CN102977091B - Fragrance alkyloyl tetrahydro-beta-carboline and the application of derivative in treatment metabolic disease thereof - Google Patents

Abstract

The invention discloses an aryl alkanoyl tetrahydro-β-carboline compound represented by structural formula (I) and related analogs or hydrates or pharmaceutically acceptable salts thereof, which contain the compound of the invention or a pharmaceutical combination thereof The application of the compound in the preparation of medicines for the treatment of various metabolic diseases.

Description

Application of aromatic alkanoyl tetrahydro-β-carboline and its derivatives in the treatment of metabolic diseases

technical field

The present invention relates to a compound represented by the following structure (I) and related derivatives, and the use of the compound or the pharmaceutical composition containing the compound in treating various metabolic diseases.

Background technique

Metabolic diseases are major diseases faced by human beings. With the rapid development of my country's economy, changes in lifestyles, increased survival pressure, intensified population aging problems and deepening urbanization, the occurrence and development of metabolic diseases have become an important obstacle to the further improvement of people's quality of life, and pose a threat to individuals and society brings a heavy economic and spiritual burden. Data show that the morbidity and mortality of metabolic diseases such as diabetes and metabolic syndrome are extremely high. Among them, diabetes is mainly divided into type 1 diabetes, type 2 diabetes and gestational diabetes, etc., of which type 2 diabetes accounts for 90% above. Type 2 diabetes manifests as insulin resistance and low insulin secretion level. On the one hand, the islet β cells, which are insulin-secreting cells, undergo significant apoptosis and decrease in number; for higher sensitivity. According to statistics, by 2011, there will be nearly 100 million confirmed diabetic patients in my country alone, and 150 million high-risk groups, ranking first; while there are 366 million patients in the world, the diabetes drug market is about 23.6 billion US dollars, and it is expected to reach 451 by 2020. One hundred million U.S. dollars. However, there is still no cure for diabetes on the market, and existing antidiabetic drugs also have significant deficiencies, such as causing hypoglycemia, obesity, abnormal liver function, increasing the risk of death such as cardiovascular disease and stroke, and the potential for long-term use. Carcinogenicity. Diabetic patients are eager to find drugs that can effectively regulate blood sugar balance and have better safety and less toxic side effects. Therefore, it is necessary to develop new anti-metabolic disease drugs targeting new targets and multiple targets.

EGFR is a member of the epidermal growth factor receptor family, and the EGFR signaling pathway plays an important regulatory role in physiological processes such as cell growth, proliferation, differentiation, apoptosis, angiogenesis, tumor invasion and metastasis. Phosphorylation of EGFR or other results of its abnormal activity may cause tumors, diabetes, immunodeficiency and cardiovascular diseases. At present, there are many drugs targeting EGFR to treat tumors and other diseases, such as antibody drugs such as cetuximab and small molecule drugs such as tinib. The TGF-β signaling pathway plays an important role in the occurrence and development of many diseases. Its overactivation can cause malignant tumors, inflammation, and fibrosis of the liver and kidney. The TGF-β signaling pathway has become a popular target in drug development. Recent studies have shown that the TGF-β signaling pathway is also highly activated in the islets of diabetic mice, and when this pathway is inhibited, it will be beneficial to the treatment of diabetes. In the TGF-β cell signaling pathway, when the pathway is activated, it can cause the phosphorylation of smad3, and then be activated. The activated smad3 will enter the nucleus from the cytoplasm, and the phosphorylated smad3 in the nucleus can participate in the regulation of many downstream genes, so trying to inhibit the phosphorylation of smad3 may be of great significance to inhibit the TGF-β signaling pathway and treat diabetes.

β-carboline compounds are a class of compounds containing an indolopyridine structure, and they are a class of alkaloids isolated from Sapotaceae, Apocynaceae and Streptomyces. According to literature reports, natural or synthetic small molecular compounds containing β-carboline or tetrahydro-β-carboline structure have various biological activities, such as antithrombotic activity, antimalarial activity, neuroprotective effect, etc. (J. Med. Chem. 2010, 3106-16). However, compounds containing this type of structure usually have several obvious shortcomings. First, the molecular mechanism of action of the compound is not clear enough, so the research on its pharmacological effect is relatively lacking; in addition, another defect of this type of compound is that the physical and chemical properties of the compound are not enough. Ideally, this largely limits the druggability studies of such compounds. Tetrahydro-β-carboline compounds also have various physiological activities, and have more favorable physical and chemical properties than carbolines. Therefore, it is necessary to creatively carry out oriented derivatization on tetrahydro-β-carboline compounds to form a new class of tetrahydro-β-carboline compounds, increase their drug-like properties, and enable them to be used in subsequent clinical applications. ex-study. The arylalkylacyltetrahydro-β-carbolines and their derivatives proposed by the present invention fulfill this need and provide other related advantages.

Contents of the invention

The present invention obtains specific aryl alkyl acyl tetrahydro-β-carboline derivatives by introducing some chemical groups into the left half of aryl alkyl acyl tetrahydro-β-carboline, which is proved to be effective on tumor growth and metastasis all have very excellent therapeutic effects, with the help of gene expression profile chip analysis and other related experimental verification, it is shown that this kind of compound is also surprisingly found that the compound of the present invention also has obvious prevention and treatment effect on metabolic diseases such as diabetes, etc., can be obvious Improved health in diabetic mice. In addition, after the introduction of some specific groups, the physical and chemical properties of the compound have changed greatly, including the water solubility and pharmacokinetic properties of the compound have been greatly improved.

The first object of the present invention is to provide a tetrahydro-β-carboline small molecular organic compound as shown in the following structural formula (I) or a hydrate or a pharmaceutically acceptable salt thereof, which has the following structural formula (I): The structure shown:

in:

m is 0-8 CH ₂ ;

n is 0-3 CH ₂ ;

It is any one of a monocyclic aromatic group, a polycyclic aromatic group, and a polycyclic aromatic group; the monocyclic aromatic group includes phenyl, azaaryl, sparse heteroaryl, and oxaaryl; the polycyclic An aromatic group and a polyheterocyclic aromatic group refer to a group containing two or more monocyclic aromatic groups.

R is _a substituent on the aromatic ring, including single substitution and multiple substitution, independently selected from one or more of the following groups: hydrogen, amino, cyano, hydroxyl, nitro, halogen, carboxyl, alkyl, alkane Oxygen, amino, cycloalkoxy, cycloamino, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, C ₃ -C ₁₂ cycloalkyl, benzyl, alkylcarbonyl, C ₂ - C ₁₂ alkenylcarbonyl, C ₃ -C ₁₂ cycloalkylcarbonyl, phenylcarbonyl, benzylcarbonyl, alkoxycarbonyl, ester, sulfoxide, sulfone, sulfinamide, sulfonamide; morpholinyl ; piperazinyl;

R ₂ is arbitrarily selected from one of the following groups: hydrogen, alkyl, halogen, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl, heterocyclic aromatic Benzyl, phenethyl, phenylpropyl, alkoxy, alkylamino, alkylcarbonyl and arylcarbonyl, morpholinomethyl, hydroxymethyl;

R ₃ and R ₄ substituents are arbitrarily selected from one or more of the following groups: hydrogen, alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, Aryl, heteroaryl, benzyl, phenethyl, phenylpropyl, amino, cyano, nitro, halogen;

R is a substituent _on the aromatic ring, independently selected from one, two or more of the following groups: hydrogen, amino, cyano, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxy, Substituted amino, cycloalkoxy, cycloalkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl, heteroaryl, benzyl , Alkylcarbonyl, C ₂ -C ₆ alkenylcarbonyl, C ₃ -C ₆ cycloalkylcarbonyl, phenylcarbonyl, benzylcarbonyl, alkoxycarbonyl, ester group, sulfoxide group, sulfone group, sulfinamide group , Sulfonamido; Morpholinyl; Piperazinyl;

The R ₆ substituent is arbitrarily selected from one of the following groups: hydrogen, alkyl, hydroxymethyl, alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkane group, C ₃ -C ₈ cycloalkenyl group, aryl group, heterocyclic aromatic group, benzyl group, phenethyl group, phenylpropyl group, alkylamino group.

In structural formula (I), when When it is a five-membered aromatic ring, it is represented by the following structural formula (II):

in:

A, B and D independently select one of nitrogen, oxygen, sulfur or CR ₅ groups; make maintain aromaticity;

The R ₇ substituent is arbitrarily selected from one of the following groups: hydrogen, alkyl, hydroxymethyl, alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkane group, C ₃ -C ₈ cycloalkenyl group, aryl group, heterocyclic aromatic group, benzyl group, phenethyl group, phenylpropyl group, alkylamino group.

In structural formula (I), when When it is a six-membered aromatic ring, it is represented by the following structural formula (III):

Wherein: E, F, G and H independently select one of nitrogen or CR ₅ groups; make Keep aromatic. In structural formula (III), when When it is a benzene ring, it is represented by the following structural formula (IV):

in:

R ₈ , R ₉ , R ₁₀ and R ₁₁ are substituents on the benzene ring, each independently selected from one of the following groups: hydrogen, amino, cyano, hydroxyl, nitro, halogen, carboxyl, alkyl, alkane Oxygen, substituted amino, cycloalkoxy, cycloalkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl, heterocyclic aryl , benzyl, alkylcarbonyl, C ₂ -C ₆ alkenylcarbonyl, C ₃ -C ₆ cycloalkylcarbonyl, phenylcarbonyl, benzylcarbonyl, alkoxycarbonyl, ester, sulfoxide, sulfone, sulfoxide Sulfonamide, sulfonamide; Morpholinyl; Piperazinyl;

In structural formula (III), when When it is a benzene ring, n is one CH ₂ , and when R ₂ , R ₃ and R ₄ are all hydrogen, it is represented by the following structural formula (V):

In structural formula (III), when When it is a benzene ring, m and n are both CH ₂ , and when R ₂ , R ₃ and R ₄ are all hydrogen, it is represented by the following structural formula (VI):

In structural formula (III), when When it is a benzene ring, m and n are both CH ₂ , when R ₂ , R ₃ and R ₄ are all hydrogen, when any three of R ₈ , R ₉ , R ₁₀ and R ₁₁ are hydrogen, It is represented by the following structural formula (VII):

Wherein X is methylene; Acyl; Amino; Oxygen; Sulphur; Sulfonyl;

R ₁₂ is arbitrarily selected from one of the following groups: hydrogen, amino, cyano, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxy, substituted amino, cycloalkoxy, cycloalkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl, heterocyclic aryl, benzyl, alkylcarbonyl, C ₂ -C ₆ alkenylcarbonyl, C ₃ -C ₆ cycloalkylcarbonyl, phenylcarbonyl, benzylcarbonyl, alkoxycarbonyl, ester, sulfoxide, sulfone, sulfinamide, sulfonamide; morpholinyl; piperazinyl; formyl Morpholine, Acylethylmorpholine, Acylpropylmorpholine; Piperazinyl, Acylmethylpiperazine, Acylethylmethylpiperazine, Acylpropylmethylpiperazine, Methylpiperazinyl; Amino Acid Residues (Glycine, Serine, Alanine, Threonine, Valine, Isoleucine, Leucine, Tyrosine, Phenylalanine, Histidine, Proline, Aspartic Acid, Methylthio amino acid, glutamic acid, tryptophan, lysine, cysteine, arginine, glutamine, asparagine), straight chain amino acid, branched chain amino acid, erythrose, threose, to Threose, allose, altrose, gulose, idose, talose, ribose, deoxyribose, xylose, arabinose, glucose, mannose, galactose, fructose, amino sugar, oligosaccharides.

In structural formula (III), when When it is a benzene ring, m and n are both CH ₂ , when R ₂ , R ₃ and R ₄ are all hydrogen, when any three of R ₈ , R ₉ , R ₁₀ and R ₁₁ are hydrogen, It is represented by the following structural formula (VII): m, n are all one CH ₂ , R ₂ , R ₃ and R ₄ are all hydrogen, when any two of R ₈ , R ₉ , R ₁₀ and R ₁₁ are When the group is hydrogen, it is represented by the following structural formula (VIII):

Wherein X and Y are respectively methylene; Acyl; Amino; Oxygen; Sulphur; Sulfonyl;

R ₁₂ and R ₁₃ are arbitrarily selected from one of the following groups: hydrogen, amino, cyano, hydroxyl, nitro, halogen, carboxyl, alkyl, alkoxy, substituted amino, cycloalkoxy, cycloalkylamine C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, aryl, heterocyclic aryl, benzyl, alkylcarbonyl, C ₂ -C ₆ alkenyl Carbonyl, C ₃ -C ₆ cycloalkylcarbonyl, phenylcarbonyl, benzylcarbonyl, alkoxycarbonyl, ester, sulfoxide, sulfone, sulfinamide, sulfonamide; morpholinyl; piperazinyl ; Formylmorpholine, acylethylmorpholine, acylpropylmorpholine; piperazinyl, acylmethylpiperazine, acylethylmethylpiperazine, acylpropylmethylpiperazine, methylpiperazinyl; Amino acid residues (glycine, serine, alanine, threonine, valine, isoleucine, leucine, tyrosine, phenylalanine, histidine, proline, aspartic acid , Methionine, Glutamic Acid, Tryptophan, Lysine, Cysteine, Arginine, Glutamine, Asparagine), Linear Amino Acids, Branched Chain Amino Acids, Erythrose, Sua Sugar, lyxose, allose, altrose, gulose, idose, talose, ribose, deoxyribose, xylose, arabinose, glucose, mannose, galactose, fructose, amino sugar, oligosaccharides.

The present invention also provides small molecule organic compounds, hydrates or pharmaceutically acceptable salts of any of the aforementioned arylalkanoyltetrahydro-β-carbolines or derivatives thereof. Wherein said acceptable salts include acid salts and alkali salts, groups suitable for contacting human or animal tissues without undue toxicity or carcinogenicity, with particular preference for those groups without irritation, allergic reaction or other complications . Included are basic or organic salts of acidic residues such as carboxylic acids, as well as inorganic and organic acidic salts of basic residues such as amines. Anions that can be used for salt formation include, but are not limited to: hydrochloride, hydrobromide, sulfate, phosphate, acetate, tartrate, salicylate, citrate, methanesulfonate, p-toluenesulfonate, lactate, acetone Acid, Maleate, Succinate, Ascorbate, Benzoate, Bicarbonate, EDTA, Formate, Glutamate, Glycolate, Hydroxymaleate, Malate, Mandelate, Sulfamate Acid, sulfonate, chloride, bromide, etc. Similarly, cations that can be used for salt formation include, but are not limited to, ammonium, ethylenediamine, choline, diethanolamine, procaine, and metals such as sodium, potassium, magnesium, aluminum, zinc, and lithium.

In some aspects of the present invention, detection labels such as radioactivity, fluorescent groups or biotin can be used to label the aryl alkanoyl tetrahydro-β-carboline compounds and related derivatives provided by the present invention.

In the present invention, aryl alkanoyl tetrahydro-β-carboline small molecule organic compounds or their hydrates or pharmaceutically acceptable salts include but are not limited to the following compounds:

N-Phenylacetyl-(6-trifluoromethyl)-1,3,4,9-tetrahydro-1H-β-carboline

N-Phenylacetyl-(6-trifluoromethoxy)-1,3,4,9-tetrahydro-1H-β-carboline

6-(2-morpholinoethyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(4-methylpiperazine)carbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(2-(Dimethylamino)ethyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(3-(Dimethylamino)propyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(4-Morpholinylphenyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(4-Dimethylaminophenyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(4-Aminosulfonyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(N,N-bis(2-hydroxyethyl))aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(2-(2-Hydroxyethoxy)ethyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Serine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Aspartic acid carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(alaninecarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Phenylalaninecarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Glutamic acid carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Prolinecarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Glycinecarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Tyrosinecarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(Histidinecarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-cyano-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Nitro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Benzyloxy-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Methoxycarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Hydroxy-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Carboxy-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-Methyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-Amino-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline

7-Amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(2-(N-morpholinyl))acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(2-(4-methylpiperazinyl))acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(2-Amino)acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(2-threonyl)amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(2-Prolinyl)amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(4-Bromobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-Methyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

8-Fluoro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

6-(2-Amino)acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

N-Phenylacetyl-6,8-difluoro-1,3,4,9-tetrahydro-1H-β-carboline

N-phenylacetyl-6,8-difluoro-9-p-bromobenzyl-1,3,4,9-tetrahydro-1H-β-carboline

9-Benzyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(4-fluorobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(4-methylcarboxylate benzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(4-Carboxybenzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(Methoxycarbonylmethyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(Carbonylmethyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

9-(4-(morpholinyl)carbonylmethyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-Methoxycarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(Valine amino)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(Alanineamino)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline

5-(3-Amino)propionylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline.

The present invention provides a pharmaceutical composition, which contains one or more aryl alkanoyl tetrahydro-β-carboline small molecule organic compounds, hydrates or pharmaceutically acceptable salts described in the present invention, and pharmaceutical acceptable carrier.

Wherein, in a specific embodiment, the composition is formulated as an injectable fluid, aerosol, cream, gel, pill, capsule, syrup, transdermal patch or excipient.

The present invention provides prodrugs of aryl alkanoyl tetrahydro-β-carboline small molecule organic compounds and related derivatives described in formula (I). "Prodrug" means that the compound itself may not fully meet the structural requirements of the compounds provided herein but undergoes in vivo changes to produce the compounds of the formulas provided herein after administration to a patient. Examples of prodrugs include, but are not limited to, esters, eg, that can be modified by the presence of functional groups such that the modification is cleaved in vivo to yield the parent compound.

The compounds of the present invention also include dimeric and multimeric compounds in which the compounds represented by formula (I) are linked in various ways.

The invention provides the use of aryl alkanoyl tetrahydro-β-carboline small molecular organic compounds, hydrates or pharmaceutically acceptable salts in the preparation of drugs for treating metabolic diseases. Among them, metabolic diseases include impaired glucose tolerance, dyslipidemia, and diabetes.

The medicine of the present invention is used alone or in combination with other medicines.

Description of drawings

Figure 1 shows the compound of the present invention and shows the therapeutic effect of the compound of the present invention on type 2 diabetic mice. Wherein, Fig. 1A shows the effect of the compound of the present invention on the blood sugar of type 2 diabetic mice, Fig. 1 B shows the effect of the compound of the present invention on the body weight of type 2 diabetic mice, and Fig. 1 C shows the effect of the compound of the present invention on the body weight of type 2 diabetic mice Effects of food intake in mice. The results show that the compound of the present invention can effectively reduce the blood glucose concentration of type 2 diabetic mice at a dose of 10 mg/kg/day, without affecting the food intake and body weight of the mice.

Fig. 2 is a graph showing the effect of the compound of the present invention on the adipose tissue of type 2 diabetic mice (hematoxylin-eosin staining). Fig. 2A is a section of adipose tissue of a normal mouse, Fig. 2B is a section of adipose tissue of a type 2 diabetic mouse, and Fig. 2C is a section of adipose tissue of a type 2 diabetic mouse after treatment with the compound of the present invention. The results show that the volume of adipocytes in type 2 diabetic mice becomes significantly larger, and the size of adipocytes in adipose tissue of type 2 diabetic mice can be slightly reduced after treatment with the compound of the present invention.

Fig. 3 is a diagram showing the effect of the compounds of the present invention on the morphology of islets in type 2 diabetic mice (hematoxylin-eosin staining). Figure 3A is a section of pancreas of a normal mouse, Figure 3B is a section of pancreas of a type 2 diabetic mouse, and Figure 3C is a section of pancreas of a type 2 diabetic mouse after treatment with the compound of the present invention. The results show that the compound of the present invention can effectively increase the volume of islets of type 2 diabetes mice, and the number of islet cells is also significantly increased.

Fig. 4 shows the effect of the compounds of the present invention on the entry of phosphorylated smad3 into the nucleus in islet tissue of type 2 diabetic mice (immunohistochemistry). Figure 4A is the immunohistochemical picture of phosphorylated smad3 in islets of normal mice, mainly distributed in the cytoplasm, and Figure 4B is the immunohistochemical picture of phosphorylated smad3 in islets of type 2 diabetic mice, mainly distributed in the nucleus, indicating that 2 The TGF-β pathway is activated in islets of type 2 diabetic mice. Figure 4C is an immunohistochemical image of phosphorylated smad3 in islets of type 2 diabetic mice after treatment with the compound of the present invention, which is mainly distributed in the cytoplasm. The results show that the compound of the present invention can significantly inhibit phosphorylated smad3 from entering the nucleus, thereby inhibiting the TGF-β signaling pathway.

detailed description

The present invention will be described in further detail in conjunction with the following specific examples and accompanying drawings, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages conceivable by those skilled in the art are all included in the present invention, and the appended claims are the protection scope.

¹ H-NMR was measured by Bruker300 or Bruker400; MS was measured by VGZAB-HS or VG-7070, and all were ESI methods unless otherwise noted; all solvents were re-distilled before use, and the anhydrous solvents used were All were obtained by drying according to the standard method; except for the instructions, all the reactions were carried out under the protection of argon and tracked by TLC, and the post-treatment was washed with saturated brine and dried with anhydrous magnesium sulfate; the purification of the products was carried out except for the instructions. Column chromatography using silica gel (200-300 mesh); the silica gel used, including 200-300 mesh and GF ₂₅₄ , are produced by Qingdao Ocean Chemical Factory or Yantai Yuanbo Silica Gel Company.

Embodiment one: the preparation of each compound

Example 1-1, Synthesis of N-phenylacetyl-(6-trifluoromethyl)-1,3,4,9-tetrahydro-1H-β-carboline (NTC001)

Take 4-trifluoromethylphenylhydrazine hydrochloride (425mg, 2mmol) in 14mL alcohol and water (volume ratio is 5/1), slowly add 4-chlorobutyraldehyde dimethyl acetal (367mg, 2.2 mmol), then warming and reflux for 5-18 hours. Complete, remove most of the solvent under reduced pressure, then adjust the pH value of the solution to 12, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, and distill off the solvent under reduced pressure to obtain the intermediate 5-trifluoroform Tritryptamine (crude product 464mg).

5-Trifluoromethyltryptamine (464mg, 2.0mmol) was dissolved in 3mL of glacial acetic acid, and 37% formaldehyde solution (45μL, 0.60mmol) was added dropwise under the protection of nitrogen to complete the addition and react overnight. Most of the acetic acid was evaporated under reduced pressure, the pH value of the solution was adjusted to 12, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the intermediate 6-trifluoromethyl-1 was obtained after purification by column chromatography. 3,4,9-Tetrahydro-1H-β-carboline (150 mg, 31% yield).

Dissolve phenylacetic acid (57mg, 0.42mmol) in dry DMF (1mL), add EDC (105mg, 0.55mmol) and HOBt (62mg, 0.46mmol) at 0°C, stir in ice bath for 10 minutes, add compound 6-3 Fluoromethyl-1,3,4,9-tetrahydro-1H-β-carboline (63 mg, 0.32 mmol). After completion, remove the ice bath, react at room temperature for 3 hours, and purify by column chromatography after routine treatment to obtain N-phenylacetyl-(6-trifluoromethyl)-1,3,4,9-tetrahydro-1H-β-carba morphine (62 mg, 66% yield). ¹ HNMR (300MHz, DMSO-d ₆ ): ¹ HNMR (300MHz, DMSO-d6): δ11.37(brs, 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).

Preparation of NTC002-52 carboline compounds shown in Example 2-52 and Table 1 (see reference below for specific process)

Embodiment 1: The compound of the present invention is to the treatment of type 2 diabetic mice

(1) Establishment of type 2 diabetes mouse model

Purchase 6-week-old ICR mice, observe them in the animal center for one week, feed them with high-fat diet (ResearchDiets company, 60% fat) for 3 weeks, weigh the mice every week, remove the mice with no significant increase in body weight after three weeks, and become obese The mice were intraperitoneally injected with 2% STZ citric acid solution at a dose of 85mg/kg, fed with high-fat feed continuously, and the blood glucose of the mice was measured two hours after the meal after three weeks, and those with a blood glucose value higher than 11.1mM were considered to be type 2 diabetes Mice, mice whose blood sugar level is around 15mM are used for animal experiments.

Postprandial blood glucose measurement method: Before postprandial blood glucose measurement, the mice were starved overnight (18:00-8:00), gavaged with 25% glucose solution at a dose of 2g/kg, and two hours later, the blood was taken by docking the tail and used a blood glucose meter. Detection of blood glucose in mice.

(2), compound of the present invention treats type 2 diabetes

Group the type 2 diabetic mice that have been successfully modeled, and ensure that the number of mice in each group is greater than or equal to 8, and that the average blood glucose levels of the mice in each group are relatively close. The compound of the present invention was dissolved in DMSO (dimethyl sulfoxide), administered intraperitoneally at 10 mg/kg every other day, and the control group was injected with the same amount of DMSO. The amount of feed for the mice was weighed every day, the food intake of the mice was calculated, the body weight of the mice was weighed every week, the postprandial blood glucose of the mice was detected every week, and the treatment was continued for 8 weeks. The results are shown in Figure 1. Wherein, it can be found from Fig. 1A that after using the compound of the present invention to treat type 2 diabetic mice for 1 week, the blood sugar of the diabetic mice is effectively reduced, and the compound of the present invention has a good effect throughout the treatment process (up to 8 weeks). The effect of reducing blood sugar concentration, blood sugar level has significant difference (p＜0.05) between control group and treatment group, Fig. 1 B shows that the compound of the present invention has no obvious effect on the body weight of mice during the treatment of this type 2 diabetic mice Figure 1C shows that the two groups of mice had similar food intake during the treatment. Example 5: Observation of tissue sections of type 2 diabetic mice after treatment with the compound of the present invention

(1) Organization and material preparation

After treating type 2 diabetic mice with the compound of the present invention for 8 weeks, the mice were sacrificed by cervical dislocation, the epididymis fat pad and pancreas were taken, fixed with 4% paraformaldehyde for 24 hours, washed with running water overnight, and dehydrated and soaked according to the following procedures. Wax: 50% alcohol 1h—75% alcohol 1h—85% alcohol 1h—95% alcohol 1h—100% alcohol 1h—alcohol 1:1 xylene 1h—xylene 40min—xylene 40min—No. 1 wax 2h—No. 2 Wax overnight - No. 3 wax for 5 hours. The wax-soaked materials were embedded, trimmed and sectioned (5 μm thick), baked at 62°C for two hours, and stored at 4°C.

(2), staining observation

Take out the cut slices and dehydrate according to the following procedure: No. 1 xylene 10 min—No. 2 xylene 10 min—Xylene 1:1 alcohol 5 min—100% alcohol 5 min—95% alcohol 2 min—85% alcohol 2 min—75% alcohol 2min.

When performing HE (hematoxylin-eosin) staining, the dehydrated slices were stained in hematoxylin for 10 minutes—clean water rinse—alcohol hydrochloric acid solution for color separation for 5 seconds—tap water turned blue (washing 5 minutes)—75% alcohol for 2 minutes—85 % Alcohol 2min—95% Alcohol 2min—Eosin Solution Dyeing for 8 Seconds—95% Alcohol Rinse—100% Alcohol 2min—Xylene 1:1 Alcohol 5min—No.1 Xylene 10min—No.2 Xylene 10min—after drying Seal the slide with neutral resin, observe and take pictures under a microscope, hematoxylin can stain the cell nucleus in blue, and eosin can stain the cytoplasm in red, and each nucleus corresponds to a cell.

Among them, Fig. 2 shows that the fat cell volume of type 2 diabetic mice (Fig. 2B) has a certain increase compared with the normal mouse fat cell volume (Fig. 2A), reflecting the characteristics of obesity in type 2 diabetic mice, while in During the treatment, the compound of the present invention has a certain effect on the volume reduction of adipocytes in type 2 diabetic mice (as shown in Figure 2B, 2C).

Figure 3 shows the results of mouse pancreas slices. The pancreas contains multiple islets. The islets can secrete insulin and are responsible for the regulation of blood sugar. Diabetic patients generally have relatively low insulin levels. It can be clearly found from Figure 3 that the islets (indicated by the arrows) in the normal mouse pancreas (Figure 3A) have clear outlines, larger volumes, and a larger number of cells (each dark nucleus corresponds to one cell), while 2 The islet volume of type 2 diabetic mice was significantly shrunk and the number of cells was lower, suggesting that insulin levels were deficient in type 2 diabetic mice (Fig. 3B). It is gratifying that after using the compound of the present invention to treat type 2 diabetic mice for 8 weeks, the volume of the islets in the pancreas of the mice was significantly increased, and the number of cells in the islets was also significantly increased (Fig. 3C), these results just show that the present invention The compound has good therapeutic effect on type 2 diabetes.

For immunohistochemical staining, put the dehydrated slices in citric acid solution and put them in a 98°C water bath for antigen retrieval for 30 minutes—slowly cool down to room temperature, then transfer to PBS solution for 10 minutes—3% H ₂ O ₂ 10 minutes—PBS solution Wash 3 times, 3min/time—goat serum blocked at room temperature for 10min—incubate with phosphorylated smad3 antibody overnight at 4°C—wash 3 times in PBS solution, 3min/time—incubate secondary antibody at room temperature for 1h—wash 3 times in PBS solution, 3min/time—HRP Incubate the solution at room temperature for 10 min—wash with PBS solution 3 times, 3 min/time—develop color with DAB (about 1-2 min), then perform hematoxylin staining for 10 min, the following steps are the same as the above HE staining steps (no need for eosin staining), Microscope observation and photography,

The result is shown in Figure 4. In the tissue section, the phosphorylated smad3 is displayed in brown, so as mentioned in the background introduction, after the TGF-β pathway is activated, the brown signal of smad3 will be combined with the blue signal in the nucleus (the nucleus can be stained blue by hematoxylin ) superimposed, and the superposition made the coloring outside the nucleus lighter, while the coloring on the nucleus was darker. Therefore, comparing Figure 4A and Figure 4B, it can be seen that the signal of phosphorylated smad3 in the islet cells of type 2 diabetic mice is enhanced, which is reflected in the overlap of the two signals on the nucleus (as shown by the arrow in Figure 4B), and the signal outside the nucleus is weakened , and after using the compound of the present invention to treat type 2 diabetic mice, the signal of phosphorylated smad3 on the nucleus was significantly weakened, and more of them were distributed in the cytoplasm outside the nucleus (Figure 4C), indicating that the compound of the present invention can be present in the islets Effectively inhibit phosphorylated smad3 into the nucleus, thereby inhibiting TGF-β signaling pathway in pancreatic islets (inhibition of TGF-β signaling pathway is helpful for the treatment of diabetes).

Reference Examples 2-52

Example 1-2, Synthesis of N-phenylacetyl-(6-trifluoromethoxy)-1,3,4,9-tetrahydro-1H-β-carboline (NTC002)

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced by 4-trifluoromethoxyphenylhydrazine, and finally compound NTC002 was obtained after purification by column chromatography, with a yield of 16%: ¹ HNMR (300MHz , DMSO-d ₆ ): δ11.17 (brs, 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).

Example 1-3, 6-(2-morpholine ethyl) aminocarbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC003) synthesis

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced by 4-hydrazinobenzoic acid methyl ester to obtain intermediate 6-(methoxycarbonyl)-N-phenylacetyl-1,3 , 4,9-tetrahydro-1H-β-carboline, followed by alkaline hydrolysis, coupled with 2-morpholine ethylamine, and finally purified by column chromatography to obtain compound NTC003, yield %: 78%. ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.12 (brs, 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).

Example 1-4, 6-(4-methylpiperazine) carbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC004) synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholinoethylamine was replaced by 4-methylpiperazine, and finally compound NTC004 was obtained after purification by column chromatography, with a yield of 81%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.11 (brs, 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).

Example 1-5, 6-(2-(dimethylamino)ethyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC005) Synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by 2-(dimethylamino)ethylamine, and finally purified by column chromatography to obtain compound NTC005, yield: 87%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.12(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).

Example 1-6, 6-(3-(dimethylamino)propyl)aminocarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC006) Synthesis

Using a method similar to the preparation of compound NTC005, 2-(dimethylamino)ethylamine was replaced by 3-(dimethylamino)propylamine, and finally purified by column chromatography to obtain compound NTC006, yield: 84 %: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.12 (brs, 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).

Example 1-7, 6-(4-morpholinylphenyl)aminocarbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC007) synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholinoethylamine was replaced by 4-morpholinoaniline, and finally compound NTC007 was obtained after column chromatography purification, yield: 65%: ¹ HNMR (300MHz, DMSO- d ₆ ): δ11.18(brs, 1H), 9.90(brs, 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).

Example 1-8, 6-(4-dimethylaminophenyl) aminocarbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC007) synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholinoethylamine was replaced by 4-dimethylaminoaniline, and finally compound NTC008 was obtained after column chromatography purification, yield: 63%: ¹ HNMR (300MHz, DMSO- d ₆ ): δ11.16(brs, 1H), 9.82(brs, 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).

Example 1-9, 6-(4-aminosulfonyl)aminocarbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC007) synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by sulfonamide, and finally purified by column chromatography to obtain compound NTC009, yield: 63%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ13 .63(brs, 1H), 12.38(brs, 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).

Embodiment 1-10, 6-(N, N-bis(2-hydroxyethyl)) aminocarbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline ( Synthesis of NTC010)

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by diethanolamine, and finally purified by column chromatography to obtain compound NTC010, yield: 60%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.04 (brs, 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).

Embodiment 1-11, 6-(2-(2-hydroxyethoxy) ethyl) aminocarbonyl-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline ( Synthesis of NTC011)

Using a method similar to the preparation of compound NTC003, 2-morpholinoethylamine was replaced by 2-(2-aminoethoxy)ethanol, and finally purified by column chromatography to obtain compound NTC011 with a yield of 63%: ¹ HNMR ( 300MHz, DMSO-d ₆ ): δ11.11(brs, 1H), 8.30(brs, 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).

Example 1-12, 6-(serine carbonyl)-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC012) synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholineethylamine was replaced by L-serine, and finally purified by column chromatography to obtain compound NTC012, yield: 45%: ¹ HNMR (300MHz, DMSO-d ₆ ) : δ12.55(brs, 1H), 11.15(brs, 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).

Example 1-13, 6-(aspartic acid carbonyl)-N-phenylacetyl--1,3,4,9-tetrahydro-1H-β-carboline (NTC013) synthesis

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by L-aspartic acid, and finally purified by column chromatography to obtain compound NTC013, yield: 41%: ¹ HNMR (300MHz, DMSO- d ₆ ): δ12.57(brs, 2H), 11.15(brs, 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).

Synthesis of Example 1-14, 6-(alanine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC014)

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by L-alanine, and finally purified by column chromatography to obtain compound NTC014 with a yield of 57%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.15(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).

Synthesis of Example 1-15, 6-(phenylalanine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC015)

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by L-phenylalanine, and finally purified by column chromatography to obtain compound NTC015 with a yield of 49%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.15(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 ).

Synthesis of Example 1-16, 6-(glutamic acid carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC016)

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by L-glutamic acid, and finally purified by column chromatography to obtain compound NTC016 with a yield of 25%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ12.44 (brs, 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).

Example 1-17, Synthesis of 6-(proline carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC017)

Using a method similar to the preparation of compound NTC003, 2-morpholine ethylamine was replaced by L-proline, and finally purified by column chromatography to obtain compound NTC017 with a yield of 64%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ12.53(brs, 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).

Synthesis of Example 1-18, 6-(glycine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC018)

Using a method similar to the preparation of compound NTC003, 2-morpholineethylamine was replaced by glycine, and finally purified by column chromatography to obtain compound NTC018 with a yield of 62%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ12. 48(brs, 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).

Example 1-19, Synthesis of 6-(tyrosine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC019)

Using a method similar to the preparation of compound NTC003, 2-morpholinoethylamine was replaced by tyrosine, and finally compound NTC019 was obtained after purification by column chromatography, with a yield of 29%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ12.52(brs, 1H), 11.14(s, 1H), 9.17(brs, 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).

Synthesis of Example 1-20, 6-(histidine carbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC020)

Using a method similar to the preparation of compound NTC003, 2-morpholinoethylamine was replaced by tyrosine, and finally purified by column chromatography to obtain compound NTC020 with a yield of 50%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.57(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).

Synthesis of Example 1-21, 6-cyano-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC021)

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced with 4-cyanophenylhydrazine hydrochloride, and finally purified by column chromatography to obtain compound NTC021 with a yield of 11%: ¹ HNMR (300MHz , DMSO-d ₆ ): δ11.53 (brs, 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).

Synthesis of Example 1-22, 6-nitro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC022)

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced by 4-nitrophenylhydrazine hydrochloride, and finally purified by column chromatography to obtain compound NTC022 with a yield of 6%: ¹ HNMR (300MHz , DMSO-d ₆ ): δ11.70 (brs, 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).

Synthesis of Example 1-23, 6-benzyloxy-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC023)

Take 5-hydroxytryptamine hydrochloride as raw material, first protect the hydroxyl group with benzyl group, then similar to Example 1-1, and finally obtain the compound NTC023 after purification by column chromatography, the yield is 20%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ10.69 (brs, 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).

Synthesis of Example 1-24, 6-(methoxycarbonyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC024)

Using a method similar to that of Example 1-1, replace 4-trifluoromethylphenylhydrazine hydrochloride with 4-carboxyphenylhydrazine hydrochloride to obtain 5-carboxytryptamine and then protect the carboxyl group with methyl ester before proceeding to follow-up After the reaction, the compound NTC024 was finally purified by column chromatography with a yield of 35%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ11.32 (brs, 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).

Synthesis of Example 1-25, 6-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC025)

Using hydrogen as a reducing agent and palladium carbon as a catalyst to reduce NTC022, the compound NTC025 was obtained after purification by column chromatography with a yield of 67%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ10.41 (brs, 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).

Synthesis of Example 1-26, 6-hydroxyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC026)

Using a method similar to the preparation of compound NTC025, compound NTC026 was obtained after purification by column chromatography with a yield of 85%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ10.50 (brs, 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).

Synthesis of Example 1-27, 6-carboxy-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC027)

NTC024 was hydrolyzed at room temperature in methanol-water mixed solution of inorganic alkali lithium hydroxide to obtain product NTC027 with 100% yield: ¹ HNMR (300MHz, DMSO-d ₆ ): δ12.35(brs, 1H), 11.26(brs, 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).

Synthesis of Example 1-28, 6-methyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC028)

3-(2,3-piperidinedione)-(4-(methoxycarbonyl)phenyl)-hydrazone (505mg, 1.93mmol, preparation method reference Syn.Comm.2007, 37, 1273-1280) Dissolve in 20ml of formic acid, stir at 80°C for 24 hours, remove the formic acid under reduced pressure, and obtain off-white solid 1-oxo-6-(methoxycarbonyl)-1,3,4,9-tetrahydro-β after conventional treatment -carboline, yield 55%. The carboline intermediate was reduced by lithium aluminum hydride and then coupled with phenylacetic acid to obtain the final product NTC028 with a yield of 26%: ¹ HNMR (300MHz, DMSO-d ₆ ): δ10.71(brs, 1H), 7.34-7.13( m, 7H), 6.85 (d, J = 8.1 Hz, 1H), 4.68 (s, 2H), 3.85-3.80 (m, 4H), 2.64-2.55 (m, 2H), 2.34 (s, 3H).

Synthesis of Example 1-29, 5-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC029)

Using a method similar to the preparation of compound NTC001, 4-nitrophenylhydrazine is replaced by trifluoromethylphenylhydrazine, and the target compound 5-nitro-N-phenylacetyl-1,3,4,9 can be obtained by preparing the liquid phase -tetrahydro-1H-β-carboline and 7-nitro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline.

Take the intermediate 5-nitro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (235mg, 0.7mmol) in a 25ml round bottom flask, add 1ml DMF to dissolve, and then Add 4ml of methanol for dilution, add 0.5% (weight ratio) of Pd/C under nitrogen atmosphere, and continue to feed hydrogen for 2h, TLC shows that the substrate disappears. The solvent was distilled off, and the target compound 5-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (159 mg. Yield: 74%) was obtained after purification by column chromatography. ¹ HNMR (DMSO, 300MHz): δ10.52(brs, 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(brs, 2H), 4.62(s, 2H), 3.84-3.78(m, 4H), 2.92(t, J=7.1Hz, 2H).

Example 1-30 Synthesis of 7-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC030)

Using a method similar to the preparation of compound NTC001, 7-nitro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline was used instead of 5-nitro-N-phenylacetyl- 1,3,4,9-tetrahydro-1H-β-carboline, purified by column chromatography to obtain 7-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β- Carboline (46 mg. Yield: 29%). ¹ H NMR (DMSO, 300MHz): δ10.20 (brs, 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(brs, 2H), 4.56(s, 2H), 3.81-3.74(m, 4H), 3.30(t, J=5.7Hz, 2H).

Embodiment 1-31 Synthesis of 5-(2-(N-morpholinyl)) acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC031)

The intermediate 5-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (50 mg, 0.16 mmol) and chloroacetyl chloride (19 μl, 0.24 mmol) were added at 0°C In the solution of triethylamine and DMF, after stirring for 2 hours, morpholine (30 μl, 0.32 mmol) was added dropwise and stirred for 5 hours. TLC detected that the starting material disappeared. The reaction solution was added to ice water, and a white solid was precipitated, which was the product (43 mg, yield 62.3%). ¹ HNMR (DMSO, 300MHz): δ10.99(brs, 1H), 9.46(brs, 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).

Example 1-325-(2-(4-methylpiperazinyl))acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC032) synthesis

Using the same method as in Example 1-31, replacing morpholine with N-methylpiperazine, the product NTC032 (33 mg, yield 57%) was obtained. ¹ H NMR (DMSO, 300MHz): δ10.98 (brs, 1H), 9.55 (brs, 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).

Example 1-33 Synthesis of 5-(2-amino)acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC033)

5-Amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (50 mg, 0.16 mmol) and Boc-L-glycine (42 mg, 0.24 mmol) were dissolved in DMF ( 3ml), EDCHCl (60mg, 0.31mol) and HOBt (36mg, 0.26mmol) were added at 0°C, and reacted at room temperature for 4 hours. After TLC detected that the raw materials disappeared, the reaction solution was added to water, extracted with ethyl acetate, washed with water, After salt washing and silica gel column purification, 137 mg of the intermediate was obtained. The above-mentioned intermediate was dissolved in dichloromethane, a solution of hydrogen chloride in 1,4-dioxane was added, and the reaction was stirred overnight at room temperature. After the reaction was complete, it was washed with water, saturated sodium carbonate, salt, and vacuum-dried to obtain the target compound (32 mg, yield 55%). ¹ HNMR (DMSO, 300MHz): δ10.95 (brs, 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).

Example 1-34 Synthesis of 5-(2-threonine base) amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC034)

Using the same method as in Example 1-33, Boc-L-glycine was replaced by Boc-L-threonine to obtain the target compound (22 mg, yield 69%). ¹ HNMR (DMSO, 300MHz): δ10.95(brs, 1H), 9.83(brs, 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).

Example 1-35 5-(2-proline base) amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC035) synthesis

Using the same method as in Example 1-33, Boc-L-glycine was replaced by Boc-L-proline to obtain the target compound (23 mg, yield 72%). ¹ HNMR (DMSO, 300MHz): δ10.96(brs, 1H), 10.22(brs, 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).

Synthesis of Example 1-36, 9-(4-bromobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC036)

Take compound 1,3,4,9-tetrahydro-1H-β-carboline (225 mg) in dichloromethane, add EDC (326 mg) and HOBt (194 mg) under an argon atmosphere, and stir under ice bath for 15 Minutes later, phenylacetic acid (218mg) was added, and the compound was stirred and reacted at room temperature for 5-8 hours. The reaction solution was poured into an ice bath, extracted twice with ethyl acetate, and the organic phase was washed with water and saturated brine. Dry over sodium sulfate and concentrate under reduced pressure to obtain a crude product. After purification by column chromatography, 336 mg of N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline was obtained with a yield of 89%. The intermediate was reacted with p-bromobenzyl bromide under the action of NaH in DMF for 1 hour to obtain NTC036 with a yield of 50%: ¹ HNMR (300MHz, DMSO): δ7.50-7.44 (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).

Example 1-37, 9-methyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (synthesis of NCT037)

N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline was reacted with p-iodomethane in DMF under the action of NaH at 0°C for 1 hour to obtain NTC037 with a yield of 80%: ¹ HNMR (DMSO, 300MHz): δ7.36-7.29(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).

Synthesis of Example 1-38, 8-fluoro-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC038)

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced by o-fluorophenylhydrazine, and finally compound NTC038 was obtained after purification by column chromatography, with a yield of 56%: ¹ HNMR (DMSO, 300MHz): δ11 .29(brs, 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).

Example 1-39, Synthesis of 6-(2-amino)acetylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC039)

Using the same method as in Example 1-33, replace 5-amino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline with 6-amino-N-phenylacetyl -1,3,4,9-tetrahydro-1H-β-carboline yielded the target compound NTC039 in 40% yield: ¹ HNMR (DMSO, 300MHz): δ10.79 (brs, 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).

Example 1-40, Synthesis of N-phenylacetyl-6,8-difluoro-1,3,4,9-tetrahydro-1H-β-carboline (NTC040)

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced by 2,4-difluorophenylhydrazine, and finally purified by column chromatography to obtain compound NTC040 with a yield of 10%: ¹ HNMR (DMSO, 300MHz): δ11.45(brs, 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).

Example 1-41, Synthesis of N-phenylacetyl-6,8-difluoro-9-p-bromobenzyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC041)

Take N-phenylacetyl-6,8-difluoro-9-p-bromobenzyl-1,3,4,9-tetrahydro-1H-β-carboline and p-bromobenzyl bromide in DMF under the action of NaH Reaction at 0°C for 1 hour yielded NTC041 with a yield of 46%: ¹ HNMR (DMSO, 300MHz): δ7.52-7.50 (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).

Synthesis of Example 1-42, 9-benzyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC042)

Using a method similar to the preparation of compound NTC037, iodomethane was replaced by benzyl bromide, and finally purified by column chromatography to obtain compound NTC042 with a yield of 58%: ¹ HNMR (300MHz, DMSO): δ7.43-7.41 (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). Synthesis of Example 1-43, 9-(4-fluorobenzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC043)

Using a method similar to the preparation of compound NTC037, iodomethane was replaced by p-fluorobenzyl bromide, and finally purified by column chromatography to obtain compound NTC043 with a yield of 72%: ¹ HNMR (300MHz, DMSO): δ7.44-7.41 (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). Synthesis of Example 1-44, 9-(4-methyl formate benzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC044)

Using a method similar to the preparation of compound NTC037, iodomethane was replaced by methyl 4-bromomethylbenzoate, and finally purified by column chromatography to obtain compound NTC044 with a yield of 79%: ¹ HNMR (300MHz, DMSO): δ7. 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).

Synthesis of Example 1-45, 9-(4-carboxybenzyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC045)

Take NTC044 and heat it to reflux in 1N NaOH aqueous solution for 1 hour, cool to adjust the pH to 1, extract with EtOAc, and distill under reduced pressure to obtain NTC045 with a yield of 99%: ¹ HNMR (300MHz, DMSO): δ12.90 (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).

Synthesis of Example 1-46, 9-(methoxycarbonylmethyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC046)

Using a method similar to the preparation of compound NTC037, iodomethane was replaced by methyl bromoacetate, and finally purified by column chromatography to obtain compound NTC046 with a yield of 75%: ¹ HNMR (300MHz, DMSO): δ7.42-7.23 (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).

Synthesis of Example 1-47, 9-(carbonylmethyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC047)

Take NTC046 and heat it to reflux in 1N NaOH aqueous solution for 1 hour, cool to adjust the pH to 1, extract with EtOAc, and distill under reduced pressure to obtain NTC047 with a yield of 99%: ¹ HNMR (300MHz, DMSO): δ12.95 (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).

Example 1-48, Synthesis of 9-(4-(morpholino)carbonylmethyl)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NTC048)

Take NTC047, EDCHCl, and HOBt and stir in DMF for 10 minutes, then add morpholine dropwise and react at room temperature for 3 hours, extract and purify to obtain NCT048 with a yield of 89%: ¹ HNMR (300MHz, DMSO): δ7.39-7.23 (m, 7H), 7.10-6.99(m2H), 5.13(s, 2H), 4.66-4.62(m, 2H), 3.88-3.79(m, 4H), 3.70-3.68(m, 2H), 3.63-3.59 (m, 4H), 3.45-3.44 (m, 2H), 2.69-2.60 (m, 2H).

Synthesis of Example 1-49, 5-methoxycarbonyl-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NCT049)

Using a method similar to the preparation of compound NTC001, 4-trifluoromethylphenylhydrazine was replaced by 3-hydrazinobenzoic acid methyl ester, and the liquid phase was prepared to obtain 5-(methoxycarbonyl)-N-phenylacetyl -1,3,4,9-Tetrahydro-1H-β-carboline NCT049, yield 16%: ¹ HNMR (DMSO, 300MHz): δ11.33 (brs, 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).

Synthesis of Example 1-50, 5-(Valine amino)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NCT050)

Using the same method as in Example 1-33, Boc-L-glycine was replaced by Boc-L-valine to obtain the target compound (22mg, yield 55%): ¹ HNMR (DMSO, 300MHz): δ10.99( brs, 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).

Synthesis of Example 1-51, 5-(alanine amino)-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NCT051)

Using the same method as in Example 1-33, Boc-L-glycine was replaced by Boc-L-alanine to obtain the target compound (27mg, yield 53%): ¹ HNMR (DMSO, 300MHz): δ10.89( brs, 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(brs, 2H), 4.63(s, 2H), 3.83-3.81(m, 4H), 3.74(s, 1H), 2.99(s, 2H), 1.28(d , 3H).

Example 1-52, Synthesis of 5-(3-amino)propionylamino-N-phenylacetyl-1,3,4,9-tetrahydro-1H-β-carboline (NCT052)

Using the same method as in Example 1-33, Boc-L-glycine was replaced by Boc-L-β-alanine to obtain the target compound (35 mg, yield 45%): ¹ HNMR (DMSO, 300 MHz): δ10. 87(brs, 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(brs, 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 (10)

1. aromatic base alkyloyl tetrahydro-beta-carboline and derivative thereof or a pharmacy acceptable salt, is characterized in that, represented by following structural formula (VII):

Wherein: X is CO or NH;

be selected from phenyl;

R ₁for the substituting group on aromatic nucleus, be selected from hydrogen;

R ₆be selected from hydrogen;

R ₁₂be selected from any one in following groups: hydroxyl, morpholinyl; Piperazinyl; Methylpiperazine base; Amino-acid residue, linear chains of amino acids, branched-chain amino acid, wherein, described amino-acid residue is selected from 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.

2. aromatic base alkyloyl tetrahydro-beta-carboline class according to claim 1 and derivative thereof or a pharmacy acceptable salt, is characterized in that, the acid salt that described acyl group tetrahydro-beta-carboline micromolecular organic compound is formed with acid; 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.

3. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 1 and 2 and derivative thereof or pharmacy acceptable salt, it is characterized in that, it is with radioactivity, fluorophor or biotin labeling.

4. the aromatic base alkyloyl tetrahydro-beta-carboline according to any one of claim 1 or 2 and derivative thereof or pharmacy acceptable salt, is characterized in that, comprising:

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-amino-sulfonyl) aminocarboxyl-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline

6-(N, N-bis-(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-(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

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

6-(2-is amino) acetylamino-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) propanoylamino-N-phenylacetyl-1,3,4,9-tetrahydrochysene-1H-β-carboline.

5. a pharmaceutical composition, wherein containing aromatic base alkyloyl tetrahydro-beta-carboline according to claim 1 and derivative thereof or pharmacy acceptable salt, and pharmaceutically acceptable carrier.

6. pharmaceutical composition according to claim 5, is characterized in that, described pharmaceutical composition is formulated into injectable fluid, aerosol, emulsifiable paste, gelifying agent, pill, capsule, syrup, transdermal patch.

7. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 1 and derivative thereof or the purposes of pharmacy acceptable salt in preparation treatment metabolic disease medicine.

8. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 1 and derivative thereof or the purposes of pharmacy acceptable salt in preparation treatment diabetes and diabetes complicated disease drug.

9. aromatic base alkyloyl tetrahydro-beta-carboline according to claim 1 and derivative thereof or the purposes of pharmacy acceptable salt in preparation treatment Metabolic syndrome disease drug.

10. the application according to any one of claim 7-9, is characterized in that, described medicine be used alone or with other drug conbined usage.