CN103864803A - Preparation of 1-(phenyl)-1, 3, 4, 9-tetrahydropyrano[3, 4-b]indole derivative and application in antitumor drugs - Google Patents

Abstract

The invention belongs to the technical field of medicinal chemistry, in particular to the preparation of a 1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole derivative and its antitumor drug The application of this compound is a tricyclic indole of tetrahydropyran, all of which belong to new compounds. Changing the spatial distance and angle of the two group angles of the 1-position and the 8-position is very important for the study of its prostaglandin EP3 receptor. At present, we have developed a new and efficient synthetic route to study a series of its derivatives, all compounds The structures of the intermediates and intermediates have been identified by NMR and liquid mass. These target compounds play an important role in antibacterial, anti-tumor, analgesic, anti-platelet aggregation, promoting the reabsorption of sodium and water in the kidney, contracting the uterus, regulating the release of neurotransmitters, promoting lipolysis of adipose tissue and anti-arrhythmia .

Description

Preparation of a 1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole derivative and its application in antitumor drugs

technical field

The present invention relates to the preparation of a new substituted 1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole derivative and its application in antitumor drugs . Slightly modified its DG-041 core structure, developed self-innovated anticoagulant drugs with high efficiency and low toxicity, and screened other biological activities. EP ₃ is most distributed in the brain, spreading throughout the central nervous system, mediating the body Fever and hyperalgesia. EP ₃ is also widely present in the stomach, kidney and uterus, and can inhibit gastric acid secretion, promote the reabsorption of sodium and water in the kidney, contract the uterus, adjust the release of neurotransmitters, and promote the lipolysis of adipose tissue, etc.

technical background

Indole and its corresponding derivatives are the basic units of many natural product structures, and mainly exist in many alkaloids in the form of various derivatives. The derivatives have a variety of biological activities, including antibacterial, antitumor, analgesic, antiplatelet aggregation, antiarrhythmia and other aspects. Such compounds come from a wide range of sources, and their derivatives can be obtained by looking for lead compounds from natural plants and undergoing structural modification. The tricyclic indoles whose third ring is tetrahydropyran that we invented slightly modified the core structure of DG-041 Indole, there have been many reports before, but there are a lot of problems. At the same time, we can solve the problem of water solubility and space distance by modifying the structure of the 8-position and 1-position. activity. Our method of introducing substituents through structural modification of the 8-position and 1-position has never been reported in literature and patents; the assessment of the spatial distance of these two angles is also very important for the study of EP3 receptors. At present, we have developed a new high-efficiency The synthetic route is of great significance to the study of a series of derivatives. the

Brief description of the invention

In this paper, 7-bromoaniline was used as the starting material, and 8-[(E)-methyl- 3-Acrylate]-1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole and its derivatives. the

First of all, the present invention provides the compound of formula (I)

Formula (I)

in:

R1 is preferably: benzaldehyde, 3,4-dichlorobenzaldehyde, 3,5-dichlorobenzaldehyde, 4-trifluoromethylbenzaldehyde, 4-nitrobenzaldehyde, 4-methoxybenzaldehyde, 3 , 4-dimethoxybenzaldehyde, 3,5-dimethylbenzaldehyde, 3-methylbenzaldehyde, 4-methylbenzaldehyde. the

R2 is preferably: methyl acrylate, ethyl acrylate, acrylic acid. the

Particular compounds of the invention include

(1) 8-[3'-(E)-methyl acrylate]-1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole) 

(2) 8-[3'-(E)-methyl acrylate]-1-(3,4-dichlorophenyl)-1,3,4,9-tetrahydropyrano[3,4-b ] indole

(3) 8-[3'-(E)-methyl acrylate]-1-(3,5-dichlorophenyl)-1,3,4,9-tetrahydropyrano[3,4-b ] indole

(4) 8-[3'-(E)-methyl acrylate]-1-(4-trifluoromethylphenyl)-1,3,4,9-tetrahydropyrano[3,4-b ] indole

(5) 8-[3'-(E)-methyl acrylate]-1-(4-nitrophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]ind Indole

(6) 8-[3'-(E)-methyl acrylate]-1-(4-methoxyphenyl)-1,3,4,9-tetrahydropyrano[3,4-b] Indole

(7) 8-[3'-(E)-methyl acrylate]-1-(3,4-dimethoxyphenyl)-1,3,4,9-tetrahydropyrano[3,4 -b]indole

(8) 8-[3'-(E)-methyl acrylate]-1-(3,5-dimethoxyphenyl)-1,3,4,9-tetrahydropyrano[3,4 -b]indole

(9) 8-[3'-(E)-methyl acrylate]-1-(3-methylphenyl)-1,3,4,9-tetrahydropyrano[3,4-b]ind Indole

(10) 8-[3'-(E)-methyl acrylate]-1-(4-methylphenyl)-1,3,4,9-tetrahydropyrano[3,4-b]ind Indole

(11) 8-[3'-(E)-ethyl acrylate]-1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole) 

(12) 8-[3'-(E)-ethyl acrylate]-1-(3,4-dichlorophenyl)-1,3,4,9-tetrahydropyrano[3,4-b ] indole

(13) 8-[3'-(E)-ethyl acrylate]-1-(3,5-dichlorophenyl)-1,3,4,9-tetrahydropyrano[3,4-b ] indole

(14) 8-[3'-(E)-ethyl acrylate]-1-(4-trifluoromethylphenyl)-1,3,4,9-tetrahydropyrano[3,4-b ] indole

(15) 8-[3'-(E)-ethyl acrylate]-1-(4-nitrophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]ind Indole

(16) 8-[3'-(E)-ethyl acrylate]-1-(4-methoxyphenyl)-1,3,4,9-tetrahydropyrano[3,4-b] Indole

(17) 8-[3'-(E)-ethyl acrylate]-1-(3,4-dimethoxyphenyl)-1,3,4,9-tetrahydropyrano[3,4 -b]indole

(18) 8-[3'-(E)-ethyl acrylate]-1-(3,5-dimethoxyphenyl)-1,3,4,9-tetrahydropyrano[3,4 -b]indole

(19) 8-[3'-(E)-ethyl acrylate]-1-(3-methylphenyl)-1,3,4,9-tetrahydropyrano[3,4-b]ind Indole

(20) 8-[3'-(E)-ethyl acrylate]-1-(4-methylphenyl)-1,3,4,9-tetrahydropyrano[3,4-b]ind Indole

(21) 8-[3'-(E)-acrylic acid]-1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole

(22) 8-[3'-(E)-acrylic acid]-1-(3,4-dichlorophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]ind Indole

(23) 8-[3'-(E)-acrylic acid]-1-(3,5-dichlorophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]ind Indole

(24) 8-[3'-(E)-acrylic acid]-1-(4-trifluoromethylphenyl)-1,3,4,9-tetrahydropyrano[3,4-b]ind Indole

(25) 8-[3'-(E)-acrylic acid]-1-(4-nitrophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole

(26) 8-[3'-(E)-acrylic acid]-1-(4-methoxyphenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole

(27) 8-[3'-(E)-acrylic acid]-1-(3,4-dimethoxyphenyl)-1,3,4,9-tetrahydropyrano[3,4-b ] indole

(28) 8-[3'-(E)-acrylic acid]-1-(3,5-dimethoxyphenyl)-1,3,4,9-tetrahydropyrano[3,4-b ] indole

(29) 8-[3'-(E)-acrylic acid]-1-(3-methylphenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole

(30) 8-[3'-(E)-acrylic acid]-1-(4-methylphenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole

Detailed description of the invention

The synthetic route of formula (I)

Description 1

7-Bromoindoledione

Get 7-bromoaniline (10g, 5.8mmol) and put it into a 500mL round bottom flask, add 250mL of water, add anhydrous sodium sulfate (63.56g, 45.2mmol) and hydroxylamine hydrochloride (13.24g, 19.1mmol) under stirring, Then 10 mL of 2 mol/L hydrochloric acid solution was added, stirred at room temperature for 5 minutes, and finally chloral hydrate (10.6 g, 11.6 mol) was added. The reaction mixture was stirred at room temperature for 15 minutes, and then reacted at 90° C. for 2 hours. After 2 hours of reaction, TLC detected that the starting material disappeared, then cooled at room temperature, filtered with suction, and dried in vacuo to obtain 13.4 g of a yellow solid. the

Take 40mL of concentrated sulfuric acid and add it to a 100mL round bottom flask, slowly add 13.4g of yellow solid into the concentrated sulfuric acid at 50°C, and react at 65°C for 30min after complete addition. Cool to room temperature after the reaction, then pour the reaction mixture into ice-water mixture, stir for 30 min, filter with suction to obtain a red solid, and dry in a vacuum oven to obtain 11.4 g of 7-bromoindoledione with a yield of 84%. It is a red solid. the

¹ H NMR (DMSO) δ: 11.137 (1H, s), 7.757-7.730 (1H, t), 7.666-7.661 (1H, d), 6.891-6.870 (1H, d).

Description 2

7-Bromoindole

Under anhydrous and oxygen-free conditions, put 3g (13.3mmol) of 7-bromoindoledione into a 250mL round bottom flask, add 10mL of anhydrous THF to dissolve it, and add 30mL (30mmol) dropwise at 0°C After the addition of borane (1M in THF), it was raised to room temperature and reacted for 48 hours. After TLC detected that the raw material disappeared, it was cooled to room temperature, and 50 mL of methanol and 100 mL of water were added in turn. Then extracted with ethyl acetate (200mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was spun off under reduced pressure, and column chromatography was purified with petroleum ether 100-200 mesh silica gel column. 800 mg of 7-bromoindole was obtained with a yield of 32%. the

Description 3

2-(7-Bromo-1H-indol-3-yl)-2-oxoacetyl chloride

Under anhydrous and oxygen-free conditions, put 7-bromoindole (2g, 10.3mmol) into a 100mL round bottom flask, dissolve it with anhydrous THF (20mL), and oxalyl chloride (3.8g, 30.9mmol ) was added slowly, and the addition was completed in about 30 minutes. Slowly rise to room temperature while reacting for 4 h, until the disappearance of the raw material detected by TLC, to obtain a tetrahydrofuran solution of 2-(7-bromo-1H-indol-3-yl)-2-oxoacetyl chloride, which is directly purified to the next step. the

Description 4

2-(7-Bromo-1H-indol-3-yl)-2-oxoacetic acid

Take H2O (10mL) and put it into a 250mL round bottom flask, cool it to ℃ with an ice-salt bath, and the 2-(7-bromo-1H-indol-3-yl)-2-oxoacetyl chloride obtained in the previous step The tetrahydrofuran solution was added slowly, and the dropwise addition was completed in about 30 minutes. After warming to room temperature, the reaction solution continued to react for 2 hours. TLC detects that the raw material disappears, 50mL EA is added, extracted three times with EA, the organic layers are combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the obtained solid is recrystallized with methanol and water to obtain pure product 2-(7- Bromo-1H-indol-3-yl)-2-oxoacetic acid (1.3 g, 95%), yellow solid. .

1HNMR (d6-DMSO, 400MHz): δ/ppm 14.00(s, 1H, COOH), 12.61(s, 1H, NH), 8.41(s, 1H, Ar-H), 8.18-8.20(d, 1H, Ar -H), 7.52-7.54(m, 1H, Ar-H), 7.20-7.24(t, 1H, Ar-H). 

ESI-MS, m/z: 265(M ^- ), 267(M ^- ).

Description 5

2-(7-Bromo-1H-indol-3-yl)ethanol

Under anhydrous and oxygen-free conditions, put 2-(7-bromo-1H-indol-3-yl)-2-oxoacetic acid (1g, 3.8mmol) into a 100mL round-bottomed flask, and add 10mL of anhydrous THF Dissolve, add _BH3 (18.7ml, 1M in THF) dropwise to the system at room temperature, complete the addition in about 10 minutes, react at room temperature for 3 hours, TLC detects that the raw materials disappear, add 10mL methanol to quench the system, add 50mL EA, and use EA was extracted three times, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by petroleum ether: ethyl acetate = 3:1, 100-200 mesh silica gel column chromatography. 2-(7-Bromo-1H-indol-3-yl)ethanol (0.55 g, 61%) was obtained as an oily solid

¹ H NMR (CDCl ₃ 400MHz): δ/ppm 8.26(s, 1H, NH), 7.52-7.55(d, 1H, Ar-H), 7.32-7.35(t, 1H, Ar-H), 7.09(s , 1H, Ar-H); 6.96-7.09(t, 1H, Ar-H), 3.85-3.90(t, 2H, CH ₂ ) 2.96-3.01(t, 2H, CH ₂ ), 1.69(s, 1H, OH).

ESI-MS, m/z: 240(M ⁺ ), 242(M ⁺ ),

Note 6

8-Bromo-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indole

Get 2-(7-bromo-1H-indol-3-yl)ethanol (200mg, 0.83mmol) and benzaldehyde (132mg, 1.3mmol) into a 50mL round bottom flask, add 10mL of toluene to dissolve it, and then Then add bismuth trifluoromethanesulfonate (0.06mg, 0.09mmol), the system was heated up to 80°C and reacted for 1 hour, TLC detected that the raw material disappeared, cooled, 20mL water was added successively, EA (50mL X3) extracted three times, and the organic layers were combined , washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, purified by petroleum ether:ethyl acetate=40:1, 100-200 mesh silica gel column chromatography to obtain 8-bromo-1-phenyl-1,3, 4,9-Tetrahydropyrano[3,4-b]indole, white solid ((150 mg, 55%)). the

¹ H NMR (CDCl ₃ 400MHz): δ/ppm 7.74-7.75 (t, 1H, Ar-H), 7.62-7.64 (d, 1H, Ar-H), 7.39-7.44 (m, 5H, Ar-H) , 7.17-7.21(t, 1H, Ar-H), 5.85(s.1H, CH) 4.31-4.34(m, 1H, CH ₂ ) 4.01(d, 1H, CH ₂ ), 3.09-3.12(d, 1H , CH ₂ ), 2.83-2.87 (d, 1H, CH ₂ ).

Description 7

8-[3'-(E)-Methyl acrylate]-1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole

Under the protection of anhydrous and oxygen-free nitrogen, take 8-bromo-1-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (0.5g, 1.5mmol) into a 50mL circle In the bottom flask, add methyl acrylate (196mg, 2.3mmol), palladium acetate (34mg, 0.15mmol), triphenylphosphine (118mg, 0.45mmol), 2mL triethylamine and 6mL DMF successively. Raise the temperature to 100 ℃, make Its reaction 7h. After the completion of the reaction as detected by TLC, cool to room temperature, add water, extract three times with EA (70mL x3), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, and use petroleum ether: ethyl acetate = 25:1 , Purified by 100-200 mesh silica gel column chromatography. Yield: 0.39 g, 75%. the

¹ H NMR (CDCl ₃ 400MHz): δ/ppm 7.87-7.91 (d, 1H, CH), 7.73-7.75 (d, 1H, Ar-H), 7.54-7.56 (d, 1H, Ar-H), 7.40 -7.44(m, 5H, Ar-H), 7.17-7.21(m, 1H, Ar-H), 6.42-6.46(d, 1H, CH), 5.85(s, 1H, CH), 4.31-4.36(m , 1H, CH ₂ ) 4.00-4.02 (m, 1H, CH ₂ ), 3.81 (s, 1H, CH 2 ), 3.10-3.14 (m, 1H, CH ₂ ), 2.83-2.87 (d, 1H, CH ₂ ) .

Note 8

8-[3'-(E)-Methyl acrylate]-1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole

Take 8-[(E)-methyl-3-acrylate]-1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole) (0.1g , 0.3mmol) into a 25mL round-bottomed flask, add 1mL of methanol and 1mL of 2N NaOH and react at 50°C for 5h, concentrate in vacuo to remove methanol, adjust to acidic ph=4 with 2N HCl hydrochloric acid at low temperature, extract with EA, concentrate in vacuo 90 mg of the product was obtained with a yield of 94%. the

¹ H NMR (CDCl ₃ 400MHz): δ/ppm 7.92-7.97 (d, 1H, CH), 7.63-7.70 (m, 1H, Ar-H), 7.53-7.56 (d, 1H, Ar-H), 7.40 -7.48(m, 5H, Ar-H), 7.15-7.20(m, 1H, Ar-H), 6.38-6.43(d.1H, CH), 5.83(s, 1H, CH), 4.31-4.36(m , 1H, CH ₂ ), 4.28-4.32 (m, 1H, CH ₂ ), 3.95-4.01 (m, 1H, CH ₂ ), 3.06-3.14 (m, 1H, CH2), 2.81-2.86 (d, 1H, CH ₂ ).

Description 9

1-(Phenyl)-1,3,4,9-Tetrahydropyrano[3,4-b]indole Derivatives Selective Inhibition of K562, TH-29, HepG2

Cells K562, HT-29, and HepG2 were purchased from Shanghai Cell Bank, and K562, TH-29, and HepG2 cells in the logarithmic phase of growth were inoculated in 96-well plates at 5×10 ³ cells/100 μL per well, at 37°C , and cultured for 24 hours under 5% CO ₂ conditions. Dissolve the drug in dimethyl sulfoxide (the drug used to determine K562 is dissolved in isopropanol hydrochloride) to prepare 5 different drug concentrations for determination (the drug concentration range is 0-10 μM), take 0.5 μL of each concentration gradient The drug solution was added to a 96-well plate and incubated at 37°C for 48 hours, the culture medium was discarded (K562 is a suspension cell, no need to discard the culture medium), and 0.5g/mL tetramethylazolazolium blue ( MTT), the optical density OD value of each well of the 96-well plate was measured at a wavelength of 490 (the optical density of K562 was measured at a wavelength of 570). Set 3-4 parallel wells for each test, and repeat 3-4 times.

The growth inhibition rate (%) of the drug on the cells=(the average OD value of the solution control group-the average OD value of the medication group)/the average OD value of the control group, and then calculate the IC of the drug according to the growth inhibition rate (%) of the cells at different drug concentrations ₅₀ value.

The experimental results of the inhibitory effect of 1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole derivatives on K562, HepG2, HT-29 cell proliferation

We selected K562, HepG2, and HT-29 as cancer cells in the experiment. It can be seen from the chart that compounds 1, 11, 21, and 30 have certain selective inhibitory effects on K562 and HepG2. However, the selective inhibitory effect of these compounds on HT-29 is relatively poor. the

The above implementation examples are only specific examples enumerated to fully illustrate the present invention, and the scope of protection of the present invention is determined by the content of the claims, not limited to the specific implementation manners. The equivalent substitutions or transformations made by those skilled in the art on the basis of the present invention without departing from the essence of the present invention are also within the protection scope of the present invention. Therefore, the gist and scope of the present invention are not limited to the contents herein. specific description. the

All content disclosed in the present invention, including the abstract and drawings, as well as all steps in any method or process disclosed, can be combined in any combination, unless certain features or steps are mutually exclusive combinations. Every feature disclosed in the present invention , including abstracts and drawings, can be used to achieve the same, equivalent or similar purpose of alternative features, unless otherwise explicitly stated, therefore, unless otherwise explicitly stated, each feature disclosed in the present invention only has equivalent or similar features A specific instance of the generic series of . Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art given the description herein. Such modifications are also intended to fall within the scope of the appended claims. the

Figure 1 is the hydrogen nuclear magnetic resonance spectrum of 2-(7-bromo-1H-indol-3-yl)ethanol. the

Figure 2 is the NMR of 8-[3'-(E)-methyl acrylate]-1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrogen spectrum. the

Figure 3 is the H NMR spectrum of 8-[3'-(E)-acrylic acid]-1-(phenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole . the

Claims (6)

1. the compound shown in structural formula (I).Or its pharmaceutically acceptable solvated compounds, inner complex, non-covalent complex or prodrug,

Structural formula (I)

It is characterized in that:

R1 is selected from phenyl, all kinds of containing substituent phenyl.

R2 is selected from acrylate, containing substituent acrylate, and vinylformic acid;

R3 is selected from H or halogen (F, Br, Cl).

2. the compound under claim structural formula 1 is that R3 is hydrogen, R1 is chosen as methyl acrylate, R1 is phenmethyl, 3,4-dichlorobenzene methyl, 3,5-dichlorobenzene methyl, 4-trifluoromethyl phenmethyl, 4-oil of mirbane methyl, 4-mehtoxybenzyl, 3,4-dimethoxy phenmethyl, 3,5-dimethyl benzene methyl, 3-methylbenzene methyl, 4-methylbenzene methyl.

3. the compound under claim structural formula 1 is that R3 is hydrogen, R1 is chosen as ethyl propenoate, R1 is phenmethyl, 3,4-dichlorobenzene methyl, 3,5-dichlorobenzene methyl, 4-trifluoromethyl phenmethyl, 4-oil of mirbane methyl, 4-mehtoxybenzyl, 3,4-dimethoxy phenmethyl, 3,5-dimethyl benzene methyl, 3-methylbenzene methyl, 4-methylbenzene methyl.

4. the compound under claim structural formula 1 is that R3 is hydrogen, R1 is chosen as vinylformic acid, R1 is phenmethyl, 3,4-dichlorobenzene methyl, 3,5-dichlorobenzene methyl, 4-trifluoromethyl phenmethyl, 4-oil of mirbane methyl, 4-mehtoxybenzyl, 3,4-dimethoxy phenmethyl, 3,5-dimethyl benzene methyl, 3-methylbenzene methyl, 4-methylbenzene methyl.

5. the synthetic route of the compound under claim structural formula 1 is as follows:

6.1-(phenyl)-1,3,4,9-tetrahydropyrans is [3,4-b] indole derivatives heavily absorbing, shrinking uterus, adjust the application in steatolysis and the antiarrhythmic drug of release, promotion fatty tissue of neurotransmitter at antibacterial, antitumor, the analgesia of preparation, platelet aggregation-against, gastric acid secretion inhibiting, promotion kidney position sodium and water also.

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