Compounds and methods for treating inflammatory and fibrotic disorders

• US 8,969,347 B2
• Filed: 10/15/2012
• Issued: 03/03/2015
• 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): NORTHINGTON DAVI, ZINNA
• Application Number:
  US13/652,247
• Publication Number:
  US 20130102597A1
• Time in Patent Office: 869 Days
• Field of Search: None
• US Class Current: 514/247
• 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 method of treating an inflammatory condition, comprising administering to a patient in need thereof a compound of formula I

2. The method of claim 1, wherein at least one of X¹, X², or X³ is haloalkoxy.

3. The method of claim 1, wherein

R¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cyano, sulfonamido, halo, alkenylenearyl, and heteroaryl;

R² is selected from the group consisting of aryl;

unsubstituted heteroaryl;

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

cycloalkyl;

unsubstituted cycloheteroalkyl and cycloheteroalkyl substituted with one to three substituents independently selected from alkyleneOH, C(O)NH₂, NH₂, aryl, haloalkyl, halo, and OH;

R⁴ is selected from the group consisting of hydrogen, haloalkyl, alkoxy, alkenyl, and alkenylenearyl; and

X⁵ is hydrogen.

4. The method of claim 1, wherein one of X¹, X², and X³ is not hydrogen.

5. The method of claim 4, wherein R² is selected from the group consisting of aryl;

unsubstituted heteroaryl;

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

cycloalkyl; and

unsubstituted cycloheteroalkyl.

6. The method of claim 5, wherein the compound of formula I is selected from the group consisting of:

7. The method of claim 1, wherein R² is selected from the group consisting of 4-pyridyl, cyclopropanyl, 2-furanyl, 4-(3,5-dimethyl)-isoxazolyl, 4-pyrazolyl, 4-(1-methyl)-pyrazolyl, 5-pyrimidinyl, 2-imidazolyl, and thiazolyl.

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

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

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

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

13. The method 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.

14. The method of claim 13, wherein the IC₅₀ is in the range of about 200 μ

M to about 800 μ

M.

15. The method 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.

16. The method of claim 1, wherein the inflammatory condition is selected from the group consisting of fibrosis;

chronic obstructive pulmonary disease;

inflammatory pulmonary fibrosis;

rheumatoid arthritis;

rheumatoid spondylitis;

osteoarthritis;

gout;

sepsis;

septic shock;

endotoxic shock;

gram-negative sepsis;

toxic shock syndrome;

myofacial pain syndrome;

Shigellosis;

asthma;

adult respiratory distress syndrome;

inflammatory bowel disease;

Crohn'"'"'s disease;

psoriasis;

eczema;

ulcerative colitis;

glomerular nephritis;

scleroderma;

chronic thyroiditis;

Grave'"'"'s disease;

Ormond'"'"'s disease;

autoimmune gastritis;

myasthenia gravis;

autoimmune hemolytic anemia;

autoimmune neutropenia;

thrombocytopenia;

pancreatic fibrosis;

chronic active hepatitis;

hepatic fibrosis;

renal disease;

renal fibrosis;

irritable bowel syndrome;

pyresis;

restenosis;

cerebral malaria;

stroke injury;

ischemic injury;

neural trauma;

Alzheimer'"'"'s disease;

Huntington'"'"'s disease;

Parkinson'"'"'s disease;

acute pain;

chronic pain;

allergies;

cardiac hypertrophy;

chronic heart failure;

acute coronary syndrome;

cachexia;

malaria;

leprosy;

leishmaniasis;

Lyme disease;

Reiter'"'"'s syndrome;

acute synoviitis;

muscle degeneration;

bursitis;

tendonitis;

tenosynoviitis;

herniated, ruptured, or prolapsed intervertebral disk syndrome;

osteopetrosis;

thrombosis;

silicosis;

pulmonary sarcosis;

bone resorption disease;

cancer;

Multiple Sclerosis;

lupus;

fibromyalgia;

AIDS;

Herpes Zoster;

Herpes Simplex;

influenza virus;

Severe Acute Respiratory Syndrome;

cytomegalovirus;

diabetes mellitus and combinations thereof.

17. The method of claim 16, wherein the inflammatory condition is fibrosis.

18. The method of claim 17, wherein the fibrosis is pulmonary fibrosis.

12. A method of treating an inflammatory condition, comprising administering to a patient in need thereof a compound selected from the group consisting of:

19. A method of treating an inflammatory condition, comprising administering to a patient in need thereof a compound selected from the group consisting of:

20. The method of claim 19, wherein the inflammatory condition is selected from the group consisting of fibrosis;

chronic obstructive pulmonary disease;

inflammatory pulmonary fibrosis;

rheumatoid arthritis;

rheumatoid spondylitis;

osteoarthritis;

gout;

sepsis;

septic shock;

endotoxic shock;

gram-negative sepsis;

toxic shock syndrome;

myofacial pain syndrome;

Shigellosis;

asthma;

adult respiratory distress syndrome;

inflammatory bowel disease;

Crohn'"'"'s disease;

psoriasis;

eczema;

ulcerative colitis;

glomerular nephritis;

scleroderma;

chronic thyroiditis;

Grave'"'"'s disease;

Ormond'"'"'s disease;

autoimmune gastritis;

myasthenia gravis;

autoimmune hemolytic anemia;

autoimmune neutropenia;

thrombocytopenia;

pancreatic fibrosis;

chronic active hepatitis;

hepatic fibrosis;

renal disease;

renal fibrosis;

irritable bowel syndrome;

pyresis;

restenosis;

cerebral malaria;

stroke injury;

ischemic injury;

neural trauma;

Alzheimer'"'"'s disease;

Huntington'"'"'s disease;

Parkinson'"'"'s disease;

acute pain;

chronic pain;

allergies;

cardiac hypertrophy;

chronic heart failure;

acute coronary syndrome;

cachexia;

malaria;

leprosy;

leishmaniasis;

Lyme disease;

Reiter'"'"'s syndrome;

acute synoviitis;

muscle degeneration;

bursitis;

tendonitis;

tenosynoviitis;

herniated, ruptured, or prolapsed intervertebral disk syndrome;

osteopetrosis;

thrombosis;

silicosis;

pulmonary sarcosis;

bone resorption disease;

cancer;

Multiple Sclerosis;

lupus;

fibromyalgia;

AIDS;

Herpes Zoster;

Herpes Simplex;

influenza virus;

Severe Acute Respiratory Syndrome;

cytomegalovirus;

diabetes mellitus and combinations thereof.

21. The method of claim 20, wherein the inflammatory condition is fibrosis.

22. The method of claim 21, wherein the fibrosis is idiopathic pulmonary fibrosis.