	US 12,343,323 B2
	Taxane-lipid-polysaccharide dual conjugates, preparation methods thereof and uses thereof
Jinghua Hu, San Diego, CA (US); Xiaohai Li, Jupiter, FL (US); Yikang Shi, Jinan (CN); Si Wang, San Diego, CA (US); Hui Wang, Tiantang Town (CN); Ang Zha, Guangzhou (CN); Fengyi Cui, Tiantang Town (CN); Anny Wang, San Diego, CA (US); Daisy J. Li, Jupiter, FL (US); Taining Zhang, Zhangjiakou (CN); and Haijun Cheng, Tiantang Town (CN)
Assigned to Santolecan Pharmaceuticals LLC, Jupiter, FL (US)
Appl. No. 17/054,706
Filed by Santolecan Pharmaceuticals LLC, Jupiter, FL (US)
PCT Filed Jun. 20, 2019, PCT No. PCT/CN2019/092101 § 371(c)(1), (2) Date Nov. 11, 2020, PCT Pub. No. WO2019/242691, PCT Pub. Date Dec. 26, 2019.
Claims priority of application No. 201810636499.3 (CN), filed on Jun. 20, 2018.
Prior Publication US 2021/0228530 A1, Jul. 29, 2021
Int. Cl. A61K 31/337 (2006.01); A61K 31/07 (2006.01); A61K 31/192 (2006.01); A61K 31/282 (2006.01); A61K 31/4745 (2006.01); A61K 31/475 (2006.01); A61K 31/506 (2006.01); A61K 31/519 (2006.01); A61K 31/7048 (2006.01); A61K 38/13 (2006.01); A61K 47/54 (2017.01); A61K 47/61 (2017.01)

CPC A61K 31/337 (2013.01) [A61K 31/07 (2013.01); A61K 31/192 (2013.01); A61K 31/282 (2013.01); A61K 31/4745 (2013.01); A61K 31/475 (2013.01); A61K 31/506 (2013.01); A61K 31/519 (2013.01); A61K 31/7048 (2013.01); A61K 38/13 (2013.01); A61K 47/543 (2017.08); A61K 47/545 (2017.08); A61K 47/61 (2017.08)]

1 Claim

1. A taxane-lipid-polysaccharide dual conjugate depicted by formula Ia or Formula Ib as shown below, or a pharmaceutically acceptable salt or solvate thereof,

wherein the taxane or the lipid unit is covalently linked to the polysaccharide via spacers, linkers, or a combination thereof, wherein the spacers and the linkers are covalently linked;

wherein the linkers comprising linker-1, linker-2 and linker-3 are same or different from each other, and wherein a branch unit in formula Ib is covalently linked to the linkers;

wherein the spacers comprising spacer-1, spacer-2, spacer-3 and spacer-4 are same or different from each other, and the number of any one of the spacers is 0 or 1;

wherein the polysaccharide is covalently linked to spacers, linkers, or a combination thereof through two conjugation sites thereof;

wherein the conjugation site to polysaccharide refers to a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group inherent to the polysaccharide;

wherein the polysaccharide is selected from dextran, hydroxyethyl starch, Ganoderma lucidum polysaccharide, or alginate, optionally carrying groups of COOH or SO₃H;

wherein the polysaccharide has a molecular weight ranging from 300 to 1,000,000; wherein the taxane consists of paclitaxel, docetaxel, cabazitaxel, milataxel, tesetaxel, ortataxel, or larotaxel;

wherein the lipid unit comprises one or more of a single molecular lipid compound, and when the lipid unit comprises more than one single molecular lipid compounds, the single molecular lipid compounds are the same or different; wherein the single molecular lipid compound is selected from alpha-linolenic acid (ALA), gamma-linoleic acid (GLA), arachidonic acid, eicosapentaic acid (EPA), docosahexaenoic acid (DHA), or vitamin A;

wherein linker-1, linker-2, and linker-3 are independently selected from the following structures: a di-substituted C_5-20alkyl, C_5-20cycloalkyl, C_5-20heterocycloalkyl, C_5-20alkenyl, C_5-20alkynyl, C_6-20aryl, or C_5-20heteroaryl; a di-substituted peptide containing 3 to 10 natural or unnatural amino acids; poly (ethylene glycol) chain with a molecular weight of 300 to 5,000; or a combination thereof; wherein the natural amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or a derivative thereof; wherein the unnatural amino acid is selected from D-alanine, D-arginine, D-asparagine, D-aspartic acid, D-cysteine, D-glutamic acid, D-glutamine, D-histidine, D-isoleucine, D-leucine, D-lysine, D-methionine, D-phenylalanine, D-proline, D-serine, D-threonine, D-tryptophan, D-tyrosine, D-valine, NH₂(CH₂)_2-10COOH or a derivative thereof; wherein the spacer-1, spacer-2, spacer-3, and spacer-4 are independently selected from the following structures: a di-substituted C_1-10alkyl, C_3-io cycloalkyl, C_3-io heterocycloalkyl, C_3-103alkenyl, C_3-io alkynyl, C_6-io aryl, or C_5-10heteroaryl; a natural amino acid, or an unnatural amino acid; a di-substituted peptide containing 2 to 3 natural or unnatural amino acids; poly (ethylene glycol) chain with a molecularweight of 100 to 500, or a combination thereof; wherein the natural amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or a derivative thereof; wherein the unnatural amino acid is selected from D-alanine, D-arginine, D-asparagine, D-aspartic acid, D-cysteine, D-glutamic acid, D-glutamine, D-histidine, D-isoleucine, D-leucine, D-lysine, D-methionine, D-phenylalanine, D-proline, D-serine, D-threonine, D-tryptophan, D-tyrosine, D-valine, NH₂(CH₂)_2ioCOOH, or a derivative thereof;

wherein the branch unit is a tri-substituted structure with 6 to 100 atoms in length and selected from an alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or a derivative thereof; and wherein the taxane-lipid-polysaccharide dual conjugate is selected from the group consisting of the following compounds: