US20110201623A1 - Crystalline Form Of A Cyclopropyl Benzamide Derivative - Google Patents

Crystalline Form Of A Cyclopropyl Benzamide Derivative Download PDF

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US20110201623A1
US20110201623A1 US13/029,362 US201113029362A US2011201623A1 US 20110201623 A1 US20110201623 A1 US 20110201623A1 US 201113029362 A US201113029362 A US 201113029362A US 2011201623 A1 US2011201623 A1 US 2011201623A1
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compound
crystalline form
disorder
2theta
angstroms
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Michael A. UCZYNSKI
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AstraZeneca AB
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    • C07—ORGANIC CHEMISTRY
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    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

Definitions

  • the present invention relates to crystalline forms of a compound (I), 4- ⁇ (1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl ⁇ -benzamide, particularly such as Form I, pharmaceutical formulations containing said compound and to the use of said active compounds in therapy.
  • the crystalline forms of 4- ⁇ (1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl ⁇ -benzamide are useful to treat at least one histamine H3 receptor associated condition.
  • the histamine H3 receptor is of current interest in developing new medicaments.
  • the H3 receptor is a presynaptic autoreceptor located both in the central and peripheral nervous systems, the skin, and in organs, such as, for example, the lung, the intestine, probably the spleen, and the gastrointestinal tract.
  • the H3 receptor has intrinsic, constitutive activity in vitro as well as in vivo (i.e., it is active in the absence of an agonist). Compounds acting as inverse agonists can inhibit this activity.
  • the histamine H3 receptor has been shown to regulate the release of histamine and also of other neurotransmitters, such as, for example, serotonin and acetylcholine.
  • histamine H3 ligands such as, for example, a histamine H3 receptor antagonist or inverse agonist may increase the release of neurotransmitters in the brain, whereas other histamine H3 ligands, such as, for example, histamine H3 receptor agonists may inhibit the biosynthesis of histamine, as well as, inhibit the release of neurotransmitters. This suggests that histamine H3 receptor agonists, inverse agonists, and antagonists could mediate neuronal activity. As a result, efforts have been undertaken to develop new therapeutics that target the histamine H3 receptor.
  • WO2009/024823 describes the synthesis of a number of cyclopropyl amide derivatives, such as, for example, 4-((trans)-2-[(4-cyclobutylpiperazin-yl)carbonyl]-cyclopropyl ⁇ -benzamide (enantiomer 1; Example 43).
  • One object of the present invention is to provide crystalline forms of compound (I), 4- ⁇ (1S, 2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl ⁇ -benzamide.
  • Another object of the present invention is to provide a crystalline form of compound (I), 4- ⁇ (1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl ⁇ -benzamide, as Form I.
  • Said compound (I) having a histamine receptor antagonist or inverse agonist effect at the H3 receptor which making them suitable to be formulated into pharmaceutical is formulations.
  • the present invention provides a crystalline form of compound (I), 4- ⁇ (1S, 2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl ⁇ -benzamide
  • One aspect of the invention relates to a crystalline form of compound (I), characterized in that said form has an XRDP pattern (Cu K ⁇ ) with at least one peak at about 18.3 °2Theta, when measured using radiation with a wavelength of about 1.54 angstroms.
  • Another aspect of the invention relates to a crystalline form of compound (I), characterized in that said form has an XRDP pattern (Cu K ⁇ ) with at least two peaks at about 4.9 and about 18.3 °2Theta, when measured using radiation with a wavelength of about 1.54 angstroms.
  • Yet another aspect of the invention relates to a crystalline form of compound (I), characterized in that said form has an XRDP pattern (Cu K ⁇ ) with at least three peaks at about 4.9, about 18.3 and about 20.4 °2Theta, when measured using radiation with a wavelength of about 1.54 angstroms.
  • Still another aspect of the invention relates to a crystalline form of compound (I), characterized in that said form has an XRDP pattern (Cu K ⁇ ) with at least four peaks at about 4.9, about 18.3, about 19.6 and about 20.4 °2Theta, when measured using radiation with a wavelength of about 1.54 angstroms.
  • a further aspect of the invention relates to a crystalline form of compound (I), characterized in that said form has an XRDP pattern (Cu K ⁇ ) with peaks at selected ° 2 Theta-values described above and with additional peaks at about 16.4 and about 16.6, °2Theta when measured using radiation with a wavelength of about 1.54 angstroms.
  • Yet a further aspect of the invention relates to a crystalline form of compound (I), characterized in that said form has an XRDP pattern (Cu K ⁇ ) with peaks at selected °2Theta-values described above and with an additional peak at about 5.3 °2Theta, when measured using radiation with a wavelength of about 1.54 angstroms.
  • Still a further aspect of the invention relates to a crystalline form of compound (I), characterized in that said form has an XRDP pattern (Cu K ⁇ ) with peaks at °2Theta-values selected from about 4.9, about 16.4, about 16.6, about 18.3, about 19.6 and about 20.4, when measured using radiation with a wavelength of about 1.54 angstroms.
  • Still a further aspect of the invention relates to a crystalline form of compound (I), characterized in that said form has an XRDP pattern (Cu K ⁇ ) with peaks at °2Theta-values selected from about 4.9, about 5.3, about 16.4, about 16.6, about 18.3, about 19.6 and about 20.4, when measured using radiation with a wavelength of about 1.54 angstroms.
  • Still a further aspect of the invention relates to a crystalline form of compound (I), characterized in that said form has an XRDP pattern (Cu K ⁇ ) with peaks at °2Theta-values selected from about 4.9, about 12.6, about 16.4, about 16.6, about 18.3, about 19.6, about 20.4, and about 23.2, when measured using radiation with a wavelength of about 1.54 angstroms.
  • Cu K ⁇ XRDP pattern
  • Still a further aspect of the invention relates to a crystalline form of compound (I), characterized in that said form has an XRDP pattern (Cu K ⁇ ) with peaks at °2Theta-values selected from about 4.9, about 5.3, about 9.0, about 12.6, about 16.4, about 16.6, about 18.3, about 19.6, about 20.4, and about 23.2, when measured using radiation with a wavelength of about 1.54 angstroms.
  • Cu K ⁇ XRDP pattern
  • Still a further aspect of the invention relates to a crystalline form of compound (I), is characterized in that said form has an XRDP pattern (Cu K ⁇ ) with peaks at from about 4.9, about 5.3, about 9.0, about 12.6, about 16.4, about 16.6, about 18.3, about 19.6, about 20.4, about 21.2, about 23.2 and about 24.6 °2Theta, when measured using radiation with a wavelength of about 1.54 angstroms.
  • Cu K ⁇ XRDP pattern
  • Yet still a further aspect of the invention relates to relates to a crystalline form of compound (I), characterized by the X-ray powder diffraction pattern essentially as shown in FIG. 1 .
  • Another embodiment relates to a crystalline form of compound (I) that has a DSC thermogram essentially as depicted in FIG. 2 .
  • a crystalline form of compound (I) has a DSC thermogram comprising an endothermic event with an onset temperature of about 225° C.
  • a crystalline form of compound (I) has a DSC thermogram comprising an endothermic event with a peak temperature of about 235° C.
  • DSC onset and peak temperatures as well as energy values may vary due to, for example, the purity of the sample and sample size and due to instrumental parameters, especially the temperature scan rate.
  • the DSC data presented are not to be taken as absolute values.
  • a person skilled in the art can set up instrumental parameters for a Differential scanning calorimeter so that data comparable to the data presented here can be collected according to standard methods, for example those described in Höhne, G. W. H. et al (1996), Differential Scanning calorimetry, Springer, Berlin.
  • the crystalline forms of compound (I) of the present invention may also exist as solvates, including hydrates.
  • the present invention also relates to the use of a crystalline form of compound (I), as hereinbefore defined.
  • a crystalline form of compound (I), as hereinbefore defined has one or more advantageous properties.
  • a crystalline form of compound (I) shows advantageous properties, such as, for example, a high melting point, a substantial lack of solvent (e.g., water) content, little or no weight loss on heating, and/or low hygroscopicity.
  • solvent e.g., water
  • such properties advantageously facilitate the manufacture, storage, formulation, and/or delivery of compound (I).
  • a crystalline form of compound (I), as described herein, for example Form I of compound (I) provide advantageous properties with regard to stability.
  • a substance can be expected to be more stable chemically in a crystalline state in comparison with the same substance in an amorphous state, as described in Haleblian and McCrone J. Pharm. Sci 1969, 58, pages 911-929, especially page 913.
  • This observation is common for small molecules (i.e. non-proteins) but not always true for macromolecules like proteins, as described in Pikal and Rigsbee, Pharm. Res. 1997, 14, pages 1379-1387, especially page 1379.
  • a crystalline state is thus beneficial for small molecules such as compound (I).
  • X-rays will be scattered by electrons in atoms in a substance. Crystalline material will diffract X-rays giving peaks in directions of constructive interference. The directions are determined by the crystal structure, including the size and shape of the unit cell. All diffraction peak °2Theta values disclosed and/or claimed herein refer to Cu K ⁇ -radiation. An amorphous (non-crystalline) material will not give such diffraction peaks. See e.g. Klug, H. P. & Alexander, L. E., X-Ray Diffraction Procedures For Polycrystalline and Amorphous Materials, 1974, John Wiley & Sons.
  • a pharmaceutical formulation comprising a crystalline form of the compound (I), such as Form I, for use in the prevention and/or treatment of conditions associated with the H3 receptor.
  • the formulation used in accordance with the present invention may be in a form suitable for oral administration, for example such as a tablet, pill, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for topical administration for example such as an ointment, patch or cream, for rectal administration for example such as a suppository and for other non-parenteral administration.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • topical administration for example such as an ointment, patch or cream
  • rectal administration for example such as a suppository and for other non-parenteral administration.
  • Suitable daily doses a crystalline form of the compound (I), such as Form I, in the treatment of a mammal, including human, are approximately 0.01 to 250 mg/kg bodyweight at per oral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration.
  • the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.
  • a crystalline form of compound (I), such as for example Form I, may be used on its own but will usually be administered in the form of a pharmaceutical formulation in which the active ingredient is in association with pharmaceutically acceptable diluents, excipients and/or inert carrier known to a person skilled in the art.
  • the pharmaceutical formulation may comprise from 0.05 to 99% w (percent by weight), for example from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
  • the invention further provides a process for the preparation of a pharmaceutical formulation of the invention which comprises mixing of a crystalline form of the compound (I), such as form I, as hereinbefore defined, with pharmaceutically acceptable diluents, excipients and/or inert carriers.
  • At least one crystalline form of the compound (I) described herein may be administered to a mammal, including human, to be used to modulate at least one histamine H3 receptor.
  • modulate refers to, for example, the activation (e.g., agonist activity) or inhibition (e.g., antagonist and inverse agonist activity) of at least one histamine H3 receptor.
  • at least one crystalline form of the compound (I) described herein may be administered to a mammal, including human, to be used as an inverse agonist of at least one histamine H3 receptor.
  • At least one crystalline form of the compound (I) described herein may be administered to a mammal, including human, to be used as an antagonist of at least one histamine H3 receptor. In another embodiment, at least one crystalline form of the compound (I) described herein may be used as an antagonist of at least one histamine H3 receptor. In yet another embodiment, at least one crystalline form of the compound (I) described herein may be used an antagonist of at least one histamine H3 receptor.
  • At least one crystalline form of the compound (I) described herein may be administered to a mammal, including human, to be used to treat one or more of a wide range of conditions or disorders in which modulating the histamine H3 receptor is beneficial. At least one crystalline form of the compound (I) described herein may administered to a mammal, including human, to be, for example, be useful to treat at least one disease of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system, or the endocrinological system.
  • Another embodiment provides a method for treating a disorder in which modulating the function of at least one histamine H3 receptor is beneficial comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of crystalline form of the compound (I).
  • One embodiment relates to the use of the crystalline form of a compound (I) in the manufacture of a medicament for the treatment of at least one disorder selected from schizophrenia, narcolepsy, excessive daytime sleepiness, obesity, attention deficit hyperactivity disorder, pain, neuropathic pain, Alzheimer's disease, cognition deficiency, and cognition deficiency associated with schizophrenia.
  • a further embodiment relates to a method for the therapy of at least one disorder selected from schizophrenia, narcolepsy, excessive daytime sleepiness, obesity, attention deficit hyperactivity disorder, pain, neuropathic pain, Alzheimer's disease, cognition deficiency, and cognition deficiency associated with schizophrenia, in a warm-blooded animal in need of such therapy, wherein the method comprises administering to the animal a therapeutically effective amount of a crystalline form of the compound (I).
  • a crystalline form of the compound (I) may be useful to treat at least one autoimmune disorder.
  • autoimmune disorders include, but are not limited to, for example, arthritis, skin grafts, organ transplants and similar surgical needs, collagen diseases, various allergies, tumors and viruses.
  • a crystalline form of the compound (I) may be useful to treat at least one psychiatric disorder.
  • Exemplary psychiatric disorders include, but are not limited to, for example, Psychotic Disorder(s) and Schizophrenia Disorder(s), such as, for example, Schizoaffective Disorder(s), Delusional Disorder(s), Brief Psychotic Disorder(s), Shared Psychotic Disorder(s), and Psychotic Disorder(s) Due to a General Medical Condition; Dementia and other Cognitive Disorder(s); Anxiety Disorder(s), such as, for example, Panic Disorder(s) Without Agoraphobia, Panic Disorder(s) With Agoraphobia, Agoraphobia Without History of Panic Disorder(s), Specific Phobia, Social Phobia, Obsessive-Compulsive Disorder(s), Stress related Disorder(s), Posttraumatic Stress Disorder(s), Acute Stress Disorder(s), Generalized Anxiety Disorder(s) and Generalized Anxiety Disorder(s) Due to a General Medical Condition; Mood Disorder(s), such as, for example, a) Depressive Disorder(s) (including but not limited to, for example, Major Depressive Disorder
  • a crystalline form of the compound (I) may be useful: i) to treat obesity or being overweight (e.g., promotion of weight loss and maintenance of weight loss), eating disorders (e.g., binge eating, anorexia, bulimia and compulsive), and/or cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non-essential food items); ii) to prevent weight gain (e.g., medication-induced or subsequent to cessation of smoking); and/or iii) to modulate appetite and/or satiety.
  • At least one solid form described herein may be suitable for treating obesity by reducing appetite and body weight and/or maintaining weight reduction and preventing rebound.
  • At least one solid form described herein may be used to prevent or reverse medication-induced weight gain, e.g., weight gain caused by antipsychotic (neuroleptic) treatment(s); and/or weight gain associated with smoking cessation.
  • a crystalline form of the compound (I) may be useful to treat at least one Neurodegenerative Disorder.
  • Exemplary Neurodegenerative Disorders include, but are not limited to, for example, conditions associated with cognitive disorder(s) or indications with deficit(s) in cognition is such as: dementia; incl. pre-senile dementia (early onset Alzheimer's Disease); senile dementia (dementia of the Alzheimer's type); Alzheimer's Disease (AD); Familial Alzheimer's disease; Early Alzheimer's disease; mild to moderate dementia of the Alzheimer's type; delay of disease progression of Alzheimer's Disease; neurodegeneration associated with Alzheimer's disease, Mild Cognitive Impairment (MCI); Amnestic Mild Cognitive Impairment (aMCI); Age-associated Memory Impairment (AAMI); Lewy body dementia; vascular dementia (VD); HIV-dementia; AIDS dementia complex; AIDS—Neurological Complications; Frontotemporal dementia (FTD); Frontotemporal dementia Parkinson's Type (FTDP); dementia pugilistica; dementia due to infectious agents or metabolic disturbances; dementia of degenerative origin; dementia-Multi-Infarc
  • a crystalline form of the compound (I) may be useful to treat at least one Neuroinflammatory Disorder including, but not limited to, for example, Multiple Sclerosis (MS), which includes, but is not limited to, for example, Relapse Remitting Multiple Sclerosis (RRMS), Secondary Progressive Multiple Sclerosis (SPMS), and Primary Progressive Multiple Sclerosis (PPMS); Parkinson's disease; Multiple System Atrophy is (MSA); Corticobasal Degeneration; Progressive Supranuclear Paresis; Guillain-Barré Syndrome (GBS); and chronic inflammatory demyelinating polyneuropathy (CIDP).
  • MS Multiple Sclerosis
  • RRMS Relapse Remitting Multiple Sclerosis
  • SPMS Secondary Progressive Multiple Sclerosis
  • PPMS Primary Progressive Multiple Sclerosis
  • Parkinson's disease Multiple System Atrophy is
  • MSA Corticobasal Degeneration
  • Progressive Supranuclear Paresis Progressive Supranuclear Paresis
  • GBS Guillain-Barré Syndrome
  • CIDP chronic inflammatory demyelinating polyn
  • a crystalline form of the compound (I) may be useful to treat at least one Attention-Deficit and Disruptive Behavior Disorder.
  • Attention-Deficit and Disruptive Behavior Disorders include, but are not limited to, for example, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), and affective disorders.
  • ADD attention deficit disorder
  • ADHD attention deficit hyperactivity disorder
  • affective disorders include, but are not limited to, for example, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), and affective disorders.
  • a crystalline form of the compound (I) may be useful to treat pain, including acute or chronic pain disorders including but not limited to, for example, Widespread pain, Localized pain, Nociceptive pain, Inflammatory pain, Central pain, Central and peripheral neuropathic pain, Diabetic neuropathic pain, Central and peripheral neurogenic pain, Central and peripheral neuralgia, Low back pain, Postoperative pain, Visceral pain, and Pelvic pain; Allodynia; Anesthesia dolorosa; Causalgia; Dysesthesia; Fibromyalgia; Hyperalgesia; Hyperesthesia; Hyperpathia; Ischemic pain; Sciatic pain; Burn-induced pain; Pain associated with cystitis including, but not limited to, interstitial cystitis; Pain associated with multiple sclerosis; Pain associated with arthritis; Pain associated with osteoarthritis; Pain associated with rheumatoid arthritis; Pain associated with pancreatitis; Pain associated with psoriasis; Pain associated with fibromyalgia; Pain
  • a crystalline form of the compound (I) may be useful to treat at least one of the following disorders Autism, Dyslexia, Jetlag, Hyperkinesias, Dystonias, Rage outbursts, Muscular Dystrophy, Neurofibromatosis, Spinal Cord Injury, Cerebral Palsy, Neurological Sequelae of Lupus and Post-Polio Syndrome.
  • a crystalline form of the compound (I) may be used for the manufacture of a medicament for the treatment of at least one autoimmune disorder, psychiatric disorder, obesity disorder, eating disorder, craving disorder, neurodegenerative disorder, neuroinflammatory disorder, Attention-Deficit and Disruptive Behaviour Disorder, and/or pain disorder described hereinabove.
  • a crystalline form of the compound (I) may be used for the treatment of at least one disorder selected from cognitive deficits in schizophrenia and Alzheimer's disease.
  • One embodiment of the invention relates to the prevention and/or treatment of Alzheimer's Disease, especially the use in symptomatic treatment of mild to moderate Alzheimer's Disease or in the treatment of mild to moderate dementia of Alzheimer type.
  • inventions relate to the prevention and/or treatment of disorders selected from the group consisting of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD) and affective disorders, wherein the affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, and dysthymia.
  • ADD attention deficit disorder
  • ADHD attention deficit hyperactivity disorder
  • affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, and dysthymia.
  • ADD attention deficit disorder
  • ADHD attention deficit hyperactivity disorder
  • affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, and dysthymia.
  • MDD major depressive disorders
  • Another aspect provides a method for treating at least one autoimmune disorder, psychiatric disorder, obesity disorder, eating disorder, craving disorder, neurodegenerative disorder, neuroinflammatory disorder, attention-deficit and disruptive behaviour disorder, and/or pain disorder in a warm-blooded animal, comprising administering to said animal in need of such treatment a therapeutically effective amount of a crystalline form of the compound (I).
  • Yet another aspect provides a method for treating at least one disorder selected from cognitive deficits in schizophrenia, narcolepsy, excessive daytime sleepiness, obesity, attention deficit hyperactivity disorder, pain, neuropathic pain, and Alzheimer's disease in a warm-blooded animal, comprising administering to said animal in need of such treatment a therapeutically effective amount of a crystalline form of the compound (I).
  • Yet another aspect provides a method for treating cognitive deficits in schizophrenia in a warm-blooded animal, comprising administering to said animal in need of such treatment a to therapeutically effective amount of a crystalline form of the compound (I).
  • Yet another aspect provides a method for treating obesity in a warm-blooded animal, comprising administering to said animal in need of such treatment a therapeutically effective amount of a crystalline form of the compound (I).
  • Yet another aspect provides a method for treating narcolepsy in a warm-blooded animal, comprising administering to said animal in need of such treatment a therapeutically effective amount of a crystalline form of the compound (I).
  • Yet another aspect provides a method for treating excessive daytime sleepiness in a warm-blooded animal, comprising administering to said animal in need of such treatment a therapeutically effective amount of a crystalline form of the compound (I).
  • One embodiment of the invention relates to the prevention and/or treatment of Alzheimer's Disease, especially the use in the delay of the disease progression of Alzheimer's Disease.
  • inventions relate to the prevention and/or treatment of disorders selected from the group consisting of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD) and affective disorders, wherein the affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, and dysthymia.
  • ADD attention deficit disorder
  • ADHD attention deficit hyperactivity disorder
  • affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, and dysthymia.
  • ADD attention deficit disorder
  • ADHD attention deficit hyperactivity disorder
  • affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, and dysthymia.
  • MDD major depressive disorders
  • Still another aspect provides a method for treating Alzheimer's disease in a warm-blooded animal, comprising administering to said animal in need of such treatment a therapeutically effective amount of a crystalline form of the compound (I).
  • Still yet another aspect provides a method for treating attention deficit hyperactivity disorder in a warm-blooded animal, comprising administering to said animal in need of such treatment a therapeutically effective amount of a crystalline form of the compound (I).
  • Yet still another aspect provides a method for treating a pain disorder in a warm-blooded animal, comprising administering to said animal in need of such treatment a therapeutically effective amount of a crystalline form of the compound (I).
  • Yet still another aspect provides a method for treating neuropathic pain in a warm-blooded is animal, comprising administering to said animal in need of such treatment a therapeutically effective amount of a crystalline form of the compound (I).
  • the warm-blooded animal is a mammalian species including, but not limited to, for example, humans and domestic animals, such as, for example, dogs, cats, and horses. In one embodiment, the warm-blooded animal is a human.
  • Another aspect provides the use of a crystalline form of the compound (I) in therapy.
  • Another embodiment provides the use of a crystalline form of the compound (I) in the manufacture of a medicament for use in therapy.
  • Another aspect of the invention is wherein a compound of formula (I) as defined herein, or a pharmaceutical composition or formulation comprising a combination comprising such a compound of formula (I) is administered, concurrently, simultaneously, sequentially, separately or adjunct with another pharmaceutically active compound or compounds selected from the following:
  • the dose required for the therapeutic or preventive treatment of a particular disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • the dosage form and the dose of the medicament may vary and will depend on various factors such as, for example the individual requirement of the animal treated.
  • the above other pharmaceutically active compound may be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR; e.g., 64th ed. 2010) or approved dosage ranges and/or dosage described in published references or as otherwise determined by one of ordinary skill in the art.
  • PDR Physicians' Desk Reference
  • Dosages can be readily ascertained by those skilled in the art based on this disclosure and the knowledge in the art. Thus, the skilled person can readily determine the amount of crystalline form and optional additives, vehicles, and/or carriers in compositions and to be administered in methods provided herein.
  • the specific dose level and frequency of dosage for any particular subject may vary and generally depends on a variety of factors, including, but not limited to, for example, the dissolution and/or bioavailability of the solid form(s) described herein; species, age, body weight, general health, sex, and diet of the subject; mode and time of administration; rate of excretion; drug combination; and severity of the particular condition.
  • the term “therapy” also includes “prevention” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • disorder also includes “condition” unless there are specific indications to the contrary.
  • a first therapeutic agent which is a H3 inhibitor
  • a second therapeutic agent which is a NMDA-receptor antagonist selected from:
  • a first therapeutic agent which is a crystalline form of compound (I), 4- ⁇ (1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl ⁇ -benzamide, such as for example Form I, and (b) a second therapeutic agent, which is memantine;
  • a first therapeutic agent which is a H3 antagonist or inverse agonist
  • a second therapeutic agent which is a acetyl choline esteras inhibitor
  • a first therapeutic agent which is a crystalline form of compound (I), 4- ⁇ (1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl ⁇ -benzamide, such as for example Form I, and (b) a second therapeutic agent, which is a donepezil.
  • a first therapeutic agent which is a crystalline form of compound (I), 4- ⁇ (1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl ⁇ -benzamide, such as for example Form I, and (b) a second therapeutic agent, which is a rivastigmine.
  • a first therapeutic agent which is a crystalline form of compound (I), 4- ⁇ (1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl ⁇ -benzamide, such as for example Form I, and (b) a second therapeutic agent, which is a galantamine.
  • a first therapeutic agent which is a H3 inhibitor and (b) a second therapeutic agent, which is a voltage-gated calcium channel inhibitor selected from:
  • a first therapeutic agent which is a crystalline form of compound (I), 4- ⁇ (1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl ⁇ -benzamide, such as for example Form I, and (b) a second therapeutic agent, which is pregabalin.
  • a first therapeutic agent which is a crystalline form of compound (I), 4- ⁇ (1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl ⁇ -benzamide, such as for example Form I, and (b) a second therapeutic agent, which is gabapentin.
  • Such combination products employ the compound of this invention within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and/or the dosage described in the publication reference.
  • the compound of formula (I), 4- ⁇ (1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl ⁇ -benzamide, dissolved or as a slurry of amorphous material may be crystallised in a suitable solvent, such as, for example dimethylsulfoxide (DMSO), water or mixtures thereof.
  • suitable solvents for crystallisation are lower alcohols, such as, for example, methanol, ethanol, 1-propanol, 2-propanol. 1-butanol and water or mixtures thereof.
  • Crystallization of the compound of formula (I) from an appropriate solvent system, containing at least one solvent may be achieved by attaining supersaturation in a solvent system by solvent evaporation, by temperature decrease, and/or via the addition of antisolvent (i.e. a solvent in which the compounds of the invention are poorly soluble) and/or by a chemical reaction.
  • antisolvent i.e. a solvent in which the compounds of the invention are poorly soluble
  • An example of a suitable solvent is DMSO and an example of a suitable antisolvent is water.
  • Crystallisation temperatures and times depend upon the concentration in the solution and the solvent system used.
  • Crystallisation may also be initiated and/or effected by way of standard techniques, for example with or without seeding with crystals of the appropriate crystalline compound of the invention.
  • the crystalline form of a compounds of formula (I) may be isolated using techniques, which are well known to those skilled in the art, for example decanting, filtering or centrifuging.
  • the crystalline form of a compounds of formula (I) may be dried using standard is techniques, which are well known to those skilled in the art.
  • a crystalline form of compound of formula (I) may be further purified by column chromatography on silica eluting with a suitable organic solvent or a mixture of solvents, such as for example mixtures of dichloromethane and methanol optionally containing ammonia in methanol.
  • FIG. 1 shows an X-ray powder diffractogram (XRDP) pattern for Form I of Compound (I).
  • FIG. 2 shows a differential scanning calorimetry (DSC) thermogram for Form I of Compound (I).
  • the chiral purity of the product was analyzed on a chiral column with UV-detection (250 nm) using isocratic method (mobile phase: Heptane/EtOH (80/20)+0.1% Diethylamine) on Chiralpak AD-H, 4.6 ⁇ 150 mm, giving an enantiomeric purity of >99% ee.
  • the solid product obtained in the first method was analysed by XRPD.
  • a representative XRPD pattern is shown in FIG. 1 . Selected peaks are provided in Table 1.
  • the XRPD pattern confirmed the solid material to be Crystalline Form I.
  • the solid product obtained in the second and third method, respectively, were analysed by XRPD and a representative XRPD pattern as shown in FIG. 1 and with selected peaks as are provided in Table 1 were obtained.
  • the XRPD pattern confirmed the solid material to be Crystalline Form I.
  • XRPD X-Ray Powder Diffraction
  • a thin flat sample was prepared on a flat zero background plate made of silicon using a spatula.
  • the plate was mounted in a sample holder and rotated in a horizontal position during measurement.
  • a diffraction pattern was collected between 2°2theta and 40°2theta in a continuous scan mode. Total time for the scan was approximately 10 minutes.
  • an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as is equipment, sample preparation or machine used).
  • intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation.
  • persons skilled in the art of X-ray powder diffraction will realize that the relative intensities of peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used.
  • the skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer.
  • the surface planarity of the sample may also have a small effect.
  • the degree of crystallinity as determined by X-ray powder diffraction data is for example greater than about 10%, is for example greater than about 20%, is for example greater than about 30%, is for example greater than about 40%, is for example greater than about 50%, is for example greater than about 60%, such as greater than about 80%, particularly greater than about 90%, more particularly greater than about 95%.
  • the degree of crystallinity as determined by X-ray powder diffraction data is greater than about 98%, wherein the % crystallinity refers to the % by weight of the total sample mass which is crystalline.
  • a manual peak search was done preceded by an angle correction against NIST SRM 676 alumina ( ⁇ -Al 2 O 3 ) standard.
  • the measured relative intensities vs. the strongest peak are given as very strong (vs) above 50%, as strong (s) between 25 and 50%, as medium (m) between 10 and 25% and as weak (w) between 5 and 10% relative peak height.
  • DSC from 25° C. to 350° C. was performed under nitrogen in an aluminum sample cup with a perforated lid using a NETZSCH DSC 204 instrument.
  • the scan rate was 10° C. per is minute.
  • the sample size was less than 1 mg.
  • DSC onset and peak temperatures as well as energy values may vary due to, for example, the purity of the sample and sample size and due to instrumental parameters, especially the temperature scan rate.
  • the DSC data presented are not to be taken as absolute values.
  • a person skilled in the art can set up instrumental parameters for a Differential scanning calorimeter so that data comparable to the data presented here can be collected according to standard methods, for example those described in Höhne, G. W. H. et al (1996), Differential Scanning calorimetry, Springer, Berlin.
  • Hexyl lithium in hexane 21 L, 48.3 moles, 2.3 M
  • Intermediate B as a 2-MeTHF solution (33.6 moles, 30 L) was added during 20 min.
  • the scavenger was filtered off via a filter with activated charcoal or equivalent (pall-filter).
  • the vessel and the filter system were washed with 2-MeTHF (53 L).
  • a pale yellow liquid resulted.
  • NaCl (3.5 kg) in H 2 O (16.4 L) was added during 15 min. at such a rate so the inner temperature remained below 15° C.
  • the organic phase was washed with NaHSO 4 ⁇ H 2 O in H 2 O (2 ⁇ (2.87 kg+16.4 L)) and NaCl in H 2 O (3.5 kg+16.4 L).
  • 2-MeTHF and H 2 O were distilled off under vacuum until a volume 85-90% of the volume prior to distillation, approximately 8 L.
  • N-Boc-piperazine 46 g, 0.25 moles
  • EtOH 415 mL
  • Acetic acid 140 mL
  • cyclobutanone 26.5 g, 0.37 moles
  • NaBH(OAc) 3 80 g, 0.36 moles, 95% w/w was added in 20 portions is over 2 h.
  • EtOH 25 mL was used for rinsing.
  • the reaction mixture was left stirring for 2 h.
  • NAOH 296 g, 3.70 moles, 50% w/w
  • H 2 O 230 mL
  • 1 H NMR spectra were recorded in the indicated deuterated solvent at 400 MHz or 500 MHz.
  • the 400 MHz spectra were obtained using a Bruker av400 NMR spectrometer equipped with a 3 mm flow injection SEI 1 H/D- 13 C probe head with Z-gradients, using a BEST 215 liquid handler for sample injection, or using a Bruker DPX400 NMRor Bruker 500 MHz ultrashield spectrometer equipped with a 4-nucleus probehead with Z-gradients. Chemical shifts are given in ppm down- and upfield from TMS. Resonance multiplicities are denoted s, d, t, q, m and br for singlet, doublet, triplet, quartet, multiplet, and broad respectively.
  • Mass spectra were run using an automated system with electrospray (+ESI) ionization. Generally, only spectra where parent masses are observed are reported. The lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine or bromine is present).
  • LC-MS analyses were recorded on a Waters LCMS equipped with a Waters X-Terra MS, C8-column, (3.5 ⁇ m, 100 mm ⁇ 3.0 mm i.d.).
  • the mobile phase system consisted of A: 10 mM ammonium acetate in water/acetonitrile (95:5) and B: acetonitrile.
  • a linear gradient was applied running from 0% to 100% B in 4-5 minutes with a flow rate of 1.0 mL/min.
  • the mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode.
  • the capillary voltage was 3 kV and the mass spectrometer was typically scanned between m/z 100-700.
  • LC-MS analyses were recorded on a Waters 2790 LCMS equipped with a Phenomenex Luna C18 (5 ⁇ m, 50 ⁇ 4.6 mm i.d.)
  • the mobile phase system consisted of A: 10 mM ammonium formate (pH 4) in water and B: acetonitrile.
  • a linear gradient was applied running from 95% to 5% B in 5 minutes with a flow rate of 2.0 mL/min.
  • the mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode.
  • the capillary voltage was 3 kV and the mass spectrometer was typically scanned between m/z 100-700.
  • LC-MS analyses were recorded on a Agilent 1200 LCMS equipped with a Zorbax SB C8 (3.5 ⁇ m, 150 ⁇ 4.6 mm i.d.)
  • the mobile phase system consisted of A: 0.05% TFA in water and B: acetonitrile. A linear gradient was applied running from 10% to 90% B in 8 minutes with a flow rate of 1.0 mL/min.
  • the mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode. The capillary voltage was 3 kV and the mass spectrometer was typically scanned between m/z 100-700.
  • ESI electrospray ion source
  • ACN acetonitrile; aq: aqueous; br: broad; Bu: butyl; calcd: calculated; Celite®: brand of diatomaceous earth filtering agent, registered trader of Celite Corporation; d: doublet; dd: doublet of doublet; ddd: doublet of doublet of doublet; dddd: doublet of doublet of doublet of doublet; DMF: N,N-dimethyl formamide; DMSO: dimethyl sulfoxide; dq: doublet of is quartet; DSC: differential scanning calorimetry; dt: doublet of triplet; DVS: dynamic vapour sorption; EDC: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride; ESI: electrospray ionization; EtOAc: ethyl acetate; EtOH: ethanol; Et: ethyl; FT-IR: Fourier-transform inf
  • the H3 binding assay was used to evaluate the ability of a compound of formula (I) to inhibit [ 3 H]-N-a-methylhistamine under the conditions as described below: All binding assays were performed in a buffer consisting of 20 mmol/L Hepes, 100 mmol/L NaCl. The pH was set at 7.4 at room temperature. Liquid handling robots were used to prepare, in drug plates, 10 points dose response curves of the compound of formula (I) (3-fold serial dilutions, starting at 10 ⁇ mol/L).
  • the assay performed in 96-well plates, consisted of 100 ⁇ L, containing 20 ⁇ L of buffer alone for total binding (column #1), 20 ⁇ L of imetit (5 ⁇ ) for the non specific binding (column #2), 20 ⁇ L of the compound of formula (I) (5 ⁇ ) at varying concentrations (column #3 to #12), plus 20 ⁇ L of [3H]-N-a-Methylhistamine (25 000 dpm/well, 1.5 nmol/L) in all wells and finally 60 ⁇ L of membranes (20 ⁇ g of protein/well) mix is added to start the reaction.
  • Membranes and SPA beads (1000 ⁇ g/well) were mixed together and incubated for 30 minutes at room is temperature prior to the start of the assay. Eight wells (column #1) were used to define total binding and 1 ⁇ mol/L imetit (eight wells, column #2) define the non-specific binding. Plates were then mixed on an orbital mixer, incubated 90 minutes at room temperature, and then read on a Trilux 384TM counter.
  • [ 35 S]GTP ⁇ S binding assay was performed in a buffer consisting of 20 mmol/L Hepes, 100 mmol/L NaCl, 10 mmol/L MgCl 2 , 3 ⁇ g/mL saponine and 10 ⁇ mol/L GDP.
  • the pH was set at 7.4 at room temperature.
  • Liquid handling robots were used to prepare, in drug plates, 10 points dose response curves of the compound of formula (I) (3-fold serial dilutions, starting at 1 ⁇ mol/L for hH3 receptors and 10 ⁇ mol/L for rH3 receptors).
  • the assay performed in 96-well plates, consisted of 120 ⁇ L, containing 20 ⁇ L of R ⁇ MH (EC80, antagonist mode), 20 ⁇ L the compound of formula (I) at varying concentrations, 20 ⁇ L of the tracer [ 35 S]GTP ⁇ S (60000 dpm/well, 0.2 nmol/L) and finally 60 ⁇ L of membranes (10 ⁇ g of protein/well for hH3) mix is added to start the reaction. Membranes, SPA beads (125 ⁇ g/well) and GDP were mixed together and incubated for 30 minutes at room temperature prior to the start of the assay. Eight wells were used to define baseline and R ⁇ MH EC 80 (30 nmol/L for hH3 receptors) define the positive control. Plates were then mixed (2 minutes) on an orbital mixer, incubated 60 minutes at room temperature, and then read on a Trilux 384TM counter.

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US20100216812A1 (en) * 2009-02-20 2010-08-26 Astrazeneca Ab Cyclopropyl Amide Derivatives
US20110201622A1 (en) * 2010-02-18 2011-08-18 Collins Craig D Solid Forms Comprising A Cyclopropyl Amide Derivative
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SG183274A1 (en) 2012-09-27
CA2788444A1 (en) 2011-08-25

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