CN115160222B - Hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof - Google Patents
Hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof Download PDFInfo
- Publication number
- CN115160222B CN115160222B CN202210733176.2A CN202210733176A CN115160222B CN 115160222 B CN115160222 B CN 115160222B CN 202210733176 A CN202210733176 A CN 202210733176A CN 115160222 B CN115160222 B CN 115160222B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- sulfanyl
- hydroxy
- acrylamide
- acid
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/38—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
Abstract
The invention relates to a hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof, belongs to the technical field of medicines, and particularly comprises a pharmaceutical composition of the compound, and application of the pharmaceutical composition as a histone deacetylase inhibitor and application of the pharmaceutical composition in preventing and/or treating diseases related to histone deacetylase, wherein the structure of the hydroxamic acid compound containing quinoline or isoquinoline is shown as a general formula I:
Description
technical field:
the invention belongs to the technical field of medicines, and particularly relates to a hydroxamic acid compound containing quinoline or isoquinoline, and preparation and application thereof, and particularly relates to application of the compound serving as a histone deacetylase inhibitor for preventing and/or treating diseases related to histone deacetylase.
The background technology is as follows:
cancer, because of its high morbidity and mortality has become a leading cause of death worldwide, is one of the most fearful killers in humans.
In the emerging field of cancer research, epigenetic alterations have an indispensable function in the development, progression and invasive metastasis of tumors. Post-translational modification of histones is a key process for epigenetic regulation, and a large number of studies indicate that abnormal decrease in histone acetylation levels is closely related to cancer and various immune diseases. Histone deacetylase HDACs are one of the key enzymes regulating the balance of histone as well as non-histone acetylation and deacetylation in vivo, and abnormal expression of HDACs is found in a variety of cancers. It follows that HDACs have become an important target for cancer research.
HDACs mediated histone deacetylation plays an important role in regulating cellular differentiation, proliferation and survival processes. Histone hyperacetylation caused by HDACs mutation or abnormal expression is closely related to proliferation, invasion and migration of tumors. Numerous studies have shown that over-expression of HDACs is observed in different types of cancer and is in most cases closely related to poor prognosis. Related researches show that the HDACs inhibitor can exert the anti-tumor effect by inducing apoptosis of tumor cells, inhibiting formation of tumor tissue microvessels and the like, so that the HDACs inhibitor is developed as a novel anti-tumor medicament.
The invention comprises the following steps:
the invention aims to overcome the defects in the prior art and provide a hydroxamic acid compound containing quinoline or isoquinoline, preparation and application thereof, and application of the compound serving as a histone deacetylase inhibitor in preventing and/or treating tumors.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the invention provides a hydroxamic acid compound containing quinoline or isoquinoline as shown in a general formula I and pharmaceutically acceptable salts or hydrates thereof.
Wherein:
x is N or CH, Y is CH or N; wherein, when X is N, Y is CH; when X is CH, Y is N;
w is carbonyl or (C) 3 -C 5 ) α, β -unsaturated carbonyl;
ring a is aryl or heteroaryl, wherein aryl or heteroaryl are each independently optionally substituted with one or more R, R is hydrogen, (C) 1 -C 6 ) Alkyl, cyano, halogen, halo (C) 1 -C 6 ) Alkyl, hydroxy, mercapto or alkoxy;
wherein the aryl is a 6-10 membered aryl; the heteroaryl is five-membered or six-membered heteroaryl, wherein 1-3 heteroatoms N, O or S are contained, and the rest ring atoms are C; the aryl is phenyl; the five-membered heteroaryl is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl; the six-membered heteroaryl is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;
preferred compounds of the present invention are those of the following structure:
x is N, then Y is CH; or X is CH, then Y is N;
w is carbonyl or (C) 3 -C 5 ) α, β -unsaturated carbonyl;
ring a is aryl or heteroaryl;
wherein the aryl is phenyl; the five-membered heteroaryl is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl; the six-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl.
Preferred compounds of the present invention are those of the following structure:
x is N, then Y is CH; or X is CH, then Y is N;
w is carbonyl or (C) 3 -C 5 ) Alpha, beta-non-crystallineSaturated carbonyl groups;
ring a is aryl or heteroaryl;
wherein the aryl is phenyl; the heteroaryl is pyridinyl, pyrazinyl;
further, when the A ring is phenyl, the phenyl is
Further, when the ring A is a pyridyl group, the pyridyl group is
Further, when the A ring is pyrazinyl, pyrazinyl is
Preferred compounds of the present invention are those of the following structure:
x is N, then Y is CH; or X is CH, then Y is N;
w is carbonyl or (C) 3 -C 5 ) α, β -unsaturated carbonyl;
ring a is aryl;
wherein the aryl is phenyl;
further, when the A ring is phenyl, the phenyl is
Preferred compounds of the present invention are those of the following structure:
x is N, then Y is CH; or X is CH, then Y is N;
w is-ch=ch-CO-;
ring a is aryl;
wherein the aryl is phenyl;
further, when the A ring is phenyl, the phenyl is
Specifically, the present invention is preferably the following compounds:
(E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-1);
(E) -N-hydroxy-3- (4- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-2);
(E) -N-hydroxy-3- (4- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-3);
(E) -N-hydroxy-3- (4- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-4);
(E) -N-hydroxy-3- (4- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-5);
(E) -N-hydroxy-3- (4- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-6);
(E) -N-hydroxy-3- (4- (N- (quinolin-8-yl) sulfanyl) phenyl) acrylamide (I-7);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-8);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-9);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-10);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-11);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-12);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-13);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-14);
(E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-15);
(E) -N-hydroxy-3- (3- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-16);
(E) -N-hydroxy-3- (3- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-17);
(E) -N-hydroxy-3- (3- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-18);
(E) -N-hydroxy-3- (3- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-19);
(E) -N-hydroxy-3- (3- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-20);
(E) -N-hydroxy-3- (3- (N- (quinolin-8-yl) sulfanyl) phenyl) acrylamide (I-21);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-22);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-23);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-24);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-25);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-26);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-27);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-28);
or a salt or hydrate thereof;
the term "halogen" as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine; "alkyl" refers to a straight or branched chain alkyl group.
According to the present invention, the pharmaceutically acceptable salt may be an inorganic acid salt or an organic acid salt; preferably, the inorganic acid salt is selected from any one of the following inorganic acid forming salts: hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; preferably, the organic acid salt is selected from any one of the following organic acid forming salts: acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, citric acid, salicylic acid, tartaric acid or p-toluenesulfonic acid.
The invention also includes prodrugs of the compounds of the invention. Pharmaceutically acceptable prodrugs mean that the prodrug itself may have a weaker activity or even no activity, but can be converted to-COOH, -NH under physiological conditions (e.g., by metabolism, solvolysis, or another form) after administration 2 Functional groups of-OH or the like, therebyA compound which forms the compound of the present invention.
The present invention includes a pharmaceutical composition containing a hydroxamic acid compound having the above-described quinoline or isoquinoline structure as an active ingredient and a pharmaceutically acceptable adjuvant. The pharmaceutical excipients comprise diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like which are conventional in the pharmaceutical field.
The pharmaceutical composition of the invention can be prepared into a plurality of dosage forms, such as injection, tablet, powder, granule, capsule, oral liquid, ointment, cream and the like. The medicaments of the various formulations can be prepared according to the conventional method in the pharmaceutical field.
The compounds of the present invention and pharmaceutical compositions comprising the compounds of the present invention may be formulated in a form suitable for intravenous, oral, rectal, parenteral, intranasal or transdermal administration, or in a form suitable for administration by inhalation or by suppository. Oral and intravenous administration are preferred.
The hydroxamic acid compounds containing quinoline or isoquinoline and the pharmaceutical compositions thereof are used as histone deacetylase inhibitors for preventing and/or treating diseases related to abnormal expression of histone deacetylase, such as various cancers including liver cancer, colon cancer, pancreatic cancer, lung cancer, gastric cancer, breast cancer, ovarian cancer and the like.
The preparation of the hydroxamic acid compound containing quinoline or isoquinoline adopts one of the following two routes:
route one:
each substituent is defined in the summary of the invention, reagents and conditions: HSO 3 Cl,12h；b.RNH 2 ,CH 2 Cl 2 ,pyridine, 1h；c.CH 3 OH,H 2 SO 4 ,4h；d.NH 2 OH,1N NaOH,CH 3 OH,1h.
Route two:
each substituent is defined in the summary of the invention, reagents and conditions: RNH (rnh) 2 ,CH 2 Cl 2 ,pyridine,2h；b.methyl acrylate,Pd(OAc) 2 ,POT,Et 3 N,CH 3 CN,60℃,12h；c.NH 2 OH,1N NaOH,CH 3 OH,1h.
The invention has the beneficial effects that:
the hydroxamic acid compounds containing quinoline or isoquinoline have good anti-tumor cell proliferation activity, and the preparation method is simple to operate and mild in condition.
The specific embodiment is as follows:
the present invention will be described in further detail with reference to examples.
Example 1: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-1)
The structural formula of the compound (I-1)
Step A: (E) Preparation of 3- (4- (chlorosulfonyl) phenyl) acrylic acid
Cinnamic acid (1 g,6.76 mmol) was added slowly in portions to chlorosulfonic acid (7.84 g,67.6 mmol) with stirring at 0deg.C, and stirring was continued for 30min before slowly returning to room temperature and stirring was continued for a further 12h. After the reaction was completed, the reaction solution was slowly dropped into ice water, and after suction filtration, a yellow solid was obtained by vacuum drying, and the solid was added to 1, 4-dioxane, and recrystallized to give (E) -3- (4- (chlorosulfonyl) phenyl) acrylic acid as white crystals (0.55 g, yield 33%).
And (B) step (B): (E) Preparation of 3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylic acid
Pyridine (1 ml) and (E) -3- (4- (chlorosulfonyl) phenyl) acrylic acid (1 g,4.06 mmol) were added sequentially to a solution of 2-aminoquinoline (0.49 g,3.4 mmol) in methylene chloride (50 ml) at 0℃with stirring. After the addition, the reaction mixture was stirred at 0℃for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give (E) -3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylic acid as a pale yellow solid (0.6 g, yield 50%).
Step C: preparation of methyl (E) -3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylate
To a solution of (E) -3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylic acid (0.6 g,1.7 mmol) in methanol (40 ml) was added 1 drop of concentrated H 2 SO 4 . After the addition, the reaction solution was heated to reflux for 4 hours. After completion of the reaction, ethyl acetate (50 ml. Times.3) was extracted, and the organic phases were combined, washed 3 times with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give methyl (E) -3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylate as a white solid (0.5 g, 80% yield).
Step D: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide
To a solution of methyl (E) -3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylate (0.5 g, 1.36 mmol) in methanol (20 ml) was slowly added dropwise a 1mol/L NaOH solution (3 ml) at 0℃with stirring, and after stirring for 10 minutes, NH was continuously slowly added dropwise thereto 2 OH solution (3 ml), after the addition, slowly returned to the chamberWarm and stir for 1h. After the completion of the reaction, the solvent was distilled off under reduced pressure, water (20 ml) was added thereto, pH was adjusted to neutrality with 2mol/L hydrochloric acid, and a solid was precipitated, suction filtration and vacuum drying were carried out to obtain (E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-1) as a white solid (0.36 g, yield 73%). Mp is 171.6-173.3 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.09(d,J＝9.0Hz,1H),7.91(d,J ＝8.3Hz,2H),7.74(d,J＝7.8Hz,1H),7.65(d,J＝8.3Hz,2H),7.59(t,J＝7.4Hz,1H),7.52(d,J＝8.3Hz,1H),7.45(d,J＝15.8Hz,1H),7.29(t,J＝7.4Hz,2H),6.53(d,J＝15.8Hz,1H). ESI-MS m/z:392.08[M+Na] + .
the compounds of examples 2-14 were prepared by the preparation method of example 1, with the appropriate choice of starting materials.
Example 2: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-2)
The structural formula of the compound (I-2)
(E) -N-hydroxy-3- (4- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-2) as a pale yellow solid in 85% yield. Mp 185.7-187.9 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.82(s,1H),9.10(s,1H),8.55(d,J＝2.5Hz, 1H),7.83(dd,J＝27.4,8.2Hz,6H),7.66(d,J＝8.4Hz,2H),7.55(t,J＝7.2Hz,1H),7.49(t,J＝7.4Hz,1H),7.42(d,J＝15.8Hz,1H),6.50(d,J＝15.8Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 3: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-3)
Compound (I-3) structural formula
(E) -N-hydroxy-3- (4- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-3) as a white solid in 79% yield. MP 228.9-230.1 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.39(d,J＝8.1Hz,1H),8.18(d,J＝6.3Hz,1H), 7.83(d,J＝8.3Hz,2H),7.65(dd,J＝8.9,1.4Hz,2H),7.61(d,J＝8.2Hz,2H),7.41(ddd,J＝11.8,8.6,8.1Hz,2H),6.98(d,J＝6.3Hz,1H),6.49(d,J＝15.8Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 4: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-4)
Compound (I-4) structural formula
(E) -N-hydroxy-3- (4- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-4) as a pale yellow solid in 77% yield. Mp 199.0-201.7 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.84(s,1H),10.45(s,1H),9.12(s,1H),8.85 (dd,J＝4.1,1.5Hz,1H),8.40(d,J＝8.5Hz,1H),7.85(d,J＝8.5Hz,1H),7.70–7.61(m,5H),7.47–7.41(m,2H),7.20(d,J＝7.4Hz,1H),6.52(d,J＝15.8Hz,1H).ESI-MS m/z:370.11[M+ H] + .
example 5: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-5)
Compound (I-5) structural formula
(E) -N-hydroxy-3- (4- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-5) as a white solid in 70% yield. MP 177.9-179.6 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.58(s,1H),8.60(d,J＝3.0Hz,1H),8.05(d,J ＝8.2Hz,1H),7.79(d,J＝8.3Hz,2H),7.74(d,J＝8.8Hz,1H),7.60(d,J＝8.2Hz,2H),7.43–7.36(m,3H),7.32(dd,J＝8.3,4.1Hz,1H),6.48(d,J＝15.8Hz,1H).ESI-MS m/z:370.11[M+ H] + .
example 6: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-6)
Compound (I-6) structural formula
(E) -N-hydroxy-3- (4- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-6) as a white solid in 73% yield. Mp 182.2-185.3 deg.c, 1 H-NMR(600MHz,DMSO-d 6 )δ8.76(dd,J＝4.1,1.4Hz,1H),8.20(d,J＝7.9Hz, 1H),7.83(t,J＝9.8Hz,3H),7.69(d,J＝8.3Hz,2H),7.62(d,J＝0.8Hz,1H),7.41(d,J＝15.8Hz, 1H),7.38(dd,J＝8.8,1.9Hz,1H),7.35(dd,J＝8.2,4.2Hz,1H),6.52(d,J＝15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 7: (E) Preparation of-N-hydroxy-3- (4- (N- (quinolin-8-yl) sulfanyl) phenyl) acrylamide (I-7)
Compound (I-7) structural formula
(E) -N-hydroxy-3- (4- (N- (quinolin-8-yl) sulfanyl) phenyl) acrylamide (I-7) as a pale yellow solid in 85% yield. Mp is 158.2-160.6 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.20(s,1H),9.36(s,1H),8.81(d,J＝2.3Hz, 1H),8.27(d,J＝8.1Hz,1H),7.89(d,J＝5.1Hz,2H),7.73–7.34(m,8H),6.49(d,J＝15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 8: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-8)
Compound (I-8) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-8) as a pale yellow solid, yield 70%. Mp is 215.5-217.7 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.38(d,J＝8.2Hz,1H),7.95(d,J＝8.3Hz,2H), 7.72(t,J＝8.5Hz,2H),7.65(d,J＝8.1Hz,2H),7.59(d,J＝6.7Hz,1H),7.56–7.50(m,1H),7.45(d,J＝15.8Hz,1H),6.97(d,J＝6.0Hz,1H),6.52(d,J＝15.8Hz,1H).ESI-MS m/z:370.11[M+ H] + .
example 9: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-9)
Compound (I-9) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-9) as a pale yellow solid in 71% yield. Mp of 225.4-228.1 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.91(s,1H),7.88(t,J＝7.9Hz,3H),7.69(d,J＝ 7.9Hz,1H),7.63(d,J＝8.2Hz,2H),7.55(t,J＝7.5Hz,1H),7.41(d,J＝15.8Hz,1H),7.36–7.32(m,1H),7.29(s,1H),6.52(d,J＝15.8Hz,1H). ESI-MS m/z:370.14[M+H] + .
example 10: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-10)
Compound (I-10) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-10) as a pale yellow solid, yield 83%. Mp is 110.1-112.2 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.87(s,1H),8.98(s,1H),8.08(d,J＝10.0 Hz,1H),8.03(d,J＝7.9Hz,1H),7.72–7.60(m,7H),7.43(d,J＝15.7Hz,1H),6.53(d,J＝15.8 Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 11: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-11)
Compound (I-11) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-11) as a white solid in 80% yield. MP 170.7-172.8 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.81(s,1H),9.12(s,1H),8.33(d,J＝5.8Hz, 1H),8.00(d,J＝5.8Hz,1H),7.70(d,J＝8.2Hz,3H),7.58(d,J＝8.2Hz,3H),7.40(dd,J＝15.0, 7.0Hz,2H),7.30(d,J＝7.5Hz,1H),6.48(d,J＝15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 12: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-12)
Compound (I-12) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-12) as a pale yellow solid, 77% yield. Mp is 166.0-168.2 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.84(s,1H),9.03(s,1H),8.30(d,J＝5.8 Hz,1H),7.89(d,J＝8.8Hz,1H),7.85(d,J＝8.4Hz,2H),7.66(d,J＝8.3Hz,2H),7.58(d,J＝5.8Hz,1H),7.46(s,1H),7.41(d,J＝15.8Hz,1H),7.35(dd,J＝8.8,1.8Hz,1H),6.52(d,J＝15.8Hz, 1H).ESI-MS m/z:370.11[M+H] + .
example 13: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-13)
Compound (I-13) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-13) as a pale yellow solid, yield 79%. Mp is 171.2-173.2 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.84(s,1H),9.15(s,1H),8.34(d,J＝5.6 Hz,1H),7.82(t,J＝7.6Hz,3H),7.71(s,1H),7.68–7.65(m,3H),7.49(dd,J＝8.8,1.9Hz,1H),7.41(d,J＝15.8Hz,1H),6.51(d,J＝15.8Hz,1H).ESI-MS m/z:370.12[M+H] + .
example 14: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-14)
Compound (I-14) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-14) as a pale yellow solid, 75% yield. Mp is 175.2-177.9 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.85(s,1H),9.37(s,1H),8.43(d,J＝5.6 Hz,1H),7.77–7.60(m,7H),7.44(d,J＝15.8Hz,1H),7.27(d,J＝7.5Hz,1H),6.52(d,J＝15.9Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 15: (E) Preparation of-N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-15)
Compound (I-15) structural formula
Step A: preparation of 3-bromo-N- (quinolin-2-yl) benzenesulfonamide
To a solution of 2-aminoquinoline (0.47 g,3.26 mmol) in methylene chloride (50 ml) was added pyridine (1 ml) and 3-bromobenzenesulfonyl chloride (1 g,3.92 mmol) under stirring at 0 ℃. After the addition, the reaction mixture was stirred at 0℃for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 3-bromo-N- (quinolin-2-yl) benzenesulfonamide as a pale yellow solid (0.91 g, yield 77%).
And (B) step (B): preparation of methyl (E) -3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylate
To acetonitrile (50 ml) was added 3-bromo-N- (quinolin-2-yl) benzenesulfonamide (1 g,2.76 mmol), methyl acrylate (0.28 g,3.31 mmol), palladium acetate (6.20 mg,0.0276 mmol), tris (o-methyl)Phenyl) phosphorus (25.20 mg,0.0828 mmol) and triethylamine (6.18 mg,5.52 mmol). At N 2 The reaction mixture was heated to 60℃under protection for reaction for 12h. After completion of the reaction, ethyl acetate (40 ml. Times.3) was extracted, and the organic phases were combined, washed 3 times with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give methyl (E) -3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylate as a white solid (0.89 g, 88% yield).
Step C: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide
To a solution of methyl (E) -3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylate (0.5 g, 1.36 mmol) in methanol (20 ml) was slowly added dropwise a 1mol/L NaOH solution (3 ml) at 0℃with stirring. After stirring for 10 minutes, NH was slowly added dropwise thereto 2 OH solution (3 ml), after the addition was completed, slowly returned to room temperature and stirring was continued for 1h. After the completion of the reaction, the solvent was distilled off under reduced pressure, water (20 ml) was added thereto, pH was adjusted to neutrality with 2mol/L hydrochloric acid, and a solid was precipitated, suction filtration and vacuum drying were carried out to obtain (E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-15) as a white solid (0.42 g, yield 85%). Mp is 197.2-199.4 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.11(s,1H),8.08(d,J＝6.5Hz, 1H),7.87(d,J＝7.8Hz,1H),7.72(d,J＝7.7Hz,1H),7.66(d,J＝7.3Hz,1H),7.58(t,J＝7.5Hz,1H),7.50(dd,J＝16.6,9.0Hz,3H),7.33–7.23(m,2H),6.59(d,J＝15.8Hz,1H).ESI-MS m/z: 370.11[M+H] + .
the compounds of examples 16-20 and examples 22-28 were prepared by the method of example 15 by selecting appropriate starting materials.
Example 16: (E) Preparation of-N-hydroxy-3- (3- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-16)
Compound (I-16) structural formula
(E) -N-hydroxy-3- (3- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-16) as a white solid in 83% yield. MP 182.7-184.4 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.81(s,1H),9.13(s,1H),8.54(d,J＝2.4Hz, 1H),8.01(s,1H),7.87–7.73(m,4H),7.69(d,J＝7.7Hz,1H),7.55–7.42(m,4H),6.52(d,J＝15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 17: (E) Preparation of-N-hydroxy-3- (3- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-17)
Compound (I-17) structural formula
(E) -N-hydroxy-3- (3- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-17) as a pale yellow solid in 79% yield. Mp 203.1-205.6 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.39(d,J＝8.1Hz,1H),8.18(d,J＝6.2Hz,1H), 8.00(s,1H),7.79(d,J＝6.3Hz,1H),7.66(d,J＝8.1Hz,1H),7.64–7.59(m,2H),7.49–7.43(m,2H),7.38(t,J＝7.3Hz,1H),6.96(d,J＝6.1Hz,1H),6.54(d,J＝15.8Hz,1H).ESI-MS m/z: 370.10[M+H] + .
example 18: (E) Preparation of-N-hydroxy-3- (3- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-18)
Compound (I-18) structural formula
/>
(E) -N-hydroxy-3- (3- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-18) as a pale yellow solid in 66% yield. MP 222.8-224.6 deg.C, 1 H-NMR(600MHz,DMSO-d 6 )δ10.79(s,1H),10.27(s,1H),9.11(s,1H),8.85 (dd,J＝4.0,1.2Hz,1H),8.42(d,J＝8.5Hz,1H),7.84(d,J＝12.6Hz,2H),7.76(d,J＝7.7Hz,1H),7.62(dd,J＝15.2,7.3Hz,2H),7.52(t,J＝7.8Hz,1H),7.48–7.40(m,2H),7.18(d,J＝7.5 Hz,1H),6.45(d,J＝15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 19: (E) Preparation of-N-hydroxy-3- (3- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-19)
Compound (I-19) structural formula
(E) -N-hydroxy-3- (3- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-19) as a pale yellow solid in 61% yield. Mp of 186.3-189.4 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.80(s,1H),9.13(s,1H),8.76–8.72(m,1H), 8.23(d,J＝8.2Hz,1H),8.01(s,1H),7.88(d,J＝9.0Hz,1H),7.80–7.72(m,2H),7.59(d,J＝1.7 Hz,1H),7.54(t,J＝7.8Hz,1H),7.50(dd,J＝9.1,2.3Hz,1H),7.48–7.40(m,2H),6.51(d,J＝15.8Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 20: (E) Preparation of-N-hydroxy-3- (3- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-20)
Compound (I-20) structural formula
(E) -N-hydroxy-3- (3- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-20) as a pale yellow solid in 90% yield. Mp 170.5-173.5 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.74(dd,J＝4.1,1.5Hz,1H),8.17(d,J＝7.8Hz, 1H),8.02(s,1H),7.79(t,J＝7.4Hz,2H),7.73(d,J＝7.7Hz,1H),7.58(s,1H),7.54(t,J＝7.8Hz,1H),7.45(d,J＝15.8Hz,1H),7.36(dd,J＝8.8,1.9Hz,1H),7.32(dd,J＝8.1,4.2Hz,1H),6.53(d,J＝15.9Hz,1H).ESI-MS m/z:370.09[M+H] + .
example 22: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-22)
Compound (I-22) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-22) as a white solid in 64% yield. Mp is 175.9-177.8 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.86(s,1H),9.10(s,1H),8.38(d,J＝8.3Hz, 1H),8.16(s,1H),7.91(d,J＝7.7Hz,1H),7.75–7.59(m,5H),7.48(d,J＝15.6Hz,3H),6.94(s,1H),6.56(d,J＝15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 23: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-23)
Compound (I-23) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-23) as a pale yellow solid, 89% yield. Mp is 92.3-95.1 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.85(s,1H),8.96(s,1H),8.11(s,1H),7.91 (d,J＝8.1Hz,1H),7.86(d,J＝7.8Hz,1H),7.76(d,J＝8.1Hz,1H),7.70(d,J＝7.7Hz,1H),7.60(t,J＝7.4Hz,1H),7.52(t,J＝7.8Hz,1H),7.46(d,J＝15.8Hz,1H),7.39(dd,J＝15.9,8.6Hz, 2H),6.56(d,J＝15.8Hz,1H).ESI-MS m/z:370.12[M+H] + .
example 24: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-24)
Compound (I-24) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-24) as a pale yellow solid, 82% yield. Mp is 175.4-177.7 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.81(s,1H),9.11(s,1H),9.07(s,1H), 8.09(s,1H),8.07(d,J＝8.1Hz,1H),8.02(d,J＝8.4Hz,1H),7.84(s,1H),7.74(d,J＝7.6Hz,1H),7.68(t,J＝7.5Hz,1H),7.66–7.61(m,2H),7.51(t,J＝7.7Hz,1H),7.42(d,J＝15.7Hz,1H), 6.46(d,J＝15.8Hz,1H).ESI-MS m/z:370.09[M+H] + .
example 25: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-25)
Compound (I-25) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-25) as a pale yellow solid, yield 69%. Mp 173.0-176.3 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.77(s,1H),10.26(s,1H),9.20(s,1H), 8.37(d,J＝5.9Hz,1H),7.90(d,J＝5.8Hz,1H),7.84(s,1H),7.79(s,1H),7.70(d,J＝7.5Hz,1H),7.64(d,J＝7.8Hz,1H),7.49(dt,J＝15.5,7.8Hz,2H),7.42(d,J＝15.8Hz,1H),7.36(d,J＝ 7.5Hz,1H),6.45(d,J＝15.8Hz,1H).ESI-MS m/z:370.09[M+H] + .
example 26: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-26)
Compound (I-26) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-26) as a white solid in 78% yield. Mp 205.3-207.7 deg.c, 1 H-NMR(600MHz,DMSO-d 6 )δ10.85(s,1H),9.12(s,1H),8.37(d,J＝5.7Hz, 1H),8.06(s,1H),8.00(d,J＝8.8Hz,1H),7.82(d,J＝7.8Hz,1H),7.77(d,J＝7.7Hz,1H),7.70(d,J＝5.7Hz,1H),7.60–7.55(m,2H),7.47(d,J＝16.3Hz,1H),7.44(d,J＝8.9Hz,1H),6.54(d, J＝15.9Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 27: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-27)
Compound (I-27) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-27) as a white solid in 65% yield. Mp is 197.2-199.5 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.83(s,1H),9.19(s,1H),8.37(d,J＝5.6Hz, 1H),8.02(s,1H),7.85(d,J＝8.9Hz,1H),7.77(dd,J＝11.6,7.6Hz,3H),7.69(d,J＝5.6Hz,1H),7.56–7.51(m,2H),7.46(d,J＝15.8Hz,1H),6.52(d,J＝15.9Hz,1H).ESI-MS m/z:370.12[M+ H] + .
example 28: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-28)
Compound (I-28) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-28) as a pale yellow solid in 88% yield. MP 142.4-145.1 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.77(s,1H),9.46(s,1H),8.37(d,J＝5.6 Hz,1H),7.89(s,1H),7.67(d,J＝7.9Hz,2H),7.65(d,J＝5.6Hz,1H),7.51(t,J＝7.8Hz,1H),7.47(t,J＝7.7Hz,2H),7.42(d,J＝15.8Hz,1H),7.18(d,J＝7.5Hz,1H),6.47(d,J＝15.8Hz, 1H).ESI-MS m/z:370.13[M+H] + .
EXAMPLE 29 in vitro anti-tumor cell proliferation Activity test of the Compounds of interest
The MTT method is adopted to test the in vitro antiproliferative activity of the target compound on two cell lines, namely A549 and MCF-7. Cells were placed in RPMI-1640 medium containing 10% Fetal Bovine Serum (FBS) and in a medium containing 5% CO 2 Is cultured in an incubator at 37 ℃. Taking cells in logarithmic growth phase at 3×10 per well 3 Density of individual cells were seeded in 96-well plates and placed in a chamber containing 5% CO 2 The culture is continued for about 18-24 hours at 37 ℃. According to the experimental design, 100 mu L of compounds with different concentration gradients are added into each hole, a blank control group is not added with compounds, a positive control group is added with Belinostat with the same concentration gradient, and the culture is continued in an incubator for 48 hours. When the acting time of the medicine reaches, avoiding each holeLight was added to 20. Mu.L of MTT solution at a concentration of 5mg/ml, incubated in an incubator for 4-6h, the culture broth was then discarded, 100. Mu.L of DMSO solution was added to each well, and shaking was performed in the absence of light for 5min. The inhibition ratio of the test compound was calculated by measuring the OD value at 570nm wavelength of a 96-well plate in a microplate reader, respectively, inhibition ratio (%) = (100% absorbance average value-compound absorbance average value)/(100% absorbance average value-blank group absorbance average value) ×100, and IC was calculated by SPSS software 50 Values.
TABLE 1 antiproliferative activity results of target compounds on two classes of cancer cell lines
/>
Claims (6)
1. The hydroxamic acid compound containing quinoline or isoquinoline as shown in the formula I and pharmaceutically acceptable salt thereof are characterized in that:
wherein, the liquid crystal display device comprises a liquid crystal display device,
x is N, Y is CH; or X is CH, then Y is N;
w is-ch=ch-CO-;
ring A is
The pharmaceutically acceptable salt refers to an acid addition salt formed by the hydroxamic acid compound containing quinoline or isoquinoline and an inorganic acid or an organic acid; the inorganic acid is selected from one of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; the organic acid is selected from acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, citric acid, salicylic acid, tartaric acid and p-toluenesulfonic acid.
2. The compound and pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is specifically one of the following compounds:
(E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-1);
(E) -N-hydroxy-3- (4- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-2);
(E) -N-hydroxy-3- (4- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-3);
(E) -N-hydroxy-3- (4- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-4);
(E) -N-hydroxy-3- (4- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-5);
(E) -N-hydroxy-3- (4- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-6);
(E) -N-hydroxy-3- (4- (N- (quinolin-8-yl) sulfanyl) phenyl) acrylamide (I-7);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-8);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-9);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-10);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-11);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-12);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-13);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-14);
(E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-15);
(E) -N-hydroxy-3- (3- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-16);
(E) -N-hydroxy-3- (3- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-17);
(E) -N-hydroxy-3- (3- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-18);
(E) -N-hydroxy-3- (3- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-19);
(E) -N-hydroxy-3- (3- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-20);
(E) -N-hydroxy-3- (3- (N- (quinolin-8-yl) sulfanyl) phenyl) acrylamide (I-21);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-22);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-23);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-24);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-25);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-26);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-27);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-28).
3. The preparation of a quinoline-or isoquinoline-containing hydroxamic acid compound according to claim 1, wherein one of the following two routes is adopted:
route one:
the substituents are defined in the claims, reagents and conditions: HSO 3 Cl,12h；b.RNH 2 ,CH 2 Cl 2 Pyridine, 1h; c.CH 3 OH,H 2 SO 4 ,4h；d.NH 2 OH,1N NaOH,CH 3 OH,1h；
Route two:
the substituents are defined in the claims, reagents and conditions: RNH (rnh) 2 ,CH 2 Cl 2 Pyridine, 2h; b. methyl acrylate, pd (OAc) 2 ,POT,Et 3 N,CH 3 CN,60℃,12h；c.NH 2 OH,1N NaOH,CH 3 OH,1h。
4. A pharmaceutical composition comprising a compound according to any one of claims 1-2 and a pharmaceutically acceptable carrier therefor.
5. Use of a compound according to any one of claims 1-2, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the prevention and/or treatment of diseases associated with histone deacetylase.
6. Use of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the prevention and/or treatment of liver cancer, colon cancer, pancreatic cancer, lung cancer, gastric cancer, breast cancer or ovarian cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210733176.2A CN115160222B (en) | 2022-06-27 | 2022-06-27 | Hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210733176.2A CN115160222B (en) | 2022-06-27 | 2022-06-27 | Hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115160222A CN115160222A (en) | 2022-10-11 |
| CN115160222B true CN115160222B (en) | 2023-10-13 |
Family
ID=83487999
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210733176.2A Active CN115160222B (en) | 2022-06-27 | 2022-06-27 | Hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115160222B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111601805A (en) * | 2017-11-27 | 2020-08-28 | 科学和工业研究协会 | Indole (sulfamoyl) N-hydroxybenzamide derivatives as selective HDAC inhibitors |
| WO2022049599A1 (en) * | 2020-09-05 | 2022-03-10 | Council Of Scientific And Industrial Research (An Indian Registered Body Incorporated Under The Regn. Of Soc. Act (Act Xxi Of 1860)) | Hdac inhibitors for idiopathic pulmonary fibrosis and other lung inflammatory disorders |
-
2022
- 2022-06-27 CN CN202210733176.2A patent/CN115160222B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111601805A (en) * | 2017-11-27 | 2020-08-28 | 科学和工业研究协会 | Indole (sulfamoyl) N-hydroxybenzamide derivatives as selective HDAC inhibitors |
| WO2022049599A1 (en) * | 2020-09-05 | 2022-03-10 | Council Of Scientific And Industrial Research (An Indian Registered Body Incorporated Under The Regn. Of Soc. Act (Act Xxi Of 1860)) | Hdac inhibitors for idiopathic pulmonary fibrosis and other lung inflammatory disorders |
Non-Patent Citations (2)
| Title |
|---|
| 4-Indolyl-N-hydroxyphenylacrylamides as potent HDAC class I and IIB inhibitors in vitro and in vivo;Samir Mehndiratta，等;European Journal of Medicinal Chemistry;第134卷;第15页图2-3、第17页表1-2 * |
| Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1;Ehab Ghazy ,等;European Journal of Medicinal Chemistry;第200卷;第4页图5、第5页表1、第9页表1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115160222A (en) | 2022-10-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102482673B1 (en) | Aromatic acetylenic or aromatic ethylenic compounds, their intermediates, manufacturing methods, drug compositions and uses | |
| JP4405602B2 (en) | Histone deacetylase inhibitor | |
| AU2016251253B2 (en) | Condensed-ring pyrimidylamino derivative, preparation method therefor, and intermediate, pharmaceutical composition and applications thereof | |
| BG107935A (en) | Tetrahydropyridine derivatives, their preparation and their use as cell proliferation inhibitors | |
| RU2600928C2 (en) | Cyanoquinoline derivatives | |
| RU2730500C2 (en) | Quinazolinone derivative, a method for production thereof, a pharmaceutical composition and use thereof | |
| KR101908333B1 (en) | Naphthylamide compound, preparation method and use thereof | |
| WO2017186140A1 (en) | Method for preparing tyrosine kinase inhibitor and derivative thereof | |
| CA3067941C (en) | Coumarin-like cyclic compound as mek inhibitor and use thereof | |
| CN107573327B (en) | Indazole-formamide-pyridone derivative and preparation method and application thereof | |
| KR20100019507A (en) | Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics | |
| CN111303121A (en) | 4-phenoxypyridine compound containing quinoxalinone and application thereof | |
| CN106660970B (en) | Quinazoline derivatives | |
| CN109280032B (en) | Pyridazinone mother nucleus structure histone deacetylase inhibitor and preparation method and application thereof | |
| CN115160222B (en) | Hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof | |
| CN110981882B (en) | Chelidonium nitric oxide donor derivatives, and preparation method and application thereof | |
| KR20120074264A (en) | Heterocyclic substituted acardite derivates and use thereof | |
| CA2493854A1 (en) | Phosphodiesterase inhibitor | |
| CN104672136B (en) | 1-substituted phenanthryl-N-alkyl (acyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivative as well as preparation method and purpose thereof | |
| CN112390781B (en) | Diaryl-substituted 1,1-ethylene compound, preparation method and application | |
| CN113072550B (en) | High-selectivity fibroblast growth factor receptor inhibitor and application thereof | |
| EA021627B1 (en) | 4-(methylaminophenoxy)pyridin-3-yl-benzamide derivatives for treating cancer | |
| CN108341774B (en) | Substituted quinolinone inhibitors | |
| CN109384727B (en) | Phthalazinone compound, preparation method, pharmaceutical composition and application thereof | |
| CN115010642B (en) | Beta-elemene imide derivative and application thereof |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |