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    Antithrombotic dual inhibitors comprising a biotin residue
    1.
    发明授权
    Antithrombotic dual inhibitors comprising a biotin residue 有权
    包含生物素残基的抗血栓双重抑制剂

    公开(公告)号：US08168595B2

    公开(公告)日：2012-05-01

    申请号：US11722444

    申请日：2005-12-21

    申请人： Martin De Kort ,  Constant Adriaan Anton Van Boeckel

    发明人： Martin De Kort ,  Constant Adriaan Anton Van Boeckel

    IPC分类号： A61K31/7052 ,  C07H15/20

    CPC分类号： B82Y5/00 ,  A61K47/61 ,  A61K47/66 ,  A61K47/665 ,  C07H15/26

    摘要： The present invention relates to compounds of the formula (I) oligosaccharide-spacer-A (1), wherein the oligosaccharide is a negatively charged oligosaccharide residue comprising two to twenty five monosaccharide units, the charge being compensated by positively charged counterions, and wherein the oligosaccharide residue is derived from an oligosaccharide which has (AT-III mediated) anti-Xa activity per se; the spacer is an essentially pharmacologically inactive flexible linking residue having a chain length of 10 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-1H-isoquinolinyl, chromanyl or the camphor group, which groups may optionally be substituted with one or more substituents selected from (1-8C)alkyl or (1-8C)alkoxy; and wherein 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 are bonded are a nonaromatic (4-8) membered ring optionally containing another heteroatom, the ring optionally being substituted with (1-8C)alkyl or SO2-(1-8C)alkyl; or a pharmaceutically acceptable salt thereof a prodrug or solvate thereof; wherein the compound of formula I further comprises at least one covalent bond with a biotin residue or an analogue thereof. The compounds of the invention have antithrombotic activity and can be used in treating or preventing thrombosis or other thrombin-related diseases. The antithrombotic activity of the compound of this invention can be neutralized in case of emergency upon administration of avidin, streptavidin and analogues thereof having high biotin affinity.

    摘要翻译： 本发明涉及寡糖 - 间隔基-A（1）的式（I）化合物，其中寡糖是含有二至二十五个单糖单元的带负电荷的寡糖残基，电荷通过带正电荷的抗衡离子补偿，其中 寡糖残基源自具有（AT-III介导的）抗Xa活性本身的寡糖; 间隔基是具有10至70个原子链长度的基本上药理学上无活性的柔性连接残基; A是残基-CH [NH-SO 2 -R 1 [CO-NR 2 -CH（4-苯甲脒）-CO-NR 3 R 4]，其中R 1是苯基，萘基，1,2,3,4-四氢萘基，（异）喹啉基 ，四氢（异）喹啉基，3,4-二氢-1H-异喹啉基，苯并二氢吡喃基或樟脑基，该基团可任选被一个或多个选自（1-8C）烷基或（1-8C）烷氧基的取代基取代; 并且其中R2和R3独立地为H或（1-8C）烷基; R4是（ - C8）烷基或（3-8C）环烷基; 或R 3和R 4与它们所键合的氮原子一起是任选地含有其它杂原子的非芳族（4-8）元环，所述环任选被（1-8C）烷基或SO 2 - （1-8C）烷基取代 ; 或其药学上可接受的盐的前药或溶剂化物; 其中式I化合物还包含与生物素残基或其类似物的至少一个共价键。 本发明化合物具有抗血栓形成活性，可用于治疗或预防血栓形成或其他凝血酶相关疾病。 在施用具有高生物素亲和力的抗生物素蛋白，链霉亲和素及其类似物时，本发明化合物的抗血栓形成活性可以在紧急情况下被中和。

    Antithrombotic Dual Inhibitors Comprising A Biotin Residue
    2.
    发明申请
    Antithrombotic Dual Inhibitors Comprising A Biotin Residue 有权
    包含生物素残基的抗血栓双重抑制剂

    公开(公告)号：US20100004186A1

    公开(公告)日：2010-01-07

    申请号：US11722444

    申请日：2005-12-21

    申请人： Martin De Kort ,  Constant Adriaan Anton Van Boeckel

    发明人： Martin De Kort ,  Constant Adriaan Anton Van Boeckel

    IPC分类号： A61K31/7052 ,  C07H15/20

    CPC分类号： B82Y5/00 ,  A61K47/61 ,  A61K47/66 ,  A61K47/665 ,  C07H15/26

    摘要： The present invention relates compounds of the formula (I) oligosaccharide-spacer-A (1), wherein the oligosaccharide is a negatively charged oligosaccharide residue comprising two to twenty five monosaccharide units, the charge being compensated by positively charged counterions, and wherein the oligosaccharide residue is derived from an oligosaccharide which has (AT-III mediated) anti-Xa activity per se; the spacer is an essentially pharmacologically inactive flexible linking residue having a chain length of 10 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-1H-isoquinolinyl, chromanyl or the camphor group, which groups may optionally be substituted with one or more substituents selected from (1-8C)alkyl or (1-8C)alkoxy; and wherein 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 are bonded are a nonaromatic (4-8) membered ring optionally containing another heteroatom, the ring optionally being substituted with (1-8C)alkyl or SO2-(1-8C)alkyl; or a pharmaceutically acceptable salt thereof a prodrug or solvate thereof; wherein the compound of formula I further comprises at least one covalent bond with a biotin residue or an analogue thereof. The compounds of the invention have antithrombotic activity and can be used in treating or preventing thrombosis or other thrombin-related diseases. The antithrombotic activity of the compound of this invention can be neutralized in case of emergency upon administration of avidin, streptavidin and analogues thereof having high biotin affinity.

    摘要翻译： 本发明涉及式（I）寡糖 - 间隔基-A（1）的化合物，其中所述寡糖是含有二至二十五个单糖单元的带负电荷的寡糖残基，所述电荷通过带正电荷的抗衡离子补偿，并且其中寡糖 残基衍生自具有（AT-III介导的）抗Xa活性本身的寡糖; 间隔基是具有10至70个原子链长度的基本上药理学上无活性的柔性连接残基; A是残基-CH [NH-SO2-R1] [CO-NR2-CH（4-苯脒）-CO-NR3R4]，其中R1是苯基，萘基，1,2,3,4-四氢萘基，（iso） 喹啉基，四氢（异）喹啉基，3,4-二氢-1H-异喹啉基，苯并二氢吡喃基或樟脑基，该基团可任选被一个或多个选自（1-8C）烷基或（1-8C）烷氧基 ; 并且其中R2和R3独立地为H或（1-8C）烷基; R4是（ - C8）烷基或（3-8C）环烷基; 或R 3和R 4与它们所键合的氮原子一起是任选地含有其它杂原子的非芳族（4-8）元环，所述环任选被（1-8C）烷基或SO 2 - （1-8C）烷基取代 ; 或其药学上可接受的盐的前药或溶剂化物; 其中式I化合物还包含与生物素残基或其类似物的至少一个共价键。 本发明化合物具有抗血栓形成活性，可用于治疗或预防血栓形成或其他凝血酶相关疾病。 在施用具有高生物素亲和力的抗生物素蛋白，链霉亲和素及其类似物时，本发明化合物的抗血栓形成活性可以在紧急情况下被中和。

    ANTITHROMBOTIC DUAL INHIBITORS COMPRISING A BIOTIN RESIDUE
    3.
    发明申请
    ANTITHROMBOTIC DUAL INHIBITORS COMPRISING A BIOTIN RESIDUE 有权
    抗生素双重抑制剂包含生物素残留

    公开(公告)号：US20120245109A1

    公开(公告)日：2012-09-27

    申请号：US13438905

    申请日：2012-04-04

    申请人： Martin DE KORT ,  Constant Adriaan Anton VAN BOECKEL

    发明人： Martin DE KORT ,  Constant Adriaan Anton VAN BOECKEL

    IPC分类号： A61K31/706 ,  A61P7/02

    CPC分类号： B82Y5/00 ,  A61K47/61 ,  A61K47/66 ,  A61K47/665 ,  C07H15/26

    摘要： The present invention relates compounds of the formula (I) oligosaccharide-spacer-A   (I), wherein the oligosaccharide is a negatively charged oligosaccharide residue comprising two to twenty five monosaccharide units, the charge being compensated by positively charged counterions, and wherein the oligosaccharide residue is derived from an oligosaccharide which has (AT-III mediated) anti-Xa activity per se; the spacer is an essentially pharmacologically inactive flexible linking residue having a chain length of 10 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-1H-isoquinolinyl, chromanyl or the camphor group, which groups may optionally be substituted with one or more substituents selected from (1-8C)alkyl or (1-8C)alkoxy; and wherein R2 and R3 are independently H or (1-8C)alkyl; R4 is (1-8C)alkyl or (3-8C)cycloalkyl; or R3 and R4 together with the nitrogen atom to which they are bonded are a nonaromatic (4-8)membered ring optionally containing another heteroatom, the ring optionally being substituted with (1-8C)alkyl or SO2-(1-8C)alkyl; or a pharmaceutically acceptable salt thereof a prodrug or solvate thereof; wherein the compound of formula I further comprises at least one covalent bond with a biotin residue or an analogue thereof. The compounds of the invention have antithrombotic activity and can be used in treating or preventing thrombosis or other thrombin-related diseases. The antithrombotic activity of the compound of this invention can be neutralized in case of emergency upon adminstration of avidin, streptavidin and analogues thereof having high biotin affinity.

    摘要翻译： 本发明涉及式（I）寡糖 - 间隔基-A（I）的化合物，其中所述寡糖是包含二至二十五个单糖单元的带负电荷的寡糖残基，所述电荷通过带正电荷的抗衡离子补偿，并且其中所述寡糖 残基衍生自具有（AT-III介导的）抗Xa活性本身的寡糖; 间隔基是具有10至70个原子链长度的基本上药理学上无活性的柔性连接残基; A是残基-CH [NH-SO2-R1] [CO-NR2-CH（4-苯脒）-CO-NR3R4]，其中R1是苯基，萘基，1,2,3,4-四氢萘基，（iso） 喹啉基，四氢（异）喹啉基，3,4-二氢-1H-异喹啉基，苯并二氢吡喃基或樟脑基，该基团可任选被一个或多个选自（1-8C）烷基或（1-8C）烷氧基 ; 并且其中R2和R3独立地为H或（1-8C）烷基; R4是（1-8C）烷基或（3-8C）环烷基; 或R 3和R 4与它们所键合的氮原子一起是任选地含有其它杂原子的非芳族（4-8）元环，所述环任选被（1-8C）烷基或SO 2 - （1-8C）烷基取代 ; 或其药学上可接受的盐的前药或溶剂化物; 其中式I化合物还包含与生物素残基或其类似物的至少一个共价键。 本发明化合物具有抗血栓形成活性，可用于治疗或预防血栓形成或其他凝血酶相关疾病。 在施用具有高生物素亲和力的抗生物素蛋白，链霉抗生物素蛋白及其类似物的紧急情况下，本发明化合物的抗血栓形成活性可被中和。