Pyridine derivatives and their applications in medicine

Abstract

Disclosed are pyridine derivatives and their application in medicine. The pyridine derivatives have good binding effect with LANCL2 protein and have significant medicinal effects on ulcerative colitis.

Description

Technical Field

[0001] The present invention relates to pyridine derivatives and their application in medicine. Background Art

[0002] Inflammatory bowel disease (IBD) is a common autoimmune disease. The current treatment for this disease is not satisfactory and has serious side effects. The common treatment for moderate to severe IBD is TNF monoclonal antibody, which is not only expensive, but also needs to be injected intravenously or subcutaneously, and there is also a risk of infection. Lanthionine C-like protein 2 (LANCL2) is a signaling pathway protein expressed in immune cells, gastrointestinal tract, neurons, testis and pancreas. Activation of the LANCL2 pathway can reduce the proinflammatory factors TNF-α, INF-γ, IL-6 and MCP1, and increase the anti-inflammatory activity of regulatory T cells. Therefore, LANCL2 agonists have the potential to treat inflammatory bowel disease (IBD). Summary of the invention

[0003] One or more embodiments of the present application provide a compound or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0004]

[0005] One or more embodiments of the present application provide a pharmaceutical composition, comprising:

[0006] (1) The compound of the present application, or a stereoisomer or a pharmaceutically acceptable salt thereof;

[0007] (2) optionally one or more other active ingredients; and

[0008] (3) Pharmaceutically acceptable carriers and / or excipients.

[0009] One or more embodiments of the present application provide use of the compound of the present application or a stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present application in the preparation of a drug for inflammatory bowel disease.

[0010] One or more embodiments of the present application provide use of the compound of the present application or a stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present application in the preparation of a LANCL2 agonist.

[0011] One or more embodiments of the present application provide the compound of the present application or a stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present application, which is used in medicine.

[0012] One or more embodiments of the present application provide a compound of the present application or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, for use in treating inflammatory bowel disease.

[0013] One or more embodiments of the present application provide a compound of the present application or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, which is used as a LANCL2 agonist.

[0014] One or more embodiments of the present application provide a method for treating inflammatory bowel disease, comprising administering the compound of the present application or a stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present application to a subject in need thereof.

[0015] One or more embodiments of the present application provide a method for activating LANCL2, comprising administering the compound of the present application or a stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present application to a subject in need thereof.

[0016] Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0017] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12C, 13C and 14C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16O, 17O and 18O, sulfur isotopes include 32S, 33S, 34S and 36S, nitrogen isotopes include 14N and 15N, fluorine isotopes include 17F and 19F, chlorine isotopes include 35Cl and 37Cl, and bromine isotopes include 79Br and 81Br.

[0018] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0019] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0020] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0021] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0022] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0023] "Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group. DETAILED DESCRIPTION

[0024] The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0025] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0026] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

[0027] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0028] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0029] Example 1

[0030] N,N'-((1s,3s,5s,7s)-adamantane-1,3-diyl)bis(6-(1H-benzo[d]imidazol-2-yl)pyridinamide)(Compound 1)

[0031] N,N'-((1s,3s,5s,7s)-adamantane-1,3-diyl)bis(6-(1H-benzo[d]imidazol-2-yl)picolinamide)

[0032]

[0033] 6-(1H-benzimidazol-2-yl)picolinic acid 1a (purchased from Chengdu Aisite Chemical Technology Co., Ltd., 1 g, 4.18 mmol) was dissolved in 4 mL of N, N-dimethylformamide, stirred at 0°C for 10 min, and N, N-diisopropylethylamine (650 g, 5.02 mmol) was added, and stirring was continued at 0°C for 10 min. 1-hydroxybenzotriazole (850 mg, 6.28 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.28 mmol) were added, and stirring was continued at 0°C for 10 min. 1,3-adamantanediamine 1b (purchased from Aikang Biotechnology, 350 mg, 2.09 mmol) was added, and the temperature was gradually raised to 80°C and stirred for 4 h. The reaction solution was cooled to room temperature, 10 mL of water was added to the reaction system, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, and spin-dried. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v)=10 / 1) to obtain compound 1 as a white solid (400 mg, 32% yield, 98% purity).

[0034] 1 H NMR (400MHz, DMSO-d6) δ = 13.33 (s, 2H), 8.47-8.51 (m, 4H), 8.13-8.20 (m, 4H), 7.76 (d ,2H),7.69(d,2H),7.33-7.24(m,4H),2.71(s,2H),2.21-2.37(m,10H),1.74(s,2H).

[0035] LC-MS m / z(ESI)=609.30[M+1].

[0036] Example 2

[0037] (2,6-diazaspiro[3.3]heptane-2,6-diyl)bis(((6-(1H-benzo[d]imidazol-2-yl]pyridin-2-yl)methanone)(Compound 2)

[0038] (2,6-diazaspiro[3.3]heptane-2,6-diyl)bis((6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)methanone)

[0039]

[0040]

[0041] 6-(1H-Benzimidazole-2-yl)picolinic acid 1a (purchased from Chengdu Aisite Chemical Technology Co., Ltd., 1 g, 4.18 mmol) was dissolved in 4 mL of N,N-dimethylformamide, stirred at 0°C for 10 min, and then N,N-diisopropylethylamine (650 mg, 5.02 mmol) was added, and stirring was continued at 0°C for 10 min. Then 1-hydroxybenzotriazole (850 mg, 6.28 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.28 mmol) were added, and stirring was continued at 0°C for 10 min. After adding 2,6-diazaspiro[3.3]heptane 2a (205 mg, 2.09 mmol), the temperature was gradually raised to 80°C for reaction for 4 h. The reaction solution was cooled to room temperature, 10 mL of water was added to the reaction system, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to obtain compound 2 as a yellow solid, 800 mg, with a yield of 73%.

[0042] 1 H NMR (400MHz, DMSO-d6) δ12.65(s,2H),8.45(d,2H),8.04(m,4H),7.72(d,4H),7.27(d,4H),5.08(m,4H),4.42(m,4H).

[0043] LC-MS m / z(ESI)=541.2[M+1].

[0044] Example 3

[0045] (R)-4-((1Z,3E)-5-(4-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperazin-1-yl)-2-methyl-5-oxopentyl-1,3-dien-1-yl)-4-hydroxy-3,5,5-trimethylcyclohex-2-en-1-one (Compound 3)

[0046] (R)-4-((1Z,3E)-5-(4-(6-(1H-benzo[d]imidazol-2-yl)picolinoyl)piperazin-1-yl)-2-methyl-5-oxopenta-1,3-dien-1-yl)-4-hydroxy-3,5,5-trimethylcyclohex-2-en-1-one

[0047]

[0048] According to the synthesis method of compound 1, 1a (purchased from Chengdu Aisite Chemical Technology Co., Ltd., 1.2 g) was reacted with 3a (180 mg) to prepare 3b, and then 3b (1.12 g) and 3c (purchased from Huajieming Biotechnology, 1.32 g) were separated according to the synthesis method of compound 1 to obtain 1.1 g of white solid compound 3, with a yield of 39.7%.

[0049] 1 H NMR (400 MHz, DMSO-d 6 )δ12.90(s,1H),8.39(dd,1H),8.13(t,1H),7.73(d,1H),7.68(d,1H),7.57(t ,1H),7.25(dt,2H),7.00(d,1H),6.13-5.98(m,2H),5.81(s,1H),5.18(d,1H), 3.71-3.59(m,4H),3.60-3.41(m,4H),2.14-2.07(m,2H),1.96-1.88(m,3H),1.81(d,3H),0.99-0.88(m,6H).

[0050] LC-MS m / z(ESI)=554.66[M+1].

[0051] Example 4

[0052] [4,4'-Bipiperidinyl]-1,1'-diacylbis((6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)methanone)(Compound 4)

[0053] [4,4'-bipiperidine]-1,1'-diylbis((6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)methanone)

[0054]

[0055] According to the synthesis method of compound 1, 1a (purchased from Chengdu Aisite Chemical Technology Co., Ltd., 760 mg) was reacted with 4a (268 mg) to prepare and separate 360 ​​mg of light yellow solid compound 4, with a yield of 37%.

[0056] 1 H NMR(400MHz,DMSO-d6)δ12.96(s,2H),8.36(ddd,2H),8.09(td,2H),7.71(s,2H),7.61-7.53(m,4H),7.23(s,5H),4.60 (s,2H),3.58(d,2H),3.08(t,2H),2.77(t,2H),2.07(s,4H),1.92-1.76(m,2H),1.62(t,2H),1.44(s,2H),1.23(s,4H).

[0057] LC-MS m / z(ESI)=612.72[M+1].

[0058] Example 5

[0059] ((3as,6as)-tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-diyl)bis((6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)methanone)(Compound 5)

[0060] ((3as,6as)-tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-diyl)bis((6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)methanone)

[0061]

[0062] According to the synthesis method of compound 1, 1a (purchased from Chengdu Aisite Chemical Technology Co., Ltd., 3.8 g) and 5a (purchased from Huajieming Biotechnology, 900 mg) were reacted to prepare and separate 400 mg of light yellow compound 5 with a yield of 9.0%.

[0063] 1H NMR (400 MHz, DMSO-d 6 )δ12.93(s,1H),12.88(s,1H),8.42(dd,1H),8.36(dd,1H),8.14(t,1H),8.08(t,1H),7.80(d,2H),7.74(d,1H),7.69(d,1H),7.61(d,1H) ,7.53(d,1H),7.33–7.16(m,4H),4.18(dd,1H),4.05(dd,1H),3.93(dd,1H),3.84(dd,1H),3.67(td,2H),3.51(td,2H),3.12–3.00(m,2H).

[0064] LC-MS m / z(ESI)=554.60[M+1].

[0065] Biological evaluation

[0066] 1. Binding affinity constant (K) for LANCL2 D )

[0067] Biacore S200 was used to measure the affinity (K) of the compounds to LANCL2. D The specific method is as follows. The LANCL2 protein was fixed on a CM5 sensor chip, and MOPS (10mM MOPS, 150mM NaCl, 5% DMSO and 0.05% Tween 20, pH 6.5) was used as the running buffer. The test compound was diluted to 0.024μM, 0.049μM, 0.098μM, 0.19μM, 0.39μM, 0.78μM, 1.56μM, 3.12μM, 6.25μM, 12.5μM and 25μM, with an injection flow rate of 30μL / min, a contact time of 90s, and a dissociation time of 900s. The results are shown in Table 1.

[0068] Table 1 Binding affinity constants (K) of the compounds of the present invention to LANCL2 protein D )

[0069] Example No. <![CDATA[K D / μM]]> Compound 1 7.3μM

[0070] Conclusion: The compounds of the present invention have good binding effect with LANCL2 protein.

[0071] 2. Pharmacokinetics (PK) in rats

[0072] 180-220g healthy adult male SD rats (purchased from Chengdu Dashuo Experimental Animal Co., Ltd.) were fasted overnight and fed uniformly 4h after administration. 80mg / kg (solvent is 0.5% MC solution) of the compound of the present invention was orally administered by gavage, and plasma, colon contents and colon tissue were collected at 0h, 0.5h, 2h, 8h and 24h, respectively. The drug concentration in the sample was determined by LC-MS / MS method, and the blood drug concentration-time curve was drawn. The main pharmacokinetic parameters were calculated by WinNonlin 6.3 software. The results are shown in Table 2.

[0073] Table 2 Pharmacokinetic experimental results in rats

[0074]

[0075] Note: ND means not detected.

[0076] Conclusion: The results of the pharmacokinetic experiment in rats showed that the compounds of the present invention were mainly distributed in the colon contents and not in the blood within 24 hours, and had good intestinal targeting.

[0077] 3. Efficacy of DSS in ulcerative colitis induced in mice

[0078] The experimental animals were SPF healthy female C57BL / 6J mice, weighing 17-20 g, a total of 80 (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.). The animals were kept in a special cage for mice, at a temperature of 20±2°C, a humidity of 40-70%, a 12-h light-dark cycle, and were fed with regular maintenance feed and had free access to water.

[0079] The mice were randomly divided into groups, with 10 mice in each group. The grouping and dosing are shown in Table 3. The animals in the model group and the drug-treated group were allowed to drink 3% DSS aqueous solution freely, and continued to drink until the ulcerative colitis model was successfully established. The DSS aqueous solution was removed and they drank water normally afterwards. The control substance (Compound 2 of Example 2 of WO2016064445 patent, purchased from MCE) and the compound of the present invention were continuously administered at any time, and the normal group and the model group were given an equal volume of solvent. The condition of the animals was observed and recorded every day, and the DAI score was calculated; at the end of the experiment, the animals were dissected, and the colon weight and length, and spleen weight were detected. The experimental results are shown in Table 3.

[0080] Table 3 Drug efficacy in DSS-induced ulcerative colitis in mice

[0081] Group Administration time / (day) DAI Rating Normal group 10 0.6 Model Group 10 4.2 Reference substance 50mg / kg 10 2.8 Compound 1 10mg / kg 10 2.8 Compound 1 50mg / kg 10 1.2

[0082] Conclusion: The experimental results show that the compound of the present invention can achieve the same therapeutic effect when the dosage is only 1 / 5 of the dosage of the reference product, and the efficacy is more significant when the dosage is 50 mg / kg.

[0083] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principle of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

2. A pharmaceutical composition, the pharmaceutical composition include: (1) The compound according to claim 1, or a pharmaceutically acceptable salt thereof; (2) one or more other active ingredients; as well as (3) Pharmaceutically acceptable carriers and / or excipients.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating inflammatory bowel disease.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 2 in the preparation of a LANCL2 agonist.

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