IP Library › Granted Patent US 8,088,790

Granted Patent B2

US 8,088,790 · App. 12/092,625 · Granted Jan 3, 2012

Hydroxy and alkoxy substituted 1

Assignee: 3M Innovative Properties Company

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Quick Facts

Patent No.: US 8,088,790
App. No.: 12/092,625
Granted: Jan 3, 2012
Kind: B2

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Abstract

1H-Imidazo[4,5-c]quinolin-4-amines with a hydroxy, alkoxy, hydroxyalkoxy, or alkoxyalkoxy substituent at the 2-position, pharmaceutical compositions containing these compounds, methods of making 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 (269)

1. A compound of the Formula I:

wherein:

R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxyC 2-4 alkylenyl, and C 1-4 alkoxyC 2-4 alkylenyl;

R is selected from the group consisting of:

halogen,

hydroxy,

alkyl,

alkenyl,

haloalkyl,

alkoxy,

alkylthio, and

—N(R 9 ) 2 ;

n is an integer from 0 to 4;

R 1 is selected from the group consisting of:

hydrogen,

—CH(R 11 )—Ar,

—CH(R 11 )—Ar′—R 4 ,

—CH(R 11 )—Ar′—Y—R 4 ,

—CH(R 11 )—Ar′—CH(R 11 )—Y—R 4 ,

—CH(R 11 )—Ar′—R 5 ,

—CH(R 11 )—Ar′—CH(R 11 )—R 5 ,

—X 1 -Het, and

—X 1 —N(R 8 )-Q-R 4 ;

Ar is selected from the group consisting of aryl and heteroaryl each of which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, and dialkylamino;

Ar′ is selected from the group consisting of arylene and heteroarylene each of which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, and dialkylamino;

Het is heterocyclyl which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo;

X 1 is C 1-6 alkylene that is optionally interrupted by one or more —O— groups;

R 11 is selected from the group consisting of hydrogen and C 1-3 alkylene;

R 3 is selected from the group consisting of:

—Z—R 4 ,

—Z—X—R 4 ,

—Z—X—Y—R 4 ,

—Z—X—Y—X—Y—R 4 , and

—Z—X—R 5 ;

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

X is 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 by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

—O—,

—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 )—,

—O—N(R 8 )-Q-,

—O—N═C(R 4 )—,

—C(═N—O—R 8 )—,

—CH(—N(—O—R 8 )-Q-R 4 )—,

Z is a bond or —O—;

R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, 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; hydroxy; mercapto; cyano; aryl; aryloxy; arylalkyleneoxy; heteroaryl; heteroaryloxy; heteroarylalkyleneoxy; heterocyclyl; amino; alkylamino; dialkylamino; (dialkylamino)alkyleneoxy; and, in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

R 5 is selected from the group consisting of:

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

R 7 is C 2-7 alkylene;

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

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

R 10 is C 3-8 alkylene;

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

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

Q is 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—, —C(R 6 )—S—, and —C(R 6 )—N(OR 9 )—;

V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and

—S(O) 2 —;

W is selected from the group consisting of a bond, —C(O)—, 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. A compound of the Formula II:

wherein:

G 1 is selected from the group consisting of:

—C(O)—R′,

α-aminoacyl,

α-aminoacyl-α-aminoacyl,

—C(O)—O—R′,

—C(O)—N(R″)R′,

—C(═NY′)—R′,

—CH(OH)—C(O)—OY′,

—CH(OC 1-4 alkyl)Y 0 ,

—CH 2 Y 1 , and

—CH(CH 3 )Y 1 ;

R′ and R″ are independently selected from the group consisting of C 1-10 alkyl, C 3-7 cycloalkyl, phenyl, and benzyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxy, C 1-6 alkyl, C 1-4 alkoxy, aryl, heteroaryl, aryl-C 1-4 alkylenyl, heteroaryl-C 1-4 alkylenyl, halo-C 1-4 alkylenyl, halo-C 1-4 alkoxy, —O—C(O)—CH 3 , —C(O)—O—CH 3 , —C(O)—NH 2 , —O—CH 2 —C(O)—NH 2 , —NH 2 , and —S(O) 2 —NH 2 , with the proviso that R″ can also be hydrogen;

α-aminoacyl is an α-aminoacyl group derived from an amino acid selected from the group consisting of racemic, D-, and L-amino acids;

Y′ is selected from the group consisting of hydrogen, C 1-6 alkyl, and benzyl;

Y 0 is selected from the group consisting of C 1-6 alkyl, carboxy-C 1-6 alkylenyl, amino-C 1-4 alkylenyl, mono-N—C 1-6 alkylamino-C 1-4 alkylenyl, and di-N,N—C 1-6 alkylamino-C 1-4 alkylenyl;

Y 1 is selected from the group consisting of mono-N—C 1-6 alkylamino, di-N,N—C 1-6 alkylamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, and 4-C 1-4 alkylpiperazin-1-yl;

R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxyC 2-4 alkylenyl, and C 1-4 alkoxyC 2-4 alkylenyl;

R is selected from the group consisting of:

halogen,

hydroxy,

alkyl,

alkenyl,

haloalkyl,

alkoxy,

alkylthio, and

—N(R 9 ) 2 ;

n is an integer from 0 to 4;

R 1 is selected from the group consisting of:

hydrogen,

—CH(R 11 )—Ar,

—CH(R 11 )—Ar′—R 4 ,

—CH(R 11 )—Ar′—Y—R 4 ,

—CH(R 11 )—Ar′—CH(R 11 )—Y—R 4 ,

—CH(R 11 )—Ar′—R 5 ,

—CH(R 11 )—Ar′—CH(R 11 )—R 5 ,

—X 1 -Het, and

—X 1 —N(R 8 )-Q-R 4 ;

X 1 is C 1-6 alkylene that is optionally interrupted by one or more —O— groups;

R 11 is selected from the group consisting of hydrogen and C 1-3 alkylene;

R 3 is selected from the group consisting of:

—Z—R 4 ,

—Z—X—R 4 ,

—Z—X—Y—R 4 ,

—Z—X—Y—X—Y—R 4 , and

—Z—X—R 5 ;

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

Y is selected from the group consisting of:

—O—,

—S(O) 0-2 —,

—S(O) 2 —N(R 8 )—,

—C(R 6 )—,

—C(R 6 )—O—,

—O—C(R 6 )—,

—O—C(R 6 )—O—,

—N(R 8 )-Q-,

—C(R 6 )—N(R 8 )—,

—O—C(R 6 )—N(R 8 )—,

—C(R 6 )—N(OR 9 )—,

—O—N(R 8 )-Q-,

—O—N═C(R 4 )—,

—C(═N—O—R 8 )—,

—CH(—N(—O—R 8 )-Q-R 4 )—,

Z is a bond or —O—;

R 5 is selected from the group consisting of:

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

R 7 is C 2-7 alkylene;

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

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

R 10 is C 3-8 alkylene;

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

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

Q is 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 9 )—, —C(R 6 )—O—, —C(R 6 )—S—, and —C(R 6 )—N(OR 9 )—;

V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and

—S(O) 2 —;

W is selected from the group consisting of a bond, —C(O)—, 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.

3. A compound of the Formula III:

wherein:

G 2 is selected from the group consisting of:

—X 2 —C(O)—R′,

α-aminoacyl,

α-aminoacyl-α-aminoacyl,

—X 2 —C(O)—O—R′,

—C(O)—N(R″)R′, and

—S(O) 2 —R′;

X 2 is selected from the group consisting of a bond; —CH 2 —O—; —CH(CH 3 )—O—; —C(CH 3 ) 2 —O—; and, in the case of —X 2 —C(O)—O—R′, —CH 2 —NH—;

α-aminoacyl is an α-aminoacyl group derived from an amino acid selected from the group consisting of racemic, D-, and L-amino acids;

R is selected from the group consisting of:

halogen,

hydroxy,

alkyl,

alkenyl,

haloalkyl,

alkoxy,

alkylthio, and

—N(R 9 ) 2 ;

n is an integer from 0 to 4;

R 1 is selected from the group consisting of:

hydrogen,

—CH(R 11 )—Ar,

—CH(R 11 )—Ar′—R 4 ,

—CH(R 11 )—Ar′—Y—R 4 ,

—CH(R 11 )—Ar′—CH(R 11 )—Y—R 4 ,

—CH(R 11 )—Ar′—R 5 ,

—CH(R 11 )—Ar′—CH(R 11 )—R 5 ,

—X 1 -Het, and

—X 1 —N(R 8 )-Q-R 4 ;

X 1 is C 1-6 alkylene that is optionally interrupted by one or more —O— groups;

R 11 is selected from the group consisting of hydrogen and C 1-3 alkylene;

R 3 is selected from the group consisting of:

—Z—R 4 ,

—Z—X—R 4 ,

—Z—X—Y—R 4 ,

—Z—X—Y—X—Y—R 4 , and

—Z—X—R 5 ;

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

Y is selected from the group consisting of:

—O—,

—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 )—,

—O—N(R 8 )-Q-,

—O—N═C(R 4 )—,

—C(═N—O—R 8 )—,

—CH(—N(—O—R 9 )-Q-R 4 )—,

Z is a bond or —O—;

R 5 is selected from the group consisting of:

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

R 7 is C 2-7 alkylene;

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

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

R 10 is C 3-8 alkylene;

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

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

V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and

—S(O) 2 —;

W is selected from the group consisting of a bond, —C(O)—, 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.

4. The compound or salt of claim 1 wherein R 1 is

—CH(R 11 )—Ar.

5. The compound or salt of claim 4 wherein R 1 is selected from the group consisting of benzyl, 1-phenylethyl, and pyridinylmethyl, each of which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, and halogen.

6. The compound or salt of claim 5 wherein R 1 is selected from the group consisting of benzyl, 4-methoxybenzyl, 1-phenylethyl, and pyridin-3-ylmethyl.

7. The compound or salt of claim 1 wherein R 1 is

—CH(R 11 )—Ar′—CH(R 11 )—Y—R 4 .

8. The compound or salt of claim 7 wherein:

each R 11 is hydrogen;

Ar′ is phenylene;

Y in —CH(R 11 )—Ar′—CH(R 1 )—Y—R 4 is —NHQ-

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

R 4 in —CH(R 11 )—Ar′—CH(R 11 )—Y—R 4 is selected from the group consisting of alkyl, aryl, heteroaryl, and arylalkylenyl

wherein alkyl, aryl, and heteroaryl are each unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, and halogen.

9. The compound or salt of claim 1 wherein R 1 is

—CH(R 11 )—Ar′—CH(R 11 )—R 5 .

10. The compound or salt of claim 9 wherein:

each R 11 is hydrogen;

Ar′ is phenylene; and

R 5 in —CH(R 11 )—Ar′—CH(R 11 )—R 5 is

wherein A is selected from the group consisting of —CH 2 —, —O—, and —N(alkyl)-, and a and b are each independently 1, 2, or 3.

11. The compound or salt of claim 10 wherein a and b are each 2.

12. The compound or salt of claim 1 wherein R 1 is

—X 1 —N(R 8 )-Q-R 4 .

13. The compound or salt of claim 12 wherein:

X 1 is C 1-4 alkylene;

R 8 in —X 1 —N(R 8 )-Q-R 4 is hydrogen;

Q in —X 1 —N(R 8 )-Q-R 4 is selected from the group consisting of —C(O)—, —S(O) 2 —, —C(R 6 )—N(R 9 )—, and —S(O) 2 —N(R 8 )—; and

R 4 in —X 1 —N(R 8 )-Q-R 4 is selected from the group consisting of alkyl, aryl, heteroaryl, heterocyclyl, and arylalkylenyl

wherein alkyl, aryl, and heteroaryl are each unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, and halogen.

14. The compound or salt of claim 12 wherein:

X 1 is C 1-4 alkylene;

R 8 in —X 1 —N(R 8 )-Q-R 4 is C 1-10 alkyl or hydroxy-C 1-10 alkylenyl;

Q in —X 1 —N(R 8 )-Q-R 4 is a bond; and

R 4 in —X 1 —N(R 8 )-Q-R 4 is selected from the group consisting of alkyl, aryl, arylalkylenyl, and heteroarylalkylenyl

wherein alkyl is optionally substituted by one or more substituents independently selected from the group consisting of alkoxy and hydroxy.

15. A compound selected from the group consisting of 4-amino-1-benzyl-1H-imidazo[4,5-c]quinolin-2-ol, 4-amino-1-(1-phenylethyl)-1H-imidazo[4,5-c]quinolin-2-ol, 4-amino-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-ol, and 4-amino-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol, or a pharmaceutically acceptable salt thereof.

16. The compound 4-amino-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 and a pharmaceutically acceptable carrier.

18. A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal.

19. A method of selectively inducing the biosynthesis of IFN-α in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 8, 2011

From: KSHIRSAGAR, TUSHAR A.; HEPPNER, PHILIP D.; LANGER, SCOTT E.

To: 3M INNOVATIVE PROPERTIES COMPANY

Reel/Frame 025757/0171 →

Continuity (2)

Provisional Application 60733952 · Nov 4, 2005

Related Publication 20090221556A1 · Sep 3, 2009