CN101037437A - Flazin analog and preparation method and application thereof - Google Patents
Flazin analog and preparation method and application thereof Download PDFInfo
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- CN101037437A CN101037437A CN 200710065801 CN200710065801A CN101037437A CN 101037437 A CN101037437 A CN 101037437A CN 200710065801 CN200710065801 CN 200710065801 CN 200710065801 A CN200710065801 A CN 200710065801A CN 101037437 A CN101037437 A CN 101037437A
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Abstract
The invention provides Flazin analog (abstract formula I compound) and the preparing method thereof, belonging to medicine synthesis field, meanwhile provides a medicine combination for preventing and treating tumor which has the formula I compound or pharmacological acceptable salt as active components and the applications in the preparation treatment and anti-tumor medicine areas of said compound and its medicine combination.
Description
Technical field:
The invention belongs to the synthetic field of medicine, be specifically related to Flazin analogue and its preparation method, and the application in treatment and prophylaxis of tumours medicine.
Background technology:
1936, Japanese scholar Higashi was separated to a hyperfluorescence compound and called after Flazin first from sake wine (Japanese rice wine), but did not determine its chemical structure (Sci.Pap.Phys.Chem.Res.Inst.1936,15,1060); Up to 1986, Japanese scholar Nakatsuka was a raw material with the Flazin that is separated to from miso (Japanesesoy sauce), by esterification, chemical reactions such as hydrogenation, just infer it chemical structure (Tetrahedron Letters.1986,27,3399-3402); 2002, American scholar Sun also was separated to Flazin from a kind of common Chinese herbal medicine kosam seeds (Brucea javanica), its spectral data of reported first, and rely on 2D-NMR (
1H-
1H COSY, HMQC, HMBC) spectroscopic techniques has carried out full ownership, simultaneously Sun finds that Flazin has anti-tumor activity, can suppress mouse mammary gland cell generation carninomatosis become (Planta Med.2002,68,730-733).The Liu Ji of Kunming Inst. of Botany, Chinese Academy of Sciences opens study group was devoted to seek lead compound always from the higher fungi secondary metabolite from 1997 research (Heterocycles.2002,57,157-163; Chem.Rev.2005,105,2723-2744; Chem.Rev.2006,106,2209-2223; Org.Lett., 2006,8,5749-5752), Dong Ze armies in 2004 etc. also are separated to Flazin from suillusgranulatus (Svillus granvlatvs), and find to have HIV (human immunodeficiency virus)-resistant activity (Chinese Traditional and Herbal Drugs.2006 first, 38,17-19).
Flazin belongs to and has 6,5 in fact, the beta-carboline alkaloid of 6 ring systems, and beta-carboline alkaloid to be a class have important biomolecule learns meaning three ring alkaloid families.As the important member of this family, many beta-carboline alkaloids (as breathing out bright alkali, banisterine) itself are exactly the natural alkaloid of biologically active.Since the potential biological activity, most of beta-carboline alkaloids of known structure synthetic preparation at present from the laboratory.Many being identified among them has potential biological activity (as patent in 1993, new beta-carboline derivatives and preparation thereof and medicinal application, publication number CN 1070403A) to mammalian central nervous system.Senile hypomnesis is treated in being used as of having, senile dementia senile memory dysfunction disease drugs such as (Alzheimer diseases) is (as patent in 2003,1-aryl-β-Ka Lin and thip-analogues thereof, its preparation method and at pharmaceutically application, publication number CN 1456560A).The quilt that has is used as medicine (IKK-2 inhibitor) research (as patent in 2006, being used for the treatment of the β-Ka Lin of inflammatory diseases, publication number CN 1802375A) of inflammatory diseases.The quilt that has is used as the drug research (as patent in 2006, carboline carboxylate derivative, its preparation method and use, publication number CN 1743326A) of cardiovascular disorder.
Also there is the patent report 'Beta '-carboline compound to be used as antitumor drug research (as patent in 2004, Yageine derivates compounds and application thereof, publication number CN 1552711A, patent in 2005,3--aryl-β-Ka Lin-1-ketone compounds and preparation method thereof and application, publication number CN 1611500A, patent in 2006, indole alkaloid derivative, Its Preparation Method And Use, publication number CN 1743327A).
So far, the Flazin analogue that does not contain formula I compound in the prior art has the report of anti-tumor activity, do not contain yet formula I compound as effective constituent at the report of treatment aspect the tumor disease.
Summary of the invention:
The purpose of this invention is to provide a class anti-tumor activity height, and the little new bio alkali Flazin analogue of toxic side effect.
Flazin analogue of the present invention, feature are to have formula I structure:
Wherein in the I structure:
R
4, R
5, R
6, R
7, R
8Can be identical or different, independently the group of representative is selected from: hydrogen, hydroxyl, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, (replacement) benzyloxy, halogen (F, Cl, Br)
R
9The group of representative is selected from: hydrogen, straight or branched (C
1-C
6) alkyl, (replacement) benzyl
R
3The group of representative is selected from: H, CH
2OH, COOH, COOCH
3, CONHNH
2, CONH
2
R
1The group of representative is selected from:
In its Chinese style II or III or the IV structure:
The group of X representative is selected from: NH, O, CH=CH, CH=N, N=CH
The group of Y representative is selected from: NH, O, CH=N
The group of Z representative is selected from: N, CH
R
10The group of representative is selected from: hydrogen, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, methylol, the etherificate methylol, the esterification methylol, halogen (F, Cl, Br), nitro, trifluoromethyl, N, N-dimethylamino
R
11, R
12, R
13, R
14The group of representative is selected from: hydrogen, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, and halogen (F, Cl, Br).
Preferred compounds of the invention are 1,2,3,4,5,6,7,8,9 structural compounds.
Another object of the present invention provides and relates to the preparation method with formula I structure carboline alkaloid Flazin analogue, mainly may further comprise the steps:
1) under the thionyl chloride effect, (replacement) L-tryptophane V and methyl alcohol generate compound VI;
2) compound VI and R
1CHO makees solvent with methylene dichloride, and at molecular sieve, trifluoroacetic acid, trichlorocyanuric acid/N, condensation under dinethylformamide/triethylamine effect, cyclization, dehydrogenation three-step reaction " are treated different things alike " and generated compound VI I;
3) compound VI I can obtain formula I structure carboline alkaloid according to alkylation, reduction, amidated, saponification, enzymatic synthesis condition conventional in the organic synthesis.
R wherein
1, R
3, R
4, R
5, R
6, R
7, R
8, R
9As defined in claim 1.
The embodiment of the invention 1 is described the preparation method of compound 1 in detail, the preparation process of this compound as shown in the formula:
It is the pharmaceutical composition with prophylaxis of tumours of being used for the treatment of of activeconstituents with formula I compound that further purpose of the present invention provides a kind of, and the application of this compound aspect the medicine of preparation treatment and prophylaxis of tumours.
Compound 1 has the remarkable vitro anti-tumor activity, to the EC of human lymphoma cell's strain (Raji), human lung carcinoma cell line (A549), human hepatoma cell strain (HepG2)
50Be respectively 0.06 μ g/mL, 0.28 μ g/mL, 0.16 μ g/mL.
Be used for the treatment of the pharmaceutical composition with prophylaxis of tumours, comprise the compound of at least a formula I or its pharmacy acceptable salt, separately or in conjunction with one or more pharmaceutically acceptable carriers as activeconstituents.
To achieve these goals, the invention provides following technical scheme:
Be used for the treatment of the medicine with prophylaxis of tumours, wherein contain formula I compound and the pharmaceutically acceptable carrier and/or the vehicle of treatment and prophylaxis of tumours significant quantity.
When The compounds of this invention is used as on the medicine, can directly use, perhaps use with the form of pharmaceutical composition.This pharmaceutical composition contains 0.1 ~ 99%, is preferably 0.5 ~ 90% The compounds of this invention, and all the other are acceptable on the pharmacology, nontoxic and inert pharmaceutically acceptable carrier and/or vehicle to humans and animals.
Described pharmaceutical carrier or vehicle are that one or more are selected from solid, semisolid and liquid diluent, filler and pharmaceutical preparation assistant agent.Described pharmaceutical composition is used with the form of per weight dose.But two kinds of form administrations of medicine oral administration of the present invention and injection (quiet notes, intramuscular injection).
Oral available its solid or liquid preparation are as pulvis, tablet, sugar-coat agent, capsule, solution, syrup, pill etc.
Inject available its solid or liquid preparation, as powder injection, solution shape injection etc.
Embodiment:
Further flesh and blood of the present invention is described below in conjunction with embodiment, but content of the present invention is not limited thereto.
The study on the synthesis of The compounds of this invention
All raw materials and/or reagent are known products, or according to the product of known operation preparation.
The structure of compound described in the embodiment synthesis step be according to routine spectroscopic techniques (
1H NMR,
13H NMR, EI-MS FAB-MS) measures.
Embodiment 1: preparation 1-(2 ' quinoline)-6-methoxyl group-β-Ka Lin-3-carboxylic acid (compound 1)
Steps A: synthetic L-5-methoxyl group-tryptophan methyl ester
In 10mmol L-5-methoxyl group-tryptophane, add the dry methyl alcohol of 100mL, under the magnetic agitation, be cooled to below-10 ℃, slowly add the 10mL thionyl chloride, allowed nature be raised to room temperature then, reheat backflow 3h.Excessive methyl alcohol and thionyl chloride are revolved in decompression, add the suitable quantity of water dissolving then, transfer pH value 9-10, use ethyl acetate extraction, merge organic phase, and anhydrous sodium sulfate drying removes solvent under reduced pressure, gets white solid 2.38g, Yield:96%, mp 89-92 ℃, C
13H
16N
2O
3.FAB
+-MS m/z:249 (M+1).
Step B: synthetic 1-(2 ' quinoline)-6-methoxyl group-β-Ka Lin-3-carboxylate methyl ester
To 1mmol L-5-methoxyl group-tryptophan methyl ester, add the 10mL dry methylene chloride in 1mmol 2-quinoline aldehyde and the 200mg 4 molecular sieves, under the nitrogen protection, behind the room temperature magnetic agitation reaction 6h, the trifluoroacetic acid that adds catalytic amount, continue reaction 24h then, add 4mL DMF and 1mL triethylamine again, be cooled to-30 ℃, add 1mmol TCCA (being dissolved among the 1mLDMF), allow it naturally cool to 0 ℃ then, keep 0 ℃ at reaction 2-3h, filtration under diminished pressure is removed 4 molecular sieves then, remove methylene dichloride under reduced pressure, add an amount of trash ice, allow it dissolve naturally, filter, recrystallizing methanol, get faint yellow solid 321.7mg, Yield:84%, mp:162-164 ℃; C
23H
17N
3O
3, FAB
+-MS m/z:384 (M+1)
+.
1H NMR (500MHz, CDCl
3) δ (ppm) 11.82 (1H, s), 9.02 (1H, d, J=8.5Hz), 8.39 (1H, s), 8.36 (1H, d, J=8.0Hz), 8.28 (1H, d, J=8.5Hz), 7.90 (1H, d, J=8.0Hz), 7.78 (2H, t, J=7.5Hz), 7.68 (1H, d, J=6.5Hz), 7.32 (1H, d, J=6.5Hz), 4.10 (3H, s), 3.91 (3H, s).
Step C: synthetic 1-(2 ' quinoline)-6-methoxyl group-β-Ka Lin-3-carboxylic acid
In 0.5mmol 1-(5 ' acetyl oxygen methylene radical-2-furans)-β-Ka Lin-3-carboxylate methyl ester, add 10mL methyl alcohol, under the magnetic agitation, add 1mL sodium hydroxide (1mol/L), reflux, TLC shows that raw material disappears, and removes solvent under reduced pressure, add the suitable quantity of water dissolving then, transfer pH value 5-6, use ethyl acetate extraction, merge organic phase, anhydrous sodium sulfate drying removes solvent under reduced pressure, get faint yellow solid 180.8mg, Yield:98%, 248-250 ℃, C
22H
15N
3O
3.FAB
+-MS m/z:370 (M+1).
1H NMR (500MHz, DMSO-d
6) δ (ppm) 12.26 (1H, s), 9.11 (1H, s), 9.05 (1H, d, J=8.0Hz), 8.77 (1H, d, J=6.5Hz), 8.62 (1H, d, J=8.0Hz), 8.09 (1H, s), 7.98 (2H, t, J=7.5Hz), 7.92 (1H, d, J=8.0Hz), 7.72 (1H, d, J=8.0Hz), 7.34 (1H, d, J=6.5Hz), 3.92 (3H, s).
Embodiment 2 preparation 1-(4 ' trifluoromethyl)-6-methoxyl group-β-Ka Lin-3-carboxylic acid (compound 2)
Steps A: synthetic 1-(4 ' trifluoromethyl)-' trifluoromethylated benzaldehyde is a raw material to 6-methoxyl group-β-Ka Lin-3-carboxylate methyl ester with L-5-methoxyl group-tryptophan methyl ester and 4, operation similar embodiment 1 step B gets faint yellow solid 340.0mg, Yield:85%, mp 165-168 ℃, C
21H
15N
2O
3F
3.FAB
+-MS m/z:401 (M+1).
1H NMR (400MHz, CDCl
3) δ (ppm) 8.89 (1H, s), 8.15 (2H, d, J=8.0Hz), 7.84 (2H, d, J=8.0Hz), 7.68 (1H, d, J=2.4Hz), 7.55 (1H, d, J=8.8Hz), 7.27 (1H, dd, J=2.4Hz, J=8.4Hz), 4.09 (3H, s), 4.00 (3H, s).
Step B: synthetic-(4 ' trifluoromethyl)-6-methoxyl group-β-Ka Lin-3-carboxylic acid is so that 1-(4 ' trifluoromethyl)-6-methoxyl group-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C gets yellow solid 191.0mg, Yield:99%, 240-244 ℃, C
20H
13N
2O
3F
3, FAB
+-MS m/z:387 (M+1).
1H NMR (500MHz, DMSO-d
6) δ (ppm) 11.87 (1H, s), 8.98 (1H, s), 8.27 (2H, d, J=8.0Hz), 8.03 (1H, d, J=2.0Hz), 7.97 (2H, d, J=8.0Hz), 7.57 (1H, d, J=8.5Hz), 7.4 (1H, dd, J=2.4Hz J=8.5Hz), 4.00 (3H, s).
Embodiment 3 preparation 1-(2 ' aminomethyl phenyl)-6-fluoro-beta-carboline-3-carboxylic acid (compound 3)
Steps A: synthetic L-5-fluoro-tryptophan methyl ester
With L-5-fluoro-tryptophane is raw material, and operation similar embodiment 1 steps A gets white solid L-5-fluoro-tryptophan methyl ester 2.24g, Yield:95%, mp 87-89 ℃, C
12H
13FN
2O
2.FAB
+-MS m/z:237 (M+1).
Step B:1-(2 ' phenyl)-6-fluoro-beta-carboline-3-carboxylate methyl ester
With L-5-fluoro-tryptophan methyl ester and 2-tolyl aldehyde is raw material, and operation similar embodiment 1 step B gets yellow solid 273.8mg, Yield:82%, 158-160 ℃, C
20H
15N
2O
2F FAB
+-MS m/z:335 (M+1).
1HNMR (500MHz, CDCl
3) δ (ppm) 10.54 (1H, s), 8.72 (1H, s), 7.71 (1H, d, J=6.7Hz), 7.42 (2H, m), 7.25 (3H, m), 7.16 (1H, m), 3.89 (3H, s), 2.13 (3H, s).
Step C:1-(2 ' phenyl)-6-fluoro-beta-carboline-3-carboxylic acid
So that 1-(2 ' phenyl)-6-fluoro-beta-carboline-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, faint yellow solid 156.8mg, Yield:98%, 236-239 ℃, C
19H
13N
2O
2F, FAB
+-MS m/z:321 (M+1).
1H NMR(500MHz，DMSO-d
6)δ(ppm)11.70(1H，s)，8.98(1H，s)，8.32(1H，d，J＝8.7Hz)，7.60(2H，t，J＝4.5Hz)，7.69(2H，m)，7.46(2H，t，J＝7.7Hz)，2.18(3H，s).
Embodiment 4 preparation 1-(4 ' p-methoxy-phenyl)-6-methyl-β-Ka Lin-3-carboxylic acid (compound 4)
Steps A: synthetic L-5-methyl-tryptophan methyl ester
With L-5-methyl-tryptophane is raw material, and operation similar embodiment 1 steps A gets white solid L-5-methyl-tryptophan methyl ester 2.27g, Yield:98%, mp 90-92 ℃, C
13H
16N
2O
2.FAB
+-MS m/z:233 (M+1).
Step B: synthetic 1-(4 ' p-methoxy-phenyl)-6-methyl-β-Ka Lin-3-carboxylate methyl ester
With L-5-methyl-tryptophan methyl ester and 1mmol 4 ' methoxybenzaldehyde is raw material, and operation similar embodiment 1 step B gets faint yellow solid 297.5mg, Yield:86%, mp 152-154 ℃, C
21H
18N
2O
3.FAB
+-MS m/z:347 (M+1).
1H NMR (400MHz, CDCl
3) δ (ppm): 8.76 (1H, s), 7.96 (1H, s), 7.87 (2H, d, J=7.0Hz), 7.41 (1H, d, J=7.5Hz), 7.37 (1H, d, J=8.0Hz), 7.03 (2H, d, J=7.5Hz), 4.01 (3H, s), 3.84 (3H, s), 2.52 (3H, s).
Step C: synthetic 1-(4 ' p-methoxy-phenyl)-6-methyl-β-Ka Lin-3-carboxylic acid is so that 1-(4 ' p-methoxy-phenyl)-6-methyl-β-Ka Lin-3-carboxylate methyl ester ester is a raw material, operation similar embodiment 1 step C gets yellow solid 162.6mg, Yield:98%, 242-245 ℃, C
20H
16N
2O
3.FAB
+-MS m/z:333 (M+1).
1H NMR (500MHz, DMSO-d
6) δ (ppm): 11.63 (1H, s), 8.71 (1H, s), 8.11 (1H, s), 7.99 (2H, d, J=8.0Hz), 7.54 (1H, d, J=8.0Hz), 7.38 (1H, d, J=8.0Hz), 7.13 (2H, d, J=6.0Hz), 2.50 (3H, s), 2.45 (3H, s).
Embodiment 5 preparation 1-(4 ' trifluoromethyl)-β-Ka Lin-3-carboxylic acid (compound 5)
Steps A: synthetic L-tryptophan methyl ester
With the L-tryptophane is raw material, and operation similar embodiment 1 steps A gets white solid L-tryptophan methyl ester 2.13g, Yield:98%, mp 87-90 ℃, C
12H
14N
2O
2.EI-MS m/z:218 (15%), 159 (10%), 130 (100%), 77 (13%).
Step B: synthetic 1-(4 ' trifluoromethyl)-β-Ka Lin-3-carboxylate methyl ester
' trifluoromethylated benzaldehyde is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 300.5mg, Yield:81%, mp 192-194 ℃, C with L-tryptophan methyl ester and 4
20H
13N
2O
2F
3.FAB
+-MS m/z:371 (M+1).
1H NMR(400MHz，CDCl
3)δ(ppm)：8.82(1H，s)，8.16(1H，d，J＝7.6Hz)，8.04(2H，d，J＝8.0Hz)，7.72(2H，d，J＝8.0Hz)，，7.54(2H，t，J＝8.0Hz)，7.32(1H，d，J＝7.6Hz)，4.00(3H，s).
Step C: synthetic 1-(4 ' trifluoromethyl)-β-Ka Lin-3-carboxylic acid
So that 1-(4 ' trifluoromethyl)-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, yellow solid 174.4mg, Yield:98%, mp 240-242 ℃, C
19H
11N
2O
2F
3.FAB
+-MS m/z:357 (M+1).
1H NMR (500MHz, DMSO-d
6) δ (ppm): 12.00 (1H, s, br), 8.94 (1H, s), 8.42 (1H, d, J=7.5Hz), 8.26 (2H, d, J=8.0Hz), 7.97 (2H, d, J=8.0Hz), 7.66 (1H, d, J=7.5Hz), 7.60 (1H, t, J=7.5Hz), 7.32 (1H, t, J=7.5Hz).
Embodiment 6 preparation 1-(4 ' bromophenyl)-6-fluoro-beta-carboline-3-carboxylic acid (compound 6)
Steps A: synthetic 1-(4 ' bromophenyl)-6-fluoro-beta-carboline-3-carboxylate methyl ester
' bromobenzaldehyde is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 331.1mg, Yield:84%, mp 158-161 ℃, C with L-5-fluoro-tryptophan methyl ester and 4
19H
12N
2O
2BrF, FAB
+-MS m/z:399 (M+1) .401 (M+1).
1H NMR (400MHz, CDCl
3) δ (ppm) 8.67 (1H, s), 7.79 (2H, d, J=8.2Hz), 7.71 (1H, d, J=6.1Hz), 7.56 (2H, d, J=8.2Hz), 7.47 (1H, m), 7.18 (1H, m), 3.89 (3H, s).
Step B: synthetic 1-(4 ' bromophenyl)-6-fluoro-beta-carboline-3-carboxylic acid
So that 1-(4 ' bromophenyl)-6-fluoro-beta-carboline-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, yellow solid 190.5mg, Yield:99%, 241-244 ℃, C
18H
10N
2O
2BrF, FAB
+-MS m/z:385 (M+1), 387 (M+1).
1H NMR (400MHz, DMSO-d
6) δ (ppm) 12.00 (1H, s), 8.97 (1H, s), 8.32 (1H, dd, J=3.8Hz J=7.2Hz), 8.03 (1H, d, J=6.6Hz), 7.84 (1H, d, J=6.6Hz), 7.68 (1H, m), 7.48 (1H, m).
Embodiment 7 preparation 1-(2 ' thiophene)-6-methoxyl group-β-Ka Lin-3-carboxylic acid (compound 7)
Steps A: synthetic 1-(2 ' thiophene)-6-methoxyl group-β-Ka Lin-3-carboxylate methyl ester
' thiophene aldehyde is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 280.5mg, Yield:83%, mp 159-152 ℃, C with L-5-methoxyl group-tryptophan methyl ester and 2
18H
14N
2O
3S, FAB
+-MS m/z:339 (M+1).
1H NMR(400MHz，CDCl
3)δ(ppm)9.21(1H，s)，8.70(1H，s)，7.71(1H，s)，7.53(1H，s)，7.47(1H，d，J＝8.8Hz)，7.41(1H，d，J＝4.0Hz)，7.18(1H，d，J＝8.8Hz)，7.07(1H，t，J＝7.2Hz)，4.06(3H，s).3.95(3H，s)
Step B: synthetic 1-(2 ' thiophene)-6-methoxyl group-β-Ka Lin-3-carboxylic acid
So that 1-(2 ' thiophene)-6-methoxyl group-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, yellow solid 158.7mg, Yield:98%, 242-245 ℃, C
17H
12N
2O
3S, FAB
+-MS m/z:325 (M+1).
1H NMR(500MHz，DMSO-d
6)δ(ppm)11.68(1H，s)，8.84(1H，s)，8.08(1H，d，J＝3.3Hz)，7.96(1H，s)，7.76(1H，d，J＝4.8Hz)，7.64(1H，d，J＝7.2Hz)，7.32(1H，t，J＝4.0Hz)，7.23(1H，m)，3.84(3H，s).
Embodiment 8 preparation 1-(2 ' aminomethyl phenyl)-6-methyl-β-Ka Lin-3-carboxylic acid (compound 8)
Steps A: synthetic 1-(2 ' aminomethyl phenyl)-6-methyl-β-Ka Lin-3-carboxylate methyl ester
' tolyl aldehyde is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 283.8mg, Yield:86%, mp 145-147 ℃ .C with L-5-methyl-tryptophan methyl ester and 2
21H
18N
2O
2, FAB
+-MS m/z:331 (M+1).
1H NMR(400MHz，CDCl
3)δ(ppm)：8.83(1H，s)，7.98(1H，s)，7.45(1H，d，J＝8.0Hz)，7.34(4H，m)，7.24(1H，d，J＝8.0Hz)，3.99(3H，s)，2.52(3H，s)，2.18(3H，s).
Step B: synthetic 1-(2 ' aminomethyl phenyl)-6-methyl-β-Ka Lin-3-carboxylic acid
So that 1-(2 ' aminomethyl phenyl)-6-methyl-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, yellow solid 154.8mg, Yield:98%, 238-240 ℃, C
20H
16N
2O
2, FAB
+-MS m/z:317 (M+1).
1H NMR (500MHz, DMSO-d
6) δ (ppm): 11.03 (1H, s), 8.70 (1H, s), 8.03 (1H, s), 7.39-7.33 (6H, m), 2.11 (3H, s), 1.74 (3H, s).
Embodiment 9 preparation 1-(2 ' bromophenyl)-6-fluoro-beta-carboline-3-carboxylic acid (compound 9)
Steps A: synthetic 1-(2 ' bromophenyl)-6-fluoro-beta-carboline-3-carboxylate methyl ester
' bromobenzaldehyde is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 339.1g, Yield:85%, mp 165-169 ℃, C with L-5-fluoro--tryptophan methyl ester and 2
19H
12N
2O
2BrF.mp: ℃; FAB
+-MS m/z:399 (M+1), 401 (M+3).
1H NMR (400MHz, CDCl
3) δ (ppm): 8.86 (1H, s), 7.83 (1H, d, J=8.0Hz), 7.71 (1H, d, J=8.0Hz), 7.55 (1H, d, J=7.5Hz), 7.46 (1H, t, J=2.5Hz), 7.42 (1H, d, J=5.0Hz), 7.35 (1H, t, J=7.5Hz), 7.29 (1H, t, J=2.0Hz), 4.00 (3H, s)
Step B: synthetic 1-(2 ' bromophenyl)-6-fluoro-beta-carboline-3-carboxylic acid
So that 1-(2 ' bromophenyl)-6-fluoro-beta-carboline-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, yellow solid 186.7mg, Yield:97%, 252-254 ℃, C
18H
11N
2O
2BrF.mp: ℃; FAB
+-MS m/z:385 (M+1), 387 (M+3).
1H NMR (500MHz, DMSO-d
6) δ (ppm): 11.74 (1H, s), 8.99 (1H, s), 8.29 (1H, d, J=8.8Hz), 7.85 (1H, d, J=7.6Hz), 7.51 (1H, t, J=8.0H), 7.47-7.39 (4H, m).
Embodiment 10 preparation 1-(5 ' acetyl-o-methyl-2-furans)-β-Ka Lin-3-carboxylate methyl ester (compound 10)
' acetyl-o-methyl-2-Furan Aldehydes is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 298.4mg, Yield:82%, m.p.153-156 ℃, C with L-tryptophan methyl ester and 5
20H
16N
2O
5.FAB
+-MS m/z:365 (M+1).
1H NMR (400MHz, CDCl
3) δ (ppm): 10.24 (1H, s), 8.73 (1H, s), 8.12 (1H, d, J=8.0Hz), 7.67 (1H, d, J=8.2Hz), 7.56 (1H, m), 7.32 (1H, m), 7.30 (1H, d, J=3.4Hz), 6.58 (1H, d, J=3.4Hz), 5.23 (2H, s), 4.02 (3H, s), 2.15 (3H, s).
Embodiment 11 preparation 1-(5 ' methylol-2-furans)-β-Ka Lin-3-carboxylic acid (compound 11)
With 1-(5 ' methylol-2-furans)-β-Ka Lin-3-carboxylate methyl ester, operation similar embodiment 1 step C, faint yellow solid 150.9mg, Yield:98%, 238-244 ℃, C
17H
12N
2O
4.FAB
+-MS m/z:309 (M+1).
1H NMR(500MHz，DMSO-d
6)δ(ppm)：11.61(1H，s，br)，8.79(1H，s)，8.36(1H，d，J＝7.6Hz)，7.81(1H，d，J＝8.0Hz)，7.60(1H，t，J＝7.5Hz)，7.40(1H，d，J＝2.7Hz)，7.31(1H，t，J＝7.5Hz)，6.60(1H，d，J＝2.6Hz)，4.66(2H，s).
Embodiment 12 preparation 1-(5 ' methylol-2-furans)-β-Ka Lin-3-methane amide (compound 12)
In 0.5mmol 1-(5 ' acetyl-o-methyl-2-furans)-β-Ka Lin-3-carboxylate methyl ester, add 10mL methyl alcohol, under the magnetic agitation, add the 2mL strong aqua, be heated to 40 ℃, TLC shows that raw material disappears, remove solvent under reduced pressure, column chromatography gets faint yellow solid 98.2mg, Yield:64%, mp 194-198 ℃, C
17H
13N
3O
3FAB
+-MS m/z:308 (M+1).
1H NMR (500MHz, DMSO-d
6) δ (ppm): 11.13 (1H, s), 8.76 (1H, s), 8.18 (1H, d, J=8.0Hz), 7.76 (1H, d, J=8.0Hz), 7.60 (1H, t, J=7.5Hz), 7.34 (1H, t, J=7.5Hz), 7.30 (1H, d, J=3.3Hz), 6.50 (1H, d, J=3.0Hz), 4.73 (2H, s).
Embodiment 13 preparation 1-(2-thiophene)-β-Ka Lin-3-formyl hydrazines (compound 13)
Steps A: synthetic 1-(2-thiophene)-β-Ka Lin-3-carboxylate methyl ester
With L-tryptophan methyl ester and 2-thiophene is raw material, and operation similar embodiment 1 step B gets faint yellow solid 261.8mg, Yield:85%, mp 151-154 ℃, C
17H
12N
2O
2S. FAB
+-MS m/z:309 (M+1).
1HNMR (400MHz, CDCl
3) δ (ppm): 8.75 (1H, s), 8.15 (1H, d, J=8.0Hz), 7.82 (1H, d, J=8.0Hz), 7.58 (2H, m), 7.47 (1H, d, J=4.0Hz), 7.33 (1H, m), 7.16 (1H, d, J=4.0Hz), 4.05 (3H, s).
Step B: synthetic 1-(2-thiophene)-β-Ka Lin-3-formyl hydrazine
In 0.5mmol 1-(2-thiophene)-β-Ka Lin-3-carboxylate methyl ester, add 10 mL methyl alcohol, under the magnetic agitation, add 2mL hydrazine hydrate (85%), be heated to 40 ℃, TLC shows that raw material disappears, and removes solvent under reduced pressure, and column chromatography gets faint yellow solid 117.0mg, Yield:76%, 268-271 ℃, C
16H
12N
4OS.FAB
+-MS m/z:309 (M+1).
1H NMR(400MHz，DMSO-d
6)δ(ppm)：11.80(1H，s)，9.31(1H，s)，8.73(1H，s)，8.37(1H，d，J＝8.0Hz)，8.16(1H，d，J＝8.0Hz)，7.77(2H，m)，7.60(1H，t，J＝7.2Hz)，7.33(1H，d，J＝4.0Hz)，7.29(1H，d，J＝3.2Hz)，4.46(2H，s).
Embodiment 14 preparation 1-(4 ' nitrophenyl)-β-Ka Lin-3-carboxylic acid (compound 14)
Steps A: synthetic 1-(4 ' nitrophenyl)-β-Ka Lin-3-carboxylate methyl ester
' nitrobenzaldehyde is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 305.3mg, Yield:88%, mp 151-154 ℃, C with L-tryptophan methyl ester and 4
19H
13N
3O
4.FAB
+-MS m/z:348 (M+1).
1HNMR (500MHz, CDCl
3) δ (ppm): 8.91 (1H, s), 8.42 (2H, d, J=8.5Hz), 8.31 (2H, d, J=8.5Hz), 8.24 (1H, d, J=7.5Hz), 7.69 (1H, d, J=7.5Hz), 7.61 (1H, t, J=7.5Hz), 7.31 (1H, t, J=7.5Hz), 4.05 (3H, s).
Step B: synthetic 1-(4 ' nitrophenyl)-β-Ka Lin-3-carboxylic acid
So that 1-(4 ' nitrophenyl)-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, yellow solid 164.8mg, Yield:99%, mp 241-244 ℃, C
18H
11N
3O
4.FAB
+-MS m/z:334 (M+1).
1H NMR(400MHz，DMSO-d
6)δ(ppm)：12.10(1H，s，br)，8.98(1H，s)，8.46(2H，d，J＝8.8Hz)，7.43(1H，d，J＝8.0Hz)，8.35(2H，d，J＝8.8Hz)，7.69(1H，d，J＝8.0Hz)，7.63(1H，t，J＝7.2Hz)，7.34(1H，t，J＝7.2Hz).
Embodiment 15 preparation 1-(4 ' fluorophenyl)-β-Ka Lin-3-carboxylic acid (compound 15)
Steps A: synthetic 1-(4 ' fluorophenyl)-β-Ka Lin-3-carboxylate methyl ester
' fluorobenzaldehyde is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 259.8mg, Yield:81%, mp 158-159 ℃, C with L-tryptophan methyl ester and 4
17H
14N
2O
2F.FAB
+-MS m/z:322 (M+1).
1HNMR (500MHz, CDCl
3) δ (ppm): 9.75 (1H, s), 8.83 (1H, s), 8.20 (1H, d, J=7.5Hz), 7.91 (2H, t, J=6.5Hz), 7.58 (2H, m), 7.35 (1H, t, J=6.5Hz), 7.18 (2H, t, J=7.5Hz), 3.96 (3H, s), 2.34 (3H, s).
13C NMR (100MHz, CDCl
3) δ (ppm): 166.8,164.4,141.9,141.1,137.3,135.0,133.8,130.4,130.3,129.7,128.7,121.7,121.5,120.7,116.7,115.7,115.5,112.0,52.3.
Step B: synthetic 1-(4 ' fluorophenyl)-β-Ka Lin-3-carboxylic acid
So that 1-(4 ' fluorophenyl)-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, yellow solid 150.4mg, Yield:98%, mp 266-269 ℃, C
16H
12N
2O
2F.FAB
+-MS m/z:308 (M+1).
1H NMR(500MHz，DMSO-d
6)δ(ppm)：11.93(1H，s，br)，8.90(1H，s)，8.41(1H，d，J＝7.5Hz)，8.12(2H，t，J＝6.0Hz)，7.68(1H，d，J＝8.0Hz)，7.59(1H，t，J＝7.5Hz)，7.45(2H，t，J＝7.5Hz)，7.32(1H，t，J＝7.5Hz).
13C NMR(100MHz，DMSO-d
6)δ(ppm)：166.7，163.5，141.5，140.6，137.2，134.4，133.9，130.9，130.8，129.5，128.7，122.0，121.8，120.4，116.3，115.6，115.5，112.7.
Embodiment 16 preparation 1-(5 ' methylol-2-furans)-8-methyl-β-Ka Lin-3-carboxylic acid (compound 16)
Steps A: synthetic L-7-methyl-tryptophan methyl ester
With L-7-methyl-tryptophane is raw material, and operation similar embodiment 1 steps A gets white solid 2.20g, Yield:95%, mp 91-94 ℃, C
13H
16N
2O
2.FAB
+-MS m/z:233 (M+1).
Step B: synthetic 1-(5 ' acetyl oxygen methylene radical-2-furans)-8-methyl-β-Ka Lin-3-carboxylate methyl ester
' acetyl oxygen methylene radical-2-Furan Aldehydes is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 325.0mg, Yield:86%, mp 165-167 ℃ .C with L-7-methyl-tryptophan methyl ester and 5
21H
18N
2O
5.FAB
+-MS m/z:379 (M+1),
1H NMR (400MHz, CDCl
3) δ (ppm): 10.12 (1H, s, br), 8.78 (1H, s), 7.97 (1H, d, J=8.0Hz), 7.62 (1H, d, J=8.0Hz), 7.45 (1H, dd, J=3.5Hz J=8.5Hz), 7.32 (1H, d, J=3.5Hz), 6.63 (1H, d, J=3.5Hz), 5.29 (2H, s), 4.02 (3H, s), 2.56 (3H, s), 2.32 (3H, s).
Step C: synthetic 1-(5 ' methylol-2-furans)-8-methyl-β-Ka Lin-3-carboxylic acid
So that 1-(5 ' acetyl oxygen methylene radical-2-furans)-8-methyl-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, yellow solid 156.8mg, Yield:98%, 249-251 ℃, C
18H
14N
2O
4.FAB
+-MSm/z:321 (M+1)
1H NMR (500MHz, DMSO-d
6) δ (ppm): 11.56 (1H, s, br), 8.77 (1H, s), 8.19 (1H, d, J=8.0Hz), 7.71 (1H, d, J=8.0Hz), 7.47 (1H, t, J=8.0Hz), 7.41 (1H, s), 6.62 (1H, s), 4.68 (2H, s), 2.86 (3H, s).
Embodiment 17 preparation 1-(5 ' methylol-2-furans)-5-methyl-β-Ka Lin-3-carboxylic acid (compound 17)
Steps A: synthetic L-4-methyl-tryptophan methyl ester
With L-4-methyl-tryptophane is raw material, operation similar embodiment 1 steps A, and, get white solid 2.28g, Yield:97%, mp 89-92 ℃, C
13H
16N
2O
2.FAB
+-MS m/z:233 (M+1).
Step B: synthetic 1-(5 ' acetyl oxygen methylene radical-2-furans)-5-methyl-β-Ka Lin-3-carboxylate methyl ester
' acetyl oxygen methylene radical-2-Furan Aldehydes is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 321.3mg, Yield:85%, mp 157-159 ℃, C with L-4-methyl-tryptophan methyl ester and 5
21H
18N
2O
5.FAB
+-MS m/z:379 (M+1)
1H NMR (400MHz, CDCl
3) δ (ppm): 10.12 (1H, s, br), 8.78 (1H, s), 8.02 (1H, d, J=8.0Hz), 7.67 (1H, d, J=8.0Hz), 7.45 (1H, t, J=8.5Hz), 7.32 (1H, d, J=3.5Hz), 6.63 (1H, d, J=3.5Hz), 5.28 (2H, s), 4.05 (3H, s), 2.56 (3H, s), 2.15 (3H, s).
Step C: synthetic 1-(5 ' methylol-2-furans)-5-methyl-β-Ka Lin-3-carboxylic acid
So that 1-(5 ' acetyl oxygen methylene radical-2-furans)-5-methyl-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, yellow solid 155.2mg, Yield:97%, 241-243 ℃, C
18H
14N
2O
4.FAB
+-MSm/z:321 (M+1)
1H NMR (500MHz, DMSO-d
6) δ (ppm): 11.50 (1H, s, br), 8.72 (1H, s), 8.19 (1H, d, J=8.0Hz), 7.71 (1H, d, J=8.0Hz), 7.47 (1H, t, J=8.0Hz), 7.41 (1H, s), 6.62 (1H, s), 4.68 (2H, s), 2.88 (3H, s).
13C NMR (125MHz, DMSO-d
6) δ (ppm): 167.0,157.1,151.2,141.4,132.1,131.6,129.8,128.6,121.8,120.9,120.3,115.3,112.8,112.7,110.7,109.1,55.9,14.8.
Embodiment 18 preparation 1-(5 ' methylol-2-furyl)-7-fluoro-beta-carboline-3-carboxylic acid (compound 18)
Steps A: synthetic L-6-fluoro-tryptophan methyl ester
With L-6-fluoro-tryptophane is raw material, and operation similar embodiment 1 steps A gets white solid L-6-fluoro-tryptophan methyl ester 2.38g, Yield:96%, mp 89-92 ℃, C
12H
13FN
2O
2.FAB
+-MS m/z:237 (M+1).
Step B: synthetic 1-(5 ' acetyl oxygen methylene radical-2-furans)-7-fluoro-beta-carboline-3-carboxylate methyl ester
' acetyl oxygen methylene radical-2-Furan Aldehydes is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 324.7mg, Yield:85%, mp 152-154 ℃, C with L-6-fluoro-tryptophan methyl ester and 5
20H
15FN
2O
5.FAB
+-MS m/z:383 (M+1).
1H NMR (400MHz, CDCl
3) δ (ppm): 10.37 (1H, s, br), 8.73 (1H, s), (8.22 1H, dd, J=1.2Hz J=8.8Hz), 7.71 (1H, dd, J=2.0Hz J=9.2Hz), 7.31 (1H, d, J=3.6Hz), (7.31 1H, dt, J=2.0Hz J=9.2Hz), 6.63 (1H, d, J=3.6Hz), 5.26 (2H, s), 4.02 (3H, s), 2.18 (3H, s).
Step C: synthetic 1-(5 ' methylol-2-furans)-6-fluoro-beta-carboline-3-carboxylic acid
So that 1-(5 ' acetyl oxygen methylene radical-2-furans)-7-fluoro-beta-carboline-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, yellow solid 161.3mg, Yield:99%, 244-246 ℃, C
17H
11FN
2O
4..FAB
+-MSm/z:327 (M+1)
1H NMR (400MHz, CDCl
3) δ (ppm): 11.75 (1H, s, br), 8.80 (1H, s), 8.43 (1H, d, J=8.4Hz), 7.53 (1H, d, J=9.2Hz), 7.38 (1H, d, J=2.4Hz), 7.18 (1H, t, J=8.4Hz), 6.61 (1H, d, J=2.4Hz), 4.66 (2H, s)
Embodiment 19 preparation 1-(5 ' methylol-2-furyl)-3-HMC (compound 19)
To 0.2mmol1-(5 ' acetyl oxygen methylene radical-2-furans)-β-Ka Lin-3-carboxylate methyl ester, among 5mL exsiccant THF and the 5mL exsiccant DMF, add 0.4mmol NaBH
4. room temperature reaction 6h under the nitrogen protection adds 1mLH then
2O, magnetic agitation 30min behind the concentrating under reduced pressure, adds 10mL H again
2O uses ethyl acetate extraction, merges organic phase, and anhydrous sodium sulfate drying removes solvent under reduced pressure, and column chromatography gets yellow solid 42.2mg, Yield:76%, mp221-223 ℃, C
17H
14N
2O
3FAB
--MS m/z:277[M-1]
- 1H NMR (500MHz, DMSO-d
6) δ (ppm): 10.86 (1H, s), 8.12 (1H, d, J=7.6Hz), 8.03 (1H, s), 7.66 (1H, d, J=8.0Hz), 7.54 (1H, t, J=8.5Hz), 7.28 (1H, t, J=3.2Hz), 6.52 (1H, d, J=3.2Hz), 4.91 (2H, s), 4.74 (2H, s).
Embodiment 20 preparation 1-(5 '-methyl-2 '-furans)-β-Ka Lin-3-carboxylic acids (compound 20)
Steps A: 1-(5 '-methyl-2 '-furans)-β-Ka Lin-3-carboxylate methyl ester
' methyl-2-Furan Aldehydes is a raw material, and operation similar embodiment 1 step B gets faint yellow solid, 269mg, Yield:88%, m.p.149-151 ℃, C with L-tryptophan methyl ester and 5
18H
14N
2O
3, FAB
+-MS m/z:307 (M+1).
1HNMR (500MHz, CDCl
3) δ (ppm): 9.63 (1H, s), 8.86 (1H, s), 8.29 (1H, d, J=7.6Hz), 7.73-7.70 (2H, m), 7.46 (1H, d, J=7.6Hz), 6.46 (1H, d, J=3.6Hz), 6.38 (1H, d, J=3.2Hz), 4.16 (3H, s), 2.54 (3H, s).
Step B:1-(5 '-methyl-2 '-furans)-β-Ka Lin-3-carboxylic acid
With 1-(5 '-methyl-2 '-furans)-β-Ka Lin-3-carboxylate methyl ester is raw material, and operation similar embodiment 1 step C gets yellow solid, 144.5mg, Yield:99%, m.p.237-240 ℃, C
17H
12N
2O
3, FAB
+-MS m/z:293 (M+1),
1H NMR (500MHz, DMSO-d
6) δ (ppm): 11.61 (1H, s), 8.78 (1H, s), 8.36 (1H, d, J=8.0Hz), 7.82 (1H, d, J=8.0Hz), 7.61 (1H, t, J=7.5Hz), 7.36 (1H, d, J=1.6Hz), 7.31 (1H, t, J=7.5Hz), 6.40 (1H, s), 2.53 (3H, s).
Embodiment 21: preparation 1-(4 ' quinoline)-6-methoxyl group-β-Ka Lin-3-carboxylic acid (compound 21)
Steps A: synthetic 1-(4 ' quinoline)-6-methoxyl group-β-Ka Lin-3-carboxylate methyl ester
' quinoline aldehyde is raw material, and operation similar embodiment 1 step B gets faint yellow solid 306.4mg, Yield:80%, mp:168-170 ℃ with L-tryptophan methyl ester and 4; C
23H
17N
3O
3, FAB
+-MS m/z:384 (M+1)
+.
1HNMR (500MHz, CDCl
3) δ (ppm) 11.85 (1H, s), 8.95 (1H, d, J=8.5Hz), 8.32 (1H, s), 8.38 (1H, d, J=8.0Hz), 8.24 (1H, d, J=8.5Hz), 7.96 (1H, d, J=8.0Hz), 7.78 (2H, t, J=7.5Hz), 7.68 (1H, d, J=6.5Hz), 7.32 (1H, d, J=6.5Hz), 4.09 (3H, s), 3.92 (3H, s).
Step C: synthetic 1-(4 ' quinoline)-6-methoxyl group-β-Ka Lin-3-carboxylic acid
So that 1-(4 ' quinoline)-6-methoxyl group-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, faint yellow solid 180.8mg, Yield:98%, 248-250 ℃, C
22H
15N
3O
3.FAB
+-MS m/z:370 (M+1).
1H NMR(500MHz，DMSO-d
6)δ(ppm)12.28(1H，s)，9.08(1H，s)，9.02(1H，d，J＝8.0Hz)，8.82(1H，d，J＝6.5Hz)，8.62(1H，d，J＝8.0Hz)，8.00(1H，s)，7.98(2H，t，J＝7.5Hz)，7.89(1H，d，J＝8.0Hz)，7.74(1H，d，J＝8.0Hz)，7.38(1H，d，J＝6.5Hz)，3.95(3H，s).
Embodiment 22: preparation 1-(2 ' quinoline)-β-Ka Lin-3-carboxylate methyl ester (compound 22)
' quinoline aldehyde is raw material, and operation similar embodiment 1 step B gets faint yellow solid 303.5mg, Yield:86%, mp:156-158 ℃ with L-tryptophan methyl ester and 4; C
22H
15N
3O
2, FAB
+-MS m/z:354 (M+1)
+.
1HNMR (500MHz, CDCl
3) δ (ppm) 9.95 (1H, s), 8.95 (1H, d, J=8.5Hz), 8.32 (1H, s), 8.38 (1H, d, J=8.0Hz), 8.24 (2H, t, J=8.0Hz), 7.96 (1H, d, J=8.0Hz), 7.94 (1H, d, J=8.0Hz), 7.78 (2H, t, J=7.5Hz), 7.68 (1H, d, J=6.5Hz), 7.32 (1H, d, J=6.5Hz), 4.01 (3H, s).
Embodiment 23: preparation 1-(2 ' quinoline)-β-Ka Lin-3-carboxylic acid (compound 23)
So that 1-(4 ' quinoline)-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, faint yellow solid 162.7mg, Yield:96%, 258-260 ℃, C
21H
13N
3O
2.FAB
+-MS m/z:340 (M+1).
1HNMR (500MHz, DMSO-d
6) δ (ppm) 12.38 (1H, s), 8.82 (1H, d, J=8.0Hz), 8.62 (1H, d, J=8.0Hz), 8.58 (1H, s), 8.44 (1H, d, J=8.0Hz), 8.26 (2H, t, J=7.5Hz), 7.98 (2H, t, J=7.5Hz), 7.89 (1H, d, J=8.0Hz), 7.74 (1H, d, J=6.5Hz), 7.38 (1H, d, J=6.5Hz), 3.98 (3H, s).
Embodiment 24: preparation 1-(2 ' indyl)-β-Ka Lin (compound 24)
' indolal is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 232.0mg, Yield:82%, mp:238-241 ℃ with look ammonia and 2; C
19H
13N
3, FAB
+-MS m/z:284 (M+1)
+.
1H NMR (500MHz, CDCl
3) δ (ppm): 10.02 (1H, s), 8.65 (1H, d, J=8.0Hz), 8.18 (1H, d, J=8.0Hz), 8.90 (1H, d, J=8.5Hz), 7.76 (1H, d, J=8.0Hz), 7.68 (1H, d, J=6.5Hz), 7.58 (2H, t, J=7.5Hz), 7.52 (1H, d, J=6.5Hz), 7.48 (2H, t, J=7.5Hz), 6.94 (1H, s).
Embodiment 25: preparation 1-(5 ' bromo-2 ' indyl)-β-Ka Lin (compound 25)
' ' indolal is a raw material to bromo-2, and operation similar embodiment 1 step B gets faint yellow solid 282.3mg, Yield:78%, mp:258-262 ℃ with look ammonia and 5; C
19H
12N
3Br, FAB
+-MS m/z:362 (M+1)
+, 364 (M+1)
+.
1H NMR(500MHz，CDCl
3)δ(ppm)：10.25(1H，s)，8.95(1H，d，J＝8.0Hz)，8.38(1H，d，J＝8.0Hz)，8.10(1H，d，J＝8.5Hz)，7.96(1H，d，J＝8.0Hz)，7.89(1H，s)，7.68(1H，d，J＝6.5Hz)，7.62(1H，d，J＝6.5Hz)，7.58(2H，t，J＝7.5Hz)，6.92(1H，s).
Embodiment 26: preparation 1-(2 ' benzofuryl)-β-Ka Lin-3-carboxylic acid (compound 26)
Steps A: synthetic 1-(2 ' benzofuryl)-β-Ka Lin-3-carboxylate methyl ester
' cumarone aldehyde is raw material, and operation similar embodiment 1 step B gets faint yellow solid 277.0mg, Yield:81%, mp:163-165 ℃ with L-tryptophan methyl ester and 2; C
21H
14N
2O
3, FAB
+-MS m/z:343 (M+1)
+.
1HNMR (500MHz, CDCl
3) δ (ppm): 11.05 (1H, s), 8.36 (1H, s), 8.05 (1H, d, J=8.5Hz), 7.98 (1H, d, J=8.0Hz), 7.78 (2H, t, J=7.5Hz), 7.48 (1H, d, J=6.5Hz), 732 (1H, d, J=6.5Hz), 7.20 (2H, t, J=7.5Hz), 6.79 (1H, s), 4.09 (3H, s).
Step C: synthetic 1-(2 ' benzofuryl)-β-Ka Lin-3-carboxylic acid
So that 1-(2 ' benzofuryl)-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, faint yellow solid 160.7mg, Yield:98%, 258-260 ℃, C
20H
12N
2O
3.FAB
+-MS m/z:329 (M+1).
1H NMR(500MHz，CDCl
3)δ(ppm)：12.18(1H，s)，8.28(1H，s)，8.11(1H，d，J＝8.5Hz)，8.02(1H，d，J＝8.0Hz)，7.82(2H，t，J＝7.5Hz)，7.54(1H，d，J＝6.5Hz)，7.38(1H，d，J＝7.0Hz)，7.26(2H，t，J＝7.5Hz)，6.76(1H，s).
Embodiment 27: preparation 1-(2 ' naphthyl)-β-Ka Lin-3-carboxylic acid (compound 27)
Steps A: synthetic 1-(2 ' naphthyl)-β-Ka Lin-3-carboxylate methyl ester
' naphthaldehyde is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 281.6mg, Yield:80%, mp:161-163 ℃ with L-tryptophan methyl ester and 2; C
23H
16N
2O
2, FAB
+-MS m/z:353 (M+1)
+.
1HNMR (500MHz, CDCl
3) δ (ppm) 9.89 (1H, s), 8.45 (1H, d, J=8.5Hz), 8.24 (1H, d, J=8.5Hz), 8.22 (1H, s), 8.18 (1H, d, J=8.0Hz), 7.96 (1H, d, J=8.0Hz), 7.78 (2H, t, J=7.5Hz), 7.65 (1H, d, J=6.5Hz), 7.51 (H, t, J=7.5Hz), 7.45 (1H, d, J=6.5Hz), 7.32 (2H, t, J=6.5Hz), 4.09 (3H, s).
Step C: synthetic 1-(2 ' naphthyl)-β-Ka Lin-3-carboxylic acid
So that 1-(2 ' naphthyl)-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, faint yellow solid 167.3mg, Yield:99%, 262-264 ℃, C
22H
14N
2O
2.FAB
+-MS m/z:339 (M+1).
1HNMR (500MHz, CDCl
3) δ (ppm): 11.85 (1H, s), 8.49 (1H, d, J=8.5Hz), 8.26 (1H, d, J=8.5Hz), 8.20 (1H, s), 8.16 (1H, d, J=8.0Hz), 7.96 (1H, d, J=8.0Hz), 7.78 (2H, t, J=7.5Hz), 7.66 (1H, d, J=7.0Hz), 7.55 (H, t, J=7.5Hz), 7.46 (1H, d, J=7.0Hz), 7.38 (2H, t, J=6.5Hz).
Embodiment 28: preparation 1-(2 ' pyridine)-β-Ka Lin-3-carboxylic acid (compound 28)
Steps A: synthetic 1-(2 ' pyridine)-β-Ka Lin-3-carboxylate methyl ester
' pyridine aldehydes is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 251.4mg, Yield:83%, mp:162-164 ℃ with L-tryptophan methyl ester and 2; C
18H
13N
3O
2, FAB
+-MS m/z:304 (M+1)
+.
1HNMR (400MHz, CDCl
3) δ (ppm) 9.84 (1H, s), 8.31 (1H, d, J=8.0Hz), 8.28 (1H, d, J=8.0Hz), 8.12 (1H, s), 7.86 (1H, d, J=7.6Hz), 7.68 (1H, d, J=7.6Hz), 7.62 (2H, t, J=7.2Hz), 7.32 (2H, t, J=6.5Hz), 3.76 (3H, s).
Step C: synthetic 1-(2 ' pyridine)-β-Ka Lin-3-carboxylic acid
So that 1-(2 ' pyridine)-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, faint yellow solid 141.6mg, Yield:98%, 260-263 ℃, C
17H
11N
3O
2.FAB
+-MS m/z:280 (M+1).
1HNMR (400MHz, DMSO-d
6) δ (ppm) 12.18 (1H, s), 8.38 (1H, d, J=8.0Hz), 8.32 (1H, d, J=7.6Hz), 8.16 (1H, s), 8.92 (1H, d, J=8.0Hz), 7.88 (1H, d, J=8.0Hz), 7.69 (2H, t, J=7.5Hz), 7.54 (2H, t, J=8.0Hz).
Embodiment 29: preparation 1-(2 ' bromophenyl)-6-methyl-β-Ka Lin-3-carboxylic acid (compound 29)
Steps A: synthetic 1-(2 ' bromophenyl)-6-methyl-β-Ka Lin-3-carboxylate methyl ester
' bromobenzaldehyde is a raw material, and operation similar embodiment 1 step B gets faint yellow solid 331.8mg, Yield:84%, mp:168-170 ℃, C with L-5-methyl-tryptophan methyl ester and 2
20H
15N
2O
2Br.FAB
+-MS m/z:395 (M+1), 397 (M+3).
1H NMR (400MHz, CDCl
3) δ (ppm): 8.88 (1H, s), 7.98 (1H, s), 7.10 (1H, d, J=8.0Hz), 7.55 (1H, d, J=7.5Hz), 7.44 (1H, d, J=7.5Hz), 7.37-7.30 (4H, m), 4.00 (3H, s), 2.52 (3H, s).
Step C: synthetic 1-(2 ' bromophenyl)-6-methyl-β-Ka Lin-3-carboxylic acid
So that 1-(2 ' bromophenyl)-6-methyl-β-Ka Lin-3-carboxylate methyl ester is a raw material, operation similar embodiment 1 step C, faint yellow solid 184.7mg, Yield:97%, 258-260 ℃, C
19H
13N
2O
2Br.FAB
+-MS m/z:381 (M+1), 383 (M+3).
1H NMR (500MHz, DMSO-d
6) δ (ppm): 11.56 (1H, s), 8.87 (1H, s), 8.17 (1H, s), 7.83 (1H, d, J=7.5Hz), 7.58 (1H, d, J=7.5Hz), 7.5 1 (1H, t, J=8.0H), 7.47-7.39 (4H, m), 2.48 (3H, s).
The pharmacological research of The compounds of this invention
Embodiment 30 antitumor experiment in vitro
Cell strain
Human promyelocytic leukemia cell strain HL60, human lymphoma cell's strain Raji, human lung carcinoma cell line A549 human lung carcinoma cell line AGZY, human hepatoma cell strain HepG2, human oophoroma cell line HO-8910 and human cervical carcinoma cell strain Hela draw from Shanghai Pharmaceutical Inst., Chinese Academy of Sciences, employing contains the perfect medium of the RPMI1640 pH7.4 of 10% calf serum, 105IU/L penicillin and 100mg/L Streptomycin sulphate, at 37 ℃, 5%CO
2The conventional cultivation under the condition.
Medicine, reagent and instrument
Medicine is Flazin analogue 1-29
The RPMI1640 substratum is a GIBOO company product; Calf serum is available from Hangzhou folium ilicis chinensis company; MTT and DMSO are Sigma company product.Cis-platinum (DDP) is that the biological Pharma Inc. in Geju City, Yunnan produces lot number: 20030501.
Super clean bench (ESCO company, RUC-6R
1), CO2gas incubator (JOUAA company, IGO-150), inverted microscope (LEICA company product, 090-135.001), microplate reader (BIO RAD680), 96/24 well culture plate (NUNCTM company product).
Method
Improvement mtt assay (J.Immunol.Meth.1983,65,55-63 are adopted in the influence of tumor cell proliferation; Cancer Res.1988,48,589-601; Chin.J.Pharm.1993,24,455-457).With HL60, Raji, A549, AGZY, HepG2, HO-8910 and the Hela cell of logarithmic phase, be adjusted into proper concn and inoculate, every hole 90 μ l into 96 well culture plates.The adherent growth cell waits to cultivate adherent back dosing in 24 hours; Be dosing behind the suspension growth cell inoculation.Every hole dosing 10 μ l, each concentration is established 3 parallel holes.The preparation of medicine (Flazin analogue 1-29) is the mother liquor that solvent is made into 10g/L with DMSO.Be diluted in the cell that adds inoculation behind the desired concn with the RPMI1640 nutrient solution again, make its final concentration be respectively 100,10,1,0.1 and 5 of 0.01mg/mL tried concentration.The positive contrast of cis-platinum DDP, with physiological saline preparation, final concentration is respectively 10,1,0.1mg/mL.Because Flazin analogue 1-29 is a coloring matter, so each concentration is all established corresponding acellular blank to get rid of the color interference of sample itself.Negative control is isopyknic nutrient solution.Solvent contrast is respectively 0.01%, 0.1% and 1% DMSO according to the difference of the set concentration of compound.Cell is put 37 ℃ after the dosing, 5%CO
2After hatching 48h (suspension cell) and 72h (attached cell) in the incubator respectively, add MTT (5g/L), every hole 20 μ l, after continuing to cultivate 4h, add three liquid [10%SDS-5% isopropylcarbinol-0.012mol/L HCl (w/v/v)], every hole 100 μ l after placement is spent the night, measure each hole A with microplate reader under the 570nm wavelength
570Value, by formula: cell proliferation inhibition rate %=[(control group A
570-administration group A
570)/control group A
570] * 100%, LOGIT method calculation of half inhibitory concentration IC
50(μ g/ml), Flazin analogue 1-29 is to the IC of the influence of tumor cell proliferation
50Data see Table 1.
Table 1 Flazin analogue anti tumor activity in vitro data
| Compound | HL60 IC 50(μg/ml) | Raji IC 50(μg/ml) | A549 IC 50(μg/ml) | AGZY IC 50(μg/ml) | HepG2 IC 50(μg/ml) | HO8910 IC 50(μg/ml) | Hela IC 50(μg/ml) |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 DDP | - - - - - - - - - - - ＞100 - - ＞100 - - - - ＞100 - - - - - - - - | 0.06 0.17 0.38 0.24 92.52 0.77 0.39 1.07 0.41 ＞100 97.76 ＞100 1.47 ＞100 ＞100 ＞100 14.78 12.17 24.18 ＞100 28.1 8.45 - 21.03 5.10 - - 29.20 33.57 | 0.28 2.90 3.36 7.98 1.33 9.95 - 9.64 1.20 ＞100 53.85 - 69.73 ＞100 - ＞100 ＞100 31.54 - - - - - - - - - - 12.90 0.02 | - - - - 15.12 - 8.44 - - - 24.12 - - - - - - - - - - - ＞100 - - 23.69 19.16 - | 0.16 2.24 0.83 11.40 19.38 14.12 - 3.75 6.29 ＞100 ＞100 ＞100 57.48 ＞100 - ＞100 ＞100 21.65 ＞100 - ＞100 ＞100 - 3.72 8.36 - - 37.02 0.48 | - - - - 0.59 - 0.31 - - - 27.49 - - - - - - - - - - - 3.52 - - 53.53 3.52 - | - - - - 10.11 - - - - - 29.07 - - - - - - - - - - - 62.55 - - ＞100 ＞100 - |
HL60-human promyelocytic leukemia cell strain; Raji--human lymphoma cell strain; The A549-human lung carcinoma cell line; The AGZY--human lung carcinoma cell line; The HepG2-human hepatoma cell strain; The HO-8910--human oophoroma cell line; The strain of Hela--human cervical carcinoma cell; DDP (cis-platinum)-positive control
The dosage form research of The compounds of this invention
Embodiment 31:
Make compound by embodiment 1-29, add vehicle, pelletizing press sheet in compound crystal and 1: 1 ratio of vehicle weight ratio.
Embodiment 32:
Make compound by embodiment 1-29, the capsule preparations method is made capsule routinely.
Embodiment 33:
Make compound by embodiment 1-29, add vehicle, pelletizing press sheet in compound crystal and 1: 2 ratio of vehicle weight ratio.
Embodiment 34:
Make compound by embodiment 1-29, add vehicle, pelletizing press sheet in compound crystal and 1: 3 ratio of vehicle weight ratio.
Embodiment 35:
Tablet: embodiment 1-29 makes compound 100mg
Starch 100mg
Corn steep liquor 17% is an amount of
Magnesium Stearate is an amount of
Embodiment 36:
Capsule: embodiment 1-29 makes compound 100mg
Starch 100mg
Magnesium Stearate is an amount of
The preparation method: embodiment 1-29 is made compound mix with auxiliary agent, sieve, uniform mixing in suitable containers is the mixture that the obtains hard gelatin capsule of packing into.
Embodiment 37:
Ampulla: embodiment 1-29 makes compound 50mg
The preparation method: embodiment 1-29 is made compound dissolution in 2 milliliters of propylene glycol, and filtration gained solution is packed under aseptic condition in the ampoule.
Claims (6)
1, Flazin analogue is characterized in that having formula I structure:
Wherein in the I structure:
R
4, R
5, R
6, R
7, R
8Can be identical or different, independently the group of representative is selected from: hydrogen, hydroxyl, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, (replacement) benzyloxy, halogen (F, Cl, Br)
R
9The group of representative is selected from: hydrogen, straight or branched (C
1-C
6) alkyl, (replacement) benzyl
R
3The group of representative is selected from: H, CH
2OH, COOH, COOCH
3, CONHNH
2, CONH
2
R
1The group of representative is selected from:
In its Chinese style II or III or the IV structure:
The group of X representative is selected from: NH, O, S, CH=CH, CH=N, N=CH
The group of Y representative is selected from: NH, O, CH=N
The group of Z representative is selected from: N, CH
R
10The group of representative is selected from: hydrogen, hydroxyl, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, methylol, the etherificate methylol, the esterification methylol, halogen (F, Cl, Br), nitro, trifluoromethyl, N, N-dimethylamino
R
11, R
12, R
13, R
14Can be identical or different, independently the group of representative is selected from: hydrogen, hydroxyl, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, and halogen (F, Cl, Br).
2, Flazin analogue according to claim 1 is characterized in that described preferred compound has following structural:
3. the preparation method who has formula I structure Flazin analogue in the claim 1 mainly may further comprise the steps:
1) under the thionyl chloride effect, (replacement) L-tryptophane V and methyl alcohol generate compound VI;
2) compound VI and R
1CHO makees solvent with methylene dichloride, and at molecular sieve, trifluoroacetic acid, trichlorocyanuric acid/N, condensation under dinethylformamide/triethylamine effect, cyclization, dehydrogenation three-step reaction " are treated different things alike " and generated compound VI I;
3) compound VI I can obtain formula I structural compounds according to alkylation, reduction, amidated, saponification, enzymatic synthesis condition conventional in the organic synthesis.
4, be used for the treatment of pharmaceutical composition with prophylaxis of tumours, comprise the compound of at least a claim 1 or its pharmacy acceptable salt, separately or in conjunction with one or more pharmaceutically acceptable carriers as activeconstituents.
5, claim 1 or 4 compound and the pharmaceutical composition application in the medicine of preparation prophylaxis of tumours.
6. claim 1 or 4 compound and the pharmaceutical composition application in the medicine of preparation treatment tumour.
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ID=38888638
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| JP2016500080A (en) * | 2012-11-26 | 2016-01-07 | 新疆華世丹薬物研究有限責任公司 | Bis β-carboline compound, production method thereof, pharmaceutical composition and use |
| CN103214486A (en) * | 2013-04-20 | 2013-07-24 | 河北大学 | Beta-carboline derivative or medicinal salt as well as preparation method and anti-tumour application thereof |
| CN103214486B (en) * | 2013-04-20 | 2016-05-11 | 河北大学 | Beta-carboline derivatives or officinal salt, its preparation method and antineoplastic application thereof |
| CN107056779A (en) * | 2017-04-25 | 2017-08-18 | 三峡大学 | A kind of schiff bases fluorescence probe QCS and preparation method thereof |
| CN107056779B (en) * | 2017-04-25 | 2019-03-12 | 三峡大学 | A kind of schiff bases fluorescence probe QCS and preparation method thereof |
| CN107118212A (en) * | 2017-05-26 | 2017-09-01 | 广西师范大学 | A kind of beta-carboline compounds and its synthetic method and application |
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Open date: 20070919 |