CXCR4 antagonists with amino acid skeleton, preparation therefor and biomedical use thereof

Patent metadata

Field	Value
Publication number	US-11400083-B2
Application number	US-201716650924-A
Country	US
Kind code	B2
Filing date	Dec 1, 2017
Priority date	Sep 28, 2017
Publication date	Aug 2, 2022
Grant date	Aug 2, 2022

Abstract

The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt or prodrug thereof.

First claim

What is claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof:

wherein n 1 and n 2 are each 1 or 2, n 3 is 3 or 4;
R 1 represents cyclohexyl;
X represents —C(═O)NR 2 , wherein R 2 represents hydrogen, or methyl;
Y represents benzene or pyridine connected at para-positions;

A represents methyl,

A can form a monocyclic or bicyclic ring together with ;
B represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, an amino acid substituent, or a group of formula (v) or (vi):

wherein B 1 and B 2 are each independently an optionally substituted cycloalkyl, aryl or heteroaryl;
wherein
(1) when B is the cycloalkyl, B is cyclopentyl, cyclohexyl, mono- or poly-substituted cyclohexyl methyl, pyridine-fused cyclohexyl;
(2) when B is the aryl, B is phenyl, biphenyl, or naphthyl;
(3) when B is the heteroaryl, B is imidazolyl, unsubstituted pyridyl, mono- or poly-substituted pyridyl;
(4) when B is the amino acid substituent, B is an L- or D-α-amino acid;
(5) when B is aryl-, heteroaryl-, saturated carbocyclic or heterocyclic ring-substituted alkyl or formyl, B is

2. The compound according to claim 1 , wherein

is an amino acid, and the amino acid is a natural or non-natural amino acid,
wherein the amino acid is an α-amino acid, a β-amino acid, or a γ-amino acid, wherein a side chain of the α-amino acid is cyclized or not cyclized with an —NH 2 terminal, and the amino acid comprises an L- or D-amino acid,
wherein the α-amino acid comprises at least one selected from a group comprising arginine, lysine, citrulline, ornithine, histidine, aspartic acid, glutamic acid, glutamine, asparagine, serine, threonine, cysteine, phenylalanine, 3-(2-naphthyl) alanine, cyclohexylalanine, tryptophan, 5-hydroxytryptophan, tyrosine, glycine, phenylglycine, cyclohexylglycine, alanine, valine, leucine, isoleucine, methionine, proline, 4-hydroxyproline, 1-amino-1-cyclohexanecarboxylic acid and 1,2,3,4-tetrahydroisoquinolyl-3-carboxylic acid.

3. The compound according to claim 1 , wherein A forms a monocyclic ring together with , and the compound of formula (I) has the following structures:

4. The compound according to claim 1 , wherein A forms a bicyclic ring together with , and the compound of formula (I) has the following structures:

5. The compound according to claim 1 , wherein the pharmaceutically acceptable salt comprises at least one selected from a group comprising trifluoroacetate, hydrochloride, acetate, sulfate, mesylate, tosylate, citrate, tartrate, fumarate, maleate and malate.

6. The compound according to claim 1 , wherein B represents hydrogen, cyclohexyl,

7. The compound according to claim 1 , comprising one of the following structures:

or a pharmaceutically acceptable salt or prodrug thereof.

8. A pharmaceutical composition, comprising a compound according to claim 1 as an active ingredient and a pharmaceutically acceptable auxiliary.

9. The pharmaceutical composition according to claim 8 , further comprising one or more other anti-HIV agents,
wherein the other anti-HIV agent comprises at least one selected form a group comprising maraviroc, enfuvirtide, zidovudine, zalcitabine, stavudine, lamivudine, nevirapine, delavirdine, abacavir, efavirenz, tenofovir, emtricitabine, etravirine, and rilpivirine.

10. The pharmaceutical composition according to claim 9 , further comprising
cisplatin, cyclophosphamide, cytarabine, 5-fluorouracil, gemcitabine, taxol, docetaxel, adriamycin, glivec, tarceva, sorafenib, dasatinib, lapatinib, sunitinib, erlotinib, gefitinib, cetuximab, or herceptin of trastuzumab.

11. The pharmaceutical composition according to claim 8 , wherein the pharmaceutical composition is used for inhibiting interaction of a chemokine CXCL12 with a CXCR4 receptor or inhibiting the CXCR4 receptor.

12. The pharmaceutical composition according to claim 8 , wherein inhibiting the CXCR4 receptor is realized by antagonizing the CXCR4 receptor,
wherein:
the pharmaceutical composition is used to block HIV from invading and infecting human target cells or to treat or prevent AIDS, or
the pharmaceutical composition is used to mobilize human bone marrow hematopoietic cells, mesenchymal stem cells or stem cells, or
the pharmaceutical composition is used to interfere with CXCL12/CXCR4-mediated cell migration and adhesion, or
the pharmaceutical composition is used to prevent or treat CXCR4-mediated tumor metastasis, invasion or growth, or
the pharmaceutical composition is used to block CXCL12/CXCR4-mediated autoimmune and inflammatory responses.

Assignees

• Univ Tsinghua

Inventors

• Huang Ziwei
• Fang Xiong
• Meng Qian
• Xu Yan
• Zhu Siyu
• Fang Xiao

Classifications

• A61P31/18

  for HIV · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61K31/165

  having aromatic rings, e.g. colchicine, atenolol, progabide · CPC title

• C07D215/40

  attached in position 8 · CPC title

• A61P35/02

  specific for leukemia · CPC title