CN114085215A - Fumaric acid amide compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof - Google Patents
Fumaric acid amide compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a fumaric acid amide compound or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof. The structural formula of the fumaric acid amide compound or the pharmaceutically acceptable salt thereof is shown as the formula (I): the fumaric acid amide compound provided by the invention can effectively degrade STING protein, DC in THP-1 cell line through ubiquitin-proteasome pathway50At 3.2 μ M, showed highly potent anti-inflammatory efficacy in vivo in a cisplatin-AKI mouse model and effectively protected mice from cisplatin-induced kidney damage.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a fumaric acid amide compound or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Background
Interferon gene Stimulators (STING) are intracellular adaptor proteins in the cytosolic DNA sensing pathway that mediate the innate immune response to pathogen invasion. It acts as a cytosolic sensor for cyclic dinucleotides from bacterial sources or 2',3' -cGAMP (2',3' -cyclic GMP-AMP) produced by cGAS (cyclic GMP-AMP synthase). Therefore, the cGAS-STING pathway plays an important role in maintaining the homeostasis of the host innate immune response. Upon stimulation, STING can trigger the production of IFN (type I interferon) and other proinflammatory mediators (e.g., cytokines). Excessive activation of STING is associated with the pathogenesis of many autoimmune and inflammatory diseases, including Aicardi-Goutieres syndrome (AGS), Systemic Lupus Erythematosus (SLE), etc., and therefore STING is considered an excellent target for the treatment of inflammation. Over the past few years, studies on STING inhibitors have been intensified. To date, efforts have been made to gradually float some small molecule inhibitors that target STING. Depending on the mechanism of action, these STING inhibitors can be divided into two broad classes: (1) competitive antagonists of endogenous STING agonists occupying a Cyclic Dinucleotide (CDN) binding site; (2) small molecule inhibitors targeting STING N-terminal transmembrane region cysteines (Cys88 and Cys91) palmitoylation.
The small molecules described above that target STING have met with some success, but because traditional small molecule inhibitors are "occupancy-driven," adaptive resistance and reactivation of STING signaling may occur following inhibitor therapy.
Therefore, there is a need to provide a more active degradation agent targeting STING.
Disclosure of Invention
The present invention is directed to solving at least one of the above problems in the prior art. Therefore, the invention provides a fumaric acid amide compound or a pharmaceutically acceptable salt thereof.
The invention also provides a preparation method of the fumaric acid amide compound or the pharmaceutically acceptable salt thereof.
The invention also provides application of the fumaric acid amide compound or the pharmaceutically acceptable salt thereof.
The invention provides a fumaric acid amide compound or a pharmaceutically acceptable salt thereof, wherein the structural formula of the fumaric acid amide compound or the pharmaceutically acceptable salt thereof is shown as the formula (I):
the invention relates to a technical scheme of a fumaric acid amide compound or a pharmaceutically acceptable salt thereof, which has at least the following beneficial effects:
the fumaric acid amide compound provided by the invention can effectively degrade STING protein in a THP-1 cell line through a ubiquitin-proteasome pathway, DC50 is 3.2 mu M, and the compound shows high-efficiency in-vivo anti-inflammatory effect in a cisplatin-AKI mouse model and effectively protects a mouse from cisplatin-induced kidney injury. This is because the inventors selected a specific α, β -unsaturated carbonyl Linker so that the fumaric acid amide-based compound had excellent activity.
The second aspect of the present invention provides a method for preparing a fumaric acid amide compound or a pharmaceutically acceptable salt thereof, comprising the steps of:
reacting the compound 4, the compound 8, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine in a third organic solvent to obtain a compound shown in the formula (I); the structural formulas of the compound 4 and the compound 8 are as follows:
according to some embodiments of the invention, compound 4 is prepared by:
s1, reacting 4-fluoroisobenzofuran-1, 3-dione, 2, 6-dioxopiperidine-3-ammonium chloride and sodium acetate in acetic acid to obtain a compound 2 a;
s2, dissolving the compound 2a, tert-butyl (6-aminohexyl) carbamate and N, N-diisopropylethylamine in a first organic solvent, heating to react to obtain a compound 3, and reacting under an acidic condition to obtain a compound 4; the structural formulas of the compound 2a and the compound 3 are as follows:
according to some embodiments of the invention, the compound 8 is prepared by:
s3, adding 5-nitrofuran-2-carbonyl chloride into a solvent of a compound 5a and N, N-diisopropylethylamine at the temperature of 0-5 ℃ to react to obtain a compound 6, and continuously reacting under an acidic condition to obtain a compound 7;
s4, dissolving the compound 7, 4-cyclopentene-1, 3-diketone and N, N-diisopropylethylamine in a second organic solvent, and heating to react to obtain a compound 8;
the structural formulas of the compound 5a, the compound 6 and the compound 7 are as follows:
the CAS number of the tert-butyl (6-aminohexyl) carbamate is 51857-17-1.
The CAS number of the 4-cyclopentene-1, 3-dione is 930-60-9.
According to some embodiments of the invention, the first solvent, the second solvent and the third solvent are each independently at least one selected from the group consisting of N, N-dimethylformamide, ethyl acetate, tetrahydrofuran.
According to some embodiments of the invention, the heating temperature in step S2 is 80-100 ℃.
According to some embodiments of the invention, in the step S2, the reaction time is 10-24 h.
According to some embodiments of the invention, the heating temperature is 25 to 35 ℃ in step S4.
According to some embodiments of the present invention, the acidic condition is that the pH of the solvent is adjusted to less than 7. Including but not limited to the addition of hydrochloric acid, sulfuric acid or nitric acid to the solvent.
According to some embodiments of the invention, the third solvent is reacted for 8 to 18 hours.
The third aspect of the invention provides the application of the fumaric acid amide compound or the pharmaceutically acceptable salt thereof in preparing STING degrading agents.
The fourth aspect of the present invention also provides a pharmaceutical composition containing the amide-based compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
General terms
As used herein, "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other adverse reactions when administered to an animal or human, and as used herein, "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, the use of such excipients for pharmaceutically active substances is well known in the art.
The "pharmaceutically acceptable salt" in the present invention includes base addition salts and acid addition salts.
Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Pharmaceutically acceptable salts of the compounds may also be prepared with pharmaceutically acceptable cations. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali metal cations, alkaline earth metal cations, ammonium cations and quaternary ammonium cations. Carbonates or bicarbonates are also possible. As the metal of the cation, sodium, potassium, magnesium, ammonium, calcium, trivalent iron or the like is used. Suitable amines include isopropylamine, trimethylamine, histidine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.
Pharmaceutically acceptable acid addition salts include inorganic or organic acid salts. Suitable acid salts include hydrochloride, formate, acetate, citrate, salicylate, nitrate, phosphate. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include, for example, formic, acetic, citric, oxalic, tartaric or mandelic, hydrochloric, hydrobromic, sulfuric or phosphoric acid; salts with organic carboxylic, sulfonic or phosphoric acid acids or N-substituted sulfamic acids, for example acetic acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, pamoic acid, nicotinic acid or isonicotinic acid; and salts with amino acids, for example the 20 alpha amino acids which are involved in protein synthesis in nature, such as glutamic acid or aspartic acid, and with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane 1, 2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene 2-sulfonic acid, naphthalene 1, 5-disulfonic acid, 2-phosphoglyceric acid or 3-phosphoglyceric acid, glucose 6-phosphate, N-cyclohexylsulfamic acid (for the formation of cyclamate salts), or with other acidic organic compounds, such as ascorbic acid.
Pharmaceutical compositions containing the compounds of the present invention may be manufactured in a conventional manner, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The appropriate formulation depends on the chosen route of administration.
Drawings
FIG. 1 is a graph of the concentration of a compound of formula (I) prepared in example 1 of the present invention as a function of time for STING degradation;
FIG. 2 is a graph showing the degradation effects of the compound of formula (I) prepared in example 1 of the present invention and the compounds of comparative examples 1 to 4;
FIG. 3 is a graph of the in vivo anti-inflammatory effect of the compound of formula (I) prepared in example 1 of the present invention;
FIG. 4 is a NMR spectrum of a compound of formula (I) prepared in example 1 of the present invention;
FIG. 5 is a NMR spectrum of a compound of formula (I) prepared in example 1 of the present invention;
FIG. 6 is a mass spectrum of the compound of formula (I) prepared in example 1 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, but the embodiments of the present invention are not limited thereto.
The reagents, methods and equipment adopted by the invention are conventional in the technical field if no special description is given.
The following examples and comparative examples employ the following starting materials:
STING small molecule inhibitor C-170: purchased from InvivoChem;
pomalidomide: purchased from InvivoChem;
MG132 available from Shanghai Michelin Biotechnology, Inc.;
bafilomycin: purchased from Dalian Meilun Biotechnology, Inc.;
all cell lines were purchased from the american type culture collection center (ATCC);
the thin layer chromatography silica gel plate adopts a Qingdao GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm;
the column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The structure of the compound is determined by Nuclear Magnetic Resonance (NMR). NMR shifts are given in units of (ppm). NMR was measured using a (Bruker Avance III 400) nuclear magnetic instrument using deuterated dimethyl sulfoxide (DMSO-de) and deuterated chloroform (CDC 1)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS);
“DC50"refers to the dosage at which 50% of the protein is degraded.
Example 1
Example 1 provides a fumaric acid amide compound or a pharmaceutically acceptable salt thereof, wherein the structural formula of the fumaric acid amide compound or the pharmaceutically acceptable salt thereof is shown in formula (i): the preparation method comprises the following steps:
preparation of Compound 4
S1. will transformA solution of compound 24-fluoroisobenzofuran-1, 3-dione (5g, 30.12mmol), 2, 6-dioxopiperidine-3-ammonium chloride (4.96g, 30.12mmol) and NaOAc (2.69g, 36.14mmol) in AcOH (100mL) was refluxed for 12 hours. The reaction mixture was poured into ice water (1000mL) and filtered to give compound 2a (7.49g, 90% yield).1H NMR(400MHz,DMSO)δ11.14(s,1H),7.95(td,J＝7.9,4.5Hz,1H),7.79(d,J＝7.3Hz,1H),7.73(t,J＝8.9Hz,1H),5.15(dd,J＝12.9,5.4Hz,1H),2.89(ddd,J＝17.2,13.9,5.4Hz,1H),2.67-2.51(m,2H),2.14-1.97(m,1H).
S2. Compound 2a (1.0g, 3.62mmol), (6-aminohexyl) carbamic acid tert-butyl ester (0.94g, 4.34mmol) and N, N-diisopropylethylamine (0.7g, 5.43mmol) are dissolved in N, N-dimethylformamide, reacted at 90 ℃ for 12 hours, the reaction mixture is poured into water (100mL) and extracted with ethyl acetate (3X 80 mL). The combined organic phases were dried under reduced pressure and concentrated. The crude product was purified by column chromatography (PE/EA ═ 6:1 to 2:1) to afford compound 3(0.39g, 23% yield).1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.56-7.48(m,1H),7.14(dd,J＝7.9,4.4Hz,1H),7.01(d,J＝8.5Hz,1H),6.42(t,J＝5.8Hz,1H),4.94(dd,J＝12.1,5.3Hz,1H),3.50-3.43(m,2H),3.42-3.34(m,2H),2.99-2.82(m,2H),2.82-2.71(m,2H),1.47(s,9H).
Compound 3(0.35g, 0.84mmol) was dissolved in EtOAc (5mL) and 4M dioxane hydrochloride solution (0.42mL, 1.68mmol) was added to the reaction. The reaction was stirred at room temperature for 6 hours. The solvent was then distilled off under reduced pressure to give compound 4(0.22g, 74% yield).
Preparation of Compound 8
1, 4-diaminobenzene (5g, 46.3mol) was dissolved in anhydrous DCM (25mL) and Boc anhydride (10.01g, 46.3mol) was added slowly. Stirring was carried out at 0 ℃ for 6 hours until complete consumption of the starting material. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (PE/EtOAc ═ 50:1) to give compound 5a as a white solid (7.2g, 75% yield).1HNMR(400MHz，DMSO)δ8.76(s，1H)，7.06(d，J＝7.6Hz，2H)，6.46(d，J＝8.7Hz，2H)，4.72(s，2H)，1.44(s，9H)。
S3, adding 5-nitrofuran-2-carbonyl chloride (1.01g, 5.76mmol) into a reaction kettle at the temperature of 0-5 DEG CCompound 5a (1.00g, 4.80mmol) and DIPEA (1.24mg, 9.6mmol) in dry DCM (10 mL). Stirred at room temperature for 3 hours. Suction filtered and washed with a small amount of DCM to give compound 6(1.42g, 85% yield) as a yellow solid.1H NMR(400MHz,DMSO)δ10.53(s,1H),9.35(s,1H),7.80(d,J＝3.9Hz,1H),7.62-7.58(m,3H),7.44(d,J＝8.7Hz,2H),1.48(s,9H).
Compound 6 was dissolved in EtOAc (5mL) and 4M dioxane hydrochloride solution (0.42mL, 1.68mmol) was added to the reaction. The reaction was stirred at room temperature for 6 hours. Compound 7 is obtained.1H NMR(400MHz,DMSO)δ10.27(s,1H),7.79(d,J＝3.7Hz,1H),7.55(d,J＝3.7Hz,1H),7.35(d,J＝8.4Hz,2H),6.56(d,J＝8.4Hz,2H),5.06(s,2H).
S4. dissolving compound 7(1.5g, 6.1mmol), 4-cyclopentene-1, 3-dione (0.71g, 7.3mmol) and N, N-diisopropylethylamine (0.94g, 7.3mmol) in anhydrous tetrahydrofuran (15mL) and heating under reflux for 4h, evaporating the solvent under reduced pressure, and adding 25mL of water to the residue. The pH was adjusted to 3-4 by slowly adding dropwise dilute hydrochloric acid, the resulting precipitate was filtered and washed with water to give Compound 8(1.5g, 0.71mmlol) (1.54g, 85% yield).1H NMR(400MHz,DMSO)δ13.12(s,1H),10.64(s,1H),10.48(s,1H),7.81(d,J＝3.5Hz,1H),7.71(d,J＝8.7Hz,2H),7.65(s,1H),7.63(s,2H),6.48(d,J＝12.1Hz,1H),6.32(d,J＝12.0Hz,1H).
Preparation of Compounds of formula (I)
After reacting the prepared compound 4(0.11g,0.29mmol), compound 8(0.1g,0.29mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.12g,0.32mmol) and N, N-diisopropylethylamine (0.11g,0.86mmol) in N, N-dimethylformamide (2mL) and stirring at room temperature for 10 hours, the reaction mixture was poured into water (20mL) and extracted with EtOAc (3X 20 mL). The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by column chromatography (DCM/MeOH 150: 1-50: 1) to give the compound of formula (i) (0.17g, 47% yield).1H NMR(400MHz,DMSO)δ11.45(s,1H),11.09(s,1H),10.60(s,1H),8.70(t,J＝5.3Hz,1H),7.82(d,J＝3.9Hz,1H),7.69(d,J＝9.0Hz,2H),7.65–7.61(m,3H),7.59–7.54(m,1H),7.08(d,J＝8.6Hz,1H),7.01(d,J＝7.0Hz,1H),6.53(t,J＝5.6Hz,1H),6.27(s,2H),5.05(dd,J＝12.9,5.3Hz,1H),3.31–3.26(m,2H),3.16(dd,J＝12.4,6.4Hz,2H),2.92–2.81(m,1H),2.68–2.55(m,2H),2.05–1.99(m,1H),1.58(s,2H),1.47(d,J＝6.0Hz,2H),1.36(s,4H).13C NMR(101MHz,DMSO)δ173.21,170.51,169.35,167.70,165.22,163.36,154.73,152.13,148.46,146.82,136.66,135.82,133.80,133.19,132.59,131.55,129.19,121.63,121.05,120.01,117.55,116.74,113.89,110.77,109.43,55.31,48.95,42.19,39.14,31.38,29.09,29.04,26.57,26.44,22.56.HRMS m/z:calcd for C34H33N7O10[M+H]+700.2289,found 700.2357.HPLC:tR 15.442min,purity 99.115％.
Comparative example 1
Selecting a STING small molecule inhibitor C-170 with a structural formula shown in the specification;
comparative example 2
Selecting Pomalidomide with a structural formula:
comparative example 3
Selecting MG132, structural formula:
comparative example 4
Selecting Bafilomycin with a structural formula as follows:
performance testing
The compound of formula (I) prepared in example 1 and the compounds of comparative examples 1 to 4 were subjected to in vitro degradation tests, which were carried out as follows:
(1) cell culture: human monocytic leukemia cells (THP-1) were cultured and maintained in RPMI 1640(Gibco, USA) containing 10% fetal bovine serum (Gibco, USA),0.05mM beta-mercaptoethanol (Macklin, CHN) and 1% penicillin streptomycin (Gibco, USA). Cells were maintained in a humidified incubator at 37 ℃ in 95% air/5% carbon dioxide.
(2) Western blot experiment: cells were plated evenly into 6-well plates and incubated with different concentrations of the compounds of formula (I) and comparative examples 1-4. Whole cell lysates were collected with RIPA lysis buffer containing 1% protease inhibitor and 1% phosphatase inhibitor. Protein concentration was quantified by BCA analysis, and equal amounts of protein were electrophoresed by 10% SDS-PAGE, transferred onto polyvinylidene fluoride transfer membrane (PVDF, 0.45 μm), and incubated overnight at 4 ℃ for different target antibodies. The primary antibodies include β -tubulin antibodies (FD0064, fdbi science), anti-STING antibodies (ab181125, Abcam). Protein expression levels were normalized to β -tublin. Strips were exposed and images recorded using a multifunctional imaging analysis system (fluorochem R, usa). The gray scale of each target band was evaluated using ImageJ software.
The compound of formula (I) prepared in example 1 was studied for anti-inflammatory efficacy in vivo
In vivo anti-inflammatory efficacy studies: 8 week old C57BL/6J male mice were purchased from southern medical university, Guangzhou laboratory animal technology development, Inc. and randomized into 4 groups after 24 hours day-night cycle, free diet and drinking water: control group, cisplatin-induced model group (25mg/kg), low dose treatment group (1, 30mg/kg) and high dose treatment group (1, 60mg/kg). mice were intraperitoneally injected with the compound of formula (i) 1 hour before cisplatin injection and continuously administered daily at the same time. 72 hours after cisplatin treatment, blood was collected from the eyeball, serum was centrifuged, and creatinine (creatinine) and urea nitrogen (BUN) concentrations were measured using a serum biochemical automatic analyzer.
As shown in figure 1, the in vitro and in vivo experiments show that the compound 1 can effectively degrade STING protein in THP-1 cell line through ubiquitin-proteasome pathway, and dose DC when 50% of protein is degraded50＝3.2μM。
As seen from FIG. 2, the degradation effect was more significant than that of the C-170 inhibitor of comparative example 1, Pomalidomide of comparative example 2, and the compounds of comparative examples 3 and 4. In addition, Bafilomycin belongs to a lysosome inhibitor, and the mixed incubation of the compound of formula (I) and Bafilomycin verifies that the degradation process is not degraded by the lysosome pathway.
In addition, in fig. 2, the concentration of MG132 is 100nM, which is the final concentration determined by preliminary experiments. 10. mu.M, 1. mu.M and 100nM were initially screened, respectively. As a result, the Western blot experiment is inaccurate due to obvious cell death after the action of the concentrations of 10 mu M and 1 mu M. The final concentration tested was selected as 100nM, which had no effect on THP-1 cell viability.
As seen from fig. 3, in the cisplatin-AKI mouse model, a control group, a cisplatin-induced model (25mg/kg), a low-dose treatment group (1, 30mg/kg), and a high-dose treatment group (1, 60mg/kg) were separately set, and the compound of formula (i) prepared in example 1 showed a highly potent in vivo anti-inflammatory efficacy in the cisplatin-AKI mouse model and effectively protected mice from cisplatin-induced kidney damage. Wherein the compound of formula (I) has a better anti-inflammatory effect when the dosage is 60 mg/kg.
From FIGS. 4 to 6, the synthesis of the compound of formula (I) has been demonstrated by NMR hydrogen, carbon and mass spectra.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A fumaric acid amide compound or a pharmaceutically acceptable salt thereof, wherein the structural formula of the fumaric acid amide compound or the pharmaceutically acceptable salt thereof is shown as formula (I):
2. the process for producing a fumaric acid amide-based compound or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of:
reacting a compound 4, a compound 8, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine in a third organic solvent to obtain a compound shown in a formula (I); the structural formulas of the compound 4 and the compound 8 are as follows:
3. the process for producing a fumaric acid amide-based compound or a pharmaceutically acceptable salt thereof as claimed in claim 2, wherein said compound 4 is produced by the steps of:
s1, reacting 4-fluoroisobenzofuran-1, 3-dione, 2, 6-dioxopiperidine-3-ammonium chloride and sodium acetate in acetic acid to obtain a compound 2 a;
s2, dissolving the compound 2a, tert-butyl (6-aminohexyl) carbamate and N, N-diisopropylethylamine in a first organic solvent, heating to react to obtain a compound 3, and reacting under an acidic condition to obtain a compound 4; the structural formulas of the compound 2a and the compound 3 are as follows:
4. the process for producing a fumaric acid amide-based compound or a pharmaceutically acceptable salt thereof as claimed in claim 2, wherein said compound 8 is produced by the steps of:
s3, adding 5-nitrofuran-2-carbonyl chloride into a solvent of a compound 5a and N, N-diisopropylethylamine at the temperature of 0-5 ℃ to react to obtain a compound 6, and continuously reacting under an acidic condition to obtain a compound 7;
s4, dissolving the compound 7, 4-cyclopentene-1, 3-diketone and N, N-diisopropylethylamine in a second organic solvent, and heating to react to obtain a compound 8;
the structural formulas of the compound 5a, the compound 6 and the compound 7 are as follows:
5. the method for preparing a fumaric acid amide compound or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 4, wherein the first solvent, the second solvent and the third solvent are each independently at least one selected from the group consisting of N, N-dimethylformamide, ethyl acetate and tetrahydrofuran.
6. The method for producing the fumaric acid amide-based compound or the pharmaceutically acceptable salt thereof according to claim 3, wherein the heating temperature in step S2 is 80-100 ℃.
7. The method for preparing a fumaric acid amide-based compound or a pharmaceutically acceptable salt thereof as claimed in claim 3, wherein the reaction time in step S2 is 10-24 h.
8. The method for producing the fumaric acid amide-based compound or the pharmaceutically acceptable salt thereof according to claim 4, wherein the heating temperature in step S4 is 25-35 ℃.
9. The use of the fumaric acid amide compound or its pharmaceutically acceptable salt according to claim 1 for the preparation of STING-degrading agent.
10. A pharmaceutical composition comprising the fumaric acid amide-based compound according to claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
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| WO2024064358A1 (en) * | 2022-09-23 | 2024-03-28 | Ifm Due, Inc. | Compounds and compositions for treating conditions associated with sting activity |
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| WO2021041664A1 (en) * | 2019-08-27 | 2021-03-04 | The Regents Of The University Of Michigan | Cereblon e3 ligase inhibitors |
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| CN113603676A (en) * | 2021-04-28 | 2021-11-05 | 浙江工业大学 | Erlotinib-based EGFR protein targeted degradation small molecule compound and preparation method and application thereof |
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| CN109928956A (en) * | 2019-02-27 | 2019-06-25 | 杭州偶联医药科技有限公司 | A kind of compound of targeting ubiquitination degradation EGFR albumen and its pharmaceutical composition and application |
| WO2021041664A1 (en) * | 2019-08-27 | 2021-03-04 | The Regents Of The University Of Michigan | Cereblon e3 ligase inhibitors |
| CN112552293A (en) * | 2019-09-25 | 2021-03-26 | 珠海宇繁生物科技有限责任公司 | PROTAC small molecular compound and application thereof |
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| WO2024064358A1 (en) * | 2022-09-23 | 2024-03-28 | Ifm Due, Inc. | Compounds and compositions for treating conditions associated with sting activity |
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