An indole compound, a preparation method therefor and application thereof

Abstract

The application discloses an indole compound, a preparation method and application thereof. Specifically, the application provides a compound as shown in formula I, a pharmaceutically acceptable salt or an enantiomer thereof, and the compound can effectively shorten sleep latency, prolong sleep time, and has a better sleep promoting effect.

Description

Technical Field

[0001] This invention relates to an indole compound, its preparation method, and its application. Background Technology

[0002] It is reported that one-quarter of the world's population suffers from insomnia. Insomnia leads to a decline in quality of life and work efficiency, and is associated with and can trigger a variety of diseases, such as neurasthenia, depression, anxiety, dementia, hypertension, arrhythmia, obesity, and metabolic disorders. Due to the fast pace of life and increased work pressure, insomnia has become a globally prevalent disease that harms health and quality of life.

[0003] Currently, the main drugs used clinically to treat insomnia include: the first generation are barbiturates, including phenobarbital, amobarbital, secobarbital, etc., whose mechanism of action is to prolong GABA. A receptor Cl - Channel opening time and enhanced GABA-mediated Cl - The first generation is benzodiazepines; the second generation consists of benzodiazepines, mainly including diazepam and oxazepam, whose mechanism of action is to increase GABA. A receptor Cl - Channel opening frequency; the third generation consists of non-benzodiazepines, including zolpidem, zopiclone, zaleplon, and eszopiclone, whose mechanism of action is to enhance the interaction between GABA and GABA. A The effect of receptors increases Cl - The frequency of channel opening or the duration of prolonged opening can cause hyperpolarization of the nerve cell membrane, thus reducing its excitability.

[0004] Because insomnia has a variety of causes and the physiological mechanisms of sleep are not yet fully understood, the development of new drugs in the global field of sedative-hypnotic drug research is slow, and existing drugs are far from meeting the needs of insomnia patients. Summary of the Invention

[0005] The technical problem this invention aims to solve is that existing drugs that can effectively shorten sleep latency and prolong sleep time are relatively limited. Therefore, this invention provides an indole compound, its preparation method, and its application. The compound of this invention, as shown in Formula I, can effectively shorten sleep latency and prolong sleep time, exhibiting superior sleep-promoting effects.

[0006] This invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, or an enantiomer thereof.

[0007]

[0008] in,

[0009] R 1 and R 2Independently, it is H, C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogens, C1-C6 alkoxy, C1-C6 alkoxy substituted with one or more halogens, halogen, -OH, -CN, -NH2 or -NO2;

[0010] R 3 H, -COOR 3a or -CONR 3b R 3c ;

[0011] R 3a R 3b and R 3c It is independently H, C1-C6 alkyl, or surrounded by one or more C6-C6 groups. 10 Aryl-substituted C1~C6 alkyl groups.

[0012] In one embodiment, certain groups in compounds represented by Formula I, their pharmaceutically acceptable salts, or their enantiomers have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment").

[0013] R 1 It can be H, C1~C6 alkyl, C1~C6 alkoxy or halogen.

[0014] In one particular scheme, R 2 For H.

[0015] In one particular scheme, R 3a R 3b and R 3c It is independently H or C1~C6 alkyl.

[0016] In a certain scheme, when R 1 and R 2 When independently a C1-C6 alkyl group, the C1-C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, for example, methyl.

[0017] In a certain scheme, when R 1 and R 2 When the C1-C6 alkyl group is independently substituted with one or more halogens, the C1-C6 alkyl group substituted with one or more halogens may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0018] In a certain scheme, when R 1 and R 2When a C1-C6 alkyl group is independently substituted with one or more halogens, the halogen in the C1-C6 alkyl group substituted with one or more halogens may be fluorine, chlorine, bromine or iodine.

[0019] In a certain scheme, when R 1 and R 2 When independently a C1-C6 alkoxy group, the C1-C6 alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy, such as methoxy.

[0020] In a certain scheme, when R 1 and R 2 When the C1-C6 alkoxy group is independently substituted with one or more halogens, the C1-C6 alkoxy group substituted with one or more halogens may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy.

[0021] In a certain scheme, when R 1 and R 2 When the C1-C6 alkoxy group is independently substituted with one or more halogens, the halogen in the C1-C6 alkoxy group substituted with one or more halogens may be fluorine, chlorine, bromine or iodine.

[0022] In a certain scheme, when R 1 and R 2 When it is a halogen on its own, the halogen can be fluorine, chlorine, bromine or iodine, such as fluorine.

[0023] In a certain scheme, when R 3a When the alkyl group is C1 to C6, the C1 to C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, for example, methyl.

[0024] In a certain scheme, when R 3b and R 3c When independently a C1-C6 alkyl group, the C1-C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, for example, ethyl or isopropyl.

[0025] In a certain scheme, when R 3a R 3b and R 3c Independently defined by one or more C6~C 10 When aryl-substituted C1-C6 alkyl groups are used, the alkyl group is substituted with one or more C6-C6 alkyl groups. 10 The C6-C of aryl-substituted C1-C6 alkyl groups 10 The aryl group can be phenyl or naphthyl, for example, phenyl.

[0026] In a certain scheme, when R 3a R 3b and R 3c Independently defined by one or more C6~C 10 When aryl-substituted C1-C6 alkyl groups are used, the alkyl group is substituted with one or more C6-C6 alkyl groups. 10 The C1-C6 alkyl groups in the aryl-substituted C1-C6 alkyl groups can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0027] In a certain scheme, when R 3a R 3b and R 3c Independently defined by one or more C6~C 10 When aryl-substituted C1-C6 alkyl groups are used, the alkyl group is substituted with one or more C6-C6 alkyl groups. 10 Aryl-substituted C1-C6 alkyl groups can be benzyl.

[0028] In one scheme, the -COOR 3a It can be -COOH or -COOCH3.

[0029] In one scheme, the -CONR 3b R 3c Can be or .

[0030] In one particular scheme, R 1 It can be H, C1-C6 alkyl, C1-C6 alkoxy, or halogen;

[0031] R 2 For H;

[0032] R 3 H, -COOR 3a or -CONR 3b R 3c ;

[0033] R 3a R 3b and R 3c It is independently H or C1~C6 alkyl.

[0034] In one particular scheme, R 3 For H, R 1 It is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; or, R 3 -COOR 3a or -CONR 3b R 3c R 1 For H.

[0035] In a certain scheme, when R 3 -COOR 3a At that time, the R 3a It is a C1~C6 alkyl group.

[0036] In one embodiment, the compound represented by Formula I is any of the following compounds:

[0037]

[0038] The present invention also provides a method for preparing a compound as shown in Formula I, comprising the following steps: reacting a compound as shown in Formula A with a compound as shown in Formula B to obtain a compound as shown in Formula I.

[0039]

[0040] Among them, R 1 R 2 and R 3 The definitions are the same as those in the previous item.

[0041] The present invention also provides a pharmaceutical composition comprising substance A and at least one pharmaceutical excipient, wherein substance A is a compound represented by Formula I, a pharmaceutically acceptable salt thereof, or an enantiomer thereof.

[0042] In this invention, the compounds shown in Formula I can also be used in combination with one or more other active ingredients; when used in combination, the active ingredients can be separate compositions for simultaneous or separate administration via the same or different routes of administration during treatment, or they can be administered together in the same pharmaceutical composition.

[0043] The present invention also provides the use of the compound represented by Formula I, its pharmaceutically acceptable salt, or the pharmaceutical composition thereof in the preparation of a medicament for treating insomnia.

[0044] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, and ammonium salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, sulfate, and mesylate salts. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.

[0045] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. It includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009) for details.

[0046] The term "multiple" refers to two or three.

[0047] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0048] The reagents and raw materials used in this invention are all commercially available.

[0049] The positive and progressive effects of this invention are: it provides an indole compound, its preparation method, and its application. Specifically, the compound of this invention, as shown in Formula I, can effectively shorten sleep latency and prolong sleep time, exhibiting a superior sleep-promoting effect. Detailed Implementation

[0050] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0051] Example 1

[0052]

[0053] Step 1: Dissolve 3-(2-aminoethyl)indole (2a) (1.00 g, 6.24 mmol, CAS: 61-54-1) in 10 mL of dichloroethane, then add EDCI (1.55 g, 8.11 mmol, CAS: 25952-53-8), DAMP (60.99 mg, 0.58 mmol, CAS: 1122-58-3), and DIPEA (5.69 mL, 34.32 mmol, CAS: 7087-68-5) sequentially. After stirring in an ice bath for 30 minutes, add... N -Boc- c 1,4-aminobutyric acid (1.52 g, 7.49 mmol, CAS: 57294-38-9), reacted overnight. After the reaction was complete, 30 mL of dichloromethane was added, and the mixture was extracted with saturated brine (30 mL × 3). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated and eluted by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1, V / V) to give a yellow oil 3a (1.23 g, yield 57%).

[0054] 3a: 1 H NMR (400 MHz, CD3OD): d 7.56 (t, J = 6.4 Hz, 1H), 7.33 (t, J =6.9 Hz, 1H), 7.08 (s, 1H), 7.07 (d, J = 7.0 Hz, 1H), 7.00 (d, J = 6.8 Hz, 1H), 3.48 (t, J = 6.6 Hz, 2H), 3.02 (t, J = 5.3 Hz, 2H), 2.95 (t, J = 6.4 Hz, 2H), 2.15 (t, J = 6.4 Hz, 2H), 1.72 (t, J = 5.8 Hz, 2H), 1.43 (s, 9H). ESI-MS: m / z 346 [M + H] + .

[0055] The following compounds 3b-3d were prepared following the same synthetic steps as 3a.

[0056] 3b: Yellow oily substance, yield 55%. 1 H NMR (400 MHz, CD3OD): d 7.18 (d, J = 8.8 Hz,1H), 7.03 (s, 1H), 7.00 (s, 1H), 6.72 (d, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.43(t, J = 7.1 Hz, 2H), 2.98 (t, J = 6.7 Hz, 2H), 2.87 (t, J = 7.1 Hz, 2H), 2.13(t, J = 7.4 Hz, 2H), 1.68 (t, J = 7.2 Hz, 2H), 1.39 (s, 9H). ESI-MS: m / z 376[M + H] + .

[0057] 3c: Yellow oily substance, yield 50%. 1 H NMR (400 MHz, CD3OD): d 7.26 (m, 1H), 7.21 (d, J = 9.9 Hz, 1H), 7.12 (s, 1H), 6.83 (t, J = 8.9 Hz, 1H), 3.44 (t, J = 6.7Hz, 2H), 3.00 (t, J = 6.4 Hz, 2H), 2.88 (t, J = 6.7 Hz, 2H), 2.15 (t, J = 6.9Hz, 2H), 1.70 (t, J = 7.2 Hz, 2H), 1.41 (s, 9H). ESI-MS: m / z 364 [M + H] + .

[0058] 3d: Yellow oily substance, yield 65%. 1 H NMR (400 MHz, CD3OD): d 7.29 (s, 1H), 7.16 (d, J = 8.2 Hz, 1H), 6.96 (s, 1H), 6.87 (d, J = 8.1 Hz, 1H), 3.40 (t,J = 6.3Hz, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.8 Hz, 2H), 2.36 (s, 3H), 2.11 (t, J = 7.1 Hz, 2H), 1.66 (t, J = 8.0 Hz, 2H), 1.38 (s, 9H). ESI-MS: m / z 360 [M + H] + .

[0059] Step 2: Dissolve 3a (1.23 g, 3.57 mmol) in 5 mL of dichloromethane. Under ice bath conditions, add 2.5 mL of trifluoroacetic acid and react for 3 hours. After the reaction is complete, heat to evaporate the solvent, and extract with n-butanol (10 mL × 3) and water (10 mL), collecting the n-butanol phase. Concentrate under reduced pressure and purify by ODS column chromatography (methanol:water = 3:2, V / V) to obtain a yellow oily product 4a (0.54 g, 61% yield).

[0060] 4a: 1 H NMR (400 MHz, CD3OD): d 7.47 (d, J = 7.8 Hz, 1H), 7.25 (d, J =8.0 Hz, 1H), 7.03 – 6.88 (m, 2H), 6.92 (t, J = 7.2 Hz, 1H). 3.41 (t, J = 7.0Hz, 2H), 2.86 (t, J = 7.1 Hz, 2H), 2.80 (t, J = 7.1 Hz, 2H), 2.21 (t, J = 6.9Hz, 2H), 1.79 (t, J = 7.2 Hz, 2H). ESI-MS: m / z 246 [M + H] + .

[0061] The following compounds 4b-4d were prepared following the same synthetic steps as 4a.

[0062] 4b: Yellow oily substance, yield 66%. 1H NMR (400 MHz, CD3OD): d 7.18 (d, J = 6.8 Hz,1H), 7.01 (s, 2H), 6.72 (d, J = 7.7 Hz, 1H), 3.79 (s, 3H), 3.44 (m, 2H), 2.87(m, 4H), 2.27 (m, 2H), 1.85 (m, 2H). ESI-MS: m / z 276 [M + H] + .

[0063] 4c: White powder, yield 69%. 1 H NMR (400 MHz, CD3OD): d 7.24 (m, 1H), 7.18 (d, J = 9.9 Hz, 1H), 7.10 (s, 1H), 6.80 (m, 1H), 3.42 (t, J = 6.0 Hz, 2H), 2.86(m, 4H), 2.27 (t, J = 5.7 Hz, 2H), 1.85 (t, J = 5.7 Hz, 2H). ESI-MS: m / z 264[M + H] + .

[0064] 4d: Yellow oily substance, yield 64%. 1 H NMR (400 MHz, CD3OD): d 7.30 (s, 1H), 7.17 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.88 (d, J = 7.8 Hz, 1H), 3.43 (m, 2H), 2.86 (m, 4H), 2.37 (s, 3H), 2.26 (s, 2H), 1.84 (s, 2H). ESI-MS: m / z 260 [M +H] + .

[0065] Step 3: Add 4a (0.54 g, 2.20 mmol). DPantothenic acid lactone (0.89 g, 11.34 mmol, CAS: 599-04-2) was added to a two-necked flask under N2 protection, dissolved in 15 mL of ethanol, and then 1.85 mL of triethylamine was added dropwise. The mixture was refluxed at 75 °C for 40 hours. After cooling to room temperature, the product was concentrated and eluted by silica gel column chromatography (dichloromethane:methanol = 30:1, V / V). The crude product was then purified by ODS column chromatography (methanol:water = 7:3, V / V) to give a yellow oily substance 1a (79 mg, 10% yield).

[0066] 1a: 1 H NMR (400 MHz, CD3OD): d 7.53 (d, J = 7.3 Hz, 1H), 7.30 (d, J =7.5 Hz, 1H), 7.13 – 6.91 (m, 3H), 3.87 (s, 1H), 3.40 (m, 4H), 3.14 (m, 2H), 2.92 (m, 2H), 2.15 (m, 2H), 1.73 (m, 2H), 0.89 (s, 6H). 13 C NMR (100 MHz, CD3OD): d 176.10, 175.39, 138.16, 128.82, 123.42, 122.30, 119.57, 119.28,113.26, 112.22, 77.48, 70.43, 41.42, 40.34, 39.37, 34.51, 26.91, 26.22,21.37, 20.97. ESI-MS: m / z 376 [M + H] + .

[0067] The following compounds 1b-1d were prepared following the same synthetic procedure as 1a.

[0068] 1b: Yellow oily substance, yield 8%. 1 H NMR (400 MHz, CD3OD): d 7.20 (d, J = 8.0 Hz,1H), 7.03 (s, 2H), 6.73 (d, J= 8.0 Hz, 1H), 3.88 (s, 1H), 3.80 (s, 3H), 3.45(m, 3H), 3.37 (m, 1H), 3.16 (m, 2H), 2.89 (m, 2H), 2.17 (m, 2H), 1.74 (m,2H), 0.91 (s, 6H). 13 C NMR (100 MHz, CD3OD): d 176.08, 175.37, 154.93, 133.39,129.11, 124.23, 113.04, 112.88, 112.55, 101.41, 77.48, 70.43, 56.38, 41.31,40.32, 39.36, 34.53, 26.91, 26.24, 21.36, 20.96. ESI-MS m / z 406 [M + H] + .

[0069] 1c: Yellow oily substance, yield 10%. 1 H NMR (400 MHz, CD3OD): d 7.23 (m, 2H), 7.10(s, 1H), 6.81 (t, J = 7.8 Hz, 1H), 3.88 (s, 1H), 3.44 (m, 3H), 3.40 (m, 1H), 3.16 (m, 2H), 2.87 (m, 2H), 2.16 (m, 2H), 1.74 (m, 2H), 0.90 (s, 6H). 13 C NMR (100 MHz, CD3OD) d 176.07, 175.40, 159.97, 157.66, 134.65, 129.14, 129.05,125.50, 113.52, 113.47, 112.99, 112.89, 110.46, 110.20, 103.99, 103.76,77.47, 70.43, 41.24, 40.32, 39.35, 34.48, 26.88, 26.12, 21.36, 20.95. ESI-MS: m / z 394 [M + H] + .

[0070] 1d: Yellow oily substance, yield 15%. 1H NMR (400 MHz, CD3OD): d 7.32 (s, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.00 (s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 3.88 (s, 1H), 3.46 (m, 3H), 3.36 (m, 1H), 3.16 (m, 2H), 2.89 (t, J = 6.6 Hz, 2H), 2.39 (s,3H), 2.16 (t, J = 7.1 Hz, 2H), 1.74 (m, 2H), 0.91 (s, 6H). 13 C NMR (100 MHz, CD3OD): d 176.09, 175.38, 136.52, 129.05, 128.61, 123.93, 123.54, 118.93,112.76, 111.94, 77.48, 70.43, 41.45, 40.33, 39.37, 34.52, 26.91, 26.23,21.68, 21.36, 20.96. ESI-MS: m / z 390 [M + H] + .

[0071] Example 2

[0072]

[0073] Step 1: Add L-tryptophan methyl ester hydrochloride (5) (1.50 g, 5.89 mmol, CAS: 7524-52-9). N -Boc- c4-aminobutyric acid (1.00 g, 4.92 mmol, CAS: 57294-38-9), EDCI (1.41 g, 7.4 mmol, CAS: 25952-53-8), DAMP (71.84 mg, 0.58 mmol, CAS: 1122-58-3), and DIPEA (5.3 mL, 35.34 mmol, CAS: 7087-68-5) were dissolved in 20 mL of tetrahydrofuran and stirred at room temperature for 10 hours. After the reaction was completed, 40 mL of dichloromethane was added, and the mixture was extracted with saturated brine (30 mL × 3). The organic phase was collected and dried with anhydrous sodium sulfate. The organic phase was concentrated and eluted by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1, V / V) to give 4-((tert-butoxycarbonyl)amino)butyryl-L-tryptophan methyl ester (6) (1.87 g, yield 93%). 1 H NMR (400 MHz, CD3OD): d 7.46 (d, J = 7.3 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.02 (m, 2H), 6.95 (t, J = 6.8 Hz, 1H), 4.66(m, 1H), 3.60 (s, 3H), 3.19 (m, 1H), 3.08 (m, 1H), 2.90 (m, 2H), 2.11 (m,2H), 1.58 (m, 2H), 1.36 (s, 9H). 13 C NMR (100 MHz, CD3OD): d 175.49, 174.10,158.52, 138.03, 128.72, 124.36, 122.45, 119.82, 119.13, 112.32, 110.80,79.95, 54.88, 52.65, 40.61, 33.95, 28.76, 28.48, 27.15. ESI-MS: m / z 404 [M +H] + .

[0074] Step 2: Add 4-((tert-butoxycarbonyl)amino)butyryl- L4-Tryptophan methyl ester (6) (1.87 g, 4.6 mmol) was dissolved in 10 mL of dichloromethane. The reaction was carried out under ice bath conditions with 2 mL of trifluoroacetic acid for 60 minutes to obtain a pale blue liquid. After the reaction, the solvent was evaporated, and the mixture was extracted with n-butanol (10 mL × 3) and water (20 mL), collecting the n-butanol phase. The concentrated phase was purified by ODS chromatography (methanol:water = 3:2, V / V) to obtain 4-aminobutyryl- L -Tryptophan methyl ester (7) (1.10 g, yield 85%). 1 H NMR (400 MHz, CD3OD): d 7.52 (d, J = 7.2 Hz, 1H), 7.34 (d, J = 7.0 Hz, 1H), 7.14 –6.97 (m, 3H), 4.73 (m, 1H), 3.66 (s, 3H), 3.30 (m, 1H), 3.14 (m, 1H), 2.81 (m, 2H), 2.29 (m, 2H), 1.81 (m, 2H). 13 C NMR (100 MHz, CD3OD): d 174.40, 174.01, 138.00, 128.63, 124.45, 122.46, 119.83,119.06, 112.38, 110.71, 54.94, 52.71, 40.10, 33.25, 28.42, 24.20. ESI-MS: m / z 304 [M + H] + .

[0075] Step 3: Add 4-aminobutyroyl- L -Tryptophan methyl ester (7) (1.10 g, 3.63 mmol), D Pantothenic acid lactone (1.17 g, 11.34 mmol, CAS: 599-04-2) was added to a two-necked flask under N2 protection, dissolved in 15 mL of ethanol, and then 3.50 mL of triethylamine was added dropwise. The mixture was refluxed at 75°C for 40 hours. It was then cooled to room temperature. Concentration was performed using TSK gel Toyopearl HW-40F (30-60 g / mL). m m, Toso Co. Ltd.) column chromatography (methanol:water = 7:3, v / v) elution. 4-(( R )-2,4-dihydroxy-3,3-dimethylbutyramido)butyryl- L-Tryptophan methyl ester (1e) (538.65 mg, yield 45%). 1 H NMR (400 MHz, CD3OD): d 7.49 (d, J = 5.6 Hz, 1H), 7.29 (d, J = 6.0 Hz, 1H), 7.05 (m, 2H), 6.99 (t, J = 4.6 Hz, 1H), 4.71 (m, 1H), 3.86 (s, 1H), 3.62 (s, 3H), 3.44 (d, J = 9.1 Hz, 1H), 3.35 (d, J = 12.3 Hz, 1H), 3.32 (d, J = 2.0 Hz, 1H), 3.27(d, J = 9.1 Hz, 1H), 3.09 (m, 2H), 2.16 (m, 2H), 1.66 (m, 2H), 0.89 (s, 6H). 13 C NMR (100 MHz, CD3OD): d 176.06, 175.33, 174.08, 138.00, 128.69, 124.40,122.45, 119.82, 119.12, 112.32, 110.78, 77.45, 70.43, 54.98, 52.67, 40.31,39.18, 34.02, 28.45, 26.69, 21.36, 20.98. ESI-MS: m / z 434[M + H] + .

[0076] Step 4: 4-(( R )-2,4-dihydroxy-3,3-dimethylbutyramido)butyryl- L Tryptophan methyl ester (1e) (538.65 mg, 1.24 mmol) was added to a 20 mL round-bottom flask, dissolved in methanol, and 1.98 mL of 1 mmol / mL NaOH aqueous solution was added dropwise. The reaction was carried out at room temperature for 40 hours. Concentration was achieved using TSK gel Toyopearl HW-40F (30-60). m m, Toso Co. Ltd.) column chromatography (pure water) elution, yielding 4-( ( R )-2,4-dihydroxy-3,3-dimethylbutyramido)butyryl-L -Tryptophan (1f) (490 mg, 95%). 1 H NMR (400 MHz, D2O) d 7.68 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.21 (s, 1H), 7.14 (t, J = 7.4 Hz, 1H), 4.59 (dd, J = 8.9, 4.7 Hz, 1H), 3.92 (s, 1H), 3.49 (d, J = 11.2 Hz, 1H), 3.39 (dd, J = 13.6, 5.7 Hz, 1H), 3.37 (d, J = 11.9 Hz, 1H), 3.10 (dd, J =14.7, 8.9 Hz, 1H), 2.88 (dt, J = 14.1, 7.2 Hz, 1H), 2.80 (dt, J = 14.1, 7.2Hz, 1H), 2.11 (brt, J = 7.4 Hz, 2H), 1.50 (tq, J = 13.7, 6.8 Hz, 2H), 0.89(s, 3H), 0.86 (s, 3H). 13 C NMR (100 MHz, D2O): d 178.58, 174.86 (×2), 136.05,127.18, 124.06, 121.72, 119.11, 118.59, 111.71, 110.39, 75.79, 68.40, 55.56,38.55, 37.87, 33.12, 27.49, 24.73, 20.51, 19.13. ESI-MS: m / z 442 [M + Na] + 420 [M + H] + .

[0077] Step 5:

[0078] 4-( R)-2,4-dihydroxy-3,3-dimethylbutyramido)butyryl- L -Tryptophan (1f) (100 mg, 0.24 mmol) dissolved in 1 mL of anhydrous N , N Add HATU (114 mg, 0.31 mmol) and DIPEA (90 mg) to dimethylformamide (DMF). m L, 0.48 mmol). After thorough mixing, add diethylamine (40 L, 0.48 mmol). m L, 0.36 mmol, CAS: 109-89-7), the reaction mixture was stirred overnight at room temperature. After the reaction was complete, dichloromethane (20 mL) was added, the reaction mixture was washed with saturated sodium bicarbonate solution, and purified by ODS column chromatography (methanol:water = 7:3, V / V) to give 1 g (50 mg, yield 44%) of yellow oil. 1 H NMR (400 MHz, CD3OD): d 7.57 (d, J = 6.9 Hz, 1H), 7.29 (d, J = 7.7 Hz,1H), 7.02 (m, 3H), 5.06 (m, 1H), 3.87 (s, 1H), 3.45 (d, J = 10.4 Hz, 1H), 3.36 (d, J = 12.4 Hz, 1H), 3.33 – 3.24 (m, 2H), 3.16 – 3.10 (m, 2H), 3.11 –3.02 (m, 4H), 2.21 (d, J = 5.6 Hz, 2H), 1.70 (d, J = 6.1 Hz, 2H), 0.90 (s,9H), 0.82 (m, 3H). 13 C NMR (100 MHz, MeOD): d 176.08, 174.79, 173.28, 137.99,128.79, 124.67, 122.49, 119.92, 119.19, 112.34, 110.73, 77.47, 70.43, 51.34,43.16, 41.80, 40.34, 39.27, 34.07, 29.79, 26.73, 21.37, 21.00, 14.08, 12.96.ESI-MS: m / z 475 [M + H] + .

[0079] Compound 1h was prepared using the same synthetic procedure as 1g.

[0080] 1h: Yellow oily substance, yield 40%. 1 H NMR (400 MHz, CD3OD): d 7.56 (m, 1H), 7.34 –7.21 (m, 1H), 7.09 – 6.92 (m, 3H), 4.54 (m, 1H), 3.85 (m, 2H), 3.44 (m, 1H),3.32 (m, 2H), 3.07 (m, 2H), 2.17 (m, 2H), 1.66 (m, 2H), 0.99 (s, 3H), 0.88 (s, 6H), 0.83 (s, 3H). 13 C NMR (100 MHz, MeOD): d 176.04, 175.09, 172.98,138.00, 128.86, 124.55, 122.39, 119.77, 119.43, 112.24, 110.98, 77.47, 70.43,55.88, 42.52, 40.33, 39.13, 34.10, 29.25, 26.73, 22.41, 22.24, 21.39, 20.99.ESI-MS: m / z 461 [M + H] + .

[0081] Example 3: Experiment on prolonging sodium pentobarbital sleep time

[0082] 1. Experimental Methods

[0083] 1.1 Experimental animals: 90 SPF grade ICR mice, 18±2g, all male, were randomly divided into 9 groups of 10 mice each.

[0084] 1.2 Experimental Conditions

[0085] SPF-grade animal room, temperature 20-26 ℃, humidity 40%-70%, light / dark alternation time 12h / 12h.

[0086] 1.3 Instruments and Reagents

[0087] Electronic scale, gavage injection, physiological saline, sodium pentobarbital

[0088] 1.4 Dosage grouping and administration time of test samples

[0089] The experimental animals were divided into 9 groups of 10 animals each: a blank control group, 6 drug administration groups (1b, 1c, 1d, 1e, 1g, 1h, 25 mg / kg), and 2 positive control groups. N -Acetyl-5-methoxytryptamine and hyperpantothenic acid). Each group of experimental animals was administered samples by gavage and physiological saline for four consecutive weeks.

[0090] 2. Experimental Procedure

[0091] 2.1 Adaptation Period

[0092] The experimental ICR mice were fed under the barrier system to adapt to the environment for 5-7 days. At the end of the adaptation period, their weight was 25±2g.

[0093] 2.2 Test Sample Administration

[0094] Each dose group of experimental animals was given the same volume of the corresponding dose concentration of the test sample by gavage daily, while the blank control group was given the same volume of physiological saline at the same time.

[0095] 2.3 Detection Indicators

[0096] Experimental animals were weighed weekly to compare whether there were significant differences in body weight among groups. One hour after sample administration, experimental animals were intraperitoneally injected with sodium pentobarbital at a dose of 48 mg / kg (0.1 ml / 10 g body weight). Individual animals were then placed in transparent cages to observe sleep latency and sleep duration. The criterion for sleep onset was the disappearance of the righting reflex for more than 60 seconds. The time from sodium pentobarbital injection to the disappearance of the righting reflex was defined as sleep latency, and the time from the disappearance to the recovery of the righting reflex was defined as sleep duration. The study compared whether different compounds could shorten the sleep latency and prolong the sleep duration in sodium pentobarbital-injected mice. Behavioral experiments were conducted daily from 10:00 PM to 12:00 AM in a quiet laboratory with normal lighting, a temperature of 24–26°C, and humidity of 40%–70%.

[0097] 3. Data processing and result determination

[0098] All data are expressed as mean ± standard deviation. Data are expressed as mean ± standard deviation (s). One-way ANOVA was performed using SPSS 19 statistical software, and LSD analysis was used for comparisons between groups. P＜ A statistically significant difference of 0.05 was observed.

[0099] 4. Experimental Results

[0100] Effect of sodium pentobarbital on prolonging sleep time

[0101] The statistical results show that after gavage administration of drugs 1b, 1c, 1d, 1e, 1g, and 1h, the sleep latency was shortened and the sleep duration was significantly increased compared to the blank control group. Furthermore, these results were superior to the two positive control drugs.

[0102] Table 1: Effects of sodium pentobarbital on sleep duration

[0103]

[0104] Note: p <0.05, p <0.01, compared with the blank control group.

Claims

1. A compound as shown in Formula I, a pharmaceutically acceptable salt thereof, or an enantiomer thereof, ， in, R 1 and R 2 Independently, it is H, C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogens, C1-C6 alkoxy, C1-C6 alkoxy substituted with one or more halogens, halogen, -OH, -CN, -NH2 or -NO2; R 3 H, -COOR 3a or -CONR 3b R 3c ; R 3a R 3b and R 3c It is independently H or C1~C6 alkyl.

2. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, or its enantiomer, characterized in that, The compound represented by Formula I, its pharmaceutically acceptable salt, or its enantiomers satisfy one or two of the following conditions: (1) R 1 It can be H, C1-C6 alkyl, C1-C6 alkoxy, or halogen; (2) R 2 For H.

3. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, or its enantiomer, characterized in that, The compound represented by Formula I, its pharmaceutically acceptable salt, or its enantiomers satisfy one or more of the following conditions: (1) When R 1 and R 2 When independently a C1-C6 alkyl group, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; (2) When R 1 and R 2 When the C1-C6 alkyl group is independently substituted with one or more halogens, the C1-C6 alkyl group substituted with one or more halogens is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl. (3) When R 1 and R 2 When the C1-C6 alkyl group is independently substituted with one or more halogens, the halogen in the C1-C6 alkyl group substituted with one or more halogens is fluorine, chlorine, bromine or iodine; (4) When R 1 and R 2 When independently a C1-C6 alkoxy group, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy. (5) When R 1 and R 2 When the C1-C6 alkoxy group is independently substituted with one or more halogens, the C1-C6 alkoxy group substituted with one or more halogens is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy. (6) When R 1 and R 2 When the C1-C6 alkoxy group is independently substituted with one or more halogens, the halogen in the C1-C6 alkoxy group substituted with one or more halogens is fluorine, chlorine, bromine or iodine; (7) When R 1 and R 2 When it is a halogen on its own, the halogen is fluorine, chlorine, bromine or iodine; (8) When R 3a When the alkyl group is C1 to C6, the C1 to C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; (9) When R 3b and R 3c When independently a C1-C6 alkyl group, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

4. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, or its enantiomer, characterized in that, The compound represented by Formula I, its pharmaceutically acceptable salt, or its enantiomers satisfy one or more of the following conditions: (1) When R 1 and R 2 When independently a C1-C6 alkyl group, the C1-C6 alkyl group is methyl; (2) When R 1 and R 2 When independently a C1-C6 alkoxy group, the C1-C6 alkoxy group is a methoxy group; (3) When R 1 and R 2 When it is a halogen on its own, the halogen is fluorine; (4) When R 3a When the alkyl group is C1-C6, the C1-C6 alkyl group is methyl; (5) When R 3b and R 3c When independently a C1-C6 alkyl group, the C1-C6 alkyl group is ethyl or isopropyl.

5. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, or its enantiomer, characterized in that, The compound represented by Formula I, its pharmaceutically acceptable salt, or its enantiomers satisfy one or two of the following conditions: (1) R 3 For H, R 1 It is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; or, R 3 -COOR 3a or -CONR 3b R 3c R 1 For H; (2) When R 3 -COOR 3a At that time, the R 3a It is a C1~C6 alkyl group.

6. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, or its enantiomer, characterized in that, The compound represented by Formula I, its pharmaceutically acceptable salt, or its enantiomers satisfy one or two of the following conditions: (1) The -COOR 3a It is -COOH or -COOCH3; (2) The -CONR 3b R 3c for or .

7. The compound of formula I as claimed in any one of claims 1-6, its pharmaceutically acceptable salt, or its enantiomer, characterized in that, The compound shown in Formula I is any of the following compounds: 。 8. A method for preparing a compound as shown in Formula I, comprising the following steps: reacting a compound as shown in Formula A with a compound as shown in Formula B to obtain a compound as shown in Formula I. ， in, R 1 R 2 and R 3 The definitions are the same as those described in any one of claims 1-7.

9. A pharmaceutical composition, characterized in that, It includes substance A and at least one pharmaceutical excipient, wherein substance A is a compound of formula I as described in any one of claims 1-7, a pharmaceutically acceptable salt thereof, or an enantiomer thereof.

10. The use of a compound of Formula I as described in any one of claims 1-7, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9 in the preparation of a medicament for treating insomnia.

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