Tertiary amine compound with indane skeleton as well as preparation method and application of tertiary amine compound

Abstract

The invention relates to a tertiary amine compound with an indane skeleton as well as a preparation method and application thereof, the compound has a nerve protection effect, and the problem of nerve injury caused by ischemia-reperfusion injury generally existing in current IS treatment can be reduced.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to a tertiary amine compound having an indane skeleton, a preparation method and an application thereof. Background Art

[0002] With the aggravation of the problem of social population aging, the incidence of stroke has been increasing year by year and is listed as the second leading cause of death and the third leading cause of disability globally. The incidence of ischemic stroke (IS) accounts for about 80% of all stroke types. At present, the best treatment option is to perform revascularization treatment within the time window. However, when blood vessels are embolized, a large amount of free radicals will be generated due to tissue damage in the ischemic tissue. After revascularization restores blood supply, excessive free radicals attack the reperfused tissue after ischemia, causing reperfusion injury (RI). Reperfusion injury greatly reduces the efficiency of revascularization treatment, and the remission rate of patients' neurological deficits is less than half.

[0003] Neuroprotective agents can inhibit the pathophysiological cascade reaction caused by ischemic injury. As an auxiliary strategy for reperfusion treatment, they can play a role in expanding the treatment time window, reducing adverse reactions, and promoting neurological function recovery. At present, although a large number of published preclinical research reports show that neuroprotection is effective in experimental stroke models, there is still no neuroprotective agent that has passed clinical phase III trials and is routinely used to treat stroke patients. The reasons for its failure may include low blood-brain barrier permeability and poor safety of the drug. Therefore, finding safe and effective new neuroprotective agents to reduce nerve damage caused by ischemia-reperfusion injury is the key scientific issue in the current prevention and treatment research of IS. Summary of the Invention

[0004] The purpose of the present invention is to provide a tertiary amine compound having an indane skeleton, a preparation method and an application thereof. The compound has a neuroprotective effect and can reduce the problem of nerve damage caused by ischemia-reperfusion injury that is prevalent in current IS treatment.

[0005] The technical solution of the present invention is as follows:

[0006] The general structural formula of the tertiary amine compound having an indane skeleton is shown as follows:

[0007]

[0008] Wherein R is phenyl or substituted phenyl, benzyl or benzyl substituted by a benzene ring, straight-chain and branched-chain alkyl; R 1 is a saturated straight-chain or branched-chain alkane group, an alkyl group containing a benzene ring, a polyethylene glycol chain; R 2 is straight-chain and branched-chain alkyl; R 3 is trifluoromethyl or a halogen element.

[0009] The halogen element is bromine or iodine.

[0010] The method for preparing the tertiary amine compound with an indan backbone as described above includes the following steps:

[0011]

[0012] 1) Dissolve the first intermediate in a methanol solution, and under N 2 protection conditions, add the primary amine compound substituted by R 1 the modifying group, and titanium tetraisopropoxide, react at 66 °C for 2 hours, add sodium cyanoborohydride, react at 66 °C until the reaction is complete, quench with saturated sodium bicarbonate solution, extract with dichloromethane, wash with saturated NaCl, then dry with anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain the second intermediate compound;

[0013] The equivalent ratio of the first intermediate compound, the primary amine compound, titanium tetraisopropoxide, and sodium cyanoborohydride is 1:1.2:3.4:2.5;

[0014] 2) Dissolve the above second intermediate in N,N-dimethylformamide (DMF), add the halide of R 2 the modifying group, and a base, react at 66 °C, after monitoring the reaction to completion by TLC, cool to room temperature, add water to quench the reaction, and after extraction, water removal, concentration, and purification by column chromatography, obtain the tertiary amine compound with an indan backbone;

[0015] The equivalent ratio of the second intermediate, the halide of the modifying group, and the base is 1:1.2:2.5.

[0016] In step 1), R in the first intermediate is any one of phenyl or substituted phenyl, benzyl or benzyl substituted by a benzene ring, and linear and branched alkyl groups.

[0017] In step 1), the R 1 primary amine compound substituted by the modifying group is as shown in III:

[0018]

[0019] Among them, R 1 is a linear and branched alkyl group.

[0020] In step 1), the halide of the R 2 modifying group of the second intermediate is as shown in formula V,

[0021]

[0022] Among them, X is bromine or iodine; R 2It is a saturated straight-chain or branched-chain alkyl group, an alkyl group containing a benzene ring, or a polyethylene glycol chain.

[0023] When X is bromine, 0.2 equivalents of potassium iodide need to be added as a catalyst.

[0024] The base in step 2) is potassium carbonate or sodium hydride.

[0025] Use of the above-mentioned tertiary amine compound having an indan skeleton in the preparation of a medicament for treating ischemic stroke reperfusion injury.

[0026] The applicant found in the structural modification and structure-activity relationship study of sertraline that introducing a long-chain alkane substitution into the secondary amine part of the sertraline structure and preparing it into a tertiary amine structure can improve its activity and reduce toxicity. To further improve the activity, safety and drug-likeness of such compounds, based on the basic characteristics of the sertraline derivatives with a side-chain tertiary amine structure obtained previously, a series of tertiary amine compounds having an indan skeleton were prepared through the transformation of "scaffold hopping", and their neuroprotective activity and safety were verified in cell and animal models.

[0027] The tertiary amine compound prepared by the method of the present invention has neuroprotective activity.

[0028] The present invention has the following advantages: The tertiary amine compound having an indan skeleton of the present invention has an obvious neuroprotective effect, can penetrate the blood-brain barrier, better play a therapeutic role, and has low toxicity, good activity and safety, and can be used for the treatment of stroke ischemic reperfusion injury.

[0029] The tertiary amine compound having an indan skeleton in the present invention has not been reported in the literature. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is a cell viability diagram of compounds 1-18 of the present invention.

[0031] Figure 2 It is an experiment on the effect of compound 1 on the infarct area and neurological function after 90 minutes of middle cerebral artery occlusion (MCAO) in mice followed by 24 hours of reperfusion.

[0032] Figure 3 It is the 1H NMR and 13C NMR spectra of compound 1.

[0033] Figure 4 It is the 1H NMR and 13C NMR spectra of compound 2.

[0034] Figure 5 It is the 1H NMR and 13C NMR spectra of compound 3.

[0035] Figure 6 It is the 1H NMR and 13C NMR spectra of compound 4.

[0036] Figure 7 1H-NMR and 13C-NMR spectra of Compound 5

[0037] Figure 8 1H-NMR and 13C-NMR spectra of Compound 6

[0038] Figure 9 1H-NMR and 13C-NMR spectra of Compound 7

[0039] Figure 10 1H-NMR and 13C-NMR spectra of Compound 8

[0040] Figure 11 1H-NMR and 13C-NMR spectra of Compound 9

[0041] Figure 12 1H-NMR and 13C-NMR spectra of Compound 10

[0042] Figure 13 1H-NMR and 13C-NMR spectra of Compound 11

[0043] Figure 14 1H-NMR and 13C-NMR spectra of Compound 12

[0044] Figure 15 1H-NMR and 13C-NMR spectra of Compound 13

[0045] Figure 16 1H-NMR and 13C-NMR spectra of Compound 14

[0046] Figure 17 1H-NMR and 13C-NMR spectra of Compound 15

[0047] Figure 18 1H-NMR and 13C-NMR spectra of Compound 16

[0048] Figure 19 1H-NMR and 13C-NMR spectra of Compound 17

[0049] Figure 20 1H-NMR and 13C-NMR spectra of Compound 18 Detailed Embodiments

[0050] In order to make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0051] Unless otherwise specified, the reagents used in this embodiment are all of analytical grade, and the progress of all chemical reactions is detected by thin-layer chromatography.

[0052] Synthesis of Tertiary Amine Compounds with Indan Skeleton in Example 1

[0053] Dissolve the first intermediate (2.0 mmol) in methanol (50.0 mL). Under N 2 protection conditions, add the corresponding amine compound (2.4 mmol) and titanium tetraisopropoxide (6.75 mmol) thereto. After reacting at 66 °C for two hours, add sodium cyanoborohydride (5.0 mmol) thereto and continue to reflux overnight at 66 °C. After the reaction is complete, quench with saturated sodium bicarbonate solution, extract with dichloromethane, and then perform a conventional water removal operation. After rotary evaporation, perform column chromatography separation to obtain a mixture of the second intermediate, concentrate it, and purify it by column chromatography (PE / acetone = 10:1).

[0054] Dissolve the second intermediate (1.0 mmol) in N,N-dimethylformamide (DMF), add the halide of the modifying group (1.2 mmol), potassium carbonate (1.2 mmol), and react at 66 °C. After the reaction is complete, add 30 mL of water and extract with DCM (20 mL × 3 times). Combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate under a rotary evaporator to obtain a mixture. This mixture is separated and purified by column chromatography (PE / acetone = 5:1) to obtain Compounds 1-18 respectively.

[0055] The structural diagrams of the tertiary amine compounds 1-18 with indan skeleton described in the present invention are shown as follows:

[0056]

[0057] Use 1H NMR and 13C NMR to determine the structure of Compound 1, colorless oil droplets, yield: 37.6%,

[0058] 1 H NMR (600 MHz, CDCl 3) δ 7.39 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.25–7.23 (m, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.01 (dd, J = 8.3, 2.0 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 4.46 (dd, J = 9.7, 7.0 Hz, 1H), 4.09–4.05 (m, 1H), 2.51 (dd, J = 12.4, 7.2 Hz, 1H), 2.48–2.44 (m, 1H), 2.35 (ddd, J = 12.0, 8.7, 5.5 Hz, 1H), 2.26 (s, 3H), 1.85 (dt, J = 12.3, 10.0 Hz, 1H), 1.54–1.47 (m, 2H), 1.32–1.25 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H).

[0059] 13 C NMR (151 MHz, CDCl 3 ) δ 145.51, 144.61, 144.58, 132.44, 130.47, 130.30, 130.19, 127.71, 127.52, 127.07, 124.70, 124.68, 68.36, 53.64, 47.68, 37.82, 34.86, 31.86, 28.33, 27.07, 22.67, 14.08.

[0060] The structure of compound 2 was determined by 1H NMR and 13C NMR. It was a colorless oil drop with a yield of 42.2%.

[0061] 1 1H NMR (600 MHz, CDCl 3 ) δ 7.42 (dd, J = 11.1, 7.8 Hz, 3H), 7.24 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 7.5 Hz, 1H), 4.49 (dd, J = 9.8, 7.0 Hz, 1H), 4.09 (dd, J = 10.4, 7.8 Hz, 1H), 2.54–2.47 (m, 2H), 2.40–2.35 (m, 1H), 2.28 (s, 3H), 1.89 (dt, J = 12.5, 10.2 Hz, 1H), 1.56–1.50 (m, 2H), 1.31–1.25 (m, 10H), 0.88 (t, J = 6.9 Hz, 3H).

[0062] 1313C NMR (151 MHz, CDCl 3 ) δ 145.26, 144.53, 144.21, 131.59, 130.03, 127.41, 126.86, 124.77, 124.60, 120.15, 68.39, 53.64, 47.93, 37.81, 34.94, 31.87, 29.61, 29.32, 28.36, 27.42, 22.66, 14.10.

[0063] The structure of compound 3 was determined by 1H NMR and 13C NMR. It was a light yellow oil drop with a yield of 34.5%.

[0064] 1 1H NMR (600 MHz, CDCl 3 ) δ 7.45 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.29 (t, J = 7.4 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.05 (dd, J = 8.2, 2.0 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 4.51 (dd, J = 9.6, 7.1 Hz, 1H), 4.11 (t, J = 9.0 Hz, 1H), 2.53 (dt, J = 13.0, 6.2 Hz, 2H), 2.43–2.39 (m, 1H), 2.31 (s, 3H), 1.90 (d, J = 11.4 Hz, 1H), 1.56 (q, J = 6.8 Hz, 2H), 1.31 (h, J = 7.9 Hz, 11H), 0.91 (t, J = 6.8 Hz, 3H).

[0065] 13 13C NMR (151 MHz, CDCl 3 ) δ 145.54, 144.61, 144.59, 132.48, 130.48, 130.33, 130.21, 127.70, 127.54, 127.08, 124.73, 124.70, 68.38, 53.70, 47.71, 37.77, 34.88, 31.88, 29.62, 29.33, 28.37, 27.41, 22.67, 14.10.

[0067] The structure of compound 4 was determined by 1H NMR and 13C NMR. It was a light yellow oil drop with a yield of 32.3%.

[0068] 1 1H NMR (600 MHz, CDCl 3) δ 7.40 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.25–7.23 (m, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 4.49–4.45 (m, 1H), 4.09–4.05 (m, 1H), 2.50 (s, 2H), 2.37 (s, 1H), 2.27 (s, 3H), 1.87 (s, 1H), 1.51 (s, 2H), 1.35 (s, 2H), 0.90 (t, J = 7.4 Hz, 3H).

[0069] 13 C NMR (151 MHz, CDCl 3 ) δ 145.51, 144.60, 144.54, 132.46, 130.48, 130.31, 130.19, 127.70, 127.54, 127.08, 124.70, 68.36, 53.40, 47.69, 37.75, 34.86, 30.54, 20.55, 14.12.

[0071] The structure of compound 5 was determined by 1H NMR and 13C NMR. It was a light yellow oil drop with a yield of 35.6%.

[0072] 1 1H NMR (600 MHz, CDCl 3 ) δ 7.78 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 6.94 (dd, J = 12.4, 8.0 Hz, 2H), 4.65 (t, J = 9.0 Hz, 1H), 4.54 (t, J = 8.3 Hz, 1H), 2.67 (dt, J = 14.5, 7.8 Hz, 1H), 2.47 (s, 1H), 2.36 (s, 1H), 2.26 (s, 3H), 1.75 (s, 1H), 1.55 (s, 2H), 1.30 (s, 10H), 0.90 (t, J = 6.9 Hz, 3H).

[0073] 13 C NMR (151 MHz, CDCl 3)δ144.80,143.97,143.76,134.90,130.90,130.36,127.52,127.05,125.47,124.93,124.82,120.32,68.33,53.67,47.02,37.77,33.27,31.88,29.61,29.33,28.34,27.41,22.67,14.12.

[0075] The structure of compound 6 was determined by \(^1H\) NMR and \(^{13}C\) NMR. It is a colorless oil drop with a yield of 37.6%.

[0076] 1 \(^1H\) NMR (600 MHz, CDCl 3 )δ7.40 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.27 (s, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.17 (t, J =

[0077] 7.4 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 4.49–4.45 (m, 1H), 4.10–4.05 (m, 1H), 2.49 (s, 2H), 2.36 (s, 1H), 2.27 (s, 3H), 1.86 (q, J = 10.6 Hz, 1H), 1.51 (s, 2H), 1.25 (s, 14H), 0.86 (t, J = 6.9 Hz, 3H).

[0078] 13 \(^{13}C\) NMR (151 MHz, CDCl 3 )δ145.49,144.62,132.44,130.48,130.31,130.19,127.71,127.55,127.08,124.71,124.70,68.35,53.61,47.67,37.83,34.86,31.90,29.66,29.65,29.60,29.33,28.34,27.39,22.68,14.11.

[0081] The structure of compound 7 was determined by \(^1H\) NMR and \(^{13}C\) NMR. It is a colorless oil drop with a yield of 41.5%.

[0082] 1 \(^1H\) NMR (600 MHz, CDCl 3)δ 7.43 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 7.1 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.01 (dd, J = 8.1, 2.1 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 4.48 (dd, J = 9.7, 7.0 Hz, 1H), 4.07 (dd, J = 10.4, 7.7 Hz, 1H), 3.64–3.57 (m, 6H), 3.52 (q, J = 7.0 Hz, 2H), 2.80–2.75 (m, 1H), 2.57 (dd, J = 12.8, 6.9 Hz, 2H), 2.39 (s, 3H), 1.86–

[0083] 1.80 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H).

[0084] 13 C NMR (151 MHz, CDCl 3 )δ 145.33, 144.66, 144.12, 132.46, 130.50, 130.36, 130.19, 127.71, 127.67, 127.16, 124.75, 124.71, 70.54, 70.09, 69.84, 68.91, 66.65, 52.36, 47.60, 39.19, 35.49, 15.12.

[0086] The structure of compound 8 was determined by 1H NMR and 13C NMR. It was a colorless oil drop with a yield of 32.1%.

[0087] 1 1H NMR (600 MHz, CDCl 3 )δ 7.32 (t, J = 7.5 Hz, 2H), 7.24 (d, J = 7.3 Hz, 1H), 7.22–7.19 (m, 2H), 7.18–7.09 (m, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 4.52 (s, 1H), 4.11 (t, J = 9.0 Hz, 1H), 2.54 (s, 2H), 2.36 (d, J = 9.4 Hz, 4H), 2.33 (s, 3H), 1.94 (s, 1H), 1.60–1.55 (m, 2H), 1.30 (s, 6H), 1.26 (s, 1H), 0.89 (t, J = 6.9 Hz, 4H).

[0088] 13 C NMR (151 MHz, CDCl 3)δ145.28,143.04,129.21,128.48,128.31,128.24,128.16,126.35,125.01,124.69,68.24,53.67,48.07,35.05,31.82,29.68,27.10,22.66,21.29,14.05.

[0089] The structure of compound 9 was determined by ¹H NMR and ¹³C NMR. It is a yellow oil drop with a yield of 33.2%.

[0090] 1 H NMR(600MHz,CDCl 3 )δ7.27(s,1H),7.25(s,1H),7.15(s,4H),6.89(d,J = 8.1Hz,2H),3.83(s,3H),3.46(dd,J = 9.1,5.5Hz,1H),2.50(s,2H),2.37(s,1H),2.20(s,2H),2.15(s,3H),1.42(s,2H),1.26(s,6H),0.87(t,J = 7.0Hz,3H).

[0091] 13 C NMR(151MHz,CDCl 3 )δ158.55,142.48,129.82,128.41,128.24,125.64,113.29,67.15,55.18,54.01,38.12,34.40,32.96,31.82,29.68,27.17,22.64,14.05.

[0092] The structure of compound 10 was determined by ¹H NMR and ¹³C NMR. It is a colorless oil drop with a yield of 36.6%.

[0093] 1 H NMR(600MHz,CDCl 3 )δ7.41–7.36(m,3H),7.28–7.26(m,1H),7.26–7.23(m,1H),7.22–7.19(m,1H),7.11(dd,J = 8.1,2.1Hz,1H),4.37(t,J = 8.2Hz,1H),3.35–3.26(m,2H),2.65(dd,J = 13.6,9.5Hz,1H),2.44–2.39(m,1H),2.31(ddd,J =

[0094] 12.1, 8.9, 5.4 Hz, 1H), 2.23 (s, 3H), 2.09 (dt, J = 12.3, 7.2 Hz, 1H), 1.58–1.48 (m, 3H), 1.33–1.27 (m, 6H), 0.90 (t, J = 6.9 Hz, 3H).

[0095] 13 C NMR (151 MHz, CDCl 3 ) δ 140.38, 139.72, 136.18, 127.51, 126.05, 125.51, 125.25, 123.64, 122.44, 122.11, 120.10, 118.40, 63.38, 48.86, 38.01, 35.47, 33.17, 27.10, 25.32, 23.60, 22.32, 17.92, 9.38.

[0097] The structure of compound 11 was determined by 1H NMR and 13C NMR. It was a colorless oil drop with a yield of 38.5%.

[0098] 1 H NMR (600 MHz, CDCl 3 ) δ 7.36–7.34 (m, 1H), 7.23 (s, 2H), 7.21 (s, 1H), 4.40 (dd, J = 9.8, 7.1 Hz, 1H), 3.01 (s, 1H), 2.45 (s, 1H), 2.35 (s, 1H), 2.27 (s, 3H), 1.52 (s, 3H), 1.34 (s, 10H), 0.90 (t, J = 6.9 Hz, 3H).

[0099] 13 C NMR (151 MHz, CDCl 3 ) δ 147.66, 144.22, 127.03, 126.18, 124.40, 122.98, 68.44, 53.62, 38.04, 36.13, 32.80, 31.90, 28.44, 27.14, 22.69, 19.52, 14.08.

[0100] The structure of compound 12 was determined by 1H NMR and 13C NMR. It was a yellow oil drop with a yield of 39.6%.

[0101] 1 H NMR (600 MHz, CDCl 3)δ 7.35 (d, J = 6.7 Hz, 1H), 7.22–7.18 (m, 3H), 4.37 (t, J = 8.5 Hz, 1H), 3.01 (td, J = 7.5, 3.9 Hz, 1H), 2.46 (dt, J = 8.9, 5.5 Hz, 1H), 2.40–2.36 (m, 2H), 2.00 (dd, J = 12.3, 7.5 Hz, 1H), 1.75–1.70 (m, 1H), 1.53 (ddt, J = 15.6, 10.9, 5.6 Hz, 2H), 1.34–1.28 (m, 6H), 1.07 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 6.8 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H).

[0102] 13 C NMR (151 MHz, CDCl 3 )δ 145.44, 144.92, 126.88, 126.15, 124.55, 123.59, 67.97, 53.64, 47.42, 37.96, 31.89, 29.00, 28.43, 27.15, 23.43, 22.68, 21.36, 16.58, 14.08.

[0103] The structure of compound 13 was determined by 1H NMR and 13C NMR. It was a colorless oil drop with a yield of 41.3%.

[0104] 1 1H NMR (600 MHz, CDCl 3 )δ 7.40 (t, J = 8.2 Hz, 2H), 7.30–7.27 (m, 2H), 7.01 (dd, J = 8.2, 2.1 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 4.41 (dd, J = 9.7, 7.0 Hz, 1H), 4.06 (dd, J = 10.4, 7.8 Hz, 1H), 2.54–2.44 (m, 2H), 2.40–2.35 (m, 1H), 1.91 (dt, J = 12.4, 10.1 Hz, 1H), 1.56–1.49 (m, 2H), 1.37–1.25 (m, 8H), 0.90 (t, J =

[0105] 6.9 Hz, 3H).

[0106] 13 C NMR (151 MHz, CDCl 3)δ146.89,144.50,143.64,132.64,130.71,130.67,130.29,130.14,127.77,127.57,126.24,121.30,67.88,53.65,47.50,37.63,34.76,31.82,28.26,27.00,22.64,14.04.

[0108] The structure of compound 14 was determined by 1H NMR and 13C NMR. It is a yellow oil drop with a yield of 31.6%.

[0109] 1 H NMR(600MHz,CDCl 3 )δ7.54(d,J = 7.8Hz,1H),7.52–7.44(m,3H),7.34(d,J = 7.7Hz,1H),6.91(s,1H),4.45(dd,J = 9.8,7.0Hz,1H),4.15(dd,J = 10.5,7.7Hz,1H),2.60–2.54(m,1H),2.50–2.39(m,2H),2.27(s,3H),2.01–1.95(m,1H),1.56–

[0110] 1.49(m,2H),1.35–1.28(m,6H),0.90(t,J = 7.0Hz,3H).

[0111] 13 C NMR(151MHz,CDCl 3 )δ145.28,143.04,129.21,128.48,128.31,128.24,128.16,126.35,125.01,124.69,68.24,53.67,48.07,35.05,31.82,29.68,27.10,22.66,21.29,14.05.

[0112] The structure of compound 15 was determined by 1H NMR and 13C NMR. It is a colorless oil drop with a yield of 41.4%.

[0113] 1 H NMR(600MHz,CDCl 3)δ7.44(d, J = 7.6 Hz, 1H), 7.40(d, J = 8.2 Hz, 1H), 7.32(d, J = 2.0 Hz, 1H), 7.28(t, J = 7.4 Hz, 1H), 7.20(t, J = 7.4 Hz, 1H), 7.06(dd, J = 8.3, 2.1 Hz, 1H), 6.88(d, J = 7.5 Hz, 1H), 4.58(dd, J = 9.9, 6.8 Hz, 1H), 4.10(dd, J = 10.6, 7.6 Hz, 1H), 2.70–2.64(m, 1H), 2.62–2.55(m, 2H), 2.44(dt, J = 12.7, 7.4 Hz, 2H), 1.86(dt, J = 12.3, 10.3 Hz, 1H), 1.54(dtt, J = 10.2, 7.5, 4.7 Hz, 2H), 1.41–1.29(m, 6H), 1.13(t, J = 7.1 Hz, 3H), 0.92(t, J = 7.0 Hz, 3H).

[0114] 13 C NMR(151MHz, CDCl 3 )δ145.61, 145.58, 144.46, 132.45, 130.46, 130.28, 130.21, 127.72, 127.37, 127.01, 124.59, 124.44, 65.47, 50.47, 47.79, 44.60, 36.70, 31.88, 28.83, 27.10, 22.70, 14.34.

[0116] The structure of compound 16 was determined by 1H NMR and 13C NMR. It was a colorless oil drop with a yield of 32.1%.

[0117] 1 1H NMR(600MHz, CDCl 3)δ 7.42 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.25–7.23 (m, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.02 (dd, J = 8.3, 2.1 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 4.67 (dd, J = 9.9, 6.9 Hz, 1H), 4.06 (dd, J = 10.6, 7.6 Hz, 1H), 2.61 (dt, J = 12.6, 7.9 Hz, 1H), 2.55 (ddd, J = 10.7, 8.3, 4.9 Hz, 2H), 2.41 (ddd, J = 12.9, 8.2, 5.0 Hz, 1H), 2.21 (dd, J = 13.1, 6.9 Hz, 1H), 1.81 (dt, J = 12.2, 10.3 Hz, 1H), 1.51 (td, J = 8.2, 4.0 Hz, 2H), 1.40–1.33 (m, 1H), 1.31–1.22 (m, 6H), 0.87 (t, J = 6.9 Hz, 4H), 0.53 (dt, J = 8.3, 4.4 Hz, 1H), 0.43 (dt, J = 8.6, 4.3 Hz, 1H), 0.10 (ddt, J = 22.0, 9.2, 4.5 Hz, 2H).

[0120] 13 C NMR (151 MHz, CDCl 3 )δ 145.56, 144.44, 132.41, 130.46, 130.25, 130.22, 130.19, 127.73, 127.36, 126.98, 124.58, 124.54, 65.59, 55.64, 50.46, 47.77, 36.67, 31.87, 28.66, 27.09, 22.70, 14.08, 10.28, 5.20, 2.84.

[0122] The structure of compound 17 was determined by 1H NMR and 13C NMR. It was a colorless oil drop with a yield of 36.9%.

[0123] 1 1H NMR (600 MHz, CDCl 3) δ 7.46 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.30 (s, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.61–4.57 (m, 1H), 4.12–4.08 (m, 1H), 2.52 (s, 1H), 2.45 (dd, J = 12.5, 6.4 Hz, 1H), 2.40 (s, 3H), 2.27 (dd, J = 12.5, 6.6 Hz, 1H), 1.89–1.82 (m, 1H), 0.95 (d, J = 6.8 Hz, 1H), 0.56 (s, 2H), 0.13 (s, 2H).

[0125] 13 C NMR (151 MHz, CDCl 3 ) δ 145.46, 144.61, 144.42, 132.46, 130.48, 130.33, 130.18, 127.69, 127.58, 127.11, 124.74, 124.69, 68.21, 58.43, 47.68, 38.22, 34.95, 9.98, 4.41, 3.40.

[0126] The structure of compound 18 was determined by 1H NMR and 13C NMR. It was a colorless oil drop with a yield of 39.3%.

[0127] 1 1H NMR (600 MHz, CDCl 3 ) δ 7.45 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.32–7.27 (m, 4H), 7.21 (dd, J = 14.0, 7.2 Hz, 4H), 7.03 (dd, J = 8.2, 2.1 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 4.50 (t, J = 8.4 Hz, 1H), 4.11 (t, J = 9.0 Hz, 1H), 2.76 (ddd, J = 15.2, 9.0, 6.6 Hz, 1H), 2.67 (ddd, J = 14.4, 8.9, 6.2 Hz, 1H), 2.52 (dtt, J = 31.6, 12.6, 6.5 Hz, 3H), 2.30 (s, 3H), 1.89 (dd, J = 14.4, 7.1 Hz, 3H).

[0128] 13 13C NMR (151 MHz, CDCl 3)δ145.48, 144.61, 142.40, 132.47, 130.49, 130.34, 130.18, 128.41, 128.29, 127.69, 127.61, 127.14, 125.69, 124.75, 124.71, 68.32, 53.18, 47.69, 37.38, 34.85, 33.43, 29.90.

[0129] Protective effects of Compounds 1 - 18 in Example 2 on OGD - damaged mouse cerebral cortical neurons in the concentration range of 0.5 - 50 μM:

[0130] (1) Cell culture:

[0131] Primary cerebral cortical neurons were extracted from pregnant C57BL / 6J mice (15 - 16 days pregnant) in this experiment. All animals in this experiment were obtained from the Experimental Animal Center of Army Medical University of the Chinese People's Liberation Army. After decapitating the pregnant mice, the uterus was immediately removed under sterile conditions and placed in a 10 - cm culture dish containing cold DMEM medium (Gibco, USA). The uterine membrane and extra - embryonic membrane were separated with forceps, the yolk sac and amnion were peeled off, the fetal mice were taken out, the scalp and skull were cut open, and the brain was removed. After separating the cerebrovascular membrane under a microscope with micro - forceps, the cerebral cortex was separated along the ventral side of the cerebellum and brainstem with sharp forceps. The cerebral cortex was transferred to a new sterile culture dish and digested with 0.125% trypsin (Gibco, USA) at 37°C for 5 min. Then, DMEM medium containing 10% fetal bovine serum (FBS, Gibco, USA), 1% penicillin - streptomycin double - antibody (Gibco, USA) was added to terminate the digestion. The tissue was gently dispersed and centrifuged for 5 min (1000×rpm, 4°C), the supernatant was discarded, the cells were resuspended, and filtered through a 70 - μm cell strainer. After counting with a counting plate, the obtained cell suspension was diluted to 4×10 5 cells / mL, and the cells were seeded into a 96 - well plate treated with poly - L - lysine (Sigma, USA) at a density of 4×10 4 cells per well, and then incubated in a 37°C constant - temperature cell incubator containing 5% CO 2 . After 4 h of incubation, the DMEM medium was replaced with serum - free neuron - specific medium (Neurobasal, Gibco, USA) supplemented with 2% B27 (Gibco, USA), 1% L - alanyl - L - glutamine (GlutaMAX, Gibco, USA) and 1% penicillin - streptomycin double - antibody solution (Gibco, USA) for continued incubation. The medium was changed every 3.5 days.

[0132] (2) Establishment of OGD injury model

[0133] After rinsing the primary cortical neurons with sugar-free Earle's balanced buffer, the medium was changed to sugar-free and serum-free DMEM medium (Gibco, USA) and incubated in an anaerobic incubator at 37 °C containing 95% N 2 and 5% CO 2 for 2 hours to establish an oxygen-glucose deprivation (OGD) model. After that, the sugar-free and serum-free DMEM medium was replaced with Neurobasal containing 2% B27, 1% GlutaMAX, 1% penicillin-streptomycin, and 0.2 - 20 μmol / L of the test compound, and incubated in a CO 2 cell incubator (5%, 37 °C) for another 24 hours.

[0134] (3) Cell viability assay:

[0135] All test compounds 1 - 18 were dissolved in DMSO to a 50 mM solution, and then diluted to 1.0 μM, 5.0 μM, and 20 μM with Neurobasal respectively. The cells in the OGD group were treated with Neurobasal containing different concentrations of the test compound for 24 hours, and the control group was added with the same concentration of DMSO as the 20 μM test compound. After 24 hours, 10 μL of Cell Counting Kit-8 (CCK8, Beyotime, China) was added to each well and incubated at 37 °C in the dark for 3 hours. After observing an obvious color change, the absorbance at 450 nm was measured using a SpectraMax i3 multi-functional microplate reader (Molecular Devices, USA). Table 1 is a summary table of the cell viability values of compounds 1 - 18, Figure 1 which is the cell viability graph.

[0136] Table 1

[0137]

[0138]

[0139] The compounds of the present invention have better neuroprotective effects than sertraline, with less toxic and side effects and significant specificity. The compounds of the present invention also showed good activity at a concentration of 20 μM, and even some could reach 1.30 or above (as described in Table 1), indicating high activity of the present invention. The present invention is the indane skeleton obtained after a more comprehensive skeletal transition of sertraline, providing a powerful transformation direction for the research and development of the treatment of ischemic reperfusion injury, and also providing a wider transformation space for the derivatives of sertraline. Therefore, the compounds of the present invention have better activity.

[0140] (4) Establishment of the MCAO model:

[0141] The animals used in the experiment were male C57BL / 6J mice (6 - 8 weeks old, 23 ± 3 g), purchased from the Experimental Animal Center of the Army Medical University of the Chinese People's Liberation Army. All experimental procedures followed the "Guide for the Care and Use of Laboratory Animals of the Chinese Academy of Medical Sciences" and were approved by the Experimental Animal Welfare and Ethics Committee of the Army Medical University of the Chinese People's Liberation Army, with the approval number AMUWEC2020522. Before the experiment, the mice were housed in an animal room with a 12 / 12 - hour light / dark cycle, a constant temperature of 25°C, and provided with appropriate food and water.

[0142] Fifteen minutes before middle cerebral artery occlusion (MCAO), the mice were anesthetized with avertin (Dowell Biotech, China) (20 μL / g). Compound 1 was dissolved in a mixed solvent containing 2% DMSO (White Shark, China), 30% PEG400 (Sangon Biotech, Shanghai), 5% Tween - 80 (Sangon Biotech, Shanghai), and 63% ddH2O to obtain a solution with a final concentration of 4 mg / mL. After the mice were anesthetized, equal volumes of Compound 1 or solvent control were injected intraperitoneally into the mice at concentrations of 10 mg / Kg or 20 mg / Kg, respectively. Then the mice were fixed on the operating table in the supine position, and the skin was disinfected and prepared. An incision was made along the midline of the neck, and under the microscope, blunt dissection was performed to expose the right common carotid artery (CCA), internal carotid artery (ICA), and external carotid artery (ECA). The distal and proximal ends of the ECA were ligated, the ICA and CCA were ligated in a single - strand manner, and the ECA was cut between the ligature lines at the distal and proximal ends. A small oblique cut was made with a micro - scissors proximal to the ligature line at the proximal end of the ECA, and the suture was slowly inserted. After the suture passed through the ECA and entered the ICA, the starting end of the ECA was tied with a single knot to relatively fix the suture to the blood vessel. Subsequently, the ligature line at the ICA end was loosened, and the suture was slowly inserted to the marked position. Ninety minutes after the suture was inserted, it was removed, the ligature line at the proximal end of the ECA was ligated, the ligature line at the CCA was loosened, and the wound was sutured after observing the restoration of blood flow. The body temperature of the animals was maintained at 37.0 ± 0.5°C throughout the surgical procedure. The sham - operation group underwent the same preparation and surgical procedures as the MCAO group, except for inserting the suture for infarction. Twenty - four hours after the operation, the neurological deficit scores of the mice were evaluated according to the Longa score. Then the mice were euthanized, the mouse brains were removed, stained with 2,3,5 - triphenyltetrazolium chloride (TTC, Sigma), and the infarct area was quantified by computer - assisted image analysis. The TTC - staining display diagram is as Figure 2 , and the summary table of MCAO data for Compound 1 is shown in Table 2.

[0143] Table 2 Summary table of MCAO data for Compound 1

[0144] Solvent group 10 mg / kg Number of samples 14 11 Number of deaths 3 1 Mortality rate (%) 21.4 9.10

Claims

1. A tertiary amine compound having a dihydroindene skeleton, characterized in that: The general structural formula of the compound is shown below: Wherein R is phenyl or substituted phenyl, benzyl or benzyl substituted with a benzene ring, straight chain or branched alkyl; R1 is a saturated straight chain or branched alkyl group, a benzene ring-containing alkyl group, or a polyethylene glycol chain; R2 is a straight chain or branched alkyl group; R3 is a trifluoromethyl group or a halogen element.

2. The compound according to claim 1, characterized in that: The halogen element is bromine or iodine.

3. The method for preparing a tertiary amine compound having a dihydroindene skeleton according to claim 1 or 2, characterized in that: The following steps are involved: 1) The first intermediate is dissolved in a methanol solution, and under N2 protection, a primary amine compound substituted with a modifying group to which R1 belongs and tetraisopropyl titanate are added, and the reaction is carried out at 66° C. for 2 hours, and sodium cyanoborohydride is added, and the reaction is carried out at 66° C. until the reaction is complete, and the reaction is quenched with a saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated NaCl, and then dried with anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a second intermediate compound; The equivalent ratio of the first intermediate compound to the primary amine compound, tetraisopropyl titanate, and sodium cyanoborohydride is 1:1.2:3.4:2.5; 2) The second intermediate is dissolved in N,N-dimethylformamide (DMF), and a halide and a base of the modification group to which R2 belongs are added, and the mixture is reacted at 66° C. After the reaction is completed by TLC monitoring, the mixture is cooled to room temperature, and water is added to quench the reaction. The mixture is extracted, dehydrated, concentrated, and purified by column chromatography to obtain a tertiary amine compound with a dihydroindene skeleton; The equivalent ratio of the second intermediate to the halide of the modifying group and the base is 1:1.2:2.

5.

4. The method according to claim 3, characterized in that In step 1), R in the first intermediate is any one of phenyl or substituted phenyl, benzyl or benzyl substituted with a benzene ring, and straight-chain or branched alkyl.

5. The method according to claim 3, characterized in that: The primary amine compound substituted with the R1 modifying group in step 1) is shown in III: R1-NH2 Type III, Among them, R1 is a straight chain or branched chain alkyl group.

6. The method according to claim 3, characterized in that In step 1), the halide of the modifying group of the second intermediate R2 is as shown in Formula V, X-R2 V-style Wherein, X is bromine or iodine; R2 is a saturated straight-chain or branched alkane group, a benzene ring-containing alkyl group, or a polyethylene glycol chain.

7. The method according to claim 6, characterized in that When X is bromine, 0.2 equivalents of potassium iodide need to be added as a catalyst.

8. The method according to claim 3, characterized in that Step 2) The base is potassium carbonate or sodium hydride.

9. Use of the tertiary amine compound having a dihydroindene skeleton according to claim 1 in the preparation of a drug for treating ischemic stroke reperfusion injury.

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