Desloratadine derivative and application thereof in preparation of peripheral neuropathy drugs

Abstract

The invention discloses a desloratadine derivative and application of the desloratadine derivative in preparation of a medicine for treating and / or preventing peripheral neuropathy. A Schwann cell model and diabetic peripheral neuropathy mice verify that the desloratadine derivative can significantly inhibit Schwann cell inflammation level and improve motor nerve conduction velocity and sensory deficiency, and has a significant effect on peripheral neuropathy, especially diabetic peripheral neuropathy.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to desloratadine derivatives and applications thereof in the preparation of drugs for peripheral neuropathy. Background Art

[0002] Diabetes is considered a major global public health threat. Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes, affecting approximately 50% of diabetic patients in later life. DPN, along with diabetic retinopathy and diabetic nephropathy, is collectively known as the diabetic triad. DPN not only causes significant physical and mental distress to patients but also severely impacts their quality of life. The prevalence of DPN is rapidly increasing worldwide. According to the International Diabetes Federation (IDF), the number of people with DPN is projected to reach 366 million by 2030, with approximately 90% of these individuals suffering from type 2 diabetes. This increasing prevalence will have a growing impact on human health and will place severe and growing pressure on productivity and economic growth in China and globally over the coming decades. Therefore, the prevention and treatment of DPN is urgent, as it will become a global public health issue.

[0003] Patients with diabetic peripheral neuropathy (DPN) often experience symptoms related to peripheral nerve dysfunction, including pain, numbness, and sensory loss. Early-stage DPN patients experience abnormal limb pain, which progresses to sensory loss and numbness in the limbs, ultimately developing diabetic foot, difficulty healing wounds, retinopathy, and multiple organ failure. Furthermore, DPN can progress to diabetic foot in later stages, leading to the risk of ulcers and amputations. The pathogenesis of diabetic peripheral neuropathy is complex. Hyperglycemia is the primary cause of peripheral neuropathy, and DPN is the result of multiple factors, including metabolic disorders, vascular damage, neurotrophic factor deficiency, cytokine abnormalities, oxidative stress, and immune factors. Glucose auto-oxidation also leads to the formation of oxidation products, which can cause cellular oxidative stress and mitochondrial dysfunction. Currently, there is no specific treatment for DPN. In addition to basic diabetes treatment, attention should also be paid to the pain that peripheral neuropathy causes patients.

[0004] Desloratadine is clinically used to relieve systemic and local symptoms of chronic idiopathic urticaria and perennial allergic rhinitis. Recently, a literature report (CN 113209098 B) has shown that desloratadine can be used for paclitaxel-induced peripheral neuropathy.

[0005] However, desloratadine has limited effects on peripheral neuropathy, especially diabetic peripheral neuropathy, and more drugs with better effects on this condition are needed. Summary of the Invention

[0006] In response to the deficiencies of the prior art, the present invention provides a series of desloratadine derivatives, which significantly improve the inhibitory effect of neuroinflammation compared to desloratadine and significantly enhance the therapeutic effect on diabetic peripheral neuropathy.

[0007] In the first aspect, the present invention provides a compound represented by formula A or a pharmaceutically acceptable salt or an isomer thereof, wherein the structure of formula A is as follows:

[0008]

[0009] R is selected from

[0010] Preferably, R is

[0011] Preferably, the pharmaceutically acceptable salt includes an inorganic acid salt or an organic acid salt, such as malate, citrate, sulfonate, and the like.

[0012] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound represented by formula A described in the first aspect, or a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable excipient.

[0013] Preferably, the pharmaceutical composition contains the compound represented by formula A or a pharmaceutically acceptable salt or isomer thereof as the sole active ingredient.

[0014] In a third aspect, the present invention provides the use of the compound represented by formula A described in the first aspect, or its pharmaceutically acceptable salt or isomer thereof, or the pharmaceutical composition described in the second aspect, in the preparation of a drug for treating and / or preventing peripheral neuropathy.

[0015] Preferably, the peripheral neuropathy is peripheral axonal neuron damage, diabetic peripheral neuropathy, hereditary peripheral neuropathy, infectious peripheral neuropathy, toxic peripheral neuropathy, nutritional deficiency peripheral neuropathy, or autoimmune peripheral neuropathy.

[0016] More preferably, the peripheral neuropathy is diabetic peripheral neuropathy.

[0017] Compared with the prior art, the present invention has the following advantages:

[0018] The present invention optimizes the structure of the compound desloratadine to obtain a series of desloratadine derivatives. Compared with desloratadine, these derivatives have more excellent neuroinflammation inhibitory effects and can significantly improve the motor nerve conduction velocity and sensory loss of diabetic peripheral neuropathy. They have great application value in the treatment of diabetic peripheral neuropathy. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Effects of different compound interventions on the expression level of inflammatory factor IL-1β in cells. * indicates p<0.05, ** Indicates p<0.01, *** Indicates p<0.001.

[0020] Figure 2 Effect of compound A1 on nerve conduction velocity in mice with type 1 diabetic peripheral neuropathy.

[0021] Figure 3 Effects of compound A1 on mechanical pain in mice with type 1 diabetic peripheral neuropathy.

[0022] Figure 4 Effect of compound A1 on thermal pain in mice with type 1 diabetic peripheral neuropathy.

[0023] Figure 2-4 The comparison between the two groups was analyzed using T test. * P<0.05, ** P<0.01, *** P<0.001, compared with the normal group (Control). Comparisons of more than two groups were performed using one-way analysis of variance. # P<0.05, ## P<0.01, ### P<0.001, compared with the model group (STZ). The comparison between the two groups was analyzed by T test. & P<0.05, && P<0.01, &&& P < 0.001, STZ + DLT (15 mg / kg) compared with STZ + A1 (20 mg / kg). DETAILED DESCRIPTION

[0024] The following examples are intended to enable those skilled in the art to more fully understand the technical solutions and implementation effects of the present invention, but the scope of protection of the present invention is not limited thereto. This section further describes the present invention in detail in conjunction with specific implementation cases, and its technical features and advantages will be clearly reflected in the description. It should be pointed out that the embodiments are only exemplary descriptions and are not intended to limit the scope of the claims of the present invention. Any detailed adjustments, equivalent replacements, or adaptive improvements based on the core principles of the present invention fall within the substantive protection scope of the present invention.

[0025] Example 1 Synthesis of Compound A1

[0026]

[0027] 3-Dimethylaminopropionic acid hydrochloride (549 mg, 1 eq) and EDCI (3 eq) were dissolved in anhydrous dichloromethane. After stirring at room temperature for 5 minutes, HOBT (1.2 eq) was added. After stirring for 15 minutes, desloratadine (DLT) (0.9 eq) was added. TLC indicated the reaction was complete. The organic layer was washed twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to afford Compound A1 (591 mg) in a 40.3% yield; HPLC analysis revealed a 99.77% yield. 1 H NMR (500MHz, CDCl3) δ8.37(d,J=4.8Hz,1H),7.42(d,J=7.6Hz,1H),7.14(m,1H),7.12–7.09(m,2H),7.08–7.07( m,1H),3.98(m,1H),3.68(m,1H),3.41–3.11(m,4H),2.99(m,2H),2.78(m,4H),2.50(s,6H),2.41–2.27(m,4H); 13 C NMR (126MHz, CDCl3) δ168.9,157.1,147.0,139.9,138.0,137.8,136.8,135.1,133.7,133.4,130. 7,129.3,126.6,122.7,55.0,44.8,43.2,43.1,32.0,31.8,31.3,30.7,30.6; HRMS(ESI):m / z[M+H] + calcd for C 24 H 29 ClN3O + :410.1999,found:410.2004.

[0028] Example 2 Synthesis of Compound A2

[0029]

[0030] The same reaction as in Example 1 was carried out except that 3-dimethylaminopropionic acid hydrochloride in Example 1 was replaced with 2-(dimethylamino)acetic acid hydrochloride (499 mg, 1 equivalent) to obtain compound A2 (784 mg). Yield: 55.4%; HPLC: 99.79%. 1 HNMR(500MHz, CDCl3)δ8.38(m,1H),7.42(d,J=7.7Hz,1H),7.15(m,1H),7.11(m,2H),7.09–7.07(m,1H),4.06(m,1H),3.85(m,1H),3.41 –3.31(m,2H),3.29–3.23(m,1H),3.16–3.02(m,3H),2.83(m,2H),2.56–2.51(m,1H),2.49–2.43(m,1H),2.40–2.31(m,2H),2.24(s,6H); 13 CNMR (126MHz, CDCl3) δ168.6,157.2,146.8,139.6,137.6,137.2,134.5,133.5,133.1,130. 6,129.1,126.3,122.4,62.8,46.5,46.1,45.6,31.8,31.6,30.7,30.5; HRMS(ESI):m / z[M+H] + calcd for C 23 H 27 ClN3O + :396.1842,found:396.1858.

[0031] Example 3 Synthesis of Compound A3

[0032]

[0033] The same method as in Example 1 was used to replace 3-dimethylaminopropionic acid hydrochloride in Example 1 with 4-acetylaminobutyric acid (248 mg) to obtain compound A3 (590 mg). Yield: 79.1%; HPLC: 99.95%; 1H NMR (500MHz, CDCl3) δ8.38 (m, 1H), 7.43 (d, J = 7.7Hz, 1H), 7.16 (m, 1H), 7.1 4–7.10(m,2H),7.09–7.08(m,1H),6.42(d,J=6.1Hz,1H),4.06–3.96(m,1H ),3.73–3.59(m,1H),3.39–3.30(m,1H),3.27–3.15(m,5H),2.95–2.70(m, 2H),2.56–2.45(m,1H),2.41–2.28(m,5H),1.92(s,3H),1.87-1.81(m,2H); 13 C NMR (126MHz, CDCl3) δ171.4,170.5,156.9,146.7,139.6,137.8,137.6,136.7,134.8,133.5,133.2,130. 5,129.1,126.3,122.5,42.9,42.8,39.7,31.8,31.6,31.1,30.5,30.3,24.5,23.4; HRMS(ESI):m / z[M+H] + calcd for C 25 H 29 ClN3O2 + :438.1948,found:438.1966.

[0034] Example 4 Synthesis of Compound A4

[0035]

[0036] As in Example 1, 3-dimethylaminopropionic acid hydrochloride in Example 1 was replaced with N-boc-aminobutyric acid (200 mg) to obtain intermediate B1. B1 (1 equivalent) was dissolved in dichloromethane, and a 4M HCl solution in 1,4-dioxane (2 equivalents) was added. The mixture was stirred for 20 minutes. TLC indicated the reaction was complete. The compound was dried in vacuo and dissolved in water. The mixture was washed twice with dichloromethane. The pH of the aqueous phase was adjusted to 8-9 with 1M sodium hydroxide solution. The aqueous phase was extracted twice with ethyl acetate. The ethyl acetate phases were combined and dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to obtain A4. Yield: 78.0%; HPLC: 100%. 1H NMR(500MHz,D2O)δ8.53(m,1H),8.34(d,J=8.1Hz,1H),7.86(t,J=6.6Hz,1 H),7.24(m,1H),7.17(m,2H),4.25–3.98(m,1H),3.88(m,1H),3.55(m,1H) ,3.45–3.36(m,1H),3.33–3.20(m,1H),3.09–2.97(m,3H),2.94–2.83(m,2 H),2.67–2.55(m,3H),2.53–2.46(m,1H),2.40–2.32(m,2H),1.97(m,2H); 13 C NMR(126MHz,D2O)δ172.7,148.4,144.6,139.8,139.2,138.4,135.2,133.8,130.2,128.9,12 6.7,126.2,125.6,45.6,45.3,42.3,42.0,39.0,30.5,29.9,29.7,22.5; HRMS(ESI):m / z[M+H] + calcd for C 23 H 27 ClN3O + :396.1842,found:396.1857.

[0037] Example 5 Synthesis of Compound A5

[0038]

[0039] Dissolve 1.93 g (19.3 mmol) of succinic anhydride (Sinopharm Group) in 10 ml of anhydrous dichloromethane (Annaige Reagent) and add 5 g (16.1 mmol) of desloratadine (Bidec Pharmaceuticals). Stir at room temperature for 2 hours. TLC indicates the reaction is complete. The solvent is concentrated in vacuo, and the crude product is purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain Intermediate B2.

[0040] Intermediate B2 (0.5 mmol, 1 equivalent) and EDCI (2 mmol, 4 equivalents) were dissolved in anhydrous dichloromethane, and DIPEA (2 mmol, 4 equivalents) was added. After stirring at room temperature for 5 minutes, DMAP (0.25 mmol, 0.5 equivalents) was added. After stirring for 15 minutes, N-boc-ethanolamine (0.6 mmol, 1.2 equivalents) was added. After 12 hours, TLC indicated the reaction was complete. The organic layer was washed twice with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to obtain Intermediate B3.

[0041] Intermediate B3 (1 equivalent) was dissolved in dichloromethane. 4M HCl dissolved in 1,4-dioxane (2 equivalents) was added and stirred for 20 minutes. TLC indicated the reaction was complete. The compound was dried in vacuo and dissolved in water. The solution was washed twice with dichloromethane. The pH of the aqueous phase was adjusted to 8-9. The aqueous phase was extracted twice with ethyl acetate. The combined ethyl acetate phases were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to afford A5. Yield: 86.3%; HPLC: 98.83%. 1 H NMR (500MHz, CDCl3) δ8.38(d,J=4.8Hz,1H),7.44(d,J=7.8Hz,1H),7.15(m, 1H),7.14–7.10(m,2H),7.10–7.08(m,1H),6.72(t,J=5.9Hz,1H),3.98(m,1 H),3.67(m,3H),3.40–3.34(m,4H),3.34–3.22(m,1H),3.22–3.10(m,1H),2 .87–2.77(m,2H),2.77–2.63(m,2H),2.59–2.43(m,3H).2.43–2.24(m,4H); 13 C NMR (126MHz, CDCl3) δ173.9,170.7,156.9,146.8,139.6,137.8,136.7,134.8,133.6,133.5,133.2,130. 6,129.2,126.4,122.5,62.0,46.2,43.0,42.9,31.6,31.1,30.9,30.5,30.3,29.0; HRMS(ESI):m / z[M+H] + calcd for C 25 H 29 ClN3O3 + :454.1897,found:454.1874.

[0042] Example 6 Synthesis of Compound A6

[0043]

[0044] Example 5: Intermediate B2 (500 mg, 0.5 mmol, 1 eq) and EDCI (2 mmol, 4 eq) were dissolved in anhydrous dichloromethane, and DIPEA (2 mmol, 4 eq) was added. After stirring at room temperature for 5 minutes, DMAP (0.25 mmol, 0.5 eq) was added. After stirring for 15 minutes, 2-(dimethylamino)-ethanol (0.6 mmol, 1.2 eq) was added. After 12 hours, TLC indicated the reaction was complete. The organic layer was washed twice with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to obtain A6 (403 mg) as a colorless oil. Yield: 68.7%; HPLC: 99.51%. 1 H NMR(500MHz, CDCl3)δ8.32(d,J=4.7Hz,1H),7.40–7.35(m,1H),7.10(m,1H),7.08–7.02(m,3H),4.24(t,J=5.5Hz,2H),3.95(m,1H),3 .75–3.17(m,1H),3.56–3.17(m,3H),3.14–3.00(m,1H),2.76(m,4H),2.61(m,4H),2.52–2.43(m,1H).2.39(s,6H),2.36–2.23(m,3H); 13 C NMR (126MHz, CDCl3) δ173.0,169.5,156.8,146.6,139.5,137.6,136.7,134.6,133.4,133.3,132.9,130.4, 129.0,126.1,122.3,61.0,57.1,46.0,44.9,42.8,31.6,31.4,30.8,30.4,29.3,28.0; HRMS(ESI):m / z[M+H] + calcd for C 27 H 33 ClN3O3 + :482.2210,found:482.2201.

[0045] Example 7 Synthesis of Compound A7

[0046]

[0047] Compound A6 (200 mg, 1 equivalent) was dissolved in 5 mL of ethyl acetate, ICH₃ (10 equivalents), and K₂CO₃ (10 equivalents) and reacted at 60°C for 16 hours. TLC indicated completion of the reaction. The solid was filtered and washed three times with ethyl acetate. The product was dissolved in anhydrous ethanol, filtered, and the filtrate was dried under vacuum. The filtrate was purified by silica gel column chromatography to afford A7 as a reddish-brown solid. Yield: 27.6%; HPLC: 94.03%. 1 H NMR(500MHz,D2O)δ8.63(s,1H),8.45(s,1H),7.87(s,1H),7.43–7.14(m,3H),4.59(s,2H),4.26–4.21(m,3H),4.08(s,1H),3.90(s ,1H),3.75(m,5H),3.49(m,2H),3.24(s,9H),3.17–3.08(m,1H),2.98(s,1H),2.83(s,1H),2.73(s,1H),2.65(s,1H),2.51(m,1H); 13 C NMR(126MHz,D2O)δ174.4,172.3,154.4,144.9,143.2,143.1,140.9,138.9,134.0,132.0,130.7,126.5,1 26.3,124.7,124.6,64.5,58.5,55.4,45.6,45.2,31.0,30.7,30.2,29.9,29.5,29.0,27.6; HRMS(ESI):m / z M + calcd for C 28 H 35 ClN3O3 + :496.2361,found:496.2369.

[0048] Example 8 Synthesis of Compound A8

[0049]

[0050] Intermediate B2 (0.5 mmol, 1 equivalent) and EDCI (2 mmol, 4 equivalents) from Example 5 were dissolved in anhydrous dichloromethane, and DIPEA (2 mmol, 4 equivalents) was added. After stirring at room temperature for 5 minutes, DMAP (0.25 mmol, 0.5 equivalents) was added. After stirring for 15 minutes, 2-benzyloxy-1-ethylamine hydrochloride (0.6 mmol, 1.2 equivalents) was added. TLC indicated the reaction was complete, and the organic layer was washed twice with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to obtain Intermediate B4.

[0051] Intermediate B4 (198 mg) and Pd / C (10 mg) were dissolved in 10 mL of anhydrous THF and reacted at room temperature under hydrogen for 8 hours. TLC indicated the reaction was complete. The reaction solution was filtered through celite and washed twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography to afford Compound A8 (114 mg). Yield: 69.0%; HPLC: 99.5%. 1 H NMR (500MHz, CDCl3) δ8.37(dd,J=4.9,1.5Hz,1H),7.43(m,1H),7.23–7.12(m,4H),7.08(m,1H),6.74(q,J=5.1Hz,1H),3.99(m,1H),3.78–3.60(m,3H ),3.46–3.31(m,4H),3.29–3.22(m,1H),3.20–3.11(m,1H),2.84(m,2H),2 .78–2.63(m,2H),2.59–2.45(m,3H),2.44–2.40(m,1H),2.39–2.28(m,2H); 13 C NMR (126MHz, CDCl3) δ173.9,170.6,157.3,146.6,139.3,139.2,137.8,136.0,135.9,133.9,133.8,129. 2,127.7,126.3,122.4,62.0,43.1,43.0,42.7,31.7,31.1,30.9,30.5,30.2,29.0; HRMS(ESI):m / z[M+H] + calcd for C 25 H 29 ClN3O3 + :454.1897,found:454.1869.

[0052] Example 9 Synthesis of Compound A9

[0053]

[0054] As in Example 6, intermediate B2 was reacted with 3,5-dimethyl-1-aminoadamantane hydrochloride (107 mg, 1.2 equivalents) to give white foamy solid A9. Yield: 47.6%; HPLC: 98.71%; 1H NMR(500MHz, CDCl3)δ8.43(d,J=4.7Hz,1H),7.47(d,J=7.7Hz,1H),7.21–7.10 (m,4H),4.23–3.94(m,1H),3.73(m,1H),3.49–3.32(m,1H),3.32–3.05(m,1H) ,2.92–2.79(m,2H),2.73–2.62(m,2H),2.52–2.24(m,4H),1.83(s,2H),1.65( s,2H),1.60(s,9H),1.39(m,1H),1.29(m,2H),1.22–1.08(m,2H),0.86(s,6H); 13 C NMR (126MHz, CDCl3) δ171.6,170.4,156.9,146.7,139.5,137.7,136.8,134.6,133.4,133.0,130.5,129.0,126.3,122.4,53.4,50. 6,47.5,46.1,42.9,42.8,42.7,40.1,32.5,32.4,31.7,31.5,31.1,30.9,30.5,30.2,30.1,30.1,29.7,28.7; HRMS(ESI):m / z[M+H] + calcd for C 35 H 43 ClN3O2 + :572.3044,found:572.3028.

[0055] Example 10 Synthesis of Compound A10

[0056]

[0057] Dissolve 2.20 g (19.3 mmol) of glutaric anhydride (Sinopharm Group) in 10 ml of anhydrous dichloromethane (Annaiji Reagent) and add 5 g (16.1 mmol) of desloratadine (Biden Pharmaceuticals). Stir at room temperature for 2 hours. TLC indicates the reaction is complete. The solvent is concentrated in vacuo, and the crude product is purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain Intermediate B5.

[0058] Intermediate B5 (0.5 mmol, 1 equivalent) and EDCI (2 mmol, 4 equivalents) were dissolved in anhydrous dichloromethane, and DIPEA (2 mmol, 4 equivalents) was added. After stirring at room temperature for 5 minutes, DMAP (0.25 mmol, 0.5 equivalents) was added. After stirring for 15 minutes, N-boc-ethanolamine (0.6 mmol, 1.2 equivalents) was added. After 12 hours, TLC indicated the reaction was complete. The organic layer was washed twice with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to obtain Intermediate B6.

[0059] Intermediate B6 (1 equivalent) was dissolved in dichloromethane. 4M HCl dissolved in 1,4-dioxane (2 equivalents) was added and stirred for 20 minutes. TLC indicated the reaction was complete. The compound was dried in vacuo and dissolved in water. The mixture was washed twice with dichloromethane. The pH of the aqueous phase was adjusted to 8-9, and the aqueous phase was extracted twice with ethyl acetate. The combined ethyl acetate phases were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to afford compound A10. Yield: 80.5%; HPLC: 98.38%. 1 H NMR (500MHz, CDCl3) δ8.38 (dd, J=7.1, 5.0Hz, 1H), 7.46 (dd, J=7.7, 3.0Hz, 1H), 7.1 6(m,1H),7.15–7.11(m,2H),7.11–7.09(m,1H),4.15–4.00(m,1H),3.69(m,3H),3. 49–3.28(m,4H),3.24(m,1H),3.11(m,2H),2.90–2.75(m,2H),2.55–2.48(m,1H),2 .47–2.39(m,3H),2.37–2.32(m,3H),2.30–2.24(m,3H),1.96(m,2H),1.40(m,1H); 13 C NMR (126MHz, CDCl3) δ173.6,171.3,156.9,146.6,139.6,137.9,137.5,136.8,134.6,133.6,133.2,130.6,129 .2,129.1,126.4,122.6,62.0,46.0,42.9,42.5,35.5,32.2,31.7,31.6,31.2,30.6,21.3; HRMS(ESI):m / z[M+H] + calcd for C 26 H 31 ClN3O3 + :468.2054,found:468.2041.

[0060] Example 11 Synthesis of Compound A11

[0061]

[0062] Example 10: Intermediate B5 (500 mg, 0.5 mmol, 1 eq) and EDCI (2 mmol, 4 eq) were dissolved in anhydrous dichloromethane, and DIPEA (2 mmol, 4 eq) was added. After stirring at room temperature for 5 minutes, DMAP (0.25 mmol, 0.5 eq) was added. After stirring for 15 minutes, 2-(dimethylamino)-ethanol (0.6 mmol, 1.2 eq) was added. After 12 hours, TLC indicated the reaction was complete. The organic layer was washed twice with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to obtain A11 (348 mg) as a colorless oil. Yield: 59.6%; HPLC: 92.87%. 1 H NMR(500MHz, CDCl3)δ8.40(t,J=4.4Hz,1H),7.44(d,J=7.7Hz,1H),7.16(m,1H),7.15–7.13( m,2H),7.11–7.09(m,1H),4.25(t,J=5.5Hz,2H),4.04(m,1H),3.69(m,1H),3.46–3.27(m,2H ),3.26–3.20(m,1H),3.18–3.09(m,1H),2.88–2.76(m,2H),2.72(m,2H),2.56–2.49(m,2H), 2.48–2.42(m,2H),2.40(m,6H),2.38–2.35(m,2H),2.33–2.30(m,2H),1.95(p,J=7.2Hz,2H); 13 C NMR (126MHz, CDCl3) δ173.3,170.8,157.1,146.8,139.6,137.7,137.0,134.7,133.5,133.2,130.6,129.1, 126.4,122.5,61.3,57.5,45.3,42.8,42.7,33.5,32.4,31.8,31.6,30.6,30.4,20.5; HRMS(ESI):m / z[M+H] + calcd for C 28 H 35 ClN3O3 + :496.2367,found:496.2352.

[0063] Example 12 Synthesis of Compound A12

[0064]

[0065] Compound A7 (200 mg, 1 equivalent) was dissolved in 5 mL of ethyl acetate, ICH3 (10 equivalents), and K2CO3 (10 equivalents) and reacted at 60°C for 16 hours. TLC indicated completion of the reaction. The solid was filtered and washed three times with ethyl acetate. The product was dissolved in anhydrous ethanol, filtered, and the filtrate was dried under vacuum. The filtrate was purified by silica gel column chromatography to afford A12 as a reddish-brown solid. Yield: 35.4%; HPLC: 99.0%. 1 H NMR(500MHz,D2O)δ8.59(d,J=6.2Hz,1H),8.43(d,J=7.9Hz,1H),7.84(t,J=7.0Hz,1H),7.36–7.25(m,3H),4.56(d,J=5.8Hz,2H),4.22(s,3 H),4.09(m,1H),3.88(m,1H),3.76–3.70(m,6H),3.58(m,1H),3.49–3 .28(m,2H),3.21(s,9H),3.04(m,2H),2.67–2.58(m,1H),2.51(m,3H); 13 C NMR(126MHz,D2O)δ174.6,173.7,154.4,144.8,143.1,143.1,140.9,138.9,134.1,131.9,130.7,1 26.3,124.7,64.5,58.3,55.4,53.8,45.5,45.5,32.8,31.9,30.9,30.1,29.4,20.0; HRMS(ESI):m / z M + calcd for C 29 H 37 ClN3O3 + :510.2518,found:510.2519.

[0066] Example 13 Synthesis of Compound A13

[0067]

[0068] Intermediate B5 in the example was used to replace intermediate B2 in example 8. After condensation and deprotection, compound A13 was obtained. Yield: 66.2%; HPLC: 98.1%; 1H NMR(500MHz, CDCl3)δ8.38(dd,J=9.9,4.8Hz,1H),7.47–7.41(m,1H),7.18(m ,3H),7.13–7.07(m,1H),6.40(s,1H),4.19–4.02(m,1H),3.71(m,3H),3.53–3 .30(m,4H),3.24(m,1H),3.11(m,1H),2.86(m,2H),2.58–2.48(m,2H),2.47– 2.42(m,1H),2.41–2.34(m,2H),2.32–2.25(m,3H),1.98(m,2H),1.26(m,1H); 13 C NMR (126MHz, CDCl3) δ173.6,171.3,157.1,146.3,139.1,138.0,137.9,137.7,136.0,135.6,134.0,129.1, 127.7,126.2,122.4,61.8,46.6,43.0,42.4,31.9,31.8,31.2,30.5,30.3,29.8,21.4; HRMS(ESI):m / z[M+H] + calcd for C 26 H 31 ClN3O3 + :468.2054,found:468.2041.

[0069] Example 14 Synthesis of Compound A14

[0070]

[0071] Same as Example 9, except that intermediate B5 was used instead of intermediate B2, compound A14 was obtained with a yield of 50.7% and a HPLC analysis of 98.2%. 1 H NMR (500MHz, CDCl3) δ8.34 (t, J=4.1Hz, 1H), 7.40 (dd, J=7.7, 1.6Hz, 1H), 7.18–6.9 9(m,4H),4.14–3.92(m,2H),3.65(m,1H),3.40–3.24(m,1H),3.15(m,2H),2.85–2. 70(m,2H),2.59–2.21(m,6H),2.12(m,2H),2.07–2.03(m,1H),1.84(m,2H),1.75(m ,2H),1.57(s,4H),1.36(m,2H),1.24–1.17(m,3H),1.15–1.02(m,2H),0.77(s,6H);13 C NMR (126MHz, CDCl3) δ171.3,156.8,146.6,139.6,137.7,137.5,136.7,134.6,133.4,133.0,130.4,129.0,126.2,122.4,60.4,55.3,5 3.4,50.6,47.5,46.4,43.3,42.6,40.1,36.5,32.3,31.6,31.5,31.3,31.1,30.5,30.3,30.1,21.6,21.0,14.2; HRMS(ESI):m / z[M+Na] + calcdfor C 36 H 44 ClNaN3O2 + :608.3022,found:608.2994.

[0072] Test Example 1: In vitro experiment on the improvement of inflammation of diabetic peripheral neuropathy by the series of compounds of the present invention

[0073] The present invention tests the effects of desloratadine derivatives on inflammation-related transcription factors in an LPS / ATP-induced in vitro inflammation model. The experiment shows that the desloratadine derivatives designed and prepared by the present invention have a significant effect on improving inflammation.

[0074] 1.1 Experimental Principle

[0075] This experiment is based on the fact that patients with diabetic peripheral neuropathy will experience neuroinflammation. Inflammation-related indicators were detected in Schwann cells to evaluate the improving effect of desloratadine derivatives on neuroinflammation in peripheral neuropathy.

[0076] 1.2 Experimental Materials and Methods

[0077] On the first day, 1×10 5Schwann cells were seeded at a density of 10 μM. After the cells attached, LPS / ATP stimulation was administered to induce the expression of inflammatory markers in Schwann cells. After administration of 10 μM of the compound, total RNA from the Schwann cells was extracted. The treated Schwann cells were placed in 1.5 mL EP tubes and lysed with 1 mL of RNAiso Plus per tube for 3-5 minutes. After lysis, 200 μL of chloroform was added, the tubes were shaken vigorously upside down, and then allowed to stand for 5 minutes. Finally, the tubes were centrifuged at 12,000 rpm / min at 4°C for 15 minutes. After centrifugation, the samples were separated into separate layers. The upper layer contained RNA, and approximately 400 μL of RNA was transferred to a new EP tube, avoiding the middle layer. 500 μL of isopropanol was then added, the tubes were mixed by inversion, and allowed to stand for 10 minutes. The tubes were centrifuged at 12,000 rpm / min at 4°C for 10 minutes. After centrifugation, the EP tubes were removed and the supernatant discarded. A small amount of precipitate would form at the bottom of the tubes. Add 1 mL of 75% ethanol for washing, then centrifuge at 12,000 rpm / min at 4°C for 10 minutes. Remove and discard the supernatant, and repeat the wash cycle. Finally, open the cap of the EP tube and air dry. Add 30 μL of DEPC water to each tube and dissolve it at 55-60°C for 10 minutes. Finally, measure the total RNA concentration using a nucleic acid quantifier. Generally, an A260 / A280 ratio between 1.8 and 2.0 is suitable. Next, use a reverse transcription kit to reverse the mRNA into cDNA. Set the reverse transcription program to 37°C for 15 minutes, 85°C for 5 seconds, and 10°C for ∞. The reverse-transcribed cDNA is subjected to real-time quantitative PCR using the SYBR Premix Ex Taq kit on a BIO-RAD CFX connect real-time system. The specific RT-PCR program is as follows: 94°C, 1 min; 95°C, 30 s; 63°C, 45 s; 72°C, 45 s; 80°C, 1 s; read the plate; repeat the above steps for 44 cycles; 72°C, 10 min; gradually increase the temperature from 50 to 95°C, reading the plate once every 0.5°C increase; 10°C, 10 min to end the program.

[0078] 1.3 Experimental Results

[0079] result Figure 1As shown, the expression level of IL-1β in the model group after LPS / ATP treatment was extremely significantly increased compared to the blank control group (p<0.001). However, after intervention with DLT (i.e., desloratadine) and compounds A1, A4, and A14, the expression levels of IL-1β were significantly or extremely significantly decreased compared to the model group (p<0.01 or p<0.001). Among them, compounds A4 and A14 had the best inhibitory effects on inflammation. Compound A14 had a significantly better (p<0.01) IL-1β-lowering effect than DLT, and compound A4 had a significantly better (p<0.05) IL-1β-lowering effect than DLT.

[0080] Test Example 2: Compound A1 improves slow motor nerve conduction velocity and sensory loss in diabetic peripheral neuropathy

[0081] The present invention detects the effect of compound A1 on motor nerve conduction velocity and pain response of diabetic peripheral neuropathy in streptozotocin (STZ)-induced type 1 diabetic mice. The experiment shows that compound A1 has the effect of significantly improving the slow motor nerve conduction velocity and sensory loss of diabetic peripheral neuropathy.

[0082] 2.1 Experimental Principle

[0083] 1) Motor Nerve Conduction Velocity Test: ① Electrode Placement: The stimulating electrode is placed on the nerve trunk, the recording electrode on the muscle belly, and the reference electrode on the tendon; the ground wire is placed between the stimulating and recording electrodes. ② Calculation of Motor Nerve Conduction Velocity: Super-intense stimulation of the distal and proximal ends of the nerve trunk will record two compound muscle action potentials in the muscle innervated by the nerve. The different latencies are measured, and the nerve conduction velocity is calculated by dividing the distance between the distal and proximal ends by the latency difference between the two points. The calculation formula is: Nerve Conduction Velocity (m / s) = Distance between the two points (cm) × 10 / Latency difference between the two points.

[0084] 2) Mechanical pain detection experiment: This experiment is based on the fact that when the rodent's paw is mechanically stimulated, they will retract their paw. Von frey can provide a stimulation force of 0.4-4.0g, and the thickness and extension length of the nylon thread determine the magnitude of the stimulation force. The experiment selects a nylon thread of appropriate thickness according to the actual situation, adjusts the appropriate extension length, and stimulates the skin vertically. The stimulation force can be adjusted by adjusting the extension and replacing the nylon thread until the nylon thread bends, thereby evaluating the mouse's response to pain. A mouse is measured six times to determine the threshold value, based on 50%threshold=(10^(x f The mechanical pain threshold of 50% mice was calculated by using kδ / 10000.

[0085] 3) Thermal pain detection experiment: The mouse was placed in one of the four compartments of the enclosure to adapt to the environment for 30 minutes. Then the infrared light source was moved under the glass plate and aimed at the sole of the mouse's right foot. The button on the infrared generator was adjusted to start the infrared stimulation. Once the mouse felt pain, it would react, such as retracting its foot, licking its foot, stomping its foot, and lifting its leg. This process would cause the infrared light source to be cut off and the heat reflex to drop suddenly, so that the reaction timer would stop timing. The withdrawal reaction time can be calculated to almost 0.1s. When many mice need to be tested, 4 compartments can be tested at the same time to improve efficiency. In order to avoid injury, the maximum stop time was controlled to 25s. The time it took for each group of animals to respond to thermal radiation was recorded. Each mouse was tested 3 times, with an interval of about 15 minutes between each test. The average retraction time of each mouse was calculated to assess the mouse's sensitivity to thermal pain.

[0086] 4) The Von frey fiber analgesia meter and infrared thermal analgesia meter were purchased from UGO.

[0087] 2.2 Experimental Materials and Methods

[0088] DPN animal model: C57BL / 6J mice were purchased from Beijing Weitonglihua. After one week of acclimatization, STZ (150 mg / kg) was injected intraperitoneally. Blood glucose was measured 4-7 days later, and mice with blood glucose levels above 16 mmol / L were selected. After successful model establishment, body weight, blood glucose, and mechanical and thermal pain were monitored weekly. Six weeks after STZ injection, mechanical and thermal pain thresholds increased, and nerve conduction velocity slowed, indicating the onset of DPN symptoms. Mice were then grouped according to body weight and blood glucose into the model group (STZ), a low-dose STZ + A1 (10 mg / kg / day) group, a high-dose STZ + A1 (20 mg / kg / day) group, and a positive compound STZ + DLT (15 mg / kg) group, with 12 mice in each group. Additionally, 12 normal mice were used as a control group (normal saline containing 2% DMSO and 4% Tween-80).

[0089] All animals were administered intragastric administration for four weeks, with both the normal and model groups receiving saline. Compound A1 solution was prepared by weighing an appropriate amount of Compound A1 powder and dissolving it in saline. Mechanical and thermal pain thresholds were monitored weekly over the four-week dosing period. Motor nerve conduction velocity was measured at week 0, week 4, week 8, and week 10 following STZ injection.

[0090] 2.3 Experimental Results

[0091] according to Figure 2 It can be seen that at the 4th week, the motor nerve conduction velocity of the other groups was significantly slower than that of the normal group, with significant differences ( ***P<0.001); in the 8th and 10th week measurements, compared with the model group, the motor nerve conduction velocity in the A1 low-dose group, A1 high-dose group, and desloratadine group was significantly faster, with significant differences ( ### P < 0.001). At week 10, the motor nerve conduction velocity in the low-dose A1 group was faster than that in the desloratadine group (ns, not significant), while the motor nerve conduction velocity in the high-dose A1 group was significantly faster (ns, not significant). && P<0.01).

[0092] according to Figure 3 It can be seen that at weeks 7, 8, 9, and 10, the mechanical pain thresholds of the A1 low-dose group, A1 high-dose group, and desloratadine group were significantly lower than those of the model group, with significant differences ( ## P<0.01, ### P < 0.001). At week 10, the mechanical pain threshold of the A1 low-dose group was comparable to that of the desloratadine group (ns, not significant), while the mechanical pain threshold of the A1 high-dose group was significantly lower ( & P<0.05).

[0093] according to Figure 4 It can be seen that at weeks 7, 8, 9, and 10, compared with the model group, the thermal pain thresholds of the A1 low-dose group, A1 high-dose group, and desloratadine group were significantly lower ( ## P<0.001, ### P < 0.001). At week 10, the heat pain threshold of the A1 low-dose group was comparable to that of the desloratadine group (ns, not significant), while the heat pain threshold of the A1 high-dose group was significantly lower ( && P<0.01).

[0094] The above results show that compound A1 can significantly improve the motor nerve conduction velocity, mechanical pain threshold, and thermal pain threshold in mice with diabetic peripheral neuropathy, and is significantly more effective than desloratadine (it can achieve the same effect as desloratadine at a lower dose, and it performs significantly better than desloratadine in all aspects when a dose slightly higher than desloratadine is used), showing its significant therapeutic effect on diabetic peripheral neuropathy.

[0095] Finally, it should be noted that the above embodiments are only used to illustrate rather than limit the technical solutions of the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the present invention can still be modified or replaced by equivalents. Any modification or partial replacement that does not depart from the spirit and scope of the present invention should be included in the scope of the claims of the present invention.

Claims

1. The compound represented by formula A or a pharmaceutically acceptable salt or isomer thereof, wherein the structure of formula A is as follows: R is selected from 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an isomer thereof, characterized in that: R is 3. A pharmaceutical composition comprising the compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable excipient.

4. The pharmaceutical composition according to claim 3, characterized in that The pharmaceutical composition contains the compound or its pharmaceutically acceptable salt or isomer as the sole active ingredient.

5. Use of the compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt or isomer thereof, or the pharmaceutical composition according to claim 3 or 4, in the preparation of a medicament for treating and / or preventing peripheral neuropathy.

6. The use according to claim 5, characterized in that The neurodegenerative disease is peripheral axonal neuron damage, diabetic peripheral neuropathy, hereditary peripheral neuropathy, infectious peripheral neuropathy, toxic peripheral neuropathy, nutritional deficiency peripheral neuropathy or autoimmune peripheral neuropathy.

7. The use according to claim 6, characterized in that The neurodegenerative disease is diabetic peripheral neuropathy.

Images