Compounds and methods for treating inflammatory and fibrotic disorders

• US 9,290,450 B2
• Filed: 04/28/2014
• Issued: 03/22/2016
• 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 D., Raveglia, Luca Francesco Mario, Vallese, Stefania, Bianchi, Ivana, Hu, Tao
• Primary Examiner(s): NORTHINGTON DAVI, ZINNA
• Application Number:
  US14/263,822
• Publication Number:
  US 20140235637A1
• Time in Patent Office: 694 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/08 Antiseborrheics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/08 : for leprosy
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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.

Claims

1. A compound of formula II:

2. The compound of claim 1, wherein X³ is substituted with one or more substituents selected from the group consisting of hydroxyl;

halo;

aryl optionally substituted with one to four groups independently selected from halo, alkyl, alkenyl, OCF₃, NO₂, CN, NC, OH, alkoxy, haloalkoxy, amino, CO₂H, CO₂alkyl, aryl, and heteroaryl;

heteroaryl optionally substituted with one to four groups independently selected from halo, alkyl, alkenyl, OCF₃, NO₂, CN, NC, OH, alkoxy, haloalkoxy, amino, CO₂H, CO₂alkyl, aryl, and heteroaryl;

cycloalkyl optionally substituted with one to three groups independently selected from alkyl, alkyleneOH, C(O)NH₂, NH₂, oxo (═

O), aryl, haloalkyl, halo, and OH;

heterocycloalkyl optionally substituted with one to three groups independently selected from alkyl, alkyleneOH, C(O)NH₂, NH₂, oxo (═

O), aryl, haloalkyl, halo, and OH; and

amino.

3. The compound of claim 2, wherein X³ is alkoxy substituted with an aryl optionally substituted with one to four groups independently selected from halo, alkyl, alkenyl, OCF₃, NO₂, CN, NC, OH, alkoxy, haloalkoxy, amino, CO₂H, CO₂alkyl, aryl, and heteroaryl.

4. The compound of claim 3, wherein X³is alkoxy substituted with an aryl optionally substituted with one to four groups independently selected from halo, alkyl, alkenyl, OCF₃, NO₂, CN, OH, alkoxy, haloalkoxy, amino, CO₂H, and CO₂alkyl.

5. The compound of claim 1, wherein X³ is alkoxy substituted with a heterocycloalkyl optionally substituted with one to three groups independently selected from alkyl, alkyleneOH, C(O)NH₂, NH₂, oxo (═

O), aryl, haloalkyl, halo, and OH.

6. The compound of claim 5, wherein the heterocycloalkyl is optionally substituted with alkyl.

7. The compound of claim 5, wherein the heterocycloalkyl is a five, six or seven membered ring selected from the group consisting of oxazole, pyrrole, imidazole, pyrazole, pyrrolidine, piperidine, piperazine, morpholine, and azepane.

8. The compound of claim 7, wherein the heterocycloalkyl is piperidine.

9. The compound of claim 7, wherein the heterocycloalkyl is N-methyl piperazine.

10. The compound of claim 7, wherein the heterocycloalkyl is pyrrolidine.

11. The compound of claim 7, wherein the heterocycloalkyl is morpholine.

12. The compound of claim 1, wherein X³ is an alkoxy substituted with amino.

13. The compound of claim 1, wherein X³ is an alkoxy substituted with N-alkyl amino or N,N-dialkyl amino.

14. The compound of claim 1, wherein R² is alkyl.

15. The compound of claim 14, wherein R² is methyl.

16. The compound or claim 1, wherein R² is haloalkyl.

17. The compound or claim 1, wherein R² is aryl optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, OCF₃, NO₂, CN, OH, alkoxy, haloalkoxy, amino, CO₂H, CO₂alkyl, aryl, and heteroaryl.

18. The compound of claim 17, wherein R² is phenyl.

19. The compound or claim 1, wherein R² is heteroaryl optionally substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF₃, NO₂, CN, OH, alkoxy, haloalkoxy, amino, CO₂H, and CO₂alkyl.

20. The compound or claim 1, wherein R¹ is hydrogen.

21. The compound or claim 1, wherein R³ is hydrogen.

22. The compound or claim 1, wherein R⁴ is hydrogen.

23. The compound or claim 1, wherein each of X¹, X², X⁴, and X⁵ is hydrogen.

24. A method for treating a fibrotic condition, comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.

25. The method of claim 24, wherein the fibrotic condition is idiopathic pulmonary fibrosis.

26. The method of claim 24, wherein the compound is administered by inhalation.

27. A pharmaceutical composition comprising a compound of claim 1, and pharmaceutically acceptable excipients.