CN113248427B - Sulfonyl nicotinic acid derivative, amido nicotinic acid derivative, preparation method and application thereof - Google Patents
Sulfonyl nicotinic acid derivative, amido nicotinic acid derivative, preparation method and application thereof Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention provides nicotinic acid sulfonamide derivatives and nicotinic acid amide derivatives, which have structures shown in a formula (I) and a formula (IV) respectively. Experimental results show that the sulfamoyl nicotinic acid derivative and the sulfamoyl nicotinic acid derivative provided by the invention have better atherosclerosis treatment activity and can be used for preparing related atherosclerosis treatment medicines.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a sulfonamide nicotinic acid derivative, an amido nicotinic acid derivative, a preparation method and application thereof.
Background
Since Ross 1999 proposed that atherosclerosis is an inflammatory disease, a number of basic and clinical studies have provided new evidence for this hypothesis, with more and more scholars forming consensus, atherosclerosis being a chronic inflammatory response caused by interactions of vascular wall endothelial cells, lipids, monocytes macrophages, vascular smooth muscle cells and platelets. In order to convert these basic studies into clinical applications AS soon AS possible, researchers have been working to find inflammatory markers of human atherosclerosis, and the role of various immune responses and inflammatory targets (CRP, IL-1, IL-6, IL-8, MCP-1) in affecting the progression of atherosclerosis has been reported successively, especially in 2017, new england medical journal reported that the CANTOS test of the IL-1 β inhibitor Canakinumab for treating atherosclerosis was successful, raising the "inflammatory hypothesis" of AS treatment to "inflammatory theory" AS a milestone for anti-inflammatory drugs for treating atherosclerosis. Although IL-1 beta is not an ideal anti-inflammatory target, canokinumab produces adverse reactions which damage immune responses while obtaining anti-inflammatory effects of atherosclerosis, drugs which combine the immune responses and the action mechanisms of the inflammatory responses in the course of atherosclerosis to develop brand-new targets become research and development hot spots of atherosclerosis treatment, and finding more ideal targets and related drugs thereof is a key problem to be solved urgently for anti-inflammatory treatment of atherosclerosis. The P2Y6R mediated extracellular nucleotide activity is involved in the occurrence and development of cardiovascular diseases, and is reflected in the aspects of promoting vascular inflammatory reaction, enhancing vascular tension, promoting contraction and proliferation of smooth muscle cells and the like. In the mouse model of P2Y6R gene knockout, vascular endothelial cells, macrophages and vascular smooth muscle cells respond significantly to UDP, while these cells are very core cells in the course of atherosclerosis. Recently, the deletion of the P2Y6R gene has been reported on Blood to inhibit atherosclerosis and plaque inflammation of mice induced by high cholesterol diet, so that the development of an antagonist aiming at the P2Y6R receptor can achieve anti-inflammatory effect by intervening in the innate immunity of organisms, and has good innovation and application prospect in the field of development of inflammatory therapeutic drugs such as atherosclerosis.
Sulfonamido nicotinic acid is an important pharmacophore in modern drug discovery. Many outstanding results indicate that the sulfonamide nicotinic acid and the amido nicotinic acid compounds have wide potential applications as pharmaceutical drugs and diagnostic agents. Especially clinical anti-inflammatory, atherosclerosis treatment and the like, a large number of sulfonamide nicotinic acid and amido nicotinic acid compounds have been successfully developed, sold and widely applied to the prevention and treatment of various diseases, and have low toxicity, high bioavailability, good biocompatibility and curative effect. Sulfonyl nicotinic acid and an amido nicotinic acid compound have wide biological activity. Researches show that the nicotinic acid heterocyclic compound has good biological activities of resisting inflammation, resisting bacteria, treating atherosclerosis, resisting viruses and the like, and has unique structure, low toxicity and excellent biological activity, so that 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 the niacin group is greatly improved after the niacin group is introduced into a plurality of micromolecular medicaments. The nicotinic acid derivative has a plurality of excellent characteristics, so that the nicotinic acid derivative becomes a great hot spot in drug development.
Disclosure of Invention
In view of the above, the technical problem to be solved by the invention is to provide a sulfonamide nicotinic acid, an amide nicotinic acid derivative, a preparation method and application thereof, and the prepared sulfonamide nicotinic acid derivative and amide nicotinic acid derivative have better atherosclerosis treatment activity.
In order to achieve the above object, the present invention provides a sulfonamide nicotinic acid derivative having a structure represented by formula (I), or an anionic form, a pharmaceutically acceptable salt thereof:
wherein R is 1 Selected from H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclyl;
n is any integer from 0 to 5;
R 2 selected from H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclyl, 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 selected from cyano, hydroxyl, cycloalkyl, alkenyl or alkoxy.
In the present invention, the anionic form refers to a carboxylic acid anionic form formed after the carboxyl group loses H ions.
In the present invention, the anionic form has the structure of 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 invention, the R 1 Preferably 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 heterocyclyl; methyl is more preferred.
The number n is preferably an integer of 0 to 5, more preferably 1 or 2, and further preferably 1.
The R is 2 Preferably H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclyl, 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, C3-C6 cycloalkyl, C2-C6 alkenyl or C1-C6 alkoxy; further preferred are cyano, hydroxy, C3-C6 cycloalkyl, C2-C3 alkenyl or C1-C3 alkoxy.
In some embodiments of the invention, the R 2 Preferably H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylethyl, allyl, methoxy, methoxyethyl, ethanolyl, propylcyano or pyrrolidinyl.
Preferably, the sulfonamide nicotinic acid derivative has any one of the following structures, or an anionic form, 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 a formula (I);
wherein R is 1 、n、R 2 Is within the same range as that ofAnd are further described.
Wherein the compound with the structure shown in the formula (III) 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:
the R is 1 、R 2 The ranges of n are the same as above, and are not described in detail herein.
The invention provides an amido nicotinic acid derivative which has a structure shown in a formula (IV), or an anionic form and pharmaceutically acceptable salt thereof:
wherein R is 3 Selected from H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclyl;
m is any integer from 0 to 5;
R 4 selected from H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclyl, 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 selected from cyano, hydroxyl, cycloalkyl, alkenyl or alkoxy.
In the present invention, the anionic form refers to a carboxylic acid anionic form formed after the carboxyl group loses H ions.
Wherein the anionic form has the structure of formula (IV-a):
in the present invention, the pharmaceutically acceptable salt is preferably one or more of hydrochloride, sulfate and phosphate.
In the invention, the R 3 Preferably 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 heterocyclyl; methyl is more preferred.
M is preferably any integer from 0 to 5; more preferably 1 or 2, and still more preferably 2.
The R is 4 Preferably H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclyl, C2-C6 alkenyl, alcoholic hydroxyl or phenyl.
The substituent of the C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, C1-C6 heterocyclic group, C2-C6 alkenyl group, alcoholic hydroxyl group or phenyl group is preferably cyano group, hydroxyl group, cycloalkyl group, alkenyl group or alkoxy group. More preferably cyano, hydroxy, C3-C6 cycloalkyl, C2-C6 alkenyl or C1-C6 alkoxy; further preferred are cyano, hydroxy, C3-C6 cycloalkyl, C2-C3 alkenyl or C1-C3 alkoxy.
In some embodiments of the invention, the R 2 Preferably H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylethyl, allyl, methoxy, methoxyethyl, ethanoyl, propylcyano or pyrrolidinyl; more preferably H, isopropyl, methoxy, ethanol, propylcyano or cyclopropylethyl.
In some embodiments of the invention, the amido-nicotinic acid derivative has any one of the following structures, or an anionic form, 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 of formula (V) with a compound with a structure of formula (VI) to obtain a compound with a structure of formula (IV);
wherein R is 3 、m、R 4 The ranges of (2) are the same and are not described in detail herein.
Wherein 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 the R is 3 、R 4 The ranges of m are the same as above, and are not described in detail herein.
The invention provides the application of the sulfamoyl nicotinic acid derivative or the sulfamoyl nicotinic acid derivative prepared by the preparation method, or the sulfamoyl nicotinic acid derivative prepared by the preparation method in preparing medicines for treating atherosclerosis.
The invention provides a medicament for treating atherosclerosis, which comprises the sulfamide nicotinic acid derivative or the sulfamide nicotinic acid derivative prepared by the preparation method, or the sulfamide nicotinic acid derivative prepared by the preparation method and auxiliary materials.
The auxiliary material can be pharmaceutically acceptable auxiliary material.
The medicine for treating atherosclerosis provided by the invention can be combined with other medicines for treating atherosclerosis.
Compared with the prior art, the invention provides the sulfonamide nicotinic acid derivative and the amido nicotinic acid derivative, and experimental results show that the sulfonamide nicotinic acid derivative and the amido nicotinic acid derivative provided by the invention have better atherosclerosis treatment activity and can be used for preparing related atherosclerosis disease treatment medicines.
Drawings
FIG. 1 is a graph showing the abnormal changes in blood lipid levels of an atherosclerotic mouse inhibited by a compound of the present invention;
FIG. 2 is a graph showing the morphological changes of aortic pathology in atherosclerosis-ameliorating mice with the compounds of the present invention.
Detailed Description
In order to further illustrate the present invention, the sulfonamide nicotinic acid derivatives, the amide 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:
6-chloro-5-nitronicotinic acid (2.02 g), di-tert-butyl dicarbonate (2.18 g), DMAP (2.7 ml) are dissolved in 20ml of pyridine solution, stirred at room temperature, monitored by TLC, extracted with ethyl acetate after the reaction is completed, dried, spin-dried and filtered through a column to obtain pure 6-chloro-5-nitronicotinic acid tert-butyl ester;
pd was added to 25ml toluene 2 (dba) 3 (0.1g)，P(N(i-Bu)CH 2 CH 2 ) 3 (0.1 g), sodium tert-butoxide (1.92 g), tert-butyl 6-chloro-5-nitronicotinate (2.58 g), 3- (piperazin-1-yl) propionitrile (1.5 g), stirring at room temperature, monitoring by TLC, extracting with ethyl acetate after the reaction is completed, drying, spin-drying, and passing through a column to obtain pure 6- (4- (2- (cyanoethyl) piperazin-1-yl) -5-nicotinate;
6- (4- (2- (cyanoethyl) piperazin-1-yl) -5-nicotinate (3.61 g) was placed in an autoclave, dissolved with ethanol, the apparatus was capped, H 2 Pumping air for three times, filling hydrogen in the kettle, sealing, heating and stirring for 4 hours, extracting with ethyl acetate, drying, spin-drying, and passing through a column to obtain pure 5-amino-6- (4- (2-cyanoethyl) piperazin-1-yl) nicotinic acid tert-butyl ester；
Dissolving tert-butyl 5-amino-6- (4- (2-cyanoethyl) piperazin-1-yl) nicotinate (3.31 g) in 20ml of pyridine solution, dropwise adding methylbenzenesulfonyl chloride (2.2 ml), 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 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 (4.86 g) 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:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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) sulphonamide) nicotinic acid:
starting from 1-isobutylpiperazine, the synthesis is described in example 1.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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 described in example 1.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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:
starting from 1- (2-cyclopropylethyl) piperazine, the synthesis is described in example 1.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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:
starting from 1-allylpiperazine, the synthesis is described in example 1.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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) sulfanyl) -6- (4- (pyrrolidin-1-yl) piperazin-1-yl) nicotinic acid:
starting from 1- (pyrrolidin-1-yl) piperazine, the synthesis is described in example 1.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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:
starting from 1-isopropylpiperazine, the synthesis is described in example 1.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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:
starting from 1- (2-methoxyethyl) piperazine, the synthesis is described in example 1.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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:
starting from 1-methylpiperazine, the synthesis is described in example 1.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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) sulphonamide) nicotinic acid:
starting from 1-methoxypiperazine, the synthesis is described in example 1.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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) sulfanyl) nicotinic acid:
starting from 1-ethylpiperazine, the synthesis is described in example 1.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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:
piperazine was used as starting material for the synthesis see example 1.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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:
6-chloro-5-nitronicotinic acid (2.02 g), di-tert-butyl dicarbonate (2.18 g), DMAP (2.7 ml) are dissolved in 20ml of pyridine solution, stirred at room temperature, monitored by TLC, extracted with ethyl acetate after the reaction is completed, dried, spin-dried and filtered through a column to obtain pure 6-chloro-5-nitronicotinic acid tert-butyl ester;
pd was added to 25ml toluene 2 (dba) 3 (0.1g)，P(N(i-Bu)CH 2 CH 2 ) 3 (0.1 g), sodium tert-butoxide (1.92 g), 6-chloro-5-nitro-nicotinic acid tert-butyl ester (2.58 g), piperazine (0.86 g), 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 5-nitro-6- (piperazin-1-yl) nicotinic acid tert-butyl ester;
tert-butyl 5-nitro-6- (piperazin-1-yl) nicotinate (3.08 g) was placed in an autoclave, dissolved with ethanol, the apparatus was capped, H 2 Pumping air for three times, filling hydrogen in a kettle, sealing, heating and stirring for 4 hours, extracting with ethyl acetate after the reaction is completed, drying, spin-drying, and passing through a column to obtain pure 5-amino-6- (piperazin-1-yl) nicotinic acid tert-butyl ester;
dissolving 5-amino-6- (piperazin-1-yl) nicotinic acid tert-butyl ester (2.78 g) in 20ml of pyridine solution, dropwise adding 3, 5-dimethylbenzoyl chloride (2.2 ml), 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 5- (3, 5-dimethylbenzamide) -6- (piperazin-1-yl) nicotinic acid tert-butyl ester;
tert-butyl 5- (3, 5-dimethylbenzamide) -6- (piperazin-1-yl) nicotinate (4.10 g) 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:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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:
starting from 1- (2-cyclopropylethyl) piperazine, the synthesis is described in example 13.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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:
starting from 3- (piperazin-1-yl) propionitrile, the synthesis is described in example 13.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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 described in example 13.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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:
starting from 1-isopropylpiperazine, the synthesis is described in example 13.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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:
starting from 1-methoxypiperazine, the synthesis is described in example 13.
The nuclear magnetic data are as follows:
1 H NMR(500MHz,DMSO-d 6 )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).
13 C NMR(125MHz,DMSO-d 6 )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 in vitro antagonistic Activity test of Compounds against P2Y6R receptor
Human P2Y6R stable HEK293 cells constructed earlier were cultured in DMEM medium (containing 10% fetal bovine serum, 100U/ml penicillin and 100. Mu.g/ml streptomycin) and inoculated into 6-well plates at a density of 5X 105cells/ml prior to the experiment, cells were grown at 37℃and 95% O 2 、5％ CO 2 Culturing under humidity. Serum-free medium was changed before the experiment to starve for 12 hours, 1 mu M compound was added to each well, 10 mu M UDP was added after 30 minutes of reaction, and after 12 hours of incubation, samples were collected to detect the content of inositol 3 phosphate (IP 3).
The inositol 3 phosphate (IP 3) enzyme-linked immunosorbent assay kit adopts a competition ELISA method. The IP3 antigen is coated on an ELISA plate, and during experiments, IP3 in a sample or a standard substance competes with the coated IP3 for binding sites on the biotin-labeled anti-IP 3 monoclonal antibody, and free components are washed off. Horseradish peroxidase-labeled avidin is added, biotin is specifically combined with avidin to form an immune complex, and free components are washed away. Adding chromogenic substrate (TMB) which is blue under the catalysis of horseradish peroxidase, addingThe stop solution turned yellow. And (3) measuring an OD value at a wavelength of 450nm by using an enzyme-labeled instrument, 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 compound holes. Drawing a standard curve of a four-parameter logic function on double-logarithmic-coordinate 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. Experiments were repeated three times, averaged and the compound pair P2Y calculated 6 IC of R 50 And SD.
The experimental results are shown in table 1:
results of in vitro antagonistic Activity test of Compounds of Table 1 on P2Y6R receptor
EXAMPLE 20 study of the therapeutic Effect of Compounds in an animal model of atherosclerosis
Taking 6- (4- (2-cyanoethyl) piperazin-1-yl) -5- ((3-methylphenyl) sulfonamide) nicotinic acid (hereinafter referred to as Compound 1) as an example, pharmacodynamic studies of such Compounds in the atherosclerosis model of mice
An LDLR-/-mouse AS model was established using High Fat Diet (HFD) and intervention was performed with 20mg/kg of Compound 1. The results showed that compound 1 was effective in inhibiting abnormal changes in atherosclerosis blood lipid levels TC, TG, LDL-C and HDL-C caused by HFD (fig. 1); meanwhile, the compound 1 can effectively improve the pathological changes of lipid deposition increase, arterial wall thickening, lumen stenosis, high collagen fiber content, intimal fibrosis and the like of the main plaque of the mice (figure 2). Proved by the experiment, the compound 1 has good treatment effect in a mouse atherosclerosis model, and shows the potential of the compound as an atherosclerosis treatment drug.
From the above examples, it is clear that 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 for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.
Claims (10)
1. A sulfonamide niacin derivative having the structure of formula (I), or an anionic form, a pharmaceutically acceptable salt thereof:
wherein R is 1 Selected from methyl;
n is any integer from 0 to 5;
R 2 selected from H, C-C6 alkoxy, pyrrolidinyl, substituted or unsubstituted C1-C6 alkyl;
the substituent of the C1-C6 alkyl is selected from cyano, hydroxy, C3-C6 cycloalkyl, C2-C3 alkenyl or C1-C6 alkoxy.
2. The sulfonamide niacin derivative according to claim 1, characterized in that n is 1 or 2;
the R is 2 Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylethyl, allyl, methoxy, methoxyethyl, propylcyano or pyrrolidinyl.
3. The sulfonamide niacin derivative according to claim 1, which has any one of the following structures, or an anionic form, a pharmaceutically acceptable salt thereof:
4. a process for the preparation of a sulfonamide nicotinic acid derivative according to any one of claims 1 to 3, comprising 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 a formula (I);
wherein R is 1 Selected from methyl;
n is any integer from 0 to 5;
R 2 selected from H, C-C6 alkoxy, pyrrolidinyl, substituted or unsubstituted C1-C6 alkyl;
the substituent of the C1-C6 alkyl is selected from cyano, hydroxy, C3-C6 cycloalkyl, C2-C3 alkenyl or C1-C6 alkoxy.
5. An amido nicotinic acid derivative having the structure of formula (iv), or an anionic form, pharmaceutically acceptable salt thereof:
wherein R is 3 Selected from methyl;
m is any integer from 0 to 5;
R 4 selected from H, C-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl;
the substituent of the C1-C6 alkyl is selected from cyano, hydroxy and C3-C6 cycloalkyl.
6. The amido nicotinic acid derivative of claim 5, wherein m is 1 or 2;
the R is 4 Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylethyl, methoxy, ethanol or propylcyano.
7. The amido nicotinic acid derivative of claim 5 having any one of the following structures, or an anionic form, pharmaceutically acceptable salt thereof:
8. the process for producing an amido-nicotinic acid derivative according to any one of claims 5 to 7, comprising the steps of:
reacting a compound with a structure of formula (V) with a compound with a structure of formula (VI) to obtain a compound with a structure of formula (IV);
wherein R is 3 Selected from methyl;
m is any integer from 0 to 5;
R 4 selected from H, C-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl;
the substituent of the C1-C6 alkyl is selected from cyano, hydroxy and C3-C6 cycloalkyl.
9. Use of a sulfonamide nicotinic acid derivative according to any one of claims 1 to 3, or an amid nicotinic acid derivative according to any one of claims 5 to 7, for the manufacture of a medicament for the treatment of atherosclerosis.
10. A medicament for treating atherosclerosis comprising the sulfonamide nicotinic acid derivative of any one of claims 1 to 3, or the amid nicotinic acid derivative of any one of claims 5 to 7 and an auxiliary material.
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