A class of compounds with arylamide structure and their applications

Abstract

The present invention discloses a class of compounds having an aromatic amide structure and their applications. The structural formula of the compound is shown below: #imgabs0# The present invention uses in vitro anti-tumor cell experiments as a carrier to evaluate the efficacy of the compound in treating various cancers. It is found that the compound has good in vitro activity and extremely high selectivity, and can be used as a precursor substance for further development to exert cancer treatment effects by selectively inhibiting aldehyde-keto reductase 1C3.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a compound having an arylamide structure and applications thereof. Background Art

[0002] Aldo-keto reductases (AKRs) are members of the nicotinamide adenine dinucleotide (NAD) phosphate (NAD(P)(H))-dependent oxidoreductase superfamily. They reduce aldehydes and ketones to their corresponding alcohols and are widely found in prokaryotes and eukaryotes. Over 190 AKRs have been identified. Due to their wide range of substrates, AKR enzymes play important roles in hormone metabolism, regulation of oxidative stress responses, drug activation and inactivation, and carcinogen detoxification.

[0003] The aldehyde-keto reductase family, group 1, subfamily C (AKR1C), has four human isoforms: AKR1C1, AKR1C2, AKR1C3, and AKR1C4. These four proteins are expressed in diverse tissues and involved in a variety of biochemical functions. AKR1C3, also known as peripheral type 5 17β-hydroxysteroid dehydrogenase (17β-HSD), reduces the androgen 4-androstene-3,17-dione (Δ4-AD) to testosterone, an androgen with a stronger affinity for the androgen receptor, and reduces the weak estrogen estrone to 17β-estradiol, an estrogen with a stronger affinity for the estrogen receptor. AKR1C3, also known as prostaglandin F synthase, catalyzes the conversion of prostaglandin D2 (PGD2) to 9α,11β-PGF2α. AKR1C3 is involved in normal physiological processes and is a key enzyme in steroid metabolism. Therefore, abnormal AKR1C3 expression can lead to hormonal imbalances, potentially causing various diseases. AKR1C3 expression levels are correlated with disease aggressiveness, making AKR1C3 a potential biomarker and therapeutic target for various cancers, including prostate cancer, castration-resistant prostate cancer, and breast cancer. AKR1C3 has also been implicated in polycystic ovary syndrome, endometriosis, cervical cancer, leukemia, lung cancer, and chronic obstructive pulmonary disease. Notably, elevated AKR1C3 expression in various tumor cells is often associated with poor prognosis, and its role in inducing tumor resistance is associated with altered drug performance. AKR1C3 catalyzes the metabolism of anthracyclines into inactive products, significantly reducing their cytotoxicity and ability to bind to tumor cell DNA, significantly diminishing their anti-tumor activity and leading to tumor resistance. Growing evidence indicates the important role of AKR1C3 in chemotherapy resistance, and inhibiting its expression or activity can reverse chemotherapy resistance in tumor cells. Currently, there are few reports in China on the biological functions and inhibitors of AKR1C3. The development of inhibitors that specifically target AKR1C3 may provide an effective therapeutic strategy for tumor treatment. AKR1C3 inhibitors can also serve as tool molecules for studying pathological mechanisms. More importantly, the discovery of effective drugs targeting AKR1C3 may provide new research directions for reversing drug resistance and address key challenges in tumor treatment. Summary of the Invention

[0004] One of the purposes of the present invention is to provide a class of compounds having an arylamide structure, the structural formula of the compound is as follows:

[0005]

[0006] Wherein: X is isoxazolyl, furyl or phenyl;

[0007] R is selected from optionally substituted C1-C7 alkyl, C5-C7 saturated nitrogen heterocycloalkyl, nitro or halogen;

[0008] Y is C or N.

[0009] Furthermore, pharmaceutically acceptable salts of the compound, such as hydrochloride, maleate, and citrate, are also provided. The pharmaceutically acceptable salts of the compound have the same or better pharmacodynamic activity as the compound.

[0010] The preparation method of the compound comprises the following steps:

[0011] (1) reacting R-substituted m-hydroxybenzoic acid or R-substituted 4-hydroxy-2-pyridinecarboxylic acid with 3,5-dimethyl-4-chloromethylisoxazole or 3-chloromethylfuran or benzyl chloride to obtain compound 2;

[0012] (2) Compound 2 reacts with 1-(5-amino-4-nitrofuran-2-yl)ethane-1-ol to obtain compound 3;

[0013] (3) Compound 3 reacts with di(aziridine-1-yl)phosphoryl chloride to obtain a compound of formula I.

[0014] The reaction route is shown below:

[0015]

[0016] A second object of the present invention is to provide the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating cancer, such as pancreatic cancer, liver cancer, etc.

[0017] The compounds of the present invention can be added with pharmaceutically acceptable carriers to prepare common pharmaceutical preparations, such as tablets, capsules, powders, syrups, liquids, suspensions, and injections, and can be added with common pharmaceutical excipients such as flavorings, sweeteners, liquid or solid fillers or diluents.

[0018] The third object of the present invention is to provide the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a selective aldehyde-keto reductase 1C3 inhibitor.

[0019] The clinical dosage of the compound of the present invention is 0.01 mg to 1000 mg / day, and may deviate from this range depending on the severity of the disease or the dosage form.

[0020] Beneficial effects: The present invention uses in vitro anti-tumor cell experiments as a carrier to evaluate the efficacy of the compound in treating various cancers. It is found that it has good in vitro activity and extremely high selectivity, and can be used as a precursor substance for further development of a cancer treatment effect by selectively inhibiting aldehyde-keto reductase 1C3. DETAILED DESCRIPTION

[0021] The preferred embodiments of the present invention will be described in detail below with reference to the examples. It should be understood that the following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. Those skilled in the art may make various modifications and substitutions to the present invention without departing from the purpose and spirit of the present invention.

[0022] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0023] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0024] Example 1

[0025] (1) Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)benzoic acid

[0026] 3-Hydroxybenzoic acid (1 g, 6.57 mmol) was dissolved in acetonitrile (20 mL) in an eggplant-shaped flask. Potassium carbonate (1.36 g, 9.86 mmol) and 4-chloromethyl-3,5-dimethylisoxazole (0.96 g, 6.57 mmol) were then added sequentially. The mixture was reacted at 70°C for 12 hours. The filtrate was collected and the solvent removed under reduced pressure to yield 3-((3,5-dimethylisoxazol-4-yl)methoxy)benzoic acid (1.51 g, 87.8% yield) as a white solid. TLC analysis revealed a single spot, a dark spot at 254 nm, and no fluorescence at 365 nm. 1 HNMR (300MHz, DMSO-d6): δ8.01(dd,J=7.7,1.5Hz,1H),7.45(td,J=7.9,1.5Hz,1H),7.05-6.98(m,2H),5.03(s,2H),2.29(s,3H),2.27(s,3H).

[0027] (2) Synthesis of 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-hydroxyethyl)-3-nitrofuran-2-ylbenzamide

[0028] 2-((3,5-dimethylisoxazol-4-yl)methoxy)benzoic acid (1 g, 4.04 mmol) was dissolved in 20 mL of DMF. HATU (2.3 g, 6.07 mmol), DIEA (1.05 g, 8.08 mmol), and 1-(5-amino-4-nitrofuran-2-yl)ethane-1-ol (0.7 g, 4.04 mmol) were added sequentially and allowed to react at room temperature overnight. The mixture was then quenched with water and transferred to a separatory funnel. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-hydroxyethyl)-3-nitrofuran-2-ylbenzamide as a yellow solid. 1 H NMR(500MHz,Chloroform)δ9.63(s,1H),7.71(s,1H),7.63(s,1H),7.15(s,1H),6.93(s,1 H),6.77(s,1H),5.15(d,J=6.0Hz,3H),2.59(s,3H),2.42(d,J=11.4Hz,4H),1.62(s,3H).

[0029] (3) Synthesis of 1-(5-(3-(3,5-dimethylisoxazol-4-yl)methoxy)benzamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 1)

[0030] 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-hydroxyethyl)-3-nitrofuran-2-ylbenzamide (1 g, 2.49 mmol) was dissolved in 20 mL of anhydrous dichloromethane, followed by the addition of triethylamine (0.4 g, 3.74 mmol) and di(aziridine-1-yl)phosphoryl chloride (0.4 g, 2.49 mmol). After reacting in an ice bath for 5 hours, the mixture was quenched with water. The mixed solution was transferred to a separatory funnel, and the organic phases were collected and combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 1-(5-(3-(3,5-dimethylisoxazol-4-yl)methoxy)benzamide)-4-nitrofuran-2-yl)ethyldi(aziridine-1-yl)phosphinate (Example 1) as a yellow oil. 1 H NMR(500MHz,Chloroform)δ9.57(s,1H),7.89(s,1H),7.53(s,1H),7.05(s,1H),6.83(s,1H),6.79( s,1H),5.15(d,J=6.0Hz,3H),4.49-4.07(m,8H),2.59(s,3H),2.32(d,J=11.4Hz,4H),1.60(s,3H).

[0031] Example 2

[0032] Synthesis of 1-(5-(3-(furan-3-ylmethoxy)benzamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 2):

[0033] Referring to the synthesis method of Example 1, 4-chloromethyl-3,5-dimethylisoxazole in Example 1 was replaced with 3-chloromethylfuran to obtain a light green oil, namely 1-(5-(3-(furan-3-ylmethoxy)benzamido)-4-nitrofuran-2-yl)ethyldi(aziridin-1-yl)phosphinate (Example 2). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1 H NMR (500MHz, Chloroform) δ9.40 (s, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.29 (s, 1H), 7.16 (d, J = 5.0Hz, 2H), 6. 90(s,1H),6.77(s,1H),6.22(s,1H),5.15(d,J=6.0Hz,3H),4.49-4.07(m,8H),2.02(s,1H),1.62(s,3H).

[0034] Example 3

[0035] Synthesis of 1-(5-(3-(benzyloxy)benzamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 3):

[0036] Referring to the synthesis method of Example 1, 4-chloromethyl-3,5-dimethylisoxazole in Example 1 was replaced with benzyl chloride to obtain a light green oil, namely 1-(5-(3-(benzyloxy)benzamido)-4-nitrofuran-2-yl)ethyldi(aziridin-1-yl)phosphinate (Example 3). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1 HNMR(500MHz,Chloroform)δ7.71(s,2H),7.63(s,2H),7.48(s,4H),7.40(s,3H),7.32(s,1H),7.15(s ,2H),7.11(s,2H),6.77(s,2H),5.14(d,J=4.0Hz,6H),4.49-4.07(m,8H),2.93(s,2H),1.63(s,6H).

[0037] Example 4

[0038] Synthesis of 1-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)pyridinamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 4):

[0039] Referring to the synthesis method of Example 1, the 3-hydroxybenzoic acid in Example 1 was replaced with 4-hydroxy-2-pyridinecarboxylic acid to obtain an off-white solid, namely 1-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)pyridinamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 4). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1 H NMR(500MHz,Chloroform)δ9.69(s,1H),8.84(s,1H),8.06(s,1H),7.95(s,1H),6.85(s,1H),5 .15(d,J=6.0Hz,3H),4.49-4.07(m,8H),2.59(s,3H),2.43(s,3H),2.09(s,1H),1.62(s,3H).

[0040] Example 5

[0041] Synthesis of 1-(5-(4-(furan-3-ylmethoxy)pyridinylamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 5):

[0042] Referring to the synthesis method of Example 2, 3-hydroxybenzoic acid in Example 2 was replaced with 4-hydroxy-2-pyridinecarboxylic acid to obtain an off-white solid, namely 1-(5-(4-(furan-3-ylmethoxy)pyridinylamido)-4-nitrofuran-2-yl)ethyldi(aziridin-1-yl)phosphinate (Example 5). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1 H NMR (500MHz, Chloroform) δ8.83 (s, 3H), 8.05 (s, 3H), 7.94 (s, 3H), 7.22 (d, J = 64.9Hz, 6H), 7. 09(s,3H),6.21(s,3H),5.15(d,J=6.0Hz,8H),4.49-4.07(m,8H),2.88(s,3H),1.62(s,9H).

[0043] Example 6

[0044] Synthesis of 1-(5-(4-(benzyloxy)pyridinylamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 6):

[0045] Referring to the synthesis method of Example 3, 3-hydroxybenzoic acid in Example 3 was replaced with 4-hydroxy-2-pyridinecarboxylic acid to obtain an off-white solid, namely 1-(5-(4-(benzyloxy)pyridinylamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 6). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1 H NMR(500MHz,Chloroform)δ8.84(s,2H),8.06(s,2H),7.94(s,2H),7.48(s,4H),7.40(s,3H),7 .32(s,1H),7.05(s,2H),5.14(d,J=4.0Hz,6H),4.49-4.07(m,8H),2.72(s,2H),1.61(s,6H).

[0046] Example 7

[0047] Synthesis of 1-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-5-ethylpyridinylamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 7):

[0048] Referring to the synthesis method of Example 1, the 3-hydroxybenzoic acid in Example 1 was replaced with 4-hydroxy-5-ethyl-2-pyridinecarboxylic acid to obtain an off-white solid, namely 1-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-5-ethylpyridinylamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 7). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1 H NMR(500MHz,Chloroform)δ8.65(s,4H),7.84(s,4H),7.08(s,4H),5.15(d,J=6.0Hz,11H),4.49- 4.07(m,8H),2.93(s,4H),2.71(s,7H),2.59(s,12H),2.43(s,12H),1.62(s,12H),1.18(s,6H).

[0049] Example 8

[0050] Synthesis of 1-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-5-isopentylpyridinylamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 8):

[0051] Referring to the synthesis method of Example 1, the 3-hydroxybenzoic acid in Example 1 was replaced with 4-hydroxy-5-isopentyl-2-pyridinecarboxylic acid to obtain an off-white solid, namely 1-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-5-isopentylpyridinylamido)-4-nitrofuran-2-yl)ethyl bis(aziridine-1-yl)phosphinate (Example 8). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1 H NMR (500MHz, Chloroform) δ8.63 (s, 5H), 7.82 (s, 5H), 7.08 (s, 5H), 5.14 (d, J = 6.1Hz, 14H), 4.49-4. 07(m,8H),2.94(s,5H),2.60(d,J=20.0Hz,25H),2.42(s,15H),1.63–1.57(m,27H),0.91(s,31H).

[0052] Example 9

[0053] Synthesis of 1-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-5-(piperidin-1-ylmethyl)pyridinamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 9):

[0054] Referring to the synthesis method of Example 1, the 3-hydroxybenzoic acid in Example 1 was replaced with 4-hydroxy-5-(piperidin-1-ylmethyl)-2-pyridinecarboxylic acid to obtain an off-white solid, namely 1-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-5-(piperidin-1-ylmethyl)pyridinecarboxylic acid (Example 9). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1 H NMR(500MHz,Chloroform)δ9.64(s,5H),8.80(s,5H),7.88(s,5H),6.83(s,5H),5.14(d,J=6.1Hz,14H),4.49-4.07( m,8H),3.65(s,10H),2.58(s,15H),2.43(d,J=10.0Hz,35H),2.29(s,5H),1.62(s,15H),1.53(s,14H),1.40(s,8H).

[0055] Example 10

[0056] Synthesis of 1-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-5-fluoropyridinylamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 10):

[0057] Referring to the synthesis method of Example 1, the 3-hydroxybenzoic acid in Example 1 was replaced with 4-hydroxy-5-fluoro-2-pyridinecarboxylic acid to obtain an off-white solid, namely 1-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-5-fluoropyridinecarboxylic acid)-4-nitrofuran-2-yl)ethyl bis(aziridine-1-yl)phosphinate (Example 10). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1 H NMR(500MHz,Chloroform)δ8.54(s,1H),7.93(s,1H),7.09(s,1H),5.15(d,J=6.0 Hz,3H),4.49-4.07(m,8H),2.90(s,1H),2.59(s,3H),2.43(s,3H),1.62(s,3H).

[0058] Example 11

[0059] Synthesis of 1-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-5-chloropyridinylamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 11):

[0060] Referring to the synthesis method of Example 1, the 3-hydroxybenzoic acid in Example 1 was replaced with 4-hydroxy-5-chloro-2-pyridinecarboxylic acid to obtain an off-white solid, namely 1-(5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-5-chloropyridinylamido)-4-nitrofuran-2-yl)ethyl bis(aziridin-1-yl)phosphinate (Example 11). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1 H NMR(500MHz,Chloroform)δ8.78(s,1H),8.13(s,1H),7.10(s,1H),5.15(d,J=6.0 Hz,3H),4.49-4.07(m,8H),2.94(s,1H),2.59(s,3H),2.43(s,3H),1.62(s,3H).

[0061] The structural formulas of the compounds synthesized in Examples 1-11 are shown in the following table:

[0062]

[0063]

[0064]

[0065] The following are the pharmacodynamic tests and results of the compounds of the present invention:

[0066] In vitro cytotoxicity assay:

[0067] Drugs and reagents: Test compounds, DMEM medium (01-050-1A), FBS fetal bovine serum (04-001-1A) were purchased from Biological Industries, and MTT thiazolyl blue reagent (KGT525500) was purchased from Keygene Biotechnology.

[0068] Instrument: THERMO Varioskan Flash full wavelength multifunctional microplate reader.

[0069] Experimental method: About 10,000 cells (PANC-1, SMMC-7721 or HepG2) were evenly mixed in 0.1 mL of DMEM medium containing 10% FBS and plated on the bottom plate of a 96-well plate. Incubate overnight at 37°C in an environment containing 5% CO2. Compounds diluted in 0.1 mL of DMEM medium at concentrations of 2.5 μM, 5 μM, 10 μM, 20 μM, 50 μM and 100 μM were treated on the cells for 24 hours. MTT reagent was then added to the well plate, and the plate was incubated at 37°C for 3 hours. The color reaction was measured at 492 nm using a spectrophotometer (Thermo, multiskan FC). The corresponding cell survival rate (SR%) of the test compound was calculated, and the IC 50 The values ​​are shown in the following table.

[0070]

[0071] From the results in the above table, it can be seen that the compounds of the present invention exhibit strong killing effects on various cancer cells and can be further developed as candidate molecules for anti-tumor drugs.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof: in: X is isoxazolyl, furyl or phenyl; R is selected from optionally substituted C1-C7 alkyl, C5-C7 saturated nitrogen heterocycloalkyl, nitro or halogen; Y is C or N.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from one of the following compounds:

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that The pharmaceutically acceptable salt is hydrochloride, maleate or citrate.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating cancer.

5. The use according to claim 4, characterized in that The drug further includes a pharmaceutically acceptable carrier.

6. A pharmaceutical composition, characterized in that The compound according to claim 1 or a pharmaceutically acceptable salt thereof is used as an effective active ingredient.

Images