CN117586210A - Dimethyl sulfide substituted 2, 3-dihydrofuran derivative and preparation method and application thereof - Google Patents

Dimethyl sulfide substituted 2, 3-dihydrofuran derivative and preparation method and application thereof Download PDF

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CN117586210A
CN117586210A CN202311532062.2A CN202311532062A CN117586210A CN 117586210 A CN117586210 A CN 117586210A CN 202311532062 A CN202311532062 A CN 202311532062A CN 117586210 A CN117586210 A CN 117586210A
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dihydrofuran
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黄宏丽
李闪
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Liaocheng University
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Abstract

The invention belongs to the technical field of medicines, and relates to a 2, 3-dihydrofuran derivative shown in a general formula I, a stereoisomer thereof, and pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein substituent Ar 1 、R 1 、R 2 Having the definitions given in the description. The invention also relates to a method for preparing the compound of the general formula I, and the related application of the compound in preparing, treating and preventing inflammatory diseases.

Description

Dimethyl sulfide substituted 2, 3-dihydrofuran derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a dimethyl sulfide substituted 2, 3-dihydrofuran derivative, a preparation method thereof and application thereof in preparing anti-inflammatory medicines.
Background
Inflammation is a basic pathological process generated by the body on the damage of tissues caused by various inflammatory stimulus factors, and is also a common disease and frequently-occurring disease. Inflammatory responses are mediated by various inflammatory mediators, and in severe cases, manifest as fever, accompanied by a massive increase in leukocytes and macrophages. It can cause severe lesions to occur in certain organs of the body. For the treatment of inflammation, NSAIDs, which are non-steroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs, NSAIDs), have evolved into drugs with excellent anti-inflammatory, analgesic and antirheumatic activity and a wide variety of drugs, and are a leading part of the world's medical output. However, prolonged administration of NSAIDs can lead to adverse effects such as gastrointestinal tract and cardiovascular toxicity. Therefore, the search for new anti-inflammatory agents with high efficacy and low toxicity is one of the key and hot spots of future research.
The 2, 3-dihydrofuran skeleton widely exists in natural products and medicines, is an important intermediate for medicine and fine chemical synthesis, and can show a certain anti-inflammatory activity. Therefore, it is of great importance to construct the framework. In recent years, the preparation method of the 2, 3-dihydrofuran derivatives mainly comprises Pd (II) -catalyzed organoboron-mediated Heck reaction, pd-catalyzed continuous reaction of allene intermediates, copper-catalyzed asymmetric [3+2] cycloaddition reaction of propynyl ester and beta-ketophosphonate, and the like. However, these reactions generally require various metal catalysts, excessive oxidizing agents, or are synthesized by multi-step reactions, and have problems such as complex synthesis, expensive heavy metals, and high synthesis cost. In view of this, it is necessary to develop a method for constructing 2, 3-dihydrofuran derivatives under mild reaction conditions and in a highly efficient green manner.
The inventor designs and synthesizes a series of novel dimethyl sulfide substituted 2, 3-dihydrofuran derivatives by using alpha-allyl-beta-ketosulfone as a substrate through sulfination reaction. The in vitro cyclooxygenase-2 (COX-2) inhibitor and the cytotoxic activity screening show that the compound has higher biological activity.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a 2, 3-dihydrofuran derivative with novel structure and application thereof; the 2, 3-dihydrofuran derivatives have strong anti-inflammatory effect, and also relate to the application of the compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparing medicines for treating inflammatory diseases, in particular to the preparation of medicines for treating and preventing inflammatory diseases.
In order to achieve the above object, the present invention provides 2, 3-dihydrofurans represented by the general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein:
Ar 1 is hydrogen, or is benzene substituted by methyl, methoxy or halogen, or is biphenyl or naphthalene group;
R 1 methyl, methoxy or halogen substituted at different positions;
R 2 is hydrogen or methyl.
The halogen is fluorine, chlorine or bromine.
The present invention provides compounds of formula I, and geometric isomers thereof, or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, selected from the group consisting of:
wherein R is 1 Is H, me, OMe, t bu, F, cl or Br;
R 1 when=h, named 2- ((methylthio) methyl) -5-phenyl-4-benzenesulfonyl-2, 3-dihydrofuran;
R 1 when=4-Me, it is named 2- ((methylthio) methyl) -5-phenyl-4-p-methylbenzenesulfonyl-2, 3-dihydrofuran;
R 1 when=4-OMe, it is named 4- (4-methoxyphenyl) sulfonyl-2- ((methylthio) methyl) -5-phenyl-2, 3-dihydrofuran;
R 1 ＝4- t bu, designated 4- (4-tert-butylphenyl) sulfonyl-2- ((methylthio) methyl) -5-phenyl-2, 3-dihydrofuran;
R 1 when=4-F, it is named 4- (4-fluorophenyl) sulfonyl-2- ((methylthio) methyl) -5-phenyl-2, 3-dihydrofuran;
R 1 when=4-Cl, it is named 4- (4-chlorophenyl) sulfonyl-2- ((methylthio) methyl) -5-phenyl-2, 3-dihydrofuran;
R 1 when=4-Br, it is named 4- (4-bromophenyl) sulfonyl-2- ((methylthio) methyl) -5-phenyl-2, 3-dihydrofuran;
R 1 when=3-Me, it is named 2- ((methylthio) methyl) -5-phenyl-4- (3-methylphenyl) sulfonyl-2, 3-dihydrofuran;
R 1 when=2-Me, the sequence is the oneNamed 2- ((methylthio) methyl) -5-phenyl-4- (2-methylphenyl) sulfonyl-2, 3-dihydrofuran;
R 1 when=2-Cl, named 2- ((methylthio) methyl) -5-phenyl-4- (2-chlorophenyl) sulfonyl-2, 3-dihydrofuran;
wherein Ar is 1 Is 2-naphthalene, 4-biphenyl, or benzene ring substituted at different positions, selected from Me, OMe, F, cl or Br; ar (Ar) 1 When =2-naphthalene-designated 4- ((4-methoxyphenyl) sulfonyl) -2- ((methylsulfanyl) methyl) -5- (naphthalen-2-yl) -2, 3-dihydrofuran; ar (Ar) 1 When=4-biphenyl-, the product is designated as 5- ([ 1,1' -diphenyl)]-4-yl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran;
Ar 1 ＝4-MeC 6 H 5 -when named 5- (4-methylphenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran;
Ar 1 ＝4-OMeC 6 H 5 -when named 5- (4-methoxyphenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylsulfanyl) methyl) -2, 3-dihydrofuran;
Ar 1 ＝4-ClC 6 H 5 -when named 5- (4-chlorophenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran;
Ar 1 ＝4-BrC 6 H 5 -when named 5- (4-bromophenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran;
Ar 1 ＝4-FC 6 H 5 -when named 5- (4-fluorophenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran;
Ar 1 ＝3-FC 6 H 5 when it is used, it is designated as 5- (3-fluorophenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran
Ar 1 ＝2-FC 6 H 5 When in use, is named as5- (2-fluorophenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylsulfanyl) methyl) -2, 3-dihydrofuran;
wherein,
R 2 =h or Me, R 3 =h, br, me or OMe;
R 2 ＝Me,R 3 when=h, named 2-methyl-2- ((methylthio) methyl) -5-phenyl-4- (4-methylphenyl) sulfonyl-2, 3-dihydrofuran;
R 2 ＝H,R 3 when=4-Br, it is named 5- (4-bromophenyl) -2- ((methylthio) methyl) -4- (4-methylphenyl) sulfonyl-2, 3-dihydrofuran;
R 2 ＝H,R 3 when=4-Me, it is named 5- (4-methylphenyl) -2- ((methylthio) methyl) -4- (4-methylphenyl) sulfonyl-2, 3-dihydrofuran;
R 2 ＝H,R 3 when=4-OMe, it is named 5- (4-methoxyphenyl) -2- ((methylthio) methyl) -4- (4-methylphenyl) sulfonyl-2, 3-dihydrofuran;
5- (4-chlorophenyl) -4- (4-fluorophenyl) sulfonyl-2- ((methylthio) methyl) -2, 3-dihydrofuran;
5- (4-methoxyphenyl) -4- (4-bromophenyl) sulfonyl-2- ((methylsulfanyl) methyl) -2, 3-dihydrofuran;
the corresponding structural formulas of the 25 compounds are as follows:
in addition, prodrugs of the derivatives of the invention are also encompassed by the invention. Prodrugs of the derivatives of the invention are derivatives of formula I, which may themselves have relatively weak or even no activity, but which, after administration, may be metabolically converted to the corresponding biologically active form under physiological conditions.
The invention can contain the derivative of the formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as active ingredients, and can be mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions.
The pharmaceutical compositions of the present invention may be formulated in several dosage forms, containing some excipients commonly used in the pharmaceutical arts. The above-mentioned several dosage forms can be made into injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment and ointment.
The carriers used in the pharmaceutical compositions of the present invention are of the usual types available in the pharmaceutical arts, including: binders, lubricants, disintegrants, co-solvents, diluents, stabilizers, suspending agents, non-pigmenting agents, flavoring agents, preservatives, solubilizing agents, matrices and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if some drugs are unstable in gastric conditions, they may be formulated as enteric coated tablets.
In-vitro anti-inflammatory activity tests show that the dimethyl sulfide substituted 2, 3-dihydrofuran derivative has anti-inflammatory activity and cytotoxicity to partial tumor cells, so that the compound can be used for preparing medicines for treating and/or preventing inflammatory diseases and preparing anti-tumor medicines.
The tumor cells are human liver cancer cells HepG-2, human colorectal cancer cells HCT116, human cervical cancer cells HeLa or human lung adenocarcinoma cells A549.
The active compounds of the present invention or pharmaceutically acceptable salts and solvates thereof are useful as anti-inflammatory agents.
The examples and preparations provided below further illustrate and exemplify the compounds of the invention and methods of preparing the same. The scope of the following examples and preparations is not intended to limit the scope of the invention in any way. The compounds of formula I according to the invention can be prepared in accordance with scheme 1 from the corresponding starting materials 1-1 (α -allyl- β -ketosulfone compounds) by sulfination.
The synthetic route is as follows:
the synthesis route comprises the steps of mixing substrate, dibromoacetophenone, sodium persulfate and dipotassium hydrogen phosphate in a molar ratio of 1:2:2:2, mixing DMF and DMSO (volume ratio v: v=20:1), and performing N at 80 ℃ 2 Atmosphere, reaction time is 48-66h.
Compared with the prior art, the compound with the dimethyl sulfide substituted 2, 3-dihydrofuran structure has the following advantages:
1. according to the invention, the dimethyl sulfide substituted 2, 3-dihydrofuran derivative with novel structure and good activity is obtained by a one-pot preparation method;
2. the invention has mild reaction conditions and simple and convenient operation; the application range of the reaction substrate is wide, the yield and the selectivity are high, the partial reaction yield can reach more than 90%, the whole reaction is safe and environment-friendly, the cost is low, the economic benefit is high, and the method belongs to green chemical synthesis; the adopted brominating reagent is low-toxicity 2-bromoacetophenone, is cheap and easy to obtain, is easy to feed, and has no pollution, and the auxiliary catalyst sodium persulfate is cheap and easy to obtain;
3. the target product of the invention has better in vitro anti-inflammatory and cytotoxic activity.
Detailed Description
The technical solutions of the present invention will be further described with reference to specific examples, but the implementation is intended to explain the present invention and should not be construed as limiting the present invention, and specific techniques or conditions are not noted in the examples, and are performed according to techniques or conditions described in the literature in the field or according to the product specifications. Unless defined otherwise, technical terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains; the test reagents used, unless specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by Bruker ARX-500, and the mass spectrum is measured by Agilent 1100 LC/MS; the reagents used are analytically pure or chemically pure.
Example 1
Preparation of 2- ((methylthio) methyl) -5-phenyl-4-p-toluenesulfonyl-2, 3-dihydrofuran (a-1)
In a reaction flask, 2- (4-methylphenyl) sulfonyl) -1-phenylpentyl-4-en-1-one substrate 1-1 (1 eq.), dibromoacetophenone (2 eq.), sodium persulfate (2 eq.), dipotassium hydrogen phosphate (2 eq.), and DMF as solvent: DMSO (v: v=20:1), N 2 The reaction was stirred at 80℃for 52h. TLC monitoring, after completion of the reaction, ethyl acetate extraction. The organic phase was concentrated under reduced pressure and finally separated by silica gel column chromatography to give compound a-1 as pale yellow oil in 75% yield.
1 H NMR(500MHz,CDCl 3 ):δ H 7.66(dd,J＝8.0,1.5Hz,2H),7.63(d,J＝8.0Hz,2H),7.45(tt,J＝8.0,6.0,1.5Hz,1H),7.39(t,J＝8.0Hz,2H),7.24(d,J＝8.0Hz,2H),4.92-4.86(m,1H),3.27(dd,J＝14.7,10.3Hz,1H),2.98(dd,J＝14.7,7.5Hz,1H),2.83(dd,J＝13.7,6.3Hz,1H),2.70(dd,J＝13.7,6.3Hz,1H),2.40(s,3H),2.13(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 163.0,143.7,138.9,130.9,129.6,129.5,128.4,127.8,127.0,110.4,80.7,38.8,37.2,21.5,16.3。
The preparation methods of the compounds of examples a-2 to a-25 are the same as those of example a-1, except that the substitution of the starting substrate is performed only according to the difference of the objective product.
Example 2
Preparation of 2- ((methylthio) methyl) -5-phenyl-4-benzenesulfonyl-2, 3-dihydrofuran (a-2)
Yield 84%, pale yellow oily compound. 1 H NMR(500MHz,CDCl 3 ):δ H 7.74(dd,J＝7.7Hz,2H),7.66(d,J＝7.7Hz,2H),7.54(t,J＝7.7Hz,1H),7.47-7.43(m,3H),7.39(t,J＝7.7Hz,2H),4.94-4.88(m,1H),3.29(dd,J＝14.7,10.5Hz,1H),3.00(dd,J＝14.7,7.3Hz,1H),2.83(dd,J＝13.7,6.0Hz,1H),2.71(dd,J＝13.7,6.0Hz,1H),2.13(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 163.5,141.8,132.8,131.0,129.5,128.9,128.3,127.8,126.9,110.1,80.8,38.8,37.1,16.4。
Example 3
Preparation of 4- (4-fluorophenyl) sulfonyl-2- ((methylthio) methyl) -5-phenyl-2, 3-dihydrofuran (a-3)
Yield 67%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.74-7.72(m,2H),7.64(d,J＝7.7Hz,2H),7.47(t,J＝7.7Hz,1H),7.39(t,J＝7.7Hz,2H),7.12-7.08(m,2H),4.96-4.90(m,1H),3.29(dd,J＝14.7,9.7Hz,1H),3.00(dd,J＝14.7,6.5Hz,1H),2.83(dd,J＝13.7,6.5Hz,1H),2.74(dd,J＝13.7,6.5Hz,1H),2.14(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 171.1,165.2(d,J＝255.5Hz),163.7,137.9(d,J＝3.3Hz),131.1,129.7(d,J＝9.3Hz),129.4,128.2,127.9,116.1(d,J＝22.6Hz),110.2,80.8,38.9,37.0,16.4。
Example 4
Preparation of 4- (4-chlorophenyl) sulfonyl-2- ((methylthio) methyl) -5-phenyl-2, 3-dihydrofuran (a-4)
Yield 80%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.66-7.63(m,4H),7.47(t,J＝7.3Hz,1H),7.41-7.38(m,4H),4.96-4.90(m,1H),3.28(dd,J＝14.5,10.5Hz,1H),3.00(dd,J＝14.5,7.5Hz,1H),2.83(dd,J＝13.7,6.0Hz,1H),2.74(dd,J＝13.7,6.0Hz,1H),2.13(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 164.0,140.3,139.4,131.1,129.4,129.2,128.4,128.2,127.9,109.9,80.9,38.8,36.9,16.4。
Example 5
Preparation of 4- (4-bromophenyl) sulfonyl-2- ((methylthio) methyl) -5-phenyl-2, 3-dihydrofuran (a-5)
Yield 73%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.64(dd,J＝8.3,1.3Hz,2H),7.57(s,4H),7.49-7.45(m,1H),7.40(t,J＝7.5Hz,2H),4.96-4.90(m,1H),3.28(dd,J＝14.5,10.5Hz,1H),3.00(dd,J＝14.5,7.5Hz,1H),2.83(dd,J＝13.5,6.0Hz,1H),2.74(dd,J＝13.5,6.0Hz,1H),2.13(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 164.1,140.8,132.2,131.1,129.4,128.5,128.2,127.9,109.8,80.9,38.8,36.9,16.4。
Example 6
Preparation of 4- (4-methoxyphenyl) sulfonyl-2- ((methylthio) methyl) -5-phenyl-2, 3-dihydrofuran (a-6)
Yield 98%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.68-7.64(m,4H),7.45(t,J＝7.3Hz,1H),7.39(t,J＝7.3Hz,2H),6.90(d,J＝8.5Hz,2H),4.94-4.86(m,1H),3.84(s,3H),3.26(dd,J＝14.7,10.3Hz,1H),2.97(dd,J＝14.7,7.0Hz,1H),2.83(dd,J＝14.0,6.0Hz,1H),2.71(dd,J＝14.0,6.0Hz,1H),2.13(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 163.1,162.6,133.5,130.8,129.4,129.2,128.5,127.8,114.1,110.8,80.7,55.6,38.8,37.2,16.3。
Example 7
Preparation of 4- (4-tert-butylphenyl) sulfonyl-2- ((methylthio) methyl) -5-phenyl-2, 3-dihydrofuran (a-7)
Yield 76%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.68-7.65(m,4H),7.46-7.43(m,3H),7.38(t,J＝7.3Hz,2H),4.94-4.87(m,1H),3.28(dd,J＝14.7,10.3Hz,1H),3.00(dd,J＝14.7,6.5Hz,1H),2.84(dd,J＝13.7,6.5Hz,1H),2.71(dd,J＝13.7,6.5Hz,1H),2.12(s,3H),1.32(s,9H)； 13 C NMR(126MHz,CDCl 3 ):δ c 163.0,156.6,138.7,130.9,129.5,128.4,127.8,126.9,125.9,110.4,80.8,38.8,37.1,35.1,31.1,16.4。
Example 8
Preparation of 2- ((methylthio) methyl) -5-phenyl-4- (3-methylphenyl) sulfonyl-2, 3-dihydrofuran (a-8)
Yield 59%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.67-7.65(m,2H),7.54-7.52(m,2H),7.47-7.44(m,1H),7.41-7.38(m,2H),7.33-7.32(m,2H),4.94-4.88(m,1H),3.28(dd,J＝14.7,10.3Hz,1H),3.00(dd,J＝14.7,7.5Hz,1H),2.83(dd,J＝13.7,6.0Hz,1H),2.72(dd,J＝13.7,6.0Hz,1H),2.35(s,3H),2.13(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 163.3,141.6,139.1,133.6,130.9,129.4,128.8,128.4,127.8,127.3,124.0,110.3,80.8,38.8,37.1,21.2,16.3。
Example 9
Preparation of 2- ((methylthio) methyl) -5-phenyl-4- (2-chlorophenyl) sulfonyl-2, 3-dihydrofuran (a-9)
Yield 91%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.95(d,J＝8.0Hz,1H),7.55(d,J＝7.0Hz,2H),7.36-7.32(m,3H),7.27-7.26(m,1H),7.26-7.20(m,2H),5.01-4.95(m,1H),3.41(dd,J＝14.5,10.0Hz,1H),3.10(dd,J＝14.5,7.5Hz,1H),2.91(dd,J＝13.7,6.5Hz,1H),2.77(dd,J＝13.7,6.5Hz,1H),2.16(s,3H). 13 C NMR(126MHz,CDCl 3 ):δ c 164.2,138.2,133.7,132.5,131.5,131.3,130.9,129.2,128.1,127.7,126.5,109.2,81.3,38.8,37.1,16.3。
Example 10
Preparation of 2- ((methylthio) methyl) -5-phenyl-4- (2-methylphenyl) sulfonyl-2, 3-dihydrofuran (a-10)
Yield 73%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.92(d,J＝8.0Hz,1H),7.63(d,J＝7.5Hz,2H),7.41-7.36(m,2H),7.32(t,J＝7.5Hz,2H),7.23(t,J＝7.5Hz,1H),7.19(d,J＝7.5Hz,1H),4.96-4.90(m,1H),3.22(dd,J＝14.7,10.7Hz,1H),2.93(dd,J＝14.7,7.7Hz,1H),2.84(dd,J＝13.7,6.0Hz,1H),2.73(dd,J＝13.7,6.0Hz,1H),2.42(s,3H),2.13(s,3H)； 13 CNMR(126MHz,CDCl 3 ):δ c 163.1,138.7,137.6,132.9,132.3,130.9,129.5,129.4,128.1,127.7,125.9,109.6,80.8,38.9,37.1,19.8,16.4。
Example 11
Preparation of 4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -5- (naphthalen-2-yl) -2, 3-dihydrofuran (a-11)
Yield 57%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 8.22(s,1H),7.90(d,J＝8.3Hz,1H),7.84(t,J＝8.3Hz,2H),7.71(dd,J＝8.5,1.0Hz,1H),7.68(d,J＝8.5Hz,2H),7.56-7.51(m,2H),6.85(d,J＝8.5Hz,2H),4.98-4.92(m,1H),3.80(s,3H),3.33(dd,J＝14.7,10.5Hz,1H),3.05(dd,J＝14.7,7.3Hz,1H),2.88(dd,J＝14.0,6.0Hz,1H),2.75(dd,J＝14.0,6.0Hz,1H),2.15(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 163.0,162.4,134.3,133.5,132.2,130.3,129.2,128.9,127.7,127.5,127.4,126.5,125.8,125.7,114.1,111.2,80.7,55.5,38.9,37.3,16.4。
Example 12
Preparation of 5- ([ 1,1' -diphenyl ] -4-yl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylsulfanyl) methyl) -2, 3-dihydrofuran (a-12)
Yield 70%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.78(d,J＝8.7Hz,2H),7.72(d,J＝8.7Hz,2H),7.62(d,J＝8.7Hz,4H),7.46(t,J＝7.5Hz,2H),7.38(t,J＝7.5Hz,1H),6.92(d,J＝8.7Hz,2H),4.94-4.88(m,1H),3.83(s,3H),3.28(dd,J＝14.7,10.5Hz,1H),2.99(dd,J＝14.7,7.3Hz,1H),2.85(dd,J＝13.7,6.0Hz,1H),2.72(dd,J＝13.7,6.0Hz,1H),2.15(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 163.1,162.1,143.6,140.1,133.5,130.0,129.2,128.8,127.8,127.2,127.1,126.4,114.1,110.7,80.6,55.6,38.8,37.3,16.3。
Example 13
Preparation of 5- (4-methoxyphenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran (a-13)
Yield 34%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.69(d,J＝8.5Hz,4H),6.92-6.89(m,4H),4.87-4.81(m,1H),3.84(s,6H),3.24(dd,J＝14.5,10.5Hz,1H),2.94(dd,J＝14.5,7.0Hz,1H),2.81(dd,J＝14.0,6.0Hz,1H),2.67(dd,J＝14.0,7.0Hz,1H),2.12(s,3H). 13 C NMR(126MHz,CDCl 3 ):δ c 163.0,162.4,161.7,133.8,131.3,129.0,120.7,114.1,113.2,109.1,80.2,55.6,55.3,38.8,37.3,16.3。
Example 14
Preparation of 5- (4-methylphenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran (a-14)
Yield 43%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.68(d,J＝8.7Hz,2H),7.58(d,J＝7.7Hz,2H),7.19(d,J＝7.7Hz,2H),6.90(d,J＝8.7Hz,2H),4.89-4.83(m,1H),3.84(s,3H),3.24(dd,J＝14.5,10.3Hz,1H),2.95(dd,J＝14.5,7.5Hz,1H),2.81(dd,J＝13.7,6.0Hz,1H),2.68(dd,J＝13.7,6.0Hz,1H),2.38(s,3H),2.12(s,3H). 13 C NMR(126MHz,CDCl 3 ):δ c 163.0,162.7,141.2,133.7,129.4,129.1,128.5,125.6,114.1,110.0,80.5,55.6,38.8,37.2,21.5,16.3。
Example 15
Preparation of 5- (4-bromophenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran (a-15)
Yield 68%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.67(d,J＝9.0Hz,2H),7.56(d,J＝8.5Hz,2H),7.52(d,J＝8.5Hz,2H),6.92(d,J＝9.0Hz,2H),4.91-4.85(m,1H),3.85(s,3H),3.23(dd,J＝14.7,10.3Hz,1H),2.94(dd,J＝14.7,7.5Hz,1H),2.81(dd,J＝13.7,6.0Hz,1H),2.69(dd,J＝13.7,6.0Hz,1H),2.12(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 163.2,161.1,133.1,131.1,129.2,127.3,125.5,114.2,111.4,80.7,55.6,38.8,37.2,16.3。
Example 16
Preparation of 5- (4-chlorophenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran (a-16)
Yield 53%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.67(d,J＝9.0Hz,2H),7.64(d,J＝8.5Hz,2H),7.36(d,J＝8.5Hz,2H),6.92(d,J＝9.0Hz,2H),4.91-4.85(m,1H),3.85(s,3H),3.24(dd,J＝14.7,10.5Hz,1H),2.95(dd,J＝14.7,7.3Hz,1H),2.81(dd,J＝13.7,6.0Hz,1H),2.69(dd,J＝13.7,6.0Hz,1H),2.12(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 163.2,161.1,137.0,133.3,130.9,129.2,128.1,126.9,114.2,111.4,80.7,55.6,38.8,37.2,16.3。
Example 17
Preparation of 5- (4-fluorophenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran (a-17)
Yield 75%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.72-7.69(m,2H),7.66(d,J＝8.7Hz,2H),7.07(t,J＝8.7Hz,2H),6.91(d,J＝8.7Hz,2H),4.90-4.84(m,1H),3.84(s,3H),3.24(dd,J＝14.5,10.0Hz,1H),2.95(dd,J＝14.5,7.5Hz,1H),2.81(dd,J＝13.7,6.0Hz,1H),2.69(dd,J＝13.7,6.0Hz,1H),2.12(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 164.1(d,J＝251.1Hz),163.2,161.3,133.3,131.8(d,J＝8.7Hz),129.1,124.5(d,J＝3.4Hz),115.0(d,J＝21.9Hz),114.2,110.8,80.6,55.6,38.8,37.2,16.3； 19 F NMR(470MHz,CDCl 3 ):δ F -108.4(s)ppm。
Example 18
Preparation of 5- (3-fluorophenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran (a-18)
Yield 67%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.68(d,J＝8.7Hz,2H),7.50(d,J＝8.0Hz,1H),7.38-7.34(m,2H),7.16-7.13(m,1H),6.92(d,J＝8.7Hz,2H),4.93-4.87(m,1H),3.85(s,3H),3.26(dd,J＝15.0,10.3Hz,1H),2.97(dd,J＝15.0,7.5Hz,1H),2.82(dd,J＝14.0,6.0Hz,1H),2.71(dd,J＝14.0,6.0Hz,1H),2.13(s,3H). 13 C NMR(126MHz,CDCl 3 ):δ c 163.2,161.9(d,J＝246.8Hz),160.7(d,J＝2.4Hz),133.2,130.3(d,J＝8.4Hz),129.4(d,J＝8.2Hz),129.2,125.5(d,J＝3.3Hz),117.8(d,J＝21.2Hz),116.4(d,J＝23.6Hz),114.2,111.9,80.8,55.6,38.8,37.2,16.3. 19 F NMR(470MHz,CDCl 3 ):δ F -112.8(s)ppm。
Example 19
Preparation of 5- (2-fluorophenyl) -4- ((4-methoxyphenyl) sulfonyl) -2- ((methylthio) methyl) -2, 3-dihydrofuran (a-19)
Yield 91%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.72(d,J＝9.0Hz,2H),7.46-7.42(m,2H),7.20(td,J＝7.5,1.0Hz,1H),7.10(t,J＝9.0Hz,1H),6.94(d,J＝9.0Hz,2H),4.97-4.91(m,1H),3.86(s,3H),3.21(dd,J＝14.5,10.0Hz,1H),2.92(dd,J＝14.5,7.5Hz,1H),2.84(dd,J＝13.7,6.0Hz,1H),2.71(dd,J＝13.7,6.0Hz,1H),2.13(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 163.2,160.9(d,J＝251.6Hz),157.8,132.8,132.3(d,J＝8.4Hz),131.4(d,J＝2.3Hz),129.5,123.6(d,J＝3.5Hz),117.3(d,J＝15.1Hz),115.6(d,J＝21.2Hz),114.2,113.7,81.8,55.6,38.7,36.0,16.3； 19 F NMR(470MHz,CDCl 3 ):δ F -111.8(s)ppm。
Example 20
Preparation of 2-methyl-2- ((methylthio) methyl) -5-phenyl-4- (4-methylphenyl) sulfonyl-2, 3-dihydrofuran (a-20)
Yield 92%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.68-7.58(m,4.0H),7.44(t,J＝7.3Hz,1.0H),7.40-7.36(m,2.0H),7.23-7.21(m,2.0H),3.50(d,J＝10.5Hz,0.3H),3.41(d,J＝10.5Hz,0.3H),3.17(dd,J＝14.7,2.7Hz,1.0H),2.99(d,J＝14.7Hz,0.3H),2.89(d,J＝14.7Hz,0.7H),2.80-2.74(m,1.4H),2.39(s,3.0H),2.10(s,2.1H),1.64(s,0.9H),1.58(s,0.9H),1.49(s,2.1H)； 13 C NMR(126MHz,CDCl 3 ):δ c 162.2,143.6,143.5,139.1,138.8,130.9,130.7,129.5,129.4,128.7,128.4,127.7,127.7,127.0,126.9,110.4,110.2,88.3,85.5,44.6,42.6,42.2,39.1,25.9,25.2,21.5,17.6。
Example 21
Preparation of 5- (4-bromophenyl) -2- ((methylthio) methyl) -4- (4-methylphenyl) sulfonyl-2, 3-dihydrofuran (a-21)
Yield 68%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.63(d,J＝8.0Hz,2H),7.57(d,J＝8.7Hz,2H),7.53(d,J＝8.7Hz,2H),7.26(d,J＝8.0Hz,2H),4.91-4.85(m,1H),3.24(dd,J＝14.7,9.7Hz,1H),2.95(dd,J＝14.7,7.5Hz,1H),2.81(dd,J＝13.7,6.0Hz,1H),2.69(dd,J＝13.7,6.0Hz,1H),2.41(s,3H),2.12(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 161.6,143.9,138.6,131.1,131.1,129.7,127.2,127.0,125.6,111.0,80.8,38.8,37.2,21.6,16.3。
Example 22
Preparation of 5- (4-methylphenyl) -2- ((methylthio) methyl) -4- (4-methylphenyl) sulfonyl-2, 3-dihydrofuran (a-22)
Yield 72%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.64(d,J＝8.3Hz,2H),7.58(d,J＝8.3Hz,2H),7.25(d,J＝8.3Hz,2H),7.20(d,J＝8.3Hz,2H),4.89-4.83(m,1H),3.24(dd,J＝14.7,10.3Hz,1H),2.95(dd,J＝14.7,7.0Hz,1H),2.82(dd,J＝13.7,6.0Hz,1H),2.68(dd,J＝13.7,6.0Hz,1H),2.40(s,3H),2.39(s,3H),2.12(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 163.2,143.6,141.3,139.0,129.5,129.4,128.5,127.0,125.5,109.5,80.6,38.7,37.2,21.5,21.5,16.3。
Example 23
Preparation of 5- (4-methoxyphenyl) -2- ((methylthio) methyl) -4- (4-methylphenyl) sulfonyl-2, 3-dihydrofuran (a-23)
Yield 61%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.70-7.68(m,2H),7.64(d,J＝8.5Hz,2H),7.24(d,J＝8.5Hz,2H),6.91-6.89(m,2H),4.88-4.82(m,1H),3.85(s,3H),3.24(dd,J＝14.5,10.0Hz,1H),2.95(dd,J＝14.5,7.5Hz,1H),2.81(dd,J＝14.0,6.5Hz,1H),2.67(dd,J＝14.0,6.5Hz,1H),2.40(s,3H),2.12(s,3H). 13 C NMR(126MHz,CDCl 3 ):δ c 162.8,161.7,143.6,139.1,131.3,129.6,126.9,120.6,113.2,108.6,80.3,55.3,38.8,37.3,21.5,16.3。
Example 24
Preparation of 5- (4-chlorophenyl) -4- (4-fluorophenyl) sulfonyl-2- ((methylthio) methyl) -2, 3-dihydrofuran (a-24)
Yield 73%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.74(dd,J＝8.5,5.0Hz,2H),7.63(d,J＝8.5Hz,2H),7.38(d,J＝8.5Hz,2H),7.13(t,J＝8.5Hz,2H),4.95-4.89(m,1H),3.25(dd,J＝14.7,10.3Hz,1H),2.96(dd,J＝14.7,7.3Hz,1H),2.81(dd,J＝13.7,6.0Hz,1H),2.72(dd,J＝13.7,6.0Hz,1H),2.12(s,3H)； 13 C NMR(126MHz,CDCl 3 ):δ c 165.1(d,J＝256.0Hz),162.3,137.6(d,J＝3.2Hz),137.3,130.9,129.7(d,J＝9.6Hz),128.2,126.6,116.3(d,J＝22.7Hz),110.5,80.8,38.8,37.0,16.4； 19 F NMR(470MHz,CDCl 3 ):δ F -104.5(s)ppm。
Example 25
Preparation of 5- (4-methoxyphenyl) -4- (4-bromophenyl) sulfonyl-2- ((methylthio) methyl) -2, 3-dihydrofuran (a-25)
Yield 55%, pale yellow oil. 1 H NMR(500MHz,CDCl 3 ):δ H 7.67(d,J＝8.0Hz,2H),7.60(d,J＝9.0Hz,2H),7.57(d,J＝8.0Hz,2H),6.91(d,J＝9.0Hz,2H),4.91-4.86(m,1H),3.85(s,3H),3.26(dd,J＝14.7,10.3Hz,1H),2.97(dd,J＝14.7 7.0Hz,1H),2.81(dd,J＝14.0,6.0Hz,1H),2.71(dd,J＝14.0,6.0Hz,1H),2.13(s,3H). 13 C NMR(126MHz,CDCl 3 ):δ c 163.9,161.9,141.1,132.2,131.3,128.4,127.8,120.3,113.3,108.0,80.5,55.3,38.8,37.1,16.4。
Pharmacological investigation of partial products of the invention
In vitro anti-inflammatory Activity assay
The anti-inflammatory activity of the compound of interest is tested. IC (integrated circuit) 50 The value is defined as the concentration of inhibition of the compound to achieve 50% inhibition of COX-2. In the experiment, celecoxib is selected as a positive control drug; COX-2 solution and test compound were added sequentially in 96-well plates. And incubating at 37 ℃ in dark for 5 minutes, and then performing fluorescence measurement; the compounds prepared in the above examples were tested for in vitro anti-inflammatory activity as shown in table 1.
TABLE 1 COX-2 anti-inflammatory Activity test
From the above test results, it can be seen that the compounds of the general formula I to be protected according to the present invention have a good COX-2 inhibitory activity in vitro, and thus exhibit a certain anti-inflammatory activity.
Cytotoxic Activity assay
And respectively testing the cytotoxic activity of the target compound on human liver cancer cells HepG-2, human colorectal cancer cells HCT116, human cervical cancer cells HeLa and human lung adenocarcinoma cells A549. In the experiment, cisplatin was selected as a positive control drug; sequentially adding cells and culture mediums with different sample concentrations into a 96-well plate, and observing the growth of the cells under the culture condition of 37 ℃; the compounds prepared in the above examples were tested for in vitro cytotoxic activity as shown in table 2.
TABLE 2 cytotoxic Activity test
From the above test results, it can be seen that the compounds of the general formula I to be protected according to the invention have good cytotoxic activity against tumor cells. Therefore, the compound has better industrial application prospect.
The compounds of the general formula I according to the invention can be administered alone, but are generally administered in admixture with a pharmaceutically acceptable carrier, which is selected according to the desired route of administration and standard pharmaceutical practice, and the novel use thereof in the pharmaceutical field is indicated below by the preparation of various pharmaceutical dosage forms of such compounds, for example tablets, capsules, injections, aerosols, suppositories, films, drops, topical liniments and ointments, respectively.
Example 2: tablet formulation
10g of the compound containing the compound of claim 1 (exemplified by the compound of example a-1) was mixed with 20g of an auxiliary material according to a pharmaceutical general tabletting method, and then compressed into 100 tablets each having a weight of 300mg.
Example 3: capsule preparation
10g of the compound containing the compound of claim 1 (exemplified by the compound of example a-1) was used, and 20g of auxiliary materials were uniformly mixed according to the requirements of pharmaceutical capsules, and then filled into hollow capsules, each capsule weighing 300mg.
Example 4: injection preparation
10g of the compound containing the compound according to claim 1 (exemplified by the compound of example a-1) was subjected to activated carbon adsorption by a conventional method of pharmacy, filtered through a 0.65 μm microporous filter membrane, and filled into nitrogen tanks to prepare water needle preparations, each of which was filled with 2mL, and a total of 100 bottles were filled.
Example 5: aerosol formulation
10g of the compound containing the compound according to claim 1 (exemplified by the compound of example a-1) was dissolved in a suitable amount of propylene glycol, and distilled water and other radiation materials were added to prepare 500mL of a clear solution.
Example 6: suppository
10g of a compound containing the compound according to claim 1 (exemplified by the compound of example a-1) is ground, added with an appropriate amount of glycerin, ground uniformly, added with melted glycerogelatin, ground uniformly, poured into a lubricant-coated mold, and 50 suppositories are obtained
Example 7: film agent
10g of the compound containing the compound according to claim 1 (exemplified by the compound of example a-1) was used, polyvinyl alcohol, glycerin for pharmaceutical use, water and the like were stirred and expanded, then heated and dissolved, filtered through a 80-mesh screen, and then the compound of example 18 was added to the filtrate and stirred and dissolved to prepare a film 100 sheets by film coating.
Example 8: drop pill
10g of the compound of claim 1 (exemplified by the compound of example a-1) and 50g of a matrix such as gelatin are heated, melted and mixed uniformly, and then dropped into low-temperature liquid paraffin to prepare a dripping pill 1000.
Example 9: external liniment
10g of the compound containing the compound of claim 1 (exemplified by the compound of example a-1) is mixed and ground with 2.5g of auxiliary materials such as an emulsifier according to a conventional pharmaceutical method, and distilled water is added to 200 mL.
Example 10: ointment preparation
10g of the compound containing the compound according to claim 1 (exemplified by the compound of example a-1) is ground and then ground with 500g of an oily base such as vaseline.
While the invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims (7)

1. A compound of formula (i), a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:
wherein Ar is 1 Is hydrogen, or is benzene substituted by methyl, methoxy or halogen, or is biphenyl or naphthalene;
R 1 methyl, methoxy, halogen substituted in different positions;
R 2 is hydrogen or methyl;
the halogen is fluorine, chlorine or bromine.
2. A compound according to claim 1, wherein the geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, is characterized by: the compound is selected from the group consisting of:
wherein R is 1 Is H, me, OMe, t bu, F, cl or Br
Wherein Ar is 1 Is 2-naphthalene, 4-biphenyl, or benzene ring substituted at different positions, selected from Me, OMe, F, cl or Br;
R 2 =h orMe，R 3 =h, br, me or OMe;
3. a compound according to claim 2, and geometric isomers thereof, or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein: the compound is selected from
4. A pharmaceutical composition comprising a compound according to any one of claims 1-2, and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, as an active ingredient, together with a pharmaceutically acceptable excipient.
5. Use of a compound according to any one of claims 1-2, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, for the manufacture of a medicament for the treatment and prophylaxis of anti-inflammatory diseases.
6. Use of a compound according to any one of claims 1-2, as well as pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, for the manufacture of an antitumor medicament.
7. The use of a compound of claim 6, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, for the manufacture of an antitumor drug, wherein the tumor cells are human hepatoma cells HepG-2, human colorectal carcinoma cells HCT116, human cervical carcinoma cells HeLa or human lung adenocarcinoma cells a549.
CN202311532062.2A 2023-11-17 2023-11-17 Dimethyl sulfide substituted 2, 3-dihydrofuran derivative and preparation method and application thereof Pending CN117586210A (en)

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