Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to 3-cyclopropylcarbonyl-3,6- diazabicyclo[3.1.1]heptane, its salt forms, pharmaceutical compositions of these salt forms, and methods for treating a wide variety of conditions and disorders.
• Compound A is a neuronal nicotinic receptor (NNR) agonist with selectivity for ⁇ 4 ⁇ 2* (a432-containing) and ⁇ 6 ⁇ 2 * (a632-containing) NNRs.
• NNR neuronal nicotinic receptor
• Compound A demonstrates efficacy in, among other things, preventing full onset of abnormal involuntary movements (AIMs) and also in attenuating existing AIMs in preclinical rodent models of levodopa-induced dyskinesias (LIDs).
• AIMs abnormal involuntary movements
• LIDs levodopa-induced dyskinesias
• Compound A reduces LIDs in non-human primates (macaques) and does not impede general activity or levodopa's (L-dopa's) effect on motor deficits.
• Compound A exhibits neuroprotective effects against MPP+ toxicity in primary cultures of rat dopamine neurons.
• Compound A significantly reduced LIDs. This effect was especially strong at a 0.10 mg/kg dose.
• Compound A did not significantly alter either total on-time (total time when L-dopa's anti-parkinsonian effects are observed) or parkinsonian disability (the effectiveness of L-dopa treatment).
• Compound A significantly decreased the percent of bad quality on-time (time characterized by troubling dyskinesia) from 50-55% to approximately 30% and correspondingly increased the percent of good quality on-time (time without troubling dyskinesia) from 45-50% to approximately 70%.
• Compound A was very well tolerated in the study, did not negatively impact the general motor activity of the animals, and did not counteract levodopa's effect on parkinsonism.
• Compound A has the following structural formula:
• PCT/US2010/058836 (WO 201 1/071758), which is incorporated by reference.
• Another synthesis, including formation of preferred salts, is disclosed in PCT/US2012/028691 , which is incorporated by reference.
• the disease or disorder is one or more tremor, including but not limited to Essential tremor, Parkinsonian tremor, Cerebellar tremor (including intention tremor and titubation), Rubral tremor (Holmes' tremor), Dystonic tremor, Wilson's disease, Tremor in multiple sclerosis, Tremor resulting from a neurodegenerative disorder other than those specifically listed, Tremor resulting from basal ganglia disease other than Parkinson's disease and dystonia, Familial tremor other than essential tremor and Wilson's disease, Tremor resulting from peripheral neuropathy, Tremor resulting from stroke, Tremor resulting from traumatic brain injury, Tumor-induced tremor, Enhanced or exaggerated physiologic tremor, Tremor resulting from metabolic disorders, Tremor resulting from chronic kidney disease, Tremor
• the disease or disorder is one or more dystonia, including but not limited to, Genetic or familial dystonia (one or more genes associated with various forms of dystonia), Myoclonic dystonia, General dystonia, lodiopathic torsion dystonia, Dystonia associated with Parkinson's disease, Dystonia associated with Wilson's disease, Focal dystonia such as, blepharospasm, cervical dystonia or torticollis, cranial dystonia, oromandibular dystonia, or spasmodic dystonia, Multifocal dystonia, Cranial dystonia or Meige's syndrome, Segmental dystonia, Hemidystonia, Torsion dystonia, Paroxysmal dystonia, Dystonia resulting from trauma, Dystonia resulting from stroke, Tumor-induced dystonia, Dystonia resulting from infection, Dystonia resulting from oxygen deprivation, Dystonia resulting from toxins (e.
• Figure 1 illustrates graphically the effects of acute propranolol and sub-chronic
• 3-Cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane may also be referred to as 3,6- diazabicyclo[3.1.1]heptan-3-yl(cyclopropyl)methanone, or, potentially, still other chemical names, depending upon the naming convention used. The choice of naming convention should not affect the scope of the present invention.
• the structure of the compound is:
• compound of the present invention refers to 3- cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane or an acid addition salt thereof.
• the acid preferably is selected from hydrochloric, p-toluenesulfonic, L-aspartic, maleic, L-glutamic, 1- hydroxy-2-naphthoic (namely, xinafoate), fumaric, galactaric, hippuric, L-mandelic, succinic, adipic, or (+)-camphoric.
• the acid addition salt is a p- toluenesulfonate, maleate, galactarate, benzoate, hippurate, xinafoate, or (+)-camphorate.
• the salt is a galactarate, benzoate, hippurate, or xinafoate.
• a most preferred salt form is a hemigalactarate.
• the phrase "compound of the present invention" includes a hydrated or a solvated salt form.
• the term "compound” may be used to mean the free base form, or alternatively, a salt form of 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane, depending on the context, which will be readily apparent.
• the term "pharmaceutically acceptable” refers to carrier(s), diluent(s), excipient(s) or salt forms that are compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.
• composition refers to a compound of the present invention optionally admixed with one or more pharmaceutically acceptable carriers, diluents, excipients, or adjuvants.
• Pharmaceutical compositions preferably exhibit a degree of stability to environmental conditions so as to make them suitable for
• the terms "effective amount,” “therapeutic amount,” or “effective dose” refer to an amount of active ingredient sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of a disorder.
• Prevention of a disorder may be manifested by delaying or preventing the progression of the disorder, as well as delaying or preventing the onset of the symptoms associated with the disorder.
• Treatment of the disorder may be manifested by a decrease or elimination of symptoms, inhibition or reversal of the progression of the disorder, as well as any other contribution to the well being of the patient.
• the effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered.
• compounds are required to be administered in an amount of less than 5 mg/kg of patient weight.
• the compounds may be administered in an amount from less than about 1 mg/kg patient weight to less than about 100 ⁇ g/kg of patient weight, and
• the effective dose of the compounds typically represent that amount administered as a single dose, or as one or more doses administered over a 24 h period.
• the effective dose of the compounds may require administering the compound in an amount of at least about 1 mg/24 hr/patient, but not more than about 1000 mg/24 hr/patient, and often not more than about 500 mg/ 24 hr/ patient.
• Potential doses may be in the range of 500 ⁇ g to 2 mg, as free base equivalents.
• substantially crystalline includes greater than 20%, preferably greater than 30%, and more preferably greater than 40% (e.g. greater than any of 50, 60, 70, 80, or 90%) crystalline.
• stable includes chemical stability and solid state stability, where the phrase “chemical stability” includes the potential to store salts of the invention in an isolated form, or in the form of a formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents, excipients, or adjuvants, such as in an oral dosage form, such as a tablet, capsule, or the like, under normal storage conditions, with an insignificant degree of chemical degradation or decomposition
• solid state stability includes the potential to store salts of the invention in an isolated solid form, or in the form of a solid formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents, excipients, or adjuvants, such as in an oral dosage form, such as a tablet, capsule, or the like, under normal storage conditions, with an insignificant degree of solid state transformation, such as crystallization, recrystallization, solid state phase transition, hydration, dehydration, solvation, or desolvation
• normal storage conditions include one or more of temperatures of between -80 °C and 50 °C, preferably between 0 °C and 40 °C and more preferably ambient temperatures, such as 15 °C to 30 °C, pressures of between 0.1 and 2 bars, preferably at atmospheric pressure, relative humidity of between 5 and 95%, preferably 10 to 60%, and exposure to 460 lux or less of UV/visible light, for prolonged periods, such as greater than or equal to six months.
• salts of the invention may be found to be less than 5%, more preferably less than 2%, and especially less than 1 %, chemically degraded or decomposed, or solid state transformed, as appropriate.
• One embodiment of the present invention includes 3-cyclopropylcarbonyl-3,6- diazabicyclo[3.1.1]heptane (Formula I) or a pharmaceutically acceptable salt thereof.
• One embodiment includes use of 3-cyclopropylcarbonyl-3,6- diazabicyclo[3.1.1]heptane or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.
• One embodiment of the present invention includes a method, use, compound for use, or use for preparation of a medicament for treating or preventing of a variety of diseases, disorders, or dysfunctions, comprising administering to a mammal in need of such treatment, a therapeutically effective amount of 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane or a pharmaceutically acceptable salt thereof.
• the disease, disorder, or dysfunction is one or more tremor, including but not limited to Essential tremor, Parkinsonian tremor, Cerebellar tremor (including intention tremor and titubation), Rubral tremor (Holmes' tremor), Dystonic tremor, Wilson's disease, Tremor in multiple sclerosis, Tremor resulting from a neurodegenerative disorder other than those specifically listed, Tremor resulting from basal ganglia disease other than Parkinson's disease and dystonia, Familial tremor other than essential tremor and Wilson's disease, Tremor resulting from peripheral neuropathy, Tremor resulting from stroke, Tremor resulting from traumatic brain injury, Tumor-induced tremor, Enhanced or exaggerated physiologic tremor, Tremor resulting from metabolic disorders, Tremor resulting from chronic kidney disease, Tremor resulting from liver failure, Tremor resulting from phenylketonuria, Orthostatic tremor, Psychogenic tremor, Drug- induced tremor,
• the disease, disorder, or dysfunction is one or more dystonia, including but not limited to, Genetic or familial dystonia (one or more genes associated with various forms of dystonia), Myoclonic dystonia, General dystonia, lodiopathic torsion dystonia, Dystonia associated with Parkinson's disease,
• Dystonia associated with Wilson's disease Focal dystonia such as, blepharospasm, cervical dystonia or torticollis, cranial dystonia, oromandibular dystonia, or spasmodic dystonia, Multifocal dystonia, Cranial dystonia or Meige's syndrome, Segmental dystonia,
• One embodiment of the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of 3-cyclopropylcarbonyl-3,6- diazabicyclo[3.1.1]heptane or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier.
• Another embodiment of the present invention includes the use of a pharmaceutical composition of the present invention in the manufacture of a medicament for treatment of central nervous system disorders and dysfunctions.
• Another embodiment of the present invention includes 3-cyclopropylcarbonyl-3,6- diazabicyclo[3.1.1 Jheptane or a pharmaceutically acceptable salt thereof with reference to any one of the Examples.
• Another embodiment of the present invention includes 3- cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance.
• structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structure except for the replacement of a hydrogen atom by deuterium or tritium, or the replacement of a carbon atom by 13 C or 14 C, or the replacement of a nitrogen atom by 15 N, or the replacement of an oxygen atom with 17 0 or 18 0 are within the scope of the invention.
• Such isotopically labeled compounds are useful as research or diagnostic tools.
• the present invention includes specific representative compounds, which are identified herein with particularity.
• the compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
• protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry.
• Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts, Protecting Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, New York (1999)). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present invention.
• the present invention also provides a method for the synthesis of compounds useful as intermediates.
• Compound A can be prepared via the coupling of a 3,6-diazabicyclo[3.1.1]heptane in which the 6-position nitrogen atom has been protected (to prevent reaction with acylating agents) with a suitable cyclopropylcarbonyl derivative (such as cyclopropylmethanoyl chloride), followed by removal of the protecting group (typically with acid).
• Cyclopropylmethanoyl chloride may be prepared by treatment of the cyclopropylcarboxylic acid with, among other reagents, thionyl chloride or oxalyl chloride.
• Compound A Another means of making Compound A is to couple a suitable 6-protected-3,6- diazabicyclo[3.1.1]heptane with a cyclopropylcarboxylic acid, followed by removal of the protecting group.
• a suitable activating agent such as ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-(benzotriazol-l-yl)- N,N,N',N'-bis(tetramethylene)uronium hexafluorophosphate (HBPyU), O-(benzotriazol-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium
• TEA triethylamine
• DCM dichloromethane
• NMP N-methyl-2-pyrrolidone
• Compound A can be made using a reaction sequence similar to that shown in Scheme 1 .
• This approach involves a ring closing process in which the anion of cyclopropylcarboxamide is reacted with a bis-electrophile, such as intermediate 6, decreasing the overall length of the synthesis compared with previously described syntheses (for instance, WO 201 1/071758).
• a bis-electrophile such as intermediate 6
• a specific example of this approach to the synthesis of Compound A is given in the Examples Section and summarized in Scheme 1 .
• the reagents used to accomplish the transformations of this approach can vary. For instance, a variety of alcohols can be used the esterification reaction, providing a variety of diester products (an example being diester 3).
• the physical properties of particular diesters may provide advantages in purification or handling.
• a variety of amines and solvents can be utilized in the ring closure of the 4-membered (azetidine) ring, a particular amine/solvent mixture providing advantages in either reactivity or product purity (including stereochemical purity).
• the reduction of the dialkyl azetidinyl-2,4-dicarboxylate (intermediate 4, for example) to the corresponding dialcohol (such as dialcohol 5) can be accomplished by a variety of reagents (e.g., borohydride and aluminumhydride reagents) in a variety of solvents.
• a reducing reagent that preserves the cis relative stereochemistry around the azetidine ring.
• Conversion of the dialcohol into a suitable bis-electrophile can be accomplished by a variety of reagents known to those of skill in the art. Reactions for converting alcohols to the corresponding halides (e.g., chlorides, bromides, iodides), as well as those for converting alcohols to sulfonates, phosphates, and the like, are all well known in the chemical literature.
• the closure of the 6-membered (piperidine) ring with cyclopropylcarboxamide can also be accomplished with a variety of reagents, including a variety of bases for production of the anion and a variety of solvents.
• the deprotection of the azetidinyl nitrogen can be accomplished by a variety of conditions, depending on the nature of the protecting group.
• radioisotope appropriate to various uses. For example, coupling of 11 C-labeled
• solid salt forms are generally preferred for oral formulations due to their tendency to exhibit these properties in a preferential way; and in the case of basic drugs, such as 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane, acid addition salts are often the preferred salt form.
• salt forms vary greatly in their ability to impart these properties, and such properties cannot be predicted with accuracy. For example, some salts are solids at ambient temperatures, while other salts are liquids, viscous oils, or gums at ambient temperatures. Furthermore, some salt forms are stable to heat and light under extreme conditions and others readily decompose under much milder conditions. Thus, the development of a suitable acid addition salt form of a basic drug for use in a pharmaceutical composition is a highly unpredictable process. There is a need for salt forms that display improved properties, including purity, stability, solubility, and bioavailability. Preferential characteristics of these novel salt forms include those that would increase the ease or efficiency of manufacture of the active ingredient and its formulation into a commercial product. Lastly, there is a need for stable polymorphic forms of these salts that allows for an increased ease or efficiency of manufacture of the active ingredient and its formulation into a commercially product.
• the degree (%) of crystallinity may be determined by the skilled person using x-ray powder diffraction (XRPD). Other techniques, such as solid state NMR, FT-IR, Raman spec- troscopy, differential scanning calorimetry (DSC) and microcalorimetry, may also be used.
• XRPD x-ray powder diffraction
• Other techniques such as solid state NMR, FT-IR, Raman spec- troscopy, differential scanning calorimetry (DSC) and microcalorimetry, may also be used.
• DSC differential scanning calorimetry
• microcalorimetry microcalorimetry
• the compounds of the present invention may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms (“polymorphs") are within the scope of the present invention.
• Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as XRPD patterns (diffractograms), solubility in various solvents, and melting point.
• the present invention includes various polymorphic forms of the salt forms of 3- cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane, including hydrates and solvates of the salts.
• Such polymorphic forms are characterized by their x-ray powder diffraction (XRPD) patterns (diffractograms).
• salt forms of 3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane may exist in solvated, for example hydrated, as well as unsolvated forms.
• the present invention encompasses all such forms.
• the present invention also includes isotopically labeled compounds wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, and oxygen, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, and 17 0.
• Such isotopically labelel compounds are useful as research or diagnostic tools.
• the present invention includes pharmaceutical compositions comprising the compound of the present invention and one or more pharmaceutically acceptable carriers, diluents, or excipients.
• Another aspect of the invention provides a process for the preparation of a pharmaceutical composition, including admixing the compound of the present invention with one or more pharmaceutically acceptable carriers, diluents or excipients.
• the manner in which the compounds of the present invention are administered can vary.
• the compounds of the present invention are preferably administered orally.
• Preferred pharmaceutical compositions for oral administration include tablets, capsules, caplets, syrups, solutions, and suspensions.
• the pharmaceutical compositions of the present invention may be provided in modified release dosage forms such as time-release tablet and capsule formulations.
• compositions can also be administered via injection, namely, intravenously, intramuscularly, subcutaneously, intraperitoneally, intraarterially, intrathecally, and intracerebroventricularly.
• Intravenous administration is a preferred method of injection.
• Suitable carriers for injection are well known to those of skill in the art and include 5% dextrose solutions, saline, and phosphate buffered saline.
• the formulations may also be administered using other means, for example, rectal administration.
• Formulations useful for rectal administration such as suppositories, are well known to those of skill in the art.
• the compounds can also be administered by inhalation, for example, in the form of an aerosol; topically, such as, in lotion form; transdermal ⁇ , such as, using a transdermal patch (for example, by using technology that is commercially available from Novartis and Alza Corporation), by powder injection, or by buccal, sublingual, or intranasal absorption.
• compositions may be formulated in unit dose form, or in multiple or subunit doses
• the administration of the pharmaceutical compositions described herein can be intermittent, or at a gradual, continuous, constant or controlled rate.
• the pharmaceutical compositions may be administered to a warm-blooded animal, for example, a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey; but advantageously is administered to a human being.
• a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey
• the time of day and the number of times per day that the pharmaceutical composition is administered can vary.
• the compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions.
• one embodiment of the present invention includes the administration of the compound of the present invention in combination with other therapeutic compounds.
• the compound of the present invention can be used in combination with other NNR ligands (such as varenicline), antioxidants (such as free radical scavenging agents), antibacterial agents (such as penicillin antibiotics), antiviral agents (such as nucleoside analogs, like zidovudine and acyclovir), anticoagulants (such as warfarin), anti-inflammatory agents (such as NSAI Ds), anti-pyretics, analgesics, anesthetics (such as used in surgery), acetylcholinesterase inhibitors (such as donepezil and galantamine), antipsychotics (such as haloperidol, clozapine, olanzapine, and quetiapine), immuno-suppressants (such as cyclosporin and methotrexate), neuroprotective agents (such as A 2 A inhibitors and caffeine), blood-brain barrier permeability enhancers, steroids (such as steroid hormones), corticosteroids (such as dexa
• One preferred use of the compounds of the present invention is the treatment and prevention of Parkinson's Disease, AIMs, and LIDs, and thus compounds of the present invention may be used in combination with pharmaceutical agents used to treat Parkinson's Disease, AIMs, and LIDs.
• agents include NNR agonists ( ⁇ 4 ⁇ 2, ⁇ 7, etc.), dopamine precursors (such as levodopa-carbidopa, levodopa-benserazide, and duodopa), dopamine agonists (such as bromocriptine, cabergoline, lisuride, pergolide, pramipexole, popinirole, talipexole, rotigotine, and apomorphine), dopa carboxylase inhibitors, MAO-B inhibitors (such as selegiline, rasagoline, and safinamide), COMT inhibitors (such as entacapone and tolcapone), antiglutamatergic agents (such as amantadine),
• Such a combination of pharmaceutically active agents may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
• the amounts of the compounds or agents and the relative timings of administration will be selected in order to achieve the desired therapeutic effect.
• the administration in combination of a compound of the present invention with other treatment agents may be in combination by administration concomitantly in: (1 ) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
• the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second. Such sequential administration may be close in time or remote in time.
• 3-Cyclopropylcarbonyl-3,6-diazabicyclo[3.1 .1 ]heptane, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such can be used for the prevention or treatment of various conditions or disorders for which other types of nicotinic compounds have been proposed or are shown to be useful as therapeutics, such as CNS disorders (including neurodegenerative disorders), inflammation, inflammatory response associated with bacterial and/or viral infection, pain, diabetes, metabolic syndrome, autoimmune disorders, dermatological conditions, addictions, obesity or other disorders described in further detail herein.
• This compound can also be used as a diagnostic agent in receptor binding studies (in vitro and in vivo).
• the compounds and their pharmaceutical compositions are useful in the treatment or prevention of a variety of CNS disorders, including neurodegenerative disorders, neuropsychiatric disorders, neurologic disorders, and addictions.
• the compounds and their pharmaceutical compositions can be used to treat or prevent cognitive deficits and dysfunctions, age-related and otherwise; attentional disorders and dementias, including those due to infectious agents or metabolic disturbances; to provide neuroprotection; to treat convulsions and multiple cerebral infarcts; to treat mood disorders, compulsions and addictive behaviors; to provide analgesia; to control inflammation, such as mediated by cytokines and nuclear factor kappa B; to treat inflammatory disorders; to provide pain relief; and to treat infections, as anti-infectious agents for treating bacterial, fungal, and viral infections.
• diseases and conditions that the compounds and pharmaceutical compositions of the present invention can be used to treat or prevent are: age-associated memory impairment (AAMI), mild cognitive impairment (MCI), age-related cognitive decline (ARCD), pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, Alzheimer's disease, cognitive impairment no dementia (CIND), Lewy body dementia, HIV-dementia, AIDS dementia complex, vascular dementia, Down syndrome, head trauma, traumatic brain injury (TBI), dementia pugilistica, Creutzfeld-Jacob Disease and prion diseases, stroke, central ischemia, peripheral ischemia, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive dysfunction in schizophrenia, cognitive deficits in schizophrenia, Parkinsonism including Parkinson's disease, postencephalitic parkinsonism, parkinsonism-dementia of Gaum, frontotemporal dementia Parkinson's Type (FTDP), Pick
• the compounds and their pharmaceutical compositions are useful in the treatment of involuntary muscle contractions or relaxations involving movements of one or more body parts, whether such is a disorder itself or as a symptom of another disorder.
• the compounds and their pharmaceutical compositions are useful in the treatment of one or more tremor, including but not limited to Essential tremor, Parkinsonian tremor, Cerebellar tremor (including intention tremor and titubation), Rubral tremor (Holmes' tremor), Dystonic tremor, Wilson's disease, Tremor in multiple sclerosis, Tremor resulting from a neurodegenerative disorder other than those specifically listed, Tremor resulting from basal ganglia disease other than Parkinson's disease and dystonia, Familial tremor other than essential tremor and Wilson's disease, Tremor resulting from peripheral neuropathy, Tremor resulting from stroke, Tremor resulting from traumatic brain injury, Tumor-induced tremor, Enhanced or exaggerated physiologic tremor, Tre
• the compounds and their pharmaceutical compositions are useful in the treatment of sustained muscle contractions resulting in twisting or repetitive movements or abnormal postures, whether such is a disorder itself or as a symptom of another disorder.
• the compounds and their pharmaceutical compositions are useful in the treatment of one or more dystonia, including but not limited to, Genetic or familial dystonia (one or more genes associated with various forms of dystonia), Myoclonic dystonia, General dystonia, lodiopathic torsion dystonia, Dystonia associated with Parkinson's disease, Dystonia associated with Wilson's disease, Focal dystonia such as,
• blepharospasm cervical dystonia or torticollis, cranial dystonia, oromandibular dystonia, or spasmodic dystonia, Multifocal dystonia, Cranial dystonia or Meige's syndrome, Segmental dystonia, Hemidystonia, Torsion dystonia, Paroxysmal dystonia, Dystonia resulting from trauma, Dystonia resulting from stroke, Tumor-induced dystonia, Dystonia resulting from infection, Dystonia resulting from oxygen deprivation, Dystonia resulting from toxins (e.g. heavy metal poisoning, carbon dioxide poisoning), and Drug-induced dystonia.
• toxins e.g. heavy metal poisoning, carbon dioxide poisoning
• Cognitive impairments or dysfunctions may be associated with psychiatric disorders or conditions, such as schizophrenia and other psychotic disorders, including but not limited to psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, and psychotic disorders due to a general medical conditions, dementias and other cognitive disorders, including but not limited to mild cognitive impairment, pre-senile dementia, Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, age-related memory impairment, Lewy body dementia, vascular dementia, AIDS dementia complex, dyslexia, Parkinsonism including Parkinson's disease, dyskinesias, levodopa-induced dyskinesias (LIDs), abnormal involuntary movements (AIMs), cognitive impairment and dementia of Parkinson's Disease, cognitive impairment of multiple sclerosis, cognitive impairment caused by traumatic brain injury, dementias due to other general medical conditions, anxiety disorders, including but not limited to panic disorder without agoraphobia, panic disorder with agoraphobia,
• Cognitive performance may be assessed with a validated cognitive scale, such as, for example, the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog).
• ADAS-cog Alzheimer's Disease Assessment Scale
• One measure of the effectiveness of the compounds of the present invention in improving cognition may include measuring a patient's degree of change according to such a scale.
• the compounds of the present invention may be used as a therapy for nicotine addiction and for other brain-reward disorders, such as substance abuse including alcohol addiction, illicit and prescription drug addiction, eating disorders, including obesity, and behavioral addictions, such as gambling, or other similar behavioral manifestations of addiction.
• substance abuse including alcohol addiction, illicit and prescription drug addiction
• eating disorders including obesity
• behavioral addictions such as gambling, or other similar behavioral manifestations of addiction.
• the treatment or prevention of diseases, disorders and conditions occurs without appreciable adverse side effects, including, for example, significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and significant effects upon skeletal muscle.
• the compounds of the present invention when employed in effective amounts, are believed to modulate the activity of the ⁇ 4 ⁇ 2* and/or ⁇ 6 ⁇ 2* NNRs without appreciable interaction with the nicotinic subtypes that characterize the human ganglia, as demonstrated by a lack of the ability to elicit nicotinic function in adrenal chromaffin tissue, or skeletal muscle, further demonstrated by a lack of the ability to elicit nicotinic function in cell preparations expressing muscle-type nicotinic receptors.
• these compounds are believed capable of treating or preventing diseases, disorders and conditions without eliciting significant side effects associated activity at ganglionic and neuromuscular sites.
• administering is believed to provide a therapeutic window in which treatment of certain diseases, disorders and conditions is provided, and certain side effects are avoided. That is, an effective dose of the compound is believed sufficient to provide the desired effects upon the disease, disorder or condition, but is believed insufficient, namely is not at a high enough level, to provide undesirable side effects.
• the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in therapy, such as a therapy described above.
• the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a CNS disorder, such as a disorder, disease or condition described hereinabove.
• the nervous system primarily through the vagus nerve, is known to regulate the magnitude of the innate immune response by inhibiting the release of macrophage tumor necrosis factor (TNF).
• TNF macrophage tumor necrosis factor
• This physiological mechanism is known as the "cholinergic antiinflammatory pathway” (see, for example, Tracey, "The Inflammatory Reflex,” Nature 420: 853-9 (2002)).
• Excessive inflammation and tumor necrosis factor synthesis cause morbidity and even mortality in a variety of diseases. These diseases include, but are not limited to, endotoxemia, rheumatoid arthritis, osteoarthritis, psoriasis, asthma, atherosclerosis, idiopathic pulmonary fibrosis, and inflammatory bowel disease.
• Inflammatory conditions that can be treated or prevented by administering the compounds described herein include, but are not limited to, chronic and acute inflammation, psoriasis, endotoxemia, gout, acute pseudogout, acute gouty arthritis, arthritis, rheumatoid arthritis, osteoarthritis, allograft rejection, chronic transplant rejection, asthma,
• Atherosclerosis mononuclear-phagocyte dependent lung injury, idiopathic pulmonary fibrosis, atopic dermatitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute chest syndrome in sickle cell disease, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcers, ulcerative colitis, acute cholangitis, aphthous stomatitis, cachexia, pouchitis, glomerulonephritis, lupus nephritis, thrombosis, and graft vs. host reaction.
• bacterial and/or viral infections are associated with side effects brought on by the formation of toxins, and the body's natural response to the bacteria or virus and/or the toxins.
• the body's response to infection often involves generating a significant amount of TNF and/or other cytokines.
• the over-expression of these cytokines can result in significant injury, such as septic shock (when the bacteria is sepsis), endotoxic shock, urosepsis, viral pneumonitis and toxic shock syndrome.
• Cytokine expression is mediated by NNRs, and can be inhibited by administering agonists or partial agonists of these receptors.
• Those compounds described herein that are agonists or partial agonists of these receptors can therefore be used to minimize the inflammatory response associated with bacterial infection, as well as viral and fungal infections. Examples of such bacterial infections include anthrax, botulism, and sepsis. Some of these compounds may also have antimicrobial properties.
• Antitoxins can also be used as adjunct therapy in combination with existing therapies to manage bacterial, viral and fungal infections, such as antibiotics, antivirals and antifungals.
• Antitoxins can also be used to bind to toxins produced by the infectious agents and allow the bound toxins to pass through the body without generating an inflammatory response. Examples of antitoxins are disclosed, for example, in U.S. Patent No. 6,310,043 to Bundle et al. Other agents effective against bacterial and other toxins can be effective and their therapeutic effect can be complemented by co-administration with the compounds described herein.
• the compounds can be administered to treat and/or prevent pain, including acute, neurologic, inflammatory, neuropathic and chronic pain.
• the compounds can be used in conjunction with opiates to minimize the likelihood of opiate addiction (e.g., morphine sparing therapy).
• opiate addiction e.g., morphine sparing therapy.
• the analgesic activity of compounds described herein can be demonstrated in models of persistent inflammatory pain and of neuropathic pain, performed as described in U.S. Published Patent Application No. 20010056084 A1 (Allgeier et al.) (e.g., mechanical hyperalgesia in the complete Freund's adjuvant rat model of inflammatory pain and mechanical hyperalgesia in the mouse partial sciatic nerve ligation model of neuropathic pain).
• the analgesic effect is suitable for treating pain of various genesis or etiology, in particular in treating inflammatory pain and associated hyperalgesia, neuropathic pain and associated hyperalgesia, chronic pain (e.g., severe chronic pain, post-operative pain and pain associated with various conditions including cancer, angina, renal or biliary colic, menstruation, migraine, and gout).
• Inflammatory pain may be of diverse genesis, including arthritis and rheumatoid disease, teno-synovitis and vasculitis.
• Neuropathic pain includes trigeminal or herpetic neuralgia, neuropathies such as diabetic neuropathy pain, causalgia, low back pain and deafferentation syndromes such as brachial plexus avulsion.
• the compounds of the present invention can be also used to prevent or treat certain other conditions, diseases, and disorders in which NNRs play a role.
• autoimmune disorders such as lupus, disorders associated with cytokine release, cachexia secondary to infection (e.g., as occurs in AIDS, AIDS related complex and neoplasia), obesity, pemphitis, urinary incontinence, overactive bladder, diarrhea, constipation, retinal diseases, infectious diseases, myasthenia, Eaton-Lambert syndrome, hypertension, preeclampsia, osteoporosis, vasoconstriction, vasodilatation, cardiac arrhythmias, type I diabetes, type II diabetes, bulimia, anorexia and sexual dysfunction, as well as those indications set forth in published PCT application WO 98/25619.
• the compounds of this invention can also be administered to treat convulsions such as those that are symptomatic of epilepsy, and to treat conditions such as syphillis and Creutzfeld-Jakob disease.
• the compounds of this invention may be used to treat a variety of dermatological disorders, including but not limited to psoriasis, dermatitis, acne, pustulosis, vitilago, and the like. Diagnostic Uses
• the compounds can be used in diagnostic compositions, such as probes, particularly when they are modified to include appropriate labels.
• the probes can be used, for example, to determine the relative number and/or function of specific receptors, particularly the ⁇ 4 ⁇ 2* and/or a6-containing receptor subtypes.
• the compounds of the present invention most preferably are labeled with a radioactive isotopic moiety such as 11 C, which can be detected using positron emission tomography (PET).
• PET positron emission tomography
• a high specific activity is desired to visualize the selected receptor subtypes at non-saturating concentrations.
• the administered doses typically are below the toxic range and provide high contrast images.
• the compounds are expected to be capable of administration in non-toxic levels.
• Determination of dose is carried out in a manner known to one skilled in the art of radiolabel imaging. See, for example, U.S. Patent No. 5,969, 144 to London et al.
• the compounds can be administered using known techniques. See, for example,
• the compounds After the compounds are administered to a subject (e.g., a human subject), the presence of that compound within the subject can be imaged and quantified by appropriate techniques in order to indicate the presence, quantity, and functionality of selected NNR subtypes.
• the compounds can also be administered to animals, such as mice, rats, dogs, and monkeys. PET imaging can be carried out using any appropriate technique and apparatus. See Villemagne et al., In: Arneric et al. (Eds.) Neuronal Nicotinic Receptors: Pharmacology and Therapeutic Opportunities, 235-250 (1998) and U.S. Patent No. 5,853,696 to Elmalch et al., each herein incporated by reference, for a disclosure of representative imaging techniques.
• the radiolabeled compounds bind with high affinity to selective NNR subtypes (e.g., ⁇ 4 ⁇ 2* and/or a6-containing) and preferably exhibit negligible non-specific binding to other nicotinic cholinergic receptor subtypes (e.g., those receptor subtypes associated with muscle and ganglia).
• the compounds can be used as agents for noninvasive imaging of nicotinic cholinergic receptor subtypes within the body of a subject, particularly within the brain for diagnosis associated with a variety of CNS diseases and disorders.
• the diagnostic compositions can be used in a method to diagnose disease in a subject, such as a human patient.
• the method involves administering to that patient a detectably labeled compound as described herein, and detecting the binding of that compound to selected NNR subtypes (e.g., ⁇ 4 ⁇ 2 * and/or a6-containing receptor subtypes).
• selected NNR subtypes e.g., ⁇ 4 ⁇ 2 * and/or a6-containing receptor subtypes.
• diagnostic tools such as PET
• Such disorders include a wide variety of CNS diseases and disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia.
• CNS diseases and disorders including Alzheimer's disease, Parkinson's disease, and schizophrenia.
• the diagnostic compositions can be used in a method to monitor selective nicotinic receptor subtypes of a subject, such as a human patient.
• the method involves administering a detectably labeled compound as described herein to that patient and detecting the binding of that compound to selected nicotinic receptor subtypes namely, the ⁇ 4 ⁇ 2* and/or a6-containing receptor subtypes.
• the compounds of this invention can be used as reference ligands in binding assays for compounds which bind to NNR subtypes, particularly the ⁇ 4 ⁇ 2* and/or a6-containing receptor subtypes.
• the compounds of this invention are preferably labeled with a radioactive isotopic moiety such as 3 H, or 14 C.
• a three-neck flask equipped with a mechanical stirrer, two reflux condensers, a cold finger, a temperature probe, a nitrogen inlet and an exhaust outlet (leading to a aqueous sodium bisulfite/sodium hydroxide trap), was charged with glutaryl chloride (350 g, 2.07 mol) followed by bromine (160 ml_, 3.12 mol).
• the resulting mixture was stirred under nitrogen and heated at gentle reflux, as the internal temperature gradually increased from 58°C to 91 °C over a period of 7 h. During the heating period and as consumption/loss of bromine was observed, additional bromine was added twice (first 90 ml_ and later 120 ml_).
• reaction mixture was then allowed to gradually cool to ambient temperature while stirring under a nitrogen atmosphere overnight. Analysis of an aliquot of the reaction mixture quenched in methanol indicated complete conversion to dimethyl 2,4-dibromoglutarate (>98 % analyzed as the based on GCMS and LCMS). This 2,4-dibromoglutaryl chloride was used without further purification in the next step.
• reaction mixture was then allowed to stir under a nitrogen atmosphere while gradually warming to ambient temperature overnight. Analysis of an aliquot of the reaction mixture diluted in methanol indicated complete consumption of 2,4- dibromoglutaryl chloride (i.e., no dimethyl 2,4-dibromoglutarate was observed) based on LCMS.
• the reaction mixture was transferred to a separatory funnel (aided with an ether rinse) and the organic solution was washed twice with water, twice with 1 M aqueous sodium bisulfite, twice with saturated aqueous sodium bicarbonate (the second wash tested alkaline with pH paper) and finally once with saturated aqueous sodium chloride.
• the mixture was stirred under nitrogen at ambient temperature (internal temperature of 18°C) after which benzylamine (707 g, 720 ml_, 6.60 mol) was added by addition funnel in one portion ( ⁇ 5 min addition time), during which time an exotherm to a maximum temperature of 55-60°C was observed.
• reaction mixture was heated at 93-95°C for 4.5 h.
• LCMS analysis of an aliquot of the reaction mixture diluted in methanol indicated complete consumption of intermediate 3 and formation of product (in addition to its trans counterpart).
• the heating was stopped and the reaction mixture was allowed to gradually cool to ambient temperature under nitrogen overnight.
• the reaction solution was then poured into a stirred biphasic mixture of 1 : 1 ethyl acetate/hexanes (8 L) and water (6 L). After agitation, the organic and aqueous phases were separated. The collected organic phase was washed successively with water, saturated aqueous sodium bicarbonate (wash tested alkaline with pH paper) and saturated aqueous sodium chloride.
• the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure, providing 790 g of adark colored oil.
• the crude material was loaded onto a silica gel plug (loading aided with a wash of a minimal amount of dichloromethane) after which elution with 15% ethyl acetate/hexanes was performed. Concentration of selected fractions under reduced pressure to give 543 g of dibenzyl N-benzylazetidine-2,4-dicarboxylate with a 82: 17 ratio of cis (Intermediate 4):trans stereochemistry and an overall chemical purity of 92%.
• methanesulfonyl chloride (109 g, 73.4 mL, 948 mmol) was added drop-wise by addition funnel over 45 min, during which time an exotherm occurred up to a maximum observed temperature of 4°C. Following the addition, the reaction mixture was allowed to gradually warm to ambient temperature while stirring under nitrogen overnight. LCMS analysis of an aliquot of the reaction mixture diluted in acetonitrile indicated consumption of starting material and formation of product. To the reaction mixture was added water (250 mL) drop-wise followed by saturated aqueous sodium bicarbonate (250 mL). The resulting biphasic mixture was stirred vigorously for 20 min and transferred to a separatory funnel, aided by a
• Anhydrous 1 -methyl-2-pyrrolidinone (N- methyl-2-pyrrolidone) (900 mL) was added and the resulting mixture was mechanically stirred under nitrogen while cooling in an ice water bath (internal temperature of 5°C).
• sodium hydride 39.4 g of a 60% dispersion in mineral oil, 980 mmol was added in portions over 30 min, as the temperature varied between 5 and 12°C.
• the resulting mixture was stirred on the cold bath for an additional 10 min.
• the cold bath was allowed to warm to ambient temperature (over 30 min), at which point a slight exotherm (to a maximum temperature of 25°C) and gas evolution were observed.
• the resulting mixture was stirred at ambient temperature for an additional 50 min (no further gas evolution), after which a solution of the bis-mesylate (Intermediate 6) (143 g, 393 mmol) in anhydrous 1 -methyl-2- pyrrolidinone (600 mL) was added to the suspension in one lot.
• the flask containing crude Intermediate 6 was rinsed with additional anhydrous 1 -methyl-2-pyrrolidinone (2 x 100 mL), each rinse being added to the reaction suspension.
• the hemigalactarate monohydrochloide salt appears to have preferential characteristics for commercialization as a drug product.
• the purpose of the study was to test Compound A in the harmaline-induced tremor assay in ICR mice. This study was performed at PsychoGenics, Inc., headquartered at 765 Old Saw Mill Road, Tarrytown, New York.
• mice Male ICR mice from Taconic (Germantown, NY) were used in this study. Upon receipt, mice were group housed in OPTI mouse ventilated cages. All animals remained group housed during the duration of the study. All mice were acclimated to the colony room for at least one week prior to testing and subsequently tested at an average age of 10 weeks. During the period of acclimation, mice were examined on a regular basis, handled, and weighed to assure adequate health and suitability. Mice were maintained on a 12/12 light/dark cycle. The room temperature was maintained between 20 and 23°C with a relative humidity maintained between 30% and 70%. Chow and water were provided ad libitum for the duration of the study. In each test, animals were randomly assigned across treatment groups.
• Compound A (0.01. 0.1 and 1 mg/kg) was administered ip twice daily for 7 days prior to testing at a dose volume of 10 ml/kg. On day 8, Compound A was administered 20 minutes prior to harmaline administration.
• mice were used in each treatment group for a total of 50 mice.
• mice Group-housed mice were brought to the experimental room for at least 1 h acclimation prior to testing. During test trials, the recorded frequencies (1-64 hertz) of activity and the number of tremor events were captured electronically.
• tremor monitor software (San Diego Instruments) in a two part process.
• FFT Fast Fourier Transform
• An output is provided showing the percentage of activity (energy) recorded at each frequency.
• a center frequency of activity between 14 - 15 Hz is chosen, along with a bandwidth of 10 Hz.
• tremor events were tabulated as short, long, and total events.
• a long event is defined as being greater than 0.5 seconds in duration, and a short event as greater than 0.3 but less than 0.5 seconds in duration.
• mice were injected with either vehicle, propranolol, or Compound A and placed in separate holding cages for 20 minutes following which mice were injected with harmaline (30 mg/kg) and placed inside the Tremor Monitor (San Diego Instruments, SDI) chamber for a 10 minute acclimation period. After habituation, tremor activity of the mice was measured for approximately 8 min. Chambers were cleaned with alcohol following each run.
• FIG. 1 graphically depicts the effects of acute propranolol and sub-chronic Compound A administration on harmaline-induced tremor events.
• the asterisks ( * p ⁇ 0.05) indicate a significant difference in short (0.3-0.5 seconds in duration), long (>0.5 seconds) and total tremor events compared to saline vehicle for respective measures.
• the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with practice of the present invention.

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