U.S. patent application number 13/505187 was filed with the patent office on 2012-08-30 for imidazo[1,2-b]pyridazine derivatives and their use as pde10 inhibitors.
This patent application is currently assigned to Janssen-Cilag, S.A.. Invention is credited to Sergio-Alvar Alonso-De Diego, Jose Manuel Bartolome-Nebreda, Susana Conde-Ceide, Oscar Delgado-Gonzalez, Gregor James MacDonald, Maria Luz Martin-Martin, Joaquin Pastor-Fernandez, Michiel Luc Maria Van Gool, Greta Constantia Peter Vanhoof.
Application Number | 20120220581 13/505187 |
Document ID | / |
Family ID | 41785825 |
Filed Date | 2012-08-30 |
United States Patent
Application |
20120220581 |
Kind Code |
A1 |
Pastor-Fernandez; Joaquin ;
et al. |
August 30, 2012 |
IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AND THEIR USE AS PDE10
INHIBITORS
Abstract
The present invention relates to novel imidazo[1,2-b]pyridazine
derivatives which are inhibitors of the phosphodiesterase 10 enzyme
(PDE10) and which are useful for the treatment or prevention of
neurological, psychiatric and metabolic disorders in which the
PDE10 enzyme is involved. The invention is also directed to
pharmaceutical compositions comprising such compounds, to processes
to prepare such compounds and compositions, to the use of such
compounds or pharmaceutical compositions for the prevention or
treatment of neurological, psychiatric and metabolic disorders and
diseases.
Inventors: |
Pastor-Fernandez; Joaquin;
(Toledo, ES) ; Bartolome-Nebreda; Jose Manuel;
(Toledo, ES) ; MacDonald; Gregor James; (Zoersel,
BE) ; Conde-Ceide; Susana; (Toledo, ES) ;
Delgado-Gonzalez; Oscar; (Valencia, ES) ; Vanhoof;
Greta Constantia Peter; (Zoersel, BE) ; Van Gool;
Michiel Luc Maria; (Madrid, ES) ; Martin-Martin;
Maria Luz; (Salamanca, ES) ; Alonso-De Diego;
Sergio-Alvar; (Madrid, ES) |
Assignee: |
Janssen-Cilag, S.A.
de las Naciones, Madrid
ES
|
Family ID: |
41785825 |
Appl. No.: |
13/505187 |
Filed: |
October 27, 2010 |
PCT Filed: |
October 27, 2010 |
PCT NO: |
PCT/EP10/66264 |
371 Date: |
April 30, 2012 |
Current U.S.
Class: |
514/232.5 ;
514/233.2; 514/248; 544/117; 544/236; 544/80 |
Current CPC
Class: |
A61P 25/28 20180101;
C07D 487/04 20130101; A61P 25/30 20180101; A61P 25/22 20180101;
A61P 25/14 20180101; A61P 3/00 20180101; A61P 25/00 20180101; A61P
25/24 20180101; A61P 25/18 20180101; A61P 25/04 20180101 |
Class at
Publication: |
514/232.5 ;
544/117; 514/233.2; 544/236; 514/248; 544/80 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/5025 20060101 A61K031/5025; A61P 25/00
20060101 A61P025/00; A61P 25/18 20060101 A61P025/18; A61P 3/00
20060101 A61P003/00; A61P 25/14 20060101 A61P025/14; A61P 25/28
20060101 A61P025/28; A61P 25/30 20060101 A61P025/30; A61P 25/04
20060101 A61P025/04; C07D 487/04 20060101 C07D487/04; A61P 25/22
20060101 A61P025/22 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 30, 2009 |
EP |
09174711.3 |
Claims
1. A compound of formula (I) ##STR00770## or a stereoisomeric form
thereof, wherein R.sup.1 is pyridinyl; pyridinyl optionally
substituted with halogen, C.sub.1-4alkyl, trifluoromethyl or
C.sub.1-4alkyloxy; tetrahydropyranyl; or NR.sup.6R.sup.7; R.sup.2
is hydrogen, C.sub.1-4alkyl, trifluoromethyl, C.sub.3-8cycloalkyl,
or C.sub.1-4alkyloxy; R.sup.3 is hydrogen, chloro, C.sub.1-4alkyl,
trifluoromethyl, or C.sub.3-8cycloalkyl; Het is a 5- or 6-membered
heterocyclic ring selected from the group consisting of pyridinyl,
pyrimidinyl, pyridazinyl, pyrrolyl, oxazolyl, thiazolyl,
imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxadiazolyl and
triazolyl; R.sup.4 is hydrogen, C.sub.1-4alkyl,
trifluoromethylC.sub.0-4alkyl, hydroxyC.sub.1-4alkyl,
difluorocyclopropylmethyl, cyclopropyldifluoroethyl,
C.sub.3-8cycloalkyl, C.sub.1-4alkyloxyC.sub.1-5alkyl,
C.sub.1-4alkyloxy, trifluoromethylC.sub.0-4alkyloxy,
C.sub.3-8cycloalkylC.sub.1-4alkyloxy,
C.sub.3-8cycloalkylC.sub.1-4alkyl,
C.sub.1-6alkyloxyC.sub.1-4alkyloxy, tetrahydropyranyl,
pyridinylmethyl, NR.sup.6aR.sup.7aC.sub.1-4alkyl or
NR.sup.6aR.sup.7a; R.sup.5 is hydrogen or C.sub.1-4alkyl; R.sup.6,
R.sup.6a, R.sup.7 and R.sup.7a are each independently hydrogen or
C.sub.1-4alkyl, or taken together with N can be a radical of
Formula (a), (b) or (c) ##STR00771## wherein each R.sup.8, if
present, independently of one another is C.sub.1-4alkyl; R.sup.9 is
hydrogen or C.sub.1-4alkyloxy; R.sup.10 is hydrogen or
C.sub.1-4alkyl; m is 0, 1, 2, 3, 4 or 5; n is 2, 3, 4, 5 or 6; o is
1 or 2; or a pharmaceutically acceptable salt or a solvate
thereof.
2. The compound according to claim 1, wherein R.sup.1 is selected
from pyridinyl; pyridinyl optionally substituted with halogen,
C.sub.1-4alkyl, trifluoromethyl or C.sub.1-4alkyloxy;
tetrahydropyranyl; and NR.sup.6R.sup.7; wherein R.sup.6 and R.sup.7
taken together with the nitrogen can be a radical of Formula (a),
(b) or (c) as defined in claim 1; R.sup.2 is selected from
hydrogen, methyl, ethyl, cyclopropyl, isopropyl, methoxy and
trifluoromethyl; R.sup.3 is selected from hydrogen, chloro, methyl,
trifluoromethyl and cyclopropyl; and Het is selected from the group
consisting of pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl,
thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxadiazolyl and
triazolyl; or a pharmaceutically acceptable salt or a solvate
thereof.
3. The compound according to claim 1, wherein R.sup.1 is selected
from pyridinyl which may be optionally substituted with halogen,
C.sub.1-4alkyl, trifluoromethyl or C.sub.1-4alkyloxy; morpholinyl;
and NR.sup.6R.sup.7; wherein R.sup.6 and R.sup.7 taken together
with the nitrogen can be a radical of Formula (a) or (c) wherein n
is 3 and o is 1; Het is selected from pyridinyl and pyrazolyl;
R.sup.4 is hydrogen, C.sub.1-4alkyl, trifluoromethylC.sub.0-4alkyl,
hydroxyC.sub.1-4alkyl, difluorocyclopropylmethyl,
cyclopropyldifluoroethyl, C.sub.3-8cycloalkyl,
C.sub.1-4alkyloxyC.sub.1-5 alkyl, C.sub.1-4alkyloxy,
trifluoromethylC.sub.0-4alkyloxy,
C.sub.3-8cycloalkylC.sub.1-4alkyloxy,
C.sub.1-6alkyloxyC.sub.1-4alkyloxy, tetrahydropyranyl,
pyridinylmethyl, NR.sup.6aR.sup.7aC.sub.1-4alkyl or
NR.sup.6aR.sup.7a; wherein R.sup.6, R.sup.6a, R.sup.7 and R.sup.7a
are each independently hydrogen or C.sub.1-4alkyl, or taken
together with the nitrogen can be a radical of formula (a), (b) or
(c), wherein n is 3, R.sup.9 is hydrogen or C.sub.1-4alkyloxy, m is
0, o is 1 and R.sup.10 is hydrogen; or a pharmaceutically
acceptable salt or a solvate thereof.
4. The compound according to claim 1, wherein R.sup.1 is selected
from morpholinyl and pyridinyl; R.sup.2 is selected from hydrogen,
methyl, ethyl, methoxy, and cyclopropyl; R.sup.3 is selected from
hydrogen, methyl, and cyclopropyl; Het is pyridinyl or pyrazolyl;
R.sup.4 is selected from ethyl; isopropyl; isobutyl;
2,2,2-trifluoroethyl; 2-hydroxy-2-methylpropyl;
2,2-difluoro-2-cyclopropylethyl; cyclopropyl; 2-methoxyethyl;
(2S)-2-methoxypropyl; 2-ethoxyethyl; ethoxymethyl;
1-ethoxy-1-methylethyl; 1-methoxy-1-methylethyl;
2-methoxy-1,1-dimethylethyl; 3-methoxy-3-methylbutyl;
3-methoxypropyl; 2-methoxy-2-methyl-propyl; 2-methoxyethoxy;
2-methoxy-2-methyl-propoxy; tetrahydro-2H-pyran-4-yl;
morpholin-4-yl; piperazin-1-yl; and (3R)-3-methoxypyrrolidin-1-yl;
and R.sup.5 is hydrogen or methyl; or a pharmaceutically acceptable
salt or a solvate thereof.
5. The compound according to claim 1, wherein R.sup.1 is selected
from morpholin-4-yl, pyridin-3-yl and pyridin-4-yl; and Het is
selected from pyridin-3-yl, pyridin-4-yl and 1H-pyrazol-4-yl; or a
pharmaceutically acceptable salt or a solvate thereof.
6. The compound according to claim 1, wherein R.sup.1 is selected
from morpholin-4-yl; and Het is pyridin-3-yl or pyridin-4-yl; or a
pharmaceutically acceptable salt or a solvate thereof.
7. The compound according to claim 1, wherein R.sup.1 is
morpholin-4-yl; R.sup.2 is methyl; R.sup.3 is hydrogen; Het is
pyridin-3-yl; R.sup.4 is 2-methoxyethyl; and R.sup.5 is hydrogen;
or a pharmaceutically acceptable salt or a solvate thereof.
8. The compound of formula (I) according to claim 1, selected from
the group consisting of
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine,
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine hydrochloride,
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine maleate,
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine monohydrate,
3-[6-(3-methoxypropyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,-
2-b]pyridazine,
3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-i-
midazo[1,2-b]pyridazine,
3-[6-(2-methoxy-1,1-dimethylethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl-
)-imidazo[1,2-b]pyridazine,
3-[6-(1-ethoxy-1-methylethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imi-
dazo[1,2-b]pyridazine,
3-[6-(1-methoxy-1-methylethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-im-
idazo[1,2-b]pyridazine,
3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imi-
dazo[1,2-b]pyridazine,
3-[6-(2-methoxyethoxy)-5-methyl-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imi-
dazo[1,2-b]pyridazine,
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(3-pyridinyl)-imidazo[1,2--
b]pyridazine,
2-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[-
1,2-b]pyridazine,
3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-morpholinyl)-imidazo[1,2-b]pyrida-
zine,
2-methoxy-3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-morpholinyl)-imida-
zo[1,2-b]pyridazine,
6-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholiny-
l)-imidazo[1,2-b]pyridazine,
6-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-
-imidazo[1,2-b]pyridazine,
2-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-6-methyl-8-(4-morpholiny-
l)-imidazo[1,2-b]pyridazine,
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,-
2-b]pyridazine,
3-[6-(ethoxymethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-b-
]pyridazine,
3-[6-(2-methoxy-2-methylpropoxy)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)--
imidazo[1,2-b]pyridazine,
2-methyl-8-(4-morpholinyl)-3-[6-(4-morpholinyl)-3-pyridinyl]-imidazo[1,2--
b]pyridazine,
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imidazo[1,2-b-
]pyridazine,
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imidazo[1,2--
b]pyridazine,
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imidazo[1,2--
b]pyridazine hydrochloride,
2-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-morpholinyl)-imidaz-
o[1,2-b]pyridazine,
3-[6-(2-methoxyethyl)-3-pyridinyl]-2,6-dimethyl-8-(4-morpholinyl)-imidazo-
[1,2-b]pyridazine,
3-[6-(2-methoxyethyl)-3-pyridinyl]-2,6-dimethyl-8-(4-pyridinyl)-imidazo[1-
,2-b]pyridazine,
3-[6-(2-ethoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2--
b]pyridazine,
3-[2-(2-methoxyethyl)-4-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine,
2-methyl-8-(4-morpholinyl)-3-[6-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl]-i-
midazo[1,2-b]pyridazine,
3-(6-ethyl-3-pyridinyl)-2-methyl-8-(4-morpholinyl)-imidazo[1,2-b]pyridazi-
ne,
3-[6-(3-methoxy-3-methylbutyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-
-imidazo[1,2-b]pyridazine,
2-methyl-8-(4-morpholinyl)-3-[6-(1-piperazinyl)-3-pyridinyl]-imidazo[1,2--
b]pyridazine,
2-methyl-3-[6-(4-morpholinyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1,2-b]-
pyridazine,
2-methyl-3-[6-(1-methylethyl)-3-pyridinyl]-8-(4-morpholinyl)-imidazo[1,2--
b]pyridazine,
3-(6-cyclopropyl-3-pyridinyl)-2-methyl-8-(4-morpholinyl)-imidazo[1,2-b]py-
ridazine,
3-[6-[(3R)-3-methoxy-1-pyrrolidinyl]-3-pyridinyl]-2-methyl-8-(4--
morpholinyl)-imidazo[1,2-b]pyridazine,
2-methyl-3-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-morpholinyl)-imidazo-
[1,2-b]pyridazine,
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-morpholinyl)-imidazo-
[1,2-b]pyridazine,
3-[1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-morpholiny-
l)-imidazo[1,2-b]pyridazine,
2-cyclopropyl-3-[1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-morph-
olinyl)-imidazo[1,2-b]pyridazine,
2-cyclopropyl-3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-8-(4-morpholin-
yl)-imidazo[1,2-b]pyridazine hydrochloride,
2-cyclopropyl-3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-8-(4-morpholin-
yl)-imidazo[1,2-b]pyridazine,
3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-2,6-dimethyl-8-(4-pyridinyl)-
-imidazo[1,2-b]pyridazine,
2-cyclopropyl-3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-8-(4-pyridinyl-
)-imidazo[1,2-b]pyridazine,
5-[2-cyclopropyl-8-(4-morpholinyl)imidazo[1,2-b]pyridazin-3-yl]-.alpha.,.-
alpha.-dimethyl-2-pyridineethanol,
3-[6-(4-morpholinyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1,2-b]pyridazin-
e,
2,6-dimethyl-8-(4-morpholinyl)-3-[6-(4-morpholinyl)-3-pyridinyl]-imidaz-
o[1,2-b]pyridazine,
2-cyclopropyl-6-methyl-3-[6-(4-morpholinyl)-3-pyridinyl]-8-(4-pyridinyl)--
imidazo[1,2-b]pyridazine,
2-cyclopropyl-3-[6-(2-methoxyethoxy)-3-pyridinyl]-6-methyl-8-(4-pyridinyl-
)-imidazo[1,2-b]pyridazine,
2-methyl-8-(4-morpholinyl)-3-[2-(4-morpholinyl)-4-pyridinyl]-imidazo[1,2--
b]pyridazine,
3-{1-[2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-8-morphol-
in-4-ylimidazo[1,2-b]pyridazine,
2-methyl-3-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-pyridinyl)-imidazo[1-
,2-b]pyridazine,
6-cyclopropyl-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-morpho-
linyl)-imidazo[1,2-b]pyridazine,
2-ethyl-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-8-(4-morpholinyl)-imidazo[-
1,2-b]pyridazine,
3-[1-[(2S)-2-methoxypropyl]-1H-pyrazol-4-yl]-2-methyl-8-(4-morpholinyl)-i-
midazo[1,2-b]pyridazine,
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2,6-dimethyl-8-(4-morpholinyl)-imi-
dazo[1,2-b]pyridazine,
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2,6-dimethyl-8-(4-pyridinyl)-imida-
zo[1,2-b]pyridazine,
2-methyl-8-(4-pyridinyl)-3-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-imi-
dazo[1,2-b]pyridazine,
2-cyclopropyl-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-8-(4-pyridinyl)-imid-
azo[1,2-b]pyridazine,
2-cyclopropyl-3-[1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-pyrid-
inyl)-imidazo[1,2-b]pyridazine,
6-chloro-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-pyridinyl)--
imidazo[1,2-b]pyridazine, and
2-cyclopropyl-3-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-pyridinyl)-imid-
azo[1,2-b]pyridazine, and the stereoisomeric forms, the
pharmaceutically acceptable salts and the solvates thereof.
9. A pharmaceutical composition comprising a therapeutically
effective amount of a compound according to claim 1 and a
pharmaceutically acceptable carrier or excipient.
10. (canceled)
11. A method for the treatment or prevention of a central nervous
system disorder selected from the group of psychotic disorders;
drug induced psychosis; anxiety disorders; movement disorders; mood
disorders; neurodegenerative disorders; disorders or conditions
comprising as a symptom a deficiency in attention and/or cognition;
drug addiction disorders; pain and metabolic disorders.
12. The method of claim 11, wherein the psychotic disorder is
selected from the group consisting of schizophrenia, delusional
disorder, schizoaffective disorder, schizophreniform disorder and
substance-induced psychotic disorder.
13. (canceled)
14. A process for preparing a pharmaceutical composition wherein a
pharmaceutically acceptable carrier is intimately mixed with a
therapeutically effective amount of a compound as defined in claim
1.
15. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel
imidazo[1,2-b]pyridazine derivatives which are inhibitors of the
phosphodiesterase 10 enzyme (PDE10) and which are useful for the
treatment or prevention of neurological, psychiatric and metabolic
disorders in which the PDE10 enzyme is involved. The invention is
also directed to pharmaceutical compositions comprising such
compounds, to processes to prepare such compounds and compositions,
to the use of such compounds or pharmaceutical compositions for the
prevention or treatment of neurological, psychiatric and metabolic
disorders and diseases.
DESCRIPTION OF THE INVENTION
Background of the Invention
[0002] Phosphodiesterases (PDEs) are a family of enzymes encoded by
21 genes and subdivided into 11 distinct families according to
structural and functional properties. These enzymes metabolically
inactivate widely occurring intracellular second messengers,
3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic
guanosine monophosphate (cGMP). These two messengers regulate a
wide variety of biological processes, including pro-inflammatory
mediator production and action, ion channel function, muscle
contraction, learning, differentiation, apoptosis, lipogenesis,
glycogenolysis, and gluconeogenesis. They do this by activation of
protein kinase A (PKA) and protein kinase G (PKG), which in turn
phosphorylate a wide variety of substrates including transcription
factors and ion channels that regulate innumerable physiological
responses. In neurons, this includes the activation of cAMP and
cGMP-dependent kinases and subsequent phosphorylation of proteins
involved in acute regulation of synaptic transmission as well as in
neuronal differentiation and survival. Intracellular concentrations
of cAMP and cGMP are strictly regulated by the rate of biosynthesis
by cyclases and by the rate of degradation by PDEs. PDEs are
hydrolases that inactivate cAMP and cGMP by catalytic hydrolysis of
the 3'-ester bond, forming the inactive 5'-monophosphate (Scheme
A).
##STR00001##
[0003] On the basis of substrate specificity, the PDE families can
be divided into three groups: i) the cAMP-specific PDEs, which
include PDE4, 7 and 8; ii) the cGMP-selective enzymes PDES and 9;
and iii) the dual-substrate PDEs, PDE1, 2 and 3, as well as PDE10
and 11.
[0004] Furthermore, PDEs are expressed differentially throughout
the organism, including the central nervous system. Different PDE
isozymes therefore may play different physiological functions.
Compounds that inhibit selectively PDE families or isozymes may
display particular therapeutic activity, fewer side effects, or
both.
[0005] The discovery of phosphodiesterase 10A (PDE10A) was reported
in 1999. Of all the 11 known PDE families, PDE10 has the most
restricted distribution with high expression only in the brain and
testes.
[0006] In the brain, PDE10A mRNA and protein are highly expressed
in a majority of striatal Medium Spiny Neurons (MSNs). This unique
distribution of PDE10A in the brain, together with its increased
pharmacological characterization, indicates a potential use of
PDE10A inhibitors for treating neurological and psychiatric
disorders like schizophrenia.
[0007] In the basal ganglia, MSNs constitute the major site for
reception and integration of cortical glutamatergic and midbrain
dopaminergic input, and form key output pathways that help
discriminate and act on relevant and irrelevant cognitive and motor
patterns.
[0008] MSNs are GABAergic projection neurons evenly distributed
between two distinct pathways. Striatonigral MSNs (in the direct
pathway) express the D.sub.1 dopamine receptor and neuropeptides
dynorphin and substance P; striatopallidal MSNs (in the indirect
pathway) express the D.sub.2 dopamine receptors and neuropeptide
enkephalin. D.sub.1 dopamine receptors are positively coupled to
cAMP production, while D.sub.2 dopamine receptors are negatively
coupled to cAMP production. These pathways affect the concentration
of extracellular dopamine and modulate motor and behavioural
responses.
PDE10 Inhibitors and Schizophrenia
[0009] Due to the predominant localisation of PDE10 in MSNs, the
majority of research on PDE10 inhibitors has focused on preclinical
models of psychosis.
[0010] On the basis of studies performed on knockout mice, the
effects of PDE10 inhibition on striatal gene expression have been
compared to the effects induced by a D.sub.1 agonist and a D.sub.2
antagonist.
[0011] Schizophrenia is a severe and chronic mental illness that
affects approximately 1% of the population. Clinical symptoms are
apparent relatively early in life, generally emerging during
adolescence or early adulthood. The symptoms of schizophrenia are
usually divided into those described as positive, including
hallucinations, delusions and disorganised thoughts and those
referred to as negative, which include social withdrawal,
diminished affection, poverty of speech and the inability to
experience pleasure. In addition, schizophrenic patients suffer
from cognitive deficits, such as impaired attention and memory. The
aetiology of the disease is still unknown, but aberrant
neurotransmitter actions have been hypothesized to underlie the
symptoms of schizophrenia. The dopaminergic hypothesis is one most
often considered, which proposes that hyperactivity of dopamine
transmission is responsible for the positive symptoms observed in
schizophrenic patients.
[0012] The efficacy of currently marketed antipsychotics correlates
their ability to inhibit the D.sub.2 dopamine receptors. Acute and
chronic administration of antipsychotics such as haloperidol has
characteristic effects on striatal gene expression. Inhibition of
PDE10A has also been observed to produce alterations in striatal
gene expression similar to those exerted by haloperidol.
[0013] Atypical antipsychotics, such as clozapine, olanzapine,
risperidone and paliperidone display lower profile of
extrapyramidal adverse effects and tardive dyskinesia associated
with acute and long-term D.sub.2 receptor blockade. However there
is still a need to develop novel antipsychotics with lower side
effects and using approaches beyond dopamine D.sub.2 receptor
blockade.
[0014] In vivo data suggest that PDE10 inhibitors can produce
catalepsy, but differently to that observed with current
antipsychotics, such as haloperidol, attributed to activation of
both direct and indirect pathway neurons in the striatum.
[0015] PDE10 inhibitors may possess a pharmacological profile
similar to that of the atypical antipsychotics, but lacking the
non-target related side effects that are often observed with the
currently available antipsychotics. Although EPS-like side effects
are observed at relatively low doses, they are relatively mild.
[0016] Since PDE10 inhibitors can be used to raise levels of cAMP
and/or cGMP within cells that express the PDE10 enzyme, for example
neurons that comprise the basal ganglia, PDE10 inhibitors may be
useful in treating schizophrenia and additionally, a variety of
conditions involving the basal ganglia, such as the conditions
described herein, for example, obesity, non-insulin dependent
diabetes, bipolar disorder, obsessive compulsive disorder and
pain.
[0017] WO 2004/087710 (Pharmacia and Upjohn Company) discloses
N-(1-ethylpropyl)-7-(6-methoxy-2-methyl-3-pyridinyl)-2,6-dimethyl-pyrrolo-
[1,2-b]pyridazin-4-amine and
7-(6-methoxy-2-methyl-3-pyridinyl)-2,6-dimethyl-N-(1-methylpropyl)-pyrrol-
o[1,2-b]pyridazin-4-amine as CRF receptor antagonists, WO
2006/102194 (Eli Lilly and Company) discloses
imidazo[1,2-b]pyridazines bearing a 5-membered aromatic ring at the
3 position and a linear alkyl substituent at the 8-position as CRF1
receptor antagonists. The CRF receptor has been validated as a
possible target for depression, anxiety, cerebrovascular disorders,
irritable bowel syndrome and congestive heart failure, but not for
schizophrenia.
[0018] There is still a great need for antipsychotic therapies with
pharmacological profile similar to that of the atypical
antipsychotics, with low extrapyramidal symptom liability.
[0019] It is the object of the present invention to provide novel
compounds that are PDE10 inhibitors. The present compounds are
centrally active, potent compounds which display efficacy in
preclinical behavior challenge models in which known clinical
useful antipsychotics display similar positive responses, such as
in the reversal of apomorphine-induced stereotypy and phencyclidine
(PCP)-induced hyperlocomotion in rodents. Additionally,
representative compounds reverse the hypolocomotion effects exerted
by SCH23390, a D1 receptor antagonist. Thus, the present compounds
may act as dopamine modulating agents, inhibiting states of
dopaminergic (D.sub.2) hyperactivity and reversing states of
dopaminergic (D.sub.2) hypoactivity.
DESCRIPTION OF THE INVENTION
[0020] The present invention relates to compounds having PDE10
inhibitory activity, said compounds having the Formula (I)
##STR00002##
and the stereoisomeric forms thereof, wherein R.sup.1 is pyridinyl;
pyridinyl optionally substituted with halogen, C.sub.1-4alkyl,
trifluoromethyl or C.sub.1-4alkyloxy; tetrahydropyranyl; or
NR.sup.6R.sup.7; R.sup.2 is hydrogen, C.sub.1-4alkyl,
trifluoromethyl, C.sub.3-8cycloalkyl, or C.sub.1-4alkyloxy; R.sup.3
is hydrogen, chloro, C.sub.1-4alkyl, trifluoromethyl, or
C.sub.3-8cycloalkyl; Het is a 5- or 6-membered heterocyclic ring
selected from the group consisting of pyridinyl, pyrimidinyl,
pyridazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,
isothiazolyl, isoxazolyl, oxadiazolyl and triazolyl; R.sup.4 is
hydrogen, C.sub.1-4alkyl, trifluoromethylC.sub.0-4alkyl,
hydroxyC.sub.1-4alkyl, difluorocyclopropylmethyl,
cyclopropyldifluoroethyl, C.sub.3-8cycloalkyl,
C.sub.1-4alkyloxyC.sub.1-5alkyl, C.sub.1-4alkyloxy,
trifluoromethylC.sub.0-4alkyloxy,
C.sub.3-8cycloalkylC.sub.1-4alkyloxy,
C.sub.3-8cycloalkylC.sub.1-4alkyl,
C.sub.1-6alkyloxyC.sub.1-4alkyloxy, tetrahydropyranyl,
pyridinylmethyl, NR.sup.6aR.sup.7aC.sub.1-4alkyl or
NR.sup.6aR.sup.7a; R.sup.5 is hydrogen or C.sub.1-4alkyl; R.sup.6,
R.sup.6a, R.sup.7 and R.sup.7a are each independently hydrogen, or
C.sub.1-4alkyl, or taken together with N can be a radical of
Formula (a), (b) or (c)
##STR00003##
wherein each R.sup.8, if present, independently of one another is
C.sub.1-4alkyl; R.sup.9 is hydrogen or C.sub.1-4alkyloxy; R.sup.10
is hydrogen or C.sub.1-4alkyl; m is 0, 1, 2, 3, 4 or 5; n is 2, 3,
4, 5 or 6; o is 1 or 2; and the pharmaceutically acceptable salts
and the solvates thereof.
[0021] The present invention also relates to a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of Formula (I) and a pharmaceutically acceptable carrier
or excipient.
[0022] Additionally, the invention relates to a compound of Formula
(I) for use as a medicament.
[0023] The invention also relates to the use of a compound
according to Formula (I) or a pharmaceutical composition according
to the invention for the manufacture of a medicament for treating
or preventing neurological, psychiatric or metabolic disorders and
diseases.
[0024] Additionally, the invention relates to the use of a compound
of Formula (I) in combination with an additional pharmaceutical
agent for the manufacture of a medicament for treating or
preventing neurological, psychiatric or metabolic disorders and
diseases.
[0025] Furthermore, the invention relates to a process for
preparing a pharmaceutical composition according to the invention,
characterized in that a pharmaceutically acceptable carrier is
intimately mixed with a therapeutically effective amount of a
compound of Formula (I).
[0026] The invention also relates to a product comprising a
compound of Formula (I) and an additional pharmaceutical agent, as
a combined preparation for simultaneous, separate or sequential use
in the treatment or prevention of neurological, psychiatric or
metabolic disorders and diseases.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The Chemical names of the compounds of the present invention
were generated according to the nomenclature rules agreed upon by
the Chemical Abstracts Service (CAS) using Advanced Chemical
Development, Inc., software (ACD/Name product version 10.01; Build
15494, 1 Dec. 2006). In case of tautomeric forms, the name of the
depicted tautomeric form of the structure was generated. However it
should be clear that the other non-depicted tautomeric form is also
included within the scope of the present invention.
DEFINITIONS
[0028] The term "halogen" or "halo" as used herein alone or as part
of another group refers to fluoro, chloro, bromo or iodo, with
fluoro or chloro being preferred.
[0029] The term "C.sub.0-4alkyl", "C.sub.1-4alkyl"
or"C.sub.1-5alkyl" as employed herein alone or as part of another
group, unless otherwise stated, refers to a saturated straight or
branched hydrocarbon radical, having unless otherwise stated, from
0 to 4, 1 to 4 or 1 to 5 carbon atoms, which is attached to the
rest of the molecule by a single bond, such as methyl, ethyl,
propyl, butyl, 1-pentyl, 1-methylethyl, 1,1-dimethylethyl,
2-methylpropyl, and 3-methylbutyl.
[0030] The term "C.sub.3-8cycloalkyl" as employed herein alone or
as part of another group unless otherwise stated, is generic to
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl.
[0031] The term "subject" as used herein, refers to an animal,
preferably a mammal (e.g. cat, dog, primate or human), more
preferably a human, who is or has been the object of treatment,
observation or experiment.
[0032] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation or
reversal of the symptoms of the disease or disorder being
treated.
[0033] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0034] As used herein, the term "treatment" is intended to refer to
all processes, wherein there may be a slowing, interrupting,
arresting or stopping of the progression of a disease, but does not
necessarily indicate a total elimination of all symptoms.
[0035] Unless otherwise stated, heterocyclic substituents in
R.sup.1 such as tetrahydropyranyl and pyridinyl may be attached to
the remainder of the molecule of formula (I) through any available
ring carbon atom. Thus, for example, when Het is pyridinyl, it may
be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, unless otherwise
specified.
[0036] Substituents covered by the term Het may be attached to the
remainder of the molecule of formula (I) through any available ring
carbon or heteroatom as appropriate, if not otherwise specified.
Het as used herein, is preferably a 5- or 6-aromatic membered
heterocyclic ring preferably bound to the imidazo[1,2-b]pyridazine
ring system through an available carbon atom of the ring. When Het
is pyridine and R.sup.5 is methyl, the R.sup.5 substituent is
placed in Het preferably in meta- or para-position relative to the
position of attachment to the imidazo[1,2-b]pyridazine core.
[0037] In one embodiment, the invention relates to a compound
according to Formula (I) or a stereochemically isomeric form
thereof, wherein
[0038] R.sup.1 is selected from pyridinyl; pyridinyl optionally
substituted with halogen, C.sub.1-4alkyl, trifluoromethyl or
C.sub.1-4alkyloxy; tetrahydropyranyl; and NR.sup.6R.sup.7; wherein
R.sup.6 and R.sup.7 taken together with the nitrogen can be a
radical of Formula (a), (b) or (c) as previously defined;
[0039] R.sup.2 is selected from hydrogen, methyl, ethyl,
cyclopropyl, isopropyl, methoxy and trifluoromethyl;
[0040] R.sup.3 is selected from hydrogen, chloro, methyl,
trifluoromethyl and cyclopropyl;
[0041] Het is selected from the group consisting of pyridinyl,
pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, pyrazolyl,
isothiazolyl, isoxazolyl, oxadiazolyl and triazolyl and
R.sup.4-R.sup.10, m, n and o are as previously defined;
[0042] or a pharmaceutically acceptable salt or a solvate
thereof.
[0043] In a more preferred embodiment, the invention relates to a
compound according to Formula (I) or a stereochemically isomeric
form thereof, wherein
[0044] R.sup.1 is selected from pyridinyl which may be optionally
substituted with halogen, C.sub.1-4alkyl, trifluoromethyl or
C.sub.1-4alkyloxy; morpholinyl; and NR.sup.6R.sup.7; wherein
R.sup.6 and R.sup.7 taken together with the nitrogen can be a
radical of Formula (a) or (c) wherein n is 3 and o is 1;
[0045] Het is selected from pyridinyl and pyrazolyl;
[0046] R.sup.4 is hydrogen, C.sub.1-4alkyl,
trifluoromethylC.sub.0-4alkyl, hydroxyC.sub.1-4alkyl,
difluorocyclopropylmethyl, cyclopropyldifluoroethyl,
C.sub.3-8cycloalkyl, C.sub.1-4alkyloxyC.sub.1-5alkyl,
C.sub.1-4alkyloxy, trifluoromethylC.sub.0-4alkyloxy,
C.sub.3-8cycloalkylC.sub.1-4alkyloxy,
C.sub.1-6alkyloxyC.sub.1-4alkyloxy, tetrahydropyranyl,
pyridinylmethyl, NR.sup.6aR.sup.7aC.sub.1-4alkyl or
NR.sup.6aR.sup.7a;
[0047] wherein R.sup.6, R.sup.6a, R.sup.7 and R.sup.7a are each
independently hydrogen or C.sub.1-4alkyl, or taken together with
the nitrogen can be a radical of formula (a), (b) or (c), wherein n
is 3, R.sup.9 is hydrogen or C.sub.1-4alkyloxy, m is 0, o is 1 and
R.sup.16 is hydrogen;
[0048] and the remaining variables R.sup.2-R.sup.5 are as
previously defined;
[0049] or a pharmaceutically acceptable salt or a solvate
thereof.
[0050] In another preferred embodiment, the invention relates to a
compound according to Formula (I) or a stereochemically isomeric
form thereof, wherein
[0051] R.sup.1 is selected from pyridinyl, morpholinyl and
pyrrolidinyl;
[0052] R.sup.4 is selected from hydrogen; methyl; ethyl; isopropyl;
isobutyl; trifluoromethyl; 2,2,2-trifluoroethyl;
2-hydroxy-2-methylpropyl; (2,2-difluorocyclopropyl)methyl;
2,2-difluoro-2-cyclopropylethyl; cyclopropyl; 2-methoxyethyl;
2-methoxypropyl; (2S)-2-methoxypropyl; 2-isopropoxyethyl;
2-ethoxyethyl; ethoxymethyl; 1-ethoxy-1-methylethyl;
1-methoxy-1-methylethyl; 2-methoxy-1,1-dimethylethyl;
3-methoxy-3-methylbutyl; 3-methoxypropyl;
2-methoxy-2-methyl-propyl; isopropoxy; 2,2,2-trifluoroethoxy;
cyclopropylmethoxy; 2-methoxyethoxy; 2-methoxy-2-methyl-propoxy;
tetrahydro-2H-pyran-4-yl; (pyridin-3-yl)methyl;
2-(pyrrolidin-1-yl)ethyl; isopropylamino; morpholin-4-yl;
pyrrolidin-1-yl; piperazin-1-yl; (3R)-3-methoxypyrrolidin-1-yl; and
(3S)-3-methoxypyrrolidin-1-yl;
[0053] R.sup.5 is hydrogen or methyl;
[0054] and R.sup.2, R.sup.3 and Het are as previously defined;
[0055] or a pharmaceutically acceptable salt or a solvate
thereof.
[0056] In yet another preferred embodiment, the invention relates
to a compound according to Formula (I) or a stereochemically
isomeric form thereof wherein
[0057] R.sup.1 is selected from morpholinyl and pyridinyl;
[0058] R.sup.2 is selected from hydrogen, methyl, ethyl, methoxy,
and cyclopropyl;
[0059] R.sup.3 is selected from hydrogen, methyl, and
cyclopropyl;
[0060] Het is pyridinyl or pyrazolyl;
[0061] R.sup.4 is selected from ethyl; isopropyl; isobutyl;
2,2,2-trifluoroethyl; 2-hydroxy-2-methylpropyl;
2,2-difluoro-2-cyclopropylethyl; cyclopropyl; 2-methoxyethyl;
(2S)-2-methoxypropyl; 2-ethoxyethyl; ethoxymethyl;
1-ethoxy-1-methylethyl; 1-methoxy-1-methylethyl;
2-methoxy-1,1-dimethylethyl; 3-methoxy-3-methylbutyl;
3-methoxypropyl; 2-methoxy-2-methyl-propyl; 2-methoxyethoxy;
2-methoxy-2-methyl-propoxy; tetrahydro-2H-pyran-4-yl;
morpholin-4-yl; piperazin-1-yl; and
(3R)-3-methoxypyrrolidin-1-yl;
[0062] and R.sup.5 is hydrogen or methyl;
[0063] or a pharmaceutically acceptable salt or a solvate
thereof.
[0064] In yet another preferred embodiment, the invention relates
to a compound according to Formula (I) or a stereochemically
isomeric form thereof wherein
[0065] R.sup.1 is selected from morpholinyl and pyridinyl;
[0066] R.sup.2 is selected from hydrogen, methyl, methoxy, and
cyclopropyl;
[0067] R.sup.3 is selected from hydrogen, methyl, and
cyclopropyl;
[0068] Het is pyridinyl or pyrazolyl;
[0069] R.sup.4 is selected from ethyl; isopropyl; isobutyl;
2,2,2-trifluoroethyl; 2-hydroxy-2-methylpropyl;
2,2-difluoro-2-cyclopropylethyl; cyclopropyl; 2-methoxyethyl;
(2S)-2-methoxypropyl; 2-ethoxyethyl; ethoxymethyl;
1-ethoxy-1-methylethyl; 1-methoxy-1-methylethyl;
2-methoxy-1,1-dimethylethyl; 3-methoxy-3-methylbutyl;
3-methoxypropyl; 2-methoxy-2-methyl-propyl; 2-methoxyethoxy;
2-methoxy-2-methyl-propoxy; tetrahydro-2H-pyran-4-yl;
morpholin-4-yl; piperazin-1-yl; and
(3R)-3-methoxypyrrolidin-1-yl;
[0070] and R.sup.5 is hydrogen or methyl;
[0071] or a pharmaceutically acceptable salt or a solvate
thereof.
[0072] In yet another preferred embodiment, the invention relates
to a compound according to Formula (I) or a stereochemically
isomeric form thereof wherein
[0073] R.sup.1 is selected from morpholinyl and pyridinyl;
[0074] R.sup.2 is selected from hydrogen, methyl, methoxy, and
cyclopropyl;
[0075] R.sup.3 is selected from hydrogen, methyl, and
cyclopropyl;
[0076] Het is pyridinyl or pyrazolyl;
[0077] R.sup.4 is selected from 2-methoxyethyl; 3-methoxypropyl;
2-methoxy-2-methylpropyl; 2-methoxy-1,1-dimethylethyl;
1-ethoxy-1-methylethyl; 1-methoxy-1-methylethyl; 2-methoxyethoxy;
ethoxymethyl; 2-methoxy-2-methylpropoxy; morpholin-4-yl;
2-ethoxyethyl; tetrahydro-2H-pyran-4-yl; ethyl;
3-methoxy-3-methylbutyl; piperazin-1-yl; isopropyl; cyclopropyl;
(3R)-3-methoxypyrrolidin-1-yl; and isobutyl;
[0078] and R.sup.5 is hydrogen or methyl;
[0079] or a pharmaceutically acceptable salt or a solvate
thereof.
[0080] More preferably, the invention relates to a compound
according to Formula (I) or a stereochemically isomeric form
thereof wherein
[0081] R.sup.1 is selected from morpholin-4-yl, pyridin-3-yl and
pyridin-4-yl;
[0082] Het is selected from pyridin-3-yl, pyridin-4-yl and
1H-pyrazol-4-yl;
[0083] and R.sup.2-R.sup.5 are as previously defined;
[0084] or a pharmaceutically acceptable salt or a solvate
thereof.
[0085] In a yet a more preferred embodiment, the invention relates
to a compound according to Formula (I), or a stereochemically
isomeric form thereof, wherein
[0086] R.sup.1 is morpholin-4-yl;
[0087] Het is pyridin-3-yl or pyridin-4-yl;
[0088] and R.sup.2-R.sup.5 are as previously defined;
[0089] or a pharmaceutically acceptable salt or a solvate
thereof.
[0090] In the most preferred embodiment, the invention relates to a
compound according to Formula (I) wherein
[0091] R.sup.1 is morpholin-4-yl;
[0092] R.sup.2 is methyl;
[0093] R.sup.3 is hydrogen;
[0094] Het is pyridin-3-yl;
[0095] R.sup.4 is 2-methoxyethyl; and
[0096] R.sup.5 is hydrogen;
[0097] or a pharmaceutically acceptable salt or a solvate
thereof.
[0098] An additional embodiment refers to compounds according to
Formula (I), wherein R.sup.3 is hydrogen and the rest of variables
are as previously defined, and the stereochemically isomeric forms
thereof and the pharmaceutically acceptable salts and solvates
thereof.
[0099] In an additional embodiment, the invention relates to
compounds according to formula (I), having the formula (I'-a) or
(I'-b)
##STR00004##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as
previously defined.
[0100] In an additional embodiment, R.sup.1 is morpholin-4-yl.
[0101] In an additional embodiment, R.sup.1 is pyridin-4-yl.
[0102] In an additional embodiment, R.sup.1 is pyridin-3-yl.
[0103] In an additional embodiment, R.sup.3 is hydrogen.
[0104] In an additional embodiment, R.sup.2 is methyl and R.sup.3
is hydrogen.
[0105] In an additional embodiment, Het is 3-pyridinyl or
4-pyridinyl.
[0106] In an additional embodiment, Het is 1H-pyrazol-4-yl.
[0107] In an additional embodiment, R.sup.4 is selected from ethyl;
isopropyl; isobutyl; 2,2,2-trifluoroethyl;
2-hydroxy-2-methylpropyl; 2,2-difluoro-2-cyclopropylethyl;
cyclopropyl; 2-methoxyethyl; (2S)-2-methoxypropyl; 2-ethoxyethyl;
ethoxymethyl; 1-ethoxy-1-methylethyl; 1-methoxy-1-methylethyl;
2-methoxy-1,1-dimethylethyl; 3-methoxy-3-methylbutyl;
3-methoxypropyl; 2-methoxy-2-methyl-propyl; 2-methoxyethoxy;
2-methoxy-2-methyl-propoxy; tetrahydro-2H-pyran-4-yl;
morpholin-4-yl; piperazin-1-yl; and
(3R)-3-methoxypyrrolidin-1-yl.
[0108] In an additional embodiment, R.sup.4 is selected from ethyl;
isopropyl; isobutyl; 2-hydroxy-2-methylpropyl; cyclopropyl;
2-methoxyethyl; 2-ethoxyethyl; ethoxymethyl;
1-ethoxy-1-methylethyl; 1-methoxy-1-methylethyl;
2-methoxy-1,1-dimethylethyl; 3-methoxy-3-methylbutyl;
3-methoxypropyl; 2-methoxy-2-methylpropyl; 2-methoxyethoxy;
2-methoxy-2-methyl-propoxy; tetrahydro-2H-pyran-4-yl;
morpholin-4-yl; piperazin-1-yl; and
(3R)-3-methoxypyrrolidin-1-yl.
[0109] In an additional embodiment, R.sup.4 is selected from ethyl;
2-hydroxy-2-methylpropyl; 2-methoxyethyl; 2-methoxy-2-methylpropyl;
2-methoxyethoxy; 2-methoxy-2-methyl-propoxy; and
morpholin-4-yl.
[0110] In an additional embodiment, the invention relates to a
compound according to formula (I'-a) of (I'-b) wherein
[0111] R.sup.1 is morpholin-4-yl;
[0112] R.sup.2 is methyl;
[0113] R.sup.3 is hydrogen;
[0114] Het is pyridin-3-yl;
[0115] R.sup.4 is 2-methoxyethyl; and
[0116] R.sup.5 is hydrogen.
[0117] In an additional embodiment, the invention relates to a
compound according to formula (I'-c)
##STR00005##
wherein R.sup.1, R.sup.2, R.sup.3 are as previously defined,
R.sup.4a is selected from the group consisting of R.sup.4a is
selected from the group consisting of hydrogen, C.sub.1-4alkyl,
trifluoromethylC.sub.0-4alkyl, hydroxyC.sub.1-4alkyl,
difluorocyclopropylmethyl, cyclopropyldifluoroethyl,
C.sub.3-8cycloalkyl, C.sub.1-4alcyloxyC.sub.1-5alkyl,
tetrahydropyranyl and pyridinylmethyl.
[0118] In an additional embodiment, R.sup.4a is selected from
hydrogen; isobutyl; 2,2,2-trifluoroethyl;
(2,2-difluorocyclopropyl)methyl; 2,2-difluoro-2-cyclopropylethyl;
2-methoxyethyl; (2S)-2-methoxypropyl; 2-methoxy-2-methyl-propyl;
tetrahydro-2H-pyran-4-yl; and (pyridin-3-yl)methyl.
[0119] In another embodiment, R.sup.4a is selected from isobutyl;
2,2,2-trifluoroethyl; 2,2-difluoro-2-cyclopropylethyl;
2-methoxyethyl; (2S)-2-methoxypropyl; and
2-methoxy-2-methyl-propyl.
[0120] Particularly preferred compounds may be selected from the
group of: [0121]
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imid-
azo[1,2-b]pyridazine (compound 1), [0122]
3-[6-(3-methoxypropyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,-
2-b]pyridazine (compound 2), [0123]
3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-i-
midazo[1,2-b]pyridazine (compound 3), [0124]
3-[6-(2-methoxy-1,1-dimethylethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl-
)-imidazo[1,2-b]pyridazine (compound 4), [0125]
3-[6-(1-ethoxy-1-methylethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imi-
dazo[1,2-b]pyridazine (compound 5), [0126]
3-[6-(1-methoxy-1-methylethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-im-
idazo[1,2-b]pyridazine (compound 6), [0127]
3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imi-
dazo[1,2-b]pyridazine (compound 7), [0128]
3-[6-(2-methoxyethoxy)-5-methyl-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imi-
dazo[1,2-b]pyridazine (compound 8), [0129]
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(3-pyridinyl)-imidazo[1,2--
b]pyridazine (compound 9), [0130]
2-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[-
1,2-b]pyridazine (compound 10), [0131]
3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-morpholinyl)-imidazo[1,2-b]pyrida-
zine (compound 11), [0132]
2-methoxy-3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-morpholinyl)-imidazo[1,-
2-b]pyridazine (compound 12), [0133]
6-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholiny-
l)-imidazo[1,2-b]pyridazine (compound 13), [0134]
6-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-
-imidazo[1,2-b]pyridazine (compound 14), [0135]
2-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-6-methyl-8-(4-morpholiny-
l)-imidazo[1,2-b]pyridazine (compound 15), [0136]
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,-
2-b]pyridazine (compound 16), [0137]
3-[6-(ethoxymethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-b-
]pyridazine (compound 17), [0138]
3-[6-(2-methoxy-2-methylpropoxy)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)--
imidazo[1,2-b]pyridazine (compound 18), [0139]
2-methyl-8-(4-morpholinyl)-3-[6-(4-morpholinyl)-3-pyridinyl]-imidazo[1,2--
b]pyridazine (compound 19), [0140]
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imidazo[1,2-b-
]pyridazine (compound 20), [0141]
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imidazo[1,2--
b]pyridazine (compound 21), [0142]
2-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-morpholinyl)-imidaz-
o[1,2-b]pyridazine (compound 22), [0143]
3-[6-(2-methoxyethyl)-3-pyridinyl]-2,6-dimethyl-8-(4-morpholinyl)-imidazo-
[1,2-b]pyridazine (compound 23), [0144]
3-[6-(2-methoxyethyl)-3-pyridinyl]-2,6-dimethyl-8-(4-pyridinyl)-imidazo[1-
,2-b]pyridazine (compound 24), [0145]
3-[6-(2-ethoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2--
b]pyridazine (compound 25), [0146]
3-[2-(2-methoxyethyl)-4-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine (compound 26), [0147]
2-methyl-8-(4-morpholinyl)-3-[6-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl]-i-
midazo[1,2-b]pyridazine (compound 27), [0148]
3-(6-ethyl-3-pyridinyl)-2-methyl-8-(4-morpholinyl)-imidazo[1,2-b]pyridazi-
ne (compound 28), [0149]
3-[6-(3-methoxy-3-methylbutyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-im-
idazo[1,2-b]pyridazine (compound 29), [0150]
2-methyl-8-(4-morpholinyl)-3-[6-(1-piperazinyl)-3-pyridinyl]-imidazo[1,2--
b]pyridazine (compound 30), [0151]
2-methyl-3-[6-(4-morpholinyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1,2-b]-
pyridazine (compound 31), [0152]
2-methyl-3-[6-(1-methylethyl)-3-pyridinyl]-8-(4-morpholinyl)-imidazo[1,2--
b]pyridazine (compound 32), [0153]
3-(6-cyclopropyl-3-pyridinyl)-2-methyl-8-(4-morpholinyl)-imidazo[1,2-b]py-
ridazine (compound 33), [0154]
3-[6-[(3R)-3-methoxy-1-pyrrolidinyl]-3-pyridinyl]-2-methyl-8-(4-morpholin-
yl)-imidazo[1,2-b]pyridazine (compound 34), [0155]
2-methyl-3-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-morpholinyl)-imidazo-
[1,2-b]pyridazine (compound 35), [0156]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-morpholinyl)-imidazo-
[1,2-b]pyridazine (compound 36), [0157]
3-[1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-morpholiny-
l)-imidazo[1,2-b]pyridazine (compound 37), [0158]
2-cyclopropyl-3-[1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-morph-
olinyl)-imidazo[1,2-b]pyridazine (compound 38), [0159]
2-methyl-3-(6-methyl-3-pyridinyl)-8-(4-morpholinyl)-imidazo[1,2-b]pyridaz-
ine (compound 39), [0160]
6-cyclopropyl-3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-2-methyl-8-(4--
pyridinyl)-imidazo[1,2-b]pyridazine (compound 40), [0161]
6-cyclopropyl-3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-morpholin-
yl)-imidazo[1,2-b]pyridazine (compound 41), [0162]
6-cyclopropyl-3-[5-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-morpholin-
yl)-imidazo[1,2-b]pyridazine (compound 42), [0163]
6-cyclopropyl-3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-2-methyl-8-(4--
morpholinyl)-imidazo[1,2-b]pyridazine (compound 43), [0164]
2-cyclopropyl-3-[6-(2-methoxyethoxy)-3-pyridinyl]-8-(4-pyridinyl)-imidazo-
[1,2-b]pyridazine (compound 44), [0165]
2-cyclopropyl-3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-8-(4-morpholin-
yl)-imidazo[1,2-b]pyridazine (compound 45), [0166]
2-cyclopropyl-3-[6-(4-morpholinyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1-
,2-b]pyridazine (compound 46), [0167]
3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-2,6-dimethyl-8-(4-morpholiny-
l)-imidazo[1,2-b]pyridazine (compound 47), [0168]
3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-2,6-dimethyl-8-(4-pyridinyl)-
-imidazo[1,2-b]pyridazine (compound 48), [0169]
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2,6-dimethyl-8-(4-pyridinyl)-imidazo[-
1,2-b]pyridazine (compound 49), [0170]
2-cyclopropyl-3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-8-(4-pyridinyl-
)-imidazo[1,2-b]pyridazine (compound 50), [0171]
3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-8-(4-morpholinyl)-imidazo[1,-
2-b]pyridazine (compound 51), [0172]
3-[6-(2-methoxyethoxy)-3-pyridinyl]-8-(4-morpholinyl)-imidazo[1,2-b]pyrid-
azine (compound 52), [0173]
2-cyclopropyl-3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-6-methyl-8-(4--
morpholinyl)-imidazo[1,2-b]pyridazine (compound 53), [0174]
5-[2-cyclopropyl-8-(4-morpholinyl)imidazo[1,2-b]pyridazin-3-yl]-.alpha.,.-
alpha.-dimethyl-2-pyridineethanol (compound 54), [0175]
2-cyclopropyl-3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-6-methyl-8-(4--
pyridinyl)-imidazo[1,2-b]pyridazine (compound 55), [0176]
2-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-6-methyl-8-(4-pyridinyl)-
-imidazo[1,2-b]pyridazine (compound 56), [0177]
3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1,2-b]pyridazi-
ne (compound 57), [0178]
6-cyclopropyl-2-methyl-3-[6-(4-morpholinyl)-3-pyridinyl]-8-(4-pyridinyl)--
imidazo[1,2-b]pyridazine (compound 58), [0179]
6-cyclopropyl-3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-pyridinyl-
)-imidazo[1,2-b]pyridazine (compound 59), [0180]
3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1,2--
b]pyridazine (compound 60), [0181]
3-[6-(4-morpholinyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1,2-b]pyridazin-
e (compound 61), [0182]
2-methyl-8-(4-morpholinyl)-3-[6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-imid-
azo[1,2-b]pyridazine (compound 62), [0183]
2-methyl-8-(4-morpholinyl)-3-[6-(trifluoromethyl)-3-pyridinyl]-imidazo[1,-
2-b]pyridazine (compound 63), [0184]
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-6-(trifluor-
omethyl)-imidazo[1,2-b]pyridazine (compound 64), [0185]
3-[6-(cyclopropylmethoxy)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo-
[1,2-b]pyridazine (compound 65), [0186]
2-methyl-3-[6-(1-methylethoxy)-3-pyridinyl]-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine (compound 66), [0187]
2-methyl-3-[2-(1-methylethoxy)-4-pyridinyl]-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine (compound 67), [0188]
2,6-dimethyl-8-(4-morpholinyl)-3-[6-(4-morpholinyl)-3-pyridinyl]-imidazo[-
1,2-b]pyridazine (compound 68), [0189]
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2,6-dimethyl-8-(4-morpholinyl)-imidaz-
o[1,2-b]pyridazine (compound 69), [0190]
2,6-dimethyl-3-[6-(4-morpholinyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1,-
2-b]pyridazine (compound 70), [0191]
2-cyclopropyl-6-methyl-3-[6-(4-morpholinyl)-3-pyridinyl]-8-(4-pyridinyl)--
imidazo[1,2-b]pyridazine (compound 71), [0192]
2-cyclopropyl-3-[6-(2-methoxyethoxy)-3-pyridinyl]-6-methyl-8-(4-pyridinyl-
)-imidazo[1,2-b]pyridazine (compound 72), [0193]
2-cyclopropyl-3-[6-(2-methoxyethoxy)-3-pyridinyl]-8-(4-morpholinyl)-imida-
zo[1,2-b]pyridazine (compound 73), [0194]
2-cyclopropyl-3-[6-(2-methoxyethoxy)-3-pyridinyl]-6-methyl-8-(4-morpholin-
yl)-imidazo[1,2-b]pyridazine (compound 74), [0195]
2-cyclopropyl-6-methyl-8-(4-morpholinyl)-3-[6-(4-morpholinyl)-3-pyridinyl-
]-imidazo[1,2-b]pyridazine (compound 75), [0196]
2-methyl-3-[6-[2-(1-methylethoxy)ethyl]-3-pyridinyl]-8-(4-morpholinyl)-im-
idazo[1,2-b]pyridazine (compound 76), [0197]
2-methyl-8-(4-morpholinyl)-3-[6-[2-(1-pyrrolidinyl)ethyl]-3-pyridinyl]-im-
idazo[1,2-b]pyridazine (compound 77), [0198]
6-cyclopropyl-2-methyl-8-(4-morpholinyl)-3-[6-(tetrahydro-2H-pyran-4-yl)--
3-pyridinyl]-imidazo[1,2-b]pyridazine (compound 78), [0199]
2-cyclopropyl-6-methyl-8-(4-morpholinyl)-3-[6-(tetrahydro-2H-pyran-4-yl)--
3-pyridinyl]-imidazo[1,2-b]pyridazine (compound 79), [0200]
2-cyclopropyl-6-methyl-8-(4-pyridinyl)-3-[6-(tetrahydro-2H-pyran-4-yl)-3--
pyridinyl]-imidazo[1,2-b]pyridazine (compound 80), [0201]
6-cyclopropyl-2-methyl-8-(4-pyridinyl)-3-[6-(tetrahydro-2H-pyran-4-yl)-3--
pyridinyl]-imidazo[1,2-b]pyridazine (compound 81), [0202]
8-(4-morpholinyl)-3-[6-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl]-imidazo[1,-
2-b]pyridazine (compound 82), [0203]
3-(6-ethyl-3-pyridinyl)-2-methyl-8-(4-pyridinyl)-imidazo[1,2-b]pyridazine
(compound 83), [0204]
2-cyclopropyl-3-(6-ethyl-3-pyridinyl)-6-methyl-8-(4-morpholinyl)-imidazo[-
1,2-b]pyridazine (compound 84), [0205]
2-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-morpholinyl)-6-(tri-
fluoromethyl)-imidazo[1,2-b]pyridazine (compound 85), [0206]
6-cyclopropyl-3-(6-ethyl-3-pyridinyl)-2-methyl-8-(4-pyridinyl)-imidazo[1,-
2-b]pyridazine (compound 86), [0207]
2-cyclopropyl-3-(6-ethyl-3-pyridinyl)-8-(4-pyridinyl)-imidazo[1,2-b]pyrid-
azine (compound 87), [0208]
3-(6-ethyl-3-pyridinyl)-2,6-dimethyl-8-(4-pyridinyl)-imidazo[1,2-b]pyrida-
zine (compound 88), [0209]
2-methyl-8-(4-morpholinyl)-3-[6-(1-pyrrolidinyl)-3-pyridinyl]-imidazo[1,2-
-b]pyridazine (compound 89), [0210]
N-(1-methylethyl)-5-[2-methyl-8-(4-morpholinyl)imidazo[1,2-b]pyridazin-3--
yl]-2-pyridinamine (compound 90), [0211]
2-methyl-8-(4-morpholinyl)-3-[2-(4-morpholinyl)-4-pyridinyl]-imidazo[1,2--
b]pyridazine (compound 91), [0212]
2-methyl-8-(4-morpholinyl)-3-[2-(1-pyrrolidinyl)-4-pyridinyl]-imidazo[1,2-
-b]pyridazine (compound 92), [0213]
N-(1-methylethyl)-4-[2-methyl-8-(4-morpholinyl)imidazo[1,2-b]pyridazin-3--
yl]-2-pyridinamine (compound 93), [0214]
6-cyclopropyl-2-methyl-8-(4-morpholinyl)-3-[6-(4-morpholinyl)-3-pyridinyl-
]-imidazo[1,2-b]pyridazine (compound 94), [0215]
2-cyclopropyl-8-(4-morpholinyl)-3-[6-(4-morpholinyl)-3-pyridinyl]-imidazo-
[1,2-b]pyridazine (compound 95), [0216]
2,6-dimethyl-3-[6-(1-piperazinyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1,-
2-b]pyridazine (compound 96), [0217]
2-methyl-3-[6-(1-piperazinyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1,2-b]-
pyridazine (compound 97), [0218]
2-cyclopropyl-8-(4-morpholinyl)-3-[6-(1-piperazinyl)-3-pyridinyl]-imidazo-
[1,2-b]pyridazine (compound 98), [0219]
6-cyclopropyl-2-methyl-3-[6-(1-piperazinyl)-3-pyridinyl]-8-(4-pyridinyl)--
imidazo[1,2-b]pyridazine (compound 99), [0220]
2-cyclopropyl-6-methyl-8-(4-morpholinyl)-3-[6-(1-piperazinyl)-3-pyridinyl-
]-imidazo[1,2-b]pyridazine (compound 100), [0221]
2-cyclopropyl-6-methyl-3-[6-(1-piperazinyl)-3-pyridinyl]-8-(4-pyridinyl)--
imidazo[1,2-b]pyridazine (compound 101), [0222]
2-cyclopropyl-3-[6-(1-piperazinyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1-
,2-b]pyridazine (compound 102), [0223]
2-methyl-8-(4-morpholinyl)-3-[2-(1-piperazinyl)-4-pyridinyl]-imidazo[1,2--
b]pyridazine (compound 103), [0224]
2-methyl-3-[6-(2-methylpropyl)-3-pyridinyl]-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine (compound 104), [0225]
2-methyl-3-[2-(2-methylpropyl)-4-pyridinyl]-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine (compound 105), [0226]
2-cyclopropyl-3-(6-ethyl-3-pyridinyl)-8-(4-morpholinyl)-imidazo[1,2-b]pyr-
idazine (compound 106), [0227]
6-cyclopropyl-3-(6-ethyl-3-pyridinyl)-2-methyl-8-(4-morpholinyl)-imidazo[-
1,2-b]pyridazine (compound 107), [0228]
3-(6-ethyl-3-pyridinyl)-2,6-dimethyl-8-(4-morpholinyl)-imidazo[1,2-b]pyri-
dazine (compound 108), [0229]
3-(6-ethyl-3-pyridinyl)-8-(4-morpholinyl)-imidazo[1,2-b]pyridazine
(compound 109), [0230]
3-(6-cyclopropyl-3-pyridinyl)-2,6-dimethyl-8-(4-morpholinyl)-imidazo[1,2--
b]pyridazine (compound 110), [0231]
3-(6-cyclopropyl-3-pyridinyl)-2-methyl-8-(4-pyridinyl)-imidazo[1,2-b]pyri-
dazine (compound 111), [0232]
3-(6-cyclopropyl-3-pyridinyl)-8-(4-morpholinyl)-imidazo[1,2-b]pyridazine
(compound 112), [0233]
3-[6-[(3S)-3-methoxy-1-pyrrolidinyl]-3-pyridinyl]-2-methyl-8-(4-morpholin-
yl)-imidazo[1,2-b]pyridazine (compound 113), [0234]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-pyridinyl)-imidazo[1-
,2-b]pyridazine (compound 114), [0235]
2-methyl-8-(4-morpholinyl)-3-[1-(3-pyridinylmethyl)-1H-pyrazol-4-yl]-imid-
azo[1,2-b]pyridazine (compound 115), [0236]
2-methyl-8-(4-morpholinyl)-3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine
(compound 116), [0237]
2-methyl-8-(4-morpholinyl)-3-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-y-
l]-imidazo[1,2-b]pyridazine (compound 117), [0238]
3-{1-[2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-8-morphol-
in-4-ylimidazo[1,2-b]pyridazine (compound 118), [0239]
2-cyclopropyl-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-8-(4-morpholinyl)-im-
idazo[1,2-b]pyridazine (compound 119), [0240]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-(1-methylethyl)-8-(4-morpholinyl-
)-imidazo[1,2-b]pyridazine (compound 120), [0241]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-(1-methylethyl)-8-(4-pyridinyl)--
imidazo[1,2-b]pyridazine (compound 121), [0242]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-8-(4-pyridinyl)-2-(trifluoromethyl-
)-imidazo[1,2-b]pyridazine (compound 122), [0243]
3-[1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-pyridinyl)-
-imidazo[1,2-b]pyridazine (compound 123), [0244]
2-methyl-3-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-pyridinyl)-imidazo[1-
,2-b]pyridazine (compound 124), [0245]
6-cyclopropyl-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-morpho-
linyl)-imidazo[1,2-b]pyridazine (compound 125), [0246]
6-cyclopropyl-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-pyridi-
nyl)-imidazo[1,2-b]pyridazine (compound 126), [0247]
2-ethyl-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-8-(4-morpholinyl)-imidazo[-
1,2-b]pyridazine (compound 127), [0248]
3-[1-(2-cyclopropyl-2,2-difluoroethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-mor-
pholinyl)-imidazo[1,2-b]pyridazine (compound 128), [0249]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-pyridinyl)-6-(triflu-
oromethyl)-imidazo[1,2-b]pyridazine (compound 129), [0250]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-morpholinyl)-6-(trif-
luoromethyl)-imidazo[1,2-b]pyridazine (compound 130),
[0251]
3-[1-[(2S)-2-methoxypropyl]-1H-pyrazol-4-yl]-2-methyl-8-(4-morphol-
inyl)-imidazo[1,2-b]pyridazine (compound 131), [0252]
2-ethyl-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-8-(4-pyridinyl)-imidazo[1,-
2-b]pyridazine (compound 132), [0253]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2,6-dimethyl-8-(4-morpholinyl)-imi-
dazo[1,2-b]pyridazine (compound 133), [0254]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2,6-dimethyl-8-(4-pyridinyl)-imida-
zo[1,2-b]pyridazine (compound 134), [0255]
2-methyl-8-(4-pyridinyl)-3-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-imi-
dazo[1,2-b]pyridazine (compound 135), [0256]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(1-pyrrolidinyl)-imidaz-
o[1,2-b]pyridazine (compound 136), [0257]
2-methyl-8-(4-morpholinyl)-3-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-i-
midazo[1,2-b]pyridazine (compound 137), [0258]
2-cyclopropyl-8-(4-morpholinyl)-3-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4--
yl]-imidazo[1,2-b]pyridazine (compound 138), [0259]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-8-(4-morpholinyl)-2-(trifluorometh-
yl)-imidazo[1,2-b]pyridazine (compound 139), [0260]
2-methoxy-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-8-(4-morpholinyl)-imidaz-
o[1,2-b]pyridazine (compound 140), [0261]
2-cyclopropyl-8-(4-pyridinyl)-3-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl-
]-imidazo[1,2-b]pyridazine (compound 141), [0262]
2-cyclopropyl-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-8-(4-pyridinyl)-imid-
azo[1,2-b]pyridazine (compound 142), [0263]
2-cyclopropyl-3-[1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-pyrid-
inyl)-imidazo[1,2-b]pyridazine (compound 143), [0264]
8-(4-morpholinyl)-3-[6-(4-morpholinyl)-3-pyridinyl]-imidazo[1,2-b]pyridaz-
ine (compound 144), [0265]
3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-morpholinyl)-2-(trifluoromethyl)--
imidazo[1,2-b]pyridazine (compound 145), [0266]
6-chloro-2-methyl-8-(4-morpholinyl)-3-[1-(2,2,2-trifluoroethyl)-1H-pyrazo-
l-4-yl]-imidazo[1,2-b]pyridazine (compound 146), [0267]
6-chloro-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-pyridinyl)--
imidazo[1,2-b]pyridazine (compound 147), [0268]
2-cyclopropyl-3-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-pyridinyl)-imid-
azo[1,2-b]pyridazine (compound 148), and [0269]
3-[5-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imidazo[1,2--
b]pyridazine (compound 149), and the stereoisomeric forms, the
pharmaceutically acceptable salts and the solvates thereof.
[0270] More preferred particular compounds are compounds 1 to 38,
and pharmaceutically acceptable salts thereof.
[0271] Other particularly preferred compounds include [0272]
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine hydrochloride (compound 1a), [0273]
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine maleate (compound 1b), [0274]
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine monohydrate (compound 1c), [0275]
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imidazo[1,2--
b]pyridazine hydrochloride (compound 21a), [0276]
2-cyclopropyl-3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-8-(4-morpholin-
yl)-imidazo[1,2-b]pyridazine hydrochloride (compound 45a), [0277]
3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-2,6-dimethyl-8-(4-pyridinyl)-
-imidazo[1,2-b]pyridazine (compound 48), [0278]
2-cyclopropyl-3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-8-(4-pyridinyl-
)-imidazo[1,2-b]pyridazine (compound 50), [0279]
5-[2-cyclopropyl-8-(4-morpholinyl)imidazo[1,2-b]pyridazin-3-yl]-.alpha.,.-
alpha.-dimethyl-2-pyridineethanol (compound 54), [0280]
3-[6-(4-morpholinyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1,2-b]pyridazin-
e (compound 61), [0281]
2,6-dimethyl-8-(4-morpholinyl)-3-[6-(4-morpholinyl)-3-pyridinyl]-imidazo[-
1,2-b]pyridazine (compound 68), [0282]
2-cyclopropyl-6-methyl-3-[6-(4-morpholinyl)-3-pyridinyl]-8-(4-pyridinyl)--
imidazo[1,2-b]pyridazine (compound 71), [0283]
2-cyclopropyl-3-[6-(2-methoxyethoxy)-3-pyridinyl]-6-methyl-8-(4-pyridinyl-
)-imidazo[1,2-b]pyridazine (compound 72), [0284]
2-methyl-8-(4-morpholinyl)-3-[2-(4-morpholinyl)-4-pyridinyl]-imidazo[1,2--
b]pyridazine (compound 91), [0285]
3-{1-[2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-8-morphol-
in-4-ylimidazo[1,2-b]pyridazine (compound 118), [0286]
2-methyl-3-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-pyridinyl)-imidazo[1-
,2-b]pyridazine (compound 124), [0287]
6-cyclopropyl-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-morpho-
linyl)-imidazo[1,2-b]pyridazine (compound 125), [0288]
2-ethyl-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-8-(4-morpholinyl)-imidazo[-
1,2-b]pyridazine (compound 127), [0289]
3-[1-[(2S)-2-methoxypropyl]-1H-pyrazol-4-yl]-2-methyl-8-(4-morpholinyl)-i-
midazo[1,2-b]pyridazine (compound 131), [0290]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2,6-dimethyl-8-(4-morpholinyl)-imi-
dazo[1,2-b]pyridazine (compound 133), [0291]
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2,6-dimethyl-8-(4-pyridinyl)-imida-
zo[1,2-b]pyridazine (compound 134), [0292]
2-methyl-8-(4-pyridinyl)-3-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-imi-
dazo[1,2-b]pyridazine (compound 135), [0293]
2-cyclopropyl-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-8-(4-pyridinyl)-imid-
azo[1,2-b]pyridazine (compound 142), [0294]
2-cyclopropyl-3-[1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-pyrid-
inyl)-imidazo[1,2-b]pyridazine (compound 143), [0295]
6-chloro-3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-pyridinyl)--
imidazo[1,2-b]pyridazine (compound 147), and [0296]
2-cyclopropyl-3-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-pyridinyl)-imid-
azo[1,2-b]pyridazine (compound 148), and the stereoisomeric forms,
the pharmaceutically acceptable salts and the solvates thereof.
[0297] For therapeutic use, salts of the compounds of formula (I)
are those wherein the counterion is pharmaceutically acceptable.
However, salts of acids and bases which are non-pharmaceutically
acceptable may also find use, for example, in the preparation or
purification of a pharmaceutically acceptable compound. All salts,
whether pharmaceutically acceptable or not, are included within the
ambit of the present invention.
[0298] The pharmaceutically acceptable salts are defined to
comprise the therapeutically active non-toxic acid addition salt
forms that the compounds according to Formula (I) are able to form.
Said salts can be obtained by treating the base form of the
compounds according to Formula (I) with appropriate acids, for
example inorganic acids, for example hydrohalic acids, in
particular hydrochloric acid, hydrobromic acid, sulphuric acid,
nitric acid and phosphoric acid; organic acids, for example acetic
acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic
acid, oxalic acid, malonic acid, succinic acid, maleic acid,
fumaric acid, malic acid, tartaric acid, citric acid,
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, cyclamic acid, salicylic acid,
p-aminosalicylic acid and pamoic acid.
[0299] Conversely, said salt forms can be converted into the free
base form by treatment with an appropriate base.
[0300] The compounds according to Formula (I) containing acidic
protons may also be converted into their therapeutically active
non-toxic base salt forms by treatment with appropriate organic and
inorganic bases. Appropriate base salt forms comprise, for example,
the ammonium salts, the alkaline and alkaline earth metal salts, in
particular lithium, sodium, potassium, magnesium and calcium salts,
salts with organic bases, e.g. primary, secondary and tertiary
aliphatic and aromatic amines such as methylamine, ethylamine,
propylamine, isopropylamine, the four butylamine isomers,
dimethylamine, diethylamine, diethanolamine, dipropylamine,
diisopropylamine, di-n-butylamine, pyrrolidine, piperidine,
morpholine, trimethylamine, triethylamine, tripropylamine,
quinuclidine, pyridine, quinoline, and isoquinoline, the
benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with
amino acids, for example arginine and lysine.
[0301] Conversely, said salt forms can be converted into the free
acid forms by treatment with an appropriate acid.
[0302] The term solvate comprises the solvent addition forms as
well as the salts thereof, which the compounds of formula (I) are
able to form. Examples of such solvent addition forms are e.g.
hydrates, alcoholates and the like.
[0303] The term "stereochemically isomeric forms" or
"stereoisomeric forms" as used hereinbefore defines all the
possible isomeric forms that the compounds of Formula (I) may
possess. Unless otherwise mentioned or indicated, the chemical
designation of compounds denotes the mixture of all possible
stereochemically isomeric forms, said mixtures containing all
diastereomers and enantiomers of the basic molecular structure. The
invention also embraces each of the individual isomeric forms of
the compounds of Formula (I) and their salts and solvates,
substantially free, i.e. associated with less than 10%, preferably
less than 5%, in particular less than 2% and most preferably less
than 1%, of the other isomers. Thus, when a compound of formula (I)
is for instance specified as (R), this means that the compound is
substantially free of the (S) isomer. Stereogenic centers may have
the R- or S-configuration; substituents on bivalent cyclic
(partially) saturated radicals may have either the cis- or
trans-configuration.
[0304] Following CAS nomenclature conventions, when two stereogenic
centers of known absolute configuration are present in a compound,
an R or S descriptor is assigned (based on Cahn-Ingold-Prelog
sequence rule) to the lowest-numbered chiral center, the reference
center. The configuration of the second stereogenic center is
indicated using relative descriptors [R*,R*] or [R*,S*], where R*
is always specified as the reference center and [R*,R*] indicates
centers with the same chirality and [R*,S*] indicates centers of
unlike chirality. For example, if the lowest-numbered chiral center
in the compound has an S configuration and the second center is R,
the stereo descriptor would be specified as S--[R*,S*].
[0305] In the framework of this application, an element, in
particular when mentioned in relation to a compound according to
Formula (I), comprises all isotopes and isotopic mixtures of this
element, either naturally occurring or synthetically produced,
either with natural abundance or in an isotopically enriched form.
Radiolabelled compounds of Formula (I) may comprise a radioactive
isotope selected from the group of .sup.3H, .sup.11C, .sup.18F,
.sup.122I, .sup.123I, .sup.125I, .sup.131I, .sup.75Br, .sup.76Br,
.sup.77Br and .sup.82Br. Preferably, the radioactive isotope is
selected from the group of .sup.3H, .sup.11C and .sup.18F.
Preparation
[0306] The compounds according to the invention can generally be
prepared by a succession of steps, each of which is known to the
skilled person. In particular, the compounds can be prepared
according to the following synthesis methods.
[0307] The compounds of Formula (I) may be synthesized in the form
of racemic mixtures of enantiomers which can be separated from one
another following art-known resolution procedures. The racemic
compounds of Formula (I) may be converted into the corresponding
diastereomeric salt forms by reaction with a suitable chiral acid.
Said diastereomeric salt forms are subsequently separated, for
example, by selective or fractional crystallization and the
enantiomers are liberated therefrom by alkali. An alternative
manner of separating the enantiomeric forms of the compounds of
Formula (I) involves liquid chromatography using a chiral
stationary phase. Said pure stereochemically isomeric forms may
also be derived from the corresponding pure stereochemically
isomeric forms of the appropriate starting materials, provided that
the reaction occurs stereospecifically.
A. Preparation of the Final Compounds
[0308] A compound of Formula (I) wherein R.sup.1, R.sup.2, R.sup.4
and R.sup.5 are as defined before, R.sup.3 is hydrogen and Het is
pyridinyl, can be prepared by reacting a compound of Formula
(Ia)
##STR00006##
wherein R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are as defined
before, with hydrogen in the presence of a suitable catalyst, such
as 10% palladium on charcoal, in a suitable inert solvent, such as
methanol or ethanol, under suitable reaction conditions, such as a
convenient temperature, typically ranging between 25.degree. C. and
40.degree. C. or with ammonium formate in the presence of a
suitable catalyst such as 10% palladium on charcoal, in a suitable
inert solvent, such as methanol, ethanol, ethyl acetate or
dichloromethane or mixtures thereof, under suitable reaction
conditions, such as heating at a convenient temperature, typically
ranging between 40.degree. C. and 100.degree. C.
[0309] A compound of Formula (I) wherein R.sup.1, R.sup.2, R.sup.4
and R.sup.5 are as defined before, R.sup.3 is C.sub.1-4alkyl or
C.sub.3-8cycloalkyl and Het is pyridinyl can be prepared by
reacting a compound of Formula (Ia) wherein R.sup.1, R.sup.2,
R.sup.4 and R.sup.5 are as defined before, with a boronic acid
derivative of Formula R.sup.3B(OH).sub.2 wherein R.sup.3 is
C.sub.1-4alkyl or C.sub.3-8cycloalkyl, in the presence of a
suitable catalyst, such as tetrakis(triphenylphosphine)palladium
(0) or palladium (II) acetate, in the presence of a suitable
phosphine ligand, such as
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, in the presence of
a suitable base, such as sodium carbonate or potassium phosphate,
in a suitable inert solvent, such as a mixture of 1,4-dioxane and
water or toluene, under suitable reaction conditions, such as
heating at a convenient temperature, either by conventional heating
or under microwave irradiation for a period of time to ensure the
completion of the reaction.
[0310] Alternatively, compounds of Formula (I) wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined before and Het
is pyridinyl, can also be prepared by reacting an intermediate of
Formula (II)
##STR00007##
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined before and halo
represents a bromo or iodo, with a boronic acid derivative of
Formula (III)
##STR00008##
where R.sup.4 and R.sup.5 are as defined before, in the presence of
a suitable catalyst, such as tetrakis(triphenylphosphine)palladium
(0), in the presence of a suitable base, such as sodium carbonate,
in a suitable inert solvent, such as a mixture of 1,4-dioxane and
water, under suitable reaction conditions, such as heating at a
convenient temperature, either by conventional heating or under
microwave irradiation for a period of time to ensure the completion
of the reaction.
[0311] Compounds of Formula (I) wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are as defined before and Het is pyridinyl, can
also be prepared by reacting an intermediate of Formula (II)
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined before and halo
represents a bromo or iodo, with a boronate derivative of Formula
(IV)
##STR00009##
where R.sup.4 and R.sup.5 are as defined before, in the presence of
a suitable catalyst, such as tetrakis(triphenylphosphine)palladium
(0), in the presence of a suitable base, such as sodium carbonate,
in a suitable inert solvent, such as a mixture of 1,4-dioxane and
water, under suitable reaction conditions, such as heating at a
convenient temperature, either by conventional heating or under
microwave irradiation for a period of time to ensure the completion
of the reaction.
[0312] Compounds of Formula (I) wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are as defined before and Het is pyridinyl, can
also be prepared by reacting an intermediate of Formula (V)
##STR00010##
with a halopyridine of Formula (VI)
##STR00011##
where R.sup.4 and R.sup.5 are as defined before and halo is bromo
or iodo, in the presence of a suitable catalyst, such as palladium
(II) acetate, in the presence of a suitable phosphine ligand, such
as butyldi-1-adamantylphosphine, in the presence of a suitable
base, such as potassium phosphate, in a suitable inert solvent,
such as N,N-dimethylformamide or N-methylpyrrolidine, under
suitable reaction conditions, such as heating at a convenient
temperature, either by conventional heating or under microwave
irradiation for a period of time to ensure the completion of the
reaction.
[0313] A compound of Formula (II) wherein R.sup.1, R.sup.2 and
R.sup.3 are as defined before, except when simultaneously R.sup.1
is NR.sup.6R.sup.7, R.sup.2 is trifluoromethyl and R.sup.3 is
chloro, and halo represents a bromo or iodo, can be prepared by
reacting a compound of Formula (V) wherein R.sup.1, R.sup.2 and
R.sup.3 are as defined before, with N-bromo- or N-iodosuccinimide,
in a suitable inert solvent, such as dichloromethane, in the
presence of a suitable acid catalyst, such as acetic acid, under
suitable reaction conditions, such as a convenient temperature,
typically ranging between -10.degree. C. and 40.degree. C.
[0314] A compound of Formula (V) wherein R.sup.1 and R.sup.2 are as
defined before and R.sup.3 is hydrogen, can also be prepared by
reacting a compound of Formula (Va)
##STR00012##
wherein R.sup.1 and R.sup.2 are as defined before, with hydrogen in
the presence of a suitable catalyst, such as 10% palladium on
charcoal, in the presence of a suitable base, such as
triethylamine, in a suitable inert solvent, such as methanol or
ethanol, under suitable reaction conditions, such as a convenient
temperature, typically ranging between 25.degree. C. and 40.degree.
C. or with ammonium formate in the presence of a suitable catalyst
such as 10% palladium on charcoal, in a suitable inert solvent,
such as methanol, ethanol, ethyl acetate or dichloromethane or
mixtures thereof, under suitable reaction conditions, such as
heating at a convenient temperature, typically ranging between
40.degree. C. and 100.degree. C.
[0315] A compound of Formula (V) wherein R.sup.1 and R.sup.2 are as
defined before, and R.sup.3 is C.sub.1-4alkyl or
C.sub.3-8cycloalkyl can be prepared by reacting a compound of
Formula (Va) wherein R.sup.1 and R.sup.2 are as defined before with
a boronic acid derivative of Formula R.sup.3B(OH).sub.2 where
R.sup.3 is C.sub.1-4alkyl or C.sub.3-8cycloalkyl, in the presence
of a suitable catalyst, such as
tetrakis(triphenylphosphine)palladium (0) or palladium (II)
acetate, in the presence of a suitable phosphine ligand, such as
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, in the presence of
a suitable base, such as sodium carbonate or potassium phosphate,
in a suitable inert solvent, such as a mixture of 1,4-dioxane and
water or toluene, under suitable reaction conditions, such as
heating at a convenient temperature, either by conventional heating
or under microwave irradiation for a period of time to ensure the
completion of the reaction.
[0316] A compound of Formula (V) wherein R.sup.1 is pyridinyl,
pyridinyl optionally substituted with halogen, C.sub.1-4alkyl,
trifluoromethyl or C.sub.1-4alkyloxy, R.sup.2 is hydrogen,
C.sub.1-4alkyl, trifluoromethyl or C.sub.3-8cycloalkyl and R.sup.3
is chloro or trifluoromethyl, can be prepared by reacting a
compound of Formula (VII)
##STR00013##
where R.sup.2 is as described before, R.sup.3 is chloro or
trifluoromethyl and halo represents chloro, bromo or iodo, with a
boronic acid derivative of Formula R.sup.1B(OH).sub.2 wherein
R.sup.1 is pyridinyl or pyridinyl optionally substituted with
halogen, C.sub.1-4alkyl, trifluoromethyl or C.sub.1-4alkyloxy, in
the presence of a suitable catalyst, such as
tetrakis(triphenylphosphine)palladium (0), in the presence of a
suitable base, such as sodium carbonate, in a suitable inert
solvent, such as a mixture of 1,4-dioxane and water, under suitable
reaction conditions, such as heating at a convenient temperature,
either by conventional heating or under microwave irradiation for a
period of time to ensure the completion of the reaction.
[0317] A compound of Formula (V) wherein R.sup.1 is
NR.sup.6R.sup.7, R.sup.2 is as described before, R.sup.3 is chloro
or trifluoromethyl and R.sup.6 and R.sup.7 are as defined before,
can be prepared by reacting a compound of Formula (VII) where
R.sup.2 is as described before, R.sup.3 is chloro or
trifluoromethyl and halo represents chloro, bromo or iodo with a
compound of Formula R.sup.6R.sup.7NH wherein R.sup.6 and R.sup.7
are as defined before, in a suitable inert solvent, such as
acetonitrile, under suitable reaction conditions, such as heating
at a convenient temperature, either by conventional heating or
under microwave irradiation for a period of time to ensure the
completion of the reaction.
[0318] Compounds of Formula (V) wherein R.sup.1 is
tetrahydropyranyl, R.sup.2 is as defined before and R.sup.3 is
chloro or trifluoromethyl, can be prepared by reacting a compound
of Formula (VIII)
##STR00014##
wherein R.sup.2 is as defined before and R.sup.3 is chloro or
trifluoromethyl, with hydrogen in the presence of a suitable
catalyst, such as 10% palladium on charcoal, in a suitable inert
solvent, such as methanol or ethanol, under suitable reaction
conditions, such as a convenient temperature, typically ranging
between 25.degree. C. and 40.degree. C. or with ammonium formate in
the presence of a suitable catalyst such as 10% palladium on
charcoal, in a suitable inert solvent, such as methanol, ethanol,
ethyl acetate or dichloromethane or mixtures thereof, under
suitable reaction conditions, such as heating at a convenient
temperature, typically ranging between 40.degree. C. and
100.degree. C.
[0319] A compound of Formula (VIII) where R.sup.2 is as defined
before and R.sup.3 is chloro or trifluoromethyl, can be prepared by
reacting a compound of Formula (VII) where R.sup.2 is as defined
before, R.sup.3 is chloro or trifluoromethyl and halo represents
chloro, bromo or iodo with 3,6-dihydro-2H-pyran-4-boronic acid
pinacol ester, in the presence of a suitable catalyst, such as
tetrakis(triphenylphosphine)palladium (0), in the presence of a
suitable base, such as sodium carbonate, in a suitable inert
solvent, such as a mixture of 1,4-dioxane and water, under suitable
reaction conditions, such as heating at a convenient temperature,
either by conventional heating or under microwave irradiation for a
period of time to ensure the completion of the reaction.
[0320] 3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester can be
obtained by procedures similar to those described in, Qiu, Y. et
al. WO 2004075846 A2.
[0321] A compound of Formula (VIIa)
##STR00015##
where R.sup.2 is hydrogen, C.sub.1-4alkyl, trifluoromethyl or
C.sub.3-8cycloalkyl and R.sup.3 is chloro or trifluoromethyl can be
prepared by reacting an intermediate of Formula (VII) wherein
R.sup.2 is hydrogen, C.sub.1-4alkyl, trifluoromethyl or
C.sub.3-8cycloalkyl, R.sup.3 is chloro or trifluoromethyl and halo
represents chloro or bromo with sodium iodide, in the presence of a
suitable acidic catalyst, such as hydriodic acid, in a suitable
inert solvent, such as acetonitrile, under suitable reaction
conditions, such as heating at a convenient temperature, either by
conventional heating or under microwave irradiation for a period of
time to ensure the completion of the reaction.
[0322] A compound of Formula (VII) where R.sup.2 is hydrogen,
C.sub.1-4alkyl, trifluoromethyl or C.sub.3-8cycloalkyl, R.sup.3 is
chloro or trifluoromethyl and halo represents chloro or bromo, can
be prepared by reacting a compound of Formula (IX)
##STR00016##
wherein R.sup.3 is chloro or trifluoromethyl and halo represents
chloro or bromo, with a compound of Formula (X)
##STR00017##
wherein R.sup.2 is hydrogen, C.sub.1-4alkyl, trifluoromethyl or
C.sub.3-8cycloalkyl and halo.sup.1 represents chloro or bromo,
either neat or in a suitable inert solvent, such as ethanol,
isopropanol or 1,2-dimethoxyethane, under suitable reaction
conditions, such as heating at a convenient temperature either by
conventional heating or under microwave irradiation for a period of
time to ensure the completion of the reaction.
[0323] A compound of Formula (IX) where R.sup.3 is chloro or
trifluoromethyl and halo represents bromo, can be prepared by
reacting an aminopyridazine of Formula (XI)
##STR00018##
with bromine, in the presence of a suitable base, such as sodium
hydrogen carbonate, in a suitable inert solvent, such as methanol,
under suitable reaction conditions, such as a convenient
temperature, typically ranging between -10.degree. C. and
25.degree. C.
[0324] A compound of Formula (IX) where R.sup.3 is chloro or
trifluoromethyl and halo represents chloro, can be obtained from an
aminopyridazine of Formula (XI) by procedures similar to those
described in Dewdney, N. et al. WO 2009077334 A1.
[0325] A compound of Formula (X) wherein R.sup.2 is hydrogen,
C.sub.1-4alkyl, trifluoromethyl or C.sub.3-8cycloalkyl and halo
represents chloro or bromo, can be obtained commercially or can be
prepared by procedures similar to those described in Gaudry, M.;
Marquet, A. Organic Syntheses. 1976, 55.
[0326] A compound of Formula (XI) where R.sup.3 is chloro can be
obtained commercially.
[0327] A compound of Formula (XI) where R.sup.3 is trifluoromethyl
can be obtained by procedures similar to those described in De
Bruyn, M. F. L. et al. WO 2007048779 A1
[0328] A compound of Formula (V) wherein R.sup.1 is
NR.sup.6R.sup.7, R.sup.2 is C.sub.1-4alkyloxy and R.sup.3 is chloro
or trifluoromethyl and R.sup.6 and R.sup.7 are as defined before,
can be prepared by reacting an intermediate of Formula (XII)
##STR00019##
wherein R.sup.1 is NR.sup.6R.sup.7, R.sup.3 is chloro or
trifluoromethyl and R.sup.6 and R.sup.7 are as defined before, with
a reagent of Formula (X) wherein R.sup.2 is C.sub.1-4alkyloxy and
halo.sup.1 represents chloro or bromo, in a suitable inert solvent,
such as methanol, under suitable reaction conditions, such as
heating at a convenient temperature either by conventional heating
or under microwave irradiation for a period of time to ensure the
completion of the reaction.
[0329] Compounds of Formula (XII) wherein R.sup.1 is
NR.sup.6R.sup.7, R.sup.3 is chloro or trifluoromethyl and R.sup.6
and R.sup.7 are as defined before can be prepared by reacting a
compound of Formula (IX) where R.sup.3 is chloro or trifluoromethyl
and halo represents chloro or bromo with a derivative compound of
formula R.sup.6R.sup.7NH wherein R.sup.6 and R.sup.7 are as defined
before, in a suitable inert solvent, such as acetonitrile, under
suitable reaction conditions, such as heating at a convenient
temperature, either by conventional heating or under microwave
irradiation for a period of time to ensure the completion of the
reaction.
[0330] Compounds of Formula (IX) can be obtained as described
before.
[0331] A compound of Formula (II) wherein R.sup.1 is
NR.sup.6R.sup.7, R.sup.2 is trifluoromethyl, R.sup.3 is chloro or
trifluoromethyl, and halo represents a iodo, can be prepared by
reacting a compound of Formula (XIII)
##STR00020##
wherein R.sup.3 is chloro or trifluoromethyl with a compound of
formula R.sup.6R.sup.7NH, where R.sup.6 and R.sup.7 are as defined
before in the presence of a suitable base, such as
N,N-diisopropylethylamine, in a suitable solvent, such as
acetonitrile, under suitable reaction conditions, such as heating
at a convenient temperature, either by conventional heating or
under microwave irradiation for a period of time to ensure the
completion of the reaction.
[0332] A compound of Formula (XIII), where R.sup.3 is chloro or
trifluoromethyl can be prepared by reacting a compound of Formula
(VII) where R.sup.2 is trifluoromethyl, R.sup.3 is chloro or
trifluoromethyl and halo represents a bromo, with
N-iodosuccinimide, in a suitable inert solvent, such as
dichlorometane, in the presence of a suitable acid catalyst, such
as trifluoroacetic acid, under suitable reaction conditions, such
as a convenient temperature, typically ranging between -10.degree.
C. and 60.degree. C.
[0333] A compound of Formula (VII) where R.sup.2 is
trifluoromethyl, R.sup.3 is chloro or trifluoromethyl and halo
represents a bromo, can be obtained as described before.
[0334] A compound of Formula (Ib)
##STR00021##
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as defined
before, R.sup.4 is Alk.sup.1-oxyethyl and Alk.sup.1 is
C.sub.1-4alkyl, can be prepared by reacting a compound of Formula
(XIV)
##STR00022##
where R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as defined before
with an alcohol of Formula Alk.sup.1-OH wherein Alk.sup.1 is
C.sub.1-4alkyl in the presence of a suitable base, such as the
sodium or potassium salt of the corresponding alcohol, in a
suitable solvent, such as the corresponding alcohol, under suitable
reaction conditions, such as heating at a convenient temperature,
either by conventional heating or under microwave irradiation for a
period of time to ensure the completion of the reaction.
[0335] Alternatively, a compound of Formula (Ib) wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.5 are as defined before, R.sup.4 is
Alk.sup.1-oxyethyl and Alk.sup.1 is C.sub.1-4alkyl, can be prepared
by reacting a compound of Formula (XIV), where R.sup.1, R.sup.2,
R.sup.3 and R.sup.5 are as defined before with an alcohol of
Formula Alk.sup.1-OH wherein Alk.sup.1 is C.sub.1-4alkyl, in the
presence of a suitable acid, such as potassium hydrogensulfate, in
a suitable solvent, such as the corresponding alcohol, under
suitable reaction conditions, such as heating at a convenient
temperature, either by conventional heating or under microwave
irradiation for a period of time to ensure the completion of the
reaction.
[0336] An alcohol of Formula Alk.sup.1-OH wherein Alk.sup.1 is
C.sub.1-4alkyl can be obtained commercially or alternatively can
also be obtained by procedures similar to those described in Morel,
P. US 2008102028 A1.
[0337] A compound of Formula (XIV) where R.sup.1, R.sup.2, R.sup.3
and R.sup.5 are as defined before can be prepared by reacting a
compound of Formula (XV)
##STR00023##
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as defined
before, with a compound of Formula (XVI)
##STR00024##
in the presence of a suitable catalyst, such as
tetrakis(triphenylphosphine)palladium (0), in the presence of a
suitable base, such as sodium carbonate, in a suitable inert
solvent, such as a mixture of 1,4-dioxane and water, under suitable
reaction conditions, such as heating at a convenient temperature,
either by conventional heating or under microwave irradiation for a
period of time to ensure the completion of the reaction.
[0338] Vinylboronic acid pinacol ester, of Formula (XVI), can be
obtained commercially.
[0339] A compound of Formula (XV) where R.sup.1, R.sup.2, R.sup.3
and R.sup.5 are as defined before, can be prepared by reacting a
compound of Formula (II) wherein R.sup.1, R.sup.2 and R.sup.3 are
as defined before and halo is bromo or iodo, with a boronic acid
derivative of Formula (XVII)
##STR00025##
where R.sup.5 is as defined before, in the presence of a suitable
catalyst, such as tetrakis(triphenylphosphine)palladium (0), in the
presence of a suitable base, such as sodium carbonate, in a
suitable inert solvent such as a mixture of 1,4-dioxane and water,
under suitable reaction conditions, such as heating at a convenient
temperature, either by conventional heating or under microwave
irradiation for a period of time to ensure the completion of the
reaction.
[0340] Compounds of Formula (II) can be obtained as described
before.
[0341] A boronic acid derivative of Formula (XVII) where R.sup.5 is
as defined before, can be obtained commercially or alternatively
can be prepared by reacting a compound of Formula (XVIII)
##STR00026##
where R.sup.5 is as defined before and halo represents a bromo or
iodo, with triisopropyl borate, in the presence of a suitable base,
such as n-butyllithium in the presence of a suitable diamine such
as N,N,N',N'-tetramethylenediamine, in a suitable inert solvent
such as diethylether, under suitable reaction conditions, such as a
convenient temperature, typically ranging between -78.degree. C.
and 25.degree. C.
[0342] A halopyridine of Formula (XVIII) where R.sup.5 is as
defined before and halo is bromo or iodo, can be obtained
commercially.
[0343] Alternatively, a compound of Formula (XV) where R.sup.1,
R.sup.2, R.sup.3 and R.sup.5 are as defined before, can be prepared
by reacting a compound of Formula (V) wherein R.sup.1, R.sup.2 and
R.sup.3 are as defined before with a halopyridine of Formula
(XVIII), where R.sup.5 is as defined before and halo represents a
bromo or iodo, in the presence of a suitable catalyst, such as
palladium (II) acetate, in the presence of a suitable phosphine
ligand, such as butyldi-1-adamantylphosphine, in the presence of a
suitable base, such as potassium phosphate, in a suitable inert
solvent, such as N,N-dimethylformamide, under suitable reaction
conditions, such as heating at a convenient temperature, either by
conventional heating or under microwave irradiation for a period of
time to ensure the completion of the reaction.
[0344] Compounds of Formula (V) can be obtained as described
before.
[0345] Compounds of Formula (Ic)
##STR00027##
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as defined
before, R.sup.4 is NR.sup.6aR.sup.7a ethyl and R.sup.6a and
R.sup.7a are as defined before, can be prepared by reacting a
compound of Formula (XIV) where R.sup.1, R.sup.2, R.sup.3 and
R.sup.5 are as defined before with a reagent of Formula
R.sup.6aR.sup.7aNH where R.sup.6a and R.sup.7a are as defined
before in the presence of a suitable base, such as sodium
tert-butoxide, in a suitable solvent, such as tetrahydrofuran,
under suitable reaction conditions, such as heating at a convenient
temperature, either by conventional heating or under microwave
irradiation for a period of time to ensure the completion of the
reaction.
[0346] A reagent of Formula R.sup.6R.sup.7NH or R.sup.6aR.sup.7aNH,
wherein R.sup.6, R.sup.6a, R.sup.7 and R.sup.7a are as defined
before, can be obtained commercially.
[0347] Compounds of Formula (I) where R.sup.1, R.sup.2, R.sup.3 and
R.sup.5 are as defined before, R.sup.4 is ethyl and Het is
pyridinyl, can also be prepared by reacting a compound of Formula
(XIV) wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as defined
before, with hydrogen in the presence of a suitable catalyst, such
as 10% palladium on charcoal, in a suitable inert solvent, such as
methanol or ethanol, under suitable reaction conditions, such as a
convenient temperature, typically ranging between 25.degree. C. and
40.degree. C. or with ammonium formate in the presence of a
suitable catalyst such as 10% palladium on charcoal, in a suitable
inert solvent, such as methanol, ethanol, ethyl acetate or
dichloromethane or mixtures thereof, under suitable reaction
conditions, such as heating at a convenient temperature, typically
ranging between 40.degree. C. and 100.degree. C.
[0348] Compounds of Formula (I) wherein R.sup.1, R.sup.2, R.sup.3
and R.sup.5 are as defined before, R.sup.4 is tetrahydropyranyl and
Het is pyridinyl, can also be prepared by reacting a compound of
Formula (XIX)
##STR00028##
where R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as defined before
with hydrogen in the presence of a suitable catalyst such as 10%
palladium on charcoal, in a suitable inert solvent such as
methanol, under suitable reaction conditions, such as a convenient
temperature, typically ranging between 25.degree. C. and 40.degree.
C. or with ammonium formate in the presence of a suitable catalyst
such as 10% palladium on charcoal, in a suitable inert solvent,
such as methanol, ethanol, ethyl acetate or dichloromethane or
mixtures thereof, under suitable reaction conditions, such as
heating at a convenient temperature, typically ranging between
40.degree. C. and 100.degree. C.
[0349] A compound of Formula (XIX) wherein R.sup.1, R.sup.2,
R.sup.3 and R.sup.5 are as defined before, can be prepared by
reacting a compound of Formula (XV) wherein R.sup.1, R.sup.2,
R.sup.3 and R.sup.5 are as defined before, with
3,6-dihydro-2H-pyran-4-boronic acid pinacol ester, in the presence
of a suitable catalyst, such as
tetrakis(triphenylphosphine)palladium (0), in the presence of a
suitable base, such as sodium carbonate, in a suitable inert
solvent, such as a mixture of 1,4-dioxane and water, under suitable
reaction conditions, such as heating at a convenient temperature,
either by conventional heating or under microwave irradiation for a
period of time to ensure the completion of the reaction.
[0350] 3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester can be
obtained as described before.
[0351] A compound of Formula (Id)
##STR00029##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5 are as defined before,
R.sup.4 is a radical of Formula (a), n is as defined before and
Alk.sup.2 is C.sub.1-4alkyl, can be prepared by reacting a compound
of Formula (XX)
##STR00030##
where R.sup.1, R.sup.2, R.sup.3, R.sup.5 and n are as defined
before with a reagent of Formula Alk.sup.2-W wherein Alk.sup.2 is
C.sub.1-4alkyl and W represents a leaving group, such as halo, e.g.
chloro, bromo or iodo, in the presence of a base, such as sodium
tert-butoxide, in the presence of a suitable crown ether, such as
18-crown-6, in a suitable solvent, such as tetrahydrofuran and
under suitable reaction conditions, such as heating at a convenient
temperature, typically ranging from 25.degree. C. to 80.degree.
C.
[0352] A reagent of Formula Alk.sup.2-W where Alk.sup.2 is
C.sub.1-4alkyl and W represents a leaving group, such as halo, e.g.
chloro, bromo or iodo can be obtained commercially.
[0353] Compounds of Formula (I) wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.5 are as defined before and R.sup.4 is NR.sup.6aR.sup.7a and
compounds of formula (XX), as previously defined, can also be
prepared by reacting a compound of Formula (XV) wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.5 are as defined before and the chlorine
atom is ortho to the pyridinyl nitrogen, with a reagent of Formula
R.sup.6aR.sup.7aNH, where R.sup.6a and R.sup.7a are as defined
before, either neat or in a suitable inert solvent, such as
acetonitrile, under suitable reaction conditions, such as heating
at a convenient temperature, either by conventional heating or
under microwave irradiation for a period of time to ensure the
completion of the reaction.
[0354] Alternatively, compounds of Formula (I) wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.5 are as defined before and R.sup.4 is
NR.sup.6aR.sup.7a, can also be prepared by reacting a compound of
Formula (XV) where R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as
defined before with a reagent of Formula R.sup.6aR.sup.7aNH, where
R.sup.6a and R.sup.7a are as defined before, in the presence of a
suitable catalyst, such as palladium (II) acetate, in the presence
of a suitable phosphine ligand, such as
racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and in the
presence of a suitable base, such as cesium carbonate, in a
suitable inert solvent, such as toluene, under suitable reaction
conditions, such as heating at a convenient temperature, either by
conventional heating or under microwave irradiation for a period of
time to ensure the completion of the reaction.
[0355] A reagent of Formula R.sup.6aR.sup.7aNH, where R.sup.6a and
R.sup.7a are as defined before, can be obtained commercially.
[0356] Compounds of Formula (Ie)
##STR00031##
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as defined
before, R.sup.4 is Alk.sup.3oxy and Alk.sup.3 is C.sub.1-4alkyl,
trifluoromethylC.sub.0-4alkyl, C.sub.3-8cycloalkylC.sub.1-4alkyl,
or C.sub.1-4alkyloxyC.sub.1-5alkyl, can be prepared by reacting a
compound of Formula (XV) where R.sup.1, R.sup.2, R.sup.3 and
R.sup.5 are as defined before and the chlorine atom is ortho to the
pyridinyl nitrogen, with a reagent of Formula Alk.sup.3--OH, where
Alk.sup.3 is C.sub.1-4alkyl, trifluoromethylC.sub.0-4alkyl,
C.sub.3-8cycloalkylC.sub.1-4alkyl, or
C.sub.1-4alkyloxyC.sub.1-5alkyl in the presence of a suitable base,
such as sodium hydride, in a suitable inert solvent such as
N,N-dimethylformamide or dimethyl sulfoxide, under suitable
reaction conditions, such as heating at a convenient temperature,
either by conventional heating or under microwave irradiation for a
period of time to ensure the completion of the reaction.
[0357] A reagent of Formula Alk.sup.3--OH wherein C.sub.1-4alkyl,
trifluoromethylC.sub.0-4alkyl, C.sub.3-8cycloalkylC.sub.1-4alkyl or
C.sub.1-4alkyloxyC.sub.1-5alkyl can be obtained commercially or can
be prepared by procedures similar to those described in Morel, P.
US 2008102028 A1.
[0358] Compounds of Formula (I) wherein R.sup.1, R.sup.2, R.sup.3
and R.sup.5 are as defined before, R.sup.4 is C.sub.1-6alkyl and
Het is pyridinyl, can also be prepared by reacting a compound of
Formula (XV) where R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as
defined before and the chlorine atom is ortho to the pyridinyl
nitrogen with a Grignard reagent of Formula R.sup.4Mghalo, where
R.sup.4 is C.sub.1-6alkyl and halo represents a chloro, bromo or
iodo, in the presence of a suitable catalyst, such as
[1,3-bis(diphenylphosphino)propane]dichloronickel (II) or iron
(III) acetylacetonate, in a suitable inert solvent, such as a
tetrahydrofuran or N-methylpyrrolidinone, under suitable reaction
conditions, such as a convenient temperature, typically ranging
between -10.degree. C. and 15.degree. C.
[0359] A Grignard reagent of Formula R.sup.4Mghalo where R.sup.4 is
C.sub.1-6alkyl and halo is chloro, bromo or iodo, can be obtained
commercially.
[0360] Alternatively, compounds of Formula (I) wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.5 are as defined before and R.sup.4 is
C.sub.1-4alkyl or C.sub.3-8cycloalkyl and Het is pyridinyl can also
be prepared by reacting a compound of Formula (XV) where R.sup.1,
R.sup.2, R.sup.3 and R.sup.5 are as defined before with a boronic
acid derivative of Formula R.sup.4B(OH).sub.2, where R.sup.4 is
C.sub.1-4alkyl or C.sub.3-8cycloalkyl, in the presence of a
suitable catalyst, such as palladium (II) acetate, in the presence
of a suitable phosphine ligand, such as
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, in the presence of
a suitable base, such as potassium phosphate, in a suitable inert
solvent, such as toluene, under suitable reaction conditions, such
as heating at a convenient temperature, either by conventional
heating or under microwave irradiation for a period of time to
ensure the completion of the reaction.
[0361] A boronic acid derivative of Formula R.sup.4B(OH).sub.2
where R.sup.4 is C.sub.1-4alkyl or C.sub.3-8cycloalkyl can be
obtained commercially.
[0362] Compounds of Formula (I) wherein R.sup.1, R.sup.2, R.sup.3
and R.sup.5 are as defined before and R.sup.4 is C.sub.1-4alkyl,
C.sub.1-4alkyloxyC.sub.1-5alkyl or trifluoromethylC.sub.0-4alkyl
and Het is pyridinyl, can also be prepared by reacting a compound
of Formula (XV) where R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as
defined before and the chlorine atom is ortho to the pyridinyl
nitrogen with an organozinc reagent of Formula Zn(R.sup.4).sub.2
where R.sup.4 represents a C.sub.1-4alkyl,
C.sub.1-4alkyloxyC.sub.1-5alkyl or trifluoromethylC.sub.0-4alkyl,
in the presence of a suitable catalyst, such as
tetrakis(triphenylphosphine)palladium (0), in a suitable inert
solvent, such as tetrahydrofuran, under suitable reaction
conditions, such as heating at a convenient temperature, either by
conventional heating or under microwave irradiation for a period of
time to ensure the completion of the reaction.
[0363] A reagent of Formula Zn(R.sup.4).sub.2 wherein R.sup.4
represents C.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-5alkyl or
trifluoromethylC.sub.0-4alkyl can be obtained commercially.
Alternatively, a reagent of Formula Zn(R.sup.4).sub.2 wherein
R.sup.4 represents C.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-5alkyl
or trifluoromethylC.sub.0-4alkyl, can be prepared by reacting a
compound of Formula R.sup.4-halo wherein R.sup.4 represents
C.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-5alkyl or
trifluoromethylC.sub.0-4alkyl and halo represents iodo, with zinc
in the presence of 1,2-dibromoethane and chlorotrimethylsilane, in
a suitable inert solvent, such as N,N-dimethylformamide, under
suitable reaction conditions such as heating at a convenient
temperature, typically ranging between 25.degree. C. and
100.degree. C.
[0364] A reagent of R.sup.4-halo wherein R.sup.4 represents
C.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-5alkyl or
trifluoromethylC.sub.0-4alkyl and halo represents iodo can be
obtained commercially or can be prepared by reacting a compound of
Formula halo-R.sup.4 wherein R.sup.4 represents C.sub.1-4alkyl,
C.sub.1-4alkyloxyC.sub.1-5alkyl or trifluoromethylC.sub.0-4alkyl
and halo represents a chloro or bromo with sodium iodide in a
suitable inert solvent, such as acetone, under suitable reaction
conditions such as a convenient temperature, typically ranging
between 25.degree. C. and 40.degree. C.
[0365] A compound of Formula halo-R.sup.4 wherein R.sup.4
represents C.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-5alkyl or
trifluoromethylC.sub.0-4alkyl and halo represents a chloro or
bromo, can be obtained commercially.
[0366] A boronic acid of Formula (III) wherein R.sup.4 and R.sup.5
are as defined before, can be obtained commercially. Alternatively,
a boronic acid of Formula (III) wherein R.sup.4 and R.sup.5 are as
defined before, can be prepared by reacting a halopyridine of
Formula (VI), wherein R.sup.4 and R.sup.5 are as defined before and
halo is bromo or iodo, with triisopropyl borate, in the presence of
a suitable base, such as n-butyllithium, in a suitable inert
solvent, such as tetrahydrofuran, under suitable reaction
conditions, such as a convenient temperature, typically ranging
between -78.degree. C. and -10.degree. C.
[0367] A boronic derivative of Formula (IV) wherein R.sup.4 and
R.sup.5 are as defined before, can be obtained commercially.
Alternatively, a compound of Formula (IV) wherein R.sup.4 and
R.sup.5 are as defined before, can also be prepared by reacting a
halopyridine of Formula (VI), wherein R.sup.4 and R.sup.5 are as
defined before and halo represents a bromo or iodo, with
bis(pinacolato)diboron in the presence of a suitable catalyst, such
as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), in
the presence of a suitable base, such as potassium acetate, in a
suitable inert solvent, such as N,N-dimethylformamide or dimethyl
sulfoxide, under suitable reaction conditions, such as heating at a
convenient temperature, either by conventional heating or under
microwave irradiation for a period of time to ensure the completion
of the reaction.
[0368] A halopyridine of Formula (VI) wherein R.sup.4 and R.sup.5
are as defined before and halo represents a bromo or iodo, can be
obtained commercially. Alternatively, a halopyridine of Formula
(VI) wherein R.sup.5 is as defined before, halo represents a bromo
and R.sup.4 is C.sub.1-6alkyl or C.sub.3-8cycloalkyl can be
prepared by reacting a di-halopyridine of Formula (XXI)
##STR00032##
where R.sup.5 is as defined before, halo.sup.1 represent a bromo
and halo.sup.2 represent a bromo or iodo ortho to the pyridinyl
nitrogen, with a reagent of Formula R.sup.4B(OH).sub.2 where
R.sup.4 represents a C.sub.1-4alkyl or C.sub.3-8cycloalkyl, in the
presence of a suitable catalyst, such as
tetrakis(triphenylphosphine)palladium(0), in a suitable inert
solvent, such as tetrahydrofuran, under suitable reaction
conditions, such as heating at a convenient temperature, either by
conventional heating or under microwave irradiation for a period of
time to ensure the completion of the reaction.
[0369] A boronic acid derivative of Formula R.sup.4B(OH).sub.2
where R.sup.4 is C.sub.1-4alkyl or C.sub.3-8cycloalkyl can be
obtained commercially.
[0370] Alternatively, a halopyridine of Formula (VI) wherein
R.sup.5 is as defined before, halo represents a bromo an R.sup.4 is
C.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-5alkyl or
trifluoromethylC.sub.0-4alkyl can be prepared by reacting a
di-halopyridine of Formula (XXI) where R.sup.5 is as defined before
and halo.sup.1 and halo.sup.2 represent independently a bromo or
iodo and halo.sup.2 is ortho to the pyridinyl nitrogen, with an
organozinc reagent of Formula Zn(R.sup.4).sub.2 where R.sup.4
represents a C.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-5alkyl or
trifluoromethylC.sub.0-4alkyl, in the presence of a suitable
catalyst, such as tetrakis(triphenylphosphine)palladium (0), in a
suitable inert solvent, such as tetrahydrofuran, under suitable
reaction conditions, such as heating at a convenient temperature,
either by conventional heating or under microwave irradiation for a
period of time to ensure the completion of the reaction.
[0371] A reagent of Formula Zn(R.sup.4).sub.2 wherein R.sup.4
represents C.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-5alkyl or
trifluoromethylC.sub.0-4alkyl can be obtained as described
before.
[0372] Compounds of Formula (VIa)
##STR00033##
wherein R.sup.5 is as defined before, Alk.sup.4 represents a
C.sub.1-4alkyl and Alk.sup.5 represents a C.sub.1-4alkyl, can be
prepared by reacting a compound of Formula (VIb)
##STR00034##
wherein R.sup.5 is as defined before and Alk.sup.4 represents a
C.sub.1-4alkyl, with a reagent of Formula Alk.sup.5.sub.2SO.sub.4
where Alk.sup.5 represents a C.sub.1-4alkyl, in the presence of a
suitable base, such as sodium hydride, in a suitable inert solvent,
such as tetrahydrofuran, under suitable reaction conditions, such
as a convenient temperature, typically ranging between -10.degree.
C. and 40.degree. C. or with a reagent of Formula Alk.sup.5-W
wherein Alk.sup.5 represents a C.sub.1-4alkyl and W represents a
leaving group, such as halo, e.g. chloro, bromo or iodo, or a
sulfonyloxy group, e.g. methylsulfonyloxy,
trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy, in the
presence of a base, such as sodium hydride or sodium tert-butoxide,
in the presence of a suitable crown ether, such as 18-crown-6, in a
suitable solvent, such as tetrahydrofuran and under suitable
reaction conditions, such as a convenient temperature, typically
ranging from 0.degree. C. to 40.degree. C.
[0373] Reagents of Formula Alk.sup.5.sub.2SO.sub.4 and Alk.sup.5-W
wherein Alk.sup.5 represents a C.sub.1-4alkyl and W represents a
leaving group, such as halo, e.g. chloro, bromo or iodo, or a
sulfonyloxy group, e.g. methylsulfonyloxy,
trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy, can be
obtained commercially.
[0374] A compound of Formula (VIc)
##STR00035##
wherein R.sup.5 is as defined before, can be prepared by reacting a
methylpyridine of Formula (VId)
##STR00036##
wherein R.sup.5 is as defined before and the methyl group is ortho
to the pyridinyl nitrogen with N,N-dimethylformamide in the
presence of a suitable base, such as lithium diisopropylamide, in a
suitable inert solvent, such as tetrahydrofuran, under suitable
reaction conditions, such as a convenient temperature, typically
ranging between -78.degree. C. and -10.degree. C., followed by
treatment with sodium borohydride in a suitable solvent, such as
methanol, under suitable reaction conditions, such as a convenient
temperature, typically ranging between -10.degree. C. and
40.degree. C.
[0375] A compound of Formula (VIe)
##STR00037##
wherein R.sup.5 is as defined before, can be prepared by reacting a
methylpyridine of Formula (VId), wherein R.sup.5 is as defined
before and the methyl group is ortho to the pyridinyl nitrogen with
acetone in the presence of a suitable base, such as lithium
diisopropylamide, in a suitable inert solvent, such as
tetrahydrofuran, under suitable reaction conditions, such as a
convenient temperature, typically ranging between -78.degree. C.
and -10.degree. C.
[0376] A methylpyridine of Formula (VId) wherein R.sup.5 is as
defined before, can be obtained commercially.
[0377] A compound of Formula (VIf)
##STR00038##
wherein R.sup.5 is as defined before, can be prepared by reacting a
di-halopyridine of Formula (XXI) where R.sup.5 is as defined
before, halo.sup.1 represents a bromo and halo.sup.2 represents a
bromo ortho to the pyridinyl nitrogen, with acetone, in the
presence of a suitable base, such as n-buthyllithium, in a suitable
inert solvent, such as toluene, under suitable reaction conditions,
such as a convenient temperature, typically ranging between
-78.degree. C. and 25.degree. C.
[0378] A di-halopyridine of Formula (XXI) where R.sup.5 is as
defined before, halo.sup.1 is a bromo and halo.sup.2 represents
bromo can be obtained commercially.
[0379] A compound of Formula (VIg)
##STR00039##
wherein R.sup.5 is as defined before, can be prepared by reacting a
compound of Formula (XXII)
##STR00040##
wherein R.sup.5 is as defined before, with sodium borohydride, in a
suitable inert solvent, such as dichloromethane, under suitable
reaction conditions, such as a convenient temperature, typically
ranging between -10.degree. C. and 40.degree. C.
[0380] A compound of Formula (XXII) wherein R.sup.5 is as defined
before and halo represents bromo, can be prepared by reacting a
compound of Formula (XXIII)
##STR00041##
wherein R.sup.5 is as defined before, with diisobutylaluminium
hydride, in a suitable inert solvent, such as dichloromethane,
under suitable reaction conditions, such as a convenient
temperature, typically ranging between -10.degree. C. and
40.degree. C.
[0381] A compound of Formula (XXIII) wherein R.sup.5 is as defined
before, can be prepared by reacting a compound of Formula
(XXIV)
##STR00042##
wherein R.sup.5 is as defined before, with a suitable alkylating
reagent such as iodomethane, in the presence of a base, such as
sodium tert-butoxide, in the presence of a suitable crown ether,
such as 18-crown-6, in a suitable solvent, such as tetrahydrofuran
and under suitable reaction conditions, such as a convenient
temperature, typically ranging between 0.degree. C. and 40.degree.
C.
[0382] A compound of Formula (XXIV) wherein R.sup.5 is as defined
before, can be obtained commercially or alternatively, can also be
obtained by reacting a compound of Formula (XXV)
##STR00043##
wherein R.sup.5 is as defined before, with potassium cyanide, in
the presence of a suitable inorganic salt, such as potassium
iodide, in a suitable solvent, such as a mixture of ethanol and
water and under suitable reaction conditions, such as heating at a
convenient temperature, typically ranging from 25.degree. C. to
100.degree. C.
[0383] A compound of Formula (XXV) wherein R.sup.5 is as defined
before, can be obtained commercially or alternatively, can also be
obtained by reacting a compound Formula (XXVI)
##STR00044##
wherein R.sup.5 is as defined before, with thionyl chloride, in a
suitable solvent, such as dichoromethane and under suitable
reaction conditions, such as a convenient temperature, typically
ranging from -10.degree. C. to 25.degree. C.
[0384] A compound of Formula (XXVI) wherein R.sup.5 is as defined
before can be obtained commercially.
[0385] Compounds of Formula (VIh)
##STR00045##
wherein R.sup.5 is as defined before, can be prepared by reacting
an amino pyridine of Formula (XXVII)
##STR00046##
where R.sup.5 is as defined before, with sodium nitrite in the
presence of a suitable inorganic salt, such as copper (I) bromide
and a suitable inorganic acid, such as hydrobromic acid, in a
suitable inert solvent, such as water, under suitable reaction
conditions, such as a convenient temperature, typically ranging
between -10.degree. C. and 25.degree. C.
[0386] An aminopyridine of Formula (XXVII) where R.sup.5 is as
defined before, can be prepared by reacting a nitropyridine of
Formula (XXVIII)
##STR00047##
where R.sup.5 is as defined before, with hydrogen in the presence
of a suitable catalyst, such as 10% palladium on charcoal, in a
suitable inert solvent, such as methanol or ethanol, under suitable
reaction conditions, such as heating at a convenient temperature,
typically ranging between 25.degree. C. and 40.degree. C.
[0387] A nitropyridine of Formula (XXVIII) where R.sup.5 is as
defined before, can be prepared by reacting an halonitropyridine of
Formula (XXIX)
##STR00048##
where R.sup.5 is as defined before and halo represents a chloro,
bromo or iodo, with 3,6-dihydro-2H-pyran-4-boronic acid pinacol
ester in the presence of a suitable catalyst, such as
tetrakis(triphenylphosphine)palladium(0), in the presence of a
suitable base, such as sodium carbonate, in a suitable inert
solvent, such as a mixture of 1,4-dioxane and water, under suitable
reaction conditions, such as heating at a convenient temperature,
either by conventional heating or under microwave irradiation for a
period of time to ensure the completion of the reaction.
[0388] A halonitropyridine of Formula (XXIX) where R.sup.5 is as
defined before and halo represents a chloro, bromo or iodo can be
obtained commercially.
[0389] 3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester can be
obtained as described before.
[0390] Compounds of Formula (VIi)
##STR00049##
wherein R.sup.5 is as defined before and Alk.sup.6 is
C.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-5alkyl or
C.sub.3-8cycloalkylC.sub.1-4alkyl and halo is a bromo or iodo, can
be prepared by reacting a di-halopyridine of Formula (XVIII) where
R.sup.5 is as defined before, halo represents a bromo or iodo and
the chlorine atom is ortho to the pyridinyl nitrogen with a reagent
of Formula Alk.sup.6--OH, where Alk.sup.6 is C.sub.1-4alkyl,
C.sub.1-4alkyloxyC.sub.1-5alkyl or
C.sub.3-8cycloalkylC.sub.1-4alkyl in the presence of a suitable
base, such as sodium hydride, in a suitable inert solvent, such as
N,N-dimethylformamide or dimethyl sulfoxide, under suitable
reaction conditions, such as heating at a convenient temperature,
either by conventional heating or under microwave irradiation for a
period of time to ensure the completion of the reaction.
[0391] A di-halo pyridine of Formula (XVIII) where R.sup.5 is as
defined before, halo represents a bromo or iodo, can be obtained
commercially.
[0392] A reagent of Formula Alk.sup.6--OH wherein Alk.sup.6 is
C.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-5alkyl or
C.sub.3-8cycloalkylC.sub.1-4alkyl, can be obtained commercially or
alternatively can also be obtained by procedures similar to those
described in Morel, P. US 2008102028 A1.
[0393] Compounds of Formula (VIj)
##STR00050##
wherein R.sup.5, R.sup.6a and R.sup.7a are as defined before and
halo represents bromo or iodo, can also be prepared by reacting a
di-halo pyridine of Formula (XVIII) where R.sup.5 is as defined
before, and halo represents a bromo or iodo and the chlorine atom
is ortho to the pyridinyl nitrogen with a compound of formula
R.sup.6aR.sup.7aNH, wherein R.sup.6a and R.sup.7a are as defined
before, either neat or in a suitable inert solvent, such as
acetonitrile, under suitable reaction conditions, such as heating
at a convenient temperature, either by conventional heating or
under microwave irradiation for a period of time to ensure the
completion of the reaction.
[0394] A reagent of Formula R.sup.6aR.sup.7aNH, wherein R.sup.6a
and R.sup.7a are as defined before, can be obtained
commercially.
[0395] A di-halo pyridine of Formula (XVIII) where R.sup.5 is as
defined before, halo represents a bromo or iodo, can be obtained
commercially.
[0396] A compound of Formula (I) wherein R.sup.1, R.sup.2, R.sup.4
and R.sup.5 are as defined before, R.sup.3 is hydrogen, Het is
pyrazolyl and R.sup.4 is attached to the nitrogen atom of the
pyrazole can be prepared by reacting a compound of Formula (If)
##STR00051##
wherein R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are as defined
before, with hydrogen in the presence of a suitable catalyst, such
as 10% palladium on charcoal, in a suitable inert solvent, such as
methanol or ethanol, under suitable reaction conditions, such as a
convenient temperature, typically ranging between 25.degree. C. and
40.degree. C. or with ammonium formate in the presence of a
suitable catalyst such as 10% palladium on charcoal, in a suitable
inert solvent, such as methanol, ethanol, ethyl acetate or
dichloromethane or mixtures thereof, under suitable reaction
conditions, such as heating at a convenient temperature, typically
ranging between 40.degree. C. and 100.degree. C.
[0397] Compounds of Formula (I) wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are as defined before, Het is pyrazolyl and
R.sup.4 is attached to the nitrogen atom of the pyrazole can be
prepared by reacting a compound of Formula (II) where R.sup.1,
R.sup.2 and R.sup.3 are as defined before and halo represents a
bromo or iodo, with a boronate of Formula (XXX)
##STR00052##
where R.sup.4 and R.sup.5 are as defined before, in the presence of
a suitable catalyst, such as tetrakis(triphenylphosphine)palladium
(0), in the presence of a suitable base, such as sodium carbonate,
in a suitable inert solvent such as a mixture of 1,4-dioxane and
water, under suitable reaction conditions, such as heating at a
convenient temperature, either by conventional heating or under
microwave irradiation for a period of time to ensure the completion
of the reaction.
[0398] A compound of Formula (XXX) wherein R.sup.4 and R.sup.5 are
as defined before and R.sup.4 is attached to the nitrogen atom of
the pyrazole, can be obtained commercially or alternatively, can be
prepared by reacting a compound of Formula (XXXI)
##STR00053##
wherein R.sup.5 is as defined before, with a reagent of Formula
R.sup.4--W wherein R.sup.4 is as defined before and W represents a
leaving group, such as halo, e.g. chloro, bromo or iodo, or a
sulfonyloxy group, e.g. methylsulfonyloxy,
trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy in the
presence of a base such as cesium carbonate or
diisopropylethylamine, in a suitable solvent, such as
N,N-dimethylformamide or acetonitrile and under suitable reaction
conditions, such as heating at a convenient temperature, either by
conventional heating or under microwave irradiation for a period of
time to ensure the completion of the reaction.
[0399] Compounds of Formula R.sup.4--W wherein R.sup.4 is as
defined before and W represents a leaving group, such as halo, e.g.
chloro, bromo or iodo, can be obtained commercially. Compounds of
formula R.sup.4--W wherein R.sup.4 is as defined before and W
represents a leaving group, such as a sulfonyloxy group, e.g.
methylsulfonyloxy, trifluoromethylsulfonyloxy, or
methylphenylsulfonyloxy can be prepared by reacting a compound of
Formula R.sup.4--OH with a sulfonyl chloride, e.g. methylsulfonyl
chloride, trifluoromethylsulfonyl chloride, or methylphenylsulfonyl
chloride in the presence of a suitable base, such as pyridine or
diisopropylethylamine, in a suitable solvent, such as
dichloromethane and under suitable reaction conditions, such as a
convenient temperature, typically ranging from -10.degree. C. to
25.degree. C.
[0400] Compounds of Formula R.sup.4--OH wherein R.sup.4 is as
defined before, can be obtained commercially.
[0401] Compounds of Formula (XXX) wherein R.sup.4 and R.sup.5 are
as defined before and R.sup.4 is attached to the nitrogen atom of
the pyrazole, can also be prepared by reacting a compound of
Formula (XXXII)
##STR00054##
wherein R.sup.4 and R.sup.5 are as defined before, with
bis(pinacolato)diboron in the presence of a suitable catalyst, such
as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), in
the presence of a suitable base, such as potassium acetate, in a
suitable inert solvent, such as N,N-dimethylformamide or dimethyl
sulfoxide, under suitable reaction conditions, such as heating at a
convenient temperature, either by conventional heating or under
microwave irradiation for a period of time to ensure the completion
of the reaction.
[0402] Compounds of Formula (XXXII) wherein R.sup.4 and R.sup.5 are
as defined before and R.sup.4 is attached to the nitrogen atom of
the pyrazole, can be prepared by reacting a 4-iodo-1H-pyrazole of
Formula (XXXIII)
##STR00055##
wherein R.sup.5 is as defined before, with a reagent of Formula
R.sup.4--W wherein R.sup.4 is as defined before and W represents a
leaving group such as halo, e.g. chloro, bromo or iodo, or a
sulfonyloxy group, e.g. methylsulfonyloxy,
trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy in the
presence of a suitable base, such as cesium carbonate or
diisopropylethylamine, in a suitable solvent, such as
N,N-dimethylformamide or acetonitrile and under suitable reaction
conditions, such as heating at a convenient temperature, either by
conventional heating or under microwave irradiation for a period of
time to ensure the completion of the reaction.
[0403] A 4-iodo-1H-pyrazole of Formula (XXXIII) where R.sup.5 is as
defined before, can be obtained commercially.
[0404] Compounds of Formula R.sup.4--W wherein R.sup.4 is as
defined before and W represents a leaving group such as halo, e.g.
chloro, bromo or iodo, can be obtained commercially.
[0405] Alternatively, compounds of formula R.sup.4--W wherein
R.sup.4 is as defined before and W represents a leaving group such
as a sulfonyloxy group, e.g. methylsulfonyloxy,
trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy can be
prepared by reacting a compound of formula R.sup.4--OH with a
sulfonyl chloride, e.g. methylsulfonyl chloride,
trifluoromethylsulfonyl chloride, or methylphenylsulfonyl chloride
in the presence of a suitable base such, as pyridine or
diisopropylethylamine, in a suitable solvent, such as
dichloromethane and under suitable reaction conditions, such as a
convenient temperature, typically ranging from -10.degree. C. to
25.degree. C.
[0406] Compounds of Formula R.sup.4--OH wherein R.sup.4 is as
defined before, can be obtained commercially.
[0407] A compound of Formula (XXXIIa)
##STR00056##
wherein R.sup.5 is as defined before and Alk.sup.7 represents
C.sub.1-4alkyl or C.sub.3-8cycloalkyl groups can be prepared by
reacting a compound of Formula (XXXIIb).
##STR00057##
wherein R.sup.5 is as defined before and Alk.sup.7 represents
C.sub.1-4alkyl or C.sub.3-8cycloalkyl groups with
(diethylamino)sulphur trifluoride in a suitable inert solvent, such
as dichloromethane, and under suitable reaction conditions, such as
convenient temperatures, typically ranging from 0.degree. C. to
25.degree. C.
[0408] A compound of Formula (XXXIIb), wherein Alk.sup.7 represents
a C.sub.1-4alkyl or C.sub.3-8cycloalkyl group can be prepared by
reacting a 4-iodo-1H-pyrazole of Formula (XXXIII) with an alpha
bromoketone of Formula (XXXV)
##STR00058##
wherein Alk.sup.7 represents a C.sub.1-4alkyl or a
C.sub.3-8cycloalkyl group, in the presence of a suitable base, such
as cesium carbonate, in a suitable inert solvent, such as
acetonitrile, under suitable reaction conditions, such as heating
at a convenient temperature, either by conventional heating or
under microwave irradiation for a period of time to ensure the
completion of the reaction.
[0409] An alpha bromoketone of Formula (XXXV) wherein Alk.sup.7 is
C.sub.1-4alkyl or C.sub.3-8cycloalkyl, can be obtained commercially
or alternatively can be obtained by procedures similar to those
described in Carverley, M. J. Tetrahedron, 1987, 43(20),
4609-19.
[0410] A compound of Formula (XXXIIc)
##STR00059##
wherein R.sup.5 is as defined before, Alk.sup.8 represents
C.sub.1-4alkyl and Alk.sup.9 represents C.sub.1-4alkyl, can be
prepared by reacting a compound of Formula (XXXVI)
##STR00060##
where R.sup.5 is as defined before and Alk.sup.8 represents
C.sub.1-4alkyl with a reagent of Formula Alk.sup.9-W wherein
Alk.sup.9 is C.sub.1-4alkyl, and W represents a leaving group such
as halo, e.g. chloro, bromo or iodo, or a sulfonyloxy group, e.g.
methylsulfonyloxy, trifluoromethylsulfonyloxy, or
methylphenylsulfonyloxy, in the presence of a suitable base, such
as sodium hydride, in a suitable solvent such as tetrahydrofuran
and under suitable reaction conditions, such as a convenient
temperature, typically ranging from 0.degree. C. to 40.degree.
C.
[0411] A reagent of Formula Alk.sup.9-W wherein Alk.sup.9 is
C.sub.1-4alkyl and W represents a leaving group such as halo, e.g.
chloro, bromo or iodo, or a sulfonyloxy group, e.g.
methylsulfonyloxy, trifluoromethylsulfonyloxy, or
methylphenylsulfonyloxy, can be obtained commercially.
[0412] A compound of Formula (XXXVI) wherein R.sup.5 is as defined
before, can be prepared by reacting a 4-iodo-1H-pyrazole of Formula
(XXXIII)
where R.sup.5 is as defined before, with a reagent of Formula
W-Alk.sup.8--OH, wherein W represents a leaving group such as halo,
e.g. chloro, bromo or iodo, or a sulfonyloxy group, e.g.
methylsulfonyloxy, trifluoromethylsulfonyloxy, or
methylphenylsulfonyloxy and Alk.sup.8 represents a C.sub.1-4alkyl,
in the presence of a suitable base, such as cesium carbonate, in a
suitable inert solvent, such as N,N-dimethylformamide, under
suitable reaction conditions, such as heating at a convenient
temperature, either by conventional heating or under microwave
irradiation for a period of time to ensure the completion of the
reaction.
[0413] A reagent of Formula W-Alk.sup.8-OH wherein W represents a
leaving group such as halo, e.g. chloro, bromo or iodo, or a
sulfonyloxy group, e.g. methylsulfonyloxy,
trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy and
Alk.sup.8 represents C.sub.1-4alkyl or C.sub.3-8cycloalkyl, can be
obtained commercially.
[0414] In order to obtain the acid addition salt forms of the
compounds according to the invention, for example the HCl salt
forms unless otherwise described, several procedures known to those
skilled in the art can be used. In a typical procedure, for
example, the free base can be dissolved in isopropanol,
diisopropylether, diethyl ether and/or dichloromethane and
subsequently, 1 to 2 equivalents of the appropriate acid, for
example a 6N HCl solution in 2-propanol or a 2N HCl solution in
diethyl ether, can be added dropwise. The mixture typically is
stirred for 10 min or longer after which the product can be
filtered off. The HCl salt is usually dried in vacuo.
[0415] It will be appreciated by those skilled in the art that in
the processes described above the functional groups of intermediate
compounds may need to be blocked by protecting groups. In case the
functional groups of intermediate compounds were blocked by
protecting groups, they can be deprotected after a reaction
step.
Pharmacology
[0416] The compounds according to the invention inhibit PDE10
enzyme activity, in particular PDE10A enzyme activity and hence
raise the levels of cAMP or cGMP within cells that express PDE10.
Accordingly, inhibition of PDE10 enzyme activity may be useful in
the treatment of diseases caused by deficient amounts of cAMP or
cGMP in cells. PDE10 inhibitors may also be of benefit in cases in
which raising the amount of cAMP or cGMP above normal levels
results in a therapeutic effect. Inhibitors of PDE10 may be used to
treat disorders of the peripheral and central nervous system,
cardiovascular diseases, cancer, gastro-enterological diseases,
endocrinological or metabolic diseases and urological diseases.
[0417] Hence, the present invention relates to a compound according
to the present invention for use as a medicine, as well as to the
use of a compound according to the invention or a pharmaceutical
composition according to the invention for the manufacture of a
medicament. The present invention also relates to a compound
according to the present invention or a pharmaceutical composition
according to the invention for use in the treatment or prevention
of, in particular treatment of, a condition in a mammal, including
a human, the treatment or prevention of which is affected or
facilitated by the inhibition of phosphodiesterase 10 enzyme. The
present invention also relates to the use of a compound according
to the present invention or a pharmaceutical composition according
to the invention for the manufacture of a medicament for the
treatment or prevention of, in particular treatment of, a condition
in a mammal, including a human, the treatment or prevention of
which is affected or facilitated by the inhibition of
phosphodiesterase 10 enzyme.
[0418] The present invention also relates to a compound according
to the invention, or a pharmaceutical composition according to the
invention for use in the treatment, prevention, amelioration,
control or reduction of the risk of various neurological,
psychiatric and metabolic disorders associated with
phosphodiesterase 10 dysfunction in a mammal, including a human,
the treatment or prevention of which is affected or facilitated by
the inhibition of phosphodiesterase 10.
[0419] Also, the present invention relates to the use of a compound
according to the invention or a pharmaceutical composition
according to the invention for the manufacture of a medicament for
treating, preventing, ameliorating, controlling or reducing the
risk of various neurological and psychiatric disorders associated
with phosphodiesterase 10 dysfunction in a mammal, including a
human, the treatment or prevention of which is affected or
facilitated by the inhibition of phosphodiesterase 10.
[0420] Where the invention is said to relate to the use of a
compound or composition according to the invention for the
manufacture of a medicament for e.g. the treatment of a mammal, it
is understood that such use is to be interpreted in certain
jurisdictions as a method of e.g. treatment of a mammal, comprising
administering to a mammal in need of such e.g. treatment, an
effective amount of a compound or composition according to the
invention.
[0421] In particular, the indications that may be treated with
PDE10 inhibitors, either alone or in combination with other drugs,
include, but are not limited to, those diseases thought to be
mediated in part by the basal ganglia, prefrontal cortex and
hippocampus.
[0422] These indications include neurological and psychiatric
disorders selected from psychotic disorders and conditions; anxiety
disorders; movement disorders; drug abuse; mood disorders;
neurodegenerative disorders; disorders or conditions comprising as
a symptom a deficiency in attention and/or cognition; pain and
metabolic disorders.
[0423] In particular, the psychotic disorders and conditions
associated with PDE10 dysfunction include one or more of the
following conditions or diseases: schizophrenia, for example of the
paranoid, disorganized, catatonic, undifferentiated or residual
type; schizophreniform disorder; schizoaffective disorder, such as
delusional or depressive type; delusional disorder;
substance-induced psychotic disorder such as psychosis induced by
alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants,
opioids, or phencyclidine; personality disorders of the paranoid
type; and personality disorder of the schizoid type.
[0424] In particular, the anxiety disorders include panic disorder;
agoraphobia; specific phobia; social phobia; obsessive-compulsive
disorder; post-traumatic stress disorder; acute stress disorder;
and generalized anxiety disorder.
[0425] In particular, movement disorders include Huntington's
disease and dyskinesia; Parkinson's disease; restless leg syndrome
and essential tremor. Additionally, Tourette's syndrome and other
tic disorders can be included.
[0426] In particular, the central nervous system disorder is a
substance-related disorder selected from the group of alcohol
abuse; alcohol dependence; alcohol withdrawal; alcohol withdrawal
delirium; alcohol-induced psychotic disorder; amphetamine
dependence; amphetamine withdrawal; cocaine dependence; cocaine
withdrawal; nicotine dependence; nicotine withdrawal; opioid
dependence and opioid withdrawal.
[0427] In particular, mood disorders and mood episodes include
depression, mania and bipolar disorders. Preferably, the mood
disorder is selected from the group of bipolar disorders (I and
II); cyclothymic disorder; depression; dysthymic disorder; major
depressive disorder and substance-induced mood disorder.
[0428] In particular, neurodegenerative disorders include
Parkinson's disease; Huntington's disease; dementia such as for
example Alzheimer's disease; multi-infarct dementia; AIDS-related
dementia or fronto temperal dementia. The neurodegenerative
disorder or condition comprises neurodegeneration of striatal
medium spiny neurons.
[0429] In particular, disorders or conditions comprising as a
symptom a deficiency in attention and/or cognition include
dementia, such as Alzheimer's disease; multi-infarct dementia;
alcoholic dementia or drug-related dementia; dementia associated
with intracranial tumours or cerebral trauma; dementia associated
with Huntington's disease; dementia associated with Parkinson's
disease; AIDS-related dementia; other diseases include delirium;
amnestic disorder; post-traumatic stress disorder; mental
retardation; a learning disorder; attention-deficit/hyperactivity
disorder (ADHD); and age-related cognitive impairment.
[0430] In particular, pain includes acute and chronic states,
severe pain, intractable pain, neuropathic pain and post-traumatic
pain.
[0431] In particular, metabolic disorders include diabetes, in
particular type 1 or type 2 diabetes, and related disorders such as
obesity. Additional related disorders include syndrome X, impaired
glucose tolerance, impaired fasting glucose, gestational diabetes,
maturity-onset diabetes of the young (MODY), latent autoimmune
diabetes adult (LADA), associated diabetic dyslipidemia,
hyperglycemia, hyperinsulinemia, dyslipidemia,
hypertriglyceridemia, and insulin resistance.
[0432] Additionally, the growth of some cancer cells is inhibited
by cAMP and cGMP, the compounds of the invention may be useful in
the treatment of cancer, such as renal carcinoma and breast
cancer.
[0433] Preferably, the psychotic disorder is selected from the
group of schizophrenia, delusional disorder, schizoaffective
disorder, schizophreniform disorder and substance-induced psychotic
disorder.
[0434] Preferably, the central nervous system disorder is a
personality disorder selected from the group of
obsessive-compulsive personality disorder and schizoid, schizotypal
disorder.
[0435] Preferably, the central nervous system disorder is a mood
disorder selected from the group of bipolar disorders (I & II),
cyclothymic disorder, depression, dysthymic disorder, major
depressive disorder and substance-induced mood disorder.
[0436] Preferably, the central nervous system disorder is
attention-deficit/hyperactivity disorder.
[0437] Preferably, the central nervous system disorder is a
cognitive disorder selected from the group of delirium,
substance-induced persisting delirium, dementia, dementia due to
HIV disease, dementia due to Huntington's disease, dementia due to
Parkinson's disease, dementia of the Alzheimer's type,
substance-induced persisting dementia and mild cognitive
impairment.
[0438] Preferably the disorders treated by the compounds of the
present invention are selected from schizophrenia;
obsessive-compulsive disorder; generalized anxiety disorder;
Huntington's disease; dyskinesia; Parkinson's disease; depression;
bipolar disorders; dementia such as Alzheimer's disease;
attention-deficit/hyperactivity disorder; drug abuse; pain;
diabetes and obesity.
[0439] Preferably, the disorders treated by the compounds of the
present invention are schizophrenia, including positive and
negative symptoms thereof, and cognitive deficits, such as impaired
attention or memory.
[0440] Of the disorders mentioned above, the treatment of anxiety,
obsessive-compulsive disorder, schizophrenia, depression,
attention-deficit/hyperactivity disorder, Alzheimer's disease and
diabetes are of particular importance.
[0441] At present, the fourth edition of the Diagnostic &
Statistical Manual of Mental Disorders (DSM-IV) of the American
Psychiatric Association provides a diagnostic tool for the
identification of the disorders described herein. The person
skilled in the art will recognize that alternative nomenclatures,
nosologies, and classification systems for neurological and
psychiatric disorders described herein exist, and that these evolve
with medical and scientific progresses.
[0442] Therefore, the invention also relates to a compound
according to the invention, for use in the treatment of any one of
the diseases mentioned hereinbefore.
[0443] The invention also relates to a compound according to the
invention for use in treating any one of the diseases mentioned
hereinbefore.
[0444] The invention also relates to a compound according to the
invention, for the treatment or prevention, in particular
treatment, of any one of the diseases mentioned hereinbefore.
[0445] The invention also relates to the use of a compound
according to the invention, for the manufacture of a medicament for
the treatment or prevention of any one of the disease conditions
mentioned hereinbefore.
[0446] The invention also relates to the use of a compound
according to the invention for the manufacture of a medicament for
the treatment of any one of the disease conditions mentioned
hereinbefore.
[0447] The compounds of the present invention can be administered
to mammals, preferably humans, for the treatment or prevention of
any one of the diseases mentioned hereinbefore.
[0448] In view of the utility of the compounds according to the
invention, there is provided a method of treating warm-blooded
animals, including humans, suffering from any one of the diseases
mentioned hereinbefore, and a method of preventing in warm-blooded
animals, including humans, any one of the diseases mentioned
hereinbefore.
[0449] Said methods comprise the administration, i.e. the systemic
or topical administration, preferably oral administration, of a
therapeutically effective amount of a compound according to the
invention to warm-blooded animals, including humans.
[0450] Therefore, the invention also relates to a method for the
prevention and/or treatment of any one of the diseases mentioned
hereinbefore comprising administering a therapeutically effective
amount of compound according to the invention to a patient in need
thereof.
[0451] The PDE10 inhibitors described herein can be used alone, in
combination or in combination with other pharmaceutical agents such
as other agents used in the treatment of psychoses, such as
schizophrenia and bipolar disorder, obsessive-compulsive disorder,
Parkinson's disease, cognitive impairment and/or memory loss, e.g.
nicotinic .alpha.-7 agonists, PDE4 inhibitors, other PDE10
inhibitors, calcium channel blockers, muscarinic m1 and m2
modulators, adenosine receptor modulators, ampakines, NMDA-R
modulators, mGluR modulators, dopamine modulators, serotonin
modulators, cannabinoid modulators, and cholinesterase inhibitors
(e.g. donepezil, rivastigmine, and galantamine). In such
combinations, the compounds of the present invention may be
utilized in combination with one or more other drugs in the
treatment, prevention, control, amelioration, or reduction of risk
of diseases or conditions for which compounds of Formula (I) or the
other drugs may have utility, where the combination of the drugs
together are safer or more effective than either drug alone.
[0452] One skilled in the art will recognize that a therapeutically
effective amount of the PDE10 inhibitors of the present invention
is the amount sufficient to inhibit the PDE10 enzyme and that this
amount varies inter alia, depending on the type of disease, the
concentration of the compound in the therapeutic formulation, and
the condition of the patient. Generally, an amount of PDE10
inhibitor to be administered as a therapeutic agent for treating
diseases in which inhibition of the PDE10 enzyme is beneficial,
such as the disorders described herein, will be determined on a
case by case by an attending physician.
[0453] Generally, a suitable dose is one that results in a
concentration of the PDE10 inhibitor at the treatment site in the
range of 0.5 nM to 200 .mu.M, and more usually 5 nM to 50 .mu.M. To
obtain these treatment concentrations, a patient in need of
treatment likely will be administered between 0.001 mg/kg to 15
mg/kg body weight, in particular from 0.01 mg/kg to 2.50 mg/kg body
weight, in particular, from 0.01 to 1.5 mg/kg body weight, in
particular from 0.1 mg/kg to 0.50 mg/kg body weight. The amount of
a compound according to the present invention, also referred to
here as the active ingredient, which is required to achieve a
therapeutical effect will, of course vary on case-by-case basis,
vary with the particular compound, the route of administration, the
age and condition of the recipient, and the particular disorder or
disease being treated. A method of treatment may also include
administering the active ingredient on a regimen of between one and
four intakes per day. In these methods of treatment the compounds
according to the invention are preferably formulated prior to
admission. As described herein below, suitable pharmaceutical
formulations are prepared by known procedures using well known and
readily available ingredients.
Pharmaceutical Compositions
[0454] The present invention also provides compositions for
preventing or treating diseases in which inhibition of the PDE10
enzyme is beneficial, such as the disorders described herein. While
it is possible for the active ingredient to be administered alone,
it is preferable to present it as a pharmaceutical composition.
Accordingly, the present invention also relates to a pharmaceutical
composition comprising a pharmaceutically acceptable carrier or
diluent and, as active ingredient, a therapeutically effective
amount of a compound according to the invention, in particular a
compound according to Formula (I), a pharmaceutically acceptable
salt thereof, a solvate thereof or a stereochemically isomeric form
thereof. The carrier or diluent must be "acceptable" in the sense
of being compatible with the other ingredients of the composition
and not deleterious to the recipients thereof.
[0455] The compounds according to the invention, in particular the
compounds according to Formula (I), the pharmaceutically acceptable
salts thereof, the solvates and the stereochemically isomeric forms
thereof, or any subgroup or combination thereof may be formulated
into various pharmaceutical forms for administration purposes. As
appropriate compositions there may be cited all compositions
usually employed for systemically administering drugs.
[0456] The pharmaceutical compositions of this invention may be
prepared by any methods well known in the art of pharmacy, for
example, using methods such as those described in Gennaro et al.
Remington's Pharmaceutical Sciences (18.sup.th ed., Mack Publishing
Company, 1990, see especially Part 8: Pharmaceutical preparations
and their Manufacture). To prepare the pharmaceutical compositions
of this invention, a therapeutically effective amount of the
particular compound, optionally in salt form, as the active
ingredient is combined in intimate admixture with a
pharmaceutically acceptable carrier or diluent, which carrier or
diluent may take a wide variety of forms depending on the form of
preparation desired for administration. These pharmaceutical
compositions are desirable in unitary dosage form suitable, in
particular, for oral, topical (for example via a nose spray, eye
drops or via a cream, gel, shampoo or the like), rectal or
percutaneous administration, by parenteral injection or by
inhalation, such as a nose spray. For example, in preparing the
compositions in oral dosage form, any of the usual pharmaceutical
media may be employed such as, for example, water, glycols, oils,
alcohols and the like in the case of oral liquid preparations such
as, for example, suspensions, syrups, elixirs, emulsions and
solutions; or solid carriers such as, for example, starches,
sugars, kaolin, diluents, lubricants, binders, disintegrating
agents and the like in the case of powders, pills, capsules and
tablets. Because of the ease in administration, oral administration
is preferred, and tablets and capsules represent the most
advantageous oral dosage unit forms in which case solid
pharmaceutical carriers are employed. For parenteral compositions,
the carrier will usually comprise sterile water, at least in large
part, though other ingredients, for example, surfactants to aid
solubility, may be included. Injectable solutions, for example, may
be prepared in which the carrier comprises saline solution, glucose
solution or a mixture of saline and glucose solution. Injectable
suspensions may also be prepared in which case appropriate liquid
carriers, suspending agents and the like may be employed. Also
included are solid form preparations that are intended to be
converted, shortly before use, to liquid form preparations. In the
compositions suitable for percutaneous administration, the carrier
optionally comprises a penetration enhancing agent and/or a
suitable wetting agent, optionally combined with suitable additives
of any nature in minor proportions, said additives do not introduce
a significant deleterious effect on the skin. Said additives may
facilitate the administration to the skin and/or may be helpful for
preparing the desired compositions. These compositions may be
administered in various ways, e.g., as a transdermal patch, as a
spot-on treatment, as an ointment.
[0457] It is especially advantageous to formulate the
aforementioned pharmaceutical compositions in unit dosage form for
ease of administration and uniformity of dosage. Unit dosage form
as used herein refers to physically discrete units suitable as
unitary dosages, each unit containing a predetermined quantity of
active ingredient calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier.
Examples of such unit dosage forms are tablets (including scored or
coated tablets), capsules, pills, powder packets, wafers,
suppositories, injectable solutions or suspensions and the like,
teaspoonfuls, tablespoonfuls, and segregated multiples thereof.
[0458] Since the compounds according to the invention are orally
administrable compounds, pharmaceutical compositions comprising aid
compounds for oral administration are especially advantageous.
[0459] In order to enhance the solubility and/or the stability of
the compounds of Formula (I) in pharmaceutical compositions, it can
be advantageous to employ .alpha.-, .beta.- or
.gamma.-cyclodextrins or their derivatives, in particular
hydroxyalkyl substituted cyclodextrins, e.g.
2-hydroxypropyl-.beta.-cyclodextrin or
sulfobutyl-.beta.-cyclodextrin. Also co-solvents such as alcohols
may improve the solubility and/or the stability of the compounds
according to the invention in pharmaceutical compositions.
[0460] The exact dosage and frequency of administration depends on
the particular compound of formula (I) used, the particular
condition being treated, the severity of the condition being
treated, the age, weight, sex, extent of disorder and general
physical condition of the particular patient as well as other
medication the individual may be taking, as is well known to those
skilled in the art. Furthermore, it is evident that said effective
daily amount may be lowered or increased depending on the response
of the treated subject and/or depending on the evaluation of the
physician prescribing the compounds of the instant invention.
[0461] Depending on the mode of administration, the pharmaceutical
composition will comprise from 0.05 to 99% by weight, preferably
from 0.1 to 70% by weight, more preferably from 0.1 to 50% by
weight of the active ingredient, and, from 1 to 99.95% by weight,
preferably from 30 to 99.9% by weight, more preferably from 50 to
99.9% by weight of a pharmaceutically acceptable carrier, all
percentages being based on the total weight of the composition.
[0462] The amount of a compound of Formula (I) that can be combined
with a carrier material to produce a single dosage form will vary
depending upon the disease treated, the mammalian species, and the
particular mode of administration. However, as a general guide,
suitable unit doses for the compounds of the present invention can,
for example, preferably contain between 0.1 mg to about 1000 mg of
the active compound. A preferred unit dose is between 1 mg to about
500 mg. A more preferred unit dose is between 1 mg to about 300 mg.
Even more preferred unit dose is between 1 mg to about 100 mg. Such
unit doses can be administered more than once a day, for example,
2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day,
so that the total dosage for a 70 kg adult is in the range of 0.001
to about 15 mg per kg weight of subject per administration. A
preferred dosage is 0.01 to about 1.5 mg per kg weight of subject
per administration, and such therapy can extend for a number of
weeks or months, and in some cases, years. It will be understood,
however, that the specific dose level for any particular patient
will depend on a variety of factors including the activity of the
specific compound employed; the age, body weight, general health,
sex and diet of the individual being treated; the time and route of
administration; the rate of excretion; other drugs that have
previously been administered; and the severity of the particular
disease undergoing therapy, as is well understood by those of skill
in the area.
[0463] A typical dosage can be one 1 mg to about 100 mg tablet or 1
mg to about 300 mg taken once a day, or, multiple times per day, or
one time-release capsule or tablet taken once a day and containing
a proportionally higher content of active ingredient.
[0464] The time-release effect can be obtained by capsule materials
that dissolve at different pH values, by capsules that release
slowly by osmotic pressure, or by any other known means of
controlled release.
[0465] It can be necessary to use dosages outside these ranges in
some cases as will be apparent to those skilled in the art.
Further, it is noted that the clinician or treating physician will
know how and when to start, interrupt, adjust, or terminate therapy
in conjunction with individual patient response.
[0466] As already mentioned, the invention also relates to a
pharmaceutical composition comprising the compounds according to
the invention and one or more other drugs for use as a medicament
or for use in the treatment, prevention, control, amelioration, or
reduction of risk of diseases or conditions for which compounds of
Formula (I) or the other drugs may have utility as well. The use of
such a composition for the manufacture of a medicament, as well as
the use of such a composition for the manufacture of a medicament
in the treatment, prevention, control, amelioration or reduction of
risk of diseases or conditions for which compounds of Formula (I)
or the other drugs may have utility are also contemplated. The
present invention also relates to a combination of a compound
according to the present invention and an additional pharmaceutical
agent. The present invention also relates to such a combination for
use as a medicine. The present invention also relates to a product
comprising (a) a compound according to the present invention, a
pharmaceutically acceptable salt thereof or a solvate thereof, and
(b) an additional pharmaceutical agent, as a combined preparation
for simultaneous, separate or sequential use in the treatment or
prevention of a condition in a mammal, including a human, the
treatment or prevention of which is affected or facilitated by the
effect of PDE10 inhibitors, in particular PDE10A inhibitors. The
different drugs of such a combination or product may be combined in
a single preparation together with pharmaceutically acceptable
carriers or diluents, or they may each be present in a separate
preparation together with pharmaceutically acceptable carriers or
diluents.
[0467] The following examples are intended to illustrate but not to
limit the scope of the present invention.
EXAMPLES
Chemistry
[0468] Several methods for preparing the compounds of this
invention are illustrated in the following Examples. Unless
otherwise noted, all starting materials were obtained from
commercial suppliers and used without further purification.
[0469] Hereinafter, the term "LCMS" means liquid
chromatography/mass spectrometry, "HPLC" means high-performance
liquid chromatography, "min." means minutes, "h." means hours,
"R.sub.t" means retention time (in minutes), "[M+H].sup.+" means
the protonated mass of the free base of the compound, "m.p." means
melting point.
[0470] Microwave assisted reactions were performed in a single-mode
reactor: Emrys.TM. Optimizer microwave reactor (Personal Chemistry
A.B., currently Biotage).
[0471] Thin layer chromatography (TLC) was carried out on silica
gel 60 F254 plates (Merck) using reagent grade solvents. Open
column chromatography was performed on silica gel, particle size 60
.ANG., mesh=230-400 (Merck) under standard techniques. Flash column
chromatography was performed using ready-to-connect cartridges from
Merck, on irregular silica gel, particle size 15-40 .mu.m (normal
phase disposable flash columns) on an SPOT or FLASH system from
Armen Instrument.
[0472] Reverse phase HPLC was performed on a C18 XBridge
30.times.100 5 .mu.m column.
[0473] .sup.1H NMR spectra were recorded either on a Bruker DPX-400
or on a Bruker AV-500 spectrometer with standard pulse sequences,
operating at 400 MHz and 500 MHz respectively. Chemical shifts
(.delta.) are reported in parts per million (ppm) downfield from
tetramethylsilane (TMS), which was used as internal standard.
[0474] Melting Point values are peak values, and are obtained with
experimental uncertainties that are commonly associated with this
analytical method. For a number of compounds, melting points were
determined in open capillary tubes either on a Mettler FP62 or on a
Mettler FP81HT-FP90 apparatus. Melting points were measured with a
temperature gradient of 10.degree. C./minute. Maximum temperature
was 300.degree. C. The melting point was read from a digital
display.
LCMS Analysis
General Procedure for HP 1100-MS Instruments (TOF, SQD or MSD)
[0475] The HPLC measurement was performed using an HP 1100 (Agilent
Technologies) system comprising a pump (quaternary or binary) with
degasser, an autosampler, a column oven, a diode-array detector
(DAD) and a column as specified in the respective methods. The MS
detector was configured with either an electrospray ionization
source or an ESCI dual ionization source (electrospray combined
with atmospheric pressure chemical ionization). Nitrogen was used
as the nebulizer gas. The source temperature was maintained either
at 140.degree. C. or 100.degree. C. Data acquisition was performed
either with MassLynx-Openlynx software or Chemsation-Agilent Data
Browser software.
General Procedure for Acquity-SQD Instrument
[0476] The HPLC (Ultra Performance Liquid Chromatography)
measurement was performed using an Acquity HPLC (Waters) system
comprising a sampler organizer, a binary pump with degasser, a four
column's oven, a diode-array detector (DAD) and a column as
specified in the respective methods. The MS detector was configured
with an ESCI dual ionization source (electrospray combined with
atmospheric pressure chemical ionization). Nitrogen was used as the
nebulizer gas. The source temperature was maintained at 140.degree.
C. Data acquisition was performed with MassLynx-Openlynx
software.
MS Procedure for LC Method 1:
[0477] High-resolution mass spectra (Time of Flight, TOF detector)
were acquired only in positive ionization mode or in
positive/negative modes by scanning from 100 to 750 umas. The
capillary needle voltage was 2.5 kV for positive mode and 2.9 kV
for negative ionization mode. The cone voltage was 20 V for both
positive and negative ionization modes. Leucine-Enkephaline was the
standard substance used for the lock mass calibration.
MS Procedure for LC Methods 2, 4, 5, and 6:
[0478] Low-resolution mass spectra (single quadrupole, SQD
detector) were acquired only in positive ionization mode or in
positive/negative modes by scanning from 100 to 1000 umas. The
capillary needle voltage was 3 kV. For positive ionization mode the
cone voltage was 20 V, 25 V or 20 V/50 V. For negative ionization
mode the cone voltage was 30 V.
MS Procedure for LC Method 3
[0479] Low-resolution mass spectra (single quadrupole, MSD
detector) were acquired in positive/negative modes by scanning from
100 to 1000 umas. The capillary needle voltage was 1.0 kV and the
fragmentor voltage was 70V for both positive and negative
ionization modes.
Method 1
[0480] In addition to the general procedure: Reversed phase HPLC
was carried out on a Sunfire-C18 column (2.5 .mu.m, 2.1.times.30
mm) from Waters, with a flow rate of 1.0 ml/min, at 60.degree. C.
The gradient conditions used are: 95% A (0.5 g/L ammonium acetate
solution+5% of acetonitrile), 5% B (acetonitrile or or
acetonitrile/methanol 1/1), to 100% B and equilibrated to initial
conditions up to 7 or 9 minutes run. Injection volume 2 .mu.L.
Method 2
[0481] In addition to the general procedure: Reversed phase HPLC
was carried out on an Eclipse Plus-C18 column (3.5 .mu.m,
2.1.times.30 mm) from Agilent, with a flow rate of 1.0 mL/min, at
60.degree. C. The gradient conditions used are: 95% A (0.5 g/L
ammonium acetate solution+5% acetonitrile), 5% B (acetonitrile or
mixture of acetonitrile/methanol, 1/1), to 100% B and equilibrated
to initial conditions up to 7 or 9 minutes run. Injection volume 2
.mu.L.
Method 3
[0482] In addition to the general procedure: Reversed phase HPLC
was carried out on an Eclipse Plus-C18 column (3.5 .mu.m,
2.1.times.30 mm) from Agilent, with a flow rate of 1.0 mL/min, at
60.degree. C. The gradient conditions used are: 95% A (0.5 g/L
ammonium acetate solution+5% acetonitrile), 5% B (acetonitrile), to
100% B in 5 0 minutes, kept till 5.15 minutes and equilibrated to
initial conditions at 5.3 minutes until 7.0 minutes. Injection
volume 2 .mu.L.
Method 4
[0483] In addition to the general procedure: Reversed phase HPLC
was carried out on a BEH-C18 column (1.7 .mu.m, 2.1.times.50 mm)
from Waters, with a flow rate of 0 8 mL/min, at 60.degree. C. The
gradient conditions used are: 95% A (0.5 g/L ammonium acetate
solution+5% acetonitrile), 5% B (mixture of acetonitrile/methanol,
1/1), to 20% A, 80% B, then to 100% B and equilibrated to initial
conditions up to 5 or 7 minutes run. Injection volume 0.5
.mu.L.
Method 5
[0484] In addition to the general procedure: Reversed phase HPLC
was carried out on a BEH-C18 column (1.7 .mu.m, 2.1.times.50 mm)
from Waters, with a flow rate of 1.0 mL/min, at 50.degree. C. The
gradient conditions used are: 95% A (0.5 g/L ammonium acetate
solution+5% acetonitrile), 5% B (acetonitrile), to 40% A, 60% B,
then to 5% A, 95% B and equilibrated to initial conditions up to 5,
7, or 9 minutes run. Injection volume 0.5 .mu.L.
Method 6
[0485] In addition to the general procedure: Reversed phase HPLC
was carried out on a BEH-C18 column (1.7 .mu.m, 2.1.times.50 mm)
from Waters, with a flow rate of 0 8 mL/min, at 50.degree. C. The
gradient conditions used are: 95% A (formic acid solution, 0.1%),
5% B (methanol), to 40% A, 60% B, then to 5% A, 95% B and
equilibrated to initial conditions up to 7.0 minutes run. Injection
volume 0.5 .mu.L.
A. Preparation of the Intermediates
Example A1
Preparation of intermediate 1:
4-Bromo-6-chloro-pyridazin-3-ylamine
##STR00061##
[0487] Bromine (7.9 ml, 154 3 mmol) was added to a stirred
suspension of 6-chloro-pyridazin-3-ylamine (20 g, 154.3 mmol) and
sodium hydrogencarbonate (25.9 g, 308.8 mol) in methanol (500 ml).
The mixture was stirred at room temperature for 16 h, then
filtered. The filtrate was diluted with ethyl acetate and washed
with a saturated solution of sodium thiosulfate, water and a
saturated solution of sodium carbonate. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo to yield intermediate 1 (24.59 g, 64%) as a
brown solid which was used in next step without further
purification. LCMS: 208 [M+H].sup.+; R.sub.t: 0.59 min (method
5).
Example A2
Preparation of intermediate 2:
6-Chloro-4-morpholin-4-yl-pyridazin-3-ylamine
##STR00062##
[0489] Morpholine (8.37 ml, 95.9 mmol) was added to a stirred
solution of intermediate 1 (2 g, 9.6 mmol) in acetonitrile (5 ml).
The mixture was stirred at 80.degree. C. for 16 h., then diluted
with dichloromethane and washed with a saturated solution of sodium
hydrogen carbonate. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash column chromatography
(silica, methanol in dichloromethane 0/100 to 30/70). The desired
fractions were collected and concentrated in vacuo to yield
intermediate 2 (1.98 g, 92%) as a pale brown solid. LCMS: 215
[M+H].sup.+; R.sub.t: 0.56 min (method 5).
Example A3
Preparation of intermediate 3: Mixture of
6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and
8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine
##STR00063##
[0491] A mixture of intermediate 1 (28.57 g, 137.1 mmol) and
chloroacetone (76.4 ml, 959.4 mmol) was stirred at 90.degree. C.
for 16 h. in a sealed tube protected from light. After cooling to
room temperature, diethylether was added and the solid formed was
filtered off and washed with further diethylether. The solid was
suspended in a saturated solution of sodium carbonate and extracted
with dichloromethane. The organic layer was dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo.
The crude products were purified by open column chromatography
(silica; dichloromethane). The desired fractions were collected and
concentrated in vacuo to yield intermediate 3 (19.5 g, 66%) as a
white solid, in a 70/30 mixture of
6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and
8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine.
C.sub.2H.sub.5Cl.sub.2N.sub.3 requires 201; Found 202 [M+H].sup.+;
R.sub.t: 1.25 min and C.sub.2H.sub.5BrClN.sub.3requires 247; Found
248 [M+H].sup.+; R.sub.t: 1.33 min (method 5).
Example A4
Preparation of intermediate 4:
8-Bromo-6-cloro-2-cyclopropyl-imidazo[1,2-b]pyridazine
##STR00064##
[0493] A mixture of intermediate 1 (5 g, 24 mmol) and
2-bromo-1-cyclopropyl-ethanone (15.25 g, 93 6 mmol) (obtained by a
procedure similar to those described in Gaudry, M.; Marquet, A.
Organic Syntheses 1976, 55) was stirred at 80.degree. C. for 16 h.
The crude product was suspended in dichloromethane and washed with
a saturated solution of sodium hydrogen carbonate. The organic
layer was separated, dried (Na.sub.2SO.sub.4), filtered and the
solvents evaporated in vacuo. The crude product was purified by
flash column chromatography (silica; dichloromethane in heptane
40/60 to 100/0). The desired fractions were collected and
concentrated in vacuo to yield intermediate 4 (4.95 g, 76%) as a
black solid. C.sub.9H.sub.7BrClN.sub.3 requires 271; Found 272
[M+H].sup.+. R.sub.t: 2.05 min (method 5).
Example A5
Preparation of intermediate 5: Mixture of
6,8-dichloro-imidazo[1,2-b]pyridazine and
8-bromo-6-chloro-imidazo[1,2-b]pyridazine
##STR00065##
[0495] A 50% wt. solution of chloroacetaldehyde in water (5.79 ml,
44 5 mmol) was added dropwise to a solution of intermediate 1 (2.34
g, 11.2 mmol) in ethanol (50 ml). The mixture was stirred at reflux
temperature for 2 h. After cooling to room temperature, the mixture
was poured onto a mixture of ice/water and ethyl acetate was added.
The mixture was basified by addition of a saturated solution of
sodium carbonate. The organic layer was separated, washed with
brine, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude products were purified by open
column chromatography (silica; 7M solution of ammonia in methanol
in dichloromethane 2/98). The desired fractions were collected and
concentrated in vacuo to yield intermediate 5 (1.5 g, 66%) as a
68/32 mixture of 6,8-dichloro-imidazo[1,2-b]pyridazine and
8-bromo-6-chloro-imidazo[1,2-b]pyridazine.
Example A6
Preparation of intermediate 6:
6-Chloro-8-iodo-2-methyl-imidazo[1,2-b]pyridazine
##STR00066##
[0497] Hydriodic acid (0.1 ml, 0.74 mmol) was added to a solution
of intermediate 3 (a 70/30 mixture of
6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and
8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine) (1 g, 4.95
mmol) and sodium iodide (2.23 g, 45.1 mmol) in acetonitrile (10
ml). The mixture was stirred at 160.degree. C. for 30 min. in a
sealed tube, under microwave irradiation and then poured onto a 10%
w/w solution of sodium carbonate. The mixture was diluted with
dichloromethane and washed with a 10% solution of sodium
thiosulfite. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash column chromatography
(silica; ethyl acetate in heptane 0/100 to 50/50). The desired
fractions were collected and concentrated in vacuo to yield
intermediate 6 (1.25 g, 86%) as a light brown solid. LCMS: 294
[M+H].sup.+; R.sub.t: 1.52 min (method 5).
Example A7
Preparation of intermediate 7:
6-Chloro-2-methyl-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00067##
[0499] Morpholine (6.48 ml, 74 2 mmol) was added to a stirred
solution of intermediate 3 (a 70/30 mixture of
6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and
8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine) (12.5 g, 58 0
mmol) and N,N-diisopropylethylamine (16.2 ml, 92.8 mmol) in
acetonitrile (40 ml). The mixture was stirred at 80.degree. C. for
16 h. and then diluted with dichloromethane and washed with a
saturated solution of ammonium chloride. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was triturated with
diethylether to yield intermediate 7 (15.4 g, 99%) as a pale brown
solid. LCMS: 253 [M+H].sup.+; R.sub.t: 1.62 min (method 5).
[0500] The following intermediates were prepared from the indicated
precursors according to a protocol analogous to A7.
Example A8
Preparation of intermediate 8:
6-Chloro-2-cyclopropyl-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00068##
[0502] From intermediate 4. Flash column chromatography (silica;
ethyl acetate in heptane 30/70) yielded intermediate 8 as a white
solid (81%). LCMS: 279 [M+H].sup.+; R.sub.t: 2.60 min (method
4).
Example A9
Preparation of intermediate 9:
6-Chloro-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00069##
[0504] From intermediate 5 (a 68/32 mixture of
6,8-dichloro-imidazo[1,2-b]pyridazine and
8-bromo-6-chloro-imidazo[1,2-b]pyridazine). Open column
chromatography (silica, dichloromethane) yielded intermediate 9 as
a pale yellow solid (66%).
Example A10
Preparation of intermediate 10:
6-Chloro-2-methoxy-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00070##
[0506] A mixture of intermediate 2 (0.7 g, 3.26 mmol) and methyl
bromoacetate (0.93 ml, 9.78 mmol) in methanol (2.5 ml) was stirred
at 130.degree. C. for 15 min under microwave irradiation. The
mixture was diluted with water and extracted with dichloromethane.
The organic layer was separated, extracted with brine, dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash column chromatography
(silica; 7 M solution of ammonia in methanol in dichloromethane
0/100 to 3/97). The desired fractions were collected and
concentrated in vacuo to yield intermediate 10 (0.314 g, 29%).
Example A11
Preparation of intermediate 11:
6-Chloro-2-methyl-8-pyridin-4-yl-imidazo[1,2-b]pyridazine
##STR00071##
[0508] Tetrakis(triphenylphosphine)palladium (0) (0.114 g, 0.10
mmol) was added to a stirred solution of intermediate 3 (a mixture
70/30 of 6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and
8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine) (0.4 g, 2.0
mmol) and 4-pyridineboronic acid (0.243 g, 2 0 mmol) in a mixture
of 1,4-dioxane (2 ml) and a saturated solution of sodium carbonate
(2 ml). The mixture was stirred at 100.degree. C. for 16 h. in a
sealed tube under nitrogen and then filtered through a pad of
diatomaceous earth. The filtrate was diluted with dichloromethane
and extracted with a saturated solution of sodium carbonate. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and
the solvents evaporated in vacuo. The crude product was purified by
column chromatography (silica; ethyl acetate in heptane 0/100 to
50/50). The desired fractions were collected and concentrated in
vacuo to yield intermediate 11 (0.26 g, 41%). LCMS: 288
[M+H].sup.+; R.sub.t: 2.17 min (method 4).
[0509] The following intermediates were prepared from the indicated
precursors according to a protocol analogous to A11.
Example A12
Preparation of intermediate 12:
6-Chloro-2-cyclopropyl-8-pyridin-4-yl-imidazo[1,2-b]pyridazine
##STR00072##
[0511] From intermediate 4. Flash column chromatography (silica;
ethyl acetate in dichloromethane 0/100 to 30/70) yielded
intermediate 12 as a pale yellow solid (52%). LCMS: 271
[M+H].sup.+; R.sub.t: 2.11 min (method 5).
Example A13
Preparation of intermediate 13:
6-Chloro-2-methyl-8-pyridin-3-yl-imidazo[1,2-b]pyridazine
##STR00073##
[0513] From intermediate 6 and 3-pyridineboronic acid. Conditions:
140.degree. C. for 15 min under microwave irradiation. Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 4/96) yielded intermediate 13 as a pale
brown solid (100%).
Example A14
Preparation of intermediate 14:
2-Methyl-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00074##
[0515] 10% Palladium on charcoal (0.421 g) was added to a
suspension of intermediate 7 (1 g, 3.96 mmol) and ammonium formate
(0.75 g, 11.9 mmol) in methanol (25 ml). The mixture was stirred at
80.degree. C. for 4 h. and at room temperature for a further 16 h.
The mixture was filtered through a pad of diatomaceous earth and
the filtrate was concentrated in vacuo. The crude product was
suspended in dichloromethane and washed with a saturated solution
of sodium hydrogen carbonate. The organic layer was separated,
dried (Na.sub.2SO.sub.4), filtered and the solvents evaporated in
vacuo to yield intermediate 14 (0.78 g, 90%) as a white solid.
LCMS: 219 [M+H].sup.+; R.sub.t: 0.98 min (method 5).
[0516] The following intermediates were prepared from the indicated
precursors according to a protocol analogous to A14.
Example A15
Preparation of intermediate 15:
2-Methoxy-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00075##
[0518] From intermediate 10. Flash column chromatography (7 M
solution of ammonia in methanol in dichloromethane 0/100 to 3/97)
yielded intermediate 15 as a pale brown solid (65%).
Example A16
Preparation of intermediate 16:
2-Cyclopropyl-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00076##
[0520] 10% Palladium on charcoal (0.391 g) was added to a mixture
of intermediate 8 (4.1 g, 14.7 mmol) and triethylamine (4.1 ml, 29
4 mmol) in a mixture of methanol (100 ml) and tetrahydrofuran (100
ml). The mixture was hydrogenated (atmospheric pressure) at room
temperature for 8 h and then filtered through a pad of diatomaceous
earth. The filtrate was concentrated in vacuo to yield intermediate
16 (3.1 g, 94%). LCMS: 219 [M+H].sup.+; R.sub.t: 0.98 min (method
5).
[0521] The following intermediates were prepared from the indicated
precursors according to a protocol analogous to A16.
Example A17
Preparation of intermediate 17:
8-Morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00077##
[0523] From intermediate 9. Precipitation from diisopropylether
yielded intermediate 17 as a pale pink solid (76%).
Example A18
Preparation of intermediate 18:
2-Cyclopropyl-8-pyridin-4-yl-imidazo[1,2-b]pyridazine
##STR00078##
[0525] From intermediate 12. Flash column chromatography (silica;
ethylacetate in heptane 0/100 to 50/50) yielded intermediate 18 as
a white solid (50%). LCMS: 237 [M+H].sup.+; R.sub.t: 1.83 min
(method 5).
Example A19
Preparation of intermediate 19:
2-Methyl-8-pyridin-3-yl-imidazo[1,2-b]pyridazine
##STR00079##
[0527] From intermediate 13. Flash column chromatography (silica, 7
M solution of ammonia in methanol in dichloromethane 0/100 to 2/98)
yielded intermediate 19 as a pale brown solid (43%). LCMS: 211
[M+H].sup.+; R.sub.t: 1.14 min (method 5).
Example A20
Preparation of intermediate 20:
2-Methyl-8-pyridin-4-yl-imidazo[1,2-b]pyridazine
##STR00080##
[0529] 10% Palladium on charcoal (1.22 g) was added to a suspension
of intermediate 11 (4 g, 16.35 mmol) in a mixture of methanol (400
ml) and dichlorometane (30 ml). The mixture was hydrogenated (40
psi) at 50.degree. C. for 6 h. and then filtered through a pad of
diatomaceous earth. The filtrate was concentrated in vacuo to yield
intermediate 20 (3 g, 86%) as a yellow solid. LCMS: 211
[M+H].sup.+; R.sub.t: 2.11 min (method 1).
Example A21
Preparation of intermediate 21:
2,6-Dimethyl-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00081##
[0531] Tetrakis(triphenylphosphine)palladium (0) (0.457 g, 0.396
mmol) was added to a stirred solution of intermediate 7 (1 g, 3.96
mmol) and methylboronic acid (1.18 g, 19.79 mmol) in a mixture of
1,4-dioxane (12 ml) and a saturated solution of sodium carbonate (4
ml). The mixture was stirred at 175.degree. C. for 45 min. in a
sealed tube under nitrogen and under microwave irradiation. The
mixture was filtered through a pad of diatomaceous earth and the
filtrate diluted with ethylacetate and washed with water. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and
the solvents evaporated in vacuo. The crude product was purified by
column chromatography (silica; ethyl acetate in heptane 20/80 to
50/50). The desired fractions were collected and concentrated in
vacuo to yield intermediate 21 (0.364 g, 40%). LCMS: 233
[M+H].sup.+; R.sub.t: 1.98 min (method 2).
[0532] The following intermediates were prepared from the indicated
precursors according to a protocol analogous to A21.
Example A22
Preparation of intermediate 22:
2,6-Dimethyl-8-pyridin-4-yl-imidazo[1,2-b]pyridazine
##STR00082##
[0534] From intermediate 11. Flash column chromatography (silica; 7
M solution of ammonia in methanol in dichloromethane 0/100 to
1.5/98.5) yielded intermediate 22 as a light yellow solid (65%).
LCMS: 225 [M+H].sup.+; R.sub.t: 2.00 min (method 2).
Example A23
Preparation of intermediate 23:
6-Cyclopropyl-2-methyl-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00083##
[0536] Palladium (II) acetate (0.066 g, 0.297 mmol) was added to a
stirred solution of intermediate 7 (0.5 g, 1.98 mmol),
cyclopropylboronic acid (0.255 g, 2.97 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.244 g, 0.594
mmol) and potassium phosphate (0.84 g, 3.96 mmol) in toluene (10
ml). The mixture was stirred at 150.degree. C. for 45 min. in a
sealed tube under nitrogen and under microwave irradiation. The
mixture was diluted with dichloromethane and washed with water. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and
the solvents evaporated in vacuo. The crude product was purified by
column chromatography (silica; ethyl acetate in heptane 0/100 to
50/50). The desired fractions were collected and concentrated in
vacuo to yield intermediate 23 (0.434 g, 85%). LCMS: 259
[M+H].sup.+; R.sub.t: 2.22 min (method 5).
[0537] The following intermediates were prepared from the indicated
precursors according to a protocol analogous to A23.
Example A24
Preparation of intermediate 24:
6-Cyclopropyl-2-methyl-8-pyridin-4-yl-imidazo[1,2-b]pyridazine
##STR00084##
[0539] From intermediate 11. Flash column chromatography (7 M
solution of ammonia in methanol in dichloromethane 0/100 to 4/96)
yielded intermediate 24 as a light yellow solid (87%). LCMS: 251
[M+H].sup.+; R.sub.t: 2.20 min (method 5).
Example A25
Preparation of intermediate 25:
2-Cyclopropyl-6-methyl-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00085##
[0541] From intermediate 8 and methylboronic acid. Flash column
chromatography (silica; ethyl acetate in dichloromethane 0/100 to
30/70) yielded intermediate 25 as a pale yellow solid (75%).
Example A26
Preparation of intermediate 26:
3-Iodo-2-methyl-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00086##
[0543] N-Iodosuccinimide (1.08 g, 4 8 mmol) was added to a stirred
solution of intermediate 14 (1 g, 4.58 mmol) in a mixture of
dichloromethane (50 ml) and acetic acid (2 ml). The mixture was
stirred at 0.degree. C. for 30 min. and then extracted with a
saturated solution of sodium carbonate and a 10% solution of sodium
thiosulfite. The organic layer was filtered over cotton wool and
the solvents evaporated in vacuo. The crude product was purified by
flash column chromatography (silica, dichloromethane in heptane
70/30 first, then ethyl acetate in heptane 10/90 to 30/70). The
desired fractions were collected and concentrated to yield
intermediate 26 (4.68 g, 83%) as a white solid. LCMS: 345
[M+H].sup.+; R.sub.t: 2.59 min (method 1).
[0544] The following intermediates were prepared from the indicated
precursors according to a protocol analogous to A26.
Example A27
Preparation of intermediate 27:
2-Cyclopropyl-3-iodo-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00087##
[0546] From intermediate 16. Flash column chromatography (silica;
ethyl acetate in dichloromethane 0/100 to 20/80) yielded
intermediate 27 as a pale brown solid (95%). LCMS: 371 [M+H].sup.+;
R.sub.t: 3.15 min (method 5).
Example A28
Preparation of intermediate 28:
3-Iodo-2,6-dimethyl-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00088##
[0548] From intermediate 21. Flash column chromatography (silica; 7
M solution of ammonia in methanol in dichloromethane 0/100 to 2/98)
yielded intermediate 28 as a white solid (77%). LCMS: 359
[M+H].sup.+; R.sub.t: 2.84 min (method 2).
Example A29
Preparation of intermediate 29:
3-Iodo-2-methyl-8-pyridin-4-yl-imidazo[1,2-b]pyridazine
##STR00089##
[0550] From intermediate 20. Flash column chromatography (silica;
ethyl acetate in dichloromethane 0/100 to 30/70) yielded
intermediate 29 as a pale yellow solid (96%). LCMS: 351
[M+H].sup.+; R.sub.t: 2.43 min (method 2).
Example A30
Preparation of intermediate 30:
3-Iodo-2,6-dimethyl-8-pyridin-4-yl-imidazo[1,2-b]pyridazine
##STR00090##
[0552] From intermediate 22. Flash column chromatography (silica;
ethyl acetate in dichloromethane 30/70 to 70/30) yielded
intermediate 30 as a pale yellow solid (72%). LCMS: 351
[M+H].sup.+; R.sub.t: 2.71 min (method 2).
Example A31
Preparation of intermediate 31:
6-Chloro-3-iodo-2-methyl-8-morpholin-1-yl-imidazo[1,2-b]pyridazine
##STR00091##
[0554] N-Iodosuccinimide (0.95 g, 4.36 mmol) was added to a stirred
solution of a mixture 70/30 of intermediate 3 (0.95 g, 3.36 mmol)
in a mixture of dichloromethane (9 ml) and acetic acid (1 ml). The
mixture was stirred at room temperature for 16 h. and then washed
with a saturated solution of sodium carbonate. The organic layer
was separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo to yield 1.33 g of crude product. A portion of
this crude product (0.5 g) was dissolved in acetonitrile (8 ml) and
morpholine (0.140 ml, 1.6 mmol) and N,N-diisopropylethylamine
(0.393 ml, 2.29 mmol) were added. The mixture was stirred at
150.degree. C. for 10 min in a sealed tube, under microwave
irradiation. The mixture was diluted with ethyl acetate and washed
with a saturated solution of ammonium chloride. The organic layer
was separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo to yield intermediate 31 (0.53 g, 69%).
Example A32
Preparation of intermediate 32:
3-Bromo-2-methyl-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00092##
[0556] N-Bromosuccinimide (0.273 g, 1.53 mmol) was added to a
stirred solution of intermediate 14 (0.335 g, 1.53 mmol) in
acetonitrile (10 ml). The mixture was stirred at room temperature
for 1 h., then diluted with ethyl acetate and washed with a
saturated solution of sodium carbonate. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica, 7 M solution of ammonia in methanol in
dichloromethane 4/96). The desired fractions were collected and
concentrated in vacuo and the crude product purified again by flash
column chromatography (silica, ethyl acetate in heptane 0/100 to
100/0). The desired fractions were collected and concentrated in
vacuo to yield intermediate 32 (0.1 g, 21.2%).
[0557] The following intermediates were prepared from the indicated
precursors according to a protocol analogous to A32.
Example A33
Preparation of intermediate 33:
3-Bromo-2-methyl-8-pyridin-4-yl-imidazo[1,2-b]pyridazine
##STR00093##
[0559] From intermediate 20. Flash column chromatography (silica; 7
M solution of ammonia in methanol in dichloromethane 0/100 to 4/96)
to yield intermediate 33 as a pale brown solid (73%).
Example A34
Preparation of intermediate 34:
3-Bromo-6-chloro-2-cyclopropyl-8-morpholin-4-yl-imidazo[1,2-b]pyridazine
##STR00094##
[0561] From intermediate 8. Flash column chromatography (silica,
dichloromethane) yielded intermediate 34 as a white solid (59%).
LCMS: 357 [M+H].sup.+; R.sub.t: 3.16 min (method 4).
Example A35
Preparation of intermediate 35:
3-(6-Chloro-pyridin-3-yl)-2-methyl-8-morpholin-4-yl-imidazo[1,2-b]pyridaz-
ine
##STR00095##
[0563] Tetrakis(triphenylphosphine)palladium (0) (0.403 g, 0.35
mmol) was added to a stirred solution of intermediate 26 (4 g, 11.6
mmol) and 2-chloropyridine-5-boronic acid (2.01 g, 12.79 mmol) in a
mixture of 1,4-dioxane (40 ml) and a saturated solution of sodium
carbonate (20 ml). The mixture was stirred at 100.degree. C. for 16
h. in a sealed tube under nitrogen and then diluted with
dichloromethane and extracted with water. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was precipitated from
methanol to yield intermediate 35 (0.364 g, 40%). LCMS: 330
[M+H].sup.+; R.sub.t: 1.90 min (method 5).
[0564] The following intermediates were prepared from the indicated
precursors according to a protocol analogous to A35.
Example A36
Preparation of intermediate 36:
3-(2-Chloro-pyridin-4-yl)-2-methyl-8-morpholin-4-yl-imidazo[1,2-b]pyridaz-
ine
##STR00096##
[0566] From intermediate 26 and 2-chloropyridine-4-boronic acid.
Precipitation from methanol yielded intermediate 36 as a pale brown
solid (95%).
Example A37
Preparation of intermediate 37:
3-(6-Chloro-pyridin-3-yl)-2-methyl-8-pyridin-4-yl-imidazo[1,2-b]pyridazin-
e
##STR00097##
[0568] From intermediate 29. Conditions: 150.degree. C. for 15 min.
under microwave irradiation. Precipitation from methanol yielded
intermediate 37 as a pale brown solid (71%).
Example A38
Preparation of intermediate 38:
2-Methyl-8-morpholin-4-yl-3-(6-vinyl-pyridin-3-yl)-imidazo[1,2-b]pyridazi-
ne
##STR00098##
[0570] Tetrakis(triphenylphosphine)palladium (0) (0.099 g, 0.086
mmol) was added to a stirred solution of intermediate 35 (0.945 g,
2.86 mmol) and vinylboronic acid pinacol ester (0.58 ml, 3.44 mmol)
in a mixture of 1,4-dioxane (20 ml) and a saturated solution of
sodium carbonate (4 ml). The mixture was stirred at 90.degree. C.
for 16 h. in a sealed tube under nitrogen. The mixture was diluted
with dichloromethane and washed with water. The organic layer was
separated, filtered over cotton and the solvents evaporated in
vacuo. The crude product was purified by flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 4/96). The desired fractions were
collected and concentrated in vacuo to yield intermediate 38 (0.159
g, 74%). LCMS: 322 [M+H].sup.+; R.sub.t: 3.66 min (method 6).
[0571] The following intermediate was prepared from the indicated
precursors according to a protocol analogous to A38.
Example A39
Preparation of intermediate 39:
2-Methyl-8-pyridin-4-yl-3-(6-vinyl-pyridin-3-yl)-imidazo[1,2-b]pyridazine
##STR00099##
[0573] From intermediate 37. Conditions: 150.degree. C. for 15 min.
under microwave irradiation. Flash column chromatography (silica;
ethyl acetate in dichloromethane 0/100 to 50/50) yielded
intermediate 39 as a yellow solid (100%). LCMS: 314 [M+H].sup.+;
R.sub.t: 1.67 min (method 5).
Example A40
Preparation of intermediate 40:
2-Methyl-8-morpholin-4-yl-3-(2-vinyl-pyridin-4-yl)-imidazo[1,2-b]pyridazi-
ne
##STR00100##
[0575] From intermediate 36. Conditions: 150.degree. C. for 15 min.
under microwave irradiation. Flash column chromatography (silica;
ethyl acetate in heptane 20/80 to 40/60) yielded intermediate 40 as
a white solid (90%). LCMS: 322 [M+H].sup.+; R.sub.t: 1.83 min
(method 5).
Example A41
Preparation of intermediate 41:
3-[6-(3,6-Dihydro-2H-pyran-4-yl)-pyridin-3-yl]-2-methyl-8-morpholin-4-yl--
imidazo[1,2-b]pyridazine
##STR00101##
[0577] Tetrakis(triphenylphosphine)palladium (0) (0.037 g, 0.032
mmol) was added to a stirred solution of intermediate 35 (0.35 g,
1.06 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester
(0.267 ml, 1.24 mmol) (obtained by procedures similar to those
described in, Qiu, Y. et al. WO 2004/075846-A2 published on
20040910) in a mixture of 1,4-dioxane (5 ml) and a saturated
solution of sodium carbonate (2 ml). The mixture was stirred at
85.degree. C. for 5 h. in a sealed tube under nitrogen, then
diluted with dichloromethane and washed with water. The organic
layer was separated, dried (MgSO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica; ethyl acetate in heptane 20/80 to 0/100).
The desired fractions were collected and concentrated in vacuo to
yield intermediate 41 (0.159 g, 62%).
Example A42
Preparation of intermediate 42:
1-Bromo-3-methoxy-3-methyl-butane
##STR00102##
[0579] Triphenylphosphine (12.3 g, 47 0 mmol) was added to a
stirred solution of 3-methoxy-3-methyl-butan-1-ol (4 ml, 31.3 mmol)
and carbon tetrabromide (15.6 g, 47 0 mmol) in dichloromethane (300
ml) at 0.degree. C. The mixture was stirred at room temperature for
18 h. and then a solution of sodium thiosulphate was added. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and
the solvents evaporated in vacuo. The crude product was triturated
with diethyl ether, filtered off and purified by flash column
chromatography (silica; petroleum ether in dichloromethane 0/100 to
50/50). The desired fractions were collected and concentrated in
vacuo to yield intermediate 42 (2.1 g, 37%).
Example A43
Preparation of intermediate 43:
1-Iodo-3-methoxy-3-methyl-butane
##STR00103##
[0581] Sodium iodide (2.9 g, 19 3 mmol) was added to a stirred
solution of intermediate 42 (1.4 g, 7.7 mmol) in dry acetone (10
ml). The mixture was stirred at reflux temperature for 3 h. and
then filtered. The filtrate was carefully concentrated in vacuo.
The crude product was purified by flash column chromatography
(silica; dichloromethane). The desired fractions were collected and
concentrated in vacuo to yield intermediate 43 (1.7 g, 81%).
[0582] The following intermediates were prepared from the indicated
precursors according to a protocol analogous to A43.
Example A44
Preparation of intermediate 44: 1-Iodo-3-methoxy-propane
##STR00104##
[0584] From 1-bromo-3-methoxy-propane. Flash column chromatography
(silica; dichloromethane) yielded intermediate 44 as a colourless
oil (84%).
Example A45
Preparation of intermediate 45:
5-Bromo-2-(2-methoxy-ethoxy)-3-methyl-pyridine
##STR00105##
[0586] 2-Methoxy-ethanol (1.18 ml, 14.95 mmol) was added dropwise
to a stirred suspension of a 60% dispersion of sodium hydride in
mineral oils (0.558 g, 13.95 mmol) in dimethylsulfoxide (30 ml).
The mixture was stirred at room temperature for 30 min. and then
2,5-dibromo-3-methylpyridine (2.5 g, 9.96 mmol) was added. The
mixture was stirred at 60.degree. C. for 1 h. and then diluted with
heptane and washed with water. The organic layer was separated,
dried (Na.sub.2SO.sub.4), filtered and the solvents evaporated in
vacuo. The crude product was purified by flash column
chromatography (silica; dichloromethane in heptanes 70/30). The
desired fractions were collected and concentrated in vacuo to yield
intermediate 45 (2.23 g, 91%).
[0587] The following intermediates were prepared from the indicated
precursors according to a protocol analogous to A45.
Example A46
Preparation of intermediate 46:
5-Bromo-2-(2-methoxy-2-methyl-propoxy)-pyridine
##STR00106##
[0589] From 2-methoxy-2-methyl-propan-1-ol (obtained by procedures
similar to those described in, Morel, P. US 2008102028-A1 published
on 20080501) and 5-bromo-2-chloro-pyridine. Flash column
chromatography (silica; dichloromethane in heptane 50/50 to 70/30)
yielded intermediate 46 as a clear syrup (75%).
Example A47
Preparation of intermediate 47:
5-Bromo-2-(2-methoxy-ethoxy)-pyridine
##STR00107##
[0591] From 2-methoxy-ethanol and 5-bromo-2-chloro-pyridine. Flash
column chromatography (silica; dichloromethane in heptane 30/70 to
70/30) yielded intermediate 47 as a colourless oil (75%). LCMS: 232
[M+H].sup.+; R.sub.t: 2.50 min (method 1).
Example A48
Preparation of intermediate 48:
5-Bromo-2-(1-ethoxy-1-methyl-ethyl)-pyridine
##STR00108##
[0593] A solution of 2-(5-bromo-pyridin-2-yl)-propan-2-ol (0.80 g,
3.70 mmol) (obtained by procedures similar to those described in,
Wang, X. et al. Tetrahedron Lett., 2000, 4335) in tetrahydrofuran
(8 ml) was added dropwise to a stirred suspension of a 60%
dispersion of sodium hydride in mineral oils (0.440 mg, 11.1 mmol)
in tetrahydrofuran (6 ml). The mixture was stirred at 0.degree. C.
for 20 min. and then iodoethane (1.27 ml, 15.9 mmol) was added
dropwise. The mixture was stirred at room temperature for 4 d.,
then diluted with dichloromethane and washed with water. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and
the solvents evaporated in vacuo. The crude product was purified by
flash column chromatography (silica; ethyl acetate in heptane 0/100
to 20/80). The desired fractions were collected and concentrated in
vacuo to yield intermediate 48 (0.7 g, 77%). LCMS: 244 [M+H].sup.+;
R.sub.t: 2.93 min (method 5).
[0594] The following intermediate was prepared from the indicated
precursors according to a protocol analogous to A48.
Example A49
Preparation of intermediate 49:
5-Bromo-2-(1-methoxy-1-methyl-ethyl)-pyridine
##STR00109##
[0596] From 2-(5-bromo-pyridin-2-yl)-propan-2-ol (obtained by
procedures similar to those described in, Wang, X. et al.;
Tetrahedron Lett., 2000, 4335) and dimethylsulfate. Flash column
chromatography (silica; dichloromethane in heptane 0/100 to 50/50)
yielded intermediate 49 as a colourless oil (69%). LCMS; 230
[M+H].sup.+; R.sub.t: 1.81 min (method 5).
Example A50
Preparation of intermediate 50:
(5-Bromo-pyridin-2-yl)-acetonitrile
##STR00110##
[0598] Potassium cyanide (0.489 g, 7.41 mmol) and potassium iodide
(0.013 g, 0.079 mmol) were added to a stirred solution of
5-bromo-2-chloromethyl-pyridine (0.9 g, 3.70 mmol) (obtained by
procedures similar to those described in, van den Heuvel, M. et
al.; J. Org. Chem., 2004, 250) in a mixture of ethanol (6 ml) and
water (2 ml). The mixture was stirred at 80.degree. C. for 6 h.,
then diluted with dichloromethane and washed with a saturated
solution of sodium hydrogen carbonate. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica; dichloromethane). The desired fractions
were collected and concentrated in vacuo to yield intermediate 50
(0.498 g, 68%).
Example A51
Preparation of intermediate 51:
2-(5-Bromo-pyridin-2-yl)-2-methyl-propionitrile
##STR00111##
[0600] Iodomethane (1.14 ml, 18.27 mmol) was added to a stirred
mixture of intermediate 50 (0.45 g, 2.28 mmol), potassium
tert-butoxide (0.64 g, 5.71 mmol) and 18-crown-6 (0.091 g, 0.34
mmol) in tetrahydrofuran (10 ml). The mixture was stirred at room
temperature for 18 h., then diluted with dichloromethane and washed
with water. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash column chromatography
(silica; dichloromethane). The desired fractions were collected and
concentrated in vacuo to yield intermediate 51 (0.503 g, 98%).
Example A52
Preparation of intermediate 52:
2-(5-Bromo-pyridin-2-yl)-2-methyl-propionaldehyde
##STR00112##
[0602] A 1 M solution of diisobutylaluminium hydride in toluene
(2.46 ml, 2.46 mmol) was added to a stirred solution of
intermediate 51 (0.503 g, 2.23 mmol) in dichloromethane (5 ml) at
-78.degree. C. under nitrogen. The mixture was allowed to warm to
room temperature and then stirred for 18 h. The mixture was cooled
down to -78.degree. C. and a further 1 M solution of
diisobutylaluminium hydride in toluene (1 ml, 1.0 mmol) was added.
The mixture was stirred at room temperature for 4 h., then a 0.5 M
sulphuric acid solution was added at -78.degree. C., after which
the reaction was diluted with dichloromethane and filtered through
a pad of diatomaceous earth. The organic layer was separated, dried
(MgSO.sub.4), filtered and the solvents evaporated in vacuo. The
crude product was purified by flash column chromatography (silica;
dichloromethane in heptane 50/50 to 100/0). The desired fractions
were collected and concentrated in vacuo to yield intermediate 52
(0.2 g, 40%).
Example A53
Preparation of intermediate 53:
2-(5-Bromo-pyridin-2-yl)-2-methyl-propan-1-ol
##STR00113##
[0604] Sodium borohydride (0.043 g, 1.14 mmol) was added to a
stirred solution of intermediate 52 (0.2 mg, 0.88 mmol) in
dichloromethane (5 ml). The mixture was stirred at room temperature
for 2 h. and then a saturated solution of sodium hydrogen carbonate
was added. The organic layer was separated, dried (MgSO.sub.4),
filtered and the solvents evaporated in vacuo. The crude product
was purified by flash column chromatography (silica; ethyl
acetate). The desired fractions were collected and concentrated in
vacuo to yield intermediate 53 (0.2 g, 40%).
Example A54
Preparation of intermediate 54:
5-Bromo-2-(2-methoxy-1,1-dimethyl-ethyl)-pyridine
##STR00114##
[0606] Iodomethane (0.16 ml, 2.61 mmol) was added to a stirred
mixture of intermediate 53 (0.20 g, 0.87 mmol), potassium
tert-butoxide (0.146 mg, 1.30 mmol) and 18-crown-6 (0.34 mg, 0.13
mmol) in tetrahydrofuran (5 ml). The mixture was stirred at room
temperature for 18 h., then diluted with dichloromethane and washed
with water. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash column chromatography
(silica; dichloromethane). The desired fractions were collected and
concentrated in vacuo to yield intermediate 54 (0.088 mg, 41%).
Example A55
Preparation of intermediate 55: 5-Bromo-2-vinyl-pyridine
##STR00115##
[0608] Tetrakis(triphenylphosphine)palladium(0) (1.82 g, 1.53 mmol)
was added to a stirred suspension of 2,5-dibromopyridine (15 g, 63
3 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (11.8
ml, 69 6 mmol) in a mixture of 1,4-dioxane (120 ml) and a saturated
solution of sodium carbonate (36 ml). The mixture was stirred at
100.degree. C. for 16 h. in a sealed tube under nitrogen. The
mixture was diluted with dichloromethane and washed with water. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and
the solvents evaporated in vacuo. The crude product was purified by
flash column chromatography (silica; dichloromethane in heptane
20/80 to 80/20). The desired fractions were collected and
concentrated in vacuo to yield intermediate 55 (6.23 g, 53%). LCMS:
184 [M+H].sup.+; R.sub.t: 2.47 min (method 3).
Example A56
Preparation of intermediate 56:
5-Bromo-2-(2-methoxyethyl)-pyridine
##STR00116##
[0610] Sodium methoxide (5.48 g, 101.6 mmol) was added to a
solution of intermediate 55 (6.23 g, 33.8 mmol) in dry methanol
(120 ml). The mixture was stirred at 90.degree. C. for 36 h. and
then further sodium methoxide (1.82 g, 33.8 mmol) was added. The
mixture was stirred at 90.degree. C. for 7 h. and the solvents
evaporated in vacuo. The crude product was dissolved in
dichloromethane and washed with water. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica; heptane in dichloromethane 70/30 to 0/100).
The desired fractions were collected and concentrated in vacuo to
yield intermediate 56 (3.78 g, 52%). LCMS: 216 [M+H].sup.+;
R.sub.t: 1.21 min (method 5).
Example A57
Preparation of intermediate 57:
1-(5-Bromo-pyridin-2-yl)-2-methyl-propan-2-ol
##STR00117##
[0612] A 2.5 M solution of n-butyllithium in pentane (8.37 ml, 20.9
mmol) was added dropwise to a stirred solution of
N,N-diisopropylamine (3.45 ml, 24 4 mmol) in dry tetrahydrofuran
(20 ml) at -78.degree. C. The mixture was stirred at 0.degree. C.
for 30 min, cooled down to -78.degree. C. and then added dropwise
to a solution of 5-bromo-2-picoline (3.0 g, 17.4 mmol) in
tetrahydrofuran (20 ml). The mixture was stirred at -78.degree. C.
for 15 min. and then acetone (3.85 ml, 52.3 mmol) was added
dropwise. The mixture was stirred at -78.degree. C. for 20 min. and
then a saturated solution of ammonium chloride was added. The
organic layer was separated and the aqueous layer was extracted
with dichloromethane. The combined organic extracts were dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash column chromatography
(silica; ethyl acetate in dichloromethane 0/100 to 20/80). The
desired fractions were collected and concentrated in vacuo to yield
intermediate 57 (1.75 g, 43%) as a colourless oil.
Example A58
Preparation of intermediate 58:
5-Bromo-2-(2-methoxy-2-methyl-propyl)-pyridine
##STR00118##
[0614] A 60% suspension of sodium hydride in mineral oils (2.36 g,
58.9 mmol) was added portionwise to a stirred solution of
intermediate 57 (2.36 g, 58.9 mmol) in tetrahydrofuran (10 ml). The
mixture was stirred at 0.degree. C. for 30 min. and then
iodomethane (3.67 ml, 58.9 mmol) was added. The mixture was stirred
at room temperature for 18 h. and then further 60% suspension of
sodium hydride in mineral oils (2.36 g, 58.9 mmol) and iodomethane
(3.67 ml, 58.9 mmol) were added. The mixture was stirred at room
temperature for 3 h. and then the solvents were evaporated in
vacuo. The crude product was diluted with dichloromethane and
washed with a saturated solution of ammonium chloride and a
saturated solution of sodium hydrogen carbonate. The organic layer
was separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica; ethyl acetate in dichloromethane 0/100 to
10/90). The desired fractions were collected and concentrated in
vacuo to yield intermediate 58 (6.90 g, 53%).
Example A59
Preparation of intermediate 59:
5-Bromo-2-(3-methoxy-propyl)-pyridine
##STR00119##
[0616] 1,2-Dibromoethane (0.237 ml, 2.75 mmol) was added to a
stirred suspension of zinc (3.6 g, 55.0 mmol) in dry
N,N-dimethylformamide (40 ml). The mixture was stirred at
90.degree. C. for 30 min. under nitrogen and then allowed to warm
to room temperature. Chlorotrimethylsilane (0.09 ml, 0.69 mmol) was
added and the mixture was stirred at room temperature for 15 min. A
solution of intermediate 44 (5.5 g, 27 5 mmol) in tetrahydrofuran
(20 ml) was added dropwise and the mixture was stirred at
45.degree. C. for 2.5 h. The excess zinc was allowed to settle for
1 h and the supernatant liquid was transferred via cannula to a
mixture of 2,5-dibromopyridine (2.17 g, 9.17 mmol) and
bis(triphenylphosphine)palladium dichloride (0.212 g, 0.18 mmol).
The mixture was stirred at 55.degree. C. for 4 h. under nitrogen,
then the solvents were evaporated in vacuo. The crude product was
partitioned between dichloromethane and a saturated solution of
sodium hydrogen carbonate. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash column chromatography
(silica, ethyl acetate in dichloromethane 0/100 to 20/80). The
desired fractions were collected and concentrated in vacuo to yield
intermediate 59 (1.4 g, 66%).
Example A60
Preparation of intermediate 60: 5-Bromo-2-ethoxymethyl-pyridine
##STR00120##
[0618] A 60% suspension of sodium hydride in mineral oils (0.073 g,
3.19 mmol) was added to a stirred solution of
5-bromo-2-(hydroxymethyl)pyridine (0.5 g, 2.66 mmol) in
tetrahydrofuran (10 ml). The mixture was stirred at 0.degree. C.
for 30 min. and then iodoethane (0.498 g, 3.19 mmol) was added. The
mixture was stirred at 60.degree. C. for 18 h., then diluted with
diethyl ether and washed with a saturated solution of ammonium
chloride in water. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo
to yield intermediate 60 (0.520 g, 90%) as a colourless oil.
Example A61
Preparation of intermediate 61:
2-(2-Methoxy-ethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyri-
dine
##STR00121##
[0620] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (II)
(0.061 g, 0.083 mmol) was added to a stirred suspension of
intermediate 56 (0.6 g, 2.77 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (0.846
g, 3.33 mmol) and potassium acetate (0.817 g, 8.33 mmol) in a
mixture of 1,4-dioxane (9 ml) and N,N-dimethylformamide (1.2 ml).
The mixture was stirred at 150.degree. C. for 40 min. in a sealed
tube under nitrogen and under microwave irradiation. The mixture
was filtered through a pad of diatomaceous earth, and the filtrate
diluted with dichloromethane and washed with water. The organic
layer was separated, dried (Na.sub.2SO.sub.4), filtered and the
solvents evaporated in vacuo to yield intermediate 61 (1.1 g, 64%,
43% purity) used in next step without further purification. LCMS:
264 [M+H].sup.+; R.sub.t: 1.55 min (method 5).
[0621] The following intermediates were prepared from the indicated
precursors according to a protocol analogous to A61.
Example A62
Preparation of intermediate 62:
2-(2-Methoxy-2-methyl-propoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-
-2-yl)-pyridine
##STR00122##
[0623] From intermediate 46 in dimethylsulfoxide as solvent,
80.degree. C., 4h. Extraction with heptane yielded intermediate 62
as a colourless oil (97%).
Example A63
Preparation of intermediate 63:
2-(2-Methoxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyr-
idine
##STR00123##
[0625] From intermediate 47 in dimethylsulfoxide as solvent,
80.degree. C., 4h. Extraction with heptane yielded intermediate 63
as a colourless oil (93%).
Example A64
Preparation of intermediate 64:
2-Ethoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine
##STR00124##
[0627] From intermediate 60 in dimethylsulfoxide as solvent,
80.degree. C., 4h. Extraction with heptane yielded intermediate 64
as a colourless oil (84%).
Example A65
Preparation of intermediate 65:
1-(4-Iodo-pyrazol-1-yl)-2-methyl-propan-2-ol
##STR00125##
[0629] A mixture of 4-iodopyrazole (3 g, 15.47 mmol),
1-chloro-2-methyl-2-propanol and cesium carbonate (8.06 g, 24.75
mmol) in N,N-dimethylformamide (30 ml) was stirred at 160.degree.
C. for 40 min in a sealed tube, under microwave irradiation. The
mixture was diluted with water and extracted with dichloromethane.
The organic layer was separated, dried (Na.sub.2SO.sub.4), filtered
and the solvents evaporated in vacuo. The crude product was
purified by flash column chromatography (silica; ethyl acetate in
heptane 20/80 to 40/60). The desired fractions were collected and
concentrated in vacuo to yield intermediate 65 (3.98 g, 97%) as a
white solid.
Example A66
Preparation of intermediate 66:
4-Iodo-1-(2-methoxy-2-methyl-propyl)-1H-pyrazole
##STR00126##
[0631] A 60% dispersion of sodium hydride in mineral oils (1.85 g,
46.23 mmol) was added portionwise to a stirred solution of
intermediate 65 (4.1 g, 15.41 mmol) in tetrahydrofuran (70 ml) at
0.degree. C. The mixture was stirred at room temperature for 15 min
and then dimethyl sulfate (3.67 ml, 66.26 mmol) was added. The
mixture was stirred at room temperature for a further 18 h. and
then partitioned between dichloromethane and a saturated solution
of sodium hydrogen carbonate. The organic layer was separated,
dried (Na.sub.2SO.sub.4), filtered and the solvents evaporated in
vacuo. The crude product was purified by flash column
chromatography (silica; ethyl acetate in heptane 0/100 to 20/80).
Desired fractions were collected and concentrated in vacuo to yield
intermediate 66 (3.32 g, 74%) as a colorless oil.
Example A67
Preparation of intermediate 67:
1-(2-Methoxy-2-methyl-propyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-1H-pyrazole
##STR00127##
[0633] [1,1'-bis(diphenylphosphino)]dichloropalladium(II) (0.026 g,
0.36 mmol) was added to a stirred solution of intermediate 66 (1.18
g, 4.21 mmol), bis(pinacolato)diboron (1.28 g, 5.06 mmol) and
potassium acetate (1.24 g, 12.64 mmol) in dimethylsulfoxide (15
ml). The mixture was stirred at 80.degree. C. for 16 h. in a sealed
tube under nitrogen. After cooling to room temperature, the mixture
was partitioned between water and heptane and then filtered over
cotton to remove the resulting black slurry. The organic layer was
separated and the aqueous layer extracted with heptane. The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered and
the solvents evaporated in vacuo to yield intermediate 67 (0.96 g,
81%) which was used in the next step without further
purification.
Example A68
Preparation of intermediate 68:
1-(2-Methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-p-
yrazole
##STR00128##
[0635] A mixture of
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1 g,
5.15 mmol), 2-bromoethyl methyl ether (0.63 ml, 6.7 mmol) and
cesium carbonate (2.52 g, 7.73 mmol) in N,N-dimethylformamide (7
ml) was stirred at 150.degree. C. for 30 min. under microwave
irradiation. The mixture was partitioned between water and diethyl
ether. The organic layer was separated, dried (Na.sub.2SO.sub.4),
filtered and the solvents evaporated in vacuo. The crude product
was purified by flash column chromatography (silica; ethyl acetate
in heptane 30/70). The desired fractions were collected and
concentrated in vacuo to yield intermediate 68 (0.88 g, 68%) as a
pale yellow oil.
Example A69
Preparation of intermediate 69:
6-chloro-2-cyclopropyl-3-[1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4-yl]-8-
-(4-morpholinyl-1)-imidazo[1,2-b]pyridazine
##STR00129##
[0637] Tetrakis(triphenylphosphine)palladium(0) (0.068 g, 0.059
mmol) was added to a stirred solution of intermediate 34 (0.30 g,
0.84 mmol) and intermediate 67 (0.446 g, 1.59 mmol) in a mixture of
1,4-dioxane (20 ml) and a saturated solution of sodium carbonate (6
ml). The mixture was stirred at 150.degree. C. for 15 min, in a
sealed tube under nitrogen and under microwave irradiation. The
mixture was diluted with dichlorometane and washed with water. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and
the solvents evaporated in vacuo. The crude product was purified by
flash column chromatography (silica: 7 M solution of ammonia in
methanol in dichloromethane 0/100 to 2/98). The desired fractions
were collected and concentrated and the crude product purified
again by flash column chromatography (silica; ethyl acetate in
heptane 10/90 to 50/50). The desired fractions were collected and
concentrated in vacuo to yield intermediate 69 (0.216 g, 59%).
LCMS: 431 [M+H].sup.+; R.sub.t: 4.30 min (method 1). This compound
is also a final compound (compound 150).
B. Preparation of the Final Compounds
Example B1
Preparation of compound 1:
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine
##STR00130##
[0639] Palladium (II) acetate (0.066 g, 0.294 mmol) was added to a
stirred solution of intermediate 14 (1.5 g, 5.89 mmol),
intermediate A56 (1.91 g, 8.83 mmol), butyldi-1-adamantylphosphine
(0.211 g, 0.59 mmol) and potassium phosphate (3.75 g, 17.7 mmol) in
N,N-dimethylformamide (10 ml). The mixture was stirred at room
temperature for 15 min. and then at 120.degree. C. for 24 h. in a
sealed tube under nitrogen. The mixture was diluted with diethyl
ether and washed with a 1% potassium hydroxide solution. The
organic layer was separated, dried (MgSO.sub.4), filtered and the
solvents evaporated in vacuo. The crude product was purified by
flash column chromatography (silica; 7 M solution of ammonia in
methanol in dichloromethane 0/100 to 40/60). The desired fractions
were collected and concentrated in vacuo. The crude product was
triturated from diisopropyl ether to yield compound 1 (1.74 g, 84%)
as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
2.54 (s, 3H), 3.13 (t, J=6.7 Hz, 2H), 3.39 (s, 3H), 3.83 (t, J=6.8
Hz, 2H), 3.88-4.04 (m, 8H), 6.10 (d, J=5.5 Hz, 1H), 7.36 (d, J=8.1
Hz, 1H), 7.98 (dd, J=8.1, 2.1 Hz, 1H), 7.99 (d, J=5.5 Hz, 1H), 8.80
(d, J=2.3 Hz, 1H).
[0640] For compound 1, the hydrochloride salt (.HCl)
(mp=164.8.degree. C. with decomposition); the maleate salt
(.C.sub.4H.sub.4O.sub.4) (mp=113.8.degree. C.) and the monohydrate
(.H.sub.2O) (DSC: dehydration at about 88.degree. C. followed by
melt at 131.9.degree. C.), were obtained following the procedures
described below.
[0641] For the formation of the hydrochloride salt (compound
1a):
[0642] To a stirred solution of compound 1 (0.5 g, 1.41 mmol) in
2-butanone (7.50 mL) was added hydrogen chloride (1 N, 1.27 mL,
1.27 mmol). The mixture was concentrated in vacuo till dry at
50.degree. C., then 2-butanone (7.50 mL) was added. Formation of a
white solid was observed and the suspension was further stirred at
room temperature overnight. The solid was filtered off and dried
overnight at 50.degree. C. to yield the hydrochloride salt (0.397
g, 72%) as a white solid.
[0643] For the formation of the maleate salt (compound 1b):
[0644] To a mixture of compound 1 (1.00 g, 2.83 mmol) and
(Z)-2-butenedioic acid (344.85 mg, 2.97 mmol), was added
1-methoxy-2-propanol (15.00 mL) and the mixture was heated to
40.degree. C. then cooled down to 0.degree. C. and stirred
overnight at 0.degree. C. Precipitation was observed, with
formation of very fine solids, giving the reaction mixture an
almost milky appearance. A small amount of these solids was set
aside and used subsequently as seeding material (see below). The
mixture was heated to 50.degree. C. The solvent was partially
evaporated to a volume of 10 mL and the reaction mixture was seeded
with original solids at 45.degree. C. Stirring was continued at
45.degree. C. for 4 hours, then at 40.degree. C. for 2 hours and
continued at 20.degree. C. overnight. The resulting solid was
filtered off, washed once with a very small amount of propylene
glycol monomethyl ether (PGME) and once with methyl tert-butyl
ether (MTBE) and dried overnight at 45.degree. C., to yield the
maleate salt (850 mg, 64%) as a white to slightly yellow solid.
[0645] For the formation of the hydrate (compound 1c), two
different procedures were used:
a) water (2 mL) was added to the solid compound (20 mg) and allowed
to slurry at 70.degree. C. for 30 minutes. The heat was turned off
and the solution mixture was allowed to continue to slurry at room
temperature for 3 days. b) water (4 mL) was added to the solid
compound (200 mg) and allowed to slurry at room temperature for 5
days.
[0646] The product was then filtered off and dried to yield the
hydrate as a solid.
[0647] The following compounds were prepared from the indicated
precursors according to a protocol analogous to B1.
Example B2
Preparation of compound 2:
3-[6-(3-methoxypropyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,-
2-b]pyridazine
##STR00131##
[0649] From intermediate 14 and intermediate 59. Flash column
chromatography (silica; ethyl acetate in heptane 20/80 to 40/60)
and precipitation from methanol yielded compound 2 as a white solid
(55%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 1.99-2.17 (m,
2H), 2.54 (s, 3H), 2.93 (t, J=7.5 Hz, 2H), 3.37 (s, 3H), 3.48 (t,
J=6.4 Hz, 2H), 3.90-4.01 (m, 8H), 6.10 (d, J=5.8 Hz, 1H), 7.31 (d,
J=7.8 Hz, 1H), 7.97 (dd, J=8.1, 2.3 Hz, 1H), 7.99 (d, J=5.8 Hz,
1H), 8.78 (d, J=1.7 Hz, 1H).
Example B3
Preparation of compound 3:
3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-i-
midazo[1,2-b]pyridazine
##STR00132##
[0651] From intermediate 14 and intermediate 58. Flash column
chromatography (silica; methanol in dichloromethane 0/100 to 2/98)
yielded compound 3 as a white solid (56%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.16 (s, 6H), 2.44 (s, 3H), 2.96 (s, 2
H), 3.22 (s, 3H), 3.80 (br t, J=4.9 Hz, 4H), 3.97 (dd, J=4.9, 4.4
Hz, 4H), 6.37 (d, J=5.8 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.99 (dd,
J=8.1, 2.3 Hz, 1H), 8.10 (d, J=5.5 Hz, 1H), 8.74 (d, J=2.1 Hz,
1H).
Example B4
Preparation of compound 4:
3-[6-(2-methoxy-1,1-dimethylethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl-
)-imidazo[1,2-b]pyridazine
##STR00133##
[0653] From intermediate 14 and intermediate 54. Flash column
chromatography (silica; ethyl acetate in dichloromethane 0/100 to
100/0) yielded compound 4 as a white solid (74%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 1.41 (s, 6H), 2.55 (s, 3H), 3.34 (s,
3H), 3.62 (s, 2H), 3.85-4.05 (m, 8H), 6.10 (d, J=5.5 Hz, 1H), 7.49
(dd, J=8.3, 0.7 Hz, 1H), 7.99 (d, J=5.5 Hz, 1H), 8.01 (dd, J=8.3,
2.3 Hz, 1H), 8.84 (dd, J=2.1, 0.7 Hz, 1H).
Example B5
Preparation of compound 5:
3-[6-(1-ethoxy-1-methylethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imi-
dazo[1,2-b]pyridazine
##STR00134##
[0655] From intermediate 14 and intermediate 48. Flash column
chromatography (silica; ethyl acetate in heptane 0/100 to 100/0)
and precipitation from diethyl ether yielded compound 5 as a white
solid (92%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 1.16
(t, J=7.1 Hz, 3H), 1.53 (s, 6H), 2.46 (s, 3H), 3.32 (q, J=6.9 Hz,
2H), 3.80 (br. t, J=4.9 Hz, 4H), 3.98 (dd, J=4.9, 4.3 Hz, 4H), 6.38
(d, J=5.8 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 8.05-8.17 (m, 2H), 8.79
(d, J=1.7 Hz, 1H).
Example B6
Preparation of compound 6:
3-[6-(1-methoxy-1-methylethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-im-
idazo[1,2-b]pyridazine
##STR00135##
[0657] From intermediate 14 and intermediate 49. Flash column
chromatography (silica; ethyl acetate in heptane 0/100 to 100/0)
and precipitation from diethyl ether yielded compound 6 as a white
solid (92%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 1.53
(s, 6 H), 2.47 (s, 3H), 3.13 (s, 3H), 3.80 (br. t, J=4.9 Hz, 4H),
3.98 (dd, J=4.9, 4.3 Hz, 4 H), 6.39 (d, J=5.8 Hz, 1H), 7.67 (d,
J=8.1 Hz, 1H), 8.05-8.16 (m, 2H), 8.81 (d, J=1.7 Hz, 1H).
Example B7
Preparation of compound 7:
3-[6-(2-methoxy-2-methylpropyl)-3-pyridinyl-2-methyl-8-(4-pyridinyl)-imid-
azol-1,2-b]pyridazine
##STR00136##
[0659] From intermediate 20 and intermediate 58. Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 2/98), reverse phase HPLC (0.1% solution
of formic acid in acetonitrile 80/20 to 0/100) and precipitation
from diethyl ether yielded compound 7 as a white solid (54%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (s, 6H), 2.57
(s, 3H), 2.99 (s, 2H), 3.23 (s, 3H), 7.46 (d, J=8.1 Hz, 1H), 7.71
(d, J=4.9 Hz, 1H), 8.07 (dd, J=8.1, 2.3 Hz, 1H), 8.32 (d, J=6.2 Hz,
2 H), 8.65 (d, J=4.9 Hz, 1H), 8.78-8.86 (m, 3H).
Example B8
Preparation of compound 8:
3-[6-(2-methoxyethoxy)-5-methyl-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imi-
dazo[1,2-b]pyridazine
##STR00137##
[0661] From intermediate 20 and intermediate 45. Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 2/98) and precipitation from diethyl ether
yielded compound 8 as a yellow solid (79%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 2.25 (s, 3H), 2.53 (s, 3H), 3.35 (s, 3H),
3.73 (br. t, J=4.6 Hz, 2H), 4.50 (br. t, J=4.9 Hz, 2H), 7.68 (d,
J=4.9 Hz, 1H), 7.88-7.93 (m, 1H), 8.30 (d, J=1.7 Hz, 1H), 8.32 (d,
J=6.4 Hz, 2H), 8.63 (d, J=4.9 Hz, 1H), 8.82 (d, J=6.1 Hz, 2H).
Example B9
Preparation of compound 9:
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(3-pyridinyl)-imidazo[1,2--
b]pyridazine
##STR00138##
[0663] From intermediate 19 and intermediate 47. Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 2/98), reverse phase HPLC (0.1% solution
of ammonium formate/ammonium hydroxide buffer pH 9 and acetonitrile
20/80 to 0/100) and precipitation from diethyl ether yielded
compound 9 as a pale yellow solid (73%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 2.54 (s, 3H), 3.33 (s, 3H), 3.71 (br. t,
J=4.6 Hz, 2H), 4.47 (br. t, J=4.6 Hz, 2H), 7.04 (d, J=8.7 Hz, 1H),
7.64 (d, J=4.9 Hz, 1H), 7.65 (d, J=4.6 Hz, 1H), 8.08 (dd, J=8.5,
2.5 Hz, 1H), 8.49 (d, J=2.6 Hz, 1H), 8.59 (d, J=4.6 Hz, 1H), 8.72
(dt, J=8.0, 1.9 Hz, 1H), 8.74 (dd, J=4.8, 1.6 Hz, 1H), 9.47 (d,
J=2.0 Hz, 1H).
Example B10
Preparation of compound 10:
2-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[-
1,2-b]pyridazine
##STR00139##
[0665] From intermediate 18 and intermediate 56. Flash column
chromatography (silica; ethyl acetate in dichloromethane 30/70 to
100/0) and precipitation from diisopropyl ether yielded compound 10
as a pale yellow solid (31%). .sup.1H NMR (400 MHz, CDCl.sub.3) 6
ppm 1.02-1.09 (m, 2H), 1.19-1.28 (m, 2H), 2.14-2.26 (m, 1H), 3.17
(t, J=6.6 Hz, 2H), 3.41 (s, 3H), 3.86 (t, J=6.7 Hz, 2H), 7.26 (d,
J=4.6 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 8.14 (dd, J=8.1, 2.3 Hz,
1H), 8.14-8.19 (m, J=6.0 Hz, 2H), 8.37 (d, J=4.6 Hz, 1H), 8.81 (d,
J=6.0 Hz, 2H), 9.03 (d, J=2.1 Hz, 1H).
Example B11
Preparation of compound 11:
3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-morpholinyl)-imidazo[1,2-b]pyrida-
zine
##STR00140##
[0667] From intermediate 17 and intermediate 56. Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 3/97) and filtration through an Isolute
SCX-2 cartridge followed by elution with a 7 M solution of ammonia
in methanol yielded compound 11 as a white solid (83%). .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 3.01 (t, J=6.6 Hz, 2H), 3.25
(s, 3H), 3.72 (t, J=6.5 Hz, 2H), 3.79 (br. t, J=4.9 Hz, 4H), 4.00
(dd, J=4.9, 4.3 Hz, 4H), 6.42 (d, J=5.8 Hz, 1H), 7.41 (d, J=8.4 Hz,
1H), 8.06 (s, 1H), 8.24 (d, J=5.8 Hz, 1H), 8.38 (dd, J=8.1, 2.3 Hz,
1H), 9.14 (d, J=1.7 Hz, 1H).
Example B12
Preparation of compound 12:
2-methoxy-3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-morpholinyl)-imidazo[1,-
2-b]pyridazine
##STR00141##
[0669] From intermediate 15 and intermediate 56. Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 3/97) and precipitation from diisopropyl
ether yielded compound 12 as a white solid (83%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 2.98 (t, J=6.7 Hz, 2H), 3.25 (s,
3H), 3.71 (t, J=6.6 Hz, 2H), 3.80 (dd, J=5.1, 4.4 Hz, 4H), 3.92
(dd, J=5.1, 4.4 Hz, 4H), 4.06 (s, 3H), 6.48 (d, J=6.0 Hz, 1H), 7.38
(d, J=8.3 Hz, 1H), 8.21 (d, J=5.8 Hz, 1H), 8.35 (dd, J=8.3, 2.3 Hz,
1H), 9.15 (d, J=2.3 Hz, 1H).
Example B13
Preparation of compound 13:
6-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholiny-
l)-imidazo[1,2-b]pyridazine
##STR00142##
[0671] From intermediate 23 and intermediate 56. Flash column
chromatography (silica; ethyl acetate in heptane 0/100 to 100/0)
yielded compound 13 as a white solid (85%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 0.93-0.96 (m, 4H), 1.88-1.97 (m, 1H), 2.53
(s, 3H), 3.13 (t, J=6.7 Hz, 2H), 3.40 (s, 3H), 3.84 (t, J=6.7 Hz,
2H), 3.87-3.92 (m, 4H), 3.92-3.98 (m, 4H), 5.98 (s, 1H), 7.33 (d,
J=8.1 Hz, 1H), 7.97 (dd, J=8.1, 2.3 Hz, 1 H), 8.85 (d, J=1.6 Hz,
1H).
Example B14
Preparation of compound 14:
6-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-
-imidazo[1,2-b]pyridazine
##STR00143##
[0673] From intermediate 24 and intermediate 56. Flash column
chromatography (silica; methanol and ethyl acetate in heptane
0/30/70 to 2/98/0) and precipitation from diisopropyl ether yielded
compound 14 as a pale yellow solid (85%). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. ppm 1.03-1.15 (m, 4H), 2.08-2.18 (m, 1H), 2.63
(s, 3H), 3.16 (t, J=6.5 Hz, 2H), 3.41 (s, 3H), 3.87 (t, J=6.6 Hz,
2H), 7.06 (s, 1H), 7.39 (d, J=8.1 Hz, 1H), 8.00 (dd, J=8.1, 2.3 Hz,
1H), 8.05 (d, J=6.1 Hz, 2H), 8.81 (d, J=6.1 Hz, 2H), 8.91 (d, J=1.7
Hz, 1H).
Example B15
Preparation of compound 15:
2-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-6-methyl-8-(4-morpholiny-
l)-imidazo[1,2-b]pyridazine
##STR00144##
[0675] From intermediate 25) and intermediate 56. Flash column
chromatography (silica; ethyl acetate in heptane 20/80 to 50/50)
yielded compound 15 as a white solid (47%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 0.91-0.98 (m, 2H), 1.03-1.13 (m, 2H),
2.05-2.15 (m, 1H), 2.41 (s, 3H), 3.13 (t, J=6.8 Hz, 2H), 3.40 (s,
3H), 3.84 (t, J=6.7 Hz, 2 H), 3.90 (br. s., 8H), 5.96 (s, 1H), 7.35
(d, J=8.1 Hz, 1H), 8.13 (dd, J=8.1, 2.3 Hz, 1 H), 9.02 (d, J=2.3
Hz, 1H).
Example B16
Preparation of compound 16:
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,-
2-b]pyridazine
##STR00145##
[0677] Tetrakis(triphenylphosphine)palladium (0) (0.034 g, 0.009
mmol) was added to a stirred solution of intermediate 26 (0.2 g,
0.58 mmol) and intermediate 63 (0.243 g, 0.87 mmol), in a mixture
of 1,4-dioxane (5 ml) and a saturated solution of sodium carbonate
(3 ml). The mixture was stirred at 80.degree. C. for 16 h. in a
sealed tube under nitrogen and then diluted with dichloromethane
and washed with water. The organic layer was separated, filtered
over cotton, and the solvents evaporated in vacuo. The crude
product was purified by flash column chromatography (silica; ethyl
acetate in dichloromethane 0/100 to 50/50). The desired fractions
were collected and concentrated in vacuo to yield compound 16
(0.151 g, 70%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.51
(s, 3H), 3.46 (s, 3H), 3.78 (t, J=4.6 Hz, 2H), 3.86-4.06 (m, 8H),
4.55 (dd, J=4.9, 4.4 Hz, 2H), 6.08 (d, J=5.5 Hz, 1H), 6.96 (d,
J=8.8 Hz, 1H), 7.92 (dd, J=8.6, 2.3 Hz, 1H), 7.97 (d, J=5.5 Hz,
1H), 8.37 (d, J=2.3 Hz, 1H).
[0678] The following compounds were prepared from the indicated
precursors according to a protocol analogous to B16.
Example B17
Preparation of compound 17:
3-[6-(ethoxymethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-b-
]pyridazine
##STR00146##
[0680] From intermediate 26 and intermediate 64. Conditions:
150.degree. C., 15 min, microwave irradiation. Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 2/98) yielded compound 17 as a white solid
(75%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.21 (t,
J=7.1 Hz, 3H), 2.45 (s, 3H), 3.60 (q, J=7.0 Hz, 2H), 3.79 (dd,
J=5.1, 4.4 Hz, 4H), 3.98 (br. t, J=4.6 Hz, 4H), 4.60 (s, 2H), 6.37
(d, J=5.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 8.10 (dd, J=8.1, 2.1 Hz,
1H), 8.10 (d, J=5.8 Hz, 1H), 8.78 (d, J=2.1 Hz, 1H).
Example B18
Preparation of compound 18:
3-[6-(2-methoxy-2-methylpropoxy)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)--
imidazo[,2-b]pyridazine
##STR00147##
[0682] From intermediate 26 and intermediate 62. Conditions:
140.degree. C., 20 min, microwave irradiation. Flash column
chromatography (silica; ethyl acetate in dichloromethane 0/100 to
50/50) yielded compound 18 as a white solid (82%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 1.32 (s, 6H), 2.51 (s, 3H), 3.32 (s,
3H), 3.90-4.01 (m, 8H), 4.30 (s, 2 H), 6.08 (d, 1H), 6.98 (dd,
J=8.6, 0.5 Hz, 1H), 7.93 (dd, J=8.6, 2.3 Hz, 1H), 7.97 (d, J=5.5
Hz, 1H), 8.37 (d, J=1.8 Hz, 1H).
Example B19
Preparation of compound 19:
2-methyl-8-(4-morpholinyl)-3-[6-(4-morpholinyl)-3-pyridinyl]-imidazo[1,2--
b]pyridazine
##STR00148##
[0684] From intermediate 26 and commercially available
1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]morpholi-
ne. Flash column chromatography (silica; ethyl acetate in heptanes
0/100 to 40/60) and flash column chromatography (silica; ethyl
acetate and dichloromethane in heptane from 0/0/100 to 20/80/0)
yielded compound 19 as a white solid (69%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 2.51 (s, 3 H), 3.58 (dd, J=5.1, 4.6 Hz,
4H), 3.85 (dd, J=5.1, 4.6 Hz, 4H), 3.95 (br. s., 8H), 6.06 (d,
J=5.8 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 7.86 (dd, J=8.8, 2.3 Hz,
1H), 7.97 (d, J=5.5 Hz, 1H), 8.43 (d, J=2.3 Hz, 1H).
Example B20
Preparation of compound 20:
3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imidazo[1,2-b-
]pyridazine
##STR00149##
[0686] From intermediate 33 and intermediate 61. Conditions:
150.degree. C., 5 min, microwave irradiation. Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 4/96) and precipitation from diisopropyl
ether yielded compound 20 as a white solid (45%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 2.66 (s, 3H), 3.16 (t, J=6.6 Hz, 2H),
3.41 (s, 3H), 3.86 (t, J=6.7 Hz, 2H), 7.24 (d, J=4.9 Hz, 1H), 7.41
(d, J=8.1 Hz, 1H), 8.02 (dd, J=8.1, 2.3 Hz, 1H), 8.09 (d, J=6.2 Hz,
2 H), 8.40 (d, J=4.9 Hz, 1H), 8.83 (d, J=6.2 Hz, 2H), 8.88 (d,
J=2.3 Hz, 1H).
Example B21
Preparation of compound 21:
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imidazo[1,2--
b]pyridazine
##STR00150##
[0688] From intermediate 33 and intermediate 63. Conditions:
150.degree. C., 15 min, microwave irradiation. Flash column
chromatography (silica; ethyl acetate in heptane 0/100 to 100/0)
and precipitation from diethyl ether yielded compound 21 as a white
solid (44%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 2.55
(s, 3H), 3.34 (s, 3H), 3.72 (br t, J=4.6 Hz, 2H), 4.48 (br t, J=4.6
Hz, 2H), 7.05 (d, J=8.7 Hz, 1H), 7.70 (d, J=4.6 Hz, 1H), 8.09 (dd,
J=8.7, 2.3 Hz, 1H), 8.33 (dd, J=4.6, 1.7 Hz, 2H), 8.49 (d, J=2.0
Hz, 1H), 8.63 (d, J=4.6 Hz, 1H), 8.82 (dd, J=4.6, 1.7 Hz, 2H).
Example B21a
Preparation of compound 21a:
3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imidazo[1,2--
b]pyridazine hydrochloride salt
##STR00151##
[0690] Hydrochloric acid (38.16 mL, 2M solution in diethyl ether)
was added to a solution of compound 21 (19.7 g, 54.51 mmol) in a
mixture of diethylether (220 mL) and dichloromethane (600 mL). The
mixture was stirred at room temperature for 2.5 h and then
concentrated in vacuo. Diethyl ether was then added, and the solid
was filtered, washed with diethyl ether and dried overnight in
vacuo, to yield compound 21a (20.94 g, 91%) as an orange solid.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 2.57 (s, 3H), 3.33
(s, 3H), 3.67-3.76 (m, 2H), 4.42-4.51 (m, 2H), 7.07 (d, J=8.7 Hz,
1H), 7.94 (d, J=4.6 Hz, 1H), 8.09 (dd, J=8.5, 2.5 Hz, 1H), 8.50 (d,
J=2.3 Hz, 1H), 8.77 (d, J=4.9 Hz, 1H), 8.88-8.98 (m, 2H), 9.09-9.17
(m, 2H).
Example B22
Preparation of compound 22:
2-cyclopropyl-3-[6-(2-methoxyethyl)-3-pyridinyl]-8-(4-morpholinyl)-imidaz-
o[1,2-b]pyridazine
##STR00152##
[0692] From intermediate 27 and intermediate 61. Conditions:
150.degree. C., 15 min, microwave irradiation. Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 7/93) and reverse phase HPLC (0.1%
solution of ammonium formate/ammonium hydroxide buffer pH 9 and
acetonitrile 80/20 to 0/100) yielded compound 22 as a white solid
(14%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.92-1.01 (m,
2H), 1.06-1.13 (m, 2H), 2.05-2.16 (m, 1H), 3.13 (t, J=6.7 Hz, 2H),
3.39 (s, 3H), 3.83 (t, J=6.7 Hz, 2H), 3.88-4.05 (m, 8H), 6.06 (d,
J=5.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.96 (d, J=5.8 Hz, 1H), 8.10
(dd, J=8.0, 2.2 Hz, 1H), 8.96 (d, J=2.3 Hz, 1H).
Example B23
Preparation of compound 23:
3-[6-(2-methoxyethyl)-3-pyridinyl]-2,6-dimethyl-8-(4-morpholinyl)-imidazo-
[1,2-b]pyridazine
##STR00153##
[0694] From intermediate 28 and intermediate 61. Conditions:
150.degree. C., 15 min, microwave irradiation. Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 2/98) and reverse phase HPLC (0.1%
solution of ammonium formate/ammonium hydroxide buffer pH 9 and
acetonitrile 80/20 to 0/100) yielded compound 23 as a white solid
(14%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.41 (s, 3H),
2.52 (s, 3H), 3.13 (t, J=6.7 Hz, 2H), 3.40 (s, 3H), 3.84 (t, J=6.7
Hz, 2H), 3.88-3.97 (m, 8H), 5.99 (s, 1H), 7.34 (d, J=8.1 Hz, 1H),
7.99 (dd, J=8.1, 2.3 Hz, 1H), 8.86 (d, J=2.3 Hz, 1H).
Example B24
Preparation of compound 24:
3-[6-(2-methoxyethyl)-3-pyridinyl]-2,6-dimethyl-8-(4-pyridinyl)-imidazo[1-
,2-b]pyridazine
##STR00154##
[0696] From intermediate 30 and intermediate 61. Conditions:
150.degree. C., 15 min, microwave irradiation. Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 2/98) and flash column chromatography
(silica; 7 M solution of ammonia in methanol in dichloromethane
0/100 to 5/95) and precipitation from diisopropyl ether yielded
compound 24 as a yellow solid (29%). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. ppm 2.62 (s, 3H), 2.64 (s, 3H), 3.16 (t, J=6.5
Hz, 2H), 3.41 (s, 3H), 3.87 (t, J=6.6 Hz, 2H), 7.12 (s, 1H), 7.40
(d, J=8.1 Hz, 1H), 8.02 (dd, J=8.1, 2.3 Hz, 1H), 8.06 (d, J=6.1 Hz,
2H), 8.81 (d, J=6.1 Hz, 2H), 8.93 (d, J=1.7 Hz, 1H).
Example B25
Preparation of compound 25:
3-[6-(2-ethoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2--
b]pyridazine
##STR00155##
[0698] A 60% dispersion of sodium hydride in mineral oils (0.2 g, 5
mmol) was added portionwise to a stirred solution of intermediate
38 (0.2 g, 0.62 mmol) in ethanol (8 ml). The mixture was stirred at
100.degree. C. for 16 h. in a sealed tube and then poured onto
water and extracted with dichloromethane. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 1/99). The desired fractions were
collected and concentrated in vacuo to yield compound 25 (0.042 g,
18%) as a white solid.
[0699] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 1.10 (t,
J=6.9 Hz, 3H), 2.44 (s, 3H), 3.02 (t, J=6.8 Hz, 2H), 3.46 (q, J=6.9
Hz, 2H), 3.72-3.84 (m, 6H), 3.97 (dd, J=4.9, 4.3 Hz, 4 H), 6.37 (d,
J=5.8 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.99 (dd, J=8.1, 2.3 Hz,
1H), 8.09 (d, J=5.8 Hz, 1H), 8.74 (d, J=1.7 Hz, 1H).
[0700] The following compound was prepared from the indicated
precursors according to aprotocol analogous to B25.
Example B26
Preparation of compound 26:
3-[2-(2-methoxyethyl)-4-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-
-b]pyridazine
##STR00156##
[0702] From intermediate 40 and sodium methoxide. Flash column
chromatography (silica; ethyl acetate in heptane 20/80 to 100/0)
yielded compound 26 as a white solid (69%). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. ppm 2.58 (s, 3H), 3.15 (t, J=6.8 Hz, 2H), 3.38
(s, 3H), 3.83 (t, J=6.8 Hz, 2H), 3.88-4.03 (m, 8H), 6.13 (d, J=5.5
Hz, 1H), 7.54 (dd, J=5.2, 1.7 Hz, 1H), 7.60 (br. s., 1H), 8.03 (d,
J=5.8 Hz, 1H), 8.64 (d, J=5.2 Hz, 1H).
Example B27
Preparation of compound 27:
2-methyl-8-(4-morpholinyl)-3-[6-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl]-i-
midazo[1,2-b]pyridazine
##STR00157##
[0704] 10% Palladium on charcoal (0.069 g) was added to a
suspension of intermediate 41 (0.245 g, 0.65 mmol) and ammonium
formate (0.122 g, 1.95 mmol) in methanol (10 ml). The mixture was
stirred at 85.degree. C. for 4 h. and then more 10% palladium on
charcoal (0.69 g) and ammonium formate (0.122 g, 1.95 mmol) were
added. The mixture was stirred at 90.degree. C. for a further 16h.
and then filtered through a pad of diatomaceous earth and the
filtrate concentrated in vacuo. The crude product was diluted with
dichloromethane and washed with water. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica; ethyl acetate in heptane 30/70 to 100/0).
The desired fractions were collected and evaporated to yield
compound 27 (0.21 g, 86%) as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.83-2.06 (m, 4 H), 2.54 (s, 3H), 2.94-3.10
(m, 1H), 3.51-3.65 (m, 2H), 3.87-4.03 (m, 8H), 4.07-4.19 (m, 2H),
6.10 (d, J=5.8 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.99 (d, J=5.5 Hz,
1H), 8.02 (dd, J=8.2, 2.2 Hz, 1H), 8.80 (d, J=2.1 Hz, 1H).
Example B28
Preparation of compound 28:
3-(6-ethyl-3-pyridinyl)-2-methyl-8-(4-morpholinyl)-imidazo[1,2-b]pyridazi-
ne
##STR00158##
[0706] 10% Palladium on charcoal (0.405 g) was added to a
suspension of intermediate 38 (2.45 g, 7.62 mmol) in a mixture of
methanol (90 ml) and ethyl acetate (90 ml). The mixture was
hydrogenated (atmospheric pressure) at room temperature for 16 h.
and then filtered through a pad of diatomaceous earth. The filtrate
was concentrated in vacuo. The crude product was purified by flash
column chromatography (silica; ethyl acetate in dichloromethane
0/100 to 100/0). The desired fractions were collected and
concentrated in vacuo. The crude product was precipitated from
diethyl ether to yield compound 28 (0.675 g, 27%) as a white solid.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 1.28 (t, J=7.7 Hz,
3H), 2.44 (s, 3H), 2.82 (q, J=7.6 Hz, 2H), 3.79 (br t, J=4.9 Hz,
4H), 3.97 (dd, J=4.9, 4.3 Hz, 4H), 6.36 (d, J=5.8 Hz, 1H), 7.41 (d,
J=8.1 Hz, 1H), 7.99 (dd, J=8.1, 2.3 Hz, 1H), 8.09 (d, J=5.8 Hz,
1H), 8.73 (d, J=1.7 Hz, 1H).
Example B29
Preparation of compound 29:
3-[6-(3-methoxy-3-methylbutyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-im-
idazo[1,2-b]pyridazine
##STR00159##
[0708] 1,2-Dibromoethane (0.016 ml, 0.19 mmol) was added to a
stirred suspension of zinc (0.337 g, 5.17 mmol) in dry
N,N-dimethylformamide (8 ml). The mixture was stirred at 90.degree.
C. for 30 min. under nitrogen and then allowed to cool down to room
temperature. Chlorotrimethylsilane (0.006 ml, 0.048 mmol) was added
and the mixture was stirred at room temperature for 15 min. A
solution of intermediate 43 (0.7 g, 2.58 mmol) in tetrahydrofuran
(3 ml) was added dropwise and the mixture was stirred at 50.degree.
C. for 1.5 h. The excess zinc was allowed to settle for 1 h and the
supernatant liquid was transferred via cannula to a second flask
charged with intermediate 35 (0.21 g, 0.64 mmol) and
tetrakis(triphenylphosphine)palladium (0) (0.015 g, 0.013 mmol).
The mixture was stirred at 55.degree. C. for 16 h. under nitrogen,
and then a saturated solution of ammonium chloride was added. The
mixture was extracted with ethyl acetate and the organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica; methanol in dichloromethane 0/100 to 2/98).
The desired fractions were collected and concentrated to yield
compound 29 (0.071 g, 28%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.26 (s, 6H), 1.86-2.07 (m, 2H), 2.53 (s, 3H),
2.79-2.99 (m, 2H), 3.26 (s, 3H), 3.80-4.11 (m, 8H), 6.09 (d, J=5.5
Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.96 (dd, J=8.1, 1.6 Hz, 1H), 7.98
(d, J=5.5 Hz, 1H), 8.78 (br. s., 1H).
Example B30
Preparation of compound 30:
2-methyl-8-(4-morpholinyl)-3-[6-(1-piperazinyl)-3-pyridinyl]-imidazo[1,2--
b]pyridazine
##STR00160##
[0710] Piperazine (4.68 g, 54.4 mmol) was added to a stirred
solution of intermediate 35 (2.7 g, 6.80 mmol) in acetonitrile (24
ml). The mixture was stirred at 120.degree. C. for 1 d. in a sealed
tube and then diluted with dichloromethane and washed with water.
The organic layer was separated, dried (Na.sub.2SO.sub.4), filtered
and the solvents evaporated in vacuo. The crude product was
purified by column chromatography (silica; 7 M solution of ammonia
in methanol in dichloromethane 0/100 to 3/97). The desired
fractions were collected and concentrated in vacuo and the crude
product was precipitated from diisopropyl ether to yield compound
30 (1.64 g, 39%) as a pale yellow solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.75 (s, 1H), 2.51 (s, 3H), 3.01 (br. t,
J=5.1 Hz, 4H), 3.59 (dd, J=5.3, 4.9 Hz, 4H), 3.83-4.07 (m, 8H),
6.06 (d, J=5.8 Hz, 1H), 6.78 (d, J=9.0 Hz, 1H), 7.83 (dd, J=8.9,
2.4 Hz, 1H), 7.97 (d, J=5.5 Hz, 1H), 8.41 (d, J=2.3 Hz, 1H).
[0711] The following compound was prepared from the indicated
precursors according to a protocol analogous to that used of
B30.
Example B31
Preparation of compound 31:
2-methyl-3-[6-(4-morpholinyl)-3-pyridinyl]-8-(4-pyridinyl)-imidazo[1,2-b]-
pyridazine
##STR00161##
[0713] From intermediate 37 and morpholine. Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 2/98) and precipitation from diethyl ether
yielded compound 31 as an orange solid (80%). M.p.>300.degree.
C. (decomposition). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
2.53 (s, 3H), 3.55 (dd, J=5.2, 4.6 Hz, 4H), 3.74 (br. t, J=4.6 Hz,
4H), 7.02 (d, J=8.7 Hz, 1H), 7.64 (d, J=4.9 Hz, 1H), 7.91 (dd,
J=8.8, 2.5 Hz, 1H), 8.32 (d, J=6.1 Hz, 2H), 8.45 (d, J=2.0 Hz, 1H),
8.59 (d, J=4.9 Hz, 1H), 8.81 (d, J=6.4 Hz, 2H).
Example B32
Preparation of compound 32:
2-methyl-3-[6-(1-methylethyl)-3-pyridinyl]-8-(4-morpholinyl)-imidazo[1,2--
b]pyridazine
##STR00162##
[0715] A 2M solution of isopropylmagnesium chloride in
tetrahydrofuran (0.758, 1.52) was added to a stirred solution of
intermediate 35 (0.25 g, 0.76 mmol) and
[1,3-bis(diphenylphosphino)propane]dichloronickel (II) (0.021 g,
0.038 mmol) in tetrahydrofuran (5 ml) at 0.degree. C. The mixture
was allowed to warm to room temperature over 1 h. and then stirred
for a further 2h. A 10% solution of ammonium chloride solution was
added and the mixture was extracted with dichloromethane. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and
the solvents evaporated in vacuo. The crude product was purified by
flash column chromatography (silica; 7 M solution of ammonia in
methanol in dichloromethane 0/100 to 2/98). The less pure fractions
were evaporated in vacuo and the residue purified again by flash
column chromatography (silica, ethyl acetate in heptane 20/80 to
60/40). The desired fractions were combined and concentrated in
vacuo to yield compound 32 (0.116 g, 45%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.36 (d, J=6.9 Hz, 6H), 2.54 (s, 3H), 3.13
(spt, J=6.9 Hz, 1H), 3.85-4.07 (m, 8H), 6.09 (d, J=5.5 Hz, 1H),
7.32 (d, J=8.1 Hz, 1H), 7.98 (dd, J=8.1, 2.1 Hz, 1H), 7.99 (d,
J=5.5 Hz, 1H), 8.79 (d, J=2.1 Hz, 1H).
Example B33
Preparation of compound 33:
3-(6-cyclopropyl-3-pyridinyl)-2-methyl-8-(4-morpholinyl)-imidazo[1,2-b]py-
ridazine
##STR00163##
[0717] Palladium (II) acetate (0.031 g, 0.14 mmol) was added to a
stirred solution of intermediate 35 (0.3 g, 0.91 mmol),
cyclopropylboronic acid (0.117 g, 1.37 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.244 g, 0.594
mmol) and potassium phosphate (0.11 g, 0.27 mmol) in toluene (5
ml). The mixture was stirred at 80.degree. C. for 1 d. in a sealed
tube under nitrogen and then diluted with dichloromethane and
washed with water. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash column chromatography
(silica; ethyl acetate in heptane 20/80 to 100/0). The desired
fractions were collected and concentrated in vacuo and the crude
product triturated with diisopropyl ether to yield compound 33
(0.091 g, 30%) as a white solid. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. ppm 1.00-1.06 (m, 2H), 1.06-1.12 (m, 2H), 2.06-2.13 (m,
1H), 2.51 (s, 3H), 3.90-4.00 (m, 8H), 6.08 (d, J=5.8 Hz, 1H), 7.26
(d, J=7.5 Hz, 4H), 7.89 (dd, J=8.1, 2.0 Hz, 1H), 7.97 (d, J=5.5 Hz,
1H), 8.69 (d, J=2.3 Hz, 1H).
Example B34
Preparation of compound 34:
3-[6-[(3R)-3-methoxy-1-pyrrolidinyl]-3-pyridinyl]-2-methyl-8-(4-morpholin-
yl)-imidazo[1,2-b]pyridazine
##STR00164##
[0719] A mixture of intermediate 35 (0.2 g, 0.61 mmol),
(R)-(+)-3-pyrrolidinol (0.21 g, 2.43 mmol) and
diisopropylethylamine (0.158 ml, 0.91 mmol) was stirred at
120.degree. C. for 3 h. The mixture was diluted with
dichloromethane and extracted with a saturated solution of ammonium
chloride. The organic layer was separated, dried (MgSO.sub.4),
filtered and the solvents evaporated in vacuo. The crude product
was dissolved in tetrahydrofuran (10 ml) and sodium tert-butoxide
(0.34 g, 3.03 mmol), 18-crown-6 (0.024 g, 0.091 mmol) and
iodomethane (0.378 ml, 6.06 mmol) were added. The mixture was
stirred at room temperature for 18 h., then diluted with
dichloromethane and washed with water. The organic layer was
separated, dried (MgSO.sub.4), filtered and the solvents evaporated
in vacuo. The crude product was purified by column chromatography
(silica; dichloromethane). The desired fractions were collected and
concentrated in vacuo to yield compound 34 (0.091 g, 30%) as a
white solid. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm
2.08-2.24 (m, 2H), 2.50 (s, 3H), 3.38 (s, 3H), 3.59 (dd, J=8.5, 5.9
Hz, 2H), 3.64-3.71 (m, 2H), 3.90-3.98 (m, 8H), 4.08-4.14 (m, 1H),
6.04 (d, J=5.5 Hz, 1H), 6.51 (d, J=8.7 Hz, 1H), 7.78 (dd, J=8.7,
2.3 Hz, 1H), 7.95 (d, J=5.5 Hz, 1H), 8.37 (d, J=2.3 Hz, 1H).
Example B35
Preparation of compound 35:
2-methyl-3-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-morpholinyl)-imidazo-
[1,2-b]pyridazine
##STR00165##
[0721] Tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.015
mmol) was added to a stirred solution of intermediate 26 (0.2 g,
0.58 mmol) and
1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(0.18 g, 0.73 mmol) in a mixture of 1,4-dioxane (8 ml) and a
saturated solution of sodium carbonate (2 ml). The mixture was
stirred at 140.degree. C. for 20 min. in a sealed tube under
nitrogen, under microwave irradiation. The mixture was filtered
through a pad of diatomaceous earth and the filtrate diluted with
dichlorometane and extracted with water. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica; ethyl acetate in dichloromethane 0/100 to
40/60). The desired fractions were collected and concentrated in
vacuo to yield compound 35 (0.14 mg, 71%) as a white solid. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. ppm 0.97 (d, J=6.6 Hz, 6H), 2.30
(spt, J=6.7 Hz, 1H), 2.61 (s, 3H), 3.89-3.97 (m, 8H), 4.01 (d,
J=7.2 Hz, 2H), 6.06 (d, J=5.8 Hz, 1H), 8.01 (s, 1H), 8.05 (d, J=5.5
Hz, 1H), 8.17 (s, 1H).
[0722] The following compounds were prepared from the indicated
precursors according to a protocol analogous to that of B35.
Example B36
Preparation of compound 36:
3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-morpholinyl)-imidazo-
[1,2-b]pyridazine
##STR00166##
[0724] From intermediate 32 and intermediate 68). Flash column
chromatography (silica; 7 M solution of ammonia in methanol in
dichloromethane 0/100 to 4/96) and precipitation from diisopropyl
ether yielded compound 36 as a white solid (57%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 2.61 (s, 3H), 3.36 (s, 3H), 3.82 (t,
J=5.4 Hz, 2H), 3.94 (br. s, 8H), 4.39 (t, J=5.4 Hz, 2H), 6.06 (d,
J=5.8 Hz, 1H), 8.04 (s, 1H), 8.05 (d, J=5.5 Hz, 1H), 8.24 (s,
1H).
Example B37
Preparation of compound 37:
3-[1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-morpholiny-
l)-imidazo[1,2-b]pyridazine
##STR00167##
[0726] From intermediate 26 and intermediate 67. Flash column
chromatography (silica; ethyl acetate and dichloromethane in
heptane 0/100/0 to 0/0/100 to 80/0/20), filtration through Isolute
SCX-2 cartridge and precipitation from diethyl ether yielded
compound 37 as a white solid (29%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 1.12 (s, 6H), 2.50 (s, 3H), 3.20 (s, 3H),
3.78 (br t, J=4.9 Hz, 4H), 3.96 (br t, J=4.9 Hz, 4H), 4.23 (s, 2H),
6.31 (d, J=5.8 Hz, 1H), 8.00 (s, 1H), 8.16 (d, J=5.8 Hz, 1H), 8.26
(s, 1 H).
Example B38
Preparation of compound 38:
2-cyclopropyl-3-[1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4-yl]-8-(4-morph-
olinyl)-imidazo[1,2-b]pyridazine
##STR00168##
[0728] 10% Palladium on activated charcoal (0.284 g) was added to a
mixture of intermediate 69 (0.125 g, 0.29 mmol) and triethylamine
(0.08 ml, 0.58 mmol) in a mixture of methanol (6 ml) and
tetrahydrofuran (6 ml). The mixture was hydrogenated (atmospheric
pressure) at room temperature for 24 h. and then filtered through a
pad of diatomaceous earth and the filtrate was concentrated in
vacuo. The crude product was purified by flash column
chromatography (silica; ethyl acetate in heptane 30/70 to 100/0).
The desired fractions were collected and concentrated in vacuo to
yield compound 38 (0.116 g, 99%) as a white solid. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 0.85-0.95 (m, 2H), 0.95-1.02 (m,
2H), 1.12 (s, 6H), 2.15-2.23 (m, 1H), 3.20 (s, 3 H), 3.71-3.83 (m,
4H), 3.85-3.98 (m, 4H), 4.23 (s, 2H), 6.30 (d, J=5.8 Hz, 1H), 8.09
(s, 1H), 8.15 (d, J=5.5 Hz, 1H), 8.32 (s, 1H).
[0729] Additional compounds were prepared from the corresponding
intermediates according to procedures similar to those described
for the synthesis of the corresponding Examples previously
described. The corresponding intermediates were prepared by
procedures similar to those previously described either in the
Experimental Part or in the Synthesis section. Compound 45 was
isolated as the corresponding hydrochloric acid salt (.HCl). The
assignment of configuration in compounds 34, 113 and 131 derives
from the reagent used in the synthesis of the compounds.
TABLE-US-00001 TABLE 1 Compounds and melting points thereof
according to formula (I) prepared according to the above methods.
(Dec means decomposition) Co. No. Ex. No. R.sup.1 R.sup.2 R.sup.3
##STR00169## M.p. (.degree. C.) 1 B1 ##STR00170## ##STR00171##
##STR00172## ##STR00173## 131.5 2 B2 ##STR00174## ##STR00175##
##STR00176## ##STR00177## 165 3 B3 ##STR00178## ##STR00179##
##STR00180## ##STR00181## 101.8 4 B4 ##STR00182## ##STR00183##
##STR00184## ##STR00185## >300 Dec. 5 B5 ##STR00186##
##STR00187## ##STR00188## ##STR00189## 135.3 6 B6 ##STR00190##
##STR00191## ##STR00192## ##STR00193## 132.5 7 B7 ##STR00194##
##STR00195## ##STR00196## ##STR00197## 126.1 8 B8 ##STR00198##
##STR00199## ##STR00200## ##STR00201## 159 9 B9 ##STR00202##
##STR00203## ##STR00204## ##STR00205## n.d. 10 B10 ##STR00206##
##STR00207## ##STR00208## ##STR00209## 241.6 11 B11 ##STR00210##
##STR00211## ##STR00212## ##STR00213## 137.8 12 B12 ##STR00214##
##STR00215## ##STR00216## ##STR00217## 190.7 13 B13 ##STR00218##
##STR00219## ##STR00220## ##STR00221## 137.2 14 B14 ##STR00222##
##STR00223## ##STR00224## ##STR00225## >300 Dec. 15 B15
##STR00226## ##STR00227## ##STR00228## ##STR00229## 122.5 16 B16
##STR00230## ##STR00231## ##STR00232## ##STR00233## n.d. 17 B17
##STR00234## ##STR00235## ##STR00236## ##STR00237## >300 Dec. 18
B18 ##STR00238## ##STR00239## ##STR00240## ##STR00241## >300
Dec. 19 B19 ##STR00242## ##STR00243## ##STR00244## ##STR00245##
n.d. 20 B20 ##STR00246## ##STR00247## ##STR00248## ##STR00249##
149.7 21 B21 ##STR00250## ##STR00251## ##STR00252## ##STR00253##
168.7 22 B22 ##STR00254## ##STR00255## ##STR00256## ##STR00257##
111.4 23 B23 ##STR00258## ##STR00259## ##STR00260## ##STR00261##
115.4 24 B24 ##STR00262## ##STR00263## ##STR00264## ##STR00265##
>300 Dec. 25 B25 ##STR00266## ##STR00267## ##STR00268##
##STR00269## n.d. 26 B26 ##STR00270## ##STR00271## ##STR00272##
##STR00273## n.d. 27 B27 ##STR00274## ##STR00275## ##STR00276##
##STR00277## 274.4 28 B28 ##STR00278## ##STR00279## ##STR00280##
##STR00281## 130.2 29 B29 ##STR00282## ##STR00283## ##STR00284##
##STR00285## >300 Dec. 30 B30 ##STR00286## ##STR00287##
##STR00288## ##STR00289## n.d. 31 B31 ##STR00290## ##STR00291##
##STR00292## ##STR00293## >300 Dec. 32 B35 ##STR00294##
##STR00295## ##STR00296## ##STR00297## 129.3 33 B33 ##STR00298##
##STR00299## ##STR00300## ##STR00301## 142.5 34 B34 ##STR00302##
##STR00303## ##STR00304## ##STR00305## 162 35 B35 ##STR00306##
##STR00307## ##STR00308## ##STR00309## n.d. 36 B36 ##STR00310##
##STR00311## ##STR00312## ##STR00313## 113.7 37 B37 ##STR00314##
##STR00315## ##STR00316## ##STR00317## 126.1 38 B38 ##STR00318##
##STR00319## ##STR00320## ##STR00321## n.d. 39 B1 ##STR00322##
##STR00323## ##STR00324## ##STR00325## 176.9 40 B1 ##STR00326##
##STR00327## ##STR00328## ##STR00329## 133.9 41 B1 ##STR00330##
##STR00331## ##STR00332## ##STR00333## 106.2 42 B1 ##STR00334##
##STR00335## ##STR00336## ##STR00337## 108.8 43 B1 ##STR00338##
##STR00339## ##STR00340## ##STR00341## 128.5 44 B1 ##STR00342##
##STR00343## ##STR00344## ##STR00345## 146.0 45 B1 ##STR00346##
##STR00347## ##STR00348## ##STR00349## n.d. 46 B1 ##STR00350##
##STR00351## ##STR00352## ##STR00353## >300 Dec. 47 B1
##STR00354## ##STR00355## ##STR00356## ##STR00357## 123.5 48 B1
##STR00358## ##STR00359## ##STR00360## ##STR00361## 159.0 49 B1
##STR00362## ##STR00363## ##STR00364## ##STR00365## 128.3 50 B1
##STR00366## ##STR00367## ##STR00368## ##STR00369## 114.1 51 B1
##STR00370## ##STR00371## ##STR00372## ##STR00373## 143.3 52 B1
##STR00374## ##STR00375## ##STR00376## ##STR00377## n.d. 53 B1
##STR00378## ##STR00379## ##STR00380## ##STR00381## 200.9 54 B1
##STR00382## ##STR00383## ##STR00384## ##STR00385## n.d. 55 B1
##STR00386## ##STR00387## ##STR00388## ##STR00389## >300 Dec. 56
B1 ##STR00390## ##STR00391## ##STR00392## ##STR00393## >300 Dec.
57 B1 ##STR00394## ##STR00395## ##STR00396## ##STR00397## 142.1 58
B1 ##STR00398## ##STR00399## ##STR00400## ##STR00401## 198.1 59 B1
##STR00402## ##STR00403## ##STR00404## ##STR00405## 119.3 60 B1
##STR00406## ##STR00407## ##STR00408## ##STR00409## 152.1 61 B1
##STR00410## ##STR00411## ##STR00412## ##STR00413## 167.7 62 B16
##STR00414## ##STR00415## ##STR00416## ##STR00417## >300 Dec. 63
B16 ##STR00418## ##STR00419## ##STR00420## ##STR00421## n.d. 64 B16
##STR00422## ##STR00423## ##STR00424## ##STR00425## 132.2 65 B16
##STR00426## ##STR00427## ##STR00428## ##STR00429## n.d. 66 B16
##STR00430## ##STR00431## ##STR00432## ##STR00433## n.d. 67 B16
##STR00434## ##STR00435## ##STR00436## ##STR00437## n.d. 68 B16
##STR00438## ##STR00439## ##STR00440## ##STR00441## 200.5 69 B16
##STR00442## ##STR00443## ##STR00444## ##STR00445## 239.4 70 B16
##STR00446## ##STR00447## ##STR00448## ##STR00449## n.d. 71 B16
##STR00450## ##STR00451## ##STR00452## ##STR00453## >300 Dec. 72
B16 ##STR00454## ##STR00455## ##STR00456## ##STR00457## 123.1 73
B16 ##STR00458## ##STR00459## ##STR00460## ##STR00461## n.d. 74 B16
##STR00462## ##STR00463## ##STR00464## ##STR00465## 99.7 75 B16
##STR00466## ##STR00467## ##STR00468## ##STR00469## 183.2 76 B25
##STR00470## ##STR00471## ##STR00472## ##STR00473## n.d. 77 B25
##STR00474## ##STR00475## ##STR00476## ##STR00477## >300 Dec. 78
B28 ##STR00478## ##STR00479## ##STR00480## ##STR00481## 177.4 79
B28 ##STR00482## ##STR00483## ##STR00484## ##STR00485## 196.2 80
B28 ##STR00486## ##STR00487## ##STR00488## ##STR00489## 195.4 81
B28 ##STR00490## ##STR00491## ##STR00492## ##STR00493## n.d. 82 B28
##STR00494## ##STR00495## ##STR00496## ##STR00497## n.d. 83 B29
##STR00498## ##STR00499## ##STR00500## ##STR00501## 153.7 84 B29
##STR00502## ##STR00503## ##STR00504## ##STR00505## 147.2 85 B30
##STR00506## ##STR00507## ##STR00508## ##STR00509## n.d. 86 B30
##STR00510## ##STR00511## ##STR00512## ##STR00513## >300 Dec. 87
B30 ##STR00514## ##STR00515## ##STR00516## ##STR00517## 140.3 88
B30 ##STR00518## ##STR00519## ##STR00520## ##STR00521## >300
Dec. 89 B31 ##STR00522## ##STR00523## ##STR00524## ##STR00525##
174.3 90 B31 ##STR00526## ##STR00527## ##STR00528## ##STR00529##
>300 Dec. 91 B31 ##STR00530## ##STR00531## ##STR00532##
##STR00533## 200.8 92 B31 ##STR00534## ##STR00535## ##STR00536##
##STR00537## n.d. 93 B31 ##STR00538## ##STR00539## ##STR00540##
##STR00541## 201.2 94 B31 ##STR00542## ##STR00543## ##STR00544##
##STR00545## 191.3 95 B31 ##STR00546## ##STR00547## ##STR00548##
##STR00549## n.d. 96 B31 ##STR00550## ##STR00551## ##STR00552##
##STR00553## 220.2 97 B31 ##STR00554## ##STR00555## ##STR00556##
##STR00557## >300 Dec. 98 B31 ##STR00558## ##STR00559##
##STR00560## ##STR00561## n.d. 99 B31 ##STR00562## ##STR00563##
##STR00564## ##STR00565## >300 Dec. 100 B31 ##STR00566##
##STR00567## ##STR00568## ##STR00569## 200.1 101 B31 ##STR00570##
##STR00571## ##STR00572## ##STR00573## 223.2 102 B31 ##STR00574##
##STR00575## ##STR00576## ##STR00577## 212.1 103 B31 ##STR00578##
##STR00579## ##STR00580## ##STR00581## n.d. 104 B33 ##STR00582##
##STR00583## ##STR00584## ##STR00585## 116.1 105 B33 ##STR00586##
##STR00587## ##STR00588## ##STR00589## 127.0 106 B33 ##STR00590##
##STR00591## ##STR00592## ##STR00593## 118.0 107 B33 ##STR00594##
##STR00595## ##STR00596## ##STR00597## 137.4 108 B33 ##STR00598##
##STR00599## ##STR00600## ##STR00601## 164.4 109 B33 ##STR00602##
##STR00603## ##STR00604## ##STR00605## n.d. 110 B34 ##STR00606##
##STR00607## ##STR00608## ##STR00609## 154.6 111 B34 ##STR00610##
##STR00611## ##STR00612## ##STR00613## 179.6 112 B34 ##STR00614##
##STR00615## ##STR00616## ##STR00617## n.d. 113 B35 ##STR00618##
##STR00619## ##STR00620## ##STR00621## n.d.
114 B36 ##STR00622## ##STR00623## ##STR00624## ##STR00625## n.d.
115 B36 ##STR00626## ##STR00627## ##STR00628## ##STR00629## n.d.
116 B36 ##STR00630## ##STR00631## ##STR00632## ##STR00633## n.d.
117 B36 ##STR00634## ##STR00635## ##STR00636## ##STR00637## n.d.
118 B36 ##STR00638## ##STR00639## ##STR00640## ##STR00641## n.d.
119 B36 ##STR00642## ##STR00643## ##STR00644## ##STR00645## n.d.
120 B36 ##STR00646## ##STR00647## ##STR00648## ##STR00649## 150.1
121 B36 ##STR00650## ##STR00651## ##STR00652## ##STR00653## 129.8
122 B36 ##STR00654## ##STR00655## ##STR00656## ##STR00657## n.d.
123 B36 ##STR00658## ##STR00659## ##STR00660## ##STR00661## n.d.
124 B36 ##STR00662## ##STR00663## ##STR00664## ##STR00665## 132.6
125 B36 ##STR00666## ##STR00667## ##STR00668## ##STR00669## 138.0
126 B36 ##STR00670## ##STR00671## ##STR00672## ##STR00673## 130.6
127 B36 ##STR00674## ##STR00675## ##STR00676## ##STR00677## 120.8
128 B36 ##STR00678## ##STR00679## ##STR00680## ##STR00681## n.d.
129 B36 ##STR00682## ##STR00683## ##STR00684## ##STR00685## 165.2
130 B36 ##STR00686## ##STR00687## ##STR00688## ##STR00689## 173.7
131 B36 ##STR00690## ##STR00691## ##STR00692## ##STR00693## n.d.
132 B36 ##STR00694## ##STR00695## ##STR00696## ##STR00697## 174.4
133 B36 ##STR00698## ##STR00699## ##STR00700## ##STR00701## 140.3
134 B36 ##STR00702## ##STR00703## ##STR00704## ##STR00705## 138.5
135 B36 ##STR00706## ##STR00707## ##STR00708## ##STR00709## n.d.
136 B39 ##STR00710## ##STR00711## ##STR00712## ##STR00713## n.d.
137 B39 ##STR00714## ##STR00715## ##STR00716## ##STR00717## n.d.
138 B39 ##STR00718## ##STR00719## ##STR00720## ##STR00721## 178.0
139 B39 ##STR00722## ##STR00723## ##STR00724## ##STR00725## 132.6
140 B39 ##STR00726## ##STR00727## ##STR00728## ##STR00729## >300
Dec. 141 B39 ##STR00730## ##STR00731## ##STR00732## ##STR00733##
n.d. 142 B39 ##STR00734## ##STR00735## ##STR00736## ##STR00737##
114.0 143 B39 ##STR00738## ##STR00739## ##STR00740## ##STR00741##
138.0 144 B39 ##STR00742## ##STR00743## ##STR00744## ##STR00745##
190.7 145 B39 ##STR00746## ##STR00747## ##STR00748## ##STR00749##
n.d. 146 A69 ##STR00750## ##STR00751## ##STR00752## ##STR00753##
n.d. 147 A69 ##STR00754## ##STR00755## ##STR00756## ##STR00757##
>300 Dec. 148 B36 ##STR00758## ##STR00759## ##STR00760##
##STR00761## 191.2 149 B1 ##STR00762## ##STR00763## ##STR00764##
##STR00765## 167.7 150 A69 ##STR00766## ##STR00767## ##STR00768##
##STR00769## n.d.
TABLE-US-00002 TABLE 2 Physico-chemical data for some compounds (nd
= not determined). Co. No. M. Wt. [M + H].sup.+ R.sub.t Method 4
381 382 3.08 5 5 381 382 3.07 5 6 367 368 2.64 5 7 373 374 2.31 5 8
376 375 2.68 5 9 361 362 2.20 5 10 371 372 2.61 5 11 339 340 1.98 5
12 369 370 2.65 5 13 393 394 2.87 5 14 385 386 2.63 5 15 393 394
3.14 5 16 369 370 2.40 5 17 353 354 2.32 5 18 397 398 2.99 5 19 380
381 2.29 5 20 345 346 1.86 5 21 361 362 2.21 5 .sup. 21a 361 362
2.20 5 22 379 380 2.83 5 23 367 368 3.30 1 24 359 360 2.17 5 25 367
368 2.41 5 26 353 354 2.0 5 27 379 380 2.28 5 28 323 324 2.44 5 29
395 396 2.78 5 30 379 380 1.25 5 31 372 373 2.15 5 32 337 338 3.43
2 33 335 336 1.99 5 34 394 395 3.00 5 35 340 341 3.39 1 36 342 343
3.02 1 37 370 371 2.31 5 38 396 397 3.03 5 39 309 310 1.98 5 40 413
414 3.06 5 41 409 410 3.26 5 42 409 410 2.72 5 43 421 422 3.31 5 44
387 388 3.03 5 45 407 408 3.33 5 46 398 399 2.92 5 47 395 396 2.81
5 48 387 388 2.61 5 49 375 376 2.55 5 50 399 400 3.08 5 51 367 368
2.44 5 52 355 356 2.32 5 53 421 422 3.61 5 54 393 394 2.74 5 55 413
414 3.36 5 56 385 386 2.89 5 57 331 332 1.76 5 58 412 413 2.92 5 59
401 402 3.03 5 60 359 360 2.19 5 61 358 359 3.31 1 62 393 394 4.07
1 63 380 381 2.29 5 64 421 422 3.16 5 65 365 366 3.38 5 66 353 354
3.35 5 67 353 354 3.35 5 68 394 395 2.58 5 69 383 384 2.71 5 70 386
387 2.45 5 71 412 413 3.21 5 72 401 402 2.40 5 73 395 396 3.26 5 74
409 410 3.55 5 75 420 421 3.41 5 76 381 382 2.74 5 77 392 393 1.34
5 78 419 420 3.08 5 79 419 420 3.36 5 80 411 412 3.11 5 81 411 412
2.78 5 82 365 366 2.18 5 83 315 316 2.23 5 84 363 364 3.61 5 85 447
448 3.88 5 86 355 356 3.07 5 87 341 342 3.03 5 88 329 330 2.56 5 89
364 365 2.84 5 90 352 353 2.56 5 91 380 381 2.28 5 92 364 365 2.72
5 93 352 353 2.51 5 94 420 421 3.16 5 95 405 406 4.34 1 96 385 386
1.26 5 97 371 372 1.08 5 98 405 406 1.86 5 99 411 412 1.68 5 100
419 420 2.07 5 101 411 412 1.89 5 102 397 398 1.68 5 103 379 380
1.33 5 104 351 352 3.20 5 105 351 352 3.07 5 106 349 350 3.28 5 107
363 364 3.33 5 108 337 338 2.78 5 109 309 310 2.35 5 110 349 350
3.10 5 111 327 328 2.54 5 112 321 322 2.61 5 113 394 395 2.42 5 114
334 335 2.03 4 115 375 376 2.57 1 116 284 285 1.98 1 117 368 369
2.68 1 118 374 375 3.12 2 119 368 369 2.48 5 120 370 371 2.70 5 121
362 363 2.45 5 122 388 389 2.31 5 123 362 363 2.87 2 124 332 333
2.56 5 125 382 383 2.58 5 126 374 375 2.39 5 127 356 357 2.18 5 128
388 389 2.75 5 129 402 403 2.59 5 130 410 411 2.94 5 131 356 357
2.81 1 132 348 349 2.69 2 133 356 357 2.75 2 134 348 349 2.64 2 135
358 359 2.84 2 136 326 327 2.91 4 137 366 367 2.69 4 138 392 393
3.11 5 139 396 397 2.63 5 140 358 359 2.30 5 141 384 385 3.08 1 142
360 361 2.95 2 143 388 389 2.84 5 144 366 367 2.16 5 145 407 408
2.88 5 146 400 401 2.7 4 147 368 369 2.67 4 148 358 359 4.11 5 149
361 362 2.11 5 LCMS data: [M + H].sup.+ means the protonated mass
of the free base of the compound, R.sub.t means retention time (in
minutes), method refers to the method used for LCMS.
D. Pharmacological Examples
[0730] The compounds provided in the present invention are
inhibitors of PDE10, particularly, of PDE10A. The behaviour of the
PDE10 inhibitors according to Formula (I) in vitro and using an
apomorphine induced stereotypy model in vivo is shown in Table 3.
The in vitro selectivity towards PDE10A, occupancy, and results
using PCP-induced hyperlocomotion, conditioned avoidance response
models, SCH-23390-induced hypolocomotion in mice and object
recognition test in rats of selected compounds are shown in tables
4 to 7.
In Vitro Assay PDE10A
[0731] Rat recombinant PDE10A (rPDE10A2) was expressed in Sf9 cells
using a recombinant rPDE10A baculovirus construct. Cells were
harvested after 48 h of infection and the rPDE10A protein was
purified by metal chelate chromatography on Ni-sepharose 6FF.
Tested compounds were dissolved and diluted in 100% DMSO to a
concentration 100 fold of the final concentration in the assay.
Compound dilutions (0.4 .mu.l) were added in 384 well plates to 20
.mu.l of incubation buffer (50 mM Tris pH 7.8, 8.3 mM MgCl.sub.2,
1.7 mM EGTA). 10 .mu.l of rPDE10A enzyme in incubation buffer was
added and the reaction was started by addition of 10 .mu.l
substrate to a final concentration of 60 nM cAMP and 0.008 .mu.Ci
.sup.3H-cAMP. The reaction was incubated for 60 minutes at room
temperature. After incubation, the reaction was stopped with 20
.mu.l of stop solution consisting of 17.8 mg/ml PDE SPA
(scintillation proximity assay) beads. After sedimentation of the
beads during 30 minutes the radioactivity was measured in a Perkin
Elmer Topcount scintillation counter and results were expressed as
cpm. For blanc values the enzyme was omitted from the reaction and
replaced by incubation buffer. Control values were obtained by
addition of a final concentration of 1% DMSO instead of compound.
The same assay principle is applied for the measurement of the
affinity of the compound for other members of the PDE family with
appropriate modifications in incubation buffer, substrate
concentration, incubation time and stop solution. An overview of
the different protocols is presented in table A. A best fit curve
is fitted by a minimum sum of squares method to the plot of % of
control value substracted with blanc value versus compound
concentration and the half maximal inhibitory concentration
(IC.sub.50) value is derived from this curve.
TABLE-US-00003 TABLE A Assay conditions for the Measurement of
Phosphodiesterase activity by SPA Incu- Final .sup.3H Incubation
bation Concentration Substrate Stop Time Enzyme Buffer Substrate
.mu.Ci/well Solution (min) hPDE1B1 B* 1 .mu.M cAMP 0.016 1* 30
hPDE2A A* 10 .mu.M cGMP 0.01 2* 40 hPDE3A A* 0.1 .mu.M cAMP 0.024
2* 60 hPDE4D3 A* 1 .mu.M cAMP 0.008 1* 60 hPDE5A3 A* 1 .mu.M cGMP
0.01 2* 60 hPDE6AB A* 0.1 .mu.M cGMP 0.01 2* 120 hPDE7A1 A* 60 nM
cAMP 0.008 1* 60 hPDE8A1 A* 0.3 .mu.M cAMP 0.01 1* 60 hPDE9A C* 60
nM cGMP 0.008 2* 60 rPDE10A2 A* 60 nM cAMP 0.008 1* 60 hPDE11A4 A*
0.3 .mu.M cGMP 0.01 1* 30 A* 50 mM Tris pH 7.8, 1.7 mM EGTA, 8.3 mM
MgCl.sub.2 B* 50 mM Tris pH 7.8, 8.3 mM MgCl.sub.2 C* 50 mM Tris pH
7.8, 5 mM MnCl.sub.2 1* 17.8 mg/ml PDE beads 2* 17.8 mg/ml PDE
beads + 200 mM ZnCl.sub.2
[0732] The compounds of the invention are generally selective for
PDE10 compared to other PDEs and there are a few that also have
affinity for PDE1B1, 4D3 and 5A3. Table 4 provides data of some
compounds according to the invention.
Apomorphine-Induced Stereotypy in Rats (APO)
[0733] Apomorphine (1.0 mg/kg, i.v.)-induced stereotypy (compulsive
sniffing, licking, chewing) was scored every 5 min over the first
hour after injection of apomorphine, following a 1 hour interval
pre-treatment with the test compound. The score system was: (3)
pronounced, (2) moderate, (1) slight, and (0) absent. Criteria for
drug-induced inhibition of stereotypy: fewer than 6 scores of 3
(0.16% false positives), fewer than 6 scores of .gtoreq.2 (0.0%
false positives), or fewer than 7 scores of .gtoreq.1 (0.81% false
positives).
PDE10 Occupancy
[0734] Dose-response or single dose experiments were performed to
measure PDE10 occupancy 1 hour after subcutaneous (s.c.) or oral
(p.o.) administration. Male Wistar rats (200 g) were treated by
s.c. or p.o. administration of various PDE10 inhibitors. The PDE10
radioligand [.sup.3H]-MP-10 (10 .mu.Ci/animal) was injected
intravenously (i.v.) 30 minutes before sacrifice. Brains were
immediately removed from the skull and rapidly frozen. Twenty
.mu.m-thick brain sections were cut using a cryostat-microtome,
thaw-mounted on microscope slides and loaded in a .beta.-imager to
quantify PDE10 occupancy in the striatum.
PCP-Induced Hyperlocomotion in Rats
Apparatus
[0735] Motor activity [horizontal activity (locomotion) and
vertical activity (rearing)] was recorded in male Wiga rats (body
weight: 175-275 g; housed overnight in groups of 7 rats) using
microprocessor-based activity monitors (MED Associates;
length.times.width.times.height: 43.2.times.43.2.times.41.5 cm)
over a period of 30 min. The resolution of the system was set at
100 msec. Total distance was defined as the distance traveled,
measured by changes in the number or location of interrupted
xy-beams (located in two arrays of 32 infrared light beams (1.25 cm
apart) perpendicular to each other in a horizontal plane 2.0 cm
above the floor). Vertical activity was defined as the number of
periods of continuous breaks reported by an infrared array of 32
light beams in a horizontal plane 13 cm above the floor. The
intensity of the light within the activity meters (measured in the
centre at floor level) ranged between 110 and 130 LUX.
PCP-Induced Hyperlocomotion in Rats
[0736] Male Wiga rats (200 to 260 g) were pretreated with test
compound or solvent (10 ml/kg, s.c.) and placed in individual
cages. At a predefined interval thereafter (60 min.), the rats were
challenged with PCP (1.25 mg/kg, i.v.) and motor activity was
measured over a period of 30 min starting immediately after the PCP
challenge. The following all-or-none criteria were adopted for
drug-induced effects: (1) inhibition (<11000 counts; 2.9% false
positives in 102 control rats), (2) blockade (<500 counts; 0.0%
false positives). The results of this test are shown in table 5
below.
Conditioned Avoidance Response (CAR) Test
Apparatus
[0737] The apparatus consisted of an inner box surrounded by an
outer box. The inner box was composed of four walls of transparent,
synthetic material (length.times.width.times.height:
30.times.30.times.30 cm), an open top, and a grid floor made of 15
pairs of iron bars (2 mm diameter; 6 mm inter-bar distance). Odd
and even bars were connected with a source of alternative current
(1.0 mA; Coulbourn Instruments Solid State Shocker/Distributor),
which could be interrupted by a switch. The outer box was composed
of the same material (length.times.width.times.height:
40.times.40.times.36 cm), also with an open top, with a distance of
5 cm between the inner and outer box on all sides. To decrease the
amount of environmental stimuli, three walls of the outer box were
made non-transparent. The front wall was left transparent to allow
the necessary inspection of the animal during the test. The upper
edge of the outer and inner box served as a target for the rats on
which to jump with fore- and hind-paws, respectively.
Avoidance Conditioning and Selection of Animals
[0738] From their arrival in the laboratory on the experimental
day, male Wiga Wistar rats (230.+-.30 g) were housed in individual
cages provided with bedding material. The rats received 5 training
sessions at 15-min time intervals over a 1-h period during which,
the rats were conditioned to avoid an electric shock: the rat was
placed on the non-electrified grid floor and the grid was
electrified 10 s later for not more than 30 s, if the rat did not
jump out of the box. Only rats that showed correct avoidance
responses in all the last 3 training sessions were included for
further experiments, and received the test compound or solvent
immediately after the last training session.
Experimental Sessions
[0739] The rats were tested 3 times, i.e. at 60, 90 and 120 min
after the injection of test compound or solvent. Latency to
avoidance was recorded. The median avoidance response obtained over
the three experimental sessions for each rat were used for further
calculations. A median avoidance latency>8 s was selected as an
all-or-none criterion for drug-induced inhibition of avoidance
(occurring in only 1.5% of solvent-pretreated control rats; n=66).
The results of this test are shown in table 5 below.
SCH-23390-Induced Hypolocomotion in Mice
[0740] SCH-23390 (0.08 mg/kg, i.v.)-induced hypolocomotion was
evaluated over a 30-min period starting immediately after the
SCH-23390 challenge in male NMRI mice pretreated 0.5 h earlier with
test compound or solvent. Averaged activity in solvent-treated
control mice was 1540.+-.559 counts (mean.+-.SD; n=103). Criterion
for drug-induced reversal of the SCH-23390-induced hypolocomotion:
total distance: >2500 counts (2.9% false positives in
controls).
Object Recognition Test
Methods
Animals
[0741] 60 female hooded-Lister rats (Charles River, UK) were used
as subjects for these studies and weighed 248 g.+-.20 g. Rats were
allowed at least a 7-day acclimatization period to the animal unit
prior to commencement of experimentation. Rats were housed in
groups of 5 under standard laboratory conditions under a 12 h
light:dark cycle, lights on at 0700 h. All testing was carried out
in the light phase. Food and water were freely provided. All
experiments were conducted in accordance with the Animals
Scientific Procedures Act, U.K. 1986 and were approved by the
University of Bradford ethical review panel.
Treatment
[0742] 40 mg of test compound was dissolved in 5 ml of 40%
hydroxypropyl .beta.-cyclodextrin (HPBC) solution. The solution was
sonicated until completely dissolved. 2 ml of sterile water was
added and the pH measured and adjusted with NaOH solution (0.1N) to
obtain pH .about.4. Finally, sterile water was added to a final
volume of 10 ml. This stock solution was then diluted in 20% HPBC
to obtain the final concentrations. 100 mg of PQ10 was dissolved in
a 40% HPBC solution and 8 mg of tartaric acid. The solution was
sonicated until completely dissolved. 5 ml of sterile water was
added and the pH measured and adjusted with NaOH solution (0.1N) to
obtain pH .about.4. Finally sterile water was added to a final
volume of 10 ml.
[0743] Test compound was administered at doses of 0.3 and 1.0 mg/kg
via the oral route 30 min prior to testing.
[0744] PQ10 was administered at a dose of 1.0 mg/kg via the oral
route 30 min prior to testing.
Object Recognition Memory
[0745] Certain pre-clinical tests allow the observation of
relatively subtle cognitive deficits in the rat that resemble
cognitive symptoms in subjects with schizophrenia. The cognitive
deficits observed are seen in behaviours such as episodic memory,
which can be measured by recognition tasks such as the novel object
recognition (NOR) paradigm. A recognition memory task allows the
comparison between presented stimuli and previously stored
information. Ennaceur, A Delacour, J (1988) A new one-trial test
for neurobiological studies of memory in rats Behav Brain Res 31:
47-59 described the NOR test in rats which was based on the
differential exploration of familiar and new objects. The NOR test
is a non-rewarded, ethologically relevant paradigm based on the
spontaneous exploratory behaviour of rats that measures episodic
memory. Each session consists of two trials. In the first trial,
the rats are exposed to two identical objects in an open field.
During the second trial, rats are exposed to two dissimilar
objects, one familiar object from the first trial and one new
object. Object recognition in rats can be measured as the
difference in time spent exploring the familiar and the new object.
Rats have been shown to spend more time exploring the new object.
It was found that rats are able to discriminate between the
familiar and the novel object when the inter-trial interval is
between 3 minutes and 1-3 hours, but not when it is greater than 24
hours, although this effect may be sex dependent in the rat. The
duration of each trial is also important as a preference for the
novel object only lasts during the first 1 or 2 minutes, after
which time preference diminishes as both objects become familiar
and are explored equally.
Procedure
[0746] Allocation of Treatment groups
[0747] Rats were randomly assigned to the 8 treatment groups
Habituation
[0748] Rats were allowed to habituate to the empty test box and the
behavioural test room environment for 1 h on day 1. Prior to
behavioural testing on day 2 rats were given a further 3 min
habituation.
Behavioural Testing
[0749] Following the 3 min habituation period, the rats were given
two 3 min trials (T1 and T2) which were separated by a 1 min
inter-trial interval in the home cage during which the objects were
changed.
T1=Trial 1, the Acquisition Trial
[0750] In this trial, the animals were allowed to explore two
identical objects (A1 and A2) for 3 min.
T2=Trial 2, the Retention Trial
[0751] In this trial, the animals explored a familiar object (A)
from T1 and a novel object (B) for 3 min. The familiar object
presented during T2 was a duplicate of the object presented in T1
in order to avoid any olfactory trails.
Object Exploration
[0752] The object exploration was defined by animals licking,
sniffing or touching the object with the forepaws whilst sniffing,
but not leaning against, turning around, standing or sitting on the
object. The exploration time (s) of each object (A1, A2, A and B)
in each trial were recorded using two stopwatches and the following
factors were calculated.
[0753] Total exploration time of both objects in the acquisition
trial (s).
[0754] Total exploration time of both objects in the retention
trial (s).
[0755] Habituation of exploratory activity. The locomotor activity
(LMA) included the exploration time, as measured by the number of
lines crossed, for both the trials.
[0756] Discrimination index (DI), which was calculated as shown
below:
time spent exploring novel object - time spent exploring familiar
object total time spent in exploring the objects ##EQU00001##
[0757] Behaviour in all trials was recorded on video for subsequent
blind scoring.
Exclusion Criteria
[0758] If an animal failed to explore one or both of the objects in
the acquisition trial, that animal was not included in the final
analysis, ie if exploration time was 0 seconds at either object in
acquisition that animal was excluded.
Statistical Analysis
[0759] All data are expressed as mean.+-.SEM, (n=3 to 10 per group)
and were analysed by a two way ANOVA (factors are: drug and
exploration time of the two objects) or one way ANOVA (LMA and DI)
with further analysis by a post-hoc student's t-test (time spent
exploring objects in acquisition and retention trials) or Dunnett's
t-test (LMA and DI). When student's t-test was used to analyse time
spent exploring objects, significance was based upon the difference
in time spent exploring the novel or familiar object, not in
comparison to vehicle. For the discrimination index Dunnett's
t-tests were used to compare values against PCP/Veh treated group,
and against the Veh/Veh group, as appropriate. Results showed that
sub-chronic PCP (2 mg/kg ip twice daily for 7 days followed by 7
days drug-free period) produced a selective cognitive deficit in
the retention phase of the NOR task in female rats.
[0760] The effects of acute treatment with compound 1 (0.3-1.0
mg/kg) or the comparator PQ10, were selective for the retention
phase of the NOR task.
TABLE-US-00004 TABLE 3 Pharmacological data for compounds according
to the invention. APO Co. PDE10A2 ED.sub.50 No. pIC.sub.50 (mg/kg)
141 8.00 n.d.* 10 7.94 1.2 50 7.84 0.8 142 7.84 5 46 7.76 n.d. 143
7.76 1.2 135 7.74 3.1* 5 7.72 n.d. 54 7.68 1.2 87 7.66 n.d. 124
7.65 1.2 6 7.63 n.d. 93 7.60 n.d. 105 7.60 n.d. 148 7.60 5 7 7.59
0.3 137 7.59 n.d. 3 7.58 0.8 20 7.56 n.d. 123 7.56 n.d. 38 7.54
n.d. 122 7.52 n.d. 26 7.51 n.d. 27 7.5 n.d. 25 7.47 n.d.* 131 7.46
3.1 115 7.45 n.d.*(a) 35 7.42 5 55 7.42 n.d. 138 7.40 n.d.*(a) 4
7.39 n.d. 29 7.36 .gtoreq.2.5 80 7.35 n.d. 102 7.35 n.d. 44 7.34
n.d. 91 7.33 1.2 2 7.33 n.d. 37 7.30 1.5 45 7.30 n.d. 76 7.30 n.d.
118 7.30 .ltoreq.10* 126 7.30 n.d. 128 7.30 n.d.(a) 56 7.29 n.d. 83
7.29 n.d. 114 7.28 n.d. 146 7.28 n.t. 104 7.27 n.d. 17 7.26 n.d.*
95 7.26 n.d.* 22 7.25 0.5 36 7.25 5 1 7.24 1.3 92 7.24 n.d. 145
7.23 n.d. 31 7.22 n.d. 119 7.21 n.d.*(a) 106 7.18 n.d. 90 7.17 n.d.
147 7.17 5 139 7.16 n.d.* 39 7.15 n.d. 132 7.15 n.d.(a) 32 7.11 5
33 7.11 .gtoreq.2.5* 24 7.10 n.d. 28 7.08 1.2 71 7.08 .gtoreq.2.5*
125 7.08 .gtoreq.2.5 67 7.06 n.d.(a) 47 7.04 n.d. 42 7.03 n.d. 133
7.02 3.1 73 7.01 n.d. 111 7.01 n.d. 117 7.01 n.t. 21 6.99 1.5 51
6.98 n.d. 134 6.98 5 19 6.97 5 98 6.96 n.d. 9 6.95 n.d. 23 6.95
n.d. 127 6.95 2.0 48 6.94 .gtoreq.2.5 88 6.94 n.d. 34 6.93 n.d. 40
6.93 n.d. 14 6.92 n.d. 16 6.92 3.1 30 6.91 7.1 72 6.91 .gtoreq.2.5*
78 6.91 n.d. 70 6.90 n.d. 77 6.89 n.d. 89 6.88 n.d.* 116 6.88
n.d.*(a) 63 6.87 n.d.(a) 97 6.85 n.d. 82 6.84 n.d. 149 6.82 n.d.
21a 6.82 n.t. 108 6.81 n.d. 68 6.80 .gtoreq.2.5* 113 6.80 n.d. 8
6.79 n.d. 65 6.79 n.d.(a) 18 6.77 5 140 6.76 n.d.(a) 66 6.75
n.d.(a) 101 6.75 n.d. 58 6.73 n.d. 96 6.73 n.d. 43 6.72 n.d. 60
6.72 n.d. 11 6.71 n.d. 13 6.71 n.d. 81 6.71 n.d. 49 6.68 n.d. 53
6.67 n.d. 130 6.66 n.d.*(a) 12 6.65 n.d. 59 6.63 n.d. 121 6.63
n.d.(a) 109 6.60 n.d. 62 6.59 n.d.* 103 6.59 n.d. 79 6.58 n.d. 86
6.58 n.d. 107 6.57 n.d. 15 6.52 n.d.* 99 6.52 n.d. 69 6.49 n.d. 144
6.49 n.t. 110 6.48 n.t. 61 6.47 1.2 84 6.43 n.t. 94 6.42 n.t. 41
6.39 n.d. 57 6.37 n.t. 112 6.37 n.t. 75 6.35 n.t. 52 6.33 n.d. 64
6.32 n.d.* 136 6.28 n.t. 74 6.23 n.t. 85 6.18 n.t. 120 6.16 n.d.(a)
100 6.14 n.t. 129 5.58 n.t. 150 n.t. n.t. pIC.sub.50 corresponds to
the -log IC.sub.50 expressed in mol/L. ED.sub.50 is the dose at
which 50% of the tested animals show the effect. n.t. means not
tested. n.d. means the compound was found not active at 2.5 or at
10 mg/kg (the latter being indicated as (a)), taken as threshold
value, and was not further tested. *means the compound was not
soluble and was tested orally as a suspension. .ltoreq.means that
the compound was found active in 60% of the animals at the
indicated dose level; .gtoreq.means that in 30% of the animals the
compound was found active at the indicated dose level.
TABLE-US-00005 TABLE 4 In vitro selectivity of compounds according
to the invention (expressed as pIC.sub.50). Co. PDE PDE PDE PDE PDE
PDE PDE PDE PDE PDE PDE No. 10A2 11A4 1B1 2A 3A 4D3 5A3 6AB 7A 8A1
9A 10 7.94 5.85 n.t. 5.18 <5 5.9 5.89 n.t. <5 n.t. <5 50
7.84 n.t. n.t. 5.16 n.t. n.t. n.t. n.t. n.t. n.t. n.t. 142 7.84
5.74 n.t. 5.26 5.29 5.55 5.94 n.t. 5.3 n.t. <5 143 7.76 5.71
n.t. 5.4 5.84 5.29 6.19 n.t. 5.23 n.t. <5 135 7.74 5.23 n.t.
<5 5.13 <5 5.59 n.t. <5 n.t. <5 54 7.68 n.t. n.t. <5
n.t. n.t. n.t. n.t. n.t. n.t. n.t. 124 7.65 5.27 n.t. 5.06 5.16
5.13 5.71 n.t. 5.27 n.t. <5 148 7.6 5.72 n.t. 5.36 5.5 5.59 5.91
n.t. 5.54 n.t. <5 7 7.59 n.t. n.t. <5 n.t. n.t. n.t. n.t.
n.t. n.t. n.t. 3 7.58 <5 n.t. <5 <5 <5 5.1 n.t. <5
n.t. <5 131 7.46 <5 n.t. <5 <5 <5 5.07 n.t. <5
n.t. <5 35 7.42 <5 n.t. <5 5.13 <5 <5 n.t. <5
n.t. <5 29 7.36 <5 n.t. 5.92 <5 <5 5.35 n.t. <5 n.t.
<5 91 7.33 <5 n.t. <5 <5 <5 5.07 n.t. <5 n.t.
<5 37 7.3 4.4 n.t. 4.27 4.96 4.51 5.22 n.t. 4.34 n.t. <4 118
7.3 <5 n.t. <5 <5 <5 5 n.t. <5 n.t. <5 146 7.28
<5 n.t. <5 <5 <5 5.72 n.t. 5.07 n.t. <5 1 7.24 4.13
5.28 4.4 4.01 4.51 4.77 4.07 4.16 4.11 <4 22 7.25 5.17 n.t. 5.23
<4.3 5.56 5.46 n.t. 4.55 n.t. <4.3 36 7.25 <5 n.t. <5
<5 <5 <5 <5 <5 <5 <5 147 7.17 5.42 n.t. <5
<5 5.42 5.93 n.t. 5.45 n.t. <5 32 7.11 <5 n.t. <5 <5
<5 <5 n.t. <5 n.t. <5 33 7.11 <5 n.t. <5 <5
<5 <5 n.t. <5 n.t. <5 28 7.08 4.52 n.t. 4.57 4.52 4.88
4.86 n.t. 4.59 n.t. <4 71 7.08 n.t. n.t. 5.64 n.t. n.t. n.t.
n.t. n.t. n.t. n.t. 125 7.08 5.35 n.t. 5.07 <5 5.68 5.9 n.t.
<5 n.t. <5 133 7.02 <5 n.t. <5 <5 <5 5.62 n.t.
<5 n.t. <5 117 7.01 5 n.t. <5 <5 <5 <5 n.t. <5
n.t. <5 21 6.99 <4.3 n.t. 4.32 <4.3 4.55 4.72 n.t. <4.3
n.t. <4.3 30 6.91 <5 n.t. <5 <5 <5 <5 n.t. <5
n.t. <5 134 6.98 5.27 n.t. 5.09 <5 5.26 6.23 n.t. 5.31 n.t.
<5 19 6.97 <5 n.t. <5 <5 <5 <5 n.t. <5 n.t.
<5 127 6.95 <5 n.t. <5 <5 <5 5.33 n.t. <5 n.t.
<5 48 6.94 n.t. n.t. <5 n.t. n.t. n.t. n.t. n.t. n.t. n.t. 16
6.92 <5 n.t. <5 <5 <5 <5 n.t. <5 n.t. <5 72
6.91 n.t. n.t. 5.98 n.t. n.t. n.t. n.t. n.t. n.t. n.t. 68 6.8 n.t.
n.t. <5 n.t. n.t. n.t. n.t. n.t. n.t. n.t. 18 6.77 <5 n.t.
<5 <5 <5 5 n.t. <5 n.t. <5 144 6.49 n.t. n.t. <5
n.t. n.t. n.t. n.t. n.t. n.t. n.t. 110 6.48 n.t. n.t. <5 n.t.
n.t. n.t. n.t. n.t. n.t. n.t. 61 6.47 <5 <5 5.1 <5 <5
5.57 n.t. <5 n.t. <5 84 6.43 n.t. n.t. <5 n.t. n.t. n.t.
n.t. n.t. n.t. n.t. 94 6.42 n.t. n.t. <5 n.t. n.t. n.t. n.t.
n.t. n.t. n.t. 57 6.37 n.t. n.t. <5 n.t. n.t. n.t. n.t. n.t.
n.t. n.t. 112 6.37 n.t. n.t. 5.09 n.t. n.t. n.t. n.t. n.t. n.t.
n.t. 75 6.35 n.t. n.t. <5 n.t. n.t. n.t. n.t. n.t. n.t. n.t. 136
6.28 n.t. n.t. <5 n.t. n.t. n.t. n.t. n.t. n.t. n.t. 74 6.23
n.t. n.t. <5 n.t. n.t. n.t. n.t. n.t. n.t. n.t. 85 6.18 n.t.
n.t. <5 n.t. n.t. n.t. n.t. n.t. n.t. n.t. 100 6.14 n.t. n.t.
<5 n.t. n.t. n.t. n.t. n.t. n.t. n.t. 129 5.58 n.t. n.t. <5
n.t. n.t. n.t. n.t. n.t. n.t. n.t.
TABLE-US-00006 TABLE 5 Pharmacological data for compounds according
to the invention in the occupancy test. SD sc % SD po % occupancy
occupancy Co. PDE10 in vivo ED.sub.50 sc ED.sub.50 po at at No.
Occ. (mg/kg) (mg/kg) 10 mg/kg 10 mg/kg 1 DR sc and po 0.48 1.4 76%
n.t. 3 DR sc 2.0 n.t. n.t. n.t. 7 DR sc 1.6 n.t. n.t. n.t. 16 SD sc
n.t. n.t. 52% n.t. 18 SD sc n.t. n.t. 46% n.t. 19 SD sc n.t. n.t.
57% n.t. 21 DR sc and po 2.6 14 61% n.t. 22 DR sc 0.94 n.t. n.t.
n.t. 28 DR sc 1.1 n.t. n.t. n.t. 30 DR sc >10 (6%)* n.t. n.t.
n.t. 35 SD sc n.t. n.t. 67% n.t. 37 DR sc 2.2 n.t. 67% n.t. 48 DR
po n.t. 4.3 n.t. 62 SD po n.t. n.t. 38% 65 SD sc n.t. n.t. 17% n.t.
66 SD sc n.t. n.t. 29% n.t. 67 SD sc n.t. n.t. 1% n.t. 114 SD sc
n.t. n.t. 72% n.t. 118 SD po n.t. n.t. 4% 121 SD sc n.t. n.t. 0%
n.t. 124 DR sc 3.0 n.t. n.t. n.t. 125 DR sc >10 (42%)* n.t. n.t.
n.t. 127 SD sc n.t. n.t. 4% n.t. 128 SD sc n.t. n.t. 40% n.t. 130
SD po n.t. n.t. n.t. 6% 131 SD sc n.t. n.t. 59% n.t. 132 SD sc n.t.
n.t. 44% n.t. 137 SD po n.t. n.t. n.t. 12% 138 SD po n.t. n.t. n.t.
11% 140 SD po n.t. n.t. n.t. 0% 142 SD sc n.t. n.t. 78% n.t. 147 SD
sc n.t. n.t. 22% n.t. 148 SD sc n.t. n.t. 66% n.t. 21a DR sc and po
2.6 14 61% n.t. Occ. means occupancy; ED.sub.50 means effective
dose; SD means single dose; DR means dose response; sc means
subcutaneous administration; po means per os, oral administration;
*the data between brackets means the % occupancy at the highest
dose tested.
TABLE-US-00007 TABLE 6 Pharmacological data for compounds according
to the invention in the PCP, CAR and SCH-23390 tests. PCP CAR
SCH-23390 Co. No. ED.sub.50 (mg/kg) ED.sub.50 (mg/kg) ED.sub.50
(mg/kg) 1 2.0 4.7 7.1 21 6.1 5.4 5
TABLE-US-00008 TABLE 7 Effects of compound 1 on short-term memory.
Day 1: The ability of acute treatment with compound 1 (0.3-1.0
mg/kg, p.o) or PQ10 (1 mg/kg, p.o) to reverse the effect of
sub-chronic PCP (2 mg/kg, i.p twice daily for seven days) on the
exploration time (s) during the retention trial (T2) of a familiar
object and a novel object in the 3 min retention trial in female
rats. PCP + PCP + PCP + Vehicle + PCP + co. no. 1 co. no. 1 PQ10
20% HPBCD 20% HPBCD (0.3 mg/kg) (1.0 mg/kg) (1 mg/kg) T2(A) 7.5
17.5 11.8 10.7 7.9 (seconds) (.+-.1.4395) (.+-.2.1042) (.+-.2.6709)
(.+-.1.8622) (.+-.1.6017) T2(B) 19.9 17.4 17.6 22.3 19.9 (seconds)
(.+-.3.6346)** (.+-.2.2716) (.+-.2.7899)* (.+-.3.2251)**
(.+-.3.247)** DI 0.3748 -0.005 0.3014 0.3335 0.4193 (.+-.0.1695)
(.+-.0.0357) (.+-.0.1405) (.+-.0.0804) (.+-.0.0772) LMA 62.8 69.5
56.5 56.4 65.5 (no. of (.+-.4.567518) (.+-.5.647517) (.+-.6.107503)
(.+-.7.212951) (.+-.5.518152) lines crossed) Data are expressed as
the mean .+-. s.e.m (n = 3-10 per group) and were analysed by ANOVA
and post-hoc student's t-test. *P < 0.05- **P < 0.01;
significant difference between time spent exploring the familiar
(A) and novel (B) object. The difference in time exploring the
novel and familiar object is analysed by student's t-test.
E. Prophetic Composition Examples
[0761] "Active ingredient" as used throughout these examples
relates to a final compound of formula (I), the pharmaceutically
acceptable salts thereof, the solvates and the stereochemically
isomeric forms thereof.
[0762] Typical examples of recipes for the formulation of the
invention are as follows:
1. Tablets
TABLE-US-00009 [0763] Active ingredient 5 to 50 mg Di-calcium
phosphate 20 mg Lactose 30 mg Talcum 10 mg Magnesium stearate 5 mg
Potato starch ad 200 mg
[0764] In this Example, active ingredient can be replaced with the
same amount of any of the compounds according to the present
invention, in particular by the same amount of any of the
exemplified compounds.
2. Suspension
[0765] An aqueous suspension is prepared for oral administration so
that each 1 milliliter contains 1 to 5 mg of one of the active
compounds, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium
benzoate, 500 mg of sorbitol and water ad 1 ml.
3. Injectable
[0766] A parenteral composition is prepared by stirring 1.5% by
weight of active ingredient of the invention in 10% by volume
propylene glycol in water.
4. Ointment
TABLE-US-00010 [0767] Active ingredient 5 to 1000 mg Stearyl
alcohol 3 g Lanoline 5 g White petroleum 15 g Water ad 100 g
[0768] In this Example, active ingredient can be replaced with the
same amount of any of the compounds according to the present
invention, in particular by the same amount of any of the
exemplified compounds.
[0769] Reasonable variations are not to be regarded as a departure
from the scope of the invention. It will be obvious that the thus
described invention may be varied in many ways by those skilled in
the art.
* * * * *