WO2019090082A1 – May 9, 2019 – MODULATORS OF THE INTEGRATED STRESS PATHWAY

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Inventors :

MARTIN, Kathleen Ann - 3450 Sacramento Street, San Francisco, CA 94118; SIDRAUSKI, Carmela - 20434 Walnut Ave, Saratoga, CA 95070; FROST, Jennifer M. - 635 Yorktown Lane, Gurnee, IL 60031; TONG, Yunsong - 1408 Braxton Road, Libertyville, IL 60048; XU, Xiangdong - 4 River Oaks Circle West, Buffalo Grove, IL 60089; XIONG, Zhaoming - 37 River Oaks Circle East, Buffalo Grove, IL 60089; DART, Michael J. - 844 Yale Lane, Highland Park, IL 60035

Owner :

CALICO LIFE SCIENCES LLC ABBVIE INC.

Application Number :

WOUS18058965

Document Number :

WO2019090082A1

Priority Date :

January 1, 1970

Filing Date :

November 2, 2018

Date of Grant/ Publication :

May 9, 2019

Class :

; C07D231 / 12; C07D233 / 64; C07D413 / 04; C07D413 / 12; C07D271 / 06; A61K31 / 4245; A61P35 / 00

Abstract

Provided herein are compounds, compositions, and methods useful for the modulation of elF2B and the integrated stress response (ISR) signaling pathway and for treating related diseases, disorders and conditions.

Claim(s)

1. A compound of Fo Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, wherein: D is a bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, or cubanyl, wherein each bridged bicyclic cycloalkyl, bridged bicyclic heterocyclyl, or cubanyl is optionally substituted on one or more available carbons with 1-4 R x ; and wherein if the bridged bicyclic heterocyclyl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted by R N1 ; L is a bond, Ci-C 6 alkylene, 2-7 membered heteroalkylene, or -0-, wherein Ci-C 6 alkylene or 2-7 membered heteroalkylene is optionally substituted with 1-5 R L1 ; R 1 is hydrogen or Ci-C 6 alkyl; W is a 5-6-membered monocyclic heteroaryl, wherein the 5-6-membered monocyclic heteroaryl is optionally substituted on one or more available carbons with 1-3 R w ; and wherein if the 5-6-membered monocyclic heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted with R N2 ; A and Z are each independently phenyl or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted on one or more available carbons with 1-5 R Y ; and wherein if the 5-6-membered heteroaryl contains a substitutable nitrogen moiety, the substitutable nitrogen may be optionally substituted with R N3 ; each R L1 is independently selected from the group consisting of Ci-C 6 alkyl, hydroxy-Ci- C 6 alkyl, halo-Ci-C 6 alkyl, amino-Ci-C 6 alkyl, cyano-Ci-C 6 alkyl, oxo, halo, cyano, -OR A , – NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , -SR E , -S(0)R D , and – S(0) 2 R D ; R N1 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-C2-C 6 alkyl, halo-C 2 -C 6 alkyl, amino-C 2 -C 6 alkyl, cyano-C 2 -C 6 alkyl, -C(0)NR B R c , -C(0)R D , -C(0)OR D , and -S(0) 2 R D ; R N2 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydro y-C2-C6 alkyl, halo-C 2 -C 6 alkyl, amino-C 2 -C 6 alkyl, cyano-C 2 -C 6 alkyl, -C(0)NR B R c , -C(0)R D , -C(0)OR D , and -S(0) 2 R D ; R N3 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-C 2 -C 6 alkyl, halo-C 2 -C 6 alkyl, amino-C 2 -C 6 alkyl, cyano-C 2 -C 6 alkyl, -C(0)NR B R c , -C(0)R D , -C(0)OR D , and -S(0) 2 R D ; R w is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alky, oxo, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, – C(0)OR D , -S(R F ) m , -S(0)R D , and -S(0) 2 R D ; each R x is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, amino-Ci-C6 alkyl, cyano-Ci-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , -SR E , -S(0)R D , and -S(0) 2 R D ; each R Y is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, hydroxy-Ci-C6 alkyl, halo-Ci-C6 alkyl, halo-Ci-C6 alkoxy, amino-Ci-C6 alkyl, cyano-Ci-C6 alky, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, – C(0)OR D , -S(R F ) m , -S(0)R D , -S(0) 2 R D , and G 1 ; or 2 R Y groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, fused aryl, or 5-6 membered fused heteroaryl, each of which is optionally substituted with 1-5 R x ; each G 1 is independently 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-3 R z ; each R z is independently selected from the group consisting of Ci-C 6 alkyl, hydroxy-Ci- C 6 alkyl, halo-Ci-C 6 alkyl, halo, cyano, -OR A , -NR B R C ,— NR B C(0)R D , -C(0)NR B R c , -C(0)R D , -C(0)OH, -C(0)OR D , and -S(0) 2 R D ; R A is, at each occurrence, independently hydrogen, Ci-C 6 alkyl, halo-Ci-C 6 alkyl, – C(0)NR B R c , -C(0)R D , or -C(0)OR D ; each of R B and R c is independently hydrogen or C i -C 6 alkyl ; or R B and R c together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1-3 R z ; each R D is independently Ci-C 6 alkyl or halo-Ci-C 6 alkyl; each R E is independently hydrogen, Ci-C 6 alkyl, or halo-Ci-C 6 alkyl; each R F is independently hydrogen, Ci-C 6 alkyl, or halo; and m is 1 when R F is hydrogen or Ci-C 6 alkyl, 3 when R F is Ci-C 6 alkyl, or 5 when R F is halo.;
2. The compound of claim 1, wherein D is a bridged bicyclic cycloalkyl or a bridged bicyclic heterocyclyl, each optionally substituted with 1-4 R x .;
3. The compound of any one of claims 1-2, wherein D is a bridged bicyclic 5-8 membered cycloalkyl or a bridged bicyclic 5-8 membered heterocyclyl, each optionally substituted with 1-4 R x;
4. The compound of any one of claims 1-3, wherein D is bicyclo[l.l.l]pentane, bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, or 2- azabicyclo[2.2.2]octane, each of which is optionally substituted with 1-4 R x groups. The compound of any one of claims 1-4, wherein D;
7. The compound of any one of claims 1-6, wherein D is substituted with 0 R .;
8. The compound of any one of claims 1-7, wherein D is;
9. The compound of any one of claims 1-6, wherein D is substituted with 1 or 2 R A .;
11. The compound of any one of claims 9-10, wherein each R is independently selected from the group consisting of oxo, -OH, -C(0)OH, -C(0)OR D , halo, and hydroxy-Ci-C 6 alkyl.;
12. The compound of any one of claims 1-11, wherein L 1 is a bond, 2-7 membered heteroalkylene or -0-, wherein 2-7 membered heteroalkylene is optionally substituted by 1-5;
13. The compound of any one of claims 1-12, wherein L 1 is a bond, 2-7 membered heteroalkylene or -0-, wherein 2-7 membered heteroalkylene is substituted by 0 R L1 .;
14. The compound of any one of claims 1-13, wherein L 1 is selected from a bond, -CH 2 O-*, -CH 2 OCH 2 -*, or -0-, wherein “-*” indicates the attachment point to A.;
15. The compound of any one of claims 1-14, wherein R 1 is hydrogen or C¾.;
16. The compound of any one of claims 1-15, wherein each of A and Z is independently phenyl or 5-6-membered heteroaryl; wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 R Y , and each R Y is independently Ci-C 6 alkyl, halo-Ci-C6 alkyl, halo, cyano, -OR A , or G 1 .;
17. The compound of any one of claims 1- 16, wherein each of A and Z is independently phenyl, pyridyl, isoxazolyl, pyrimidinyl, or pyrazolyl, each of which is optionally substituted with 1-5 R Y groups.;
18. The compound of any one of claims 1- 17, wherein each of A and Z is selected from the roup consisting of:;
19. The compound of any one of claims 1- 18, wherein A is phenyl, pyridyl, pyrimidinyl, or isoxazolyl, each of which is optionally substituted with 1-2 R Y groups.;
20. The compound of any one of claims 1- 19, wherein A is selected from the group consistin of:;
21. The compound of any one of claims 1-20, wherein Z is phenyl, pyridyl, isoxazolyl, pyrimidinyl, or pyrazolyl, each of which is optionally substituted with 1-3 R Y groups.;
22. The compound of any one of claims 1-21, wherein Z is selected from the group consisting of: wherein R is hydrogen or CH 3 .;
23. The compound of any one of claims 1-22, wherein each R Y is independently hydrogen, chloro, fluoro, CF 3 , CHF 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH(CH 3 ) 2 , or CN.;
claim 21: 24. The compound of any one of claims 1-23, wherein W is an oxadiazole, pyrrole, imidazole, pyrazole, triazole, or oxazole moiety, each of which is optionally substituted with 1-3 R w groups, and each R w is independently Ci-C 6 alkyl, halo-Ci-C6 alkyl, halo, cyano, or -OR A .;
claim 22: 25. The compound of claim 24, wherein W is a 1,3,4-oxadiazole or 1,2,4-oxadiazole.;
claim 23: 26. The compound of claim 24, wherein W is a 1,2,4-triazole. 27. The compound of any one of claims 1-26, wherein W is selected from the group consistin of: wherein each R is independently selected from the group consisting of hydrogen, chloro, fluoro, CF 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , and CN, and wherein R N2 is hydrogen or CH 3 . The compound of any one of claims 1-27, wherein W is selected from the group;
claim 24: 29. The compound of any one of claims 1-28, wherein the compound of Formula (I) is a compound of Formula (I-a): Formula (I-a) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, wherein: D is bicyclo[l. l.l]pentanyl or bicyclo[2.2.2]octanyl, each of which is optionally substituted with 1-4 R x groups; L 1 is CH 2 O-*, CH 2 OCH 2 -*, or -0-, wherein “-*” indicates the attachment point to A;
W is an oxadiazole, pyrrole, imidazole, pyrazole, triazole, or oxazole moiety, each of which is optionally substituted on one or more available carbons with 1-3 R w groups; and wherein imidazole and triazole may be optionally substituted on an available nitrogen with hydrogen or CH 3 ; A is phenyl, isoxazolyl, or pyridyl, each of which is optionally substituted with 1-5 R Y groups; Z is phenyl, pyridyl, isoxazolyl, pyrmidinyl, or pyrazolyl, each of which is optionally substituted on one or more available carbons with 1-5 R Y groups; and wherein pyrazolyl may be optionally substituted on an available nitrogen with hydrogen or CH 3 ; each R w is independently chloro, fluoro, CF 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , or CN; each R x is independently fluoro, oxo, OH, OCH 3 , C(0)OH, or C(0)OCH 3 ; each R Y is independently chloro, fluoro, CF 3 , CHF 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH(CH 3 ) 2 , or CN; or 2 R Y groups on adjacent atoms, together with the atoms to which they are attached form a furanyl, pyrrolyl, or dioxolanyl ring, each of which is optionally substituted with 1-2 R x ; and R 1 is hydrogen.;
claim 25: 30. The compound of any one of claims 1-29, wherein the compound of Formula (I) is a compound of Formula (I-b): Formula (I-b) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 26: 31. The compound of any one of claims 1-30, wherein the compound of Formula (I) is a compound of Formula (I-c): Formula (I-c) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 27: 32. The compound of any one of claims 1-31, wherein the compound of Formula (I) is a compound of Formula (I-d): Formula (I-d) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 28: 33. The compound of any one of claims 1-32, wherein the compound of Formula (I) is a compound of Formula (I-e-1), Formula (I-e-2), Formula (I-e-3), Formula (I-e-4), Formula (I-e- 5), Formula (I-e-6), Formula (I-e-7), Formula (I-e-8), or Formula (I-e-9): Formula (I-e-1) Formula (I-e-2) Formula (I-e-4) Formula (I-e-5) Formula (I-e-6) Formula (I-e-7) Formula (I-e-8) Formula (I-e-9) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 29: 34. The compound of any one of claims 1-29, wherein the compound of Formula (I) is a compound of Formula (I-f): Formula (I-f) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 30: 35. The compound of any one of claims 1-29 and 34, wherein the compound of Formula (I) is a compound of Formula (I-g): Formula (I-g) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 31: 36. The compound of any one of claims 1-29 and 34-35, wherein the compound of Formula (I) is a compound of Formula (I-h) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof, wherein each of W, Z, and R Y is defined as for Formula (I).;
claim 32: 37. The compound of any one of claims 1-29 and 34-36, wherein the compound of Formula (I) is a compound of Formula (I-i-1), Formula (I-i-2), Formula (I-i-3), Formula (I-i-4), Formula (I-i-5), Formula (I-i-6), -9): Formula (I-i-1) Formula (I-i-2) Formula (I-i-3) Formula (I-i-4) Formula (I-i-5) Formula (I-i-6) Formula (I-i-7) Formula (I-i-8) Formula (I-i-9) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, N-oxide, or stereoisomer thereof.;
claim 33: 38. The compound of any one of claims 1-37, wherein the compound is selected from any compound set forth in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer, or stereoisomer thereof.;
claim 34: 39. A pharmaceutically acceptable composition comprising a compound of any one of claims 1-38 and a pharmaceutically acceptable carrier.;
claim 35: 40. A composition for use in treating a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss condition, an ocular disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease in a subject, wherein the composition comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or N-oxide, stereoisomer thereof as described in any one of claims 1-38.;
claim 36: 41. The composition of claim 40, wherein the neurodegenerative disease comprises a leukodystrophy, a leukoencephalopathy, a hypomyelinating or demyelinating disease, an intellectual disability syndrome, a cognitive impairment, a glial cell dysfunction, or a brain injury.;
claim 37: 42. The composition of any one of claims 40 or 41, wherein the neurodegenerative disease comprises vanishing white matter disease, childhood ataxia with CNS hypo myelination, Alzheimer’s disease, amyotrophic lateral sclerosis, Creutzfeldt- Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker disease, Huntington’s disease, dementia, kuru, multiple sclerosis, Parkinson’s disease, or a prion disease.;
claim 38: 43. The composition of any one of claims 40-42, wherein the neurodegenerative disease comprises vanishing white matter disease.;
claim 39: 44. The composition of claim 40, wherein the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or a cancer of the secretory cells.;
claim 40: 45. The composition of claim 40, wherein the inflammatory disease comprises postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes, Guillain- Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren’s syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet’s disease, Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves’ ophthalmopathy, inflammatory bowel disease, Addison’s disease, vitiligo, asthma, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis. 46. The composition of claim 40, wherein the musculoskeletal disease comprises muscular dystrophy, multiple sclerosis, amyotropic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, spinal cord spasticity, spinal muscle atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, cramp fasciculation syndrome, Freidrich’s ataxia, a muscle wasting disorder, an inclusion body myopathy, motor neuron disease, or paralysis.;
claim 41: 47. The composition of claim 40, wherein the metabolic disease comprises non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.;
claim 42: 48. The composition of claim 40, wherein the mitochondrial disease is associated with or is a result of mitochondrial dysfunction, one or more mitochondrial protein mutations, or one or more mitochondrial DN A mutations.;
claim 43: 49. The composition of claim 40 or 48, wherein the mitochondrial disease is a mitochondrial myopathy. 50. The composition of any one of claims 40 and 48-49, wherein the mitochondrial disease is selected from the group consisting of Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS, or maternally inherited Leigh syndrome), mitochondrial DNA depletion syndromes (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonus epilepsy with ragged red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber’s hereditary optic neuropathy (LHON), and Pearson syndrome.;
claim 44: 51. The composition of claim 40, wherein the autoimmune disease is selected from the group consisting of Achalasia, Addison’s disease, Adult Still’s disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalomyelitis, Autoimmune hepatitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Balo disease, Behcet’s disease, Benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan’s syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn’s disease, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressier’ s syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with Polyangiitis, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), Hypogammaglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert- Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere’s disease, Microscopic polyangiitis (MP A), Mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neonatal Lupus, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndrome type I, Polyglandular syndrome type II, Polyglandular syndrome type III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud’s phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren’s syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac’s syndrome, Sympathetic ophthalmia (SO), Takayasu’s arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Vogt-Koyanagi-Harada Disease, and Wegener’s granulomatosis (or Granulomatosis with Polyangiitis (GPA)).;
claim 45: 52. The composition of claim 40, wherein the viral infection is selected from the group consisting of influenza, human immunodeficiency virus (HIV) and herpes.;
claim 46: 53. The composition of claim 40, wherein the skin disease is selected from the group consisting of acne, alopecia areata, basal cell carcinoma, Bowen’s disease, congenital erythropoietic porphyria, contact dermatitis, Darier’s disease, disseminated superficial actinic porokeratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), extra-mammary Paget’s disease, epidermolysis bullosa simplex, erythropoietic protoporphyria, fungal infections of nails, Hailey-Hailey disease, herpes simplex, hidradenitis suppurativa, hirsutism, hyperhidrosis, ichthyosis, impetigo, keloids, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, melasma, mucous membrane pemphigoid, pemphigoid, pemphigus vulgaris, pityriasis lichenoides, pityriasis rubra pilaris, plantar warts (verrucas), polymorphic light eruption, psoriasis, plaque psoriasis, pyoderma gangrenosum, rosacea, scabies, scleroderma, shingles, squamous cell carcinoma, sweet’s syndrome, urticaria and angioedema and vitiligo.;
claim 47: 54. The composition of claim 40, wherein the fibrotic disease is selected from the group consisting of adhesive capsulitis, arterial stiffness, arthrofibrosis, atrial fibrosis, cardiac fibrosis, cirrhosis, congenital hepatic fibrosis, Crohn’s disease, cystic fibrosis, Dupuytren’s contracture, endomyocardial fibrosis, glial scar, hepatitis C, hypertrophic cardiomyopathy, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, interstitial lung disease, keloid, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, non-alcoholic fatty liver disease, old myocardial infarction, Peyronie’s disease, pneumoconiosis, pneumonitis, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, scleroderma/systemic sclerosis, silicosis and ventricular remodeling. 55. The composition of claim 40, wherein the hemoglobin disease is selected from the group consisting of “dominant” ?-thalassemia, acquired (toxic) methemoglobinemia, carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS/?- thalassemia, HbE^-thalassemia, HbSC disease, homozygous a + -thalassemia (phenotype of a°- thalassemia), Hydrops fetalis with Hb Bart’s, sickle cell anemia/disease, sickle cell trait, sickle ?- thalassemia disease, a + -thalassemia, a°-thalassemia, a-Thalassemia associated with myelodysplastic syndromes, a-Thalassemia with mental retardation syndrome (ATR), ?°- Thalassemia, + -Thalassemia, ?-Thalassemia, ?-Thalassemia, ?-Thalassemia major, ?- Thalassemia intermedia, ??-Thalassemia, and ???? -Thalassemia.;
claim 48: 56. The composition of claim 40, wherein the kidney disease is selected from the group consisting of Abderhalden-Kaufmann-Lignac syndrome (Nephropathic Cystinosis), Abdominal Compartment Syndrome, Acetaminophen-induced Nephrotoxicity, Acute Kidney Failure/ Acute Kidney Injury, Acute Lobar Nephroma, Acute Phosphate Nephropathy, Acute Tubular Necrosis, Adenine Phosphoribosyltransferase Deficiency, Adenovirus Nephritis, Alagille Syndrome, Alport Syndrome, Amyloidosis, ANCA Vasculitis Related to Endocarditis and Other Infections, Angiomyolipoma, Analgesic Nephropathy, Anorexia Nervosa and Kidney Disease, Angiotensin Antibodies and Focal Segmental Glomerulosclerosis, Antiphospholipid Syndrome, Anti-TNF-a Therapy-related Glomerulonephritis, APOL1 Mutations, Apparent Mineralocorticoid Excess Syndrome, Aristolochic Acid Nephropathy, Chinese Herbal Nephropathy, Balkan Endemic Nephropathy, Arteriovenous Malformations and Fistulas of the Urologic Tract, Autosomal Dominant Hypocalcemia, Bardet-Biedl Syndrome, Bartter Syndrome, Bath Salts and Acute Kidney Injury, Beer Potomania, Beeturia, ?-Thalassemia Renal Disease, Bile Cast Nephropathy, BK Polyoma Virus Nephropathy in the Native Kidney, Bladder Rupture, Bladder Sphincter Dyssynergia, Bladder Tamponade, Border-Crossers’ Nephropathy, Bourbon Virus and Acute Kidney Injury, Burnt Sugarcane Harvesting and Acute Renal Dysfunction, Byetta and Renal Failure, Clq Nephropathy, C3 Glomerulopathy, C3 Glomerulopathy with Monoclonal Gammopathy, C4 Glomerulopathy, Calcineurin Inhibitor Nephrotoxicity, Callilepsis Laureola Poisoning, Cannabinoid Hyperemesis Acute Renal Failure, Cardiorenal syndrome, Carfilzomib- Induced Renal Injury, CFHR5 nephropathy, Charcot-Marie-Tooth Disease with Glomerulopathy, Chinese Herbal Medicines and Nephrotoxicity, Cherry Concentrate and Acute Kidney Injury, Cholesterol Emboli, Churg-Strauss syndrome, Chyluria, Ciliopathy, Cocaine and the Kidney, Cold Diuresis, Colistin Nephrotoxicity, Collagenofibrotic Glomerulopathy, Collapsing Glomerulopathy, Collapsing Glomerulopathy Related to CMV, Combination Antiretroviral (cART) Related-Nephropathy, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), Congenital Nephrotic Syndrome, Congestive Renal Failure, Conorenal syndrome (Mainzer-Saldino Syndrome or Saldino-Mainzer Disease), Contrast Nephropathy, Copper Sulphate Intoxication, Cortical Necrosis, Crizotinib-related Acute Kidney Injury, Cryocrystalglobulinemia, Cryoglobuinemia, Crystalglobulin-Induced Nephropathy, Crystal- Induced Acute Kidney injury, Crystal-Storing Histiocytosis, Cystic Kidney Disease, Acquired, Cystinuria, Dasatinib-Induced Nephrotic-Range Proteinuria, Dense Deposit Disease (MPGN Type 2), Dent Disease (X-linked Recessive Nephrolithiasis), DHA Crystalline Nephropathy, Dialysis Disequilibrium Syndrome, Diabetes and Diabetic Kidney Disease, Diabetes Insipidus, Dietary Supplements and Renal Failure, Diffuse Mesangial Sclerosis, Diuresis, Djenkol Bean Poisoning (Djenkolism), Down Syndrome and Kidney Disease, Drugs of Abuse and Kidney Disease, Duplicated Ureter, EAST syndrome, Ebola and the Kidney, Ectopic Kidney, Ectopic Ureter, Edema, Swelling, Erdheim-Chester Disease, Fabry’s Disease, Familial Hypocalciuric Hypercalcemia, Fanconi Syndrome, Fraser syndrome, Fibronectin Glomerulopathy, Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy, Fraley syndrome, Fluid Overload, Hypervolemia, Focal Segmental Glomerulosclerosis, Focal Sclerosis, Focal Glomerulosclerosis, Galloway Mowat syndrome, Giant Cell (Temporal) Arteritis with Kidney Involvement, Gestational Hypertension, Gitelman Syndrome, Glomerular Diseases, Glomerular Tubular Reflux, Glycosuria, Goodpasture Syndrome, Green Smoothie Cleanse Nephropathy, HANAC Syndrome, Harvoni (Ledipasvir with Sofosbuvir)-Induced Renal Injury, Hair Dye Ingestion and Acute Kidney Injury, Hantavirus Infection Podocytopathy, Heat Stress Nephropathy, Hematuria (Blood in Urine), Hemolytic Uremic Syndrome (HUS), Atypical Hemolytic Uremic Syndrome (aHUS), Hemophagocytic Syndrome, Hemorrhagic Cystitis, Hemorrhagic Fever with Renal Syndrome (HFRS, Hantavirus Renal Disease, Korean Hemorrhagic Fever, Epidemic Hemorrhagic Fever, Nephropathis Epidemica), Hemosiderinuria, Hemosiderosis related to Paroxysmal Nocturnal Hemoglobinuria and Hemolytic Anemia, Hepatic Glomerulopathy, Hepatic Veno- Occlusive Disease, Sinusoidal Obstruction Syndrome, Hepatitis C-Associated Renal Disease, Hepatocyte Nuclear Factor ??-Associated Kidney Disease, Hepatorenal Syndrome, Herbal Supplements and Kidney Disease, High Altitude Renal Syndrome, High Blood Pressure and Kidney Disease, HIV- Associated Immune Complex Kidney Disease (HIVICK), HIV- Associated Nephropathy (HIVAN), HNFlB-related Autosomal Dominant Tubulointerstitial Kidney Disease, Horseshoe Kidney (Renal Fusion), Hunner’s Ulcer, Hydroxychloroquine-induced Renal Phospholipidosis, Hyperaldosteronism, Hypercalcemia, Hyperkalemia, Hypermagnesemia, Hypernatremia, Hyperoxaluria, Hyperphosphatemia, Hypocalcemia, Hypocomplementemic Urticarial Vasculitic Syndrome, Hypokalemia, Hypokalemia-induced renal dysfunction, Hypokalemic Periodic Paralysis, Hypomagnesemia, Hyponatremia, Hypophosphatemia, Hypophosphatemia in Users of Cannabis, Hypertension, Hypertension, Monogenic, Iced Tea Nephropathy, Ifosfamide Nephrotoxicity, IgA Nephropathy, IgG4 Nephropathy, Immersion Diuresis, Immune-Checkpoint Therapy-Related Interstitial Nephritis, Infliximab-Related Renal Disease, Interstitial Cystitis, Painful Bladder Syndrome (Questionnaire), Interstitial Nephritis, Interstitial Nephritis, Karyomegalic, Ivemark’s syndrome, JC Virus Nephropathy, Joubert Syndrome, Ketamine- Associated Bladder Dysfunction, Kidney Stones, Nephrolithiasis, Kombucha Tea Toxicity, Lead Nephropathy and Lead-Related Nephrotoxicity, Lecithin Cholesterol Acyltransferase Deficiency (LCAT Deficiency), Leptospirosis Renal Disease, Light Chain Deposition Disease, Monoclonal Immunoglobulin Deposition Disease, Light Chain Proximal Tubulopathy, Liddle Syndrome, Lightwood- Albright Syndrome, Lipoprotein Glomerulopathy, Lithium Nephrotoxicity, LMX1B Mutations Cause Hereditary FSGS, Loin Pain Hematuria, Lupus, Systemic Lupus Erythematosis, Lupus Kidney Disease, Lupus Nephritis, Lupus Nephritis with Antineutrophil Cytoplasmic Antibody Seropositivity, Lupus Podocytopathy, Lyme Disease- Associated Glomerulonephritis, Lysinuric Protein Intolerance, Lysozyme Nephropathy, Malarial Nephropathy, Malignancy- Associated Renal Disease, Malignant Hypertension, Malakoplakia, McKittrick-Wheelock Syndrome, MDMA (Molly; Ecstacy; 3,4-Methylenedioxymethamphetamine) and Kidney Failure, Meatal Stenosis, Medullary Cystic Kidney Disease, Urolodulin- Associated Nephropathy, Juvenile Hyperuricemic Nephropathy Type 1, Medullary Sponge Kidney, Megaureter, Melamine Toxicity and the Kidney, MELAS Syndrome, Membranoproliferative Glomerulonephritis, Membranous Nephropathy, Membranous-like Glomerulopathy with Masked IgG Kappa Deposits, MesoAmerican Nephropathy, Metabolic Acidosis, Metabolic Alkalosis, Methotrexate- related Renal Failure, Microscopic Polyangiitis, Milk-alkalai syndrome, Minimal Change Disease, Monoclonal Gammopathy of Renal Significance, Dysproteinemia, Mouthwash Toxicity, MUC1 Nephropathy, Multicystic dysplastic kidney, Multiple Myeloma, Myeloproliferative Neoplasms and Glomerulopathy, Nail-patella Syndrome, NARP Syndrome, Nephrocalcinosis, Nephrogenic Systemic Fibrosis, Nephroptosis (Floating Kidney, Renal Ptosis), Nephrotic Syndrome, Neurogenic Bladder, 9/11 and Kidney Disease, Nodular Glomerulosclerosis, Non-Gonococcal Urethritis, Nutcracker syndrome, Oligomeganephronia,

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