CN115073543B - Compound prodrug of JAK inhibitor and preparation and application thereof - Google Patents
Compound prodrug of JAK inhibitor and preparation and application thereof Download PDFInfo
- Publication number
- CN115073543B CN115073543B CN202210853391.6A CN202210853391A CN115073543B CN 115073543 B CN115073543 B CN 115073543B CN 202210853391 A CN202210853391 A CN 202210853391A CN 115073543 B CN115073543 B CN 115073543B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- methyl
- reaction
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The application discloses a compound prodrug of a JAK inhibitor, and preparation and application thereof, wherein the compound prodrug of the JAK inhibitor is shown as a formula 1.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a compound serving as a prodrug and capable of delivering a JAK inhibitor to the gastrointestinal tract in a targeted manner, and a preparation method and application thereof.
Background
The JAK-STAT pathway is an important signaling pathway, mediates intracellular signaling of various cytokines, and is involved in many important biological processes such as proliferation, differentiation, apoptosis, and immunoregulation of cells. Cytokine stimulation signals are conducted through the JAK-STAT pathway. The JAK-STAT pathway conducts extracellular chemical signals through the cell membrane to gene promoters located on nuclear DNA, ultimately affecting alterations in the level of DNA transcription and activity in cells, and is closely associated with a variety of autoimmune diseases including rheumatoid arthritis and Inflammatory Bowel Disease (IBD).
Inflammatory bowel disease, consisting of Ulcerative Colitis (UC) and Crohn's Disease (CD), is a chronic recurrent disease characterized by intestinal inflammation, tissue damage, abdominal pain, frequent persistent diarrhea, weight loss, rectal bleeding, fatigue, and the like. At present, 5-aminosalicylate, sulfasalazine, immunosuppressant (such as methotrexate, thiopurine and tacrolimus), hormone and the like are mainly used as small-molecule medicaments for treating inflammatory bowel diseases. In recent years, JAK inhibitors have also brought new treatment options for inflammatory bowel disease.
However, oral JAK inhibitors carry a series of adverse events such as increased risk of thrombosis, cardiac risk and lymphoma, which are positively correlated with drug concentration in blood, and therefore, there is a need to develop drugs with low blood exposure but enriched and exposed in the gastrointestinal tract, which can reduce the above-mentioned side effects, as well as other side effects such as liver damage, elevated blood pressure and elevated cholesterol, while providing therapeutic benefits to the gastrointestinal tract. Because inflammatory bowel diseases occur on the luminal surface of the gastrointestinal tract, ulcerative colitis is mainly inflammation and ulceration of the mucosal layers of the rectum and the large intestine, whereas drugs are generally absorbed more in the small intestine but less in the rectum and the large intestine, in addition, the intestinal flora can produce beta-glucuronidase, and glucuronidase in the intestinal tract or bile can be converted into prototypes, so that the development of drugs capable of being released at fixed points in the inflammatory parts of the intestinal tract is a good strategy for improving safety and effectiveness.
Disclosure of Invention
The invention provides a novel compound which can be used as a prodrug for targeted delivery of a JAK inhibitor to the gastrointestinal tract or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
In one aspect, the present invention provides a compound represented by formula 1 or a pharmaceutically acceptable salt thereof:
in formula 1, Y represents NO 2 Or NH 2 。
In some embodiments, the compound of formula 1 is represented by:
formula 1-1 formula 1-2
Compound B or a salt thereof can be produced after contacting formula 1-1 and formula 1-2 with a beta-glucuronidase. The cleavage scheme is as follows:
the compounds of formulae 1-1 and 1-2 have very weak JAK kinase inhibitory activity, very low oral bioavailability, but with greatly improved solubility compared to compound B, and once firmly released in the colon following oral administration, their colon/plasma exposure is significantly increased compared to compound B itself administered orally. The compound of formula 1-1 is more stable than the compound of formula 1-2 and sustained release of compound B is superior at the colonic site.
In another aspect, the present invention also provides the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases. The subject of treatment is a mammal, especially a human.
In some embodiments, the gastrointestinal inflammatory disease is ulcerative colitis.
In some embodiments, the gastrointestinal inflammatory disease is crohn's disease.
In some embodiments, the gastrointestinal inflammatory disease is irritable bowel syndrome.
Detailed Description
The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.
Example 1: (2S,3S,4S,5R,6S) -6- (4- ((((2- (4- (3-amino-1- (3- (cyanomethyl) -1- (1- (3-fluoro-2- (trifluoromethyl) isonicotinyl) piperidin-4-yl) azetidin-3-yl) -1-methyl) azetidin-1-yl) piperidineH-Pyrazol-4-yl) -substituted benzeneN-methyl-7H-Pyrrole [2,3-d]Pyrimidine-7-carboxamide) ethyl) (methyl) carbamoyl) oxy) methyl) -2-nitrophenoxy) -3,4, 5-trihydroxytetrahydro-2H-Synthetic route for pyran-2-carboxylic acid:
step A: (2S,3R,4S,5S,6S) -2- (4-formyl-2-nitrophenoxy) -6- (methoxycarbonyl) tetrahydro-2H-Pyran-3, 4, 5-triacetic acid triesters
Will (2)R,3R,4S,5S,6S) -2-bromo-6- (methoxycarbonyl) tetrahydro-2H-Pyran-3, 4, 5-triacetic acid triester (9 g,23 mmol,1.0 eq) and 4-hydroxy-3-nitrobenzaldehyde (3.8g, 23 mmol,1.0 eq) were added to 150 mL of acetonitrile, and silver oxide (6.3 g,27 mmol,1.2 eq) was added in portions at room temperature, after which the reaction was allowed to proceed overnight at room temperature with exclusion of light. TLC monitors the reaction completion, the reaction system is filtered through kieselguhr, the filter cake is rinsed several times with acetonitrile, the filtrate is collected, evaporated to dryness, and the residue is chromatographed on a silica gel column to obtain the product (10 g, yield: 91%).
And B: (2S,3R,4S,5S,6S) -2- (4- (hydroxymethyl) -2-nitrophenoxy) -6- (methoxycarbonyl) tetrahydro-2H-Pyran-3, 4, 5-triacetic acid triesters
Will (2)S,3R,4S,5S,6S) -2- (4-formyl-2-nitrophenoxy) -6- (methoxycarbonyl) tetrahydro-2H-Pyran-3, 4, 5-triacetic acid triester (10g, 20.7 mmol,1.0 eq) was added to a mixture of 100 mL of methylene chloride and 20 mL of isopropyl alcohol, and sodium borohydride (0.47g, 12.4 mmol,0.6 eq) was slowly added in portions under ice bath, and the reaction was completed at room temperature for 2 hours. TLC monitors the reaction is finished, water is added into the reaction system to quench the reaction, dichloromethane is used for extracting a water phase, and organic phases are combined. The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, the residue was slurried with anhydrous ethanol, the suspension was filtered, and the filter cake was collected to give the product (7.5 g, yield: 75%).
And C: (2S,3R,4S,5S,6S)-2-(4-(((1H-Imidazole-1-carbonyl) oxy) methyl) -2-nitrophenoxy) -6- (methoxycarbonyl) tetrahydro-2H-Pyran-3, 4, 5-triacetic acid triesters
Will (2)S,3R,4S,5S,6S) -2- (4- (hydroxymethyl) -2-nitrophenoxy) -6- (methoxycarbonyl) tetrahydro-2H-Pyran-3, 4, 5-triacetic acid triester (800 mg,1.6 mmol,1.0 eq) and carbonyldiimidazole (350 mg,2.1 mmol,1.3 eq) were added to 15 mL of methylene chloride, and stirred at room temperature for 3 hours.
Step D: (2S,3S,4S,5R,6S) -2- (methoxycarbonyl) -6- (4- (((methyl (2- (methylamino) ethyl) carbamoyl) oxy) methyl) -2-nitrophenoxy) tetrahydro-2H-Pyran-3, 4, 5-triacetic acid triesters
Under ice bath, sequentially adding N 1 ，N 2 Dimethyl ethane-1, 2-diamine (510 mg,5.8 mmol,3.5 eq) and acetic acid (350 mg,5.8 mmol,3.5 eq) were added to 15 mL of dichloromethane, the ice bath was maintained under stirring for 0.5 hour, and the above-prepared (2, 2) solution was addedS,3R,4S,5S,6S)-2-(4-(((1H-Imidazole-1-carbonyl) oxy) methyl) -2-nitrophenoxy) -6- (methoxycarbonyl) tetrahydro-2H-A methylene chloride solution of pyran-3, 4, 5-triacetic acid triester (955 mg,1.0 mmol,1.0 eq) was added dropwise to the reaction system, and the reaction was carried out at room temperature for 1 hour after completion of the dropwise addition. The reaction system was added to water to quench the reaction, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give the product (990 mg, yield: 100%) which was used directly in the next step.
And E, step E:4- (3-amino-1- (3- (cyanomethyl) -1- (1- (3-fluoro-2- (trifluoromethyl) isonicotinyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -7H-pyrrole [2,3-d]Pyrimidine-7-carboxylic acid p-nitrophenyl ester
Under ice bath, 2- (3- (3-amino-4- (7))H-pyrrole [2,3-d]Pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (1- (3-fluoro-2- (trifluoromethyl) isonicotinoyl) piperidin-4-yl) azetidin-3-yl) acetonitrile (853 mg,1.5 mmol,1.0 eq, i.e. ready to useCompound B) andN,Ndiisopropylethylamine (290 mg,1.5 mmol,1.5 q) was added to 4 mLN,NTo a mixture of dimethylformamide and 8 mL of acetonitrile, 4-nitrophenyl chloroformate (363 mg,1.8 mmol,1.2 eq) was added while maintaining an ice bath, and the mixture was reacted at room temperature for 6 hours.
Step F: (2S,3R,4S,5S,6S) -2- (4- ((((2- (4- (3-amino-1- (3- (cyanomethyl) -1- (1- (3-fluoro-2- (trifluoromethyl) isonicotinoyl) piperidin-4-yl) azetidin-3-yl) -1-yl) azetidin-3-yl) piperidineH-pyrazol-4-yl) -N-methyl-7H-pyrrole [2,3-d]Pyrimidine-7-carboxamide) ethyl) (methyl) carbamoyl) oxy) methyl) -2-nitrophenoxy) -6- (methoxycarbonyl) tetrahydro-2-carboxylic acidH-pyran-3, 4, 5-triacetic acid triester
To the 4- (3-amino-1- (3- (cyanomethyl) -1- (1- (3-fluoro-2- (trifluoromethyl) isonicotinoyl) piperidin-4-yl) azetidin-3-yl) -1 prepared in step E under ice bathH-pyrazol-4-yl) -7H-pyrrole [2,3-d]To a solution of p-nitrophenyl pyrimidine-7-carboxylate (1.1g, 1.5mmol, 1.0 eq) was added (2)S,3S,4S,5R,6S) -2- (methoxycarbonyl) -6- (4- (((methyl (2- (methylamino) ethyl) carbamoyl) oxy) methyl) -2-nitrophenoxy) tetrahydro-2H-A solution of pyran-3, 4, 5-triacetoxy triester (0.99 g,1.65 mmol, 1.1eq) in methylene chloride was reacted at room temperature overnight after the addition. The reaction system was added to water to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was subjected to silica gel column chromatography to give the product (375 mg, yield: 21%).
G: (2S,3S,4S,5R,6S) -6- (4- ((((2- (4- (3-amino-1- (3- (cyanomethyl) -1- (1- (3-fluoro-2- (trifluoromethyl) isonicotinoyl) piperidin-4-yl) azetidin-3-yl) -1-yl) azetidin-3-yl) piperidineH-Pyrazol-4-yl) -substituted benzeneN-methyl-7H-Pyrrole [2,3-d]Pyrimidine-7-carboxamide) ethyl) (methyl) carbamoyl) oxy) methyl) -2-nitrophenoxy) -3,4, 5-trihydroxytetrahydro-2H-Pyran-2-carboxylic acids
Will (2)S,3R,4S,5SS,6S) -2- (4- ((((2- (4- (3-amino-1- (3- (cyanomethyl) -1- (1- (3-fluoro-2- (trifluoromethyl) isonicotinoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) propanoic acid)N-methyl-7H-pyrrole [2,3-d]Pyrimidine-7-carboxamide) ethyl) (methyl) carbamoyl) oxy) methyl) -2-nitrophenoxy) -6- (methoxycarbonyl) tetrahydro-2H-pyran-3, 4, 5-triacetoxy triester (375mg, 0.3 mmol,1.0 eq) was dissolved in 5 mL of tetrahydrofuran and 5 mL of water, and lithium hydroxide monohydrate (51 mg,1.2 mmol,4.0 eq) was added under ice bath for 0.5 hour after the addition. After the reaction was monitored by LC-MS, the reaction was quenched with acetic acid to adjust the system pH to 5 to 6, the system was evaporated to dryness, and the residue was purified by C18 column to give the product (220 mg, yield: 67%).
LC-MS：m/z =1054[M+H] + .
1 H-NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.76 -8.67 (m, 2H), 8.57-8.14 (d, 1H), 7.91 (dd, J = 9.3, 4.5 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.9 Hz, 1H), 7.31 (s, 1H), 6.37 (s, 2H), 5.50 (s, 1H), 5.28 (d, J = 4.5 Hz, 2H), 5.17 -4.68 (m, 3H), 4.09 (s, 1H), 3.97 (d, J = 9.6 Hz, 1H), 3.70 (s, 3H), 3.62 -3.45 (m, 6H), 3.43-3.20 (m, 6H), 3.14 -3.06 (m, 2H), 2.97 (d, J = 36.9 Hz, 4H), 2.54 (s, 2H), 1.75 (s, 1H), 1.65 (s, 1H), 1.21 (d, J = 15.7 Hz, 2H).
Example 2: (2S,3S,4S,5R,6S) -6- (2-amino-4- ((((2- (4- (3-amino-1- (3- (cyanomethyl) -1- (1- (3-fluoro-2- (trifluoromethyl) isonicotinyl) piperidin-4-yl) azetidin-3-yl) -1-yl) azetidin-3-yl) azetidin-1-yl) piperidineH-Pyrazol-4-yl) -N-methyl-7H-Pyrrole [2,3-d]Pyrimidine-7-carboxamide) ethyl) (methyl) carboxamide) oxy) methyl) phenoxy) -3,4, 5-trihydroxytetrahydro-2H-Pyran-2-carboxylic acids
The product of example 1 (100 mg,0.1 mmol,1.0 eq) was dissolved in 10 mL of ethanol, 50 mg of palladium on carbon was added at room temperature, and after the addition, the reaction was carried out overnight by introducing hydrogen at room temperature. The reaction was monitored by LC-MS for completion, the reaction system was filtered, the filter cake was rinsed with methanol, the filtrate was collected, the filtrate was evaporated to dryness, and the residue was purified by C18 column to give the product (25 mg, yield: 26%).
LC-MS：m/z =1024[M+H] + .
1 H-NMR (400 MHz, DMSO-d6) δ8.76 (s, 1H), 8.67 (d, J = 4.6 Hz, 1H), 8.61 (t, J = 6.8 Hz, 1H), 8.26 (s, 2H), 7.91 (t, J = 4.6 Hz, 1H), 7.62 -7.51 (m, 1H), 7.33 (d, 1H), 6.98 -6.89 (m, 1H), 6.65 (s, 1H), 6.46 (d, J = 7.5 Hz, 1H), 6.36 (s, 2H), 4.91 (d, 2H), 4.65 (d, 1H), 4.52 (s, 1H), 4.08 (d, J = 7.5 Hz, 2H), 3.80-3.61 (m, 4H), 3.60-3.18 (m, 14H), 3.13 -2.82 (m, 6H), 2.55 -2.53 (m, 2H), 1.81-1.67 (m, 1H), 1.67 -1.57 (m, 1H), 1.34 -1.21 (m, 2H).
Example 3: evaluation of effects
50 1. Enzymatic activity (IC) assay
A JAK1/JAK2 kinase activity detection platform is established by adopting Lance Ultra principle, and the activity of the compound is determined. In the assay plate, the enzyme, ulight-labeled polypeptide substrate, ATP and assay compound are mixed and the reaction is incubated. After the reaction, EDTA is added to stop the reaction, and Eu-labeled antibody is added at the same time for detection. The assay plate was analyzed using Envision from PE in TR-FRET format and data are expressed as readings of 665nm and 615nm, respectively, fluorescence signals. Wherein a high ratio of 665nm/615nm indicates a high enzyme activity, and a low ratio of 665nm/615nm indicates a low enzyme activity.
Reagent: kinase (JAK 1/JAK 2), substrate (ULight-JAK-1 peptide and ATP), detection reagent (Eu-W1024 Anti-phosphotyrosine and EDTA).
The instrument comprises the following steps: echo, envision.
Test compounds were dissolved in 10 mM DMSO and stored in a nitrogen cabinet for long periods of time. 10. Mu.L of a 10 mM test compound solution was diluted to 1 mM working solution, and diluted 3-fold with Echo for a total of 11 concentrations. The concentration of the compound in the final reaction system was 10. Mu.M to 0.17 nM. Add 5. Mu.L of enzyme and polypeptide substrate mixture to the test plate using an electric pipettor, centrifuge the test plate, and place the test plate at room temperature (23) o C) Incubating for 15 minutes; add ATP-containing kinase buffer (1 mM final concentration) to the assay plate using an electric pipette, centrifuge the assay plate, and bring the assay plate to room temperature using an aluminum foil seal plate (23) o C) Incubate for 90 minutes. Terminating the reaction, adding the detection reagent to the detection plate using an electronic pipettor, centrifuging the detection plate, and placing the detection plate at room temperature using an aluminum foil seal plate (23) o C) Incubating for half an hour; the signal value of the reaction plate was measured by Envision instrument. The results are shown in Table 1.
2. Stability of the Compounds of the examples in beta-glucuronidase from E.coli
To characterize the stability of the compounds of the examples in the presence of β -glucuronidase, the compounds of example 1-2 (30 μ M in DMSO) were incubated in the presence of β -glucuronidase from E.coli (100 units/ml in 0.1M potassium phosphate buffer) at 37 ℃ for a time period of 0 to 90 minutes. Incubations were quenched at time points 0, 1,2, 3, 5, 10, 15, 30, 60, and 90 minutes. Samples were analyzed using an LC-MS system.
The experiment shows that: the compounds of examples 1-2 all disappeared rapidly (half-life <5 minutes) and were accompanied by rapid metabolism into the active molecule compound B. This demonstrates that the compounds of the examples can be rapidly metabolized by β -glucuronidase.
3. Solubility test
Accurately weighing a proper amount of a test sample, adding 1 mL of water, standing at 25 ℃, shaking for 30 seconds every 5 minutes for 30 minutes, observing the dissolution state, and detecting the solubility of each compound by an HPLC external standard correction method, wherein the solubility comparison results of the compounds of the examples are shown in Table 2.
4. Stability test
Placing 10 mg/mL of each test sample aqueous solution into a penicillin bottle, plugging and sealing, placing the penicillin bottle in a stability test box with the temperature of 40 +/-2 ℃ and the relative humidity of 60 +/-2% for 30 days, and inspecting the total impurity content change of the test sample aqueous solution before and after placing through HPLC detection. The results are shown in Table 3.
5. Pharmacokinetic experiments
Female SD rats were grouped, 3 per time point, and test compound sample suspensions (10 mg/kg) were each administered orally in a single gavage. Animals were fasted overnight prior to the experiment, with the fasting time ranging from 10 hours prior to dosing to 4 hours post-dosing. Blood was collected at 0.5, 1,2, 4, 8, 12 and 24 hours after oral group administration and gastrointestinal tissues were collected by isolation. Using a small animal anaesthesia machine to perform isoflurane anaesthesia, then collecting 0.3mL of whole blood through an eyeground venous plexus, placing the whole blood in a heparin anticoagulation tube, and sampling the whole blood in 4 o C. Centrifugation is carried out at 4000rpm for 5min, and the plasma is transferred to a centrifuge tube and stored at-80 ℃ until analysis. After the colon tissue is taken down, the fecal contents are gently taken out, washed with saline and patted dry, and then the tissue is homogenized after adding the homogenization buffer solution and frozen until analysis. Plasma and tissue homogenate samples were processed and analyzed for the concentration of test compound by LC/MS/MS. The results of the pharmacokinetic experiments are shown in table 4.
The experimental results show that: after the compound of the embodiment 1-2 of the invention is orally taken, the exposure amount of the active metabolite compound B in the plasma of rats is very low and is far lower than the drug concentration in the plasma when the compound B is directly orally taken; the exposure in colon tissue was very high, much higher than the drug concentration in colon when compound B was taken directly orally. The medicine with low blood exposure but enriched and exposed in the intestinal tract can avoid safety events, bring benefit to treatment of intestinal tract diseases, reduce other side effects related to the medicine, such as liver injury, blood pressure increase, cholesterol increase and the like, and provide good theoretical support for treating intestinal tract inflammatory diseases.
Claims (8)
1. A compound represented by formula 1 or a pharmaceutically acceptable salt thereof, wherein Y in formula 1 represents NO 2 Or NH 2
2. A pharmaceutical composition, comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof according to claim 1.
3. A process for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof as claimed in claim 1, comprising the reaction steps of:
4. the use of a compound of formula 1 as claimed in claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the inhibition of JAK.
5. Use of a compound of formula 1 or a pharmaceutically acceptable salt thereof as claimed in claim 1 for the manufacture of a medicament for the treatment of a disease selected from gastrointestinal inflammatory diseases.
6. The use of claim 5, wherein the gastrointestinal inflammatory disease is ulcerative colitis.
7. The use according to claim 5, wherein the gastrointestinal inflammatory disease is Crohn's disease.
8. The use according to claim 5, wherein the gastrointestinal inflammatory disease is irritable bowel syndrome.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210853391.6A CN115073543B (en) | 2022-07-20 | 2022-07-20 | Compound prodrug of JAK inhibitor and preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210853391.6A CN115073543B (en) | 2022-07-20 | 2022-07-20 | Compound prodrug of JAK inhibitor and preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115073543A CN115073543A (en) | 2022-09-20 |
| CN115073543B true CN115073543B (en) | 2022-11-15 |
Family
ID=83258962
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210853391.6A Active CN115073543B (en) | 2022-07-20 | 2022-07-20 | Compound prodrug of JAK inhibitor and preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115073543B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115873001A (en) * | 2022-11-24 | 2023-03-31 | 上海市皮肤病医院 | Novel application of JAK degrading agent based on proteolysis targeting chimera technology (PROTAC) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3380486B1 (en) * | 2015-11-24 | 2020-02-19 | Theravance Biopharma R&D IP, LLC | Prodrugs of a jak inhibitor compound for treatment of gastrointestinal inflammatory disease |
| US10472366B2 (en) * | 2017-03-08 | 2019-11-12 | Theravance Biopharma R&D Ip, Llc | Glucuronide prodrugs of tofacitinib |
| RU2019142472A (en) * | 2017-05-23 | 2021-06-24 | ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи, ЭлЭлСи | Glucuronide prodrugs of Janus kinase inhibitors |
| WO2020034987A1 (en) * | 2018-08-15 | 2020-02-20 | 江苏豪森药业集团有限公司 | Prodrug containing glucuronide derivative of jak inhibitor, preparation method therefor, and uses thereof |
-
2022
- 2022-07-20 CN CN202210853391.6A patent/CN115073543B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN115073543A (en) | 2022-09-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI703147B (en) | Prodrugs of a jak inhibitor compound for treatment of gastrointestinal inflammatory disease | |
| US6476041B1 (en) | 1,4 substituted piperidinyl NMDA/NR2B antagonists | |
| RU2763898C2 (en) | Lsd1 inhibitor, as well as its production method and its application | |
| JP2002529467A (en) | Pyrazolopyrimidinone compounds effective in treating erectile dysfunction | |
| JP6813720B1 (en) | 2,6-diaminopyridine compound | |
| JP2018172405A (en) | Glycosidase inhibitors and uses thereof | |
| JP5809279B2 (en) | Novel compounds of reverse turn analogues and their production and use | |
| NO321536B1 (en) | 3 <alpha> -Hydroxy-3 <beta> -methoxymethyl-21-heterocyclic substituted steroids with anesthetic activity | |
| AU2007352397A1 (en) | Viral inhibitors | |
| CN115073543B (en) | Compound prodrug of JAK inhibitor and preparation and application thereof | |
| JP2022537103A (en) | N-(Phenyl)-indole-3-sulfonamide derivatives and related compounds as GPR17 modulators for treating CNS disorders such as multiple sclerosis | |
| JP2018508583A (en) | Salt of quinazoline derivative and process for producing the same | |
| WO2019154395A1 (en) | Tetrahydroisoquinoline compound, preparation method therefor, pharmaceutical composition containing same, and use thereof | |
| EP1301516B1 (en) | Modulators of protein tyrosine phosphatases (ptpases) | |
| CN107987072A (en) | Benzazole compounds as CRTH2 inhibitor | |
| CN112778318B (en) | Pyrimidopyrazole derivatives for inhibiting xanthine oxidase activity, and preparation method and application thereof | |
| US6613903B2 (en) | Modulators of protein tyrosine phosphatases (PTPases) | |
| CN116496280B (en) | Deuterated acrylamide JAK3 inhibitor medicine and application thereof | |
| WO2019096112A1 (en) | Substituted benzimidazole compound and composition comprising same | |
| CN114133397B (en) | Evodiamine compound and preparation method and application thereof | |
| CN111763173B (en) | Phenethyl imidazole derivative and application thereof | |
| CN110092799B (en) | Cyclic compound, preparation method and application thereof | |
| TWI826013B (en) | Crystal forms of imidazolinone derivatives | |
| EP4089086A1 (en) | Crystal form of pyrrolidinyl urea derivative and application thereof | |
| WO2022247885A1 (en) | Crystal and salt of triheterocyclic compound and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |