CGAS in systemic lupus erythematosus (SLE)

Patent metadata

Field	Value
Publication number	US-10329258-B2
Application number	US-201615564995-A
Country	US
Kind code	B2
Filing date	Apr 26, 2016
Priority date	Apr 30, 2015
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

Abstract

The present invention provides therapeutic strategies for treatment of severe debilitating diseases associated with IFN-I due to cGAS activation. In one aspect, the invention provides compounds of Formula (I): [Formula should be inserted here] and pharmaceutical uses thereof. In another aspect, the invention provides methods for treating an autoimmune disease or a monogenic disorder by administering an effective amount of a compound of Formula (I).

First claim

What is claimed:

1. A compound of Formula (I) or a prodrug thereof,

wherein
R 1 is —OH, —NH 2 , —N(H)C(O)R 7 or —NO 2 ;
R 2 is —H or —OCH 3 ;
R 3 and R 4 are independently —H or —CH 3 ;
R 5 and R 6 are independently —H, —CH 3 , —CH 2 CH 2 SH,

R 7 is —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —OCH 2 CH 2 CH 2 CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , —CF 3 , —CH 2 CF 3 or

 and
n is 2 or 3.

2. The compound of claim 1 , wherein
R 1 is —NH 2 or —N(H)C(O)R 7 ;
R 2 is —OCH 3 ;
R 3 is —CH 3 ;
R 4 is —H;
R 5 is —CH 3 ;
R 6 is

R 7 is —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —OCH 2 CH 2 CH 2 CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , —CF 3 , —CH 2 CF 3 or

 and
n is 2.

3. The compound of claim 1 , wherein
R 1 is —NH 2 or —N(H)C(O)R 7 ;
R 2 is —OCH 3 ;
R 3 is —CH 3 ;
R 4 is —H;
R 5 is —CH 3 ;
R 6 is

R 7 is —OCH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CF 3 or

 and
n is 2.

4. The compound of claim 1 , wherein
R 1 is —NH 2 ;
R 2 is —OCH 3 ;
R 3 is —CH 3 ;
R 4 is —H;
R 5 is —CH 3 ;
R 6 is

 and
n is 2.

5. The compound of claim 2 , wherein
R 1 is —NH 2 ;
R 2 is —OCH 3 ;
R 3 is —CH 3 ;
R 4 is —H;
R 5 is —CH 3 ;
R 6 is

 and
n is 2.

6. The compound of claim 2 , wherein
R 1 is —NH 2 ;
R 2 is —OCH 3 ;
R 3 is —CH 3 ;
R 4 is —H;
R 5 is —CH 3 ;
R 6 is

 and
n is 2.

7. The compound of claim 2 , wherein R 1 is N(H)C(O)R 7 .

8. The compound of claim 2 , wherein
R 1 is —N(H)C(O)R 7 ;
R 2 is —OCH 3 ;
R 3 is —CH 3 ;
R 4 is —H;
R 5 is —CH 3 ;
R 6 is

 and
n is 2.

9. The compound of claim 2 , wherein
R 1 is —N(H)C(O)CH 2 CH 2 CH 2 CH 2 CH 3 ;
R 2 is —OCH 3 ;
R 3 is —CH 3 ;
R 4 is —H;
R 5 is —CH 3 ;
R 6 is

 and
n is 2.

10. The compound of claim 2 , wherein
R 1 is —N(H)C(O)CF 3 ;
R 2 is —OCH 3 ;
R 3 is —CH 3 ;
R 4 is —H;
R 5 is —CH 3 ;
R 6 is

 and
n is 2.

11. The compound of claim 2 , wherein
R 1 is —N(H)C(O)R 7 ;
R 2 is —OCH 3 ;
R 3 is —CH 3 ;
R 4 is —H;
R 5 is —CH 3 ;
R 6 is

R 7 is

 and
n is 2.

12. A compound of Formula (II) or a prodrug thereof,

wherein
R 1 is —Cl, —OH, —NH 2 , or —NO 2 ;
R 6 is

 and
n is 3 or 4.

13. A compound of Formula (I) or a prodrug thereof,

wherein
R 1 is —H, —Cl, —OH, —NH 2 or —NO 2 ;
R 2 is —H or —OCH 3 ;
R 3 and R 4 are independently —H or —CH 3 ;
R 5 and R 6 are independently —H, —CH 3 , —CH 2 CH 2 SH,

 and
n is 2 or 3.

14. The compound of claim 13 , wherein R 1 is —NH 2 ; R 2 is —OCH 3 ; R 3 is —CH 3 ; R 4 is —H; R 5 is —CH 3 ; R 6 is

and n is 2.

15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

16. A method for the treatment of an autoimmune disease or a monogenic disorder, the method comprising administering an effective amount of a compound of claim 1 or a prodrug thereof, to a patient in need thereof, wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, inflammatory bowel disease, diabetes mellitus, Sjögren's syndrome, scleroderma, and polymyositis, and wherein the monogenic disorder is Aicardi-Goutiéres's Syndrome.

17. A method for the treatment of an autoimmune disease or a monogenic disorder, the method comprising administering an effective amount of a compound of Formula (III) or a prodrug thereof,

wherein
R 1 is —H, halogen, —OH, —OCH 3 , —NH 2 , —NMe 2 , —N(H)C(O)R 7 or —NO 2 ,
wherein R 7 is —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —OCH 2 CH 2 CH 2 CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , —CF 3 , —CH 2 CF 3 or

ring X is absent or

 wherein R 2 is —H, halogen, —NMe 2 , —OCH 3 or —OCH 2 CH 3 ;
X is —H, —NH 2 ,

 wherein
R 3 is —H or —CH 3 ;
R 4 is —H or —CH 3 ;
R 5 and R 6 are independently —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 SH, —CH 2 CH 2 OH,

R Y is —NO 2 , —C(O)OCH 2 CH 3 or —N(H)SO 2 Me; and
n is 2 or 3;

to a patient in need thereof, wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, inflammatory bowel disease, diabetes mellitus, Sjögren's syndrome, scleroderma, and polymyositis, and wherein the monogenic disorder is Aicardi-Goutiéres's Syndrome.

Assignees

• Univ Washington

Inventors

• Elkon Keith
• An Jie
• Minie Mark
• Sasaki Tomikazu
• Woodward Joshua J

Classifications

• C07D219/12 Primary

  Amino-alkylamino radicals attached in position 9 · CPC title

• C07D219/10

  attached in position 9 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61K31/4353

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title