IP Library › Granted Patent US 7,648,997

Granted Patent B2

US 7,648,997 · App. 10/595,058 · Granted Jan 19, 2010

Hydroxylamine substituted imidazoquinolines

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Quick Facts

Patent No.: US 7,648,997
App. No.: 10/595,058
Granted: Jan 19, 2010
Kind: B2

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Abstract

Imidazo-containing compounds (e.g., imidazoquinolines, imidazonaphthyridines, imidazopyridines) with a hydrox-ylamine substituent at the 1-position, pharmaceutical compositions containing the compounds, intermediates, and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.

Claims (346)

1. A compound of the formula (II):

wherein:

X is selected from the group consisting of —CH(R 9a )-alkylene- and —CH(R 9a )-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

a bond,

—C(O)—,

—C(S)—,

—S(O) 2 —,

—S(O) 2 —N(R 8 )—,

C(O)—O—,

—C(O)—N(R 8 )—,

—C(S)—N(R 8 )—,

—C(O)—N(R 8 )—S(O) 2 —,

—C(O)—N(R 8 )—C(O)—,

—C(S)—N(R 8 )—C(O)—,

—C(O)—C(O)—,

—C(O)—C(O)—O—, and

—C(═NH)—N(R 8 )—;

R 1 and R′ are independently selected from the group consisting of

hydrogen,

alkyl,

alkenyl,

aryl,

arylalkylenyl,

heteroaryl,

heteroarylalkylenyl,

heterocyclyl, and

heterocyclylalkylenyl,

wherein the alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl group is unsubstituted or substituted by one or more substituents selected from the group consisting of:

hydroxyl,

alkyl,

haloalkyl,

hydroxyalkyl,

alkoxy,

dialkylamino,

—S(O) 0-2 -alkyl,

—S(O) 0-2 -aryl,

—NH—S(O) 2 -alkyl,

—NH—S(O) 2 -aryl,

haloalkoxy,

halogen,

nitrile,

nitro,

aryl,

heteroaryl,

heterocyclyl,

aryloxy,

arylalkyleneoxy,

—C(O)—O-alkyl,

—C(O)—N(R 8 ) 2 ,

—N(R 8 )—C(O)-alkyl,

—O—C(O)-alkyl, and

—C(O)-alkyl;

or R 1 and R′ together with the nitrogen atom and Y′ to which they are bonded can join to form a ring selected from the group consisting of:

R A and R B are taken together to form a fused aryl ring, wherein the aryl ring is unsubstituted or substituted by one or more R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group;

R is selected from the group consisting of:

halogen,

hydroxyl,

alkyl,

alkenyl,

haloalkyl,

alkoxy,

alkylthio, and

—N(R 9 ) 2 ;

R 2 is selected from the group consisting of:

—R 11 ,

—X″—R 11 , and

—X″—Y′″—R 11 ;

R 3 is selected from the group consisting of:

—Z—R 4 ,

—Z—X′—R 4 ,

—Z—X′—y—R 4 , and

—Z—X′—R 5 ;

each X′ is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;

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

each Y is independently selected from the group consisting of:

—S(O) 0-2 —,

—S(O) 2 —N(R 8 )—,

—C(R 6 )—,

—C(R 6 )—O—,

—O—C(R 6 )—,

—O—C(O)—O—,

—N(R 8 )-Q-,

—C(R 6 )—N(R 8 )—,

—O—C(R 6 )—N(R 8 )—,

—C(R 6 )—N(OR 9 )—,

each Y′″ is independently selected from the group consisting of:

—S(O) 0-2 —,

—S(O) 2 —N(R 8 )—,

—C(R 6 )—,

—C(R 6 )—O—,

—O—C(R 6 )—,

—O—C(O)—O—,

—N(R 8 )—O—,

—C(R 6 )—N(R 8 )—,

—O—C(R 6 )—N(R 8 )—, and

—C(R 6 )—N(OR 9 )—;

Z is a bond or —O—;

each R 4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alklheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxyl, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylannino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

each R 5 is independently selected from the group consisting of:

each R 6 is independently selected from the group consisting of ═O and ═S;

each R 7 is independently C 2-7 alkylene;

each R 8 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkoxy—C 1-10 alkylenyl, and aryl—C 1-10 alkylenyl;

each R 9 is independently selected from the group consisting of hydrogen and alkyl;

R 9a is selected from the group consisting of hydrogen and alkyl which is optionally interrupted by one or more —O— groups;

each R 10 is independently C 3-8 alkylene;

each R 11 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, wherein the alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, and alkynyl, oxo;

each A is independently selected from the group consisting of —O—, —C(O)—, —CH 2 —, —S(O) 0-2 —, and —N(R 4 )—;

each Q is independently selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;

each W is independently selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;

each V is independently selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —; and

a and b are independently integers from 1 to 6 with the proviso that a+b is ≦7;

or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 wherein X is —C 3-5 alkylene- or —CH 2 CH 2 OCH 2 CH 2 —.

3. The compound or salt of claim 1 wherein R′ is selected from the group consisting of hydrogen and C 1-4 alkyl.

4. The compound or salt of claim 1 wherein Y′ is —C(O)—, —S(O) 2 —, or —C(O)—N(R 8 )—.

5. The compound or salt of claim 1 wherein R 1 is selected from the group consisting of C 1-6 alkyl and pyridyl.

6. The compound or salt of claim 1 wherein R 1 is selected from the group consisting of alkyl, alkenyl, aryl, and heteroaryl, each of which is optionally substituted by one or more substituents selected from the group consisting of —O-alkyl, —O-aryl, —S-alkyl, —S-aryl, halogen, —O—C(O)-alkyl, —C(O)—O-alkyl, haloalkoxy, haloalkyl, and aryl.

7. The compound or salt of claim 1 wherein R 2 is selected from the group consisting of hydrogen, alkyl, and alkoxyalkylenyl.

8. The compound or salt of claim 7 wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, ethoxymethyl, 2-methoxyethyl, and methoxymethyl.

9. The compound or salt of claim 1 wherein R 2 is selected from the group consisting of:

hydrogen,

alkyl,

alkenyl,

alkylene-Y″-alkyl, and

alkylene-Y″-alkenyl,

wherein the alkyl or alkenyl group is unsubstituted or substituted by one or more substituents selected from the group consisting of:

hydroxyl,

halogen,

—N(R 8a ) 2 ,

—C(O)—C 1-10 alkyl,

—C(O)—O—C 1-10 alkyl, and

N 3 ;

wherein:

Y″ is —O— or —S(O) 0-2 —; and

each R 8a is independently selected from the group consisting of hydrogen, C 1-10 alkyl, and C 2-10 alkenyl.

10. The compound or salt of claim 1 wherein R A and R B form a fused aryl ring wherein the aryl ring is unsubstituted.

11. A compound of the formula (III):

wherein:

X is selected from the group consisting of —CH(R 9a )-alkylene- and —CH(R 9a )-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

a bond,

—C(O)—,

—C(S)—,

—S(O) 2 —,

—S(O) 2 —N(R 8 )—,

—C(O)—O—,

—C(O)—N(R 8 )—,

—C(S)—N(R 8 )—,

—C(O)—N(R 8 )—S(O) 2 —,

—C(O)—N(R 8 )—C(O)—,

—C(S)—N(R 8 )—C(O)—,

—C(O)—C(O)—,

C(O)—C(O)—O—, and

—C(═NH)—N(R 8 )—;

each R is independently selected from the group consisting of:

halogen,

hydroxyl,

alkyl,

alkenyl,

haloalkyl,

alkoxy,

alkylthio, and

—N(R 9 ) 2 ;

R 1 and R′ are independently selected from the group consisting of:

hydrogen,

alkyl,

alkenyl,

aryl,

arylalkylenyl,

heteroaryl,

heteroarylalkylenyl,

heterocyclyl, and

heterocyclylalkylenyl,

hydroxyl,

alkyl,

haloalkyl,

hydroxyalkyl,

alkoxy,

dialkylamino,

—S(O) 0-2 -alkyl,

—S(O) 0-2 -aryl,

—NH—S(O) 2 -alkyl,

—NH—S(O) 2 -aryl,

haloalkoxy,

halogen,

nitrile,

nitro,

aryl,

heteroaryl,

heterocyclyl,

aryloxy,

arylalkyleneoxy,

—C(O)—O-alkyl,

—C(O)—N(R 8 ) 2 ,

—N(R 8 )—C(O)-alkyl,

—O—C(O)-alkyl, and

—C(O)-alkyl;

or R 1 and R′ together with the nitrogen atom and Y′ to which they are bonded can join to form a ring selected from the group consisting of:

R 2 is selected from the group consisting of:

—R 11 ,

—X″—R 11 , and

—X″—Y′″—R 11 ;

R 3 is selected from the group consisting of:

—Z—R 4 ,

—Z—X′—R 4 ,

—Z—X′—Y—R 4 , and

—Z—X′—R 5 ;

each Y is independently selected from the group consisting of:

—S(O) 0-2 —,

—S(O) 2 —N(R 8 )—,

—C(R 6 )—,

—C(R 6 )—O—,

—O—C(R 6 )—,

—O—C(O)—O—,

—N(R 8 )-Q-,

—C(R 6 )—N(R 8 )—,

—O—C(R 6 )—N(R 8 )—,

—C(R 6 )—N(OR 9 )—,

each Y″′ is independently selected from the group consisting of:

—S(O) 0-2 —,

—S(O) 2 —N(R 8 )—,

—C(R 6 )—,

—C(R 6 )—O—,

—O—C(R 6 )—,

—O—C(O)—O—,

—N(R 8 )—O—,

—C(R 6 )—N(R 8 )—,

—O—C(R 6 )—N(R 8 )—,

—C(R 6 )—N(OR 9 )—;

Z is a bond or —O—;

each R 5 is independently selected from the group consisting of:

each R 6 is independently selected from the group consisting of ═O and ═S;

each R 7 is independently C 2-7 alkylene;

each R 8 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkoxy—C 1-10 alkylenyl, and aryl-C 1-10 alkylenyl;

each R 9 is independently selected from the group consisting of hydrogen and alkyl;

R 9a is selected from the group consisting of hydrogen and alkyl which is optionally interrupted by one or more —O— groups;

each R 10 is independently C 3-8 alkylene;

each A is independently selected from the group consisting of —O—, —C(O)—, —CH 2 —, —S(O) 0-2 —, and —N(R 4 )—;

each Q is independently selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 0 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;

each W is independently selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;

each V is independently selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;

a and b are independently integers from 1 to 6 with the proviso that a+b is ≦7;

n is an integer from 0 to 4; and

m is 0 or 1, with the proviso that when m is 1, n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

12. The compound or salt of claim 11 wherein X is —C 3-5 alkylene- or —CH 2 CH 2 OCH 2 CH 2 —.

13. The compound or salt of claim 11 wherein R′ is selected from the group consisting of hydrogen and C 1-4 alkyl.

14. The compound or salt of claim 11 wherein Y′is —C(O)—, —S(O) 2 —, or —C(O)—N(R 8 )—.

15. The compound or salt of claim 11 wherein R 1 is selected from the group consisting of C 1-6 alkyl and pyridyl.

16. The compound or salt of claim 11 wherein R 1 is selected from the group consisting of alkyl, alkenyl, aryl, and heteroaryl, each of which is optionally substituted by one or more substituents selected from the group consisting of —O-alkyl, —O-aryl, —S-alkyl, —S-aryl, halogen, —O—C(O)-alkyl, —C(O)—O-alkyl, haloalkoxy, haloalkyl, and aryl.

17. The compound or salt of claim 11 wherein R 2 is selected from the group consisting of hydrogen, alkyl, and alkoxyalkylenyl.

18. The compound or salt of claim 17 wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, ethoxymethyl, 2-methoxyethyl, and methoxymethyl.

19. The compound or salt of claim 11 wherein R 2 is selected from the group consisting of:

hydrogen,

alkyl,

alkenyl,

alkylene—Y″-alkyl, and

alkylene—Y″-alkenyl,

wherein the alkyl or alkenyl group is unsubstituted or substituted by one or more substituents selected from the group consisting of:

hydroxyl,

halogen,

N(R 8a ) 2 ,

—C(O)—C 1-10 alkyl,

—C(O)—O—C 1-10 alkyl, and

—N 3 ,

wherein:

Y″ is —O— or —S(O) 0-2 —; and

each R 8a is independently selected from the group consisting of hydrogen, C 1-10 alkyl, and C 2-10 alkenyl.

20. The compound or salt of claim 11 wherein m and n are each 0.

21. A compound of the formula (V):

wherein:

X is selected from the group consisting of —CH(R 9a )-alkylene- and —CH(R 9a )-alkenylene-;

Y′ is selected from the group consisting of

a bond,

—C(O)—,

—C(S)—,

—S(O)2-,

—S(O) 2 —N(R 8a )—,

—C(O)—O—,

C(O)—N(R 8a )

C(S)—N(R 8a )—,

C(O)N(R 8a )—S(O) 2 —,

C(O)—N(R 8a )—C(O)—,

—C(S)—N(R 8a )—C(O)—, and

—C(O)—C(O)—O—;

R 1 is selected from the group consisting of:

hydrogen,

alkyl,

alkenyl,

aryl,

alkylene-aryl,

alkylene-heteroaryl,

alkylene-heterocyclyl,

heteroaryl, and

heterocyclyl,

wherein the alkyl, alkenyl, aryl, arylalkylenyl, heteroarylalkylenyl, heterocyclylalkylenyl, heteroaryl or heterocyclyl group is unsubstituted or substituted by one or more substituents selected from the group consisting of:

hydroxyl,

alkyl,

haloalkyl,

hydroxyalkyl,

—O-alkyl,

—S(O) 0-2 -alkyl,

—S(O) 0-2 -aryl,

—O-haloalkyl,

halogen,

nitrile,

nitro,

aryl,

heteroaryl,

heterocyclyl,

—O-aryl,

—O-alkylene-aryl,

—C(O)—O-alkyl,

—C(O)—N(R 8a ) 2 ,

N(R 8a )—C(O)-alkyl,

—O—C(O)-alkyl, and

—C(O)-alkyl;

each R is independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxyl, and trifluoromethyl;

R 2 is selected from the group consisting of:

hydrogen,

alkyl,

alkenyl,

alkylene-Y″-alkyl,

alkylene-Y″-alkenyl, and

alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:

hydroxyl,

halogen,

—N(R 8a ) 2 ,

—C(O)—C 1-10 alkyl,

—C(O)—O—C 1-10 alkyl, and

N 3 ;

Y″ is —O— or —S(O) 0-2 —;

each R 8a is independently selected from the group consisting of hydrogen, C 1-10 alkyl, and C 2-10 alkenyl;

R 9a is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more —O— groups; and

n is an integer from 0 to 4;

or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 in combination with a pharmaceutically acceptable carrier.

23. A method of inducing INF and/or TNF biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal.

24. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 11 in combination with a pharmaceutically acceptable carrier.

25. A method of inducing INF and/or TNF biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 11 to the animal.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 11, 2011

From: COLEY PHARMACEUTICAL GROUP, INC.

To: 3M INNOVATIVE PROPERTIES COMPANY

Reel/Frame 026732/0337 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 11, 2007

From: 3M COMPANY; 3M INNOVATIVE PROPERTIES COMPANY

To: COLEY PHARMACEUTICAL GROUP, INC.

Reel/Frame 019945/0698 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 23, 2006

From: KSHIRSAGAR, TUSHAR A.; AMOS, DAVID T.; DELLARIA, JR., JOSEPH F.; HEPPNER, PHILIP D.; LANGER, SCOTT E.; ZIMMERMANN, BERNHARD M.

To: 3M INNOVATIVE PROPERTIES COMPANY

Reel/Frame 017047/0290 →