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Methods for treating vascular leak syndrome

A technique for vascular leak syndrome, applied in the treatment of vascular leak syndrome, treatment of vascular leak caused by the presence of pathogens, treatment of vascular leak caused by inflammatory disease, treatment of metastatic renal cell carcinoma and metastatic In the field of melanoma, it can solve the problems of limiting doses and stopping treatment

Inactive Publication Date: 2012-02-29
AERPIO TERAPYUTIKS INK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

VLS limits the dose of IL-2 that can be administered to humans and in some cases requires cessation of treatment

Method used

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  • Methods for treating vascular leak syndrome
  • Methods for treating vascular leak syndrome
  • Methods for treating vascular leak syndrome

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0430] 4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-phenylpropionylamino]-2-(4-ethylthiazol-2-yl)ethyl} Phenylsulfamic acid (5)

[0431] Preparation of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl ester (1): 2-(S)-tert-butoxycarbonyl at 0°C To a solution of amino-3-(4-nitrophenyl)-propionic acid and N-methylmorpholine (1.1 mL, 9.65 mmol) in DMF (10 mL) was added dropwise isobutyl chloroformate (1.25 mL, 9.65 mmol). The mixture was stirred at 0 °C for 20 min, after which NH 3 (g) Pass the reaction mixture for 30 minutes. The reaction mixture was concentrated and the residue was dissolved in EtOAc with 5% citric acid, water, 5% NaHCO 3 , water and brine successively, dried (Na 2 SO 4 ), filtration and concentration in vacuo gave a residue which was triturated with an EtOAc / petroleum ether mixture to afford 2.2 g (74%) of the desired product as a white solid.

[0432] Preparation of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]carbamate tert-butyl ester ...

Embodiment 2

[0472] 4-{(S)-2-(S)-2-(tert-butoxycarbonylamino)-3-phenylpropionylamino-2-(2-phenylthiazol-4-yl)}phenylsulfamate Acid (9)

[0473] Preparation of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester (6): at 0°C, to 2-( S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g, 4.0 mmol) in THF (20 mL) was added dropwise triethylamine (0.61 mL, 4.4 mmol) , followed by the addition of isobutyl chloroformate (0.57 mL, 4.4 mmol). The reaction mixture was stirred at 0 °C for 20 minutes and filtered. The filtrate was treated with diazomethane (-16 mmol) in ether at 0 °C. The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo. The resulting residue was dissolved in EtOAc and washed successively with water and brine, dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified on silica (hexane / EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product as a light yellow solid. 1 H NMR (300MHz...

Embodiment 3

[0492] 4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropionylamino]-2-(2-ethylthiazol-4-yl)ethyl}benzene Aminosulfonic acid (13)

[0493] Preparation of (S)-1-[(S)-1-(2-ethylthiazol-4-yl)-2-(4-nitrophenyl)-ethyl]amino-1-oxo-3-phenyl Methyl propan-2-ylcarbamate (12): Propylthioamide (69 mg, 0.78 mmol) and (S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3 -Oxybutan-2-ylcarbamate (7) (0.300g, 0.77mmol) in CH 3 The mixture in CN (4 mL) was refluxed for 2 hours. The reaction mixture was cooled to room temperature and diethyl ether was added to precipitate the intermediate product 2-(nitrophenyl)-(S)-1-(4-ethylthiazol-2-yl)ethylamine, and the The precipitate was isolated as the hydrobromide salt by filtration. The hydrobromide salt was mixed with diisopropylethylamine (0.38 mL, 2.13 mmol), 1-hydroxybenzotriazole (107 mg, 0.71 mmol) and (S)-(2-methoxycarbonyl-amino) - 3-Phenylpropanoic acid (175 mg, 0.78 mmol) was dissolved together in DMF (8 mL). The mixture was stirred at 0 °C for...

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Abstract

Disclosed are methods for treating Vascular Leak Syndrome. Further disclosed are methods for treating vascular leakage due to inflammatory diseases, inter alia, sepsis, lupus, irritable bowel disease. Yet further disclosed are methods for treating renal cell carcinoma and melanoma. Still further disclosed are methods for reducing metastasis of malignant cells and / or preventing the proliferation of carcinoma cells via spreading due to vascular leakage.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to provisional application serial number 61 / 144,022 filed January 12, 2009 and provisional application serial number 61 / 184,985 filed June 8, 2009. The entire disclosures of both cited applications are hereby incorporated by reference. technical field [0003] Disclosed herein are methods for treating vascular leak syndrome. Further disclosed herein are methods for treating vascular leakage caused by inflammatory diseases, especially sepsis, lupus, irritable bowel disease. Also disclosed herein are methods for treating vascular leakage caused by the presence of a pathogen. The present invention further discloses methods for treating metastatic renal cell carcinoma and metastatic melanoma. Background technique [0004] Vascular leakage is characterized by hypotension, peripheral edema, and hypoalbuminemia. Vascular leakage can occur as a side effect of disease, especially disease cau...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/82A61K31/41
CPCA61K31/41A61K31/426A61K31/427A61K45/06C07D277/34C07D417/06A61K31/4245A61K31/428A61K31/433A61K31/4439A61K31/497A61K31/538C07D277/28C07D277/60C07D277/64C07D417/04C07D417/12A61P1/00A61P1/04A61P17/02A61P29/00A61P31/00A61P31/04A61P31/12A61P33/02A61P35/00A61P7/00A61P9/00A61P9/14A61K2300/00A61K31/10
Inventor R·塞尔维茨K·G·彼得斯
Owner AERPIO TERAPYUTIKS INK
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