Novel therapeutic compounds

• US 20090069288A1
• Filed: 07/15/2008
• Published: 03/12/2009
• Est. Priority Date: 07/16/2007
• Status: Abandoned Application

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbvie Incorporated
• Inventors: Li, Bin, Wang, Lu, Hobson, Adrian D., Gordon, Thomas D., Cusack, Kevin P., Breinlinger, Eric C., Stoffel, Robert H., Grongsaard, Pintipa, Wallace, Grier A.
• Application Number:
  US12/218,364
• Publication Number:
  US 20090069288A1
• Time in Patent Office: Days
• US Class Current: 514/210.180
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 249/06 with aryl radicals directly attached to ring atoms
• CPC Class Codes: C07D 249/10 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 261/14 Nitrogen atoms
• CPC Class Codes: C07D 261/18 Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 273/02 having two nitrogen atoms and only one oxygen atom
• CPC Class Codes: C07D 333/36 Nitrogen atoms
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

Disclosed herein are novel compounds of Formula (I),

wherein the variables are defined as herein. The compounds of Formula (I) are useful as kinase inhibitors and as such would be useful in treating certain conditions and diseases, especially inflammatory conditions and diseases as well as proliferative disorders such as cancer.

Claims

1. A compound of Formula (I)

and pharmaceutically acceptable salts, isomers, prodrugs and biologically active metabolites thereof wherein

Y is N is or CH;

A is selected from the group consisting of optionally substituted heteroaryl, optionally

substituted heterocyclyl and

wherein

a is 0 or 1 and E, G, J, Q and M are each independently selected from the group consisting of CR_a, O, N and S provided that at least one of E, G, J, Q and M is CR_a;

no more than one of E, G, J, Q and M is O; and

no more than one of E, G, J, Q and M is S;

L¹ and L² are each independently selected from the group consisting of a bond, —

C(O)NH—

, —

NHC(O)—

, —

SO₂NH—

, —

NHSO₂—

, —

CH₂N(H)—

, —

N(H)CH₂—

, —

CH₂S— and

—

SCH₂—

, provided that either L¹ or L² is a bond but L¹ and L² are not bonds at the same time;

D is selected from the group consisting of aryl, heteroaryl, heterocyclyl and (C₃-C₉)cycloalkyl;

R¹ and R² are each independently selected from the group consisting of halogen, CF₃, CN, OH, OCF₃, optionally substituted (C₁-C₆)alkyl, —

C(O)—

O—

(C₁-C₆)alkyl, NR^aR^b, —

(CH₂)_x-optionally substituted aryl, —

(CH₂)_x-optionally substituted (C₃-C₆)cyclyl, —

(CH₂)_x-optionally substituted heteroaryl, —

(CH₂)_x-optionally substituted heterocyclyl, —

NR^a-optionally substituted (C₃-C₆)cycloalkyl, —

O-optionally substituted (C₁-C₆)alkyl, —

O-optionally substituted (C₃-C₆)cycloalkyl, —

O-heterocyclyl —

O-aryl, —

O-heteroaryl, —

NR^a-optionally substituted heteraryl, —

NR^a-optionally substituted aryl, SO₂NR^aR^b and CH₂NR^aNR provided that R¹ and R² are not both —

(CH₂)_x-optionally substituted heterocyclyl or —

(CH₂)_x-optionally substituted heteroaryl at the same time;

R^a and R^b are each independently selected from H and optionally substituted (C₁-C₆)alkyl;

R^c is independently selected from the group consisting of CF₃, CCl₃, optionally substituted (C₁-C₆)alkyl, —

C(O)-optionally substituted (C₁-C₆)alkyl, —

C(O)—

O-optionally substituted (C₁-C₆)alkyl and oxo;

m is 0, 1 or 2;

n is 0, 1 or 2;

p is 0, 1 or 2; and

x is 0, 1 or 2;

provided that the compound is not

2. The compound according to claim 1, wherein A is

3. The compound according to claim 2, wherein A is selected from the optionally substituted group consisting of furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyranyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl and 1H-[1,2,4]triazolyl.

4. The compound according to claim 3, wherein D is selected from the group consisting of benzofuranyl, indanyl, indazolyl, indolyl, 2,3-dihydro-1H-indolyl, oxadiazolyl, phenyl, pyrazolyl, pyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thienyl and

5. The compound according to claim 4, wherein R¹ and R² are independently selected from the group consisting of Br, C₁, CF₃, CN, OH, OCF₃, CH₃, —

CH(CH₃)₂, OCH₃, OCH(CH₃)₂, —

C(O)OCH₂CH₃, -optionally substituted (C₁-C₆)alkyl, —

NR^a-optionally substituted (C₁-C₆)alkyl, N(CH₃)₂, —

(CH₂)_x-optionally substituted aryl, —

(CH₂)_x-optionally substituted (C₃-C₆)cycloalkyl, —

(CH₂)_x-optionally substituted heteroaryl, morpholinyl, —

(CH₂)_x-optionally substituted azetidinyl, —

(CH₂)_x-optionally substituted pyrrolidinyl, —

(CH₂)_x-optionally substituted piperidinyl, —

NH-optionally substituted (C₃-C₆)alkyl, NH-optionally substituted (C₃-C₆)cycloalkyl, —

O-optionally substituted (C₃-C₆)cycloalkyl and —

O-tetrahydrofuranyl.

6. The compound according to claim 5, wherein A is selected from the optionally substituted group consisting of isoxazolyl, oxadiazolyl, oxazolyl, pyranyl, pyrazolyl, thienyl and 1H-[1,2,4]triazolyl.

7. The compound according to claim 6, wherein Y is CH.

8. The compound according to claim 7, wherein L¹ and L² are selected from the group consisting of a bond, —

C(O)NH—

, —

NHC(O)—

, SO₂NH— and

—

NHSO₂—

.

9. The compound according to claim 8, wherein D is selected from the group consisting of indanyl, indazolyl, phenyl, pyrazolyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and

10. The compound according to claim 9, wherein R¹ and R² are each independently selected from the group consisting of C₁, CF₃, CH₃, OCF₃, OCH₃, OCH(CH₃)₂, —

C(O)OCH₂CH₃, N(CH₃)₂, morpholinyl, —

(CH₂)-optionally substituted azetidinyl, —

(CH₂)-optionally substituted pyrrolidinyl, —

(CH₂)-optionally substituted piperidinyl, NH-optionally substituted (C₃-C₆)cycloalkyl and —

O-tetrahydrofuranyl.

11. The compound according to claim 10, wherein D is selected from the group consisting of indanyl, phenyl, pyrazolyl, tetrahydroisoquinolinyl and tetrahydroquinolinyl.

12. The compound according to claim 11, wherein A is selected from the optionally substituted group consisting of isoxazolyl, oxadiazolyl, oxazolyl, pyranyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl and 1H-[1,2,4]triazolyl.

13. The compound according to claim 12, wherein L¹ and L² are selected from the group consisting of a bond, —

C(O)NH— and

—

NHC(O)—

.

14. The compound according to claim 13, wherein R¹ and R² are each independently selected from the group consisting of Cl, CF₃, CH₃, OCF₃, OCH₃, OCH(CH₃)₂, —

C(O)OCH₂CH₃, N(CH₃)₂, —

(CH₂)-optionally substituted azetidinyl, —

(CH₂)-optionally substituted pyrrolidinyl, —

(CH₂)-optionally substituted piperidinyl, and NH-optionally substituted (C₃-C₆)cycloalkyl.

15. The compound according to claim 14, wherein A is selected from the optionally substituted group consisting of isoxazolyl, oxadiazolyl, pyranyl, pyrazolyl, thienyl and 1H-[1,2,4]triazolyl.

16. The compound according to claim 15, wherein D is selected from the group consisting of indanyl, phenyl and pyrazolyl.

17. The compound according to claim 16, wherein each R^c is independently selected from the group consisting of CF₃, CCl₃, t-butyl, —

C(O)—

OCH₂CH₃, —

C(O)—

OCH₂CH₂CH₃, and oxo.

18. The compound according to claim 17 and pharmaceutically acceptable salts thereof wherein A is selected from the optionally substituted group consisting of isoxazolyl, pyrazolyl, thienyl and 1H-[1,2,4]triazolyl.

19. The compound according to claim 18, wherein each R^c is independently selected from the group consisting of CF₃, CCl₃, —

C(O)—

OCH₂CH₃, —

C(O)—

OCH₂CH₂CH₃ and oxo.

20. A method of treating a condition in a patient comprising administering a therapeutically effective amount of a compound of claim 1 or a physiologically acceptable salt thereof to said patient, wherein said condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, sepsis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn'"'"'s disease, lupus, multiple sclerosis, juvenile chronic arthritis, Lyme arthritis, reactive arthritis, septic arthritis, spondyloarthropathy, systemic lupus erythematosus, an ocular condition, a cancer, a solid tumor, fibrosarcoma, osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, an cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), Abetalipoprotemia, Acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, alpha-1 antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti cd3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, hypersensitivity reactions, hyperkinetic movement disorders, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, aortic and peripheral aneurysms, hypothalamic-pituitary-adrenal axis evaluation, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, transplants, trauma/hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, vital encephalitis/aseptic meningitis, vital-associated hemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson'"'"'s disease, xenograft rejection of any organ or tissue, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, small bowel transplant rejection, spinal ataxia, bundle branch block, Burkitt'"'"'s lymphoma, burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chromic myelocytic leukemia, chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia, chronic salicylate intoxication, colorectal carcinoma, congestive heart failure, conjunctivitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, Dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetic ateriosclerotic disease, Diffuses Lewy body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down'"'"'s Syndrome in middle age, drug-induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, Epstein Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich'"'"'s ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallerrorden-Spatz disease, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, Asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza A, ionizing radiation exposure, iridocyclitis/uveitis/optic neuritis, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, kidney transplant rejection, legionella, leishmaniasis, lipedema, liver transplant rejection, lymphederma, malaria, malignant Lymphoma, malignant histiocytosis, malignant melanoma, meningococcemia, metabolic/idiopathic, migraine headache, mitochondrial multi-system disorder, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine-Thomas Shi-Drager and Machado-Joseph), myasthenia gravis, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodyplastic syndrome, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies, neutropenic fever, non-hodgkins lymphoma, occlusion of the abdominal aorta and its branches, occulsive arterial disorders, okt3 therapy, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic carcinoma, paraneoplastic syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, Kaposi'"'"'s sarcoma, Hodgkin'"'"'s disease, lymphoma, myeloma, leukaemia, malignant ascites, hematopoietic cancers, Crow-Fukase (POEMS) syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), a diabetic condition such as insulin-dependent diabetes mellitus glaucoma, diabetic retinopathy or microangiopathy, sickle cell anaemia, chronic inflammation, synovitis, glomerulonephritis, graft rejection, Lyme disease, von Hippel Lindau disease, pemphigoid, Paget'"'"'s disease, fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma or edema following burns, trauma, radiation, stroke, hypoxia, ischemia, ovarian hyperstimulation syndrome, post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, menometrorrhagia, endometriosis, pulmonary hypertension, infantile hemangioma, or infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa or toxoplasmosis, Progressive supranucleo Palsy, primary pulmonary hypertension, radiation therapy, Raynaud'"'"'s phenomenon and disease, Refsum'"'"'s disease, regular narrow QRS tachycardia, renovascular hypertension, restrictive cardiomyopathy, sarcoma, senile chorea, Senile Dementia of Lewy body type, shock, skin allograft, skin changes syndrome, ocular or macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser treatment complications, conjunctivitis, Stargardt'"'"'s disease, Eales disease, retinopathy, macular degeneration, restenosis, ischemia/reperfusion injury, ischemic stroke, vascular occlusion, carotid obstructive disease, ulcerative colitis, inflammatory bowel disease, diabetes, diabetes mellitus, insulin dependent diabetes mellitus, allergic diseases, dermatitis scleroderma, graft versus host disease, organ transplant rejection (including but not limited to bone marrow and solid organ rejection), acute or chronic immune disease associated with organ transplantation, sarcoidosis, disseminated intravascular coagulation, Kawasaki'"'"'s disease, nephrotic syndrome, chronic fatigue syndrome, Wegener'"'"'s granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington'"'"'s chorea, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, Addison'"'"'s disease, idiopathic Addison'"'"'s disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type II, Schmidt'"'"'s syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia greata, seronegative arthopathy, arthropathy, Reiter'"'"'s disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, peripheral vascular disorders, peritonitis, pernicious anemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Disease Syndrome, Acquired Immunodeficiency Related Diseases, Hepatitis A, Hepatitis B, Hepatitis C, His bundle arrythmias, HIV infection/HIV neuropathy, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, chronic wound healing, cryptogenic fibrosing alveolitis, post-inflammatory interstitial lung disease, interstitial pneumonitis, pneumocystis carinii pneumonia, pneumonia, connective tissue disease associated interstitial lung disease, mixed connective tissue disease, associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polymyositis associated lung disease, Sjö

gren'"'"'s disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasulitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, acute and chronic pain (different forms of pain), Goodpasture'"'"'s syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still'"'"'s disease, systemic sclerosis, Sjö

gren'"'"'s syndrome, Takayasu'"'"'s disease/arteritis, autoimmune thrombocytopaenia, toxicity, transplants, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto'"'"'s disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo, acute liver disease, chronic liver diseases, alcoholic cirrhosis, alcohol-induced liver injury, choleosatatis, idiosyncratic liver disease, Drug-Induced hepatitis, Non-alcoholic Steatohepatitis, allergy and asthma, group B streptococci infection, mental disorders (e.g., depression and schizophrenia), Th2 Type and Th1 Type mediated diseases, and diseases involving inappropriate vascularization, e.g., diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings. In addition, such compounds may be useful in the treatment of disorders such as ascites, effusions, and exudates, including, e.g., macular edema, cerebral edema, acute lung injury, adult respiratory distress syndrome, proliferative disorders such as restenosis, fibrotic disorders such as hepatic cirrhosis and atherosclerosis, mesangial cell proliferative disorders such as diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, and glomerulopathies, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, ischemia/reperfusion injury, peptic ulcer Helicobacter related diseases, virally-induced angiogenic disorders, preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, acute idiopathic polyneuritis, acuter or chronic immune disease associated with organ transplantation, acute inflammatory demyelinating polyradiculoneuropathy, acute ischemia, adult Still'"'"'s disease, allergy, anaphylaxis, anti-phospholipid antibody syndrome, aplastic anemia, atopic eczema, atopic dermatitis, autoimmune dermatitis, autoimmune diabetes, autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hepatitis, autoimmune hearing loss, autoimmune lymphoproliferative syndrome, autoimmune myocarditis, autoimmune neutropenia, autoimmune premature ovarian failure, autoimmune thrombocytopenia, autoimmune uveitis, Behcet'"'"'s disease, blepharitis, bronchiectasis, bullous pemphigoid, catastrophic antiphospholipid syndrome, celiac disease, cervical spondylosis, chronic ischemia, cicatricial pemphigoid, clinical isolated syndrome with risk for multiple sclerosis, childhood onset psychiatric disorder, dacrocystitis, dermatomyositis, disc herniation, disc prolapse, drug induced immune hemolytic anemia, endophthalmitis, episcleritis, erythema multiforme, erythema multiforme major, gestational pemphigoid, Guillain-Barre syndrome, heart failure, Hughes syndrome, idiopathic Parkinson'"'"'s disease, idiopathic interstitial pneumonia, IgE-mediated allergy, immune hemolytic anemia, inclusion body myositis, infectious ocular inflammatory disease, inflammatory demyelinating disease, inflammatory heart disease, inflammatory kidney disease, IPF/UIP, iritis, keratitis, keratojuntivitis sicca, Kussmaul disease or Kussmaul-Meier disease, Landry'"'"'s paralysis, Langerhan'"'"'s cell hisiocytosis, livedo reticularis, microscopic polyangiitis, morbus bechterev, motor neuron disorders, mucous membrane pemphigoid, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, relapsing remitting multiple sclerosis, multiple organ failure, myelodysplastic syndrome, nerve root disorder, neuropathy, Non-A Non-B hepatitis, osteolysis, ovarian cancer, pauciarticular JRA, peripheral artery occlusive disease (PAOD), periphral vascular disease (PVD), peripheral artery disease, phlebitis, polychondritis, polymyalgia rheumatica, poliosis, polyarticular JRA, polyendocrine deficiency syndrome, polymyositis, post-pump syndrome, primary parkinsonism, prostatitis, psoratic arthropathy, pure red cell aplasia, primary adrenal insufficiency, Reiter'"'"'s disease, recurrent neuromyelitis optica, rheumatic heart disease, SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis), scleroderma, secondary amyloidosis, shock lung, sciatica, secondary adrenal insufficiency, septic arthritis, seronegative arthopathy, silicone associated connective tissue disease, Sneddon-Wilkinson Dermatosis, spondilitis ankylosans, Stevens-Johnson Syndrome, systemic inflammatory response syndrome, temporal arteritis, toxoplasmic retinitis, toxic epidermal necrolysis, TRAPS (Tumor Necrosis factor receptor), type 1 allergic reaction, type II diabetes, urticaria, usual interstitial pneumonia, vernal conjunctivitis, viral retinitis, Vogt-Koyanagi-Harada syndrome (VKH syndrome) and wet macular degeneration.