Catechol ether compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a catechol ether compound as well as a pharmaceutical composition and application thereof. The structure of the compound is as shown in a formula I, the compound further comprises pharmaceutically acceptable salt of the compound, the compound has PDE4 inhibition and antioxidation dual functions, has inhibition and removal effects on PDE4 and free radical DPPH at the same time at the micromolar concentration level, shows anti-inflammatory and antioxidative stress dual effects in vivo and in vitro, and can be used for preparing a medicine for preventing and treating PDE4 and free radical DPPH. Therefore, the compound has a wide application prospect in the aspect of treating diseases related to inflammation and oxidative stress. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a catechol ether compound, its pharmaceutical composition and application, and in particular to a catechol ether compound having dual effects of PDE inhibition and antioxidant, its pharmaceutical composition and application. Background Art

[0002] Cyclic nucleotide phosphodiesterases (PDEs) are a unique class of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to 5'-AMP and 5'-GMP. The physiological function of PDE4 is to hydrolyze cyclic adenosine monophosphate (cAMP) to 5'-AMP. It is involved in a variety of physiological processes and is a drug treatment target for a variety of inflammatory diseases.

[0003] PDE4 inhibitors have therapeutic effects on autoimmune and inflammatory diseases, mainly including pneumonia, dermatitis, atopic dermatitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, autoimmune inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), sepsis, multiple sclerosis, etc. PDE4 inhibitors already have drugs for treating COPD in respiratory diseases. Drugs for asthma, pulmonary fibrosis, etc. are in the clinical research stage. In addition, in recent years, PDE4 inhibitors have also shown potential applications in the treatment of cardiovascular and cerebrovascular diseases. There are research reports on the therapeutic effects of PDE4 inhibitors on cardiovascular and cerebrovascular diseases including atherosclerosis, ischemia-reperfusion injury, ischemic stroke, vascular cognitive impairment, etc., as well as mental diseases including depression, anxiety, etc.; neurodegenerative diseases including Alzheimer's disease, idiopathic Parkinson's disease, etc.

[0004] Although PDE4 inhibitors have great application potential in the treatment of the above diseases, currently marketed and in-research PDE4 inhibitors generally have the side effect of vomiting. Developing PDE4 inhibitors with better tolerance and therapeutic effects is a key technical problem in this field. Developing multifunctional / multitarget PDE4 inhibitors to achieve a synergistic pharmacological effect and a therapeutic effect of enhancing efficacy and reducing toxicity is an important technical means to solve this technical problem.

[0005] Oxidative stress and inflammation coexist and are inseparable in many diseases. Free radicals are important factors leading to oxidative stress and inflammation and are closely related to the occurrence and development of a variety of diseases. Free radical scavengers, as antioxidants and tissue protectants, have broad application prospects in the treatment of cardiovascular and cerebrovascular diseases closely related to free radicals. Edaravone is the only marketed free radical scavenger drug at present. As a neuroprotective agent, it is widely used clinically in the treatment of acute ischemic stroke. In recent years, a drug Radicava with the same composition as edaravone has been approved for marketing for the treatment of amyotrophic lateral sclerosis.

[0006] In addition, edaravone, as a free radical scavenger, also has a protective effect in many disease and tissue injury animal models such as myocardial, pulmonary, gastrointestinal, hepatic, and renal injuries, has a therapeutic effect on cardiovascular diseases such as acute myocardial infarction, atherosclerosis, and heart failure, and has a protective effect on the heart, blood vessels, and brain by scavenging free radicals, anti-apoptosis, anti-necrosis, and anti-cytokine effects. Therefore, new free radical scavengers have great application potential and clinical needs in the field of cardiovascular and cerebrovascular diseases. SUMMARY OF THE INVENTION

[0007] OBJECT OF THE INVENTION: The first object of the present invention is to provide a catechol ether compound, the second object is to provide a pharmaceutical composition containing the compound, and the third object is to provide an application of the compound and its pharmaceutical composition in the preparation of PDE inhibitor drugs.

[0008] TECHNICAL SOLUTION: The catechol ether compound of the present invention has the structure of formula I, and also includes its pharmaceutically acceptable salts:

[0009]

[0010] Wherein:

[0011] R 1 、R 2 are selected from C1-C4 alkyl, C1-C4 haloalkyl, 3-6 membered cycloalkyl, C1-C4 alkyl substituted with 3-6 membered cycloalkyl;

[0012] R 3 、R 4 、R 5 are selected from hydrogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, amino, halogen;

[0013] Ring A does not exist or is selected from a 5-6 membered heterocyclic ketone containing one N, O, S, and the heterocyclic ketone has at least one ketone carbonyl.

[0014] Preferably, the catechol ether compound has the structure of formula II or formula III:

[0015]

[0016] Wherein:

[0017] R 1 、R 2 are selected from C1-C4 alkyl, C1-C4 haloalkyl, 3-5 membered cycloalkyl, C1-C4 alkyl substituted with 3-5 membered cycloalkyl;

[0018] R 3 、R4 and R 5 is selected from hydrogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, amino, halogen, and among R 3 and R 4 and R 5 at most two are selected from the same substituents.

[0019] More preferably, in the said structure:

[0020] R 1 and R 2 are selected from C1-C4 alkyl, C1-C4 fluoroalkyl, 3-5 membered cycloalkyl, C1-C4 alkyl substituted by 3-5 membered cycloalkyl;

[0021] R 3 and R 4 and R 5 are selected from hydrogen, hydroxyl, and among R 3 and R 4 and R 5 at most two are selected from the same substituents.

[0022] Even more preferably, in the said structure:

[0023] R 1 and R 2 are selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclopentyl, cyclopropylmethyl.

[0024] Even more preferably, when the compound has the structure of formula III, any one of R 3 and R 4 is hydroxyl;

[0025] When the compound has the structure of formula II, any one of R 3 and R 4 and R 5 is hydroxyl or R 3 and R 4 and R 3 and R 5 and R 4 and R 5 are all hydroxyl.

[0026] Most preferably, the catechol ether compounds are selected from any one of the following compounds:

[0027]

[0028]

[0029] Oxidative stress and inflammation are closely related pathophysiological processes, especially in PDE4-related central nervous, cardiovascular, and immune system diseases. One of these two processes can easily be induced by the other. On the one hand, inflammation can lead to excessive oxidative stress. On the other hand, some free radicals can initiate intracellular signal cascades and enhance the expression of pro-inflammatory cytokines. PDE4 inhibitors act on the cAMP / PKA-CREB-BDNF signaling pathway, have neuroprotective and anti-neuroinflammatory effects, and can improve cognitive dysfunction after stroke. Accordingly, the present invention designed and synthesized a class of bifunctional molecules with phosphodiesterase 4 inhibitory activity and antioxidant activity, which can play a therapeutic role in stroke and other central diseases related to nerve injury, degeneration, and inflammation through multiple effects such as free radical scavenging, increasing the neuroprotective factor BDNF, inhibiting neuroinflammation, and improving cognition.

[0030] The synthetic routes and methods of the compounds described in the present invention are as follows:

[0031] Method 1:

[0032] Four bromophenol raw materials, namely 3,4-dihydroxybromobenzene, 3,5-dihydroxybromobenzene, 4-hydroxybromobenzene, or 3-hydroxybromobenzene, react with the 3,4-dialkoxybenzaldehyde intermediate in a triethylamine solution containing acetic acid and triphenylphosphine by heating until the reaction is complete. Extract with ethyl acetate / water, combine the organic phases, remove water with anhydrous sodium sulfate, filter and concentrate the organic phase, and separate by silica gel column chromatography with petroleum ether / ethyl acetate to obtain stilbene series compounds.

[0033]

[0034] Method 2:

[0035] 4-Hydroxyindolinone reacts with the 3,4-dialkoxybenzaldehyde intermediate in a piperidine ethanol solution by heating until the reaction is complete. Extract with ethyl acetate / water, combine the organic phases, remove water with anhydrous sodium sulfate, filter and concentrate the organic phase, and separate by silica gel column chromatography with petroleum ether / ethyl acetate to finally obtain benzylidene-indol-2-one series compounds.

[0036]

[0037] Wherein, the pharmaceutically acceptable salt is a salt formed by the compound and an acid selected from any one of the following: hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, ferulic acid.

[0038] "Pharmaceutically acceptable salts" refer to salts of a compound prepared from a compound having specific substituents with a relatively non-toxic acid or base. When a compound contains a relatively acidic functional group, the base addition salt can be obtained by contacting the free form of such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When a compound contains a relatively basic functional group, the acid addition salt can be obtained by contacting the free form of such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, where the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates), sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, etc.; and organic acid salts, where the organic acids include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and similar acids; organic acid salts also include salts of organic acids such as amino acids (such as arginine, etc.), glucuronic acid, etc. When certain specific compounds contain both basic and acidic functional groups, they can thus be converted into either base or acid addition salts. Preferably, the salt is contacted with a base or an acid in a conventional manner, and then the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0039] "Pharmaceutically acceptable salts" can be synthesized from parent compounds containing acid radicals or basic groups by conventional chemical methods. Generally, the preparation method of such salts is to react these compounds in the form of free acids or bases with a stoichiometric amount of an appropriate base or acid in water, an organic solvent or a mixture of both. Generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0040] The pharmaceutical composition described in the present invention comprises the catechol ether compounds described in the present invention and a pharmaceutically acceptable carrier.

[0041] The pharmaceutical composition also contains a pharmaceutically acceptable carrier.

[0042] "Pharmaceutically acceptable carrier" can be an excipient widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional drug composition, and can also provide methods to enable the active ingredient to dissolve at a desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredient after the subject receives the composition administration. The pharmaceutical excipients described above can be inert fillers, or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients described above can include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesive agent, glidant, wetting agent, gelling agent, absorption retardant, dissolution inhibitor, enhancer, adsorbent, buffer, chelating agent, preservative, colorant, flavoring agent and sweetening agent.

[0043] The drug composition described in the present invention can be prepared by any method known to those skilled in the art according to the disclosed content. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.

[0044] The drug composition described in the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The drug composition of the present invention can also be a controlled-release or sustained-release dosage form (such as liposomes or microspheres). Examples of solid oral preparations include but are not limited to powders, capsules, cachets, soft capsules and tablets. Examples of liquid preparations for oral or mucosal administration include but are not limited to suspensions, emulsions, elixirs and solutions. Examples of topical preparations include but are not limited to emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of preparations for parenteral administration include but are not limited to injection solutions, dry powder preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, injection suspensions and injection emulsions. Examples of other suitable preparations of the drug composition include but are not limited to eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0045] The catechol ether compound or its drug composition described in the present invention is applied to the preparation of PDE inhibitor drugs.

[0046] Preferably, the drug is an antioxidant and anti-inflammatory drug, having the dual functions of PDE4 inhibition and antioxidant. More preferably, it is a drug for preventing and / or treating chronic obstructive pulmonary disease, psoriasis, arthritis disease, stroke, amyotrophic lateral sclerosis.

[0047] Beneficial effects: Compared with the prior art, the present invention has the following remarkable advantages:

[0048] This class of compounds has dual functions of PDE4 inhibition and antioxidant activity. At a concentration of 10 μmol / L, the inhibition rates for PDE4 and DPPH are optimally greater than 50%. At a concentration of 100 μmol / L, its antioxidant activity is significantly better than that of edaravone, with definite curative effects. It exerts a synergistic effect through antioxidant stress and anti-inflammatory actions, and has broad application prospects. Detailed implementation methods

[0049] The technical solutions of the present invention will be further described below in conjunction with the embodiments.

[0050] Example 1

[0051]

[0052] 3,4-Dihydroxybromobenzene (1 mmol) and 3-cyclopentyloxy-4-methoxystyrene (1 mmol) were heated and reacted in a triethylamine solution containing palladium acetate (0.04 mmol) and triphenylphosphine (0.08 mmol) at 80 °C for 36 hours until the reaction was complete. The mixture was extracted three times with ethyl acetate / water, and the organic phases were combined. After drying with anhydrous sodium sulfate, filtering, and concentrating the organic phase, the product was obtained by silica gel column chromatography with petroleum ether / ethyl acetate. 1 H NMR (300 MHz, DMSO) δ 9.07 (s, 1H), 8.92 (s, 1H), 7.40 (d, J = 4.3 Hz, 1H), 7.12 (d, J = 1.9 Hz, 1H), 7.05 - 6.96 (m, 4H), 6.71 (d, J = 8.2 Hz, 2H), 4.92 - 4.83 (m, 1H), 3.75 (s, 3H), 1.95 - 1.88 (m, 2H), 1.73 (s, 6H), 1.58 (s, 2H).

[0053] Example 2

[0054]

[0055] Prepared according to the method of Example 1 using 3-cyclopentyloxy-4-methoxystyrene and 3,5-dihydroxybromobenzene. 1 HNMR (300 MHz, DMSO) δ 9.25 (s, 2H), 7.16 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 1.9 Hz, 1H), 7.01 - 6.83 (m, 3H), 6.41 (d, J = 2.1 Hz, 2H), 6.13 (t, J = 2.1 Hz, 1H), 4.93 - 4.82 (m, 1H), 3.75 (s, 3H), 1.97 - 1.84 (m, 2H), 1.79 - 1.66 (m, 4H), 1.64 - 1.51 (m, 2H).

[0056] Example 3

[0057]

[0058] Prepared according to the method of Example 1 using 3-cyclopentyloxy-4-methoxystyrene and 3-hydroxybromobenzene. 1 HNMR(300MHz,DMSO)δ9.40(s,1H),7.19(d,J=2.0Hz,1H),7.16 - 7.07(m,2H),7.06 - 6.91(m,5H),6.66(ddd,J=8.0,2.4,1.0Hz,1H),4.87(td,J=5.9,2.8Hz,1H),3.76(s,3H),1.97 - 1.84(m,2H),1.80 - 1.68(m,4H),1.64 - 1.52(m,2H).

[0059] Example 4

[0060]

[0061] Prepared according to the method of Example 1 using 3-cyclopentyloxy-4-methoxystyrene and 4-hydroxybromobenzene. 1 HNMR(300MHz,DMSO)δ9.53(s,1H),7.42 - 7.35(m,2H),7.13(d,J=2.0Hz,1H),7.03(dd,J=8.3,2.0Hz,1H),7.01 - 6.86(m,3H),6.76(d,J=8.6Hz,2H),4.87(td,J=5.9,3.0Hz,1H),3.75(s,3H),1.97 - 1.84(m,2H),1.81 - 1.67(m,4H),1.64 - 1.51(m,2H).

[0062] Example 5

[0063]

[0064] Prepared according to the method of Example 1 using 3,4-dimethoxystyrene and 4-hydroxybromobenzene. 1 HNMR(300MHz,DMSO)δ9.54(s,1H),7.39(d,J=8.7Hz,2H),7.18(d,J=2.0Hz,1H),7.03(d,J=6.8Hz,1H),6.99 - 6.91(m,3H),6.78 - 6.74(m,2H),3.81(s,3H),3.76(s,3H).

[0065] Example 6

[0066]

[0067] Prepared according to the method of Example 1 using 3-ethoxy-4-methoxystyrene and 4-hydroxybromobenzene. 1 HNMR(300MHz,DMSO)δ9.53(d,J=0.9Hz,1H),7.38(d,J=8.4Hz,2H),7.16(d,J=1.9Hz,1H),7.03(d,J=9.1Hz,1H),6.97-6.88(m,3H),6.76(d,J=8.6Hz,2H),4.06(q,J=7.0Hz,2H),3.76(s,3H),1.35(t,J=7.0Hz,3H).

[0068] Example 7

[0069]

[0070] Prepared according to the method of Example 1 using 3-isopropoxy-4-methoxystyrene and 4-hydroxybromobenzene. 1 HNMR(300MHz,DMSO)δ9.54(s,1H),7.38(d,J=8.6Hz,2H),7.16(d,J=2.0Hz,1H),7.05(dd,J=8.3,1.9Hz,1H),7.03-6.86(m,3H),6.76(d,J=8.5Hz,2H),4.61(p,J=6.0Hz,1H),3.75(s,3H),1.28(s,3H),1.26(s,3H).

[0071] Example 8

[0072]

[0073] Prepared according to the method of Example 1 using 3-cyclopropylmethoxy-4-methoxystyrene and 4-hydroxybromobenzene. 1 HNMR(300MHz,DMSO)δ9.53(s,1H),7.38(d,J=8.7Hz,2H),7.14(d,J=1.9Hz,1H),7.04-6.96(m,4H),6.75(d,J=8.6Hz,2H),3.85(d,J=7.0Hz,2H),3.77(s,3H),1.40-1.18(m,2H),0.68-0.52(m,2H),0.44-0.29(m,2H).

[0074] Example 9

[0075]

[0076] Prepared according to the method of Example 1 using 3,4 - diethoxystyrene and 4 - hydroxybromobenzene. 1 HNMR(300MHz, DMSO) δ9.54(s, 1H), 7.38(d, J = 8.6Hz, 2H), 7.16(d, J = 2.0Hz, 1H), 7.05 - 6.88(m, 4H), 6.76(d, J = 8.6Hz, 2H), 4.11 - 3.97(m, 4H), 1.33(q, J = 7.0Hz, 6H).

[0077] Example 10

[0078]

[0079] Prepared according to the method of Example 1 using 3 - cyclopentyloxy - 4 - difluoromethoxy - styrene and 4 - hydroxybromobenzene. 1 HNMR(300MHz, DMSO) δ9.63(s, 1H), 7.43(d, J = 8.6Hz, 2H), 7.29(d, J = 1.4Hz, 1H), 7.22(s, 0.26H, CF 2 H), 7.19 - 7.07(m, 3H), 7.05 - 6.94(m, 1.50H, ArH and CF 2 H), 6.78(d, J = 8.5Hz, 2H), 6.72(s, 0.26H, CF 2 H), 5.05 - 4.81(m, 1H), 2.02 - 1.87(m, 2H), 1.82 - 1.67(m, 4H), 1.68 - 1.56(m, 2H).

[0080] Example 11

[0081]

[0082] Prepared according to the method of Example 1 using 3 - ethoxy - 4 - difluoromethoxy - styrene and 4 - hydroxybromobenzene. 1 HNMR(300MHz, DMSO) δ9.64(s, 1H), 7.42(d, J = 8.6Hz, 2H), 7.32(d, J = 1.6Hz, 1H), 7.30(s, 0.26H, CF 2 H), 7.22 - 7.09(m, 3H), 7.06 - 6.96(m, 1.50H, CH and CF 2 H), 6.82 - 6.75(m, 2.25H, ArH and CF 2H), 4.15 (d, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H).

[0083] Example 12

[0084]

[0085] Prepared according to the method of Example 1 using 3 - isopropoxy - 4 - difluoromethoxy - styrene and 4 - hydroxybromobenzene. 1 HNMR(300MHz, DMSO) δ 9.63 (s, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.33 (s, 1H), 7.26 (s, 0.27H, CF 2 H), 7.20 - 7.09 (m, 3H), 7.04 - 6.95 (m, 1.50H, CH and CF 2 H), 6.82 - 6.74 (m, 2.25H, ArH and CF 2 H), 4.72 (hept, J = 6.0 Hz, 1H), 1.32 (s, 3H), 1.30 (s, 3H).

[0086] Example 13

[0087]

[0088] Prepared according to the method of Example 1 using 3 - cyclopropylmethoxy - 4 - difluoromethoxy - styrene and 4 - hydroxybromobenzene. 1 H NMR(300MHz, DMSO) δ 9.63 (s, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.32 - 7.28 (m, 1.25H, ArH and CF 2 H), 7.21 - 7.09 (m, 3H), 7.06 - 6.95 (m, 1.50H, CH and CF 2 H), 6.82 - 6.75 (m, 2.25H, ArH and CF 2 H), 3.95 (d, J = 7.0 Hz, 2H), 1.29 - 1.22 (m, 1H), 0.64 - 0.54 (m, 2H), 0.42 - 0.31 (m, 2H).

[0089] Example 14

[0090]

[0091] 5-Hydroxyindol-2-one (1 mmol) and 3-cyclopentyloxy-4-methoxybenzaldehyde (1 mmol) were heated and reacted in an ethanol solution containing piperidine (0.02 ml) at 80 °C for 12 hours until the reaction was complete. The mixture was extracted three times with ethyl acetate / water, and the organic phases were combined. The water was removed with anhydrous sodium sulfate, and then the organic phase was filtered and concentrated. The product was obtained by silica gel column chromatography with petroleum ether / ethyl acetate. 1 HNMR(400MHz,DMSO)δ10.23(s,1H),8.98(s,1H),8.72(d,J=2.0Hz,1H),7.75(dd,J=8.5,2.0Hz,1H),7.59(s,1H),7.09(s,1H),7.04(d,J=8.5Hz,1H),6.62(s,2H),4.87-4.80(m,1H),3.83(s,3H),2.06-1.98(m,2H),1.80-1.70(m,4H),1.62-1.56(m,2H).

[0092] Example 15

[0093]

[0094] Prepared according to the method of Example 14 using 5-hydroxyindol-2-one and 3,4-dimethoxybenzaldehyde. 1 H NMR(300MHz,DMSO)δ10.26(s,1H),9.00(s,1H),8.71(d,J=2.0Hz,1H),7.84(dd,J=8.6,2.0Hz,1H),7.61(s,1H),7.40(dd,J=8.6,7.4Hz,1H),7.09-7.02(m,2H),6.62(d,J=1.4Hz,2H),3.84(s,3H),3.83(s,3H).

[0095] Example 16

[0096]

[0097] Prepared according to the method of Example 14 using 5-hydroxyindol-2-one and 3-ethoxy-4-methoxybenzaldehyde. 1 HNMR(400MHz,DMSO)δ10.23(s,1H),8.98(s,1H),8.69(s,1H),7.81(d,J=8.5Hz,1H),7.59(s,1H),7.15-6.98(m,2H),6.63(s,2H),4.10(q,J=7.0Hz,2H),3.84(s,3H),1.38(t,J=7.1Hz,3H).

[0098] Example 17

[0099]

[0100] Prepared according to the method of Example 14 using 5-hydroxyindol-2-one and 3-isopropoxy-4-methoxybenzaldehyde. 1 H NMR(300MHz,DMSO)δ10.26(s,1H),9.02(s,1H),8.73(d,J=2.1Hz,1H),7.78(dd,J=8.6,2.0Hz,1H),7.61(s,1H),7.11-7.03(m,2H),6.64(s,2H),4.63(p,J=6.1Hz,1H),3.84(s,3H),1.34(s,3H),1.32(s,3H).

[0101] Example 18

[0102]

[0103] Prepared according to the method of Example 14 using 5-hydroxyindol-2-one and 3-cyclopropylmethoxy-4-methoxybenzaldehyde. 1 H NMR(300MHz,DMSO)δ10.26(s,1H),9.02(s,1H),8.67(d,J=2.0Hz,1H),7.83(dd,J=8.6,1.9Hz,1H),7.60(s,1H),7.09-7.04(m,2H),6.63(s,2H),3.88-3.84(m,5H),1.32-1.29(m,1H),0.63-0.59(m,2H),0.37-0.33(m,2H).

[0104] Example 19

[0105]

[0106] Prepared according to the method of Example 14 using 5-hydroxyindol-2-one and 3,4-diethoxybenzaldehyde. 11H NMR (300 MHz, DMSO) δ 10.24 (s, 1H), 8.99 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.6, 2.0 Hz, 1H), 7.58 (s, 1H), 7.08 (t, J = 1.4 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 1.4 Hz, 2H), 4.91 (d, J = 6.5 Hz, 1H), 4.09 (q, J = 6.9 Hz, 2H), 2.01 - 1.89 (m, 2H), 1.82 - 1.66 (m, 4H), 1.65 - 1.54 (m, 2H), 1.37 (t, J = 7.0 Hz, 3H).

[0107] Example 20

[0108]

[0109] Prepared according to the method of Example 14 using 5-hydroxyindol-2-one and 3-cyclopentyloxy-4-difluoromethoxy-benzaldehyde. 1 1H NMR (300 MHz, DMSO) δ 10.34 (s, 1H), 9.07 (s, 1H), 8.72 (d, J = 1.9 Hz, 1H), 7.74 (dd, J = 8.4, 1.9 Hz, 1H), 7.66 (s, 1H), 7.37 (s, 0.26H, CF 2 H), 7.22 (d, J = 8.3 Hz, 1H), 7.12 (m, 1.50H, CH and CF 2 H), 6.87 (s, 0.25H, CF 2 H), 6.73 - 6.58 (m, 2H), 4.97 - 4.86 (m, 1H), 2.12 - 1.99 (m, 2H), 1.85 - 1.69 (m, 4H), 1.66 - 1.55 (m, 2H).

[0110] Example 21

[0111]

[0112] Prepared according to the method of Example 14 using 5-hydroxyindol-2-one and 3-ethoxy-4-difluoromethoxy-benzaldehyde. 1 1H NMR (300 MHz, DMSO) δ 10.33 (s, 1H), 9.08 (s, 1H), 8.68 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.44 (s, 0.27H, CF 2H), 7.30 - 7.07 (m, 2.50H, ArH and CF 2 H), 6.94 (s, 0.28H, CF 2 H), 6.65 (s, 2H), 4.17 (q, J=6.9 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H).

[0113] Example 22

[0114]

[0115] Prepared according to the method of Example 14 using 5 - hydroxyindol - 2 - one and 3 - isopropoxy - 4 - difluoromethoxy - benzaldehyde. 1 H NMR(300 MHz, DMSO) δ 10.33 (s, 1H), 9.08 (s, 1H), 8.71 (d, J=1.9 Hz, 1H), 7.74 (dd, J=8.5, 1.9 Hz, 1H), 7.66 (s, 1H), 7.40 (s, 0.31H, CF 2 H), 7.23 (d, J=8.3 Hz, 1H), 7.16 - 7.11 (m, 1.50H, ArH and CF 2 H), 6.90 (s, 0.28H, CF 2 H), 6.66 (d, J=2.1 Hz, 2H), 4.68 (p, J=6.1 Hz, 1H), 1.37 (s, 3H), 1.35 (s, 3H).

[0116] Example 23

[0117]

[0118] Prepared according to the method of Example 14 using 5 - hydroxyindol - 2 - one and 3 - cyclopropylmethoxy - 4 - difluoromethoxy - benzaldehyde. 1 H NMR(300 MHz, DMSO) δ 10.34 (s, 1H), 9.08 (s, 1H), 8.65 (d, J=1.9 Hz, 1H), 7.81 (dd, J=8.5, 1.9 Hz, 1H), 7.65 (s, 1H), 7.45 (s, 0.29H, CF 2 H), 7.28 - 7.18 (m, 1.50H, ArH andCF 2 H), 7.11 (d, J=1.9 Hz, 1H), 6.95 (s, 0.28H, CF 2H), 6.66 (d, J = 2.3 Hz, 2H), 3.96 (d, J = 7.1 Hz, 2H), 1.33 (dq, J = 7.3, 4.4, 3.7 Hz, 1H), 0.65 - 0.54 (m, 2H), 0.41 - 0.32 (m, 2H).

[0119] Example 24: Evaluation of the in vitro COX-2 inhibitory activity and DPPH radical scavenging activity of the example compounds

[0120] 1. Experimental method

[0121] Test method for the inhibitory activity of PDE4 enzyme activity: The specific operation is based on the instruction manual of the kit IMAP FP Explorer Kit (MOLECULAR DEVICES, Cat. No. R8124, Lot. No. 3171238). Add the buffer containing PDE4B1 (BPS, CatNo. 60041, Lot. No. 90520) to the 384-well plate containing the DMSO solution of the test compound, and incubate at room temperature for 15 min. Then add the FAM-cAMP substrate solution to the reaction solution plate containing the enzyme activity and the compound, and incubate at room temperature for 60 min. Finally, add the termination buffer and incubate at room temperature for 1 h. Test using a multifunctional microplate reader (PerkinElmer EnVision), and the fluorescence signal is tested at an excitation wavelength of 485 nM and an emission wavelength of 530 nM. The negative control experiment uses the buffer without PDE4B1 enzyme, and two parallel experiments are carried out for each test sample.

[0122] In vitro DPPH free radical scavenging experiment method: DPPH (2,2-diphenyl-1-picrylhydrazyl) was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. Add 100 μl of the methanol solution of DPPH (200 μM) to the 96-well plate, and then add 100 μl of the methanol solution containing the compound or the methanol blank solvent, and incubate at 37 °C for 30 min. The OD value at 515 nM is measured by a microplate reader.

[0123] 2. Experimental results

[0124] Table 1. Results of the inhibitory and scavenging activities of the example compounds on PDE4 and DPPH

[0125] Compound PDE4% Inhibition Rate (10 μM) DPPH% Scavenging Rate (40 μM) Example 1 ＞50％ ＞50％ Example 2 ＞50％ ＞50％ Example 3 ＞50％ ＞10％ Example 4 ＞50％ ＞20％ Example 5 ＞50％ ＞20％ Example 6 ＞50％ ＞20％ Example 7 ＞50％ ＞20％ Example 8 ＞50％ ＞20％ Example 9 ＞50％ ＞20％ Example 10 ＞50％ ＞20％ Example 11 ＞50％ ＞20％ Example 12 ＞50％ ＞20％ Example 13 ＞50％ ＞20％ Example 14 ＞50％ ＞50％ Example 15 ＞50％ ＞50％ Example 16 ＞50％ ＞50％ Example 17 ＞50％ ＞50％ Example 18 ＞50％ ＞50％ Example 19 ＞50％ ＞50％ Example 20 ＞50％ ＞50％ Example 21 ＞50％ ＞50％ Example 22 ＞50％ ＞50％ Example 23 ＞50％ ＞50％

[0126] As shown in Table 1, the compounds designed in the present invention all have PDE4 inhibitory activity and at the same time have free radical scavenging activity.

[0127] Example 25: Evaluation of the biological antioxidant effect of the example compounds

[0128] 1. Antioxidant effect evaluation method

[0129] To further clarify the antioxidant effect of the patented compound, we used a lipid peroxidation model of mouse liver, brain, and lung tissues induced by ferrous iron as a biological oxidative stress model. The level of lipid peroxidation product malondialdehyde (MDA) was used as an oxidative stress marker, and the inhibition rate of the compound on the production of MDA was calculated as an antioxidant activity index to test the antioxidant biological activity of the compound. After the mice were sacrificed, liver, brain, and lung tissues were taken, and tissue homogenates were prepared with 10% saline. Each 200 μl of tissue homogenate was used as a test sample, and the inducer FeCl 2 (1 mM), the free radical scavenger positive control drug edaravone, or the compound of the example (250 μM) were added successively, and incubated at 37 °C for 60 minutes. Then, a commercial MDA kit A003-2 (Nanjing Jiancheng Bioengineering Institute) was used to detect the level of malondialdehyde in the tissue homogenate according to the instructions, and the inhibition rate of the compound on the production of MDA was calculated.

[0130] 2. Experimental results

[0131] Table 2. Inhibitory effect of the compound of the example on the generation of lipid peroxidation product MDA in iron-induced liver, lung, and brain tissues

[0132]

[0133] As shown in Table 2, the compound designed by the present invention has significant antioxidant activity, which is superior to the free radical scavenging positive drug edaravone.

[0134] Example 25: Evaluation of the anti-inflammatory effect of the compound of the example

[0135] 1. Method for evaluating anti-inflammatory effect

[0136] RAW 264.7 cells were seeded into 96-well plates at a rate of 2 × 10 4 cells / well and cultured in a CO 2 2 cell incubator for 12 hours until the cell confluence reached about 80%. An inflammatory cell model was established by inducing RAW 264.7 cells with LPS at a final concentration of 10 ng / ml. The compound of the preventive example or the PDE4 inhibitor positive control drug rolipram was added 1 hour before LPS induction. After LPS induction for 12 hours, the cell culture medium was taken, centrifuged at 3500 rpm for 10 min at 4 °C, and the supernatant was collected for testing the content of the inflammatory cytokine TNF-α. According to the instructions of the mouse TNF-α ELISA kit, after incubation at 37 °C and washing the plate, the secondary antibody was added, incubated at 37 °C and washed the plate, the chromogenic agent was added and incubated at 37 °C, and finally the stop solution was added. The OD value at 450 nM was measured with an enzyme-linked immunosorbent assay reader.

[0137] 2. Experimental results

[0138] Table 3. Inhibitory effect of the compounds of the examples on the production of TNF-α by LPS-induced RAW264.7 cells

[0139] Compound Concentration (μM) TNF-α Inhibition Rate Rolipram 10 ＞20％ Example 11 10 ＞20％ Example 21 10 ＞20％

[0140] As shown in Table 3, the compounds designed in the present invention exhibited certain anti-inflammatory activities, comparable to the PDE4 inhibitor positive drug rolipram.

Claims

1. A catechol ether compound, characterized in that it has the structure of formula I and also includes its pharmaceutically acceptable salts: Wherein: R 1 、R 2 is selected from C1-C4 alkyl, C1-C4 haloalkyl, 3-6 membered cycloalkyl, C1-C4 alkyl substituted with 3-6 membered cycloalkyl; R 3 、R 4 、R 5 is selected from hydrogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, amino, halogen; Ring A does not exist or is selected from 5- to 6-membered heterocyclic ketones containing one N or O, and the heterocyclic ketone has at least one ketone carbonyl.

2. The catechol ether compound according to claim 1, characterized in that it has the structure of formula II or formula III: Wherein: R 1 、R 2 is selected from C1-C4 alkyl, C1-C4 haloalkyl, 3-5 membered cycloalkyl, C1-C4 alkyl substituted by 3-5 membered cycloalkyl; R 3 、 R 4 、 R 5 is selected from hydrogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, amino, halogen, and R 3 、 R 4 、 R 5 at most two of which are selected from the same substituents.

3. The catechol ether compound according to claim 2, characterized in that in the structure: R 1 、R 2 selected from C1-C4 alkyl, C1-C4 fluoroalkyl, 3-5 membered cycloalkyl, C1-C4 alkyl substituted with 3-5 membered cycloalkyl; R 3 、R 4 、R 5 is selected from hydrogen, hydroxyl, R 3 、R 4 、R 5 At most two of them are selected from the same substituents.

4. The catechol ether compound according to claim 3, characterized in that in the structure: R 1 、R 2 is selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclopentyl, cyclopropylmethyl.

5. The catechol ether compound according to claim 3, characterized in that When the compound has the structure of Formula III, any one of R 3 and R 4 is a hydroxyl group; When the compound has the structure of formula II, R 3 , R 4 , R 5 in any one of them is a hydroxyl group or R 3 and R 4 , R 3 and R 5 , R 4 and R 5 are all hydroxyl groups.

6. The catechol ether compound according to claim 1, characterized in that it is selected from the following compounds:

7. The catechol ether compound according to claim 1, characterized in that the pharmaceutically acceptable salt is a salt formed by the compound and an acid selected from any one of the following: hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, ferulic acid.

8. A pharmaceutical composition, characterized in that it contains the catechol ether compound according to claim 1 and a pharmaceutically acceptable carrier.

9. Use of the catechol ether compound according to claim 1 or the pharmaceutical composition according to claim 8 in the preparation of PDE inhibitors and free radical scavenger drugs.

10. The use according to claim 9, characterized in that the drug is a drug for preventing and / or treating chronic obstructive pulmonary disease, psoriasis, arthritis diseases, stroke, amyotrophic lateral sclerosis.

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