CN106008500A - Corynantheidine compounds and preparation method thereof - Google Patents
Corynantheidine compounds and preparation method thereof Download PDFInfo
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- CN106008500A CN106008500A CN201610355504.4A CN201610355504A CN106008500A CN 106008500 A CN106008500 A CN 106008500A CN 201610355504 A CN201610355504 A CN 201610355504A CN 106008500 A CN106008500 A CN 106008500A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Abstract
The invention belongs to the field of medicine and pharmacology, and relates to corynantheidine compounds and a preparation method thereof. The corynantheidine compounds adopt the structures shown in formulas (1) and (2). According to the corynantheidine compounds and the preparation method thereof, tryptamine is adopted as a starting material, and multiple steps of reactions of the Pictet-Spengler reaction, the butyl aluminum lithium hydrogen reduction, the Knoevenagel/hetero-Diels+/-Alder cascade reaction, the hydrogenation reaction and the like are adopted to obtain the corynantheidine analogues with the general formulas (1) and (2). The corynantheidine analogues are the new compounds with direct vascular dilation activity, and have the advantages that the synthetic method is simple and convenient, and easy to control, and the synthesized products are large in yield and high in purity; the prepared products are good in self stability, have a wide modification range, can be used for preparing peripheral vascular dilation type antihypertensive drug candidates, and can be used as potential pharmacological tools.
Description
The application is application number 201310552303X, the applying date2013-11-07, denomination of invention:Corynantheine bases chemical combination
The divisional application of thing and preparation method thereof
Technical field
The invention belongs to medicine, relate to corynantheine alkaloid compound and preparation method thereof.The present invention is with tryptamines for rising
Beginning raw material, through multistep reaction, synthesis obtains corynantheine alkali analog and derivant thereof；Described preparation method has operability
By force, reaction condition is simple, it is easy to control, product purity advantages of higher；The product self stability prepared is good, can be used for preparation and expands
Open peripheral blood tubing resisting hypertension drug candidate, and can be as a kind of potential pharmacological tool.
Background technology
Ramulus Uncariae Cum Uncis (Ucaria) is traditional Chinese medicine for lowering blood pressure, and its main antihypertensive compositions is its contained biology after deliberation
Alkali.In recent years, showing the research of alkaloid in Ramulus Uncariae Cum Uncis, this Alkaloid has a feature of high-efficiency low-toxicity, and corynantheine alkali
(corynantheine) it is one of alkaloid present in Ramulus Uncariae Cum Uncis, so far, there is not yet about corynantheine alkali and similar compound thereof
Monomer medicine activity report research.
It is main by the method that rhynochophylla is carried out natural product extraction currently for the research of alkaloid in Ramulus Uncariae Cum Uncis,
Due to the Rhomotoxine complicated component extracted, the content of each effective monomer fails to understand it is the limitation place of current method.
Summary of the invention
It is an object of the invention to provide corynantheine alkaloid compound and preparation method thereof.
More specifically, the invention provides there is formula (1) and the corynantheine alkaloid compound of (2) structure and preparation side thereof
Method and the application as Pimobendane thing.
Corynantheine alkaloid compound of the present invention, has formula (1) and the structure of (2),
Wherein, R1For hydroxyl, acetoxyl group, propionyloxy, benzyloxy；
R2For hydroxyl, acetoxyl group, propionyloxy, benzyloxy, benzoyloxy, phenyl ring has methyl, halogen, methoxyl group
Substituted benzoyloxy, 1-4 the substituted siloxy of carbon.
Corynantheine alkaloid compound of the present invention passes through following reaction equation (1), (2) and (3) synthetic reaction: reaction equation
(1):
Reagent: (a) (OC2H5) 2CHCH2COOC2H5, TFA, DCM；(b)Cbz-Cl,DCM；(c)(Boc)2O,DCM；(d)
DIHALH,THF；(e)1,2-dihydroxy-furan,EDDA,Meldrum's acid,toluene；(f)K2CO3,H2,
MeOH.；Reaction equation (2):
Reagent: (a) (CH3O)2O,DMAP,TEA,DCM；(b)C2H5COCl,DCM；(c)TBDMSCl,imidazole,
DMF；(d)TEA,parachlorobenzoyl chloride,DCM；(e)TEA,parachlorobenzoyl fluoride,
DCM；
Reaction equation (3):
Reagent:: (i) (CH3O)2O,DMAP,TEA,DCM；(ii)C2H5COCl,DCM；(iii)TBDMSCl,
imidazole,DMF；(iv)TEA,parachlorobenzoyl chloride,DCM；(v)TEA,parachlorobenzoyl
fluoride,DCM；
In above-mentioned reaction equation (1), with tryptamines as raw material, reacted by Pictet-Spengler, the benzyloxycarbonyl group acyl of amine
Changing, the tertbutyloxycarbonyl of amine is acylated, and lithium aluminium hydride reduction synthesis Conan is because of alkali analog 3-ethoxy-4-benzyloxycarbonyl group-1-uncle
Butyl oxygen carbonyl-1,2,3,4-Tetrahydrocarboline (5)；With intermediate 1-ethoxycarbonymetyl-N2-benzyloxycarbonyl group-N12-tertbutyloxycarbonyl
1,2,3,4-Tetrahydrocarboline (4) is initiation material, through butyl aluminum lithium hydrogen reduction, Knoevenagel/hetero-Diels ±
Alder cascade reaction, and hydrogenation hydrogenation reaction acquisition Conan is because of alkali analog 15-first boc methyl-20-ethoxy-N1-uncle
Butyl oxo carbonyl-indole (2,3-c) octahydro quinolizine (8)；
In above-mentioned reaction equation (2), with 3-ethoxy-4-benzyloxycarbonyl group-1-tertiary butyl oxycarbonyl-1,2,3,4-Tetrahydrocarbolines
(5) it is Material synthesis corynantheine alkali analog 9-11；
In above-mentioned reaction equation (3), with 15-first boc methyl-20-ethoxy-N1-tert-butyl group oxo carbonyl-indole (2,3-
And octahydro quinolizine (8) is Material synthesis corynantheine alkali analog 12-16 c)；
More specifically, the preparation method of the corynantheine alkaloid compound of the present invention, it is characterised in that comprise the following steps:
1) by 15-first boc methyl-20-ethoxy-N1-tert-butyl group oxo carbonyl-indole (2,3-c) octahydro quinolizine are molten
In anhydrous methylene chloride, it is sequentially added into triethylamine, DMAP, acetic anhydride, after being stirred at room temperature 1-2 hour, washes
Reactant liquor, dichloromethane extracts, and merges organic facies, and solvent evaporated, column chromatography obtains 15-first boc methyl-20-first carbonyl oxygen second
Base-N1-tert-butyl group oxo carbonyl-indole (2,3-c) octahydro quinolizine；
2) by 15-first boc methyl-20-ethoxy-N1-tert-butyl group oxo carbonyl-indole (2,3-c) octahydro quinolizine are molten
In anhydrous methylene chloride, adding propionyl chloride, after being stirred at room temperature 1-2 hour, washed reaction liquid, dichloromethane extracts, and is associated with
Machine phase, solvent evaporated, column chromatography obtains 15-first boc methyl-20-second carbonyl oxygen ethyl-N1-tert-butyl group oxo carbonyl-indole (2,
3-c) and octahydro quinolizine；
3) by 15-first boc methyl-20-ethoxy-N1-tert-butyl group oxo carbonyl-indole (2,3-c) octahydro quinolizine are molten
In anhydrous DMF, it is sequentially added into imidazoles, t-butyldimethyl silane chlorine, after being stirred at room temperature 2-3 hour, adds
Entering dichloromethane extraction, washed reaction liquid, merge organic facies, solvent evaporated, column chromatography obtains the 15-first tertiary fourth of boc methyl-20-
Base dimethyl-silicon alcoxyl ethyl-N1-tert-butyl group oxo carbonyl-indole (2,3-c) octahydro quinolizine；
4) by 15-first boc methyl-20-ethoxy-N1-tert-butyl group oxo carbonyl-indole (2,3-c) octahydro quinolizine are molten
In anhydrous methylene chloride, it is sequentially added into triethylamine, parachlorobenzoyl chloride, after being stirred at room temperature 2-3 hour, washed reaction liquid, closes
And organic facies, solvent evaporated, column chromatography obtains 15-first boc methyl-20-to chlorobenzene carbonyl oxygen ethyl-N1-tert-butyl group oxo carbonyl
Base-indole (2,3-c) octahydro quinolizine；
5) by 15-first boc methyl-20-ethoxy-N1-tert-butyl group oxo carbonyl-indole (2,3-c) octahydro quinolizine are molten
In anhydrous methylene chloride, it is sequentially added into triethylamine, to fluorobenzoyl chloride, after being stirred at room temperature 2-3 hour, washed reaction liquid, closes
And organic facies, solvent evaporated, column chromatography obtains 15-first boc methyl-20-to fluorobenzene carbonyl oxygen ethyl-N1-tert-butyl group oxo carbonyl
Base-indole (2,3-c) octahydro quinolizine.
Wherein, described step 4) in 15-first boc methyl-20-ethoxy-N1-tert-butyl group oxo carbonyl-indole (2,
3-c) and octahydro quinolizine 8 is prepared as follows:
1) being dissolved in dichloromethane by tryptamines, be sequentially added into 3,3-diethoxy ethyl propionate, trifluoroacetic acid, room temperature is stirred
After mixing 30 hours in saturated sodium bicarbonate and reactant liquor, dichloromethane extraction organic facies, solvent evaporated, column chromatography obtains 1-ethoxy
Carbonyl methyl isophthalic acid, 2,3,4-Tetrahydrocarboline；
2) 1-ethoxycarbonymetyl-1,2,3,4-Tetrahydrocarbolines are dissolved in dichloromethane, are sequentially added into triethylamine, 4-diformazan
Aminopyridine, chloroformyl benzyl ester, the most dry solvent after being stirred at room temperature 2 hours, column chromatography obtains 1-ethoxycarbonymetyl-N2-benzyloxy carbonyl
Base-1,2,3,4-Tetrahydrocarboline；
3) by 1-ethoxycarbonymetyl-N2-benzyloxycarbonyl group-1,2,3,4-Tetrahydrocarbolines are dissolved in dichloromethane, add successively
Enter two t-butyl carbonate, DMAP, 2 hour after solvent evaporated be stirred at room temperature, column chromatography obtain 1-ethoxycarbonymetyl-
N2-benzyloxycarbonyl group-N12-tertbutyloxycarbonyl 1,2,3,4-Tetrahydrocarboline；
4) by 1-ethoxycarbonymetyl-N2-benzyloxycarbonyl group-N12-tertbutyloxycarbonyl 1,2,3,4-Tetrahydrocarboline is dissolved in anhydrous
In oxolane, at-78 DEG C under nitrogen protection, add diisobutyl aluminium hydride, with hydrochloric acid after keeping low temperature to continue to stir 3 hours
Solution cancellation is reacted, and extracts organic facies, is evaporated, and column chromatography obtains 1-carbonyl methyl-N2-benzyloxycarbonyl group-N12-tertbutyloxycarbonyl-1,
2,3,4-Tetrahydrocarboline；
5) by 1-carbonyl methyl-N2-benzyloxycarbonyl group-N12-tertbutyloxycarbonyl 1,2,3,4-Tetrahydrocarbolines are dissolved in toluene, add
EDDA, DHF, isopropylidene malonate, ultrasonic reaction 12 hours, solvent evaporated, post layer under 60 degree
1-(oxolane also (2,3-b) pyrans-4 '-carbonyl-1 '-methyl)-N is obtained after analysis2-benzyloxycarbonyl group-N12-tert-butyl group oxygen carbonyl
Base-1,2,3,4-Tetrahydrocarboline；
6) by 1-(oxolane also (2,3-b) pyrans-4 '-carbonyl-1 '-methyl)-N2-benzyloxycarbonyl group-N12-tert-butyl group oxygen
Carbonyl-1,2,3,4-Tetrahydrocarbolines are dissolved in methanol, add palladium carbon, potassium carbonate, acutely concussion reaction 9 hours, steaming in hydrogen atmosphere
Dry solvent, column chromatography obtains 15-first boc methyl-20-ethoxy-N1-tert-butyl group oxo carbonyl-indole (2,3-c) octahydro
Quinolizine.
Compared with the prior art the present invention has the most a little and effect:
Synthesized corynantheine alkali analog is the new compound with direct diastolic blood vessel activity, and its pharmacologically active is strong
In natural product Ramulus Uncariae cum Uncis alkali, and it is simple to have synthetic route, it is easy to control, and ingredient requirement limitation is little, and productivity is high, it is simple to a large amount of
The features such as production, product self stability is good, has scope of modifying widely, can be used for preparation research expansion peripheral blood tubing and resists
Hypertension drug, and can be as a kind of potential pharmacological tool.
Accompanying drawing explanation
Fig. 1 is that the compound diastole of the present invention is shunk by the complete isolated vascular circle of 1 μM of phyenlephrinium induction generation
Effect, the most all data represent with mean ± standard deviation, N=4-6.
Detailed description of the invention
1: chemical synthesis and preparation
All solvents employed in the present invention, raw material and reagent if not otherwise specified, are analytical pure or chemical pure；Molten
The Non-aqueous processing of agent is conventionally carried out.
Product separates, the instrument of qualification and method: tlc silica gel GF254, column chromatography silochrom (200-300 mesh),
It is Haiyang Chemical Plant, Qingdao to produce；TLC passes through 154nm ultraviolet detection；Nuclear magnetic resonance, NMR uses Varian VXR-500 nuclear-magnetism altogether
Vibration Meter measures, and hydrogen is composed, and carbon is composed with TMS as internal standard.
1.1 synthesis 1-ethoxycarbonymetyl-1,2,3,4-Tetrahydrocarboline (formula 2)
In 500ml round-bottomed flask, it is sequentially added into 200ml and is dissolved with dichloromethane and the 30ml3 of 8g (50mmol) tryptamines,
After 3-diethoxy ethyl propionate, being slowly added dropwise 12ml trifluoroacetic acid under agitation, be stirred at room temperature 30 hours, reaction completes
After regulate pH=7.0, dichloromethane extractive reaction liquid three times with saturated sodium bicarbonate solution, merge organic facies and also use anhydrous slufuric acid
Sodium is dried, and solvent evaporated obtains brown oil, with dichloromethane: methanol=60:1, and the silica gel column chromatography of 300 mesh obtains product
10.9g, yield 84.5%.
(M+H)+:259.159；1H NMR(400Hz,CDCl3)δ:8.64(s,1H,N1-H), 7.49 (d, J=7.68Hz,
1H,H10), 7.34 (d, J=7.93Hz, 1H, H11),7.18-7.08(m,2H,H9,H12), 4.48 (t, J=6.61Hz, 1H, H3),
4.23(dd,J1=14.23Hz, J2=7.09Hz, 2H, H16),3.27-3.07(m,2H,H5), 2.83 (d, J=6.45Hz, 2H,
H5), 2.75 (t, J=4.94Hz, 2H, H14),1.98(s,1H,N4-H), 1.30 (t, J=9.07Hz, 3H, H17)；13CNMR
(CDCl3)δ:135.386,134.876,127.008,121.634,119.187,118.036,110.893,108.865,
61.052,48.672,41.865,40.721,22.479,14.116.
Data show that synthetic product is correct.
1.2 synthesis 1-ethoxycarbonymetyl-N2-benzyloxycarbonyl group-1,2,3,4-Tetrahydrocarboline (formula 3)
In 500ml round-bottomed flask, add 200ml and be dissolved with the dichloromethane solution of 4g (15mmol) compound 2, successively
Add 6.38ml triethylamine, after 0.352g4-dimethylamino naphthyridine, be slowly added dropwise 4.30ml chloroformyl benzyl ester under agitation,
After being stirred at room temperature 2 hours, washing quencher reaction, extraction merges organic facies and is dried with anhydrous sodium sulfate, and solvent evaporated obtains deeply
Yellow oil, with petroleum ether: ethyl acetate=15:1, the silica gel of 300 mesh is successively analysed and is obtained product 4.8g, yield 81.6%.
(M+H)+:392.1；1H NMR(400Hz,CDCl3)δ:8.28(s,1H,N1-H), 7.60 (d, J=7.44Hz, 2H,
H10,H11), 7.55 (d, J=3.13Hz, 4H, H21,H22,H24,H25), 7.25 (t, J=8.22Hz, 1H, H23), 7.15 (t, J=
7.04Hz,1H,H12),7.08(s,1H,H9),5.94-5.88(m,1H,H3),5.14(s,2H,H19),1.28(s,3H,H17),
4.31-4.07(m,2H,H16), 3.53 (dd, J1=12.91Hz, J2=6.54Hz, 2H, H5), 3.42 (dd, J1=9.39Hz,
J2=7.04Hz, 1H, H14), 3.29 (dd, J1=9.39Hz, J2=1.18Hz, 1H, H14), 2.98 (t, J=6.65Hz, 2H,
H6)；13CNMR(CDCl3)δ:169.447,156.312,136.720,136.545,136.065,128.533,128.487,
128.327,128.144,128.068,124.234,122.656,122.305,122.229,113.317,110.291,
66.693,63.903,41.156,40.584,31.588,14.688,14.398.
Data show that synthetic product is correct.
1.3 synthesis 1-ethoxycarbonymetyl-N2-benzyloxycarbonyl group-N12-tertbutyloxycarbonyl 1,2,3,4-Tetrahydrocarboline (formula 4)
In 500ml round-bottomed flask, add 200ml and be dissolved with the dichloromethane solution of 1g (2.5mmol) compound 3,
It is sequentially added into 2.82g Bis(tert-butoxycarbonyl)oxide, 0.195g DMAP under conditions of stirring, is stirred at room temperature 2 hours,
Having reacted rear solvent evaporated and obtained yellow oil, with petroleum ether: ethyl acetate=15:1,300 mesh silica gel column chromatographies separate
Compound, obtains product 1.1g, yield 89.4%.
(M+H)+:493.1；1H NMR(400Hz,CDCl3)δ:7.43-7.29(m,9H,H9,H10,H11,H12,H21,H22,
H23,H24,H25), 6.32 (dd, J1=38.84Hz, J2=9.34Hz, 1H, H3), 5.16 (d, J=14.96Hz, 2H, H19),
4.07(m,2H,H16), 3.32 (t, J=8.51Hz, 1H, H5), 3.06 (d, J=14.28Hz, 1H, H5),2.95-2.82(m,
2H,H14),2.79-2.69(m,2H,H6),1.60(s,9H,H27,H28,H29), 1.18 (t, J=6.94Hz, 3H, H17)；13CNMR(CDCl3)δ:170.118,155.374,149,687,136.560,136.202,133.824,128.533,
128.434,128.350,128.159,127.961,127.748,122.907,122.777,118.051,115.787,
115.299,77.313,67.715,60.595,49.770,39.029,36.719,28.143,21.175,14.040.
Data show that synthetic product is correct.
1.4 synthesis 3-ethoxy-4-benzyloxycarbonyl group-1-tertiary butyl oxycarbonyl-1,2,3,4-Tetrahydrocarboline (formula 5)
1-ethoxycarbonymetyl-N is added in 250ml round-bottomed flask2-benzyloxycarbonyl group-N12-tertbutyloxycarbonyl 1,2,3,4-tetra-
Hydrogen carboline (1g, 2.0mmol), with anhydrous methylene chloride dissolve, under conditions of being stirred at room temperature add sodium borohydride (84mg,
2.2mmol), stirring 1 hour is continued.Reaction 1M hydrochloric acid solution quencher, washed reaction liquid, dichloromethane extraction mixed liquor three
Secondary, merge organic facies, anhydrous sodium sulfate is dried after being spin-dried for and obtains pale yellow oil.With petroleum ether: ethyl acetate=4:1,300
Mesh silica gel column chromatography obtains product 0.8g, productivity 88.9%.
(M+H)+:451；1H NMR(400Hz,cdcl3)δ:7.40-7.22(m,9H,H9,H10,H11,H12,H19,H20,H21,
H22,H23),5.24(dd,2H,H17,J1=21.72Hz, J2=12.13Hz), 4.42 (dd, 1H, J1=13.5Hz, J2=
5.87Hz), 3.65 (t, 2H, J=10.95Hz), 3.46 (s, 1H, H5),3.18-3.12(m,1H,H5),2.87-2.79(m,1H,
H6),2.73-2.68(m,1H,H6),2.37-2.31(m,1H,-OH),2.05-1.89(m,2H,H14),1.73(s,9H,H26,
H27,H28)；13CNMR(cdcl3)δ:156.586,149.871,136.240,136.011,134.998,128.541,
128.259, 128.175,127.855,124.279,122.831,122.694,117.746,115.703,76.992,
67.707,58.887,49.587,36.795,35.537,28.127,28.036,21.190.
1.5 synthesis 1-carbonyl methyl-N2-benzyloxycarbonyl group-N12-tertbutyloxycarbonyl-1,2,3,4-Tetrahydrocarboline (formula 6)
In 250ml three-necked bottle, add 50ml dissolved the dry tetrahydrofuran of 1g (2.0mmol) compound 4, use nitrogen
Get rid of the air in three-necked bottle.It is slowly added dropwise diisobutyl aluminium hydride 5.65ml under-78 DEG C of stirring conditions, keeps low temperature stirring anti-
Answer 3 hours, rapidly system is warmed to room temperature after the hydrochloric acid solution regulation pH=7.0 of 1M after completing, is evaporated reactant liquor organic facies, two
Chloromethanes extraction residual liquid three times, merges organic facies and is dried with anhydrous sodium sulfate, and sucking filtration obtains pale yellow oil.With oil
Ether: ethyl acetate=15:1,300 mesh silica gel column chromatographies obtain product 0.63g, productivity 70.3%.
(M+MeOH+Na)+:503；1H NMR(400Hz,CDCl3)δ:9.95(s,1H,H15),7.56(m,2H,H10,H11),
7.29(m,5H,H19,H20,H21,H22,H23), 6.58 (d, J=9.78Hz, 1H, H12), 6.43 (d, J=9.39Hz, 1H, H9),
5.57-5.51(m,1H,H3),5.21(m,2H,H17),3.29-3.22(m,2H,H5),3.03-2.99(m,2H,H14),2.78-
2.71(m,2H,H6),1.64(s,9H,H25,H26,H27)；13CNMR(CDCl3)δ:201.198,155.603,149.764,
136.576,136.301,136.034,129.051,128.968,128.480,128.152,128.015,123.075,
122.945,118.196,116.122,115.551,76.718,67.608,49.983,47.818,36.307,29.690,
20.565.
Data show that synthetic product is correct.
1.6 synthesis 1-(oxolane also (2,3-b) pyrans-4 '-carbonyl-1 '-methyl)-N2-benzyloxycarbonyl group-N12-tertiary fourth
Base oxygen carbonyl-1,2,3,4-Tetrahydrocarboline (formula 7)
In 500ml ultraphonic pipe, add 100ml dissolved 750mg (1.67mmol) compound 5, be sequentially added into 29.6mg
(0.335mmol) EDDA, 351.6mg (5.022mmol) DHF, 244.7mg (1.674mmol) the third two
The sub-diisopropyl ester of acid, is sealed at 60 DEG C ultrasonic 12 hours, and after completing, solvent evaporated obtains pale yellow oil, with petroleum ether:
Ethyl acetate=4:1,300 mesh silica gel column chromatographies obtain product 420mg, productivity 45.0%
(M+H)+:561.3；1H NMR(400Hz,CDCl3)δ:7.33-7.24(m,9H,H9,H10,H11,H12,H25,H26,
H27,H28,H29),6.17-6.14(m,1H,H18),5.21(s,2H,H23), 5.05 (d, J=4.69Hz, 1H, H3),3.94(t,J
=8.61Hz, 2H, H19),3.27-3.23(m,2H,H5), 2.82 (t, J=5.87Hz, 2H, H6),2.53-2.51(m,1H,
H21),2.44-2.41(m,2H,H16),2.08-2.04(m,2H,H20),1.93-1.88(m,1H,H15),1.84-1.77(m,2H,
H14),1.73(s,9H,H31,H32,H33)；13CNMR(CDCl3)δ:170.545,156.068,150.320,136.537,
136.194,135.684,128.853,128.777,128.617,128.556,128.320,128.228,124.462,
122.976,118.204,115.863,114.926,106.357,77.473,68.797,67.677,50.372,49.793,
39.928,36.833,34.333,28.897,28.288,28.196,21.288.
Data show that synthetic product is correct.
1.7 synthesis 15-first boc methyl-20-ethoxy-N1-tert-butyl group oxo carbonyl-indole (2,3-c) octahydro quinoline
Piperazine (formula 8)
In 500ml hydrogenation pipe, add 100ml be dissolved with the dry methanol of 1g (1.78mmol) compound 6, be sequentially added into
100mg (0.5mmol) potassium carbonate, 35.6mg (0.36mmol) palladium carbon, under hydrogen atmosphere, acutely concussion is reacted 9 hours, anti-after terminating
Answering liquid having sucking filtration on diatomaceous buchner funnel to remove palladium carbon, solvent evaporated obtains pale yellow oil, with petroleum ether: acetic acid
Ethyl ester=2:1,300 mesh silica gel column chromatographies obtain product 480mg, productivity 61.0%.
(M+H)+:443.0；1H NMR(400Hz,CDCl3) δ: 7.44 (d, J=7.05Hz, 1H, H10),7.30-7.26(m,
3H,H9,H11,H12),5.12(s,2H,H22), 4.81 (d, J=20.74Hz, 1H, H28),3.95-3.82(m,2H,H5),3.32
(s,3H,H20),2.83-2.80(m,1H,H3),2.75-2.68(m,4H,H6,H18),2.16-2.12(m,2H,H17),2.09-
2.04(m,2H,H14),1.94-1.92(m,1H,H15),1.71(s,9H,H24,H25,H26),1.62-1.59(m,1H,H16),
1.25-1.18(m,2H,H21)；13CNMR(CDCl3)δ:173.602,150.549,135.485,133.580,127.839,
122.694,121.642,118.150,115.208,114.057,77.320,59.215,55.952,55.533,54.489,
51.607,33.044,32.389,31.924,29.698,28.150,20.451,18.492.
Data show that synthetic product is correct.
1.8 synthesis 3-first carbonyl oxygen ethyl-4-benzyloxycarbonyl group-1-tertbutyloxycarbonyl-1,2,3,4-Tetrahydrocarboline (formula 9)
3-ethoxy-4-benzyloxycarbonyl group-1-tertiary butyl oxycarbonyl-1,2,3,4-tetrahydrochysene is added in 250ml round-bottomed flask
Carboline (100mg, 0.22mmol), 4-DMAP (5mg, 0.04mmol), TEA (46mg, 0.46mmol), it is dissolved in anhydrous dichloromethane
Alkane, adds acetic anhydride (26mg, 0.25mmol), is stirred at room temperature 2 hours.Washed reaction liquid, dichloromethane extraction mixed liquor three times,
Merging organic facies, anhydrous sodium sulfate is spin-dried for after drying, obtains pale yellow oil.With petroleum ether: ethyl acetate=10:1 is for stream
Dynamic phase, 300 mesh silica gel column chromatographies obtain product 86.4mg, productivity 79.8%.
(M+H)+:493.1；1H NMR(400Hz,cdcl3)δ:7.41-7.21(m,9H,H9,H10,H11,H12,H21,H22,
H23,H24,H25),5.19-5.11(m,2H,H19),4.56-4.51(m,1H,H3),4.29-4.11(m,2H,H15),3.26-3.21
(m,1H,H5),2.89-2.81(m,1H,H5),2.72-2.65(m,1H,H6),2.39-2.26(m,1H,H6),2.06(s,2H,
H14),1.98(s,3H,H17),1.60(s,9H,H28,H29,H30)；13CNMR(cdcl3)δ:171.139,155.717,
149.809,136.568,136.232,134.731,128.685,128.495,128.426,128.167,128.022,
127.778,124.394,122.823,117.982,115.795,115.230,77.343,67.662,61.639,50.037,
36.597,32.275,28.173,21.236.
1.9 synthesis 3-second carbonyl oxygen ethyl-4-benzyloxycarbonyl group-1-tertbutyloxycarbonyl-1,2,3,4-Tetrahydrocarboline (compounds
10)
3-ethoxy-4-benzyloxycarbonyl group-1-tertiary butyl oxycarbonyl-1,2,3,4-tetrahydrochysene is added in 250ml round-bottomed flask
Carboline (100mg, 0.22mmol), is dissolved in anhydrous methylene chloride, adds propionyl chloride (20mg, 0.25mmol), is stirred at room temperature 1 little
Time.Washed reaction liquid, dichloromethane extraction mixed liquor three times, merge organic facies, anhydrous sodium sulfate is spin-dried for after drying, obtains yellowish
Color grease.With petroleum ether: ethyl acetate=10:1 is flowing phase, and 300 mesh silica gel column chromatographies obtain product 95.0mg, productivity
85.3%.
(M+H)+:507.2；1H NMR(400Hz,cdcl3)δ:7.43-7.21(m,9H,H9,H10,H11,H12,H21,H22,
H23,H24,H25),5.29-5.11(m,2H,H20),4.56-4.51(m,1H,H3),4.30-4.24(m,2H,H15),3.27-3.22
(m,1H,H5),2.89-2.85(m,1H,H5),2.72-2.68(m,2H,H6),2.38-2.22(m,2H,H17),2.05-1.97
(m,2H,H14),1.72(s,9H,H29,H30,H31)；13CNMR(cdcl3)δ:174.463,155.687,149.771,136.545,
135.920,134.754,128.678,128.464,128.403,128.129,127.984,127.748,124.363,
124.241,122.793,117.960,115.772,77.297,67.631,61.517,50.105,36.574,32.305,
28.150,27.998,27.464,27.380,21.213,8.947.
1.10 synthesis 3-benzyloxyethyl-4-benzyloxycarbonyl group-1-tertbutyloxycarbonyl-1,2,3,4-Tetrahydrocarboline (compound 11)
3-ethoxy-4-benzyloxycarbonyl group-1-tertiary butyl oxycarbonyl-1,2,3,4-tetrahydrochysene is added in 250ml round-bottomed flask
Carboline (100mg, 0.22mmol), is dissolved in anhydrous tetrahydro furan, be slowly added at 0 DEG C add sodium hydrogen (6.3mg,
0.26mmol), bromobenzyl (41.4mg, 0.24mmol), stirs 4 hours at 0 DEG C.Washed reaction liquid, dichloromethane extraction mixing
Liquid three times, merges organic facies, and anhydrous sodium sulfate is spin-dried for after drying, obtains pale yellow oil.With petroleum ether: ethyl acetate=
15:1 is flowing phase, and 300 mesh silica gel column chromatographies obtain product 89.0mg, productivity 75.0%.
(M+H)+:541；1H NMR(400Hz,cdcl3)δ:7.52-7.14(m,12H,H10,H11,H17,H18,H19,H20,
H21,H26,H27,H28,H29,H30),7.05(d,1H,H12, J=6.65Hz), 7.00 (s, 1H, H9),5.43-5.32(m,2H,
H15),5.19-5.05(m,2H,H24),4.59-4.42(m,1H,H3),4.15(t,2H,H23, J=5.48Hz), 3.33-3.28
(m,1H,H5),3.00-2.94(m,1H,H5),2.81-2.78(m,2H,H6),2.11-2.07(m,2H,H22),1.49(s,9H,
H33,H34,H35)；13CNMR(cdcl3)δ:155.794,153.301,137.102,136.553,134.860,134.380,
128.754,128.701,128.480,128.411,127.984,127.778,127.672,127.390,126.597,
126.078,126.017,121.969,119.553,118.303,109.993,108.728,81.970,77.023,67.372,
63.697,47.757,37.756,33.189,27.701,20.756.
1.11 synthesis 15-first boc methyl-20-first carbonyl oxygen ethyl-N1-tert-butyl group oxo carbonyl-indole (2,3-c) eight
Hydrogen quinolizine (formula 12)
In the round-bottomed flask of 250ml, add 100ml dissolve 100mg (0.23mmol) 15-first boc methyl-20-hydroxyl
Ethyl-N1-tert-butyl group oxo carbonyl-indole (2,3-c) the dichloromethane solution of octahydro quinolizine, under conditions of stirring successively
Add 26mg (0.25mmol) acetic anhydride, 5mg (0.04mmol) DMAP, 46mg (0.46mmol) triethylamine, room
After temperature stirring added 50ml dichloromethane after 1-2 hour, washing three times, after merging organic facies, anhydrous sodium sulfate is dried, and is evaporated molten
Agent obtains brown oil.With petroleum ether: ethyl acetate=10:1,300 mesh silica gel column chromatographies obtain product 87.6mg, productivity
78.6%.
(M+H)+:485.4；1H NMR(400Hz,CDCl3) δ: 7.94 (d, J=7.43Hz, 1H, H10),7.42(dd,J1=
7.04Hz,J2=6.26Hz, 1H, H11),7.29-7.22(m,2H,H9,H12), 4.14 (t, J=6.65Hz, 2H, H22),3.73
(s,3H,H20),3.00-2,82(m,4H,H5,H6),2.70-2.66(dd,J1=8.22Hz, J2=4.31Hz, 3H, H3,H18),
2.63-2.60(m,1H,H15),2.06(s,4H,H17,H24), 2.02 (d, J=3.92Hz, 2H, H14),1.98-1,83(m,3H,
H24),1.68(s,9H,H26,H27,H28), 1.61 (d, J=2.73Hz, 1H, H16)；13CNMR(CDCl3)δ:173.289,
171.254,150.488,136.728,136.560,129.242,123.784,122.549,117.952,116.991,
115.177,83.701,62.920,55.830,54.016,53.421,51.500,37.131,35.027,33.479,
29.667,28.905,28.127,21.457,21.000.
Data show that synthetic product is correct.
1.12 synthesis 15-first boc methyl-20-second carbonyl oxygen ethyl-N1-tert-butyl group oxo carbonyl-indole (2,3-c) eight
Hydrogen quinolizine (formula 13)
In the round-bottomed flask of 250ml, add 100ml dissolve 100mg (0.23mmol) 15-first boc methyl-20-hydroxyl
Ethyl-N1-tert-butyl group oxo carbonyl-indole (2,3-c) the dry methylene chloride solution of octahydro quinolizine, under conditions of stirring
It is slowly added dropwise 20mg (0.25mmol) propionyl chloride, is stirred at room temperature 1 hour, washed reaction liquid after completing, dichloromethane extraction mixing
Liquid three times, merges organic facies, is dried after being spin-dried for and obtains pale brown oil thing.With petroleum ether: ethyl acetate=10:1,300 mesh silicon
Plastic column chromatography obtains product 96mg, productivity 83.8%.
(M+H)+:499.2；1H NMR(400Hz,CDCl3) δ: 7.93 (d, J=7.82Hz, 1H, H10), 7.42 (d, J=
7.04Hz,1H,H11),7.28-7.21(m,2H,H9,H12), 4.16 (t, J=6.65Hz, 2H, H22),3.73(s,3H,H20),
2.95-2.86(m,3H,H3,H5),2.79-2.72(m,1H,H6), 2.70-3.66 (t, J=7.43Hz, 3H, H6,H18),2.59-
2.56 (d, J=14.48Hz, 1H, H15),2.34(dd,J1=15.26Hz, J2=7.43Hz, 2H, H17),2.05-1,99(m,
2H,H24),1.88-1.81(m,2H,H14),1.68(s,9H,H27,H28,H29),1,58(s,1H,H16),1.33-1.28(m,2H,
H21), 1.15 (t, J=7.44Hz, 3H, H25)；174.608,173.342,150.541,137.277,136.537,129.356,
123.647,122.488,117.921,115.124,83.594,62.889,56.295,54.435,51.470,51.233,
37.230,35.187,33.662,32.000,31.344,29.667,28.143,27.571,21.953,9.115.
Data show that synthetic product is correct.
1.13 synthesis 15-first boc methyl-20-t-butyldimethyl silane oxygen ethyl-N1-tert-butyl group oxo carbonyl-Yin
Diindyl (2,3-c) octahydro quinolizine (formula 14)
In the round-bottomed flask of 250ml, add 100ml dissolve 100mg (0.23mmol) 15-first boc methyl-20-hydroxyl
Ethyl-N1-tert-butyl group oxo carbonyl-indole (2,3-c) the DMF solution of octahydro quinolizine, be sequentially added into
1.36mg (0.02mmol) imidazoles, 38.1mg (0.25mmol) tert-butyl chloro-silicane, it is stirred at room temperature 1-2 hour, completes
Rear washed reaction liquid, dichloromethane extraction mixed liquor three times, merge organic facies, be dried after being spin-dried for and obtain pale brown oil thing.With
Petroleum ether: ethyl acetate=10:1,300 mesh silica gel column chromatographies obtain product 108mg, productivity 84.4%.
(M+H)+:499.2；1H NMR(400Hz,CDCl3) δ: 7.93 (d, J=7.82Hz, 1H, H10), 7.42 (d, J=
7.04Hz,1H,H11),7.28-7.21(m,2H,H9,H12), 4.16 (t, J=6.65Hz, 2H, H22),3.73(s,3H,H20),
2.95-2.86(m,3H,H3,H5),2.79-2.72(m,1H,H6), 2.70-3.66 (t, J=7.43Hz, 3H, H6,H18),2.59-
2.56 (d, J=14.48Hz, 1H, H15),2.34(dd,J1=15.26Hz, J2=7.43Hz, 2H, H17),2.05-1,99(m,
2H,H24),1.88-1.81(m,2H,H14),1.68(s,9H,H27,H28,H29),1,58(s,1H,H16),1.33-1.28(m,2H,
H21), 1.15 (t, J=7.44Hz, 3H, H25)；174.608,173.342,150.541,137.277,136.537,129.356,
123.647,122.488,117.921,115.124,83.594,62.889,56.295,54.435,51.470,51.233,
37.230,35.187,33.662,32.000,31.344,29.667,28.143,27.571,21.953,9.115.
Data show that synthetic product is correct.
1.14 synthesis 15-first boc methyl-20-are to chlorobenzene carbonyl oxygen ethyl-N1-tert-butyl group oxo carbonyl-indole (2,3-c)
And octahydro quinolizine (formula 15)
In the round-bottomed flask of 250ml, add 100ml dissolve 100mg (0.23mmol) 15-first boc methyl-20-hydroxyl
Ethyl-N1-tert-butyl group oxo carbonyl-indole (2,3-c) the dry methylene chloride solution of octahydro quinolizine, under conditions of stirring
It is sequentially added into 25.6mg (0.25mmol) triethylamine, 21.0mg (0.17mmol) DMAP, 44.3mg
(0.25mmol) parachlorobenzoyl chloride, is stirred at room temperature 1-2 hour, washed reaction liquid after completing, dichloromethane extraction mixed liquor three
Secondary, merge organic facies, be dried after being spin-dried for and obtain pale brown oil thing.With petroleum ether: ethyl acetate=10:1,300 mesh silicagel column
Chromatography obtains product 115mg, productivity 86.2%.
(M+H)+:581.4；1H NMR(400Hz,CDCl3)δ:7.96(dd,J1=17.6Hz, J2=8.99Hz, 2H, H10,
H11),7.43-7.22(m,6H,H9,H12,H25,H26,H27,H28), 4.41 (t, J=8.9Hz, 2H, H22),3.70(s,3H,H20),
2.97 (dd, J1=11.35Hz, J2=2.74Hz, 2H, H5),2.90-2.75(m,3H,H6,H3), 2.71 (d, J=7.43Hz,
2H,H18),2.26(s,1H,H15),2.18-1.99(m,4H,H14,H17),1.94-1.87(m,1H,H16),1.69(s,9H,H30,
H31,H32),1.67(s,2H,H21)；13CNMR(CDCl3)δ:173.289,165.734,150.526,139.228,136.964,
136.560,130.934,129.295,128.769,128.632,123.761,122.556,117.960,117.144,
115.169,83.670,63.758,56.196,54.321,53.444,51.477,37.199,35.164,33.654,
32.061,29.561,28.006,21.785.
Data show that synthetic product is correct.
1.15 synthesis 15-first boc methyl-20-are to fluorobenzene carbonyl oxygen ethyl-N1-tert-butyl group oxo carbonyl-indole (2,3-c)
And octahydro quinolizine (formula 16)
In the round-bottomed flask of 250ml, add 100ml dissolve 100mg (0.23mmol) 15-first boc methyl-20-hydroxyl
Ethyl-N1-tert-butyl group oxo carbonyl-indole (2,3-c) the dry methylene chloride solution of octahydro quinolizine, under conditions of stirring
It is sequentially added into 25.6mg (0.25mmol) triethylamine, 21.0mg (0.17mmol) DMAP, 39.6mg
(0.25mmol) to fluorobenzoyl chloride, it is stirred at room temperature 1-2 hour, washed reaction liquid after completing, dichloromethane extraction mixed liquor three
Secondary, merge organic facies, be dried after being spin-dried for and obtain pale brown oil thing.With petroleum ether: ethyl acetate=10:1,300 mesh silicagel column
Chromatography obtains product 114mg, productivity 87.9%.
(M+H)+:565.26；1H NMR(400Hz,CDCl3)δ:8.05(dd,J1=9.00Hz, J2=3.52Hz, 2H,
H10,H11),7.45-7.00(m,6H,H9,H12,H25,H26,H27,H28), 4.40 (t, J=6.26,2H, H22),3.69(s,3H,
H20), 3,06 (t, J=6.26Hz, 2H, H5), 2.90 (d, J=7.04Hz, 2H, H6),2.76(dd,J1=12.13Hz, J2=
3.52Hz,1H,H3), 2.69 (d, J=7.04Hz, 2H, H18), 2.21 (d, J=3.13Hz, 1H, H15),2.11-1.93(m,4H,
H14,H17),1.74(s,1H,H16),1.68(s,9H,H30,H31,H32), 1.66 (d, J=4.3Hz, 2H, H21)；13CNMR
(CDCl3)δ:173.205,166.916,165.620,164.393,150.480,136.576,132.101,132.009,
131.918,129.173,126.482,123.890,122.602,117.990,115.535,114.872,106.212,
83.800,63.461,55.754,53.429,51.485,50.570,37.115,35.011,33.799,31.970,29.667,
28.120,21.267.
Data show that synthetic product is correct.
The compound that table 1 present invention prepares:
2: pharmacologically active detects:
There is the corynantheine alkali analog of formula (1) and (2), carry out in vitro zoopery, Pharmacological Results according to a conventional method
Display, described compound has the activity directly expanding blood vessel, can be further used for preparing antihypertensive drug candidate, especially
It it is the expansion antihypertensive medicine of peripheral blood tubing.
The preparation of 2.1 blood vessel isolated experiment physiological liquids:
Physiological solt solution (Physiological Salt Solution, PSS) its composition is (mM): sodium chloride 115.5,
Potassium chloride 4.6, sodium dihydrogen phosphate 1.3, sodium bicarbonate 22, calcium chloride 2 2.5, magnesium sulfate 4 1.2, glucose 11.1at pH
7.4. weigh glucose 1.98g and sodium bicarbonate powder 2.268g, pour in 1L large beaker, add about 800ml deionization water-soluble
Solve, be simultaneously introduced the sodium chloride of 100 times, potassium chloride, sodium dihydrogen phosphate, magnesium sulfate mother solution 10ml.After mix homogeneously, add 10ml
Calcium chloride mother liquor, adjusting pH is 7.4, is settled to 1L.After solution is added vascular ring bath, persistently use 95%O2And 5%CO2Mixed
Conjunction gas is saturated and utilizes thermostatic water bath to keep physiological liquid at 37 DEG C
The configuration of 2.2 compound solutions:
Accurate Weigh Compound 6-16, with dehydrated alcohol as solvent, preparation becomes the mother solution of 100mM, utilizes ethanol progressively
Dilution becomes 10mM, the solution of 1mM, 100uM, 10uM totally five concentration.During experiment, take 10ul solution and join containing 10ml raw
In the bath of reason saline solution so that it is final concentration of 1 × 10 in bath-4M,1×10-5M,1×10-6M,1×10-7M,1×
10-8M。
The preparation of 2.3 noradrenaline cellulose solutions:
Weighing norepinephrine and add deionized water to be diluted to concentration be 1mM ,-20 DEG C of refrigerator subpackages save backup.Experiment
Time in bath add 10ul solution so that it is bath pipe in final concentration of 10-4M。
With noradrenaline cellulose solution, (concentration described in experiment is in bath pipe the compound method of 2.4 acetylcholine solution
The final concentration of reagent).
2.5 in vitro SD male rat isolated aorta ring strain experiments
Preparatory work of experiment work operates with reference to isolated rat aortic annulus tension force experimental standard, measures compound and receives PE induction
The impact of the antiotasis of contracting.After vascular ring is stable in Kerbs ' physiological liquid, compound group and solvent control group add 10-6M
PE, shrink reach plateau value after, compound group accumulation addition 1 × 10-8M、1×10-7M、1×10-6M、1×10-5M、1×10-4M
Compound, solvent control group accumulation add corresponding isopyknic solvent.Observe and record the change of thoracic aorta ring strain, with
Add 10-6The maximum shrinkage amplitude of the vascular ring of M induction is 100%, calculates after adding variable concentrations compound vasoconstrictive
Amplitude accounts for diastole amplitude and 10 after the percentage ratio of maximum shrinkage amplitude, i.e. dosing-6The vascular ring maximum shrinkage amplitude of M PE induction
Percentage ratio.Set up concentration-response curve, observe compound for causing vasoconstrictive diastole effect.Every vascular ring is only surveyed
One compound.
2.6 statistical method:
To add 10-6The amplitude peak that M PE induction vascular ring shrinks is 100%, after calculating cumulative variable concentrations compound
The change of blood vessel maximum diastole percentage ratio, i.e. diastole amplitude and 10 after dosing-6The vascular ring of M PE induction shrinks amplitude peak
Percentage ratio, obtains the change to blood vessel maximum diastole percentage ratio under variable concentrations of each compound.Experimental data uses blood vessel
The change reflection medicine effect of ring strain value, unit is g.All data represent with mean ± standard deviation, with GraphPad Prism
5 softwares complete.
2.7 experimental results:
The pharmacological results shows: 1) addition of etoh solvent does not affect the tension force of aortic annulus；2) 15 newly synthesizedization
Compound there are 14 tensiometers reducing isolated vascular circle reveal the activity of expansion blood vessel；3) wherein compound 5 and 8 shows
Best pharmacologically active (IC50=2.173,1.293 μMs), 8 compounds all show than natural product Ramulus Uncariae cum Uncis alkali (IC50=
128.5 μMs) higher pharmacologically active.
Table 2 is the half-inhibition concentration IC of the compound of the present invention50(the vasodilatory amplitude of compound is maximum collapse width
Concentration required during degree half).
Table 2
*:No vasodilatory activity。
Claims (5)
1. the corynantheine alkali analog of formula (1)
Wherein, R1For hydroxyl, acetoxyl group, propionyloxy, benzyloxy.
2. the preparation method of the corynantheine alkali analog described in claim 1, it is characterised in that by following reaction equation
(1), (2) and (3),
Wherein, in reaction equation (1), with tryptamines as raw material, being reacted by Pictet-Spengler, the benzyloxycarbonyl group of amine is acylated, amine
Tertbutyloxycarbonyl be acylated, lithium aluminium hydride reduction synthesis Conan because of alkali analog 3-ethoxy-4-benzyloxycarbonyl group-1-tert-butyl group oxygen
Carbonyl-1,2,3,4-Tetrahydrocarboline (5)；With intermediate 1-ethoxycarbonymetyl-N2-benzyloxycarbonyl group-N12-tertbutyloxycarbonyl 1,2,3,
4-Tetrahydrocarboline (4) is initiation material, and through butyl aluminum lithium hydrogen reduction, Knoevenagel/hetero-Diels ± Alder goes here and there
Connection reaction, and hydrogenation hydrogenation reaction acquisition Conan is because of alkali analog 15-first boc methyl-20-ethoxy-N1-tert-butyl group oxygen
For carbonyl-indole (2,3-c) octahydro quinolizine (8)；
In reaction equation (2), with 3-ethoxy-4-benzyloxycarbonyl group-1-tertiary butyl oxycarbonyl-1,2,3,4-Tetrahydrocarbolines (5) are former
Material synthesis corynantheine alkali analog 9-11；
In reaction equation (3), with 15-first boc methyl-20-ethoxy-N1-tert-butyl group oxo carbonyl-indole (2,3-c) octahydro
Quinolizine (8) is Material synthesis corynantheine alkali analog 12-16；
3. the preparation method as described in claim 2, it is characterised in that by reaction equation (1), (2) and (3) synthesis corynantheine alkali
Compounds 5,8-16.
4. the corynantheine alkaloid compound of claim 1 purposes in preparing antihypertensive medicine, described medicine is expansion
The antihypertensive medicine of peripheral blood tubing.
5. the corynantheine alkaloid compound 5,8-16 that the preparation method of claim 2 prepares is in preparing antihypertensive medicine
Purposes, described medicine is the expansion antihypertensive medicine of peripheral blood tubing.
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Citations (1)
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| US4528289A (en) * | 1982-02-12 | 1985-07-09 | Dr. Willmar Schwabe Gmbh & Co. | Corynantheine derivates, processes for their preparation, and their use |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4528289A (en) * | 1982-02-12 | 1985-07-09 | Dr. Willmar Schwabe Gmbh & Co. | Corynantheine derivates, processes for their preparation, and their use |
Non-Patent Citations (1)
| Title |
|---|
| HONGRUI LIU ET AL.: "Synthesis and evaluation of tetrahydro β-carboline derivatives as anticancer agents", 《JOURNAL OF CHINESE PHARMACEUTICAL SCIENCES》 * |
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