WO2011070029A1 - Amino oxazine derivatives - Google Patents

Amino oxazine derivatives Download PDF

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Publication number
WO2011070029A1
WO2011070029A1 PCT/EP2010/069098 EP2010069098W WO2011070029A1 WO 2011070029 A1 WO2011070029 A1 WO 2011070029A1 EP 2010069098 W EP2010069098 W EP 2010069098W WO 2011070029 A1 WO2011070029 A1 WO 2011070029A1
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WIPO (PCT)
Prior art keywords
methyl
amino
phenyl
fluoro
carboxylic acid
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PCT/EP2010/069098
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English (en)
French (fr)
Inventor
David Banner
Hans Hilpert
Harald Mauser
Alexander V. Mayweg
Mark Rogers-Evans
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F. Hoffmann-La Roche Ag
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Application filed by F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Priority to EP10790920.2A priority Critical patent/EP2509966B1/en
Priority to MX2012005810A priority patent/MX2012005810A/es
Priority to RU2012126083/04A priority patent/RU2012126083A/ru
Priority to KR1020127017733A priority patent/KR101437750B1/ko
Priority to JP2012542524A priority patent/JP2013513568A/ja
Priority to CA2780693A priority patent/CA2780693A1/en
Priority to BR112012013322A priority patent/BR112012013322A2/pt
Priority to CN2010800555310A priority patent/CN102652129A/zh
Publication of WO2011070029A1 publication Critical patent/WO2011070029A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to 5,6-dihydro-4H-[l ,3]oxazin-2-ylamine compounds of the formula
  • R 1 is hydrogen or Ci_7-alkyl
  • R 2 is hydrogen or Ci_7-alkyl; or R 1 and R 2 together with the C atom they are attached to form a C3_7-cycloalkyl ring;
  • R 3 is Ci_7-alkyl or C3_7-cycloalkyl; or R 2 and R 3 together with the C atoms they are attached to form a C3_7-cycloalkyl or a 3- to 7-membered O-heterocyclyl ring;
  • R 4 is selected from the group consisting of hydrogen, Ci_7-alkyl, halogen, cyano and C 1-7 - alkoxy;
  • R 5 is i) aryl, unsubstituted or substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, halogen-Ci_7-alkyl, Ci_7-alkoxy, halogen-Ci_7-alkoxy, cyano, hydroxy-Ci_7-alkyl, oxo and phenyl, ii) heteroaryl, unsubstituted or substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, halogen-Ci_7-alkyl, Ci_7-alkoxy, halogen-Ci_7- alkoxy, cyano, hydroxy-Ci_7-alkyl, oxo and phenyl, iii) Ci_7-alkyl, unsubstituted or substituted by one, two, three, four or five groups individually selected from the group consisting of halogen,
  • the invention is also concerned with the manufacture of compounds of formula I, with pharmaceutical compositions containing them and their use as medicaments.
  • the compounds of formula I are inhibitors of BACE2 and may therefore be useful in the treatment of type 2 diabetes and other metabolic disorders.
  • Type 2 diabetes is caused by insulin resistance and inadequate insulin secretion from pancreatic beta-cells leading to poor blood-glucose control and hyperglycemia (M Prentki & CJ Nolan, "Islet beta-cell failure in type 2 diabetes.” J. Clin. Investig. 2006, 116(7), 1802-1812).
  • Patients with T2D have an increased risk of microvascular and macrovascular disease and a range of related complications including diabetic nephropathy, retinopathy and cardiovascular disease.
  • Tmem27 has been identified as a protein promoting beta-cell proliferation (P Akpinar, S Kuwajima, J Krutzfeldt, M Stoffel, "Tmem27: A cleaved and shed plasma membrane protein that stimulates pancreatic ⁇ cell proliferation", Cell Metab. 2005, 2, 385-397) and insulin secretion (K Fukui, Q Yang, Y Cao, N Takahashi et al, "The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation", Cell Metab. 2005, 2, 373-384).
  • Tmem27 is a 42 kDa membrane glycoprotein which is constitutively shed from the surface of beta-cells, resulting from a degradation of the full-length cellular Tmem27.
  • Overexpression of Tmem27 in a transgenic mouse increases beta-cell mass and improves glucose tolerance in a DIO model of diabetes [K Fukui, Q Yang, Y Cao, N Takahashi et al, "The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation", Cell Metab.
  • Tmem27 A cleaved and shed plasma membrane protein that stimulates pancreatic ⁇ cell proliferation", Cell Metab. 2005, 2, 385-397.
  • siRNA knockout of Tmem27 in a rodent beta-cell proliferation assay reduces the proliferation rate, indicating a role for Tmem27 in control of beta-cell mass.
  • BACE2 cleaves a peptide based on the sequence of Tmem27.
  • the closely related protease BACEl does not cleave this peptide and selective inhibition of BACEl alone does not enhance proliferation of beta-cells.
  • BACEl (BACE for beta-site APP-cleaving enzyme, also known as beta-secretase) has been implicated in the pathogenesis of Alzheimer disease and in the formation of myelin sheaths in peripheral nerve cells.
  • BACE2 The close homo log BACE2 is a membrane-bound aspartyl protease and is co localised with Tmem27 in rodent pancreatic beta-cells (G Finzi, F Franzi, C Placidi, F Acquati et al, "BACE2 is stored in secretory granules of mouse and rat pancreatic beta cells", Ultrastruct Pathol. 2008, 32(6), 246-251). It is also known to be capable of degrading APP (I Hussain, D Powell, D Howlett, G Chapman et al, "ASP1 (BACE2) cleaves the amyloid precursor protein at the ⁇ - secretase site" Mol Cell Neurosci.
  • IL-1R2 P Kuhn, E Marjaux, A Imhof, B De Strooper et al, "Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase" J. Biol. Chem. 2007, 282(16), 11982-11995).
  • BACE2 Inhibition of BACE2 is therefore proposed as a treatment for type 2 diabetes with the potential to preserve and restore beta-cell mass and stimulate insulin secretion in pre-diabetic and diabetic patients. It is therefore an object of the present invention to provide selective BACE2 inhibitors. Such compounds are useful as therapeutically active substances, particularly in the treatment and/or prevention of diseases which are associated with the inhibition of BACE2.
  • the compounds of the present invention exceed the compounds known in the art, inasmuch as they are strong and selective inhibitors of BACE2. They are expected to have an enhanced therapeutic potential compared to the compounds already known in the art and can be used for the treatment and prevention of diabetes, particularly type 2 diabetes, metabolic syndrome and a wide range of metabolic disorders.
  • Structures depicted herein are also meant to include compounds that differ only in the presence of one or more iso topically enriched atoms. For example wherein one or more hydrogen atoms are replaced by deuterium, or one or more carbon atoms are replaced by a 13C- or 14C-enriched carbon are within the scope of this invention.
  • halogen refers to fluorine (fluoro, F), chlorine (chloro, CI), bromine (bromo, Br) and iodine (iodo, I), with fluorine, chlorine and bromine being particular, and with fluorine and chlorine being more particular. Most particular is F.
  • lower alkyl or “Ci_7-alkyl” alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 7 carbon atoms, particularly a straight or branched-chain alkyl group with 1 to 6 carbon atoms and particularly particular a straight or branched-chain alkyl group with 1 to 4 carbon atoms.
  • Ci_ 7 alkyl groups examples include methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls and the isomeric heptyls, particularly methyl and ethyl and most particular methyl.
  • lower alkoxy or "Ci_ 7 -alkoxy” refers to the group R'-O-, wherein R' is lower alkyl and the term “lower alkyl” has the previously given significance.
  • lower alkoxy groups are methoxy (MeO, OMe), ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy, particularly methoxy and ethoxy.
  • lower halogenalkyl or “halogen-Ci_ 7 -alkyl” refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a halogen atom, particularly f uoro or chloro, most particularly fluoro.
  • halogen atom particularly f uoro or chloro
  • the particular lower halogenalkyl groups are trif uoromethyl, difluoromethyl, trif uoro ethyl, 2,2-difluoroethyl, fluoromethyl and chloromethyl, with trifluoromethyl or difluoromethyl being especially particular.
  • lower halogenalkoxy or "halogen-Ci_7-alkoxy” refers to lower alkoxy groups as defined above wherein at least one of the hydrogen atoms of the lower alkoxy group is replaced by a halogen atom, particularly fluoro or chloro, most particularly fluoro.
  • halogenated lower alkoxy groups are trifluoromethoxy, difluoromethoxy, fluormethoxy and chloromethoxy, with trifluoromethoxy being especially particular.
  • lower hydroxyalkyl or "hydroxy-Ci_7-alkyl” refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a hydroxy group.
  • lower hydroxyalkyl groups are hydro xymethyl or hydroxyethyl.
  • cycloalkyl or "C3_7-cycloalkyl” denotes a saturated carbocyclic group containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Especially particular are cyclopropyl, cyclobutyl and cyclopentyl. Specific is cyclopropyl.
  • 3- to 7-membered O-heterocyclyl ring denotes a saturated 3- to 7-membered heterocyclyl ring containing at least one oxygen atom, such as oxirane, oxetane, tetrahydrofurane, tetrahydropurane and oxepane.
  • a tetrahydrofurane (furyl) ring is particular.
  • Specific is oxetanyl.
  • aryl refers to an aromatic monocyclic or multicyclic ring system having 6 to 14 carbon atoms, particularly 6 to 10 carbon atoms. Particular aryl groups are phenyl and naphthyl, with phenyl being most particular.
  • heteroaryl refers to an aromatic or partly unsaturated 5- or 6-membered ring which comprises at least one heteroatom selected from nitrogen, oxygen and/or sulphur, and can in addition comprise one or three atoms selected from nitrogen, oxygen and/or sulphur, such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 6-oxo-l,6-dihydropyridazinyl, 5-oxo-4,5- dihydropyrazinyl, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, triazolyl and thiazolyl.
  • heteroaryl further refers to bicyclic aromatic or partly unsaturated groups comprising two 5- or 6-membered rings, in which one or both rings can contain one, two or three atoms selected from nitrogen, oxygen or sulphur, such as quinolinyl, isoquinolinyl, cinnolinyl, pyrazolo[l ,5-a]pyridyl, imidazo[l ,2-a]pyridyl, thieno[2,3-c]pyridyl, quinoxalinyl, benzo[b]thienyl, benzo thiazolyl, benzo triazolyl, indolyl, indazolyl and 3,4-dihydro-lH-isoquinolinyl.
  • heteroaryl groups are thienyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, 6-oxo-l,6-dihydropyridazinyl, 5-oxo-4,5- dihydropyrazinyl and imidazo[l ,2-a]pyridyl, with thienyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl and pyrazinyl being more particular and pyridyl being most particular.
  • lH-pyrazolyl benzo[b]thiophenyl, isoxazolyl, oxazolyl, pyrazinyl, pyridinyl, pyrimidinyl, thiazolyl, thieno[2,3-c]pyridinyl and thiophenyl
  • lH-pyrazole-3-yl benzo[b]thiophene-2-yl, isoxazole-3-yl, oxazole-4-yl, pyrazine-2-yl, pyridine-2-yl, pyrimidine-2- yl, thiazol-4-yl, thieno[2,3-c]pyridine-7-yl and thiophene-2-yl.
  • compositions of formula I can form pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the pharmaceutically acceptable salts of the compounds of formula I are the acid addition salts with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids, such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, lactic acid, trifluoro acetic acid, citric acid, fumaric acid, maleic acid, malonic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid, succinic acid or salicylic acid.
  • Particularly particular pharmaceutically acceptable salts of compounds of formula I are the acid addition salts
  • the compounds of formula I can also be solvated, e.g., hydrated.
  • the solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration).
  • pharmaceutically acceptable salts also includes physiologically acceptable solvates.
  • “Isomers” are compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non-superimposable mirror images are termed “enantiomers”, or sometimes optical isomers. A carbon atom bonded to four non-identical substituents is termed a "chiral center”.
  • Chiral molecules are optically active, i.e., they have the ability to rotate the plane of plane-polarized light.
  • Compounds of present invention can have one or more chiral centers and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. Whenever a chiral center is present in a chemical structure, it is intended that all stereoisomers associated with that chiral center are encompassed by the present invention.
  • the invention relates to compounds of the formula I, wherein
  • R 1 is hydrogen or Ci_7-alkyl
  • R 2 is hydrogen or Ci_7-alkyl; or R 1 and R 2 together with the C atom they are attached to form a C 3 _7-cycloalkyl ring;
  • R 3 is Ci_7-alkyl or C3-7-cycloalkyl; or R 2 and R 3 together with the C atoms they are attached to form a C 3 _7-cycloalkyl or a 3- to 7-membered O-heterocyclyl ring;
  • R 4 is selected from the group consisting of hydrogen, Ci_7-alkyl, halogen, cyano and C 1-7 - alkoxy;
  • R 5 is i) aryl, unsubstituted or substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, halogen-Ci_7-alkyl, Ci_7-alkoxy, halogen-Ci_7-alkoxy, cyano, hydroxy-Ci_7-alkyl, oxo and phenyl, ii) heteroaryl, unsubstituted or substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, halogen-Ci_7-alkyl, Ci_7-alkoxy, halogen-Ci_7- alkoxy, cyano, hydroxy-Ci_7-alkyl, oxo and phenyl, iii) Ci_7-alkyl, unsubstituted or substituted by one, two, three, four or five groups individually selected from the group consisting of halogen,
  • R is hydrogen or Ci_7-alkyl
  • R 2 is hydrogen or Ci_7-alkyl; or R 1 and R 2 together with the C atom they are attached to form a C3_7-cycloalkyl ring; R 3 is Ci_7-alkyl or C 3 _7-cycloalkyl; or R 2 and R 3 together with the C atoms they are attached to form a C3_7-cycloalkyl or a 3- to 7-membered O-heterocyclyl ring;
  • R 4 is selected from the group consisting of hydrogen, Ci_7-alkyl, halogen, cyano and C 1-7 - alkoxy;
  • R 5 is aryl or heteroaryl, said aryl or heteroaryl being unsubstituted or substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, halogen-Ci_7- alkyl, Ci_7-alkoxy, halogen-Ci_7-alkoxy, cyano, hydroxy-Ci_7-alkyl, oxo and phenyl; or pharmaceutically acceptable salts thereof.
  • the invention relates to compounds of the formula I, wherein R 1 is hydrogen;
  • R 2 is hydrogen
  • R 3 is Ci_ 7 -alkyl
  • R 4 is halogen
  • R 5 is lH-pyrazolyl, benzo[b]thiophenyl, isoxazolyl, oxazolyl, pyrazinyl, pyridinyl, pyrimidinyl, thiazolyl, thieno[2,3-c]pyridinyl, thiophenyl, phenyl, ethyl, cyclopropyl and oxetanyl being unsubstituted or substituted as defined herein; or pharmaceutically acceptable salts thereof.
  • the invention relates to compounds of formula I as herein described, wherein R 1 and R 2 together with the C atom they are attached to form a C 3 _7- cycloalkyl ring.
  • the invention relates to compounds of formula I as herein described, wherein R 2 and R 3 together with the C atom they are attached to form a In a particular embodiment, the invention relates to compounds of formula I as herein described, wherein R 2 and R 3 together with the C atom they are attached to form a C 3 _7-cycloalkyl ring. In a particular embodiment, the invention relates to compounds of formula I as herein described, wherein R 2 and R 3 together with the C atom they are attached to form a In a particular embodiment, the invention relates to compounds of formula I as herein described, wherein R 2 and R 3 together with the C atom they are attached to form furyl. In a particular embodiment, the invention relates to compounds of formula I as herein described, wherein R 1 and R 2 together with the C atom they are attached to form a cyclopropyl.
  • the invention relates to compounds of formula I as herein described, wherein R 1 and R 2 are hydrogen.
  • the invention relates to compounds of formula I as herein described, wherein R 1 is hydrogen.
  • the invention relates to compounds of formula I as herein described, wherein R 2 is hydrogen.
  • the invention relates to compounds of formula I as herein described, wherein R 3 is Ci_7-alkyl. In a particular embodiment, the invention relates to compounds of formula I as herein described, wherein R 3 is methyl.
  • the invention relates to compounds of formula I as herein described, wherein R 3 is ethyl.
  • the invention relates to compounds of formula I as herein described, wherein R 4 is hydrogen or halogen.
  • the invention relates to compounds of formula I as herein described, wherein R 4 is halogen.
  • the invention relates to compounds of formula I as herein described, wherein R 4 is fluoro.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is heteroaryl, said heteroaryl being unsubstituted or substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, halogen-Ci_7-alkyl, Ci_7-alkoxy, halogen-Ci_7-alkoxy, cyano, hydroxy-Ci_7-alkyl, oxo and phenyl.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is heteroaryl selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 6-oxo-l,6-dihydropyridazinyl, 5-oxo-4,5-dihydropyrazinyl, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, pyrazolo[l ,5-a]pyridyl, imidazo[l ,2- ajpyridyl, thieno[2,3-c]pyridyl, quinoxal
  • the invention relates to compounds of formula I as herein described, wherein R 5 is heteroaryl selected from the group consisting of thienyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, 6-oxo-l,6-dihydropyridazinyl, 5-oxo-4,5- dihydropyrazinyl and imidazo[l ,2-a]pyridyl, said heteroaryl being unsubstituted or substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, halogen- Ci_7-alkyl, Ci_7-alkoxy, halogen-Ci_7-alkoxy, cyano, hydroxy-Ci_7-alkyl, oxo and phenyl.
  • R 5 is heteroaryl selected from the group consisting of thienyl, oxazoly
  • the invention relates to compounds of formula I as herein described, wherein R 5 is heteroaryl selected from the group consisting of thienyl, oxazolyl, pyridyl, pyrimidinyl and pyrazinyl, said heteroaryl being unsubstituted or substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, halogen-Ci_7-alkyl, Ci_ 7-alkoxy, halogen-Ci_7-alkoxy, cyano, hydroxy-Ci_7-alkyl, oxo and phenyl.
  • R 5 is heteroaryl selected from the group consisting of thienyl, oxazolyl, pyridyl, pyrimidinyl and pyrazinyl, said heteroaryl being unsubstituted or substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, hal
  • the invention relates to compounds of formula I as herein described, wherein R 5 is heteroaryl selected from the group consisting of thienyl, oxazolyl, pyridyl, pyrimidinyl and pyrazinyl substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, halogen-Ci_7-alkyl, Ci_7-alkoxy, halogen-Ci_7-alkoxy, cyano, hydroxy-Ci_7-alkyl, oxo and phenyl.
  • R 5 is heteroaryl selected from the group consisting of thienyl, oxazolyl, pyridyl, pyrimidinyl and pyrazinyl substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, halogen-Ci_7-alkyl, Ci_7-alkoxy, halogen-Ci_
  • the invention relates to compounds of formula I as herein described, wherein R 5 is heteroaryl selected from the group consisting of IH-pyrazolyl, benzo[b]thiophenyl, isoxazolyl, oxazolyl, pyrazinyl, pyridinyl, pyrimidinyl, thiazolyl, thieno[2,3- c]pyridinyl and thiophenyl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of Ci_7-alkyl, halogen, halogen-Ci_7-alkoxy, halogen- Ci_7-alkyl, Ci_7-alkoxy, cyano and phenyl.
  • R 5 is heteroaryl selected from the group consisting of IH-pyrazolyl, benzo[b]thiophenyl, isoxazolyl, oxazolyl, pyrazinyl, pyridinyl
  • the invention relates to compounds of formula I as herein described, wherein R 5 is heteroaryl selected from the group consisting of IH-pyrazolyl, thiazolyl, oxazolyl, pyridinyl, substituted by one or two substituents selected from the group consisting of Ci_7-alkyl, halogen and cyano.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is IH-pyrazolyl.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is thiazolyl. In a particular embodiment, the invention relates to compounds of formula I as herein described, wherein R 5 is oxazolyl.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is pyridinyl.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is heteroaryl selected from the group consisting of lH-pyrazole-3-yl, benzo[b]thiophene-2-yl, isoxazole-3-yl, oxazole-4-yl, pyrazine-2-yl, pyridine-2-yl, pyrimidine-2- yl, thiazol-4-yl, thieno[2,3-c]pyridine-7-yl and thiophene-2-yl, said heteroaryl being unsubstituted or substituted by one or two groups selected from the group consisting of methyl, fluoro, chloro, difluoromethoxy, trifluoroethoxy, trifluoromethyl, methoxy, cyano and phenyl.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is phenyl, said phenyl being unsubstituted or substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, halogen-Ci_7-alkyl, C 1-7 - alkoxy, halogen-Ci_ 7 -alkoxy, cyano, hydroxy-Ci_ 7 -alkyl, oxo and phenyl.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is phenyl, substituted by one or two halogen.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is Ci_ 7 -alkyl, unsubstituted or substituted by one, two, three, four or five halogen.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is ethyl, substituted by one, two, three, four or five fluoro.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is C3- 7 -cycloalkyl ring, unsubstituted or substituted by one, two or three groups selected from the group consisting of halogen and halogen-Ci_ 7 -alkyl.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is cyclopropyl, by one or two groups selected from the group consisting of fluoro and trifluoromethyl.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is 3- to 7-membered O-heterocyclyl ring, unsubstituted or substituted by one, two or three groups selected from the group consisting of Ci_ 7 -alkyl, halogen, halogen-Ci_ 7 - alkyl, Ci_ 7 -alkoxy, halogen-Ci_ 7 -alkoxy, cyano and hydroxy-Ci_ 7 -alkyl.
  • the invention relates to compounds of formula I as herein described, wherein R 5 is oxetanyl, substituted by methyl.
  • the invention relates to compounds of formula I as herein described, selected from the group consisting of
  • the invention relates to compounds of formula I as herein described, selected from the group consisting of
  • the invention relates to compounds of formula I as herein described, selected from the group consisting of
  • the invention relates to compounds of formula I as herein described, selected from the group consisting of
  • 6-chloro-pyridine-2-carboxylic acid [3-((S)-2-amino-4-methyl-5,6-dihydro-4H-[l,3]oxazin-4- yl)-4-fluoro-phenyl]-amide, 3,5-difluoro-pyridine-2-carboxylic acid [3-((S)-2-amino-4-methyl-5,6-dihydro-4H-[l,3]oxazin- 4-yl)-4-fluoro-phenyl]-amide,
  • the invention relates to a process to synthesize compounds of formula I as herein described, which process comprises reacting an amine of the formula II
  • R 1 to R 4 are as defined herein and Boc is the protecting group tert- butyloxycarbonyl, with a carboxylic acid of the formula III wherein R 5 is as defined herein, in the presence of a coupling reagent under basic conditions to obtain a compound of the formula IV
  • the invention relates to pharmaceutical compositions comprising a compound of formula I as described herein and a pharmaceutically acceptable carrier and/or adjuvant.
  • the invention relates to compounds of formula I as described herein for use as medicaments.
  • the invention relates to compounds of formula I as described herein for use as medicaments for the treatment or prevention of diseases which are associated with inhibition of BACE2 activity.
  • the invention relates to compounds of formula I as described herein for use as medicaments for the treatment or prevention of diabetes, particularly type 2 diabetes.
  • the invention relates to compounds of formula I as described herein for use as medicaments for the treatment or prevention of type 2 diabetes.
  • the invention relates to a method for the treatment of diseases which are associated with the inhibition of BACE 2 activity, particularly for the treatment of type 2 diabetes, which method comprises administering a therapeutically active amount of a compound of formula I as described herein to a human being or animal.
  • the invention relates to the use of compounds of formula I as described herein for the preparation of medicaments for the treatment or prevention of diseases which are associated with the inhibition of BACE2 activity.
  • the invention relates to the use of compounds of formula I as described herein for the preparation of medicaments for the treatment or prevention of diabetes, particularly type 2 diabetes.
  • R 3 signifies Ci_7-alkyl.
  • Compounds of formula I of the present invention are particular, wherein R 3 is methyl or ethyl.
  • Another group of particular compounds are those, wherein or R 2 and R 3 together with the C atoms they are attached to form a C3_7-cycloalkyl or a 3- to 7-membered O-heterocyclyl ring, with those compounds being more particular, wherein R 2 and R 3 together with the C atoms they are attached to form a 3- to 7-membered O-heterocyclyl ring.
  • compounds of formula I according to the invention are particular, wherein R 4 is hydrogen or halogen. More particularly, R 4 is halogen.
  • compounds of formula I, wherein R 4 is hydrogen or fluoro with those compounds of formula I, wherein R 4 is fluoro being most particular.
  • R 5 is heteroaryl, said heteroaryl being unsubstituted or substituted by one, two or three groups selected from the group consisting of Ci_7-alkyl, halogen, halogen-Ci_7-alkyl, Ci_7-alkoxy, halogen-Ci_7-alkoxy, cyano, hydroxy-Ci_7-alkyl, oxo and phenyl.
  • Particularly particular compounds of formula I of the present invention are the following: 3,5-dichloro-pyridine-2-carboxylic acid [3-((S)-2-amino-4-methyl-5,6-dihydro-4H-[l ,3]oxazin- 4-yl)-4-fluoro-phenyl]-amide,
  • HC1 formic acid and trifluoro acetic acid
  • CF3COOH trifluoro acetic acid
  • the compounds of formula I can exist in tautomeric forms, e.g. in the following tautomeric form:
  • Compounds of formula I possess one asymmetric carbon atom and can exist in the form of optically pure enantiomers and mixtures of enantiomers such as, for example, racemates.
  • the optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbens or eluant).
  • the invention embraces all of these forms.
  • the compounds of general formula I in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
  • Physiologically acceptable and metabolically labile derivatives, which are capable of producing the parent compounds of general formula I in vivo are also within the scope of this invention.
  • protecting group denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry.
  • Protecting groups can be removed at the appropriat point.
  • Exemplary protecting groups are amino -protecting groups, carboxy-protecting groups or hydroxy-protecting groups.
  • protecting group in context with amines denotes groups intended to protect an amino group and includes benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), Fmoc (9- Fluorenylmethyloxycarbonyl), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert- butoxycarbonyl (BOC), and trifluoroacetyl. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., John Wiley & Sons, Inc., New York, NY, 1991, chapter 7; E.
  • IC50 half maximal inhibitory concentration
  • IC50 values can be converted logarithmically to pIC50 values (-log IC50), in which higher values indicate exponentially greater potency.
  • the IC50 value is not an absolute value but depends on experimental conditions e.g. concentrations employed.
  • the IC50 value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22:3099).
  • inhibitor denotes a compound which competes with, reduces or prevents the binding of a particular ligand to particular receptor or which reduces or prevents the inhibition of the function of a particular protein.
  • therapeutically effective amount denotes an amount of a compound of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
  • treating includes (1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state, (2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or (3) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
  • Appropriate coupling agents are carbodiimides or uranium salts, such as for example ⁇ , ⁇ '- carbonyldiimidazole (CDI), N,AT-dicyclohexylcarbodiimide (DCC), N-(3- dimethylaminopropy ⁇ -A ⁇ -ethyl-carbodiimide-hydrochloride (EDCI), 0-(benzotriazol- 1 -yl)- tetrafluoroborate (TBTU) and l-[bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU).
  • CDI ⁇ , ⁇ '- carbonyldiimidazole
  • DCC N,AT-dicyclohexylcarbodiimide
  • EDCI N-(3- dimethylaminopropy ⁇ -A ⁇ -ethyl-carbodi
  • the term "under basic conditions” means the presence of a base, particularly an alkylamine such as diisopropylethylamine (DIE A) or triethylamine (TEA), or a tertiary amine such as N- methylmorpholine or 4-(dimethylamino)-pyridine.
  • a base particularly an alkylamine such as diisopropylethylamine (DIE A) or triethylamine (TEA), or a tertiary amine such as N- methylmorpholine or 4-(dimethylamino)-pyridine.
  • DIE A diisopropylethylamine
  • TAA triethylamine
  • a tertiary amine such as N- methylmorpholine or 4-(dimethylamino)-pyridine.
  • DMF N,N-dimethylformamide
  • DMAc dimethylacetamide
  • Particular mineral acids for the deprotection are sulfuric acid or hydrochloric acid, more particularly hydrochloric acid in a solvent such as an ether, particularly diethyl ether or 1,4- dioxane, or neat trifluoro acetic acid.
  • the invention further relates to compounds of formula I as defined above obtainable according to a process as defined above.
  • the conversion of the sulfinyl imine A to the sulfmamide ester B or Ba proceeds stereoselectively by the chiral directing group as described by Tang & Ellman.
  • the sulfinyl imine A can be reacted with a titanium enolate generated from e.g. an alkyl acetate, particularly methyl acetate, LDA and chlorotriisopropoxytitanium at low temperature, particularly at -78°C in a solvent such as an ether, e.g. diethyl ether or more particularly THF.
  • Hydrolysis of the chiral directing group in the sulfmamide ester B to give the amino ester C can be accomplished with a mineral acid, e.g. sulfuric acid or particularly hydrochloric acid in a solvent such as an ether, e.g. diethyl ether or more particularly 1,4-dioxane.
  • a mineral acid e.g. sulfuric acid or particularly hydrochloric acid
  • a solvent such as an ether, e.g. diethyl ether or more particularly 1,4-dioxane.
  • Aminoalcohol D can be prepared by the reduction of the methylester with an alkali hydride, particularly lithium borohydride or lithium aluminium hydride in a solvent such as an ether, e.g. diethyl ether or more particularly THF.
  • an alkali hydride particularly lithium borohydride or lithium aluminium hydride
  • a solvent such as an ether, e.g. diethyl ether or more particularly THF.
  • Aminooxazine E can be prepared by a two-step procedure involving first the reaction of amino alkohol D and cyanogenbromide in a solvent such as an ether, particularly THF, followed by reaction with a mineral acid, particularly hydrochloric acid in a solvent such as THF.
  • Boc-protected Aminooxazine F can be prepared by reaction of aminooxazine with di-tert- butyl-dicarbonate with an alkylamine such as TEA or particularly diisopropylamine in a solvent such as an ether, particularly THF.
  • the reduction of the nitro group in the Boc-protected Aminooxazine F to the aniline G can be accomplished by hydrogenation using a catalysts such as Pd/C in protic solvents, such as alcohols, perferrabyl ethanol or methanol.
  • Amide coupling of the aniline G and a carboxylic acid to give the amide H can be effected with a carbodiimide, e.g. DCC or EDCI in a solvent such as dichloromethane.
  • Deprotection of the tert-butyloxycarbonyl group in H is effected with trif uoro acetic acid in a solvent such as dichloromethane .
  • hydrolysis of the chiral directing group and the t-butyl ester in the sulfmamide ester Ba to give the amino acid Ca can be accomplished with a mineral acid, e.g. sulfuric acid or particularly hydrochloric acid in a solvent such as an ether, e.g.
  • the reduction of the amino acid Ca to give the amino alcohol Da can be effected with an alkali hydride, e.g. lithium borohydride or lithium aluminium hydride or a borane, perferably BH 3 -THF complex in an ether as solvent, e.g. diethyl ether or more particularly THF.
  • Ring closure of the amino alcohol Da to give the amino oxazine Ea can be prepared by a two-step procedure involving first the reaction of the amino alcohol Da and cyanogenbromide in a solvent such as an ether, particularly THF, followed by reaction with a mineral acid, particularly hydrochloric acid in a solvent such as THF.
  • the reduction of the nitro group in the intermediate Ea to give the aniline Fa can be accomplished by hydrogenation using a catalyst such as Pd/C in protic solvents, such as alcohols, particularly methanol or more particularly ethanol.
  • aminooxazines K can be prepared from an amino alcohol such as Jb (preparation described in WO 2009091016) by a two-step procedure involving first the reaction of amino alcohol J and cyanogenbromide in a solvent such as an ether, particularly THF, followed by reaction with a mineral acid, particularly hydrochloric acid in a solvent such as THF.
  • a solvent such as an ether, particularly THF
  • nitro group in K to give Eb was best performed according to the standard procedure involving sulfuric acid and nitric acid at low temperature, preferably at 0°C.
  • the reduction of the nitro group in aminooxazine Eb to the aniline Fb can be accomplished by hydrogenation using a catalyst such as Pd/C in protic solvents, such as alcohols, particularly methanol or more particularly ethanol.
  • Amide coupling of the aniline Fb and a carboxylic acid to give the amides I can be effected with a carbodiimide, e.g. DCC, EDCI or preferably DMTMM in a suitable solvent such as methanol.
  • a carbodiimide e.g. DCC, EDCI or preferably DMTMM in a suitable solvent such as methanol.
  • the compounds of formula I of the present invention can be used as medicaments for the treatment of diseases which are associated with the inhibition of BACE2.
  • the compounds of formula I of the present invention can be used as medicaments for the treatment of diseases which are associated with the inhibition of BACE2.
  • the compounds of formula I of the invention will be useful in preserving and restoring beta-cell function and stimulating insulin secretion in diabetic patients and in non-diabetic patients who have impaired glucose tolerance or who are in a pre-diabetic condition. They may be useful in treating type 1 diabetes or in delaying or preventing a patient with type 2 diabetes from needing insulin therapy.
  • the compounds of formula I are further useful to ameliorate hyperinsulinemia, which often occurs in diabetic or pre-diabetic patients and in reducing the risks associated with metabolic syndrome, they may also be useful in treating vascular diseases such as hypertension.
  • the expression 'diseases which are associated with the inhibition of BACE2 activity' means diseases such as metabolic and cardiovascular diseases, in particular diabetes, more particularly type 2 diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, pre-diabetes, metabolic syndrome, diabetes type 1, complications of diabetes including diabetic nephropathy, diabetic retinopathy and diabetic neuropathy, chronic kidney disease, dyslipidemia, atherosclerosis, myocardial infarction, hypertension and further metabolic and cardiovascular disorders.
  • diseases such as metabolic and cardiovascular diseases, in particular diabetes, more particularly type 2 diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, pre-diabetes, metabolic syndrome, diabetes type 1, complications of diabetes including diabetic nephropathy, diabetic retinopathy and diabetic neuropathy, chronic kidney disease, dyslipidemia, atherosclerosis, myocardial infarction, hypertension and further metabolic and cardiovascular disorders.
  • the expression 'diseases which are associated with the inhibition of BACE2 activity' relates to diabetes, particularly type II diabetes, impaired glucose tolerance, pre-diabetes, metabolic syndrome and hypertension. More particularly, the expression 'diseases which are associated with the inhibition of BACE2 activity' relates to diabetes, most particularly type 2 diabetes.
  • the invention also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant. More specifically, the invention relates to pharmaceutical compositions useful for the treatment of diseases which are associated with the inhibition of BACE2 activity.
  • the invention relates to compounds of formula I as defined above for use as medicaments, particularly as medicaments for the treatment or prevention of diseases which are associated with the inhibition of BACE2 activity.
  • compounds of formula I for use in diabetes particularly type 2 diabetes.
  • the invention in another aspect, relates to a method for the treatment or prevention of diseases which are associated with the inhibition of BACE2 activity, which method comprises administering a therapeutically active amount of a compound of formula I to a human being or animal.
  • a method for the treatment of diabetes, particularly type 2 diabetes, is particular.
  • the invention further relates to the use of compounds of formula I as defined above for the treatment of diseases which are associated with the inhibition of BACE2 activity.
  • the invention relates to the use of compounds of formula I as defined above for the preparation of medicaments for the treatment or prevention of diseases which are associated with the inhibition of BACE2 activity.
  • the compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g., in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g., in the form of suppositories, parenterally, e.g., in the form of injection solutions or suspensions or infusion solutions, or topically, e.g., in the form of ointments, creams or oils. Oral administration is particular.
  • the production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials.
  • lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft gelatine capsules).
  • Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like.
  • Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils.
  • Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
  • Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • Usual stabilizers preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
  • the dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 to 1000 mg, especially about 1 to 300 mg, comes into consideration. Depending on severity of the disease and the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g., in 1 to 3 dosage units.
  • the pharmaceutical preparations conveniently contain about 1-500 mg, particularly 1-100 mg, of a compound of formula I.
  • the following examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.
  • DCC N,N'-diisopropyl-carbodiimide
  • DIEA diisopropylethylamine
  • DMAc dimethylacetamide
  • DMAP 4-dimethylaminopyridine
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EDCI N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride
  • HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-3 ⁇ 4]pyridinium- 3-oxide hexafluorophosphate
  • HC1 hydrogen chloride
  • HPLC high performance liquid chromatography
  • LDA lithium diisopropylamide
  • MS mass spectrum
  • NMR nuclear magnetic resonance
  • TEA triethylamine
  • THF tetrahydrofuran.
  • the mixture was treated with a solution of the sulfinyl imine A (17.1 mmol) in THF (10 ml) and stirring was continued at -78 °C for 3 h.
  • the mixture was quenched with saturated aqueous NH 4 C1 solution (150 ml) and the mixture was filtered over dicalite. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried and evaporated. The residue was chromato graphed on silica using a mixture of heptane and ethylacetate as eluent to give the pure sulfmamide ester B.
  • the 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid was prepared as follows: a) To a solution of 3-hydroxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.3 mmol) in N,N-dimethylformamide (2.0 ml) was added at 22 °C sodium hydride (55% in oil, 64 mg) and stirring was continued until gas evolution ceased. The suspension was cooled to 0 °C and treated with trifluoro ethyl trifluormethanesulfonate (728 mg) and stirring was continued at 22 °C for 2 hours.
  • Assay for BACE inhibition by measuring cellular TMEM27 cleavage uses the principle of inhibition of human TMEM27 cleavage by endogenous cellular BACE2 in the Insle rat cell line and shedding from the cell surface into the culture medium, followed by detection in an ELISA assay. Inhibition of BACE2 prevents the cleavage and shedding in a dose-dependent manner.
  • the stable cell line "INS-TMEM27” represents an INSle-derived cell line with inducible expression (using the TetOn system) of full-length hTMEM27 in a doxycycline-dependent manner.
  • the cells are cultured throughout the experiment in RPMI1640 + Glutamax (Invitrogen) Penicillin/Streptomycin, 10% Fetal bovine serum, 100 mM pyruvate, 5 mM beta- mercaptoethanol, 100 micrograms/ml G418 and lOOmicrogram/ml hygromycin and are grown inadherent culture at 37 °C in a standard C0 2 cell culture incubator.
  • Glutamax Invitrogen
  • Penicillin/Streptomycin 10% Fetal bovine serum
  • 100 mM pyruvate 100 mM pyruvate
  • 5 mM beta- mercaptoethanol 100 micrograms/ml G418 and lOOmicrogram/ml hygromycin
  • INS-TMEM27 cells are seeded in 96-well plates. After 2 days in culture, BACE2 inhibitor is added in a range of concentrations as required by the assay and after a further two hours, doxycycline is added to a final concentration of 500ng/ml. The cells are incubated for a further 46 hours and the supernatant harvested for detection of shed TMEM27. An ELISA assay (using a pair of mouse anti-human-TMEM27 antibodies, raised against the extracellular domain of TMEM27) is used for detection of TMEM27 in the culture medium. An IC 50 for BACE2 inhibition is calculated using the ELISA readout for each inhibitor concentration with standard curve-fitting software XLfit (IDBS) for the Excel spreadsheet program.
  • IDBS standard curve-fitting software XLfit
  • Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
  • the active ingredient is sieved and mixed with micro crystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water.
  • the granulate is mixed with sodium starch glycolate and magnesiumstearate and compressed to yield kernels of 120 or 350 mg respectively.
  • the kernels are lacquered with an aqueous solution / suspension of the above mentioned film coat.
  • Capsules containing the following ingredients can be manufactured in a conventional manner: Ingredients Per capsule
  • Injection solutions can have the following composition:
  • the active ingredient is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part).
  • the pH is adjusted to 5.0 by Acetic Acid.
  • the volume is adjusted to 1.0 ml by addition of the residual amount of water.
  • the solution is filtered, filled into vials using an appropriate overage and sterilized.
  • Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner:
  • Soya bean oil HO.O mg
  • Iron oxide yellow 1.1 mg
  • the active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size.
  • the filled soft gelatin capsules are treated according to the usual procedures.
  • Example E Sachets containing the following ingredients can be manufactured in a conventional manner:
  • Microcristalline cellulose (AVICEL PH 102) 1400.0 mg
  • Flavoring additives 1.0 mg
  • the active ingredient is mixed with lactose, microcristalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water.
  • the granulate is mixed with magnesium stearate and the flavouring additives and filled into sachets.

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Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8168630B2 (en) 2007-04-24 2012-05-01 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US8173642B2 (en) 2005-10-25 2012-05-08 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8207164B2 (en) 2009-07-24 2012-06-26 Novartis Ag Oxazine derivatives and their use in the treatment of neurological disorders
EP2511268A1 (en) * 2009-12-11 2012-10-17 Shionogi & Co., Ltd. Oxazine derivative
WO2012139993A1 (en) * 2011-04-11 2012-10-18 F. Hoffmann-La Roche Ag 1,3 oxazines as bace1 and/or bace2 inhibitors
WO2012147763A1 (ja) 2011-04-26 2012-11-01 塩野義製薬株式会社 オキサジン誘導体およびそれを含有するｂａｃｅ１阻害剤
WO2012156284A1 (en) * 2011-05-16 2012-11-22 F. Hoffmann-La Roche Ag 1,3-oxazines as bace1 and/or bace2 inhibitors
WO2012168164A1 (en) * 2011-06-07 2012-12-13 F. Hoffmann-La Roche Ag Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors
WO2012168175A1 (en) * 2011-06-07 2012-12-13 F. Hoffmann-La Roche Ag [1,3]oxazines
US8338413B1 (en) 2012-03-07 2012-12-25 Novartis Ag Oxazine derivatives and their use in the treatment of neurological disorders
WO2013041499A1 (en) * 2011-09-21 2013-03-28 F. Hoffmann-La Roche Ag N-(3-(2-amino-6,6-difluoro-4,4a,5,6,7,7a-hexahydro-cyclopenta[e][1,3]oxazin-4-yl)-phenyl)-amides as bace1 inhibitors
JPWO2011071109A1 (ja) * 2009-12-11 2013-04-22 塩野義製薬株式会社 アミノ基を有する縮合ヘテロ環化合物
US8524897B2 (en) 2011-01-12 2013-09-03 Novartis Ag Crystalline oxazine derivative
US8563543B2 (en) 2009-10-08 2013-10-22 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
US8569310B2 (en) 2009-10-08 2013-10-29 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use
US8637508B2 (en) 2011-01-13 2014-01-28 Novartis Ag Heterocyclic derivatives and their use in the treatment of neurological disorders
US8637504B2 (en) 2008-06-13 2014-01-28 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US8653067B2 (en) 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
WO2014059185A1 (en) 2012-10-12 2014-04-17 Amgen Inc. Amino - dihydrothiazine and amino - dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
WO2014065434A1 (en) * 2012-10-24 2014-05-01 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having bace1 inhibitory activity
US8729071B2 (en) 2009-10-08 2014-05-20 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
WO2014078314A1 (en) 2012-11-15 2014-05-22 Amgen Inc. Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
JP2014515382A (ja) * 2011-05-27 2014-06-30 エフ．ホフマン−ラ ロシュ アーゲー Ｂａｃｅ１及び／又はｂａｃｅ２阻害剤としてのスピロ−［１，３］−オキサジン及びスピロ−［１，４］−オキサゼピン誘導体
WO2014134341A1 (en) 2013-03-01 2014-09-04 Amgen Inc. Perfluorinated 5,6-dihydro-4h-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2014138484A1 (en) 2013-03-08 2014-09-12 Amgen Inc. Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2014173917A1 (en) * 2013-04-26 2014-10-30 F. Hoffmann-La Roche Ag Synthesis of bace1 inhibitors
US8927721B2 (en) 2010-10-29 2015-01-06 Shionogi & Co., Ltd. Naphthyridine derivative
JP2015512445A (ja) * 2012-04-03 2015-04-27 イーライ リリー アンド カンパニー テトラヒドロピロロチアジン化合物
US9018219B2 (en) 2010-10-29 2015-04-28 Shionogi & Co., Ltd. Fused aminodihydropyrimidine derivative
US9145426B2 (en) 2011-04-07 2015-09-29 Merck Sharp & Dohme Corp. Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
WO2015156421A1 (en) 2014-04-11 2015-10-15 Shionogi & Co., Ltd. Dihydrothiazine and dihydrooxazine derivatives having bace1 inhibitory activity
US9163011B2 (en) 2011-08-25 2015-10-20 Novartis Ag Oxazine derivatives and their use in the treatment of disease
US9181236B2 (en) 2011-08-22 2015-11-10 Merck Sharp & Dohme Corp. 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use
US9221839B2 (en) 2011-04-07 2015-12-29 Merck Sharp & Dohme Corp. C5-C6 oxacyclic-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
WO2016150785A1 (en) 2015-03-20 2016-09-29 F. Hoffmann-La Roche Ag Bace1 inhibitors
US9489013B2 (en) 2012-12-20 2016-11-08 Merck Sharp & Dohme Corp. C6-azaspiro iminothiadiazine dioxides as bace inhibitors, compositions, and their use
US9499502B2 (en) 2011-04-13 2016-11-22 Merck Sharp & Dohme Corp. 5-substituted iminothiazines and their mono- and dioxides as BACE inhibitors, compositions, and their use
US9550762B2 (en) 2014-08-08 2017-01-24 Amgen, Inc. Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
US11629154B2 (en) 2018-04-27 2023-04-18 Shionogi & Co., Ltd. Tetrahydropyranooxazine derivatives having selective BACE1 inhibitory activity

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015514073A (ja) * 2012-03-20 2015-05-18 エラン ファーマシューティカルズ， リミテッド・ライアビリティ・カンパニー スピロ環式ジヒドロ−チアジンおよびジヒドロ−オキサジンｂａｃｅ阻害剤、ならびにその組成物および使用
US9045477B2 (en) * 2013-03-15 2015-06-02 Epizyme, Inc. Substituted 6,5-fused bicyclic heteroaryl compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006009653A1 (en) * 2004-06-16 2006-01-26 Wyeth Amino-5,5-diphenylimidazolone derivatives for the inhibition of beta-secretase
US20070027199A1 (en) * 2005-07-29 2007-02-01 Wyeth Cycloalkyl amino-hydantoin compounds and use thereof for beta-secretase modulation
WO2009091016A1 (ja) 2008-01-18 2009-07-23 Eisai R & D Management Co., Ltd. 縮合アミノジヒドロチアジン誘導体

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE244564T1 (de) * 1999-02-09 2003-07-15 Univ Virginia Felbamat-derivate
WO2004043916A1 (en) * 2002-11-12 2004-05-27 Merck & Co., Inc. Phenylcarboxamide beta-secretase inhibitors for the treatment of alzheimer's disease
WO2006041404A1 (en) * 2004-10-15 2006-04-20 Astrazeneca Ab Substituted amino-compounds and uses thereof
CN103936690B (zh) 2005-10-25 2016-06-08 盐野义制药株式会社 氨基二氢噻嗪衍生物
EP2147914B1 (en) * 2007-04-24 2014-06-04 Shionogi&Co., Ltd. Aminodihydrothiazine derivatives substituted with cyclic groups
GB0912778D0 (en) * 2009-07-22 2009-08-26 Eisai London Res Lab Ltd Fused aminodihydro-oxazine derivatives
EP2511269A4 (en) * 2009-12-11 2013-04-24 Shionogi & Co FUSED HETEROCYCLIC COMPOUND HAVING AN AMINO GROUP

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006009653A1 (en) * 2004-06-16 2006-01-26 Wyeth Amino-5,5-diphenylimidazolone derivatives for the inhibition of beta-secretase
US20070027199A1 (en) * 2005-07-29 2007-02-01 Wyeth Cycloalkyl amino-hydantoin compounds and use thereof for beta-secretase modulation
WO2009091016A1 (ja) 2008-01-18 2009-07-23 Eisai R & D Management Co., Ltd. 縮合アミノジヒドロチアジン誘導体

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
E. HASLAM: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
G FINZI; F FRANZI; C PLACIDI; F ACQUATI ET AL.: "BACE2 is stored in secretory granules of mouse and rat pancreatic beta cells", ULTRASTRUCT PATHOL., vol. 32, no. 6, 2008, pages 246 - 251
I HUSSAIN; D POWELL; D HOWLETT; G CHAPMAN ET AL.: "ASPl (BACE2) cleaves the amyloid precursor protein at the (3- secretase site", MOL CELL NEUROSCI., vol. 16, 2000, pages 609 - 619
K FUKUI; Q YANG; Y CAO; N TAKAHASHI ET AL.: "The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation", CELL METAB., vol. 2, 2005, pages 373 - 384
LL BAGGIO; DJ DRUCKER: "Therapeutic approaches to preserve islet mass in type 2 diabetes", ANNU. REV. MED., vol. 57, 2006, pages 265 - 281
M PRENTKI; CJ NOLAN: "Islet beta-cell failure in type 2 diabetes", J. CLIN. INVESTIG., vol. 116, no. 7, 2006, pages 1802 - 1812
M PRENTKI; CJ NOLAN: "Islet beta-cell failure in type 2 diabetes.", J. CLIN. INVESTIG., vol. 116, no. 7, 2006, pages 1802 - 1812
P AKPINAR; S KUWAJIMA; J KR3TZFELDT; M STOFFEL: "Tmem27: A cleaved and shed plasma membrane protein that stimulates pancreatic 0 cell proliferation", CELL METAB., vol. 2, 2005, pages 385 - 397
P KUHN; E MARJAUX; A IMHOF; B DE STROOPER ET AL.: "Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase", J. BIOL. CHEM., vol. 282, no. 16, 2007, pages 11982 - 11995
P ZIMMET; KGMM ALBERTI; J SHAW: "Global and societal implications of the diabetes epidemic", NATURE, vol. 414, 2001, pages 782 - 787
S WILD; G ROGLIC; A GREEN; R.SICREE; H KING: "Global prevalence of diabetes", DIABETES CARE, vol. 27, no. 5, 2004, pages 1047 - 1053
ST.W. WRIGHT ET AL., TETRAHEDRON LETT., vol. 38, 1997, pages 7345
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Synthesis", 1991, JOHN WILEY & SONS, INC.
T.P. TANG; J.A. ELLMAN, J. ORG. CHEM., vol. 64, 1999, pages 12
T.W. GREENE: "Protective Groups in Organic Synthesis", 1981, JOHN WILEY AND SONS

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WO2012139993A1 (en) * 2011-04-11 2012-10-18 F. Hoffmann-La Roche Ag 1,3 oxazines as bace1 and/or bace2 inhibitors
JP2014510769A (ja) * 2011-04-11 2014-05-01 エフ．ホフマン−ラ ロシュ アーゲー Ｂａｃｅ１及び／又はｂａｃｅ２阻害剤としての１，３−オキサジン
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US8785436B2 (en) 2011-05-16 2014-07-22 Hoffmann-La Roche Inc. 1,3-oxazines as BACE 1 and/or BACE2 inhibitors
WO2012156284A1 (en) * 2011-05-16 2012-11-22 F. Hoffmann-La Roche Ag 1,3-oxazines as bace1 and/or bace2 inhibitors
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JP2015512445A (ja) * 2012-04-03 2015-04-27 イーライ リリー アンド カンパニー テトラヒドロピロロチアジン化合物
US9556135B2 (en) 2012-10-12 2017-01-31 Amgen, Inc. Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
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JP2016501827A (ja) * 2012-10-24 2016-01-21 塩野義製薬株式会社 Ｂａｃｅ１阻害作用を有するジヒドロオキサジンまたはオキサゼピン誘導体
US9758513B2 (en) 2012-10-24 2017-09-12 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
WO2014065434A1 (en) * 2012-10-24 2014-05-01 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having bace1 inhibitory activity
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US9489013B2 (en) 2012-12-20 2016-11-08 Merck Sharp & Dohme Corp. C6-azaspiro iminothiadiazine dioxides as bace inhibitors, compositions, and their use
US9296734B2 (en) 2013-03-01 2016-03-29 Amgen Inc. Perfluorinated 5,6-dihydro-4H-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
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US9611261B2 (en) 2013-03-08 2017-04-04 Amgen Inc. Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
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US9085576B2 (en) 2013-03-08 2015-07-21 Amgen Inc. Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2014173917A1 (en) * 2013-04-26 2014-10-30 F. Hoffmann-La Roche Ag Synthesis of bace1 inhibitors
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WO2015156421A1 (en) 2014-04-11 2015-10-15 Shionogi & Co., Ltd. Dihydrothiazine and dihydrooxazine derivatives having bace1 inhibitory activity
US9550762B2 (en) 2014-08-08 2017-01-24 Amgen, Inc. Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2016150785A1 (en) 2015-03-20 2016-09-29 F. Hoffmann-La Roche Ag Bace1 inhibitors
US11629154B2 (en) 2018-04-27 2023-04-18 Shionogi & Co., Ltd. Tetrahydropyranooxazine derivatives having selective BACE1 inhibitory activity

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