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WO2014015125A1 - Sels de dérivé aminodihydrothiazine condensé et applications associées - Google Patents

Sels de dérivé aminodihydrothiazine condensé et applications associées Download PDF

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Publication number
WO2014015125A1
WO2014015125A1 PCT/US2013/051056 US2013051056W WO2014015125A1 WO 2014015125 A1 WO2014015125 A1 WO 2014015125A1 US 2013051056 W US2013051056 W US 2013051056W WO 2014015125 A1 WO2014015125 A1 WO 2014015125A1
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Prior art keywords
amino
fluorophenyl
pyrazine
trifluoromethyl
fluoromethyl
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PCT/US2013/051056
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English (en)
Inventor
Yoko Ito
Ikuo Kushida
Branko MITASEV
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Eisai R&D Management Co., Ltd.
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Publication of WO2014015125A1 publication Critical patent/WO2014015125A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to new salts of a fused aminodihydrothiazine derivative and pharmaceutical uses thereof.
  • Alzheimer's disease is characterized by degeneration and loss of neurons as well as formation of senile plaques and neurofibrillary tangles.
  • a symptom-improving agent typified by an acetylcholinesterase inhibitor, and a fundamental remedy to inhibit progression of the disease has not yet been developed. It is necessary to develop a method for controlling the causative pathology in order to create a fundamental remedy for Alzheimer's disease.
  • ⁇ -proteins as breakdown products of amyloid precursor proteins (hereinafter referred to as APP) are highly involved in degeneration and loss of neurons and onset of symptoms of dementia.
  • ⁇ -proteins have, as main components, ⁇ 40 consisting of 40 amino acids and ⁇ 42 with two amino acids added at the C- terminal.
  • the ⁇ 40 and ⁇ 42 proteins are known to be highly prone to aggregation and to be the main components of senile plaques.
  • ⁇ 40 and ⁇ 42 are increased by mutations in APP and presenilin genes associated with familial Alzheimer's disease (Jonsson et al, Nature 201 , 488, 2 August, 96-99).
  • a compound that reduces production of ⁇ 40 and ⁇ 42 is predicted to inhibit disease progression or be a prophylactic agent for Alzheimer's type dementia (AD).
  • AD Alzheimer's type dementia
  • AD Alzheimer' s-type dementia
  • ⁇ 40 and ⁇ 42 amyloidogenic conditions
  • ⁇ deposition may be a causative factor in cognitive impairment associated with Down' s syndrome.
  • Another common co-morbidity in Down' s syndrome is diabetes, being seven times more likely in individuals with Down's syndrome than the general population, and this increased frequency may be attributed to a gene product of chromosome 21 , the triplication of all or some of which is characteristic of Down's syndrome (trisomy 21).
  • BACE2 inhibitors may be useful for the treatment of diabetes. Accordingly, a dual BACEl/2 inhibitor may provide an effective treatment for amyloid pathology and diabetes in the general or Down's syndrome populations.
  • Examples of other neurodegenerative diseases that might be treatable or preventable with a compound that reduces progression of ⁇ 40 and ⁇ 42 include cerebrovascular amyloid angiopathy (CAA), mild cognitive impairment (MCI), memory loss, presenile dementia, senile dementia, hereditary cerebral hemorrhage with amyloidosis, and other degenerative dementias such as dementias of mixed vascular and degenerative origin, dementia associated with supranuclear palsy, dementia associated with cortical basal degeneration, dementia associated with Parkinson's Disease (PD), and dementia associated with diffuse Lewy Body type of AD.
  • CAA cerebrovascular amyloid angiopathy
  • MCI mild cognitive impairment
  • MCI mild cognitive impairment
  • memory loss presenile dementia
  • senile dementia hereditary cerebral hemorrhage with amyloidosis
  • other degenerative dementias such as dementias of mixed vascular and degenerative origin, dementia associated with supranuclear palsy, dementia associated with cortical basal degeneration, dementia associated with
  • ⁇ 40 and ⁇ 42 Further conditions that might be treatable or preventable with a compound that reduces progression of ⁇ 40 and ⁇ 42 include type 2 diabetes, Creutzfield- Jakob Disease (CJD), peripheral nerve injury, peripheral neuropathy, progressive supra-nuclear palsy, stroke, amyotrophic lateral sclerosis (ALS), autoimmune diseases, inflammation, arterial thrombosis, anxiety disorders, psychotic disorders, epilepsy, seizures, convulsions, stress disorders, vascular amyloidosis, pain, Gerstmann-Straeussler-Scheinker syndrome, scrapie, encephalopathy, spino cerebellar ataxia, Wilson's Disease, Graves Disease, Huntington's Disease, Whipple's Disease, Kostmann Disease, glaucoma, hereditary cerebral hemorrhage with amyloidosis, cerebral hemorrhage with amyloidosis, vascular amyloidosis, brain inflammation, fragile X syndrome, stroke, Tourette'
  • ⁇ is produced by the cleavage of APP by beta-secretase (BACE1) and subsequently by gamma-secretase. For this reason, attempts have been made to create gamma-secretase and beta-secretase inhibitors in order to inhibit ⁇ production.
  • BACE1 beta-secretase
  • WO2009/09101 describes a series of fused aminodihydrothiazine derivatives having an ⁇ production inhibitory effect.
  • PCT/EP2012/050833 is N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a- tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine- 2-carboxamide free base.
  • the active compound In the manufacture of pharmaceutical products it is important that the active compound is in a form that can be conveniently manipulated and processed in order to obtain a commercially- viable manufacturing process. In this regard, the chemical stability and physical stability of the active compound are important factors.
  • the active compound and pharmaceutical compositions containing it must be capable of being effectively stored over long periods of time without exhibiting any significant change in physico-chemical characteristics (e.g. density, hygroscopicity and solubility).
  • Figure 1 X-Ray Powder Diffraction Pattern of N-(3-((4aS,5S,7aS)-2-amino-5- (trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide free base Form B Polymorph.
  • Figure 2 X-Ray Powder Diffraction Pattern of N-(3-((4aS,5S,7aS)-2-amino-5- (trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-fui [3,4-d][l,3]thiazin-7a-yl)-4- fluoi phenyl)-5-(fluoiOmethyl)pyrazine-2-carboxamide free base Form A Polymorph.
  • Figure 4 X-Ray Powder Diffraction Pattern of N-(3-((4aS,5S,7aS)-2-amino-5- (trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluoiOphenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono-malonate anhydrate.
  • Figure 5 DVS of N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a- tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine- 2-carboxamide mono-malonate anhydrate.
  • Figure 6 X-Ray Powder Diffraction Pattern of N-(3-((4aS,5S,7aS)-2-amino-5- (trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5 -(fluoromethyl)pyrazine-2-carboxamide mono-hippurate anhydrate.
  • Figure 7 DVS of N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a- tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine- 2-carboxamide mono-hippurate anhydrate.
  • Figure 8 Single Crystal X-ray Structure of N-(3-((4aS,5S,7aS)-2-amino-5- (trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5 -(fluoromethyl)pyrazine-2-carboxamide mono-malonate anhydrate.
  • Figure 9 Single Crystal X-ray Structure of N-(3-((4aS,5S,7aS)-2-amino-5- (trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fiuorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono-hippurate anhydrate.
  • N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro- 4H-furo[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2- carboxamide was generated using ChemBioDraw Ultra 11.0 or 12.0, and denotes the compound depicted in Figure A.
  • the present invention provides a salt which is N-(3-
  • malonate denotes a salt of malonic acid (CH 2 (COOH) 2 ). In the present specification this salt may be referred to as the "malonate salt”.
  • the malonate salt of the present invention has good physico-chemical properties and is suitable for pharmaceutical use.
  • the stoichiometric ratio of malonic acid and N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4- d] [1 ,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide in the malonate salt is approximately 1 :1, i.e. in the range 1 :0.9 to 1 : 1.1.
  • the salt of this embodiment may be referred to as the 'mono-malonate salt'.
  • the present invention encompasses solvates (e.g. a hydrate) of the malonate salt.
  • the malonate salt is an anhydrate (i.e. a crystalline phase that does not contain water).
  • a salt is an anhydrate and is non- hygroscopic if it has a water uptake value of less than 2% as measured by the increase in mass determined by Dynamic Vapor Sorption (DVS) from 5% to 95% relative humidity at 25 °C.
  • DVS Dynamic Vapor Sorption
  • the present invention provides a salt which is N-(3-
  • a mono- malonate salt which is an anhydrate and has a water uptake value of less than 1.5 % as measured by the increase in mass determined by DVS from 5%> to 95% relative humidity at 25 °C.
  • the malonate salt of the invention has crystalline properties.
  • the malonate salt is at least 50 % crystalline.
  • the malonate salt is at least 60%> crystalline; in a still further embodiment at least 70% crystalline; and in a yet further embodiment at least 80% crystalline.
  • the malonate salt is from 50%, 60%, 70%, 80% or 90% to 95% or 100% crystalline. Crystallinity can be estimated by conventional X-ray diffractometry techniques or differential scanning calorimetry.
  • a diffraction angle (20) in X-ray powder diffractometry may have an error margin of +/- 0.2°. Therefore, in embodiments of the present invention where diffraction angles are quoted, the margin of error for X-ray powder diffraction peaks (expressed in degrees is 2 ⁇ ) is +/- 0.2°. Unless otherwise stated, X-ray powder diffraction peaks quoted in the present specification were measured using X rays generated from a Cu target.
  • the present invention provides a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono-malonate anhydrate salt, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ +/- 0.2°): 16.2 and 18.5.
  • the present invention provides a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono-malonate anhydrate salt, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ +/- 0.2°): 9.2 and 18.5.
  • the present invention provides a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono-malonate anhydrate salt, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ +/- 0.2°): 9.2 and 16.2.
  • the present invention provides a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoiOmethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono-malonate anhydrate salt, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ +/- 0.2°): 9.2, 16.2 and 18.5.
  • the present invention provides a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono-malonate anhydrate salt, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ +/- 0.2°):
  • the mono-malonate anhydrate salt of the present invention displays good manufacturability of a standard suitable for use in pharmaceutical development.
  • the malonate salt of the present invention may be prepared by dissolving or suspending N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H- furo[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide free base in a suitable solvent with heating as necessary, adding malonic acid and stirring the mixture, optionally with cooling or sonification, until crystallisation occurs, and then recovering the malonate salt crystals by conventional methods.
  • Suitable solvents that may be used in the preparation of the malonate salt include ethanol, 1-propanol, 2-propanol 1-butanol, 2-butanol, acetone, THF, acetonitrile, ethyl acetate, isopropyl acetate, toluene or heptane (e.g. when mixed with polar solvents), water (e.g. when mixed with a suitable alcohol such as 2-propanol), methyl tert-butyl ether, and mixtures thereof.
  • the solvent used is 2-propanol.
  • the present invention provides a process of preparing N-(3- ((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4- d] [1 ,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono- malonate anhydrate, comprising
  • step (iii) optionally after step (i) or (ii), heating the composition to a temperature in the range of 25 °C to solvent reflux temperature,
  • composition of (i) may be a suspension or solution of N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide free base.
  • the solvent is 2-propanol.
  • malonic acid may for example be added as a solid, as a solution in a suitable solvent, or as a suspension.
  • in step (ii) malonic acid is added as a suspension in 2-propanol.
  • the molar ratio of malonic acid to free base in the composition prepared in step (ii) is in the range of 1.2:1 to 1 : 1.
  • the composition prepared in step (i) is heated to a temperature in the range of 70 to 82°C prior to the addition of the malonic acid in step (ii).
  • the suspension prepared in step (ii) is cooled to a temperature in the range of -10 to 25°C to allow crystals of N-(3- ((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4- d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono- malonate anhydrate to form.
  • the present invention provides a salt which is N-(3- ((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4- d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoiOmethyl)pyrazine-2-carboxamide hippurate.
  • hippurate denotes a salt of hippuric acid (benzoylaminoethanoic acid). In the present specification this salt may be referred to as the "hippurate salt”.
  • the hippurate salt of the present invention has good physico- chemical properties and is suitable for pharmaceutical use.
  • the stoichiometric ratio of hippuric acid and N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4- d] [ 1 ,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide in the hippurate salt is approximately 1 :1, i.e. in the range of 1 : 0.9 to 1 : 1.1.
  • the salt of this embodiment may be referred to as the 'mono-hippurate salt'.
  • the present invention encompasses solvates (e.g. a hydrate) of the hippurate salt.
  • the hippurate salt is an anhydrate (i.e. a crystalline phase that does not contain water).
  • a salt is an anhydrate and is non- hygroscopic if it has a water uptake value of less than 2% as measured by the increase in mass determined by DVS from 5% to 95% relative humidity at 25 °C.
  • the present invention provides a salt which is N-(3- ((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4- d] [1 ,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono- hippurate anhydrate.
  • a mono- hippurate salt which is an anhydrate and has a water uptake value of less than 2 % as measured by the increase in mass determined by DVS from 5% to 95% relative humidity at 25 °C.
  • the hippurate salt of the invention has crystalline properties.
  • the hippurate salt is at least 50 % crystalline.
  • the hippurate salt is at least 60% crystalline; in a still further embodiment at least 70% crystalline; and in a yet further embodiment at least 80% crystalline.
  • the hippurate salt is from 50%, 60%, 70%, 80% or 90% to 95% or 100% crystalline. Crystallinity can be estimated by conventional X-ray diffractometry techniques or differential scanning calorimetry.
  • a diffraction angle (2 ⁇ ) in X-ray powder diffractometry may have an error margin of +/- 0.2°. Therefore, in embodiments of the present invention where diffraction angles are quoted, the margin of error for X-ray powder diffraction peaks (expressed in degrees is 2 ⁇ ) is +/- 0.2°. Unless otherwise stated, X-ray powder diffraction peaks quoted in the present specification were measured using X rays generated from a Cu target.
  • the present invention provides a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono-hippurate anydrate salt, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ +/- 0.2°): 14.0 and 18.2.
  • the present invention provides a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono-hippurate anydrate salt, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ +/- 0.2°): 14.0 and 22.6.
  • the present invention provides a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono-hippurate anydrate salt, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ +/- 0.2°): 18.2 and 22.6.
  • the present invention provides a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono-hippurate anydrate salt, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ +/- 0.2°): 14.0, 18.2 and 22.6.
  • the present invention provides a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydiO-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono-hippurate anydrate salt, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ +/- 0.2°):
  • the mono-hippurate anydrate salt of the present invention displays good manufacturability of a standard suitable for use in pharmaceutical development.
  • the hippurate salt of the present invention may be prepared by dissolving or suspending N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H- furo[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide free base in a suitable solvent with heating as necessary, adding hippuric acid and stirring the mixture, optionally with cooling or sonification, until crystallisation occurs, and then recovering the hippurate salt crystals by conventional methods.
  • Suitable solvents that may be used in the preparation of the hippurate salt include ethanol, 1-propanol, 2-propanol 1-butanol, 2-butanol, acetone, THF, acetonitrile, ethyl acetate, isopropyl acetate, toluene or heptane (e.g. when mixed with polar solvents), water (e.g. when mixed with a suitable alcohol such as 2-propanol), methyl tert-butyl ether, and mixtures thereof.
  • the solvent used is 2-propanol.
  • the present invention provides a process of preparing N-(3- ((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4- d] [1 ,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide mono- hippurate anhydrate, comprising
  • the solvent is 2-propanol.
  • (i) is in the range of 1.25: 1 to 1 : 1.
  • the composition of (i) is heated to a temperature in the range of 65 to 82°C.
  • the composition is cooled to a temperature in the range of -10 to 25°C to allow crystals of N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)- 4a,5,7,7a-tetrahydi -4H-furo[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5- (fluoromethyl)pyrazine-2-carboxamide mono-hippurate anhydrate to form.
  • composition of (i) may be for example be prepared by (a) preparing a composition of N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro- 4H-furo[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2- carboxamide free base in a suitable solvent; (b) adding hippuric acid to the composition; and (c) optionally after step (a) or (b), heating the composition to a temperature in the range of 25 °C to solvent reflux temperature.
  • N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H- furo[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide free base may be prepared according to the procedures described in
  • PCT/EP2012/050833 (WO2012/098213), for example by the procedure described on page 90 of WO2012/098213.
  • Analysis of different batches of free base material prepared by this procedure revealed that at least two different polymorphs of the free base could be formed and difficulties were encountered in selectively preparing a single polymorph using this preparation.
  • two of the polymorphic forms identified (Form A and Form B) were found to have very similar melting points and batch to batch variation in each polymorph's melting point was recorded. Batch variability was also observed in hygroscopicity measurements for Form A.
  • N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H- fuiO[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide contains three chiral centers located on the tetrahydrofuro-thiazinyl ring.
  • the stereochemical configuration at each of these chiral centers is preferably S, i.e. they are (4aS,5S,7aS) stereoisomers.
  • the (4aS,5S,7aS) stereoisomers may be present as a mixture with one or more of the other possible stereoisomers, for example in a racemic or diastereomeric mixture.
  • the present invention provides N-(3-((4aS,5S,7aS)-2-amino- 5-(trifluoi methyl)-4a,5,7,7a-tetrahydro-4H-fuiO[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt which is stereochemically pure at the (4aS,5S,7aS) chiral centers.
  • stereochemically pure denotes a compound which has 80 % or greater by weight of the (4aS,5S,7aS) stereoisomer and 20% or less by weight of other stereoisomers (weight based on free base).
  • the salt has 90 % or greater by weight of the (4aS,5S,7aS) stereoisomer and 10% or less by weight of other stereoisomers.
  • the salt has 95 % or greater by weight of the (4aS,5S,7aS) stereoisomer and 5% or less by weight of other stereoisomers.
  • the salt has 97 % or greater by weight of the (4aS,5S,7aS) stereoisomer and 3% or less by weight of other stereoisomers.
  • the present invention also includes isotopically-labelled versions of the salts wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the salt of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, phosphorous, chlorine, technetium and iodine, such as H, 3 H, n C, 14 C, 13 N, 15 0, 18 F, 32 P, 99m Tc, 123 I and 131 I.
  • isotopically-labelled salts are for example useful in drug and/or substrate tissue distribution assays. 3 H and 14 C are considered useful due to their ease of preparation and detectability.
  • n C, 15 0 and 18 F isotopes are considered useful in PET (positron emission tomography), and 99m Tc, 123 I and 1 1 I isotopes are considered useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
  • Isotopically labelled salts of this invention can generally be prepared by carrying out the procedures described herein below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the present invention further provides a N-(3-((4aS,5S,7aS)-2-amino-5-
  • the salt of the present invention may be useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by ⁇ and typified by Alzheimer-type dementia (AD) or Down's syndrome. It may be used to reduce both ⁇ 40 and ⁇ 42. Furthermore, it may have a BACE 1 and / or a BACE 2 inhibitory effect.
  • the present invention provides a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention for inhibiting production of amyloid- ⁇ protein.
  • the present invention provides a N-(3-((4aS,5S,7aS)-2-amino- 5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention for inhibiting beta-site amyloid- ⁇ precursor protein cleaving enzyme 1 (BACE 1) ⁇
  • the present invention provides a N-(3-((4aS,5S,7aS)-2-amino- 5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention, for use in treating or preventing Alzheimer-type dementia (AD).
  • AD Alzheimer-type dementia
  • the present invention provides a N-(3-((4aS,5S,7aS)-2-amino- 5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention, for use in treating Down's syndrome.
  • the invention provides the use of a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention for the manufacture of a medicament for the treatment or prevention of Alzheimer-type dementia (AD).
  • AD Alzheimer-type dementia
  • the invention provides the use of a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention for the manufacture of a medicament for the treatment of Down' syndrome.
  • the invention provides a method of treating or preventing Alzheimer-type dementia (AD) involving administering to a human subject in need thereof a therapeutically or prophylactically effective amount of a N-(3-((4aS,5S,7aS)- 2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention.
  • AD Alzheimer-type dementia
  • the invention provides a method of treating Down's Syndrome involving administering to a human subject in need thereof a therapeutically effective amount of a N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H- furo[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention.
  • the term "effective amount” means an amount sufficient to cause a benefit to the subject or at least to cause a change in the subject's condition.
  • the present invention further provides a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydi -4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention for use in treating type 2 diabetes.
  • the present invention further provides the use of a N-(3- ((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4- d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention for the manufacture of a medicament for the treatment or prevention of type 2 diabetes.
  • the present invention provides a method of treating or preventing type 2 diabetes involving administering to a human subject in need thereof a therapeutically or prophylactically effective amount of a N-(3-((4aS,5S,7aS)-2-amino-5- (trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention.
  • a further aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H- fui [3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention in association with a pharmaceutically acceptable carrier.
  • the composition may be in any suitable form, depending on the intended method of administration. It may for example be in the form of a tablet, capsule or liquid for oral administration, or of a solution or suspension for administration parenterally.
  • N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H- furo [3 ,4-d] [ 1 ,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention can be formulated by a conventional method.
  • Preferable examples of the dosage form include tablets, coated tablets such as film tablets and sugar-coated tablets, fine granules, granules, powders, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye drops, nasal drops, ear drops, cataplasms and lotions.
  • These solid preparations such as tablets, capsules, granules and powders can contain generally 0.01 to 100 wt%, and preferably 0.1 to 100 wt% of the malonate or hippurate salt as the active ingredient.
  • the active ingredient is formulated by blending ingredients generally used as materials for a pharmaceutical preparation and adding an excipient, a disintegrant, a binder, a lubricant, a colorant and a corrective typically used, and adding a stabilizer, an emulsifier, an absorbefacient, a surfactant, a pH adjuster, a preservative and an antioxidant where necessary, for example, using a conventional method.
  • ingredients include animal and vegetable oils such as soybean oil, beef tallow and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; a silicone resin; silicone oil; surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil and a polyoxyethylene-polyoxypropylene block copolymer; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, a carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerol, propylene
  • excipient used examples include lactose, corn starch, saccharose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide.
  • binder used include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a polypropylene glycol-polyoxyethylene block copolymer and meglumine.
  • disintegrant used include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and
  • carboxymethylcellulose calcium examples include magnesium stearate, talc, polyethylene glycol, silica and hydrogenated vegetable oil.
  • examples of the colorant used include those permitted to be added to pharmaceuticals.
  • examples of the corrective used include cocoa powder, menthol, empasm, mentha oil, borneol and cinnamon powder.
  • the ingredients are not limited to the above additive ingredients.
  • an oral preparation may be prepared by adding the malonate or hippurate salt according to the present invention, an excipient and, where necessary, a binder, a disintegrant, a lubricant, a colorant, a corrective and the like, and then forming the mixture into powder, fine granules, granules, tablets, coated tablets, capsules or the like by a conventional method. Tablets or granules may be appropriately coated, for example, sugar coated, where necessary.
  • a syrup or an injection preparation is prepared by adding a pH adjuster, a solubilizer, an isotonizing agent and the like, and a solubilizing agent, a stabilizer and the like where necessary by a conventional method.
  • the injection may be a previously prepared solution, or may be powder itself or powder containing a suitable additive, which is dissolved before use.
  • the injection can contain usually 0.01 to 100 wt%, and preferably 0.1 to 100 wt% of the active ingredient.
  • a liquid preparation for oral administration such as a suspension or a syrup can contain usually 0.01 to 100 wt%, and preferably 0.1 to 100 wt% of the active ingredient.
  • an external preparation can be prepared by any conventional method without specific limitations.
  • a base material any of various materials usually used for a pharmaceutical, a quasi drug, a cosmetic or the like can be used.
  • the base material include materials such as animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals and purified water.
  • a pH adjuster, an antioxidant, a chelator, a preservative and fungicide, a colorant, a flavor or the like can be added where necessary.
  • ingredients such as an ingredient having a differentiation inducing effect, a blood flow enhancer, a bactericide, an antiphlogistic, a cell activator, vitamin, amino acid, a humectant and a keratolytic agent can be blended where necessary.
  • the dose of the N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a- tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine- 2-carboxamide salt according to the present invention may be varied according to the degree of symptoms, age, sex, body weight, mode of administration, and specific type of disease.
  • the active ingredient is orally administered to an adult at about 30 ⁇ g to 10 g, preferably 100 ⁇ g to 5 g, and more preferably 100 ⁇ g to 1 g per day, or is administered to an adult by injection at about 30 ⁇ g to 1 g, preferably 100 ⁇ g to 500 mg, and more preferably 100 ⁇ g to 300 mg per day, in one or several doses, respectively.
  • N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoiOmethyl)-4a,5,7,7a-tetrahydro-4H- furo[3,4-d][l,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention may be used in combination with other therapeutic agents, for example medicaments claimed to be useful as either disease modifying or symptomatic treatments of a neurodegenerative disease such as
  • the present invention provides a pharmaceutical product comprising, in combination, a N-(3- ((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4- d] [1 ,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention, and at least one further active ingredient useful in treating a neurodegenerative disease.
  • the neurodegenerative disease is Alzheimer-type dementia (AD) or Down's syndrome.
  • Suitable examples of such further active ingredients may be symptomatic agents, for example those known to modify cholinergic transmission such as Ml and M3 muscarinic receptor agonists or allosteric modulators, M2 muscarinic antagonists, M4 agonists or positive allosteric modulators (PAMs), acetylcholinesterase inhibitors (such as tetrahydroaminoacridine, donepezil hydrochloride and rivastigmine), nicotinic receptor agonists or allosteric modulators (such as a7 agonists or allosteric modulators or ⁇ 4 ⁇ 2 agonists or allosteric modulators), PPAR agonists (such as PPARy agonists), 5- HT 4 receptor agonists or partial agonists, histamine H3 antagonists, 5-HT 6 receptor antagonists or 5HTi A receptor ligands and NMDA receptor antagonists or modulators such as memantine, 5-HT 2 A antagonists, 5-HT 7 antagonist
  • SNRIs selective and unselective norepinephrine reuptake inhibitors
  • potential disease modifying agents such as gamma secretase inhibitors or modulators, alpha secretase activators or modulators, amyloid aggregation inhibitors, amyloid antibodies, tau aggregation inhibitors or tau phosphorylation/kinase inhibitors, tau dephosphorylation / phosphatase activators, mitogen-activated protein kinase kinase 4 (MKK4/MEK4/MAP2K4) inhibitors, c-Jun N-terminal kinase (JNK) inhibitors, casein kinase inhibitors, MK2 (mitogen activated protein kinase-activated protein kinase 2) inhibitors, MARK
  • TTBK1 tau-tubulin kinase- 1
  • Such other therapeutic agents may be calcium channel blockers, HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) and lipid lowering agents, NGF (nerve growth factor) mimics, antioxidants, GPR3 ligands, plasmin activators, neprilysin (NEP) activators, IDE (insulin degrading enzyme) activators, melatonin MT1 and/or MT2 agonists, TLX/NR2E1 (tailless X receptor) ligands, GluRl ligands, RAGE (receptor for advanced glycation end-products) antagonists, EGFR (epidermal growth factor receptor) inhibitors, FPRL-1 (formyl peptide-like receptor- 1) ligands, GABA antagonists, and MICAL (molecule interacting with casL) inhibitors, e.g.
  • HMG-CoA 3-hydroxy-3-methyl-glutaryl-CoA reducta
  • oxoreductase inhibitors CB1 antagonists/inverse agonists, non-steroidal anti-inflammatory drugs (NSAIDs), anti-inflammatory agents (for example agents that could be used to treat neuroinflammation either by enhancing or reducing neuroinflammation), amyloid precursor protein (APP) ligands, anti-amyloid vaccines and / or antibodies, agents that promote or enhance amyloid efflux and / or clearance, histone deacetylase (HDAC) inhbitors, EP2 antagonists, 11 -beta HSD1 (hydroxysteroid dehydrogenase) inhibitors, liver X receptor (LXR) agonists or PAMs, lipoprotein receptor-related protein (LRP) mimics and / or ligands and/or enhancers and/or inhibitors, butyryl cholinesterase inhibitors, kynurinic acid antagonists and / or inhibitors of kynurenine aminotransferease (KAT), orphanin FQ / nociceptin (
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a N-(3-((4aS,5S,7aS)-2- amino-5-(trifluoiOmethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide salt according to the present invention, and at least one further active ingredient selected from:
  • cholinesterase inhibitors e.g. donepezil, galantamine, rivastigamine
  • NMDA receptor antagonists e.g. memantine and pharmaceutically acceptable salts thereof, and any other compounds which elicit their effects by a similar mechanism of action
  • 5-HT 6 antagonists e.g. SB-742457 and pharmaceutically acceptable salts thereof
  • HMGCoA reductase inhibitors e.g. lovastatin, rosuvastatin, atorvastatin,
  • simvastatin simvastatin, fluvastatin, pitavastatin, pravastatin and pharmaceutically
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Consequently, the pharmaceutical product may, for example be a pharmaceutical composition comprising the first and further active ingredients in admixture.
  • the pharmaceutical product may for example comprise the first and further active ingredients in separate pharmaceutical preparations suitable for
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • N-(((3S,4R,5S)-3-(2-Fluorophenyl)-4-(hydroxymethyl)-5- (trifluoi methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide (31.1 g) was dissolved in pyridine (150 mL), and the mixture cooled to -20°C. Trifluoromethanesulfonic anhydride (14.0 mL) was added dropwise over 30 min and the reaction was allowed to warm to 0°C. After stirring for 2 h, the reaction was quenched by the addition of ammonium chloride (sat., aq., 400 mL) and extracted with EtOAc (3 x 500 mL).
  • N-((4aS,5S,7aS)-7a-(2-Fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro- 4H-furo[3,4-d][l,3]thiazin-2-yl)benzamide (21.5 g) was dissolved in methanol (160 mL), l,8-diazabicyclo[5.4.0]undec-7-ene (16.29g) was added, and the solution was heated to reflux (heating block temperature 80°C).
  • N-((4aS,5S,7aS)-7a-(2-Fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro- 4H-furo[3,4-d][l,3]thiazin-2-yl)benzamide (5.15 g) was dissolved in TFA (75 mL), and the solution was cooled to 0°C. Sulfuric acid (cone, 20 mL) was added, followed by fuming nitric acid (2 mL) dropwise over 20 mins. After stirring at 0°C for 90 mins, the reaction mixture was poured onto ice (200 g) and basified to pH 12 with 6N NaOH (aq.).
  • fert-Butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluoiOphenyl)-5-(trifluoromethyl)- 4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-2-yl)carbamate 500 mg was dissolved in DCM (10 mL) and 5-fluoromethyl-pyrazine-2-carboxylic acid (223 mg), N,N- diisopropylethylamine (521 mg) and (lH-benzotriazol-l-yloxy)tripyrrolidin-l- yl)phosphonium hexafluorophophate (750 mg) were added.
  • reaction mixture was stirred at RT for 1 h, and sodium bicarbonate (sat., aq., 50 mL) was added.
  • the mixture was extracted with EtOAc (2 x 75 mL), the combined organic portions were dried over MgSC , evaporated and purified by silica gel chromatography (0% to 30%
  • reaction vessel was charged with toluene (3.2 L), THF (0.60 L) and acrolein
  • the mixture was stirred for 30 mins, and ⁇ , ⁇ - dimethylhydroxylamine hydrochloride (0.67 kg, 6.72 mol) was added in portions while maintaining temperature below 10 °C.
  • the reaction mixture was warmed to rt and stirred over 14 h.
  • the reaction mixture was cooled to 3.2 °C and imidazole (100.7 g, 1.48 mol) was charged in two portions.
  • the reaction mixture was warmed to rt and water (1.4 kg) was added, followed by methyl fert-butyl ether (14.0 L).
  • the organic phase was washed with 2.0 N aq. HC1 (1.0 L and 0.7 L), followed by sat. aq. NaHC0 3 (1.2 L) and sat. aq.
  • oxime (1.085 kg, 3.328 mol) in xylenes (6.9 L) was added hydroquinone (86.2g, 0.8 mol) at rt. The solution was heated to 128 °C (internal temperature) for 18 h. The solution was cooled to rt, and hexanes (7.0 L) was added, followed by 4.0 M aq. HCl (2.4 L). The reaction mixture was stirred for 1 h, and filtered. To the solid was added water (2.0 L), methyl teri-butyl ether (7.0 L) and 25% wt. aq. NaOH (0.4 L).
  • the aq. layer was extracted once with methyl tert-butyl ether (7.0 L), the organics were combined, washed with 27% aq. NaCl (2.0 L) and concentrated under vacuum to a black oil (512.0g, 56%).
  • Zinc (389.2 g, 5.95 mol) was placed in a reaction vessel, and water was added (893 mL). Acetic acid (135 mL, 2.38 mol) was added while maintaining the temperature below 10 °C. After 15 min, 6a-(2-fluorophenyi)-4- (trifluoromethyl)hexahydrofuro[3,4-c]isoxazole (550.0 g, 1.98 mol) was added as a solution in THF (665 mL). The reaction mixture was stirred over 16 h at rt.
  • Flow rate may be adjusted ⁇ 0.2 ml/min to obtain specified retention times.
  • the heterogeneous mixture was heated to 45 °C for 1 h.
  • the mixture was cooled to ambient temperature, and EtOAc (1.38 L) was added.
  • the aqueous layer was extracted with EtOAc (0.75 L).
  • the organics were combined, washed with saturated aq. NaHC0 3 (500 mL) and saturated aq. NaCl (500 mL).
  • the organics were concentrated under vacuum to afford the title compound as a brown oil (184.1 g, 91.6 % yield accounting for residual solvents).
  • Fuming nitric acid 39.8 mL, 0.948 mol was added over 30 min, while the temperature was maintained below 10 °C. After 1.5 h at 0-10 °C, the reaction mixture was slowly quenched by transferring into an aq. solution of NaOH (575 g, 14.4 mol) in water (4.6 L) cooled to 5 °C. The resulting suspension was stirred for 1 h at 21 °C. The suspension was then filtered and the solid rinsed with cold water (920 mL). The solid was dried under vacuum until constant weight, and then dissolved into ethanol (1.05 L). The solution was heated to 35 °C, and cone.
  • the reaction mixture was stirred at 40-45 °C >3 hours and monitored by HPLC.
  • the reaction mixture was cooled to 15-20 °C and water (140 mL) was charged. After 10-15 minutes charged 28% ammonium hydroxide (175 mL) while controlling the temperature below 30 °C.
  • EtOAc (245 mLO was added and the reaction mixture was stirred for 30 minutes at ambient temperature.
  • the aqueous phase was separated and back-extracted with EtOAc (490 mL).
  • the organic phases were combined and washed with 15% aq. NaCl (140 mL) and water (140 mL).
  • the organic layer was filtered over Celite (1.0 Wt) and rinsed with EtOAc (140 mL).
  • Free base Form B polymorph Crude free base (1.56 g) was suspended in 13.3 mL 1-propanol and heated to 90 °C. The solution was cooled to 0 °C and filtered. The solid was rinsed with 1-propanol (3.9 mL) and dried under vacuum to afford 1.23g of a solid.
  • n-propane phosphonic acid anhydride T3P, 2.82 kg, 4.429 mol, 50 wt % in EtOAc
  • T3P n-propane phosphonic acid anhydride
  • the mixture was heated to 45 °C and held for ca 1.5 hours.
  • the mixture was cooled to 30 °C and water (2.7 L) was added.
  • the mixture was further cooled to 0-10 °C.
  • EtOAc (3.38L) and 3.0N aq NaOH (5.37 L, 16.104 mol) were added with temperature below 30 °C to achieve a pH ⁇ 10.
  • the bottom aqueous phase was back-extracted with EtOAc (4.73 L).
  • the resulting suspension was cooled to 20 °C. After 1 hour at 20 °C the suspension was filtered and the solid was rinsed with 2-propanol (3.68 mL). The solid was dried until constant weight to afford the title compound (2.10 g, 94%).
  • the 1H NMR were recorded on a Varian 400 Mhz instrument with vNMR 6.1C software.
  • the malonic acid content was confirmed to be approximately 1 : 1 by ion chiOmatography (IC) with electrical conductivity detection, and by single crystal X-ray analysis.
  • the hippuric acid content was confirmed to be approximately 1 :1 by ion chromatography (IC) with electrical conductivity detection, and by single crystal X-ray analysis.
  • X-ray powder diffraction peaks for the L-tartrate salt (expressed in degrees 2 ⁇ +/- 0.2°) include: 5.8, 10.4, 17.1, 20.8.
  • Each sample is placed on the platform of an X ray system, and analyzed under the following conditions.
  • Slit divergence slit 0.5 mm (Height limiting slit 2 mm), scatter slit open, receiving slit open
  • Scan range: 5° to 35°
  • DSC Differential scanning calorimetry
  • Each sample is accurately weighed into an aluminium pan with a pinhole punched in the lid, and then heated under a nitrogen-purge atmosphere from 25 to 200 °C at 10 °C/min using an empty pan as reference.
  • the temperature axis and the cell constant in both thermal analyses are calibrated with indium in advance. The followings are measurement conditions.
  • Atmosphere N 2 gas (40 niL/min)
  • test sample (7 to 13 mg) is humidified in an isothermal chamber where RH conditions are regulated from 5% to 95% at 25 °C by adjusting relative flow rates of dry (0% RH) and moist (100% RH) nitrogen.
  • the sample weight is measured every 2 min with the microbalance.
  • the weight stability criterion employed for the equilibrium is either of the folio wings.
  • a water uptake value of less than 2% was recorded by DVS (relative humidity from 5% to 95% at 25 °C).
  • the melting point of Form B displayed batch to batch differences but as measured by DSC (onset) was recorded to be in the range of 173 °C to 175 °C.
  • a water uptake value of greater than 10% was recorded by DVS (relative humidity from 5% to 95% at 25 °C). This was reversible. Moreover, batch variability was observed with subsequent batches of material giving water uptake values in the range of 4 to 5%. The melting point of Form A displayed batch to batch differences but as measured by DSC (onset) was recorded to be in the range of 165 to 172 °C.
  • a DVS isotherm plot of N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)- 4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4-fiuorophenyl)-5- (fluoromethyl)pyrazine-2-carboxamide mono-malonate anhydrate is presented in Figure 5 1 .
  • the water uptake is approximately 1.1% as measured by the increase in mass determined by DVS from 5% to 95% relative humidity at 25 °C.
  • Area% refers to HPLC Area% analysis.
  • Wt/Wt refers to weight/weight HPLC analysis
  • the cell dispersion was filtered through a 40- ⁇ nylon mesh (BD Falcon #352340) to remove the remaining cell mass, and thus a neuronal cell suspension was obtained.
  • the neuronal cell suspension was diluted with the medium above and then plated in a volume of 100 ⁇ , /well at an initial cell density of 3.25 x 10 5 cells/ml in poly- D-lysine coated 96-well culture plate
  • the plated cells were cultured in the culture plate at 37°C in 5% C0 2 -95% air for 24hrs. The total amount of the medium was replaced with 'assay Neurobasal medium' (as above excluding heat inactivated FCS), and then the cells were cultured for a further five days.
  • the drug was added to the culture plate on Day 6 of culture as follows. 8 point compound serial dilutions were generated in DMSO at a concentration of xlOOO that of the final assay concentration (FAC). Compound solutions were then prepared by adding 999ul of 'Assay Neurobasal media' (as described in above section) to lul of DMSO compound stock. The total amount of the medium was removed from each of the cell plate wells, and ⁇ , ⁇ of 'Assay Neurobasal media' was added followed by 60ul of compound solution. The final DMSO concentration was 0.1%.
  • the cells were cultured for either 1 or 3 days after addition of the compound for ABx-40 and ABx-42 assays respectively. 150 ⁇ 1 of sample medium was collected and used as the ELISA sample.
  • N-(3-((4aS,5S,7aS)-2-amino-5- (trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][l,3]thiazin-7a-yl)-4- fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide free base had an IC50 value ( ⁇ 40) of 0.006 ⁇ .

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Abstract

La présente invention concerne de nouveaux sels d'un dérivé aminodihydrothiazine condensé et leurs applications pharmaceutiques.
PCT/US2013/051056 2012-07-19 2013-07-18 Sels de dérivé aminodihydrothiazine condensé et applications associées WO2014015125A1 (fr)

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US10011610B2 (en) 2015-04-29 2018-07-03 Eli Lilly And Company Selective BACE1 inhibitors

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US9029367B2 (en) 2013-06-18 2015-05-12 Eli Lilly And Company BACE inhibitors
US9169271B2 (en) 2013-06-18 2015-10-27 Eli Lilly And Company BACE inhibitors
US9522923B2 (en) 2015-02-23 2016-12-20 Eli Lilly And Company Selective BACE1 inhibitors
US10011610B2 (en) 2015-04-29 2018-07-03 Eli Lilly And Company Selective BACE1 inhibitors

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