Phenol amide derivative and application thereof

Abstract

The invention provides a phenolic amide derivative and application thereof, relates to application of a compound and a composition thereof in preparation of cosmetics or medicines for preventing, treating and relieving acne, and provides a medicine or cosmetic composition which comprises a therapeutically effective amount of compound, or at least one of a racemate, a stereoisomer, a geometric isomer, a tautomer, an isotope label, a hydrate, a solvate, a polymorphic substance, a metabolite, a prodrug and pharmaceutically acceptable salt or ester. The present invention provides the prevention, treatment or alleviation of skin problems associated with Propionibacterium acnes, including comedo, acne, folliculitis; according to the phenolic amide derivative with a novel structure, the structural type of the phenolic amide compound is enriched, the activity of inhibiting propionibacterium acnes is increased on the basis of retaining the anti-inflammatory activity of the phenolic amide compound, and the aim of treating both symptoms and root causes of skin problems related to the propionibacterium acnes is achieved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and more specifically, to a phenolamide derivative and its applications. Background Technology

[0002] Acne is one of the most common chronic inflammatory diseases of the pilosebaceous unit worldwide, affecting over 640 million people. The proliferation of Propionibacterium acnes is closely related to the development of acne. Propionibacterium acnes breaks down triglycerides in sebum into free fatty acids, stimulating the proliferation and hyperkeratosis of keratinocytes at the hair follicle duct, further narrowing and blocking the hair follicle opening. Simultaneously, free fatty acids also have a chemotactic effect on inflammatory cells, triggering an inflammatory response.

[0003] Phenolic amides are naturally occurring bioactive compounds found in many plants, known for their antioxidant, anti-inflammatory, and anticancer activities. Literature reports that phenolic amides exert their anti-inflammatory effects through a triple mechanism: inhibiting pro-inflammatory factors (TNF-α / NF-κB / NO), blocking immune cell activation (neutrophils / mast cells), and activating antioxidant defenses (Nrf2 / HO-1). (RSCadvances, 2015, 5(104): 85806-85815.; Bioengineered, 2024, 15(1): 2305029.) For example, the phenolic amide compound Melodamide A exerts its anti-inflammatory effect by selectively inhibiting p38 MAPK phosphorylation and blocking the production of superoxide anions by neutrophils; Avenanthramide C effectively blocks TNF-α-induced inflammatory responses by inhibiting the MAPK / NF-κB signaling axis, downregulating MMP-9 expression and IL-6 secretion. (Planta medica,2013,79(03 / 04):288-294; Frontiers in pharmacology,2021,12:621854.)

[0004] Existing phenolamide compounds can improve acne symptoms through anti-inflammatory effects, but they cannot fundamentally solve the skin problems caused by the proliferation of Propionibacterium acnes. Therefore, when applying phenolamide compounds to cosmetics or drugs for the prevention, treatment, and relief of acne, it is necessary to endow the compounds with antibacterial activity. Thus, a phenolamide derivative and its application are proposed. Summary of the Invention

[0005] The purpose of this invention is to address the problems raised in the existing background technology. To achieve the above-mentioned objective, this invention provides the following technical solution: a phenolamide derivative, comprising a compound having the structure shown in formula (I) or formula (II) and its racemic, stereoisomer, geometric isomer, tautomer, isotope label, hydrate, solvate, polymorph, metabolite, prodrug, pharmaceutically acceptable salt or ester;

[0006] Among them, R 1 R 2 Each group is independently selected from those substituted with one, two, or more hydrogens, hydroxyl groups, halogens, cyano groups, carboxyl groups, amino groups, alkyl groups, alkenyl groups, alkoxy groups, alkenyloxy groups, alkynyloxy groups, aminoalkyloxy groups, alkylcarbonyloxy groups, acyl groups, or amide groups; R3 is selected from allyl, isopentenyl, geranyl, or farnesyl; n is selected from C 0-10 Alkyl, C 2-10 Alkenyl group.

[0007] As a preferred technical solution of the present invention, R 1 R 2 Each is independently selected from one, two, or more hydrogen, hydroxyl, alkyl, or alkoxy groups; R3 is selected from isopentenyl or geranyyl; n is selected from C 0-3 Alkyl, C 2-3 Alkenyl group.

[0008] As a preferred embodiment of the present invention, the structure of formula (I) or formula (II) is selected from the following compounds: .

[0009] A phenolamide derivative pharmaceutical composition comprising a therapeutically effective amount of the compound and at least one of its racemic, stereoisomer, geometric isomer, tautomer, isotope label, hydrate, solvate, polymorph, metabolite, prodrug, pharmaceutically acceptable salt or ester.

[0010] As a preferred embodiment of the present invention, it further includes one or more pharmaceutically acceptable excipients.

[0011] As a preferred embodiment of the present invention, one or more therapeutic agents are also included.

[0012] A cosmetic composition of phenolamide derivatives includes at least one of the following: a compound and its racemic, stereoisomer, geometric isomer, tautomer, isotope label, hydrate, solvate, polymorph, metabolite, prodrug, pharmaceutically acceptable salt or ester.

[0013] As a preferred embodiment of the present invention, it also includes one or more excipients accepted in cosmetics.

[0014] The use of a phenolamide derivative in the preparation of medicaments for the prevention, treatment or relief of skin problems associated with Propionibacterium acnes.

[0015] A phenolamide derivative is used for skin problems related to Propionibacterium acnes, including pimples, acne, and folliculitis.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention provides a class of phenolamide derivatives with novel structures, which enriches the structural types of phenolamide compounds. While retaining the anti-inflammatory activity of phenolamide compounds, it increases the activity of inhibiting Propionibacterium acnes, and can achieve both symptomatic and radical treatment of skin problems related to Propionibacterium acnes. Attached Figure Description Figure 1 The representative compound of this invention exhibits inhibitory activity against Propionibacterium acnes biofilm; Figure 2 This invention represents the inhibitory activity of the compound on NO levels in cells; Figure 3 The representative compound of this invention exhibits inhibitory activity against IL-6 levels in cells; Figure 4 This invention represents the inhibitory activity of the compound on TNF-α levels in cells. Detailed Implementation

[0017] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are specific implementations of the present invention and are not limited to all embodiments.

[0018] Therefore, the following detailed description of embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely illustrates some embodiments of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0019] It should be noted that, in the absence of conflict, the embodiments and features and technical solutions in the embodiments of the present invention can be combined with each other. It should be noted that similar reference numerals and letters in the following figures indicate similar items. Therefore, once an item is defined in one figure, it does not need to be further defined and explained in subsequent figures.

[0020] Example 1: 2-(3,4-dimethoxybenzamido)-4,5-dimethoxy-3-(3-methyl-2-buten-1-yl)benzoic acid (compound 1)

[0021] Step a: Methyl 5-methoxy-4-[(2-methylbut-3-yn-2-yl)oxy]-2-nitrobenzoate (intermediate 1-2) Add the intermediate methyl 4-hydroxy-5-methoxy-2-nitrobenzoate (5.4 g, 17.1 mmol), 3-chloro-3-methyl-1-butyne (6.2 g, 59.9 mmol), and cesium carbonate (11.2 g, 34.3 mmol) to a 300 mL dry round-bottom flask. N, N - Dimethylformamide (50 mL). The mixture was reacted at room temperature for 48 h under argon protection. After the reaction was complete, the mixture was extracted with ethyl acetate (1000 mL), the organic layer was washed with saturated sodium bicarbonate aqueous solution (3000 mL) and saturated sodium chloride aqueous solution (3000 mL), dried over anhydrous sodium sulfate, and the impurities were removed with activated carbon (5.0 g). The solids were removed by filtration, and the filtrate was evaporated under reduced pressure to obtain 4.6 g of brown oil, with a yield of 91.7%. 1 H NMR (400 MHz, Chloroform- d )

[0022]

[0023] HRMS(ESI): m / z[M+Na] + calcd for[C 14 H 16 NO6Na] + :316.0797,found:316.0793.

[0024] Step b: Methyl 5-methoxy-4-[(2-methylbut-3-en-2-yl)oxy]-2-nitrobenzoate (intermediate 1-3) Intermediate 1-2 (4.0 g, 13.7 mmol) was placed in a dry round-bottom flask, and pyridine (5 mL), Lindlar catalyst (2.0 g), and dichloromethane (50 mL) were added. The mixture was stirred overnight at room temperature under hydrogen atmosphere. After the reaction was complete, the catalyst was removed by filtration, and the mixture was washed with dichloromethane. The filtrate was washed successively with 1N hydrochloric acid (100 mL), saturated sodium bicarbonate aqueous solution (80 mL × 3), and saturated sodium chloride aqueous solution (80 mL × 3). The mixture was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 3.8 g of a yellow oily substance, with a yield of 94.0%.

[0025] 1 H NMR (400 MHz, Chloroform- d δ7.55(s, 1H), 7.11(s, 1H), 6.20(m, J =5.9, 1.0 Hz, 1H), 4.97(dd, J =9.4,5.9 Hz,1H),3.98(s,3H),3.91(s,3H),1.04(s,3H),1.02(s,3H). 13 C NMR (101 MHz, Chloroform- d ) δ166.2,152.8,148.1,140.9,136.8,125.0,123.1,111.6,110.8,56.7,53.3,24.1,22.8(2C) HRMS (ESI): m / z[M+Na] + calcd for[C 14 H 18 NO6Na] + :318.0954,found:318.0941.

[0026] Step c: Methyl 4-hydroxy-5-methoxy-3-(3-methylbut-2-en-1-yl)-2-nitrobenzene (intermediate 1-4) Intermediate 1-3 (420.0 mg, 1.4 mmol) was placed in a dry round-bottom flask, and toluene (10 mL) was added. The mixture was stirred at 140 °C under argon atmosphere. After the reaction was complete, the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated sodium bicarbonate aqueous solution (50 mL × 3) and saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain 410.0 mg of a brown oily substance, with a yield of 99.3%.

[0027] 1 H NMR (400 MHz, DMSO- d 6) δ 10.46 (s, 1H), 7.36(s,1H),5.02–4.97(m,1H),3.92(s,3H),3.78(s,3H), 3.19(d, J =6.9 Hz, 2H), 1.63(s, 3H), 1.60(s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ163.8,149.4,148.1,145.6,133.0,121.2,120.7,112.8,110.9,56.8,53.0,25.8,24.6,18.1. HRMS (ESI): m / z[M+Na] + calcd for[C 14 H 18 NO6Na] + :318.0954,found:318.0941.

[0028] Step d: Methyl 4,5-dimethoxy-3-(3-methylbut-2-en-1-yl)-2-nitrobenzoate (intermediate 1-5) Intermediate 1-4 (260.0 mg, 0.9 mmol) was placed in a dry round-bottom flask, and 10 mL of acetonitrile, potassium carbonate (260.0 mg, 1.8 mmol), and methyl iodoform (497.0 mg, 3.5 mmol) were added. The mixture was stirred at room temperature under argon atmosphere. After the reaction was complete, the mixture was extracted with ethyl acetate (20 mL), concentrated, and purified by silica gel column chromatography to give 248.2 mg of a yellow oil, with a yield of 91.2%.

[0029] 1 H NMR (400 MHz, Chloroform- d ) δ7.37(s, 1H), 5.04(t, J =7.0 Hz,1H),3.93(s,3H),3.89(s,3H),3.86(s,3H),3.30(d, J =7.0 Hz, 2H), 1.71 (d, J =1.4 Hz, 3H), 1.66(d, J =1.4 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ163.9,153.1,150.8,145.0,133.6,129.0,120.5,118.5,111.8,60.9,56.2,52.9,25.6,25.2,17.8. HRMS (ESI): m / z[M+H] + calcd for[C 15 H 20 NO6] + :310.1291,found:310.1301.

[0030] Step e: Methyl 2-amino-4,5-dimethoxy-3-(3-methylbut-2-en-1-yl)benzoate (intermediates 1-6) Intermediate 1-5 (248.0 mg, 0.8 mmol) was placed in a dry round-bottom flask, and anhydrous ethanol (6 mL), tetrahydrofuran (3 mL), saturated ammonium chloride solution (1 mL), and reduced iron powder (248.0 mg) were added. The mixture was stirred at 80 °C under argon atmosphere. After the reaction was complete, the mixture was extracted with ethyl acetate (20 mL), concentrated, and purified by silica gel column chromatography to give 209.4 mg of a yellow oil, with a yield of 93.6%.

[0031] 1 H NMR (400 MHz, DMSO- d 6) δ7.22(s, 1H), 6.15(s, 2H), 5.04(t, J =6.6 Hz, 1H), 3.78(s,3H),3.72(s,3H),3.71(s,3H), 3.25(d, J =6.8 Hz, 2H), 1.74(s, 3H), 1.64(s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ168.2,152.7,145.8,143.3,132.1,121.9,120.9,111.9,104.4,60.6,56.3,51.8,25.9,23.4,18.2. HRMS (ESI): m / z[M+H] + calcd for[C 15 H 22 NO4] + :280.1549,found:280.1556.

[0032] Step f: 2-(3,4-dimethoxybenzamido)-4,5-dimethoxy-3-(3-methyl-2-buten-1-yl)benzoic acid (compound 1) Take intermediates 1-6 (150.0 mg, 0.7 mmol), 3,4-dimethoxybenzoic acid (195.0 mg, 1.1 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (322.0 mg, 0.9 mmol), and diisopropylethylamine (110.0 mg, 0.9 mmol). N,N Dimethylformamide (5 mL) was placed in a dry 25 mL round-bottom flask and stirred overnight at 70 °C. After the reaction was complete, the mixture was concentrated under reduced pressure, and 10 mL of methanol and 2 M NaOH (2 mL) were added. The mixture was stirred at room temperature under argon atmosphere. After the reaction was complete, the solvent was removed under reduced pressure, diluted with water (30 mL), acidified with 1 N hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 82.4 mg of a yellow oil, with a yield of 27%.

[0033] 1 H NMR (400 MHz, Chloroform- d ) δ12.25(s,1H),8.98(s,1H),7.63–7.31(m,3H), 6.90(d, J =8.3 Hz,1H),5.10(t,1H),3.94(s,3H),3.92(s,3H), 3.89(s, 3H), 3.88(s, 3H), 3.44(d, J =6.8 Hz,2H),1.65(s,3H),1.57(s,3H). 13 C NMR (151 MHz, Chloroform- d )

[0034] HRMS (ESI): m / z[MH] - calcd for[C 23 H 26 NO7] - :428.1709,found:428.171.

[0035] Example 2: 2-[(2,4-dimethoxybenzamido)]-4,5-dimethoxy-3-(3-methyl-2-buten-1-yl)benzoic acid (compound 2)

[0036] The preparation was carried out according to the method of Example 1, except that 3,4-dimethoxybenzoic acid in step f was replaced with 2,4-dimethoxybenzoic acid. 162.3 mg of a pale yellow solid was obtained, with a yield of 54%.

[0037] 1 H NMR (600 MHz, Chloroform- d ) δ 9.77 (s, 1H), 8.21 (d, J =8.8 Hz,1H),7.36(s,1H),6.60(dd, J =8.8, 2.2 Hz, 1H), 6.49(d, J =2.3 Hz, 1H), 5.18–4.93(m,1H),3.89(s,3H),3.88(s,3H),3.87(s,3H),3.85(s,3H), 3.38(d, J =6.7 Hz, 2H), 1.60 (s, 3H), 1.58 (s, 3H). 3 C NMR (151 MHz, Chloroform- d )

[0038] HRMS (ESI): m / z[MH] - calcd for[C 23 H 26 NO7] -:428.1709,found:428.1719.

[0039] Example 3: 2-[(2-3,4-dimethoxyphenyl)acetamido)]-4,5-dimethoxy-3-(3-methyl-2-buten-1-yl)benzoic acid (compound 3)

[0040] The preparation was carried out according to the method of Example 1, except that 3,4-dimethoxybenzoic acid in step f was replaced with 3,4-dimethoxyphenylacetic acid. 96.2 mg of a pale yellow solid was obtained, with a yield of 31%.

[0041] 1 H NMR (400 MHz, DMSO- d 6) δ9.49(s,1H),8.72(s,1H),7.28(s,1H),6.95(s,1H),6.83(m, J =8.3 Hz, 2H), 4.92(t, J =7.1 Hz,1H),3.82(s,3H),3.72(s, J =6.6 Hz, 9H), 3.51 (s, 2H), 3.18 (d, J =6.5 Hz,2H),1.62(s,3H),1.54(s,3H). 13 C NMR (101 MHz, DMSO- d 6)

[0042] HRMS (ESI): m / z[MH] - calcd for[C 24 H 28 NO7] - :444.2022,found:444.2029.

[0043] Example 4: 2-[(3-3,4-dimethoxyphenyl)propamido)]-4,5-dimethoxy-3-(3-methyl-2-buten-1-yl)benzoic acid (compound 4)

[0044] The preparation was carried out according to the method of Example 1, except that 3,4-dimethoxybenzoic acid in step f was replaced with 3,4-dimethoxyphenylpropionic acid. 54.4 mg of a pale yellow solid was obtained, with a yield of 17%.

[0045] 1 H NMR (400 MHz, Chloroform- d ) δ8.52(s,1H),8.03(s,1H),7.40(s,1H),6.75(s,3H), 5.02(t, J =6.8 Hz,1H),3.85(s,6H),3.83(s,6H),3.29(d, J =6.8 Hz, 2H), 2.97(t, J =7.8 Hz,2H),2.71–2.62(t,2H),1.66(s,3H),1.65(s,3H). 13 C NMR (101 MHz, Chloroform- d )

[0046] HRMS (ESI): m / z[MH] - calcd for[C 25 H 30 NO7] - :456.2022,found:456.2043.

[0047] Example 5: 2-Cinnamamido-4,5-dimethoxy-3-(3-methyl-2-buten-1-yl)benzoic acid (Compound 5)

[0048] The preparation was carried out according to the method of Example 1, except that 3,4-dimethoxybenzoic acid in step f was replaced with cinnamic acid. 146.7 mg of a pale yellow solid was obtained, with a yield of 53%.

[0049] 1 H NMR (400 MHz, Chloroform- d )δ8.54(s,1H),7.80–7.31(m,7H),6.62(d, J =15.7Hz, 1H), 5.22–4.93(m,1H),3.87(s,3H),3.85(s,3H),3.43(d,J =6.9 Hz,2H),1.71(s,3H),1.67(s,3H). 13 C NMR (151 MHz, Chloroform- d )

[0050] HRMS (ESI): m / z[MH] - calcd for[C 23 H 24 NO5] - :394.165,found:394.166.

[0051] Example 6: (E)-2-[(3-4-hydroxyphenyl)acrylamido)]-4,5-dimethoxy-3-(3-methyl-2-buten-1-yl)benzoic acid (compound 6)

[0052] The preparation was carried out according to the method of Example 1, except that 3,4-dimethoxybenzoic acid in step f was replaced with trans-4-hydroxycinnamic acid. 57.6 mg of a pale yellow solid was obtained, with a yield of 20%.

[0053] 1 H NMR (400 MHz, DMSO- d 6) δ9.52(s,1H),8.05(s,1H),7.56–7.23(m,4H), 6.81(d, J =8.5 Hz, 2H), 6.63(d, J =15.7 Hz,1H),5.17–4.94(m,1H),3.87(s,3H),3.80(s,3H), 3.31(d, J =6.9 Hz, 2H), 1.68(s, 3H), 1.61(s, 3H). 13 C NMR (101 MHz, DMSO- d 6)

[0054] HRMS (ESI): m / z[MH] - calcd for[C23 H 24 NO6] - :410.1604,found:410.1610.

[0055] Example 7: (E)-2-[(3-3-hydroxyphenyl)acrylamido)]-4,5-dimethoxy-3-(3-methyl-2-buten-1-yl)benzoic acid (compound 7)

[0056] The preparation was carried out according to the method of Example 1, except that 3,4-dimethoxybenzoic acid in step f was replaced with m-hydroxycinnamic acid. 144 mg of a pale yellow solid was obtained, with a yield of 50%.

[0057] 1 H NMR (400 MHz, DMSO- d 6)δ11.65(s,1H),8.60(s,1H),8.54(s,1H), 6.38(d, J =15.8 Hz, 1H), 6.29(s, 1H), 6.23(t, J =7.8 Hz, 1H), 6.02(d, J =7.7 Hz,1H),5.98(s,1H),5.87–5.47(m,2H), 4.14–3.86(m,1H),2.85(s,3H),2.76(s,3H), 2.17(d, J =4.3 Hz,2H),0.65(s,3H),0.58(s,3H). 13 C NMR (101 MHz, DMSO- d 6)

[0058] HRMS (ESI): m / z[MH] - calcd for[C 23 H 24 NO6] - :410.1604,found:410.1598.

[0059] Example 8: (E)-2-[(3-3,4-dimethoxyphenyl)acrylamido)]-4,5-dimethoxy-3-(3-methyl-2-buten-1-yl)benzoic acid (compound 8)

[0060] The preparation was carried out according to the method of Example 1, except that 3,4-dimethoxybenzoic acid in step f was replaced with 3,4-dimethoxycinnamic acid. 95.7 mg of a pale yellow solid was obtained, with a yield of 30%.

[0061] 1 H NMR (400 MHz, Chloroform- d ) δ8.52(s,1H),8.03(s,1H),7.40(s,1H),6.75(s,3H),5.02(t, J =6.8 Hz,1H),3.85(s,6H),3.83(s,6H), 3.29(d, J =6.8 Hz, 2H), 2.97(t, J =7.8 Hz,2H),2.71–2.62(t,2H),1.66(s,3H),1.65(s,3H). 13 C NMR (101 MHz, Chloroform- d )

[0062] HRMS (ESI): m / z[MH] - calcd for[C 25 H 28 NO7] - :454.1866,found:454.1874.

[0063] Example 9: 6-Benzamido-2-hydroxy-4-methoxy-3-(3-methyl-but-2-en-1-yl)benzoic acid (compound 9)

[0064] Step a: Methyl 6-bromo-2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)benzoate (intermediate 2-2) 261 mg (1 mmol) of methyl 2-bromo-6-hydroxy-4-methoxybenzoate and 5 mL of dry toluene were added to a dry 25 mL round-bottom flask. The mixture was stirred at 0 °C for 15 min under argon protection. Sodium hydride (31 mg, 1.3 mmol) was added, and the mixture was stirred at 0 °C for 30 min. Then, the mixture was transferred to 120 °C and stirred for another 30 min. 1-Bromo-3-methyl-2-butene (194 mg, 1.3 mmol) was added dropwise to the mixture, and the reaction was continued with stirring for 5 h. The reaction was quenched with 20 mL of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (30 mL × 3), the organic layer was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The solid was purified by silica gel column chromatography to obtain a white solid. Yield: 87.8%.

[0065] 1 H NMR (400 MHz, Chloroform- d )δ11.43(s,1H),6.70(s,1H), 5.08(t, J =7.1 Hz,1H),3.87(s,3H),3.78(s,3H), 3.23(d, J =7.1 Hz,3H),1.69(s,4H),1.59(s,4H). 13 C NMR (101 MHz, Chloroform- d ) δ170.2,161.7,161.0,132.1,121.5,120.9,116.8,110.1,107.1,55.8,52.0,25.7,22.1,17.7. HRMS (ESI): m / z[M+Na] + calcd for[C 14 H 18 BrO4Na] + :351.0208,found:351.0208.

[0066] Step b: Methyl 2-acetoxy-6-bromo-4-methoxy-3-(3-methylbut-2-en-1-yl)benzoate (intermediate 2-3) In a dry 25 mL round-bottom flask, intermediate 2-2 (352 mg, 1 mmol), DAMP (24.4 mg, 0.2 mmol), triethylamine (202 mg, 2 mmol), acetic anhydride (204 mg, 2 mmol), and tetrahydrofuran (5 mL) were added. The mixture was stirred at room temperature for 2 h under argon protection. After the reaction was complete as monitored by TLC, the solvent was removed under reduced pressure, and the mixture was extracted with dichloromethane (30 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a yellow oily substance in 82.5% yield.

[0067] 1 H NMR (400 MHz, Chloroform- d )δ6.97(s,1H), 5.04(t, J =7.0 Hz, 1H), 3.88(s, 3H), 3.85(s, 3H) 3.17(d, J =7.0 Hz, 2H), 2.26(s, 3H), 1.70 (s, 3H), 1.65 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ170.2,169.0,161.7,161.0,132.1,121.5,120.9,116.8,110.1,107.1,55.8,52.0,25.7,22.1,20.3,17.7. HRMS(ESI): m / z[M+Na] + calcd for[C 16 H 20 BrO5Na] + :393.0314,found:393.0312.

[0068] Step c: 6-Benzamido-2-hydroxy-4-methoxy-3-(3-methyl-but-2-en-1-yl)benzoic acid (compound 9) Intermediate 2-3 (445 mg, 1.2 mmol), benzamide (121 mg, 1 mmol), xantphos (34 mg), Pd2(dba)3 (18 mg), and cesium carbonate (413 mg, 1.27 mmol) were added to a dry 10 mL pressure-resistant flask. The mixture was stirred overnight at 120 °C under argon protection. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Methanol (10 mL) and 8% NaOH (2 mL) were added, and the mixture was stirred at room temperature under argon for 12 h. After the reaction was complete, the solvent was removed under reduced pressure, and the mixture was dissolved in water (30 mL). The aqueous layer was acidified with 1 N HCl, filtered, and the filter cartridge was collected to obtain 115.1 mg of a pale yellow solid, with a yield of 27%.

[0069] 1 H NMR (400 MHz, DMSO- d 6) δ 11.72 (s, 1H), 10.05(s,1H),8.06–7.86(m,3H),7.73–7.50(m,3H),5.97(s,1H), 5.14(t, J =7.1 Hz,1H),3.86(s,3H),3.23(d, J =7.2 Hz,2H),1.72(s,3H),1.63(s,3H). 13 C NMR (101 MHz, DMSO- d 6)

[0070] HRMS (ESI): m / z[MH] - calcd for[C 20 H 20 NO5] - :354.1341,found:354.1355.

[0071] Example 10: 2-Hydroxy-4-methoxy-3-(3-methyl-but-2-en-1-yl)-6-(2-phenylacetamido)benzoic acid (Compound 10)

[0072] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 2-phenylacetamide. 79.8 mg of a pale yellow solid was obtained, with a yield of 18%.

[0073] 1H NMR (400 MHz, Chloroform- d ) δ11.30(s,1H),9.79(s,1H),8.96(s,1H),8.10(s,1H),7.38(td, J =5.8, 2.8 Hz, 3H), 7.31(dd, J =7.4, 2.1 Hz, 2H), 5.18(t, J =7.2 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 2H), 3.34 (d, J =7.2 Hz, 2H), 1.80 (s, 3H), 1.69 (s, 3H). 13 C NMR (101 MHz, Chloroform- d )

[0074] HRMS(ESI):m / z[MH] - calcd for[C 21 H 22 NO5] - :368.1498,found:368.1512.

[0075] Example 11: 2-Hydroxy-4-methoxy-3-(3-methyl-but-2-en-1-yl)-6-(3-phenylpropionamido)benzoic acid (Compound 11)

[0076] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 3-phenylpropionamide. 87.4 mg of a pale yellow solid was obtained, with a yield of 19%.

[0077] 1 H NMR (400 MHz, DMSO- d 6) δ 10.66 (s, 1H), 9.72(s,1H),7.68(s,1H),7.43–7.04(m,5H),5.30–5.02(m,2H), 3.79 (s, 3H), 3.18 (d, J =7.1 Hz, 2H), 2.92(t, J=7.7 Hz,2H),1.70(s,3H),1.60(s,3H). 13 C NMR (101 MHz, DMSO- d 6)

[0078] HRMS (ESI): m / z[MH] - calcd for[C 22 H 24 NO5] - :382.1654,found:382.1664.

[0079] Example 12: 6-Cinnamamido-2-hydroxy-4-methoxy-3-(3-methyl-but-2-en-1-yl)benzoic acid (Compound 12)

[0080] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with cinnamamide. 54.9 mg of a pale yellow solid was obtained, with a yield of 12%.

[0081] 1 H NMR (600 MHz, DMSO-) d 6) δ 14.36 (s, 1H), 7.87 (s, 1H) 7.67(d, J =7.2 Hz, 2H), 7.53 (d, J =15.6 Hz, 1H), 7.42(dt, J =14.0, 6.7 Hz, 3H), 6.63(d, J =15.7 Hz,1H),5.15–5.10(m,1H),3.74(s,3H), 3.18–3.12(m,2H),1.70(s,3H),1.60(s,3H),1.55(s,1H). 13 C NMR (101 MHz, DMSO- d 6)

[0082] HRMS(ESI):m / z[MH] - calcd for[C 22 H22 NO5] - :380.1498,found:380.1509.

[0083] Example 13: (E)-6-[3-(3,4-dimethoxyphenyl)acrylamido]-2-hydroxy-4-methoxy-3-(3-methyl-but-2-en-1-yl)benzoic acid (compound 13)

[0084] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 3,4-dimethoxycinnaminamide. 74.2 mg of a pale yellow solid was obtained, with a yield of 14%.

[0085] 1 H NMR (600 MHz, DMSO-) d 6) δ10.87(s,1H),9.93(s,1H),8.32(s,1H),7.86(s,1H), 7.54(d, J =15.5 Hz, 1H), 7.32(s, 1H), 7.21(d, J =8.5 Hz, 1H), 7.00(d, J =8.3 Hz, 1H), 6.74(d, J =15.6 Hz, 1H), 5.12(td, J =7.1, 3.5 Hz, 1H), 3.83 (d, J =2.6 Hz, 6H), 3.80 (s, 3H), 3.21 (d, J =7.2 Hz,2H),1.71(s,3H),1.62(s,3H). 13 C NMR (151 MHz, DMSO- d 6)

[0086] HRMS (ESI): m / z[MH] - calcd for[C 24 H 26 NO7] - :440.1709,found:440.1720.

[0087] Example 14: 2-Hydroxy-4-methoxy-6-(3-methoxybenzamido)-3-(3-methyl-but-2-en-1-yl)benzoic acid (Compound 14)

[0088] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 3-methoxybenzamide. 74.0 mg of a pale yellow solid was obtained, with a yield of 16%.

[0089] 1 H NMR (600 MHz, DMSO-) d 6) δ15.07(s,1H),13.86(s,1H),7.94(s,1H), 7.59(d, J =7.6 Hz,1H),7.55(s,1H),7.45(t, J =7.9 Hz, 1H), 7.14(dd, J =8.2, 2.6 Hz, 1H), 5.13(t, J =7.0 Hz,1H),3.83(s,3H),3.76(s,3H), 3.16(d, J =7.2 Hz,2H),1.70(s,3H),1.60(s,3H). 13 C NMR (151 MHz, DMSO- d 6)

[0090] HRMS (ESI): m / z[MH] - calcd for[C 21 H 22 NO6] - :384.1447,found:384.1451.

[0091] Example 15: 2-Hydroxy-4-methoxy-6-(3-methylbenzamido)-3-(3-methyl-but-2-en-1-yl)benzoic acid (Compound 15)

[0092] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 3-methylbenzamide. 102.0 mg of a pale yellow solid was obtained, with a yield of 23%.

[0093] 1 H NMR (400 MHz, DMSO- d 6) δ11.70(s,1H),10.45(s,1H),9.97(s,1H),7.96(s,1H),7.80–7.65(m,2H),7.42(dd, J =4.7, 1.9 Hz, 2H), 5.11(t, J =7.1 Hz, 1H), 3.83 (s, 3H), 3.21(d, J =7.2 Hz,2H),2.38(s,3H),1.70(s,2H),1.61(s,3H). 13 C NMR (101 MHz, DMSO- d 6)

[0094] HRMS(ESI):m / z[MH] - calcd for[C 21 H 22 NO5] - :368.1498,found:368.1501.

[0095] Example 16: 6-(2,4-dimethoxybenzamido)-2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (compound 16)

[0096] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 2,4-dimethoxybenzamide. 94.7 mg of a pale yellow solid was obtained, with a yield of 19%.

[0097] 1 H NMR (600 MHz, Chloroform- d and DMSO- d 6) δ12.84(s,1H),11.66(s,1H),9.72(s,1H),8.15(s,1H), 7.96(d, J =8.6 Hz,1H),6.76–6.62(m,2H),5.12(t,1H),3.94(s,3H), 3.86(s, 3H), 3.83(s, 3H), 3.21(d, J =7.2 Hz, 2H), 1.71(s, 3H), 1.62(s, 3H). 13 C NMR (151 MHz, DMSO- d 6)

[0098] HRMS(ESI):m / z[MH] - calcd for[C 22 H 24 NO7] - :414.1553,found:414.1552.

[0099] Example 17: 6-(3,4-dimethoxybenzamido)-2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (compound 17)

[0100] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 3,4-dimethoxybenzamide. 84.7 mg of a pale yellow solid was obtained, with a yield of 17%.

[0101] 1 H NMR (400 MHz, Chloroform- d and DMSO- d 6) δ11.43(s,1H),9.61(s,1H),9.57(s,1H), 8.10(d, J =3.0 Hz, 1H), 7.81(d, J =27.6 Hz,1H),7.59–7.33(m,2H),7.10–6.78(m,1H),5.34–4.89(m,1H), 4.07–3.56 (m, 9H), 3.19 (d, J =7.6 Hz, 2H), 1.68 (s, 3H), 1.58 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6)

[0102] HRMS(ESI):m / z[MH] - calcd for[C 22 H 24 NO7] - :414.1553,found:414.1557.

[0103] Example 18: 6-[2-(3,4-dimethoxyphenyl)acetamido]-2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (compound 18)

[0104] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 3,4-dimethoxyphenylacetamide. 128.8 mg of a pale yellow solid was obtained, with a yield of 25%.

[0105] 1 H NMR (400 MHz, Chloroform- d ) δ11.29(s,1H),10.00(s,1H),8.60–8.10(m,1H),8.04(s,1H),7.04–6.69(m,3H),

[0106] 13 C NMR (101 MHz, DMSO- d 6)

[0107] HRMS(ESI):m / z[MH] - calcd for[C 23 H 26 NO7] - :428.1709,found:428.1715.

[0108] Example 19: 6-[3-(3,4-dimethoxyphenyl)propamido]-2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (compound 19)

[0109] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 3,4-dimethoxyphenylpropionamide. 53.2 mg of a pale yellow solid was obtained, with a yield of 10%.

[0110] 1H NMR (400 MHz, Chloroform- d )

[0111] 3.30(d, J =7.1 Hz, 2H), 2.98(d, J =7.7 Hz, 2H), 2.71(d, J =7.7 Hz, 2H), 1.76 (s, 3H), 1.67 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6)

[0112] HRMS(ESI):m / z[MH] - calcd for[C 24 H 28 NO7] - :442.1866,found:442.1878.

[0113] Example 20: 6-(3-hydroxybenzamido)-2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (compound 20)

[0114] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 3-hydroxybenzamide. 66.9 mg of a pale yellow solid was obtained, with a yield of 15%.

[0115] 1 H NMR (600 MHz, DMSO-) d 6) δ13.81(s,1H),9.99(s,1H),9.96(s,1H),9.82(s,1H),7.96(s,1H),7.52–7.23(m,3H),6.97(d, J =8.1 Hz, 1H), 5.13(t, J =6.6 Hz,1H),3.80(s,3H),3.18(d, J =7.4 Hz,2H),1.71(s,3H),1.61(s,3H). 13 C NMR (101 MHz, DMSO-d 6)

[0116] HRMS(ESI):m / z[MH] - calcd for[C 20 H 20 NO6] - :370.1291,found:370.1299.

[0117] Example 21: 6-(4-hydroxybenzamido)-2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (compound 21)

[0118] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 4-hydroxybenzamide. 80.2 mg of a pale yellow solid was obtained, with a yield of 18%.

[0119] 1 H NMR (400 MHz, DMSO- d 6) δ14.75(s,1H),10.15(s,1H),7.95(s,1H), 7.87(d, J =8.7 Hz, 2H), 6.88 (d, J =8.7 Hz,2H),5.18–5.10(m,1H), 3.76 (s, 3H), 3.16 (d, J =7.2 Hz,2H),1.71(s,3H),1.60(s,3H). 13 C NMR (101 MHz, DMSO- d 6)

[0120] HRMS(ESI):m / z[MH] - calcd for[C 20 H 20 NO6] - :370.1291,found:370.1301.

[0121] Example 22: (E)-6-[3-(3-hydroxyphenyl)acrylamido]-2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (compound 22)

[0122] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 3-hydroxycinnaminamide. 42.5 mg of a pale yellow solid was obtained, with a yield of 9%.

[0123] 1 H NMR (400 MHz, DMSO- d 6) δ14.14(s,1H),9.64(s,1H),9.07(s,1H),7.94(s,1H), 7.88 (s, 1H), 7.43 (d, J =15.7 Hz, 1H), 7.22(t, J =7.8 Hz, 1H), 7.07 (d, J =7.6 Hz, 1H), 7.01(s, 1H), 6.80(dd, J =8.1, 2.4 Hz, 1H), 6.53(d, J =15.7 Hz, 1H), 5.12(t, J =7.2 Hz,1H),3.74(s,3H),3.14(d, J =7.1 Hz,2H),1.69(s,3H),1.59(s,3H). 13 C NMR (101 MHz, DMSO- d 6)

[0124] HRMS(ESI):m / z[MH] - calcd for[C 22 H 22 NO6] - :396.1447,found:396.1449.

[0125] Example 23: (E)-6-[3-(4-hydroxyphenyl)acrylamido]-2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (compound 23)

[0126] The preparation was carried out according to the method of Example 9, except that benzamide in step c was replaced with 4-hydroxycinnaminamide. 56.7 mg of a pale yellow solid was obtained, with a yield of 12%.

[0127] 1 H NMR (600 MHz, DMSO-) d 6) δ11.65(s,1H),10.10(s,1H),9.68(s,1H),9.37(s,1H),7.79(s,1H),7.48(d, J =15.6 Hz, 1H), 7.23(t, J =7.8 Hz, 1H), 7.09(d, J =7.5 Hz, 1H), 7.04 (s, 1H), 6.83 (d, J =7.6 Hz, 1H), 6.68 (d, J =15.6 Hz, 1H), 5.12(t, J =7.3 Hz, 1H), 3.81 (s, 3H), 3.20 (d, J =7.2 Hz,2H),1.71(s,3H),1.61(s,3H). 13 C NMR (101 MHz, DMSO- d 6)

[0128] HRMS(ESI):m / z[MH] - calcd for[C 22 H 22 NO6] - :396.1447,found:396.1447.

[0129] Example 24: (E)-3-[(E)-3,7-dimethyloct-2,6-dien-1-yl]-2-hydroxy-6-[(E)3-(4-hydroxyphenyl)acrylamido]-4-methoxybenzoic acid (Compound 24)

[0130] Step a: Methyl 6-bromo-2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)benzoate (intermediate 3-1) Methyl 2-bromo-6-hydroxy-4-methoxybenzoate (261 mg, 1 mmol) and dried toluene (5 mL) were added to a dry 25 mL round-bottom flask. The mixture was stirred at 0 °C for 15 min under argon protection. Sodium hydride (24 mg, 1.2 mmol) was added, and the mixture was stirred at 0 °C for 30 min, then transferred to 120 °C and stirred for 30 min. Geraniyl chloride (217 mg, 1.2 mmol) was added dropwise to the mixture, and the reaction was stirred for 5 h. The reaction was quenched with saturated ammonium chloride aqueous solution (20 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The solution was purified by silica gel column chromatography to give 180 mg of white solid, yield 45.3%.

[0131] 1 H NMR (400 MHz, Chloroform- d ) δ11.44(s,1H),6.70(s,1H),5.15–5.03(m,1H),5.04–4.94(m,1H),3.88(s,3H), 3.78 (s, 3H), 3.24 (d, J =7.1 Hz,2H),2.09–1.95(m,2H),1.95–1.81(m,2H), 1.68(d, J =1.3 Hz,3H),1.57(s,3H),1.50(s,3H). 13 C NMR (101 MHz, Chloroform- d )

[0132] HRMS(ESI): m / z[M+Na] + calcd for[C 19 H 26 BrO4Na] + :419.0834,found:419.0811.

[0133] Step b: Methyl 2-acetoxy-6-bromo-3-(3,7-dimethyloct-2,6-dien-1-yl)-4-methoxybenzoate (intermediate 3-2)

[0134] In a dry 25 mL round-bottom flask, intermediate 3-1 (900 mg, 2.3 mmol), DAMP (55 mg, 0.45 mmol), triethylamine (465 mg, 4.6 mmol), acetic anhydride (469 mg, 4.6 mmol), and tetrahydrofuran (5 mL) were added. The mixture was stirred at room temperature for 2 h under argon protection. The solvent was removed under reduced pressure, and the mixture was extracted with dichloromethane (30 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1 g of a yellow oil, with a yield of 99.0%.

[0135] 1 H NMR (400 MHz, DMSO- d 6)

[0136] 13 C NMR (101 MHz, Chloroform- d )

[0137] HRMS(ESI): m / z[M+Na] + calcd for[C 21 H 28 BrO5Na] + :461.0940,found:461.0948.

[0138] Step c: (E)-3-[(E)-3,7-dimethyloct-2,6-dien-1-yl]-2-hydroxy-6-[(E)3-(4-hydroxyphenyl)acrylamido]-4-methoxybenzoic acid (compound 24) Intermediate 3-2 (527 mg, 1.2 mmol), 4-hydroxycinnamonamide (163 mg, 1 mmol), xantphos (34 mg), Pd2(dba)3 (18 mg), and cesium carbonate (413 mg, 1.27 mmol) were added to a dry 10 mL pressure-resistant flask. The mixture was stirred overnight at 120 °C under argon protection. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Methanol (10 mL) and 8% NaOH (2 mL) were added, and the mixture was stirred at room temperature under argon protection for 12 h. After the reaction was complete, the solvent was removed under reduced pressure, and the mixture was dissolved in water (30 mL). The aqueous layer was acidified with 1 N HCl, filtered, and the filter cartridge was collected to obtain 88.4 mg of an off-white solid, with a yield of 16%.

[0139] 1 H NMR (400 MHz, DMSO- d 6) δ12.75(s,1H),12.04(s,1H),10.08(s,1H),9.68(s,1H), 7.62(d, J =15.6 Hz,1H),7.45–7.10(m,2H),7.04–6.70(m,2H),6.59–6.10(m,2H),

[0140] 1.71(s,3H),1.61(s,3H),1.53(s,3H). 13 C NMR (101 MHz, DMSO- d 6)

[0141] HRMS(ESI):m / z[MH] - calcd for[C 27 H 30 NO6] - :464.2073,found:464.2085.

[0142] Example 25: (E)-3-[(E)-3,7-dimethyloct-2,6-dien-1-yl]-2-hydroxy-6-[(E)-3-(3-hydroxyphenyl)acrylamido]-4-methoxybenzoic acid (Compound 25)

[0143] The preparation was carried out according to the method of Example 24, except that 4-hydroxycinnaminamide in step c was replaced with 3-hydroxycinnaminamide. 83.7 mg of a pale yellow solid was obtained, with a yield of 15%.

[0144] 1 H NMR (400 MHz, DMSO- d 6)

[0145] 6.70(s,1H),5.79–5.50(m,2H),5.18–5.10(m,1H), 5.09–5.01(t, 1H), 3.73(s, 3H), 3.17(d, J =7.1 Hz,2H),2.05–1.95(m,2H),1.89–1.86(m,2H), 1.71(s,3H),1.61(s,3H),1.53(s,3H). 13 C NMR (151 MHz, DMSO- d 6)

[0146] HRMS(ESI):m / z[MH] - calcd for[C 27 H 30 NO6] - :464.2073,found:464.2069.

[0147] Example 26: (E)-3-(3,7-dimethyloct-2,6-dien-1-yl)-2-hydroxy-6-(4-hydroxybenzamido)-4-methoxybenzoic acid (Compound 26)

[0148] The preparation was carried out according to the method of Example 24, except that 4-hydroxycinnamonamide in step c was replaced with 4-hydroxybenzamide. 110.7 mg of a pale yellow solid was obtained, with a yield of 21%.

[0149] 1 H NMR (400 MHz, DMSO- d 6)δ14.77(s,2H),10.20(s,2H),7.95(s,1H), 7.87(d, J =8.4 Hz, 2H), 6.88 (d, J =8.7 Hz, 2H), 5.14(t, J =7.2 Hz, 1H), 5.05(t, J =7.0 Hz, 1H), 3.75 (d, J =3.1 Hz, 3H), 3.16(d, J =7.1 Hz,2H),2.05–1.93(m,2H), 1.89(t, J =7.7 Hz,2H),1.71(s,3H),1.61(s,3H),1.54(s,3H). 13 C NMR (101 MHz, DMSO- d 6)

[0150] HRMS(ESI):m / z[MH] - calcd for[C 25 H 28 NO6] - :438.1917,found:438.1923.

[0151] Example 27: (E)-3-(3,7-dimethyloct-2,6-dien-1-yl)-2-hydroxy-6-(3-hydroxybenzamido)-4-methoxybenzoic acid (Compound 27)

[0152] The preparation was carried out according to the method of Example 24, except that 4-hydroxycinnamonamide in step c was replaced with 3-hydroxybenzamide. 137 mg of a pale yellow solid was obtained, with a yield of 26%.

[0153] 1 H NMR (400 MHz, DMSO- d 6) δ12.75(s,1H),12.04(s,1H),11.08(s,1H),9.45(s,1H), 7.37–7.31(m,2H),7.06(s,1H),6.83(d, J =7.1 Hz,1H),6.70(s,1H),5.79–5.50(m,2H), 5.18–5.10(m,1H),5.09–5.01(t,1H),3.72(s,3H),2.05–1.95(m,2H),1.89–1.86(m,2H),1.71(s,3H),1.61(s,3H),1.53(s,3H). 13 C NMR (151 MHz, DMSO- d 6)

[0154] HRMS(ESI):m / z[MH] - calcd for[C 25 H 28 NO6] - :438.1917,found:438.1927.

[0155] The following experiments illustrate the application of representative compounds of general formula (I) or (II) of the present invention in the treatment of skin problems related to Propionibacterium acnes, such as acne, pimples, and folliculitis.

[0156] Biological Example 1: Antibacterial Activity of Representative Compounds of the Invention Weigh 2-4 mg of the sample to be tested, add DMSO to prepare a stock solution with a concentration of 10.24 mg / mL for later use.

[0157] MIC determination: Add 40 μL of sample stock solution to the first well of a 96-well plate, and 40 μL of BHI liquid medium to both the negative and positive controls. Then add 160 μL of BHI liquid medium. Add 100 μL of medium to each of the remaining wells outside the first well, and perform serial dilutions starting from the first well. After dilution, add 100 μL of medium to each well of the negative control group, and 100 μL of a 1×10⁻⁶ concentration to each of the remaining wells. 8 Mix the bacterial suspension at CFU / mL and incubate at 37℃ under anaerobic conditions for 72 h. Observe the bacterial growth in the 96-well plate. The concentration corresponding to the well with no colony growth (colon <0.2 mm) is the MIC of the sample.

[0158] MBC assay: MBC = the lowest compound concentration that can reduce the number of surviving colonies to ≤0.1% of the original inoculum (i.e., a sterilization rate ≥99.9%). From the 96-well plate of the MIC experiment, select wells with no visible bacterial growth (including wells with MIC and higher concentrations) and take 10 μL of bacterial suspension using a sterile inoculating loop. Spread the bacterial suspension evenly onto BHI solid agar plates (2-3 replicates per concentration). Place the plates in an anaerobic jar and add an anaerobic bag. Incubate anaerobicly at 37℃ for 72 h and observe whether colonies form on the plates.

[0159] The results showed that the representative compound of the present invention could inhibit the proliferation of Propionibacterium acnes and kill Propionibacterium acnes at a certain concentration. Table 1 shows the MIC and MBC of compounds of formula (I) or (II).

[0160] Biological Example 2: Anti-biofilm activity of representative compounds of the present invention Adjust the bacterial suspension to 1× 490 μL of bacterial culture was added to each well of a 24-well polystyrene plate. The control group received 10 μL of blank culture medium, while the experimental group received 10 μL of culture medium containing 1.6 mg / mL of the test sample (to achieve a final compound concentration of 32 μg / mL). The plates were incubated anaerobicly at 37°C for 72 h to allow biofilm formation. After discarding airborne bacteria, the plates were gently washed three times with PBS to remove unattached cells. The plates were then fixed with 500 μL of methanol for 30 min, stained with 0.1% crystal violet for 10 min, and rinsed with PBS until no free dye remained. 33% glacial acetic acid was added as a desorption staining agent, and the plates were shaken to mix thoroughly. The absorbance (OD value) at 570 nm was measured using a microplate reader, and the biofilm inhibition rate was calculated using a formula.

[0161] The results showed that the representative compound of this invention can inhibit the formation of Propionibacterium acnes biofilm, such as Figure 1 As shown.

[0162] Biological Example 3: Anti-inflammatory Activity of Representative Compounds of the Invention RAW264.7 macrophages in good condition and logarithmic growth phase were seeded at a density of 4 × 10⁴ cells / well in 96-well plates and cultured for 12 h to allow them to adhere. Then, the cells were treated with 100 µL of serum-free medium for 12 h until they reached approximately 70%-80% confluence. Finally, 1 μg / mL LPS was added for 24 h of treatment, and a blank control group was set up. After 24 h of compound treatment, 50 µL of cell supernatant was carefully aspirated. Following the NO detection kit instructions, 50 µL of Griess Reagent I and 50 µL of Griess Reagent II were added, and the absorbance was measured at 540 nm using a microplate reader. The NO concentration was determined using a simultaneously established standard curve. Another 50 µL of cell supernatant was aspirated, and the absorbance was measured at 450 nm using a microplate reader, following the ELISA kit instructions. The concentrations of IL-6 and TNF-α in each group were calculated using a pre-established standard curve.

[0163] All data are expressed as mean ± standard deviation (n=3). ## P < 0.01 compared with the Model group; # P < 0.05 compared with the Model group.

[0164] All data are expressed as mean ± standard deviation (n=3). ## P < 0.01 compared to the Model group.

[0165] All data are expressed as mean ± standard deviation (n=3). ## P < 0.01 compared with the Model group; ## P < 0.05 compared with the Model group.

[0166] In summary, the representative compound of this invention retains the anti-inflammatory activity of phenolamide compounds and can inhibit the secretion of NO, IL-6 and TNFα by macrophages under LPS stimulation; at the same time, it increases the activity of inhibiting Propionibacterium acnes, thus achieving both symptomatic and radical treatment of skin problems related to Propionibacterium acnes.

[0167] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of the claims of this application. Terminology Definitions and Explanations The definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the embodiments, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0168] The term “optional” (or “optionally”, “optionally”) in the general formula definition of this application means the case of being substituted by zero or one or more substituents. For example, “optionally substituted by one, two or more R” means that it may not be substituted by R (no substitution) or may be substituted by one, two or more R.

[0169] "More than three" means three or more.

[0170] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "0-10" is equivalent to describing each integer value in the numerical range "0-10", namely 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0171] The term "C0-10 alkyl" should be understood to mean straight-chain and branched alkyl groups having 0 to 10 carbon atoms, and "C0-3 alkyl" means straight-chain and branched alkyl groups having 0, 1, 2, or 3 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0172] The term "C2-10 alkenyl" should be understood to refer to a straight-chain or branched monovalent hydrocarbon group containing one or more double bonds and having 2 to 10 carbon atoms, preferably "C2-3 alkenyl". "C2-3 alkenyl" should be understood to preferably refer to a straight-chain or branched monovalent hydrocarbon group containing one double bond and having 2 or 3 carbon atoms. The double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0173] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0174] Those skilled in the art will understand that the compounds shown in formula (I) or formula (II) can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts. The present invention provides pharmaceutically acceptable salts of compounds of formula (I), which may be selected from salts formed by compounds of formula I with alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or with organic bases that provide physiologically acceptable cations, such as salts formed with the following bases: sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, betaine, monoethanolamine, caffeine, urea, nicotinamide, isonicotinic acid, dimethylglucosamine, ethylglucosamine, glucosamine, meglumine, lysine, arginine, choline, ammonia, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, diethanolamine, sarcosine, serine, trihydroxymethylaminomethane, aminopropylene glycol, tromethamine, diethylamine, and imidazole.

[0175] The compounds of the present invention may exist as solvates (such as hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0176] Depending on their molecular structure, the compounds of the present invention can be chiral, and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention encompass isomers of each chiral carbon in the R or S configuration, or mixtures thereof, and racemates. The compounds of the present invention or their intermediates can be isolated as enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in both R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0177] The corresponding stable isomers can be separated using known methods, such as extraction, filtration, or column chromatography.

[0178] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0179] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms).

[0180] The above embodiments are only used to illustrate the present invention and are not intended to limit the technical solutions described herein. Although the present invention has been described in detail with reference to the above embodiments, the present invention is not limited to the specific embodiments described above. Therefore, any modifications or equivalent substitutions to the present invention, as well as all technical solutions and improvements that do not depart from the spirit and scope of the invention, are covered within the scope of the claims of the present invention.

Claims

1. A phenolamide derivative, characterized in that, This includes compounds having the structure shown in Formula (I) or Formula (II) and their racemates, stereoisomers, geometric isomers, tautomers, isotopic labels, hydrates, solvates, polymorphs, metabolites, prodrugs, pharmaceutically acceptable salts or esters; Equation (I) is as follows: ； Equation (II) is as follows: ； Among them, R 1 R 2 Each group is independently selected from those substituted with one, two, or more hydrogens, hydroxyl groups, halogens, cyano groups, carboxyl groups, amino groups, alkyl groups, alkenyl groups, alkoxy groups, alkenyloxy groups, alkynyloxy groups, aminoalkyloxy groups, alkylcarbonyloxy groups, acyl groups, or amide groups; R3 is selected from allyl, isopentenyl, geranyl, or farnesyl; n is selected from C 0-10 Alkyl, C 2-10 Alkenyl group.

2. The phenolamide derivative according to claim 1, characterized in that, R 1 R 2 Each is independently selected from one, two, or more hydrogen, hydroxyl, alkyl, or alkoxy groups; R3 is selected from isopentenyl or geranyyl; n is selected from C 0-3 Alkyl, C 2-3 Alkenyl group.

3. A phenolamide derivative according to claim 2, characterized in that, The structure of formula (I) or formula (II) is selected from the following compounds: 。 4. A phenolamide derivative pharmaceutical composition, characterized in that, The compound comprising a therapeutically effective amount of at least one of the following: racemic mixture, stereoisomer, geometric isomer, tautomer, isotope label, hydrate, solvate, polymorph, metabolite, prodrug, pharmaceutically acceptable salt or ester.

5. The phenolamide derivative pharmaceutical composition according to claim 4, characterized in that, It also includes one or more pharmaceutically acceptable excipients.

6. The phenolamide derivative pharmaceutical composition according to claim 5, characterized in that, It also includes one or more therapeutic agents.

7. A cosmetic composition containing phenolamide derivatives, characterized in that, It includes at least one of the compounds described in any one of claims 1 to 3 and their racemates, stereoisomers, geometric isomers, tautomers, isotopic labels, hydrates, solvates, polymorphs, metabolites, prodrugs, pharmaceutically acceptable salts or esters.

8. The cosmetic composition of a phenolamide derivative according to claim 7, characterized in that, It also includes one or more excipients accepted on cosmetics.

9. The application of a phenolamide derivative according to any one of claims 1 to 3, characterized in that, Applications of compounds and their racemates, stereoisomers, geometric isomers, tautomers, isotopic labels, hydrates, solvates, polymorphs, metabolites, prodrugs, pharmaceutically acceptable salts or esters in the preparation of medicaments for the prevention, treatment or relief of skin problems associated with Propionibacterium acnes.

10. The application of a phenolamide derivative according to any one of claims 1 to 3, characterized in that, It is used for skin problems related to Propionibacterium acnes, including pimples, acne, and folliculitis.

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