Vinblastine halogenated hydrocarbon compound, preparation method and application thereof

Abstract

The application discloses a vinpocetine halogenated hydrocarbon compound and a preparation method and application thereof. The application reduces the ester group at the 14th position of vinpocetine into a hydroxyl group, and connects a halogenated hydrocarbon to form a compound. The inventors find that the derivative contains a vinpocetine parent structure, retains a basic structure composed of five ring groups of vinpocetine A, B, C, D and E, can provide a compound source for biological activity screening, and has important application value for drug screening and the pharmaceutical industry. The inventors find that the skeleton compound has an inhibitory effect on PDE1A, has a pharmacological activity of expanding blood vessels, and can be applied to preparation of an anti-stroke drug. The application has the advantages of simple operation, easy-to-obtain raw materials, good air stability, wide applicability, and good compatibility with various halogenated hydrocarbons.

Description

Technical Field

[0001] This invention relates to the fields of chemical technology and traditional Chinese medicine, and in particular to a vinpocetine halogenated hydrocarbon biochemical, its preparation method, and its application. Background Technology

[0002] Stroke, commonly known as apoplexy, is a major disease threatening people's health and has become the leading cause of death among residents. It exhibits a clear seasonality, occurring more frequently in cold seasons, and is mainly divided into hemorrhagic stroke and ischemic stroke. Hemorrhagic stroke includes intracerebral hemorrhage, intraventricular hemorrhage, and subarachnoid hemorrhage, with a mortality rate of 10%–25% of all strokes. Ischemic stroke, also known as cerebral infarction, accounts for 75%–90% of all strokes. Stroke has many complications, the most common being cerebral edema and increased intracranial pressure, post-infarction hemorrhagic transformation, urinary dysfunction, and urinary tract infection. Currently, the treatment of ischemic stroke mainly involves thrombolysis, antiplatelet therapy, anticoagulation, and volume expansion to improve cerebral blood circulation. Most patients are prone to severe neurological dysfunction, affecting their daily lives. The only FDA-approved treatment is thrombolysis with recombinant tissue plasminogen activator (t-PA). Although this drug is highly effective, it is only effective within 4.5 hours of onset and can cause cerebral hemorrhage, so only a small number of patients can benefit. Even with successful thrombolysis, most survivors still suffer from permanent neurological deficits. A recent statistic from the World Stroke Organization shows that stroke has become the second leading cause of death and the third leading cause of death and disability worldwide, placing a huge burden on the global economy. Stroke prevention and control in China also face enormous challenges. According to statistics, in 2018, the mortality rate from cerebrovascular diseases in China was 149.49 per 100,000, with 1.57 million deaths. Stroke has become the third leading cause of death after malignant tumors and heart disease.

[0003] Studies have shown that PDE1 plays a role in many physiological and pathological processes: PDE1A can regulate the level of cGMP in vascular smooth muscle cells, thereby regulating the tension of vascular smooth muscle to achieve vasodilation and alleviate ischemic stroke. Vinpocetine has many related cellular targets, the first of which was discovered: cyclic nucleotide phosphodiesterase 1 (PDE1). It can regulate cAMP / cGMP degradation by affecting phosphodiesterase (PDE1A), relaxing brain smooth muscle cells and increasing cerebral blood flow. Therefore, vinpocetine is often used to treat ischemic stroke.

[0004] Vinpocetine, also known as ethyl apovincamine-22-acetate, is a semi-synthetic indole alkaloid extracted from the periwinkle (Catharanthus roseus) of the Apocynaceae family. Developed by the Hungarian company Gedeon Richter and launched in 1978, it has been used in Europe for over 30 years. Highly lipid-soluble, it easily crosses the blood-brain barrier and enters brain tissue, thus being widely used for cerebrovascular diseases such as stroke and cognitive impairment. Vinpocetine can also be used to protect neurons, reduce inflammation, combat aging, and treat insomnia and depression. However, due to its first-pass effect in the liver, low bioavailability, and poor patient compliance with repeated dosing, secondary development of vinpocetine to improve its shortcomings is currently a hot research topic. Summary of the Invention

[0005] The purpose of this invention is to provide a vinpocetine halohydrocarbon compound, its preparation method, and its application. It is an important class of pharmaceutical intermediate analogs and drug molecule analogs, which have significant application value for drug screening and the pharmaceutical industry. Moreover, its synthesis method is very economical and simple.

[0006] This invention also discovered: vinpocetine halohydrocarbon compounds having a structure as shown in general formula (I):

[0007]

[0008] In the formula, R is an aromatic compound;

[0009] Specifically, it is one of the following structures:

[0010]

[0011] The method for preparing vinpocetine haloalkanes involves using vinpocetine as a substrate and anhydrous tetrahydrofuran as a solvent. The ester group at position 14 is reduced to a hydroxyl group using lithium aluminum hydride to obtain an intermediate. The corresponding haloalkanes are then reacted with the intermediate in anhydrous tetrahydrofuran solvent under NaH catalysis to obtain vinpocetine haloalkanes derivatives. The reaction route is as follows:

[0012]

[0013] In the formula, R represents an aromatic compound.

[0014] During the feeding process, after adding the intermediate and catalyst NaH to anhydrous tetrahydrofuran solvent, the mixture was stirred in an ice bath for 30 minutes before adding the haloalkane and reacting at room temperature.

[0015] The application of the vinpocetine halohydrocarbon compound in the preparation of drugs that inhibit PDE1A enzyme.

[0016] The application of the vinpocetine halohydrocarbon compound in the preparation of drugs that inhibit PDE1A enzyme.

[0017] The pharmaceutical application of vinpocetine haloalkanes as PDE1A inhibitors. Using the above-described technique, vinpocetine was used as a substrate, and the ester group at position 14 was reduced to a hydroxyl group using lithium aluminum hydride reagent to obtain the target product, a yellow solid with a yield of 82%. Subsequently, NaH and the intermediate were dissolved in THF, stirred at 0°C, and then different haloalkanes were added and stirred at room temperature to obtain the target product.

[0018] The beneficial effects of this invention are as follows: This type of derivative contains the parent structure of vinpocetine, retaining the basic structure composed of the five rings A, B, C, D, and E of vinpocetine. It can provide a compound source for bioactivity screening, and has significant application value in drug screening and the pharmaceutical industry. Furthermore, the inventors discovered that this scaffold compound has an inhibitory effect on PDE1A and possesses vasodilatory pharmacological activity, making it applicable to the preparation of anti-stroke drugs. This invention is simple and easy to operate, uses inexpensive and readily available raw materials, has good air stability, wide applicability, and good compatibility with various halogenated hydrocarbons. Attached Figure Description

[0019] Figure 1 For compounds 4 and 25; molecular docking diagrams with PDE1A;

[0020] Figure 2 The image shows the proton NMR spectrum of compound 2.

[0021] Figure 3 The image shows the carbon NMR spectrum of compound 2.

[0022] Figure 4 The image shows the 1H NMR spectrum of compound 3.

[0023] Figure 5 The image shows the carbon NMR spectrum of compound 3.

[0024] Figure 6 The image shows the 1H NMR spectrum of compound 4.

[0025] Figure 7 The image shows the carbon NMR spectrum of compound 4.

[0026] Figure 8 The image shows the 1H NMR spectrum of compound 5.

[0027] Figure 9 The image shows the carbon NMR spectrum of compound 5.

[0028] Figure 10 The NMR fluorine spectrum of compound 5 is shown below.

[0029] Figure 11The 1H NMR spectrum of compound 16;

[0030] Figure 12 The image shows the carbon NMR spectrum of compound 16.

[0031] Figure 13 The NMR fluorine spectrum of compound 16;

[0032] Figure 14 The 1H NMR spectrum of compound 25;

[0033] Figure 15 This is the carbon NMR spectrum of compound 25. Detailed Implementation

[0034] Example 1: Vinpocetine (1 equivalent) and lithium aluminum hydride (4 equivalents) were dissolved in THF (20 mL) and stirred at room temperature for 48 hours. After the reaction was complete (monitored by TLC), the solution was eluent with dichloromethane:methanol = 14:1 and 5% ammonia. After column chromatography and rotary evaporation, a yellow solid (compound 1) was obtained, with a yield of 82%.

[0035] Preparation in this embodiment: Compound 1 (1 equivalent) was dissolved in anhydrous THF (2 mL), and NaH (3 equivalents) was added. After stirring in an ice bath for 30 minutes, benzyl bromide (3 equivalents) was added, and the reaction was carried out at room temperature for 18 hours. After the reaction was completed (monitored by TLC), methanol (0.5 mL) was added to quench the reaction, the solvent was recovered, and the product was purified by column chromatography (dichloromethane:methanol = 20:1) (v:v). Product 2 was a yellow oil with a yield of 90%.

[0036] The preparation methods for compounds 3 to 25 are the same as those for compound 2, with the same feed ratio, to obtain compounds 3 to 25. The reaction yields are shown in Table 1.

[0037] Table 1 Chemical structures of vinpocetine halohydrocarbon compounds

[0038]

[0039] Preparation 2 in this example: a yellow oily substance, yield 90%. 1H NMR (400MHz, CDCl3) δ7.65–7.62(m,1H),7.41–7.39(m,1H),7.31–7.28(m,2H),7.25–7.18(m,3H),7.14 –7.04(m,2H),5.00(s,1H),4.67(dd,J=12.7,0.8Hz,1H),4.62–4.55(m,2H),4.41(d,J=12.7Hz,1H),4. 10(s,1H),3.32–3.27(m,1H),3.22–3.14(m,1H),3.02–2.93(m,1H),2.71–2.58(m,2H),2.48–2.43(m,1 H),1.94–1.85(m,1H),1.74–1.62(m,2H),1.41–1.33(m,2H),1.14–1.06(m,1H),0.95(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ137.79,133.98,131.94,131.22,128.97,128.38,127.91,127.70,122.05,119.81,119.36,118 .10,112.83,107.96,71.16,69.35,56.10,51.80,45.20,36.85,30.06,27.42,20.66,16.42,8.96.HRMS(ESI):Exact masscalcd for C 27 H 30 N2O[M+H]+:399.2358, found 399.2428.

[0040] In this embodiment, preparation 3: a yellow oily substance with a yield of 87%. 1H NMR (400MHz, CDCl3) δ7.74–7.72(m,1H),7.52–7.50(m,1H),7.30–7.28(m,1H),7.24–7.22(m,1H),7.20–7 .15(m,4H),5.11(s,1H),4.76(dd,J=12.8,0.8Hz,1H),4.67–4.62(m,2H),4.50(d,J=12.8Hz,1H),4.21(s, 1H),3.44–3.39(m,1H),3.33–3.26(m,1H),3.14–3.04(m,1H),2.83–2.73(m,2H),2.60–2.52(m,1H),2.40( s,3H),2.03–1.96(m,1H),1.83–1.78(m,2H),1.52–1.45(m,2H),1.25–1.21(m,1H),1.06(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ138.15,137.80,134.17,132.22,128.84,128.57,128.38,125.10,122.29,120.00,119.28,118.22 ,113.06,107.96,71.43,69.47,56.34,51.89,45.27,37.00,29.92,27.51,21.48,20.56,16.50,8.99.HRMS(ESI):Exact mass calcd for C 28 H 32 N2O[M+H]+:413.2515, found 413.2584.

[0041] In this example, preparation 4 yielded a yellow oily substance with a yield of 85%. 1H NMR (400MHz, CDCl3) δ7.69–7.67(m,1H),7.46–7.44(m,1H),7.21–7.17(m,3H),7.15–7.13(m,1H),7 .09(s,2H),5.06(s,1H),4.74(d,J=12.7Hz,1H),4.65–4.56(m,2H),4.50(d,J=12.7Hz,1H),4.21(s, 1H),3.46–3.43(m,1H),3.34–3.27(m,2H),3.09–3.00(m,2H),2.82(s,1H),2.66–2.61(m,1H),2.29( s,3H),2.02–1.97(m,1H),1.84–1.81(m,2H),1.47(s,1H),1.26–1.17(m,1H),1.01(t,J=7.4Hz,3H). 13 C NMR (100MHz, CDCl3) δ138.17,137.71,134.33,132.47,128.81,128.64,128.60,128.39,125.09,122.66,120.24,118.79,118. 32,113.15,107.77,71.58,69.39,56.61,51.95,45.23,37.10,29.50,27.50,21.47,20.09,16.40,8.94.HRMS(ESI):Exactmass calcd for C 28 H 32 N2O[M+H]+:413.2515, found 413.2579.

[0042] In this example, a yellow oily substance was prepared in a yield of 83%. 1H NMR (400MHz, CDCl3) δ7.65–7.63(m,1H),7.44–7.42(m,1H),7.25–7.20(m,2H),7.17–7.07(m,2H),6. 98–6.93(m,2H),5.02(s,1H),4.70(d,J=12.7Hz,1H),4.60–4.52(m,2H),4.42(d,J=12.7Hz,1H),4.12 (s,1H),3.35–3.30(m,1H),3.25–3.17(m,1H),3.05–2.96(m,1H),2.73–2.61(m,2H),2.50–2.44(m,1H ),1.97–1.88(m,1H),1.77–1.64(m,2H),1.44–1.36(m,2H),1.16–1.08(m,1H),0.98(t,J=7.5Hz,3H). 13 C NMR(100MHz, CDCl3)δ162.38(d,J=245.7Hz),133.99,133.65,133.62,131.90,131.30,129.63(d,J=8.1Hz),122.07,11 9.88,119.49,118.18,115.25(d,J=21.4Hz),112.78,108.09,70.47,69.51,56.12,51.82,45.23,36.89,30.10,27.45. 19 F NMR(377MHz,CDCl3)δ-114.70.HRMS(ESI):Exact mass calcd for C 27 H 29 FN2O[M+H]+:417.2264found 417.2328.

[0043] In this example, a yellow oily substance was prepared in a yield of 73%. 1H NMR (400MHz, CDCl3) δ7.69–7.67(m,1H),7.47–7.45(m,1H),7.28–7.24(m,1H),7.21–7.17(m,1H),7.14–7.11(m,1H ),7.07–7.05(m,1H),7.03–7.00(m,1H),6.98–6.93(m,1H),5.05(s,1H),4.76(d,J=12.8Hz,1H),4.66–4.58(m,2H), 4.47(d,J=12.8Hz,1H),4.18(s,1H),3.40–3.35(m,1H),3.30–3.22(m,1H),3.07–3.01(m,1H),2.76–2.71(m,2H),2. 58–2.53(m,1H),1.99–1.94(m,1H),1.79–1.74(m,2H),1.45–1.41(m,1H),1.22–1.13(m,1H),1.00(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3): δ 163.00 (d, J = 246.3Hz), 140.59 (d, J = 7.2Hz), 134.13, 131.96, 130.77, 130.02, 129.94, 128.96, 123.23 (d, J = 2.9Hz), 122. 37,120.10,119.47,118.33,114.64(d,J=21.2Hz),112.86,108.11,70.5 3,69.68,56.27,51.88,45.26,37.04,29.96,27.49,20.53,16.46,8.99. 19 F NMR (376MHz, CDCl3): δ-113.11.HRMS (ESI): Exact mass calcd for C 27 H 29 FN2O[M+H]+:417.2264found 417.2344.

[0044] In this example, 7 was prepared as a yellow oily substance with a yield of 74%. 1H NMR (400MHz, CDCl3) δ7.66–7.64(m,1H),7.43–7.41(m,1H),7.36–7.32(m,1H),7.24–7.19(m,1H),7.16– 7.12(m,1H),7.11–6.98(m,3H),5.07(s,1H),4.72–4.65(m,3H),4.46(d,J=12.7Hz,1H),4.12(s,1H),3.3 4–3.30(m,1H),3.24–3.16(m,1H),3.04–2.95(m,1H),2.73–2.67(m,1H),2.63–2.61(m,1H),2.50–2.44(m ,1H),1.95–1.90(m,1H),1.76–1.68(m,2H),1.44–1.35(m,2H),1.16–1.08(m,1H),0.98(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ160.63(d,J=246.6Hz),133.98,131.84,131.24,130.24(d,J =4.2Hz), 129.40 (d, J = 8.1Hz), 128.98, 124.96 (d, J = 14.6Hz), 124.12 (d, J = 3.6Hz), 122.07,119.83,119.55,118.11,115.19(d,J=21.5Hz)112.78,107.99,69.74,64. 48(d,J=3.9Hz),56.14,51.81,45.22,36.88,29.98,27.42,20.67,16.43,8.89.19F NMR(377MHz,CDCl3)δ-137.39.HRMS(ESI):Exact mass calcd forC 27 H 29 FN2O[M+H]+:417.2264 found 417.2338.

[0045] In this example, a yellow oily substance was prepared in a yield of 71%. 1H NMR (400MHz, CDCl3) δ7.69–7.67(m,1H),7.48–7.46(m,1H),7.27–7.23(m,2H),7.21–7.19(m,2H),7.17–7. 14(m,1H),7.13–7.11(m,1H),5.04(s,1H),4.76(d,J=12.8Hz,1Hz),4.64–4.52(m,2H),4.44(d,J=12.8Hz, 1H),4.11(s,1H),3.38–3.33(m,1H),3.27–3.21(m,1H),3.08–3.99(m,1H),2.75–2.64(m,2H),2.53–2.48( m,1H),1.98–1.93(m,1H),1.77–1.72(m,2H),1.46–1.40(m,2H),1.18–1.11(m,1H),1.01(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ136.44,133.95,133.35,131.84,131.24,129.07,129.03,128.45,122.05,119.87,119.51,118.1 7,112.74,108.08,70.39,69.67,56.03,51.78,45.19,36.86,30.06,27.42,20.70,16.42,8.99.HRMS(ESI):Exactmass calcd for C 27 H 29 ClN2O[M+H]+:433.1968, found 433.2034.

[0046] In this example, a yellow oily substance was prepared, with a yield of 82%. 1H NMR (400MHz, CDCl3) δ7.57–7.55(m,1H),7.36–7.34(m,1H),7.16(s,1H),7.14–7.10(m,3H),7.08–7.05( m,1H),7.03–6.99(m,1H),4.93(s,1H),4.65(d,J=12.9Hz,1H),4.54–4.44(m,2H),4.33(d,J=12.9Hz,1H) ,4.02(s,1H),3.28–3.21(m,1H),3.17–3.10(m,1H),2.96–2.87(m,1H),2.66–2.55(m,2H),2.45–2.39(m ,1H),1.86–1.78(m,1H),1.68–1.59(m,2H),1.36–1.28(m,2H),1.07–0.99(m,1H),0.88(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ140.07,134.34,134.06,131.92,130.85,129.71,128.98,127.86,125.81,122.30,120.04,119.51,1 18.29,112.83,108.12,70.52,69.76,56.21,51.84,45.22,37.00,29.94,27.44,20.55,16.46,8.98.HRMS(ESI):Exactmass calcd for C 27 H 29 ClN2O[M+H]+:433.1968, found 433.2035.

[0047] In this example, 10 was prepared as a yellow oily substance with a yield of 62%. 1H NMR (400MHz, CDCl3) δ7.69–7.67(m,1H),7.48–7.46(m,1H),7.26–7.11(m,6H),5.04(s,1H) ,4.76(d,J=12.8Hz,1H),4.64–4.52(m,2H),4.44(d,J=12.8Hz,1H),4.11(s,1H),3.38–3.33 (m,1H),3.27–3.21(m,1H),3.08–2.99(m,1H),2.75–2.64(m,2H),2.53–2,48(m,1H),1.98–1 .93(m,1H),1.77–1.72(m,2H),1.46–1.40(m,2H),1.18–1.13(m,1H),1.01(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ140.08,134.30,133.99,131.82,131.20,129.67,129.06,127.82,127.80,125.78,122.15,119.94,119 .62,118.23,112.78,108.15,70.43,69.75,56.10,51.82,45.22,36.92,30.05,27.44,20.69,16.46,8.98.HRMS(ESI):Exact mass calcd for C 27 H 29 ClN2O[M+H]+:433.1968, found 433.2042.

[0048] In this example, 11 was prepared as a yellow oily substance with a yield of 82%. 1 H NMR (400MHz, CDCl3) δ8.36–8.34(m,2H),7.41–7.36(m,2H),7.32–7.27(m,2H),7.26–7.24( m,1H),7.21–7.08(m,1H),3.87(s,1H),3.31–3.26(m,1H),3.21–3.13(m,1H),2.91–2.81(m ,2H),2.64–2.52(m,2H),2.45–2.33(m,3H),2.04–1.99(m,1H),1.74–1.70(m,1H),1.64–1. 59(m,1H),1.47–1.44(m,2H),1.38–1.33(m,2H),1.02–0.98(m,1H),0.91(t,J=7.6Hz,3H). 13C NMR (100MHz, CDCl3) δ137.79,133.99,131.94,131.22,128.97,128.38,127.91,127.70,122.06,119.82,119.36,118 .10,112.83,107.96,71.16,69.35,56.10,51.79,45.20,36.84,30.05,27.42,20.66,16.42,8.95.HRMS(ESI):Exact mass calcd for C 27 H 29 BrN2O[M+H]+:477.1463,found477.1524.

[0049] In this example, 12: a yellow oily substance was prepared with a yield of 62%. 1 H NMR (400MHz, CDCl3) δ7.68–7.66(m,1H),7.47–7.43(m,2H),7.40–7.38(m,1H),7.21–7.10(m,4H),5. 04(s,1H),4.77(d,J=12.8Hz,1H),4.64–4.55(m,2H),4.44(d,J=12.8Hz,1H),4.11(s,1H),3.38–3.33 (m,1H),3.28–3.21(m,1H),3.08–2.99(m,1H),2.77–2.70(m,1H),2.67–2.64(m,1H),2.54–2.49(m,1H ),1.96–1.91(m,1H),1.77–1.70(m,2H),1.46–1.40(m,2H),1.18–1.10(m,1H),1.00(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ140.43,134.05,131.88,131.28,130.82,130.81,130.04,129.12,126.33,122.59,122.23,120.01,119.7 1,118.30,112.85,108.24,70.45,69.85,56.20,51.90,45.31,36.99,30.09,27.51,20.75,16.53,9.03.HRMS(ESI):Exactmass calcd for C 27 H 29 BrN2O[M+H]+:477.1463,found 477.1526.

[0050] In this example, 13 was prepared as a yellow oily substance with a yield of 93%. 1 H NMR (400MHz, CDCl3) δ7.71–7.68(m,1H),7.49–7.46(m,1H),7.44–7.38(m,2H),7.21–7.05(m,4H),5.0 8(s,1H),4.78(d,J=12.8Hz,1H),4.72–4.65(m,2H),4.53(d,J=12.8Hz,1H),4.12(s,1H),3.36–3.31( m,1H),3.25–3.14(m,1H),3.05–2.96(m,1H),2.74–2.67(m,1H),2.65–2.62(m,1H),2.51–2.45(m,1H) ,1.97–1.90(m,1H),1.75–1.70(m,2H),1.45–1.37(m,2H),1.17–1.091(m,1H),0.99(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ137.33,134.01,132.41,131.83,131.19,129.13,128.99,128.89,127.40,122.49,122.15,119.88,119.6 8,118.16,112.81,108.03,70.45,70.13,56.08,51.85,45.25,36.91,30.06,27.44,20.67,16.44,8.98.HRMS(ESI):Exactmass calcd for C 27 H 29 BrN2O[M+H]+:477.1463,found 477.1526.

[0051] In this example, 14 was prepared as a yellow oily substance with a yield of 78%. 1H NMR (400MHz, CDCl3) δ7.68–7.66(m,1H),7.55–7.53(m,2H),7.48–7.46(m,1H),7.36–7.34(m,2H),7.2 0–7.10(m,2H),5.05(s,1H),4.82(d,J=12.8Hz,1H),4.72–4.62J(m,2H),4.48(d,J=12.8Hz,1H),4.10 (s,1H),3.43–3.34(m,1H),3.29–3.20(m,1H),3.07–2.98(m,1H),2.75–2.65(m,2H),2.54–2.48(m,1H ),1.97–1.90(m,1H),1.78–1.69(m,2H),1.46–1.39(m,2H),1.16–1.09(m,1H),0.99(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ143.62,133.98,132.16,131.64,131.17,129.09,127.84,122.20,120.05,119.88,118.85,118.34 ,112.67,111.31,108.30,70.28,70.17,56.05,51.84,45.25,37.00,30.12,27.46,20.68,16.45,9.03.HRMS(ESI):Exact masscalcd for C 28 H 29 N3O[M+H]+:424.2311, found 424.2390.

[0052] In this example, 15 was prepared as a yellow oily substance with a yield of 76%. 1H NMR (400MHz, CDCl3) δ7.70–7.68(m,1H),7.61–7.59(m,1H),7.46–7.45(m,3H),7.35–7.31(m,1H),7 .21–7.17(m,1H),7.14–7.10(m,1H),5.14(s,1H),4.86–4.79(m,3H),4.56(d,J=12.9Hz,1H),4.16(s ,1H),3.42–3.37(m,1H),3.30–3.22(m,1H),3.07–2.98(m,1H),2.76–2.72(m,2H),2.59–2.53(m,1H) ,2.01–1.93(m,1H),1.82–1.77(m,2H),1.51–1.41(m,2H),1.18–1.10(m,1H),1.02(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ141.62,134.00,132.82,132.51,131.62,130.36,128.77,128.60,128.01,122.37,120.03,119.67,118.23 ,117.23,112.69,111.07,107.95,70.36,68.68,56.21,51.78,45.15,36.96,29.63,27.31,20.27,16.31,8.87.HRMS(ESI):Exact mass calcd for C 28 H 29 N3O[M+H]+:424.2311, found 424.2393.

[0053] In this example, 16 was prepared as a yellow oily substance with a yield of 82%. 1H NMR(400MHz,CDCl3)δ7.76–7.74(m,1H),7.57–7.55(m,2H),7.52–7.50(m,1H),7.41–7.39(m,2H),7.25–7.21(m,1H),7.19–7.15(m,1H),5.09(s,1H),4.85(d,J=12.9Hz,1H),4.76–4.66(m,2H),4.51(d,J=12.9Hz,1H),4.13(s,1H),3.40–3.36(m,1H),3.30–3.22(m,1H),3.09–3.03(m,1H),2.79–2.73(m,1H),2.70(s,1H),2.56–2.50(m,1H),2.02–1.97(m,1H),1.80–1.75(m,2H),1.49–1.42(m,2H),1.21–1.14(m,1H),1.04(t,J=7.5Hz,3H). 13 C NMR(100MHz,CDCl3):δ142.19,133.98,131.77,131.19,129.71(q,J=32.6Hz),129.07,127.61,125.21(q,J=3.9Hz),124.20(q,J=270.5Hz),122.11,119.95,119.67,118.24,112.72,108.15,70.33,70.02,55.96,51.75,45.18,36.90,30.10,27.41,20.65,16.38,8.96; 19 F NMR(376MHz,CDCl3):δ-62.30.HRMS(ESI):Exact mass calcd for C 28 H 29 F3N2O[M+H]+:467.2232,found 467.2327.

[0054] In this example, 17 was prepared as a yellow oily substance with a yield of 74%. ¹H NMR (400 MHz, CDCl₃) δ 7.76–7.74 (m, ¹H), 7.60 (s, ¹H), 7.55–7.48 (m, 3H), 7.43–7.40 (m, ¹H), 7.25–7.21 (m, ¹H), 7.18–7.14 (m, ¹H), 5.09 (s, ¹H), 4.82 (d, J = 12.8 Hz, ¹H), 4.74–4.66 (m, 2H), 4.51 (d, J = 12.8 Hz, ¹H). ,4.16(s,1H),3,41–3.36(m,1H),3.30–3.22(m,1H),3.11–3.02(m,1H),2.79–2.67(m,2H),2.56–2.50(m ,1H),2.01–2.96(m,1H),1.82–1.74(m,2H),1.50–1.42(m,2H),1.21–1.14(m,1H),1.04(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ139.05,133.98,131.71,131.19,130.92,130.71(q,J=32.3Hz),129.07,128.86,124.44(q,J=3.8Hz),124.32(q,J=3.8Hz),12 4.13(q,J=272.4Hz),122.14,119.97,119.70,118.24,112.72,108.19,70 .30,69.86,56.11,51.82,45.23,36.94,30.06,27.43,20.68,16.43,8.91. 19 F NMR(377MHz,CDCl3)δ-62.55.HRMS(ESI):Exact mass calcd for C 28 H 29 F3N2O[M+H]+:467.2232,found467.2294.

[0055] In this example, 18 was prepared as a yellow oily substance with a yield of 63%. 1H NMR (400MHz, CDCl3) δ7.76–7.74(m,1H),7.62–7.56(m,4H),7.51–7.36(m,6H),7.24–7.20(m,1H),7.18– 7.14(m,1H),5.11(s,1H),4.80(d,J=12.8Hz,1H),4.75–4.70(m,2H),4.52(d,J=12.8Hz,1H),4.18(s,1H) ,3.38–3.34(m,1H),3.29–3.21(m,1H),3.10–3.03(m,1H),2.79–2.73(m,1H),2.70(s,1H),2.56–2.51(m ,1H),2.02–1.96(m,1H),1.81–1.76(m,2H),1.50–1.42(m,2H),1.23–1.16(m,1H),1.05(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ140.88,140.70,136.94,134.08,132.06,131.24,129.04,128.86,128.44,127.39,127.17,127.13,122.16,119 .92,119.48,118.20,112.93,108.05,71.01,69.56,56.16,51.82,45.25,36.95,30.09,27.49,20.70,16.48,9.03.HRMS(ESI):Exact mass calcd for C 33 H 34 N2O[M+H]+:475.2671,found475.2754.

[0056] In this example, 19 was prepared as a yellow solid with a yield of 58% and a melting point of 86-88℃. 1H NMR (400MHz, CDCl3) δ8.03–8.01(m,1H),7.87–7.81(m,2H),7.69–7.67(m,1H),7.52–7.41(m,4H),7.38– 7.34(m,1H),7.14–7.07(m,2H),5.14–5.09(m,3H),4.83(dd,J=12.9,0.6Hz,1H),4.52(d,J=12.9Hz,1H), 4.13(s,1H),3.39–3.34(m,1H),3.28–3.21(m,1H),3.07–2.99(m,1H),2.75–2.68(m,2fH),2.55–2.49(m ,1H),1.96–1.88(m,1H),1.80–1.72(m,2H),1.48–1.40(m,2H),1.32–1.12(m,1H),1.01(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ133.95,133.67,133.24,132.02,131.72,131.17,128.95,128.70,128.36,126.74,126.04,125.74,125.05,124.13,121 .99,119.75,119.36,118.01,112.90,107.91,69.79,69.43,56.07,51.73,45.14,36.76,29.90,27.35,20.66,16.38,8.90.HRMS(ESI):Exact mass calcd forC 31 H 32 N2O[M+H]+:449.2515, found 449.2588.

[0057] In this example, 20 was prepared as a yellow solid with a yield of 79% and a melting point of 89-91℃. 1H NMR (400MHz, CDCl3) δ7.84–7.81(m,2H),7.77–7.75(m,2H),7.72–7.70(m,2H),7.49–7.47(m,2H),7. 41–7.39(m,1H),7.23–7.14(m,2H),5.06(s,1H),4.88–4.84(m,2H),4.77(d,J=12.9Hz,1H),4.47(d,J =12.9Hz,1H),3.96(s,1H),3.32–3.25(m,1H),3.11–2.95(m,2H),2.74–2.63(m,2H),2.48–2.41(m,1H) ),1.97–1.89(m,1H),1.78–1.66(m,2H),1.45–1.38(m,2H),1.17–1.10(m,1H),1.00(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ135.53,134.08,133.24,133.02,132.16,131.23,129.08,128.09,127.94,127.69,126.64,126.08,125.96,125.84,122 .13,119.90,119.46,118.18,112.98,108.03,71.54,69.78,56.07,51.74,45.22,36.85,29.98,27.44,20.72,16.44,9.01.HRMS(ESI):Exact mass calcd for C 31 H 32 N2O[M+H]+:449.2515,found449.2609.

[0058] In this example, 21 was prepared as a yellow oily substance with a yield of 75%. 1H NMR (400MHz, CDCl3) δ7.70–7.68(m,1H),7.46–7.44(m,1H),7.19–7.09(m,3H),6.90(s,2H),5.05( s,1H),4.74(d,J=12.8Hz,1H),4.65–4.52(m,2H),4.43(d,J=12.8Hz,1H),4.11(s,1H),3.42–3.33 (m,1H),3.28–3.20(m,1H),3.08–2.98(m,2H),2.77–2.65(m,1H),2.54–2.49(m,1H),2.26(s,6H), 1.95–1.88(m,1H),1.77–1.68(m,2H),1.46–1.39(m,2H),1.18–1.14(m,1H),0.99(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ137.81,137.72,134.00,132.09,131.25,129.25,128.96,125.80,121.99,119.77,119.26,118.04 ,112.96,107.87,71.34,69.43,56.15,51.82,45.19,36.79,29.94,27.41,21.25,20.68,16.44,8.90.HRMS(ESI):Exact masscalcd for C 29 H 34 N2O[M+H]+:427.2671, found 427.2759.

[0059] In this example, 22: a yellow oily substance was prepared with a yield of 56%. 1H NMR (400MHz, CDCl3) δ7.71–7.69(m,1H),7.49–7.48(m,1H),7.23–7.19(m,1H),7.16–7.13(m,1H),6.83–6.82( m,2H),6.73–6.68(m,1H),5.06(s,1H),4.79(d,J=12.8Hz,1H),4.66–4.56(m,2H),4.48(d,J=12.8Hz,1H),4.16 (s,1H),3.40–3.35(m,1H),3.29–3.22(m,1H),3.09–3.00(m,1H),2.78–2.72(m,1H),2.68–2.66(m,1H),2.55–2 .50(m,1H),2.00–2.95(m,1H),1.79–1.73(m,2H),1.49–1.42(m,2H),1.21–1.13(m,1H),1.02(t,J=7.5Hz,3H). 13 C NMR(100MHz,CDCl3)δ163.04(dd,J=248.7,12.6Hz),142.17(t,J=8.8Hz),1 33.96,131.62,131.19,129.08,122.19,120.01,119.79,118.29,112.66,1 10.17(d,J=6.9Hz),109.98(d,J=6.8Hz),108.24,102.88(t,J=25.3Hz),69 .88,69.84,56.03,51.81,45.22,36.98,30.14,27.44,20.69,16.44,8.97. 19 FNMR(377MHz,CDCl3)δ-109.69.HRMS(ESI):Exact mass calcd for C 27 H 28 F2N2O[M+H]+:435.2170,found 435.2242.

[0060] In this example, 23 was prepared as a yellow oily substance with a yield of 81%. 1H NMR (400MHz, CDCl3) δ7.67–7.65(m,1H),7.54–7.53(m,1H),7.47–7.45(m,1H),7.30–7.29(m,2H),7.22–7.18( m,1H),7.15–7.11(m,1H),5.02(s,1H),4.84(d,J=12.9Hz,1H),4.65–4.59(m,1H),4.51(d,J=12.9Hz,1H),4.43 –4.39(m,1H),4.05(s,1H),3.38–3.33(m,1H),3.28–3.20(m,1H),3.07–2.99(m,1H),2.73–2.65(m,2H),2.55–2 .49(m,1H),1.95–1.90(m,1H),1.77–1.70(m,2H),1.43–1.42(m,2H),1.15–1.07(m,1H),0.99(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ142.26,133.98,133.17,131.77,131.07,129.27,129.15,128.43,122.93,122.28,120.08,119.83 ,118.42,112.75,108.38,70.27,69.83,56.14,51.88,45.26,37.00,30.01,27.48,20.70,16.53,9.04.HRMS(ESI):Exact mass calcd for C 27 H 28 Br2N2O[M+H]+:555.0568,found555.0635.

[0061] In this example, a yellow oily substance (24 g) was prepared with a yield of 52%. 1H NMR (400MHz, CDCl3) δ7.53–7.51(m,1H),7.45–7.43(m,1H),7.16–7.08(m,3H),5.99–5.96(m,1H),5.05(s, 1H),4.71(d,J=12.8Hz,1H),4.61–4.54(m,1H),4.38(d,J=12.8Hz,1H),4.20(s,1H),3.83(s,1H),3.61(s, 3H),3.40–3.35(m,1H),3.31–3.23(m,1H),3.07–3.00(m,1H),2.77–2.71(m,1H),2.57–2.52(m,1H),2.23( s,3H),1.98–1.91(m,1H),1.81–1.74(m,2H),1.50–1.41(m,2H),1.18–1.13(m,1H),1.01(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ147.14,138.59,134.05,131.71,128.97,122.40,120.15,119.89,118.35,112.69,108.21,107.0 3,105.30,69.08,61.15,56.36,51.89,45.29,37.09,36.32,29.93,27.49,20.57,16.49,13.53,8.99.HRMS(ESI):Exact mass calcd for C 26 H 32 N4O[M+H]+:417.5690, found 417.2663.

[0062] In this example, a yellow oily substance (25%) was prepared with a yield of 86%. 1H NMR (400MHz, CDCl3) δ7.43–7.41(m,1H),7.38–7.36(m,1H),7.16–7.07(m,2H),7.04(s,1H),5. 54(d,J=12.8Hz,1H),5.25(d,J=12.8Hz,1H),4.46(s,1H),4.43(d,J=0.8Hz,1H),3.57–3.52(m ,1H),3.43–3.39(m,1H),3.31(s,2H),3.08–3.00(m,2H),2.89–2.82(m,1H),2.79–2.73(m,1H) ,2.12–2.06(m,1H),1.94–1.87(m,1H),1.51(s,2H),1.22–1.14(m,2H),1.00(t,J=7.4Hz,1H). 13 C NMR (100MHz, CDCl3) δ173.60,135.43,134.13,130.84,128.20,128.08,123.41,120.60,119.92,118.63,111 .94,107.74,69.27,66.90,57.59,51.72,44.97,37.25,28.55,27.15,19.07,16.04,8.65.HRMS(ESI):Exact mass calcd for C 24 H 26 ClN3OS[M+H]+:440.1485,found 440.2039.

[0063] Pharmacological Example 1: Component Target Docking

[0064] To understand the potential interaction between the most active vinpocetine derivative and the PDE1A protease, we coupled compounds 4 and 25 to the active site of the PDE1A protease, respectively.

[0065] I. Specific methods for preparing molecular docking ligands and receptors

[0066] Ligand preparation: use The LigPrep module in Maestro software ( 2018-1: Maestro version 11.5, (LLC, New York, NY) prepared the compound, using OPLS3 for energy minimization; the molecule was ionized at pH 7.0 ± 2.0 while maintaining its chirality.

[0067] Protein preparation: Retrieve the crystal structure of the corresponding protein from the protein database, prepare the protein using the ProteinPreparation Wizard module, and then set the protein active site as the docking position.

[0068] Molecular docking: employing The ligand docking module in the software uses additional precision (XP) for the re-docking stage after docking. The relevant threshold is the default ligand docking score, which is calculated by the default scoring function. An absolute value of the docking score higher than 5 can be used to determine whether the compound is active.

[0069] Table 2. Analysis of Docking Results

[0070]

[0071] Experimental conclusions: The docking scores of compounds 4 and 25 with the PDE1A protein model were -12.027 and -11.326, respectively, while the gliding model values ​​were -69.613 kcal / mol and -82.876 kcal / mol, respectively. The A and B rings of compound 4 formed two π-π interactions with PHE 420, and the introduced benzene ring was stabilized at the binding site through a π-π interaction with PHE 101. For compound 25, the A and B rings formed three π-π interactions with PHE 388 and PFE 101. Furthermore, the introduced thiazole ring also formed a hydrogen bond with TYR 218 at a distance of [missing information]. Due to the increased additional interaction between the ligand and the protein, the inhibitory activity is greatly enhanced, and the ligand-protein complex is thus more stable.

[0072] Pharmacological Example 2: PDE1A Enzyme Activity Experiment

[0073] I. Experimental Materials

[0074] BMS-345541 (Sigma, St. Louis, MO, USA); MOPS, Proclin 200 and DL-Dithiothreitol (DTT) (Sigma, St. Louis, MO, USA); Fluorescein (FAM)-cyclic-3′,5′-AMP and Enzyme-IMAP Assays Kit (Molecular Devices Inc, CA, USA); PDE1A (BPS Bioscience Inc, San Diego, CA); [γ-32P]ATP (MP Biomedicals, Irvine, CA, USA); PMSF (Sigma, St. Louis, MO, USA).

[0075] II. Experimental Instruments

[0076] FORMA 700 ultra-low temperature freezer, Thermo Fisher Scientific; YC-300L pharmaceutical storage cabinet, Zhongke Meiling Cryogenic Technology Co., Ltd.; Direct-Q with pump ultrapure water system, Millopore; SW-CJ-2FD ultra-clean workbench: Suzhou Purification Equipment Co., Ltd. F200 PRO filter-type multi-functional microplate reader, Tecan; Phosphorimaging, Bio-rad, USA.

[0077] III. Experimental Methods

[0078] Preparation of the phosphodiesterase reaction system: The reagents from the Enzyme-IMAP Assays kit were prepared to contain 40 mM MOPS, pH 7.5, 0.5 mM EDTA, 15 mM MgCl2, 0.15 mg / mL BSA, 1 mM DTT, 0.05% Proclin 200, 15 ng / mL PDE1A, and 100 nM FAM-cyclic-3′,5′-AMP, with a final volume of 50 μL. Preparation of the test drug: The test compound was dissolved in 10% DMSO and diluted to the required working concentration. 5 μL of the diluted solution was added to 50 μL of the reaction mixture to ensure a drug concentration of 1% in all reactions. 5 μL of distilled water containing 1% DMSO was added to the kinase reaction system as the kinase control wells. The blank control wells did not contain PDE1A. After incubating the reaction mixture at 25°C for 1 hour, 100 μL of diluted binding agent was added to each well, followed by slow shaking incubation at 25°C for 1 hour. Polarization fluorescence (FP) values ​​of the samples were detected using a 360 nm excitation filter and a 480 nm emission filter. The inhibition percentage was calculated using the following formula: Inhibition percentage % = [1 - (FP drug - FP control) / (FP enzyme - FP control)] × 100%. The IC50 was calculated by fitting a nonlinear regression curve using GraphPad Prism software. 50 value.

[0079] Table 3 shows the inhibitory effects of compounds 1-25 on PDE1A.

[0080] Compound numbering <![CDATA[IC 50 (μM)]]> Compound numbering <![CDATA[IC 50 (μM) <!-- 11 -->]]> 1 20.32±1.11 14 15.65±1.09 2 19.22±2.25 15 45.15±2.27 3 8.52±0.68 16 57.74±2.96 4 3.53±0.25 17 48.37±1.44 5 17.18±3.75 18 44.82±2.26 6 25.58±1.23 19 54.27±1.84 7 28.72±1.15 20 89.64±5.34 8 48.82±2.55 21 10.04±0.85 9 72.14±3.89 22 46.39±1.94 10 35.02±1.85 23 58.19±3.20 11 54.85±3.42 24 63.65±3.85 12 12.47±1.06 25 2.08±0.16 13 88.26±3.26 Changchun Xiting 17.25±1.21

[0081] Experimental conclusions: The results show that compounds 3, 4, 5, 12, 14, 21, and 25 exhibit superior inhibitory activity compared to vinpocetine. For benzene ring-substituted derivatives, introducing electron-donating groups onto the benzene ring enhances inhibitory activity. In particular, compound 4, with a p-methyl substitution on the benzene ring, shows a five-fold increase in inhibitory activity compared to vinpocetine, with an IC50 value of [missing value]. 50 The value was 3.53 ± 0.25 μM. Among the heterocyclic substitutions, compound 25, with a 3-chlorothiazolium ring substitution, showed 8-fold higher inhibitory activity against PDE1A than vinpocetine, with an IC50 value of 3.53 ± 0.25 μM. 50 The value was 2.08 ± 0.16 μM. However, the inhibitory activity of compounds with stereohindered biphenyl and naphthyl ring groups was significantly reduced.

Claims

1. A vinpocetine halohydrocarbon compound, characterized in that: The compound has a structure as shown in general formula (Ⅰ): ， In the formula, R represents an aromatic compound; Specifically, it can be one of the following structures: 。 2. A method for preparing the vinpocetine halohydrocarbon compound as described in claim 1, characterized in that: Using vinpocetine as a substrate and anhydrous tetrahydrofuran as a solvent, the ester group at position 14 was reduced to a hydroxyl group using lithium aluminum hydride; an intermediate was obtained. The corresponding haloalkane was then reacted with the intermediate in anhydrous tetrahydrofuran solvent under NaH catalysis to obtain vinpocetine haloalkane compounds; the reaction route is as follows: In the formula, R represents an aromatic compound.

3. The method for preparing vinpocetine halohydrocarbon compounds according to claim 2, characterized in that: After adding the intermediate and catalyst NaH to anhydrous tetrahydrofuran solvent, the mixture was stirred in an ice bath for 30 minutes before adding the haloalkane and reacting at room temperature.

4. The use of the vinpocetine halohydrocarbon compound as described in claim 1 in the preparation of a drug for inhibiting PDE1A enzyme.

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