Crystalline forms of 4-[2-(4-methylphenylsulfanyl)-phenyl] piperidine with combined serotonin and norepinephrine reuptake inhibition for the treatment of neuropathic pain

Abstract

Crystalline forms of 4-[2-(4-methylphenylsulfanyl)-phenyl]piperidine and salts thereof are provided e.g. for the treatment of neuropathic pain.

1 . Compound I, which is 4-[2-(4-methylphenyl-sulfanyl)phenyl]piperidine 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof in a crystalline form provided said compound is not 4-[2-(4-methylphenylsulfanyl)phenyl]-piperidine hydrochloride addition salt. 
     
     
         2 . The compound according to  claim 1 , which compound is the HBr addition salt. 
     
     
         3 - 4 . (canceled) 
     
     
         5 . The compound according to  claim 1 , which compound is the DL-lactic acid addition salt. 
     
     
         6 - 7 . (canceled) 
     
     
         8 . The compound according to  claim 1 , which compound is the glutaric acid addition salt (1:1). 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The compound according to  claim 1 , which compound is the malonic acid addition salt (1:1). 
     
     
         12 . The compound according to  claim 11 , which compound is characterized by peaks in an XRPD at 10.77°, 16.70°, 19.93° and 24.01°2θ, or at 6.08°, 10.11°, 18.25° and 20.26°2θ. 
     
     
         13 . The compound according to  claim 11 , which compound is characterised by an XRPD as depicted in  FIG. 9  or  10 . 
     
     
         14 . The compound according to  claim 1  which compound is L-aspartic acid addition salt (1:1) or L-aspartic acid addition salt hydrate (1:1). 
     
     
         15 . The compound according to  claim 1  which compound is glutamic acid addition salt (1:1) or glutamic acid addition salt monohydrate. 
     
     
         16 . (canceled) 
     
     
         17 . A pharmaceutical composition comprising a compound according to  claim 1  together with a pharmaceutically acceptable excipient. 
     
     
         18 . A method of treating a disease selected from chronic pain, depression in partial responders, treatment resistant depression, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, hot flushes, sleep apnea, alcohol, nicotine or carbohydrate craving, substance abuse, alcohol or drug abuse, emesis, eating disorders, IBS, affective disorders, depression, major depressive disorder, postnatal depression, depression associated with bipolar disorder, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia or stress urinary incontinence, the method comprising administering to a patient in need thereof an therapeutically effective amount of a compound according  claim 1 . 
     
     
         19 . The method according to  claim 18 , wherein said disease is chronic pain. 
     
     
         20 . The method according to  claim 19 , wherein said chronic pain is selected from phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuropathy, complex regional pain syndrome (CPRS), trigeminal neuralgia/trigeminus neuralgia/tic douloureux, surgical intervention (e.g. post-operative analgesics), diabetic vasculopathy, capillary resistance or diabetic symptoms associated with insulitis, pain associated with angina, pain associated with menstruation, pain associated with cancer, dental pain, headache, migraine, tension-type headache, trigeminal neuralgia, temporomandibular joint syndrome, myofascial pain muscular injury, fibromyalgia syndrome, bone and joint pain (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture bone pain due to osteoarthritis, osteoporosis, bone metastases or unknown reasons, gout, fibrositis, myofascial pain, thoracic outlet syndromes, upper back pain or lower back pain (wherein the back pain results from systematic, regional, or primary spine disease (radiculopathy), pelvic pain, cardiac chest pain, non-cardiac chest pain, spinal cord injury (SCI)-associated pain, central post-stroke pain, cancer neuropathy, AIDS pain, sickle cell pain and geriatric pain. 
     
     
         21 . The method according to  claim 20 , wherein said chronic pain is neuropathic pain. 
     
     
         22 . The method according to  claim 21 , wherein said neuropatic pain is selected from hyperpathia, hyperalgesia, neuropathy, diabetic neuropathy, neuritis, neuralgia, hyperesthesia, causalgia, and allodynia. 
     
     
         23 - 32 . (canceled) 
     
     
         33 . The compound of  claim 14 , which compound is characterized by peaks in an XRPD at 11.05°, 20.1°, 20.60° and 25.00°2θ, or at 7.80°, 13.80°, 14.10° and 19.63°2θ. 
     
     
         34 . The compound according to  claim 33 , which compound is characterised by an XRPD as depicted in  FIG. 17  or  18 .