IP Library › Granted Patent US 9,533,990
Granted Patent B2
US 9,533,990 · App. 14/549,777 · Granted Jan 3, 2017

Inhibitors of secretion of hepatitis B virus antigens

Inventors: Xiaodong Xu (Doylestown, PA); Andrea Cuconati (Oreland, PA); Timothy M. Block (Doylestown, PA); Tong Xiao (Edison, NJ)
Assignees: Drexel University; Baruch S. Blumberg Institute; Arbutus Biopharma, Inc.
C07D487/04A61K31/519A61K45/06
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Quick Facts
Patent No.
US 9,533,990
App. No.
14/549,777
Granted
Jan 3, 2017
Kind
B2
Abstract

Pharmaceutical compositions of the invention comprise triazolopyrimidines useful for the treatment of hepatitis virus in a patient.

Claims (99)

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the R-enantiomer of at least one selected from the group consisting of:

7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

5-(4-Chlorophenyl)-7-(2,6-dichlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine;

5-(4-Chlorophenyl)-7-(2,6-difluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine;

7-(2-Chloro-4-fluorophenyl)-5-(4-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(2-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(3-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(4-fluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

5-(4-Bromophenyl)-7-(2-chloro-6-fluorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(4-ethylphenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(4-methoxyphenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

5-([1,1′-Biphenyl]-4-yl)-7-(2-chloro-6-fluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(naphthalen-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(3,4-dichlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(2,4-dichlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(2,4-difluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(3,4-dimethylphenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine; and

7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine.

2. The pharmaceutical composition of claim 1 , comprising the R-enantiomer of at least one selected from the group consisting of:

7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine; and

5-(4-Chlorophenyl)-7-(2,6-difluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine.

3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the S-enantiomer of at least one selected from the group consisting of:

7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

5-(4-Chlorophenyl)-7-(2,6-dichlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine;

5-(4-Chlorophenyl)-7-(2,6-difluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine;

7-(2-Chloro-4-fluorophenyl)-5-(4-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(2-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(3-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(4-fluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

5-(4-Bromophenyl)-7-(2-chloro-6-fluorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(4-ethylphenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(4-methoxyphenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

5-([1,1′-Biphenyl]-4-yl)-7-(2-chloro-6-fluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(naphthalen-2-yl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(3,4-dichlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(2,4-dichlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(2,4-difluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

7-(2-Chloro-6-fluorophenyl)-5-(3,4-dimethylphenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine; and

7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine.

4. The pharmaceutical composition of claim 3 , comprising the S-enantiomer of at least one selected from the group consisting of:

7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine; and

5-(4-Chlorophenyl)-7-(2,6-difluorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the R,S-isomer of at least one selected from the group consisting of:

cis-7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-5-(4-Chlorophenyl)-7-(2,6-dichlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-5-(4-Chlorophenyl)-7-(2,6-difluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-4-fluorophenyl)-5-(4-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chlorophenyl)-5-(4-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-5-(4-Chlorophenyl)-7-(4-isopropylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-5-(4-Chlorophenyl)-7-phenyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(2-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(3-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(4-fluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-5-(4-Bromophenyl)-7-(2-chloro-6-fluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(4-ethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(4-methoxyphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine;

cis-5-([1,1′-Biphenyl]-4-yl)-7-(2-chloro-6-fluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]-triazolo[1,5-a]pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(naphthalen-2-yl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]-triazolo[1,5-a]pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo-[1,5-a]pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(3,4-dimethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo-[1,5-a]pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-phenyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(pyridin-2-yl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine; and

cis-7-(2-Chloro-6-fluorophenyl)-5-(6-methoxypyridin-3-yl)-4,5,6,7-tetrahydro-[1,2,4]-triazolo[1,5-a]pyrimidine.

6. The pharmaceutical composition of claim 5 , comprising the R,S-enantiomer of at least one selected from the group consisting of:

cis-7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine; and

cis-5-(4-Chlorophenyl)-7-(2,6-difluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the S,R-isomer of at least one selected from the group consisting of:

cis-7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-5-(4-Chlorophenyl)-7-(2,6-dichlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-5-(4-Chlorophenyl)-7-(2,6-difluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-4-fluorophenyl)-5-(4-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chlorophenyl)-5-(4-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-5-(4-Chlorophenyl)-7-(4-isopropylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-5-(4-Chlorophenyl)-7-phenyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(2-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(3-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(4-fluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-5-(4-Bromophenyl)-7-(2-chloro-6-fluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(4-ethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(4-methoxyphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine;

cis-5-([1,1′-Biphenyl]-4-yl)-7-(2-chloro-6-fluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]-triazolo[1,5-a]pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(naphthalen-2-yl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]-triazolo[1,5-a]pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo-[1,5-a]pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(3,4-dimethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo-[1,5-a]pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-phenyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine;

cis-7-(2-Chloro-6-fluorophenyl)-5-(pyridin-2-yl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5- a ]-pyrimidinc; and

cis-7-(2-Chloro-6-fluorophenyl)-5-(6-methoxypyridin-3-yl)-4,5,6,7-tetrahydro-[1,2,4]-triazolo[1,5-a]pyrimidine.

8. The pharmaceutical composition of claim 7 , comprising the S,R-enantiomer of at least one selected from the group consisting of:

cis-7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine; and

cis-5-(4-Chlorophenyl)-7-(2,6-difluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]-pyrimidine.

9. The composition of claims 1 , further comprising an antiviral compound.

10. The composition of claim 9 , wherein the antiviral compound is a nucleoside antiviral compound, a nucleotide antiviral compound, or any mixtures thereof.

11. A method for treating a hepatitis virus infection in a patient, the method comprising administering an effective amount of the composition of claim 1 to a patient in need thereof.

12. The method of claim 11 , wherein the hepatitis virus is a hepadnaviridae family virus or hepatitis delta virus.

13. The method of claim 11 , wherein the hepatitis virus is hepatitis B virus.

Assignments (7)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 17, 2016
From: CUCONATI, ANDREA; XU, XIAODONG
To: INSTITUTE FOR HEPATITIS AND VIRUS RESEARCH
Reel/Frame 040363/0645 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 17, 2016
From: BLOCK, TIMOTHY
To: PHILADELPHIA HEALTH & EDUCATION CORPORATION D/B/A DREXEL UNIVERSITY COLLEGE OF MEDICINE
Reel/Frame 040363/0693 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 17, 2016
From: XIAO, TONG
To: PHARMABRIDGE, INC.
Reel/Frame 040363/0711 →
MERGER Recorded Nov 17, 2016
From: PHILADELPHIA HEALTH & EDUCATION CORPORATION
To: DREXEL UNIVERSITY
Reel/Frame 040363/0748 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 17, 2016
From: PHARMABRIDGE, INC.
To: ENANTIGEN THERAPEUTICS, INC.
Reel/Frame 040363/0768 →
CHANGE OF NAME Recorded Nov 17, 2016
From: INSTITUTE FOR HEPATITIS AND VIRUS RESEARCH
To: BARUCH S. BLUMBERG INSTITUTE
Reel/Frame 040645/0197 →
MERGER Recorded Apr 6, 2016
From: ENANTIGEN THERAPEUTICS, INC.
To: ARBUTUS BIOPHARMA, INC.
Reel/Frame 038207/0912 →
Continuity (3)
Continuation 13877870
Provisional Application 61389321 · Oct 4, 2010
Related Publication 20150087659A1 · Mar 26, 2015