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    KISSPEPTIDE-PENTASACCHARIDE CONJUGATES
    5.
    发明申请
    KISSPEPTIDE-PENTASACCHARIDE CONJUGATES 有权

    公开(公告)号：US20140206627A1

    公开(公告)日：2014-07-24

    申请号：US14236694

    申请日：2012-08-01

    申请人： Marion Blomenrohr ,  Martin De Kort ,  Miranda Maria Cornelia Van Der Lee ,  Jeffry Abraham Jacobus Wisse

    发明人： Marion Blomenrohr ,  Martin De Kort ,  Miranda Maria Cornelia Van Der Lee ,  Jeffry Abraham Jacobus Wisse

    IPC分类号： C07K9/00

    CPC分类号： C07K9/001 ,  A61K47/48092 ,  A61K47/549

    摘要： The invention relates to kisspeptide-pentasaccharide conjugates having the general formula (I) wherein Z1 is Tyr or D-Tyr; Z3 is Trp, Hyp, Phe or Lys(R2); Z5 is Thr, Aib or Ala; Z7 is Gly or azaGly; Z8 is Leu; or Z7 and Z8 together represent; Z10 is Phe or Trp; n is 0 or 1; or R2, when present, represents a pentasaccharide derivative having the formula (II) wherein R is methyl or SO3X; X is a positively charged counterion; with the proviso that when R2 is present, R1 is H or (C1-6) alkylcarbonyl; R3 is H or (C1-3)alkyl; and L represents a pharmacologically inactive linker moiety having 10-50 atoms; or a pharmaceutically acceptable salt thereof; to pharmaceutical compositions comprising the same as well as to the use of said kisspeptide-pentasaccharide conjugates in the treatment of female infertility.

    摘要翻译： 本发明涉及具有通式（I）的亲肽肽 - 五糖共轭物，其中Z 1是Tyr或D-Tyr; Z3是Trp，Hyp，Phe或Lys（R2）; Z5是Thr，Aib或Ala; Z7是Gly或azaGly; Z8是Leu; 或Z7和Z8一起表示; Z10是Phe或Trp; n为0或1; 或R2，当存在时，表示具有式（II）的五糖衍生物，其中R是甲基或SO 3 X; X为正电荷的抗衡离子; 条件是当R 2存在时，R 1是H或（C 1-6）烷基羰基; R3是H或（C1-3）烷基; L代表具有10-50个原子的药理学无活性接头部分; 或其药学上可接受的盐; 涉及包含该药物组合物的药物组合物以及所述亲肽肽 - 五糖共轭物在治疗女性不孕症中的用途。

    Antithrombotic dual inhibitors comprising a biotin residue
    7.
    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
    8.
    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。

    Kisspeptide-pentasaccharide conjugates
    9.
    发明授权
    Kisspeptide-pentasaccharide conjugates 有权
    亲水 - 五糖共轭物

    公开(公告)号：US09127038B2

    公开(公告)日：2015-09-08

    申请号：US14236694

    申请日：2012-08-01

    申请人： Marion Blomenrohr ,  Martin De Kort ,  Miranda Maria Cornelia Van Der Lee ,  Jeffry Abraham Jacobus Wisse

    发明人： Marion Blomenrohr ,  Martin De Kort ,  Miranda Maria Cornelia Van Der Lee ,  Jeffry Abraham Jacobus Wisse

    IPC分类号： C07K9/00 ,  A61K47/48

    CPC分类号： C07K9/001 ,  A61K47/48092 ,  A61K47/549

    摘要： The invention relates to kisspeptide-pentasaccharide conjugates having the general formula (I) wherein Z1 is Tyr or D-Tyr; Z3 is Trp, Hyp, Phe or Lys(R2); Z5 is Thr, Aib or Ala; Z7 is Gly or azaGly; Z8 is Leu; or Z7 and Z8 together represent; Z10 is Phe or Trp; n is 0 or 1; or R2, when present, represents a pentasaccharide derivative having the formula (II) wherein R is methyl or SO3X; X is a positively charged counterion; with the proviso that when R2 is present, R1 is H or (C1-6) alkylcarbonyl; R3 is H or (C1-3)alkyl; and L represents a pharmacologically inactive linker moiety having 10-50 atoms; or a pharmaceutically acceptable salt thereof; to pharmaceutical compositions comprising the same as well as to the use of said kisspeptide-pentasaccharide conjugates in the treatment of female infertility.

    摘要翻译： 本发明涉及具有通式（I）的亲肽肽 - 五糖共轭物，其中Z 1是Tyr或D-Tyr; Z3是Trp，Hyp，Phe或Lys（R2）; Z5是Thr，Aib或Ala; Z7是Gly或azaGly; Z8是Leu; 或Z7和Z8一起表示; Z10是Phe或Trp; n为0或1; 或R2，当存在时，表示具有式（II）的五糖衍生物，其中R是甲基或SO 3 X; X为正电荷的抗衡离子; 条件是当R 2存在时，R 1是H或（C 1-6）烷基羰基; R3是H或（C1-3）烷基; L代表具有10-50个原子的药理学无活性接头部分; 或其药学上可接受的盐; 涉及包含该药物组合物的药物组合物以及所述亲肽肽 - 五糖共轭物在治疗女性不孕症中的用途。

    Anticoagulant Antithrombotic Dual Inhibitors Comprising a Biotin Label
    10.
    发明申请
    Anticoagulant Antithrombotic Dual Inhibitors Comprising a Biotin Label 有权
    包含生物素标签的抗凝血剂抗血栓双重抑制剂

    公开(公告)号：US20100029582A1

    公开(公告)日：2010-02-04

    申请号：US12083212

    申请日：2006-10-06

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

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

    IPC分类号： A61K31/715 ,  C07H3/06 ,  A61P7/02

    CPC分类号： C07H15/04 ,  A61K47/54 ,  A61K47/557 ,  A61K47/60 ,  C07H3/06 ,  C07H15/08 ,  C07H15/18

    摘要： The present invention relates compounds of the formula: oligosaccharide-spacer-(GpIIb/IIIa antagonist), wherein the oligosaccharide is a negatively charged oligosaccharide residue comprising four 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-II mediated) anti-Xa activity per se; the spacer is a bond or an essentially pharmacologically inactive linking residue; the GpIIb/IIIa antagonist is a residue mimicking the RGD and/or K(QA)GD fragment of fibrinogen, comprising a carboxylate moiety and a basic moiety located within the residue at a distance of 10-20 Å from each other; or a pharmaceutically acceptable salt thereof or a prodrug or a solvate thereof; wherein the compound of formula I further comprises at least one covalent bond with a biotin label or an analogue thereof. The compounds of the invention have antithrombotic activity and can be used in treating or preventing thrombotic 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： 本发明涉及下式的化合物：寡糖 - 间隔基（GpIIb / IIIa拮抗剂），其中寡糖是包含四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 残基衍生自具有（AT-II介导的）抗Xa活性本身的寡糖; 间隔基是键或基本上药理学上无活性的连接残基; GpIIb / IIIa拮抗剂是模拟纤维蛋白原的RGD和/或K（QA）GD片段的残基，其包含位于残基内的羧基部分和位于彼此间隔10-20处的碱性部分; 或其药学上可接受的盐或其前药或溶剂合物; 其中式I化合物还包含与生物素标记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。