阅读说明：本技术 吡咯并䓬酮稠环衍生物及其合成方法与应用 (Pyrrolone fused ring derivatives, and methods for synthesizing and using the same ) 是由 屈川华 宋桂廷 黄玖红 于 2021-09-07 设计创作，主要内容包括：本发明涉及有机合成技术领域,尤其涉及吡咯并酮稠环衍生物及其合成方法与应用,合成方法为将对亚甲基醌类化合物、对甲苯磺酰基甲基异腈、1,8-二氮杂双环[5.4.0]十一碳-7-烯溶解在乙腈中,随后置于80℃油浴中,搅拌10小时,通过薄层色谱监测后,将反应混合物减压浓缩,然后在硅胶柱上使用石油醚/乙酸乙酯＝10/1～5/1作为洗脱剂进行分离,得到吡咯并酮稠环衍生物。本发明使用简单易得的对亚甲基醌类化合物和对甲苯磺酰基甲基异腈作为起始原料,通过有机碱促进的多米诺过程一步操作快速合成出吡咯并酮稠环衍生物,整个合成方法不需要过渡金属或化学计量氧化剂参与,操作工艺简单；合成的吡咯并酮稠环衍生物具有抗肿瘤活性,可用作制备抗肿瘤药物。(The invention relates to the technical field of organic synthesis, in particular to pyrrolo The ketone fused ring derivative is prepared with p-methylene quinone compound, p-toluenesulfonyl methyl isonitrile and 1, 8-dinitrogenHetero-bicyclo [5.4.0]Undec-7-ene was dissolved in acetonitrile, followed by stirring in an oil bath at 80 ℃ for 10 hours, followed by monitoring by thin layer chromatography, concentrating the reaction mixture under reduced pressure, and then separating on a silica gel column using petroleum ether/ethyl acetate 10/1-5/1 as an eluent to give a pyrrolo-pyrrole A ketone fused ring derivative. The method uses simple and easily obtained p-methylene quinone compounds and p-toluenesulfonylmethyl isonitrile as starting materials to quickly synthesize the pyrrolo-pyrrole by one-step operation in a domino process promoted by organic base The whole synthesis method does not need transition metal or stoichiometric oxidant, and the operation process is simple; synthetic pyrrolo)

1. PyrroloThe ketone condensed ring derivative is characterized in that the structural general formula of the derivativeThe structural formula (I):

wherein R is¹Is tert-butyl, Ar is aryl or heteroaryl;

or the structural formula of the derivative is shown as compound 11:

2. pyrrolo according to claim 1The ketone condensed ring derivative is characterized in that Ar is phenyl, 4-methoxyphenyl, 4- (dimethylamino) phenyl, 3,4, 5-trimethoxyphenyl, 2-bromophenyl, 1' -biphenyl, 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxybenzaldehyde-2-yl) phenyl, 4-bromobenzo [ d ] d][1,3]Dioxyl-5-yl, 5-methylfuran-2-yl, thiophen-3-yl.

3. Pyrrolo according to claim 1 or 2A ketone fused ring derivative selected from the group consisting of:

5, 7-di-tert-butyl-3-phenylcyclohepta [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-3- (4-methoxyphenyl) cyclohepta [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-3- (4- (dimethylamino) phenyl) cyclohepta [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-3- (3,4, 5-trimethoxyphenyl) cyclohepta [ b ] pyrrol-6 (1H) -one;

3- (2-bromophenyl) -5, 7-di-tert-butylcycloheptane [ b ] pyrrol-6 (1H) -one;

3- ([1,1' -biphenyl ] -4-yl) -5, 7-di-tert-butylcycloheptane [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) phenyl) cyclohepta [ b ] pyrrol-6 (1H) -one;

3- (4-bromobenzo [ d ] [1,3] dioxol-5-yl) -5, 7-di-tert-butylcycloheptane [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-3- (5-methylfuran-2-yl) cyclohepta [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-3- (thiophen-3-yl) cyclohepta [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-1- ((3, 5-di-tert-butyl-4-hydroxyphenyl) (4-methoxyphenyl) methyl) -3-phenylcycloheptan [ b ] pyrrol-6 (1H) -one.

4. Pyrrolo according to claim 1, 2 or 3The synthesis method of the ketone fused ring derivative is characterized in that the synthesis route of the compound with the structural formula (I) as the general formula is as follows:

the synthetic route for compound 11 is as follows:

5. pyrrolo according to claim 4The synthesis method of the ketone fused ring derivative is characterized in that the synthesis method of the compound with the structural formula (I) as the general formula is as follows:

in the dry reactionIn the tube, p-methylene quinone compound, p-toluenesulfonylmethyl isonitrile, 1, 8-diazabicyclo [5.4.0]]Dissolving undec-7-ene in acetonitrile, placing the obtained reaction mixture in an oil bath at 80 ℃, stirring for 10 hours, monitoring through thin-layer chromatography, concentrating the reaction mixture under reduced pressure, and separating on a silica gel column by using petroleum ether/ethyl acetate (10/1-5/1) as an eluent to obtain pyrrolo-pyrroleA ketone fused ring derivative.

6. Pyrrolo according to claim 5A process for producing a condensed-ring ketone derivative, characterized in that the p-methylene quinone compound, p-toluenesulfonylmethionitrile, 1, 8-diazabicyclo [5.4.0]]The molar ratio of undec-7-ene is 1:2: 2.

7. Pyrrolo according to claim 4A method for synthesizing a ketone fused ring derivative, characterized in that the method for synthesizing the compound 11 is as follows:

s1, dissolving 0.2mmol of 4-benzylidene-2, 6-di-tert-butylcyclohexa-2, 5-diene-1-one, 0.4mmol of 1- ((isocyano methyl) sulfonyl) -4-methylbenzene and 0.06mmol of 1, 8-diazabicyclo [5.4.0] undec-7-ene in 1mL of acetonitrile in a dry reaction tube, placing the obtained mixture in an oil bath at 80 ℃, stirring for reaction for 10 hours, monitoring by TLC, concentrating the obtained reactant under reduced pressure, and separating on a silica gel column by using petroleum ether/ethyl acetate (10/1-5/1) as an eluent to obtain an intermediate product;

s2. in a dry reaction tube, 0.16mmol of the intermediate obtained in S2, 0.24mmol of 2, 6-di-tert-butyl-4- (4-methoxybenzylidene) cyclohexa-2, 5-dien-1-one, 0.32mmol of 1, 8-diazabicyclo [5.4.0] undec-7-ene were dissolved in 1mL of acetonitrile, followed by stirring in an oil bath at 80 ℃ for 10 hours and monitoring by TLC, after completion of the reaction, concentration in vacuo was carried out to remove acetonitrile, and purification was carried out by column chromatography using ethyl acetate/hexane 5% to 10% as an eluent to obtain compound 11.

8. Pyrrolo according to any one of claims 1 to 3Application of the ketone fused ring derivative in preparing antitumor drugs.

9. Pyrrolo according to claim 8The application of the ketone fused ring derivative in preparing antitumor drugs is characterized in that the derivative is used for preparing antitumor drugs for treating pancreatic cancer cells, colon cancer cells, prostate cancer cells, breast cancer cells and head and neck squamous cell carcinoma cells.

10. Pyrrolo according to claim 9Use of a fused ketone ring derivative for the preparation of an antineoplastic drug, wherein said antineoplastic drug comprises a pyrroloKetone fused ring derivatives or pharmaceutically acceptable salts, hydrates or combinations thereof and auxiliary materials.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to pyrroloKetone fused ring derivatives, and synthetic methods and applications thereof.

Background

Ketones orPhenolic ketones are a class of non-benzene 7-membered aromatic units with carbonyl groups, are the core skeleton of various natural products such as colchicine, theaflavins, pareto ketones, and have various biological activities such as antimitotic, antipathogenic, anticancer, antiviral and antifungal activities. Thus, from 1950 s to 1960 s, people were pairedKetones orThe synthesis of phenolic ketones has been extensively studied. Early synthetic strategies focused on the use of various stoichiometric oxidants such as Br₂、NBS、KMnO₄And PCl₅By direct oxidation to convert 7-membered carbocyclic rings to simple structuresKetones orPhenolic ketone, then constructing a mixture containingKetones orA natural product of a phenolic ketone. The fact that 7-membered carbocyclic rings, especially cycloheptatriene, are not readily available limits thisKetones orAnd (3) synthesizing a phenolic ketone compound. The current synthesisKetones orThe most common method of phenolic ketones is based on cyclopropanation of a benzene ring with carbene, forming a strongly strained cyclopropanated benzene ring derivative which can be converted into various 7-membered carbocyclic skeletons by ring expansion, the resulting 7-membered carbocyclic rings being a mixture which can then be converted into a compound by the above-mentioned oxidation conditionsKetones orA phenolic ketone. From a summary of the above synthetic methods, we can seeKetones orThe synthesis steps of the phenolic ketone are complicated, an equivalent amount of oxidant is needed, side reactions are more, and the separation is difficult.

In addition, at presentKetones orMany studies on the structure of phenolic ketones have been carried out, but pyrroloThe novel ketone fused ring compound and the biological activity thereof are not reported at present.

Disclosure of Invention

In view of the above, it is an object of the present invention to provide pyrroloThe method uses simple and easily obtained p-methylene quinone compound and p-toluenesulfonyl methyl isonitrile as starting materials to quickly synthesize the pyrrolo-pyrrole by one-step operation of a domino process promoted by organic baseThe whole synthesis method does not need transition metal or stoichiometric oxidant, and the operation process is simple; synthetic pyrroloThe ketone fused ring derivative has antitumor activity and can be used for preparing antitumor drugs.

The invention solves the technical problems by the following technical means:

in one aspect of the invention, there is provided a pyrroloA ketone fused ring derivative having the general structural formula (I):

wherein R is¹Is tert-butyl, Ar is aryl or heteroaryl;

or the structural formula of the derivative is shown as compound 11:

preferably, Ar is phenyl, 4-methoxyphenyl, 4- (dimethylamino) phenyl, 3,4, 5-trimethoxyphenyl, 2-bromophenyl, 1' -biphenyl, 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) phenyl, 4-bromobenzo [ d ] [1,3] dioxol-5-yl, 5-methylfuran-2-yl, thiophen-3-yl.

Preferably, the derivative is selected from the following compounds:

5, 7-di-tert-butyl-3-phenylcyclohepta [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-3- (4-methoxyphenyl) cyclohepta [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-3- (4- (dimethylamino) phenyl) cyclohepta [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-3- (3,4, 5-trimethoxyphenyl) cyclohepta [ b ] pyrrol-6 (1H) -one;

3- (2-bromophenyl) -5, 7-di-tert-butylcycloheptane [ b ] pyrrol-6 (1H) -one;

3- ([1,1' -biphenyl ] -4-yl) -5, 7-di-tert-butylcycloheptane [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) phenyl) cyclohepta [ b ] pyrrol-6 (1H) -one;

3- (4-bromobenzo [ d ] [1,3] dioxol-5-yl) -5, 7-di-tert-butylcycloheptane [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-3- (5-methylfuran-2-yl) cyclohepta [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-3- (thiophen-3-yl) cyclohepta [ b ] pyrrol-6 (1H) -one;

5, 7-di-tert-butyl-1- ((3, 5-di-tert-butyl-4-hydroxyphenyl) (4-methoxyphenyl) methyl) -3-phenylcycloheptan [ b ] pyrrol-6 (1H) -one.

Another aspect of the present invention is to provide the above-mentioned pyrroloThe synthesis method of the ketone fused ring derivative comprises the following steps of synthesizing a compound with the general formula (I):

the synthetic route for compound 11 is as follows:

preferably, the compound of formula (i) is synthesized as follows:

in a dry reaction tube, p-methylene quinone compound, p-toluenesulfonylmethyl isonitrile, 1, 8-diazabicyclo [5.4.0]]Dissolving undec-7-ene in acetonitrile, placing the obtained reaction mixture in an oil bath at 80 ℃, stirring for 10 hours, monitoring through thin-layer chromatography, concentrating the reaction mixture under reduced pressure, and separating on a silica gel column by using petroleum ether/ethyl acetate (10/1-5/1) as an eluent to obtain pyrrolo-pyrroleA ketone fused ring derivative.

Preferably, the molar ratio of the p-methylene quinone compound, the p-toluenesulfonylmethyl isonitrile, and the 1, 8-diazabicyclo [5.4.0] undec-7-ene is 1:2: 2.

Preferably, the synthesis method of the compound 11 is as follows:

s1, dissolving 0.2mmol of 4-benzylidene-2, 6-di-tert-butylcyclohexa-2, 5-diene-1-one, 0.4mmol of 1- ((isocyano methyl) sulfonyl) -4-methylbenzene and 0.06mmol of 1, 8-diazabicyclo [5.4.0] undec-7-ene in 1mL of acetonitrile in a dry reaction tube, placing the obtained mixture in an oil bath at 80 ℃, stirring for reaction for 10 hours, monitoring by TLC, concentrating the obtained reactant under reduced pressure, and separating on a silica gel column by using petroleum ether/ethyl acetate (10/1-5/1) as an eluent to obtain an intermediate product;

s2. in a dry reaction tube, 0.16mmol of the intermediate obtained in S2, 0.24mmol of 2, 6-di-tert-butyl-4- (4-methoxybenzylidene) cyclohexa-2, 5-dien-1-one, 0.32mmol of 1, 8-diazabicyclo [5.4.0] undec-7-ene were dissolved in 1mL of acetonitrile, followed by stirring in an oil bath at 80 ℃ for 10 hours and monitoring by TLC, after completion of the reaction, concentration in vacuo was carried out to remove acetonitrile, and purification was carried out by column chromatography using ethyl acetate/hexane 5% to 10% as an eluent to obtain compound 11.

In addition, the invention also provides the pyrroloApplication of the ketone fused ring derivative in preparing antitumor drugs.

The above pyrroloThe ketone condensed ring derivative can be used for preparing an anti-tumor medicament for treating pancreatic cancer cells, colon cancer cells, prostate cancer cells, breast cancer cells and head and neck squamous cell carcinoma cells, and the anti-tumor medicament comprises pyrroloKetone fused ring derivatives or pharmaceutically acceptable salts, hydrates or combinations thereof and auxiliary materials.

The pyrrolo-pyrrole is synthesized in one step by the simple and easily obtained raw materials, such as p-toluenequinone and p-toluenesulfonylmethyl isocyano, through a domino process promoted by organic baseFused ring ketone derivatives in which the isocyano group is inserted as a C1 structural unit into the C-C bond of a phenol to give a strong strained tricyclic nor-cadiene tautomerStable, under mild thermal conditions, it undergoes an azacyclo-propylidene cyclohexenone toRearrangement of the ketone and removal of the p-toluenesulfonyl group to give the pyrroloA ketone derivative. The synthetic method of the invention allows the formation of three C-C bonds in a single reaction in a metal-free manner, thereby efficiently and rapidly assembling a wide variety of pyrroloA ketone fused derivative. The method has originality and relates to a series of new chemical phenomena such as: insertion of isonitriles into carbon-carbon bonds of aromatic rings and aziridinocyclohexenones toA ketone rearrangement; in addition, the compounds are tested for in vitro tumor cell inhibitory activity, and the results show that the compounds have obvious inhibitory action on human prostate cancer, colon cancer, pancreatic cancer, head and neck cancer and breast cancer, have antitumor activity and can be used for preparing antitumor drugs.

Therefore, the present invention has the following technical advantages:

(1) the synthesis method uses simple and easily obtained p-methylene quinone compound (p-QMs) and p-toluenesulfonyl methylisonitrile (TosMIC) as starting materials, and promotes one-step operation by organic alkali to quickly synthesize the pyrrolo-pyrroleKetone fused ring derivatives, the insertion of carbon-carbon bonds of the aromatic ring by isonitriles and the conversion of aziridinocyclohexenones to aziridinocyclohexenonesThe ketone rearrangement is a novel chemical phenomenon, and no relevant report exists at present.

(2) Pyrrolo of the inventionThe ketone fused ring compound has obvious inhibition effect on human prostate cancer, colon cancer, pancreatic cancer, head and neck cancer and breast cancer, especially the effect of the compound 9 is most obvious, the growth inhibition rate of the compound 9 with 10 mu M can reach 90 percent, and the test proves that the compound 9 has obvious inhibition effect on the proliferation of prostate cancer cells, the pyrrolo-pyrrole compound of the inventionThe ketone fused ring compound has antitumor activity, and can be used for preparing antitumor drugs.

(3) The synthetic method of the invention does not need transition metal or stoichiometric oxidant, has simple operation process, and can obtain pyrrolo by one step through series connection stepsThe ketone thick derivative has simple and easily obtained raw materials.

Drawings

FIG. 1 is a graph showing the effect of 10. mu.M of compounds 1-11 on the growth of pancreatic, colon, prostate, breast, head and neck squamous cell carcinoma cell lines;

FIG. 2 is a graph of the effect of varying concentrations of Compound 9 on the viability of prostate cancer cells;

FIG. 3 is a graph of the effect of 2.5 μ M Compound 9 on prostate cancer cell growth at different times;

FIG. 4 is a graph showing the clonogenic effect of Compound 9 on PC3 cells;

FIG. 5 is a nuclear magnetic map of Compound 1;

FIG. 6 is a nuclear magnetic map of Compound 2;

FIG. 7 is a nuclear magnetic map of Compound 3;

FIG. 8 is a nuclear magnetic map of Compound 4;

FIG. 9 is the nuclear magnetic map of Compound 5;

FIG. 10 is the nuclear magnetic map of Compound 6;

FIG. 11 is the nuclear magnetic map of Compound 7;

FIG. 12 is the nuclear magnetic map of Compound 8;

FIG. 13 is a nuclear magnetic map of Compound 9;

FIG. 14 is a nuclear magnetic map of Compound 10;

FIG. 15 is a nuclear magnetic map of Compound 11.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Pyrrolo of the inventionThe ketone fused ring derivatives mainly have two types, one type is a compound taking a structural formula (I) as a general formula:

wherein R is¹Is tert-butyl, Ar is aryl or heteroaryl, specifically, Ar is phenyl, 4-methoxyphenyl, 4- (dimethylamino) phenyl, 3,4, 5-trimethoxyphenyl, 2-bromophenyl, 1' -biphenyl, 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) phenyl, 4-bromobenzo [ d][1,3]Dioxol-5-yl, 5-methylfuran-2-yl, thiophen-3-yl;

pyrrolo of the inventionAnother class of ketone fused ring derivatives has the formula Compound 11:

pyrrolo of formula (I)The synthetic route for the ketone fused ring derivatives is as follows:

in particular, pyrrolo of formula (I)The synthesis method of the ketone fused ring derivative comprises the following steps:

in an oven-dried 10mL reaction tube, 0.2mmol of p-methylene quinone (p-QMs), 0.4mmol of p-toluenesulfonylmethionitrile (TosMIC), 60. mu.L of 0.4mmol of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) was dissolved in 1mL of acetonitrile (MeCN), the resulting reaction mixture was stirred in an oil bath at 80 ℃ for 10 hours and monitored by Thin Layer Chromatography (TLC), the reaction mixture was concentrated under reduced pressure, and then separated on a silica gel column using petroleum ether/ethyl acetate (10/1-5/1), preferably ethyl acetate/hexane (6/1) as an eluent to give the target compound pyrrolo-pyrroleA ketone fused ring derivative.

The product testing conditions in the following examples are as follows:

recording on a 400MHz solid nuclear magnetic resonance spectrometer (Bruker AVANCE III 400MHz) with Tetramethylsilicon (TMS) as an internal standard¹H and¹³C NMR。¹h NMR data are reported below: chemical shifts, in ppm (δ), multiplicity (s ═ singlet, d ═ doublet, t ═ triplet, m ═ multiplet), coupling constant (Hz), relative intensity;¹³the C NMR data are reported below: chemical shift (ppm).

HPLC-MS analysis the following bars were used on a Shimadzu-2020LC-MS instrumentCarrying out: a Shim-pack VPODS C18 column (reversed phase, 150X 2.0 mm); 80% acetonitrile and 20% water were used over 10.0 minutes; the flow rate is 0.4 ml/min; the detection range of the ultraviolet photodiode array is 200-300 nm. The product was passed through a Biotage Isolera^TMA Spektra system and a hexane/ethyl acetate solvent system. All reagents and solvents were purchased from commercial sources and used without further purification.

For a more clear understanding of the pyrrolo of the inventionKetone fused ring derivatives were tested in the following 11 examples.

Example 1

Pyrrolo of the exampleThe ketone fused ring derivative is compound 1: 5, 7-di-tert-butyl-3-phenylcyclohepta [ b]Pyrrole-6 (1H) -one, in particular, compound 1 has the following chemical formula:

synthesis of Compound 1 of this example pyrrolo according to formula (I)The synthesis method of the ketone fused ring derivative is carried out, wherein R in the methylene quinone compound is¹Is tert-butyl and Ar is phenyl. The specific synthesis method, raw material formula and process conditions are according to the formula of formula (I) as the pyrroloThe synthesis of the ketone fused ring derivative was carried out to obtain the yellow solid compound 1 with a melting point of 219-. The nuclear magnetic diagram of compound 1 is shown in figure 5.

¹H NMR(400MHz,CDCl₃)δ8.80(s,1H),7.62(s,1H),7.45(d,J＝4.3Hz,4H),7.35–7.30(m,2H),7.06(d,J＝2.5Hz,1H),1.42(s,9H),1.39(s,9H)ppm；¹³C NMR(100MHz,CDCl₃)δ195.4,148.2,147.1,134.6,132.0,128.8,128.6 126.6,125.2,123.5,121.0,119.2,118.8,38.2,38.1,31.9,31.7ppm；HRMS(ESI)m/z calcd for C₂₃H₂₈NO⁺(M+H)⁺334.2165,found m/z 334.2160.

Example 2

Pyrrolo of the exampleThe ketone fused ring derivative is compound 2: 5, 7-di-tert-butyl-3- (4-methoxyphenyl) cyclohepta [ b)]Pyrrole-6 (1H) -one, specifically, Compound 2 has the following chemical structure:

synthesis of Compound 2 of this example pyrrolo according to formula (I)The synthesis method of the ketone fused ring derivative is carried out, wherein R in the methylene quinone compound is¹Is tert-butyl, and Ar is 4-methoxyphenyl. The specific synthesis method, raw material formula and process conditions are according to the formula of formula (I) as the pyrroloThe synthesis method of the ketone fused ring derivative is carried out, and the light yellow solid compound 2 is finally obtained, wherein the melting point is 202-. The nuclear magnetic diagram of compound 2 is shown in figure 6.

¹H NMR(400MHz,CDCl₃)δ8.77(s,1H),7.59(s,1H),7.36(d,J＝8.6Hz,2H),7.31(s,1H),7.00(d,J＝8.4Hz,3H),3.86(s,3H),1.42(s,9H),1.39(s,9H)ppm；¹³C NMR(100MHz,CDCl₃)δ195.3,158.5,148.1,146.9,131.9,129.7,127.0,124.9,123.6,121.1,119.2,118.4,114.2,55.4,38.1,38.1,31.9,31.7ppm；HRMS(ESI)m/z calcd for C₂₄H₃₀NO₂ ⁺(M+H)⁺364.2271,found m/z 364.2282.

Example 3

Pyrrolo of the exampleThe ketone fused ring derivative is compound 3: 5, 7-di-tert-butyl-3- (4- (dimethylamino) phenyl) cyclohepta [ b ]]Pyrrole-6 (1H) -one, specifically, Compound 3 has the following chemical structure:

synthesis of Compound 3 of this example pyrrolo according to formula (I)The synthesis method of the ketone fused ring derivative is carried out, wherein R in the methylene quinone compound is¹Is tert-butyl, and Ar is 4- (dimethylamino) phenyl. The specific synthesis method, raw material formula and process conditions are according to the formula of formula (I) as the pyrroloThe synthesis method of the ketone fused ring derivative is carried out, and finally the brown solid compound 3 is obtained, wherein the melting point is 147-. The nuclear magnetic diagram of compound 3 is shown in fig. 7.

¹H NMR(400MHz,CDCl₃)δ8.58(s,1H),7.65(s,1H),7.34(d,J＝8.5Hz,2H),7.30(s,1H),7.00(d,J＝2.4Hz,1H),6.84(d,J＝8.5Hz,2H),3.00(s,6H),1.42(s,9H),1.39(s,9H)ppm；¹³CNMR(100MHz,CDCl₃)δ195.2,149.5,147.9,146.7,131.8,129.4,125.5,123.9,122.7,121.1,119.2,118.0,112.9,40.7,38.1,38.1,31.9,31.7ppm；HRMS(ESI)m/z calcd for C₂₅H₃₃N₂O⁺(M+H)⁺377.2587,found m/z 377.2584.

Example 4

The true bookPyrrolo of examplesThe ketone fused ring derivative is compound 4: 5, 7-di-tert-butyl-3- (3,4, 5-trimethoxyphenyl) cyclohepta [ b]Pyrrole-6 (1H) -one, specifically, Compound 4 has the following chemical structure:

synthesis of Compound 4 of this example pyrrolo according to formula (I)The synthesis method of the ketone fused ring derivative is carried out, wherein R in the methylene quinone compound is¹Is tert-butyl, Ar is 3,4, 5-trimethoxyphenyl. The specific synthesis method, raw material formula and process conditions are according to the formula of formula (I) as the pyrroloThe synthesis method of the ketone fused ring derivative is carried out, and the yellow brown solid compound 4 is finally obtained, wherein the melting point is 205-208 ℃, and the yield is 80%. The nuclear magnetic diagram of compound 4 is shown in figure 8.

¹H NMR(400MHz,CDCl₃)δ9.04(s,1H),7.67(s,1H),7.34(s,1H),7.08(d,J＝2.5Hz,1H),6.67(s,2H),3.92(s,3H),3.90(s,6H),1.41(d,J＝5.7Hz,18H)ppm；¹³C NMR(100MHz,CDCl₃)δ195.4,153.4,148.4,147.0,136.8,132.1,130.4,125.1,123.5,120.8,119.2,118.6,105.6,61.0,56.1,38.1,38.1,32.0,31.7ppm；HRMS(ESI)m/z calcd for C₂₆H₃₄NO₄ ⁺(M+H)⁺424.2482,found m/z 424.2477.

Example 5

Pyrrolo of the exampleThe ketone fused ring derivative is compound 5: 3- (2-bromophenyl) -5, 7-di-tert-butylCycloheptane [ b ]]Pyrrole-6 (1H) -one, specifically, Compound 5 has the following chemical structure:

synthesis of Compound 5 of this example pyrrolo according to formula (I)The synthesis method of the ketone fused ring derivative is carried out, wherein R in the methylene quinone compound is¹Is tert-butyl, and Ar is 2-bromophenyl. The specific synthesis method, raw material formula and process conditions are according to the formula of formula (I) as the pyrroloThe synthesis method of the ketone fused ring derivative is carried out, and the yellow brown solid compound 5 is finally obtained, wherein the melting point is 210-215 ℃, and the yield is 77%. The nuclear magnetic diagram of compound 5 is shown in figure 9.

¹H NMR(400MHz,DMSO)δ11.75(s,1H),7.70(d,J＝7.9Hz,1H),7.45(s,1H),7.39(t,J＝7.3Hz,1H),7.31(d,J＝7.4Hz,1H),7.27–7.20(m,2H),7.04(s,1H),1.31(s,9H),1.19(s,9H)ppm；¹³C NMR(100MHz,DMSO)δ194.2,146.7,145.5,135.6,133.4,133.2,131.8,129.5,128.2,124.2,124.2,122.6,122.0,121.2,120.2,38.1,38.0,31.8,31.8ppm；HRMS(ESI)m/z calcd for C₂₃H₂₇BrNO⁺(M+H)⁺412.1271,found m/z 412.1284.

Example 6

Pyrrolo of the exampleThe ketone fused ring derivative is compound 6: 3- ([1,1' -Biphenyl)]-4-yl) -5, 7-di-tert-butylcycloheptane [ b ]]Pyrrole-6 (1H) -one, specifically, Compound 6 has the following chemical structure:

synthesis of Compound 6 of this example pyrrolo according to formula (I)The synthesis method of the ketone fused ring derivative is carried out, wherein R in the methylene quinone compound is¹Is tert-butyl, and Ar is 1,1' -biphenyl. The specific synthesis method, raw material formula and process conditions are according to the formula of formula (I) as the pyrroloThe synthesis of the ketone fused ring derivative was carried out to obtain the final yellow solid compound 6 with a melting point of 163 ℃ and a yield of 73%. The NMR chart of Compound 6 is shown in FIG. 10.

¹H NMR(400MHz,CDCl₃)δ8.64(s,1H),7.68(dd,J＝10.7,7.1Hz,5H),7.53(d,J＝8.1Hz,2H),7.48(dd,J＝12.8,5.2Hz,2H),7.37(d,J＝7.3Hz,1H),7.32(s,1H),7.12(d,J＝2.4Hz,1H),1.44(s,9H),1.41(s,9H)ppm；¹³C NMR(100MHz,CDCl₃)δ195.3,148.4,147.2,140.8,139.4,133.6,132.1,128.9,128.8,127.5,127.3,127.0,124.9,123.4,121.0,119.0,118.7,38.2,38.1,31.9,31.7ppm；HRMS(ESI)m/z calcd for C₂₉H₃₂NO⁺(M+H)⁺410.2478,found m/z 410.2473.

Example 7

Pyrrolo of the exampleThe ketone fused ring derivative is compound 7: 5, 7-di-tert-butyl-3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) phenyl) cyclohepta [ b]Pyrrole-6 (1H) -one, specifically, Compound 7 has the following chemical formula:

synthesis of Compound 7 of this examplePyrroloThe synthesis method of the ketone fused ring derivative is carried out, wherein R in the methylene quinone compound is¹Is tert-butyl, and Ar is 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxybenzaldehyde-2-yl) phenyl. The specific synthesis method, raw material formula and process conditions are according to the formula of formula (I) as the pyrroloThe synthesis of the ketone fused ring derivatives was carried out to give the yellow solid compound 7 in 59% yield at 224 ℃ and 226 ℃. The nuclear magnetic map of compound 7 is shown in fig. 11.

¹H NMR(400MHz,CDCl₃)δ8.63(s,1H),7.89(d,J＝7.7Hz,2H),7.62(s,1H),7.47(d,J＝7.7Hz,2H),7.29(s,1H),7.11(d,J＝2.4Hz,1H),1.42(s,9H),1.37(s,21H)ppm；¹³C NMR(100MHz,CDCl₃)δ195.2,148.5,147.3,137.4,135.2,132.1,127.8,125.2,123.4,118.9,118.8,83.8,38.1,38.1,31.9,31.7,24.9ppm；HRMS(ESI)m/z calcd for C₂₉H₃₉BNO₃ ⁺(M+H)⁺460.3018,found m/z 460.3024.

Example 8

Pyrrolo of the exampleThe ketone fused ring derivative is compound 8: 3- (4-bromobenzo [ d ]][1,3]Dioxo-5-yl) -5, 7-di-tert-butylcycloheptane [ b]Pyrrole-6 (1H) -one, specifically, Compound 8 has the following chemical structure:

synthesis of Compound 8 of this example pyrrolo according to formula (I)Synthesis of ketone fused ring derivativesWherein R in the p-methylene quinone compound¹Is tert-butyl, Ar is 4-bromobenzo [ d][1,3]Dioxol-5-yl. The specific synthesis method, raw material formula and process conditions are according to the formula of formula (I) as the pyrroloThe synthesis of the ketone fused ring derivative was carried out to obtain the yellow solid compound 8 with a melting point of 212 ℃ and a yield of 96%. The nuclear magnetic map of compound 8 is shown in figure 12.

¹H NMR(400MHz,DMSO)δ11.73(s,1H),7.54–7.47(m,1H),7.38–7.31(m,1H),7.22(dd,J＝4.1,2.7Hz,1H),7.17–7.07(m,1H),6.97–6.87(m,1H),6.18–6.09(m,2H),1.37(s,9H),1.27(s,9H)ppm；¹³C NMR(100MHz,DMSO)δ194.1,148.1,147.6,146.6,145.4,131.6,128.6,124.3,122.8,121.9,121.3,120.2,114.8,113.0,112.4,102.6,38.1,37.9,31.9,31.8ppm；HRMS(ESI)m/z calcd for C₂₄H₂₇BrNO₃ ⁺(M+H)⁺456.1169,found m/z 456.1167.

Example 9

Pyrrolo of the exampleThe ketone fused ring derivative is compound 9: 5, 7-di-tert-butyl-3- (5-methylfuran-2-yl) cyclohepta [ b]Pyrrole-6 (1H) -one, specifically, Compound 9 has the following chemical formula:

synthesis of Compound 9 of this example pyrrolo according to formula (I)The synthesis method of the ketone fused ring derivative is carried out, wherein R in the methylene quinone compound is¹Is tert-butyl, Ar is 5-methylfuran-2-yl. The specific synthesis method, raw material formula and process conditions are as shown in the general formula (I)Pyrrolo ofThe synthesis method of the ketone fused ring derivative is carried out, and finally the brown yellow solid compound 9 is obtained, wherein the melting point is 130-. The nuclear magnetic map of compound 9 is shown in figure 13.

¹H NMR(400MHz,CDCl₃)δ8.65(s,1H),7.83(s,1H),7.26(s,1H),7.21(d,J＝2.6Hz,1H),6.30(d,J＝3.0Hz,1H),6.08(d,J＝2.8Hz,1H),2.37(s,3H),1.44(s,9H),1.41(s,9H)ppm；¹³CNMR(100MHz,CDCl₃)δ195.1,150.6,148.5,147.7,147.3,131.8,123.6,119.8,118.8,117.8,115.5,107.1,105.9,38.2,38.1,31.9,31.6,13.6ppm；HRMS(ESI)m/z calcd for C₂₂H₂₈NO₂ ⁺(M+H)⁺338.2115,found m/z 338.2112.

Example 10

Pyrrolo of the exampleThe ketone fused ring derivative is compound 10: 5, 7-di-tert-butyl-3- (thien-3-yl) cyclohepta [ b]Pyrrole-6 (1H) -one, specifically, compound 10 has the following chemical structure:

synthesis of Compound 10 of this example pyrrolo according to formula (I)The synthesis method of the ketone fused ring derivative is carried out, wherein R in the methylene quinone compound is¹Is tert-butyl, Ar is 5-methylfuran-2-yl. The specific synthesis method, raw material formula and process conditions are according to the formula of formula (I) as the pyrroloThe synthesis method of the ketone condensed ring derivative is carried out, and finally, a brown yellow solid is obtainedCompound 10, melting point 104-. The nuclear magnetic map of compound 10 is shown in figure 14.

¹H NMR(400MHz,CDCl₃)δ8.78(s,1H),7.78(s,1H),7.29(d,J＝3.6Hz,2H),7.13(dd,J＝5.5,2.9Hz,2H),7.11–7.07(m,1H),1.42(d,J＝2.8Hz,18H)ppm；¹³C NMR(100MHz,CDCl₃)δ195.2,148.6,147.4,136.4,132.1,127.7,124.4,124.0,123.3,120.9,119.1,118.9,118.0,38.2,38.1,31.9,31.7ppm；HRMS(ESI)m/z calcd for C₂₁H₂₆NOS⁺(M+H)⁺340.1730,found m/z 340.1728.

Example 11

Pyrrolo of the exampleThe ketone fused ring derivative is compound 11: 5, 7-di-tert-butyl-1- ((3, 5-di-tert-butyl-4-hydroxyphenyl) (4-methoxyphenyl) methyl) -3-phenylcycloheptane [ b]Pyrrole-6 (1H) -one, specifically, Compound 11 has the following chemical formula:

the synthetic route for compound 11 of this example is as follows:

specifically, the synthesis method of the compound 11 is as follows:

s1: in an oven dried 10mL reaction tube, 0.2mmol of 4-benzylidene-2, 6-di-tert-butylcyclohexa-2, 5-dien-1-one, 0.4mmol of 1- ((isocyano methyl) sulfonyl) -4-toluene, 0.06mmol of 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) were dissolved in 1mL acetonitrile (MeCN), and the mixture was placed in an 80 ℃ oil bath and stirred for reaction for 10h and monitored by TLC. The reaction mixture was then concentrated under reduced pressure and separated on a silica gel column using petroleum ether/ethyl acetate 10/1-5/1 as eluent to give 79mg of intermediate in 81% yield.

S2: in an oven dried 10mL reaction tube, 79mg of 0.16mmol of the intermediate, 78mg of 0.24mmol of 2, 6-di-tert-butyl-4- (4-methoxybenzylidene) cyclohexa-2, 5-dien-1-one, 49uL of 0.32mmol of 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) were dissolved in 1mL of acetonitrile (MeCN), and the mixture was stirred in an 80 ℃ oil bath for 10 hours and monitored by TLC. After completion of the reaction, the mixture was concentrated under vacuum to remove acetonitrile, and the residue was purified by column chromatography (ethyl acetate/hexane 5% to 10%, and ethyl acetate/hexane 6% was used in this example) to give the target 76mg of yellow solid compound 11 with a melting point of 223-. The nuclear magnetic map of compound 11 is shown in figure 15.

¹H NMR(400MHz,CDCl₃)δ7.63(s,1H),7.40(q,J＝7.4Hz,4H),7.32(s,1H),7.30(d,J＝7.3Hz,1H),7.07(d,J＝8.4Hz,2H),6.95(s,2H),6.89(d,J＝8.4Hz,2H),6.65(s,1H),6.61(s,1H),5.25(s,1H),3.81(s,3H),1.38(s,9H),1.36(s,18H),1.27(s,9H)ppm；¹³C NMR(100MHz,CDCl₃)δ194.9,159.2,153.6,147.1,147.0,136.3,134.9,132.2,131.6,129.6,129.5,128.6,126.3,125.2,123.8,122.8,122.4,122.3,118.2,114.1,64.7,55.3,38.3,38.1,34.4,31.8,31.6,30.2ppm；HRMS(ESI)m/z calcd for C₄₅H₅₆NO₃ ⁺(M+H)⁺658.4255,found m/z 658.4254.

Example 12

In this example, compounds 1-11 were tested for anti-tumor activity using human tumor cell lines AspC-1, HCT116, PC3, MDA-MB-231, SCC-15, CAL33, all of which were purchased from American Type Culture Collection (ATCC). AsPC-1 cells were cultured in RPMI-1640 medium, HCT116 in McCoy's5A medium, PC3 in F12K medium, and MDA-MB-231, SCC-15, CAL33 in DMEM medium. All media were supplemented with 10% Fetal Bovine Serum (FBS) to provide growth factors for cell growth at 37 deg.C with 5% CO₂The constant temperature incubator. The culture steps are as follows:

(1) subjecting tumor cells in logarithmic growth phase to pancreatinAfter digestion, the cells were resuspended in complete medium, the cell concentration was determined with a cell counter, and the cells were diluted to 3X 10 with the corresponding complete medium⁴Per mL;

(2) inoculating 100 μ L of cell suspension into each well of a 96-well plate, and incubating overnight in a cell incubator;

(3) diluting compounds 1-11 to 20 μ M with complete medium corresponding to the cells, adding 100 μ L of compound diluent to each well of a 96-well plate to give a final compound concentration of 10 μ M, adding 3 duplicate wells for each compound, adding DMSO (dimethylsulfoxide) in the same volume as the compound as a control group, and culturing the cells in a cell culture box for 72 hours;

(4) detecting the inhibition effect of the compounds 1-11 on the survival ability of each tumor cell through an MTT experiment, distributing and treating the tumor cells with the compounds 1-11 for 72 hours respectively, adding 20 mu L of MTT solution with the concentration of 5mg/mL into each hole, and continuously incubating for 4 hours at 37 ℃;

(5) discarding the cell culture solution, adding 150 μ L DMSO to dissolve the cells, and detecting OD value (OD570) at 570nm with enzyme labeling instrument;

(6) data were processed and relative survival was calculated from OD570 of compound-treated and control-treated groups, cell survival ═ OD570_{Compound (I)}/OD570_DMSO。

The inhibition rates of compounds 1 to 11 against the respective tumor cells are shown in table 1.

TABLE 1 pyrroloAntitumor Activity of Keto fused Ring derivatives

The experimental results are as follows: the effects of 10. mu.M of compounds 1-11 on the growth of pancreatic, colon, prostate, breast, head and neck squamous cell carcinoma cell lines are shown in FIG. 1. The data in figure 1 show that the compounds 1-11 all have certain inhibition effects on the growth capacities of pancreatic cancer cells, colon cancer cells, prostate cancer cells, breast cancer cells and head and neck squamous cell carcinoma cells, and especially the compound 9 has good inhibition effects on the growth capacities of 6 tested tumor cells. Experimental results show that the compound 9 described by the invention can inhibit the growth of tumor cells, has good antitumor activity, and can be applied to preparation of antitumor drugs, especially antitumor drugs for prostate cancer.

To examine the effect of compound 9 at various concentrations on the viability of prostate cancer cells, PC3 and DU145 cells were diluted with 10% FBS-containing F12K medium and DMEM medium, respectively, to a final cell concentration of 2X 10⁴And each cell per mL, then respectively inoculating 100 mu L of cell suspension into a 96-well plate, adding compound 9 after the cells are attached to the wall to make the final concentration of the compound be 0 mu M, 1.25 mu M, 2.5 mu M, 5 mu M, 10 mu M and 20 mu M, adding 5 repeated wells for each concentration, and detecting the influence of different concentrations of compound 9 on the survival capability of PC3 and DU145 cells by using an MTT method after the compound is treated for 72 hours. The experimental result is shown in fig. 2, with the increase of the compound concentration, the survival ability of two prostate cancer cells is obviously reduced, which indicates that the compound 9 has certain inhibitory activity to two prostate cancer tumor cells and has better activity in PC3 cells. Half-lethal concentrations of compound 9 on prostate cancer cells PC3 and DU145 were 2.1 μ M and 6.2 μ M, respectively.

In order to more intuitively and truly reflect the inhibition effect of the compound 9 on the growth of the prostate cancer cells, the cultured tumor cells are photographed in real time through a high content analysis system, so that the inhibition effect of the compound 9 on the growth of the prostate cancer cells is detected. As shown in fig. 3, after 2.5 μ M compound 9 treated PC3 and DU145 cells, respectively, the number of PC3 cells did not change significantly over time, whereas the number of DU145 cells slightly increased and cell proliferation was inhibited. The number of cells in the control group is obviously increased, and the cell proliferation is normal. The 2.5 mu M compound 9 can obviously inhibit the proliferation of the prostate cancer cells PC3 and DU 45.

To further verify the inhibitory effect of compound 9 on the proliferative capacity of prostate cancer cells, a clonogenic experiment was performed based on the experiment of fig. 3. Will be 1 × 10³A single PC3 cell was seeded in 6-well platesCultured overnight at 37 ℃ in a 5% carbon dioxide cell culture chamber. Cells were treated with compound 9 at 0. mu.M, 1.25. mu.M and 2.5. mu.M for 48 hours, and then replaced with fresh complete medium for further culture for 4 days. The effect of compound 9 on the clonality of prostate cancer cells was examined by fixing the cells with 4% paraformaldehyde and staining with 1% crystal violet solution. The results are shown in fig. 4, and compound 9 can significantly inhibit the clonogenic capacity of PC3 cells. Further, compound 9 was shown to inhibit prostate cancer cell proliferation.

The experiments prove that the compound 9 has a remarkable inhibition effect on the proliferation of prostate cancer cells.

Accordingly, the pyrrolo of the present inventionThe ketone fused ring derivative can be used for preparing antitumor drugs, in particular to antitumor drugs for treating pancreatic cancer cells, colon cancer cells, prostate cancer cells, breast cancer cells and head and neck squamous cell carcinoma cells, and the antitumor drugs comprise pyrroloKetone fused ring derivatives or pharmaceutically acceptable salts, hydrates or combinations thereof and auxiliary materials.

Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention as defined in the appended claims. The techniques, shapes, and configurations not described in detail in the present invention are all known techniques.