WO2016029767A1 - 2-烷氧基苯甲酰芳胺类化合物及其药物用途 - Google Patents

2-烷氧基苯甲酰芳胺类化合物及其药物用途 Download PDF

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WO2016029767A1
WO2016029767A1 PCT/CN2015/085077 CN2015085077W WO2016029767A1 WO 2016029767 A1 WO2016029767 A1 WO 2016029767A1 CN 2015085077 W CN2015085077 W CN 2015085077W WO 2016029767 A1 WO2016029767 A1 WO 2016029767A1
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pyridin
benzamide
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benzyloxy
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PCT/CN2015/085077
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French (fr)
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叶德泳
李亚莉
周璐
王鹏辉
楚勇
龚昊隽
黄祺
陈彦
张志宽
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复旦大学
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Priority to CA2958927A priority Critical patent/CA2958927C/en
Priority to KR1020177005985A priority patent/KR102544838B1/ko
Priority to EP15836903.3A priority patent/EP3196191B1/en
Priority to US15/513,340 priority patent/US10196359B2/en
Priority to JP2017511211A priority patent/JP6644770B2/ja
Publication of WO2016029767A1 publication Critical patent/WO2016029767A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/04—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
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to 2-alkoxybenzoyl arylamine compounds and pharmaceutical uses thereof, in particular to 2-alkoxybenzoyl arylamine compounds and their preparation in sphingomyelin synthase inhibitors Uses and use in the manufacture of a medicament for the prevention or treatment of atherosclerosis, fatty liver, obesity and type 2 diabetes.
  • Atherosclerosis is one of the main pathological basis of many cardiovascular and cerebrovascular diseases. Therefore, research on anti-atherosclerotic drugs has become a hot spot in the field of drug research and development. Studies have also shown that atherosclerosis is characterized by the appearance of yellow matter containing cholesterol, fat, etc.
  • dyslipidemia is the most important inducer of atherosclerosis, and the formation of atheroma and arteriosclerosis is closely related to the abnormal expression of lipid components.
  • dyslipidemia refers to abnormal lipid metabolism or transport, resulting in higher than normal plasma lipids and increased blood viscosity.
  • the main manifestations are low-density lipoprotein (LDL) and very low-density lipoprotein (verylow).
  • VLDL -density lipoprotein
  • HDL high-density lipoprotein
  • statins can reduce the level of LDL cholesterol in plasma by inhibiting the key enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG Co-A reductase) in the process of cholesterol biosynthesis.
  • HMG Co-A reductase 3-hydroxy-3-methylglutaryl coenzyme A reductase
  • sphingomyelin synthase inhibitor PPAR agonist
  • CETP cholesterol ester transfer protein
  • PLTP phospholipid transfer protein
  • SM sphingomyelin
  • SM sphingomyelin
  • its metabolic enzymes mediate a series of cellular processes while causing lipoprotein changes, indicating that they are in atherosclerosis Hardening plays an important role in the development process.
  • sphingomyelin can induce atherosclerosis through a variety of pathways: (1) inhibition of triglyceride (TG) lipolysis (Park TS, Panek RL, et al. Atherosclerosis. 2006, 189 (2): 264- 72.); (2) delaying the clearance of lipoprotein residues that cause AS (Schlitt A, Hojjati MR, et al. J Lipid Res. 2005, 46(2): 196-200.); (3) affecting HDL mediation Guided reverse cholesterol transport, causing cholesterol clearance disorder (Sano O, Kobayashi A, et al. J Lipid Res. 2007, 48 (11): 2377-84; Marmillot P, Patel S, et al. Metabolism.
  • TG triglyceride
  • ceramide and SM synthesis or decomposition related products are regulators of cell proliferation, activation, and apoptosis, affecting the growth and stability of atherosclerotic plaque (Park, T .-S.; Panek, RL; et al. Circulation. 2004, 110, 3465-3471.).
  • SM-rich LDL has strong cohesion and adhesion, which makes it easier for macrophages to accumulate in the arterial wall to form foam cells and promote AS (Fan Y, Shi S, et al. Arterioscler Thromb Vasc Biol, 2010 , 30:2114-20.);
  • SMS Sphingomyelin synthase
  • PC ceramide and lecithin
  • SMS2 deficiency can prevent obesity and insulin resistance induced by high-fat diet, while in the liver of SMS2 knockout mice, it is difficult to observe large mature fat plaques, indicating that SMS2 is involved in the liver.
  • the formation of fatty plaques can induce the development of obesity and type 2 diabetes (Susumu Mitsutake, Kota Zama, et al. Journal of Biological Chemistry. 2011, 286 (32), 28544-28555).
  • a decrease in SM in plasma caused by SMS2 deficiency can improve insulin sensitivity in animal tissues and throughout the body (Li Z, Zhang H, et al. Mol. Cell. Biol. 2011, 31(20): 4205-4218). Therefore, sphingomyelin synthase small molecule inhibitors can prevent and treat metabolic syndrome such as obesity, fatty liver and type 2 diabetes.
  • the object of the present invention is to overcome the defects and deficiencies of the prior art, to provide 2-alkoxybenzoylarylamine compounds and their pharmaceutical uses, in particular to 2-alkoxybenzoylarylamines and their preparation Use in sphingomyelin synthase inhibitors and in the preparation of a medicament for the prevention or treatment of atherosclerosis, fatty liver, obesity and type 2 diabetes.
  • a first object of the present invention is to provide a 2-alkoxybenzoylarylamine compound or a pharmaceutically acceptable salt thereof; the 2-alkoxybenzoylarylamine compound having the formula I The free base or salt of the structure shown,
  • X, Y and Z represent a C atom or an N atom, but X, Y and Z are not simultaneously selected from C atoms;
  • G represents a phenyl group, a substituted phenyl group and a naphthyl group, and when Y and X or Y and Z are simultaneously selected from In the case of a C atom, G is selected from a substituted phenyl or naphthyl group; especially when G is a substituted phenyl group, the substituent thereon is selected from the group consisting of halogen, nitro, cyano, trifluoromethoxy, carboxyl, ester, Any one or two of a benzyloxy group, a C 1 -C 7 alkyl group or a C 1 -C 7 alkoxy group; and R represents H, a halogen, a nitro group or a C 1 -C 4 alkoxy group.
  • G is a substituted phenyl group
  • the substituents thereon are oF, mF, pF, o-Cl, m-Cl, p-Cl, o-Br, m-Br, p-Br, o-NO.
  • the compound of the present invention contains a basic group which can form a salt with an acid, and a salt of the derivative can be formed by a usual means.
  • organic acid salts such as acetates, citrates, fumarates, maleates, oxalates, malates, citrates, succinates, tartrates, lactates, camphorsulfonic acids Salt, besylate, p-toluenesulfonate, methanesulfonate, trifluoroacetate, triflate, etc.
  • mineral acid salts such as hydrohalic acid (hydrofluoric acid, hydrochloric acid, hydrobromine Acid, hydroiodic acid salt, sulfate, phosphate, nitrate, and the like. Or may form glutamate or aspartate with an amino acid such as glutamic acid or aspartic acid.
  • Preferred salts are the hydrochloride salt, the hydrobromide salt.
  • the present invention also includes a solvate of a 2-alkoxybenzoylarylamine compound, and the solvent thereof is preferably water, ethanol or methanol.
  • a second object of the present invention is to provide the use of a 2-alkoxybenzoylarylamine compound of the formula I for the preparation of a sphingomyelin synthase small molecule inhibitor.
  • the invention adopts high performance liquid chromatography (HPLC) fluorescence quantitative detection method reported in the literature to determine the inhibitory activity of the 2-alkoxybenzoyl arylamine compound represented by the formula I on the sphingomyelin synthase inhibitor (Xiaodong Deng; Hong Sun; et al.
  • a 2-alkoxybenzoylarylamine compound of the formula I and a salt or solvate thereof for the prevention and treatment of diseases caused by abnormally increased levels of sphingomyelin, such as atherosclerosis.
  • the present invention confirmed by experiments that the compound has significantly higher inhibitory activity against SMS2 than D609 and D2 compared with the prior art sphingomyelin synthase small molecule inhibitors D609 and D2; physical and chemical properties such as water solubility and stability It is superior to D609 and D2; and it does not contain potential toxic groups, and has potential toxic and side effects. It can be used to treat diseases caused by abnormal increase in sphingomyelin levels such as atherosclerosis, fatty liver, obesity and type 2 diabetes. drug.
  • the above-mentioned medicament of the present invention may further comprise one or more pharmaceutically acceptable carriers, including conventional diluents, excipients, fillers, binders, wetting agents, disintegrating agents in the pharmaceutical field.
  • An absorption enhancer, a surfactant, an adsorption carrier, a lubricant, etc., if necessary, a flavoring agent, a sweetener or the like may be added.
  • the invention has the beneficial effects that the 2-alkoxybenzoyl arylamine compound provided is a novel structure of sphingomyelin synthase inhibitor with submicron order of molecular level inhibitory activity and good potential. And the application prospects can be further made into drugs for treating atherosclerosis, fatty liver, obesity and type II diabetes.
  • the conditions of the synthesis of the compound of the formula I-17 in the fifth step of the first embodiment are as follows, from 2-hydroxy-N-(pyridin-3-yl)benzamide (compound 7) and the commercially available corresponding substituted benzyl bromide (compound 8- 1a to 8-1t) give the compounds of the formulae I-1 to I-16 and the formulas I-18 to I-20, specifically: 2-(2-fluorobenzyloxy)-N-(pyridin-3-yl)benzene Formamide (Formula I-1); 2-(3-Fluorobenzyloxy)-N-(pyridin-3-yl)benzamide (Formula I-2); 2-(3-Nitrobenzyloxy) -N-(pyridin-3-yl)benzamide (Formula I-3); 2-(3-Cyanobenzyloxy)-N-(pyridin-3-yl)benzamide (Formula I-4) ; 2-((4-methoxy)benzyloxy)
  • a compound of the formula I- is obtained from 2-hydroxy-N-(pyridin-3-yl)benzamide (Compound 7) and the corresponding substituted benzyl bromide (Compounds 8-2a, 8-2b and 8-2d).
  • Formula I-23 and Formula I-25 specifically: 2-((2-methyl-5-fluoro)benzyloxy)-N-(pyridin-3-yl)benzamide (Formula I-21 2-((3-methoxy)benzyloxy)-N-(pyridin-3-yl)benzamide (Formula I-23); 2-((2,5-dimethoxy)benzyl Oxy)-N-(pyridin-3-yl)benzamide (Formula I-25).
  • the compounds 8-2e and 8-2f were directly obtained from the compounds 10e and 10f by sodium borohydride reduction and phosphorus bromide bromination, respectively. Used in the next step of the reaction.
  • the compounds 8-3a to 8-3g were obtained by reacting the compounds 13g to 13m with phosphorus bromide, respectively, and can be directly used without purification.
  • the next step is the reaction.
  • compound 11a is reacted with 1-bromo-4-chlorobutane, 1-bromo-5-chloropentane, 1-bromo-6-chlorohexane and n-bromoheptane, respectively, to give compound 13n-13p and compound. 13r.
  • the compounds 8-4a to 8-4e were respectively obtained from the compounds 13n to 13r by phosphorus bromination, and used directly in the next step reaction. .
  • compounds 8-4f and 8-4g were obtained by reduction of sodium borohydride and phosphorus bromide bromination from 10 g of compound and 10 h, and directly used. In the next step of the reaction.
  • the compound of the formula I-42 is obtained from 2-hydroxy-N-(pyridin-3-yl)benzamide (Compound 7) and the corresponding substituted benzyl alcohol.
  • ⁇ I-44 specifically: 2-((2-trifluoromethyl)benzyloxy)-N-(pyridin-3-yl)benzamide (Formula I-42); 2-((2-A) 5--5-chloro)benzyloxy)-N-(pyridin-3-yl)benzamide (Formula I-43); 2-((2-Methyl-3-chloro)benzyloxy)-N- (pyridin-3-yl)benzamide (formula I-44).
  • the compound 2-(() was obtained from 2-hydroxy-N-(pyridin-3-yl)benzamide (Compound 7) and 1-naphthylmethanol. Naphthalen-1-yl)methoxy)-N-(pyridin-3-yl)benzamide (Formula I-45).
  • the conditions of the compound of formula I-17 were synthesized according to the fifth step of Example 1, from 2-hydroxy-N-(pyridin-3-yl)benzamide (Compound 7) and the substituted benzyl bromide obtained above (Compound 8-5)
  • the compound 14 was obtained, and the preparation of the compound of the formula I-48 in the first step of Example 7 was carried out, and the compound 14 was hydrolyzed by LiOH to synthesize the compound of the formula I-47.
  • the compound 11b was obtained from the reduction of the compound 9c by sodium borohydride.
  • the compounds 13w and 13x were respectively reacted with phosphorus bromide to obtain the compounds 8-6a to 8-6b, which can be directly used in the next step. reaction.
  • the compound 5a is reacted with 2-aminopyridine and 5-aminopyrimidine respectively to obtain the compound of the formula I-52 and the formula I-53, specifically: 2- Benzyloxy-N-(pyridin-2-yl)benzamide (Formula I-52); 2-benzyloxy-N-(pyrimidin-5-yl)benzamide (Formula I-53).
  • Example 10 Synthesis of a compound of Formula I-54, Formula I-55, Formula I-56, Formula I-57, Formula I-58, Formula I-59, and Formula I-60
  • the compound 3a was prepared from the compound 2a, and the compounds 2b to 2f obtained in the above reaction and the commercially available methyl 4-methoxysalicylate (compound 2g) were respectively reacted with a substituted benzyl bromide. Compounds 3b to 3h were obtained.
  • the compound 4a was prepared from the compound 3a, and the compounds 3b to 3h were separately hydrolyzed to obtain the compounds 4b to 4h.
  • the compounds 4b to 4h are respectively subjected to acid chloride and amidation to obtain a compound of the formula I-54 to the formula I-60, specifically: 5-chloro- 2-((2,6-Dichloro)benzyloxy)-N-(pyridin-3-yl)benzamide (Formula I-54); 5-Chloro-2-((2-chloro-5-fluoro) Benzyloxy)-N-(pyridin-3-yl)benzamide (Formula I-55); 4-Chloro-2-(2-chlorobenzyloxy)-N-(pyridin-3-yl)benzene Formamide (Formula I-56); 2-(2-Chlorobenzyloxy)-5-nitro-N-(pyridin-3-yl)benzamide (Formula I-57); 4-bromo-2- (2-Chlorobenzyloxy)-N-(pyridin-3-yl)benzamide (Formula I-57); 4-bromo-2- (2-Chlorobenz
  • hydrochlorides of the compounds of the formulae I-16, I-21, I-29, I-32, I-33, I-34, I-36, I-39 and I-43 were separately prepared by the methods described above.
  • Example 12 Determination of inhibition of sphingomyelin synthase 2 by 2-alkoxybenzoyl arylamine compounds in vitro Experimental apparatus and materials
  • Vortex mixer (Shanghai Jingke Industrial Co., Ltd. model XW-80A)
  • HPLC column Agilent C18RP (250 mm x 4.6 mm 5 ⁇ m).
  • DMPC Purchased from Santa Cruz (USA), dissolved in ethanol at a concentration of 40 mM.
  • the organic solvents used were purchased from Shanghai Sinopharm Co., Ltd., methanol was chromatographically pure, water was Milli-Q pump filtered, deionized, ultra-pure water ultrafiltration through 0.22 ⁇ m membrane, and other bio-consumable materials were purchased from domestic companies.
  • SMS test buffer (Buffer2) configuration: (100 mM hydroxyethylpyridazine ethanesulfuric acid, 30 mM MnCl 2 , 3% defatted bovine serum albumin): hydroxyethylpiperazine ethanesulfuric acid (4-(2- Hydroxyethyl)-1-peperazineethanesulfonic acid, Hepes), 1.1916 g, MnCl 2 ⁇ 4H 2 O 0.2969 g, 0.3 g of fatty acid free BSA (Bovine serum albumin), dissolved in distilled water, and made up to 50 mL.
  • Buffer2 (100 mM hydroxyethylpyridazine ethanesulfuric acid, 30 mM MnCl 2 , 3% defatted bovine serum albumin): hydroxyethylpiperazine ethanesulfuric acid (4-(2- Hydroxyethyl)-1-pe
  • test compound solution accurately weigh 1 to 2 mg of each test compound, and firstly prepare an 6 mM stock solution by adding an appropriate amount of DMSO. Take a volume of the DMSO stock solution of the test compound, and then add an appropriate amount of DMSO to dilute the test compound to the desired concentration of the solution.
  • the insect cell homogenate with high expression of SMS2 was prepared by Xu Yanhui, research group of Fudan University Biomedical Research Institute.
  • the inhibitory activity of the compound of the formula I-1 to I-60 against sphingomyelin synthase 2 was determined.
  • the activity test results showed that the 2-alkoxybenzoyl arylamine compound had a submicromolar activity; the activity results were:
  • the 6 mM DMSO stock solution of the test compound was subjected to gradient dilution to prepare 5 concentration gradient solutions, and 10 ⁇ L of each was added to the test system of the first step of Example 12, and the sample was prepared according to the method of the first step of Example 12.
  • the Asm values of the compounds at 5 concentrations were determined by high performance liquid chromatography.
  • the inhibition rates at 5 concentrations were calculated and fitted to obtain a half-inhibitory concentration IC 50 .
  • Each compound was tested in parallel for 3 groups.
  • the half-inhibitory concentration (IC 50 ) of the compound formulas I-1 to I-60 for SMS2 is shown in Table 1:
  • I-42 2.1 I-43 1.1 I-44 3.8 I-45 2.6 I-46 >100 I-47 >100 I-48 >100 I-49 4.1 I-50 11.6 I-51 >50 I-52 11.7 I-53 >25 I-54 >25 I-55 >25 I-56 >50 I-57 >100 I-58 >50 I-59 >100 I-60 >50

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Abstract

一种如式I所示的2-烷氧基苯甲酰芳胺类化合物，其药学上可接受的盐、或以其为有效活性成分的药物组合物在预防和治疗由于鞘磷脂水平异常增加所引起疾病的药物中的应用，其中R、X、Y、Z和G如说明书所定义，所述疾病包括动脉粥样硬化、脂肪肝、肥胖和Ⅱ型糖尿病等代谢综合症。

Description

2-烷氧基苯甲酰芳胺类化合物及其药物用途 技术领域
本发明属药物化学领域，涉及2-烷氧基苯甲酰芳胺类化合物及其药物用途，具体涉及2-烷氧基苯甲酰芳胺类化合物及其在制备鞘磷脂合酶抑制剂中的用途以及在制备预防或治疗动脉粥样硬化、脂肪肝、肥胖和Ⅱ型糖尿病的药物中的用途。
背景技术
据报道，在我国，随着经济社会的发展和人口的老龄化，心脑血管病发病率与死亡率近年显著增加至除肿瘤外总死因的第2位，已经成为危害人类健康的主要疾病之一。研究显示，动脉粥样硬化(atherosclerosis，AS)是许多心脑血管疾病的主要病理基础之一，因此，抗动脉粥样硬化药物的研究成为当前药物研发领域的热点。研究还显示，动脉粥样硬化表现为大、中动脉内膜出现含胆固醇、类脂肪等的黄色物质，从而导致血栓形成、供血障碍等；虽然其分子病理尚未完全阐明，但业内公认在已知的诸多因素中血脂异常是动脉粥样硬化形成的最重要的诱导因素，并且粥瘤和动脉硬化的形成与脂质成分的异常表达密切相关。通常，血脂异常是指脂肪代谢或转运异常导致血浆中脂质高于正常，血液粘稠度增高，其主要表现为低密度脂蛋白(low-density lipoprotein,LDL)和极低密度脂蛋白(verylow-density lipoprotein,VLDL)水平升高以及高密度脂蛋白(high-density lipoprotein,HDL)水平下降，因此，降低LDL和(或)升高HDL可以起到调节血脂的作用，并且调血脂药亦成为临床上用于抗动脉粥样硬化的主要药物。
临床上常用的调血脂药主要有他汀类、贝特类、胆酸结合树脂类、烟酸等。其中，他汀类药物通过抑制胆固醇生物合成过程中的关键酶-3-羟基-3-甲基戊二酰辅酶A还原酶(HMG Co-A还原酶)，降低血浆中LDL胆固醇的水平，能减少冠心病的发病率(Linsel-Nitschke P,Tall AR.Nat.Rev.Drug.Discov,2005,4,193-206)。然而，有研究表明使用普伐他汀(pravastatin)或阿托伐他汀(atorvastatin)强化治疗冠心患者后，LDL胆固醇水平虽有不同程度降低，但仍然存在心血管病的高发病率(Cannon CP,Braunwald E,et a1.N Engl J Med,2004,350:l495-l504)，因 此，通过单独降低LDL胆固醇水平带来的治疗效果存在一定的限度；还有研究显示他汀类药物存在着横纹肌溶解等严重的不良反应。
随着研究的深入，有研究提出了多种抗动脉粥样硬化的潜在药物靶标如：鞘磷脂合酶抑制剂、PPAR激动剂、胆固醇酯转移蛋白(CETP)抑制剂、输注载脂蛋白、肝脏X受体激活剂和磷脂转移蛋白(PLTP)抑制剂等；尤其是鞘磷脂(Sphingomyelin,SM)及其代谢酶在引起脂蛋白改变的同时介导一系列细胞过程，表明其在动脉粥样硬化发生发展进程中扮演着重要的角色。
研究表明，鞘磷脂能通过多种途径诱发动脉粥样硬化：(1)抑制甘油三酯(TG)的脂解(Park TS,Panek RL,et al.Atherosclerosis.2006,189(2):264-72.)；(2)延缓致AS的脂蛋白残粒的清除(Schlitt A,Hojjati MR,et al.J Lipid Res.2005,46(2):196-200.)；(3)影响HDL介导的胆固醇逆向转运，造成胆固醇清除障碍(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)神经酰胺及SM合成或分解的相关产物是细胞增殖、激活、凋亡的调节因子，影响着动脉粥样硬化斑块的生长与稳定(Park,T.-S.；Panek,R.L.；et al.Circulation.2004,110,3465-3471.)。(5)富含SM的LDL具有很强的凝聚和黏附，导致巨噬细胞更易于在动脉壁滞留聚集而形成泡沫细胞从而促进AS(Fan Y,Shi S,et al.Arterioscler Thromb Vasc Biol,2010,30:2114-20.)；
流行病学调查也显示，人类SM水平与动脉粥样硬化(AS)存在独立的相关性，血浆SM浓度是动脉粥样硬化的独立危险因子，在评价动脉粥样硬化发展过程中具有指标性的意义(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.)；动物实验研究已经显示对SM从头生物合成的抑制确实能有效降低apoE-KO小鼠的血浆胆固醇及甘油三脂水平，升高HDL-胆固醇含量，从而阻止AS病变的发展(Park,T.-S.；Panek,R.L.；et al.Circulation.2004,110,3465-3471.)；因此，业内认为降低血浆中鞘磷脂水平或抑制SM的合成可达到减缓或阻止动脉粥样硬化发生发展的目的。
还有研究发现，鞘磷脂合酶(Sphingomyelin synthase,SMS)可调节神经酰胺(ceramide)与卵磷脂(PC)合成SM，是鞘磷脂从头合成途径最后一步的关键酶。进 一步的研究发现，SMS直接调控SM水平，SMS的过度表达是动脉粥样硬化病变组织中的普遍现象，也是动脉粥样硬化病变发生的关键指标之一(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.)。动物实验显示SMS2和apoE双基因敲除小鼠模型的主动脉弓动脉粥样硬化斑块显著减小，头臂动脉中SM等脂质水平显著降低，同时对小鼠的正常生理未见影响(Fan Y,Shi S,et al.Arterioscler.Thromb.Vasc Biol,2010,30:2114-20.)，表明SMS催化合成SM的反应处于鞘磷脂生物合成循环的最后环节，抑制其活性引起潜在的毒副反应较小；因此，综上研究结果，业内展望，通过抑制鞘磷脂合酶降低鞘磷脂水平可成为治疗动脉粥样硬化的新方法，鞘磷脂合酶作为抗动脉粥样硬化的新靶标具有潜在优越性，鞘磷脂合酶抑制剂将成为新型的抗动脉粥样硬化的治疗药物。
除此之外，有研究发现SMS2缺乏可以防止高脂饮食诱导的肥胖和胰岛素抵抗，同时在SMS2基因敲除小鼠的肝脏中，很难观察到大的成熟的脂肪斑块，表明SMS2参与肝脏脂肪斑块的形成且可诱导肥胖和Ⅱ型糖尿病的发生(Susumu Mitsutake,Kota Zama,et al.Journal of Biological Chemistry.2011,286(32),28544-28555)。SMS2缺乏导致的血浆中SM的降低可以改善动物组织和整个身体中胰岛素的敏感性(Li Z,Zhang H,et al.Mol.Cell.Biol.2011,31(20):4205-4218)。因此，鞘磷脂合酶小分子抑制剂将可以预防和治疗肥胖、脂肪肝和Ⅱ型糖尿病等代谢综合症。
目前有文献报道的鞘磷脂合酶抑制剂之一是D609(Aimin Meng；Chiara Luberto；et al.Experimental Cell Research,2004,292,385–392.)，该化合物的酶抑制活性较弱(IC50＝375μM)，且化学结构上含有原磺酸酯而使得结构高度不稳定(Bai,A.et al.J.Pharmacol.Exp.Ther.2004,309,1051-1059)，半衰期短；此外，有研究采用同源模建的方法首次构建出hSMS1(人类SMS1型)的三维蛋白结构模型(Zhang Ya；Lin Fu；et al.Chin.J.Chem.2011,29,2421-2429)，确定了鞘磷脂合酶上底物结合的活性位点，并用生物学实验进行了验证(Calvin Yeang；Shweta Varshney；et al.Biochimica et Biophysica Acta,2008,1781,610–617.)；采用该三维蛋白结构模型和经过验证的酶与底物结合的活性位点，发现了鞘磷脂合酶小分子 抑制剂化合物D2(Xiaodong Deng,Fu Lin,et al.European Journal of Medicinal Chemistry,2014,73,1-7)，其体外对SMS2的抑制活性(IC50＝13.5μM)虽较D609高，但仍存在如下缺陷：对SMS2的抑制活性有待提高，其含有潜在毒性风险较大的氰基基团，并且水溶性和稳定性等理化性质不佳。
发明内容
本发明的目的在于克服现有技术的缺陷和不足，提供2-烷氧基苯甲酰芳胺类化合物及其药物用途，具体涉及2-烷氧基苯甲酰芳胺类化合物及其在制备鞘磷脂合酶抑制剂中的用途以及在制备用于预防或治疗动脉粥样硬化、脂肪肝、肥胖和Ⅱ型糖尿病的药物中的用途。
本发明的第一个目的是提供2-烷氧基苯甲酰芳胺类化合物或其药学上可接受的盐；所述的2-烷氧基苯甲酰芳胺类化合物是具有如式I所示结构的游离碱或盐，
Figure PCTCN2015085077-appb-000001
式中X、Y和Z代表C原子或者N原子，但X、Y和Z不可同时选自C原子；G代表苯基、取代苯基和萘基，当Y与X或者Y与Z同时选自C原子时，G选自取代苯基或者萘基；尤其地当G为取代苯基时，其上的取代基选自卤素，硝基，氰基，三氟甲氧基，羧基，酯基，苄氧基，C1-C7的烷基或者C1-C7的烷氧基等其中任意一个或者两个；R代表H，卤素，硝基或者C1-C4的烷氧基。
进一步的，当G为取代苯基时，其上的取代基为o-F，m-F，p-F，o-Cl，m-Cl，p-Cl，o-Br，m-Br，p-Br，o-NO2，m-NO2，p-NO2，o-CN，m-CN，p-CN，o-OCF3，m-OCF3，p-OCF3，o-COOH，m-COOH，p-COOH，o-COOEt，m-COOEt，p-COOEt，o-OBn，m-OBn，p-OBn，o-OCH2CO2C2H5，m-OCH2CO2C2H5，o-OCH2COOH，m-OCH2COOH，C1-C7的烷基或者C1-C7的烷氧基中的任意一个或者两个。
更具体的，描述为式Ⅰ-1～式Ⅰ-60的化合物：
Figure PCTCN2015085077-appb-000002
Figure PCTCN2015085077-appb-000003
Figure PCTCN2015085077-appb-000004
Figure PCTCN2015085077-appb-000005
本发明化合物含有碱性基团可与酸成盐，采用普通手段可以形成衍生物的盐。包括有机酸盐如乙酸盐、枸橼酸盐、富马酸盐、马来酸盐、草酸盐、苹果酸盐、柠檬酸盐、琥珀酸盐、酒石酸盐、乳酸盐、樟脑磺酸盐、苯磺酸盐、对甲苯磺酸盐、甲磺酸盐、三氟醋酸盐、三氟甲磺酸盐等；无机酸盐如氢卤酸(氢氟酸、氢氯酸、氢溴酸、氢碘酸)盐、硫酸盐、磷酸盐、硝酸盐等。或与氨基酸，如谷氨酸或天冬氨酸可形成谷氨酸盐或天冬氨酸盐。优选的盐为盐酸盐、溴氢酸盐。
本发明还包括2-烷氧基苯甲酰芳胺类化合物的溶剂合物，其溶剂优选为水、乙醇或甲醇。
本发明的第二个目的是提供式Ⅰ所示的2-烷氧基苯甲酰芳胺类化合物在制备鞘磷脂合酶小分子抑制剂中的用途。本发明采用文献报道的高效液相色谱(HPLC)荧光定量检测方法测定式Ⅰ所示的2-烷氧基苯甲酰芳胺类化合物对鞘磷脂合酶抑制剂的抑制活性(Xiaodong Deng；Hong Sun；et al.Analytical Letters,2012,45:12,1581-1589)，通过其中的NBD-ceramide和NBD-sphingomyelin的含量变化计算出抑制剂对鞘磷脂合酶催化神经酰胺转化为鞘磷脂的活性的改变。
基于高效液相色谱(HPLC)荧光定量法的活性测试实验表明，式Ⅰ所示的2-烷氧基苯甲酰芳胺类化合物具有亚微摩尔级的鞘磷脂合酶抑制活性，是抑制鞘磷脂合酶的有效成分；高效液相色谱(HPLC)荧光定量方法检测所述化合物对鞘磷脂合酶2(SMS2)的抑制活性为：
1)2-(2-氟苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-1)在5μM下的抑制率为53.8％；
2)2-(3-氟苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-2)在5μM下的抑制率为69.3％；
3)2-(3-硝基苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-3)在50μM下的抑制率为64.6％；
4)2-(3-氰基苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-4)在50μM下的抑制率为66.0％；
5)2-((4-甲氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-5)在50μM下的抑制率为23.0％；
6)2-(2-氰基苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-6)在50μM下的抑制率为50.0％；
7)2-(3-氯苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-7)在5μM下的抑制率为70.6％；
8)2-(3-溴苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-8)在50μM下的抑制率为67.1％；
9)2-(4-溴苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-9)在50μM下的抑制率为14.7％；
10)2-((3-甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-10)在50μM下的抑制率为69.5％；
11)2-((2-甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-11)在5μM下的抑制率为71.3％；
12)2-((2-硝基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-12)在50μM下的抑制率为35.5％；
13)2-((4-硝基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-13)在50μM下的抑制率为11.8％；
14)2-((4-甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-14)在50μM下的抑制率为69.0％；
15)2-((4-氰基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-15)在50μM下的抑制率为15.0％；
16)2-((2-氯-5-氟)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-16)在5μM下的 抑制率为75.7％。
17)2-((2,6-二氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-17)在5μM下的抑制率为77.2％。
18)2-((2-氟-3-氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-18)在5μM下的抑制率为55.2％。
19)4-((2-(吡啶-3-基氨基甲酰基)苯氧基)甲基)苯甲酸乙酯(式Ⅰ-19)在10μM下的抑制率为2.9％。
20)2-((4-三氟甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-20)在10μM下的抑制率为3.9％。
21)2-((2-甲基-5-氟)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-21)在10μM下的抑制率为84.7％。
22)2-(3-((2-(吡啶-3-基氨基甲酰基)苯氧基)甲基)苯氧基)乙酸乙酯(式Ⅰ-22)在10μM下的抑制率为15.3％。
23)2-((3-甲氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-23)在10μM下的抑制率为59.8％。
24)2-((2-甲氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-24)在10μM下的抑制率为89.4％。
25)2-((2,5-二甲氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-25)在10μM下的抑制率为78.9％。
26)2-((2-苄氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-26)在10μM下的抑制率为76.9％。
27)2-((2-乙基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-27)在5μM下的抑制率为78.4％。
28)2-((4-乙基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-28)在10μM下的抑制率为10.1％。
29)2-((2,6-二甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-29)在10μM下的抑制率为88.8％。
30)2-((2-乙氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-30)在10μM下的抑制率为86.3％。
31)2-((2-甲氧基-5-氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-31)在10μM下的抑制率为92.4％。
32)2-((2-氯-6-氟)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-32)在10μM下的抑制率为82.3％。
33)2-((2,5-二氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-33)在10μM下的抑制率为87.9％。
34)2-(2-(4-氯丁氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-34)在10μM下的抑制率为85.5％。
35)2-(2-(5-氯戊氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-35)在10μM下的抑制率为91.3％。
36)2-(2-(6-氯己氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-36)在10μM下的抑制率为91.5％。
37)2-((2-己氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-37)在10μM下的抑制率为90.2％。
38)2-((2-庚氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-38)在10μM下的抑制率为90.5％。
39)2-((5-氯-2-己氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-39)在5μM下的抑制率为85.5％。
40)2-((5-氯-2-庚氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-40)在5μM下的抑制率为87.1％。
41)2-((3-三氟甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-41)在10μM下的抑制率为10.0％。
42)2-((2-三氟甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-42)在5μM下的抑制率为65.5％。
43)2-((2-甲基-5-氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-43)在5μM下的抑制率为74.8％。
44)2-((2-甲基-3-氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-44)在5μM下的抑制率为47.0％。
45)2-((萘-1-基)甲氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-45)在10μM下的抑 制率为78.0％。
46)4-((2-(吡啶-3-基氨基甲酰基)苯氧基)甲基)苯甲酸(式Ⅰ-46)在10μM下的抑制率为2.6％。
47)2-(2-((2-(吡啶-3-基氨基甲酰基)苯氧基)甲基)苯氧基)乙酸(式Ⅰ-47)在10μM下的抑制率为7.4％。
48)2-(3-((2-(吡啶-3-基氨基甲酰基)苯氧基)甲基)苯氧基)乙酸(式Ⅰ-48)在10μM下的抑制率为3.0％。
49)2-((5-氯-2-(3-甲氧丙氧基))苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-49)在10μM下的抑制率为75.3％。
50)2-((5-氯-2-(2-甲氧乙氧基))苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-50)在10μM下的抑制率为54.2％。
51)2-((5-氯-2-(2-吗啡啉乙氧基))苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-51)在10μM下的抑制率为24.9％。
52)2-苄氧基-N-(吡啶-2-基)苯甲酰胺(式Ⅰ-52)在100μM下的抑制率为60.1％。
53)2-苄氧基-N-(嘧啶-5-基)苯甲酰胺(式Ⅰ-53)在10μM下的抑制率为38.4％。
54)5-氯-2-((2,6-二氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-54)在10μM下的抑制率为42.3％。
55)5-氯-2-((2-氯-5-氟)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-55)在10μM下的抑制率为31.7％。
56)4-氯-2-(2-氯苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-56)在10μM下的抑制率为20.0％。
57)2-(2-氯苄氧基)-5-硝基-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-57)在10μM下的抑制率为1.7％。
58)4-溴-2-(2-氯苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-58)在10μM下的抑制率为19.4％。
59)2-(2-氯苄氧基)-5-甲氧基-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-59)在10μM下的抑制率为7.2％。
60)2-(2-氯苄氧基)-4-甲氧基-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-60)在10μM下的抑制率为13.3％。
本发明的进一步目的是提供式Ⅰ所示的2-烷氧基苯甲酰芳胺类化合物及其盐类或溶剂合物在制备预防和治疗由鞘磷脂水平异常增加引起疾病如动脉粥样硬化、脂肪肝、肥胖和Ⅱ型糖尿病的药物中的用途。
本发明通过实验证实，所述的化合物与现有技术的鞘磷脂合酶小分子抑制剂D609和D2相比，其对SMS2的抑制活性显著高于D609和D2；水溶性和稳定性等理化性质优于D609和D2；且其不含有潜在的毒性基团，潜在的毒副作用小，可以制备治疗由鞘磷脂水平异常增加所引起的疾病如动脉粥样硬化、脂肪肝、肥胖和Ⅱ型糖尿病的药物。
本发明的上述药物中还可以含有一种或多种药学上可接受的载体，所述载体包括药学领域的常规稀释剂，赋形剂，填充剂，粘合剂，湿润剂，崩解剂，吸收促进剂，表面活性剂，吸附载体，润滑剂等，必要时还可以加入香味剂，甜味剂等。
本发明的有益效果在于，所提供的2-烷氧基苯甲酰芳胺类化合物是一类结构新颖的鞘磷脂合酶抑制剂，具有亚微摩尔级的分子水平抑制活性，具有良好的潜力和应用前景，可进一步制成为治疗动脉粥样硬化、脂肪肝、肥胖和Ⅱ型糖尿病的药物。
具体实施方式
实施例1：制备2-((2,6-二氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-17)
一、2-苄氧基苯甲酸甲酯(化合物3a)的合成
Figure PCTCN2015085077-appb-000006
将11.4g(75mmol，1.0eq)水杨酸甲酯在室温条件下溶于200ml丙酮，搅拌均匀后向其中加入15.52g(112.5mmol，1.5eq)碳酸钾，然后缓慢滴加13.5g(78.75 mmol，1.05eq)溴苄，滴加完毕后加热至回流反应3.0h。TLC检测原料消失，停止加热。冷至室温，减压抽滤除去固体，丙酮洗涤滤饼两次，合并滤液并经浓缩得到无色透明油状物18.06g，产率99.4％，该粗产物可不经纯化直接进行下步反应。MS(ESI)(m/z):243.1(M+H)+。
二、2-苄氧基苯甲酸(化合物4a)的合成
Figure PCTCN2015085077-appb-000007
将2-苄氧基苯甲酸甲酯(化合物3a)18.17g(75mmol,1.0eq)溶于75ml甲醇中，搅拌均匀，在室温条件下滴加75ml NaOH的水溶液(4mol/L)。滴毕，在室温反应4.5h，反应体系变为澄清透明溶液，TLC检测原料消失。蒸除甲醇，冰浴条件下向体系滴加2M HCl(aq)，调体系pH至5-6，体系中析出白色固体，过滤并经真空干燥，称重得到15.0g白色固体，收率87.6％，该产物可不经纯化直接进行下步反应。MS(ESI)(m/z):227.1(M-H)-。
三、2-苄氧基-N-(吡啶-3-基)苯甲酰胺(化合物6a)的合成
Figure PCTCN2015085077-appb-000008
向干燥的单口烧瓶中加入0.55g(2.4mmol,1.2eq)2-苄氧基苯甲酸(化合物4a)，之后加入7.25ml二氯亚砜，搅拌约5min，再加入2滴吡啶，搅拌加热回流反应2.5h后，TLC检测原料点消失。减压蒸除二氯亚砜，得到淡黄色蜡状物化合物5a。该粗产品可不经纯化直接用于下步反应。
将0.19g(2mmol,1.0eq)3-氨基吡啶溶于10ml干燥的二氯甲烷中，之后加入 0.32ml(4mmol,2.0eq)吡啶并搅拌均匀。在冰水浴条件下，缓慢向其中滴加上步反应所得的化合物5a的二氯甲烷溶液。滴毕，在室温反应2h，后用水洗反应体系2次，饱和NaCl洗2次，无水Na2SO4干燥，浓缩得到0.53g淡黄色固体。用PE：EA＝2:1的混合溶剂对粗产品进行重结晶纯化，得到白色粉末状固体0.28g(化合物6a)，产率46.7％。经检测，结构正确，检测结果如下：m.p 107.6-108.9℃.MS(ESI)(m/z):305.2(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.36(s,1H),8.68(d,J＝2.3Hz,1H),8.27(dd,J＝4.7,1.3Hz,1H),8.10(d,J＝8.3Hz,1H),7.69(dd,J＝7.6,1.6Hz,1H),7.57–7.50(m,3H),7.40–7.32(m,4H),7.30(d,J＝8.3Hz,1H),7.11(t,J＝7.4Hz,1H),5.25(s,2H).
四、2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)的合成
Figure PCTCN2015085077-appb-000009
将5.01g(16.46mmol,1.0eq)2-苄氧基-N-(吡啶-3-基)苯甲酰胺(化合物6a)溶于85ml甲醇，向其中加入10％Pd/C，然后在室温条件下，3个大气压的氢气压力下反应2h。抽滤除去Pd/C，将滤液浓缩得到3.47g白色粉末状固体(化合物7)，收率98.6％。经检测，结构正确，检测结果如下：MS(ESI)(m/z):215.1(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 11.65(s,1H),10.53(s,1H),8.88(d,J＝2.4Hz,1H),8.35(dd,J＝4.7,1.4Hz,1H),8.17(ddd,J＝8.3,2.4,1.5Hz,1H),7.95(dd,J＝7.9,1.6Hz,1H),7.49–7.39(m,2H),7.04–6.95(m,2H).
五、2-((2,6-二氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-17)的合成
将0.21g(1.0mmol，1.0eq)2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)溶解于6ml丙酮中，之后加入0.28g(2.0mmol，2.0eq)碳酸钾，再加入0.24g(1.0mmol，1.0eq)2,6-二氯苄溴(化合物8-1q)，反应1.0h，蒸除丙酮，加入水，EA萃取，再用饱和NaCl洗2次有机层，无水Na2SO4干燥，浓缩得到0.34g黄褐色油状物。用PE：EA＝2:1的流动相对粗产品进行柱层析纯化，得到淡黄色粉末状固体(式 Ⅰ-17)0.24g，产率64.9％。经检测，结构正确，检测结果如下：m.p 115.0-116.4℃.MS(ESI)(m/z):373.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.16(s,1H),8.51(d,J＝2.4Hz,1H),8.25(dd,J＝4.7,1.4Hz,1H),8.05–7.98(m,1H),7.71(dd,J＝7.6,1.6Hz,1H),7.63–7.53(m,3H),7.47(dd,J＝9.0,7.0Hz,2H),7.33(dd,J＝8.3,4.7Hz,1H),7.18(t,J＝7.3Hz,1H),5.43(s,2H).
实施例2：合成式Ⅰ-1，Ⅰ-2，Ⅰ-3，Ⅰ-4，Ⅰ-5，Ⅰ-6，Ⅰ-7，Ⅰ-8，Ⅰ-9，Ⅰ-10，Ⅰ-11，Ⅰ-12，Ⅰ-13，Ⅰ-14，Ⅰ-15，Ⅰ-16，Ⅰ-18，Ⅰ-19，Ⅰ-20的化合物
Figure PCTCN2015085077-appb-000010
Figure PCTCN2015085077-appb-000011
Figure PCTCN2015085077-appb-000012
参照实施实例一中第五步合成化合物式Ⅰ-17的条件，从2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)和市售的相应取代苄溴(化合物8-1a～8-1t)得到化合物式Ⅰ-1至Ⅰ-16和式Ⅰ-18至Ⅰ-20,具体为：2-(2-氟苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-1)；2-(3-氟苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-2)；2-(3-硝基苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-3)；2-(3-氰基苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-4)；2-((4-甲氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-5)；2-(2-氰基苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-6)；2-(3-氯苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-7)；2-(3-溴苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-8)；2-(4-溴苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-9)；2-((3-甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-10)；2-((2-甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-11)；2-((2-硝基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-12)；2-((4-硝基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-13)；2-((4-甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-14)；2-((4-氰基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-15)；2-((2-氯-5-氟)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-16)；2-((2-氟-3-氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-18)；4-((2-(吡啶-3-基氨基甲酰基)苯氧基)甲基)苯甲酸乙酯(式Ⅰ-19)；2-((4-三氟甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-20)。
经检测，结构正确，检测结果如下：
式Ⅰ-1m.p 101.6-102.5℃.MS(ESI)(m/z):323.2(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.56(s,1H),8.86(d,J＝1.8Hz,1H),8.39(dd,J＝4.9,1.1Hz,1H),8.22(d,J＝8.4Hz,1H),7.68(dd,J＝7.6,1.7Hz,1H),7.66–7.61(m,1H),7.60–7.53(m,2H),7.44–7.34(m,2H),7.25(dd,J＝9.8,8.9Hz,1H),7.19(td,J＝7.5,0.8Hz,1H),7.14(t,J＝7.5Hz,1H),5.33(s,2H).
式Ⅰ-2m.p 102.8-104.2℃.MS(ESI)(m/z):323.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.40(s,1H),8.76(d,J＝2.4Hz,1H),8.29(dd,J＝4.7,1.4Hz,1H),8.18–8.10(m,1H),7.67(dd,J＝7.6,1.6Hz,1H),7.57–7.50(m,1H),7.45–7.34(m,4H),7.27(d,J＝8.3Hz,1H),7.19–7.09(m,2H),5.27(s,2H).
式Ⅰ-3m.p 138.2-141.1℃.MS(ESI)(m/z):350.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.43(s,1H),8.79(s,1H),8.27(d,J＝4.6Hz,1H),8.19(d,J＝7.3Hz,2H),8.14(d,J＝7.2Hz,1H),7.75(d,J＝7.8Hz,2H),7.62(d,J＝7.5Hz,1H),7.50(t,J＝7.9Hz,1H),7.36(dd,J＝7.7,4.8Hz,1H),7.23(d,J＝8.3Hz,1H),7.10(t,J＝7.4Hz,1H),5.39(s,2H).
式Ⅰ-4m.p 150.2-152.6℃.MS(ESI)(m/z):330.1(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.41(s,1H),8.80(s,1H),8.27(d,J＝4.1Hz,1H),8.11(d,J＝8.2Hz,1H),7.97(s,1H),7.84(d,J＝7.8Hz,1H),7.77(d,J＝7.7Hz,1H),7.62(d,J＝7.4Hz,1H),7.59–7.47(m,2H),7.36(dd,J＝8.1,4.7Hz,1H),7.24(d,J＝8.3Hz,1H),7.10(t,J＝7.4Hz,1H),5.27(s,2H).
式Ⅰ-5m.p 114.9-118.4℃.MS(ESI)(m/z):335.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.34(s,1H),8.63(s,1H),8.25(d,J＝4.6Hz,1H),8.07(d,J＝8.4Hz,1H),7.68(d,J＝7.6Hz,1H),7.52(t,J＝7.9Hz,1H),7.47(d,J＝8.5Hz,2H),7.34(dd,J＝8.3,4.7Hz,1H),7.29(d,J＝8.3Hz,1H),7.08(t,J＝7.5Hz,1H),6.91(d,J＝8.5Hz,2H),5.15(s,2H),3.72(s,3H).
式Ⅰ-6m.p 122.8-125.2℃.MS(ESI)(m/z):330.1(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.32(s,1H),8.67(s,1H),8.25(d,J＝4.2Hz,1H),8.08(d,J＝8.3Hz,1H),7.88(d,J＝7.6Hz,1H),7.78(t,J＝10.8Hz,1H),7.67(dd,J＝12.1,7.0Hz,2H),7.53(dd,J＝9.0,4.4Hz,2H),7.33(dd,J＝12.6,6.5Hz,2H),7.13(t,J＝7.4Hz,1H),5.41(s,2H).
式Ⅰ-7m.p 125.1-125.6℃.MS(ESI)(m/z):339.2(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.40(s,1H),8.79(d,J＝2.4Hz,1H),8.29(dd,J＝4.7,1.4Hz,1H),8.20–8.07(m,1H),7.66(dd,J＝7.7,1.6Hz,2H),7.58–7.50(m,1H),7.50–7.44(m,1H),7.43–7.33(m,3H),7.28(d,J＝8.3Hz,1H),7.12(t,J＝7.4Hz,1H),5.25(s,2H).
式Ⅰ-8m.p 151.4-152.4℃.MS(ESI)(m/z):384.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.39(s,1H),8.78(s,1H),8.26(d,J＝4.6Hz,1H),8.11(d,J＝8.2Hz,1H),7.77(s,1H),7.63(d,J＝7.5Hz,1H),7.51(dd,J＝14.6,7.6Hz,3H),7.35(dd,J＝8.2,4.8Hz,1H),7.30(t,J＝7.8Hz,1H),7.25(d,J＝8.4Hz,1H),7.10(t,J＝7.4Hz,1H),5.22(s,2H).
式Ⅰ-9m.p 147.2-148.7℃.MS(ESI)(m/z):384.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.36(s,1H),8.72(d,J＝2.3Hz,1H),8.26(d,J＝4.6Hz,1H),8.10(d,J＝8.3Hz,1H),7.63(d,J＝7.5Hz,1H),7.54(d,J＝8.3Hz,2H),7.48(t,J＝8.9Hz,3H),7.35(dd,J＝8.3,4.7Hz,1H),7.24(d,J＝8.4Hz,1H),7.08(t,J＝7.5Hz,1H),5.21(s,2H).
式Ⅰ-10m.p 151.9-153.6℃.MS(ESI)(m/z):319.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.37(s,1H),8.68(s,1H),8.26(d,J＝4.7Hz,1H),8.11(d,J＝8.3Hz,1H),7.67(d,J＝7.6Hz,1H),7.52(t,J＝7.8Hz,1H),7.34(t,J＝6.4Hz,2H),7.28(d,J＝8.1Hz,2H),7.22(t,J＝7.5Hz,1H),7.10(dd,J＝12.8,6.3Hz,2H),5.18(s,2H),2.20(s,3H).
式Ⅰ-11m.p 95.9-98.0℃.MS(ESI)(m/z):319.2(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.37(s,1H),8.61(d,J＝2.4Hz,1H),8.27(dd,J＝4.7,1.4Hz,1H),8.09–8.02(m,1H),7.69(dd,J＝7.6,1.7Hz,1H),7.58–7.52(m,1H),7.50(d,J＝7.5Hz,1H),7.39–7.32(m,2H),7.28–7.21(m,2H),7.15(ddd,J＝17.3,11.2,4.7Hz,2H),5.26(s,2H),2.34(s,3H).
式Ⅰ-12m.p 110.7-112.9℃.MS(ESI)(m/z):350.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.42(s,1H),8.76(d,J＝2.3Hz,1H),8.28(dd,J＝4.7,1.4Hz,1H),8.13(dt,J＝8.2,2.0Hz,2H),7.84(d,J＝7.5Hz,1H),7.69–7.54(m,3H),7.52–7.45(m,1H),7.36(dd,J＝8.3,4.7Hz,1H),7.24(d,J＝8.3Hz,1H),7.11(td,J＝7.5,0.7Hz,1H),5.60(s,2H).
式Ⅰ-13m.p 142.4-144.6℃.MS(ESI)(m/z):350.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.43(s,1H),8.79(s,1H),8.27(d,J＝4.6Hz,1H),8.19(d,J＝7.3Hz,2H),8.14(d,J＝7.2Hz,1H),7.75(d,J＝7.8Hz,2H),7.62(d,J＝7.5Hz,1H),7.50(t,J＝7.9Hz,1H),7.36(dd,J＝7.7,4.8Hz,1H),7.23(d,J＝8.3Hz,1H),7.10(t,J＝7.4Hz,1H),5.39(s,2H).
式Ⅰ-14m.p 133.3-137.6℃.MS(ESI)(m/z):319.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.35(s,1H),8.66(s,1H),8.26(d,J＝4.6Hz,1H),8.08(d,J＝8.3Hz,1H),7.68(d,J＝7.5Hz,1H),7.51(t,J＝7.8Hz,1H),7.41(d,J＝7.2Hz,2H),7.34(dd,J＝7.9,4.6Hz,1H),7.28(d,J＝8.3Hz,1H),7.15(d,J＝7.2Hz,2H),7.08(t,J＝7.4Hz,1H),5.18(s,2H),2.27(s,3H).
式Ⅰ-15m.p 139.1-140.5℃.MS(ESI)(m/z):330.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.40(s,1H),8.76(s,1H),8.27(d,J＝4.7Hz,1H),8.12(d,J＝8.3Hz,1H),7.85–7.78(m,2H),7.68(d,J＝7.8Hz,2H),7.62(d,J＝7.5Hz,1H),7.50(t,J＝7.8Hz,1H),7.36(dd,J＝8.2,4.6Hz,1H),7.22(d,J＝8.3Hz,1H),7.09(t,J＝7.4Hz,1H),5.33(s,2H).
式Ⅰ-16m.p 118.0-119.2℃.MS(ESI)(m/z):357.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.41(s,1H),8.76(d,J＝2.4Hz,1H),8.29(dd,J＝4.7,1.4Hz,1H),8.17–8.11(m,1H),7.66(dd,J＝7.5,1.6Hz,1H),7.59–7.48(m,3H),7.38(dd,J＝8.3,4.7Hz,1H),7.31(d,J＝8.3Hz,1H),7.25(td,J＝8.5,3.1Hz,1H),7.15(t,J＝7.4Hz,1H),5.30(s,2H).式Ⅰ-16的盐酸盐m.p 167.3-169.0℃.
式Ⅰ-18m.p 149.8-150.6℃.MS(ESI)(m/z):357.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.33(s,1H),8.72(d,J＝2.4Hz,1H),8.28(dd,J＝4.7,1.4Hz,1H),8.14–8.08(m,1H),7.66(dd,J＝7.6,1.7Hz,1H),7.63–7.51(m,3H),7.39–7.32(m,2H),7.21(t,J＝7.9Hz,1H),7.14(t,J＝7.5Hz,1H),5.36(s,2H).
式Ⅰ-19m.p 93.7-97.0℃.MS(ESI)(m/z):377.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.42(s,1H),8.76(d,J＝1.8Hz,1H),8.27(d,J＝4.2Hz,1H),8.18–8.12(m,1H),7.91(d,J＝8.2Hz,2H),7.67–7.60(m,3H),7.54–7.47(m,1H),7.35(dd,J＝8.3,4.7Hz,1H),7.24(d,J＝8.4Hz,1H),7.09(t,J＝7.5Hz,1H),5.31(s,2H),4.28(q,J＝7.1Hz,2H),1.28(t,J＝7.1Hz,3H).
式Ⅰ-20m.p 144.6-147.8℃.MS(ESI)(m/z):373.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.41(s,1H),8.77(d,J＝2.1Hz,1H),8.27(d,J＝4.6Hz,1H),8.11(d,J＝8.3Hz,1H),7.76–7.67(m,4H),7.67–7.61(m,1H),7.50(t,J＝7.9Hz,1H),7.35(dd,J＝8.3,4.7Hz,1H),7.24(d,J＝8.4Hz,1H),7.09(t,J＝7.5Hz,1H),5.34(s,2H).
实施例3：合成式Ⅰ-21，Ⅰ-22，Ⅰ-23，Ⅰ-24，Ⅰ-25，Ⅰ-26的化合物
一、化合物8-2a～8-2d的合成
Figure PCTCN2015085077-appb-000013
Figure PCTCN2015085077-appb-000014
将1.10g(8mmol,1.0eq)2-甲氧基苯甲醛(化合物10c)溶解于12ml无水乙醇中，加入0.32g(8mmol,1.0eq)96％NaBH4，室温反应3.0h，加少量水淬灭反应，蒸除乙醇，加入15ml水，用EA(20ml*2)萃取，再用饱和NaCl洗2次有机层，无水Na2SO4干燥，浓缩得到1.02g无色透明油状物(化合物13c)，收率92.3％。参照上述反应操作，分别从化合物10a、10b和10d制备得到化合物13a、13b和13d。
将1.02g(7.38mmol,1.0eq)化合物13c溶于40ml CH2Cl2，在冰水浴条件下加入0.84ml(8.90mmol,1.2eq)PBr3，室温反应1.0h后加入少量饱和NaHCO3洗有机相1次，再加入饱和NaCl溶液洗2次，无水Na2SO4干燥有机层，过滤蒸干，得到1.15g微红色油状物(化合物8-2c)，收率77.5％。该粗产物不需纯化可直接进行下步反应。参照上述反应操作，分别从化合物13a、13b和13d制备得到化合物8-2a、8-2b和8-2d。
二、化合物式Ⅰ-21，Ⅰ-23，Ⅰ-24和Ⅰ-25的合成
Figure PCTCN2015085077-appb-000015
Figure PCTCN2015085077-appb-000016
将0.32g(1.5mmol，1.0eq)2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)溶解于9ml丙酮中，之后加入0.42g(3.0mmol，2.0eq)碳酸钾，再加入0.30g(1.5mmol，1.0eq)2-甲氧基苄溴(化合物8-2c)，反应1.0h，蒸除丙酮，加入水，EA萃取，再用饱和NaCl洗2次有机层，无水Na2SO4干燥，浓缩得到黄褐色油状物。用PE：EA＝2:1的流动相对粗产品进行柱层析纯化，得到0.27g白色粉末状固体(式Ⅰ-24)，产率76.2％。
参照上述反应，从2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)和相应的取代苄溴(化合物8-2a、8-2b和8-2d)得到化合物式Ⅰ-21、式Ⅰ-23和式Ⅰ-25，具体为：2-((2-甲基-5-氟)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-21)；2-((3-甲氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-23)；2-((2,5-二甲氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-25)。
经检测，结构正确，检测结果如下：
式Ⅰ-21m.p 156.2-157.7℃.MS(ESI)(m/z):337.0(M+H)+.1H NMR(600MHz,DMSO-d6)δppm 11.05(d,J＝6.3Hz,1H),9.21(s,1H),8.59(d,J＝5.3Hz,1H),8.47(d,J＝7.7Hz,1H),7.90(dt,J＝9.1,4.7Hz,1H),7.63(dd,J＝7.5,1.7Hz,1H),7.60–7.55(m,1H),7.36(d,J＝8.4Hz,1H),7.28(dd,J＝10.0,2.7Hz,1H),7.23(dd,J＝8.2,6.0Hz,1H),7.14(t,J＝7.4Hz,1H),7.02(td,J＝8.5,2.8Hz,1H),5.24(s,2H),2.28(s,3H).式Ⅰ-21的盐酸盐m.p 156.2-157.7℃.
式Ⅰ-23m.p 168.6-171.0℃.MS(ESI)(m/z):335.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.37(s,1H),8.72(d,J＝2.3Hz,1H),8.28(dd,J＝4.7,1.3Hz,1H),8.11(d,J＝8.4Hz,1H),7.69(dd,J＝7.6,1.6Hz,1H),7.59–7.48(m,1H),7.36(dd,J＝8.3,4.7Hz,1H),7.29(dd,J＝12.8,5.0Hz,2H),7.18–7.03(m,3H),6.89(dd,J＝8.1,2.2Hz,1H),5.23(s,2H),3.67(s,3H).
式Ⅰ-24m.p 136.4-137.6℃.MS(ESI)(m/z):335.0(M+H)+.1H NMR(600MHz,DMSO-d6)δppm 10.34(s,1H),8.59(d,J＝2.4Hz,1H),8.28(dd,J＝4.7,1.4Hz,1H),8.09–8.01(m,1H),7.76(dd,J＝7.6,1.7Hz,1H),7.56–7.50(m,2H),7.38–7.31(m,3H),7.14–7.06(m,2H),6.93(td,J＝7.4,0.7Hz,1H),5.26(s,2H),3.78(s,3H).
式Ⅰ-25MS(ESI)(m/z):365.1(M+H)+.1H NMR(400MHz,DMSO-d6)δppm10.38(s,1H),8.65(s,1H),8.26(d,J＝4.1Hz,1H),8.08(d,J＝8.2Hz,1H),7.72(d,J＝7.4Hz,1H),7.52(t,J＝7.7Hz,1H),7.34(dd,J＝8.0,4.7Hz,1H),7.29(d,J＝8.3Hz,1H),7.11(dd,J＝15.2,4.9Hz,2H),6.96(d,J＝8.9Hz,1H),6.86(dd,J＝8.9,2.6Hz,1H),5.19(s,2H),3.71(s,3H),3.55(s,3H).
三、化合物8-2e和8-2f的合成
Figure PCTCN2015085077-appb-000017
Figure PCTCN2015085077-appb-000018
将1.47g(12mmol，1.0eq)3-羟基苯甲醛(化合物9b)溶于30ml丙酮，加入3.30g(24mmol，2.0eq)碳酸钾和1.34ml(12mmol，1.0eq)溴乙酸乙酯，室温搅拌过夜。除去溶剂，EA萃取10ml*2，饱和NaCl洗2次，无水Na2SO4干燥，浓缩得到黄色透明油状物粗产品，采用PE:EA＝6:1的流动相柱层析纯化，得到1.50g微黄色透明油状物(化合物10e)。参照上述方法，以水杨醛(化合物9a)和溴苄为原料制备得到化合物10f。
参照实施实例3中第一步合成化合物8-2a～8-2d的条件，分别从化合物10e和10f经硼氢化钠还原和三溴化磷溴代反应得到化合物8-2e和8-2f，直接用于下步反应。
四、化合物式Ⅰ-22和Ⅰ-26的合成
Figure PCTCN2015085077-appb-000019
Figure PCTCN2015085077-appb-000020
参照实施实例1中第五步合成化合物式Ⅰ-17的条件，从2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)和相应的取代苄溴(化合物8-2e和8-2f)得到化合物式Ⅰ-22和式Ⅰ-26，具体为：2-(3-((2-(吡啶-3-基氨基甲酰基)苯氧基)甲基)苯氧基)乙酸乙酯(式Ⅰ-22)；2-((2-苄氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-26)。
经检测，结构正确，检测结果如下：
式Ⅰ-22MS(ESI)(m/z):407.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm11.11(s,1H),9.27(s,1H),8.61(d,J＝5.3Hz,1H),8.54(d,J＝7.8Hz,1H),7.97(dd,J＝8.5,5.5Hz,1H),7.64(d,J＝7.5Hz,1H),7.53(t,J＝7.8Hz,1H),7.26(dt,J＝10.4,5.9Hz,2H),7.13–7.04(m,3H),6.82(d,J＝6.9Hz,1H),5.21(s,2H),4.71(s,2H),4.11(q,J＝7.1Hz,2H),1.16(t,J＝7.1Hz,3H).
式Ⅰ-26MS(ESI)(m/z):411.2(M+H)+.1H NMR(400MHz,DMSO-d6)δppm11.10(s,1H),9.21(s,1H),8.61(d,J＝5.1Hz,1H),8.44(d,J＝8.5Hz,1H),7.95(dd,J＝8.3,5.5Hz,1H),7.67(d,J＝7.4Hz,1H),7.49(dd,J＝13.5,7.0Hz,2H),7.38(d,J＝7.2Hz,2H),7.31–7.21(m,5H),7.08(t,J＝8.3Hz,2H),6.89(t,J＝7.4Hz,1H),5.29(s,2H),5.13(s,2H).
实施例4：合成式Ⅰ-27，Ⅰ-28，Ⅰ-29，Ⅰ-30，Ⅰ-31，Ⅰ-32和Ⅰ-33的化合物一、化合物8-3a～8-3g的合成
Figure PCTCN2015085077-appb-000021
Figure PCTCN2015085077-appb-000022
将0.30g(2mmol，1.0eq)2-乙基苯甲酸(化合物12a)溶于16ml干燥的THF，在冰浴条件下滴加4ml(4mmol，2.0eq)1M的BH3/THF溶液，滴毕在室温反应3.0h。除去溶剂，在冰水浴条件下加入1M HCl(aq)至不再产生气泡后，用EA萃取(10ml*2)，合并萃取液，用饱和NaHCO3洗2次，饱和NaCl洗2次，无水Na2SO4干燥，浓缩得到淡黄色油状物粗产品(化合物13g)，可不经纯化直接进行下步反应。参照上述还原反应的操作，分别对化合物12b～12g进行还原，得到相应的苄醇中间体化合物13h～13m。
参照实施实例3中第一步合成化合物8-2a～8-2d的条件，分别从化合物13g～13m经三溴化磷溴代反应得到化合物8-3a～8-3g，可不经纯化直接用于下步反应。
二、化合物式Ⅰ-27，Ⅰ-28，Ⅰ-29，Ⅰ-30，Ⅰ-31，Ⅰ-32和Ⅰ-33的合成
Figure PCTCN2015085077-appb-000023
Figure PCTCN2015085077-appb-000024
参照实施实例1中第五步合成化合物式Ⅰ-17的条件，从2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)和相应的取代苄溴(化合物8-3a～8-3g)得到化合物式Ⅰ-27～Ⅰ-33，具体为：2-((2-乙基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-27)；2-((4-乙基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-28)；2-((2,6-二甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-29)；2-((2-乙氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-30)；2-((2-甲氧基-5-氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-31)；2-((2-氯-6-氟)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-32)；2-((2,5-二氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-33)。
经检测，结构正确，检测结果如下：
式Ⅰ-27MS(ESI)(m/z):333.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm11.06(s,1H),9.18(d,J＝1.6Hz,1H),8.60(d,J＝5.3Hz,1H),8.44(d,J＝8.5Hz,1H),7.94(dd,J＝8.5,5.4Hz,1H),7.64(dd,J＝7.6,1.6Hz,1H),7.61–7.55(m,1H),7.49(d,J＝7.4Hz,1H),7.40(d,J＝8.3Hz,1H),7.26(dt,J＝13.9,6.5Hz,2H),7.19–7.10(m,2H),5.27(s,2H),2.68(q,J＝7.5Hz,2H),1.12(t,J＝7.5Hz,3H).
式Ⅰ-28m.p 164.8-167.1℃.MS(ESI)(m/z):333.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 11.17(s,1H),9.27(s,1H),8.64(d,J＝5.3Hz,1H),8.57(d,J＝8.6Hz,1H),8.00(dd,J＝8.4,5.6Hz,1H),7.63(d,J＝6.7Hz,1H),7.52(t,J＝7.8Hz,1H),7.40(d,J＝7.8Hz,2H),7.27(d,J＝8.4Hz,1H),7.16(d,J＝7.8Hz,2H),7.08(t,J＝7.5Hz,1H),5.19(s,2H),2.54(q,J＝7.5Hz,2H),1.11(t,J＝7.6Hz,3H).
式Ⅰ-29MS(ESI)(m/z):333.1(M+H)+.1H NMR(400MHz,DMSO-d6)δppm11.07(s,1H),9.08(d,J＝1.8Hz,1H),8.57(d,J＝5.2Hz,1H),8.30(d,J＝8.6Hz,1H),7.91(dd,J＝8.5,5.5Hz,1H),7.58(dd,J＝13.8,4.6Hz,2H),7.45(d,J＝8.2Hz,1H),7.11(dd,J＝13.3,7.1Hz,2H),7.00(d,J＝7.5Hz,2H),5.18(s,2H),2.31(s,6H).式Ⅰ-29盐酸盐m.p 145.7-148.5℃.
式Ⅰ-30MS(ESI)(m/z):349.2(M+H)+.1H NMR(400MHz,DMSO-d6)δppm10.34(s,1H),8.53(d,J＝1.7Hz,1H),8.25(d,J＝4.5Hz,1H),8.03(d,J＝8.4Hz,1H),7.77(dd,J＝7.6,1.4Hz,1H),7.57–7.47(m,2H),7.32(dd,J＝12.9,6.2Hz,3H),7.10(t,J＝7.5Hz,1H),7.02(d,J＝8.2Hz,1H),6.90(t,J＝7.4Hz,1H),5.24(s,2H),3.99(q,J＝6.9Hz,2H),1.20(t,J＝6.9Hz,3H).
式Ⅰ-31m.p 119.0-122.8℃.MS(ESI)(m/z):369.1(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.39(s,1H),8.74(d,J＝2.2Hz,1H),8.27(dd,J＝4.7,1.3Hz,1H),8.11(ddd,J＝8.3,2.3,1.5Hz,1H),7.67(dd,J＝7.6,1.6Hz,1H),7.56–7.48(m,2H),7.38–7.31(m,2H),7.27(d,J＝8.3Hz,1H),7.10(t,J＝7.5Hz,1H),7.04(d,J＝8.8Hz,1H),5.18(s,2H),3.77(s,3H).
式Ⅰ-32MS(ESI)(m/z):357.0(M+H)+.1H NMR(600MHz,DMSO-d6)δppm10.87(s,1H),9.11(s,1H),8.57(d,J＝4.8Hz,1H),8.38(s,1H),7.90(s,1H),7.66–7.58(m,2H),7.50–7.44(m,2H),7.36(d,J＝8.1Hz,1H),7.28(t,J＝8.9Hz,1H),7.17(t,J＝7.5Hz,1H),5.33(s,2H).式Ⅰ-32的盐酸盐m.p 177.3-179.1℃.
式Ⅰ-33MS(ESI)(m/z):372.9(M+H)+.1H NMR(600MHz,DMSO-d6)δppm11.18–11.07(m,1H),9.26(s,1H),8.65–8.48(m,2H),7.94(d,J＝4.7Hz,1H),7.70–7.63(m,2H),7.62–7.56(m,1H),7.53(d,J＝8.5Hz,1H),7.42(dd,J＝8.5,2.5Hz,1H),7.35(d,J＝8.3Hz,1H),7.17(t,J＝7.5Hz,1H),5.30(s,2H).式Ⅰ-33 的盐酸盐m.p 185.0-186.9℃.
实施例5：合成式Ⅰ-34，Ⅰ-35，Ⅰ-36，Ⅰ-37，Ⅰ-38，Ⅰ-39和Ⅰ-40的化合物一、化合物8-4a～8-4e的合成
Figure PCTCN2015085077-appb-000025
Figure PCTCN2015085077-appb-000026
将2.00g(16mmol，1.0eq)水杨醇(化合物11a)溶于100ml乙腈，加入5.20g(37.6mmol，2.35eq)碳酸钾和4.00g(24mmol，1.5eq)正溴己烷，在60℃反应10h，过滤，滤液浓缩得到粗产品，用PE:EA＝25:1至PE:EA＝9:1的流动相柱层析得到1.80g淡黄色透明油状物(化合物13q)，收率54.1％。参照上述方法，将化合物11a分别与1-溴-4-氯丁烷、1-溴-5-氯戊烷、1-溴-6-氯己烷和正溴庚烷反应得到化合物13n～13p和化合物13r。
参照实施实例3中第一步合成化合物8-2a～8-2d的条件，分别从化合物13n～13r经三溴化磷溴代反应得到化合物8-4a～8-4e，直接用于下步反应。
二、化合物式Ⅰ-34，Ⅰ-35，Ⅰ-36，Ⅰ-37和Ⅰ-38的合成
Figure PCTCN2015085077-appb-000027
Figure PCTCN2015085077-appb-000028
参照实施实例1中第五步合成化合物式Ⅰ-17的条件，从2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)和相应的取代苄溴(化合物8-4a～8-4e)得到化合物式Ⅰ-34～Ⅰ-38，具体为：2-(2-(4-氯丁氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-34)；2-(2-(5-氯戊氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-35)；2-(2-(6-氯己氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-36)；2-((2-己氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-37)；2-((2-庚氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-38)。
经检测，结构正确，检测结果如下：
式Ⅰ-34MS(ESI)(m/z):411.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm10.96(s,1H),9.15(d,J＝1.8Hz,1H),8.60(d,J＝5.1Hz,1H),8.40(d,J＝8.7Hz,1H),7.93(dd,J＝8.5,5.4Hz,1H),7.72(dd,J＝7.6,1.7Hz,1H),7.61–7.54(m,1H),7.50–7.45(m,1H),7.31(dd,J＝10.2,5.0Hz,2H),7.13(t,J＝7.3Hz,1H),7.05(d,J＝8.1Hz,1H),6.91(t,J＝7.3Hz,1H),5.26(s,2H),4.03(t,J＝5.7Hz,2H),3.64(t,J＝6.1Hz,2H),1.88–1.72(m,4H).式Ⅰ-34的盐酸盐m.p 127.4-128.1℃.
式Ⅰ-35MS(ESI)(m/z):425.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm10.95(s,1H),9.14(d,J＝1.7Hz,1H),8.60(d,J＝5.1Hz,1H),8.39(d,J＝9.2Hz,1H),7.93(dd,J＝8.5,5.4Hz,1H),7.73(dd,J＝7.6,1.6Hz,1H),7.61–7.54(m,1H),7.47(d,J＝6.3Hz,1H),7.32(dd,J＝10.7,4.8Hz,2H),7.14(t,J＝7.4Hz,1H),7.05(d,J＝8.1Hz,1H),6.91(t,J＝7.4Hz,1H),5.26(s,2H),3.99(t,J＝6.2Hz,2H),3.58(t,J＝6.6Hz,2H),1.76–1.62(m,4H),1.52–1.42(m,2H).
式Ⅰ-36MS(ESI)(m/z):439.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm10.90–10.79(m,1H),9.06(d,J＝12.3Hz,1H),8.56(d,J＝5.2Hz,1H),8.31(d,J＝8.5Hz,1H),7.87(t,J＝9.5Hz,1H),7.76(d,J＝7.6Hz,1H),7.62–7.55(m,1H),7.48(d,J＝7.4Hz,1H),7.33(t,J＝7.1Hz,2H),7.14(t,J＝7.5Hz,1H),7.05(d,J＝ 8.3Hz,1H),6.92(t,J＝7.4Hz,1H),5.27(s,2H),3.98(t,J＝6.3Hz,2H),3.57(t,J＝6.6Hz,2H),1.64(dd,J＝13.1,6.5Hz,4H),1.43–1.31(m,4H).式Ⅰ-36的盐酸盐m.p 113.7-115.4℃.
式Ⅰ-37MS(ESI)(m/z):405.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm11.04(s,1H),9.18(s,1H),8.62(s,1H),8.42(d,J＝6.6Hz,1H),7.97(s,1H),7.71(d,J＝6.8Hz,1H),7.60–7.42(m,2H),7.25(d,J＝7.6Hz,2H),7.17–6.83(m,3H),5.22(s,2H),3.92(s,2H),1.59(s,2H),1.27(dd,J＝17.1,8.5Hz,2H),1.18(d,J＝21.4Hz,4H),0.76(s,3H).
式Ⅰ-38MS(ESI)(m/z):419.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm11.00(s,1H),9.16(s,1H),8.61(d,J＝5.1Hz,1H),8.40(d,J＝8.4Hz,1H),7.95(dd,J＝8.4,5.5Hz,1H),7.72(dd,J＝7.6,1.4Hz,1H),7.54(t,J＝7.1Hz,1H),7.46(d,J＝6.8Hz,1H),7.27(t,J＝7.7Hz,2H),7.10(t,J＝7.4Hz,1H),7.01(d,J＝8.2Hz,1H),6.88(t,J＝7.4Hz,1H),5.23(s,2H),3.93(t,J＝6.3Hz,2H),1.66–1.54(m,2H),1.34–1.23(m,2H),1.23–1.06(m,6H),0.78(t,J＝6.9Hz,3H).
三、化合物8-4f和8-4g的合成
Figure PCTCN2015085077-appb-000029
Figure PCTCN2015085077-appb-000030
将4.70g(30mmol，1.0eq)5-氯水杨醛(化合物9c)溶于150ml乙腈，加入10.35g(75mmol，2.5eq)碳酸钾和7.43g(45mmol，1.5eq)正溴己烷，在60℃反应10h，过滤，滤液浓缩得到淡黄色透明油状物(化合物10g)。参照上述方法化合物9c和正溴庚烷反应得到化合物10h。参照实施实例3中第三步合成化合物8-2e和8-2f的条件，从化合物10g和10h经硼氢化钠还原和三溴化磷溴代反应得到化合物8-4f和8-4g，直接用于下步反应。
四、化合物式Ⅰ-39和Ⅰ-40的合成
Figure PCTCN2015085077-appb-000031
Figure PCTCN2015085077-appb-000032
参照实施实例1中第五步合成化合物式Ⅰ-17的条件，从2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)和相应的取代苄溴(化合物8-4f和8-4g)得到化合物式Ⅰ-39和Ⅰ-40，具体为：2-((5-氯-2-己氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-39)；2-((5-氯-2-庚氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-40)。
经检测，结构正确，检测结果如下：
式Ⅰ-39MS(ESI)(m/z):439.2(M+H)+.1H NMR(400MHz,DMSO-d6)δppm11.18(s,1H),9.27(d,J＝1.8Hz,1H),8.64(d,J＝5.4Hz,1H),8.56(d,J＝8.7Hz,1H),8.00(dd,J＝8.6,5.5Hz,1H),7.65(dd,J＝7.6,1.5Hz,1H),7.58–7.51(m,1H),7.45(d,J＝2.6Hz,1H),7.26(dd,J＝12.2,5.7Hz,2H),7.11(t,J＝7.5Hz,1H),7.02(d,J＝8.8Hz,1H),5.17(s,2H),3.95(t,J＝6.4Hz,2H),1.68–1.58(m,2H),1.32(dd,J＝14.4,7.1Hz,2H),1.22(dt,J＝7.1,4.7Hz,4H),0.80(t,J＝7.0Hz,3H).式Ⅰ-39的盐酸盐m.p 155.3-158.0℃.
式Ⅰ-40MS(ESI)(m/z):453.3(M+H)+.1H NMR(400MHz,DMSO-d6)δppm11.16(s,1H),9.26(d,J＝2.0Hz,1H),8.64(d,J＝5.3Hz,1H),8.54(d,J＝8.7Hz,1H),7.99(dd,J＝8.6,5.5Hz,1H),7.66(dd,J＝7.6,1.6Hz,1H),7.58–7.52(m,1H),7.46(d,J＝2.6Hz,1H),7.26(dd,J＝12.4,5.8Hz,2H),7.12(t,J＝7.5Hz,1H),7.02(d,J＝8.9Hz,1H),5.17(s,2H),3.95(t,J＝6.4Hz,2H),1.69–1.57(m,2H),1.38–1.28(m,2H),1.27–1.11(m,6H),0.80(t,J＝6.9Hz,3H).Ⅰ-40的盐酸盐m.p156.9-159.2℃.
实施例6：合成式Ⅰ-41，Ⅰ-42，Ⅰ-43，Ⅰ-44和Ⅰ-45的化合物
一、化合物13u的合成
Figure PCTCN2015085077-appb-000033
参照实施实例3中第一步合成化合物13a～13d的条件，以化合物10i为原料经硼氢化钠还原反应得到化合物13u，可不经纯化直接用于下步反应。
二、化合物式Ⅰ-41的合成
Figure PCTCN2015085077-appb-000034
将0.20g(0.75mmol，1.5eq)Ph3P和0.12ml(0.75mmol，1.5eq)DEAD溶于10ml干燥的THF，然后在冰浴条件下滴加0.11g(0.5mmol，1.0eq)2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)的5mlTHF溶液，之后再滴加0.10g(0.55mmol，1.1eq)化合物13u的5mlTHF溶液。滴毕，在室温反应2.0h后除去THF，向残余物中加入15mlEA和10ml水，并用稀盐酸调体系PH＝2，分出EA层后将水层用NaOH(aq)调至pH＝8～9，析出固体，过滤得到白色粉末状固体粗产物。用PE:EA＝2:1的流动相对粗产品进行柱层析纯化，得到白色粉末状固体0.04g，产率21.5％。
经检测，结构正确，检测结果如下：式Ⅰ-41m.p 70.2-72.9℃.MS(ESI)(m/z):373.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.41(s,1H),8.75(d,J＝2.3Hz,1H),8.25(dd,J＝4.7,1.4Hz,1H),8.09(ddd,J＝8.3,2.4,1.5Hz,1H),7.91(s,1H),7.79(d,J＝7.6Hz,1H),7.68–7.49(m,4H),7.36–7.26(m,2H),7.13–7.07 (m,1H),5.31(s,2H).
三、化合物式Ⅰ-42，Ⅰ-43和Ⅰ-44的合成
Figure PCTCN2015085077-appb-000035
Figure PCTCN2015085077-appb-000036
参照实施实例6中第二步合成化合物式Ⅰ-41的条件，从2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)和相应的取代苄醇得到化合物式Ⅰ-42～Ⅰ-44，具体为：2-((2-三氟甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-42)；2-((2-甲基-5-氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-43)；2-((2-甲基-3-氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-44)。
经检测，结构正确，检测结果如下：
式Ⅰ-42m.p 73.6-75.1℃.MS(ESI)(m/z):373.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.37(s,1H),8.67(d,J＝2.4Hz,1H),8.28(dd,J＝4.7,1.4Hz,1H),8.13–8.07(m,1H),7.88(d,J＝7.6Hz,1H),7.79(d,J＝7.6Hz,1H),7.71–7.61(m,2H),7.61–7.52(m,2H),7.36(dd,J＝8.3,4.7Hz,1H),7.27(d,J＝8.3Hz,1H),7.14(t,J＝7.4Hz,1H),5.40(s,2H).
式Ⅰ-43MS(ESI)(m/z):353.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm11.20(s,1H),9.26(s,1H),8.62(d,J＝5.3Hz,1H),8.54(d,J＝8.6Hz,1H),7.97(dd,J＝8.5,5.5Hz,1H),7.60(d,J＝7.6Hz,1H),7.55(d,J＝7.4Hz,1H),7.47(s,1H),7.36(d,J＝8.4Hz,1H),7.24–7.17(m,2H),7.12(t,J＝7.5Hz,1H),5.20(s,2H),2.27(s,3H).式Ⅰ-43的盐酸盐m.p 177.8-178.9℃.
式Ⅰ-44m.p 98.6-100.5℃.MS(ESI)(m/z):353.1(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.37(s,1H),9.00(s,1H),8.66(d,J＝1.9Hz,1H),8.26(d,J＝4.1Hz,1H),8.07(d,J＝8.7Hz,1H),7.64–7.57(m,2H),7.39(d,J＝7.9Hz,1H),7.37–7.31(m,2H),7.15(t,J＝7.8Hz,1H),7.09(t,J＝7.4Hz,1H),5.27(s,2H),2.33(s,3H).
四、化合物式Ⅰ-45的合成
参照实施实例6中第二步合成化合物式Ⅰ-41的条件，从2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)和1-萘基甲醇得到化合物2-((萘-1-基)甲氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-45)。
经检测，结构正确，检测结果如下：式Ⅰ-45m.p 91.4-93.9℃.MS(ESI)(m/z):355.1(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.23(s,1H),8.99(s,1H),8.31(d,J＝2.3,1H),8.25–8.14(m,2H),7.95(dd,J＝13.3,5.3,2H),7.84–7.78(m,1H),7.75–7.68(m,2H),7.64–7.43(m,4H),7.23(dd,J＝8.3,4.7,1H),7.13(t,J＝7.4,1H),5.72(s,2H).
实施例7：合成式Ⅰ-46，Ⅰ-47和Ⅰ-48的化合物
一、化合物式Ⅰ-46和Ⅰ-48的合成
Figure PCTCN2015085077-appb-000037
将0.63g(1.67mmol，1.0eq)化合物式Ⅰ-19溶解于7.5ml甲醇中，在冰水浴条件下缓慢加入7.5ml LiOH水溶液(0.45mol/L)，室温反应12h后，蒸除甲醇，在冰水浴条件下向剩余物中滴加1mol/L的HCl(aq)，调体系pH值至2～3，过滤干燥得到0.49g白色粉末状固体化合物(式Ⅰ-46)，产率为84.5％。
经检测，结构正确，检测结果为：m.p.256.6-258.0℃.MS(ESI)(m/z):349.0(M+H)+.347.0(M-H)-.1H NMR(400MHz,DMSO-d6)δppm 12.98(s,1H),10.40(s,1H),8.76(d,J＝2.1Hz,1H),8.29(dd,J＝4.7,1.2Hz,1H),8.16(d,J＝8.4 Hz,1H),7.92(d,J＝8.2Hz,2H),7.74–7.59(m,3H),7.58–7.46(m,1H),7.38(dd,J＝8.3,4.7Hz,1H),7.28(d,J＝8.3Hz,1H),7.12(t,J＝7.4Hz,1H),5.34(s,2H).
Figure PCTCN2015085077-appb-000038
将0.20g(0.49mmol，1.0eq)化合物式Ⅰ-22溶解于3.0ml甲醇中，在冰水浴条件下缓慢加入3.0ml LiOH水溶液(0.45mol/L)，室温反应0.5h后，蒸除甲醇，在冰水浴条件下向剩余物中滴加1mol/L的HCl(aq)，调体系pH值至3～4，过滤干燥得到0.10g白色粉末状固体化合物式Ⅰ-48，产率为53.8％。
经检测，结构正确，检测结果为：m.p 203.6-205.9℃.MS(ESI)(m/z):379.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.42(s,1H),8.79(s,1H),8.28(s,1H),8.10(d,J＝7.3Hz,1H),7.67(d,J＝6.9Hz,1H),7.50(d,J＝7.1Hz,1H),7.37(s,1H),7.26(d,J＝5.8Hz,2H),7.18–7.02(m,3H),6.85(d,J＝7.4Hz,1H),5.20(s,2H),4.63(s,2H).
二、化合物式Ⅰ-47的合成
Figure PCTCN2015085077-appb-000039
参照实施实例3中第三步合成化合物8-2e和8-2f的条件，首先化合物9a与溴乙酸乙酯进行亲核取代制备得到10j，再经硼氢化钠还原和三溴化磷溴代得到化合物8-5，可直接用于下步反应。
Figure PCTCN2015085077-appb-000040
参照实施实例1中第五步合成化合物式Ⅰ-17的条件，从2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)和上述所得的取代苄溴(化合物8-5)得到化合物14，再参照实施实例7第一步中化合物式Ⅰ-48的制备，将化合物14经LiOH水解合成化合物式Ⅰ-47。
经检测，结构正确，检测结果为：m.p 179.9-183.8℃.MS(ESI)(m/z):379.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 13.14(s,1H),10.62(s,1H),8.89(d,J＝1.9Hz,1H),8.43(dd,J＝5.0,1.1Hz,1H),8.22(d,J＝8.4Hz,1H),7.74(dd,J＝7.6,1.7Hz,1H),7.62(dd,J＝8.4,5.0Hz,1H),7.59–7.48(m,2H),7.36–7.28(m,2H),7.13(t,J＝7.5Hz,1H),7.00(d,J＝8.2Hz,1H),6.94(t,J＝7.4Hz,1H),5.33(s,2H),4.77(s,2H).
实施例8：合成式Ⅰ-49，Ⅰ-50和Ⅰ-51的化合物
一、化合物8-6a和8-6b的合成
Figure PCTCN2015085077-appb-000041
Figure PCTCN2015085077-appb-000042
参照实施实例3中第一步中合成化合物13a～13d的条件，从化合物9c经硼氢化钠还原反应得到化合物11b。
将上述所得的0.48g(3mmol，1.0eq)4-氯-2-(羟甲基)苯酚(化合物11b)溶于 7.5mlDMF，加入2.49g(18mmol，6.0eq)碳酸钾和2.75g(18mmol，6.0eq)1-溴-3-甲氧基丙烷，在100℃反应10h，向体系加入20ml水，EA萃取15ml*2，萃取液经饱和NaCl洗2次，无水Na2SO4干燥，浓缩得到黄色透明油状物粗产品，用PE:EA＝10:1的流动相柱层析，得到0.33g淡黄色透明油状物(化合物13w)，收率48％。参照上述方法，以化合物11b与1-溴-2-甲氧基乙烷为原料，制备得到化合物13x。
参照实施实例5中第一步中合成化合物8-4a～8-4e的条件，化合物13w和13x分别经三溴化磷溴代反应得到化合物8-6a～8-6b，可直接用于下步反应。
二、化合物式Ⅰ-49和Ⅰ-50的合成
Figure PCTCN2015085077-appb-000043
Figure PCTCN2015085077-appb-000044
参照实施实例1中第五步合成化合物式Ⅰ-17的条件，从2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)和相应的取代苄溴(化合物8-6a和8-6b)得到化合物式Ⅰ-49和Ⅰ-50，具体为：2-((5-氯-2-(3-甲氧丙氧基))苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-49)；2-((5-氯-2-(2-甲氧乙氧基))苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-50)。
经检测，结构正确，检测结果如下：
式Ⅰ-49MS(ESI)(m/z):427.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm10.36(s,1H),8.67(d,J＝2.3Hz,1H),8.26(dd,J＝4.7,1.4Hz,1H),8.12–8.06(m,1H),7.70(dd,J＝7.6,1.7Hz,1H),7.53(dd,J＝12.3,2.2Hz,2H),7.37–7.30(m, 2H),7.28(d,J＝8.3Hz,1H),7.11(t,J＝7.4Hz,1H),7.05(d,J＝8.8Hz,1H),5.19(s,2H),4.01(t,J＝6.2Hz,2H),3.36(t,J＝6.2Hz,2H),3.13(s,3H),1.87(p,J＝6.2Hz,2H).
式Ⅰ-50MS(ESI)(m/z):413.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm10.35(s,1H),8.71(d,J＝2.3Hz,1H),8.27(dd,J＝4.7,1.4Hz,1H),8.10(ddd,J＝8.3,2.4,1.5Hz,1H),7.69(dd,J＝7.6,1.7Hz,1H),7.55(d,J＝2.5Hz,1H),7.53–7.49(m,1H),7.37–7.34(m,1H),7.32(dd,J＝8.9,2.6Hz,1H),7.25(d,J＝8.3Hz,1H),7.12(d,J＝7.5Hz,1H),7.07(d,J＝8.9Hz,1H),5.19(s,2H),4.11(t,J＝4.4Hz,2H),3.59(t,J＝4.4Hz,2H),3.21(s,3H).
三、化合物式Ⅰ-51的合成
Figure PCTCN2015085077-appb-000045
将3.14g(20mmol，1.0eq)5-氯-2-羟基苯甲醛(化合物9c)溶于100ml丙酮，加入11.0g(80mmol，4.0eq)碳酸钾和3.62ml(48mmol，2.4eq)甲氧甲基氯(MOMCl)，在30℃反应1.0h，过滤，滤液浓缩得粗产物。用PE:EA＝25:1的流动相柱层析纯化粗产物，得到1.50g无色透明油状物(化合物10k)，收率为37.3％。
参照实施实例3中第三步合成化合物8-2e和8-2f的条件，化合物10k经硼氢化钠还原得到化合物13y，可直接用于下步反应。
将0.80g(3.0mmol，1.5eq)Ph3P和0.48ml(3.0mmol，1.5eq)DEAD溶于20ml干燥的THF，然后在冰浴条件下滴加0.43g(2.0mmol，1.0eq)2-羟基-N-(吡啶-3-基)苯甲酰胺(化合物7)的10mlTHF溶液，之后再滴加0.41g(2.0mmol，1.0eq)化合物13y的10mlTHF溶液。滴毕，在室温反应2.0h后除去THF得到黄褐色 油状物。用PE:EA＝2:1的流动相对上述油状物进行柱层析纯化，得到0.74g白色固体(化合物15)，产率92.5％。
将0.53g(1.32mmol,1.0eq)化合物15溶于24ml甲醇，在冰水浴条件下向其中滴加0.24ml HCl(con)，滴加完毕，加热至55℃反应10h，蒸除甲醇得到0.39g白色固体(化合物16)，收率83.0％。
将0.13g(0.50mmol，1.5eq)Ph3P和0.08ml(0.50mmol，1.5eq)DEAD溶于2ml干燥的THF，然后在冰浴条件下滴加0.12g(0.33mmol，1.0eq)化合物16的1ml THF溶液，之后再滴加0.04g(0.33mmol，1.0eq)2-吗啡啉乙醇的1ml THF溶液。滴毕，在室温反应2.0h后除去THF得到黄色油状物。用PE:EA＝1:1的流动相对上述油状物进行柱层析纯化，得到40mg白色蜡状固体(化合物式Ⅰ-51)，产率25.3％。
经检测，结构正确，检测结果如下：式Ⅰ-51MS(ESI)(m/z):468.0(M+H)+.1H NMR(400MHz,CDCl3)δppm 10.02(s,1H),8.32–8.18(m,3H),8.09(s,1H),7.58–7.48(m,1H),7.47–7.30(m,2H),7.25–7.21(m,1H),7.15(dd,J＝16.4,8.1Hz,2H),6.98(d,J＝8.7Hz,1H),5.20(s,2H),4.08(t,J＝5.6Hz,2H),3.54–3.43(m,4H),2.60(t,J＝5.6Hz,2H),2.38–2.26(m,4H).
实施例9：合成式Ⅰ-52和式Ⅰ-53的化合物
Figure PCTCN2015085077-appb-000046
参照实施实例1中第三步由化合物5a制备化合物6a的方法，将化合物5a分别与2-氨基吡啶和5-氨基嘧啶反应，得到化合物式Ⅰ-52和式Ⅰ-53，具体为：2-苄氧基-N-(吡啶-2-基)苯甲酰胺(式Ⅰ-52)；2-苄氧基-N-(嘧啶-5-基)苯甲酰胺(式Ⅰ-53)。
经检测，结构正确，检测结果如下：
式Ⅰ-52m.p 112.3-114.9℃.MS(ESI)(m/z):305.2(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.58(s,1H),8.30(dd,J＝4.8,1.0Hz,1H),8.22(d,J＝8.3Hz,1H),7.86(dd,J＝7.7,1.7Hz,1H),7.84–7.77(m,1H),7.53(dd,J＝13.9,4.5Hz,3H),7.39–7.28(m,4H),7.12(dt,J＝12.3,4.1Hz,2H),5.34(s,2H).
式Ⅰ-53m.p 145.3-148.9℃.MS(ESI)(m/z):306.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.53(s,1H),9.00(s,2H),8.88(s,1H),7.68(dd,J＝7.6,1.6,1H),7.57–7.45(m,3H),7.33(ddd,J＝16.5,10.5,5.3,4H),7.10(t,J＝7.5,1H),5.24(s,2H).
实施例10：合成式Ⅰ-54，式Ⅰ-55，式Ⅰ-56，式Ⅰ-57，式Ⅰ-58，式Ⅰ-59和式Ⅰ-60的化合物
Figure PCTCN2015085077-appb-000047
Figure PCTCN2015085077-appb-000048
将0.86g(5mmol,1.0eq)5-氯水杨酸(化合物1a)溶于7ml甲醇中，在冰浴条 件下向上述溶液中滴加0.90g(7mmol,1.4eq)二氯亚砜。滴毕，回流反应7.0h，冷至室温，除去甲醇，得到淡黄色油状物0.90g(化合物2b)，该粗产物可不经纯化直接进行下步反应。参照该方法，分别从4-氯水杨酸(化合物1b)、5-硝基水杨酸(化合物1c)、4-溴水杨酸(化合物1d)和5-甲氧基水杨酸(化合物1e)制备得到相应的水杨酸甲酯化合物2c～2f。
参照实施实例1中第一步由化合物2a制备化合物3a的方法，以上步反应所得的化合物2b～2f以及市售的4-甲氧基水杨酸甲酯(化合物2g)分别与取代溴苄反应得到化合物3b～3h。再参照实施实例1中第二步由化合物3a制备化合物4a的方法，将化合物3b～3h分别水解得到化合物4b～4h。参照实施实例1中第三步由化合物4a制备化合物6a的方法，将化合物4b～4h分别经酰氯化和酰胺化反应得到化合物式式Ⅰ-54～式Ⅰ-60，具体为：5-氯-2-((2,6-二氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-54)；5-氯-2-((2-氯-5-氟)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-55)；4-氯-2-(2-氯苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-56)；2-(2-氯苄氧基)-5-硝基-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-57)；4-溴-2-(2-氯苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-58)；2-(2-氯苄氧基)-5-甲氧基-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-59)；2-(2-氯苄氧基)-4-甲氧基-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-60)。
经检测，结构正确，检测结果如下：
式Ⅰ-54m.p 129.2-131.9℃.MS(ESI)(m/z):407.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.27(s,1H),8.54(d,J＝2.3Hz,1H),8.24(dd,J＝4.6,1.2Hz,1H),7.99(d,J＝8.3Hz,1H),7.64(d,J＝2.6Hz,1H),7.61(dd,J＝8.7,2.7Hz,1H),7.53–7.40(m,4H),7.31(dd,J＝8.3,4.7Hz,1H),5.37(s,2H).
式Ⅰ-55m.p 153.3-154.7℃.MS(ESI)(m/z):391.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.51(s,1H),8.75(d,J＝1.4Hz,1H),8.29(d,J＝4.2Hz,1H),8.11(d,J＝8.3Hz,1H),7.65(d,J＝2.5Hz,1H),7.57(dd,J＝8.8,2.6Hz,1H),7.52(dd,J＝8.8,5.1Hz,1H),7.45(dd,J＝9.4,2.9Hz,1H),7.36(dd,J＝8.3,4.8Hz,1H),7.32(d,J＝8.9Hz,1H),7.21(td,J＝8.5,3.0Hz,1H),5.27(s,2H).
式Ⅰ-56m.p 117.6-121.7℃.MS(ESI)(m/z):373.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.32(s,1H),8.62(d,J＝2.3Hz,1H),8.26(dd,J＝4.6,1.1Hz,1H),8.06(d,J＝8.4Hz,1H),7.68(d,J＝8.2Hz,1H),7.65(d,J＝7.7Hz,1H),7.49(d,J＝7.9Hz,1H),7.47(d,J＝1.5Hz,1H),7.40–7.27(m,3H),7.19(dd,J＝ 8.2,1.5Hz,1H),5.34(s,2H).
式Ⅰ-57m.p 175.7-177.9℃.MS(ESI)(m/z):384.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.56(s,1H),8.69(d,J＝2.3Hz,1H),8.46(d,J＝2.9Hz,1H),8.42(dd,J＝9.1,2.9Hz,1H),8.31–8.27(m,1H),8.08(d,J＝8.4Hz,1H),7.67–7.61(m,1H),7.55(d,J＝9.2Hz,1H),7.50(d,J＝7.9Hz,1H),7.37(dd,J＝7.8,5.6Hz,2H),7.31(t,J＝7.4Hz,1H),5.45(s,2H).
式Ⅰ-58m.p 117.6-120.1℃.MS(ESI)(m/z):417.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.32(s,1H),8.62(d,J＝2.3Hz,1H),8.26(dd,J＝4.7,1.4Hz,1H),8.05(ddd,J＝8.3,2.3,1.5Hz,1H),7.64(dd,J＝7.6,1.5Hz,1H),7.59(t,J＝5.2Hz,2H),7.49(dd,J＝7.9,1.1Hz,1H),7.34(qdd,J＝15.9,7.5,1.4Hz,4H),5.33(s,2H).
式Ⅰ-59m.p 97.3-99.8℃.MS(ESI)(m/z):369.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.36(s,1H),8.64(d,J＝2.3Hz,1H),8.29–8.23(m,1H),8.07(d,J＝8.5Hz,1H),7.63(d,J＝6.4Hz,1H),7.48(d,J＝7.9Hz,1H),7.39–7.22(m,5H),7.10(dd,J＝9.0,3.1Hz,1H),5.25(s,2H),3.75(s,3H).
式Ⅰ-60m.p 122.1-124.4℃.MS(ESI)(m/z):369.0(M+H)+.1H NMR(400MHz,DMSO-d6)δppm 10.05(s,1H),8.46(d,J＝2.3Hz,1H),8.23(dd,J＝4.7,1.3Hz,1H),8.01(d,J＝8.4Hz,1H),7.82–7.76(m,1H),7.71(dd,J＝7.4,1.3Hz,1H),7.53(dd,J＝7.9,1.0Hz,1H),7.41(td,J＝7.7,1.7Hz,1H),7.35(td,J＝7.5,1.1Hz,1H),7.30(dd,J＝8.3,4.7Hz,1H),6.86(d,J＝2.1Hz,1H),6.71(dd,J＝8.7,2.2Hz,1H),5.37(s,2H),3.84(s,3H).
实施例11：制备式Ⅰ-16，Ⅰ-21，Ⅰ-24，Ⅰ-27，Ⅰ-29，Ⅰ-32，Ⅰ-33，Ⅰ-34，Ⅰ-36，Ⅰ-39，Ⅰ-40和Ⅰ-43化合物的盐酸盐
一、化合物式Ⅰ-24的盐酸盐的制备
将0.33g(1.0mmol,1.0eq)化合物式Ⅰ-24溶于10ml干燥的乙酸乙酯中，在冰水浴条件下向上述溶液中滴加1.2ml(1.5mmol,1.5eq)HCl(g)的乙酸乙酯溶液(c＝1.25mol/L)，反应10min后抽滤干燥得到0.24g白色粉末状固体，收率64.9％。式Ⅰ-24的盐酸盐m.p 154.4-157.2℃.
二、化合物式Ⅰ-27的盐酸盐的制备
将0.42g(1.26mmol,1.0eq)化合物式Ⅰ-27溶于13ml干燥的乙酸乙酯中，在冰水浴条件下向上述溶液中滴加1.5ml(1.75mmol,1.5eq)HCl(g)的乙酸乙酯溶液(c＝1.25mol/L)，反应10min后抽滤干燥得到0.33g白色粉末状固体，收率70.8％。式Ⅰ-27的盐酸盐m.p 158.0-161.3℃.
三、化合物式Ⅰ-40的盐酸盐的制备
将0.23g(0.5mmol,1.0eq)化合物式Ⅰ-40溶于5ml干燥的乙酸乙酯中，在冰水浴条件下向上述溶液中滴加0.6ml(0.75mmol,1.5eq)HCl(g)的乙酸乙酯溶液(c＝1.25mol/L)，反应10min后抽滤干燥得到0.16g白色粉末状固体，收率64.0％。式Ⅰ-40的盐酸盐m.p 156.9-159.2℃.
参照上述方法，分别制备得到化合物式Ⅰ-16，Ⅰ-21，Ⅰ-29，Ⅰ-32，Ⅰ-33，Ⅰ-34，Ⅰ-36，Ⅰ-39和Ⅰ-43的盐酸盐。
实施例12：测定2-烷氧基苯甲酰芳胺类化合物体外对鞘磷脂合酶2的抑制作用实验仪器与材料
1.电热恒温水浴锅(上海一恒科技有限公司)
2.旋涡混合器(上海精科实业有限公司型号XW-80A)
3.高速离心机(型号Eppendorf 5804R)
4.高效液相色谱Agilent 1100(Agilent Technologies,Palo Alto,CA,USA)，配四元泵，真空脱气，FLD荧光检测器。
5.HPLC色谱柱：Agilent C18RP(250mm×4.6mm 5μm)。
6.DMPC.购自Santa Cruz(USA)，用乙醇溶解，浓度为40mM。
7.C6-NBD-Ceramide(6-((N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoyl)-sphi ngosine).购自Santa Cruz(USA).用乙醇溶解，浓度为1.16mM。
8.C6-NBD-SM.(N-(N-(7-nitro-2,1,3-benzoxadiazol-4-yl)-epsilon-aminohexanoyl)sphingosylph osphoryl choline).购自Sigma-Aldrich(USA)，用乙醇溶解，浓度为1mg/mL。
9.所用有机溶剂均购于上海国药试剂公司，甲醇为色谱纯，水为Milli-Q泵过滤，去离子化，经0.22μm膜超滤的超纯水，其他生物耗材购于国产公司。
10.SMS酶提取匀浆缓冲液(Buffer1)的配置：(50mM三羟甲基氨基甲烷盐酸盐 pH 7.4,5％无水蔗糖,1mM乙二胺四乙酸)：取1.2114g三羟甲基氨基甲烷盐酸盐tris(hydroxymethyl)aminomethane hydrochloride,Tris-HCl)溶解于100mL蒸馏水中，加入84mL 0.1mol/L的盐酸，将混合液定容至200mL。称取无水蔗糖(sucrose)10g，乙二胺四乙酸(EDTA)58.45mg，溶解于上述溶液中。
11.SMS测试缓冲液(Buffer2)的配置：(100mM羟乙基呱嗪乙硫磺酸,30mM MnCl2,3％脱脂牛血清蛋白)：取羟乙基哌嗪乙硫磺酸(4-(2-hydroxyethyl)-1-peperazineethanesulfonic acid,Hepes)1.1916g，MnCl2·4H2O0.2969g，脱脂牛血清蛋白(fatty acid free BSA,Bovine serum albumin)0.3g，蒸馏水溶解，定容至50mL。
12.配制待测化合物溶液：精确称取各待测化合物1～2mg，首先加入适量的DMSO精确配制成6mM的储备溶液。取一定体积的待测化合物的DMSO储备溶液，再加入适量体积的DMSO将待测化合物稀释至所需浓度的溶液。
13.SMS2高表达的昆虫细胞匀浆由复旦大学生物医学研究院徐彦辉课题组制备。
一、2-烷氧基苯甲酰芳胺类化合物对鞘磷脂合酶2的抑制活性检测
将250μL三蒸水、30μL Buffer2、4μL SMS2高表达的昆虫细胞匀浆液(总蛋白含量为0.5μg/μL)和10μL待测化合物的DMSO溶液或者空白的DMSO溶液，加至1.5mL的eppendorf管中，涡旋振荡30秒，在37℃水浴中孵育0.5h。之后加入3μL DMPC的乙醇溶液(40mM)和3μL C6-NBD-Ceramide的乙醇溶液(1.16mM)，涡旋振荡30秒后，在37℃水浴下孵育2.0h。取出，加入600μL的无水乙醇，涡旋振荡1分钟。在10000rpm离心10min后取出600μL上清液于4℃下储存，供高效液相色谱分析备用。
参考文献(Xiaodong Deng；Hong Sun；et al.Analytical Letters,2012,45:12,1581-1589)，采用与文献相同的高效液相色谱方法进行上述所制备样品的荧光定量分析。分析并记录空白组、阳性对照组(化合物D2)及待测化合物组样品中C6-NBD-SM与C6-NBD-Ceramide在对应HPLC谱图上的峰面积Asm值和Acer值，每个化合物平行测定3次，依据下述公式计算出待测化合物的抑制率，
Figure PCTCN2015085077-appb-000049
依据上述方法，测定化合物式Ⅰ-1～Ⅰ-60体外对鞘磷脂合酶2的抑制活性， 活性测试结果表明，所述的2-烷氧基苯甲酰芳胺类化合物具有亚微摩尔级的活性；活性结果为：
1)2-(2-氟苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-1)在5μM下的抑制率为53.8％；
2)2-(3-氟苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-2)在5μM下的抑制率为69.3％；
3)2-(3-硝基苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-3)在50μM下的抑制率为64.6％；
4)2-(3-氰基苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-4)在50μM下的抑制率为66.0％；
5)2-((4-甲氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-5)在50μM下的抑制率为23.0％；
6)2-(2-氰基苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-6)在50μM下的抑制率为50.0％；
7)2-(3-氯苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-7)在5μM下的抑制率为70.6％；
8)2-(3-溴苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-8)在50μM下的抑制率为67.1％；
9)2-(4-溴苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-9)在50μM下的抑制率为14.7％；
10)2-((3-甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-10)在50μM下的抑制率为69.5％；
11)2-((2-甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-11)在5μM下的抑制率为71.3％；
12)2-((2-硝基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-12)在50μM下的抑制率为35.5％；
13)2-((4-硝基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-13)在50μM下的抑制率为11.8％；
14)2-((4-甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-14)在50μM下的抑 制率为69.0％；
15)2-((4-氰基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-15)在50μM下的抑制率为15.0％；
16)2-((2-氯-5-氟)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-16)在5μM下的抑制率为75.7％。
17)2-((2,6-二氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-17)在5μM下的抑制率为77.2％。
18)2-((2-氟-3-氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-18)在5μM下的抑制率为55.2％。
19)4-((2-(吡啶-3-基氨基甲酰基)苯氧基)甲基)苯甲酸乙酯(式Ⅰ-19)在10μM下的抑制率为2.9％。
20)2-((4-三氟甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-20)在10μM下的抑制率为3.9％。
21)2-((2-甲基-5-氟)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-21)在10μM下的抑制率为84.7％。
22)2-(3-((2-(吡啶-3-基氨基甲酰基)苯氧基)甲基)苯氧基)乙酸乙酯(式Ⅰ-22)在10μM下的抑制率为15.3％。
23)2-((3-甲氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-23)在10μM下的抑制率为59.8％。
24)2-((2-甲氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-24)在10μM下的抑制率为89.4％。
25)2-((2,5-二甲氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-25)在10μM下的抑制率为78.9％。
26)2-((2-苄氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-26)在10μM下的抑制率为76.9％。
27)2-((2-乙基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-27)在5μM下的抑制率为78.4％。
28)2-((4-乙基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-28)在10μM下的抑制率为10.1％。
29)2-((2,6-二甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-29)在10μM下的抑制率为88.8％。
30)2-((2-乙氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-30)在10μM下的抑制率为86.3％。
31)2-((2-甲氧基-5-氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-31)在10μM下的抑制率为92.4％。
32)2-((2-氯-6-氟)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-32)在10μM下的抑制率为82.3％。
33)2-((2,5-二氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-33)在10μM下的抑制率为87.9％。
34)2-(2-(4-氯丁氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-34)在10μM下的抑制率为85.5％。
35)2-(2-(5-氯戊氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-35)在10μM下的抑制率为91.3％。
36)2-(2-(6-氯己氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-36)在10μM下的抑制率为91.5％。
37)2-((2-己氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-37)在10μM下的抑制率为90.2％。
38)2-((2-庚氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-38)在10μM下的抑制率为90.5％。
39)2-((5-氯-2-己氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-39)在5μM下的抑制率为85.5％。
40)2-((5-氯-2-庚氧基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-40)在5μM下的抑制率为87.1％。
41)2-((3-三氟甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-41)在10μM下的抑制率为10.0％。
42)2-((2-三氟甲基)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-42)在5μM下的抑制率为65.5％。
43)2-((2-甲基-5-氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-43)在5μM下 的抑制率为74.8％。
44)2-((2-甲基-3-氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-44)在5μM下的抑制率为47.0％。
45)2-((萘-1-基)甲氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-45)在10μM下的抑制率为78.0％。
46)4-((2-(吡啶-3-基氨基甲酰基)苯氧基)甲基)苯甲酸(式Ⅰ-46)在10μM下的抑制率为2.6％。
47)2-(2-((2-(吡啶-3-基氨基甲酰基)苯氧基)甲基)苯氧基)乙酸(式Ⅰ-47)在10μM下的抑制率为7.4％。
48)2-(3-((2-(吡啶-3-基氨基甲酰基)苯氧基)甲基)苯氧基)乙酸(式Ⅰ-48)在10μM下的抑制率为3.0％。
49)2-((5-氯-2-(3-甲氧丙氧基))苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-49)在10μM下的抑制率为75.3％。
50)2-((5-氯-2-(2-甲氧乙氧基))苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-50)在10μM下的抑制率为54.2％。
51)2-((5-氯-2-(2-吗啡啉乙氧基))苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-51)在10μM下的抑制率为24.9％。
52)2-苄氧基-N-(吡啶-2-基)苯甲酰胺(式Ⅰ-52)在100μM下的抑制率为60.1％。
53)2-苄氧基-N-(嘧啶-5-基)苯甲酰胺(式Ⅰ-53)在10μM下的抑制率为38.4％。
54)5-氯-2-((2,6-二氯)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-54)在10μM下的抑制率为42.3％。
55)5-氯-2-((2-氯-5-氟)苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-55)在10μM下的抑制率为31.7％。
56)4-氯-2-(2-氯苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-56)在10μM下的抑制率为20.0％。
57)2-(2-氯苄氧基)-5-硝基-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-57)在10μM下的抑制率为1.7％。
58)4-溴-2-(2-氯苄氧基)-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-58)在10μM下的抑制率为19.4％。
59)2-(2-氯苄氧基)-5-甲氧基-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-59)在10μM下的抑制率为7.2％。
60)2-(2-氯苄氧基)-4-甲氧基-N-(吡啶-3-基)苯甲酰胺(式Ⅰ-60)在10μM下的抑制率为13.3％。
二、2-烷氧基苯甲酰芳胺类化合物Ⅰ-1～Ⅰ-60对鞘磷脂合酶2的半数抑制浓度(IC50)测定
将待测化合物6mM的DMSO储备溶液进行梯度稀释，配制5个浓度梯度的溶液并分别取10μL添加至实施例12第一步的测试体系中，按照实施例12第一步的方法制备样品并经高效液相色谱方法测定化合物在5个浓度下的Asm值，分别计算5个浓度下的抑制率并拟合得到半数抑制浓度IC50，每个化合物平行测定3组。化合物式Ⅰ-1～Ⅰ-60对SMS2的半数抑制浓度(IC50)如表1所示：
表1.化合物式Ⅰ-1～Ⅰ-60对鞘磷脂合酶2的半数抑制浓度
式Ⅰ IC50(μM)
D609 375a
D2 56.2b
Ⅰ-1 3.5
Ⅰ-2 1.6
Ⅰ-3 >50
Ⅰ-4 60.7
Ⅰ-5 >100
Ⅰ-6 31.8
Ⅰ-7 1.4
Ⅰ-8 >50
Ⅰ-9 >100
Ⅰ-10 >25
Ⅰ-11 1.5
Ⅰ-12 >50
Ⅰ-13 >100
Ⅰ-14 >25
Ⅰ-15 >100
Ⅰ-16 0.7
Ⅰ-17 0.7
Ⅰ-18 3.1
Ⅰ-19 >100
Ⅰ-20 >100
Ⅰ-21 0.7
Ⅰ-22 >100
Ⅰ-23 5.7
Ⅰ-24 0.8
Ⅰ-25 2.8
Ⅰ-26 2.2
Ⅰ-27 0.9
Ⅰ-28 >100
Ⅰ-29 0.9
Ⅰ-30 1.2
Ⅰ-31 0.7
Ⅰ-32 1.5
Ⅰ-33 1.0
Ⅰ-34 1.4
Ⅰ-35 0.7
Ⅰ-36 0.5
Ⅰ-37 0.7
Ⅰ-38 0.5
Ⅰ-39 0.5
Ⅰ-40 0.4
Ⅰ-41 >100
Ⅰ-42 2.1
Ⅰ-43 1.1
Ⅰ-44 3.8
Ⅰ-45 2.6
Ⅰ-46 >100
Ⅰ-47 >100
Ⅰ-48 >100
Ⅰ-49 4.1
Ⅰ-50 11.6
Ⅰ-51 >50
Ⅰ-52 11.7
Ⅰ-53 >25
Ⅰ-54 >25
Ⅰ-55 >25
Ⅰ-56 >50
Ⅰ-57 >100
Ⅰ-58 >50
Ⅰ-59 >100
Ⅰ-60 >50
a参考文献值.b实验测定值.

Claims (7)

  1. 式(I)结构所示的2-烷氧基苯甲酰芳胺类化合物或其药学上可接受的盐；
    Figure PCTCN2015085077-appb-100001
    式中，
    X、Y和Z选自C原子或者N原子，但X、Y和Z不可同时选自C原子；
    G选自苯基、取代苯基和萘基；当Y与X或者Y与Z同时选自C原子时，G选自取代苯基或者萘基。
    R选自H，卤素，硝基或者C1-C4的烷氧基。
  2. 按权利要求1所述的2-烷氧基苯甲酰芳胺类化合物或其药学上可接受的盐，其特征在于：所述G为取代苯基时，其上的取代基选自卤素、硝基、氰基、三氟甲氧基、羧基、酯基、苄氧基、C1-C7的烷基或者C1-C7的烷氧基的其中任意一个或者两个。
  3. 根据权利要求1或2所述的2-烷氧基苯甲酰芳胺类化合物或其药学上可接受的盐，其特征在于，所述的药学上可接受的盐为盐酸盐、溴氢酸盐。
  4. 权利要求1～3任一权项所述的式(I)结构所示的2-烷氧基苯甲酰芳胺类化合物或其药学上可接受的盐与医学上可接受的载体组成的药物组合物。
  5. 权利要求1～3任一权项所述的式(I)结构所示的2-烷氧基苯甲酰芳胺类化合物或其药学上可接受的盐在制备鞘磷脂合酶小分子抑制剂中的用途。
  6. 权利要求1～3任一权项所述的式(I)结构所示的2-烷氧基苯甲酰芳胺类化合物或其药学上可接受的盐在制备预防和治疗由鞘磷脂水平异常增加所引起疾病的药物中的用途。
  7. 按权利要求6所述的用途，其中所述由鞘磷脂水平异常增加所引起的疾病为动脉粥样硬化、脂肪肝、肥胖或Ⅱ型糖尿病及其相关代谢综合症。
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