IP Library › Granted Patent US 10,487,081

Granted Patent B2

US 10,487,081 · App. 16/166,355 · Granted Nov 26, 2019

Guanidine substituted imidazo[4,5-c] ring compounds

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 10,487,081
App. No.: 16/166,355
Granted: Nov 26, 2019
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Imidazo[4,5-c] ring compounds, (particularly imidzao[4,5-c]quinolines, 6,7,8,9-tetrahydroimidazo[4,5-c]quinolines, imidazo[4,5-c]naphthyridines, and 6,7,8,9-tetrahydroimidazo[4,5-c]naphthyridine compounds) having a guanidine substituent at the 1-position, pharmaceutical compositions containing the compounds, and methods of making the compounds are disclosed. Methods of use of the compounds as immune response modifiers, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are also disclosed.

Claims (84)

1. A method of inducing cytokine biosynthesis in an animal, comprising administering an effective amount of a compound of Formula I to the animal:

wherein:

R 3 and R 4 are taken together to form a fused benzene ring, a fused pyridine ring, a fused cyclohexene ring, or a fused tetrahydropyridine ring; wherein the fused benzene ring, fused pyridine ring, fused cyclohexene ring, or fused tetrahydropyridine ring is either unsubstituted or substituted by one or more R groups;

R is selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, haloalkyl, —C(O)—O-alkyl, —C(O)—OCH 2 Ph, —C(O)—O-aryl, amino, alkylamino, and dialkylamino, aryl, arylalkylenyl, aryloxyalkylenyl, arylalkyleneoxy, aryloxy, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkyenyl, heteroarylalkyleneoxy, and heteroaryloxy, wherein the alkyl, aryl, arylalkylenyl, aryloxyalkylenyl, arylalkyleneoxy, aryloxy, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkyenyl, heteroarylalkyleneoxy, and heteroaryloxy groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkyleneoxy, nitrile, amino, alkylamino, and dialkylamino;

R 1 is selected from the group consisting of —W—X—N(R 5 )—C(═NH)—NH 2 , —W—Z—N(R 5 )—C(═NH)—NH 2 , and

W is selected from the group consisting of a covalent bond, —O—, and —NH—;

X is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein any of the alkylene, alkenylene, and alkynylene groups can be optionally interrupted by one or more —O— groups;

Z is selected from the group consisting of

—X-arylene-X—,

—X-heteroarylene-X—,

—X-arylene-, and

—X-heteroarylene-;

R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, —O-alkyl, hydroxyalkylenyl, alkoxyalkylenyl, alkylaminoalkylenyl, hydroxyl, —CH 2 —NH—O-alkyl, and —CH 2 NHC(O)-alkyl;

R 5 is selected from the group consisting of hydrogen, alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and cycloalkylalkylenyl, wherein any of the alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and cycloalkylalkylenyl groups can be either unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkoxy, alkyl, haloalkyl, and nitrile;

Q is selected from the group consisting of a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 —O—CH 2 —, and —OCH 2 —;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein R 3 and R 4 are taken together to form a fused benzene ring, a fused pyridine ring, or a fused cyclohexene ring, and wherein the fused benzene ring, fused pyridine ring, or fused cyclohexene ring is either unsubstituted or substituted by one and only one R group.

3. The method of claim 1 , wherein R 1 is selected from the group consisting of —W—X—N(H)—C(═NH)—NH 2 , and

—W—Z—N(H)—C(═NH)—NH 2 .

4. The method of claim 1 , wherein W is a covalent bond or —O—.

5. The method of claim 1 , wherein X is alkylene optionally interrupted by one or more —O— groups.

6. The method of claim 5 , wherein X is selected from the group consisting of —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 C(CH 3 ) 2 —, —CH 2 C(CH 3 ) 2 CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2 , —CH 2 CH 2 —O—CH 2 CH 2 —O—CH 2 CH 2 —, —(CH 2 ) 2-4 —(OCH 2 CH 2 —) 1-5 , and —(CH 2 ) 2-6 —(OCH 2 CH 2 —) 1-4 .

7. The method of claim 1 , wherein Z is —C 1-5 alkylene-arylene-C 1-5 alkylene- or —C 1-5 alkylene-heteroarylene-C 1-5 alkylene-.

8. The method of claim 7 , wherein Z is —CH 2 -phenylene-CH 2 —.

9. The method of claim 1 , wherein R 2 is selected from the group consisting hydrogen, alkyl, alkoxyalkylenyl, alkylaminoalkylenyl, and hydroxyalkylenyl.

10. The method of claim 9 , wherein R 2 is selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 NHCH 3 , —CH 2 NHCH 2 CH 3 , —CH 2 CH 2 NHCH 3 , —CH 2 OH, and —CH 2 CH 2 OH.

11. The method of claim 10 , wherein R 2 is selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , and —CH 2 CH 2 OCH 3 .

12. The method of claim 1 , wherein the compound of Formula I is a compound of Formula XIII:

wherein:

R 1B is selected from the group consisting of —X B —N(R 5B )—C(═NH)—NH 2 , —Z B —N(R 5B )—C(═NH)—NH 2 , and

X B is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein any of the alkylene, alkenylene, and alkynylene groups can be optionally interrupted by one or more —O— groups;

Z B is selected from the group consisting of

—X B -arylene-X B —,

—X B -heteroarylene-X B —,

—X B -arylene-, and

—X B -heteroarylene-;

R 2B is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, —O-alkyl, hydroxyalkylenyl, alkoxyalkylenyl, alkylaminoalkylenyl, hydroxyl, —CH 2 —NH—O-alkyl, and —CH 2 NHC(O)-alkyl;

R 5B is selected from the group consisting of hydrogen, alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and cycloalkylalkylenyl, wherein any of the alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and cycloalkylalkylenyl groups can be either unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkoxy, alkyl, haloalkyl, and nitrile;

Q B is selected from the group consisting of a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 —O—CH 2 —, and —OCH 2 —;

or a pharmaceutically acceptable salt thereof.

13. The method of claim 12 , wherein R 1B is selected from the group consisting of —X B —N(H)—C(═NH)—NH 2 , and —Z B —N(H)—C(═NH)—NH 2 .

14. The method of claim 12 , wherein X B is alkylene optionally interrupted by one or more —O— groups; and

Z B is —C 1-5 alkylene-arylene-C 1-5 alkylene- or —C 1-5 alkylene-heteroarylene-C 1-5 alkylene-.

15. The method of claim 12 , wherein Z B is —CH 2 -phenylene-CH 2 —.

16. The method of claim 12 , wherein X B is selected from the group consisting of —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 C(CH 3 ) 2 —, —CH 2 C(CH 3 ) 2 CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2 —O—CH 2 CH 2 —, —(CH 2 ) 2-4 —(OCH 2 CH 2 —) 1-5 , and —(CH 2 ) 2-6 —(OCH 2 CH 2 —) 1-4 .

17. The method of claim 12 wherein the method comprises administering an admixture of the compound of Formula I and a pharmaceutically acceptable carrier.

18. A method of inducing biosynthesis of IFN-alpha in an animal comprising administering an effective amount a compound of Formula I to the animal:

wherein:

R 1 is selected from the group consisting of —W—X—N(R 5 )—C(═NH)—NH 2 , —W—Z—N(R 5 )—C(═NH)—NH 2 , and

W is selected from the group consisting of a covalent bond, —O—, and —NH—;

Z is selected from the group consisting of

—X—arylene-X—,

—X—heteroarylene-X—,

—X—arylene-, and

—X—heteroarylene-;

or a pharmaceutically acceptable salt thereof.

19. The method of claim 18 , wherein R 3 and R 4 are taken together to form a fused benzene ring, a fused pyridine ring, or a fused cyclohexene ring, and wherein the fused benzene ring, fused pyridine ring, or fused cyclohexene ring is either unsubstituted or substituted by one and only one R group.

20. The method of claim 18 , wherein R 1 is selected from the group consisting of —W—X—N(H)—C(═NH)—NH 2 , and

—W—Z—N(H)—C(═NH)—NH 2 .

21. The method of claim 18 , wherein W is a covalent bond or —O—.

22. The method of claim 18 , wherein X is alkylene optionally interrupted by one or more —O— groups.

23. The method of claim 22 , wherein X is selected from the group consisting of —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 C(CH 3 ) 2 —, —CH 2 C(CH 3 ) 2 CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2 —O—CH 2 CH 2 —, —(CH 2 ) 2-4 —(OCH 2 CH 2 —) 1-5 , and —(CH 2 ) 2-6 —(OCH 2 CH 2 —) 1-4 .

24. The method of claim 18 , wherein Z is —C 1-5 alkylene-arylene-C 1-5 alkylene- or —C 1-5 alkylene-heteroarylene-C 1-5 alkylene-.

25. The method of claim 24 , wherein Z is —CH 2 -phenylene-CH 2 —.

26. The method of claim 18 , wherein R 2 is selected from the group consisting hydrogen, alkyl, alkoxyalkylenyl, alkylaminoalkylenyl, and hydroxyalkylenyl.

27. The method of claim 26 , wherein R 2 is selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 NHCH 3 , —CH 2 NHCH 2 CH 3 , —CH 2 CH 2 NHCH 3 , —CH 2 OH, and —CH 2 CH 2 OH.

28. The method of claim 26 , wherein R 2 is selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , and —CH 2 CH 2 OCH 3 .

29. The method of claim 18 , wherein the compound of Formula I is a compound of Formula XIII:

wherein:

R 1B is selected from the group consisting of —X B —N(R 5B )—C(═NH)—NH 2 , —Z B —N(R 5B )—C(═NH)—NH 2 , and

Z B is selected from the group consisting of

—X B -arylene-X B —,

—X B -heteroarylene-X B —,

—X B -arylene-, and

—X B -heteroarylene-;

30. A method of claim 18 , wherein the method comprises administering an admixture of the compound of Formula I and a pharmaceutically acceptable carrier.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 1, 2024

From: 3M INNOVATIVE PROPERTIES COMPANY

To: SOLVENTUM INTELLECTUAL PROPERTIES COMPANY

Reel/Frame 066430/0295 →