ARYL- AND HETEROARYL-SUBSTITUTED TETRAHYDROBENZO-1,4-DIAZEPINES AND USE THEREOF TO BLOCK REUPTAKE OF NOREPINEPHRINE, DOPAMINE, AND SEROTONIN

摘要

Disclosed are 1-aryl-4-alkyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepines as represented by the general formula I(A-D), wherein: X represents a phenyl, benzo[1,3]dioxolyl, or naphthyl each optionally substituted from 1 to 3 times with halogen, -S(O)2R14, CN, or alkyl which may be optionally substituted with R10; R1 is alkyl; R2, R3, R5, R6, R7 and R8 are each hydrogen; R4 is halogen, NR12R13 or else R4 is piperazinyl, phenyl, pyridyl, 2-oxo-pyridin-1-yl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrazolyl, [1,2,4]triazolo[4,3-a]pyridinyl or [1,2,4]triazolo[1,5-a]pyridinyl, optionally substituted from 1 to 4 times R9; R9 is independently selected at each occurrence from NR12R13, S(O)2R14, C(O)R15 or alkyl which may be optionally substituted with R10; R10 is halogen; R12 and R13 are each independently H or a 5 or 6-membered monocyclic heterocycle; R14 is alkyl; R15is NR12R13; or a pharmaceutically acceptable salt thereof. Representative compounds include 7 -fluoro-4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[e ][1,4]diazepine, 7-fluoro-1-(3-fluorophenyl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, 1-(benzo[d][1,3]dioxol-5-yl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine and 7-(4-(ethylsulfonyl)piperazin-1-yl)-4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine. Further disclosed is a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound as defined above, for treating a disorder selected from pain, attention deficit hyperactivity disorder (ADHD), cognition impairment, anxiety disorders, panic disorder, bipolar disorder, manic depression, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), acute stress disorder, social phobia, simple phobias, pre-menstrual dysphoric disorder (PMDD), social anxiety disorder (SAD), major depressive disorder (MDD), postnatal depression, dysthymia, depression associated with Alzheimer's disease, Parkinson's disease, obesity, anorexia nervosa, bulimia nervosa, binge eating disorder, analgesia, substance abuse disorders, chemical dependencies, drug addiction, neurodegenerative diseases, Parkinson's disease, sleep related eating disorder, stress urinary incontinence (SUI), migraine, diabetic neuropathy, fibromyalgia syndrome (FS), chronic fatigue syndrome (CFS), sexual dysfunction, premature ejaculation, male impotence, and thermoregulatory disorders.