NZ617507B2 - Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors - Google Patents
Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors Download PDFInfo
- Publication number
- NZ617507B2 NZ617507B2 NZ617507A NZ61750712A NZ617507B2 NZ 617507 B2 NZ617507 B2 NZ 617507B2 NZ 617507 A NZ617507 A NZ 617507A NZ 61750712 A NZ61750712 A NZ 61750712A NZ 617507 B2 NZ617507 B2 NZ 617507B2
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- New Zealand
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- compound
- formula
- halogen
- alkoxy
- disease
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
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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
Abstract
The present disclosure provides compounds of formula (I) having BACE1 and/or BACE2 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present disclosure are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease and type 2 diabetes. Examples of compounds of formula (I) are: (S)-N-(3-(2-amino-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide and (S)-N-(3-(2-amino-5,5-difluoro-4-(fluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide. or prophylactic treatment of e.g. Alzheimer's disease and type 2 diabetes. Examples of compounds of formula (I) are: (S)-N-(3-(2-amino-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide and (S)-N-(3-(2-amino-5,5-difluoro-4-(fluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide.
Description
Case 27483
Halogen-alkyl-1,3 Oxazines as BACE1 and/or BACE2 inhibitors
Background Art
Alzheimer’s disease (AD) is a neurodegenerative disorder of the central nervous system
and the leading cause of a progressive dementia in the elderly population. Its clinical symptoms
are impairment of memory, cognition, temporal and local orientation, judgment and reasoning
but also severe emotional disturbances. There are currently no treatments available which can
prevent the disease or its progression or stably reverse its clinical symptoms. AD has become a
major health problem in all societies with high life expectancies and also a significant economic
burden for their health systems.
AD is characterized by 2 major pathologies in the central nervous system (CNS), the
occurrence of amyloid plaques and neurofibrillar tangles (Hardy et al., The amyloid hypothesis
of Alzheimer's disease: progress and problems on the road to therapeutics, Science. 2002 Jul
19;297(5580):353-6, Selkoe, Cell biology of the amyloid beta-protein precursor and the
mechanism of Alzheimer's disease, Annu Rev Cell Biol. 1994;10:373-403). Both pathologies are
also commonly observed in patients with Down’s syndrome (trisomy 21), which also develop
AD-like symptoms in early life. Neurofibrillar tangles are intracellular aggregates of the
microtubule-associated protein tau (MAPT). Amyloid plaques occur in the extracellular space;
their principal components are Aβ-peptides. The latter are a group of proteolytic fragments
derived from the β-amyloid precursor protein (APP) by a series of proteolytic cleavage steps.
Several forms of APP have been identified of which the most abundant are proteins of 695, 751
and 770 amino acids length. They all arise from a single gene through differential splicing. The
Aβ-peptides are derived from the same domain of the APP but differ at their N- and C-termini,
the main species are of 40 and 42 amino-acid length. There are several lines of evidence which
strongly suggest that aggregated Aβ-peptides are the essential molecules in the pathogenesis of
AD: 1) amyloid plaques formed of Aβ-peptides are invariably part of the AD pathology; 2) Aβ-
peptides are toxic for neurons; 3) in Familial Alzheimer’s Disease (FAD) the mutations in the
disease genes APP, PSN1, PSN2 lead to increased levels of Aβ-peptides and early brain
amyloidosis; 4) transgenic mice which express such FAD genes develop a pathology which bears
many resemblances to the human disease. Aβ-peptides are produced from APP through the
sequential action of 2 proteolytic enzymes termed β- and γ-secretase. β-Secretase cleaves first in
the extracellular domain of APP approximately 28 amino acids outside of the trans-membrane
domain (TM) to produce a C-terminal fragment of APP containing the TM- and the
cytoplasmatic domain (CTFβ). CTFβ is the substrate for γ-secretase which cleaves at several
adjacent positions within the TM to produce the Aβ peptides and the cytoplasmic fragment. The
γ-secretase is a complex of at least 4 different proteins, its catalytic subunit is very likely a
presenilin protein (PSEN1, PSEN2). The β-secretase (BACE1, Asp2; BACE stands for β-site
SMU / 28.03.2012
APP-cleaving enzyme) is an aspartyl protease which is anchored into the membrane by a
transmembrane domain (Vassar et al., Beta-secretase cleavage of Alzheimer's amyloid precursor
protein by the transmembrane aspartic protease BACE, Science. 1999 Oct 22;286(5440):735). It
is expressed in many tissues of the human organism but its level is especially high in the CNS.
Genetic ablation of the BACE1 gene in mice has clearly shown that its activity is essential for
the processing of APP which leads to the generation of Aβ-peptides, in the absence of BACE1
no Aβ-peptides are produced (Luo et al., Mice deficient in BACE1, the Alzheimer's beta-
secretase, have normal phenotype and abolished beta-amyloid generation, Nat Neurosci. 2001
Mar;4(3):231-2, Roberds et al., BACE knockout mice are healthy despite lacking the primary
beta-secretase activity in brain: implications for Alzheimer's disease therapeutics, Hum Mol
Genet. 2001 Jun 1;10(12):1317-24). Mice which have been genetically engineered to express the
human APP gene and which form extensive amyloid plaques and Alzheimer’s disease like
pathologies during aging fail to do so when β-secretase activity is reduced by genetic ablation of
one of the BACE1 alleles (McConlogue et al., Partial reduction of BACE1 has dramatic effects
on Alzheimer plaque and synaptic pathology in APP Transgenic Mice. J Biol Chem. 2007 Sep
7;282(36):26326). It is thus presumed that inhibitors of BACE1 activity can be useful agents for
therapeutic intervention in Alzheimer’s disease (AD).
Type 2 diabetes (T2D) is caused by insulin resistance and inadequate insulin secretion from
pancreatic β-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. In 2000, an estimated 171 million people had the condition with the expectation that this
figure will double by 2030 (S Wild, G Roglic, A Green, R.Sicree & H King, “Global prevalence
of diabetes”, Diabetes Care 2004, 27(5), 1047-1053), making the disease a major healthcare
problem. The rise in prevalence of T2D is associated with an increasingly sedentary lifestyle and
high-energy food intake of the world’s population (P Zimmet, KGMM Alberti & J Shaw,
“Global and societal implications of the diabetes epidemic” Nature 2001, 414, 782-787).
β-Cell failure and consequent dramatic decline in insulin secretion and hyperglycemia
marks the onset of T2D. Most current treatments do not prevent the loss of β-cell mass
characterizing overt T2D. However, recent developments with GLP-1 analogues, gastrin and
other agents show that preservation and proliferation of β-cells is possible to achieve, leading to
an improved glucose tolerance and slower progression to overt T2D (LL Baggio & DJ Drucker,
“Therapeutic approaches to preserve islet mass in type 2 diabetes”, Annu. Rev. Med. 2006, 57,
265-281).
Tmem27 has been identified as a protein promoting beta-cell proliferation (P Akpinar, S
Kuwajima, J Krützfeldt, M Stoffel, “Tmem27: A cleaved and shed plasma membrane protein
that stimulates pancreatic β 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 β-cells, resulting
from a degradation of the full-length cellular Tmem27. Overexpression of Tmem27 in a
transgenic mouse increases β-cell mass and improves glucose tolerance in a diet-induced obesity
DIO model of diabetes. Furthermore, siRNA knockout of Tmem27 in a rodent β-cell
proliferation assay (e.g. using INS1e cells) reduces the proliferation rate, indicating a role for
Tmem27 in control of β-cell mass.
In the same proliferation assay, BACE2 inhibitors also increase proliferation. However,
BACE2 inhibition combined with Tmem27 siRNA knockdown results in low proliferation rates.
Therefore, it is concluded that BACE2 is the protease responsible for the degradation of
Tmem27. Furthermore, in vitro, BACE2 cleaves a peptide based on the sequence of Tmem27.
The closely related protease BACE1 does not cleave this peptide and selective inhibition of
BACE1 alone does not enhance proliferation of β-cells.
The close homolog BACE2 is a membrane-bound aspartyl protease and is co-localized
with Tmem27 in human pancreatic β -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 β-secretase site” Mol Cell Neurosci. 2000, 16, 609-619), 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) and
ACE2. The capability to degrade ACE2 indicates a possible role of BACE2 in the control of
hypertension.
Inhibition of BACE2 is therefore proposed as a treatment for T2D with the potential to
preserve and restore β-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.
Furthermore, the formation, or formation and deposition, of β-amyloid peptides in, on or
around neurological tissue (e.g., the brain) are inhibited by the present compounds, i.e. inhibition
of the Aβ-production from APP or an APP fragment.
Inhibitors of BACE1 and/or BACE2 can in addition be used to treat the following diseases:
IBM (inclusion body myositis) (Vattemi G. et al., Lancet. 2001 Dec 8;358(9297):1962-4),
Down’s Syndrome (Barbiero L. et al, Exp Neurol. 2003 Aug;182(2):335-45), Wilson’s Disease
(Sugimoto I. et al., J Biol Chem. 2007 Nov 30;282(48):34896-903), Whipple’s disease (Desnues
B. et al., Clin Vaccine Immunol. 2006 Feb;13(2):170-8), SpinoCerebellar Ataxia 1 and
SpinoCerebellar Ataxia 7 (Gatchel J.R. et al., Proc Natl Acad Sci U S A 2008 Jan
29;105(4):1291-6), Dermatomyositis (Greenberg S.A. et al., Ann Neurol. 2005 Can;57(5):664-
78 and Greenberg S.A. et al., Neurol 2005 Can;57(5):664-78), Kaposi Sarcoma (Lagos D. et al,
Blood, 2007 Feb 15; 109(4):1550-8), Glioblastoma multiforme (E-MEXP-2576,
http://www.ebi.ac.uk/microarray-as/aer/result?queryFor=PhysicalArrayDesign&aAccession=A-
MEXP-258), Rheumatoid arthritis (Ungethuem U. et al, GSE2053), Amyotrophic lateral
sclerosis (Koistinen H. et al., Muscle Nerve. 2006 Oct;34(4):444-50 and Li Q.X. et al, Aging
Cell. 2006 Apr;5(2):153-65), Huntington’s Disease (Kim Y.J. et al., Neurobiol Dis. 2006
Can;22(2):346-56. Epub 2006 Jan 19 and Hodges A. et al., Hum Mol Genet. 2006 Mar
;15(6):965-77. Epub 2006 Feb 8), Multiple Mieloma (Kihara Y. et al, Proc Natl Acad Sci U S
A. 2009 Dec 22;106(51):21807-12), Malignant melanoma (Talantov D. et al, Clin Cancer Res.
2005 Oct 15;11(20):7234-42), Sjogren syndrome (Basset C. et al., Scand J Immunol. 2000
Mar;51(3):307-11), Lupus erythematosus (Grewal P.K. et al, Mol Cell Biol. 2006,
Jul;26(13):4970-81), Macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous
arthritis, Breast cancer (Hedlund M. et al, Cancer Res. 2008 Jan 15;68(2):388-94 and Kondoh K.
et al., Breast Cancer Res Treat. 2003 Mar;78(1):37-44), Gastrointestinal diseases (Hoffmeister A.
et al, JOP. 2009 Sep 4;10(5):501-6), Autoimmune/inflammatory diseases (Woodard-Grice A.V.
et al., J Biol Chem. 2008 Sep 26;283(39):26364-73. Epub 2008 Jul 23), Rheumatoid Arthritis
(Toegel S. et al, Osteoarthritis Cartilage. 2010 Feb;18(2):240-8. Epub 2009 Sep 22),
Inflammatory reactions (Lichtenthaler S.F. et al., J Biol Chem. 2003 Dec 5;278(49):48713-9.
Epub 2003 Sep 24), Arterial Thrombosis (Merten M. et al., Z Kardiol. 2004 Nov;93(11):855-63),
Cardiovascular diseases such as Myocardial infarction and stroke (Maugeri N. et al., Srp Arh
Celok Lek. 2010 Jan;138 Suppl 1:50-2) and Graves disease (Kiljański J. et al, Thyroid. 2005
Jul;15(7):645-52).
The present invention provides novel compounds of formula I, their manufacture,
medicaments based on a compound in accordance with the invention and their production as well
as the use of compounds of formula I for the manufacture of medicaments for use in the control
or prevention of illnesses such as Alzheimer’s disease and type 2 diabetes. Furthermore the
invention relates to use of compounds of formula I for the manufacture of medicaments for the
treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory
diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and
stroke, dermatomyositis, Down’s Syndrome, gastrointestinal diseases, Glioblastoma multiforme,
Graves Disease, Huntington’s Disease, inclusion body myositis (IBM), inflammatory reactions,
Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile
idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid
arthritis, Sjogren syndrome, SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whipple’s
Disease and Wilson’s Disease. The novel compounds of formula I have improved
pharmacological properties.
Field of the Invention
The present invention provides halogen-alkyl-[1,3]oxazinylamines having BACE1
and/or BACE2 inhibitory properties, their manufacture, pharmaceutical compositions containing
them and their use as therapeutically active substances.
Summary of the Invention
The present invention provides a compounds of formula I,
HN O
wherein the substituents and variables are as described below and in the claims, or a
pharmaceutically acceptable salt thereof.
The present compounds have Asp2 (β-secretase, BACE1 or Memapsin-2) inhibitory
activity and can therefore be used in the therapeutic and/or prophylactic treatment of diseases
and disorders characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or
β-amyloid plaques and further deposits, particularly Alzheimer's disease. And/or the present
compounds have BACE2 inhibitory activity and can therefore be used in the therapeutic and/or
prophylactic treatment of diseases and disorders such as type 2 diabetes and other metabolic
disorders.
Detailed Description of the Invention
The present invention provides a compound of formula I and their pharmaceutically
acceptable salts thereof, the preparation of the above mentioned compounds, medicaments
containing them and their manufacture as well as the use of the above mentioned compounds for
the manufacture of medicaments for the therapeutic and/or prophylactic treatment of diseases
and disorders which are associated with inhibition of BACE1 and/or BACE2 activity, such as
Alzheimer’s disease and type 2 diabetes. Furthermore, the formation, or formation and
deposition, of β-amyloid plaques in, on or around neurological tissue (e.g., the brain) are
inhibited by the present compounds by inhibiting the Aβ production from APP or an APP
fragment.
The following definitions of the general terms used in the present description apply
irrespectively of whether the terms in question appear alone or in combination with other groups.
Unless otherwise stated, the following terms used in this Application, including the
specification and claims, have the definitions given below. It must be noted that, as used in the
specification and the appended claims, the singular forms “a”, “an,” and “the” include plural
referents unless the context clearly dictates otherwise.
The term "C -alkyl", alone or in combination with other groups, stands for a hydrocarbon
radical which can be linear or branched, with single or multiple branching, wherein the alkyl
group in general comprises 1 to 6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl,
isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (tert-butyl), isopentyl,
2-ethyl-propyl, 1,2-dimethyl-propyl and the like. The term "C -alkyl", alone or in combination
with other groups, stands for a hydrocarbon radical which can be linear or branched, wherein the
alkyl group comprises 1 to 3 carbon atoms. Particular “C -alkyl” groups are "C -alkyl".
1-6 1-3
Specific groups are methyl and ethyl. Most specific is methyl.
The term “halogen-C -alkyl”, alone or in combination with other groups, refers to C -
1-6 1-6
alkyl as defined herein, which is substituted by one or multiple halogen, in particular 1-5
halogen, more particular 1-3 halogen, most particular 1 halogen or 3 halogen. Particular halogen
is fluoro. Particular “halogen-C -alkyl” is fluoro-C -alkyl. Examples are fluoromethyl,
1-6 1-6
difluoromethyl, trifluoromethyl and the like. Specific groups are difluoromethyl (-CHF ) or
fluoromethyl (-CH F).
The term “cyano-C -alkyl”, alone or in combination with other groups, refers to C -
1-6 1-6
alkyl as defined herein, which is substituted by one or multiple cyano, in particular 1 cyano.
Particular “cyano-C -alkyl” group is cyanomethyl.
The term “cycloalkyl-C -alkyl”, alone or in combination with other groups, refers to C -
1-6 1-6
alkyl as defined herein, which is substituted by one or multiple cycloalkyl as defined herein, in
particular one cycloalkyl. Particular “cycloalkyl-C -alkyl” group is cyclopentyl-methyl.
The term “C -alkoxy-C -alkyl”, alone or in combination with other groups, refers to C
1-6 1-6 1-
-alkyl as defined herein, which is substituted by one or multiple C -alkoxy as defined herein,
6 1-6
in particular 1 C -alkoxy. Particular “C -alkoxy-C -alkyl” group is methoxy-methyl.
1-6 1-6 1-6
The term “cyano”, alone or in combination with other groups, refers to N≡C- (NC-).
The term "halogen", alone or in combination with other groups, denotes chloro (Cl), iodo
(I), fluoro (F) and bromo (Br). Particular “halogen” groups are Cl and F. Specific group is F.
The term "heteroaryl", alone or in combination with other groups, refers to an aromatic
carbocyclic group of having a single 4 to 8 membered ring or multiple condensed rings
comprising 6 to 14, in particular 6 to 10 ring atoms and containing 1, 2 or 3 heteroatoms
individually selected from N, O and S, in particular 1 N, in which group at least one heterocyclic
ring is aromatic. Examples of "heteroaryl" groups include benzofuryl, benzoimidazolyl, 1H-
benzoimidazolyl, benzooxazinyl, benzoxazolyl, benzothiazinyl, benzothiazolyl, benzothienyl,
benzotriazolyl, furyl, imidazolyl, indazolyl, 1H-indazolyl, indolyl, isoquinolinyl, isothiazolyl,
isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), 1H-pyrazolyl, pyrazolo[1,5-a]pyridinyl,
pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl,
6,7-dihydro-5H-[1]pyrindinyl and the like. Particular "heteroaryl" group is pyridinyl.
The term "C -alkoxy", alone or in combination with other groups, stands for an
-O-C -alkyl radical which can be linear or branched, with single or multiple branching, wherein
the alkyl group in general comprises 1 to 6 carbon atoms, for example, methoxy (OMe, MeO),
ethoxy (OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (iso-butoxy),
2-butoxy (sec-butoxy), t-butoxy (tert-butoxy), isopentyloxy (i-pentyloxy) and the like. Particular
“C -alkoxy” are groups with 1 to 4 carbon atoms. Specific group is methoxy.
The term “halogen-C -alkoxy”, alone or in combination with other groups, refers to C -
1-6 1-6
alkoxy as defined herein, which is substituted by one or multiple halogens, in particular fluoro.
Particular “halogen-C -alkoxy” groups are fluoro-C -alkoxy. Specific groups are
1-6 1-6
difluoromethoxy and trifluoromethoxy.
The term “cycloalkyl-C -alkoxy”, alone or in combination with other groups, refers to C
1-6 1-
-alkoxy as defined herein, which is substituted by one or multiple cycloalkyl as defined herein,
in particular one cycloalkyl.
The term “C -alkenyl-C -alkoxy”, alone or in combination with other groups, refers to
2-6 1-6
C -alkoxy as defined herein, which is substituted by one or multiple C -alkenyl as defined
1-6 2-6
herein, in particular one C -alkenyl.
The term “C -alkynyl-C -alkoxy”, alone or in combination with other groups, refers to
2-6 1-6
C -alkoxy as defined herein, which is substituted by one or multiple C -alkynyl as defined
1-6 2-6
herein, in particular one C -alkynyl.
The term “cycloalkyl”, alone or in combination with other groups, denotes a monovalent
saturated monocyclic or bicyclic hydrocarbon group of 3 to 6 ring carbon atoms, particularly a
monovalent saturated monocyclic hydrocarbon group of 3 to 5 ring carbon atoms. Bicyclic
means consisting of two saturated carbocycles having two carbon atoms in common, i.e. the
bridge separating the two rings is either a single bond or a chain of one or two carbon atoms.
Particular C -cycloalkyl groups are monocyclic. Examples are cyclopropyl, cyclobutanyl,
cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are
bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl or adamantanyl. Particular “cycloalkyl” groups are
cyclopropyl or cyclopentyl.
The term “C -alkynyl”, alone or in combination with other groups, denotes a monovalent
linear or branched saturated hydrocarbon group of 2 to 6 carbon atoms, in particular from 2 to 4
carbon atoms, and comprising one or two triple bonds. Examples of C -alkynyl include ethynyl,
propynyl, propynyl and n-butynyl. Specific group is propynyl.
The term “halogen-C -alkynyl”, alone or in combination with other groups, refers to C -
2-6 2-6
alkynyl as defined herein, which is substituted by one or multiple halogen, in particular 1-5
halogen, more particular 1-3 halogen, most particular one halogen or 3 halogens. Particular
halogen is fluoro.
The term “cyano-C -alkynyl”, alone or in combination with other groups, refers to C -
2-6 2-6
alkynyl as defined herein, which is substituted by one or multiple cyano, in particular one cyano.
The term “cycloalkyl-C -alkynyl”, alone or in combination with other groups, refers to
C -alkynyl as defined herein, which is substituted by one or multiple cycloalkyl as defined
herein, in particular one cycloalkyl.
The term “C -alkoxy-C -alkynyl”, alone or in combination with other groups, refers to
1-6 2-6
C -alkynyl as defined herein, which is substituted by one or multiple C -alkoxy as defined
2-6 1-6
herein, in particular one C -alkoxy.
The term “C -alkenyl”, alone or in combination with other groups, denotes a monovalent
linear or branched saturated hydrocarbon group of 2 to 6 carbon atoms, in particular from 2 to 4
carbon atoms, and comprising one, two or three double bonds. Examples of C -alkenyl include
ethenyl, propenyl and the like.
The term “halogen-C -alkenyl”, alone or in combination with other groups, refers to C -
2-6 2-6
alkenyl as defined herein, which is substituted by one or multiple halogen, in particular 1-5
halogen, more particular 1-3 halogen, most particular one halogen or 3 halogen. Particular
halogen is fluoro.
The term “cyano-C -alkenyl”, alone or in combination with other groups, refers to C -
2-6 2-6
alkenyl as defined herein, which is substituted by one or multiple cyano, in particular one cyano.
The term “cycloalkyl-C -alkenyl”, alone or in combination with other groups, refers to
C -alkenyl as defined herein, which is substituted by one or multiple cycloalkyl as defined
herein, in particular one cycloalkyl.
The term “C -alkoxy-C -alkenyl”, alone or in combination with other groups, refers to
1-6 2-6
C -alkenyl as defined herein, which is substituted by one or multiple C -alkoxy as defined
2-6 1-6
herein, in particular one C -alkoxy.
The term “aryl” denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system
comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl.
Specific group is phenyl.
The term "pharmaceutically acceptable salts" refers to salts that are suitable for use in
contact with the tissues of humans and animals. Examples of suitable salts with inorganic and
organic acids are, but are not limited to acetic acid, citric acid, formic acid, fumaric acid,
hydrochloric acid, lactic acid, maleic acid, malic acid, methane-sulfonic acid, nitric acid,
phosphoric acid, p-toluenesulphonic acid, succinic acid, sulfuric acid, sulphuric acid, tartaric
acid, trifluoroacetic acid and the like. Particular are formic acid, trifluoroacetic acid and
hydrochloric acid. Particular are hydrochloric acid, trifluoroacetic acid and fumaric acid.
The terms “pharmaceutically acceptable carrier” and “pharmaceutically acceptable
auxiliary substance” refer to carriers and auxiliary substances such as diluents or excipients that
are compatible with the other ingredients of the formulation.
The term "pharmaceutical composition" encompasses a product comprising specified
ingredients in pre-determined amounts or proportions, as well as any product that results, directly
or indirectly, from combining specified ingredients in specified amounts. Particularly it
encompasses a product comprising one or more active ingredients, and an optional carrier
comprising inert ingredients, as well as any product that results, directly or indirectly, from
combination, complexation or aggregation of any two or more of the ingredients, or from
dissociation of one or more of the ingredients, or from other types of reactions or interactions of
one or more of the ingredients.
The term “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.
The term “half maximal inhibitory concentration” (IC ) denotes the concentration of a
particular compound required for obtaining 50% inhibition of a biological process in vitro. IC
values can be converted logarithmically to pIC values (-log IC ), in which higher values
50 50
indicate exponentially greater potency. The IC value is not an absolute value but depends on
experimental conditions e.g. concentrations employed. The IC value can be converted to an
absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973)
22:3099). The term “inhibition constant” (Ki) denotes the absolute binding affinity of a
particular inhibitor to a receptor. It is measured using competition binding assays and is equal to
the concentration where the particular inhibitor would occupy 50% of the receptors if no
competing ligand (e.g. a radioligand) was present. Ki values can be converted logarithmically to
pKi values (-log Ki), in which higher values indicate exponentially greater potency.
“Therapeutically effective amount” means an amount of a compound that, when
administered to a subject for treating a disease state, is sufficient to effect such treatment for the
disease state. 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 judgment of the attending medical or veterinary
practitioner, and other factors.
The terms “treating”, “contacting” and “reacting” when referring to a chemical reaction
means adding or mixing two or more reagents under appropriate conditions to produce the
indicated and/or the desired product. It should be appreciated that the reaction which produces
the indicated and/or the desired product can not necessarily result directly from the combination
of two reagents which were initially added, i.e., there can be one or more intermediates which
are produced in the mixture which ultimately leads to the formation of the indicated and/or the
desired product.
The term “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 appropriate point. Exemplary protecting groups are
amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. The term
“amino-protecting group” (here also P ) denotes groups intended to protect an amino group and
includes benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), 9-Fluorenylmethyloxycarbonyl
(FMOC), 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. Haslam, “Protective Groups in Organic Chemistry”, J. G. W. McOmie,
Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene, “Protective Groups in
Organic Synthesis”, John Wiley and Sons, New York, NY, 1981. The term “protected amino
group” refers to an amino group substituted by an amino-protecting groups. Particular amino-
protecting groups are tert-butoxycarbonyl group and dimethoxytrityl.
The term “aromatic” denotes the conventional idea of aromaticity as defined in the
literature, in particular in IUPAC - Compendium of Chemical Terminology, 2nd, A. D.
McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).
The term “pharmaceutically acceptable excipient” denotes any ingredient having no
therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers,
tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating
pharmaceutical products.
Whenever a chiral carbon is present in a chemical structure, it is intended that all
stereoisomers associated with that chiral carbon are encompassed by the structure as pure
stereoisomers as well as mixtures thereof.
The invention also provides pharmaceutical compositions, and methods of preparing the
aforementioned compounds.
All separate embodiments can be combined.
One embodiment of the invention is a compound of formula I,
HN O
wherein
R is aryl or heteroaryl, each unsubstituted or substituted by 1-4 substituents individually
selected from C -alkyl, cyano, cyano-C -alkyl, cycloalkyl, cycloalkyl-C -alkenyl,
1-6 1-6 2-6
cycloalkyl-C -alkynyl, cycloalkyl-C -alkyl, cycloalkyl-C -alkoxy, halogen, halogen-
2-6 1-6 1-6
C -alkenyl, halogen-C -alkynyl, halogen-C -alkyl, halogen-C -alkoxy, C -alkoxy,
2-6 2-6 1-6 1-6 1-6
C -alkoxy-C -alkyl, C -alkoxy-C -alkenyl, C -alkoxy-C -alkynyl, C -alkenyl,
1-6 1-6 1-6 2-6 1-6 2-6 2-6
C -alkynyl, C -alkenyl-C -alkoxy and C -alkynyl-C -alkoxy;
2-6 2-6 1-6 2-6 1-6
R is selected from the group consisting of
i) hydrogen, and
ii) halogen,
R is halogen-C -alkyl;
R and R are both hydrogen or both halogen;
R is selected from the group consisting of
i) hydrogen, and
ii) C -alkyl,
R is selected from the group consisting of
i) hydrogen, and
ii) C -alkyl,
or pharmaceutically acceptable salts thereof.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is heteroaryl substituted by 1-2 substituents individually selected from C -
alkyl, cyano, cyano-C -alkyl, cycloalkyl, cycloalkyl-C -alkenyl, cycloalkyl-C -alkynyl,
1-6 2-6 2-6
cycloalkyl-C -alkyl, cycloalkyl-C -alkoxy, halogen, halogen-C -alkenyl, halogen-C -
1-6 1-6 2-6 2-6
alkynyl, halogen-C -alkyl, halogen-C -alkoxy, C -alkoxy, C -alkoxy-C -alkyl, C -
1-6 1-6 1-6 1-6 1-6 1-6
alkoxy-C -alkenyl, C -alkoxy-C -alkynyl, C -alkenyl, C -alkynyl, C -alkenyl-C -
2-6 1-6 2-6 2-6 2-6 2-6 1-6
alkoxy and C -alkynyl-C -alkoxy.
2-6 1-6
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is pyridinyl substituted by cyano.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is 5-cyano-pyridineyl.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is hydrogen.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is halogen.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is F.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is fluoro-C -alkyl.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is –CHF .
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is –CH F.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R and R are halogen.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R and R are F.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R and R are H.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is H.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is C -alkyl.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is methyl.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is H.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is C -alkyl.
A certain embodiment of the invention provides a compound of formula I as described
herein, wherein R is methyl.
A certain embodiment of the invention provides a compound of formula I as described
herein, which is (S)-N-(3-(2-amino(difluoromethyl)-5,6-dihydro-4H-1,3-oxazinyl)
fluorophenyl)cyanopicolinamide.
A certain embodiment of the invention provides a process for preparing a compound of
formula I as defined herein, which process comprises reacting a compound of formula I’ to a
compound of formula I
HN O
I’
2 3 4 5 6 7
wherein R , R , R , R , R and R are as defined herein.
A certain embodiment of the invention provides a compound of formula I as described
herein, whenever prepared by a process as defined above.
A certain embodiment of the invention provides a compound of formula I as described
herein for use as therapeutically active substance.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as inhibitor of BACE1 and/or BACE2 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as inhibitor of BACE1 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as inhibitor of BACE2 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as inhibitor of BACE1 and BACE2 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid
oligomers and/or β-amyloid plaques and further deposits or Alzheimer's disease.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of Alzheimer's disease.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of Alzheimer's disease, diabetes or type 2 diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory
diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and
stroke, dermatomyositis, Down’s Syndrome, gastrointestinal diseases, Glioblastoma multiforme,
Graves Disease, Huntington’s Disease, inclusion body myositis (IBM), inflammatory reactions,
Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile
idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid
arthritis, Sjogren syndrome, SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whipple’s
Disease or Wilson’s Disease.
A certain embodiment of the invention provides a pharmaceutical composition comprising
a compound of formula I as described herein and a pharmaceutically acceptable carrier and/or a
pharmaceutically acceptable auxiliary substance.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the use in inhibition of BACE1 and/or
BACE2 activity.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the use in inhibition of BACE1
activity.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the use in inhibition of BACE2
activity.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the use in inhibition of BACE1 and
BACE2 activity.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid
oligomers and/or β-amyloid plaques and further deposits or Alzheimer's disease.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of Alzheimer's disease.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory
diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and
stroke, dermatomyositis, Down’s Syndrome, gastrointestinal diseases, Glioblastoma multiforme,
Graves Disease, Huntington’s Disease, inclusion body myositis (IBM), inflammatory reactions,
Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile
idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid
arthritis, Sjogren syndrome, SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whipple’s
Disease or Wilson’s Disease.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of Alzheimer's disease, diabetes or type 2 diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of Alzheimer's disease.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of type 2 diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory
diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and
stroke, dermatomyositis, Down’s Syndrome, gastrointestinal diseases, Glioblastoma multiforme,
Graves Disease, Huntington’s Disease, inclusion body myositis (IBM), inflammatory reactions,
Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile
idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid
arthritis, Sjogren syndrome, SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whipple’s
Disease or Wilson’s Disease.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in inhibition of BACE1 and/or BACE2 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in inhibition of BACE1 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in inhibition of BACE2 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in inhibition of BACE1 and BACE2 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of diseases and disorders
characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid
plaques and further deposits or Alzheimer's disease.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of Alzheimer's disease.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of Alzheimer's disease,
diabetes or type 2 diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of amyotrophic lateral
sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast
cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis,
Down’s Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease,
Huntington’s Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma,
Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis,
granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren
syndrome, SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whipple’s Disease or Wilson’s
Disease.
Also described herein is a method for the use in inhibition of BACE1 and/or BACE2
activity, particularly for the therapeutic and/or prophylactic treatment of diseases and disorders
characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid
plaques and further deposits, Alzheimer's disease, diabetes or type 2 diabetes, which method
comprises administering compound of formula I as described herein to a human being or animal.
Also described herein is a method for the use in the therapeutic and/or prophylactic
treatment of Alzheimer's disease, diabetes or type 2 diabetes, which method comprises
administering a compound of formula I as described herein to a human being or animal.
Also described herein is a method for the use in the therapeutic and/or prophylactic
treatment of Alzheimer's disease, which method comprises administering a compound of formula
I as described herein to a human being or animal.
Also described herein is a method for the use in the therapeutic and/or prophylactic
treatment of diabetes, which method comprises administering a compound of formula I as
described herein to a human being or animal.
Also described herein is a method for the use in the therapeutic and/or prophylactic
treatment of type 2 diabetes, which method comprises administering a compound of formula I as
described herein to a human being or animal.
Also described herein is a method for the use in the therapeutic and/or prophylactic
treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory
diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and
stroke, dermatomyositis, Down’s Syndrome, gastrointestinal diseases, Glioblastoma multiforme,
Graves Disease, Huntington’s Disease, inclusion body myositis (IBM), inflammatory reactions,
Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile
idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid
arthritis, Sjogren syndrome, SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whipple’s
Disease or Wilson’s Disease, which method comprises administering a compound of formula I
as described herein to a human being or animal.
Furthermore, the invention includes all optical isomers, i.e. diastereoisomers,
diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and/or tautomers
as well as their solvates of the compounds of formula I.
The skilled person in the art will recognize that the compounds of formula I can exist in
tautomeric form
HN O
All tautomeric forms are encompassed in the present invention.
The compounds of formula I can contain one or more asymmetric centers and can therefore
occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers. Additional asymmetric centers can be present depending upon the
nature of the various substituents on the molecule. Each such asymmetric centre will
independently produce two optical isomers and it is intended that all of the possible optical
isomers and diastereomers in mixtures and as pure or partially purified compounds are included
within this invention. The present invention is meant to encompass all such isomeric forms of
these compounds. The independent syntheses of these diastereomers or their chromatographic
separations can be achieved as known in the art by appropriate modification of the methodology
disclosed herein. Their absolute stereochemistry can be determined by the x-ray crystallography
of crystalline products or crystalline intermediates which are derivatized, if necessary, with a
reagent containing an asymmetric centre of known absolute configuration. If desired, racemic
mixtures of the compounds can be separated so that the individual enantiomers are isolated. The
separation can be carried out by methods well known in the art, such as the coupling of a racemic
mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture,
followed by separation of the individual diastereomers by standard methods, such as fractional
crystallization or chromatography. Stereoisomers of compounds of formula I are compounds of
formula Ia or compounds of formula Ib, in particular compounds of formula Ia, wherein the
residues have the meaning as described in any of the embodiments.
Ia Ib
In the embodiments, where optically pure enantiomers are provided, optically pure
enantiomer means that the compound contains > 90 % of the desired isomer by weight, in
particular > 95 % of the desired isomer by weight, or more pparticular > 99 % of the desired
isomer by weight, said weight percent based upon the total weight of the isomer(s) of the
compound. Chirally pure or chirally enriched compounds can be prepared by chirally selective
synthesis or by separation of enantiomers. The separation of enantiomers can be carried out on
the final product or alternatively on a suitable intermediate.
The compounds of formula I can be prepared in accordance with the following schemes. The
starting material is commercially available or can be prepared in accordance with known
methods. Any previously defined residues and variables will continue to have the previously
defined meaning unless otherwise indicated.
Difluoroketones of general formula E1 can be prepared by reaction of an aryllithium or
arylmagnesium compound with ethyl difluoroacetate as described in Tetrahedron 2005, 61(19),
4671 and J. Org. Chem. 2006, 71(9), 3545.
Sulfinyl imines of general formula E2 can be prepared in analogy to T.P. Tang & J.A.
Ellman, J. Org. Chem. 1999, 64, 12, by condensation of an aryl ketone E1 and a sulfinamide, e.g.
an alkyl sulfinamide, most particularly (S)-(–)- or (R)-(+)-tert-butylsulfinamide, in the presence
of a Lewis acid such as e.g. a titanium(IV)alkoxide, more particularly titanium(IV)ethoxide in a
solvent such as an ether, e.g. diethyl ether or more particularly tetrahydrofuran.
The conversion of the sulfinyl imine E2 to the sulfinamide ester E3 can proceed
stereoselectively by the chiral directing group as described by Tang & Ellman. The sulfinyl
imine E2 can be reacted in a Reformatsky reaction with a zinc enolate, activated zinc powder at
ambient to elevated temperature, particularly at 23 to 60 °C in a solvent such as an ether, e.g.
diethyl ether or more particularly tetrahydrofuran. The zinc enolate is generated from an alkyl
bromoacetate or propionate optionally substituted by additional halogen, e.g. particularly ethyl
bromoacetate, ethyl bromo-fluoro-acetate, ethyl bromodifluoroacetate or ethyl 2-bromofluoro-
propionate. The sulfinyl imine E2 can also be reacted with with an alkyl acetate optionally
substituted by a halogen-alkoxy group, like e.g. methyl acetate or ethyl 2-(2,2,2-
trifluoroethoxy)acetate, in presence of a strong base such as lithium diisopropylamide at 0 to -78
°C in the presence of a titanium(IV) reagent such as chlorotitaniumtriisopropoxide an inert
solvent such as an ether, e.g. diethyl ether or more particularly tetrahydrofuran.
The alcohol of formula E4 can be prepared by the reduction of an ethylester of formula E3
with an alkali hydride, particularly lithium borohydride or lithium aluminum hydride, in a
solvent such as an ether, e.g. diethyl ether or more particularly tetrahydrofuran.
Hydrolysis of the chiral directing group in the sulfinamide alcohol of formula E4 to give
the aminoalcohol of formula E5 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, tetrahydrofuran or
more particularly 1,4-dioxane.
The aminooxazine of formula E6 can be prepared by reaction of an aminoalcohol of
formula E5 with cyanogen bromide in a solvent such as an alcohol, particularly ethanol.
Protection of the amino group in compounds of formula E6 to produce aryl bromides of
formula E7 can be performed with triarylmethyl chlorides, such as triphenylmethyl chloride (Tr-
Cl), p-methoxyphenyldiphenylmethyl chloride (MMTr-Cl), di(p-methoxyphenyl)phenylmethyl
chloride (DMTr-Cl) or tri(p-methoxyphenyl)methyl chloride (TMTr-Cl), particularly DMTr-Cl,
under basic conditions, e.g. in the presence of an amine, such as triethylamine or
diisopropylethylamine, in a chlorinated solvent, such as dichloromethane or chloroform, at
temperatures between 0 °C and ambient temperature.
Aryl bromides of formula E7 can be reacted with ammonia equivalents, such as
benzophenone imine, in the presence of a suitable transition metal catalyst, such as
bis(dibenzylideneacetone)palladium (0) ((dba) Pd) or tris(dibenzylideneacetone)dipalladium (0)
((dba) Pd )), and a suitable ligand, such as rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (rac-
BINAP), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-PHOS) or 2-di-tert-
butylphosphino-2',4',6'-triisopropylbiphenyl (t-Bu X-PHOS), in the presence of a base, such as
sodium tert-butoxide, potassium phosphate or cesium carbonate, in a suitable solvent, such as
toluene or 1,4-dioxane, under an inert atmosphere, such as nitrogen or argon, at temperatures
between 80 and 110 °C, to produce compounds of formula E8.
Deprotection of both amino groups in compounds of formula E8 can be achieved by a one-
pot procedure by first reacting it with a strong organic acid, such as trifluoroacetic acid, in
chlorinated solvents, such as dichloromethane or chloroform, under anhydrous conditions at
temperatures between 0 °C and ambient temperature to cleave the P -group. Then the addition of
water to cleave the benzophenone imine and reaction at ambient temperature produces diamines
of formula E9.
Amide coupling of diamines of formula E9 and carboxylic acids to give amides of formula
I.2 can be effected in a solvent such as methanol with 4-(4,6-dimethoxy[1.3.5]triazinyl)
methylmorpholinium chloride hydrate (DMTMM) or other condensating agents, such as O-
(benzotriazolyl)-N,N,N’,N’-tetramethyluronium.-hexafluorophosphate (HBTU) or O-(7-
azabenzotriazolyl)- N,N,N’,N’-tetramethyluronium-hexafluorophosphate (HATU), in the
presence of an amine, such as triethylamine or diisopropylethylamine, in a solvent, such as
acetonitrile or N,N-dimethylformamide, at temperatures between 0 °C and ambient temperature.
Br F Br
CHF O
F F F
E1 E2 E3
NH O
N O OH OH
NH NH
Br Br Br
CHF CHF
E6 E5
P : e.g. Tr, MMTr, DMTr, TMTr
NH-P NH-P NH
N O N O N O
Br N H N
CHF CHF
F F F
Scheme E: Synthesis of compounds of formula I.2.
Fluoroketones of general formula F1 can be prepared by reaction of the corresponding
hydroxyketones with e.g. nonafluoro-n-butanesulfonyl fluoride and triethylamine
trihydrofluoride in presence of an organic base, e.g. triethylamine, in inert solvents like toluene
or chlorinated solvents, e.g. dichloroethane or dichloromethane, preferably dichloromethane, at
temperatures between -20 and 30 °C, preferably at 0 °C.
Sulfinyl imines of general formula F2 can be prepared in analogy to T.P. Tang & J.A.
Ellman, J. Org. Chem. 1999, 64, 12, by condensation of an aryl ketone F1 and a sulfinamide, e.g.
an alkyl sulfinamide, most particularly (S)-(–)- or (R)-(+)-tert-butylsulfinamide, in the presence
of a Lewis acid such as e.g. a titanium(IV)alkoxide, more particularly titanium(IV)ethoxide in a
solvent such as an ether, e.g. diethyl ether or more particularly tetrahydrofuran.
The conversion of the sulfinyl imine F2 to the sulfinamide ester F3 can proceed
stereoselectively by the chiral directing group as described by Tang & Ellman. The sulfinyl
imine F2 can be reacted in a Reformatsky reaction with a zinc enolate, activated zinc powder at
ambient to elevated temperature, particularly at 23 to 60 °C in a solvent such as an ether, e.g.
diethyl ether or more particularly tetrahydrofuran. The zinc enolate is generated from an alkyl
bromoacetate or propionate optionally substituted by additional halogen, e.g. particularly ethyl
bromoacetate, ethyl bromo-fluoro-acetate, ethyl bromodifluoroacetate or ethyl 2-bromofluoro-
propionate.
The alcohol of formula F4 can be prepared by the reduction of an ethylester of formula F3
with an alkali hydride, particularly lithium borohydride or lithium aluminum hydride, in a
solvent such as an ether, e.g. diethyl ether or more particularly tetrahydrofuran.
Hydrolysis of the chiral directing group in the sulfinamide alcohol of formula F4 to give
the aminoalcohol of formula F5 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, tetrahydrofuran or
more particularly 1,4-dioxane.
The aminooxazine of formula F6 can be prepared by reaction of an aminoalcohol of
formula F5 with cyanogen bromide in a solvent such as an alcohol, particularly ethanol.
The nitro derivative of formula F7 can be prepared by nitration of the oxazine F6 following
a standard procedure involving neat sulfuric acid and fuming nitric acid without using a solvent.
The reduction of the nitro group in compounds of formula F7 to give anilines of formula
F8 can be accomplished by hydrogenation using a catalyst, such as palladium on carbon, in
protic solvents, such as alcohols, in particular ethanol or methanol.
Amide coupling of diamines of formula F8 and carboxylic acids to give amides of formula
I.3 can be effected in a solvent such as methanol with 4-(4,6-dimethoxy[1.3.5]triazinyl)
methylmorpholinium chloride hydrate (DMTMM) or other condensating agents, such as O-
(benzotriazolyl)-N,N,N’,N’-tetramethyluronium.-hexafluorophosphate (HBTU) or O-(7-
azabenzotriazolyl)- N,N,N’,N’-tetramethyluronium-hexafluorophosphate (HATU), in the
presence of an amine, such as triethylamine or diisopropylethylamine, in a solvent, such as
acetonitrile or N,N-dimethylformamide, at temperatures between 0 °C and ambient temperature.
S S COOEt
F F F
F F F
F1 F2
O OH
H N O OH
F F F
N H N
F6 F5
H N O H N H N
2 2 2
F F F
N N N
O N H N R N
F F F
F F F
F7 F8 I.3
Scheme F: Synthesis of compounds of formula I.3.
The corresponding pharmaceutically acceptable salts with acids can be obtained by standard
methods known to the person skilled in the art, e.g. by dissolving the compound of formula I in a
suitable solvent such as e.g. dioxane or tetrahydrofuran (THF) and adding an appropriate amount
of the corresponding acid. The products can usually be isolated by filtration or by
chromatography. The conversion of a compound of formula I into a pharmaceutically acceptable
salt with a base can be carried out by treatment of such a compound with such a base. One
possible method to form such a salt is e.g. by addition of 1/n equivalents of a basic salt such as
e.g. M(OH) , wherein M = metal or ammonium cation and n = number of hydroxide anions, to a
solution of the compound in a suitable solvent (e.g. ethanol, ethanol-water mixture,
tetrahydrofuran-water mixture) and to remove the solvent by evaporation or lyophilisation.
Particular salts are hydrochloride, formate and trifluoroacetate. Specific is hydrochloride.
Insofar as their preparation is not described in the examples, the compounds of formula I as
well as all intermediate products can be prepared according to analogous methods or according
to the methods set forth herein. Starting materials are commercially available, known in the art or
can be prepared by methods known in the art or in analogy thereto.
It will be appreciated that the compounds of general formula I in this invention can be
derivatised at functional groups to provide derivatives which are capable of conversion back to
the parent compound in vivo.
Pharmacological Tests
The compounds of formula I and their pharmaceutically acceptable salts possess valuable
pharmacological properties. It has been found that the compounds of the present invention are
associated with inhibition of BACE1 and/or BACE2 activity. The compounds were investigated
in accordance with the test given hereinafter.
Cellular Aβ-lowering assay:
a) Human HEK293 cells which are stably transfected with a vector expressing a cDNA of
the human APP wt gene (APP695) were used to assess the potency of the compounds in a
cellular assay. The cells were seeded in 96-well microtiter plates in cell culture medium (Iscove,
plus 10% (v/v) fetal bovine serum, glutamine, penicillin/streptomycin) to about 80% confluence
and the compounds were added at a 10x concentration in 1/10 volume of medium without FCS
containing 8% DMSO (final concentration of DMSO was kept at 0.8% v/v). After 18-20 hrs
incubation at 37 °C and 5% CO in a humidified incubator the culture supernatant was harvested
for the determination of Aβ40 concentrations. 96well ELISA plates (e.g., Nunc MaxiSorb) were
coated with monoclonal antibody which specifically recognize the C-terminal end of Aβ40
(Brockhaus et al., NeuroReport 9, 1481-1486; 1998). After blocking of non-specific binding sites
with e.g. 1% BSA and washing, the culture supernatants were added in suitable dilutions
together with a horseradish peroxidase-coupled Aβ detection antibody (e.g., antibody 4G8,
Senetek, Maryland Heights, MO) and incubated for 5 to 7 hrs. Subsequently the wells of the
microtiter plate were washed extensively with Tris-buffered saline containing 0.05% Tween 20
and the assay was developed with tetramethylbenzidine/H O in citric acid buffer. After stopping
the reaction with one volume 1 N H SO the reaction was measured in an ELISA reader at 450
nm wavelength. The concentrations of Aβ in the culture supernatants were calculated from a
standard curve obtained with known amounts of pure Aβ peptide.
b) Alternatively, the Abeta 40 AlphaLISA Assay can be used. The HEK293 APP cells were
seeded in 96 well Microtiter plates in cell culture medium (Iscove’s, plus 10% (v/v) fetal bovine
serum, penicillin/streptomycin ) to about 80% confluency and the compounds were added at a 3x
concentration in 1/3 volume of culture medium ( final DMSO concentration was kept at 1 % v/v).
After 18-20 hrs incubation at 37°C and 5% CO in a humidified incubator, the culture
supernatants were harvested for the determination of Aβ 40 concentrations using Perkin-Elmer
Human Amyloid beta 1-40 ( high specificity ) Kit ( Cat# AL275C ).
In a Perkin-Elmer White Optiplate-384 ( Cat# 6007290 ), 2ul culture supernatants were
combined with 2μl of a 10X AlphaLISA Anti-hAβAcceptor beads + Biotinylated Antibody
Anti-Aβ 1-40 Mix ( 50 μg/mL / 5nM ). After 1 hour room temperature incubation, 16μl of a 1.25
X preparation of Streptavidin (SA) Donor beads (25μg/mL ) were added and incubated for 30
minutes in the Dark. Light Emission at 615 nm was then recorded using EnVision-Alpha Reader.
Levels of Aβ 40 in the culture supernatants were calculated as percentage of maximum signal
(cells treated with 1% DMSO without inhibitor). The IC50 values were calculated using the
Excel XLfit software.
Assay for BACE inhibition by measuring cellular TMEM27 cleavage:
The assay uses the principle of inhibition of human TMEM27 cleavage by endogenous
cellular BACE2 in the Ins1e 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 INS1e-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-
mercatptoethanol, 100 micrograms/ml G418 and 100 microgram/ml hygromycin and are grown
inadherent culture at 37 °C in a standard CO cell culture incubator.
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 500 ng/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 EC for BACE2 inhibition is calculated using the ELISA readout for each inhibitor
concentration with standard curve-fitting software such as XLFit for the Excel spreadsheet
program.
For example, an IC value of 0.0039 μM was obtained for example 1 (BACE1 cell act.
Aβ40) and for example 2 an IC value of 0.40 μM was obtained.
Pharmaceutical Compositions
The compounds of formula I and the pharmaceutically acceptable salts can be used as
therapeutically active substances, e.g. in the form of pharmaceutical preparations. The
pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets,
dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. The administration
can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in
the form of injection solutions.
The compounds of formula I and the pharmaceutically acceptable salts thereof can be
processed with pharmaceutically inert, inorganic or organic carriers for the production of
pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its
salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées
and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable
oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the
active substance no carriers are however usually required in the case of soft gelatin capsules.
Suitable carriers for the production of solutions and syrups are, for example, water, polyols,
glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or
hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can, moreover, contain pharmaceutically acceptable
auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers,
sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents
or antioxidants. They can also contain still other therapeutically valuable substances.
Medicaments containing a compound of formula I or a pharmaceutically acceptable salt
thereof and a therapeutically inert carrier are also provided by the present invention, as is a
process for their production, which comprises bringing one or more compounds of formula I
and/or pharmaceutically acceptable salts thereof and, if desired, one or more other
therapeutically valuable substances into a galenical administration form together with one or
more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, have to be adjusted to the
individual requirements in each particular case. In the case of oral administration the dosage for
adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula
I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage
can be administered as single dose or in divided doses and, in addition, the upper limit can also
be exceeded when this is found to be indicated.
The following examples illustrate the present invention without limiting it, but serve
merely as representative thereof. The pharmaceutical preparations conveniently contain about 1-
500 mg, in particular 1-100 mg, of a compound of formula I. Examples of compositions
according to the invention are:
Example A
Tablets of the following composition are manufactured in the usual manner:
ingredient mg/tablet
25 100 500
Compound of formula I 5 25 100 500
Lactose Anhydrous DTG 125 105 30 150
Sta-Rx 1500 6 6 6 60
Microcrystalline Cellulose 30 30 30 450
Magnesium Stearate 1 1 1 1
Total 167 167 167 831
Table 1: possible tablet composition
Manufacturing Procedure
1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granules at 50°C.
3. Pass the granules through suitable milling equipment.
4. Add ingredient 5 and mix for three minutes; compress on a suitable press.
Example B-1
Capsules of the following composition are manufactured:
ingredient mg/capsule
25 100 500
Compound of formula I 5 25 100 500
Hydrous Lactose 159 123 148 -
Corn Starch 25 35 40 70
Talk 10 15 10 25
Magnesium Stearate 1 2 2 5
Total 200 200 300 600
Table 2: possible capsule ingredient composition
Manufacturing Procedure
1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add ingredients 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.
The compound of formula I, lactose and corn starch are firstly mixed in a mixer and then in
a comminuting machine. The mixture is returned to the mixer; the talc is added thereto and
mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatin
capsules.
Example B-2
Soft Gelatin Capsules of the following composition are manufactured:
ingredient mg/capsule
Compound of formula I 5
Yellow wax 8
Hydrogenated Soya bean oil 8
Partially hydrogenated plant oils 34
Soya bean oil 110
Total 165
Table 3: possible soft gelatin capsule ingredient composition
ingredient mg/capsule
Gelatin 75
Glycerol 85 % 32
Karion 83 8 (dry matter)
Titan dioxide 0.4
Iron oxide yellow 1.1
Total 116.5
Table 4: possible soft gelatin capsule composition
Manufacturing Procedure
The compound of formula I 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 C
Suppositories of the following composition are manufactured:
ingredient mg/supp.
Compound of formula I 15
Suppository mass 1285
Total 1300
Table 5: possible suppository composition
Manufacturing Procedure
The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to
45°C. Thereupon, the finely powdered compound of formula I is added thereto and stirred until it
has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to
cool; the suppositories are then removed from the moulds and packed individually in wax paper
or metal foil.
Example D
Injection solutions of the following composition are manufactured:
ingredient mg/injection solution.
Compound of formula I 3
Polyethylene Glycol 400 150
acetic acid q.s. ad pH 5.0
water for injection solutions ad 1.0 ml
Table 6: possible injection solution composition
Manufacturing Procedure
The compound of formula I 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.
Example E
Sachets of the following composition are manufactured:
ingredient mg/sachet
Compound of formula I 50
Lactose, fine powder 1015
Microcrystalline cellulose (AVICEL PH 102) 1400
Sodium carboxymethyl cellulose 14
Polyvinylpyrrolidon K 30 10
Magnesium stearate 10
Flavoring additives 1
Total 2500
Table 7: possible sachet composition
Manufacturing Procedure
The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium
carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The
granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets.
Experimental Part
The following examples are provided for illustration of the invention. They should not be
considered as limiting the scope of the invention, but merely as being representative thereof.
Synthesis of the intermediate difluoroketones E1
Intermediate E1.1
Br F
A solution of diisopropylamine (12.7 g, 17.9 ml, 126 mmol) and tetrahydrofuran (375 ml)
was cooled to –78 °C and n-BuLi (1.6 M in hexane) (78.6 ml, 126 mmol) was added dropwise.
After stirring for 10 min commercially available 1-bromofluorobenzene {CAS[4604]} (20
g, 12.4 ml, 114 mmol) was added dropwise at max. –60 °C. Stirring was continued at –70 °C for
2.5 hours. Then ethyl difluoroacetate (17.0 g, 13.7 ml, 137 mmol) was added dropwise and the
mixture was warmed to –10 °C and then quenched by pouring the mixture onto 1 M HCl. The
mixture was extracted twice with ethyl acetate, dried over sodium sulphate, filtered and
evaporated to give a yellow liquid (34 g; 118%). The residue was chromatographed on 200 g
silica gel with cyclohexane/ethyl acetate 3:1 to give 1-(5-bromofluorophenyl)-2,2-
difluoroethanone (26.5 g, 105 mmol, 91.6 % yield) as a yellow liquid. MS (EI): m/z = 252.0
[M] and 254.0 [M+2] .
Synthesis of the intermediate sulfinyl imines E2
Intermediate E2.1
Br F
To a solution of 1-(5-bromofluorophenyl)-2,2-difluoroethanone (intermediate E1.1)
(13.2 g, 52.2 mmol) and (S)-(-)methylpropanesulfinamide (6.96 g, 57.4 mmol) in
tetrahydrofuran (104 ml) was added at 23 °C titanium(IV) ethoxide (21.4 g, 19.5 ml, 93.9 mmol).
The yellow solution was stirred at 70 °C for 3 hours. The cooled reaction mixture was poured
into ice water, diluted with ethyl acetate and filtered through a pad of Dicalite. The organic layer
was separated and washed with brine and then dried over Na SO . Removal of the solvent in
vacuum left a yellow oil (18.25 g), which was purified by silica column chromatography 200 g,
SiO with dichloromethane/heptane 1:1 to give (S,E)-N-(1-(5-bromofluorophenyl)-2,2-
difluoroethylidene)methylpropanesulfinamide (14.49 g, 40.7 mmol, 78.0 % yield) as a
yellow oil. MS (ISP): m/z = 355.9 [M+H] and 357.9 [M+2+H] .
Syntheses of the intermediate sulfinamide esters E3.1 and E3.2
H COOMe COOMe
E3.1 E3.2
To a solution of diisopropylamine (6.52 g, 9.19 ml, 64.5 mmol) in tetrahydrofuran (115 ml)
was added at - 70 °C n- BuLi (1.6 M in hexane) (40.3 ml, 64.5 mmol) dropwise and stirring was
continued for 15 min at - 70 °C. The solution was treated with methyl acetate (4.77 g, 5.13 ml,
64.5 mmol) and after 30 min chlorotitanium triisopropoxide (0.85 M in THF) (85.7 ml, 72.85
mmol) was added dropwise and stirring was continued at - 70 °C for 30 min. The mixture was
treated with a solution of (S,E)-N-(1-(5-bromofluorophenyl)-2,2-difluoroethylidene)
methylpropanesulfinamide (intermediate E2.1) (8.2 g, 23.0 mmol) in tetrahydrofuran (76.4 ml)
and stirring was continued at - 70 °C for 2 hours. The mixture was quenched with saturated
aqueous NH Cl solution (100 ml), diluted with ethyl acetate (200 ml) and the mixture was
filtered over dicalite. The organic layer was separated and washed with water and brine. The
aqueous layers were rextracted with ethyl acetate. The combined organic layers were dried over
Na SO , filtered and evaporated to give a yellow oil (11.5 g; 116%). The residue was
chromatographed on 50 g silica gel with ethyl acetate/heptane 0-50% to give a 1:1
diastereomeric mixture of methyl 3-(5-bromofluorophenyl)((S)-1,1-
dimethylethylsulfinamido)-4,4-difluorobutanoate (7 g, 16.3 mmol, 70.7 % yield) as a colourless
oil. MS (ISP): m/z = 430.2 [M+H] and 432.1 [M+2+H] .
Chiral separation of methyl 3-(5-bromofluorophenyl)((S)-1,1-
dimethylethylsulfinamido)-4,4-difluorobutanoate (3.8 g, 8.83 mmol) by preparative chiral HPLC
on Reprosil Chiral NR column with eluent 5% EtOH/n-heptane to give (S)-methyl 3-(5-bromo-
2-fluorophenyl)((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (1.55 g, 3.6 mmol,
40.8 % yield) as a colourless oil and (R)-methyl 3-(5-bromofluorophenyl)((S)-1,1-
dimethylethylsulfinamido)-4,4-difluorobutanoate (1.65 g, 3.83 mmol, 43.4 % yield) as a
colorless oil.
Synthesis of the intermediate sulfinamide alcohols E4
Intermediate E4.1
(S)-methyl 3-(5-bromofluorophenyl)((S)-1,1-dimethylethylsulfinamido)-4,4-
difluorobutanoate (intermediate E3.1) (1.65 g, 3.83 mmol) was dissolved in tetrahydrofuran (80
ml) and lithium borohydride (668 mg, 30.7 mmol) was addded at 5 °C in two portions. The
turbid solution was stirred at 23 °C for 16 hours. The reaction mixture was poured into ice water
and ethyl acetate was added. Saturated NH Cl solution (50 ml) was added slowly and the
mixture was stirred vigorously for 45 min until the gas evolution finished. The organic layer was
separated, dried over Na SO , filtered and evaporated to give a yellow oil. The residue was
purified by chromatography on 50 g silica gel with ethyl acetate/heptane 0-80% to give (S)-N-
((S)(5-bromofluorophenyl)-1,1-difluorohydroxybutanyl)methylpropane
sulfinamide (815 mg, 2.03 mmol, 52.8 % yield) as a colourless oil. MS (ISN): m/z = 399.9 [M-
H] and 401.9 [M+2-H] .
Synthesis of the intermediate amino alcohols E5
Intermediate amino alcohol E5.1
To a solution of (S)-N-((S)(5-bromofluorophenyl)-1,1-difluorohydroxybutan
yl)methylpropanesulfinamide (intermediate E4.1) (810 mg, 2.01 mmol) in THF (40 ml)
was added conc. HCl (595 mg, 496 µl, 6.04 mmol) at 23 °C. The mixture was stirred for 4 hours
at 23 °C. Poured into 1 M Na CO -solution., extracted with ethyl acetate and dried over Na SO .
2 3 2 4
Removal of solvent in vacuum left (S)amino(5-bromofluorophenyl)-4,4-difluorobutan-
1-ol (570 mg, 1.91 mmol, 95.0 % yield) as a light yellow oil. The crude product was used in the
next step without further purification. MS (ISP): m/z = 298.1 [M+H] and 300.1 [M+2+H] .
Syntheses of the intermediate amino oxazines E6
Intermediate amino oxazine E6.1
To a solution of (S)amino(5-bromofluorophenyl)-4,4-difluorobutanol
(intermediate E5.1) (570 mg, 1.91 mmol) in ethanol (10 ml) was added under Argon cyanogen
bromide (313 mg, 2.87 mmol) at 23 °C . The mixture was stirred in a sealed tube for 16 hours at
80 °C. Poured into ice water and saturated. NaHCO -solution and then extracted with
dichloromethane. The organic layer was dried over Na SO , filtered and evaporated to give a
light yellow oil (620 mg), which was purified by flash chromatography on 20 g silica gel with
ethyl acetate/heptane 0-50% to give (S)(5-bromofluorophenyl)(difluoromethyl)-5,6-
dihydro-4H-1,3-oxazinamine (250 mg, 774 µmol, 40.5 % yield) as a white solid. MS (ISP):
m/z = 323.0 [M+H] and 325.0 [M+2+H] .
Synthesis of the intermediate DMTr-protected amino oxazines E7
Intermediate E7.1
NHDMTr
To a solution of (S)(5-bromofluorophenyl)(difluoromethyl)-5,6-dihydro-4H-1,3-
oxazinamine(intermediate E6.1) (372 mg, 1.15 mmol) in dichloromethane (10 ml) was added
at 0 °C 4,4'-(chloro(phenyl)methylene)bis(methoxybenzene) (585 mg, 1.73 mmol). The reaction
mixture was stirred at 23 °C for 16 hours. Extraction with water, then drying of the organic layer
over Na SO , filtration, evaporation. Chromatography on 20 g silica gel with ethyl
acetate/heptane 0-50% gave the (S)-N-(bis(4-methoxyphenyl)(phenyl)methyl)(5-bromo
fluorophenyl)(difluoromethyl)-5,6-dihydro-4H-1,3-oxazinamine (725 mg, 1.1 mmol, 95.6
% yield) as a white foam. MS (ISP): m/z = 625.2 [M+H] and 627.3 [M+2+H] .
Synthesis of the intermediate imines E8
Intermediate E8.1
NHDMTr
Ph N
Under argon in a sealed tube were added to a solution of (S)-N-(bis(4-
methoxyphenyl)(phenyl)methyl)(5-bromofluorophenyl)(difluoromethyl)-5,6-dihydro-
4H-1,3-oxazinamine (intermediate E7.1) (725 mg, 1.16 mmol) in toluene (15 ml) sodium tert-
butoxide (334 mg, 3.48 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (73.8 mg,
174 µmol) and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (60.0 mg, 58.0 µmol)
and benzophenone imine (420 mg, 389 µl, 2.32 mmol), the tube was sealed under argon and the
mixture was stirred at 105 °C for 4 h. The brown solution was extracted with ethyl acetate/water.
The organic layer was washed with brine, dried over Na SO , filtered and evaporated to give a
brown oil. The residue was chromatographed on 20 g silica gel with ethyl acetate 0-50% to give
(S)-N-(bis(4-methoxyphenyl)(phenyl)methyl)(difluoromethyl)(5-
(diphenylmethyleneamino)fluorophenyl)-5,6-dihydro-4H-1,3-oxazinamine (525 mg, 723
µmol, 62.4 % yield) as a yellow oil. MS (ISP): m/z = 726.8 [M+H] .
Syntheses of the intermediate anilines E9
Intermediate aniline E9.1
HN O
To a solution of (S)-N-(bis(4-methoxyphenyl)(phenyl)methyl)(difluoromethyl)(5-
(diphenylmethyleneamino)fluorophenyl)-5,6-dihydro-4H-1,3-oxazinamine (intermediate
E8.1) (525 mg, 723 µmol) in dichloromethane (20 ml) was added at 23 °C trifluoroacetic acid
(4.12 g, 2.79 ml, 36.2 mmol) and the mixture was stirred at 23 °C for 1 hour, whereupon 1 M
HCl (14.5 ml, 14.5 mmol) and dioxane (40 ml) were added and the mixture was stirred
vigorously at 23 °C for 60 hours. Poured into 1 M Na CO -solution, extracted with
dichloromethane, washed the organic layer with brine and dried over Na SO . Removal of the
solvent in vacuum left a brown oil. The residue was purified by chromatography on 5 g silica gel
with dichloromethane/methanol/ammonium hydroxide 110:10:1 to give (S)(5-amino
fluorophenyl)(difluoromethyl)-5,6-dihydro-4H-1,3-oxazinamine (82 mg, 316 µmol, 43.7 %
yield) as a light brown solid. MS (ISP): m/z = 259.9 [M+H] .
Synthesis of the intermediate fluoroketones F1
Intermediate F1.1
A solution of 1-(2-fluorophenyl)hydroxyethanone [CAS 2187717; WO9857925, ex.
16) (2.77 g, 18.0 mmol) in dichloromethane (42 ml) was treated consecutively at 0 °C with
triethylamine (6.36 g, 62.8 mmol), triethylamine trihydrofluoride (3.05 g, 18.0 mmol) and
nonafluoro-n-butanesulfonyl fluoride (8.48 g, 26.9 mmol). The tube was sealed and the reaction
mixture stirred overnight at room temperature. For the workup, the dark red solution was poured
on a saturated solution of sodium hydrogencarbonate and ice, then extracted with
dichloromethane. The organic layer was separated, dried over sodium sulphate and evaporated.
The crude material was purified by flash chromatography on silica gel (Telos Flash Silica) using
dichloromethane as the eluent to give the 2-fluoro(2-fluoro-phenyl)-ethanone (1.23 g, 61 %
yield) as a yellow semisolid.
Synthesis of the intermediate sulfinyl imines F2
Intermediate F2.1
In a manner analogous to that described for the preparation of sulfinyl imine E2.1 the
reaction of 2-fluoro(2-fluoro-phenyl)-ethanone with (R)-tert-butylsulfinamide yielded the (R)-
2-methyl-propanesulfinic acid [2-fluoro(2-fluoro-phenyl)-eth-(E)-ylidene]-amide (62 %
yield) as an orange oil. MS (ISP): m/z = 260.2 [M+H] .
Syntheses of the intermediate sulfinamide esters F3
Intermediate F3.1
COOEt
In a dry apparatus under an inert atmosphere a suspension of freshly activated zinc powder
(504 mg, 7.7 mmol) and copper(I) chloride (76.4 mg, 0.77 mmol) in dry tetrahydrofuran (3 ml)
was heated to reflux for 30 minutes. The suspension was cooled to room temperature and a
solution of ethyl 2-bromo-2,2-difluoroacetate (391 mg, 247 µl, 1.93 mmol) in tetrahydrofuran
(1.5 ml) was added dropwise. After 10 minutes a solution of (R)-N-(2-fluoro(2-
fluorophenyl)ethylidene)methylpropanesulfinamide (200 mg, 771 µmol) (intermediate
F2.1) in tetrahydrofuran (1.5 ml) was added dropwise. After 1 hour the reaction mixture was
cooled with ice and ethanol (80 µl) was added. The mixture was filtered over a layer of
Dicalite® and the filtrate evaporated at reduced pressure. The residue was dissolved in ethyl
acetate and treated consecutively with a saturated solution of ammonium chloride, sodium
hydrogencarbonate and with brine. The organic layer was dried over sodium sulphate and
evaporated at reduced pressure. The crude product was purified by flash chromatography on
silica gel using a 2:1-mixture of heptane and ethyl acetate as the eluent to give the (S)-2,2,4-
trifluoro(2-fluoro-phenyl)((R)methyl-propanesulfinylamino)-butyric acid ethyl ester
(184 mg, 62% yield) as a colorless oil. MS (ISP): m/z = 384.3 [M+H] .
Synthesis of the intermediate sulfinamide alcohols F4
Intermediate F4.1
(S)-2,2,4-trifluoro(2-fluoro-phenyl)((R)methyl-propanesulfinylamino)-butyric
acid ethyl ester (intermediate F3.1) (177 mg, 461 µmol) was dissolved in tetrahydrofuran (4 ml)
and at 0 °C lithium borohydride (2 M solution in tetrahydrofuran; (461 µl, 921 µmol) was added
dropwise. After 30 minutes the reaction was complete. For the workup, the reaction mixture was
poured into a mixture of ice water and a saturated solution of ammonium chloride. Thereafter,
the mixture was extracted with ethyl acetate (3x), the organic layers were combined, washed
with brine, dried over sodium sulphate and evaporated at reduced pressure. The resulting product
was pure enough to be engaged in the next step without further purification. The 2-methyl-
propanesulfinic acid [(S)-2,2-difluorofluoromethyl(2-fluoro-phenyl)hydroxy-propyl]-
amide (153 mg, 97 % yield) was obtained as a white foam. MS (ISN): m/z = 342.2 [M+H] .
Synthesis of the intermediate amino alcohols F5
Intermediate amino alcohol F5.1
A solution of 2-methyl-propanesulfinic acid [(S)-2,2-difluorofluoromethyl(2-
fluoro-phenyl)hydroxy-propyl]-amide (intermediate F4.1) (145.5 mg, 426 µmol) in methanol
(2.5 ml) was cooled to 0 °C and treated with hydrochloric acid (4 M in dioxane; (533 µl, 2.13
mmol). The solution was left to warm to room temperature and stirred for 1 hour. After removal
of the solvent at reduced pressure the solid residue was dissolved in water (5 ml), then extracted
with ethyl acetate (2 x 10 ml). The organic layers were extracted with water (5 ml), thereafter the
combined aqueous layers treated with a solution of sodium carbonate (2 M) to adjust the pH to 9-
. Extraction with ethyl acetate (3 x 35 ml), combination of the organic layers and evaporation
at reduced pressure after drying over sodium sulphate yielded the crude (S)amino-2,2,4-
trifluoro(2-fluoro-phenyl)-butanol (78 mg, 78 % yield) as a colorless oil. Evaporation of
the first 2 ethyl acetate layers followed by the treatment with a solution of sodium carbonate and
proceeding as described above yielded another fraction (22 mg) of product. MS (ISN): m/z =
238.1 [M+H] .
Syntheses of the intermediate amino oxazines F6
Intermediate amino oxazine F6.1
H N O
In a manner analogous to that described for the preparation of intermediate E6.1, the
reaction of (S)amino-2,2,4-trifluoro(2-fluoro-phenyl)-butanol (intermediate F5.1) with
cyanogen bromide yielded after purification by preparative HPLC the (S)-5,5-difluoro
fluoromethyl(2-fluoro-phenyl)-5,6-dihydro-4H-[1,3]oxazinylamine (44 mg, 41 % yield) as
a white solid. MS (ISP): m/z = 263.1 [M+H] .
Syntheses of the intermediate nitro oxazines F7
Intermediate nitro oxazine F7.1
H N O
O N F
A dispersion of (S)-5,5-difluorofluoromethyl(2-fluoro-phenyl)-5,6-dihydro-4H-
[1,3]oxazinylamine (intermediate F6.1) (32.5 mg, 124 µmol) in sulfuric acid (1.01 g, 554 µl,
9.92 mmol) was cooled to 0 °C and stirring was continued until a complete solution was obtained.
At 0 °C fuming nitric acid (12.1 mg, 8.68 µl, 174 µmol) was added in one portion and stirring
continued for 2 hours. For the workup, the solution was added dropwise to a mixture of crushed
ice and water. With an aqueous solution of sodium hydroxide (6 M) the pH was adjusted to 7-8.
The aqueous layer was extracted three times with ethyl acetate, thereafter the combined organic
layers were washed with brine, then dried over sodium sulphate and evaporated at reduced
pressure. The (S)-5,5-difluorofluoromethyl(2-fluoronitro-phenyl)-5,6-dihydro-4H-
[1,3]oxazinylamine (39 mg, quantitative yield) was obtained as a light yellow solid and was
engaged in the following step without further purification. MS (ISP): m/z = 308.3 [M+H] .
Syntheses of the intermediate anilines F8
Intermediate aniline F8.1
H N O
A solution of (S)-5,5-difluorofluoromethyl(2-fluoronitro-phenyl)-5,6-dihydro-4H-
[1,3]oxazinylamine (intermediate F7.1) (38.2 mg, 120 µmol) in ethanol (2 ml) was
hydrogenated at atmospheric pressure using palladium (10% on carbon) (6.4 mg, 6 µmol) as the
catalyst during 15 hours at room temperature. The reaction mixture was filtrated over a layer of
Dicalite®, which was washed with ethanol (2 x 10 ml). The combined solutions of ethanol were
evaporated at reduced pressure. The (S)(5-aminofluoro-phenyl)-5,5-difluoro
fluoromethyl-5,6-dihydro-4H-[1,3]oxazinylamine (36 mg, quantitative yield) was obtained as
a light red solid and was engaged in the following step without further purification. MS (ISP):
m/z = 278.2 [M+H] .
The following examples have a basic group. Depending on the reaction and purification
conditions they were isolated in either the free base form, or as a salt, or in both free base and
salt forms.
Example 1
(S)-N-(3-(2-amino(difluoromethyl)-5,6-dihydro-4H-1,3-oxazinyl)fluorophenyl)
cyanopicolinamide
To a solution of commercially available 5-cyanopicolinic acid (55.5 mg, 375 µmol) in
methanol (5 ml) was added at 0 °C 4-(4,6-dimethoxy[1.3.5]triazinyl)methylmorpholinium
chloride hydrate (129 mg, 437 µmol) and the colourless solution was stirred at 0 °C for 30 min.
Then a solution of (S)(5-aminofluorophenyl)(difluoromethyl)-5,6-dihydro-4H-1,3-
oxazinamine (intermediate E9.1) (81 mg, 312 µmol) in methanol (5 ml) was added dropwise
at 0 °C via syringe. The reaction mixture was stirred at 23 °C for 16 h. Poured into 1 M Na CO -
sol., extracted with dichloromethane, washed the organic layer with brine and dried over Na SO .
Removal of the solvent in vacuum left a light brown oil which was chromatographed on 20 g
silica gel with dichloromethane/methanol 0-10% to give (S)-N-(3-(2-amino(difluoromethyl)-
,6-dihydro-4H-1,3-oxazinyl)fluorophenyl)cyanopicolinamide (89 mg, 229 µmol, 73.2
% yield) as a white solid. MS (ISP): m/z = 390.0 [M+H] .
Example 2
(S)-N-(3-(2-amino-5,5-difluoro(fluoromethyl)-5,6-dihydro-4H-1,3-oxazinyl)
fluorophenyl)cyanopicolinamide
H N O
In a manner analogous to that described in Example 1, the condensation of (S)(5-
aminofluoro-phenyl)-5,5-difluorofluoromethyl-5,6-dihydro-4H-[1,3]oxazinylamine
(intermediate F8.1) and 5-cyanopicolinic acid yielded the title compound (35 mg, 74 % yield) as
a light yellow foam. MS (ISP): m/z = 408.4 [M+H] .
Claims (28)
1. A compound of formula I, HN O wherein 5 R is aryl or heteroaryl, each unsubstituted or substituted by 1-4 substituents individually selected from C -alkyl, cyano, cyano-C -alkyl, cycloalkyl, cycloalkyl-C -alkenyl, 1-6 1-6 2-6 cycloalkyl-C -alkynyl, cycloalkyl-C -alkyl, cycloalkyl-C -alkoxy, halogen, halogen- 2-6 1-6 1-6 C -alkenyl, halogen-C -alkynyl, halogen-C -alkyl, halogen-C -alkoxy, C -alkoxy, 2-6 2-6 1-6 1-6 1-6 C -alkoxy-C -alkyl, C -alkoxy-C -alkenyl, C -alkoxy-C -alkynyl, C -alkenyl, 1-6 1-6 1-6 2-6 1-6 2-6 2-6 10 C -alkynyl, C -alkenyl-C -alkoxy and C -alkynyl-C -alkoxy; 2-6 2-6 1-6 2-6 1-6 R is selected from the group consisting of i) hydrogen, and ii) halogen, R is halogen-C -alkyl; 15 R and R are both hydrogen or both halogen; R is selected from the group consisting of i) hydrogen, and ii) C -alkyl, R is selected from the group consisting of 20 i) hydrogen, and ii) C -alkyl, or pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, wherein R is heteroaryl substituted by 1-2 substituents individually selected from C -alkyl, cyano, cyano-C -alkyl, cycloalkyl, cycloalkyl-C - 1-6 1-6 2-6 25 alkenyl, cycloalkyl-C -alkynyl, cycloalkyl-C -alkyl, cycloalkyl-C -alkoxy, halogen, 2-6 1-6 1-6 halogen-C -alkenyl, halogen-C -alkynyl, halogen-C -alkyl, halogen-C -alkoxy, C - 2-6 2-6 1-6 1-6 1-6 alkoxy, C -alkoxy-C -alkyl, C -alkoxy-C -alkenyl, C -alkoxy-C -alkynyl, C - 1-6 1-6 1-6 2-6 1-6 2-6 2-6 alkenyl, C -alkynyl, C -alkenyl-C -alkoxy and C -alkynyl-C -alkoxy. 2-6 2-6 1-6 2-6 1-6
3. A compound according to any of claims 1-2, wherein R is pyridinyl substituted by cyano. 30
4. A compound according to any of claims 1-3, wherein R is halogen.
5. A compound according to any of claims 1-4, wherein R is F.
6. A compound according to any of claims 1-5, wherein R is –CHF .
7. A compound according to any of claims 1-6, wherein R is –CH F.
8. A compound according to any of claims 1-7, wherein R and R are H. 5
9. A compound according to any of claims 1-7, wherein R and R are halogen.
10. A compound according to claim 9, wherein R and R are F.
11. A compound according to any of claims 1-10, wherein R is H.
12. A compound according to any of claims 1-11, wherein R is H.
13. A compound according to any of claims 1-12, which is (S)-N-(3-(2-amino 10 (difluoromethyl)-5,6-dihydro-4H-1,3-oxazinyl)fluorophenyl)cyanopicolinamide.
14. A compound according to any of claims 1-12, which is (S)-N-(3-(2-amino-5,5-difluoro (fluoromethyl)-5,6-dihydro-4H-1,3-oxazinyl)fluorophenyl)cyanopicolinamide.
15. A process for preparing a compound of formula I as defined in any of claims 1 to 14, which process comprises reacting a compound of formula I’ to a compound of formula I HN O 15 I’ 2 3 4 5 6 7 wherein R , R , R , R , R and R are as defined in any of claim 1-12.
16. A compound of formula I according to any of claims 1-14, whenever prepared by a process as defined in claim 15.
17. A compound of formula I according to any of claims 1-14 for use as therapeutically active 20 substance.
18. A compound of formula I according to any of claims 1-14 for the use as therapeutically active substance for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid plaques and further deposits or Alzheimer's disease.
19. A compound of formula I according to any of claims 1-14 for the use as therapeutically active substance for the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes.
20. A compound of formula I according to any of claims 1-14 for the use as therapeutically 5 active substance for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down’s Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington’s Disease, inclusion body myositis (IBM), inflammatory 10 reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whipple’s Disease or Wilson’s Disease.
21. A pharmaceutical composition comprising a compound of formula I according to any of 15 claims 1-14 and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary substance.
22. Use of a compound of formula I according to any of claims 1-14 for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of Alzheimer's disease.
23. Use of a compound of formula I according to any of claims 1-14 for the manufacture of a 20 medicament for the therapeutic and/or prophylactic treatment of diabetes.
24. Use of a compound of formula I according to any of claims 1-14 for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, 25 dermatomyositis, Down’s Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington’s Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rheumatoid arthritis, Sjogren syndrome, SpinoCerebellar Ataxia 1, 30 SpinoCerebellar Ataxia 7, Whipple’s Disease or Wilson’s Disease.
25. The use according to claim 23, wherein the diabetes is type 2 diabetes.
26. A compound of formula (I) according to claim 1 substantially as herein described with reference to any example thereof.
27. A process according to claim 15 for preparing a compound of formula (I) substantially as herein described with reference to any example thereof.
28. A pharmaceutical composition according to claim 21 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11169007 | 2011-06-07 | ||
EP11169007.9 | 2011-06-07 | ||
PCT/EP2012/060457 WO2012168164A1 (en) | 2011-06-07 | 2012-06-04 | Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ617507A NZ617507A (en) | 2015-07-31 |
NZ617507B2 true NZ617507B2 (en) | 2015-11-03 |
Family
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