CN113861194B - Pyrrolopyridine-containing bisamide imidazole compound and preparation method and application thereof - Google Patents
Pyrrolopyridine-containing bisamide imidazole compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a pyrrolopyridine-containing bisamide imidazole compound and a preparation method and application thereof. The chemical structure of the pyrrolopyridine-containing bisamide imidazole compound is shown as a formula (I). The compound provided by the invention has anti-inflammatory activity (inhibiting the generation of NO and the release of inflammatory cytokines), can effectively inhibit the generation of NO in RAW264.7 cells induced by Lipopolysaccharide (LPS), shows higher in-vivo anti-inflammatory efficacy in a DSS-induced colitis mouse model, and has NO obvious toxicity. The pyrrolopyridine bisamide imidazole-containing compound is expected to be a novel efficient and safe anti-IBD drug.
Description
Technical Field
The invention belongs to the field of organic small molecule medicines, and particularly relates to a pyrrolopyridine-containing bisamide imidazole compound, and a preparation method and application thereof.
Background
Inflammatory enteritis (IBD) is a high autoimmune disease in humans, and is clinically manifested by repeated abdominal pain, diarrhea, abdominal mass, mucous bloody stool, intestinal obstruction, intestinal perforation, weight loss, and the like. With the rising incidence in western countries, inflammatory bowel disease has become an important disease affecting human health. According to the pathological characteristics and the different disease sites, the disease is classified into Ulcerative Colitis (UC) and Crohn's Disease (CD). When intestinal homeostasis is imbalanced, intestinal mucosal permeability is increased, leading to an impaired intestinal mucosal barrier function, mediating the development of IBD. Compared with normal mucosal lamina propria macrophages, the intestinal mucosal macrophages in lesion local colon tissues of patients with active IBD are remarkably increased in number and tend to be more activated, which indicates that the intestinal macrophages play an important role in the occurrence and development of IBD. Bone marrow-derived macrophages can be induced by different stimuli to polarize to form macrophages of different phenotypes and functions, mainly M1 type and M2 type. Among them, M1-type macrophages secrete a large amount of proinflammatory cytokines after being stimulated and activated, and decompose L arginine to generate NO and Reactive Oxygen Species (ROS) through high-expression Inducible Nitric Oxide Synthase (iNOS), participate in processes such as phagocytosis of bacteria, chemotaxis of inflammatory cells, promotion of Th1 and Th17 cell-mediated immune response, and the like, exert host immune functions, and cause inflammatory injury of intestinal tissues of IBD patients.
There are many drugs currently used for treating IBD, mainly including aminosalicylates (such as sulfasalazine or mesalamine (5-ASA)), adrenoglucocorticoids (such as prednisolone), immunosuppressants (such as thiopurine or methotrexate), biologicals (such as TNF inhibitors), and the like. The glucocorticoid can quickly relieve symptoms by combining with glucocorticoid receptor in nucleus, has anti-inflammatory effect, is suitable for acute attack of IBD, and has no effect on sufficient treatment of aminosalicylic acid. However, systemic side effects caused by gastrointestinal absorption, such as acquired infection, diabetes, osteoporosis and the like, limit the applicability of glucocorticoids. In recent years, oral formulations of Budesonide (Budesonide) and Beclomethasone (Beclomethasone) have received attention because of their high local anti-inflammatory activity and low systemic side effects. These drugs are delivered to the intestinal mucosa specifically after oral administration. The medicine can be quickly and effectively inactivated after being absorbed by intestinal tracts, thereby playing a local anti-inflammatory role. Due to the complexity of IBD, these drugs are only partially effective and have toxicity problems, and thus there is still a need to develop novel anti-IBD drugs that are highly effective and safe.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a pyrrolopyridine bisamide imidazole compound which has anti-inflammatory bioactivity, is nontoxic and is expected to be a novel anti-IBD medicament.
The above object of the present invention is achieved by the following technical solutions:
a pyrrolopyridine-contained bisamide imidazole compound and pharmaceutically acceptable salts thereof are disclosed, wherein the chemical structure of the compound is shown as the formula (I):
the specific name of the compound is N' - (2- (1H-pyrrolo [2,3-b ] pyridine-3-yl) -1H-imidazole-4-carbonyl) pyridine formylhydrazine.
The term "pharmaceutically acceptable salt" refers to a salt that has the properties of being biologically effective and salt-forming compound and that does not produce adverse reactions when administered to a mammal, preferably a human. In the present invention, the pharmaceutically acceptable salt is mainly an acid salt. Pharmaceutically acceptable salts include inorganic or organic salts; examples of pharmaceutically acceptable salts include, but are not limited to, carbonate, hydrochloride, hydrobromide, sulfate, bisulfate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalenesulfonate and p-toluenesulfonate.
The preparation method of the pyrrolopyridine-containing bisamide imidazole compound comprises the following steps:
s1, reacting 3, 3-dibromo-1, 1, 1-trifluoropropan-2-one with 1H-pyrrolo [2,3-b ] pyridine-3-formaldehyde in the presence of ammonia water and formaldehyde to obtain an intermediate 1;
s2, acidifying the intermediate 1 to obtain an intermediate 2;
s3, reacting the intermediate 2 with pyridine formylhydrazine to obtain the pyrrolopyridine-containing bisamide imidazole compound;
the intermediate 1 is 3- (4- (trifluoromethyl) -1H-imidazol-2-yl) -1H-pyrrolo [2,3-b ] pyridine; the intermediate 2 is 2- (1H-pyrrolo [2,3-b ] pyridine-3-yl) -1H-imidazole-4-carboxylic acid.
Preferably, in S1, the molar ratio of 3, 3-dibromo-1, 1, 1-trifluoropropan-2-one to 1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde is 1-1.2: 1.
Preferably, in S1, the intermediate 1 is prepared by dissolving 3, 3-dibromo-1, 1, 1-trifluoropropan-2-one in an aqueous solution, then adding 1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde, ammonia water and formaldehyde and stirring overnight.
S1, the chemical reaction is as follows:
preferably, in s1, intermediate 1 is directly subjected to the reaction of s2 without purification.
Preferably, in S2, the intermediate 1 is acidified by dissolving the intermediate 1 in an ethanol aqueous solution, adding sodium hydroxide, stirring, cooling to room temperature, and acidifying with hydrochloric acid to obtain the intermediate 2.
S3, the chemical reaction is as follows:
preferably, in S3, the intermediate 2 is dissolved in DMF, and is reacted with pyridine formylhydrazine in the presence of BOP under alkaline conditions, and the reaction product is separated to obtain the pyrrolopyridine-containing bisamide imidazole compound.
S3, the chemical reaction is as follows:
the application of the pyrrolopyridine-containing bisamide imidazole compound and pharmaceutically acceptable salts thereof in preparing anti-inflammatory drugs.
The application of the pyrrolopyridine-contained bisamide imidazole compound and the pharmaceutically acceptable salt thereof in preparing anti-inflammatory drugs for inhibiting the generation of NO and the release of inflammatory cytokines.
The application of the pyrrolopyridine-contained bisamide imidazole compound and the pharmaceutically acceptable salt thereof in preparing the medicines for treating inflammatory enteritis is provided.
Compared with the prior art, the invention has the following beneficial effects:
the invention discloses a pyrrolopyridine-bisamide imidazole-containing compound, which has anti-inflammatory activity, can effectively inhibit NO generation in RAW264.7 cells induced by Lipopolysaccharide (LPS), shows high in-vivo anti-inflammatory efficacy in a DSS-induced colitis mouse model, and has NO obvious toxicity. Is expected to be a novel high-efficiency and safe anti-IBD drug.
Drawings
FIG. 1 is a hydrogen spectrogram of nuclear magnetic resonance of the pyrrolopyridine-containing bisamide imidazole compound.
FIG. 2 is a graph showing that the pyrrolopyridine bisamide-containing imidazole compounds of the present invention inhibit the release of inflammatory cytokines at the protein level.
FIG. 3 is a signal diagram of the pyrrolopyridine-containing bisamide imidazole compound for inhibiting TLR 4-NF-kB and NLRP 3-caspase-1.
FIG. 4 is a graph showing the effect of pyrrolopyridine bisamide imidazole-containing compounds of the present invention on the treatment and protection of mice against DSS-induced colitis.
Detailed Description
Example 1 (Synthesis of the pyrrolopyridine-containing bisamide imidazole-based Compound)
Preparation of Compound (I)
S1. to an aqueous solution of sodium acetate (2.5mmol), 3-dibromo-1, 1, 1-trifluoropropan-2-one (1.2mmol) was added and stirred at 90 ℃ for 30 minutes to dissolve 3, 3-dibromo-1, 1, 1-trifluoropropan-2-one in water. Then adding 1H-pyrrolo [2,3-b ]]Pyridine-3-carbaldehyde (1mmol), NH4OH (10mmol) and methanol and stirring overnight to give 3- (4- (trifluoromethyl) -1H-imidazol-2-yl) -1H-pyrrolo [2,3-b]The crude pyridine (intermediate 1) is directly fed into the next step.
The chemical reaction formula of the step S1 is as follows:
s2, dissolving the intermediate 1 crude product (1mmol) obtained in the step S1 in H2O/C2H5To a solution in OH (1:9, 100mL) and then addedSodium hydroxide solid (10mmol) was added and the resulting mixture was stirred at 90 ℃ for 2 h. Cooling the mixture to room temperature, adding hydrochloric acid to acidic conditions to obtain 2- (1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -1H-imidazole-4-carboxylic acid (intermediate 2).
The chemical reaction formula of the step S2 is as follows:
s3. take intermediate 2(1mmol) obtained in step S2. dissolve in DMF solution, then add TEA (2mmol), BOP (2mmol) and pyridine carbohydrazide (1mmol) and stir overnight. And adding water into the reaction mixture, and purifying by silica gel flash column chromatography to obtain the pyrrolopyridine bisamide imidazole compound.
The process route of the method for synthesizing the pyrrolopyridine-containing bisamide imidazole compound is as follows:
the obtained yellow solid is identified by nuclear magnetic resonance spectrum and mass spectrum, and the identification result is as follows:1h NMR (400MHz, DMSO) δ 13.40(s,1H),13.21(s,1H),10.52(s,1H),10.11(s,1H),8.74(t, J ═ 6.8Hz,2H), 8.12-8.02 (m,2H),7.79(s,1H), 7.70-7.65 (m,1H),7.61(d, J ═ 8.4Hz,1H),7.45(t, J ═ 7.6Hz,1H),7.25(t, J ═ 7.5Hz, 1H). Mass spectrum M/z 346.1(M-H)-. From the above identification results, it was found that the obtained yellow solid was N' - (2- (1H-pyrrolo [2, 3-b))]Pyridine-3-yl) -1H-imidazole-4-carbonyl) pyridine formhydrazide with a structural formula
The overall yield of the process described in this example was calculated to be 13%.
Example 2 (anti-inflammatory Activity study)
The in vitro/in vivo anti-inflammatory activity of the compounds of the invention was demonstrated using the following assay. These effects indicate that the compounds of the present invention inhibit Lipopolysaccharide (LPS) -induced NO production in RAW264.7 macrophages, and that Lipopolysaccharide (LPS) stimulates NO release in macrophages, playing an important role in inflammatory conditions. In addition, in vivo animal experiments show that the compound can obviously reduce DSS-induced colonic inflammation. The specific test method is as follows:
(1) lipopolysaccharide (LPS) stimulates NO release in macrophages and plays an important role in inflammatory conditions. Therefore, we evaluated the inhibitory effect of the newly synthesized compounds of formula (i) on LPS-induced NO production in RAW264.7 cells. To rule out the possibility that inhibition of NO production was due to cytotoxicity of these compounds, MTT-based cell viability assays were performed in RAW264.7 cells treated with single compounds and LPS for 48 hours. RAW264.7 cells were plated at 1X 105cells/mL density in 96-well culture plates, 37 ℃ and 5% CO2. After 24 hours, cells stimulated with LPS from E.coli (final concentration 100ng/mL) were treated with different compounds (10. mu.M) in DMEM supplemented with 10% FBS for 24 hours. Nitrite concentration in the culture medium was measured by a colorimetric assay based on Griess reaction. Briefly, 50 μ L of medium was collected, added to a 96-well plate, and reacted with 1% sulfanilamide, 0.1% naphthylethylenediamine dihydrochloride, and 2.5% phosphoric acid at room temperature for 10 minutes in the absence of light. The plate was read at 540nm compared to sodium nitrite as a standard. For each experiment, LPS stimulated NO release was assigned as 100%.
Inhibition of NO production in RAW264.7 cells stimulated by LPS by the compounds of formula (I) was tested. As shown in table 1:
TABLE 1 inhibition of NO production in RAW264.7 cells stimulated by LPS by the compounds of formula (I)
The results of the above in vitro experiments show that the compound of formula (I) shows the highest NO inhibitory activity with an inhibition rate of 83%, which is better than that of the positive control dexamethasone (75%), without causing significant cytotoxicity (IC)50>50μM)。
(2) Macrophages stimulated by LPS may express proinflammatory cytokines such as IL-6, IL-1 β, and TNF α. Therefore, we investigated the inhibitory effect of compounds on IL-6, IL-1. beta. and TNF. alpha. expression at the protein level. As shown in FIG. 2, the compounds of formula (I) inhibited the expression of IL-6 (FIG. 2A), IL-1 β (FIG. 2B) and TNF α (FIG. 2C) concentration-dependently. These results indicate that the compounds of formula (I) in addition to inhibiting NO production, also down-regulate the expression of other inflammatory mediators at the protein level, such as IL-6, IL-1 β and TNF α. The compounds reduce the protein levels of IL-6(A), IL-1 β (B) and TNF α (C) in LPS-stimulated macrophages. Not determined, LPS group compared to control group###＝p<0.001；**＝p<0.01 compared to LPS group (n ═ 3).
(3) In LPS-stimulated macrophages, the compounds reduced the expression of pp65 and caspase1 at the mRNA level, but not TLR 4; the compounds reduced the expression of TLR4, pp65, NLRP3 and caspase1 at protein level in LPS-stimulated macrophages (n-3), as shown in figure 3.
(4) To explore the in vivo anti-inflammatory activity of the compounds of formula (I) of the present invention, we used the acute DSS colitis model to evaluate their in vivo anti-inflammatory effects. Except for the control group, each mouse was given 3.5% DSS solution and treated with compound (25mg/kg) orally for 5 days. To determine if the model was successful, we collected the colon and performed histopathological and immunohistochemical analyses. As shown in fig. 4, histopathological and immunohistochemical analysis showed that mice taking DSS exhibited crypt abscesses, loss of goblet cells and mucus layer, and significant infiltration of neutrophils into the lamina propria (fig. 4B, 4E, arrows) compared to the negative control group (fig. 4A, 4C). The colon structure of the treatment group of the compound of formula (I) of the invention is almost intact and the inflammatory cells are few (FIGS. 4C and 4F), which shows that the compound of formula (I) of the invention can obviously reduce DSS-induced colonic inflammation.
According to the in vivo and in vitro experimental results, the compound shown as the formula (I) can effectively inhibit the generation of NO in RAW264.7 cells induced by LPS, and shows high in vivo anti-inflammatory efficacy without obvious toxicity in a DSS-induced colitis mouse model. The compound is a potent anti-inflammatory compound, which may potentially be developed as a novel therapy for the treatment of inflammatory bowel disease.
Claims (10)
1. A pyrrolopyridine-bisamide imidazole-containing compound and pharmaceutically acceptable salts thereof are characterized in that the chemical structure of the compound is shown as the formula (I):
2. the pyrrolopyridine-containing bisamide imidazole compounds and the pharmaceutically acceptable salts thereof according to claim 1, wherein the pharmaceutically acceptable salts are acid salts.
3. The preparation method of the pyrrolopyridine-bisamide-containing imidazole compound according to claim 1, which is characterized by comprising the following steps:
s1, reacting 3, 3-dibromo-1, 1, 1-trifluoropropan-2-one with 1H-pyrrolo [2,3-b ] pyridine-3-formaldehyde in the presence of ammonia water and formaldehyde to obtain an intermediate 1;
s2, acidifying the intermediate 1 to obtain an intermediate 2;
s3, reacting the intermediate 2 with pyridine formylhydrazine to obtain the pyrrolopyridine-contained bisamide imidazole compound;
the intermediate 1 is 3- (4- (trifluoromethyl) -1H-imidazol-2-yl) -1H-pyrrolo [2,3-b ] pyridine; the intermediate 2 is 2- (1H-pyrrolo [2,3-b ] pyridine-3-yl) -1H-imidazole-4-carboxylic acid.
4. The preparation method according to claim 3, wherein in S1, the molar ratio of 3, 3-dibromo-1, 1, 1-trifluoropropan-2-one to 1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde is 1 to 1.2: 1.
5. The process of claim 3, wherein in S1, intermediate 1 is directly reacted in S2. without purification.
6. The preparation method according to claim 3, wherein in S2, the intermediate 1 is acidified by dissolving the intermediate 1 in an ethanol aqueous solution, adding sodium hydroxide, stirring, cooling to room temperature, and acidifying with hydrochloric acid to obtain the intermediate 2.
7. The preparation method according to claim 3, wherein in S3, the intermediate 2 is dissolved in DMF, and is reacted with pyridine carbohydrazide in the presence of BOP under alkaline conditions, and the reaction product is separated to obtain the pyrrolopyridine-containing bisamide imidazole compound.
8. The use of pyrrolopyridine-containing bisamide imidazole compounds and pharmaceutically acceptable salts thereof as claimed in claim 1 for the preparation of anti-inflammatory agents.
9. The use of pyrrolopyridine-containing bisamide imidazole compounds and pharmaceutically acceptable salts thereof according to claim 1 for the preparation of anti-inflammatory drugs that inhibit the production of NO and the release of inflammatory cytokines.
10. The use of a pyrrolopyridine-containing bisamide imidazole compound and a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for the treatment of inflammatory bowel disease.
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| CN109843322A (en) * | 2016-08-26 | 2019-06-04 | 百时美施贵宝公司 | The inhibitor and its application method of indole amine 2,3-dioxygenase |
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| CN113396145A (en) * | 2018-10-15 | 2021-09-14 | 盖罗发现有限责任公司 | PFKFB3 inhibitors and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109843322A (en) * | 2016-08-26 | 2019-06-04 | 百时美施贵宝公司 | The inhibitor and its application method of indole amine 2,3-dioxygenase |
| CN110088105A (en) * | 2016-12-16 | 2019-08-02 | 詹森药业有限公司 | The micromolecular inhibitor of JAK family kinase |
| CN113396145A (en) * | 2018-10-15 | 2021-09-14 | 盖罗发现有限责任公司 | PFKFB3 inhibitors and uses thereof |
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| 《Novel 4- Aryl-2(1H)-phthalazinone Derivatives as Cyclooxygenase-2 Inhibitors: Synthesis, Molecular Modeling Study and Evaluation as Promising Anti-inflammatory Agents》;Hasabelnaby, Sherifa;《Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry》;20151231;第14卷(第3期);全文 * |
| 《Synthesis and anti-inflammatory evaluation of some condensed [4-(3,4-dimethylphenyl)-1(2H)-oxo-phthalazin-2-yl]acetic acid hydrazide》;Abd alla, Mosaad S. M.;《European Journal of Medicinal Chemistry》;20101231;第45卷(第4期);全文 * |
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