Cyclopropyl quinoline compound as well as preparation method and application thereof

Abstract

The invention discloses a cyclopropyl quinoline compound as well as a preparation method and application thereof. The cyclopropyl quinoline compound disclosed by the invention has a structure as shown in a formula I: # imgabs0 #, wherein R1 is selected from H, halogen, alkyl of C1-6 and alkoxy of C1-6; and R2 is selected from H, halogen, alkyl of C1-6 and alkoxy of C1-6. The series of compounds have a relatively strong protection effect on nerve cells, and have a wide development prospect as a neuroprotective agent.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a cyclopropyl-fused quinoline compound, a preparation method and an application thereof. Background Art

[0002] Stroke is one of the common cardiovascular and cerebrovascular diseases. The incidence of ischemic stroke accounts for about 80% of the total stroke, seriously threatening human health. In the past decade, research has mainly focused on exploring more effective treatment strategies to reduce stroke-induced death and disability. A variety of drugs have been explored in clinical trials and animal models, but there is still a lack of effective treatment strategies. In addition, there is no preventive use of neuroprotective agents. Therefore, new compounds with new structural features and new mechanisms of action are needed, and this field has a broad market and clinical demand.

[0003] Therefore, it is necessary to develop a compound with novel structure and promising for use as a neuroprotective agent. Summary of the Invention

[0004] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, in the first aspect, the present invention provides a cyclopropyl-fused quinoline compound, which has a strong protective effect on nerve cells.

[0005] In the second aspect, the present invention also provides a preparation method of the cyclopropyl-fused quinoline compound.

[0006] In the third aspect, the present invention also provides a pharmaceutical composition.

[0007] In the fourth aspect, the present invention also provides an application.

[0008] According to the first aspect of the present invention, there is provided a cyclopropyl-fused quinoline compound having the structure shown in Formula I:

[0009]

[0010] Wherein, R1 is selected from H, halogen, C 1～6 alkyl, C 1～6 alkoxy; R2 is selected from H, halogen, C 1～6 alkyl, C 1～6 alkoxy.

[0011] According to a preferred embodiment of the present invention, R1 is selected from H, halogen, C 1～3 alkyl.

[0012] According to a preferred embodiment of the present invention, R2 is selected from H, halogen, C 1～3 alkyl.

[0013] According to a preferred embodiment of the present invention, the cyclopropylquinoline compound is selected from the following structural formula:

[0014]

[0015] The cyclopropylquinoline compounds according to the embodiments of the present invention have at least the following beneficial effects:

[0016] The invention provides a series of novel 2-trifluoromethyl-substituted cyclopropylquinoline compounds; the series of compounds have a strong protective effect on nerve cells and have broad development prospects as a neuroprotective agent.

[0017] According to a second aspect of the present invention, there is provided a method for preparing the cyclopropylquinoline compound as described in the first aspect of the present invention, comprising the following steps:

[0018] Trimethyl sulfoxide iodide, compound 1, a base and an organic solvent are mixed and reacted to obtain an intermediate I; and the intermediate I is heated to obtain;

[0019] Wherein, the structural formulas of the compound 1 and intermediate I are as follows:

[0020]

[0021] The definitions of R1 and R2 in the present invention are the same as those mentioned above.

[0022] According to a preferred embodiment of the present invention, the molar ratio of the compound 1, trimethyl sulfoxide iodide and the base is 1:(2-3):(2-3).

[0023] According to a preferred embodiment of the present invention, the molar ratio of the compound 1 to the organic solvent is 1:(1-2).

[0024] According to a preferred embodiment of the present invention, the base includes at least one of potassium tert-butoxide, sodium tert-butoxide and triethylamine.

[0025] According to a preferred embodiment of the present invention, the organic solvent includes at least one of tetrahydrofuran, acetonitrile, toluene and N,N-dimethylformamide.

[0026] According to a preferred embodiment of the present invention, in step S2, the heating temperature is 100-120°C.

[0027] According to a preferred embodiment of the present invention, in step S2, the heating time is 6 to 8 hours.

[0028] According to a preferred embodiment of the present invention, a purification step is further included after the reaction is completed.

[0029] According to a preferred embodiment of the present invention, the purification includes column chromatography.

[0030] According to a preferred embodiment of the present invention, the conditions of the column chromatography include: the mesh number of the silica gel column is 200 - 300 meshes; the mobile phase component is petroleum ether: ethyl acetate = 90:1.

[0031] The preparation method of the cyclopropyl - fused quinoline compounds according to the embodiment of the present invention has at least the following beneficial effects:

[0032] In the present invention, by using compound 1 as a reaction raw material, the reaction can occur to obtain cyclopropyl - fused quinoline compounds without the use of a metal catalyst. Therefore, this method does not require the use of a metal catalyst and has the advantage of high economy.

[0033] Furthermore, this method is a one - pot preparation method, which has the advantages of simple operation and mild conditions.

[0034] The third aspect of the present invention provides a pharmaceutical composition, including the cyclopropyl - fused quinoline compounds described in the first aspect of the present invention; and pharmaceutically acceptable excipients.

[0035] The fourth aspect of the present invention provides the use of the cyclopropyl - fused quinoline compounds described in the first aspect of the present invention; or the pharmaceutical composition described in the third aspect of the present invention as a neuroprotective agent.

[0036] Definitions and general terms

[0037] "C 1～6 alkyl" means an alkyl group having 1 - 6 carbon atoms in total, including straight - chain alkyl groups of C 1-6 with straight - chain alkyl groups of C 1-6 branched - chain alkyl groups and C 3-6 cycloalkyl groups. For example, it can be a straight - chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms in total, a branched - chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms in total, or a cycloalkyl group having 3, 4, 5 or 6 carbon atoms in total. For example, it can be methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, tert - butyl, n - pentyl, isopentyl, n - hexyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, etc. The same explanation applies to "C 1-3 alkyl", except that the number of carbon atoms is different.

[0038] "C 1～6 alkoxy" means an alkoxy group having 1 - 6 carbon atoms in total, including straight - chain alkoxy groups of C 1-6 with straight - chain alkoxy groups of C 1-6 branched - chain alkoxy groups and C 2-6The cycloalkyloxy group can be, for example, a straight-chain alkoxy group having 1, 2, 3, 4, 5 or 6 carbon atoms in total, a branched-chain alkoxy group having 1, 2, 3, 4, 5 or 6 carbon atoms in total, or a cycloalkyloxy group having 2, 3, 4, 5 or 6 carbon atoms in total, and can be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, etc. For " 1-3 The alkoxy group" has a similar explanation, except that the number of carbon atoms is different.

[0039] "Halogen" includes any one or more of fluorine, chlorine, bromine and iodine.

[0040] "Pharmaceutically acceptable excipients" include any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder, glidant or lubricant, and the like, suitable for the particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988 - 1999, Marcel Dekker, New York, the combined content of the literature herein indicates that different excipients can be applied to the formulation of pharmaceutically acceptable compositions and their known preparation methods. Except to the extent that any conventional excipient is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other components of the pharmaceutically acceptable composition in a harmful manner, their use is also contemplated within the scope of the present invention. Substances that can serve as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene - polypropylene - block polymers; lanolin; sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; diol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen - free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solution; and other non - toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; release agents; coating materials; sweetening agents; flavoring agents; fragrances; preservatives, and antioxidants.

[0041] Other features and advantages of the present invention will be set forth in the following description, and in part will be obvious from the description, or may be learned by practice of the present invention. Brief Description of the Drawings

[0042] The above and / or additional aspects and advantages of the present invention will become apparent and be readily understood from the description of the embodiments in conjunction with the following drawings, where:

[0043] Figure 1 1H NMR spectrum of the synthesized product in Example 1 1 1H NMR spectrum.

[0044] Figure 2 13C NMR spectrum of the synthesized product in Example 1 13 13C NMR spectrum.

[0045] Figure 3 1H NMR spectrum of the synthesized product in Example 2 1 1H NMR spectrum.

[0046] Figure 4 13C NMR spectrum of the synthesized product in Example 2 13 13C NMR spectrum.

[0047] Figure 5 1H NMR spectrum of the synthesized product in Example 3 1 1H NMR spectrum.

[0048] Figure 6 13C NMR spectrum of the synthesized product in Example 3 13 13C NMR spectrum.

[0049] Figure 7 1H NMR spectrum of the synthesized product in Example 4 1 1H NMR spectrum.

[0050] Figure 8 13C NMR spectrum of the synthesized product in Example 4 13 13C NMR spectrum.

[0051] Figure 9 1H NMR spectrum of the synthesized product in Example 5 1 1H NMR spectrum.

[0052] Figure 10 13C NMR spectrum of the synthesized product in Example 5 13 13C NMR spectrum.

[0053] Figure 11 1H NMR spectrum of the synthesized product in Example 6 1 1H NMR spectrum.

[0054] Figure 12 13C NMR spectrum of the synthesized product in Example 6 13 13C NMR spectrum.

[0055] Figure 13 Activity diagram of the compound prepared in the embodiment of the present invention on nerve cells;

[0056] Figure 14 Cytotoxicity graph of the compound prepared for this invention against nerve cells. Detailed implementation manners

[0057] The following are specific embodiments of this invention, and the technical solutions of this invention will be further described in combination with the embodiments. However, this invention is not limited to these embodiments.

[0058] The reagents, methods, and equipment used in this invention are all conventional reagents, methods, and equipment in this technical field unless otherwise specified.

[0059] Example 1

[0060] This example provides a cyclopropyl-fused quinoline compound I-1; its reaction equation and preparation steps are as follows:

[0061]

[0062] In a 15 mL conventional reaction tube, a stir bar, dimethylsulfoxonium iodide (132 mg, 0.6 mmol), potassium tert-butoxide (67 mg, 0.6 mmol), and tetrahydrofuran (2 mL) were successively added and reacted at room temperature for 2 hours. Then, a trifluoromethyl-phenylacetamide chloroformate compound (69 mg, 0.2 mmol) was added and reacted at room temperature for 3 hours to obtain an intermediate; the intermediate was then reacted at 100 °C for 8 h.

[0063] After the reaction was completed, the reaction system was filtered by suction using diatomaceous earth, and separated by silica gel (200 - 300 mesh) column chromatography (the mobile phase component was petroleum ether:ethyl acetate = 90:1) to obtain 49 mg of a yellow oily liquid product.

[0064] Perform 1 1H NMR, 13 13C NMR analysis on the yellow oily liquid. The detection data (the corresponding spectra are as Figure 1 and Figure 2 shown) are as follows:

[0065] (1) 1 1H NMR (500 MHz, Chloroform-d) δ 7.67 (d, J = 2.3 Hz, 1H), 7.42–7.33 (m, 5H), 7.18 (dd, J = 8.4, 2.3 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 2.53 (d, J = 1.0 Hz, 2H), 0.40 (s, 1H).

[0066] (2) 1313C NMR (126 MHz, CDCl3) δ 156.5, 156.3, 156.0, 155.7, 140.7, 140.0, 132.6, 130.3, 130.1, 130.0, 129.14, 129.06, 128.9, 128.2, 123.5, 121.3, 119.1, 116.9, 77.3, 77.0, 76.8, 34.6, 25.1, 13.4.

[0067] From 1 1H NMR, 13 It can be known from the 1H NMR and 13C NMR test results that the yellow oily liquid product is a 2-trifluoromethyl-substituted cyclopropylquinoline compound.

[0068] Yield calculation method of 2-trifluoromethyl-substituted cyclopropylquinoline compounds:

[0069] Yield = mass of yellow oily liquid product / (theoretical mass of 2-trifluoromethyl-substituted cyclopropylquinoline compounds) * 100% = mass of yellow oily liquid product / (molar mass of 2-trifluoromethyl-substituted cyclopropylquinoline compounds * theoretical molar amount of 2-trifluoromethyl-substituted cyclopropylquinoline compounds) * 100%.

[0070] The yield of Example 1 calculated from the above is = 49 / (321.05 * 0.2) * 100% = 77%.

[0071] Example 2

[0072] This example provides a cyclopropylquinoline compound I-2; its reaction equation and preparation steps are as follows:

[0073]

[0074] A magnetic stir bar, dimethylsulfoxide iodide (132 mg, 0.6 mmol), potassium tert-butoxide (67 mg, 0.6 mmol) and tetrahydrofuran (2 mL) were successively added to a 15 mL conventional reaction tube and reacted at room temperature for 2 hours, then a trifluoromethyl-phenylacetamide chloroester compound (65 mg, 0.2 mmol) was added and reacted at room temperature for 3 hours to obtain an intermediate; the intermediate was heated to 100 °C and reacted for 8 h.

[0075] After the reaction was completed, the reaction system was filtered by suction with diatomaceous earth, and separated by silica gel (200 - 300 mesh) column chromatography (mobile phase component: petroleum ether: ethyl acetate = 90:1) to obtain 51 mg of a yellow oily liquid product.

[0076] Perform 1 1H NMR, 1313C NMR analysis, the test data (the corresponding spectrograms are as shown in Figure 3 and Figure 4 ) are as follows:

[0077] (1) 1 1H NMR (400 MHz, Chloroform-d) δ 7.64 (dd, J = 8.7, 5.6 Hz, 1H), 7.43–7.33 (m, 5H), 7.03–6.97 (m, 1H), 6.73 (dd, J = 9.3, 2.9 Hz, 1H), 2.55–2.46 (m, 2H), 0.44 (t, J = 3.9 Hz, 1H).

[0078] (2) 13 13C NMR (101 MHz, CDCl3) δ 163.8, 161.4, 154.3, 153.99, 153.96, 153.64, 153.61, 153.3, 140.5, 135.02, 135.00, 133.7, 133.6, 132.4, 132.3, 130.2, 129.0, 128.3, 124.5, 121.8, 119.0, 116.3, 114.9, 114.7, 114.4, 114.2, 77.3, 77.2, 77.0, 76.7, 34.8, 34.8, 24.5, 13.1.

[0079] From the 1 1H NMR and 13 13C NMR test results, it can be known that the yellow oily liquid product is a 2-trifluoromethyl-substituted cyclopropyl-fused quinoline compound.

[0080] The yield calculation method of the 2-trifluoromethyl-substituted cyclopropyl-fused quinoline compound is the same as that in Example 1. The yield of Example 2 = 51 / (305.08 * 0.2) * 100% = 83%.

[0081] Example 3

[0082] This example provides a cyclopropyl-fused quinoline compound I-3; its reaction equation and preparation steps are as follows:

[0083]

[0084] A magnetic stir bar, dimethylsulfoxonium iodide (132 mg, 0.6 mmol), potassium tert-butoxide (67 mg, 0.6 mmol) and tetrahydrofuran (2 mL) were successively added to a 15 mL conventional reaction tube and reacted at room temperature for 2 hours, then trifluoromethyl-phenylacetamide chloroester compound (65 mg, 0.2 mmol) was added and reacted at room temperature for 3 hours to obtain an intermediate; the intermediate was heated to 100 °C and reacted for 8 h.

[0085] After the reaction was completed, the reaction system was filtered by suction using diatomaceous earth, and separated by silica gel (200 - 300 mesh) column chromatography (the mobile phase was composed of petroleum ether: ethyl acetate = 90:1) to obtain 45 mg of a yellow oily liquid product.

[0086] The yellow oily liquid was subjected to 1 1H NMR, 13 13C NMR analysis, and the detection data (the corresponding spectra are as shown in Figure 5 and Figure 6 ) are as follows:

[0087] (1) 1 1H NMR (500 MHz, Chloroform - d) δ 7.66 (dd, J = 7.9, 1.4 Hz, 1H), 7.37–7.30 (m, 3H), 7.23 (td, J = 7.5, 1.4 Hz, 1H), 7.11–7.05 (m, 2H), 7.00 (dd, J = 7.7, 1.5 Hz, 1H), 2.50 (dd, J = 9.9, 4.8 Hz, 1H), 2.44 (dd, J = 9.9, 4.2 Hz, 1H), 0.42 (t, J = 4.4 Hz, 1H).

[0088] (2) 13 13C NMR (101 MHz, CDCl3) δ 163.5, 161.0, 155.0, 154.6, 154.26, 153.9, 138.5, 137.1, 137.1, 132.1, 132.0, 131.0, 130.6, 129.3, 127.8, 127.3, 124.5, 121.8, 119.0, 116.3, 115.8, 115.6, 77.3, 77.2, 77.0, 76.7, 33.9, 24.9, 13.3.

[0089] From the 1 1H NMR, 13 13C NMR test results, it can be known that the yellow oily liquid product is a 2 - trifluoromethyl - substituted cyclopropyl - fused quinoline compound.

[0090] The yield calculation method of the 2 - trifluoromethyl - substituted cyclopropyl - fused quinoline compound is the same as that in Example 1. The yield of Example 3 = 45 / (305.08 * 0.2) * 100% = 73%.

[0091] Example 4

[0092] This example provides a cyclopropyl - fused quinoline compound I - 4; its reaction equation and preparation steps are as follows:

[0093]

[0094] A magnetic stir bar, trimethylsulfoxonium iodide (132 mg, 0.6 mmol), potassium tert-butoxide (67 mg, 0.6 mmol) and tetrahydrofuran (2 mL) were successively added to a 15 mL conventional reaction tube and reacted at room temperature for 2 hours. Then, a trifluoromethyl-phenylacetamide chloroester compound (65 mg, 0.2 mmol) was added and reacted at room temperature for 3 hours to obtain an intermediate; the intermediate was heated to 100 °C and reacted for 8 h.

[0095] After the reaction was completed, the reaction system was filtered by suction using diatomaceous earth, and separated by silica gel (200 - 300 mesh) column chromatography (mobile phase component: petroleum ether: ethyl acetate = 90:1) to obtain 45 mg of a yellow oily liquid product.

[0096] The yellow oily liquid was subjected to 1 1H NMR, 13 13C NMR analysis, and the detection data (the corresponding spectra are as shown in Figure 7 and Figure 8 ) are as follows:

[0097] (1) 1 1H NMR (500 MHz, Chloroform-d) δ 7.67 (dd, J = 7.8, 1.4 Hz, 1H), 7.34–7.27 (m, 2H), 7.23 (td, J = 7.5, 1.4 Hz, 1H), 7.18 (q, J = 4.2 Hz, 3H), 7.06 (dd, J = 7.8, 1.5 Hz, 1H), 2.50 (qd, J = 9.8, 4.0 Hz, 2H), 2.38 (s, 3H), 0.40 (t, J = 4.0 Hz, 1H).

[0098] (2) 13 13C NMR (126 MHz, CDCl3) δ 155.0, 154.8, 154.5, 154.2, 141.2, 138.5, 138.5, 131.4, 131.1, 130.5, 129.2, 128.7, 128.6, 128.0, 127.3, 127.1, 123.8, 121.6, 119.4, 117.2, 77.3, 77.2, 77.0, 76.8, 34.7, 24.9, 21.3, 13.2.

[0099] From the 1 1H NMR, 13 13C NMR detection results, it can be known that the yellow oily liquid is a 2-trifluoromethyl-substituted cyclopropylquinoline compound.

[0100] The yield calculation method of 2-trifluoromethyl-substituted cyclopropylquinoline compounds is the same as that in Example 1. The yield of Example 4 = 45 / (301.11*0.2)*100% = 74%.

[0101] Example 5

[0102] This example provides a cyclopropylquinoline compound I-5; its reaction equation and preparation steps are as follows:

[0103]

[0104] A magnetic stir bar, trimethylsulfoxonium iodide (132 mg, 0.6 mmol), potassium tert-butoxide (67 mg, 0.6 mmol) and tetrahydrofuran (2 mL) were successively added to a 15 mL conventional reaction tube and reacted at room temperature for 2 hours. Then, a trifluoromethyl-phenylacetamide chloroester compound (65 mg, 0.2 mmol) was added and reacted at room temperature for 3 hours to obtain an intermediate; the intermediate was heated to 100 °C and reacted for 8 h.

[0105] After the reaction was completed, the reaction system was filtered through diatomaceous earth, and separated by silica gel (200-300 mesh) column chromatography (mobile phase component: petroleum ether: ethyl acetate = 90:1) to obtain 48 mg of a yellow oily liquid product.

[0106] Perform 1 1H NMR, 13 13C NMR analysis on the yellow oily liquid. The detection data (the corresponding spectra are as shown in Figure 9 and Figure 10 ) are as follows:

[0107] (1) 1 1H NMR (500 MHz, Chloroform-d) δ 7.67 (dd, J = 7.9, 1.4 Hz, 1H), 7.31 (td, J = 7.6, 1.5 Hz, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 7.24–7.19 (m, 3H), 7.06 (dd, J = 7.7, 1.5 Hz, 1H), 2.52–2.46 (m, 2H), 2.40 (s, 3H), 0.39 (t, J = 3.5 Hz, 1H).

[0108] (2) 1313C NMR (126 MHz, CDCl3) δ 155.0, 154.8, 154.5, 154.2, 138.6, 138.4, 137.8, 131.5, 130.4, 130.2, 129.4, 129.2, 127.9, 127.1, 123.8, 121.6, 119.4, 117.2, 77.3, 77.2, 77.0, 76.8, 34.5, 25.1, 21.1, 13.2.

[0109] From 1 1H NMR 13 and 13C NMR test results, it can be known that the yellow oily liquid is a 2-trifluoromethyl-substituted cyclopropylquinoline compound.

[0110] The yield calculation method of the 2-trifluoromethyl-substituted cyclopropylquinoline compound is the same as that in Example 1. The yield of Example 5 = 48 / (301.11 * 0.2) * 100% = 80%.

[0111] Example 6

[0112] This example provides a cyclopropylquinoline compound I-6; its reaction equation and preparation steps are as follows:

[0113]

[0114] A magnetic stir bar, dimethylsulfoxonium iodide (132 mg, 0.6 mmol), potassium tert-butoxide (67 mg, 0.6 mmol) and tetrahydrofuran (2 mL) were successively added to a 15 mL conventional reaction tube and reacted at room temperature for 2 hours, then trifluoromethyl-phenylacetamide chloroester compound (65 mg, 0.2 mmol) was added and reacted at room temperature for 3 hours; the intermediate was heated to 100 °C and reacted for 8 h.

[0115] After the reaction was completed, the reaction system was filtered by suction through diatomaceous earth, and separated by silica gel (200 - 300 mesh) column chromatography (mobile phase component: petroleum ether: ethyl acetate = 90:1) to obtain 49 mg of yellow oily liquid product.

[0116] The yellow oily liquid was subjected to 1 1H NMR 13 and 13C NMR analysis, and the test data (the corresponding spectra are as shown in Figure 11 and Figure 12 are as follows:

[0117] (1) 11H NMR (500 MHz, Chloroform-d) δ 7.50 (d, J = 1.9 Hz, 1H), 7.42–7.32 (m, 5H), 7.04 (dd, J = 7.9, 1.9 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 2.50 (dd, J = 9.9, 4.5 Hz, 1H), 2.45 (dd, J = 9.9, 3.8 Hz, 1H), 2.36 (s, 3H), 0.40 (t, J = 4.2 Hz, 1H).

[0118] (2) 13 13C NMR (126 MHz, CDCl3) δ 155.0, 154.7, 154.5, 154.2, 141.3, 138.5, 137.0, 130.9, 130.3, 130.1, 128.7, 128.3, 127.9, 127.7, 123.8, 121.6, 119.4, 117.2, 77.3, 77.0, 76.8, 34.5, 24.8, 20.7, 13.2.

[0119] From 1 1H NMR 13 and 13C NMR test results, it can be known that the yellow oily liquid is a 2-trifluoromethyl-substituted cyclopropylquinoline compound.

[0120] The yield calculation method of the 2-trifluoromethyl-substituted cyclopropylquinoline compound is the same as that in Example 1. The yield of Example 6 = 49 / (301.11 * 0.2) * 100% = 82%.

[0121] Performance test

[0122] The cyclopropylquinoline compounds I-1 to I-6 prepared in Examples 1 to 6 of the present invention were subjected to the following activity tests.

[0123] A formaldehyde damage model was established using 0.3 mM formaldehyde in the human neuroblastoma cell line SH-SY5Y, and the effect of the compound on cell viability was evaluated by the CCK-8 assay. Cells in good growth condition and in the logarithmic growth phase were selected and seeded into 96-well plates (1×105 cells / well, 100 μL / well). After overnight attachment, the medium was changed, and the cells were co-incubated with different concentrations of the compound, with 3 replicates in each group. The cells were cultured at 37 °C and 5% CO2 for 12 hours. Subsequently, the old medium was discarded, and 100 μL of 0.3 mM formaldehyde + different concentrations of the compound was added to each well, and the cells were further cultured in a 37 °C and 5% CO2 incubator for 12 hours. After culturing for the predetermined time, the old medium was discarded, 100 μL of SH-SY5Y basal medium + 10 μL of CCK-8 solution was added to each well, and the cells were incubated in the dark at 37 °C and 5% CO2 in the incubator for 3 hours. The absorbance at 450 nm of each group was measured by an enzyme-linked immunosorbent assay (ELISA) reader to analyze the cell viability of SH-SY5Y under different treatments.

[0124] The experimental results are as Figure 13 shown. The experimental results show that the treatment with 0.3 mM formaldehyde significantly inhibited the survival of SH-SY5Y. Compared with the model group, the cell viability was enhanced to varying degrees after treatment with the compounds prepared in Examples 1-6 of the present invention. Among them, the cell viability was most significantly restored after treatment with 10 μM of Example 5, and the relative survival rate increased by 34.84%. Therefore, this series of compounds has a strong protective effect on nerve cells and has broad development prospects as a neuroprotective agent.

[0125] Furthermore, the cytotoxicity of the compound was evaluated by the CCK-8 assay in the human neuroblastoma cell line SH-SY5Y. Cells in good growth condition and in the logarithmic growth phase were selected and seeded into 96-well plates (1×105 cells / well, 100 μL / well). After overnight attachment, the medium was changed, and the cells were co-incubated with different concentrations of the compound, with 3 replicates in each group. The cells were cultured at 37 °C and 5% CO2 for 24 hours. After culturing for the predetermined time, the old medium was discarded, 100 μL of SH-SY5Y basal medium + 10 μL of CCK-8 solution was added to each well, and the cells were incubated in the dark at 37 °C and 5% CO2 in the incubator for 3 hours. The absorbance at 450 nm of each group was measured by an enzyme-linked immunosorbent assay (ELISA) reader to analyze the cell viability of SH-SY5Y under different treatments.

[0126] The results are as Figure 14 shown. The experimental results show that low-dose compounds had no effect on cell viability, but as the concentration increased, cell viability was inhibited.

[0127] The above has made a detailed description in connection with the embodiments of the present invention. However, the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the scope of knowledge possessed by those of ordinary skill in the art to which the present invention pertains.

Claims

1. A cyclopropyl-fused quinoline compound, characterized in that, It has the structure shown in Formula I: Among them, R1 is selected from H, halogen, C 1～6 alkyl, C 1～6 alkoxy; R2 is selected from H, halogen, C 1～6 alkyl, C 1～6 alkoxy.

2. The cyclopropyl-fused quinoline compound according to claim 1, wherein R1 is selected from H, halogen, C 1～3 alkyl groups.

3. The cyclopropyl-fused quinoline compound according to claim 1 or 2, wherein R2 is selected from H, halogen, C 1～3 alkyl groups.

4. The cyclopropyl-fused quinoline compound according to claim 1 or 2, characterized in that, The cyclopropylquinoline compounds are selected from the following structural formulas:

5. A method for preparing a cyclopropylquinoline compound as described in any one of claims 1 to 4, characterized in that, It includes the following steps: Mix trimethylsulfoxonium iodide, Compound 1, a base, and an organic solvent and react them to obtain Intermediate I; then heat Intermediate I to obtain the product. Among them, the structural formulas of Compound 1 and Intermediate I are as follows:

6. The preparation method according to claim 5, characterized in that, The molar ratio of Compound 1, trimethylsulfoxonium iodide, and the base is 1:(2 - 3):(2 - 3).

7. The preparation method according to claim 5, wherein The base includes at least one of potassium tert-butoxide, sodium tert-butoxide, and triethylamine.

8. The preparation method according to claim 5, characterized in that In step S2, the heating temperature is 100 - 120 °C.

9. A pharmaceutical composition, characterized in that, It includes the cyclopropylquinoline compound according to any one of claims 1 - 4; and a pharmaceutically acceptable excipient.

10. Use of the cyclopropylquinoline compound according to any one of claims 1 - 4; or the pharmaceutical composition according to claim 9 as a neuroprotective agent.

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