CN116947853A - Echinococcosis-resistant medicine, preparation method and medical application thereof - Google Patents
Echinococcosis-resistant medicine, preparation method and medical application thereof Download PDFInfo
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- CN116947853A CN116947853A CN202310838632.4A CN202310838632A CN116947853A CN 116947853 A CN116947853 A CN 116947853A CN 202310838632 A CN202310838632 A CN 202310838632A CN 116947853 A CN116947853 A CN 116947853A
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- Prior art keywords
- compound
- ylmethyl
- group
- bipiperidin
- echinococcosis
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
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- Health & Medical Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to the field of pharmaceutical chemistry, relates to an anti-echinococcosis medicament, a preparation method and medical application thereof, in particular to a beta-carboline anti-echinococcosis compound, a preparation method thereof, a compound and medical application of a medicinal composition containing the compound in preparation of medicaments for preventing or treating echinococcosis.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a series of beta-carboline derivatives, a preparation method and medical application thereof, wherein different sites of the beta-carboline are modified, a series of beta-carboline analogues are designed and synthesized, and the medical application of the compounds, in particular to the application in preparing medicines for preventing or treating echinococcosis.
Background
Echinococcosis, also known as echinococcosis, is caused by infection of echinococcosis-causing hosts with echinococcosis adults or larvae of the tapephase, and is a zoonosis involving numerous hosts (Lancet, 2003, 362:1295-304). There are two main types in our country: cystic echinococcosis (Cystic Echinococcosis, CE) is caused by echinococcus granulosus (Echinococcus granulosus, E.g); the echinococcosis (Alveolar Echinococcosis, AE) is caused by echinococcosis multifilialis. The disease is well developed in the animal husbandry and is a global public health problem (int.j. Infec. Des.2019,79,89). In our country, cystic echinococcosis is mainly distributed in northwest and southwest regions, where the Qinghai-Tibet plateau is the region of heavy epidemic of the disease (adv. Parasitol.2017,95, 315-493). Surgical treatment has so far been the treatment of choice for echinococcosis, but this method presents a certain risk and places high demands on medical conditions and physician techniques (Acta trop 2020,203: 105283). Therefore, drug therapy is attracting more and more attention as an auxiliary therapeutic means.
Peganum harmala L is a perennial herb of the genus Peganum in the family Tribulaceae, and is mainly distributed in North China (Food CH & Em. Toxicol.2010,48 (3), 839-845;Food CH&Em.Toxicol.2017,103,261-269; toxins (Basel) 2015,7 (11), 4507-4518). The beta-carboline is a three-membered ring alkaloid in the seeds of the peganum harmala of peganaceae, and is a benzoindole structure. It inhibits the synthesis of topoisomerase, cyclin-dependent kinase and DNA and can be incorporated into DNA, thus having a broad range of biological activities. Studies have shown that the β -carboline derivative Harmine (HM) has various pharmacological actions such as antiparasitic (tetra H & Edron Lett.2010,51 (4), 583-585;J.Drug Target.2004,12 (3), 165-175), bactericidal (Fisterapia.2010, 81 (7), 779-782), antitumor (Oncol. Rep.2017,38 (5), 2927-2934; phytomedicine.2017,28,10-18; altern. Med.2017, 1-7), antidepressant (prog. Neuropyschohardacol. Biol. Psychiary.2017, 79 (Pt B), 258-267;Brain Res.Bull.2018,137,294-300). The subject group found that HM has a good anti-echinococcosis activity, and that the combination of harmine and the commonly used anti-echinococcosis drug Albendazole (ABZ) in clinic can exert a synergistic effect. However, HM has a certain neurotoxicity, which can cause vomiting, tremors, hallucinations and even death in patients, thus limiting clinical application and development.
Based on this, the subject group surrounds the HM mother nucleus, and five structural sites of the beta-carboline ring 1, 2,3, 7,9 and the like are subjected to structural modification and reconstruction, so as to improve the activity of treating cystic echinococcosis and reduce the neurotoxicity (patent number: CN 105998014B). The prior research of the team discovers that HM derivatives DH-330 and DH-004 have better curative effect on CE and LC thereof 50 Values 41.55 + -9.48 μM, 47.77+ -18.99 μM, respectively, are superior to HM (LC) 50 = 250.39 ±92.11 μm, patent No.: CN105998014 a). However, DH-330 has only 32.91% inhibition of echinococcus granulosus growth in mice at low doses of 25mg/kg, and it is well known that echinococcosis treatment is a long-term administration process, and thus how to find more effective derivatives, thereby further reducing the dose or the administration course, improving patient compliance and reducing occurrence of adverse reactions has been required to be studied intensively.
Disclosure of Invention
According to the background, the invention modifies different sites of beta-carboline, designs and synthesizes a class of echinococcosis-resistant compounds with killing effect on echinococcosis granulosa, and provides a preparation method of the compounds, a medicinal composition containing the compounds, pharmaceutically acceptable salts thereof and medicinal application thereof.
The technical scheme is as follows:
in a first aspect, the invention discloses a compound, which is a compound represented by formula I, II, or a pharmaceutically acceptable salt thereof:
wherein R is 1 Selected from the group consisting ofor-CH 3 ；
R 2 Selected from the group consisting of
R 3 Selected from the group consisting of
R 4 Selected from the group consisting of
In some embodiments, the compound of formula i is selected from: 1a:4- ((4-hydroxypiperidin-1-yl) methyl) -N- (1- (4-methoxyphenyl) -9H-pyrido [3,4-b ] indol-3-yl) benzamide
1b: n- (1- (3-methoxyphenyl) -9H-pyridin [3,4-b ] indol-3-yl) -4- ((4-methyl-1, 4-diaza-1-yl) methyl) benzamide
1c:4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) -N- (1- (3, 4-dimethoxyphenyl) -9H-pyridin [3,4-b ] indol-3-yl) benzamide
1d: n- (1- (3, 4-dimethoxyphenyl) -9H-pyrido [3,4-b ] indol-3-yl) -4- ((4-methyl-1, 4-diaza-1-yl) methyl) benzamide
1e:4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) -N- (1-methyl-9H-pyridin [3,4-b ] indol-3-yl) benzamide
1f:4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) -N- (1- (p-tolyl) -9H-pyridin [3,4-b ] indol-3-yl) benzamide
1g:4- ((4-methyl-1, 4-diaza-1-yl) methyl) -N- (1- (3, 4, 5-trimethoxyphenyl) -9H-pyridin [3,4-b ] indol-3-yl) benzamide
In some embodiments, the compound of formula ii is selected from: 2a: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (4-methoxyphenyl) -9H-pyridine [3,4-b ] indole-3-carboxamide
2b: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (3-methoxyphenyl) -9H-pyridine [3,4-b ] indole-3-carboxamide
2c: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (3, 4-dimethoxyphenyl) -9H-pyrido [3,4-b ] indole-3-carboxamide
2d: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (2-methoxyphenyl) -9H-pyridine [3,4-b ] indole-3-carboxamide
2e: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (2, 3-dimethoxyphenyl) -9H-pyrido [3,4-b ] indole-3-carboxamide
2f: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (2, 4-dimethoxyphenyl) -9H-pyridine [3,4-b ] indole-3-carboxamide
2g: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (3, 5-dimethoxyphenyl) -9H-pyrido [3,4-b ] indole-3-carboxamide
In a second aspect, the invention also provides a method for preparing the compound.
The preparation method of the compound I comprises the following steps:
compounds 1-1R 1 Performing Pictet-Spengler reaction on CHO and L-tryptophan under acidic conditions to obtain an intermediate 1-2;
the carboxyl of the intermediate 1-2 is converted into methyl ester to obtain an intermediate 1-3;
oxidizing the intermediate 1-3 to obtain an intermediate 1-4; the intermediate 1-4 is converted into the intermediate 1-5 after being treated by hydrazine hydrate, and the hydrazine group of the intermediate 1-5 is formed in NaNO 2 Converting into azido to generate intermediate 1-6 in the presence, and converting intermediate 1-6 into amino to generate intermediate 1-7 through Curtis rearrangement; intermediate 1-7 reacts with p-chloromethylbenzoyl chloride to generate intermediate 1-8; intermediates 1-8 and compounds 1-9R 2 H undergoes nucleophilic substitution reaction to obtain a target compound I;
in some embodiments, the compounds of formula I can be prepared by: starting from L-tryptophan and compound 1-1 (corresponding aldehyde R 1 CHO) to a Pictet-Spengler reaction to form intermediate 1-2, which is then converted to methyl ester intermediate 1-3. Intermediate 1-3 is KMnO in DMF 4 Oxidation to obtain intermediate 1-4, which is converted to intermediate 1-5 after treatment with hydrazine hydrate. 1-5 hydrazine groups in NaNO 2 Conversion to azido groups in the presence of 1-6, at H 2 Conversion to amino groups by Curtis rearrangement in the presence of HAc in O yields intermediates 1-7. Reaction of 1-7 with p-chloromethylbenzoyl chloride in DCM in the presence of TEA produced intermediate 1-8. At K 2 CO 3 And KI, intermediates 1-8 and compounds 1-9 (different secondary amines R 2 H) Nucleophilic substitution reactions take place in acetonitrile to form the target compound i.
In some embodiments, the synthetic route for compound i comprises:
the preparation method of the compound II comprises the following steps:
compounds 2-1R 3 CHO and L-tryptophan are subjected to Pictet-Spengler reaction under acidic condition to obtain an intermediate 2-2,
oxidizing the intermediate 2-2 to obtain an intermediate 2-3;
4-nitrobenzyl bromide and Compound 2-4R 4 H undergoes nucleophilic substitution reaction to obtain an intermediate 2-5, and the nitro group of the intermediate 2-5 is reduced to amino group to obtain an intermediate 2-6;
the intermediate 2-3 and the intermediate 2-6 generate a target compound II through an amide condensation reaction;
in some embodiments, the compounds of formula II can be prepared by: starting from L-tryptophan and the compound 2-1 (corresponding aldehyde R 3 CHO) to generate 2-2. Intermediate 2-2 is KMnO in DMF 4 Oxidation gives intermediate 2-3. At K 2 CO 3 And KI in acetonitrile with the compound 2-4R 4 Nucleophilic substitution reaction of H secondary amine to obtain intermediate 2-5, and subsequent reaction in CH 3 In OH with Pd/C and H 2 Reduction gives intermediate 2-6. Intermediate 2-3 and intermediate 2-6 in DCM are subjected to an amide condensation reaction in the presence of EDCI and DMAP to yield the target compound II.
In some embodiments, the synthetic route for compound ii comprises:
in a third aspect, the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.
The dosage forms of the pharmaceutical composition of the present invention may be prepared by those skilled in the art according to conventional methods in the pharmaceutical arts. For example, the active ingredient is admixed with one or more carriers (also known as excipients) and then formulated into desired dosage forms, including tablets, capsules, granules, aerosols; can also be made into intravenous injection or intravenous injection freeze-dried agent according to the conventional production method of injection.
In a fourth aspect, the invention also provides application of the compound and the pharmaceutical composition in preparing medicines for preventing or treating echinococcosis.
The beneficial effects are that: the compound of the invention has the following excellent properties: the stability of the compound (1) is higher. The compound of (2) is readily available synthetically. (3) The compounds 1a, 1c, 1e are effective in inhibiting echinococcosis granulosa growth. (4) Compound 1a inhibited echinococcosis growth in a concentration-dependent manner, and was able to completely inhibit echinococcosis growth at low concentrations. (5) Compound 1a inhibited echinococcosis granulosa growth and was superior to the positive drug Albendazole (ABZ) and compound DH-003. (6) Compound 1a has good safety compared to harmine.
Experiments prove that the compound disclosed by the invention also has the following excellent properties: 1a proved to be the best compound, and at an initial concentration of 1. Mu.M, it was found that more than 50% of echinococcosis granulosa Protopanum (PSCs) died after 2 days of intervention with derivative 1a and was dose-dependent. In addition, 1a also showed significant morphological changes compared to ABZ and HM controls. Finally, in the echinococcosis granulosa protonode experiments with derivatives, 1a may lead to protonode injury and loss of viability. In this experiment, the in vitro activity of the beta-carboline derivative 1a is superior to that of the positive drug Albendazole (ABZ) and the lead compound Harmine (HM). Subsequently, in vivo pharmacodynamic studies were performed on 1 a. The results indicate that the reduction in cyst weight of the 1a treated mice was statistically significant compared to the model control group and also statistically significant after 28 days of treatment compared to the ABZ and HM treated groups. The wet weight reduction rate of the 1a low dose (12.5 mg/kg) was comparable to that of the ABZ and HM high dose group (50 mg/kg) for 14 days of treatment; the wet weight reduction rate of the 1a capsule can reach 76.87% up to 28 days of treatment, and is 1.39 times and 1.35 times of that of the ABZ and HM treatment groups at the same dosage respectively. Thus, 1a has a very pronounced anti-bag worm effect. Overall, our study showed that 1a is a very promising candidate for anti-echinococcosis drugs.
Drawings
FIG. 1 is a schematic representation of the results of an in vitro mortality study of compounds 1a-1g and 2a-2g on echinococcus granulosus PSCs.
FIG. 2 is a schematic representation of the results of an in vitro study of anti-echinococcosis PSCs in compounds 1a-1g and 2a-2g, wherein compounds 1a, 1c, 1e were found to significantly inhibit PSCs and alter their morphology, in a dose-dependent manner.
FIG. 3 is a schematic diagram showing the results of pharmacokinetic studies performed on compounds 1a, 1c, and 1 e.
FIG. 4 is a graphical representation of the results of in vivo treatment of echinococcosis granulosa infected mice after 14 days and 30 days of compound 1a intervention.
FIG. 5 is a schematic diagram of the results of observing the effect of compound 1a on the structure of the insect-encapsulating vesicles in mice at an ultra-micro level using transmission electron microscopy.
FIG. 6 is a schematic diagram of the results of compound 1a on the toxicity of brain tissue and the structure of hippocampal neurons in mice infected with echinococci granulosa.
Detailed Description
The following is a further detailed description of the present invention, by way of example, showing specific embodiments.
1. Synthesis of intermediates
Example 1: the intermediate 1-2 was synthesized by dissolving L-tryptophan (10.20 g,50mmol,1.0 eq) as a starting material in 80ml CH 3 Adding compound 1-1R into COOH solution 1 CHO (55 mmol,1.1 eq) was stirred for 3 hours at 90 ℃. After the reaction, the reaction solution is adjusted to pH=5-6 by using 2M NaOH solution, a large amount of yellow solid is precipitated, and the yellow solid, namely an intermediate 1-2, is obtained by suction filtration and vacuum drying.
Example 2: intermediate 1-3 was synthesized by dissolving intermediate 1-2 (50 mmol,1.0 eq) in 140ml methanol and slowly adding SOCl dropwise with vigorous stirring at-5℃ 2 (17.85 g,150mmol,3.0 eq) and after 0.5 hours the reaction mixture was addedAnd (3) refluxing for 4 hours under heat, concentrating under reduced pressure to remove the solvent after the reaction is finished, adding a proper amount of water into the concentrate for dissolving, adjusting the pH to 8 with a 1M NaOH solution, precipitating a yellow solid, filtering, and drying the filter cake under reduced pressure to obtain the yellow solid, namely an intermediate 1-3.
Example 3: the intermediate 1-4 was synthesized by dissolving intermediate 1-3 (50 mmol,1.0 eq) in 150ml DMF solvent and adding KMnO in portions with mechanical stirring at-5 ℃ 4 (11.05 g,70mmol,1.4 eq) and stirring for 1 hour, after the reaction, the reaction solution is filtered off with suction, the filtrate is added into 200ml of cold water, a precipitate is separated out, and a light brown solid, namely an intermediate 1-4, is obtained by filtering.
Example 4: intermediate 1-5 Synthesis procedure intermediate 1-4 (50 mmol,1.0 eq) was dissolved in 130ml methanol, 88.20ml 85% hydrazine hydrate (75.00 g,1500mmol,30.0 eq) was added thereto, heated to reflux for 4 hours, cooled to 0 ℃ after completion of the reaction, and suction filtered to give a pale brown solid. And adding a large amount of cold water into the filtrate, continuously precipitating solids, carrying out suction filtration, and drying the filter cake under reduced pressure to obtain a product, namely an intermediate 1-5.
Example 5: the intermediate 1-6 was synthesized by dissolving intermediate 1-5 (50 mmol,1.0 eq) in 100ml of 2MHCl solution, followed by NaNO 2 (10.35 g,150mmol,3.0 eq) in 80ml H 2 In O, mechanically stirring at-5 ℃ to obtain NaNO 2 Slowly dripping the solution into the 1-5 solution, continuously stirring for 1 hour, regulating the pH of the reaction solution to 8 by using a 1M NaOH solution, precipitating solid, carrying out suction filtration, and drying to obtain a light yellow solid, namely an intermediate 1-6.
Example 6: the intermediate 1-7 was synthesized by dissolving intermediate 1-6 (50 mmol,1.0 eq) in 150ml H 2 And (3) heating and refluxing in a mixed solution of O and glacial acetic acid (1:1) for 5 hours at 90 ℃, concentrating under reduced pressure after the reaction is finished to remove the solvent, and purifying the crude product by column chromatography to obtain a pale yellow solid, namely an intermediate 1-7.
Example 7: intermediate 1-8 was synthesized by dissolving intermediate 1-7 (2 mmol,1.0 eq) in 5ml of anhydrous dichloromethane, adding triethylamine (0.81 g,8mmol,4.0 eq), further dissolving p-chloromethylbenzoyl chloride (0.38 g,2mmol,1.0 eq) in 3ml of anhydrous dichloromethane, and slowly dropwise adding the solution to the 1-7 solution at-5℃in ice bath, after 0.5 hours, the reaction was completed. The dichloromethane solvent in the reaction solution was removed by concentration under reduced pressure, 100mL of water was added, ethyl acetate (3X 20 mL) was used for extraction, the organic phases were combined, washed with clean water (30 mL. Times.2), saturated brine (30 mL) was used for washing, the organic phase was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain pale yellow solid, intermediate 1-8.
Example 8: synthesis procedure of intermediate 2-2 referring to example 1, starting material L-tryptophan and compound 2-1R are used 3 CHO。
Example 9: the procedure for the synthesis of intermediate 2-3 is described in example 3.
Example 10: the intermediate 2-5 is synthesized by dissolving 4-nitrobenzyl bromide (1.0 eq) in anhydrous acetonitrile, adding compound 2-4R 4 H (2.0 eq). The reaction solution was stirred at room temperature for 5 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. To the residue was added water and ethyl acetate, extracted, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give yellow solid intermediate 2-5.
Example 11: intermediate 2-6 is synthesized by dissolving intermediate 2-5 (1.0 eq) in a mixed solution of ethanol and water (about 1.7:1), adding iron powder (5.0 eq) and ammonium chloride (10.0 eq), and reacting at 85 ℃ for 2 hours. After the reaction was completed, ethanol was removed by concentration under reduced pressure, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purifying the crude product by column chromatography to obtain the product, namely the intermediate 2-6.
2. Synthesis of target Compound
Example 12: the synthesis of the target compound 1a comprises the steps of preparing 4- (chloromethyl) -N- (1- (4-methoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) benzamide (1 mmol,0.44 g) was dissolved in acetonitrile (8 ml), and 4-hydroxypiperidine (1.5 mmol,0.15 g), potassium carbonate (2.0 mmol,0.28 g) and potassium iodide (0.1 mmol,0.02 g) were added sequentially and reacted overnight at room temperature. After the reaction was completed, acetonitrile was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=100:1) to obtain 0.48g of a pale yellow solid, and the yield was 94%. 1 H NMR(DMSO-d 6 ,300MHz): 1 H NMR(400MHz,DMSO)δ11.4(s,1H,NH),10.5(s,1H,NH),8.7(s,1H,Ar-H),8.2(d,J＝7.9Hz,1H,Ar-H),8.0(d,J＝8.0Hz,4H,Ar-H),7.6(d,J＝8.3Hz,1H,Ar-H),7.5(m,1H,Ar-H),7.4(d,J＝7.8Hz,2H,Ar-H),7.2(m,1H,Ar-H),7.1(d,J＝8.4Hz,2H,Ar-H),4.6(s,1H,OH),3.8(s,3H,OCH 3 ),3.5(s,2H,CH 2 ),2.9(m,2H,CH 2 ),2.4(s,1H,CH),2.0(s,2H,CH 2 ),1.7(s,2H,CH 2 ),1.4(d,J＝11.0Hz,2H,CH 2 ). 13 C NMR(101MHz,DMSO)δ165.7,160.2,143.3,142.6,140.1,131.7,130.9,130.6,130.3,129.2,128.7,128.3,122.0,121.5,119.8,114.5,112.9,105.0,55.8,55.4,51.2,45.9.HRMS(ESI)m/z calcd for C 31 H 31 N 4 O 3 ,507.2396；found,507.2239[M+H] + 。
Example 13: the synthesis of the target compound 1b comprises the step of synthesizing 4- (chloromethyl) -N- (1- (4-methoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) benzamide (1 mmol,0.44 g) was dissolved in acetonitrile (8 ml), and N-methyl homopiperazine (1.5 mmol,0.17 g), potassium carbonate (2.0 mmol,0.28 g) and potassium iodide (0.1 mmol,0.02 g) were added sequentially and reacted overnight at room temperature. After the reaction was completed, acetonitrile was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=100:1) to obtain 0.49g of a pale yellow solid, with a yield of 94%. 1 H NMR(400MHz,DMSO-d 6 )δ11.42(s,1H,NH),10.55(s,1H,NH),8.68(s,1H,Ar-H),8.17(d,J＝7.9Hz,1H,Ar-H),8.01(m,4H,Ar-H),7.59(d,J＝8.2Hz,1H,Ar-H),7.51–7.43(m,3H,Ar-H),7.18(m,1H,Ar-H),7.11(d,J＝8.3Hz,2H,Ar-H),3.81(s,3H,OCH 3 ),3.69(s,2H,CH 2 ),3.24–3.12(m,6H,CH 2 ),2.97(m,2H,CH 2 ),2.79(m,3H,CH 3 ),1.93(m,2H,CH 2 ). 13 C NMR(101MHz,DMSO)δ165.6,160.2,143.3,142.6,140.1,133.9,131.7,130.9,130.3,128.9,128.4,122.0,121.5,119.8,114.5,113.0,105.0,61.4,56.4,55.8,54.7,53.8,49.5,45.7,44.0,23.9.MS(ESI)m/z:574[M+H] + .HRMS(ESI)m/z calcd for C 32 H 34 N 5 O 2 ,520.2712；found,520.2705[M+H] + 。
Example 14: the synthesis of the target compound 1c comprises the step of synthesizing 4- (chloromethyl) -N- (1- (3, 4-dimethoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) benzamide (1 mmol,0.47 g) was dissolved in acetonitrile (8 ml) and 4-piperidyl piperidine (1.5 mmol,0.25 g) was added sequentially) Potassium carbonate (2.0 mmol,0.28 g) and potassium iodide (0.1 mmol,0.02 g) were reacted overnight at room temperature. After the reaction was completed, acetonitrile was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=100:1) to obtain 0.56g of a pale yellow solid, and the yield was 93%. 1 H NMR(400MHz,DMSO-d 6 )δ11.46(s,1H,NH),10.60(s,1H,NH),8.75(s,1H,NH),8.24(d,J＝7.9Hz,1H,Ar-H),8.08(d,J＝8.0Hz,2H,Ar-H),7.65(d,J＝8.4Hz,3H,Ar-H),7.56(t,J＝7.6Hz,1H,Ar-H),7.46(d,J＝8.0Hz,2H,Ar-H),7.35(s,1H,Ar-H),7.25(t,J＝7.4Hz,1H,Ar-H),7.20(d,J＝8.1Hz,1H,Ar-H),3.90(d,J＝13.7Hz,6H,OCH 3 ),3.58(s,2H),2.98–2.90(m,4H,CH 2 ),2.00(d,J＝11.8Hz,4H,CH 2 ),1.78–1.63(m,7H,CH 2 ),1.52(s,1H,CH),1.26–1.16(m,3H,CH 2 ). 13 C NMR(101MHz,DMSO-d 6 )δ170.4,154.6,154.0,148.0,147.3,145.1,138.6,136.4,135.7,135.5,133.9,133.5,133.1,132.1,126.3,126.2,124.6,117.7,117.3,116.9,67.7,66.2,60.9,60.7,56.8,54.2,50.7,34.2,31.0,28.2,27.1.MS(ESI)m/z:604[M+H] + .HRMS(ESI)m/z calcd for C 37 H 42 N 5 O 3 ,604.3287；found,604.3279[M+H] + 。
Example 15: the synthesis of the target compound 1d comprises the step of synthesizing 4- (chloromethyl) -N- (1- (3, 4-dimethoxy phenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) benzamide (1 mmol,0.47 g) was dissolved in acetonitrile (8 ml), and N-methyl homopiperazine (1.5 mmol,0.17 g), potassium carbonate (2.0 mmol,0.28 g) and potassium iodide (0.1 mmol,0.02 g) were added sequentially and reacted overnight at room temperature. After the reaction was completed, acetonitrile was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=100:1) to obtain 0.52g of pale yellow solid, and the yield was 95%. 1 H NMR(400MHz,DMSO-d 6 )δ11.46(s,1H,NH),10.60(s,1H,NH),8.75(s,1H,NH),8.24(d,J＝7.9Hz,1H,Ar-H),8.07(d,J＝8.0Hz,2H,Ar-H),7.68–7.61(m,3H,Ar-H),7.55(t,J＝7.6Hz,1H,Ar-H),7.50(d,J＝7.9Hz,2H,Ar-H),7.39–7.34(m,1H,Ar-H),7.25(t,J＝7.5Hz,1H,Ar-H),7.20(d,J＝8.1Hz,1H,Ar-H),3.90(d,J＝13.8Hz,6H,OCH 3 ),3.73(s,2H),2.98–2.88(m,6H,CH 2 ),2.77–2.72(m,2H,CH 2 ),2.70–2.62(m,3H,CH 3 ),1.88–1.83(m,2H,CH 2 ). 13 C NMR(101MHz,DMSO-d 6 )δ170.4,154.6,154.0,148.2,148.0,147.3,145.1,140.3,138.5,136.4,135.7,135.5,133.6,133.5,133.1,132.2,124.6,117.7,117.3,116.9,66.5,62.0,61.9,60.9,60.7,60.5,58.8,58.7,50.3,30.5.MS(ESI)m/z:550[M+H] + .HRMS(ESI)m/z calcd for C 33 H 36 N 5 O 3 ,550.2818；found,550.2811[M+H] + 。
Example 16: the synthesis of target compound 1e is carried out by synthesizing 4-chloromethyl-N- (1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) benzamide (1 mmol,0.35 g) was dissolved in acetonitrile (8 ml), 4-piperidyl piperidine (1.5 mmol,0.25 g), potassium carbonate (2.0 mmol,0.28 g) and potassium iodide (0.1 mmol,0.02 g) were added sequentially and reacted overnight at room temperature. After the reaction was completed, acetonitrile was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=100:1) to obtain 0.45g of a pale yellow solid, with a yield of 94%. 1 H NMR(400MHz,DMSO-d 6 )δ11.54(s,1H,NH),10.52(s,1H,NH),8.67(s,1H,Ar-H),8.19(d,J＝7.9Hz,1H,Ar-H),8.06(d,J＝8.0Hz,2H,Ar-H),7.62–7.49(m,2H,Ar-H),7.42(d,J＝8.0Hz,2H,Ar-H),7.27–7.18(m,1H,Ar-H),3.52(s,2H,CH 2 ),2.87(d,J＝11.1Hz,2H,CH 2 ),2.77(s,3H,CH 3 ),2.61(s,3H,CH,CH 2 ),1.98–1.91(m,2H,CH 2 ),1.75(d,J＝11.6Hz,2H,CH 2 ),1.61–1.19(m,10H,CH 2 ). 13 CNMR(101MHz,DMSO-d 6 )δ165.4,142.9,142.8,141.8,140.4,133.7,132.7,129.5,129.0,128.5,128.2,122.2,121.7,119.6,112.4,103.9,63.5,62.6,62.0,53.0,50.0,31.4,27.5,25.6,20.4.MS(ESI)m/z:482[M+H] + .HRMS(ESI)m/z calcd for C 30 H 36 N 5 O,482.2920；found,482.2912[M+H] + 。
Example 17: the synthesis of the target compound 1f comprises the steps of preparing 4-chloromethyl-N- (1-p-tolyl) -9H-pyrido [3,4-b ]]Indol-3-yl) benzamide (1 mmol,0.43 g) was dissolved in acetonitrile (8 ml), and 4-piperidyl piperidine (1.5 mmol,0.25 g), potassium carbonate (2.0 mmol,0.28 g) and potassium iodide (0.1 mmol,0.02 g) were added sequentially and reacted overnight at room temperature. After the reaction, acetonitrile is removed by decompression concentration, and the crude product is purified by column chromatography (dichloromethane: methyl)Alcohol=100:1), 0.54g of a pale yellow solid was obtained, with a yield of 97%. 1 H NMR(400MHz,DMSO-d 6 )δ11.41(s,1H,NH),10.57(s,1H,NH),8.76(s,1H,Ar-H),8.24(d,J＝7.9Hz,1H,Ar-H),8.06(d,J＝8.2Hz,2H,Ar-H),8.02–7.98(m,2H,Ar-H),7.63(d,J＝8.2Hz,1H,Ar-H),7.57–7.52(m,1H,Ar-H),7.44(d,J＝7.8Hz,4H,Ar-H),7.25(t,J＝7.5Hz,1H,Ar-H),3.53(s,2H,CH 2 ),2.95(s,1H,CH),2.87(d,J＝11.0Hz,2H,CH 2 ),2.45(s,3H,CH 3 ),2.00–1.90(m,2H,CH 2 ),1.71(d,J＝11.4Hz,2H,CH 2 ),1.54–1.36(m,8H,CH 2 ),1.32–1.18(m,4H,CH 2 ). 13 CNMR(101MHz,DMSO-d 6 )δ165.7,143.3,142.9,142.6,140.2,138.6,135.4,133.7,131.8,131.1,129.7,129.0,128.9,128.3,122.0,121.5,119.9,112.9,105.4,62.6,62.1,53.1,50.0,27.7,26.0,21.5.MS(ESI)m/z:558[M+H] + .HRMS(ESI)m/z calcd for C 36 H 40 N 5 O,558.3233；found,558.3223[M+H] + 。
Example 18: 1g of the target compound was synthesized by the procedure of 4-chloromethyl-N- (1- (3, 4, 5-trimethoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) benzamide (1 mmol,0.50 g) was dissolved in acetonitrile (8 ml), and N-methyl homopiperazine (1.5 mmol,0.17 g), potassium carbonate (2.0 mmol,0.28 g) and potassium iodide (0.1 mmol,0.02 g) were added sequentially and reacted overnight at room temperature. After the reaction was completed, acetonitrile was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=100:1) to obtain 0.54g of a pale yellow solid, with a yield of 94%. 1 H NMR(400MHz,DMSO-d 6 )δ11.48(s,1H,NH),10.61(s,1H,NH),8.77(s,1H,Ar-H),8.25(d,J＝7.9Hz,1H,Ar-H),8.09(d,J＝7.8Hz,2H,Ar-H),7.68–7.45(m,4H,Ar-H),7.27(d,J＝10.5Hz,3H,Ar-H),3.94(s,6H,OCH 3 ),3.78(s,3H,OCH 3 ),3.21(d,J＝28.8Hz,4H,CH 2 ),2.84(s,3H,CH 3 ),2.72(d,J＝13.6Hz,4H,CH 2 ),1.96(s,2H,CH 2 ),1.23(s,2H,CH 2 ). 13 C NMR(101MHz,DMSO-d 6 )δ165.7,153.5,143.5,143.3,142.6,140.4,138.4,133.7,133.6,131.7,131.1,128.8,128.3,122.1,121.5,119.9,112.9,106.4,105.5,61.7,60.6,57.3,56.4,55.8,54.1,45.6,25.9.MS(ESI)m/z:580[M+H] + .HRMS(ESI)m/z calcd for C 34 H 38 N 5 O 4 ,580.2924；found,580.2916[M+H] + 。
Example 19: the synthesis of the target compound 2a comprises the steps of synthesizing 1- (4-methoxyphenyl) -9H-pyrido [3,4-b]Indole-3-carboxylic acid (1 mmol,0.32 g) was dissolved in anhydrous dichloromethane (10 ml), EDCI (2 mmol,0.38 g), DMAP (0.5 mmol,0.06 g) was added followed by 4- (1, 4' -bipiperidine)]1' -ylmethyl) aniline (1 mmol,0.27 g) was reacted overnight at room temperature. After the reaction was completed, methylene chloride was removed by concentration under reduced pressure, and the crude product was purified by column chromatography to obtain 0.45g (92%) of a pale yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,1H,NH),10.46(s,1H,NH),8.92(s,1H,Ar-H),8.45(d,J＝8.1Hz,1H,Ar-H),8.21(d,J＝8.3Hz,2H,Ar-H),7.87(d,J＝8.1Hz,2H,Ar-H),7.73(d,J＝8.3Hz,1H,Ar-H),7.62(t,J＝7.8Hz,1H,Ar-H),7.28(dd,J＝38.3,8.3Hz,5H,Ar-H),3.91(s,3H,OCH 3 ),2.99(t,J＝15.2Hz,6H,CH 2 ),1.99(t,J＝12.4Hz,4H,CH 2 ),1.71(d,J＝21.9Hz,7H,CH 2 ,CH),1.51(s,2H,CH 2 ),1.21(d,J＝18.6Hz,2H,CH 2 ). 13 C NMR(101MHz,DMSO-d 6 )δ165.7,160.2,143.3,142.6,140.1,133.8,131.7,130.9,130.6,130.3,129.1,128.7,128.3,122.0,121.5,119.8,114.5,112.9,105.0,73.0,63.6,62.0,55.8,55.0,52.8,45.9,30.9,29.5,22.6.MS(ESI)m/z:574[M+H] + .HRMS(ESI)m/z calcd for C 36 H 40 N 5 O 2 ,574.3182；found,574.3171[M+H] + .
Example 20: the synthesis of the target compound 2b comprises the steps of synthesizing 1- (3-methoxyphenyl) -9H-pyrido [3,4-b]Indole-3-carboxylic acid (1 mmol,0.32 g) was dissolved in anhydrous dichloromethane (10 ml), EDCI (2 mmol,0.38 g), DMAP (0.5 mmol,0.06 g) was added followed by 4- (1, 4' -bipiperidine)]1' -ylmethyl) aniline (1 mmol,0.27 g) was reacted overnight at room temperature. After the reaction was completed, methylene chloride was removed by concentration under reduced pressure, and the crude product was purified by column chromatography to obtain 0.54g (94%) of a pale yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H,NH),10.45(s,1H,NH),8.98(s,1H,Ar-H),8.47(d,J＝7.9Hz,1H,Ar-H),7.85(d,J＝8.1Hz,2H,Ar-H),7.79–7.71(m,3H,Ar-H),7.65–7.58(m,2H,Ar-H),7.34(t,J＝7.5Hz,1H,Ar-H),7.29(d,J＝8.1Hz,2H,Ar-H),7.17(dd,J＝8.2,2.6Hz,1H,Ar-H),3.95(s,3H,OCH 3 ),3.41(s,2H,CH 2 ),2.95(s,1H,CH),2.86(d,J＝11.1Hz,2H,CH 2 ),1.89(t,J＝11.5Hz,3H,CH 2 ),1.70(d,J＝12.0Hz,2H,CH 2 ),1.50(d,J＝8.7Hz,7H,CH 2 ),1.41–1.35(m,2H,CH 2 ),1.27–1.19(m,2H,CH 2 ). 13 C NMR(101MHz,DMSO-d 6 )δ163.7,160.1,142.2,141.2,139.8,139.2,137.8,135.0,134.1,130.6,130.5,129.7,129.2,122.6,121.6,121.5,120.8,120.4,115.4,114.6,114.1,113.3,62.6,62.1,55.7,53.0,50.0,31.4,27.6,25.9,24.5,22.5.MS(ESI)m/z:574[M+H] + .HRMS(ESI)m/z calcd for C 36 H 40 N 5 O 2 ,574.3182；found,574.3172[M+H] + .
Example 21: the synthesis of the target compound 2c comprises the steps of synthesizing 1- (3, 4-dimethoxy phenyl) -9H-pyrido [3,4-b]Indole-3-carboxylic acid (1 mmol,0.35 g) was dissolved in anhydrous dichloromethane (10 ml), EDCI (2 mmol,0.38 g), DMAP (0.5 mmol,0.06 g) was added followed by 4- (1, 4' -bipiperidine)]1' -ylmethyl) aniline (1 mmol,0.27 g) was reacted overnight at room temperature. After the reaction was completed, methylene chloride was removed by concentration under reduced pressure, and the crude product was purified by column chromatography to give 0.55g (91%) of a pale yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ11.93(s,1H,NH),10.48(s,1H,NH),8.92(s,1H,Ar-H),8.45(d,J＝7.9Hz,1H,Ar-H),7.88–7.82(m,2H,Ar-H),7.79(d,J＝2.1Hz,1H,Ar-H),7.77–7.70(m,2H,Ar-H),7.64–7.58(m,1H,Ar-H),7.37–7.27(m,3H,Ar-H),7.24(d,J＝8.4Hz,1H,Ar-H),3.97(s,3H,OCH 3 ),3.91(s,3H,OCH 3 ),3.44(s,2H,CH 2 ),2.88(d,J＝11.0Hz,2H,CH 2 ),2.61(s,2H,CH 2 ),1.92(m,2H,CH 2 ),1.75(d,J＝12.1Hz,2H,CH 2 ),1.58–1.47(m,6H,CH 2 ),1.43–1.37(m,2H,CH 2 ),1.24(m,1H,CH),0.91–0.77(m,2H,CH 2 ). 13 C NMR(101MHz,DMSO-d 6 )δ163.7,150.2,149.5,142.1,141.4,139.7,137.9,134.8,130.4,130.3,129.8,121.8,121.7,120.3,113.5,112.8,112.3,62.7,62.0,56.2,56.1,52.8,49.9,27.4.MS(ESI)m/z:604[M+H] + .HRMS(ESI)m/z calcd for C 37 H 42 N 5 O 3 ,604.3287；found,604.3276[M+H] + 。
Example 22: the synthesis step of the target compound 2d is to synthesize 1- (2-methoxyphenyl) -9H-pyrido [3,4-b]Indole-3-carboxylic acid (1 mmol,0.32 g) was dissolved in anhydrous dichloromethane (10 ml), EDCI (2 mmol,0.38 g), DMAP (0.5 mmol,0.06 g) was added followed by 4- (1, 4' -bipiperidine)]1' -ylmethyl) aniline (1 mmol,0.27 g) was reacted overnight at room temperature. After the reaction was completed, methylene chloride was removed by concentration under reduced pressure, and the crude product was purified by column chromatography to obtain 0.45g (92%) of a pale yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ11.51(s,1H,NH),10.38(s,1H,NH),8.97(s,1H,Ar-H),8.44(d,J＝8.0Hz,1H,Ar-H),7.85(d,J＝8.2Hz,2H,Ar-H),7.72(d,J＝7.4,1.8Hz,1H,Ar-H),7.66(m,3H,Ar-H),7.32(m,J＝8.0Hz,4H,Ar-H),7.24(m,1H,Ar-H),3.82(s,3H,OCH 3 ),3.55(s,2H,CH 2 ),2.68(m,2H,CH 2 ),2.33(m,2H,CH 2 ),1.98(m,2H,CH 2 ),1.86(m,6H,CH 2 ),1.35(m,4H,CH 2 ),0.90(m,2H,CH 2 ). 13 C NMR(101MHz,DMSO-d 6 )δ163.7,157.6,149.7,141.7,140.4,139.4,137.7,136.2,134.2,132.3,131.0,129.6,122.6,121.4,120.4,120.2,114.0,112.9,112.0,62.6,62.0,55.6,53.2,50.1,27.9,26.4,24.9.MS(ESI)m/z:574[M+H] + .HRMS(ESI)m/z calcd for C 36 H 40 N 5 O 2 ,574.3182；found,574.3173[M+H] + 。
Example 23: the synthesis of target compound 2e is to synthesize 1- (2, 3-dimethoxy phenyl) -9H-pyrido [3,4-b]Indole-3-carboxylic acid (1 mmol,0.35 g) was dissolved in anhydrous dichloromethane (10 ml), EDCI (2 mmol,0.38 g), DMAP (0.5 mmol,0.06 g) was added followed by 4- (1, 4' -bipiperidine)]1' -ylmethyl) aniline (1 mmol,0.27 g) was reacted overnight at room temperature. After the completion of the reaction, methylene chloride was removed by concentration under reduced pressure, and the crude product was purified by column chromatography to give 0.53g (90%) of a pale yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ11.49(s,1H,NH),10.34(s,1H,NH),9.00(s,1H,Ar-H),8.45(d,J＝7.8Hz,1H,Ar-H),7.80(d,J＝8.5Hz,2H,Ar-H),7.65(d,J＝8.2Hz,1H,Ar-H),7.59(m,1H,Ar-H),7.35(m,6H,Ar-H),3.95(s,3H,OCH 3 ),3.62(s,3H,OCH 3 ),3.40(s,2H,CH 2 ),2.84(d,J＝11.1Hz,2H,CH 2 ),2.41(m,4H,CH 2 ),1.88(m,2H,CH 2 ),1.65(d,J＝12.1Hz,2H,CH 2 ),1.46(m,6H,CH 2 ),1.37(m,2H,CH 2 ). 13 CNMR(101MHz,DMSO-d 6 )δ165.3,146.2,144.4,138.6,134.2,133.9,131.5,129.9,129.5,129.4,126.4,120.5,115.9,73.0,63.5,62.6,53.3,28.0,26.6.MS(ESI)m/z:604[M+H] + .HRMS(ESI)m/z calcd for C 37 H 42 N 5 O 3 ,604.3287；found,604.3280[M+H] + 。
Example 24: the synthesis step of the target compound 2f is to synthesize 1- (2, 4-dimethoxy phenyl) -9H-pyrido [3,4-b]Indole-3-carboxylic acid (1 mmol,0.35 g) was dissolved in anhydrous dichloromethane (10 ml), EDCI (2 mmol,0.38 g), DMAP (0.5 mmol,0.06 g) was added followed by 4- (1, 4' -bipiperidine)]1' -ylmethyl) aniline (1 mmol,0.27 g) was reacted overnight at room temperature. After the reaction was completed, methylene chloride was removed by concentration under reduced pressure, and the crude product was purified by column chromatography to obtain 0.57g (93%) of a pale yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ11.45(s,1H,NH),10.37(s,1H,NH),8.93(s,1H,Ar-H),8.42(d,J＝7.9Hz,1H,Ar-H),7.86(m,2H,Ar-H),7.65(m,2H,Ar-H),7.58(m,1H,Ar-H),7.35(m,3H,Ar-H),6.84(d,J＝2.3Hz,1H,Ar-H),6.79(d,J＝8.4,2.4Hz,1H,Ar-H),3.92(s,3H,OCH 3 ),3.81(s,3H,OCH 3 ),3.48(s,2H,CH 2 ),2.93(d,J＝11.1Hz,4H,CH 2 ),2.01(m,4H,CH 2 ),1.72(m,6H,CH 2 ),1.25(m,2H,CH 2 ),0.96(m,2H,CH 2 ). 13 C NMR(101MHz,DMSO-d 6 )δ168.4,163.8,162.1,158.7,141.6,140.5,139.3,138.0,136.3,133.0,129.9,128.9,128.8,122.5,121.5,120.4,120.2,119.7,113.6,112.9,106.1,98.9,62.9,61.5,56.1,56.0,55.9,55.9,52.0,49.6,26.41,23.86,22.8,21.7.MS(ESI)m/z:604[M+H] + .HRMS(ESI)m/z calcd for C 37 H 42 N 5 O 3 ,604.3287；found,604.3276[M+H] + .
Example 25: the synthesis of 2g of the target compound is carried out by reacting 1- (3, 5-dimethoxyphenyl) -9H-pyrido [3,4-b ]]Indole-3-carboxylic acid (1 mmol,0.35 g) was dissolved in anhydrous dichloromethane (10 ml), EDCI (2 mmol) was added0.38 g), DMAP (0.5 mmol,0.06 g) and then 4- (1, 4' -bipiperidine)]1' -ylmethyl) aniline (1 mmol,0.27 g) was reacted overnight at room temperature. After the reaction was completed, methylene chloride was removed by concentration under reduced pressure, and the crude product was purified by column chromatography to give 0.55g (91%) of a pale yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,1H,NH),10.46(s,1H,NH),8.97(s,1H,Ar-H),8.46(d,J＝7.9Hz,1H,Ar-H),7.86(m,2H,Ar-H),7.72(d,J＝8.2Hz,1H,Ar-H),7.62(m,1H,Ar-H),7.34(m,5H,Ar-H),6.73(m,1H,Ar-H),3.92(s,6H,OCH 3 ),3.51(s,2H,CH 2 ),2.95(d,J＝11.5Hz,4H,CH 2 ),2.09(m,4H,CH 2 ),1.71(m,6H,CH 2 ),1.25(m,2H,CH 2 ),0.96(m,2H,CH 2 ). 13 C NMR(101MHz,DMSO-d 6 )δ163.6,161.2,149.0,142.1,141.2,139.7,135.0,133.9,130.5,129.7,129.2,122.6,121.6,120.8,120.4,114.2,113.3,107.3,107.2,101.6,62.7,62.0,55.9,52.7,49.0,27.3,25.4,24.1.MS(ESI)m/z:604[M+H] + .HRMS(ESI)m/z calcd for C 37 H 42 N 5 O 3 ,604.3287；found,604.3277[M+H] + 。
3. Effect verification
Example 26: in vitro anti-echinococcosis Protonode (PSCs) activity study
1. Experimental method
At 37℃and 5% CO 2 Under conditions, about 250 PSCs were implanted in each well of a 96-well plate. The derivatives were dissolved in DMSO, added to each well (containing 200 μl of medium) to give a final concentration of 1 μΜ, incubated for 2 days, and initially screened. Further studies have been carried out on derivatives having good therapeutic effects. The dose dependence of the derivatives was tested at final concentrations of 0.5, 1 and 5 μm. PSCs cultured in medium containing 1% DMSO served as controls. The effect of the derivative on the morphology and structural integrity of PSCs was observed under a microscope daily over a period of 4 consecutive days and its viability was assessed using the eosin excretion assay. A total of 100. Mu.L of 1% eosin was added per well. After 2min, the PSCs were observed under an inverted microscope (dead PSCs stained red and live PSCs colorless). Experiments were repeated 3 times and the average was taken. After the drug treatment, the treated PSCs were collected and observed by scanning electron microscopy. At the same time PSCs were collected into 1.5mL EP tubes, fixed with 4% paraformaldehyde solution, dehydrated, paraffin embedded, sectioned, stained and observed for histopathological changes under an inverted microscope.
2. Experimental results
The effect of the target compounds 1a-1g and 2a-2g on echinococcosis protonode in vitro was tested first, with ABZ and HM as positive controls, and after 2 days of intervention, echinococcosis was collected by first dosing with echinococcosis granulosa at an initial concentration of 1 μm. The survival rate of 1% DMSO, ABZ, HM group was higher, and the metacercaria granulosa protonode activity of the derivative group was all in a decreasing trend, wherein the in vitro effect was most remarkable for compounds 1a, 1c and 1e (figure 1). Furthermore, we tested the LC of all target compounds against echinococci granulosa protonode head 50 . The results are shown in Table 1, LC of all target compounds after introduction of different substituents at the 1-and 3-positions of the beta-carboline ring 50 Between 1.61 and 18.13 mu M, which are superior to the positive drugs ABZ and HM. Among them, the compounds 1a, 1c, 1e have the most remarkable anti-echinococcosis effect, which is obviously better than HM derivative DH-330. On this basis, compounds 1a, 1c, 1e were selected as preferred compounds for further investigation.
TABLE 1 in vitro anti-echinococcosis Activity of HM and target Compounds
The SAR of the target compounds 1a-1g and 2a-2g were initially analyzed according to the in vitro evaluation described above. And (3) researching the in-vitro anti-echinococcosis effect of the compound to preliminarily obtain the structure activity relationship of the target compound. Encouraging LC of the compound after introduction of different substituents at the 1-and 3-positions of the beta-carboline ring 50 Between 1.61 and 18.13 mu M, the anti-PSCs capability of the target compound is better than that of the positive medicines ABZ, HM, DH-330 and DH-004, which shows that compared with the prior art, the target compound isThe compounds can significantly improve the growth inhibition rate of the echinococcus granulosus of mice at low dosage, thereby further reducing the dosage or the treatment course of taking medicines.
On this basis, compounds 1a, 1c, 1e were selected as preferred compounds for further investigation.
Based on the above results, at three doses of high (5. Mu.M), medium (1. Mu.M) and low (0.5. Mu.M), echinococcosis granulosus protonode was collected after 1, 2,3 and 4 days of drug treatment, and the dose and time dependence of the target compound on the killing effect of echinococcosis granulosus protonode was studied, and each of the compounds 1a, 1c and 1e had dose and time dependence. Three compounds killed the vast majority of echinococcosis granulosa protonodes at 5 μm concentrations after four days of intervention (fig. 2A).
The morphological observations under the light microscope are consistent with the results of the vitality measurements, and FIG. 2B shows that the changes in morphology of the echinococcosis granulosa praecox at a dose of 5. Mu.M for 4 days of intervention with compounds 1a, 1c, 1e, are more severe, meaning that the more insect death. The echinococcosis granulosa protonode head cultured for 4 days by further collecting the medicine intervention is subjected to HE staining, pathological changes of the echinococcosis granulosa are observed, and fig. 2C shows that 1% of DMSO group worm body calcium particles are clear, the whole structure is complete, and the boundary is clear. The HM and ABZ insect bodies shrink, the edges are irregular, and the insect bodies partially fall off. The whole insect body of the compound 1a is in a cavitation shape, the matrix is dissolved and disappears, and the edge structure is disintegrated. In contrast, the insects of groups 1c and 1e shrink, the small hooks on the top protrusions fall off, the edge structure is fuzzy, and the part has a cavitation sample. The scanning electron microscope result is shown in fig. 2D, the morphological structure of the original node of the echinococcosis granulosa of the blank control group and the 1% DMSO group is complete, and the head process is complete and the micro-hair is clearly visible; after HM and ABZ (5 mu M) intervention for 2 days, the echinococcosis granulosa original joint sucker is relatively complete, and only the crust, the hook and the like fall off. 1a, 1c and 1e under the same dose and time of intervention, the ultrastructure of PSCs is found to have changed significantly, including the disintegration of the outer skin of the proto-head segment, the collapse or the absence of the hook and the suction cup. It can be seen that these 3 derivatives have a remarkable anti-echinococcosis effect in vitro.
Based on the availability of derivatives 1a, 1c and 1e on PSCs, further use of derivatives 1a, 1c and 1e at a concentration of 100 μm intervened in the bag for 4 hours. Figure 2E shows that the 1% DMSO group vesicles remained normal in shape, smooth in surface, and the germinal and stratum corneum were intact. The damage of HM and ABZ groups to the bag worm capsules is not obvious, and only the vesicle expansion degree is reduced; in contrast, the vesicles treated with compounds 1a, 1c, 1e showed complete destruction, with the germinal layer collapsing markedly, separating from the stratum corneum and forming dense aggregates within the vesicles. In summary, the modification strategy of the 1-position and the 3-position of the beta-carboline ring is beneficial to improving the anti-echinococcosis activity of the compound, wherein the compounds 1a, 1c and 1e are worthy of further study.
Example 27:1a, 1c, 1e
1. Experimental method
The selected derivatives were subjected to pharmacokinetic studies in Wistar rats. Derivatives 1a, 1c and 1e were administered intravenously and orally to rats (230-250 g, 3 animals per time point). Rats were dosed intravenously, orally, 5mg/kg, 50mg/kg, respectively. The derivative was dissolved in 5% DMSO and 95% saline intravenous dose and saline abdominal cavity. Blood samples (1.0 mL) were collected at 0.033, 0.083, 0.17, 0.33, 0.5, 1, 2,4, 6, 12h after intravenous and 0.083, 0.25, 0.5, 1, 2,4, 6, 8, 12, 24h after intraperitoneal doses, respectively, placed in a centrifuge tube containing heparin sodium, and plasma was separated by centrifugation at 4 ℃. Plasma samples were extracted by adding acetonitrile containing a universal internal standard (carbamazepine). Samples were centrifuged at 12,000 rpm for 20 minutes at 4 ℃, and supernatants were collected and analyzed. The concentration of the compounds in the plasma was determined by high performance liquid chromatography and analyzed by non-compartmental method using WinNonlin software.
2. Experimental results
The results showed that the peak concentration, area under the drug-time curve and bioavailability of group 1a were higher than those of derivatives 1c, 1e after 3 derivatives were injected intraperitoneally and caudally, respectively (fig. 3 and table 2). Furthermore, the half-life of the three derivatives can be increased by intraperitoneal administration, compared to intravenous administration. Furthermore, we studied the pharmacokinetic properties of derivatives 1a, 1c, 1e using gavage, but the results indicate that three derivatives are metabolized very rapidly after gavage and that little compound is detected in the blood samples (data not shown). Based on the superior pharmacokinetic properties of compound 1a and the significant anti-artemia activity, we performed subsequent studies with compound 1a as the preferred compound.
Table 2 pharmacokinetic parameters of compounds 1a, 1c, 1e
Note (note): absolute bioavailability = AUC 0→∞(ip) ×D iv /AUC 0→∞(iv) ×D iP ×100％； * P compared with group 1a<0.05, ** Group 1a compared with P<0.01(bioavailability＝AUC 0→∞(ip) ×D iv /AUC 0→∞(iv) ×D iP ×100％； * compared with 1a group，P<0.05, ** compared with HBN 5 group，P<0.01)
Example 28: investigation of anti-echinococcosis Activity of Compound 1a in vivo
1. Experimental method
For infection in mice, PSCs were pre-cultured in vitro to produce small cysts (micro-cysts, 200-300 μm in diameter). 25 microcapsules were transplanted intraperitoneally per mouse and suspended in 0.4mL of RPMI 1640 medium. About 180 days after infection, the moldabilities were examined by B-ultrasound, and the moldparticles were randomly divided into 10 groups of 6 mice each. (1) model administration of 0.1mL/10g/day saline; (2) ABZ (high, medium, low) dose groups, 50, 25, 12.5 mg/kg/day ABZ suspension, respectively; (3) HM (high, medium, low) dose groups, 50, 25, 12.5 mg/kg/day HM solution, respectively; (4) 1a (high, medium, low) dose groups, 50, 25, 12.5 mg/kg/day 1a solution, respectively. Continuous intraperitoneal administration of 14d and 28d, daily monitoring of weight change and survival of mice during treatment, mice were sacrificed after the end of administration, abdominal sacs were isolated, weighed, and the reduction in the cyst wet weight = (average cyst weight of model control group-average cyst weight of treated group)/average cyst weight of model control group x 100%, and the treatment effect was evaluated based on ultrastructural change of cysts. Meanwhile, the brain tissue of the mice after 28 days of treatment is observed under an HE staining optical microscope; hippocampal tissue was also observed under a transmission electron microscope.
2. Experimental results
After the molded mice were randomly divided into 10 groups, the animals were euthanized for visual appearance after 14 days and 28 days of treatment by intraperitoneal administration, and vesicle tissues were isolated from each experimental mouse and weight was measured. Observing animals, the number of original joints in the infected mice is large, the mice are transparent, the tension is high, and the cyst fluid is clear. The mice in group 1a had a small number of vesicles, low wall tension, mostly translucent or hard calcified nodules with yellowish cyst fluid, and more pronounced effect after 28 days of treatment (fig. 4b, d). The results of the inhibition rate are shown in Table 3, wherein the inhibition rate of the compound 1a group can reach 76.87%, the inhibition rate is improved by about 1.4 times compared with the ABZ group and the HM group, and the compound 1a has a dose-dependent trend on the inhibition effect of the compound 1a on the growth of the protonodus in the mice. The treatment effect of the drug was analyzed after 14 days and 28 days, and the average cyst wet weight was reduced to a different extent after each drug treatment compared to the model group, and was statistically significant (fig. 4a, c). The mean wet cyst weight was significantly reduced after 14 days of treatment of mice with compound 1a in each of the corresponding dose groups compared to ABZ, and was statistically significant. While the average wet cyst weight was statistically significant in the HM high dose alone group compared to the 1a high dose group (fig. 4A). Furthermore, the mean wet cyst weight was significantly reduced after 28 days of treatment of mice with compound 1a in each of the corresponding dose groups compared to ABZ and HM (fig. 4C). Therefore, it is preferable that compound 1a can effectively inhibit growth of echinococcus granulosus in mice, and is superior to positive drugs ABZ and HM in that the in vivo cyst inhibition rate of compound 1a is higher than that of compound DH-330 (cyst inhibition rate 32.91%) even at a dose of 25 mg/kg. In conclusion, the compound 1a has excellent anti-echinococcosis activity and is hopeful to become a potential anti-echinococcosis candidate drug.
Table 3 effect of compound 1a on mice 14 days and 28 days after infection with echinococcosis granulosa (n=6)
Note：Data were indicated as tH&E mean±standard error(SEM) *** P<0.001, ** P<0.01, * P<0.05.
On the basis of the therapeutic activity of 1a in vivo, it was further confirmed by TEM (fig. 5) that 1a showed optimal effectiveness against the artemia vesicles at the ultrastructural level. The structures of the cornea layer and the germinal layer of the model group are normal and clear, the micro-fluff between the cornea layer and the germinal layer is large in quantity and orderly arranged, the cell structure of the germinal layer is normal, and nucleolus is clear. The ABZ (50 mg/kg) and HM (50 mg/kg) dose groups had reduced microvilli, the germinal layer structure was unclear and the cells were reduced, but the nucleoli was clear. Group 1a showed vacuole-like structures, cell structure destruction and nucleolus disappearance in addition to microvilli disappearance, germinal layer cytopenia, and structural porosity at the same dose.
To study brain tissue toxicity of compound 1a, kunming mice were dosed with compound 1a for 28 days. H & E staining results showed (FIG. 6A), the control, ABZ and 1a groups had a large number of pyramidal cells, a compact arrangement, a clear visualization of the nucleus and cytoplasm, while the HM group had a reduced number of pyramidal cells, a clear cell degeneration, a loose arrangement of cells and a swelling deformation. Also, the mouse hippocampal tissue was observed using transmission electron microscopy, the control, ABZ and 1a group hippocampal neurons were normal in cell structure, orderly in cristae alignment, less heterochromatin, no damage to both organelles and nuclei, whereas the HM group mouse hippocampal neurons showed perinuclear widening, partial mitochondrial membrane and cristae were incomplete, synaptic damage was manifested as a blurred synaptic gap, and increased postsynaptic compactification (fig. 6B). Therefore, the toxicity of the derivative 1a to the brain tissue of the mice is obviously reduced by modifying the HM, and the problems of neurotoxicity and the like caused by the HM are avoided. Compound 1a holds promise for further investigation as a potential candidate drug against echinococcosis.
Claims (10)
1. A compound of formula i, ii, or a pharmaceutically acceptable salt thereof:
wherein R is 1 Selected from the group consisting ofor-CH 3 ；
R 2 Selected from the group consisting of
R 3 Selected from the group consisting of
R 4 Selected from the group consisting of
2. The compound of claim 1, wherein the compound of formula i is selected from the group consisting of:
1a:4- ((4-hydroxypiperidin-1-yl) methyl) -N- (1- (4-methoxyphenyl) -9H-pyrido [3,4-b ] indol-3-yl) benzamide
1b: n- (1- (3-methoxyphenyl) -9H-pyridin [3,4-b ] indol-3-yl) -4- ((4-methyl-1, 4-diaza-1-yl) methyl) benzamide
1c:4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) -N- (1- (3, 4-dimethoxyphenyl) -9H-pyridin [3,4-b ] indol-3-yl) benzamide
1d: n- (1- (3, 4-dimethoxyphenyl) -9H-pyrido [3,4-b ] indol-3-yl) -4- ((4-methyl-1, 4-diaza-1-yl) methyl) benzamide
1e:4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) -N- (1-methyl-9H-pyridin [3,4-b ] indol-3-yl) benzamide
1f:4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) -N- (1- (p-tolyl) -9H-pyridin [3,4-b ] indol-3-yl) benzamide
1g:4- ((4-methyl-1, 4-diaza-1-yl) methyl) -N- (1- (3, 4, 5-trimethoxyphenyl) -9H-pyridin [3,4-b ] indol-3-yl) benzamide
3. The compound of claim 1, wherein the compound of formula ii is selected from the group consisting of:
2a: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (4-methoxyphenyl) -9H-pyridine [3,4-b ] indole-3-carboxamide
2b: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (3-methoxyphenyl) -9H-pyridine [3,4-b ] indole-3-carboxamide
2c: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (3, 4-dimethoxyphenyl) -9H-pyrido [3,4-b ] indole-3-carboxamide
2d: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (2-methoxyphenyl) -9H-pyridine [3,4-b ] indole-3-carboxamide
2e: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (2, 3-dimethoxyphenyl) -9H-pyrido [3,4-b ] indole-3-carboxamide
2f: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (2, 4-dimethoxyphenyl) -9H-pyridine [3,4-b ] indole-3-carboxamide
2g: n- (4- ([ 1,4 '-bipiperidin ] -1' -ylmethyl) phenyl) -1- (3, 5-dimethoxyphenyl) -9H-pyrido [3,4-b ] indole-3-carboxamide
4. A process for the preparation of a compound as claimed in claim 1, wherein the process for the preparation of compound i comprises:
compounds 1-1R 1 Performing Pictet-Spengler reaction on CHO and L-tryptophan under acidic conditions to obtain an intermediate 1-2;
the carboxyl of the intermediate 1-2 is converted into methyl ester to obtain an intermediate 1-3;
oxidizing the intermediate 1-3 to obtain an intermediate 1-4; the intermediate 1-4 is converted into the intermediate 1-5 after being treated by hydrazine hydrate, and the hydrazine group of the intermediate 1-5 is formed in NaNO 2 Converting into azido to generate intermediate 1-6 in the presence, and converting intermediate 1-6 into amino to generate intermediate 1-7 through Curtis rearrangement; intermediate 1-7 reacts with p-chloromethylbenzoyl chloride to generate intermediate 1-8; intermediates 1-8 and compounds 1-9R 2 H undergoes nucleophilic substitution reaction to obtain a target compound I;
5. the process for the preparation of compounds according to claim 1 or 4, wherein the synthetic route for compound i comprises:
6. the process for preparing a compound according to claim 1, wherein the process for preparing compound ii comprises:
compounds 2-1R 3 CHO and L-tryptophan are subjected to Pictet-Spengler reaction under acidic condition to obtain an intermediate 2-2,
oxidizing the intermediate 2-2 to obtain an intermediate 2-3;
4-nitrobenzyl bromide and Compound 2-4R 4 H undergoes nucleophilic substitution reaction to obtain an intermediate 2-5, and the nitro group of the intermediate 2-5 is reduced to amino group to obtain an intermediate 2-6;
the intermediate 2-3 and the intermediate 2-6 generate a target compound II through an amide condensation reaction;
7. the process for the preparation of compounds according to claim 1 or 6, wherein the synthetic route for compound ii comprises:
8. a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.
9. Use of a compound according to any one of claims 1-3 for the manufacture of a medicament for the prevention and/or treatment of echinococcosis.
10. Use of the pharmaceutical composition of claim 8 for the preparation of a medicament for the prevention and/or treatment of echinococcosis.
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