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    GLP-1 DERIVATIVES AND USES THEREOF
    2.
    发明公开
    GLP-1 DERIVATIVES AND USES THEREOF 审中-公开

    公开(公告)号：EP3423481A1

    公开(公告)日：2019-01-09

    申请号：EP17708491.0

    申请日：2017-03-02

    申请人： Novo Nordisk A/S

    发明人： KOFOED, Jacob ,  KODRA, János, Tibor ,  LINDEROTH, Lars ,  GARIBAY, Patrick, William

    IPC分类号： C07K14/605 ,  A61K38/26

    摘要： The invention relates to GLP-1 analogues and derivatives having a Trp at a position corresponding to position 8 of GLP-1(7-37), and their pharmaceutical use e.g. in the treatment of type 2 diabetes. These Trp8 compounds are very stable against degradation by DPP-IV, while maintaining the capability to bind to and activate the GLP-1 receptor. The derivatives have one or two substituents (P-L) attached to a Lys residue of the GLP-1 analogue via an optional Branching group (B), wherein P is a Protracting moiety such as a fatty diacid, and L is a linker consisting of one or more linker elements such as, for example, 8-amino-3,6-dioxaoctanoic acid. Examples of compounds of the invention include the 8W variants of liraglutide and dulaglutide. The invention also relates to a method for the fully recombinant preparation of 8W GLP-1 analogues and derivatives which is more simple and thereby cheaper as compared to the preparation of known GLP-1 analogues that have been DPP-IV stabilised by inclusion of one or more non-coded amino acids.

    GLP-1 RECEPTOR AGONIST COMPOUNDS WITH A MODIFIED N-TERMINUS
    3.
    发明公开
    GLP-1 RECEPTOR AGONIST COMPOUNDS WITH A MODIFIED N-TERMINUS 审中-公开
    具有修饰的N-末端的GLP-1受体激动剂化合物

    公开(公告)号：EP2512518A1

    公开(公告)日：2012-10-24

    申请号：EP10793244.4

    申请日：2010-12-16

    申请人： Novo Nordisk A/S

    发明人： KODRA, János, Tibor ,  MADSEN, Johnny

    IPC分类号： A61K47/48 ,  C07D233/64 ,  C07K14/605

    CPC分类号： C07K14/65 ,  A61K38/00 ,  A61K47/542 ,  A61K47/60 ,  C07K14/605 ,  G01N2333/605

    摘要： The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 37 of GLP-1 (7-37) (SEQ ID NO: 1), a second K residue at a position corresponding to position 26 of GLP-1 (7-37), and a maximum of ten amino acid modifications as compared to GLP-1 (7-37), wherein the first K residue is designated K 37 , and the second K residue is designated K 26 , which derivative comprises two albumin binding moieties attached to K 26 and K 37 , respectively, wherein the albumin binding moiety comprises a protracting moiety selected from: €ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 1:€ƒ€ƒ€ƒ€ƒ€ƒHOOC-(CH 2 ) x -CO-* €ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 2:€ƒ€ƒ€ƒ€ƒ€ƒHOOC-C 6 H 4 -O-(CH 2 ) y -CO-* €ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 3:€ƒ€ƒ€ƒ€ƒ€ƒR 1 -C 6 H 4 -(CH 2 ) z -CO-* €ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 4:€ƒ€ƒ€ƒ€ƒ€ƒHOOC-C 4 SH 2 -(CH 2 ) w -CO-* in which x is an integer in the range of 6-18, y is an integer in the range of 3-17, z is an integer in the range of 1-5, R 1 is a group having a molar mass not higher than 150 Da, and w is an integer in the range of 6-18; with the proviso that when the protracting moiety is Chem. 1, the albumin binding moiety further comprises a linker of formula Chem. 5: *-NH-(CH 2 ) 2 -(O-(CH 2 ) 2 ) k -O-(CH 2 ) n -CO-*, wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptides and side chain intermediates. The derivatives are suitable for oral administration.

    摘要翻译： 本发明涉及具有修饰的N-末端的GLP-1受体激动剂化合物。 该化合物具有式Chem。 1：Y-Z-P，其中P代表缺乏两个N端氨基酸残基的GLP-1受体激动剂肽的片段; 而Y-Z代表新型His-Ala模拟物。 GLP-1受体激动剂化合物的实例衍生自人GLP-1（7-37），毒蜥外泌肽-4（1-39）或GLP-1A（1-37）。 本发明还涉及这些化合物的衍生物，特别是具有能够延长这些化合物的体内作用持续时间的一种或多种白蛋白结合侧链的化合物。 本发明的肽和衍生物具有良好的效力，长期的药代动力学特征，对胃肠酶降解稳定，和/或具有高的口服生物利用度。 这些性质对于开发用于皮下，静脉内和/或特别是口服给药的GLP-1受体激动剂化合物是重要的。 本发明还涉及用于制备本发明的GLP-1受体激动剂化合物的中间产物。

    DOUBLE-ACYLATED GLP-1 DERIVATIVES
    7.
    发明授权
    DOUBLE-ACYLATED GLP-1 DERIVATIVES 有权
    双酰化GLP-1衍生物

    公开(公告)号：EP2513140B1

    公开(公告)日：2015-11-04

    申请号：EP10788095.7

    申请日：2010-12-16

    申请人： Novo Nordisk A/S

    发明人： GARIBAY, Patrick, William ,  SPETZLER, Jane ,  KODRA, János, Tibor ,  LINDEROTH, Lars ,  LAU, Jesper ,  SAUERBERG, Per

    IPC分类号： C07K14/605 ,  A61K47/48

    CPC分类号： C07K14/65 ,  A61K38/00 ,  A61K47/542 ,  A61K47/60 ,  C07K14/605 ,  G01N2333/605

    摘要： The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 37 of GLP-1 (7-37) (SEQ ID NO: 1), a second K residue at a position corresponding to position 26 of GLP-1 (7-37), and a maximum of ten amino acid modifications as compared to GLP-1 (7-37), wherein the first K residue is designated K 37 , and the second K residue is designated K 26 , which derivative comprises two albumin binding moieties attached to K 26 and K 37 , respectively, wherein the albumin binding moiety comprises a protracting moiety selected from: €ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 1:€ƒ€ƒ€ƒ€ƒ€ƒHOOC-(CH 2 ) x -CO-* €ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 2:€ƒ€ƒ€ƒ€ƒ€ƒHOOC-C 6 H 4 -O-(CH 2 ) y -CO-* €ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 3:€ƒ€ƒ€ƒ€ƒ€ƒR 1 -C 6 H 4 -(CH 2 ) z -CO-* €ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 4:€ƒ€ƒ€ƒ€ƒ€ƒHOOC-C 4 SH 2 -(CH 2 ) w -CO-* in which x is an integer in the range of 6-18, y is an integer in the range of 3-17, z is an integer in the range of 1-5, R 1 is a group having a molar mass not higher than 150 Da, and w is an integer in the range of 6-18; with the proviso that when the protracting moiety is Chem. 1, the albumin binding moiety further comprises a linker of formula Chem. 5: *-NH-(CH 2 ) 2 -(O-(CH 2 ) 2 ) k -O-(CH 2 ) n -CO-*, wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptides and side chain intermediates. The derivatives are suitable for oral administration.

    DOUBLE-ACYLATED GLP-1 DERIVATIVES
    8.
    发明公开
    DOUBLE-ACYLATED GLP-1 DERIVATIVES 有权
    ZWEIFACH ACYLIERTE GLP-1-DERIVATE

    公开(公告)号：EP2513140A1

    公开(公告)日：2012-10-24

    申请号：EP10788095.7

    申请日：2010-12-16

    申请人： Novo Nordisk A/S

    发明人： GARIBAY, Patrick, William ,  SPETZLER, Jane ,  KODRA, János, Tibor ,  LINDEROTH, Lars ,  LAU, Jesper ,  SAUERBERG, Per

    IPC分类号： C07K14/605 ,  A61K47/48

    CPC分类号： C07K14/65 ,  A61K38/00 ,  A61K47/542 ,  A61K47/60 ,  C07K14/605 ,  G01N2333/605

    摘要： The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 37 of GLP-1 (7-37) (SEQ ID NO: 1), a second K residue at a position corresponding to position 26 of GLP-1 (7-37), and a maximum of ten amino acid modifications as compared to GLP-1 (7-37), wherein the first K residue is designated K 37 , and the second K residue is designated K 26 , which derivative comprises two albumin binding moieties attached to K 26 and K 37 , respectively, wherein the albumin binding moiety comprises a protracting moiety selected from: €ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 1:€ƒ€ƒ€ƒ€ƒ€ƒHOOC-(CH 2 ) x -CO-* €ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 2:€ƒ€ƒ€ƒ€ƒ€ƒHOOC-C 6 H 4 -O-(CH 2 ) y -CO-* €ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 3:€ƒ€ƒ€ƒ€ƒ€ƒR 1 -C 6 H 4 -(CH 2 ) z -CO-* €ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem. 4:€ƒ€ƒ€ƒ€ƒ€ƒHOOC-C 4 SH 2 -(CH 2 ) w -CO-* in which x is an integer in the range of 6-18, y is an integer in the range of 3-17, z is an integer in the range of 1-5, R 1 is a group having a molar mass not higher than 150 Da, and w is an integer in the range of 6-18; with the proviso that when the protracting moiety is Chem. 1, the albumin binding moiety further comprises a linker of formula Chem. 5: *-NH-(CH 2 ) 2 -(O-(CH 2 ) 2 ) k -O-(CH 2 ) n -CO-*, wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptides and side chain intermediates. The derivatives are suitable for oral administration.

    摘要翻译： 本发明涉及GLP-1类似物的衍生物，其类似物包含在对应于GLP-1（7-37）（SEQ ID NO：1）的第37位的位置处的第一个K残基， 对应于GLP-1（7-37）的位置26的位置和与GLP-1（7-37）相比最多10个氨基酸修饰，其中第一个K残基指定为K 37，第二个K残基 被指定为K 26，该衍生物分别包含与K 26和K 37连接的两个白蛋白结合部分，其中白蛋白结合部分包含选自以下的伸展部分：€€€€ƒ€ƒ€ƒ€ƒChem 。 1：€ƒ€ƒ€ƒ€ƒHOOC-（CH 2）x -CO- *€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem。 2：€ƒ€ƒ€ƒ€ƒHOOC-C 6 H 4 -O-（CH 2）y -CO- *€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem。 3：€ƒ€ƒ€ƒ€ƒR1 -C 6 H 4 - （CH 2）z -CO- *€ƒ€ƒ€ƒ€ƒ€ƒ€ƒChem。 4：€ƒ€ƒ€ƒHOOC-C 4 SH 2 - （CH 2）w -CO- *其中x是6-18的整数，y是3的整数 -17，z为1-5的整数，R 1为摩尔质量不高于150Da的基团，w为6-18的整数; 条件是当伸长部分是Chem。 如图1所示，白蛋白结合部分还包含式Chem的接头。 5：* -NH-（CH 2）2 - （O-（CH 2）2）k -O-（CH 2）n -CO- *，其中k是1-5的整数，n 是1-5的整数; 或其药学上可接受的盐，酰胺或酯。 本发明还涉及其药物用途，例如用于治疗和/或预防所有形式的糖尿病和相关疾病，以及相应的新型肽和侧链中间体。 该衍生物适合口服给药。

    INSULIN DERIVATIVES
    9.
    发明公开
    INSULIN DERIVATIVES 有权
    胰岛素衍生物

    公开(公告)号：EP1846446A1

    公开(公告)日：2007-10-24

    申请号：EP06707955.8

    申请日：2006-02-01

    申请人： NOVO NORDISK A/S

    发明人： MADSEN, Peter ,  TAGMOSE, Tina, Møller ,  KODRA, János, Tibor ,  GARIBAY, Patrick, William ,  HOEG-JENSEN, Thomas ,  JONASSEN, Ib

    IPC分类号： C07K14/62 ,  A61K38/28

    CPC分类号： A61K38/28 ,  C07K14/62

    摘要： The present invention relates to insulin derivatives having a side chain attached either to the -amino group of the N-terminal amino acid residue of the B chain or to the amino group of a Lys residue present in the B chain of the parent insulin via an amide bond which side chain comprises at least one aromatic group; at least one free carboxylic acid group or a group which is negatively charged at neutral pH, a fatty acid moiety with 4 to 22 carbon atoms in the carbon chain; and possible linkers which link the individual components in the side chain together via amide bonds.