U.S. patent application number 14/330041 was filed with the patent office on 2014-10-30 for 1,4 oxazepines as bace1 and/or bace2 inhibitors.
The applicant listed for this patent is Hoffmann-La Roche Inc.. Invention is credited to Hans Hilpert, Robert Narquizian.
Application Number | 20140323469 14/330041 |
Document ID | / |
Family ID | 45571554 |
Filed Date | 2014-10-30 |
United States Patent
Application |
20140323469 |
Kind Code |
A1 |
Hilpert; Hans ; et
al. |
October 30, 2014 |
1,4 OXAZEPINES AS BACE1 AND/OR BACE2 INHIBITORS
Abstract
This invention relates to compounds of the formula ##STR00001##
wherein and R.sup.1 to R.sup.3 are as described herein, or to
pharmaceutically acceptable salts thereof. These compounds are
BACE1 and/or BACE2 inhibitors and can be used as pharmaceuticals
for the therapeutic and/or prophylactic treatment of diseases such
as Alzheimer's disease, diabetes, particularly type 2 diabetes, and
other metabolic disorders.
Inventors: |
Hilpert; Hans;
(Muenchenstein, CH) ; Narquizian; Robert;
(Zaessingue, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hoffmann-La Roche Inc. |
Nutley |
NJ |
US |
|
|
Family ID: |
45571554 |
Appl. No.: |
14/330041 |
Filed: |
July 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13369322 |
Feb 9, 2012 |
8815841 |
|
|
14330041 |
|
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|
Current U.S.
Class: |
514/211.15 ;
514/211.01; 540/544 |
Current CPC
Class: |
C07D 267/10 20130101;
A61P 21/00 20180101; A61P 21/02 20180101; A61P 29/00 20180101; A61P
7/02 20180101; A61P 9/10 20180101; A61P 25/00 20180101; A61P 9/00
20180101; C07D 417/14 20130101; A61P 3/10 20180101; A61P 25/14
20180101; A61P 1/00 20180101; A61P 37/02 20180101; C07D 413/12
20130101; A61P 19/02 20180101; A61P 25/28 20180101; A61P 35/00
20180101 |
Class at
Publication: |
514/211.15 ;
540/544; 514/211.01 |
International
Class: |
C07D 417/14 20060101
C07D417/14; C07D 267/10 20060101 C07D267/10; C07D 413/12 20060101
C07D413/12 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 18, 2011 |
EP |
11155051.3 |
Claims
1. A compound of the formula I ##STR00040## wherein R.sup.1 is H or
F; R.sup.2 is C.sub.1-7-alkyl; and R.sup.3 is --(C.dbd.O)--R.sup.4
or R.sup.5, wherein R.sup.4 is heteroaryl substituted by one
substituent selected from the group consisting of
C.sub.3-7-cycloalkyl-C.sub.1-7-alkoxy-,
C.sub.3-7-cycloalkyl-C.sub.2-7-alkynyl-,
C.sub.1-7-alkoxy-C.sub.2-7-alkynyl-, unsubstituted heteroaryl,
unsubstituted C.sub.3-7-cycloalkyl and C.sub.1-7-alkyl-S--, or
R.sup.4 is heteroaryl substituted by one halogen and one amidyl;
and R.sup.5 is C.sub.3-7-cycloalkyl-C.sub.1-7-alkyl-; or a
pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein R.sup.1 is F.
3. The compound of claim 1, wherein R.sup.1 is H.
4. The compound of claim 1, wherein R.sup.2 is Me.
5. The compound of claim 1, wherein R.sup.2 is Et.
6. The compound of claim 1, wherein R.sup.3 is
C.sub.3-7-cycloalkyl-C.sub.1-7-alkyl-.
7. The compound of claim 6, wherein R.sup.3 is
cyclopropyl-CH.sub.2--.
8. The compound of claim 7, which is
(5R,6R)-5-[5-(Cyclopropylmethyl-amino)-2-fluoro-phenyl]-6-fluoro-5-methyl-
-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine.
9. The compound of claim 1, wherein R.sup.3 is
--(C.dbd.O)--R.sup.4.
10. The compound of claim 9, wherein R.sup.4 is pyridinyl
substituted by one halogen and one amidyl.
11. The compound of claim 10, which is
(R)--N2-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-
-5-yl)-4-fluorophenyl)-3-fluoropyridine-2,5-dicarboxamide
formate.
12. The compound of claim 9, wherein R.sup.4 is pyridinyl
substituted by one substituent selected from the group consisting
of C.sub.3-7-cycloalkyl-C.sub.1-7-alkoxy-,
C.sub.3-7-cycloalkyl-C.sub.2-7-alkynyl-,
C.sub.1-7-alkoxy-C.sub.2-7-alkynyl-, unsubstituted heteroaryl and
unsubstituted C.sub.3-7-cycloalkyl.
13. The compound of claim 12, selected from the group consisting of
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-6-(cyclopropylmethoxy)picolinamide formate,
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(thiazol-2-yl)picolinamide formate,
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(cyclopropylethynyl)picolinamide formate,
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-cyclopropylpicolinamide formate, and
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-.beta.-methoxyprop-1-ynyl)picolinamide
formate.
14. The compound of claim 9, wherein R.sup.4 is pyrazinyl
substituted by C.sub.1-7-alkyl-S--.
15. The compound of claim 14, which is
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(methylthio)pyrazine-2-carboxamide
formate.
16. The compound of claim 9, wherein R.sup.4 is oxazolyl
substituted by C.sub.3-7-cycloalkyl.
17. The compound of claim 16, which is
(R)--N-(3-(3-amino-5-ethyl-6,6-difluoro-2,5,6,7-tetrahydro-1,4-oxazepin-5-
-yl)-4-fluorophenyl)-5-cyclopropyloxazole-4-carboxamide.
18. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of formula I ##STR00041## wherein
R.sup.1 is H or F; R.sup.2 is C.sub.1-7-alkyl; and R.sup.3 is
--(C.dbd.O)--R.sup.4 or R.sup.5, wherein R.sup.4 is heteroaryl
substituted by one substituent selected from the group consisting
of C.sub.3-7-cycloalkyl-C.sub.1-7-alkoxy-,
C.sub.3-7-cycloalkyl-C.sub.2-7-alkynyl-,
C.sub.1-7-alkoxy-C.sub.2-7-alkynyl-, unsubstituted heteroaryl,
unsubstituted C.sub.3-7-cycloalkyl and C.sub.1-7-alkyl-S--, or
R.sup.4 is heteroaryl substituted by one halogen and one amidyl;
and R.sup.5 is C.sub.3-7-cycloalkyl-C.sub.1-7-alkyl-; or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable excipient.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application is a divisional of U.S. application Ser.
No. 13/369,322, filed Feb. 9, 2012, which, in turn, claims the
benefit of priority to European Patent Application No 11155051.3,
filed Feb. 18, 2011, which is hereby incorporated by reference in
its entirety.
BACKGROUND OF THE INVENTION
[0002] 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.
[0003] AD is characterized by two 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
A.beta.-peptides. The latter are a group of proteolytic fragments
derived from the .beta.-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 A.beta.-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
A.beta.-peptides are the essential molecules in the pathogenesis of
AD: 1) amyloid plaques formed of A.beta.-peptides are invariably
part of the AD pathology; 2) A.beta.-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
A.beta.-peptides and early brain amyloidosis; 4) transgenic mice
which express such FAD genes develop a pathology which bears many
resemblances to the human disease. A.beta.-peptides are produced
from APP through the sequential action of 2 proteolytic enzymes
termed .beta.- and .gamma.-secretase. .beta.-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 (CTF.beta.). CTF.beta. is the substrate for
.gamma.-secretase which cleaves at several adjacent positions
within the TM to produce the A.beta. peptides and the cytoplasmic
fragment. The .gamma.-secretase is a complex of at least four
different proteins, its catalytic subunit is very likely a
presenilin protein (PSEN1, PSEN2). The .beta.-secretase (BACE1,
Asp2; BACE stands for .beta.-site 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
A.beta.-peptides, in the absence of BACE1 no A.beta.-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 March; 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
.beta.-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 AD.
[0004] Type 2 diabetes (T2D) is caused by insulin resistance and
inadequate insulin secretion from pancreatic .beta.-cells leading
to poor blood-glucose control and hyperglycemia (M Prentki & C
J 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, K G M M Alberti & J Shaw, "Global and
societal implications of the diabetes epidemic" Nature 2001, 414,
782-787).
[0005] .beta.-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 .beta.-cell mass
characterizing overt T2D. However, recent developments with GLP-1
analogues, gastrin and other agents show that preservation and
proliferation of .beta.-cells is possible to achieve, leading to an
improved glucose tolerance and slower progression to overt T2D (L L
Baggio & D J Drucker, "Therapeutic approaches to preserve islet
mass in type 2 diabetes", Annu. Rev. Med. 2006, 57, 265-281).
[0006] Tmem27 has been identified as a protein promoting beta-cell
proliferation (P Akpinar, S Kuwajima, J Krutzfeldt, M Stoffel,
"Tmem27: A cleaved and shed plasma membrane protein that stimulates
pancreatic .beta. cell proliferation", Cell Metab. 2005, 2,
385-397) and insulin secretion (K Fukui, Q Yang, Y Cao, N Takahashi
et al., "The HNF-1 target Collectrin controls insulin exocytosis by
SNARE complex formation", Cell Metab. 2005, 2, 373-384). Tmem27 is
a 42 kDa membrane glycoprotein which is constitutively shed from
the surface of .beta.-cells, resulting from a degradation of the
full-length cellular Tmem27. Overexpression of Tmem27 in a
transgenic mouse increases .beta.-cell mass and improves glucose
tolerance in a diet-induced obesity DIO model of diabetes.
Furthermore, siRNA knockout of Tmem27 in a rodent .beta.-cell
proliferation assay (e.g. using INS1e cells) reduces the
proliferation rate, indicating a role for Tmem27 in control of
.beta.-cell mass.
[0007] 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
.beta.-cells.
[0008] The close homolog BACE2 is a membrane-bound aspartyl
protease and is co-localized with Tmem27 in human pancreatic
.beta.-cells (G Finzi, F Franzi, C Placidi, F Acquati et al.,
"BACE2 is stored in secretory granules of mouse and rat pancreatic
beta cells", Ultrastruct Pathol. 2008, 32(6), 246-251). It is also
known to be capable of degrading APP (I Hussain, D Powell, D
Howlett, G Chapman et al., "ASP1 (BACE2) cleaves the amyloid
precursor protein at the .beta.-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.
[0009] 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 August;
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 February; 13(2):170-8),
SpinoCerebellar Ataxia 1 and SpinoCerebellar Ataxia 7 (Gatchel J.
R. et al., Proc Natl Acad Sci USA 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 February
15; 109(4):1550-8), Glioblastoma multiforme (E-MEXP-2576,
http://www.ebi.ac.uk/microarray-as/aer/result?queryFor=PhysicalArrayDesig-
n &aAccession=A-MEXP-258), Rheumatoid arthritis (Ungethuem U.
et al, GSE2053), Amyotrophic lateral sclerosis (Koistinen H. et
al., Muscle Nerve. 2006 October; 34(4):444-50 and Li Q. X. et al,
Aging Cell. 2006 April; 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; 15(6):965-77.
Epub 2006 Feb. 8), Multiple Mieloma (Kihara Y. et al, Proc Natl
Acad Sci USA. 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 March;
51(3):307-11), Lupus erythematosus (Grewal P. K. et al, Mol Cell
Biol. 2006, July; 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 March;
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 February; 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 November;
93(11):855-63), Cardiovascular diseases such as Myocardial
infarction and stroke (Maugeri N. et al., Srp Arh Celok Lek. 2010
January; 138 Suppl 1:50-2) and Graves disease (Kilja ski J. et al,
Thyroid. 2005 July; 15(7):645-52).
SUMMARY OF THE INVENTION
[0010] The present invention provides
2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamines having BACE1 and/or
BACE2 inhibitory properties, their manufacture, pharmaceutical
compositions containing them and their use as therapeutically
active substances.
[0011] In particular, the present invention provides compounds of
the formula
##STR00002##
wherein R.sup.1 to R.sup.3 are as described below, or to
pharmaceutically acceptable salts thereof
[0012] The compounds of the invention have Asp2 (.beta.-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 .beta.-amyloid levels and/or
.beta.-amyloid oligomers and/or .beta.-amyloid plaques and further
deposits, particularly Alzheimer's disease. In addition, the
compounds of formula I 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.
[0013] The present invention to provides selective BACE1 inhibitors
with enhanced therapeutic and pharmacological properties compared
to the compounds already known in the art. The formation, or
formation and deposition, of .beta.-amyloid plaques in, on or
around neurological tissue (e.g., the brain) is inhibited by such
compounds by blocking the A.beta. production from APP or an APP
fragment. Therefore, such compounds are useful as therapeutically
active substances, particularly in the control or prevention of
Alzheimer's disease.
[0014] Inhibition of BACE2 is proposed as a treatment for type 2
diabetes (T2D) with the potential to preserve and restore
.beta.-cell mass and stimulate insulin secretion in pre-diabetic
and diabetic patients. Therefore, the present invention provides
selective BACE2 inhibitors with enhanced therapeutic and
pharmacological properties compared to the compounds already known
in the art. 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 such as
type 2 diabetes.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The present invention provides novel compounds of formula I
having BACE1 and/or BACE2 inhibitory properties, their manufacture,
pharmaceutical compositions containing the compounds of the present
invention, the production of such pharmaceutical compositions as
well as the use of the compounds of formula I in the treatment or
prevention of diseases such as Alzheimer's disease and type 2
diabetes.
[0016] Unless otherwise indicated, the following definitions are
set forth to illustrate and define the meaning and scope of the
various terms used to describe the invention.
[0017] The term "halogen", alone or in combination with other
groups, refers to fluoro, chloro, bromo and iodo, in particular
fluoro (F).
[0018] The term "amidyl", alone or in combination with other
groups, refers to --C(.dbd.O)--NH.sub.2.
[0019] The term "C.sub.1-7-alkyl", alone or in combination with
other groups, signifies a straight-chain or branched-chain
hydrocarbon group with 1 to 7 carbon atoms, in particular a
straight or branched-chain hydrocarbon group with 1 to 6 carbon
atoms and more particularly a straight or branched-chain
hydrocarbon group with 1 to 4 carbon atoms. Examples of
straight-chain and branched C.sub.1-7 alkyl groups are methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the
isomeric pentyls, the isomeric hexyls and the isomeric heptyls, in
particular methyl (Me) and ethyl (Et). More particular is
methyl.
[0020] The term "C.sub.1-7-alkoxy", alone or in combination with
other groups, refers to the group R'--O--, wherein R' is
C.sub.1-7-alkyl as described herein. Examples of "C.sub.1-7-alkoxy"
include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
isobutoxy, sec.-butoxy and tert.-butoxy, preferably methoxy
(MeO).
[0021] The term "C.sub.3-7-cycloalkyl", alone or in combination
with other groups, denotes a monovalent saturated monocyclic or
bicyclic hydrocarbon group of 3 to 7 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.sub.3-7-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 "C.sub.3-7-cycloalkyl" is cyclopropyl.
[0022] The term "heteroaryl", alone or in combination with other
groups, refers to a cyclic aromatic group having a single 4 to 8
membered ring or multiple condensed rings containing 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 N and O, in
which group at least one heterocyclic ring is aromatic. Examples of
"heteroaryl" include benzofuryl, benzoimidazolyl,
1H-benzoimidazolyl, benzoxazinyl, 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"
are pyridinyl, oxazolyl, pyrazinyl and thiazolyl. Specific examples
are pyridine-2-yl, oxazol-4-yl, pyrazin-2-yl and thiazol-2-yl.
[0023] The term "C.sub.2-7-alkynyl", alone or in combination with
other groups, denotes a monovalent linear or branched hydrocarbon
group of 2 to 7 carbon atoms, in particular from 2 to 4 carbon
atoms, containing one, two or three triple bonds. Examples of
C.sub.2-7-alkynyl include ethynyl, propynyl, prop-2-ynyl,
isopropynyl and n-butynyl. Specific examples are ethynyl and
propynyl.
[0024] The term "C.sub.1-7-alkoxy-C.sub.2-7-alkynyl", alone or in
combination with other groups, refers to a "C.sub.1-7-alkoxy" as
defined herein linked via a "C.sub.2-7-alkynyl" as defined herein.
A specific example is 3-methoxy-prop-1-ynyl.
[0025] The term "C.sub.3-7-cycloalkyl-C.sub.2-7-alkynyl", alone or
in combination with other groups, refers to a
"C.sub.3-7-cycloalkyl" as defined herein linked via a
"C.sub.2-7-alkynyl" as defined herein. A specific example is
cyclopropylethynyl.
[0026] The term "C.sub.3-7-cycloalkyl-C.sub.1-7-alkoxy", alone or
in combination with other groups, refers to a
"C.sub.3-7-cycloalkyl" as defined herein linked via a
"C.sub.1-7-alkoxy" as defined herein. A specific example is
cyclopropylmethoxy.
[0027] The term "C.sub.3-7-cycloalkyl-C.sub.1-7-alkyl", alone or in
combination with other groups, refers to a "C.sub.3-7-cycloalkyl"
as defined herein linked via a "C.sub.1-7-alkyl" as defined herein.
A specific example is cyclopropylmethyl.
[0028] The term "C.sub.1-7-alkyl-S--", alone or in combination with
other groups, refers to a C.sub.1-7-alkyl as defined herein linked
via --S--.
[0029] The term "coupling agent" refers to an agent selected from
the group consisting of carbodiimides or uronium salts, such as for
example N,N'-carbonyldiimidazole (CDI),
N,N'-dicyclohexylcarbodiimide (DCC),
N-.beta.-dimethylaminopropyl)-N'-ethyl-carbodiimide-hydrochloride
(EDCI), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU) and
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid-
e hexafluorophosphate (HATU).
[0030] The term "under basic conditions", refers to the presence of
a base, in particular an alkylamine such as diisopropylethylamine
(DIEA) or triethylamine (TEA), or a tertiary amine such as
N-methylmorpholine or 4-(dimethylamino)-pyridine.
[0031] The term "triazine derivative" for example refers to
4-(4,6-dimethoxy-1,3,5-triazin-2yl)-4-methyl-morpholiniumchloride.
[0032] The term "protic solvent" refers to a solvent that has a
hydrogen atom bound to an oxygen atom as in a hydroxyl group or
bound to a nitrogen atom as in an amine group, which hydrogen is
dissociable. Examples are alcohols, in particular ethanol or
methanol.
[0033] The term "polar solvent" refers to molecules whose electric
charges are unequally distributed within the molecule. Examples
include water and alcohols, in particular methanol.
[0034] The term "mild oxidant" refers, for example, to
tert-butylhydroperoxide.
[0035] The term "oxonium salt" refers to salts containing oxonium
([H.sub.3O.sup.+]) as cation.
[0036] The term "ammonium salt" refers to salts containing ammonium
([NH.sub.4.sup.+]) as cation.
[0037] 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. 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.
[0038] 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. Preferably 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.
[0039] 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.
[0040] The term "half maximal inhibitory concentration" (IC.sub.50)
denotes the concentration of a particular compound required for
obtaining 50% inhibition of a biological process in vitro.
IC.sub.50 values can be converted logarithmically to pIC.sub.50
values (-log IC.sub.50), in which higher values indicate
exponentially greater potency. The IC.sub.50 value is not an
absolute value but depends on experimental conditions e.g.
concentrations employed. The IC.sub.50 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.
[0041] "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.
[0042] The term "as defined herein" and "as described herein" when
referring to a variable incorporates by reference the broad
definition of the variable as well as preferred, more preferred and
most preferred definitions, if any.
[0043] 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 "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).
[0044] 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.
[0045] The compounds of formula I can also be solvated, e.g.,
hydrated. The solvation can be effected in the course of the
manufacturing process or can take place e.g. as a consequence of
hygroscopic properties of an initially anhydrous compound of
formula I (hydration). The term "pharmaceutically acceptable salts"
also includes physiologically acceptable solvates.
[0046] "Isomers" are compounds that have identical molecular
formulae but that differ in the nature or the sequence of bonding
of their atoms or in the arrangement of their atoms in space.
Isomers that differ in the arrangement of their atoms in space are
termed "stereoisomers". Stereoisomers that are not mirror images of
one another are termed "diastereoisomers", and stereoisomers that
are non-superimposable mirror images are termed "enantiomers", or
sometimes optical isomers. A carbon atom bonded to four
non-identical substituents is termed a "chiral center". 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.
[0047] All separate embodiments can be combined.
[0048] The present invention provides compounds of the formula
##STR00003##
wherein
R.sup.1 is H or F;
[0049] R.sup.2 is C.sub.1-7-alkyl; and R.sup.3 is
--(C.dbd.O)--R.sup.4 or R.sup.5, wherein R.sup.4 is heteroaryl
substituted by one substituent selected from the group consisting
of C.sub.3-7-cycloalkyl-C.sub.1-7-alkoxy-,
C.sub.3-7-cycloalkyl-C.sub.2-7-alkynyl-,
C.sub.1-7-alkoxy-C.sub.2-7-alkynyl-, unsubstituted heteroaryl,
unsubstituted C.sub.3-7-cycloalkyl and C.sub.1-7-alkyl-S--, or
R.sup.4 is heteroaryl substituted by one halogen and one amidyl;
and R.sup.5 is C.sub.3-7-cycloalkyl-C.sub.1-7-alkyl-; or a
pharmaceutically acceptable salt thereof
[0050] A certain embodiment provides a compound of formula I as
described herein, wherein
R.sup.1 is F;
R.sup.2 is Me; and
[0051] R.sup.3 is --(C.dbd.O)--R.sup.4, wherein R.sup.4 is
pyridinyl substituted by one substituent selected from the group
consisting of C.sub.3-7-cycloalkyl-C.sub.1-7-alkoxy-,
C.sub.3-7-cycloalkyl-C.sub.2-7-alkynyl-,
C.sub.1-7-alkoxy-C.sub.2-7-alkynyl-, or R.sup.4 is pyridinyl
substituted by one F and one amidyl; or a pharmaceutically
acceptable salt thereof
[0052] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.1 is F, R.sup.2 is Me, R.sup.3 is
--(C.dbd.O)--R.sup.4 and R.sup.4 is 3-fluoro-5-amido-pyridin-2-yl,
6-(cyclopropylmethoxy)-pyridin-2-yl,
5-(cyclopropylethynyl)-pyridin-2-yl or
5-(3-methoxyprop-1-ynyl)-pyridin-2-yl.
[0053] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.1 is F.
[0054] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.1 is H.
[0055] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.2 is Me.
[0056] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.2 is Et.
[0057] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.3 is
C.sub.3-7-cycloalkyl-C.sub.1-7-alkyl-.
[0058] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.3 is cyclopropyl-CH.sub.2--.
[0059] A certain embodiment provides a compound of formula I as
described herein, which is
(5R,6R)-5-[5-(Cyclopropylmethyl-amino)-2-fluoro-phenyl]-6-fluoro-5-methyl-
-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine.
[0060] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.3 is --(C.dbd.O)--R.sup.4.
[0061] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is pyridinyl substituted by one
halogen and one amidyl.
[0062] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is pyridinyl substituted by one F
and one amidyl.
[0063] A certain embodiment provides a compound of formula I as
described herein, which is
(R)--N2-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-
-5-yl)-4-fluorophenyl)-3-fluoropyridine-2,5-dicarboxamide
formate.
[0064] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is pyridinyl substituted by one
substituent selected from the group consisting of
C.sub.3-7-cycloalkyl-C.sub.1-7-alkoxy-,
C.sub.3-7-cycloalkyl-C.sub.2-7-alkynyl-,
C.sub.1-7-alkoxy-C.sub.2-7-alkynyl-, unsubstituted heteroaryl and
unsubstituted C.sub.3-7-cycloalkyl.
[0065] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is pyridinyl substituted by
C.sub.3-7-cycloalkyl-C.sub.1-7-alkoxy-.
[0066] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is pyridinyl substituted by
C.sub.3-7-cycloalkyl-C.sub.2-7-alkynyl-.
[0067] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is pyridinyl substituted by
C.sub.1-7-alkoxy-C.sub.2-7-alkynyl-.
[0068] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is pyridinyl substituted by
unsubstituted heteroaryl.
[0069] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is pyridinyl substituted by
unsubstituted thiazol-2-yl.
[0070] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is pyridinyl substituted by
unsubstituted C.sub.3-7-cycloalkyl.
[0071] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is pyridinyl substituted by
unsubstituted cyclopropyl.
[0072] A certain embodiment provides a compound of formula I as
described herein, selected from the group consisting of
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-6-(cyclopropylmethoxy)picolinamide formate,
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(thiazol-2-yl)picolinamide formate,
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(cyclopropylethynyl)picolinamide formate,
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-cyclopropylpicolinamide formate, and
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(3-methoxyprop-1-ynyl)picolinamide
formate.
[0073] A certain embodiment provides a compound of formula I as
described herein, which is
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-6-(cyclopropylmethoxy)picolinamide
formate.
[0074] A certain embodiment provides a compound of formula I as
described herein, which is
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(thiazol-2-yl)picolinamide formate.
[0075] A certain embodiment provides a compound of formula I as
described herein, which is
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(cyclopropylethynyl)picolinamide
formate.
[0076] A certain embodiment provides a compound of formula I as
described herein, which is
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-cyclopropylpicolinamide formate.
[0077] A certain embodiment provides a compound of formula I as
described herein, which is
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(3-methoxyprop-1-ynyl)picolinamide
formate.
[0078] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is pyrazinyl substituted by
C.sub.1-7-alkyl-S--.
[0079] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is pyrazinyl substituted by
methyl-S--.
[0080] A certain embodiment provides a compound of formula I as
described herein, which is
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(methylthio)pyrazine-2-carboxamide
formate.
[0081] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is oxazolyl substituted by
C.sub.3-7-cycloalkyl.
[0082] A certain embodiment provides a compound of formula I as
described herein, wherein R.sup.4 is oxazolyl substituted by
cyclopropyl.
[0083] A certain embodiment provides a compound of formula I as
described herein, which is
(R)--N-(3-(3-amino-5-ethyl-6,6-difluoro-2,5,6,7-tetrahydro-1,4-oxazepin-5-
-yl)-4-fluorophenyl)-5-cyclopropyloxazole-4-carboxamide.
[0084] A certain embodiment provides a compound of formula I as
described herein, selected from the group consisting of
(R)--N2-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-
-5-yl)-4-fluorophenyl)-3-fluoropyridine-2,5-dicarboxamide formate,
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-6-(cyclopropylmethoxy)picolinamide formate,
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(cyclopropylethynyl)picolinamide formate,
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-.beta.-methoxyprop-1-ynyl)picolinamide
formate, and
(5R,6R)-5-[5-(Cyclopropylmethyl-amino)-2-fluoro-phenyl]-6-fluoro-5-me-
thyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine.
[0085] A certain embodiment provides a compound of formula I as
described herein, selected from the group consisting of
(R)--N2-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-
-5-yl)-4-fluorophenyl)-3-fluoropyridine-2,5-dicarboxamide formate,
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-6-(cyclopropylmethoxy)picolinamide formate,
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(cyclopropylethynyl)picolinamide formate,
and
(R)--N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-5-(3-methoxyprop-1-ynyl)picolinamide
formate.
[0086] A certain embodiment provides a process for the manufacture
of compounds of formula I as defined herein, which process
comprises
a) reacting an amine of the formula II with a carboxylic acid of
the formula III in the presence of a coupling reagent under basic
conditions or with the help of a triazine derivative to obtain a
compound of formula Ia
##STR00004##
wherein R.sup.1, R.sup.2 and R.sup.4 are as defined herein, or
alternatively, b) reacting an amine of the formula II with a
compound of formula IV, wherein R is hydrogen or C.sub.1-7-alkyl,
in the presence of acetic acid and sodium triacetoxyborohydride to
obtain a compound of formula Ib
##STR00005##
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as defined
herein.
[0087] The invention further provides a compound of formula I as
defined above obtainable according to a process as defined
herein.
[0088] A certain embodiment of the invention provides a compound of
formula I as defined herein and a pharmaceutically acceptable
carrier and/or excipient.
[0089] A certain embodiment of the invention provides a compound of
formula I as defined herein for use as medicaments.
[0090] A certain embodiment of the invention provides a compound of
formula I as defined herein for use in the therapeutic and/or
prophylactic treatment of Alzheimer's disease and/or type 2
diabetes.
[0091] A certain embodiment of the invention provides a compound of
formula I as defined herein for use in the therapeutic and/or
prophylactic treatment of Alzheimer's disease.
[0092] A certain embodiment of the invention provides a compound of
formula I as defined herein for use in the therapeutic and/or
prophylactic treatment of type 2 diabetes.
[0093] A certain embodiment of the invention provides a compound of
formula I as defined 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.
[0094] A certain embodiment of the invention provides a compound of
formula I as defined herein for the preparation of medicaments for
the therapeutic and/or prophylactic treatment of Alzheimer's
disease and/or type 2 diabetes.
[0095] A certain embodiment of the invention provides a compound of
formula I as defined herein for the preparation of medicaments for
the therapeutic and/or prophylactic treatment of Alzheimer's
disease.
[0096] A certain embodiment of the invention provides a compound of
formula I as defined herein for the preparation of medicaments for
the therapeutic and/or prophylactic treatment of type 2
diabetes.
[0097] A certain embodiment of the invention provides a method for
the therapeutic and/or prophylactic treatment of diseases which can
be ameliorated with the inhibition of BACE1 and/or BACE 2 activity,
particularly for the treatment of Alzheimer's disease and type 2
diabetes, which method comprises administering a therapeutically
active amount of a compound of formula I as described herein to a
human being or animal.
[0098] A certain embodiment of the invention provides a compound of
formula I as defined herein for use in the manufacture of a
medicament for use in the therapeutic and/or prophylactic treatment
of Alzheimer's disease and/or type 2 diabetes.
[0099] A certain embodiment of the invention provides a compound of
formula I as defined 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.
[0100] A certain embodiment of the invention provides a compound of
formula I as defined herein for the preparation of medicaments for
the therapeutic and/or prophylactic treatment of Alzheimer's
disease and/or type 2 diabetes.
[0101] A certain embodiment of the invention provides a method for
the therapeutic and/or prophylactic treatment of diseases which can
be ameliorated with the inhibition of BACE1 and/or BACE 2 activity,
particularly for the treatment of Alzheimer's disease and type 2
diabetes, which method comprises administering a therapeutically
active amount of a compound of formula I to a human being or
animal.
[0102] A certain embodiment of the invention provides a method for
the therapeutic and/or prophylactic treatment of diseases which can
be ameliorated with the inhibition of BACE1 and/or BACE 2 activity,
particularly 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 or Wilson's Disease
which method comprises administering a therapeutically active
amount of a compound of formula I to a human being or animal.
[0103] As described herein before, the compounds of formula I of
the invention will be useful in preserving and restoring beta-cell
function and stimulating insulin secretion in diabetic patients and
in non-diabetic patients who have impaired glucose tolerance or who
are in a pre-diabetic condition. They can be useful in treating
type 1 diabetes or in delaying or preventing a patient with type 2
diabetes from needing insulin therapy. The compounds of formula I
are further useful to ameliorate hyperinsulinemia, which often
occurs in diabetic or pre-diabetic patients and in reducing the
risks associated with metabolic syndrome, they can also be useful
in treating vascular diseases such as hypertension.
[0104] Thus, the expression `diseases which can be ameliorated with
the inhibition of BACE2 activity` means diseases such as metabolic
and cardiovascular diseases, in particular diabetes, more
particularly type 2 diabetes, gestational diabetes, impaired
fasting glucose, impaired glucose tolerance, insulin resistance,
pre-diabetes, metabolic syndrome, diabetes type 1, complications of
diabetes including diabetic nephropathy, diabetic retinopathy and
diabetic neuropathy, chronic kidney disease, dyslipidemia,
atherosclerosis, myocardial infarction, hypertension and further
metabolic and cardiovascular disorders.
[0105] In particular, the expression `diseases which can be
ameliorated with the inhibition of BACE2 activity` relates to
diabetes, particularly type 2 diabetes, impaired glucose tolerance,
pre-diabetes, metabolic syndrome and hypertension. More
particularly, the expression `diseases which are associated with
the inhibition of BACE2 activity` relates to diabetes, particularly
type 2 diabetes.
[0106] 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.
[0107] In more detail, compounds of formula I according to the
present invention can be prepared by the methods and procedures
given below. Some typical procedures for the preparation of
compounds of formula I are illustrated in Schemes A (R.sup.12=H, Br
or NO.sub.2):
[0108] Sulfinyl imines of general formula A2 can be prepared in
analogy to T. P. Tang & J. A. Ellman, J. Org. Chem. 1999, 64,
12, by condensation of an aryl ketone and a sulfinamide, e.g. an
alkyl sulfinamide, most preferably (R)-(+)-tert-butylsulfinamide in
the presence of a Lewis acid such as e.g. a titanium(IV)alkoxyde,
more preferably titanium(IV)ethoxide in a solvent such as an ether,
e.g. diethyl ether or more preferably THF.
[0109] The conversion of the sulfinyl imine A2 to the sulfinamide
ester A3 proceeds stereoselectively by the chiral directing group
as described by Tang & Ellman. The sulfinyl imine A2 can be
reacted with a titanium enolate generated from e.g. an alkyl
acetate, preferably ethyl acetate, LDA and
chlorotriisopropoxytitanium at low temperature, preferably at
-78.degree. C. in a solvent such as an ether, e.g. diethyl ether or
more preferably THF. Alternatively sulfinamide ester A3 can be
produced from sulfinyl imine A2 by Reformatsky reaction of a
bromoacetic ester derivative and zinc dust, optionally in the
presence of copper(I) chloride, in a solvent such as an ether, e.g.
diethyl ether or more preferably THF, at temperatures from 0 to
70.degree. C., preferably at 23.degree. C.
[0110] Sulfinamide ester A3 can be reduced to the alcohol A4 by the
reduction of the ethylester with an alkali hydride, preferably
lithium borohydride or lithium aluminium hydride in a solvent such
as an ether, e.g. diethyl ether or more preferably THF.
[0111] Alkylation of the alcohol A4 to the nitrile A5 can be
accomplished with a suitable mild base preferably silver(I) oxide
in a solvent such as THF or CH.sub.2Cl.sub.2, more preferably
CH.sub.2Cl.sub.2 in the presence of an alkylating catalyst such as
tertra butyl ammonium iodide.
[0112] Hydrolysis of the chiral directing group in the nitrile A5
to give the amino nitrile A6 can be accomplished with a mineral
acid, e.g. sulfuric acid or preferably hydrochloric acid in a
solvent such as an ether, e.g. diethyl ether or more preferably
1,4-dioxane.
[0113] Aminooxazepine A7 can be prepared by the reaction of amino
nitrile A6 and trimethyl aluminium in a solvent such as an xylene,
preferably toluene.
##STR00006##
[0114] Introduction of the nitro group in A7 to give A8 was best
performed according to the standard procedure involving sulfuric
acid and nitric acid at low temperature, preferably at 0.degree.
C.
[0115] The reduction of the nitro group in aminooxazepine A8 to the
aniline A9 can be accomplished by hydrogenation using a catalysts
such as Pd/C in protic solvents, such as alcohols, preferably
ethanol or methanol.
[0116] Amide coupling of the aniline A9 and a carboxylic acid to
give the amide Ia can be effected with a carbodiimide, e.g. DCC or
EDCI in a solvent such as dichloromethane or in particular with a
triazine derivative,
4-(4,6-dimethoxy-1,3,5-triazin-2yl)-4-methyl-morpholiniumchloride
in an alcohol in particular methanol.
[0117] Target amines Ib can be prepared via reductive amination of
aniline A9 and a carbonyl compound performed with a borohydride
reducing agent, e.g. sodium borohydride, preferable sodium
triacetoxyborohydride and an weak acid, e.g. acetic acid in a
solvent such as tetrahydrofuran or dichloromethane.
[0118] Compounds of formula I can form pharmaceutically acceptable
salts. The term "pharmaceutically acceptable salts" refers to those
salts which retain the biological effectiveness and properties of
the free bases or free acids, which are not biologically or
otherwise undesirable. Preferably, the pharmaceutically acceptable
salts of the compounds of formula I are the acid addition salts
with physiologically compatible mineral acids, such as hydrochloric
acid, sulfuric acid, sulfurous acid or phosphoric acid; or with
organic acids, such as methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, formic acid, acetic acid, propionic acid,
glycolic acid, pyruvic acid, oxylic acid, lactic acid,
trifluoroacetic acid, citric acid, fumaric acid, maleic acid,
malonic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic
acid, succinic acid or salicylic acid. In addition,
pharmaceutically acceptable salts can be prepared from addition of
an inorganic base or an organic base to the free acid. Salts
derived from an inorganic base include, but are not limited to, the
sodium, potassium, lithium, ammonium, calcium, magnesium salts and
the like. Salts derived from organic bases include, but are not
limited to salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins, such as
isopropylamine, trimethylamine, diethylamine, triethylamine,
tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine,
piperidine, polymine resins and the like. The compound of formula I
can also be present in the form of zwitterions. Particular
pharmaceutically acceptable salts of compounds of formula I are the
acid addition salts such as the hydrochloride salts, the formate
salts or trifluoroacetate salts. Specific are the formate salts
(salts of formic acid).
[0119] 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. dioxan or 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).sub.n, 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.
[0120] 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.
[0121] It will be appreciated that the compounds of general formula
I in this invention can be derivatized at functional groups to
provide derivatives which are capable of conversion back to the
parent compound in vivo.
Pharmacological Tests
[0122] The compounds of formula I and their pharmaceutically
acceptable salts possess valuable pharmacological properties.
Compounds of the present invention are associated with inhibition
of BACE1 and/or BACE2 activity. The compounds were investigated in
accordance with the tests given hereinafter.
Cellular A.beta.-Lowering Assay:
[0123] 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 10.times. 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.degree. C. and
5% CO.sub.2 in a humidified incubator the culture supernatant was
harvested for the determination of A.beta.40 concentrations. 96
well ELISA plates (e.g., Nunc MaxiSorb) were coated with monoclonal
antibody which specifically recognize the C-terminal end of
A.beta.40 (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 A.beta. 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.sub.2O.sub.2 in citric acid buffer. After
stopping the reaction with one volume 1 N H.sub.2SO.sub.4 the
reaction was measured in an ELISA reader at 450 nm wavelength. The
concentrations of A.beta. in the culture supernatants were
calculated from a standard curve obtained with known amounts of
pure A.beta. peptide.
Assay for BACE Inhibition by Measuring Cellular TMEM27
Cleavage:
[0124] 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.
[0125] 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.degree. C. in a standard CO.sub.2 cell
culture incubator.
[0126] 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.
[0127] 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.sub.50
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.
[0128] The preferred compounds according to formula I have an
inhibitory activity in the above assay (IC.sub.50) preferably of 5
nM to 50 .mu.M, more preferably of 5 nM to 1 .mu.M.
[0129] For example, the following compounds showed the following
IC.sub.50 values in the assay described above:
TABLE-US-00001 Cellular assay Cellular assay TMEM27 Abeta40
Examples IC.sub.50 [.mu.M] IC.sub.50 [.mu.M] 1 14.56998 0.35 2 --
-- 3 5.73 0.01 4 0.66187 2.4 5 0.10322 0.01 6 0.31103 0.02 7
0.12292 0.025 8 0.837 0.07 9 0.02256 0.028
Pharmaceutical Compositions
[0130] The compounds of formula I and the pharmaceutically
acceptable salts can be used as therapeutically active substances,
e.g. in the form of pharmaceutical compositions. The pharmaceutical
compositions can be administered orally, e.g. in the form of
tablets, coated tablets, dragees, 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.
[0131] 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 compositions. 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, dragees
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.
[0132] The pharmaceutical compositions 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.
[0133] The invention also provides pharmaceutical compositions
containing a compound of formula I or a pharmaceutically acceptable
salt thereof and a therapeutically inert carrier as well as 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.
[0134] The dosage at which compounds of the invention can be
administered 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, especially from
about 1 to 500 mg per day, of a compound of formula I or of the
corresponding amount of a pharmaceutically acceptable salt thereof.
Depending on severity of the disease and the precise
pharmacokinetic profile of the compound, 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.
[0135] The following examples illustrate the present invention
without limiting it, but serve merely as representative thereof.
Examples of compositions according to the invention are:
Example A
[0136] Tablets of the following composition are manufactured in the
usual manner:
TABLE-US-00002 TABLE 1 possible tablet composition mg/tablet
ingredient 5 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
Manufacturing Procedure:
[0137] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified
water. 2. Dry the granules at 50.degree. 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
[0138] Capsules of the following composition are manufactured:
TABLE-US-00003 TABLE 2 possible capsule ingredient composition
mg/capsule ingredient 5 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
Manufacturing Procedure:
[0139] 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.
[0140] 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
[0141] Soft Gelatin Capsules of the following composition are
manufactured:
TABLE-US-00004 TABLE 3 possible soft gelatin capsule ingredient
composition 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-US-00005 TABLE 4 possible soft gelatin capsule 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
Manufacturing Procedure
[0142] 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
[0143] Suppositories of the following composition are
manufactured:
TABLE-US-00006 TABLE 5 possible suppository composition ingredient
mg/supp. Compound of formula I 15 Suppository mass 1285 Total
1300
Manufacturing Procedure
[0144] The suppository mass is melted in a glass or steel vessel,
mixed thoroughly and cooled to 45.degree. 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
[0145] Injection solutions of the following composition are
manufactured:
TABLE-US-00007 TABLE 6 possible injection solution composition
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
Manufacturing Procedure
[0146] 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
[0147] Sachets of the following composition are manufactured:
TABLE-US-00008 TABLE 7 possible sachet composition ingredient
mg/sachet Compound of formula I 50 Lactose, fine powder 1015
Microcrystalline cellulose (AVICEL PH 102) 1400 Sodium
carboxymethyl cellulose 14 Polyvinylpyrrolidone K 30 10 Magnesium
stearate 10 Flavoring additives 1 Total 2500
Manufacturing Procedure
[0148] 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.
EXAMPLES
General
[0149] MS: Mass spectra (MS) were measured either with ion spray
positive or negative (ISP or ISN) method on a Perkin-Elmer SCIEX
API 300 or with electron impact method (EI, 70 eV) on a Finnigan
MAT SSQ 7000 spectrometer.
Abbreviations:
[0150] DCC=N,N'-diisopropyl-carbodiimide, DCE=1,2-dichloroethane,
DCM=dichloromethane, DIEA=diisopropylethylamine,
DMAc=dimethylacetamide, DMAP=4-dimethylaminopyridine,
DMF=N,N-dimethylformamide, DMSO=dimethyl sulfoxide,
EDCI=N-.beta.-dimethylaminopropyl)-N'-ethyl-carbodiimide
hydrochloride,
HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-
-oxide hexafluorophosphate, HCl=hydrogen chloride, HPLC=high
performance liquid chromatography, LDA=lithium diisopropylamide,
MS=mass spectrum, NMR=nuclear magnetic resonance,
TEA=triethylamine, TBME=tert-butyl methyl ether, and
THF=tetrahydrofuran.
[0151] 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.
[0152] Synthesis of the intermediate
1-(2-fluoro-5-nitro-phenyl)-propan-1-one A1A
##STR00007##
[0153] To a solution of the 1-(2-fluoro-phenyl)-propan-1-one (99
mmol) in concentrated sulfuric acid (80 ml) cooled down to
-30.degree. C. was added slowly fuming nitric acid (8 ml) over 20
min and the solution was stirred at -30.degree. C. for 15 min. The
mixture was slowly poured into a stirred mixture of 200 ml of water
and 400 g ice. The aqueous phase was extracted with ethyl acetate,
the organic layer was extracted again with water and aqueous
NaHCO.sub.3 1 M. The organic layer was dried over Na.sub.2SO.sub.4,
evaporated and the residue was purified by chromatography on silica
using a mixture of heptane and ethylacetate as eluent to afford the
pure nitro intermediate J. MS (ISP): m/z=198.1 [M+H]+.
Synthesis of the Intermediate Sulfinyl Imines A2
General Procedure:
[0154] To a solution of the (R)-(+)-tert-butylsulfinamide (66 mmol)
in THF (350 ml) was added subsequently the ketone A1 (72.6 mmol)
and titanium(IV)ethoxide (132 mmol) and the solution was stirred at
reflux temperature for 5 h. The mixture was cooled to 22.degree.
C., treated with brine (400 ml), the suspension was stirred for 10
min and filtered over dicalite. The layers were separated, the
aqueous layer was extracted with ethyl acetate, the combined
organic layers were washed with water, dried and concentrated in
vacuo. The residue was purified by chromatography on silica using
cylohexane/ethyl acetate to give the pure sulfinyl imine A2.
##STR00008##
[0155] Starting from 1-(2-fluorophenyl)-ethanone, the product
(R)-2-methyl-propane-2-sulfinic acid
[1-(2-fluorophenyl)-(E)-ethylidene]-amide was obtained as pale
brown oil. MS (ISP): m/z=242.3 [M+H].sup.+.
##STR00009##
[0156] Starting from 1-(2-fluoro-phenyl)-propan-1-one, the product
2-methyl-propane-2-sulfinic acid
[1-(2-fluoro-phenyl)-prop-(E)-ylidene]-amide was obtained as pale
yellow oil. MS: m/z=256.2 [M+H].sup.+.
Synthesis of the Intermediate Sulfinamide Esters A3
General Procedure:
[0157] In a dry apparatus a suspension of freshly activated zinc
powder (1.63 g, 24.9 mmol) in dry THF (70 ml) was heated under
inert atmosphere to reflux. A solution of the sulfinyl imine A2
(24.9 mmol) and the bromo-acetate (24.9 mmol) in dry THF (15 ml)
was added dropwise over a period of 15 min and the suspension was
heated to reflux for 5 h. The cooled mixture was partitioned
between aqueous saturated NH.sub.4Cl and ethyl acetate, the organic
layer was dried and evaporated. The crude material was purified by
flash chromatography using heptane/ethyl acetate to give the
sulfinamide ester A3.
##STR00010##
[0158] Starting from (R)-2-methyl-propane-2-sulfinic acid
[1-(2-fluorophenyl)-(E)-ethylidene]-amide and ethyl
2-bromo-2-fluoroacetate, the faster eluting minor isomer
(2S,3R)-ethyl
3-((R)-1,1-dimethylethylsulfinamido)-2-fluoro-3-(2-fluorophenyl)butanoate
(intermediate A3A) was obtained as a dark brown oil. MS (ISP):
m/z=348.2 [M+H].sup.+.
[0159] The second fraction contained the slower eluting major
isomer (2R,3R)-ethyl
3-((R)-1,1-dimethylethylsulfinamido)-2-fluoro-3-(2-fluorophenyl)butanoate
(intermediate A3B) as a brown oil. MS (ISP): m/z=348.2
[M+H].sup.+.
##STR00011##
[0160] Starting from (R)-2-methyl-propane-2-sulfinic acid
[1-(2-fluorophenyl)-(E)-ethylidene]-amide the product
(R)-2,2-difluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylam-
ino)-butyric acid ethyl ester was obtained as a pale yellow oil.
MS: m/z=366.1 [M+H].sup.+.
##STR00012##
[0161] Starting from 2-methyl-propane-2-sulfinic acid
[1-(2-fluoro-phenyl)-prop-(E)-ylidene]-amide the product
(R)-2,2-difluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylam-
ino)-pentanoic acid ethyl ester was obtained as a colorless oil.
MS: m/z=380.2 [M+H].sup.+.
Synthesis of the Intermediate Sulfinamide Alcohols A4
General Procedure:
[0162] A solution of the sulfinamide ester A3 (12.7 mmol) in dry
THF (50 ml) was treated at 0.degree. C. with lithium borohydride
(25.3 mmol) and stirring was continued at 0.degree. C. for 4 h. The
reaction mixture was quenched by addition of acetic acid (2 ml) and
water (50 ml), extracted with ethyl acetate and the organic layer
was dried and evaporated. The residue was purified by
chromatography on silica using a mixture of n-heptane and ethyl
acetate to give the pure intermediate sulfinamide alcohol A4.
##STR00013##
[0163] Starting from (2R,3R)-ethyl
3-((R)-1,1-dimethylethylsulfinamido)-2-fluoro-3-(2-fluorophenyl)butanoate-
, the product (R)-2-methyl-propane-2-sulfinic acid
[(1R,2R)-2-fluoro-1-(2-fluoro-phenyl)-3-hydroxy-1-methyl-propyl]-amide
was obtained as pale red crystals. MS (ISP): m/z=306.1
[M+H].sup.+.
##STR00014##
[0164] Starting from
(R)-2,2-difluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylam-
ino)-butyric acid ethyl ester, the product
2-methyl-propane-2-sulfinic acid
[(R)-2,2-difluoro-1-(2-fluoro-phenyl)-3-hydroxy-1-methyl-propyl]-ami-
de was obtained as a white solid. MS (ISP): m/z=324.2
[M+H].sup.+.
##STR00015##
[0165] Starting from
(R)-2,2-difluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylam-
ino)-pentanoic acid ethyl ester, the product
2-methyl-propane-2-sulfinic acid
[(R)-1-ethyl-2,2-difluoro-1-(2-fluoro-phenyl)-3-hydroxy-propyl]-amid-
e was obtained as a white solid. MS (ISP): m/z=338.1
[M+H].sup.+.
Synthesis of the Intermediate Sulfinamide Nitrile A5
General Procedure:
[0166] To a solution of the sulfinamide alcohol A4 (4.1 mmol) in
dichloromethane (23 ml) was subsequently added at 22.degree. C.
2-bromoacetonitrile (6.2 mmol), silver(I) oxide (1.9 g) and
tetrabutylammonium iodide (0.30 g) and stirring was continued for 2
h. The suspension was filtered, the filtrate was washed with
aqueous saturated NaHCO.sub.3 solution, the organic layer was dried
and evaporated to give the crude sulfinamide nitrile A5 which was
used without further purification.
##STR00016##
[0167] Starting from (R)-2-methyl-propane-2-sulfinic acid
[(R1R,2R)-2-fluoro-1-(2-fluoro-phenyl)-3-hydroxy-1-methyl-propyl]-amide,
the product
(R)--N-((2R,3R)-4-(cyanomethoxy)-3-fluoro-2-(2-fluorophenyl)butan-2-yl)-2-
-methylpropane-2-sulfinamide was obtained as a pale yellow oil. MS
(ISP): m/z=345.2 [M+H].sup.+.
##STR00017##
[0168] Starting from 2-methyl-propane-2-sulfinic acid
[(R)-2,2-difluoro-1-(2-fluoro-phenyl)-3-hydroxy-1-methyl-propyl]-amide,
the product 2-methyl-propane-2-sulfinic acid
[(R)-3-cyanomethoxy-2,2-difluoro-1-(2-fluoro-phenyl)-1-methyl-propyl]-ami-
de was obtained as a pale yellow oil. MS (ISP): m/z=363.2
[M+H].sup.+.
##STR00018##
[0169] Starting from 2-methyl-propane-2-sulfinic acid
[(R)-1-ethyl-2,2-difluoro-1-(2-fluoro-phenyl)-3-hydroxy-propyl]-amide,
the product 2-methyl-propane-2-sulfinic acid
[(R)-3-cyanomethoxy-1-ethyl-2,2-difluoro-1-(2-fluoro-phenyl)-propyl]-amid-
e was obtained as a pale yellow oil. MS (ISP): m/z=377.3
[M+H].sup.+.
Synthesis of the Intermediate Amino Nitrile A6
General Procedure:
[0170] A solution of the sulfinamide nitrile A5 (4.25 mmol) in
1,4-dioxane (20 ml) was treated with a solution of HCl in
1,4-dioxane (4 M, 5.3 ml) and stirring was continued at 22.degree.
C. for 1 h. The mixture was diluted with ethyl acetate, washed with
saturated aqueous Na.sub.2CO.sub.3 solution, the organic layer was
dried and evaporated. The crude material was purified on silica
using n-heptane/ethyl acetate to give the pure amino nitrile
A6.
##STR00019##
[0171] Starting from
(R)--N-((2R,3R)-4-(cyanomethoxy)-3-fluoro-2-(2-fluorophenyl)butan-2-yl)-2-
-methylpropane-2-sulfinamide, the product
2-((2R,3R)-3-amino-2-fluoro-3-(2-fluorophenyl)butoxy)acetonitrile
was obtained as a pale yellow oil. MS (ISP): m/z=241.1
[M+H].sup.+.
##STR00020##
[0172] Starting from 2-methyl-propane-2-sulfinic acid
[(R)-3-cyanomethoxy-2,2-difluoro-1-(2-fluoro-phenyl)-1-methyl-propyl]-ami-
de, the product
[(R)-3-amino-2,2-difluoro-3-(2-fluoro-phenyl)-butoxy]-acetonitrile
was obtained as a pale yellow oil. MS (ISP): m/z=259.1
[M+H].sup.+.
##STR00021##
[0173] Starting from 2-methyl-propane-2-sulfinic acid
[(R)-3-cyanomethoxy-1-ethyl-2,2-difluoro-1-(2-fluoro-phenyl)-propyl]-amid-
e, the product
[(R)-3-amino-2,2-difluoro-3-(2-fluoro-phenyl)-pentyloxy]-acetonitrile
was obtained as a pale yellow oil. MS: m/z=273.1 [M+H].sup.+.
Synthesis of the Intermediate 1,4-Oxazepine A7
General Procedure:
[0174] To a solution of the amino nitrile A6 (2.20 mmol) in toluene
(38 ml) was added at 22.degree. C. a solution of AlMe.sub.3 in
toluene (2 M, 1.2 ml) and the mixture was heated to 80.degree. C.
for 1 h. The mixture was cooled to 0.degree. C., diluted with
saturated aqueous Na.sub.2CO.sub.3 and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were
dried, evaporated and the residue purified by chromatography on
NH.sub.2-silica using n-heptane/ethyl acetate to give the pure
1,4-oxazepine A7.
##STR00022##
[0175] Starting from
2-((2R,3R)-3-amino-2-fluoro-3-(2-fluorophenyl)butoxy)acetonitrile,
the product
(5R,6R)-6-fluoro-5-(2-fluorophenyl)-5-methyl-2,5,6,7-tetrahydro-1-
,4-oxazepin-3-amine was obtained as a pale yellow solid. MS (ISP):
m/z=241.2 [M+H].sup.+.
##STR00023##
[0176] Starting from
[(R)-3-amino-2,2-difluoro-3-(2-fluoro-phenyl)-butoxy]-acetonitrile,
the product
(R)-6,6-difluoro-5-(2-fluoro-phenyl)-5-methyl-2,5,6,7-tetrahydro--
[1,4]oxazepin-3-ylamine was obtained as a white solid. MS (ISP):
m/z=259.1 [M+H].sup.+.
##STR00024##
[0177] Starting from
[(R)-3-amino-2,2-difluoro-3-(2-fluoro-phenyl)-pentyloxy]-acetonitrile,
the product
(R)-5-ethyl-6,6-difluoro-5-(2-fluoro-phenyl)-2,5,6,7-tetrahydro-[1,4]oxaz-
epin-3-ylamine was obtained as a brown oil. MS: m/z=273.1
[M+H].sup.+.
Intermediate Nitrobenzene A8
General Procedure:
[0178] To a solution of the intermediate 1,4-oxazepine A7 (1.2
mmol) in sulfuric acid (5.0 ml) was added at 0.degree. C. red
fuming nitric acid (1.9 mmol) over a period of 20 min and stirring
was continued for 30 min. The solution was dropped slowly into
ice/water (60 ml), the pH was adjusted to 9 by addition of aqueous
4 N NaOH and extracted with ethyl acetate. The organic layer was
dried, evaporated and the residue purified by chromatography on
silca-NH.sub.2 using n-heptane/ethyl acetate to give the
nitrobenzene A8.
##STR00025##
[0179] Starting from
(5R,6R)-6-fluoro-5-(2-fluorophenyl)-5-methyl-2,5,6,7-tetrahydro-1,4-oxaze-
pin-3-amine the product
(5R,6R)-6-fluoro-5-(2-fluoro-5-nitro-phenyl)-5-methyl-2,5,6,7-tetrahydro--
[1,4]oxazepin-3-ylamine was obtained as a pale yellow solid. MS
(ISP): m/z=286.2 [M+H].sup.+.
##STR00026##
[0180] Starting from
(R)-6,6-difluoro-5-(2-fluoro-phenyl)-5-methyl-2,5,6,7-tetrahydro-[1,4]oxa-
zepin-3-ylamine the product
(R)-6,6-difluoro-5-(2-fluoro-5-nitro-phenyl)-5-methyl-2,5,6,7-tetrahydro--
[1,4]oxazepin-3-ylamine was obtained as a white solid. MS (ISP):
m/z=304.1 [M+H].sup.+.
##STR00027##
[0181] Starting from
(R)-5-ethyl-6,6-difluoro-5-(2-fluoro-phenyl)-2,5,6,7-tetrahydro-[1,4]oxaz-
epin-3-ylamine the product
(R)-5-ethyl-6,6-difluoro-5-(2-fluoro-5-nitro-phenyl)-2,5,6,7-tetrahydro-[-
1,4]oxazepin-3-ylamine was obtained as a pale yellow solid. MS:
m/z=318.1 [M+H].sup.+.
Synthesis of the Intermediate Aniline A9
General Procedure:
[0182] A suspension of the intermediate nitrobenzene A8 (1.0 mmol)
in ethanol (9 ml) and Pd/C (10%, 100 mg) was hydrogenated at
22.degree. C. and atmospheric pressure for 2 h. The suspension was
filtered and the residue evaporated to give the crude aniline A10
which was used without further purification.
##STR00028##
[0183] Starting from
(5R,6R)-6-fluoro-5-(2-fluoro-5-nitro-phenyl)-5-methyl-2,5,6,7-tetrahydro--
[1,4]oxazepin-3-ylamine the product
(5R,6R)-5-(5-amino-2-fluorophenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1-
,4-oxazepin-3-amine was obtained as a pale yellow solid. MS (ISP):
m/z=256.3 [M+H].sup.+.
##STR00029##
[0184] Starting from
(R)-6,6-difluoro-5-(2-fluoro-5-nitro-phenyl)-5-methyl-2,5,6,7-tetrahydro--
[1,4]oxazepin-3-ylamine the product
(R)-5-(5-amino-2-fluoro-phenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro--
[1,4]oxazepin-3-ylamine was obtained as a white solid. MS (ISP):
m/z=274.1 [M+H].sup.+.
##STR00030##
[0185] Starting from
(R)-5-ethyl-6,6-difluoro-5-(2-fluoro-5-nitro-phenyl)-2,5,6,7-tetrahydro-[-
1,4]oxazepin-3-ylamine the product
(R)-5-(5-amino-2-fluoro-phenyl)-5-ethyl-6,6-difluoro-2,5,6,7-tetrahydro-[-
1,4]oxazepin-3-ylamine was obtained as a pale yellow solid. MS:
m/z=288.1 [M+H].sup.+.
Synthesis of the Amides Ia from the Anilines A9
General Procedure:
[0186] To a solution of the acid (0.16 mmol) in MeOH (1 ml) was
added at 22.degree. C.
4-(4,6-dimethoxy-1,3,5-triazin-2yl)-4-methyl-morpholiniumchloride
(0.19 mmol) and stirring was continued at 0.degree. C. for 30 min.
To the mixture was added a solution of the aniline A9 (0.15 mmol)
in MeOH (2 ml) and stirring was continued at 0.degree. C. for 2 h.
The mixture was diluted with saturated aqueous Na.sub.2CO.sub.3,
the MeOH was evaporated and the aqueous solution was extracted with
ethyl acetate. The organic layer was dried, evaporated and the
residue was purified on preparative HPLC RP18 column using a
gradient of water/HCOOH (99.9:0.1)->MeOH to give the formiate
salt or a gradient of water/NEt.sub.3 (99.9:0.1)->CH.sub.3CN to
give the free base of the amide Ia.
Synthesis of the Amines Ib from the Anilines A9 by Reductive
Amination
General Procedure:
[0187] To a solution of the aniline A9 (0.1 mmol) in
dichloromethane (0.7 ml) was subsequently added at 22.degree. C.
the carbonyl compound (0.11 mmol), acetic acid (0.2 mmol) and
sodium triacetoxyborohydride (0.14 mmol) and stirring of the
mixture was continued for 18 h. The mixture was diluted with water
(1 ml), the organic layer was washed with saturated aqueous
NaHCO.sub.3, dried and evaporated. The residue was purified by
chromatography on a silica-NH.sub.2 column using dichloromethane to
give the amines Ib
Example 1
(R)--N2-(3-(3-Amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin--
5-yl)-4-fluorophenyl)-3-fluoropyridine-2,5-dicarboxamide
formate
##STR00031##
[0189] The coupling of
(R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1-
,4-oxazepin-3-amine (intermediate A9B) and
5-carbamoyl-3-fluoro-pyridine-2-carboxylic acid (prepared according
to Hori, A. et al., Int. Patent Application Publ. No. WO2009151098)
yielded the title compound as an off-white amorphous material. MS
(ISP): m/z=440.2 [M+H].sup.+.
Example 2
(R)--N-(3-(3-Amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-
-yl)-4-fluorophenyl)-6-(cyclopropylmethoxy)picolinamide formate
##STR00032##
[0191] The coupling of
(R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1-
,4-oxazepin-3-amine (intermediate A9B) and
6-cyclopropylmethoxy-pyridine-2-carboxylic acid yielded the title
compound as an off-white amorphous material. MS (ISP): m/z=449.2
[M+H].sup.+.
[0192] The 6-cyclopropylmethoxy-pyridine-2-carboxylic acid was
obtained as follows:
[0193] A solution of 6-chloro-pyridine-2-carboxylic acid (9.46
mmol) in dry dimethylsulfoxide (5 ml) was treated with
cyclopropyl-methanol (14.1 mmol) followed by powdered potassium
hydroxide (37.8 mmol). The reaction mixture was then irradiated in
a microwave oven at 100.degree. C. for 90 minutes. For the workup,
the reaction mixture was quenched with aqueous citric acid (10%, pH
4-5), then extracted with ethyl acetate (5.times.30 ml), followed
by extraction with a mixture of methanol and dichloromethane (20%;
5.times.100 ml). The combined organic layers were washed with brine
(200 ml), dried and evaporated at reduced pressure. Lyophilization
of the residue yielded the 6-chloro-pyridine-2-carboxylic acid as a
brown solid (48% of theory) MS (ISP): m/z=195.0 [M+H].sup.+.
Example 3
(R)--N-(3-(3-Amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-
-yl)-4-fluorophenyl)-5-(thiazol-2-yl)picolinamide formate
##STR00033##
[0195] The coupling of
(R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1-
,4-oxazepin-3-amine (intermediate A9B) and
5-thiazol-2-yl-pyridine-2-carboxylic acid (prepared according to
Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016)
yielded the title compound as an off-white amorphous material. MS
(ISP): m/z=462.2 [M+H].sup.+.
Example 4
(R)--N-(3-(3-Amino-5-ethyl-6,6-difluoro-2,5,6,7-tetrahydro-1,4-oxazepin-5--
yl)-4-fluorophenyl)-5-cyclopropyloxazole-4-carboxamide
##STR00034##
[0197] The coupling of
(R)-5-(5-amino-2-fluoro-phenyl)-5-ethyl-6,6-difluoro-2,5,6,7-tetrahydro-[-
1,4]oxazepin-3-ylamine (intermediate A9C) and
5-cyclopropyl-oxazole-4-carboxylic acid yielded the title compound
as a white solid. MS: m/z=423.2 [M+H].sup.+.
Example 5
(R)--N-(3-(3-Amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-
-yl)-4-fluorophenyl)-5-(methylthio)pyrazine-2-carboxamide
formate
##STR00035##
[0199] The coupling of
(R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1-
,4-oxazepin-3-amine (intermediate A9B) and
5-methylsulfanyl-pyrazine-2-carboxylic acid (prepared according to
Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016)
yielded the title compound as an off-white solid. MS (ISP):
m/z=426.1 [M+H].sup.+.
Example 6
(R)--N-(3-(3-Amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-
-yl)-4-fluorophenyl)-5-(cyclopropylethynyl)picolinamide formate
##STR00036##
[0201] The coupling of
(R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1-
,4-oxazepin-3-amine (intermediate A9B) and
5-cyclopropylethynyl-pyridine-2-carboxylic acid (prepared according
to Suzuki, Y. et al., Int. Patent Application Publ. No.
WO2009091016) yielded the title compound as an off-white solid. MS
(ISP): m/z=443.3 [M+H].sup.+.
Example 7
(R)--N-(3-(3-Amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-
-yl)-4-fluorophenyl)-5-cyclopropylpicolinamide formate
##STR00037##
[0203] The coupling of
(R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1-
,4-oxazepin-3-amine (intermediate A9B) and
5-cyclopropyl-pyridine-2-carboxylic acid (prepared according to
Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016)
yielded the title compound as an amorphous light yellow material.
MS (ISP): m/z=419.2 [M+H].sup.+.
Example 8
(R)--N-(3-(3-Amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-
-yl)-4-fluorophenyl)-5-.beta.-methoxyprop-1-ynyl)picolinamide
formate
##STR00038##
[0205] The coupling of
(R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1-
,4-oxazepin-3-amine (intermediate A9B) and
5-.beta.-methoxy-prop-1-ynyl)-pyridine-2-carboxylic acid (prepared
according to Suzuki, Y. et al., Int. Patent Application Publ. No.
WO2009091016) yielded the title compound as a white solid. MS
(ISP): m/z=410.2 [M+H].sup.+.
Example 9
(5R,6R)-5-(5-(Cyclopropylmethylamino)-2-fluorophenyl)-6-fluoro-5-methyl-2,-
5,6,7-tetrahydro-1,4-oxazepin-3-amine
##STR00039##
[0207] The reductive amination of
(5R,6R)-5-(5-amino-2-fluorophenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1-
,4-oxazepin-3-amine (intermediate A9A) and cyclopropanecarbaldehyde
yielded the title compound as a colorless solid. MS: m/z=310.4
[M+H].sup.+.
* * * * *
References