N-substituted oseltamivir derivatives with antimicrobial activity

Patent metadata

Field	Value
Publication number	US-12378208-B2
Application number	US-202017596207-A
Country	US
Kind code	B2
Filing date	Jun 23, 2020
Priority date	Jun 24, 2019
Publication date	Aug 5, 2025
Grant date	Aug 5, 2025

Abstract

Provided herein are oseltamivir analogs useful for the treatment and prevention of viral infections, pharmaceutical compositions comprising the same and methods preparation and use thereof.

First claim

What is claimed:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
A is O; or —(C=A)- is —(CH 2 )—;
Ar 1 is selected from the group consisting of:

wherein R 2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, —(C═O)R, —(C═O)OR, —(C═O)NR 2 , —(C═NR)NR 2 , —(S═O)R, —S(O) 2 R, —S(O) 2 OR, —S(O) 2 NR 2 , —(P═O)(OR) 2 , or —(CR 2 ) m Y; and R 3 for each instance is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, OR, SR, NR 2 , —(C═O)R, —(C═O)OR, —O(C═O)R, —O(C═O)OR, —(C═O)NR 2 , —(NR)(C═O)R, —(NR)(C═O)OR, —O(C═O)NR 2 , —O(C═NR)NR 2 , —NR)(C═O)NR 2 , —(C═NR)NR 2 , —(NR)(C═NR)NR 2 , —(S═O)R, —S(O) 2 R, —S(O) 2 OR, —S(O) 2 NR 2 , —OS(O) 2 R, —(NR)S(O) 2 R, —OS(O) 2 OR, —OS(O)NR 2 , —(NR)S(O) 2 NR 2 , —(NR)S(O) 2 OR, —(P═O)(OR) 2 , halide, nitrile, nitro, or —(CR 2 ) m Y, wherein m for each occurrence is a whole number selected from 1-10; R for each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and Y for each occurrence is selected from the group consisting of OR, SR, NR 2 , —(C═O)R, —(C═O)OR, —O(C═O)R, —O(C═O)OR, —(C═O)NR 2 , —(NR)(C═O)R, —(NR)(C═O)OR, —O(C═O)NR 2 , —O(C═NR)NR 2 , —(NR)(C═O)NR 2 , —(C═NR)NR 2 , —(NR)(C═NR)NR 2 , —(S═O)R, —S(O) 2 R, —S(O) 2 OR, —S(O) 2 NR 2 , —OS(O) 2 R, —(NR)S(O) 2 R, —OS(O) 2 OR, —OS(O) 2 NR 2 , —(NR)S(O) 2 NR 2 , —(NR)S(O) 2 OR, and —(P═O)(OR) 2 ; and
R 1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

2. The compound of claim 1 , wherein the compound has the Formula III:

or a pharmaceutically acceptable salt thereof, wherein
A is O—; or —(C=A)- is —(CH2)-;
Ar 1 is selected from the group consisting of:

wherein R 2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, —(C═O)R, —(C═O)OR, —(C═O)NR 2 , —(C═NR)NR 2 , —(S═O)R, —S(O) 2 R, —S(O) 2 OR, —S(O) 2 NR 2 , —(P═O)(OR) 2 , or —(CR 2 ) m Y; and R 3 for each instance is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, OR, SR, NR 2 , —(C═O)R, —(C═O)OR, —O(C═O)R, —O(C═O)OR, —(C═O)NR 2 , —(NR)(C═O)R, —(NR)(C═O)OR, —O(C═O)NR 2 , —O(C═NR)NR 2 , —NR)(C═O)NR 2 , —(C═NR)NR 2 , —(NR)(C═NR)NR 2 , —(S═O)R, —S(O) 2 R, —S(O) 2 OR, —S(O) 2 NR 2 , —OS(O) 2 R, —(NR)S(O) 2 R, —OS(O) 2 OR, —OS(O)NR 2 , —(NR)S(O) 2 NR 2 , —(NR)S(O) 2 OR, —(P═O)(OR) 2 , halide, nitrile, nitro, or —(CR 2 ) m Y, wherein m for each occurrence is a whole number selected from 1-10; R for each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and Y for each occurrence is selected from the group consisting of OR, SR, NR 2 , —(C═O)R, —(C═O)OR, —O(C═O)R, —O(C═O)OR, —(C═O)NR 2 , —(NR)(C═O)R, —(NR)(C═O)OR, —O(C═O)NR 2 , —O(C═NR)NR 2 , —(NR)(C═O)NR 2 , —(C═NR)NR 2 , —(NR)(C═NR)NR 2 , —(S═O)R, —S(O) 2 R, —S(O) 2 OR, —S(O) 2 NR 2 , —OS(O) 2 R, —(NR)S(O) 2 R, —OS(O) 2 OR, —OS(O) 2 NR 2 , —(NR)S(O) 2 NR 2 , —(NR)S(O) 2 OR, and —(P═O)(OR) 2 ; and
R 1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

3. The compound of claim 2 , wherein Ar 1 is selected from the group consisting of:

wherein R 2 is hydrogen, heterocycloalkyl, aryl, aralkyl, or heteroaryl; and R 3 is heterocycloalkyl, aryl, aralkyl, or heteroaryl.

4. The compound of claim 1 , wherein the compound is selected from the group consisting of:

wherein n is 0, 1, or 2; p is 0, 1, or 2; and each of R 3 and R 4 for each occurrence is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, OR, SR, NR 2 , —(C═O)R, —(C═O)OR, —O(C═O)R, —O(C═O)OR, —(C═O)NR 2 , —(NR)(C═O)R, —(NR)(C═O)OR, —O(C═O)NR 2 , —O(C═NR)NR 2 , —(NR)(C═O)NR 2 , —(C═NR)NR 2 , —(NR)(C═NR)NR 2 , —(S═O)R, —S(O) 2 R, —S(O) 2 OR, —S(O) 2 NR 2 , —OS(O) 2 R, —(NR)S(O) 2 R, —OS(O) 2 OR, —OS(O) 2 NR 2 , —(NR)S(O) 2 NR 2 , —(NR)S(O) 2 OR, —(P═O)(OR) 2 , halide, nitrile, nitro, or —(CH 2 ) m Y, wherein in for each occurrence is a whole number selected from 1-10; R for each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and Y for each occurrence is selected from the group consisting of OR, SR, NR 2 , —(C═O)R, —(C═O)OR, —O(C═O)R, —O(C═O)OR, —(C═O)NR 2 , —(NR)(C═O)R, —(NR)(C═O)OR, —O(C═O)NR 2 , —O(C═NR)NR 2 , —(NR)(C═O)NR 2 , —(C═NR)NR 2 , —(NR)(C═NR)NR 2 , —(S═O)R, —S(O) 2 R, —S(O) 2 OR, —S(O) 2 NR 2 , —OS(O) 2 R, —(NR)S(O) 2 R, —OS(O) 2 OR, —OS(O) 2 NR 2 , —(NR)S(O) 2 NR 2 , —(NR)S(O) 2 OR, and —(P═O)(OR) 2 .

5. The compound of claim 4 , wherein n is 0; and R 4 for each occurrence is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, OR, NR 2 , —(C═O)R, —(C═O)OR, —O(C═O)R, —O(C═O)OR, —(C═O)NR 2 , —(NR)(C═O)R, —(NR)(C═O)OR, —O(C═O)NR 2 , —O(C═NR)NR 2 , —(NR)(C═O)NR 2 , —(C═NR)NR 2 , —(NR)(C═NR)NR 2 , —(S═O)R, —S(O) 2 R, —S(O) 2 OR, —S(O) 2 NR 2 , —OS(O) 2 R, —(NR)S(O) 2 R, —OS(O) 2 OR, —OS(O) 2 NR 2 , —(NR)S(O) 2 NR 2 , —(NR)S(O) 2 OR, —(P═O)(OR) 2 , halide, nitrile, nitro, or —(CH 2 ) m Y, wherein m is 1-6; and R for each occurrence is independently hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl.

6. The compound of claim 1 , wherein the compound is selected from the group consisting of:

7. The compound of claim 1 , wherein the compound is selected from the group consisting of:

8. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable carrier.

9. A method of preparing a compound of claim 1 , the method comprising:
contacting a compound of Formula IV:

Assignees

• Univ Hong Kong Polytechnic
• Univ Hong Kong Chinese

Inventors

• Ma Cong
• Yang Xiao
• Ye Jiqing
• Chan Paul Kay-Sheung
• Chan Wan Yi

Classifications

• C07D307/52

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• C07D261/08

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• A61K31/42

  Oxazoles · CPC title

• A61K31/415

  1,2-Diazoles · CPC title

• A61K31/341

  not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine · CPC title