Quaternary ammonium salt compound of 3-hydroxyisonicotinic acid dexcamphanol ester and pharmaceutical application of quaternary ammonium salt compound

Abstract

The invention discloses a quaternary ammonium salt compound of 3-hydroxy isonicotinic acid dexcamphanol ester, the structure of which is shown as a formula I, R is selected from saturated or unsaturated C1-C6 alkyl and substituted or unsubstituted benzyl, the substituent group of # imgabs0 # benzyl is selected from halogen, C1-C3 alkyl, C1-C3 alkoxy and C1-C3 halogen substituted alkyl, # imgabs1 # R1 is selected from NH2, C1-C4 alkyl, C1-C4 alkoxy, phenyl and phenoxyl, and the substituent group of # imgabs0 # benzyl is selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, phenyl and phenoxyl. R2 is selected from H and C1-C3 alkyl groups; x is selected from bromine and iodine. The compound disclosed by the invention has a good anti-inflammatory effect and can be used for preparing medicines for treating inflammation-related diseases. The invention also discloses an application of the quaternary ammonium salt compound of the 3-hydroxyisonicotinic acid dexcamphanol ester in preparation of medicines for treating inflammation-related diseases. # imgabs2 #

Description

Technical Field

[0001] The invention belongs to the pharmaceutical field and relates to a quaternary ammonium salt compound of 3-hydroxyisonicotinic acid dextranol ester and its pharmaceutical use. Background Art

[0002] During the inflammatory response, macrophages play an important role in initiating, maintaining, and resolving inflammatory responses. Lipopolysaccharide (LPS) is one of the main components of the cell wall of Gram-negative bacteria and has a strong immunostimulatory ability. RAW264.7 macrophages, as a type of mouse-derived immune cell, will be activated when stimulated by external factors (such as LPS), secreting numerous inflammatory factors (such as NO, IL-1β, TNF-α, etc.) and producing an inflammatory response. The amount of inflammatory factors can indirectly reflect the severity of inflammation and is a quantitative indicator of the severity of inflammation. Summary of the invention

[0003] In the previous study, the inventors found a class of 2-hydroxynicotinate or nicotinate derivatives (CN118206481A), which have good neuroprotective effects and good therapeutic effects on central inflammation-related diseases such as stroke, neuropathic pain, depression, etc. The inventors further found that the 3-hydroxyisonicotinic acid nicotinate derivatives (control compound, i.e., compound 1a) obtained by structural modification of the compounds did not show obvious anti-inflammatory effects. The inventors unexpectedly found that the quaternary ammonium salt of 3-hydroxyisonicotinic acid nicotinate showed significant anti-inflammatory effects; at the same time, the inventors also found that the half-life of the compounds was short, so after the drug was locally administered, it could play an anti-inflammatory role, enter the blood and be quickly metabolized, and have better safety. Therefore, it is more suitable for local administration: such as sprays for respiratory inflammation and eye drops for eye inflammation. Local administration may achieve better efficacy and safety and is widely used in clinical practice. For example: cortisol drugs have good anti-inflammatory effects, but they are also accompanied by toxicity during treatment. After loteprednol is applied to the eyes, it is quickly metabolized into inactive products, which reduces systemic toxicity, and its anti-inflammatory effect is stronger than prednisolone. Budesonide can reach the entire lungs by atomizing and inhaling a 1%-5% solution, which can inhibit airway hyperresponsiveness and reduce glandular secretions. It can also promote airway dilation, reduce airway mucus secretion, and improve lung ventilation function. Inhalation therapy directly reaches the target organ, has a fast onset of action, small reactions, and high safety.

[0004]

[0005] The object of the present invention is to provide a quaternary ammonium salt compound of 3-hydroxyisonicotinic acid dextranol ester.

[0006] The objective of the present invention is achieved through the following technical solutions:

[0007] The quaternary ammonium salt compound of 3-hydroxyisonicotinic acid dextranol ester has a structure as shown in Formula I:

[0008]

[0009] Wherein, R is selected from saturated or unsaturated C1-C6 hydrocarbon group, substituted or unsubstituted benzyl group, The substituents of the benzyl group are selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 halogen-substituted alkyl, R1 is selected from NH2, C1-C4 alkyl, C1-C4 alkoxy, phenyl, phenoxy; R2 is selected from H, C1-C3 alkyl; X is selected from bromine, iodine.

[0010] Preferably, R is selected from substituted or unsubstituted benzyl, C1-C3 alkyl, The substituents of the benzyl group are selected from fluorine, methyl, methoxy, trifluoromethane, The position of the substituent can be located at the ortho, meta or para position of the existing substituent on the benzene ring; R1 is selected from NH2, C1-C4 alkyl, C1-C4 alkoxy, phenyl, phenoxy; R2 is selected from H, methyl; R3, R4, R5 are independently selected from H, methyl; X = bromine, iodine.

[0011] More preferably, R is selected from substituted or unsubstituted benzyl, The substituent of the benzyl group is selected from fluorine, methyl, methoxy, and trifluoromethane, and the position of the substituent is located in the para position of the existing substituent of the benzene ring; R3=R4=R5=H; R3=methyl, R4=R5=H; R3=H, R4=R5=methyl; X=bromine, iodine.

[0012] Specifically, the quaternary ammonium salt compound of 3-hydroxyisonicotinic acid dextranol ester has the following structure:

[0013]

[0014]

[0015] Another object of the present invention is to provide the use of the quaternary ammonium salt compound of 3-hydroxyisonicotinic acid dextranol ester in the preparation of drugs for treating inflammation-related diseases.

[0016] The inflammation-related diseases are rheumatoid arthritis, eye inflammation, respiratory tract inflammation and the like.

[0017] Specifically, the eye inflammation is conjunctivitis.

[0018] Another object of the present invention is to provide a pharmaceutical composition for treating inflammation-related diseases, wherein the pharmaceutical composition uses the quaternary ammonium salt compound of 3-hydroxyisonicotinic acid dextran as an active ingredient and is prepared into a pharmaceutically acceptable dosage form with pharmaceutically acceptable excipients.

[0019] Preferably, the dosage form is a solution, a spray, a patch, a gel, etc.

[0020] Another object of the present invention is to provide use of the pharmaceutical composition in preparing drugs for treating inflammation-related diseases.

[0021] Beneficial effects of the present invention:

[0022] The quaternary ammonium salts of 3-hydroxyisonicotinic acid dextranol ester of the present invention have good anti-inflammatory effects and can be used to prepare drugs for treating inflammation-related diseases. Since the quaternary ammonium salt structure exists in the quaternary ammonium salts of 3-hydroxyisonicotinic acid dextranol ester, the compounds are difficult to enter the central nervous system and have better safety for peripheral inflammation-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The compound of the present invention has an inhibitory effect on the swelling of the paw of rats caused by carrageenan. DETAILED DESCRIPTION

[0024] The following examples are intended to enable those skilled in the art to fully understand the present invention, but are not intended to limit the present invention in any way.

[0025] Example 1

[0026] Synthesis of target compounds

[0027] 1.1) Synthesis of 1-methyl-3-hydroxyisonicotinic acid dextranol iodide (Compound 1)

[0028] Synthesis route:

[0029]

[0030] Step (1): isonicotinic acid (5.00 mmol), borneol (5.50 mmol), dicyclohexylcarbodiimide (7.50 mmol) and 4-dimethylaminopyridine (2.50 mmol) were reacted in dichloromethane (8 mL) at room temperature for 12 h; after the reaction was completed, the mixture was filtered; the filtrate was taken, the filtrate was spin-dried, 100 mL of ethyl acetate was added to dissolve it, and the mixture was washed three times with saturated brine, each time with 100 mL of saturated brine, the organic layer was collected, dried, and then purified by normal phase silica gel chromatography (petroleum ether: ethyl acetate = 20:1 V / V) to obtain compound 1a (control compound) as a white powder with a yield of 73%.

[0031] Step (2): Compound 1a (1.00 mmol) was dissolved in 5 mL of acetonitrile, iodomethane (1.00 mmol) was added, and the mixture was reacted at 80°C for 6 h. After the reaction was completed, the mixture was spin-dried, dissolved in 100 mL of ethyl acetate, and washed three times with 100 mL of saturated brine. The organic layer was collected, dried, and purified by normal phase silica gel chromatography (petroleum ether: ethyl acetate = 10:1 V / V) to obtain compound 1 as a yellow powder. The yield was 69%.

[0032] 1 H NMR (400MHz, DMSO-d6) (ppm): δ7.03(t,1H),6.28(d,2H),5.01-4.07(m,1H),2.34-2.26(m,1H),2.0 4-1.98(m,1H),1.71-1.63(m,2H),1.29-1.10(m,2H),1.05-1.03(m,1H),0.87(s,3H),0.82(s,6H). 1 H NMR (400MHz, DMSO-d6) δ8.56-8.45(m,2H),8.17(d,J=6.0Hz,1H),5.05(dt,J=9.8,2.9Hz,1H),4.28(s,3H),2.36(ddt,J=13.8,10.0, 4.0Hz,1H),1.93(dt,J=13.0,4.9Hz,1H),1.70(hept,J=4.1Hz,2H),1.34-1.17(m,2H),1.14-1.07(m,1H),0.89(s,3H),0.84(s,6H).

[0033] 13 C NMR (101MHz, DMSO-d6) δ163.77,155.20,136.86,132.04,128.00,82.51,49.35,48.86,48.15,44.74,36.55,28.02,27.27,20.03,19.16,13.93.

[0034] 1.2) Synthesis of 1-(2,3-allyl)-3-hydroxyisonicotinic acid dextranol bromide (Compound 2)

[0035] Referring to the synthesis method of compound 1, isonicotinate and 3-bromopropylene were used as raw materials, methyl iodide in step (2) of compound 1 was replaced with an equal molar amount of 3-bromopropylene, and the rest was the same as step (2) of compound 1 to synthesize compound 2.

[0036]

[0037] Yellow solid;1 H NMR(400MHz,Chloroform-d)δ9.20(s,1H),9.09(d,J=6.2Hz,1H),8.23(d,J=6.3Hz,1H),6.14(ddt,J =16.7,9.9,6.7Hz,1H),5.72(d,J=16.9Hz,1H),5.62(d,J=6.7Hz,2H),5.56(d,J=10.1Hz,1H),5.16( d,J=9.8Hz,1H),2.46(ddt,J=14.2,9.3,4.1Hz,1H),1.96(m,J=13.6,9.3,4.1Hz,1H),1.79(dq,J=14 .9,4.2Hz,2H),1.45-1.27(m,2H),1.14(dd,J=14.1,3.4Hz,1H),0.93(s,3H),0.89(d,J=4.2Hz,6H).

[0038] 13 C NMR(101MHz,Chloroform-d)δ165.20,158.22,136.39,135.66,129.49,128.26,127.99 ,125.35,84.86,64.32,49.39,48.22,44.86,36.63,27.99,27.31,19.71,18.91,13.67.

[0039] 1.3) Synthesis of 1-(2-methyl-2-allyl)-3-hydroxyisonicotinic acid dextranol bromide (Compound 3)

[0040] Referring to the synthesis method of compound 1, isonicotinate and 2-methyl-3-bromopropene were used as raw materials, methyl iodide in step (2) of compound 1 was replaced with an equal molar amount of 2-methyl-3-bromopropene, and the rest was the same as step (2) of compound 1 to synthesize compound 3.

[0041]

[0042] Yellow solid; 1H NMR(400MHz,Chloroform-d)δ9.14(s,1H),9.05(d,J=6.2Hz,1H),8.24(d,J=6.0Hz,1H),5.55(s,2H),5.20(dd,J=13.2,7.9Hz,3H),2.47(td,J =9.8,4.8Hz,1H),1.96(dt,J=9.6,4.3Hz,1H),1.80(s,5H),1.42-1.29( m,2H),1.17-1.13(m,1H),0.93(d,J=1.7Hz,3H),0.90(d,J=2.7Hz,6H).

[0043] 13 C NMR(101MHz,Chloroform-d)δ165.17,158.17,137.61,136.47,135.91,128.47,127.92,11 9.87,84.96,67.87,49.40,48.23,44.87,36.63,27.99,27.31,19.86,19.71,18.91,13.66.

[0044] 1.4) Synthesis of 1-(3-methyl-2-butyl)-3-hydroxyisonicotinic acid dextranol bromide (Compound 4)

[0045] Referring to the synthesis method of compound 1, isonicotinate and 3-methyl-1-bromobutene were used as raw materials, methyl iodide in step (2) of compound 1 was replaced with an equal molar amount of 3-methyl-1-bromobutene, and the rest was the same as step (2) of compound 1 to synthesize compound 4.

[0046]

[0047] Yellow solid; 1 H NMR (400MHz, Chloroform-d) δ9.15 (s, 1H), 9.03 (d, J = 6.2 Hz, 1H), 8.20 (d, J = 6. 1Hz,1H),5.50(s,3H),5.17-5.12(m,1H),2.43(tt,J=9.1,4.6Hz,1H),1.99-1. 93(m,1H),1.90(s,3H),1.87(s,1H),1.83(s,3H),1.76(d,J=9.3Hz,1H),1.42- 1.24(m,2H),1.12(dd,J=14.1,3.8Hz,1H),0.91(s,3H),0.87(d,J=5.1Hz,6H).

[0048] 13 C NMR(101MHz,Chloroform-d)δ165.09,157.88,146.45,135.55,128.31,127.97,115.25,84.71 ,60.21,49.36,48.20,44.85,36.62,34.59,27.98,27.29,26.07,19.70,19.13,18.89,13.65.

[0049] 1.5) Synthesis of 1-(2-cyclohexyl)-3-hydroxyisonicotinic acid dextranol bromide (Compound 5)

[0050] Referring to the synthesis method of compound 1, isonicotinate and 1-bromo-2-cyclohexene were used as raw materials, methyl iodide in step (2) of compound 1 was replaced with an equal molar amount of 1-bromo-2-cyclohexene, and the rest was the same as step (2) of compound 1 to synthesize compound 5.

[0051]

[0052] Yellow solid; 1H NMR (400 MHz, Chloroform-d) δ9.32-9.12 (m, 2H), 8.27 (s, 1H), 6.46 (dt, J = 7.6, 3.7 Hz, 1H), 6.03-5.80 (m, 2H), 5.16 (d, J = 9.7 Hz, 1H), 2.46 (m, J = 19.0, 9.6, 5.4 Hz, 2H), 2.33 -2.14(m,2H),1.97(m,J=23.4,11.8,6.4Hz,2H),1.87-1.74(m,3H),1.66(dd,J=15.0, 7.6Hz,1H),1.42-1.25(m,2H),1.17-1.11(m,1H),0.92(s,3H),0.88(d,J=3.2Hz,6H).

[0053] 13 C NMR(101MHz,Chloroform-d)δ165.01,157.87,139.22,135.04,134.73,128.94,128.38,121.48,8 4.82,67.96,49.38,48.22,44.86,36.67,32.40,28.02,27.33,24.55,19.71,18.91,18.64,13.68.

[0054] 1.6) Synthesis of 1-benzyl-3-hydroxyisonicotinic acid dextranol bromide (Compound 6)

[0055]

[0056] Referring to the synthesis method of compound 1, using isonicotinoic acid dextran and benzyl bromide as raw materials, the iodomethane in step (2) of compound 1 was replaced with an equal molar amount of benzyl bromide, and the rest was the same as step (2) of compound 1 to synthesize compound 6.

[0057] Yellow solid; 1 H NMR (400MHz, Chloroform-d) δ9.15 (s, 1H), 9.03 (d, J = 6.2 Hz, 1H), 8.20 (d, J = 6. 1Hz,1H),5.50(s,3H),5.17-5.12(m,1H),2.43(tt,J=9.1,4.6Hz,1H),1.99-1. 93(m,1H),1.90(s,3H),1.87(s,1H),1.83(s,3H),1.76(d,J=9.3Hz,1H),1.42- 1.24(m,2H),1.12(dd,J=14.1,3.8Hz,1H),0.91(s,3H),0.87(d,J=5.1Hz,6H).

[0058] 13 C NMR(101MHz,Chloroform-d)δ165.09,157.88,146.45,135.55,128.31,127.97,115.25,84.71 ,60.21,49.36,48.20,44.85,36.62,34.59,27.98,27.29,26.07,19.70,19.13,18.89,13.65.

[0059] 1.7) Synthesis of 1-(4-methylbenzyl)-3-hydroxyisonicotinic acid dextranol bromide (Compound 7)

[0060] Referring to the synthesis method of compound 1, using isonicotinoic acid dextran and 4-methylbenzyl bromide as raw materials, the iodomethane in step (2) of compound 1 was replaced with an equal molar amount of 4-methylbenzyl bromide, and the rest was the same as step (2) of compound 1 to synthesize compound 7.

[0061]

[0062] Yellow solid; 1HNMR(400MHz,DMSO-d6)δ8.67(s,2H),8.19(d,J=6.1Hz,1H),7.41(d,J=7.7H z,2H),7.23(d,J=7.8Hz,2H),5.77(s,2H),5.03(d,J=9.8Hz,1H),2.35(d,J= 11.0Hz,1H),2.27(s,3H),1.91(d,J=11.7Hz,1H),1.68(q,J=8.2,5.2Hz,2H) ,1.24(dd,J=35.3,11.3Hz,2H),1.12-1.06(m,1H),0.87(s,3H),0.83(s,6H).

[0063] 13 C NMR(101MHz,DMSO-d6)δ163.63,155.90,139.66,135.76,135.67,132.66,131.41,130.29,129.6 7,128.71,82.51,63.86,49.34,48.15,44.74,36.52,28.00,27.27,21.30,20.01,19.15,13.89.

[0064] 1.8) Synthesis of 1-(4-fluorobenzyl)-3-hydroxyisonicotinic acid dextranol bromide (Compound 8)

[0065] Referring to the synthesis method of compound 1, using isonicotinoic acid dextran and 4-fluorobenzyl bromide as raw materials, the iodomethane in step (2) of compound 1 was replaced with an equal molar amount of 4-fluorobenzyl bromide, and the rest was the same as step (2) of compound 1 to synthesize compound 8.

[0066]

[0067] Yellow solid; 1 H NMR(400MHz,Chloroform-d)δ9.39(s,1H),9.31(d,J=6.1Hz,1H),8.18(t,J=4.3H z,1H),7.83-7.73(m,2H),7.03(td,J=8.5,3.0Hz,2H),6.32(d,J=2.6Hz,2H),5.1 6-5.09(m,1H),2.43(m,J=9.7,3.9Hz,1H),1.89(m,J=13.2,9.2,4.6Hz,1H),1.82 -1.68(m,2H),1.44-1.21(m,2H),1.09(dt,J=14.2,3.2Hz,1H),0.93-0.82(m,9H).

[0068] 13 C NMR(101MHz,Chloroform-d)δ165.39,164.94,162.45,158.14,136.58,135.87,132.28,128.58,127.83 ,127.39,116.88,116.66,84.98,64.00,49.37,48.22,44.82,36.57,27.95,27.27,19.68,18.87,13.62.

[0069] 1.9) Synthesis of 1-(4-trifluoromethylbenzyl)-3-hydroxyisonicotinic acid dextranol bromide (Compound 9)

[0070] Referring to the synthesis method of compound 1, using isonicotinoic acid dextran and 4-trifluoromethylbenzyl bromide as raw materials, the iodomethane in step (2) of compound 1 was replaced with an equal molar amount of 4-trifluoromethylbenzyl bromide, and the rest was the same as step (2) of compound 1 to synthesize compound 9.

[0071]

[0072] Yellow solid; 1 HNMR(400MHz,Chloroform-d)δ9.18(s,1H),8.68(d,J=6.2Hz,1H),8.05(d,J=6.3Hz,1H) ,7.80(d,J=7.9Hz,2H),7.61(d,J=8.1Hz,2H),6.24(s,2H),5.10(dd,J=9.9,2.9Hz,1H), 2.41(ddt,J=14.0,8.6,4.0Hz,1H),1.93(m,J=13.3,9.1,4.0Hz,1H),1.82-1.70(m,2H), 1.36-1.22(m,2H),1.08(dd,J=13.9,3.4Hz,1H),0.90(s,3H),0.88(s,3H),0.85(s,3H).

[0073] 13 C NMR(101MHz,Chloroform-d)δ164.60,160.47,138.07,136.60,132.33,132.01,131.89,130.07,129.47,128.20,126 .64,126.60,126.56,124.97,122.26,83.75,63.82,49.28,48.13,44.87,36.70,27.99,27.30,19.69,18.87,13.63.

[0074] 1.10) Synthesis of 1-(4-methoxybenzyl)-3-hydroxyisonicotinic acid dextranol bromide (Compound 10)

[0075] Referring to the synthesis method of compound 1, using isonicotinoic acid dextran and 4-methoxybenzyl bromide as raw materials, the iodomethane in step (2) of compound 1 was replaced with an equal molar amount of 4-methoxybenzyl bromide, and the rest was the same as step (2) of compound 1 to synthesize compound 10.

[0076]

[0077] Yellow solid; 1 H NMR(400MHz,Chloroform-d)δ9.46-9.10(m,2H),8.22-8.11(m,1H),7.63(d,J=7.9Hz, 2H),6.85(d,J=7.6Hz,2H),6.18(s,2H),5.16-5.10(m,1H),3.75(s,3H),2.43(ddt,J=1 3.9,8.8,4.0Hz,1H),1.92(m,J=13.3,9.1,4.0Hz,1H),1.76(dd,J=13.5,4.3Hz,2H),1 .43-1.23(m,2H),1.10(dd,J=14.0,3.5Hz,1H),0.91(s,3H),0.88(s,3H),0.86(s,3H).

[0078] 13 C NMR(101MHz,Chloroform-d)δ165.38,161.03,158.00,136.25,135.78,131.75,127.89,127.48,124.3 1,115.09,84.86,64.99,55.50,49.37,48.21,44.84,36.59,31.57,27.97,27.29,19.69,18.88,13.64.

[0079] 1.11) Synthesis of 1-(4-methylformylbenzyl)-3-hydroxyisonicotinic acid dextranol bromide (Compound 11)

[0080] Referring to the synthesis method of compound 1, using isonicotinate and 4-methylbenzyl bromide as raw materials, the iodomethane in step (2) of compound 1 was replaced with an equal molar amount of 4-methylbenzyl bromide, and the rest was the same as step (2) of compound 1 to synthesize compound 11.

[0081]

[0082] Yellow solid; 1 H NMR (400MHz, DMSO-d6) δ8.70(d,J=11.1Hz,2H),8.22(d,J=6.2Hz,1H),7.98(d,J= 7.9Hz,2H),7.62(d,J=8.1Hz,2H),5.93(s,2H),5.04(d,J=9.8Hz,1H),3.82(s,3H) ,2.35(td,J=10.3,9.8,5.2Hz,1H),1.93(m,J=12.7,9.3,4.2Hz,1H),1.74-1.64( m,2H),1.30-1.17(m,2H),1.09(dd,J=13.8,3.5Hz,1H),0.88(s,3H),0.83(s,6H).

[0083] 13 C NMR(101MHz,DMSO-d6)δ166.25,163.63,156.08,139.46,136.19,136.11,132.89,130.87,130.40,1 29.69,128.86,82.54,63.36,52.91,49.35,48.15,44.74,36.52,28.01,27.27,20.01,19.15,13.90.

[0084] 1.12) Synthesis of 1-(4-formylbenzyl)-3-hydroxyisonicotinic acid dextranol bromide (Compound 12)

[0085] Referring to the synthesis method of compound 1, using isonicotinoic acid dextran and 4-formylbenzyl bromide as raw materials, the iodomethane in step (2) of compound 1 was replaced with an equal molar amount of 4-formylbenzyl bromide, and the rest was the same as step (2) of compound 1 to synthesize compound 11.

[0086]

[0087] Yellow solid; 1H NMR (400MHz, DMSO-d6) δ8.77-8.66(m,2H),8.22(d,J=6.0Hz,1H),7.96(d,J=8.1H z,2H),7.61(d,J=8.2Hz,2H),5.95(s,2H),5.04(dt,J=9.8,2.9Hz,1H),2.34(ddt ,J=13.8,9.9,3.9Hz,1H),1.93(m,J=12.9,9.4,4.1Hz,1H),1.68(m,J=4.5,4.0Hz ,2H),1.31-1.16(m,2H),1.09(dd,J=13.8,3.4Hz,1H),0.87(s,3H),0.82(s,6H).

[0088] 13 C NMR(101MHz,DMSO-d6)δ167.29,163.60,156.00,138.96,136.18,136.09,132.87,132.11,130.53,1 29.59,128.84,82.54,63.40,55.47,49.34,48.14,44.73,36.51,28.00,27.27,20.00,19.14,13.90.

[0089] 1.13) Synthesis of 1-(3,3-dimethyl-2-butanone)-3-hydroxyisonicotinic acid dextranol bromide (Compound 13)

[0090] Referring to the synthesis method of compound 1, using isonicotinoic acid dextran and 1-bromo-3,3-dimethyl-2-butanone as raw materials, the iodomethane in step (2) of compound 1 was replaced with an equal molar amount of 1-bromo-3,3-dimethyl-2-butanone, and the rest was the same as step (2) of compound 1 to synthesize compound 13.

[0091]

[0092] Yellow solid; 1H NMR (400 MHz, DMSO-d6) δ8.52 (s, 1H), 8.43 (d, J = 6.3 Hz, 1H), 8.26 (d, J = 6.1 Hz, 1H), 6.04 (s, 2H), 5.07 (d, J = 9.8 Hz, 1H), 2.37 (td, J = 10.1, 5.1 Hz, 1H), 1.96 (m, J = 12.9, 9.6, 4.4 Hz, 1H), 1.75-1.67 (m, 2H), 1.35-1.23 (m, 2H), 1.19 (s, 9H), 1.12 (d, J = 4.1 Hz, 1H), 0.89 (s, 3H), 0.85 (d, J = 3.9 Hz, 6H).

[0093] 13 C NMR(101MHz,DMSO-d6)δ206.94,163.71,155.28,137.39,137.28,133.06,128.07,82.64,6 6.00,49.37,48.17,44.76,43.59,36.51,31.55,28.01,27.31,26.19,20.03,19.17,13.93.

[0094] 1.14) Synthesis of 1-(3-phenyl-2-keto)-3-hydroxyisonicotinic acid dextranol bromide (Compound 14)

[0095] Referring to the synthesis method of compound 1, isonicotinoic acid dextran and 1-bromo-3-phenyl-2-one were used as raw materials, methyl iodide in step (2) of compound 1 was replaced with an equal molar amount of 1-bromo-3-phenyl-2-one, and the rest was the same as step (2) of compound 1 to synthesize compound 14.

[0096]

[0097] Yellow solid; 1H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.55(d,J=6.3Hz,1H),8.32(d,J=6.0Hz,1H),8.02(d,J= 7.8Hz,2H),7.76(t,J=7.4Hz,1H),7.63(t,J=7.7Hz,2H),6.46(s,2H),5.09(d,J=9.7Hz,1H), 2.37(dd,J=9.7,4.4Hz,1H),1.99(m,J=12.7,9.2,4.1Hz,1H),1.70(dd,J=8.8,4.5Hz,2H),1. 28(dt,J=26.8,10.9Hz,2H),1.16(dd,J=13.9,3.4Hz,1H),0.90(s,3H),0.86(d,J=6.6Hz,6H).

[0098] 13 C NMR(101MHz,DMSO-d6)δ190.93,163.69,155.38,137.71,137.52,135.28,134.08,133.25,129.68,1 28.85,128.17,82.64,67.28,49.39,48.18,44.77,36.53,31.59,28.02,27.33,20.04,19.18,13.94.

[0099] 1.15) Synthesis of 1-(2-acetamido)-3-hydroxyisonicotinic acid dextranol bromide (Compound 15)

[0100] Referring to the synthesis method of compound 1, isonicotinoic acid dextran and 1-bromo-2-acetamide were used as raw materials, methyl iodide in step (2) of compound 1 was replaced with an equal molar amount of 1-bromo-2-acetamide, and the rest was the same as step (2) of compound 1 to synthesize compound 15.

[0101]

[0102] Yellow solid; 1H NMR (400MHz, DMSO-d6) δ8.57(s,1H),8.52(d,J=6.3Hz,1H),8.21(d,J=6.2Hz,1H ),7.99(s,1H),7.69(s,1H),5.38(s,2H),5.06(dt,J=9.7,2.8Hz,1H),2.38(dt, J=14.0,4.2Hz,1H),1.95(m,J=12.8,9.4,4.2Hz,1H),1.70(q,J=4.2Hz,2H),1.3 3-1.22(m,2H),1.13(dd,J=13.9,3.5Hz,1H),0.89(s,3H),0.85(d,J=3.1Hz,6H).

[0103] 13 C NMR(101MHz,DMSO-d6)δ166.39,163.71,155.00,137.61,137.56,133.01,127.72,8 2.59,62.43,49.37,48.17,44.75,36.51,31.51,27.99,27.30,20.03,19.17,13.92.

[0104] 1.16) Synthesis of 1-(2-ethyl acetate)-3-hydroxyisonicotinic acid dextranol bromide (Compound 16)

[0105] Referring to the synthesis method of compound 1, using isonicotinoyl isonicotinate and ethyl 1-bromo-2-acetate as raw materials, the iodomethane in step (2) of compound 1 was replaced with an equal molar amount of ethyl 1-bromo-2-acetate, and the rest was the same as step (2) of compound 1 to synthesize compound 16.

[0106]

[0107] Yellow solid; 1H NMR (400 MHz, Chloroform-d) δ 9.29 (s, 1H), 9.12 (d, J = 6.3 Hz, 1H), 8.22 (d, J = 6.0 Hz, 1H), 6.24 (s, 2H), 5.16 (d, J = 9.8 Hz, 1H), 3.80 (s, 3H), 2.45 (ddt, J = 14.2, 9.2, 4.3 Hz, 1H), 1.94 (m, J = 13.5, 9.1, 3.8 Hz, 1H), 1.77 (dd, J = 14.5, 4.4 Hz, 2H), 1.43-1.25 (m, 2H), 1.14 (dd, J = 13.9, 3.4 Hz, 1H), 0.92 (s, 3H), 0.88 (s, 6H).

[0108] 13 C NMR(101MHz,Chloroform-d)δ166.02,165.32,157.74,138.62,137.59,128.30,127.27 ,84.92,61.63,53.98,49.40,48.23,44.85,36.57,27.96,27.29,19.70,18.89,13.65.

[0109] 1.17) Synthesis of 1-(2-phenylacetate)-3-hydroxyisonicotinic acid dextranol bromide (Compound 17)

[0110] Referring to the synthesis method of compound 1, isonicotinoic acid dextran and 1-bromo-2-phenyl acetate were used as raw materials, methyl iodide in step (2) of compound 1 was replaced with an equal molar amount of 1-bromo-2-phenyl acetate, and the rest was the same as step (2) of compound 1 to synthesize compound 17.

[0111]

[0112] Yellow solid; 1 HNMR(400MHz,Chloroform-d)δ9.40(s,1H),9.25(d,J=6.3Hz,1H),8.13(d,J=6.3 Hz,1H),7.31-7.16(m,5H),6.62(s,2H),5.13(dt,J=9.9,2.9Hz,1H),2.46(m,J=1 3.7,8.8,4.4Hz,1H),1.91(m,J=13.3,9.1,4.1Hz,1H),1.84-1.74(m,2H),1.43-1 .22(m,2H),1.12(dd,J=14.1,3.4Hz,1H),0.93(s,3H),0.90(s,3H),0.88(s,3H).

[0113] 13 C NMR(101MHz,Chloroform-d)δ165.44,164.69,157.81,150.03,138.67,137.75,129.66,129.53,127.68,127 .20,126.74,121.66,115.54,85.13,61.85,49.41,48.24,44.83,36.55,27.98,27.29,19.70,18.89,13.67.

[0114] Example 2

[0115] Effects of target compounds on the proliferation of RAW264.7 macrophages in vitro

[0116] RAW264.7 macrophages were digested and counted, and 7×10 4 100 μL of RAW264.7 cell suspension of 1 μg / mL was added to each well of a 96-well cell culture plate; the plate was cultured in a 37°C, 5% CO2 incubator for 24 h; the old culture medium was discarded, 100 μL of the corresponding drug-containing culture medium was added to each well of the experimental group (the compound was diluted to 6 μmol / L with the culture medium), and a negative control group was set up (100 μL of drug-free culture medium was added to each well), and the plates were cultured in a 37°C, 5% CO2 incubator for 24 h; 20 μL of CCK-8 was added to each well, and the plates were cultured in an incubator for 2 h-3 h; the plates were gently mixed on a shaker for 10 min to remove bubbles in the 96-well plate; the OD value of each well was read by an enzyme reader at λ=450 nm, and the inhibition rate was calculated. The results are shown in Table 1.

[0117] Inhibition rate (%) = (OD value of negative control group - OD value of experimental group) / OD value of negative control group × 100%

[0118] Table 1. Inhibitory effect of compounds on the growth of RAW264.7 macrophages (6 μmol / L)

[0119] Compound Inhibition rate Compound Inhibition rate Compound Inhibition rate Compound 1 C Compound 7 B Compound 13 C Compound 2 B Compound 8 B Compound 14 C Compound 3 B Compound 9 B Compound 15 C Compound 4 B Compound 10 B Compound 16 C Compound 5 B Compound 11 C Compound 17 C Compound 6 B Compound 12 C Compound 1a C

[0120] Note: A: 20%-11%, B: 10%-5%, C: 5%-0%.

[0121] It can be seen from Table 1 that at a concentration of 6 μmol / L, the cytotoxicity of the compounds of the present invention is less than 10%, indicating good safety.

[0122] Example 3

[0123] Effects of target compounds on inflammatory factors in RAW264.7 macrophages induced by lipopolysaccharide

[0124] RAW264.7 cells were digested and counted, and 7×10 4100 μL of RAW264.7 cell suspension of 1 μg / mL was added to each well of a 96-well cell culture plate; the plate was cultured in a 37°C, 5% CO2 incubator for 24 h; the old culture medium was discarded, 100 μL of the corresponding drug-containing culture medium was added to each well of the experimental group (the drug was diluted to 1 μmol / L with the culture medium), and a negative control group (100 μL of drug-free culture medium was added to each well) and a model group (100 μL of drug-free culture medium was added to each well) were set up at the same time, and the plates were cultured in a 37°C, 5% CO2 incubator for 2 h. Lipopolysaccharide (LPS, final concentration of 100 μg / L) was added to the experimental group and the model group and incubated for 24 h. The supernatant was collected and the contents of IL-1β and TNF-α were detected according to the instructions of the ELISA kit, as shown in Table 2.

[0125] Table 2. Effects of compounds on inflammatory factors in RAW264.7 macrophages induced by lipopolysaccharide (1 μmol / L)

[0126] TNF-α IL-1β TNF-α IL-1β TNF-α IL-1β Negative control group 52.5 22.7 Compound 6 C E Compound 13 B D Model Group 208.4 97.5 Compound 7 C E Compound 14 B D Compound 1 B D Compound 8 C E Compound 15 B D Compound 2 C E Compound 9 C E Compound 16 B D Compound 3 C E Compound 10 C E Compound 17 B D Compound 4 C E Compound 11 B D Compound 1a A C Compound 5 C E Compound 12 B D

[0127] Note: A: 200-151, B: 150-101, C: 100-76, D: 75-51, E: 50-25.

[0128] It can be seen from Table 2 that the compounds of the present invention have a significant inhibitory effect on the inflammatory factors increased in RAW264.7 macrophages induced by lipopolysaccharide.

[0129] Example 4

[0130] Inhibitory effect of compounds (intraperitoneal injection) on carrageenan-induced swelling in rat paws

[0131] SD rats (male, SPF grade, 6-8 weeks old, weighing 250-280g) were randomly divided into groups, 6 rats in each group. The normal group and the model group were intravenously injected with the same amount of solvent (5% DMSO), and each drug group was intraperitoneally injected with 5 mg / kg of each compound (compound concentration 0.5 mg / mL). 0.5h after administration, the normal group was subcutaneously injected with 100 μL of normal saline at the toes of the hind limbs, and the other groups were injected with 100 μL of 1% carrageenan. The toe volume of the rats was measured at 0h, 1h, and 2h after the injection of carrageenan, and the foot swelling rate (%) of the rats was calculated.

[0132] Foot swelling rate = (plantar volume after inflammation - plantar volume before inflammation) / plantar volume before inflammation × 100%.

[0133] The results are as follows Figure 1 As shown, it can be seen that the compound of the present invention has a significant inhibitory effect on the swelling of the paw of rats induced by carrageenan.

[0134] Example 5

[0135] Study on drug metabolism of compound 6 after single intravenous injection in rats

[0136] Animals: Male SD rats, 3 in each group.

[0137] Solvent: 5% DMSO + 20% PEG400 + 10% Solutol + 65% physiological saline.

[0138] Blood collection time: 0.0833h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h.

[0139] The main pharmacokinetic parameters of compound 6 in rats after a single intravenous injection (IV) of 2 mg / kg were: C max 24.3 ng / mL, T max 0.0833h, T 1 / 2 0.166h, AUC 0-T 7.97 hr·ng / mL, AUC 0-∞ 8.43 hr·ng / mL, V z is 62316mL / kg, CL is 259712mL / hr / kg, MRT 0-t 0.163h, MRT 0-∞ It is 0.208h.

[0140] Preliminary drug metabolism studies showed that compound 6 was rapidly metabolized in animals. The other 16 target compounds also showed similar characteristics to compound 6 in animals, with shorter half-lives.

[0141] Example 6

[0142] Inhibitory effect of compound 6 on acute inflammation induced by 30% croton oil in rabbit eyes

[0143] Animal: Rabbit.

[0144] Solvent: 0.1% poloxamer + 0.1% nonoxynol 4 + 1.8% mannitol + 2.0% glycerol + 95.8% normal saline.

[0145] Compound 6 eye drops group (2.0 mg / mL, prepared with solvent), positive control group (0.5% cortisone acetate eye drops) and negative control group (0.1% poloxamer + 0.1% nonoxynol 4 + 1.8% mannitol + 2.0% glycerol + 95.8% saline) were set up, with 3 rabbits in each group. 50 μL of 30% croton oil was accurately dripped into the rabbit's eyes using a micropipette. After the croton oil was dripped, the drug was continued to drip into the eyes, once every 0.5 hours, for a total of 4 times. After 2 hours, it was changed to once every 1 hour, for a total of 4 times, with 50 μL dripped each time. The changes in conjunctival inflammation of the rabbits were scored according to the conjunctival inflammation scoring standard 4 hours and 8 hours after the croton oil was dripped into the eyes.

[0146] Table 3. Scoring criteria for conjunctival inflammation

[0147] Eye symptoms Points 1. Conjunctival congestion (1) Normal blood vessels 0 (2) Blood vessels become congested and appear bright red 1 (3) The blood vessels are dark red due to congestion and are difficult to distinguish 2 (4) Diffuse congestion with a purple-red color 3 2. Conjunctival edema (1) No edema 0 (2) Mild edema 1 (3) Obvious edema with partial ectropion of the eyelid 2 (4) Edema to the point where the eyelids are nearly half closed 3 3. Secretion (1) No secretion 0 (2) Small amount of secretion 1 (3) Secretions make the eyelids and eyelashes wet or sticky 2 (4) Secretions make the entire eye area moist or sticky 3

[0148] Table 4. Effect of compound 6 on croton oil-induced conjunctivitis in rabbits (n=3, X±SD)

[0149] Inflammation score 4h Inflammation score 8h Negative control group 8.55±0.36 8.32±0.33 Positive control group 4.89±0.69 3.15±0.48 Compound 6 eye drops group 5.06±0.47 3.32±0.41

[0150] The experimental results are shown in Table 4, which shows that the compound of the present invention has a significant inhibitory effect on croton oil-induced conjunctivitis in rabbits.

Claims

1. A quaternary ammonium salt compound of 3-hydroxyisonicotinic acid dextranol ester having a structure as shown in Formula I: in, R is selected from saturated or unsaturated C1-C6 hydrocarbon group, substituted or unsubstituted benzyl group, The substituents of the benzyl group are selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 halogen-substituted alkyl, R1 is selected from NH2, C1-C4 alkyl, C1-C4 alkoxy, phenyl, phenoxy; R2 is selected from H, C1-C3 alkyl; X is selected from bromine, iodine.

2. The quaternary ammonium salt compound of 3-hydroxyisonicotinic acid dextranol ester according to claim 1, characterized in that: R is selected from substituted or unsubstituted benzyl, C1-C3 alkyl, The substituents of the benzyl group are selected from fluorine, methyl, methoxy, trifluoromethane, The position of the substituent can be located at the ortho, meta or para position of the existing substituent on the benzene ring; R1 is selected from NH2, C1-C4 alkyl, C1-C4 alkoxy, phenyl, phenoxy; R2 is selected from H, methyl; R3, R4, R5 are independently selected from H, methyl; X = bromine, iodine.

3. The quaternary ammonium salt compound of 3-hydroxyisonicotinic acid dextranol ester according to claim 2, characterized in that: R is selected from substituted or unsubstituted benzyl, The substituent of the benzyl group is selected from fluorine, methyl, methoxy, and trifluoromethane, and the position of the substituent is located in the para position of the existing substituent of the benzene ring; R3=R4=R5=H; R3=methyl, R4=R5=H; R3=H, R4=R5=methyl; X=bromine, iodine.

4. The quaternary ammonium salt compound of 3-hydroxyisonicotinic acid dextranol ester having the structure shown below:

5. Use of the quaternary ammonium salt of 3-hydroxyisonicotinic acid dextranol ester according to any one of claims 1 to 4 in the preparation of a drug for treating inflammation-related diseases.

6. The use according to claim 5, characterized in that: The inflammation-related diseases are rheumatoid arthritis, eye inflammation, and respiratory tract inflammation.

7. A pharmaceutical composition for treating inflammation-related diseases, characterized in that: The pharmaceutical composition uses the quaternary ammonium salt compound of 3-hydroxyisonicotinic acid dextranol ester according to any one of claims 1 to 4 as an active ingredient and is prepared into a pharmaceutically acceptable dosage form with pharmaceutically acceptable excipients.

8. The pharmaceutical composition according to claim 7, characterized in that: The dosage form is solution, spray, patch and gel.

9. Use of the pharmaceutical composition according to claim 7 in preparing a medicament for treating inflammation-related diseases.

10. The use according to claim 9, characterized in that: The inflammation-related diseases are rheumatoid arthritis, eye inflammation, and respiratory tract inflammation.

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