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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
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  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/38—Nitrogen atoms
  • C07D231/40—Acylated on said nitrogen atom
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms

Definitions

• the present invention relates to compounds with ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR) agonistic activity, processes for their preparation, pharmaceutical compositions containing the same and the use thereof for the treatment of neurological, psychiatric, inflammatory diseases.
• ⁇ 7 nAChR nicotinic acetylcholine receptor
• Agents that bind to nicotinic acetylcholine receptors have been indicated as useful in the treatment and/or prophylaxis of various diseases and conditions, particularly psychotic diseases, neurodegenerative diseases involving a dysfunction of the cholinergic system, and conditions of memory and/or cognition impairment, including for example, schizophrenia, anxiety, mania, depression, manic depression, Tourette's syndrome, Parkinson's disease, Huntington's disease, cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognition deficit, attention deficit, Attention Deficit Hyperactivity Disorder), and other uses such as treatment of nicotine addiction, inducing smoking cessation, treating pain (e.g.
• the invention provides novel compounds acting as full or partial agonists at the ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR), pharmaceutical compositions containing the same compounds and the use thereof for the treatment of diseases that may benefit from the activation of the alpha 7 nicotinic acetylcholine receptor such as neurological, neurodegenerative, psychiatric, cognitive, immunological, inflammatory, metabolic, addiction, nociceptive, and sexual disorders, in particular Alzheimer's disease, schizophrenia, and/or others.
• diseases that may benefit from the activation of the alpha 7 nicotinic acetylcholine receptor
• diseases that may benefit from the activation of the alpha 7 nicotinic acetylcholine receptor
• diseases that may benefit from the activation of the alpha 7 nicotinic acetylcholine receptor
• diseases that may benefit from the activation of the alpha 7 nicotinic acetylcholine receptor
• Figure 1 X-ray patterns of various crystal forms of hyrochloric salt.
• FIG. 1 DSC scan of various crystal forms of hydrochloric salt.
• FIG. 3 TGA of various crystal forms of hydrochloric salt.
• FIG. 6 DVS of hydrochloric salt (crystal III) (data from pre-selection minute);
• Figure 7 DVS of hydrochloric salt (crystal V).
• Figure 8 Effect of pH and HCl equivalence on HCl salt formation.
• Figure 11 Conversion of mono-HCl to Form II by decreasing the pH (slurried overnight).
• Figure 14 X-ray diffraction pattern of 5-(4-acetyl-l ,4-diazepan-l-yl)-N-(5- (4-methoxyphenyl)-lH-pyrazol-3-yl)pentanamide hydrochloric salt Form I.
• Figure 16 DSC scan of 5-(4-acetyl-l ,4-diazepan-l-yl)-N-(5-(4- methoxyphenyl)-lH-pyrazol-3-yl)pentanamide hydrochloric salt Form II.
• Figure 17 TGA thermogram of 5-(4-acetyl-l,4-diazepan-l-yl)-N-(5-(4- methoxyphenyl)-lH-pyrazol-3-yl)pentanamide hydrochloric salt Form II.
• Figure 18 X-ray diffraction pattern of 5-(4-acetyl-l,4-diazepan-l-yl)-N-(5- (4-methoxyphenly)-lH-pyrazol-3-yl)pentanamide hydrochloric salt Form II.
• the invention provides a compound of Formula (I):
• R" is Cl-C3 alkyl; j is 0 or 1 ;
• R is a 5- to 10-member aromatic or heteroaromatic ring; m is 0, 1, 2, or 3;
• Y represents, independently from one another when m is greater than 1, halogen; hydroxy; mercapto; cyano; nitro; amino; linear, branched or cyclic (C1-C6) alkyl, trihaloalkyl, di- or trihaloalkoxy, alkoxy, or alkylcarbonyl; (C3-C6) cycloalkyl-(Cl-C ⁇ ) alkoxy; (C3-C6) cycloalkyl-(Cl -C6) alkyl; linear, branched, or cyclic (C1-C6) alkylcarbonylamino; mono- or di-, linear, branched, or cyclic (C1-C6) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic (C1-C6) alkylsulphonylamino; linear, branched, or cyclic (C1 -C6) alkylsulphonyl; mono- or di-, linear
• the invention provides compounds of Formula (I) wherein:
• T is butane- 1 ,4-diyl optionally substituted with one or more (C1-C3) alkyl, halogen; z is N or O;
• R ⁇ independently from one another for p 2, is selected from the group consisting of mono- or di- [linear, branched or cyclic (C1-C6) alkyljaminocarbonyl; linear, branched or cyclic (C1-C6) alkyl, alkoxy, acyl;
• particularly preferred compounds of Formula (I) are those in which:
• T is butane- 1,4-diyl
• z is N or O
• R' is selected from the group consisting of linear, branched or cyclic (C1-C6) alkyl, alkoxy, acyl; j is 0;
• R is a 5- to 10-member aromatic or heteroaromatic ring; q, q', R, Y and m are as defined under Formula (I);
• T is butane- 1,4-diyl; z is N; p is 1 ;
• R' is (Cl -C6) acyl; j is O;
• R is phenyl, pyridyl, thienyl; indolyl; m is 0, 1 or 2;
• the invention provides compounds, hereafter referred to as Gl of Formula (I), wherein:
• T is propane-l,3-diyl optionally substituted with (C1-C3) alkyl, halogen;
• z is CH 2 , N, O;
• T is propane- 1 ,3-diyl optionally substituted with (C1-C3) alkyl, halogen;
• q and q' are, independently from one another, 1 or 2; p is 0 or 1 ;
• R' is selected from the group consisting of linear, branched or cyclic (C1-C6) alkyl, alkoxy, acyl; j is O;
• R, Y and m are as defined under Formula (I);
• T is propane-l,3-diyl; z is CH 2 ; q and q' are, independently from one another, 1 or 2; p is 0 or 1 ;
• R' is selected from the group consisting of linear, branched or cyclic (C1-C6) alkyl
• R is phenyl, pyi ⁇ dyl, naphthyl; m is 1 or 2;
• Y represents, independently from one another when m is greater than 1, halogen; hydroxy; linear, branched or cyclic (C1-C6) alkyl, trihalo alkyl, di- or trihaloalkoxy, alkoxy; (C3-C6) cycloalkyl-(Cl-C ⁇ ) alkoxyl.
• certain inventive compounds are those in which Q-R is
• T is propane- 1, 3 -diyl optionally substituted with (C1 -C3) alkyl, halogen; z is CH 2 ;
• Q is q and q' are, independently from one another, 1 or 2; p is 0 or 1 ;
• R' is selected from the group consisting of linear, branched or cyclic (C1-C6) alkyl, alkoxy, acyl; j is 0;
• R, Y and m are as defined under Formula (I);
• a fourth group of preferred compounds under Gl are those in which T is propane-l,3-diyl; z is CH 2 ; q and q' are, independently from one another, 1 or 2; p is 0 or 1 ; R' is selected from the group consisting of linear, branched or cyclic (C1-C6) alkyl; j is 0;
• R is phenyl, pyridyl, naphthyl; m is 1 or 2;
• Y represents, independently from one another when m is greater than 1 , halogen; hydroxy; linear, branched or cyclic (C 1 -C6) alkyl, trihaloalkyl, di- or trihaloalkoxy, alkoxy; (C3-C6) cycloalkyl-(Cl -C6) alkoxyl.
• Compounds of the invention can be in the form of free bases or acid addition salts, preferably salts with pharmaceutically acceptable acids.
• the invention also provides separated isomers and diastereoisomers of compounds of Formula (I), or mixtures thereof (e.g. racemic and diastereomeric mixtures), as well as isotopic compositions.
• Pharmacological activity of a representative group of compounds of Formula (I) was demonstrated in an in vitro assay utilising cells stably transfected with the alpha 7 nicotinic acetylcholine receptor and cells expressing the alpha 1 and alpha 3 nicotinic acetylcholine receptors and 5HT3 receptor as controls for selectivity.
• prodrugs of one or more compounds of Formula (I) may be provided according to the present invention in any of a variety of useful forms, for example as pharmaceutically acceptable salts, as particular crystal forms, etc.
• prodrugs of one or more compounds of Formula (I) are provided.
• Various forms of prodrugs are known in the art, for example as discussed in Bundgaard (ed.). Design of Prodrugs, Elsevier (1985); Widder et al. (ed.), Methods in En ⁇ ymology, vol. 4, Academic Press (1985); Kgrogsgaard-Larsen et al.
• Agents that bind to nicotinic acetylcholine receptors have been indicated as useful in the treatment and/or prophylaxis of various diseases and conditions, particularly psychotic diseases, neurodegenerative diseases involving a dysfunction of the cholinergic system, and conditions of memory and/or cognition impairment, including, for example, schizophrenia, anxiety, mania, depression, manic depression, Tourette's syndrome, Parkinson's disease, Huntington's disease, cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognition deficit, attention deficit, Attention Deficit Hyperactivity Disorder), and other uses such as treatment of nicotine addiction, inducing smoking cessation, treating pain (i.e., analgesic use), providing neuroprotection, and treating jetlag.
• various diseases and conditions including, for example, schizophrenia, anxiety, mania, depression, manic depression, Tourette's syndrome, Parkinson's disease, Huntington's disease, cognitive disorders (such as Alzheimer's disease,
• a method of treating a patient, especially a human, suffering from any of psychotic diseases, neurodegenerative diseases involving a dysfunction of the cholinergic system, and/or conditions of memory and/or cognition impairment including, for example, schizophrenia, anxiety, mania, depression, manic depression, Tourette's syndrome, Parkinson's disease, Huntington's disease, and/or cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognition deficit, attention deficit, Attention Deficit Hyperactivity Disorder) comprising administering to the patient an effective amount of a compound according to Formula (I).
• Neurodegenerative disorders whose treatment is included within the methods of the present invention include, but are not limited to, treatment and/or prophylaxis of Alzheimer's diseases, Pick's disease (Friedland, Dementia, (1993) 192-203; Procter, Dement Geriatr Cogn Disord. (1999) 80-4; Sparks, Arch Neurol. (1991) 796-9; Mizukami, Acta Neuropathol. (1989) 52-6; Hansen, Am J Pathol. (1988) 507-18), diffuse Lew)' Body disease, progressive supranuclear palsy (Steel- Richardson syndrome, see Whitehouse, J Neural Transm Suppl. (1987) 24: 175-82; Whitehouse, Arch Neurol.
• Parkinson's disease synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado- Joseph disease/spinocerebellar ataxia type 3, olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar, pseudobulbar palsy, spinal muscular atrophy, spinobulbar muscular atrophy (Kennedy's disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease, Kugelberg- Welander disease, Tay-Sach's disease, Sandhoff disease, familial spastic disease, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, prion diseases (such as Creutzfeldt- Jakob, Gerstmann- Straussler-Scheinker disease, Kuru and fatal familial insomnia), and neurodegenerative disorders resulting from cerebral ischemia or infarction including embo
• ⁇ JnACh receptor agonists such as the compounds of the present invention can be used to treat age-related dementia and other dementias and conditions with memory loss including age-related memory loss, senility, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica, alcoholism related dementia (Korsakoff Syndrome) and frontal lobe dementia.
• age-related dementia and other dementias and conditions with memory loss including age-related memory loss, senility, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica, alcoholism related dementia (Korsakoff Syndrome) and frontal lobe dementia.
• WO 99/62505. Tomimoto Dement Geriatr Cogn Disord. (2005), 282-8; Tohgi - J Neural Transm. (1996), 1211-20
• Amyloid precursor protein (APP) and A ⁇ peptides derived therefrom, e.g., A ⁇ l -42 and other fragments, are known to be involved in the pathology of Alzheimer's disease.
• the A ⁇ l-42 peptides are not only implicated in neurotoxicity but also are known to inhibit cholinergic transmitter function. Further, it has been determined that A ⁇ peptides bind to ⁇ 7nACh receptors.
• the inflammatory reflex is an autonomic nervous system response to an inflammatory signal. Upon sensing an inflammatory stimulus, the autonomic nervous system responds through the vagus nerve by releasing acetylcholine and activating nicotinic ⁇ 7 receptors on macrophages. These macrophages in turn release cytokines.
• Dysfunctions in this pathway have been linked to human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis.
• Macrophages express the nicotinic ⁇ 7 receptor and it is likely this receptor that mediates the cholinergic anti-inflammatory response. See for example Czura, C J et al., J. Intern. Med., (2005) 257(2), 156-66; Wang, H. et al Nature (2003) 421 : 384-388; de Jonge British Journal of Pharmacology (2007) 151, 915-929.
• the mammalian sperm acrosome reaction is an exocytosis process important in fertilization of the ovum by sperm.
• ⁇ 7nAChR Activation of an ⁇ 7 nAChR on the sperm cell has been shown to be essential for the acrosome reaction (Son, J. -H. and Meizel, S. Biol. Reproduct. 68: 1348-1353, 2003).
• nicotinic receptors have been implicated as playing a role in the body's response to alcohol ingestion.
• ⁇ 7nACh receptor agonists such as compounds provided herein, therefore, are also usedul in the treatment of these disorders, diseases, and conditions.
• agonists for the ⁇ 7nACh receptor subtypes can also be used in the treatment of nicotine addiction, inducing smoking cessation, treating pain, and treating jetlag, obesity, diabetes, sexual and fertility disorders (eg. Premature ejaculation or vaginal dryness, see US6448276), drug abuse (Solinas, Journal of Neuroscience (2007) 27(21), 5615-5620), and inflammation (Wang H, et al. (2003) Nature 421 :384-388).
• Chem. 276, 13541-13546) and protein-aggregation mediated neuronal degeneration (Kelton, M. C. et al.(2000) Brain Cogn 43, 274-282).
• a direct involvement of receptors comprising the ⁇ 7 subtype has been invoked (Shimohama, S. et al. (1998) Brain Res. 779, 359-363; Kihara, T., et al. (2001) J.Biol.Chem. 276, 13541-13546; Kelton, M. C, et al. (2000) Brain Cogn 43, 274-282; Kern, W. R. (2000) Behav. Brain Res.
• a method of treating a patient, especially a human, suffering from age-related dementia and other dementias and conditions with memory loss comprising administering to the patient an effective amount of a compound according to Formula (I).
• the present invention includes methods of treating patients suffering from memory impairment due to, for example, mild cognitive impairment due to aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt- Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia and other neurological conditions, as well as HIV and cardiovascular diseases, comprising administering an effective amount of a compound according to Formula (I).
• a method of treating and/or preventing dementia in an Alzheimer's patient which comprises administering to the subject a therapeutically effective amount of a compound according to Formula (I) to inhibit the binding of an amyloid beta peptide (preferably, A ⁇ l-42) with nACh receptors, preferable ⁇ 7nACh receptors, most preferably, human ⁇ 7nACh receptors (as well as a method for treating and/or preventing other clinical manifestations of Alzheimer's disease that include, but are not limited to, cognitive and language deficits, apraxias, depression, delusions and other neuropsychiatric symptoms and signs, and movement and gait abnormalities).
• the present invention also provides methods for treating other amyloidosis diseases, for example, hereditary cerebral angiopathy, nonneuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle- Wells syndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis, chronic hemodialysis anthropathy, and Finnish and Iowa amyloidosis.
• other amyloidosis diseases for example, hereditary cerebral angiopathy, nonneuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle- Wells syndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis, chronic hemodialysis anthropathy, and Finnish and Iowa amyloidosis.
• nicotinic receptors have been implicated as playing a role in the body's response to alcohol ingestion.
• agonists for ⁇ 7nACh receptors can be used in the treatment of alcohol withdrawal and in anti-intoxication therapy.
• a method of treating a patient for alcohol withdrawal or treating a patient with anti-intoxication therapy comprising administering to the patient an effective amount of a compound according to Formula (I).
• Agonists for the ⁇ 7nACh receptor subtypes can also be used for neuroprotection against damage associated ⁇ vith strokes and ischemia and glutamate- induced excitotoxicity.
• a method of treating a patient to provide for neuroprotection against damage associated with strokes and ischemia and glutamate-induced excitotoxicity comprising administering to the patient an effective amount of a compound according to Formula (I).
• Agonists for the ⁇ 7nACh receptor subtypes can also be used in the treatment of nicotine addiction, inducing smoking cessation, treating pain, and treating jetlag, obesity, diabetes, sexual and fertility disorders (eg. Premature ejaculation or vaginal dryness, see US 6448276), drug abuse (Solinas, Journal of Neuroscience (2007) 27(21), 5615-5620), and inflammation.
• a method of treating a patient suffering from nicotine addiction, pain, jetlag, obesity and/or diabetes or a method of inducing smoking cessation in a patient comprising administering to the patient an effective amount of a compound according to Formula (I).
• the inflammatory reflex is an autonomic nervous system response to an inflammatory signal.
• the autonomic nervous system responds through the vagus nerve by releasing acetylcholine and activating nicotinic ⁇ 7 receptors on macrophages. These macrophages in turn release cytokines. Dysfunctions in this pathway have been linked to human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis. Macrophages express the nicotinic oc7 receptor and it is likely this receptor that mediates the cholinergic anti-inflammatory response.
• compounds with affinity for the ⁇ 7nACh receptor on macrophages may be useful for human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis. See, e.g., Czura, C J et al., J. Intern. Med., (2005) 257(2), 156-66, Wang, H. et al Nature (2003) 421 : 384-388; de Jonge British Journal of Pharmacology (2007) 151, 915-929.
• a method of treating a patient e.g., a mammal, such as a human
• an inflammatory disease such as, but not limited to, rheumatoid arthritis, diabetes or sepsis
• administering comprising administering to the patient an effective amount of a compound according to Formula (I).
• the mammalian sperm acrosome reaction is an exocytosis process important in fertilization of the ovum by sperm.
• Activation of an ⁇ 7 nAChR on the sperm cell has been shown to be essential for the acrosome reaction (Son, J.— H. and Meizel, S. Biol, Reproduct. 68: 1348-1353 2003). Consequently, selective ⁇ 7 agents demonstrate utility for treating fertility disorders.
• labeled derivatives of the compounds of Formula (I) can be used in neuroimaging of the receptors within, e.g., the brain.
• labeled agents in vivo imaging of the receptors can be performed using, for example PET imaging.
• the condition of memory impairment is manifested by impairment of the ability to learn new information and/or the inability to recall previously learned information.
• Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntingdon's disease, Pick's disease, Creutzfeldt-Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline.
• Dosage of the compounds for use in therapy may vary depending upon, for example, the administration route, the nature and severity of the disease. In general, an acceptable pharmacological effect in humans may be obtained with daily dosages
• one or more compounds of formula (I) are administered in combination with one or more other other pharmaceutically active agents.
• the phrase "in combination”, as used herein, refers to agents that are simultaneously administered to a subject. It will be appreciated that two or more agents are considered to be administered "in combination" whenever a subject is simultaneously exposed to both (or more) of the agents. Each of the two or more agents may be administered according to a different schedule; it is not required that individual doses of different agents be administered at the same time, or in the same composition. Rather, so long as both (or more) agents remain in the subject's body, they are considered to be administered "in combination".
• compounds of Formula (I), in forms as described herein may be administered in combination with one or more other modulators of ⁇ 7 nicotinic acetylcholine receptors.
• compounds of Formula (I), in forms as described herein may be administered in combination with one or more other anti-psychotic agents, pain relievers, antiinflammatories, or other pharmaceutically active agents.
• Effective amounts of a wide range of other pharmaceutically active agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other pharmaceutically active agent's optimal effective amount range.
• the compound of Formula (I)and the other pharmaceutically active agent can act additively or, in some embodiments, synergistically.
• the effective amount of the compound of Formula (I) is less than its effective amount would be where the other pharmaceutically active agent is not administered.
• the compound of Formula (I) and the other pharmaceutically active agent act synergistically.
• the patient in need of treatment is being treated with one or more other pharmaceutically active agents.
• the patient in need of treatment is being treated with at least two other pharmaceutically active agents.
• the other pharmaceutically active agent is selected from the group consisting of one or more anti-depressant agents, anti-anxiety agents, anti-psychotic agents, or cognitive enhancers.
• antidepressants include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-I receptor antagonists, monoamine oxidase inhibitors (MAOs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, ⁇ - adrenoreceptor antagonists, and atypical antidepressants.
• SSRIs selective serotonin reuptake inhibitors
• NK-I receptor antagonists include monoamine oxidase inhibitors (MAOs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitor
• Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics.
• Suitable tertiary amine tricyclics and secondary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dothiepin, butriptyline, iprindole, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline.
• Suitable selective serotonin reuptake inhibitors include fluoxetine, citolopram, escitalopram, fluvoxamine, paroxetine and sertraline.
• Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcypromine.
• Suitable reversible inhibitors of monoamine oxidase include moclobemide.
• Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include venlafaxine, nefazodone. milnacipran, and duloxetine.
• Suitable CRF antagonists include those compounds described in International Patent Publication Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.
• Suitable atypical anti-depressants include bupropion, lithium, nefazodone, trazodone and viloxazine.
• Suitable NK-I receptor antagonists include those referred to in International Patent Publication WO 01/77100.
• Anti-anxiety agents that can be used in combination with the compounds of Formula (I) include without limitation benzodiazepines and serotonin IA (5-HT IA ) agonists or antagonists, especially 5-HT 1A partial agonists, and corticotropin releasing factor (CRF) antagonists.
• benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam.
• Exemplary suitable 5-HT JA receptor agonists or antagonists include buspirone, flesinoxan, gepirone and ipsapirone.
• Anti-psychotic agents that are used in combination with the compounds of Formula (I) include without limitation aliphatic phethiazine, a piperazine phenothiazine, a butyrophenone, a substituted benzamide, and a thioxanthine. Additional examples of such drugs include without limitation haloperidol, olanzapine, clozapine, risperidone, pimozide, aripiprazol, and ziprasidone. In some cases, the drug is an anticonvulsant, e.g., phenobarbital, phenytoin, primidone, or carbamazepine.
• an anticonvulsant e.g., phenobarbital, phenytoin, primidone, or carbamazepine.
• Cognitive enhancers that are used in combination with the compounds of Formula (I) include, without limitation, drugs that modulate neurotransmitter levels (e.g., acetylcholinesterase or cholinesterase inhibitors, cholinergic receptor agonists or serotonin receptor antagonists), drugs that modulate the level of soluble A ⁇ , amyloid fibril formation, or amyloid plaque burden (e.g., ⁇ -secretase inhibitors, ⁇ - secretase inhibitors, antibody therapies, and degradative enzymes), and drugs that protect neuronal integrity (e.g., antioxidants, kinase inhibitors, caspase inhibitors, and hormones).
• neurotransmitter levels e.g., acetylcholinesterase or cholinesterase inhibitors, cholinergic receptor agonists or serotonin receptor antagonists
• drugs that modulate the level of soluble A ⁇ , amyloid fibril formation, or amyloid plaque burden e.g., ⁇ -secretas
• cholinesterase inhibitors e.g., tacrine (COGNEX ® ), donepezil (ARICEPT ® ) . , rivastigmine (EXELON ® ) galantamine (REMINYL ® ), metrifonate, physostigmine, and Huperzine A
• NMDA N-methyl-D-aspartate
• agonists e.g., dextromethorphan, memantine, dizocilpine maleate (MK-801), xenon, remacemide, eliprodil, amantadine, D-cycloserine, felbamate, ifenprodil, CP-101606 (Pfizer), Delucemine, and compounds described in U.S.
• Patent Nos. 6,821,985 and 6,635,270 ampakines (e.g., cyclothiazide, aniracetam, CX-516 (Ampalex®), CX-717, CX-516, CX-614, and CX-691 (Cortex Pharmaceuticals, Inc. Irvine, CA), 7-chloro-3-methyl-3-4-dihydro-2H- 1,2,4- benzothiadiazine S,S-dioxide (see Zivkovic et al., 1995, J. Pharmacol. Exp. Therap., 272:300-309; Thompson et al, 1995, Proc. Natl. Acad. Sci.
• ampakines e.g., cyclothiazide, aniracetam, CX-516 (Ampalex®), CX-717, CX-516, CX-614, and CX-691 (Cortex Pharmaceuticals, Inc. Irvine, CA), 7-chloro-3-methyl-3-4-dihydro-2H- 1,2,4-
• WO 94/02475, WO 96/38414, WO 97/36907, WO 99/51240, and WO 99/42456 benzodiazepine (BZD)/GABA receptor complex modulators
• BZD benzodiazepine
• GABA receptor complex modulators e.g., progabide, gengabine, zaleplon, and compounds described in U.S. Patent No. 5,538,956, 5,260,331 , and 5,422,355
• serotonin antagonists e.g., 5HT receptor modulators, 5HT 1 A antagonists or agonists (including without limitation lecozotan and compounds described in U.S. Patent Nos. 6,465,482, 6,127,357, 6,469,007, and 6,586,436, and in PCT Publication No.
• WO 97/03982 and 5-HT 6 antagonists (including without limitation compounds described in U.S. Patent Nos. 6,727,236, 6,825,212, 6,995,176, and 7,041 ,695)); nicotinics (e.g., niacin); muscarinics (e.g., xanomeline, CDD-0102, cevimeline, talsaclidine, oxybutin, tolterodine, propivei ⁇ ne, tropsium chloride and darifenacin); monoamine oxidase type B (MAO B) inhibitors (e.g., rasagiline, selegiline, deprenyl, lazabemide, saf ⁇ namide, clorgyline, pargyline, N-(2-aminoethyl)-4-chlorobenzamide hydrochloride, and N-(2-aminoethyl)-5(3- fluorophenyl)-4-thi
• anti-amyloid or amyloid lowering agents e.g., bapineuzumab and compounds described in U.S. Patent No. 6,878,742 or U.S. Patent Application Publication Nos.
• statins and peroxisome proliferators activated receptor (PPARS) modulators e.g., gemfibrozil (LOPID ® ), fenof ⁇ brate (TRICOR ® ), rosiglitazone maleate (AVANDIA ® ), pioglitazone (Actos TM ), rosiglitazone (Avandia TM ), clofibrate and bezafibrate); cysteinyl protease inhibitors; an inhibitor of receptor for advanced glycation endproduct (RAGE) (e.g.
• RAGE advanced glycation endproduct
• neurotropic agents e.g., Cerebrolysin ® , piracetam, oxiracetam, AIT-082 (Emilieu, 2000, Arch. Neurol.
• beta-secretase (BACE) inhibitors beta-secretase (BACE) inhibitors, ⁇ -secretase, immunophilins, caspase-3 inhibitors, Src kinase inhibitors, tissue plasminogen activator (TPA) activators, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) modulators, M4 agonists, JNK3 inhibitors, LXR agonists, H3 antagonists, and angiotensin IV antagonists.
• BACE beta-secretase
• ⁇ -secretase immunophilins
• caspase-3 inhibitors Src kinase inhibitors
• TPA tissue plasminogen activator
• AMPA alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
• cognition enhancers include, without limitation, acetyl- 1- carnitine, citicholine, huperzine, DMAE (dimethylaminoethanol), Bacopa monneiri extract, Sage extract, L-alpha glyceryl phosphoryl choline, Ginko biloba and Ginko biloba extract, Vinpocetine, DHA, nootropics including Phenyltropin, Pikatropin (from Creative Compounds, LLC, Scott City, MO), besipirdine, linopirdine, sibopirdine, estrogen and estrogenic compounds, idebenone, T-588 (Toyama Chemical, Japan), and FK960 (Fujisawa Pharmaceutical Co. Ltd.).
• Cognitive enhancers that act through one or more of the above mechanisms are also within the scope of this invention.
• the compound of Formula (I) and cognitive enhancer act additively or, in some embodiments, synergistically.
• the effective amount of the compound or pharmaceutically acceptable salt of the compound of the invention is less than its effective amount would be where the cognitive enhancer agent is not administered.
• a cognitive enhancer and a compound of Formula (I) are co-administered to an animal
• the effective amount of the cognitive enhancer is less than its effective amount would be where the compound or pharmaceutically acceptable salt of the invention is not administered.
• a cognitive enhancer and a compound of Formula (I)of the invention are co-administered to an animal in doses that are less than their effective amounts would be where they were no co-administered. In these cases, without being bound by theory, it is believed that the compound of Formula (I) and the cognitive enhancer act synergistically.
• the other pharmaceutically active agent is an agent useful for treating Alzheimer's disease or conditions associate with Alzheimer's disease, such as dementia.
• agents useful for treating Alzheimer's disease include, without limitation, donepezil, rivastigmine, galantamine, memantine, and tacrine.
• the compound of Formula (I) is administered together with another pharmaceutically active agent in a single administration or composition.
• compositions comprising an effective amount of the compound of Formula (I) and an effective amount of another pharmaceutically active agent within the same composition can be administered.
• a composition comprising an effective amount of the compound of Formula (I) and a separate composition comprising an effective amount of another pharmaceutically active agent can be concurrently administered.
• an effective amount of the compound of Formula (I) is administered prior to or subsequent to administration of an effective amount of another pharmaceutically active agent.
• the compound of Formula (I) is administered while the other pharmaceutically active agent exerts its therapeutic effect, or the other pharmaceutically active agent is administered while the compound of Formula (I) exerts its preventative or therapeutic effect.
• the invention provides a composition comprising an effective amount of the compound of Formula (I)of the present invention and a pharmaceutically acceptable carrier.
• the composition further comprises a second pharmaceutically active agent.
• the composition further comprises a pharmaceutically active agent selected from the group consisting of one or more other antidepressants, anti-anxiety agents, anti-psychotic agents or cognitive enhancers.
• a pharmaceutically active agent selected from the group consisting of one or more other antidepressants, anti-anxiety agents, anti-psychotic agents or cognitive enhancers.
• Antidepressants, anti-anxiety agents, anti-psychotic agents and cognitive enhancers suitable for use in the composition include the antidepressants, anti-anxiety agents, anti-psychotic agents and cognitive enhancers provided above.
• the pharmaceutically acceptable carrier is suitable for oral administration and the composition comprises an oral dosage form.
• one or more compounds of Formula (I) is administered in combination with antidepressant drug treatment, antipsychotic drug treatment, and/or anticonvulsant drug treatment.
• a compound of Formula (I) is administered in combination with one or more selective serotonin reuptake inhibitors (SSRIs) (for example, fluoxetine, citalopram, escitalopram oxalate, fluvoxamine maleate, paroxetine, or sertraline), tricyclic antidepressants (for example, desipramine, amitriptyline, amoxipine, clomipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, dothiepin, butriptyline, iprindole, or lofepramine).
• SSRIs selective serotonin reuptake inhibitors
• tricyclic antidepressants for example, desipramine, amitriptyline, amoxipine, clomipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, dothiepin, butriptyline, iprindo
• a compound of Formula (I) is administered in combination with a monoamine oxidase inhibitor (MAOI) (for example, phenelzine, isocarboxazid, or tranylcypromine), a serotonin and norepinepherine reuptake inhibitor (SNRI) (for example, venlafaxine, nefazodone, milnacipran, duloxetine), a norepinephrine reuptake inhibitor (NRI) (for example, reboxetine), a partial 5-HTi A agonist (for example, buspirone), a 5-HT2A receptor antagonist (for example, nefazodone), a typical antipsychotic drug, or an atypical antipsychotic drug.
• MAOI monoamine oxidase inhibitor
• SNRI serotonin and norepinepherine reuptake inhibitor
• NRI norepinephrine reuptake inhibitor
• NRI norepineph
• antipsychotic drugs examples include aliphatic phethiazine, a piperazine phenothiazine, a butyrophenone, a substituted benzamide, and a thioxanthine. Additional examples of such drugs include haloperidol, olanzapine, clozapine, risperidone, pimozide, aripiprazol, and ziprasidone.
• the drug is an anticonvulsant, e.g. , phenobarbital, phenytoin, primidone, or carbamazepine.
• the compound of Formula (I) is administered in combination with at least two drugs that are antidepressant drugs, antipsychotic drugs, anticonvulsant drugs, or a combination thereof.
• the invention refers to a pharmaceutical composition containing one or more compounds of Formula (I), in association with pharmaceutically acceptable carriers and excipients.
• the pharmaceutical compositions can be in the form of solid, semi-solid or liquid preparations, preferably in form of solutions, suspensions, powders, granules, tablets, capsules, syrups, suppositories, aerosols or controlled delivery systems.
• the compositions can be administered by a variety of routes, including oral, transdermal, subcutaneous, intravenous, intramuscular, rectal and intranasal, and are preferably formulated in unit dosage form, each dosage containing from about 1 to about 1000 mg, preferably from 1 to 600 mg of the active ingredient.
• the compounds of the invention can be in the form of free bases or as acid addition salts, preferably salts with pharmaceutically acceptable acids.
• the invention also includes separated isomers and diastereomers of compounds I, or mixtures thereof (e.g. racemic mixtures). The principles and methods for the preparation of pharmaceutical compositions are described for example in Remington's Pharmaceutical Science, Mack Publishing Company, Easton (PA).
• one or more compounds of Formula (I), in any desirable form can be administered neat or as a component of a pharmaceutical composition that comprises a physiologically acceptable carrier or vehicle.
• a pharmaceutical composition of the invention can be prepared using standard methods, for example admixing the compound(s) and a physiologically acceptable carrier, excipient, or diluent. Admixing can be accomplished using methods well known for admixing a compound of Formula (I)and a physiologically acceptable carrier, excipient, or diluent.
• compositions i.e., comprising one or more compounds of Formula (I), in an appropriate form, can be administered orally.
• provided pharmaceutical compositions can be administered by any other convenient route, for example, parenterally (e.g., subcutaneously, intravenously, etc., by infusion or bolus injection, etc), by absorption through epithelial or mucocutaneous linings (e.g. , oral, rectal, vaginal, and intestinal mucosa, etc.), etc. Administration can be systemic or local.
• Various known delivery systems including, for example, encapsulation in liposomes, microparticles, microcapsules, and capsules, can be used.
• Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin.
• administration will result of release of the compound (and/or one or more metabolites thereof) into the bloodstream.
• the mode of administration may be left to the discretion of the practitioner.
• provided pharmaceutical compositions are administered orally; in some embodiments, provided pharmaceutical compositions are administered intravenously.
• This can be achieved, for example, by local infusion during surgery, topical application, e.g. , in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or edema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
• a compound of Formula (I) into the central nervous system, circulatory system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal injection, paraspinal injection, epidural injection, enema, and by injection adjacent to the peripheral nerve.
• Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
• Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
• the compound of Formula (I) can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
• one or more compounds of Formula (I) can be delivered in a vesicle, in particular a liposome (see Langer, Science 249: 1527-1533, 1990 and Treat et a , Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and 353-365, 1989).
• one or more compounds of Formula (I) can be delivered in a controlled-release system or sustained-release system ⁇ see, e.g. , Goodson, in Medical Applications of Controlled Release, vol. 2, pp. 115-138, 1984).
• Other controlled or sustained-release systems discussed in the review by Langer, Science 249: 1527-1533, 1990 can be used.
• a pump can be used (Langer, Science 249:1527-1533, 1990; Sefton, CRC CHt Ref. Biomed. Eng. 14:201 , 1987; Buchwald et al , Surgery 88:507, 1980; and Saudek et al. , N. Engl. J Med. 321 :574, 1989).
• polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 2:61 , 1983; Levy et al , Science 228: 190, 1935; During et al, Ann. Neural. 25:351 , 1989; and Howard et al. , J. Neurosurg. 71 : 105, 1989).
• compositions can optionally comprise a suitable amount of a physiologically acceptable excipient.
• physiologically acceptable excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
• useful physiologically acceptable excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
• auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
• a physiologically acceptable excipient that is sterile when administered to an animal is utilized.
• physiologically acceptable excipients are desirably stable under the conditions of manufacture and storage and will typically be preserved against the contaminating action of microorganisms.
• Water is a particularly useful excipient when a compound of Formula (I) is administered intravenously.
• Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions.
• Suitable physiologically acceptable excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
• Provided pharmaceutical compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
• Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups, and elixirs.
• a compound of Formula (I) can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fat.
• a liquid carrier can contain other suitable pharmaceutical additives including solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators.
• suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g.
• cellulose derivatives including sodium carboxymethyl cellulose solution
• alcohols including monohydric alcohols and polyhydric alcohols, e.g. , glycols
• oils e.g., fractionated coconut oil and arachis oil
• the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
• Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
• the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
• compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
• pharmaceutical compositions in the form of a capsule are provided.
• suitable physiologically acceptable excipients are described in Remington 's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro, ed., 19th ed. 1995).
• compositions for oral delivery can be in the form of tablets, lozenges, buccal forms, troches, aqueous or oily suspensions or solutions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
• Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
• the carrier in powders, can be a finely divided solid, which is an admixture with the finely divided compound or pharmaceutically acceptable salt of the compound.
• the compound or pharmaceutically acceptable salt of the compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
• the powders and tablets can contain up to about 99% of the compound or pharmaceutically acceptable salt of the compound.
• Capsules may contain mixtures of one or more compounds of Formula (I) with inert fillers and/or diluents such as pharmaceutically acceptable starches (e.g. , corn, potato, or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (such as crystalline and microcrystalline celluloses), flours, gelatins, gums, etc.
• inert fillers and/or diluents such as pharmaceutically acceptable starches (e.g. , corn, potato, or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (such as crystalline and microcrystalline celluloses), flours, gelatins, gums, etc.
• Tablet formulations can be made by conventional compression, wet granulation, or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents (including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins.
• Surface modifying agents include nonionic and anionic
• surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
• compositions when in a tablet or pill form, provided pharmaceutical compositions can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time.
• Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions.
• fluid from the environment surrounding the capsule can be imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
• delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
• a time-delay material such as glycerol monostearate or glycerol stearate can also be used.
• Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In some embodiments, the excipients are of pharmaceutical grade.
• compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection. Generally . , the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent.
• a compound of Formula (I) is to be administered by infusion
• it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
• an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
• one or more compounds of Formula (I) can be administered transdermally through the use of a transdermal patch.
• Transdermal administrations include administrations across the surface of the body and the inner linings of the bodily passages including epithelial and mucosal tissues. Such administrations can be carried out using the present in lotions, creams, foams, patches, suspensions, solutions, and suppositories (e.g. , rectal or vaginal).
• Transdermal administration can be accomplished through the use of a transdermal patch containing one or more compounds of Formula (I) (in an appropriate form) and a carrier that is inert to the compound or pharmaceutically acceptable salt of the compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
• the carrier may take any number of forms such as creams or ointments, pastes, gels, or occlusive devices.
• the creams or ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
• a variety of occlusive devices may be used to release the compound or pharmaceutically acceptable salt of the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing a compound of Formula (I) with or without a carrier, or a matrix containing the active ingredient.
• One or more compounds of Formula (I) may be administered rectally or vaginally in the form of a conventional suppository.
• Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point . , and glycerin.
• Water-soluble suppository bases such as polyethylene glycols of various molecular weights, may also be used.
• One or more compounds of Formula (I) can be administered by controlled-release or sustained-release means or by delivery devices that are known to those of ordinary skill in the art.
• dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
• Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
• the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained- release.
• a controlled- or sustained-release composition comprises a minimal amount of a compound of Formula (I) to treat or prevent one or more disorders, diseases or conditions associated with activity of ⁇ 7 nicotinic acetylcholine receptors.
• Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased compliance by the animal being treated.
• controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the compound or a pharmaceutically acceptable salt of the compound, and can thus reduce the occurrence of adverse side effects.
• Controlled- or sustained-release compositions can initially release an amount of one or more compounds of Formula (I) that promptly produces a desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the compound to maintain this level of therapeutic or prophylactic effect over an extended period of time.
• the compound can be released from the dosage form at a rate that will replace the amount of the compound being metabolized and excreted from the body.
• Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.
• provided pharmaceutical compositions deliver an amount of a compound of Formula (I) that is effective in the treatment of one or more disorders, diseases, or conditions associated with activity (or inactivity) of ⁇ 7 nicotinic acetylcholine receptors.
• in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges.
• the precise dose to be employed can also depend on the route of administration, the condition, the seriousness of the condition being treated, as well as various physical factors related to the individual being treated, and can be decided according to the judgment of a health-care practitioner.
• Equivalent dosages may be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months.
• Effective dosage amounts described herein typically refer to total amounts administered; that is, if more than one compound of Formula (I) is administered, the effective dosage amounts correspond to the total amount administered.
• the effective amount of a compound of Formula (I) for use as described herein will typically range from about 0.001 mg/kg to about 600 mg/kg of body weight per day, in some embodiments, from about 1 mg/kg to about 600 mg/kg body weight per day, in another embodiment, from about 10 mg/kg to about 400 mg/kg body weight per day, in another embodiment, from about 10 mg/kg to about 200 mg/kg of body weight per day, in another embodiment, from about 10 mg/kg to about 100 mg/kg of body weight per day, in another embodiment, from about 1 mg/kg to about 10 mg/kg body weight per day, in another embodiment, from about 0.001 mg/kg to about 100 mg/kg of body weight per day, in another embodiment, from about 0.001 mg/kg to about 10 mg/kg of body weight per day, and in another embodiment, from about 0.001 mg/kg to about 1 mg/kg of body weight per day.
• compositions are provided in unit dosage form, e.g. , as a tablet, capsule, powder, solution, suspension, emulsion, granule, or suppository.
• the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
• the unit dosage form can be packaged compositions, for example, packeted powders, vials, ampoules, pref ⁇ lled syringes or sachets containing liquids.
• a unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
• Such unit dosage form may contain, for example, from about 0.01 mg/kg to about 250 mg/kg, and may be given in a single dose or in two or more divided doses. Variations in the dosage will necessarily occur depending upon the species, weight and condition of the patient being treated and the patient's individual response to the medicament.
• the unit dosage form is about 0.01 to about 1000 mg. In another embodiment, the unit dosage form is about 0.01 to about 500 mg; in another embodiment, the unit dosage form is about 0.01 to about 250 mg; in another embodiment, the unit dosage form is about 0.01 to about 100 mg; in another embodiment, the unit dosage form is about 0.01 to about 50 mg; in another embodiment, the unit dosage form is about 0.01 to about 25 mg; in another embodiment, the unit dosage form is about 0.01 to about 10 mg; in another embodiment, the unit dosage form is about 0.01 to about 5 mg; and in another embodiment, the unit dosage form is about 0.01 to about 10 mg;
• a compound of Formula (I) can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans.
• Animal model systems can be used to demonstrate safety and efficacy.
• an ⁇ -haloalkanoylchloride 1 (hereby exemplified by a co-bromoalkanoyl chloride) is reacted with a suitable heterocyclic amine 2 in a solvent such as for example but not limited to dichloromethane, dimethylformamide, dimethylacetamide, tetrahydrofurane, ethyl acetate and the like, or mixtures thereof, in the presence of a base such as for example but not limited to triethylamine, Hunig's base (diisopropylethylamine) or an inorganic base such as for example potassium carbonate, to afford the coupling amide product 3 which may or may be not isolated and purified.
• a solvent such as for example but not limited to dichloromethane, dimethylformamide, dimethylacetamide, tetrahydrofurane, ethyl acetate and the like, or mixtures thereof, in the presence of a base such as for example but not limited to
• Amide 3 is then reacted in a suitable solvent such as but not limited to dichloromethane, dimethylformamide, or dimethylacetamide with an amine X, which may be or may not be used in excess, in the presence or absence of an additional base such as triethylamine or Hunig's base to afford subject matter compounds of Formula (I).
• a suitable solvent such as but not limited to dichloromethane, dimethylformamide, or dimethylacetamide
• an amine X which may be or may not be used in excess, in the presence or absence of an additional base such as triethylamine or Hunig's base to afford subject matter compounds of Formula (I).
• an ⁇ -haloalkanoic acid is suitably activated using an agent such for example but not limited to as l ,l '-carbonyldiimidazole in a solvent such as for example dichloromethane, dimethylformamide or mixtures thereof and reacted with a suitable heterocyclic amine to afford the intermediate ⁇ -haloalkanoic acid amide 3, which may or may be not isolated and purified.
• an agent such for example but not limited to as l ,l '-carbonyldiimidazole in a solvent such as for example dichloromethane, dimethylformamide or mixtures thereof and reacted with a suitable heterocyclic amine to afford the intermediate ⁇ -haloalkanoic acid amide 3, which may or may be not isolated and purified.
• Amide 3 is then reacted in a suitable solvent such as but not limited to dichloromethane, dimethylformamide, or dimethylacetamide with an amine X, which may be or may not be used in excess, in the presence or absence of an additional base such as triethylamine or Hunig's base to afford subject matter compounds of Formula (I).
• a suitable solvent such as but not limited to dichloromethane, dimethylformamide, or dimethylacetamide
• an amine X which may be or may not be used in excess, in the presence or absence of an additional base such as triethylamine or Hunig's base to afford subject matter compounds of Formula (I).
• an ⁇ -aminoalkanoic acid is suitably activated using an agent such for example but not limited to as l,r-carbonyldiimidazole in a solvent such as for example dichloromethane, dimethylformamide or mixtures thereof and reacted with a suitable heterocyclic amine to afford subject matter compounds of Formula (I).
• an agent such for example but not limited to as l,r-carbonyldiimidazole in a solvent such as for example dichloromethane, dimethylformamide or mixtures thereof and reacted with a suitable heterocyclic amine to afford subject matter compounds of Formula (I).
• an ⁇ -aminoalkanoic acid 5 is suitably activated using an agent such for example but not limited to as l,r-carbonyldiimidazole in a solvent such as for example dichloromethane, dimethylformamide or mixtures thereof and reacted with a suitable bromoheterocyclic amine to afford bromoheteroarylamides of formula 7, which are then reacted further under cross- coupling conditions, for example Suzuki conditions, to afford subject matter compounds of Formula (I).
• an agent such for example but not limited to as l,r-carbonyldiimidazole in a solvent such as for example dichloromethane, dimethylformamide or mixtures thereof and reacted with a suitable bromoheterocyclic amine to afford bromoheteroarylamides of formula 7, which are then reacted further under cross- coupling conditions, for example Suzuki conditions, to afford subject matter compounds of Formula (I).
• Scheme 5 shows one possible route towards the synthesis of chain-substituted acids 5, precursors to compounds of Formula (I)
• an alkyl-substituted malonic acid diester it treated with base, such as for example but not limited to sodium hydride in a solvent such as tetrahydrofurane or dimethylformamide and reacted with an ⁇ , ⁇ -dihaloalkane.
• the disubstituted malonic acid diester thus obtained is hydrolysed and mono-decarboxylated by treatement with a strong acid, such as for example hydrobromic acid. Esterification is then carried out, for example by treatement with methanol and a catalytic amount of acid. Substitution of the co-halogen may be accomplished by the use of a suitable amine heating in a solvent like toluene, but not limited to this solvent.
• hydrolysis of the ester function with an aqueous base affords intermediates of formula 5 which can be activated as described to afford compounds of Formula (I).
• the compounds of Formula (I), their optical isomers or diastereomers can be purified or separated according to well-known procedures, including but not limited to chromatography with a chiral matrix and fractional crystallisation.
• HPLC-MS analyses were performed with a Waters 2795 separation module equipped with a Waters Micromass ZQ (ES ionisation) and Waters PDA 2996, using a Waters XTerra MS CI S 3.5 ⁇ m 2.1x50mm column.
• Preparative HLPC was run using a Waters 2767 system with a binary Gradient Module Waters 2525 pump and coupled to a Waters Micromass ZQ (ES) or Waters 2487 DAD, using a Supelco Discovery HS Cl 8 5.0 ⁇ m 10x21.2mm column
• Aryl or heteroaryl methyl carboxylate were commercially available or were synthesized according to the following standard procedure: the aryl or heteroaryl carboxylic acid (32 mmol) was dissolved in MeOH (40 niL) and sulfuric acid (ImL) was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated aqueous NaHCO3 solution. The organic phase was dried and evaporated under reduced pressure, and the crude was used without further purification.
• the reaction was then allowed to cool down to room temperature and the solid formed was filtered and then dissolved in water.
• the solution was then acidified with 2N HCl solution and at pH between 2-6 (depending on the ring substitution on the aryl/heteroaryl system) the product precipitated and was filtered off. If no precipitation occurred, the product was extracted with DCM.
• Aryl- or heteroaryl-carboxylic acid methyl esters are commercially available or were synthesized under the standard procedure, as described in general procedure Al .
• Yields were generally between 65 and 90%.
• POCl 3 (2 eq with respect to the aryl/heteroaryl acetophenone) were added dropwise to 4 molar equivalents of anhydrous DMF cooled down to O 0 C, at such a rate that the temperature did not exceed 1O 0 C.
• the acetophenone (1 eq) was then added dropwise and the reaction was allowed to reach room temperature.
• the reaction was then stirred for further 30' and then 0.4 mmol of hydroxylamine hydrochloride were added.
• the reaction was then heated up to 50°C, after which heating was removed and additional 4 eq. of hydroxylamine hydrochloride were added portionwise (at such a rate that the temperature never exceeded 120°C).
• the reaction was then stirred until the temperature of the mixture spontaneously decreased to 25°C.
• Water (100 mL) were then added and the mixture was extracted with diethyl ether. The organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was used for the next step without further purification.
• the product was prepared according to the general procedure for aminopyrazole synthesis (route Al) from 2-trifluoromethyl -benzoic acid methyl ester (3.1 g, 14.0 mmol, 1.0 eq). The crude was precipitated from HCl to give the title product as a yellow solid (2.8 g, yield: 94%).
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2).
• the crude was purified through Si column (eluent: DCM) and dried to give the title product (0.6 g, 20% Yield).
• the product was prepared according to the general procedure for aminopyrazole synthesis (route Al), refluxing the mixture overnight and then for 2 h at 110°C.
• the crude product was extracted with DCM and used in the following step without further purification (2.2 g, yield: 76%).
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2).
• the crude was purified through Si column (eluent: DCM) and washed with water, extracted and dried to give the title product (0.25 g, yield 10%).
• the product was prepared according to the general procedure for aminopyrazole synthesis (route Al) from 2-chloro-4-fluoiO-benzoic acid methyl ester (0.7 g, 3.7 mmol, 1.0 eq).
• the crude product was extracted with DCM and used in the following step without further purification (0.4 g, yield: 60%).
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2). The crude was dissolved in DCM, washed with sat NaHCO3, extracted and dried to give the title product (0.12 g, yield 26%).
• the product was prepared according to the general procedure for aminopyrazole synthesis (route Al) from 5-tert-Butyl-thiophene-2-carboxylic acid methyl ester (3.0 g, 15.0 mmol, 1.0 eq).
• the crude product was extracted with DCM and used in the following step without further purification (2.7 g, yield: 86%).
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2). The crude was washed with water and precipitated to give the title product (2.7 g, yield 91%).
• the product was prepared according to the general procedure for aminopyrazole synthesis (route Al) from 3-Chloro-2-methyl-benzoic acid methyl ester (3.1 g, 16.8 mmol, 1.0 eq).
• the crude product was precipitated form water and used in the following step without further purification (2.4 g, yield: 74%).
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2).
• the crude product was purified through SiO 2 column (20 g) with gradient elution from 100% EtOAc to EtOAc-MeOH 80:20.
• the title product (1.3 g, yield 50%) was obtained.
• the product was prepared according to the general procedure for aminopyrazole synthesis (route Al) from 2-ethyl-benzoic acid methyl ester (2.9 g, 17.6 mmol, 1.0 eq).
• the crude product was extracted with DCM as a yellow oil and used in the following step without further purification (2.8 g, yield: 92%).
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2).
• the crude product was purified through SiO 2 column (20 g) with gradient elution from 100% EtOAc to EtOAc-MeOH 80:20.
• the title product (1.2 g, yield 40%) was obtained
• the product was prepared according to the general procedure for aminopyrazole synthesis (route Al) from 4-methoxy-benzoic acid methyl ester (3.0 mL, 18.0 mmol, 1.0 eq), NaH (1.4 g, 36.0 mmol, 2.0 eq) and propionitrile (6.1 mL, 84.9 mmol, 4.7 eq).
• the crude was purified through Si-column (eluent exane/ethyl acetate) to give 2.1 g of title product (yield: 62%).
• the product was prepared according to the general procedure for aminopyrazole synthesis (route Al) from 4-trifluoromethyl ⁇ benzoic acid methyl ester (3.0 g, 14.7 mmol, 1.0 eq), NaH (1.2 g, 29.4 mmol, 2.0 eq) and propionitrile (4.9 niL, 69.4 mmol, 4.7 eq).
• the crude product was extracted with DCM and used in the following step without further purification (3.2 g, yield: 96%),
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2). The crude product was washed with basic water and dried, and the title product (2.8 g, yield 84%) was used without further purification
• the product was prepared according to the general procedure for aminopyrazole synthesis from 4-cyclopropylmethoxy-2-methyl-benzoic acid methyl ester (route Albis), 0.54 g of the title product was extracted from water and dried (yield 69%) and used directly for the next step.
• the product was prepared according to the general procedure from 3-Chloro- 4-cyclopropylmethoxy-benzoic acid methyl ester (route Albis). 0.74 g of the title product was extracted from water and dry (yield 81 %) and used directly for the next step.
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2).
• the crude product was purified through SiO 2 column (gradient elution from Ethyl Acetate-cycloexane 1 : 1 to Ethyl Acetate-MeOH 90:10). 650 mg of the title product (yield 52%) were obtained.
• the product was prepared according to the general procedure (route A Ibis). The mixture was acidified with HCl IM and the organic phase separated and dried, to give 0.79 g of the title product (yield 79%) which was used directly for the next step.
• the product was prepared according to the general procedure (route Albis). The mixture was acidified with HCl IM and the organic phase separated and dried, to give 0.91 g of the title product (yield 90%) which was used directly for the next step.
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2).
• the crude product was purified through SiOo column (gradient elution from EtOAc-cycloexane 1 :1 to Ethyl Acetate:MeOH 90: 10). 750 mg of the title product (yield 79%) were obtained.
• the product was prepared according to the general procedure (route A Ibis). The mixture was acidified with HCl IM and the organic phase separated and dried, to give 1.24 g of the title product (yield 99%) which was used directly for the next step.
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2).
• the crude product was purified through SiO 2 column (gradient elution from EtOAc-cycloexane 1 : 1 to Ethyl Acetate:MeOH 90:10). 220 mg of the title product (yield 50%) were obtained.
• the product was prepared according to the general procedure for aminopyrazole synthesis (route Al) from pyridine-2-carboxylic acid methyl ester (3.0 g, 21.9 mmol, 1.0 eq). The crude was precipitated from HCl to give the title product as a solid (2.2 g, yield: 69%) which was used directly for the next step.
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2).
• the crude product was dissolved in EtOAc, washed with NaHCO 3 , dried and evaporated. NMR analysis showed that a major portion of the crude mixture was still in the opened form: the mixture was then dissolved in CH 3 COOH and heated at 8O 0 C overnight, to allow for ring closure of the opened form.
• the product was then recovered as the acylated form, which was de-acylated stirring with HCl 6N at 6O 0 C overnight obtaining the title product (0.816 g, yield 60%).
• the product was prepared according to the general procedure for aminopyrazole synthesis (route Al bis) from 3-difluoromethoxy-benzoic acid methyl ester (1.5 g, 7.4 mmol, 1.0 eq). The crude was precipitated by addition of aqueous HCl to give the product which was used directly for the next step.
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2).
• the crude product was purified through Si-column with gradient elution from 100% EtOAc to EtOAc-MeOH 90: 10. 1.45 g of title product (yield 87%) was obtained.
• the product was prepared according to the general procedure for ⁇ -aminoester synthesis (route Cl). After filtration of the excess 2-methyl ⁇ yi ⁇ olidine 5 the organic phase was concentrated under reduced pressure to give 4.1 g of the aminoester as an oil (yield 99%) which was used in the next step without further purification.
• Homomorpholine (1.0 g, 7.3 mmol, 1.2 eq) was dissolved in toluene (15 mL) and 4-bromo-2-methyl-butyric acid methyl ester (0.9 g, 6.1 mmol, 1.0 eq) was added and the reaction stirred at reflux for 3 hours. Removal of the solvent and of the excess amine at reduced pressure gave the methyl ester as an oil.
• the crude product was diluted with H2O (10 mL) and MeOH (2 mL) and 1.0M NaOH aq solution (0.3 g, 7.0 eq) was added and the reaction stirred at reflux for 18 hours. After cooling to room temperature, the mixture was concentrated at reduced pressure to remove the organic solvent and the water.
• Acetyl guanidine (2.6 g, 25.7 mmol, 3.0 eq) was dissolved in anhydrous DMF (40 mL) and 2-bromo-l-(4-trifluoromethoxy-phenyl)-ethanone (2.4 g, 8.6 mmol, 1.0 eq) was added; the mixture ⁇ vas stirred at room temperature for 4 days. DMF was removed under reduced pressure, the residue was washed with water, filtered and dried over sodium sulphate; after crystallization from MeOH 0.7 g of the title compound were recovered (yield 30%).
• 5-Bromo-pentanoic acid [5-(4-methoxy-phenyl)-lH-pyrazol-3-yl]-amide (0.106 g, 0.6 mmol) is dissolved in DMF (2 mL), sodium iodide (0.045g, 0.6 mmol) is added followed by 4-methylpiperidine (0.054 mL, 1.5 mmol) and diisopropylethylamine (0.052 mL, 0.6 mmol, 1 eq). The reaction is stirred under N 2 at + 50°C for 18 hrs.
• Bromopyrazole is mixed with K 2 CO 3 and KI in 10 volumes of acetone at room temperature and N-acetylhomopiperazine was added over 1 hr. The reaction mixture was stirred until the reaction was complete. The mixture was filtered, removing the inorganics, washed with acetone and distilled to 2 volumes. The freebase was extracted into methyl THF/EtOH and washed with NaCl and NaHCO 3 . The solvent was replaced with EtOH, a strength of the solution was determined, and 0.93 eq of HCl based on the available freebase was added to a mixture of acetone, ethanol and water. Careful monitoring of the pH yielded crystalline product in a 70% overall yield and the desired form 1. d) Fourth approach di) 5-(4-methoxy-phenyl-lH-pyrazol-3-ylamine
• the 2-methoxy derivative was purified by SiO 2 chromatography, eluting with a DCM/MeOH gradient (from 100% DCM to 90/10 DCM/MeOH); the 3-methoxy derivative was triturated with Et 2 O. Yields were generally 65-90%. dii) 5-bromo-pentanoic acid [5-(4-methoxy-phenyl)-lH-pyrazol-3-yl] amide
• N-acetylhomopiperazine (0.062 kg, 0.057 L, 0.434 mol) was added via addition funnel to the reactor over a minimum of 45 min., maintaining the temperature in the range of 25-30 0 C.
• the addition funnel was rinsed with 0.05 L acetone.
• a white mixture persisted.
• the mixture was stirred (235 rpm) in the range of 25-30 0 C for a minimum of 16 h, forming a white/yellow mixture.
• the reaction progress was monitored by HPLC and was considered complete when there was ⁇ 2% of the starting material (bromopyrazole) and ⁇ 2% of the iodopyrazole present.
• a homogeneous 5% solution of sodium bicarbonate (0.03 kg) in water (0.57 L) at 25°C was used to wash organic layer, stirring for a minimum of 5 min. at 10-15°C.
• the agitation was stopped to allow the layers to settle, the product being in the upper layer.
• the layers were separated, keeping any emulsion in the upper organic layer.
• the organic layer was retained and concentrated to a volume of 0.35 L, forming a hazy solution.
• the mixture was chased with ethanol to remove residual water.
• a solution of 5% HCl (0.042 kg, 0.036 L) in acetone (0.174 L) and alcohol solution (0.0174 L of ethanol: acetone (91 :9) v/v) was prepared and stirred until homogeneous at 1O 0 C.
• 0.05 L of water was added to form a clear solution.
• One third of the 5% HCl solution (0.076 L) was added to the reactor over a minimum of 20 min., maintaining the temperature in the range of 20- 25 0 C.
• a second third of the 5% HCl solution (0.076 L) was then added to the reactor over a minimum of 20 min., maintaining the temperature in the range of 20-25 0 C.
• the contents of the reactor were seeded with 75 mg of 5-(4-acetyl-[l ,4]diazepan-l- yl)-N-[5-(4-methoxy-phenyl)-lH ⁇ pyrazol-3-yl]-pentanamide HCl (e.g., Form 1), followed by the addition of the last third of 5% HCl solution (0.076 L) over a minimum of 20 min., maintaining the temperature in the range of 20-25 0 C. Another 0.08 equiv. of the 5% HCl solution (0.023 L) was then added to the reactor over a minimum of 30 min., maintaining the temperature in the range of 20-25 0 C. Judicious monitoring of pH was performed to attain the desired pH range of 5.2-5.8.
• the mixture was stirred at 20-25°C for a minimum of Ih, forming a thin suspension.
• Acetone (0.6 L) was added over a minimum of 60 min., maintaining the temperature in the range of 20-25 0 C.
• the mixture was stirred at 20-25°C for a minimum of 60 min.
• Acetone (1.5 L) was added to the reactor over a minimum of 3 hr., maintaining the temperature in the range of 20-25 0 C, forming a thick suspension.
• the mixture was then stirred at 20-25 0 C for a minimum of 12 h. Crystallization was considered complete when there was ⁇ 20% of the product present in the mother liquor.
• the present Example describes the preparation of the hydrochloride salt form of 5-(4-Acetyl-[l,4]diazepan-l-yl)-pentanoic acid [5-(4-methoxy-phenyl)-2H- pyrazol-3-yl]-amide.
• the hydrochloric acid salt form readily adopted a solid form. Indeed, at least four different crystalline forms (i.e., polymorphs) were observed for the hydrochloric acid salt form (see below).
• Differential scanning calorimetry data were collected for each solid form achieved using a DSC (TA instruments, model Ql OOO) under the following parameters: 50 niL/min purge gas(N 2 ); scan range 40 to 200°C, scan rate 10°C/min.
• Thermogravimetric analysis data were collected using a TGA instruments (Mettler Toledo, model TGA/SDTA 85Ie) under the following parameters: 40 ml/min purge gas(N 2 ); scan range 30 to 25O 0 C, scan rate 10°C/min.
• X-ray data were acquired using an X-ray powder diffractometer (Bruker-axs, model DS advance) having the following parameters: voltage 40 kV, current 40.0 mA, scan range (2 ⁇ ) 5 to 30°, scan step size 0.01 °, total scan time 33 minutes, VANTEC detector, and antiscattering slit 1 mm.
• Figures 1-7 show characterization data for hydrochloride salt forms.
• the hydrochloride salt was polymorphic, adopting crystalline forms exhibiting DSC endotherms at 119°C (Form III), 127 0 C (Form IV), 167 0 C (Form II), and 186°C (Form I).
• Another form, potentially an ethanol solvate, exhibited multiple endotherms, corresponding to 1) desolvation at about 100 0 C, 2) Form I at about 183°C, and 3) possibly another polymorph at about 200 0 C.
• the Crystal Form Table below illustrates certain characteristics of observed hydrochloride salt crystal forms: Crystal Form Table
• Form I (186°C) is relatively non-hygroscopic, gaining only about 0.5% moisture when equilibrated at RH less than or equal to 70%. At 70-100% RH, Form I gains at least about 12% moisture, but loses it without significant hysteresis on decreasing RH. Evidence of a hydrochloride hydrate was not observed.
• the present Example describes characterization of two surprisingly non-hygroscopic crystal forms (Forms I and II, as described above) of a hydrochloride salt of 5-(4-Acetyl-[l,4]diazepan-l-yl)-pentanoic acid [5-(4-methoxy- phenyl)-2H-pyrazol-3-yl]-amide:
• Form I picks up moisture at relative humidity (RH) of about 50% and absorbs up to about 2% water eventually (90% RH) and loses the water as RH decreases ( ⁇ 50%).
• RH relative humidity
• Form I also exhibits characteristic X-ray peaks at 2 ⁇ of 15.3° and 21.9°, plus or minus about 0.3°, depending upon the machine and measurement method utilized.
• Form II picks up moisture at RH of about 20% and absorbs up to 7% water eventually (RH of 90%) and holds 2% at low RH (0%).
• Form II also exhihbits characteristic X-ray peaks at 2 ⁇ of 20.2° and 24.9°, plus or minus about 0.3°, depending upon the machine and measurement method utilized.
• Differential scanning calorimetry data were collected for each solid form achieved using a DSC (TA instruments, model QlOOO) under the following parameters: 50 mL/min purge gas(N 2 ); scan range 40 to 200 0 C, scan rate 10°C/min.
• Thermogravimetric analysis data were collected using a TGA instruments (Mettler Toledo, model TGA/SDTA 85 Ie) under the following parameters: 40 ml/min purge gas(N 2 ); scan range 30 to 250 0 C, scan rate 10°C/min.
• X-ray data were acquired using an X-ray powder diffractometer (Bruker-axs, model D8 advance) having the following parameters: voltage 40 kV, current 40.0 mA, scan range (2 ⁇ ) 3.7 to 30°, scan step size 0.01 °, total scan time 33 minutes, VANTEC detector, and anti scattering slit 1 mm.
• the present Example describes the preparation of crystal form I of the hydrochloride salt of 5-(4-Acetyl-[l ,4]diazepan-l-yl)-pentanoic acid [5-(4-methoxy- phenyl)-2H-pyrazol-3-yl]-amide.
• a seed of crystal form I of the hydrochloride salt of 5-(4-Acetyl- [l,4]diazepan-l-yl)-pentanoic acid [5-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-amide was added. 0.18 ml diluted HCl solution was added slowly. Around two minutes later, 0.18 ml diluted HCl solution was added slowly. Around two minutes later, another 0.18 ml diluted HCl solution was added slowly. The mixture was heated to about 40-50°C, and then was left at room temperature while stirring overnight. The crystals were filtered and washed with 1.5 ml acetone, and were dried at 45 0 C for about 6 hours.
• the product was prepared according to the general synthetic method for the one-pot synthesis of ⁇ -amino-alkanoic acid (lH-pyrazol-3-yl-5-aryl)-amides.
• the crude product was purified with SiO2 column (5 g) with gradient elution from 100% DCM to DCM-NH3 (2N MeOH solution) 95 :5.
• the product was prepared according to the general procedure for amjnopyrazole synthesis (route Al).
• the product was prepared according to the general synthetic method for the one-pot synthesis of ⁇ -amino-alkanoic acid (lH-pyrazol-3-yl-5-aryl)-amides.
• the crude product was purified with SiO2 column (2 g) with gradient elution from 100% DCM to DCM-NH3 (2N MeOH solution) 95:5.
• the product was prepared according to the general synthetic method for the one-pot synthesis of ⁇ -amino-alkanoic acid (lH-pyrazol-3-yl-5-aryl)-amides.
• the product was prepared according to a modification of general route Al .
• methyl-3-fluorobenzoate (3 g, 18 mmol) in dry toluene (25 niL) under N 2 .
• NaH 50-60% dispersion in mineral oil, 1.44 g, 36 mmol
• the product was prepared according to the general synthetic method for the one-pot synthesis of ⁇ -amino-alkanoic acid (lH-pyrazol-3-yl-5-aryl)-amides.
• a solution of 5-bromovaleryl chloride (0.125 mL, 0.94 mmol) in dry DMA (1 niL) was cooled to -1O 0 C (ice/water bath) under N 2 ; 5-(3-Fluoro-phenyl) ⁇ 2H ⁇ pyrazol-3- ylamine (177 mg, 0.94 mmol) and diisopropylethylamine (0.324 mL, 1.88 mmol) in dry DMA (1 ml) were added.
• the product was prepared according to a modification of route Al .
• the product was prepared according to a modification of route A2. To a solution of 3-oxo-3-pyridin-4-yl-propionitrile (1.86 g, 12.74 mmoL) in absolute EtOH (35 mL) hydrazine monohydrate (0.74 mL, 15.29 mmol) was added and the reaction was heated at reflux for 2 hours. The reaction mixture was then allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The crude product obtained was washed with ether to afford the title compound (yield: 39%).
• the product was prepared according to the general synthetic method for the one-pot synthesis of ⁇ -amino-alkanoic acid (lH-pyrazol-3-yl-5-aryl)-amides.
• a solution of 5-bromovaleryl chloride (0.125 niL, 0.94 mmol) in dry DMA (1 mL) was cooled to -1 O 0 C (ice/water bath) under N 2 ;
• 5-Pyridin-4-yl-lH-pyrazol-3-ylamine 151 mg. 0.94 mmol
• diisopropylethylamine 0.324 mL, 1.88 mmol
• dry DMA (1 ml) were added.
• the reaction was left stirring for Ih at O 0 C and then azepane (0.265 mL. 2.35 mmol) and NaI (0.94 mmol, 1 eq) were added.
• the product was prepared according to the general synthetic method for the one-pot synthesis of ⁇ - amino -alkanoic acid (lH-pyrazol-3-yl-5-aryl)-amides.
• a solution of 5-bromohexanoyl chloride (0.144 mL, 0.94 mmol) in dry DMA (1 mL) was cooled to -1 O 0 C (ice/water bath) under N 2 ; 5-(4-methoxy-phenyl)-lH-pyrazol-3- ylamine (178 nig, 0.94 mmol) and diisopropylethylamine (0.324 mL, 1.88 mmol) were added in dry DMA (1 ml).
• reaction mixture was heated at 6O 0 C until LC-MS analysis showed complete conversion of the bromo-intermediate, at which point the reaction was cooled down and the solvent was removed under reduced pressure. The residue was dissolved in DCM (2 mL) and washed with saturated Na 2 CO 3 solution.
• the product was prepared according to the general procedure for aminopyrazole synthesis (route Al), The mixture of methyl 2-methylbenzoate (3.0 mL, 20.0 mmol, 1.0 eq) and NaH (1.6 g 5 40.0 mmol, 2.0 eq) in dry toluene (20 niL) was heated at 8O 0 C and then propionitrile (6.7 mL, 94.4 mmol, 4.7 eq) was added dropwise: the reaction was heated for 18 hours. The crude product was dissolved in water and extracted with DCM 5 and it was used in the following step without further purification (3.04 g, yield: 88%).
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2).
• the crude product was purified through SiO2 column (20 g) with gradient elution from 100% ethyl acetate (EtOAc) to EtOAc-MeOH 80:20.
• EtOAc ethyl acetate
• the product was prepared according to the general procedure for aminopyrazole synthesis from 4-Cyclopropylmethoxy-3-fluoro-benzoic acid methyl ester (route Albis). 0.84 g of the title product was extracted from water and dried over sodium sulphate (yield 88%) and used directly for the next step.
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2).
• the crude product was purified through SiO2 column with gradient elution from 100% Ethyl Acetate to EtOAc-MeOFI 90: 10.
• the title product (576 mg, 65% yield) was obtained.
• the product was prepared according to the general synthetic method for the synthesis of ⁇ -amino-alkanoic acid (lH-pyrazol-3-yl-5-aryl)-amides via the amino acid route, starting from 5-(4-Cyclopropylmethoxy-3-fluoiO-phenyl)-2H-pyrazol-3- ylamine (123.5 mg, 0.5 mmol, 1.0 eq). 130 mg of title compound were recovered as its formate salt after preparative HPLC purification (67% yield).
• the product was prepared from 3-(4-isopropoxy-phenyl)-3-oxo-propionitrile according to general procedure for aminopyrazole synthesis (route A2).
• the solvent was removed under reduced pressure, water (10 mL) was added, and the title product (1.0 g, 94% yield) was precipitated as a vellow solid and used for the next step without further purification.
• the product was prepared according to the general procedure for aminopyrazole synthesis (route A Ibis) from 1 -ethyl- lH-indole-3-carboxylic acid methyl ester (860.0 mg, 4.2 mmol, 1.0 eq). 820.0 mg of the title product (yield 91 %) were obtained and used directly for the next step.
• the product was prepared according to general procedure for aminopyrazole synthesis (route A2) starting from 3-(l -ethyl-lH-indol-3-yl)-3-oxo-propionitrile (820 mg, 3.87 mmol, 1.0 eq). The solvent was removed under reduced pressure; the solid residue was washed with EtOH to obtain the title product (612 mg, 70% yield).
• the product was prepared according to the general synthetic method for the synthesis of ⁇ -amino-alkanoic acid (lH-pyrazol-3-yl-5-arylVamides via the amino acid route, starting from 5-(l-ethyl-lH-indol-3-yl)-2H-pyrazol-3-ylamine (99.0 mg, 0.5 mmol, 1.0 eq) and 4-pyrrolidin-l -yl-butyric acid (118 mg, 0.75 mmol).
• the crude product was purified via preparative HPLC; the title product (77.0 mg, 42% yield) was obtained as formate salt.
• the product was prepared according to the general procedure (route Albis). from 4-cyclopropylmethoxy-benzoic acid methyl ester (1.17 g, 5.9 mmol, 1.0 eq). The reaction was allowed to cool down to room temperature, the solid formed was filtered and dissolved in H 2 O. The solution was acidified to pH 4 and the solid formed was filtered, affording 1.2 g of 3-(4-cyclopropylmethoxy-phenyl)-3-oxo- propioniti ⁇ le that was used directly for the next step.
• the product was prepared according to the general synthetic method for the synthesis of ⁇ -amino-alkanoic acid (lH-pyrazol-3-yl-5-aryl)-amides via the amino acid route, starting from 5-(4-cyclopropylmethoxy-phenyl)-2H-pyrazol-3-ylamine (152.9 mg, 0.7 mmol, 1.0 eq) and 4-piperidin-l-yl-butyric acid (168 mg, 1.0 mmol, 1.5 eq).
• the crude product was purified via preparative HPLC; 72.0 mg of the title product (28% yield) was obtained as a formate salt.
• the product was prepared according to the general procedure for aminopyrazole synthesis from 872.0 mg (4.3 mmol, 1.0 eq) of 4-difluoromethoxy- benzoic acid methyl ester (route Albis). 818.5 mg of the title product (yield 90%) were used directly for the following step.
• the product was prepared according to the general procedure for aminopyrazole synthesis (route A2), The crude product was purified through SiO 2 column with gradient elution from 100% EtOAc to EtOAc-MeOH 80:20. The title product (826 mg, 59% yield) was obtained.
• the product was prepared according to the general synthetic method for the synthesis of ⁇ -amino-alkanoic acid (lH-pyrazol-3-yl-5-aryl)-amides via the amino acid route, starting from 5-(4-difluoromethoxy-phenyl)-2H-pyrazol-3-ylamine (149.0 mg, 0.7 mmol, 1.0 eq). 90.0 mg of title compound were recovered as its formate salt after preparative HPLC purification (35% yield).

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