CN102526052B - Application of a 2-glycosylquinoline compound in the preparation of anti-acetylcholinesterase drugs - Google Patents

Abstract

The invention discloses the application of a 2-glycosyl quinoline compound in the preparation of anti-acetylcholinesterase drugs. The 2-glycosylquinoline compound has the structural formula shown in formula (I), wherein R ₁ , R ₂ , R ₃ and R ₄ are independently selected from -H, -OCH ₃ or -Br. The preparation method of the 2-glycosylquinoline compound can be carried out with reference to the prior art. The 2-glycosylquinoline compound of the present invention has strong solubility in water, high bioavailability, strong inhibitory activity on acetylcholinesterase, and broad application prospects in the preparation of anti-acetylcholinesterase drugs; The preparation route of the 2-glycosylquinoline compound is simple, the cost is low, the environmental pollution is small, and it is suitable for large-scale industrial production;

Description

Application of a 2-glycosylquinoline compound in the preparation of anti-acetylcholinesterase drugs

technical field

The invention belongs to the fields of medicine and chemical industry, and in particular relates to the application of a 2-glycosyl quinoline compound in the preparation of anti-acetylcholinesterase drugs.

Background technique

Alzheimer's disease (AD), also known as senile dementia or Alzheimer's disease, is a degenerative disease of the central nervous system mainly characterized by progressive cognitive impairment and memory impairment. The main clinical manifestations of the disease are memory loss, persistent cognitive decline, movement disorders, and gradual loss of independent living ability in severe cases, accompanied by a series of psychiatric symptoms. Prevalence studies put the number of Alzheimer's cases in the United States at 4.5 million in 2000. For every 5-year increase in age, the percentage of patients with Alzheimer's disease will double. At present, AD disease has become the second largest disease that threatens the health of middle-aged and elderly people besides cardiovascular and cerebrovascular diseases.

There are several hypotheses about the pathogenesis of the disease, among which the cholinergic hypothesis of memory dysfunction proposed by Bartus and his collaborators in 1982 has been generally accepted. The hypothesis holds that the reduction of cholinergic nerve function is the main mechanism of AD pathogenesis. The cholinergic nerves in the brain of patients are most susceptible to damage. As the disease progresses, 90% of the cholinergic neurons will be destroyed, which will reduce the level of acetylcholine (Ach) in the brain, and the degree of reduction is significantly related to the decline in the cognitive ability of patients. And continue throughout the course of the disease. Dysfunction of the acetylcholinergic system is inseparable from the activity of acetylcholinesterase (AChE). Therefore, it is of great significance to prepare and discover acetylcholinesterase inhibitors with novel structure and strong activity.

Quinoline is a compound with good biological activity, and its derivatives have been widely used in the field of medicine. Nagarajan et al disclosed a one-pot synthesis method for 2-glycosyl quinoline compounds in Carbohydrate Research [J]. Esterase drugs have not been reported.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies of the prior art and provide the application of 2-glycosyl quinoline compounds in the preparation of anti-acetylcholinesterase drugs. The 2-glycosyl quinoline compound has significant activity of inhibiting acetylcholinesterase, and has broad application prospects in the preparation of anti-acetylcholinesterase drugs.

Above-mentioned purpose of the present invention is achieved by following technical scheme:

A kind of application of 2-glycosyl quinoline compound in the preparation anti-acetylcholinesterase medicine, described 2-glycosyl quinoline compound has structural formula as shown in formula (I):

Wherein, R ₁ , R ₂ , R ₃ and R ₄ are independently selected from -H, -OCH ₃ or -Br.

As a preferred version, the 2-glycosyl quinoline compound is preferably:

A compound of formula (I) in which R ₁ , R ₂ , R ₃ and R ₄ are all -H;

Or R ₂ and R ₃ are -H, R ₁ and R ₄ are -OCH ₃ formula (I) compounds;

Or R ₁ and R ₄ are -H, R ₂ and R ₃ are -OCH ₃ formula (I) compounds;

Or R ₂ and R ₄ are -Br, R ₁ and R ₃ are -H compound of formula (I).

The preparation method of described 2-glycosyl quinoline compound comprises the steps:

(1) Under the action of sodium bicarbonate, D-glucose and acetylacetone generate β-D-acetonyl glucoside;

(2) dissolving anthranilaldehyde or substituted anthranilaldehyde and β-D-acetonyl glucoside in methanol, and reacting in the presence of pyrrolidine to obtain the 2-glycosylquinoline compound.

As a most preferred solution, in step (2), the amount of pyrrolidine used is most preferably 25 mol% relative to the amount of anthranilaldehyde or substituted anthranilaldehyde.

As a most preferred solution, in step (2), the temperature of the reaction is most preferably 60-120°C.

As a preferred version, the 2-glycosylquinoline compound prepared in step (2) can be purified by passing through a column, and the eluent used for passing through the column has a volume ratio of ethyl acetate: isopropanol: water=16 : 2:1 mixed solution.

The preparation method of the 2-glycosylquinoline compound of the present invention can also refer to the method of the prior art such as Carbohydrate Research [J]. 2009, 1028-1031.

Compared with the prior art, the present invention has the following beneficial effects: the 2-glycosylquinoline compound of the present invention has strong solubility in water, high bioavailability, and it has strong inhibitory activity on acetylcholinesterase, and it is used in the preparation of anti-acetylcholinesterase. The acetylcholinesterase drug has broad application prospects; the preparation route of the 2-glycosylquinoline compound is simple, the cost is low, and the environmental pollution is small, and it is suitable for large-scale industrial production.

Detailed ways

The present invention will be further described below in conjunction with specific examples, but the specific examples do not limit the present invention in any way.

The synthesis of embodiment 1 intermediate β-D-acetonyl glucoside

Preparation route:

Weigh 1~5g of D-glucose and 0.5~2.5g of sodium bicarbonate into a round bottom flask, add distilled water and stir at room temperature for 10~30min, then add 1~5g of acetylacetone and stir in an oil bath at 50~120℃ Under the reaction 2 ~ 10h. Stop the reaction, cool and then extract with carbon dichloride, adjust the pH to 7 with dilute hydrochloric acid, remove water under reduced pressure and then add methanol, the inorganic salt precipitates because it is insoluble in methanol, and can be removed by filtration (or through a silica gel column). The product can be obtained by removing the solvent under reduced pressure. The yield is about 77%, m.p: 122-124°C.

Embodiment 2, the synthesis of compound A1

Preparation route:

Weigh 0.5 mmol of 2-aminobenzaldehyde and 0.5 mmol of β-acetonyl glucoside into a round bottom flask, add methanol, and stir at room temperature to dissolve them. Add 25 mol% pyrrolidine (relative to 2-aminobenzaldehyde), and follow the reaction with TLC in an oil bath at 60-120°C until the reaction remains unchanged. The reaction was stopped and cooled, and the solvent in the reaction was removed under reduced pressure, and the pure product was obtained by passing through the column with ethyl acetate:isopropanol:water=16:2:1 (v/v/v).

White solid; mp: 257-258°C; IR (KBr, cm ^-1 ): 3482(vs), 3385(s), 3329(s), 3104(m), 2908(m), 1601(m), 1563 (w), 1427(m), 1298(s), 1127(m), 1088(vs), 1033(s), 838(m), 763(m); ¹ H NMR (DMSO-d ₆ ): δ8 .23(dd, J=2.8Hz, J=5.2Hz, 1H, Ar-H), 7.94(t, J=7.2Hz, 2H, Ar-H), 7.72(s, 1H, Ar-H), 7.55 (d, J=8.0Hz, 2H, Ar-H), 5.20(s, 1H), 5.00(s, 1H), 4.91(s, 1H), 4.33(s, H), 3.58(s, 1H), 3.56(s, 1H), 3.47(s, 1H), 3.43(s, 1H), 3.21(s, 1H), 3.20(s, 1H), 3.02(s, 2H), 2.91(t, J=16.0Hz , 2H); ¹³ C NMR (DMSO-d ₆ ): δ161.0, 147.6, 136.1, 129.7, 128.8, 128.1, 127.0, 126.1, 123.1, 81.0, 79.6, 78.6, 74.5, 70.8, 61.6, 41.7; ESI- MS m/zcalcd for C ₁₆ H ₁₉ NO ₅ ([M+1] ⁺ ): 305.13. Found ([M+1] ⁺ ): 306.44, ([M+23] ⁺ ): 328.41. Anal. Calcd for C _16H19NO5 : C, 62.94; H, 6.27; N, _4.59 ; Found _: C, 62.88; H, 6.34; N, 4.49.

The synthesis of embodiment 3 compound A2

The preparation method is the same as in Example 2, except that 3,6-dimethoxy-2-aminobenzaldehyde is used instead of 2-aminobenzaldehyde to obtain compound A2.

White solid; mp: 121-122°C; IR (KBr, cm ^-1 ): 3522(s), 3268(s), 2871(s), 1619(s), 1604(s), 1346(s), 1263 (vs), 1117(vs), 1090(vs), 1043(s), 908(m), 723(m); ¹ H NMR (DMSO-d ₆ ): δ8.33(s, 1H, Ar-H ), 7.52(s, 1H, Ar-H), 7.02(s, 1H, Ar-H), 6.85(s, 1H, Ar-H), 5.25(s, 1H), 4.96(s, H), 4.88 (s, 1H), 4.30(s, 1H), 4.15(s, 1H), 3.89(s, 3H), 3.88(s, 3H), 3.17(s, 2H), 3.09-2.97(m, 3H), 2.87 (d, J=8.0H, 1H); ¹³ C NMR (DMSO-d ₆ ): δ164.6, 153.9, 153.2, 144.5, 135.0, 127.5, 124.4, 113.1, 108.7, 85.7, 84.5, 79.3, 75.5, 66.4, 60.9, 60.8.0, 46.5; ESI-MS m/z calcd for C ₁₈ H ₂₃ NO ₇ ([M+1] ⁺ ): 365.15, Found: ([M+1] ⁺ ): 366.44, ([ M+23] ⁺ ): 388.32, ([2M+23] ⁺ ): 752.87; Anal. Calcd for C ₁₈ H ₂₃ NO ₇ : C, 59.17; H, 6.34; N, 3.83; Found: C, 59.25; H , 6.43; N, 3.77.

Embodiment 4, the synthesis of compound A3

The preparation method is the same as in Example 2, except that 4,5-dimethoxy-2-aminobenzaldehyde is used instead of 2-aminobenzaldehyde to obtain compound A3.

White solid; mp: 122-123°C; IR (KBr, cm ^-1 ): 3400(m), 2945(m), 1703(w), 1625(m), 1509(m), 1420(m), 1256 (s), 1080(m), 1002(m), 856(m); ¹ H NMR (DMSO-d6): δ8.01(d, J=8.0Hz, 1H, Ar-H), 7.31(d, J=8.0Hz, 1H, Ar-H), 7.28(s, 1H, Ar-H), 7.25(s, Ar-H), 5.00(s, 3H), 4.24(s, 2H), 3.88(s, 3H), 3.85(s, 3H), 3.55(s, 2H), 3.47(d, J=8.0Hz, 4H), 3.35(d, J=20.0Hz, 5H), 3.17(t, J=8.0Hz, 3H), 3.08(d, J=12.0Hz, 2H), 3.47(t, J=8.0Hz, 4H), 2.99(t, J=8.0Hz, 3H), 2.80(t, J=8.0Hz, 2H) ; ¹³ C NMR (DMSO-d ₆ ): δ158.1, 152.3, 149.2, 144.4, 134.5, 122.2, 120.9, 107.7, 105.9, 80.9, 79.7, 78.6, 74.4, 70.8, 61.6, 56.0, 49.0, 43.4; ESI -MS m/z calcd for C ₁₈ H ₂₃ NO ₇ ([M+1] ⁺ ): 365.15. Found: ([M+1] ⁺ ): 366.37, (2[M+23] ⁺ ): 753.04; Anal .Calcd for _C18H23NO7 : C, 59.17; H, _6.34 ; N _, 3.83; Found: C, 59.21; H, 6.39; N, 3.79.

Embodiment 5, the synthesis of compound A4

The preparation method is the same as in Example 2, except that 3,5-dibromo-2-aminobenzaldehyde is used instead of 2-aminobenzaldehyde to obtain compound A4.

White solid; mp: 164-165°C; IR (KBr, cm ^-1 ): 3304(s), 2874(m), 1648(m), 1589(s), 1542(w), 1443(m), 1306 (m), 1186(m), 1083(s), 1037(s), 979(s), 863(s), 768(m); ESI-MS m/z calcd for C ₁₆ H ₁₇ Br ₂ NO ₅ ([M+1] ⁺ ): 460.95; Found ([M+1] ⁺ ): 462.28, ([M+3] ⁺ ): 464.27, ([M+5] ⁺ ): 466.32.

Embodiment 6 The inhibitory effect of 2-glycosylquinoline compound of the present invention on acetylcholinesterase

Inhibitory Activity Test Method:

Using thioacetylcholine as a substrate and chemically labeled 5,5-dithiobis(2-nitrobenzoic acid) as a color reagent, the inhibitory activity of the sample on AchE was determined in a sample tube. Its reaction formula is:

Thioacetylcholine+H ₂ O+AchE→CH ₃ CO-AchE+thiocholine

Thiocholine+5,5-dithiobis(2-nitrobenzoic acid)→5-thio-2-nitrobenzoic acid

Thioacetylcholine is hydrolyzed by acetylcholinesterase to produce thiocholine, which can react with 5,5-dithiobis(2-nitrobenzoic acid), and the generated 5-thio-2-nitrobenzoic acid can be detected at 412nm produce characteristic UV absorption.

Take 7 sample tubes, add 30uL 4mg/mL 5,5-dithiobis(2-nitrobenzoic acid) respectively, add 0, 5, 10, 15, 20, 30, 50uL, 1.0mM sample solution , with 0.1M pH 8.0 phosphate buffer solution to make up to 950uL, add 10uL of 1.0mg/mL acetylcholinesterase solution respectively, and keep warm at 37°C for 15min. Immediately add 40uL of 2mg/mL thioacetylcholine solution, and immediately measure its A value (A _n ) at 412nm after shaking well. The reference was 0.1M pH 8.0 phosphate buffer solution.

Relative enzyme activity without sample = (A _n /A _control )×100

The relative activity of the enzyme was plotted against the concentration of the inhibitor, and the IC ₅₀ value (inhibitor concentration when the enzyme activity was inhibited by 50%) of each compound was obtained according to the inhibition curve. The measured results are shown in Table 1:

Table 12-glycosyl quinoline compound anti-acetylcholinesterase inhibitory effect

^a Positive control drug --- tacrine

It can be seen from Example 6 that the 2-glycosylquinoline compound of the present invention has a strong inhibitory activity on acetylcholinesterase, and has broad application prospects in the preparation of anti-acetylcholinesterase drugs.

Claims (6)

1. the application of 2-glycosyl quinoline chemical compound in the preparation anti-acetylcholinesterasemedicine medicine is characterized in that described 2-glycosyl quinoline chemical compound has structural formula shown in formula I:

（Ⅰ）；

Wherein, R ₁, R ₂, R ₃And R ₄Independently be selected from-H ,-OCH ₃Or-Br.

2. the application of 2-glycosyl quinoline chemical compound in the preparation anti-acetylcholinesterasemedicine medicine according to claim 1 is characterized in that described 2-glycosyl quinoline chemical compound is:

R ₁, R ₂, R ₃And R ₄Be-the formula I chemical compound of H;

Or R ₂And R ₃For-H, R ₁And R ₄For-OCH ₃The formula I chemical compound;

Or R ₁And R ₄For-H, R ₂And R ₃For-OCH ₃The formula I chemical compound;

Or R ₂And R ₄For-Br, R ₁And R ₃Formula I chemical compound for-H.

3. the application of 2-glycosyl quinoline chemical compound in the preparation anti-acetylcholinesterasemedicine medicine according to claim 1 is characterized in that the preparation method of described 2-glycosyl quinoline chemical compound comprises the steps:

(1) under the effect of sodium bicarbonate, D-glucose and acetylacetone,2,4-pentanedione generate β-D-acetonyl Fructus Vitis viniferae carbon glycosides;

(2) with the o-Aminobenzaldehyde of o-Aminobenzaldehyde or replacement and β-D-acetonyl Fructus Vitis viniferae carbon glycosides with dissolve with methanol, in the presence of pyrrolidine, react, obtain described 2-glycosyl quinoline chemical compound.

4. as the application of 2-glycosyl quinoline chemical compound as described in the claim 3 in the preparation anti-acetylcholinesterasemedicine medicine, it is characterized in that in the step (2), the consumption of described pyrrolidine is the 25mol% with respect to the o-Aminobenzaldehyde consumption of o-Aminobenzaldehyde or replacement.

5. as the application of 2-glycosyl quinoline chemical compound as described in the claim 3 in the preparation anti-acetylcholinesterasemedicine medicine, it is characterized in that in the step (2), the temperature of described reaction is 60 ~ 120 ℃.

6. as the application of 2-glycosyl quinoline chemical compound as described in the claim 3 in the preparation anti-acetylcholinesterasemedicine medicine, it is characterized in that, described 2-glycosyl quinoline chemical compound carries out purification by crossing post, and crossing the used eluent of post is that volume ratio is ethyl acetate: the mixed solution of isopropyl alcohol: water=16:2:1.