CN101429198A - Banisterine derivant and uses thereof - Google Patents

Banisterine derivant and uses thereof Download PDF

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Publication number
CN101429198A
CN101429198A CNA2007101800273A CN200710180027A CN101429198A CN 101429198 A CN101429198 A CN 101429198A CN A2007101800273 A CNA2007101800273 A CN A2007101800273A CN 200710180027 A CN200710180027 A CN 200710180027A CN 101429198 A CN101429198 A CN 101429198A
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Prior art keywords
beta
carboline
methyl
hydrogen
phenylpropyl
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CN101429198B (en
Inventor
曹日晖
武嘉林
于富生
王子厚
彭文烈
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HUASHIDAN PHARMACEUTICAL RESEARCH Co Ltd XINJIANG
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HUASHIDAN PHARMACEUTICAL RESEARCH Co Ltd XINJIANG
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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

Harmine derivative and application thereof
Technical Field
The invention belongs to the field of pharmaceutical compounds, and relates to a beta-carboline alkaloid compound and application thereof, in particular to a harmine derivative and application thereof in antitumor drugs.
Background
Harmine and its analogues have wide pharmacological action, mainly two aspects: neuro-activity and anti-tumor activity. The neuroactivity of harmine and its derivatives is mainly manifested by excitation of cerebral cortex, motor center, spinal cord, etc., and can cause hallucination, tremor, paroxysmal convulsion, excitation of pons, and some specific actions and extremity stiffness; in the research on the antitumor effect of harmine extracted from harmine seeds, two mixed alkaloids of harmine and harmine have obvious cytotoxic effect on 6 in-vitro cultured human tumor cell strains, obvious tumor inhibiting effect on 3 hybrid mouse transplantation tumors and 3 human cancer nude mouse transplants, and synergistic effect with cisplatin or adriamycin.
The grandma et al can carry out the clinical researches such as antitumor pharmacology and toxicology on harmine monomer, including the researches on the dosage forms such as capsules, pulse release capsules and microspheres and the quality standard, stability, pharmacokinetics, pharmacological toxicology and the like, but the clinical application cannot be declared due to the discovery of the remarkable neurotoxicity (mainly manifested as jumping, tremor, distortion and the like) of harmine.
Subsequently, researchers modify the chemical structure of harmine to obtain an ideal anti-tumor structure. However, the presently disclosed harmine derivatives still have low antitumor activity. For example, CN1552711A and WO/2004/106335 disclose that the chemical structure of peganum harmala is systematically modified, and peganum harmala derivatives with obviously improved in-vivo anti-tumor activity and obviously reduced neurotoxicity are found, but the tumor inhibition rate of the modified compounds on a tumor-bearing mouse test model is only 46.9% at most.
In conclusion, most of the existing harmine derivatives have low antitumor activity or high neurotoxicity and no clinical application prospect, so an improved harmine derivative is urgently needed to meet clinical requirements.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a new harmel derivative which has high anti-tumor activity, no neurotoxicity and clinical application prospect.
The invention also aims to provide the application of the compound in preparing medicaments for treating cancers.
The invention also provides a pharmaceutical composition comprising these compounds together with a pharmaceutically acceptable carrier and/or excipient.
The present invention provides compounds of formula I:
Figure A200710180027D00111
wherein,
R1is selected from hydrogen and C1-6Alkyl, heterocyclyl, aldehyde, carboxyl, carboxylate, CH ═ nnhc (o) NH2、CH＝NNHC(S)NH2、CH＝NOH、CH＝NOCH3CONHRa, COORb, CH ═ CHRc, CH ═ NRd and NHRd, where,
ra is hydrogen or C1-6Alkyl, mono C1-6Alkylamino or amino acid residues;
rb is a sugar residue, wherein the sugar is a hexose, a pentose, a disaccharide or an acyclic sugar;
rc is aryl or heterocyclyl;
rd is C1-6Alkyl or C1-6An alkylamino group;
R2is selected from hydrogen and C1-6Alkyl, aryl (C)1-6) An alkyl group;
x is selected from organic acid radical or inorganic acid radical; or, R2And X are absent at the same time;
R3selected from hydrogen, aldehyde group, CH (OH) SO3Na、CH＝NNHC(O)NH2、CH＝NNHC(S)NH2CONHRa, COORb, CH ═ CHRc and CH ═ NRd,
wherein Ra, Rb, Rc and Rd are as defined above;
R7is selected from hydrogen, hydroxy, C1-15Alkoxy, aryl (C)1-6) Alkoxy, COCH2CONHRa、COCH2COORb; wherein,
ra and Rb are as defined above;
R9is selected from hydrogen and C1-6Alkyl, hydroxy-C1-6Alkyl, aryl (C)1-6) An alkyl group;
with the following conditions:
(1) when R is1、R2、R7And R9When both are hydrogen, R3Cannot be hydrogen or CONHCH2CH2NH2；
(2) When R is1When it is methyl, R2、R3、R7、R9Cannot be simultaneously hydrogen;
(3) when R is1Is methyl, R7Is methoxy and R2、R3When both are hydrogen, R9Can not be hydrogen, C1-4Alkyl, hydroxyethyl, benzyl or phenylpropyl;
(4) when R is1Is methyl and R2、R3And R9When both are hydrogen, R7Can not be C1-10An alkoxy group;
(5) when R is1Is methyl, R7Is methoxy, R9Is n-propyl and R2When methyl, X is not bromine or iodine;
(6) when R is1、R3And R7Are both hydrogen and R9When it is phenylpropyl, R2And not hydrogen, benzyl, 4-fluorobenzyl, 3-chlorobenzyl or phenylpropyl;
(7) when R is1、R3、R7When both are hydrogen, R2And R9Can not be simultaneously methyl, benzyl or ethyl;
(8) when R is1Is methyl, R3Is hydrogen, R7Is methoxy and R9When it is phenylpropyl, R2And can not be ethyl, butyl, benzyl, 4-fluorobenzyl and phenylpropyl;
(9) when R is1Is methyl, R2And R3Are both hydrogen and R9When it is phenylpropyl, R7Can not be hydrogen, hydroxy, C3-8Alkoxy and phenyl (C)1-3) An alkoxy group;
(10) when R is1Is methyl, R2Is benzyl, R3Is hydrogen and R9When it is phenylpropyl, R7Can not be hydrogen, hydroxy, C1-8Alkoxy and phenyl (C)1-3) An alkoxy group;
(11) when R is1Is 3-chlorobenzyl and R2、R3、R7When all are hydrogen, R9Cannot be phenylpropyl;
(12) when R is1Is NHRd and R2、R3、R7When all are hydrogen, R9Cannot be hydrogen; rd is as defined above;
(13) when R is1Is hydrogen or methyl, R2、R7、R9When both are hydrogen, R3Cannot be CONH (CH)2)nNH2(n-2 or 4), CONHCH2CH2OH；
(14) When R is1Is hydrogen or methyl, R3Is CONH (CH)2)nNH2(n-2 or 4) or CONHCH2CH2OH、R2And R7When both are hydrogen, R9And not methyl, ethyl, n-butyl, benzyl or pentafluorobenzyl.
A compound of formula I and salts thereof, wherein,
R1preferably selected from hydrogen, pyridyl, aldehyde, carboxyl, carboxylic ester, carboxylic salt, CH ═ NNHC (S) NH2CONHRa, COORb, CH ═ CHRc and NHRd, where,
ra is C1-2Alkyl, mono C2-6An alkylamino group or an L-amino acid residue,
rb is glucose, xylose, ribose, deoxyribose or acyclic sugar,
rc is a phenyl group or a heterocyclic group,
rd is C1-2Alkyl or C2-6An alkylamino group.
A compound of formula I and salts thereof, wherein,
R1more preferably selected from hydrogen, pyridyl, ethyl carboxylate, sodium carboxylate, CH-NNHC (S) NH2CONHRa, COORb, CH ═ CHRc and NHRd, where,
ra is L-phenylalanine residue, L-tryptophan residue, L-tyrosine residue,
rb is glucose, ribose or deoxyribose,
rc is 4-methoxyphenyl or 4-nitrophenyl,
rd is C2-4An alkylamino group.
A compound of formula I and salts thereof, wherein,
R2preferably selected from hydrogen, benzyl, phenylpropyl, sulfonic acid groups;
x is chlorine or bromine; or, R2And X are absent at the same time.
Compounds of formula (I) and salts thereof, wherein,
R3preferably selected from hydrogen, aldehyde groups, CH-NNHC (S) NH2CONHRa, COORb, CH ═ CHRc and CH ═ NRd, where,
ra is C1-2Alkyl, mono C2-6An alkylamino group or an L-amino acid residue,
rb is glucose, xylose, ribose, deoxyribose or acyclic sugar,
rc is a phenyl group or a heterocyclic group,
rd is C1-2Alkyl or C2-6An alkylamino group.
A compound of formula I and salts thereof, wherein,
R3more preferably selected from hydrogen, aldehyde groups, CH ═ NNHC (S) NH2CONHRa, COORb, CH ═ CHRc and CH ═ NRd, where,
ra is mono C2-6Alkylamino, L-phenylalanine residue, L-tryptophan residue or(ii) an L-tyrosine residue,
rb is glucose, ribose or deoxyribose,
rc is 4-methoxyphenyl or 4-nitrophenyl,
rd is C2-4An alkylamino group.
A compound of formula I and salts thereof, wherein,
R3particularly preferably from hydrogen, CH-NNHC (S) NH2CONHRa and CH ═ CHRc, where,
ra is C6An alkylamino L-phenylalanine residue or an L-tyrosine residue,
rc represents 4-methoxyphenyl or 4-nitrophenyl.
A compound of formula I and salts thereof, wherein,
R7preferably selected from hydrogen, n-butoxy, COCH2CONHRa and COCH2COORb, wherein,
ra is an L-phenylalanine residue, an L-tryptophan residue or an L-tyrosine residue,
rb is glucose, ribose or deoxyribose.
A compound of formula I and salts thereof, wherein R7More preferably hydrogen or n-butoxy.
A compound of formula I and salts thereof, wherein R9Preferably hydrogen, n-butyl or phenylpropyl.
A compound of formula I and salts thereof, wherein R9More preferably n-butyl or phenylpropyl.
A compound of formula I and salts thereof, wherein,
R1preferably selected from hydrogen, pyridyl, aldehyde, carboxylic acid, carboxylic ester, carboxylic salt, CH ═ nnhc(s) NH2CONHRa, COORb, CH ═ CHRc and NHRd, where,
ra is C1-2Alkyl, mono C2-6An alkylamino group or an L-amino acid residue,
rb is glucose, xylose, ribose, deoxyribose or acyclic sugar,
rc is a phenyl group or a heterocyclic group,
rd is C1-2Alkyl or C2-6An alkylamino group;
R2is selected from hydrogen, benzyl, phenylpropyl, sulfonic acid group;
x is chlorine or bromine; or, R2And X are absent at the same time;
R3selected from hydrogen, aldehyde groups, CH ═ NNHC (S) NH2CONHRa, COORb, CH ═ CHRc and CH ═ NRd, where,
ra is C1-2Alkyl, mono C2-6An alkylamino group or an L-amino acid residue,
rb is glucose, xylose, ribose, deoxyribose or acyclic sugar,
rc is a phenyl group or a heterocyclic group,
rd is C1-2Alkyl or C2-6An alkylamino group;
R7selected from hydrogen, n-butoxy, COCH2CONHRa and COCH2COORb, wherein,
ra is an L-phenylalanine residue, an L-tryptophan residue or an L-tyrosine residue,
rb is glucose, ribose or deoxyribose;
R9selected from hydrogen, n-butyl and phenylpropyl.
A compound of formula I and salts thereof, wherein,
R1more preferably selected from the group consisting of hydrogen, pyridyl, sodium carboxylate, (4 '-methoxy) styryl, (4' -nitro) styryl, aldehyde group, acetal groupThiosemicarbazide groups, CONHRa and NHRd, wherein,
ra is an L-tyrosine residue or an L-phenylalanine residue,
rd represents C2-4An alkylamino group;
R2selected from hydrogen, benzyl, phenylpropyl or sulfonic acid groups;
x is selected from chlorine or bromine; or, R2And X are absent at the same time;
R3selected from hydrogen, CH ═ NNHC (S) NH2CONHRa and CH ═ CHRc, where,
ra is an L-phenylalanine residue or an L-tyrosine residue,
rc is 4-methoxyphenyl or 4-nitrophenyl;
R7selected from hydrogen, n-butoxy, COCH2CONHRa and COCH2COORb, wherein,
ra is an L-phenylalanine residue, an L-tryptophan residue or an L-tyrosine residue;
rb is glucose, ribose or deoxyribose;
R9selected from hydrogen, n-butyl and phenylpropyl.
A compound of formula I and salts thereof, wherein,
R1particularly preferred are compounds selected from pyridyl, sodium carboxylate, (4 '-methoxy) styryl, (4' -nitro) styryl, CH ═ nnhc(s) NH2CONHRa or NHRd, wherein,
ra is an L-tyrosine residue or an L-phenylalanine residue,
rd is C2-4An alkylamino group;
R2selected from hydrogen and benzyl; x is selected from chlorine and bromine; or, R2And X are absent at the same time;
R3is hydrogen;
R7selected from hydrogen, n-butoxy, COCH2CONHRa and COCH2COORb, wherein,
ra is selected from the group consisting of an L-phenylalanine residue and an L-tyrosine residue;
rb is selected from glucose, ribose and deoxyribose;
R9selected from n-butyl and phenylpropyl.
Preferred compounds according to the invention are selected from any one of the following compounds:
7-hydroxy-9-ethyl-1-methyl-beta-carboline,
7-hydroxy-9-n-butyl-1-methyl-beta-carboline,
7-hydroxy-9-isobutyl-1-methyl-beta-carboline,
7-ethoxy-9-ethyl-1-methyl-beta-carboline,
7-isopropoxy-9-ethyl-1-methyl-beta-carboline,
7-n-butoxy-9-ethyl-1-methyl-beta-carboline,
7-isobutoxy-9-ethyl-1-methyl-beta-carboline,
7-n-decyloxy-9-ethyl-1-methyl-beta-carboline,
7-benzyloxy-9-ethyl-1-methyl-beta-carboline,
7-pentafluorobenzyloxy-9-ethyl-1-methyl-beta-carboline,
7-phenylpropyloxy-9-ethyl-1-methyl-beta-carboline,
7-ethoxy-9-n-butyl-1-methyl-beta-carboline,
7-isopropoxy-9-n-butyl-1-methyl-beta-carboline,
7-n-butyloxy-9-n-butyl-1-methyl-beta-carboline,
7-isobutanyloxy-9-n-butyl-1-methyl-beta-carboline,
7- (3' -pentane) oxy-9-n-butyl-1-methyl-beta-carboline,
7- (3 ', 3 ', 3 ' -trifluoro-2-hydroxy) propaneoxy-9-n-butyl-1-methyl-beta-carboline,
7-n-octyloxy-9-n-butyl-1-methyl-beta-carboline,
7-n-decaalkoxy-9-n-butyl-1-methyl-beta-carboline,
7-benzyloxy-9-n-butyl-1-methyl-beta-carboline,
7-pentafluorobenzyloxy-9-n-butyl-1-methyl-beta-carboline,
7-phenylpropylalkoxy-9-n-butyl-1-methyl-beta-carboline,
7-n-butoxy-9-isobutyl-1-methyl-beta-carboline,
7-isobutoxy-9-isobutyl-1-methyl-beta-carboline,
7-n-decaalkoxy-9-isobutyl-1-methyl-beta-carboline,
7-benzyloxy-9-isobutyl-1-methyl-beta-carboline,
7-phenylpropyloxy-9-isobutyl-1-methyl-beta-carboline,
7-ethoxy-2-benzyl-9-ethyl-1-methyl-beta-carboline bromide,
7-n-butoxy-2-benzyl-9-ethyl-1-methyl-beta-carboline bromide salt,
7-isobutoxy-2-benzyl-9-ethyl-1-methyl-beta-carboline bromine salt,
7-benzyloxy-2-benzyl-9-ethyl-1-methyl-beta-carboline bromide,
7-pentafluorobenzyloxy-2-benzyl-9-ethyl-1-methyl-beta-carboline bromide,
7-phenylpropyloxy-2-benzyl-9-ethyl-1-methyl-beta-carboline bromide salt,
7-benzyloxy-2-benzyl-9-n-butyl-1-methyl-beta-carboline bromide,
7-n-octyloxy-2-benzyl-9-n-butyl-1-methyl-beta-carboline bromide salt,
7-isobutoxy-2-benzyl-9-n-butyl-1-methyl-beta-carboline bromine salt,
7-n-butoxy-2-benzyl-9-isobutyl-1-methyl-beta-carboline bromide salt,
7-isobutoxy-2-benzyl-9-isobutyl-1-methyl-beta-carboline bromide salt,
7-n-decaalkoxy-2-benzyl-9-isobutyl-1-methyl-beta-carboline bromide,
7-benzyloxy-2-benzyl-9-isobutyl-1-methyl-beta-carboline bromide,
7-phenylpropyloxy-2-benzyl-9-isobutyl-1-methyl-beta-carboline bromide salt,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-beta-carboline-3-carboxylic acid ethyl ester,
ethyl 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-ethyl-beta-carboline-3-carboxylate,
ethyl 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl-beta-carboline-3-carboxylate,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl-beta-carboline-3-carboxylic acid,
n-hydroxyethyl-1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-beta-carboline-3-carboxamide,
n-hydroxyethyl-1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-ethyl-beta-carboline-3-carboxamide,
n-hydroxyethyl-1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-N-butyl-beta-carboline-3-carboxamide,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-beta-carboline,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-ethyl-beta-carboline,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl-beta-carboline,
ethyl beta-carboline-1-carboxylate,
ethyl 9-n-butyl-beta-carboline-1-carboxylate,
9-n-butyl-beta-carboline-1-carboxylic acid,
3-hydroxymethyl-9-ethyl-beta-carboline,
3-hydroxymethyl-9-n-butyl-beta-carboline,
3-hydroxymethyl-9-benzyl-beta-carboline,
3-hydroxymethyl-9- (4' -fluoro) benzyl-beta-carboline,
3-hydroxymethyl-9-phenylpropyl-beta-carboline,
3-hydroxymethyl-9-n-butyl-1-methyl-beta-carboline,
3-hydroxymethyl-9-benzyl-1-methyl-beta-carboline,
3-hydroxymethyl-9- (4' -fluoro) benzyl-1-methyl-beta-carboline,
3-hydroxymethyl-9-phenylpropyl-1-methyl-beta-carboline,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-3-hydroxymethyl-9-n-butyl-beta-carboline,
3-aldehyde-9-ethyl-beta-carboline,
3-aldehyde-9-n-butyl-beta-carboline,
3-aldehyde-9-benzyl-beta-carboline,
3-formyl-9-phenylpropyl-beta-carboline,
3-aldehyde-9-n-butyl-1-methyl-beta-carboline,
3-aldehyde-9-benzyl-1-methyl-beta-carboline,
3-aldehyde-9- (4' -fluoro) benzyl-1-methyl-beta-carboline,
3-aldehyde-9-phenylpropyl-1-methyl-beta-carboline,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-3-aldehyde-9-n-butyl-beta-carboline,
9-ethyl-beta-carboline-3-aldehyde thiosemicarbazone,
9-n-butyl-beta-carboline-3-aldehyde thiosemicarbazone,
9-benzyl-beta-carboline-3-aldehyde thiosemicarbazone,
9-phenylpropyl-beta-carboline-3-aldehyde thiosemicarbazone,
9-n-butyl-1-methyl-beta-carboline-3-aldehyde thiosemicarbazone,
9-benzyl-1-methyl-beta-carboline-3-aldehyde thiosemicarbazone,
9-phenylpropyl-1-methyl-beta-carboline-3-aldehyde thiosemicarbazone
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl-beta-carboline-3-aldehyde thiosemicarbazone,
3-hydroxymethyl-2-benzyl-9-n-butyl-beta-carboline bromide,
3-hydroxymethyl-9-phenylpropyl-2-benzyl-beta-carboline bromide,
3-aldehyde-2-benzyl-9-n-butyl-beta-carboline bromide,
3-aldehyde-9-phenylpropyl-2-benzyl-beta-carboline bromide,
3-aldehyde-9-n-butyl-beta-carboline sodium bisulfite addition salt,
3-aldehyde-9-phenylpropyl-beta-carboline sodium bisulfite addition salt,
3-aldehyde-9-phenylpropyl-1-methyl-beta-carboline sodium bisulfite addition salt,
1-aldehyde-beta-carboline-3-carboxylic acid ethyl ester,
1-aldehyde-9-butyl-beta-carboline-3-carboxylic acid ethyl ester,
1-aldehyde-9-butyl-beta-carboline,
1-aldehyde-9-phenylpropyl-beta-carboline,
3-carboethoxyl-9-butyl-beta-carboline-1-aldehyde thiosemicarbazone,
9-phenylpropyl-beta-carboline-1-aldehyde thiosemicarbazone,
3-carboethoxyl-9-butyl-beta-carboline-1-aldehyde hydroxylamine acetal,
9-butyl-beta-carboline-1-aldehyde hydroxylamine acetal,
3-carboethoxyl-9-phenylpropyl-beta-carboline-1-aldehyde hydroxylamine carboxylate,
9-phenylpropyl-beta-carboline-1-aldehyde shrinkage methoxamine,
n- (4-beta-carboline-phenoxyacetyl) phenylalanine ethyl ester,
n- (4-beta-carboline-phenoxyacetyl) tyrosine ethyl ester,
n- (4-beta-carboline-phenoxyacetyl) phenylalanine,
n- (4-beta-carboline-phenoxyacetyl) tyrosine,
n- (9-N-butyl-beta-carboline-3-formyl) phenylalanine methyl ester,
n- (9-N-butyl-beta-carboline-3-formyl) valine methyl ester,
n- (9-N-butyl-beta-carboline-3-formyl) phenylalanine ethyl ester,
n- (9-N-butyl-beta-carboline-3-formyl) alanine methyl ester,
n- (9-N-butyl-beta-carboline-3-formyl) methionine ethyl ester,
n- (9-N-butyl-beta-carboline-3-formyl) tryptophan ethyl ester,
n- (9-N-butyl-1-methyl-beta-carboline-3-formyl) phenylalanine ethyl ester,
n- (9-N-butyl-1-methyl-beta-carboline-3-formyl) methionine ethyl ester,
n- (9-N-butyl-1-methyl-beta-carboline-3-formyl) tryptophan methyl ester,
n- (9-benzyl-beta-carboline-3-formyl) phenylalanine ethyl ester,
n- (9-benzyl-beta-carboline-3-formyl) methionine ethyl ester,
n- (9-benzyl-beta-carboline-3-formyl) tryptophan methyl ester,
n- (1-methyl-beta-carboline-3-formyl) alanine methyl ester,
n- (1-methyl-beta-carboline-3-formyl) methionine ethyl ester,
n- (1-methyl-beta-carboline-3-formyl) phenylalanine ethyl ester,
n- (1-methyl-beta-carboline-3-formyl) tryptophan methyl ester,
n- (9-phenylpropyl-beta-carboline-3-formyl) alanine methyl ester,
n- (9-phenylpropyl-beta-carboline-3-formyl) methionine ethyl ester,
n- (9-phenylpropyl-beta-carboline-3-formyl) valine ethyl ester,
n- (9-N-butyl-beta-carboline-3-formyl) tyrosine methyl ester,
n- (9-phenylpropyl-beta-carboline-3-formyl) phenylalanine ethyl ester,
n- (9-N-butyl-beta-carboline-3-formyl) methionine,
n- (9-N-butyl-beta-carboline-3-formyl) phenylalanine,
n- (9-benzyl-beta-carboline-3-formyl) methionine,
n- (9-N-butyl-beta-carboline-3-formyl) tyrosine,
n- (9-phenylpropyl-beta-carboline-3-formyl) alanine,
n- (9-phenylpropyl-beta-carboline-3-formyl) methionine,
n- (9-phenylpropyl-beta-carboline-3-formyl) phenylalanine,
n- (9-phenylpropyl-beta-carboline-3-formyl) valine,
n- (2-benzyl-9-phenylpropyl-beta-carboline-3-formyl) phenylalanine ethyl ester bromide salt,
n- (2-benzyl-9-phenylpropyl-beta-carboline-3-formyl) methionine ethyl ester bromide salt,
n- (9-N-butyl-1-methyl-beta-carboline-7-oxyacetyl) methionine ethyl ester,
n- (9-N-butyl-1-methyl-beta-carboline-7-oxyacetyl) tyrosine ethyl ester,
n- (9-phenylpropyl-1-methyl-beta-carboline-7-oxyacetyl) tyrosine ethyl ester,
n- (9-N-butyl-1-methyl-beta-carboline-7-oxyacetyl) methionine,
n- (9-N-butyl-1-methyl-beta-carboline-7-oxyacetyl) tyrosine,
n- (9-phenylpropyl-1-methyl-beta-carboline-7-oxyacetyl) tyrosine,
n- (beta-carboline-1-formyl) methionine ethyl ester,
n- (beta-carboline-1-formyl) phenylalanine ethyl ester,
n- (9-methyl-beta-carboline-1-formyl) methionine ethyl ester,
n- (9-methyl-beta-carboline-1-formyl) phenylalanine ethyl ester,
n- (beta-carboline-1-formyl) methionine,
n- (beta-carboline-1-formyl) phenylalanine,
n- (9-methyl-beta-carboline-1-formyl) methionine,
n- (9-methyl-beta-carboline-1-formyl) phenylalanine,
1-O- (9-n-butyl-beta-carboline-3-formyl) -2, 3, 4-tri-O-benzoyl-beta-D-pyran type ribose,
1-O- (9-benzyl-beta-carboline-3-formyl) -2, 3, 4-tri-O-benzoyl-beta-D-pyran type ribose,
1-O- (9-phenylpropyl-beta-carboline-3-formyl) -2, 3, 4-tri-O-benzoyl-beta-D-pyran type ribose,
1-O- (9-n-butyl-beta-carboline-3-formyl) -2, 3, 4, 5-tetra-O-acetyl-beta-D-pyran glucose,
1-O- (9-benzyl-beta-carboline-3-formyl) -2, 3, 4, 5-tetra-O-acetyl-beta-D-pyran glucose,
1-O- (9-phenylpropyl-beta-carboline-3-formyl) -2, 3, 4, 5-tetra-O-acetyl-beta-D-pyran glucose,
7-beta-D-glucopyranosyloxy-1-methyl-9-n-butyl-beta-carboline,
7-beta-D-glucopyranosyloxy-9-phenylpropyl-1-methyl-beta-carboline,
1- (p-beta-D-glucopyranosyloxy-phenyl) -beta-carboline,
7-beta-D-pyran xyloxy-9-n-butyl-1-methyl-beta-carboline,
7-beta-D-pyran xyloxy-9-phenylpropyl-1-methyl-beta-carboline,
1-styryl-beta-carboline,
1- (4' -methoxy-styryl) -beta-carboline,
1- (3 ', 4 ', 5 ' -trimethoxy-styryl) -beta-carboline,
1- (4' -methoxy-styryl) -9-n-butyl-beta-carboline,
1- (4' -methoxy-styryl) -9-phenylpropyl-beta-carboline,
1- (4' -methoxy-styryl) -7-n-butoxy-9-phenylpropyl-beta-carboline,
1- (4' -nitro-styryl) -9-acetyl-beta-carboline,
1- (4' -nitro-styryl) -9-phenylpropyl-beta-carboline,
1- (4' -nitro-styryl) -7-n-butoxy-9-phenylpropyl-beta-carboline,
1- (4' -methoxy-styryl) -2-benzyl-beta-carboline bromide,
1- (4' -methoxy-styryl) -2-benzyl-9-n-butyl-beta-carboline bromide salt,
1- (4' -methoxy-styryl) -9-phenylpropyl-2-benzyl-beta-carboline bromide salt,
1- (4' -methoxy-styryl) -7-n-butoxy-9-phenylpropyl-2-benzyl-beta-carboline bromide salt,
1- (4' -nitro-styryl) -9-acetyl-2-benzyl-beta-carboline bromide salt,
1- (4' -nitro-styryl) -7-n-butoxy-9-phenylpropyl-2-benzyl-beta-carboline bromide salt,
1- (3' -pyridyl) -9-n-butyl-beta-carboline,
1- (3' -pyridyl) -9-benzyl-beta-carboline,
1- (2' -aminoethyl) carbamoyl-9-phenylpropyl-beta-carboline,
1- (2' -amino) ethylamino-9-n-butyl-beta-carboline,
1- (2' -amino) ethylamino-9-phenylpropyl-beta-carboline.
The above preferred compounds and their addition salts with pharmaceutically acceptable acids or bases form part of the complete disclosure of the present invention. Suitable salts of the compounds of the invention, which are obtained depending on the substitution, are all acid addition salts or all salts with bases. Particular mention may be made of the salts of pharmacologically acceptable inorganic acids, organic acids, inorganic bases and organic bases commonly used in the pharmaceutical industry. These suitable salts are, on the one hand, water-soluble, in particular water-soluble, acid addition salts, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, pamoic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid.
The invention also relates to a pharmaceutical composition comprising one or more compounds of formula I together with usual pharmaceutical excipients and/or adjuvants.
Among the pharmaceutical compositions according to the invention, mention may in particular be made of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal or transdermal, nasal, lingual, ocular or respiratory, rectal administration, in particular tablets or dragees, sublingual tablets, capsules, suppositories, aerosols, creams, ointments, dermal gels, injectable or drinkable preparations, eye drops, nasal drops and the like.
The compounds of the invention have anti-tumor activity, so the invention also provides the application of the compounds in preparing medicaments for treating tumors.
As a medicament, useful dosages will vary with the age and weight of the patient, the route of administration, the nature and severity of the disease and any other treatment to which it is subjected.
Definition of
"C" referred to in the invention1-6Alkyl "means having 1-6 carbonsStraight or branched alkyl radicals of atoms, "C1-6Alkylamino "refers to a straight or branched alkylamino radical having 1 to 6 carbon atoms," C1-6Alkoxy "means a straight or branched chain alkylamino group having 1 to 6 carbon atoms, and so on;
"phenyl" may be optionally substituted with one or more of the same or different substituent groups including hydroxy, amino, nitro, halogen, C1-2Alkoxy radical, C1-2An alkylamino group;
"aryl" shall be phenyl, naphthyl, tetrahydronaphthyl, dihydronaphthyl, each optionally substituted with one or more identical or different groups; the substituent is selected from hydroxyl, nitro, halogen, amino and C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Alkyl acyl radical, C1-6Alkoxycarbonyl group, C1-6An alkoxycarbonylamino group;
"Heterocyclyl" shall be a saturated or unsaturated mono-or bicyclic radical, of aromatic or non-aromatic character, having 5 to 12 ring atoms, containing 1, 2 or 3 identical or different heteroatoms selected from oxygen, nitrogen, sulphur, the heterocycle being understood as optionally substituted by one or more identical or different substituents selected from halogen, hydroxy, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino groups, such as, but not limited to, pyridyl, thienyl, furyl, imidazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, pyrrolyl and pyrazolyl;
"amino" shall be optionally substituted by one or two C1-6Alkyl substitution;
the "sugar" should be optionally substituted by one or more identical or different groups selected from C1-4An alkyl acyl or aryl acyl group;
other symbols, terms and abbreviations used in the present application have meanings well known in the art unless otherwise indicated.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Instrument and reagent
RE-52C rotary evaporator purchased from Henan Prohua instruments;
the UV-8 type ultraviolet sample application analyzer is purchased from a stannless Kodak instrument factory;
the YRT-3 melting point tester is purchased from precision instruments factories of Tianjin university;
ZAB-HS Dual focusing magnetic mass spectrometer was purchased from VG, United kingdom;
bruker Equinox55 model fourier transform infrared spectrometer, KBr pellet;
INOVA500 superconducting nmr was purchased from Varian corporation, usa;
Mercury-Plus300 superconducting NMR was purchased from Varian, USA;
the domestic chemical reagents are purchased from Guangzhou chemical reagent factory and national drug group chemical reagent company;
imported chemicals were purchased from beijing bailing wafer chemicals corporation; the chemical intermediates used in the invention were prepared according to the methods disclosed in the literature.
Synthesis scheme 1
Figure A200710180027D00241
The following compounds of examples 1-21 can be accomplished by synthetic scheme 1:
example 17-hydroxy-9-ethyl-1-methyl-beta-carboline (1)
Step A: 7-methoxy-9-ethyl-1-methyl-beta-carboline
Mixing harmine (2.12g, 10mmol), DMF (50ml), and 60% NaH (0.6g, 15mmol), stirring at room temperature for 10min, adding iodoethane (15mmol), stirring at room temperature for reaction, and TLC tracking detection. After the reaction, the reaction mixture was poured into 100ml of ice water, stirred at room temperature for 2 hours, filtered, and washed with a large amount of water to obtain a pale yellow solid. Dissolving the solid in absolute ethyl alcohol, adjusting the pH value to 2 by using concentrated hydrochloric acid, then concentrating under reduced pressure until the solid is dry, wherein the absolute ethyl alcohol carries water for 3 times to obtain yellow oily matter, recrystallizing by using acetone, and filtering to obtain white crystals, namely hydrochloride of the product. The product was used in the next reaction without further purification.
And B: 7-hydroxy-9-ethyl-1-methyl-beta-carboline
7-methoxy-9-ethyl-1-methyl-beta-carboline hydrochloride (10mmol), glacial acetic acid (100ml) and 40% hydrobromic acid (75ml) are mixed, heated under reflux, monitored by TLC (developing solvent: acetone/petroleum ether ═ 1:1), after the reaction is completed, the reaction mixture is poured into 300ml of ice water, the pH is adjusted to 6 with 10M sodium hydroxide under stirring, and then the pH is adjusted to 8 with sodium bicarbonate. Filtering and washing with a large amount of water to obtain an off-white solid. Dissolving the solid in absolute ethyl alcohol, decolorizing with active carbon, filtering, concentrating under reduced pressure, and recrystallizing with absolute ethyl alcohol to obtain white granular crystals 1.8g, yield 80%, mp 258-.
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)δ 9.74(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，NCH2CH3)；2.92(3H，s，CH3)；1.31-1.34(3H，m，N CH2CH3).
Example 27-hydroxy-9-n-butyl-1-methyl-beta-carboline (2)
The procedure is as in example 1, using n-butyl iodide as alkylating agent in step A. Obtaining 2.2g of white crystals with the yield of 87 percent and the temperature of mp 205-;
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-d6)δ 9.72(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，NCH2CH2CH2CH3)；2.91(3H，s，CH3)；1.67-1.74(2H，m，NCH2CH2CH2CH3)；1.36-1.40(2H，m，NCH2CH2CH2CH3)；0.92-0.94(2H，m，NCH2CH2CH2CH3).
example 37-hydroxy-9-isobutyl-1-methyl-beta-carboline (3)
The procedure is as in example 1, using 1-iodo-2-methylpropane as alkylating agent in step A. Obtaining white crystals 2.0g, the yield is 79 percent, and the temperature is 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-d6)δ 9.70(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，NCH2CH[CH3]2)；2.90(3H，s，CH3)；2.11-2.17(1H，m，NCH2CH[CH3]2)；0.85-0.87(6H，s，NCH2CH[CH3]2)。
example 47-isobutoxy-9-ethyl-1-methyl-. beta. -carboline (4)
Mixing 7-hydroxy-9-ethyl-1-methyl-beta-carboline (2.0mmol), DMF (30ml) and 60% sodium hydride (0.2g and 5mmol), stirring at room temperature for 5min, then adding 1-bromo-2-methylpropane (5mmol), stirring at room temperature for reaction, performing TLC tracking detection (developing agent: acetone/petroleum ether ═ 1:1), after the reaction is finished, pouring the reaction mixture into water, adding 10M sodium hydroxide, stirring at room temperature for reaction overnight, filtering, washing with a large amount of water to obtain an off-white solid. Dissolving the solid in anhydrous ethanol, adjusting pH to 3-4 with concentrated hydrochloric acid, concentrating under reduced pressure, adding water in anhydrous ethanol for several times, and recrystallizing with acetone or acetone/diethyl ether to obtain white or light yellow solid. Dissolving the solid in a mixed solution of ethyl acetate/water, alkalifying with sodium bicarbonate, extracting with ethyl acetate, combining organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and recrystallizing with an ether/petroleum ether mixed solution (1:1) to obtain 0.39g of white crystals, wherein the yield is 69%, and mp 127-;
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，CDCl3)δ 8.26-8.27(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，NCH2CH3)；3.85-3.86(2H，d，OCH2CH[CH3]2)；3.02(3H，s，CH3)；2.14-2.19(1H，m，OCH2CH[CH3]2)；1.42-1.45(3H，m，NCH2CH3)，1.07-1.09(6H，m，OCH2CH[CH3]2).
example 57-benzyloxy-9-ethyl-1-methyl-beta-carboline (5)
The procedure is as in example 4, but benzyl bromide is used as alkylating agent. Obtaining white crystals of 0.55g, the yield is 87 percent, and the temperature is 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，CDCl3)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，OCH2Ph)；4.50-4.55(2H，m，NCH2CH3)；3.03(3H，s，CH3)；1.37-1.43(3H，m，NCH2CH3).
example 67-Phenylpropoxy-9-ethyl-1-methyl-beta-carboline (6)
The procedure is as in example 4, but 1-bromo-3-phenylpropane is used as alkylating agent. Obtaining 0.52g of white crystals with the yield of 76 percent and mp 110-;
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，CDCl3)δ 8.26-8.27(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，NCH2CH3)；4.09-4.11(2H，m，OCH2CH2CH2Ph)；3.02(3H，s，CH3)；2.86-2.89(2H，m，OCH2CH2CH2Ph)；2.13-2.21(3H，m，NCH2CH3)；1.41-1.44(2H，m，OCH2CH2CH2Ph).
example 77-Isocyanatooxy-9-n-butyl-1-methyl-beta-carboline (7)
The procedure is as in example 4, but using 1-bromo-2-methylpropane as alkylating agent and 7-hydroxy-9-n-butyl-1-methyl- β -carboline as starting material. Obtaining white crystal 0.48g, yield 77%, mp91-92 deg.C;
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，CDCl3)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，NCH2CH2CH2CH3)；3.86-3.87(2H，d，OCH2CH[CH3]2)；3.07(3H，s，CH3)；2.14-2.19(1H，m，OCH2CH[CH3]2)；1.79-1.85(2H，m，NCH2CH2CH2CH3)；1.43-1.48(2H，m，NCH2CH2CH2CH3)；1.08-1.10(6H，m，OCH2CH[CH3]2)；0.98-1.01(3H，m，NCH2CH2CH2CH3).
example 87- (3 ', 3 ', 3 ' -trifluoro-2-hydroxy) propaneoxy-9-n-butyl-1-methyl-beta-carboline (8)
The procedure is as in example 7, but 3-bromo-1, 1, 1-trifluoro-2-propanol is used as alkylating agent. Obtaining white crystals of 0.56g, the yield of 76 percent and mp 162-;
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，CDCl3)δ 8.23-8.24(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，OCH2CH(OH)CF3，NCH2CH2CH2CH3)；2.94(3H，s，CH3)；1.66-1.73(2H，m，NCH2CH2CH2CH3)；1.36-1.41(2H，m，NCH2CH2CH2CH3)；0.90-0.98(3H，m，NCH2CH2CH2CH3).
example 97-benzyloxy-9-n-butyl-1-methyl-beta-carboline (9)
The procedure is as in example 7, but benzyl bromide is used as alkylating agent. Obtaining white crystals of 0.57g, the yield is 83 percent, and the temperature is mp 121-;
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，CDCl3)δ 8.27-8.28(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，OCH2Ph)；4.41-4.44(2H，m，NCH2CH2CH2CH3)；3.05(3H，s，CH3)；1.75-1.78(2H，m，NCH2CH2CH2CH3)；1.38-1.43(2H，m，NCH2CH2CH2CH3)；0.94-0.97(3H，m，NCH2CH2CH2CH3).
example 107-Pentafluorobenzyloxy-9-n-butyl-1-methyl-beta-carboline (10)
The procedure is as in example 7, but using α -bromo- (2, 3, 4, 5, 6-pentafluoro) toluene as alkylating agent. Obtaining white crystals of 0.63g, the yield is 73 percent, and the temperature is mp 121-;
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，CDCl3)δ 8.27-8.28(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，OCH2Ph)；4.41-4.44(2H，m，NCH2CH2CH2CH3)；3.05(3H，s，CH3)；1.75-1.78(2H，m，NCH2CH2CH2CH3)；1.38-1.43(2H，m，NCH2CH2CH2CH3)；0.94-0.97(3H，m，NCH2CH2CH2CH3).
example 117-n-butoxy-9-isobutyl-1-methyl-beta-carboline (11)
The procedure is as in example 4, but using n-butyl iodide as alkylating agent and 7-hydroxy-9-isobutyl-1-methyl-beta-carboline as starting material. Obtaining light yellow oily matter 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，CDCl3)δ 8.27-8.28(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，OCH2CH2CH2CH3)；4.08-4.11(2H，m，NCH2CH[CH3]2)；3.07(3H，s，CH3)；2.24-2.27(1H，m，NCH2CH[CH3]2)；1.82-1.88(2H，m，OCH2CH2CH2CH3)；1.54-1.58(2H，m，OCH2CH2CH2CH3)；1.00-1.03(3H，m，2H，m，OCH2CH2CH2CH3)；0.93-0.95(6H，m，NCH2CH[CH3]2).
example 127-n-decaalkoxy-9-isobutyl-1-methyl-beta-carboline (12)
The procedure is as in example 11, but 1-iododecane is used as alkylating agent. Obtaining white crystal 0.59g, yield 75%, mp 62-64 deg.C;
FAB-MS m/e(M+1)395；
IR(KBr)3431，2950，2922，2849，1625，1567，1447，1335，1254，1202，1142，809；
1H-NMR(500MHz，CDCl3)δ 8.27-8.28(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，NCH2CH[CH3]2)；4.07-4.09(2H，m，OCH2[CH2]8CH3)；3.03(3H，s，CH3)；2.23-2.29(1H，m，NCH2CH[CH3]2)；1.82-1.88(2H，m，OCH2CH2[CH2]7CH3)；1.48-1.54(2H，m，OCH2CH2CH2[CH2]6CH3)；1.28-1.40(12H，m，OCH2CH2CH2[CH2]6CH3)；0.93-0.94(6H，d，NCH2CH[CH3]2)；0.87-0.90(3H，m，O[CH2]9CH3).
example 137-Phenylpropoxy-9-isobutyl-1-methyl- β -carboline (13)
The procedure is as in example 11, but 1-bromo-3-phenylpropane is used as alkylating agent. Obtaining white crystal 0.54g, yield 74%, mp 94-95 deg.C;
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，CDCl3)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，NCH2CH[CH3]2)；4.09-4.11(2H，m，OCH2CH2CH2Ph)；3.04(3H，s，CH3)；2.86-2.89(2H，m，OCH2CH2CH2Ph)；2.15-2.26(3H，m，NCH2CH[CH3]2，OCH2CH2CH2Ph)；0.92-0.93(6H，d，NCH2CH[CH3]2).
example 147-isobutoxy-2-benzyl-9-ethyl-1-methyl-beta-carboline bromide (14)
Mixing 7-isobutoxy-9-ethyl-1-methyl-beta-carboline (1mmol), ethyl acetate (50ml) and benzyl bromide (20mmol), heating and refluxing, tracking and detecting by TLC, stopping refluxing after most of reaction raw materials are reacted, cooling reaction mixed liquid, filtering, and washing by using a proper amount of ethyl acetate to obtain a yellow solid. Recrystallizing the solid with anhydrous ethanol for 3 times to obtain light yellow crystal 0.36g, yield 79%, mp222-224 deg.C;
FAB-MS m/e 373；
IR(KBr)3420，2959，1622，1454，1372，1259，1223，1134，1034，1010，826，736；
1H-NMR(500MHz，DMSO-d6)δ 8.78-8.79(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，NCH2Ph)；4.70-4.75(2H，m，NCH2CH3)；3.99-4.01(2H，m，OCH2CH[CH3]2)；3.11(3H，s，CH3)；2.11-2.14(1H，m，OCH2CH[CH3]2)；1.38-1.41(3H，m，NCH2CH3)；1.05-1.06(6H，m，OCH2CH[CH3]2)。
example 157-benzyloxy-2-benzyl-9-ethyl-1-methyl-beta-carboline bromide (15)
The procedure is as in example 14, but 7-benzyloxy-9-ethyl-1-methyl- β -carboline is used as the starting material for the reaction. Obtaining light yellow crystal 0.4g, yield 82%, mp 240-;
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-d6)δ 8.80-8.82(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，NCH2Ph)；5.36(2H，s，NCH2Ph)；4.71-4.75(2H，m，NCH2CH3)；3.11(3H，s，CH3)；1.37-1.40(3H，m，NCH2CH3)。
example 167-Phenylpropoxy-2-benzyl-9-ethyl-1-methyl- β -carboline bromide (16)
The procedure is as in example 14, but 7-phenylpropyloxy-9-ethyl-1-methyl- β -carboline is used as the starting material for the reaction. Obtaining light yellow crystal 0.40g with yield of 78 percent and 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-d6)δ 8.80-8.81(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，NCH2Ph)；4.69-4.73(2H，m，NCH2CH3)；4.23-4.25(1H，m，OCH2CH2CH2Ph)；3.11(3H，s，CH3)；2.80-2.83(2H，m，OCH2CH2CH2Ph)；2.10-2.15(2H，m，OCH2CH2CH2Ph)；1.37-1.39(3H，m，NCH2CH3)。
example 177-benzyloxy-2-benzyl-9-n-butyl-1-methyl- β -carboline bromide (17)
The procedure is as in example 14, but 7-benzyloxy-9-n-butyl-1-methyl- β -carboline is used as the starting material for the reaction. Obtaining light yellow crystal 0.42g with the yield of 82 percent and mp 229-;
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-d6)δ 8.80-8.81(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，NCH2Ph)；5.37(2H，s，OCH2Ph)；4.63-4.66(2H，m，NCH2CH2CH2CH3)；3.09(3H，s，CH3)；1.68-1.71(2H，m，NCH2CH2CH2CH3)；1.30-1.34(2H，m，NCH2CH2CH2CH3)；0.86-0.89(3H，m，NCH2CH2CH2CH3).
example 187-isobutoxy-2-benzyl-9-n-butyl-1-methyl-. beta. -carboline bromide salt (18)
The procedure is as in example 14, but 7-isobutoxy-9-n-butyl-1-methyl-. beta. -carboline is used as starting material for the reaction. Obtaining light yellow crystal 0.40g, yield 83%, mp 247-;
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-d6)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，NCH2Ph)；4.64-4.67(2H，m，NCH2CH2CH2CH3)；4.20-4.22(2H，m，OCH2[CH2]6CH3)；3.09(3H，s，CH3)；1.71-1.82(2H，m，NCH2CH2CH2CH3)；1.46-1.49(2H，m，OCH2CH2[CH2]5CH3)；1.26-1.37(12H，m，NCH2CH2CH2CH3，O[CH2]2[CH2]5CH3)；0.85-0.94(6H，m，N[CH2]3CH3，O[CH2]7CH3)。
example 197-n-butoxy-2-benzyl-9-isobutyl-1-methyl- β -carboline bromide salt (19)
The procedure is as in example 14, but 7-n-butoxy-9-isobutyl-1-methyl- β -carboline is used as the starting material for the reaction. Obtaining light yellow crystal 0.40g with yield of 84 percent and 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-d6)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，CH2Ph)；4.53-4.54(2H，d，OCH2CH2CH2CH3)；4.20-4.22(2H，m，NCH2CH[CH3]2)；3.06(3H，s，CH3)；2.04-2.09(1H，m，NCH2CH[CH3]2)；1.77-1.82(2H，m，OCH2CH2CH2CH3)；1.47-1.55(2H，m，OCH2CH2CH2CH3)；0.96-0.99(3H，m，OCH2CH2CH2CH3)；0.83-0.84(6H，d，NCH2CH[CH3]2)。
example 207-n-decaalkoxy-2-benzyl-9-isobutyl-1-methyl- β -carboline bromide (20)
The procedure is as in example 14, but 7-n-decaalkoxy-9-isobutyl-1-methyl- β -carboline is used as starting material for the reaction. Obtaining light yellow crystal 0.46g with yield of 78 percent and mp 202-;
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-d6)δ 8.82-8.84(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，CH2Ph)：4.53-4.55(2H，d，NCH2CH[CH3]2)；4.20-4.22(2H，m，OCH2[CH2]8CH3)；3.07(3H，s，CH3)；2.04-2.10(1H，m，NCH2CH[CH3]2)；1.77-1.83(2H，m，OCH2CH2[CH2]7CH3)；1.44-1.50(2H，m，OCH2CH2CH2[CH2]6CH3)；1.26-1.36(12H，m，OCH2CH2CH2[CH2]6CH3)；0.83-0.86(9H，m，O[CH2]9CH3，NCH2CH[CH3]2).
example 217-Phenylpropoxy-2-benzyl-9-isobutyl-1-methyl- β -carboline bromide (21)
The procedure is as in example 14, but 7-phenylpropyloxy-9-isobutyl-1-methyl- β -carboline is used as the starting material for the reaction. Obtaining light yellow crystal 0.39g with yield of 72 percent and 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-d6)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，CH2Ph)；4.52-4.54(2H，d，NCH2CH[CH3]2)；4.21-4.24(2H，m，OCH2CH2CH2Ph)；3.06(3H，s，CH3)；2.80-2.83(2H，m，OCH2CH2CH2Ph)；2.03-2.14(3H，m，NCH2CH[CH3]2，OCH2CH2CH2Ph)；0.82-0.83(6H，m，NCH2CH[CH3]2).
synthesis scheme 2
Figure A200710180027D00351
The following compounds of examples 22-27 can be accomplished by synthetic scheme 2:
example 221- (3 ', 4 ', 5 ' -trimethoxy) phenyl-beta-carboline-3-carboxylic acid ethyl ester (22)
Step A: 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-1, 2, 3, 4-tetrahydro-beta-carboline-3-carboxylic acid
L-tryptophan (40.8g, 200mol), 3, 4, 5-trimethoxybenzaldehyde (40g, 200mol) and glacial acetic acid 250ml are mixed and heated under reflux for 3 hours; pouring the reaction mixed solution into ice water, adjusting the pH value to 5-6 by sodium hydroxide to precipitate a light yellow solid, filtering, washing with water, and drying to obtain 76.0g of the light yellow solid, wherein the light yellow solid can be directly used for the next reaction without purification.
And B: 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-1, 2, 3, 4-tetrahydro-beta-carboline-3-carboxylic acid ethyl ester
Mixing 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-1, 2, 3, 4-tetrahydro-beta-carboline-3-carboxylic acid (76.0g), 1000ml of absolute ethyl alcohol and thionyl chloride (30ml), heating and refluxing for 6 hours, evaporating the ethyl alcohol under reduced pressure, dissolving the residue in cold water, alkalifying sodium bicarbonate, extracting ethyl acetate, combining organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a yellow oily substance, recrystallizing the ethyl acetate to separate out white crystals, filtering, washing with diethyl ether, and drying to obtain 53.0g of a white solid. Further purification is not required and the product can be used directly in the next reaction.
And C: 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-beta-carboline-3-carboxylic acid ethyl ester
Mixing ethyl 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-1, 2, 3, 4-tetrahydro-beta-carboline-3-carboxylate (53.0g, 130mmol), sulfur (16g, 500mmol) and xylene (250ml), heating and refluxing for 10 hours, cooling, precipitating yellow crystals, filtering, washing with cold xylene, then fully washing with petroleum ether, and drying to obtain yellow solid. Recrystallizing the solid with ethyl acetate to obtain 46.3g of white crystals, wherein the yield is 87%, and the temperature is mp 229-;
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，CDCl3)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，OCH2CH3)；3.87-3.89(9H，m，OCH3)；1.47-1.50(3H，m，OCH2CH3).
example 23 Ethyl 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl-beta-carboline-3-carboxylate (23)
Mixing ethyl 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-beta-carboline-3-carboxylate (4.1g, 10mmol) and DMF (200ml), stirring at room temperature until the mixture is clear, adding 60% NaH (1.2g, 30mmol), stirring until no bubbles are generated, dropwise adding n-butyl iodide (30mmol), stirring at room temperature for reaction, and tracking by TLC. And after the reaction is finished, pouring the reaction mixture into ice water, extracting with ethyl acetate, combining organic phases, washing with water, washing with saturated saline, adding 100ml of ethanol, adjusting the pH value to 2-3 with concentrated hydrochloric acid, concentrating under reduced pressure until the mixture is dry, adding absolute ethanol with water for several times to obtain yellow oily matter, and recrystallizing with acetone to obtain a yellow solid. Dissolving the solid in water, alkalifying with sodium bicarbonate, extracting with ethyl acetate, combining organic phases, washing with water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, recrystallizing the residue with diethyl ether to obtain white crystals 3.2g, with a yield of 69%, and mp 138-;
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，CDCl3)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，OCH2CH3)；3.95-3.98(2H，m，NCH2CH2CH2CH3)；3.89-3.91(9H，m，OCH3)；1.46-1.49(5H，m，OCH2CH3，NCH2CH2CH2CH3)；0.95-0.99(2H，m，NCH2CH2CH2CH3)；0.70-0.73(3H，m，NCH2CH2CH2CH3).
example 241- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl-beta-carboline-3-carboxylic acid (24)
Mixing ethyl 9-n-butyl-1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-beta-carboline-3-carboxylate (5mmol), ethanol (100ml), sodium hydroxide (2.0g, 50mmol) and water (200ml), stirring at room temperature for 24 hours, cooling with ice water, adjusting the pH value to 5-6 with concentrated hydrochloric acid, evaporating the ethanol under reduced pressure, separating out a yellow solid, filtering, washing with water, drying to obtain 2.0g of the yellow solid, the yield is 97%, and the mp 215-;
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，CDCl3)δ 8.93(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，NCH2CH2CH2CH3)；3.78-3.82(9H，m，OCH3)；1.39-1.45(2H，m，NCH2CH2CH2CH3)；0.91-0.95(2H，m，NCH2CH2CH2CH3)；0.65-0.68(3H，m，NCH2CH2CH2CH3)。
example 25N-hydroxyethyl-1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-N-butyl-. beta. -carboline-3-carboxamide (25)
Ethyl 9-n-butyl-1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-beta-carboline-3-carboxylate (10mmol), absolute ethyl alcohol (150ml), 60% sodium hydride (15mmol) and hydroxyethylamine (10ml) are heated, refluxed and detected by TLC tracking, after the reaction is finished, the reaction mixed solution is poured into the mixed solution of ice water and ethyl acetate, an ethyl acetate layer is separated, a water layer is extracted by ethyl acetate, organic phases are combined, washed by water, washed by saturated salt water, dried by anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized by ethyl acetate/petroleum ether to obtain 3.6g of white crystals, the yield is 74%, and 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，CDCl3)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，OCH3，NCH2CH2CH2CH3)；3.85-3.87(2H，m，NHCH2CH2OH)；3.66-3.69(2H，m，NHCH2CH2OH)；1.44-1.51(2H，m，NCH2CH2CH2CH3)；0.94-1.02(2H，m，NCH2CH2CH2CH3)；0.71-0.74(3H，s，NCH2CH2CH2CH3)。
example 261- (3 ', 4 ', 5 ' -trimethoxy) phenyl-beta-carboline (26)
Step A was the same as in example 22.
And B: mixing a compound 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-1, 2, 3, 4-tetrahydro-beta-carboline-3-carboxylic acid (38.2g) and water (1000ml), heating to boiling, adding potassium dichromate (180g) and glacial acetic acid (240ml) under stirring, preserving heat for reacting for 10 minutes, cooling the reaction mixed solution to room temperature by using ice water, adding sodium bisulfite (90g), stirring for reacting for 5 minutes, neutralizing the reaction mixed solution to pH8 by using sodium hydroxide, extracting by using ethyl acetate, and concentrating to dryness to obtain a tan oily substance; recrystallizing with anhydrous ethanol to obtain 20g of white crystals with the yield of 60 percent and the temperature of mp 167-;
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，CDCl3)δ 8.79(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，OCH3).
example 271- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl-beta-carboline (27)
Mixing 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-beta-carboline (1.67g, 5mmol) and DMF (100ml), stirring at room temperature until the mixture is clear, adding 60% NaH (0.6g, 15mmol), stirring until no bubbles are generated, dropwise adding n-butyl iodide (15mmol), stirring at room temperature for reaction, tracking and detecting by TLC (thin layer chromatography), pouring the reaction mixture into ice water after the reaction is finished, extracting with ethyl acetate, combining extract liquor, washing with water, washing with saturated saline, adding 100ml of ethanol, adjusting the pH to 2-3 with concentrated hydrochloric acid, concentrating under reduced pressure until the reaction is dry, adding water in absolute ethanol for several times to obtain yellow oily matter, recrystallizing with acetone, and separating out yellow crystals. Filtering, washing with acetone and washing with diethyl ether. Dissolving the solid in water, alkalifying with sodium bicarbonate, extracting with ethyl acetate, washing with water, drying with anhydrous sodium sulfate, decolorizing with activated carbon, filtering, concentrating under reduced pressure, recrystallizing the residue with diethyl ether or diethyl ether/petroleum ether to obtain white crystal 1.4g, yield 83%, mp 118-;
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，CDCl3)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，NCH2(CH2)2CH3)；3.89-3.92(9H，m，OCH3)；1.44-1.47(2H，m，NCH2CH2CH2CH3)；0.94-1.01(2H，m，NCH2CH2CH2CH3)；0.70-0.73(3H，m，2H，m，NCH2CH2CH2CH3).
synthesis scheme 3
Figure A200710180027D00391
The following compounds of examples 28-30 can be prepared by synthetic scheme 3:
example 28 Ethyl β -carboline-1-carboxylate (28)
Step A: ethyl 1, 2, 3, 4-tetrahydro-beta-carboline-1-carboxylate
Mixing tryptamine hydrochloride (19.61g, 100mmol), ethyl glyoxylate (30.6g, 250mmol) and absolute ethyl alcohol (400ml), stirring at room temperature for reaction for 3 hours, heating and refluxing for 5 hours, distilling under reduced pressure to remove ethanol to obtain light yellow oily matter, and recrystallizing acetone to obtain light yellow solid, namely the hydrochloride of the product. Dissolving hydrochloride in water, alkalifying with sodium bicarbonate, extracting with ethyl acetate, combining organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, decoloring with activated carbon, filtering, concentrating under reduced pressure to obtain yellow oily matter, and recrystallizing with diethyl ether/petroleum ether to obtain 21.3g of yellow needle-like crystal which can be directly used for the next reaction without purification.
And B: ethyl beta-carboline-1-carboxylic acid ester
Mixing ethyl 1, 2, 3, 4-tetrahydro-beta-carboline-1-carboxylate (12.2g, 50mmol), xylene (200ml) and sulfur (4.8g, 150mmol), heating and refluxing for 6 hours, and cooling in a refrigerator to separate out yellow solid; filtering, washing with a small amount of dimethylbenzene, washing with a large amount of petroleum ether, and recrystallizing with ethanol to obtain white crystals 8.4g with a yield of 70%, wherein mp 124-;
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，CDCl3)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，OCH2CH3)；1.53-1.56(3H，m，OCH2CH3).
example 29 Ethyl 9-n-butyl-. beta. -carboline-1-carboxylate (29)
Mixing ethyl beta-carboline-1-carboxylate (2.4g, 10mmol), DMF (50ml) and 60% sodium hydride (0.6g, 20mmol), stirring at room temperature for reaction for 5 minutes, adding n-butyl iodide (5ml), stirring at room temperature, tracking and detecting by TLC, pouring the reaction liquid into cold water after the reaction is finished, extracting by ethyl acetate, combining organic phases, washing by water, adding 50ml of ethanol, acidifying by concentrated hydrochloric acid, concentrating under reduced pressure to dryness, adding anhydrous ethanol with water, recrystallizing by acetone, separating out yellow solid, filtering, and washing by diethyl ether. Dissolving the solid in water, alkalifying with sodium bicarbonate, extracting with ethyl acetate, mixing organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, decolorizing with activated carbon, concentrating under reduced pressure to dryness, and recrystallizing with diethyl ether to obtain light yellow oily substance 2.2g with yield of 74%;
FAB-MS m/e(M+1)297.
example 309-n-butyl-. beta. -carboline-1-carboxylic acid (30)
Mixing ethyl 9-n-butyl-beta-carboline-1-carboxylate (1.48g, 5mmol), water (50ml), ethanol (30ml) and sodium hydroxide (1.2g, 30mmol), stirring at room temperature for 12 hours, cooling the reaction solution by using ice water, adjusting the pH value to about 6.0 by using concentrated hydrochloric acid, evaporating under reduced pressure to remove ethanol to obtain yellow solid, filtering, washing with water, drying, recrystallizing by using absolute ethanol to obtain light yellow solid 1.3g, wherein the yield is 97%, and the mp 133-;
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，CDCl3)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，NCH2CH2CH2CH3)；1.64-1.67(2H，m，NCH2CH2CH2CH3)；1.20-1.25(2H，m，NCH2CH2CH2CH3)；0.83-0.86(3H，t，NCH2CH2CH2CH3)
synthesis scheme 4
Figure A200710180027D00411
The following compounds of examples 31-45 can be prepared by synthetic scheme 4:
example 313-hydroxymethyl-9-benzyl-beta-carboline (31)
Ethyl 9-benzyl-beta-carboline-3-carboxylate (10mmol), THF (200ml), LiBH4(30mmol) were mixed, and the reaction was stirred at room temperature, followed by TLC (petroleum ether/acetone: 1/1), after completion of the reaction, the reaction mixture was slowly poured into 200ml of ice water, stirred for 10 minutes, concentrated hydrochloric acid was added dropwise to pH2, and stirred at room temperature for 4 hours. Cooling the mixture by using ice water, adjusting the pH value to 9 by using a sodium hydroxide solution, extracting by using ethyl acetate, washing by using water, washing by using saturated salt water, drying by using anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and recrystallizing by using acetone to obtain 1.5g of white crystals, wherein the yield is 52 percent, and the temperature is 121 ℃ under mp 120;
FAB-MS m/e(M+1)289；
IR(KBr)3170，2938，1627，1559，1495，1467，1363，1264，1205，1048；
1H-NMR(500MHz，CDCl3)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，CH2PhH)；4.94(2H，m，CH2OH)；4.01(1H，s，CH2OH)。
example 323-hydroxymethyl-9-phenylpropyl-beta-carboline (32)
The procedure is as in example 31, but using ethyl 9-phenylpropyl- β -carboline-3-carboxylate as starting material. Obtaining white crystals 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，CDCl3)δ 8.73(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，CH2OH)；4.36-4.40(2H，m，NCH2CH2CH2Ph)；2.70-2.73(2H，m，NCH2CH2CH2Ph)；2.22-2.29(2H，m，NCH2CH2CH2Ph)。
example 333-hydroxymethyl-9-n-butyl-1-methyl-. beta. -carboline (33)
The procedure is as in example 31, but using ethyl 9-n-butyl-1-methyl- β -carboline-3-carboxylate as starting material. Obtaining white crystals 2.1g, the yield is 78 percent, mp 115-116 ℃;
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，CDCl3)δ 8.79-8.81(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，CH2OH)；5.15-5.19(2H，m，NCH2CH2CH2CH3)；3.77(3H，s，CH3)；2.46-2.54(2H，m，NCH2CH2CH2CH3)；2.08-2.18(2H，m，NCH2CH2CH2CH3)；1.66-1.69(3H，m，NCH2CH2CH2CH3)。
example 343-hydroxymethyl-9- (4' -fluoro) benzyl-1-methyl-beta-carboline (34)
The procedure is as in example 31, but using ethyl 9- (4' -fluoro) benzyl-1-methyl- β -carboline-3-carboxylate as starting material. Obtaining 2.3g of white crystals with the yield of 72 percent and mp 114-;
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，CDCl3)δ 8.13-8.16(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，CH2Ph)；4.91(2H，s，CH2OH)；2.91(3H，s，CH3)
example 351- (3 ', 4 ', 5 ' -trimethoxy) phenyl-3-hydroxymethyl-9-n-butyl-. beta. -carboline (35)
The operation is as in example 31, but using ethyl 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl- β -carboline-3-carboxylate as starting material. Obtaining 3.2g of white crystals with the yield of 76 percent and 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，CDCl3)δ 8.30-8.31(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，CH2OH)；3.93-3.97(2H，m，NCH2CH2CH2CH3)；3.80(6H，s，OCH3)；3.75(3H，s，OCH3)；1.31-1.39(2H，m，NCH2CH2CH2CH3)；0.86-0.92(2H，m，NCH2CH2CH2CH3)；0.62-0.66(3H，m，NCH2CH2CH2CH3)。
example 363-formyl-9-benzyl- β -carboline (36)
3-hydroxy-9-benzyl-beta-carboline (10mmol), acetonitrile (250ml), active MnO2(100mmol) were mixed, heated to reflux and checked by TLC. After the reaction, MnO was removed by filtration2And concentrating under reduced pressure to dryness to obtain a yellow solid. Dissolving the solid in ethyl acetate, decolorizing with activated carbon, concentrating under reduced pressure, and recrystallizing with acetone to obtain white crystal 2.1g with yield of 73%, and mp 139-;
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，CDCl3)δ 10.31(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，CH2Ph)。
example 373-formyl-9-phenylpropyl-beta-carboline (37)
The procedure is as in example 36, but 3-hydroxymethyl-9-phenylpropyl- β -carboline is used as the starting material. Obtaining white crystals 2.2g, the yield is 70 percent, 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，CDCl3)δ 10.83(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，NCH2CH2CH2Ph)；2.79-2.82(2H，m，NCH2CH2CH2Ph)；2.34-2.38(2H，m，NCH2CH2CH2Ph)。
example 383-aldehyde-9-n-butyl-1-methyl-beta-carboline (38)
The procedure is as in example 36, but 3-hydroxymethyl-9-n-butyl-1-methyl- β -carboline is used as the starting material. Obtaining white crystals 1.9g with the yield of 71 percent and 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，CDCl3)δ 10.45(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，NCH2CH2CH2CH3)；3.27(3H，s，CH3)；1.87-1.93(2H，m，NCH2CH2CH2CH3)；1.46-1.52(2H，m，NCH2CH2CH2CH3)；0.99-1.03(3H，m，NCH2CH2CH2CH3)。
example 393-formyl-9- (4' -fluoro) benzyl-1-methyl- β -carboline (39)
The procedure is as in example 36, but using 3-hydroxymethyl-9- (4' -fluoro) benzyl-1-methyl- β -carboline as the starting material. Obtaining 2.1g of white crystals with the yield of 66 percent and the temperature of mp 137-139 ℃;
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，CDCl3)δ 10.32(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，NCH2Ph)；3.04(3H，s，CH3)。
example 401- (3 ', 4 ', 5 ' -trimethoxy) phenyl-3-carboxaldehyde-9-n-butyl-. beta. -carboline (40)
The operation is as in example 36, but 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-3-hydroxymethyl-9-n-butyl-beta-carboline is used as the starting material for the reaction. Obtaining 3.0g of white crystals with the yield of 72 percent and mp 150-;
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，CDCl3)δ 10.26(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，NCH2CH2CH2CH3)；3.93(3H，s，OCH3)；3.91(6H，s，OCH3)；1.48-1.56(2H，m，NCH2CH2CH2CH3)；0.96-1.06(2H，m，NCH2CH2CH2CH3)；0.73-0.76(3H，m，NCH2CH2CH2CH3).
example 419-benzyl- β -carboline-3-carboxaldehyde thiosemicarbazone (41)
3-aldehyde-9-benzyl-beta-carboline (2mmol), thiosemicarbazide (2mmol) and absolute ethyl alcohol (100ml) are mixed, heated and refluxed for 12 hours, and light yellow solid is precipitated in the reaction process. Cooled to room temperature and filtered to obtain a yellow solid. Recrystallizing with anhydrous ethanol for three times to obtain yellow solid 0.48g, with yield of 67%, mp244-246 deg.C;
FAB-MS m/e(M+1)360；
IR(KBr)3393，3279，3175，3025，2924，2748，1626，1596，1538，1497，1465，1360，1332，1296，1214，1097，1003，734；
1H-NMR(500MHz，DMSO-d6)δ 11.53(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，NCH2Ph)。
example 429-Phenylpropyl-beta-carboline-3-carboxaldehyde thiosemicarbazone (42)
The procedure is as in example 41, but 3-formyl-9-phenylpropyl- β -carboline is used as the starting material. Obtaining yellow solid 0.51g, yield 68%, mp 225-;
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-d6)δ 11.53(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，NCH2CH2CH2Ph)；2.65-2.69(2H，m，NCH2CH2CH2Ph)；2.10-2.18(2H，m，NCH2CH2CH2Ph)。
example 439-n-butyl-1-methyl-. beta. -carboline-3-carboxaldehyde thiosemicarbazone (43)
The procedure is as in example 41, but 3-formyl-9-n-butyl-1-methyl- β -carboline is used as the starting material. Obtaining yellow solid 0.4g with 59 percent of yield and 216 ℃ of mp 214-;
FAB-MS m/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-d6)δ 11.52(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，NCH2CH2CH2CH3)；2.98(3H，s，CH3)；1.71-1.80(2H，m，NCH2CH2CH2CH3)；1.34-1.43(2H，m，NCH2CH2CH2CH3)；0.90-0.94(3H，m，NCH2CH2CH2CH3).
example 449- (4' -fluoro) benzyl-1-methyl-beta-carboline-3-carboxaldehyde thiosemicarbazone (44)
The procedure is as in example 41, but using 3-formyl-9- (4' -fluoro) benzyl-1-methyl- β -carboline as the starting material. Obtaining yellow solid 0.52g with yield of 66 percent and 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-d6)δ 11.54(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，NCH2Ph)；2.90(3H，s，CH3).。
example 451- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl-. beta. -carboline-3-carboxaldehyde thiosemicarbazone (45)
The procedure is as in example 41, but using 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-3-formyl-9-n-butyl- β -carboline as the starting material. Obtaining 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-d6)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，NCH2CH2CH2CH3)；3.81(6H，s，OCH3)；3.77(3H，s，OCH3)；1.36-1.42(2H，m，NCH2CH2CH2CH3)；0.89-0.95(2H，m，NCH2CH2CH2CH3)；0.64-0.68(2H，m，NCH2CH2CH2CH3)。
synthesis scheme 5
The following compounds of examples 46-47 can be prepared by synthetic scheme 5:
example 463-hydroxymethyl-9-phenylpropyl-2-benzyl-beta-carboline bromide (46)
Mixing 3-hydroxymethyl-9-phenylpropyl-beta-carboline (0.25g, 1mmol), ethyl acetate (50ml) and benzyl bromide (10ml), heating and refluxing for 12 hours, cooling the reaction liquid, filtering, washing with diethyl ether to obtain yellow solid. Adding the yellow solid into 100ml of absolute ethyl alcohol, heating for dissolving, filtering while the solution is hot, concentrating the filtrate under reduced pressure to 40ml, and recrystallizing in a refrigerator to obtain 0.40g of yellow crystals, wherein the yield is 80%, and the temperature is mp 241-;
FAB-MS m/e 407；
IR(KBr)3228，3026，3004，2942，1641，1606，1513，1458，1338，1205，1132，1089，740；
1H-NMR(500MHz，DMSO-d6)δ 9.97(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，CH2Ph)；4.87(2H，s，CH2OH)；4.70-4.74(2H，m，NCH2CH2CH2Ph)；2.67-2.71(2H，m，NCH2CH2CH2Ph)；2.19-2.23(2H，m，NCH2CH2CH2Ph).
example 473-formyl-9-phenylpropyl-2-benzyl- β -carboline bromide (47)
The procedure is as in example 46, but 3-formyl-9-phenylpropyl- β -carboline is used as the starting material. Obtaining yellow crystals 0.16g with the yield of 32 percent and 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-d6)δ 10.31(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，CH2Ph)；4.87(2H，s，CH2OH)；4.83-4.87(2H，m，NCH2CH2CH2Ph)；2.70-2.74(2H，m，NCH2CH2CH2Ph)；2.26-2.29(2H，m，NCH2CH2CH2Ph).
synthesis scheme 6
Figure A200710180027D00491
The following compound of example 48 can be accomplished by synthetic scheme 6:
example 483-formyl-9-phenylpropyl-beta-carboline sodium bisulfite addition salt (48)
Adding 3-aldehyde-9-phenylpropyl-beta-carboline (2mmol) into 25ml of sodium bisulfite saturated solution, stirring at room temperature for reaction for 12 hours, filtering, and washing with 50% ethanol solution to obtain light yellow solid. Dissolving the light yellow solid in 100ml of 50% ethanol solution, heating and refluxing until the solution is clear, filtering while the solution is hot, cooling the filtrate to room temperature to precipitate white solid, filtering, washing with 50% ethanol solution, and drying to obtain 0.14g of white solid, wherein the yield is 32.3%, and the mp 132-; FAB-MS m/e 418.
Synthesis scheme 7
Figure A200710180027D00492
The following compounds of examples 49-51 can be prepared by synthetic scheme 7:
example 491-formyl-9-phenylpropyl-beta-carboline (49)
Placing 9-phenylpropyl-1-methyl-beta-carboline (10mmol) and selenium dioxide (20mmol) in a 100ml round bottom flask, adding 50ml of freshly steamed 1, 4-dioxane, heating and refluxing for 4 hours, filtering while hot, washing with a small amount of ethyl acetate, concentrating the filtrate under reduced pressure, adding a small amount of silica gel, spin-drying, performing silica gel column chromatography, and performing V (petroleum ether): v (ethyl acetate) ═ 10: 1-4: 1, eluting, collecting product spots, and concentrating under reduced pressure to obtain yellow solid with the yield of 70 percent and mp 69-70 ℃;
ESI-MS for C21H18N2O[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(CDCl3，300MHz)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，NCH2)，2.72(2H，m，NCH2CH2CH2)，2.14(2H，t，NCH2CH2)；
example 509-Phenylphenyl-beta-carboline-1-carboxaldehyde thiosemicarbazone (50)
Adding 1-aldehyde-9-phenylpropyl-beta-carboline (1mmol), thiosemicarbazide (1mmol) and ethanol (30ml) into a50 ml round-bottom flask, stirring and refluxing the mixture in oil bath at 85 ℃ for overnight to separate out yellow crystals, concentrating the mixture under reduced pressure to about 10ml, recrystallizing the mixture in a refrigerator, performing suction filtration, and drying the mixture to obtain yellow crystals, wherein the yield is 77%, and mp 187-188 ℃;
ESI-MS for C22H21N5S[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，NCH2)，2.66(2H，m，NCH2CH2)，2.03(2H，m，NCH2CH2CH2).
example 519-phenylpropyl-beta-carboline-1-aldehyde methoxamine (51)
Weighing sodium hydroxide (1mmol) in a small beaker, adding about 1ml of water for dissolving, then adding methoxyamine (1mmol), adding the mixture into a50 ml round-bottom flask containing ethanol solution (30ml) of 1-aldehyde-9-phenylpropyl-beta-carboline (1mmol) after the mixture is completely dissolved, stirring for 2 hours at room temperature, tracking and detecting by TLC, stopping reaction after the reaction is completed, concentrating under reduced pressure, standing in a refrigerator, and performing suction filtration to obtain yellow crystals, wherein the yield is 82%, and the mp 123-phase is 124 ℃;
ESI-MS for C22H21N3O，[M+H]+ Calcd：343，Found：344；
1H-NMR(CDCl3，300MHz)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，NCH2)，2.85(2H，t，NCH2CH2CH2)，2.31(2H，m，NCH2CH2)，1.66(3H，S，OCH3)；
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。
scheme 8
Figure A200710180027D00511
The following compounds of examples 52-53 can be prepared by synthetic scheme 8:
example 52N- (4-. beta. -carboline-phenoxyacetyl) phenylalanine ethyl ester (52)
Step A: 1- (4' -hydroxy) phenyl-1, 2, 3, 4-tetrahydro-beta-carboline-3-carboxylic acid
Adding L-tryptophan (12.24g, 60mmol), p-hydroxybenzaldehyde (7.38g, 60mmol) and glacial acetic acid (150ml) into a 250ml round bottom flask, stirring the mixture in oil bath at 85 ℃ for 10h to precipitate white solid, stopping the reaction, cooling to room temperature, pouring the mixture into ice water, adjusting the pH to 5-6 with sodium hydroxide solution, standing in a refrigerator for 2-3h, filtering, washing with water, and drying to obtain light yellow solid with the yield of 96 percent and the temperature of mp 233-.
And B: 1- (4' -hydroxy) phenyl-beta-carbolines
Adding 1- (4' -hydroxy) phenyl-1, 2, 3, 4-tetrahydro-beta-carboline-3-carboxylic acid (50mmol) into 500ml of water, heating to boil, then adding 350ml of 10% potassium dichromate solution and 100ml of glacial acetic acid under stirring, continuing heating and stirring for reaction for 5 minutes, cooling the reaction liquid to room temperature, performing suction filtration, dissolving the obtained solid with sodium hydroxide solution, filtering out insoluble impurities, adjusting the pH of the filtrate with HCl to 6-7, separating out a large amount of yellow precipitates, performing suction filtration, and drying to obtain a yellow solid with the yield of 60%. Can be directly used for the next reaction without purification.
And C: 1- (4' -ethoxycarbonylmethyleneoxy) phenyl-beta-carbolines
1- (4' -hydroxy) phenyl-beta-carboline (5.2g, 20mmol), anhydrous potassium carbonate (40mmol) ground into powder and 100ml of dried acetone are added into a 250ml round bottom flask, heated and stirred in an oil bath at 70 ℃, ethyl chloroacetate (40mmol) is added dropwise after refluxing for 1h, and the reflux is continued overnight. TLC tracking detection, after the reaction is finished, suction filtration is carried out, the filtrate is decompressed and spin-dried, silica gel column chromatography is carried out (V (petroleum ether): V (ethyl acetate): 3:1 elution) to obtain yellow solid, the yield is 90 percent, and mp 175-;
ESI-MS for C21H18N2O3[M+H]+，Calcd：346.38 Found：347.40；
IR(KBr，cm-1)ν：3362，3056，2975，2877，1751，1606，1506，1462，1278，1232，1070，832，746，604；
1H-NMR(CDCl3，300MHz)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，CH2)，4.04(2H，s，OCH2CO2)，1.27(3H，t，CH3)；
13C-NMR(CDCl3，300MHz)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: stirring and refluxing 80ml of 1- (4' -ethoxycarbonylmethyleneoxy) phenyl-beta-carboline (30mmol), 80ml of sodium hydroxide (150mmol) aqueous solution and 80ml of ethanol in an oil bath for 1.5 hours, adjusting the pH to 5-6 by using 10% HCl solution after the reaction is finished, separating out yellow flocculent precipitate, standing and cooling in a refrigerator, filtering yellow solid by suction, drying, obtaining the yield of 95%, and keeping the temperature at 194 ℃ under mp 192-;
ESI-MS for C19H14N2O3[M-H]-，Calcd：318.33 Found：317.35；
IR(KBr，cm-1)ν：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(1H，m，H-7)，7.10(2H，m，ArH)，4.71(2H，s，CH2).
step E: n- (4-beta-carboline-phenoxyacetyl) phenylalanine ethyl ester
Adding the solid obtained in the step D (5mmol), a condensing agent N, N' -carbonyldiimidazole (10mmol) and 30ml of dry DMF into a50 ml round bottom flask, stirring in a water bath at 50 ℃ for 1h, adding L-phenylalanine ethyl ester (5mmol), stirring in a water bath at 50 ℃ for further reaction for 24h, detecting by TLC tracking, stopping the reaction after the reaction is finished, concentrating under reduced pressure to obtain an oily substance, separating by a silica gel column, and adding V (petroleum ether): eluting with V (ethyl acetate) ═ 4:1, collecting product points, and concentrating under reduced pressure to obtain white needle crystals with a yield of 81%, mp 102-;
ESI-MS for C30H27N3O4[M+H]+，Calcd：493.55，Found：494.65；
IR(KBr，cm-1)ν：3413，3060，2977，1625，1565，1533，1437，749；
1H-NMR(CDCl3，300MHz)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，OCH2CO)，4.21(2H，q，CO2CH2)，3.18(2H，d，ArCH2)，1.26(3H，t，CH3)；
13C-NMR(CDCl3，300MHz)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.
example 53N- (4-. beta. -carboline-phenoxyacetyl) phenylalanine (53)
Dissolving a compound N- (4-beta-carboline-phenoxyacetyl) phenylalanine ethyl ester (1mmol) in 10ml of absolute ethyl alcohol, adding 10ml of aqueous solution of NaOH (5mmol), and heating and refluxing for reaction for 1.5 hours. After the reaction is completed, evaporating partial ethanol, neutralizing with 2M hydrochloric acid to reach the pH value of 5, freezing, standing for precipitation, and performing suction filtration to obtain a yellow solid with the yield of 94 percent and the yield of mp 151-152 ℃;
ESI-MS for C28H23N3O4[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，OCH2CO)，4.56-4.51(1H，m，CH)，3.12-3.02(2H，d，ArCH2)；
13C-NMR(DMSO，300MHz)δ：173.28，168.12，158.64，142.54，141.73，138.86，138.14，133.42，132.13130.28，129.82，128.87，127.11，122.18，121.54，120.13，115.58，114.07，113.11，67.52，54.01，37.40。
synthesis scheme 9
Figure A200710180027D00541
The following compounds of examples 54-61 can be prepared by synthetic scheme 9:
example 54 ethyl N- (9-N-butyl-. beta. -carboline-3-formyl) phenylalanine (54)
Step A: synthesis of L-phenylalanine ethyl ester
Dispersing 10mmol L-phenylalanine in 100ml absolute ethyl alcohol, placing in a low temperature reactor, cooling to-5 deg.C, stirring, slowly adding 0.8ml (10mmol) thionyl chloride dropwise at low temperature, clarifying the solution after dropwise addition, heating to room temperature, and continuing stirring for 10 hours. After the reaction is finished, removing excessive methanol and thionyl chloride under reduced pressure to obtain hydrochloride of the L-phenylalanine ethyl ester.
Dissolving L-phenylalanine ethyl ester hydrochloride in absolute ethyl alcohol, adding 2 times of absolute BaO, stirring at room temperature overnight, standing, performing suction filtration, and performing reduced pressure rotary evaporation to recover ethanol to obtain amino acid ester; or adding saturated NaHCO into the aqueous solution of the amino acid ester hydrochloride3Or Na2CO3The solution is brought to pH8, extracted with ethyl acetate or diethyl ether and anhydrous MgSO4Drying and recovering ethyl acetate to obtain the L-phenylalanine ethyl ester.
And B: n- (9-N-butyl-beta-carboline-3-formyl) phenylalanine ethyl ester
9-n-butyl-beta-carboline-3-carboxylic acid (5mmol), CDI (5.5mmol) and 20mL dry DMF were placed in a50 mL round bottom flask and stirred at room temperature for 0.5 h, then the compound L-phenylalanine methyl ester (5mmol) was added and stirred at room temperature or up to 40 ℃ for 8 h and the reaction was followed by TLC. After the reaction is finished, performing reduced pressure rotary evaporation to recover DMF, separating the product by column chromatography (petroleum ether/ethyl acetate), and recrystallizing the product by ethanol to obtain white crystals with the yield of 92 percent and mp 107-;
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，CDCl3)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，NCH2)；4.19(2H，q，OCH2)；3.29(2H，d，CHCH2Ph)；1.92(2H，m，CH2)；1.42(2H，m，CH2)；1.25(3H，t，CH3)；0.98(3H，t，CH3).
example 55N- (9-N-butyl-. beta. -carboline-3-formyl) methionine ethyl ester (55)
The procedure is as in example 54, but using L-methionine ethyl ester as starting material. Obtaining white crystals with the yield of 95 percent and mp 100-;
ESI-MS m/e 428[M+H]+；
IR(KBr)3372，3050，2956，2927，2858，1730，1674，1625，1518，1495，1211，745cm-1；
1H-NMR(300MHz，CDCl3)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)；7.51(1H，d，ArH)；7.35(1H，t，ArH)；5.00(1H，m，CH)；4.43(2H，t，NCH2)；4.27(2H，q，OCH2)；2.67(2H，m，SCH2)；2.41-2.17(2H，m，CHCH2)；2.14(3H，s，SCH3)；1.92(2H，m，CH2)；1.42(2H，m，CH2)；1.33(3H，t，CH3)；0.97(3H，t，CH3).
example 56N- (9-benzyl-beta-carboline-3-formyl) phenylalanine ethyl ester (56)
The procedure is as in example 54, but 9-benzyl- β -carboline-3-carboxylic acid and ethyl-L-phenylalanine are used as starting materials. Obtaining white crystals with the yield of 96 percent and the temperature of mp 147-;
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，CDCl3)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，NCH2Ph)；5.12(1H，m，CH)；4.19(2H，q，OCH2)；3.28(2H，d，CHCH2)；1.24(3H，t，CH3).
example 57 Ethyl N- (9-phenylpropyl-. beta. -carboline-3-carbonyl) valine (57)
The operation is as in example 54, but 9-phenylpropyl-beta-carboline-3-carboxylic acid and L-valine ethyl ester are used as reaction starting materials. Obtaining white crystals with the yield of 82 percent and the temperature of mp 123-;
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，CDCl3)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，NCH2)；4.26(2H，q，OCH2)；2.74(2H，t，CH2Ph)；2.40-2.26(3H，m，CH2，CH(CH3)2)；1.33(3H，t，CH3)；1.07(6H，t，2CH3).
example 58N- (9-phenylpropyl-. beta. -carboline-3-formyl) phenylalanine ethyl ester (58)
The procedure is as in example 54, but 9-phenylpropyl-beta-carboline-3-carboxylic acid and ethyl L-phenylalanine are used as starting materials. Obtaining white crystals with the yield of 89 percent and 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，CDCl3)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，NCH2)；4.20(2H，q，OCH2)；3.29(2H，d，CHCH2)；2.73(2H，t，CH2Ph)；2.28(2H，m，CH2)；1.25(3H，t，CH3)；
13C NMR(75MHz，CDCl3)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.
example 59N- (9-N-butyl-. beta. -carboline-3-formyl) phenylalanine (59)
Dissolving N- (9-N-butyl-beta-carboline-3-formyl) phenylalanine ethyl ester (1mmol) in 10ml of absolute ethyl alcohol, adding 10ml of aqueous solution of NaOH (5mmol), and heating and refluxing for reaction for 1.5 hours. After the reaction is completed, part of the alcohol solution is evaporated, neutralized to pH5 with 2M hydrochloric acid, and frozen and placed to precipitate. Obtaining yellow solid with the yield of 94 percent and 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-d6)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，NCH2)；3.25(2H，m，CHCH2)；1.80(2H，m，CH2)；1.26(2H，m，CH2)；0.86(3H，t，CH3).
example 60N- (9-phenylpropyl-. beta. -carboline-3-formyl) phenylalanine (60)
The procedure is as in example 59, but using N- (9-N-butyl-. beta. -carboline-3-formyl) phenylalanine ethyl ester as starting material. Obtaining yellow crystals with the yield of 97 percent and mp 179-180 ℃;
ESI-MS m/e 477[M-H]-；
IR(KBr)3376，3027，2929，2860，1735，1626，1591，1526，1500，1210，746，cm-1；
1H-NMR(300MHz，DMSO-d6)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，NCH2)；3.24(2H，m，CHCH2)；2.65(2H，t，CH2Ph)；2.13(2H，m，CH2).
example 61N- (2-benzyl-9-phenylpropyl-beta-carboline-3-formyl) phenylalanine ethyl ester bromide salt (61)
Dissolving N- (9-phenylpropyl-beta-carboline-3-formyl) phenylalanine ethyl ester (10mmol) in ethyl acetate (100ml), adding benzyl bromide (150mmol), heating, stirring, refluxing for 24h, then placing in a refrigerator for crystallization, performing suction filtration, washing with ethyl acetate, and drying to obtain the product. Recrystallizing with anhydrous ethanol to obtain yellow crystals with the yield of 40 percent and the temperature of mp 188-;
ESI-MS m/e 597[M-Br]+；
IR(KBr)3410，3181，3027，2983，2939，2851，1736(C＝O)，1670(C＝O)，1633，1541，1515，1457，1341，1244，748cm-1；
1H-NMR(300MHz，DMSO-d6)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(15H，m，15ArH)；6.00(2H，t，N+CH2Ph)；4.75(3H，CH，NCH2)；4.11(2H，q，OCH2)；3.05(2H，m，CHCH2)；2.63(2H，t，CH2Ph)；2.19(2H，m，CH2)；1.13(3H，t，CH3)；
13C NMR(75MHz，DMSO-d6)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.
synthesis scheme 10
Figure A200710180027D00591
The following compounds of examples 62-67 can be accomplished by synthetic scheme 10:
example 62N- (9-N-butyl-1-methyl-. beta. -carboline-7-oxoacetyl) methionine ethyl ester (62)
Step A: 7- (ethoxycarbonylmethyleneoxy) -9-n-butyl-1-methyl-beta-carboline
Adding 7-hydroxy-9-n-butyl-1-methyl-beta-carboline (10mmol) into a 100mL round-bottom flask, and grinding the mixture into powder2CO3(20mmol) and dry acetone (50ml) were refluxed at 70 ℃ for half an hour, ethyl chloroacetate (20mmol) was slowly added dropwise, followed by TLC. After the reaction is finished, cooling to room temperature, carrying out suction filtration, washing a filter cake for three times by using acetone, evaporating the solvent to obtain a brown yellow liquid, and separating by using column chromatography (petroleum ether/ethyl acetate) to obtain a product.
And B: 7- (oxyacetic acid) -9-n-butyl-1-methyl-beta-carboline
And (3) dissolving the product obtained in the step A in 30ml of absolute ethanol, adding 30ml of 5 times of NaOH aqueous solution, heating and refluxing for 2 hours, cooling the reaction solution, evaporating part of the ethanol solution, neutralizing with 2M hydrochloric acid until the pH value is 5, cooling, separating out solids, carrying out suction filtration, and drying to obtain a grass green solid.
And C: n- (9-N-butyl-1-methyl-beta-carboline-7-oxyacetyl) methionine ethyl ester
7-Oxoacetoxy-9-n-butyl-1-methyl-beta-carboline (5mmol), CDI (5.5mmol) and 20ml dry DMF were placed in a50 ml round bottom flask and stirred at room temperature for 0.5 h, then the compound L-methionine ethyl ester (5mmol) was added and stirred at 40 ℃ for 5 h, followed by TLC. After the reaction is finished, distilling off DMF under reduced pressure, separating the product by column chromatography (petroleum ether/ethyl acetate), and recrystallizing the product by ethanol to obtain white crystals with the yield of 83 percent and the temperature of 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，CDCl3)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，COCH2)；4.47(2H，t，NCH2)；4.24(2H，q，OCH2)；3.03(3H，s，ArCH3)；2.51(2H，t，SCH2)；2.29-2.03(2H，m，CHCH2)；2.05(3H，s，SCH3)；1.81(2H，m，CH2)；1.47(2H，m，CH2)；1.30(3H，t，CH3)；1.00(3H，t，CH3)。
example 63N- (9-N-butyl-1-methyl- β -carboline-7-oxoacetyl) tyrosine ethyl ester (63)
The procedure is as in example 62, but using L-tyrosine ethyl ester as starting material. Obtaining white crystals with the yield of 84 percent and the temperature of mp 183-184 ℃;
ESI-MS m/e 491[M+H]+；
IR(KBr)3410(O-H)，3305，3060，2934，2871，1743，1629，1551，15121452，1237，1193，816cm-1；
1H-NMR(300MHz，CDCl3)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，COCH2)；4.39(2H，t，NCH2)；3.79(3H，s，OCH3)；3.10(1H，d，CHCH2)；2.98(3H，s，ArCH3)；1.75(2H，m，CH2)；1.41(2H，m，CH2)；0.95(3H，t，CH3)。
example 64N- (9-phenylpropyl-1-methyl-beta-carboline-7-oxoacetyl) tyrosine ethyl ester (64)
The procedure is as in example 62, but using 7-hydroxy-9-phenylpropyl-1-methyl- β -carboline and L-methionine ethyl ester as starting materials. Obtaining white crystals with the yield of 86 percent and the temperature of mp 147-;
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，CDCl3)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，COCH2)；4.36(2H，t，NCH2)；3.80(3H，s，OCH3)；3.11(1H，d，CHCH2)；2.82(3H，s，ArCH3)；2.71(2H，t，CH2Ph)；2.07(2H，m，CH2).
example 65N- (9-N-butyl-1-methyl-beta-carboline-7-oxoacetyl) methionine (65)
Dissolving N- (9-N-butyl-1-methyl-beta-carboline-7-oxyacetyl) methionine ethyl ester (1mmol) in 10ml of absolute ethyl alcohol, adding 10ml of aqueous solution of NaOH (5mmol), heating and refluxing for 2 hours, neutralizing with 2M hydrochloric acid until the pH is 5 after the reaction is finished, evaporating under reduced pressure to remove part of ethanol until solid is separated out, freezing and standing, carrying out suction filtration, and carrying out infrared drying to obtain yellow solid, yellow crystals with the yield of 97%, and mp 191-plus 193 ℃;
ESI-MS m/e 443[M-H]-；
IR(KBr)3415，3236，30572923，2866，1722，1625，1600，1540，1463，1191，812cm-1；
1H-NMR(300MHz，DMSO-d6)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，COCH2)；4.60(2H，t，NCH2)；4.40(`H，q，CH)；3.18(3H，s，ArCH3)；2.44(2H，t，SCH2)；1.98(5H，CHCH2，SCH3)；1.75(2H，m，CH2)；1.37(2H，m，CH2)；0.90(3H，t，CH3)。
example 66N- (9-N-butyl-1-methyl-beta-carboline-7-oxoacetyl) tyrosine (66)
The procedure is as in example 65, but using N- (9-N-butyl-1-methyl-. beta. -carboline-7-oxoacetyl) tyrosine ethyl ester as starting material. Obtaining yellow crystals with the yield of 96 percent and 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-d6)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，COCH2)；4.55(2H，t，NCH2)；4.43(1H，m，CH)；3.18(3H，s，ArCH3)；2.95(2H，m，CHCH2)；1.72(2H，m，CH2)；1.33(2H，m，CH2)；0.88(3H，t，CH3).
example 67N- (9-phenylpropyl-1-methyl- β -carboline-7-oxoacetyl) tyrosine (67)
The procedure is as in example 65, but using N- (9-phenylpropyl-1-methyl-. beta. -carboline-7-oxoacetyl) tyrosine ethyl ester as starting material. Obtaining yellow crystals with the yield of 98 percent and 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-d6)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，COCH2)；4.36(2H，t，NCH2)；3.80(3H，s，OCH3)；3.11(1H，d，CHCH2)；2.82(3H，s，ArCH3)；2.71(2H，t，CH2Ph)；2.07(2H，m，CH2).
synthesis scheme 11
Figure A200710180027D00621
The following compounds of examples 68-69 can be prepared by synthetic scheme 11:
example 68N- (. beta. -carboline-1-formyl) phenylalanine ethyl ester (68)
Beta-carboline-1-carboxylic acid (5mmol), CDI (5.5mmol) and 20mL of dried DMF were placed in a50 mL round bottom flask and stirred at room temperature for 0.5 h, then the compound L-phenylalanine ethyl ester (5mmol) was added and stirred at 40 ℃ for 8 h, followed by thin layer chromatography TLC. After the reaction is finished, distilling off DMF under reduced pressure, separating the product by column chromatography (petroleum ether/ethyl acetate), and recrystallizing the product by ethanol to obtain white crystals with the yield of 94 percent and mp 104-;
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，CDCl3)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，OCH2CH3)；3.29(2H，m，CHCH2)；1.26(3H，t，CH3).
example 69N- (. beta. -carboline-1-formyl) phenylalanine (69)
Dissolving N- (beta-carboline-1-formyl) phenylalanine ethyl ester (1mmol) in 10mL of absolute ethyl alcohol, adding 10mL of aqueous solution of NaOH (5mmol), and heating and refluxing for reaction for 1.5 hours. After the reaction is finished, neutralizing the solution with 2M hydrochloric acid to a pH value of 5, evaporating part of ethanol under reduced pressure until solid is separated out, freezing and standing the solution, performing suction filtration, and performing infrared drying to obtain yellow solid, wherein the yield is 97 percent, and mp 229-;
ESI-MS m/e358[M-H]-；
IR(KBr)3420，3382，3336，3060，2950，1728，1621，1526，1222，739cm-1；
1H-NMR(300MHz，DMSO-d6)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，CHCH2).
synthesis scheme 12
The following compounds of examples 70-73 can be prepared by synthetic scheme 12:
example 701-O- (9-n-butyl-. beta. -carboline-3-formyl) -2, 3, 4-tri-O-benzoyl-. beta. -D-pyran-type ribose (70)
Step A: 1-bromo-2, 3, 4-tri-O-benzoyl-alpha-D-pyranoribose
10g D-ribose was added to 80mL of anhydrous pyridine, and after dissolving by slight heating, 36mL of benzoyl chloride was added dropwise under cooling in an ice bath, and the mixture was reacted at room temperature for 24 hours. Adding small amount of ice water and chloroform for 50m, separating organic phase, and sequentially adding 20% H2SO4Saturated Na2CO3Saturated NaCl solution washed 2 times each, anhydrous Na2SO4Drying, and recovering chloroform to obtain red syrup.
The resulting syrup was dissolved in 25mL of dichloromethane, 56mL of 33% HBr-glacial acetic acid was added dropwise at 0 ℃ and stirred at room temperature for 24 hours. Adding 50mL of CH2Cl2After dilution, the mixture was poured into 200mL of ice-water, stirred to separate the organic phase, dissolved and poured into ice-water. Saturated Na for organic phase2CO3Washing with solution to Ph>7, washing with a saturated NaCl solution to neutrality, evaporating dichloromethane under reduced pressure, and then washing with diethyl ether to obtain 18.6g of a white solid with a yield of 53.2%.
And B: 1-O- (9-n-butyl-beta-carboline-3-formyl) -2, 3, 4-tri-O-benzoyl-beta-D-pyran ribose
Adding 9-n-butyl-beta-carboline-3-carboxylic acid (1mmoL) and 5ml CH into a 100ml three-necked bottle2Cl21mmol of tetrabutylammonium bromide (TBAB) and 5ml of H2O is stirred at 50 ℃ and after stabilization, 5ml of 1.2mmol of NaOH in water are added dropwise to obtain a clear two-phase. Then, 0.8mmol 1-bromo-2, 3, 4-tri-O-benzoyl-alpha-D-pyranoribose in 5ml CH were slowly added with vigorous stirring2Cl2The solution was stirred overnight. TLC tracking detectionMeasuring, cooling the reaction solution to room temperature after the reaction is finished, separating out an organic phase, extracting an aqueous phase by dichloromethane, combining the organic phase, washing by using a 5% NaOH solution and water, and then using anhydrous Na2SO4Drying, evaporating the solvent to dryness, and separating the obtained crude product by column chromatography (petroleum ether/ethyl acetate) to obtain a white solid with the yield of 88 percent and mp 102-;
IR(KBr)3063，2958，2871，1725，1589，1501，1459，1258，1097，713cm-1；
1H-NMR(300MHz，CDCl3)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，NCH2)；4.30(1H，d，CH)；1.94(2H，m，CH2)；1.41(2H，m，CH2)；0.98(3H，t，CH3).
example 711-O- (9-phenylpropyl-beta-carboline-3-formyl) -2, 3, 4-tri-O-benzoyl-beta-D-pyran-type-ribose (71)
The procedure is as in example 70, but using 9-phenylpropyl-beta-carboline-3-carboxylic acid as the starting material. Obtaining white solid with yield of 87 percent and mp 98-100 ℃;
IR(KBr)3062，3030，2938，2871，1725，1584，1499，1454，1259，1097，710cm-1；
1H-NMR(300MHz，CDCl3)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，NCH2)；4.33(1H，dd，CH)；2.76(2H，t，CH2Ph)；2.31(2H，m，CH2).
example 721-O- (9-n-butyl-. beta. -carboline-3-formyl) -2, 3, 4, 5-tetra-O-acetyl-. beta. -D-glucopyranose (72)
Step A: 1-bromo-2, 3, 4, 5-tetra-O-acetyl-alpha-D-glucopyranose
10ml of anhydrous pyridine was added to 10g of glucose, and 25ml of acetic anhydride was added thereto to carry out a reaction at room temperature for 24 hours. Adding a small amount of ice water and 50ml of chloroform, separating the organic phase, and sequentially adding 20% H2SO4Saturated Na2CO3Saturated NaCl solution washed 2 times each, anhydrous Na2SO4Drying, and recovering chloroform to obtain red syrup. The resulting syrup was dissolved in 25ml of methylene chloride, 56ml of 33% HBr-ice HOAc was added dropwise at 0 ℃ and stirred at room temperature for 24 hours. Adding 50ml of CH2Cl2After dilution, the mixture was poured into 200ml of ice-water quickly, the organic phase was separated by stirring, dissolved and poured into ice-water. Saturated Na for organic phase2CO3Washing with solution to Ph>7, washing the solution with saturated NaCl to neutrality, spin-drying the solvent dichloromethane, and washing with petroleum ether to obtain a white solid 12.9g, with a yield of 55.7%, m.p.88-89 ℃.
And B: 1-O- (9-n-butyl-beta-carboline-3-formyl) -2, 3, 4, 5-tetra-O-acetyl-beta-D-pyran glucose
Adding 9-n-butyl-beta-carboline-3-carboxylic acid (1mmol), dichloromethane (5mL), tetrabutylammonium bromide (TBAB) (1mmol) and H (5mL) into a three-necked bottle (100mL)2O is stirred at 50 ℃ and after stabilization, 5ml of 1.2mmol of NaOH in water are added dropwise to obtain a clear two-phase. Then, 0.8mmol 1-bromo-2, 3, 4, 5-tetra-O-acetyl-alpha-D-glucopyranose 5mLCH was slowly added with vigorous stirring2Cl2The solution was stirred overnight. After TLC detection reaction, cooling to room temperature, separating out organic phase, using CH for aqueous phase2Cl2Extracting, combining organic phases, washing with 5% NaOH solution and water, and then using anhydrous Na2SO4Drying, evaporating the solvent, and separating the obtained crude product by column chromatography (petroleum ether/ethyl acetate) to obtain white solid with yield of 85%, mp 124-126 deg.C；
IR(KBr)3638，3413，3057，2955，2930，2871，2872，1754(C＝O)，1584，1501，1466，1226，1085，751cm-1；
1H-NMR(300MHz，CDCl3)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，CH2)；5.23(1H，t，CH)；4.46(2H，t，CH2)；4.34(1H，d，CH)；4.17(1H，d，CH)；4.00(1H，d，CH)；2.08-1.99(12H，4COCH3)1.92(2H，m，CH2)；1.40(2H，m，CH2)；0.96(3H，t，CH3).
Example 731-O- (9-phenylpropyl-beta-carboline-3-formyl) -2, 3, 4, 5-tetra-O-acetyl-beta-D-glucopyranose (73)
The procedure is as in example 72, but using 9-phenylpropyl-beta-carboline-3-carboxylic acid as starting material. Obtaining white solid with the yield of 84 percent and mp 133-134 ℃;
IR(KBr)3431，3060，3027，2948，1755(C＝O)，1583，1500，1465，1224，1068，750cm-1；
1H-NMR(300MHz，CDCl3)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，CH2)；5.23(1H，t，CH)；4.45(2H，t，CH2)；4.33(1H，d，CH)；4.17(1H，d，CH)；4.00(1H，d，CH)；2.74(2H，t，CH2)；2.29(2H，m，CH2)；2.10-1.99(12H，COCH3).
synthesis scheme 13
Figure A200710180027D00671
The following compounds of examples 74-75 can be prepared by synthetic scheme 13:
example 747-beta-D-glucopyranosyloxy-9-phenylpropyl-1-methyl-beta-carboline (74)
Step A: 1-bromo-2, 3, 4, 5-tetra-O-acetyl-alpha-D-glucopyranose
The operation was the same as in example 72.
And B: 7-beta-D-glucopyranosyloxy-9-n-butyl-1-methyl-beta-carboline
Adding 7-hydroxy-9-phenylpropyl-1-methyl-beta-carboline (3mmol), tetrabutylammonium bromide (TBAB) (0.5mmol) and 20ml H into a 250ml three-necked bottle2O and 20ml CH2Cl2Heated to 50 ℃ under reflux and then slowly added dropwise with 20ml of 10mmol KOH in water until a clear two-phase mixture is obtained. Then, under vigorous stirring, another 6mmol of 1-bromo-2, 3, 4, 5-tetra-O-acetyl-alpha-D-glucopyranose in 20ml of CH are slowly added dropwise2Cl2The solution was reacted at 50 ℃ for 20 hours. Cooling to room temperature, separating organic phase from aqueous phase with CH2Cl2Extracting, combining organic phases, washing with 5% NaOH solution and water, anhydrous Na2SO4Drying, evaporating solvent, and separating by column chromatography (chloroform/methanol) to obtain non-deprotected glycoside in the form of reddish brown syrup.
The intermediate product obtained in the above step was added to 20ml of anhydrous methanol, and 20ml of 0.2M MeONa/MeOH solution was added thereto, and the reaction was stirred at room temperature overnight. After TLC detection reaction is completed, evaporating the solvent to dryness, separating by column chromatography (chloroform/methanol), and recrystallizing with anhydrous ethanol to obtain white crystals with the yield of 45 percent and mp 212-213 ℃;
IR(KBr)3423，3027，2924，2857，1627，1575，1448，1238，1074，701，624cm-1；
1H-NMR(300MHz，DMSO-d6)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，CH2)；3.47(2H，t，CH2)；2.77(3H，s，CH3)；2.72(2H，m，CH2)；2.00(2H，m，CH2)；
13C NMR(75MHz，DMSO-d6)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.
example 757-D-Pyranosyl-xyloxy-9-n-butyl-1-methyl-beta-carboline (75)
Step A: 1-bromo-2, 3, 4-tri-O-benzoyl-alpha-D-xylopyranose
The procedure is as in step A of example 72.
And B: 7-beta-D-pyran xyloxy-9-n-butyl-1-methyl-beta-carboline
The procedure is as in example 74, but using 7-hydroxy-9-n-butyl-1-methyl-. beta. -carboline as starting material. Obtaining white crystals with the yield of 42 percent and the temperature of 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-d6)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，CH2)；3.32(1H，d，CH)；2.94(3H，s，CH3)；1.72(2H，m，CH2)；1.35(2H，m，CH2)；0.91(3H，t，CH3)。
synthesis scheme 14
Figure A200710180027D00681
The following compounds of examples 76-83 can be prepared by synthetic scheme 14:
example 761- (4' -methoxy-styryl) -9-n-butyl-beta-carboline (76)
Mixing 9-n-butyl-1-methyl-beta-carboline (10mmol), acetic anhydride (50ml) and 4-methoxy-benzaldehyde (100mmol), stirring at room temperature for 30 minutes, heating and refluxing for 72 hours, and tracking and detecting by TLC; after the reaction is finished, cooling the reaction liquid to room temperature, pouring the reaction liquid into 200ml of cold water, alkalifying with sodium bicarbonate, extracting with ethyl acetate, combining organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, dissolving the residue in anhydrous ethanol, adjusting the pH to 1-2 with a saturated solution of hydrogen chloride and ethanol, concentrating under reduced pressure to dryness, recrystallizing the residue with acetone, and filtering to obtain a yellow solid. Dissolving the yellow solid in 50ml of water, alkalifying with sodium bicarbonate, extracting with ethyl acetate, combining organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, performing silica gel column chromatography on the residue, and recrystallizing with acetone/petroleum ether (1/2). Obtaining 1.6g of light yellow needle-shaped crystal with the yield of 45 percent and mp 115-;
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，CDCl3)δ 8.46-8.47(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，NCH2CH2CH2CH3)；3.85(3H，s，OCH3)；1.96-2.02(2H，m，NCH2CH2CH2CH3)；1.49-1.51(2H，m，NCH2CH2CH2CH3)；0.99-1.02(3H，m，NCH2CH2CH2CH3).
example 771- (4' -methoxy-styryl) -9-phenylpropyl-beta-carboline (77)
The procedure is as in example 76, but using 9-phenylpropyl-1-methyl- β -carboline as the starting material. Obtaining 2.2g of light yellow needle-shaped crystal with the yield of 53 percent and 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，CDCl3)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，NCH2CH2CH2Ph)；3.86(3H，s，OCH3)；2.75-2.78(2H，m，NCH2CH2CH2Ph)；2.30-2.33(2H，m，NCH2CH2CH2Ph).
example 781- (4' -methoxy-styryl) -7-n-butoxy-9-phenylpropyl-beta-carboline (78)
The procedure is as in example 76, but using 7-n-butoxy-9-phenylpropyl-1-methyl- β -carboline as the starting material. Obtaining light yellow needle crystal 2.7g, yield 55%, mp 110-;
FAB-MS m/e(M+1)491；
IR(KBr)3430，3030，2964，2937，2869，1631，1556，15101439，1414，1335，1246，1206，1148，1068，1032，964，822；
1H-NMR(500MHz，CDCl3)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，NCH2CH2CH2Ph)；3.97-4.00(2H，t，OCH2CH2CH2CH3)；3.86(3H，s，OCH3)；2.76-2.79(2H，m，NCH2CH2CH2Ph)；2.22-2.34(2H，m，NCH2CH2CH2Ph)；1.82-1.85(2H，m，OCH2CH2CH2CH3)；1.55-1.58(2H，m，OCH2CH2CH2CH3)；1.01-1.04(3H，t，OCH2CH2CH2CH3).
example 791- (4' -Nitro-styryl) -7-n-butoxy-9-phenylpropyl-beta-carboline (79)
The procedure is as in example 76, but 4-nitro-benzaldehyde and 7-n-butoxy-9-phenylpropyl-1-methyl- β -carboline are used as starting materials for the reaction. Obtaining light red needle-shaped crystals 3.2g with the yield of 63 percent and mp 170-;
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，CDCl3)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，NCH2CH2CH2Ph)；4.01-4.05(2H，t，OCH2CH2CH2CH3)；2.79-2.82(2H，t，NCH2CH2CH2Ph)；2.31-2.35(2H，m，NCH2CH2CH2Ph)；1.84-1.88(2H，m，OCH2CH2CH2CH3)；1.56-1.60(2H，m，OCH2CH2CH2CH3)；1.04-1.07(3H，t，OCH2CH2CH2CH3).
example 801- (4' -methoxy-styryl) -2-benzyl-9-n-butyl-. beta. -carboline bromide salt (80)
Mixing 1- (4' -methoxy-styryl) -9-n-butyl-beta-carboline (2mmol), ethyl acetate (50ml) and benzyl bromide (20mmol), heating and refluxing for 5 hours, cooling the reaction liquid to room temperature, filtering, and washing with ethyl acetate to obtain a yellow solid. The yellow solid is dissolved in 50ml of absolute ethyl alcohol, heated and refluxed until the yellow solid is clear, filtered while hot, cooled to room temperature, and recrystallized in a refrigerator. 0.49g of yellow granular crystals are obtained with a yield of 44%, mp 197-.
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-d6)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，CH2Ph)；4.51-4.54(2H，m，NCH2CH2CH2CH3)；3.82(3H，s，OCH3)；1.53-1.60(2H，m，NCH2CH2CH2CH3)；0.97-1.02(2H，m，NCH2CH2CH2CH3)；0.63-0.66(3H，m，NCH2CH2CH2CH3)
Example 811- (4' -methoxy-styryl) -9-phenylpropyl-2-benzyl- β -carboline bromide (81)
The procedure is as in example 81, but using 1- (4' -methoxy-styryl) -9-phenylpropyl- β -carboline as starting material. 0.73g of yellow granular crystals are obtained with a yield of 60%, mp 207-.
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-d6)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，CH2Ph)；4.59-4.62(2H，t，NCH2CH2CH2Ph)；3.84(3H，s，OCH3)；2.49-2.51(2H，m，NCH2CH2CH2Ph)；2.28-2.30(2H，m，NCH2CH2CH2Ph).
Example 821- (4' -methoxy-styryl) -7-n-butoxy-9-phenylpropyl-2-benzyl- β -carboline bromide salt (82)
The procedure is as in example 81, but using 1- (4' -methoxy-styryl) -7-n-butoxy-9-phenylpropyl- β -carboline as starting material. 0.85g of yellow granular crystals are obtained with a yield of 70 percent, mp 207-.
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-d6)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，CH2Ph)；4.52-4.55(2H，m，NCH2CH2CH2Ph)；4.16-4.19(2H，t，OCH2CH2CH2CH3)；3.83(3H，s，OCH3)；2.28-2.31(2H，m，NCH2CH2CH2Ph)；1.76-1.88(4H，m，NCH2CH2CH2Ph，OCH2CH2CH2CH3)；1.48-1.53(2H，m，OCH2CH2CH2CH3)；0.96-0.99(3H，t，OCH2CH2CH2CH3)
Example 831- (4' -Nitro-styryl) -7-n-butoxy-9-phenylpropyl-2-benzyl- β -carboline bromide (83)
The procedure is as in example 81, but using 1- (4' -nitro-styryl) -7-n-butoxy-9-phenylpropyl- β -carboline as starting material. 0.9g of yellow granular crystals are obtained with a yield of 66%, mp 228-.
FAB-MS m/e 596；
IR(KBr)3046，3027，2954，2930，2867，1619，1522，1454，1431，1345，1231，1138，1061，971，836；
1H-NMR(500MHz，DMSO-d6)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，CH2Ph)；4.49-4.53(2H，m，2H，t，NCH2CH2CH2Ph)；4.17-4.20(2H，t，OCH2CH2CH2CH3)；2.29-2.33(2H，t，2H，m，NCH2CH2CH2Ph)；1.78-1.90(4H，m，NCH2CH2CH2Ph，OCH2CH2CH2CH3，)；1.48-1.54((2H，m，OCH2CH2CH2CH3)；0.96-1.00(3H，t，OCH2CH2CH2CH3).
Synthesis scheme 15
Figure A200710180027D00731
The following compounds of examples 84-85 can be prepared by synthetic scheme 15:
example 841- (3' -pyridyl) -9-n-butyl-beta-carboline (84)
Step A: synthesis of 1- (3' -pyridyl) -beta-carboline
L-tryptophan (20.4 g, 100mmol) and 200ml glacial acetic acid were mixed and heated to dissolve the solid; then, 3-aldehyde-pyridine (4.8ml) was added thereto, and stirred at room temperature for 2 hours, followed by heating under reflux. TLC was used to monitor the progress of the reaction until the reaction was complete. The reaction was concentrated to dryness, the residue was mixed with 100ml of glacial acetic acid, heated for 5 minutes and KMnO was added in portions4(200mmol), refluxing for 1 hour, concentrating under reduced pressure, evaporating to remove glacial acetic acid, adding 300ml of water into residues, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and recrystallizing with ethyl acetate to obtain the product 1- (3' -pyridyl) -beta-carboline.
And B: 1- (3' -pyridyl) -9-n-butyl-beta-carboline
Mixing 1- (3' -pyridyl) -beta-carboline (2.45g, 10mmol), DMF (50ml) and 60% sodium hydride (0.6g, 20mmol), stirring at room temperature for reaction for 10min, adding n-butyl iodide (30mmol), stirring at room temperature for reaction, tracking and detecting by TLC, pouring the reaction solution into cold water after the reaction is finished, extracting by ethyl acetate, combining organic phases, washing by water, adding 50ml of ethanol, acidifying by concentrated hydrochloric acid, concentrating under reduced pressure to dryness, adding absolute ethanol with water, recrystallizing by acetone, separating out yellow solid, filtering, and washing by diethyl ether. Dissolving the solid with water, alkalifying with sodium bicarbonate, extracting with ethyl acetate, combining organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, decoloring with activated carbon, concentrating under reduced pressure to dryness, recrystallizing with diethyl ether to obtain light yellow crystals 0.41g, yield 83.6%, mp: 133 ℃ and 135 ℃;
FAB-MS m/e(M+1)302
1H-NMR(CDCl3)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，CH3CH2CH2CH2)；1.32-1.36(2H，m，CH3CH2CH2CH2)；0.85-0.91(2H，m，CH3CH2CH2CH2)；0.63-0.67(3H，t，CH3CH2CH2CH2)。
example 851- (3' -pyridyl) -9-benzyl-beta-carboline (85)
The procedure is as in example 84, but benzyl bromide is used as alkylating agent. Obtaining light yellow crystal 0.43g with the yield of 81.7 percent and mp 155-;
FAB-MS m/e(M+1)336；
IR(KBr)1650-3050，1620，1479，1445，1353，1214，1191，1044，841；
1H-NMR(CDCl3)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)；7.46-7.51(2H，m Py-H)；7.32-7.36(1H，t，Py-H)；4.01-4.07(2H，t，CH3CH2)；0.99(3H，s，CH3CH2)。
synthesis scheme 16
Figure A200710180027D00741
The following compound of example 86 can be prepared by synthetic route 16:
example 861- (2' -aminoethyl) carbamoyl-9-phenylpropyl-beta-carboline (86)
Step A: preparation of ethyl 9-phenylpropyl-beta-carboline-1-carboxylate
Mixing ethyl beta-carboline-1-carboxylate (2.4g, 10mmol), DMF (50ml) and 60% sodium hydride (0.6g, 20mmol), stirring at room temperature for reaction for 5 minutes, adding 1-bromo-3-phenyl-propane (50mmol), stirring at room temperature, tracking and detecting by TLC, after the reaction is finished, pouring the reaction liquid into cold water, extracting by ethyl acetate, combining organic phases, washing by water, adding 50ml of ethanol, acidifying by concentrated hydrochloric acid, concentrating under reduced pressure to dryness, carrying out anhydrous ethanol with water, and recrystallizing by acetone to obtain a pale yellow solid, namely ethyl 9-phenylpropyl-beta-carboline-1-ethyl carboxylate hydrochloride, wherein the pale yellow solid can be directly used for the next reaction without further purification.
And B: 1- (2' -aminoethyl) carbamoyl-9-phenylpropyl-beta-carbolines
Mixing ethyl 9-phenylpropyl-beta-carboline-1-carboxylate hydrochloride (2.0mmol) and 30ml of ethylenediamine, stirring at room temperature for reacting overnight, performing thin-layer chromatography (TLC) tracking reaction, pouring the reaction mixed solution into 50ml of water after the reaction is finished, extracting dichloromethane, combining organic phases, washing with water, washing with saturated saline, drying with anhydrous magnesium sulfate, concentrating under reduced pressure, and recrystallizing with acetone/petroleum ether (v/v 3:1) to obtain a light yellow solid. Dissolving the light yellow solid in 20ml of absolute ethanol, adding saturated HCl-ethanol solution, adjusting the pH to 2.0, then evaporating the ethanol solution, and recrystallizing acetone to obtain the hydrochloride of the product, wherein the temperature is mp 221-.
FAB-MS m/e(M+1)373；
IR(KBr，cm-1)ν：3432，3054，2929，1625，1496，1454，749；
1H-NMR(300MHz，D2O)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，NCH2)；3.61(2H，t，CH2)；3.20(2H，t，CH2)；2.47(2H，t，CH2Ph)；1.91(2H，m，CH2).
Synthesis scheme 17
Figure A200710180027D00751
The following compounds of examples 87-88 can be prepared by synthetic scheme 17:
example 871- (2' -amino) ethylamino-9-n-butyl- β -carboline (87)
Step A: synthesis of 1-keto-1, 2, 3, 4-tetrahydro-beta-carboline
L-tryptamine (9.0g, 56mmol) and 800ml toluene were mixed, heated to dissolution, then the reaction was allowed to cool to room temperature and triethylamine (13.8g, 136.6mmol) was added; under vigorous stirring, 6.7g of triphosgene in 35ml of toluene solution was added dropwise and stirring was continued at room temperature for 30 minutes; then, the temperature was gradually increased and 13.0ml of 30% hydrogen bromide/glacial acetic acid solution was added dropwise, followed by heating under reflux for 30 minutes after the addition. After cooling, 300ml of water and 300ml of ethyl acetate are added, after vigorous shaking, the organic phase is taken off, the aqueous layer is extracted once more with 300ml of ethyl acetate, the organic phases are combined, dried over anhydrous magnesium sulfate and the residue is crystallized from methanol/ethyl acetate (1:1) to give 5.72g of white crystals, mp 184 ℃.
And B: synthesis of 1-keto-1, 2-dihydro-beta-carboline
Adding 1-keto-1, 2, 3, 4-tetrahydro-beta-carboline (2.5g, 13.4mmol), DDQ (15mmol) and 100ml tetrahydrofuran into a 250ml round-bottom flask, reacting at room temperature for 5 hours, and performing thin-layer chromatography (TLC) tracking detection; after the reaction, the reaction was stopped, THF was distilled off under reduced pressure, 200ml of a 5% sodium hydroxide solution was added, and the mixture was stirred for 10 minutes, filtered by suction, and washed with water to give 2.25g of a pale gray solid.
And C: synthesis of 1-bromo-beta-carboline
Adding 1-keto-1, 2-dihydro-beta-carboline (0.74g, 4.0mmol), tribromooxyphosphorus (8.0g, 28.0mmol) and 10ml anisole into a50 ml round-bottom flask, heating at 120 ℃ for reaction overnight, and tracking and detecting by TLC; after the reaction, the reaction was stopped, 100ml of water was added, the mixture was made alkaline with 5% aqueous sodium hydroxide solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and the crude product was separated by column to give a pale yellow solid 0.81g, mp 152-.
Step D: synthesis of 1-bromo-9-n-butyl-beta-carboline
Dissolving n-butyl iodide (4.0mmol) in 10ml of DMF, adding 60% sodium hydride (4.0mmol), stirring at room temperature for 15 minutes, adding 1-bromo-beta-carboline (1.50mmol), stirring at room temperature for 2 hours, tracking and detecting by Thin Layer Chromatography (TLC), stopping the reaction after the reaction is finished, adding 50ml of water, extracting by ethyl acetate, combining organic phases, drying by anhydrous magnesium sulfate, separating the crude product by a column to obtain light yellow solid 0.42g, and performing mp63-65 ℃.
Step E: 1- (2' -amino) ethylamino-9-butyl-beta-carboline
Mixing 1-bromo-9-butyl-beta-carboline (0.30g, 1.0mmol), cuprous iodide (0.30g) and ethylenediamine (30ml), heating and refluxing for 10 hours, and tracking and detecting by TLC; after the reaction, the solvent was evaporated under reduced pressure, 100ml of water was added to the residue, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and the crude product was separated by column to give 0.23g of yellow mucilage, with a yield of 82%. Dissolving the yellow mucus in 20ml of absolute ethanol, adding saturated HCl-ethanol solution, adjusting the pH to 2.0, evaporating the ethanol solution under reduced pressure, and recrystallizing acetone to obtain hydrochloride (pale yellow solid) of the product, wherein mp 224-.
FAB-MS m/e(M+1)283；
IR(KBr，cm-1)ν：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，NCH2)，4.03(2H，t，CH2)，3.20(2H，t，CH2)，1.61(2H，m，CH2)，1.15(2H，m，CH2)，0.80(3H，t，CH3).
Example 881- (2' -amino) ethylamino-9-phenylpropyl- β -carboline (88)
Steps A, B and C are the same as example 87;
step D: synthesis of 1-bromo-9-phenylpropyl-beta-carboline
Adding 1-bromo-3-phenylpropane (3.0mmol), potassium iodide (3.0mmol) and 10ml DMF into a50 ml round bottom flask, stirring at room temperature for reaction for 2 hours, then adding 60% NaH (3.0mmol), stirring at room temperature for 15 minutes, then adding 1-bromo-beta-carboline (0.25g and 1.0mmol), stirring at room temperature for 2 hours, tracking and detecting by TLC, stopping the reaction after the reaction is finished, adding 50ml of water into the reaction mixture, extracting by ethyl acetate, combining organic phases, drying by anhydrous magnesium sulfate, and separating a crude product by a column to obtain a light yellow solid, wherein the m.p. is 0.34-114 ℃.
Step E: synthesis of 1- (2' -amino) ethylamino-9-phenylpropyl-beta-carboline
Mixing 1-bromo-9-phenylpropyl-beta-carboline (0.37g, 1.0mmol), cuprous iodide (0.30g) and ethylenediamine (30ml), heating and refluxing for 10 hours, tracking and detecting by TLC, after the reaction is finished, evaporating the solvent under reduced pressure, adding 100ml of water into the residue, extracting by ethyl acetate, combining organic phases, drying by anhydrous magnesium sulfate, and separating the crude product by a column to obtain 0.30g of yellow mucus. Dissolving the yellow mucus in 20ml of absolute ethanol, adding saturated HCl-ethanol solution, adjusting the pH to 2.0, evaporating the ethanol solution under reduced pressure, and recrystallizing acetone to obtain light yellow solid, namely hydrochloride of the product, wherein mp 256-phase 258 ℃.
FAB-MS m/e(M+1)：345；
IR(KBr，cm-1)ν：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，NCH2)，4.00(2H，t，CH2)，3.18(2H，t，CH2)，2.56(2H，t，CH2Ph)，1.96(2H，m，CH2)；
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.
Example 89 in vitro anti-cancer screening assay
Respectively selecting Hela (cervical cancer cell) and HepG2Cell lines (human liver cancer cells), BGC (human gastric cancer cells), Bel7402 (human liver cancer cells), MCF-7 (human breast cancer cells) and the like are tested by adopting an MTT method.
The specific method comprises the following steps: the cell lines with good growth state and logarithmic growth phase are respectively treated by 1 × 104Inoculating the mixture into a 96-well plate, culturing in an incubator containing 5% CO2 at 37 deg.C for 24 hr, discarding the old solution, replacing the fresh culture solution, adding sterilized compound, culturing for 48 hr, discarding the culture solution, adding 20ul of RPMI1640 culture solution containing 5mg/ml MTT into each well, culturing for 4 hr, carefully removing the supernatant, adding 100. mu.l of DMSO into each well, shaking for about 10min to dissolve the precipitate, and detecting the OD value with a microplate reader at 490 nm. Cell viability was determined for each sample concentration using the following formula:
percent survival%
Plotting cell viability against log drug concentration and determining IC for each sample by plotting50The value is obtained.
The test results are shown in Table 1.
TABLE 1 Harmine derivatives in vitro antitumor screening results (IC)50uM)
Compound numbering Hela Bel7402 BGC HepG2 MCF7
Harmine 60.0 54.3 68.2 46.2 103
1 134 70.0 165 160 106
2 89.8 69.5 90.2 81.5 46.9
3 16.4 213 114 140 197
4 23.3 21.9 29.8 20.8 13.2
5 283 152.9 17.2 15.5 158
6 30.2 13.5 11.9 11.4 105
7 40.7 25.6 23.4 15.3 21.6
8 145 62.0 96.4 114 33.1
9 47.0 148 17.2 17.8 16.9
10 112 152 18.3 13.6 142
11 20.8 42.5 12.1 12.1 7.2
12 2.0 127 74.1 149 144
13 27.6 134 18.5 27.7 19.5
14 4.9 3.2 10.6 9.6 11.1
15 56.3 3.57 66.1 49.9 67.6
16 2.2 2.4 7.6 7.6 2.8
17 2.2 3.62 44.4 2.7 97
18 3.9 2.7 4.6 4.2 10.4
19 1.8 2.6 5.3 6.9 5.3
20 1.6 5.8 2.0 2.4 1.8
21 1.4 1.3 2.5 4.0 9.2
24 166 187 36.2 208 115
25 418 418 37.2 87.4 104
26 19.6 43.8 43.1 63.2 31.7
27 44.2 42.5 27.5 51.9 51.8
30 172 172 120 79.6 138
31 72.9 117 132 166 96.2
32 39.1 57.5 63.6 70.5 52.5
33 100 122 127 128 107
34 99.0 87.5 111 59.1 62.1
35 32.8 65.9 47.5 72.1 49.6
36 106 149 79.7 175 62.8
40 64.6 119 47.5 126 87.1
41 44.9 8.7 2.1 44.5 29.1
42 81.7 26.4 10.3 45.6 38.9
43 216 137 123 97.6 102
44 98.3 148 167 65.8 157
45 45.9 67.5 102 126 169
46 18.6 25.2 54.8 19.2 46.7
47 26.3 40.2 30.9 69.8 51.2
48 32.3 63.8 38.7 44.4 32.4
49 158 124 257 216 99.3
50 23.6 54.2 41.0 116 86.3
52 212 167 124 254 79.4
53 184 251 98.7 121 231
54 135 159 18.9 71.4 129
56 98.5 103 152 230 106
58 150 162 142 225 96.2
59 68.6 102 165 132 205
60 58.6 95.3 128 165 204
61 46.7 51.2 23.7 36.5 29.8
68 118 152 98.6 181 192
69 125 124 106 97.4 213
70 258 156 175 115 64.5
72 125 158 95.3 165 76.4
73 118 65 159 129 105
74 259 230 124 118 112
76 88.8 29.7 141 66.2 38.1
77 92 243 219 92.9 79.0
80 6.7 7.7 21.8 6.7 4.6
81 4.5 6.9 0.5 2.1 5.8
82 6.8 1.6 7.1 8.9 6.9
83 2.9 1.5 4.1 1.3 3.6
As can be seen from Table 1, most of the compounds have certain in vitro anti-tumor activity, and some of the compounds have significant in vitro anti-tumor activity, wherein the compounds 16, 19, 20, 21, 80, 81, 82 and 83 and the like have IC (integrated Circuit) values for all 5 human tumor cell lines50The values are all less than 10uM, which shows that the in vitro content is obviously superior to that of harmineAnti-tumor activity.
Example 90 acute toxicity test in mice
Kunming breed mouse (provided by Shanghai laboratory animal center of Chinese academy of sciences, qualification No. Huhui syndrome No. 107), weight 19-20g, half female and half male. One group of 10 mice each. The solvent adopts physiological saline and 0.5 percent CMC-Na solution; according to the pre-test result, five-gear dosage is designed for each sample, and the dosage interval is 0.8 times. After weighing each sample, adding a small amount of Tween 80 to moisten and aid dissolution during experiments, and then gradually adding 0.5% CMC-Na solution to the required concentration. The experimental volume was 0.5ml/20g mouse. A single intraperitoneal administration is adopted. The Kunming mice are taken and randomly grouped according to sex, each group is respectively administrated in the abdominal cavity according to the dosage setting, and the instant reaction of the mice after administration is observed. Dead animals were observed dissectively, surviving animals were observed for two additional weeks, and animal deaths were recorded for two weeks. After two weeks, the surviving animals were dissected and the parenchymal organ was observed for pathological examination. Based on the number of deaths in each group of animals, the half-Lethal Dose (LD) of the drug was calculated by the Bliss method50A value); the Maximum Tolerated Dose (MTD) was determined for the less toxic compounds.
The results of the tests are shown in Table 2 below.
EXAMPLE 91 in vivo anticancer assay
Kunming breed mice (provided by Shanghai laboratory animal center of Chinese academy of sciences, certification number: Huhui syndrome No. 107) with weight of 18-20g, both male and female, and the same sex was used in each batch of experiments. Antitumor experiment C57BL/6 mice and Kunming mice 8-10 mice, negative controls are two groups; the tumor source adopts mouse Lewis lung cancer and S180 sarcoma (maintained by pharmacological passage of Shanghai pharmaceutical industry research institute); the solvent adopts physiological saline and 0.5 percent CMC-Na solution; the tested medicine is set to be high and low two dosage groups, and LD is respectively administrated in the abdominal cavity by a single administration of the medicine501/5, 1/10 of value as benchmark; weighing each sample to be tested, adding a small amount of Tween-80 for wetting and dissolving aid during experiment, and gradually adding 0.5% CMC-Na solution to the required concentration. The experimental volume is 0.5ml/20g of mouse. The preparation is administered to abdominal cavity 1 time per day for 10 days, and 10 times. The negative control was given an equal volume of the corresponding solvent, and the dosing regimen was all intraperitoneal, 1 time per day for 10 consecutive days. Positive control Cyclophosphamide (CTX) was administered once daily for 7 consecutive days at a dose of 30 mg/kg. Adopting an in vivo anti-tumor axillary subcutaneous inoculation model: taking tumor source with vigorous growth under aseptic condition, homogenizing to obtain about 1 × 1070.2 ml/mouse is inoculated to the axilla of the corresponding host subcutaneously, the administration is carried out according to the experimental design scheme on the next day, each group of animals is killed in about three weeks, the tumor is dissected and weighed, and the tumor inhibition rate is calculated according to the following formula:
percent tumor inhibition is [ (average tumor weight in negative control group-average tumor weight in administration group)/average tumor weight in negative control group ] × 100%
After administration, the mice were observed for immediate response, with emphasis on the presence of neurotoxic symptoms such as jumping, tremor, and torsion.
The results of the tests are shown in Table 2 below.
TABLE 2 test results of acute toxicity and antitumor activity of harmine derivatives in mice
Figure A200710180027D00811
Note: neurotoxicity is indicated by "+", wherein "+ + + +", indicates significant neurotoxicity; "-" indicates no neurotoxicity.
As can be seen from table 2, none of the compounds were neurotoxic except that harmine showed significant neurotoxicity. The tumor inhibition rates of the dehydroharmine on two tumor-bearing mouse experimental models of Lewis lung cancer and sarcoma S180 are 34.1% and 15.3%, respectively, while the tumor inhibition rates of the compounds 8, 14, 54 and 82 on the tumor-bearing mouse experimental model of Lewis lung cancer are over 40%, and the tumor inhibition rates of the compounds 11, 14, 16, 17, 18, 41, 42, 54 and 82 on the tumor-bearing mouse experimental model of sarcoma S180 are over 40%, wherein the tumor inhibition rates of the compounds 14, 16, 17, 54 and 82 on the tumor-bearing mouse experimental model of sarcoma S180 are over 50%, and particularly, the tumor inhibition rate of the compound 14 on the sarcoma S180 is up to 67.4%.

Claims (18)

1. A harmine derivative is characterized by the following compounds of general formula (I) and salts thereof:
formula (I)
Wherein,
R1is selected from hydrogen and C1-6Alkyl, heterocyclyl, aldehyde, carboxyl, carboxylate, CH ═ nnhc (o) NH2、
CH＝NNHC(S)NH2、CH＝NOH、CH＝NOCH3、CONHRa、COORb、CH＝CHRc、
CH ═ NRd and NHRd, where,
ra is hydrogen or C1-6Alkyl, mono C1-6Alkylamino or amino acid residues;
rb is a sugar residue, wherein the sugar is a hexose, a pentose, a disaccharide or an acyclic sugar;
rc is aryl or heterocyclyl;
rd is C1-6Alkyl or C1-6An alkylamino group;
R2is selected from hydrogen and C1-6Alkyl, aryl (C)1-6) An alkyl group;
x is selected from organic acid radical or inorganic acid radical; or, R2And X are absent at the same time;
R3selected from hydrogen, aldehyde group, CH (OH) SO3Na、CH＝NNHC(O)NH2、CH＝NNHC(S)NH2、
CONHRa, COORb, CH ═ CHRc, and CH ═ NRd,
wherein Ra, Rb, Rc and Rd are as defined above;
R7is selected from hydrogen, hydroxy, C1-15Alkoxy, aryl (C)1-6) Alkoxy, COCH2CONHRa、
COCH2COORb; wherein,
ra and Rb are as defined above;
R9is selected from hydrogen and C1-6Alkyl, hydroxy-C1-6Alkyl, aryl (C)1-6) An alkyl group; with the following conditions:
(1) when R is1、R2、R7And R9When both are hydrogen, R3Cannot be hydrogen or CONHCH2CH2NH2；
(2) When R is1When it is methyl, R2、R3、R7、R9Cannot be simultaneously hydrogen;
(3) when R is1Is methyl, R7Is methoxy and R2、R3When both are hydrogen, R9Can not be hydrogen, C1-4Alkyl radicalHydroxyethyl, benzyl or phenylpropyl;
(4) when R is1Is methyl and R2、R3And R9When both are hydrogen, R7Can not be C1-10An alkoxy group;
(5) when R is1Is methyl, R7Is methoxy, R9Is n-propyl and R2When methyl, X is not bromine or iodine;
(6) when R is1、R3And R7Are both hydrogen and R9When it is phenylpropyl, R2And not hydrogen, benzyl, 4-fluorobenzyl, 3-chlorobenzyl or phenylpropyl;
(7) when R is1、R3、R7When both are hydrogen, R2And R9Can not be simultaneously methyl, benzyl or ethyl;
(8) when R is1Is methyl, R3Is hydrogen, R7Is methoxy and R9When it is phenylpropyl, R2And can not be ethyl, butyl, benzyl, 4-fluorobenzyl and phenylpropyl;
(9) when R is1Is methyl, R2And R3Are both hydrogen and R9When it is phenylpropyl, R7Can not be hydrogen, hydroxy, C3-8Alkoxy and phenyl (C)1-3) An alkoxy group;
(10) when R is1Is methyl, R2Is benzyl, R3Is hydrogen and R9When it is phenylpropyl, R7Can not be hydrogen, hydroxy, C1-8Alkoxy and phenyl (C)1-3) An alkoxy group;
(11) when R is1Is 3-chlorobenzyl and R2、R3、R7When all are hydrogen, R9Cannot be phenylpropyl;
(12) when R is1Is NHRd and R2、R3、R7When all are hydrogen, R9Cannot be hydrogen; rd is as defined above;
(13) when R is1Is hydrogen or methyl, R2、R7、R9When both are hydrogen, R3Cannot be CONH (CH)2)nNH2(n-2 or 4), CONHCH2CH2OH；
(14) When R is1Is hydrogen or methyl, R3Is CONH (CH)2)nNH2(n-2 or 4) or CONHCH2CH2OH、R2And R7When both are hydrogen, R9And not methyl, ethyl, n-butyl, benzyl or pentafluorobenzyl.
2. The compound according to claim 1, wherein,
R1is selected from hydrogen, pyridyl, aldehyde, carboxyl, carboxylic ester, carboxylic salt, CH ═ NNHC (S) NH2、CONHRa、
COORb, CH ═ CHRc, and NHRd, where,
ra is C1-2Alkyl, mono C2-6An alkylamino group or an L-amino acid residue,
rb is glucose, xylose, ribose, deoxyribose or acyclic sugar,
rc is a phenyl group or a heterocyclic group,
rd is C1-2Alkyl or C2-6An alkylamino group.
3. The compound according to claim 2, wherein,
R1is selected from hydrogen, pyridyl, carboxylic acid ethyl ester, carboxylic acid sodium, CH ═ NNHC (S) NH2、CONHRa、COORb、
CH ═ CHRc and NHRd, where,
ra is L-phenylalanine residue, L-tryptophan residue, L-tyrosine residue,
rb is glucose, ribose or deoxyribose,
rc is 4-methoxyphenyl or 4-nitrophenyl,
rd is C2-4An alkylamino group.
4. The compound according to claim 1, wherein,
R2is selected from hydrogen, benzyl, phenylpropyl, sulfonic acid group; x is chlorine or bromine; or, R2And X are simultaneously absent。
5. The compound according to claim 1, wherein,
R3selected from hydrogen, aldehyde groups, CH ═ NNHC (S) NH2CONHRa, COORb, CH ═ CHRc and CH ═ NRd, where,
ra is C1-2Alkyl, mono C2-6An alkylamino group or an L-amino acid residue,
rb is glucose, xylose, ribose, deoxyribose or acyclic sugar,
rc is a phenyl group or a heterocyclic group,
rd is C1-2Alkyl or C2-6An alkylamino group.
6. The compound according to claim 5, wherein,
R3selected from hydrogen, aldehyde groups, CH ═ NNHC (S) NH2CONHRa, COORb, CH ═ CHRc and CH ═ NRd, where,
ra is mono C2-6An alkylamino group, an L-phenylalanine residue, an L-tryptophan residue or an L-tyrosine residue,
rb is glucose, ribose or deoxyribose,
rc is 4-methoxyphenyl or 4-nitrophenyl,
rd is C2-4An alkylamino group.
7. The compound of claim 6 and salts thereof, wherein,
R3selected from hydrogen, CH ═ NNHC (S) NH2CONHRa and CH ═ CHRc, where,
ra is C6An alkylamino L-phenylalanine residue or an L-tyrosine residue,
rc represents 4-methoxyphenyl or 4-nitrophenyl.
8. The compound according to claim 1, wherein,
R7selected from hydrogen, n-butoxy, COCH2CONHRa and COCH2COORb of which，
Ra is an L-phenylalanine residue, an L-tryptophan residue or an L-tyrosine residue,
rb is glucose, ribose or deoxyribose.
9. The compound of claim 8, wherein R is7Is hydrogen or n-butoxy.
10. The compound of claim 1, wherein R is9Selected from hydrogen, n-butyl and phenylpropyl.
11. The compound of claim 10, wherein R is9Is n-butyl.
12. The compound of claim 10, wherein R is9Is phenylpropyl.
13. The compound according to claim 1, wherein,
R1is selected from hydrogen, pyridyl, aldehyde, carboxylic acid, carboxylic ester, carboxylic salt, CH ═ NNHC (S) NH2、
CONHRa, COORb, CH ═ CHRc and NHRd, where,
ra is C1-2Alkyl, mono C2-6An alkylamino group or an L-amino acid residue,
rb is glucose, xylose, ribose, deoxyribose or acyclic sugar,
rc is a phenyl group or a heterocyclic group,
rd is C1-2Alkyl or C2-6An alkylamino group;
R2is selected from hydrogen, benzyl, phenylpropyl, sulfonic acid group;
x is chlorine or bromine; or, R2And X are absent at the same time;
R3selected from hydrogen, aldehyde groups, CH ═ NNHC (S) NH2CONHRa, COORb, CH ═ CHRc and CH ═ NRd,
wherein,
ra is C1-2Alkyl, mono C2-6An alkylamino group or an L-amino acid residue,
rb is glucose, xylose, ribose, deoxyribose or acyclic sugar,
rc is a phenyl group or a heterocyclic group,
rd is C1-2Alkyl or C2-6An alkylamino group;
R7selected from hydrogen, n-butoxy, COCH2CONHRa and COCH2COORb, wherein,
ra is an L-phenylalanine residue, an L-tryptophan residue or an L-tyrosine residue,
rb is glucose, ribose or deoxyribose;
R9selected from hydrogen, n-butyl and phenylpropyl.
14. The compound according to claim 13, wherein,
R1selected from the group consisting of hydrogen, pyridyl, sodium carboxylate, (4 '-methoxy) styryl, (4' -nitro) styryl, aldehyde group, thiosemicarbazone group, CONHRa and NHRd, wherein,
ra is an L-tyrosine residue or an L-phenylalanine residue,
rd represents C2-4An alkylamino group;
R2selected from hydrogen, benzyl, phenylpropyl or sulfonic acid groups;
x is selected from chlorine or bromine; or, R2And X are absent at the same time;
R3selected from hydrogen, CH ═ NNHC (S) NH2CONHRa and CH ═ CHRc, where,
ra is an L-phenylalanine residue or an L-tyrosine residue,
rc is 4-methoxyphenyl or 4-nitrophenyl;
R7selected from hydrogen, n-butoxy, COCH2CONHRa and COCH2COORb, wherein,
ra is an L-phenylalanine residue, an L-tryptophan residue or an L-tyrosine residue;
rb is glucose, ribose or deoxyribose;
R9selected from hydrogen,N-butyl and phenylpropyl.
15. The compound according to claim 14, wherein,
R1selected from the group consisting of pyridyl, sodium carboxylate, (4 '-methoxy) styryl, (4' -nitro) styryl,
CH＝NNHC(S)NH2CONHRa or NHRd, wherein,
ra is an L-tyrosine residue or an L-phenylalanine residue,
rd is C2-4An alkylamino group;
R2selected from hydrogen and benzyl; x is selected from chlorine and bromine; or, R2And X are absent at the same time;
R3is hydrogen;
R7selected from hydrogen, n-butoxy, COCH2CONHRa and COCH2COORb, wherein,
ra is selected from the group consisting of an L-phenylalanine residue and an L-tyrosine residue;
rb is selected from glucose, ribose and deoxyribose;
R9selected from n-butyl and phenylpropyl.
16. A compound of formula I selected from:
7-hydroxy-9-ethyl-1-methyl-beta-carboline,
7-hydroxy-9-n-butyl-1-methyl-beta-carboline,
7-hydroxy-9-isobutyl-1-methyl-beta-carboline,
7-isobutoxy-9-ethyl-1-methyl-beta-carboline,
7-benzyloxy-9-ethyl-1-methyl-beta-carboline,
7-phenylpropyloxy-9-ethyl-1-methyl-beta-carboline,
7-isobutanyloxy-9-n-butyl-1-methyl-beta-carboline,
7- (3 ', 3 ', 3 ' -trifluoro-2-hydroxy) propaneoxy-9-n-butyl-1-methyl-beta-carboline,
7-benzyloxy-9-n-butyl-1-methyl-beta-carboline,
7-n-butoxy-9-isobutyl-1-methyl-beta-carboline,
7-n-decaalkoxy-9-isobutyl-1-methyl-beta-carboline,
7-phenylpropyloxy-9-isobutyl-1-methyl-beta-carboline,
7-isobutoxy-2-benzyl-9-ethyl-1-methyl-beta-carboline bromine salt,
7-benzyloxy-2-benzyl-9-ethyl-1-methyl-beta-carboline bromide,
7-phenylpropyloxy-2-benzyl-9-ethyl-1-methyl-beta-carboline bromide salt,
7-benzyloxy-2-benzyl-9-n-butyl-1-methyl-beta-carboline bromide,
7-isobutoxy-2-benzyl-9-n-butyl-1-methyl-beta-carboline bromine salt,
7-n-butoxy-2-benzyl-9-isobutyl-1-methyl-beta-carboline bromide salt,
7-n-decaalkoxy-2-benzyl-9-isobutyl-1-methyl-beta-carboline bromide,
7-phenylpropyloxy-2-benzyl-9-isobutyl-1-methyl-beta-carboline bromide salt,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-beta-carboline-3-carboxylic acid ethyl ester,
ethyl 1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl-beta-carboline-3-carboxylate,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl-beta-carboline-3-carboxylic acid,
n-hydroxyethyl-1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-N-butyl-beta-carboline-3-carboxamide,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-beta-carboline,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl-beta-carboline,
ethyl beta-carboline-1-carboxylate,
ethyl 9-n-butyl-beta-carboline-1-carboxylate,
9-n-butyl-beta-carboline-1-carboxylic acid,
3-hydroxymethyl-9-benzyl-beta-carboline,
3-hydroxymethyl-9-phenylpropyl-beta-carboline,
3-hydroxymethyl-9-n-butyl-1-methyl-beta-carboline,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-3-hydroxymethyl-9-n-butyl-beta-carboline,
3-aldehyde-9-benzyl-beta-carboline,
3-formyl-9-phenylpropyl-beta-carboline,
3-aldehyde-9-n-butyl-1-methyl-beta-carboline,
3-aldehyde-9- (4' -fluoro) benzyl-1-methyl-beta-carboline,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-3-aldehyde-9-n-butyl-beta-carboline,
9-benzyl-beta-carboline-3-aldehyde thiosemicarbazone,
9-phenylpropyl-beta-carboline-3-aldehyde thiosemicarbazone,
9-n-butyl-1-methyl-beta-carboline-3-aldehyde thiosemicarbazone,
1- (3 ', 4 ', 5 ' -trimethoxy) phenyl-9-n-butyl-beta-carboline-3-aldehyde thiosemicarbazone,
3-hydroxymethyl-9-phenylpropyl-2-benzyl-beta-carboline bromide,
3-aldehyde-9-phenylpropyl-2-benzyl-beta-carboline bromide,
3-aldehyde-9-phenylpropyl-1-methyl-beta-carboline sodium bisulfite addition salt,
1-aldehyde-9-phenylpropyl-beta-carboline,
9-phenylpropyl-beta-carboline-1-aldehyde thiosemicarbazone,
9-phenylpropyl-beta-carboline-1-aldehyde shrinkage methoxamine,
n- (4-beta-carboline-phenoxyacetyl) phenylalanine ethyl ester,
n- (9-N-butyl-beta-carboline-3-formyl) phenylalanine ethyl ester,
n- (9-N-butyl-beta-carboline-3-formyl) methionine ethyl ester,
n- (9-benzyl-beta-carboline-3-formyl) phenylalanine ethyl ester,
n- (9-phenylpropyl-beta-carboline-3-formyl) valine ethyl ester,
n- (9-phenylpropyl-beta-carboline-3-formyl) phenylalanine ethyl ester,
n- (9-phenylpropyl-beta-carboline-3-formyl) phenylalanine,
n- (2-benzyl-9-phenylpropyl-beta-carboline-3-formyl) phenylalanine ethyl ester bromide salt,
n- (beta-carboline-1-formyl) phenylalanine ethyl ester,
n- (beta-carboline-1-formyl) phenylalanine,
1-O- (9-n-butyl-beta-carboline-3-formyl) -2, 3, 4-tri-O-benzoyl-beta-D-pyran type ribose,
1-O- (9-phenylpropyl-beta-carboline-3-formyl) -2, 3, 4-tri-O-benzoyl-beta-D-pyran type ribose,
1-O- (9-n-butyl-beta-carboline-3-formyl) -2, 3, 4, 5-tetra-O-acetyl-beta-D-pyran glucose,
1-O- (9-phenylpropyl-beta-carboline-3-formyl) -2, 3, 4, 5-tetra-O-acetyl-beta-D-pyran glucose,
7-beta-D-glucopyranosyloxy-9-phenylpropyl-1-methyl-beta-carboline,
7-beta-D-pyran xyloxy-9-n-butyl-1-methyl-beta-carboline,
1- (4' -methoxy-styryl) -9-n-butyl-beta-carboline,
1- (4' -methoxy-styryl) -9-phenylpropyl-beta-carboline,
1- (4' -methoxy-styryl) -7-n-butoxy-9-phenylpropyl-beta-carboline,
1- (4' -nitro-styryl) -7-n-butoxy-9-phenylpropyl-beta-carboline,
1- (4' -methoxy-styryl) -2-benzyl-9-n-butyl-beta-carboline bromide salt,
1- (4' -methoxy-styryl) -9-phenylpropyl-2-benzyl-beta-carboline bromide salt,
1- (4' -methoxy-styryl) -7-n-butoxy-9-phenylpropyl-2-benzyl-beta-carboline bromide salt,
1- (4' -nitro-styryl) -7-n-butoxy-9-phenylpropyl-2-benzyl-beta-carboline bromide salt,
1- (3' -pyridyl) -9-n-butyl-beta-carboline,
1- (3' -pyridyl) -9-benzyl-beta-carboline,
1- (2' -aminoethyl) carbamoyl-9-phenylpropyl-beta-carboline,
1- (2' -amino) ethylamino-9-n-butyl-beta-carboline, and
1- (2' -amino) ethylamino-9-phenylpropyl-beta-carboline.
17. The use of a compound of formula I as claimed in any one of claims 1 to 16 for the manufacture of a medicament for the treatment of cancer.
18. A pharmaceutical composition comprising one or more compounds of formula I according to any one of claims 1 to 16 together with usual pharmaceutical excipients and/or adjuvants.
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