Alpha-hydroxycarboxylic acid derivatives having adamantyl groups, and methods of making and using the same

Abstract

The application belongs to the field of pharmaceutical chemistry and provides an alpha-hydroxycarboxylic acid derivative with adamantyl, a preparation method and application thereof, stereoisomers or pharmaceutically acceptable salts thereof, and has the following general structure formula I: wherein, when X=O in the general formula, n=0 or 1, and A is a lipophilic group or a hydrophilic group; when X=N in the general formula, n=0-3, and A is one of an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aryl-heterocyclic group, a heteroaryl-heterocyclic group, a tetrahydropyrrole group, a piperazine group, a piperidine group, a morpholinyl group and other cyclic amines, and a substituted derivative of the above groups. The structural formula is as shown in formula I, and the alpha-hydroxycarboxylic acid derivative with adamantyl has good inhibitory activity on influenza viruses and can be developed into a new generation of M2 inhibitors, thereby laying a good foundation for the development of anti-influenza drugs.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and particularly relates to an α-hydroxycarboxylic acid derivative having an adamantyl group, its preparation method, and its application. Background Technology

[0002] Influenza viruses are the main culprit behind annual seasonal influenza (flu) outbreaks and sporadic pandemics, impacting public health and safety systems. Currently, vaccination is the most effective way to prevent influenza; however, it only provides prevention, while treatment requires medication.

[0003] Currently, the Chinese Center for Disease Control and Prevention recommends the following treatments: neuraminidase (NA) inhibitors, hemagglutinin (HA) inhibitor arbidol, and RNA polymerase inhibitors favipiravir and mabaloxavir. M2 inhibitors (amantadine and adalimumab) are no longer recommended for clinical use due to drug resistance issues. However, the parasitic nature of influenza viruses and the high variability of their antigens make it difficult for these chemotherapeutic drugs to maintain their effectiveness, leading to varying degrees of drug resistance. Some seasonal influenza A viruses (H1N1) are resistant to oseltamivir and peramivir, and resistant strains of mabaloxavir have also been isolated clinically. Combination therapy with antiviral drugs with different mechanisms of action can enhance treatment efficacy or reduce the emergence of drug-resistant strains. Since the development trend of influenza and viral mutations are still unpredictable, the development of anti-influenza drugs is a hot topic in drug development and represents the first line of defense against influenza in response to potential pandemics.

[0004] The main reason for resistance to amantadine M2 inhibitors is mutations in the transmembrane region of the M2 protein, especially the S31N mutation. Specifically, the mechanism involves the mutation of a serine residue (Ser) on the M2 ion channel to glutamine (Asn), which reduces the size of the drug binding site, preventing the binding of amantadine and rimantadine in the pore and blocking proton conduction. Currently, amantadine inhibitors against M2-S31N resistance have been reported in the literature. These inhibitors were discovered by the DeGrado and Wang research group in the United States, who summarized the pharmacophore model of M2-S31N inhibitors and reported a series of amantadine analogs. The common characteristics of these inhibitors are: a hydrophobic skeleton + methylene bridge + hydrophobic five (or six)-membered aromatic ring.

[0005] From a drug design perspective, adamantane is considered a "lipophilic bullet," which can increase the hydrophobicity and structural stability of drugs. It also lacks rotatable bonds, resulting in only a minimal loss of conformational entropy when binding to target proteins. Furthermore, adamantane derivatives are a popular area of ​​research in antiviral drug development; for example, adamantane derivatives can treat influenza, herpes simplex virus, hepatitis C virus, and HIV.

[0006] Therefore, based on the structural characteristics of M2-S31N inhibitors and adamantane ethylamine reported in the literature, the designed novel adamantane derivatives are expected to be developed into a new generation of M2 inhibitor anti-influenza drugs. Summary of the Invention

[0007] The purpose of this invention is to provide an α-hydroxycarboxylic acid derivative with adamantyl group, its preparation method and application, which has good inhibitory activity against influenza virus.

[0008] This invention is achieved by providing an α-hydroxycarboxylic acid derivative having an adamantyl alkyl group, its stereoisomer or pharmaceutically acceptable salt, having the following general structural formula I:

[0009]

[0010] In the general formula, when X = 0, n = 0 or 1, and A is a lipophilic group or a hydrophilic group;

[0011] In the general formula, when X = N, n = 0 to 3, and A is one of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl-heterocyclic, heteroaryl-heterocyclic, tetrahydropyrrole, piperazine, piperidine, morpholino, and other cyclic amines, as well as substituted derivatives of the above groups.

[0012] Further technical solutions may be selected from any of the following structural formulas:

[0013]

[0014] A method for preparing an α-hydroxycarboxylic acid derivative having an adamantyl group, the synthetic route is as follows:

[0015]

[0016] Includes the following steps:

[0017] Step 1: Using 2-adamantyl-α-keto acid 1 as a raw material, and cis-N-p-toluenesulfonylaminoindanol 2 under the action of a condensing agent, an ester intermediate 3 is generated;

[0018] Step 2: Compound 3 obtained in Step 1 is subjected to a nucleophilic addition reaction with 2-methylthiophene lithium prepared in situ at low temperature to obtain compound 5;

[0019] Step 3: The compound 5 obtained in Step 2 is subjected to hydrolysis under LiOH / CH3OH / THF conditions to obtain carboxylic acid derivative 6;

[0020] Step 4: Take the carboxylic acid compound 6 obtained in Step 3 above and condense it with different substituted primary amines (R-NH2) using a condensing agent to obtain target compounds I-1 to I-4, I-7 to I-17; or react compound 6 with brominated products under NaHCO3 to generate ester compounds I-5 and I-6.

[0021] In a further technical solution, the molar ratio of α-keto acid 1 to the catalyst in step one is 1:05-1.5, the selected catalyst is EDCI·HCl / DMAP or TBTU, and the solvent is dichloromethane or THF.

[0022] In a further technical solution, the reaction temperature in step two is -78℃, and the reaction time is 3-5 hours.

[0023] In a further technical solution, the solvent ratio selected in step three is tetrahydrofuran:methanol:water in a volume ratio of 2:3:1, and the temperature is 60-80℃.

[0024] In a further technical solution, the catalyst used to form the amide in step four is CDI or EDCI·HCl / HOBt, the solvent is dichloromethane, and the temperature is room temperature (25°C).

[0025] An α-hydroxycarboxylic acid derivative having an adamantyl group, and the application of its pharmaceutically acceptable salts, hydrates, and solvates in the preparation of antiviral drugs for influenza.

[0026] A further technical solution is that the influenza virus is influenza A H3N2 (A / Hong Kong / 8 / 68strain, amantadine-sensitive strain) or H1N1 (A / WSN / 1933, amantadine-resistant strain).

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] This invention provides an α-hydroxycarboxylic acid derivative with an adamantyl group, its preparation method, and its application. The derivative, with the structural formula shown in Formula I, exhibits good inhibitory activity against influenza viruses and can be developed into a new generation of M2 inhibitors, laying a good foundation for the development of anti-influenza drugs. This invention also provides a method for preparing the above-mentioned compound, which easily yields a series of compounds. In vitro anti-influenza virus experiments show that the compounds improved by this invention have certain inhibitory activity against both wild-type (H3N2) and variant (H1N1) influenza viruses, with relatively low toxicity. The activity of some compounds is comparable to that of the positive control drug oseltamivir, demonstrating that these compounds and their pharmaceutically acceptable salts, hydrates, and solvates can be used in the preparation of anti-influenza virus drugs. This invention also provides a pharmaceutical composition containing the above-mentioned compounds, which can be formulated into tablets, capsules, and suspensions as needed, possessing significant development value and economic benefits for the prevention and treatment of influenza. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0030] The specific implementation of the present invention will be described in detail below with reference to specific embodiments.

[0031] The term "pharmaceutically acceptable salt" refers to a common, non-toxic salt formed by reacting α-hydroxycarboxylic acid derivatives I-7 to I-11 with an adamantyl group that are basic and can react with inorganic or organic acids. Examples include hydrochlorides, hydrobroms, sulfates, nitrates, phosphates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, oxalates, citrates, mandelates, nicotinates, tartrates, palmitates, malates, succinates, and maleates.

[0032] The term "stereoisomer" refers to compounds that have the same chemical formula but differ in the spatial arrangement of atoms or groups.

[0033] A pharmaceutical composition comprising an α-hydroxycarboxylic acid derivative having an adamantyl group, and at least one pharmaceutically acceptable excipient, comprising the α-hydroxycarboxylic acid derivative having an adamantyl group as shown in Formula I, and its pharmaceutically acceptable salts, hydrates, solvates, and stereoisomers. The term "pharmaceutical excipient" refers to various excipients conventionally used in pharmaceuticals, such as excipients, diluents, controlled-release agents, stabilizers, disintegrants, humectants, surfactants, etc.

[0034] Basic steps, synthesis of 2-(adamantane-1-yl)-2-oxoacetic acid (1)

[0035]

[0036] Add 1-adamantyl ketone (3.0 g, 17 mmol, 1 equiv) and water (50 mL) to a round-bottom flask (250 mL). At 0 °C, add pyridine (4.1 mL, 51 mmol, 3 equiv), potassium hydroxide (KOH, 1.12 g, 20 mmol, 1.18 equiv), and then add solid potassium permanganate (KMnO4, 5.37 g, 34 mmol, 2 equiv) in portions. After the addition is complete, stir magnetically at 60 °C, attach a reflux apparatus, and place a balloon to absorb the gas. Monitor the reaction by thin-layer chromatography (TLC). After 3 h, the reaction is complete. Filter while hot and wash the filter flask (10 mL × 3) with hot water. Combine the filtrates, adjust the pH to 1 with concentrated hydrochloric acid, extract with ethyl acetate (50 mL × 3), wash the organic phase with saturated brine (80 mL × 2), dry with anhydrous Na2SO4, filter with a small funnel plugged with defatted cotton, remove the solvent by vacuum distillation, and obtain adamantane-1-ylglyoxylic acid intermediate 1 (3.22 g, yield 91.0%), a white solid.

[0037] Synthesis of (1S,2R)-1-((4-methylphenyl)sulfonamido)-2,3-dihydro-1H-inden-2-yl 2-(adamantane-1-yl)-2-oxoacetate (3)

[0038]

[0039] To a 250 mL round-bottom flask, add α-keto acid 1 (2.08 g, 10 mmol, 1 equiv) and dichloromethane (100 mL), and stir at 0 °C. Add EDC·HCl (2.875 g, 15 mmol, 1.5 equiv) and 4-dimethylaminopyridine (DMAP, 2.44 g, 20 mmol, 2 equiv). Finally, add cis-N-p-toluenesulfonylaminoindanol 7 (3.03 g, 10 mmol, 1 equiv) in portions, and stir at room temperature. Monitor the reaction by thin-layer chromatography; the reaction is complete after 12 h. Extracted with ethyl acetate (50 mL × 3), the organic phase was washed once with dilute hydrochloric acid to remove organic base, then washed with saturated brine (80 mL × 2), dried over anhydrous Na2SO4, filtered through a small funnel plugged with defatted cotton, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15:1-1:1) to give intermediate 3 (3.0 g, yield 60.8%). 1HNMR(400MHz,Chloroform-d)δ8.33(d,J=8.8Hz,1H),7.79(d,J=8.2Hz,2H),7.40(d, J=8.2Hz,2H),7.26-7.18(m,2H),7.13(t,J=7.5Hz,1H),6.82(d,J=7.5Hz,1H),5.42(t d,J=5.0,1.5Hz,1H),5.05(dd,J=8.8,5.0Hz,1H),3.25(dd,J=17.2,5.0Hz,1H),2.87( d,J=17.2,1H),2.40(s,3H),1.98-1.93(m,3H),1.80-1.78(m,3H),1.75-1.57(m,9H). 13 C NMR (100MHz, CDCl3) δ200.5,162.6,144.0,139.3,138.1,137.8,130.0,128.9 ,127.8,127.2,125.1,124.3,76.6,59.9,45.1,37.5,37.2,36.3,27.6,21.7.

[0040] Synthesis of (1S,2R)-1-((4-methylphenyl)sulfonamido)-2,3-dihydro-1H-inden-2-yl(S)-2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)ethyl acetate (5)

[0041]

[0042] To a 250 mL round-bottom flask, add ester compound 3 (3.46 g, 7 mmol, 1 equiv) and dissolve it in anhydrous tetrahydrofuran (20 mL) under an anhydrous and oxygen-free environment in a glove box. To another 25 mL round-bottom flask, add 2-methylthiophene (1.38 g, 14 mmol, 2 equiv) and dissolve it in anhydrous tetrahydrofuran (100 mL) under an anhydrous and oxygen-free environment in a glove box. Place the flask at -78 °C and cool for a few minutes. Then, slowly add n-butyllithium (4.2 mL, 2.5 mol / L) dropwise and continue the reaction at -78 °C. After 1 hour of reaction, use a syringe to aspirate starting material 7 and slowly add it dropwise to the round-bottom flask. Monitor the reaction by thin-layer chromatography; the reaction is complete after 3 hours. The reaction was quenched with an appropriate amount of ammonium chloride solution, extracted with ethyl acetate (80 mL × 3), the organic phase was washed with saturated brine (150 mL × 2), dried over anhydrous Na2SO4, filtered through a small funnel plugged with defatted cotton, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 15:1-6:1) to give intermediate 5 (3.60 g, yield 86.9%), a white crystal.1 HNMR(400MHz,DMSO-d6)δ8.30(d,J=10.2Hz,1H),7.56(d,J=8.2Hz,2H),7.27-7.23(m,2H),7.21- 7.18(m,2H),7.01(d,J=8.2Hz,2H),6.80(d,J=3.5Hz,1H),6.74(dd,J=3.5,1.2Hz,1H),5.91(s,1H ),4.97(dd,J=10.1,4.8Hz,1H),4.77(t,J=4.6Hz,1H),3.13(dd,J=17.2,4.5Hz,1H),2.74(d,J=17 .2Hz,1H),2.45(s,3H),2.28(s,3H),1.83(s,3H),1.54(d,J=12.6Hz,6H),1.41(d,J=12.6Hz,6H). 13 C NMR (100MHz, CDCl3) δ173.2,144.1,139.4,139.4,139.1,138.7,137.6,130.1,128.9,127.7,127.2,126.0 ,125.2,124.5,124.0,83.0,79.1,59.8,40.6,37.1,36.8,36.6,28.6,21.7,15.1.LC-MS(ESI)m / z:[M+Na] + Calcd forC 33 H 37 NO5S2,614.21,Found 614.0.

[0043] Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)acetic acid 9

[0044]

[0045] To a round-bottom flask (250 mL), add ester compound 5 (3.6 g, 6.09 mmol, 1 equiv) obtained in the previous step, tetrahydrofuran (40 mL), and methanol (60 mL), followed by LiOH·H₂O (1.28 g, 30.45 mmol, 5 equiv) and water (20 mL). Stir the mixture magnetically at 60 °C and attach a reflux reflux apparatus. Monitor the reaction by thin-layer chromatography. After 24 h, the reaction is complete. Remove tetrahydrofuran by vacuum distillation, and extract with water, dichloromethane, and 10% sodium hydroxide solution, retaining the aqueous phase. The aqueous phase was adjusted to pH 1 with dilute hydrochloric acid and extracted with ethyl acetate in reverse phase (10 mL × 3). The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous Na2SO4, filtered through a small funnel plugged with defatted cotton, and concentrated under reduced pressure to give 6-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)acetic acid (65 mg, yield 96.6%). 1 H NMR(400mHz,DMSO-d6)δ6.86(d,J=3.5Hz,1H),6.63(dd,J=3.5,1.2Hz,1H),2.36(s,3H), 1.91(t,J=3.3Hz,3H),1.76(d,J=12.0Hz,3H),1.63–1.52(m,6H),1.48(d,J=12.0Hz,3H). 13 CNMR(100mHz,DMSO)δ174.3,141.3,137.6,125.4,124.4,81.4,36.5,36.0,28.0,14.7,14.6.

[0046] Example 1: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophene-2-yl)-N-(2-morpholinoline ethyl)acetamide (I-9)

[0047]

[0048] Add starting material 6 (122.4 mg, 0.4 mmol, 1 equiv) to a round-bottom flask (25 mL), dissolve it in a suitable amount of dichloromethane, and add N,N'-carbonyldiimidazole (CDI, 104.7 mg, 0.8 mmol, 2 equiv) in portions. Stir magnetically at room temperature for 2 h. Add 4-(2-aminoethyl)morpholine 10 (104.7 mg, 0.8 mmol, 2 equiv), and continue the reaction at room temperature. Monitor the reaction by thin-layer chromatography. After 5 h, the reaction is complete. Extract with dichloromethane (15 mL × 3), wash the organic phase with saturated brine (20 mL × 2), dry with anhydrous Na2SO4, filter with defatted cotton plugged with a small funnel, and rotary evaporate under reduced pressure to obtain a yellow oil. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate, 5:1-0:1) to obtain the target product I-9 (91 mg, yield 54.5%), a white powder.

[0049] LC-MS(ESI)m / z:[M+H] + Calcd for C 23 H 34 N2O3S,592.21,Found,592.1; IR(KBr)ν(cm -1 ): 3430, 3418, 3402, 3054, 2907, 2850, 2801, 1651, 1526, 1473, 1452, 1363, 1344, 1117; 1HNMR (400m Hz, CDCl3) δ7.24(t,J=5.2Hz,1H),6.95(d,J=3.5Hz,1H),6.63(dd,J=3.5,1.2Hz,1H),3.67(t,J=4. 6Hz,4H),3.45-3.37(m,1H),3.30(dt,J=19.6,5.8Hz,2H),2.48(td,J=5.6,1.2Hz,2H),2.44-2.42 (m,7H),1.98(p,J=3.0Hz,3H),1.85(dq,J=12.2,2.3Hz,3H),1.69-1.63(m,6H),1.60-1.55(m,3H); 13 C NMR (100mHz, CDCl3) δ172.3,140.8,139.7,125.4,124.3,82.9,67.1,57.0,53.4,40.5,36.9,36.5,35.8,28.7,15.1.

[0050] Example 2: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)-N-((bicyclo[2.2.1]heptane-2-yl)methyl)acetamide (I-4)

[0051] In a 25 mL round-bottom flask, carboxylic acid 6 (94.8 mg, 0.31 mmol), 5-norbornene-2-methylamine (40.1 mg, 0.3255 mmol, 1.05 equiv.), and 3 mL of dichloromethane were added and stirred at room temperature to dissolve. Then, EDCI·HCl (65.4 mg, 0.341 mmol, 1.1 equiv.) and HOBt (46.1 mg, 0.341 mmol, 1.1 equiv.) were added sequentially, and the reaction was carried out at room temperature for 6 hours. The reaction was quenched with an appropriate amount of water, and the product was extracted three times (15 mL) with dichloromethane. The organic phase was washed twice with dilute hydrochloric acid and twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 185 mg of product as a white solid, with a yield of 59.7%.

[0052] 1 H NMR(400mHz,DMSO-d6)δ7.60(q,J=5.2Hz,1H),6.87(d,J=3.5Hz,1H),6.61( d,J=3.5Hz,1H),6.16–6.14(m,1H),6.05–5.98(m,1H),5.83(s,1H),2.86–2. 62(m,3H),2.36(s,3H),2.29–2.16(m,1H),1.89(s,3H),1.83-1.71(m,4H),1 .61-1.42(m,10H),1.35-1.26(m,1H),1.23-1.17(m,1H),0.53-0.48(m,1H). 13 C NMR (100mHz, CDC) l3 )δ171.9,140.5,139.8,137.8,132.2,125.5,124.3,82.9,49.6,44.5,43.5,42.5,40.5,39.0,38.8,36.9,36.5,28.7,15.1.

[0053] Example 3: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)-N-(propynyl-1-yl)acetamide (I-1)

[0054] Replacing 4-(2-aminoethyl)morpholine with propargylamine in Example 1, and following the same procedures as in Example 1, the target compound was synthesized as a white powder with a yield of 77.6%. 1H NMR (400mHz, CDCl3) δ7.43–7.22(m,1H),7.17(d,J=7.3Hz,1H),6.99(d,J=3.5Hz,1H),6.67(d,J=3.5Hz,1H),4.18–4.11(m,1H) ,4.07–4.00(m,1H),2.79(s,1H),2.47(s,3H),2.25(t,J=2.6Hz,1H),2.07-2.00(m,3H),1.96-1.88(m,3H),1.73-1.61(m,9H). 13 CNMR (100mHz, CDCl3) δ172.1,140.1,139.6,125.8,124.4,83.1,79.5,71.8,40.7,36.8,36.4,29.1,28.7,15.2.

[0055] Example 4: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)-N-((tetrahydrofuran-3-yl)methyl)acetamide (I-2)

[0056] In Example 2, 5-norbornene-2-methylamine was replaced with 3-aminomethyl-tetrahydrofuran, and the other operating steps were the same as in Example 2. The target compound was synthesized as a white solid with a yield of 78.8%.

[0057] 1 H NMR (400mHz, CDCl3) δ7.09 (s, 1H), 6.94 (d, J = 3.5Hz, 1H), 6.63 (d, J = 3.5Hz, 1H), 3.88–3.82 (m, 1H), 3.82–3.67 (m, 2H), 3.50 (dd, J = 8.2, 5. 5Hz,1H),3.39–3.16(m,2H),2.90–2.88(m,1H),2.54–2.45(m,1H),2.43(s,3H),2.03-1.98(m,4H),1.92-1.82(m,3H),1.67-1.58(m,10H). 13 C NMR (100mHz, CDCl3) δ172.5,139.9,125.6,124.3,83.0,71.6,71.5,67.9,67.9,42.3,40.5,39.2,39.2,36.8,36.5,30.2,28.7,15.2.

[0058] Example 5: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)-N-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-3-yl)acetamide (Ⅰ-3)

[0059] The 4-(2-aminoethyl)morpholine in Example 1 was replaced with (1R,2R,3R,5S)-3-pinelanamine, and the other operating steps were the same as in Example 1. The target compound was synthesized as a white powder with a yield of 26.3%.

[0060] 1 H NMR(300mHz, CDCl3) δ6.95(d,J=3.5Hz,1H),6.77(d,J=8.6Hz,1H),6.64(d,J=3.6Hz,1H),4.3 4-4.23(m,1H),2.89(s,1H),2.67-2.57(m,1H),2.44(s,3H),2.41-2.37(m,1H),2.00-1.95(m ,3H),1.89(d,J=12.5Hz,3H),1.84-1.75(m,2H),1.65(d,J=16.0Hz,6H),1.51(dd,J=6.0,2.0 Hz,1H),1.27(d,J=9.2Hz,1H),1.22(s,3H),1.07(s,3H),1.05(s,3H),0.85(d,J=9.8Hz,1H). 13 C NMR (100mHz, CDCl3) δ171.3,140.3,140.1,125.6,124.2,82.9,48.0,47.6,46. 5,41.7,40.5,38.6,37.1,36.9,36.6,35.4,29.8,28.7,28.1,23.4,21.1,15.2.

[0061] Example 6: Synthesis of ((prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)acetate (Ⅰ-5);

[0062]

[0063] In a 100 mL round-bottom flask, perillyl alcohol (456.7 mg, 3 mmol), triphenylphosphine (865.6 mg, 3.3 mmol), and 20 mL of dichloromethane were added. The reaction solution was cooled to 0 °C, and NBS (587.4 mg, 3.3 mmol) was added in portions with magnetic stirring. After the addition was complete, the ice-water bath was removed, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, the solvent was removed under reduced pressure, and then n-hexane was added several times. A solid precipitated out. The solid was filtered, and the filtrate was purified under reduced pressure to remove the solvent. Silica gel column chromatography (eluent: n-hexane) yielded 464 mg of the brominated product as a colorless liquid, with a yield of 72.0%.

[0064]

[0065] In a 25 mL round-bottom flask, starting material 6 (54 mg, 0.176 mmol), the brominated compound obtained in the previous step (75 mg, 0.352 mmol), and 1 mL of DMF were added. NaHCO3 (29.6 mg, 0.352 mmol) was added all at once while stirring at room temperature. The mixture was stirred at room temperature in the dark for 6 hours, and TLC showed complete reaction. The mixture was transferred to a separatory funnel and extracted three times with 10 mL of ethyl acetate, washed twice with water, and washed twice with saturated brine. The extract was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was then subjected to silica gel column chromatography to obtain 47 mg of the target compound (Ⅰ-5) as a colorless viscous liquid, with a yield of 60.6%.

[0066] 1 H NMR(400mHz, CDCl3) δ6.90(d,J=3.5Hz,1H),6.63(d,J=3.5Hz,1H),5.87(s,1H),4.79-4.67(m,3H),4.63-4.55(m,1H),4.05 (s,1H),2.44(s,3H),2.20-2.12(m,4H),2.02-1.95(m,4H),1.93-1.78(m,5H),1.75(s,3H),1.68-1.61(m,6H),1.55(s,2H). 13 C NMR (75mHz, CDCl3) δ174.0,149.3,140.3,138.9,131.8,128.1,125.8,124.7, 109.0,82.4,70.9,40.6,36.9,36.3,30.5,28.6,27.6,27.2,26.9,20.9,15.2.

[0067] Example 7: Synthesis of (6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl-2-adamantane-1-yl)methyl 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)acetate (Ⅰ-6);

[0068] Replacing perillol with myrtol in Example 6, and following the same procedures as in Example 6, the target compound was synthesized as a colorless viscous liquid with a yield of 89.7%.

[0069] 1 H NMR(400mHz, CDCl3)δ6.87(d,J=3.5Hz,1H),6.62(dd,J=3.5,1.2Hz,1H),5.73–5.67(m,1H),4.72 (dd,J=11.8,1.2Hz,1H),4.51(dd,J=11.8,1.2Hz,1H),4.12(s,1H),2.43(s,3H),2.44-2.42(m,1H ),2.36-2.28(m,2H),2.25(td,J=5.6,1.6Hz,1H),2.13(ddq,J=4.6,3.1,1.6Hz,1H),1.98(t,J=3 .2Hz,3H),1.85-1.77(m,3H),1.68-1.55(m,9H),1.29(s,3H),1.21(d,J=8.7Hz,1H),0.85(s,3H). 13 C NMR (100mHz, CDCl3) δ174.2,142.2,140.3,138.9,125.8,124.7,124.1,82 .4,69.9,43.9,40.6,38.2,36.9,36.4,31.7,31.4,28.7,26.1,21.1,15.2.

[0070] Example 8: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)acetamide (I-7);

[0071] In Example 2, 5-norbornene-2-methylamine was replaced with 4-methyl-1-piperazineethylamine, and the other operating steps were the same as in Example 2. The target compound was synthesized as a white solid with a yield of 37.8%.

[0072] 1H NMR (400mHz, DMSO-d6) δ7.59(t,J=5.6Hz,1H),6.86(d,J=3.5Hz,1H),6.61(dd,J=3.5,1.2Hz,1H),5.85(s,1H),3.31–3.26(m,1H),3 .09–3.02(m,1H),2.46–2.19(m,12H),2.13(s,3H),1.89(s,3H),1.75(d,J=12.0Hz,3H),1.61-1.51(m,6H),1.46(d,J=12.0Hz,3H). 13 C NMR (100mHz, CDCl3) δ172.4,140.9,139.7,125.4,124.3,82.8,56.5,55.1,52.8,46.1,40.4,36.9,36.5,35.9,28.8,15.2.

[0073] Example 9: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)-N-(1-(4-methylpiperidin-4-yl)methyl)acetamide (I-8);

[0074] In Example 2, 5-norbornene-2-methylamine was replaced with (1-methyl-4-piperidin-)methylamine, and the other operating steps were the same as in Example 2. The target compound was synthesized as a white solid with a yield of 40.0%.

[0075] 1 H NMR (400mHz, DMSO-d6) δ7.62(t,J=5.8Hz,1H),6.86(d,J=3.5Hz,1H),6.61(d,J=3.5Hz,1H),5.85(s,1H),2.98(d,J=6.2Hz,2H),2.72–2.68(m,2H) ,2.36(s,3H),2.10(s,3H),1.91–1.86(m,3H),1.79-1.75(m,4H),1.74-1 .70(m,1H),1.56(d,J=12.0Hz,6H),1.51-1.43(m,6H),1.18-1.06(m,2H). 13 C NMR (100mHz, CDCl3) δ172.4,140.2,139.9,125.6,124.2,83.0,55.5,46.4,44.8,40.4,36.8,36.5,35.4,30.1,30.1,28.7,15.1.

[0076] Example 10: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)-N-((4-methylmorpholino-2-yl)methyl)acetamide (I-10)

[0077] The 4-(2-aminoethyl)morpholine in Example 1 was replaced with 4-methylmorpholine-2-methylamine, and the other operating steps were the same as in Example 1. The target compound was synthesized as a white solid with a yield of 22.8%.

[0078] 1 H NMR (400mHz, CDCl3) δ7.21 (s, 1H), 6.94 (dd, J = 3.7, 1.7Hz, 1H), 6.62 (s, 1H), 3.88– 3.82(m,1H),3.71–3.60(m,2H),3.58–3.47(m,1H),3.23–3.11(m,1H),2.74(t,J=11 .2Hz,1H),2.68(d,J=11.5Hz,1H),2.42(s,3H),2.29(s,3H),2.12(tt,J=11.6,3.3 Hz,1H),2.00-1.95(m,3H),1.92-1.85(m,4H),1.62(t,J=12.2Hz,9H),1.25(s,1H). 13 C NMR (100mHz, CDCl3) δ172.6,140.2,139.9,125.6,124.3,83.1,83.0,77.4,74.5,66.4 ,57.7,57.6,54.6,46.2,46.1,41.7,41.7,40.5,40.5,36.9,36.509,36.5,28.7,15.2.

[0079] Example 11: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)-N-(3-(pyrrolidone-1-yl)propyl)acetamide (I-11)

[0080] Replacing 4-(2-aminoethyl)morpholine with 1-(3-aminopropyl)pyrrolidine in Example 1, and following the same procedures as in Example 1, the target compound was synthesized as a white, foamy solid with a yield of 58.2%. 1H NMR (400mHz, DMSO-d6) δ7.96(t,J=6.0Hz,1H),6.88(d,J=3.5Hz,1H),6.62(d,J=3.5Hz,1H),5.89(s,1H),3.19 –3.14(m,3H),3.00(t,J=6.8Hz,3H),2.36(s,3H),1.89(s,8H),1.80(s,3H),1.77(s,2H),1.61-1.42(m,10H). 13 C NMR (75mHz, CDCl3) δ174.3,141.6,140.3,126.6,124.9,83.6,78.5,78.1,77.6,54.6,41.1,38.6,37.8,29.6,27.8,24.2,16.1.

[0081] Example 12: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)-N-((1S,4S)-4-hydroxycyclohexane)acetamide (I-12)

[0082] In Example 2, 5-norbornene-2-methylamine was replaced with cis-4-aminocyclohexanol hydrochloride. The other operating steps were the same as in Example 2. The target compound was synthesized as a white solid with a yield of 68.8%. 1 H NMR (400mHz, DMSO-d6) δ7.23(d,J=8.0Hz,1H),6.87(d,J=3.5Hz,1H),6.62(d,J=3.5Hz,1H),5.91(s,1H),4.4 2(d,J=3.0Hz,1H),3.70–3.57(m,2H),2.36(s,3H),1.89(s,3H),1.80(d,J=12.0Hz,3H),1.62-1.44(m,17H). 13 C NMR (100mHz, DMSO-d6) δ170.8,139.8,138.0,125.5,123.2,81.1,64.3,45.3,35.5,30.6,30.6,27.7,26.8,26.4,14.3.

[0083] Example 13: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophene-2-yl)-N-(2-hydroxyphenylethyl)acetamide (I-13)

[0084] Replacing 4-(2-aminoethyl)morpholine with 2-(2-aminoethyl)phenol in Example 1, and following the same procedures as in Example 1, the target compound was synthesized as a white solid with a yield of 44.2%.1 H NMR (400mHz, DMSO-d6) δ9.38 (s, 1H), 7.65 (t, J = 5.4Hz, 1H), 7.06 (dd, J = 7.4, 1.2Hz, 1H), 7.00 (td, J = 7.8, 1.2Hz, 1H), 6.86 (d, J = 3.5Hz, 1H), 6.78 (dd, J = 8.0, 1.2Hz, 1H), 6.70 (td, J = 7.8, 1.2Hz, 1H), 6.61 (dd, J = 3. 5,1.2Hz,1H),5.82(s,1H),3.46-3.37(m,1H),3.24-3.17(m,1H),2.76-2.64(m,2H),2.36(s,3H),1.91-1 .81(m,3H),1.72(d,J=12.4Hz,3H),1.55(d,J=12.1Hz,3H),1.44(t,J=12.1Hz,6H),1.17(t,J=7.2Hz,1H). 13 C NMR(100mHz,DMSO-d6)δ172.2,155.3,140.4,138.4,130.1,127.2,125.9,125.4, 123.5,118.9,114.89,81.7,59.8,39.4,36.6,35.9,29.6,28.1,20.8,14.7,14.1.

[0085] Example 14: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophene-2-yl)-N-(3-hydroxy-4-methoxyphenethyl)acetamide (I-14)

[0086] In Example 2, 5-norbornene-2-methylamine was replaced with 5-(2-aminoethyl)-2-methoxyphenol, and the other operating steps were the same as in Example 2. The target compound obtained was a white solid with a yield of 38.1%.

[0087] 1H NMR (400mHz, DMSO-d6) δ8.83 (s, 1H), 7.63 (t, J = 5.4Hz, 1H), 6.86 (d, J = 3.5Hz, 1H), 6.80 (d, J=8.2Hz,1H),6.65(d,J=2.1Hz,1H),6.61(d,J=3.5Hz,1H),6.58(dd,J=8.2,2.1Hz,1H),5. 81(s,1H),3.72(s,3H),3.44-3.37(m,1H),3.20-3.11(m,1H),2.59(t,J=7.0Hz,2H),2.36( s,3H),1.86(s,3H),1.72(d,J=12.0Hz,3H),1.55(d,J=12.0Hz,3H),1.46(d,J=10.8Hz,6H). 13 C NMR(100mHz,DMSO-d6)δ172.1,146.4,146.1,140.4,138.3,131.8,125.9,1 23.6,119.0,115.9,112.2,81.7,55.6,39.4,36.6,35.9,34.5,28.1,14.7.

[0088] Example 15: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)-N-(2-(1H-indol-3-yl)ethyl)acetamide (I-15)

[0089] In Example 2, 5-norbornene-2-methylamine was replaced with tryptamine, and the other operating steps were the same as in Example 2. The target compound obtained was a white solid with a yield of 61.2%.

[0090] 1 H NMR (400mHz, DMSO-d6) δ10.81(s,1H),7.75(t,J=5.6Hz,1H),7.57(d,J=7.8Hz,1H),7.32(d ,J=8.0Hz,1H),7.16(d,J=1.2Hz,1H),7.06(t,J=7.2Hz,1H),6.97(t,J=7.2Hz,1H),6.87(d, J=3.5Hz,1H),6.62(dd,J=3.5,1.2Hz,1H),5.83(s,1H),3.52-3.44(m,1H),3.37-3.28(m,1 H),2.90-2.79(m,2H),2.36(s,3H),1.86(s,3H),1.74(d,J=12.0Hz,3H),1.56-1.41(m,9H). 13C NMR (100mHz, DMSO-d6) δ172.2,140.4,138.4,136.3,127.2,125.9,123.6,122. 7,120.9,118.4,118.2,111.6,111.3,81.7,39.5,36.6,35.9,28.1,25.2,14.7.

[0091] Example 16: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)acetamide (I-16)

[0092] In Example 2, 5-norbornene-2-methylamine was replaced with 5-methoxytryptamine, and the other operating steps were the same as in Example 2. The target compound obtained was a white solid with a yield of 67.0%.

[0093] 1 H NMR (400mHz, DMSO-d6) δ10.64(s,1H),7.73(t,J=5.6Hz,1H),7.21(d,J=8.7Hz,1H),7.12( d,J=2.4Hz,1H),7.07(d,J=2.4Hz,1H),6.87(d,J=3.5Hz,1H),6.71(dd,J=8.7,2.4Hz,1H) ,6.62(d,J=2.3Hz,1H),5.84(s,1H),3.76(s,3H),3.51-3.42(m,1H),3.33-3.25(m,1H),2 .81(t,J=7.0Hz,2H),2.36(s,3H),1.86(s,3H),1.75(d,J=12.0Hz,3H),1.56-1.42(m,9H). 13 C NMR (100mHz, CDCl3) δ172.2,154.2,140.4,139.8,131.6,127.8,125.5,124.3,123. 0,112.8,112.5,112.1,100.6,82.9,56.1,40.4,39.5,36.8,36.4,28.7,25.3,15.2.

[0094] Example 17: Synthesis of 2-(adamantane-1-yl)-2-hydroxy-2-(5-methylthiophen-2-yl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)acetamide (I-17)

[0095] In Example 2, 5-norbornene-2-methylamine was replaced with 5-chlorotryptamine hydrochloride, and the other operating steps were the same as in Example 2. The target compound obtained was a white solid with a yield of 78.5%.

[0096] 1 H NMR (400mHz, DMSO-d6) δ11.03 (s, 1H), 7.77 (t, J = 5.2Hz, 1H), 7.63 (s, 1H), 7.34 (d,J=8.6Hz,1H),7.25(s,1H),7.05(d,J=8.6Hz,1H),6.86(d,J=3.5Hz,1H),6.6 1(d,J=3.5Hz,1H),5.83(s,1H),3.51-3.42(m,1H),3.31-3.24(m,1H),2.88-2. 79(m,2H),2.36(s,3H),1.85(s,3H),1.73(d,J=12.0Hz,3H),1.56-1.39(m,9H). 13 C NMR (100mHz, CDCl3) δ172.2,140.3,139.9,134.8,128.6,125.5,125.4,124.4,123. 6,122.6,118.4,113.0,112.3,83.0,40.5,39.6,36.8,36.5,29.9,28.7,25.2,15.2.

[0097] Experiment 1: In vitro anti-influenza virus activity test

[0098] To evaluate the in vitro anti-influenza virus activity of the synthesized compounds, the following virus strains were selected: amantadine-sensitive virus strain A / Hong Kong / 8 / 68 (H3N2) and amantadine-resistant virus strain A / WS / 33 (H1N1). After amplification in chicken embryos, the median infectious dose (TCID) of these virus strains was determined using the Reed-Muench method. 50 Subsequently, the anti-influenza activity of the test compounds was verified by a CPE inhibition assay on infected MDCK cells. Amantadine (AMD) and oseltamivir phosphate (OSV-P) were dissolved in MEM, and the test drugs were dissolved in DMSO and stored at room temperature.

[0099] (1) Antiviral efficacy test

[0100] Centrifuge at 10,000 rpm for 1 minute to remove the drug to the bottom of the tube. Then add 100 μL DMSO and dissolve in MEM culture medium containing 1.5 μg / mL TPCK to achieve the desired concentration. The final DMSO concentration is 0.5%. Wash the 96-well plate monolayer once with PBS and add approximately 100 TCID50.50 100 μL of virus dilution was added to each well and incubated at 37°C in a 5% CO2 incubator for 2 hours. The virus solution was discarded, and serially diluted drugs (37.6–1.2 μM) were added at 2-fold serial concentrations, with four replicates per concentration. The cells were incubated at 37°C in a 5% CO2 incubator for 48 hours. Cytopathic effect (CPE) was observed under a microscope. If all cells in the control group had died, it indicated that the influenza virus had completely infected the cells, causing CPE. The presence of CPE was recorded according to a 6-level standard (as shown in Table 1). The cell culture plate was tapped, and the culture medium was carefully aspirated. 50 μL of 1:10 CCK8 assay reagent was added to each well. The plates were then incubated at 37°C for 2 hours, and the A450 absorbance was measured. The half-maximal effective concentration (EC50) of the drug was calculated using Prism non-regression analysis. 50 The results are shown in Table 1.

[0101] (2) Compound toxicity test (MTT method) experimental procedure

[0102] Take healthy MDCK cells at a ratio of 2 × 10⁶ cells per well. 4 MDCK cells were seeded in 96-well plates and incubated at 37°C with 5% CO2 for 24 hours until a monolayer formed. After 24 hours, the culture supernatant was aspirated, and the 96-well plates were washed twice with 50 μL / well sterile phosphate-buffered saline (PBS). The compound was then diluted 5-fold with serum-free MEM, and 50 μL / well of the compound was added to each well of the 96-well plate. Cells were cultured at 37°C with CO2. After 48 hours, 5 mg / mL freshly prepared MTT solution was added to each well, and the plates were incubated at 37°C for 4 hours. The dissolution medium was then removed. The absorbance of each well was measured at 490 nm using a CLARIOstar multifunction microplate reader (BMG Labtech, Germany). Formazan crystals were dissolved in DMSO (100 μL / well). Cell viability (%) = OD value of compound well / average OD value of control well. TC of each compound... 50 The values ​​were obtained by analyzing the data using a nonlinear regression model with the software Graph Prism 6, and the results are shown in Table 1.

[0103] Table 1. In vitro anti-influenza activity data

[0104]

[0105]

[0106] Data are presented as themean±SD of the results of two or three independent tests.a EC50represents halfmaximal effective concentration.b TC50represents 50% cytotoxic concentration,as determined by themTT cell viabilitytest.c SI is the drug selectivity index,the TC50 / EC50 ratio(H1N1).dN.A.,Noactivity

[0107] As shown in Table 1, the adamantyl alkyl α-hydroxycarboxylic acid derivatives provided by this invention exhibit varying degrees of inhibitory activity against both wild-type (H3N2) and variant (H1N1) influenza viruses, with their EC50... 50 The activity levels were relatively low. Among them, compound I-16, which exhibited excellent inhibitory activity, showed inhibitory activities of 0.92 μM and 0.55 μM against the two virus strains, respectively. Its activity was comparable to that of the first-line anti-influenza drug oseltamivir, and it also had the best selectivity index, indicating that the compound had low toxicity and showed potential for further development into a new anti-influenza drug.

[0108] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An α-hydroxycarboxylic acid derivative having an adamantyl group, characterized in that, Choose any one of the following structural formulas: 。 2. The method for preparing the α-hydroxycarboxylic acid derivative having an adamantyl group according to claim 1, characterized in that, Includes the following steps: Step 1: Using 2-adamantyl-α-keto acid 1 as a raw material, and cis- N - p-Toluenesulfonylaminoindanol 2, under the action of a condensing agent, generates ester intermediate 3: ； Step 2: The ester intermediate 3 obtained in Step 1 is subjected to a nucleophilic addition reaction with 2-methylthiophene lithium prepared in situ from compound 4 at low temperature to obtain compound 5: ； Step 3: Compound 5 obtained in Step 2 is subjected to hydrolysis under the conditions of LiOH·H2O, CH3OH, and THF to obtain carboxylic acid derivative 6. ； Step 4: Take the carboxylic acid derivative 6 obtained in Step 3 above and condense it with primary amines of different substitutions using a condensing agent to obtain target compounds I-1 to I-4, I-7 to I-17; or react the carboxylic acid derivative 6 with brominated products under NaHCO3 to generate ester compounds I-5 and I-6.

3. The method for preparing the α-hydroxycarboxylic acid derivative having an adamantyl group according to claim 2, characterized in that, In step one, the molar ratio of 2-adamantyl-α-keto acid 1 to the condensing agent is 1:05-1.

5. The selected condensing agent is EDCI▪HCl, DMAP or TBTU, and the solvent is dichloromethane or THF.

4. The method for preparing the α-hydroxycarboxylic acid derivative having an adamantyl group according to claim 2, characterized in that, In step two, the reaction temperature is -78 ℃ and the reaction time is 3-5 h.

5. The method for preparing the α-hydroxycarboxylic acid derivative having an adamantyl group according to claim 2, characterized in that, The solvent ratio selected in step three is tetrahydrofuran:methanol:water in a volume ratio of 2:3:1, and the temperature is 60-80 ℃.

6. The method for preparing the α-hydroxycarboxylic acid derivative having an adamantyl group according to claim 2, characterized in that, The condensing agent used in step four is CDI, EDCI-HCl, or HOBt, the solvent is dichloromethane, and the temperature is room temperature (25°C).

7. The use of the adamantyl alkyl α-hydroxycarboxylic acid derivative of claim 1, and its pharmaceutically acceptable salt, in the preparation of an antiviral drug.

8. The use of the adamantyl alkyl α-hydroxycarboxylic acid derivative according to claim 7, and its pharmaceutically acceptable salt, in the preparation of an antiviral drug, characterized in that, The influenza virus in question is either influenza A, H3N2 or H1N1.

Images