CN105439914B

CN105439914B - 4 aminoacyl phenoxy acetamide class compounds and its medicinal usage

Info

Publication number: CN105439914B
Application number: CN201410476100.1A
Authority: CN
Inventors: 叶德泳; 李亚莉; 周璐; 邓晓东; 楚勇; 董艳萍
Original assignee: Fudan University
Current assignee: Fudan University
Priority date: 2014-09-17
Filing date: 2014-09-17
Publication date: 2017-07-11
Anticipated expiration: 2034-09-17
Also published as: CN105439914A

Abstract

The invention belongs to medicinal chemistry art, it is related to 4 aminoacyl phenoxy acetamide class compounds and its medicinal usage shown in Formulas I structure, wherein described G, Z, R, m and n are consistent with the detailed description in the content of the invention.Such compound can suppress sphingomyelins synthase activity, can be used to treat the disease caused by sphingomyelin levels increase extremely.The present invention further includes compound as shown in Formulas I structure, its pharmaceutically acceptable salt or the pharmaceutical composition with it as effective active composition in prevention and treatment due to the application in the disease caused by sphingomyelin levels increase extremely.The disease caused by sphingomyelin levels increase extremely includes atherosclerosis, fatty liver, obesity and metabolic syndrome etc. type II diabetes.

Description

4- aminoacyls phenoxy acetamide class compound and its medicinal usage

Technical field

The invention belongs to medicinal chemistry art, it is related to 4- aminoacyls phenoxy acetamide class compound and its medicinal usage, specifically It is related to 4- aminoacyls phenoxy acetamide class compound and its purposes in sphingomyelins synthase inhibitor is prepared and is preparing in advance Anti- or treatment is increased the purposes in the medicine of diseases caused by sphingomyelin levels extremely.

Background technology

It is reported that with the development and the aging of population of economic society, China's cardiovascular and cerebrovascular diseases incidence and mortality In recent years the 2nd of total cause of the death in addition to tumour is increased significantly to, one of principal disease of harm human health is had become.Research is aobvious Show, atherosclerosis (atherosclerosis, AS) is one of main pathological basis of many cardiovascular and cerebrovascular diseases, therefore, The focus in field is researched and developed in the research of Antiatherosclerosis medicine as current medical.Study and also show, atherosclerosis table Now for the yellow substance containing cholesterol, class fat etc. occurs in big or middle endarterium, so as to cause thrombosis, blood supply disorder etc.； Although its molecular pathology is not yet illustrated completely, generally acknowledge that dyslipidemia is atherosclerosis in known factors in the industry The most important inducement for being formed, and the formation of atheroma and artery sclerosis and the unconventionality expression of lipid components are closely related. Generally, dyslipidemia refers to fat metabolism or transhipment is abnormal causes in blood plasma lipid higher than normal, and blood viscosity increases, its master Show as low-density lipoprotein (low-density lipoprotein, LDL) and VLDL (very low- Density lipoprotein, VLDL) level raise and HDL (high-density lipoprotein, HDL) level decline, therefore, reduce LDL and (or) raise HDL can play a part of adjust blood fat, and lipid regulating agent also into To be clinically used for the key agents of antiatherosclerosis.

Clinically conventional lipid regulating agent mainly has Statins, fibrates, bile acid-binding resin class, nicotinic acid etc..Wherein, he Spit of fland class medicine is by suppressing the key enzyme -3-hydroxy-3-methylglutaryl-coenzyme A reductase during Biosynthesis of cholesterol (HMG Co-A reductases), reduces the level of LDL-C in blood plasma, can reduce the incidence of disease (Linsel- of coronary heart disease Nitschke P,Tall AR.Nat.Rev.Drug.Discov,2005,4,193-206).However, there are some researches show using general After cutting down statin (pravastatin) or Atorvastatin (atorvastatin) intensive treatment coronary disease patient, LDL-C level Though there is reduction in various degree, but still there is high incidence (Cannon CP, Braunwald E, the et a1.N of cardiovascular disease Engl J Med,2004,350:L495-l504), therefore, by individually reduce LDL-C horizontal stripes come therapeutic effect deposit In certain limit；Also research display statins has the serious adverse reaction such as rhabdomyolysis.

With going deep into for research, have and researched and proposed the potential drug target of various antiatherosclerosis such as：Sphingomyelins Synthase inhibitor, PPAR activators, CETP (CETP) inhibitor, infusion apolipoprotein, liver X receptor activation Agent and PLTP (PLTP) inhibitor etc.；Especially sphingomyelins (Sphingomyelin, SM) and its metabolic enzyme are causing Lipoprotein mediates a series of cell processes while change, shows that it occurs to play the part of emphatically in development process in atherosclerosis The role for wanting.

Research shows that sphingomyelins can induce atherosclerosis by number of ways：(1) fat of triglycerides (TG) is suppressed Solution (Park TS, Panek RL, et al.Atherosclerosis.2006,189 (2):264-72.)；(2) delay to cause AS's Removing (Schlitt A, Hojjati MR, et al.J Lipid Res.2005,46 (2) of remnant lipoprotein:196-200.)； (3) reverse cholesterol transport of influence HDL mediations, causes cholesterol removing obstacles (Sano O, Kobayashi A, et al.J Lipid Res.2007,48(11):2377-84；Marmillot P,Patel S,et al.Metabolism.2007,56 (2):251-9.)；(4) ceramide and SM synthesis or decompose associated products be cell propagation, activation, apoptosis regulation because Son, affects growth and stabilization (Park, the T.-S. of atherosclerotic plaque；Panek,R.L.；et al.Circulation.2004,110,3465-3471.)；(5) LDL rich in SM has very strong cohesion and sticks, and causes huge Phagocyte is easier to be detained aggregation and form foam cells so as to promote AS (Fan Y, Shi S, et in arterial wall al.Arterioscler Thromb Vasc Biol,2010,30:2114-20.)。

Epidemiology survey shows that mankind SM levels have independent correlation, blood plasma SM with atherosclerosis (AS) Concentration is the independent risk factor of atherosclerosis, the meaning during progression of atherosclerosis is evaluated with index (Jiang,X.-C.；Paultre,F.；et al.Arterioscler.Thromb.Vasc.Biol.2000,20,2614- 2618；Zhiqiang Li；Maria J.Basterr；et al.Biochimica et Biophysica Acta.2005, 1735,130–134.)；Animal experiment study has shown that can effectively reduce apoE- really to the suppression of SM from the beginning biosynthesis The plasma cholesterol and triglyceride level of KO mouse, raise HDL- cholesterol levels, so as to prevent the development of AS lesions (Park,T.-S.；Panek,R.L.；et al.Circulation.2004,110,3465-3471.)；Therefore, drop is thought in the industry The synthesis of low blood plasma sphingomyelin level or suppression SM can reach the purpose for slowing down or preventing atherosclerosis from developing.

Additionally, researcher has found the adjustable ceramide of sphingomyelins synthase (Sphingomyelin synthase, SMS) (ceramide) synthesize SM with lecithin (PC), be the key enzyme of sphingomyelins de novo synthesis final step.Further grind Study carefully discovery, SMS direct regulation and control SM levels, the overexpression of SMS is the universal phenomenon in atherosclerotic lesion tissue, is also One of the key index that atherosclerotic lesion occurs (Xian-cheng Jiang；Furcy Paultre；et al.Arterioscler.Thromb.Vasc Biol.2000,20,2614-2618；Zhiqiang Li；Tiruneh K.et al.Biochimica et Biophysica Acta,2007,1771,1186–1194.).Zoopery shows SMS2 and apoE The Aortic Arch Atherosclerosis patch of Double knockout mice model is substantially reduced, and the lipid level such as SM shows in brachiocephalic artery Writing reduces, while having no influence (Fan Y, Shi S, et on the normal physiological of mouse al.Arterioscler.Thromb.Vasc Biol,2010,30:2114-20.), show that SMS is catalyzed and synthesized at the reaction of SM In the final tache of sphingomyelins biosynthesis circulation, suppress its activity and cause potential toxicity smaller；Therefore, to sum up study As a result, look forward in the industry, be expected to treat the new method of atherosclerosis by suppressing sphingomyelins synthase reduction sphingomyelin levels, Sphingomyelins synthase has potential superiority as the new target drone of antiatherosclerosis, and sphingomyelins synthase inhibitor will be expected to turn into The medicine of new antiatherosclerosis.

In addition, studies have found that SMS2 lacks the obesity and insulin resistance that can prevent high fat diet from inducing, together When in the liver of SMS2 knock out mice, it is difficult to it was observed that big ripe fatty patch, show that SMS2 participates in liver fat The formation of fat patch and generation (Susumu Mitsutake, the Kota Zama, et of inducible fat and type II diabetes al.Journal of Biological Chemistry.2011,286(32),28544-28555).SMS2 lacks caused blood The reduction of SM can improve sensitiveness (Li Z, the Zhang H, et of insulin in animal tissue and whole body in slurry al.Mol.Cell.Biol.2011,31(20):4205-4218).Therefore, sphingomyelins synthase micromolecular inhibitor can prevent The metabolic syndrome such as, fatty liver fat with treatment and type II diabetes.

It is D609 (Aimin Meng to have one of sphingomyelins synthase inhibitor of document report at present；Chiara Luberto； Et al.Experimental Cell Research, 2004,292,385-392.), suppression of the compound to sphingomyelins synthase Make and use weaker (IC₅₀=375 μM), and caused containing former sulphonic acid ester in its chemical constitution structure height it is unstable (Bai, A.et al.J.Pharmacol.Exp.Ther.2004,309,1051-1059), half-life short；Additionally, having research using homologous The method that mould is built constructs three-dimensional protein structure model (the Zhang Ya of hSMS1 (mankind SMS1 types) first；Lin Fu；et Al.Chin.J.Chem.2011,29,2421-2429), it is determined that the avtive spot of Binding Capacity on sphingomyelins synthase, and with life (Calvin Yeang are verified in thing experiment；Shweta Varshney；et al.Biochimica et Biophysica Acta,2008,1781,610–617.)；Enzyme and bottom using the three-dimensional protein structure model and by checking The avtive spot that thing is combined, it was found that sphingomyelins synthase molecule inhibitor compounds D2 (Xiaodong Deng, Fu Lin, et Al.European Journal of Medicinal Chemistry, 2014,73,1-7), it lives to the suppression of SMS2 in vitro Though property increases compared with D609, following defect is still suffered from：Inhibitory activity to SMS2 has much room for improvement, and it contains genotoxic potential wind The physicochemical properties such as nearly larger cyano group, and water-soluble and stability are not good.

The content of the invention

Defect and deficiency it is an object of the invention to overcome prior art, there is provided 4- aminoacyl phenoxy acetamide class chemical combination Thing and its medicinal usage, and in particular to 4- aminoacyls phenoxy acetamide class compound and its in sphingomyelins synthase inhibitor is prepared Purposes and prepare prepare for prevent or treat by sphingomyelin levels extremely increase diseases caused medicine in use On the way, institute's book is stated disease including atherosclerosis, fatty liver, obesity and type II diabetes etc..

First purpose of the invention is to provide 4- aminoacyls phenoxy acetamide class compound or its is pharmaceutically acceptable Salt；Described 4- aminoacyl phenoxy acetamide class compounds are the free alkali or salt with the structure as shown in formula (I),

G is phenyl, 2- pyridine radicals, 4- pyridine radicals, 4- bromophenyls, 2- fluorophenyls, 3- fluorophenyls, 4- fluorophenyls, 4- in formula Methoxyphenyl, 4- aminomethyl phenyls；Z is sulfuryl (- SO₂-) or carbonyl (- C=O-)；R is o-F, m-F, p-F, p-Cl, p- Br, o-OMe, m-OMe, p-OMe, o-NO₂, o-CN or o-OCF₃In any one or two substitution bases；N is 0 or 1；m It is 0 or 1 or 2.

The compound of -1~formula I -19 of formula I can be further described as：

The compounds of this invention contains basic group can form the salt of derivative using common means with acid into salt；Bag Include acylate such as acetate, citrate, fumarate, maleate, oxalates, malate, citrate, butanedioic acid Salt, tartrate, lactate, camsilate, benzene sulfonate, tosilate, mesylate, trifluoroacetate, trifluoro Mesylate etc.；Inorganic acid salt such as halogen acids (hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid) salt, sulfate, phosphate, nitric acid Salt etc..Or and amino acid, such as glutamic acid or aspartic acid can form glutamate or aspartate.Preferred salt is hydrochloric acid Salt, hydrogen bromide salt.

The solvate of 4- aminoacyls phenoxy acetamide class compound of the present invention also belongs to protection scope of the present invention, its solvent Preferably water, ethanol or methyl alcohol.

The 4- aminoacyl phenoxy acetamide class compounds that second object of the present invention is to provide shown in formula (I) are preparing sheath Purposes in phosphatide synthase micromolecular inhibitor.The present invention is examined using high performance liquid chromatography (HPLC) fluorescent quantitation of document report Survey method determines inhibitory activity of the 4- aminoacyls phenoxy acetamide class compound shown in formula (I) to sphingomyelins synthase (Xiaodong Deng；Hong Sun；et al.Analytical Letters,2012,45:12,1581-1589), by it In NBD-ceramide and NBD-sphingomyelin changes of contents calculate inhibitor to sphingomyelins synthase be catalyzed nerve Acid amides is converted into the active change of sphingomyelins.

Active testing based on high performance liquid chromatography (HPLC) fluorescent quantitation is tested and shown, the 4- aminoacyls shown in formula (I) Base phenoxy acetamide class compound has the sphingomyelins synthase inhibitory activity of sub-micromolar level, is the effective of suppression sphingomyelins synthase Composition；High performance liquid chromatography (HPLC) fluorescent quantitation method detects that suppression of the compound to sphingomyelins synthase 2 (SMS2) is lived Property is：

1) N- (4- methoxy-benzyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -1) is at 100 μM Under inhibiting rate be 49.9%；

2) N- (4- bromobenzyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -2) is under 10 μM Inhibiting rate is 55.3%；

3) N- (2- luorobenzyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -3) is under 25 μM Inhibiting rate is 50.2%；

4) N- (3- luorobenzyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -4) is under 10 μM Inhibiting rate is 48.4%；

5) N- (4- chlorphenyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -5) is under 10 μM Inhibiting rate is 60.5%；

6) N- (2- nitrobenzophenones) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -6) is under 100 μM Inhibiting rate be 2.2%；

7) N- (2- cyano-phenyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -7) is under 100 μM Inhibiting rate be 26.9%；

8) 2- (4- (N- phenethyls sulfamoyl) phenoxy group)-N- (2- (trifluoromethoxy) phenyl) acetamide (formula I -8) Inhibiting rate under 100 μM is 23.5%；

9) N- (4- methoxyphenyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -9) is at 100 μM Under inhibiting rate be 19.0%；

10) N- (3- methoxyphenyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -10) is in 10 μ Inhibiting rate under M is 59.4%；

11) N- (the fluoro- 2- methoxyphenyls of 4-) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -11) Inhibiting rate under 100 μM is 38.6%；

12) 4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies)-N- (4- methyl-benzyls) benzamide (formula I -12) Inhibiting rate under 100 μM is 8.2%；

13) 4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies)-N- (4- methoxy-benzyls) benzamide (formula I - 13) inhibiting rate under 100 μM is 5.6%；

14) 4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies)-N- (4- luorobenzyls) benzamide (formula I -14) exists Inhibiting rate under 100 μM is 27.6%；

15) 4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies)-N- (2- luorobenzyls) benzamide (formula I -15) exists Inhibiting rate under 100 μM is 29.3%；

16) 4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies)-N- (3- luorobenzyls) benzamide (formula I -16) exists Inhibiting rate under 100 μM is 26.2%.

17) N- (4- bromobenzyls) -4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies) benzamide (formula I -17) exists Inhibiting rate under 100 μM is 19.1%.

18) 4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies)-N- (pyridine -2- ylmethyls) benzamide (formula I - 18) inhibiting rate under 100 μM is 10.7%.

19) 4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies)-N- (pyridin-4-yl) benzamide (formula I -19) Inhibiting rate under 100 μM is 42.7%.

The further object of the present invention is to provide 4- aminoacyls phenoxy acetamide class compound and its esters shown in formula (I) Or solvate for prevent and treat by sphingomyelin levels extremely increase cause disease for example atherosclerosis, fatty liver, Purposes in the medicine of fat and type II diabetes.

The present invention experiments prove that, the sphingomyelins synthase little molecules in inhibiting of compound disclosed by the invention and prior art Agent D609 is compared with D2, and its inhibitory activity to SMS2 is significantly higher than D609 and D2；The physicochemical property such as stability and water solubility is excellent In D609 and D2；And it does not contain potential toxophore, potential toxic and side effect is small, can be as treatment by sphingomyelin levels The abnormal medicine for increasing caused disease such as atherosclerosis, fatty liver, obesity and type II diabetes.

One or more pharmaceutically acceptable carrier can also be contained in said medicine, the carrier is led including pharmacy The conventional thinner in domain, excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient, surfactant, absorption Carrier, lubricant etc., it may also be necessary to add flavouring agent, sweetener etc..

It is a novel class formation the beneficial effects of the present invention are the 4- aminoacyl phenoxy acetamide class compounds for being provided Sphingomyelins synthase inhibitor, with sub-micromolar level molecular level inhibitory activity, with good potentiality and application prospect, The medicine for the treatment of atherosclerosis, fatty liver, obesity and type II diabetes can be further made for.

Specific embodiment

Embodiment 1：Prepare N- (4- chlorphenyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -5)

First, the synthesis of 4- hydroxy phenyls -1- sulfonic acid chlorides (compound 4)

1.96g (10mmol, 1.0eq) p-hydroxy benzenyl sulfonate sodium is dissolved in 3.7ml thionyl chlorides, 0.06ml is added DMF, is finished, and 3.5h is reacted at 60 DEG C, afterwards pours into frozen water reaction solution, stirs 5min, is extracted with dichloromethane, uses saturation Brine It organic phase, anhydrous Na₂SO₄Dry, concentration obtains the crude product of 1.93g water white transparency oily things, can not purify straight Connect for the next step.MS(ESI)(m/z):193.0(M+H)⁺。

2nd, the synthesis of 4- hydroxy-ns-phenethyl benzsulfamide (compound 6)

1.21g (10mmol, 1.0eq) phenyl ethylamine is dissolved in 5ml dichloromethane, 1.6ml pyridines are added dropwise thereto.In ice bath Under, to the dichloromethane solution 5ml that 1.93g (10mmol, 1.0eq) 4- hydroxyl benzene sulfonyl chlorides are added dropwise in above-mentioned solution, drip Finish, room temperature reaction 1.5h.Add 1N salt pickling reaction solution 1 time, then 2 times, anhydrous Na are washed with saturation NaCl₂SO₄Dry, be concentrated to give To crude product.Crude product is recrystallized with dichloromethane, obtains 1.00g faint yellow solids, two-step reaction yield 37.0%.

After testing, structure is correct, and testing result is as follows：MS(ESI)(m/z):276.0(M-H)^-.¹H NMR(400MHz, DMSO-d₆) δ ppm 10.37 (s, 1H), 7.61 (d, J=8.6Hz, 2H), 7.44 (t, J=5.7Hz, 1H), 7.26 (t, J= 7.3Hz, 2H), 7.19 (d, J=6.7Hz, 1H), 7.14 (d, J=7.4Hz, 2H), 6.90 (d, J=8.6Hz, 2H), 2.90 (dd, J=14.2,6.7Hz, 2H), 2.66 (t, J=7.5Hz, 2H)

3rd, the synthesis of the chloro- N- of 2- (4- chlorphenyls) acetamide (compound 2-e)

1.27g (10mmol, 1.0eq) 4- chloroanilines are added in mixed solution of the 1.6ml pyridines with 20ml water, in ice Under the conditions of bath, 1.69g (15mmol, 1.5eq) chloracetyl chloride is added dropwise thereto.1.0h is reacted at 0 DEG C, to adding 50ml in system Water, filtering, leaches solid and dries to obtain 0.77g white powdery solids, purified can not be directly used in the next step, yield 37.7%.

4th, the synthesis of N- (4- chlorphenyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -5)

By 0.20g (1.0mmol, 1.0eq) 2- chloro- N- (4- chlorphenyls) acetamide, 0.42g (1.5mmol, 1.5eq) 4- Hydroxy-n-phenethyl benzsulfamide, 0.41g (3mmol, 3.0eq) potassium carbonate, 33mg KIs are added sequentially to 12ml acetone In, react 7.0h at 60 DEG C.To 20ml dichloromethane is added in system after removing solvent, (10ml × 2) are washed with water, use saturation NaCl is washed 2 times, anhydrous sodium sulfate drying, filtering, and concentration obtains 0.28g white solid crude products.With 9ml ethyl acetate to thick product Product are recrystallized, and obtain 0.13g white powdery solids, yield 29.5%.

After testing, structure is correct, and testing result is as follows：m.p 179.8-181.6℃.MS(ESI)(m/z):445.0(M+ H)⁺.¹H NMR(400MHz,DMSO-d₆) δ ppm 10.29 (s, 1H), 7.71 (d, J=8.7Hz, 2H), 7.65 (d, J= 8.7Hz, 2H), 7.58 (t, J=5.7Hz, 1H), 7.37 (d, J=8.8Hz, 2H), 7.24 (t, J=7.3Hz, 2H), 7.17 (d, J=7.1Hz, 1H), 7.13 (dd, J=7.6,5.4Hz, 4H), 4.81 (s, 2H), 2.91 (q, J=7.0Hz, 2H), 2.65 (t, J =7.5Hz, 2H)

Embodiment 2：Formula I -1, I -2, I -3, I -4, I -6, I -7, I -8, I -9, I -10, I -11 synthesis

First, the synthesis of midbody compound 2-a~2-d and 2-f~2-k

With reference to the condition of the 3rd step synthesis compound 2-e in embodiment 1, from the benzylamine or aniline and chloracetyl chloride of substitution Prepare midbody compound 2-a~2-d and 2-f~2-k.

2nd, Formula I -1, I -2, I -3, I -4, I -6, I -7, I -8, I -9, I -10, I -11 synthesis

Synthesize the condition of Formula I -5 with reference to the 4th step in embodiment 1, from 4- hydroxy-ns-phenethyl benzsulfamide (compound 6) and midbody compound 2-a~2-d and 2-f~2-k obtain Formula I -1 to I -4 and formula I -6 to I -11, tool Body is：N- (4- methoxy-benzyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -1)；N- (4- bromobenzyls Base) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -2)；N- (2- luorobenzyls) -2- (4- (N- phenethyl ammonia Sulfonyl) phenoxy group) acetamide (formula I -3)；N- (3- luorobenzyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -4)；N- (2- nitrobenzophenones) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -6)；N- (2- cyano group Phenyl) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -7)；2- (4- (N- phenethyls sulfamoyl) benzene oxygen Base)-N- (2- (trifluoromethoxy) phenyl) acetamide (formula I -8)；N- (4- methoxyphenyls) -2- (4- (N- phenethyl sulfonamides Base) phenoxy group) acetamide (formula I -9)；N- (3- methoxyphenyls) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -10)；N- (the fluoro- 2- methoxyphenyls of 4-) -2- (4- (N- phenethyls sulfamoyl) phenoxy group) acetamide (formula I -11).

After testing, structure is correct, and testing result is as follows：

The m.p 129.8-131.7 DEG C .MS (ESI) (m/z) of formula I -1:455.2(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 8.64 (t, J=6.0Hz, 1H), 7.70 (d, J=8.8Hz, 2H), 7.58 (t, J=5.6Hz, 1H), 7.25 (t, J =7.3Hz, 2H), 7.20-7.08 (m, 7H), 6.84 (d, J=8.6Hz, 2H), 4.62 (s, 2H), 4.25 (d, J=6.0Hz, 2H), (t, J=7.5Hz, the 2H) of 3.70 (s, 3H), 2.90 (q, J=7.2Hz, 2H), 2.65

The m.p 152.6-154.7 DEG C .MS (ESI) (m/z) of formula I -2:503.0(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 8.74 (t, J=5.8Hz, 1H), 7.71 (d, J=8.6Hz, 2H), 7.58 (t, J=5.7Hz, 1H), 7.48 (d, J =8.2Hz, 2H), 7.25 (t, J=7.3Hz, 2H), 7.18 (d, J=8.2Hz, 3H), 7.12 (t, J=8.2Hz, 4H), 4.65 (s, 2H), 4.29 (d, J=5.9Hz, 2H), 2.90 (q, J=13.7,6.8Hz, 2H), 2.65 (t, J=7.5Hz, 2H)

The m.p 144.9-146.7 DEG C .MS (ESI) (m/z) of formula I -3:443.0(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 8.71 (t, J=5.9Hz, 1H), 7.70 (d, J=8.8Hz, 2H), 7.58 (t, J=5.8Hz, 1H), 7.25 (t, J =8.1Hz, 4H), 7.21-7.07 (m, 7H), 4.66 (s, 2H), 4.37 (d, J=5.9Hz, 2H), 2.89 (q, J=6.8Hz, 2H), 2.65 (t, J=7.5Hz, 2H)

The m.p 139.4-141.6 DEG C .MS (ESI) (m/z) of formula I -4:443.1(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 8.76 (t, J=5.9Hz, 1H), 7.71 (d, J=8.5Hz, 2H), 7.58 (t, J=5.8Hz, 1H), 7.32 (dd, J =13.9,7.7Hz, 1H), 7.25 (t, J=7.1Hz, 2H), 7.18 (d, J=6.7Hz, 1H), 7.12 (t, J=6.7Hz, 4H), 7.04 (dd, J=17.6,7.8Hz, 3H), 4.67 (s, 2H), 4.34 (d, J=5.7Hz, 2H), 2.89 (q, J=6.8Hz, 2H), 2.65 (t, J=7.3Hz, 2H)

The m.p 182.0-185.1 DEG C .MS (ESI) (m/z) of formula I -6:456.0(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 10.83 (s, 1H), 8.07 (dd, J=8.3,1.3Hz, 2H), 7.78-7.72 (m, 3H), 7.60 (t, J=5.5Hz, 1H), 7.41-7.34 (m, 1H), 7.27-7.15 (m, 5H), 7.12 (d, J=6.9Hz, 2H), 4.87 (s, 2H), 2.91 (dd, J =13.0,7.2Hz, 2H), 2.64 (t, J=7.5Hz, 2H)

The m.p 169.4-172.4 DEG C .MS (ESI) (m/z) of formula I -7:436.2(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 10.44 (s, 1H), 7.83 (dd, J=7.8,1.1Hz, 1H), 7.73 (d, J=8.8Hz, 2H), 7.71-7.67 (m, 1H), 7.62 (t, J=6.8Hz, 2H), 7.38 (dd, J=11.8,4.3Hz, 1H), 7.24 (t, J=7.3Hz, 2H), 7.17 (d, J=8.6Hz, 3H), 7.15-7.11 (m, 2H), 4.90 (s, 2H), 2.91 (q, J=7.2Hz, 2H), 2.65 (t, J=7.5Hz, 2H).

The m.p 124.3-126.6 DEG C .MS (ESI) (m/z) of formula I -8:495.0(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 9.92 (s, 1H), 7.85 (dd, J=8.0,1.4Hz, 1H), 7.71 (d, J=8.9Hz, 2H), 7.59 (t, J= 5.6Hz, 1H), 7.44-7.38 (m, 1H), 7.36 (dd, J=7.9,1.4Hz, 1H), 7.29 (dd, J=7.8,1.5Hz, 1H), 7.27-7.21 (m, 2H), 7.17 (d, J=7.2Hz, 1H), 7.14-7.10 (m, 4H), 4.88 (s, 2H), 2.90 (q, J= 7.2Hz, 2H), 2.65 (t, J=7.5Hz, 2H)

The m.p 172.7-174.4 DEG C .MS (ESI) (m/z) of formula I -9:441.1(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 10.00 (s, 1H), 7.71 (d, J=8.7Hz, 2H), 7.57 (t, J=5.2Hz, 1H), 7.51 (d, J=8.9Hz, 2H), 7.24 (t, J=7.2Hz, 2H), 7.17 (d, J=7.3Hz, 1H), 7.16-7.10 (m, 4H), 6.88 (d, J=8.9Hz, 2H), (t, J=7.5Hz, the 2H) of 4.76 (s, 2H), 3.70 (s, 3H), 2.91 (dd, J=13.1,6.9Hz, 2H), 2.65

The m.p 107.0-108.0 DEG C .MS (ESI) (m/z) of formula I -10:441.1(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 10.13 (s, 1H), 7.71 (d, J=8.7Hz, 2H), 7.57 (s, 1H), 7.30 (s, 1H), 7.28-7.10 (m, 9H), (t, J=7.5Hz, the 2H) of 6.65 (d, J=7.9Hz, 1H), 4.79 (s, 2H), 3.70 (s, 3H), 2.91 (s, 2H), 2.65

The m.p 161.3-163.5 DEG C .MS (ESI) (m/z) of formula I -11:459.2(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 9.33 (s, 1H), 7.92-7.84 (m, 1H), 7.72 (d, J=8.5Hz, 2H), 7.58 (s, 1H), 7.24 (t, J= 7.2Hz, 2H), 7.15 (dd, J=17.4,8.9Hz, 5H), 7.00 (d, J=10.9Hz, 1H), 6.74 (t, J=8.5Hz, 1H), (t, J=7.5Hz, the 2H) of 4.84 (s, 2H), 3.83 (s, 3H), 2.90 (s, 2H), 2.65

Embodiment 3：Prepare 4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies)-N- (4- methyl-benzyls) benzoyl Amine (formula I -12)

First, the chloro- N- of synthetic intermediate 2- (4- chlorobenzyls) acetamide (compound 2-l)

5.00g (35mmol, 1.0eq) 4- chlorobenzylamines are added in mixed solution of the 5.6ml pyridines with 70ml water, in ice Under the conditions of bath, 5.90g (52.5mmol, 1.5eq) chloracetyl chloride is added dropwise thereto.1.0h is reacted at 0 DEG C, is added in system 175ml water, filtering, leaches solid and dries to obtain 6.50g faint yellow solids, and yield 84.4%, the crude product purified can not be carried out The next step.

2nd, synthesis 4-HBA methyl esters (compound 8)

To 10.00g (72mmol) 4-HBA (compound 7) and 20mL methyl alcohol is added in reaction bulb, under ice bath To dropwise addition 6.8mL (94mmol) thionyl chloride in above-mentioned system.The stirring reaction at 70 DEG C afterwards, after TLC monitoring reactions terminate, To being slowly added to 20ml water in system.It is extracted with ethyl acetate afterwards, saturated sodium-chloride washing organic layer, anhydrous Na₂SO₄Dry, Filtering, removes ethyl acetate, obtains 10.00g white solids, yield 90.9%, and it is anti-that the crude product purified can not carry out lower step Should.

3rd, 4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies) methyl benzoate (compound 9) is synthesized

To addition 5.00g (22mmol) compound 2-l, 3.41g (22mmol) compound 8,6.32g potassium carbonate in reaction bulb With 100mL acetonitriles, the stirring reaction at 68 DEG C.After TLC monitoring reactions terminate, acetonitrile is removed, to addition 100ml water in residue Afterwards, extracted with dichloromethane, extract is washed through saturated sodium-chloride, anhydrous Na₂SO₄Dry, be concentrated to give 7.23g pale yellow colored solids Body crude product, thick yield 94.5%, crude product purified can not carry out the next step.

4th, 4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies) benzoic acid (compound 10) is synthesized

To addition 4.00g (12mmol) compound 9,1.16g (48mmol) LiOH.H in reaction bulb₂O、12ml H₂O and 12ml THF, the stirring reaction at 40 DEG C.After TLC monitoring reactions terminate, THF is removed, pH to 5-6 is adjusted with 4N HCl, filtered, Dry, obtain 1.80g yellow solids, yield 93.8%.MS(ESI)(m/z):318.1(M-H)^-.

5th, 4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies)-N- (4- methyl-benzyls) benzamide (formula is synthesized Ⅰ-12)

To addition 0.13g (0.41mmol, 1.0eq) compound 10,49.3mg (0.41mmol, 1.0eq) 4- in reaction bulb Methylbenzylamine, 0.13g (0.41mmol, 1.0eq) EDCI, 60mg (0.41mmol, 1.0eq) HOBt and 10mL CH₂Cl₂.In room The lower stirring reaction of temperature, after TLC monitoring reactions terminate, to addition 10ml water in system, then uses CH₂Cl₂Extraction, saturated sodium-chloride is washed Wash organic layer, anhydrous Na₂SO₄Dry, filtering is concentrated to give crude product, through column chromatography, obtains 0.10g white solids, yield 58.2%.

After testing, structure is correct, and testing result is as follows：m.p 203.4-204.5℃.MS(ESI)(m/z):423.1(M+ H)⁺.¹H NMR(400MHz,DMSO-d₆) δ ppm 8.88 (t, J=5.9Hz, 1H), 8.73 (t, J=6.1Hz, 1H), 7.88 (d, J=8.8Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 7.27 (d, J=8.4Hz, 2H), 7.20 (d, J=8.0Hz, 2H), 7.13 (d, J=7.9Hz, 2H), 7.04 (d, J=8.8Hz, 2H), 4.64 (s, 2H), 4.43 (d, J=5.9Hz, 2H), 4.34 (d, J= 6.1Hz,2H),2.27(s,3H).

Embodiment 4：Synthesis Formula I -13, I -14, I -15, I -16, I -17, I -18 and I -19

Synthesize the condition of Formula I -12 with reference to the 5th step in embodiment 3, from 4- (2- ((4- chlorobenzyls) amino) - 2- oxoethoxies) benzoic acid (compound 10) and corresponding amine prepares Formula I -13 to I -19, specially：4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies)-N- (4- methoxy-benzyls) benzamide (formula I -13)；4-(2-((4- Chlorobenzyl) amino) -2- oxoethoxies)-N- (4- luorobenzyls) benzamide (formula I -14)；4- (2- ((4- chlorobenzyls) ammonia Base) -2- oxoethoxies)-N- (2- luorobenzyls) benzamide (formula I -15)；4- (2- ((4- chlorobenzyls) amino) -2- oxo second Epoxide)-N- (3- luorobenzyls) benzamide (formula I -16)；N- (4- bromobenzyls) -4- (2- ((4- chlorobenzyls) amino) -2- oxos Ethyoxyl) benzamide (formula I -17)；4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies)-N- (pyridine -2- ylmethyls) Benzamide (formula I -18)；4- (2- ((4- chlorobenzyls) amino) -2- oxoethoxies)-N- (pyridin-4-yl) benzamide (formula Ⅰ-19)。

After testing, structure is correct, and testing result is as follows：

The m.p 194.9-197.3 DEG C .MS (ESI) (m/z) of formula I -13:439.1(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 8.86 (t, J=5.9Hz, 1H), 8.73 (t, J=6.1Hz, 1H), 7.87 (d, J=8.8Hz, 2H), 7.38-7.35 (m, 2H), 7.25 (dd, J=12.2,8.6Hz, 4H), 7.03 (d, J=8.9Hz, 2H), 6.88 (d, J=8.7Hz, 2H), 4.63 (s, 2H), 4.39 (d, J=5.9Hz, 2H), 4.33 (d, J=6.1Hz, 2H), 3.72 (s, 3H)

The m.p 188.1-189.5 DEG C .MS (ESI) (m/z) of formula I -14:427.1(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 8.94 (t, J=6.0Hz, 1H), 8.73 (t, J=6.1Hz, 1H), 7.89 (s, 1H), 7.87 (s, 1H), 7.39- 7.33 (m, 4H), 7.27 (d, J=8.4Hz, 2H), 7.18-7.12 (m, 2H), 7.04 (d, J=8.8Hz, 2H), 4.64 (s, 2H), 4.45 (d, J=5.9Hz, 2H), 4.33 (d, J=6.1Hz, 2H)

The m.p 164.3-167.9 DEG C .MS (ESI) (m/z) of formula I -15:427.1(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 8.91 (t, J=5.8Hz, 1H), 8.73 (t, J=6.1Hz, 1H), 7.89 (d, J=8.9Hz, 2H), 7.39-7.33 (m, 3H), 7.33-7.25 (m, 3H), 7.17 (dt, J=7.5,4.8Hz, 2H), 7.05 (d, J=8.9Hz, 2H), 4.64 (s, 2H), 4.51 (d, J=5.7Hz, 2H), 4.33 (d, J=6.1Hz, 2H)

The m.p 191.3-194.5 DEG C .MS (ESI) (m/z) of formula I -16:427.1(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 8.98 (t, J=5.6Hz, 1H), 8.74 (t, J=5.6Hz, 1H), 7.90 (d, J=8.6Hz, 2H), 7.42-7.33 (m, 3H), 7.28 (d, J=8.2Hz, 2H), 7.19-7.00 (m, 5H), 4.65 (s, 2H), 4.49 (d, J=5.7Hz, 2H), 4.34 (d, J=5.9Hz, 2H)

The m.p 199.1-200.6 DEG C .MS (ESI) (m/z) of formula I -17:489.1(M+H)⁺.¹H NMR(400MHz,DMSO- d₆) δ ppm 8.96 (t, J=5.6Hz, 1H), 8.73 (t, J=5.7Hz, 1H), 7.88 (d, J=8.5Hz, 2H), 7.52 (d, J =8.2Hz, 2H), 7.37 (d, J=8.2Hz, 2H), 7.28 (d, J=7.9Hz, 4H), 7.05 (d, J=8.5Hz, 2H), 4.64 (s, 2H), 4.44 (d, J=5.6Hz, 2H), 4.34 (d, J=5.9Hz, 2H)

The MS (ESI) (m/z) of formula I -18:410.0(M+H)⁺.¹H NMR(400MHz,DMSO-d₆) δ ppm8.85 (d, J= 5.1Hz, 1H), 8.55 (td, J=8.0,1.4Hz, 1H), 8.02-7.90 (m, 4H), 7.37 (dd, J=6.1,4.4Hz, 2H), (s, the 2H) of 7.28 (d, J=8.5Hz, 2H), 7.07 (d, J=8.9Hz, 2H), 4.83 (s, 2H), 4.66 (s, 2H), 4.32

The MS (ESI) (m/z) of formula I -19:396.1(M+H)⁺.¹H NMR(400MHz,DMSO-d₆)δppm10.47(s,1H), 8.77 (s, 1H), 8.47 (s, 2H), 7.99 (d, J=7.3Hz, 2H), 7.80 (s, 2H), 7.46-7.21 (m, 4H), 7.13 (d, J =7.2Hz, 2H), 4.69 (s, 2H), 4.35 (s, 2H)

Embodiment 5：The hydrochloride of prepare compound formula I -19

0.40g (1.0mmol, 1.0eq) Formula I -19 is dissolved in the dry ethyl acetate of 10ml, in ice-water bath bar To the ethyl acetate solution (c=1.25mol/L) that 1.2ml (1.5mmol, 1.5eq) HCl (g) is added dropwise in above-mentioned solution under part, instead Suction filtration is dried to obtain 0.34g white powdery solids, yield 79.1% after answering 10min.The hydrochloride m.p 193.0- of formula I -19 197.0℃.

Embodiment 6：Determine inhibitory action of the 4- aminoacyls phenoxy acetamide class Compound ira vitro to sphingomyelins synthase 2

Laboratory apparatus and material

1. electric-heated thermostatic water bath (Shanghai one permanent Science and Technology Ltd.)

2. vortex mixer (upper Nereid section Industrial Co., Ltd. model XW-80A)

3. supercentrifuge (model Eppendorf 5804R)

4. high performance liquid chromatography Agilent 1100 (Agilent Technologies, Palo Alto, CA, USA), matches somebody with somebody Quaternary pump, vacuum outgas, FLD fluorescence detectors.

5.HPLC chromatographic columns：Agilent C18RP(250mm×4.6mm 5μm).

6.DMPC. is purchased from Santa Cruz (USA), is dissolved with ethanol, and concentration is 40mM.

7.C6-NBD-Ceramide(6-((N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino) Hexanoyl)-sphi ngosine) purchased from Santa Cruz (USA) ethanol dissolvings, concentration is 1.16mM to.

8.C6-NBD-SM.(N-(N-(7-nitro-2,1,3-benzoxadiazol-4-yl)-epsilon- Aminohexanoyl) sphingosylph osphoryl choline) be purchased from Sigma-Aldrich (USA), it is molten with ethanol Solution, concentration is 1mg/mL.

9. organic solvent used by is purchased from Shanghai traditional Chinese medicines Reagent Company, and methyl alcohol is chromatographically pure, and water is filtered for Milli-Q pumps, Deionization, through 0.22 μm of ultra-pure water of film ultrafiltration, other biological consumptive material is purchased from domestic company.

10.SMS enzymes extract the configuration of homogenate buffer (Buffer1)：(50mM Tri(Hydroxymethyl) Amino Methane Hydrochlorides pH 7.4,5% anhydrous sucrose, 1mM ethylenediamine tetra-acetic acids)：Take 1.2114g Tri(Hydroxymethyl) Amino Methane Hydrochlorides tris (hydroxymethyl) aminomethane hydrochloride, Tris-HCl) it is dissolved in 100mL distilled water, add The hydrochloric acid of 84mL 0.1mol/L, 200mL is settled to by mixed liquor.Weigh anhydrous sucrose (sucrose) 10g, ethylenediamine tetra-acetic acid (EDTA) 58.45mg, is dissolved in above-mentioned solution.

The configuration of 11.SMS assay buffers (Buffer2)：(100mM ethoxy croak piperazine second thiosulfonic acids, 30mM MnCl₂, 3% defatted bovine albumin)：Take hydroxyethyl piperazine second thiosulfonic acid (4- (2-hydroxyethyl) -1- Peperazineethanesulfonic acid, Hepes) 1.1916g, MnCl₂·4H₂O0.2969g, defatted bovine albumin (fatty acid free BSA, Bovine serum albumin) 0.3g, distills water dissolves, is settled to 50mL.

12. prepare testing compound solution：Each 1~2mg of testing compound is weighed, appropriate DMSO is firstly added and is configured to The stock solution of 6mM.The stock solution of the testing compound of certain volume is taken, the DMSO of appropriate volume is added by test compounds Thing is diluted to the solution of required concentration.

The insect cell homogenate of 13.SMS2 expression high is standby by Fudan University's biomedical research institute Xu Yan brightness project team systems.

First, 4- aminoacyls phenoxy acetamide class compound is detected to the inhibitory activity of sphingomyelins synthase 2

By 250 μ L tri-distilled waters, 30 μ L Buffer2,4 μ L SMS2 expression high insect cell homogenate (total protein content Be 0.5 μ g/ μ L) and 10 μ L testing compounds DMSO solution (3mM) or the DMSO solution of blank, add to 1.5mL's In eppendorf pipes, vortex oscillation 30 seconds is incubated 0.5h in 37 DEG C of water-baths.The ethanol solution of 3 μ L DMPC is added afterwards The ethanol solution (1.16mM) of (40mM) and 3 μ L C6-NBD-Ceramide, vortex oscillation is incubated after 30 seconds under 37 DEG C of water-baths 2.0h.Take out, add the absolute ethyl alcohol of 600 μ L, vortex oscillation 1 minute.Taken out on 600 μ L after 10000rpm centrifugations 10min Clear liquid is standby for efficient liquid phase chromatographic analysis in being stored at 4 DEG C.

Bibliography (Xiaodong Deng；Hong Sun；et al.Analytical Letters,2012,45:12, 1581-1589), using the quantitative fluorescence analysis for carrying out with document identical efficient liquid-phase chromatography method above-mentioned prepared sample. Analyze and record blank group, positive controls (compound D2) and C6-NBD-SM and C6-NBD- in testing compound group sample Peak area Asm values and Acer value of the Ceramide on correspondence HPLC spectrograms, each compound parallel determination 3 times, then under State the inhibiting rate that formula calculates testing compound.

According to the above method, the external inhibitory activity to sphingomyelins synthase 2 of Formula I -1~I -19, activity knot are determined It is really：

2nd, 4- aminoacyl phenoxy acetamide classes -1~I -19 pair of half-inhibition concentration of sphingomyelins synthase 2 of chemical compounds I is determined (IC₅₀)

The DMSO stock solutions of testing compound 6mM are carried out into gradient dilution, 5 solution of concentration gradient and difference is prepared Take 10 μ L to be added in the test system of the first step of embodiment 6, sample is prepared and through efficient according to the method for the first step of embodiment 6 Liquid-phase chromatography method determines Asm value (compound D2 be positive control) of the compound under 5 various concentrations, and 5 are calculated respectively Inhibiting rate under individual various concentrations and fitting obtains half-inhibition concentration IC₅₀, 3 groups of each compound parallel determination.Formula I -1~I -19 couple of half-inhibition concentration (IC of SMS2₅₀) it is shown in Table 1：

1. Formula of table, I -1~I -19 couple of half-inhibition concentration (IC of sphingomyelins synthase 2₅₀)

Compound	IC₅₀(μM)
		D609	375^a
Formula I -1	60.0
		Formula I -2	3.6
Formula I -3	15.0
		Formula I -4	4.3
Formula I -5	2.8

Formula I -6	>100
		Formula I -7	85
Formula I -8	90
		Formula I -9	100
Formula I -10	3.6
		Formula I -11	80
Formula I -12	>100
		Formula I -13	>100
Formula I -14	100
		Formula I -15	100
Formula I -16	100
		Formula I -17	>100
Formula I -18	>100
		Formula I -19	75
D2	56.2^b

^aBibliography value^bMeasured value of experiment.

Claims

1. the 4- aminoacyls phenoxy acetamide class compound shown in formula (I) structure is different by sphingomyelin levels in preparation prevention and treatment Often increase the purposes in the medicine of the disease for causing；

Wherein, G is phenyl；Z is sulfuryl (- SO₂-)；R is selected from o-F, m-F, p-Cl, p-Br, a substitution base in m-OMe；N is 0 or 1；M is 2.

2. the purposes as described in claim 1, it is characterised in that the described disease for causing that increased extremely by sphingomyelin levels is Atherosclerosis, fatty liver, obesity or diabetes.