公开(公告)号：US09708383B2

公开(公告)日：2017-07-18

申请号：US13882947

申请日：2011-11-09

申请人： Alice Ravn Madsen ,  Birgit Wieczorek ,  Jacob Kofoed ,  Jesper Lau ,  Jane Spetzler ,  Janos Tibor Kodra ,  Lars Linderoth ,  Patrick William Garibay ,  Per Sauerberg ,  Thomas Kruse

发明人： Alice Ravn Madsen ,  Birgit Wieczorek ,  Jacob Kofoed ,  Jesper Lau ,  Jane Spetzler ,  Janos Tibor Kodra ,  Lars Linderoth ,  Patrick William Garibay ,  Per Sauerberg ,  Thomas Kruse

IPC分类号： A61K38/00 ,  C07K14/605 ,  A61K47/48

CPC分类号： C07K14/605 ,  A61K47/542

摘要： The invention relates to a derivative of a GLP-1 analog, which analog comprises a first K residue at a position corresponding to position 18 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 1, Chem. 2, and Chem. 3: HOOC—(CH2)x—CO—*  Chem. 1: HOOC—C6H4—O—(CH2)y—CO—*  Chem. 2: R2—C6H4—(CH2)z—CO—*,  Chem. 3: 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, and R2 is a group having a molar mass not higher than 150 Da; and the linker comprises *—NH—(CH2)2—(O—(CH2)2)k—O—(CH2)n—CO—*.  Chem. 4: 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.

公开(公告)号：US20130288960A1

公开(公告)日：2013-10-31

申请号：US13882947

申请日：2011-11-09

申请人： Alice Ravn Madsen ,  Birgit Wieczorek ,  Jacob Kofoed ,  Jesper Lau ,  Jane Spetzler ,  Janos Tibor Kodra ,  Lars Linderoth ,  Patrick William Garibay ,  Per Sauerberg ,  Thomas Kruse

发明人： Alice Ravn Madsen ,  Birgit Wieczorek ,  Jacob Kofoed ,  Jesper Lau ,  Jane Spetzler ,  Janos Tibor Kodra ,  Lars Linderoth ,  Patrick William Garibay ,  Per Sauerberg ,  Thomas Kruse

IPC分类号： C07K14/605

CPC分类号： C07K14/605 ,  A61K47/542

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 18 of GLP-1 (7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve amino acid changes as compared to GLP-1 (7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 1, Chem. 2, and Chem. 3: Chem.: HOOC—(CH2)x—CO—* Chem. 2: HOOC—C6H4-0-(CH2)y—CO—* Chem. 3: R2—C6H4—(CH2)z—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, and R2 is a group having a molar mass not higher than 150 Da; and the linker comprises Chem. 4: *—NH—(CH2)2-(0-(CH2)2)k-0-(CH2)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18位的位置处的第一个K残基，另一个的第二个K残基 位置和与GLP-1（7-37）相比最多12个氨基酸变化; 该衍生物分别包含通过接头分别连接到所述第一和第二K残基的两个伸长部分，其中伸长部分选自Chem。 1，Chem。 2和Chem。 3：化学式：HOOC-（CH2）x-CO- * 2：HOOC-C6H4-0-（CH2）y-CO- * Chem。 3：R2-C6H4-（CH2）z-CO- *，其中x是6-18的整数，y是3-17的整数，z是1的整数 -5和R2是摩尔质量不高于150Da的基团; 连接体包括Chem。 4：* -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。 该衍生物适用于口服给药。

公开(公告)号：US20130053311A1

公开(公告)日：2013-02-28

申请号：US13516312

申请日：2010-12-16

申请人： Christoph Kalthoff ,  Jesper Lau ,  Jane Spetzler ,  Patrick William Garibay ,  Jacob Kofoed ,  Lars Linderoth

发明人： Christoph Kalthoff ,  Jesper Lau ,  Jane Spetzler ,  Patrick William Garibay ,  Jacob Kofoed ,  Lars Linderoth

IPC分类号： A61K38/26 ,  A61P3/10 ,  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 GLP-1 analogue which comprises a histidine (H) residue at a position corresponding to position 31 of GLP-1 (7-37) (SEQ ID NO: 1), a glutamine (Q) residue at a position corresponding to position 34 of GLP-1 (7-37) (SEQ ID NO: 1), and a maximum of ten amino acid modifications as compared to GLP-1 (7-37) (SEQ ID NO: 1); wherein the H residue is designated H31, and the Q residue is designated Q34; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to derivatives thereof, as well as the pharmaceutical use of these analogues and derivatives, for example in the treatment and/or prevention of all forms of diabetes and related diseases. The invention furthermore relates to corresponding novel side chain intermediates. The derivatives are suitable for oral administration.

摘要翻译： 本发明涉及GLP-1类似物，其包含在对应于GLP-1（7-37）（SEQ ID NO：1）的第31位的位置处的组氨酸（H）残基，位置上的谷氨酰胺（Q）残基 对应于GLP-1（7-37）（SEQ ID NO：1）的位置34，与GLP-1（7-37）（SEQ ID NO：1）相比最多为10个氨基酸修饰。 其中H残基指定为H31，Q残基指定为Q34; 或其药学上可接受的盐，酰胺或酯。 本发明还涉及其衍生物，以及这些类似物和衍生物的药物用途，例如用于治疗和/或预防所有形式的糖尿病和相关疾病。 本发明还涉及相应的新型侧链中间体。 该衍生物适用于口服给药。

公开(公告)号：US08815802B2

公开(公告)日：2014-08-26

申请号：US13516312

申请日：2010-12-16

申请人： Christoph Kalthoff ,  Jesper Lau ,  Jane Spetzler ,  Patrick William Garibay ,  Jacob Kofoed ,  Lars Linderoth

发明人： Christoph Kalthoff ,  Jesper Lau ,  Jane Spetzler ,  Patrick William Garibay ,  Jacob Kofoed ,  Lars Linderoth

IPC分类号： A61K38/26 ,  A61P3/10 ,  C07K14/605 ,  A61K38/00 ,  C07K14/65

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

摘要： The invention relates to a GLP-1 analog which comprises a histidine (H) residue at a position corresponding to position 31 of GLP-1(7-37) (SEQ ID NO: 1), a glutamine (Q) residue at a position corresponding to position 34 of GLP-1 (7-37) (SEQ ID NO: 1), and a maximum of ten amino acid modifications as compared to GLP-1 (7-37) (SEQ ID NO: 1); wherein the H residue is designated H31, and the Q residue is designated Q34; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to derivatives thereof, as well as the pharmaceutical use of these analogs and derivatives, for example in the treatment and/or prevention of all forms of diabetes and related diseases. The invention furthermore relates to corresponding novel side chain intermediates. The derivatives are suitable for oral administration.

摘要翻译： 本发明涉及GLP-1类似物，其在对应于GLP-1（7-37）（SEQ ID NO：1）的位置31的位置处的组氨酸（H）残基，位置上的谷氨酰胺（Q）残基 对应于GLP-1（7-37）（SEQ ID NO：1）的位置34，与GLP-1（7-37）（SEQ ID NO：1）相比最多为10个氨基酸修饰。 其中H残基指定为H31，Q残基指定为Q34; 或其药学上可接受的盐，酰胺或酯。 本发明还涉及其衍生物，以及这些类似物和衍生物的药物用途，例如用于治疗和/或预防所有形式的糖尿病和相关疾病。 本发明还涉及相应的新型侧链中间体。 该衍生物适用于口服给药。

公开(公告)号：US20130338068A1

公开(公告)日：2013-12-19

申请号：US13883946

申请日：2011-11-09

申请人： Jacob Kofoed ,  Jesper Lau ,  Lars Linderoth ,  Patrick William Garibay ,  Thomas Kruse

发明人： Jacob Kofoed ,  Jesper Lau ,  Lars Linderoth ,  Patrick William Garibay ,  Thomas Kruse

IPC分类号： C07K14/605

CPC分类号： C07K14/605 ,  A61K47/542

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 18 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from HOOC—(CH2)x—CO-*, and  Chem. 1: HOOC—C6H4-0-(CH2)y—CO-*,  Chem. 2: in which x is an integer in the range of 6-18, and y is an integer in the range of 3-17; and the linker comprises *-NH—(CH2)q—CH[(CH2)w—NH2]—CO-*,  Chem. 3: wherein q is an integer in the range of 0-5, and w is an integer in the range of 0-5; 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 potent, protracted, and 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18位的位置处的第一个K残基，另一个的第二个K残基 位置和与GLP-1（7-37）相比最多12个氨基酸变化; 该衍生物分别包含通过接头分别连接到所述第一和第二K残基的两个伸长部分，其中伸长部分选自HOOC-（CH 2）x -CO- *和Chem。 1：HOOC-C6H4-0-（CH2）y-CO- *，Chem。 2：其中x是6-18的整数，y是3-17的整数; 并且连接体包含* -NH-（CH 2）q-CH [（CH 2）w -NH 2] -CO - *， 3：其中q是0-5的整数，w是0-5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。 衍生物有效，延长，适合口服。

公开(公告)号：US09006178B2

公开(公告)日：2015-04-14

申请号：US13883946

申请日：2011-11-09

申请人： Jacob Kofoed ,  Jesper Lau ,  Lars Linderoth ,  Patrick William Garibay ,  Thomas Kruse

发明人： Jacob Kofoed ,  Jesper Lau ,  Lars Linderoth ,  Patrick William Garibay ,  Thomas Kruse

IPC分类号： A61K38/26 ,  A61P3/10 ,  A61P7/12 ,  C07K14/605 ,  A61K38/28 ,  C07K5/00 ,  C07K7/00 ,  C07K16/00 ,  C07K17/00 ,  A61K47/48

CPC分类号： C07K14/605 ,  A61K47/542

摘要： The invention relates to a derivative of a GLP-1 analog, which analog comprises a first K residue at a position corresponding to position 18 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 1: HOOC—(CH2)x—CO—*, and Chem. 2: HOOC—C6H4-0-(CH2)y—CO—*, in which x is an integer in the range of 6-18, and y is an integer in the range of 3-17; and the linker comprises Chem. 3: *—NH—(CH2)q—CH[(CH2)w—NH2]—CO—*, wherein q is an integer in the range of 0-5, and w is an integer in the range of 0-5; 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 potent, protracted, and 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18位的位置处的第一个K残基，另一个的第二个K残基 位置和与GLP-1（7-37）相比最多12个氨基酸变化; 该衍生物分别包含通过接头分别连接到所述第一和第二K残基的两个伸长部分，其中伸长部分选自Chem。 1：HOOC-（CH 2）x-CO- *，和Chem。 2：HOOC-C6H4-0-（CH2）y-CO- *，其中x是6-18的整数，y是3-17的整数; 连接体包括Chem。 3：* -NH-（CH 2）q-CH [（CH 2）w -NH 2] -CO- *，其中q是0-5的整数，w是0-5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。 衍生物有效，延长，适合口服。

公开(公告)号：US08648041B2

公开(公告)日：2014-02-11

申请号：US12970196

申请日：2010-12-16

申请人： Patrick William Garibay ,  Lars Linderoth ,  Jesper Lau ,  Per Sauerberg

发明人： Patrick William Garibay ,  Lars Linderoth ,  Jesper Lau ,  Per Sauerberg

IPC分类号： A61K38/22 ,  C07K14/575

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 K37, and the second K residue is designated K26, which derivative comprises two albumin binding moieties attached to K26 and K37, respectively, wherein the albumin binding moiety comprises a protracting moiety selected from:Chem. 1, Chem. 2, Chem. 3 or Chem. 4; or a pharmaceutically acceptable salt, amide, or ester thereof.

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， 相对于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K37，第二个K残基是 命名为K26，该衍生物分别包含与K26和K37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下列的伸长部分： 1，Chem。 2，Chem。 3或Chem。 4; 或其药学上可接受的盐，酰胺或酯。

公开(公告)号：US20100292133A1

公开(公告)日：2010-11-18

申请号：US12676453

申请日：2008-09-05

申请人： Jane Spetzler ,  Lauge Schäffer ,  Jesper Lau ,  János Tibor Kodra ,  Kjeld Madsen ,  Patrick William Garibay ,  Jacob Kofoed ,  Steffen Reedtz-Runge ,  Henning Thøgersen ,  Igrid Pettersson

发明人： Jane Spetzler ,  Lauge Schäffer ,  Jesper Lau ,  János Tibor Kodra ,  Kjeld Madsen ,  Patrick William Garibay ,  Jacob Kofoed ,  Steffen Reedtz-Runge ,  Henning Thøgersen ,  Igrid Pettersson

IPC分类号： C07K14/605 ,  A61K38/26 ,  A61P3/10 ,  A61P3/00 ,  A61P3/06 ,  A61P3/08 ,  A61P9/10 ,  A61P9/00

CPC分类号： C07K14/605 ,  A61K38/00

摘要： The invention relates to truncated GLP-1 analogues, in particular a GLP-1 analogue which is a modified GLP-1(7-35) (SEQ ID No 1) having: i) a total of 2, 3, 4, 5 6, 7, 8, or 9 amino acid substitutions as compared to GLP-1(7-35), including a) a Glu residue at a position equivalent to position 22 of GLP-1(7-35), and b) an Arg residue at a position equivalent to position 26 of GLP-1(7-35); as well as derivatives thereof, and therapeutic uses and compositions. These analogues and derivatives are highly potent, have a good binding affinity to the GLP-1 receptor, also to the extracellular domain of the GLP-1 receptor, which is of potential relevance achieving long-acting, stable GLP-1 compounds with a potential for once weekly administration.

摘要翻译： 本发明涉及截短的GLP-1类似物，特别是GLP-1类似物，其是修饰的GLP-1（7-35）（SEQ ID No.1），其具有：i）总共2,3,4,5,6 ，7,8或9个氨基酸取代，其包括a）在等同于GLP-1（7-35）的位置22的位置上的Glu残基，和b）Arg 在等同于GLP-1（7-35）的第26位的位置上的残基; 以及其衍生物，以及治疗用途和组合物。 这些类似物和衍生物是高度有效的，对GLP-1受体以及GLP-1受体的细胞外结构域具有良好的结合亲和力，这与具有潜在的长效，稳定的GLP-1化合物具有潜在的相关性 每周一次行政。

公开(公告)号：US20110082079A1

公开(公告)日：2011-04-07

申请号：US12676451

申请日：2008-09-05

申请人： Jane Spetzler ,  Lauge Schäffer ,  Jesper Lau ,  Thomas Kruse ,  Patrick William Garibay ,  Steffen Runge ,  Henning Thøgersen ,  Ingrid Petersson

发明人： Jane Spetzler ,  Lauge Schäffer ,  Jesper Lau ,  Thomas Kruse ,  Patrick William Garibay ,  Steffen Runge ,  Henning Thøgersen ,  Ingrid Petersson

IPC分类号： A61K38/22 ,  C07K14/575 ,  A61P3/10 ,  A61P9/12 ,  A61P3/04 ,  A61P9/10 ,  A61P1/00 ,  A61P1/04

CPC分类号： C07K14/605 ,  A61K38/26

摘要： The invention relates to protracted Glucagon-Like Peptide-1 (GLP-1) derivatives and therapeutic uses thereof. The GLP-1 derivative of the invention comprises a modified GLP-1(7-37) sequence having a total of 2-12 amino acid modifications, including Glu22 and Arg26, and being derivatised with an albumin binding residue or pegylated in position 18, 20, 23, 30, 31, 34, 36, 37, or 39. These compounds are useful in the treatment or prevention of diabetes type 2 and related diseases. The compounds are potent, stable, have long half-lives, a high affinity of binding to albumin, and/or a high affinity of binding to the extracellular domain of the GLP-1 receptor (GLP-1R), all of which is of potential relevance for the overall aim of achieving long-acting, stable and active GLP-1 derivatives with a potential for once weekly administration.

摘要翻译： 本发明涉及长效的胰高血糖素样肽-1（GLP-1）衍生物及其治疗用途。 本发明的GLP-1衍生物包含具有总共2-12个氨基酸修饰的修饰的GLP-1（7-37）序列，包括Glu22和Arg26，并用白蛋白结合残基衍生或在18位聚乙二醇化， 20,23,30,31,34,36,37或39.这些化合物可用于治疗或预防2型糖尿病和相关疾病。 该化合物是有效的，稳定的，具有长的半衰期，与白蛋白结合的高亲和力，和/或与GLP-1受体（GLP-1R）细胞外结构域结合的高亲和力，所有这些都是 对于实现长效，稳定和活性的GLP-1衍生物的总体目标的潜在相关性，具有每周一次行政的潜力。

公开(公告)号：US20100261637A1

公开(公告)日：2010-10-14

申请号：US12676310

申请日：2008-09-05

申请人： Jane Spetzler ,  Lauge Schäffer ,  Jesper Lau ,  Thomas Kruse ,  Patrick William Garibay ,  Søren Østergaard ,  Steffen Reedtz-Runge ,  Henning Thøgersen

发明人： Jane Spetzler ,  Lauge Schäffer ,  Jesper Lau ,  Thomas Kruse ,  Patrick William Garibay ,  Søren Østergaard ,  Steffen Reedtz-Runge ,  Henning Thøgersen

IPC分类号： A61K38/26 ,  C07K14/00 ,  A61P3/10 ,  A61P3/04 ,  A61P9/10

CPC分类号： C07K14/001 ,  A61K38/00 ,  A61K38/16 ,  A61K38/17 ,  A61K38/22 ,  A61K38/26 ,  A61K47/50 ,  A61K47/51 ,  A61K47/54 ,  A61K47/542 ,  A61K47/543 ,  A61K47/545 ,  A61K47/56 ,  A61K47/60 ,  C07K14/00 ,  C07K14/575 ,  C07K14/57563 ,  C07K14/605

摘要： The invention relates to protracted peptide derivatives such as Glucagon-Like Peptide-1 (GLP-1), exendin-4, and analogues thereof, as well as therapeutic uses thereof. The peptide derivative of the invention comprises a peptide wherein at least one amino acid residue is derivatized with A-B-C-, or A-B-C-D-. These compounds are useful in the treatment or prevention of diabetes type 2 and related diseases. The compounds are potent, have a low ratio of binding affinity to the GLP-1 receptor in the presence of high/low albumin concentrations, have long half-lives, and have a high affinity of binding to albumin, all of which is of potential relevance for the overall aim of achieving long-acting, stable and active GLP-1 derivatives with a potential for once weekly administration.

摘要翻译： 本发明涉及长时间肽衍生物如胰高血糖素样肽-1（GLP-1），毒蜥外泌肽-4及其类似物，以及其治疗用途。 本发明的肽衍生物包含肽，其中至少一个氨基酸残基用A-B-C-或A-B-C-D-衍生化。 这些化合物可用于治疗或预防2型糖尿病和相关疾病。 该化合物是有效的，在高/低白蛋白浓度存在下具有低的GLP-1受体结合亲和力比，具有长的半衰期，并且具有与白蛋白结合的高亲和力，所有这些都是潜在的 与实现长效，稳定和活跃的GLP-1衍生物的总体目标相关，具有每周行政一次的潜力。