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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/56—Amides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/36—Opioid-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
  • C07C55/02—Dicarboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/235—Saturated compounds containing more than one carboxyl group
  • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
  • C07C59/255—Tartaric acid

Definitions

• the present invention relates to (-)-(2f?,3S)-2-amino-3-hydroxy-3-pyridin- 4-yl-1 -pyrrolidin-1 -yl-propan-1 -one (L)-(+) tartrate salt (i.e., the monotartrate salt), its synthesis and use as an analgesic in the treatment of pain, or its use in the treatment of a cognitive disorder.
• L 4-yl-1 -pyrrolidin-1 -yl-propan-1 -one
• tartrate salt i.e., the monotartrate salt
• the free base of the present salt including the various stereoisomeric forms of the free base, viz., (+/-)-e/yi ?ro-2-amino-3- hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one, (+/-)-i ?reo-2-amino-3- hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one, as well as the
• the present invention is directed to (-)-(2f?,3S)-2-amino-3-hydroxy-3-pyridin-4-yl-1-pyrrolidin-1 -yl-propan-1 -one (L)- (+) tartrate, i.e., the monotartrate salt.
• Other names for this salt include: DL- f/?reo-2-amino-3-hydroxy-3-(pyridin-4-yl)-1 -(pyrrolidin-1 -yl)propan-1 -one
• the salt is a crystalline material.
• the salt exhibits an X-ray powder diffraction spectrum having characteristic peaks expressed in degrees (2 ⁇ ) at
• the present invention is directed to a pharmaceutical composition
• a pharmaceutical composition comprising the aforementioned tartrate salt, and at least one pharmaceutically acceptable carrier.
• the present invention is directed to a method of treating pain (such as chronic pain) in a mammal, said method comprising administering to said mammal in need thereof, a therapeutically effective amount of the salt of claim 1 .
• the present invention is directed to a process for preparing (-)-(2f?,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan- 1 -one (L)-(+) tartrate salt, said process comprising:
• step (a) of the above-mentioned process intermediate 1 is not isol d and is represented by the structure
• step (a) of the above-mentioned process intermediate 2 is not isolated and is represented by the structure
• the suitable solvent comprises methanol.
• the present invention is directed to (-)-(2f?,3S)- 2-amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one (L)-(+) tartrate salt made by the above-mentioned process.
• Figure 1 is a 1 H-NMR (dmso-d6) spectrum of crude (-)-(2R,3S)-2-Amino- 3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one L-(+)tartrate (ON- PYRAM I DE L Tartrate).
• Figure 2 is a Differential Scanning Calorimetry (DSC) spectrum of a 1 st crop of crude (-)-(2R,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl- propan-1 -one L-(+)tartrate (ON-PYRAMIDE L Tartrate).
• DSC Differential Scanning Calorimetry
• Figures 3A and 3B shows superimposed Raman spectra of a crude (1 st crop) of (-)-(2R,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan- 1 -one L-(+)tartrate and a standard recrystallized sample.
• Figures 4 shows Raman spectrum of a purified sample of (-)-(2R,3S)-2- Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one L-(+)tartrate.
• the sample is crystalline and corresponds to form A.
• Figure 5 shows a 1 H-NMR (dmso-d6) spectrum of a recrystallized (from acetone) sample of (-)-(2R,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 - yl-propan-1 -one L-tartrate.
• Figure 6 shows a 1 H-NMR (dmso-d6) spectrum of a purified crystalline sample (form A) of (-)-(2R,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 - yl-propan-1 -one L-tartrate.
• Table 1 The chemical shifts, multiplicity integration and the chemical groups they represent are listed in Table 1 .
• Figure 7 shows a 13 C NMR spectrum (dmso-d6) of a recrystallized sample of (-)-(2R,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl- propan-1 -one L-(+)tartrate.
• Figure 8 shows the PXRD pattern of a purified sample of (-)-(2R,3S)-2- Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one L-(+)tartrate.
• the sample is crystalline and corresponds to form A.
• the peak details are provided in Table 2.
• Figure 9 shows a TG-FTIR spectrum of a sample of (-)-(2R,3S)-2-Amino- 3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one L-(+)tartrate.
• the sample decomposed above 160°C.
• the released water vapor and possible gaseous degradation products were identified by FTIR spectroscopy.
• Figure 10 shows a Differential Scanning Calorimetry (DSC) of a sample of (-)-(2R,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one- L-(+) tartrate.
• the first scan (solid line) shows overlapping melting and degradation at ⁇ 160°C, which agrees with the TG-FTIR results.
• the second scan (dotted line) shows only a glass transition (T g ) at 160°C. No crystallization was observed. The exothermic event at 225°C observed in the second scan can be attributed to further degradation.
• Figure 1 1 shows a Dynamic Vapor Sorption (DVS) spectrum of a sample of (-)-(2R,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one- L-(+) tartrate.
• the sample is very hygroscopic (water uptake above 80% r.h.) and deliquescent. The deliquescence was visually confirmed. Additionally, the weight continued to increase even after the relative humidity (RH) had already started to decrease.
• RVS Dynamic Vapor Sorption
• Figure 12 shows the Raman spectrum of an amorphous sample of (-)-
• Figure 13 shows the PXRD pattern of an amorphous sample of (-)- (2R,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one-L-(+) tartrate.
• Figure 14 shows a 1 H-NMR spectrum of an amorphous sample of (-)- (2R,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one-L-(+) tartrate.
• Figure 15 shows a TG-FTIR spectrum of an amorphous sample of (-)- (2R,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one-L-(+) tartrate.
• the sample contains approximately 8% MeOH and traces of water. Degradation was observed above 160°C.
• Figure 16 shows a DSC scan of an amorphous sample of (-)-(2R,3S)-2-
• Figure 17 shows a DVS spectrum of an amorphous sample of (-)- (2R,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one-L-(+) tartrate.
• the sample is very hygroscopic and deliquescent. The deliquescence was visually confirmed. Additionally, the weight continued to increase even after r.h. had already started to decrease.
• the dihydrochloride was the first salt prepared and characterized. It was found to be hygroscopic and not well suited for development (although it can be easily handled in the isolation on large scale).
• acetic acid L-Aspartic acid, benzoic acid, citric acid, D-gluconic acid, D- glucuronic acid, hippuric acid, hydrochloric acid, (-)-L malic acid, (+)-L-lactic acid, maleic acid, L-malic acid, (+)-L-mandelic acid, 1 -hydroxy-2-naphthoic acid, oleic acid, palmitic acid, pamoic acid, phosphoric acid, saccharin, stearic acid, succinic acid, sulfuric acid.
• the L-mandelate and the stearate showed the most promising physicochemical properties.
• L- mandelate salt was seriously considered for development, however, this study was halted considering potential toxicological issues. After weighing all the information (stability, toxicity consideration, etc.) it was decided that the L- tartrate salt (i.e., mono-L-tartrate) would be the best candidate for further development.
• This salt is made in four steps from commercially available starting materials.
• the first step is the synthesis of racemic hydrochloride salt, i.e., (+/- )-DL-i ?reo-2-amino-3-hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one dihydrochloride, and is shown schematically below:
• Step 1 Synthesis of (+/-)-DL-fftreo-2-amino-3-hvdroxy-3-pyridin-4-yl-1 - pyrrolidin-1 -yl-propan-1 -one dihydrochloride
• the dihydrochloride salt threo-form is isolated and purified by crystallization to give pure (+/-)-DL-i ?reo-2-amino-3- hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one dihydrochloride.
• the detailed manufacturing process is given below:
• (+/-)-DL-i ?reo-2-amino-3-hydroxy-3-pyridin-4-yl-1-pyrrolidin-1-yl-propan- 1-one dihydrochloride is resolved, in the second step, into its chiral enantiomers by chemical resolution using commercially available di-p-toluoyl-L-tartaric acid (L-DTTA), giving the resolved, chiral, (-)-(2R,3S)-2-Amino-3-hydroxy-3-pyridin- 4-yl-1-pyrrolidin-1-yl-propan-1-one di-p-toluoyl-L-tartrate.
• L-DTTA di-p-toluoyl-L-tartaric acid
• Step 3a Free base formation
• Step 3 contains three sub-steps.
• step 3a the (-)-(2R,3S)-2-Amino-3- hydroxy-3-pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one di-p-toluoyl-L-tartrate (ON- PYRAMIDE DPTL Tartrate) is treated with aqueous KOH/Ethanol and acetone to give the corresponding free base, i.e., (-)-(2R,3S)-2-Amino-3-hydroxy-3- pyridin-4-yl-1 -pyrrolidin-1 -yl-propan-1 -one (ON-PYRAMID free base).
• Step 4 Synthesis of purified (-)-(2R,3S)-2-Amino-3-hvdroxy-3-pyridin-4-yl- 1 -pyrrolidin-1 -yl-propan-1 -one L-tartrate (ON-PYRAMIDE L Tartrate)
• the amorphous form was prepared by lyophilization from MeOH/H 2 0 and characterized by FT Raman (Fig.12), PXRD (Powder X-Ray Diffraction; Fig. 13), 1 H-NMR (Fig. 14), TG-FTIR
• the monotartrate salt of the invention has analgesic and/or
• An art-accepted model or assay for measuring an analgesic effect of a compound in chronic pain is the model known as Kim and Chung 1992, Pain 150, pp 355-363 ⁇ Chung model).
• This model involves the surgical ligation of the L5 (and optionally the L6) spinal nerves on one side in experimental animals. Rats recovering from the surgery gain weight and display a level of general activity similar to that of normal rats. However, these rats develop abnormalities of the foot, wherein the hind paw is moderately everted and the toes are held together. More importantly, the hind paw on the side affected by the surgery appears to become sensitive to low- threshold mechanical stimuli and will perceive pain instead of the faint sensation of touch.
• tactile allodynia This sensitivity to normally non-painful touch, called “tactile allodynia", develops within the first week after surgery and lasts for at least two months.
• the allodynia response includes lifting the affected hind paw to escape from the stimulus, licking the paw and holding it in the air for many seconds. None of these responses is normally seen in the control group.
• rats are anesthetized before surgery. The surgical site is shaved and prepared either with betadine or Novacaine. Incision is made from the thoracic vertebra XIII down toward the sacrum.
• Muscle tissue is separated from the spinal vertebra (left side) at the L4 - S2 levels.
• the L6 vertebra is located and the transverse process is carefully removed with a small rongeur to expose the L4 - L6 spinal nerves.
• the L5 and L6 spinal nerves are isolated and tightly ligated with 6-0 silk thread. The same procedure is done on the right side as a control, except no ligation of the spinal nerves is performed.
• the wounds are sutured.
• a small amount of antibiotic ointment is applied to the incised area, and the rat is transferred to the recovery plastic cage under a regulated heat-temperature lamp.
• i.p. administration the compounds are formulated in H 2 0 and given in a volume of 1 ml/kg body weight by injecting into the intraperitoneal cavity.
• p.o. administration the compounds are formulated in H 2 0 and given in a volume of 1 ml/kg body weight using an 18-gauge, 3 inch gavage needle that is slowly inserted through the esophagus into the stomach.
• Tactile allodynia is assessed via von Frey hairs, which are a series of fine hairs with incremental differences in stiffness. Rats are placed in a plastic cage with a wire mesh bottom and allowed to acclimate for approximately 30 minutes. To establish the pre-drug baseline, the von Frey hairs are applied perpendicularly through the mesh to the mid-plantar region of the rats' hind paw with sufficient force to cause slight buckling and held for 6-8 seconds. The applied force has been calculated to range from 0.41 to 15.1 grams. If the paw is sharply withdrawn, it is considered a positive response. A normal animal will not respond to stimuli in this range, but a surgically ligated paw will be withdrawn in response to a 1 -2 gram hair. The 50% paw withdrawal threshold is determined using the method of Dixon, W.J., Ann. Rev. Pharmacol. Toxicol.
• Tactile allodynia is measured prior to and 15, 30, and 60 minutes after drug administration.
• the post-drug threshold is compared to the pre-drug threshold and the percent reversal of tactile sensitivity is calculated based on a normal threshold of 15.1 grams.
• the monotartrate salt of the invention may be administered at pharmaceutically effective dosages.
• dosages are normally the minimum dose necessary to achieve the desired therapeutic effect; in the treatment of chronic pain, this amount would be roughly that necessary to reduce the discomfort caused by the pain to tolerable levels.
• doses generally will be in the range 0.1 -5000 mg/day; more preferably in the range 1 to 3000 mg/day, still more preferably in the range of 10 mg to 1000 mg/day.
• the actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the pain, the age and weight of the patient, the patient's general physical condition, the cause of the pain, and the route of administration.
• the salt of the present invention is useful in the treatment of pain in a mammal; particularly a human being.
• the patient will be given the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like.
• other routes may be desirable or necessary, particularly if the patient suffers from nausea.
• Such other routes may include, without exception, transdermal, intraperitonial, parenteral, subcutaneous, intranasal, intrathecal, intramuscular, intravenous and intrarectal modes of delivery.
• Another aspect of the invention is drawn to therapeutic compositions comprising the novel compounds of the invention and pharmaceutically acceptable salts of these compounds and a pharmaceutically acceptable excipient.
• Such an excipient may be a carrier or a diluent; this is usually mixed with the active compound, or permitted to dilute or enclose the active compound.
• the carrier may be solid, semi-solid, or liquid material that acts as an excipient or vehicle for the active compound.
• the formulations may also include wetting agents, emulsifying agents, preserving agents, sweetening agents, and/or flavoring agents. If used as in an ophthalmic or infusion format, the formulation will usually contain one or more salt to influence the osmotic pressure of the formulation.
• the invention is directed to methods for the treatment of pain, particularly chronic pain, through the administration of the salt of the present invention to a mammal in need thereof.
• the compound will usually be formulated in a form consistent with the desired mode of delivery.
• the salt of the present invention as an immunostimulant is administered subject to the same basic principles as compounds having analgesic activity, in doses which are best determined on a case-by-case and/or species-by-species and, in case of humans, at times on a patient-by-patient basis.
• the effective dose will be in the range of 10 ⁇ g/kg to 200 mg/kg.
• the salt of the present invention may also be used to treat a cognitive disorder in a subject in need of such treatment.
• the dosage for such treatment for human adults such doses generally will be in the range 0.1 -5000 mg/day; more preferably in the range 1 to 3000 mg/day, still more preferably in the range of 10 mg to 1000 mg/day.
• the actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the cognitive disorder, the age and weight of the patient, the patient's general physical condition, the cause of the cognitive disorder, and the route of administration.
• the effective dose will be in the range of 10 ⁇ g/kg to 200 mg/kg.
• cognitive disorder means any condition characterized by a deficit in mental activities associated with thinking, learning, or memory. Examples of such disorders include agnosias, amnesias, aphasias, apraxias, deliriums, dementias, and learning disorders.
• the cause of a cognitive disorder may be unknown or uncertain.
• the cognitive disorder may be associated with (that is, be caused by or occur in the presence of) other conditions characterized by damage to or loss of neurons or other structures involved in the transmission of signals between neurons.
• cognitive disorders may be associated with neurodegenerative diseases such as Alzheimer's disease, corticobasal degeneration, Creutzfeldt-Jacob disease, frontotemporal lobar degeneration,
• Huntington disease multiple sclerosis, normal pressure hydrocephalus, organic chronic brain syndrome, Parkinson's disease, Pick disease, progressive supranuclear palsy, or senile dementia (Alzheimer type); it may be associated with trauma to the brain, such as that caused by chronic subdural hematoma, concussion, intracerebral hemorrhage, or with other injury to the brain, such as that cause by infection (e.g., encephalitis, meningitis, septicemia) or drug intoxication or abuse.
• trauma such as that caused by chronic subdural hematoma, concussion, intracerebral hemorrhage, or with other injury to the brain, such as that cause by infection (e.g., encephalitis, meningitis, septicemia) or drug intoxication or abuse.
• Cognitive disorders may also be associated with other conditions which impair normal functioning of the central nervous system, including psychiatric disorders such as anxiety disorders, dissociative disorders, mood disorders, schizophrenia, and somatoform and factitious disorders; it may also be associated with conditions of the peripheral nervous system, such as chronic pain.
• the salt of this invention may be used to treat agnosias, amnesias, aphasias, apraxias, deliriums, dementias, learning disorders and other cognitive disorders regardless of whether their cause is known or not.
• dementias which may be treated with the salt of the present invention include AIDS dementia complex, Binswanger's disease, dementia with Lewy Bodies, frontotemporal dementia, multi-infarct dementia, Pick's disease, semantic dementia, senile dementia, and vascular dementia.
• Examples of learning disorders which may be treated with the salt of the present invention include Asperger's syndrome, attention deficit disorder, attention deficit hyperactivity disorder, autism, childhood disintegrative disorder, and Rett syndrome.
• Examples of aphasia which may be treated with the salt of the present invention include progressive non-fluent aphasia.
• the salt of the present invention also be used to treat patient having deficits in mental activities that are mild or that otherwise do not significantly interfere with daily life.
• Mild cognitive impairment is an example of such a condition: a patient with mild cognitive impairment displays symptoms of dementia (e.g., difficulties with language or memory) but the severity of these symptoms is such that a diagnosis of dementia may not be appropriate.
• the salt may be used to treat mild cognitive impairment and other, similarly less severe forms of cognitive disorders.

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  • 2014-08-14 PT PT147555353T patent/PT3033327T/pt unknown
  • 2014-08-14 ES ES14755535.3T patent/ES2664749T3/es active Active
  • 2014-08-14 HU HUE14755535A patent/HUE036381T2/hu unknown
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• 2015
  • 2015-06-26 NO NO15174003A patent/NO2960430T3/no unknown
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