阅读说明：本技术 一类吲哚衍生物及其制备方法和应用 (Indole derivatives and preparation method and application thereof ) 是由 朱东亚 厉廷有 周其冈 秦亚娟 于 2021-09-28 设计创作，主要内容包括：本发明公开了一类吲哚衍生物及其制备方法和应用,属于制药技术领域；所述吲哚衍生物为通式(Ⅰ)所代表的化合物：所述通式(Ⅰ)中,R-(1)＝H、1-5个碳原子的直链或支链烷基、苄基、苯乙基、烷基取代的苄基或烷基取代的苯乙基；R-(2)＝H、1-6个碳原子的直链或支链烷基；R-(3)＝H、1-6个碳原子的直链或支链烷基、-(CH-(2))-(n)CONH-(2)或-(CH-(2))-(m)CO-(2)R-(5),其中R-(5)＝H、1-6个碳原子的直链或支链烷基；R-(4)＝H、1-6个碳原子的直链或支链烷基,或本发明提供的吲哚衍生物可有效抑制nNOS-SERT的偶联,用于抗抑郁时,可快速起效,从而可避免目前抗抑郁药物存在的诸多副作用。(The invention discloses indole derivatives, a preparation method and application thereof, belonging to the technical field of pharmacy; the indole derivative is a compound represented by the general formula (I): in the general formula (I), R 1 H, a straight or branched chain alkyl group of 1 to 5 carbon atoms, benzyl, phenethyl, alkyl-substituted benzyl or alkyl-substituted phenethyl; r 2 H, straight or branched alkyl of 1 to 6 carbon atoms; r 3 H, straight or branched alkyl of 1 to 6 carbon atoms, - (CH) 2 ) n CONH 2 Or- (CH) 2 ) m CO 2 R 5 Wherein R is 5 H, straight or branched alkyl of 1 to 6 carbon atoms; r 4 H, a linear or branched alkyl group of 1 to 6 carbon atoms, or The indole derivative provided by the invention can effectively inhibit the coupling of nNOS-SERT, and can quickly take effect when being used for resisting depression, thereby avoiding a plurality of side effects of the existing antidepressant drugs.)

1. An indole derivative, characterized in that the indole derivative is a compound represented by the general formula (I):

in the general formula (I), R₁H, straight-chain or branched alkyl of 1 to 5 carbon atoms, benzyl, phenethyl or alkyl-substituted benzyl or alkyl-substituted phenethyl, R₂H or a straight or branched alkyl group of 1 to 6 carbon atoms, R₃H, straight or branched alkyl of 1 to 6 carbon atoms or- (CH)₂)_nCONH₂Or- (CH)₂)_mCO₂R₅Wherein R is₅H or a straight or branched alkyl group of 1 to 6 carbon atoms; r₄H, a straight or branched alkyl group of 1 to 6 carbon atoms, M is any integer from 1 to 5, and n is any integer from 1 to 6。

2. The indole derivative of claim 1, wherein the chemical structure of the indole derivative is any one of:

3. the use of the indole derivatives of claim 1 or 2 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of depression and anxiety.

4. The use of claim 3, wherein the pharmaceutically acceptable salt comprises a sodium salt, a potassium salt, a hydrochloride salt, a hydrobromide salt, a nitrate salt, a perchlorate salt, a phosphate salt, a sulfate salt, a formate salt, an acetate salt, an aconate salt, an ascorbate salt, a benzenesulfonate salt, a benzoate salt, a cinnamate salt, a citrate salt, a heptanoate salt, a fumarate salt, a glutamate salt, a glycolate salt, a lactate salt, a maleate salt, a malonate salt, a mandelate salt, a methanesulfonate salt, a naphthalene-2 sulfonate salt, a phthalate salt, a salicylate salt, a sorbate salt, a stearate salt, a succinate salt, a tartrate salt, or a p-toluenesulfonate salt.

Technical Field

The invention belongs to the technical field of pharmacy, and particularly relates to indole derivatives, and a preparation method and application thereof.

Background

Depression is a common mental disorder disease, mainly manifested as depressed mood, decreased interest, anhedonia, and the like. Some patients with severe symptoms may also experience anxiety, suicidality, suicidal ideation, etc. Studies have shown that approximately 3 million people suffer major depression at some time during their lifetime. Suicide is the most serious problem of depression, and its incidence accounts for about 15% of depression patients.

5-hydroxytryptamine (5-hydroxytryptamine, 5-HT or serotonin) is a monoamine neurotransmitter that is strongly associated with depression, and numerous studies have shown that the occurrence of depression is strongly associated with low levels of 5-HT in the brain. 5-hydroxytryptamine reuptake inhibitors (SSRIs) sertraline, paroxetine, fluoxetine, fluvoxamine and citalopram are clinically widely used antidepressant drugs. These drugs exert antidepressant effects by inhibiting reuptake of 5-hydroxytryptamine in the brain, increasing the concentration of monoamine transmitters in the synaptic cleft. The drugs have the common side effects of nausea, somnolence, sweating, dizziness, sexual dysfunction, hypertension, anxiety, dry mouth, dizziness, constipation and the like, so that the compliance of patients is poor. The slow response is another important defect of the medicine, the curative effect needs 3-4 weeks, and the medicine has obvious clinical delay effect. Due to the side effects of drugs, some patients have abandoned drug therapy without waiting for the drug to act. Therefore, the development of novel antidepressant drugs based on a new mechanism, quick response and less side effects has important clinical value.

S-ketamine (esketamine) was approved in the us for treatment of treatment-resistant depression in 2019. Ketamine is a fast-acting antidepressant drug that acts primarily on NMDA receptors (J Med Chem,2020,63, 13514-. Ketamine, however, has dose-dependent side effects of dizziness, nausea, vomiting, and hypersalivation, and in addition, it can lead to psychological separation (psychological isolation). Higher doses or prolonged use of ketamine can cause some persistent and significant symptoms of neuropsychiatric diseases, such as symptoms associated with schizophrenia, cognitive impairment, and the like. Another serious drawback is the risk of abuse of ketamine. These deficiencies limit their widespread use in clinical practice (Molecules,2020,25, 5777).

The nucleus ventriculi medialis is the main source of 5-hydroxytryptamine in forebrain, and the serotonin transporter or 5-HT transporter (SERT or 5-hydroxytryptamine, 5-HTT) is a key modulator for transmitting signals by 5-HT and is the action target of SSRIs antidepressant drugs. SERT is a Na dependent⁺/Cl^-The high-affinity transmembrane transporter has 12 transmembrane regions, and the N terminal and the C terminal are both positioned in cytoplasm, the gene polymorphism of SERT is found to be closely related to the occurrence of depression, and other researches show that the deletion of SERT in the dorsal raphe nucleus can promote the reduction of the activity of 5-HT neurons to cause depression. Neuronal nitric oxide synthase (nNOS) is a synthase that catalyzes the synthesis of NO in the central nervous system and is abundantly expressed in DRN. Studies have shown that the nNOS PDZ domain can bind to the C-terminus of SERT, thereby affecting the distribution of SERT on the cell membrane. nNOS-SERT coupling of the DRN region can regulate 5-HT neuronal firing. Therefore, a drug capable of releasing or inhibiting nNOS-SERT coupling is developed, and can play a rapid antidepressant role by increasing the discharge frequency of 5-HT neurons and releasing 5-HT in a large amount.

Anxiety disorders are neurological disorders characterized primarily by generalized, persistent anxiety or recurrent panic attacks, often accompanied by autonomic nervous symptoms and motor stress. Benzodiazepines are the most important drugs for clinical treatment of anxiety, but the drugs have sedative/hypnotic side effects. Currently, 5-hydroxytryptamine reuptake inhibitors are also used in the treatment of anxiety disorders. Also, 5-hydroxytryptamine reuptake inhibitors are slow acting in the treatment of anxiety. The disclosed drugs that are capable of uncoupling or inhibiting nNOS-SERT coupling may also exert a rapid anxiolytic effect.

Disclosure of Invention

In order to overcome the technical problems of slow response and multiple side effects of the existing antidepressant drugs, the invention provides an indole derivative, a preparation method and application thereof, wherein the indole derivative can effectively inhibit the coupling of nNOS-SERT so as to play a role in quick antidepressant action.

In order to achieve the purpose, the invention provides the following technical scheme:

the invention provides an indole derivative, which is a compound represented by a general formula (I):

in the general formula (I), R₁H, straight-chain or branched alkyl of 1 to 5 carbon atoms, benzyl, phenethyl or alkyl-substituted benzyl or alkyl-substituted phenethyl, R₂H or a straight or branched alkyl group of 1 to 6 carbon atoms, R₃H, straight or branched alkyl of 1 to 6 carbon atoms or- (CH)₂)_nCONH₂Or- (CH)₂)_mCO₂R₅Wherein R is₅H or a straight or branched alkyl group of 1 to 6 carbon atoms; r₄H or a linear or branched alkyl group of 1 to 6 carbon atoms, M is any integer from 1 to 5, and n is any integer from 1 to 6.

Preferably, the chemical structure of the indole derivative is any one of the following:

the invention also provides the application of the indole derivative and the pharmaceutically acceptable salt thereof in preparing the medicines for treating depression and anxiety.

Preferably, the pharmaceutically acceptable salt includes a sodium salt, a potassium salt, a hydrochloride salt, a hydrobromide salt, a nitrate salt, a perchlorate salt, a phosphate salt, a sulfate salt, a formate salt, an acetate salt, an aconate salt, an ascorbate salt, a benzenesulfonate salt, a benzoate salt, a cinnamate salt, a citrate salt, a heptanoate salt, a fumarate salt, a glutamate salt, a glycolate salt, a lactate salt, a maleate salt, a malonate salt, a mandelate salt, a methanesulfonate salt, a naphthalene-2 sulfonate salt, a phthalate salt, a salicylate salt, a sorbate salt, a stearate salt, a succinate salt, a tartrate salt or a p-toluenesulfonate salt.

Compared with the prior art, the invention has the following beneficial effects:

the present antidepressant drug developed based on monoamine hypothesis and used clinically generally has the defects of slow effect, multiple side effects and the like, and the indole derivative provided by the invention is a novel antidepressant and anxiolytic drug, can effectively inhibit the coupling of nNOS-SERT, has the characteristic of fast effect, and can avoid a plurality of side effects of the present antidepressant drug.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for the embodiments will be briefly described below, and it is apparent that the drawings in the following description are only some embodiments of the present invention.

FIG. 1 is a graph showing the results of SW-9 releasing nNOS-SERT coupling, wherein (a) is the result of SW-9 releasing nNOS-SERT coupling in HEK 293T; (b) the SW-9 is injected into the abdominal cavity to release the identification result of nNOS-SERT coupling;

FIG. 2 is a graph showing the effect of intraperitoneal injection of solvent and SW-9 with different concentrations on depression behavior of mice, wherein (a) is a statistic result of TST immobility time caused by intraperitoneal injection of solvent, SW-92 h of 1mg/kg, SW-5 mg/kg and SW-92 h of 5 mg/kg; (b) carrying out statistics on FST immobility time caused by 1mg/kg, 2.5mg/kg and 5mg/kg SW-92 h of an intraperitoneal injection solvent; (c) is the result of the influence of an intraperitoneal injection solvent and 5mg/kg SW-924 h on the time of TST immobility; (d) the effect of 5mg/kg SW 924 h on FST immobility time for intraperitoneal injection of solvent;

FIG. 3 is a graph showing the results of a study on the intraperitoneal injection of SW-9 to rapidly reverse the depressive behavior of mice, in which (a) the reverse result of the 10mg/kg intraperitoneal injection of SW-92 h on the reduction of the immobilization time of TST caused by CMS; (b) the reverse result of the decrease of FST immobility time caused by CMS by injecting SW-92 h of 10mg/kg into the abdominal cavity; (c) the reverse result of the decrease of the SPT sugar water preference rate caused by CMS by injecting SW-92 h of 10mg/kg into the abdominal cavity;

FIG. 4 is a graph of the results of a study of the rapid reversal of depressive behavior in mice by gavage SW-9, in which (a) is the reversal of CMS-induced reduction in TST immobility time by SW-92 h at 10 mg/kg; (b) is the reversal result of the decrease of FST immobility time caused by CMS by SW-92 h of gavage 10 mg/kg; (c) is the reversal result of the decrease of the SPT sugar water preference rate caused by CMS by SW-92 h of intragastric administration of 10 mg/kg;

FIG. 5 is a graph of SW-9 brain tissue drug concentration versus time for mice administered to the tail vein.

Detailed Description

Reference will now be made in detail to various exemplary embodiments of the present invention, which will provide those skilled in the art with a full understanding of the present invention, and should not be taken as limiting the invention but rather as a more detailed description of certain aspects, features and embodiments of the invention. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

The experimental mice used in the following effect verification examples were SPF-grade ICR male mice weighing 22 ± 2g, purchased from the animal center of the Nanjing medical university, and certified card number: SPFNJMU 001189.

Example 1

Synthesis of indole derivative 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid sodium salt (SW-9):

the synthetic route is as follows:

2-methyl-5-nitrobenzoic acid is catalyzed by sulfuric acid to be methyl esterified (2), nitro is catalyzed to be hydrogenated into amino (3), iodine chloride is iodinated at 4-position to obtain 5-amino-4-iodine-2-methyl benzoic acid methyl ester (4), then Pd catalyzed Sonogashira coupling reaction (5) and subsequent Pd catalyzed cyclization reaction are used for constructing 5-methyl-2-pentyl indole-6-formic acid methyl ester (6), then alkylation reaction with halohydrocarbon is carried out at 1-position (7), the obtained product and acrylic acid are reacted at 3-position to obtain 3-carboxyl ethylated product (8), the product and IBCF acid anhydride are reacted with ammonia water to obtain amide (9), alkali is hydrolyzed into carboxylic acid (10), and then the product and calculated amount of NaOH are reacted to obtain 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-sodium formate (SW-9), the specific steps are as follows:

(a) synthesis of methyl 2-methyl-5-nitrobenzoate (2): a1000 mL flask was charged with 2-methyl-5-nitrobenzoic acid (1,40g,221mmol) and 400mL of methanol, 24mL of 98% sulfuric acid was added with stirring, and the mixture was refluxed at 75 ℃ for 8 hours. After the reaction, the reaction flask was placed in an ice-water bath to precipitate a large amount of solid, which was then subjected to suction filtration and dried to obtain 32g of methyl 2-methyl-5-nitrobenzoate (2) as a yellow solid in 74% yield.¹H NMR(400MHz,CDCl₃)δ:8.76(d,J＝4Hz,1H),8.22(dd,J＝4,8Hz,1H),7.42(d,J＝8Hz,1H),3.94(s,3H),2.71(s,3H).MS(ESI,m/z):196.1[M+H]⁺。

(b) Synthesis of methyl 5-amino-2-methylbenzoate (3): adding the methyl 2-methyl-5-nitrobenzoate (2,30g,182mmol) obtained in the step (a), 500mL of methanol and 1.13g of 10% palladium carbon into a 1000mL flask, replacing air in a reaction system by hydrogen for 3 times, stirring at room temperature under the condition of hydrogen, and continuously supplementing hydrogen until the volume of an air balloon is not obviously changed any more. After the reaction, insoluble matter was removed by suction filtration, and the filtrate was collected and spin-dried to obtain 22.8g of methyl 5-amino-2-methylbenzoate (3) as a dark brown viscous oily liquid in a yield of 76%.

(c) Synthesis of methyl 5-amino-4-iodo-2-methylbenzoate (4): adding methyl 5-amino-2-methylbenzoate (3,20g,121mmol), calcium carbonate (21g,210mmol), methanol 200mL, and water 20mL obtained in step (b) to a 500mL flask to prepare a solution 1; iodine monochloride (22g,123mmol) was dissolved in 132mL of dichloromethane to prepare solution 2; slowly dropping the solution 2 into the solution 1 under the ice bath condition, raising the temperature to room temperature after the dropping is finished, and stirring for 8 hours. After the reaction, 25% Na was added to the reaction system₂SO₃Quenching the solution for 1h, filtering, washing the filter residue with methanol for 3 times, collecting the filtrate, concentrating the filtrate, adding ethyl acetate to dissolve, washing with saturated saline solution for 2 times, collecting the organic layer, and drying with anhydrous sodium sulfate. The filtrate was filtered and concentrated to give a dark brown oil, which was subjected to silica gel column chromatography (PE: EA ═ 10:1) to give 18g of methyl 5-amino-4-iodo-2-methylbenzoate (4) as a pale yellow solid in a yield of 45%.¹H NMR(400MHz,CDCl₃)δ:7.54(s,1H),7.28(s,1H),4.03(s,2H),3.85(s,3H),2.41(s,3H).MS(ESI,m/z):292[M+H]⁺。

(d) Synthesis of 5-amino-4- (1-heptynyl) -2-methyl-benzoic acid methyl ester (5): to a dry 250mL flask was added 100mL of redistilled DMF, 5-amino-4-iodo-2-methyl-benzoic acid methyl ester from step (c) (4,16g,55mmol), PdCl₂(PPh₃)₂1.92g, 0.528g of CuI and 240mL of triethylamine are stirred continuously under the conditions of ice-water bath and Ar protection, 1-heptyne (7.84mL and 60mmol) is slowly added into the reaction system by a syringe, and after the dropwise addition is finished, the temperature is raised to room temperature and the stirring is carried out for 8 hours. After the reaction, the reaction solution was filtered, the filtrate was collected, diluted with ethyl acetate, washed with saturated brine for 2 times, the organic layer was collected, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave a dark brown solid, which was chromatographed on silica gel (PE: EA: 10:1) to give 12.34g of methyl 5-amino-4- (1-heptynyl) -2-methylbenzoate (5) as a dark brown solid in 87% yield.¹H NMR(400MHz,CDCl₃)δ:7.27(s,1H),7.11(s,1H),4.11(s,2H),3.85(s,3H),2.46(t,J＝7.1Hz,2H),2.42(s,3H),1.63(m,2H),1.48–1.32(m,4H),0.92(t,J＝7.2Hz,3H).MS(ESI,m/z):260.2[M+H]⁺。

(e) Synthesis of methyl 5-methyl-2-pentyl-1H-indole-6-carboxylate (6):to a dry 250mL flask was added 100mL of redistilled DMF, methyl 5-amino-4- (1-heptynyl) -2-methylbenzoate from step (d) (5,12g,46.3mmol), PdCl₂(PhCN)₂3.6g, under the protection of Ar at 80 ℃, and stirring for 4 hours. After the reaction, the reaction mixture was filtered, the filtrate was collected, diluted with an appropriate amount of ethyl acetate, washed with saturated brine for 2 times, the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid, which was subjected to silica gel column chromatography (PE: EA ═ 10:1) to give 5-methyl-2-pentyl-1H-indole-6-carboxylic acid methyl ester (6) as a yellow solid in an amount of 10.3g with a yield of 86%.¹H NMR(400MHz,CDCl₃)δ:8.08(s,1H),7.98(s,1H),7.33(s,1H),6.17(s,1H),3.89(s,3H),2.74(t,J＝7.6Hz,2H),2.67(s,3H),1.77–1.65(m,2H),1.35(m,4H),0.90(t,J＝7.0Hz,3H).MS(ESI,m/z):258.1[M-H]^-。

(f) Synthesis of 1, 5-dimethyl-2-pentyl-indole-6-carboxylic acid methyl ester (7): to a dry 100mL flask was added 50mL of redistilled DMF, methyl 5-methyl-2-pentyl-1H-indole-6-carboxylate (6,9g,34.7mmol) from step (e), methyl iodide (6.4g,45.1mmol), 60% sodium hydride (1.53g,38.2mmol) was added slowly with stirring to generate a large amount of bubbles, and stirred at 80 ℃ overnight. After the reaction is finished, ice water is slowly added to quench redundant sodium hydride, an appropriate amount of ethyl acetate is added to dilute the sodium hydride, the mixture is washed with water for three times, an organic layer is collected, dried by anhydrous sodium sulfate and filtered, a yellow solid is obtained after the filtrate is concentrated, and silica gel column chromatography (PE: EA is 10:1) is carried out to obtain a light yellow solid, namely 8.1g of 1, 5-dimethyl-2-pentyl-indole-6-methyl formate (7), wherein the yield is 85%.¹H NMR(400MHz,CDCl₃)δ:7.94(s,1H),7.31(s,1H),6.15(s,1H),3.89(s,3H),3.61(s,3H),2.73–2.60(m,5H),1.68(m,2H),1.39(m,4H),0.92(t,J＝7.0Hz,3H).MS(ESI,m/z):296.2[M+Na]⁺。

(g) Synthesis of 1, 5-dimethyl-2-pentyl-6- (methoxycarbonyl) -indole-3-propionic acid (8): to a dry pressure bottle was added methyl 1, 5-dimethyl-2-pentyl-indole-6-carboxylate (7,8g,29.3mmol) obtained in step (f), acrylic acid (4.65g,62.5mmol), acetic acid 13.4mL, acetic anhydride 5.6mL, stirred at 90 ℃ for 3h, cooled to room temperature, and stirred for an additional 8 h. After the reaction is finished, adding a proper amount of ethyl acetate to dissolve, washing for 3 times, collecting an organic layer, drying by anhydrous sodium sulfate, filtering, and concentrating the filtrateThe yellow oily liquid is obtained, silica gel column chromatography (PE: EA is 4:1) is carried out to obtain yellow viscous oily matter, and the yellow viscous oily matter is frozen and dried to remove acetic acid, so as to obtain 7.32g of yellow solid 1, 5-dimethyl-2-amyl-6- (methoxycarbonyl) -indole-3-propionic acid (8), and the yield is 72%.¹H NMR(400MHz,CDCl₃)δ:7.95(s,1H),7.31(s,1H),3.91(s,3H),3.69(s,3H),3.04(t,J＝8.0Hz 2H),2.76(t,J＝8.0Hz 2H),2.69–2.64(m,5H),1.66–1.49(m,2H),1.42–1.31(m,4H),0.91(t,J＝7.0Hz,3H).MS(ESI,m/z):344.2[M-H]^-。

(h) Synthesis of 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid methyl ester (9): to a dry 100mL flask was added 35mL of dry tetrahydrofuran, 1, 5-dimethyl-2-pentyl-6- (methoxycarbonyl) -indole-3-propionic acid (8,7g,20.3mmol) obtained in step (g) and 3.1mL of triethylamine, and isobutyl chloroformate (2.8mL,21.3mmol) was added under ice-bath conditions, followed by stirring for 30 minutes until the reaction solution became turbid, 26% aqueous ammonia (7.56mL,50.7mmol) was added, the reaction solution became clear, and the reaction solution was stirred at room temperature for 4 hours to cause a large amount of precipitate to appear. After the reaction is finished, the solvent is dried by spinning, a proper amount of ethyl acetate is added for dissolving, the solution is washed for 2 times, an organic layer is collected, dried by anhydrous sodium sulfate and concentrated to a small volume, a large amount of petroleum ether is rapidly added under ice bath, a white solid is separated out, and the white solid 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-methyl formate (9) is obtained after suction filtration and drying, wherein the yield is 75 percent.¹H NMR(400MHz,CDCl₃)δ:7.94(s,1H),7.31(s,1H),5.30(s,2H),3.91(s,3H),3.69(s,3H),3.05(t,J＝8Hz,2H),2.77(t,J＝8Hz,2H),2.69(s,3H),2.53(t,J＝8Hz,2H),1.59–1.50(m,2H),1.42–1.30(m,4H),0.90(t,J＝7.1Hz,3H).MS(ESI,m/z):367.2[M+Na]⁺。

(i) Synthesis of 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid (10): to a dry 100mL flask were added 50mL of a mixed solvent of tetrahydrofuran, water, methanol 6:2:1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid methyl ester (9,2g,6.06mmol) obtained in step (h), lithium hydroxide (0.44g,18.2mmol), and the mixture was stirred at room temperature for 48 h. After the reaction is finished, concentrating the reaction solution to a small volume, adding a proper amount of water for dissolving, adding 2N hydrochloric acid solution for adjusting the pH to 1, separating out white solid, performing suction filtration, washing with a proper amount of water, and drying to obtain the productWhite yellow solid, silica gel column Chromatography (CH)₂Cl₂MeOH ═ 20:1) gave 1.52g of 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid (10) as a white solid in 79% yield.¹H NMR(400MHz,DMSO-d₆)δ:7.90(s,1H),7.32(s,1H),7.28(s,1H),6.73(s,1H),3.66(s,3H),2.85(t,J＝8Hz,2H),2.76(t,J＝8Hz,2H),2.59(s,3H),2.29(t,J＝8Hz,2H),1.58–1.46(m,2H),1.36–1.31(m,4H),0.88(t,J＝7.0Hz,3H).MS(ESI,m/z):329.2[M-H]^-。

(j) Synthesis of 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid sodium salt (SW-9): to a dry 50mL flask was added 20mL of redistilled tetrahydrofuran, 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid from step (i) (10,1g,3.03mmol), 1N sodium hydroxide solution (3.03mL,3.03mmol), and stirred at room temperature for 2 h. After the reaction, the solvent was dried by rotary drying, and freeze-dried to obtain 1.06g of 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid sodium (SW-9) as a white solid with a yield of 99%.

Example 2

Synthesis of indole derivative 5-methyl-1-ethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid sodium salt (SW-14):

the synthetic route is as follows:

the intermediate 6 undergoes alkylation reaction (12) at the 1-position, then reacts with acrylic acid to obtain a product (13) which is 3-propylated, then amidation (14), hydrolysis (15) and salt-forming reaction of the 6-ester to obtain 1-ethyl-5-methyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid (SW-14), and the specific steps are as follows:

(a) synthesis of 5-methyl-1-ethyl-2-pentyl-indole-6-carboxylic acid methyl ester (12): starting from compound 6(2.5g,9.7mmol) obtained in example 1, the synthesis was the same as in step (f) of example 1 except that methyl iodide was changed to ethyl bromide, and silica gel column chromatography (PE: EA ═ 10:1) was performed after the reaction to obtain 1g of compound 5-methyl-1-ethyl-2-pentyl-indole-6-carboxylic acid methyl ester (12) with a yield of 36%.¹H NMR(400MHz,CDCl₃)δ:7.97(s,1H),7.34(s,1H),6.19(s,1H),4.15(q,J＝7.2Hz,2H),3.91(s,3H),2.72(t,J＝8.0Hz,2H),2.67(s,3H),1.80–1.72(m,2H),1.48–1.38(m,4H),1.35(t,J＝7.2Hz,3H),0.93(t,J＝7.1Hz,3H).MS(ESI,m/z):310.2[M+Na]⁺。

(b) Synthesis of 5-methyl-1-ethyl-2-pentyl-6- (methoxycarbonyl) -indole-3-propionic acid (13): starting from compound 12(1g,3.5mmol), the synthesis was performed as in step (g) of example 1, except that silica gel column chromatography (PE: EA ═ 4:1) was performed after the reaction to give 0.89g of compound 5-methyl-1-ethyl-2-pentyl-6- (methoxycarbonyl) -indole-3-propionic acid (13) with a yield of 71%. MS (ESI, M/z) 358.2[ M-H]^-。

(c) Synthesis of 5-methyl-1-ethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid methyl ester (14):

starting from compound 13(0.89g,2.5mmol), the synthesis was performed as in example 1, step (h) to give the compound methyl 5-methyl-1-ethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylate (14), 0.48g, 54% yield.¹H NMR(400MHz,DMSO-d₆)δ:7.90(s,1H),7.36(s,1H),7.28(s,1H),6.75(s,1H),4.16(q,J＝6.9Hz,2H),3.82(s,3H),2.85(t,J＝8.0Hz,2H),2.75(t,J＝8.0Hz,2H),2.59(s,3H),2.35–2.23(m,2H),1.61–1.47(m,2H),1.37–1.34(m,4H),1.24(t,J＝7.1Hz,3H),0.88(t,J＝7.0Hz,3H).MS(ESI,m/z):381.3[M+Na]⁺。

(d) Synthesis of 5-methyl-1-ethyl-2-pentyl-3-propionamido-indole-6-carboxylic acid (15): starting from compound 14(0.48g,1.3mmol), the synthesis was performed as in step (i) of example 1, followed by silica gel column Chromatography (CH)₂Cl₂MeOH ═ 20:1) to give 0.34g of the compound 5-methyl-1-ethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid (15) in 73% yield.¹H NMR(400MHz,DMSO-d₆)δ:7.89(s,1H),7.31(s,1H),7.28(s,1H),6.74(s,1H),4.14(q,J＝7.2Hz,2H),2.84(t,J＝8.0Hz,2H),2.74(t,J＝8.0Hz,2H),2.59(s,3H),2.29(t,J＝8.0Hz,2H),1.60–1.47(m,2H),1.36–1.34(m,4H),1.24(t,J＝7.1Hz,3H),0.88(t,J＝7.0Hz,3H).MS(ESI,m/z):343.2[M-H]^-。

(e) Synthesis of 5-methyl-1-ethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid sodium salt (SW-14): starting from compound 15(0.34g,0.99mmol), the synthesis was performed as in step (j) of example 1 to give 0.35g of the compound 5-methyl-1-ethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid sodium salt (SW-14) in 97% yield.

Example 3

Synthesis of disodium 1, 5-dimethyl-2-pentyl-3- (2-carboxyethyl) -indole-6-carboxylate (SW-10) and disodium 5-methyl-1-ethyl-2-pentyl-3- (2-carboxyethyl) -indole-6-carboxylate (SW-15):

the synthetic route is as follows:

the intermediate 8 and 13 respectively obtain 1, 5-dimethyl-2-pentyl-3- (2-carboxyethyl) indole-6-carboxylic acid disodium salt (SW-10) and 1-ethyl-5-methyl-2-pentyl-3- (2-carboxyethyl) indole-6-carboxylic acid disodium salt (SW-15) through hydrolysis (17, 19) and salt forming reaction, and the specific steps are as follows:

(a) synthesis of 1, 5-dimethyl-2-pentyl-3- (2-carboxyethyl) -indole-6-carboxylic acid (17): to a dry 50mL flask were added 18mL of methanol, 1, 5-dimethyl-2-pentyl-6- (methoxycarbonyl) -indole-3-propionic acid (8,2g,5.79mmol), 1N sodium hydroxide solution (18mL,18mmol) and stirred at room temperature for 12 h. After the reaction is finished, the reaction solution is concentrated to a small volume, a proper amount of water is added for dissolution, the pH value is adjusted to 1 by 2N hydrochloric acid solution, white solid is separated out, the filtration is carried out, a proper amount of water is used for washing, and the drying is carried out, so that 1.66g of the white solid 1, 5-dimethyl-2-pentyl-3- (2-carboxyethyl) -indole-6-formic acid (17) is obtained, and the yield is 86%.¹H NMR(400MHz,DMSO-d₆)δ:12.20(s,2H),7.91(s,1H),7.32(s,1H),3.67(s,3H),2.89(t,J＝7.6Hz,2H),2.76(t,J＝7.6Hz,2H),2.59(s,3H),2.46(t,J＝7.6Hz,2H),1.58–1.46(m,2H),1.38–1.26(m,4H),0.88(t,J＝8.0Hz,3H).MS(ESI,m/z):329.2[M-H]^-。

Synthesis of 5-methyl-1-ethyl-2-pentyl-3- (2-carboxyethyl) -indole-6-carboxylic acid (19): the synthesis method is the same as that of the compound 17, and the compound 13(0.3g,0.83mmol) is used as the starting material to obtain the compound 5-methyl-1-ethyl-2-pentyl-3- (2-carboxyethyl) -indoleIndole-6-carboxylic acid (19)0.26g, 89% yield.¹HNMR(400MHz,DMSO-d₆)δ:12.21(s,2H),7.91(s,1H),7.32(s,1H),4.16(q,J＝6.9Hz,2H),2.88(t,J＝7.7Hz,2H),2.75(t,J＝8.0Hz,2H),2.59(s,3H),2.46(t,J＝8.0Hz,2H),1.59–1.47(m,2H),1.40–1.29(m,4H),1.24(t,J＝7.1Hz,3H),0.88(t,J＝6.9Hz,3H).MS(ESI,m/z):344.2[M-H]^-。

(b) Synthesis of disodium 1, 5-dimethyl-2-pentyl-3- (2-carboxyethyl) -indole-6-carboxylate (SW-10): to a dry 50mL flask were added 20mL of methanol, 1, 5-dimethyl-2-pentyl-3- (2-carboxyethyl) -indole-6-carboxylic acid (17,1g,3.02mmol), 1N sodium hydroxide solution (6.04mL,6.04mmol), and stirred at room temperature for 2 h. After the reaction was completed, the solvent was dried by rotary drying, and freeze-dried to obtain a white solid, i.e., 1.13g of disodium 1, 5-dimethyl-2-pentyl-3- (2-carboxyethyl) -indole-6-carboxylate (SW-10), in 99% yield.

Synthesis of disodium 5-methyl-1-ethyl-2-pentyl-3- (2-carboxyethyl) -indole-6-carboxylate (SW-15): the synthesis method is the same as that of SW-10, starting from compound 19(0.26g,0.75mmol), the compound 5-methyl-1-ethyl-2-pentyl-3- (2-carboxyethyl) -indole-6-carboxylic acid disodium salt (SW-15)0.29g is obtained with a yield of 99%.

Example 4

Synthesis of disodium 5-methyl-2-pentyl-6- (carboxymethyl) -1H-indole-6-carboxylate (SW-20) and sodium 5-methyl-2-pentyl-3- (2-hydroxyethyl) -1H-indole-6-carboxylate (SW-21):

the synthetic route is as follows:

the intermediate 6 reacts with oxalyl chloride to obtain a compound 21 modified by 3-methyl oxalate, and is condensed (22) with phenylhydrazides and then NaBH is used₄Reducing to simultaneously obtain 5-methyl-2-pentyl-3- (methoxycarbonylmethyl) indole-6-formate (23) and 5-methyl-2-pentyl-3- (2-hydroxyethyl) indole-6-formate (24), hydrolyzing and salifying the 23 and 24 to respectively obtain 5-methyl-2-pentyl-3- (carboxymethyl) indole-6-formic acid disodium salt (SW-20) and 5-methyl-2-pentyl-3- (2-hydroxyethyl) indole-6-formic acid disodium salt (SW-21), and the preparation method has the advantages of reducing to obtain the 5-methyl-2-pentyl-3- (methoxycarbonylmethyl) indole-6-formate disodium salt (SW-20) and the 5-methyl-2-pentyl-3- (2-hydroxyethyl) indole-6-formic acid disodium salt (SW-21) simultaneouslyThe method comprises the following steps:

(a) synthesis of 5-methyl-2-pentyl-3- (2-methoxy-2-oxoacetyl) -1H-indole-6-carboxylic acid methyl ester (21): to a dry 100mL flask was added 5-methyl-2-pentyl-1H-indole-6-carboxylic acid methyl ester (6, 5g,19.3mmol), redistilled diethyl ether 50mL, oxalyl chloride (4.9mL,57.9mmol) was added dropwise under ice bath conditions, the temperature was raised to room temperature, stirred for 3H, and methanol (3.85mL,96.5mmol) was added under ice bath conditions, stirred for 15 min. After the reaction is finished, the solvent is dried by spinning, an appropriate amount of ethyl acetate is added for dissolving, the solution is washed for three times, and an organic layer is collected and dried by anhydrous sodium sulfate. Filtration, concentration of the filtrate and silica gel column chromatography (PE: EA ═ 3:1) gave 4.75g of methyl 5-methyl-2-pentyl-3- (2-methoxy-2-oxoacetyl) -1H-indole-6-carboxylate (21) as a pale yellow solid in 71% yield.¹H NMR(400MHz,CDCl₃)δ:9.93(s,1H),8.01(s,1H),7.75(s,1H),3.97(s,3H),3.88(s,3H),3.00(t,J＝8.0Hz,2H),2.66(s,3H),1.76–1.65(m,2H),1.37–1.26(m,4H),0.86(t,J＝7.1Hz,3H).MS(ESI,m/z):368.2[M+Na]⁺。

(b) Synthesis of methyl 5-methyl-2-pentyl-3- (2-methoxy-2-oxo-1- (2- (benzenesulfonyl) hydrazono) ethyl) -1H-indole-6-carboxylate (22): to a dry 250mL flask was added methyl 5-methyl-2-pentyl-3- (2-methoxy-2-oxoacetyl) -1H-indole-6-carboxylate (21,4g,11.59mmol), p-toluenesulfonylhydrazide (5.40g,28.97mmol), methanol 150mL, and Ar under protection, heated to 80 deg.C and refluxed for 16H. After the reaction is finished, the organic solvent is dried in a spinning mode, an appropriate amount of ethyl acetate is added for dissolving, the solution is washed for 3 times, an organic layer is collected, and anhydrous sodium sulfate is dried. Filtration, concentration of the filtrate and silica gel column chromatography (PE: EA ═ 5:1) gave 4.23g of methyl 5-methyl-2-pentyl-3- (2-methoxy-2-oxo-1- (2- (benzenesulfonyl) hydrazono) ethyl) -1H-indole-6-carboxylate (22) as a pale yellow solid in 73% yield. 1H NMR (400MHz, DMSO-d)₆)δ:11.64(s,1H),11.09(s,1H),7.93(s,1H),7.72(d,J＝8.3Hz,2H),7.41(d,J＝8.0Hz,2H),6.84(s,1H),3.83(s,3H),3.70(s,3H),2.52(s,3H),2.45(t,J＝9.6Hz,2H),2.39(s,3H),1.54–1.43(m,2H),1.19–1.12(m,4H),0.80(t,J＝6.9Hz,3H).MS(ESI,m/z):536.2[M+Na]⁺。

(c) Synthesis of methyl 5-methyl-2-pentyl-3- (2-methoxy-2-oxoethyl) -1H-indole-6-carboxylate (23) and methyl 5-methyl-2-pentyl-3- (2-hydroxyethyl) -1H-indole-6-carboxylate (24):

to a dry 250mL flask was added methyl 5-methyl-2-pentyl-3- (2-methoxy-2-oxo-1- (2- (benzenesulfonyl) hydrazono) ethyl) -1H-indole-6-carboxylate (22,3g,6.01mmol), 50mL of redistilled tetrahydrofuran, NaBH₄(4.73g,125mmol) under Ar protection, heating to 80 ℃, and refluxing for 10 h. After the reaction is finished, the reaction product is cooled to room temperature, 2N hydrochloric acid solution is slowly dripped under the ice bath condition until no bubbles are generated, the organic solvent is dried, an appropriate amount of ethyl acetate is added for dissolution, the solution is washed for three times by water, an organic layer is collected, dried by anhydrous sodium sulfate, filtered, the filtrate is concentrated, silica gel column chromatography (PE: EA is 3:1) is carried out, and 120mg of 5-methyl-2-pentyl-3- (2-methoxy-2-oxoethyl) -1H-indole-6-methyl formate (23) as a white solid is obtained, wherein the yield is 12.06%.¹H NMR(400MHz,DMSO-d₆)δ:11.12(s,1H),7.87(s,1H),7.26(s,1H),3.81(s,3H),3.68(s,2H),3.57(s,3H),2.70(t,J＝9.6Hz,2H),2.57(s,3H),1.67–1.57(m,2H),1.31–1.25(m,4H),0.87(t,J＝6.0Hz,3H).MS(ESI,m/z):330.2[M-H]^-. To give 180mg of methyl 5-methyl-2-pentyl-3- (2-hydroxyethyl) -1H-indole-6-carboxylate (24) as a pale yellow solid in 19.76% yield;¹H NMR(400MHz,CDCl₃)δ:8.30(s,1H),7.97(s,1H),7.33(s,1H),3.89(s,3H),3.83(t,J＝6.6Hz,2H),2.95(t,J＝6.7Hz,2H),2.73(t,J＝8.0Hz,2H),2.68(s,3H),1.69–1.61(m,2H),1.34–1.30(m,4H),0.89–0.87(m,3H).MS(ESI,m/z):302.2[M-H]^-。

(d) synthesis of 5-methyl-2-pentyl-3- (carboxymethyl) -1H-indole-6-carboxylic acid (25): to a dry 50mL flask was added 5-methyl-2-pentyl-3- (2-methoxy-2-oxoethyl) -1H-indole-6-carboxylic acid methyl ester (23,120mg,0.396mmol), methanol 2.6mL, 1N sodium hydroxide solution (2.6mL,2.6mmol), and the mixture was stirred at room temperature for 24H. After the reaction is finished, the organic solvent is dried in a spinning mode, a proper amount of water is added for dissolving, the pH value is adjusted to 1 by 2N hydrochloric acid solution, white solid is separated out, the white solid is filtered, washed by a proper amount of water and dried, 107mg of 5-methyl-2-pentyl-3- (carboxymethyl) -1H-indole-6-formic acid (25) is obtained, and the yield is 97%. 1H NMR (400MHz, DMSO-d)₆)δ:12.20(s,2H),11.03(s,1H),7.86(s,1H),7.23(s,1H),3.55(s,2H),2.69(t,J＝7.6Hz,2H),2.56(s,3H),1.71–1.56(m,2H),1.37–1.24(m,4H),0.86(t,J＝6.8Hz,3H).MS(ESI,m/z):302.1[M-H]^-。

(e) Synthesis of disodium 5-methyl-2-pentyl-3- (carboxymethyl) -1H-indole-6-carboxylate (SW-20): to a dry 50mL flask was added 5-methyl-2-pentyl-3- (carboxymethyl) -1H-indole-6-carboxylic acid (25,107mg,0.353mmol), methanol 1mL, 1N sodium hydroxide solution (0.706mL,0.706mmol), and stirred at room temperature for 2H. After the reaction, the organic solvent was spin-dried, and freeze-dried to obtain 122mg of disodium 5-methyl-2-pentyl-3- (carboxymethyl) -1H-indole-6-carboxylate (SW-20) as a pale yellow solid, in 99% yield.

(f) Synthesis of 5-methyl-2-pentyl-3- (2-hydroxyethyl) -1H-indole-6-carboxylic acid (27): to a dry 50mL flask was added 5-methyl-2-pentyl-3- (2-hydroxyethyl) -1H-indole-6-carboxylic acid methyl ester (24,180mg,0.594mmol), methanol 2mL, 1N sodium hydroxide solution (1.93mL,1.93mmol), and stirred at room temperature for 12H. After the reaction is finished, the organic solvent is dried by spinning, a proper amount of water is added for dissolving, the pH value is adjusted to 1 by 2N hydrochloric acid solution, ethyl acetate is extracted for three times, an organic layer is collected, dried by anhydrous sodium sulfate, filtered, and filtrate is dried by spinning to obtain 157mg of a brown viscous oily substance 5-methyl-2-amyl-3- (2-hydroxyethyl) -1H-indole-6-formic acid (27), and the yield is 91%.¹H NMR(400MHz,DMSO-d₆)δ:12.15(s,1H),10.89(s,1H),7.84(s,1H),7.24(s,1H),3.50(t,J＝7.5Hz,2H),2.76(t,J＝7.5Hz,2H),2.68(t,J＝7.6Hz,2H),2.57(s,3H),1.70–1.57(m,2H),1.38–1.26(m,4H),0.86(t,J＝6.9Hz,3H).MS(ESI,m/z):288.2[M-H]^-。

(g) Synthesis of 5-methyl-2-pentyl-3- (2-hydroxyethyl) -1H-indole-6-carboxylic acid sodium salt (SW-21): to a dry 50mL flask were added 5-methyl-2-pentyl-3- (2-hydroxyethyl) -1H-indole-6-carboxylic acid (27,157mg,0.543mmol), methanol 1mL, and 1N sodium hydroxide solution (0.543mL,0.543mmol), and the mixture was stirred at room temperature for 2H. After the reaction, the organic solvent was removed by rotary evaporation, and lyophilized to obtain 165mg of 5-methyl-2-pentyl-3- (2-hydroxyethyl) -1H-indole-6-carboxylic acid sodium salt (SW-21) as a brown solid with a yield of 98%.

Example 5

1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid- (2-morpholinyl) ethyl ester (SW-9A), 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid- (2- (piperidin-1-yl)) ethyl ester (SW-9B), 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid- (2- (tetrahydropyrrole-1-yl)) ethyl ester (SW-9C) and 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) - Synthesis of indole-6-carboxylic acid- (2- (4-methylpiperazin-1-yl)) ethyl ester (SW-9D):

the synthetic route is as follows:

the intermediate 9 is respectively subjected to transesterification with 4-hydroxyethyl morpholine, N-hydroxyethyl piperidine, N-hydroxyethyl pyrrolidine and 1-hydroxyethyl-4-methylpiperazine to obtain 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid- (2-morpholinyl) ethyl ester (SW-9A), 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid- (2- (piperidin-1-yl)) ethyl ester (SW-9B), 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid- (2- (tetrahydro-ethylpiper-ol) Pyrrol-1-yl)) ethyl ester (SW-9C) and 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -indole-6-carboxylic acid- (2- (4-methylpiperazin-1-yl)) ethyl ester (SW-9D) by the following specific steps:

synthesis of SW-9A: to a dry 100mL flask was added 4-hydroxyethylmorpholine (1.06mL,8.76mmol) and 15mL of redistilled tetrahydrofuran, and 60% sodium hydride (0.23g,5.82mmol) was slowly added under ice-bath conditions, followed by stirring for 1H, to which was slowly added 1, 5-dimethyl-2-pentyl-3- (2-carbamoylethyl) -1H-indole-6-carboxylic acid methyl ester (1.00g,2.92mmol) dissolved in 15mL of dry tetrahydrofuran, and after the dropwise addition, the mixture was stirred at room temperature for 3H. After the reaction is finished, ice water is slowly added until no bubbles are generated, an appropriate amount of ethyl acetate is added for dissolution, the mixture is washed with water for three times, and an organic layer is collected and dried by anhydrous sodium sulfate. Filtration, concentration of the filtrate and silica gel column chromatography (DCM: MeOH ═ 20:1) gave 0.51g of white solid in 39.3% yield. 1H NMR (400MHz, CDCl)₃)δ7.92(s,1H),7.31(s,1H),5.33(d,J＝20.3Hz,2H),4.46(t,J＝5.9Hz,2H),3.76–3.70(m,4H),3.68(s,3H),3.05(t,J＝7.6Hz,2H),2.78(dt,J＝15.4,6.9Hz,4H),2.68(s,3H),2.59(s,4H),2.52(t,J＝7.6Hz,2H),1.75(s,2H),1.36(d,J＝3.2Hz,4H),0.90(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3)δ174.93,168.54,142.06,134.88,130.42,121.88,119.99,112.24,109.45,67.09,61.70,57.35,53.96,36.96,31.76,29.87,29.82,24.66,22.59,20.36,14.08.MS(ESI,m/z):444.2883[M+H]⁺。

Synthesis of SW-9B: referring to the synthesis method of SW-9A, the product was obtained as a white solid with a yield of 35.1%.¹H NMR(400MHz,CDCl₃)δ7.94(s,1H),7.30(s,1H),5.37(d,J＝29.1Hz,2H),4.47(t,J＝6.1Hz,2H),3.68(s,3H),3.04(t,J＝7.6Hz,2H),2.78(dt,J＝15.7,7.0Hz,4H),2.68(s,3H),2.53(dd,J＝16.7,8.7Hz,6H),1.60(dd,J＝19.6,14.2Hz,6H),1.45(s,2H),1.39–1.31(m,4H),0.89(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl₃)δ175.03,168.52,142.01,134.89,130.47,130.38,121.89,119.95,112.32,109.41,61.99,57.48,54.84,36.97,31.76,29.86,29.81,25.88,24.65,24.16,22.58,20.38,14.08.MS(ESI,m/z):442.3187[M+H]⁺。

Synthesis of SW-9C: referring to the synthesis method of SW-9A, the product was obtained as a white solid with a yield of 33.2%.¹H NMR(400MHz,CDCl₃)δ7.96(s,1H),7.30(s,1H),5.39(d,J＝26.7Hz,2H),4.49(s,2H),3.68(s,3H),3.00(d,J＝29.8Hz,4H),2.70(d,J＝17.3Hz,9H),2.51(s,2H),1.83(s,4H),1.54(s,2H),1.35(s,4H),0.89(s,3H).13C NMR(101MHz,CDCl3)δ175.01,168.39,142.10,134.87,130.59,130.43,121.60,119.97,112.40,109.42,63.10,54.74,54.61,36.97,31.76,29.91,29.82,24.66,23.60,22.61,20.36,14.10.MS(ESI,m/z):428.3020[M+H]⁺。

Synthesis of SW-9D: referring to the synthesis method of SW-9A, the product was obtained as a white solid with a yield of 37.5%.¹H NMR(400MHz,CDCl₃)δ7.91(s,1H),7.31(s,1H),5.38(d,J＝21.0Hz,2H),4.45(t,J＝5.8Hz,2H),3.68(s,3H),3.04(t,J＝7.5Hz,2H),2.83(t,J＝5.8Hz,2H),2.80–2.71(m,5H),2.67(s,8H),2.51(t,J＝7.6Hz,2H),2.41(s,3H),1.55(s,2H),1.35(s,4H),0.89(t,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)δ174.93,168.47,142.10,134.86,130.42,121.73,120.00,112.26,109.45,61.86,56.65,54.86,52.46,45.43,36.97,31.76,29.91,29.83,24.66,22.63,22.60,20.35,14.11.MS(ESI,m/z):457.3177[M+H]⁺。

Example 6

Synthesis of sodium 5-methyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-carboxylate (SW-31), sodium 1, 5-dimethyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-carboxylate (SW-35):

the synthetic route is as follows:

the intermediates 6 and 7 react with 2- ((ethoxycarbothioyl) thio) acetic acid to respectively obtain intermediates 28 and 32 of 3-carboxymethylation, the generated carboxylic acid is hydrolyzed to obtain 30 and 34 by using IBCF/ammonia water to prepare amide 29 and 33, 6-ester group, and salifying is carried out to obtain 5-methyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-sodium formate (SW-31) and 1, 5-dimethyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-sodium formate (SW-35), and the specific steps are as follows:

(a) synthesis of 2- ((ethoxycarbothioyl) thio) acetic acid: adding bromoacetic acid (0.91g,6.55mmol) and 5mL of distilled water into a 100mL round-bottom flask, adding potassium ethylxanthate (1.00g,6.24mmol) in batches under ice bath conditions, removing the ice bath, stirring at room temperature for 1h, then cooling the reaction to 0 ℃, stirring for 3h, after the reaction is finished, acidifying with diluted hydrochloric acid, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating to obtain a white solid, and directly carrying out the next reaction.

(b) Synthesis of 6- (methoxycarbonyl) -5-methyl-2-pentyl-1H-indole-3-acetic acid (28): to a dry 100mL round bottom flask was added 5-methyl-2-pentyl-1H-indole-6-carboxylic acid methyl ester (6,2g,7.72mmol), ((ethoxythiomethyl) thio) acetic acid (1.39g,7.72mmol), dried ethyl acetate 10mL, refluxed at 90 ℃ for 10min under argon protection, lauroyl peroxide (LPO,3.08g,7.72mmol) was added, reacted overnight, ethyl acetate was extracted 3 times after the reaction was finished, the organic phase was collected, dried over anhydrous sodium sulfate and concentrated to give a red oil, and silica gel column chromatography (PE: EA ═ 6:1) gave 0.57g of a red solid with a yield of 23.3%.¹H NMR(400MHz,CDCl₃)δ8.03(s,1H),7.83(s,1H),6.23(s,1H),3.96(s,2H),3.88(s,3H),2.74(t,J＝7.7Hz,2H),2.59(s,3H),1.79–1.64(m,2H),1.42–1.29(m,4H),0.90(t,J＝6.9Hz,3H).¹³C NMR(101MHz,CDCl₃)δ176.71,169.53,143.91,132.98,132.58,128.95,123.94,123.42,112.98,98.39,51.85,35.73,31.59,28.73,28.49,22.51,16.66,14.05.MS(ESI)calcd for C₁₈H₂₃NO₄[M+H]⁺:318.1705；found:m/z 318.1690.

(c) Synthesis of 5-methyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-carboxylic acid methyl ester (29): adding 5mL of dry tetrahydrofuran, 2- (6- (methoxycarbonyl) -5-methyl-2-pentyl-1H-indole-3-acetic acid (28,0.55g,1.73mmol) and 0.26mL of triethylamine into a dry 100mL flask, adding isobutyl chloroformate (0.24mL,1.82mmol) under ice bath conditions, stirring for 30min, enabling the reaction solution to become turbid, adding 26% ammonia water (0.65mL,4.33mmol), enabling the reaction solution to become clear, stirring for 4H at room temperature, allowing a large amount of precipitate to appear, after the reaction is finished, drying the solvent, adding an appropriate amount of ethyl acetate to dissolve, washing for 2 times, collecting an organic layer, drying anhydrous sodium sulfate, concentrating to a small volume, and performing silica gel column chromatography (PE: EA is 1:1) to obtain an orange solid, namely 5-methyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-carboxylic acid methyl ester (29)0.41g, yield 75.0%.¹H NMR(400MHz,CDCl₃)δ8.46(s,1H),7.83(s),6.22(s,1H),5.46(d,J＝66.0Hz,1H),3.88(d,J＝1.6Hz,2H),2.77–2.70(m,5H),2.56(s,2H),1.73-1.68(m,2H),1.38–1.30(m,4H),0.88(dd,J＝9.8,4.3Hz,3H).¹³C NMR(101MHz,CDCl₃)δ173.64,169.55,144.52,133.18,132.41,128.70,124.48,124.21,113.15,98.01,52.00,38.21,31.60,28.74,28.48,22.52,16.56,14.08.MS(ESI)calcd for C₁₈H₂₄N₂O₃[M+H]⁺:317.1865；found:m/z 317.1872.

(d) Synthesis of 5-methyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-carboxylic acid (30): to a dry 100mL flask was added 5mL of methanol, 5-methyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-carboxylic acid methyl ester (29,0.35g,1.11mmol),2.2mL of 1N NaOH solution, heated to 60 deg.C, reacted overnight, after completion of the reaction, the solvent was removed, appropriate amount of water was added, acidified with dilute hydrochloric acid, extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated yellow oil, silica gel column chromatography (silica gel column) ((DCM: MeOH ═ 32:1) gave 0.24g of yellow solid in 71.6% yield.¹H NMR(400MHz,DMSO-d₆)δ12.20(s,1H),10.99(d,J＝1.2Hz,1H),7.65(s,1H),7.05(d,J＝150.3Hz,2H),6.21(s,1H),3.64(s,2H),2.67(t,J＝7.6Hz,2H),2.43(s,3H),1.71–1.59(m,2H),1.31–1.25(m,4H),0.84(t,J＝6.8Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ172.64,170.81,143.83,133.40,132.72,127.41,126.27,123.98,112.39,98.10,37.31,31.54,28.90,28.31,22.46,16.88,14.47.MS(ESI)calcd for C₁₇H₂₂N₂O₃[M+H]⁺:303.1709；found:m/z303.1725.

(e) Synthesis of sodium 5-methyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-carboxylate (SW-31): after obtaining compound 30, SW-31 was prepared in 98% yield according to the synthetic method of compound SW-21 of example 4 step (g).

(f) Synthesis of 6- (methoxycarbonyl) -1, 5-dimethyl-2-pentyl-1H-indole-3-acetic acid (32): starting from compound 7, the synthesis of compound 28 in step (b) gave red solid (32) with a yield of 20.5%.¹H NMR(400MHz,CDCl₃)¹³C NMR(101MHz,CDCl₃)δ7.83(s,1H),6.23(s,1H),3.97(s,2H),3.90(s,3H),3.67(d,J＝2.8Hz,3H),2.74–2.68(m,2H),2.59(s,3H),1.77–1.68(m,2H),1.46–1.36(m,4H),0.93(t,J＝7.1Hz,3H).¹³C NMR(101MHz,CDCl₃)δ177.57,169.65,145.38,134.59,131.53,128.66,123.33,111.62,97.44,51.87,35.75,31.76,29.66,28.17,27.10,22.56,16.66,14.12.MS(ESI)calcd for C19H25NO4[M+H]⁺:332.1862；found:m/z 332.1868.

(g) Synthesis of methyl 1, 5-dimethyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-carboxylate (33): after compound 32 was obtained, according to the synthesis method of compound 29 in step (c), orange solid (33) was obtained with a yield of 82.4%.¹H NMR(400MHz,CDCl₃)¹³C NMR(101MHz,CDCl₃)δ7.82(s,1H),6.24(s,1H),5.34(d,J＝27.3Hz,2H),3.90(d,J＝8.3Hz,5H),3.69(s,3H),2.76–2.69(m,2H),2.58(s,3H),1.79-1.69(m,2H),1.44–1.34(m,4H),0.92(t,J＝7.1Hz,3H).¹³C NMR(101MHz,CDCl₃)δ177.54,169.65,145.41,134.59,131.52,128.67,123.34,123.28,111.65,97.43,51.89,35.73,31.76,29.67,28.17,27.10,22.57,16.67,14.12.MS(ESI)calcd for C₁₉H₂₆N₂O₃[M+H]⁺:331.2022；found:m/z 331.2022.

(h) Synthesis of 1, 5-dimethyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-carboxylic acid (34): after compound 33 was obtained, according to the synthesis method of compound 30 in step (d), yellow-white solid (34) was obtained with a yield of 70.0%.¹H NMR(400MHz,DMSO-d₆)δ12.32(s,1H),7.71(s,1H),7.05(d,J＝153.4Hz,2H),6.27(s,1H),3.63(d,J＝13.1Hz,5H),2.69(t,J＝7.1Hz,2H),2.44(s,3H),1.64(s,2H),1.34(s,4H),0.86(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ172.53,170.91,144.80,134.56,131.57,127.57,126.53,124.40,110.77,97.89,37.15,31.64,29.83,28.15,26.67,22.48,16.86,14.48.MS(ESI)calcd for C₁₈H₂₄N₂O₃[M+H]⁺:317.1865；found:m/z 317.1857。

(i) Synthesis of 1, 5-dimethyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-carboxylic acid sodium salt (SW-35): to a dry 50mL flask was added 5mL of redistilled tetrahydrofuran, 1, 5-dimethyl-2-pentyl-3- (2-amino-2-oxoethyl) -1H-indole-6-carboxylic acid (34,120mg,0.38mmol), 1N sodium hydroxide solution (0.38mL,0.38mmol), and stirred at room temperature overnight. After the reaction was completed, the solvent was dried by rotary drying, and freeze-dried to obtain 122mg of a white solid with a yield of 95.1%.

Effect test example 1

Identification of SW-9 unlysed nNOS-SERT conjugates in cells and animal models

nNOS and SERT plasmids were transfected into HEK293T cells simultaneously, 10. mu.M of small molecule compound SW-9 was incubated in HEK293T cultured in vitro, and an equal amount of solvent was added to HEK293T cultured in vitro in a control group (Vehicle group), and the effect of small molecule compound SW-9 on nNOS-SERT coupling was examined after 3h using co-immunoprecipitation. The results are shown in FIG. 1a, showing that SW-9 is able to significantly reduce the level of nNOS-SERT complex. Further, SW-9(10mg/kg) was intraperitoneally administered to the mice, and an equivalent amount of physiological Saline (Saline) was injected to the control group, and nNOS-SERT coupling in the DRN region was detected after 3 hours, and as a result, SW-9 was found to be able to significantly release nNOS-SERT coupling as shown in FIG. 1 b.

Effect test example 2

Antidepressant-like effects of SW-9

40 mice were divided into 4 groups at random, and each group was divided into a solvent group (vehicle group), an SW-9 low dose group, an SW-9 medium dose group and an SW-9 high dose group, and SW-9 was intraperitoneally injected into mice in the SW-9 low dose group, the SW-9 medium dose group and the SW-9 high dose group at 1mg/kg, 2.5mg/kg and 5mg/kg, respectively, and the solvent group was injected with the same amount of solvent. After 2h, Tail Suspension Test (TST), Forced Swim Test (FST), and sugar water preference test (SPT) were performed. As a result, it was found that an antidepressant-like phenotype could be observed by intraperitoneal administration of 2.5mg/kg, 5mg/kg for 2h, and the immobility time of both FST and TST was significantly reduced, as shown in FIG. 2 a; whereas, with a 24h i.p. dose of SW-9 of only 5mg/kg, the immobility time of FST and TST was reduced, as shown in FIG. 2 b. These results indicate that intraperitoneal SW-9 injection has extremely rapid antidepressant-like effect, but the drug effect is weakened after 24h, and the antidepressant-like effect of SW-9(1mg/kg) with low dose is not obvious.

Effect test example 3

Rapid-onset antidepressant effect of SW-9 intraperitoneal injection

Dividing 30 mice into 3 groups randomly, namely a blank Control group (Control), a CMS group and a CMS + SW-9 group respectively, carrying out CMS depression molding on the mice of the CMS group and the CMS + SW-9 group for 1 month, detecting the success of molding after 1 month, injecting SW-9(10mg/kg) into the abdominal cavity of the mice of the CMS + SW-9 group, injecting an equivalent solvent into the abdominal cavity of the mice of the blank Control group and the CMS group, and carrying out TST, FST and SPT behavioral detection after 2 hours. The results show that SW-9 was able to rapidly reverse the prolonged immobility time of CMS model mice in TST (as shown in FIG. 3 a) and FST (as shown in FIG. 3 b). The selectivity of CMS mice for sugar water uptake decreased significantly, but SW-9 intraperitoneal injection rapidly increased the sugar water preference rate in the depression model (as shown in FIG. 3 c). These results demonstrate that SW-9 intraperitoneal injection can exert a rapid antidepressant effect.

Effect test example 4

Rapid-onset antidepressant action of SW-9 intragastric administration

Dividing 30 mice into 3 groups randomly, namely a blank Control group (Control), a CMS group and a CMS + SW-9 group respectively, carrying out CMS depression molding on the mice of the CMS group and the CMS + SW-9 group for 1 month, detecting the success of molding after 1 month, carrying out intragastric SW-9(10mg/kg) on the mice of the CMS + SW-9 group, carrying out intragastric solvent filling on the mice of the blank Control group and the CMS group with equal amount, and carrying out the behavioral detection of TST, FST and SPT after 2 hours on the mice. The results show that SW-9 was able to rapidly reverse the prolongation of immobility time of CMS model mice in TST (FIG. 4a) and FST (FIG. 4 b). The selectivity of CMS mice for sugar water intake decreased significantly, but SW-9 gavage rapidly increased the sugar water preference rate in the depression model (FIG. 4 c). These results demonstrate that SW-9 gavage can exert a rapid antidepressant effect.

Effect test example 5

Test of the ability of SW-9 to pass the blood brain Barrier

SW-9(25mg/Kg) was administered to the tail vein of mice, and the concentration of SW-9 in the brain tissue homogenate was measured at 1min, 3min, 5min, 7min, 9min, 11min, 13min, 15min, 17min, 20min, and 30min after administration, as shown in Table 1 and FIG. 5.

TABLE 1

Time/min	Drug concentration/(ng/g)
		1	919.6
3	912.82
		5	584.97
7	583.51
		9	446.37
11	484.45
		13	389.76
15	353.61
		17	230.34
20	292.35
		30	307.02

Through experiments, the bioavailability of the compound SW-9 administered by intragastric administration when the administration dose of the mouse is 25mg/Kg and the initial judgment of the capability of the compound to penetrate the blood brain barrier when the mouse is administered with 25mg/Kg intravenously are studied. The results show that when the mouse is administrated with 25mg/Kg intravenously, the main pharmacokinetic parameters are as follows: AUC (0- ∞): 2001.815mg/L min, t1/2 z: 4.903min, Tmax: 1min, Cmax: 159.39 mg/L; when the mouse is administrated with 25mg/Kg by gavage, the main pharmacokinetic parameters are as follows: AUC (0- ∞): 1784.779mg/L min, t1/2 z: 57.095min, Tmax: 3min, Cmax: 27.99 mg/L. When the mouse is administrated at the dose of 25mg/Kg, the bioavailability of the compound SW-9 administrated by gastric gavage is 89.16%. After the mouse is intravenously administrated with 25mg/Kg, SW-9 with a certain concentration can be detected in the brain within 30 min.

The results show that the compound SW-9 mouse has quick absorption by gavage administration, high bioavailability, can permeate blood brain barrier, has good pharmacokinetic property, is expected to overcome the problem that the current common clinical antidepressant is only effective to partial patients and has slow onset time, and becomes a novel antidepressant which is effective in oral administration and quick in onset.

The verification of the above effects was carried out by replacing SW-9 with the compounds SW-10, SW-14, SW-15, SW-20, SW-21, SW-9A, SW-9B, SW-9C, SW-9D, SW-31 and SW-35, and the results obtained were comparable to those of SW-9.

The above description is only for the preferred embodiment of the present invention, and the protection scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical scope of the present invention, the technical solution and the inventive concept of the present invention equivalent or change within the technical scope of the present invention.