DE KORT, MARTIN,VAN BOECKEL, CONSTANT ADRIAAN ANTON
申请号：
CA2592436
公开号：
CA2592436C
申请日:
2005.12.21
申请国别(地区):
CA
年份:
2012
代理人:
摘要：
The present invention relates compounds of the formula (I) oligosaccharide-spacer-A (I), wherein the oligosaccharide is a negatively chargedoligosaccharide residue comprising two to twenty five monosaccharide units,the charge being compensated by positively charged counterions, and whereinthe oligosaccharide residue is derived from an oligosaccharide which has (AT-III mediated) anti-Xa activity per se； the spacer is an essentiallypharmacologically inactive flexible linking residue having a chain length of10 to 70 atoms； A is the residue -CH[NH-SO2-R1] [CO-NR2-CH(4-benzamidine)-CO-NR3R4], wherein R1 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl,(iso)quinolinyl, tetrahydro(iso)quinolinyl, 3,4-dihydro-lH-isoquinolinyl,chromanyl or the camphor group, which groups may optionally be substitutedwith one or more substituents selected from (l-8C)alkyl or (1-8C)alkoxy； andwherein R2 and R3 are independently H or (1-8C)alkyl； R4 is (-8C)alkyl or (3-8C)cycloalkyl； or R3 and R4 together with the nitrogen atom to which they arebonded are a nonaromatic (4-8)membered ring optionally containing anotherheteroatom, the ring optionally being substituted with (l-8C)alkyl or SO2-(I-8C)alkyl； or a pharmaceutically acceptable salt thereof a prodrug or solvatethereof； wherein the compound of formula I further comprises at least onecovalent bond with a biotin residue or an analogue thereof. The compounds ofthe invention have antithrombotic activity and can be used in treating orpreventing thrombosis or other thrombin-related diseases. The antithromboticactivity of the compound of this invention can be neutralized in case ofemergency upon adminstration of avidin, streptavidin and analogues thereofhaving high biotin affinity.
