SMALL MOLECULAR LUNG-TARGETING DRUG

• US 20190029997A1
• Filed: 08/02/2016
• Published: 01/31/2019
• Est. Priority Date: 03/17/2016
• Status: Active Grant

• Current Assignee: Yaopharma Company Limited (Shanghai Fosun Pharmaceutical (Group) Co., Ltd.)
• Original Assignee: Yaopharma Company Limited (Shanghai Fosun Pharmaceutical (Group) Co., Ltd.)
• Inventors: ZHANG, Zhirong, ZHOU, Meiling, ZHANG, Yan
• Granted Patent: US 10,639,295 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/555 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07D 493/04 Ortho-condensed systems

Abstract

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable formulation prepared using the compound and the salt. The compound represented by formula (I) or the pharmaceutically acceptable salt exhibits significantly higher buildup and concentration in the lungs compared to other tissues, a longer dwell time in the lungs, and/or elevated pharmaceutical efficacy.

Claims

1. A small molecular lung-targeting compound with a structure represented by Formula I:

2. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein:

m=1;

n=0;

R₁, R₂, R₃, R₄ are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, mercapto, cyano, C1˜

C4 alkyl, and C1˜

C4 alkoxy;

X is

3. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein:

D is optionally selected from the group consisting of podophyllotoxin, tripterine, triptolide, gemcitabine, fluorouracil, chlorambucil, cortisone, prednisone, zidovudine, cefradine, and analog or derivative thereof, and D links with X by forming a covalent bond.

4. The compound according to claim 3, which is

5. The compound according to claim 4, which is:

6. The compound according to claim 4, which is:

7. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is a salt formed from the compound and an inorganic acid or an organic acid, comprising hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, niacin, camphoric acid, gluconic acid, glucuronic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, sulfamic acid and p-toluenesulfonic acid.

8. A method for preparing the compound or the pharmaceutically acceptable salt thereof represented by formula I according to claim 1, comprising:

reacting

9. The method according to claim 8, wherein:

m=1;

n=0;

L is a hydroxyl group;

R₁, R₂, R₃ and R₄ are hydrogen;

A is

10. The method according to claim 9, wherein 4β

-amino-4′

-demethylepipodophyllotoxin is subjected to a reaction with N,N,N′

-trimethyl-N′

-(4-carboxybenzyl)-1,3-propanediamine to give compound DC.

11. The method according to claim 9, wherein 4β

-amino-4′

-demethylepipodophyllotoxin is subjected to a reaction with 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid to give compound DP.

12. A method for preventing or controlling pneumonia, bronchitis, lung tumor, rejection after lung transplantation or other lung disease, comprising administrating to the subject in need thereof an effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 1.

13. A pharmaceutically acceptable preparation, comprising the compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the preparation is selected from tablet, suppository, soft capsule or hard capsule, solution, suspension or aerosol, injection, lyophilized powders for injection, sustained-release controlled-release preparation and particle drug delivery system, and wherein the preparation is administered by a manner of mouth, nasal, rectal, transdermal or injection.

14. The preparation according to claim 13, which is an injection and administered by injection.