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Binding proteins to inhibitors of coagulation factors

A technology of anticoagulants and binding fragments, which can be used in immunoglobulins, blood diseases, drug combinations, etc., and can solve problems such as hapten-specific antibody obstruction

Inactive Publication Date: 2014-03-05
BAYER IP GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, isolation of hapten-specific antibodies from display libraries is hampered by the need to chemically modify the molecules to immobilize the target during the "biopanning" step

Method used

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  • Binding proteins to inhibitors of coagulation factors
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  • Binding proteins to inhibitors of coagulation factors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0297] N-({(5S)-3-[4-(2-allyl-3-oxomorpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidine-5- Methyl)-5-chlorothiophene-2-carboxamide [mixture of diastereoisomers]

[0298]

[0299] 10.9g (25.0mmol) 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxo Oxazolidine-5-yl}methyl)-2-thiophenecarboxamide (recorded in WO01 / 047919) was dissolved in 250ml THF, and 62.5ml (10.5g, 62.5mmol) of 1N hexamethyl Lithium hexamethyldisilazide-THF-solution. After 30 minutes, 2.4ml (4.4g, 26.2mmol) of 3-iodo-2-propene was added dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred at this room temperature for 16 hours. Then saturated aqueous ammonium chloride and ethyl acetate were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethan...

Embodiment 1B

[0302] N-({(5S)-3-[4-(2-allyl-3-oxomorpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidine-5- methyl)-5-chlorothiophene-2-carboxamide [optically pure diastereomer 2]

[0303]

[0304] 5.7 g (12.0 mmol) of the isomers of the compound from Example 1A were separated according to Method 1B, yielding 2.5 g of Example 1B (2nd eluting compound).

[0305] LC-MS (Method 3A): Rt = 0.95 min; MS (ESIpos): m / z = 476 [M+H]+.

[0306] HPLC (Method 1C): Rt=4.15 min

Embodiment 1C

[0308] 5-Chloro-N-{[(5S)-3-{4-[2-(3-hydroxypropyl)-3-oxomorpholin-4-yl]phenyl}-2-oxo-1, 3-oxazolidin-5-yl]methyl}thiophene-2-carboxamide [optically pure diastereoisomer]

[0309]

[0310] 2.5g (5.25mmol) of the compound from Example 1B was dissolved in 35ml of THF, and 1ml (1.41g, 11.6mmol) of 0.5mol 9-boronbicyclo[3.3.1]nonane in THF was added at 10 to 15°C - solution. The reaction mixture was warmed to room temperature and stirred at this temperature for 1.5 h. 13.1 ml (1.05 g, 26.3 mmol) of 2N sodium hydroxide solution was added dropwise at 0 to 5°C. Then 4.6ml of 36% hydrogen peroxide solution was added dropwise, while the temperature of the water bath (bath) did not exceed 30°C. After 30 minutes, ethyl acetate and water were added. The organic phase is separated. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with aqueous sodium bisulfite, dried over sodium sulfate, filtered and concentrated under reduced pressure. ...

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Abstract

The present invention relates to the identification and use of antigen-binding regions, antibodies, antigen-binding antibody fragments and antibody mimetics, neutralizing the anti-coagulant effect of an anticoagulant in vitro and / or in vivo. Antibodies and functional fragments of the invention and antibody mimetics can be used to specifically reverse the pharmacological effect of an anticoagulant e.g. a FXa inhibitor for therapeutic (antidote) and / or diagnostic purposes. The invention also provides nucleic acid sequences encoding foregoing molecules, vectors containing the same, pharmaceutical compositions and kits with instructions for use.

Description

technical field [0001] The present invention relates to the identification and use of antigen binding regions, antibodies, antigen binding antibody fragments and antibody mimetics that interact with and neutralize therapeutic inhibitors of coagulation factors. [0002] Antibody mimetics, antibodies and functional fragments of the invention can be used to specifically reverse the pharmacological effects of eg FXa inhibitors for therapeutic (antidote) and / or diagnostic purposes. The present invention also provides nucleic acid sequences encoding the above molecules, vectors containing the nucleic acid sequences, pharmaceutical compositions and kits with instructions for use. Background technique [0003] The usual limitations of anticoagulant drugs are the risk of bleeding associated with the treatment and the limited ability to rapidly reverse their activity in emergency situations. Although the emerging anticoagulant rivaroxaban (rivaroxaban) is a new drug with proven toler...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/44A61K39/00
CPCC07K2317/55C07K16/44A61K2300/00C07K2317/76A61K2039/505A61P7/02A61P7/04
Inventor F·迪特默A·布奇穆勒C·格德斯A·特尔斯迪根M·J·格诺斯L·林登A·哈伦加J·格鲁德金斯卡-高宝M·杰斯科M·沙弗尔J·博肯费尔德H·鲍尔森R·芬纳恩A·迈耶-巴奇米德A·埃克尔S·格利文S·斯泰尼格
Owner BAYER IP GMBH
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