CN115400114A - Application of non-steroidal organic selenium compound in preparation of medicine for treating or preventing intestinal inflammation related diseases - Google Patents

Application of non-steroidal organic selenium compound in preparation of medicine for treating or preventing intestinal inflammation related diseases Download PDF

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CN115400114A
CN115400114A CN202110589395.3A CN202110589395A CN115400114A CN 115400114 A CN115400114 A CN 115400114A CN 202110589395 A CN202110589395 A CN 202110589395A CN 115400114 A CN115400114 A CN 115400114A
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毕秀丽
陈天桥
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Liaoning University
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Abstract

The invention relates to an application of a non-steroidal organic selenium compound in preparing a medicament for treating or preventing intestinal inflammation related diseases. The invention verifies through experiments that the non-steroidal organic selenium compound shown in the general formula (I) can obviously inhibit the mouse abdominal cavity macrophage activation induced by an exogenous stimulant LPS and the subsequent induced inflammatory effect; meanwhile, the compound can inhibit DSS-induced colitis in mice and can be used as a potential therapeutic drug for inflammatory bowel diseases. R is a ‑R b ‑C(W)‑O‑L‑SeCN (I)。

Description

Application of non-steroidal organic selenium compound in preparation of medicine for treating or preventing intestinal inflammation related diseases
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of selenium-containing compounds in preparation of medicines for treating Inflammatory Bowel Diseases (IBD) including Ulcerative Colitis (UC) and Crohn's Disease (CD).
Background
Inflammatory Bowel Disease (IBD) is a chronic, idiopathic Inflammatory disease of the intestinal tract caused by the dysfunction of the immune system of the gastrointestinal tract, characterized by the repeated formation of mucosal lesions and ulcers, which can affect the entire gastrointestinal tract and the mucosal layer, resulting in intestinal lesions and dysfunction, clinically manifested as diarrhea, abdominal pain, fatigue, malnutrition, and even bloody stool. Inflammatory bowel disease includes Ulcerative Colitis (UC) and Crohn's Disease (CD). UC occurs frequently in any age, 15-30 years old and 50-70 years old, and mainly invades rectum and colon and is distributed diffusely. CD can also occur at any age, affecting any part of the gastrointestinal tract, most commonly the ileum and distal colon, in segmented and saltatory distributions. The pathogenesis of IBD is very complex, the cause is not clear at present, and IBD is not cured completely at present because of intractable relapse. In recent years, the prevalence of IBD in the world has been on the rise.
Ulcerative Colitis (UC) is a recurrent Inflammatory Bowel Disease (IBD) characterized by chronic and recurrent inflammation of the gastrointestinal tract. The intestinal tract is affected by UC in the colon and rectum, and inflammation is mainly seen in the mucosal layer. The pathogenesis of colitis is complex and involves an interaction between the genetic, immune and environmental factors of the patient. Studies have shown that one of the major factors in the onset of colitis is excessive mucosal immune response caused by an imbalance in the regulation of the intestinal immune cells. The intestinal tract is the largest organ digested and absorbed by human body, and the intestinal mucosal barrier, intestinal epithelial cells and immune cells are taken as important components to play an important role in preventing invasion of foreign pathogens in the digestive and absorption process of human body, but among a plurality of complex pathogenic factors involved in the pathological process of IBD, intestinal injury caused by excessive action of inflammation and immune response is an important factor for IBD. In addition, excessive ROS production is observed in inflamed mucosa in IBD patients. In IBD models established with Lipopolysaccharides (LPS), dextran Sulfate Sodium (DSS), trinitrobenzene sulfonic acid (TNBS), and the like, the IBD models are mainly characterized by unbalanced intestinal epithelial cell replacement, intestinal physical barrier dysfunction, intestinal oxidative damage, and intestinal mucositis reaction, and are accompanied by a large amount of pro-inflammatory factors such as Nitric Oxide (NO), interleukin IL-1 β, reactive Oxygen Species (ROS), and the like. Currently, immunosuppressive and anti-inflammatory drugs are used to relieve IBD, which can shorten the duration of the disease, but these treatments have major side effects when used for a long time. Therefore, new adjunctive therapies are needed to overcome the limitations of current pharmacological treatments.
Clinical data show that the prevalence rate of IBD is increasing, UC is abundant in Chinese patient population, the incidence rate of UC is nearly twice of that of CD, and the UC is characterized by late diagnosis, serious disease and stage lesion. The UC is difficult to be treated thoroughly due to the reasons of easy relapse, unclear pathogenesis, complex pathogenesis and the like. UC patients generally receive drug therapy including steroids, immunosuppressants and aminosalicylic acid drugs, but the drug therapy also brings great toxic and side effects to the patients, the patients are always exposed to the risks of various diseases such as infection, hearing impairment or tinnitus after long-term administration, the toxic and side effects brought by the drugs often limit the patients to stop using the drugs, no IBD safe treatment scheme exists at present, and new drugs without side effects are urgently needed.
Mouse peritoneal macrophages (RAW 264.7), a species of immune cell, play a crucial role in maintaining intestinal mucosal homeostasis and defending against pathogen invasion. RAW264.7 can be divided into two subtypes: classical activated macrophages (M1 macrophages), polarized M1 macrophages secrete a variety of inflammatory mediators including tumor necrosis factor alpha (TNF-alpha), IL-6, IL-18, IL-1 beta and a large amount of Reactive Oxygen Species (ROS), etc., mediating inflammatory responses; alternatively activated macrophages (M2 macrophages) promote tissue repair and remodeling. The M1/M2 paradigm imbalance can cause the generation of chronic inflammatory diseases such as IBD and the like, and is characterized in that the generation of IL-1 beta, IL-6 and iNOS is increased, and the amount of secreted IL-10 is reduced, thereby damaging the integrity of the mucosal barrier which is migrated from the intestinal lamina propria. Macrophages play an important role in the pathogenesis of IBD, and macrophages in the normal human colon account for about one fifth of the total number of cells, and the macrophages recognize and phagocytose foreign microorganisms through pattern recognition receptors on the surface of the macrophages, so that intestinal homeostasis is maintained. However, intestinal injury caused by inflammation and immune response disorder due to excessive macrophage activation is an important factor in the pathogenesis of IBD. At present, the treatment of IBD is non-specific and studies indicate that inhibition of intestinal macrophage over-activation may be one of the effective methods for treating and preventing enteritis.
Therefore, it is of great importance to develop drugs for treating or preventing diseases associated with inflammatory bowel diseases.
Disclosure of Invention
The invention aims to provide application of an organic selenium derivative shown in a general formula (I) as an active ingredient in preparation of a medicament for treating or preventing intestinal inflammation related diseases.
The technical scheme adopted by the invention is as follows: the application of non-steroidal organic selenium compounds in preparing medicines for treating or preventing intestinal inflammation related diseases is disclosed, wherein the non-steroidal organic selenium compounds have a structure shown in a general formula (I):
R a -R b -C(W)-O-L-SeCN (I)
wherein the content of the first and second substances,
R a represents aryl or heteroaryl, optionally substituted by one, two or three substituents selected from: phenyl, methylsulfonylphenyl C 1-4 Alkyl, halobenzoyl, halophenylamino, benzoyl, C 1-4 Alkylphenylamino, halogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkoxy radical, C 1-4 Alkyl acyl radical, C 1-4 Alkylamino, halogeno C 1-4 An alkyl group;
R b is a straight or branched alkylene or alkenylene chain of 1 to 4 carbon atoms, or is a direct covalent bond;
w is selected from O, S and Se;
l is a straight or branched alkylene chain of 1 to 4 carbon atoms.
Preferably, ra is selected from unsubstituted or substituted phenyl, indenyl, naphthyl, phenylaminophenyl, benzoylphenyl, benzopyrryl, benzopyrrolidinyl and phenylpyrrolidooxacyclohexyl;
wherein the substituent is selected from phenyl and methylsulfonylphenyl C 1-4 Alkyl, halophenyl-formyl, phenyl-formyl, C 1-4 Alkylphenylamino, halogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkyl, halo C 1-4 Alkoxy, acyl, C 1-4 Alkyl acyl, acyloxy, C 1-2 Alkyl acyloxy, C 1-2 An alkylamino group; and the number of the first and second electrodes,
wherein the heteroaryl group is selected from the group consisting of a benzopyrroliyl group, a benzopyrrolidinyl group, and a phenylpyrrolidinooxeclocyclohexyl group.
Preferably, W is O.
Preferably, R a Selected from phenyl, phenylaminophenyl, benzoylphenyl, indenyl, benzopyrryl, benzopyrrolidinyl and benzopyrrolidino-oxacyclohexyl, and R a Optionally substituted with one or two substituents selected from: halogen selected from fluorine, chlorine, bromine, iodine, phenyl, phenylamino, benzoyl, methoxy, straight or branched alkyl of 1 to 4 carbon atoms, C 1-4 An alkoxy group.
Preferably, L is (CH) 2 ) 2 Or (CH) 2 ) 3 。
Preferably, the non-steroidal organoselenium compound is selected from the following compounds:
Figure BDA0003088938160000031
a pharmaceutical composition is prepared from non-steroidal organic selenium compound as effective component and pharmaceutically acceptable excipient and/or carrier.
The pharmaceutical composition provided by the invention can additionally comprise other pharmaceutical active ingredients besides the non-steroidal organic selenium compound with the general formula (I) or the pharmaceutically acceptable salt thereof. The pharmaceutical compositions of the invention may be prepared by conventional techniques, for example as described in Remington: the method described in The Science and Practice of Pharmacy, 19 th edition, 1995, which is incorporated herein by reference. The compositions may be presented in conventional forms, such as capsules, tablets, aerosols, solutions, suspensions or topical application forms.
Typical compositions comprise a compound of the invention and a pharmaceutically acceptable excipient or carrier. For example, the active compound is typically admixed with, or diluted by, a carrier, or enclosed within a carrier which may be in the form of an ampoule, capsule, sachet (sachet), paper or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, the carrier can be a solid, semi-solid, or liquid material that serves as a carrier, excipient, or medium for the active compound. The active compound may be adsorbed on a particulate solid carrier (e.g. contained in a sachet). Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugars, cyclodextrins, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono-and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
The formulations may be mixed with adjuvants which do not deleteriously react with the active compound. These additives may include wetting agents, emulsifying and suspending agents, salts for influencing osmotic pressure, buffering and/or coloring substances, preservatives, sweeteners or flavorings. The composition may also be sterilized, if desired.
The route of administration may be any route which is effective for transporting the active compounds of the invention to the appropriate or desired site of action, for example the oral, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal or parenteral routes, for example the rectal, depot (depot), subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solutions or ointments route, the oral route being preferred.
If a solid carrier is used for oral administration, the formulation may be tableted, placed in a hard gelatin capsule as a powder or pellet, or it may be in the form of a troche (troche) or lozenge. If a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.
Injectable dosage forms typically comprise an aqueous or oily suspension, which may be formulated using suitable dispersing or wetting agents and suspending agents. Injectable forms may be in solution phase or in suspension prepared with solvents or diluents. Acceptable solvents or carriers include sterile water, ringer's solution, or isotonic saline solution. Alternatively, sterile oils may be employed as a solvent or suspending agent. Preferably, the oil or fatty acid is non-volatile and comprises a natural or synthetic oil, a fatty acid, a monoglyceride, diglyceride, or triglyceride.
For injection, the formulation may also be a powder suitable for reconstitution with a suitable solution as described above. Examples of these include, but are not limited to, freeze-dried, spin-dried or spray-dried powders, amorphous powders, granules, precipitates or microparticles. For injections, the formulation may optionally include stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations of these agents. The compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. The unit dosage form for injection may be in ampoules or in multi-dose containers.
The formulations of the present invention may be designed to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by methods well known in the art. Thus, the formulation may also be formulated for controlled release or slow release.
The compounds of the present invention are effective over a wide dosage range. For example, in the treatment of adults, a dose of about 0.05 to about 5000mg, preferably about 1 to about 2000mg, more preferably about 2 to about 2000mg per day may be used. Typical dosages are from about 10mg to about 1000mg per day. When selecting a patient treatment regimen, it may often be necessary to start with a higher dose and reduce the dose when the condition is controlled. The precise dosage will depend upon the activity of the compound, the mode of administration, the desired treatment, the form of administration, the subject to be treated and the weight of the subject to be treated, as well as the preferences and experience of the attending physician or veterinarian.
Typically, the compounds of the invention are dispensed in unit dosage forms containing from about 0.05mg to about 1000mg of the active ingredient per unit dose and a pharmaceutically acceptable carrier.
In general, dosage forms suitable for oral, nasal, pulmonary or transdermal administration include from about 125 μ g to about 1250mg, preferably from about 250 μ g to about 500mg, more preferably from about 2.5mg to about 250mg of the compound in admixture with a pharmaceutically acceptable carrier or diluent.
The dosage form may be administered once daily, or more than once daily, e.g., twice daily or three times daily. Alternatively, the dosage form may be administered less frequently than once daily, for example every other day or weekly, if deemed appropriate by the prescribing physician.
The pharmaceutical compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquids or gels. Tablets and capsules for oral administration may be in a form suitable for unit dose administration and may contain conventional excipients, such as: binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (PVP); fillers such as lactose, sugars, corn flour, calcium phosphate, sorbitol or glycine; tablet lubricants such as magnesium stearate, silicon dioxide, talc, polyethylene glycol or silicon dioxide; disintegrants such as potato starch; acceptable lubricants such as sodium lauryl sulfate. The tablets may be coated according to known methods of conventional pharmaceutical practice. Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or tinctures, or may be prepared as a dry substance for reconstitution with water or other suitable vehicle before use. These liquid preparations may contain conventional additives such as suspending agents (e.g., sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats and oils). Emulsifying agents (e.g. lecithin, sorbitol monooleate or acacia), non-aqueous vehicles (including edible oils such as almond oil, fractionated coconut oil, fats and oils such as glycerol, propylene glycol or ethanol), preservatives (e.g. methyl or propyl p-hydroxybenzoic acid or sorbic acid), and if desired conventional flavouring or colouring agents.
The percentage of active substance in the pharmaceutical composition of the present invention is variable because the pharmaceutical formulation must be formulated in a suitable proportion of the dosage to achieve the desired therapeutic effect. In general, the pharmaceutical preparations according to the invention should be administered orally or by injection in a dose of 1 to 15mg of active substance per 70kg of body weight per day.
The invention has the beneficial effects that: the invention verifies through experiments that the non-steroidal organic selenium compound shown in the general formula (I) can obviously inhibit mouse abdominal cavity macrophage activation induced by an exogenous stimulant LPS and the subsequent inflammation effect, and meanwhile, the compounds 1-43 and 1-44 have obvious inhibition effect on DSS-induced mouse colitis, which suggests that the non-steroidal organic selenium compound can be used as a potential treatment drug for inflammatory bowel disease related diseases.
Drawings
FIG. 1 is a graph showing the effect of 9 non-steroidal organoselenium compounds on the viability of LPS-activated RAW264.7 cells.
FIG. 2 is a graph showing the effect of 9 non-steroidal organoselenium compounds on the release of Nitrite from LPS-activated RAW264.7 cells.
FIG. 3a is a graph of the effect of compounds 1A-40, 1A-46, 1-43 and 1-44 on the level of iNOS mRNA in LPS-activated RAW264.7 cells.
FIG. 3b is the effect of compounds 1A-39, 1A-49, 1-40 and 1-39 and 1A-38 on the level of iNOS mRNA in LPS-activated RAW264.7 cells.
FIG. 4a is a graph of the effect of compounds 1A-40, 1A-46, 1-43 and 1-44 on the level of IL-1. Beta. MRNA in LPS-activated RAW264.7 cells.
FIG. 4b is a graph of the effect of compounds 1A-39, 1A-49, 1-40 and 1-39 and 1A-38 on the IL-1. Beta. MRNA levels in LPS-activated RAW264.7 cells.
FIG. 5a is a graph of the effect of compounds 1A-40, 1A-46, 1-43 and 1-44 on the level of IL-18mRNA in LPS activated RAW264.7 cells.
FIG. 5b is the effect of compounds 1A-39, 1A-49, 1-40 and 1-39 and 1A-38 on the level of IL-18mRNA from LPS-activated RAW264.7 cells.
FIG. 6a is a graph of the effect of compounds 1A-40, 1A-46, 1-43 and 1-44 on LPS activated RAW264.7 cellular NOX2 subunit p47phox mRNA levels.
FIG. 6b is a graph of the effect of compounds 1A-39, 1A-49, 1-40 and 1-39 and 1A-38 on LPS activated RAW264.7 cellular NOX2 subunit p47phox mRNA levels.
FIG. 7a is a graph of the effect of compounds 1-43 on DSS-induced colitis in mice.
Figure 7b is the effect of compounds 1-44 on DSS-induced colitis in mice.
FIG. 7c is the effect of Compounds 1-43 on colitis disease Activity index DAI.
FIG. 7d is the effect of compounds 1-44 on colitis disease Activity index DAI.
Detailed Description
The following examples are intended to further illustrate the invention and should not be construed as limiting the scope of the invention in any way.
Preparation of the Compound of example 1 (I) preparation of Compounds 1-39
The reaction formula is as follows:
Figure BDA0003088938160000071
a50 ml flask was charged with Compound II-a (100mg, 1.0 eq) and 10ml of anhydrous tetrahydrofuran, and 2-selenoethanol (54mg, 1.2 eq), DCC (62mg, 1.0 eq) and DMAP (44mg, 1.2 eq) were sequentially added under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion. The solvent was removed by distillation under the reduced pressure, and the residue was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) =1 as a mobile phase, resulting in a pale yellow solid, i.e., compound 1-39, 120mg, yield 86%.
Nuclear magnetic resonance 1 H NMR(400MHz,CDCl 3 ):δ2.24(s,3H,-CH 3 ),2.88(s,3H,CH 3 ),3.16(t,2H,J＝8.00Hz,CH 2 ),3.64(s,2H,CH 2 ),3.85(t,2H,J＝8.00Hz,CH 2 ),6.55(t,1H,J＝8.00Hz,ArH),6.80(d,1H,J＝8.00Hz,ArH),7.11(d,1H,J＝4.00Hz,ArH),7.17(s,1H,CH),7.58(d,2H,J＝8.00Hz,ArH),7.73(d,2H,J＝8.00Hz,ArH).
13 C NMR(100MHz,CDCl 3 ):δ11.3,26.2,34.9,43.3,51.2,107.1(d,J＝24Hz),113.9(d,J＝22Hz),122.9,129.4,129.8,130.9,132.4,138.3,140.2,141.4,145.6,147.8(d,J＝9.5Hz),163.2,163.9,165.5,174.8.
19 F NMR(CDCl 3 ,376MHz):δ＝-112.1(s,F).
ESI-MS:471.4([M+1] + ).
Preparation of (di) Compounds 1-40
The reaction formula is as follows:
Figure BDA0003088938160000081
in a 50ml flask, compound II-b (100mg, 1.0 eq) and 10ml of anhydrous tetrahydrofuran were charged, and 2-selenoethanol (72mg, 1.2 eq), DCC (82mg, 1.0 eq) and DMAP (59mg, 1.2 eq) were sequentially added under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion of the reaction. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) = 1.
Nuclear magnetic resonance 1 H NMR(400MHz,CDCl 3 )：δ1.50(d,3H,J＝7.20Hz,CH 3 ),3.13(t,2H,J＝4.00Hz,CH 2 ),3.70(q,1H,J＝7.20Hz,CH),3.81(t,2H,J＝4.00Hz,CH 2 ),7.04-7.11(m,2H,ArH),7.31-7.42(m,4H,ArH),7.46-7.50(m,2H,ArH).
13 C NMR(100MHz,CDCl 3 ):δ18.3,24.2,48.4,53.8,114.7(d,J＝24Hz),124.2,129.1,129.3,129.5,130.4,131.8,136.4,144.5(d,J＝8Hz),159.8,162.5,165.3,178.6.
19 F NMR(CDCl 3 ,376MHz):δ＝-112.2(s,F).
ESI-MS:377.3([M+1] + ).
Preparation of (tri) Compounds 1 to 43
The reaction formula is as follows:
Figure BDA0003088938160000082
in a 50ml flask, compound II-c (100mg, 1.0 eq) and 10ml of anhydrous tetrahydrofuran were charged, and 2-selenoethanol (54mg, 1.2 eq), DCC (62mg, 1.0 eq) and DMAP (44mg, 1.2 eq) were sequentially added under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion of the reaction. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) =1 as a mobile phase, yielding a white solid, i.e., compound 1-43, 120mg, 84% yield.
Nuclear magnetic resonance 1 H NMR(400MHz,CDCl 3 ):δ2.12(s,3H,CH 3 ),3.03(t,2H,J＝8.00Hz,CH 2 ),3.60(t,2H,J＝8.00Hz,CH 2 ),3.64(s,3H,CH 3 ),6.68(d,1H,J＝8.00Hz,ArH),6.86(d,1H,J＝8.00Hz,ArH),7.11(m,1H,ArH),7.60(d,2H,J＝8.00Hz,ArH),7.65(d,2H,J＝8.00Hz,ArH).
13 C NMR(100MHz,CDCl 3 ):δ14.2,26.3,33.5,56.7,101.1,103.7,112.9,114.6,116.4,129.4,130.4,131.3,131.8,133.4,134.2,139.4,157.3,166.7.
ESI-MS:476.8([M+1] + ).
Preparation of (tetra) Compounds 1-44
The reaction formula is as follows:
Figure BDA0003088938160000091
a50 ml flask was charged with Compound II-d (100mg, 1.0 eq) and 10ml of anhydrous tetrahydrofuran, and 2-selenoethanol (72mg, 1.2 eq), DCC (82mg, 1.0 eq) and DMAP (59mg, 1.2 eq) were sequentially added under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion of the reaction. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) =1 as a mobile phase, resulting in a pale yellow solid, i.e., compound 1-44, 100mg, yield 65%.
Nuclear magnetic resonance 1 H NMR(400MHz,CDCl 3 ):δ1.48(d,3H,J＝8.00Hz,CH 3 ),2.12-2.16(m,2H,CH 2 ),3.03(m,2H,CH 2 ),3.68(q,1H,J＝8.00Hz,CH),7.40-7.46(m,3H,ArH),7.61-7.67(m,3H,ArH),7.76-7.82(m,3H,ArH).
13 C NMR(100MHz,CDCl 3 ):δ17.5,31.2,38.5,47.6,102.6,128.0,128.6,129.2,129.7,130.4,131.0,131.5,137.6,138.8,142.2,172.6,193.9.
ESI-MS:387.3([M+1] + ).
(V) preparation of Compound 1A-38
The reaction formula is as follows:
Figure BDA0003088938160000092
in a 50ml flask, compound II-e (100mg, 1.0 eq) and 10ml of anhydrous tetrahydrofuran were charged, and 2-selenoethanol (76mg, 1.2 eq), DCC (86mg, 1.0 eq) and DMAP (62mg, 1.2 eq) were sequentially added under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion of the reaction. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) =1 as a mobile phase, resulting in a pale yellow solid, compound 1A-38, 115mg, 73% yield.
Nuclear magnetic resonance 1 H NMR(400MHz,DMSO):δ2.08(s,3H,CH 3 ),2.32(s,3H,CH 3 ),3.15(t,2H,J＝8.00Hz,CH 2 ),3.67(t,2H,J＝8.00Hz,CH 2 ),6.60–6.64(m,2H,ArH),6.96-6.99(m,1H,ArH),7.06-7.08(m,2H,ArH),7.15-7.17(m,1H,ArH),8.10(d,1H,J＝4.00Hz,ArH),9.67(s,1H,NH).
13 C NMR(100MHz,DMSO):δ13.8,21.2,23.8,48.4,114.8,117.7,119.2,124.4,126.2,126.8,131.1,131.4,134.8,137.3,138.6,147.2,172.5,174.6.
ESI-MS:374.1([M+1] + ).
(VI) preparation of Compound 1A-39
The reaction formula is as follows
Figure BDA0003088938160000101
In a 50ml flask, compound II-f (100mg, 1.0 eq) and 10ml of anhydrous tetrahydrofuran were charged, and 2-selenoethanol (61mg, 1.2 eq), DCC (70mg, 1.0 eq) and DMAP (50mg, 1.2 eq) were sequentially added under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion of the reaction. The solvent was removed by distillation under the reduced pressure, and the residue was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) =1 as a mobile phase, resulting in a pale yellow solid, i.e., compound 1A-39, 100mg, yield 69%.
Nuclear magnetic resonance 1 H NMR(400MHz,CDCl 3 ):δ3.06-3.09(m,2H,CH 2 ),3.68-3.72(m,2H,CH 2 ),3.76(s,2H,CH 2 ),6.48–6.50(m,1H,ArH),6.25(d,1H,J＝8.00Hz,ArH),6.83-6.86(m,1H,ArH),7.03-7.06(m,1H,ArH),7.20-7.24(m,2H,ArH),7.53(d,2H,J＝8.00Hz,ArH),7.67(s,1H,NH).
13 C NMR(100MHz,CDCl 3 ):δ24.9,41.5,51.7,115.6,120.7,124.3,125.8,127.5,129.3,130.4,137.1,143.0,175.8.
ESI-MS:428.0([M+1] + ).
Preparation of (hepta) Compound 1A-40
The reaction formula is as follows
Figure BDA0003088938160000111
A50 ml flask was charged with 10ml of anhydrous tetrahydrofuran and compound II-g (100mg, 1.0 eq), and 2-selenoethanol (52mg, 1.2 eq), DCC (72mg, 1.0 eq) and DMAP (51mg, 1.2 eq) were sequentially added under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) =1 as a mobile phase, resulting in a pale yellow solid, i.e., compound 1A-40, 120mg, yield 81%.
Nuclear magnetic resonance 1 H NMR(400MHz,CDCl 3 ):δ0.88(t,3H,J＝8.00Hz,CH 3 ),1.30(t,3H,J＝8.00Hz,CH 3 ),1.92-2.14(m,2H,CH 2 ),2.75-2.83(m,4H,2×CH 2 ),3.12(q,2H,J＝8.00Hz,CH 2 ),3.16(q,2H,J＝8.00Hz,CH 2 ),3.65-3.71(m,2H,CH 2 ),3.92-4.00(m,2H,CH 2 ),6.94(d,1H,J＝8.00Hz,ArH),7.02(t,1H,J＝8.00Hz,ArH),7.36(d,1H,J＝8.00Hz,ArH).
13 C NMR(100MHz,CDCl 3 ):δ8.6,14.1,23.3,25.7,26.4,32.3,46.7,57.8,62.1,77.5,110.4,117.3,120.5,121.2,127.3,127.4,135.2,135.9,162.1,170.3.
ESI-MS:422.0([M+1] + ).
(VIII) preparation of Compound 1A-46
The reaction formula is as follows
Figure BDA0003088938160000112
In a 50ml flask, compound II-h (100mg, 1.0 eq) and 10ml of anhydrous tetrahydrofuran were charged, and 3-selenocyanopropanol (76mg, 1.2 eq), DCC (86mg, 1.0 eq) and DMAP (62mg, 1.2 eq) were sequentially added under ice-cooling, and the reaction was stirred for 12 hours and monitored by TLC for completion. The solvent was distilled off under reduced pressure, and the extract was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) =1 as a mobile phase, resulting in a pale yellow solid, i.e., compound 1A-46, 120mg, yield 75%.
Nuclear magnetic resonance 1 H NMR(400MHz,CDCl 3 ):δ2.11(s,3H,CH 3 ),2.10-2.22(m,2H,CH 2 ),2.28(s,3H,CH 3 ),3.15(t,2H,J＝8.00Hz,CH 2 ),3.48(q,2H,J＝8.00Hz,CH 2 ),6.48–6.50(m,1H,ArH),6.55(t,1H,J＝8.00Hz,ArH),6.82(d,1H,J＝8.00Hz,ArH),6.90(d,1H,J＝8.00Hz,ArH),7.00(t,1H,J＝8.00Hz,ArH),7.08(d,1H,J＝8.00Hz,ArH),7.12-7.18(m,1H,ArH),7.37(d,1H,J＝8.00Hz,ArH).
13 C NMR(100MHz,CDCl 3 ):δ13.9,21.4,26.4,32.5,37.8,105.7,114.2,115.4,116.3,122.3,124.8,126.3,127.2,131.2,132.3,137.9,138.3,146.5,171.4.
ESI-MS:388.0([M+1] + ).
Preparation of (nine) Compound 1A-49
The reaction formula is as follows
Figure BDA0003088938160000121
In a 50ml flask, compound II-i (100mg, 1.0 eq) and 10ml of anhydrous tetrahydrofuran were charged, and 3-selenocyanopropanol (57mg, 1.2 eq), DCC (72mg, 1.0 eq) and DMAP (51mg, 1.2 eq) were sequentially added under ice-cooling to stir the reaction for 12 hours, and the completion of the reaction was monitored by TLC. The solvent was removed by distillation under the reduced pressure, and the residue was separated by silica gel column chromatography using ethyl acetate (V): petroleum ether (V) =1 as a mobile phase, resulting in a pale yellow solid, i.e., compound 1A-49, 105mg, yield 77%.
Nuclear magnetic resonance 1 H NMR(400MHz,CDCl 3 :δ0.98(t,3H,J＝8.00Hz,CH 3 ),1.35(t,3H,J＝8.00Hz,CH 3 ),1.80-1.92(m,2H,CH 2 ),2.08–2.13(m,2H,CH 2 ),2.38-2.41(m,1H,CH),2.77-2.82(m,5H,CH 2 ,CH 2 ,CH),2.30–2.38(m,1H,CH),3.09-3.16(m,1H,CH),3.50-3.57(m,1H,CH),4.00–4.12(m,2H,CH 2 ),6.72(brs,1H,NH),6.88-6.92(m,1H,ArH),7.00-7.05(m,1H,ArH),7.54(d,1H,J＝8.00Hz,ArH).
13 C NMR(100MHz,CDCl3):δ8.3,15.4,23.2,24.3,27.3,31.2,31.9,38.4,44.2,61.4,75.4,101.8,108.2,116.9,120.2,120.8,126.6,127.4,132.8,134.2,170.1.
ESI-MS:436.1([M+1] + ).
Example 2 biological and pharmacological evaluation of 9 non-steroidal organoselenium Compounds (one) Effect of 9 non-steroidal organoselenium compounds on LPS-activated RAW264.7 cell viability
The method comprises the following steps: the principle of detecting the cell survival rate by adopting the CCK-8 method is that in the presence of an electronic coupling reagent 1-Methoxy-5-methylphenazinium dimethyl sulfate (1-Methoxy PMS), WST-8 contained in the CCK-8 reagent can be reduced into a very water-soluble orange-yellow substance Formazan (Formazan) by dehydrogenase in cells, and the amount of the Formazan production content is in direct proportion to the amount of the living cells. The faster the cells proliferated, the greater the amount of color developed by the solution, and the absorbance of the solution at 450nm was used to calculate cell viability.
1. RAW264.7 cells in good growth state were centrifuged and counted and diluted to density and then centrifuged at 2 × 10 per well 4 The number of cells was seeded in a 96-well plate at 100. Mu.l per well for about 18h, and an equal volume of PBS solution was added to the peripheral wells of the seeded wells.
2. The composition comprises a blank control group, an LPS stimulation and non-steroidal organic selenium compound group and an LPS and sulindac positive drug group. When the cells attached to the wall and grown to the appropriate density, the corresponding compounds at each concentration were added for treatment for 24h.
3. After 24h of treatment with each compound, 10. Mu.l of CCK-8 solution was added to each well and allowed to react for 1h with gentle shaking.
4. After the reaction is finished, detecting the OD value of each hole at the wavelength of 450nm by using an enzyme-labeling instrument, and calculating the cell survival rate
Cell viability = OD of experimental group/OD of control group × 100%.
As shown in FIG. 1, it can be seen from FIG. 1 that 9 organoselenium compounds have no significant toxic side effects on RAW264.7 cells in different concentration gradients (3. Mu.M, 10. Mu.M, 30. Mu.M, 100. Mu.M), except that 1A-49 and 1A-40 have significant toxic side effects on cells at a high concentration of 100. Mu.M.
(II) influence of 9 non-steroidal organic selenium compounds on release of Nitrite by RAW264.7 cells activated by LPS
The method comprises the following steps: indirectly measuring the content of NO by adopting a Griess method: the detection principle is that NO is easily oxidized into nitrite (NO 2-) in cells or solution, the nitrite reacts with Griess reagent under an acidic condition to generate the diazo compound and the diazo compound is a purple red complex, and the NO level is in direct proportion to the amount of the diazo compound. The NO content in the cell supernatant was reflected by a quantitative measurement of the OD of the diazo compound.
After LPS stimulated RAW264.7 cells, LPS activated RAW264.7 cells were treated with 9 non-steroidal organoselenium compounds (3, 10, 30, 100. Mu.M) and 300. Mu.M sulindac for 24h and cell supernatants were collected.
2. Taking out the Griess I and Griess II reagents from a refrigerator at the temperature of 20 ℃ below zero, and placing the reagents in a laboratory for half an hour for unfreezing.
3. The standard and experimental groups were divided on a 96-well plate, and each concentration standard (concentration 1,2.5,5, 10, 20, 40, 60, 100. Mu.M, 3 replicate wells per concentration) was added to each standard well at 50. Mu.l/well. 50 μ l of cell supernatant was added to the wells, and each set was replicated in 5 wells.
4. Add 50. Mu.l Griess I to each well with a line gun, shake the 96-well plate gently from side to side, cover with tinfoil, and react for 10min in the dark.
5. Then, 50. Mu.l of Griess II was added to each well, and the 96-well plate was shaken gently from side to side, covered with tin foil, and reacted for 10min in the dark.
6. The absorbance OD of the 96-well plate was measured at 540nm with a microplate reader.
7. And calculating and drawing a standard curve, and calculating the corresponding NO concentration of each hole according to the marked curve.
As shown in FIG. 2, it can be seen from FIG. 2 that the release amount of Nitrite was reduced by the 9 organoselenium compounds under different concentration gradients (3. Mu.M, 10. Mu.M, 30. Mu.M, 100. Mu.M). The organic selenium compounds 1-40, 1-44, 1-43 and 1A-49 have better effect.
(III) Effect of 9 non-steroidal organoselenium Compounds on the level of iNOS mRNA in LPS-activated RAW264.7 cells
The method comprises the following steps: after LPS stimulated RAW264.7 cells, LPS activated RAW264.7 cells were treated with 9 non-steroidal organoselenium compounds (10, 30. Mu.M) and 300. Mu.M sulindac for 24h and collected.
2. mRNA was extracted sequentially with 1mL Trizol, 0.2mL nucleic acid extract, 0.45mL isopropanol, 0.8mL 75% ethanol wash, and 40. Mu.L DEPC water according to the nucleic acid extraction kit instructions.
3. According to the specification of the cDNA synthesis kit, firstly, 1ug of mRNA volume is added into a PCR centrifuge tube, then 2.0ul of gDNA is added to remove DNA contained in mRNA, RNase Free dH2O is added to the mRNA to 10ul, the mixture is centrifuged briefly, and the mixture is incubated at 42 ℃ for 3min and then placed on ice. The reverse transcription system was prepared on ice using a 200ul PCR tube according to the instructions, mixed well and centrifuged briefly. Reverse transcription was performed in a PCR instrument at 95 ℃ for 15s and 42 ℃ for 15 min. After completion of reverse transcription, the cDNA concentration was measured and recorded at 260/280.
4. Preparing a reaction system according to the instructions of a qualitative real-time PCR reaction kit, and setting conditions to pre-denature for 10min at 95 ℃, denature for 15s at 95 ℃, anneal for 60s at 60 ℃, extend for 30s at 72 ℃, melt curve for 15s at 95 ℃, 40 cycles for 1min at 60 ℃ and react for 15s at 95 ℃. After completion of the reaction, data were stored using the GAPDH gene as an internal control, 2 -△△Ct C resulting from the method on each geneAnd (5) carrying out difference analysis on the T value.
Inducible Nitric Oxide Synthase (iNOS) is a catalytic enzyme for the production of body active nitrogen. When the body is injured, the expression level of iNOS is up-regulated, and a large amount of NO is released. Therefore, the influence of different concentrations of the 9 organic selenium compounds on the transcription level of iNOS in RAW264.7 cells activated by LPS is detected by an experimental application quantitative PCR method. As shown in FIGS. 3a and 3b, it can be seen from FIGS. 3a and 3b that the LPS-induced iNOS expression level in RAW264.7 cells was significantly decreased by the addition of the organoselenium compound to the cells treated with the organoselenium compound.
(IV) Effect of 9 non-steroidal organoselenium Compounds on IL-1. Beta. MRNA levels in LPS-activated RAW264.7 cells
The method comprises the following steps: the same as the third method.
The content of IL-1 beta mRNA transcribed by the activated RAW264.7 cells is detected by using a qRCR method. IL-1 beta is a proinflammatory factor in inflammatory responses, and when an inflammatory signaling pathway is activated, a large number of neuroinflammatory factors are released, causing cell damage. As a result, as shown in FIGS. 4a and 4b, it can be seen from FIGS. 4a and 4b that the IL-1. Beta. MRNA level was significantly increased in the LPS group compared to the Control group. After 9 organic selenium compounds are added, the IL-1 beta mRNA level is obviously reduced after treatment at the concentration of 10 mu M and 30 mu M for a period of time.
(V) Effect of 9 non-steroidal organoselenium Compounds on IL-18mRNA levels in LPS-activated RAW264.7 cells
The method comprises the following steps: the same as the third method.
The content of the IL-18mRNA transcribed by the activated RAW264.7 cells is detected by a qPCR method. IL-18 is also a proinflammatory factor in the inflammatory response. As shown in FIGS. 5a and 5b, it can be seen from FIGS. 5a and 5b that the IL-18mRNA transcription level of LPS group was significantly increased compared to that of Control group. After 9 organic selenium compounds are added and treated at the concentration of 10 mu M and 30 mu M for a period of time, IL-18mRNA is down-regulated, wherein the down-regulation of 1-43, 1-44 and 1A-49 is more obvious.
(six) Effect of 9 non-steroidal organoselenium Compounds on LPS activated RAW264.7 cellular NOX2 subunit p47phox mRNA levels
The method comprises the following steps: the same as the third method.
The content of p47phox mRNA transcribed by the activated RAW264.7 cells was determined by the qRCR method. NOX2 (NADPH oxidase 2) is nicotinamide adenine dinucleotide oxidase (NADPH oxidase), is distributed in neutral granules and phagocytes, thymus, colon and the like, and is involved in regulating cell proliferation, differentiation, apoptosis, intercellular signal pathways and the like. NOX2 is a complex composed of six subunits, gp91phox, p22phox, p47phox, p67phox, p40phox and GTPase Rac. Wherein two subunits of gp91phox and p22phox are located on plasma membrane, and four subunits of p47phox, p67phox, p40phox and GTP enzyme Rac are located in cytoplasm. phosphorylation of p47phox can carry p67phox, and p40phox can be transferred to cell membrane to combine with p22phox to regulate NOX2 assembly. p47phox plays a very important role, and NOX2 is one of the main sources of ROS, and excessive NOX 2-mediated release of ROS can lead to oxidative stress, causing inflammation. As shown in fig. 6a and 6b, it can be seen from fig. 6a and 6b that p47phoxmRNA levels were significantly increased in LPS group compared to Control group. After 9 organoselenium compounds were added, treatment at both 10. Mu.M and 30. Mu.M concentrations for a period of time reduced p47phox mRNA levels, with 1-43, 1-44 and 1A-40 being particularly significant.
(VII) influence of non-steroidal organic selenium compounds 1-43 and 1-44 on DSS-induced colitis in mice
The method comprises the following steps: 60C 57 mice were divided into 6 groups of control, DSS model, DSS +1-43, DSS +1-44 and 1-44, each group consisting of 10 mice. Mice are adaptively bred under breeding conditions for one week, DSS induces colitis after one week, distilled water is always drunk by a blank group, a DSS model group and a medicine group are changed into 3.5% DSS solution, and the model is built for seven days, and during the period, the weight, the excrement shape and the bleeding condition are weighed daily to comprehensively calculate whether a colitis activity index (Disease activity index DAI) evaluation model is successful or not. The calculation formula is as follows: DAI = (body mass index + stool shape + bleeding score)/3.
After the molding was successful, the administration group was administered at 20mg/kg for 15 days, and then the colon was taken out from the sacrificed mice, and the length of the colon was measured. As shown in FIGS. 7a to 7b, it can be seen from FIGS. 7a to 7b that the colon was significantly shortened in the DSS group and significantly restored in the mice after the treatment with the administration of 1-43 and 1-44, compared to the control group. Shows that the compounds 1-43 and 1-44 can reduce and recover the DSS-induced colitis of mice.
FIGS. 7c and 7d are colitis Disease activity index (Disease activity index DAI), and as can be seen from FIGS. 7c and 7d, the DAI in the DSS group was significantly increased and the DAI in the mice of groups 1-43 and 1-44 administered with the NSAID was significantly decreased, compared to the blank control group, indicating that colitis in the mice was treated and improved.

Claims (9)

1. The application of the non-steroidal organic selenium compound in preparing the medicine for treating or preventing the diseases related to the intestinal inflammation is characterized in that the non-steroidal organic selenium compound has a structure shown in a general formula (I):
R a -R b -C(W)-O-L-SeCN (I)
wherein the content of the first and second substances,
R a represents an aryl or heteroaryl group, optionally substituted by one, two or three substituents selected from: phenyl, methylsulfonylphenyl C 1-4 Alkyl, halobenzoyl, halophenylamino, benzoyl, C 1-4 Alkylphenylamino, halogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkoxy radical, C 1-4 Alkyl acyl radical, C 1-4 Alkylamino, halogeno C 1-4 An alkyl group;
R b is a linear or branched alkylene chain or alkenylene chain of 1 to 4 carbon atoms, or is a direct covalent bond;
w is selected from O, S and Se;
l is a straight or branched alkylene chain of 1 to 4 carbon atoms.
2. Use according to claim 1, characterized in that: ra is selected from unsubstituted or substituted phenyl, indenyl, naphthyl, phenylaminophenyl, benzoylphenyl, benzopyrryl, benzopyrrolidinyl and benzopyrrolidinooxeyclohexyl;
wherein the substituent is selected from phenyl and methylsulfonylphenyl C 1-4 Alkyl, halophenyl-formyl, phenyl-formyl, C 1-4 Alkylphenylamino, halogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkyl, halo C 1-4 Alkoxy, acyl, C 1-4 Alkyl acyl, acyloxy, C 1-2 Alkyl acyloxy, C 1-2 An alkylamino group; and the number of the first and second electrodes,
wherein the heteroaryl group is selected from the group consisting of a benzopyrroliyl group, a benzopyrrolidinyl group, and a phenylpyrrolidinooxeclocyclohexyl group.
3. Use according to claim 1, wherein W is O.
4. Use according to claims 1-3, wherein R is a Selected from phenyl, phenylaminophenyl, benzoylphenyl, indenyl, benzopyrryl, benzopyrrolidinyl and benzopyrrolidino-oxacyclohexyl, and R a Optionally substituted with one or two substituents selected from: halogen selected from fluorine, chlorine, bromine, iodine, phenyl, phenylamino, benzoyl, methoxy, straight-chain or branched alkyl of 1 to 4 carbon atoms, C 1-4 An alkoxy group.
5. Use according to claims 1-3, wherein L is (CH) 2 ) 2 Or (CH) 2 ) 3 。
6. Use according to claim 1, characterized in that said non-steroidal organoselenium compounds are selected from the following compounds:
Figure FDA0003088938150000021
7. the use according to claim 1 or 6, wherein the non-steroidal organoselenium compound is used as an active ingredient to prepare a pharmaceutical composition together with pharmaceutically acceptable excipients and/or carriers.
8. The use of claim 1 or 6, wherein the intestinal inflammation-related disorder comprises inflammatory bowel disease.
9. The use according to claim 8, wherein the inflammatory bowel disease comprises ulcerative colitis and Crohn's disease.
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