CN116675673A - 3, 5-bis (aryl) -4-methylphenidate derivatives, preparation method and application thereof - Google Patents
3, 5-bis (aryl) -4-methylphenidate derivatives, preparation method and application thereof Download PDFInfo
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- CN116675673A CN116675673A CN202310665571.6A CN202310665571A CN116675673A CN 116675673 A CN116675673 A CN 116675673A CN 202310665571 A CN202310665571 A CN 202310665571A CN 116675673 A CN116675673 A CN 116675673A
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- bis
- aryl
- nmr
- dmso
- compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Animal Behavior & Ethology (AREA)
- Rheumatology (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The application discloses a 3, 5-bis (aryl) -4-methylphenidate derivative, a preparation method and application thereof. The 3, 5-bis (aryl) -4-piperidone derivatives of the present application exhibit good anti-inflammatory activity and are useful for the treatment of inflammatory diseases such as rheumatoid arthritis.
Description
Technical Field
The application relates to the technical field of pharmaceutical chemistry, in particular to a 3, 5-bis (aryl) -4-methylphenidate derivative, a preparation method and application thereof.
Background
Rheumatoid Arthritis (RA) is an autoimmune disease characterized by synovial cell proliferation, joint swelling, and joint pain. The clinical symptoms of RA are mainly inflammatory lesions of systemic polyarthritis, and the onset of the disease has the characteristics of chronicity, peripherally, symmetry and the like. As the condition progresses, rheumatoid arthritis affects multiple other organs in other parts of the body, such as the heart, lungs, and kidneys. The nuclear factor- κb (NF- κb) and mitogen-activated protein kinase (MAPK) signaling pathways are classical inflammatory pathways that promote osteoclast proliferation and differentiation, causing bone erosion and bone destruction, playing an important role in the progression of RA. In studies of synovial cells in RA patients, inhibition of NF- κB pathway activation may inhibit the progression of arthritis and pathological damage to joints. The MAPK pathway is divided into three components: extracellular signal regulated kinase (ERK), c-Jun n-terminal kinase (JNK) and p38 MAPK. JNK and p38 are mainly activated by stress stimuli or inflammatory cytokines. They all affect the development of inflammation. Elevated NF- κB expression in synovial tissue of RA patients is associated with overexpression of inflammatory mediators such as TNF- α, IL-6, and the like. Studies have shown that p38 regulates the production of cytokines such as macrophage TNF- α, while JNK inhibitors are effective in reducing bone destruction in adjuvanted arthritic rats. The pathogenesis of RA involves chronic inflammation, various inflammatory stimuli (e.g., bacterial endotoxin Lipopolysaccharide (LPS) and other foreign antigens). Inflammatory stimuli can induce macrophages to migrate to the contact site to produce TNF- α, IL-6, promoting inflammatory responses, so studies using macrophage activation can reflect the inflammatory process of RA.
Curcumin is a natural component with anti-inflammatory and anti-cancer activity, including anti-Rheumatoid Arthritis (RA), but its clinical application is limited by its unstable structure, low bioavailability, false positive, etc. Therefore, based on the pharmacodynamic structure of curcumin and literature reports, optimization of curcumin analogues is receiving a great deal of attention. Of these, (3E, 5E) -3, 5-di (arylalkene) -4-piperidone (BAP) is typical, and has excellent anti-inflammatory and antitumor activities by inhibiting NF- κB activation. For example, fluoro-substituted 3, 5-bis (2-fluorobenzenediene) -4-piperidone (EF 24, FIG. 1) can inhibit tumor growth and metastasis by inhibiting NF- κB signaling. Curcumin allylated monocarbonyl analogs show potent anti-inflammatory activity against LPS-induced Acute Lung Injury (ALI) in rats by inhibiting the expression of IL-6, IL-1B, TNF-a and VCAM-1 in Beas-2B cells.
Disclosure of Invention
The application aims to: the application provides a 3, 5-bis (aryl) -4-methylphenidate derivative, a preparation method and application thereof, which are used for solving the problems in the prior art.
The technical scheme is as follows: the application provides a 3, 5-bis (aryl) -4-methylphenidate derivative, which has the following structural formula:
wherein R is 1 Is phenyl, said phenyl being substituted with one or more R a Group substitution, R a Selected from halogen, C 1 C8 alkyl or C 1 ~C 8 A haloalkyl group; r is R 2 Is a pyridyl group.
Preferably, said R a Selected from F or trifluoromethyl.
Preferably, said R 1 Selected from the following groups:
。
preferably, said R 2 Is 3-pyridyl or 4-pyridyl.
The present application further provides a process for the preparation of 3, 5-bis (aryl) -4-methylphenidate derivatives comprising the steps of:
adding into solventn-methylpiperidone and->In the presence of a catalyst, the reaction is carried out to obtain a product, wherein the reaction formula is as follows:
in some embodiments, the 3, 5-bis (aryl) -4-methylphenidate derivatives of the present application are synthesized as follows:
the substituents of compounds 2a-s, compounds 4a-s, and compounds 5a-s are shown below:
preferably, the product is purified by silica gel column chromatography, the solvent of the column chromatography is in volume ratio of
Petroleum ether, ethyl acetate and methanol in the ratio of 8-10 to 1 to obtain the purified product.
Preferably, the solvent comprises one or more of methanol and acetic acid.
Preferably, the catalyst is sodium hydroxide or hydrogen chloride.
The application further provides a pharmaceutical composition comprising the 3, 5-bis (aryl) -4-methylphenidate derivative or the 3, 5-bis (aryl) -4-methylphenidate derivative prepared by the preparation method.
The pharmaceutical composition of the application comprises one or more of the 3, 5-bis (aryl) -4-methylphenidate derivatives. The pharmaceutical composition of the application can be one or more of the 3, 5-bis (aryl) -4-methylphenidate derivatives described in any one of the above technical schemes and other compounds, or one or more of the 3, 5-bis (aryl) -4-methylphenidate derivatives described in any one of the above technical schemes.
The application further provides application of the 3, 5-bis (aryl) -4-methylphenidate derivative or the 3, 5-bis (aryl) -4-methylphenidate derivative prepared by the preparation method in preparation of anti-inflammatory drugs.
The application further provides application of the 3, 5-bis (aryl) -4-methylphenidate derivative or the 3, 5-bis (aryl) -4-methylphenidate derivative prepared by the preparation method in preparation of medicines for treating rheumatoid arthritis.
Description of the terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patent documents, published disclosures, etc. to which the application is referred are incorporated by reference in their entirety unless otherwise indicated. The same term has multiple definitions as in the present application, and the definitions in this section control.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claims. It is noted that, in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is also noted that "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," "include," and the like are not limiting.
"substituted" means that a hydrogen atom is replaced with a substituent.
The term "halogen", "halo" as used herein refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
The term "haloalkyl" as used herein refers to a straight or branched alkyl group substituted with halogen (preferably fluorine, chlorine, bromine, iodine), wherein "alkyl" is as defined above.
Examples of "haloalkyl" as used herein include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl.
The beneficial effects are that: the 3, 5-bis (aryl) -4-piperidone derivatives of the present application exhibit good anti-inflammatory activity and are useful for the treatment of inflammatory diseases such as rheumatoid arthritis.
Drawings
FIG. 1 shows a nuclear magnetic pattern of the compound BAP 4b of the present application, wherein A is 1 HNMR hydrogen spectrogram, B is 13 CNMR carbon profile.
FIG. 2 shows the results of cytotoxicity and anti-inflammatory activity tests of a compound of the application BAP 4k, wherein A shows the structure of the BAP 4k compound and B shows the inhibition of the anti-inflammatory factor IL-6 by the compound BAP 4k, expressed as P<0.1; * Represent P<0.01, compared with the control group, # # represents P<0.001, panel c shows the results of flow cytometry detection after incubation of cells with compound BAP4 k;
FIG. 3 shows the results of activated expression of the compounds BAP 4k of the present application in inhibiting NF- κB and MAPK, wherein A is LPS-induced RAW264.7 cellsIn which, the expression results of IkBα and P65 related to NF-kB, B-C are the expression results of P-IkBα and IkBα, P-P65 and P65, D is the expression results of MAPK related JNK, ERK, P38 protein and phosphorylation in RAW264.7 cell induced by LPS, E-G is the expression results of P-ERK, ERKp-JNK, JNK, P-P38 and P38, compared with LPS group, the expression results of P is shown in the following formula<0.05; * Represent P<0.01; * Represents P<0.001. Compared with the control group: # # represents P<0.001;
FIG. 4 is a graph showing the effect of the compound of the present application on BAP 4k on paw swelling, arthritis index and body weight of rats, wherein, graph A is a schematic diagram of the process of arthritis model establishment, and graphs B-D are the results of the changes of the paw swelling degree, arthritis index and body weight of rats, respectively;
FIG. 5 shows the pathological effect of the compound BAP 4k of the present application on the joints of rats, wherein, A shows the staining result of the ankle joints HE of rats, B shows the inflammation evaluation result of joint tissues, C shows the effect of the compound BAP 4k on the spleen of immune organs, D shows the effect of the compound BAP 4k on the thymus of immune organs, the data are mean value.+ -. Standard deviation, n=3, compared with the control group, ## p<0.01, ### p<0.001, compared to the AIA group, * p<0.1, ** p<0.01, *** p<0.001。
Detailed Description
1. Test materials and test methods
1.1 chemical reagents were purchased from Le research technologies Co., ltd (Beijing) and BID medicine technologies Co., ltd (Shanghai).
1.2 test methods
(1) In dimethyl sulfoxide (DMSO-d 6) solvent with Tetramethylsilane (TMS) as internal standard, use is made of 1 HNMR, bruker Avance 400MHz or 600MHz spectrometer and 13 the spectra were recorded by C-NMR, bruker Avance 100MHz or 150MHz spectrometer. Chemical shift (δ) is in ppm and coupling constant (J) is in Hz. All melting factors were measured on a digital melting factor meter.
(2) Cytotoxicity experiment: mouse RAW264.7 cells were supplied by procall (ChinaWuhan, china) and cultured in dmem+10% fetal bovine serum and 1% streptomycin/penicillin antibiotic complete medium. Cells in the logarithmic growth phase were taken and subjected to the following test. Cytotoxicity was detected using CCK-8 according to the manufacturer's instructions. Cells were grown and treated in 96-well plates and incubated with CCK-8 reagent for 1 hour at 37 ℃. Absorbance was measured at 450 nm.
(3) Anti-inflammatory Activity assay: RAW264.7 cells were randomly grouped. Cells were re-exposed for 24h in the presence of 1.0. Mu.g/mL LPS. After treatment, cells were collected and analyzed. TNF-alpha and IL-6 were measured according to the ELISA double-antibody sandwich kit detection instructions, and the absorbance at 450nm was measured on an ELISA apparatus after the detection was completed. A standard curve was established for each measurement in pg/mL.
(4) Western blotting experiment: RAW264.7 cells (2.0X10 per well in 6-well plate) 6 Individual cells) were exposed to the drug for 2 hours and then to 1.0 μg/mL LPS for 24 hours. Cleavage was performed with a potent RIPA lysate containing phosphatase inhibitors (RIPA lysate: phosphatase inhibitor=99:1). After completion of the sonication on ice, centrifugation. After determining the protein concentration, the protein solution was boiled. Protein samples were electrophoresed on 10% polyacrylamide gel. Proteins were transferred to PVDF membranes and incubated with 5% skim milk for 2 hours. The antibodies were then incubated overnight at 4℃with IκB- α, p-IκB- α, p65, p-p65, JNK2, p-JNK, p-38, p-p38, ERK, p-ERK, β -actin (antibodies purchased from Cell Signaling Technoligy, USA). Incubation with goat anti-rabbit IgG/HRP antibody (Solarbio, beijin, china) for 1.0h at room temperature. The test was performed using ECL developer (Novland Biopharma, shanghai, china). Protein intensity was measured with Image Lab software and analyzed with ImageJ software.
(5) Apoptosis experiments: RAW264.7 cells at 2X 10 5 Density of individual/well was seeded in 12-well plates. Then treated with 4k (0.275,0.55 and 1.1. Mu.M) for 24 hours. Cells were collected in centrifuge tubes and washed twice with pre-chilled PBS. The PBS was discarded after centrifugation. Cells were suspended in 200mL of binding buffer. Then 5mL of Lannexin V-FITC and 5mL of propidium iodide (BD Biosciences, san Jose, calif., USA) were added sequentially to the solution. Apoptosis was detected by flow cytometry (BD FACS Cal ibur). Finally, the cells were analyzed by flow cytometry.
(6) Animal feeding: male SPF-grade SD rats, 6 weeks old, 150-180 grams, purchased from Peng Yue laboratory animal Breeding Co., ltd. [ qualification number: SYXK (land) 2018-0029, jinan ]. Animals were kept in standard temperature (20.+ -. 1.0 ℃), humidity (50%.+ -. 10%) and photoperiod 12h animals room, given standard diet, free feed and drinking water, and adapted to the experiment 7 days ago. All experimental related procedures were approved by the laboratory animal ethics committee of the coastal state medical college.
(7) AIA induction and treatment: except for the control group, complete Freund's Adjuvant (CFA) was mixed with rotary shaking and 100. Mu.L was injected into the left hind paw of the rat to induce inflammatory reaction. To establish an adjuvant-induced rheumatoid arthritis (AIA) model, control rats were injected with an equal amount of physiological saline at the same site. On day 10 after AIA induction, saline was injected intraperitoneally into the control group and AIA group; MTX group oral treatment. Methotrexate (7.6 mg/kg suspended in 0.5% cmc-Na) was taken weekly; the 4k groups were injected intraperitoneally.
(8) Foot swelling and weight measurement: the body weight and foot swelling of the rats were measured every 3 days before and after molding, and the arthritis index was evaluated. Paw swelling = post-inflammatory volume-pre-inflammatory volume. Grade 0, normal, no redness and swelling; grade 1, redness or swelling of the toe joint; grade 2, redness and swelling of the toe joint and metatarsal region; grade 3, red and swollen ankle joint; grade 4, redness and swelling of ankle joint, joint dysfunction
(9) And (3) immune index detection: spleen and thymus were removed, wet weighed on an electronic balance, and spleen and thymus factors were calculated in thousands of units. Immune organ index (%) =immune organ weight (mg)/rat body weight (g).
(10) Joint histopathological examination: rat ankle section entrusted with the Lafeil Biotech Co. The left hind paw of the rat was peeled off, fixed with 4% paraformaldehyde for 72h, and decalcified with 12% EDTA for 28d. Conventional dehydration, embedding, cutting into 4 μm paraffin sections, HE staining and light observation. After pathological evaluation, the inflammatory cell infiltration degree is classified into 4 grades, namely 0 grade, namely no inflammatory cell infiltration; grade 0, no inflammatory cell infiltration; grade level; 1, weak inflammatory cell infiltration; grade level; 2, slightly soaking; grade level; 3, moderately inflammatory cells infiltrate; and grade; 4, infiltration of a large number of inflammatory cells. Synovial cell proliferation is classified as grade 3, grade 0 normal no proliferation; grade 1, basically normal, little hyperplasia; grade 2, moderate hyperplasia; grade 3, obvious synovial cell proliferation and mass adhesion of synovial cells.
2. Synthesis of Compounds
Example 1: synthesis of Compounds 4a-s
Compound 4a (BAP 4 a)
(E)-3-((E)-3-fluorobenzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
To 5mL of methanol were added 3-pyridinecarboxaldehyde (0.54 g,5.00 mmol), n-methylphenidate (0.57 g,5.00 mmol) and 3-fluorobenzaldehyde (0.62 g,5.00 mmol). 2mL of 10% NaOH solution was taken at 25℃and stirred for 6 hours, and the reaction was observed by TLC. After the reaction was completed, the precipitate was extracted and filtered, and silica gel column chromatography (petroleum ether: ethyl acetate: methanol=10:10:1) was performed to obtain compound 4a as a yellow powder in 67% yield.
Mp:136.3~137.6℃; 1 H NMR(600MHz,DMSO)δ8.72(d,J=2.3Hz,1H),8.59(dd,J
=4.9,1.6Hz,1H),7.92(dt,J=8.0,2.0Hz,1H),7.60(d,J=7.3Hz,2H),7.52(dt,J=13.5,7.8Hz,2H),7.35(t,J=7.9Hz,2H),7.30-7.24(m,1H),3.75(s,4H),2.40(s,3H). 13 C NMR(100MHz,DMSO)δ183.42,160.22(d,J=249.6Hz),137.46,133.64,132.21(d,J=8.6Hz),132.07,131.03,129.72(d,J=4.0Hz),129.34,127.05,124.89(d,J=3.3Hz),121.61(d,J=13.3Hz),116.02(d,J=21.6Hz),46.58.
Compound 4b (BAP 4 b)
(E)-3-((E)-4-fluorobenzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 4-fluorobenzaldehyde. The product obtained was a yellow powder with a yield of 68%
Mp:135.2~136.8℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.72(s,1H),8.59(d,J=4.8Hz,1H),7.94-7.89(m,1H),7.64-7.55(m,4H),7.50(dd,J=7.9,4.8Hz,1H),7.32(t,J=8.9Hz,2H),3.74(d,J=12.5Hz,4H),2.40(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.70,162.88(d,J=247.5Hz),151.59,150.06,137.61,135.98,134.34,133.74(d,J=2.5Hz),133.38(d,J=8.5Hz),131.60,131.04,124.18,116.28(d,J=21.1Hz),56.74,56.61,45.72.
As shown in FIG. 2, compound 4b (BAP-4 b) 1 The H NMR spectra showed chemical shifts of 7.61ppm and 7.62ppm as two single peaks due to the two protons of the central methylphenidate bilaterally asymmetric α, β -unsaturated ketone drug group. Meanwhile, due to the asymmetry of BAP-4b, the two methylene 1H NMR signals of piperidone split into 3.75ppm and 3.73ppm. Similarly, in 13 In the C NMR spectrum, two methylene carbons split into two carbon signals, such as 56.74ppm and 56.61ppm. Furthermore, the characteristic peak of chemical shift at 186.70ppm corresponds to the carbonyl carbon atom of piperidone. BAP-4b contains 4-fluorobenzene substitutions resulting in four split carbon signals in the carbon spectrum, 162.87ppm (d, j=246.1 Hz), 133.75ppm (d, j=2.0 Hz), 133.38ppm (d, j=8.6 Hz) and 116.28 (d, j=21.3 Hz), respectively, which confirm the correctness of the BAP-4b structure.
Compound 4c (BAP 4 c)
(E)-1-methyl-3-(pyridin-3-ylmethylene)-5-((E)-3-(trifluoromethyl)benzylidene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 3-methylbenzaldehyde. The product was obtained as a yellow powder in 55% yield.
Mp:129.7~132.5℃;
1 H NMR(600MHz,25℃,DMSO-d 6 )δ8.74(d,J=1.8Hz,1H),8.60(dd,J=4.7,1.2Hz,1H),7.94(d,J=8.0Hz,1H),7.67(s,1H),7.61-7.49(m,2H),7.46(s,1H),7.29-7.19(m,2H),3.78(s,2H),3.36(s,2H),2.32(s,3H).
13 C NMR(150MHz,DMSO-d6)δ186.75,151.66,150.15,137.66,136.09(d,J=3Hz),135.85,135.61,134.27,133.73,132.01,129.99(q,J=31.5Hz),127.44(q,J=4.5Hz),126.05(q,J=4.0Hz),124.52(d,J=271.5Hz),124.21,56.53(d,J=24.7Hz),45.60.
Compound 4d (BAP 4 d)
(E)-3-((E)-2,3-difluorobenzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 2, 3-difluorobenzaldehyde. The product was obtained as a yellow powder in 70% yield.
Mp:134.6~136.2℃;
1 H NMR(600MHz,25℃,DMSO-d 6 )δ8.73(d,J=2.2Hz,1H),8.60(dd,J=4.8,1.5Hz,1H),7.93(dt,J=8.0,1.7Hz,1H),7.65(s,2H),7.60-7.41(m,2H),7.41-7.22(m,2H),3.77(s,2H),3.64(s,2H),2.37(s,3H).
13 C NMR(150MHz,25℃,DMSO-d 6 )δ186.34,151.70,150.31(dd,J=244.5,12.0Hz),150.22,148.48(dd,J=250.0,12.8Hz),137.71,136.89,135.62,132.57,130.92,126.58(d,J=4.5Hz),126.00,125.52(d,J=12Hz),125.04(d,J=9.9Hz),124.20,118.81(d,J=16.8Hz),56.72,56.33,45.56.
Compound 4e (BAP 4 e)
(E)-3-((E)-3,4-difluorobenzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 3, 4-difluorobenzaldehyde. The product was obtained as a yellow powder in 59% yield.
Mp:127.2~128.9℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.71(d,J=2.3Hz,1H),8.59(dd,J=4.8Hz,1.5Hz,1H),7.91(dt,J=8.1Hz,2.2Hz,1H),7.66–7.58(m,2H),7.58–7.47(m,3H),7.38(m,J=9.6Hz,4.0Hz,2.0Hz,1H),3.76(s,2H),3.71(s,2H),2.40(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.70,151.64,150.21(dd,J=249.0Hz,12Hz),149.79(dd,J=244.5Hz,12Hz),137.64,135.86,134.91,133.21,132.71(d,J=9.9Hz),131.85,128.28,124.19,119.82(d,J=17.4Hz),118.35(d,J=17.4Hz),56.60,56.48,45.67.
Compound 4f (BAP 4 f)
(E)-3-((E)-2,4-difluorobenzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 2, 4-difluorobenzaldehyde. The product was obtained as a yellow powder in 56% yield.
Mp:147.0~149.0℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.62(d,J=2.3Hz,1H),8.49(dd,J=4.8,1.6Hz,1H),7.82(d,J=8.0Hz,1H),7.52(d,J=8.7Hz,2H),7.49–7.36(m,1H),7.33–7.24(m,2H),7.11(t,J=9.8Hz,1H),3.65(d,J=1.4Hz,4H),2.26(s,3H).
13 C NMR(150MHz,DMSO-d6)δ186.36,162.26(d,J=249Hz),161.22(d,J=250.5Hz),151.67,150.18,137.68,135.70,135.66,132.76(dd,J=9.9,3.6Hz),132.34,130.97,126.33(d,J=3.9Hz),124.20,119.41(dd,J=13.6,3.7Hz),112.52(dd,J=21.9,3.5Hz),105.01(t,J=26.4Hz),56.72,56.40,45.60.
Compound 4g (BAP 4 f)
(E)-3-((E)-2,5-difluorobenzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 2, 5-difluorobenzaldehyde. The product was obtained as a yellow powder in 42% yield.
Mp:156.1~157.2℃;
1 HNMR(600MHz,25℃,DMSO-d 6 )δ8.73(d,J=2.1Hz,1H),8.60(dd,J=4.8,1.5Hz,1H),7.96-7.91(m,1H),7.64(s,1H),7.59(s,1H),7.51(dd,J=7.9,4.8Hz,1H),7.43-7.31(m,3H),3.77(s,2H),3.66(s,2H),2.38(s,3H).
13 C NMR(150MHz,25℃,DMSO-d 6 )δ186.39,158.32(d,J=240Hz),157.02(d,J=244.02Hz),151.70,150.22,137.70,136.87,135.62,132.52,130.91,126.19,124.20,124.17-124.01(t,J=27Hz),118.33(dd,J=24.2,9.1Hz),117.80(dd,J=25.1,9.2Hz),117.45(d,J=24.9Hz),56.72,56.13,45.55.
Compound 4h (BAP 4 h)
(E)-3-((E)-2,6-difluorobenzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 2, 6-difluorobenzaldehyde. The product was obtained as a yellow powder in 33% yield.
Mp:136.4~138.0℃;
1 HNMR(600MHz,25℃,DMSO-d 6 )δ10.12(s,3H),8.74(d,J=1.8Hz,1H),8.60(dd,J=4.7,1.2Hz,1H),7.94(d,J=8.0Hz,1H),7.67(s,1H),7.61-7.49(m,2H),7.46(s,1H),7.29-7.19(m,2H),3.78(s,2H),3.34(d,J=20.8Hz,3H),2.32(s,3H).
13 C NMR(150MHz,25℃,DMSO-d 6 )δ185.74,160.08(d,J=247.5Hz),160.04(d,J=247.5Hz),155.07,151.92,151.73,150.27,137.91(d,J=50.1Hz),136.51,135.34,133.20,132.34(d,J=10.6Hz),130.90,124.84,124.20,122.39,112.57(d,J=4.4Hz),112.43(d,J=4.1Hz),112.15(d,J=19.6Hz).56.90,56.32,45.40(s).
Compound 4i (BAP 4 i)
(E)-3-((E)-3,5-difluorobenzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 3, 5-difluorobenzaldehyde. The product was obtained as a yellow powder in 72% yield.
Mp:145.5~147.1℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.73(d,J=2.2Hz,1H),8.60(dd,J=4.8,1.6Hz,1H),7.93(d,J=8.0Hz,1H),7.62(s,1H),7.56(s,1H),7.51(dd,J=8.0,4.7Hz,1H),7.33(tt,J=9.4,2.4Hz,1H),7.26(d,J=6.4Hz,2H),3.76(s,4H),2.40(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.76,162.76(d,J=245.1,13.6Hz),151.67,150.17,138.44(t,J=9.8Hz),137.66,136.22,135.79,132.82,132.06,130.92,124.19,113.77(d,J=25.8Hz),105.06(t,J=25.8Hz),56.59,56.35,45.61.
Compound 4j (BAP 4 j)
(E)-3-((E)-2,4-bis(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 2, 4-dimethylbenzaldehyde. The product was obtained as a yellow powder in 45% yield.
Mp:158.2.5~159.7℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.74(d,J=2.2Hz,1H),8.60(dd,J=4.8Hz,1.6Hz,1H),8.18–8.10(m,2H),7.94(dt,J=8.1Hz,2.0Hz,1H),7.80–7.73(m,2H),7.67(d,J=2.2Hz,1H),7.51(m,J=8.1Hz,4.8Hz,0.8Hz,1H),3.77(s,2H),3.54(s,2H),2.32(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.18,151.76,150.33,137.77,135.35,133.24,132.65,130.87,130.14(d,J=4.5Hz),129.75(q,J=33.0Hz),129.12(q,J=30.0Hz),123.76(q,J=270.0Hz),123.67(q,J=271.5Hz),129.86,129.64,129.12(dd,J=61.3,30.3Hz),124.23,123.65(q,J=6Hz),56.72,55.58,45.35.
Compound 4k (BAP 4 k)
(E)-3-((E)-3,5-bis(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 3, 5-bis (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 36% yield.
Mp:133.0~134.7℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.74(d,J=2.3Hz,1H),8.60(dd,J=4.8,1.6Hz,1H),8.15(d,J=7.9Hz,3H),7.94(dt,J=8.1,2.1Hz,1H),7.77(d,J=2.2Hz,1H),7.65(d,J=2.2Hz,1H),7.52(ddd,J=8.0,4.8,0.9Hz,1H),3.79(s,2H),3.77(s,2H),2.39(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.63,170.78,151.71,150.22,137.73(d,J=13.7Hz),137.11,135.70,132.28(d,J=30.0Hz),131.04(q,J=31.5Hz),130.93(d,J=3.7Hz),124.21,123.65(q,J=271.5Hz),56.57,55.91,45.40.
Compound 4l (BAP 4 l)
(E)-3-((E)-2-fluoro-3-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 2-fluoro-3- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 57% yield.
Mp:133.3~135.1℃;
1 H NMR(600MHz,25℃,DMSO-d 6 )δ8.73(d,J=2.3Hz,1H),8.60(d,J=4.8Hz,1H),7.99-7.89(m,1H),7.82(dt,J=28.8,7.4Hz,2H),7.73-7.60(s,2H),7.58-7.42(m,2H),3.78(s,2H),3.64(s,2H),2.33(s,3H).
13 C NMR(150MHz,25℃,DMSO-d 6 )δ186.27,157.43(d,J=257.7Hz),151.70,150.23,137.72,137.34,136.01,135.56,132.70,130.89(d,J=1.5Hz),128.38(d,J=3Hz),125.59(d,J=3.9Hz),124.46(d,J=12.5Hz),124.21,123.00(q,J=272.3Hz),117.56(d,J=30Hz),56.71,56.12,45.50.
Compound 4m (BAP 4 m)
(E)-3-((E)-2-fluoro-4-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 2-fluoro-4- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 40% yield.
Mp:123.8~125.3℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.73(d,J=2.5Hz,1H),8.60(dd,J=4.8Hz,1.6Hz,1H),7.93(dt,J=8.0Hz,2.1Hz 1H),7.82(dd,J=10.4Hz,1.6Hz,1H),7.74–7.59(m,4H),7.54–7.45(m,1H),3.78(s,2H),3.65(s,2H),2.37(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.32,160.42(d,J=249.0Hz),151.74,150.27,137.73(d,J=3.3Hz),135.56,132.68(d,J=24.9Hz),131.49(q,J=32.4,8.6Hz),127.09(d,J=13.4Hz),123.66(q,J=271.5Hz),121.96,113.79(d,J=13.4Hz),56.74,56.20,45.52.
Compound 4n (BAP 4 n)
(E)-3-((E)-2-fluoro-5-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 2-fluoro-5- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 41% yield.
Mp:133.0~134.7℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.74(d,J=2.3Hz,1H),8.60(dd,J=4.7,1.6Hz,1H),7.93(dt,J=7.9,2.0Hz,1H),7.89(ddd,J=8.6,4.5,2.4Hz,1H),7.81(dd,J=6.7,2.4Hz,1H),7.67–7.63(m,2H),7.59(t,J=9.3Hz,1H),7.51(ddd,J=8.0,4.8,0.9Hz,1H),3.79(s,2H),3.61(s,2H),2.36(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.26,162.43(d,J=254.6Hz),151.73,150.25,137.57,137.41,135.55,132.74,130.91,129.09(dd,J=10.0,4.1Hz),128.66(t,J=4.1Hz),126.18(d,J=3.5Hz),126.01(d,J=33.0Hz),124.22,124.12,123.93(dq,J=270.0Hz),117.66(d,J=23.6Hz),56.72,55.95,45.44.
Compound 4o (BAP 4 o)
(E)-3-((E)-2-fluoro-6-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 2-fluoro-6- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 43% yield.
Mp:133.0~134.7℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.74(d,J=2.3Hz,1H),8.61(dd,J=4.8,1.6Hz,1H),7.93(dt,J=8.0,2.0Hz,1H),7.79–7.65(m,4H),7.62–7.48(m,2H),3.77(s,2H),3.26(s,2H),2.28(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ185.65,159.14(d,J=246.9Hz),151.72,150.30,138.71,137.78,135.24,133.54,131.88(d,J=9.5Hz),130.87,129.44(dq,J=28.5Hz,J=3Hz),124.81,124.19,123.71(q,J=276.0Hz),122.92,121.48(d,J=19.5Hz),121.09(d,J=23.4Hz),56.70,55.73(d,J=5.6Hz),45.20.
Compound 4p (BAP 4 p)
(E)-3-((E)-3-fluoro-4-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 3-fluoro-4- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 38% yield.
Mp:147.0~149.0℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.73(d,J=2.3Hz,1H),8.60(dd,J=4.8,1.6Hz,1H),7.93(dt,J=8.1,2.0Hz,1H),7.87(t,J=7.9Hz,1H),7.67(d,J=11.9Hz,1H),7.63(q,J=2.3Hz,2H),7.54(dt,2H),3.77(s,4H),2.40(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.72,160.02,158.34(d,J=252.0Hz),151.71,150.23,142.05(d,J=8.5Hz),137.44(d,J=81.0Hz),135.70,132.32,130.91,127.98(d,J=5.1Hz),127.16,124.22,123.91,122.10(dq,J=271.5Hz),118.85(d,J=21.1Hz),116.86(dd,J=32.2,12.4Hz),56.61,56.31,45.56.
Compound 4q (BAP 4 q)
(E)-3-((E)-3-fluoro-5-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 3-fluoro-5- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 35% yield.
Mp:120.4~122.1℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.72(d,J=2.3Hz,1H),8.59(dd,J=4.9Hz,1.6Hz,1H),7.92(dt,J=8.1Hz,2.0Hz,1H),7.80–7.70(m,2H),7.70–7.59(m,3H),7.50(dd,J=7.9Hz,4.8Hz,1H),3.83(s,2H),3.69(s,2H),2.39(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.09,161.78(d,J=246.0Hz),151.09,149.59,136.06,135.13,131.84,131.61,131.01,125.73,123.93,123.60,123.01(q,J=271.5Hz),122.11(q,J=3Hz),120.47(d,J=21Hz),113.11(q,J=31.5Hz),55.98,55.55,44.92.
Compound 4r (BAP 4 r)
(E)-3-((E)-4-fluoro-2-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 1 except that 3-fluorobenzaldehyde was replaced with 4-fluoro-2- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 39% yield.
Mp:164.0~166.0℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.73(d,J=2.3Hz,1H),8.60(dd,J=4.8,1.6Hz,1H),7.93(dt,J=8.1,2.0Hz,1H),7.87(t,J=7.9Hz,1H),7.67(d,J=11.9Hz,1H),7.63(q,J=2.3Hz,2H),7.54(dt,2H),3.77(s,4H),2.40(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.75,159.19(d,J=253.6Hz),151.71,150.23,142.06(d,J=8.7Hz),137.71,137.21,135.74,132.30(d,J=3.6Hz),130.92,128.01(dd,J=4.9Hz),127.15(d,J=3.5Hz),124.22,123.01(d,J=271.9Hz),122.11,118.85(d,J=21.1Hz),116.85(d,J=31.5Hz),56.63,56.32,45.57.
Compound 4s (BAP 4 s)
(E)-3-((E)-4-fluoro-3-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-3-ylmethylene)piperidin-4-one
The synthesis was the same as in example 1 except that 3-fluorobenzaldehyde was replaced with 4-fluoro-3- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 43% yield.
Mp:126.5~128.5℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.73(d,J=2.3Hz,1H),8.60(dd,J=4.8,1.6Hz,1H),7.93(ddt,J=8.1,4.0,2.0Hz,2H),7.90-7.84(m,1H),7.68(d,J=2.1Hz,1H),7.66–7.59(m,2H),7.51(ddd,J=8.0,4.8,0.8Hz,1H),3.79–3.72(m,4H),2.39(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.66,159.26(d,J=255.0Hz),151.66,150.16,137.66,137.15(d,J=8.6Hz),135.83,135.37,132.82,132.25(d,J=3.7Hz),132.01,130.97,129.96(q,J=4.7Hz),124.21,122.88(q,J=270.0Hz),118.17(dd,J=20.8,1.2Hz),117.48(qd,J=33.0,12.0Hz),56.60,56.32,45.59.
Example 2: synthesis of Compounds 5a-s
Compound 5a (BAP 5 a)
(E)-3-((E)-3-fluorobenzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
In a 25mL beaker, 4-pyridylaldehyde (0.54 g,5.00 mmol), n-methylpiperidone (0.57 g,5.00 mmol) and 3-fluorobenzaldehyde (0.62 g,5.00 mmol) were dissolved in 10mL of acetic acid, and dry hydrogen chloride gas was continuously injected for 45min, stirred at 25℃for 10 hours, and the reaction was followed by TLC at a certain moment. After the reaction was completed, the precipitate was extracted and filtered. After dissolving the precipitate in distilled water, the pH was changed to 8-9 with 10% NaOH solution. The resulting precipitate was chromatographed on a silica gel column (petroleum ether: ethyl acetate: methanol=10:10:1) to give compound 5a as a yellow powdery solid in 65% yield.
Mp:107.5~110.1℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.71-8.64(m,2H),7.60(s,1H),7.56-7.49(m,2H),7.49-7.44(m,2H),7.37(t,J=8.1Hz,2H),7.29(td,J=8.7,2.6Hz,1H),3.76(t,J=2.6Hz,4H),2.40(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.92,162.55(d,J=241.7Hz),150.51,142.19,137.71,137.26(d,J=8.4Hz),135.05,134.28,132.24,131.19(d,J=7.8Hz),127.11(d,J=3.2Hz),124.66,117.35(d,J=22.3Hz),116.64(d,J=21.2Hz),56.60,56.48,45.63.
Compound 5b (BAP 5 b)
(E)-3-((E)-4-fluorobenzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 4-fluorobenzaldehyde. The product obtained was a yellow powder with a yield of 63%
Mp:145.4~147.4℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.66(d,J=5.3Hz,2H),7.66-7.55(m,3H),7.52(s,1H),7.45(d,J=4.9Hz,2H),7.32(t,J=8.7Hz,2H),3.74(s,4H),2.39(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.85,162.94(d,J=246.5Hz),150.51,142.27,137.79,134.66,133.64,133.46(d,J=8.1Hz),132.03,131.54(d,J=3.5Hz),124.66,116.32(d,J=21.2Hz),56.73,56.49,45.68.
Compound 5c (BAP 5 c)
(E)-1-methyl-3-(pyridin-4-ylmethylene)-5-((E)-3-(trifluoromethyl)benzylidene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 3-methylbenzaldehyde. The product was obtained as a yellow powder in 52% yield.
Mp:104.7~106.4℃;
1 H NMR(600MHz,25℃,DMSO-d 6 )δ8.67(dd,J=4.6,1.4Hz,2H),7.86(s,1H),7.79(t,J=7.3Hz,2H),7.76-7.67(m,2H),7.54(s,1H),7.49-7.44(m,2H),3.77(dd,J=4.1,1.4Hz,4H),2.39(s,3H).
13 C NMR(150MHz,25℃,DMSO-d 6 )δ186.85,150.52,142.17,137.65,136.00,135.74(d,J=37.8Hz),134.15(d,J=41.4Hz),134.01,132.39,130.31,129.99(q,J=31.5Hz),127.74-127.28(d,J=3Hz),127.15,126.11(d,J=3.4Hz),124.45(q,J=271Hz),124.26,56.45(d,J=6.3Hz),45.56.
Compound 5d (BAP 5 d)
(E)-3-((E)-2,3-difluorobenzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 2, 3-difluorobenzaldehyde. The product was obtained as a yellow powder in 65% yield.
Mp:136.2~138.1℃;
1 H NMR(600MHz,25℃,DMSO-d 6 )δ8.67(dd,J=4.5,1.5Hz,2H),7.65(d,J=8.5Hz,1H),7.58-7.50(s,2H),7.47(dd,J=4.8,1.3Hz,2H),7.32(ddd,J=9.1,7.7,4.9Hz,2H),3.76(d,J=9.7Hz,2H),3.67(d,J=21.5Hz,2H),2.37(s,3H).
13 C NMR(150MHz,25℃,DMSO-d 6 )δ186.47,150.52,150.36(dd,J=244.5,12.8Hz),148.50(dd,J=247.5,13.5Hz),142.09,137.40,136.75,132.95,126.56(d,J=2.6Hz),126.27,125.52(d,J=10.5Hz),124.96(d,J=9.9Hz),124.67,118.89(d,J=16.9Hz),56.57,56.31,45.51.
Compound 5e (BAP 5 e)
(E)-3-((E)-3,4-difluorobenzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 3, 4-difluorobenzaldehyde. The product was obtained as a yellow powder in 38% yield.
Mp:106.4~107.6℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.75–8.61(m,2H),7.68–7.60(m,1H),7.59–7.49(m,3H),7.45(d,J=5.1Hz,2H),7.42–7.35(m,1H),3.74(s,4H),2.39(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.38,149.79(dd,J=247.5Hz),149.33(dd,J=244.5Hz),137.20,134.32,133.04,132.18(d,J=4.7Hz),127.89(dd,J=6.9,3.1Hz),124.20,119.40(d,J=17.4Hz),117.91(d,J=17.4Hz),55.99,45.15.
Compound 5f (BAP 5 f)
(E)-3-((E)-2,4-difluorobenzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 2, 4-difluorobenzaldehyde. The product was obtained as a yellow powder in 52% yield.
Mp:164.0~166.0℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.69–8.65(m,2H),7.62(s,1H),7.55(s,2H),7.46(d,J=4.6Hz,2H),7.45–7.35(m,1H),7.22(td,J=8.4,2.4Hz,1H),3.76(s,2H),3.64(s,2H),2.37(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.54,163.34(d,J=249Hz),161.25(d,J=250.5Hz),150.54,142.16,137.50,135.55,132.77,132.73,126.62(d,J=3.9Hz),124.68,119.35(dd,J=12.8,3.6Hz),112.55(dd,J=21.1,3.7Hz),105.04(t,J=26.4Hz),56.57,56.38,45.56.
Compound 5g (BAP 5 g)
(E)-3-((E)-2,5-difluorobenzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 2, 5-difluorobenzaldehyde. The product was obtained as a yellow powder in 53% yield.
Mp:161.0~163.0℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.67(d,J=6.1Hz,2H),7.59(s,1H),7.55(s,1H),7.47(d,J=6.3Hz,2H),7.44–7.31(m,3H),3.76(s,2H),3.66(s,2H),2.37(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.57,158.71(dd,J=240,3Hz),157.05(dd,J=244.5,3Hz),150.55,142.10,137.43,136.77,132.92,126.47,124.69,124.06(dd,J=16.1,8.7Hz),118.44(dd,J=24.3,9.1Hz),117.83(dd,J=24.9,8.8Hz),117.46(d,J=25.0Hz),56.58,56.12,45.51.
Compound 5h (BAP 5 h)
(E)-3-((E)-2,6-difluorobenzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 2, 6-difluorobenzaldehyde. The product was obtained as a yellow powder in 30% yield.
Mp:133.0~134.7℃;
1 H NMR(600MHz,25℃,DMSO-d 6 )δ8.68(d,J=6.0Hz,2H),7.61-7.52(m,2H),7.49-7.43(m,3H),7.24(t,J=8.2Hz,2H),3.77(s,2H),3.40-3.26(m,4H),2.31(s,3H).
13 C NMR(150MHz,25℃,DMSO-d 6 )δ185.97,160.08(d,J=247.5Hz),160.03(d,J=247.5Hz),150.52,142.09,138.07,137.23,133.49,132.43(t,J=10.5Hz),124.69,122.63,112.57(d,J=4.4Hz),112.43(d,J=4.0Hz),112.09(t,J=19.7Hz),56.79,56.32,45.39.
Compound 5i (BAP 5 i)
(E)-3-((E)-3,5-difluorobenzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 3, 5-difluorobenzaldehyde. The product was obtained as a yellow powder in 66% yield.
Mp:139.0~141.9℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.69-8.65(m,2H),7.56(d,J=2.2Hz,1H),7.53(d,J=2.2Hz,1H),7.48-7.44(m,2H),7.34(tt,J=9.3,2.4Hz,1H),7.27(h,J=4.7Hz,2H),3.75(dd,J=4.4,2.2Hz,4H),2.39(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.95,162.79(d,J=245.3,12.7Hz),150.54,142.12,138.37(t,J=9.8Hz),137.62,136.13,133.12,132.46,124.68,113.83(dd,J=19.9,5.1Hz),105.15(t,J=25.8Hz),56.46,56.34,45.57.
Compound 5j (BAP 5 j)
(E)-3-((E)-2,4-bis(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 2, 4-dimethylbenzaldehyde. The product was obtained as a yellow powder in 36% yield.
Mp:150.8~152.2℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.71–8.61(m,2H),8.23–8.02(m,2H),7.83–7.68(m,2H),7.58(d,J=2.2Hz,1H),7.50–7.38(m,2H),3.76(s,2H),3.54(s,2H),2.30(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.33,150.56,142.03,137.73(d,J=28.4Hz),137.13,133.61,132.64,130.15(d,J=4.5Hz),129.92(d,J=34.5Hz),128.99,123.75(q,J=271.5Hz),123.66(q,J=273.0Hz),124.72,123.67(q,J=4.5Hz),56.56,55.55,45.30.
Compound 5k (BAP 5 k)
(E)-3-((E)-3,5-bis(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 3, 5-bis (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 38% yield.
Mp:131.5~132.5℃;
1 H NMR(600MHz,25℃,DMSO-d 6 )δ8.68(dd,J=4.5,1.6Hz,2H),8.16(s,3H),7.77(s,1H),7.56(s,1H),7.47(dd,J=4.8,1.3Hz,2H),3.78(d,J=5.8Hz,4H),2.38(s,3H).
13 C NMR(150MHz,25℃,DMSO-d 6 )δ186.79,150.55,142.06,137.66,137.49,
136.96,137.57(d,J=25.1Hz),137.22,132.64(d,J=42.7Hz),131.25(d,J=32.7Hz),
131.03(q,J=33Hz),130.98(d,J=9Hz),130.92,124.68,123.64(q,J=271Hz),122.80(t,J=4.5Hz),56.14(d,J=81.9Hz),45.37.
Compound 5l (BAP 5 l)
(E)-3-((E)-2-fluoro-3-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 2-fluoro-3- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 55% yield.
Mp:133.6~135.6℃;
1 H NMR(600MHz,25℃,DMSO-d 6 )δ8.68(d,J=5.9Hz,2H),7.83(dt,J=29.4,7.2Hz,2H),7.66(s,1H),7.57(s,1H)7.54(dd,J=21.2,13.4Hz,2H),7.47(d,J=5.8Hz,2H),3.78(s,2H),3.66(s,2H),2.36(s,3H).
13 C NMR(150MHz,25℃,DMSO-d 6 )δ186.41,157.46(d,J=257.8Hz),150.53,142.06,136.00,133.07,128.45(d,J=4.3Hz),125.87(d,J=4.8Hz),125.59(d,J=3.9Hz),123.49(q,J=270Hz),124.68,124.39(d,J=12.4Hz),117.57(dd,J=32.3,12.4Hz),56.56,56.11,45.46.
Compound 5m (BAP 5 m)
(E)-3-((E)-2-fluoro-4-(trifluoromethyyl)benzylidene)-1-methyyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 2-fluoro-4- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 32% yield.
Mp:129.7~131.1℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.69-8.65(m,2H),7.82(dd,J=10.4Hz,1.7Hz,1H),7.69(td,J=8.7Hz,8.3Hz,4.2Hz,2H),7.65(m,1H),7.56(d,J=2.3Hz,1H),7.49-7.45(m,2H),3.77(s,2H),3.65(s,2H),2.36(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.49,160.44(d,J=249.0Hz),150.55,142.07,137.61,137.37,133.13,132.60,131.55(q,J=32.5,8.6Hz),127.01(d,J=13.4Hz),123.64(q,J=271.5Hz),126.12(d,J=3.8Hz),124.70,124.55,122.74,121.97,120.93,113.80(dd,J=26.0,3.9Hz),56.59,56.17,45.47.
Compound 5n (BAP 5 n)
(E)-3-((E)-2-fluoro-5-(trifluoromethyl)benzylidene)-1-methyyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 2-fluoro-5- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 38% yield.
Mp:133.0~134.7℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.68–8.67(m,2H),7.90(ddd,J=8.6,4.5,2.3Hz,1H),7.82(dd,J=6.7,2.4Hz,1H),7.64(s,1H),7.61–7.56(m,2H),7.48–7.46(m,2H),3.78(s,2H),3.62(s,2H),2.35(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.44,162.45(d,J=254.5Hz),150.56,142.08,137.35(d,J=10.3Hz),133.12,126.48(d,J=2.6Hz),126.39–125.64(m),124.70,123.85(d,J=15.0Hz),123.75(q,J=270.0Hz),117.69(d,J=23.5Hz),56.56,55.92,45.39.
Compound 5o (BAP 5 o)
(E)-3-((E)-2-fluoro-6-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 2-fluoro-6- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 41% yield.
Mp:133.0~134.7℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.70–8.66(m,2H),7.75–7.69(m,3H),7.61(d,J=2.3Hz,1H),7.53(q,J=2.3Hz,1H),7.49–7.45(m,2H),3.76(d,J=2.3Hz,2H),3.27(s,2H),2.27(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ185.81,159.14(d,J=247.0Hz),150.53,142.06,138.61,137.00,133.92,131.93(d,J=8.8Hz),129.86–128.96(m),125.16,124.70,123.71(q,J=273.0Hz),122.90(tt,J=10.0,4.3Hz),121.39(d,J=19.7Hz),121.10(d,J=23.4Hz),56.54,55.68(d,J=5.1Hz),45.14.
Compound 5p (BAP 5 p)
(E)-3-((E)-3-fluoro-4-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 3-fluoro-4- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 38% yield.
Yellow powder;yield:38%;Mp:164.0~166.0℃; 1 H NMR(600MHz,DMSO-d 6 )δ8.67(d,J=6.0Hz,1H),7.87(t,J=8.0Hz,1H),7.68(d,J=11.9Hz,1H),7.63(s,1H),7.54(d,J=10.4Hz,1H),7.47(d,J=6.2Hz,1H),3.77(s,2H),2.39(s,3H). 13 C NMR(150MHz,DMSO-d 6 )δ186.89,160.05,158.26(d,J=268.5Hz),150.55,142.08,141.95(d,J=12Hz),137.30(d,J=67.8Hz),132.65(d,J=18.0Hz),128.05,127.20(d,J=3.7Hz),124.69,122.24(dq,J=271.5Hz),118.89(d,J=21.1Hz),117.07,56.47,56.29,45.52.
Compound 5q (BAP 5 q)
(E)-3-((E)-3-fluoro-5-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 3-fluoro-5- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 35% yield.
Mp:162.8~164.2℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.72–8.63(m,2H),7.80–7.71(m,2H),7.72–7.64(m,2H),7.54(d,J=2.2Hz,1H),7.50–7.42(m,2H),3.77(s,4H),2.39(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.91,162.40(d,J=246.0Hz),150.55,142.10,138.67(d,J=9.0Hz),137.59,136.59,132.68(d,J=19.7Hz),131.85,124.53,124.38,123.81,123.80(d,J=4.2Hz),123.60(q,J=271.5Hz),122.73,121.12(d,J=22.3Hz),113.73(d,J=25.6Hz),56.45,56.14,45.49.
Compound 5r (BAP 5 r)
(E)-3-((E)-4-fluoro-2-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as that of example 2 except that 3-fluorobenzaldehyde was replaced with 4-fluoro-2- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow powder in 33% yield.
Mp:133.0~134.7℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.69–8.65(m,2H),7.78(dd,J=9.1,2.7Hz,1H),7.75(d,J=4.5Hz,1H),7.65(td,J=8.5,2.7Hz,1H),7.61–7.54(m,2H),7.49–7.45(m,2H),3.76(d,J=2.4Hz,2H),3.54(d,J=2.0Hz,2H),2.32(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.42,162.02(d,J=249.3Hz),150.55,142.09,137.25,136.35,134.00(d,J=8.4Hz),133.29,130.37,130.11(dq,J=30.0,J=9Hz),129.66,124.69,123.11(q,J=271.5Hz),120.10(d,J=20.8Hz),115.17–114.53(m),56.59,55.73,45.39.
Compound 5s (BAP 5 s)
(E)-3-((E)-4-fluoro-3-(trifluoromethyl)benzylidene)-1-methyl-5-(pyridin-4-ylmethylene)piperidin-4-one
The synthesis was the same as in example 1 except that 3-fluorobenzaldehyde was replaced with 4-fluoro-3- (trifluoromethyl) benzaldehyde. The product was obtained as a yellow solid powder in 52% yield.
Mp:136.2~138.1℃;
1 H NMR(600MHz,DMSO-d 6 )δ8.66(d,J=6.1Hz,2H),7.92(d,J=7.0Hz,1H),7.90-7.82(m,1H),7.67(s,1H),7.65–7.57(m,1H),7.53(s,1H),7.45(d,J=6.1Hz,2H),3.75(d,J=9.6Hz,4H),2.38(s,3H).
13 C NMR(150MHz,DMSO-d 6 )δ186.77,159.28(d,J=255.3Hz),150.51,142.14,137.61,137.18(d,J=8.9Hz),135.23,133.10,132.40,132.15(d,J=3.7Hz),130.00(q,J=4.6Hz),124.66,122.85(q,J=271.5Hz),118.17(dd,J=20.5,0.7Hz),117.48(qd,J=31.5,12.0Hz),56.45,56.30,45.54.
3. Evaluation of results
3.1 cytotoxic and anti-inflammatory Activity
In vitro cytotoxicity evaluation was performed by CCK-8 method, and all experiments were repeated 3 times in parallel to obtain the survival mean. The survival of RAW264.7 cells treated with compounds 4a-s and compounds 5a-s (BAPs, 5.0. Mu.M) is shown in Table 1. After RAW264.7 cells are treated by 5 mu MBAPs, the survival rate of the RAW264.7 cells is more than 85%, and the synthesized BAPs are proved to have no obvious toxic effect on the RAW264.7 cells. Compounds 4b,4e,5k and 5n were more toxic to RAW264.7 cells, resulting in only 85-90% cell viability, but this did not affect the next screening for anti-inflammatory activity.
TABLE 1
In RA, TNF- α and IL-6 are the primary pro-inflammatory cytokines that initiate bone damage. TNF- α and IL-6 may cause bone damage by indirectly inducing RANKL expression through binding to receptors. Thus, blocking TNF- α or IL-6 may delay or prevent the progression of bone destruction in RA. The inflammation model established by stimulating RAW264.7 cells by LPS is used for basic research of anti-inflammatory drugs, is beneficial to screening drug targets and anti-inflammatory active ingredients, and is beneficial to development of anti-inflammatory drugs. PDTC (Pyrrolidine dithiocarbamate, μM) was used as a positive control. All experiments were performed in parallel 3 times and the average expression (%) is shown in table 1. We clearly see that LPS stimulated RAW264.7 cells showed a TNF- α expression of 90.3.+ -. 1.5% after PDTC (5.0. Mu.M) irradiation.
The monofluoro BAPs 4a, 4b, 5a and 5b have little inhibition effect on TNF-alpha release, and the expression rate is higher than that of the positive control PDTC. For the bifluorinated substituted 4d-i and 5d-i,2, 5-F-3-pyridinyl substituted 4g and 2, 6-F-3-pyridinyl substituted 4h showed better anti-inflammatory activity, with expression rates of TNF- α of only 67.7% and 68.5% after LPS stimulated RAW264.7 cells were treated with compound 4g and compound 4h, respectively. More interestingly, 5g of the 4-pyridyl substituted compound also exhibited an expression rate of 81.2%.
Changing substituents to 3-CF 3 This inhibition was significantly improved after substitution of BAP 4c and BAP 5c, with TNF- α release levels of 82.2% and 82.9%, respectively. There was no difference in inhibition of 3-pyridyl substitution and 4-pyridyl substitution in BAPs. For 2,4-CF 3 Substituted 4j and 5j, inhibition was hardly improved. Substitution of substituent positions by 3,5-CF 3 BAP 4k and BAP 5k are obtained, the anti-inflammatory activity of the BAP 4k and the BAP 5k is obviously improved, and the expression rate of TNF-alpha in RAW264.7 cells stimulated by LPS can reach 64.8% and 78.5% respectively. In particular, compound 4k, BAP has the strongest inhibitory effect on TNF- α expression. Overall, the results indicate that the substituent effect of BAPs has a significant effect on TNF-a expression in LPS-stimulated RAW264.7 cells.
Screening for anti-inflammatory Activity shows 2-F, 3-CF 3 Substituted Compounds 4l, 2-F, 4-CF 3 Substituted Compounds 4m, 2-F, 5-CF 3 Substituted compounds 5n, 2-F, 6-CF 3 Substituted compounds 5o and 4-F, 2-CF 3 The substituted compound 4r has a moderate inhibitory effect on TNF- α expression. Their expression rates in LPS-stimulated RAW264.7 cells were 71.9%, 78.2%, 79.9%, 71.4% and 78.5%, respectively. There was no significant improvement over compound 4 k.
From the results, it can be seen that the activity of monofluoro-substituted BAP is lower than that of monotrifluoromethyl-substituted BAP. Next, 3,5-CF 3 The performance of the substituent is obviously better than that of other substituents, and in addition, the performance of the 3-pyridine substituent is obviously better than that of 4-a pyridine substituent. In combination with toxicity and anti-inflammatory activity, compound 4k (shown in panel a of fig. 2) was selected for continued subsequent biological evaluation.
The anti-IL-6 effect of compound 4k is shown in FIG. 2, panels B and C, with IL-6 expression reduced to 72% after PDTC (5. Mu.M) exposure. The lead compound BAP 32 (1.1 μm) with better anti-inflammatory activity is used as a controlThe expression rate was reduced to 65% after exposure, lower than PDTC. The expression rate of the compound BAP 4k after exposure is reduced to 59%, which is superior to PDTC containing BAP 32. The experimental result shows that the compound 4k can effectively reduce the concentration of TNF-alpha and IL-6 and has good anti-inflammatory effect.
3.2BAP 4k inhibits NF-. Kappa.B and MAPK activation
The NF- κB and MAPK signal pathways are classical inflammatory pathways, which promote proliferation and differentiation of osteoclasts, thereby causing bone erosion and bone destruction. Therefore, NF- κB and MAPK signaling pathways play an important role in the disease progression of RA, and are important targets for the treatment of chronic immune-mediated inflammatory diseases such as RA. Typically, inactive NF- κB is inactivated in the cytoplasm, while inflammatory stimuli (LPS or other external stimuli) lead to release and nuclear translocation of NF- κB, and phosphorylation of the p65-IκBα complex. The MAPK signaling pathway is closely related to NF- κB. Thus, we sought to reveal whether the inhibition of inflammation by compound 4k was associated with NF- κB and MAPK activation. Thus, we further examined the expression of NF-. Kappa.b-related proteins and mapk-related proteins, including IκB-. Alpha., p65, JNK, ERK, and p38. Analysis of IκB- α, p65 in RAW264.7 cells treated with LPS by Western blotting gave the results shown in FIG. 3, panel A, which shows that LPS intervention for 24h induced phosphorylation of IκB- α, p65 protein and upregulation of JNK, ERK, p protein phosphorylation compared to control. After treatment with compound 4k at different concentrations (0.275, 0.55 and 1.1 μm), LPS-induced protein phosphorylation expression levels were significantly reduced as expected. As shown in panel C of FIG. 3, NF- κb-related expression levels of IκB- α and p65 proteins were significantly reduced and significantly dose-dependent (panel B of FIG. 3 and panel C of FIG. 3) as compared to LPS-induced groups. As shown in the D plot of fig. 3, the expression level of mapk-associated JNK, ERK, p38 protein decreased significantly in turn with increasing concentration of compound 4 k. Obvious dose dependence was seen (E-G in fig. 3). The results show that the compound 4k can significantly inhibit LPS-induced NF- κb related IκB- α, p65 protein and mapk related JNK, ERK, p protein phosphorylation. This also suggests that 4k may inhibit LPS-induced activation of NF- κB and MAPK in RAW264.7 cells and is dose dependent.
3.3 Compound 4k has an effect on paw swelling, arthritis index values and body weight in AIA rats
The progression of RA is characterized by joint erythema, pain, and synovial hyperplasia. Adjuvant arthritis model is a classical model of RA, and rats developed swelling pain, synovial hyperplasia and bone injury after induction of inflammation with complete Freund's adjuvant. Compound 4k performed well in the LPS-induced RAW264.7 anti-inflammatory activity assay. To further determine the anti-RA efficacy of 4k, the present application used complete Fever's adjuvant as an inducer to build an adjuvant-type arthritis model for efficacy studies (shown in panel a of fig. 4). In the present application, CFA establishment and paw swelling and arthritis index increased significantly. Thus, paw swelling and the arthritis index are important indicators of inflammation measurement. First, starting on day 0, the foot volume of the rat was measured every 3 days (shown in fig. 4, panel B). Compared to AIA, the Methotrexate (MTX) and 4k (10 mg/kg) groups inhibited rat foot swelling for 15 days. However, by 24d, paw swelling was significantly lower in the 4k group (10 mg/kg) than in the AIA group. Secondly, to assess the development of inflammation, we simultaneously assessed the arthritis coefficient. There was no significant difference in the AIA group arthritis scores at the beginning of the score at day 12 post-dose (shown in figure 5, panel C). When administered continuously, 4kMTX (10 mg/kg) showed a significant advantage in inhibiting foot swelling. Finally, body weight is an important index for evaluating experimental toxicity in a compound body, and the change of body weight can be used as an important index for rat toxicity. Body weight was measured every three days from day 10 (shown in figure 5, panel D). The MTX group had significantly reduced body weight compared to the AIA group and the control group, which may be related to MTX toxicity, but had no significant effect on body weight after 4k injection.
From the results, the 3, 5-bis (aryl) -4-methylphenidate derivative has potential RA resistance and is expected to be a potential multifunctional medicament for clinically treating inflammatory diseases such as rheumatoid arthritis and the like.
Claims (10)
1. A 3, 5-bis (aryl) -4-methylphenidate derivative having the following structural formula:
wherein R is 1 Is phenyl, said phenyl being substituted with one or more R a Group substitution, R a Selected from halogen, C 1 ~C 8 Alkyl or C 1 ~C 8 A haloalkyl group; r is R 2 Is a pyridyl group.
2. The 3, 5-bis (aryl) -4-methylphenidate derivative according to claim 1, characterized in that R a Selected from F or trifluoromethyl.
3. The 3, 5-bis (aryl) -4-methylphenidate derivative according to claim 1, characterized in that R 1 Selected from the following groups:
。
4. the 3, 5-bis (aryl) -4-methylphenidate derivative according to claim 1, characterized in that R 2 Is 3-pyridyl or 4-pyridyl.
5. A process for the preparation of 3, 5-bis (aryl) -4-methylphenidate derivatives according to claim 1, characterized by the following steps:
adding R into solvent 2 -CHO, n-methylpiperidoneIn the presence of a catalyst, the catalyst,the reaction is carried out to obtain a product, and the reaction formula is as follows:
6. the preparation method according to claim 5, wherein the product is purified by silica gel column chromatography, and the solvent of the column chromatography is petroleum ether, ethyl acetate and methanol in a volume ratio of 8-10:8-10:1, so as to obtain the purified product.
7. The method according to claim 5, wherein the solvent comprises one or more of methanol and acetic acid; and/or the number of the groups of groups,
the catalyst is sodium hydroxide or hydrogen chloride.
8. A pharmaceutical formulation comprising a 3, 5-bis (aryl) -4-methylphenidate derivative according to any one of claims 1 to 4 or a 3, 5-bis (aryl) -4-methylphenidate derivative prepared by the preparation process according to any one of claims 5 to 7.
9. Use of a 3, 5-bis (aryl) -4-methylphenidate derivative according to any one of claims 1 to 4 or a 3, 5-bis (aryl) -4-methylphenidate derivative prepared by the preparation method according to any one of claims 5 to 7 for the preparation of an anti-inflammatory drug.
10. Use of a 3, 5-bis (aryl) -4-methylphenidate derivative according to any one of claims 1 to 4 or a 3, 5-bis (aryl) -4-methylphenidate derivative prepared by a preparation method according to any one of claims 5 to 7 in the preparation of a medicament for the treatment of rheumatoid arthritis.
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