MX2008001186A - Methods and compositions for the treatment of neuropathies and related disorders - Google Patents

Abstract

The present invention provides novel compositions and methods for treating symptoms associated with neuropathic disorders such as hyperalgesia, allodynia, and parasthesias, using a l-aryl-3-azabicyclo[3.1.0]hexane. The invention further relates to the useof l-aryl-3-azabicyclo[3.1.0]hexanes in pharmaceutical compositions and methods for treating neuropathic disorders and related symptoms in mammals. Patients amenable to treatment according to the invention include those suffering from diabetic neuropathies, post-herpetic neuralgia, trigeminal neuralgia, chronic lower back pain, sciatica, idiopathic and post-traumatic neuropathies, HIV-associated neuropathic pain, among many other neuropathic disorders and related symptoms.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT OF NEUROPATHIES AND RELATED DISORDERS Technical Field The present invention relates to compositions and methods for treating neuropathic disorders and associated symptoms, including neuropathic pain. Background of the Invention Neuropathic disorders are often complex in their etiology, and individuals suffering from neuropathy often have multiple and variable adverse symptoms. Among the most common severe and adverse symptoms that accompany neuropathic disorders is a syndrome commonly referred to as "neuropathic pain". Neuropathic pain is characterized and distinguished from acute, nociceptive pain (for example pain caused by a burn or surgical incision), by different neurological and sensory characteristics that make its treatment refractory to standard treatments for nociceptive pain. Neurological and sensory characteristics distinct from neuropathic disorders include varying allodynia (a painful response to non-harmful stimuli, such as contact with clothing), hyperalgesia (a highlighted or extreme sensitivity). to painful stimuli), paraesthesia (abnormal sensations such as itching, burning, stinging or tingling); hyperesthesia (sensitivity highlighted to natural stimuli); and diestesias (unpleasant sensations produced by ordinary stimuli). These various symptoms of "pain" are grouped in a differential way among patients with neuropathic disorders, and can be continuous or paroxysmal in presentation. Neuropathic disorders are most commonly attributed to injury or pathogenesis that directly or indirectly affect the central and / or peripheral nervous system. By virtue of these underlying pathogenic changes, which can be produced by various insults, in the range of viral infections of the central nervous system to amputation of a limb, neuropathies are commonly associated with aberrant somatosensory processing in the central and / or peripheral nervous system. The accompanying sensory symptoms of neuropathy are typically qualitatively different from nociceptive pain, producing exaggerated or inappropriate responses to stimuli, or different sensations such as burn, pricking, itching, penetrating, lacerating or sensory-type electrical shock. These adverse sensory conditions are commonly referred to as "neuropathic pain", but they are different neuropathic symptoms compared to nociceptive pain. Neuropathic disorders may be accompanied by a group of comorbid symptoms other than neuropathic pain-for example, depression, insomnia, fatigue, mood disorders, post-traumatic stress, withdrawal, and / or loss of mental and / or physical function. Other symptoms of neuropathic disorders that may be causative of, evoked by secondary neuropathic pain, include somatic stress symptoms, such as increased blood pressure, heart rate, and respiration. Another distinctive aspect of neuropathic disorders is the chronic nature of the accompanying symptoms, which often persist for many weeks, up to three months or more. Neuropathic conditions in this way impose a lasting loss of quality and function in the lives of patients or sufferers. In addition to chronic neuropathic pain, various chronic side effects are well documented for neuropathic patients-including increased risk of heart disease, reduced immunity, increased risk of disease, and prolonged psychological disorders. Surveillance and disuse of painful parts of the body occur frequently in patients with neuropathy, which may lead to other adverse consequences such as weakening or muscle atrophy, muscle tension or spasm, shortening or loss of tendon and ligament elasticity and associated loss of function (eg, reduced range of motion), and weakening of bones associated with increased risk of fracture. While there may be many underlying causes of neuropathies, they are very often triggered by injury or direct damage to the central and / or peripheral nervous system. Exemplary forms of neuropathy and related disorders and symptoms associated with neuropathy, include diabetic neuropathy; peripheral neuropathy, distal symmetric polyneuropathy; post herpetic neuralgia; trigeminal neuralgia; neuropathy related to alcoholism; sensory neuropathy of HIV; sciatica; spinal cord injury; post-stroke neuropathy; multiple sclerosis; Parkinson's disease; idiopathic or post-traumatic neuropathy; mononeuritis; neuropathy associated with cancer; peripheral nerve trauma; nerve transection; carpal tunnel injury; certain forms of chronic lower back pain; neuropathy associated with Fabry disease; vasculitic neuropathy; neuropathy associated with Guillain-Barre syndrome; and neuropathy of arrest or entrapment. Through this broad spectrum, neuropathies affect a vast number of patients around the world, and result in billions of dollars of annual costs for health care and lost productivity. For example, among the estimated 150 million people with diabetes worldwide, diabetic neuropathy affects up to 50% of this large patient population. Although neuropathic symptoms are most often activated by injury, the precipitation injury does not require direct damage to the nervous system. In many cases, factors that precipitate neuropathies are indirect-for example, nerves can be infiltrated or compressed by tumors, strangulated by scar tissue or inflamed by infection. In this way, a number of injuries, diseases and indirect conditions can result in neuropathic disorders, including: abnormality of diet or absorption; vitamin deficiency; heavy metal poisoning; complex regional pain syndrome; fibromyalgia; Wallenberg syndrome; connective tissue disease; plexus irradiation; ischemic irradiation; hematomyelia; discrafism; understanding of tumor; arteriovenous malformation; syphilitic myelitis; comelis myelotomy; arachnoiditis; root avulsion; disk compensation with prolapse; lumbar and cervical pain; reflex sympathetic dystrophy; post pain thoracotomy; post mastectomy pain; phantom limb syndrome; and various other chronic pain syndromes. It is widely understood that neuropathic pain represents a phenomenon other than ordinary pain pain (ie, normal adaptive pain responses classified as nociceptive or systemic pain). Although neuropathic or nociceptive pain may share some common characteristics, its differential diagnosis and treatment is well recognized. In addition to the distinctive features noted above, nociceptive pain typically arises from acute trauma (eg sprains or sprains, broken bones, torn ligaments, burns and cuts), which occur in or near damaged tissues, and usually resolves once that the causal lesion is abated and the damaged tissues are healed. Nociceptive pain therefore typically comprises acute pain symptoms mediated by nociceptors-sensory neurons that respond to stimuli associated with tissue injury. Nociceptive pain is also generally self-limiting and serves to protect biological function by signaling damage or insult to current tissue. In contrast, neuropathic pain and other neuropathy-related symptoms typically persist for months, or even for years-more beyond the apparent healing of damaged tissues. The chronic nature of most neuropathic disorders greatly complicates the treatment. Among the most significant complications in this context is the requirement for long-term medication or other intervention to treat and manage neuropathic disorders and related symptoms, including neuropathic pain. Current drug therapies for neuropathic disorders are severely limited in terms of selection, efficacy and side effects of the drug. Treatments currently practiced for neuropathic disorders include the use of a variety of compounds with various mechanisms of activity, such as amitriptyline, carbamazepine, phenytoin, mexiletine, neurontine, gabapentin and duloxetine. These and other drugs currently used for neuropathic treatments often provide low efficacy for treating symptoms of neuropathies, and are commonly associated with adverse side effects. The safety / efficacy profiles of current neuropathic drugs can be especially problematic in the case of long-term use, as is typically necessary since it is typically necessary to manage symptoms of neuropathy.

Most invasive treatments for neuropathic disorders include stimulation of the epidural spinal cord; deep brain stimulation; neurectomy and rhizotomy. Each of these methods has been tried with limited success for patients with neuropathy, sometimes resulting in increased pain, for example due to deafferation. The available armament of drugs to treat neuropathic disorders is fundamentally different from the group of analgesics and other compounds commonly used to treat nociceptive pain. The assembly of various drugs used to manage symptoms of neuropathies is generally not prescribed nor recognized as effective in the treatment of nociceptive pain. Similarly, while nociceptive pain in general responds well to opioids and other conventional analgesics, such as non-spheroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors, neuropathic pain and other symptoms of neuropathy generally do not respond or have a response insufficient to these conventional drug regimens to treat nociceptive pain. The refractory nature of neuropathic disorders for treatment using NSAIDS, (for example ibuprofen, acetaminophen, aspirin and celecoxibide) and opioids (for example morphine, oxymorphone, and codeine) it is well documented (Max, et al., Clin.And Pharm.Therapy, 43: 363; Max, et al., Neurology 38: 1427, (1988)). In view of the above, there is an important need, unsatisfied, in the art, for alternative compositions and methods to treat neuropathic disorders and related adverse conditions and symptoms including neuropathic pain. Compendium of Exemplary Modalities of the Invention It is therefore an object of the present invention to provide novel and improved compositions and methods and methods for treating and preventing neuropathic disorders and related conditions in mammalian subjects. The invention achieves these objectives and satisfies additional objects and advantages by providing novel and surprising compositions and methods for treating neuropathies and related symptoms, accompanying neuropathic disorders, including but not limited to paresthesias, allodynia, hyperalgesia and other sensory symptoms of neuropathies often referred to. as neuropathic pain, in mammals. The present methods and compositions are directed to methods, compounds or formulations employing an effective amount of 1-aryl-3-azabicyclo [3.1.0] hexane, sufficient to alleviate one or more symptoms of neuropathy in a mammalian subject.

In more detailed embodiments, the compositions and methods of the invention for treating neuropathic disorders employ an effective amount of a compound or formulation comprising l-aryl-3-azabicyclo [3.1.0] hexane having at least one substitute on the phenyl ring / aril. In exemplary embodiments, methods and compositions of the invention for treating neuropathic disorders and related symptoms, they employ a novel 1-aryl-3-azabicyclo [3.1.0] hexane having at least one substitution on the aryl ring and characterized at least in part by the formula I, following: Formula I wherein Ar is a phenyl or other aromatic group having at least one substitution on the aryl ring, and wherein R is chosen from for example hydrogen C? -6 alkyl, halo (C? -6) alkyl, C3.9 cycloalkyl , C? _5 alkoxy (Ci-β) alkyl, carboxy (C1-3) alkyl, C1-3 alkanoyl, carbamate, halo (C? _3) alkoxy (Ci-β) alkyl, C1-3 alkylamino (C? -6) ) alkyl, and di (C1-3) alkylamino (C? -6) alkyl, cyano (C? -6) alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl. In certain detailed embodiments, the compounds and formulations of the invention for treating neuropathic disorders and / or related symptoms comprise an l-aryl-3-azabicyclo [3.1.0] hexane having an aza substitution in place of the hydrogen associated with the the "3" position. In other detailed embodiments of the invention, the compounds and formulations of the invention for treating neuropathic disorders and / or related symptoms comprise an l-aryl-3-azabicyclo [3.1.0] hexane having at least one substitution on the aryl ring, as well as an aza substitution in nitrogen in the "3" position. In further detailed embodiments, the compounds and formulations of the invention for treating neuropathic disorders and / or related symptoms comprise an l-aryl-3-azabicyclo [3.1.0] hexane having two or more substituents on the phenyl / aryl ring. In other detailed embodiments, the compounds and formulations of the invention for treating neuropathic disorders and / or related symptoms, comprise a 1-aryl-3-azabicyclo [3.1.0] hexane having multiple substitutions on the aryl ring, combined with a combination "aza" in nitrogen in position "3". Mammalian subjects susceptible to treatment using the methods and compositions of the invention include but are not limited to human subjects and other mammals suffering from neuropathic pain syndromes and / or exhibit one or more symptoms related to neuropathic pain. Subjects with these target groups for treatment include for example patients who present neuropathic pain associated with diabetic neuropathy, diabetic peripheral neuropathy, distal symmetric polyneuropathy, post-herpetic neuralgia, trigeminal neuralgia, pain secondary to alcoholism, sciatica, pain after stroke, multiple sclerosis, herpes, idiopathic and post-traumatic neuropathy and mononeuritis, neuropathic pain associated with HIV, cancer, carpal tunnel syndrome, neuropathy associated with Fabry disease, vasculitic neuropathy, neuropathy associated with Guillain-Barre syndrome, abnormality of diet or absorption, pain of spinal cord injury, chronic lower back pain, iatrogenic induced neuropathies, deficiencies in vitamins, heavy metal poisoning, complex regional pain syndrome, fibromyalgia, peripheral nerve trauma, entrapment neuropathy, nerve transection, Wallenberg syndrome, disease of connective tissue, plexus irradiation, ischemic irradiation, hematomyelia, dyschaphism, tumor compression, arteriovenous malformation, syphilitic myelitis, commissural myelotomy, arachnoiditis, root avulsion, prolapse disc compression, cervical and lumbar pain, reflex sympathetic dystrophy, phantom limb syndrome and other debilitating and chronic pain syndromes. These and other objects are effectively treated by administering to the subject an effective amount of an l-aryl-3-azabicyclo [3.1.0] hexane to alleviate one or more symptoms of a neuropathic disorder in the subject. The methods and therapeutic formulations of the invention may employ l-aryl-3-azabicyclo [3.1.0] hexanes in a variety of forms including pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates and / or prodrugs or combinations thereof. Within further aspects of the invention, combinatorial formulations and methods are provided, which employ an effective amount of an l-aryl-3-azabicyclo [3.1.0] hexane and one or more additional active agents, which are formulated combinatorially or administered in a coordinated manner with l-aryl-3-azabicyclo [3.1.0] - hexane, or one or more co-ordinates, treatment method without drug administered in the coordinated with l-aryl-3-azabicyclo [3.1.0] hexane, to alleviate one or more symptoms associated with a neuropathic disorder in a mammalian subject. Exemplary combinatorial formulations and coordinated treatment methods in this context employ an l-aryl-3-azabicyclo [3.1.0] hexane in combination with one or more conventional drugs or non-drug treatment methods to treat accompanying symptoms to neuropathic disorders, including but not limited to not limited, to: amitriptyline; carbamazepine; phenytoin; mexiletine; neurontin; gabapentin; duloxetine; baclofen; tramadol; antiarrhythmics; antiepileptics; anti-convulsants; capsaicin cream; Membrane stabilizing drugs; N-methyl-D-aspartate receptor (NMDA = N-methyl-D-aspartate) antagonists; surgery; transcutaneous electrical nerve stimulation; spinal cord stimulation epidural; neuroectomy; rhizotomy; injury in dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. The above objects and additional objects, features, aspects and advantages of the present invention are further explained and described in the following detailed description. Brief Description of the Drawings Figure 1, Panel A is a graph of experimental results demonstrating that (±) -1- (4-methylphenyl) -3-azabicyclo [3.1.0] hexane (bicifadine HCl) suppresses mechanical hyperalgesia in the Chung model of neuropathic pain. Bicfifadine is as effective as a nearly lethal dose of morphine to block mechanical hyperalgesia. The efficacy of bicifadine for treating neuropathic symptoms in this model is specific, as indicated by data showing that bicifadine has no effect on the pain threshold in the uninjured leg (Panel B). *, **; Significantly different from the vehicle group, P < 0.05, 0.01, respectively, Student's t-test. Figure 2, Panel A, is a graph of experimental results demonstrating that (±) -l- (4-methylphenyl) -3-azabicyclo [3.1.0] hexane hydrochloride (bicifadine HCl) suppresses thermal hyperalgesia in the Chung model of neuropathic pain. Bicfifadine is as effective as an almost lethal dose of morphine to block mechanical hyperalgesia. The efficacy of bicifadine for treating neuropathic symptoms in this model is specific, as indicated by data showing that bicifadine has no effect on the pain threshold in the uninjured leg (Panel B). *, **; Significantly different from the vehicle group, P < 0.05, 0.01, respectively, Student's t-test.

Figure 3, Panel A is a graph of experimental results demonstrating that l- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane suppresses mechanical hyperalgesia in the Chung model of neuropathic pain. The efficacy of 1- (3, -dichlorophenyl) -3-azabicyclo [3.1.0] hexane for treating neuropathic symptoms in this model is specific, as indicated by data showing that the compound has no effect on the pain threshold in the uninjured leg (Panel B). *, **; Significantly different from the vehicle group, P < 0.05, 0.01, respectively, Student's t-test. Figure 3, Panel A is a graph of experimental results demonstrating that l- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane suppresses thermal hyperalgesia in the Chung model of neuropathic pain. The efficacy of 1- (3, -dichlorophenyl) -3-azabicyclo [3.1.0] hexane for treating neuropathic symptoms in this model is specific, as indicated by data showing that the compound has no effect on the pain threshold in the uninjured leg (Panel B). *, **; Significantly different from the vehicle group, P < 0.05, 0.01, respectively, Student's t-test. Figure 5 is a graph of experimental results demonstrating that bicifadine alleviates symptoms of neuropathy (mechanical hyperalgesia) in the rat model of Streptozotocin-induced diabetes (STZ) of neuropathy. *, Significantly different from the vehicle group, P < 0.05, 0.01, respectively, Student's t-test. Detailed Description of Exemplary Modalities of the Invention The present invention provides novel compositions and methods for treating and / or avoiding symptoms associated with neuropathic disorders in mammalian subjects including humans. The therapeutic and prophylactic formulations and methods of the invention employ an effective amount of l-aryl-3-azabicyclo [3.1.0] hexane, which when administered to a mammalian subject effectively treats or prevents a neuropathic disorder, one or more symptoms or conditions of a neuropathic disorder, in the subject. In various embodiments, the methods and compositions of the invention employ one or more substituted aryl-3-azabicyclo [3.1.0] hexanes substituted aryl and / or aza, characterized at least in part, by the formula I, below: Formula I wherein Ar is a phenyl or other aryl group, which optionally has at least one substitution on the aryl ring, and wherein R is H or an optional aza substituent selected from, for example, hydrogen, C? -6 alkyl, halo ( C6-6) alkyl, C3-9 cycloalkyl, C1-5 alkoxy (C6-6) alkyl, carboxy (C1-3) alkyl, C1-3 alkanoyl, carbamate, halo (C1-3) alkoxy (C6-6) alkyl, C1-3 alkylamino (C6-6) alkyl, and di (C1-3) alkylamino (Ci-e) alkyl, cyano (C6-6) alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl.

As used herein, the structural designation "Ar" represents a phenyl or other aromatic group. An aromatic group designates cyclically conjugated systems of 4n + 2 electrons, that is with 6, 10, 14 etc. p electrons; a saturated monocyclic, bicyclic or tricyclic heterocycle representing a ring system consisting of 1, 2 or 3 rings and comprising at least one heteroatom selected from O, N or S, the ring system contains only single bonds; a heterocycle, monocyclic, bicyclic or partially saturated tricyclic which represents a ring system consisting of 1, 2 or 3 rings and comprising at least one heteroatom selected from 0, N or S, and at least one double bond provided that the ring system is not a aromatic ring system; a monocyclic, bicyclic or aromatic tricyclic heterocycle which represents an aromatic ring system consisting of 1, 2 or 3 rings and comprises at least one heteroatom selected from 0, N or S. The term "phenyl" as used herein refers to a carbocyclic ring system having an aromatic ring. The phenyl group can also be fused to a cyclohexane ring or cyclopentane. The phenyl and aromatic groups of this invention may be optionally substituted. An illustrative assembly or set of substituted aryl 1-aryl-3-azabicyclo [3.1.0] hexanes for use within this aspect of the invention is provided in Table 1, below. In each of these exemplary compounds, there is no aza substituent (ie, the hydrogen associated with nitrogen in the "3" position has been retained), however it is further contemplated that the exemplified aryl substitutions may be combined with aza substitutions as described then to give "bisubstituted" compounds as candidates for treat neuropathic disorders and related symptoms as described here. TABLE 1 l-aryl-3-azabicyclo [3.1.0] hexanes Aril Substituted Exemplary 1- (4-fluorophenyl) -3-rnethyl-3- 3-methyl-1- (4-trifluoromethyl) aza-bicyclo [3.1.0] hexane phenyl) -3-aza-bi-clo [3.1.O-Hexane 1- (3-chlorophenyl) -3-methyl-3- (4- (3-methyl-3-aza-bicyclo [3.1.0] aza-bicyclo [3.1.0] hexane-hexan-1-yl) phenyl) methane amine In certain exemplary embodiments of the invention, the compositions and methods effective to treat neuropathies and related symptoms employ a substituted aryl-3-azabicyclo [3.1.0] hexane aryl, selected from (±) -1- (4- hydrochloride methylphenyl) -3-azabicyclo [3.1.0] hexane (bicifadine HCl), bicifadine enantiomers, other bicifadine salts, bicifadine prodrugs, polymorphs, hydrates and solvates bicifadine, or any combination of the previous forms of bicifadine. In more detailed embodiments, bicifadine hydrochloride is used within the formulations and therapeutic methods of the invention. Bicifadine HCl, ((1) -1- (4-methylphenyl) -3-azabicyclo [3.1.0] hexane hydrochloride, also referred to as 1- (p-tolyl) -3-azabicyclohydrochloride [3.1.0] hexane) is described as a non-narcotic analgesic in the US Patent No. 4,231,935 and the U.S. Patent. No. 4,196,120 (incorporated herein by reference). Bicifadine, represented (as a free base) by structural formula II, has then been reported to be potent and active in the "Randall-Selitto" test, an animal model of acute inflammatory pain (see, for example, Epstein et al., J. Med. Chem. 24 (5): 481, 1981; Epstein et al., NIDA Res. Monogr., pp. 93-98, 1982). Both opiates (for example, morphine and codeine) and NSAIDs (for example, aspirin), compounds used to treat acute pain, are also active in this model. In this model, inflammatory pain is produced by injection of yeast extract into the plantar surface of the rat paw. Consistent with these studies, bicifadine have been confirmed to have analgesic action to treat nociceptive pain in humans. In particular, bicifadine is has reported that it is as effective as codeine and tramadol, two analgesics commonly used to treat nociceptive pain, to relieve pain after dental surgery (Czobor P., et al., 2003); (Czobor P., et al., 2004). Formula II Bicifadine HCl also exists in at least two polymorphic crystalline forms, designated polymorphic A and B forms (for example, as described in U.S. Patent Application Serial No. 10 / 702,397, incorporated herein by reference). Other polymorphic forms of bicifadine hydrochloride may exist and are equally candidates for use within methods and compositions of the invention for treating a neuropathic disorder and / or related symptoms. Polymorphs include compounds with identical chemical structure but different internal structures. Additionally, many organic compounds pharmacologically active substances are regularly crystallized by incorporating second foreign molecules, especially solvent molecules, into the crystal structure of the main pharmacologically active compound forming pseudo polymorphs. When the second molecule is a solvent molecule, the pseudo polymorphs can also be referred to as solvates. All of these additional forms of bicifadine are equally useful within the anti-incontinence methods and formulations of the invention. The polymorph A form of HCl bicifadine can be formed, for example, by methods described in U.S. Pat. No. 4,231,935 and U.S. Patent No. 4,196,120 (each of which is incorporated herein by reference). The polymorph B form can be formed, for example, by methods described in the U.S. patent application. serial number 10 / 702,397, related international application PCT / US2003 / 035099 (International publication number WO04 / 043920), and provisional patent application of the US. Priority serial number 60 / 424,982 (each incorporated by reference). For example, polymorph B can be formed from polymorph A through the application of kinetic energy and through crystallization techniques. In one modality, kinetic energy in the form of shaking, milling or crushing can be applied to a pure composition of polymorph A or a mixture of forms A and B, particularly at select temperatures, for example from about -200 degrees C to about 50 degrees C, in another embodiment from about -200 degrees C to about 35 degrees C, in an additional mode of about -200 degrees C to about 0 degrees C. In another embodiment, polymorph B can be crystallized from a solution of polymorph A which is heated and allowed to cool under defined conditions of temperature and time to form polymorph B. Under select conditions, the preparation of pure polymorph A of bicifadine, or mixtures of polymorph A and B of bicifadine, can be processed to give desired compositions containing enriched amounts of polymorph B, for example in the range of about at least 10%, to about 10- 20%, 20-35%, 35-50%, 50-70%, 70-85%, 85-95%, and up to 95-99% or greater (by weight) of polymorph Bicifadine B in the composition. The polymorphs of HCl bicifadine can be characterized by their infrared effects and / or their X-ray powder diffraction pattern. As described in U.S. Patent Application. serial number 10 / 702,397 incorporated above, analysis of the X-ray diffraction (XRPD X-ray powder diffraction) of the polymorphs A and B forms of racemic bicifadine hydrochloride were performed with a X-ray powder diffractometer Shimadzu XRD-6000 using Cu Ka radiation. • Bicifadine was loaded in the machine as a crystalline powder. The instrument is equipped with a thin focus X-ray tube. The tube voltage and amperage were adjusted to 40 kV and 40 mA, respectively. The divergence and dispersion slots were adjusted to 1 degree and the receiving slot was adjusted to 0.15 mm. Diffracted radiation is detected by a Nal flash detector. A continuous theta-a-theta scan at 3 / min (0.4 sec / 0.02 degrees of step) from 2.5 to 40 degrees 2? I was employed. A silicone standard is analyzed to verify instrument alignment. Data were collected and analyzed using XRD-6000 v.4.1. The X-ray powder diffraction pattern of the polymorph A form of racemic bicifadine hydrochloride is given in terms of spacing "d" and relative intensities (I) as follows (s = strong, m = medium, w = weak, v = much, d = diffuse) and these terms are set forth in the following Table 2, and the X-ray powder diffraction pattern of form B of bicifadine hydrochloride is set forth in Table 3 below: TABLE 2 Positions Peak, Spacings-d, and Intensities for Polymorph A of Bicifadine Hydrochloride 2 (9 (degrees) d (A) Ia . 35 16.50 Vs . 61 8.33 Vs 11. 45 7.72 W 15.22 5.82 W 15.93 5.56 W 16.97 5.22 W 18.37 4.83 W 20.04 4.43 Md . 26 4.38 Md 21. 22 4.18 M 21.89 4.06 S 23.12 3.84 Md 23. 54 3.78 W 26.63 3.34 M Wd 27. 83 3.20 28. 32 3.15 Wd Wd 30.67 2.91 32. 03 2.79 37. 57 2.39 W 38.20 2.35 W a -s = strong, m = medium, w = weak, v = much, d = diffuse TABLE 3 Positions Peak, Spacings-d, and Intensities for the Polymorph Form B Bicifadine Hydrochloride 2T (degrees) d (Á) Ia 5.08 17.39 Vs 10.07 8.77 S 15.19 5.83 s 16.83 5.27 s 18.64 4.76 Md 18.76 4.73 Md 19.64 4.52 W 20.16 4.40 M 21.96 4.05 M 22.37 3.97 S 23.16 3.84 W 24.00 3.70 W 25.27 3.52 D 27.33 3.26 Md 27.74 3.21 M 29. 00 3.08 M 30.43 2.93 Md 31.84 2.80 Wd 32.29 2.77 W 35.27 2.54 Wd 35.64 2.52 W s = strong, m = medium, w = weak, v = much, d = diffuse Table 2 and Table 3 represent the XRPD pattern of the peak positions of bicifadine hydrochloride Form A and Form B respectively having reduced particle sizes. The results in these tables show that the difference between the XRPD patterns of Form A and Form B at a reduced particle size. However, there are key peaks at determined angles in this pattern that identify the polymorph B form of bicifadine hydrochloride and are typically present in the XRPD pattern of the polymorph form B regardless of its particle size. These angles, expressed as 2? (degrees), locate these main peaks, which alone or in any distinctive combination distinguish the polymorph bicifadine form B of form A, using Cu Ka radiation, are: 5.08; 10.07; 20.16; 25.17; and 30.43. The infrared spectra are obtained for each one of the samples using an infrared Fourier transform spectrophotometer (FT-IR) Magna-IR 860® (Thomas Nicolet) equipped with a medium IR / lj Ever-Glo source, an extended interval potassium bromide beam separator (KBr) ), and an adulterated triglycine sulfate detector (DTGS). The spectrophotometer measures the intensity of the infrared light bands of each of the samples at determined wavelengths. A diffuse reflectance accessory (the Collector ™, Thermo Spectra-Tech) is used for sampling. Each spectrum represents 256 co-aggregated scans collected from 400-4000 cm "1 at a spectral resolution of 4 cm" 1. Sample preparation consists of placing the sample of crystals containing powder either in polymorph Form A or Form B in a cup with a diameter of 13 mm and inhibits the area of the material with a frosted or frosted glass slide. A set of background data is acquired with an in situ alignment mirror. The reflectance R is the proportion, at a certain wave number, of the light intensity of the sample / light intensity of the background set. A Log 1 / R spectrum (R = reflectance) acquired by taking a relationship of these two data sets (the light intensities of sample and background) with each other. The infrared spectrum of polymorph A or hydrochloride racemic bicifadine as a dry crystalline powder, as provided in Table 4, shows the main peaks indicated, which characterize this polymorph. The infrared spectrum of polymorph B of racemic bicifadine hydrochloride as a dry crystalline powder, as provided in Table 5, shows the main peaks indicated, which characterize this polymorph.

TABLE 4 Positions Infrared Peak For Hydrochloride Polymorph Bicifadina Form A. All values in wave numbers (cm-1) 3949 1088 2923 1068 2431 1050 2280 900 2091 825 1895 781 1790 714 1595 689 1522 652 1430 574 1376 533 1233 437 TABLE 5 Positions of Infrared Peak for Hydrochloride Polymorph Bicifadina Form B. All values in wave numbers (cm-1) 3185 1111 2769 1022 2437 963 2276 904 2108 891 1908 856 1804 818 1658 783 1596 719 1518 684 1453 660 1403 637 1343 580 1305 532 1274 475 1209 422 1131 Table 4 and Table 5 provide the complete patterns of the infrared peak positions with respect to the polymorph Form A and polymorph Form B of bicifadine hydrochloride, respectively. However, there are certain key peaks within this pattern, which are associated with the polymorph Form B of bicifadine hydrochloride and are sufficient to characterize this polymorph, individually or in any distinctive combination. These peaks, expressed in wave numbers (cm Y are: 2108; 891; 856; 719; and 660. The formulations of bicifadine for treating neuropathies and related symptoms within the invention may comprise any polymorphic or amorphous crystalline form of the compound, or In its exemplary embodiments, effective therapeutic dosage forms for treating mammalian subjects exhibiting a neuropathic disorder, will comprise substantially pure polymorph bicifadine HCl (meaning that it has a concentration of 90-95% form A in weight of total bicifadine present), essentially "pure form B" or any mixture of polymorph forms A and B. In certain embodiments, the composition may contain from about 10% to 98% polymorph form B. In other embodiments, it may be present in the formulation more than about 50% polymorph form B, greater than about 75% polymorph B or greater than about 90% polymorph B. In additional embodiments , one or more Enantiomers (+) or (-) isolates of bicifadine are employed within the methods and compositions of the invention to treat neuropathies and related symptoms. The (+) and (-) enantiomers of bicifadine and methods for resolving these enantiomers to give essentially pure compositions of the respective enantiomers are reported by Epstein et al. (J. Med. Chem. 24 (5): 81, 1981; NIDA Res. Monoar., Pp. 93-98, 1982). See also the U.S. Patent. Number 4,131,611; Patent of the U.S.A. Number 4,118,417; Patent of the U.S.A. Number 4,196,120; Patent of the U.S.A. Number 4,231,935; and U.S. Pat. Number 4,435,419, each incorporated herein by reference). In exemplary embodiments, effective therapeutic dosage forms for treating mammalian subjects having a neuropathic disorder, will comprise (+) essentially pure bicifadine (i.e. having a concentration of 90-95% of the (+) enantiomer by weight of the total bicifadine present ), (-) essentially pure bicifadine, or any racemic mixture of the (+) and (-) enantiomeric forms of bicifadine. In certain embodiments, the composition may contain from about 10% to 98% of (+) or (-) of bicifadine. In other embodiments, there may be present in the formulation more than about 50% (+) or (-) of bicifadine, more than about 75% (+) or (-) of bicifadine or more than about 90% (+) or (-) of bicifadine. In other detailed embodiments, the compositions and methods of the invention for treating neuropathic disorders and / or related symptoms employ l-aryl-3-azabicyclo [3.1.0] hexane having an "aza" substitution at the nitrogen at the position 3'. In related modalities, a bi-substituted l-aryl-3-azabicyclo [3.1.0] hexane is characterized in the present compositions and methods having at least one substitution in the aryl ring, and in addition, aza substitution in the nitrogen in the "3" position " As used herein, the terms "aza substitution" and "aza-substituted" refer to l-aryl-3-azabicyclo [3.1.0] hexanes wherein a hydrogen normally associated with the nitrogen in the "3" position has been replaced with a different substituent, as exemplified below. Within exemplary compositions and methods for treating neuropathic disorders and / or related symptoms employing "bi-substituted" l-aryl-3-azabicyclo [3.1.0] hexanes, compositions and methods containing or employing these compounds having at least a substitution in the aryl ring, as well as replacement aza, that is to say characterized in part by the Formula III, following: Formula III wherein for example R is chosen from C? -6 alkyl, halo (Ci-β) alkyl, C3-9 cycloalkyl, C? alkoxy (Ci-β) alkyl, carboxy (C1-3) alkyl, C1-3 alkanoyl , carbamate, halo (C? _3) alkoxy (C? _6) alkyl, C1-3 alkylamino (Ci-β) alkyl, and di (C1-3) alkylamino (Ci-β) alkyl, cyano (Ci-β) alkyl , methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl; and wherein for example Ri is selected from halogen, C1-3 alkyl, C2_4 alkenyl, C2_4 alkynyl, halo (C1-3) alkyl, cyano, hydroxy, C3_5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy (C1-3) alkyl, carboxy (C1-3) alkyl, C1-3 alkanoyl, halo (C1-3) alkoxy, nitro, amino, C1-3 alkylamino, and di (C1-3) alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro and trifluoromethoxy. In other exemplary embodiments, bi-substituted (aryl- and aza-substituted) compounds for use within the methods and compositions of the invention to treat a neuropathic disorder and / or one or more related symptoms, they are characterized, at least in part by formula IV below, which describes in an exemplary manner a methyl substitution on the aryl ring in the same position as is found in bicifadine. Formula IV wherein for example R is selected from C? -6 alkyl, halo (Ci-β) alkyl, C3-9 cycloalkyl, C1-5 alkoxy (Ci-6) alkyl, carboxy (C1-3) alkyl, C1-3 alkanoyl , carbamate, halo (C1-3) alkoxy (C6-6) alkyl, C3-3 alkylamino (Ci-β) alkyl, and di (C1-3) alkylamino (C6-6) alkyl, cyano (C6-6) alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl.

An illustrative set of bi-substituted l-aryl-3-azabicyclo [3.1.0] hexanes for use within the methods and compositions of the invention for treating a neuropathic disorder and / or one or more related symptoms are provided in the following Table 6. In each of these exemplary compounds, the hydrogen associated with the nitrogen in the "3" position has been replaced with a different aza substituent, as illustrated. Table 6 Exemplary Aza-substituted hexanes-3-azabicyclo [3.1.0] hexanes 3-met? L-1-p-tol? L-3-aza-3-et? L-1-p-tol? L-3-azabicyclo? 1 O-hexane b? C? Clo [3 1 0] exano - 3- (2-me b? C? Clo [3 1 OJhexano Yza. b "cW oihexane The aryl-substituted and aza-substituted l-aryl-3-azabicyclo [3.1.0] hexanes for use within the methods and compositions of the invention for treating a neuropathic disorder and / or one or more related symptoms are useful in any of a variety of forms, including pharmaceutically acceptable, active salts, solvates, polymorph hydrates and / or prodrugs of compounds described herein or any combination thereof. In further detailed embodiments, the methods and compositions of the invention for treating a neuropathic disorder and / or one or more related symptoms employ l-aryl-3-azabicyclo [.1.0] hexane having two or more constituents in the aryl ring. In more detailed aspects, these multiple aryl-substituted compounds for use within the method and compositions of the invention for treating neuropathic disorders and / or related symptoms, are characterized at least in part by Formula V, below: Formula V wherein Ri and R2 are independently for example halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo (C3-3) alkyl, cyano, hydroxy, C3_5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy (C1-3) alkyl, carboxy (C1-3) alkyl, C1-3 alkanoyl, halo (C1-3) alkoxy, nitro, amino, C 1-3 alkylamino, and di (C 1-3) alkylamino, methyl, ethyl, fluorine, chlorine, trifluoromethyl, cyano and trifluoromethoxy. In an exemplary embodiment, the methods and compositions of the invention for treating a neuropathic disorder and / or one or more related symptoms employ a multiple aryl-substituted azabicyclo [3.1.0] hexane comprising a racemic or enantiomeric form of 1- ( 3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane. The racemic form of this compound was described in U.S. Pat. Number 4,435,419 (incorporated herein by reference). Additional description regarding this compound and its enantiomeric forms, processes for solving the enantiomeric forms and therapeutic uses proposed for the compound, is provided in US Pat. Number 4,196,120; the U.S. Patent Number 4,231,935; the U.S. Patent Number 6,204,284; the U.S. Patent Number 6,372,919; the U.S. Patent Number 10 / 466,457; the U.S. Patent Number 10 / 920,748; the U.S. Patent Number 6,659,887; the U.S. Patent Number 6,716,868; the U.S. Patent Number 10 / 764,371; the U.S. Patent Number 10 / 764,373; the U.S. Patent Number 10 / 764,375 (each incorporated herein by reference). Both the (+ -) -1- (3,4-dichlorophenyl) -3- racemic azabicyclo [3.1.0] hexane and its respective (+) and (-) enantiomeric forms provide useful candidate compounds for the methods and compositions of the invention for treating a neuropathic disorder and / or one or more related symptoms, as exemplified by continuation. As described further below, a large set of novel multiple aryl-substituted candidate compounds are also provided for use within the methods and compositions of the present invention for treating neuropathic disorders and / or related symptoms. These novel multiple aryl-substituted candidate compounds, which have been developed and characterized as illustrative embodiments of the invention, include the following (Table 7): Table 7 Exemplary l-aryl-3-azabicyclo [3.1.0] hexanes having multiple substitutions in the aryl ring. 1- (3-Chloro-4-fluorophenyl) -3-methyl-3- 1- (3,4-difluorophenyl) -3-methyl-3- 3-methyl-1- (naphthalen-2-yl) - 3- aza-bicyclo [3.1.Ojhexano aza-bic¡clo [3.1.Ojhexano aza-bicyclo [3.1.0] hexane 1- (2,4-difluorophenyl) -3-methyl-3- 1- (3-fluoro-4-methylphenyl) -3-methyl-3- 1- (4-fluoro-3-methylphenyl) -3-methyl- 3- aza-bicyclo [3.1.OJhexane aza-bicyclo [3.1.0] hexane aza-bicyclo [3.1.Ojhexano 1- (3-chloro-4-nitrophenyl) -3-methyl-3- 1- (5-chloro-2,4-dinitrophenyl) -3-methyl-3-1 - (2,4-dichlorophenyl) -3- metit-3-aza-bicyclo [3.1.0] hexane aza-bicyclo [3.1.0] hexane aza-bicyclo [3.1.Ojhexano 1- (3-c! Gold-4-fluorophenyl) -3-aza-bicyclo [3.1.0] hexane It will be understood that the multiple exemplary aryl-substituted compounds identified in Table 7 are illustrative and that the present modifications comprise multiple aryl substitutions can vary to comprise other substituents, can still include still further substituents (ie three or more substitutions on the aryl ring), combined together, or additionally combined with a "substitution" aza "as described herein, to give yet additional additional candidate compounds to be used within the methods and compositions of the invention to treat a neuropathic disorder and / or one or several related symptoms. For example, certain embodiments of the invention employ a compound of an illustrative set of 1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexanes having multiple substitutions (e.g. as illustrated by multiple chloro substitutions) in the aryl ring, combined with an "aza substitution" in the nitrogen in the "3" position. These aza-substituted l- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexanes useful as candidate compounds within the methods and compositions of the invention for treating a neuropathic disorder and / or one or several related symptoms include the following, exemplary compounds, which have been developed and characterized as illustrative modalities (Table 8). The present compounds are illustrate as hydrochloride salts, while it will be understood that the invention encompasses all forms of the compounds as described herein, including free base forms, and all pharmaceutically acceptable salts, polymorphs, solvates, hydrates and prodrugs. Table 8 Exemplary l-aryl-3-azabicyclo [3.1.0] hexanes having multiple substitutions in the aryl ring combined with aza substitution. 1- (3r4-dichlorophenyl) -3- alkylhydrochloride of 1- (3,4-dichlorophenyl) -3- propyl-3-azabicycloP .1.O-hexane butyl-3-azabicyclo [3.1.Ojhexapo 3 - . 3 - isobutyl-3-izobicyclo [3. . exano 1- (3,4-dichlorophenyl) -3- hydrochloride 3-tert-butyl-1- hydrochloride. { 3,4-dichlorophenyl) cyclopropyl-3-azabi cycle [3.1.Ojhexano -3-? za-b ic icl or [3.1.OJhexano Within related aspects of the invention, enantiomeric forms of l-aryl-3-azabicyclo [3.1.0] hexanes having single or multiple substitutions on the aryl ring, optionally combined with an aza substitution, as described above, are employed within of the methods and compositions of the invention for treating a neuropathic disorder and / or one or several related symptoms. In certain embodiments, the methods and compositions of the invention employ enantiomers, diesteromers and others steroisomeric forms of the described compounds, including racemic and resolved forms and their mixtures. The present invention encompasses all of these forms including all resolved racemic and isomeric forms and mixtures thereof. Enantiomeric forms of active compounds within the methods and compositions of the invention can be resolved and isolated according to methods that are well known to those of ordinary skill in the art, including but not limited to, formation of salts or diesteroisomeric complexes that can be separated by methods including but not limited to: crystallization; gas-liquid or liquid chromatography; selective reaction of an enantiomer with a specific enantiomer reagent, for example oxidation or enzymatic reduction, followed by separation of the modified and unmodified enantiomers; and gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, for example silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation. When the compounds here described contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended to include both geometric isomers E and Z. All tautomers are intended to be encompassed by the present invention equally. Exemplary enantiomers of l-aryl-3-azabicyclo [3.1.0] hexanes having single or multiple substitutions on the aryl ring for use within the invention, which have been resolved and characterized as illustrative modalities, include the following (Table 9) : Table 9 Exemplary enantiomeric compounds (1R) -1- (3,4-Dichlorophenyl) -3-methyl- (1S) -1- (3,4-dichlorophenyl) -3-methyl-3-aza-bicyclo [3.1.Ojhexane 3-aza-bicyclo [3.1.Ojhexano (1R) -1- (3,4-dichlorophenyl) -3-ethyl- (1S) -1- (3,4-dichlorophenol) -3-etl-3-aza-bicyclo [3.1.Ojhexane 3 -aza-bicycles [3.1.Ojhexano (1R) -1- (3,4-Dichlorophenyl) -3-propyl- (1S) -1- (3,4-dichlorophenyl) -3-propyl-3-aza-bicyclo [3.1. 0] hexane 3-aza-b-cyclo [3.1.O-Hexane (1 R) -3-Butyl-1- (3,4-dichlorophenyl) - (1 S) -3-butyl-1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.O-Hexane 3-aza -bicycle [3.1.OJhexano (1 R) -1 - (3,4-Dichlorophenyl) -3-isobutyl- (1S) -1- (3,4-dichlorophenyl) -3-isobutyl-3-aza-bicyclo [3.1.O-Hexane 3-aza- bicycles [3.1.OJhexano (1 R) -1 - (3,4-dichlorophenyl) -3-isopropyl- (1S) -1- (3,4-dichlorophenyl) -3-isopropyl-3-aza-bicyclo [3.1.0] hexane 3-aza-bicyclo [3.1.OJhexane (1R) -3-cyclo (1S) -3-cyclopropyl-1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.O-Hexane 3-aza-bicyclo [3.1.O-Hexane] (1R) -3-tert-Butyl-1- (3,4-dichlorophenyl) - (1 S) -3-tert-butyl-1 - (3,4-dichlorophenyl) -3-aza-bicyclo [3.1 .OJhexane 3-aza-bicyclo [3.1. OJhexano As noted above, in certain embodiments, the methods and compositions of the invention for treating a neuropathic disorder and / or one or more related symptoms employ pharmaceutically acceptable base and acid addition salts of the compounds described above. Suitable acid addition salts are formed of acids, which form non-toxic salts and are examples of hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, hydrogen phosphate, nitrate, phosphate and hydrogen phosphate. Examples of pharmaceutically acceptable addition salts include acid addition salts, organic and inorganic. The pharmaceutically acceptable salts include but are not limited to metal salts, such as sodium salt, potassium salt, cesium salt and the like; alkali metal salts such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylene diamine salt and the like; salts of organic acids such as acetate, citrate, lactate, succinate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and similar; and amino acid salts such as arginate, asparginate, glutamate, tartrate, gluconate and the like. Suitable base salts are formed from bases, which form non-toxic salts and are examples of aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine. In other detailed embodiments, the methods and compositions of the invention for treating a neuropathic disorder and / or one or more related symptoms employ prodrug of the compounds described above. Prodrugs are considered to be any covalently linked carriers that release the active precursor drug in vivo. Examples of prodrugs useful within the invention include esters or amides with hydroxyalkyl or aminoalkyl as a substituent, and these can be prepared by reacting these compounds as described above with anhydrides such as succinic anhydride. The invention described herein will also be understood to encompass methods and compositions for treating a neuropathic disorder and / or various related symptoms using in vivo metabolic products of the compounds described above (either generated in vivo after administration of the present precursor compound, or directly administered in the form of the metabolic product itself). These products can resulting, for example, from oxidation, reduction, hydrolysis, amidation, esterification and the like of the compound administered, primarily due to enzymatic processes. Accordingly, the invention includes methods and compositions of the invention for treating a neuropathic disorder and / or one or more related symptoms employing compounds produced by a process comprising contacting a compound as described above with a mammalian subject for a period of time. enough time to give a metabolic product of it. These products are typically identified by preparing a radiolabelled compound of the invention, administering it parenterally in a detectable dose to an animal such as rat, mouse, guinea pig, monkey or human, allowing sufficient time for metabolism to occur and isolate its products from Conversion of urine, blood or other biological samples. It will also be understood that the invention described herein encompasses the methods and compositions of the invention for treating a neuropathic disorder and / or one or more related symptoms employing the above-described compounds isotopically labeled having one or more atoms replaced by an atom having an Mass or different mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F and 36C1, respectively. l-Aryl-3-azabicyclo [3.1.0] hexanes for use within the compositions and methods of the invention for treating neuropathic disorders and / or related symptoms, include l-aryl-3-azabicyclo [3.1.0] hexanes aryl - and / or aza-substituted, bi-substituted and aryl-substituted multiple here described, as well as, without limitation, all the "anti-neuro-active" l-aryl-3-azabicyclo [3.1.0] hexanes "(ie all compounds that are effective after administration to a mammalian subject in an effective amount, to treat or prevent a neuropathic disorder, or one or more symptoms associated with a neuropathic disorder in the subject) as well as all pharmaceutically acceptable active salts, polymorphs, enantiomers, solvates, hydrates and / or prodrugs of these compounds and all combinations of the above compounds or their different chemical forms as noted above. As used herein, prodrugs include any 1-aryl-3-azabicyclo [3.1.0] hexane as described herein, covalently linked with a second chemical compound or portion as a "carrier", wherein the carrier releases the active 1-aryl-3-azabicyclo [3.1.0] hexane in vivo. Examples of prodrugs include esters or amides of any of the compounds described herein, including the compounds illustrated in any of Formulas I-V, for example using hydroxyalkyl or aminoalkyl as a substituent, these prodrugs can be prepared by reacting precursor l-aryl-3-azabicyclo [3.1.0] hexane with anhydrides such as succinic anhydride. The l-aryl-3-azabicyclo [3.1.0] hexanes for use within the invention will also be understood to include in vivo metabolic products of the compounds described above. These products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification and the like of the compound administered, primarily due to enzymatic processes. Accordingly, the invention includes methods and formulations comprising metabolically processed compounds, produced by exposing 1-aryl-3-azabicyclo [3.1.0 J hexane as described herein to a physiological compartment within a mammal for a period of time sufficient to generate a metabolic product of l-aryl-3-azabicyclo [3.1.0] hexane. These products can be easily identified by preparing a radiolabelled l-aryl-3-azabicyclo [3.1.0] hexane, administering it to a mammalian subject (eg, parenterally, allowing sufficient time for metabolism to occur, and isolating the metabolic conversion products of the compound administered from the subject's urine, blood or other biological samples) The present invention is also understood to encompass methods and related compositions, wherein the l-aryl-3-azabicyclo [3.1.0] hexanes present are labeled with a detectable label portion for various known clinical uses and diagnostics, for example, l-aryl-3-azabicyclo [ 3.1.0 J hexanes can be labeled isotopically by having one or more atoms replaced by an atom that has a different mass or atomic mass number Examples of isotopes that can be incorporated into the described compounds include isotopes of hydrogen, carbon, nitrogen, oxygen , phosphorus, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F and 36C1, respectively. Labeling measures useful in this context can include any detectable chemical moiety, for example conventional fluorophores, chemiluminescers and enzymes (for example alkaline phosphatase, peroxidase and β-galactosidase). Enzyme labels are easily detected by adding a corresponding chromogenic substance and detecting the fluorescent signal or color resulting. As noted above, l-aryl-3-azabicyclo [3.1.0] hexanes for use within methods and compositions of the invention to treat or prevent neuropathic disorders and / or related symptoms, will be useful in base and addition salts. pharmaceutically acceptable acids thereof. Suitable acid addition salts are formed from acids, which form non-toxic salts, exemplified by hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate and hydrogen phosphate salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, including but not limited to: metal salts, such as sodium salts, potassium salts, cesium salts and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylene diamine salt and the like; salts of organic acids such as acetate, citrate, lactate, succinate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and similar; and amino acid salts such as arginate, asparginate, glutamate, tartrate, gluconate and the like. Convenient base salts are formed from bases, which form non-toxic salts and examples are the aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts. The various l-aryl-3-azabicyclo [3.1.0] hexanes for use within the methods and compositions of the invention for treating a neuropathic disorder and / or one or several related symptoms can be produced according to a variety of synthetic methods known as well as by traditional methods, previously not described, as illustrated here below. Methods available for synthesizing 3-azabicyclo [3.1.0] substituted aryl hexanes are limited. Bicifadine hydrochloride has been previously produced as described in the U.S. Patent. No. 4,131,611, Patent of the U.S.A. No. 4,196,120, Patent of the U.S.A. No. 4,231,935, and Epstein et al., J. Med. Chem. 24: 481, 1981. An exemplary prior synthetic method for producing bicifadine hydrochloride is set forth in Scheme A, below. Scheme A This synthetic scheme begins with the preparation of 2-bromo-2- (p-tolyl) -acetate in 3 stages. Dimethyl-1- (4-methylphenyl) -1,3-cyclopropanedicarboxylate is prepared from the bromoester which reacts with methyl acrylate. The diester is converted to the diacid, which is condensed with urea to produce 1- (p-tolyl) -1,2-cyclopropanedicarboximide. Then, 1- (p-tolyl) -1-cyclopropanedicarboxamide is reduced to an amine by Vitride® and converted to the hydrochloride salt to result in bicifadine hydrochloride. The U.S. Patent No. 4,118,417 describes a process for resolving a (+) -1- (p-methylphenyl) -1,2-cyclopropanedicarboxylic acid with S - (-) - l- (l- naphthyl) ethylamine, and its conversion to (+) - biphenylene, as illustrated below in Synthetic Scheme B. (-) - Bicyfarnide is also reported to be produced from (-) -1- (p-) acid methylphenyl) -1,2-cyclopropanedicarboxylic acid. Scheme B Additional methods and compositions for producing bicifadine and other substituted l-aryl-3-azabicyclo [3.1.0] hexanes. The reaction scheme 1 below generally establishes an exemplary process for preparing from a known methyl 2-bromo-2-p-tolylacetate or methyl 2-chloro-2-p-tolylacetate. Bromine or chloroacetate react with acrylonitrile to provide methyl 2-cyano-l-p-tolylcyclopropanecarboxylate, which is then reduced to amino alcohol by reducing agents such as lithium aluminum hydride (LAH) or sodium hydride aluminum (SAH) or NaBH4 with ZnCl2. Cyclization of the amino alcohol with S0C12 or P0C13 will provide l- (4-methylphenyl) -3-azabicyclo [3.1.0] hexane. The cyclization of 4-aminobutan-1-ol substituted by S0C12 or POCI3 in the pyrrolidine ring system was reported by Armarego et al., J. Chem. Soc. [Section C: Organic] 19: 3222-9, 1971, and in patent publication PL 120095 B2, CAN 99: 158251 by Szalacke et al. Oxyalyl chloride, phosphorus tribromide, phosphorus tribromide, oxyalyl bromide can be used for the same purpose. Methyl 2-bromo-2-p-tolylacetate or methyl 2-chloro-2-p-tolylacetate can be synthesized from p-methyl benzoylaldehyde or methyl-2-p-tolylacetate as illustrated in Reaction Scheme IA. Reaction Scheme 1 Reduction . { JCf Reagents: (a) NaOMe; (b) LiAIH4; (c) SOCI2; (d) POCI3 Reaction Scheme ÍA Reagents (a) CHCl3, NaOH; (b) SOCI2; (c) MeOH; (d) NaBr03, NaHS03 Reaction Scheme 2 below illustrates another exemplary process for transforming methyl 2-cyano-l-p-tolylcyclopropanecarboxylate to a desired compound or intermediate of the invention. The hydrolysis of the cyano ester provides the potassium salt which can then be converted to the cyano acid. The reduction and cyclization of 2-cyano-l-p-tolylcyclopropanecarboxylic acid with LAH or LiAlH (OMe) 3 according to the procedure established in Vilsmaier et al., Tetrahedron 45: 3683-3694, 1989, will generate bicifadine.

In addition, cyano-1-p-tolylcyclopropanecarboxylic acid can be hydrogenated and cyclized to amide, which is then reduces to bicifadine. Reaction Scheme 2 X = Cl c Br Hydrolysis Reagents (a) NaOMß, (b) KOH, (c) HCl, (d) L? AIH (OMe) 3 or AH, or SAH.defiesHCI, (e) H2 / Pd 0 H2 N? The following Reaction scheme 3 describes an alternative exemplary process for converting methyl 2-cyano-1-p-tolylcyclopropanecarboxylate into a desired compound or intermediate of the invention. Methyl 2-cyano-1-p-tolylcyclopropanecarboxylate is reduced and cyclized in 1-p-tolyl-3-aza-bicyclo [3.1.0] hexan-2-one, which is then reduced in bicifadine (Marazzo et al., Arkivoc v: 156-169, 2004). Reaction Scheme 3 Reagents: (a) H2 / Pd or H2 / Ni; (b) B2H6 or BH3 or LAH.fter HCI The following reaction scheme 4 provides another exemplary process for preparing bicifadine. Reaction of 2-p-tolylacetonitrile with (±) -epiclorohydrin gives approximately a 65% yield of 2- (hydroxymethyl) -1-p-tolylcyclopropanecarbonitrile (85% cis) with the trans isomer as one of the by-products (Cabadio et al., Fr. Bollettino Chimico Farmacéutico 117: 331-42, 1978; Mouzin et al., Svnthesis 4: 304-305, 1978). The methyl 2-cyano-l-p-tolylcyclopropanecarboxylate can then be reduced to the amino alcohol by a reducing agent such as LAH, SAH or NaBH4 with ZnCl2 or by catalytic hydrogenation. Cyclization of the amino alcohol with S0C12 or P0C13 provides 1- (4-methylphenyl) -3-azabicyclo [3.1.0] hexane. The cyclization of 4-aminobutene-l-ol substituted by S0C12 or P0C13 in the pyrrolidine ring system has been previously reported (Armarego et al., J. Chem. Soc. [Section C: Organic] 19: 3222-9, 1971 and the patent publication PL 120095 B2, CAN 99: 158251). Reaction Scheme 4 The Reaction scheme 5 provides an exemplary process for synthesizing the hydrochloride of (IR, 5S) - (+) - 1- (4-methylphenyl) -3-azabicyclo [3.1.0] hexane or (+) - bicifadine. Using (S) - (+) -Epichlorohydrin as a starting material in the same process written in Scheme 4, it is ensured that the final product has chirality with IR (Cabadio et al., Fr. Bollettino Chimico Farmacéutico 117: 331-42 , 1978). Reaction Scheme 5 Reaction Scheme 6 provides an exemplary process for preparing the hydrochloride of (SS, 5R) - (-) -1- (4-methylphenyl) -3-azabicyclo [3.1.0] hexane or (-) - bicifadine. Using (R) - (-) -Epichlorohydrin as a starting material in the same process described in Scheme 4, will ensure a final product with IS chirality (Cabadio et al., Fr. Bollettino Chimico Farmacéutico 117: 331-42, 1978) . Reaction Scheme 6 and Squ ema Reagents: (a) NaNH2, (b) LAH, (c) SOCI2, (d) POCI3 XX H Reaction HCl 7 provides an alternative exemplary process for transforming 2- (hydroxymethyl) -1-p- tolylcyclopropancarbonitrile to a desired compound or intermediate of the invention by an oxidation and cyclization reaction. Using chiral starting materials, (+) - epichlorohydrin or (-) - epichlorohydrin will carry the corresponding (+) - or (-) - bicifadine through the same reaction sequences. Reaction Scheme 7 88% cis Hydrogenation Cyclization ReaCTIvOS. (a) NaNH2, (b) K n04, (c) H2 / Ni or Pl. (d) B2Hß or BH3 or LAH Reaction Scheme 8 provides an exemplary process for transforming the epichlorohydrin to a desired intermediate compound of the invention by a replacement reaction and cyclization. The reaction of methyl 2-p-tolylacetate with epichlorohydrin gives methyl 2- (hydroxymethyl) -1-p-tolylcyclopropanecarboxylate with the desired cis isomer as the main product. The alcohol becomes an OR3 group such as -O- mesylate, -O-tosylate, -O-nosylate, -O-brosylate, -0-trifluoromethanesulfonate. Then 0R3 is replaced by a primary amine NH2R4, where R4 is a nitrogen protecting group such as a 3,4-dimethoxy-benzyl group or other known protection group. Nitrogen protection groups are well known to those of skill in the art, see for example "Nitrogen Protecting Groups in Organic Synthesis", John Wiley and sons, New York, N.Y., 1981, Chapter 7; "Nitrogen Protecting Groups in Organic Chemistry", Plenum Press, New York, N.Y., 1973, Chapter 2; see also T. W. Green and P. G. Wuts in "Protective Groups in Organic Chemistry, 3rd edition" John Wiley & Sons, Inc. New York, N.Y., 1999. When the nitrogen protecting group is no longer required, it can be removed by methods well known in the art. This replacement reaction is followed by a cyclization reaction that provides the amide which is then reduced in amine by a reducing agent such as LAH. Finally, the protection group is removed to give bicifadine. Using (S) - (+) - Chiral pyrrolidinohydrin as starting material leads to (1R, 5S) - (+) -1- (4-methylphenyl) -3-azabicyclo [3.1.0] hexane or (+) hydrochloride -bicifadine with the same reaction sequence. Similarly, the (R) - (-) -Epichlorohydrin will carry the hydrochloride of (SS, 5R)) - (-) -1- (4-methylphenyl) -3- azabicyclo [3.1.0] hexane or (-) -bicifadine Reaction Scheme 8 ccyvie 0 Replacement Cycling RESOURCES: (a) NaNH2; (b) MsCI, (c) NH2-R4, () LAH c SAH or BH3. (e) HCl Reaction scheme 9 provides an exemplary process for transforming the diol to a desired compound or intermediate of the invention. The reduction of the diester gives the diol which is then converted to an OR3 group such as -O-mesylate, -O-tosylate, -0-nosylate, -O-brosylate, -O-trifluoromethanesulfonate. Then OR3 is replaced by a primary amine NH2R6, where Re is a nitrogen protecting group such as the group 3, -dimethoxy-benzyl or other protection groups known in the art (for example allyl amine, tert-butyl amine). When the nitrogen protection group does not more is required, it can be removed by methods known to those skilled in the art. Reaction Scheme 9 H HCl Reagents- (a) NaO e, (b) NaBH ,,, (c) sCi, (d) NH3, (e) NH2-Rβ, (f) H2 / Pd c acid deprotection Reaction scheme 10 provides an exemplary process for resolving l-p-tolyl-3-aza-bicyclo [3.1.0] hexane in (+) - and (-) - biphenylene. The resolution of amines through tartaric salts is generally known to those skilled in the art. For example, using 0, 0-Dibenzoyl-2R, 3R-Tartaric acid (made by acylating L (+) - tartaric acid with benzoyl chloride) in dichloroethane / methanol / water, methamphetamine racemic can be resolved with 80-95% yield, with an optical purity of 85-98% (Synthetic Communications 29: 4315-4319, 1999). Reaction Scheme 10 (+/-) - Bicifadine (+) -Bicifadine (-) - Bicifadine (-) - icifadine ReaCtlVOS (a) L - (-) - DBTA, (b) NaOH, lies) HCl in 1PA (C) D - (+) - DBTA Reaction Scheme 11 R = Me (1). Et (2), Propyl (3), 1-pr? Pll (), CIClOpropyl (5), i-butyl (6), t-butyl (7), (CH2) 2OCH3 (8) Enantiomers of compounds within the present invention can be prepared as illustrated in Scheme 12: Reaction Scheme 12 Alternatively, enantiomers of the compounds of the present invention can be prepared as illustrated in Scheme 13 using alkylation reaction conditions exemplified in Scheme 11. Reaction Scheme 13 To produce additional substituted l-Aryl-3-Azabicyclo [3.1.0] hexanes for use within the methods and compositions of the invention for treating a neuropathic disorder and / or one or more related symptoms, the following provides a general procedure for alkylation of 3-azabicyclo [3, 1, 0] hexanes. To a stirred solution of 3-azabicyclo [3, 1, 0] hexane (1 eq) in anhydrous DMF DMF (15 mL) is added disopropylethylamine (DIPEA) (1.3 eq). The reaction mixture is stirred at room temperature for 20 minutes then alkyl halides (1.3 eg) are added to the reaction mixture and then allowed to stir at room temperature for 2 hours and analyzed by TLC. If unreacted starting material remains, the reactions are heated to 50 degrees C and maintained overnight. The reactions were reduced under high vacuum then dissolved in dichloromethane (20 mL) and washed with water (20 mL). The mixture is passed through a separate phase cartridge. The organic fractions were collected and filtered through a 2 g silica cartridge, the fractions were monitored by TLC, the fractions containing the desired product were combined, reduced and analyzed by NMR- ^. The following compounds were prepared by the following general procedures described above: Synthesis of 3-Methyl-l-p-tolyl-3-aza-bicyclo 13. 1.01 hexane. 0.6871 g (yield: 51%). The compound is analyzed by nuclear magnetic resonance, NMR, confirming the structure produced and the resulting NMR data are cited below. XH NMR (300 MHz, "56-DMS0) d 7.10-7.03 (m, 4H, ArH), 3.28 (d, 1H, J = 8.5 Hz, NCH2), 3.07 (d, 1H, J = 8.8 Hz, NCH2) , 2.55 (d, 1H, J = 8.4 Hz, NCH2), 2.47 (dd, 1H, J = 8.8 Hz, 5.1 Hz, NCH2), 2.37 (s, 3H, NCH3), 2.30 (s, 3H, ArCH3), 1.65 (m, 1H, CH2CH), 1.38 (t, 1H, J = 4.0 Hz, CHCH2), 0.77 (dd, 1H, J = 8.1 Hz, 4.4 Hz, CHCH2).

Synthesis of 3-Ethyl-l-p-tolyl-3-aza-bicyclo r 3.1.01 hexane. 1.0324 g (yield: 72%) XH NMR (300 MHz, 6-DMSO) d 7.11-7.04 (m, 4H, ArH), 3.35 (d, 1H, J = 8.4 Hz, NCH2), 3.12 (d, 1H , J = 8.5 Hz, NCH2), 2. 56-2.43 (m, 4H, 2 x NCH2, CH3CH2), 2.32 (s, 3H, NCH3), 1.66 (m, 1H, CH2CH), 1.39 (t, 1H, J = 4.4 Hz, CHCH2), 1.09 (t , 3H, J = 7.4 Hz, CH2CH3), 0.78 (dd, 1H, J = 7.7 Hz, 4.0 Hz, CHCH2). Synthesis of 3-Propyl-l-p-tolyl-3-aza-bicyclo f3.1.01 hexane. 0.9284 g (yield: 60%) 1H NMR (300 MHz, 6-DMSO) d 7.11-7.04 (m, 4H, ArH), 3.34 (d, 1H, J = 8.4 Hz, NCH2), 3.12 (d, 1H , J = 8.9 Hz, NCH2), 2.55 (d, 1H, J = 8.5 Hz, NCH2), 2.44 (m, 3H, NCH2, CH2CH2CH3), 2.32 (s, 3H, ArCH3), 1.66 (m, 1H, CH2CH ), 1. 50 (m, 2H, CH2CH2CH3), 1.39 (t, 1H, J = 4.3 Hz, CHCH2), 0.90 (t, 3H, J = 7.4 Hz, CH2CH3), 0.77 (dd, 1H, J = 7.7 Hz, 4.1 Hz , CHCH2). Synthesis of 3-Isopropyl-l-p-tolyl-3-aza-bicyclo f3.1.01 hexane. 0.6645 g (yield: 43%) XH NMR (300 MHz,? 6-DMSO) d 7.76-7.05 (m, 4H, ArH), 3.38 (d, 1H, J = 8.5 'Hz, NCH2), 3.15 (d, 1H, J = 8.8 Hz), 2.62 (d, 1H, J = 8.4 Hz, NCH2), 2.52 (dd, 1H, J = 8.8 Hz, 3.7 Hz, NCH2), 2.47 (m, 1H, NCH2), 2.32 ( s, 3H, ArCH3), 1.66 (m, 1H, CH2CH), 1.37 (t, 1H, J = 4.0 Hz, NCH2), 1.07 (dd, 6H, J = 3.7 Hz, 6.7 Hz, ((CH3) 2CH) , 0.76 (dd, 1H, J = 8.1 Hz, 4.1 Hz, CHCH2) Synthesis of 3-Isobutyl-lp-tolyl-3-aza-bicyclo r3.1.01 hexane 0.8059 g (yield: 49%) 1ti NMR (300 MHz, ¿6-DMSO) d 7.25 - 7.05 (m, 4H, ArH), 3.30 (d, 1H, J = 8.4 Hz, NCH2), 3.08 (d, 1H, J = 8.5 Hz, NCH2), 2. 51 (d, 1H, J = 8.1 Hz, NCH2), 2.45 (dd, 1H, J = 8.4 Hz, 3.6 Hz, NCH2), 2.34 (s, 3H, ArCH3), 2.23 (d, 2H, J = 7.0 Hz ), NCH2CH), 1.74 (m, 1H, CH2CH (CH3) 2), 1.65 (m, 1H, CH2CH), 1.43 (t, 1H, J = 4.1 Hz, CHCH2), 0.89 (d, 6H, J = 6.7 Hz, CH (CH3) 2), 0.74 (dd, 1H, J = 8.1 Hz, 3.7 Hz, CHCH2). Synthesis of 3- (2-methoxyethyl) -l-p-tolyl-3-aza-bicyclo 13.1.01 hexane. 0.092 g (yield: 5%) 1 H NMR (300 MHz, 6-DMSO) d 71.4-7.02 (m, 4H, ArH), 3.46 (t, 3H, J = 5.7 Hz, NCH2CH2OCH3), 3.34 (s, 3H, OCH3), 3.12 (d, 1H, J = 8.5 Hz, NCH2), 2.67 (t, 2H, J = 5.9Hz, NCH2CH2) CH3 ), 2.60 (d, 1H, J = 8.4 Hz, NCH2), 2.50 (dd, 1H, J = 8.8 Hz, 5.1 Hz, NCH2), 2.31 (s, 3H, ArCH3), 1.63 (m, 1H, CH2CH) , 1.40 (t, 1H, J = 4.1 Hz, CHCH2), 0.76 (dd, 1H, J = 8.0 Hz, 4.4 Hz, CHCH2). Synthesis of l-p-Tolyl-3-tri luoromethyl-3-aza-bicyclo [3.1.01 hexane. To a stirred solution of bicifadine (free base) (1 g, 4.77 mmol) and dibromodifluoromethane (0.87 mL, 9.54 mmol) in DMSO (10 mL) are added tetrakis (dimethylam ethylene (2.4 mL, 10.5 mmol) per drops at room temperature. ambient. Upon complete addition, the reaction is stirred at room temperature overnight. The reaction mixture is filtered to remove solid by-products. The filtrate is divided between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (50 mL), the organic fractions are collected, dried over magnesium sulfate, filtered and reduced. The crude residue is purified by column chromatography [SiO 2 (30 g): (90 EtOAc: 8 MeOH: 2 NH 4 OH)] to give the required material as a yellow oil 0.6050 g (53%). X H NMR (300 MHz, <6-DMSO) d 7.16-7.06 (m, 4H, ArH), 3.97 (t, 1H, J = 6.3 Hz, NCH2), 3.78 (s, 3H, NCH2), 2.34 (s) , 3H, ArCH3), 1.87 (m, 1H, CHCH2), 1.19 (t, 1H, J = 5.5 Hz, CHCH2), 0.87 (m, 1H, CHCH2). Synthesis of l-p-Tolyl-3- (2, 2, 2-trifluoroethyl) -3-aza-bicyclo [3.1.01 hexane. A solution of (2 g, 9.54 mmol) and triethylamine (1.33 mL, 9.54 mmol) and 2,2,2-trifluoroethyltrichloromethane sulfonate (0.7 mL, 4.4 mmol) in toluene (20 mL) warms the reflux and maintains at this temperature until complete conversion by TLC is observed. The reaction mixture is partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic fractions were isolated, dried over magnesium sulfate, filtered and reduced. Crude material is purified by column chromatography [SiO2 (30 g): (90 EtOAc: 8 MeOH: 2 NH4OH)] to give the required material as a yellow oil, 0.9149 g (75%). X H NMR (300 MHz, d 6-DMSO) 7.26-7.05 (m, 4H, ArH), 3.44 (d, 1H, J = 8.1 Hz, NCH2), 3.23-3.08 (m, 3H, CH2CF3, NCH2), 2.90 (d, 1H, J = 8.1 Hz, NCH2), 2.84 (dd, 1H, J = 8.1 Hz, 4.1 Hz, NCH2), 2.37 (s, 3H, ArCH3), 1.71 (m, 1H, CH2CH), 1.38 ( t, 1H, J = 4.4 Hz, CHCH2), 0.83 (dd, 1H, J = 7.7 Hz, 4.0 Hz, CHCH2). General Procedure for Formation of Hydrochloride Salt. To a stirred solution of the free base (1 mol equiv.) In anhydrous diethyl ether (5 mL) is added 1M HCl in ether (5 mol equiv.) Per drops. Before addition complete, the reaction mixture is stirred at an ice bath temperature for 30 minutes. The resulting solids are isolated by filtration, wash with cold diethyl ether (5 m). The isolated solids are dried in the oven and canalized by 1 H-NMR, 13 C-NMR and MS. Synthesis of 3-Methyl-l-p-tolyl-3-aza-bicyclo f3.1.01 hexane hydrochloride. 1ti NMR (300 MHz, d6-DMSO) d 11.36 (s, 1H, NHC1), 7.20-7.12 (m, 4H, ArH), 3.86 (dd, 1H, J = 11.0 Hz, 5.1 Hz, NCH2), 3.60 ( dd, 1H, J = 11.1 Hz, 5.2 Hz, NCH2), 3.53 - 3.43 (m, 2H, 2 * NCH2), 2.80 (s, 3H, NCH3), 2.28 (s, 3H, ArCH3), 2.07 (m, 1H, CHCH2), 1.81 (t, 1H, J = 5.2 Hz, CHCH2), 1.02 (t, 1H, J = 7.4 Hz, CHCH2); 13 C NMR (75 MHz, 6-DMSO) d 136.0, 135.7, 128.9, 126.5, 58.5, 55.9, 29.9, 23.0, 20.5, 15.2; MS (m / z) 188 (MH +, 100). Synthesis of 3-Ethyl-l-p-tolyl-3-aza-bicyclo f3.1.01 hexane hydrochloride. 1 H NMR (300 MHz,> 6-DMSO) d 1.06 (s, 1H, NHC1), 3.92 (dd, 1H, J = 11.0 Hz, 5.1 Hz, NCH3), 3.64 (dd, 1H, J = 11.0 Hz , 5.5 Hz, NCH2), 3.50 - 3.39 (m, 2H, 2 NCH2), 3.20 (m, 2H, NCH2CH3), 2. 29 (s, 3H, ArCH3), 2.09 (m, 1H, CHCH2), 1.81 (m, 1H, CHCH2), 1.29 (t, 3H, J = 7.4 Hz, NCH2CH3), 1.02 (t, 1H, J = 6.6 Hz, CHCH2); 13 C NMR (75 MHz, 6-DMSO) d = 136.1, 135.7, 128.9, 126.4, 56.7, 54.2, 49.4, 29.5, 22.5, 20.5, 15.5, 10.4; MS (m / z) 202 (MH +, 100).

Synthesis of 3-Propyl-l-p-tolyl-3-aza-bicyclohydrochloride [3.1.01 hexane. ? ti NMR (300 MHz, d 6 -DMSO) d 11.13 (s, 1H, NHC1), 7.34 - 7.14 (m, 4H, ArH), 3.90 (dd, 1H, J = 11.1 Hz, 5.2 Hz, NCH2), 3.63 (dd, 1H, J = 11.0 Hz, 5.5 Hz, NCH2), 3.52-3.39 (m, 2H, 2 NCH2), 3.07 (m, 2H, NCH2CH2CH3), 2.29 (s, 3H, ArCH3), 2.08 (m, 1H, CHCH2), 1.84 (m, 1H, CHCH2), 1.76 (m, 2H, NCH2CH2CH3), 1.01 ( t, 1H, J = 6.6 Hz, CHCH2), 0.89 (t, 3H, J = 7.3 Hz, NCH2CH2CH3); 13 C NMR (75 MHz, 6-DMSO) d 136.9, 136.5, 129.7, 127.3, 57.9, 56.7, 55.5, 30.4, 23. 4, 21.3, 19.1, 16.3, 11.7; MS (m / z) 216 (MH +, 100). Synthesis of 3-Isopropyl-l-p-tolyl-3-aza-bicyclo f3.1.01 hexane hydrochloride. X H NMR (300 MHz, 6-DMSO) d 11.01 (s, 1H, NHC1), 7.21 - 7.14 (m, 4H, ArH), 3.91 (dd, 1H, J = 11.0 Hz, 5.5 Hz, NCH2), 3.61 (dd, 1H, J = 11.0 Hz, 5.5 Hz, NCH2), 3.54 - 3.34 (m, 3H, 2 NCH2, NCH (CH3) 2), 2.29 (s, 3H, ArCH3), 2.10 (m, 1H, CHCH2 ), 1.90 (t, 1H, J = 5.5 Hz, CHCH2), 1.36 (t, 6H, J = 7.0 Hz, NCH (CH3) 2), 0.98 (t, 1H, J = 6.2 Hz, CHCH2); 13 C NMR (75 MHz, 6-DMSO) d 136.5, 135.9, 129.1, 126. 7, 58.3, 56.3, 53.6, 22.9, 20.8, 18.7, 18.6, 15.9; MS (m / z) 216 (MH +, 100). Synthesis of 3-Isobutyl-l-p-tolyl-3-aza-bicyclo-hydrochloride Í3.1.01 hexane. X H NMR (300 MHz,? 6-DMSO) d 10.67 (s, 1H, NHC1), 7.21 - 7.14 (m, 4H, ArH), 4.01 (dd, 1H, J = 11.0 Hz, 5.5 Hz, NCH2), 3.73 (dd, 1H, J = 11.1 Hz, 5.6 Hz, NCH2), 3.52 (m, 2H, 2 NCH2), 3.05 (t , 2H, J = 5.6 Hz, CH2CH (CH3) 2), 2.29 (s, 3H, ArCH3), 2.08 (m, 2H, CH2CH (CH3) 2, CHCH2), 2.00 (t, 1H, J = 7.0 Hz, CHCH2), 1.00 (d, 7H, J = 3.3 Hz, NCH2CH (CH3) 2, CHCH2); 13 C NMR (75 MHz, 6-DMSO) d = 144.5, 144.1, 137.2, 134.9, 70.5, 66.5, 64.1, 38.2, 33.4, 31.1. 29.3, 28.9, 24.1; MS (m / z) 230 (MH +, 100). Synthesis of 3- (2-Methoxyethyl) -1-p-tolyl-3-aza-bicyclo f3.1.01 hexane hydrochloride. XH NMR (300 MHz, 6-DMSO) d 7.21 - 7.14 (m, 4H, ArH), 3.90 (dd, 1H, J = 11.0 Hz, 5.2 Hz, NCH2), 3.78 (m, 2H, NCH2CH2OCH3), 3.67 (dd, 1H, J = 11.0 Hz, 5.1 Hz, NCH2), 3.54 (m, 2H, 2 x NCH2), 3.41 (m, 2H, NCH2CH2OCH3), 3.31 (s, 3H, NCH2CH2OCH3), 2.29 (s, 3H, ArCH3), 2.09 ( m, 1H, CHCH2), 1. 75 (t, 1H, J = 5.9 Hz, CHCH2), 1.02 (t, 1H, J = 6.6 Hz, CHCH2); 13 C NMR (75 MHz, "56-DMSO) d 144.4, 144.2, 137.2, 134.9, 75.2, 66.4, 66.4, 63.9, 61.8, 37.9, 30.9, 28.8, 23.6; MS (m / z) 232 (MH +, 100). Synthesis of l-p-Tolyl-3-trif hydrochloride luoromethyl-3-aza-bicyclo [3.1.01 hexane. 1ti NMR (300 MHz, 6-DMSO) d 7.14 '(s, 4H, ArH), 3.94-3.49 (m, 4H, 4 x NCH2), 2.28 (s, 3H, ArCH3), 2.01 (m, 1H, CHCH2) , 1.09 (t, 1H, J = 5.2 Hz, CHCH2), 0.89 (t, 1H, J = 4.8 Hz, CHCH2); 13 C NMR (75 MHz, 6-DMSO) d 155.5, 151.7, 145. 4, 143.6, 137.2, 134.7, 60.8, 60.3, 57.7, 57.2, 38.8, 38.2, 31.8, 31.3, 28.8, 26.4, 26.3; MS (m / z) 242 (MH +, 5). Synthesis of l-p-Tolyl-3- (2,2,2-trifluoroethyl) -3-aza-bicyclo [3.1.01 hexane] hydrochloride. 1 H NMR (300 MHz, 6-DMSO) d 7.18-7.12 (m, 4 H, Ar H), 4.01 (m, 2 H, 2 x NCH 2), 3.75 (m, 1 H, NCH 2), 2.51 (m, 3 H, NCH 2 CF 3 , NCH2), 2.28 (s, 3H, ArCH3), 2.00 (m, 1H, CHCH2), 1.70 (m, 1H, CHCH2), 0.96 (m, 1H, CHCH2); 13 C NMR (75 MHz, 6-DMSO) d 145.32, 143.79, 137.21, 134.82, 67.26, 64.41, 61.95, 61.56, 61.13, 60.71, 38.61, 31.70, 28.85; MS (m / z) 256 (MH +, 100). To produce additional compounds for use within the methods and compositions of the invention for treating a neuropathic disorder and / or one or more related symptoms, including multiple aryl substituted and / or aza-substituted compounds as described above, additional synthetic intermediates and methods Here they are provided as described below. Diagram of Reaction 14 Reagents: (a), i) RNH2, THF, reflux i) NaOAc, Ac20; (b) Suzuki coupling (c) Cyclopropanation; (d) SAH, LiCl, then HCl; (e), i) BH3 / THF, ii) HCI / Et20 Synthesis of 1- (3,4-dichlorophenyl) -3-oxa-bicyclo [3.1.01 hexane-2,4-dione] To a stirred solution of l- (3,4-dichlorophenyl) -cyclopropane-1,2-dicarboxylic acid (J. Med. Chem. 1981,24481-490) (28.3 g) in acetyl chloride (142 ml) is heated to reflux for 3 hours, cool to room temperature and evaporate. The oil is dissolved in toluene (100 ml) and evaporated to dryness. This is then repeated two more times before crushing the semi-solid in hexane (100 ml). The solid is filtered off, washed with hexane and extracted dry under nitrogen atmosphere to give a brown solid, yield = 26.7 g (101%); NMRH (300 MHz, CDC13) d 7.52-7.46 (m, 2H, ArH), 7.27-7.24 (m, 1H, ArH), 3.35-3.30 (m, 1H, CH), 2.13-2.10 (m, 1H, CH ), 1.97-1.95 (m, 1H, CH). Synthesis of 2- (tert-butylcarbamoyl) -2- (3,4-dichlorofenyl) cyclopropanecarboxylic acid. tetrahydrofuran (THF) (365 ml) is added tert-butylamine (23 ml) with the temperature remaining below 20 degrees C. The suspension is then stirred at room temperature for 1 hour where thin layer chromatography (TLC) (50% ethyl acetate in hexanes) indicates complete reaction. The solvent is removed by evaporation and the resulting sticky mass is used raw in the next reaction. Synthesis of 3-tert-butyl-1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.0] hexan-2, 4-dione J & A stirred suspension of 2- (tert-butylcarbamoyl) -2- (3,4-dichlorophenyl) -cyclopropane-carboxylic acid and sodium acetate (4.3 g) in acetic anhydride (145 ml) is heated under reflux for 4 hrs where TLC (50% ethyl acetate in hexanes) indicates complete reaction such that the solvent is removed by evaporation and the oil is absorbed on silica (49.7 g). The product is then purified by column chromatography [SiO2 (503.7 g): (10% EtOAc in hexanes)] to give the required material as a yellow oil. In a yield of 23.7 g (73%); X H NMR (300 MHz, CDC13) d 7.52-7.46 (m, 2 H, Ar H), 7.23-7.20 (m, 1 H, Ar H), 2.64-2.60 (m, 1 H, CH), 1.72-1.66 (m, 2 H, CH ), 1.52 (s, 9H, Bufc) Synthesis of 3- tert -butyl-1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.0] hexan-2-one To a stirred solution of 3-tert-butyl-1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.0] hexan-2, 4-dione (23.7 g) in THF (395 ml) at 5 ° C. A solution of borane in THF (1M, 304 ml) is added at a temperature that is maintained below 5 degrees C. The solution is then heated to reflux for 2 hrs, where TLC (20% ethyl acetate in hexanes) ) indicates complete reaction. The solution is cooled to 0 degrees centigrade and neutralized by the addition of dilute HCl (6M, 400 ml) with the temperature remaining below 10 degrees C. The THF is removed by evaporation and the white solid is filtered off and dried. 45 degrees C in vacuo overnight, resulting in 17.0 g (75%) of the desired product; ^ NMR (300 MHz, CDC13) d 7.71 (d, 1H, J = 2.4 Hz, ArH), 7.57 (d, 1H, J = 8.4 Hz, ArH), 7.36 (dd, 1H, J = 8.4 Hz, J = 2.4 Hz, ArH), 4.86 (br s, 2H, CH2), 3.69-3.63 (m, 1H, CH), 3.46-3.43 (m, 1H, CH), 2.37-2.31 (m, 1H, CH), 1.45 -1.42 (m, 1H, CH), 1.32 (s, 9H, Bu *) MS (m / z) 299 (MH +, 100). Synthesis of 3-tert-butyl-1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.0] hexane To a stirred solution of 3-tert.-l- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.0] hexan-2, -one (15.1 g) in THF (270 ml) is added a borane solution in THF (1M; 304 ml) at 20 degrees C. The solution is then heated at reflux for 16 h where the TLC (20% ethyl acetate in hexanes) indicates incomplete reaction such that the solution is cooled at room temperature an additional portion of borane in THF (1M, 130 ml) is added at 20 degrees C. The solution is again heated to reflux and maintained for 24 h. TLC indicates approximately 50% reaction, such that the solution is cooled to 0 degrees C and neutralized by the addition of dilute HCl (6M, 400 ml) with the temperature remaining below 10 degrees C. THF is evaporated The white solid is filtered off and the aqueous phase extracted with ethyl acetate (3 x 250 ml). The aqueous phase is basified with NaOH (5M; 500 ml) and the product extracted into ether (3 x 200 ml), dried (MgSO 4) and evaporated to give a colorless oil in a yield of 5.9 g (41%). The 3-tert-butyl-1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.0] hexane is added to a solution of maleic acid (2.3 g) in methanol (11.5 ml) and stored at - 20 degrees C during the night. The solid is filtered off, washed with methanol (2.5 ml) and dried at 45 degrees C in vacuo overnight, resulting in the salt 1- (3,4-dichloro-phenyl) -3-tert-butyl-3-aza-bicyclo [3.1.0] -hexane maleate 1.1 g (5%); ^ NMR (300 MHz, CDC13) d 7.31-7.19 (m, 2H, ArH), 6.95-6.91 (m, 1H, ArH), 3.28 (d, 1H, J = 8.4 Hz, CH), 3.10 (d, 1H , J = 8.4 Hz, CH), 2.48-2.40 (m, 4H, CH), 1.68-1.62 (m, 1H, CH), 1.47-1.33 (m, 5H, CH), 0.92-0.87 (m, 3H, CH3), 0.77-0.74 (, 1H, CH) MS (m / z) 284 (M +, 100). Synthesis of 1- (3,4-dichloro-phenyl) -3-r-butyl-3- aza-bicyclo [3.1.0] -hexane To a stirred solution of 1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.0] hexane-2,4-dione) (15.8 g) in N, N-dimethylformamide (DMF) (63 ml) sodium hydride is added (60% by weight in oil, 2.5 g) with the temperature remaining below 20 degrees C. The suspension is then stirred at room temperature for 20 minutes before bromobutane (9.9 ml) is added. The solution after stir at room temperature for 24 h when TLC (20% ethyl acetate in hexane) indicates complete reaction. The solution is neutralized in water (500 ml), extracted with ether (2 x 250 ml) and the extracts washed with water (2 x 250 ml), saturated brine (2 x 250 ml), dried (MgSO 4) and evaporated, giving per result 15.6 g of 3-butyl-1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.0] hexan-2,4-dione (81%). The imide (3-butyl-1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.0] hexan-2,4-dione) is dissolved in THF (310 ml) and a THF burane solution ( 1M; 225 ml) is added at a temperature which is maintained below 5 degrees C. The solution is then heated at reflux for 4 hrs, where the TLC (20% ethyl acetate in hexane) indicates complete reaction. The solution is cooled to 0 degrees centigrade and neutralized by the addition of dilute HCl (6M, 200 ml) at the temperature maintained below 10 degrees C. The solution is then extracted with ether (2 x 200 ml), the phase The aqueous phase is basified with sodium hydroxide (5M, 480 ml), extracted with ether (3 x 150 ml), the extracts are combined, dried (MgSO 4) and evaporated to give a crude yield of 3.2 g. The oil is added to HCl in ether (2M, 20 mL), stored overnight at -20 degrees C and the resulting solid separated by filtration and washed with ether (2 x 10 mL) TLC (20% ethyl acetate in hexanes). ) indicates two components, such that the solids dissolves in water (50 ml) basify with solid K2C03 at pH and extracted with ether (3 x 100 ml). The extracts were extracted (MgSO4) and evaporated. The product is then purified by chromatography [SiO2 (22.7 g): (x0% EtOAc in hexanes)] to give the required material as a yellow oil. 0.7 g (5%); ^ NMR (300 MHz, CDC13) d 7.16-7.06 (m, 4H, ArH), 3.97 (t, 1H, J = 6.3 Hz, NCH2), 3.78 (s, 3H, NCH2), 2.34 (s, 3H, ArCH3), 1.87 (m, 1H, CHCH2), 1. 19 (t, 1H, J = 5.5 Hz, CHCH2), 0.87 (m, 1H, CHCH2) MS (m / z) 188 (MH +, 100) Synthesis of 2- (Propylcarbamoyl) -2- (3, 4- dichlorophenyl) cyclopropanecarboxylic acid To a stirred solution of 1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.0] hexan-2,4-dione) (12.8 g) in THF (175 ml) is added to n-propylamine ( 8.6 ml) with the temperature remaining below 20 degrees C. The suspension is then stirred at room temperature for 1 hr where TLC (50% ethyl acetate in hexane) indicates complete reaction. The solvent is separated by evaporation and the resulting sticky mass is used raw in the next reaction. Synthesis of 3-Propyl-1- (3, -dichlorophenyl) -3-aza-bicyclo [3.1.0] hexan-2,4-dione A stirred suspension of the above amide 2- (Propylcarbamoyl) -2- (3, -dichlorophenyl) cyclopropanecarboxylic acid and sodium acetate (4.1 g) in acetic anhydride (68 ml) is heated at reflux for 4 h where TLC (ethyl) 50% acetate in hexanes) indicates complete reaction such that the solvent is removed by evaporation and the oil is abso onto silica (14.4 g).

The product is purified by column chromatography [Si02 (147.2 g): (20% EtOAc in hexanes)] to give the required material as a yellow oil, 4.6 g (31% over three steps). Synthesis of 1- (3,4-dichloro-phenyl) -3-n-propyl-3-aza-bicyclo [3.1.0] -hexane hydrochloride To a stirred solution of 3-propyl-1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.0] hexane-2,4-dione (4.6 g) in THF (92 ml) at 5 degrees C , it is added to a solution of borane in THF (1M, 69 ml) with a temperature that is kept below 5 degrees C. The solution is then heated to reflux for 4 h where TLC (20% ethyl acetate in hexanes) indicates full reaction The solution is cooled to 0 degrees C and neutralized by the addition of dilute HCl (6M, 250 ml) with the temperature remaining below 10 degrees C. The TFC separates by evaporation and the aqueous phase extracted with ether (2 x 250 ml) ). The aqueous phase is basified with NaOH (5M, 250 ml) and the product extracted into ether (2 x 150 ml), dried (MgSO 4) and evaporated to give a colorless oil, 2.3 g (17%). The oil is dissolved in ether (30 ml) and a solution of HCl in ether (2M, 30 ml) is added. The suspension then stores at -20 degrees C overnight. The solid is filtered off, washed with ether (20 ml) and dried at 40 degrees C in-vacuo overnight, yield = 1.3 g (50%); XH NMR (300 MHz, CDC13) d 12.56 (br s, 1H, NH +), 7.66-7.55 (m, 1H, ArH), 7.26 (s, 1H, ArH), 7.02-6.99 (m, 1H, ArH), 4.12 -4.10 (m, 1H, CH), 4.09-3.90 (m, 1H, CH), 3.18-3.01 (m, 4H, CH2), 2.40-2.36 (m, 1H, CH), 2.02-1.98 (m, 3H, CH), 1.18-0.95 (m, 4H, CH2) MS (m / z) 270 (MH +, 100) Chiral separation of 1- (3,4-dichloro-f-enyl) -3- thi? Ethyl-3-aza-bicyclo- [3.1.0] hexane (1 R) -1 - (3,4-Dichlorophenyl) -3-methyl-3- (1 S) -1 - (3,4-dichlorophenyl) -3-methyl-3-aza-bicyclo [3.1. OJhexano aza-bicyclo [3.1. OJhexane A solution of racemic 1- (3, 4-dichloro-phenyl) -2-oxo-3-methyl-3-aza-bicyclo- [3.1.0] hexane (0.75 g) is prepared using methanol (10 mL) . This solution is then injected onto a CHIRALCEL® OD-H 5 μm column and an isocratic run is started with UV supervision at 275 μm, flow rate 60 mL / min; Mobile Phase: 95: 5 C02 / MeOH + 2% DEA. Peaks are collected separately and concentrated to dryness under reduced pressure to give the desired eluates as a first elution enantiomer and a second elution enantiomer. Preparatory method SFC: Column: 250 x 20 mm CHIRALCEL® OD-H 5 μm Mobile phase: 95: 5 C02 / MeOH + 2% DEA. Flow rate: 60 ml / min Detection: UV 275 nm Temperature: 15 ° C Output pressure: 150 bar An HPLC analytical method was developed in order to control the purity of the fractions collected. HPLC analytical method: Column: 250 x 4.6 mm CHIRALCEL® OD-H 5 m Mobile phase: 98: 2: 0.1 n-heptane / 2-PrOH / DEA Flow rate: 0.5 ml / min Detection: DAD 250 nm Temperature: 25 ° C Synthesis of the first eluting enantiomer of 1- (3, -dichloro-phenyl) -3-methyl-3-azabicyclo [3.1.0] -hexane hydrochloride To a stirred solution of the first elution 1- (3, 4-dichloro-phenyl) -3-methyl-3-aza-bicyclo [3.1.0] -hexane (117 mg) in ether (5 ml) is added to a solution of HCl in ether (2M, 5 ml). The suspension is then stored at -20 degrees C overnight. The solid is filtered off, washed with ether (5 ml) and dried in vacuo overnight, yield = 57.8 mg (43%); : HRMN (300 MHz, CDC13) d 12.85 (s, 1H, NH +), 7.43-7.03 (m, 3H, ArH), 4.16-3.97 (m, 1H, CH), 3.31-2.93 (m, 3H, CH) , 2.35 (s, 1H, CH), 2.05 (s, 1H, CH), 1.57 (s, 3H, CH3) MS (m / z) 242 (MH +, 100).

Synthesis of the second eluting enantiomer of 1- (3,4-dichloro-phenyl) -3-methyl-3-aza-bicyclo [3.1.0] -hexane hydrochloride To a stirred solution of the second eluate 1- (3, 4- dichloro-phenyl) -3-methyl-3-aza-bicyclo [3.1.0] -hexane (143 mg) dissolved in ether (5 ml) is added to a solution of HCl in ether (2M, 5 ml). The suspension then stores at -20 degrees C overnight. The solid is filtered off, washed with ether (5 ml) and dried overnight in vacuo, yield = 59.4 mg (36%); X H NM (300 MHz, CDC13) d 12.85 (s, 1H, NH +), 7.43-7.03 (m, 3H, ArH), 4.16-3.97 (m, 1H, CH), 3.31-2.93 (m, 3H, CH) , 2.35 (s, 1H, CH), 2.05 (s, 1H, CH), 1.57 (s, 3H, CH3) MS (m / z) 242 (MH +, 100). The following description illustrates an exemplary synthesis method for producing compounds of the invention, which is illustrative of the general synthesis scheme Scheme 14, as described above. Synthesis of N-methyl bromomaleimido A solution of bromomalieic anhydride (aldrich) (52.8 g, 0.298 mol) in diethyl ether (250 mL) was added. cool to 5 degrees C. A 2M solution of methylamine in THF (298 mL, 0.596 mol, 2 eq.) is added per drop for 1 hour and the reaction is stirred for an additional 30 minutes, keeping the temperature below 10 degrees C. The resulting precipitate is filtered, washed with diethyl ether (2 x 100 mL) and air dried for 30 minutes then suspended in acetic anhydride (368 mL) and sodium acetate (12.2 g, 0.149 mol, 0.5 eq.) Is added. The reaction is heated to 60 degrees C for 2 hours then the solvent is removed in vacuo. The residue is taken up in DCM (500 mL) and washed with saturated sodium bicarbonate solution (2 x 500 mL) and water (2 x 300 mL). The organic reactions are dried over MgSO4 (89 g), filtered and reduced in vacuo. The resulting oil is formed in a mixture at constant boiling temperature with toluene (4 x 100 mL) to give N-methyl bromomaleimide as a beige solid (41.4 g, 73%); XH NMR (300 MHz, CDC13) ..6.95 (1H, s, CH), 3.07 (3H, s, CH3N). Synthesis of N-methyl- (3-chloro-4-fluorophenyl) maleimido N-Methyl bromomalleimide (20.3 g, 0.107 mol), 3-chloro-4-fluorobenzene boronic acid (20.5 g, 0.117 mol, 1.1 eq.), Cesium fluoride (35.8 g, 0.235 mol, 2.2 eq.) And sodium chloride. 1, 1'-bis-dienylphosphinoferrocene palladium (4.3 g, 0.005 mol, 5 mol%) is suspended in 1,4-dioxane and stirred at room temperature for 1 hour then heated to 40 degrees C for 2 hours. The reaction is filtered and the solvents are removed in vacuo. The dark brown residue is recovered in DCM (100 mL), then filtered through silica (100 g), eluting with 1.5 L of DCM. Solvents are removed in vacuo and the resulting solid forms in hexagon sludge (100 ml) and filters. The cake is washed with an additional portion of hexane (100 ml) and dried to give N-methyl- (3-chloro-4-fluorophenyl) maleimido as a pale orange solid, (19.0 g, 74%); 1 H NMR (300 MHz, CDC13) 8.04-8.01 (1H, dd, J = 6.9, 2.1 Hz, ArH), 7.86-7.81 (1H, m, ArH), 7.22-7.19 (1H, t, J = 9 Hz, ArH), 6.71 (1H, s, CH), 3.07 (3H, s, CH3); MS (m / z) 239 [MH +] (60), 241 (20). Synthesis of 1- (3-chloro-4-fluorophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexan-2, 4-dione Trimethylsulfoxonium chloride (2.5 g, 0.019 mol, 1.2 eq.) And sodium hydride (0.8 g of a 60% dispersion in mineral oil, 0.019 mol, 1.2 eq.) Is suspended in THF (180 mL) and warms the reflux (66 degrees C) for 2.5 hours. The reaction is cooled to 50 degrees C and a solution of N-methyl- (3-chloro-4-fluorophenyl) maleimido (6) (3.8 g, 0.016 mol, 1 eq.) In THF (20 mL) is added in a portion. The reaction is heated to 50 degrees C for 2 hours and then cooled to room temperature. IMS (5 mL) is added to neutralize any unreacted sodium hydride and the solvent is removed in vacuo. The residue is taken up in DCM (150 mL) and washed with water (4 x 150 mL), dried over MgSO4 (32 g), filtered and the solvents are removed in vacuo. The reaction is purified by column chromatography (60 g silica eluting with 4: 1 hexane: ethyl acetate (500 mL)). The solvents are removed in vacuo to give 1- (3-chloro-4-fluorophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane-2,4-dione as a pale yellow solid (1.6 g, 40%); XH NMR (300 MHz, CDC13) 7.45-7.43 (1H, dd, J = 6.6, 2.1 Hz, ArH), 7.30-7.27 (1H, m, ArH), 7. 16-7.10 (1H, t, J = 8.7 Hz, ArH), 2.91 (3H, s, CH3), 2.74-2.70 (1H, dd, J = 8.1, 3.9 Hz, CH), 1.87-1.84 (1H, t, J = 4.2 Hz, CH), 1.81-1.76 (1H, dd, J = 8.1, 4.8 Hz, CH). Synthesis of 1- (3-chloro-4-fluorophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane Borane (1 M complex in THF, 31.5 mL, 0.032 mol, 5 eq.) Is cooled to < 0 degrees C and a solution of (7) (1.6 g, 0.006 mol) in THF (30 mL) is added dropwise, maintaining the temperature at < 0 degrees C. The reaction is heated to room temperature for 15 minutes then heated to reflux (67 degrees C) for 2.5 hours. The reaction is cooled to < 0 degrees C and neutralizes with the addition by drops of 6 M HCl (14 mL, temperature maintained at <; 0 degrees C). The solvents are removed in vacuo and the resulting white residue divided between 5 M NaOH (50 mL) and diethyl ether (50 mL). The aqueous layer is re-extracted with an additional 50 mL of diethyl ether, then the combined organic fractions are washed with water (3 x 75 mL), dried over MgSO (14 g), filtered and the solvents are removed in vacuo to give a yellow oil. . A 2 M solution of HCl in diethyl ether (12 mL) is added and thereaction is cooled to < Or degrees C to precipitate the HCl salt. The solid is washed with HCl / ether (3 x 6 mL) to give 1- (3-chloro-4-fluorophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane as a pale yellow solid, 774 mg, 47% yield; XH NMR (300 MHz, CDC13) 12.74 (1H, br-s, N + H), 7.26-7.24 (1H, m, ArH), 7.15-7.04 (2H, m, ArH), 4.12-4.06 (1H, dd, J = 10.8, 5.4 Hz, CH2), 3.96- 3.90 (1H, dd, J = 11.1, 5.1 Hz, CH2), 3.36-3.30 (1H, m, CH2), 3.24-3.18 (1H, t, J = 9.3 Hz, CH2), 2.91 (3H, s, CH3), 2.29-2.26 (1H, dd, J = 6.9, 4.8 Hz, CH), 2.03-1.97 (1H, q, J = 4.2 Hz, CH), 1.22-1.17 (1H, m, CH); MS (m / z) 226 [MH +] (100), 228 [MH + 2J. With respect to the above synthesis schemes and / or as otherwise used herein unless otherwise specified, Ar denotes a phenyl or other aromatic group having multiple substitutions on the aryl ring and R is chosen for example from hydrogen and C? -6 alkyl, halo (Ci-e) alkyl, C3-9 cycloalkyl, C1-5 alkoxy (C? -6) alkyl, carboxy (Ci-3) alkyl, C? -3 alkanoyl, carbamate, halo (C? -3) alkoxy (C? E) alkyl, C1-3 alkylamino (Ci-d) alkyl and di (C? 3) alkylamino (C? -6) alkyl, cyano (C? -) alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl. For the purpose of further describing the invention, including new compounds and methods synthetics described herein, the following terms and definitions are provided by way of example. The term "halogen" as used herein, refers to bromine, chlorine, fluorine or iodine. In one embodiment, halogen is chlorine. In another embodiment, halogen is bromine. The term "hydroxy" as used herein refers to -OH or -0. "The term" alkyl "as used herein refers to aliphatic groups of straight chains or branched chains containing 1-20 carbon atoms, some times 1-7 carbon atoms and in certain embodiments 1-4 carbon atoms This definition also applies to the alkyl portion of the alkoxy, alkanoyl and aralkyl groups In one embodiment, the alkyl is a methyl group. "includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom In one embodiment, the alkoxy group contains from 1 to 4 carbon atoms Modalities of alkoxy groups include, but are not limited to, groups methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy Modalities of the substituted alkoxy groups Include halogenated alkoxy groups In a further embodiment, the alkoxy groups may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, phenylcarbonyloxy, alkoxycarbonyloxy, phenyloxycarbonyloxy, carboxylate, alkylcarbonyl, phenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, phenylamino, diphenylamino, and alkylphenylamino), acylamino (including alkylcarbonylamino, phenylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, phenylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylphenyl, or aromatic or heteroaromatic portions. Exemplary halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy. The term "nitro", as used here alone or in combination refers to a group -N02. The term "amino" as used herein refers to the group -NRR ', where R and R' can independently be hydrogen, alkyl, phenyl, alkoxy, or heterophenyl. The term "aminoalkyl" as used herein represents a more detailed selection compared to "amino" and refers to the group --NRR ', where R and R' can independently be hydrogen or (C1-C4) alkyl. The term "trifluoromethyl" as used herein, refers to --CF3. The term "trifluoromethoxy" as used herein, refers to -OCF3. The term "cycloalkyl" as used herein, refers to a cyclic saturated hydrocarbon ring system containing from 3 to 7 carbon atoms which may be optionally substituted. Exemplary embodiments include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, the cycloalkyl group is cyclopropyl. In another embodiment, the (cycloalkyl) alkyl group contains from 3 to 7 carbon atoms in the cyclic portion and 1 to 4 carbon atoms in the alkyl portion. In certain embodiments, the group (cycloalkyl) alkyl is cyclopropylmethyl. Alkyl groups are optionally substituted from one to three substituents selected from the group consisting of halogen, hydroxy and amino. The terms "alkanoyl" and "alkanoyloxy" as used herein refer respectively to -C (0) -alkyl groups and -O-C (O) -alkyl groups, each optionally They contain 2-5 carbon atom. Specific moieties of the alkanoyl and alkanoyloxy groups are acetyl and acetoxy, respectively. The term "aroyl" used alone or in combination herein refers to a phenyl radical derived from an aromatic carboxylic acid, such as the optionally substituted benzoic or naphthoic acid. The term "aralkyl" as used herein refers to a phenyl group attached to the 4-pyridinyl ring through an alkyl group, often to one containing 1-4 carbon atoms. An exemplary aralkyl group is benzyl. The term "nitrile" or "cyano" as used herein, refers to the group -CN. The term "pyrrolidin-1-yl" as used herein refers to the structure: .N pirrolldln-1-il The term "morpholino" as used herein refers to the structure: morfollno The term "dialkylamino" refers to an amino group having two added alkyl groups which may be the same or different. The term "alkenyl" refers to a linear or branched alkenyl group of 2 to 10 carbon atoms having 1 to 3 double bonds. Exemplary embodiments include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butylene, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, 1,3-octadienyl, 2-nonenyl, 1,3-nonadienyl, 2- decenny, etc. The term "alkynyl" as used herein refers to a linear or branched alkynyl group of 2 to 10 carbon atoms having 1 to 3 triple bonds. Exemplary alkynyls include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 4-pentynyl, 1-octynyl, 6- methyl-1-heptinyl, and 2-decinyl. The term "hydroxyalkyl" alone or in combination refers to a previously defined alkyl group, where one or some hydrogen atoms, sometimes a hydrogen atom, has been replaced by a hydroxyl group. Examples include hydroxymethyl, hydroxyethyl and 2-hydroxyethyl.

The term "aminoalkyl" as used herein refers to a group NRR ', wherein R and R 1 can independently be hydrogen or (C 1 -C 4) alkyl. The term "alkylaminoalkyl" refers to an alkylamino group linked to an alkyl group (i.e., a group has a general structure -alkyl-NH-alkyl or -alkyl-N (alkyl) (alkyl)). Such groups include, but are not limited to, mono- and di- (Ci-Cß alkyl) amino C?-C8 alkyl, in which each alkyl may be the same or different. The term "dialkylaminoalkyl" refers to alkylamino groups linked to an alkyl group. Examples include, but are not limited to, N, N-dimethylaminomethyl, N, N-dimethylaminoethyl N, N-dimethylaminopropyl, and the like. The term dialkylaminoalkyl also includes groups where the bridging alkyl portion is optionally substituted. The term "haloalkyl" refers to an alkyl group substituted with one or more halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl, trifluoromethyl, perfluoropropyl, 8-chlorononyl and the like. The term "carboxyalkyl" as used herein refers to the substituent -R '-COOH where R' is alkylene; and carbalkoxyalkyl refer to -R '-COOR where R' and R are alkylene and alkyl respectively. In certain embodiments, alkyl refers to a branched chain hydrocarbyl radical of 1-6 carbon atoms with a straight or saturated chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl , 2-methylpentyl, n-hexyl, and so on. Alkylene is the same as alkyl except that the group is divalent. The term "alkoxyalkyl" refers to an alkylene group substituted with an alkoxy group. For example, methoxyethyl [CH3OCH2CH2-] and ethoxymethyl (CH3CH2OCH2-] both are C3 alkoxyalkyl groups The term "carboxy", as used herein, represents a group of the formula -COOH.The term "alkanoylamino" refers to the groups alkyl, alkenyl or alkynyl containing the group-C (O) - followed by -N (H) -, for example acetylamino, propanoylamino and butanoylamino and the like The term "carbonylamino" refers to the group - -NR-CO-CH2 -R ', where R and R' can be independently selected from hydrogen or (Ci-C4) alkyl The term "carbamoyl" as used herein refers to -O-C (0) NH2.

The term "carbamyl" as used herein refers to a functional group in which a nitrogen atom is directly bonded to a carbonyl, ie, as in --NRC (= 0) R 'or -C (= 0) NRR' , wherein R and R 'can be hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, cycloalkyl, phenyl, heterocycle, or heterophenyl. The term "alkylsulfonylamino" as used herein refers to the group -NHS (0) 2Ra where Ra is an alkyl as defined above. In certain detailed embodiments, the methods and compositions of the invention for treating or preventing neuropathic disorders and / or related symptoms employ a compound or formulation comprising an l-aryl-3-azabicyclo [3.1.0] hexane having at least one substituent in the phenyl / aryl ring. In alternate embodiments, the methods and compositions of the invention for the treatment or prevention of neuropathic disorders and / or related symptoms employ an l-aryl-3-azabicyclo [3.1.0] hexane having two or more substituents on the phenyl ring. aril. In other detailed embodiments, the methods and compositions of the invention for the treatment or prevention of neuropathic disorders and / or symptoms They use an l-aryl-3-azabicyclo [3.1.0] hexane with a substitution of nitrogen at the position "3". In further detailed embodiments of the invention, the methods and compositions of the invention for the treatment or prevention of neuropathic disorders and / or related symptoms employ bisubstituted l-aryl-3-azabicyclo [3.1.0] hexanes with at least one substitution at the aryl ring, also as an aza substitution on the nitrogen at position? 3 '. L-aryl-3-azabicyclo [3.1.0] hexanes useful for use in the methods and compositions of the invention for the treatment or prevention of neuropathic disorders and / or related symptoms include l-aryl-3 compounds substituted and bisubstituted azobicyclo [3.1.0] hexanes described herein, also as, without limitation, pharmaceutically acceptable salts, polymorphisms, solutes, hydrates and / or active prodrugs of these compounds, or combinations thereof. The methods and compositions of the invention are effective in treating and / or preventing a variety of symptoms and conditions associated with neuropathic disorders in mammalian subjects. A wide range of mammalian subjects, including human subjects, are susceptible to treatment using the formulations and methods of the invention. These subjects include, but are not limited to, humans and other mammalian subjects suffering from one or a combination of the following disorders, conditions and / or symptoms: diabetic neuropathy; diabetic peripheral neuropathy (including distal symmetric polyneuropathy); post-herpetic neuralgia, trigeminal neuralgia; neuropathy associated with alcoholism; sciatica; post-stroke pain; multiple sclerosis; herpes; post-traumatic or idiopathic neuropathy and mononeuritis; neuropathy associated with HIV; Cancer; carpal tunnel syndrome; neuropathy associated with Fabry's disease; vasculitic neuropathy; neuropathy associated with Guillain-Barre syndrome; chronic pain of the lower back and induced iatrogenic neuropathies (e.g., as one or those induced by antitumor agents taxol and paclitaxel, and by certain antiretroviral drugs), abnormalities of absorption or diet; damage to the spinal cord; vitamin deficiency; heavy metal poisoning; pain due to the complex regional syndrome; fibromyalgia; peripheral nerve trauma; entrapment neuropathy; nerve transection; Wallenberg syndrome; connective tissue disease; plexus irradiation; ischemic irradiation; hematomyelia; discrafism; tumor compression; arteriovenous malformation; syphilitic myelitis; comisural myelotomy; arachnoiditis; root avulsion; compression of the prolapsed disc; lumbar and cervical pain; sympathetic reflex dystrophy, phantom limb syndrome; among other syndromes, conditions and chronic neuropathic symptoms. As noted above, a major adverse symptom associated with neuropathies is neuropathic pain, which is typically associated with aberrant somatosensory processes in the central or peripheral nervous system. In contrast to nociceptive pain, neuropathic pain is often described as "burning," "electric," "itching," and "lacerating." Additionally, considering that nociceptive pain is mediated by the stimulation of A-delta and C-polymodal pain receptors (eg, by bradykinin histamine, substance P, etc.), neuropathic pain is typically caused at least in part by damage a, or pathological changes in the central and / or peripheral nerves. Examples of pathological changes to the nerves include prolonged central or peripheral neuronal sensitization, central sensitization related to damage to the nervous system by inhibiting functions, and abnormal interactions between the sympathetic and somatic nervous system.

Neuropathic symptoms which may be characterized as a "neuropathic pain", and which are treatable or prevented using the formulations and methods of the invention include for example: allodynia (painful response to a noxious stimulus); tactile allodynia (painful response to a normally non-harmful touch); hyperalgesia (extreme or increased sensitivity to a painful stimulus); thermal hyperalgesia (exaggerated pain response to noxious temperatures); mechanical hyperalgesia (exaggerated pain in response to normally harmful movements of the body); paresthesias (abnormal sensations such as itching, burning, swelling or stinging); hyperesthesia (enhanced sensitivity to a natural stimulus); and dysesthesias (unpleasant sensations produced by an ordinary stimulus). It is common to believe that after nerve damage, the peripheral nerves begin to degenerate, starting at the site of damage and progressing to the terminal nerve. This process sometimes refers to Wallerian degeneration, which has been extensively characterized in animal models (eg, the spinal nerve ligation model (Chung), which is widely accepted in the specialty as a useful model of neuropathic conditions and for the selection and effective characterization of drugs to treat symptoms associated with neuropathies in mammals, including humans). During degeneration, the axoplasm gradually disintegrates and the axole is fragmented. Schwann cells and macrophages phagocytose myelin spoils. This process activates the secretion of a series of known and unknown cytokines and growth factors, including interferons, tumor necrosis factor alpha (TNFa), nerve growth factor (NGF), and interleukins. These cytokines and growth factors influence the structure and function of both distant and adjacent tissues, including induction by apoptosis in a number of peripheral cells and the production of trophic factors required for the regeneration of both nerves and peripheral cells. The development of hyperalgesia in the damaged nerve in animals is thought to rise from early electrophysiological events such as "damage by shock" that alters the neuronal influx of calcium to activate kinases such as protein kinase A and C, and extracellular regulation of the kinases (ERKs = extracellular regulated kinases), which leads to proliferation, chemotaxis and other cellular activations at the site of damage and physiological changes in the body of the cells; and intermediate events such as retrograde damage signals that include growth factors and target-derived cytokines. These events can occur from hours to weeks after nerve damage resulting in pain and hypersensitivity for the duration of the process. Primary hyperalgesia, caused by sensitization of C fibers, occurs immediately within the area of damage. Secondary hyperalgesia, caused by sensitization of dorsal antler neurons, occurs in undamaged areas around the lesion. Trophic factors such as nerve growth factor (NGF) and tumor necrosis factor-a (TNF-a) produced by Schwann cells and macrophages then invading the damaged nerve are correlated with the principle of hyperalgesia. Thus, changes in endogenous, systemic, or local levels of these and other growth factors and cytokines will often be useful as diagnostic indices to select susceptible subjects for treatment according to the methods and compositions of the invention on a specific patient base. Interestingly, both NGF and TNF-a also have positive degenerative effects on damaged nerves, but cause pain in both damaged and undamaged nerves and result in thermal hyperalgesia and mechanical allodynia in undamaged animals. Similar responses have been seen in humans. As noted above, analgesics, including NSAIDs and opiates, which are effective for the treatment or general of nociceptive pain, are rarely effective for neuropathic pain (The Lancet, 353: 1959-1966, 1999). For example, morphine has a strongly analgesic effect on nociceptive pain, but does not exhibit remarkable / sufficient activity to relieve neuropathic pain. In fact, resistance to morphine therapy will provide a useful diagnostic index to differentiate subjects with pain associated with neuropathy amenable to treatment using the methods and compositions of the invention (see, eg, Crosby et al., J. Pain Symptom Manage. 19 (1): 35-9, 2000; Chen et al., J. Neurophysiol. 8_7: 2726-2733, 2002; Shir et al., Harefuah 118 (8): 452-4, 1990, each incorporated herein by reference). Accordingly, in certain aspects of the invention the composition and methods herein are directed towards treatments of a neuropathic disorder in individuals whose pain symptoms are insufficiently alleviated by opioid treatments, and / or for treatments using another class of drugs. effective analgesics for the treatment of nociceptive pain, such as NSAIDs. In In this context, patients presenting neuropathic disorders who will be susceptible to treatment using the compositions and methods of the invention will show a reduction of less than 50% in the severity or frequency of their pain symptoms followed by the administration of a therapeutic agent for nociceptive pain (eg, an opiate or NSAID) compared to those treated with placebo or other appropriate subjects as controls. In certain cases, the subject patient will show a reduction of less than 30%, 20% or 10%, or a non-measurable reduction in the severity or frequency of the pain symptoms after receiving the nociceptive pain drug, compared to Control subjects exhibiting similar symptoms of pain. In view of the distinct etiology of the sensory symptoms associated with neuropathies, the activity and uses described here for bicifadine and other l-aryl-3-azabicyclo [3.1.0] hexanes have not been predicted with an expectation of success by people with ordinary skill in the specialty. This discussion here marks the first discovery and documentation that bicifadine and other l-aryl-3-azabicyclo [3.1.0] hexanes are potent and effective in alleviating the symptoms of neuropathic pain in animal models widely accepted by those with dexterity in the art as reasonably predictive and correlative for drug efficacy and treatment methods in other mammals, including humans. In particular, the methods and compositions of the invention have been tested and shown to be effective in the spinal nerve (Chung) ligation model (see, eg, Bennett, GJ, Chung, JM, Honore, M., and Seltzer, Z. "Models of Neuropathic Pain. In: Current Protocols in Neuroscience" (JN Crawley, CR Gerfen, MA Rogawski, DR Sibley, P. Skolnick, and S. Wray, eds.) Pp. 9.14.1-9.14. 16. John Wiley &Sons, New York (2003); Morrow, T.J. "Animal Models of Painful Diabetic Neuropathy: The STZ rat model. "In: Current Protocols in Neuroscience (J. N. Crawley, C. R. Gerfen, M. A. Rogawski, D. R. Sibley, P. Skolnick, and S. Wray, eds.) Pp. 9.18.1-9.18.11. John Wiley & Sons, New York (2004), each one incorporated here by reference). The findings disclosed here based on widely accepted models of neuropathic pain (ie, the spinal nerve ligation model and STZ induced diabetes model), using well-accepted endpoints of models with symptoms associated with neuropathy, including thermal and mechanical hyperalgesia, as described above, show that the methods and compositions of the invention are effective for the treatment of symptoms associated with neuropathies, including neuropathic pain in mammalian subjects. The methods and compositions of the invention for the treatment or prevention of neuropathic disorders and / or related symptoms generally employ an effective amount of an l-aryl-3-azabicyclo [3.1.0] hexane described above, optionally formulated with one or more additional components, such as carriers, buffers, excipients, physiologically compatible preservatives and the like. As used herein, the term l-aryl-3-azabicyclo [3.1.0] hexane includes all active and effective members of this group that are useful for the treatment or prevention of a neuropathic disorder and / or related symptom (s). (s), as exemplified by the various formulations of the pooled compounds described herein, as well as all the active derivatives, enantiomers, salts, polymorphs, solvents, hydrates, and / or prodrugs of these disclosed compounds. The l-aryl-3-azabicyclo [3.1.0] hexanes selected for use in the therapeutic compositions and methods herein will be therapeutically effective and well tolerated among mammalian subjects, in useful and commercially feasible dose amounts as indicated below , and without unacceptable adverse side effects. In more detailed modalities, the compounds, compositions and methods of this invention are therapeutically effective in alleviating one or more neuropathic conditions and / or related symptoms identified herein, including any combination of these neuropathic conditions and / or related symptoms, without unacceptable adverse side effects. In certain embodiments, the therapeutic methods and compositions of the invention effectively treat and / or prevent a condition of neuropathy or symptom, while avoiding or reducing one or more side effects associated with a current alternate drug treatment for neuropathy. In this context, the methods and compositions of the invention for the treatment of a neuropathic disorder and / or related symptom (s) will often result in a reduction or elimination of one or more side effect (s) observed with alternate drug or non-drug treatments for neuropathies, including, but not limited to, sedation, respiratory deterioration, sleep impairment, lightheadedness, loss of motor functions, disorientation, memory loss or other cognitive impairments, mood disorders, constipation, mouth dry, low blood pressure, weight gain, rash, dyspepsia, problems with cardiac function, dependence and / or extraction, among other side effects.

The l-Aryl-3-azabicyclo [3.1.0] hexanes for use with the methods and compositions of the invention can be rationally formulated with a carrier and / or various excipients, vehicles, stabilizers, buffers, preservatives, pharmaceutically acceptable, etc. The compounds operable in these aspects of the invention can be selected from a number of several exemplary candidate compounds described herein using well-known methods, including the various animal models described below. These and other methods can be used to select, identify, and determine optimal doses and combinations of the compounds described herein. In the therapeutic methods and compositions of the invention, an l-Aryl-3-azabicyclo [3, 1.0] hexane selected for use in a composition or method for treating or preventing a neuropathic disorder and / or related symptom (s) will be formulated for therapeutic use in an "effective amount", "therapeutic amount", or "effective dose". These terms collectively describe either an effective amount or dose of a compound as described herein that is sufficient to choose a desired therapeutic or pharmacological effect in a mammalian subject-typically resulting in a measurable reduction in an occurrence, frequency or severity of a disorder. neuropathic, and / or one or more associated symptoms with a neuropathic disorder, in the subject. In certain embodiments, when a compound of the invention is administered to treat a neuropathic disorder, for example a neuropathic disorder characterized by one or more neuropathic pain symptom (s), an effective amount of the compounds will be an amount sufficient in vivo to retard or eliminate the onset of one or more symptoms associated with neuropathic disorder, for example one or more symptoms of neuropathic pain. Formulations and therapeutically effective doses may alternatively be determined by a formulation / dose administration which produces a decrease in the occurrence, frequency or severity of one or more symptoms of a neuropathic disorder, for example a decrease in the frequency or intensity of one or more symptom (s) of neuropathic pain. An effective amount of an l-aryl-3-azabicyclo [3.1.0] hexane in this context will typically produce a detectable, therapeutic reduction in the nature or severity, occurrence, frequency and / or duration of one or more symptoms associated with the condition. or white neuropathic disorder. Therapeutically effective amounts, and dosage regimens, of the l-aryl-3-azabicyclo [3.1.0] hexane compositions of the invention, include pharmaceutically effective salts, solutes, hydrates, polymorphs or prodrugs, which will be easily determined by those with ordinary skill in the specialty, often based on clinical routine or specific patient factors. Alternatively, the effectiveness of the methods and compositions of the invention for the treatment or prevention of a neuropathic disorder and / or related symptom (s) can be demonstrated by various numerical scale rating and evaluation systems including, but not limited to, the neuropathic pain scale, numerical rate scale, visual analog scale, pain face scale, brief pain inventory, McGill pain questionnaire, or the initial tool of pain assessment, all of which clinical rate systems They are well known and widely accepted in science to predict the clinical efficacy of neuropathic treatments. Using the neuropathic pain scale from 1 to 10, for example, the effectiveness of the compounds and methods of the invention can be demonstrated by a decrease in. the numerical values of a patient's appreciation of the pain over time in the treatment. The decrease can be a real decrease minus one point on the scale to nine points on the scale, or a decrease of any value in between. Quantities and therapeutically effective dose regimens of l-aryl-3-azabicyclo [3.1.0] hexanes in these contexts will be easily determinable by those with ordinary skill in the art, often based on clinical routines or patient-specific factors. Suitable administration routes for the 1-aryl-3-azabicyclo [3.1.0] hexanes and related of the invention for the treatment or prevention of neuropathic disorder and / or symptom (s) associated formulations include, but not limited to, oral , buccal, nasal, aerosol, topical, transdermal, mucosal, injectable, slow release, controlled release, although also various other routes of administration, devices and known methods can be employed equally. Useful injectable administration methods include, but are not limited to, intravenous, intramuscular, intraperitoneal, intraspinal, intrathecal, intracerebroventricular, intraarterial, and subcutaneous injection. Suitable amounts of effective dose units of l-aryl-3-azabicyclo [3.1.0] hexanes for mammalian subjects may be in a range of about 1 to 1200 mg, 50 to 1000 mg, 75 to 900 mg, 100 to 800 mg , or 150 to 600 mg. In certain embodiments, the effective dose unit will be selected in narrower ranges, for example, from 10 to 25 mg, 30 to 50 mg, 75 to 100 mg, 100 to 150 mg, 150 to 250 mg or 250 to 500 mg. These and other dose amounts effective units can be administered in a single dose, or in the multiple daily form, weekly or monthly dose, for example in a dose regime comprising from 1 to 5, or 2-3, doses administered per day, per week, or per month. In exemplary embodiments, doses of 10 to 25 mg, 30 to 50 mg, 75 to 100 mg, 100 to 200 mg (anticipated dose concentration), or 250 to 500 mg, are administered one, two, three or four times per day. In more detailed modalities, doses of 50-75 mg, 100-150 mg, 150-200 mg, 250-400 mg, or 400-600 mg are administered once, twice daily or three times daily. In alternate embodiments, the doses are calculated based on body weight, and can be administered, for example, in amounts of about 0.5 mg / kg to about 30 mg / kg per day, lmg / kg to about 15 mg / kg per day , lmg / kg at approximately 10mg / kg per day, 2mg / kg at approximately 20mg / kg per day, 2mg / kg at approximately 10mg / kg per day or 3mg / kg at approximately 15mg / kg per day. The amount, the distribution and the mode of administration of the compounds of the invention comprise an effective amount of an l-aryl-3-azabicyclo [3.1.0] hexane will be routinely adjusted on an individual basis, depending on such factors as the weight , age, gender, and condition of the individual, pattern of the presentation of the symptom, where the administration is prophylactic or therapeutic, and on the basis of other known factors that affect drug administration, absorption, pharmacokinetics, including half-life, and efficacy. An effective dose or multiple dose treatment regimen for the compounds of the invention will ordinarily be selected to approximate the dosage regimen that is necessary and sufficient to substantially prevent or alleviate one or more symptom (s) of a neuropathic disorder, for example, a or more symptom (s) of neuropathic pain, in the subject, as described here. Thus, following the administration of an l-aryl-3-azabicyclo [3.1.0] hexane according to the formulations and methods of the invention, test subjects will exhibit 10%, 20%, 30%, 50% or a greater reduction, up to 75-90%, or 95% or greater, reduction, in one or more symptoms associated with the target of neuropathy, comparing placebo-treated or other suitable control subjects. In further aspects of the invention, combinatorial formulations and coordinate administration methods are provided which employ an effective amount of one or more l-aryl-3-azabicyclo [3.1.0] hexanes, including pharmaceutically effective eniantiómeros, salts, solvates, hydrates , polymorphs or prodrugs of them, and one or more active agent (s) that is / are formulated combinatorially or co-administered with l-aryl-3-azabicyclo [3.1.0] hexane (s) -producing a combinatorial formulation or coordinated method of administration that is effective to modulate, lighten, treat or prevent one or more symptom (s) of a white neuropathic condition in a mammalian subject. Exemplary combinatorial formulations and methods of coordinated treatment in this context employ an l-aryl-3-azabicyclo [3.1.0] hexane in combination with one or more additional treatment agents or adjuncts or methods of treating neuropathy, for example one or more of the following agents and methods of treating neuropathy: NSAIDs, including but not limited to aspirin, ibuprofen and C0X-2 inhibitors, synthetic and natural opiates including but not limited to oxycodone, meperidine, morphine, and codeine; mexiletine; baclofen; tramadol; antiarrhythmics; anticonvulsants (eg, lamotrigine, gabapentin, valproic acid, topiramate, famotodine, phenobarbital, diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital, primidone, carbamazepine, ethosuximide, mesoximide, fensuximide, trimethadione, benzodiazepines such as diazepam, phenacemide, acetazolamide, progabide, clonazepam, divalproex sodium, injection of magnesium sulfate, metarbital, parametadione, phenytoin sodium, valproate sodium, clobazam, sultiam, dilantin, diphenylan and L-5-hydroxytriptophane); capsaicin cream; membrane stabilizing drug (e.g., lidocaine); receptor N-methyl-D-aspartate (NMDA) antagonists such as ketamine, surgery; transcutaneous electrical stimulation of the nerve; stimulation of the epidural spinal cord; neurectomy; rhizotomy; injury of the entrance of the root of the dorsal area; cordotomy; thalamotomy; and neuroablation. In order to practice a method of the invention of coordinated treatment for neuropathy, an l-aryl-3-azabicyclo [3.1.0 J hexane as described herein is administered, simultaneously or sequentially in a coordinated treatment protocol with one or more of the agents secondary or therapeutic adjuncts or methods described above. Coordinated administration can be done simultaneously or sequentially in one or the other order, and here may be the period of time while only one or both (or all) of the therapeutic active agents, individually and / or collectively, exercise their biological activities. One distinguishing aspect of all methods of coordinated treatment is that 1-aryl-3-azabicyclo [3.1.0] hexane exerts at least some detectable therapeutic activity as described herein, and / or produces a favorable clinical response, which it may or may not be in conjunction with a secondary clinical response provided by the secondary therapeutic agent. Often, the coordinated administration of an l-aryl-3-azabicyclo [3.1.0] hexane with a secondary therapeutic people as contemplated herein will produce an enhancement of therapeutic response beyond the therapeutic response elicited by one or the other or both. 1-aryl-3-azabicyclo [3.1.0] hexane and / or the secondary therapeutic agent alone. Pharmaceutical dosage forms of the l-aryl-3-azabicyclo [3.1.0] hexanes in the present invention can include one or more new excipients or additives, including, without limitation, binders, dispensers, lubricants, emulsifiers, suspending agents, sweeteners , flavorings, preservatives, buffers, wetting agents, disintegrants, effervescent agents and other conventional excipients and additives. The compositions of the invention for treating neuropathic disorders can thus include any or combinations of the following: a pharmaceutically acceptable carrier or excipient; other medicinal agent (s); pharmaceutical agent (s); adjuvants; shock absorbers; conservatives; diluents; and various other pharmaceutical additives and agents known for dexterity in the art. These formulations Additional additives and agents will often be biologically inactive and may be administered to patients without causing harmful side effects or interactions with the active agent. If desired, the l-aryl-3-azabicyclo [3.1.0] hexanes of the invention can be. administered in a controlled release form by the use of a slow release carrier, such as a hydrophilic, slow release polymer. Exemplary controlled release agents in this context included, but not limited to, hydroxypropyl methyl cellulose, having a viscosity in the range of about 100 cps to about 100,000 cps. The l-aryl-3-azabicyclo [3.1.0] hexanes and related compositions of the invention will often be formulated and administered in an oral dosage form, optionally in combination with a carrier or other additive (s). Suitable common carriers for pharmaceutical formulation technology, include but are not limited to, microcrystalline cellulose, lactose, sucrose, fructose, glucose dextrose, or other sugars, calcium phosphate dibasic, calcium sulfate, cellulose, methylcellulose, cellulose derivatives, kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, or other sugar alcohols, dry starch, dextrin, maltodextrin or others polysaccharides, inositol, or mixtures thereof. Exemplary forms of oral dosage units for use in this invention include tablets, which may be prepared by any conventional method of preparing oral dosage unit dosage forms, such as tablets, may contain one or more additional ingredients in the formulation conventional, including, but not limited to, release modifying agents, glidants, compression aids, disintegrants, lubricants, ligaments, flavorants, flavor enhancer, sweeteners and / or preservatives. Suitable lubricants include stearic acid, magnesium stearate, such as, calcium stearate, hydrogenated vegetable oil, sodium benzoate, carbowax Leucine, magnesium lauryl sulfate, colloidal silicon dioxide, and glyceryl monostearate. Suitable gliders include colloidal silica, smoked silicon dioxide, silica, gypsum, and glyceryl monostearate. Substances which may be used to cover include hydroxypropyl cellulose, titanium oxide, talc, sweeteners and colorants. The aforementioned effervescent and disintegrating agents are useful in the formulation of rapidly disintegrating tablets known to those skilled in the art. These typically disintegrate in the mouth in less than one minute, and often in less than thirty seconds. By effervescent agent is meant a couple, typically an organic acid and a carbonate or bicarbonate. Additional compositions of the invention comprise an l-aryl-3-azabicyclo [3.1.0] hexane prepared and administered in any of a variety of inhalation or nasal administration forms known in the art. Devices capable of depositing the aerosolized formulations of l-aryl-3-azabicyclo [3.1.0] hexane in the breast cavity or pulmonary alveoli of a patient include inhalers with dose meters, nebulizers, dry powder generators, sprinklers, and the like . Methods and compositions suitable for the pulmonary administration of drugs for systemic effects are also known in the art. Suitable formulations, where the carrier is a liquid, for administration, such as, for example, a nasal spray or as nasal drops, may include aqueous or oily solutions of l-aryl-3-azabicyclo [3.1.0] hexanes and any ingredient ( s) inactive or additional assets. Intranasal administration allows the passage of the compound to the bloodstream directly after the administration of an effective amount of the compound to the nose, without requiring the product to be deposited in the lung. In addition, intranasal administration may directly achieve, or enhance, the administration of the active compound in the central nervous system. For intranasal and pulmonary administration, a liquid aerosol formulation often contains an l-aryl-3-azabicyclo [3.1.0] hexane as described herein combined with a dispersing agent and / or a physiologically acceptable diluent. Alternating dry powder aerosol formulations may contain a finely divided solid form of the present compound and a dispersing agent allowing rapid dispersion of the dry powder particles. With any of the liquid or dry powder aerosol formulations, the formulation must be aerosolized into small liquid or solid particles to ensure that the aerosolized dose reaches the mucous membranes of the nasal or lung passage. The term "aerosol particle" is used herein to describe suitable liquid or solid particles of a sufficiently small particle diameter, e.g. in a range of approximately 2-5 microns, for the nasal or pulmonary distribution for white alveolar membranes or mucous membranes. Other considerations include the construction of the delivery devices, additional components in the formulation, and particle characteristics. These aspects of pulmonary or nasal administration of drugs are well known in the art, and manipulation of formulations, aerosolization means, and construction of administration devices, is at the level of ordinary skill in the art. Additional compositions and methods of the invention are provided for topical administration of l-aryl-3-azabicyclo [3.1.0] hexanes for the treatment of neuropathic disorders in mammals. The topical compositions may comprise an l-aryl-3-azabicyclo [3.1.0] hexane and any other active or inactive component (s) incorporated in a dermatological or acceptable mucosal carrier, including in the form of aerosol sprays, powders, patches Dermal, bars, granules, creams, pastes, gels, lotions, syrups, ointments, impregnated sponges, cotton applicators, or as a solution or suspension in a liquid charged, non-aqueous liquid, oil in water emulsion, or liquid emulsion of water in oil. These topical compositions may offer the dissolution or dispersion of l-aryl-3-azabicyclo [3.1.0] hexane in a portion of water or other solvents or liquids to be incorporated into the topical composition or delivery devices. Transdermal administration can be enhanced by the addition of a dermal penetration enhancer known to those skilled in the art. The formulations Suitable for such dosage forms incorporate excipients commonly used herein, particularly means, e.g. structure or matrix, to maintain drug absorption for a prolonged period of time, for example 24 hrs. However, additional formulations of l-aryl-3-azabicyclo [3.1.0] hexanes for the treatment of neuropathic disorders are provided for parenteral administration, including sterile aqueous and non-aqueous injection solutions which may optionally contain antioxidants, shock absorbers, bacteriostats and / or solutes which give the formulation isotonic with the blood of the mammalian subject; and an aqueous and non-aqueous sterile suspension which may include suspending agents and / or thickening agents. The formulations can be presented in unit dose or multiple dose containers. These and other formulations of the invention may also include polymers for prolonged release following parenteral administration. Extemporaneous injection solutions, emulsions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary dosage unit formulations are these contained in a daily dose or unit, your daily dose, as described here above, or an appropriate fraction thereof, of the active ingredient (s). In other detailed embodiments, the l-aryl-3-azabicyclo [3.1.0] hexane compositions can be encapsulated to be administered in microcapsules, microparticles, or microspheres, prepared, for example, by coacervation techniques or by interphase polymerization, for example , hydroxymethylcellulose or gelatin microcapsules and poly (.methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. The pharmaceutical agents and formulations of the present invention will typically be sterile or easily sterilizable, biologically inert, and easily administered. The following examples illustrate certain embodiments of the present invention, and will not be construed as limiting the present disclosure. The evidence provided in these examples demonstrates that l-aryl-3-azabicyclo [3.1.0] hexanes as described herein are effective in the treatment of neuropathic disorders and related symptoms, including neuropathic pain, in mammals.

Examples Bicifadine was tested in two models of neuropathic pain accepted by the specialty - a model of neuropathic pain produced by spinal nerve ligation (Kim, et al., 1992) and diabetic rat model - streptozotocin (STZ) -induced ( Morrow, T.J., 2004). In the spinal nerve ligation model (described in detail in Example 1, below), rats were orally administered bicifadine or morphine three weeks after surgery. Sixty minutes later, mechanical hyperalgesia was measured based on the amount of force required to cause the rats to remove the injured leg (Figure 1, panel A), compared to the uninjured leg (Figure 1, Panel B). As can be seen in Figure 1, panel A bicifadine produced a statistically significant increase in the amount of pressure of the rats to be able to tolerate the compared vehicle. In addition, bicifadine was more potent than morphine in this respect. Of this, the amount of morphine required to produce an effect equivalent to bicifadine in this pain neuropathy model is close to the lethal dose. The ability of bicifadine to alleviate the symptoms associated with neuropathic disorder is further demonstrated in Figure 2, which represents the thermal hyperalgesic responses based on the sensitivity of the rats for the application of thermal stimuli in the lesion (Figure 2, panel A), compared with the uninjured leg (Figure 2, panel B). The observation that bicifadine does not affect the pressure threshold or responses for the application of heat in the uninjured leg (Figure 1, panel B, Figure 2, panel B) indicate that the analgesia produced by bicifadine as evidence in the Chung's model is not due to the weakening of the animal by the drug. Bicifadine also increases the amount of pressure that an animal could resist on the injured leg in the STZ model of diabetic neuropathy (see, Example 3, below, Figure 5). In this figure the increase of the sensitivity of the animal to mechanical pressure is illustrated with a decrease in the amount of force applied producing extraction or removal compared to control rats (not treated with STZ). Bicifadine is able to restore the amount of pressure tolerated in these diabetic rats to values close to those obtained in control animals (Figure 5). Example 1 Bicifadine Effectively Reduces Tactile Hyperalgesia and Thermal Hyperalgesia in the Ligation Model of the Spinal Nerve The Tight Ligation of the Spinal Nerve in Rats It is associated with hyperalgesia, allodynia and spontaneous pain, and provides an accepted model for peripheral neuropathic pain in humans. The male Sprague-Dawley Rj: Sd rats (IOPS Han) weighing 218-260 g at the beginning of the procedure were anesthetized (sodium pentobarbital 40 mg / kg ip) and an incision was made at the L4-S2 level to expose the spinal nerves left L5 and L6, which were closely linked (4-0 silk suture) distal to the root of the dorsal ganglion and before the entrance of the Asian nerve, as first described by Kim and Chung (Pain, 50: 355-363, 1992). The wound was then sutured, and the rats received an injection of clamoxil i.m. (lOOmg / kg s.c.) and they were allowed to recover. Four weeks after the surgery, when the state of chronic pain was fully installed, the rats were subjected to tactile and thermal stimulation consecutively of both hind legs the injured and the non-injured. The above procedure resulted in mechanical (tactile) allodynia in the left hind paw estimated by the pressure record at which the affected paw (ipsilateral to the damaged nerve site) was removed from the graded stimulus (von Frey filaments a range of 4.0 at 148.1 mN) applied perpendicularly to the surface of the plant of the leg (between the bearings) through observation in wire mesh cages. The paw withdrawal threshold (PWT) was determined by a sequential increase and decrease in the strength of the stimulus and by analyzing the threshold data using a nonparametric Dixon test, as described by Chaplan et. al., 1994. Normal rats and rats with sham surgery (isolated but untied nerves) were removed at least 148.1 mN (equivalent to 15 g) of unanswered pressure. The rats with ligated spinal nerve respond to as little as 4.0 mN (equivalent to zero, 41 g) of pressure in the affected paw. Rats are included in the study only if they do not exhibit motor dysfunction (e.g., dragged or loose leg) and its PWT was less than 39.2 mN (equivalent to 4.0g). Three weeks after surgery the rats were treated with the tested compounds or control diluents (PBS) once by s.c. injection. and PWT is determined every day after seven days. The PWT values observed for the rats treated with an effective amount of a tested compound of l-aryl-3-azabicyclo [3.1.0] hexane described herein will be measurablely increased compared to the PWT values observed by the control animals. For tactile stimulation, the animal was placed under an inverted plastic acrylic box (18 x 11.5 x 13 cm) on a grid floor. The end of a Von Frey electronic test (Bioseb, model 1610) was then applied with increased strength on the injured and uninjured hind legs and the force that induces the removal of the leg was automatically recorded. This procedure was carried out 3 times and the average force per leg was calculated. For thermal stimulation, the apparatus (model 7200, Ugo Basile, Italy) consists of individual plastic acrylic boxes (17 x 11 x 13 cm) placed on a raised glass floor. A rat was placed in the box and left free to habituate for 10 minutes. A source of infrared radiation (96 + 10 mW / cm2) was then located under the injured and uninjured hind legs and the paw-withdrawal latency was automatically recorded. In order to prevent tissue damage the heat source was automatically turned off after 45 seconds. The behavioral test was carried out two weeks after the surgery. Before receiving the drug treatment all animals were subjected to tactile stimulation and assigned a treatment group based on their response to pain. Eight rats were studied by group, and the tests were done blindly.

Bicifadine was evaluated at the indicated doses, administered p.o. 60 minutes after the test, and compared with a vehicle in a control group. Morphine (128 mg / kg p.o.), used as a reference substance, was administered under the same experimental conditions. The data were analyzed by comparing the responses of the injured legs in the treatment groups with the control vehicle group using paired and unpaired Student t tests. As demonstrated in Figures 1 and 2, the effectiveness of bicifadine was suppressed by mechanical and thermal hyperalgesia in the Chung model of chronic neuropathic pain. The rats treated with the vehicle (open bars) showed a significant reduction in the threshold for removal of the paw on the injured side retinal of the application of mechanical pressure (Figure 1, Panel A) or thermal stimulus (Figure 2, Panel TO) . Side-by-side comparisons in these figures show that morphine, at a dose close to lethal, causes a significant increase in the threshold for the nociceptive response (shaded bars). As shown in the figures, 50 mg / kg PO of bicifadine resulted in a significant increase in the force required to induce leg withdrawal compared to treatment of the vehicle, on the injured legs. In addition, all tested doses of bicifadine (12.5-100 mg / kg PO) resulted in a significant increase in paw withdrawal latency in response to a thermal stimulus. The magnitude of this effect was approximately equivalent to the lethal dose of morphine, 128 mg / kg PO. Example 2 1- (3,4-Dichlorophenyl) -3-azabicyclo [3.1.0] hexane Effectively Reduces Tactile Hyperalgesia and Thermal Hyperalgesia in the Spinal Nerve Ligation Model In the present example, another exemplary substituted l-aryl-3-azabicyclo [3.1.0] hexane was evaluated for its ability to alleviate the symptoms associated with neuropathy in the model (Chung) of spinal nerve ligation of neuropathic pain. In this study, a multiple-aryl-substituted compound, as described above, 1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane was tested according to the procedures described above in Example 1. l- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane was administered for testing in animals at the doses indicated po, 60 minutes before the test, and compared to a vehicle in the control group. The data was analyzed by Comparison of injured leg responses in the treatment groups with the vehicle control group using paired and unpaired Student t tests, as described in Example 1. As demonstrated in Figures 3 and 4, respectively, 1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane potently suppresses tactile allodynia in the Chung model of neuropathic pain, and thermal hyperalgesia suppresses dose-dependent test subjects. The vehicle-treated rats (open bars) showed a significant reduction in threshold to remove the legs from the injured side following the application of mechanical pressure (Figure 3, Panel A) or thermal stimuli (Figure 4, Panel A). The administration of 1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane to subjects results in a significant increase in the force required to induce paw withdrawal compared to those treated with the vehicle, injured legs, also as a significant increase in the latency of paw withdrawal in response to a thermal stimulus. Figure 3, Panel B, and Figure 4, Panel B (responses on the non-injured side) demonstrate that these effects are not due to the animal's debilitation. Example 3 Bicifadine Effectively Relieves Symptoms of Neuropathy in the Streptozotocin-Induced Rat Diabetes Model Sprague Dawley Rj: SD rats (IOPS Han) thinking 218-260 g at the beginning of the experiment, were included in this study for the induction of diabetes . These were divided into control groups with vehicle and treated with streptozotocin against rats were housed in a temperature-controlled room (19.5-24.5 degrees Celsius) and a relative humidity (45-65%) with cycles of 12 hours of light / dark , in with ad libitum access to filter the water tap and chow laboratory granules from the beginning to the end of the study. On day 0, diabetes was induced to poor intraperitoneal injection of streptozotocin (STZ, 75 mg / Kg) to rats. On day 23, to confirm the presence of diabetes in the rats administered with STZ, hyperglycemia was measured using blood glucose strips. Animals with blood sugar levels less than 250 mg / 1 were not used in the additional investigations. The animals found useful for inclusion in additional investigations were dosed orally with bicifadine at the doses indicated, and the nociceptive threshold was approved 60 minutes later. The nociceptive threshold was evaluated using a nociceptive mechanical stimulus (Paw pressure test). An increase in pressure was applied to the hind paw of the animal until a nociceptive response was reached (Vocalization or removal of the paw). The pain threshold (grams of contact pressure) was measured on both hind legs. The results are expressed as a nociceptive threshold (mean + SEM) in grams of contact pressure for each group, calculated from the individual nociceptive threshold (means of the values of the nociceptive thresholds obtained for both hind legs). The statistical significance between the groups treated with bicifadine and the diabetic group treated with the vehicle was determined by the Krusaka-Wallis test, using the residual variance after a one-way analysis of variance (P <0.05). As demonstrated by the data provided in Figure 5, bicifadine reduces mechanical hyperalgesia in rats with diabetic neuropathy. Twenty-three days later the diabetes was induced in rats with STZ, in rats with significant manifestations of diabetes were orally administered with vehicle or bicifadine, and their nociceptive thresholds determined 60 minutes after. Vehicle-treated rats showed a significant reduction in paw pressure required to produce a nociceptive response (Paw withdrawal or squealing). In contrast, diabetic rats treated with 12.5 and 25 mg / kg of bicifadine (closed bars) showed a significant increase (P <0.05) in the nociceptive threshold Relative to diabetic animals treated with the vehicle (open bars). Example 4 Chronic Constriction Damage Model Another useful model to demonstrate the efficacy of the methods and compositions of the invention for treating a neuropathic disorder and / or related symptom (s) is the chronic constriction damage model. In this model, a unilateral peripheral hyperalgesia occurs in rats by nerve ligation (Bennett, et al., Pain, 33: 87-107, 1988). Sprague-Dawley rats (250-350 g) are prestigious with sodium pentobarbital and the Asian nerve is exposed at the mid-level adjusted by a weight dissection. It is through the biceps femoris. A section of the nerve (about 7 mm), proximal to the sciatic trifurion, is released from the tissue and saved to four positions with chromic gut suture, with the suture tied with approximately 1 mm of space between ligatures. The incision is closed in layers and at animals were allowed to recover. Thermal hyperalgesia is measured using a paw withdrawal test (Hargreaves, et al., Pain, 32: 77-88, 1988). For the execution of the test, the Animals are habituated on a high vibrio floor and a temperature radiator source that direct the middle floor of the hind legs (territory of the sciatic nerve) through the glass floor with 20 seconds cutting to prevent skin damage. The latencies for the withdrawal reflex on both hind legs were recorded. The legs with the ligated nerves showed a lower latency to the withdrawal of the paw compared to those not operated or those of the legs operated falsely. The responses to the tested compounds are evaluated at different times of oral administration to determine the beginning and duration of the effect of the compound. When the test is run, groups of rats received the vehicle or compound orally tested three times daily for five days. The latency of the withdrawal of the legs can be measured every day ten minutes. before and two or three hours after the first daily dose. The effectiveness of the compounds is calculated as the mean of the percentage decrease in hyperalgesia compared to the group treated with the vehicle. The potencies of the compound can be expressed as the minimum dose Effective (MED) in mg / Kg / day that produces a decrease in the percentage in the hyperalgesia that is statistically significant, where the% of the anti-hyperalgesic effect can be calculated as follows: 2 (Average of the group with vehicle - Average of the group with compound) (Average vehicle group) x 100. Animals treated with the active, l-aryl-3-azabicyclo [3.1.0] hexane compounds described herein will exhibit detectable decreases in hyperalgesia compared to the control animals. Example 5 Partial Sciatic Nerve Model of Induced Neuropathy Another useful model to demonstrate the efficacy of the methods and compositions of the invention for treating a neuropathic disorder and / or related symptom (s) is the partial ligation model of the neuropathic pain sciatic nerve. , which produces hyperalgesia in rats (Seltzer et al., Pain, 43: 205-218, 1990). The partial ligation of the left sciatic nerve is performed under the inhalation of enflurane / 02 anesthesia. Following the induction of anesthesia, the left thigh of the rat is shaved and the sciatic nerve exposed to a high narrow level through a small incision and is carefully cleaned or surrounded by connective tissue to a site near the trochanter just distal to the point at which the nerve branches of the semitendinosus turn off the Posterior biceps of the common sciatic nerve. A 7-0 silk suture is inserted into the nerve with a 3/8 curve, an inverted and closely linked minisguja, so that the dorsal 1/3 to 1/2 of the thicker nerve is supported by the ligature. The wound is closed with a single muscle suture (7-0 silk) and a Michelle bra. Following the surgery, the area of the wound is sprinkled with antibiotic powder. The rats with the fake treatment underwent an identical surgical procedure except that the sciatic nerve was not manipulated. Following the surgery, the animals are weighed and placed on a hot pad until they recovered from the anesthesia. The animals were then returned to their cages until the beginning of behavioral tests. Responses to behavioral tests are evaluated at different times after an administration to determine the onset and duration of the effect of the compound. When the test is performed, the groups of rats receive the vehicle or test compound orally three times a day for 5 days. The latencies of the withdrawal of the legs can be measured every day 10 minutes before and two or three hours after the first daily dose. The animal is estimated to respond to Harmful mechanical stimuli when determining the threshold of removal of the hind paw to a noxious mechanical stimulus using an analgesimeter (Model 7200, Ugo Basile, Italy), as described by Stein, 1988. The maximum weight that can be applied to the hind paw it is placed at 250 g and the end point is taken as the complete removal of the leg. Example 6 Behavioral Tests for Mechanical Allodynia Other useful models demonstrated efficacy of the methods and compositions of the invention for the treatment of a neuropathic disorder and / or related symptom (s) using alternative protocols for the assessment of allodynia behavior. Tests on animals, such as those described in the example above, can also be tested for sensitivity to non-harmful mechanical stimuli to determine the response of the hind paw threshold for von Frey hair stimulation of the plantar surface of the bearing (Igarashi et al., Spine 25: 2975-80, 2000). The rats are acclimated by suspending them in a 6-mm wire grid and having the plantar surface of the soles of their legs stimulated with von Frey filaments. Three days before surgery, animals are used to acclimatize animals for movements and leg thrust. The responses to the test compounds are evaluated at different times after oral administration to determine the onset and duration of the effect of the compound. When the test is executed, groups of rats will receive the vehicle or test compound orally three times a day for 5 days. The latency of the paw withdrawal can be measured every day 10 minutes before and two or three hours after the daily dose. The latencies of the removal of the leg are measured using filaments. The filaments are calibrated between 1-15 g force are applied to the surface of the leg only until the filament is curved, for a total of two applications approximately 2 to 3 seconds apart and varying in location as well as to avoid sensitization. If the rat does not remove its paw after two applications of a given filament, the next harder filament is tested in the same way. When the rat removes its leg, the measurement is checked to ensure that there is an absence of response to the next harder filament. The force in grams of the filament that causes a positive response is recorded by the first reaction. After 5 minutes the same procedure is executed again. The baseline test is executed three days before the start of the experiment to accommodate the animals for the test procedure and to verify that they have normal responses. If the rat removes its leg, this force in grams is recorded as a second reaction. A positive response is identified as an animal that responds to a gram of filament strength of less than 5 grams. The animals treated with the test compounds show a decrease in the sensitivity for the pressure, approaching a normal reaction. Example 7 Pin Puncture Test Another useful model for demonstrating the efficacy of the methods and compositions of the invention for treating a neuropathic disorder and / or related symptom (s) is the pin prick test model. In this model, the rats are confined to clear plastic cages on a raised wire mesh floor with holes of ~ 1 cm in diameter. The end or tip of the safety pin is pressed against the skin of the plantar heel so that the skin is hollowed out but does not penetrate. The normal pin prick response is a reflex of small amplitude, short duration nocifensive withdrawal. Following damage to the nerve, the response is greatly increased in amplitude and duration and the animal will often lick the stimulated site. The responses to the test compounds are evaluated at different times after oral administration to determine the onset and duration of the effect of the compound. When the test is performed, groups of rats receive the vehicle or test compound orally three times a day for 5 days. The reactions can be measured every day 10 minutes before and two or three hours after the first daily dose. A decrease in amplitude and / or duration of the withdrawal indicates the effectiveness of the test compound. Example 8 Cold Allodynia Test Another useful model to demonstrate the efficacy of the methods and compositions of the invention for treating a neuropathic disorder and / or related symptom (s) is the cold allodynia test model. In one such method (Bennett, et al., Pain, 33: 87-107, 1988), the rats are placed for 20 minutes on a metal plate cooled to 4 degrees Celsius by circulating water below it. The number and duration of the nocifensive withdrawal reflexes that occur when the symptomatic leg of the animal touches the floor are measured. These values can be compared with those obtained with the metal floor heated to 30 degrees Celsius.

The effectiveness of the test compounds can be determined by evaluation at different times after oral administration to determine the onset and duration of the effect of the compound. When the test is performed, groups of rats that received any vehicle or test compound orally three times a day for 5 days. The reactions can be measured every day 10 minutes before and two or three hours after the first daily dose. An increase in the amount of time before removal and / or decrease in the duration of removal of the symptomatic leg indicates the effectiveness of the test compound. Although the above invention has been described in detail by way of example for purposes of clarity of understanding, persons of ordinary skill in the art will understand that certain changes and modifications may be practiced within the scope of the appended claims which are presented for the purpose of illustration and not limitation. In this context, the invention is not limited to particular formulations, processes, and materials discussed herein, as such formulations, process steps, and materials may vary somewhat. Also, the terminology used here is used to describe particular embodiments only, and is not intended to limit the invention embodied in the claims. Several publications and other reference information have been cited in the description by economy of description. Each of these references is incorporated herein by reference in its entirety for all purposes. Noticeable, however, that the various publications discussed herein are incorporated only for prior disclosure by the filing date of the present application, and the inventors reserve the right to precede such disclosure by virtue of a prior invention. References Armarego et al., J. Chem. Soc. [Section C: Organic J -19: 3222-9, 1971. Bennett, GJ and Xie, YK "Ane mononeuropathy in rat that produces disorders of pain sensation like those seen in man . " In: Pain, 33: 87-107, 1988. Bennett, G.J., Chung, J.M., Honore, M., and Seltzer, Z. "Models of Neuropathic Pain, In: Current Protocols in Neuroscience" (J. N. Crawley, C. R. Gerfen, M. A. Rogawski, D. R. Sibley, P. Skolnick, and S. Wray, eds.) Pp. 9.14.1-9.14.16. John Wiley & Sons, New York (2003).

Cabadio et al., Fr. Bollettino Chimico Farmacéutico 117: 331-42, 1978.

Chaplan, S. R .; Bach, F. W .; Pogrel, J. W.; Chung, J. M.; Yaksh, T. L. "Quantitative assessment of tactile allodynia in the rat paw." In: J. Neurosci. Meth. 53: 55-63 (1994). Chen et al., J. Neurophysiol. 87: 2726-2733, 2002. Crosby et al., J. Pain Symptom Manage. 19 (1): 35-9, 2000. Czobor P., et al., Stark J., Beer G., Petti S., Lippa A., Brown J., Beer B. "A Double-Blind, Placebo Controlled Randomized Study of DOV220.075 (bicifadine) SR and Codeine 60 mg in the Treatment of Post-Operative Dental Pain. " Presented at t the 2nd Annual Scien tific Meeting March 20 - 23, 2003 Chicago, IL. American Pain Society Abstract Da tabase a t http: // www. ampainsoc.org/abstract/2003/data/index.html. (Poster # 915)); Czobor P., Stark J., Beer G., Brown J., Sunshine A., Konery S., Turpin M., Olson N., Otero A., Lippa A., Beer B. "A two center double-blind, placebo-controlled randomized study of DOV 220,075 (bicifadine) SR and Tramadol 100 mg in the treatment of post-operative dental pain. "In: Pain, 2004: 5 (1), Supplement 1, p59.

Presented at t the Joint APS and Canadian Pain Society Annual Meeting (23rd APS Annual Scientific Meeting) May 6-9, 2004, Vancouver, BC Canada. American Pain Society Abstract Da tabase a t http: // www. ampainsoc. org / abstract / 2004 / data / index. html (Poster # 801) Epstein et al., NIDA Res. Monogr. pp. 93-98, 1982. Epstein et al., J. Med. Chem. 24 (5): 481, 1981. Hargreaves, K., Dubner, R., Brown, F., Flores, C, and Joris, J. "A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia." In: Pain 32: 77-88 (1988). Igarashi et al., Spine, 2_5: 2975-80 (2000). Kim, S. H .; Chung, J. M. "An experimental model for neuropathy produced by segmental spinal nerve ligation in the rat." In: Pain, 50: 355-363, (1992); and "The streptozotocin (STZ) -induced diabetic rat model" (see, e.g., Morrow, T.J., 2004.) "Animal Models of Painful Diabetic Neuropathy: The STZ rat model. "In: Current Protocols in Neuroscience (J.N.

Crawley, C.R. Gerfen, M.A. Rogawski, D.R. Sibley, P.

Skolnick, and S. Wray, eds.) Pp. 9.18.1-9.18.11. John Wiley & Sons, New York.

Marazzo et al., Arkivoc v: 156-169, 2004.

Max, M.B., Schafer, S.C., Culnane M., et al., "Association of pain relief with side effects in postherpetic neuralgia: a single dose study of clonidine, codeine, ibuprofen, and placebo." In: Clinical and Pharmacological Therapy, 43_: 363 (1988). Max, M.B., Schafer, S.C., Culnane, M., et al., "Amitriptyline, but not lorazepam, postherpetic neuralgia reliefs." In: Neurology, 38: 1427 (1988). Morrow, T.J. "Animal Models of Painful Diabetic Neuropathy: The STZ rat model. "In: Current Protocols in Neuroscience (J.N. Crawley, C.R. Gerfen, M.A. Rogawski, D.R. Sibley, P. Skolnick, and S. Wray, eds.) Pp. 9.18.1-9.18.11. John Wiley & Sons, New York (2004). Mouzin et al., Synthesis 4: 304-305, 1978. "Nitrogen Protecting Groups in Organic Synthesis," John Wiley and Sons, New York, N.Y., 1981, Chapter 7; "Nitrogen Protecting Groups in Organic Chemistry," Plenum Press, New York, N.Y., 1973, Chapter 2; see also, W. W. Green and P. G. M. Wuts in "Protective Groups in Organic Chemistry, 3rd edition" John Wiley & Sons, Inc. New York, N.Y., 1999. Seltzer, Z., Dubner, R., and Shir, Y. "A Novel Behavioral Model of Neuropathic Pain Disorders Produced in Rats by Partial Sciatic Nerve Injury. "In: Pain, 43: 205-218 (1990).

Shir et al., Harefuah 118 (8): 452-4, 1990. Stein, C, "Unilateral Inflammation of the Hindpaw in Rats as a Model of Prolonged Noxious Stimulation: Alterations in Behavior and Nociceptive Thresholds. "In: Pharmacol. Biochem. Beh 31: 451-455, 1988. Vilsmaier et al., Tetrahedron 45: 3683-3694, 1989 Woolf, C.J., Mannion, R. J. "Neuropathic Pain: Aetiology, Symptoms, Mechanisms, and Management." In: The Lancet, 353 (9168): 1959-1964 (1999) Provisional Patent Application of the U.S.A.

No. 60 / 424,982 U.S. Patent Application. Serial No. 10 / 466,457 U.S. Patent Application. Serial No. 10 / 702,397 U.S. Patent Application. Serial No. 10 / 764,371 U.S. Patent Application Serial No. 10 / 764,371. Serial No. 10 / 764,373 Patent Application of the US. Serial number / 764,375 U.S. Patent Application. Serial number / 920,748 Patent of the U.S.A. No. 4,118,417 Patent of the U.S.A. No. 4,196,120 Patent of the U.S.A. No. 4,435,419 Patent of the U.S.A. No. 4,131,611 Patent of the U.S.A. No. 4,231,935 Patent of the U.S.A. No. 6,204,284 Patent of the U.S.A. No. 6,372,919 Patent of the U.S.A. No. 6,659,887 Patent of the U.S.A. No. 6,716,868 PCT / US2003 / 035099 (International Publication Patent Publication PL 120095 B2, CAN 99: 158251 by Szalacke et al.

Claims (71)

1. CLAIMS 1. Method for preventing or treating a neuropathic disorder in a mammal, characterized in that it comprises administering to the subject an effective amount of a compound of the formula I. Formula I wherein Ar is a phenyl or other aromatic group having at least one substitution on the aryl ring, and wherein R is selected from hydrogen, C? -6 alkyl, halo (C? -6) alkyl, C3-9 cycloalkyl, C1-5 alkoxy (Ci-β) alkyl, carboxy (C1-3) alkyl, C3_3 alkanoyl, carbamate, halo (C3_3) alkoxy (C3_d) alkyl, C1-3 alkylamino (Ci_3) alkyl, and di (C1-3) alkylamino (Ci-β) alkyl, cyano (C6-6) alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl.
2. 2. The method according to claim 1, characterized in that the compound is selected from bicifadine, bicifadine enantiomers, bicifadin salts, bicifadin prodrugs, polymorphs, hydrates and solvates of bicifadine and combinations thereof.

   3. The method according to claim 2, characterized in that the compound is HCl bicifadine. 4. The method according to claim 2, characterized in that the compound comprises a (+) enantiomer of bicifadine. 5. The method according to claim 4, characterized in that the compound is administered in a formulation that is substantially free of an (-) enantiomer of bicifadine. 6. The method according to claim 2, characterized in that the compound comprises a (+) of bicifadine. The method according to claim 6, characterized in that the compound is administered in a formulation that is substantially free of a (+) enantiomer of bicifadine. 8. The method according to claim 2, characterized in that the compound comprises a polymorph B form of bicifadine. The method according to claim 8, characterized in that the compound is administered in a formulation that is substantially free of a polymorph A form of bicifadine. 10. The method of compliance with claim 1, characterized in that the compound is selected from the group consisting of: 1 - . 1- (4-fluorophenyl) -3-methyl-3-aza-3-methyl-1- (- (trifluoromethyl) phenyl) -bicyclo [3.1. OJhexane 3-aza-bicyclo [3.1.OJhexano 1- (3-chlorophenyl) -3-methyl-3-aza- (4- (3-methyl-3-aza-bicyclo [3.1.0] hexane-cyclo [3.1.0Jhexane 1 -yl) phenyl) methanamine and its pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, and active prodrugs. 11. The method according to claim 1, characterized in that the compound is selected from the group consisting of: 3-methyl-1-p-tolyl-3-aza-3-ethyl-1-p-tolyl-3-azabicyclo [3.1. OJhexano bicycles [3.1. OJhexano 3-propyl-1-p-tolyl-3-aza-3-isopropyl-1-p-tolyl-3-aza-3-isobutyl-1-p-tolyl-3-azabicyclo [3.1. OJhexano bicycles [3.1.OJhexano bicycles [3.1. OJhexano p-tolyl-3- (2,2,2-trifluoroethyl) -3. { 2-methoxyethyl) -1-p-tolyl-1-p-tolyl-3- (trifluoromethyl) -1- 3-aza-bicyclo [3.1.O-Hexane 3-aza-bicyclo [3.1.O-hexane 3-aza-bicyclo [3.1 .OJhexano and their pharmaceutically acceptable active salts, solvates, hydrates, polymorphs, enantiomers and prodrugs. 12. Method for preventing or treating a neuropathic disorder - in a mammalian subject comprising administering to the subject an effective amount of a compound of formula III: Formula III wherein R is chosen for example from C? -6 alkyl, halo (C? -β) alkyl, C3-9 cycloalkyl, C1-5 alkoxy (Ci-β) alkyl, carboxy (C1-3) alkyl, C1-3 alkanoyl, carbamate, halo (C? -3) alkoxy (C? _6) alkyl, C1-3 alkylamino (C? _6) alkyl and di (Ci-3) alkylamino (Ci-β) alkyl, cyano (Ci-e) alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl; and wherein Ri is selected from halogen, C1-3 alkyl, C2-4 alkenyl, C2_4 alkynyl, halo (C1-3) alkyl, cyano, hydroxy, C3_5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy (Ci-3) alkyl, carboxy (C1-3) alkyl, C1-3 alkanoyl, halo (C? -3) alkoxy, nitro, amino, C1-3 alkylamino,. and di (C? -3) alkylamino, methyl, ethyl, fluorine, chloro, trifluoromethyl, cyano, nitro, and trifluoromethoxy. 13. The method according to claim 12, characterized in that the compound is selected from the group consisting of: 3-methyl-1-p-tolyl-3-aza-3-ethyl-1-p-tolyl-3-azabicyclo [3.1. OJhexano bicycles [3.1. OJhexano 3-pro aza-3-isobutii-1-p-tolyl-3-azabicyclo [3.1.0] hexane bicyclo [3.1. OJhexano bicycles [3.1. OJhexano 3- (2-methoxyethyl) -1-p-tolyl-1-p-tolyl-3- (trifluoromethyl) -1-p-tolyl-3- (2,2,2-trifluoroethyl) -3-aza-bicyclo [ 3.1.OJhexano 3-aza-bicyclo [3.1. OJhexane 3-aza-bicyclo [3.1.OJhexano and their pharmaceutically acceptable active salts, solvates, hydrates, polymorphs, enantiomers and prodrugs. 14. Method for preventing or treating a neuropathic disorder in a mammalian subject, comprising administering to the subject an effective amount of a compound of formula IV: Formula IV wherein R is selected from C? _6 alkyl, halo (C? _6) alkyl, C3-9 cycloalkyl, C1-5 alkoxy (C1-6) alkyl, carboxy (Ci-3) alkyl, C1-3 alkanoyl, carbamate, halo (C1-3) alkoxy (C? _?) alkyl, C? -3 alkylamino (Ci-β) alkyl and di (Ci-3) alkylamino (C? -6) alkyl, cyano (C? -6) alkyl , methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl. 15. The method according to claim 14, characterized in that the compound is selected from: 3-methyl-1-hydrochloride of 3-et? l-1- p-tol? l-3-aza-b? c? clo p-tol? l-3-aza-b? c? clo [3 1 OJhexano [3 1 Ojhexano 3-propyl-1- hydrochloride 3-? -propyl-1-hydrochloride of 3-? sobutyl-1 p-tol? l-3-aza-b? c? clo p-tol? l-3-aza-b? c? clo p-tol? l-3-aza-b? c? clo [3 1 Ojhexano [3 1 Ojhexano [3 1 Ojhexano 3- (2-methox? et? l) -1- hydrochloride of 1-p-tol? l-3-hydrochloride of 1-p-tol? l-3-p-tol? l-3-aza- b? c? clo (trifluoromethyl) -3-aza-b? c? clo (2,2,2-tpfluoroet? l) -3-aza- [3 1 Ojhexano [3 1 Ojhexano b? c? clo [3 1 Ojhexano and their pharmaceutically acceptable active salts, solvates, hydrates, polymorphs, enantiomers and prodrugs. 16. Method for preventing or treating one or more symptoms resulting from a neuropathic disorder in a mammalian subject, characterized in that it comprises administering to the subject an effective amount of a 1-aryl-3-azabicyclo [3.1.0] hexane. 17. The method according to claim 16, characterized in that l-aryl-3-azabicyclo [3.1.0] hexane is selected from bicifadine, bicifadine enantiomers, bicifadine salts, bicifadine prodrugs, polymorphs, hydrates and solvates. bicifadina and its combinations. 18. The method according to claim 17, characterized in that l-aryl-3-azabicyclo [3.1.0] hexane is bicifadine HCl. 19. Method for preventing or treating one or more symptoms resulting from a neuropathic disorder in a mammalian subject, comprising administering to the subject an effective amount of the compound of formula V: Formula V III wherein Ri and R2 each are chosen from halogen, C? _3 alkyl, C2.4 alkenyl, C2-4 alkynyl, halo (C? _3) alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy (C1-3) alkyl, carboxy (C1-3) alkyl, C1-3 alkanoyl, halo (C1-3) alkoxy, nitro, amino, C1-3 alkylamino, and di (C? _ 3) alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, and trifluoromethoxy. The method according to claim 19, characterized in that the compound is selected from the group consisting of: 1- (3-Chloro-4-fluorophenyl) -3-methyl-3- 1- (3,4-difluorophenyl) -3-methyl-3- 3 -methyl- (naphthalen-2-yl) -3-aza- bicycle [3.1. OJhexano aza-bícycle [3.1. OJhexano aza-bicyclo [3.1. OJhexano 1 - . 1 - . 1 - (2, 4-d ifl Xuorofßn ti) -3-metií-3- 1- (3-fluoro-methylphenyl) -3-methyl-3- 1- (4-fluoro-methylphenyl) -3-methyl -3- aza-bicyclo [3.1.OJhexano aza-bicyclo [3.1.OJhexano aza-bici or [3.1.OJhexano 1 - . 1 - (3-Chloro-4-nitrophenol) -3-methyl-3- 1- (5-chloro-2,4-dinitrophenyl) -3-methyl-3-1 - (2,4-dichlorophen) il) -3-methyl-3-aza-bicyclo [3.1.OJhexane aza-bicyclo [3.1. OJhexano aza-bícycle [3.1. OJhexano 1 - (3-chloro-4-fluorophenyl) -3-aza-bicido [3.1.OJhexano and its pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates and prodrugs. The method according to claim 19, characterized in that the compound is 1- (3,4-dichlorophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane, or its salt, polymorph, solvates, hydrates or pharmaceutically acceptable prodrug. 22. The method according to claim 19, characterized in that the compound is (+) -1- (3,4-dichlorophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane substantially free of its ( -) corresponding enantiomer or its salt, polymorph, pharmaceutically acceptable solvates, hydrates or prodrugs. The method according to claim 19, characterized in that the compound is (-) -1- (3,4-dichlorophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane substantially free of its ( +) corresponding enantiomer or its pharmaceutically acceptable salt, polymorph, solvate, hydrate or prodrug. 24. The method according to claim 19, characterized in that the compound is 1- (3,4-dichlorophenyl) -3-ethyl-3-aza-bicyclo [3.1.0] hexane, or its pharmaceutically acceptable salt, polymorph, solvate, hydrate or prodrug. 25. The method according to claim 19, characterized in that the compound is (+) -1- (3,4-dichlorophenyl) -3-ethyl-3-aza-bicyclo [3.1.0] hexane substantially free of its (-) corresponding enantiomer, or its salt, polymorph, solvate, hydrate, or pharmaceutically acceptable prodrugs. 26. The method according to claim 19, characterized in that the compound is (-) -1- (3,4-dichlorophenyl) -3-ethyl-3-aza-bicyclo [3.1.0] hexane substantially free of its ( +) or its pharmaceutically acceptable salt, polymorph, solvate, hydrate, or prodrug.

   27. The method according to claim 19, characterized in that the compound is 1- (3,4-dichlorophenyl) -3-propy1-3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, solvate, hydrate, or pharmaceutically acceptable prodrug. The method according to claim 19, characterized in that the compound is 1- (3,4-dichlorophenyl) -3-butyl-3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, pharmaceutically acceptable solvate, hydrate, or prodrug. 29. The method according to claim 19, characterized in that the compound is 1- (3,4-dichlorophenyl) -3-isobutyl-3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, pharmaceutically acceptable solvate, hydrate, or prodrug. 30. The method according to claim 19, characterized in that the compound is 1- (3,4-dichlorophenyl) -3-isopropy1-3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, pharmaceutically acceptable solvate, hydrate, or prodrug. 31. The method according to claim 19, characterized in that the compound is 1- (3,4-dichlorophenyl) -3-cyclopropyl-3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, pharmaceutically acceptable solvate, hydrate, or prodrug.

   32. The method according to claim 19, characterized in that the compound is 3-tert-butyl-1- (3,4-dichlorophenyl) -3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, pharmaceutically acceptable solvate, hydrate, or prodrug. 33. The method according to claim 19, characterized in that the compound is selected from the group consisting of: 1- (3,4-dichlorophenyl) -3- hydrochloride hydrochloride. { 3,4-didorofer? I1) -3- pro? Il-3 -azabicido .1.OJhexano bt? Il -3-azabicicl or [3.1.OJhexano il) -3- 1- (3"4-dichlorophenyl) -3-isopropyl-3-azabicyclo [3.1.OJhexane isobutyl-3-azabiddo hydrocarbon. { 3.1.Ojhexano 1- (3,4-Dichlorophenyl) -3- hydrochloride of 3-tert-butyl-1- (3,4-dtclorophenyl) cycloprefil -3-azabicyclo [3.1.OJhexane -3 azabicyclo [ 3.1.OJhexano and its pharmaceutically acceptable salts, polymorphs, enantiomers, solvates, hydrates, and prodrugs. 34. The method according to claim 19, characterized in that the compound is 1- (3-chloro-4-fluorophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, solvate, hydrate, or pharmaceutically acceptable prodrug. 35. The method according to claim 19, characterized in that the compound is 1- (3,4-difluorophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, solvate , hydrate, or pharmaceutically acceptable prodrug. 36. The method according to claim 19, characterized in that the compound is 3-methyl-1- (naphthalen-2-yl) -3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, pharmaceutically acceptable solvate, hydrate, or prodrug.

   37. The method according to claim 19, characterized in that the compound is 1- (2,4-difluorophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, solvate, hydrate , or pharmaceutically acceptable prodrug. 38. The method according to claim 19, characterized in that the compound is 1- (3-fluoro-4-methylphenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, solvate, hydrate, or pharmaceutically acceptable prodrug. 39. The method according to claim 19, characterized in that the compound is 1- (4-fluoro-3-methylphenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, solvate, hydrate, or pharmaceutically acceptable prodrug. 40. The method according to claim 19, characterized in that the compound is 1- (3-chloro-4-nitrophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, solvate, hydrate, or pharmaceutically acceptable prodrug. 41. The method according to claim 19, characterized in that the compound is 1- (5-chloro-2,4-dinitrophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane, or its salt, pharmaceutically acceptable enantiomer, polymorph, solvate, hydrate, or prodrug.

   42. The method according to claim 19, characterized in that the compound is 1- (2,4-dichlorophenyl) -3-methyl-3-aza-bicyclo [3.1. OJ hexane, or its pharmaceutically acceptable salt, enantiomer, polymorph, solvate, hydrate, or prodrug. 43. The method according to claim 19, characterized in that the compound is 1- (3-chloro-4-fluorophenyl) -3-methyl-3-aza-bicyclo [3.1.0] hexane, or its salt, enantiomer, polymorph, solvate, hydrate, or pharmaceutically acceptable prodrug. 44. The method according to any of claims 1, 2, 11, 12, 13, 14, 15, 16, 19, 20 or 33, characterized in that the effective amount comprises between about 1 to about 600 mg. 45. The method according to any of claims 1, 2, 11, 12, 13, 14, 15, 16, 19, 20 or 33, characterized in that the effective amount comprises between about 25 to about 200 mg. 46. The method according to any of claims 1, 2, 11, 12, 13, 14, 15, 16, 19, 20 or 33, characterized in that the method is effective to reduce a Neuropathic Pain Scale of the subject below of a value less than about 10. 47. The method according to any one of claims 1, 2, 11, 12, 13, 14, 15, 16, 19, 20 or 33, characterized in that the method is effective to reduce a Neuropathic Pain Scale of the subject by at least one value. 48. The method according to claim 1, characterized in that it further comprises administering to the subject in a coordinated manner one or more secondary therapeutic agents or treatment methods selected from the group consisting of ** non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); N-methyl-D-aspartate (NMDA) receptor antagonists; surgery; electrical stimulation of transcutaneous nerves; spinal cord stimulation epidural; neurectomy; rhizotomy; lesion of dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. 49. The method according to claim 2, characterized in that it further comprises administering to the subject in a coordinated manner one or more secondary therapeutic agents or treatment methods selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); N-methyl-D-aspartate (NMDA) receptor antagonists; surgery; electrical stimulation of transcutaneous nerves; spinal cord stimulation epidural; neurectomy; rhizotomy; lesion of dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. 50. The method according to claim 10, characterized in that it further comprises administering to the subject in a coordinated manner one or more secondary therapeutic agents or treatment methods selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); N-methyl-D-aspartate (NMDA) receptor antagonists; surgery; electrical stimulation of transcutaneous nerves; spinal cord stimulation epidural; neurectomy; rhizotomy; lesion of dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. 51. The method according to claim 11, characterized in that it further comprises administering to the subject in a coordinated manner one or more secondary therapeutic agents or treatment methods selected from the group consisting of anti-cancer drugs. inflammatory non-spheroidal; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); N-methyl-D-aspartate (NMDA) receptor antagonists; surgery; electrical stimulation of transcutaneous nerves; spinal cord stimulation epidural; neurectomy; rhizotomy; lesion of dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. 52. The method according to claim 12, characterized in that it further comprises administering to the subject in a coordinated manner one or more secondary therapeutic agents or treatment methods selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); N-methyl-D-aspartate (NMDA) receptor antagonists; electrical stimulation of transcutaneous nerves; spinal cord stimulation epidural; neurectomy; rhizotomy; lesion of dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. 53. The method according to claim 13, characterized in that it also comprises administering to the subject in a coordinated fashion one or more secondary therapeutic agents or treatment methods selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); N-methyl-D-aspartate (NMDA) receptor antagonists; surgery; electrical stimulation of transcutaneous nerves; spinal cord stimulation epidural; neurectomy; rhizotomy; lesion of dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. 54. The method according to claim 14, characterized in that it further comprises administering to the subject in a coordinated manner one or more secondary therapeutic agents or treatment methods selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); N-methyl-D-aspartate (NMDA) receptor antagonists; surgery; electrical stimulation of transcutaneous nerves; spinal cord stimulation epidural; neurectomy; rhizotomy; lesion of dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. 55. The method according to claim 15, characterized in that it further comprises administering to the subject in a coordinated manner one or more secondary therapeutic agents or treatment methods selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); N-methyl-D-aspartate (NMDA) receptor antagonists; surgery; electrical stimulation of transcutaneous nerves; spinal cord stimulation epidural; neurectomy; rhizotomy; lesion of dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. 56. The method according to claim 16, characterized in that it further comprises administering to the subject in a coordinated manner one or more secondary therapeutic agents or treatment methods selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g. lidocaine); N-methyl-D- receptor antagonists aspartate (NMDA); surgery; electrical stimulation of transcutaneous nerves; spinal cord stimulation epidural; neurectomy; rhizotomy; lesion of dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. 57. The method according to claim 19, characterized in that it further comprises administering to the subject in a coordinated manner one or more secondary therapeutic agents or treatment methods selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); N-methyl-D-aspartate (NMDA) receptor antagonists; surgery; electrical stimulation of transcutaneous nerves; spinal cord stimulation epidural; neurectomy; rhizotomy; lesion of dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. 58. The method according to claim 20, characterized in that it further comprises administering to the subject in a coordinated manner one or more secondary therapeutic agents or treatment methods selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); N-methyl-D-aspartate (NMDA) receptor antagonists; surgery; electrical stimulation of transcutaneous nerves; spinal cord stimulation epidural; neurectomy; rhizotomy; lesion of dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. 59. The method according to claim 33, characterized in that it further comprises administering to the subject in a coordinated manner one or more secondary therapeutic agents or treatment methods selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); N-methyl-D-aspartate (NMDA) receptor antagonists; surgery; electrical stimulation of transcutaneous nerves; spinal cord stimulation epidural; neurectomy; rhizotomy; lesion of dorsal root entrance area; cordotomy; thalamotomy; and neuroablation. 60. A composition for preventing or treating a neuropathic disorder in a mammalian subject, characterized in that it comprises: a compound of the formula I Formula I wherein Ar is a phenyl or other aromatic group having at least one substitution on the aryl ring, and wherein R is selected from hydrogen, C? _6 alkyl, halo (C? _6) alkyl, C3-9 cycloalkyl, C1- 5 alkoxy (C6-6) alkyl, carboxy (Ci-3) alkyl, C1-3 alkanoyl, carbamate, halo (C1-3) alkoxy (C6-6) alkyl, C1-3 alkylamino (C6-6) alkyl , and di (C? _ 3) alkylamino (Ci-β) alkyl, cyano '(C? -6) alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl; and one or more secondary therapeutic agents selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); and N-methyl-D-aspartate (NMDA) receptor antagonists. 61. A composition for preventing or treating a neuropathic disorder in a mammalian subject, characterized in that it comprises: a first therapeutic agent selected from the group consisting of bicifadine, bicifadine enantiomers, bicifadine salts, bicifadine prodrugs, polymorphs, hydrates, and bicifadine solvates, and combinations thereof; and one or more secondary therapeutic agents selected from the group consisting of one or more secondary therapeutic agents selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); and N-methyl-D-aspartate (NMDA) receptor antagonists. 62. A composition for preventing or treating a neuropathic disorder in a mammalian subject, characterized in that it comprises: a first therapeutic compound selected from the group consisting of: 1- (4-fluorophenyl) -3-methyl-3-aza-3-methyl-1- (- (trifluoromethyl) phenyl) -bicyclo [3.1. OJhexane 3-aza-bicyclo [3.1.OJhexano its 1- (3-chlorophenyl) -3-methyl-3-aza- (4- (3-methyl-3-aza-bicyclo [3.1.O-hexahexicyclo [3.1. OJhexane 1-yl) phenyl) methanamine salts, solvates, hydrates, polymorphs, enantiomers, and pharmaceutically acceptable active prodrugs; and one or more secondary therapeutic agents selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); and N-methyl-D-aspartate (NMDA) receptor antagonists. 63. A composition for preventing or treating a neuropathic disorder in a mammalian subject, characterized in that it comprises: a first therapeutic compound selected from the group consisting of: 3-cpethyl-1-p-tolyl-3-aza-3-ethyl-1-p-tolyl-3-aza-btcyclo [3.1.OJhexane bicyclo [3.1.0Jhexan 3-pn ii -1-p-to lyl-3-aza-3-isopropyl-1-p-tolyl-3-aza-3-isobutyl-1-p-toli l-3-aza--i ni *. hir-irir »f? 1 pihovn t m * 3- (2-methoxyethyl) -1-p-tolyl-1-p-tolyl-3- (trifluoromethyl) -1-p-tolyl-3- (2,2,2-trifluoroethyl). 1 ?? nvmM? 3-aza-bicycloI3,1.Olhexane 3-aza-bicyclo [3.1.OJhexane and their pharmaceutically acceptable active salts, solvates, hydrates, polymorphs, enantiomers and prodrugs; and one or more secondary therapeutic agents selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); and N-methyl-D-aspartate (NMDA) receptor antagonists. 64. A composition for preventing or treating a neuropathic disorder in a mammalian subject, characterized in that it comprises: a compound of the formula III: Formula III wherein R is selected from C? _6 alkyl, halo (C? _6) alkyl, C3-9 cycloalkyl, C1-5 alkoxy (C? _6) alkyl, carboxy (C? _ 3) alkyl, C1-3 alkanoyl, carbamate halo (C1-3) alkoxy (C6-6) alkyl, C1-3 alkylamino (C-?) alkyl and di (C? 3) alkylamino (Ci-e) alkyl, cyano (Ci-β) alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl and 2-methoxyethyl; Y wherein Ri is selected from halogen, C? -3 alkyl, C2_4 alkenyl, C2-4 alkynyl, halo (C? _3) alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy (Ci -3) alkyl, carboxy (C? _3) alkyl, C? _3 alkanoyl, halo (C? 3) alkoxy, nitro, amino, C? _3 alkylamino, and di (Ci-3) alkylamino, methyl, ethyl, fluorine , chloro, trifluoromethyl, cyano, nitro, and trifluoromethoxy; and one or more secondary therapeutic agents selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); and N-methyl-D-aspartate (NMDA) receptor antagonists. 65. A composition for preventing or treating a neuropathic disorder in a mammalian subject, characterized in that it comprises: a first therapeutic agent selected from the group consisting of: 3-methyl-1-p-tolyl-3-aza-3-ethyl-1-p-tolyl-3-azabicyclo [3.1. OJhexano bicycles [3.1. OJhexano 3-propyl-1-p-tolyl-3-aza-3-isopropyl-1-p-totyl-3-aza-3-isobutyl-1-p-tolyl-3-azabicyclo [3.1. OJhexano bicycles [3.1. OJhexano bicycles [3.1. OJhexano 3- (2-methoxyethyl) -1-p-tolyl-1-p-tolyl-3- (trifluoromethyl) -1-p-tolyl-3- (2,2,2-tifluoroethyl) -3-aza- bicyclo [3.1.OJhexane 3-aza-bicyclo [3.1.OJhexane 3-aza-bicyclo [3.1.OJhexano and their pharmaceutically acceptable active salts, solvates, hydrates, polymorphs, enantiomers and prodrugs; and one or more secondary therapeutic agents selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); and N-methyl-D-aspartate (NMDA) receptor antagonists.

   66. A composition for preventing or treating a neuropathic disorder in a mammalian subject, characterized in that it comprises: a compound of formula IV: Formula IV wherein R is selected from C? _6 alkyl, halo (C? _6) alkyl, C3_g cycloalkyl, C1-5 alkoxy (C? -6) alkyl, carboxy (Ci-3) alkyl, C1-3 alkanoyl, carbamate, halo (C1-3) alkoxy (Ci-6) alkyl, C1-3 alkylamino (C6-6) alkyl and di (C3-) alkylamino (Ci-β) alkyl, cyano (Ci-e) alkyl, methyl, ethyl , trifluoromethyl, trifluoroethyl and 2-methoxyethyl; and one or more secondary therapeutic agents selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); and N-methyl-D-aspartate (NMDA) receptor antagonists. 67. A composition for preventing or treating a neuropathic disorder in a mammalian subject, characterized because - it comprises: a first therapeutic agent selected from the group consisting of: 3-methyl-1- hydrochloric acid 3-ethyl-1-p-tol? l-3-aza-b? c? clo p-tol? l-3-aza-b? c? clo hydrochloride [3 1 Ojhexano [3 1 Ojhexano 3-Propyl-1- hydrochloride 3-? -propyl-1-hydrochloride 3-? -butbutyl-1- p-tol? l-3-aza-b? c? clo p-tol l-3-aza-b? c? clo p-tol? l-3-aza-b? c? cl [3 1 Ojhexano [3 1 Ojhexano [3 1 Ojhexano 3- (2-methoxy? et? l) -1- hydrochloride of 1-p-tol? l-3-hydrochloride of 1-p-tol? l-3-p-tol? l-3-aza- b? c? clo (tnfluoromethyl) -3-aza-b? c? clo (2,2,2-tpfluoroet? l) -3-aza- [3 1 0jhexano [3 1 Ojhexano b? c? clo [3 1 0jhexano and their pharmaceutically acceptable active salts, solvates, hydrates, polymorphs, enantiomers and prodrugs; and one or more secondary therapeutic agents selected from the group consisting of anti-inflammatory drugs are not spheroidal; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); and N-methyl-D-aspartate (NMDA) receptor antagonists. 68. A composition for preventing or treating a neuropathic disorder in a mammalian subject, characterized in that it comprises: a first therapeutic compound comprising an l-aryl-3-azabicyclo [3.1.0] hexane or its salt, solvate, hydrate, polymorph, pharmaceutically acceptable enantiomer or prodrug; and one or more secondary therapeutic agents selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); and N-methyl-D-aspartate (NMDA) receptor antagonists. 69. A composition for preventing or treating a neuropathic disorder in a mammalian subject, characterized in that it comprises: a first therapeutic compound of the formula V Formula V III wherein Ri and R2 each are chosen from halogen, C? _3 alkyl, C2-alkenyl, C2_4 alkynyl, halo (C? _3) alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy (C? _3) alkyl, carboxy (C1-3) alkyl, C1-3 alkanoyl, halo (C? -3) alkoxy, nitro, amino, Cx-3 alkylamino, and di (C? _ 3) alkylamino, methyl , ethyl, fluoro, chloro, trifluoromethyl, cyano, and trifluoromethoxy; and one or more secondary therapeutic agents selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); and N-methyl-D-aspartate (NMDA) receptor antagonists. 70. A composition for preventing or treating a neuropathic disorder in a mammalian subject, characterized in that it comprises: a first therapeutic compound selected from the group consisting of: - (3-chloro-4-fluorophenyl) -3-methyl-3-1 - (3,4-difl tuo-rofenii) -3-methyl-3- 3-rnethyl- 1 - (naphtha le n-2-tl) - 3 - aza-bicyclo [3.1.OJh exano aza-bicyclo [3.1.OJhexano aza-bic? Clo [3.1. OJhexano - (3-Cbro-4-nitrophenyl) -3-methyl-3- 1- (5-chloro-2,4-dinitrophenyl) -3-methyl-3-1 - (2,4-dichlorophen-yl) -3- mettl-3-aza-bicyclo [3.1.OJhexane aza-bicyclo [3.1.0] hexane aza-bicyclo [3.1. OJhexano - (3-loro-4-fiuorofentf) -3-aza-bictcloß.1. OJhexano and its pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates and prodrugs; and one or more secondary therapeutic agents selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); and N-methyl-D-aspartate (NMDA) receptor antagonists. 71. A composition for preventing or treating a neuropathic disorder in a mammalian subject, characterized in that it comprises: a first therapeutic compound selected from the group consisting of: 1- hydrochloride. { 3,4-Diororenyl) -3- 1'34-dflorophenyl) -3- propyl-3-azabicycloP.1.0] hexane butyl-3-azabctclo [3.1.O-Hexane] 1- (3,4-dictorophene) -3- hydrochloride hydrochloride of 3-tert-toutii-1 - (3,4-dictorafeniI) cictopropyl-3-azabiciclof3.1.OJhexane -3-az3-bicyclo [3.1.GJhexano and its pharmaceutically acceptable salts, polymorphs, enantiomers, solvates, hydrates, and prodrugs; and one or more secondary therapeutic agents selected from the group consisting of non-spheroidal anti-inflammatory drugs; COX-2 inhibitors; natural and synthetic opiates; mexiletine; baclofen; tramadol; anti arrhythmic; anticonvulsants; capsaicin cream; membrane stabilizing drugs (e.g., lidocaine); and N-methyl-D-aspartate (NMDA) receptor antagonists.