CN111072582A - N-hydroxy aromatic heterocyclic-2-formamide compound and preparation method and application thereof - Google Patents

N-hydroxy aromatic heterocyclic-2-formamide compound and preparation method and application thereof Download PDF

Info

Publication number
CN111072582A
CN111072582A CN201811233364.9A CN201811233364A CN111072582A CN 111072582 A CN111072582 A CN 111072582A CN 201811233364 A CN201811233364 A CN 201811233364A CN 111072582 A CN111072582 A CN 111072582A
Authority
CN
China
Prior art keywords
compound
phenyl
substituent
branched alkyl
straight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201811233364.9A
Other languages
Chinese (zh)
Inventor
王进欣
杨侃
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to CN201811233364.9A priority Critical patent/CN111072582A/en
Publication of CN111072582A publication Critical patent/CN111072582A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • 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
    • A61P9/12—Antihypertensives

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to an N-hydroxy aromatic heterocycle-2-formamide compound, and a preparation method and application thereof. The specific structure of the compound provided by the invention is shown in formula I, and the invention also provides a formulaA synthesis method of the compound in the formula I and the inhibitory activity of the compound on acid sphingomyelinase. The compound can be used for developing medicaments related to treatment of Atherosclerosis (AS), diabetes, emphysema, pulmonary edema, pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, pulmonary hypertension, non-alcoholic fatty liver disease, Alzheimer's Disease (AD), Multiple Sclerosis (MS), cerebral apoplexy and depression.

Description

N-hydroxy aromatic heterocyclic-2-formamide compound and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a compound shown as a formula I, a preparation method thereof and application thereof in related diseases.
Figure BSA0000172320290000011
Background
Ceramide is an important second messenger, plays an important role in signal transduction, and is involved in various cell functions such as regulation of cell growth, proliferation and mutation, induction of apoptosis, regulation of protein secretion, participation in immune process and inflammatory reaction (progression in Lipid Research, 2016, 61: 51-62).
Hydrolysis of sphingomyelin by acid sphingomyelinase is the fastest and most direct route for the production of ceramides in vivo, to date, a number of endogenous and exogenous factors including tumor necrosis factor- α (TNF- α), interleukin- β (IL- β), interferon-gamma, etc., as well as oxidative stress, ionizing radiation, ultraviolet radiation, heat shock, trauma, bacterial infections, and chemical agents, etc., have been found to activate acid sphingomyelinase, leading to the massive production and accumulation of ceramides.
A large number of studies show that the acid sphingomyelinase-ceramide pathway is involved in the processes of inflammation, Apoptosis, oxidative stress and the like in vivo and is closely related to the occurrence and development of various diseases (Progress in Lipid Research, 2016, 61: 51-62; Apoptosis, 2015, 20: 607-620). Diseases in which acid sphingomyelinase has been implicated include Atherosclerosis (AS), diabetes, emphysema, pulmonary edema, pulmonary fibrosis and Cystic Fibrosis (CF), nonalcoholic fatty liver, Alzheimer's Disease (AD), Multiple Sclerosis (MS), depression, etc. (The FASEB Journal, 2008, 22: 3419-.
By inhibiting acid sphingomyelinase, ceramide can be recovered to normal level, and related diseases can be effectively relieved. However, only substrate analogues, diphosphates, 3, 5-diphosphinositols and a few natural products have been reported as direct inhibitors of acid sphingomyelinase. The reported inhibitor has the defects of poor selectivity, poor drug-like property, poor phosphatase stability, poor membrane permeability and the like, and cannot be applied to the drug development of related diseases (Cell physiol. biochem.2010, 26: 01-08).
Therefore, acid sphingomyelinase is a potential therapeutic target, and the development of novel inhibitors for the development of candidate drugs for treating related diseases is urgently needed.
Disclosure of Invention
The invention provides a compound serving as a novel direct acid sphingomyelinase inhibitor, a preparation method and application thereof in medicines.
The compound provided by the invention is shown as a formula I:
Figure BSA0000172320290000021
in the formula I, Ar is an aromatic ring, and benzene, pyridine, pyridazine, pyrazine and pyrimidine are selected; r1Is a mono-or di-substituent on the aromatic ring, selected from C4-C8Straight-chain or branched alkyl, aryl, heterocyclyl, -CH2OR2、-CH2N(R3)R2、-CH2CH2R2、-CH2SR2、-OR2、-N(R3)R2；n＝0-3。
X, Y and Z are respectively the same or different and are respectively selected from C, N, O, S to form an unsaturated five-membered heterocyclic ring selected from oxazole, isoxazole, oxadiazole, imidazole, pyrazole, thiazole, isothiazole, pyrrole, furan and thiophene.
Wherein the aryl group represented by R is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl.
Wherein the heterocyclic group represented by R means an aromatic five-or six-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms. The heterocyclic radical is unsubstituted or monosubstituted, and the substituent is selected from phenyl and C3-C8Straight or branched alkyl of (2), C3-C6Cycloalkyl of, OR2。
Wherein the substituent phenyl is unsubstituted, mono-substituted or di-substituted, and the substituent is selected from F, Cl, Br and CF3、CN、C3-C8Straight or branched alkyl of (2), C3-C6Cycloalkyl of, OR1。
Wherein R in said substituent2Selected from H, C1-C4Straight or branched alkyl of (2), C3-C6Cycloalkyl, phenyl, benzyl; r3 is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl.
The term alkanyl as used herein includes saturated alkyl groups and unsaturated alkyl groups.
Another object of the present invention is to provide a process for the preparation of a compound of formula I:
the synthesis of the compound of formula I is as follows:
Figure BSA0000172320290000022
heating the intermediate 1 and oxalyl chloride monoethyl ester in a phosphorus oxychloride solvent for reaction after acylation to obtain an intermediate 2; reacting the intermediates 3 and 4 with a solvent under an alkaline condition, and then heating to obtain an intermediate 5; heating the intermediate 6 and hydroxylamine hydrochloride or hydrazine hydrochloride in a solvent for cyclization to obtain an intermediate 7; finally, aminolysis of the intermediate 2, 5 or 7 in a methanol solution of hydroxylamine potassium to obtain the target compound.
The invention also provides the application of the compound as an acid sphingomyelinase inhibitor.
Still another object of the present invention is to provide the use of the above-mentioned acid sphingomyelinase inhibitor or a pharmaceutically acceptable salt, ester or prodrug thereof for the preparation of a medicament for treating related diseases, including atherosclerosis, diabetes, emphysema, pulmonary edema, pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, pulmonary hypertension, non-alcoholic fatty liver disease, alzheimer's disease, multiple sclerosis, cerebral stroke, depression.
Detailed Description
The present invention will be further illustrated by the following examples, but the present invention is not limited to the following examples.
Example 1 part of the compound synthesis of the invention.
Preparation of ethyl 5- (4 '-chloro- [1, 1' -biphenyl ] -4-yl) -1, 3, 4-oxadiazole-2-carboxylate
Figure BSA0000172320290000031
100mg (0.41mmol) of the starting material was put in an eggplant type bottle, 10mL of methylene chloride and triethylamine (41mg, 0.41mmol) were added, and then a methylene chloride solution of oxalyl chloride monoethyl ester (46mg, 0.41mmol) was added dropwise thereto, followed by stirring at room temperature for 5min after completion of the dropwise addition. After the reaction is finished, removing the solvent by rotary evaporation, adding 3mL of phosphorus oxychloride for dissolution, heating to reflux for 2h, cooling to room temperature, then carrying out rotary drying on the reaction solution, adding 50mL of ethyl acetate for dissolution, washing with sodium bicarbonate water solution for 2 times, washing with saline water for 1 time, drying with anhydrous sodium sulfate, purifying by column chromatography to obtain 68mg of a target compound, wherein the yield is 51%, the product is a white solid, M.P.187-189 ℃,1H-NMR(300MHz，CDCl3)：δ8.26-8.23(m，2H)，7.75-7.72(m，2H)，7.60-7.57(m，2H)，7.48-7.45(m，2H)，4.57(q，J＝7.20Hz)，2H)，1.50(t，J＝6.90Hz，3H)；ESI-MS m/z：329.1[M+H]+。
preparation of 5- (4 '-chloro- [1, 1' -biphenyl ] -4-yl) -N-hydroxy-1, 3, 4-oxadiazole-2-carboxamide (I-1)
Figure BSA0000172320290000032
100mg (0.305mmol) of the starting material was dissolved in 2mL of methanol, 2mL of a 1.76M solution of hydroxylamine in potassium in methanol was added, the mixture was stirred at room temperature for 6 hours under nitrogen protection, and 15% aqueous HCl was added to adjust the mixture to acidic, whereby 63mg of the final product was precipitated in a yield of 65.6%. M.P.208-209 ℃,1H-NMR(300MHz，DMSO-d6)：δ12.13(s，1H)，9.87(s，1H)，8.28-8.25(m，2H)，8.08-8.05(m，2H)，7.94-7.91(m，2H)，7.70-7.67(m，2H)；ESI-MS m/z：316.1[M+H]+。
n-hydroxy-5- (4-isobutoxyphenyl) -1, 3, 4-oxadiazole-2-carboxamide (I-2)
Figure BSA0000172320290000033
Referring to the synthesis of I-1, 61mg of a white solid was obtained in 63.9% yield, M.P.177-178 deg.C,1H-NMR(300MHz，DMSO-d6)：δ12.09(s，1H)，9.70(s，1H)，8.00-7.97(m，2H)，7.16-7.13(m，2H)，3.84(d，J＝6.0Hz，2H)，2.07-1.98(m，1H)，0.99-0.96(m，6H)；ESI-MS m/z：278.2[M+H]+。
5- (4- (benzyloxy) -3-methoxyphenyl) -N-hydroxy-1, 3, 4-oxadiazole-2-carboxamide (I-3)
Figure BSA0000172320290000034
Referring to the synthesis method of I-1, 49mg of white solid was obtained with a yield of 50.9%, M.P.180-181 ℃,1H-NMR(300MHz，DMSO-d6)：δ12.16(s，1H)，9.75(s，1H)，7.67-7.65(m，1H)，7.59(m，1H)，7.49-7.29(m，6H)，5.21(s，2H)，3.89(s，3H)；13C-NMR(75MHz，DMSO-d6)：δ165.19，157.50，151.81，149.82，136.83，128.96，128.55，128.46，121.11，115.57，113.91，110.18，70.43，56.21；ESI-MS m/z：342.1[M+H]+。
5- (4-butoxy-3-methoxyphenyl) -N-hydroxy-1, 3, 4-oxadiazole-2-carboxamide (I-4)
Figure BSA0000172320290000041
Referring to the synthesis method of I-1, 56mg of white solid was obtained with a yield of 58.4%, M.P.178-179 ℃,1H-NMR(300MHz，DMSO-d6)：δ11.99(s，1H)，9.59(s，1H)，7.53-7.50(m，1H)，7.42(m，1H)，7.08-7.05(m，1H)，3.94(t，J＝6.0Hz，2H)，3.74(s，3H)，1.63-1.58(m，2H)，1.35-1.28(m.2H)，0.81(t，J＝6.0Hz，3H)；13C-NMR(75MHz，DMSO-d6)：δ165.24，157.47，152.27，151.27，149.66，121.25，115.12，113.33，110.13，68.52，56.22，31.07，19.16，14.12；ESI-MS m/z：308.2[M+H]+。
3- (4- (4-chlorophenoxy) methyl) phenyl-N-hydroxy-1, 2, 4-oxadiazole-5-carboxamide (I-5)
Figure BSA0000172320290000042
Dissolving the raw materials with tetrahydrofuran, adding triethylamine, dropwise adding a tetrahydrofuran solution of oxalyl chloride monoethyl ester under ice bath, stirring at room temperature for 5min after dropwise adding, filtering to remove solids, heating the filtrate to reflux, reacting for 4 hours to obtain a 1, 2, 4-oxadiazole cyclization intermediate, then obtaining a white solid product by adopting the same synthetic method as I-1 with the yield of 54 percent,1H-NMR(300MHz，DMSO-d6)：δ12.30(s，1H)，9.89(s，1H)，8.08-8.06(m，2H)，7.68-7.65(m，2H)，7.36-7.33(m，2H)，7.08-7.05(m，2H)，5.22(s，2H)；ESI-MS m/z：346.1[M+H]+。
3- (4- (3-chlorophenoxy) methyl) phenyl-N-hydroxy-1, 2, 4-oxadiazole-5-carboxamide (I-6)
Figure BSA0000172320290000043
Referring to the synthesis method of I-5, the white solid product was obtained with a yield of 42%,1H-NMR(300MHz，DMSO-d6)：δ12.04(s，1H)，9.92(s，1H)，8.09-8.07(m，2H)，7.69-7.66(m，2H)，7.33(m，1H)，7.14(m，1H)，7.03(m，1H)，5.25(s，2H)；ESI-MS m/z：346.1[M+H]+。
3- (4- (2-chlorophenoxy) methyl) phenyl-N-hydroxy-1, 2, 4-oxadiazole-5-carboxamide (I-7)
Figure BSA0000172320290000044
Referring to the synthesis method of I-5, the white solid product is obtained with the yield of 60 percent,1H-NMR(300MHz，DMSO-d6)：δ12.32(s，1H)，9.95(s，1H)，8.11-8.08(m，2H)，7.77-7.69(m，2H)，7.40(m，1H)，7.34-7.23(m，2H)，6.99(m，1H)，5.33(s，2H)；ESI-MS m/z：346.1[M+H]+。
3- (4- (2-fluorophenoxy) methyl) phenyl-N-hydroxy-1, 2, 4-oxadiazole-5-carboxamide (I-8)
Figure BSA0000172320290000051
Referring to the synthesis method of I-5, the white solid product is obtained with a yield of 68 percent,1H-NMR(300MHz，DMSO-d6)：δ12.30(s，1H)，9.93(s，1H)，8.11-8.03(m，2H)，7.72-7.69(m，2H)，7.39(m，1H)，7.34-7.23(m，2H)，6.98(m，1H)，5.32(s，2H)；ESI-MS m/z：330.1[M+H]+。
3- (4- (2-chlorophenoxy) methyl) phenyl-N-hydroxy-1, 2, 4-oxadiazole-5-carboxamide (I-9)
Figure BSA0000172320290000052
Referring to the synthesis method of I-5, the white solid product was obtained with a yield of 54%,1H-NMR(300MHz，DMSO-d6)：δ12.33(s，1H)，9.95(s，1H)，8.16-8.09(m，2H)，7.78-7.70(m，2H)，7.42(m，1H)，7.29-7.21(m，2H)，6.90(m，1H)，5.32(s，2H)；ESI-MS m/z：380.1[M+H]+。
preparation of ethyl 5- (4- (benzyloxy) phenyl) isoxazole-3-carboxylate
Figure BSA0000172320290000053
100mg (0.336mmol) of the starting material was taken, 2mL of anhydrous ethanol was added to dissolve the starting material, then hydroxylamine hydrochloride (23mg, 0.336mmol) was added and the mixture was warmed to reflux, reacted for 2 hours and cooled to room temperature, 5mL of water was added to the reaction solution and extracted three times with 30mL of ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. 68mg of white solid is obtained, the yield is 74.6 percent, the molecular weight is between M.P.121 and 123 ℃,1H-NMR(300MHz，CDCl3)：δ7.76-7.73(m，2H)，7.45-7.32(m，1H)，7.05-7.05(m，2H)，6.80(s，1H)，4.56(q，J＝7.20Hz，2H)，1.44(t，J＝7.20Hz，3H)；ESI-MS m/z：324.1[M+H]+。
preparation of 5- (4- (benzyloxy) phenyl) -N-hydroxyiso-3-carboxamide (I-10)
Figure BSA0000172320290000054
Dissolving 100mg (0.310mmol) of raw material in 2mL of methanol, adding 2mL of 1.76M solution of hydroxylamine potassium in methanol, stirring at room temperature for 6h under the protection of nitrogen, adding 15% HCl aqueous solution to adjust to acidity, precipitating 54mg of final product white solid, obtaining a yield of 56.3%, M.P.186-188 ℃,1H-NMR(300MHz，DMSO-d6)：δ11.55(s，1H)，9.41(s，1H)，7.88-7.85(m，2H)，7.49-7.35(m，5H)，7.20-7.17(m，3H)，5.21(s，2H)；ESI-MS m/z：311.1[M+H]+。
n-hydroxy-5- (4-isobutoxyphenyl) isoxazole-3-carboxamide (I-11)
Figure BSA0000172320290000061
Referring to the synthesis method of I-5, 62mg of white solid was obtained with a yield of 64.9%, M.P.158-159 ℃,1H-NMR(300MHz，DMSO-d6)：δ11.39(s，1H)，9.25(s，1H)，7.72-7.69(m，2H)，7.04-6.95(m，3H)，3.70(d，J＝6.0Hz，2H)，1.95-1.86(m，1H)，0.87-0.85(m，6H)；ESI-MS m/z：277.2[M+H]+。
5- (4-butoxyphenyl) -N-hydroxy-1H-pyrazole-3-carboxamide (I-12)
Figure BSA0000172320290000062
Referring to the synthesis method of I-5, hydrazine hydrochloride is used for replacing hydroxylamine hydrochloride to construct a pyrazole ring, and finally, 51mg of white solid is obtained, the yield is 53.4 percent, the reaction temperature is M.P.212-213 ℃,1H-NMR(300MHz，DMSO-d6)：δ13.38(s，1H)，11.02(s，1H)，9.01(s，1H)，7.71-7.68(m，2H)，7.02-6.96(m，3H)，4.00(t，J＝6.60Hz，2H)，1.75-1.66(m，2H)，1.75-1.66(m，2H)，1.51-1.38(m，2H)，0.94(t，J＝7.20Hz，3H)；ESI-MS m/z：276.2[M+H]+。
the compound of example 2 was tested for inhibition of acid sphingomyelinase activity.
The acid sphingomyelinase can hydrolyze sphingomyelin in cells to generate ceramide, different enzyme activities catalyze different amounts of products aiming at a certain amount of fluorescently-labeled reaction substrates, and the level of the enzyme activities can be inspected by detecting the content of the products. The invention carries out experimental design according to the principle. Extracting protein from cultured cells, adding buffer solution and fluorescence labeled reaction substrate, adding compounds with different concentrations, setting blank control group, performing fluorescence analysis after reaction, and calculating IC of compound50The value is obtained.
The specific results are shown in the table:
table 1: acid sphingomyelinase inhibitory Activity of some of the Compounds of the invention
Figure BSA0000172320290000063

Claims (8)

1. A hydroxamic acid containing compound having the structure represented by formula I:
Figure FSA0000172320280000011
or a pharmaceutically acceptable salt of a compound of formula (I);
in the formula I, Ar is an aromatic ring, and benzene, pyridine, pyridazine, pyrazine and pyrimidine are selected; r1Is a mono-or di-substituent on the aromatic ring, selected from C4-C8Straight-chain or branched alkyl, aryl, heterocyclyl, -CH2OR2、-CH2N(R3)R2、-CH2CH2R2、-CH2SR2、-OR2、-N(R3)R2；n＝0-3；
X, Y and Z are respectively the same or different and are respectively selected from C, N, O, S to form an unsaturated five-membered heterocyclic ring selected from oxazole, isoxazole, oxadiazole, imidazole, pyrazole, thiazole, isothiazole, pyrrole, furan and thiophene;
wherein the aryl group represented by R is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl;
wherein the heterocyclic group represented by R means an aromatic five-or six-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms. The heterocyclic radical is unsubstituted or monosubstituted, and the substituent is selected from phenyl and C3-C8Straight or branched alkyl of (2), C3-C6Cycloalkyl of, OR2；
Wherein R in said substituent1Selected from H, C1-C4Straight chain alkyl group of (1), C1-C4Branched alkyl radical, C3-C6Cycloalkyl, phenyl, benzyl; r2Selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl;
wherein the substituent phenyl is unsubstituted, mono-substituted or di-substituted, and the substituent is selected from F, Cl, Br and CF3、CN、C3-C8Straight or branched alkyl of (2), C3-C6Cycloalkyl of, OR2。
2. The compound of claim 1, wherein R is a para-substituent of the phenyl ring selected from the group consisting of phenyl, -CH2OR1、-CH2N(R2)R1、-CH2CH2R1、-CH2SR1、-OR1、-N(R2)R1；
The phenyl is unsubstituted, mono-substituted or di-substituted, and the substituent is selected from F, Cl, Br and CF3、C3-C8Straight or branched alkyl of (2), C3-C6Cycloalkyl groups of (a);
wherein R in said substituent2Selected from H, C1-C4Straight or branched alkyl of (2), C3-C6Cycloalkyl, phenyl, benzyl, benzothiazol-2-yl; r3Selected from H, methyl, ethyl, n-propyl, isopropyl,And (3) cyclopropyl.
3. The compound of claim 2, wherein Ar is selected from the group consisting of benzene, pyridine; r1Selected from 4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, -CH2OR2、-CH2N(R3)R2、-CH2CH2R2；
Wherein R in said substituent1Is selected from-C4H9、-C5H11、-C6H13Phenyl, p-chlorophenyl, m-chlorophenyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-bromophenyl, m-bromophenyl, o-bromophenyl, benzothiazol-2-yl; r2Selected from H, methyl, ethyl.
4. A compound according to claims 1-3, formula I is prepared as follows:
Figure FSA0000172320280000012
heating the intermediate 1 and oxalyl chloride monoethyl ester in a phosphorus oxychloride solvent for reaction after acylation to obtain an intermediate 2; reacting the intermediates 3 and 4 with a solvent under an alkaline condition, and then heating to obtain an intermediate 5; heating the intermediate 6 and hydroxylamine hydrochloride or hydrazine hydrochloride in a solvent for cyclization to obtain an intermediate 7; finally, aminolysis of the intermediate 2, 5 or 7 in a methanol solution of hydroxylamine potassium to obtain the target compound.
5. According to claim 4, the base used for the reaction of intermediates 3 and 4 is selected from triethylamine, N-diisopropylethylamine, pyridine, and the solvent used is selected from tetrahydrofuran, pyridine, N-dimethylformamide, 1, 4-dioxane, and toluene; the solvent used for preparing intermediate 7 from intermediate 6 is selected from methanol, ethanol, isopropanol, n-propanol, and n-butanol.
6. The use of the compounds and pharmaceutical compositions according to claims 1-3 as inhibitors of acid sphingomyelinase.
7. The use of the compounds and pharmaceutical compositions according to claims 1-6 for the treatment of atherosclerosis, diabetes, emphysema, pulmonary edema, pulmonary fibrosis, chronic obstructive pulmonary disease, pulmonary hypertension, cystic fibrosis, non-alcoholic fatty liver disease, alzheimer's disease, multiple sclerosis, stroke, depression.
8. The use of compounds and pharmaceutical compositions according to claims 1-6 for the treatment of atherosclerosis, diabetes, cystic fibrosis, chronic obstructive pulmonary disease, pulmonary hypertension, depression.
CN201811233364.9A 2018-10-18 2018-10-18 N-hydroxy aromatic heterocyclic-2-formamide compound and preparation method and application thereof Pending CN111072582A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811233364.9A CN111072582A (en) 2018-10-18 2018-10-18 N-hydroxy aromatic heterocyclic-2-formamide compound and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201811233364.9A CN111072582A (en) 2018-10-18 2018-10-18 N-hydroxy aromatic heterocyclic-2-formamide compound and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN111072582A true CN111072582A (en) 2020-04-28

Family

ID=70309992

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811233364.9A Pending CN111072582A (en) 2018-10-18 2018-10-18 N-hydroxy aromatic heterocyclic-2-formamide compound and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN111072582A (en)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001038322A1 (en) * 1999-11-23 2001-05-31 Methylgene, Inc. Inhibitors of histone deacetylase
TW200524575A (en) * 2003-10-27 2005-08-01 S Bio Pte Ltd Biaryl linked hydroxamates: preparation and pharmaceutical applications
CN1684957A (en) * 2002-08-02 2005-10-19 阿根塔发明有限公司 Substituted thienyl-hydroxamic acids as histone deacetylase inhibitors
CN101148442A (en) * 2007-09-14 2008-03-26 中国药科大学 Histone deacetylase inhibitor and its preparation method and use
WO2013059582A2 (en) * 2011-10-20 2013-04-25 Nupotential, Inc. Small molecule inhibitors of histone deacteylases
US20140051708A1 (en) * 2011-04-11 2014-02-20 Nerviano Medical Sciences S.R.L. Pyrazolyl-pyrimidine derivatives as kinase inhibitors
CN108329330A (en) * 2017-01-20 2018-07-27 复旦大学 2- benzyloxies Ben Ji oxazoles and pyridine compounds and their and its medicinal usage

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001038322A1 (en) * 1999-11-23 2001-05-31 Methylgene, Inc. Inhibitors of histone deacetylase
US6541661B1 (en) * 1999-11-23 2003-04-01 Methylgene, Inc. Inhibitors of histone deacetylase
CN1684957A (en) * 2002-08-02 2005-10-19 阿根塔发明有限公司 Substituted thienyl-hydroxamic acids as histone deacetylase inhibitors
TW200524575A (en) * 2003-10-27 2005-08-01 S Bio Pte Ltd Biaryl linked hydroxamates: preparation and pharmaceutical applications
CN101148442A (en) * 2007-09-14 2008-03-26 中国药科大学 Histone deacetylase inhibitor and its preparation method and use
US20140051708A1 (en) * 2011-04-11 2014-02-20 Nerviano Medical Sciences S.R.L. Pyrazolyl-pyrimidine derivatives as kinase inhibitors
WO2013059582A2 (en) * 2011-10-20 2013-04-25 Nupotential, Inc. Small molecule inhibitors of histone deacteylases
CN108329330A (en) * 2017-01-20 2018-07-27 复旦大学 2- benzyloxies Ben Ji oxazoles and pyridine compounds and their and its medicinal usage

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JOHANNA SENGER ET AL.: "Synthesis and Biological Investigation of Oxazole Hydroxamates as Highly Selective Histone Deacetylase 6 (HDAC6) Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
JOHANNA SENGER ET AL.: "Synthesis and Biological Investigation of Oxazole Hydroxamates as Highly Selective Histone Deacetylase 6 (HDAC6) Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 59, no. 4, 10 December 2015 (2015-12-10), pages 1545 - 1555, XP055497385, DOI: 10.1021/acs.jmedchem.5b01493 *
JOHANNA SENGER ET AL.: "Synthesis and Biological Investigation of Oxazole Hydroxamates as Highly Selective Histone Deacetylase 6 (HDAC6) Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, pages 1545 - 1555, XP055497385, DOI: 10.1021/acs.jmedchem.5b01493 *
STN REGISTRY: "RN 2200283-69-6 等", pages 1 - 8 *

Similar Documents

Publication Publication Date Title
US11220486B2 (en) Inhibitors of low molecular weight protein tyrosine phosphatase and uses thereof
JP3149186B2 (en) Substituted sulfonamides as selective beta-3 agents for the treatment of diabetes and obesity
US5561142A (en) Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity
CN114573575B (en) Oxygen-containing five-membered heterocyclic compound, synthesis method, pharmaceutical composition and application
US9475800B2 (en) Azetidine derivatives
JP2010510191A (en) 2-Carboxythiophene derivatives as antiviral agents
EP2393809B1 (en) Derivatives of azaspiranyl-alkylcarbamates of 5-member heterocyclic compounds, preparation thereof and therapeutic use thereof
EP2385036A1 (en) N-acyl anthranilic acid derivative or salt thereof
JP2000516593A (en) Substituted sulfonamides as selective β agonists used in the treatment of diabetes and obesity
CN103998434B (en) Thiazole and application thereof as DHODH inhibitor
EP2391611B1 (en) Thiadiazole and oxadiazole derivatives, preparation thereof, and therapeutic use thereof
CZ291040B6 (en) Trisubstituted phenyl derivatives and pharmaceutical composition containing them
JP2006518341A (en) Hydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors
KR20090033912A (en) Chemical compounds
WO2001057044A1 (en) Pyridoxazine derivatives
EP1590321B1 (en) Aryl alkyl carbamate derivatives production and use thereof in therapy
MX2011001678A (en) Azetidine polysubstituted compounds, preparation thereof, and therapeutic application thereof.
JP2002531553A (en) New compound
JPH04221368A (en) 3,5-di-tert-butyl-4-hydroxyphenylthiazolyl, oxazolyl and imidazolylmethanone and analogues as antiinflammatories
AU2005320544B2 (en) Pyrimidinylisoxazol derivative
WO2008129129A1 (en) Heterocyclic phenyl carbamates as novel faah-inhibitors
JP4824668B2 (en) Heteroaryl-alkyl carbamate derivatives, processes for their preparation and their use as FAAH enzyme inhibitors
CN111072582A (en) N-hydroxy aromatic heterocyclic-2-formamide compound and preparation method and application thereof
CN109369554B (en) Hydroxamic acid-containing substituted heterocyclic compound and preparation method and application thereof
JPH0256471A (en) Novel (hetero)aryl substituted diazole derivative, its production and adaptation thereof to treatment

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination