CA2822842C – June 4, 2019 – FAAH INHIBITORS

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Inventors :

HUDSON, COLLEEN; BARDEN, TIMOTHY C.; JIA, JAMES; MERMERIAN, ARA; PENG, BO; YANG, JANE; YU, XIANG, Y.; SPROTT, KEVIN; FRETZEN, ANGELIKA

Owner :

IRONWOOD PHARMACEUTICALS, INC.

Application Number :

CA2822842

Document Number :

CA2822842C

Priority Date :

January 1, 1970

Filing Date :

December 22, 2011

Date of Grant/ Publication :

June 4, 2019

Class :

; C07D401 / 12; A61K31 / 404; A61P25 / 04; C07D401 / 14; C07D403 / 12; C07D403 / 14; C07D471 / 04

Abstract

The present disclosure relates to compounds useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH). The disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment or prevention of various disorders. Compounds of the invention are described in Table 1.

Claim(s)

A compound selected from Table 1, or a pharmaceutically acceptable salt thereof; (Table 1) Structure Compound Number 0Me roP a V- OMe O HN-Qü Vi OMe nnNJ o YA 0Me u . / ° ~Q-a Vi OMe “rtv° X/’OMe yrQ F O vi>- F A compound of Table 1 selected from the group consisting of compound numbers 30, 31, 32, 33, 34, 40, 41, 43, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 75, 77, 79, 85, 87, 88, 90, 94, 95, 96, 97, 98, 99, 100, and 101. A compound of Table 1 selected from the group consisting of compound numbers;
4. A compound of Table 1 selected from the group consisting of compound numbers 13,;
5. A compound of Table 1 selected from the group consisting of compound numbers 13, 28, 29, 32, 34, 40, 41, 43, 60, 61, 77, 79, 81, 82, 84, 87, and;
6. A compound of Table 1 selected from the group consisting of compound numbers 29, 34,41,77, 79, 81, 82, and 87.;
7. A compound of Table 1 selected from the group consisting of compound numbers 34, 41,77, 79, 81, 82, and 87.;
8. A pharmaceutical composition comprising a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or adjuvant.;
9. The pharmaceutical composition of claim 8, further comprising at least one additional therapeutic agent.;
10. The pharmaceutical composition of claim 9, wherein the additional therapeutic agent is chosen from the group consisting of painkillers, non-steroidal anti-inflammatory drugs (NSAIDs), cannabinoid receptor agonists, opiate receptor agonists, anti-infective agents, sodium channel blockers, N-type calcium channel blockers, local anesthetics, VR1 agonists and antagonists, agents used for migraines, topical agents used in the treatment of localized pruritus, anti-inflammatory and/or immunosuppressive agents, agents designed to treat tobacco abuse (e.g., nicotine receptor partial agonists and nicotine replacement therapies), ADD/ ADHD agents, agents to treat alcoholism such as opioid antagonists, agents for reducing alcohol withdrawal symptoms such as benzodiazepines and beta-blockers, antihypertensive agents such as ACE inhibitors and Angiotensin II Receptor blockers, Renin inhibitors, vasodilators, agents used to treat glaucoma such as direct-acting Miotics (cholinergic agonists), indirect-acting Miotics (cholinesterase inhibitors) or Carbonic anhydrase inhibitors, selective adrenergic agonists, Osmotic diuretics, antidepressants such as SSRIs, tricyclic antidepressants, dopaminergic antidepressants, cognitive improvement agents, acetylcholinesterase inhibitors, anti-emetic agents (e.g., 5HT3 antagonists), neuroprotective agents, neuroprotective agents currently under investigation, antipsychotic medications, agents used for multiple sclerosis, disease-modifying anti-rheumatic drugs (DMARDS), biological response modifiers (BRMs), COX-2 selective inhibitors, COX-1 inhibitors, immunosuppressives, PDE4 inhibitors, corticosteroids, histamine HI receptor antagonists, histamine H2 receptor antagonists, proton pump inhibitors, leukotriene antagonists, 5-lipoxygenase inhibitors, nicotinic acetylcholine receptor agonists, P2X3 receptor antagonists, NGF agonists and antagonists, NK1 and NK2 antagonists, NMDA antagonist, potassium channel modulators, GABA modulators, anti-cancer agents such as tyrosine kinase inhibitors, anti-hyperlipidemia drugs, appetite suppressing agents, antidiabetic medications such as insulin, GI (gastrointestinal) agents, and serotonergic and noradrenergic modulators.;
11. A method for the treatment or prevention of pain comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1 -7 or pharmaceutical composition according to any one of claims 8-10.;
12. The method according to claim 11, wherein the pain is chronic pain, acute pain, perioperative pain (e.g., associated with surgery), postoperative pain (e.g., associated with orthopedic surgery, gynecological surgery, abdominal surgery, incisions, oral surgery), visceral pain, abdominal pain, pelvic pain, abdominal discomfort, inflammatory pain, cancer pain, headache pain, pain associated with a cough, neuropathic pain, deafferentation pain, chronic nociceptive pain, dental pain (such as odontalgia), bone pain, joint pain, myofascial pain (e.g., muscular injury, fibromyalgia), pain associated with fibromyalgia, labor pain, pain associated with injuries, pain resulting from trauma, pain resulting from allergies, pain resulting from dermatitis, pain resulting from immunodeficiency, pain resulting from Hodgkin’s disease, pain resulting from Myasthenia gravis, pain resulting from nephrotic syndrome, pain resulting from scleroderma, pain resulting from thyroiditis, central and peripheral pathway mediated pain, pain associated with injuries or age, menstrual pain, neurogenic pain, dysmenorrheal pain, migraines, allodynia, hyperalgesia, back pain, pain caused by inflammation (e.g., arthritis, osteoarthritis, spondylitis, rheumatoid arthritis, Crohn’s disease and irritable bowel syndrome) and pain associated with bums.;
13. A method for the treatment or prevention of autoimmune disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.;
14. The method according to claim 13, wherein the autoimmune disorder is selected from the group consisting of alopecia areata (also known as systemic sclerosis (SS)), amyloses, amyotrophic lateral sclerosis, ankylosing spondylarthritis, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison’s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet’s disease, cardiomyopathy, celiac sprue-dermatitis hepetiformis; chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CIPD), cicatricial pemphigoid, cold agglutinin disease, connective tissue diseases, crest syndrome, Crohn’s disease, Degos’ disease, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, graft vs. host disease, transplantation rejection, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin-dependent diabetes mellitus, juvenile chronic arthritis (Still’s disease), juvenile rheumatoid arthritis, lupus erythematosus, Meniere’s disease, multiple sclerosis, myasthenia gravis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud’s phenomena, reactional arthritis, Reiter’s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma (progressive systemic sclerosis (PSS), Sjogren’s syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, undifferentiated spondylarthritis, uveitis, vitiligo, and Wegener’s granulomatosis.;
15. A method for the treatment or prevention of disease-states or indications that are accompanied by inflammatory processes comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.;
16. The method according to claim 15, wherein the disease-state or indication that are accompanied by inflammatory processes are chosen from the group consisting of: lung diseases such as asthma, bronchitis, allergic rhinitis, emphysema, adult respiratory distress syndrome (ARDS), pigeon fancier’s disease, farmer’s lung, chronic obstructive pulmonary disease (COPD), asthma including allergic asthma (atopic or nonatopic) as well as exercise-induced bronchoconstriction, occupational asthma, viralor bacterial exacerbation of asthma, other non-allergic asthmas and “wheezy-infant syndrome”, pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis; rheumatic diseases, autoimmune diseases, musculoskeletal diseases such as all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica, reactive arthritis, rheumatic soft tissue diseases, inflammatory soft tissue diseases of other genesis, arthritic symptoms in degenerative joint diseases (arthroses),); tendinitis, bursitis, osteoarthritis, traumatic arthritis, gout (metabolic arthritis),); collagenoses of any genesis (e.g., systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren syndrome, Still disease, Felty syndrome), osteoporosis and other bone resorption diseases; allergic diseases including all forms of allergic reactions, (e.g., allergic rhinitis, allergic conjunctivitis infectious parasitic, angioneurotic edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc.), anaphylactic shock (anaphylaxis), urticaria, angioneurotic edema, delayed or immediate hypersensitivity, and contact dermatitis; vascular diseases such as panarteritis nodosa, polyarteritis nodosa, periarteritis nodosa, arteritis temporalis, Wegner granulomatosis, giant cell arthritis, atherosclerosis, reperfusion injury, myocardial ischemia, thrombosis, and erythema nodosum; dermatological diseases such as dermatitis, psoriasis, sunburn, bums, and eczema; renal, urinary and pancreatic diseases such as nephrotic syndrome and all types of nephritis (such as glomerulonephritis), pancreatitis, bladder hyper-flexia following bladder inflammation, urinary incontinence or vesicle inflammation, uresesthesia urgency, overactive bladder, urinary frequency, interstitial cystitis and or chronic prostatitis; hepatic diseases such as acute liver cell disintegration; acute hepatitis of various genesis (such as viral, toxic, drug-induced) and chronically aggressive and/or chronically intermittent hepatitis, liver fibrosis associated with liver injury or disease, including fibrosis caused or exacerbated by alcoholic liver cirrhosis, chronic viral hepatitis, non-alcoholic steatohepatitis and primary liver cancer; gastrointestinal diseases such as ulcers, inflammatory bowel diseases, regional enteritis (Crohn’s disease), ulcerated colitis, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, esophagitis, NSAID-induced ulcer, non-ulcerative dyspepsia and gastroesophageal reflux disease; neurodegenerative diseases such as the neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, cerebral ischemia, seizures, spinal cord injury, neurodegeneration associated with multiple sclerosis, or the like, neuroprotection and neurogenesis.; eye diseases such as allergic keratitis, uveitis, or iritis, conjunctivitis, blepharitis, neuritis nervi optici, choroiditis, glaucoma and sympathetic ophthalmia; diseases of the ear, nose, and throat (ENT) area such as tinnitus, allergic rhinitis, hay fever, gingivitis, otitis externa, caused by contact eczema, infection, and otitis media; progressive central nervous system or neurological diseases such as brain edema, particularly tumor-related brain edema, multiple sclerosis, spasticity associated with multiple sclerosis, acute encephalomyelitis, meningitis, acute spinal cord injury, trauma, cognitive disorders such as, dementia, particularly degenerative dementia including senile dementia, Alzheimer’s disease, Parkinson’s disease and CreutzfeldtJacob disease, Huntington’s chorea, Pick’s disease, amyotrophic lateral sclerosis (ALS), vascular dementia including multi-infarct dementia, dementia associated with intracranial space occupying lesions, infections, related conditions such as HIV infection, Guillain-Barre syndrome, myasthenia gravis, stroke, various forms of seizures (such as nodding spasms), and hyperactivity, dyskinesias; blood diseases such as acquired hemolytic anemia, aplastic anemia, and idiopathic thrombocytopenia; tumor diseases such as acute lymphatic leukemia, Hodgkin’s disease, malignant lymphoma, lymphogranulomatoses, lymphosarcoma, solid malignant tumors, colorectal polyps, extensive métastasés, other proliferative disorders such as diabetic retinopathy and tumor angiogenesis (e.g., wet macular degeneration); endocrine diseases such as endocrine opthalmopathy, endocrine orbitopathia, thyrotoxic crisis, Thyroiditis de Quervain, Hashimoto thyroiditis, Morbus Basedow, granulomatous thyroiditis, struma lymphomatosa, Graves disease, type I diabetes (such as insulin-dependent diabetes); organ and tissue transplantations and graft-versus-host diseases; severe states of shock such as septic shock, anaphylactic shock, and systemic inflammatory response syndrome (SIRS); viral or bacterial parasitic infectious disease for example AIDS and meningitis; and various other disease-states or conditions including, restenosis following percutaneous transluminal coronary angioplasty, acute and chronic pain, atherosclerosis, reperfusion injury, congestive heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, necrotizing enterocolitis and syndromes associated with hemodialysis, leukopheresis, granulocyte transfusion, sarcoidosis, gingivitis, pyrexia, edema resulting from trauma associated with bums, sprains or fracture, cerebral edema and angioedema, and diabetes such as diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance and diabetic symptoms associated with insulitis (e.g., Hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion).;
claim 15: 1 7. A method for the treatment or prevention of a gastrointestinal disease or disorder comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.;
claim 16: 1 8. The method of claim 1 7, wherein the disease or disorder is chosen from the group consisting of functional gastrointestinal disorders, ulcers, inflammatory bowel diseases (IBD), regional enteritis (Crohn’s disease), ulcerative colitis, diarrhea, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, functional dyspepsia, diverticulitis, gastrointestinal bleeding, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis, nonulcerative dyspepsia and gastroesophageal reflux disease.;
claim 17: 19. A method for the treatment or prevention of pruritus, comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.;
claim 18: 20. The method according to claim 1 9, wherein the pruritus is dermal pruritus, neuropathic pruritus, neurogenic pruritus or psychogenic pruritus.;
claim 19: 21. A method for the treatment or prevention of a substance abuse-related syndrome, disorder, diseases or withdrawal symptom comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.;
claim 20: 22. The method according to claim 2 1, wherein the substance abuse-related syndrome, disorder, disease or withdrawal symptom is chosen from the group consisting of drug abuse and drug withdrawal, wherein the abused substances include alcohol, amphetamines, amphetamine-like substances, caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin, barbiturates, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics, benzodiazepines, or combinations of any of the foregoing; and the withdrawal symptoms include tobacco craving or nicotine dependency, addiction, or withdrawal.;
claim 21: 23. A method for the treatment or prevention of a psychiatric disorder comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.;
claim 22: 24. The method according to claim 23, wherein the psychiatric disorder is chosen from the group consisting of depressions (including major depressive disorder, bipolar depression, unipolar depression, single or recurrent major depressive episodes (e.g., with or without psychotic features, catatonic features, and/or melancholic features), postpartum onset, seasonal affective disorder, dysthymic disorders (e.g., with early or late onset and with or without atypical features), neurotic depression and social phobia, depression accompanying dementia, depression associated with fibromyalgia, anxiety, psychosis, social affective disorders, and/or cognitive disorders), manic-depressive psychoses, bipolar disorders, extreme psychotic states such as mania, schizophrenia, and excessive mood swings where behavioral stabilization is desired, post-traumatic stress disorder, panic disorder, compulsive disorders, obsessive compulsive disorder, stereotypic, self-injurious and reptitive behaviors, trichtillomania, psychiatric tremors such as dyskinesia, dyskinesia associated with Parkinson’s disease, dystonia or spasticity, dystonia or spasticity associated with multiple sclerosis, attention disorders such as ADHD (attention deficit hyperactivity disorders), hyperactivity, hyperactivity disorders, restless leg syndrome, periodic limb movement disorder, autism, anxiety states, generalized anxiety, an impulse control disorder (e.g., pathological gambling, compulsive shopping, hypersexuality), a compulsion disorder, a dopamine dysregulation syndrome, agoraphobia, as well as those behavioral states characterized by social withdrawal.;
claim 23: 25. A method for the treatment or prevention of a neurological or neurodegenerative disorder comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.;
claim 24: 26. The method according to claim 25, wherein the neurological or neurodegenerative disorder is chosen from the group consisting of dementia, particularly degenerative dementia including senile dementia, Alzheimer’s disease, Pick’s disease, Huntingdon’s chorea, Parkinson’s disease, prion disease and CreutzfeldtJakob disease and motor neuron disease, vascular dementia (including multi-infarct dementia), dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV infection); dementia in Parkinson’s disease, metabolism, toxins, anoxia, vitamin deficiency, mild cognitive impairment associated with aging, particularly AgeAssociated Memory Impairment; amyotrophic lateral sclerosis (ALS), multiple sclerosis, spasticity associated with multiple sclerosis, epilepsy, ischemia, traumatic head, brain injury, brain inflammation, eye injury, strokeneuroinflammation, neurodegeneration or decreased brain activity associated with stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, hypoxia, hypoglycemia, gas poisoning, drug intoxication, diabetes mellitus, edema, spinal cord injury, cerebral ischemia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, seizures or the like.;
claim 25: 27. A method for the treatment or prevention of an ocular disorder comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.;
claim 26: 28. The method according to claim 27, wherein the ocular disorder is chosen from the group consisting of glaucoma (such as normal tension glaucoma), glaucoma-associated intraocular pressure retinitis, retinopathies, uveitis, acute injury to the eye tissue (e.g. conjunctivitis), high intraocular pressure, family history of glaucoma, glaucoma in the contralateral eye and high myopia.;
claim 27: 29. A method for the treatment or prevention of an appetite-related disorder comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.;
claim 28: 30. The method of claim 29, wherein the appetite-related disorder is chosen from the group consisting of emesis, vomiting and nausea, food behavioral problems, feeding disorders such as anorexias, cachexias, wasting conditions, bulimia, obesity, obesity-related disorders such as diabetes type II, or hyperlipidemia.;
claim 29: 31. A method for the treatment or prevention of a gynecological disorder comprising administering, alone or in combination, a therapeutically acceptable dose of a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.;
claim 30: 32. The method of claim 3 1, wherein the gynecological disorder is uterus contraction caused by hormones, prostanoid-induced muscle contraction such as premature labor, menstrual cramps, menstrual irregularity or dysmenorrhea.;
claim 31: 33. A method for the treatment or prevention of a sleep disorder comprising administering, alone or in combination, a pharmaceutically acceptable dose of a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.;
claim 32: 34. The method of claim 33, wherein the sleep disorder is chosen from the group consisting of insomnia, night terrors, nightmares, vivid dreaming, restlessness, bruxism, somnambulism, narcolepsy, circadian rhythm adjustment disorders, sleep disorders associated with neurological or mental disorders or with pain.;
claim 33: 35. A method for the treatment of prevention of a urinary system disorder comprising administering, alone or in combination, a pharmaceutically acceptable dose of a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.;
claim 34: 36. The method of claim 35, wherein the urinary system disorder is chosen from the group consisting of overactive bladder and interstitial cystitis.;
claim 35: 37. The method according to any of claims 1 1 to 36, wherein the patient is a human.;
claim 36: 38. The method according to any of claims 11 to 36, wherein the patient is a companion animal, exotic animal or a farm animal such as a dog, cat, mouse, rat, hamster, gerbil, guinea pig, rabbit, horse, pig or cow.;
claim 37: 39. A method of inhibiting FAAH in a biological sample, comprising contacting said biological sample with a compound according to any one of claims 1-7 or pharmaceutical composition according to any one of claims 8-10.

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