CN102977091A - Application of aromatic alkanoyl tetrahydro-beta-carboline and derivative thereof in treatment of metabolic disease - Google Patents
Application of aromatic alkanoyl tetrahydro-beta-carboline and derivative thereof in treatment of metabolic disease Download PDFInfo
- Publication number
- CN102977091A CN102977091A CN2012104390337A CN201210439033A CN102977091A CN 102977091 A CN102977091 A CN 102977091A CN 2012104390337 A CN2012104390337 A CN 2012104390337A CN 201210439033 A CN201210439033 A CN 201210439033A CN 102977091 A CN102977091 A CN 102977091A
- 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
Links
- 0 CC1C(C2)C(C)(C)C(C)C2*1 Chemical compound CC1C(C2)C(C)(C)C(C)C2*1 0.000 description 6
Images
Abstract
The present invention discloses an aromatic alkanoyl tetrahydro-beta-carboline compound represented by a structural formula (I), and related analogs thereof or hydrates or pharmaceutically acceptable salts thereof, and the application of the compound or pharmaceutical compositions containing the compound in the preparation of drugs for treatment of various metabolic 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 in the various metabolic diseases for the treatment of.
Background technology
Metabolic disease all is the 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 metabolic disease 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.Data show that the sickness rate such as metabolic disease such as diabetes, metabolic syndromes and mortality ratio all are in high position, and wherein diabetes mainly are divided into type 1 diabetes, diabetes B and gestational diabetes etc., and wherein diabetes B accounts for more than 90%.Diabetes B shows as insulin resistant and lower insulin secretion level, its islet beta-cell apoptosis as insulin secretory cell is obvious on the one hand, quantity reduces, obstacle appears in insulin signaling pathway on the other hand, and the Regular Insulin effect is organized no longer Regular Insulin is shown as higher susceptibility.According to statistics, by 2011, only the diabetic subject of China conclusive evidence nearby 100,000,000, and the high risk population has 1.5 hundred million, and height ranks first; And the total patient 3.66 hundred million in the whole world, diabetes medicament market probably has 23,600,000,000 dollars, expects the year two thousand twenty and will reach 45,100,000,000 dollars.But still without the medicine of curing diabetes, also there is very large obvious deficiency in existing antidiabetic medicine in the market, as causes the potential carinogenicity of the dead risk such as hypoglycemia, obesity, dysfunction of liver, increase cardiovascular disorder and apoplexy and life-time service.The diabetic subject urgently wishes to find effective adjusting blood glucose balance, and has the medicine that better security reaches less toxic side effect, therefore, needs the antimetabolic disease medicament 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 has too TGF-signal β path in the diabetic mice pancreas islet, 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 chip gene expression profile analysis and other relevant experimental verification; show this compounds through the screening find in surprise that also the compounds of this invention also has obvious prevention effect to metabolic disease such as diabetes etc., can obviously improve the healthy state of diabetic mice.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
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, thin assorted 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 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, it is represented by following structural formula (VI):
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, 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; Dredge; 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, pectinose, 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 all being 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 all being 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; Dredge; 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, pectinose, 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, hydrate or the pharmacy acceptable salt purposes in preparation treatment metabolic disease medicine.Wherein metabolic disease comprise that glucose-tolerant is impaired, hyperlipemia and diabetes etc.
Medicine of the present invention uses separately or unites use with other drug.
Description of drawings
Figure 1 shows that the compounds of this invention is depicted as the compounds of this invention to the result for the treatment of figure of diabetes B mouse.Wherein, Figure 1A is depicted as the compounds of this invention to the impact of diabetes B mouse blood sugar, and Figure 1B is depicted as the compounds of this invention to the impact of diabetes B Mouse Weight, and Fig. 1 C is depicted as the compounds of this invention to the impact of diabetes B mouse food intake.The result shows, the compounds of this invention can effectively reduce diabetes B mouse blood sugar concentration under 10 mg/kg/twos' day dosage, and does not affect food intake and the body weight of mouse.
Figure 2 shows that the compounds of this invention affects figure (hematoxylin-eosin staining) to diabetes B mouse fatty tissue.Fig. 2 A is the section of normal mouse fatty tissue, and Fig. 2 B is the section of diabetes B mouse fatty tissue, and Fig. 2 C is diabetes B mouse fatty tissue section after using the compounds of this invention to treat.The result shows that it is large that diabetes B mouse adipocyte volume obviously becomes, and can faintly reduce the size of adipocyte in the diabetes B mouse fatty tissue after the treatment of use the compounds of this invention.
Figure 3 shows that the compounds of this invention affects figure (hematoxylin-eosin staining) to diabetes B mouse islets form.Fig. 3 A is the section of normal mouse pancreas, and Fig. 3 B is the section of diabetes B mouse pancreas, and Fig. 3 C is diabetes B mouse pancreas section after using the compounds of this invention to treat.The result shows that the compounds of this invention can effectively increase the pancreas islet volume of diabetes B mouse, and the quantity of islet cells also significantly increases.
Figure 4 shows that the compounds of this invention in diabetes B mouse islets tissue, the smad3 of phosphorylation is entered the nuclear figure of impact (immunohistochemical methods).Fig. 4 A is the smad3 immunohistochemical methods figure of phosphorylation in the normal mouse pancreas islet, mainly be distributed in the tenuigenin, Fig. 4 B is the smad3 immunohistochemical methods figure of phosphorylation in the diabetes B mouse islets, mainly be distributed in the nucleus, show that TGF-β path is in active state in the diabetes B mouse islets, Fig. 4 C mainly is distributed in the tenuigenin for using the smad3 immunohistochemical methods figure of phosphorylation in the rear diabetes B mouse islets of the compounds of this invention treatment.The result shows that the smad3 that the compounds of this invention can significantly suppress phosphorylation enters nucleus, thereby suppresses TGF-signal β path.
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 Bruker 300 or Bruker 400 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 temperature rising reflux 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 one: the compounds of this invention is to the treatment of diabetes B mouse
(1), the foundation of diabetes B mouse model
Purchase ICR mouse in 6 age in week, after animal center is observed a week, high lipid food (Research Diets company, 60% fat) fed for 3 weeks, weighing Mouse Weight weekly, remove the mouse that body weight does not obviously increase after three weeks, obesity mice is pressed the citric acid solution of the dosage disposable celiac injection 2%STZ of 85mg/kg, high lipid food continues to feed, measure after the meal two hours blood glucoses of mouse after three weeks, what blood glucose value was higher than 11.1mM thinks the diabetes B mouse, gets the mouse of blood glucose value about 15mM and carries out experimentation on animals.
The postprandial blood sugar measuring method: before postprandial blood sugar was measured, mouse hunger was spent the night (18:00-8:00), presses the glucose solution of the dosage gavage 25% of 2g/kg, and docking is got blood and detected mouse blood sugar with blood glucose meter after two hours.
(2), the compounds of this invention treatment diabetes B
Get the diabetes B mice group of modeling success, guarantee every group of mouse quantity more than or equal to 8, and every group of mouse average blood sugar value is more approaching.The compounds of this invention is pressed every other day intraperitoneal administration of 10mg/kg with DMSO (methyl-sulphoxide) dissolving, the DMSO of the same amount of control group injection.Weighing every day mouse feed amount is calculated the mouse food-intake, and the weighing Mouse Weight detects weekly the mouse postprandial blood sugar weekly, treats continuously for 8 weeks, and the result as shown in Figure 1.Wherein, from Figure 1A, can find, use the compounds of this invention treatment diabetes B mouse after 1 week, blood glucose in diabetic mice just effectively reduces, and the compounds of this invention (reached for 8 weeks) and all has good lowering blood glucose concentration in whole therapeutic process effect, glucose level has significant difference (p＜0.05) between control group and treatment group, Figure 1B shows the compounds of this invention not significantly impact of body weight on mouse in this diabetes B mouse therapeutic process, and Fig. 1 C shows that then two groups of mouse have similar food intake in therapeutic process.Embodiment five: the diabetes B mouse is being observed with the tissue slice after the compounds of this invention treatment
(1), organization material is prepared
Stand-by the compounds of this invention treatment diabetes B mouse is after 8 weeks, take off cervical vertebra execution mouse and get epididymal adipose tissues pad and pancreas, 4% Paraformaldehyde 96 is fixed 24 hours, flowing water flushing tissue spends the night, and dewaters and waxdip by following program: 1: 1 dimethylbenzene 1h-of 50% alcohol 1h-75% alcohol 1h-85% alcohol 1h-95% alcohol 1h-100% alcohol 1h-alcohol dimethylbenzene 40min-dimethylbenzene 40min-1 wax 2h-2 wax wax 5h that spends the night-No. 3.Material behind the waxdip carries out embedding, repair section (5 μ m are thick) behind the sheet, 62 ℃ of baking sheets two hours, 4 ℃ of materials that preservation cuts.
(2), dyeing is observed
The slice, thin piece that taking-up cuts dewaters by following program: 1: 1 alcohol 5min-100% of No. 1 dimethylbenzene 10min-2 dimethylbenzene 10min-dimethylbenzene alcohol 5min-95% alcohol 2min-85% alcohol 2min-75% alcohol 2min.
When carrying out HE (hematoxylin-eosin) dyeing, slice, thin piece after dehydration 10min-flushing with clean water-5 seconds-tap water of alcohol hydrochloric acid soln color separation anti-blue (flushing 5min) 8 seconds-95% alcohol rinses of-75% alcohol 2min-85% alcohol 2min-95% alcohol 2min-Yihong solution-dyed that dye in phenodin are washed 1: 1 alcohol 5min-1 of-100% alcohol 2min-dimethylbenzene dimethylbenzene 10min-2 dimethylbenzene 10min-and are dried the rear resinene mounting of using, microscopic examination is taken pictures, result such as Fig. 5, shown in Figure 6, phenodin can be the nuclei dyeing au bleu, and Yihong can be dyed redness to tenuigenin, and each is checked and answers a cell.
Wherein show among Fig. 2, diabetes B mouse adipocyte volume (Fig. 2 B) compared with normal mouse adipocyte volume (Fig. 2 A) is compared certain increase, the characteristics of diabetes B mouse obesity have been embodied, and in therapeutic process, the compounds of this invention reduces that certain effect is arranged (such as Fig. 2 B, 2C) to the volume of diabetes B mouse adipocyte.
Fig. 3 is shown as mouse pancreas section result, comprises a plurality of pancreas islet in the pancreas, and pancreas islet energy excreting insulin is responsible for the regulation and control of blood sugar, and the diabetic insulin level is generally also relatively low.From Fig. 3, can clearly find, pancreas islet (shown in the arrow) clear-cut in the normal mouse pancreas (Fig. 3 A), volume is larger, cell quantity more (the corresponding cell of each dark nucleus), and the obvious atrophy of pancreas islet volume of diabetes B mouse, cell quantity is lower, and prompting diabetes B mouse islets element level lacks (Fig. 3 B).Pleasurable is, use the compounds of this invention treatment diabetes B mouse after 8 weeks, the volume of pancreas islet obviously increases in the mouse pancreas, and cell quantity also significantly increases (Fig. 3 C) in the pancreas islet, and these results are just showing that the compounds of this invention has preferably therapeutic action to diabetes B.
When carrying out immunohistochemical staining, the slice, thin piece after the dehydration changes PBS solution 10min-3%H over to after citric acid solution places 98 ℃ of water-bath antigen retrieval 30min-slowly to be down to stop up temperature putting into
2O
210min-PBS solution is washed 3 times, 4 ℃ of overnight incubation of 3min/ time-lowlenthal serum room temperature sealing 10min-phosphorylation smad3 antibody-PBS solution is washed 3 times, 3min/ time-two anti-incubated at room 1h-PBS solution are washed 3 times, 3min/ time-HRP solution incubated at room 10min-PBS solution is washed 3 times, 3min/ time-DAB develops the color (about 1-2min), then carries out brazilwood extract dyeing 10min, and following step is not with above-mentioned HE staining procedure (need carry out Yihong dyeing), microscopic examination is taken pictures
Result such as Fig. 4 show.In the tissue slice, the smad3 of phosphorylation is shown as brown, so as described in background introduction, after TGF-β path is activated, the brown signal of smad3 can overlap with the blue signal (nucleus can be dyed blueness by phenodin) in the nuclear, make outer painted the shoaling of nuclear after the coincidence, and painted darker on the nuclear.So, comparison diagram 4A and Fig. 4 B are as seen, the smad3 of phosphorylation signal in the diabetes B Mice Islet Cells strengthens, be presented as that two kinds of signals overlap (shown in arrow among Fig. 7 B) at nuclear, the signal weakening that nuclear is outer, and after using the compounds of this invention to the treatment of diabetes B mouse, the signal of the smad3 of phosphorylation on nuclear obviously weakens, more be distributed in (Fig. 4 C) in the extranuclear tenuigenin, show that the compounds of this invention can enter nuclear by the smad3 of establishment phosphorylation in pancreas islet, thereby in pancreas islet, suppress TGF-signal β path (inhibition TGF-signal β path helps the treatment to diabetes).
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 1-30 7-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 1-31 5-(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 1-32 5-(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 1-33 5-(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 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, B oc-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 1-35 5-(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 and refluxed 1 hour in the NaOH of 1N heated in water solution, 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 and refluxed 1 hour in the NaOH of 1N heated in water solution, 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 m 2H), 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 (17)
1. an aromatic base alkyloyl tetrahydro-beta-carboline and derivative or its hydrate or pharmacy acceptable salt is characterized in that, are 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, dredge 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
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
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:
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, pectinose, 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 be respectively methylene radical, acyl group, amino, oxygen, dredge or any one of 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, pectinose, 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 purposes in preparation treatment metabolic disease medicine according to claim 1-8.
15. each described aromatic base alkyloyl tetrahydro-beta-carboline and derivative thereof or its hydrate or the pharmacy acceptable salt purposes in preparation treatment diabetes and diabetes complicated disease drug according to claim 1-8.
16. each described aromatic base alkyloyl tetrahydro-beta-carboline and derivative thereof or its hydrate or the pharmacy acceptable salt purposes in preparation treatment metabolic syndrome medicine according to claim 1-8.
17. each described application is characterized in that according to claim 14-16, described medicine uses separately or unites use with other drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210439033.7A CN102977091B (en) | 2012-11-06 | 2012-11-06 | Fragrance alkyloyl tetrahydro-beta-carboline and the application of derivative in treatment metabolic disease thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210439033.7A CN102977091B (en) | 2012-11-06 | 2012-11-06 | Fragrance alkyloyl tetrahydro-beta-carboline and the application of derivative in treatment metabolic disease thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102977091A true CN102977091A (en) | 2013-03-20 |
| CN102977091B CN102977091B (en) | 2016-03-09 |
Family
ID=47851482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210439033.7A Active CN102977091B (en) | 2012-11-06 | 2012-11-06 | Fragrance alkyloyl tetrahydro-beta-carboline and the application of derivative in treatment metabolic disease thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102977091B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2012
- 2012-11-06 CN CN201210439033.7A patent/CN102977091B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102977091B (en) | 2016-03-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7902237B2 (en) | Heterocyclic compounds as pharmaceutical agents | |
| TW584560B (en) | Pharmaceutical composition of substituted indolealkanoic acids for reducing serum glucose and triglyceride levels and inhibiting angiogenesis | |
| CN102424681B (en) | Acyl-tetrahydro-beta-carboline compound as well as derivatives, application and preparation method thereof | |
| NO332005B1 (en) | New pyridopyrazines, their use, medicament containing at least one such compound and process for the preparation of such a medicament | |
| JP2010523490A (en) | Novel imidazo [4,5-b] pyridine-7-carboxamide 704 | |
| JPWO2010007943A1 (en) | Nitrogen-containing heterocyclic compounds | |
| JP6293266B2 (en) | Composition for the treatment of hypertension and / or fibrosis | |
| US7442696B2 (en) | Mineralocorticoid receptor modulator compounds, processes for their preparation, and their uses | |
| JPWO2010007944A1 (en) | Nitrogenous bicyclic heterocyclic compounds | |
| CN101503402B (en) | 2-aniline pyrimidine derivative, as well as preparation and uses thereof | |
| EA020609B1 (en) | IMIDAZO[1,2-a]PYRIDIN-2-YLPHENYL DERIVATIVES TO BE USED IN CANCER TREATMENT | |
| CN102977092B (en) | Fragrance alkyloyl tetrahydro-beta-carboline and the application of derivative in treatment malignant tumour thereof | |
| CN107151233B (en) | Hydrazone-containing pyrimidine derivative and application thereof | |
| CN104530038A (en) | Amide imidazole derivative and application thereof | |
| CN102977091B (en) | Fragrance alkyloyl tetrahydro-beta-carboline and the application of derivative in treatment metabolic disease thereof | |
| US10450295B2 (en) | Method of using an indolinone molecule and derivatives for inhibiting liver fibrosis and hepatitis | |
| CN102268000A (en) | Novel spiroheterocyclic compound and application of same serving as therapeutic agent | |
| US9399644B2 (en) | [1,3] dioxolo [4,5-G] quinoline-6(5H)thione derivatives as inhibitors of the late SV40 factor (LSF) for use in treating cancer | |
| JP2021521179A (en) | Morpholine derivative as an inhibitor of VPS34 | |
| CN101638395A (en) | Heterocyclic analog of diphenylethlene compound and application thereof | |
| Samuel | Synthesis and Evaluation of Indole Cyanoacrylic Acids as Anticancer Agents | |
| CN103694195A (en) | Heterocyclic aromatic micromolecule organic compounds and derivatives, preparation method and medical application | |
| EP3027605B1 (en) | Novel indazole compounds and a process for the preparation thereof | |
| CN104529905A (en) | N-3-benzimidazole bisamide derivative as well as preparation method and application thereof | |
| Cavalheiro | Synthesis of 5-methylene (thio) ureas (thio) barbiturates as potential xanthine oxidase inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |