CN109824594B - Songcoline derivatives, pharmaceutical compositions and uses thereof - Google Patents

Songcoline derivatives, pharmaceutical compositions and uses thereof Download PDF

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CN109824594B
CN109824594B CN201910183030.3A CN201910183030A CN109824594B CN 109824594 B CN109824594 B CN 109824594B CN 201910183030 A CN201910183030 A CN 201910183030A CN 109824594 B CN109824594 B CN 109824594B
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songorine
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郭锐华
王江茗
乔武
吴文惠
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Shanghai Ocean University
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Abstract

The invention discloses a Songcoline derivative, a pharmaceutical composition and an application thereof, wherein the Songcoline derivative (1-17) or a pharmaceutically acceptable salt or solvent compound thereof is shown as the following formula:

Description

Songcoline derivatives, pharmaceutical compositions and uses thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a Songcoline derivative, a pharmaceutical composition thereof and application thereof in preparing medicines for treating type II diabetes, obesity, cardiovascular diseases and mental diseases or B-type G protein-coupled receptor antagonist medicines.
Background
G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, with about 800 class-labeled GPCRs in the human genome. Many different signal transduction receptors are included. GPCRs bind chemicals surrounding cells and activate a series of signaling pathways that result in changes in the internal state of the cell. GPCRs are involved in the regulation of a number of human functions, such as the visual, olfactory, taste, behavior, immune and nervous systems. GPCRs are one of the major targets of drugs, and about 40% to 50% of drugs exert drug effects by binding to GPCRs. Therefore, GPCRs are considered to have a wide range of potential applications in new therapeutic drugs. Type B G protein-coupled receptors, also known as secretory G protein-coupled receptors, are peptide receptors that bind physiologically important peptide hormones to transmit downstream cellular signals. Structurally, the B-type G protein-coupled receptor consists of an extracellular N-terminal domain (ECD) of 120-residues and a 7-transmembrane domain (TMD) of 310-residues and 420-residues. Type B G protein-coupled receptors are important drug targets for the treatment of a variety of human diseases, including type II diabetes, obesity, cardiovascular disease, and psychiatric disorders, but small molecule drugs directed against such G protein-coupled receptors have not yet emerged in the market.
Type II diabetes, also known as adult-onset diabetes or non-insulin-dependent diabetes, accounts for about 90% of the total number of people with diabetes, and is one of the diseases seriously harming human health. Unlike type 1 diabetic patients, type II diabetic patients do not completely lose insulin function, but have a relatively deficient insulin content in the body due to decreased insulin sensitivity or insulin resistance, and thus require external intervention to stimulate insulin secretion or direct insulin injection. The pathogenesis of the disease is liver glycogen hypersecretion, insulin resistance and functional disorder of islet beta cells. In recent years, the incidence and mortality of type II diabetes are high, and a hot and difficult problem in the international medical community has been formed. The main current treatment is mainly in regulating the pathway of glucose metabolism to stimulate insulin secretion, thereby lowering the blood sugar of the patient. At present, insulin secretion promoters (such as glibenclamide and repaglinide), metformin and alpha-glucosidase inhibitors (such as acarbose) are the mainstream blood sugar reducing drugs, but the drugs can only be used for symptomatic treatment, and drugs for treating type II diabetes are still lacking.
In conclusion, the medicine for treating the type II diabetes has great market demand, but the existing medicine for treating the type II diabetes clinically can only be used for symptomatic treatment and cannot be used for causal treatment, so that the development of a new generation of medicine for treating the type II diabetes, which has high clinical efficiency and small toxic and side effects, has strong market competitiveness and market prospect. In the prior art, no report of a pharmaceutical composition with songorine derivatives (1-17) as active ingredients exists, and no report of the application of the songorine derivatives as B-type G protein-coupled receptor inhibitors in pharmaceutical compositions and the preparation of medicaments for treating diseases such as II type diabetes, obesity, cardiovascular diseases, mental diseases and the like exists.
Disclosure of Invention
The main purpose of the present invention is to provide songorine derivatives (1-17).
Another object of the present invention is to provide a pharmaceutical composition comprising the above songorine derivatives (1-17) as an active ingredient.
Still another object of the present invention is to provide the use of the songorine derivatives (1-17), or pharmaceutically acceptable salts or solvent compounds thereof, or the pharmaceutical composition thereof in preparing a medicament for treating type II diabetes, obesity, cardiovascular diseases and psychiatric diseases, or a medicament for inhibiting type B G protein-coupled receptors.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
in a first aspect, derivatives (1-17) of songorine of formula (i) or a pharmaceutically acceptable salt or solvate thereof, formula (II):
Figure BDA0001991919230000021
wherein the Sonogoling derivative (12) is shown as formula (IIb), the Sonogoling derivatives (1-11, 13-17) are shown as (IIa), and R is1、R2And R3Respectively as shown in the following table:
Figure BDA0001991919230000022
Figure BDA0001991919230000031
further, the pharmaceutically acceptable salts include:
organic and inorganic salts of the songorine derivatives (1-17); wherein,
the inorganic salts include, but are not limited to, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate;
the organic acid salts include, but are not limited to, acetates, oxalates, maleates, tartrates, citrates, succinates, malonates;
or further comprising adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumerate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, picrate, or the like of said songorine derivative (1-17), Stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate;
or further comprises alkali metal, alkaline earth metal, ammonium and N + (C1-4 alkyl) 4 salts of the Sonogoling derivative (1-17); wherein the alkali metal or alkaline earth metal comprises sodium, lithium, potassium, calcium, magnesium;
or further comprises halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates and aromatic sulfonates of the Songolin derivatives (1-17).
In a third aspect, a pharmaceutical composition comprising the songorine derivative (1-17) described above, or a pharmaceutically acceptable salt or solvent compound thereof as an active ingredient, and a pharmaceutically acceptable carrier, diluent or excipient.
Further, in the pharmaceutical composition, the content of the songorine derivative (1-17) or the pharmaceutically acceptable salt or the solvate thereof as an active ingredient is 0.1% -99%.
Furthermore, in the pharmaceutical composition, the content of the songorine derivative (1-17) or the pharmaceutically acceptable salt or the solvate thereof as an active ingredient is 0.5% -90%.
In a fourth aspect, the use of the Sonogoling derivative (1-17), or its pharmaceutically acceptable salt or solvate, or the pharmaceutical composition thereof for the preparation of a medicament for treating or preventing a disease or disorder associated with cancer
(II) agents for the treatment of type II diabetes, obesity, cardiovascular disease and psychiatric disorders, or
(ii) use in the manufacture of a medicament for use as a B-type G protein-coupled receptor antagonist.
Further, the use is realized by inhibiting B-type G protein coupled receptors through the songorine derivatives (1-17) or pharmaceutically acceptable salts or solvent compounds thereof.
Furthermore, the medicament is in the dosage form of powder, tablets, oral liquid or capsules, and can be administered according to the dosage per unit weight in injection (intravenous injection, intramuscular injection) and/or oral administration.
Furthermore, the songorine derivatives (1-17), or pharmaceutically acceptable salts or solvent compounds thereof, or the pharmaceutical composition can be used directly.
Compared with the prior art, the invention has the beneficial effects that:
aiming at the problem that the existing clinical medicine for treating the type II diabetes can only be used for symptomatic treatment and cannot be used for causal treatment, the songorine derivative (1-17) or the pharmaceutically acceptable salt or the solvent compound thereof or the pharmaceutical composition can be used as an effective component for preparing the medicine for treating the type II diabetes or the B-type G protein-coupled receptor inhibitor medicine with high clinical efficiency and small toxic and side effects. Provides a new method for treating type II diabetes, obesity, cardiovascular diseases and mental diseases.
Detailed Description
In order to better understand the essence of the present invention, the results of pharmacological actions of songorine and derivatives I and II (1-17) of the present invention will be illustrated by the following test examples, which are not intended to limit the present invention.
And (3) testing: inhibition of B-type G-protein coupled receptors by Songcoline and derivatives I and II (1-17) thereof
1. Materials and methods
1.1 materials: songcoline and its derivatives I and II (1-17); dimethylsulfoxide (DMSO) (national pharmaceutical group chemical agents limited); distilled water (self-made); a G protein coupled receptor enzyme linked immunosorbent assay kit (Shanghai Sheng Engineer Co., Ltd., including standard, sample diluent, standard diluent, enzyme labeling reagent, 30 times concentrated eluent, color developing agent A, color developing agent B, stop solution, 96-hole enzyme label plate embedded with B type G protein coupled receptor solid phase antibody, sealing plate membrane, etc.).
1.2 Instrument: a microplate reader (SH-1000); a constant temperature incubator (LRH-150), and the like.
1.3 Experimental procedures: weighing 1mg of songorine and derivatives I and II (1-17) thereof respectively in a 1mL centrifuge tube, adding 300 mu LDMSO to dissolve completely, and diluting with distilled water to 1mL to obtain 1mg/mL stock solution. Diluting the stock solution with sample diluent to 10 μ g/mL, 0.1 μ g/mL, 1ng/mL and 10ng/L in sequence to obtain four dilutions with concentration gradient, and storing at 4 deg.C.
Respectively and fully mixing 15 mu L of the diluted solution under the four concentration gradients with 15 mu L of the diluted standard substance, and incubating at the constant temperature of 37 ℃ for 10min to obtain reaction liquid. And (3) carefully adding 25 mu L of reaction liquid into a 96-well enzyme label plate embedded with a B-type G protein-coupled receptor solid-phase antibody, slightly flapping, discharging air bubbles, fully mixing, covering a sealing plate membrane, and incubating at the constant temperature of 37 ℃ for 30min, wherein a standard substance is used as a positive control. And after incubation is finished, discarding and patting the liquid in the enzyme label plate, washing the liquid by using diluted 30-time concentrated washing liquid, discarding and patting the liquid, repeating for 5 times, and immersing the sample hole and the control hole in the washing liquid added each time without overflowing. After washing, 25. mu.L of enzyme-labeled reagent was added to each well, the plate-sealing membrane was covered, and incubation was carried out at 37 ℃ for 30 min. And after the incubation is finished, discarding the liquid in the enzyme label plate, patting the liquid dry, washing the liquid with diluted 30-time concentrated washing liquid, discarding the liquid, patting the liquid dry, and repeating the steps for 5 times. Then, 25. mu.L of developer A and 25. mu.L of developer B were added to each well, and the mixture was left to react at 37 ℃ for 10min in the dark. When the color reaction was completed, 25. mu.L of stop buffer was added to each well to stop the reaction. Finally, absorbance was measured at 450nm with a microplate reader.
1.4 calculation of B-type G protein-coupled receptor inhibition ratio by drug: according to the absorbance values under different concentrations, the inhibition rate of songorine and derivatives I and II (1-17) thereof on B-type G protein coupled receptors under four concentration gradients can be calculated, and the formula is as follows: inhibition rate ═ OD (positive control) -OD (sample) ]/OD (positive control) × 100%.
1.5 calculation of half inhibitory concentration of drug on B-type G protein-coupled receptor: from the data calculated under 1.4, a regression equation was obtained by fitting a concentration-inhibition curve using Origin2017, and the concentration of the drug at which 50% of the B-type G protein-coupled receptor was inhibited, i.e., the 50% Inhibitory Concentration (IC), was calculated50)。
2. As a result: the final result was at 50% Inhibitory Concentration (IC)50) Is evaluated, wherein IC50<3.21nM is superior to Sonogoling, IC50The inhibition effect of B-type G protein coupled receptor is more than 3.21nM and is inferior to that of Songolin. Specific results are shown in table 2:
TABLE 2 inhibition ratio and IC of Sonogoling derivatives (1-9) for B-type G-protein coupled receptors50(nM)
No. Inhibition rate% (10ng/L) IC50
I 62.8 3.21
1 65.2 0.51
2 48.6 2.62
3 65.9 0.59
4 77.4 0.14
5 49.8 8.68
6 85.3 0.08
7 55.0 5.91
8 37.7 4.50
9 57.1 0.29
10 46.3 ＞10
11 39.4 ＞10
12 68.7 0.23
13 54.6 9.99
14 34.6 ＞10
15 73.3 0.55
16 36.4 ＞10
17 50.3 3.65
The results show that the Sonogoling derivatives 1, 2, 3, 4, 6, 9, 12 and 15 have certain inhibition effect on B-type G protein coupled receptors in vitro.
The preparation process and the pharmaceutical composition of the present invention are further illustrated by the following examples. The preparation method of Songcoline derivative II (1-17) comprises using Songcoline (I) as raw material.
Example 1
Figure BDA0001991919230000071
The molecular formula is as follows: c26H35NO5
Molecular weight: 441
The characteristics are as follows: white amorphous powder
Figure BDA0001991919230000072
The molecular formula is as follows: c24H33NO4
Molecular weight: 399
The characteristics are as follows: white amorphous powder
The synthesis method comprises the following steps:
compound I (50mg,0.14mmol) and 4-dimethylaminopyridine (DMAP,17.1mg,0.14mmol) were dissolved in anhydrous pyridine (2mL), acetyl chloride (0.2mL,0.34mmol) was slowly added dropwise at room temperature, and the reaction mixture was stirred at room temperature until the reaction of the starting materials was completed. The reaction mixture was slowly poured into ice water (20mL), dichloromethane (20 mL. times.3) was extracted, and the dichloromethane layer was washed with saturated sodium bicarbonate (20 mL. times.3) and saturated brine (15mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate/diethylamine (15:1:1), to obtain compound 1(12.1mg, 18%) and compound 2(10.6mg, 19%).
Spectral data:
1:1H NMR(CDCl3,500MHz)δ:5.25(1H,s),5.03(1H,s),5.01(1H,s),4.96(1H,t,J＝7.6Hz),3.09(1H,m),2.51(2H,m,J＝6.4Hz),2.11(3H,s),2.03(3H,s),2.01(2H,m),1.96(2H,d,J＝12.4Hz),1.95(1H,d,J＝2.1Hz),1.56(2H,m),1.69(3H,t,J＝6.2Hz),1.58-1.24(6H,m),1.22(1H,t,J＝8.8Hz),1.09(1H,m),0.98(1H,m),0.75(3H,s)；13C NMR(CDCl3,125MHz)δ:208.9,170.6,170.3,145.2,112.9,74.4,65.7,56.9,54.3,50.7,50.4,49.8,49.0,44.1,37.8,37.3,36.7,34.3,32.3,29.7,26.7,25.8,23.1,21.9,21.5,13.5；ESI-MS:m/z 464.5[M+Na]+.
2:1H NMR(CDCl3,500MHz)δ:5.64(1H,s),5.24(1H,s),4.94(1H,s),3.37(1H,m,J＝7.4Hz),3.01(2H,m),2.40(2H,m,J＝6.3Hz),2.21(2H,d,J＝12.2),2.11(3H,s),1.94(1H,m),1.55(2H,m,J＝3.3Hz,9.2Hz),1.43(2H,m),1.42(2H,m),1.40-1.23(6H,m),1.11(3H,t,J＝6.2Hz),0.87(1H,m),0.76(3H,s)；13C NMR(CDCl3,125MHz)δ:209.6,170.6,145.3,112.6,77.3,70.2,65.7,57.2,54.0,52.2,50.9,49.3,43.4,38.0,37.4,36.5,34.2,32.2,32.1,29.7,26.1,23.5,21.5,13.6；ESI-MS:m/z 422.2[M+Na]+.
example 2
Figure BDA0001991919230000081
The molecular formula is as follows: c28H39NO5
Molecular weight: 469
The characteristics are as follows: white amorphous powder
The synthesis method comprises the following steps:
compound I (50mg,0.14mmol) and DMAP (17.1mg,0.14mmol) were dissolved in anhydrous pyridine (2mL), propionic anhydride (0.29mL,0.34mmol) was added dropwise slowly at room temperature, and the reaction mixture was stirred at room temperature until the starting material reaction was complete. The reaction mixture was slowly poured into ice water (20mL), dichloromethane (20 mL. times.3) was extracted, the dichloromethane layer was washed with saturated sodium bicarbonate (20 mL. times.3) and saturated brine (15mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate/diethylamine (15:1:1), to obtain 310.5mg of a white solid compound in 16% yield.
Spectral data:
1H NMR(CDCl3,500MHz)δ:5.35(1H,s),5.23(1H,s),4.93(1H,s),3.68(1H,t,J＝7.51Hz),2.53(1H,m),2.49(2H,m,J＝6.7Hz),2.42-2.43(4H,m),2.21(2H,d,J＝12.4Hz),2.04(2H,m),2.01(1H,d,J＝1.7Hz),1.83-1.38(4H,m),1.27-1.26(6H,m),1.26-1.17(6H,m),1.17(3H,t,J＝6.4Hz),1.16(3H,s),0.94(1H,m)；13C NMR(CDCl3,125MHz)δ:209.5,173.9,172.5,149.8,148.1,123.1,112.0,76.7,76.4,74.0,65.5,50.6,50.4,44.0,42.9,36.7,34.2,32.3,31.4,30.2,29.7,28.4,28.3.27.5,27.4,24.0,23.8,13.5；ESI-MS:m/z 470.1[M+H]+.
example 3
Figure BDA0001991919230000091
The molecular formula is as follows: c30H43NO5
Molecular weight: 497
The characteristics are as follows: white amorphous powder
Figure BDA0001991919230000092
The molecular formula is as follows: c26H37NO4
Molecular weight: 427
The characteristics are as follows: white amorphous powder
The synthesis method comprises the following steps:
compound I (50mg,0.14mmol) and DMAP (17.1mg,0.14mmol) were dissolved in anhydrous pyridine (2mL), butyric anhydride (0.55mL,0.34mmol) was added dropwise slowly at room temperature, and the reaction mixture was stirred at room temperature until the reaction of the starting materials was complete. The reaction mixture was slowly poured into ice water (20mL), dichloromethane (20 mL. times.3) was extracted, the dichloromethane layer was washed with saturated sodium bicarbonate (20 mL. times.3) and saturated brine (15mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate/diethylamine (10:1:1), to obtain compound 4(18.8mg, 27%) and compound 5(37.1mg, 62%)
Spectral data:
4:1H NMR(CDCl3,500MHz)δ:5.38(1H,s),5.32(1H,s),5.05(1H,s),4.32(1H,t,J＝7.1Hz),3.52(1H,m),2.40(2H,m,J＝6.5Hz),2.35-2.32(4H,m),2.20-1.88(4H,m),1.97(1H,d,J＝4.5Hz),1.80-1.53(8H,m),1.44-1.32(4H,m),1.28(1H,t,J＝9.1Hz),1.16(1H,m),1.14(3H,t,J＝6.5Hz),1.04-1.01(6H,m),0.92(1H,m),0.75(3H,s)；13C NMR(CDCl3,125MHz)δ:209.3,173.1,172.8,150.7,112.9,76.1,74.2,69.6,57.1,56.8,52.4,50.2,48.9,48.6,44.0,37.8,37.7,36.8,35.3,35.2,34.1,27.1,25.7,23.5,18.5,18.3,13.7,13.6,12.5；ESI-MS:m/z 498.1[M+H]+.
5:1H NMR(CDCl3,500MHz)δ:5.24(1H,s),5.16(1H,s),5.05(1H,s),2.94(1H,m),2.45(2H,t,J＝6.5Hz),2.36(2H,t,J＝8.2Hz)2.32(1H,t,J＝2.5Hz),2.26-2.19(6H,m),1.94(1H,d,J＝1.5Hz),1.58(1H,s),1.57-1.42(8H,m),1.32(1H,t,J＝8.5Hz),1.19(1H,m),1.07(6H,m,J＝6.5Hz),0.93(1H,m),0.61(3H,s)；13C NMR(CDCl3,125MHz)δ:208.9,173.1,145.2,112.9,73.9,65.6,65.5,57.0,50.5,50.4,48.7,43.8,42.3,37.7,37.0,36.8,36.7,34.2,32.3,29.7,26.7,25.7,25.5,18.4,18.3,13.5；ESI-MS:m/z 428.1[M+H]+.
example 4
Figure BDA0001991919230000101
The molecular formula is as follows: c29H39NO7
Molecular weight: 501
The characteristics are as follows: brown amorphous powder
The synthesis method comprises the following steps:
compound I (50mg,0.14mmol), DMAP (17.1mg,0.14mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.8g,4.20mmol) were dissolved in anhydrous dichloromethane (2mL), methoxyacetic acid (0.26mL,0.34mmol) was slowly added dropwise at room temperature, and the reaction mixture was stirred at room temperature until the starting material was completely reacted. The reaction mixture was slowly poured into ice water (20mL), dichloromethane (20 mL. times.3) was extracted, the dichloromethane layer was washed with saturated sodium bicarbonate (20 mL. times.3) and saturated brine (15mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography with petroleum ether/ethyl acetate/diethylamine (40:1:1) as eluent to give 5.6mg of a brown solid in 8% yield.
Spectral data:
1H NMR(CDCl3,500MHz)δ:5.72(1H,s),5.26(1H,s),5.12(1H,s),4.98(1H,t,J＝7.9Hz),3.88(2H,s),3.42(2H,s),3.29(3H,s),3.09(3H,m),2.45(2H,m,J＝6.4Hz),2.29-2.01(5H,m),1.99(1H,d,J＝1.4Hz),1.98-1.57(4H,m),1.39-1.24(6H,m),1.07(3H,t,J＝6.5Hz),0.87(1H,m),0.74(3H,s)；13C NMR(CDCl3,125MHz)δ:208.4,169.9,169.6,144.8,113.4,77.3,75.1,70.4,70.2,65.7,59.4,56.9,54.2,50.9,50.6,50.3,49.8,49.2,44.0,37.6,37.3,36.6,34.2,32.3,29.3,26.7,25.7,13.5；ESI-MS:m/z 524.1[M+Na]+.
example 5
Figure BDA0001991919230000111
The molecular formula is as follows: c30H43NO7
Molecular weight: 529
The characteristics are as follows: brown amorphous powder
The synthesis method comprises the following steps:
compound I (50mg,0.14mmol), DMAP (17.1mg,0.14mmol) and EDC & HCl (0.8g,4.20mmol) were dissolved in anhydrous dichloromethane (2mL), ethoxyacetic acid (0.32mL,0.34mmol) was slowly added dropwise at room temperature, and the reaction mixture was stirred at room temperature until the starting material was completely reacted. The reaction mixture was slowly poured into ice water (20mL), dichloromethane (20 mL. times.3) was extracted, the dichloromethane layer was washed with saturated sodium bicarbonate (20 mL. times.3) and saturated brine (15mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography with petroleum ether/ethyl acetate/diethylamine (15:1:1) as eluent to give 48.9mg of a brown solid in 66% yield.
Spectral data:
1H NMR(CDCl3,500MHz)δ:5.69(1H,s),5.24(1H,s),4.96(1H,s),4.41(3H,t,J＝7.8Hz),4.09(2H,s),3.55-3.51(4H,m),3.06(1H,s),2.31(2H,m,J＝6.2Hz),2.30-1.97(4H,m),1.97(1H,d,J＝2.01Hz),1.96-1.55(4H,m),1.55-1.20(12H,m),1.05(3H,t,J＝5.8Hz),1.02(1H,m),0.72(3H,s)；13C NMR(CDCl3,125MHz)δ:208.4,170.1,169.8,144.8,113.2,77.3,68.8,68.4,67.3,67.1,65.8,56.8,54.2,50.6,50.2,49.8,49.2,43.9,37.6,37.2,36.6,34.1,32.2,31.4,30.1,29.6,26.6,25.7,14.9,13.4；ESI-MS:m/z 552.3[M+Na]+.
example 6
Figure BDA0001991919230000112
The molecular formula is as follows: c29H35NO4
Molecular weight: 461
The characteristics are as follows: white amorphous powder
The synthesis method comprises the following steps:
compound I (50mg,0.14mmol), DMAP (17.1mg,0.14mmol) and EDC & HCl (0.8g,4.20mmol) were dissolved in anhydrous dichloromethane (2mL), benzoic acid (41.02mg,0.34mmol) was added slowly at room temperature, and the reaction was stirred at room temperature until the starting material was reacted completely. The reaction mixture was slowly poured into ice water (20mL), dichloromethane (20 mL. times.3) was extracted, the dichloromethane layer was washed with saturated sodium bicarbonate (20 mL. times.3) and saturated brine (15mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography with petroleum ether/ethyl acetate/diethylamine (20:1:1) as eluent to give 10.9mg of a white solid in a yield of 17%.
Spectral data:
1H NMR(CDCl3,500MHz)δ:7.83(2H,m),7.55(2H,m),7.22(2H,m),5.32(1H,s),5.16(1H,s),5.09(1H,s),2.88(1H,m),2.38(2H,m,J＝6.3Hz),2.30-1.89(5H,m),2.15(2H,d,J＝3.5Hz),1.89(1H,m),1.89-1.63(4H,m),1.61(1H,m,J＝3.4Hz,4.2Hz),1.48-1.12(5H,m),1.11(2H,t,J＝6.3Hz),0.74(3H,s)；13C NMR(CDCl3,125MHz)δ:209.1,177.4,155.3,138.2,138.1,129.6,129.6,129.0,129.0,124.9,118.3,78.3,71.5,69.0,59.1,58.2,51.8,50.5,48.6,47.3,43.2,35.8,35.5,34.7,29.3,24.6,27.3,25.9,14.0；ESI-MS:m/z 462.2[M+H]+.
example 7
Figure BDA0001991919230000121
The molecular formula is as follows: c31H37NO4
Molecular weight: 487
The characteristics are as follows: yellow amorphous powder
The synthesis method comprises the following steps:
compound I (50mg,0.14mmol), DMAP (17.1mg,0.14mmol) and EDC & HCl (0.8g,4.20mmol) were dissolved in anhydrous dichloromethane (2mL), cinnamic acid (49.8mg,0.34mmol) was added slowly at room temperature, and the reaction was stirred at room temperature until the starting material was reacted completely. The reaction mixture was slowly poured into ice water (20mL), dichloromethane (20 mL. times.3) was extracted, the dichloromethane layer was washed with saturated sodium bicarbonate (20 mL. times.3) and saturated brine (15mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography with petroleum ether/ethyl acetate/diethylamine (30:1:1) as eluent to give 7.5mg of a yellow solid in an yield of 11%.
Spectral data:
1H NMR(CDCl3,500MHz)δ:7.43(2H,d,J＝6.5Hz),7.55(3H,d,J＝15.6Hz),7.14(1H,d,J＝7.4Hz),6.49(1H,d,J＝14.8Hz),5.36(1H,s),5.32(1H,s),5.03(1H,s),3.40(2H,m),2.90(2H,m),2.37(2H,m,J＝6.1Hz),2.25(2H,m,J＝9.3Hz,3.3Hz),2.21(2H,m),2.05-1.61(4H,m),2.02(1H,s),1.61-1.25(4H,m),1.58(1H,s),1.25(1H,t,J＝9.0Hz),1.15(2H,m),0.98(1H,m),0.72(3H,s)；13C NMR(CDCl3,125MHz)δ:207.7 169.2,151.7,143.5,137.0,129.6,129.6,129.5,129.0,129.0,118.5,113.2,109.7,79.2,70.6,67.1,59.9,56.2,55.6,52.6,50.0,46.2,43.8,42.4,36.0,35.5,33.9,29.4,27.8,25.6,14.1；ESI-MS:m/z 488.1[M+H]+.
example 8
Figure BDA0001991919230000131
The molecular formula is as follows: c22H33NO3
Molecular weight: 359
The characteristics are as follows: white amorphous powder
Figure BDA0001991919230000132
The molecular formula is as follows: c22H33NO3
Molecular weight: 359
The characteristics are as follows: white amorphous powder
The synthesis method comprises the following steps:
compound I (50mg,0.14mmol) and sodium borohydride (7.94mg,0.21mmol) were dissolved in absolute ethanol (2mL) at room temperature and the reaction was stirred at 50-60 deg.C until the starting material was completely reacted. The reaction mixture was slowly poured into ice water (20mL), extracted with dichloromethane (20 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography, eluting with petroleum ether/acetone/diethylamine (10:1:1), to give compound 10(30.1mg, 60%) and compound 11(23.6mg, 47%).
Spectral data:
10:1H NMR(CDCl3,500MHz)δ:5.32:(1H,s),5.10(1H,s),4.18(1H,s),2.53(1H,m,J＝3.5Hz,4.5Hz),2.40(2H,t,J＝6.1Hz),2.39(1H,t,J＝7.7Hz),2.22(2H,m),2.06(1H,m),2.04(1H,d,J＝2.0Hz),1.72(2H,m),1.64(2H,m),1.59(2H,s),1.36-1.26(6H,m),1.28(1H,s),1.23(1H,m),1.09(3H,m,J＝6.3Hz),0.86(2H,m),0.75(3H,s)；13C NMR(CDCl3,125MHz)δ:154.6,111.8,76.8,69.8,67.2,58.3,52.6,51.0,48.4,43.7,37.1,35.9,33.8,32.6,31.4,29.7,27.2,26.4,23.5,22.7,14.1,13.4；ESI-MS:m/z 360.1[M+H]+.
11:1H NMR(CDCl3,500MHz)δ:5.16(1H,s),5.13(1H,s),4.17(1H,s),2.53(1H,m,J＝3.6Hz,4.5Hz),2.45(2H,t,J＝6.3Hz),2.25(2H,m),2.11(1H,m),2.01(2H,m),1.76(2H,m),1.63(2H,m),1.60(2H,s),1.36-1.32(6H,m),1.31(1H,s),1.24(1H,t,J＝7.1Hz),1.09(3H,m,J＝6.0Hz),0.85(2H,m),0.77(3H,s)；13C NMR(CDCl3,125MHz)δ:159.1,108.7,76.8,69.7,66.0,58.2,52.9,50.2,48.2,43.9,36.5,36.1,34.1,31.4,30.7,29.7,28.6,26.4,23.4,22.7,14.1,13.1；ESI-MS:m/z 360.1[M+H]+.
example 9
Figure BDA0001991919230000141
The molecular formula is as follows: c29H36ClNO6
Molecular weight: 529
The characteristics are as follows: brown amorphous powder
The synthesis method comprises the following steps:
to a 50mL round bottom flask, compound I (50mg,0.14mmol), m-chloroperoxybenzoic acid (14.49mg,0.08mmol) and solvent anhydrous dichloromethane (2mL) were added at room temperature and dissolved completely, and the reaction solution was stirred at 50-60 ℃ until the starting material was reacted completely. The reaction mixture was slowly poured into ice water (20mL), dichloromethane (20 mL. times.3) was extracted, the dichloromethane layer was washed with saturated sodium bicarbonate (20 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography, eluting with petroleum ether/acetone/diethylamine (30:1:1), to give 16.3mg of a brown solid, in 22% yield.
Spectral data:
1H NMR(CDCl3,500MHz)δ:8.56(1H,m),7.75(1H,m),7.55(1H,m),7.49(1H,t,J＝7.9Hz),3.89(1H,s),3.77(2H,m),3.34(1H,t,J＝7.1Hz),2.90(1H,t,J＝2.7Hz),2.42(2H,m,J＝6.3Hz),2.29(2H,m),1.85(2H,m),1.82(2H,m),1.74(2H,m),1.4(1H,s),1.45(1H,s),1.30(1H,s),1.25(1H,t,J＝8.7Hz),1.22(4H,m),1.17(1H,s),1.15(1H,m),1.12(3H,t,J＝6.5Hz),0.91(1H,m),0.72(3H,s)；13C NMR(CDCl3,125MHz)δ:209.8,159.8,134.1,133.2,130.6,129.9,129.0,124.5,94.1,70.6,70.3,67.8,61.4,59.1,52.3,52.2,48.8,47.6,45.2,43.8,37.2,36.0,35.9,34.5,29.6,29.5,27.2,25.5,14.1；ESI-MS:m/z 530.2[M+H]+.
example 10
Figure BDA0001991919230000151
The molecular formula is as follows: c22H29NO3
Molecular weight: 355
The characteristics are as follows: white amorphous powder
Figure BDA0001991919230000152
The molecular formula is as follows: c22H27NO3
Molecular weight: 353
The characteristics are as follows: white amorphous powder
The synthesis method comprises the following steps:
in a 50mL round-bottomed flask, under an ice-water bath, Compound I (50mg,0.14mmol), dessimutan's oxidant (0.2g,0.28mmol) and anhydrous dichloromethane (2mL) as a solvent were added and dissolved completely, and the reaction solution was stirred at room temperature until the reaction of the starting materials was completed. The reaction mixture was slowly poured into ice water (20mL), dichloromethane (20 mL. times.3) was extracted, the dichloromethane layer was washed with saturated sodium hydrogen sulfite (20 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography, eluting with petroleum ether/acetone/diethylamine (7:1:1), to purify the objective compound 13(10.9mg, 22%) and compound 14(15.3mg, 33%).
Spectral data:
13:1H NMR(CDCl3,500MHz)δ:6.00(1H,s),5.75(1H,s),3.47(1H,t,J＝7.3Hz),2.90(1H,m),2.42(2H,m),2.30-1.96(4H,m),1.92(1H,d,J＝2.5Hz),1.90-1.74(4H,m),1.56(1H,s),1.54(1H,t,J＝9.0Hz),1.51-1.21(5H,s),1.14(3H,t,J＝6.4Hz),0.98(1H,t,J＝6.5Hz),0.66(3H,s)；13C NMR(CDCl3,125MHz)δ:208.4,205..2,142.3,118.9,69.8,66.0,65.8,59.6,56.8,52.5,49.7,46.4,46.3,42.6,40.2,38.5,37.4,33.9,30.8,27.0,25.7,13.4；ESI-MS:m/z 356.5[M+H]+.
14:1H NMR(CDCl3,500MHz)δ:6.03(1H,s),5.56(1H,s),2.92(1H,m),2.41(2H,m),2.37-2.31(2H,m),2.29-2.00(5H,m),1.93-1.55(5H,m),1.53-1.41(3H,m),1.26(1H,t,J＝6.9Hz),1.10(3H,t,J＝6.1Hz),0.72(3H,s)；13C NMR(CDCl3,125MHz)δ:214.0,208.3,204.4,142.0,119.5,69.8,62.5,61.4,57.0,54.8,53.4,50.6,42.2,41.1,41.0,39.5,39.0,38.8,34.3,29.3,24.8,13.3；ESI-MS:m/z 354.5[M+H]+.
example 11
Figure BDA0001991919230000161
The molecular formula is as follows: c22H32N2O3
Molecular weight: 372
The characteristics are as follows: white amorphous powder
The synthesis method comprises the following steps:
a50 mL round bottom flask was charged with Compound I (50mg,0.14mmol), KOH (11.8mg,0.21mmol), hydroxylamine hydrochloride (14.6mg,0.21mmol) and anhydrous ethanol (2mL) as a solvent, and the reaction was stirred at 50-60 deg.C until the starting material reaction was complete. The reaction mixture was slowly poured into ice water (20mL), extracted with dichloromethane (20 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography with petroleum ether/ethyl acetate/diethylamine (7:1:1) as eluent, to purify the objective compound 15(17.2mg, 33%).
Spectral data:
1H NMR(CDCl3,500MHz)δ:7.92(1H,s),5.27(1H,s),5.16(1H,s),4.07(1H,m),3.91(1H,s),3.31(1H,t,J＝7.1Hz),2.52(2H,m,J＝6.2Hz),2.21-1.87(5H,m),1.71-1.46(4H,m),1.56(1H,m),1.45-1.19(4H,m),1.37(1H,t,J＝8.6Hz),1.32(1H,s),1.19(1H,m),1.11(3H,s),0.92(1H,m),0.88(3H,s)；13C NMR(CDCl3,125MHz)δ:153.9,149.3.129.5,76.7,69.1,59.1,52.3,51.0,49.5,48.4,48.2,45.0,42.1,41.2,36.7,35.2,32.6,29.9,29.5,25.4,27.6,13.8；ESI-MS:m/z373.0[M+H]+.
example 12
Figure BDA0001991919230000171
The molecular formula is as follows: c31H44N2O6
Molecular weight: 540
The characteristics are as follows: white amorphous powder
Figure BDA0001991919230000172
The molecular formula is as follows: c28H40N2O5
Molecular weight: 484
The characteristics are as follows: white amorphous powder
The synthesis method comprises the following steps:
a50 mL round-bottomed flask was charged with compound 15(25mg,0.07mmol), DMAP (8.21mg,0.07mmol), EDC & HCl (0.4g,2.01mmol), propionic anhydride (0.21mL,0.16mmol) and solvent anhydrous dichloromethane (2mL), and the reaction mixture was stirred at room temperature until the reaction of the starting materials was complete. The reaction mixture was slowly poured into ice water (20mL), extracted with dichloromethane (20 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by silica gel column chromatography with petroleum ether/acetone/diethylamine (10:1:1) as eluent to give the objective compound 16(9.4mg, 26%) and compound 17(10.1mg, 31%).
Spectral data:
16:1H NMR(CDCl3,500MHz)δ:5.49(1H,s),5.15(1H,s),5.05(1H,s),4.31(1H,t,J＝5.0Hz),3.91(1H,m),2.66(2H,m,J＝7.0Hz),2.56(2H,m,J＝7.0Hz),2.41(4H,m),2.31-1.89(5H,m),1.51(2H,m),1.45(2H,m),1.31(2H,m),1.28(3H,t,J＝7.5Hz),1.26-1.24(4H,m),1.22(3H,m,J＝7.0Hz),1.20(2H,m),1.18(1H,m),1.08(3H,t,J＝6.5Hz),1.01(1H,m),0.71(3H,s)；13CNMR(CDCl3,125MHz)δ:174.0,173.3,171.6,167.4,148.0,113.5,75.7,73.9,65.5,56.9,50.5,50.1,49.8,49.5,44.2,41.9,38.3,37.6,35.8,34.0,29.0,7.2,28.1,27.8,27.1,24.5,26.3,13.5,9.1,8.9,8.8；ESI-MS:m/z 541.3[M+H]+.
17:1H NMR(CDCl3,500MHz)δ:5.47(1H,s),5.17(1H,s),5.12(1H,s),4.10(1H,m),3.44(1H,t,J＝7.0Hz),3.01(2H,m,J＝6.5Hz),2.75(2H,m,J＝6.5Hz),2.55(2H,m,J＝6.5Hz),2.29-1.98(4H,m),1.88(1H,m),1.72-1.25(15H,m),1.27(3H,m),1.24(1H,t,J＝8.5Hz),1.21(1H,s),0.92(1H,m),0.70(3H,s)；13C NMR(CDCl3,125MHz)δ:175.2,174.0,167.6,157.4,107.6,78.9,68.9,66.3,58.9,53.4,51.5,51.4,47.0,45.6,42.7,42.2,35.9,35.8,35.1,29.6,28.4,28.1,27.1,26.8,25.4,11.1,6.1,5.8；ESI-MS:m/z 522.7[M+K]+.
example 13
The songgaoling and the derivative (1) thereof are prepared according to the method of the example 1, and the excipient is added according to the weight ratio of 9:1 of the songgaoling to the excipient to prepare powder.
Example 14
The songgaoling and the derivative (6) thereof are prepared according to the method of the embodiment 4, and the excipient is added according to the weight ratio of 5:1 of the songgaoling to the excipient, and then the mixture is granulated and tabletted.
Example 15
Songcoline and its derivative (7) are prepared according to the method of example 5, and then oral liquid is prepared according to the conventional oral liquid preparation method.
Example 16
The songgaoling and the derivatives (13, 14) thereof are prepared according to the method of the embodiment 10, and the excipients are added according to the weight ratio of 5:1 of the songgaoling to the excipients, and then the capsules are prepared.
Example 17
Songcoline and its derivative (15) are prepared according to the method of example 11, and the excipient is added according to the weight ratio of 3:1 to the excipient to prepare capsules.

Claims (7)

1. Songcoline derivatives, or pharmaceutically acceptable salts thereof, selected from any of the following structures:
Figure FDA0003463127850000011
2. a pharmaceutical composition comprising the songorine derivative according to claim 1, or a pharmaceutically acceptable salt thereof, as an active ingredient, together with a pharmaceutically acceptable carrier, diluent or excipient.
3. The pharmaceutical composition according to claim 2, wherein the songorine derivative or a pharmaceutically acceptable salt thereof is contained in an amount of 0.1 to 99% as an active ingredient.
4. The pharmaceutical composition according to claim 2 or 3, wherein the songorine derivative or a pharmaceutically acceptable salt thereof is contained in an amount of 0.5 to 90% as an active ingredient.
5. Use of the songorine derivative according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 2 to 4 for the preparation of (i) a medicament for the treatment of type II diabetes, obesity, cardiovascular diseases and psychiatric disorders or (II) a medicament which is a type B G protein-coupled receptor antagonist.
6. The use according to claim 5, characterized in that the inhibition of type B G protein-coupled receptors is achieved by means of said Songolin derivative, or a pharmaceutically acceptable salt thereof, as active ingredient.
7. Use according to claim 5, wherein the medicament is in the form of a powder, tablet, oral liquid or capsule, administered in an injectable and/or oral form, including intravenous and intramuscular injection, in a dose per unit of body weight.
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