Derivative of depside acid compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of compound synthesis and application, and particularly discloses a derivative of a depleted acid compound as well as a preparation method and application thereof, the technical key point is that the derivative of the depleted acid compound is a compound as shown in formula I, and the derivative is applied to preparation of a medicine for treating psoriasis. The invention provides a novel depside compound derivative with good PDE4D inhibitory activity, and the derivative is applied to preparation of drugs for treating psoriasis and provides important guiding significance for development of a safer and more effective novel PDE4 inhibitor.

Description

Technical Field

[0001] The present invention relates to the technical field of compound synthesis and application, and in particular to a derivative of a desphenolic acid compound and a preparation method and application thereof. Background Art

[0002] Phosphodiesterase 4 (PDE4) is an important member of the phosphodiesterase family, which is mainly responsible for hydrolyzing cyclic adenosine monophosphate (cAMP) to regulate the concentration of intracellular cAMP. By inhibiting the activity of PDE4, the cAMP level can be increased, activating the downstream protein kinase A (PKA) pathway, and then regulating a variety of cellular physiological processes, including neuronal plasticity, synaptic transmission, memory formation, anti-inflammatory response, etc.

[0003] Currently, PDE4 inhibitors have been widely studied for the treatment of a variety of diseases, including: Central nervous system diseases: such as Alzheimer's disease, Parkinson's disease, schizophrenia and depression. PDE4 inhibitors improve cognitive function and neuroinflammation by regulating the cAMP / PKA / CREB pathway. Inflammatory diseases: such as chronic obstructive pulmonary disease (COPD), atopic dermatitis, inflammatory bowel disease (IBD), etc. PDE4 inhibitors exert anti-inflammatory effects by inhibiting the activation of inflammatory cells and the release of inflammatory factors. Fibrotic diseases: such as idiopathic pulmonary fibrosis (IPF) and liver fibrosis. Studies have found that PDE4 inhibitors can reduce fibrosis by regulating the synthesis and degradation of the extracellular matrix.

[0004] Although PDE4 inhibitors have shown great potential in disease treatment, their clinical application still faces some challenges, mainly due to dose-dependent gastrointestinal side effects (such as nausea and vomiting). In order to overcome these side effects, researchers are committed to developing new PDE4 inhibitors. The main strategies include: Structural optimization: Improving the selectivity and bioavailability of inhibitors through molecular design and structural modification. Structural derivatization is an important means to improve the activity of compounds. For example: Intramolecular cyclization: Cyclization at the 2 and 3 positions and the introduction of alkyl carboxylic acid groups at the C-6 position or the introduction of crotonic acid groups at the C-1 position can significantly improve the PDE4 inhibitory activity. Substituent optimization: When the alkyl chain length on the substituent is 6-7 carbons, the activity is stronger; when a benzyl group is introduced at the C-6 position, the activity is also stronger. Heterocyclic introduction: The introduction of aryloxy and heterocyclic groups, such as chlorothiophene, at different positions on the pyridine ring can enhance the PDE4 inhibitory activity.

[0005] The inventors of the present application have found through research that stone flowers (such as plants of the family Meliaceae) contain a variety of chemical components, including proteins, sugars, anthraquinones, steroids, triterpenes, phenols, flavonoids and volatile oils. Compounds with PDE4 inhibitory activity may exist in these components. At present, compounds with PDE4 inhibitory activity isolated from stone flowers have not been clearly reported. Developing new PDE4 inhibitors from stone flowers can further optimize the activity of the compounds through structural derivatization, providing potential drug candidates for the treatment of diseases.

[0006] Psoriasis (commonly known as "psoriasis") is an immune-mediated chronic, recurrent, inflammatory skin disease with a complex pathogenesis, mainly related to genetics, immune abnormalities and environmental factors. At present, PDE4 inhibitors have certain application prospects in the treatment of psoriasis, but their side effects, efficacy limitations and administration routes still need to be further optimized. The development of new, safer and more effective PDE4 inhibitors is of far-reaching significance.

[0007] To this end, the present application aims to provide a derivative of a desphenolic acid compound and a preparation method and use thereof to solve the above-mentioned problems. Summary of the invention

[0008] The purpose of the present invention is to solve the prior art problems raised in the above background technology and to provide a derivative of desphenolic acid compounds and a preparation method and use thereof.

[0009] The above-mentioned purpose of the present invention is achieved like this:

[0010] The present invention provides a depsipeptide derivative and a pharmaceutically acceptable salt thereof, the general structural formula of which is as follows (I):

[0011]

[0012] Furthermore, the derivative is selected from the following compounds:

[0013]

[0014]

[0015] Furthermore, the derivative is selected from the following compounds:

[0016]

[0017] Another aspect of the present invention provides a method for preparing a depsipeptide derivative and a compound 9 in a pharmaceutically acceptable salt thereof:

[0018] In a 250 ml round-bottom flask, 500 mg of 3-hydroxy-4-methoxybenzoic acid was added, and 150 ml of dimethyl sulfoxide was added to dissolve it. Then, 820 mg of K2CO3 was added, and then 444 μl of ethyl bromide was added dropwise. After reacting for 8 hours, the mixture was extracted with ethyl acetate, washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed using petroleum ether / ethyl acetate as eluent, and 49 mg of the product was added with 73 mg of EDCI and 47 mg of HOBT, and mixed with 31 mg of 3-amino-5-methylphenol, and stirred. The mixture was reacted overnight, and the upper layer was extracted with ethyl acetate / water. After being spin-dried, the mixture was developed with petroleum ether / ethyl acetate (1:1) and separated by PTLC to obtain compound 9.

[0019] Another aspect of the present invention provides a method for preparing a compound 11 in a depsipeptide derivative and a pharmaceutically acceptable salt thereof:

[0020] In a 250 ml round-bottom flask, 500 mg of 3-hydroxy-4-methoxybenzoic acid was added, and 150 ml of dimethyl sulfoxide was added to dissolve it. Then, 820 mg of K2CO3 was added, and then 637 μl of bromocyclopentane was added dropwise. After reacting for 8 h, the mixture was extracted with ethyl acetate, washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed using petroleum ether / ethyl acetate as eluent. 53 mg of the product was added with 65 mg of EDCI and 42 mg of HOBT, and mixed with 28 mg of 3-amino-5-methylphenol, and the mixture was reacted overnight. The upper layer was extracted with ethyl acetate / water, and the mixture was developed with petroleum ether / ethyl acetate and separated by PTLC to obtain compound 11.

[0021] Another aspect of the present invention provides a use of a depsipeptide derivative and a pharmaceutically acceptable salt thereof in the preparation of a drug for treating psoriasis.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. The scheme of the present invention synthesizes new depsipeptide derivatives with good PDE4D inhibitory activity, which are used in the preparation of drugs for the treatment of psoriasis, providing important guidance for the development of safer and more effective new PDE4 inhibitors;

[0024] 2. Compounds 9 and 11 of the depsipeptide derivatives synthesized by the present invention have simple structures and have stronger PDE4 inhibitory activity than the natural compound 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Schematic diagram of the binding between the model compound and PDE4D-CD in the embodiment of the present invention;

[0026] Figure 2 It is the active compound 1 and its derivatives in the examples of the present invention. DETAILED DESCRIPTION

[0027] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0028] The implementation of the present invention is described in detail below in conjunction with specific embodiments.

[0029] With reference to the drawings, the following are preferred embodiments of the present invention.

[0030] The solution provided by the embodiment of the present invention is a derivative of a desphenolic acid compound and a pharmaceutically acceptable salt thereof, as well as a preparation method and its use in preparing a drug for treating psoriasis. The two hydroxyl groups at the head of the compound respectively form hydrogen bond interactions with the main chain carbonyl groups Y159 and N321, and form indirect interactions with D201 and D318 through hydrogen bonds mediated by water molecules, and the tail carboxylic acid forms hydrogen bond interactions with D201, E230, and Y271 (such as Figure 1 On this basis, the present invention implements the synthesis of structural analogs of compound 1, a total of 13 compounds of 5 categories (such as Figure 2 shown).

[0031] The following is a specific implementation of the implementation scheme of the present invention:

[0032] 1. Compound 1 is a unique black tea acid analogue in Parmelia serrana, and the synthesis of its derivatives:

[0033] (1) Synthesis of compound 2a:

[0034]

[0035] In a 100-ml round-bottom flask, 1 g (5.56 mmol) of 3,5-dihydroxypentylbenzene was added, and 25 ml of dimethyl sulfoxide was added and stirred to fully dissolve. 570 μl (6.15 mmol) of phosphorus oxychloride was added dropwise within 20 min under 0°C ice bath conditions, and the mixture was stirred at room temperature for 4 h. Water was added under ice bath conditions to quench the reaction, and the mixture was stirred for 0.5 h. The mixture was extracted with saturated NaHCO3 aqueous solution / ethyl acetate, and the mixture was washed with saturated NaCl aqueous solution. The organic phase was dried over anhydrous Na2SO4, and silica gel column chromatography was performed using petroleum ether / ethyl acetate (15:1→7:1) as the eluent to obtain 1.1 g of the product with a yield of 95%. 1H NMR(400MHz, CDCl3-d1,δ):12.43(s,1H,C2-OH),10.01(s,1H,CHO),8.00(s,1H,4C-OH),6.25(t, 2H,C3,5-H),2.77(t,2H,C1'-H),1.59(m,2H,C2'-H),1.32(m,4H,C3',4'-H),0.87(m,3H,C5'-H).

[0036] (2) Synthesis of compound 2b:

[0037]

[0038] In a 50-ml round-bottom flask, 50 mg (0.24 mmol) of 2a was added, and 15 ml of acetone was added to dissolve it. Then, 51 mg (0.48 mmol) of Na2CO3 was added, and 22.7 μl (0.24 mmol) of dimethyl sulfate was added while stirring. The mixture was heated and stirred at 50°C overnight, extracted with saturated aqueous NaHCO3 solution / ethyl acetate, and washed with saturated aqueous NaCl solution. The organic phase was dried over anhydrous Na2SO4, and silica gel column chromatography was performed with petroleum ether / ethyl acetate (15:1→8:1) as the eluent to obtain 32 mg of the product with a yield of 60%. 1 H NMR(400MHz, CDCl3-d1,δ):12.51(s,1H,C2-OH),10.07(s,1H,CHO),6.27(q,2H,C3,5-H),3.82(s ,3H,C4-Me),2.81(t,2H,C1'-H),1.63(m,2H,C2'-H),1.34(m,4H,C3',4'-H),0.89(m,3H,C5'-H).

[0039] (3) Synthesis of compound 2c:

[0040]

[0041] In a 100 ml round-bottom flask, 150 mg (0.72 mmol) of 2a was added, 25 ml of dimethyl sulfoxide was added to dissolve it, 144 mg (1.44 mmol) of KHCO3 was added, 171 μl (1.44 mmol) of benzyl bromide was added dropwise, and the reaction was allowed to proceed overnight. The reaction solution was extracted with ethyl acetate and water, the organic layer was spin-dried, 186 mg (1.55 mmol) of NaH2PO3 dihydrate was added, and the solution was dissolved with 25 ml of DMSO / H2O (10:1) system, and 140 mg (1.55 mmol) of NaClO2 in 10 ml of aqueous solution was added dropwise under ice bath conditions, the reaction was continued for 24 h, the pH was adjusted to 1 with 1N hydrochloric acid, the solution was extracted with ethyl acetate, the solution was washed with saturated aqueous NaCl solution, the organic phase was dried over anhydrous Na2SO4, and the product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (8:1) as the eluent to obtain 242 mg of the product with a yield of 83%.

[0042] (4) Synthesis of compound 2d:

[0043]

[0044] In a 100 ml round-bottom flask, 150 mg (0.37 mmol) of 2c was added, and 25 ml of ethyl acetate was added to dissolve it. 45 mg (37 μmol) of 10% palladium carbon was added for hydrogenation. After filtering the palladium carbon from the product, it was dissolved in 25 ml of dimethyl sulfoxide. 74 mg (0.74 mmol) of KHCO3 was added, and 88 μl (0.74 mmol) of benzyl bromide was added dropwise. The reaction was allowed to proceed overnight, and the product was extracted with saturated NaHCO3 aqueous solution / ethyl acetate. The product was washed with saturated NaCl aqueous solution, and the organic phase was dried over anhydrous Na2SO4. The product was chromatographed on a silica gel column using petroleum ether / ethyl acetate (15:1→6:1) as the eluent to obtain 111 mg of the product with a yield of 95%.

[0045] (5) Synthesis of Compound 2:

[0046]

[0047] In a 10 ml round-bottom flask, 15 mg (37 μmol) of 2c was added, 3 ml of dimethyl sulfoxide was added to dissolve, 8.6 mg (44 μmol) of EDCI, 6.0 mg (44 μmol) of HOBT were added, and the mixture was stirred with 12 mg (37 μmol) of 2d. The mixture was reacted overnight, and the upper layer was extracted with ethyl acetate / water. 4.5 mg (3.7 μmol) of 10% palladium carbon was added for hydrogenation. After the palladium carbon was removed from the product by filtration, the mixture was extracted with saturated NaHCO3 aqueous solution / ethyl acetate, and the mixture was washed with saturated NaCl aqueous solution. The organic phase was dried over anhydrous Na2SO4, and silica gel column chromatography was performed with petroleum ether / ethyl acetate (3:1→1:1) as the eluent to obtain 11 mg of the product with a yield of 70%.

[0048] (6) Synthesis of compound 3a:

[0049]

[0050] In a 10 ml round-bottom flask, 15 mg (68 μmol) of 2b was added, 3 ml of dimethyl sulfoxide was added to dissolve, 7.0 mg (70 μmol) of KHCO3 was added, 8.3 μl (70 μmol) of benzyl bromide was added dropwise, and the reaction was allowed to react overnight. The reaction solution was extracted with ethyl acetate and water, the organic layer was spin-dried, 4 ml of tetrahydrofuran was added to dissolve, 5.1 mg (136 μmol) of NaBH4 was added under ice bath, and a drop of acetic acid was added to catalyze the reaction. After 1.5 h of reaction, the product was extracted with ethyl acetate / water, washed with saturated NaCl aqueous solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed with petroleum ether / ethyl acetate (30:1→6:1) as eluent to obtain 20 mg of the product with a yield of 96%. 1 H NMR(400MHz, CDCl3-d1,δ):7.38(m,4H,Bn-ArH),6.39(dd,2H,C3,5-H),5.08(s,2H,Bn-H),4.70(d,2H,C1-CH2),3.79(s, 3H,C4-OMe),2.66(m,2H,C1'-H),2.16(t,1H,C1CH2-OH),1.61(m,2H,C2'-H),1.35(m,4H,C3',4'-H),0.90(m,3H,C5'-H).

[0051] (7) Synthesis of compound 3b:

[0052]

[0053] In a 10 ml round-bottom flask, 20 mg (65 μmol) of 3a was added, and 3 ml of dioxane was added to dissolve it. 9.3 μl (72 μmol) of tetramethylsilane bromide was added dropwise. The reaction was allowed to proceed overnight, and the mixture was extracted with ethyl acetate / water. The mixture was washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. The mixture was chromatographed on a silica gel column using petroleum ether / ethyl acetate (30:1→6:1) as the eluent to obtain 20 mg of the product with a yield of 82%.

[0054] (8) Synthesis of Compound 3:

[0055]

[0056] In a 10 ml round-bottom flask, 20 mg (53 μmol) 3b and 17 mg (54 μmol) 2d were added, 3 ml of dioxane was added to dissolve, and 8.8 mg (64 μmol) K2CO3 was added to catalyze the reaction. After 8 h of reaction, the upper layer was extracted with ethyl acetate / water, and 6.4 mg (5.3 μmol) 10% palladium carbon was added for hydrogenation. After the product was filtered to remove palladium carbon, it was extracted with ethyl acetate / water, washed with saturated NaCl aqueous solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed with petroleum ether / ethyl acetate (1:1) as the eluent, and 85% acetonitrile was used for preparation and purification to obtain 17 mg of the product with a yield of 75%. 1 H NMR(400MHz,CDCl3-d1,δ):12.59(s,1H,C2-OH),6.37(dd,2H,C3',5'-H),6.28(dd,2H,C3,5-H),6.25(s,1H,C2'-OH),3.95(s,2H,C1'-C H2),3.74(s,3H,C4'-OMe),2.84(m,2H,C1"'-H),2.77(m,2H,C1"'-H),1.29(m,12H,C2",3",4",2"',3"',4"'-H),0.86(m,6H,C5",5"'-H).

[0057] (9) Synthesis of compound 4a:

[0058]

[0059] In a 250 ml round-bottom flask, 5 g (40 mmol) of 3,4-dihydroxytoluene was added, and 100 ml of dichloromethane was added to dissolve it. 44 ml (44 mmol) of 1 M bromine solution in dichloromethane was added dropwise, and the mixture was heated to 75 °C. After reacting for 6 h, water was added to quench the mixture, and dichloromethane / water was used for extraction. The organic layer was directly spin-dried (a small-scale experiment was conducted using DCM / methanol as the eluent for silica gel column chromatography, and serious column hanging was found). The purity of the product was 95%.

[0060] (10) Synthesis of compound 4b:

[0061]

[0062] In a 500ml round-bottom flask, 8.1g (40mmol) 4a was added, and 150ml dimethyl sulfoxide was added to dissolve it. Then 12g (87mmol) K2CO3 was added, and after stirring, 10ml (87mmol) benzyl bromide was added dropwise. The temperature was slowly raised to 153 degrees Celsius and refluxed. After 6h, the heating was stopped and cooled to room temperature. The product was extracted with ethyl acetate / water, washed with saturated NaCl aqueous solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed with petroleum ether / ethyl acetate (30:1) as the eluent. The raw material was hung on the column to obtain 9.2g of the product with a yield of 61%. 1 HNMR (400MHz, CDCl3-d1, δ): 7.37 (m, 10H, Bn-H), 7.11 (s, 1H, C3-H), 6.82 (s, 1H, C6-H), 5.11 (d, 4H, Bn-CH2), 2.28 (s, 3H, C5-CH3).

[0063] (11) Synthesis of compound 4c:

[0064]

[0065] In a 500 ml round-bottom flask, 7.5 g (19.6 mmol) of 4b which had been freeze-dried with liquid nitrogen for 2 h, dried in an oven at 105 °C for 0.5 h and then cooled to room temperature was added. 150 ml of anhydrous tetrahydrofuran was added to dissolve the mixture. The mixture was protected with argon and the gas was replaced three times. The mixture was stirred at -78 °C for 5 min for equilibrium. Then 8.25 ml (20.6 mmol) of 2.5 N n-butyl lithium tetrahydrofuran solution was added. After stirring for 15 min, 6.34 ml (78.4 mmol) of ultra-dry dimethyl sulfoxide was added dropwise. After the addition was complete, the reaction was moved to room temperature overnight. 75 ml of 1 N hydrochloric acid aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate / water and washed with saturated NaCl aqueous solution. The organic phase was dried over anhydrous Na2SO4 and eluted with petroleum ether / ethyl acetate (30:1→6:1) for silica gel column chromatography to obtain 2.1 g of the product with a yield of 33%.

[0066] (12) Synthesis of compound 4d:

[0067]

[0068] In a 250ml round-bottom flask, 2g (6mmol) 4c and 1.8g (15mmol) dihydrate NaH2PO3 were added and dissolved with 100ml DMSO / H2O (10:1) system. 1.35g (15mmol) NaClO2 in 50ml aqueous solution was added dropwise under ice bath condition. The reaction was carried out for 24h, and the pH was adjusted to 1 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic phase was dried over anhydrous Na2SO4 and chromatographed on a silica gel column with petroleum ether / ethyl acetate (8:1) as the eluent to obtain 1.7g of the product with a yield of 81%.

[0069] (13) Synthesis of Compound 4:

[0070]

[0071] In a 10 ml round-bottom flask, add 15 mg (43 μmol) 2d, add 3 ml dimethyl sulfoxide to dissolve, add 9.2 mg (47 μmol) EDCI, 6.4 mg (47 μmol) HOBT, and 13 mg (43 μmol) 1-16d, mix and stir, react overnight, extract the upper layer with ethyl acetate / water, add 4.8 mg (4.3 μmol) 10% palladium carbon for hydrogenation, filter the product to remove palladium carbon, extract with saturated NaHCO3 aqueous solution / ethyl acetate, wash with saturated NaCl aqueous solution, dry the organic phase with anhydrous Na2SO4, and perform silica gel column chromatography with petroleum ether / ethyl acetate (3:1→1:1) as eluent to obtain 11 mg product with a yield of 68%.

[0072] (14) Synthesis of compound 5a:

[0073]

[0074] 1 g (8.06 mmol) of 3,5-dihydroxytoluene was added to a 100 ml round-bottom flask, and 25 ml of dimethyl sulfoxide was added and stirred to fully dissolve. 827 μl (8.92 mmol) of phosphorus oxychloride was added dropwise within 20 min under ice bath condition at 0°C, and stirred at room temperature for 4 h. Water was added under ice bath condition to quench the reaction, and stirred for 0.5 h. The mixture was extracted with saturated NaHCO3 aqueous solution / ethyl acetate, and washed with saturated NaCl aqueous solution. The organic phase was dried over anhydrous Na2SO4, and silica gel column chromatography was performed with petroleum ether / ethyl acetate (15:1→7:1) as eluent to obtain 1.16 g of the product with a yield of 95%.

[0075] (15) Synthesis of compound 5b:

[0076]

[0077] In a 100 ml round-bottom flask, 150 mg (0.99 mmol) of 5a was added, 25 ml of dimethyl sulfoxide was added to dissolve it, 197 mg (1.97 mmol) of KHCO3 was added, 234 μl (1.97 mmol) of benzyl bromide was added dropwise, and the reaction was allowed to proceed overnight. The reaction solution was extracted with ethyl acetate and water, the organic layer was spin-dried, 255 mg (2.12 mmol) of NaH2PO3 dihydrate was added, and the solution was dissolved with 25 ml of DMSO / H2O (10:1) system, and 192 mg (2.12 mmol) of NaClO2 in 10 ml of aqueous solution was added dropwise under ice bath conditions, the reaction was continued for 24 h, the pH was adjusted to 1 with 1N hydrochloric acid, the solution was extracted with ethyl acetate, the solution was washed with saturated aqueous NaCl solution, the organic phase was dried over anhydrous Na2SO4, and silica gel column chromatography was performed with petroleum ether / ethyl acetate (8:1) as the eluent to obtain 293 mg of the product with a yield of 85%.

[0078] (16) Synthesis of compound 5c:

[0079]

[0080] In a 100 ml round-bottom flask, 150 mg (0.43 mmol) of 5b was added, and 25 ml of ethyl acetate was added to dissolve it. 52 mg (43 μmol) of 10% palladium carbon was added for hydrogenation. The product was filtered to remove the palladium carbon and then dissolved in 25 ml of dimethyl sulfoxide. 86 mg (0.86 mmol) of KHCO3 was added, and 103 μl (0.86 mmol) of benzyl bromide was added dropwise. The reaction was allowed to proceed overnight, and the mixture was extracted with saturated NaHCO3 aqueous solution / ethyl acetate. The mixture was washed with saturated NaCl aqueous solution, and the organic phase was dried over anhydrous Na2SO4. The product was chromatographed on a silica gel column using petroleum ether / ethyl acetate (15:1→6:1) as the eluent to obtain 101 mg of the product with a yield of 96%.

[0081] (17) Synthesis of Compound 5:

[0082]

[0083] In a 10 ml round-bottom flask, add 15 mg (43 μmol) 4d, add 3 ml dimethyl sulfoxide to dissolve, add 9.2 mg (47 μmol) EDCI, 6.4 mg (47 μmol) HOBT, and mix with 11 mg (43 μmol) 2d, and react overnight. Extract the upper layer with ethyl acetate / water, add 4.8 mg (4.3 μmol) 10% palladium carbon for hydrogenation, filter the product to remove palladium carbon, extract with saturated NaHCO3 aqueous solution / ethyl acetate, wash with saturated NaCl aqueous solution, dry the organic phase with anhydrous Na2SO4, and perform silica gel column chromatography with petroleum ether / ethyl acetate (3:1→1:1) as eluent to obtain 10 mg of product with a yield of 73%.

[0084] (18) Synthesis of Compound 6:

[0085]

[0086] In a 25 ml round-bottom flask, 30 mg (165 μmol) of 3,4-dimethoxybenzoic acid was added, 10 ml of dimethyl sulfoxide was added to dissolve, 38 mg (198 μmol) of EDCI, 25 mg (198 μmol) of HOBT, and 20 mg (163 μmol) of 3-amino-5-methylphenol were added, mixed and stirred, and reacted overnight. The upper layer was extracted with ethyl acetate / water, and then dried and developed with petroleum ether / ethyl acetate (1:1) for PTLC separation to obtain 25 mg of product with a yield of 53%.

[0087] 1 H NMR(400MHz, CDCl3-d1,δ):7.72(s,1H,C1-NH),7.50(s,1H,C2'-H),7.48(s,1 H,C6-H),7.36(d,1H,C6'-H),6.92(d,1H,C5'-H),6.71(s,1H,C2-H),6.48(s,

[0088] 1H,C4-H), 3.97(s,3H,C3'-OMe), 3.95(s,3H,C4'-OMe), 2.30(m,3H,C5-Me).

[0089] (19) Synthesis of Compound 7:

[0090]

[0091] In a 25 ml round-bottom flask, 30 mg (165 μmol) of 3,4-dimethoxybenzoic acid was added, 10 ml of dimethyl sulfoxide was added to dissolve, 38 mg (198 μmol) of EDCI, 25 mg (198 μmol) of HOBT, and 20 mg (165 μmol) of 3,5-dimethylaniline were added and stirred, and the mixture was reacted overnight. The upper layer was extracted with ethyl acetate / water, and then dried by spin drying and developed with petroleum ether / ethyl acetate (1:1) for PTLC separation to obtain 30 mg of the product with a yield of 63%. 1 H NMR(400MHz, CDCl3-d1,δ):7.69(s,1H,C1-NH),7.50(s,1H,C2'-H),7.37(d,1H,C6'-H),7.27(s,2H ,C2,6-H),6.91(d,1H,C5'-H),6.80(s,1H,C4-H),3.95(d,6H,C3',4'-OMe),2.33(s,6H,C3,5-Me).

[0092] (20) Synthesis of Compound 8:

[0093]

[0094] In a 50 ml round-bottom flask, 50 mg (275 μmol) of 3,4-dimethoxybenzoic acid was added, and 20 ml of dimethyl sulfoxide was added to dissolve it. After adding 40 μl (551 μmol) of dichlorothionyl, the mixture was stirred for half an hour, and then 41 mg (275 μmol) of 2-hydroxymethyl-5-aminophenylboronic acid was added and mixed and stirred. 22 mg (550 μmol) of NaOH was added twice. After reacting for 4 hours, the upper layer was extracted with ethyl acetate / water, and the mixture was dried by spin drying and developed with petroleum ether / ethyl acetate (1:1) for PTLC separation to obtain 15 mg of the product with a yield of 17%. 1 H NMR(400MHz, CDCl3-d1,δ):7.86(s,1H,C1-NH),7.85(s,1H,C2-H),7.84(d,1H,C6-H),7.51(s,1H,C2'-H), 7.40(d,1H,C6'-H),7.38(d,1H,C5-H),6.92(d,1H,C5'-H),5.09(s,2H,C4-CH2),3.96(d,6H,C3',4'-OMe).

[0095] (21) Synthesis of Compound 9:

[0096]

[0097] In a 250 ml round-bottom flask, 500 mg (2.98 mmol) of 3-hydroxy-4-methoxybenzoic acid was added, 150 ml of dimethyl sulfoxide was added to dissolve, 820 mg (5.94 mmol) of K2CO3 was added, and then 444 μl (5.94 mmol) of ethyl bromide was added dropwise. After reacting for 8 h, the mixture was extracted with ethyl acetate, washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed using petroleum ether / ethyl acetate (3:1) as the eluent. 49 mg of the product was added with 73 mg (378 μmol) of EDCI, 47 mg (378 μmol) of HOBT, and 31 mg (252 μmol) of 3-amino-5-methylphenol, mixed and stirred, and reacted overnight. The upper layer was extracted with ethyl acetate / water, and after being spin-dried, the mixture was developed with petroleum ether / ethyl acetate (1:1) for PTLC separation to obtain 24 mg of the product with a yield of 31%. 1H NMR(400MHz,CD3OD-d4,δ):7.72(s,1H,C1-NH),7.61(d,1H,C6'-H),7.47(s,1H,C2'-H),7.35(s,1H,C6-H),6.91(d,1H,C5'-H),6.76( s,1H,C3-OH),6.64(s,1H,C2-H),6.48(s,1H,C4-H),4.20(q,2H,C1”-H),3.94(s,3H,C4’-OMe),2.29(s,3H,C5-H),1.50(t,3H,C2”-H).

[0098] (22) Synthesis of compound 10:

[0099]

[0100] In a 250 ml round-bottom flask, 500 mg (2.98 mmol) of 3-hydroxy-4-methoxybenzoic acid was added, 150 ml of dimethyl sulfoxide was added to dissolve, 820 mg (5.94 mmol) of K2CO3 was added, and then 476 μl (5.94 mmol) of 2-bromopropane was added dropwise. After reacting for 8 h, the mixture was extracted with ethyl acetate, washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed using petroleum ether / ethyl acetate (3:1) as the eluent. 53 mg of the product was added with 73 mg (378 μmol) of EDCI, 47 mg (378 μmol) of HOBT, and 31 mg (252 μmol) of 3-amino-5-methylphenol, and the mixture was stirred and reacted overnight. The upper layer was extracted with ethyl acetate / water, and after being spin-dried, the mixture was developed with petroleum ether / ethyl acetate (1:1) for PTLC separation to obtain 26 mg of the product with a yield of 33%. 1 H NMR(400MHz,CD3OD-d4,δ):7.53(d,1H,C6'-H),7.49(s,1H,C2'-H),7.04(s,1H,C6-H),7.02(d,1H,C5'-H),6.86(s, 1H,C2-H),6.38(s,1H,C4-H),4.60(p,1H,C2”-H),3.86(s,3H,C4’-OMe),2.23(s,3H,C5-H),1.30(d,6H,C1”,3”-H).

[0101] (23) Synthesis of Compound 11:

[0102]

[0103] In a 250 ml round-bottom flask, 500 mg (2.98 mmol) of 3-hydroxy-4-methoxybenzoic acid was added, 150 ml of dimethyl sulfoxide was added to dissolve, 820 mg (5.94 mmol) of K2CO3 was added, and then 637 μl (5.94 mmol) of bromocyclopentane was added dropwise. After reacting for 8 h, the mixture was extracted with ethyl acetate, washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed using petroleum ether / ethyl acetate (3:1) as the eluent. 53 mg of the product was added with 65 mg (338 μmol) of EDCI, 42 mg (336 μmol) of HOBT, and 28 mg (225 μmol) of 3-amino-5-methylphenol, mixed and stirred, and reacted overnight. The upper layer was extracted with ethyl acetate / water, and after being spin-dried, the mixture was developed with petroleum ether / ethyl acetate (1:1) for PTLC separation to obtain 30 mg of the product with a yield of 39%. 1 H NMR(400MHz,CD3OD-d4,δ):7.51(d,1H,C6'-H),7.47(s,1H,C2'-H),7.04(s, 1H,C6-H),7.00(d,1H,C5'-H),6.87(s,1H,C2-H),6.38(s,1H,C4-H),3.85(s ,3H,C4'-OMe),2.23(s,3H,C5-H),2.15(t,1H,C1”-H),2.01(m,2H,C2”,C5”- H),1.88(m,2H,C2”,5”-H),1.73(m,2H,C3”,C4”-H),1.62(m,2H,C3”,C4”-H).

[0104] (24) Synthesis of compound 12a:

[0105]

[0106] 100 mg (0.69 mmol) of 1-naphthol was added to a 50 ml round-bottom flask, and 10 ml of dimethyl sulfoxide was added to dissolve it. 229 μl (2.08 mmol) of titanium tetrachloride was added, and then 94 μl (1.04 mmol) of 1,1-dichloromethyl ether was added dropwise. After reacting for 2.5 h, ice water and 1N HCl were added to quench, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed using petroleum ether / ethyl acetate (20:1→3:1) as the eluent to obtain 69 mg of compound 12a (yield 58%) and 46 mg of compound 12b (yield 39%).

[0107] (25) Synthesis of compound 12c:

[0108]

[0109] In a 25 ml round-bottom flask, 22 mg (128 μmol) of 12a and 100 mg (0.64 mmol) of NaH2PO3 dihydrate were added and dissolved with 10 ml of DMSO / H2O (10:1) system. Under ice bath conditions, 57.6 mg (0.64 mmol) of NaClO2 in 5 ml of aqueous solution was added dropwise. The reaction was carried out for 24 h, and the pH was adjusted to 1 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic phase was dried over anhydrous Na2SO4 and chromatographed on a silica gel column with petroleum ether / ethyl acetate (3:1→1:1) as the eluent to obtain 23 mg of the product with a yield of 95%.

[0110] (26) Synthesis of Compound 12:

[0111]

[0112] In a 25 ml round-bottom flask, 23 mg (122 μmol) of 12c was added, 10 ml of dimethyl sulfoxide was added to dissolve, 35 mg (183 μmol) of EDCI, 25 mg (185 μmol) of HOBT, and 15 mg (122 μmol) of 3-amino-5-methylphenol were added and stirred, and the mixture was reacted overnight. The upper layer was extracted with ethyl acetate / water, and then dried and developed with petroleum ether / ethyl acetate (1:1) for PTLC separation to obtain 25 mg of the product with a yield of 70%. 1 H NMR(400MHz, CDCl3-d1,δ):8.27(d,1H,C3'-H),8.25(d,1H,C6'-H),7.58(d,1H,C10'-H),7.53(dd,1H,C4'-H),7.4 6(dd,1H,C5'-H),7.15(s,1H,C6-H),6.91(s,1H,C2-H),6.84(d,1H,C9'-H),6.42(s,1H,C4-H),2.26(s,3H,C5-Me).

[0113] (27) Synthesis of compound 13a:

[0114]

[0115] In a 50ml round-bottom flask, add 100mg (448μmol) 7-bromo-1-naphthol, add 10ml dimethyl sulfoxide to dissolve, add 148μl (1.35mmol) titanium tetrachloride, then dropwise add 62μl (675μmol) 1,1-dichloromethyl ether, react for 2.5h, quench with ice water and 1N HCl, extract with ethyl acetate, wash with saturated NaCl aqueous solution, dry the organic phase with anhydrous Na2SO4, and perform silica gel column chromatography with petroleum ether / ethyl acetate (20:1→3:1) as the eluent to obtain 64mg compound 13a (yield 57%) and 43mg compound 13b (yield 38%). 13a: 1 H NMR (400MHz, CDCl3-d1, δ): 10.16 (s, 1H, CHO), 9.21 (d, 1H, C3-H), 8.47 (s, 1H, C6-H), 7.86 (d, 1H, C10-H), 7.78 (d, 1H, C4-H), 6.95 (d, 1H, C9-H).

[0116] (28) Synthesis of compound 13c:

[0117]

[0118] In a 25 ml round-bottom flask, 62 mg (248 μmol) of 13a and 194 mg (1.24 mmol) of NaH2PO3 dihydrate were added and dissolved with 10 ml of DMSO / H2O (10:1) system. Under ice bath conditions, 224 mg (2.48 mmol) of NaClO2 in 5 ml of aqueous solution was added dropwise. The reaction was continued for 24 h. The pH was adjusted to 1 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. The mixture was chromatographed on a silica gel column with petroleum ether / ethyl acetate (3:1) as the eluent to obtain 66 mg of the product with a yield of 100%.

[0119] (29) Synthesis of compound 13d:

[0120]

[0121] In a 25 ml round-bottom flask, 66 mg (248 μmol) of 13c was added, 10 ml of dimethyl sulfoxide was added to dissolve, 72 mg (372 μmol) of EDCI, 47 mg (372 μmol) of HOBT, and 15 mg (248 μmol) of 3-amino-5-methylphenol were added and stirred, and the mixture was reacted overnight. The upper layer was extracted with ethyl acetate / water, extracted with saturated aqueous NaHCO3 solution / ethyl acetate, washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed with petroleum ether / ethyl acetate (2:1→1:1) as the eluent to obtain 22 mg of the product with a yield of 24%.

[0122] (30) Synthesis of compound 13:

[0123]

[0124] In a 10 ml round-bottom flask, 22 mg (59 μmol) 13d, 6 mg (5.9 μmol) Pd(PPh3)2Cl2 and 27 mg (177 μmol) K2CO3 were added and dissolved in 2.5 ml toluene / water (4:1). The argon gas was replaced and stirred at room temperature for 5 min. Then, 32 μl (118 μmol) of 3.5 M tetrahydrofuran solution of trimethylcyclotriboroxine was added. The mixture was heated to 99 ° C and reacted for 4 h. The upper layer was extracted with ethyl acetate / water, and the mixture was dried and developed with petroleum ether / ethyl acetate (1:1) for PTLC separation to obtain 12 mg of the product with a yield of 65%. 1 HNMR(400MHz, CDCl3-d1,δ):8.14(s,1H,C3'-H),8.05(s,1H,C6'-H),7.51(d,1H,C10'-H),7.39(d,1H,C4'-H),7.1 4(s,1H,C6-H),6.91(s,1H,C2-H),6.81(d,1H,C9'-H),6.42(s,1H,C4-H),2.50(s,3H,C5'-Me),2.26(s,3H,C5-Me).

[0125] (31) Synthesis of compound 14a:

[0126]

[0127] In a 50 ml round-bottom flask, 100 mg (448 μmol) of 6-bromo-1-naphthol was added, 10 ml of dimethyl sulfoxide was added to dissolve, 148 μl (1.35 mmol) of titanium tetrachloride was added, and then 62 μl (675 μmol) of 1,1-dichloromethyl ether was added dropwise. After reacting for 2.5 h, ice water and 1N HCl were added to quench, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed using petroleum ether / ethyl acetate (20:1→3:1) as the eluent to obtain 60 mg of compound 14a (yield 54%) and 39 mg of compound 14b (yield 35%).

[0128] (32) Synthesis of compound 14c:

[0129]

[0130] In a 25 ml round-bottom flask, 60 mg (240 μmol) of 14a and 194 mg (1.24 mmol) of NaH2PO3 dihydrate were added and dissolved with 10 ml of DMSO / H2O (10:1) system. Under ice bath conditions, 224 mg (2.48 mmol) of NaClO2 in 5 ml of aqueous solution was added dropwise. The reaction was continued for 24 h. The pH was adjusted to 1 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. The mixture was chromatographed on a silica gel column with petroleum ether / ethyl acetate (3:1) as the eluent to obtain 64 mg of the product with a yield of 100%.

[0131] (33) Synthesis of compound 14d:

[0132]

[0133] In a 25 ml round-bottom flask, 64 mg (240 μmol) of 14c was added, and 10 ml of dimethyl sulfoxide was added to dissolve it. Then, 72 mg (372 μmol) of EDCI and 47 mg (372 μmol) of HOBT were added. The mixture was mixed and stirred with 15 mg (248 μmol) of 3-amino-5-methylphenol. The mixture was reacted overnight. The upper layer was extracted with ethyl acetate / water, and then with saturated aqueous NaHCO3 solution / ethyl acetate. The mixture was washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. The product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1→1:1) as the eluent to obtain 18 mg of the product with a yield of 20%.

[0134] (34) Synthesis of compound 14:

[0135]

[0136] In a 10 ml round-bottom flask, 18 mg (49 μmol) 14d, 4 mg (4.9 μmol) Pd(PPh3)2Cl2 and 20 mg (148 μmol) K2CO3 were added and dissolved in 2.5 ml toluene / water (4:1). The mixture was replaced with argon protection and stirred at room temperature for 5 min. Then, 29 μl (100 μmol) of 3.5 M tetrahydrofuran solution of trimethylcyclotriboroxine was added. The mixture was heated to 99°C and reacted for 4 h. The upper layer was extracted with ethyl acetate / water, and the mixture was dried and developed with petroleum ether / ethyl acetate (1:1) for PTLC separation to obtain 9 mg of the product with a yield of 60%. 1HNMR(400MHz, CDCl3-d1,δ):8.17(d,1H,C6'-H),8.02(s,1H,C3'-H),7.54(d,1H,C10'-H),7.32(d,1H,C5'-H),7.1 5(s,1H,C6-H),6.92(s,1H,C2-H),6.77(d,1H,C9'-H),6.42(s,1H,C4-H),2.49(s,3H,C4'-Me),2.27(s,3H,C5-Me).

[0137] 2. PDE4 inhibitory activity of synthetic compounds:

[0138] The activity of the synthesized compounds was tested, and the results showed that compounds 9 and 11 exhibited stronger PDE4 inhibitory activity than natural compound 1 at a concentration of 1 μM, as shown in Table 1 below.

[0139] Table 1 PDE4 inhibitory activity of some synthetic compounds

[0140]

[0141] In summary, the compounds 9 and 11 in the depsipeptide derivatives synthesized in the above embodiments of the present invention have simple structures and have stronger PDE4 inhibitory activity than the natural compound 1, which provides important indicative significance for the development of safer and more effective new PDE4 inhibitors.

[0142] The above description is only 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 in the protection scope of the present invention.

Claims

1. A derivative of a depsipeptide compound and a pharmaceutically acceptable salt thereof, characterized in that: Its general structural formula is as follows (I):

2. The depsipeptide derivative and its pharmaceutically acceptable salt according to claim 1, characterized in that: The derivatives are selected from the following compounds:

3. A depsipeptide derivative and a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The derivatives are selected from the following compounds:

4. A depsipeptide derivative and a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: The preparation method of compound 9 is: In a 250 ml round-bottom flask, 500 mg of 3-hydroxy-4-methoxybenzoic acid was added, and 150 ml of dimethyl sulfoxide was added to dissolve it. Then, 820 mg of K2CO3 was added, and then 444 μl of ethyl bromide was added dropwise. After reacting for 8 hours, the mixture was extracted with ethyl acetate, washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed using petroleum ether / ethyl acetate as eluent, and 49 mg of the product was added with 73 mg of EDCI, 47 mg of HOBT, and 31 mg of 3-amino-5-methylphenol. The mixture was stirred and reacted overnight. The upper layer was extracted with ethyl acetate / water, and after being spin-dried, it was developed with petroleum ether / ethyl acetate (1:1) for PTLC separation to obtain compound 9.

5. The depsipeptide derivative and its pharmaceutically acceptable salt according to claim 3, characterized in that: The preparation method of compound 11 is: In a 250 ml round-bottom flask, 500 mg of 3-hydroxy-4-methoxybenzoic acid was added, and 150 ml of dimethyl sulfoxide was added to dissolve it. Then, 820 mg of K2CO3 was added, and then 637 μl of bromocyclopentane was added dropwise. After reacting for 8 h, the mixture was extracted with ethyl acetate, washed with saturated aqueous NaCl solution, and the organic phase was dried over anhydrous Na2SO4. Silica gel column chromatography was performed using petroleum ether / ethyl acetate as eluent. 53 mg of the product was added with 65 mg of EDCI and 42 mg of HOBT, and mixed with 28 mg of 3-amino-5-methylphenol, and the mixture was reacted overnight. The upper layer was extracted with ethyl acetate / water, and the mixture was developed with petroleum ether / ethyl acetate and separated by PTLC to obtain compound 11.

6. Use of a depsipeptide derivative and a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating psoriasis.

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