ALPHA-KETOAMIDES AND DERIVATIVES THEREOF

• US 20100273797A1
• Filed: 07/02/2010
• Published: 10/28/2010
• Est. Priority Date: 09/11/2003
• Status: Abandoned Application

• Current Assignee: iTherx Pharma, Inc.
• Original Assignee: iTherx Pharma, Inc.
• Inventors: Saiah, Eddine, Sullivan, Robert, Roberts, Edward, Ernst, Justin, Montalban, Antonio Garrido, Ceide, Susana Conde, Wang, Zhijun, Larson, Christopher, Nakanishi, Hiroshi, Miller, Stephen, Kahl, Jeffrey, Boman, Erik, Delaet, Nancy G. J., Dahl, Russell
• Application Number:
  US12/829,701
• Publication Number:
  US 20100273797A1
• Time in Patent Office: Days
• US Class Current: 514/236.500
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• 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 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/10 Expectorants
• 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 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• 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 19/10 : for osteoporosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• 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 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• 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 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/14 : Decongestants or antiallergics
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/08 : for leprosy
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• 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 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 : of the pancreatic 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 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: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 207/40 : 2,5-Pyrrolidine-diones
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/40 : Acylated on said nitrogen atom
• CPC Class Codes: C07D 239/47 : One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 249/12 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 253/075 : Two hetero atoms, in positions 3 and 5
• CPC Class Codes: C07D 295/088 : to an acyclic saturated chain
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides low molecular weight compounds useful as cytokine inhibitors, and compositions thereof. In particular, compounds of the invention are useful as anti-inflammatory agents. There are further provided methods for the preparation of such agents and their use in preventing or treating conditions medicated by cytokines such as arthritis.

Claims

1. A method of treating a disease mediated by cytokines which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula IA:

2. The method according to claim 1, wherein the cytokine-mediated disease is rheumatoid arthritis, osteoarthritis, Crohn'"'"'s disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter'"'"'s syndrome, gouty arthritis, Behcet'"'"'s disease, spondylitis, endometriosis, non-articular inflammatory conditions, acute or chronic pain, stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery Disease, acute coronary syndrome, Takayasu arteritis, cardiac failure, hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, atherosclerosis, allergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinal ischemia, diabetic retinopathy, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection, respiratory tract inflammation, psoriasis, eczema, atopic dermatitis, contact dermatitis, acne, Guillain-Barre syndrome, Parkinson'"'"'s disease, Huntington'"'"'s disease, Alzheimer'"'"'s disease, amyotrophic lateral sclerosis, multiple sclerosis and other demyelinating diseases, viral and bacterial meningitis, CNS trauma, spinal cord injury, seizures, convulsions, olivopontocerebellar atrophy, AIDS dementia complex, MERRF and MELAS syndromes, Leber'"'"'s disease, Wemicke'"'"'s encephalophathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett'"'"'s syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety and schizophrenia, aneurism, epilepsy, diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome, obesity, anorexia and bulimia nervosa, bone resorption diseases, osteopetrosis, osteoporosis, sepsis, HIV, HCV, malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, Castleman'"'"'s disease, stem-cell therapy targets, or drug resistance.

3. The method of claim 1, wherein the cytokine mediated disease is rheumatoid arthritis, osteoarthritis, Crohn'"'"'s disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, acute synovitis, Reiter'"'"'s syndrome, gouty arthritis, Behcet'"'"'s disease, spondylitis, endometriosis, non-articular inflammatory conditions, acute or chronic pain.

4. The method of claim 2, wherein the cytokine mediated disease is stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery Disease, acute coronary syndrome, Takayasu arteritis, cardiac failure, hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, or atherosclerosis.

5. The method of claim 2, wherein the cytokine mediated disease is rheumatoid arthritis and the compound of Formula IA is administered with one or more active ingredients A, wherein A is an NSAID, immunosuppressive drug, immunomodulatory drug, cytostatic drug, angiogenesis inhibitor, biological agent, glucocorticosteroid or inhibitor of cell adhesion molecule LFA-1 or ICAM-1.

6. The method of claim 1, wherein G is phenyl, naphthyl, cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.

7. The method of claim 1 wherein L is a covalent bond, a C₁-C₉ alkoxy, —

C(O)O—

, —

NH—

or —

O—

.

8. The method of claim 1, wherein Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl.

9. The method of claim 1, wherein each R¹ is independently C_3-10 branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C_3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, or isothiazolyl;

each of which is optionally substituted with 1 to 5 halogen, C_1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C_3-8 cycloalkyl, C_5-8 cycloalkenyl, hydroxy, cyano, C_1-3 alkoxy which is optionally partially or fully halogenated and NH₂C(O) or mono- or di-(C_1-3 alkyl)aminocarbonyl.

10. The method of claim 1, wherein each R¹ is independently C_3-10 branched or unbranched alkyl.

11. The method of claim 1, wherein each R² is independently —

OR′

, —

OR⁶, —

C(O)R′

, —

C(O)OR′

, —

C(O)NR′

₂, —

NR′

₂, —

NO₂, —

S(O)_mR″

, —

NR′

—

SO₂R″

, —

NR′

C(O)NR′

R′

, —

NR′

C(S)NR′

R′

, —

NR′

C(O)OR′

or —

SO₂NR′

₂.

12. The method of claim 1, wherein R³ is phenyl, pyridazinyl or pyridyl, each of which is optionally partially or fully halogenated and optionally substituted with C_1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, hydroxy, oxo, cyano, C_1-3 alkoxy optionally partially or fully halogenated, nitro, amino, or mono- or di-(C_1-3 alkyl)amino;

C_1-6 alkyl or C_1-6 alkoxy, each optionally partially or fully halogenated or optionally substituted with R¹⁷, amino, OR¹⁸, C_1-5 mono- or di-alkylamino optionally substituted with R¹⁹;

R²⁰C(O)N(R²¹)—

, R²²O—

, R²³R²⁴NC(O)—

, R²⁶(CH₂)_mC(O)N(R²¹)—

or R²⁶C(O)(CH₂)_mN(R²¹)—

.

13. The method of claim 1, wherein X is C═

O.

14. The method of claim 1, wherein Ar is —

(Y)-naphthyl-, Y is —

C(O)—

, or —

C(═

NOH)— and

G is phenyl or pyridyl.

15. The method of claim 14, wherein each R¹ is independently a substituted or unsubstituted straight or branched C_1-10 alkyl.

16. The method of claim 15, wherein each R³ is independently R²³R²⁴N—

C(O)—

, R²⁰—

C(O)—

NR²¹—

, or OR²².

17. The method of claim 16, wherein each R² is independently —

NR′

SO₂R″

, —

Cl, —

Br, —

F, —

C(O)—

NR′

₂ substituted or unsubstituted straight or branched C_1-6 alkyl, —

NR′

₂, or —

OR′

.

18. The method of claim 1, wherein Ar is —

(Y)-naphthyl-, Y is —

C(O)—

, or —

C(═

NOH)—

, and G is pyrazolyl, thienyl or isoxazolyl.

19. The method of claim 18, wherein each R¹ is independently a substituted or unsubstituted straight or branched C_1-10 alkyl.

20. The method of claim 19, wherein each R³ is independently phenyl or pyridinyl, optionally substituted with one, two, or three —

F, —

Cl, substituted or unsubstituted C_1-6 branched or unbranched alkyl or substituted or unsubstituted C_1-4 alkoxy.