Patent Publication Number: US-2006019968-A1

Title: Use of compounds active on the sigma receptor for the treatment of neuropathic pain

Description:
FIELD OF THE INVENTION  
      The present invention refers to the use of compounds active on the sigma receptor for the treatment of the symptoms of neuropathic pain, especially certain subtypes of neuropathic pain, as well as treatment of the disease causing the symptoms, the prevention or the prophylaxis of the symptoms of neuropathic pain, especially certain subtypes of neuropathic pain, as well as the prevention or the prophylaxis of the disease causing the symptoms.  
     BACKGROUND OF THE INVENTION  
      The treatment of pain conditions is of great importance in medicine. There is currently a world-wide need for additional pain therapy. The pressing requirement for a specific treatment of pain conditions or as well a treatment of specific pain conditions which is right for the patient, which is to be understood as the successful and satisfactory treatment of pain for the patients, is documented in the large number of scientific works which have recently and over the years appeared in the field of applied analgesics or on basic research on nociception.  
      PAIN is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP, Classification of chronic pain, 2 nd  Edition, IASP Press (2002), 210). Even though pain is always subjective its causes or syndromes can be classified.  
      Especially neuropathic pain which in the past years has developed into a major health problem in broad areas of the population needs a very specific treatment, especially considering that any treatment of neuropathic pain is extremely sensitive to the causes behind the pain, be it the disease ultimately causing it or the mechanistic pathway over which it develops.  
      Therefore, it was the underlying problem solved by this invention to find new ways of treating neuropathic pain.  
      So, the main object of this invention is the use of a compound binding to the sigma receptor in the production of a medicament for the treatment of neuropathic pain.  
      This/these compound/s may be in neutral form, the form of a base or acid, in the form of a salt, preferably a physiologically acceptable salt, in the form of a solvate or of a polymorph and/or in the form of in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable ration.  
      While working on compounds binding to the sigma receptor and with models like knock-out mice it was surprisingly found out that neuropathic pain is connected to the sigma receptor so that compounds binding to the sigma receptor were acting on neuropathic pain with a high potency.  
      “Treating” or “treatment” as used in this application are defined as including the treatment of the symptoms—of neuropathic pain, especially certain subtypes of neuropathic pain—as well as treatment of the disease or disease consequences causing the symptoms, the prevention or the prophylaxis of the symptoms—of neuropathic pain, especially certain subtypes of neuropathic pain—as well as the prevention or the prophylaxis of the disease or disease consequences causing the symptoms. Preferably “treating” or “treatment” as used in this application are defined as including the treatment of the symptoms—of neuropathic pain, especially certain subtypes of neuropathic pain—as well as treatment of the disease consequences causing the symptoms, the prevention or the prophylaxis of the symptoms—of neuropathic pain, especially certain subtypes of neuropathic pain—as well as the prevention or the prophylaxis of the disease consequences causing the symptoms. Most preferably “treating” or “treatment” as used in this application are defined as including the treatment of the symptoms—of neuropathic pain, especially certain subtypes of neuropathic pain, and the prevention or the prophylaxis of the symptoms—of neuropathic pain, especially certain subtypes of neuropathic pain.  
      “The sigma receptor/s” as used in this application is/are well known and defined using the following citation: This binding site represents a typical protein different form opioid, NMDA, dopaminergic, and other known neurotransmitter or hormone receptor families (G. Ronsisvalle et al. Pure Appl. Chem. 73, 1499-1509 (2001)).  
      Pharmacological data based on ligand binding studies, anatomical distribution and biochemical features distinguish at least two subtypes of a receptors (R. Quiron et al., Trends Pharmacol. Sci. 13, 85-86 (1992); M. L. Leitner, Eur. J. Pharmacol. 259, 65-69 (1994); S. B. Hellewell and W. D. Bowen; Brain Res. 527, 244-253 (1990)) (G. Ronsisvalle et al. Pure Appl. Chem. 73, 1499-1509 (2001)). The protein sequence of the sigma receptors (Sigma 1 (σ1) and Sigma 2 (σ2)) is known (e.g. Prasad, P. D. et al., J. Neurochem. 70 (2), 443-451 (1998)) and they show a very high affinity for e.g. pentazocine. Another selective ligand is a compound known as NE-100 (Chaki, S. et al., Eur. J. Pharmacol. 251, R1-R2 (1994)).  
      “Compound/s binding to the sigma receptor” as used in this application is/are defined as having ≧95% displacement using 1 mM ( 1 H-pentazocine) and a K m  Value in their binding to the sigma receptor ≦50 nM (in regards to any one of the sigma receptor subtypes).  
      Compounds binding to the sigma receptor generally also known as sigma ligands are well known in the art with many of them falling under the definition for “Compound/s binding to the sigma receptor” set up above. Still even though there are many uses known for sigma ligands such as antipsychotic drugs, anxiolytics antidepressants, the treatment of stroke, antiepileptic drugs and many other indications including ant-migraine and general pain (mostly analgesia) there is nowhere any mentioning of these compounds being useful against neuropathic pain.  
      Compounds which have an affinity to the sigma receptor known in the art are listed below. Some of these compounds do not only bind to sigma (and not all with high affinities) and so only part of these listed compounds do fall under the definition of “Compound/s binding to the sigma receptor” defined above, namely e.g. NE-100 and Haloperidol but also many others.  
                                                          3-PPP   Fluoxetine   Quetiapine           8-OH-DPAT   Fluspirilene   Remoxipride           A-01   Gevotroline   Repinotan           A-85380   GR-218231   RGH-1756           Abaperidone   Granisetron   Rimeazole           ABT-089   Haloperidol   Risperidone           ABT-702   Harmaline   Ro-64-6198           AC-915   ICA-17043   RS-102221           AH-9700   Ifenprodil   RS-67333           Ainiitan   Igmesine   RS-67506           Altinicline   Iloperidone   S-15535           Alvameline   Imipramine   S-33084           Amantadine   L-687384   S33113           Amiodarone   L-745870   SA-4503           Amisulpride   Lamotrigine   Safinamide           Amperosized   Lanepitant   Sertindole           Apomorphine   LEK-8829   SH 3/28           Aptiganel   LR-172   SH-1/57           Asenapine   LU-29253   SH-2/21           Astemizole   Mazapertine   SH-3/24           Atomoxetine   MCL-0129   Siramesine           AZ-21666   MDL-100907   SK&amp;F-10047           Azasetron   MDL-28815   SKF-10047               Memntine   SL-650155               Metanicotine   Spiperone               Metoclopramide   SR-31742A               Mizolastine   SSR-125329A           Belaperidone   MJ-139801   SSR-240600           Benzoylecgonine   Mosapramine   Sulpiride           Blonanserin   MR-22   Sultopride           BMY-14802   MS-377   Sumatriptan           Bradyzide   Nafadotride   T-82           Bromperidol   NAS-181   Tacrine           Buspirone   NE-100   Tamoxifen           Carabersat   NE-535   Tebanicline           Chlorpromazine   NE-537   Terfenadine           Cilansetron   Nemonapride   Testosterone           Cisapride hydrate   NGD-94-1   Tiapride           Clomipramine   NNC-05-1869   Tiospirone           Clorgyline   NPC-16377   Tolterodine           Clozapine   NRA-0154   Tranylcypromine           CNS-5161   NS-1209   Trifluoperazine           Co-2-6749   Ocaperidone   Vanoxerine           Cocaine   Olanzapine   Vilazodone           D-02   Ondansetron   XJ-448           Deramciclane   Opipramol   YM-50001           Dextromethorphan   Pargyline   YM-53389           Dihydroergotamine   PD-143188   YM-57158           Ditolylguanidine   PD-172760   YZ-011           Dizocilpine   Pentazocine   YZ-011           Donepezil   Perospirone   Zanapezil           DuP-734   Phencyclidine   ZD-6021               Physostigmine   Ziprasidone               Pipamperone   Zotepine           Eltoprazine   Preclamol           FH-510   Progesterone                      
 
      “Neuropathic pain” is defined by the ISAP as “pain initiated or caused by a primary lesion or dysfunction in the nervous system” (IASP, Classification of chronic pain, 2 nd  Edition, IASP Press (2002), 210). For the purpose of this invention included under this heading or to be treated as synonymous is “Neurogenic Pain” which is defined by the IASP as “pain initiated or caused by the primary lesion, dysfunction or transitory perturbation in the peripheral or central nervous system.  
      The term “salt” is to be understood as meaning any form of the active compound according to the invention in which this assumes an ionic form or is charged and is coupled with a counter-ion) a cation or anion) or is in solution. By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes which are complexed via ionic interactions.  
      The term “physiologically acceptable salt” is understood in particular, in the context of this invention, as salt (as defined above) formed either with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated—especially if used on humans and/or mammals—or with at least one, preferably inorganic, cation which are physiologically tolerated—especially if used on humans and/or mammals. Examples of physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, hydrobromide, monohydrobromide, monohydrochloride or hydrochloride, methiodide, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, hippuric acid picric acid and/or aspartic acid. Examples of physiologically tolerated salts of particular bases are slats of alkali metals and alkaline earth metals and with NH 4 .  
      The term “solvate” according to this invention is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate.  
      It is to be understood that the use according to the invention is restricted to neuropathic pain in regards to all the pain types mentioned in here.  
      In a highly preferred embodiment of the use according to the invention the neuropathic pain is allodynia.  
      According to the IASP “allodynia” is defined as “a pain due to a stimulus which does not normally provoke pain” (IASP, Classification of chronic pain, 2 nd  Edition, IASP press (2002), 210).  
      In another preferred embodiment of the use according to the invention the neuropathic pain, or especially the allodynia, is central pain.  
      According to the IASP “central pain” is defined as “a pain initiated or caused by a primary lesion or dysfunction in the central nervous system” (IASP, Classification of chronic pain, 2 nd  Edition, IASP Press (2002), 211).  
      In another embodiment of the use according to the invention the neuropathic pain, or especially the allodynia, is peripheral neuropathic pain or peripheral neurogenic pain.  
      According to the IASP “Peripheral neuropathic pain” is defined by the IADP as “pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system” and “Peripheral neurogenic pain” as “pain initiated or caused by a primary lesion, dysfunction or transitory perturbation in the peripheral nervous system” (IASP, Classification of chronic pain, 2 nd  Edition, IASP Press (2002), 213).  
      In another preferred embodiment of the use according to the invention the neuropathic pain, or especially the allodynia, is causalgia.  
      According to the IASP “causalgia” is defined as “a syndrome of sustained burning pain, allodynia and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes” (IASP, Classification of chronic pain, 2 nd  Edition, IASP Press (2002), 210).  
      In another preferred embodiment of the use according to the invention the neuropathic pain, or especially the allodynia, is hyperesthesia.  
      According to the IASP “hyperesthesia” is defined as “increased sensitivity to stimulation, excluding the senses” (IASP, Classification of chronic pain, 2 nd  Edition, IASP Press (2002), 211).  
      In another preferred embodiment of the use according to the invention the neuropathic pain, or especially the allodynia, is neuralgia.  
      According to the IASP “neuralgia” is defined as “Pain in the distribution of a nerve or nerves” (IASP, Classification of chronic pain, 2 nd  Edition, IASP Press (2002), 212).  
      In another preferred embodiment of the use according to the invention the neuropathic pain, or especially the allodynia, is neuritis.  
      According to the IASP “neuritis” is defined as “Inflammation of a nerve or nerves” (IASP, Classification of chronic pain, 2 nd  Edition, IASP Press (2002), 212).  
      In another preferred embodiment of the use according to the invention the neuropathic pain, or especially the allodynia, is neuropathy.  
      According to the IASP “neuritis” is defined as “a disturbance of function or pathological change in a nerve: in one nerve mononeuropathy, in several nerves mononeuropathy multiplex, if diffuse and bilateral, polyneuropathy” (IASP, Classification of chronic pain, 2 nd  Edition, IASP Press (2002), 212).  
      In another preferred embodiment of the use according to the invention the neuropathic pain is hyperalgesia.  
      According to the IASP “hyperalgesia” is defined as “an increased response to a stimulus which is normally painful (IASP, Classification of chronic pain, 2 nd  Edition, IASP Press (2002), 211).  
      In another preferred embodiment of the use according to the invention the neuropathic pain is hyperpathia.  
      According to the IASP “hyperpathia” is defined as “a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold” (IASP, Classification of chronic pain, 2 nd  Edition, IASP Press (2002), 212).  
      The IASP draws the following difference between “allodynia”, “hyperalgesia” and “hyperpathia” (IASP, Classification of chronic pain, 2 nd  Edition, IASP Press (2002), 212):  
                                                          Allodynia   Lowered threshold   Stimulus and response                   mode differ           Hyperalgesia   Increased response   Stimulus and response rate                   are the same           Hyperpathia   Raised threshold;   Stimulus and response rate               Increased response   may be the same or                   different                      
 
      In a very preferred embodiment of the invention the medicament is used for the treatment of neuropathic pain in which the stimulus evoking the neuropathic pain is mechanical.  
      In another embodiment of the invention the medicament is used for the treatment of neuropathic pain in which the stimulus evoking the neuropathic pain is thermal.  
      In a very preferred embodiment of the invention the compound binding to the sigma receptor used is acting on the sigma receptor as an antagonist.  
      In another embodiment of the invention the compound binding to the sigma receptor used is acting on the sigma receptor as an antagonist.  
      In another embodiment of the invention the compound binding to the sigma receptor used is acting on the sigma receptor as an agonist.  
      In another embodiment of the invention the compound binding to the compound binding to the sigma receptor used is acting on the sigma receptor as a mixed agonist/antagonist, a partial agonist or a partial antagonist.  
      In a very preferred embodiment of the invention the sigma receptor to which the “compound binding to the sigma receptor” is binding to is the sigma 1 receptor. Under this embodiment “Compound/s binding to the sigma receptor” as used in this application is/are defined as having ≧95% displacement using 1 mM ( 1 H-pentazocine) and a K m  Value in their binding to the sigma 1 receptor ≦50 nM (in regards to any one of the sigma receptor subtypes).  
      In another embodiment of the invention the sigma receptor to which the “compound binding to the sigma receptor” is binding to is the sigma 2 receptor. Under this embodiment “Compound/s binding to the sigma receptor” as used in this application is/are defined as having ≧95% displacement using 1 mM ( 1 H-pentazocine) and a K m  Value in their binding to the sigma 2 receptor ≦50 nM (in regards to any one of the sigma receptor subtypes).  
      In human therapeutics, the dose administered can be quite low depending on the route of administration and is well known in the art because many sigma compounds are known therapeutics.  
      Any medicament according to the invention contains the active ingredient as well as optionally at least one auxiliary material and/or additive and/or optionally another active ingredient.  
      The auxiliary material and/or additive can be specifically selected from conserving agents, emulsifiers and/or carriers for parenteral application. The selection of these auxiliary materials and/or additives and the amounts to be used depends upon how the pharmaceutical composition is to be applied. Examples include here especially parenteral like intravenous or intramuscular application formulation but which could also be used for other administration routes.  
      Routes of Administration can include intramuscular injection, intraveneous injection, subcutaneous injection, sublingual, bucal, patch through skin, oral ingestion, implantable osmotic pump, collagen implants, aerosols or suppository.  
      Included in this invention are especially also methods of treatments of a patient or a mammal, including men, suffering form neuropathic pain using compounds binding to the sigma receptor.  
      The examples and figures in the following section describing pharmacological trials are merely illustrative and the invention cannot be considered in any way as being restricted to these applications. 
    
    
     FIGURES  
       FIG. 1 ) refers to example 1 and shows the test protocol for all tests with von Frey Filaments.  
       FIG. 2    a  to  c ) refer to example 2 and show the effect of NE-100 a specific sigma receptor inhibitor in a model of neuropathic pain, especially mechanical allodynia.  
       FIG. 2   a ) shows the dose dependency of the treatment with NE-100 to show analgesia in capsaicin-induced neuropathic pain.  
       FIG. 2   b ) demonstrates that the treatment with NE-100 is effective specifically in neuropathic pain or mechanical allodynia and not general pain as shown by the different efficacy depending on the force of the von-Frey filaments with 0.5 g being typically in the range of neuropathic pain/allodynia and 4 g clearly being in the general pain field.  
       FIG. 2   c ) proofs that the effect of the treatment with NE-100 is clearly connected to its sigma inhibitor activity, as PRE-084 is a well known sigma receptor agonist.  
       FIGS. 3    a  to  d ) refer to example 3 and shows the effect of antisense ODNs against sigma (1) receptor.  
       FIG. 3   a ) shows the test protocol for Oligodesoxynucleotid (ODN) tests with von Frey filaments.  
       FIG. 3   b ) shows the influence of the wash-out period on the effect t of treatment with antisense ODN, with two known antisense ODN (by KING . . . and UEDA . . . ) being used proving their highly significant effect on neuropathic pain in the von-Frey model. Still after 7 days washout the effect is gone as has to be expected from antisense ODN.  
      Mismatches do not have any significant effect.  
       FIG. 3   c ) shows the effectiveness and dose dependency with two known antisense ODNs (by KING and UEDA) testing with von Frey filaments. Mismatches do not have any significant effect.  
       FIG. 3   d ) demonstrates that the treatment with two known antisense ODNs is effective specifically in neuropathic pain or mechanical allodynia and not general pain as shown by the different efficacy depending on the force of the von-Frey filaments with 0.5 g being typically in the range of neuropathic pain/allodynia and 4 g clearly being in the general pain field.  
       FIG. 4 ) refers to example 4 and demonstrates clearly that KO-Mice having the sigma (1) receptor (called “mutantes”) are not susceptible anymore to the neuropathic pain-/or allodynia-inducing effects of capsaicin independent of the dose given compared to wild-type mice (called “salvajes”). This is clearly demonstrating the truth of the role of sigma receptors in neuropathic pain and allodynia and strengthens the claim to the role of all compounds binding to the sigma-receptor in neuropathic pain/allodynia. 
    
    
     EXAMPLES  
     Example 1  
     Von Frey-Model  
      The von Frey model is a model for neuropathic pain especially hyperalgesia/allodynia, stimulated mechanically.  
      Interest of the model:  
     
         
         
           
              The injection of capsaicin to experimental animals produces acute pain followed y hyperalgesia/allodynia  
              The mechanisms involved in capsaicin-induced acute pain and hyperalgesia are relatively well known (mainly activation of peripheral nociceptors and sensitization of spinal cord neurons, respectively) 
 
 Hypothesis 
 
              Capsaicin-induced hyperalgesia/allodynia is due to the release in the spinal cord of several substances including excitatory aminoacids (EA). Since sigma ligands modulate the effect of EA they would also modulate capsaicin-induced hyperalgesia/allodynia.  
           
         
       
    
       FIG. 1 ) shows the test protocol for all tests with von Frey filaments. After habituation mice were according to  FIG. 1  first treated with the test-compound (or not in controls). Then capsaicin (1% DMSO) is injected into their paw resulting in developing pain in the effected paw. The effected paw is then treated with a mechanical stimulus and then the latency time before the paw is withdrawn is measured.  
     Example 2  
     Effect of NE-100 in the Von Frey-Model  
      NE-100 is a well known compound with high affinity to the sigma receptor, more specifically a known specific inhibitor of Sigma 1. This pharmacological test showed the effect of NE-100 a specific sigma receptor inhibitor in the von-frey model described in example 1, a model of neuropathic pain.  
      As shown in  FIG. 2   a ) there is a dose dependency of the treatment with NE-100 showing analgesia in capsaicin-induced neuropathic pain.  
      As demonstrated in  FIG. 2   b ) the treatment with NE-100 is effective specifically in neuropathic pain or mechanical allodynia and not general pain as shown by the different efficacy depending on the force of the von-Frey filaments with 0.5 g being typically in the range of neuropathic pain/allodynia and 4 g clearly being in the general pain field. Further as shown in  FIG. 2   c ) there is clear evidence that the effect of the treatment with NE-100 is clearly connected to its sigma inhibitor activity, as PRE-084 is a well known sigma receptor agonist counteracting the effect of NE- 100 .  
     Example 3  
     Effect of Antisense ODN Against Sigma Receptor in the Von Frey-Model  
      2 well known antisense Oligodesoxynucleotides (ODN) against the sigma 1 receptor (KING et al. . . . and UEDA et al. . . . ) were synthesized and according to the protocol shown in  FIG. 3   a ) given on 4 consecutive days i.c.v. followed by a wash-out period and von-Frey tests according to example 1.  
      As can be seen in  FIG. 3   b ) both antisense ODNs show a strong effect on day one after treatment with mismatches not having any significant effect. This effect is washed out after 7 days as can be expected from antisense ODN.  
      The effectiveness and dose dependency is demonstrated in  FIG. 3   c ). Mismatches do not have any significant effect.  
      Further as demonstrated in  FIG. 3   d ) the treatment with the two known antisense ODNs is effective specifically in neuropathic pain or mechanical allodynia and not general pain as shown by the different efficacy depending on the force of the von-Frey filaments with 0.5 g being typically in the range of neuropathic pain/allodynia and 4 g clearly being in the general pain field.  
     Example 4  
     Effect of the Von Frey-Model on KO Mice  
      KO mice lacking the sigma 1 receptor were prepared according to WO 2004/52092 and tested in comparison to wild-type mice in the von-Frey model. As demonstrated in  FIG. 4 ) KO-Mice not having the sigma (1) receptor (called “mutantes”) are not susceptible anymore to the neuropathic pain/or allodynia inducing effects of capsaicin independent of the dose given compared to wild-type mice (called “slavajes”). This is clearly demonstrating the truth of the role of sigma receptors in neuropathic pain and allodynia and strengthens the claim to the role of all compounds binding to the sigma-receptor in neuropathic pain/allodynia.