Compounds and methods for treating inflammatory and fibrotic disorders

• US RE47,142 E1
• Filed: 11/06/2014
• Issued: 11/27/2018
• Est. Priority Date: 06/03/2008
• Status: Active Grant

• Current Assignee: Intermune Incorporated (Roche Holding AG)
• Original Assignee: Intermune Incorporated (Roche Holding AG)
• Inventors: Kossen, Karl, Seiwert, Scott D., Serebryany, Vladimir, Ruhrmund, Donald, Beigelman, Leonid, Raveglia, Luca Francesco Mario, Vallese, Stefania, Bianchi, Ivana, Hu, Tao
• Primary Examiner(s): Chong, Yong
• Application Number:
  US14/534,450
• Time in Patent Office: 1,482 Days
• Field of Search: 514247, 5142521, 514300, 514345, 5142342, 544239, 546113, 546290
• CPC Class Codes: C07D 213/22 containing two or more pyridine rings directly linked together, e.g. bipyridyl
• CPC Class Codes: C07D 213/63 One oxygen atom
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/69 Two or more oxygen atoms
• CPC Class Codes: C07D 213/71 to which a second hetero atom is attached
• CPC Class Codes: C07D 213/85 in position 3
• CPC Class Codes: C07D 237/14 Oxygen atoms
• CPC Class Codes: C07D 239/36 as doubly bound oxygen atom or as unsubstituted hydroxy radical
• CPC Class Codes: C07D 239/54 as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07D 241/18 Oxygen or sulfur atoms
• CPC Class Codes: C07D 251/10 having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Disclosed are compounds and methods for treating inflammatory and fibrotic disorders, including methods of modulating a stress activated protein kinase (SAPK) system with an active compound, wherein the active compound exhibits low potency for inhibition of the p38 MAPK; and wherein the contacting is conducted at a SAPK-modulating concentration that is at a low percentage inhibitory concentration for inhibition of the p38 MAPK by the compound. Also disclosed are derivatives and analogs of pirfenidone, useful for modulating a stress activated protein kinase (SAPK) system.

Mederski et al., Tetrahedron (1999), 55(44), 12757-12770.*

Azuma et al., “A placebo control and double blind phase II clinical study of pirfenidone in patients with idiopathic pulmonary fibrosis in Japan”, Am J Respir Crit Care Med., 165:A729 (2002).

Badger, et al., “Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function”, J. Pharmacol. Exp. Ther. 279:1453-61 (1996).

Claims

1. A compound of formula II (II)

2. The compound of claim 1, wherein one of X¹, X², and X³ is not hydrogen.

5. The compound of claim 1, wherein R¹ is selected from the group consisting of hydrogen, 4-pyridyl, cyclopropanyl, 2-furanyl, cyano, H₂NSO₂, (CH₃)₂NSO₂, fluoro, 4-(3,5-dimethyl)-isoxazolyl, 4-pyrazolyl, 4-(1-methyl)-pyrazolyl, 5-pyrimidinyl, 2-imidazolyl, and thiazolyl.

6. The compound of claim 1, wherein at least one of X¹, X², or X³ is alkyl or cycloalkyl.

7. The compound of claim 1, wherein at least one of X¹, X², or X³ is haloalkyl.

8. The compound of claim 1, wherein at least one of X¹, X², or X³ is alkenyl.

9. The compound of claim 1, wherein at least one of X¹, X², or X³ is amino.

10. The compound of claim 1 having a structure selected from the group consisting of:

11. The compound of claim 1, wherein the compound exhibits an IC₅₀ in a range of about 100 μ

M to about 1000 μ

M for inhibition of p38 MAPK.

12. The compound of claim 11, wherein the compound exhibits an IC₅₀ is in the range of about 200 μ

M to about 800 μ

M.

13. The compound of claim 1, wherein the compound exhibits an EC₅₀ in the range of about 0.1 μ

M to about 1000 μ

M for inhibition of TNFα

secretion in a bodily fluid in vivo.

14. A composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

15. The compound of claim 2, wherein R² is selected from the group consisting of substituted or unsubstituted aryl;

unsubstituted heteroaryl;

heteroaryl substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF₃, NO₂, CN, NC, OH, alkoxy, haloalkoxy, amino, CO₂H, and CO₂alkyl;

haloalkylcarbonyl;

cycloalkyl;

hydroxylalkyl;

sulfonamido; and

unsubstituted cycloheteroalkyl;

or R² and R¹ together form an optionally substituted 5-membered nitrogen-containing heterocyclic ring.

16. The compound of claim 15, selected from the group consisting of:

3. A compound having a structure of formula (III) or formula (IV)

4. The compound of claim 3, wherein X⁷ is hydrogen.

18. The compound of claim 3 having a structure selected from the group consisting of:

17. A compound selected from the group consisting of:

19. A compound selected from the group consisting of: