CN102977092A - Application of aromatic alkanoyl tetrahydro-beta-carboline and derivative thereof in treatment of cancer - Google Patents
Application of aromatic alkanoyl tetrahydro-beta-carboline and derivative thereof in treatment of cancer Download PDFInfo
- Publication number
- CN102977092A CN102977092A CN2012104390430A CN201210439043A CN102977092A CN 102977092 A CN102977092 A CN 102977092A CN 2012104390430 A CN2012104390430 A CN 2012104390430A CN 201210439043 A CN201210439043 A CN 201210439043A CN 102977092 A CN102977092 A CN 102977092A
- Authority
- CN
- China
- Prior art keywords
- group
- carboline
- base
- aromatic base
- tetrahydrochysene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
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- 231100001231 less toxic Toxicity 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical group OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- FQJPGBZNJWNVQO-UHFFFAOYSA-N methyl 3-hydrazinylbenzoate Chemical class COC(=O)C1=CC=CC(NN)=C1 FQJPGBZNJWNVQO-UHFFFAOYSA-N 0.000 description 1
- NLWBJPPMPLPZIE-UHFFFAOYSA-N methyl 4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C=C1 NLWBJPPMPLPZIE-UHFFFAOYSA-N 0.000 description 1
- PUVXAQCVNJUHKG-UHFFFAOYSA-N methyl 4-hydrazinylbenzoate Chemical class COC(=O)C1=CC=C(NN)C=C1 PUVXAQCVNJUHKG-UHFFFAOYSA-N 0.000 description 1
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- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一种由结构式(I)表示的芳香基烷酰基四氢-β-咔啉类化合物及相关类似物或其水合物或药学上可接受的盐，含有本发明化合物或其药物组合物在制备治疗各种恶性肿瘤以及肿瘤转移等疾病药物的用途。
The invention discloses an aryl alkanoyl tetrahydro-β-carboline compound represented by structural formula (I) and related analogs or hydrates or pharmaceutically acceptable salts thereof, which contain the compound of the invention or a pharmaceutical combination thereof The medicine is used in the preparation of medicines for treating various malignant tumors, tumor metastasis and other diseases.
Description
Technical field
The present invention relates to a kind ofly as shown in the formula compound and the related derivatives shown in the structure (I), and this compounds or the pharmaceutical composition that contains this compounds are as the purposes of the relative diseases such as the various malignant growths for the treatment of and metastases.
Background technology
Malignant tumour is one of major disease of facing mankind.Along with China's rapid economic development, lifestyle change, survival pressure improves, problem of an aging population aggravation and urbanization degree are constantly deepened, the generation of malignant tumour and development have become the significant obstacle that hinders the further raising of people's living standard, and give individual and social heavy economy and the mental burden brought.The whole world is died from malignant tumour person and be approximately 6,900,000 people every year, and new cases are about 8,700,000, and expecting the year two thousand thirty will have 1,200 ten thousand people to die from cancer, so the research and development of antitumor drug are in very crucial status always.But at present on the market antitumor drug major part is all for single drug target or without clear and definite target spot, and the not ideal enough and long-term prescription of effect easily causes chemical sproof generation.Tumour patient urgently wishes to find antitumous effect better, and has the medicine that better security reaches less toxic side effect, therefore, needs the antitumor drug for novel targets and many target spots of Development of Novel.
EGFR is one of Epidermal Growth Factor Receptor Family member, and the EGFR signal path is all being brought into play important regulating effect in the physiological processs such as the growth of cell, propagation, differentiation, apoptosis, vasculogenesis, invasion and metastasis of tumor.EGFR phosphorylation or other cause its active unusual result all might cause the generation of tumour, diabetes, immune deficiency and cardiovascular disorder.There are at present a plurality of medicines to treat the diseases such as tumour by targeting EGFR, such as antibody drugs such as Cetuximabs and for Buddhist nun's micromolecular medicine.TGF-signal β path all has vital role in the genesis of numerous diseases, can cause the fibrosis of malignant tumour, inflammation, liver and kidney behind its overactivity, and TGF-signal β path has become the popular target in the medicament research and development.Recently studies show that the height activation that also has TGF-signal β path in the diabetic mice pancreas islet with bar, and after this path is suppressed, will be conducive to the treatment of diabetes.In TGF-β cell signal path, after path is activated, can cause the phosphorylation of smad3, and then be activated.Smad3 after the activation can enter nucleus from tenuigenin, the smad3 of phosphorylation can participate in the many polygenic regulation and control in downstream in nucleus, so thereby the phosphorylation of managing to suppress smad3 may be significant for suppressing TGF-signal β path treatment diabetes.
The β-carboline compounds is the compound that a class contains the trypoline structure, and they are the alkaloids that separate out from Sapotaceae, Apocynaceae and streptomyces (Streptomyces) etc.According to the literature, natural origin or the synthetic micromolecular compound that contains β-carboline or tetrahydro-beta-carboline structure have many-sided biological activity, such as; anti-thrombosis activity; antimalarial active, neuroprotective etc. (J.Med.Chem.2010,3106-16).But the compound that contains this class formation has several obvious deficiencies usually, and at first, the compound molecule mechanism of action is clear and definite not, therefore the research of its pharmacological action just relatively is short of; In addition, the physico-chemical property that it is exactly compound that this compounds also has a defective is not ideal enough, and this has limited the patent medicine Journal of Sex Research of this compounds to a great extent.The tetrahydro-beta-carboline compounds has many-sided physiologically active equally, and has more favorably physico-chemical property than carboline.Therefore need creatively to carry out at the tetrahydro-beta-carboline compounds derivatize of guidance quality, form the novel tetrahydro-beta-carboline compound of a class, increase its quasi-medicated property, cause and to carry out follow-up medicinal preclinical study.Aromatic base alkyl acyl tetrahydro-beta-carboline and derivative thereof that the present invention proposes have satisfied this requirement, and other associated advantages is provided.
Summary of the invention
The present invention is by after introducing some chemical groups to the left-half of aromatic base alkyl acyl tetrahydro-beta-carboline; obtaining specific aromatic base alkyl acyl tetrahydro-beta-carboline analog derivative is proved to be growth and metastasis of tumours is all had very excellent result for the treatment of; by the relevant experimental verification of chip gene expression profile analysis and other, show that this compounds is probably as the antitumor drug candidate of many target spots (comprising Urogastron EGFR and transforming growth factor β receptor TGF β R etc.).In addition, after introducing portion was divided specific group, great change had occured in the physico-chemical property of compound, and water-soluble, pharmacokinetic property that comprises compound etc. has larger improvement.
First purpose of the present invention provide a kind of shown in following structural formula (I) tetrahydro-beta-carboline micromolecular organic compound or its hydrate or pharmacy acceptable salt, it has the structure shown in structural formula (I):
Wherein:
M is 0-8 CH
2
N is 0-3 CH
2
R
1Be the substituting group on the aromatic nucleus, comprise single replace and polysubstituted, independently be selected from one or more in the following groups: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, cycloalkyloxy, cyclammonium base, C
2-C
12Thiazolinyl, C
2-C
12Alkynyl, C
3-C
12Cycloalkyl, benzyl, alkyl-carbonyl, C
2-C
12Alkenyl carbonyl, C
3-C
12Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl;
R
2Be selected from arbitrarily in the following groups: hydrogen, alkyl, halogen, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkoxyl group, alkylamino radical, alkyl-carbonyl and aromatic base carbonyl, morpholine methyl, methylol;
R
3And R
4Substituting group is selected from arbitrarily one or more in the following groups: hydrogen, alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, amino, cyano group, nitro, halogen;
R
5Be the substituting group on the aromatic nucleus, independently be selected from respectively in the following groups one, two or more: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, substituted amido, cycloalkyloxy, cycloalkanes amido, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, alkyl-carbonyl, C
2-C
6Alkenyl carbonyl, C
3-C
6Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl;
R
6Substituting group is selected from arbitrarily in the following groups: hydrogen, alkyl, methylol, alkoxyl group, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkenyl group, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkylamino radical.
In the structural formula (I), when
During for the 5-membered aromatic ring, it is represented by following structural formula (II):
Wherein:
A, B and D select nitrogen, oxygen, sulphur or CR independently
5One of them group; Make
Keep aromaticity;
R
7Substituting group is selected from arbitrarily in the following groups: hydrogen, alkyl, methylol, alkoxyl group, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkenyl group, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkylamino radical.
In the structural formula (I), when
During for hexa-atomic aromatic nucleus, it is represented by following structural formula (III):
Wherein: E, F, G and H select nitrogen or CR independently
5One of them group; Make
Keep aromaticity.
In the structural formula (III), when
During for phenyl ring, it is represented by following structural formula (IV):
Wherein:
R
8, R
9, R
10And R
11Be the substituting group on the phenyl ring, independently be selected from respectively in the following groups: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, substituted amido, cycloalkyloxy, cycloalkanes amido, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, alkyl-carbonyl, C
2-C
6Alkenyl carbonyl, C
3-C
6Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl;
In the structural formula (III), when
During for phenyl ring, n is 1 CH
2, R
2, R
3And R
4When all being hydrogen, it is represented by following structural formula (V):
In the structural formula (III), when
During for phenyl ring, m, n are 1 CH
2, R
2, R
3And R
4When all being hydrogen, its by
Following structural formula (VI) expression:
In the structural formula (III), when
During for phenyl ring, m, n section is 1 CH
2, R
2, R
3And R
4When section is hydrogen, work as R
8,
R
9, R
10And R
11When wherein any three groups were hydrogen, it was represented by following structural formula (VII):
Wherein X is methylene radical; Acyl group; Amino; Oxygen; Sulphur; Alkylsulfonyl;
R
12Be selected from arbitrarily in the following groups: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, substituted amido, cycloalkyloxy, cycloalkanes amido, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, alkyl-carbonyl, C
2-C
6Alkenyl carbonyl, C
3-C
6Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl; Formyl morpholine, acyl ethyl morpholine, acyl propyl group morpholine; Piperazinyl, acyl methylpiperazine, acyl ethyl-methyl piperazine, acyl propyl group methylpiperazine, methylpiperazine base; Amino-acid residue (glycine, Serine, L-Ala, Threonine, α-amino-isovaleric acid, Isoleucine, leucine, tyrosine, phenylalanine, Histidine, proline(Pro), aspartic acid, methionine(Met), L-glutamic acid, tryptophane, Methionin, halfcystine, arginine, glutamine, l-asparagine), straight chain amino acid, branched-chain amino acid, erythrose, threose, lyxose, allose, altrose, gulose, idose, talose, ribose, ribodesose, wood sugar, I sugar, glucose, seminose, semi-lactosi, fructose, aminosugar, oligosaccharides.
In the structural formula (III), when
During for phenyl ring, m, n are 1 CH
2, R
2, R
3And R
4When section is hydrogen, work as R
8, R
9, R
10And R
11When wherein any three groups were hydrogen, it was represented by following structural formula (VII): m, n are 1 CH
2, R
2, R
3And R
4When section is hydrogen, work as R
8, R
9, R
10And R
11When wherein any two groups were hydrogen, it was represented by following structural formula (VIII):
Wherein X and Y are respectively methylene radical; Acyl group; Amino; Oxygen; Sulphur; Alkylsulfonyl;
R
12And R
13Be selected from arbitrarily in the following groups: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, substituted amido, cycloalkyloxy, cycloalkanes amido, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, alkyl-carbonyl, C
2-C
6Alkenyl carbonyl, C
3-C
6Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl; Formyl morpholine, acyl ethyl morpholine, acyl propyl group morpholine; Piperazinyl, acyl methylpiperazine, acyl ethyl-methyl piperazine, acyl propyl group methylpiperazine, methylpiperazine base; Amino-acid residue (glycine, Serine, L-Ala, Threonine, α-amino-isovaleric acid, Isoleucine, leucine, tyrosine, phenylalanine, Histidine, proline(Pro), aspartic acid, methionine(Met), L-glutamic acid, tryptophane, Methionin, halfcystine, arginine, glutamine, l-asparagine), straight chain amino acid, branched-chain amino acid, erythrose, threose, lyxose, allose, altrose, gulose, idose, talose, ribose, ribodesose, wood sugar, I sugar, glucose, seminose, semi-lactosi, fructose, aminosugar, oligosaccharides.
The present invention also provides small molecules organic compound, hydrate or the pharmacy acceptable salt of aforementioned arbitrary aromatic base alkyloyl tetrahydro-beta-carboline class or derivatives thereof.Wherein said acceptable salt comprises hydrochlorate and alkali salt, is applicable to contact people or animal tissues and can not produces the group of excessive toxicity or carinogenicity, selects especially preferentially that those are non-stimulated, the group of anaphylaxis or other complication.The alkalescence or the organic salt that comprise acidic residues (such as carboxylic acid), and mineral acid and the organic acid salt of alkaline residue (such as amine).The negatively charged ion that can be used for salify comprises but does not limit: the salt acid group, the Hydrogen bromide root, sulfate radical, phosphate radical, acetate moiety, tartrate anion, salicylate, citrate, methanesulfonate, the tosic acid root, lactate, the acetone acid group, maleate, amber acid radical, the Vitamin C acid group, benzoate anion, bicarbonate radical, the ethylenediamine tetraacetic acid (EDTA) root, formate, glutamate, the ethanol acid group, the hydroxymaleic acid root, malate, the almond acid group, the thionamic acid root, sulfonate radical, chlorion, bromide anion etc.Similarly, the positively charged ion that can be used for salify comprises but does not limit: ammonium, quadrol, choline, diethanolamine, PROCAINE HCL, PHARMA GRADE and sodium Metal 99.5, potassium, magnesium, aluminium, zinc and lithium etc.
The present invention can come mark aromatic base alkyloyl provided by the invention tetrahydro-beta-carboline compounds and related derivatives with certification marks such as radioactivity, fluorophor or vitamin Hs in some aspects.
Among the present invention, aromatic base alkyloyl tetrahydro-beta-carboline micromolecular organic compound or its hydrate or pharmacy acceptable salt include but not limited to following compounds:
N-phenylacetyl-(6-trifluoromethyl)-1,3,4,9-tetrahydrochysene-1H-β-carboline
N-phenylacetyl-(6-trifluoromethoxy)-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(2-morpholine ethyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(4-methylpiperazine) carbonyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(2-(dimethylamino) ethyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(3-(dimethylamino) propyl group) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(4-morpholinyl phenyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(4-dimethylamino phenyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(4-amino-sulfonyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(N, N-two (2-hydroxyethyl)) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(2-(2-hydroxyl-oxethyl) ethyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(Serine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(aspartic acid carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(L-Ala carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(phenylalanine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(L-glutamic acid carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(proline(Pro) carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(glycine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(tyrosine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(Histidine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-cyano group-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-nitro-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-benzyloxy-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-methoxycarbonyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-hydroxy-n-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-carboxy-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-methyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-amino-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline
7-amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(2-(N-morpholinyl)) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(2-(4-methylpiperazine base)) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline 5-(2-is amino) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(2-Threonine base) amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(2-proline(Pro) base) amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(4-bromobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-methyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
8-fluoro-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(2-is amino) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
N-phenylacetyl-6,8-two fluoro-1,3,4,9-tetrahydrochysene-1H-β-carboline
N-phenylacetyl-6,8-two fluoro-9-be to bromobenzyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-benzyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(4-luorobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(4-methyl-formiate benzyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(4-carboxyl benzyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(methoxycarbonyl methyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(carbonyl methyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(4-(morpholinyl) carbonyl methyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-methoxycarbonyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(α-amino-isovaleric acid is amino)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(L-Ala is amino)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(3-is amino) propionyl amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline.
The invention provides a kind of pharmaceutical composition, wherein contain one or more aromatic base alkyloyl tetrahydro-beta-carboline micromolecular organic compound of the present invention, hydrate or pharmacy acceptable salt, and pharmaceutically acceptable carrier.
Wherein, in a specific embodiments, described composition is formulated into injectable fluid, aerosol, emulsifiable paste, gelifying agent, pill, capsule, syrup, transdermal patch or vehicle.
The invention provides the prodrug of the described aromatic base alkyloyl of formula (I) tetrahydro-beta-carboline micromolecular organic compound and related derivatives." prodrug " refers to that compound itself can not exclusively satisfy the structural requirement of compound that this paper provides but change the compound produce formula that this paper provides in by body after to patient's administration.The example of prodrug includes but not limited to ester, for example can carry out modification by the functional group that exists, and is produced described parent compound after the fracture thereby modify in vivo.
The compounds of this invention also comprises dimer and the polymer compounds that compound shown in the formula (I) is connected with various mode of connection.
The invention provides aromatic base alkyloyl tetrahydro-beta-carboline micromolecular organic compound and related derivatives, hydrate or the pharmacy acceptable salt purposes in suppressing the growth and metastasis of tumours medicine.
In one embodiment, described tumour cell includes but not limited to head and neck cancer cell, thyroid carcinoma cell, esophageal cancer cell, nasopharyngeal carcinoma cell, liver cancer cell, lung carcinoma cell, prostate cancer cell, skin cancer cell, osteocarcinoma cell, cervical cancer cell, colon-cancer cell, pancreatic cancer cell, breast cancer cell, leukemia cell, ovarian cancer cell, stomach cancer cell, transitional cell bladder carcinoma cell line, kidney cancer cell, skin cancer cell, cancer cell of oral cavity, malignant lymphatic oncocyte etc.
The present invention also provides aromatic base alkyloyl tetrahydro-beta-carboline compounds and the application of related derivatives in the medicine of preparation treatment malignant tumour; Wherein, described malignant tumour comprises head and neck cancer, thyroid carcinoma, the esophageal carcinoma, nasopharyngeal carcinoma, liver cancer, lung cancer, prostate cancer, skin carcinoma, osteocarcinoma, cervical cancer, intestinal cancer, carcinoma of the pancreas, mammary cancer, leukemia, ovarian cancer, cancer of the stomach, bladder cancer, kidney, skin carcinoma, oral carcinoma, malignant lymphoma.
The present invention also provides aromatic base alkyloyl tetrahydro-beta-carboline compounds and related derivatives or its hydrate or the application of pharmacy acceptable salt in the medicine of preparation treatment Malignant tumor of bonal metastasis and recurrence; Wherein, described malignant tumour comprises head and neck cancer, thyroid carcinoma, the esophageal carcinoma, nasopharyngeal carcinoma, liver cancer, lung cancer, prostate cancer, skin carcinoma, osteocarcinoma, cervical cancer, intestinal cancer, carcinoma of the pancreas, mammary cancer, leukemia, ovarian cancer, cancer of the stomach, bladder cancer, kidney, skin carcinoma, oral carcinoma, malignant lymphoma.
The present invention also provides aromatic base alkyloyl tetrahydro-beta-carboline compounds and related derivatives or its hydrate or the application of pharmacy acceptable salt in preparation antineoplaston medicine, and described medicine is used for bringing out the antineoplaston after acquired resistance causes the chemotherapy failure.
The present invention also provides aromatic base alkyloyl tetrahydro-beta-carboline compounds and related derivatives or its hydrate or the application of pharmacy acceptable salt in the molten bone bone injury medicine of preparation treatment.
The present invention also provides the application in the medicine of the lung failure that preparation treatment tumour causes of aromatic base alkyloyl tetrahydro-beta-carboline micromolecular organic compound or its hydrate or pharmacy acceptable salt.
Medicine of the present invention uses separately or unites use with other drug.
Description of drawings
Figure 1 shows that the result of the inhibiting rate (%) that the compounds of this invention is bred Human Prostate Cancer Cells PC-3 under 10 micromoles per liter concentration.
Figure 2 shows that the result of the inhibiting rate (%) that the compounds of this invention is bred human lung carcinoma cell H1299 when different concns.
Figure 3 shows that the result of the inhibiting rate (%) that the compounds of this invention moves Human Prostate Cancer Cells PC-3 under 10 micromoles per liter concentration.
Figure 4 shows that the compounds of this invention to the as a result figure of human lung cancer cell A549's clonality impact, wherein, 4 culture dish from left to right drug level are respectively 0,1,5,10 μ mol/L.
Figure 5 shows that the compounds of this invention is to the inhibiting as a result figure of lung cancer in nude mice growth.Wherein, Fig. 5 A is the administration the 7th, 14 of taking by the living animal imaging system, after 21 and the 28th days to the result for the treatment of photo of mouse nonsmall-cell lung cancer, dash area represents fluorescent signal among the figure, shows that this zone has tumour cell to assemble, and cell aggregation heighten degree from outside to inside; Fig. 5 B is the graph of a relation of gross tumor volume and administration fate, and Fig. 5 C is the tumour body weight change of administration group and control group mice.
Figure 6 shows that inhibition that the compounds of this invention shifts the mammary cancer lung and on the as a result figure of the impact of mouse survival rate.Wherein, the administration the 7th of taking by the living animal imaging system of the compounds of this invention of various dose, the result for the treatment of photo that after 14 and the 21st days mouse breast cancer lung is shifted among Fig. 6 A, shade represents fluorescent signal among the figure, show that this zone has tumour cell to assemble, and cell aggregation heighten degree from outside to inside; Fig. 6 B calculates the amount that the mouse breast cancer lung shifts by the living animal imaging system, and Fig. 6 C is the variation of administration Integral animal experiment model small mouse survival rate after 20 days.
Embodiment
In conjunction with following specific embodiments and the drawings, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Under the spirit and scope that do not deviate from inventive concept, variation and advantage that those skilled in the art can expect all are included in the present invention, and take appending claims as protection domain.
1H-NMR measures with Bruker300 or Bruker400 type instrument; MS measures with VG ZAB-HS or VG-7070 type instrument, is the ESI method except indicating; All solvents all pass through re-distillation before use, and employed anhydrous solvent all is to obtain by the standard method drying treatment; Except explanation, it all is to carry out under argon shield and follow the tracks of with TLC that institute responds, during aftertreatment all through saturated common salt washing and anhydrous magnesium sulfate drying process; The purifying of product all uses the column chromatography of silica gel (200-300 order) except explanation; Employed silica gel comprises 200-300 order and GF
254Be Haiyang Chemical Plant, Qingdao or the production of the rich silica gel company of Yantai edge.
Embodiment one: the preparation of each compound
Embodiment 1-1, N-phenylacetyl-(6-trifluoromethyl)-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC001) synthetic
Get 4-trifluoromethyl phenyl hydrazine hydrochloride (425mg, 2mmol) in 14mL alcohol and water (volume ratio is 5/1), at room temperature slowly drip 4-chlorobutyraldehyde dimethyl acetal (367mg, 2.2mmol), then heated up cocurrent flow 5-18 hour.Complete, most of solvent is removed in decompression, then pH is adjusted to 12, uses ethyl acetate extraction three times, merges organic phase, uses anhydrous sodium sulfate drying, gets intermediate 5-trifluoromethyl tryptamines (crude product 464mg) after the underpressure distillation desolventizing.
5-trifluoromethyl tryptamines (464mg, 2.0mmol) is dissolved in the 3mL Glacial acetic acid, drips 37% formaldehyde solution (45 μ L, 0.60mmol) under nitrogen protection, finish, reaction is spent the night.Remove most of acetic acid under reduced pressure, pH is adjusted to 12, ethyl acetate extraction, anhydrous sodium sulfate drying removes solvent under reduced pressure, gets intermediate 6-Trifluoromethyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (150mg, productive rate 31%) behind the column chromatography purification.
Get toluylic acid (57mg, 0.42mmol) be dissolved among the dry DMF (1mL), at 0 ℃ of lower EDC (105mg, 0.55mmol) and HOBt (62mg, 0.46mmol) of adding, ice bath stirred 10 minutes, add compound 6-Trifluoromethyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (63mg, 0.32mmol).Complete, remove ice bath, room temperature reaction 3 hours, column chromatography purification gets N-phenylacetyl-(6-trifluoromethyl)-1,3,4 after the conventional processing, 9-tetrahydrochysene-1H-β-carboline (62mg, productive rate 66%).
1H?NMR(300MHz，DMSO-d
6)：
1H?NMR(300MHz，DMSO-d6)：δ11.37(br?s，1H)，7.77(d，J＝9.3Hz，1H)，7.49(d，J＝8.4Hz，1H)，7.32-7.24(m，6H)，4.74(s，2H)，3.87-3.84(m，4H)，2.73-2.66(m，2H).
The preparation of the compounds of NTC002-52 carboline shown in embodiment 2-52, the table 1 (detailed process sees below the literary composition reference)
Embodiment two: the compounds of this invention reaches the inhibition that tumor cell clone is formed ability to the restraining effect of the propagation such as human lung carcinoma cell, prostate cancer cell, breast cancer cell and colon cancer cell, migration under doses
(1), the cultivation of cell
Used cell such as head and neck cancer cell, thyroid carcinoma cell, esophageal cancer cell, nasopharyngeal carcinoma cell, liver cancer cell, lung carcinoma cell, prostate cancer cell, skin cancer cell, osteocarcinoma cell, cervical cancer cell, colon-cancer cell, pancreatic cancer cell, breast cancer cell, leukemia cell, ovarian cancer cell, stomach cancer cell, transitional cell bladder carcinoma cell line, kidney cancer cell, skin cancer cell, cancer cell of oral cavity, malignant lymphatic oncocyte etc. are all available from Chinese Academy of Sciences's Shanghai cell bank in this experiment, adherent culture is at 37 ℃ of constant incubators (humidity 95%, CO
25%) in, substratum is that DMEM high glucose medium (Gibco) contains 10% foetal calf serum (Front).
(2), SRB (sulphonyl rhodamine) method is measured cell proliferation
(1) the PC-3 cell is with 5 * 10
3/ hole density is seeded in the 96 orifice plate culture plates, overnight incubation.
(2) add successively the different concns compound, make its final concentration be respectively 1 μ M, 2.5 μ M, 5 μ M, 10 μ M, 25 μ M, 50 μ M, control group add equivalent DMSO (establishing 6 multiple holes for every group), continue to cultivate 24 hours.
(3) every Kong Jialeng TCA (trichoroacetic acid(TCA), 10%, w/V) fixing, hatch 30min for 4 ℃.
(4) the flowing water flushing is 5 times, and is air-dry.
(5) every hole add 50 μ L SRB dye liquors (4%, w/V), incubated at room 10min dyeing.
(6) with the dye liquor sucking-off, every hole adds 1% acetic acid, 100 μ L to be washed 5 times, removes not combination dye.
(7) after air-dry, every hole adds 100 μ L100mM Tris solution, the SRB dyestuff of concussion dissolving combination.96 orifice plates are placed microplate reader (SPECTRA MAX190), and 515nm measures the OD value.The impact of statistical study medicine on cell proliferation level.The result as shown in Figure 1, wherein: the compounds of this invention has very significantly inhibition to the propagation of human prostate cell H1299 when 10.0 μ mol/L, see Fig. 1.Majority of compounds has inhibition to prostate cancer cell propagation, in the cited compound of part, compound inhibiting rates to prostate cancer cell PC-3 proliferation activity under 10.0 μ mol/L concentration such as NTC001, NTC002, NTC005, NTC007, NTC008, NTC011, NTC015, NTC021, NTC026, NTC028, NTC033, NTC036, NTC038, NTC042, NTC045, NTC049 and NTC052 reach 60%
More than.
The compounds of this invention also has significant inhibition to human lung carcinoma cell, sees Fig. 2.From similar experiment, can find, the compounds of this invention also has the inhibition of highly significant to the propagation of Non-small cell lung carcinoma cell H1299, and the result shows that compound N TC002, NTC008, NTC028, NTC036 and NTC038 etc. suppress very remarkable to the propagation of H1299 cell.
In addition, the compounds of this invention also has similar implementation result in the inhibition to proliferation activities such as neck cancer cells, thyroid carcinoma cell, esophageal cancer cell, nasopharyngeal carcinoma cell, liver cancer cell, lung carcinoma cell, skin cancer cell, osteocarcinoma cell, cervical cancer cell, colon-cancer cell, pancreatic cancer cell, breast cancer cell, leukemia cell, ovarian cancer cell, stomach cancer cell, transitional cell bladder carcinoma cell line, kidney cancer cell, skin cancer cell, cancer cell of oral cavity, malignant lymphatic oncocytes.
(3), the compounds of this invention is to the restraining effect of tumor cell migration.
Cell can be along cultivating the plane to the less componental movement of cell when vitro culture.Utilize this phenomenon, artificial " drawing " goes out one " scar " in the culture hole that covers with cell, and then the cell of " scar " both sides can finally be covered with this zone again to " scar " regional movement, i.e. the effect of so-called " scar healing ".According to cell quantity and " scar healing " degree of moving to " scar " zone, can judge the motor capacity of cell.
Prostate cancer cell PC-3 is seeded to 12 orifice plates, and cell is at 37 ℃ of 5%CO
2Cultivate 24h in the incubator, grow to 100% to cell and expire.Change serum free medium, continue to cultivate 12h.In covering with the culture hole of cell, along the vertical cut of culture hole diameter, with PBS wash cell twice behind the cut with the sterilization tip of 10 μ l, the cell that will float is washed away, adds the 1.0ml perfect medium in every hole.In the cell cultures hole, add the different concns medicine respectively, culture plate is put into CO
2Incubator, 37 ℃ are continued cellar culture 24h.Microscopically observation of cell want the to rule situation of componental movement is taken pictures.The migration of statistical study various dose medicine group enters the cell quantity of scribe area, determines the impact of medicine on cell migration ability.
Part of test results as shown in Figure 3, Fig. 3 A is the tumor cell migration design sketch, Fig. 3 B is the migration effect statistics, in 4 kinds of compounds that the cell cut migration experimental model of prostate cancer cell PC-3 is tested, migration has very significantly inhibition to PC-3 when 10 μ M concentration for compound N TC028, NTC038, illustrates that this compounds has obviously suppressed the migration of this tumour cell in this migration models.
In addition, the compounds of this invention also has similar implementation result in the inhibition to migratory activities such as neck cancer cells, thyroid carcinoma cell, esophageal cancer cell, nasopharyngeal carcinoma cell, liver cancer cell, lung carcinoma cell, skin cancer cell, osteocarcinoma cell, cervical cancer cell, colon-cancer cell, pancreatic cancer cell, breast cancer cell, leukemia cell, ovarian cancer cell, stomach cancer cell, transitional cell bladder carcinoma cell line, kidney cancer cell, skin cancer cell, cancer cell of oral cavity, malignant lymphatic oncocytes.
(4), clone forming method (colony formation): the propagation that detects the external formation clone of tumour cell with become the knurl ability
Tumour cell can form macroscopic solid tumor by autotomy propagation is final in vivo, in vitro models, can reflect that it generates the power of solid tumor ability in vivo according to the power of the clonality of tumour cell.
With tumour cell with 1x10
3The density of individual/ware is inoculated in the 35mm culture dish, divides into groups behind the cultivation 24h, adds respectively the testing compound of different concns, makes its final concentration be respectively 1.0 μ mol/L, 5.0 μ mol/L, and 10.0 μ mol/L, control group adds the DMSO of equivalent.Continue to cultivate, changed a subculture and respective concentration compound in per 3 days.After 21 days, discard substratum, PBS washes 3 times, and 4% Paraformaldehyde 96 room temperature is 10min fixedly, 1% violet staining 10min, tap water flushing.Microscopically is taken pictures, and calculates cell clonal formation quantity.Experimental result as shown in Figure 4.Wherein, compound N TC003, NTC015, NTC023, NTC029, NTC035 and NTC047 have obvious restraining effect to non-small cell lung cancer cell (such as the A549 cell) clonality, can find out from statistic data, compound has inhibition about 20% to clone's ability of this strain lung carcinoma cell under 1.0 μ mol/L mass actions, the basic clone who suppresses this lung carcinoma cell forms under 5.0 μ mol/L concentration, and the clone who suppresses this lung carcinoma cell under 10.0 μ mol/L concentration fully forms, and illustrates that from the another one angle this compounds has the effect of very strong inhibition tumor growth.
Embodiment three: the compounds of this invention is to the therapeutic action of nonsmall-cell lung cancer
This experimental simulation clinically nonsmall-cell lung cancer growth and the morbidity and the therapeutic process that shift.4-6 week nude mice is at 5 * 104 mouse non-small cell lung cancer cells of lung's in-situ injection PC-9.After the lotus knurl 7 days, mouse is equally divided into 4 groups at random, is respectively control group, 1.0mg/kg/day dosed administration group, 2.5mg/kg/day dosed administration group and 5.0mg/kg/day dosed administration group.The administration group is respectively according to corresponding dosage intraperitoneal injection of drugs, and control group is injected equivalent solvent (DMSO).Continue medication to 21 days, adopt mouse living imaging technology (IVIS), observe tumour cell to the mouse lung transfer case.
The result as shown in Figure 5, Fig. 5 be behind medication 21 days (the 28th day) to the result for the treatment of figure of mouse nonsmall-cell lung cancer (by the living animal imaging system picture of taking pictures, since in the tumour cell with fluorescence, can utilize fluorescence to determine the position of tumour cell and what, the darker representative fluorescent signal of shadow color is stronger, show that this zone has tumour cell to assemble, and cell aggregation heighten degree from outside to inside.Result such as Fig. 5 A and 5B, compound N TC002, the NTC008, NTC015, NTC023, NTC032, NTC035 and the NTC039 that are presented at 1.0mg/kg/day dosage can suppress the growth of lung cancer, 2.5mg/kg/day the compound of dosage can significantly suppress the growth of lung cancer, the compound of 5.0mg/kg/day dosage then suppresses the growth of lung cancer substantially.Can find that from Fig. 5 C four groups of Mouse Weights no significant difference of comparing shows that from the another side this type of mouse has stronger tolerance to this compounds, toxicity of compound is less.
Embodiment four: the therapeutic action that the compounds of this invention shifts the mammary cancer lung at nude mice tail vein injection model
In the 4-6 female Bal b/c mouse left ventricle injection 5 * 10 in age in week
4Individual/breast cancer cell MDA-MB-231 only, be equally divided into three groups by Mouse Weight, be respectively control group, 1.0mg/kg/day dosed administration group and 5.0mg/kg/day dosed administration group.Calculate the transfer quantity of breast cancer cell by living animal fluorescence imaging system (IVIS) routine observation, shift the impact of process with clear and definite this compound for the mammary cancer lung, and calculate the mouse survival rate.The result as shown in Figure 6, wherein:
(1) Fig. 6 A is shown as the result for the treatment of figure of medication mouse breast cancer lung metastasis model after 20 days (by the living animal imaging system picture of taking pictures, since in the tumour cell with fluorescence, can utilize fluorescence to determine the position of tumour cell and what, shade represents this zone among the figure has tumour cell to assemble, and tumour cell assembles what the shade of shade represents, and cell aggregation heighten degree from outside to inside.Because this breast cancer model is often transferred to lung, so visible control group mice lung has a large amount of tumour cells to shift.But under 1.0mg/kg/ days dosage of compound (NTC001, NTC005, NTC008, NTC015, NTC023, NTC032, NTC037, NTC043 and NTC049), lung only has a small amount of tumour cell to assemble, and under 5.0mg/kg/ days dosage, substantially can't see the imaging that tumour cell is transferred to lung.
What (2) Fig. 6 B showed is Fig. 6 A result's statistical graph, compares with control group, and the distribution of mouse metastatic lesion has reduced respectively more than 60% and 90%, as shown in the figure, illustrates that this compounds has obvious restraining effect to the lung transfer of mammary cancer.
(3) by Fig. 6 C as can be known, to the separate groups of mice administration after 20 days, control group mice substantially all can't be survived, and administration group (compound N TC001, NTC005, NTC008, NTC015, NTC023, NTC032, NTC037, NTC043 and NTC049) mouse mouse survival rate under the dosage of 1mg/kg/day and 5mg/kg/day is increased to respectively 50% and 80%, and obvious compound has the castering action of highly significant to the mouse survival rate.
Reference example 2-52
Embodiment 1-2, N-phenylacetyl-(6-trifluoromethoxy)-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC002) synthetic
Adopt the similar method with preparation compound N TC001, the 4-trifluoromethyl phenyl hydrazine is replaced as 4-trifluoromethoxy phenylhydrazine, finally by getting compound N TC002, productive rate 16% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.17 (br s, 1H), 7.39-7.32 (m, 3H), 7.29-7.24 (m, 4H), 7.00 (d, J=8.4Hz, 1H), 4.72 (s, 2H), 3.86-3.82 (m, 4H), 2.88-2.61 (m, 2H)..
Synthesizing of embodiment 1-3,6-(2-morpholine ethyl) aminocarboxyl-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC003)
Adopt the similar method with preparation compound N TC001; the 4-trifluoromethyl phenyl hydrazine is replaced as 4-hydrazino-benzoic acid methyl esters; get intermediate 6-(methoxycarbonyl)-N-phenylacetyl-1; 3,4,9-tetrahydrochysene-1H-β-carboline; then through basic hydrolysis; again with the coupling of 2-morpholine ethylamine, finally by getting compound N TC003, productive rate %:78% behind the column chromatography purification.
1H?NMR(300MHz，DMSO-d
6)：δ11.12(br?s，1H)，8.24-8.22(m，1H)，7.95(d，J＝16.2Hz，1H)，7.59-7.56(m，1H)，7.33-7.24(m，6H)，4.71(s，2H)，3.87-3.82(m，4H)，3.57(t，J＝4.5Hz，4H)，3.42-3.33(m，2H)，2.73-2.72(m，2H)，2.51-2.50(m，2H)，2.44-2.43(m，4H)。
Synthesizing of embodiment 1-4,6-(4-methylpiperazine) carbonyl-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC004)
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as the 4-methylpiperazine, finally by getting compound N TC004, productive rate 81% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.11 (br s, 1H), 7.45-7.42 (m, 1H), (7.34-7.23 m, 6H), 7.10-7.05 (m, 1H), (4.71 s, 2H), 3.86-3.82 (m, 4H), 3.51-3.45 (m, 4H), (2.71-2.61 m, 2H), 2.31-2.30 (m, 4H), 2.19 (s, 3H).
Synthesizing of embodiment 1-5,6-(2-(dimethylamino) ethyl) aminocarboxyl-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC005)
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as 2-(dimethylamino) ethylamine, finally by getting compound N TC005, productive rate: 87% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.12 (brs, 1H), 8.21 (s, 1H), (7.99-7.94 m, 1H), 7.58 (d, J=8.1Hz, 1H), 7.33-7.24 (m, 6H), 4.72 (s, 2H), 3.87-3.85 (m, 4H), (2.73-2.62 m, 2H), 2.50-2.45 (m, 4H), 2.21 (s, 6H).
Synthesizing of embodiment 1-6,6-(3-(dimethylamino) propyl group) aminocarboxyl-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC006)
Adopt the similar method with preparation compound N TC005,2-(dimethylamino) ethylamine is replaced as 3-(dimethylamino) propyl group amine, finally by getting compound N TC006, productive rate: 84% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.12 (br s, 1H), 8.36 (s, 1H), 7.97-7.92 (m, 1H), 7.58 (d, J=8.4Hz, 1H), 7.33-7.24 (m, 6H), 4.72 (s, 2H), 3.87-3.85 (m, 4H), (3.29 t, J=6.3Hz, 2H), 2.72-2.61 (m, 2H), 2.27 (t, J=6.9Hz, 2H), (2.14 s, 6H), 1.68-1.64 (m, 2H).
Synthesizing of embodiment 1-7,6-(4-morpholinyl phenyl) aminocarboxyl-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC007)
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as the 4-morpholinyl phenylamine, finally by getting compound N TC007, productive rate: 65% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.18 (br s, 1H), 9.90 (br s, 1H), (8.13-8.07 m, 1H), 7.71-7.63 (m, 3H), (7.40-7.25 m, 6H), 6.93 (d, J=8.1Hz, 2H), 4.74 (s, 2H), 3.88-3.86 (m, 4H), 3.74 (s, 4H), 3.07 (s, 4H), 2.77-2.66 (m, 2H).
Synthesizing of embodiment 1-8,6-(4-dimethylamino phenyl) aminocarboxyl-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC007)
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as the 4-dimethylamino-aniline, finally by getting compound N TC008, productive rate: 63% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.16 (br s, 1H), 9.82 (br s, 1H), 8.13-8.08 (m, 1H), 7.70 (d, J=8.4Hz, 1H), (7.58 d, J=7.5Hz, 2H), 7.39-7.25 (m, 6H), 6.72 (d, J=9.0Hz, 2H), (4.74 s, 2H), 3.88-3.86 (m, 4H), (2.86 s, 6H), 2.76-2.65 (m, 2H).
Synthesizing of embodiment 1-9,6-(4-amino-sulfonyl) aminocarboxyl-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC007)
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as sulfanilamide (SN), finally by getting compound N TC009, productive rate: 63% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 13.63 (br s, 1H), 12.38 (br s, 1H), 8.20-7.93 (m, 2H), (7.74-7.67 m, 2H), 7.61-7.52 (m, 1H), 7.44-7.24 (m, 7H), (4.72 s, 2H), 3.88-3.86 (m, 4H), 2.73-2.65 (m, 2H).
Synthesizing of embodiment 1-10,6-(N, N-two (2-hydroxyethyl)) aminocarboxyl-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC010)
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as diethanolamine, finally by getting compound N TC010, productive rate: 60% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.04 (br s, 1H), 7.46-7.42 (m, 1H), 7.32-7.24 (m, 6H), (7.08 d, J=7.8Hz, 1H), 4.71 (s, 4H), 3.86-3.84 (m, 4H), 3.50-3.45 (m, 8H), 2.68-2.61 (m, 2H).
Synthesizing of embodiment 1-11,6-(2-(2-hydroxyl-oxethyl) ethyl) aminocarboxyl-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC011)
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as 2-(2-amino ethoxy) ethanol, finally by getting compound N TC011, productive rate 63% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.11 (br s, 1H), 8.30 (br s, 1H), (7.80-7.95 m, 1H), 7.69-7.58 (m, 1H), (7.33-7.23 m, 6H), 4.72 (s, 2H), (4.60 s, 1H), 3.87 (s, 4H), (3.54-3.52 m, 4H), 3.46-3.45 (m, 4H), 2.72-2.62 (m, 2H).
Synthesizing of embodiment 1-12,6-(Serine carbonyl)-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC012)
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as Serine, finally by getting compound N TC012, productive rate: 45% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 12.55 (br s, 1H), 11.15 (br s, 1H), (8.17 d, J=5.7Hz, 1H), 8.06-8.01 (m, 1H), 7.63 (d, J=7.5Hz, 1H), (7.36-7.24 m, 5H), 4.72 (s, 2H), (4.49 s, 1H), 3.87 (s, 4H), (3.81 s, 2H), 2.74-2.63 (m, 2H).
Synthesizing of embodiment 1-13,6-(aspartic acid carbonyl)-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC013)
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as L-Aspartic acid, finally by getting compound N TC013, productive rate: 41% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 12.57 (br s, 2H), 11.15 (br s, 1H), (8.53 d, J=5.7Hz, 1H), 8.02-7.97 (m, 1H), 7.60 (d, J=7.8Hz, 1H), (7.35-7.24 m, 5H), 4.79-4.72 (m, 3H), (3.87 s, 4H), 2.89-2.82 (m, 1H), 2.75-2.63 (m, 3H).
Embodiment 1-14,6-(L-Ala carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC014) synthetic
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as ALANINE, finally by getting compound N TC014, productive rate 57% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.15 (s, 1H), 8.34 (d, J=5.1Hz, 1H), 8.05-7.99 (m, 1H), 7.62 (d, J=8.1Hz, 1H), 7.35-7.24 (m, 5H), (4.72 s, 2H), 4.38 (t, J=6.6Hz, 1H), 3.87 (s, 4H), 2.74-2.63 (m, 2H), 1.39 (d, J=6.6Hz, 3H).
Embodiment 1-15,6-(phenylalanine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC015) synthetic
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as L-Phe, finally by getting compound N TC015, productive rate 49% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.15 (s, 1H), 8.28 (d, J=6.0Hz, 1H), 7.96-7.90 (m, 1H), 7.53 (d, J=7.8Hz, 1H), 7.29-7.14 (m, 10H), (4.71 s, 2H), 4.58 (s, 1H), (3.86 s, 4H), 3.23-3.18 (m, 1H), (3.14-3.06 m, 1H), 2.72-2.61 (m, 2H).
Embodiment 1-16,6-(L-glutamic acid carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC016) synthetic
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as Pidolidone, finally by getting compound N TC016, productive rate 25% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 12.44 (br s, 2H), 11.16 (s, 1H), 8.41 (s, 1H), 8.07-8.01 (m, 1H), 7.63 (d, J=8.1Hz, 1H), 7.35-7.24 (m, 5H), (4.72 s, 2H), 4.42 (s, 1H), (3.87 s, 4H), 2.74-2.63 (m, 2H), (2.36-2.29 m, 2H), 1.23-1.15 (m, 2H).
Embodiment 1-17,6-(proline(Pro) carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC017) synthetic
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as L-PROLINE, finally by getting compound N TC017, productive rate 64% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 12.53 (br s, 1H), 11.14 (s, 1H), (7.63-7.58 m, 1H), 7.29-7.24 (m, 7H), (4.72 s, 2H), 4.41 (s, 1H), (3.86 s, 4H), 3.56 (s, 2H), (2.71-2.63 m, 2H), 2.25 (s, 1H), 1.87 (s, 3H).
Embodiment 1-18,6-(glycine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC018) synthetic
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as glycine, finally by getting compound N TC018, productive rate 62% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 12.48 (br s, 1H), 11.15 (s, 1H), (8.62 s, 1H), 8.03-7.98 (m, 1H), (7.61 d, J=8.7Hz, 1H), 7.36-7.24 (m, 5H), 4.72 (s, 2H), (3.92 s, 2H), 3.87-3.85 (m, 4H), 2.73-2.63 (m, 2H).
Embodiment 1-19,6-(tyrosine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC019) synthetic
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as tyrosine, finally by getting compound N TC019, productive rate 29% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 12.52 (br s, 1H), 11.14 (s, 1H), (9.17 br s, 1H), 8.39 (d, J=8.1Hz, 1H), 7.98-7.94 (m, 1H), (7.55 d, J=8.4Hz, 1H), (7.33-7.09 m, 6H), 7.10 (d, J=8.4Hz, 2H), 6.63 (d, J=8.4Hz, 2H), 4.72 (s, 2H), 4.54 (s, 1H), (3.87-3.85 m, 4H), 3.09-2.97 (m, 2H), 2.73-2.63 (m, 2H).
Embodiment 1-20,6-(Histidine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC020) synthetic
Adopt the similar method with preparation compound N TC003,2-morpholine ethylamine is replaced as tyrosine, finally by getting compound N TC020, productive rate 50% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.57 (s, 1H), 11.36 (s, 1H), (8.27 s, 1H), 7.99-7.93 (m, 1H), (7.62-7.54 m, 2H), 7.37-7.18 (m, 6H), (6.81 s, 1H), 4.71 (s, 2H), (4.51-4.47 m, 1H), 3.87-3.84 (m, 4H), (3.15-3.06 m, 2H), 2.72-2.62 (m, 2H).
Embodiment 1-21,6-cyano group-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC021) synthetic
Adopt the similar method with preparation compound N TC001, the 4-trifluoromethyl phenyl hydrazine is replaced as 4-cyano group hydrazinobenzene hydrochloride salt, finally by getting compound N TC021, productive rate 11% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.53 (br s, 1H), 7.93 (s, 1H), 7.48 (d, J=8.4Hz, 1H), 7.39 (d, J=8.4Hz, 1H), 7.31-7.23 (m, 5H), (4.73 s, 2H), 3.87-3.83 (m, 4H), 2.73-2.63 (m, 2H).
Embodiment 1-22,6-nitro-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC022) synthetic
Adopt the similar method with preparation compound N TC001, the 4-trifluoromethyl phenyl hydrazine is replaced as the 4-nitrophenyl hydrazine hydrochloride, finally by getting compound N TC022, productive rate 6% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 11.70 (br s, 1H), 8.40 (d, J=9.0Hz, 1H), 7.98-7.94 (m, 1H), 7.48 (d, J=9.0Hz, 1H), 7.32-7.24 (m, 5H), (4.74 s, 2H), 3.88-3.85 (m, 4H), 2.73-2.69 (m, 2H).
Embodiment 1-23,6-benzyloxy-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC023) synthetic
Getting the serotonine hydrochloride is raw material,, use first the benzyl protection hydroxyl, similar to embodiment 1-1 afterwards, finally by getting compound N TC023, productive rate 20% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 10.69 (br s, 1H), 7.52-7.18 (m, 11H), 7.01-6.97 (m, 1H), (6.77-7.73 m, 1H), 5.06 (s, 2H), 4.68 (s, 2H), 3.85-3.79 (m, 4H), 2.66-2.53 (m, 2H).
Embodiment 1-24,6-(methoxycarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC024) synthetic
Adopt the method similar to embodiment 1-1,4-trifluoromethyl phenyl hydrazine hydrochloride be replaced as the 4-hydrazinobenzoic acid hydrochloride, get behind the 5-carboxyl tryptamines and carry out again subsequent reactions with methyl esters protection carboxyl first, finally by behind the column chromatography purification compound N TC024, productive rate 35%:
1H NMR (300MHz, DMSO-d
6): δ 11.32 (br s, 1H), 8.10-8.06 (m, 1H), 7.71-7.67 (m, 1H), 7.40-7.22 (m, 6H), 4.73 (s, 2H), 3.87-3.83 (m, 7H), 2.73-2.63 (m, 2H).
Embodiment 1-25,6-amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC025) synthetic
Employing hydrogen is reductive agent, and palladium carbon is that catalyzer reduces to NTC022, finally by getting compound N TC025, productive rate 67% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 10.41 (br s, 1H), 7.35-7.25 (m, 7H), 7.02 (d, J=8.4Hz, 1H), 6.59-6.54 (m, 1H), 6.46 (d, J=8.4Hz, 1H), (4.67 s, 2H), 3.89-3.82 (m, 4H), 2.60-2.54 (m, 2H).
Embodiment 1-26,6-hydroxy-n-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC026) synthetic
Adopt the similar method with preparation compound N TC025, finally by getting compound N TC026, productive rate 85% behind the column chromatography purification:
1H NMR (300MHz, DMSO-d
6): δ 10.50 (br s, 1H), 8.59-5.56 (m, 1H), (7.34-7.23 m, 5H), 7.07 (d, J=8.7Hz, 1H), 6.68-6.64 (m, 1H), (6.53 d, J=8.7Hz, 1H), (4.65 s, 2H), 3.85-3.79 (m, 4H), 2.58-2.51 (m, 2H).
Embodiment 1-27,6-carboxy-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC027) synthetic
In the methanol-water mixing solutions of mineral alkali lithium hydroxide, the NTC024 room temperature water is solved product NTC027, productive rate 100%:
1H NMR (300MHz, DMSO-d
6): δ 12.35 (br s, 1H), 11.26 (br s, 1H), 8.22 (s, 1H), (7.64-7.61 m, 1H), 7.34-7.25 (m, 6H), 3.96 (s, 2H), (3.75-3.74 m, 2H), 3.38-3.35 (m, 2H), 2.82-2.78 (m, 2H).Embodiment 1-28,6-methyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC028) synthetic
With 3-(2,3-dioxopiperidine)-(4-(methoxycarbonyl) phenyl)-hydrazone (505mg, 1.93mmol, preparation method's reference Syn.Comm.2007,37,1273-1280) be dissolved in the 20ml formic acid, 80 ℃ of lower stirrings 24 hours, decompression is except formic acid removal, get pale solid 1-oxygen-6-(methoxycarbonyl)-1,3,4 after the conventional processing, the 9-tetrahydro-beta-carboline, productive rate 55%.This carboline intermediate gets final product NTC028 with the toluylic acid coupling, productive rate 26% after the lithium aluminium hydride reduction:
1H NMR (300MHz, DMSO-d
6): δ 10.71 (br s, 1H), 7.34-7.13 (m, 7H), 6.85 (d, J=8.1Hz, 1H), 4.68 (s, 2H), 3.85-3.80 (m, 4H), 2.64-2.55 (m, 2H), 2.34 (s, 3H).
Embodiment 1-29,5-amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC029) synthetic
Adopt the similar method with preparation compound N TC001, the 4-nitrophenyl hydrazine is substituted trifluoromethyl phenyl hydrazine, can obtain target compound 5-nitro-N-phenylacetyl-1 by the preparation liquid phase; 3,4,9-tetrahydrochysene-1H-β-carboline and 7-nitro-N-phenylacetyl-1; 3,4,9-tetrahydrochysene-1H-β-carboline.
Get intermediate 5-nitro-N-phenylacetyl-1; 3; 4; 9-tetrahydrochysene-1H-β-carboline (235mg, 0.7mmol) is in the 25ml round-bottomed flask, after the adding 1ml DMF dissolving; the methyl alcohol dilution that adds again 4ml; the Pd/C that under nitrogen atmosphere, adds 0.5% (weight ratio), continue to pass into hydrogen 2h after, the TLC display substrate disappears.Evaporate solvent, behind column chromatography purification, obtain target compound 5-amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (159mg.Productive rate: 74%).
1H?NMR(DMSO，300MHz)：δ10.52(br?s，1H)，7.34-7.21(m，5H)，6.69(dd，J＝7.5Hz，7.8Hz，1H)，6.53(d，J＝8.1Hz，1H)，6.13(d，J＝7.5Hz，1H)，4.72(br?s，2H)，4.62(s，2H)，3.84-3.78(m，4H)，2.92(t，J＝7.1Hz，2H)。
Embodiment 1-307-amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC030) synthetic
Adopt the similar method with preparation compound N TC001; with 7-nitro-N-phenylacetyl-1,3,4; 9-tetrahydrochysene-1H-β-carboline substitutes 5-nitro-N-phenylacetyl-1; 3,4,9-tetrahydrochysene-1H-β-carboline; behind column chromatography purification, obtain 7-amino-N-phenylacetyl-1; 3,4,9-tetrahydrochysene-1H-β-carboline (46mg.Productive rate: 29%).
1H?NMR(DMSO，300MHz)：δ10.20(br?s，1H)，7.31-7.18(m，5H)，6.96(dd，J＝8.4Hz，1H)，6.45(d，1H)，6.30(d，J＝8.4Hz，1H)，4.60(br?s，2H)，4.56(s，2H)，3.81-3.74(m，4H)，3.30(t，J＝5.7Hz，2H)。
Embodiment 1-315-(2-(N-morpholinyl)) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC031) synthetic
With intermediate 5-amino-N-phenylacetyl-1; 3; 4; 9-tetrahydrochysene-1H-β-carboline (50mg, 0.16mmol) adds in triethylamine and the DMF solution at 0 ℃ with chloroacetyl chloride (19 μ l, 0.24mmol); stir after 2 hours; be added dropwise to morpholine (30 μ l, 0.32mmol) stirring reaction 5 hours, TLC detects to raw material and disappears.Reaction solution is added in the frozen water, separate out white solid, be product (43mg, productive rate 62.3%).
1H?NMR(DMSO，300MHz)：δ10.99(br?s，1H)，9.46(br?s，1H)，7.53(d，J＝6.9Hz，1H)，7.28-7.23(m，5H)，7.08-7.06(m，1H)，6.97-6.93(m，1H)，4.69(s，2H)，3.86(s，4H)，3.62(s，4H)，3.10(s，2H)，2.87(s，2H)，2.54(s，4H)。
Embodiment 1-325-(2-(4-methylpiperazine base)) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC032) synthetic
Adopt the method identical with embodiment 1-31, morpholine is replaced with N methyl piperazine, obtain product NTC032 (33mg, productive rate 57%).
1H?NMR(DMSO，300MHz)：δ10.98(br?s，1H)，9.55(br?s，1H)，7.59(d，J＝7.8Hz，1H)，7.28-7.21(m，5H)，7.03(d，J＝7.8Hz，1H)，6.94(dd，J＝7.8Hz，7.8Hz，1H)，4.68(s，2H)，3.84(s，4H)，3.06(s，2H)，2.91(s，2H)，2.46(s，4H)，2.35(s，4H)，2.16(s，3H)。
Embodiment 1-335-(2-amino) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC033) synthetic
With 5-amino-N-phenylacetyl-1,3,4; 9-tetrahydrochysene-1H-β-carboline (50mg, 0.16mmol) is dissolved among the DMF (3ml) with Boc-L-glycine (42mg, 0.24mmol); add EDC HCl (60mg, 0.31mol) and HOBt (36mg, 0.26mmol) under 0 ℃ of C condition; reaction is 4 hours under the normal temperature, and TLC after detecting the raw material disappearance is added to the water reaction solution; ethyl acetate extraction; washing, salt is washed, and obtains the 137mg intermediate behind the silicagel column purifying.Above-mentioned intermediate is dissolved in the methylene dichloride, adds the Isosorbide-5-Nitrae-dioxane solution of hydrogenchloride, the stirring at normal temperature reaction is spent the night.The after washing that reacts completely, saturated sodium carbonate is washed, and salt is washed, and vacuum is drained and is obtained target compound (32mg, productive rate 55%).
1H?NMR(DMSO，300MHz)：δ10.95(br?s，1H)，7.56(d，J＝7.5Hz，1H)，7.30-7.22(m，5H)，7.05(d，J＝7.8Hz，1H)，6.94(dd，J＝7.5Hz，7.8Hz，1H)，4.68(s，2H)，3.84-3.82(m，4H)，3.25(s，2H)，2.95(s，2H)。
Embodiment 1-345-(2-Threonine base) amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC034) synthetic
Adopt the method identical with embodiment 1-33, the Boc-L-glycine is replaced with the Boc-L-Threonine obtain target compound (22mg, productive rate 69%).
1H?NMR(DMSO，300MHz)：δ10.95(br?s，1H)，9.83(br?s，1H)，7.66-7.58(m，1H)，7.28-7.23(m，5H)，7.08-7.03(m，1H)，6.98-6.93(m，1H)，4.69(s，2H)，4.14-4.01(m，1H)，3.94-3.83(m，5H)，3.51-3.48(m，1H)，3.01-2.96(m，2H)，1.40-1.34(m，2H)，1.19-1.14(m，3H)。
Embodiment 1-355-(2-proline(Pro) base) amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC035) synthetic
Adopt the method identical with embodiment 1-33, the Boc-L-glycine is replaced with the Boc-L-proline(Pro) obtain target compound (23mg, productive rate 72%).
1H?NMR(DMSO，300MHz)：δ10.96(br?s，1H)，10.22(br?s，1H)，7.73-7.62(m，1H)，7.28-7.20(m，5H)，7.03-7.01(m，1H)，6.98-6.90(m，1H)，4.70(s，2H)，3.93-3.70(m，5H)，3.97-3.73(m，4H)，2.08-2.02(m，1H)，1.85-1.67(m，2H)，1.67-1.61(m，2H)。
Embodiment 1-36,9-(4-bromobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC036) synthetic
Get compound 1,3,4,9-tetrahydrochysene-1H-β-carboline (225mg) is in methylene dichloride, under argon atmosphere, add EDC (326mg) and HOBt (194mg), stirring added toluylic acid (218mg) after 15 minutes under ice bath, and this compound at room temperature stirring reaction 5-8 hour is in reaction soln impouring ice bath, with twice of ethyl acetate extraction, organic phase after water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Obtain N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline 336mg, productive rate 89% through behind the column chromatography purification.This intermediate obtained NTC036, productive rate 50% in 1 hour in a ℃ reaction under the NaH effect with to the bromobenzyl bromine in DMF:
1H NMR (300MHz, DMSO): δ 7.50-7.44 (m, 4H), 7.29-7.25 (m, 4H), (7.24-6.96 m, 5H), 5.36 (s, 2H), 4.70-4.67 (m, 2H), 3.86-3.76 (m, 4H), 2.71-2.65 (m, 2H).
Embodiment 1-37,9-methyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NCT037's is synthetic)
Get N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline obtained NTC037, productive rate 80% in 1 hour 0 ℃ of reaction under the NaH effect with to methyl iodide in DMF:
1H NMR (DMSO, 300MHz): δ 7.36-7.29 (m, 2H), 7.25-7.20 (m, 5H), 7.05-7.00 (m, 1H), 7.95-6.89 (m, 1H), 4.69 (s, 2H), 3.81 (s, 2H), 3.75-3.71 (t, J=5.7Hz, 2H), 3.56 (s, 3H), (3.26 t, J=5.7Hz, 2H).
Embodiment 1-38,8-fluoro-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC038) synthetic
Adopt the similar method with preparation compound N TC001, the 4-trifluoromethyl phenyl hydrazine is replaced as adjacent fluorine phenylhydrazine, finally by getting compound N TC038, productive rate 56% behind the column chromatography purification:
1H NMR (DMSO, 300MHz): δ 11.29 (br s, 1H), 7.24-7.15 (m, 6H), (6.88-6.81 m, 2H), 4.67 (s, 2H), 3.81-3.77 (m, 4H), 2.93 (s, 2H), 2.88-2.61 (m, 2H).
Embodiment 1-39,6-(2-amino) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC039) synthetic
Adopt the method identical with embodiment 1-33, with 5-amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline replaces with 6-amino-N-phenylacetyl-1,3,4, and 9-tetrahydrochysene-1H-β-carboline obtains target compound NTC039, productive rate 40%:
1H NMR (DMSO, 300MHz): δ 10.79 (br s, 1H), 7.75-7.73 (m, 1H), (7.35-7.16 m, 8H), 4.69 (s, 2H), 3.86-3.80 (m, 4H), 3.24 (s, 2H), 2.64-2.55 (m, 2H).
Embodiment 1-40, N-phenylacetyl-6,8-two fluoro-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC040) synthetic
Adopt the similar method with preparation compound N TC001, the 4-trifluoromethyl phenyl hydrazine is replaced as the 2,4 difluorobenzene hydrazine, finally by getting compound N TC040, productive rate 10% behind the column chromatography purification:
1H NMR (DMSO, 300MHz): δ 11.45 (br s, 1H), 7.34-7.20 (m, 5H), (7.06-7.02 m, 1H), 6.94-6.86 (m, 1H), 4.71 (s, 2H), 3.86-3.80 (m, 4H), 2.65-2.55 (m, 2H).
Embodiment 1-41, N-phenylacetyl-6,8-two fluoro-9-be to bromobenzyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC041) synthetic
Get N-phenylacetyl-6,8-two fluoro-9-are to bromobenzyl-1,3,4, and 9-tetrahydrochysene-1H-β-carboline obtained NTC041, productive rate 46% in 1 hour 0 ℃ of reaction under the NaH effect with to the bromobenzyl bromine in DMF:
1H NMR (DMSO, 300MHz): δ 7.52-7.50 (m, 2H), 7.32-7.11 (m, 6H), (6.97-6.89 m, 3H), 5.40 (s, 2H), 4.72 (s, 2H), 3.86-3.78 (m, 4H), 2.67-2.62 (m, 2H).
Embodiment 1-42,9-benzyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC042) synthetic
Adopt the similar method with preparation compound N TC037, methyl iodide be replaced into the benzyl bromine, finally behind column chromatography purification, get compound N TC042, productive rate 58%:
1H NMR (300MHz, DMSO): δ 7.43-7.41 (m, 2H), 7.31-7.23 (m, 8H), (7.08-7.03 m, 4H), 5.37 (s, 2H), 4.72-4.69 (m, 2H), 3.86-3.75 (m, 4H), 2.71-2.65 (m, 2H).
Embodiment 1-43,9-(4-luorobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC043) synthetic
Adopt the similar method with preparation compound N TC037, methyl iodide be replaced into fluorobenzyl bromide, finally behind column chromatography purification, get compound N TC043, productive rate 72%:
1H NMR (300MHz, DMSO): δ 7.44-7.41 (m, 2H), 7.31-7.21 (m, 5H), (7.17-7.01 m, 6H), 5.36 (s, 2H), 4.71-4.68 (m, 2H), 3.86-3.77 (m, 4H), 2.73-2.65 (m, 2H).
Embodiment 1-44,9-(4-methyl-formiate benzyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC044) synthetic
Adopt the similar method with preparation compound N TC037, methyl iodide be replaced into the 4-bromomethyl-benzoic acid methyl ester, finally behind column chromatography purification, get compound N TC044, productive rate 79%:
1H NMR (300MHz, DMSO): δ 7.90-7.87 (m, 2H), (7.45-7.31 m, 3H), 7.29-7.14 (m, 9H), 5.47 (s, 2H), (4.69-4.65 m, 2H), 4.28 (m, 3H), 3.86-3.74 (m, 4H), (2.67-2.53 m, 2H).
Embodiment 1-45,9-(4-carboxyl benzyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC045) synthetic
Get NTC044 the NaOH of 1N heated in water solution cocurrent flow 1 hour, PH to 1 is regulated in cooling, and with the EtOAc extraction, underpressure distillation obtains NTC045, productive rate 99%:
1H NMR (300MHz, DMSO): δ 12.90 (s, 1H) 7.87-7.84 (m, 2H), 7.45-7.39 (m, 3H), (7.32-7.24 m, 4H) 7.20-7.06 (m, 4H), (5.48 s, 2H), 4.71-4.66 (m, 2H), 3.86-3.75 (m, 4H), (2.67-2.64 m, 2H).
Embodiment 1-46,9-(methoxycarbonyl methyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC046) synthetic
Adopt the similar method with preparation compound N TC037, methyl iodide be replaced into methyl bromoacetate, finally behind column chromatography purification, get compound N TC046, productive rate 75%:
1H NMR (300MHz, DMSO): δ 7.42-7.23 (m, 7H), 7.10-7.02 (m, 2H), (5.09 s, 2H), 4.76-4.67 (m, 2H), 3.88-3.80 (m, 4H), 3.68 (s, 3H), 2.69-2.60 (m, 2H).
Embodiment 1-47,9-(carbonyl methyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC047) synthetic
Get NTC046 the NaOH of 1N heated in water solution cocurrent flow 1 hour, PH to 1 is regulated in cooling, and with the EtOAc extraction, underpressure distillation obtains NTC047, productive rate 99%:
1H NMR (300MHz, DMSO): δ 12.95 (s, 1H) 7.41-7.26 (m, 7H), 7.11-7.01 (m, 2H), 4.96-4.93 (m, 2H), 4.77-4.68 (m, 2H), (3.88-3.80 m, 4H), 2.69-2.60 (m, 2H).
Embodiment 1-48,9-(4-(morpholinyl) carbonyl methyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NTC048) synthetic
Get NTC047, EDCHCl, HOBt and stirred in DMF 10 minutes, drip morpholine again and also reacted at normal temperatures 3 hours, extraction, purifying obtain NCT048, productive rate 89%:
1H NMR (300MHz, DMSO): δ 7.39-7.23 (m, 7H), 7.10-6.99 (m2H), 5.13 (s, 2H), (4.66-4.62 m, 2H), 3.88-3.79 (m, 4H), 3.70-3.68 (m, 2H), (3.63-3.59 m, 4H), 3.45-3.44 (m, 2H), 2.69-2.60 (m, 2H).
Embodiment 1-49,5-methoxycarbonyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NCT049) synthetic
Adopt the similar method with preparation compound N TC001, the 4-trifluoromethyl phenyl hydrazine is replaced as 3-hydrazino-benzoic acid methyl esters, obtain 5-(methoxycarbonyl)-N-phenylacetyl-1 by preparation liquid phase liquid phase; 3; 4,9-tetrahydrochysene-1H-β-carboline NCT049, productive rate 16%:
1H NMR (DMSO, 300MHz): δ 11.33 (br s, 1H), 7.96 (d, J=7.5Hz, 7.8Hz, 1H), 7.61 (d, J=7.5Hz, 1H), 7.47 (dd, J=7.5Hz, 1H), 7.34-7.24 (m, 5H), (4.76 s, 2H), 3.87-3.84 (m, 7H), 2.63 (d, 2H).
Embodiment 1-50,5-(α-amino-isovaleric acid amino)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NCT050) synthetic
Adopt the method identical with embodiment 1-33, the Boc-L-glycine replaced with the Boc-L-α-amino-isovaleric acid obtain target compound (22mg, productive rate 55%):
1H NMR (DMSO, 300MHz): δ 10.99 (br s, 1H), 9.73 (s, 1H), (7.53 d, J=7.5Hz, 1H), 7.27-7.22 (m, 5H), (7.04 d, J=7.8Hz, 1H), 6.94 (dd, J=7.5Hz, 7.8Hz, 1H), 4.69 (s, 2H), 3.84-3.81 (m, 4H), 2.93 (s, 1H), 2.77 (s, 2H), (2.28 s, 1H), 0.97-0.87 (m, 6H).
Embodiment 1-51,5-(L-Ala amino)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NCT051) synthetic
Adopt the method identical with embodiment 1-33, the Boc-L-glycine replaced with the Boc-L-L-Ala obtain target compound (27mg, productive rate 53%):
1H NMR (DMSO, 300MHz): δ 10.89 (br s, 1H), 9.70 (s, 1H), (7.84 d, J=7.5Hz, 1H), 7.25-7.21 (m, 5H), (7.19 d, J=7.8Hz, 1H), 7.02 (dd, J=7.5Hz, 7.8Hz, 1H), 5.11 (br s, 2H), 4.63 (s, 2H), 3.83-3.81 (m, 4H), 3.74 (s, 1H), (2.99 s, 2H), 1.28 (d, 3H).
Embodiment 1-52,5-(3-amino) propionyl amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline (NCT052) synthetic
Adopt the method identical with embodiment 1-33, the Boc-L-glycine replaced with the Boc-L-β-alanine obtain target compound (35mg, productive rate 45%):
1H NMR (DMSO, 300MHz): δ 10.87 (br s, 1H), 9.69 (s, 1H), 7.84 (d, J=7.5Hz, 1H), 7.24-7.20 (m, 5H), 7.18 (d, J=7.8Hz, 1H), 7.02 (dd, J=7.5Hz, 7.8Hz, 1H), 5.11 (br s, 2H), 4.48 (s, 2H), (3.85-3.81 m, 4H), 3.03 (t, J=5.4Hz, 2H), (2.99 s, 2H), 1.28 (t, J=5.4Hz, 2H).
Claims (16)
1. an aromatic base alkyloyl tetrahydro-beta-carboline and derivative or its hydrate or pharmacy acceptable salt is characterized in that,
Represented by following structural formula (I):
Wherein:
M is 0-8 CH
2
N is 0-3 CH
2
Be in monocycle aromatic base, many cyclophanes perfume base, the many heterocyclic aromatic bases any one; Described monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Described many cyclophanes perfume base and many heterocyclic aromatic bases refer to comprise the group of two and plural monocycle aromatic base;
R
1Be the substituting group on the aromatic nucleus, comprise single replace and polysubstituted, be selected from the following groups any one or a plurality of: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, cycloalkyloxy, cyclammonium base, C
2-C
12Thiazolinyl, C
2-C
12Alkynyl, C
3-C
12Cycloalkyl, benzyl, alkyl-carbonyl, C
2-C
12Alkenyl carbonyl, C
3-C
12Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl;
R
2Be selected from any one in the following groups: hydrogen, alkyl, halogen, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkoxyl group, alkylamino radical, alkyl-carbonyl and aromatic base carbonyl, morpholine methyl, methylol;
R
3And R
4Be selected from the following groups any one or a plurality of: hydrogen, alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, amino, cyano group, nitro, halogen;
R
5Be the substituting group on the aromatic nucleus different positions, comprise single replace and polysubstituted, be selected from the following groups any one, two or more: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, substituted amido, cycloalkyloxy, cycloalkanes amido, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, alkyl-carbonyl, C
2-C
6Alkenyl carbonyl, C
3-C
6Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl; Monosaccharide groups; Oligosaccharyl;
R
6Be selected from any one in the following groups: hydrogen, alkyl, methylol, alkoxyl group, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkenyl group, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkylamino radical.
2. aromatic base alkyloyl tetrahydro-beta-carboline and derivative or its hydrate or the pharmacy acceptable salt shown in according to claim 1 is characterized in that, represented by following structural formula (II):
Wherein:
A, B and D are nitrogen, oxygen, sulphur or CR
5In any one; Make
Keep aromaticity;
M is 0-8 CH
2
N is 0-3 CH
2
R
1Be the substituting group on the aromatic nucleus, comprise single replace and polysubstituted, be selected from the following groups any one or a plurality of: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, cycloalkyloxy, cyclammonium base, C
2-C
12Thiazolinyl, C
2-C
12Alkynyl, C
3-C
12Cycloalkyl, benzyl, alkyl-carbonyl, C
2-C
12Alkenyl carbonyl, C
3-C
12Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl;
R
2Be selected from any one in the following groups: hydrogen, alkyl, halogen, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkoxyl group, alkylamino radical, alkyl-carbonyl and aromatic base carbonyl, morpholine methyl, methylol;
R
3And R
4Be selected from the following groups any one or a plurality of: hydrogen, alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, amino, cyano group, nitro, halogen;
R
6And R
7Be selected from any one in the following groups: hydrogen, alkyl, methylol, alkoxyl group, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkenyl group, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkylamino radical.
3. aromatic base alkyloyl tetrahydro-beta-carboline and derivative or its hydrate or the pharmacy acceptable salt shown in according to claim 1 is characterized in that, represented by following structural formula (III):
Wherein:
E, F, G and H are nitrogen or CR
5Make
Keep aromaticity;
M is 0-8 CH
2
N is 0-3 CH
2
R
1Be the substituting group on the aromatic nucleus, comprise single replace and polysubstituted, be selected from the following groups any one or a plurality of: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, cycloalkyloxy, cyclammonium base, C
2-C
12Thiazolinyl, C
2-C
12Alkynyl, C
3-C
12Cycloalkyl, benzyl, alkyl-carbonyl, C
2-C
12Alkenyl carbonyl, C
3-C
12Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl;
R
2Be selected from any one in the following groups: hydrogen, alkyl, halogen, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkoxyl group, alkylamino radical, alkyl-carbonyl and aromatic base carbonyl, morpholine methyl, methylol;
R
3And R
4Be selected from the following groups any one or a plurality of: hydrogen, alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, amino, cyano group, nitro, halogen;
R
6Be selected from any one in the following groups: hydrogen, alkyl, methylol, alkoxyl group, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkenyl group, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkylamino radical.
4. aromatic base alkyloyl tetrahydro-beta-carboline and derivative or its hydrate or the pharmacy acceptable salt shown in according to claim 3 is characterized in that, represented by following structural formula (IV):
Wherein:
M is 0-8 CH
2
N is 0-3 CH
2 
Be in monocycle aromatic base, many cyclophanes perfume base, the many heterocyclic aromatic bases any one; Described monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Described many cyclophanes perfume base and many heterocyclic aromatic bases refer to comprise the group of two and plural monocycle aromatic base;
R
1Be the substituting group on the aromatic nucleus, comprise single replace and polysubstituted, be selected from the following groups any one or a plurality of: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, cycloalkyloxy, cyclammonium base, C
2-C
12Thiazolinyl, C
2-C
12Alkynyl, C
3-C
12Cycloalkyl, benzyl, alkyl-carbonyl, C
2-C
12Alkenyl carbonyl, C
3-C
12Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl;
R
2Be selected from any one in the following groups: hydrogen, alkyl, halogen, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkoxyl group, alkylamino radical, alkyl-carbonyl and aromatic base carbonyl, morpholine methyl, methylol;
R
3And R
4Be selected from the following groups any one or a plurality of: hydrogen, alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, amino, cyano group, nitro, halogen;
R
6Be selected from any one in the following groups: hydrogen, alkyl, methylol, alkoxyl group, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkenyl group, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkylamino radical;
R
8, R
9, R
10And R
11Be the substituting group on the phenyl ring, be selected from respectively any one in the following groups: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, substituted amido, cycloalkyloxy, cycloalkanes amido, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, alkyl-carbonyl, C
2-C
6Alkenyl carbonyl, C
3-C
6Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl; Monosaccharide groups; Oligosaccharyl.
5. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 4 and derivative thereof or its hydrate or pharmacy acceptable salt is characterized in that, when n is 1 CH
2, R
2, R
3And R
4When being respectively hydrogen, represented by following structural formula (V):
Wherein:
M is 0-8 CH
2
Be in monocycle aromatic base, many cyclophanes perfume base, the many heterocyclic aromatic bases any one; Described monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Described many cyclophanes perfume base and many heterocyclic aromatic bases refer to comprise the group of two and plural monocycle aromatic base;
R
1Be the substituting group on the aromatic nucleus, comprise single replace and polysubstituted, be selected from the following groups any one or a plurality of: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, cycloalkyloxy, cyclammonium base, C
2-C
12Thiazolinyl, C
2-C
12Alkynyl, C
3-C
12Cycloalkyl, benzyl, alkyl-carbonyl, C
2-C
12Alkenyl carbonyl, C
3-C
12Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl;
R
6Be selected from any one in the following groups: hydrogen, alkyl, methylol, alkoxyl group, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkenyl group, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkylamino radical;
R
8, R
9, R
10And R
11Be the substituting group on the phenyl ring, be selected from respectively any one in the following groups: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, substituted amido, cycloalkyloxy, cycloalkanes amido, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, alkyl-carbonyl, C
2-C
6Alkenyl carbonyl, C
3-C
6Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl; Monosaccharide groups; Oligosaccharyl.
6. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 4 and derivative thereof or its hydrate or pharmacy acceptable salt is characterized in that, work as m, and n is respectively 1 CH
2, R
2, R
3And R
4When being respectively hydrogen, represented by following structural formula (VI):
Wherein:
Be in monocycle aromatic base, many cyclophanes perfume base, the many heterocyclic aromatic bases any one; Described monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Described many cyclophanes perfume base and many heterocyclic aromatic bases refer to comprise the group of two and plural monocycle aromatic base;
R
1Be the substituting group on the aromatic nucleus, comprise single replace and polysubstituted, independently be selected from the following groups any one or a plurality of: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, cycloalkyloxy, cyclammonium base, C
2-C
12Thiazolinyl, C
2-C
12Alkynyl, C
3-C
12Cycloalkyl, benzyl, alkyl-carbonyl, C
2-C
12Alkenyl carbonyl, C
3-C
12Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl;
R
6Be selected from any one in the following groups: hydrogen, alkyl, methylol, alkoxyl group, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkenyl group, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkylamino radical;
R
8, R
9, R
10And R
11Be the substituting group on the phenyl ring, independently be selected from respectively in the following groups any one: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, substituted amido, cycloalkyloxy, cycloalkanes amido, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, alkyl-carbonyl, C
2-C
6Alkenyl carbonyl, C
3-C
6Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl; Monosaccharide groups; Oligosaccharyl.
7. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 4 and derivative thereof or its hydrate or pharmacy acceptable salt is characterized in that, work as m, and n is respectively 1 CH
2, R
2, R
3And R
4Be respectively hydrogen, R
8, R
9, R
10And R
11In any three when being respectively hydrogen, represented by following structural formula (IV):
Wherein: X is any one of methylene radical, acyl group, amino, oxygen, sulphur or alkylsulfonyl;
Be in monocycle aromatic base, many cyclophanes perfume base, the many heterocyclic aromatic bases any one; Described monocycle aromatic base comprises phenyl, azepine aromatic base, thia aromatic base, oxa-aromatic base; Described many cyclophanes perfume base and many heterocyclic aromatic bases refer to comprise the group of two and plural monocycle aromatic base;
R
1Be the substituting group on the aromatic nucleus, comprise single replace and polysubstituted, independently be selected from the following groups any one or a plurality of: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, cycloalkyloxy, cyclammonium base, C
2-C
12Thiazolinyl, C
2-C
12Alkynyl, C
3-C
12Cycloalkyl, benzyl, alkyl-carbonyl, C
2-C
12Alkenyl carbonyl, C
3-C
12Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl;
R
6Be selected from any one in the following groups: hydrogen, alkyl, methylol, alkoxyl group, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkenyl group, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkylamino radical;
R
12Be selected from any one in the following groups: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, substituted amido, cycloalkyloxy, cycloalkanes amido, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, alkyl-carbonyl, C
2-C
6Alkenyl carbonyl, C
3-C
6Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl; Formyl morpholine, acyl ethyl morpholine, acyl propyl group morpholine; Piperazinyl, acyl methylpiperazine, acyl ethyl-methyl piperazine, acyl propyl group methylpiperazine, methylpiperazine base; Amino-acid residue, straight chain amino acid, branched-chain amino acid, erythrose, threose, lyxose, allose, altrose, gulose, idose, talose, ribose, ribodesose, wood sugar, I sugar, glucose, seminose, semi-lactosi, fructose, aminosugar, oligosaccharides; Wherein, described amino-acid residue comprises glycine, Serine, L-Ala, Threonine, α-amino-isovaleric acid, Isoleucine, leucine, tyrosine, phenylalanine, Histidine, proline(Pro), aspartic acid, methionine(Met), L-glutamic acid, tryptophane, Methionin, halfcystine, arginine, glutamine or l-asparagine.
8. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 4 and derivative thereof or its hydrate or pharmacy acceptable salt is characterized in that, when m, n are respectively 1 CH
2, R
2, R
3And R
4Be respectively hydrogen, R
8, R
9, R
10And R
11In any two when being respectively hydrogen, represented by following structural formula (VIII):
Wherein: X and Y are respectively any one of methylene radical, acyl group, amino, oxygen, sulphur or alkylsulfonyl;
R
1Be the substituting group on the aromatic nucleus, comprise single replace and polysubstituted, independently be selected from the following groups any one or a plurality of: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, amido, cycloalkyloxy, cyclammonium base, C
2-C
12Thiazolinyl, C
2-C
12Alkynyl, C
3-C
12Cycloalkyl, benzyl, alkyl-carbonyl, C
2-C
12Alkenyl carbonyl, C
3-C
12Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl;
R
6Be selected from any one in the following groups: hydrogen, alkyl, methylol, alkoxyl group, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkenyl group, aromatic base, heterocyclic aromatic base, benzyl, styroyl, hydrocinnamyl, alkylamino radical;
R
12And R
13Be selected from any one in the following groups: hydrogen, amino, cyano group, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxyl group, substituted amido, cycloalkyloxy, cycloalkanes amido, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Cycloalkyl, aromatic base, heterocyclic aromatic base, benzyl, alkyl-carbonyl, C
2-C
6Alkenyl carbonyl, C
3-C
6Naphthene base carbonyl, phenylcarbonyl group, benzyloxycarbonyl group, carbalkoxy, ester group, sulfoxide group, sulfuryl, sulfonamido, sulfoamido; Morpholinyl; Piperazinyl; Formyl morpholine, acyl ethyl morpholine, acyl propyl group morpholine; Piperazinyl, acyl methylpiperazine, acyl ethyl-methyl piperazine, acyl propyl group methylpiperazine, methylpiperazine base; Amino-acid residue, straight chain amino acid, branched-chain amino acid, erythrose, threose, lyxose, allose, altrose, gulose, idose, talose, ribose, ribodesose, wood sugar, I sugar, glucose, seminose, semi-lactosi, fructose, aminosugar, oligosaccharides; Wherein, described amino-acid residue comprises glycine, Serine, L-Ala, Threonine, α-amino-isovaleric acid, Isoleucine, leucine, tyrosine, phenylalanine, Histidine, proline(Pro), aspartic acid, methionine(Met), L-glutamic acid, tryptophane, Methionin, halfcystine, arginine, glutamine or l-asparagine.
One kind according to claim 1-8 in each described aromatic base alkyloyl tetrahydro-beta-carboline class and derivative or its hydrate or pharmacy acceptable salt, it is characterized in that, comprise the acid salt that described acyl group tetrahydro-beta-carboline micromolecular organic compound and acid form; Wherein, described acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, tartrate, Whitfield's ointment, citric acid, methylsulfonic acid, tosic acid, lactic acid, pyruvic acid, toxilic acid or succsinic acid.
10. each described aromatic base alkyloyl tetrahydro-beta-carboline and derivative or its hydrate or pharmacy acceptable salt is characterized in that it is with radioactivity, fluorophor or biotin labeling according to claim 1-8.
11. each described aromatic base alkyloyl tetrahydro-beta-carboline and derivative or its hydrate or pharmacy acceptable salt is characterized in that according to claim 1-8, comprising:
N-phenylacetyl-(6-trifluoromethyl)-1,3,4,9-tetrahydrochysene-1H-β-carboline
N-phenylacetyl-(6-trifluoromethoxy)-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(2-morpholine ethyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(4-methylpiperazine) carbonyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(2-(dimethylamino) ethyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(3-(dimethylamino) propyl group) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(4-morpholinyl phenyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(4-dimethylamino phenyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(4-amino-sulfonyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(N, N-two (2-hydroxyethyl)) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(2-(2-hydroxyl-oxethyl) ethyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(Serine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(aspartic acid carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(L-Ala carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(phenylalanine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(L-glutamic acid carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(proline(Pro) carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(glycine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(tyrosine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(Histidine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-cyano group-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-nitro-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-benzyloxy-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-methoxycarbonyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-hydroxy-n-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-carboxy-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-methyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-amino-N-phenylacetyl--1,3,4,9-tetrahydrochysene-1H-β-carboline
7-amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(2-(N-morpholinyl)) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(2-(4-methylpiperazine base)) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(2-is amino) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(2-Threonine base) amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(2-proline(Pro) base) amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(4-bromobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-methyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
8-fluoro-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
6-(2-is amino) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
N-phenylacetyl-6,8-two fluoro-1,3,4,9-tetrahydrochysene-1H-β-carboline
N-phenylacetyl-6,8-two fluoro-9-be to bromobenzyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-benzyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(4-luorobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(4-methyl-formiate benzyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(4-carboxyl benzyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(methoxycarbonyl methyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(carbonyl methyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
9-(4-(morpholinyl) carbonyl methyl)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-methoxycarbonyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(α-amino-isovaleric acid is amino)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(L-Ala is amino)-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline
5-(3-is amino) propionyl amino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline.
12. a pharmaceutical composition wherein contains each described aromatic base alkyloyl tetrahydro-beta-carboline and derivative or its hydrate or pharmacy acceptable salt among the claim 1-8, and pharmaceutically acceptable carrier.
13. pharmaceutical composition according to claim 12 is characterized in that, described pharmaceutical composition is formulated into injectable fluid, aerosol, emulsifiable paste, gelifying agent, pill, capsule, syrup, transdermal patch or vehicle.
14. each described aromatic base alkyloyl tetrahydro-beta-carboline and derivative thereof or its hydrate or the pharmacy acceptable salt application in the medicine of preparation treatment malignant tumour according to claim 1-8; Wherein, described malignant tumour comprises head and neck cancer, thyroid carcinoma, the esophageal carcinoma, nasopharyngeal carcinoma, liver cancer, lung cancer, prostate cancer, skin carcinoma, osteocarcinoma, cervical cancer, intestinal cancer, carcinoma of the pancreas, mammary cancer, leukemia, ovarian cancer, cancer of the stomach, bladder cancer, kidney, skin carcinoma, oral carcinoma and malignant lymphoma.
15. each described aromatic base alkyloyl tetrahydro-beta-carboline and derivative thereof or its hydrate or the pharmacy acceptable salt application in the medicine of preparation treatment Malignant tumor of bonal metastasis and recurrence according to claim 1-8; Wherein, described malignant tumour comprises head and neck cancer, thyroid carcinoma, the esophageal carcinoma, nasopharyngeal carcinoma, liver cancer, lung cancer, prostate cancer, skin carcinoma, osteocarcinoma, cervical cancer, intestinal cancer, carcinoma of the pancreas, mammary cancer, leukemia, ovarian cancer, cancer of the stomach, bladder cancer, kidney, skin carcinoma, oral carcinoma, malignant lymphoma.
16. each described application is characterized in that according to claim 14-15, described medicine uses separately or unites use with other drug.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105669666A (en) * | 2016-01-08 | 2016-06-15 | 华东师范大学 | Small molecule compound YF-452 and application thereof in preparation of anti-angiogenesis drugs |
| CN108727370A (en) * | 2018-05-25 | 2018-11-02 | 华东师范大学 | The tetrahydro-beta-carboline micromolecular organic compound and its derivative and medical usage of a kind of hydroxyl substitution |
| CN114591323A (en) * | 2022-03-17 | 2022-06-07 | 济南大学 | A class of hydroxamic acid histone deacetylase inhibitors containing tetrahydrocarboline structure and preparation method and use thereof |
| US11414423B1 (en) | 2019-02-27 | 2022-08-16 | The Regents Of The University Of California | Substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles for treating brain disorders |
| CN116836160A (en) * | 2022-03-25 | 2023-10-03 | 华东师范大学 | Fluoro-phenylacetyl tetrahydro-beta-carboline micromolecule organic compound for targeting tumor dryness and medical application thereof |
| US12295959B2 (en) | 2021-12-15 | 2025-05-13 | Delix Therapeutics, Inc. | Phenoxy and benzyloxy substituted psychoplastogens and uses thereof |
| US12343337B2 (en) | 2016-09-29 | 2025-07-01 | The Regents Of The University Of California | Compounds for increasing neural plasticity |
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| CN102424681A (en) * | 2011-10-24 | 2012-04-25 | 华东师范大学 | Acyl-tetrahydro-beta-carboline compound as well as derivatives, application and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102424681A (en) * | 2011-10-24 | 2012-04-25 | 华东师范大学 | Acyl-tetrahydro-beta-carboline compound as well as derivatives, application and preparation method thereof |
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| CN105669666A (en) * | 2016-01-08 | 2016-06-15 | 华东师范大学 | Small molecule compound YF-452 and application thereof in preparation of anti-angiogenesis drugs |
| US12343337B2 (en) | 2016-09-29 | 2025-07-01 | The Regents Of The University Of California | Compounds for increasing neural plasticity |
| CN108727370A (en) * | 2018-05-25 | 2018-11-02 | 华东师范大学 | The tetrahydro-beta-carboline micromolecular organic compound and its derivative and medical usage of a kind of hydroxyl substitution |
| US11414423B1 (en) | 2019-02-27 | 2022-08-16 | The Regents Of The University Of California | Substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles for treating brain disorders |
| US12325710B2 (en) | 2019-02-27 | 2025-06-10 | The Regents Of The University Of California | Substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles for treating brain disorders |
| US12295959B2 (en) | 2021-12-15 | 2025-05-13 | Delix Therapeutics, Inc. | Phenoxy and benzyloxy substituted psychoplastogens and uses thereof |
| CN114591323A (en) * | 2022-03-17 | 2022-06-07 | 济南大学 | A class of hydroxamic acid histone deacetylase inhibitors containing tetrahydrocarboline structure and preparation method and use thereof |
| CN116836160A (en) * | 2022-03-25 | 2023-10-03 | 华东师范大学 | Fluoro-phenylacetyl tetrahydro-beta-carboline micromolecule organic compound for targeting tumor dryness and medical application thereof |
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