CN112707895A - Isoindoline derivative compound, preparation method and application - Google Patents

Isoindoline derivative compound, preparation method and application Download PDF

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CN112707895A
CN112707895A CN202011609074.7A CN202011609074A CN112707895A CN 112707895 A CN112707895 A CN 112707895A CN 202011609074 A CN202011609074 A CN 202011609074A CN 112707895 A CN112707895 A CN 112707895A
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孙晶
王玉珍
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Abstract

The invention belongs to the field of medicines, and relates to an isoindoline derivative compound, a preparation method and application thereof. The structural formula of the isoindoline derivative compound is shown as a formula I:
Figure DDA0002871135930000011
pharmacological studies show that the invention is preparedThe prepared compound can be used as a metabolic regulator for preparing medicines for treating or preventing metabolic diseases such as diabetes and hyperglycemia.

Description

Isoindoline derivative compound, preparation method and application
Technical Field
The invention belongs to the field of medicines, and relates to an isoindoline derivative compound, a preparation method and application thereof in preparing medicines for treating or preventing metabolic diseases such as diabetes and hyperglycemia.
Background
The metabolic syndrome (overweight, obesity, type2diabetes mellitus (T2 DM) and lipid metabolism disorder) is directly related to various diseases such as cardiovascular diseases, non-alcoholic fatty liver diseases, tumors and the like, the prevalence rate is increased rapidly in recent years, and increasingly heavy burden is brought to the society.
The data indicate that the morbidity and mortality of metabolic diseases such as diabetes, metabolic syndrome and the like are in a very high position, wherein the diabetes is mainly divided into type 1 diabetes, type2diabetes, gestational diabetes and the like, and the type2diabetes accounts for more than ninety percent. Diabetes is a chronic syndrome of sugar metabolism disorder caused by insufficient insulin secretion or abnormal physiological action of human body, and then the disorder of metabolism of various substances such as protein, fat, water, electrolyte and the like. Type i diabetes mellitus type i diabetes patients who are autoimmune-compromised by pancreatic cells have insulin-secreting ability and may even produce too much, but do not function effectively, leaving insulin possibly in a relatively deficient state.
Diabetes causes hyperglycemia and high free fatty acids, initiating oxidative stress, while activation of oxidative stress signaling pathways leads to insulin resistance, impaired insulin secretion, and diabetic vasculopathy, and most diabetic patients are accompanied by obesity and hyperglycemia. According to statistics, only one hundred million high diabetic patients confirmed in China are in the top position in the near future and 3.66 hundred million patients are shared all over the world in 2011, and the diabetes medicine market probably has 439 hundred million dollars. However, no medicine for curing diabetes exists in the market at present, and the existing antidiabetic medicine also has obvious defects, such as causing hypoglycemia, obesity, abnormal liver function, increasing death risks of cardiovascular diseases and apoplexy and the like, and potential carcinogenicity in long-term use. Diabetes patients urgently hope to find a medicine which effectively regulates the blood sugar balance, has better safety and smaller toxic and side effects, so that a novel metabolic disease resistant medicine aiming at a new target point and multiple target points needs to be developed.
The isoindoline derivative compound is innovatively synthesized, so that the blood sugar can be effectively reduced, the insulin resistance is increased, the fat content is reduced, the anti-obesity and blood sugar reducing activities are remarkable, a brand new compound for treating metabolic diseases is expected to be obtained, and reports of related structures are not found in the prior art.
Disclosure of Invention
In view of the above problems, the present invention aims to provide a preparation method and applications of isoindoline derivatives, which are effective in reducing blood sugar, increasing insulin resistance, reducing fat content, and having significant anti-obesity and blood sugar reducing activities, and can be used for preparing drugs for treating or preventing metabolic diseases. In order to achieve the purpose, the invention adopts the following technical scheme.
The isoindoline derivative compound has the following structural general formula I:
Figure BDA0002871135910000021
in the formula: r1Is selected from-H or-CH3，R2Is selected from-H or-CH3。
The invention also aims to provide a synthetic route of the isoindoline derivative compound shown as the formula I:
Figure BDA0002871135910000022
of partial compounds1H-NMR (400MHz) and13C-NMR (125MHz) was as follows:
compound 1:1H-NMR(400MHz,CDCl3)δ:1.44(s,9H),4.38(d,1H),4.48(d,1H),6.16(s,1H),6.36(d,1H),6.64(d,1H),6.73(d,1H),7.11(m,2H),7.24(m,1H),7.35(m,1H),7.77(d,1H),12.50(d,1H).13C-NMR(125MHz,CDCl3)δ:28.27,49.59,60.95,80.53,112.48,115.08,121.72,123.67,124.12,125.00,125.69,126.1,136.55,137.78,143.93,147.3,154.16,154.71.
compound 2:1H-NMR(400MHz,CDCl3)δ:1.46(s,9H),2.00(s,3H),4.41(m,2H),6.10(m,1H),6.16(d,1H),6.74(d,1H),7.12(m,2H),7.36(m,2H),7.78(d,1H),12.49(d,1H).13C-NMR(125MHz,CDCl3)δ:9.74,28.27,49.59,60.95,80.53,115.65,122.54,123.67,125.00,125.69,126.1,136.55,137.78,138.42,143.93,153.64,154.16.
compound 3:1H-NMR(400MHz,CDCl3)δ:1.42(s,9H),3.01(s,3H),4.41(m,2H),6.10(m,1H),6.16(d,1H),6.76(d,1H),7.09(m,2H),7.33(m,2H),7.77(d,1H),12.51(d,1H).13C-NMR(125MHz,CDCl3)δ:9.62,28.32,49.58,60.95,80.53,115.63,122.41,123.73,125.00,125.65,126.15,136.52,137.79,138.42,143.93,153.36,155.16.
the isoindoline derivative compound provided by the invention has good effects of resisting obesity and reducing blood sugar, and can effectively reduce blood sugar, reduce insulin resistance and reduce fat content. The isoindoline derivative compound has positive significance in treating or preventing metabolic diseases such as hyperglycemia, diabetes and obesity, and can be further studied.
The application of the drug for preventing or treating metabolic diseases or the pharmaceutically acceptable salt or solvate thereof in preparing the drug for treating or preventing metabolic diseases such as diabetes, hyperglycemia and obesity, in particular to the application of an isoindoline derivative compound in preparing the drug for treating or preventing diabetes, hyperglycemia and obesity.
Compared with the prior art, the invention has the following beneficial effects:
the compounds of the present invention have excellent effects in the treatment or prevention of diabetes, hyperglycemia and obesity. Further, it can be seen from the research results provided by the present invention that: the compound of the invention can effectively reduce blood sugar, increase insulin resistance, reduce fat content, resist obesity and have obvious blood sugar reducing activity. In conclusion, the isoindoline derivative compound has a good development prospect when being used for preparing a medicament for treating or preventing metabolic diseases.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
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FIG. 1: the isoindoline derivative compound obtained by the invention has a treatment effect on type2diabetes mice.
FIG. 2: the isoindoline derivative compound obtained by the invention has influence on fat cells.
FIG. 3: the isoindoline derivative compound obtained by the invention has in-vivo influence on glucose homeostasis of mice.
Detailed Description
The following synthetic examples, biological test results, are used to further illustrate the invention, but are not meant to limit the invention.
Synthesis examples
Example 1 preparation of Compound 1
(1) Synthesis of tert-butyl 1- (1H-imidazol-2-yl) isoindoline-2-carboxylate:
Figure BDA0002871135910000041
to a 4-neck round-bottom flask (250mL) equipped with a stirrer at the top and a nitrogen inlet was added tert-butyl 1- (hydroxymethyl) isoindoline-2-carboxylate (9.80g, 39.31mmol) and dichloromethane (25 mL). The solution was cooled to an internal temperature below 5 ℃ (range 0-5 ℃). A solution of potassium bromide (0.94g, 7.86mmol) in water (5ml) was added in one portion. TEMPO (0.12g, 0.79mmol) was then added as a single solid. A solution of potassium bicarbonate (7.87g, 78.61mmol) in water (50ml) was added dropwise over 10 minutes. After stirring for 10 minutes, a 10 wt% sodium hypochlorite (29.26g) solution was added over 1 hour, maintaining the internal temperature between 0-5 ℃. After the reaction was complete, a solution of sodium thiosulfate (3.11g, 19.66mmol) in water (20mL) was added over 15 minutes with stirring. The mixture was then warmed to room temperature, the layers were separated and the aqueous phase was extracted with dichloromethane (20ml), the organic phases were combined, concentrated to dryness under reduced pressure and the residue was dissolved in acetonitrile (10 ml).
The acetonitrile solution was cooled to below 5 deg.C (range 0-5 deg.C). Aqueous ammonia (6.12mL of 28% aqueous solution) was added to the system over 1 hour, maintaining the internal temperature between 0-5 deg.C, glyoxal (2.5mL, 55.03mmol, 40% aqueous solution) was added over 1 hour, and the temperature was maintained with stirring for 19 hours. After completion of the reaction, the reaction was diluted with ethyl acetate (50ml), and the organic phase was washed twice with saturated brine. Concentrated to dryness under reduced pressure and recrystallized from toluene and n-heptane to give 1- (1H-imidazol-2-yl) isoindoline-2-carboxylic acid tert-butyl ester as an off-white solid, 8.96g, 79.9% yield.
1H-NMR(400MHz,CDCl3)δ:1.42(s,9H),4.34(d,1H),4.44(d,1H),6.25(s,1H),6.92(d,1H),7.02(d,1H),7.25-7.45(m,4H).13C-NMR(125MHz,CDCl3)δ:28.33,48.56,61.78,81.20,118.44,124.45,124.48,125.86,128.81,130.00,136.96,137.32,144.01,154.42.LC-MS(ESI,pos,ion)m/z:286.15[M+H].
(2) Synthesis of tert-butyl 1- (5-bromo-1H-imidazol-2-yl) isoindoline-2-carboxylate:
Figure BDA0002871135910000051
to a clean flask (100L) equipped with a stirrer at the top was added tert-butyl 1- (1H-imidazol-2-yl) isoindoline-2-carboxylate (8.96g, 31.40mmol) and methanol (25 mL). The mixture was stirred at 20 ℃ for about 45 minutes under nitrogen to ensure that all solids were dissolved. The solution was cooled to-20 ℃. N-bromosuccinimide (12.30g, 69.08mmol) was added portionwise to the system while maintaining the temperature below-10 ℃. Water (80mL) was added to the reaction mixture. The temperature of the feed solution rises to about 15-20 ℃. An additional 85mL of water was added over about 30 minutes. During the second addition of water, product crystallization had begun. The system was kept stirring for 30 minutes at 15-20 ℃. Additional water (30mL) was then added over 1.5 hours. The solid was filtered and the filter cake was washed with 10 volumes of aqueous methanol (methanol: H)2O ═ 5:8) to give 1- (5-bromo-1H-imidazol-2-yl) isoindoline-2-carboxylic acid tert-butyl ester as pale yellow crystals, 9.37g, 81.9% yield.
1H-NMR(400MHz,CDCl3)δ:1.42(s,9H),4.34(d,1H),4.44(d,1H),6.25(s,1H),7.25-7.45(m,4H),7.62(s,1H).13C-NMR(125MHz,CDCl3)δ:28.33,48.56,62.01,81.20,108.79,124.45,125.86,128.45,128.81,130.00,136.96,137.32,141.44,154.42.LC-MS(ESI,pos,ion)m/z:364.06[M+H].
(3) Synthesis of tert-butyl 1- (5-bromo-4-chloro-1H-imidazol-2-yl) isoindoline-2-carboxylate:
Figure BDA0002871135910000061
to a solution of tert-butyl 1- (5-bromo-1H-imidazol-2-yl) isoindoline-2-carboxylate (9.37g, 25.72mmol) in MeOH (100mL) was added NCS (3.95g, 29.6mmol) and the resulting reaction mixture was stirred at room temperature for about 15 hours. The reaction mixture was then concentrated to dryness in vacuo. The residue was slurried with water for two hours, filtered and washed with a mixed solvent of MeOH and water (v/v ═ 9:1) and dried under vacuum at 40 ℃ to give 1- (5-bromo-4-chloro-1H-imidazol-2-yl) isoindoline-2-carboxylic acid tert-butyl ester as a pale yellow solid, 9.93g, 96.8% yield.
1H-NMR(400MHz,CDCl3)δ:1.42(s,9H),4.34(d,1H),4.44(d,1H),6.30(s,1H),7.29(t,1H),7.37(m,2H),7.43(d,1H).13C-NMR(125MHz,CDCl3)δ:28.33,48.56,62.82,81.20,106.06,124.45,125.86,128.81,130.00,133.53,134.09,136.96,137.32,154.42.LC-MS(ESI,pos,ion)m/z:400.02[M+H].
(4) Synthesis of tert-butyl 1- (4-chloro-1H-imidazol-2-yl) isoindoline-2-carboxylate:
Figure BDA0002871135910000062
to a solution of tert-butyl 1- (5-bromo-4-chloro-1H-imidazol-2-yl) isoindoline-2-carboxylate (9.93g, 24.91mmol) in MeOH (30mL) was added water (9mL), EDTA (8.74g), aqueous ammonia (28%, 9.35mL), and Zn powder (4.89 g). The resulting system was heated to 45 ℃ and stirred at this temperature for 7 hours. The remaining Zn powder was filtered off, ethyl acetate (50mL) and saturated brine (50mL) were added to the filtrate, stirred for 30 minutes, the layers were separated, and the organic phase was washed with an aqueous citric acid solution (0.5%, 50 mL). The solvent was removed by concentration under reduced pressure at 50 ℃ and the resulting crude product was dissolved in MeOH (27mL) and water (90mL) was added slowly over 1 hour at room temperature. After 2 hours of crystallization, filtration and drying were carried out to give 1- (4-chloro-1H-imidazol-2-yl) isoindoline-2-carboxylic acid tert-butyl ester as an off-white solid, 6.44g, 80.9% yield.
1H-NMR(400MHz,CDCl3)δ:1.42(s,9H),4.34(d,1H),4.44(d,1H),5.86(s,1H),7.11(s,1H),7.25-7.45(m,4H).13C-NMR(125MHz,CDCl3)δ:28.33,48.56,62.62,81.20,112.53,124.45,125.86,127.55,128.81,130.00,135.27,136.96,137.32,154.42.LC-MS(ESI,pos,ion)m/z:320.11[M+H].
(5) Synthesis of Compound 1:
Figure BDA0002871135910000071
1- (4-chloro-1H-imidazol-2-yl) isoindoline-2-carboxylic acid tert-butyl ester (1.14g, 3.58mmol) was dissolved in 20mL H2In a mixed solvent of EtOH (1: 1). 2-Furanylboronic acid (0.45g, 4.00mmol) and potassium carbonate (0.29g, 2.10mmol) were added to the mixture. Then PdNPs catalyst (0.4 mmol% Pd) was added and the mixture was stirred vigorously under nitrogen at 60 ℃ for 10 minutes. The reaction mixture was added to 0.2mol/L sodium hydroxide solution (15mL) and extracted twice with ethyl acetate (20 mL). The organic phases were combined and crystallized by natural evaporation in air to give the product tert-butyl 1- (4- (furan-2-yl) -1H-imidazol-2-yl) isoindoline-2-carbonate (compound 1) as a bright yellow solid, 1.13g, 90% yield.
Example 2 Synthesis of Compound 2
Figure BDA0002871135910000072
1- (4-chloro-1H-imidazol-2-yl) isoindoline-2-carboxylic acid tert-butyl ester (1.60g, 5.00mmol) was dissolved in 20mL H2In a mixed solvent of EtOH (1: 1). 4-Methylfuranyl-2-boronic acid (0.76g, 6mmol) and potassium carbonate (0.69g, 5.00mmol) are added to the mixture. Then PdNPs catalyst (0.4 mmol% Pd) was added and the mixture was stirred vigorously under nitrogen at 60 ℃ for 10 minutes. The reaction mixture was added to 0.2mol/L sodium hydroxide solution (30mL) and extracted twice with ethyl acetate (40 mL). The organic phases are combined and naturally volatilized in the air to crystallize to obtain the yellow solid product 1- (4- (furan-2-yl) -1H-imidazol-2-yl) isoindoline-2-carbonic acid tert-butyl ester (compound 2)) 1.67g, yield 91.5%.
Example 3 Synthesis of Compound 3
Figure BDA0002871135910000081
1- (4-chloro-1H-imidazol-2-yl) isoindoline-2-carboxylic acid tert-butyl ester (1.60g, 5.00mmol) was dissolved in 20mL H2In a mixed solvent of EtOH (1: 1). 5-Methylfuranyl-2-boronic acid (0.76g, 6mmol) and potassium carbonate (0.69g, 5.00mmol) are added to the mixture. Then PdNPs catalyst (0.4 mmol% Pd) was added and the mixture was stirred vigorously under nitrogen at 60 ℃ for 10 minutes. The reaction mixture was added to 0.2mol/L sodium hydroxide solution (30mL) and extracted twice with ethyl acetate (40 mL). The organic phases were combined and the crystals were allowed to evaporate naturally in air to give the product tert-butyl 1- (4- (furan-2-yl) -1H-imidazol-2-yl) isoindoline-2-carbonate (compound 3) as a yellow solid, 1.48g, 80.9% yield.
Test example 1 therapeutic Effect of the Compound of the present invention on type2 diabetic mice
ICR mice of 6 weeks old were purchased, acclimatized for one week, then fed with high fat diet (60% fat) for three weeks, and the mice were weighed weekly. Three weeks later, mice without obvious weight increase were removed, and obese mice were intraperitoneally injected with 2% Streptozotocin (STZ) citric acid solution at a dose of 85mg/kg at one time, and were fed with high-fat diet continuously, and after three weeks, mice were measured for two hours of postprandial blood glucose, and mice with blood glucose values higher than 11.1mM were considered to be type2diabetes mice, and mice with blood glucose values around 15mM were taken for further experiments.
And (3) grouping the type2diabetes mellitus mice successfully modeled to ensure that the number of the mice in each group is more than or equal to 8 and the average blood sugar value of the mice in each group is relatively close. The compound obtained by the invention is dissolved by DMSO (dimethyl sulfoxide), and the same amount of DMSO is injected into a control group which is administrated to the abdominal cavity every other day according to 10 mg/kg. The results of weighing the feed amount of the mice every day, calculating the food intake amount of the mice every week, weighing the weight of the mice every week, detecting the postprandial blood sugar of the mice for continuous treatment for 8 weeks are shown in figure 1, and the results show that the compound obtained by the invention has good effect of reducing the blood sugar concentration when being used for treating type2 diabetes.
Test example 2 effects of the compound obtained by the present invention on adipocytes.
Hematoxylin-eosin staining (HE staining) is one of the staining methods commonly used in paraffin section technology. The colon tissue is placed in a prepared fixative (10% formalin, Bouin's fixative) and the water is gradually removed from the tissue mass using low to high concentration alcohol as dehydrating agent. Then placing the tissue block in a transparent agent xylene for transparency, and replacing alcohol in the tissue block with xylene. Placing the transparent tissue block in melted paraffin, and placing the tissue block in a paraffin dissolving box for heat preservation. And embedding after the paraffin is completely immersed in the tissue block. The embedded wax blocks are fixed on a microtome and cut into thin sections, typically 5-8 microns thick. The cut sheets, which often crease, are placed in heated water to be ironed, then are attached to glass slides, and are dried in a thermostat at 45 ℃. Before staining, paraffin in the sections is removed by xylene, and H & E staining is carried out by high-concentration to low-concentration alcohol and finally distilled water. The HE staining process is to stain the sections after the distilled water is added into the hematoxylin water solution for several minutes. The acid water and ammonia water are separated in color for several seconds each. The water is flushed for 1 hour and then distilled water is added for a moment. Dehydrating in 70% and 90% ethanol for 10 min. Dyeing for 2-3 minutes in alcohol eosin staining solution. The dyed slices are dehydrated by pure alcohol and then are transparent by xylene. The transparent sections were dropped with Canadian gum and mounted with a coverslip. After the gum is slightly dried, a label is attached, and a picture is taken under a microscope for observation.
The results are shown in fig. 2, the fat cell volume of the type2diabetes mouse is increased to a certain extent compared with the fat cell volume of the normal mouse, the characteristic of obesity of the type2diabetes mouse is reflected, and the compound has a certain effect on the reduction of the fat cell volume of the type2diabetes mouse in the treatment process.
Test example 3 Effect of the compound obtained by the present invention on glucose homeostasis in mice.
The effect of the compounds obtained according to the invention on the glucose homeostasis of mice was observed using the Oral Glucose Tolerance Test (OGTT). 8-week-old male C57bl/6N mice were fasted for 18 hours and randomized (N-8). The resulting compound of the invention was administered by oral delivery through a gavage needle (p.o. administration in a volume of 100 uL). 30 minutes after administration of the test compound, glucose was orally administered to the mice at a dose of 5 g/kg. Blood glucose levels were determined at the time points shown using a glucometerleitexl (bayer). As a result, as shown in FIG. 3, the compound obtained by the present invention was effective in reducing blood glucose in mice.
The compound prepared by the invention has positive significance in preventing and treating metabolic diseases such as diabetes and hyperglycemia, and provides a new research idea for the research and development of medicines of metabolic regulators.

Claims (5)

1. An isoindoline derivative compound, the chemical structural general formula of which is shown in formula I,
Figure FDA0002871135900000011
in the formula: r1Is selected from-H or-CH3，R2Is selected from-H or-CH3。
2. The isoindoline derivative compound of formula I according to claim 1, wherein the synthesis route is as follows:
3. a process for the preparation of isoindoline derivatives according to claim 1, comprising the steps of:
Figure FDA0002871135900000012
4. use of isoindoline derivatives according to claim 1 as metabolic modulators.
5. The use according to claim 4, characterized in that the compounds obtained according to the invention are used as metabolic modulators for the preparation of medicaments for the treatment or prevention of metabolic disorders such as diabetes and hyperglycemia, preferably obesity, type2diabetes, prediabetes, metabolic syndrome, myocardial metabolic risk, cardiovascular diseases, arteriosclerosis, atherosclerosis and the like.
CN202011609074.7A 2020-12-30 2020-12-30 Isoindoline derivative compound, preparation method and application Withdrawn CN112707895A (en)

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