Title:
LYMPHATIC MEDIATED TRANSPORT-BASED TRIGLYCERIDE PRODRUG, AND PREPARATION METHOD THEREFOR
Document Type and Number:
WIPO Patent Application WO/2020/156307
Kind Code:
A1
Abstract:
The present invention relates to the technical field of pharmacy, relates to a lymphatic mediated transport-based triglyceride prodrug, and specifically relates to a triglyceride prodrug of different joining chains in a lymphatic mediated transport, the preparation thereof and an application thereof in drug delivery. The present invention provides a prodrug of different connection bonds and a synthesis method therefor. The structure of the prodrug is as shown below. X, R1, R2, n, and m are described in the claims and description. According to the prodrug provided by the present invention, the digestion and absorption mechanism of glycerol in the gastrointestinal tract is simulated by using the structure of triglycerides, the lymphatic transport of drugs is promoted, the first pass effect is avoided, and the prodrug has the targeting property and can obviously enhance or improve the drug oral bioavailability.
Inventors:
SUN JIN (CN)
HE ZHONGGUI (CN)
TIAN CHUTONG (CN)
HE ZHONGGUI (CN)
TIAN CHUTONG (CN)
Application Number:
PCT/CN2020/073144
Publication Date:
August 06, 2020
Filing Date:
January 20, 2020
Export Citation:
Assignee:
UNIV SHENYANG PHARMACEUTICAL (CN)
International Classes:
C07D305/14; A61K31/337; A61K47/54; A61P3/06; A61P29/00; A61P35/00
Domestic Patent References:
| WO2020028787A1 | 2020-02-06 | |||
| WO2019216433A1 | 2019-11-14 | |||
| WO2019213333A1 | 2019-11-07 | |||
| WO2019126378A1 | 2019-06-27 | |||
| WO2019126374A1 | 2019-06-27 |
Foreign References:
| CN109851593A | 2019-06-07 | |||
| CN106715456A | 2017-05-24 | |||
| CN108137482A | 2018-06-08 |
Other References:
TIAN, CHUTONG ET AL.: "Effcient Intestinal Digestion and On Site Tumor-Bioactivation are the Two Important Determinants for Chylomicron-Mediated Lymph-Targeting Triglyceride- Mimetic Docetaxel Oral Prodrugs", ADVANCED SCIENCE, vol. 6, no. 24, 25 October 2019 (2019-10-25), XP055726490, ISSN: 2198-3844
HU , LUOJUAN ET AL.: "Glyceride-Mimetic Prodrugs Incorporating Self-ImmolativeSpacers Promote Lymphatic Transport, Avoid First-Pass Metabolism, and Enhance Oral Bioavailability", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 55, 2 August 2016 (2016-08-02), pages 13700 - 13705, XP055454903, ISSN: 1521-3773
GERHARD, K. E. S .: "Synthesis and in Vitro Degradation of Testosterone-Lipid Conjugates", ARCHIVES OF PHARMACAL RESEARCH, vol. 328, no. 3, 31 December 1995 (1995-12-31), pages 271 - 276, XP001023958, ISSN: 1521-4184, DOI: 10.1002/ardp.19953280313
GERHARD, K. E. S.: "Synthesis and in Vitro Degradation of Testosterone-Lipid Conjugates", ARCHIVES OF PHARMACAL RESEARCH, vol. 328, no. 3, 31 December 1995 (1995-12-31), pages 271 - 276, XP001023958, ISSN: 1521-4184, DOI: 10.1002/ardp.19953280313
LONSHAKOV, D. V. ET AL.: "SYNTHESIS AND PROPERTIES OF 3-AZIDO-3'- DEOXYTHYMIDINE DERIVATIVES OF GLYCEROLIPIDS", PHARMACEUTICAL CHEMISTRY JOURNAL, vol. 44, no. 10, 31 October 2010 (2010-10-31), pages 557 - 563, XP055726494, ISSN: 1573-9031
MURIEL, L. ET AL.: "Synthesis and biological evaluation of two glycerolipidic prodrugs of didanosine for direct lymphatic delivery against HIV", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, no. 8, 25 January 2007 (2007-01-25), pages 2237 - 2240, XP022009240, ISSN: 1464-3405, DOI: 10.1016/j.bmcl.2007.01.062
BERANGERE GAUCHER ET AL.: "Prodrugs of HIV protease inhibitors-saquinavir, indinavir and nelfinavir-derived from diglycerides or amino acids: synthesis, stability and anti-HIV activity", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 2, no. 3, 5 January 2004 (2004-01-05), pages 345 - 357, XP002370284, ISSN: 1477-0539, DOI: 10.1039/b313119j
D'YAKOVAL. N. ET AL.: "Lymphotropic Prodrugs Based on 2', 3'-Didehydro-3'-deoxy- thymidine. Synthesis and Sensitivity to Hydrolysis", RUSSIAN JOURNAL OF ORGANIC CHEMISTRY, vol. 47, no. 10, 31 December 2011 (2011-12-31), pages 1588 - 1593, XP009529058, ISSN: 1070-4280
REDASANI, V. K. ET AL.: "Synthesis and Evaluation of Glyceride Prodrugs of Naproxen", JOURNAL OF MEDICINAL CHEMISTRY, vol. 3, 30 September 2013 (2013-09-30), pages 87 - 92, XP055726496, ISSN: 2164-313X
PHARMAZIE, vol. 60, no. 2, 2005, pages 110 - 114
JOURNAL OF MEDICINAL CHEMISTRY, vol. 22, no. 6, 1979, pages 683 - 687
J. ANDROL., vol. 24, 2003, pages 716 - 720
ARCH. PHARM., vol. 328, 1995, pages 271 - 276
ANGEWANDTE CHEMIE, vol. 55, no. 44, 2016, pages 13904 - 13909
See also references of EP 3919481A4
HU , LUOJUAN ET AL.: "Glyceride-Mimetic Prodrugs Incorporating Self-ImmolativeSpacers Promote Lymphatic Transport, Avoid First-Pass Metabolism, and Enhance Oral Bioavailability", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 55, 2 August 2016 (2016-08-02), pages 13700 - 13705, XP055454903, ISSN: 1521-3773
GERHARD, K. E. S .: "Synthesis and in Vitro Degradation of Testosterone-Lipid Conjugates", ARCHIVES OF PHARMACAL RESEARCH, vol. 328, no. 3, 31 December 1995 (1995-12-31), pages 271 - 276, XP001023958, ISSN: 1521-4184, DOI: 10.1002/ardp.19953280313
GERHARD, K. E. S.: "Synthesis and in Vitro Degradation of Testosterone-Lipid Conjugates", ARCHIVES OF PHARMACAL RESEARCH, vol. 328, no. 3, 31 December 1995 (1995-12-31), pages 271 - 276, XP001023958, ISSN: 1521-4184, DOI: 10.1002/ardp.19953280313
LONSHAKOV, D. V. ET AL.: "SYNTHESIS AND PROPERTIES OF 3-AZIDO-3'- DEOXYTHYMIDINE DERIVATIVES OF GLYCEROLIPIDS", PHARMACEUTICAL CHEMISTRY JOURNAL, vol. 44, no. 10, 31 October 2010 (2010-10-31), pages 557 - 563, XP055726494, ISSN: 1573-9031
MURIEL, L. ET AL.: "Synthesis and biological evaluation of two glycerolipidic prodrugs of didanosine for direct lymphatic delivery against HIV", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, no. 8, 25 January 2007 (2007-01-25), pages 2237 - 2240, XP022009240, ISSN: 1464-3405, DOI: 10.1016/j.bmcl.2007.01.062
BERANGERE GAUCHER ET AL.: "Prodrugs of HIV protease inhibitors-saquinavir, indinavir and nelfinavir-derived from diglycerides or amino acids: synthesis, stability and anti-HIV activity", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 2, no. 3, 5 January 2004 (2004-01-05), pages 345 - 357, XP002370284, ISSN: 1477-0539, DOI: 10.1039/b313119j
D'YAKOVAL. N. ET AL.: "Lymphotropic Prodrugs Based on 2', 3'-Didehydro-3'-deoxy- thymidine. Synthesis and Sensitivity to Hydrolysis", RUSSIAN JOURNAL OF ORGANIC CHEMISTRY, vol. 47, no. 10, 31 December 2011 (2011-12-31), pages 1588 - 1593, XP009529058, ISSN: 1070-4280
REDASANI, V. K. ET AL.: "Synthesis and Evaluation of Glyceride Prodrugs of Naproxen", JOURNAL OF MEDICINAL CHEMISTRY, vol. 3, 30 September 2013 (2013-09-30), pages 87 - 92, XP055726496, ISSN: 2164-313X
PHARMAZIE, vol. 60, no. 2, 2005, pages 110 - 114
JOURNAL OF MEDICINAL CHEMISTRY, vol. 22, no. 6, 1979, pages 683 - 687
J. ANDROL., vol. 24, 2003, pages 716 - 720
ARCH. PHARM., vol. 328, 1995, pages 271 - 276
ANGEWANDTE CHEMIE, vol. 55, no. 44, 2016, pages 13904 - 13909
See also references of EP 3919481A4
Attorney, Agent or Firm:
SHENYANG FEIYANG LINGRUI INTELLECTUAL PROPERTY AGENCY (GENERAL PARTNERSHIP) (CN)
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