CN101429198B - Banisterine derivant and uses thereof - Google Patents
Banisterine derivant and uses thereof Download PDFInfo
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- CN101429198B CN101429198B CN 200710180027 CN200710180027A CN101429198B CN 101429198 B CN101429198 B CN 101429198B CN 200710180027 CN200710180027 CN 200710180027 CN 200710180027 A CN200710180027 A CN 200710180027A CN 101429198 B CN101429198 B CN 101429198B
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Abstract
The invention relates to a yageine derivative and salts of compounds. The invention synthesizes the novel yageine derivative compounds which can strengthen the antineoplastic activity and reduce the toxicity of a nervous system through the structural modification to locus 1, 2, 3, 7 and 9 of beta-carboline parent nuclei of yageine. The compounds can be used for preparing drugs used to treat various tumor diseases through the screening study of in vivo and in vitro anti-tumor experimental models.
Description
Technical field
The invention belongs to the medical compounds field, it relates to beta-carboline alkaloid compounds and application thereof, more specifically, relates to Yageine derivates and the application in antitumor drug thereof.
Background technology
Yageine and analogue thereof have widely pharmacological action, mainly contain two aspects: neural activity and anti-tumor activity.The neural activity of yageine and derivative thereof is mainly manifested in has excitation to pallium and motor center, spinal cord etc., can cause hallucinations, tremble, paroxysmal is fainted from fear, excited pons and cause some specificity action and four limbs stiff; In the research to the antitumor action of the total alkaloid of harmaline that from seed of peganum harmala, extracts, two kinds of mixed biologic alkali finding yageine and banisterine have significant cytotoxicity to 6 kinds of vitro culture human tumor cell lines, 3 kinds of hybrid mouse transplanted tumors and 3 kinds of people's cancer nude mice grafts there are obvious tumor-inhibiting action, have share synergy with cis-platinum or Zorubicin.
The first-class preclinical studies such as antitumor pharmacy, pharmacology and toxicity that the yageine monomer is carried out in grandson hall, comprise researchs such as the formulation such as capsule, pulse released capsule agent and microballoon and quality standard thereof, stability, pharmacokinetics, pharmacological toxicologies, but owing to the remarkable neurotoxicity of finding yageine (main manifestations is for jumping, tremble and distortion etc.) is failed to declare clinical.
Thereafter, the researchist transforms and modifies the chemical structure of yageine, in the hope of obtaining antineoplastic ideal structure.But the anti-tumor activity of disclosed Yageine derivates is still lower at present.For example CN1552711A and WO/2004/106335 disclose the transformation of the chemical structure of harmine having been carried out system, found that anti-tumor in vivo is active and obviously improved and the significantly reduced harmine derivative of neurotoxicity, but the compound of these transformations also only has 46.9% to the tumour inhibiting rate of tumor-bearing mice trial model is the highest.
In sum, existing Yageine derivates is mostly because anti-tumor activity is lower or neurotoxicity is larger, and without potential applicability in clinical practice, therefore demanding a kind of improved Yageine derivates urgently satisfies clinical demand.
Summary of the invention
For solving the defective of above-mentioned prior art, the invention provides the harmine derivative that the new anti-tumor activity of a class is high, do not have neurotoxicity and have potential applicability in clinical practice.
Another object of the present invention provides the purposes of above-claimed cpd aspect the medicine of preparation treatment cancer.
The present invention also provides a kind of pharmaceutical composition, and it comprises these compounds and pharmaceutically acceptable carrier and/or vehicle.
The invention provides the compound of formula I:
Wherein,
R
1To be selected from hydrogen, C
1-6Alkyl, heterocyclic radical, aldehyde radical, carboxyl, carboxylicesters, carboxylate salt,
CH=NNHC (O) NH
2, CH=NNHC (S) NH
2, CH=NOH, CH=NOCH
3, CONHRa, COORb, CH=CHRc, CH=NRd and NHRd, wherein,
Ra is hydrogen, C
1-6Alkyl, single C
1-6Alkylamino or amino-acid residue;
Rb is saccharide residue, and wherein, sugar is hexose, five-carbon sugar, disaccharides or without cyclohexanol;
Rc is aryl or heterocyclic radical;
Rd is C
1-6Alkyl or C
1-6Alkylamino;
R
2To be selected from hydrogen, C
1-6Alkyl, aryl (C
1-6) alkyl;
X is selected from organic acid or inorganic acid radical; Perhaps, R
2Do not exist simultaneously with X;
R
3Be selected from hydrogen, aldehyde radical, CH (OH) SO
3Na, CH=NNHC (O) NH
2, CH=NNHC (S) NH
2, CONHRa, COORb, CH=CHRc and CH=NRd,
Wherein, Ra, Rb, Rc and Rd are as defined above;
R
7To be selected from hydrogen, hydroxyl, C
1-15Alkoxyl group, aryl (C
1-6) alkoxyl group, COCH
2CONHRa, COCH
2COORb; Wherein,
Ra and Rb are as defined above;
R
9To be selected from hydrogen, C
1-6Alkyl, hydroxyl-C
1-6Alkyl, aryl (C
1-6) alkyl;
Condition is:
(1), works as R
1, R
2, R
7And R
9When all being hydrogen, R
3Can not be hydrogen or CONHCH
2CH
2NH
2
(2), work as R
1During for methyl, R
2, R
3, R
7, R
9Can not be hydrogen simultaneously;
(3), work as R
1Be methyl, R
7Be methoxyl group and R
2, R
3When being hydrogen, R
9Can not be hydrogen, C
1-4Alkyl, hydroxyethyl, benzyl or hydrocinnamyl;
(4), work as R
1Be methyl and R
2, R
3And R
9When being hydrogen, R
7Can not be C
1-10Alkoxyl group;
(5), work as R
1Be methyl, R
7Be methoxyl group, R
9Be n-propyl and R
2During for methyl, X is not bromine and iodine;
(6), work as R
1, R
3And R
7All be hydrogen and R
9During for hydrocinnamyl, R
2Can not be hydrogen, benzyl, 4-fluoro benzyl, 3-chloro benzyl or hydrocinnamyl;
(7), work as R
1, R
3, R
7When all being hydrogen, R
2And R
9Can not be methyl, benzyl or ethyl simultaneously;
(8), work as R
1Be methyl, R
3Be hydrogen, R
7Be methoxyl group and R
9During for hydrocinnamyl, R
2Can not be ethyl, butyl, benzyl, 4-fluoro benzyl and hydrocinnamyl;
(9), work as R
1Be methyl, R
2And R
3All be hydrogen and R
9During for hydrocinnamyl, R
7Can not be hydrogen, hydroxyl, C
3-8Alkoxyl group and phenyl (C
1-3) alkoxyl group;
(10), work as R
1Be methyl, R
2Be benzyl, R
3Be hydrogen and R
9During for hydrocinnamyl, R
7Can not be hydrogen, hydroxyl, C
1-8Alkoxyl group and phenyl (C
1-3) alkoxyl group;
(11), work as R
1Be 3-chloro benzyl and R
2, R
3, R
7When entirely being hydrogen, R
9It can not be hydrocinnamyl;
(12), work as R
1Be NHRd and R
2, R
3, R
7When entirely being hydrogen, R
9Can not be hydrogen; Rd is as defined above;
(13), work as R
1Be hydrogen or methyl, R
2, R
7, R
9When being hydrogen, R
3Can not be CONH (CH
2)
nNH
2(n=2 or 4), CONHCH
2CH
2OH;
(14), work as R
1Be hydrogen or methyl, R
3Be CONH (CH
2)
nNH
2(n=2 or 4) or CONHCH
2CH
2OH, R
2And R
7When being hydrogen, R
9Can not be methyl, ethyl, normal-butyl, benzyl or PFBBR.
The compound of formula I and salt thereof, wherein,
R
1Preferably be selected from hydrogen, pyridyl, aldehyde radical, carboxyl, carboxylicesters, carboxylate salt, CH=NNHC (S) NH
2, CONHRa, COORb, CH=CHRc and NHRd, wherein,
Ra is C
1-2Alkyl, single C
2-6Alkylamino or L-amino-acid residue,
Rb is glucose, wood sugar, ribose, ribodesose or without cyclohexanol,
Rc is phenyl or heterocyclic radical,
Rd is C
1-2Alkyl or C
2-6Alkylamino.
The compound of formula I and salt thereof, wherein,
R
1Be more preferably and be selected from hydrogen, pyridyl, carboxylic acid, ethyl ester, carboxylic acid sodium, CH=NNHC (S) NH
2, CONHRa, COORb, CH=CHRc and NHRd, wherein,
Ra is L-Phe residue, L-tryptophane residue, TYR residue,
Rb is glucose, ribose or ribodesose,
Rc is 4-p-methoxy-phenyl or 4-nitrophenyl,
Rd is C
2-4Alkylamino.
The compound of formula I and salt thereof, wherein,
R
2Preferably be selected from hydrogen, benzyl, hydrocinnamyl, sulfonic group;
X is chlorine or bromine; Perhaps, R
2Do not exist simultaneously with X.
Compound compound and the salt thereof of formula I, wherein,
R
3Preferably be selected from hydrogen, aldehyde radical, CH=NNHC (S) NH
2, CONHRa, COORb, CH=CHRc and CH=NRd, wherein,
Ra is C
1-2Alkyl, single C
2-6Alkylamino or L-amino-acid residue,
Rb is glucose, wood sugar, ribose, ribodesose or without cyclohexanol,
Rc is phenyl or heterocyclic radical,
Rd is C
1-2Alkyl or C
2-6Alkylamino.
The compound of formula I and salt thereof, wherein,
R
3Be more preferably and be selected from hydrogen, aldehyde radical, CH=NNHC (S) NH
2, CONHRa, COORb, CH=CHRc and CH=NRd, wherein,
Ra is single C
2-6Alkylamino, L-Phe residue, L-tryptophane residue or TYR residue,
Rb is glucose, ribose or ribodesose,
Rc is 4-p-methoxy-phenyl or 4-nitrophenyl,
Rd is C
2-4Alkylamino.
The compound of formula I and salt thereof, wherein,
R
3Particularly preferably be to be selected from hydrogen, CH=NNHC (S) NH
2, CONHRa and CH=CHRc, wherein,
Ra is C
6Alkylamino L-Phe residue or TYR residue,
Rc is representative 4-p-methoxy-phenyl or 4-nitrophenyl.
The compound of formula I and salt thereof, wherein,
R
7Preferably be selected from hydrogen, n-butoxy, COCH
2CONHRa and COCH
2COORb, wherein,
Ra is L-Phe residue, L-tryptophane residue or TYR residue,
Rb is glucose, ribose or ribodesose.
The compound of formula I and salt thereof, wherein R
7More preferably hydrogen or n-butoxy.
The compound of formula I and salt thereof, wherein R
9Be preferably hydrogen, normal-butyl or hydrocinnamyl.
The compound of formula I and salt thereof, wherein R
9More preferably normal-butyl or hydrocinnamyl.
The compound of formula I and salt thereof, wherein,
R
1Preferably be selected from hydrogen, pyridyl, aldehyde radical, carboxylic acid group, carboxylicesters, carboxylate salt, CH=NNHC (S) NH
2, CONHRa, COORb, CH=CHRc and NHRd, wherein,
Ra is C
1-2Alkyl, single C
2-6Alkylamino or L-amino-acid residue,
Rb is glucose, wood sugar, ribose, ribodesose or without cyclohexanol,
Rc is phenyl or heterocyclic radical,
Rd is C
1-2Alkyl or C
2-6Alkylamino;
R
2To be selected from hydrogen, benzyl, hydrocinnamyl, sulfonic group;
X is chlorine or bromine; Perhaps, R
2Do not exist simultaneously with X;
R
3Be selected from hydrogen, aldehyde radical, CH=NNHC (S) NH
2, CONHRa, COORb, CH=CHRc and CH=NRd, wherein,
Ra is C
1-2Alkyl, single C
2-6Alkylamino or L-amino-acid residue,
Rb is glucose, wood sugar, ribose, ribodesose or without cyclohexanol,
Rc is phenyl or heterocyclic radical,
Rd is C
1-2Alkyl or C
2-6Alkylamino;
R
7Be selected from hydrogen, n-butoxy, COCH
2CONHRa and COCH
2COORb, wherein,
Ra is L-Phe residue, L-tryptophane residue or TYR residue,
Rb is glucose, ribose or ribodesose;
R
9Be selected from hydrogen, normal-butyl and hydrocinnamyl.
The compound of formula I and salt thereof, wherein,
R
1Be more preferably and be selected from hydrogen, pyridyl, carboxylic acid sodium, (4 '-methoxyl group) styryl, (4 '-nitro) styryl, aldehyde radical, thiosemicarbazone base, CONHRa and NHRd, wherein,
Ra is TYR residue or L-Phe residue,
Rd represents C
2-4Alkylamino;
R
2Be selected from hydrogen, benzyl, hydrocinnamyl or sulfonic group;
X is selected from chlorine or bromine; Perhaps, R
2Do not exist simultaneously with X;
R
3Be selected from hydrogen, CH=NNHC (S) NH
2, CONHRa and CH=CHRc, wherein,
Ra is L-Phe residue or TYR residue,
Rc is 4-p-methoxy-phenyl or 4-nitrophenyl;
R
7Be selected from hydrogen, n-butoxy, COCH
2CONHRa and COCH
2COORb, wherein,
Ra is L-Phe residue, L-tryptophane residue or TYR residue;
Rb is glucose, ribose or ribodesose;
R
9Be selected from hydrogen, normal-butyl and hydrocinnamyl.
The compound of formula I and salt thereof, wherein,
R
1Particularly preferably be to be selected from pyridyl, carboxylic acid sodium, (4 '-methoxyl group) styryl, (4 '-nitro) styryl, CH=NNHC (S) NH
2, CONHRa or NHRd, wherein,
Ra is TYR residue or L-Phe residue,
Rd is C
2-4Alkylamino;
R
2Be selected from hydrogen and benzyl; X is selected from chlorine and bromine; Perhaps, R
2Do not exist simultaneously with X;
R
3Be hydrogen;
R
7Be selected from hydrogen, n-butoxy, COCH
2CONHRa and COCH
2COORb, wherein,
Ra is selected from L-Phe residue and TYR residue;
Rb is selected from glucose, ribose and ribodesose;
R
9Be selected from normal-butyl and hydrocinnamyl.
According to the present invention, preferred compound is selected from following any one compound:
7-hydroxyl-9-ethyl-1-methyl-β-carboline,
7-hydroxyl-9-normal-butyl-1-methyl-β-carboline,
7-hydroxyl-9-isobutyl--1-methyl-β-carboline,
7-oxyethyl group-9-ethyl-1-methyl-β-carboline,
7-isopropoxy-9-ethyl-1-methyl-β-carboline,
7-n-butoxy-9-ethyl-1-methyl-β-carboline,
7-isobutoxy-9-ethyl-1-methyl-β-carboline,
7-decane oxygen base-9-ethyl-1-methyl-β-carboline,
7-benzyloxy-9-ethyl-1-methyl-β-carboline,
7-five fluorine benzyloxy-9-ethyl-1-methyl-β-carboline,
7-benzene propoxy--9-ethyl-1-methyl-β-carboline,
7-oxyethyl group-9-normal-butyl-1-methyl-β-carboline,
7-isopropoxy-9-normal-butyl-1-methyl-β-carboline,
7-normal butane oxygen base-9-normal-butyl-1-methyl-β-carboline,
7-isobutyl alkoxyl group-9-normal-butyl-1-methyl-β-carboline,
7-(3 '-pentane) oxygen base-9-normal-butyl-1-methyl-β-carboline,
7-(3 ', 3 ', 3 '-three fluoro-2-hydroxyls) the third alkoxyl group-9-normal-butyl-1-methyl-β-carboline,
7-octane oxygen base-9-normal-butyl-1-methyl-β-carboline,
7-decane oxygen base-9-normal-butyl-1-methyl-β-carboline,
7-benzyloxy-9-normal-butyl-1-methyl-β-carboline,
7-five fluorine benzyloxy-9-normal-butyl-1-methyl-β-carboline,
7-phenylpropyl alcohol alkoxyl group-9-normal-butyl-1-methyl-β-carboline,
7-n-butoxy-9-isobutyl--1-methyl-β-carboline,
7-isobutoxy-9-isobutyl--1-methyl-β-carboline,
7-decane oxygen base-9-isobutyl--1-methyl-β-carboline,
7-benzyloxy-9-isobutyl--1-methyl-β-carboline,
7-benzene propoxy--9-isobutyl--1-methyl-β-carboline,
7-oxyethyl group-2-benzyl-9-ethyl-1-methyl-β-carboline bromine salt,
7-n-butoxy-2-benzyl-9-ethyl-1-methyl-β-carboline bromine salt,
7-isobutoxy-2-benzyl-9-ethyl-1-methyl-β-carboline bromine salt,
7-benzyloxy-2-benzyl-9-ethyl-1-methyl-β-carboline bromine salt,
7-five fluorine benzyloxy-2-benzyl-9-ethyl-1-methyl-β-carboline bromine salt,
7-benzene propoxy--2-benzyl-9-ethyl-1-methyl-β-carboline bromine salt,
7-benzyloxy-2-benzyl-9-normal-butyl-1-methyl-β-carboline bromine salt,
7-n-octyloxy-2-benzyl-9-normal-butyl-1-methyl-β-carboline bromine salt,
7-isobutoxy-2-benzyl-9-normal-butyl-1-methyl-β-carboline bromine salt,
7-n-butoxy-2-benzyl-9-isobutyl--1-methyl-β-carboline bromine salt,
7-isobutoxy-2-benzyl-9-isobutyl--1-methyl-β-carboline bromine salt,
7-decane oxygen base-2-benzyl-9-isobutyl--1-methyl-β-carboline bromine salt,
7-benzyloxy-2-benzyl-9-isobutyl--1-methyl-β-carboline bromine salt,
7-benzene propoxy--2-benzyl-9-isobutyl--1-methyl-β-carboline bromine salt,
1-(3 ', 4 ', 5 '-trimethoxy) phenyl-β-carboline-3-carboxylic acid, ethyl ester,
Ethyl 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-ethyl-β-carboline-3-carboxylicesters,
Ethyl 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-carboxylicesters,
1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-carboxylic acid,
N-hydroxyethyl-1-(3 ', 4 ', 5 '-trimethoxy) phenyl-β-carboline-3-methane amide,
N-hydroxyethyl-1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-ethyl-β-carboline-3-methane amide,
N-hydroxyethyl-1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-methane amide,
1-(3 ', 4 ', 5 '-trimethoxy) phenyl-β-carboline,
1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-ethyl-β-carboline,
1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-normal-butyl-β-carboline,
Ethyl β-carboline-1-carboxylicesters,
Ethyl 9-normal-butyl-β-carboline-1-carboxylicesters,
9-normal-butyl-β-carboline-1-carboxylic acid,
3-methylol-9-ethyl-β-carboline,
3-methylol-9-normal-butyl-β-carboline,
3-methylol-9-benzyl-β-carboline,
3-methylol-9-(4 '-fluorine) benzyl-β-carboline,
3-methylol-9-hydrocinnamyl-β-carboline,
3-methylol-9-normal-butyl-1-methyl-β-carboline,
3-methylol-9-benzyl-1-methyl-β-carboline,
3-methylol-9-(4 '-fluorine) benzyl-1-methyl-β-carboline,
3-methylol-9-hydrocinnamyl-1-methyl-β-carboline,
1-(3 ', 4 ', 5 '-trimethoxy) phenyl-3-methylol-9-normal-butyl-β-carboline,
3-aldehyde radical-9-ethyl-β-carboline,
3-aldehyde radical-9-normal-butyl-β-carboline,
3-aldehyde radical-9-benzyl-β-carboline,
3-aldehyde radical-9-hydrocinnamyl-β-carboline,
3-aldehyde radical-9-normal-butyl-1-methyl-β-carboline,
3-aldehyde radical-9-benzyl-1-methyl-β-carboline,
3-aldehyde radical-9-(4 '-fluorine) benzyl-1-methyl-β-carboline,
3-aldehyde radical-9-hydrocinnamyl-1-methyl-β-carboline,
1-(3 ', 4 ', 5 '-trimethoxy) phenyl-3-aldehyde radical-9-normal-butyl-β-carboline,
9-ethyl-β-carboline-3-aldehyde radical thiosemicarbazone,
9-normal-butyl-β-carboline-3-aldehyde radical thiosemicarbazone,
9-benzyl-β-carboline-3-aldehyde radical thiosemicarbazone,
9-hydrocinnamyl-β-carboline-3-aldehyde radical thiosemicarbazone,
9-normal-butyl-1-methyl-β-carboline-3-aldehyde radical thiosemicarbazone,
9-benzyl-1-methyl-β-carboline-3-aldehyde radical thiosemicarbazone,
9-hydrocinnamyl-1-methyl-β-carboline-3-aldehyde radical thiosemicarbazone
1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-aldehyde radical thiosemicarbazone,
3-methylol-2-benzyl-9-normal-butyl-β-carboline bromine salt,
3-methylol-9-hydrocinnamyl-2-benzyl-β-carboline bromine salt,
3-aldehyde radical-2-benzyl-9-normal-butyl-β-carboline bromine salt,
3-aldehyde radical-9-hydrocinnamyl-2-benzyl-β-carboline bromine salt,
3-aldehyde radical-9-normal-butyl-β-carboline sodium bisulfite additive salt,
3-aldehyde radical-9-hydrocinnamyl-β-carboline sodium bisulfite additive salt,
3-aldehyde radical-9-hydrocinnamyl-1-methyl-β-carboline sodium bisulfite additive salt,
1-aldehyde radical-β-carboline-3-carboxylic acid, ethyl ester,
1-aldehyde radical-9-butyl-β-carboline-3-carboxylic acid, ethyl ester,
1-aldehyde radical-9-butyl-β-carboline,
1-aldehyde radical-9-hydrocinnamyl-β-carboline,
3-carboxylic acid, ethyl ester base-9-butyl-β-carboline-1-aldehyde radical thiosemicarbazone,
9-hydrocinnamyl-β-carboline-1-aldehyde radical thiosemicarbazone,
3-carboxylic acid, ethyl ester base-9-butyl-β-carboline-1-aldehyde radical contracting azanol,
9-butyl-β-carboline-1-aldehyde radical contracting azanol,
3-carboxylic acid, ethyl ester base-9-hydrocinnamyl-β-carboline-1-aldehyde contracting azanol,
9-hydrocinnamyl-β-carboline-1-aldehyde contracting Vasoxyl,
N-(4-β-carboline-benzene oxygen acetyl) phenylalanine ethyl ester,
N-(4-β-carboline-benzene oxygen acetyl) tyrosine ethyl ester,
N-(4-β-carboline-benzene oxygen acetyl) phenylalanine,
N-(4-β-carboline-benzene oxygen acetyl) tyrosine,
N-(9-normal-butyl-β-carboline-3-formyl) phenylalanine methyl ester,
N-(9-normal-butyl-β-carboline-3-formyl) valine methyl ester,
N-(9-normal-butyl-β-carboline-3-formyl) phenylalanine ethyl ester,
N-(9-normal-butyl-β-carboline-3-formyl) alanine methyl ester,
N-(9-normal-butyl-β-carboline-3-formyl) methionine(Met) ethyl ester,
N-(9-normal-butyl-β-carboline-3-formyl) tryptophane ethyl ester,
N-(9-normal-butyl-1-methyl-β-carboline-3-formyl) phenylalanine ethyl ester,
N-(9-normal-butyl-1-methyl-β-carboline-3-formyl) methionine(Met) ethyl ester,
N-(9-normal-butyl-1-methyl-β-carboline-3-formyl) tryptophan methyl ester,
N-(9-benzyl-β-carboline-3-formyl) phenylalanine ethyl ester,
N-(9-benzyl-β-carboline-3-formyl) methionine(Met) ethyl ester,
N-(9-benzyl-β-carboline-3-formyl) tryptophan methyl ester,
N-(1-methyl-β-carboline-3-formyl) alanine methyl ester,
N-(1-methyl-β-carboline-3-formyl) methionine(Met) ethyl ester,
N-(1-methyl-β-carboline-3-formyl) phenylalanine ethyl ester,
N-(1-methyl-β-carboline-3-formyl) tryptophan methyl ester,
N-(9-hydrocinnamyl-β-carboline-3-formyl) alanine methyl ester,
N-(9-hydrocinnamyl-β-carboline-3-formyl) methionine(Met) ethyl ester,
N-(9-hydrocinnamyl-β-carboline-3-formyl) α-amino-isovaleric acid ethyl ester,
N-(9-normal-butyl-β-carboline-3-formyl) L-Tyrosine methyl ester,
N-(9-hydrocinnamyl-β-carboline-3-formyl) phenylalanine ethyl ester,
N-(9-normal-butyl-β-carboline-3-formyl) methionine(Met),
N-(9-normal-butyl-β-carboline-3-formyl) phenylalanine,
N-(9-benzyl-β-carboline-3-formyl) methionine(Met),
N-(9-normal-butyl-β-carboline-3-formyl) tyrosine,
N-(9-hydrocinnamyl-β-carboline-3-formyl) L-Ala,
N-(9-hydrocinnamyl-β-carboline-3-formyl) methionine(Met),
N-(9-hydrocinnamyl-β-carboline-3-formyl) phenylalanine,
N-(9-hydrocinnamyl-β-carboline-3-formyl) α-amino-isovaleric acid,
N-(2-benzyl-9-hydrocinnamyl-β-carboline-3-formyl) phenylalanine ethyl ester bromine salt,
N-(2-benzyl-9-hydrocinnamyl-β-carboline-3-formyl) methionine(Met) ethyl ester bromine salt,
N-(9-normal-butyl-1-methyl-β-carboline-7-oxygen acetyl) methionine(Met) ethyl ester,
N-(9-normal-butyl-1-methyl-β-carboline-7-oxygen acetyl) tyrosine ethyl ester,
N-(9-hydrocinnamyl-1-methyl-β-carboline-7-oxygen acetyl) tyrosine ethyl ester,
N-(9-normal-butyl-1-methyl-β-carboline-7-oxygen acetyl) methionine(Met),
N-(9-normal-butyl-1-methyl-β-carboline-7-oxygen acetyl) tyrosine,
N-(9-hydrocinnamyl-1-methyl-β-carboline-7-oxygen acetyl) tyrosine,
N-(β-carboline-1-formyl) methionine(Met) ethyl ester,
N-(β-carboline-1-formyl) phenylalanine ethyl ester,
N-(9-methyl-β-carboline-1-formyl) methionine(Met) ethyl ester,
N-(9-methyl-β-carboline-1-formyl) phenylalanine ethyl ester,
N-(β-carboline-1-formyl) methionine(Met),
N-(β-carboline-1-formyl) phenylalanine,
N-(9-methyl-β-carboline-1-formyl) methionine(Met),
N-(9-methyl-β-carboline-1-formyl) phenylalanine,
1-O-(9-normal-butyl-β-carboline-3-formyl radical)-2,3,4-three-O-benzoyl-β-D-pyranose form ribose,
1-O-(9-benzyl-β-carboline-3-formyl radical)-2,3,4-three-O-benzoyl-β-D-pyranose form ribose,
1-O-(9-hydrocinnamyl-β-carboline-3-formyl radical)-2,3,4-three-O-benzoyl-β-D-pyranose form ribose,
1-O-(9-normal-butyl-β-carboline-3-formyl radical)-2,3,4,5-four-O-ethanoyl-β-D-glucopyranose,
1-O-(9-benzyl-β-carboline-3-formyl radical)-2,3,4,5-four-O-ethanoyl-β-D-glucopyranose,
1-O-(9-hydrocinnamyl-β-carboline-3-formyl radical)-2,3,4,5-four-O-ethanoyl-β-D-glucopyranose,
7-β-D-glucopyranose Oxy-1-methyl-9-normal-butyl-β-carboline,
7-β-D-glucopyranose oxygen base-9-hydrocinnamyl-1-methyl-β-carboline,
1-(p-β-D-glucopyranose oxygen base-phenyl)-β-carboline,
7-β-D-pyranose form wood glycosyloxy-9-normal-butyl-1-methyl-β-carboline,
7-β-D-pyranose form wood glycosyloxy-9-hydrocinnamyl-1-methyl-β-carboline,
1-styryl-β-carboline,
1-(4 '-methoxyl group-styryl)-β-carboline,
1-(3 ', 4 ', 5 '-trimethoxy-styryl)-β-carboline,
1-(4 '-methoxyl group-styryl)-9-normal-butyl-β-carboline,
1-(4 '-methoxyl group-styryl)-9-hydrocinnamyl-β-carboline,
1-(4 '-methoxyl group-styryl)-7-n-butoxy-9-hydrocinnamyl-β-carboline,
1-(4 '-nitro-styryl)-9-ethanoyl-β-carboline,
1-(4 '-nitro-styryl)-9-hydrocinnamyl-β-carboline,
1-(4 '-nitro-styryl)-7-n-butoxy-9-hydrocinnamyl-β-carboline,
1-(4 '-methoxyl group-styryl)-2-benzyl-β-carboline bromine salt,
1-(4 '-methoxyl group-styryl)-2-benzyl-9-normal-butyl-β-carboline bromine salt,
1-(4 '-methoxyl group-styryl)-9-hydrocinnamyl-2-benzyl-β-carboline bromine salt,
1-(4 '-methoxyl group-styryl)-7-n-butoxy-9-hydrocinnamyl-2-benzyl-β-carboline bromine salt,
1-(4 '-nitro-styryl)-9-ethanoyl-2-benzyl-β-carboline bromine salt,
1-(4 '-nitro-styryl)-7-n-butoxy-9-hydrocinnamyl-2-benzyl-β-carboline bromine salt,
1-(3 '-pyridyl)-9-normal-butyl-β-carboline,
1-(3 '-pyridyl)-9-benzyl-β-carboline,
1-(2 '-amino-ethyl) carbamyl-9-hydrocinnamyl-β-carboline,
1-(2 '-amino) ethylamino--9-normal-butyl-β-carboline,
1-(2 '-amino) ethylamino--9-hydrocinnamyl-β-carboline.
The formed additive salt of above-mentioned preferred compound and they and pharmaceutically acceptable acid or alkali consists of the part of complete content of the present invention.Compound of the present invention refers to all acid salt or all salt with alkali according to the suitable salt that the difference that replaces obtains.What mention especially is to be generally used for the salt that acceptable mineral acid, organic acid, mineral alkali and organic bases are made on the pharmacology of pharmacy industry.The salt that these are suitable, water miscible on the one hand, water miscible acid salt in particular, is pounced on acid, stearic acid, toluenesulphonic acids, methanesulfonic or 3-hydroxy-2-naphthoic acid at described sour example hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, maltonic acid, phenylformic acid, 2-(4-(2-hydroxybenzoyl)) phenylformic acid, butyric acid, sulphosalicylic acid, toxilic acid, lauric acid, oxysuccinic acid, FUMARIC ACID TECH GRADE, succsinic acid, oxalic acid, tartrate.
The invention still further relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises compound and common medicinal excipient and/or the auxiliary material of one or more formulas I.
In according to pharmaceutical composition of the present invention, can mention especially and be applicable to oral, parenteral (intravenously, muscle or subcutaneous), through skin or transdermal, intranasal, through tongue, through those of eye or breathing, rectal administration, especially tablet or drageeing, Sublingual tablet, capsule, suppository, aerosol, creme, ointment, skin gel, injectable or drinkable preparation, eye drops, nasal drop etc.
Compound of the present invention has anti-tumor activity, so the present invention also provides the application of these compounds in preparation medicine for treating tumor thing.
As medicine, useful dosage because of patient age and body weight, route of administration, disease character and seriousness with and any other treatment of being accepted different.
Definition
" the C that mentions among the present invention
1-6Alkyl " refer to have straight or branched the alkyl, " C of 1-6 carbon atom
1-6Alkylamino " refer to have straight or branched the alkylamino, " C of 1-6 carbon atom
1-6Alkoxyl group " refer to have the straight or branched alkylamino of 1-6 carbon atom, the rest may be inferred;
" phenyl " can at random be replaced by one or more identical or different substituted radicals, and described substituting group comprises hydroxyl, amino, nitro, halogen, C
1-2Alkoxyl group, C
1-2Alkylamino;
" aryl " should be phenyl, naphthyl, tetralyl, dihydro naphthyl, randomly replaced by one or more identical or different groups separately; Described substituting group is selected from hydroxyl, nitro, halogen, amino, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylamino, C
1-6Alkyl acyl, C
1-6Alkoxy carbonyl, C
1-6Alkoxycarbonyl amino;
" heterocyclic radical " should be saturated or undersaturated single or bicyclic groups, have aromatics or non-aromatic feature, have 5 to 12 annular atomses, contain 1,2 or 3 identical or different heteroatomss, heteroatoms is selected from oxygen, nitrogen, sulphur, heterocycle can be understood to and can randomly be replaced by one or more identical or different substituting groups that described substituting group is selected from halogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylamino for example, can be but is not limited to pyridyl, thienyl, furyl, imidazolyl, pyrazinyl, pyrimidyl, tetrazyl, pyrryl and pyrazolyl;
" amino " should be can be randomly by one or two C
1-6Alkyl replaces;
" sugar " should be and can randomly be replaced by one or more identical or different groups, and this group is selected from C
1-4Alkyl acyl or aryl-acyl;
The symbol that uses among other the application, term and abbreviation unless otherwise indicated, all have implication known in the art.
Embodiment
Below in conjunction with specific embodiment the present invention is elaborated.
One, instrument and reagent
The RE-52C Rotary Evaporators gives magnificent instrument plant available from Henan;
UV-8 type ultraviolet point sample analyser is available from Keda Instrument Plant, Wuxi;
The YRT-3 melting point detector is available from Precision Instrument Factory, Tianjin Univ.;
ZAB-HS double focusing magnetic mass spectrometer is available from Britain VG company;
Bruker Equinox 55 type Fourier transformation infrared spectrometers, the KBr compressing tablet;
The INOVA500 NMR spectrometer with superconducting magnet is available from U.S. Varian company;
The Mercury-Plus300 NMR spectrometer with superconducting magnet is available from U.S. Varian company;
Domestic chemical reagent is available from Guangzhou Chemical Reagent Factory, chemical reagents corporation of traditional Chinese medicines group;
The import chemical reagent is available from Beijing lark prestige chemical reagents corporation; The chemical intermediate that uses in the invention is all according to the disclosed method preparation of documents and materials.
Synthetic route 1
The compound of following examples 1-21 can be finished by synthetic route 1:
Embodiment 1 7-hydroxyl-9-ethyl-1-methyl-β-carboline (1)
Steps A: 7-methoxyl group-9-ethyl-1-methyl-β-carboline
Yageine (2.12g, 10mmol), DMF (50ml), 60%NaH (0.6g, 15mmol) mix, and stirring at room 10min adds iodoethane (15mmol), the stirring at room reaction, and TLC follows the tracks of detection.React complete, reaction mixture is poured in the 100ml frozen water, stirring at room 2 hours is filtered, and massive laundering gets light yellow solid.Above-mentioned solid is dissolved in dehydrated alcohol, transfers pH to 2 with concentrated hydrochloric acid, be evaporated to subsequently driedly, dehydrated alcohol band water 3 times gets yellow oil, and acetone recrystallization filters, and gets white crystal, is the hydrochloride of product.Need not to be further purified can be directly used in next step should.
Step B:7-hydroxyl-9-ethyl-1-methyl-β-carboline
7-methoxyl group-9-ethyl-1-methyl-β-carboline hydrochloride (10mmol), Glacial acetic acid (100ml), 40% Hydrogen bromide (75ml) mix, reflux, TLC follows the tracks of and detects (developping agent: acetone/sherwood oil=1: 1), react complete, reaction mixture is poured in the 300ml frozen water, stir the lower 10M sodium hydroxide of using first and regulate pH to 6, then regulate pH to 8 with sodium bicarbonate.Filter, massive laundering gets pale solid.In dehydrated alcohol, activated carbon decolorizing filters with above-mentioned dissolution of solid, concentrating under reduced pressure, and the dehydrated alcohol recrystallization gets white granular crystal 1.8g, yield 80%, mp 258-260 ℃.FAB-MS m/e(M+1)227；
IR(KBr)3500-1750，1627，1568，1451，1410，1347，1315，1260，1215，1092，983，821；
1H-NMR(500MHz，DMSO-d6)δ9.74(1H，s，OH)；8.12-8.13(1H，d，H-3)；7.96-7.97(1H，d，H-4)；7.78-7.79(1H，H-5)；6.91-6.92(1H，m，H-6)；6.73-6.75(1H，m，H-8)；4.48-4.52(2H，m，NCH
2CH
3)；2.92(3H，s，CH
3)；1.31-1.34(3H，m，NCH
2CH
3).
Embodiment 2 7-hydroxyl-9-normal-butyl-1-methyl-β-carboline (2)
Operation uses iodo-n-butane as alkylating reagent in steps A with embodiment 1.
Get white crystal 2.2g, yield 87%, mp 205-206 ℃;
FAB-MS m/e(M+1)255；
IR(KBr)3500-1750，1618，1566，1492，1451，1413，1325，1238，1187，1137，1112，980；
1H-NMR(500MHz，DMSO-d
6)δ9.72(1H，s，OH)；8.12-8.13(1H，d，J＝5.0Hz，H-3)；7.95-7.97(1H，d，J＝8.5Hz，H-4)；7.78-7.79(1H，d，J＝5.0Hz，H-5)；6.90-6.91(1H，m，H-6)；6.72-6.75(1H，m，H-8)；4.41-4.44(2H，m，NCH
2CH
2CH
2CH
3)；2.91(3H，s，CH
3)；1.67-1.74(2H，m，NCH
2CH
2CH
2CH
3)；1.36-1.40(2H，m，NCH
2CH
2CH
2CH
3)；0.92-0.94(2H，m，NCH
2CH
2CH
2CH
3).
Embodiment 3 7-hydroxyl-9-isobutyl--1-methyl-β-carboline (3)
Operation uses 1-iodo-2-methylpropane as alkylating reagent in steps A with embodiment 1.Get white crystal 2.0g, yield 79%, mp 246-248 ℃;
FAB-MS m/e(M+1)255；
IR(KBr)3500-1750，1626，1568，1447，1392，1203，1136，977，820；
1H-NMR(500MHz，DMSO-d
6)δ9.70(1H，s，OH)；8.13-8.14(1H，d，H-3)；7.95-7.97(1H，d，H-4)；7.79-7.80(1H，d，H-5)；6.93(1H，s，H-6)；6.72-6.74(1H，d，H-8)，4.26-4.27(2H，d，NCH
2CH[CH
3]
2)；2.90(3H，s，CH
3)；2.11-2.17(1H，m，NCH
2CH[CH
3]
2)；0.85-0.87(6H，s，NCH
2CH[CH
3]
2)。
Embodiment 4 7-isobutoxy-9-ethyl-1-methyl-β-carboline (4)
7-hydroxyl-9-ethyl-1-methyl-β-carboline (2.0mmol), DMF (30ml), 60% sodium hydride (0.2g, 5mmol) are mixed stirring at room 5min, add subsequently 1-bromo-2-methylpropane (5mmol), the stirring at room reaction, TLC follows the tracks of and detects (developping agent: acetone/sherwood oil=1: 1), react complete, reaction mixture is poured into water, add 10M sodium hydroxide, the stirring at room reaction is spent the night, and filters, massive laundering gets pale solid.Solid is dissolved in dehydrated alcohol, transfers pH to 3-4 with concentrated hydrochloric acid, concentrating under reduced pressure, dehydrated alcohol band water number, acetone or acetone/diethyl ether recrystallization get white or light yellow solid.Solid is dissolved in the mixing solutions of ethyl acetate/water, sodium bicarbonate alkalization, ethyl acetate extraction, merge organic phase, washing, saturated salt washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, ether/sherwood oil mixing solutions (1: 1) recrystallization gets white crystal 0.39g, yield 69%, mp 127-128 ℃;
FAB-MS m/e(M+1)283；
IR(KBr)3042，2961，2925，2871，1622，1566，1450，1349，1263，1214，1142，1101，1044，808；
1H-NMR(500MHz，CDCl
3)δ8.26-8.27(1H，d，H-3)；7.94-7.96(1H，d，H-4)；7.71-7.72(1H，d，H-5)；6.85-6.89(2H，m，H-6，H-8)；4.51-4.56(2H，m，NCH
2CH
3)；3.85-3.86(2H，d，OCH
2CH[CH
3]
2)；3.02(3H，s，CH
3)；2.14-2.19(1H，m，OCH
2CH[CH
3]
2)；1.42-1.45(3H，m，NCH
2CH
3)，1.07-1.09(6H，m，OCH
2CH[CH
3]
2).
Embodiment 5 7-benzyloxy-9-ethyl-1-methyl-β-carboline (5)
Operation is with embodiment 4, but the use cylite is as alkylating reagent.Get white crystal 0.55g, yield 87%, mp 177-178 ℃;
FAB-MS m/e(M+1)317；
IR(KBr)3032，2967，2925，2871，1621，1564，1446，1261，1213，1134，1001，837，810；
1H-NMR(500MHz，CDCl
3)δ 8.26-8.27(1H，d，H-3)；7.97-7.99(1H，d，H-4)；7.72-7.74(1H，d，H-5)；7.25-7.50(5H，m，PhH)；6.95-6.97(2H，m，H-6，H-8)；5.16(2H，s，0CH
2Ph)；4.50-4.55(2H，m，NCH
2CH
3)；3.03(3H，s，CH
3)；1.37-1.43(3H，m，NCH
2CH
3).
Embodiment 6 7-benzene propoxy--9-ethyl-1-methyl-β-carboline (6)
Operation is with embodiment 4, but use 1-bromo-3-phenyl-propane is as alkylating reagent.Get white crystal 0.52g, yield 76%, mp 110-111 ℃;
FAB-MS m/e(M+1)345；
IR(KBr)3030，2950，2924，2871，1623，1561，1447，1392，1210，1136，1089，1040，966，805；
1H-NMR(500MHz，CDCl
3)δ8.26-8.27(1H，d，H-3)；7.95-7.97(1H，d，H-4)；7.72-7.73(1H，d，H-5)；7.19-7.31(5H，m，PhH)；6.83-6.89(2H，m，H-6，H-8)；4.50-4.54(2H，m，NCH
2CH
3)；4.09-4.11(2H，m，OCH
2CH
2CH
2Ph)；3.02(3H，s，CH
3)；2.86-2.89(2H，m，OCH
2CH
2CH
2Ph)；2.13-2.21(3H，m，NCH
2CH
3)；1.41-1.44(2H，m，OCH
2CH
2CH
2Ph).
Embodiment 7 7-isobutyl alkoxyl groups-9-normal-butyl-1-methyl-β-carboline (7)
Operation is with embodiment 4, but use 1-bromo-2-methylpropane is made reaction raw materials as alkylating reagent with 7-hydroxyl-9-normal-butyl-1-methyl-β-carboline.Get white crystal 0.48g, yield 77%, mp91-92 ℃;
FAB-MS m/e(M+1)311；
IR(KBr)3423，2962，2928，2868，1622，1564，1447，1411，1366，1242，1198，1139，1043，810；
1H-NMR(500MHz，CDCl
3)δ 8.26-8.27(1H，d，H-3)；7.96-7.97(1H，d，H-4)；7.76-7.77(1H，d，H-5)；6.85-6.91(2H，m，H-6，H-8)；4.45-4.48(2H，m，NCH
2CH
2CH
2CH
3)；3.86-3.87(2H，d，OCH
2CH[CH
3]
2)；3.07(3H，s，CH
3)；2.14-2.19(1H，m，OCH
2CH[CH
3]
2)；1.79-1.85(2H，m，NCH
2CH
2CH
2CH
3)；1.43-1.48(2H，m，NCH
2CH
2CH
2CH
3)；1.08-1.10(6H，m，OCH
2CH[CH
3]
2)；0.98-1.01(3H，m，NCH
2CH
2CH
2CH
3).
Embodiment 8 7-(3 ', 3 ', 3 '-three fluoro-2-hydroxyls) the third alkoxyl group-9-normal-butyl-1-methyl-β-carboline (8)
Operation is with embodiment 7, but use 3-bromo-1,1, the 1-Trifluoro-2-propanol is as alkylating reagent.Get white crystal 0.56g, yield 76%, mp 162-164 ℃;
FAB-MS m/e(M+1)367；
IR(KBr)3061，2961，2932，2837，1624，1568，1497，1453，1410，1351，1241，1134，1048，810；
1H-NMR(500MHz，CDCl
3)δ8.23-8.24(1H，d，H-3)；7.92-7.94(1H，d，H-4)；7.72-7.73(1H，d，H-5)；6.87-6.89(2H，m，H-6，H-8)；6.64(1H，s，OH)；4.20-4.53(5H，m，OCH
2CH(OH)CF
3，NCH
2CH
2CH
2CH
3)；2.94(3H，s，CH
3)；1.66-1.73(2H，m，NCH
2CH
2CH
2CH
3)；1.36-1.41(2H，m，NCH
2CH
2CH
2CH
3)；0.90-0.98(3H，m，NCH
2CH
2CH
2CH
2).
Embodiment 9 7-benzyloxy-9-normal-butyl-1-methyl-β-carboline (9)
Operation is with embodiment 7, but the use cylite is as alkylating reagent.Get white crystal 0.57g, yield 83%, mp 121-122 ℃;
FAB-MS m/e(M+1)345；
IR(KBr)3424，3036，2957，2929，2866，1622，1565，1495，1448，1408，1377，1349，1240，1192，1139，1009，813，731；
1H-NMR(500MHz，CDCl
3)δ8.27-8.28(1H，d，H-3)；7.97-7.99(1H，d，H-4)；7.75-7.76(1H，d，H-5)；7.25-7.50(5H，m，PhH)；6.92-6.99(2H，m，H-6，H-8)；5.22(2H，s，OCH
2Ph)；4.41-4.44(2H，m，NCH
2CH
2CH
2CH
3)；3.05(3H，s，CH
3)；1.75-1.78(2H，m，NCH
2CH
2CH
2CH
3)；1.38-1.43(2H，m，NCH
2CH
2CH
2CH
3)；0.94-0.97(3H，m，NCH
2CH
2CH
2CH
3).
Embodiment 10 7-five fluorine benzyloxy-9-normal-butyl-1-methyl-β-carboline (10)
Operation is with embodiment 7, but uses alpha-brominated-(2,3,4,5,6-, five fluorine) toluene as alkylating reagent.Get white crystal 0.63g, yield 73%, mp 121-122 ℃;
FAB-MS m/e(M+1)435；
IR(KBr)3424，3036，2957，2929，2866，1622，1565，1495，1448，1408，1377，1349，1240，1192，1139，1009，813，731；
1H-NMR(500MHz，CDCl
3)δ8.27-8.28(1H，d，J＝5.5Hz，H-3)；7.97-7.99(1H，d，J＝8.5Hz，H-4)；7.75-7.76(1H，d，J＝5.5Hz，H-5)；7.25-7.50(5H，m，PhH)；6.92-6.99(2H，m，H-6，H-8)；5.22(2H，s，OCH
2Ph)；4.41-4.44(2H，m，NCH
2CH
2CH
2CH
3)；3.05(3H，s，CH
3)；1.75-1.78(2H，m，NCH
2CH
2CH
2CH
3)；1.38-1.43(2H，m，NCH
2CH
2CH
2CH
3)；0.94-0.97(3H，m，NCH
2CH
2CH
2CH
3).
Embodiment 11 7-n-butoxy-9-isobutyl--1-methyl-β-carboline (11)
Operation is with embodiment 4, but the use iodo-n-butane is made reaction raw materials as alkylating reagent with 7-hydroxyl-9-isobutyl--1-methyl-β-carboline.Get faint yellow oily thing 0.48g, yield 78%;
FAB-MS m/e(M+1)311；
IR(KBr)2956，2868，2485，1625，1574，1468，1432，1336，1255，1204，1141，1043，804；
1H-NMR(500MHz，CDCl
3)δ8.27-8.28(1H，d，H-3)；7.97-7.98(1H，d，H-4)；7.79-7.80(1H，d，H-5)；6.87-6.91(2H，m，H-6，H-8)；4.28-4.29(2H，m，OCH
2CH
2CH
2CH
3)；4.08-4.11(2H，m，NCH2CH[CH3]2)；3.07(3H，s，CH
3)；2.24-2.27(1H，m，NCH2CH[CH3]2)；1.82-1.88(2H，m，OCH
2CH
2CH
2CH
3)；1.54-1.58(2H，m，OCH
2CH
2CH
2CH
3)；1.00-1.03(3H，m，2H，m，OCH
2CH
2CH
2CH
3)；0.93-0.95(6H，m，NCH2CH[CH3]2).
Embodiment 12 7-decane oxygen base-9-isobutyl--1-methyl-β-carbolines (12)
Operation is with embodiment 11, but use 1-iodo ten alkane are as alkylating reagent.Get white crystal 0.59g, yield 75%, mp 62-64 ℃;
FAB-MS m/e(M+1)395；
IR(KBr)3431，2950，2922，2849，1625，1567，1447，1335，1254，1202，1142，809；
1H-NMR(500MHz，CDCl
3)δ8.27-8.28(1H，d，H-3)；7.95-7.97(1H，d，H-4)；7.75-7.76(1H，d，H-5)；6.86-6.89(2H，m，H-6，H-8)；4.27-4.28(2H，d，NCH
2CH[CH
3]
2)；4.07-4.09(2H，m，OCH
2[CH
2]
8CH
3)；3.03(3H，s，CH
3)；2.23-2.29(1H，m，NCH
2CH[CH
3]
2)；1.82-1.88(2H，m，OCH
2CH
2[CH
2]
7CH
3)；1.48-1.54(2H，m，OCH
2CH
2CH
2[CH
2]
6CH
3)；1.28-1.40(12H，m，OCH
2CH
2CH
2[CH
2]
6CH
3)；0.93-0.94(6H，d，NCH
2CH[CH
3]
2)；0.87-0.90(3H，m，O[CH
2]
9CH
3).
Embodiment 13 7-benzene propoxy--9-isobutyl--1-methyl-β-carboline (13)
Operation is with embodiment 11, but use 1-bromo-3-phenyl-propane is as alkylating reagent.Get white crystal 0.54g, yield 74%, mp 94-95 ℃;
FAB-MS m/e(M+1)373；
IR(KBr)3041，2958，1621，1567，1448，1405，1339，.1253，1196，1139，1050，977，817；
1H-NMR(500MHz，CDCl
3)δ 8.27-8.28(1H，d，H-3)；7.96-7.98(1H，d，H-4)；7.76-7.78(1H，d，H-5)；7.19-7.31(5H，m，PhH)；6.88-6.91(1H，m，H-6)；6.84-6.85(1H，m，H-8)；4.26-4.27(2H，d，NCH
2CH[CH
3]
2)；4.09-4.11(2H，m，OCH
2CH
2CH
2Ph)；3.04(3H，s，CH
3)；2.86-2.89(2H，m，OCH
2CH
2CH
2Ph)；2.15-2.26(3H，m，NCH
2CH[CH
3]
2，OCH
2CH
2CH
2Ph)；0.92-0.93(6H，d，NCH
2CH[CH
3]
2).
Embodiment 14 7-isobutoxy-2-benzyl-9-ethyl-1-methyl-β-carboline bromine salt (14)
7-isobutoxy-9-ethyl-1-methyl-β-carboline (1mmol), ethyl acetate (50ml), cylite (20mmol) are mixed, reflux, TLC follows the tracks of detection, the most of reaction of question response raw material is complete, stop to reflux, with the reaction mixture cooling, filter, an amount of ethyl acetate washing gets yellow solid.With dehydrated alcohol recrystallization 3 times of above-mentioned solid, get light yellow crystal 0.36g, yield 79%, mp222-224 ℃;
FAB-MS m/e 373；
IR(KBr)3420，2959，1622，1454，1372，1259，1223，1134，1034，1010，826，736；
1H-NMR(500MHz，DMSO-d
6)δ8.78-8.79(1H，d，H-3)；8.61-8.62(1H，d，H-4)；8.37-8.39(1H，d，H-5)；7.35-7.43(4H，m，H-6，H-8，PhH)；7.19-7.21(2H，d，PhH)；7.09-7.11(1H，m，PhH)；6.05(2H，s，NCH
2Ph)；4.70-4.75(2H，m，NCH
2CH
3)；3.99-4.01(2H，m，OCH
2CH[CH
3]
2)；3.11(3H，s，CH
3)；2.11-2.14(1H，m，OCH
2CH[CH
3]
2)；1.38-1.41(3H，m，NCH
2CH
3)；1.05-1.06(6H，m，OCH
2CH[CH
3]
2)。
Embodiment 15 7-benzyloxy-2-benzyl-9-ethyl-1-methyl-β-carboline bromine salt (15)
Operation is with embodiment 14, but use 7-benzyloxy-9-ethyl-1-methyl-β-carboline is as reaction raw materials.Get light yellow crystal 0.4g, yield 82%, mp 240-242 ℃;
FAB-MS m/e 407；
IR(KBr)3437，3005，2969，1620，1577，1452，1335，1260，1210，1133，1034，994，823，731；
1H-NMR(500MHz，DMSO-d
6)δ8.80-8.82(1H，d，H-3)；8.63-8.65(1H，d，H-4)；8.40-8.42(1H，d，H-5)；7.53-7.56(3H，m，H-6，H-8，PhH)；7.35-7.45(6H，m，PhH)；7.17-7.21(3H，m，PhH)；6.06(2H，s，NCH
2Ph)；5.36(2H，s，NCH
2Ph)；4.71-4.75(2H，m，NCH
2CH
3)；3.11(3H，s，CH
3)；1.37-1.40(3H，m，NCH
2CH
3)。
Embodiment 16 7-benzene propoxy--2-benzyl-9-ethyl-1-methyl-β-carboline bromine salt (16)
Operation is with embodiment 14, but use 7-benzene propoxy--9-ethyl-1-methyl-β-carboline is as reaction raw materials.Get light yellow crystal 0.40g, yield 78%, mp 189-191 ℃;
FAB-MS m/e 435；
IR(KBr)3410，2989，2933，2876，1623，1453，1370，1341，1260，1220，1134，1035，824，732；
1H-NMR(500MHz，DMSO-d
6)δ 8.80-8.8 1(1H，d，H-3)；8.63-8.64(1H，d，H-4)；8.39-8.41(1H，d，H-5)；7.11-7.43(12H，m，PhH，H-6，H-8)；6.06(2H，s，NCH
2Ph)；4.69-4.73(2H，m，NCH
2CH
3)；4.23-4.25(1H，m，OCH
2CH
2CH
2Ph)；3.11(3H，s，CH
3)；2.80-2.83(2H，m，OCH
2CH
2CH
2Ph)；2.10-2.15(2H，m，OCH
2CH
2CH
2Ph)；1.37-1.39(3H，m，NCH
2CH
3)。
Embodiment 17 7-benzyloxy-2-benzyl-9-normal-butyl-1-methyl-β-carboline bromine salt (17)
Operation is with embodiment 14, but use 7-benzyloxy-9-normal-butyl-1-methyl-β-carboline is as reaction raw materials.Get light yellow crystal 0.42g, yield 82%, mp 229-230 ℃;
FAB-MS m/e 435；
IR(KBr)3423，3028，2957，2927，2868，1622，1579，1495，1454，1373，1247，1200，1135，1028，819，733；
1H-NMR(500MHz，DMSO-d
6)δ8.80-8.81(1H，d，H-3)；8.63-8.64(1H，d，H-4)；8.40-8.42(1H，d，H-5)；7.17-7.55(12H，m，H-6，H-8，PhH)；6.05(2H，s，NCH
2Ph)；5.37(2H，s，OCH
2Ph)；4.63-4.66(2H，m，NCH
2CH
2CH
2CH
3)；3.09(3H，s，CH
3)；1.68-1.71(2H，m，NCH
2CH
2CH
2CH
3)；1.30-1.34(2H，m，NCH
2CH
2CH
2CH
3)；0.86-0.89(3H，m，NCH
2CH
2CH
2CH
3).
Embodiment 18 7-isobutoxy-2-benzyl-9-normal-butyl-1-methyl-β-carboline bromine salt (18)
Operation is with embodiment 14, but use 7-isobutoxy-9-normal-butyl-1-methyl-β-carboline is as reaction raw materials.Get light yellow crystal 0.40g, yield 83%, mp 247-249 ℃;
FAB-MS m/e 401；
IR(KBr)3401，3020，2957，2869，1620，1578，1456，1377，1247，1207，1137，1012，821，721；
1H-NMR(500MHz，DMSO-d
6)δ 8.80-8.81(1H，d，H-3)；8.62-8.64(1H，d，H-4)；8.37-8.40(1H，m，H-5)；7.35-7.43(4H，m，PhH)；7.19-7.20(2H，m，PhH)，H-6)；7.08-7.10(1H，m，H-8)；6.05(2H，s，NCH
2Ph)；4.64-4.67(2H，m，NCH
2CH
2CH
2CH
3)；4.20-4.22(2H，m，OCH
2[CH
2]
6CH
3)；3.09(3H，s，CH
3)；1.71-1.82(2H，m，NCH
2CH
2CH
2CH
3)；1.46-1.49(2H，m，OCH
2CH
2[CH
2]
5CH
3)；1.26-1.37(12H，m，NCH
2CH
2CH
2CH
3，O[CH
2]
2[CH
2]
5CH
3)；0.85-0.94(6H，m，N[CH
2]
3CH
3，O[CH
2]
7CH
3)。
Embodiment 19 7-n-butoxy-2-benzyl-9-isobutyl--1-methyl-β-carboline bromine salt (19)
Operation is with embodiment 14, but use 7-n-butoxy-9-isobutyl--1-methyl-β-carboline is as reaction raw materials.Get light yellow crystal 0.40g, yield 84%, mp 246-248 ℃;
FAB-MS m/e 401；
IR(KBr)3410，2957，2927，2867，1620，1576，1457，1375，1253，1209，1138，1030，828；
1H-NMR(500MHz，DMSO-d
6)δ 8.81-8.12(1H，d，H-3)；8.64-8.65(1H，d，H-4)；8.37-8.39(1H，d，H-5)；7.35-7.44(4H，m，PhH)；7.17-7.19(2H，d，H-6，H-8)；7.08-7.10(1H，m，PhH)；6.04(2H，s，CH
2Ph)；4.53-4.54(2H，d，OCH
2CH
2CH
2CH
3)；4.20-4.22(2H，m，NCH
2CH[CH
3]
2)；3.06(3H，s，CH
3)；2.04-2.09(1H，m，NCH
2CH[CH
3]
2)；1.77-1.82(2H，m，OCH
2CH
2CH
2CH
3)；1.47-1.55(2H，m，OCH
2CH
2CH
2CH
3)；0.96-0.99(3H，m，OCH
2CH
2CH
2CH
3)；0.83-0.84(6H，d，NCH
2CH[CH
3]
2)。
Embodiment 20 7-decane oxygen base-2-benzyl-9-isobutyl--1-methyl-β-carboline bromine salt (20)
Operation is with embodiment 14, but use 7-decane oxygen base-9-isobutyl--1-methyl-β-carboline is as reaction raw materials.Get light yellow crystal 0.46g, yield 78%, mp 202-203 ℃;
FAB-MS m/e 485；
IR(KBr)3409，2957，2924，2852，1621，1579，1456，1375，1252，1219，1137，1030，820，726；
1H-NMR(500MHz，DMSO-d
6)δ8.82-8.84(1H，d，H-3)；8.65-8.66(1H，d，H-4)：8.38-8.40(1H，d，H-5)；7.37-7.43(4H，m，PhH)；7.18-7.20(2H，d，H-6，H-8)；7.07-7.09(1H，d，PhH)；6.06(2H，s，CH
2Ph)：4.53-4.55(2H，d，NCH
2CH[CH
3]
2)；4.20-4.22(2H，m，OCH
2 [CH
2]
8CH
3)；3.07(3H，s，CH
3)；2.04-2.10(1H，m，NCH
2CH[CH
3]
2)；1.77-1.83(2H，m，OCH
2CH
2[CH
2]
7CH
3)；1.44-1.50(2H，m，OCH
2CH
2CH
2[CH
2]
6CH
3)；1.26-1.36(12H，m，OCH
2CH
2CH
2[CH
2]
6CH
3)；0.83-0.86(9H，m，O[CH
2]
9CH
3，NCH
2CH[CH
3]
2).
Embodiment 21 7-benzene propoxy--2-benzyl-9-isobutyl--1-methyl-β-carboline bromine salt (21)
Operation is with embodiment 14, but use 7-benzene propoxy--9-isobutyl--1-methyl-β-carboline is as reaction raw materials.Get light yellow crystal 0.39g, yield 72%, mp 204-206 ℃;
FAB-MS m/e 463；
IR(KBr)3410，3023，2957，2871，1621，1579，1454，1253，1216，1137，1032，821，728；
1H-NMR(500MHz，DMSO-d
6)δ 8.81-8.83(1H，d，H-3)；8.65-8.66(1H，d，H-4)；8.39-8.41(1H，d，H-5)；7.11-7.44(13H，m，PhH，H-6，H-8)；6.05(2H，s，CH
2Ph)；4.52-4.54(2H，d，NCH
2CH[CH
3]
2)；4.2 1-4.24(2H，m，OCH
2CH
2CH
2Ph)；3.06(3H，s，CH
3)；2.80-2.83(2H，m，OCH
2CH
2CH
2Ph)；2.03-2.14(3H，m，NCH
2CH[CH
3]
2，OCH
2CH
2CH
2Ph)；0.82-0.83(6H，m，NCH
2CH[CH
3]
2).
Synthetic route 2
The compound of following examples 22-27 can be finished by synthetic route 2:
Embodiment 22 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-β-carboline-3-carboxylic acid, ethyl ester (22)
Steps A: 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid
L-Trp (40.8g, 200mol), 3,4,5-Trimethoxybenzaldehyde (40g, 200mol) and Glacial acetic acid 250ml mix, reflux 3 hours; Reaction mixture is poured in the frozen water, and sodium hydroxide is regulated pH to 5-6, namely separates out faint yellow solid, filter, and washing, drying gets faint yellow solid 76.0g, does not need purifying, can be directly used in next step reaction.
Step B:1-(3 ', 4 ', 5 '-trimethoxy) phenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid, ethyl ester
1-(3 ', 4 ', 5 '-trimethoxy) phenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (76.0g), dehydrated alcohol 1000ml and thionyl chloride (30ml) mix, heating reflux reaction 6 hours removes ethanol under reduced pressure, and residue is dissolved in cold water, the sodium bicarbonate alkalization, ethyl acetate extraction merges organic phase, washing, the saturated salt washing, anhydrous sodium sulfate drying filters, concentrating under reduced pressure, get yellow oil, re-crystallizing in ethyl acetate is separated out white crystal, filter, the ether washing, drying gets white solid 53.0g.Do not need to be further purified, can be directly used in next step reaction.
Step C:1-(3 ', 4 ', 5 '-trimethoxy) phenyl-β-carboline-3-carboxylic acid, ethyl ester
1-(3 ', 4 ', 5 '-trimethoxy) phenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid, ethyl ester (53.0g, 130mmol), sulphur (16g, 500mmol), dimethylbenzene (250ml) mix reflux 10 hours, yellow crystals is separated out in cooling, filters, the cold xylene washing, sherwood oil fully washs subsequently, and drying gets yellow solid.With above-mentioned solid re-crystallizing in ethyl acetate, get white crystal 46.3g, yield 87%, mp 229-230 ℃;
FAB-MS m/e(M+1)407；
IR(KBr)3252，2991，2940，2832，1711，1625，1588，1501，1455，1391，1248，1127，1006，840，745；
1H-NMR(500MHz，CDCl
3)δ 9.28(1H，s，NH)；8.80(1H，s，H-4)；8.20-8.22(1H，d，H-8)；7.58-7.63(2H，m，H-5，H-6)；7.36-7.39(1H，.m，H-7)；4.51-4.55(2H，m，OCH
2CH
3)；3.87-3.89(9H，m，OCH
3)；1.47-1.50(3H，m，OCH
2CH
3).
Embodiment 23 ethyl 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-carboxylicesters (23)
1-(3 ', 4 ', 5 '-trimethoxy) phenyl-β-carboline-3-carboxylic acid, ethyl ester (4.1g, 10mmol), DMF (200ml) mix, and stirring at room is to clarification, add 60%NaH (1.2g, 30mmol), be stirred to without Bubble formation, drip iodo-n-butane (30mmol), the stirring at room reaction, TLC follows the tracks of detection.React complete, reaction mixture is poured in the frozen water, ethyl acetate extraction merges organic phase, washing, the saturated salt washing adds ethanol 100ml, and concentrated hydrochloric acid is regulated pH to 2～3, is evaporated to dried, dehydrated alcohol band water number gets yellow oil, and acetone recrystallization gets yellow solid.Solid is soluble in water, the sodium bicarbonate alkalization, ethyl acetate extraction merges organic phase, washing, anhydrous sodium sulfate drying filters, and concentrating under reduced pressure, residue ether recrystallization gets white crystal 3.2g, yield 69%, mp 138-139 ℃;
FAB-MS m/e(M+1)463；
IR(KBr)3433，3065，2933，1711，1621，1583，1505，1450，1413，1368，1260，1237，1128，1006，739；
1H-NMR(500MHz，CDCl
3)δ 8.89(1H，s，H-4)；8.25-8.26(1H，d，H-8)；7.62-7.65(1H，m，H-5)；7.47-7.49(1H，d，H-6)；7.36-7.39(1H，m，H-7)；6.83(2H，s，PhH)；4.51-4.55(2H，m，OCH
2CH
3)；3.95-3.98(2H，m，NCH
2CH
2CH
2CH
3)；3.89-3.91(9H，m，OCH3)；1.46-1.49(5H，m，OCH
2CH
3，NCH
2CH
2CH
2CH
3)；0.95-0.99(2H，m，NCH
2CH
2CH
2CH
3)；0.70-0.73(3H，m，NCH
2CH
2CH
2CH
3).
Embodiment 24 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-carboxylic acid (24)
Ethyl 9-normal-butyl-1-(3 ', 4 ', 5 '-trimethoxy) phenyl-β-carboline-3-carboxylicesters (5mmol), ethanol (100ml), sodium hydroxide (2.0g, 50mmol), water (200ml) mixes stirring at room reaction 24 hours, frozen water cooling, concentrated hydrochloric acid is transferred pH to 5～6, and decompression steams ethanol, separates out yellow solid, filter, washing, drying gets yellow solid 2.0g, yield 97%, mp 215-216 ℃;
FAB-MS m/e(M+1)435；
IR(KBr)3300，2962，2873，1736，1620，1584，1506，1456，1410，1362，1304，1238，1125，1002，957，824，737；
1H-NMR(500MHz，CDCl
3)δ8.93(1H，s，H-4)；8.45-8.47(1H，d，H-8)；7.64-7.73(2H，m，H-5，H-6)；7.35-7.38(1H，m，H-7)；6.91(2H，s，PhH)；3.99-4.02(2H，m，NCH
2CH
2CH
2CH
3)；3.78-3.82(9H，m，OCH
3)；1.39-1.45(2H，m，NCH
2CH
2CH
2CH
3)；0.91-0.95(2H，m，NCH
2CH
2CH
2CH
3)；0.65-0.68(3H，m，NCH
2CH
2CH
2CH
3)。
Embodiment 25 N-hydroxyethyl-1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-methane amide (25)
Ethyl 9-normal-butyl-1-(3 ', 4 ', 5 '-trimethoxy) phenyl-β-carboline-3-carboxylicesters (10mmol), dehydrated alcohol (150ml), 60% sodium hydride (15mmol), oxyethylamine (10ml), reflux, TLC follows the tracks of detection, reaction is finished, in the mixed solution with reaction mixture impouring frozen water and ethyl acetate, tell ethyl acetate layer, the water layer ethyl acetate extraction, merge organic phase, washing, saturated salt washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, recrystallization from ethyl acetate/petroleum ether gets white crystal 3.6g, yield 74%, mp197-198 ℃;
FAB-MS m/e(M+1)478；
IR(KBr)3354，2955，2932，2871，1644，1620，1584，1533，1503，1446，1368，1231，1129，1055，1004，735；
1H-NMR(500MHz，CDCl
3)δ 8.96(1H，s，H-4)；8.25-8.26(1H，d，H-8)；7.61-7.65(1H，m，H-5)；7.46-7.47(1H，d，H-6)；7.35-7.38(1H，m，H-7)；6.80(2H，s，PhH)；3.91-3.98(5H，m，OCH
3，NCH
2CH
2CH
2CH
3)；3.85-3.87(2H，m，NHCH
2CH
2OH)；3.66-3.69(2H，m，NHCH
2CH
2OH)；1.44-1.51(2H，m，NCH
2CH
2CH
2CH
3)；0.94-1.02(2H，m，NCH
2CH
2CH
2CH
3)；0.71-0.74(3H，s，NCH
2CH
2CH
2CH
3)。
Embodiment 26 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-β-carbolines (26)
Steps A is identical with the operation of embodiment 22.
Step B: compound 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (38.2g), water (1000ml) mixes, be heated to boiling, stir lower add potassium bichromate (180g) and Glacial acetic acid (240ml), insulation reaction 10 minutes, frozen water cooling reaction mixture is to room temperature, add sodium bisulfite (90g), stirring reaction 5 minutes uses sodium hydroxide neutralization reaction mixed solution to pH 8, ethyl acetate extraction subsequently, be concentrated into driedly, get brown oily matter; The dehydrated alcohol recrystallization gets white crystal 20g, yield 60%, mp167-169 ℃;
FAB-MS m/e(M+1)335；
IR(KBr)3556，3309，2937，2832，1624，1583，1502，1456，1404，1346，1232，1126，1000，827，751；
1H-NMR(500MHz，CDCl
3)δ8.79(1H，s，NH)；8.52-8.53(1H，d，H-3)；8.14-8.16(1H，d，H-5)；7.91-7.92(1H，d，H-8)；7.52-7.57(2H，m，H-6，H-7)；7.29-7.32(1H，m，H-4)；7.13(2H，s，PhH)；3.90(9H，s，OCH
3).
Embodiment 27 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-normal-butyl-β-carboline (27)
1-(3 ', 4 ', 5 '-trimethoxy) phenyl-β-carboline (1.67g, 5mmol), DMF (100ml) mixes, and stirring at room adds 60%NaH (0.6g to clarification, 15mmol), be stirred to without Bubble formation, drip iodo-n-butane (15mmol), the stirring at room reaction, TLC follows the tracks of detection, reacts complete, reaction mixture is poured in the frozen water, ethyl acetate extraction, combining extraction liquid, washing, the saturated salt washing, add ethanol 100ml, concentrated hydrochloric acid is regulated pH to 2～3, is evaporated to dried, dehydrated alcohol band water number, get yellow oil, acetone recrystallization is separated out yellow crystals.Filter, acetone is washed, the ether washing.Solid is soluble in water, the sodium bicarbonate alkalization, ethyl acetate extraction, washing, anhydrous sodium sulfate drying, activated carbon decolorizing filters, concentrating under reduced pressure, residue gets white crystal 1.4g with ether or ether/sherwood oil recrystallization, yield 83%, mp 118-119 ℃;
FAB-MS m/e(M+1)391；
IR(KBr)3013，2959，2931，2835，1617，1582，1505，1450，1410，1362，1238，1123，997，831，751；
1H-NMR(500MHz，CDCl
3)δ 8.49-8.50(1H，d，H-3)；8.17-8.19(1H，d，H-8)；7.98-7.99(1H，d，H-5)；7.57-7.61(1H，m，H-7)；7.43-7.45(1H，d，H-6)；7.30-7.32(1H，m，H-4)；6.83(2H，s，PhH)；3.98-4.01(2H，m，NCH
2(CH
2)
2CH
3)；3.89-3.92(9H，m，OCH
3)；1.44-1.47(2H，m，NCH
2CH
2CH
2CH
3)；0.94-1.01(2H，m，NCH
2CH
2CH
2CH
3)；0.70-0.73(3H，m，2H，m，NCH
2CH
2CH
2CH
3).
Synthetic route 3
The compound of following examples 28-30 can be finished by synthetic route 3:
Embodiment 28 ethyls β-carboline-1-carboxylicesters (28)
Steps A: ethyl 1,2,3,4-tetrahydro-beta-carboline-1-carboxylicesters
Tryptamine hydrochloride (19.61g, 100mmol), glyoxylic acid ethyl ester (30.6g, 250mmol) and dehydrated alcohol (400ml) mix, stirring at room reaction 3 hours, then reflux is 5 hours, removes ethanol under reduced pressure, get faint yellow oily thing, acetone recrystallization gets faint yellow solid, is product and gets hydrochloride.Hydrochloride is water-soluble, sodium bicarbonate alkalization, ethyl acetate extraction, merge organic phase, washing, saturated salt washing, anhydrous sodium sulfate drying, activated carbon decolorizing filters concentrating under reduced pressure, get yellow oil, ether/sherwood oil recrystallization gets yellow needle-like crystal 21.3g, does not need purifying can be directly used in next step reaction.
Step B: ethyl β-carboline-1-carboxylicesters
Ethyl 1,2,3,4-tetrahydro-beta-carboline-1-carboxylicesters (12.2g, 50mmol), dimethylbenzene (200ml), sulphur (4.8g, 150mmol) mix, reflux 6 hours, refrigerator is cold to be put, and separates out yellow solid; Filter, wash with a small amount of dimethylbenzene first, wash with bulk petroleum ether subsequently, ethyl alcohol recrystallization gets white crystal 8.4g, yield 70%, mp 124-125 ℃;
FAB-MS m/e(M+1)241；
IR(KBr)3397，3061，2979，2898，1675，1625，1467，1314，1255，1214，1190，1074，846，727；
1H-NMR(500MHz，CDCl
3)δ 9.93(1H，s，NH)；8.60-8.61(1H，d，H-3)；8.14-8.16(2H，m，H-4，H-5)；7.56-7.63(2H，m，H-7，H-8)；7.32-7.35(1H，m，H-6)；4.59-4.63(2H，m，OCH
2CH
3)；1.53-1.56(3H，m，OCH
2CH
3).
Embodiment 29 ethyl 9-normal-butyl-β-carbolines-1-carboxylicesters (29)
Ethyl β-carboline-1-carboxylicesters (2.4g, 10mmol), DMF (50ml), 60% sodium hydride (0.6g, 20mmol) mix, stirring at room reaction 5 minutes, add iodo-n-butane (5ml), stirring at room, TLC follows the tracks of detection, reacts complete, reaction solution is poured in the cold water, and ethyl acetate extraction merges organic phase, washing adds ethanol 50ml, the concentrated hydrochloric acid acidifying, be evaporated to dried, dehydrated alcohol band water, acetone recrystallization, separate out yellow solid, filter, the ether washing.Solid is water-soluble, sodium bicarbonate alkalization, ethyl acetate extraction merges organic phase, washing, the saturated salt washing, anhydrous sodium sulfate drying, activated carbon decolorizing is evaporated to driedly, and the ether recrystallization gets light yellow oil 2.2g, yield 74%;
FAB-MS m/e(M+1)297.
Embodiment 30 9-normal-butyl-β-carbolines-1-carboxylic acid (30)
Ethyl 9-normal-butyl-β-carboline-1-carboxylicesters (1.48g, 5mmol), water (50ml), ethanol (30ml), sodium hydroxide (1.2g, 30mmol) mix, stirring at room reaction 12 hours, reaction solution cools off with frozen water, and concentrated hydrochloric acid is regulated pH about 6.0, remove ethanol under reduced pressure, get yellow solid, filter, washing, drying, the dehydrated alcohol recrystallization gets light yellow solid 1.3g, yield 97%, mp 133-134 ℃;
FAB-MS m/e(M+1)269；
IR(KBr)3008，2955，2873，1667，1622，1594，1516，1467，1309，1242，1208，1127，1094，1014，893，838，752；
1H-NMR(500MHz，CDCl
3)δ 8.35-8.40(3H，m，H-3，H-4，H-5)；7.77-7.79(1H，d，H-6)；7.66-7.70(1H，t，H-7)；7.33-7.37(1H，t，H-8)；4.62-4.65(2H，t，NCH
2CH
2CH
2CH
3)；1.64-1.67(2H，m，NCH
2CH
2CH
2CH
3)；1.20-1.25(2H，m，NCH
2CH
2CH
2CH
3)；0.83-0.86(3H，t，NCH
2CH
2CH
2CH
3)
Synthetic route 4
The compound of following examples 3 1-45 can be finished by synthetic route 4:
Embodiment 31 3-methylol-9-benzyl-β-carboline (31)
Ethyl 9-benzyl-β-carboline-3-carboxylicesters (10mmol), THF (200ml), LiBH
4(30mmol) after the mixing, the stirring at room reaction, TLC (sherwood oil/acetone=1/1) follows the tracks of detection, reacts complete, and reaction mixture is slowly poured in the 200ml frozen water, and stirring reaction 10 minutes drips concentrated hydrochloric acid to pH 2, stirring at room 4 hours.Mixture cools off with frozen water, and sodium hydroxide solution is regulated pH value to 9, ethyl acetate extraction, and washing, saturated salt is washed, and anhydrous sodium sulfate drying is evaporated to driedly, and acetone recrystallization gets white crystal 1.5g, yield 52%, mp 120-121 ℃;
FAB-MS m/e(M+1)289；
IR(KBr)3170，2938，1627，1559，1495，1467，1363，1264，1205，1048；
1H-NMR(500MHz，CDCl
3)δ 8.73(1H，s，H-1)；8.13-8.15(1H，H-4)；7.96(1H，s，H-5)；7.54-7.58(1H，m，H-8)；7.41-7.43(1H，d，H-7)；7.28-7.31(1H，m，H-6)；7.11-7.27(5H，m，PhH)；5.51(2H，s，CH
2PhH)；4.94(2H，m，CH
2OH)；4.01(1H，s，CH
2OH)。
Embodiment 32 3-methylol-9-hydrocinnamyl-β-carboline (32)
Operation is with embodiment 31, but uses ethyl 9-hydrocinnamyl-β-carboline-3-carboxylicesters to be raw material.Get white crystal 2.0g, yield 63%, mp 98-100 ℃;
FAB-MS m/e(M+1)317；
IR(KBr)3382，3031，2949，2929，2860，1622，1550，1496，1468，1333，1278，1242，1064，1006，872，753；
1H-NMR(500MHz，CDCl
3)δ8.73(1H，s，H-1)；8.12-8.14(1H，d，H-4)；7.94(1H，s，H-6)；7.56-7.60(1H，m，H-5)；7.36-7.38(1H，d，H-8)；7.15-7.38(6H，m，H-7，PhH)；4.94(2H，s，CH
2OH)；4.36-4.40(2H，m，NCH
2CH
2CH
2Ph)；2.70-2.73(2H，m，NCH
2CH
2CH
2Ph)；2.22-2.29(2H，m，NCH
2CH
2CH
2Ph)。
Embodiment 33 3-methylol-9-normal-butyl-1-methyl-β-carboline (33)
Operation is with embodiment 31, but uses ethyl 9-normal-butyl-1-methyl-β-carboline-3-carboxylicesters to be raw material.Get white crystal 2.1g, yield 78%, mp115-116 ℃;
FAB-MS m/e(M+1)269；
IR(KBr) 3153，2967，2918，2838，1619，1557，1477，1362，1278，1245，1208，1075，988，871，741；
1H-NMR(500MHz，CDCl
3)δ 8.79-8.8 1(1H，m，H-4)；8.52(1H，s，H-6)；8.28-8.32(1H，m，H-5)；8.14-8.16(1H，d，H-8)；7.96-8.00(1H，m，H-7)；5.61(2H，s，CH
2OH)；5.15-5.19(2H，m，NCH
2CH
2CH
2CH
3)；3.77(3H，s，CH
3)；2.46-2.54(2H，m，NCH
2CH
2CH
2CH
3)；2.08-2.1 8(2H，m，NCH
2CH
2CH
2CH
3)；1.66-1.69(3H，m，NCH
2CH
2CH
2CH
3)。
Embodiment 34 3-methylol-9-(4 '-fluorine) benzyl-1-methyl-β-carbolines (34)
Operation is with embodiment 31, but uses ethyl 9-(4 '-fluorine) benzyl-1-methyl-β-carboline-3-carboxylicesters to be raw material.Get white crystal 2.3g, yield 72%, mp114-115 ℃;
FAB-MS m/e(M+1)321；
IR(KBr)3188，3044，2925，2870，1619，1564，1506，1477，1456，1345，1282，1208，1125，1039，839，744；
1H-NMR(500MHz，CDCl
3)δ8.13-8.16(1H，m，H-4)；7.87(1H，s，H-6)；7.52-7.59(1H，m，H-5)；7.25-7.36(2H，m，H-7，H-8)；7.25-7.26(1H，m，PhH)；6.91-6.98(4H，m，PhH)；5.74(2H，s，CH
2Ph)；4.91(2H，s，CH
2OH)；2.91(3H，s，CH
3)
Embodiment 35 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-3-methylol-9-normal-butyl-β-carboline (35) operates with embodiment 31, but uses ethyl 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-carboxylicesters is raw material.Get white crystal 3.2g, yield 76%, mp 127-128 ℃;
FAB-MS m/e(M+1)421；
IR(KBr)3338，3181，3061，2986，2832，1621，1583，1505，1465，1409，1366，1297，1235，1179，1126，1051，998，833，739；
1H-NMR(500MHz，CDCl
3)δ 8.30-8.3 1(1H，d，H-4)；8.20(1H，s，H-6)；7.57-7.65(2H，m，H-5，H-8)；7.25-7.29(1H，m，H-7)；6.84(2H，s，PhH)；4.72-4.74(2H，d，CH
2OH)；3.93-3.97(2H，m，NCH
2CH
2CH
2CH
3)；3.80(6H，s，OCH
3)；3.75(3H，s，OCH
3)；1.31-1.39(2H，m，NCH
2CH
2CH
2CH
3)；0.86-0.92(2H，m，NCH
2CH
2CH
2CH
3)；0.62-0.66(3H，m，NCH
2CH
2CH
2CH
3)。
Embodiment 36 3-aldehyde radical-9-benzyl-β-carboline (36)
3-hydroxyl-9-benzyl-β-carboline (10mmol), acetonitrile (250ml), active MnO
2(100mmol) mix, reflux, TLC follows the tracks of detection.React complete, remove by filter MnO
2, be evaporated to driedly, get yellow solid.Solid is dissolved in ethyl acetate, activated carbon decolorizing, concentrating under reduced pressure, acetone recrystallization gets white crystal 2.1g, yield 73%, mp 139-140 ℃;
FAB-MS m/e(M+1)287；
IR(KBr)3061，2938，2814，2724，1702，1622，1579，1497，1464，1358，1332，1268，1178，1055，1025，901，728；
1H-NMR(500MHz，CDCl
3)δ10.31(1H，s，CHO)；8.97(1H，s，H-1)；8.80(1H，s，H-4)；8.26-8.28(1H，d，H-6)；7.66-7.70(1H，m，H-5)；7.54-7.56(1H，d，H-7)；7.42-7.46(1H，m，H-8)；7.15-7.31(5H，m，PhH)；5.64(2H，s，CH
2Ph)。
Embodiment 37 3-aldehyde radical-9-hydrocinnamyl-β-carboline (37)
Operation is with embodiment 36, but uses 3-methylol-9-hydrocinnamyl-β-carboline to be reaction raw materials.Get white crystal 2.2g, yield 70%, mp 97-98 ℃;
FAB-MS m/e(M+1)315；
IR(KBr)3386，3061，3024，2929，2884，2791，2710，1702，1622，1579，1501，1467，1369，1333，1252，1175，1023，905，738；
1H-NMR(500MHz，CDCl
3)δ10.83(1H，s，CHO)；9.32(1H，s，H-1)；8.96(1H，s，H-4)；8.35-8.37(1H，d，H-6)；7.85-7.89(1H，m，H-5)；7.55-7.61(2H，m，H-7，H-8)；7.13-7.30(5H，m，PhH)；4.64-4.67(2H，m，NCH
2CH
2CH
2Ph)；2.79-2.82(2H，m，NCH
2CH
2CH
2Ph)；2.34-2.38(2H，m，NCH
2CH
2CH
2Ph)。
Embodiment 38 3-aldehyde radical-9-normal-butyl-1-methyl-β-carboline (38)
Operation is with embodiment 36, but uses 3-methylol-9-normal-butyl-1-methyl-β-carboline to be reaction raw materials.Get white crystal 1.9g, yield 71%, mp 103-104 ℃;
FAB-MS m/e(M+1)267；
IR(KBr)3342，3059，3019，2958，2930，2869，1679，1619，1570，1456，1370，1337，1297，1248，1196，1112，961，736；
1H-NMR(500MHz，CDCl
3)δ10.45(1H，s，CHO)；8.67(1H，s，H-4)；8.21-8.23(1H，d，H-6)；7.40-7.73(3H，m，H-5，H-7，H-8)；4.61-4.65(2H，m，NCH
2CH
2CH
2CH
3)；3.27(3H，s，CH
3)；1.87-1.93(2H，m，NCH
2CH
2CH
2CH
3)；1.46-1.52(2H，m，NCH
2CH
2CH
2CH
3)；0.99-1.03(3H，m，NCH
2CH
2CH
2CH
3)。
Embodiment 39 3-aldehyde radical-9-(4 '-fluorine) benzyl-1-methyl-β-carbolines (39)
Operation is with embodiment 36, but uses 3-methylol-9-(4 '-fluorine) benzyl-1-methyl-β-carboline to be reaction raw materials.Get white crystal 2.1g, yield 66%, mp137-139 ℃;
FAB-MS m/e(M+1)319；
IR(KBr)3339，3060，3020，2948，1678，1616，1564，1511，1458，1381，1335，1294，1258，1206，1126，966，837，739；
1H-NMR(500MHz，CDCl
3)δ10.32(1H，s，CHO)；8.68(1H，s，H-4)；8.24-8.26(1H，d，H-6)；7.62-7.66(1H，m，H-5)；7.41-7.45(2H，m，H-7，H-8)；6.93-7.01(4H，m，PhH)；5.88(2H，s，NCH
2Ph)；3.04(3H，s，CH
3)。
Embodiment 40 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-3-aldehyde radical-9-normal-butyl-β-carboline (40)
Operation is with embodiment 36, and phenyl-3-methylol-9-normal-butyl-β-carboline is reaction raw materials but use 1-(3 ', 4 ', 5 '-trimethoxy).Get white crystal 3.0g, yield 72%, mp 150-151 ℃;
FAB-MS m/e(M+1)419；
IR(KBr)3059，3002，2958，2809，1694，1618，1582，1505，1464，1410，1363，1244，1203，1124，1001，969，851，754；
1H-NMR(500MHz，CDCl
3)δ10.26(1H，s，CHO)；8.76(1H，s，H-4)；8.25-8.27(1H，d，H-6)；7.64-7.68(1H，m，H-5)；7.49-7.51(1H，d，H-8)；7.38-7.42(1H，m，H-7)；6.84(2H，s，PhH)；3.98-4.02(2H，m，NCH
2CH
2CH
2CH
3)；3.93(3H，s，OCH
3)；3.91(6H，s，OCH
3)；1.48-1.56(2H，m，NCH
2CH
2CH
2CH
3)；0.96-1.06(2H，m，NCH
2CH
2CH
2CH
3)；0.73-0.76(3H，m，NCH
2CH
2CH
2CH
3).
Embodiment 41 9-benzyl-β-carbolines-3-aldehyde radical thiosemicarbazone (41)
3-aldehyde radical-9-benzyl-β-carboline (2mmol), thiosemicarbazide (2mmol), dehydrated alcohol (100ml) mix reflux 12 hours, the faint yellow solid of separating out in the reaction process.Be cooled to room temperature, filter, get yellow solid.Dehydrated alcohol recrystallization three times gets yellow solid 0.48g, yield 67%, mp244-246 ℃;
FAB-MS m/e(M+1)360；
IR(KBr)3393，3279，3 175，3025，2924，2748，1626，1596，1538，1497，1465，1360，1332，1296，1214，1097，1003，734；
1H-NMR(500MHz，DMSO-d
6)δ11.53(1H，s，NH)；9.07(1H，s，NH)；9.02(1H，s，H-1)；8.27-8.30(3H，m，H-4，H-8，CH＝NNH)；8.09(1H，s，H-5)；7.75-7.77(1H，d，H-7)；7.59-7.64(1H，m，CH＝N)；7.27-7.36(6H，m，H-6，PhH)；5.78(2H，s，NCH
2Ph)。
Embodiment 42 9-hydrocinnamyl-β-carbolines-3-aldehyde radical thiosemicarbazone (42)
Operation is with embodiment 41, but uses 3-aldehyde radical-9-hydrocinnamyl-3-carboline to be reaction raw materials.Get yellow solid 0.51g, yield 68%, mp 225-226 ℃;
FAB-MS m/e(M+1)388；
IR(KBr)3385，3237，3160，3025，2936，1626，1593，1527，1495，1354，1331，1292，1246，1087，834，743；
1H-NMR(500MHz，DMSO-d
6)δ11.53(1H，s，NH)；9.05(1H，s，NH)；8.94(1H，s，H-1)；8.24-8.30(3H，m，H-4，H-8，CH＝NNH)；8.08(1H，s，H-5)；7.60-7.69(2H，m，H-7，CH＝N)；7.23-7.35(6H，m，H-6，PhH)；4.52-4.55(2H，m，NCH
2CH
2CH
2Ph)；2.65-2.69(2H，m，NCH
2CH
2CH
2Ph)；2.10-2.18(2H，m，NCH
2CH
2CH
2Ph)。
Embodiment 43 9-normal-butyl-1-methyl-β-carboline-3-aldehyde radical thiosemicarbazone (43)
Operation is with embodiment 41, but uses 3-aldehyde radical-9-normal-butyl-1-methyl-β-carboline to be reaction raw materials.Get yellow solid 0.4g, yield 59%, mp 214-216 ℃;
FAB-MSm/e(M+1)340；
IR(KBr)3404，3275，3168，3104，2958，2927，2864，2769，1620，1600，1532，1453，1367，1329，1247，1203，1063，819，735；
1H-NMR(500MHz，DMSO-d
6)δ11.52(1H，s，NH)；8.91(1H，s，NH)；8.30(1H，s，H-4)；8.22-8.24(2H，m，H-8，CH＝NNh)；8.06(1H，s，H-5)；7.72-7.74(1H，m，H-7)；7.59-7.63(1H，m，，CH＝N)；7.31-7.34(1H，m，H-6)；4.57-4.68(2H，m，NCH
2CH
2CH
2CH
3)；2.98(3H，s，CH
3)；1.71-1.80(2H，m，NCH
2CH
2CH
2CH
3)；1.34-1.43(2H，m，NCH
2CH
2CH
2CH
3)；0.90-0.94(3H，m，NCH
2CH
2CH
2CH
3).
Embodiment 44 9-(4 '-fluorine) benzyl-1-methyl-β-carboline-3-aldehyde radical thiosemicarbazone (44)
Operation is with embodiment 41, but uses 3-aldehyde radical-9-(4 '-fluorine) benzyl-1-methyl-β-carboline to be reaction raw materials.Get yellow solid 0.52g, yield 66%, mp 244-245 ℃;
FAB-MS m/e(M+1)392；
IR(KBr)3401，3271，3175，3104，2939，2769，1623，1601，1530，1455，1359，1329，1288，1213，1155，1103，1061，1003，838，742；
1H-NMR(500MHz，DMSO-d
6)δ11.54(1H，s，NH)；8.97(1H，s，NH)；8.28-8.31(2H，m，H-4，H-8)；8.21(1H，s，CH＝NNH)；8.09(1H，s，H-5)；7.66-7.69(1H，d，J＝10.5Hz，CH＝N)；7.57-7.61(1H，m，H-7)；7.33-7.36(1H，m，H-6)；6.98-7.14(4H，m，PhH)；5.91(2H，s，NCH
2Ph)；2.90(3H，s，CH
3).。
Embodiment 45 1-(3 ', 4 ', 5 '-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-aldehyde radical thiosemicarbazone (45)
Operation is with embodiment 41, and phenyl-3-aldehyde radical-9-normal-butyl-β-carboline is reaction raw materials but use 1-(3 ', 4 ', 5 '-trimethoxy).Get yellow solid 0.73g, yield 74%, mp 145-147 ℃;
FAB-MS m/e(M+1)492；
IR(KBr)3525，3351，3150，2958，2936，2827，1618，1572，1538，1503，1462，1436，1332，1233，1127，1098，978，834，733；
1H-NMR(500MHz，DMSO-d
6)δ 11.59(1H，s，NH)；9.10(1H，s，NH)；8.26-8.35(3H，m，H-4，H-8，CH＝NNH)；8.13(1H，s，H-5)；7.61-7.70(2H，d，CH＝N，H-7)；7.33-7.37(1H，m，H-6)；6.88(2H，s，PhH)；3.93-3.97(2H，m，NCH
2CH
2CH
2CH
3)；3.81(6H，s，OCH
3)；3.77(3H，s，OCH
3)；1.36-1.42(2H，m，NCH
2CH
2CH
2CH
3)；0.89-0.95(2H，m，NCH
2CH
2CH
2CH
3)；0.64-0.68(2H，m，NCH
2CH
2CH
2CH
3)。
Synthetic route 5
The compound of following examples 46-47 can be finished by synthetic route 5:
Embodiment 46 3-methylol-9-hydrocinnamyl-2-benzyl-β-carboline bromine salt (46)
3-methylol-9-hydrocinnamyl-β-carboline (0.25g, 1mmol), ethyl acetate (50ml) and cylite (10ml) are mixed, heating reflux reaction 12 hours, the reaction solution cooling is filtered, and the ether washing gets yellow solid.Yellow solid is added in the 100ml dehydrated alcohol, heating for dissolving, filtered while hot, filtrate decompression is concentrated into 40ml, and the refrigerator recrystallization gets yellow crystals 0.40g, yield 80%, mp 241-242 ℃;
FAB-MS m/e 407；
IR(KBr)3228，3026，3004，2942，1641，1606，1513，1458，1338，1205，1132，1089，740；
1H-NMR(500MHz，DMSO-d
6)δ9.97(1H，s，H-1)；8.93(1H，s，H-4)；8.60-8.62(1H，d，J＝10.0Hz，H-6)；7.97-7.99(2H，m，H-5，H-7)；7.11-7.52(11H，m，H-8，PhH)；6.10(2H，s，CH
2Ph)；4.87(2H，s，CH
2OH)；4.70-4.74(2H，m，NCH
2CH
2CH
2Ph)；2.67-2.71(2H，m，NCH
2CH
2CH
2Ph)；2.19-2.23(2H，m，NCH
2CH
2CH
2Ph).
Embodiment 47 3-aldehyde radical-9-hydrocinnamyl-2-benzyl-β-carboline bromine salt (47)
Operation is with embodiment 46, but uses 3-aldehyde radical-9-hydrocinnamyl-β-carboline to be reaction raw materials.Get yellow crystals 0.16g, yield 32%, mp 180-181 ℃;
FAB-MS m/e 405；
IR(KBr)2965，2930，1709，1630，1522，1457，1340，1254，1178，1106，772；
1H-NMR(500MHz，DMSO-d
6)δ10.31(1H，s，H-1)；10.20(1H，s，H-4)；9.53(1H，s，H-6)；8.70-8.72(1H，d，J＝10.0Hz，H-5)；8.08-8.10(1H，d，J＝10.5Hz，H-7)；7.96-8.00(1H，m，H-8)；7.11-7.66(10H，m，PhH)；6.50(2H，s，CH
2Ph)；4.87(2H，s，CH
2OH)；4.83-4.87(2H，m，NCH
2CH
2CH
2Ph)；2.70-2.74(2H，m，NCH
2CH
2CH
2Ph)；2.26-2.29(2H，m，NCH
2CH
2CH
2Ph).
Synthetic route 6
The compound of following examples 48 can be finished by synthetic route 6:
Embodiment 48 3-aldehyde radical-9-hydrocinnamyl-β-carboline sodium bisulfite additive salt (48)
3-aldehyde radical-9-hydrocinnamyl-β-carboline (2mmol) is added in the 25ml sodium bisulfite saturated solution, and stirring at room reaction 12 hours is filtered, and 50% ethanolic soln washing gets faint yellow solid.Faint yellow solid is dissolved in the ethanolic soln of 100ml 50%, reflux, until the solution clarification, filtered while hot, filtrate is cooled to room temperature, separates out white solid, filters 50% ethanolic soln washing, drying gets white solid 0.14g, yield 32.3%, mp 132-133 ℃; FAB-MS m/e 418.
Synthetic route 7
The compound of following examples 49-51 can be finished by synthetic route 7:
Embodiment 49 1-aldehyde radical-9-hydrocinnamyl-β-carboline (49)
9-hydrocinnamyl-1-methyl-β-carboline (10mmol), tin anhydride (20mmol) are placed the 100ml round-bottomed flask, then add the new Isosorbide-5-Nitrae-dioxane that steams of 50ml, reflux 4 hours, filtered while hot, and with the washing of a small amount of ethyl acetate, filtrate decompression is concentrated to be added a small amount of silica gel again and is spin-dried for, silica gel column chromatography, V (sherwood oil): V (ethyl acetate)=10: 1-4: 1 wash-out, collect the product point, concentrating under reduced pressure, get yellow solid, productive rate 70%, mp 69-70 ℃;
ESI-MS for C
21H
18N
2O[M+H]
+，Calcd：314，Found：337；
IR(KBr，cm
-1)3059，3028，2943，2917，2826，1703，1620，1541，1442，1419，1369，1340，1182，1086，1038，930，858，828，754，744；
1H-NMR(CDCl
3，300MHz)δ：10.30(1H，s，CHO)，8.64(1H，d，H-3)，8.18-8.13(2H，t，H-4，H-8)，7.62(1H，t，ArH)，7.39-7.34(2H，m，ArH)，7.29-7.26(2H，m，ArH)，7.18-7.14(3H，m，ArH)，4.91(2H，m，NCH
2)，2.72(2H，m，NCH
2CH
2CH
2)，2.14(2H，t，NCH
2CH
2)；
Embodiment 50 9-hydrocinnamyl-β-carbolines-1-aldehyde radical thiosemicarbazone (50)
In the 50ml round-bottomed flask, add 1-aldehyde radical-9-hydrocinnamyl-β-carboline (1mmol), thiosemicarbazide (1mmol) and ethanol (30ml), spend the night in 85 ℃ of oil bath stirring and refluxing, there is yellow crystals to separate out, is evaporated to about 10ml, the refrigerator recrystallization, suction filtration, dry yellow crystals, productive rate 77%, mp 187-188 ℃ of getting;
ESI-MS for C
22H
21N
5S[M+H]
+，Calcd：387，Found：388；
1H-NMR(DMSO，300MHz)δ：12.14(1H，s，NH)，8.80(1H，s，H-3)，8.62(1H，m，ArH)，8.57-8.54(2H，m，ArH)，8.44(1H，m，ArH)，7.77(2H，s，ArH)，7.41(1H，s，ArH)，7.21-7.19(2H，d，ArH)，7.13-7.11(2H，d，ArH)，4.72(2H，s，NCH
2)，2.66(2H，m，NCH
2CH
2)，2.03(2H，m，NCH
2CH
2CH
2).
Embodiment 51 9-hydrocinnamyl-β-carbolines-1-aldehyde contracting Vasoxyl (51)
Weighing sodium hydroxide (1mmol) is in small beaker, add about 1ml water dissolution, add again Vasoxyl (1mmol), fill in the 50ml round-bottomed flask of ethanol (30ml) of 1-aldehyde radical-9-hydrocinnamyl-β-carboline (1mmol) until its complete molten rear adding, stirring at room 2 h, TLC follows the tracks of detection, until its rear stopped reaction that reacts completely, concentrating under reduced pressure, refrigerator is placed, suction filtration gets yellow crystals, productive rate 82%, mp 123-124 ℃;
ESI-MS for C
22H
21N
3O，[M+H]
+ Calcd：343，Found：344；
1H-NMR(CDCl
3，300MHz)δ：8.53(1H，d，H-3)，8.16-8.13(2H，s，ArH，CHN)，7.67-7.61(1H，m，ArH)，7.38-7.36(1H，m，ArH)，7.36-7.33(1H，m，ArH)，7.30-7.25(3H，m，ArH)，7.21-7.18(3H，m，ArH)，4.74(2H，t，NCH
2)，2.85(2H，t，NCH
2CH
2CH
2)，2.31(2H，m，NCH
2CH
2)，1.66(3H，S，OCH
3)；
13C-NMR(DMSO，300MHz)δ：142.18，141.48，140.27，137.23，131.37，130.62，128.94，128.71，126.53，123.01，121.58，120.28，119.66，117.89，113.98，111.12，43.82，32.86，32.09。
Synthetic route 8
The compound of following examples 52-53 can be finished by synthetic route 8:
Embodiment 52 N-(4-β-carboline-benzene oxygen acetyl) phenylalanine ethyl ester (52)
Steps A: 1-(4 '-hydroxyl) phenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid
In the 250ml round-bottomed flask, add L-Trp (12.24g, 60mmol), p-Hydroxybenzaldehyde (7.38g, 60mmol) and Glacial acetic acid (150ml), 10h is stirred in 85 ℃ of oil baths of mixture, and the adularescent solid is separated out, stopped reaction, after being cooled to room temperature, with mixture impouring frozen water, transfer pH to 5-6 with sodium hydroxide solution, refrigerator is placed 2-3h, suction filtration, washing, dry, get faint yellow solid, productive rate 96%, mp 233-235 ℃.
Step B:1-(4 '-hydroxyl) phenyl-β-carboline
With 1-(4 '-hydroxyl) phenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (50mmol) adds in the 500ml water, be heated to boil after, stir lower potassium bichromate solution and the 100ml Glacial acetic acid that successively adds 350ml 10%, continue heated and stirred reaction 5 minutes, cool off reaction solution to room temperature, suction filtration, the gained solid with the sodium hydroxide solution dissolving, leaches insolubles impurity again, and filtrate is transferred pH to 6-7 with HCl, there are a large amount of yellow mercury oxides to separate out, suction filtration, drying, get yellow solid, productive rate 60%.Do not need purifying can be directly used in next step reaction.
Step C:1-(the inferior methoxyl group of 4 '-ethoxy carbonyl) phenyl-β-carboline
In the 250ml round-bottomed flask, add 1-(4 '-hydroxyl) phenyl-β-carboline (5.2g, the acetone 100ml that 20mmol), crosses through Anhydrous potassium carbonate (40mmol) and the drying of grind into powder, 70 ℃ of oil bath heated and stirred, drip ethyl chloroacetate (40mmol) behind the backflow 1h, continue to reflux and spend the night.TLC follows the tracks of detection, reacts complete, suction filtration, and filtrate decompression is spin-dried for, and silica gel column chromatography (V (sherwood oil): V (ethyl acetate)=3: 1 wash-outs) gets yellow solid, productive rate 90%, mp 175-176 ℃;
ESI-MS for C
21H
18N
2O
3[M+H]
+，Calcd：346.38 Found：347.40；
IR(KBr，cm
-1)v：3362，3056，2975，2877，1751，1606，1506，1462，1278，1232，1070，832，746，604；
1H-NMR(CDCl
3，300MHz)δ：8.44(1H，d，ArH)，8.36(1H，d，ArH)，8.13(1H，d，ArH)，8.08(1H，d，ArH)，7.63(1H，t，ArH)，7.51(1H，d，ArH)，4.24(2H，q，CH
2)，4.04(2H，s，OCH
2CO
2)，1.27(3H，t，CH
3)；
13C-NMR(CDCl
3，300MHz)δ：168.91，158.11，142.83，141.03，138.99，133.74，132.16，129.92，129.70，128.47，121.79，120.13，115.05，113.66，112.06，65.50，61.74，14.52。
Step D:1-(the inferior methoxyl group of 4 '-ethoxy carbonyl) phenyl-β-carboline (30mmol), sodium hydroxide (150mmol) aqueous solution 80ml, with ethanol 80ml, oil bath stirring and refluxing 1.5 hours, reaction is finished, and transfers pH to 5-6 with 10%HC1 solution, there is yellow flocks to separate out, refrigerator is placed cooling, the yellow solid of suction filtration, oven dry, productive rate 95%, mp 192-194 ℃;
ESI-MS for C
19H
14N
2O
3[M-H]
-，Calcd：318.33 Found：317.35；
IR(KBr，cm
-1)v：3368，3053，2972，2839，1727，1689，1587，1459，1421，1334，1241，1144，1022，958，739，667，605；
1H-NMR(DMSO，300MHz)δ：11.47(1H，s，NH)，8.39(1H，d，H-3)，8.22(1H，d，H-4)，8.04(1H，d，H-8)，7.95(2H，d，ArH)，7.62(1H，d，H-5)，7.52(1H，m，H-6)，7.23(1 H，m，H-7)，7.10(2H，m，ArH)，4.71(2H，s，CH
2).
Step e: N-(4-β-carboline-benzene oxygen acetyl) phenylalanine ethyl ester
In the 50ml round-bottomed flask, add step D gained solid (5mmol), condensing agent N, the DMF of the two imidazoles (10mmol) of N`-carbonyl and 30ml drying, behind 50 ℃ of stirring in water bath 1h, add L-Phe ethyl ester (5mmol), 50 ℃ of water-baths continue stirring reaction 24h again, and TLC follows the tracks of detection, react complete, stopped reaction is evaporated to oily matter, and silicagel column separates, V (sherwood oil): V (ethyl acetate)=4: 1 wash-outs, collect the product point, concentrating under reduced pressure gets white raphide, productive rate 81%, mp 102-103 ℃;
ESI-MS for C
30H
27N
3O
4[M+H]
+，Calcd：493.55，Found：494.65；
IR(KBr，cm
-1)v：3413，3060，2977，1625，1565，1533，1437，749；
1H-NMR(CDCl
3，300MHz)δ：8.55(1H，s，NH)，8.53(1H，d，H-3)，8.15(1H，s，H-4)，7.94-7.91(3H，m，ArH)，7.53-7.52(2H，m，ArH，CONH)，7.34-7.22(4H，m，ArH)，7.13-7.06(5H，m，ArH)，4.96(1H，m，CH)，4.56(2H，S，OCH
2CO)，4.21(2H，q，CO
2CH
2)，3.18(2H，d，ArCH
2)，1.26(3H，t，CH
3)；
13C-NMR(CDCl
3，300MHz)δ：171.24，167.96，157.54，142.50，140.82，139.41，135.75，133.66，132.82，129.91，129.44，128.82，127.44，122.03，121.92，120.36，115.42，113.80，111.96，67.47，62.02，53.11，38.38，14.49.
Embodiment 53N-(4-β-carboline-benzene oxygen acetyl) phenylalanine (53)
Compound N-(4-β-carboline-benzene oxygen acetyl) phenylalanine ethyl ester (1mmol) is dissolved in the 10ml dehydrated alcohol, adds the 10ml aqueous solution of NaOH (5mmol), heating reflux reaction 1.5 hours again.After reacting completely, boil off part ethanol, be neutralized to pH 5 with 2M hydrochloric acid again, the freezing placement waits to separate out, and suction filtration gets yellow solid, yield 94%, mp 151-152 ℃;
ESI-MS for C
28H
23N
3O
4[M-H]
-，Calcd：465.50 Found：464.60；
IR(KBr，cm
-1)3409，3061，2925，1667，1628，1509，1383，1236，1182，1058，832，749；
1H-NMR(DMSO，300MHz)δ：11.47(1H，s，COOH)，8.40(1H，d，H-3)，8.35(1H，d，H-4)，8.23(1H，d，H-8)，8.06(1H，d，H-5)，7.96-7.93(2H，m，ArH)，7.64-7.62(1H，d，CONH，H-4)，7.56-7.50(1H，m，ArH)，7.28-7.17(5H，m，ArH)，7.10-7.07(2H，m，ArH)，4.59(2H，S，OCH
2CO)，4.56-4.51(1H，m，CH)，3.12-3.02(2H，d，ArCH
2)；
13C-NMR(DMSO，300MHz)δ：173.28，168.12，158.64，142.54，141.73，138.86，138.14，133.42，132.13 130.28，129.82，128.87，127.11，122.18，121.54，120.13，115.58，114.07，113.11，67.52，54.01，37.40。
Synthetic route 9
The compound of following examples 54-61 can be finished by synthetic route 9:
Embodiment 54 N-(9-normal-butyl-β-carboline-3-formyl) phenylalanine ethyl ester (54)
Steps A: L-Phe ethyl ester synthetic
The 10mmol L-Phe is disperseed to be in the 100ml dehydrated alcohol, place the low-temp reaction device to be cooled to-5 ℃ and stirring, slowly drip 0.8ml (10mmol) thionyl chloride under the low temperature, dropwise the solution clarification, rise to room temperature and continue stirring 10 hours.React complete, excessive methanol and sulfur oxychloride are removed in decompression, namely get the hydrochloride of L-Phe ethyl ester.
The L-Phe carbethoxy hydrochloride is dissolved in the dehydrated alcohol, adds 2 times of anhydrous BaO of amount, stirred overnight at room temperature leaves standstill rear suction filtration, and the vacuum rotary steam Recycled ethanol obtains amino acid ester; Perhaps in the aqueous solution of amino acid ester hydrochloride, add saturated NaHCO
3Or Na
2CO
3Solution, to pH8, with ethyl acetate or extracted with diethyl ether, anhydrous MgSO
4Drying reclaims ethyl acetate, namely gets the L-Phe ethyl ester.
Step B:N-(9-normal-butyl-β-carboline-3-formyl) phenylalanine ethyl ester
The DMF of 9-normal-butyl-β-carboline-3-carboxylic acid (5mmol), CDI (5.5mmol) and 20ml drying is placed the 50mL round-bottomed flask, stirring at room 0.5 hour, then add compound L-phenylalanine methyl ester (5mmol), room temperature or stirred 8 hours when rising to 40 ℃, TLC follows the tracks of reaction.After reaction finished, vacuum rotary steam reclaimed DMF, and product separates through column chromatography (petrol ether/ethyl acetate), and ethyl alcohol recrystallization gets white crystal, yield 92%, mp 107-108 ℃;
ESI-MS m/e 444[M+H]
+；
IR(KBr)3370(N-H)，3063，3028，2959，2928，2872，1735，1665，1624，1586，1516，1494，1199，750cm
-1；
1H-NMR(300MHz，CDCl
3)δ：8.88(1H，s，ArH)；8.76(1H，s，ArH)；8.61(1H，d，CONH)；8.20(1H，d，ArH)；7.62(1H，t，ArH)；7.49(1H，d，ArH)；7.36-7.20(6H，m，6ArH)；5.13(1H，q，CH)；4.42(2H，t，NCH
2)；4.19(2H，q，OCH
2)；3.29(2H，d，CHCH
2Ph)；1.92(2H，m，CH
2)；1.42(2H，m，CH
2)；1.25(3H，t，CH
3)；0.98(3H，t，CH
3).
Embodiment 55N-(9-normal-butyl-β-carboline-3-formyl) methionine(Met) ethyl ester (55)
Operation is with embodiment 54, but use METHIONINE ethyl ester is as reaction raw materials.Get white crystal, yield 95%, mp 100-102 ℃;
ESI-MS m/e 428[M+H]
+；
IR(KBr)3372，3050，2956，2927，2858，1730，1674，1625，15 18，1495，1211，745cm
-1；
1H-NMR(300MHz，CDCl
3)δ：8.91(1H，s，ArH)；8.80(1H，s，ArH)；8.70(1H，d，CONH)；8.21(1H，d，ArH)；7.64(1H，t，ArH)；7.5 1(1H，d，ArH)；7.35(1H，t，ArH)；5.00(1H，m，CH)；4.43(2H，t，NCH
2)；4.27(2H，q，OCH
2)；2.67(2H，m，SCH
2)；2.41-2.17(2H，m，CHCH
2)；2.14(3H，s，SCH
3)；1.92(2H，m，CH
2)；1.42(2H，m，CH
2)；1.33(3H，t，CH
3)；0.97(3H，t，CH
3).
Embodiment 56N-(9-benzyl-β-carboline-3-formyl) phenylalanine ethyl ester (56)
Operation is with embodiment 54, but use 9-benzyl-β-carboline-3-carboxylic acid and L-Phe ethyl ester are as reaction raw materials.Get white crystal, yield 96%, mp 147-149 ℃;
ESI-MS m/e 478[M+H]
+；
IR(KBr)3383，3060，3031，2979，2931，2867，1734，1665，1619，1584，1513，1459，1205，734，697cm
-1；
1H-NMR(300MHz，CDCl
3)δ：8.91(1H，s，ArH)；8.70(1H，s，ArH)；8.58(1H，d，CONH)；8.23(1H，d，ArH)；7.60(1H，t，ArH)；7.48(1H，d，ArH)；7.36(1H，t，ArH)；7.29-7.13(10H，m，10ArH)；5.62(2H，s，NCH
2Ph)；5.12(1H，m，CH)；4.19(2H，q，OCH
2)；3.28(2H，d，CHCH
2)；1.24(3H，t，CH
3).
Embodiment 57N-(9-hydrocinnamyl-β-carboline-3-formyl) α-amino-isovaleric acid ethyl ester (57)
Operation is with embodiment 54, but use 9-hydrocinnamyl-β-carboline-3-carboxylic acid and Valine ethyl ester are as reaction raw materials.Get white crystal, yield 82%, mp 123-125 ℃;
ESI-MS m/e 459[M+H]
+；
IR(KBr)3366(N-H)，3061，3027，2960，1730，1669，1588，1518，1463，1193，746cm
-1；
1H-NMR(300MHz，CDCl
3)δ：8.90(1H，s，ArH)；8.71(1H，s，ArH)；8.63(1H，d，CONH)；8.20(1H，d，ArH)；7.60(1H，t，ArH)；7.41-7.15(7H，m，7ArH)；4.81(1H，m，CH)；4.43(2H，t，NCH
2)；4.26(2H，q，OCH
2)；2.74(2H，t，CH
2Ph)；2.40-2.26(3H，m，CH
2，CH(CH
3)
2)；1.33(3H，t，CH
3)；1.07(6H，t，2CH
3).
Embodiment 58N-(9-hydrocinnamyl-β-carboline-3-formyl) phenylalanine ethyl ester (58)
Operation is with embodiment 54, but use 9-hydrocinnamyl-β-carboline-3-carboxylic acid and L-Phe ethyl ester are as reaction raw materials.Get white crystal, yield 89%, mp 109-111 ℃;
FAB-MS m/e 507[M+H]
+；
IR(KBr)3381，3034，2935，2862，1741，1661，1590，1509，1459，1197，746cm
-1；
1H-NMR(300MHz，CDCl
3)δ：8.88(1H，s，ArH)；8.66(1H，s，ArH)；8.61(1H，d，CONH)；8.19(1H，d，ArH)；7.61(1H，t，ArH)；7.41-7.15(12H，m，12ArH)；5.14(1H，m，CH)；4.41(2H，t，NCH
2)；4.20(2H，q，OCH
2)；3.29(2H，d，CHCH
2)；2.73(2H，t，CH
2Ph)；2.28(2H，m，CH
2)；1.25(3H，t，CH
3)；
13C NMR(75 MHz，CDCl
3)δ：171.86，165.29，141.61，140.56，139.65，137.82，136.60，130.34，129.65，129.04，128.91，128.80，128.69，128.45，127.14，126.56，122.43，121.76，120.68，114.66，109.94，61.69，53.96，43.26，38.97，33.51，30.65，14.59.
Embodiment 59 N-(9-normal-butyl-β-carboline-3-formyl) phenylalanine (59)
N-(9-normal-butyl-β-carboline-3-formyl) phenylalanine ethyl ester (1mmol) is dissolved in the 10ml dehydrated alcohol, adds the 10ml aqueous solution of NaOH (5mmol), heating reflux reaction 1.5 hours again.After reacting completely, boil off part alcohol liquid, be neutralized to pH5 with 2M hydrochloric acid again, the freezing placement waits to separate out.Get yellow solid, yield 94%, mp 190-192 ℃;
ESI-MS m/e 436[M-H]
-；
IR(KBr)3346，3030，2927，2853，1734，1636，1590，1521，1500，1201，742cm
-1；
1H-NMR(300MHz，DMSO-d
6)δ：9.03(1H，s，ArH)；8.80(1H，s，ArH)；8.63(1H，d，CONH)；8.39(1H，d，ArH)；7.75(1H，d，ArH)；7.63(1H，t，ArH)；7.31(1H，t，ArH)；7.26-7.14(5H，m，5ArH)；4.82(1H，q，CH)；4.55(2H，t，NCH
2)；3.25(2H，m，CHCH
2)；1.80(2H，m，CH
2)；1.26(2H，m，CH
2)；0.86(3H，t，CH
3).
Embodiment 60 N-(9-hydrocinnamyl-β-carboline-3-formyl) phenylalanine (60)
Operation is with embodiment 59, but uses N-(9-normal-butyl-β-carboline-3-formyl) phenylalanine ethyl ester to be raw material.Get yellow crystals, yield 97%, mp 179-180 ℃;
ESI-MSm/e 477[M-H]
-；
IR(KBr)3376，3027，2929，2860，1735，1626，1591，1526，1500，1210，746，cm
-1；
1H-NMR(300MHz，DMSO-d
6)δ：9.02(1H，s，ArH)；8.86(1H，s，ArH)；8.73(1H，d，CONH)；8.40(1H，d，ArH)；7.72(1H，d，ArH)；7.65(1H，t，ArH)；7.33(1H，t，ArH)；7.25-7.14(10H，m，10ArH)；4.90(1H，m，CH)；4.60(2H，t，NCH
2)；3.24(2H，m，CHCH
2)；2.65(2H，t，CH
2Ph)；2.1 3(2H，m，CH
2).
Embodiment 61N-(2-benzyl-9-hydrocinnamyl-β-carboline-3-formyl) phenylalanine ethyl ester bromine salt (61)
N-(9-hydrocinnamyl-β-carboline-3-formyl) phenylalanine ethyl ester (10mmol) is dissolved in the ethyl acetate (100ml), adds cylite (150mmol), heated and stirred backflow 24h, then place the refrigerator crystallization, suction filtration, the ethyl acetate washing is drying to obtain product.The dehydrated alcohol recrystallization gets yellow crystals, yield 40%, mp 188-189 ℃;
ESI-MS m/e 597[M-Br]
+；
IR(KBr)3410，3181，3027，2983，2939，2851，1736(C＝O)，1670(C＝O)，1633，1541，1515，1457，1341，1244，748 cm
-1；
1H-NMR(300MHz，DMSO-d
6)δ：9.98(1H，s，ArH)；9.80(1H，d，CONH)；8.65(1H，s，ArH)；8.52(1H，d，ArH)；8.01(1H，d，ArH)；7.92(1H，t，ArH)；7.56(1H，t，ArH)；7.33-7.04(1 5H，m，15ArH)；6.00(2H，t，N
+CH
2Ph)；4.75(3H，CH，NCH
2)；4.11(2H，q，OCH
2)；3.05(2H，m，CHCH
2)；2.63(2H，t，CH
2Ph)；2.19(2H，m，CH
2)；1.13(3H，t，CH
3)；
13C NMR(75MHz，DMSO-d
6)δ：171.06(C＝O)，162.31(C＝O)，145.22，141.46，137.37，136.39，135.86，135.37，133.42，131.92，131.82，129.86，129.44，129.08，128.80，128.59，127.50，126.47，124.51，123.24，119.97，119.38，112.51，61.86，61.47，55.32，44.71，37.32，33.03，31.05，14.81.
Synthetic route 10
The compound of following examples 62-67 can be finished by synthetic route 10:
Embodiment 62 N-(9-normal-butyl-1-methyl-β-carboline-7-oxygen acetyl) methionine(Met) ethyl ester (62) steps A: 7-(the inferior methoxyl group of ethoxy carbonyl)-9-normal-butyl-1-methyl-β-carboline
In the 100mL round-bottomed flask, add 7-hydroxyl-9-normal-butyl-1-methyl-β-carboline (10mmol), grind to form the anhydrous K of powdery
2CO
3(20mmol) with dry acetone (50ml), after 70 ℃ of lower half an hour of refluxing, slowly drip ethyl chloroacetate (20mmol), TLC follows the tracks of detection.React complete after, be down to room temperature, suction filtration, filter cake are with washing with acetone three times, solvent evaporated obtains the liquid of brown color, separates through column chromatography (petrol ether/ethyl acetate), namely gets product.
Step B:7-(fluoroacetic acid base)-9-normal-butyl-1-methyl-β-carboline
The steps A product is dissolved in the 30ml dehydrated alcohol, adds the aqueous solution 30ml of 5 times of amount NaOH again, heating reflux reaction 2 hours is after the reaction solution cooling, steam except behind the part ethanolic soln, be neutralized to pH5 with 2M hydrochloric acid again, solid is separated out after the cooling, suction filtration, oven dry gets the grass green solid.Step C:N-(9-normal-butyl-1-methyl-β-carboline-7-oxygen acetyl) methionine(Met) ethyl ester
The DMF of 7-fluoroacetic acid base-9-normal-butyl-1-methyl-β-carboline (5mmol), CDI (5.5mmol) and 20ml drying is placed the 50ml round-bottomed flask, stirring at room 0.5 hour, then add compound L-methionine(Met) ethyl ester (5mmol), stirred 5 hours in the time of 40 ℃, TLC follows the tracks of detection.React complete, remove DMF under reduced pressure, product separates through column chromatography (petrol ether/ethyl acetate), and ethyl alcohol recrystallization gets white crystal, yield 83%, mp 119-121 ℃;
ESI-MS m/e 473 [M+H]
+；
IR(KBr)3296，3068，2925，2866，1739，1670，1626，1542，1448，1199，809cm
-1；
1H-NMR(300MHz，CDCl
3)δ：8.30(1H，d，ArH)；8.02(1H，d，CONH)；7.78(1H，d，ArH)；7.34(1H，d，ArH)；6.94(1H，d，ArH)；6.91(1H，s，ArH)；4.83(1H，m，CH)；4.67(2H，q，COCH
2)；4.47(2H，t，NCH
2)；4.24(2H，q，OCH
2)；3.03(3H，s，ArCH
3)；2.51(2H，t，SCH
2)；2.29-2.03(2H，m，CHCH
2)；2.05(3H，s，SCH
3)；1.81(2H，m，CH
2)；1.47(2H，m，CH
2)；1.30(3H，t，CH
3)；1.00(3H，t，CH
3)。
Embodiment 63N-(9-normal-butyl-1-methyl-β-carboline-7-oxygen acetyl) tyrosine ethyl ester (63)
Operation is with embodiment 62, but uses the TYR ethyl ester to be raw material.Get white crystal, yield 84%, mp 183-184 ℃;
ESI-MS m/e 491[M+H]
+；
IR(KBr)3410(O-H)，3305，3060，2934，2871，1743，1629，1551，1512 1452，1237，1193，816cm
-1；
1H-NMR(300MHz，CDCl
3)δ：8.13(1H，d，ArH)；7.83(1H，d，CONH)；7.56(1H，d，ArH)；7.03(2H，2ArH)；6.88(2H，d，ArH)；6.81(1H，s，ArH)；6.71(2H，d，ArH)；5.30(1H，s，OH)；4.94(1H，m，CH)；4.63(2H，t，COCH
2)；4.39(2H，t，NCH
2)；3.79(3H，s，OCH
3)；3.10(1H，d，CHCH
2)；2.98(3H，s，ArCH
3)；1.75(2H，m，CH
2)；1.41(2H，m，CH
2)；0.95(3H，t，CH
3)。
Embodiment 64 N-(9-hydrocinnamyl-1-methyl-β-carboline-7-oxygen acetyl) tyrosine ethyl ester (64)
Operation is with embodiment 62, but uses 7-hydroxyl-9-hydrocinnamyl-1-methyl-β-carboline and METHIONINE ethyl ester to be raw material.Get white crystal, yield 86%, mp 147-151 ℃;
ESI-MS m/e 553[M+H]
+；
IR(KBr)3411，3303，3062，3027，2927，2860，1743，1629，1575，1515，1465，1236，1205，827，751cm
-1；
1H-NMR(300MHz，CDCl
3)δ：8.07(1H，d，ArH)；7.71(1H，d，CONH)；7.44(1H，d，ArH)；7.30(2H，2ArH)；7.23(1H，1ArH)；7.15(2H，d，ArH)；7.04(1H，d，ArH)；6.89(2H，d，ArH)；6.79(1H，d，ArH)；6.74(2H，d，ArH)；6.55(1H，s，ArH)；4.95(1H，m，CH)；4.50(2H，q，COCH
2)；4.36(2H，t，NCH
2)；3.80(3H，s，OCH
3)；3.11(1H，d，CHCH
2)；2.82(3H，s，ArCH
3)；2.71(2H，t，CH
2Ph)；2.07(2H，m，CH
2).
Embodiment 65N-(9-normal-butyl-1-methyl-β-carboline-7-oxygen acetyl) methionine(Met) (65)
N-(9-normal-butyl-1-methyl-β-carboline-7-oxygen acetyl) methionine(Met) ethyl ester (1mmol) is dissolved in the 10ml dehydrated alcohol, adds the 10ml aqueous solution of NaOH (5mmol) again, heating reflux reaction 2 hours reacts complete, is neutralized to pH 5 with 2M hydrochloric acid, remove part ethanol under reduced pressure to there being solid to separate out, freezing placement, suction filtration, infrared drying, get yellow solid, yellow crystals, yield 97%, mp 191-193 ℃;
ESI-MS m/e 443[M-H]
-；
IR(KBr)3415，3236，3057 2923，2866，1722，1625，1600，1540，1463，1191，812cm
-1；
1H-NMR(300MHz，DMSO-d
6)δ：12.80(1H，s，COOH)；8.56(1H，d，CONH)；8.50(1H，d，ArH)；8.38(2H，2ArH)；7.34(1H，d，ArH)；7.12(1H，d，ArH)；4.80(2H，t，COCH
2)；4.60(2H，t，NCH
2)；4.40(`H，q，CH)；3.1 8(3H，s，ArCH
3)；2.44(2H，t，SCH
2)；1.98(5H，CHCH
2，SCH
3)；1.75(2H，m，CH
2)；1.37(2H，m，CH
2)；0.90(3H，t，CH
3)。
Embodiment 66 N-(9-normal-butyl-1-methyl-β-carboline-7-oxygen acetyl) tyrosine (66)
Operation is with embodiment 65, but raw material uses N-(9-normal-butyl-1-methyl-β-carboline-7-oxygen acetyl) tyrosine ethyl ester.Get yellow crystals, yield 96%, mp 169-171 ℃;
ESI-MS m/e 475[M-H]
-；
IR(KBr)3405(O-H)，3249，3067，2927，2870，1735，1626，1575，1515，1465，1227，1193，817cm
-1；
1H-NMR(300MHz，DMSO-d
6)δ：12.80(1H，s，COOH)；9.20(1H，d，CONH)；8.48(1H，d，ArH)；8.35(2H，2ArH)；7.26(1H，s，ArH)；7.05(1H，d，ArH)；6.95(2H，d，2ArH)；6.54(2H，d，2ArH)；4.72(2H，s，COCH
2)；4.55(2H，t，NCH
2)；4.43(1H，m，CH)；3.18(3H，s，ArCH
3)；2.95(2H，m，CHCH
2)；1.72(2H，m，CH
2)；1.33(2H，m，CH
2)；0.88(3H，t，CH
3).
Embodiment 67N-(9-hydrocinnamyl-1-methyl-β-carboline-7-oxygen acetyl) tyrosine (67)
Operation is with embodiment 65, but raw material uses N-(9-hydrocinnamyl-1-methyl-β-carboline-7-oxygen acetyl) tyrosine ethyl ester.Get yellow crystals, yield 98%, mp 171-173 ℃;
ESI-MS m/e 537[M-H]
-；
IR(KBr)3406，3250，3063，2925，2865，1737，1625，1576，1543，1515，1224，815，702cm
-1；
1H-NMR(300MHz，DMSO-d
6)δ：8.07(1H，d，ArH)；7.71(1H，d，CONH)；7.44(1H，d，ArH)；7.30(2H，2ArH)；7.23(1H，1ArH)；7.15(2H，d，ArH)；7.04(1H，d，ArH)；6.89(2H，d，ArH)；6.79(1H，d，ArH)；6.74(2H，d，ArH)；6.55(1H，s，1ArH)；4.95(1H，m，CH)；4.50(2H，q，COCH
2)；4.36(2H，t，NCH
2)；3.80(3H，s，OCH
3)；3.11(1H，d，CHCH
2)；2.82(3H，s，ArCH
3)；2.71(2H，t，CH
2Ph)；2.07(2H，m，CH
2).
Synthetic route 11
The compound of following examples 68-69 can be finished by synthetic route 11:
Embodiment 68N-(β-carboline-1-formyl) phenylalanine ethyl ester (68)
The DMF of β-carboline-1-carboxylic acid (5mmol), CDI (5.5mmol) and 20mL drying places the 50ml round-bottomed flask, stirring at room 0.5 hour, then add compound L-phenylalanine ethyl ester (5mmol), stirred 8 hours in the time of 40 ℃, thin-layer chromatography TLC follows the tracks of detection.React complete, remove DMF under reduced pressure, product separates through column chromatography (petrol ether/ethyl acetate), and ethyl alcohol recrystallization gets white crystal, yield 94%, mp 104-106 ℃;
ESI-MS m/e 388[M+H]
+(B)，410[M+Na]
+，426[M+K]
+；
IR(KBr)3370，3058，2980，2931，1737，1659，1627，1573，1520，1207，737cm
-1；
1H-NMR(300MHz，CDCl
3)δ：10.19(1H，s，NH)，8.59(1H，d，J＝7.8Hz，CONH)；8.38(1H，d，J＝4.8Hz，ArH)；8.12(1H，d，J＝7.8Hz，ArH)；8.07(1H，d，J＝4.8Hz，ArH)；7.58-7.51(2H，m，NH，ArH)；7.32-7.26(6H，m，ArH)；5.09(1H，q，CH)；4.22(2H，q，OCH
2CH
3)；3.29(2H，m，CHCH
2)；1.26(3H，t，CH
3).
Embodiment 69N-(β-carboline-1-formyl) phenylalanine (69)
N-(β-carboline-1-formyl) phenylalanine ethyl ester (1mmol) is dissolved in the 10ml dehydrated alcohol, adds the 10mL aqueous solution of NaOH (5mmol), heating reflux reaction 1.5 hours again.React complete, be neutralized to pH5 with 2M hydrochloric acid, remove part ethanol under reduced pressure to there being solid to separate out, freezing placement, suction filtration, infrared drying gets yellow solid, yield 97%, mp 229-231 ℃;
ESI-MS m/e 358[M-H]
-；
IR(KBr)3420，3382，3336，3060，2950，1728，1621，1526，1222，739cm
-1；
1H-NMR(300MHz，DMSO-d
6)δ：13.04(1H，s，COOH)；11.72(1H，s，NH)，8.87(1H，d，CONH)；8.35(2H，2ArH)；8.24(1H，d，ArH)；7.73(1H，d，ArH)；7.53(1H，d，ArH)；7.28-7.13(6H，m，ArH)；4.82(1H，q，CH)；3.27(2H，CHCH
2).
Synthetic route 12
The compound of following examples 70-73 can be finished by synthetic route 12:
Embodiment 70 1-O-(9-normal-butyl-β-carboline-3-formyl radical)-2,3,4-three-O-benzoyl-β-D-pyranose form ribose (70)
Steps A: 1-bromo-2,3,4-three-O-benzoyl-α-D-ribopyranose
Get 10 g D-riboses and add the 80mL anhydrous pyridine, after the low-grade fever dissolving, under the ice bath cooling, drip the 36ml Benzoyl chloride, room temperature reaction 24 hours.Add a small amount of frozen water, chloroform 50m is little, separate organic phase after, use successively 20%H
2SO
4, saturated Na
2CO
3, saturated NaCl solution respectively washs anhydrous Na 2 times
2SO
4Drying reclaims chloroform, gets red syrup.
The gained syrup is dissolved in the 25ml methylene dichloride, and 0 ℃ of lower 56mL 33%HBr-Glacial acetic acid that drips stirred 24 hours under room temperature again.Add 50mL CH
2Cl
2After the dilution, pour into rapidly in the 200 mL frozen water, the stirring and segregation organic phase is poured in the frozen water after the dissolving.The saturated Na of organic phase
2CO
3Solution is washed till Ph＞7, and saturated NaCl solution is washed till neutrality, removes methylene dichloride under reduced pressure, then washes with ether, gets white solid 18.6g, productive rate 53.2%.
Step B:1-O-(9-normal-butyl-β-carboline-3-formyl radical)-2,3,4-three-O-benzoyl-β-D-pyranose form ribose
Get the 100ml there-necked flask, add 9-normal-butyl-β-carboline-3-carboxylic acid (1mmoL), 5ml CH
2Cl
2, 1mmol Tetrabutyl amonium bromide (TBAB) and 5ml H
2O stirs under 50 ℃ of temperature, after stablizing, drips the 5ml aqueous solution of 1.2mmol NaOH, makes to become the clarification two-phase.Then, under vigorous stirring, slowly add 0.8mmol 1-bromo-2,3, the 5ml CH of 4-three-O-benzoyl-α-D-ribopyranose
2Cl
2Solution, stirring is spent the night.TLC follows the tracks of detection, reacts complete, and reaction solution is down to room temperature, isolates organic phase, and the water dichloromethane extraction merges organic phase, with 5%NaOH solution and water washing, uses anhydrous Na again
2SO
4Drying, after the solvent evaporated, the gained crude product separates through column chromatography (petrol ether/ethyl acetate), gets white solid, yield 88%, mp 102-104 ℃;
IR(KBr)3063，2958，2871，1725，1589，1501，1459，1258，1097，713 cm
-1；
1H-NMR(300MHz，CDCl
3)δ：9.03(1H，s，ArH)，8.94(1H，s，ArH)；8.27(1H，d，ArH)；8.02(3H，t，ArH)；7.92(2H，d，ArH)；7.68(1H，t，ArH)；7.53(3H，t，ArH)；7.43-7.24(9H，m，ArH)；6.74(1H，s，CH)；6.24(1H，s，CH)；5.83(1H，s，CH)；5.76(1H，s，CH)；4.60(1H，d，CH)；4.48(2H，t，NCH
2)；4.30(1H，d，CH)；1.94(2H，m，CH
2)；1.41(2H，m，CH
2)；0.98(3H，t，CH
3).
Embodiment 71 1-O-(9-hydrocinnamyl-β-carboline-3-formyl radical)-2,3,4-three-O-benzoyl-β-D-pyranose form ribose (71)
Operation is with embodiment 70, but uses 9-hydrocinnamyl-β-carboline-3-carboxylic acid to be raw material.Get white solid, yield 87%, mp 98-100 ℃;
IR(KBr)3062，3030，2938，2871，1725，1584，1499，1454，1259，1097，710cm
-1；
1H-NMR(300MHz，CDCl
3)δ：8.94(1H，s，ArH)，8.92(1H，s，ArH)，8.27(1H，d，ArH)；8.04(2H，d，ArH)；8.01(2H，d，ArH)；7.94(2H，d；ArH)；7.65(1H，t，ArH)；7.60-7.15(16H，m，ArH)；6.76(1H，d，CH)；6.22(1H，t，CH)；5.84(1H，t，CH)；5.77(1H，q，CH)；4.57(1H，dd，CH)；4.48(2H，t，NCH
2)；4.33(1H，dd，CH)；2.76(2H，t，CH
2Ph)；2.31(2H，m，CH
2).
Embodiment 72 1-O-(9-normal-butyl-β-carboline-3-formyl radical)-2,3,4,5-four-O-ethanoyl-β-D-glucopyranose (72)
Steps A: 1-bromo-2,3,4,5-four-O-ethanoyl-α-D-Glucopyranose
Get 10g glucose and add the 10ml anhydrous pyridine, add again diacetyl oxide 25ml, room temperature reaction 24 hours.Add a small amount of frozen water, chloroform 50ml, after the separation organic phase, use successively 20%H
2SO
4, saturated Na
2CO
3, saturated NaCl solution respectively washs anhydrous Na 2 times
2SO
4Drying reclaims chloroform, gets red syrup.The gained syrup is dissolved in the 25ml methylene dichloride, and 0 ℃ of lower 56ml 33%HBr-ice HOAc that drips stirred 24 hours under room temperature again.Add 50ml CH
2Cl
2After the dilution, pour into rapidly in the 200ml frozen water, the stirring and segregation organic phase is poured in the frozen water after the dissolving.The saturated Na of organic phase
2CO
3Solution is washed till Ph＞7, and saturated NaCl solution is washed till neutrality, is spin-dried for methylene chloride, and sherwood oil is washed, and gets white solid 12.9g, productive rate 55.7%, m.p.88-89 ℃.
Step B:1-O-(9-normal-butyl-β-carboline-3-formyl radical)-2,3,4,5-four-O-ethanoyl-β-D-glucopyranose
Get the 100mL there-necked flask, add 9-normal-butyl-β-carboline-3-carboxylic acid (1mmol), 5ml methylene dichloride, 1mmol Tetrabutyl amonium bromide (TBAB) and 5 mL H
2O stirs under 50 ℃ of temperature, after stablizing, drips the 5ml aqueous solution of 1.2mmol NaOH, makes to become the clarification two-phase.Then, under vigorous stirring, slowly add 0.8 mmol 1-bromo-2,3,4,5 mLCH of 5-four-O-ethanoyl-α-D-Glucopyranose
2Cl
2Solution, stirring is spent the night.The TLC detection reaction is down to room temperature after finishing, and isolates organic phase, water CH
2Cl
2Extraction merges organic phase, with 5%NaOH solution and water washing, uses anhydrous Na again
2SO
4Drying, after the solvent evaporated, the gained crude product separates through column chromatography (petrol ether/ethyl acetate), gets white solid, yield 85%, mp 124-126 ℃;
IR(KBr)3638，3413，3057，2955，2930，2871，2872，1754(C＝O)，1584，1501，1466，1226，1085，751cm
-1；
1H-NMR(300MHz，CDCl
3)δ：9.00(1H，s，ArH)，8.86(1H，s，ArH)；8.25(1H，d，ArH)；7.66(1H，t，ArH)；7.53(1H，d，ArH)；7.39(1H，t，ArH)；6.13(1H，d，CH)；5.43(2H，m，CH
2)；5.23(1H，t，CH)；4.46(2H，t，CH
2)；4.34(1H，d，CH)；4.17(1H，d，CH)；4.00(1H，d，CH)；2.08-1.99(12H，4COCH
3)1.92(2H，m，CH
2)；1.40(2H，m，CH
2)；0.96(3H，t，CH
3).
Embodiment 73 1-O-(9-hydrocinnamyl-β-carboline-3-formyl radical)-2,3,4,5-four-O-ethanoyl-β-D-glucopyranose (73)
Operation is with embodiment 72, but uses 9-hydrocinnamyl-β-carboline-3-carboxylic acid to be raw material.Get white solid, yield 84%, mp 133-134 ℃;
IR(KBr)3431，3060，3027，2948，1755(C＝O)，1583，1500，1465，1224，1068，750cm
-1；
1H-NMR(300MHz，CDCl
3)δ：8.91(1H，s，ArH)，8.85(1H，s，ArH)；8.24(1H，d，ArH)；7.64(1H，t，ArH)；7.42(2H，t，ArH)；7.30-7.22(3H，m，3ArH)；7.15(2H，d，ArH)；6.13(1H，d，CH)；5.42(2H，m，CH
2)；5.23(1H，t，CH)；4.45(2H，t，CH
2)；4.33(1H，d，CH)；4.17(1H，d，CH)；4.00(1H，d，CH)；2.74(2H，t，CH
2)；2.29(2H，m，CH
2)；2.10-1.99(12H，COCH
3).
Synthetic route 13
The compound of following examples 74-75 can be finished by synthetic route 13:
Embodiment 74 7-β-D-glucopyranose oxygen base-9-hydrocinnamyl-1-methyl-β-carboline (74) steps A: 1-bromo-2,3,4,5-four-O-ethanoyl-α-D-Glucopyranose operates with embodiment 72.
Step B:7-β-D-glucopyranose oxygen base-9-normal-butyl-1-methyl-β-carboline
Get the 250ml three-necked bottle, add 7-hydroxyl-9-hydrocinnamyl-1-methyl-β-carboline (3 mmol), Tetrabutyl amonium bromide (TBAB) (0.5mmol), 20ml H
2O and 20ml CH
2Cl
2, be heated under 50 ℃ of temperature and reflux, slowly drip again the 20ml aqueous solution of 10mmol KOH, to becoming the clarification two-phase.Then, under vigorous stirring, slowly drip again 6mmol 1-bromo-2,3,4, the 20ml CH of 5-four-O-ethanoyl-α-D-Glucopyranose
2Cl
2Solution, 50 ℃ of lower reaction 20h.After being down to room temperature, isolate organic phase, water CH
2Cl
2Extraction merges organic phase, with 5%NaOH solution and water washing, anhydrous Na
2SO
4Drying after the solvent evaporated, is separated through column chromatography (chloroform/methanol), gets the not glucosides compound of Deprotection, is the sorrel syrupy shape.
Intermediate product of upper step is added in the 20ml anhydrous methanol, and the MeONa/MeOH solution 20ml stirring at room reaction that adds again 0.2M is spent the night.After the TLC detection reaction was complete, solvent evaporated was separated through column chromatography (chloroform/methanol), and the dehydrated alcohol recrystallization gets white crystal, yield 45%, mp 212-213 ℃;
IR(KBr)3423，3027，2924，2857，1627，1575，1448，1238，1074，701，624cm
-1；
1H-NMR(300MHz，DMSO-d
6)δ：8.14(1H，d，ArH)，8.08(1H，d，ArH)；7.87(1H，d，ArH)；7.29-7.17(6H，m，ArH)；6.93(1H，dd，ArH)；5.36(1H，d，CH)；5.14(1H，d，CH)；5.08(1H，d，CH)；5.02(1H，d，CH)；4.67(1H，t，CH)；4.52(2H，t，CH
2)；3.47(2H，t，CH
2)；2.77(3H，s，CH
3)；2.72(2H，m，CH
2)；2.00(2H，m，CH
2)；
13C NMR(75MHz，DMSO-d
6)δ：159.13，143.19，141.76，141.06，137.86，135.28，129.20，128.99，126.60，123.04，115.87，113.20，111.18，101.35，97.52，77.99，77.61，74.10，70.65，61.55，44.59，33.06，32.67，23.34.
Embodiment 75 7-β-D-pyranose form wood glycosyloxy-9-normal-butyl-1-methyl-β-carboline (75)
Steps A: 1-bromo-2,3,4-three-O-benzoyl-α-D-xylopyranose preparation method is with the steps A of embodiment 72.
Step B:7-β-D-pyranose form wood glycosyloxy-9-normal-butyl-1-methyl-β-carboline
Operation is with embodiment 74, but use 7-hydroxyl-9-normal-butyl-1-methyl-β-carboline is as raw material.Get white crystal, yield 42%, mp 236-238 ℃;
IR(KBr)3384，3212，3030，2959，2932，2871，1626，1566，1497，1453，1242，1188，1082，1056，815，604cm
-1；
1H-NMR(300MHz，DMSO-d
6)δ：8.13(1H，d，ArH)，7.90(1H，d，ArH)；7.70(1H，d，ArH)；7.04(1H，s，ArH)；6.93(1H，d，ArH)；4.96(1H，d，CH)；4.39(2H，t，CH)；3.93(1H，dd，CH)；3.56(1H，m，CH)；3.48(2H，t，CH
2)；3.32(1H，d，CH)；2.94(3H，s，CH
3)；1.72(2H，m，CH
2)；1.35(2H，m，CH
2)；0.91(3H，t，CH
3)。
Synthetic route 14
The compound of following examples 76-83 can be finished by synthetic route 14:
Embodiment 76 1-(4 '-methoxyl group-styryl)-9-normal-butyl-β-carboline (76)
9-normal-butyl-1-methyl-β-carboline (10mmol), diacetyl oxide (50ml) and 4-methoxyl group-phenyl aldehyde (100mmol) mix, stirring at room 30 minutes, and then reflux is 72 hours, and TLC follows the tracks of detection; React complete, pour in the 200ml cold water after reaction solution is cooled to room temperature, the sodium bicarbonate alkalization, ethyl acetate extraction merges organic phase, washing, the saturated salt washing, anhydrous sodium sulfate drying filters, concentrating under reduced pressure, residue is dissolved in dehydrated alcohol, regulates pH to 1～2 with the Hydrochlorine-Ethanol saturated solution, be evaporated to dried, the residue acetone recrystallization filters, and gets yellow solid.Yellow solid is dissolved in 50ml water, the sodium bicarbonate alkalization, ethyl acetate extraction merges organic phase, washing, the saturated salt washing, anhydrous sodium sulfate drying filters concentrating under reduced pressure, residue silica gel column chromatography, acetone/sherwood oil (1/2) recrystallization.Get faint yellow needle-like crystal 1.6g, yield 45%, mp 115-117 ℃;
FAB-MS m/e(M+1)357；
IR(KBr)3433，3060，2962，2925，2864，1626，1604，1555，1446，1414，1361，1291，1237，1176，1028，961，815；
1H-NMR(500MHz，CDCl
3)δ8.46-8.47(1H，d，H-3)；8.11-8.13(1H，d，H-4)；7.86-7.87(1H，d，H-5)；7.46-7.77(6H，m，H-6，H-7，H-8，PhH)；7.28-7.28(2H，m，PhH)；6.94-6.96(2H，d，-CH＝CH-)；4.56-4.59(2H，m，NCH
2CH
2CH
2CH
3)；3.85(3H，s，OCH
3)；1.96-2.02(2H，m，NCH
2CH
2CH
2CH
3)；1.49-1.51(2H，m，NCH
2CH
2CH
2CH
3)；0.99-1.02(3H，m，NCH
2CH
2CH
2CH
3).
Embodiment 77 1-(4 '-methoxyl group-styryl)-9-hydrocinnamyl-β-carboline (77)
Operation is with embodiment 76, but use 9-hydrocinnamyl-1-methyl-β-carboline is as reaction raw materials.Get faint yellow needle-like crystal 2.2g, yield 53%, mp 136-137 ℃;
FAB-MS m/e(M+1)419；
IR(KBr)3053，3030，2970，2922，2841，1630，1603，1555，1509，1446，1415，1361，1328，1291，1242，1222，1171，1032，966，821；
1H-NMR(500MHz，CDCl
3)δ 8.46-8.47(1H，d，H-3)；8.10-8.12(1H，d，H-4)；7.66-7.86(3H，m，H-5，H-6，H-7)；7.53-7.55(3H，m，H-8，PhH)；7.15-7.33(7H，m，PhH)；6.94-6.95(2H，d，-CH＝CH-)；4.58-4.61(2H，m，NCH
2CH
2CH
2Ph)；3.86(3H，s，OCH
3)；2.75-2.78(2H，m，NCH
2CH
2CH
2Ph)；2.30-2.33(2H，m，NCH
2CH
2CH
2Ph).
Embodiment 78 1-(4 '-methoxyl group-styryl)-7-n-butoxy-9-hydrocinnamyl-β-carboline (78)
Operation is with embodiment 76, but use 7-n-butoxy-9-hydrocinnamyl-1-methyl-β-carboline is as reaction raw materials.Get faint yellow needle-like crystal 2.7g, yield 55%, mp 110-111 ℃;
FAB-MSM/e(M+1)491；
IR(KBr)3430，3030，2964，2937，2869，1631，1556，1510 1439，1414，1335，1246，1206，1148，1068，1032，964，822；
1H-NMR(500MHz，CDCl
3)δ 8.41-8.45(1H，d，H-3)；7.94-7.96(1H，d，H-4)；7.74-7.75(1H，d，H-5)；7.54-7.55(2H，d，H-6，H-8)；7.18-7.28(7H，m，PhH)；6.94-6.96(2H，d，-CH＝CH-)；6.85-6.88(1H，m，PhH)；6.65-6.66(1H，m，PhH)；4.49-4.53(2H，t，NCH
2CH
2CH
2Ph)；3.97-4.00(2H，t，OCH
2CH
2CH
2CH
3)；3.86(3H，s，OCH
3)；2.76-2.79(2H，m，NCH
2CH
2CH
2Ph)；2.22-2.34(2H，m，NCH
2CH
2CH
2Ph)；1.82-1.85(2H，m，OCH
2CH
2CH
2CH
3)；1.55-1.58(2H，m，OCH
2CH
2CH
2CH
3)；1.01-1.04(3H，t，OCH
2CH
2CH
2CH
3).
Embodiment 79 1-(4 '-nitro-styryl)-7-n-butoxy-9-hydrocinnamyl-β-carboline (79)
Operation is with embodiment 76, but use 4-nitro-phenyl aldehyde and 7-n-butoxy-9-hydrocinnamyl-1-methyl-β-carboline are as reaction raw materials.Get light red needle-like crystal 3.2g, yield 63%, mp170-171 ℃;
FAB-MS m/e(M+1)506；
IR(KBr)3056，3028，2958，2933，2869，1617，1590，1506，1422，1334，1229，1157，1107，1042，965，814；
1H-NMR(500MHz，CDCl
3)δ 8.47-8.48(1H，d，H-3)；8.26-8.28(1H，d，H-4)；7.98-8.00(1H，d，H-5)；7.67-7.91(5H，m，H-6，H-8，PhH)；7.19-7.33(6H，m，PhH)；6.90-6.93(1H，dd，CH＝CH)；6.70(1H，s，CH＝CH)；4.51-4.54(2H，t，NCH
2CH
2CH
2Ph)；4.01-4.05(2H，t，OCH
2CH
2CH
2CH
3)；2.79-2.82(2H，t，NCH
2CH
2CH
2Ph)；2.31-2.35(2H，m，NCH
2CH
2CH
2Ph)；1.84-1.88(2H，m，OCH
2CH
2CH
2CH
3)；1.56-1.60(2H，m，OCH
2CH
2CH
2CH
3)；1.04-1.07(3H，t，OCH
2CH
2CH
2CH
3).
Embodiment 80 1-(4 '-methoxyl group-styryl)-2-benzyl-9-normal-butyl-β-carboline bromine salt (80) 1-(4 '-methoxyl group-styryl)-9-normal-butyl-β-carboline (2mmol), ethyl acetate (50ml) and cylite (20mmol) mix, reflux 5 hours, the cooling reaction solution is to room temperature, filter, the ethyl acetate washing gets yellow solid.Yellow solid is dissolved in the 50ml dehydrated alcohol, and reflux is to clarification, and filtered while hot is cooled to room temperature, the refrigerator recrystallization.Get yellow particle shape crystal 0.49g, yield 44%, mp 197-198 ℃.
FAB-MS m/e 447；
IR(KBr)3412，3001，2957，2931，2867，1621，1605，1512，1463，1337，1247，1175，1028，976，810；
1H-NMR(500MHz，DMSO-d
6)δ 8.97-8.98(1H，d，H-3)；8.90-8.91(1H，d，H-4)；8.58-8.59(1H，d，H-5)；7.86-7.97(2H，m，H-6，H-8，PhH)；7.51-7.62(5H，m，H-7，PhH)；7.19-7.34(5H，m，PhH)；7.03-7.05(2H，m，-CH＝CH-)；6.06(2H，s，CH
2Ph)；4.51-4.54(2H，m，NCH
2CH
2CH
2CH
3)；3.82(3H，s，OCH
3)；1.53-1.60(2H，m，NCH
2CH
2CH
2CH
3)；0.97-1.02(2H，m，NCH
2CH
2CH
2CH
3)；0.63-0.66(3H，m，NCH
2CH
2CH
2CH
3)
Embodiment 81 1-(4 '-methoxyl group-styryl)-9-hydrocinnamyl-2-benzyl-β-carboline bromine salt (81)
Operation is with embodiment 81, but uses 1-(4 '-methoxyl group-styryl)-9-hydrocinnamyl-β-carboline to be raw material.Get yellow particle shape crystal 0.73g, yield 60%, mp 207-209 ℃.
FAB-MS m/e 509；
IR(KBr)3412，3029，3002，2936，2837，1622，1606，1515，1457，1339，1256，1179，1033，971，820；
1H-NMR(500MHz，DMSO-d
6)δ 8.98-8.99(1h，d，H-3)；8.89-8.90(1H，d，H-4)；8.57-8.59(1H，d，H-5)；7.88-7.93(2H，m，H-6，H-7)；7.03-7.04(15H，m，H-8，PhH)；6.82-6.84(2H，d，-CH＝CH-)；6.07(2H，s，CH
2Ph)；4.59-4.62(2H，t，NCH
2CH
2CH
2Ph)；3.84(3H，s，OCH
3)；2.49-2.5 1(2H，m，NCH
2CH
2CH
2Ph)；2.28-2.30(2H，m，NCH
2CH
2CH
2Ph).
Embodiment 82 1-(4 '-methoxyl group-styryl)-7-n-butoxy-9-hydrocinnamyl-2-benzyl-β-carboline bromine salt (82)
Operation is with embodiment 81, but uses 1-(4 '-methoxyl group-styryl)-7-n-butoxy-9-hydrocinnamyl-β-carboline to be raw material.Get yellow particle shape crystal 0.85g, yield 70%, mp 207-209 ℃.
FAB-MS m/e 581；
IR(KBr)3450，2997，2956，2934，2869，1619，1577，1514，1454，1345，1257，1232，1176，1139，1034，974，814；
1H-NMR(500MHz，DMSO-d
6)δ 8.87-8.88(IH，d，H-3)；8.68-8.69(1H，d，H-4)；8.40-8.42(1H，d，H-5)；7.52-7.60(3H，m，H-6，H-8，PhH)；6.99-7.36(13H，m，PhH)；6.86-6.87(2H，d，-CH＝CH-)；5.98(2H，s，CH
2Ph)；4.52-4.55(2H，m，NCH
2CH
2CH
2Ph)；4.16-4.19(2H，t，OCH
2CH
2CH
2CH
3)；3.83(3H，s，OCH
3)；2.28-2.31(2H，m，NCH
2CH
2CH
2Ph)；1.76-1.88(4H，m，NCH
2CH
2CH
2Ph，OCH
2CH
2CH
2CH
3)；1.48-1.53(2H，m，OCH
2CH
2CH
2CH
3)；0.96-0.99(3H，t，OCH
2CH
2CH
2CH
3)
Embodiment 83 1-(4 '-nitro-styryl)-7-n-butoxy-9-hydrocinnamyl-2-benzyl-β-carboline bromine salt (83)
Operation is with embodiment 81, but uses 1-(4 '-nitro-styryl)-7-n-butoxy-9-hydrocinnamyl-β-carboline to be raw material.Get yellow particle shape crystal 0.9g, yield 66%, mp 228-229 ℃.
FAB-MSM/e 596；
IR(KBr)3046，3027，2954，2930，2867，1619，1522，1454，1431，1345，1231，1138，1061，971，836；
1H-NMR(500MHz，DMSO-d
6)δ 8.92-8.93(1H，d，H-3)；8.74-8.76(1H，d，H-4)；8.43-8.45(1H，d，H-5)；8.31-8.34(2H，m，H-6，H-8)；7.86-8.01(3H，m，PhH)；7.08-7.33(11H，m，PhH)6.86-6.88(2H，dd，CH＝CH)；6.01(2H，s，CH
2Ph)；4.49-4.53(2H，m，2H，t，NCH
2CH
2CH
2Ph)；4.17-4.20(2H，t，OCH
2CH
2CH
2CH
3)；2.29-2.33(2H，t，2H，m，NCH
2CH
2CH
2Ph)；1.78-1.90(4H，m，NCH
2CH
2CH
2Ph，OCH
2CH
2CH
2CH
3，)；1.48-1.54((2H，m，OCH
2CH
2CH
2CH
3)；0.96-1.00(3H，t，OCH
2CH
2CH
2CH
3).
Synthetic route 15
The compound of following examples 84-85 can be finished by synthetic route 15:
Embodiment 84 1-(3 '-pyridyl)-9-normal-butyl-β-carboline (84)
Synthesizing of steps A: 1-(3 '-pyridyl)-β-carboline
L-Trp 20.4g (100mmol) and 200ml glacial acetic acid mix, and heating makes dissolution of solid; Then add 3-aldehyde radical-pyridine (4.8ml), stirring at room 2 hours, then reflux.TLC monitoring reaction process, question response is complete.Reaction solution is concentrated into dried, residue is mixed with the 100ml glacial acetic acid, heated 5 minutes, add KMnO in batches
4(200mmol), refluxed 1 hour, concentrating under reduced pressure steams except glacial acetic acid, and residue adds water 300ml, and ethyl acetate extraction merges organic phase, anhydrous sodium sulfate drying, and concentrating under reduced pressure, re-crystallizing in ethyl acetate namely gets product 1-(3 '-pyridyl)-β-carboline.
Step B:1-(3 '-pyridyl)-9-normal-butyl-β-carboline
1-(3 '-pyridyl)-β-carboline (2.45g, 10mmol), DMF (50ml), 60% sodium hydride (0.6g, 20mmol) mix stirring at room reaction 10min, add iodo-n-butane (30mmoL), the stirring at room reaction, TLC follows the tracks of detection, reacts complete, reaction solution is poured in the cold water, ethyl acetate extraction merges organic phase, washing, add ethanol 50ml, the concentrated hydrochloric acid acidifying, be evaporated to dried, dehydrated alcohol band water, acetone recrystallization, separate out yellow solid, filter, the ether washing.With the solid water dissolution, the sodium bicarbonate alkalization, ethyl acetate extraction merges organic phase, washing, the saturated salt washing, anhydrous sodium sulfate drying, activated carbon decolorizing is evaporated to dried, the ether recrystallization gets pale yellow crystals 0.41g, yield 83.6%, mp:133-135 ℃;
FAB-MS m/e(M+1)302
1H-NMR(CDCl
3)8.89-8.89(1H，d，H-5)；8.75-8.77(1H，dd，H-3)；8.55-8.56(1H，d，H-4)；8.19-8.21(1H，dd，H-8)；8.03-8.05(1H，d，H-6)；7.98-8.01(1H，m，H-7)；7.60-7.64(1H，m，Py-H)；7.45-7.50(2H，m Py-H)；7.31-7.35(1H，t，Py-H)；3.96-4.00(2H，t，CH
3CH
2CH
2CH
2)；1.32-1.36(2H，m，CH
3CH
2CH
2CH
2)；0.85-0.91(2H，m，CH
3CH
2CH
2CH
2)；0.63-0.67(3H，t，CH
3CH
2CH
2CH
2)。
Embodiment 85 1-(3 '-pyridyl)-9-benzyl-β-carboline (85)
Operation is with embodiment 84, but the use cylite is as alkylating reagent.Get pale yellow crystals 0.43g, yield 81.7%, mp 155-156 ℃;
FAB-MS m/e(M+1)336；
IR(KBr)1650-3050，1620，1479，1445，1353，1214，1191，1044，841；
1H-NMR(CDCl
3)8.90-8.91(1H，d，H-5)；8.76-8.78(1H，dd，H-3)；8.55-8.56(1H，d，H-4)；8.20-8.22(1H，d，H-8)；8.04-8.05(1H，d，H-6)；7.99-8.02(1H，m，H-7)；7.60-7.65(1H，m，Py-H)；7.46-7.5 1(2H，m Py-H)；7.32-7.36(1H，t，Py-H)；4.01-4.07(2H，t，CH
3CH
2)；0.99(3H，s，CH
3CH
2)。
Synthetic route 16
The compound of following examples 86 can be finished by synthetic route 16:
Embodiment 86 1-(2 '-amino-ethyl) carbamyl-9-hydrocinnamyl-β-carboline (86)
Steps A: the preparation of ethyl 9-hydrocinnamyl-β-carboline-1-carboxylic acid, ethyl ester
Ethyl β-carboline-1-carboxylicesters (2.4g, 10mmol), DMF (50ml), 60% sodium hydride (0.6g, 20mmol) mixes, stirring at room reaction 5 minutes, add 1-bromo-3-phenyl-propane (50mmoL), stirring at room, TLC follows the tracks of detection, reacts complete, reaction solution is poured in the cold water, ethyl acetate extraction merges organic phase, washing, add ethanol 50ml, the concentrated hydrochloric acid acidifying, be evaporated to dried, dehydrated alcohol band water, acetone recrystallization, get light yellow solid, be ethyl 9-hydrocinnamyl-β-carboline-1-carboxylic acid, ethyl ester hydrochloride, need not be further purified and to be directly used in next step reaction.
Step B:1-(2 '-amino-ethyl) carbamyl-9-hydrocinnamyl-β-carboline
Ethyl 9-hydrocinnamyl-β-carboline-1-carboxylic acid, ethyl ester hydrochloride (2.0 mmol) and 30ml quadrol mix, and the stirring at room reaction is spent the night, and thin-layer chromatography TLC follows the tracks of reaction, react complete, reaction mixture is poured in the 50ml water, and dichloromethane extraction merges organic phase, washing, the saturated salt washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure, acetone/sherwood oil (v/v 3: 1) recrystallization gets light yellow solid.Light yellow solid is dissolved in the 20ml dehydrated alcohol, adds saturated HCl-ethanolic soln, transfer to pH to 2.0, steam subsequently except ethanolic soln, acetone recrystallization gets the hydrochloride of product, mp 221-223 ℃.
FAB-MS m/e(M+1)373；
IR(KBr，cm
-1)v：3432，3054，2929，1625，1496，1454，749；
1H-NMR(300MHz，D
2O)δ：8.32(1H，d，ArH)；8.22(1H，d，ArH)；8.10(1H，d，ArH)；7.65(1H，t，ArH)；7.46(1H，t，ArH)；7.30(1H，t，ArH)；7.02-6.84(5H，m，5ArH)；4.27(2H，t，NCH
2)；3.61(2H，t，CH
2)；3.20(2H，t，CH
2)；2.47(2H，t，CH
2Ph)；1.91(2H，m，CH
2).
Synthetic route 17
The compound of following examples 87-88 can be finished by synthetic route 17:
Embodiment 87 1-(2 '-amino) ethylamino--9-normal-butyl-β-carboline (87)
Steps A: 1-ketone group-1,2,3,4-tetrahydro-beta-carboline synthetic
L-tryptamines (9.0g, 56mmol) and 800ml toluene mix, and are heated to dissolving, subsequently reaction solution are down to room temperature, add triethylamine (13.8g, 136.6mmol); Under the vigorous stirring, drip the 35ml toluene solution of 6.7g triphosgene, and continue at room temperature to stir 30 minutes; Then heat up gradually and drip 13.0ml30% hbr/acetic acid solution, reheat after dropwising and refluxed 30 minutes.Add 300ml water and 300ml ethyl acetate after the cooling, behind the concuss, take out organic phase, water layer is used the 300ml ethyl acetate extraction once again, merges organic phase, anhydrous magnesium sulfate drying, resistates crystallization in methanol/ethyl acetate (1: 1) gets white crystal 5.72g, mp184 ℃.
Step B:1-ketone group-1,2-dihydro-β-carboline synthetic
Get the 250ml round-bottomed flask, add 1-ketone group-1,2,3,4-tetrahydro-beta-carboline (2.5g, 13.4mmol), DDQ (15mmol), 100ml tetrahydrofuran (THF), room temperature reaction 5 hours, thin-layer chromatography TLC follows the tracks of detection; Reaction is finished, and stopped reaction removes THF under reduced pressure, adds the solution 200ml of 5% sodium hydroxide, stirs 10 minutes, suction filtration, washes to get light gray solid 2.25g.
Synthesizing of step C:1-bromo-β-carboline
Get the 50ml round-bottomed flask, add 1-ketone group-1,2-dihydro-β-carboline (0.74g, 4.0mmol), tribromo oxygen phosphorus (8.0g, 28.0mmol), 10ml methyl-phenoxide spend the night in 120 ℃ of lower reacting by heating, and TLC follows the tracks of detection; Reaction is finished, and stopped reaction adds water 100ml, transfers to alkalescence with 5% aqueous sodium hydroxide solution, and ethyl acetate extraction merges organic phase, anhydrous magnesium sulfate drying, and crude product separates through post, obtains light yellow solid 0.81g, mp 152-153 ℃.
Synthesizing of step D:1-bromo-9-normal-butyl-β-carboline
Iodo-n-butane (4.0mmol) is dissolved in 10ml DMF, adds subsequently 60% sodium hydride (4.0mmol), stirring at room is after 15 minutes, add 1-bromo-β-carboline (1.50mmol), stirring at room 2 hours, thin-layer chromatography TLC follows the tracks of detection, reaction is finished, and stopped reaction adds water 50ml, ethyl acetate extraction, merge organic phase, anhydrous magnesium sulfate drying, crude product separates through post, get light yellow solid 0.42g, mp63-65 ℃.
Step e: 1-(2 '-amino) ethylamino--9-butyl-β-carboline
1-bromo-9-butyl-β-carboline (0.30g, 1.0mmol), cuprous iodide (0.30g) and quadrol (30ml) mix, heating reflux reaction 10 hours, and TLC follows the tracks of detection; Reaction is finished, and the pressure reducing and steaming solvent adds water 100ml in the residue, and ethyl acetate extraction merges organic phase, anhydrous magnesium sulfate drying, and crude product separates through post, gets yellow mucus 0.23g, yield 82%.Yellow mucus is dissolved in the 20ml dehydrated alcohol, adds saturated HCl-ethanolic soln, transfer to pH to 2.0, remove ethanolic soln under reduced pressure, acetone recrystallization gets the hydrochloride (light yellow solid) of product, mp 224-225 ℃.
FAB-MS m/e(M+1)283；
IR(KBr，cm
-1)v：3388，3257，2952，2924，2854，1639，1604，1535，1498，1459，1343，754；
1H-NMR(300MHz，DMSO)δ：8.30(1H，d，ArH)，8.24(3H，s，3N
+H)，7.89(1H，d，ArH)，7.86(1H，d，ArH)，7.77(1H，d，ArH)，7.67(1H，t，ArH)，7.35(1H，t，ArH)，4.88(2H，t，NCH
2)，4.03(2H，t，CH
2)，3.20(2H，t，CH
2)，1.61(2H，m，CH
2)，1.15(2H，m，CH
2)，0.80(3H，t，Ch
3).
Embodiment 88 1-(2 '-amino) ethylamino--9-hydrocinnamyl-β-carboline (88)
Steps A, B and C are with embodiment 87;
Synthesizing of step D:1-bromo-9-hydrocinnamyl-β-carboline
Get 50 ml round-bottomed flasks, add 1-bromo-3-phenyl-propane (3.0mmol), potassiumiodide (3.0mmol), 10ml DMF, stirring at room reaction 2 hours, add subsequently 60%NaH (3.0mmol), stirring at room added 1-bromo-β-carboline (0.25g after 15 minutes, 1.0mmol), stirring at room 2 hours, TLC follows the tracks of detection, and reaction is finished, stopped reaction, add water 50ml in the reaction mixture, ethyl acetate extraction merges organic phase, anhydrous magnesium sulfate drying, crude product separates through post, gets light yellow solid 0.34g, m.p.113-114 ℃.
Synthesizing of step e: 1-(2 '-amino) ethylamino--9-hydrocinnamyl-β-carboline
1-bromo-9-hydrocinnamyl-β-carboline (0.37g, 1.0mmol), cuprous iodide (0.30g), quadrol (30ml) mix, heating reflux reaction 10 hours, TLC follows the tracks of detection, reaction is finished, pressure reducing and steaming solvent, residue add water 100ml, ethyl acetate extraction, merge organic phase, anhydrous magnesium sulfate drying, crude product separates through post, gets yellow mucus 0.30g.Yellow mucus is dissolved in the 20ml dehydrated alcohol, adds saturated HCl-ethanolic soln, transfer to pH to 2.0, remove ethanolic soln under reduced pressure, acetone recrystallization gets light yellow solid, is the hydrochloride of product, mp 256-258 ℃.
FAB-MS m/e(M+1)：345；
IR(KBr，cm
-1)v：3407，3269，3027，2921，2853，1638，1605，1537，1405，1460，1344，752；
1H-NMR(300MHz，DMSO)δ：8.29(1H，d，ArH)，8.19(3H，s，3N
+H)，7.84(1H，d，ArH)，7.76(2H，d，2ArH)，7.65(1H，t，ArH)，7.36(1H，t，ArH)，7.22-7.05(5H，m，5ArH)，4.91(2H，t，NCH
2)，4.00(2H，t，CH
2)，3.18(2H，t，CH
2)，2.56(2H，t，CH
2Ph)，1.96(2H，m，CH
2)；
13C-NMR(75MHz，DMSO)δ：143.65，143.07，141.68，134.92，130.46，130.01，128.88，128.72，126.47，123.00，122.85，121.90，120.92，112.05，107.36，45.20，38.24，33.15，32.74.
The test of embodiment 89 In Vitro Anti cancer screenings
Select respectively Hela (cervical cancer cell), HepG
2The cell strains such as (human liver cancer cell), BGC (gastric carcinoma cells), Bel7402 (human liver cancer cell), MCF-7 (human breast cancer cell) adopt mtt assay to test.
Concrete grammar is as follows: respectively growth conditions is good, be in the cell strain of logarithmic phase with 1 * 10
4The concentration of individual/ml is inoculated in 96 orifice plates, and the incubator that place 37 ℃, contains 5%CO2 was cultivated 24 hours, abandoned old liquid, renew bright nutrient solution, add the compound of sterilising treatment, continue to cultivate after 48 hours, discard nutrient solution, every hole adds the RPMI1640 nutrient solution that 20ul contains 5mg/ml MTT, continue to cultivate 4 hours, carefully remove supernatant after, every hole adds the DMSO of 100 μ l, about 10min dissolution precipitation that vibrates detects OD value, wavelength 490nm with microplate reader subsequently.Obtain cell survival rate under each sample concentration with following formula:
The average OD value of the average OD value/control group of survival rate %=sample sets * 100%
To the mapping of drug level logarithm, obtain the IC of each sample with cell survival rate by graphing method
50Value.
Test-results sees Table 1.
Table 1 Yageine derivates extracorporeal anti-tumor the selection result (IC
50UM)
Can find out that from table 1 most compounds all have certain anti tumor activity in vitro, part of compounds has significant anti tumor activity in vitro, wherein compound 16,19,20,21,80,81, the IC to all 5 strain human tumor cell lines such as 82 and 83
50Value shows the anti tumor activity in vitro that significantly is better than yageine all less than 10uM.
Embodiment 90 acute toxicity test in mice
Kunming mouse (Chinese Academy of Sciences's Shanghai Experimental Animal Center provides, conformity certification number: No. the 107th, Shanghai dynamic circuit connector card word), and body weight 19-20g, male and female half and half.One group of per 10 mouse.Solvent adopts physiological saline and 0.5%CMC-Na solution; According to pre-test result, five grades of dosage of each sample design, 0.8 times of dosage spacing.Behind each sample weighing, add the moistening hydrotropy of a small amount of tween 80 during experiment, then add gradually 0.5%CMC-Na solution to desired concn and get final product.Experiment volume 0.5ml/20g mouse.Adopt the single intraperitoneal administration.Get Kunming mouse, by the sex random packet, each group according to dosage arranges respectively intraperitoneal administration, the immediate reaction after the administration of observation mouse.Dead animal carries out anatomic observation, and surviving animals continues to observe for two weeks, and records animal dead situation in two weeks.After two weeks surviving animals is dissected, observe the pathology of parenchymal viscera, the internal organs with solid lesion are done the pathology inspection.According to the death toll of each treated animal, calculate the medial lethal dose (LD of medicine with the Bliss method
50Value); Obtain maximum tolerated dose (MTD) for the less compound of toxicity.
Test-results sees the following form 2.
The test of embodiment 91 vivo antitumors
Kunming mouse (Chinese Academy of Sciences's Shanghai Experimental Animal Center provides, conformity certification number: No. the 107th, Shanghai dynamic circuit connector card word), body weight is 18-20g, male and female all can, same sex is used in every batch of experiment.Anti-tumor experiment C
57One group of BL/6 mouse and a Kunming mouse 8-10 mouse, negative control respectively is two groups; Mice Bearing Lewis Lung Cancer, S180 sarcoma (gone down to posterity keep by pharmacological room of Shanghai Institute of Pharmaceutical Industry) are adopted in the knurl source; Solvent adopts physiological saline and 0.5%CMC-Na solution; Tested medicine is established high and low two dosage groups, respectively with this medicine abdominal cavity single-dose LD
501/5,1/10 of value is benchmark; Take by weighing each given the test agent, add the moistening hydrotropy of a small amount of Tween-80 during experiment, add gradually 0.5%CMC-Na solution to desired concn and get final product.The experiment volume is the 0.5ml/20g mouse.Intraperitoneal administration, every day 1 time, successive administration 10 days, administration is 10 times altogether.Negative control is given isopyknic coordinative solvent, and dosage regimen is abdominal channels, every day 1 time, continuous 10 days.Positive control ring phosphonic amide (CTX) is pressed the dosage of 30mg/kg, once a day, and continuous 7 days.Adopt anti-tumor in vivo armpit subcutaneous vaccination model: get eugonic knurl source under the aseptic condition, standby into about 1 * 10 with the homogenate legal system
7The cell suspension of/ml, in corresponding host's armpit subcutaneous vaccination 0.2ml/ mouse, about three weeks put to death each treated animal by the administration of experimental design scheme next day, cuts open to get tumour and weigh, and is calculated as follows tumour inhibiting rate:
The average knurl of the average knurl weight-administration of tumour inhibiting rate %=[(negative control group group is heavy)/the average knurl of negative control group is heavy] * 100%
After administration, observe simultaneously the immediate reaction of mouse, the neurotoxicity symptom such as whether primary part observation occurs jumping, trembles, distortion.
Test-results sees the following form 2.
The chmice acute toxicity of table 2 Yageine derivates and anti-tumor activity test result
Annotate: neurotoxicity is with "+" expression, and wherein " +++" expression has significant neurotoxicity; "-" expression does not have neurotoxicity.
As seen from Table 2, except yageine showed significant neurotoxicity, all the other compounds did not all have neurotoxicity.Yageine is respectively 34.1% and 15.3% to the tumour inhibiting rate of Lewis lung cancer and two tumor-bearing mice experimental models of sarcoma S180, and compound 8,14, the tumour inhibiting rate of the tumor-bearing mice experimental model of 54 and 82 pairs of Lewis lung cancer surpasses 40%, compound 11,14,16,17,18,41,42, the tumour inhibiting rate of the tumor-bearing mice experimental model of 54 and 82 couples of sarcoma S180 surpasses 40%, wherein compound 14,16,17, the tumour inhibiting rate of the tumor-bearing mice experimental model of 54 and 82 couples of sarcoma S180 surpasses 50%, especially, the tumour inhibiting rate of 14 couples of sarcoma S180 of compound is up to 67.4%.
Claims (3)
1. the compound with antitumous effect is selected from: 7-isobutoxy-2-benzyl-9-ethyl-1-methyl-β-carboline bromine salt and 7-benzene propoxy--2-benzyl-9-ethyl-1-methyl-β-carboline bromine salt.
2. the application of compound as claimed in claim 1 in preparation treatment cancer therapy drug.
3. pharmaceutical composition, described pharmaceutical composition comprises compound and common medicinal excipient and/or the auxiliary material of one or more claims 1.
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| US9168247B2 (en) | 2010-06-25 | 2015-10-27 | Facultes Universitaires Notre Dame De La Paix | Beta carboline derivatives useful in the treatment of proliferative disorders |
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| CN102796124B (en) * | 2011-05-26 | 2017-06-06 | 新疆华世丹药物研究有限责任公司 | Double β carbolines alkaloid compounds, its preparation method and its pharmaceutical composition and purposes |
| CN111012779A (en) * | 2011-10-25 | 2020-04-17 | 新疆华世丹药物研究有限责任公司 | Application of harmine derivative in preparation of antibacterial drugs |
| CN103509011B (en) * | 2012-06-18 | 2015-09-09 | 首都医科大学 | 1-(4-hydroxyl-3-formamido group acidic group-phenyl)-β-carboline, preparation, anti-inflammatory and anti-tumor activity and application |
| AU2013305591B2 (en) | 2012-08-24 | 2017-04-13 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
| US10011614B2 (en) | 2012-11-26 | 2018-07-03 | Xinjiang Huashidan Pharmaceutical Research Co., Ltd | Bis-β-carboline compound and preparation method, pharmaceutical composition and use thereof |
| CN102977096B (en) * | 2012-12-07 | 2014-12-17 | 中国药科大学 | Harmine derivative anti-tumor prodrug with target characteristic |
| WO2015070234A2 (en) | 2013-11-11 | 2015-05-14 | Board Of Regents Of The University Of Texas System | Neuroprotective compounds and use thereof |
| WO2015070237A1 (en) | 2013-11-11 | 2015-05-14 | Board Of Regents Of The University Of Texas System | Neuroprotective chemicals and methods for identifying and using same |
| CN112174954A (en) * | 2019-07-01 | 2021-01-05 | 南京农业大学 | Beta-carboline amide compound containing beta-arylamine and application of beta-carboline amide compound as agricultural bactericide |
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