CN113248427A - Sulfonamide nicotinic acid derivative, amido nicotinic acid derivative, preparation method and application thereof - Google Patents
Sulfonamide nicotinic acid derivative, amido nicotinic acid derivative, preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a nicotinic acid sulfonamide derivative and a nicotinic acid amide derivative, which have structures shown in a formula (I) and a formula (IV) respectively. Experimental results show that the sulfonamide nicotinic acid derivative and the amide nicotinic acid derivative provided by the invention have good activity for treating atherosclerosis, and can be used for preparing related atherosclerosis treatment medicines.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a sulfonamide nicotinic acid derivative, an amido nicotinic acid derivative, and a preparation method and application thereof.
Background
Since the 1999 theory that Ross proposed that atherosclerosis is an inflammatory disease, a chronic inflammatory response caused by the interaction of vascular endothelial cells, lipids, mononuclear macrophages, vascular smooth muscle cells and platelets, a large number of basic and clinical studies have provided new evidence for this hypothesis. In order to convert these basic studies into clinical applications AS soon AS possible, researchers have been working on finding inflammatory markers of human atherosclerosis, and the roles of various immune responses and inflammatory targets (CRP, IL-1, IL-6, IL-8, MCP-1) in influencing the progression of atherosclerosis are reported successively, and particularly, the CANTOS test of treating atherosclerosis by using an IL-1 β inhibitor Canakinumab was reported to be successful in the new england medical journal in 2017, so that the "inflammation hypothesis" of AS treatment is raised to the "inflammation theory", and the "inflammation hypothesis" of AS treatment is a milestone of treating atherosclerosis by using an anti-inflammatory drug. Although IL-1 beta is not an ideal anti-inflammatory target, Canakinumab produces adverse reactions damaging immune response while obtaining the anti-inflammatory efficacy of atherosclerosis, the development of a brand new target medicament by combining the action mechanism of immune response and inflammatory response in the course of atherosclerosis becomes a research and development hotspot of atherosclerosis treatment, and the search for a more ideal target and related medicaments is a key problem to be solved urgently for the anti-inflammatory treatment of atherosclerosis. The activity of the extracellular nucleotides mediated by the P2Y6R participates in the occurrence and development of cardiovascular diseases, and is reflected in the aspects of promoting vascular inflammatory reaction, enhancing vascular tension, promoting the contraction and proliferation of smooth muscle cells and the like. In a mouse model of P2Y6R gene knockout, the response of vascular endothelial cells, macrophages and vascular smooth muscle cells to UDP is obviously weakened, and the cells in the groups are the core cells in the atherosclerotic process. Recently, Blood reports that deletion of P2Y6R gene can inhibit atherosclerosis and plaque inflammation induced by high cholesterol diet, so that development of antagonists aiming at P2Y6R receptor can achieve anti-inflammatory effect by intervening in innate immunity of organism, and has good innovation and application prospect in the development field of drugs for treating inflammation such as atherosclerosis.
Sulfonamide nicotinic acids are important pharmacophores in modern drug discovery. Many outstanding results show that the sulfonamide nicotinic acid and amide nicotinic acid compounds have wide potential application as medicinal medicaments and diagnostic agents. Especially clinical anti-inflammatory, treat atherosclerosis, etc., a large number of sulfonamide nicotinic acid, amide nicotinic acid compounds have been developed successfully, sold and widely used for preventing and treating various diseases, it has low toxicity, high bioavailability, good biocompatibility and curative effect. The sulfonamide nicotinic acid and amide nicotinic acid compounds have wide biological activity. Research shows that the nicotinic acid heterocyclic compound has good biological activities of resisting inflammation and bacteria, treating atherosclerosis, resisting virus and the like, and has unique structure, low toxicity and excellent biological activity, so the nicotinic acid heterocyclic compound is widely applied to various fields of chemistry, medicine, biology, material science and the like. By utilizing the principle of activity superposition, the activity of a plurality of small molecular drugs is greatly improved after nicotinic acid groups are introduced. The nicotinic acid derivative is a hot spot in drug development due to the excellent characteristics of the nicotinic acid derivative.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide sulfonamide nicotinic acid and amide nicotinic acid derivatives, and preparation methods and applications thereof, wherein the prepared sulfonamide nicotinic acid and amide nicotinic acid derivatives have good activity for treating atherosclerosis.
In order to achieve the above object, the present invention provides a nicotinic acid sulfonamide derivative having a structure represented by formula (I), or an anionic form or a pharmaceutically acceptable salt thereof:
wherein R is1Selected from H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclyl;
n is any integer of 0-5;
R2selected from H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclic group, C2-C6 alkenyl, alcoholic hydroxyl or phenyl;
the substituents of the C1-C6 alkyl, the C3-C6 cycloalkyl, the C1-C6 alkoxy, the C1-C6 heterocyclic group, the C2-C6 alkenyl, the alcoholic hydroxyl or the phenyl are selected from cyano, hydroxyl, cycloalkyl, alkenyl or alkoxy.
In the present invention, the anion form refers to an anion form of carboxylic acid formed after the carboxyl group loses H ion.
In the present invention, the anionic form has a structure represented by the following formula (I-a):
in the present invention, the pharmaceutically acceptable salt is preferably one or more of hydrochloride, sulfate and phosphate.
In the present invention, R is1Preferably H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclyl; more preferably H, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C1-C6 heterocyclic group; more preferably methyl.
The n is preferably an integer of 0 to 5, more preferably 1 or 2, and further preferably 1.
The R is2Preferably H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclic group, C2-C6 alkenyl, alcoholic hydroxyl or phenyl.
The substituent of the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclic group, C2-C6 alkenyl, alcoholic hydroxyl or phenyl is preferably cyano, hydroxyl, cycloalkyl, alkenyl or alkoxy; more preferably cyano, hydroxy, cycloalkyl of C3-C6, alkenyl of C2-C6 or alkoxy of C1-C6; more preferably a cyano group, a hydroxyl group, a cycloalkyl group having 3 to 6 carbon atoms, an alkenyl group having 2 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms.
In some embodiments of the invention, R is2Preferably H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylethyl, allyl, methoxy, methoxyethyl, ethanol, propionitrile or pyrrolidinyl.
Preferably, the nicotinic acid sulfonamide derivative has any one of the following structures, or an anionic form and a pharmaceutically acceptable salt thereof:
the invention provides a preparation method of the sulfonamide nicotinic acid derivative, which comprises the following steps:
reacting a compound with a structure shown in a formula (II) with a compound with a structure shown in a formula (III) to obtain a sulfonamide nicotinic acid derivative shown in the formula (I);
wherein R is1、n、R2The same scope is defined above, and is not described herein.
The compound with the structure of the formula (III) is prepared by reacting 6-chloro-5-nitronicotinic acid and piperazine to obtain an intermediate, and then reducing nitro.
The reaction equation of the preparation method is as follows:
the R is1、R2And n is as above, and is not described herein again.
The invention provides a nicotinic acid amide derivative which has a structure shown in a formula (IV) or an anion form and pharmaceutically acceptable salt thereof:
wherein R is3Selected from H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclyl;
m is any integer of 0-5;
R4selected from H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclic group, C2-C6 alkenyl, alcoholic hydroxyl or phenyl;
the substituents of the C1-C6 alkyl, the C3-C6 cycloalkyl, the C1-C6 alkoxy, the C1-C6 heterocyclic group, the C2-C6 alkenyl, the alcoholic hydroxyl or the phenyl are selected from cyano, hydroxyl, cycloalkyl, alkenyl or alkoxy.
In the present invention, the anion form refers to an anion form of carboxylic acid formed after the carboxyl group loses H ion.
Wherein the anionic form has a structure represented by the following formula (IV-a):
in the present invention, the pharmaceutically acceptable salt is preferably one or more of hydrochloride, sulfate and phosphate.
In the present invention, R is3Preferably H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclyl; more preferably H, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C1-C6 heterocyclic group; more preferably methyl.
M is preferably any integer of 0-5; more preferably 1 or 2, and still more preferably 2.
The R is4Preferably H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclic group, C2-C6 alkenyl, alcoholic hydroxyl or phenyl.
The substituents of the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclic group, C2-C6 alkenyl, alcoholic hydroxyl or phenyl are preferably cyano, hydroxyl, cycloalkyl, alkenyl or alkoxy. More preferably cyano, hydroxy, cycloalkyl of C3-C6, alkenyl of C2-C6 or alkoxy of C1-C6; more preferably a cyano group, a hydroxyl group, a cycloalkyl group having 3 to 6 carbon atoms, an alkenyl group having 2 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms.
In some embodiments of the invention, R is2Preferably H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylethyl, allyl, methoxy, methoxyethyl, ethanolyl, propionylcyano or pyrrolidinyl; more preferably H, isopropyl, methoxy, ethanol, propionitrile or cyclopropylethyl.
In some embodiments of the invention, the amidonicotinic acid derivative has any one of the following structures, or an anionic form, a pharmaceutically acceptable salt thereof:
the invention discloses a preparation method of the amido nicotinic acid derivative, which comprises the following steps:
reacting a compound with a structure shown in a formula (V) with a compound with a structure shown in a formula (VI) to obtain a compound with a structure shown in a formula (IV);
wherein R is3、m、R4The same scope is defined above, and is not described herein.
The compound with the structure shown in the formula (VI) is prepared by reacting 6-chloro-5-nitronicotinic acid with piperazine to obtain an intermediate, and then reducing nitro.
The reaction equation of the preparation method is as follows:
wherein, R is3、R4The range of m is the same as above, and is not described herein again.
The invention provides the application of the sulfonamide nicotinic acid derivative or the sulfonamide nicotinic acid derivative prepared by the preparation method, or the acylamino nicotinic acid derivative prepared by the preparation method in preparing a medicament for treating atherosclerosis.
The invention provides a medicament for treating atherosclerosis, which comprises the sulfonamide nicotinic acid derivative or the sulfonamide nicotinic acid derivative prepared by the preparation method, or the acylamino nicotinic acid derivative prepared by the preparation method and auxiliary materials.
The auxiliary material can be pharmaceutically acceptable auxiliary material.
The medicament for treating atherosclerosis provided by the invention can be combined with other medicaments for treating atherosclerosis.
Compared with the prior art, the invention provides the sulfonamide nicotinic acid derivative and the acylamino nicotinic acid derivative, and experimental results show that the sulfonamide nicotinic acid derivative and the acylamino nicotinic acid derivative have better activity for treating atherosclerosis and can be used for preparing medicaments for treating related atherosclerosis diseases.
Drawings
FIG. 1 is a graph showing the abnormal changes in the blood lipid levels of atherosclerotic mice inhibited by compounds of the present invention;
FIG. 2 is a graph showing that the compound of the invention improves the pathological tissue morphology of aorta of an atherosclerotic mouse.
Detailed Description
In order to further illustrate the present invention, the sulfonamide nicotinic acid derivatives and the amido nicotinic acid derivatives, the preparation methods and applications thereof provided by the present invention are described in detail below with reference to examples.
Example 1
Synthesis of 6- (4- (2-cyanoethyl) piperazin-1-yl) -5- ((3-methylphenyl) sulfonamide) nicotinic acid:
dissolving 6-chloro-5-nitronicotinic acid (2.02g), di-tert-butyl dicarbonate (2.18g) and DMAP (2.7ml) in 20ml of pyridine solution, stirring at room temperature, monitoring by TLC, extracting with ethyl acetate after the reaction is finished, drying, spin-drying and passing through a column to obtain pure 6-chloro-5-nitronicotinic acid tert-butyl ester;
pd was added to 25ml of toluene2(dba)3(0.1g)，P(N(i-Bu)CH2CH2)3(0.1g), sodium tert-butoxide (1.92g), tert-butyl 6-chloro-5-nitronicotinate (2.58g), 3- (piperazin-1-yl) propionitrile (1.5g), stirred at room temperature, monitored by TLC, extracted with ethyl acetate after completion of the reaction, dried, spun-dried and passed through a column to give pure 6- (4- (2- (cyanoethyl) piperazin-1-yl) -5-nicotinate;
6- (4- (2- (cyanoethyl) piperazin-1-yl) -5-nicotinate (3.61g) was placed in an autoclave, dissolved in ethanol, the apparatus covered, H2Pumping and ventilating for three times, filling hydrogen into the kettle, sealing, heating and stirring for 4 hours, extracting with ethyl acetate after the reaction is finished, drying, spin-drying, and passing through a column to obtain pure 5-amino-6- (4- (2-cyanoethyl) piperazine-1-yl) nicotinic acid tert-butyl ester;
dissolving tert-butyl 5-amino-6- (4- (2-cyanoethyl) piperazin-1-yl) nicotinate (3.31g) in 20ml pyridine solution, adding dropwise methyl benzenesulfonyl chloride (2.2ml), stirring at room temperature, monitoring by TLC, extracting with ethyl acetate after completion of the reaction, drying, spin-drying, and passing through a column to give pure tert-butyl 6- (4- (2-cyanoethyl) piperazin-1-yl) -5- ((3-methylphenyl) sulfonamide) nicotinate;
tert-butyl 6- (4- (2-cyanoethyl) piperazin-1-yl) -5- ((3-methylphenyl) sulfonamide) nicotinic acid (4.86g) was dissolved in 40ml dichloromethane, added dropwise to 1.5ml trifluoroacetic acid, stirred at room temperature, monitored by TLC, extracted with ethyl acetate after completion of the reaction, dried, spun-dried and chromatographed to give the pure title compound.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ8.65(d,J＝1.1Hz,1H),7.73(ddd,J＝7.2,3.5,1.4Hz,1H),7.61(d,J＝4.5Hz,3H),7.37(d,J＝1.3Hz,1H),3.50(t,J＝5.1Hz,4H),3.01(t,J＝7.6Hz,2H),2.73(t,J＝7.5Hz,2H),2.57(t,J＝5.1Hz,4H),2.42(s,3H).
13C NMR(125MHz,DMSO-d6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,118.85,117.56,53.40,52.43,47.44,21.27,14.43.
example 2
Synthesis of 6- (4-isobutylpiperazin-1-yl) -5- ((3-methylphenyl) sulfonamide) nicotinic acid:
the synthesis method of the compound is shown in example 1 by taking 1-isobutyl piperazine as a raw material.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ8.78(d,J＝1.3Hz,1H),7.78–7.71(m,1H),7.65–7.58(m,3H),7.37(d,J＝1.3Hz,1H),3.50(t,J＝5.1Hz,4H),2.57(t,J＝5.1Hz,4H),2.42(s,3H),2.08(d,J＝6.9Hz,2H),1.68(dp,J＝13.7,6.8Hz,1H),0.85(d,J＝6.8Hz,6H).
13C NMR(125MHz,DMSO-d6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,66.88,52.83,47.44,25.20,21.27,20.82.
example 3
Synthesis of 6- (4- (2-hydroxyethyl) piperazin-1-yl) -5- ((3-methylphenyl) sulfonamide) nicotinic acid:
starting from 2- (piperazin-1-yl) ethan-1-ol, the synthesis is as described in example 1.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ8.64(d,J＝1.3Hz,1H),7.73(ddt,J＝7.9,5.2,2.2Hz,1H),7.65–7.58(m,3H),7.37(d,J＝1.3Hz,1H),4.25(t,J＝4.9Hz,1H),3.58(td,J＝7.2,5.0Hz,2H),3.50(t,J＝5.1Hz,4H),2.64(t,J＝5.1Hz,4H),2.58(t,J＝7.2Hz,2H),2.42(s,3H).
13C NMR(125MHz,DMSO-d6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,59.93,58.30,52.88,47.44,21.27.
example 4
Synthesis of 6- (4- (2-cyclopropylethyl) piperazin-1-yl) -5- ((3-methylphenyl) sulfonamide) nicotinic acid:
the synthesis method of the compound is shown in example 1 by taking 1- (2-cyclopropylethyl) piperazine as a raw material.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ8.68(d,J＝1.3Hz,1H),7.71(tt,J＝5.3,2.6Hz,1H),7.61(d,J＝4.9Hz,2H),7.54–7.49(m,1H),7.37(d,J＝1.3Hz,1H),3.50(t,J＝5.1Hz,4H),2.57(t,J＝5.1Hz,4H),2.49–2.40(m,5H),1.42(q,J＝7.4Hz,2H),1.00(hept,J＝7.0Hz,1H),0.37(tt,J＝7.3,4.2Hz,2H),0.22(tt,J＝7.3,4.2Hz,2H).
13C NMR(125MHz,DMSO-d6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,55.26,52.43,47.44,31.12,21.27,10.30,5.57.
example 5
Synthesis of 6- (4-allylpiperazin-1-yl) -5- ((3-methylphenyl) sulfonamide) nicotinic acid:
the synthesis method of the compound is shown in example 1 by taking 1-allyl piperazine as a raw material.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ8.65(d,J＝1.1Hz,1H),7.73(td,J＝4.9,2.5Hz,1H),7.61(t,J＝4.1Hz,3H),7.37(d,J＝1.3Hz,1H),5.84(ddt,J＝14.3,12.4,6.2Hz,1H),5.19–5.12(m,2H),3.50(t,J＝5.1Hz,4H),3.01(dd,J＝6.1,1.2Hz,2H),2.55(t,J＝5.1Hz,4H),2.42(s,3H).
13C NMR(125MHz,DMSO-d6)δ166.73,150.45,149.13,138.73,137.96,134.53,132.62,128.72,128.28,124.91,123.14,117.56,61.55,52.35,47.44,21.27.
example 6
Synthesis of 5- ((3-methylphenyl) sulfonamido) -6- (4- (pyrrolidin-1-yl) piperazin-1-yl) nicotinic acid:
the synthesis method of the compound is shown in example 1 by taking 1- (pyrrolidine-1-yl) piperazine as a raw material.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ8.67(d,J＝1.3Hz,1H),7.73(tt,J＝5.3,2.6Hz,1H),7.70–7.65(m,1H),7.61(d,J＝4.9Hz,2H),7.37(d,J＝1.3Hz,1H),3.12(t,J＝5.1Hz,4H),2.79(ddd,J＝10.1,7.6,4.6Hz,8H),2.42(s,3H),1.97–1.87(m,4H).
13C NMR(125MHz,DMSO-d6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,53.42,52.97,48.57,22.66,21.27.
example 7
Synthesis of 6- (4-isopropylpiperazin-1-yl) -5- ((3-methylphenyl) sulfonamide) nicotinic acid:
the synthesis method of the compound is shown in example 1 by taking 1-isopropylpiperazine as a raw material.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ8.73(d,J＝1.3Hz,1H),7.71(tt,J＝5.2,2.6Hz,1H),7.67–7.58(m,3H),7.37(d,J＝1.3Hz,1H),3.50(t,J＝4.9Hz,4H),2.69(hept,J＝6.9Hz,1H),2.54(t,J＝4.9Hz,4H),2.42(s,3H),1.00(d,J＝6.8Hz,6H).
13C NMR(125MHz,DMSO-d6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,54.57,50.90,47.75,21.27,18.30.
example 8
Synthesis of 6- (4- (2-methoxyethyl) piperazin-1-yl) -5- ((3-methylphenyl) sulfonamide) nicotinic acid:
the synthesis method of the compound is shown in example 1 by taking 1- (2-methoxyethyl) piperazine as a raw material.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ8.65(d,J＝1.3Hz,1H),7.76–7.69(m,1H),7.65–7.59(m,3H),7.37(d,J＝1.3Hz,1H),3.53–3.43(m,6H),3.25(s,3H),2.98(t,J＝7.2Hz,2H),2.64(t,J＝5.1Hz,4H),2.42(s,3H).
13C NMR(125MHz,DMSO-d6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,70.81,58.91,55.94,52.88,47.44,21.27.
example 9
Synthesis of 5- ((3-methylphenyl) sulfonamide) -6- (4-methylpiperazin-1-yl) nicotinic acid:
the synthesis method is shown in example 1 by taking 1-methylpiperazine as a raw material.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ8.64(d,J＝1.3Hz,1H),7.72–7.64(m,2H),7.61(d,J＝4.9Hz,2H),7.37(d,J＝1.3Hz,1H),3.50(t,J＝5.1Hz,4H),2.60(s,3H),2.44–2.35(m,7H).
13C NMR(125MHz,DMSO-d6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,54.46,46.96,44.73,21.27.
example 10
Synthesis of 6- (4-methoxypiperazin-1-yl) -5- ((3-methylphenyl) sulfonamide) nicotinic acid:
the synthesis method of the compound is shown in example 1 by taking 1-methoxypiperazine as a raw material.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ8.79(d,J＝1.3Hz,1H),7.62(dd,J＝6.1,1.2Hz,4H),7.37(d,J＝1.3Hz,1H),3.49(s,3H),3.25(t,J＝5.1Hz,4H),2.78(t,J＝5.1Hz,4H),2.42(s,3H).
13C NMR(125MHz,DMSO-d6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,60.71,55.29,48.14,21.27.
example 11
Synthesis of 6- (4-ethylpiperazin-1-yl) -5- ((3-methylphenyl) sulfonamido) nicotinic acid:
the synthesis method of the compound is shown in example 1 by taking 1-ethylpiperazine as a raw material.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ8.77(d,J＝1.3Hz,1H),7.78–7.71(m,1H),7.65–7.59(m,3H),7.37(d,J＝1.3Hz,1H),3.50(t,J＝5.1Hz,4H),2.57(t,J＝5.1Hz,4H),2.44–2.34(m,5H),0.96(t,J＝8.0Hz,3H).
13C NMR(125MHz,DMSO-d6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,52.16,52.05,47.44,21.27,12.04.
example 12
Synthesis of 5- ((3-methylphenyl) sulfonamide) -6- (piperazin-1-yl) nicotinic acid:
the synthesis method is shown in example 1 by taking piperazine as a raw material.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ8.64(d,J＝1.3Hz,1H),7.72–7.63(m,2H),7.61(d,J＝4.9Hz,2H),7.37(d,J＝1.3Hz,1H),3.38(t,J＝5.0Hz,4H),2.65(t,J＝5.0Hz,4H),2.42(s,3H),1.80(s,1H).
13C NMR(125MHz,DMSO-d6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,47.97,45.61,21.27.
example 13
Synthesis of 5- (3, 5-dimethylbenzamide) -6- (piperazin-1-yl) nicotinic acid:
dissolving 6-chloro-5-nitronicotinic acid (2.02g), di-tert-butyl dicarbonate (2.18g) and DMAP (2.7ml) in 20ml of pyridine solution, stirring at room temperature, monitoring by TLC, extracting with ethyl acetate after the reaction is finished, drying, spin-drying and passing through a column to obtain pure 6-chloro-5-nitronicotinic acid tert-butyl ester;
pd was added to 25ml of toluene2(dba)3(0.1g)，P(N(i-Bu)CH2CH2)3(0.1g), sodium tert-butoxide (1.92g), tert-butyl 6-chloro-5-nitronicotinate (2.58g), piperazine (0.86g), stirred at room temperature, monitored by TLC, extracted with ethyl acetate after completion of the reaction, dried, spun-dried, and passed through a column to give pure tert-butyl 5-nitro-6- (piperazin-1-yl) nicotinate;
5-Nitro-6- (piperazin-1-yl) nicotinic acid tert-butyl ester (3.08g) was placed in an autoclave, dissolved with ethanol, the apparatus was covered, H2Pumping and ventilating for three times, filling hydrogen into the kettle, sealing, heating and stirring for 4 hours, extracting with ethyl acetate after the reaction is finished, drying, spin-drying, and passing through a column to obtain pure 5-amino-6- (R)Piperazin-1-yl) nicotinic acid tert-butyl ester;
dissolving tert-butyl 5-amino-6- (piperazin-1-yl) nicotinate (2.78g) in 20ml pyridine solution, adding 3, 5-dimethylbenzoyl chloride (2.2ml) dropwise, stirring at room temperature, monitoring by TLC, extracting with ethyl acetate after completion of the reaction, drying, spin-drying, and passing through a column to give pure tert-butyl 5- (3, 5-dimethylbenzamide) -6- (piperazin-1-yl) nicotinate;
tert-butyl 5- (3, 5-dimethylbenzamide) -6- (piperazin-1-yl) nicotinate (4.10g) was dissolved in 40ml dichloromethane, added dropwise to 1.5ml trifluoroacetic acid, stirred at room temperature, monitored by TLC, extracted with ethyl acetate after completion of the reaction, dried, spun-dried, and passed through a column to give the pure title compound.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ9.72(s,1H),9.16(d,J＝1.3Hz,1H),8.50(d,J＝1.3Hz,1H),7.54(d,J＝2.0Hz,2H),7.40–7.34(m,1H),3.38(t,J＝5.1Hz,4H),2.65(t,J＝5.1Hz,4H),2.34(s,5H),1.78(s,1H).
13C NMR(125MHz,DMSO-d6)δ166.73,166.23,152.10,149.07,135.74,134.51,132.49,127.00,126.45,122.70,121.61,47.97,45.61,20.82.
example 14
Synthesis of 6- (4- (2-cyclopropylethyl) piperazin-1-yl) -5- (3, 5-dimethylbenzamido) nicotinic acid:
the synthesis method of the compound is shown in example 13 by taking 1- (2-cyclopropylethyl) piperazine as a raw material.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ9.72(s,1H),9.15(d,J＝1.1Hz,1H),8.50(d,J＝1.3Hz,1H),7.55(d,J＝1.9Hz,2H),7.37(q,J＝1.8Hz,1H),3.50(t,J＝5.2Hz,4H),2.57(t,J＝5.2Hz,4H),2.45(t,J＝7.6Hz,2H),2.34(s,5H),1.42(q,J＝7.4Hz,2H),0.99(hept,J＝6.9Hz,1H),0.40–0.33(m,2H),0.24–0.16(m,2H).
13C NMR(125MHz,DMSO-d6)δ166.73,166.23,152.10,149.07,135.74,134.51,132.49,127.00,126.45,122.70,121.61,55.26,52.43,47.44,31.12,20.82,10.30,5.57.
example 15
Synthesis of 6- (4- (2-cyanoethyl) piperazin-1-yl) -5- (3, 5-dimethylbenzamido) nicotinic acid:
the synthesis procedure is described in example 13, starting from 3- (piperazin-1-yl) propionitrile.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ9.71(s,1H),9.12(d,J＝1.3Hz,1H),8.49(d,J＝1.3Hz,1H),7.54(d,J＝2.0Hz,2H),3.50(t,J＝5.2Hz,4H),3.01(t,J＝7.6Hz,2H),2.73(t,J＝7.5Hz,2H),2.57(t,J＝5.2Hz,4H),2.34(s,5H).
13C NMR(125MHz,DMSO-d6)δ166.73,166.23,152.10,149.07,135.74,134.51,132.49,127.00,126.45,122.70,121.61,118.85,53.40,52.43,47.44,20.82,14.43.
example 16
Synthesis of 5- (3, 5-dimethylbenzamido) -6- (4- (2-hydroxyethyl) piperazin-1-yl) nicotinic acid:
starting from 2- (piperazin-1-yl) ethan-1-ol, the synthesis is as described in example 13.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ9.77(s,1H),9.19(d,J＝1.3Hz,1H),8.51(d,J＝1.3Hz,1H),7.57–7.52(m,2H),7.40–7.35(m,1H),4.25(t,J＝4.9Hz,1H),3.58(td,J＝7.2,5.0Hz,2H),3.50(t,J＝5.1Hz,4H),2.67–2.55(m,6H),2.34(s,5H).
13C NMR(125MHz,DMSO-d6)δ166.73,166.23,152.10,149.07,135.74,134.51,132.49,127.00,126.45,122.70,121.61,59.93,58.30,52.88,47.44,20.82.
example 17
Synthesis of 5- (3, 5-dimethylbenzamide) -6- (4-isopropylpiperazin-1-yl) nicotinic acid:
the synthesis method of the compound takes 1-isopropylpiperazine as a raw material, and is shown in example 13.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ9.77(s,1H),9.13(d,J＝1.3Hz,1H),8.46(d,J＝1.3Hz,1H),7.54(d,J＝2.0Hz,2H),7.37(tt,J＝2.2,1.2Hz,1H),3.50(t,J＝5.1Hz,4H),2.68(h,J＝6.8Hz,1H),2.54(t,J＝5.1Hz,4H),2.34(s,5H),1.00(d,J＝6.8Hz,6H).
13C NMR(125MHz,DMSO-d6)δ166.73,166.23,152.10,149.07,135.74,134.51,132.49,127.00,126.45,122.70,121.61,54.57,50.90,47.75,20.82,18.30.
example 18
Synthesis of 5- (3, 5-dimethylbenzamido) -6- (4-methoxypiperazin-1-yl) nicotinic acid:
the synthesis method of the compound takes 1-methoxy piperazine as a raw material, and is shown in example 13.
The nuclear magnetic data are as follows:
1H NMR(500MHz,DMSO-d6)δ9.77(s,1H),9.15(d,J＝1.1Hz,1H),8.49(d,J＝1.3Hz,1H),7.55(d,J＝2.0Hz,2H),7.40–7.35(m,1H),3.49(s,3H),3.25(t,J＝5.2Hz,4H),2.78(t,J＝5.2Hz,4H),2.34(s,5H).
13C NMR(125MHz,DMSO-d6)δ166.73,166.23,152.10,149.07,135.74,134.51,132.49,127.00,126.45,122.70,121.61,60.71,55.29,48.14,20.82.
EXAMPLE 19 testing of P2Y6R receptor antagonistic Activity in vitro
The human P2Y6R stable HEK293 cells constructed in the previous stage are cultured in DMEM medium (containing 10% fetal calf serum, 100U/ml penicillin and 100 mu g/ml streptomycin), and are inoculated to a 6-well culture plate before the experiment, the inoculation density is 5 multiplied by 105cells/ml, the cells are cultured at 37 ℃ and 95% O2、5％CO2Culturing under humidity condition. Starving the culture medium before the experiment for 12h, adding 1 mu M compound into each hole, reacting for 30min, adding 10 mu M UDP, incubating for 12h, collecting samples, and detecting the content of intracellular 3-phosphoinositide (IP 3).
The enzyme linked immunosorbent assay kit for 3-phosphoinositide (IP3) adopts a competitive ELISA method. The enzyme label plate is coated with IP3 antigen, IP3 in the sample or standard substance competes with coated IP3 for the binding site of the biotin-labeled anti-IP 3 monoclonal antibody during the experiment, and the free components are washed away. Adding horse radish peroxidase labeled avidin, specifically combining biotin with avidin to form immune complex, and washing off free components. Adding chromogenic substrate (TMB), wherein the TMB is blue under the catalysis of horseradish peroxidase, and becomes yellow after adding stop solution. Measuring OD value at 450nm wavelength by using a microplate reader, wherein the concentration of IP3 is inversely proportional to the OD450 value, and calculating the concentration of IP3 in the sample by drawing a standard curve. And finally, calculating the average OD value of each group of multiple holes. Drawing a standard curve of a four-parameter logic function on log-log graph paper by taking the concentration as an abscissa and the OD value as an ordinate; the concentration of IP3 in the sample was calculated from the standard curve. The experiment was repeated three times, averaged and the compound pair P2Y calculated6IC of R50And SD.
The results of the experiment are shown in table 1:
table 1 results of the test for P2Y6R receptor antagonistic activity in vitro
EXAMPLE 20 study of therapeutic Effect of Compounds in animal models of atherosclerosis
Taking 6- (4- (2-cyanoethyl) piperazine-1-yl) -5- ((3-methylphenyl) sulfonamide) nicotinic acid (hereinafter referred to as compound 1) as an example, the pharmacodynamics research of the compound in a mouse atherosclerosis model is researched
LDLR-/-mouse AS models were established with High Fat Diet (HFD) and were treated with 20mg/kg of compound 1 for intervention. The results show that the compound 1 can effectively inhibit abnormal changes of atherosclerotic blood lipid levels TC, TG, LDL-C and HDL-C caused by HFD (figure 1); meanwhile, the compound 1 can effectively improve pathological changes of mouse main plaque such as increased lipid deposition, artery wall thickening, lumen narrowing, high collagen fiber content, intimal fibrosis and the like (figure 2). The compound 1 is proved to have good treatment effect in a mouse atherosclerosis model, and the potential of the compound as a medicament for treating atherosclerosis is shown.
As can be seen from the examples, the sulfonamide nicotinic acid and the amide nicotinic acid derivatives prepared by the invention have better activity of treating atherosclerosis.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (10)
1. A nicotinic acid sulfonamide derivative having a structure represented by formula (I), or an anionic form, pharmaceutically acceptable salt thereof:
wherein R is1Selected from H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclyl;
n is any integer of 0-5;
R2selected from H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclic group, C2-C6 alkenylAlcoholic hydroxyl or phenyl;
the substituents of the C1-C6 alkyl, the C3-C6 cycloalkyl, the C1-C6 alkoxy, the C1-C6 heterocyclic group, the C2-C6 alkenyl, the alcoholic hydroxyl or the phenyl are selected from cyano, hydroxyl, cycloalkyl, alkenyl or alkoxy.
2. The nicotinic acid sulfonamide derivative of claim 1, wherein R is1Is selected from methyl;
n is 1 or 2;
the R is2Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylethyl, allyl, methoxy, methoxyethyl, ethanolyl, propionitrile or pyrrolidinyl.
3. The nicotinic acid sulfonamide derivative of claim 1, having any of the following structures, or an anionic form, pharmaceutically acceptable salt thereof:
4. the method for producing a sulfonamide nicotinic acid derivative according to any one of claims 1 to 3, which comprises the steps of:
reacting a compound with a structure shown in a formula (II) with a compound with a structure shown in a formula (III) to obtain a sulfonamide nicotinic acid derivative shown in the formula (I);
wherein R is1Selected from H, halogen, nitro, cyano, alkyl, alkoxyA group, cycloalkyl or heterocyclyl;
n is any integer of 0-5;
R2selected from H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclic group, C2-C6 alkenyl, alcoholic hydroxyl or phenyl;
the substituent of the C1-C6 alkyl is selected from cyano, hydroxyl, cycloalkyl, alkenyl or alkoxy.
5. A nicotinic acid amide derivative having a structure represented by formula (IV), or an anionic form, pharmaceutically acceptable salt thereof:
wherein R is3Selected from H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclyl;
m is any integer of 0-5;
R4selected from H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclic group, C2-C6 alkenyl, alcoholic hydroxyl or phenyl;
the substituents of the C1-C6 alkyl, the C3-C6 cycloalkyl, the C1-C6 alkoxy, the C1-C6 heterocyclic group, the C2-C6 alkenyl, the alcoholic hydroxyl or the phenyl are selected from cyano, hydroxyl, cycloalkyl, alkenyl or alkoxy.
6. The amidonicotinic acid derivative of claim 5 wherein R is3Is selected from methyl;
m is 1 or 2;
the R is2Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylethyl, allyl, methoxy, methoxyethyl, ethanolyl, propionitrile or pyrrolidinyl.
7. The amidonicotinic acid derivative of claim 5 having the structure of any one of the following, or an anionic form, a pharmaceutically acceptable salt thereof:
8. the method for preparing an amidonicotinic acid derivative according to any one of claims 5 to 7, comprising the steps of:
reacting a compound with a structure shown in a formula (V) with a compound with a structure shown in a formula (VI) to obtain a compound with a structure shown in a formula (IV);
wherein R is3Selected from H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclyl;
m is any integer of 0-5;
R4selected from H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclic group, C2-C6 alkenyl, alcoholic hydroxyl or phenyl;
the substituent of the C1-C6 alkyl is selected from cyano, hydroxyl, cycloalkyl, alkenyl or alkoxy.
9. Use of the sulfonamide nicotinic acid derivative according to any of claims 1 to 3 or the sulfonamide nicotinic acid derivative prepared by the preparation method according to claim 4, or the amido nicotinic acid derivative according to any of claims 5 to 7 or the amido nicotinic acid derivative prepared by the preparation method according to claim 8 for the preparation of a medicament for treating atherosclerosis.
10. A medicament for treating atherosclerosis, which comprises the sulfonamide nicotinic acid derivative as described in any one of claims 1 to 3 or the sulfonamide nicotinic acid derivative prepared by the preparation method as described in claim 4, or the acylamino nicotinic acid derivative as described in any one of claims 5 to 7 or the acylamino nicotinic acid derivative prepared by the preparation method as described in claim 8, and an auxiliary material.
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Non-Patent Citations (8)
| Title |
|---|
| ACS: "RN: 1021296-13-8", 《STN REGISTRY数据库》, 16 May 2008 (2008-05-16), pages 1021296 - 13 * |
| ACS: "RN: 1021296-17-2", 《STN REGISTRY数据库》, 16 May 2008 (2008-05-16), pages 1021296 - 17 * |
| ACS: "RN: 1021296-19-4", 《STN REGISTRY数据库》, 16 May 2008 (2008-05-16), pages 1021296 - 19 * |
| ACS: "RN: 933234-26-5", 《STN REGISTRY数据库》, 29 April 2007 (2007-04-29), pages 933234 - 26 * |
| ACS: "RN: 950279-61-5", 《STN REGISTRY数据库》, 11 October 2007 (2007-10-11), pages 950279 - 61 * |
| ACS: "RN: 950279-65-9", 《STN REGISTRY数据库》, 11 October 2007 (2007-10-11), pages 950279 - 65 * |
| ACS: "RN: 950279-73-9", 《STN REGISTRY数据库》, 11 October 2007 (2007-10-11), pages 950279 - 73 * |
| ZHOU MENGZE等: "The role of P2Y6R in cardiovascular diseases and recent development of P2Y6R antagonists", 《DRUG DISCOVERY TODAY》, vol. 25, no. 3, 31 March 2020 (2020-03-31), pages 568 - 573, XP086086955, DOI: 10.1016/j.drudis.2019.12.015 * |
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