry, Science Press, 1977,768).The chemical structural formula of eleagnine is as follows:
Eleagnine
The inventor notices, after this Alkaloid dehydrogenation aromatisation or retentive activity or enhanced activity, kept anti-tumor activity by (obtaining yageine) after the banisterine dehydrogenation after for example.The inventor is also noted that the water-soluble degree of this Alkaloid is all low, and bioavailability is all poor.Also there is same problem in eleagnine.In order to overcome these problems, the present invention introduces diazanyl then with eleagnine dehydrogenation aromatisation, amino ethylamino, and amino acid residue provides a series of dehydro eleagnine derivatives.
Summary of the invention
Technical problem to be solved by this invention is with eleagnine dehydrogenation aromatisation, introduces diazanyl then, amino ethylamino, and amino acid residue provides a series of dehydro eleagnine derivatives to overcome the defective of above-mentioned eleagnine.
Technical problem to be solved by this invention realizes by following approach:
A kind of dehydro eleagnine derivative has the structure of following general formula I,
General formula I
Wherein R is diazanyl, amino ethylamino, dehydro eleagnine-3-formamido group ethylamino or amino acid residue.
In the above-mentioned general formula compound, wherein said L-amino acid residue is glycine residue, L-alanine residue, L-valine residue, L-threonine residues, L-phenylalanine residue, L-tyrosine residue, L-leucine residue, L-isoleucine residue, L-proline residue, L-glutaminic acid residue or L-serine residue.
Another technical problem to be solved by this invention provides the synthetic method of above-mentioned general formula compound.
The synthetic method of dehydro eleagnine derivative of the present invention may further comprise the steps:
1) reaction of L-tryptophan and acetaldehyde generates the 1-methyl isophthalic acid under acid catalysis, and 2,3,4-tetrahydrochysene-B-carboline-3-carboxylic acid,
2) with the 1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-B-carboline-3-carboxylic acid and SOCl
2, methanol reaction generates the 1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-B-carboline-3-carboxylate methyl ester,
3) with the 1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-B-carboline-3-carboxylate methyl ester oxidation generates yageine-3-carboxylate methyl ester,
4) dehydro eleagnine-3-carboxylate methyl ester saponification is generated dehydro eleagnine-3-carboxylic acid, then be translated into the active ester of dehydro eleagnine-3-carboxylic acid, active ester and the aminoacid reaction with dehydro eleagnine-3-carboxylic acid at last promptly gets general formula compound of the present invention.
In the above-mentioned synthetic method, wherein the used acid of catalysis L-tryptophan and acetaldehyde reaction is mineral acid in the step 1), is preferably 98% sulphuric acid; Used oxidant is KMnO4 in the step 3); Alkali in the step 4) that dehydro eleagnine-3-carboxylate methyl ester saponification is used is strong inorganic base, is preferably NaOH; Wherein the active ester of the yageine-3-carboxylic acid that reacts with L-aminoacid in the step 4) is the commonly used active ester during polypeptide synthesizes, and for example paranitrophenol ester, N-BTA ester and N-hydroxy-succinamide ester are preferably the N-hydroxy-succinamide ester; Amino acid residue described in the step 4) is glycine residue, L-alanine residue, L-valine residue, L-threonine residues, L-phenylalanine residue, L-tyrosine residue, L-leucine residue, L-isoleucine residue, L-proline residue, L-glutaminic acid residue or L-serine residue.
The pharmacophore of dehydro eleagnine is a B-carboline, the flexible side-chains connection is introduced in the 3-position of B-carboline can reduce the toxicity enhanced activity, and the indole alkaloid of aromatisation is introduced aminoacid can strengthen its biological activity.The present invention introduces aminoacid in the 3-position of dehydro eleagnine can significantly improve its dissolubility, can strengthen dehydro eleagnine absorption in vivo and transhipment accordingly, thereby can significantly improve its anti-histamine activity and smooth muscle relaxation activity.
Description of drawings
The synthetic route chart of Fig. 1 The compounds of this invention, wherein AA is an amino acid residue;
The specific embodiment
Specify the present invention below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
The preparation of The compounds of this invention intermediate
One, 1-methyl isophthalic acid, 2,3, the preparation of 4-tetrahydrochysene-B-carboline-3-carboxylic acid
Stir down 2.0g L-tryptophan is mixed with 0.2ml98% sulphuric acid and 20ml water, in solution, add 2ml40% acetaldehyde then, behind the room temperature reaction 6h, have colorless solid to separate out, use NaHCO
3Neutralization reaction solution leaves standstill 1h to PH6-7, sucking filtration, and dry 2.2g (95%) title compound that gets is colorless solid, mp286-288 ℃.
Two, 1-methyl isophthalic acid, 2,3, the preparation of 4-tetrahydrochysene-B-carboline-3-carboxylate methyl ester
Cryosel is bathed down and slowly drip 1mlSOCl in 10ml methanol
2, remove ice bath behind the reaction 15min, in solution, add the 2g1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-B-carboline-3-carboxylic acid, room temperature reaction spends the night.Have faint yellow solid to separate out, to PH7, leave standstill sucking filtration behind the 15min with 10% sodium carbonate neutralization reaction mixture, 2g (94%) title compound, be the oyster solid.
Three, the preparation of dehydro eleagnine-3-carboxylate methyl ester (1)
(A) 5g (20mmol) 1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-B-carboline-3-carboxylate methyl ester is dissolved in 50ml DMF.Cryosel is bathed and is stirred gradation down and reacts a large amount of heat releases toward interior adding 4.5g (28mmol) KMnO4.Reaction 1h recession deicing is bathed, and room temperature reaction spends the night.The reactant mixture sucking filtration, filtrate chamber's relaxing the bowels with purgatives of warm nature dries up, the light yellow solid that obtains soaks with methanol, leach black residue, filtrate decompression is concentrated into dried, and the yellow solid that obtains merges with the black residue that leaches and uses recrystallizing methanol, gets shallow 3.2g (65%) title compound, be yellow solid, mp.243-244 ℃.FAB-MS：m/e 241[M+H]
+。
(B) with 2.5g (10mmol) 1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-B-carboline-3-carboxylate methyl ester, 0.7g (20mmol) sulfur powder and 20ml anhydrous dimethyl benzene mix and refluxed 4 days.Have a large amount of hydrogen sulfide gas to emit in the reaction, the bottle wall has red crystals to separate out.Stopped reaction places refrigerator overnight with reactant liquor, and filter next day.Filtering residue is washed with the 7ml cold xylene earlier, washes with petroleum ether then, gets 1.6g (67%) title compound, is coffee-like solid, 242 ℃ of mp.
(C) psychrolusia and in stir fast down toward 0.5g (2.1mmol) 1-methyl isophthalic acid, 2,3, add 2.25g (5.1mmol) in 4-tetrahydro-b-carboline-3-carboxylate methyl ester and the 10ml glacial acetic acid, lead tetra-acetate.Reactant mixture stirs 15min, adds 0.5g (5.1mmol) oxalic acid, restir 1h, the precipitation of collecting off-white color.The precipitation of collecting is washed with small amount of methanol, is suspended in 75ml water and chloroform (1: 2v/v) in the mixed solution then.Suspension neutralizes with sodium bicarbonate, filters.Filtering residue is washed with minimum of chloroform, and merging filtrate is told chloroform layer.(3 * 10ml), the chloroform layer of merging spends the night with anhydrous sodium sulfate drying water layer, filters, and filtrate decompression is concentrated into dried, gets 0.25g (50%) title compound, is yellow solid, 242 ℃ of mp with chloroform extraction.
Four, the preparation of dehydro eleagnine-3-carboxylic acid (2)
5g1-methyl-B-carboline-3-carboxylate methyl ester is dissolved in 120ml 2N NaOH, be heated to 60 ℃ of reaction 4h, solid dissolves gradually, and solution becomes clarification, cessation reaction, put and be chilled to room temperature, be neutralized to neutrality, have a large amount of yellow solids to separate out with concentrated hydrochloric acid, standing over night in the refrigerator, sucking filtration gets 3.86g (82%) title compound, is yellow solid, mp292 ℃.FAB-MS(m/e)241[M+H]
+。
The preparation of embodiment 1 N-dehydro eleagnine-3-formylglycine (6a)
240mg (1.0mmol) dehydro eleagnine-3-carboxylic acid is dissolved in the 15ml anhydrous tetrahydro furan, cryosel is bathed and is stirred and adds 116mg (1.0mmol) N-hydroxy-succinamide and 200mg (1.0mmol) DCC down, reactant mixture reacts 2h under ice bath, room temperature reaction 24h.When TLC detected no raw material, reactant mixture filtered, adds 75mg (1.0mmol) glycine in filtrate.Reactant mixture stirring at room 40h, TLC (CHCl
3: CH
3OH=10: 1) show that glycine disappears.Reactant mixture is evaporated to dried.Purification by silica gel column chromatography is washed, used to residue with ether, obtains 226mg (80%) title compound, is colorless solid.Mp170-171℃，FAB-MS(m/e)284[M+H]
+IR(KBr)3434，3363，3232，3087，2960，1660，1604，1580，1545，1453，1373cm
-1.
1H-NMR(DMSO-d6)δ＝11.97(s，1H)，8.83(t，J＝8.2Hz，1H)，8.68(s，1H)，8.36(d，J＝7.8Hz，1H)，7.66(d，J＝8.1Hz，1H)，7.59(t，J＝7.5Hz，1H)，7.29(t，J＝7.5Hz，1H)，4.07(d，J＝4.6Hz，2H)，2.88(s，3H).
The preparation of embodiment 2.N-dehydro eleagnine-3-formyl-L-alanine (6b)
With the operation of embodiment 1, obtain 241mg (81%) title compound from 89mg L-alanine, be colorless solid.Mp216-218℃，[α]
D＝+2(C＝0.5，EtOH/DMSO，4∶1)，FAB-MS(m/e)298[M+H]
+，IR(KBr)3433，3364，3239，3080，2961，1660，1604，1589，1545，1452，1374cm
-1.
1H-NMR(DMSO-d6)δ＝11.98(s，1H)，8.69(d，J＝5.2Hz，1H)，8.68(s，1H)，8.36(d，J＝7.8Hz，1H)，7.65(d，J＝8.1Hz，1H)，7.59(t，J＝7.5Hz，1H)，7.31(t，J＝8.1Hz，1H)，4.53(m，J＝5.1Hz，1H)，2.89(s，3H)，1.47(d，J＝6.9Hz，3H)。
The preparation of embodiment 3.N-dehydro eleagnine-3-formyl-L-valine (6c)
With the operation of embodiment 1, obtain 263mg (81%) title compound from 117mg L-valine, be colorless solid.Mp170-172℃，[α]
D＝+6(C＝0.5，EtOH/DMSO，4∶1)，FAB-MS(m/e)326[M+H]
+IR(KBr)3433，3359，3230，3087，2965，1660，1603，1580，1547，1455，1370cm
-1.
1H-NMR(DMSO-d6)δ＝11.98(s，1H)，8.69(d，J＝4.9Hz，1H)，8.68(s，1H)，8.36(d，J＝7.8Hz，1H)，7.65(d，J＝8.1Hz，1H)，7.59(t，J＝7.5Hz，1H)，7.31(t，J＝8.1Hz，1H)，4.53(m，J＝5.1Hz，1H)，2.89(s，3H)，1.47(d，J＝6.9Hz，3H，).
The preparation of embodiment 4.N-dehydro eleagnine-3-formyl-L-phenylalanine (6d)
With the operation of embodiment 1, obtain 328mg (88%) title compound from 165mg L-phenylalanine, be colorless solid.Mp168-170℃，[α]
D＝+3(C＝0.5，EtOH/DMSO，4∶1)，FAB-MS(m/e)374[M+H]
+，IR(KBr)3435，3364，3232，3082，2960，1660，1601，1585，1551，1452，1374，760cm
-1.
1H-NMR(DMSO-d6)δ＝12.12(s，1H)，8.70(s，1H)，8.35(d，J＝8.1Hz，1H)，7.67(d，J＝7.8Hz，1H)，7.62(t，J＝7.5Hz，1H)，7.32(t，J＝7.8Hz，1H)，7.30(t，J＝7.5Hz，1H)，7.28(d，J＝7.6Hz，2H)，7.25(t，J＝7.4Hz，2H)，4.82(t，J＝6.3Hz，1H)，3.25(d，J＝4.9Hz，2H)，2.85(s，3H).
The preparation of embodiment 5.N-dehydro eleagnine-3-formyl-L-threonine (6e)
With the operation of embodiment 1, obtain 245mg (75%) title compound from 119mg L-threonine, be colorless solid.Mp194-195℃，[α]
D＝+6(C＝0.5，EtOH/DMSO，4∶1)，FAB-MS(m/e)327[M+H]
+.IR(KBr)3433，3358，3239，3080，2960，1665，1604，1580，1547，1452，1376cm
-1.
1H-NMR(DMSO-d6)δ＝11.97(s，1H)，8.90(m，J＝5.2Hz，1H)，8.68(s，1H)，8.38(d，J＝7.8Hz，1H)，7.69(d，J＝8.1Hz，1H)，7.67(t，J＝7.5Hz，1H)，7.34(t，J＝7.5Hz，1H)，4.51(d，J＝5.0Hz，1H)，4.32(m，J＝5.0Hz，1H)，3.16(s，1H)，2.95(s，3H)，1.16(d，J＝6.3Hz，3H).
The preparation of embodiment 6.N-dehydro eleagnine-3-formyl-L-tyrosine (6f)
With the operation of embodiment 1, obtain 293mg (75%) title compound from 181mg L-tyrosine, be colorless solid.Mp268-270℃，[α]
D＝-27(C＝0.5，EtOH/DMSO，4∶1)，FAB-MS(m/e)390[M+H]
+，IR(KBr)3430，3361，3236，3084，2962，1662，1600，1583，1549，1450，1378，762cm
-1.
1H-NMR(DMSO-d6)δ＝12.16(s，1H)，10.82(s，1H)，8.75(s，1H)，8.63(m，J＝5.2Hz，1H)，8.34(d，J＝7.8Hz，1H)，7.66(d，J＝7.8Hz，1H)，7.58(t，J＝7.5Hz，1H)，7.29(t，J＝7.5Hz，1H)，6.98(d，J＝7.5Hz，2H)，6.61(d，J＝7.5Hz，2H)，4.51(m，J＝5.1Hz，1H)，3.14(d，J＝5.3Hz，2H)，2.82(s，3H).
The preparation of embodiment 7.N-dehydro eleagnine-3-formyl-L-leucine (6g)
With the operation of embodiment 1, obtain 295mg (87%) title compound from 131mg L-leucine, be colorless solid.Mp140-140℃，[α]
D＝+5(C＝0.5，EtOH/DMSO，4∶1)，FAB-MS(m/e)340[M+H]
+，IR(KBr)3433，3365，3238，3087，2960，1664，1602，1581，1547，1452，1380cm
-1.
1H-NMR(DMSO-d6)δ＝11.99(s，1H)，8.69(s，1H)，8.59(d，J＝8.7Hz，1H)，8.35(d，J＝7.8Hz，1H)，7.66(d，J＝7.8Hz，1H)，7.57(t，J＝7.5Hz，1H)，7.29(t，J＝7.5Hz，1H)，4.60(d，J＝5.1Hz，1H)，2.86(s，3H)，1.79-1.99(m，J＝5.1Hz，2H)，1.17(m，J＝5.2Hz，1H)，0.94(d，J＝6.0Hz，6H).
The preparation of embodiment 8.N-dehydro eleagnine-3-formyl-L-isoleucine (6h)
With the operation of embodiment 1, obtain 244mg (72%) title compound from 131mg L-isoleucine, be colorless solid.Mp131-132℃[α]
D＝+3(C＝0.5，EtOH/DMSO，4∶1)，FAB-MS(m/e)340[M+H]
+，IR(KBr)3435，3364，3244，3087，2960，1664，1602，1583，1546，1453，1380cm
-1.
1H-NMR(DMSO-d6)δ＝12.02(s，1H)，8.70(s，1H)，8.57(d，J＝8.7Hz，1H)，8.36(d，J＝7.8Hz，1H)，7.66(d，J＝8.1Hz，1H)，7.60(t，J＝7.5Hz，1H)，7.30(t，J＝7.5Hz，1H)，4.53(d，J＝5.1Hz，H)，2.86(s，3H)；2.01(m，J＝5.2Hz，1H)，1.21-1.30(m，J＝5.0Hz，2H)，0.96(d，J＝6.9Hz，3H)，0.84(t，J＝5.3Hz，3H).
The preparation of embodiment 9.N-dehydro eleagnine-3-formyl-L-proline (6i)
With the operation of embodiment 1, obtain 258mg (80%) title compound from 115mg L-proline, be colorless solid.Mp145-147℃，FAB-MS(m/e)324[M+H]
+，IR(KBr)3431，3362，3241，3085，2962，1661，1600，1585，1545，1450，1383cm
-1.
1H-NMR(DMSO-d6)δ＝11.84(s，1H)，8.57(s，1H)，8.43(s，1H)，8.31(d，J＝7.2Hz，1H)，7.63(d，J＝8.1Hz，1H)，7.57(t，J＝7.5Hz，1H)，7.27(t，J＝7.5Hz，1H)，4.49(m，J＝6.2Hz，1H)，3.71(t，J＝6.6Hz，2H)，2.81(s，3H)，2.24(m，J＝6.2Hz，2H)，2.05(t，J＝6.5Hz，2H).
The preparation of embodiment 10.N-dehydro eleagnine-3-formyl-L-glutamic acid (6j)
With the operation of embodiment 1, obtain 266mg (75%) title compound from 147mg L-glutamic acid, be colorless solid.300 ℃ of (decomposition) [α] of Mp
D=+4 (C=0.5, EtOH/DMSO, 4: 1) FAB-MS (m/e) 356[M+H]
+.IR (KBr) 3435,3364,3245,3088,2965,1664,1602,1583,1544,1452,1380cm
-1.
1H-NMR (DMSO-d6) δ=11.99 (s, 1H), 11.87 (s, 1H), 8.73 (s, 1H), 8.30 (d, J=7.8Hz, 1H), 7.60 (d, J=7.8Hz, 1H), 7.55 (t, J=7.5Hz, 1H), 7.27 (t, J=7.2Hz, 1H), 3.30 (m, J=5.8Hz, 1H), 2.79 (s, 3H), 1.90 (t, J=4.5Hz, 2H), 1.13 (m, J=5.5Hz, 2H).
The preparation of embodiment 11.N-dehydro eleagnine-3-formyl-L-aspartic acid (6k)
With the operation of embodiment 1, obtain 273mg (80%) title compound from 133mg L-aspartic acid, be colorless solid.Mp 220-221℃[α]
D＝+5(C＝0.5，EtOH/DMSO，4∶1)，FAB-MS(m/e)342[M+H]
+IR(KBr)3430，3368，3241，3087，2963，1668，1604，1585，1542，1455，1382cm
-1.
1H-NMR(DMSO-d6)δ＝12.02(s，1H)，1189(s，1H)，8.72(s，1H)，8.31(d，J＝7.8Hz，1H)，7.58(d，J＝7.8Hz，1H)，7.55(t，J＝7.5Hz，1H)，7.27(t，J＝7.2Hz，1H)；3.26(m，J＝5.9Hz，1H)，2.81(s，3H)，1.85(d，J＝6.2Hz，2H)。
The preparation of embodiment 12.N-dehydro eleagnine-3-formyl-L-serine (6l)
With the operation of embodiment 1, obtain 250mg (80%) title compound from 105mg L-serine, be colorless solid.Mp168-170 ℃ of (decomposition) [α]
D=+5 (C=0.5, EtOH/DMSO, 4: 1), FAB-MS (m/e) 313[M+H]
+IR (KBr) 3433,3370,3243,3085,2966,1666,1601,1589,1549,1456,1380cm
-1.
1H-NMR (DMSO-d6) δ=12.02 (s, 1H), 8.67 (s, 1H), 8.56 (d, J=8.1Hz, 1H), 8.35 (d, J=7.8Hz, 1H), 7.66 (d, J=7.8Hz, 1H), 7.58 (t, J=7.5Hz, 1H), 7.29 (t, J=7.5Hz, 1H), 4.72 (m, J=5.8Hz, 1H), 3.12 (d, J=5.9Hz, 2H) 2.83 (s, 3H).
The preparation of embodiment 13. dehydro eleagnines-3-formylhydrazine (3)
2.5ml (50.0mmol) N
2H
4.H
2O and 2.0mlCH
3The mixed solution of OH is heated to 80 ℃, in solution, add 480mg (2mmol) B-carboline-3-carboxylate methyl ester that is dissolved in 10ml chloroform and 2ml methanol mixed solution, 2.5h in add, mixture stirring at room to thin layer detects no raw material point, there are a large amount of white solids to separate out, concentrating under reduced pressure removes and desolvates, and residue uses column chromatography (CHCl
3/ MeOH 3: 1, v/v), gets 180mg (38%) title compound, for getting yellow solid, mp.294-295 ℃, FAB-MS (m/e) 241[M+H]
+, 1H-NMR (DMSO-d6) 11.90 (s, 1H), 8.63 (s, 1H), 8.34 (d, J=7.8Hz, 1H), 7.63 (d, J=8.1Hz, 1H, H-5), 7.56 (t, J=7.5Hz, 1H), 7.26 (t, J=7.5Hz, 1H), 4.60 (m, 1H), 2.80 (s, 3H).
The preparation of embodiment 14.3-ethylamino-dehydro eleagnine-3-Methanamide (4)
12ml (180mmol) 1, the 2-ethylenediamine is heated to 85-90 ℃, in solution, add 1g (4.2mmol) B-carboline-3-carboxylate methyl ester that is dissolved in 30ml chloroform and 10ml methanol mixed solution, 2.5h in add, mixture is back to thin layer and detects no raw material point, concentrating under reduced pressure removes and desolvates, and residue uses column chromatography (CHCl
3/ MeOH, 3: 1, v/v), get 797mg (71%) title compound, be yellow solid, mp172-173 ℃.Obtain the product of 20mg (1.78%) 1 and two molecule 1s-methyl-B-carboline-3-carboxylic acid reaction during column chromatography for separation, i.e. N, N '-two dehydro eleagnines-3-formyl ethylenediamine (5).
N, Mp210-211 ℃ of N '-two dehydro eleagnines-3-formyl ethylenediamine (5), FAB-MS (m/e) 477[M+H]
+, 1H-NMR (DMSO-d6) 11.92 (s, 2H), 8.66 (s, 2H), 8.34 (d, J=7.8Hz, 2H), 7.63 (d, J=8.1Hz, 1H), 7.57 (t, J=7.5Hz, 1H), 7.27 (t, J=7.5Hz, 1H), 3.24-3.42 (m, 4H), 2.80 (s, 6H).
The anti-histamine activity of test example 1 The compounds of this invention
One, test material:
1, for test agent: chemical compound 1,2,3,4,5,6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6i, 6j, 6k, 6l that the embodiment of the invention is prepared.
2, laboratory animal: 200-250g Cavia porcellus, male and female are not limit (available from Department Of Medicine, Peking University's laboratory animal portion)
Two, test method and result
The 200-250g Cavia porcellus, male and female are not limit, the head of fiercelying attack is put to death Cavia porcellus, open the abdominal cavity rapidly, take out near the partial ileum of returning blind hole, put into the culture dish that fills tyrode's solution, be divided into the 1.5-2.0cm segment with shears, with the tyrode's solution content of flush away intestinal segment gently, get that wherein two sections are fixed on the brandreth and wholely immerse that (end is fixed in the Magnus' bath, the other end is connected on the tonotransducer), all the other intestinal segments are put into and are filled the triangular flask of using the saturated tyrode's solution of oxygen in advance, and 4 ℃ of preservations (in 24 hours) are standby.Add the 15ml tyrode's solution in the Magnus' bath, contain 5%CO with suitable speed (40 bubbles of per minute bell) feeding
2Oxygen, the water bath with thermostatic control water temperature is controlled at 38 ℃ ± 0.5 ℃, intestinal segment adds the pretension of 0.5-1 gram, incubation was measured after 0.5 hour.
Start monitor, add the solution (being dissolved in 5: 1 mixed solvents of ethanol or ethanol and dimethyl sulfoxide) of one of 15ul blank solvent or each testing sample in the Magnus' bath, be incubated adding (3.5*10 after 5 minutes
-4G/ml) 1.5ul histamine solution (final concentration 3.5*10
-8G/ml), recording curve reaches and stops record after the highest.Clean intestinal segment three times (15ml*3) with the constant temperature tyrode's solution, start monitor, treat to repeat above-mentioned experiment after the baseline stability.Ileum tension force under measuring space blank solvent and the testing sample effect, with the tensile meansigma methods of ileum (being designated as 100%) under the blank solvent effect of adjacent twice mensuration is that benchmark calculates the tensile percent of ileum under the testing sample effect, measure six data points, calculate mean tension percent A, then 1-A is the suppression ratio I of this sample under this concentration, use the SPSS software statistics, the results are shown in Table 1.(add 1.5ul histamine solution and sample solution in the Magnus' bath when measuring anti-histamine activity, add blank solvent and sample solution in the Magnus' bath when measuring " ileum tension force ")
Table 1 chemical compound anti-histamine activity of the present invention
| Chemical compound | Suppression ratio, | P | |
| 1 2 3 4 5 6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l | 7.7±0.0264 5.7±0.0288 10.7±0.0328 24.8±0.05120 41.3±0.03930 11.7±0.0388 -19.3±0.1040 -19.3±0.1040 23.3±0.0634 -15.3±0.0717 -9.00±0.0363 -50.0±0.0657 3.17±0.2032 26.3±0.0534 -16.7±0.0814 36.9±0.0635 -7.50±0.08040 | ＜0.05 ＜0.05 ＜0.05 ＜0.01 ＜0.01 ＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＞0.05 ＜0.01 ＞0.05 ＜0.01 ＜0.01 ＜0.01 ＞0.05 |
N=6, the final concentration of chemical compound are 10
-1Mol/l
Result of the test shows that chemical compound of the present invention has very high anti-histamine activity.
Test example 2 The compounds of this invention ileum diastole activity
One, test material:
1, for test agent: chemical compound 1,2,3,4,5,6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6i, 6j, 6k, 6l that the embodiment of the invention is prepared.
2, laboratory animal: 200-250g Cavia porcellus, male and female are not limit (available from Department Of Medicine, Peking University's laboratory animal portion)
Two, test method and result
The 200-250g Cavia porcellus, male and female are not limit, the head of fiercelying attack is put to death Cavia porcellus, open the abdominal cavity rapidly, take out near the partial ileum of returning blind hole, put into the culture dish that fills tyrode's solution, be divided into the 1.5-2.0cm segment with shears, with the tyrode's solution content of flush away intestinal segment gently, getting wherein two sections is fixed on special shelf and (goes up and wholely immerse that (end is fixed in the Magnus' bath, the other end is connected on the tonotransducer), all the other intestinal segments are put into and are filled the triangular flask of using the saturated tyrode's solution of oxygen in advance, and 4 ℃ of preservations (in 24 hours) are standby.Add the 15ml tyrode's solution in the Magnus' bath, contain 5%CO with suitable speed (40 bubbles of per minute bell) feeding
2Oxygen, Huan's tepidarium water temperature is controlled at 38 ℃ ± 0.5 ℃, intestinal segment adds the pretension of 0.5-1 gram, incubation was measured after 1 hour.
Start monitor, add one of 15ul blank solvent or each testing sample solution (testing sample is dissolved in ethanol or ethanol and 5: 1 mixed solvents of dimethyl sulfoxide) in the Magnus' bath, be incubated 5 minutes and make baseline stability.Ileum tension force under measuring space blank solvent and the testing sample effect, with the tensile meansigma methods of ileum under the blank solvent effect of adjacent twice mensuration is that benchmark calculates the tensile percent of ileum under the testing sample effect, measure six data points, calculate average diastole tension force percent B.The percent of diastole ileum and theoretical value 0 (diastolic rate of non-activity chemical compound and suppression ratio are 0) are done one-way ANOVA significance test, the results are shown in Table 2.
Table 2. chemical compound diastole of the present invention ileum activity
| Chemical compound | Diastolic | P | |
| 1 2 3 4 5 6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l | 21.0±4.07 11.5±5.07 41.0±6.07 51.0±7.07 57.3±1.75 0.83±2.04 24.0±4.82 32.8±6.82 17.8±3.06 27.5±6.35 15.2±4.07 68.2±4.35 17.5±9.48 66.2±3.35 37.5±9.52 70.5±3.44 17.8±5.23 | ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＞0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 |
N=6, final concentration are 10
-1Mol/l
Result of the test shows that chemical compound of the present invention has stronger smooth muscle relaxation activity.
Claims (9)
1, class dehydro eleagnine-3-formamido group acid derivative is the structure of following general formula I:
General formula I
Wherein R is an amino acid residue; Wherein said amino acid residue is glycine residue, L-alanine residue, L-valine residue, L-threonine residues, L-phenylalanine residue, L-tyrosine residue, L-leucine residue, L-isoleucine residue, L-proline residue, L-glutaminic acid residue or L-serine residue.
2, the synthetic method of the described compound of Formula I of claim 1 may further comprise the steps:
1) reaction of L-tryptophan and acetaldehyde generates the 1-methyl isophthalic acid under acid catalysis, and 2,3,4-tetrahydrochysene-B-carboline-3-carboxylic acid,
2) with the 1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-B-carboline-3-carboxylic acid and SOCl
2, methanol reaction generates the 1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-B-carboline-3-carboxylate methyl ester,
3) with the 1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-B-carboline-3-carboxylate methyl ester oxidation generates removes dehydro eleagnine-3-carboxylate methyl ester,
4) dehydro eleagnine-3-carboxylate methyl ester saponification is generated dehydro eleagnine-3-carboxylic acid, then be translated into the active ester of dehydro eleagnine-3-carboxylic acid, active ester and the aminoacid reaction with dehydro eleagnine-3-carboxylic acid at last promptly gets general formula compound of the present invention.
3, according to the described synthetic method of claim 2, the used acid of catalysis L-tryptophan and acetaldehyde reaction is mineral acid in the step 1).
4, according to the described synthetic method of claim 2, wherein used oxidant is KMnO in the step 3)
4
5, according to the described synthetic method of claim 2, wherein the alkali that dehydro eleagnine-3-carboxylate methyl ester saponification is used is strong inorganic base in the step 4).
6, according to the described synthetic method of claim 2, wherein the active ester of the dehydro eleagnine-3-carboxylic acid that reacts with L-aminoacid in the step 4) is the paranitrophenol ester, N-BTA ester or N-hydroxy-succinamide ester.
7, the purposes of the described compound of Formula I of claim 1 in preparation histamine receptor antagonists medicine.
8, the purposes of the described compound of Formula I of claim 1 in preparation smooth muscle relaxation agent medicine.
9, a kind of have anti-histamine activity or an active pharmaceutical composition of diastole smooth muscle, contains the compound of Formula I and the pharmaceutically acceptable carrier of the described structure of claim 1.
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| CN104177377B (en) * | 2013-05-20 | 2020-04-10 | 新疆华世丹药物研究有限责任公司 | 3-diamine β -carboline alkali compound, preparation method thereof, pharmaceutical composition thereof and application thereof |
| CN104744494A (en) * | 2013-12-27 | 2015-07-01 | 新疆华世丹药物研究有限责任公司 | 7 site-connected bis(beta-carboline alkaloid) compound and its preparation method, pharmaceutical composition and use |
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| CN1215333A (en) * | 1996-04-04 | 1999-04-28 | 弗·哈夫曼-拉罗切有限公司 | Use of derivativ |
| CN1370778A (en) * | 2001-12-20 | 2002-09-25 | 浙江医药股份有限公司新昌制药厂 | Beta-tetrahydro carboline carboxylic acid, its RGD conjugate, their synthesis and medical application |
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| CN1215333A (en) * | 1996-04-04 | 1999-04-28 | 弗·哈夫曼-拉罗切有限公司 | Use of derivativ |
| CN1370778A (en) * | 2001-12-20 | 2002-09-25 | 浙江医药股份有限公司新昌制药厂 | Beta-tetrahydro carboline carboxylic acid, its RGD conjugate, their synthesis and medical application |
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