CN117551018A - (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione and preparation method and application thereof - Google Patents
(R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione and preparation method and application thereof Download PDFInfo
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- CN117551018A CN117551018A CN202311492929.6A CN202311492929A CN117551018A CN 117551018 A CN117551018 A CN 117551018A CN 202311492929 A CN202311492929 A CN 202311492929A CN 117551018 A CN117551018 A CN 117551018A
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- Prior art keywords
- compound
- pyrrolidine
- dione
- benzyl
- chlorophenyl
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- -1 (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione Chemical compound 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
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- 239000002904 solvent Substances 0.000 claims description 18
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 12
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione and a preparation method and application thereof, belonging to the technical field of pharmaceutical chemistry. The (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione provided by the invention has a structure shown in a formula A, is novel in structure, has a good inhibition effect on receptor interaction protein kinase 1, so as to inhibit programmed cell necrosis, and can be further used for preparing a programmed cell necrosis inhibitor, a receptor interaction protein kinase inhibitor or a medicament for treating or relieving systemic inflammatory response syndrome.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione or pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Background
Programmed cell necrosis is defined as a death receptor-mediated, cysteine-containing aspartic proteolytic enzyme (Caspase) -independent mode of cell death. When Tumor Necrosis Factor (TNF) induces cell death, TNF receptor 1 (TNFR 1) binds to TNF at the cell membrane, and TNFR1 undergoes a conformational change and enters the cell to form a complex with other proteins. Wherein receptor interacting protein kinase 1 (RIPK 1) can be linked to transforming growth factor beta kinase 1 (transforming growth factor-beta-activatedkinase 1, tak 1), activate the nuclear factor κb (NF- κb) pathway, inhibiting cell death; when cells are stimulated by apoptosis, mitochondria release a second, mitochondrial-derived, caspase activator (Smac) protein into the cytoplasm, depriving it of the activity of inhibiting caspase 8 (cysteinyl aspartate specific proteinase, caspase 8), thereby promoting apoptosis; however, when Caspase 8 is inhibited, receptor interacting protein kinase 1 (RIPK 1) and receptor interacting protein kinase 3 (RIPK 3) form complexes and bind to mixed lineage kinase domain-like proteins (mLKL) to trigger programmed cell necrosis, releasing a large number of molecules associated with injury (DAMPS) while inducing inflammatory responses. This process is defined as "programmed cell necrosis" and ultimately leads to cell leakage, cytoplasmic granulation, organelles, or cell swelling.
Currently, the few classes of prior art inhibitors of apoptosis result in limited selectivity of clinical drug candidates.
Disclosure of Invention
The invention aims to provide (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione, and a preparation method and application thereof, and the (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione provided by the invention has a novel structure and good inhibition effect on receptor interaction protein kinase 1, so that the aim of inhibiting programmed cell necrosis is fulfilled.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione or pharmaceutically acceptable salts thereof, wherein the (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione has a structure shown in a formula A:
the invention provides a preparation method of (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione, which comprises the following steps:
mixing the compound I, the compound II and alkali metal with a first solvent, and performing a first substitution reaction to obtain a racemic compound III;
chiral separation is carried out on the racemization compound III to obtain a compound IV;
mixing the compound IV with a compound V, alkali metal hydride and a second solvent, and performing a second substitution reaction to obtain (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione;
the structural formulas of the compound I, the compound II, the racemic compound III, the compound IV and the compound V are shown in the formula I, the formula II, the formula III, the formula IV and the formula V in sequence;
in the formula II and the formula V, X is independently-Cl, -Br or-I.
Preferably, the alkali metal is sodium or potassium; the first solvent is liquid ammonia and/or dimethylamine; the molar ratio of the compound I to the compound II to the alkali metal is 1: (1.0-1.5): (1.0-2.2).
Preferably, the temperature of the first substitution reaction is-80-30 ℃ and the time is 3-10 h.
Preferably, the chiral separation is a chiral chromatographic column separation; the eluent used for chiral separation comprises an eluent A and an eluent B, wherein the eluent A is n-heptane or n-hexane, and the eluent B is ethanol or isopropanol;
the elution mode of chiral separation is gradient elution; the gradient elution procedure was:
the volume fraction of the eluent A is reduced from 100% to 5% at a constant speed within 0-20 min, and the volume fraction of the eluent B is increased from 0% to 95% at a constant speed.
Preferably, the alkali metal hydride is sodium hydride; the second solvent is N, N-dimethylamide, tetrahydrofuran or dimethyl sulfoxide; the molar ratio of the compound IV to the compound V to the alkali metal hydride is 1: (1.0-1.5): (1.0-2.2).
Preferably, the temperature of the second substitution reaction is 25-50 ℃ and the time is 3-5 h.
The invention provides application of the (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione or pharmaceutically acceptable salt thereof in preparing a programmed cell necrosis inhibitor.
The invention provides application of the (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione or pharmaceutically acceptable salt thereof in preparing a receptor interaction protein kinase inhibitor.
The invention provides application of (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione or pharmaceutically acceptable salt thereof in preparing a medicament for treating or relieving systemic inflammatory response syndrome.
The invention provides (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione, which has a structure shown in a formula A. The (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione provided by the invention has novel structure, and has good inhibition effect on receptor interaction protein kinase 1, so that the receptor interaction protein kinase 1 can inhibit programmed cell necrosis, and can be further used for preparing a programmed cell necrosis inhibitor, a receptor interaction protein kinase inhibitor or a medicament for treating or relieving systemic inflammatory response syndrome, and has good practicability and application prospect.
Detailed Description
The invention provides (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione or pharmaceutically acceptable salts thereof, wherein the (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione has a structure shown in a formula A:
the invention provides a preparation method of (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione, which comprises the following steps:
mixing the compound I, the compound II and alkali metal with a first solvent, and performing a first substitution reaction to obtain a racemic compound III;
chiral separation is carried out on the racemization compound III to obtain a compound IV;
mixing the compound IV with a compound V, alkali metal hydride and a second solvent, and performing a second substitution reaction to obtain (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione;
the structural formulas of the compound I, the compound II, the racemic compound III, the compound IV and the compound V are shown in the formula I, the formula II, the formula III, the formula IV and the formula V in sequence;
in the formula II and the formula V, X is independently-Cl, -Br or-I.
In the present invention, unless otherwise specified, all materials are commercially available or prepared by methods well known to those skilled in the art.
The invention mixes the compound I, the compound II and the alkali metal with a first solvent to carry out a first substitution reaction to obtain a racemization compound III. In the present invention, the alkali metal is preferably sodium or potassium, more preferably sodium; the first solvent is preferably liquid ammonia and/or dimethylamine, more preferably liquid ammonia. The amount of the second solvent used in the present invention is not particularly limited, and may be any amount known to those skilled in the art. In the present invention, the molar ratio of the compound I, the compound II and the alkali metal is preferably 1: (1.0-1.5): (1.0 to 2.2), more preferably 1:1.1:1.6. the temperature of the first substitution reaction is preferably-80-30 ℃, more preferably-78-25 ℃; the time is preferably 3 to 10 hours, more preferably 3 to 8 hours. In the invention, before the first substitution reaction, the first solvent and alkali metal are mixed under the protection of nitrogen, and the first mixture is obtained by first stirring; mixing the first mixed material with the compound I, and performing second stirring to obtain a second mixed material; and mixing the second mixture with the compound II to perform a first substitution reaction. In the present invention, the time of the first stirring is preferably 1 to 2 hours, more preferably 1 hour; the second stirring time is preferably 0.3 to 0.6 hours, more preferably 0.5 hours. The stirring mode is not particularly limited, and a stirring mode conventional in the art can be adopted. In the present invention, the first substitution reaction preferably includes a first stage reaction and a second stage reaction which are sequentially performed. The temperature of the first-stage reaction is preferably-80 to-50 ℃, more preferably-78 to-65 ℃; the time is preferably 1 to 2 hours, more preferably 1 hour. The temperature of the second stage reaction is preferably 20-30 ℃, more preferably 20-25 ℃; the time is preferably 2 to 3 hours, more preferably 2 hours. After the first substitution reaction is finished, preferably adding solid ammonium chloride into the reacted feed liquid to quench the reaction, adding diethyl ether to carry out rotary evaporation, distilling liquid ammonia under reduced pressure to remove the liquid ammonia, and collecting residues; ice and concentrated hydrochloric acid were added to the residue and stirred until ice cubes were melted, extracted with ethyl acetate, and the organic layer was collected and concentrated under reduced pressure to give racemic compound III by silica gel column purification. In the present invention, the number of times of the extraction is preferably 2 to 4 times, more preferably 3 times. In the present invention, the eluent used for the purification of the silica gel column is preferably a mixture of petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate is preferably 10:1.
after the racemic compound III is obtained, chiral separation is carried out on the racemic compound III to obtain a compound IV. In the present invention, the chiral separation is preferably chiral chromatographic column separation; the eluent used for chiral separation preferably comprises eluent A and eluent B; the eluent a is preferably n-heptane or n-hexane, more preferably n-heptane; the eluent B is preferably ethanol or isopropanol, more preferably isopropanol. In the invention, the elution mode of chiral separation is preferably gradient elution; the gradient elution procedure is preferably: the volume fraction of the eluent A is reduced from 100% to 5% at a constant speed within 0-20 min, and the volume fraction of the eluent B is increased from 0% to 95% at a constant speed.
After the compound IV is obtained, the compound IV is mixed with the compound V, alkali metal hydride and a second solvent for a second substitution reaction to obtain (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione. In the present invention, the alkali metal hydride is preferably sodium hydride; the second solvent is preferably N, N-dimethylamide, tetrahydrofuran or dimethylsulfoxide, more preferably N, N-dimethylamide. The amount of the second solvent used in the present invention is not particularly limited, and may be any amount known to those skilled in the art. The molar ratio of compound IV, compound V and alkali metal hydride according to the invention is preferably 1: (1.0-1.5): (1.0 to 2.2), more preferably 1:1.5:1.5. the temperature of the second substitution reaction is preferably 25-50 ℃, more preferably 25-30 ℃; the time is preferably 3 to 5 hours, more preferably 4 hours. In the invention, the compound IV is preferably added into the second solvent to obtain a first mixed material; adding alkali metal hydride into the first mixed material, and stirring to obtain a second mixed material; and mixing the second mixed material with the compound V to perform a second substitution reaction. In the present invention, the stirring time is preferably 15 minutes. After the second substitution reaction is finished, the invention preferably adds water quenching reaction into the material liquid after the reaction, extracts by ethyl acetate, collects the organic layer and dries by anhydrous sodium sulfate, filters, decompresses and concentrates the filtrate, and purifies the residue by silica gel column to obtain (R) -1-benzyl-3- (4-chlorphenyl) pyrrolidine-2, 5-diketone. In the present invention, the number of times of the extraction is preferably 2 to 4 times, more preferably 3 times. In the present invention, the eluent used for the purification of the silica gel column is preferably a mixture of petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate is preferably 2:1.
the invention also provides application of the (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione or pharmaceutically acceptable salt thereof in preparing a programmed cell necrosis inhibitor. The method of application of the present invention is not particularly limited, and may be any application method known to those skilled in the art.
The invention also provides application of the (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione or pharmaceutically acceptable salt thereof in preparing a receptor interaction protein kinase inhibitor. The method of application of the present invention is not particularly limited, and may be any application method known to those skilled in the art.
The invention also provides application of the (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione or pharmaceutically acceptable salt thereof in preparing medicines for treating or relieving systemic inflammatory response syndrome. The method of application of the present invention is not particularly limited, and may be any application method known to those skilled in the art.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The room temperature conditions in the examples and test examples were 20-25 ℃;
GSK2982772 in the test example is a positive control drug, chinese name: (S) -5-benzyl-N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,4] oxetan-3-yl) -1H-1,2, 4-triazole-3-carboxamide; commodity model: t7151; purchased from beijing enoki technologies limited.
Example 1
(1) Preparation of 3- (4-chlorobenzyl) pyrrolidine-2, 5-dione (i.e. racemic compound III) is shown in the following scheme:
liquid ammonia (100 mL) was added to a three-necked flask, sodium (268 mg,16 mmol) was added under nitrogen protection at-78deg.C, and the mixture was stirred and mixed for 1h; then adding the compound I (990 mg,10 mmol) and stirring and mixing for 0.5h, then adding the compound II (1771 mg,11 mmol), stirring and reacting for 1h at-78 ℃ and stirring and reacting for 2h at room temperature; then adding solid ammonium chloride (1.6 g,30 mmol) into the obtained feed liquid for quenching reaction, adding diethyl ether (200 mL) for rotary evaporation, distilling off liquid ammonia under reduced pressure, and collecting residues; ice (50 mL) and concentrated hydrochloric acid (5 mL) with the concentration of 12mol/L are added into the residue and stirred until the ice is melted; the organic layers were then combined and concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent a mixture of petroleum ether and ethyl acetate, volume ratio of petroleum ether to ethyl acetate 10:1) to give 3- (4-chlorobenzyl) pyrrolidine-2, 5-dione (1.2 g, 53% yield).
3- (4-chlorobenzyl) pyrrolidine-2, 5-dione 1 The H NMR data are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.32-7.29(m,2H),7.18-7.12(m,2H),3.44-3.24(m,1H),3.15-3.07(m,1H),2.90-2.80(m,2H),2.55-2.70(m,1H).
(2) Preparation of (R) -3- (4-chlorobenzyl) pyrrolidine-2, 5-dione (i.e., compound IV) is shown in the following scheme:
the 3- (4-chlorobenzyl) pyrrolidine-2, 5-dione (1.0 g) was subjected to chiral separation using a chiral column, wherein the eluent used for the chiral separation was isopropanol and n-heptane, and the elution procedure was: the volume fraction of n-heptane was decreased from 100% to 5% at a constant rate and the volume fraction of isopropanol was increased from 0% to 95% at a constant rate for 0-20 min to give (R) -3- (4-chlorobenzyl) pyrrolidine-2, 5-dione (0.49 g).
(R) -3- (4-chlorobenzyl) pyrrolidine-2, 5-dione 1 The H NMR data are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.32-7.29(m,2H),7.18-7.12(m,2H),3.46-3.25(m,1H),3.15-3.07(m,1H),2.92-2.80(m,2H),2.53-2.67(m,1H).
(3) The preparation of (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione is shown in the following scheme:
(R) -3- (4-chlorobenzyl) pyrrolidine-2, 5-dione (223.6 mg,1 mmol) was added to anhydrous DMF (15 mL), naH (60 mg,1.5 mmol) was added thereto and mixed for 15min with stirring, then compound V (190 mg,1.5 mmol) was added thereto, the reaction was stirred at room temperature for 3h, then water (30 mL) was added thereto to quench the reaction, ethyl acetate was used for three times (30 mL each), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column (eluent used was a mixture of petroleum ether and ethyl acetate, the volume ratio of petroleum ether and ethyl acetate was 2:1) to give (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione (270 mg, yield 86%).
(R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione 1 The H NMR data are as follows: 1 1H NMR(400MHz,CDCl 3 )δ7.40-7.22(m,7H),7.11-7.06(m,2H),4.86(s,2H),3.43-3.22(m,1H),3.14-3.10(m,1H),2.90-2.82(m,2H),2.53-2.67(m,1H).
test example 1
1. Necrosis prolapse induction and cell viability assay
Firstly, dissolving a compound to be tested into a mother solution with the concentration of 20mmol/L by using dimethyl sulfoxide (DMSO), and then, completely culturing according to DMEM (various amino acids and glucose): smac (mitochondrial derived second Caspasts activator) analog (15. Mu. Mol/L): Z-VAD-FMK ((3S) -5-fluoro-3- [ [ (2S) -2- [ [ (2S) -3-methyl-2- (benzyloxycarboxamido) butanoyl ] amino ] propionyl ] amino ] -4-oxopentanoic acid methyl ester) (30 mmol/L) =1000: 1:1, continuously split charging the SZ working solution into clean EP, then sucking a certain volume of compound mother solution, and adding the compound mother solution into the split charged SZ working solution to obtain a certain concentration of dosing working solution (for on-site preparation).
Human colorectal adenocarcinoma cells (HT-29 cells) in the logarithmic growth phase are taken for digestion and counting, the density is adjusted to 20000/mL, 96-well plates are taken, 100 mu L of Phosphate Buffer Saline (PBS) is added to each well around, 100 mu L of the cell suspension is uniformly added to each other well, and the cells are placed in an incubator for culturing until the cells are completely attached. After the cells were completely adherent, the old medium was gently aspirated, 100. Mu.L of the above-described dosing working solution (3 duplicate wells per concentration) was added to each well, incubated in an incubator for 30min, then TNF- α (2 ng/well) was added to each well, incubated for 24h, 100. Mu.L of CellTiter-LumitM luminescence reagent was added to each well, and the wells were transferred to a white 96-well plate and the luminescence value was detected in a multifunctional microplate reader. The test activities of (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione are shown in Table 1.
2. Affinity assay for RIP proteins
In most experiments, kinase-tagged T7 phage strains were prepared in E.coli hosts derived from BL21 strain. Coli was cultured to log phase, infected with T7 phage, and shake cultured at 32 ℃ until lysis. The lysate was centrifuged and filtered to remove cell debris. The remaining kinase was produced in HEK-293 cells and subsequently detected by a real-time fluorescent quantitative nucleic acid amplification detection system (qPCR) using DNA markers. The streptavidin-coated magnetic beads are treated with biotinylated small molecule ligands at room temperature for 30min, and affinity resin is generated for kinase detection. Blocking the ligand with excess biotin and washing with blocking buffer (SeaBlock (Pierce)) wherein Bovine Serum Albumin (BSA) is 1% by mass, tween20 (Tween 20) is 0.05% by mass, dithiothreitol (DTT) is 1 mmol/L) to remove unbound ligand and reduce non-specific binding.
Binding reactions were assembled by binding kinase, ligand affinity beads and test compound (i.e., (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione prepared in example 1) in 1-fold binding buffer (20% SeaBlock, 0.17-fold PBS), tween20 at 0.05% by mass and DTT at a concentration of 6 mmol/L. Test compounds were prepared as 111X stock in 100% dmso. Affinity assay values (Kd) were determined using 11-point 3-fold dilution series and 3 DMSO control points. All compounds used for Kd measurements were distributed by acoustic transmission in 100% dmso (non-contact gel). The compound was then directly diluted into the assay solution to give a final mass percent DMSO of 0.9%. All reactions were performed on polypropylene 384 well plates. The final volume of each assay plate was 0.02mL. Incubate for 1h at room temperature with shaking, wash the affinity beads with wash buffer (1-fold PBS, 0.05% wt. Tween 20). The microspheres were then resuspended in elution buffer (1-fold PBS, 0.05% Tween20 by mass, 0.5. Mu. Mol/L non-biotinylated affinity ligand) and incubated for 30min with shaking at room temperature. The concentration of kinase in the eluate was determined by qPCR. The test activities of (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione are shown in Table 1.
TABLE 1 anti-procedural cell necrosis Activity of (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione prepared in example 1 and receptor interaction protein (RIP 1) affinity Activity
As can be seen from Table 1, the (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione prepared by the method provided by the invention has the capability of resisting programmed cell necrosis and has an affinity effect with RIP1 target proteins.
Although the foregoing embodiments have been described in some, but not all, embodiments of the invention, it should be understood that other embodiments may be devised in accordance with the present embodiments without departing from the spirit and scope of the invention.
Claims (10)
1. (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione or a pharmaceutically acceptable salt thereof, said (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione having a structure represented by formula a:
2. a process for the preparation of (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione according to claim 1, comprising the steps of:
mixing the compound I, the compound II and alkali metal with a first solvent, and performing a first substitution reaction to obtain a racemic compound III;
chiral separation is carried out on the racemization compound III to obtain a compound IV;
mixing the compound IV with a compound V, alkali metal hydride and a second solvent, and performing a second substitution reaction to obtain (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione;
the structural formulas of the compound I, the compound II, the racemic compound III, the compound IV and the compound V are shown in the formula I, the formula II, the formula III, the formula IV and the formula V in sequence;
in the formula II and the formula V, X is independently-Cl, -Br or-I.
3. The method of claim 2, wherein the alkali metal is sodium or potassium; the first solvent is liquid ammonia and/or dimethylamine; the molar ratio of the compound I to the compound II to the alkali metal is 1: (1.0-1.5): (1.0-2.2).
4. A method according to claim 2 or 3, wherein the first substitution reaction is carried out at a temperature of-80 to 30 ℃ for a period of 3 to 10 hours.
5. The method of claim 2, wherein the chiral separation is a chiral chromatographic column separation; the eluent used for chiral separation comprises an eluent A and an eluent B, wherein the eluent A is n-heptane or n-hexane, and the eluent B is ethanol or isopropanol;
the elution mode of chiral separation is gradient elution; the gradient elution procedure was:
the volume fraction of the eluent A is reduced from 100% to 5% at a constant speed within 0-20 min, and the volume fraction of the eluent B is increased from 0% to 95% at a constant speed.
6. The method of claim 2, wherein the alkali metal hydride is sodium hydride; the second solvent is N, N-dimethylamide, tetrahydrofuran or dimethyl sulfoxide; the molar ratio of the compound IV to the compound V to the alkali metal hydride is 1: (1.0-1.5): (1.0-2.2).
7. The method according to claim 2 or 6, wherein the second substitution reaction is carried out at a temperature of 25 to 50 ℃ for 3 to 5 hours.
8. Use of (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione, or a pharmaceutically acceptable salt thereof, according to claim 1 in the preparation of a programmed cell necrosis inhibitor.
9. Use of (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione, or a pharmaceutically acceptable salt thereof, according to claim 1 in the preparation of a receptor-interacting protein kinase inhibitor.
10. Use of (R) -1-benzyl-3- (4-chlorophenyl) pyrrolidine-2, 5-dione, or a pharmaceutically acceptable salt thereof, according to claim 1 in the manufacture of a medicament for treating or alleviating systemic inflammatory response syndrome.
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| DE KONING等: "Succinimide", E-EROS ENCYCLOPEDIA OF REAGENTS FOR ORGANIC SYNTHESIS, 15 April 2001 (2001-04-15), pages 1 - 2 * |
| YUANYUAN LIU等: "Iridium-Catalyzed Asymmetric Hydrogenation of a-Alkylidene Succinimides", ANGEW. CHEM. INT. ED., no. 52, 18 January 2013 (2013-01-18), pages 2203 - 2206 * |
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