WO2022002225A1 - 一种吲哚衍生物及其应用 - Google Patents
一种吲哚衍生物及其应用 Download PDFInfo
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- WO2022002225A1 WO2022002225A1 PCT/CN2021/104138 CN2021104138W WO2022002225A1 WO 2022002225 A1 WO2022002225 A1 WO 2022002225A1 CN 2021104138 W CN2021104138 W CN 2021104138W WO 2022002225 A1 WO2022002225 A1 WO 2022002225A1
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- WIPO (PCT)
- Prior art keywords
- halogen
- methyl
- alkyl
- cyclopentyl
- hydrogen
- Prior art date
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- C—CHEMISTRY; METALLURGY
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Definitions
- the invention belongs to the field of medicinal chemistry, and relates to an indole derivative, a preparation method thereof and its use in preparing a medicine for preventing and/or treating indications related to S1P receptor-related disorders.
- Sphingosine 1-phosphate receptor belongs to the family of G protein-coupled receptors, and five subtypes have been found, named S1PR1, 2, 3, 4 and 5 respectively. Different subtypes are distributed differently in each tissue. Among them, S1PR1, 2 and 3 are widely distributed, S1PR4 is mainly expressed in blood cells and lymphocytes, and S1PR5 is expressed in the skin and central system. S1PR1 can produce immunosuppression by controlling the migration of lymphocytes, and S1PR3 can cause acute toxicity and bradycardia, resulting in side effects.
- S1PR1 modulators can be used to treat various immune diseases such as multiple sclerosis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, atopic dermatitis, eosinophilic esophagitis, alopecia areata, primary Cholangitis, pyoderma gangrenosum, psoriasis, rheumatoid arthritis, graft versus host disease, etc.
- immune diseases such as multiple sclerosis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, atopic dermatitis, eosinophilic esophagitis, alopecia areata, primary Cholangitis, pyoderma gangrenosum, psoriasis, rheumatoid arthritis, graft versus host disease, etc.
- S1PR modulators have been marketed for multiple sclerosis, Novartis' fingolimod (target S1PR1, 3, 4, 5) and sinimod (target S1PR1, 5), and ozanimod of BMS (target S1PR1, 5), in which ozanimod has completed phase III clinical studies for ulcerative colitis in addition to multiple sclerosis, and phase III clinical trials for Crohn's disease are in progress.
- IBD Inflammatory bowel disease
- UC ulcerative colitis
- CD Crohn's disease
- the main treatment drugs for IBD are 5-aminosalicylic acid, glucocorticoids, and immunosuppressive drugs, but they have limited efficacy and are accompanied by many immunosuppressive adverse reactions.
- the treatment of IBD is entering the biological era of immune regulation, mainly including pro-inflammatory cytokine inhibitors, anti-inflammatory cytokines, cell adhesion
- the rapid development of these drugs has greatly enriched the treatment of IBD, and opened up new ideas for the treatment of IBD, especially severe and refractory IBD. But there are still many treated patients who do not experience remission, and up to 80% of CD patients and 30% of UC patients ultimately require surgery. There is also a huge unmet medical need in this area.
- the object of the present invention is to provide a new indole derivative, its preparation method and its use.
- the indole derivatives of the present invention have high activity and good safety, and are ideal S1P receptor modulators.
- the present invention adopts the following technical solutions:
- One aspect of the present invention provides an indole derivative represented by the general formula (I):
- Z 1 and Z 2 are each independently selected from N or CR a ;
- R 1 , R 3 , R 4 are each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, 3- to 8-membered cycloalkyl, or 3- to 8-membered heterocyclyl;
- R 2 is selected from (CR b R c ) m -(Cy) p -(CR b R c ) n -COOH, (CR b R c ) m -(Cy) p -(CR b R c ) n -OH, (CR b R c) m - (Cy) p - (CR b R cb) n -CN , or (CR b R c) m - (Cy) p - (CR b R c) n -CONR b R c;
- R a , R b , R c are each independently selected from hydrogen, halogen or C 1-6 alkyl;
- Cy is selected from 3 to 8 membered cycloalkyl or heterocyclyl
- R 5 is selected from 3-8 yuan cycloalkyl or heterocyclyl
- R 6 is selected from halogen or halogen substituted methyl
- the heterocyclyl contains 1-3 selected N, heteroatoms O, S; said alkyl, alkoxy, cycloalkyl, or heterocyclyl optionally substituted with 0-6 halo, C 1-6 Alkyl or C 1-6 alkoxy substituted;
- n are each independently selected from an integer from 0 to 3.
- R 1 is selected from hydrogen, halogen or C 1-4 alkyl; preferably, R 1 is selected from fluorine, chlorine, methyl, ethyl, isopropyl or tert-butyl; more preferably, R 1 is selected from chlorine, methyl or ethyl.
- Z 1 and Z 2 are selected from CR a ;
- R 2 is selected from (CR b R c ) m -(Cy) p -(CR b R c ) n -COOH, (CRR b R c ) m - (Cy) p - (CR b R c) n -OH , or (CR b R c) m - (Cy) p - n -CN (CR b R c);
- R a , R b , and R c are each independently selected from hydrogen or C 1-6 alkyl; preferably, R a , R b , and R c are all hydrogen;
- Cy is selected from 3 to 8 membered cycloalkyl or heterocyclyl
- the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S; the alkyl, cycloalkyl or heterocyclic group is optionally replaced by 0-6 halogen, C 1-6 alkyl or C 1-6 alkoxy substitution;
- n are each independently selected from an integer from 0 to 3.
- Z 1 , Z 2 are selected from CH, and R 2 is (CH 2 ) 2 COOH or (CH 2 ) 3 COOH;
- R 3 is hydrogen, fluoro, chloro, methyl, ethyl, isopropyl or tert-butyl; preferably, R 3 is hydrogen, fluorine or methyl; more preferably, R 3 is hydrogen or fluoro; more preferably, R 3 is hydrogen.
- R 4 is hydrogen, fluoro, chloro, methyl, ethyl, isopropyl or tert-butyl; preferably, R 3 is hydrogen, fluorine or methyl; more preferably, R 4 is hydrogen or fluoro; more preferably, R 4 is hydrogen.
- R 5 is selected from 3 to 8 membered cycloalkyl optionally substituted with 0 to 3 halogens or C 1-6 alkyl, preferably cyclobutyl, cyclopentyl or cyclohexyl, more preferably is cyclopentyl.
- R 6 is selected from fluoro, monofluoromethyl, difluoromethyl or trifluoromethyl, preferably fluoro or trifluoromethyl.
- R 1 is selected from chlorine, methyl or ethyl
- R 2 is selected from (CH 2 ) 2 -COOH or (CH 2 ) 3 -COOH
- R 3 , R 4 are hydrogen
- R 5 is ring Amyl
- R 6 is trifluoromethyl.
- the described indole derivative has the structure shown in the general formula (I-1):
- R 1 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;
- R 2 is selected from (CR b R c ) m -COOH; m is selected from an integer from 0 to 3;
- R b , R c are each independently selected from hydrogen, halogen or C 1-6 alkyl
- R 5 is selected from 3-8 yuan cycloalkyl or heterocyclyl
- R 6 is selected from halogen or halogen substituted methyl
- heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, heteroatoms O, S; said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally substituted with 0-6 halo, C 1- 6 alkyl or C 1-6 alkoxy substituted.
- R 1 is selected from hydrogen, halogen, C 1-3 alkyl
- R 2 is selected from (CR b R c ) m- COOH
- m is selected from an integer from 0 to 3
- R b , R c each independently selected from hydrogen, halogen or C 1-3 alkyl
- R 5 is selected from 5- to 7-membered cycloalkyl
- R 6 is selected from halogen or halogen-substituted methyl
- the alkyl and cycloalkyl are optionally 0-3 halogen, C 1-3 alkyl substituted.
- R 1 is selected from halogen, C 1-3 alkyl
- R 2 is selected from (CH 2 ) m- COOH
- m is independently selected from an integer from 2 to 3
- R 5 is selected from 5 to 7-membered cycloalkyl
- R 6 is selected from halogen or methyl substituted with 1-3 halogens.
- R 1 is selected from F, Cl, methyl, ethyl
- R 2 is selected from (CH 2 ) m- COOH
- m is independently selected from an integer from 2 to 3
- R 5 is selected from Cyclopentyl, cyclohexyl
- R 6 is selected from F, Cl, trifluoromethyl, difluoromethyl, fluoromethyl.
- the indole derivatives of the present invention include but are not limited to the following compounds:
- the indole derivatives of the present invention include but are not limited to the following compounds:
- Another object of the present invention is to provide the synthetic method of indole derivative represented by general formula (I'-1), comprising the following steps:
- Method 1 Convert fragment A1 into indole ring intermediate 1-1, intermediate 1-1 is connected to fragment B1 on indole ring N to obtain intermediate 2-1, and intermediate 2-1 is then reacted with fragment C1 to obtain intermediate Body 3-1:
- Method 2 The fragment A1 is first reacted with the fragment C1 to obtain the intermediate 1'-1, the intermediate 1'-1 is further converted into the indole ring precursor intermediate 2'-1, and the intermediate 2'-1 is connected to the fragment B1 Intermediate 3-1 is obtained:
- Z 1 and Z 2 are each independently selected from N or CR a ;
- R 1 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, 3- to 8-membered cycloalkyl or 3-8 yuan heterocyclyl group;
- R 5 is selected from 3-8 yuan cycloalkyl or heterocyclyl;
- R 6 is selected from halogen or halogen-substituted methyl group;
- R a is independently selected from hydrogen, halo or C 1-6 alkyl;
- R 7 is a hydroxyl protecting group, preferably C 1-6 alkyl or benzyl
- R 8 is selected from amino or nitro
- R 9 is C 1-6 alkyl
- X is halogen, preferably chlorine or bromine
- X' is selected from hydrogen or halogen, preferably hydrogen, chlorine or bromine;
- r and q are each independently selected from an integer of 1 to 3.
- Z 1 and Z 2 are each independently selected from N or CR a ;
- R 1 is selected from chlorine, methyl or ethyl;
- R 5 is cyclopentyl, and
- R 6 is trifluoromethyl.
- R 7 is methyl or benzyl;
- R 8 is amino or nitro;
- R 9 is methyl or ethyl;
- X is chlorine;
- X' is hydrogen or bromine; .
- Z 1 and Z 2 are defined as C, the defined indole derivatives are shown in formula (I'), and the preparation method thereof includes the following steps:
- Method 1 Convert fragment A into indole ring intermediate 1, connect fragment B to indole ring N of intermediate 1 to obtain intermediate 2, and then react intermediate 2 with fragment C to obtain intermediate 3:
- Method 2 The fragment A is first reacted with the fragment C to obtain the intermediate 1', the intermediate 1' is further converted into the indole ring precursor intermediate 2', and the intermediate 2' is connected to the fragment B to obtain the intermediate 3:
- R 1 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;
- R 5 is selected from 3 to 8 membered Cycloalkyl or heterocyclyl;
- R 6 is selected from halogen or halogen-substituted methyl; that is, R 1 , R 5 , R 6 are as defined in claim 1;
- R 7 is a hydroxyl protecting group, preferably C 1-6 alkyl or benzyl
- R 8 is amino or nitro
- R 9 is C 1-6 alkyl
- X is halogen, preferably chlorine or bromine
- X' is selected from hydrogen or halogen, preferably hydrogen, chlorine or bromine;
- r and q are each independently selected from an integer of 1 to 3.
- R 1 is selected from F, Cl, methyl, ethyl
- R 5 is selected from cyclopentyl, cyclohexyl
- R 6 is selected from F, Cl, trifluoromethyl, difluoromethyl, fluoromethyl. That is, R 1 , R 5 and R 6 are as defined in claim 4; R 7 is methyl or benzyl; R 8 is amino or nitro; R 9 is methyl or ethyl; X is chlorine; X' is hydrogen or Bromine; r, q are each independently selected from integers from 1 to 3.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the indole derivative of general formula (I) and a pharmaceutically acceptable carrier thereof.
- the present invention also relates to the indole derivative of general formula (I), or a pharmaceutical composition containing an effective amount of the indole derivative of general formula (I) in the preparation of a method for treating and/or preventing S1P receptor-related disorders. Use in medicine for disease.
- the S1P receptor-related disorder is selected from Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis, multiple sclerosis, atopic dermatitis, eosinophilic Esophagitis, alopecia areata, primary cholangitis, pyoderma gangrenosum, graft-versus-host disease, amyotrophic lateral sclerosis, systemic lupus erythematosus, type I diabetes arteriosclerosis, atherosclerosis, scleroderma disease, autoimmune hepatitis, acne, microbial and viral infections.
- the present invention has the following advantages compared with the prior art:
- the compound provided by the invention has novel structure and strong activity, and provides a new method for preventing or treating including but not limited to ulcerative colitis and Crohn's disease by effectively regulating the S1P corresponding receptor. Compared with the prior art, the compounds of the present invention have higher activity and better efficacy.
- Figure 1 Gross anatomy of the colon of rats in each group after TNBS modeling and continuous administration for 7 days.
- the structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS), and the purity was determined by liquid high pressure chromatography (HPLC).
- NMR nuclear magnetic resonance
- MS mass spectrometry
- HPLC liquid high pressure chromatography
- the thin layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
- the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm-0.2mm, and the size of the TLC separation and purification products is 0.4mm-0.5mm.
- reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
- Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
- Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
- the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
- the solution refers to an aqueous solution.
- reaction temperature is room temperature, which is 20°C to 30°C.
- the raw materials and reagents used in the present invention can be prepared by conventional methods or commercially available unless otherwise specified.
- 2-Methyl-4-methoxyaniline (1a) (5.0 g, 36.4 mmol) was dissolved in toluene (20 mL), and boron trichloride (37 mL, 1M dichloromethane solution) was added successively at -78 °C, Titanium tetrachloride (37 mL, 1M in dichloromethane) and chloroacetonitrile (3.1 g, 41 mmol).
- the reaction solution was heated to 90°C and stirred for 3h.
- a 2M aqueous hydrochloric acid solution (30 mL) was added to the reaction system, and the mixture was stirred at 85° C. for 45 min.
- Step 6 3-(5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-7-methyl-1H-indol-1-yl)propionic acid (1)
- reaction solution was concentrated under reduced pressure, and the residue was prepared by high pressure liquid chromatography (acetonitrile/water (containing 0.1% formic acid, gradient elution) to obtain 3-(5-((4-cyclopentyl-3-(trifluoro) as a white solid.
- Methyl)benzyl)oxy)-7-methyl-1H-indol-1-yl)propionic acid (1) (50.5 mg, yield: 34.7%).
- Step 6 3-(5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-7-ethyl-1H-indol-1-yl)propionic acid (2)
- the third step ethyl 3-(7-chloro-5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1H-indol-1-yl)propanoate (3d )
- the fourth step 3-(7-chloro-5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1H-indol-1-yl)propionic acid (3)
- the fifth step 3-(5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-7-methyl-1H-indol-1-yl)propylmethylsulfonic acid Acetate (4f)
- Step 7 4-(5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-7-methyl-1H-indol-1-yl)butanoic acid (4)
- the first step 3-(7-chloro-5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1H-indol-1-yl)propan-1-ol ( 5a)
- Step 2 3-(7-Chloro-5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1H-indol-1-yl)propylmethanesulfonic acid Ester (5b)
- the third step 4-(7-Chloro-5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1H-indol-1-yl)butyronitrile (5c)
- Step 4 4-(7-Chloro-5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1H-indol-1-yl)butanoic acid (5)
- Example 1 Using ethyl 2-(5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1H-indol-1-yl)acetate (6d) as raw material, Example 1 was used Compound 2-(5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1H-indol-1-yl)acetic acid (6) was synthesized by the synthetic method of the sixth step in the above.
- Example 7 Determination of the activity of S1P1 high-expressing cells
- the buffer was prepared according to the preparation method in the manual of LiveBLAzerTM-Fluorescence Resonance Energy Transfer B/G Loading Kit.
- test results are basically the same.
- Example 8 Treatment of animal colitis [2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced ulcerative colitis in rats]
- TNBS 2,4,6-trinitrobenzenesulfonic acid
- TNBS comes from Dalian Meilun Biotechnology Co., Ltd.
- the animals were fasted (without water) for 24 hours, and after inhalation anesthesia with isoflurane, all rats were infused with 0.5ml/rat of TNBS ethanol solution (18mg TNBS/rat) through the rectum with a latex tube, and the length of the tube into the rectum was about 8cm. After the hose was withdrawn, the isoflurane anesthesia was maintained and the rat was kept in an elevated and inclined state for 15 min.
- TNBS ethanol solution 18mg TNBS/rat
- rats were randomly divided into 5 groups: model group, positive control drug sulfasalazine (SASP, 360mg/kg) group, test substance Example 3 compound (3mg/kg) group, test substance Etrasimod (3mg/kg) group. /kg) group, test substance Ozanimod (10mg/kg) group.
- SASP positive control drug sulfasalazine
- the compound of Example 3 of the present invention has a purity of 99.74%.
- Etrasimod prepared according to the literature method (the second isomer of Example 1.29 of WO2010/011316A1), purity: 98.47%.
- Sulfasalazine enteric-coated tablets produced by Shanghai Fuda Pharmaceutical Co., Ltd., 0.25g/tablet. Enteric-coated film-coated tablets, after removing the coating, show yellow to brownish-yellow color.
- Test Substance Example 3 Compound and Etrasimod solution preparation: respectively take 27 mg of test substance and dissolve in 45 mL of solvent to obtain the corresponding test substance solution.
- Ozanimod Dissolve 90 mg of Ozanimod in 45 mL of solvent to obtain an Ozanimod solution.
- SASP solution preparation 6 sulfasalazine enteric-coated tablets were ground and added to 41.7 mL of 0.5% CMC-Na, and dissolved by ultrasonic to obtain SASP solution.
- the rats On the next day after TNBS modeling, the rats had loose stools, and some of the rat feces were formed or semi-formed, but the feces were obviously bloody.
- the model rats were accompanied by symptoms of reduced diet, fatigue, weight loss, piloerection and dull hair.
- the blood in the stool and loose stools of the rats in each group improved slowly over time.
- the excretion of the feces of the rats in each group gradually returned to normal, and the rats with abnormal defecation showed a decrease in the amount of defecation.
- the symptoms of pus and blood in the stool of the rats in each administration group did not show a significant improvement trend after modeling.
- DSS dextran sodium sulfate molecular weight 36000-50000, from MP Biomedical Company.
- Preparation of molding agent preparation of 3.5% DSS: 49 g of DSS plus 1400 mL of high-temperature sterilized water.
- mice were divided into groups according to body weight, 10 mice in each group. Dosing by gavage (or blank) once a day in Table 4 below.
- solvent 1 Mix 0.66mL DMSO, 1.32mL Solutol and 11.22mL Saline to prepare 13.2mL solvent 1;
- Preparation of the compound solution of Example 3 Take 39.6 mg of the compound of Example 3 and dissolve it in 13.2 mL of solvent 1 to obtain the compound solution 1 of Example 3; respectively, dilute the compound solution 1 of Example 3 with solvent 1 to prepare a concentration of 2 mg/ mL, 1 mg/mL, 0.6 mg/mL of the compound solution of Example 3;
- Etrasimod solution take 6mg Etrasimod and dissolve it in 6mL of solvent 2 to obtain Etrasimod solution;
- Example 3 the purity of the compound in Example 3 was 99.74%, Ozanimod and Etrasimod were prepared according to the method described in Example 8, and the purity was 99.78% and 98.47%, respectively.
- mice were weighed every two days. After the mice started to drink the 3.5% DSS solution freely, their body weight almost stopped. From the sixth day of continuous modeling, the mice in the model group and the administration group showed obvious weight loss, and with the increase of modeling days, the weight loss became more obvious. The body weight of mice increased with the increase of feeding days; during day6-day9, the daily body weight of 3.5% DSS-induced ulcerative colitis mice was significantly different from that of the blank group (P ⁇ 0.05). There was no significant difference between the administration groups, and the results are shown in Table 5-1 and Table 5-2.
- mice were observed for fecal shape, bleeding or not every two days and scored.
- Stool condition scoring standard shape: normal (grade 1), soft stool (grade 2), loose stool (grade 3); traits: normal (grade 1), faint redness (grade 2), gross bloody stool (grade 3).
- mice After the mice drank the 3.5% DSS solution freely for 5 days, most of the mice in the model group developed bloody stools. With the increase of time, the bloody stools became more and more obvious, and the stools gradually turned into soft and loose stools. The stools were scored on day 8. It also reached the peak. On day 8, 3.5% DSS was replaced with autoclaved water, and the administration was continued. One day later, the compound of Example 3 (30 mg/kg), the compound of Example 3 (20 mg/kg), the compound of Example 3 (20 mg/kg) and Example 3 were dissected one day later.
- the compound (10mg/kg) and the compound of Example 3 (6mg/kg) can obviously improve the bloody stool and loose stool of mice, and compared with the model group, there is a statistically significant difference (P ⁇ 0.05), Ozanimod (20mg/kg) kg) and Etrasimod (10 mg/kg) groups did not significantly improve the feces of animals, and the results are shown in Table 6.
- the animals were dissected on the next day (day 9) after the last administration (8 consecutive days), the colon was isolated, the colon was photographed as a whole and the length of the colon was measured, then the colon was longitudinally dissected along the mesenteric side, the contents were removed, weighed and the integrity of the colon mucosa was observed . The colon was then fixed in 10% formalin.
- mice continuously drank 3.5% DSS solution freely for 7 days and continued to be given autoclaved water for 1 day, and their colons atrophied.
- the colon weight of the mice in the model group was significantly reduced compared with the mice in the blank group that drank autoclaved water freely, with a statistically significant difference (P ⁇ 0.05).
- the blank group had a statistically significant difference (P ⁇ 0.001) (Table 7).
- the compound of Example 3 which was orally administered to the test substance by oral gavage for 8 consecutive days, had a certain effect of inhibiting colon atrophy in mice.
- the colon weight of each administration group was significantly heavier than that of the model group, among which the compound of Example 3 (20 mg/kg), the compound of Example 3 (10 mg/kg), the compound of Example 3 (6 mg/kg), and Etrasimod (10 mg/kg) Compared with the model group, the colon weight has a statistically significant difference (P ⁇ 0.05), and the colon length of the compound of Example 3 (30mg/kg), the compound of Example 3 (20mg/kg), and Ozanimod (20mg/kg) is longer than that of the model group group, and the results are shown in Table 7.
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Abstract
提供一种通式(I-1)所示的吲哚衍生物及其在制备预防和/或治疗与S1P受体相关障碍的适应症的药物中的用途。所述吲哚衍生物在不同位点分别被R 1、R 2、R 5和R 6取代，修饰后的吲哚衍生物具有优异的生物活性，是理想的高效S1P受体调节剂。通式（I-1）化合物可用于治疗和/或预防克罗恩病、溃疡性结肠炎、银屑病、类风湿性关节炎、多发性硬化症、特应性皮炎、嗜酸细胞性食管炎、斑秃、原发性胆管炎、坏疽性脓皮症、移植物抗宿主病、肌肉萎缩性侧索硬化症、系统性红斑狼疮、I型糖尿病动脉硬化、动脉粥样硬化、硬皮病、自身免疫性肝炎、痤疮、微生物感染和病毒感染等多种自身免疫和炎性疾病。
Description
本申请要求2020年07月03日向中国国家知识产权局提交的，专利申请号为202010638390.0，发明名称为“一种吲哚衍生物及其应用”的在先申请的优先权。该申请的全文通过引用的方式结合于本申请中。
本发明属于医药化学领域，涉及一种吲哚衍生物、其制备方法及其在制备预防和/或治疗与S1P受体相关障碍相关适应症的药物中的用途。
磷酸鞘氨醇受体(sphingosine 1-phosphate receptor，S1PR)属于G蛋白偶联受体家族，目前已发现5种亚型，分别称为S1PR1、2、3、4和5。不同亚型在各组织中分布不同。其中，S1PR1、2和3分布广泛，S1PR4主要表达于血液细胞和淋巴细胞，S1PR5表达于皮肤和中枢系统。S1PR1可通过控制淋巴细胞的迁移而产生免疫抑制，S1PR3可导致急性毒性及心动过缓，从而产生副作用。
S1PR1调节剂可用来治疗各种免疫性疾病，如多发性硬化症、溃疡性结肠炎、克罗恩病、系统性红斑狼疮、特应性皮炎、嗜酸细胞性食管炎、斑秃、原发性胆管炎、坏疽性脓皮症、银屑病、类风湿性关节炎、移植物抗宿主病等。
S1PR调节剂已有3个用于多发性硬化症的药物上市，分别为诺华的芬戈莫德(靶点S1PR1、3、4、5)和西尼莫德(靶点S1PR1、5)，以及BMS的ozanimod(靶点S1PR1、5)，其中ozanimod除了多发性硬化症外，还完成了用于溃疡性结肠炎的Ⅲ期临床研究，用于克罗恩病的Ⅲ期临床试验正在进行中。此外还有多款药物在研发中，如强生的进入NDA状态的多发性硬化症药物ponesimod，Arena公司处于Ⅲ期临床研究的溃疡性结肠炎和克罗恩病药物etrasimod，Idorsia处于Ⅱ期临床研究的系统性红斑狼疮药物cenerimod等。
炎症性肠病(IBD)是一种病因不明的慢性肠道疾病，主要类型为溃疡性结肠炎(UC)和克罗恩病(CD)。IBD影响了全世界500万人，欧美等发达国家已经经历过快速发展阶段，目前发病率约30/10万。亚洲成为增加最快的地区，近几十年 来新发病例开始飙升。目前我国IBD总病例数约40万，是IBD发病率最高的亚洲国家，特别是近10年，UC增长2.3倍多，CD增长甚至达到15倍多。
IBD的治疗药物主要有5-氨基水杨酸、糖皮质激素、免疫抑制剂三类经典药物，但疗效有限且伴随很多免疫抑制不良反应。随着大量关于IBD的研究以及循证医学的发展对治疗产生的积极的推进作用，IBD的治疗正进入免疫调节的生物学时代，主要包括促炎细胞因子抑制剂、抗炎细胞因子、细胞粘附分子抑制剂、T细胞抗体等，这些药物的迅速发展极大地丰富了IBD的治疗，开拓了IBD尤其是重症难治性IBD治疗的新思路。但至今仍有许多接受治疗的患者并没有得到缓解，高达80％的CD患者和30％的UC患者最终需要接受手术。该领域还有巨大的医疗需求未被满足。
发明内容
本发明的目的在于提供一种新的吲哚衍生物、其制备方法及其用途。本发明的吲哚衍生物活性高，安全性好，是理想的S1P受体调节剂。
为实现本发明的目的，本发明采用以下技术方案：
本发明一方面提供了一种通式(I)所示的吲哚衍生物：
其中，
Z
1、Z
2各自独立地选自N或CR
a；
R
1、R
3、R
4各自独立地选自氢、卤素、C
1-6烷基、C
1-6烷氧基、3至8元环烷基或3至8元杂环基；
R
2选自(CR
bR
c)
m-(Cy)
p-(CR
bR
c)
n-COOH、(CR
bR
c)
m-(Cy)
p-(CR
bR
c)
n-OH、(CR
bR
c)
m-(Cy)
p-(CR
bR
cb)
n-CN或(CR
bR
c)
m-(Cy)
p-(CR
bR
c)
n-CONR
bR
c；
R
a、R
b、R
c各自独立地选自氢、卤素或C
1-6烷基；
Cy选自3至8元环烷基或杂环基；
R
5选自3至8元环烷基或杂环基；
R
6选自卤素或卤素取代的甲基；
所述杂环基含有1至3个选择N、O、S的杂原子；所述烷基、烷氧基、环烷基、或杂环基任选被0-6个卤素、C
1-6烷基或C
1-6烷氧基取代；
m、p、n各自独立地选自0至3的整数。
在一个实施方案中，R
1选自氢、卤素或C
1-4烷基；优选地，R
1选自氟、氯、甲基、乙基、异丙基或叔丁基；更优选地，R
1选自氯、甲基或乙基。
在一个实施方案中，Z
1、Z
2选自CR
a；R
2选自(CR
bR
c)
m-(Cy)
p-(CR
bR
c)
n-COOH、(CRR
bR
c)
m-(Cy)
p-(CR
bR
c)
n-OH或(CR
bR
c)
m-(Cy)
p-(CR
bR
c)
n-CN；
其中，R
a、R
b、R
c各自独立地选自氢或C
1-6烷基；优选地，R
a、R
b、R
c均为氢；
Cy选自3至8元环烷基或杂环基；
所述杂环基含有1至3个选自N、O、S的杂原子；所述烷基、环烷基或杂环基任选被0-6个卤素、C
1-6烷基或C
1-6烷氧基取代；
m、p、n各自独立地选自0至3的整数。
在一个实施方案中，Z
1、Z
2选自CH、R
2为(CH
2)
2COOH或(CH
2)
3COOH；
在一个实施方案中，R
3为氢、氟、氯、甲基、乙基、异丙基或叔丁基；优选地，R
3为氢，氟或甲基；更优选地，R
3为氢或氟；进一步优选地，R
3为氢。
在一个实施方案中，R
4为氢、氟、氯、甲基、乙基、异丙基或叔丁基；优选地，R
3为氢，氟或甲基；更优选地，R
4为氢或氟；进一步优选地，R
4为氢。
在一个实施方案中，R
5选自任选被0至3个卤素或C
1-6烷基取代的3至8元环烷基，优选为环丁基，环戊基或环己基，更优选为环戊基。
在一个实施方案中，R
6选自氟、一氟甲基、二氟甲基或三氟甲基，优选氟或三氟甲基。
在一个实施方案中，R
1选自氯、甲基或乙基；R
2选自(CH
2)
2-COOH或(CH
2)
3-COOH；R
3、R
4为氢；R
5为环戊基、R
6为三氟甲基。
作为优选，所述的吲哚衍生物，具有通式(I-1)所示结构:
其中，
R
1选自氢、卤素、C
1-6烷基、C
1-6烷氧基、3-8元环烷基或3-8元杂环烷基；
R
2选自(CR
bR
c)
m-COOH；m选自0至3的整数；
R
b、R
c各自独立地选自氢、卤素或C
1-6烷基；
R
5选自3至8元环烷基或杂环基；
R
6选自卤素或卤素取代的甲基；
所述杂环烷基含有1至3个选自N、O、S的杂原子；所述烷基、烷氧基、环烷基或杂环基任选被0-6个卤素、C
1-6烷基或C
1-6烷氧基取代。
在一个实施方案中，R
1选自氢、卤素、C
1-3烷基；R
2选自(CR
bR
c)
m-COOH；m选自0至3的整数；R
b、R
c各自独立地选自氢、卤素或C
1-3烷基；R
5选自5至7元环烷基；R
6选自卤素或卤素取代的甲基；所述烷基、环烷基任选被0-3个卤素、C
1-3烷基取代。
在一个更具体的实施方案中，R
1选自卤素、C
1-3烷基；R
2选自(CH
2)
m–COOH；m独立地选自2至3的整数；R
5选自5至7元环烷基；R
6选自卤素或被1-3个卤素取代的甲基。
在一个更具体的实施方案中，R
1选自F、Cl、甲基、乙基；R
2选自(CH
2)
m–COOH；m独立地选自2至3的整数；R
5选自环戊基、环己基；R
6选自F、Cl、三氟甲基、二氟甲基、氟代甲基。
作为优选，本发明的吲哚衍生物包括但不限于如下化合物：
作为进一步的优选，本发明的吲哚衍生物包括但不限于如下化合物：
本发明的另一个目的是提供通式(I’-1)所示吲哚衍生物的合成方法，包括以下步骤：
(1)、使用片段A1、B1、C1通过两种方法制备中间体3-1：
方法一：将片段A1转化成吲哚环中间体1-1，中间体1-1吲哚环N上接入片段B1得中间体2-1，中间体2-1再与片段C1反应得中间体3-1：
方法二：将片段A1先与片段C1反应得中间体1’-1，中间体1’-1进一步转化成吲哚环前体中间体2’-1，中间体2’-1接入片段B1得中间体3-1：
(2)、中间体3-1经水解反应或还原为羟基后经CN取代、水解，制得通式(I’-1)化合物：
其中，Z
1、Z
2各自独立地选自N或CR
a；R
1独立地选自氢、卤素、C
1-6烷基、C
1-6烷氧基、3至8元环烷基或3至8元杂环基；R
5选自3至8元环烷基或杂环基；R
6选自卤素或卤素取代的甲基；R
a独立地选自氢、卤素或C
1-6烷基；
R
7为羟基保护基，优选C
1-6烷基或苄基；
R
8选自氨基或硝基；
R
9为C
1-6烷基；
X为卤素，优选为氯或溴；
X’选自氢或卤素，优选为氢、氯或溴；
r、q各自独立地选自1至3的整数。
在一个实施方案中，Z
1、Z
2各自独立地选自N或CR
a；R
1选自氯、甲基或乙基；R
5为环戊基、R
6为三氟甲基。R
7为甲基或苄基；R
8为氨基或硝基；R
9为甲基或乙基；X为氯；X’为氢或溴；r、q各自独立地选自1至3的整数。
在一个更为具体的实施方案中，Z
1、Z
2被限定为C，限定后的吲哚衍生物如式(I’)所示，其制备方法包括以下步骤：
(1)、使用片段A、B、C通过两种方法制备中间体3：
方法一：将片段A转化成吲哚环中间体1，中间体1吲哚环N上接入片段B得中间体2，中间体2再与片段C反应得中间体3：
方法二：将片段A先与片段C反应得中间体1’，中间体1’进一步转化成吲哚环前体中间体2’，中间体2’接入片段B得中间体3：
(2)、中间体3经水解反应或还原为羟基后经CN取代、水解，制得通式(I)化合物：
其中，R
1选自氢、卤素、C
1-6烷基、C
1-6烷氧基、3-8元环烷基或3-8元杂环烷基；R
5选自3至8元环烷基或杂环基；R
6选自卤素或卤素取代的甲基；即R
1、R
5、R
6定义同权利要求1；
R
7为羟基保护基，优选C
1-6烷基或苄基；
R
8为氨基或硝基；
R
9为C
1-6烷基；
X为卤素，优选为氯或溴；
X’选自氢或卤素，优选为氢、氯或溴；
r、q各自独立地选自1至3的整数。
在具体的实施方案中：R
1选自F、Cl、甲基、乙基；R
5选自环戊基、环己基；
R
6选自F、Cl、三氟甲基、二氟甲基、氟代甲基。即R
1、R
5、R
6定义同权利要求4；R
7为甲基或苄基；R
8为氨基或硝基；R
9为甲基或乙基；X为氯；X’为氢或溴；r、q各自独立地选自1至3的整数。
本发明还提供一种药物组合物，所述药物组合物含有通式(I)所述的吲哚衍生物及其药物可接受的载体。
本发明还涉及通式(I)所述的吲哚衍生物、或者含有有效量通式(I)所述的吲哚衍生物的药物组合物在制备治疗和/或预防S1P受体相关障碍的疾病的药物中的用途。
作为优选，所述的S1P受体相关障碍的疾病选自克罗恩病、溃疡性结肠炎、、银屑病、类风湿性关节炎、多发性硬化症、特应性皮炎、嗜酸细胞性食管炎、斑秃、原发性胆管炎、坏疽性脓皮症、移植物抗宿主病、、肌肉萎缩性侧索硬化症、系统性红斑狼疮、I型糖尿病动脉硬化、动脉粥样硬化、硬皮病、自身免疫性肝炎、痤疮、微生物感染和病毒感染。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明提供的化合物结构新颖，活性强，通过有效调节S1P相应受体，提供了一种预防或治疗包括且不限于溃疡性结肠炎和克罗恩病的新方法。本发明化合物具有与现有技术相比具有更高的活性与更好的药效。
图1TNBS造模及连续给药7天后，各组大鼠结肠大体解剖图。
下面结合具体实施例对本发明做进一步详细的说明，但本发明并不限于以下实施例。
化合物的结构通过核磁共振(NMR)或质谱(MS)确定，纯度通过液相高压色谱仪(HPLC)测定。NMR的测定使用Bruker AVANCE-400核磁共振仪，溶剂为氘代二甲基亚砜(DMSO-d
6)或氘代甲醇(CD
3OH)，内标为四甲基硅烷(TMS)，化学位移以ppm为单位。MS的测定使用安捷伦6120质谱仪。HPLC使用安捷伦1200DAD高压液相色谱仪测定。高压液相制备色谱使用Waters的设备。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板。薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空，充入氢气，反复操作3次。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
TNBS：2,4,6-三硝基苯磺酸
DMSO：二甲亚砜
SASP：柳氮磺吡啶
Solutol：15-羟基硬脂酸聚乙二醇酯
DSS：葡聚糖硫酸钠
Saline：氯化钠盐溶液
CMC-Na：羧甲基纤维素钠
本发明所用的原料和试剂若无说明均可通过常规方法制备得到或市售购得。
实施例1
3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙酸(1)
第一步：1-(2-氨基-5-甲氧基-3-甲基苯基)-2-氯乙酮(1b)
将2-甲基-4-甲氧基苯胺(1a)(5.0g，36.4mmol)溶解在甲苯(20mL)中，-78℃下依次加入三氯化硼(37mL，1M二氯甲烷溶液)、四氯化钛(37mL，1M二氯甲烷溶液)和氯乙腈(3.1g，41mmol)。反应液加热至90℃搅拌3h。向反应体系中加入2M的盐酸水溶液(30mL)，于85℃搅拌45min。反应体系中加入饱和碳酸氢钠溶液(100mL)，用二氯甲烷(100mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:5)得到黄色固体1-(2-氨基-5-甲氧基-3-甲基苯基)-2-氯乙酮(1b)(4.30g，产率：55.2％)。
MS(ESI)m/z:214[M+1]。
第二步：5-甲氧基-7-甲基-1H-吲哚(1c)
将1-(2-氨基-5-甲氧基-3-甲基苯基)-2-氯乙酮(1b)(4.3g，20.1mmol)溶解在1,4-二氧六环(20mL)和水(2mL)中，然后加入硼氢化钠(844mg，22.3mmol)。反应体系加热至120℃搅拌反应1h。将反应液减压浓缩，残留物中加入水(20mL)，用乙酸乙酯(40mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:5)得到白色固体5-甲氧基-7-甲基-1H-吲哚(1c)(3.0g，产率：92.5％)。
1H NMR(400MHz,CDCl
3)δ8.06-7.75(s,1H),7.07(t,J＝2.8Hz,1H),6.95(d,J＝2.1Hz,1H),6.68(d,J＝1.4Hz,1H),6.46(dd,J＝2.9,2.1Hz,1H),3.81(s,3H),2.38(s,3H)。
MS(ESI)m/z:162[M+1]。
第三步：3-(5-甲氧基-7-甲基-1H-吲哚-1-基)丙酸乙酯(1d)
反应瓶中依次加入乙腈(5mL)、5-甲氧基-7-甲基-1H-吲哚(1c)(1.0g，6.2mmol)、丙烯酸乙酯(2.5g，24.8mmol)和1,8-二氮杂双环[5.4.0]-7-十一碳烯(1.9g，12.4mmol)。反应液加热到50℃，搅拌2h。反应液减压浓缩，残余物用水(10mL)稀释，用乙酸乙酯(20mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:5)得到黄色固体3-(5-甲氧基-7-甲基-1H-吲哚-1-基)丙酸乙酯(1d)(1.4g，产率：86.4％)。
MS(ESI)m/z:262[M+1]。
第四步：3-(5-羟基-7-甲基-1H-吲哚-1-基)丙酸甲酯(1e)
将3-(5-甲氧基-7-甲基-1H-吲哚-1-基)丙酸乙酯1d(1.3g，5.0mmol)溶解在二氯甲烷(10mL)中，-78℃下加入三溴化硼(5mL，33％的二氯甲烷溶液)。反应液升至室温搅拌16h。加入甲醇(5mL)，反应液减压浓缩。残余物用水(10mL)稀释，用乙酸乙酯(20mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝3:5)得黄色油状物3-(5-羟基-7-甲基-1H-吲哚-1-基)丙酸甲酯1e(100mg，产率:8.6％)。
MS(ESI)m/z:234[M+1]。
第五步：3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙酸甲酯(1f)
3-(5-羟基-7-甲基-1H-吲哚-1-基)丙酸甲酯1e(100mg，0.43mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入4-(氯甲基)-1-环戊基-2-(三氟甲基)苯(225mg，0.86mmol)和碳酸铯(421mg，1.29mmol)。反应液加热到50℃搅拌2h。加水(10mL)稀释，用乙酸乙酯(20mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:5)，得到无色油状3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙酸甲酯1f(150mg，产率：76.1％)。
MS(ESI)m/z:460[M+1]。
第六步：3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙酸(1)
将3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙酸甲酯1f(150mg，0.33mmol)溶解在甲醇(5mL)和水(1mL)中，加入氢氧化锂一水合物(55mg，1.31mmol)。反应液加热到50℃搅拌4h。用10％的盐酸水溶液调pH至6。反应液减压浓缩，残余物用高压液相色谱制备(乙腈/水(含0.1％甲酸，梯度洗脱)，得到白色固体3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙酸(1)(50.5mg，产率：34.7％)。
1H NMR(400MHz,CD
3OD)δ12.42(s,1H),7.70(d,J＝10.0Hz,2H),7.63(d,J＝8.0Hz,1H),7.22(d,J＝3.1Hz,1H),6.94(d,J＝2.4Hz,1H),6.63(d,J＝1.9Hz,1H),6.28(d,J＝3.1Hz,1H),5.11(s,2H),4.52(t,J＝7.1Hz,2H),3.27-3.22(m,1H),2.68(t,J＝7.1Hz,2H),2.63(s,3H),2.00(m,2H),1.84(m,2H),1.72-1.55(m,4H)。
MS(ESI)m/z:446[M+1]。
实施例2
3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-乙基-1H-吲哚-1-基)丙酸(2)
第一步：2-乙基-4-甲氧基-1-硝基苯(2b)
-15℃下，1-甲氧基-4-硝基苯2a(5g，32.65mmol)的四氢呋喃(100mL)溶液中加入1M的乙烯基溴化镁溶液(75.10mL)。反应液在-15℃下搅拌2h。加入2,3-二氯-5,6-二氰基-1,4-苯醌(12.60g，55.51mmol)，反应液继续在-40℃下搅拌3h。向反应液中加入饱和氯化铵水溶液(50mL)，用乙酸乙酯(100mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:5)得到深黄色油状物2-乙基-4-甲氧基-1-硝基苯2b(2.55g，产率：43.10％)。
MS(ESI)m/z:182[M+1]。
第二步：7-乙基-5-甲氧基-1H-吲哚(2c)
2-乙基-4-甲氧基-1-硝基苯(2b)(1g，5.52mmol)溶于四氢呋喃(10mL)中，降 温至-40℃，加入1M的乙烯基溴化镁溶液(16.56mL)。反应液在-40℃搅拌4h。往反应液里加入水(50mL)，用乙酸乙酯(100mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:5)，得深黄色油状7-乙基-5-甲氧基-1H-吲哚(2c)(200mg，产率：20.7％)。
MS(ESI)m/z:176[M+1]。
第三步：3-(7-乙基-5-甲氧基-1H-吲哚-1-基)丙酸乙酯(2d)
反应瓶中依次加入乙腈(3mL)、7-乙基-5-甲氧基-1H-吲哚(2c)(200mg，1.14mmol)、丙烯酸乙酯(571.35mg，5.71mmol)和1,8-二氮杂双环[5.4.0]-7-十一碳烯(347.53mg，2.28mmol)，升温至60℃，搅拌16h。将反应液减压浓缩，残余物用水(5mL)稀释，用乙酸乙酯(10mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:5)，得棕色油状3-(7-乙基-5-甲氧基-1H-吲哚-1-基)丙酸乙酯(2d)(260mg，产率：82.7％)。
MS(ESI)m/z:276[M+1]。
第四步：3-(7-乙基-5-羟基-1H-吲哚-1-基)丙酸乙酯(2e)
-78℃下将3-(7-乙基-5-甲氧基-1H-吲哚-1-基)丙酸乙酯(2d)(100mg，0.36mmol)加入到三溴化硼溶液(5mL，33％的二氯甲烷溶液)中，室温搅拌1h。加入甲醇(5mL)，用饱和碳酸氢钠溶液调节pH为7。加入水(20mL)，用乙酸乙酯(40mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝2:5)纯化所得残余物，得到淡黄色油状3-(7-乙基-5-羟基-1H-吲哚-1-基)丙酸乙酯(2e)(90mg，产率：94.8％)。
MS(ESI)m/z:262[M+1]。
第五步：3-[5-[[4-环戊基-3-(三氟甲基)苄基]氧]-7-乙基-1H-吲哚-1-基]丙酸乙 酯(2f)
向溶于N,N-二甲基甲酰胺(2mL)的3-(7-乙基-5-羟基-1H-吲哚-1-基)丙酸乙酯(2e)(80mg，0.31mmol)溶液中加入4-(氯甲基)-1-环戊基-2-(三氟甲基)苯(80.42mg，0.31mmol)和碳酸铯(199.49mg，0.61mmol)。加热到60℃搅拌2h。反应液用水(5mL)稀释，用乙酸乙酯(10mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:5)，得到棕色油状3-[5-[[4-环戊基-3-(三氟甲基)苄基]氧]-7-乙基-1H-吲哚-1-基]丙酸乙酯(2f)(50mg，产率：33.5％)。
MS(ESI)m/z:488[M+1]。
第六步：3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-乙基-1H-吲哚-1-基)丙酸(2)
以3-[5-[[4-环戊基-3-(三氟甲基)苄基]氧]-7-乙基-1H-吲哚-1-基]丙酸乙酯(2f)为原料，采用实施例1中第六步的合成方法合成化合物3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-乙基-1H-吲哚-1-基)丙酸(2)。
1H NMR(400MHz,CDCl
3)δ7.70(s,1H),7.59(d,J＝8.0Hz,1H),7.48(d,J＝8.1Hz,1H),7.04(d,J＝2.9Hz,1H),6.98(d,J＝1.8Hz,1H),6.77(s,1H),6.41(d,J＝2.9Hz,1H),5.06(s,2H),4.58(t,J＝7.1Hz,2H),3.43-3.31(m,1H),2.98(q,J＝7.4Hz,2H),2.81(t,J＝7.0Hz,2H),2.08(m,2H),1.86(m,2H),1.73(m,2H),1.60(m,2H),1.36(t,J＝7.4Hz,3H)。
MS(ESI)m/z:460[M+1]。
实施例3
3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙酸(3)
第一步：2-氯-4-((4-环戊基-3-(三氟甲基)苄基)氧)-1-硝基苯(3b)
3-氯-4-硝基苯酚(3a)(1g，5.76mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入4-(氯甲基)-1-环戊基-2-(三氟甲基)苯(1.51g，5.76mmol)和碳酸铯(3.75g，11.52mmol)。80℃反应3h。反应液用水(20mL)稀释，用乙酸乙酯(30mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:20)，得到棕色油状2-氯-4-((4-环戊基-3-(三氟甲基)苄基)氧)-1-硝基苯(3b)(2.1g，产率：91.2％)。
MS(ESI)m/z:400[M+1]。
第二步：7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚(3c)
反应瓶中加入2-氯-4-((4-环戊基-3-(三氟甲基)苄基)氧)-1-硝基苯(3b)(2.1g，5.25mmol)和四氢呋喃(20mL)，-40℃下加入1M的乙烯基溴化镁溶液(15.76mL)。反应液在-40℃搅拌6h。向反应液中加入饱和氯化铵(20mL)，用乙酸乙酯(40mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:20)，得棕色油状的7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚(3c)(900mg，产率：43.5％)。
MS(ESI)m/z:394[M+1]。
第三步：3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙酸乙酯(3d)
反应瓶中依次加入乙腈(50mL)、7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚(3c)(900mg，2.29mmol)、丙烯酸乙酯(1.14g，11.43mmol)和1,8-二氮杂双环[5.4.0]-7-十一碳烯(695.80mg，4.57mmol)。把反应液加热到60℃，搅拌16h。反应液减压浓缩，残余物用水(20mL)稀释，用乙酸乙酯(40mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:10)，得到淡黄色油状3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙酸乙酯(3d)(1.1g，产率：97.4％)。
MS(ESI)m/z:494[M+1]。
第四步：3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙酸(3)
以3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙酸乙酯(3d)为原料，采用实施例1中第六步的合成方法合成化合物3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙酸(3)。
1H NMR(400MHz,DMSO-d
6)δ12.42(s,1H),7.71(d,J＝11.1Hz,2H),7.64(d,J＝8.1Hz,1H),7.35(d,J＝3.1Hz,1H),7.15(d,J＝2.3Hz,1H),6.94(d,J＝2.2Hz,1H),6.40(d,J＝3.1Hz,1H),5.16(s,2H),4.65(t,J＝7.1Hz,2H),3.29-3.20(m,1H),2.74(t,J＝7.1Hz,2H),2.05-1.95(m,2H),1.90-1.77(m,2H),1.64(m,4H)。
MS(ESI)m/z:466[M+1]。
实施例4
4-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丁酸(4)
第一步：1-环戊基-4-[(3-甲基-4-硝基-苯酚基)甲基]-2-(三氟甲基)苯(4b)
3-甲基-4-硝基苯酚(4a)(1.2g，7.84mmol)的N，N-二甲基甲酰胺(10mL)溶液中加入4-(氯甲基)-1-环戊基-2-(三氟甲基)苯(2.06g，7.84mmol)和碳酸铯(5.11g，15.67mmol)。加热至80℃搅拌2h。反应液用水(10mL)稀释，用乙酸乙酯(30mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩后得到淡黄色固体1-环戊基-4-[(3-甲基-4-硝基-苯酚基)甲基]-2-(三氟甲基)苯(4b)(2.9g，产率：97.5％)。
MS(ESI)m/z:380[M+1]。
第二步：5-[[4-环戊基-3-(三氟甲基)苄基]氧]-7-甲基-1H-吲哚(4c)
-40℃下，向1-环戊基-4-[(3-甲基-4-硝基-苯酚基)甲基]-2-(三氟甲基)苯(4b)(500mg，1.32mmol)的四氢呋喃(5mL)中加入1M的乙烯基溴化镁溶液(7.91mL)。反应液在-40℃下搅拌1h。加入饱和氯化铵溶液(30mL)，用乙酸乙酯(60mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:20)，得黄色油状5-[[4-环戊基-3-(三氟甲基)苄基]氧]-7-甲基-1H-吲哚(4c)(160mg，产率：32.5％)。
MS(ESI)m/z:374[M+1]。
第三步：3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙酸乙酯(4d)
反应瓶中依次加入乙腈(5mL)、5-[[4-环戊基-3-(三氟甲基)苄基]氧]-7-甲基-1H-吲哚(4c)(520mg，1.39mmol)、丙烯酸乙酯(697.09mg，6.96mmol)和1,8-二氮杂双环[5.4.0]-7-十一碳烯(424.00mg，2.79mmol)。60℃下搅拌16h。反应液减压浓缩，残余物用水(5mL)稀释，用乙酸乙酯(10mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:5)，得淡黄色油状3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙酸乙酯(4d)(420mg，产率：63.7％)，。
MS(ESI)m/z:474[M+1]。
第四步：3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙烷-1-醇(4e)
将3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙酸乙酯(4d)(420mg，0.89mmol)溶解在四氢呋喃(5mL)中，0℃下加入氢化二异丁基铝溶液(1.5M,1.18mL)。室温反应1h。反应液中加入十水硫酸钠，过滤。滤液减压浓缩，用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:5)，得到标题产物3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙烷-1-醇(4e)(350mg，产率：91.4％)。
MS(ESI)m/z:432[M+1]。
第五步：3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙基甲基磺酸酯(4f)
将3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙烷-1-醇(4e)(350mg，0.81mmol)和三乙胺(164.16mg，1.62mmol，0.23mL)溶解在二氯甲烷(5mL)中。0℃下加入甲基磺酰氯(185.83mg，1.62mmol)，室温搅拌1h。反应液中加入水(5mL)，用乙酸乙酯(10mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩得到淡黄色固体3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙基甲基磺酸酯(4f)(240mg，产率：58.1％)。
MS(ESI)m/z:510[M+1]。
第六步：4-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丁腈(4g)
3-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丙基甲基磺酸酯(4f)(240mg，0.47mmol)溶于N,N-二甲基甲酰胺(5mL)的溶液中加入氰化钠(115.41mg，2.35mmol)。加热至90℃，搅拌16h。反应液中加入水(5mL)，用乙酸乙酯(10mL)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩得到白色固体4-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丁腈(4g)(190mg，产率：91.6％)。
MS(ESI)m/z:441[M+1]。
第七步：4-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丁酸(4)
将4-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丁腈(4g)(180mg，0.41mmol)溶于乙醇(2mL)和水(0.5mL)的混合溶液中，加入氢氧化钠(16.35mg，0.41mmol)。升温至100℃搅拌6h。反应液冷却至室温后减压浓缩，加入水(10mL)。用盐酸水溶液调节pH至6，用乙酸乙酯(20mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残余物用高压液相色谱制备(乙腈/水(含0.1％甲酸)，梯度洗脱)，得白色固体4-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-7-甲基-1H-吲哚-1-基)丁酸(4)(39.71mg，产率：21.1％)。
1H NMR(400MHz,DMSO-d
6)δ7.70(d,J＝11.2Hz,2H),7.63(d,J＝8.1Hz,1H),7.21(d,J＝3.0Hz,1H),6.95(d,J＝2.2Hz,1H),6.63(d,J＝1.7Hz,1H),6.30(d,J＝3.0Hz,1H),5.11(s,2H),4.29(t,J＝7.2Hz,2H),3.27-3.23(m,1H),2.62(s,3H),2.20(t,J＝7.3Hz,2H),2.04-1.95(m,2H),1.94-1.79(m,4H),1.72-1.54(m,4H)。MS(ESI)m/z:460[M+1]。
实施例5
4-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丁酸(5)
第一步：3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙烷-1-醇(5a)
0℃下，3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙酸乙酯(3d)(200mg，0.40mmol)的四氢呋喃(10mL)溶液中加入氢化二异丁基铝溶液(1.5 M,0.54mL)。室温搅拌1h。反应液中加入十水硫酸钠，过滤。滤液减压浓缩，用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:5)，得到无色油状的3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙烷-1-醇(5a)(150mg，产率:82.0％)。
MS(ESI)m/z:452[M+1]。
第二步：3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙基甲基磺酸酯(5b)
反应瓶中加入二氯甲烷(10mL)、3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙烷-1-醇(5a)(150mg，0.33mmol)和三乙胺(100.76mg，1.00mmol)。0℃下加入甲基磺酰氯(76.05mg，0.66mmol)。室温搅拌1h。反应液中加入水(5mL)，用乙酸乙酯(10mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩后得到淡黄色固体3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙基甲基磺酸酯(5b)(160mg，产率:90.9％)。
MS(ESI)m/z:530[M+1]。
第三步：4-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丁腈(5c)
将3-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丙基甲基磺酸酯(5b)(160mg，0.30mmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入氰化钠(14.80mg，0.30mmol)。加热至90℃，反应16h。反应液中加入水(5mL)，用乙酸乙酯(10mL×3)萃取。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩后得到白色固体4-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丁腈(5c)(120mg，产率：86.2％)。
MS(ESI)m/z:461[M+1]。
第四步：4-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丁酸(5)
以4-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丁腈(5c)为原料，采用实施例4中第七步的合成方法合成化合物4-(7-氯-5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)丁酸(5)。
1H NMR(400MHz,DMSO-d
6)δ12.14(s,1H),7.71(d,J＝10.9Hz,2H),7.64(d,J＝8.0Hz,1H),7.35(d,J＝2.7Hz,1H),7.15(d,J＝1.6Hz,1H),6.94(s,1H),6.42(d,J＝2.8Hz,1H),5.16(s,2H),4.44(t,J＝6.8Hz,2H),3.24(m,1H),2.17(t,J＝7.3Hz,2H),1.97(m,4H),1.84(s,2H),1.72-1.55(m,4H)。
MS(ESI)m/z:480[M+1]。
实施例6
2-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)乙酸(6)
第一步：2-(5-(苄氧基)-1H-吲哚-1-基)乙酸乙酯(6b)
5-(苄氧基)-1H-吲哚(6a)(1.0g，4.5mmol)的N,N-二甲基甲酰胺(30mL)中，0℃下加入氢化钠(215mg，5.4mmol)。保温反应30min。加入2-溴乙酸乙酯(899mg，5.4mmol)。升至室温搅拌30min。反应液中加入水(10mL)和乙酸乙酯(200mL)。用饱和食盐水(30mL×3)洗涤。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:10)，得到黄色固体2-(5-(苄氧基)-1H-吲哚-1-基)乙酸乙酯(6b)(1.1g，产率：79.4％)。
MS(ESI)m/z:310[M+1]。
第二步：2-(5-羟基-1H-吲哚-1-基)乙酸乙酯(6c)
2-(5-(苄氧基)-1H-吲哚-1-基)乙酸乙酯(6b)(500mg，1.6mmol)的四氢呋喃(15mL)溶液中加入10％的钯炭(50mg)。用氢气置换体系中的气体三次。反应在氢气氛下加热到40℃，搅拌24h。过滤，滤饼用四氢呋喃(10mL)洗涤。合并有机相，减压浓缩得棕色油状2-(5-羟基-1H-吲哚-1-基)乙酸乙酯(6c)粗品，直接用于下一步反应。
MS(ESI)m/z:220[M+1]。
第三步：2-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)乙酸乙酯(6d)
将2-(5-羟基-1H-吲哚-1-基)乙酸乙酯(6c)(400mg，1.83mmol)溶解在N,N-二甲基甲酰胺(20mL)中，加入4-(氯甲基)-1-环戊基-2-(三氟甲基)苯(574mg，2.19mmol)和碳酸铯(1.78g，5.49mmol)。加热至60℃搅拌2h。加入乙酸乙酯(100mL)稀释，用饱和氯化钠溶液(20mL×3)洗涤。有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用硅胶柱色谱纯化(乙酸乙酯:石油醚(v/v)＝1:10)，得到黄色油状2-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)乙酸乙酯(6d)(520mg，物)，两步产率:64.0％。
MS(ESI)m/z:446[M+1]。
第四步：2-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)乙酸(6)
以2-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)乙酸乙酯(6d)为原料，采用实施例1中第六步的合成方法合成化合物2-(5-((4-环戊基-3-(三氟甲基)苄基)氧)-1H-吲哚-1-基)乙酸(6)。
1H NMR(400MHz,DMSO-d
6)δ7.71(d,J＝10.5Hz,2H),7.63(d,J＝8.1Hz,1H),7.27(dd,J＝5.9,2.8Hz,2H),7.13(d,J＝2.3Hz,1H),6.85(dd,J＝8.8,2.4Hz,1H),6.33(d,J＝3.0Hz,1H),5.15(s,2H),4.92(s,2H),3.28-3.20(m,1H),1.99(m,2H),1.90-1.76(m,2H),1.72-1.55(m,4H)。
MS(ESI)m/z:418[M+1]。
实施例7：S1P1高表达细胞活性的测定
以下实验通过β-arrestin assay检测化合物对S1P1高表达细胞的活性。
1、实验材料
2、实验仪器
3、实验步骤
第一天：细胞种板及化合物处理
(1)首先，使用Echo纳升级移液工作站在培养板中将化合物以10μM浓度起始、进行4倍梯度稀释成10个浓度点，每个浓度点2复孔。
(2)用FreeStyle
TM表达培养基重悬细胞，调整细胞密度以使每40μL悬液含细胞7500个。在细胞培养板的板孔中加入测试浓度的样品，并于相应孔中加入40μL细胞悬液。
(3)将上述细胞板置于37℃、5％CO
2的培养箱中孵育过夜。
第二天：检测及数据分析
(1)缓冲液参照LiveBLAzerTM-荧光共振能量转移B/G上样试剂盒说明书中的制备方法来制备。
(2)向各孔中加入8uL检测试剂，摇动混匀1分钟，再以1000转/分钟离心10秒，23℃避光孵育2小时。
(3)用Envision多功能酶标仪进行检测。
(4)利用PrismDemo软件分析数据并拟合曲线。
4、实验结果
| 化合物编号 | IC 50(nM) |
| Etrasimod | 4.712 |
| 实施例1化合物 | 0.51 |
| 实施例2化合物 | 3.274 |
| 实施例3化合物 | 0.1477 |
| 实施例4化合物 | 1.727 |
| 实施例5化合物 | 0.2507 |
| 实施例6化合物 | 174.6 |
经过多次、不同实验批次的测试，测试结果基本一致。
实施例8：动物结肠炎治疗[2,4,6-三硝基苯磺酸(TNBS)诱导大鼠溃疡性结肠炎]
造模剂的配制：5ml TNBS+8.953ml无水乙醇+26.741灭菌注射用水。
TNBS来源于大连美伦生物科技有限公司。
SPF级雄性SD大鼠来源：上海斯莱克实验动物有限责任公司。
实验开始时动物年龄：8-10周龄；
实验开始时动物体重：250g左右；
适应环境时间：5-7天；
动物禁食(不禁水)24h，以异氟烷吸入麻醉后，所有大鼠采用乳胶软管经直肠灌入0.5ml/只的TNBS乙醇溶液(18mgTNBS/只)，软管进入直肠的长度约为8cm。抽出软管后继续保持异氟烷麻醉状态并使大鼠保持臀部抬高倾斜状态15min。
造模后的大鼠随机分成5组：模型组、阳性对照药柳氮磺吡啶(SASP，360mg/kg)组、受试物实施例3化合物(3mg/kg)组、受试物Etrasimod(3mg/kg)组、受试物Ozanimod(10mg/kg)组。
造模后3h各组动物按应给予药液经口灌胃开始给药(表1)，5mL/kg体重(柳氮磺吡啶组为10mL/kg)，1次/天，连续7天，每天观察动物的粪便及有否死亡发生。第8天CO
2过量麻醉处死动物，随后解剖，摘取整个结肠组织，沿肠系膜侧纵向剖开后清洗结肠内容物，称重并测量结肠长度，测量溃疡面积，观察大体情况并拍照，最后，将结肠置于10％福尔马林中固定，待做H&E染色并进行病理组织学分析(炎症、杯状细胞、病变深度、溃疡程度、隐窝脓肿)。
其中，本发明实施例3化合物，纯度：99.74％。
Etrasimod，按文献方法(WO2010/011316A1之实施例1.29之第2异构体)制备得到，纯度：98.47％。
Ozanimod，按文献方法(WO2011/060392A1之化合物86)制备得到，纯度：99.78％。
柳氮磺吡啶肠溶片，上海福达制药有限公司生产,0.25g/片。肠溶薄膜衣片，除去包衣后，显黄色至棕黄色。
Solutol：北京凤礼精求医药股份有限公司。
溶剂配制：
DMSO、Solutol和0.9％氯化钠溶液按体积比5:10:85混合，配制溶剂。
受试物实施例3化合物和Etrasimod溶液配制：分别取27mg受试物，溶于45mL溶剂中得对应的受试物溶液。
Ozanimod：取90mg Ozanimod溶于45mL溶剂中得Ozanimod溶液。
SASP溶液配制：6片柳氮磺吡啶肠溶片经研磨后加入41.7mL 0.5％的CMC-Na中，超声溶解，得SASP溶液。
由于受SASP药制剂辅料因素，悬浮于0.5％CMC-Na时浓度不宜过大，否则悬浮不均匀且流动性较差，因此SASP给药体积较实施例3化合物和Etrasimod增大一倍。
表1、各组给药剂量
实验过程中，除Ozanimod组外，其他给药组各死亡一只动物。
实验结果
粪便
TNBS造模次日大鼠有稀便发生，部分大鼠粪便成型或半成型，但粪便明显带血。造模大鼠伴有饮食减少、疲倦、消瘦、竖毛、毛发无光泽的症状。各组大 鼠的便血及稀便状态均随时间缓慢改善，4天后各组均有大鼠粪便排泄逐渐恢复正常，排便异常大鼠表现为排便量减少。各给药组大鼠在造模后出现脓血便的症状与同一时间点模型组大鼠比较未出现明显改善的趋势。
体重
模型组及各给药组大鼠经TNBS造模后，体重呈下降趋势，给药后第4天开始体重呈增长趋势。Etrasimod组大鼠体重与模型组比较相似，而柳氮磺吡啶、实施例3化合物均表现出一定抑制大鼠体重下降的趋势，结果见表2。
表2
结肠大体观
造模及连续给药7天后，模型组及给药组大鼠呈现程度不同的结肠坏死及修复状态。结肠损伤症状严重者腹腔大量积液，结肠损伤部位与周围组织严重粘连。剖开结直肠后可见肠粘膜呈不同程度的坏死状，坏死粘膜呈现黑色，结肠壁增厚明显。病变结肠组织无弹性、肠壁增生明显、且结肠明显缩短。各组别大鼠的大体解剖观从优到差显示：实施例3化合物组>柳氮磺吡啶组>Etrasimod组>Ozanimod组(如附图1所示)。
结肠重量、结肠长度、溃疡面积
连续7天经口灌胃给药后，TNBS诱导的溃疡性结肠炎大鼠结肠重量均降低。受试物的药效强度依次为：实施例3化合物(3mg/kg)>Etrasimod(3mg/kg)>柳氮磺吡啶(360mg/kg)>模型组>Ozanimod(10mg/kg)。结果见表3。
表3
经过多次重复试验，结果与本次基本一致。
实施例9：动物结肠炎治疗(DSS诱导小鼠溃疡性结肠炎)
DSS葡聚糖硫酸钠分子量：36000-50000，来源于MP生物医疗公司。
造模剂的配制：3.5％DSS的配制：49g DSS加高温灭菌水1400mL。
SPF级雄性C57BL/6小鼠来源：北京维通利华实验动物技术有限公司。
实验开始时动物年龄：6-8周龄；
实验开始时动物体重：22-25g；
适应环境时间：3-5天；
小鼠根据体重平均分组，每组10只。按下表4每天一次灌胃给药(或空白)。
表4
动物给予3.5％DSS溶液自由饮水造模(造模当天记为day1)，2天更换一次造模剂，连续造模7天，随后(day8)将3.5％DSS换成普通饮用水继续饲养1天。
溶液配制：
溶剂1配制：将0.66mL DMSO、1.32mL Solutol和11.22mL Saline混合，配成13.2mL溶剂1；
溶剂2配制：将0.3mL DMSO、0.6mL Solutol和5.1mL Saline混合，配成6mL溶剂2；
实施例3化合物溶液的配制：取39.6mg实施例3化合物，溶于13.2mL溶剂1中，得实施例3化合物溶液1；分别将实施例3化合物溶液1用溶剂1稀释，制备浓度为2mg/mL、1mg/mL、0.6mg/mL的实施例3化合物溶液；
Etrasimod溶液：取6mg Etrasimod，溶于6mL溶剂2中得Etrasimod溶液；
Ozanimod溶液：取12mg Etrasimod，溶于6mL溶剂2中得Ozanimod溶
液；
注：每两天配制一次，4℃冰箱保存。
其中，实施例3化合物纯度为99.74％，Ozanimod、Etrasimod按实施例8所述方法制备得到，纯度分别为99.78％、98.47％。
实验结果
小鼠体重
每两日称重小鼠的体重。小鼠开始自由饮用3.5％DSS溶液后，体重几乎不再增长。从连续造模第六天开始，模型组及给药组小鼠出现较明显的体重下降，并随着造模天数的增加，体重下降越明显；而正常饮用高压灭菌水的空白对照组小鼠，随着饲养天数的增加，体重呈增加趋势；在day6-day9期间，3.5％DSS诱导的溃疡性结肠炎小鼠每日体重与空白组相比，具有统计学的显著性差异(P<0.05)。各给药组之间没有明显差异，结果见表5-1和表5-2。
表5-1
表5-2
注：#p<0.05、##p<0.01、###p<0.001vs.空白对照
小鼠粪便
每两日观察小鼠的粪便形状、有否出血并进行评分。粪便情况评分标准：形状：正常(1级)，软便(2级)，稀便(3级)；性状：正常(1级)，隐隐发红(2级)，肉眼血便(3级)。
小鼠连续自由饮用3.5％DSS溶液5天后，大多造模组小鼠都出现血便情况，随着时间的增加，血便情况越发明显，粪便也逐渐转为软便稀便，在day8时粪便情况评分也达到顶峰，在day8时把3.5％DSS换成高压灭菌水，并继续给药，一天后解剖时实施例3化合物(30mg/kg)、实施例3化合物(20mg/kg)、实施例3化合物(10mg/kg)、实施例3化合物(6mg/kg)具有明显改善小鼠血便、稀便的作用，相较于模型组具有统计学的显著性差异(P<0.05)，Ozanimod(20mg/kg)、Etrasimod(10mg/kg)组动物的大便情况没有明显的改善，结果见表6。
表6
注：*p<0.05、**p<0.01、***p<0.001vs.模型对照
小鼠结肠重量及长度
末次给药后(连续8天)次日(day9)解剖动物，分离结肠，结肠整体拍照并测量结肠长度，随后沿肠系膜侧纵向剖开结肠，清除内容物，称重并观察结肠粘膜的完整性。随后将结肠置于10％福尔马林中固定。
小鼠连续自由饮用3.5％DSS溶液7天，再继续给予1天高压灭菌水后，其结肠萎缩。模型组小鼠结肠重量与自由饮用高压灭菌水的空白组小鼠相比明显减小，具有统计学的显著性差异(P<0.05)；同时，模型组小鼠结肠长度也明显缩短，与空白组比较具有统计学的显著性差异(P<0.001)(表7)。
连续8天经口灌胃给予受试物实施例3化合物具有一定抑制小鼠结肠萎缩的作用。各给药组结肠重量均明显重于模型组，其中实施例3化合物(20mg/kg)、实施例3化合物(10mg/kg)、实施例3化合物(6mg/kg)、Etrasimod(10mg/kg)结肠重量与模型组比较具有统计学的显著性差异(P<0.05)，实施例3化合物(30mg/kg)、实施例3化合物(20mg/kg)、Ozanimod(20mg/kg)的结肠长度长于模型组，结果见表7。
表7
| 组别 | N | 结肠重量(g) | 结肠长度(cm) |
| 空白对照 | 10 | 0.162±0.01* | 52.367±2.01*** |
| 模型 | 8 | 0.138±0.01 | 40.916±1.5 |
| 实施例3化合物(30mg/kg) | 9 | 0.162±0.01 | 41.311±1.25 |
| 实施例3化合物(20mg/kg) | 9 | 0.163±0.01* | 44.892±1.83 |
| 实施例3化合物(10mg/kg) | 9 | 0.164±0.01* | 39.638±0.76 |
| 实施例3化合物(6mg/kg) | 9 | 0.164±0.01* | 39.061±1.17 |
| Ozanimod(20mg/kg) | 7 | 0.157±0.01 | 43.82±1.6 |
| Etrasimod(10mg/kg) | 9 | 0.169±0.01* | 37.417±1.18 |
注：***p<0.001,*p<0.05vs.模型
死亡
至试验周期结束时，Ozanimod组死亡3只动物，模型组死亡2只动物，其余给药组均死亡1只动物。
Claims (10)
- 一种具有通式(I-1)所示结构的吲哚衍生物；
其中，R 1选自氢、卤素、C 1-6烷基、C 1-6烷氧基、3-8元环烷基或3-8元杂环烷基；R 2选自(CR bR c) m-COOH；m选自0至3的整数；R b、R c各自独立地选自氢、卤素或C 1-6烷基；R 5选自3至8元环烷基或杂环基；R 6选自卤素或卤素取代的甲基；所述杂环烷基含有1至3个选自N、O、S的杂原子；所述烷基、烷氧基、环烷基或杂环基任选被0-6个卤素、C 1-6烷基或C 1-6烷氧基取代。 - 根据权利要求1所述的吲哚衍生物，其特征在于：R 1选自氢、卤素、C 1-3烷基；R 2选自(CR bR c) m-COOH；m选自0至3的整数；R b、R c各自独立地选自氢、卤素或C 1-3烷基；R 5选自5至7元环烷基；R 6选自卤素或卤素取代的甲基；所述烷基、环烷基任选被0-3个卤素、C 1-3烷基取代。
- 根据权利要求2所述的吲哚衍生物，其特征在于：R 1选自卤素、C 1-3烷基；R 2选自(CH 2) m–COOH；m独立地选自2至3的整数；R 5选自5至7元环烷基；R 6选自卤素或被1-3个卤素取代的甲基。
- 根据权利要求3所述的吲哚衍生物，其特征在于：R 1选自F、Cl、甲基、乙基；R 2选自(CH 2) m–COOH；m独立地选自2至3的整数；R 5选自环戊基、环己基；R 6选自F、Cl、三氟甲基、二氟甲基、氟代甲基。
- 根据权利要求1所述的吲哚衍生物，其特征在于：所述化合物选自：
- 一种制备通式(I’)所示吲哚衍生物的方法，包括以下步骤：
(1)、使用片段A、B、C通过两种方法制备中间体3：
方法一：将片段A转化成吲哚环中间体1，中间体1吲哚环N上接入片段B得中间体2，中间体2再与片段C反应得中间体3：
方法二：将片段A先与片段C反应得中间体1’，中间体1’进一步转化成吲哚环前体中间体2’，中间体2’接入片段B得中间体3：
(2)、中间体3经水解反应或还原为羟基后经CN取代、水解，制得通式(I)化合物：
其中，R 1、R 5、R 6定义同权利要求1；R 7为羟基保护基，优选C 1-6烷基或苄基；R 8为氨基或硝基；R 9为C 1-6烷基；X为卤素，优选为氯或溴；X’选自氢或卤素，优选为氢、氯或溴；r、q各自独立地选自1至3的整数。 - 如权利要求6所述的制备方法，其特征在于：R 1、R 5、R 6定义同权利要求3或4；R 7为甲基或苄基；R 8为氨基或硝基；R 9为甲基或乙基；X为氯；X’为氢或溴；r、q各自独立地选自1至3的整数。
- 一种药物组合物，其特征在于，含有权利要求1～5任意一项所述的吲哚衍生物及其药物可接受的载体。
- 根据权利要求1～5任意一项所述的吲哚衍生物或根据权利要求8所述的药物组合物在制备治疗和/或预防S1P受体相关障碍的疾病的药物中的用途。
- 根据权利要求9所述的用途，其特征在于:所述S1P受体相关障碍的疾病选自克罗恩病、溃疡性结肠炎、银屑病、类风湿性关节炎、多发性硬化症、特应性皮炎、嗜酸细胞性食管炎、斑秃、原发性胆管炎、坏疽性脓皮症、移植物抗宿主病、、肌肉萎缩性侧索硬化症、系统性红斑狼疮、I型糖尿病动脉硬化、动脉粥样硬化、硬皮病、自身免疫性肝炎、痤疮、微生物感染和病毒感染。
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| CN101291908A (zh) * | 2005-08-23 | 2008-10-22 | Irm责任有限公司 | 免疫抑制剂化合物和组合物 |
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