U.S. patent application number 14/817676 was filed with the patent office on 2015-11-26 for 1',3'-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2h,1'h-[1,4']bipyridinyl-2- '-ones.
The applicant listed for this patent is ADDEX PHARMA, SA, JANSSEN PHARMACEUTICALS, INC.. Invention is credited to JOSE MARIA CID-NUNEZ, GUILLAUME ALBERT JACQUES DUVEY, TERRY PATRICK FINN, ROBERT JOHANNES LUTJENS, GREGOR JAMES MACDONALD, ANDRES AVELINO TRABANCO-SUAREZ.
Application Number | 20150336930 14/817676 |
Document ID | / |
Family ID | 39930548 |
Filed Date | 2015-11-26 |
United States Patent
Application |
20150336930 |
Kind Code |
A1 |
CID-NUNEZ; JOSE MARIA ; et
al. |
November 26, 2015 |
1',3'-Disubstituted-4-Phenyl-3,4,5,6-Tetrahydro-2H,1'H-[1,4']Bipyridinyl-2-
'-Ones
Abstract
The present invention relates to novel compounds, in particular
novel pyridinone derivatives according to Formula (I) ##STR00001##
wherein all radicals are as defined in the application and claims.
The compounds according to the invention are positive allosteric
modulators of metabotropic receptors--subtype 2 ("mGluR2") which
are useful for the treatment or prevention of neurological and
psychiatric disorders associated with glutamate dysfunction and
diseases in which the mGluR2 subtype of metabotropic receptors is
involved. In particular, such diseases are central nervous system
disorders selected from the group of anxiety, schizophrenia,
migraine, depression, and epilepsy. The invention is also directed
to pharmaceutical compositions and processes to prepare such
compounds and compositions, as well as to the use of such compounds
for the prevention and treatment of such diseases in which mGluR2
is involved.
Inventors: |
CID-NUNEZ; JOSE MARIA;
(TOLEDO, ES) ; TRABANCO-SUAREZ; ANDRES AVELINO;
(TOLEDO, ES) ; MACDONALD; GREGOR JAMES; (BEERSE,
BE) ; DUVEY; GUILLAUME ALBERT JACQUES; (GENEVA,
CH) ; LUTJENS; ROBERT JOHANNES; (GENEVA, CH) ;
FINN; TERRY PATRICK; (GENEVA, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JANSSEN PHARMACEUTICALS, INC.
ADDEX PHARMA, SA |
TITUSVILLE
GENEVA |
NJ |
US
CH |
|
|
Family ID: |
39930548 |
Appl. No.: |
14/817676 |
Filed: |
August 4, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13803267 |
Mar 14, 2013 |
9132122 |
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14817676 |
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12677618 |
Jun 3, 2010 |
9114138 |
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PCT/EP2008/007551 |
Sep 12, 2008 |
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13803267 |
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Current U.S.
Class: |
514/278 ;
514/318; 546/17; 546/194 |
Current CPC
Class: |
A61K 9/2013 20130101;
A61K 9/2059 20130101; A61K 31/4545 20130101; A61P 25/06 20180101;
A61P 25/16 20180101; A61P 25/34 20180101; C07D 491/107 20130101;
C07D 493/10 20130101; A61P 25/14 20180101; C07D 401/04 20130101;
A61P 25/24 20180101; A61P 25/10 20180101; A61K 47/44 20130101; A61P
3/04 20180101; A61K 45/06 20130101; A61P 25/30 20180101; A61P 25/08
20180101; A61P 25/22 20180101; A61K 31/5377 20130101; A61P 25/28
20180101; A61K 31/5377 20130101; A61P 25/36 20180101; A61P 25/18
20180101; A61K 9/10 20130101; A61P 25/12 20180101; A61K 31/4545
20130101; A61K 9/2009 20130101; A61K 9/0019 20130101; A61K 9/08
20130101; A61K 31/444 20130101; C07D 211/86 20130101; A61K 9/0014
20130101; A61P 25/32 20180101; A61K 47/10 20130101; A61P 25/00
20180101; A61P 9/10 20180101; A61K 9/2018 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101 |
International
Class: |
C07D 401/04 20060101
C07D401/04; C07D 491/107 20060101 C07D491/107 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 14, 2007 |
EP |
07116390.1 |
Claims
1. A compound having the formula (I) ##STR00131## or a
stereochemically isomeric form thereof, wherein R.sup.1 is
C.sub.1-6alkyl; or C.sub.1-3alkyl substituted with
C.sub.3-7cycloalkyl, phenyl, or phenyl substituted with halo,
trifluoromethyl or trifluoromethoxy; R.sup.2 is halo,
trifluoromethyl, C.sub.1-3alkyl or cyclopropyl; R.sup.3 is
hydrogen, fluoro, hydroxyl, hydroxyC.sub.1-3alkyl,
hydroxyC.sub.1-3alkyloxy, fluoroC.sub.1-3alkyl,
fluoroC.sub.1-3alkyloxy or cyano; and Ar is phenyl substituted with
n radicals R.sup.4, wherein n is 1, 2 or 3; R.sup.4 is selected
from the group consisting of hydrogen, halo, C.sub.1-3alkyl,
hydroxyC.sub.1-3alkyl, polyhaloC.sub.1-3alkyl, cyano, hydroxyl,
amino, carboxyl, C.sub.1-3alkyloxyC.sub.1-3alkyl,
C.sub.1-3alkyloxy, polyhaloC.sub.1-3alkyloxy,
C.sub.1-3alkylcarbonyl, mono- and di(C.sub.1-3alkyl)amino, and
morpholinyl; or two vicinal R.sup.4 radicals taken together form a
bivalent radical of formula --N.dbd.CH--NH-- (a), --CH.dbd.CH--NH--
(b), or --O--CH.sub.2--CH.sub.2--NH-- (c); or R.sup.3 and a R.sup.4
radical in ortho position taken together form a bivalent radical of
formula --CH.sub.2--O-- (d), or --O--CH.sub.2-- (e); or a
pharmaceutically acceptable salt or a solvate thereof.
2. The compound according to claim 1 wherein R.sup.1 is 1-butyl,
2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or
2-(cyclopropyl)-1-ethyl; R.sup.3 is hydrogen, fluoro or cyano; and
Ar is phenyl substituted with halo, trifluoromethyl, morpholinyl or
hydroxyC.sub.1-3alkyl; or a pharmaceutically acceptable salt or a
solvate thereof
3. The compound according to claim 1 wherein R.sup.1 is 1-butyl,
3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
R.sup.2 is chloro; R.sup.3 is hydrogen or fluoro; and Ar is phenyl
substituted with at least one halo, hydroxyC.sub.1-3 alkyl, or a
combination thereof; or a pharmaceutically acceptable salt or a
solvate thereof.
4. The compound according to claim 1 wherein R.sup.1 is 1-butyl,
3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
R.sup.2 is chloro; R.sup.3 is hydrogen or fluoro; and Ar is phenyl
substituted with at least two fluoro groups; or a pharmaceutically
acceptable salt thereof.
5. The compound according to claim 1 wherein said compound is:
##STR00132## or a pharmaceutically acceptable salt or a solvate
thereof.
6. The compound according to claim 1 wherein said compound is:
##STR00133##
7. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 and a pharmaceutically
acceptable carrier or excipient.
8. A pharmaceutical composition comprising a therapeutically
effective amount of a compound having the structure ##STR00134##
and a pharmaceutically acceptable carrier or excipient.
9. A method for treating or preventing a central nervous system
disorder in a human patient selected from the group of anxiety
disorder, depression, psychotic disorder, or epilepsy or convulsive
disorder, the method comprising administering to the patient in
need thereof a compound of claim 1, or a pharmaceutically
acceptable salt or a solvate thereof.
10. The method of claim 9, wherein the central nervous system
disorder is an anxiety disorder, selected from the group of
agoraphobia, generalized anxiety disorder (GAD),
obsessive-compulsive disorder (OCD), panic disorder, posttraumatic
stress disorder (PTSD), social phobia and other phobias.
11. The method of claim 10, wherein the anxiety disorder is
generalized anxiety disorder (GAD).
12. The method of claim 9, wherein the central nervous system
disorder is a psychotic disorder selected from the group of
schizophrenia, schizoaffective disorder, and schizophreniform
disorder.
13. The method of claim 13, wherein the psychotic disorder is
schizophrenia.
14. The method of claim 9, wherein the central nervous system
disorder is epilepsy or convulsive disorder.
15. The method of claim 14, wherein the epilepsy or a convulsive
disorder is generalized nonconvulsive epilepsy, generalized
convulsive epilepsy, petit mal status epilepticus, grand mal status
epilepticus, partial epilepsy with or without impairment of
consciousness, infantile spasms, or epilepsy partialis
continua.
16. The method of claim 9, wherein the central nervous system
disorder is depression.
17. A method for treating or preventing a central nervous system
disorder in a human patient selected from the group of anxiety
disorder, psychotic disorder, or epilepsy or convulsive disorder,
the method comprising administering to the patient in need thereof
a compound of claim 5, or a pharmaceutically acceptable salt or a
solvate thereof.
18. The method of claim 17, wherein the central nervous system
disorder is an anxiety disorder, selected from the group of
agoraphobia, generalized anxiety disorder (GAD),
obsessive-compulsive disorder (OCD), panic disorder, posttraumatic
stress disorder (PTSD), social phobia and other phobias.
19. The method of claim 18, wherein the anxiety disorder is
generalized anxiety disorder (GAD).
20. The method of claim 17, wherein the central nervous system
disorder is a psychotic disorder selected from the group of
schizophrenia, schizoaffective disorder, and schizophreniform
disorder.
21. The method of claim 20, wherein the psychotic disorder is
schizophrenia.
22. The method of claim 17, wherein the central nervous system
disorder is epilepsy or convulsive disorder.
23. The method of claim 22, wherein the epilepsy or a convulsive
disorder is generalized nonconvulsive epilepsy, generalized
convulsive epilepsy, petit mal status epilepticus, grand mal status
epilepticus, partial epilepsy with or without impairment of
consciousness, infantile spasms, or epilepsy partialis
continua.
23. The method of claim 17, wherein the central nervous system
disorder is depression.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 13/803,267, filed on Mar. 14, 2013, which is a
continuation application of U.S. application Ser. No. 12/677,618,
filed on Jun. 3, 2010, which is a U.S. National Phase Application
under 35 USC 371 of International Application PCT/EP2008/007551,
filed Sep. 12, 2008, which claims priority to European Application
No. 07116390.1, filed Sep. 14, 2007. Each application is hereby
incorporated herein by reference in its entirety for all
purposes.
FIELD OF THE INVENTION
[0002] The present invention relates to novel
pyridinone-derivatives which are positive allosteric modulators of
the metabotropic glutamate receptor subtype 2 ("mGluR2") and which
are useful for the treatment or prevention of neurological and
psychiatric disorders associated with glutamate dysfunction and
diseases in which the mGluR2 subtype of metabotropic receptors is
involved. The invention is also directed to pharmaceutical
compositions comprising such compounds, to processes to prepare
such compounds and compositions, and to the use of such compounds
for the prevention or treatment of neurological and psychiatric
disorders and diseases in which mGluR2 is involved.
BACKGROUND OF THE INVENTION
[0003] Glutamate is the major amino acid neurotransmitter in the
mammalian central nervous system. Glutamate plays a major role in
numerous physiological functions, such as learning and memory but
also sensory perception, development of synaptic plasticity, motor
control, respiration, and regulation of cardiovascular function.
Furthermore, glutamate is at the centre of several different
neurological and psychiatric diseases, where there is an imbalance
in glutamatergic neurotransmission.
[0004] Glutamate mediates synaptic neurotransmission through the
activation of ionotropic glutamate receptors channels (iGluRs), and
the NMDA, AMPA and kainate receptors which are responsible for fast
excitatory transmission.
[0005] In addition, glutamate activates metabotropic glutamate
receptors (mGluRs) which have a more modulatory role that
contributes to the fine-tuning of synaptic efficacy.
[0006] Glutamate activates the mGluRs through binding to the large
extracellular amino-terminal domain of the receptor, herein called
the orthosteric binding site. This binding induces a conformational
change in the receptor which results in the activation of the
G-protein and intracellular signaling pathways.
[0007] The mGluR2 subtype is negatively coupled to adenylate
cyclase via activation of G.alpha.i-protein, and its activation
leads to inhibition of glutamate release in the synapse. In the
central nervous system (CNS), mGluR2 receptors are abundant mainly
throughout cortex, thalamic regions, accessory olfactory bulb,
hippocampus, amygdala, caudate-putamen and nucleus accumbens.
[0008] Activating mGluR2 was shown in clinical trials to be
efficacious to treat anxiety disorders. In addition, activating
mGluR2 in various animal models was shown to be efficacious, thus
representing a potential novel therapeutic approach for the
treatment of schizophrenia, epilepsy, addiction/drug dependence,
Parkinson's disease, pain, sleep disorders and Huntington's
disease.
[0009] To date, most of the available pharmacological tools
targeting mGluRs are orthosteric ligands which activate several
members of the family as they are structural analogs of
glutamate.
[0010] A new avenue for developing selective compounds acting at
mGluRs is to identify compounds that act through allosteric
mechanisms, modulating the receptor by binding to a site different
from the highly conserved orthosteric binding site.
[0011] Positive allosteric modulators of mGluRs have emerged
recently as novel pharmacological entities offering this attractive
alternative. Various compounds have been described as mGluR2
positive allosteric modulators. WO2004/092135 (NPS & Astra
Zeneca), WO2004/018386, WO2006/014918 and WO2006/015158 (Merck),
W02001/56990 (Eli Lilly) and WO2006/030032 (Addex & Janssen
Pharmaceutica) describe respectively phenyl sulfonamide,
acetophenone, indanone, pyridylmethyl sulfonamide and pyridinone
derivatives as mGluR2 positive allosteric modulators. None of the
specifically disclosed compounds therein are structurally related
to the compounds of the present invention.
[0012] It was demonstrated that such compounds do not activate the
receptor by themselves. Rather, they enable the receptor to produce
a maximal response to a concentration of glutamate which by itself
induces a minimal response. Mutational analysis has demonstrated
unequivocally that the binding of mGluR2 positive allosteric
modulators does not occur at the orthosteric site, but instead at
an allosteric site situated within the seven transmembrane region
of the receptor.
[0013] Animal data are suggesting that positive allosteric
modulators of mGluR2 have effects in anxiety and psychosis models
similar to those obtained with orthosteric agonists. Allosteric
modulators of mGluR2 were shown to be active in fear-potentiated
startle, and in stress-induced hyperthermia models of anxiety.
Furthermore, such compounds were shown to be active in reversal of
ketamine- or amphetamine-induced hyperlocomotion, and in reversal
of amphetamine-induced disruption of prepulse inhibition of the
acoustic startle effect models of schizophrenia. (J. Pharmacol.
Exp. Ther. 2006, 318, 173-185; Psychopharmacology 2005, 179,
271-283).
[0014] Recent animal studies further reveal that the selective
positive allosteric modulator of metabotropic glutamate receptor
subtype 2 biphenyl-indanone (BINA) blocks a hallucinogenic drug
model of psychosis, supporting the strategy of targeting mGluR2
receptors for treating glutamatergic dysfunction in schizophrenia.
(Mol. Pharmacol. 2007, 72, 477-484).
[0015] Positive allosteric modulators enable potentiation of the
glutamate response, but they have also been shown to potentiate the
response to orthosteric mGluR2 agonists such as LY379268 or DCG-IV.
These data provide evidence for yet another novel therapeutic
approach to treat above mentioned neurological and psychiatric
diseases involving mGluR2, which would use a combination of a
positive allosteric modulator of mGluR2 together with an
orthosteric agonist of mGluR2.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The present invention relates to compounds having
metabotropic glutamate receptor 2 modulator activity, said
compounds having the Formula (I)
##STR00002##
and the stereochemically isomeric forms thereof, wherein R.sup.1 is
C.sub.1-6alkyl; or C.sub.1-3alkyl substituted with
C.sub.3-7cycloalkyl, phenyl, or phenyl substituted with halo,
trifluoromethyl or trifluoromethoxy; R.sup.2 is halo,
trifluoromethyl, C.sub.1-3alkyl or cyclopropyl; R.sup.3 is
hydrogen, fluoro, hydroxyl, hydroxyC.sub.1-3alkyl,
hydroxyC.sub.1-3alkyloxy, fluoroC.sub.1-3alkyl,
fluoroC.sub.1-3alkyloxy or cyano; and Ar is unsubstituted phenyl;
or phenyl substituted with n radicals R.sup.4, wherein n is 1, 2 or
3; R.sup.4 is selected from the group consisting of hydrogen, halo,
C.sub.1-3alkyl, hydroxyC.sub.1-3alkyl, polyhaloC.sub.1-3alkyl,
cyano, hydroxyl, amino, carboxyl, C.sub.1-3alkyloxyC.sub.1-3alkyl,
C.sub.1-3alkyloxy, polyhaloC.sub.1-3alkyloxy,
C.sub.1-3alkylcarbonyl, mono- and di(C.sub.1-3alkyl)amino, and
morpholinyl; or two vicinal R.sup.4 radicals taken together form a
bivalent radical of formula
--N.dbd.CH--NH-- (a),
--CH.dbd.CH--NH-- (b), or
--O--CH.sub.2--CH.sub.2--NH-- (c); or [0017] R.sup.3 and a R.sup.4
radical in ortho position taken together form a bivalent radical of
formula
[0017] --CH.sub.2--O-- (d), or
--O--CH.sub.2-- (e);
and the pharmaceutically acceptable salts and solvates thereof.
[0018] In one embodiment, the invention relates to a compound of
Formula (I) or a stereochemically isomeric form thereof wherein
R.sup.1 is C.sub.1-6alkyl; or C.sub.1-3alkyl substituted with
C.sub.3-7cycloalkyl, phenyl, or phenyl substituted with halo,
trifluoromethyl or trifluoromethoxy; R.sup.2 is halo,
trifluoromethyl, C.sub.1-3alkyl or cyclopropyl; R.sup.3 is
hydrogen, fluoro, hydroxyl, hydroxyC.sub.1-3alkyl,
hydroxyC.sub.1-3alkyloxy, fluoroC.sub.1-3alkyl,
fluoroC.sub.1-3alkyloxy or cyano; and Ar is unsubstituted phenyl,
or phenyl substituted with n radicals R.sup.4, wherein n is 1, 2 or
3, R.sup.4 is selected from the group consisting of hydrogen, halo;
C.sub.1-3alkyl; hydroxyC.sub.1-3alkyl, polyhaloC.sub.1-3alkyl;
cyano; hydroxy; amino; carboxyl; C.sub.1-3alkyloxyC.sub.1-3alkyl;
C.sub.1-3alkyloxy; polyhaloC.sub.1-3alkyloxy;
C.sub.1-3alkylcarbonyl; mono- and di(C.sub.1-3alkyl)amino, and
morpholinyl; or two vicinal R.sup.4 radicals taken together form a
bivalent radical of formula
--N.dbd.CH--NH-- (a),
--CH.dbd.CH--NH-- (b), or
--O--CH.sub.2--CH.sub.2--NH-- (c);
and the pharmaceutically acceptable salts and solvates thereof
[0019] In one embodiment, the invention relates to a compound
according to Formula (I) or a stereochemically isomeric form
thereof, wherein [0020] R.sup.1 is 1-butyl, 2-methyl-1-propyl,
3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
[0021] R.sup.2 is chloro, bromo, cyclopropyl or trifluoromethyl;
[0022] R.sup.3 is hydrogen, fluoro or cyano; and [0023] Ar is
unsubstituted phenyl; or phenyl substituted with halo,
trifluoromethyl, morpholinyl or hydroxyC.sub.1-3alkyl; [0024] or a
pharmaceutically acceptable salt or solvate thereof.
[0025] In one embodiment, the invention relates to a compound
according to Formula (I) or a stereochemically isomeric form
thereof, wherein
R.sup.1 is 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or
2-(cyclopropyl)-1-ethyl; R.sup.2 is chloro; R.sup.3 is hydrogen or
fluoro; and Ar is unsubstituted phenyl; or phenyl substituted with
hydroxyC.sub.1-3 alkyl; or a pharmaceutically acceptable salt or
solvate thereof
[0026] In one embodiment the invention relates to the compound
[0027]
3'-Chloro-1'-cyclopropylmethyl-4-phenyl-3,4,5,6-tetrahydro-2H,1'H-[1,4']b-
ipyridinyl-2'-one (E1) or [0028]
1'-Butyl-3'-chloro-4-phenyl-3,4,5,6-tetrahydro-2H,1'H-[1,4']bipyridinyl-2-
'-one (E2).
[0029] The notation C.sub.1-3alkyl as a group or part of a group
defines a saturated, straight or branched, hydrocarbon radical
having from 1 to 3 carbon atoms, such as methyl, ethyl, 1-propyl
and 1-methylethyl; e.g. hydroxyC.sub.1-3alkyl for example defines
hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and
1-hydroxy-1-methylethyl.
[0030] The notation C.sub.1-6alkyl as a group or part of a group
defines a saturated, straight or branched, hydrocarbon radical
having from 1 to 6 carbon atoms such as methyl, ethyl, 1-propyl,
1-methylethyl, 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl,
1-pentyl, 1-hexyl and the like.
[0031] The notation C.sub.3-7cycloalkyl defines a saturated, cyclic
hydrocarbon radical having from 3 to 7 carbon atoms, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
[0032] The notation halo or halogen as a group or part of a group
is generic for fluoro, chloro, bromo, iodo.
[0033] 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.
[0034] 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 acid, 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.
[0035] Conversely said salt forms can be converted into the free
base form by treatment with an appropriate base.
[0036] 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 earth alkaline metal salts, in
particular lithium, sodium, potassium, magnesium and calcium salts,
salts with organic bases, e.g. the benzathine,
N-methyl-D-glucamine, hybramine salts, and salts with amino acids,
for example arginine and lysine.
[0037] Conversely, said salt forms can be converted into the free
acid forms by treatment with an appropriate acid.
[0038] 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.
[0039] The term "stereochemically isomeric 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.
[0040] 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*]. If ".alpha."
and ".beta." are used: the position of the highest priority
substituent on the asymmetric carbon atom in the ring system having
the lowest ring number, is arbitrarily always in the ".alpha."
position of the mean plane determined by the ring system. The
position of the highest priority substituent on the other
asymmetric carbon atom in the ring system (hydrogen atom in
compounds according to Formula (I)) relative to the position of the
highest priority substituent on the reference atom is denominated
".alpha.", if it is on the same side of the mean plane determined
by the ring system, or ".beta.", if it is on the other side of the
mean plane determined by the ring system.
[0041] 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, 18F, 122I,
123I, 125I, 131I, 75Br, 76Br, 77Br and 82Br. Preferably, the
radioactive isotope is selected from the group of .sup.3H, .sup.11C
and .sup.18F.
Preparation
[0042] 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.
[0043] 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
Experimental Procedure 1
[0044] The compounds according to Formula (I), in the case of
R.sup.2 being halogen, can be prepared by reacting an intermediate
of Formula (II) with an N-halosuccinimide reagent, such as
N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide,
according to reaction scheme (1). This reaction is performed in a
suitable reaction-inert and aprotic solvent, such as, for example,
dichloromethane or 1,2-dichloroethane, stirring the reaction
mixture at a suitable temperature, typically at room temperature,
for the required time to achieve completion of the reaction,
usually 1 hour. In reaction scheme (1), R.sup.2 is halogen and all
other variables are defined as in Formula (I).
##STR00003##
Experimental Procedure 2
[0045] Alternatively, compounds according to Formula (I) can be
prepared by reacting an intermediate of Formula (III) with an
intermediate of Formula (IV), which can be either commercially
available or may be synthesized by procedures well known to anyone
skilled in the art, according to reaction scheme (2). This reaction
is performed in a suitable reaction-inert solvent such as, for
example, toluene, in the presence of a suitable base such as, for
example, sodium tert-butoxide, a metal-based catalyst, specifically
a palladium catalyst, such as palladium(II) acetate, and a suitable
ligand, such as for example
[1,1'-binaphthalene]-2,2'-diylbis[diphenylphosphine] (BINAP),
heating for a suitable period of time that allows the completion of
the reaction, for example at 100.degree. C. for 16 hours in a
sealed tube. In reaction scheme (2), Z.sup.a is a group suitable
for Pd mediated coupling with amines, such as, for example, a
halogen or triflate. All other variables are defined as in Formula
(I).
##STR00004##
[0046] Such intermediates of Formula (II) and Formula (III) may be
prepared according to reaction schemes (3) to (11) (see below). The
transformations of different functional groups present in the final
compounds, into other functional groups according to Formula (I),
can be performed by synthesis methods well known by the person
skilled in the art.
[0047] Additionally, compounds according to Formula (I) can be
prepared by a skilled person using art known procedures by further
modifications of compounds of Formula (I): [0048] Alkylation of
compounds of Formula (I) that contain in their structure one or
more hydroxy-substituents with a suitable alkylating agent such as
for example 2-fluorethyl tosylate under thermal conditions using a
suitable base such as for example sodium hydride, in a suitable
reaction-inert solvent such as, for example 1,2-dimethoxyethane or
dimethylformamide. [0049] Fluorination of compounds of Formula (I)
that contain in their structure one or more hydroxy-substituents
with a suitable fluorinating agent, such as for example
(diethylamino)sulfur trifluoride. This reaction may be performed in
a suitable reaction-inert solvent such as, for example,
dichloromethane, under a moderately low temperature such as, for
example, a temperature ranging from -78.degree. C. to 30.degree. C.
during, for example, 0.5 to 12 hours. [0050] Reaction of compounds
of Formula (I) that contain in their structure one or more
hydroxy-substituents with an alcohol derivative by using a suitable
coupling system such as, for example,
di-tert-butylazodicarboxylate/triphenylphosphine under thermal
conditions.
B. Preparation of the Intermediates
Experimental Procedure 3
[0051] Intermediates of Formula (II) can be prepared by reacting an
intermediate of Formula (V) with an intermediate of Formula (IV)
according to reaction scheme (3). This reaction is performed in a
suitable reaction-inert solvent such as, for example, toluene, in
the presence of a suitable base such as, for example, sodium
tert-butoxide, a metal-based catalyst, specifically a palladium
catalyst, such as palladium(II) acetate, and a suitable ligand,
such as for example
[1,1'-binaphthalene]-2,2'-diylbis[diphenylphosphine] (BINAP),
heating for a suitable period of time that allows the completion of
the reaction, for example at 100.degree. C. for 16 hours in a
sealed tube. In reaction scheme (3), all variables are defined as
in Formula (I).
##STR00005##
Experimental Procedure 4
[0052] Intermediates of Formula (III-a) and (III-b) can be prepared
by reacting an intermediate of Formula (VI), wherein Y is H or
R.sup.2 (as defined as in Formula I), with a suitable halogenating
agent such as, for example, phosphorus oxybromide. This reaction
may be performed in a suitable reaction-inert solvent such as, for
example, DMF, at a moderately elevated temperature such as, for
example, 110.degree. C., for a suitable period of time that allows
the completion of the reaction, for instance 1 hour. In reaction
scheme (4), variable R.sup.1 is defined as in Formula (I).
##STR00006##
Experimental Procedure 5
[0053] Intermediates of Formula (III-c) can be prepared by reacting
an intermediate of Formula (VI-a) with triflic anhydride (also
called trifloromethanesulfonic anhydride). The reaction may be
performed in a suitable reaction-inert solvent such as, for
example, dichloromethane, in the presence of a base such as, for
example, pyridine at a low temperature such as, for example,
-78.degree. C. In reaction scheme (5), all variables are defined as
in Formula (I).
##STR00007##
Experimental Procedure 6
[0054] Intermediates of Formula (VI) can be prepared by
hydrogenolysis of intermediates of Formula (VII-a, VII-b or VII-c),
in a suitable reaction-inert solvent such as, for example, ethanol,
in the presence of a catalyst such as, for example, 10% palladium
on activated carbon, for a period of time that ensures the
completion of the reaction, typically at room temperature and 1
atmosphere of hydrogen for 2 hours. In reaction scheme (6),
variable R.sup.1 is defined as in Formula (I).
##STR00008##
Experimental Procedure 7
[0055] Alternatively, intermediates of Formula (VI), wherein
Y=halogen, can be prepared by reacting an intermediate of Formula
(VII-d) in a mixture of acetic acid and hydrobromic acid, and
heating the mixture at a temperature and for the time required to
allow completion of the reaction, typically at 130.degree. C. for
30 minutes under microwave irradiation. In reaction scheme (7),
variable R.sup.1 is defined as in Formula (I).
##STR00009##
Experimental Procedure 8
[0056] Intermediates of Formula (VII-a) can be prepared by art
known procedures by reacting commercially available
4-benzyloxy-1H-pyridin-2-one with a commercially available
alkylating agent of Formula (VIII), in which Z.sup.b is a suitable
leaving group, using a base such as, for example, K.sub.2CO.sub.3,
and, optionally an iodine salt such as, for example, KI, in an
inert solvent such as, for example, acetonitrile or DMF, at a
moderately high temperature such as, for example, 80-120.degree.
C., for a suitable period of time that allows the completion of the
reaction, for example 16 hours. In reaction scheme (8), variable
R.sup.1 is defined as in Formula (I) and Z.sup.b is a suitable
leaving group such as, for example, halogen.
##STR00010##
Experimental Procedure 9
[0057] Intermediates of Formula (VII-b) can be prepared by reacting
an intermediate of Formula (VII-e), wherein Y is iodine, with
commercially available methyl
2,2-difluoro-2-(fluorosulfonyl)acetate, in a suitable
reaction-inert solvent such as, for example, DMF, in presence of a
suitable copper salt such as copper(I) iodide, heating for a
suitable period of time that allows the completion of the reaction,
for example at 100.degree. C. for 5 hours. In reaction scheme (9),
variable R.sup.1 is defined as in Formula (I).
##STR00011##
Experimental Procedure 10
[0058] Intermediates of Formula (VII-d) can be prepared by reacting
an intermediate of Formula (VII-a) with a commercially available
N-halosuccinimide, such as N-chloro-(NCS), N-bromo-(NBS) or
N-iodosuccinimide (NIS), in a suitable reaction-inert solvent such
as, for example, DMF, dichloromethane or acetic acid, typically at
room temperature for 1 to 24 hours. In reaction scheme (10),
variable R.sup.1 is defined as in Formula (I).
##STR00012##
Experimental Procedure 11
[0059] Intermediates of Formula (VII-c) can be prepared by reacting
an intermediate of Formula (VII-d) with a C.sub.1-3alkyl- or
cyclopropyl-boronic acid derivative, such as cyclopropyl-boronic
acid or methyl-boronic acid, in a suitable reaction-inert solvent
such as, for example, 1,4-dioxane, in the presence of a suitable
palladium catalyst-complex such as, for example,
[1,1'-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)--DCM
complex, and in the presence of a suitable base such as sodium
hydrogencarbonate, heating for a suitable period of time that
allows the completion of the reaction, for example at 175.degree.
C. for 20 minutes under microwave irradiation. In reaction scheme
(11), variable R.sup.1 is defined as in Formula (I).
##STR00013##
Experimental Procedure 12
[0060] Intermediates of formula (IV) can be prepared by
deprotection of the piperidine nitrogen in an intermediate of
formula (IX) wherein L is a suitable protecting group for the
nitrogen atom of a piperidine derivative, such as for example
tert-butoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzyl and
methyl, applying art known procedures, according to reaction scheme
(12). In reaction scheme (12), all variables are defined as in
formula (I).
##STR00014##
Experimental Procedure 13
[0061] Intermediates of formula (IV-a) can be prepared by
hydrogenation of an intermediate of formula (X) applying art known
procedures, according to reaction scheme (13). In reaction scheme
(13), Ar is defined as in formula (I).
##STR00015##
Experimental Procedure 14
[0062] Intermediates of formula (IX-a) can be prepared by
hydrogenation of an intermediate of formula (XI) wherein L is a
suitable protecting group for the nitrogen atom of a
tetrahydropyridine derivative, such as for example
tert-butoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzyl and
methyl, applying art known procedures, according to reaction scheme
(14). In reaction scheme (14), Ar is defined as in Formula (I).
##STR00016##
Experimental Procedure 15
[0063] Intermediates of formula (X) can be prepared by deprotection
of the tetrahydropyridine nitrogen in an intermediate of formula
(XI) wherein L is a suitable protecting group for the nitrogen atom
of a tetrahydropyridine derivative, such as for example
tert-butoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzyl and
methyl, applying art known procedures, according to reaction scheme
(15). In reaction scheme (15), Ar is defined as in formula (I).
##STR00017##
Experimental Procedure 16
[0064] Intermediates of formula (XI) can be prepared by reacting an
intermediate of formula (XII) with an intermediate of formula
(XIII) according to reaction scheme (16). The reaction may be
performed in a suitable reaction-inert solvent, such as, for
example, 1,4-dioxane, or mixtures of inert solvents such as, for
example, 1,4-dioxane/DMF, in the presence of a suitable base, such
as, for example, aqueous NaHCO.sub.3 or Na.sub.2CO.sub.3, a
suitable catalyst, such as for example a Pd-complex catalyst such
as, for example, Pd(PPh.sub.3).sub.4, under thermal conditions such
as, for example, heating the reaction mixture at 150.degree. C.
under microwave irradiation, during, for example, 10 minutes. In
reaction scheme (16), all variables are defined as in formula (I);
Z.sup.e is a group suitable for Pd mediated coupling with boronic
acids or boronic esters, such as, for example, a halo or triflate;
L is a suitable protecting group for the nitrogen atom of a
tetrahydropyridine derivative, such as for example
tert-butoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzyl and
methyl and R.sub.4 and R.sub.5 are hydrogen or C.sub.1-4alkyl, or
may be taken together to form for example a bivalent radical of
formula --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or
--C(CH.sub.3).sub.2C(CH.sub.3).sub.2--.
##STR00018##
Experimental Procedure 17
[0065] Intermediates of formula (IV) wherein R.sub.3 represents
fluoro or C.sub.1-3alkyl substituted with fluoro, said R.sub.3
being represented by --L.sub.1-F wherein L.sub.1 represents
C.sub.1-3alkyl or a covalent bond, and said intermediates being
represented by formula (IV-b), can be prepared by art known
procedures by reacting an intermediate of formula (IX-b) wherein L
is a suitable protecting group for the nitrogen atom of the
piperidine moiety, such as for example tert-butoxycarbonyl,
ethoxycarbonyl, benzyloxycarbonyl, benzyl and methyl, with a
suitable fluorinating agent such as for example
(diethylamino)sulfur trifluoride, resulting in an intermediate of
formula (IX-c) according to reaction scheme (17) step (a). The
reaction may be performed in a suitable reaction-inert solvent,
such as, for example, dichloromethane. The reaction may be
performed under a moderately low temperature such as, for example,
a temperature ranging from -78.degree. C. to 30.degree. C. during
for example 0.5 to 12 hours. The resulting intermediate of formula
(IX-c) can then be transformed according to reaction scheme (17)
step (b), in an intermediate of Formula (IV-b) by deprotection of
the piperidine nitrogen applying art known procedures, such as for
example those described in experimental procedure 15 herein above.
In reaction scheme (17), Ar is defined as in formula (I).
##STR00019##
Experimental Procedure 18
[0066] Intermediates of formula (IV) wherein R.sub.3 represents
C.sub.1-3alkyloxy substituted with fluoro, said C.sub.1-3alkyloxy
being represented by Q, said R.sub.3 being represented by -Q-F, and
said intermediates being represented by formula (IV-d), can be
prepared by art known procedures by reacting a hydroxyl-substituted
intermediate of formula (IX-d) wherein L is a suitable protecting
group for the nitrogen atom of the piperidine moiety, such as for
example tert-butoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl,
benzyl and methyl, with a suitable fluorinating agent such as
(diethylamino)sulfur trifluoride, resulting in an intermediate of
formula (IX-e) according to reaction scheme (18) step (a). The
reaction can be performed in a suitable reaction-inert solvent,
such as, for example, dichloromethane, under a moderately low
temperature such as, for example, a temperature ranging from
-78.degree. C. to 30.degree. C. during for example 0.5 to 12 hours.
The intermediate of Formula (IX-e) can then be transformed
according to reaction scheme (18) step (b) in an intermediate of
Formula (IV-d) by deprotection of the piperidine nitrogen applying
art known procedures, such as for example those described in
experimental procedure 17 hereinabove. In reaction scheme (18), Ar
is defined as in formula (I).
##STR00020##
Experimental Procedure 19
[0067] Intermediates of formula (IX-b) wherein L1 represents
CH.sub.2, said intermediates being represented by formula (IX-f),
can be prepared by reacting an intermediate of formula (XIV)
wherein L is a suitable protecting group for the nitrogen atom of
the piperidine moiety, such as for example tert-butoxycarbonyl,
ethoxycarbonyl, benzyloxycarbonyl, benzyl and methyl, with a
suitable reducing agent, such as for example, lithium aluminium
hydride, according to reaction scheme (19). The reaction may be
performed in a suitable solvent, such as for example
tetrahydrofuran, at a moderately low temperature such as, for
example from -20.degree. C. In reaction scheme (19) Ar is defined
as in formula (I)
##STR00021##
[0068] The starting materials according to Formulas (VIII), (IX-b),
(IX-d), (XII), (XIII) and XIV are either commercially available or
may be prepared according to conventional reaction procedures
generally known by those skilled in the art.
Pharmacology
[0069] The compounds provided in this invention are positive
allosteric modulators of metabotropic glutamate receptors, in
particular they are positive allosteric modulators of mGluR2. The
compounds of the present invention do not appear to bind to the
glutamate recognition site, the orthosteric ligand site, but
instead to an allosteric site within the seven transmembrane region
of the receptor. In the presence of glutamate or an agonist of
mGluR2, the compounds of this invention increase the mGluR2
response. The compounds provided in this invention are expected to
have their effect at mGluR2 by virtue of their ability to increase
the response of such receptors to glutamate or mGluR2 agonists,
enhancing the response of the receptor. 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 for
treating or preventing, in particular treating, a condition in a
mammal, including a human, the treatment or prevention of which is
affected or facilitated by the neuromodulatory effect of allosteric
modulators of mGluR2, in particular positive allosteric modulators
thereof. 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 manufacture of a medicament for
treating or preventing, in particular treating, a condition in a
mammal, including a human, the treatment or prevention of which is
affected or facilitated by the neuromodulatory effect of allosteric
modulators of mGluR2, in particular positive allosteric modulators
thereof. The present invention also relates to a compound according
to the present invention or a pharmaceutical composition according
to the invention for treating or preventing, in particular
treating, a condition in a mammal, including a human, the treatment
or prevention of which is affected or facilitated by the
neuromodulatory effect of allosteric modulators of mGluR2, in
particular positive allosteric modulators thereof.
[0070] 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 glutamate dysfunction in a mammal, including a human, the
treatment or prevention of which is affected or facilitated by the
neuromodulatory effect of positive allosteric modulators of
mGluR2.
[0071] 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.
[0072] In particular, the neurological and psychiatric disorders
associated with glutamate dysfunction, include one or more of the
following conditions or diseases: acute neurological and
psychiatric disorders such as, for example, cerebral deficits
subsequent to cardiac bypass surgery and grafting, stroke, cerebral
ischemia, spinal cord trauma, head trauma, perinatal hypoxia,
cardiac arrest, hypoglycemic neuronal damage, dementia (including
AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea,
amyotrophic lateral sclerosis, ocular damage, retinopathy,
cognitive disorders, idiopathic and drug-induced Parkinson's
disease, muscular spasms and disorders associated with muscular
spasticity including tremors, epilepsy, convulsions, migraine
(including migraine headache), urinary incontinence, substance
tolerance, substance withdrawal (including substances such as, for
example, opiates, nicotine, tobacco products, alcohol,
benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis,
schizophrenia, anxiety (including generalized anxiety disorder,
panic disorder, and obsessive compulsive disorder), mood disorders
(including depression, mania, bipolar disorders), trigeminal
neuralgia, hearing loss, tinnitus, macular degeneration of the eye,
emesis, brain edema, pain (including acute and chronic states,
severe pain, intractable pain, neuropathic pain, and post-traumatic
pain), tardive dyskinesia, sleep disorders (including narcolepsy),
attention deficit/hyperactivity disorder, and conduct disorder.
[0073] In particular, the condition or disease is a central nervous
system disorder selected from the group of anxiety disorders,
psychotic disorders, personality disorders, substance-related
disorders, eating disorders, mood disorders, migraine, epilepsy or
convulsive disorders, childhood disorders, cognitive disorders,
neurodegeneration, neurotoxicity and ischemia.
[0074] Preferably, the central nervous system disorder is an
anxiety disorder, selected from the group of agoraphobia,
generalized anxiety disorder (GAD), obsessive-compulsive disorder
(OCD), panic disorder, posttraumatic stress disorder (PTSD), social
phobia and other phobias.
[0075] Preferably, the central nervous system disorder is a
psychotic disorder selected from the group of schizophrenia,
delusional disorder, schizoaffective disorder, schizophreniform
disorder and substance-induced psychotic disorder
[0076] Preferably, the central nervous system disorder is a
personality disorder selected from the group of
obsessive-compulsive personality disorder and schizoid, schizotypal
disorder.
[0077] Preferably, 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.
[0078] Preferably, the central nervous system disorder is an eating
disorder selected from the group of anorexia nervosa and bulimia
nervosa.
[0079] 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.
[0080] Preferably, the central nervous system disorder is
migraine.
[0081] Preferably, the central nervous system disorder is epilepsy
or a convulsive disorder selected from the group of generalized
nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal
status epilepticus, grand mal status epilepticus, partial epilepsy
with or without impairment of consciousness, infantile spasms,
epilepsy partialis continua, and other forms of epilepsy.
[0082] Preferably, the central nervous system disorder is
attention-deficit/hyperactivity disorder.
[0083] 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.
[0084] Of the disorders mentioned above, the treatment of anxiety,
schizophrenia, migraine, depression, and epilepsy are of particular
importance.
[0085] 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.
[0086] Because such positive allosteric modulators of mGluR2,
including compounds of Formula (I), enhance the response of mGluR2
to glutamate, it is an advantage that the present methods utilize
endogenous glutamate.
[0087] Because positive allosteric modulators of mGluR2, including
compounds of Formula (I), enhance the response of mGluR2 to
agonists, it is understood that the present invention extends to
the treatment of neurological and psychiatric disorders associated
with glutamate dysfunction by administering an effective amount of
a positive allosteric modulator of mGluR2, including compounds of
Formula (I), in combination with an mGluR2 agonist.
[0088] 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.
Pharmaceutical Compositions
[0089] The 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.
[0090] 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.
[0091] To prepare the pharmaceutical compositions of this
invention, an 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 administration orally, rectally,
percutaneously, by parenteral injection or by inhalation. 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 obviously employed. For parenteral
compositions, the carrier will usually comprise sterile water, at
least in large part, though other ingredients, for example, 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, which 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, as an ointment.
[0092] 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,
and segregated multiples thereof.
[0093] 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.
[0094] 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.
[0095] As already mentioned, the invention also relates to a
pharmaceutical composition comprising the compounds according to
the invention and 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 as well as to the use of such a composition for
the manufacture of a medicament. The present invention also relates
to a combination of a compound according to the present invention
and a mGluR2 orthosteric agonist. 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) a mGluR2 orthosteric
agonist, 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 neuromodulatory effect of mGluR2
allosteric modulators, in particular positive mGluR2 allosteric
modulators. 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.
[0096] The following examples are intended to illustrate but not to
limit the scope of the present invention.
Chemistry
[0097] 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.
[0098] Hereinafter, "THF" means tetrahydrofuran; "DMF" means
N,N-dimethylformamide; "EtOAc" means ethyl acetate; "DCM" means
dichloromethane; "DME" means 1,2-dimethoxyethane; "DCE" means
1,2-dichloroethane; "DIPE" means diisopropylether; "DMSO" means
dimethylsulfoxide; "BINAP" means[1,1'-binaphthalene]-2,2'-diylbis
[diphenylphosphine]; "DBU" means
1,8-diaza-7-bicyclo[5.4.0]undecene; Xantphos means
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenylphosphine]; MeOH
means methanol; "q.s." means quantum sufficit; "M.P." means melting
point;
[0099] Microwave assisted reactions were performed in a single-mode
reactor: Initiator.TM. Sixty EXP microwave reactor (Biotage AB), or
in a multimode reactor: MicroSYNTH Labstation (Milestone,
Inc.).
Description 1
4-Benzyloxy-1-cyclopropylmethyl-1H-pyridin-2-one (D1)
##STR00022##
[0101] Bromomethyl-cyclopropane (3.68 g, 27.33 mmol) and potassium
carbonate (10.3 g, 74.52 mmol) were added to a solution of
4-benzyloxy-1H-pyridin-2-one (5.0 g, 24.84 mmol) in acetonitrile
(200 ml) and the mixture was heated at reflux for 16 hours. The
reaction mixture was filtered through diatomaceous earth and
concentrated in vacuo. The crude residue was then triturated with
diethylether to yield pure D1 (6.32 g, 98%) as a white solid.
Description 2
1-Cyclopropylmethyl-4-hydroxy-1H-pyridin-2-one (D2)
##STR00023##
[0103] A mixture of intermediate D1 (2.0 g, 7.83 mmol) and a
catalytic amount of 10% palladium on activated carbon in ethanol
(300 ml) was stirred under a hydrogen atmosphere for two hours. The
mixture was filtered through diatomaceous earth and the solvent was
evaporated in vacuo to yield intermediate D2 (1.3 g, 100%) that was
used without further purification.
Description 3
4-Bromo-1-cyclopropylmethyl-1H-pyridin-2-one (D3)
##STR00024##
[0105] Phosphorus oxybromide (5.4 g, 18.9 mmol) was added to a
solution of intermediate D2 (1.42 g, 8.6 mmol) in DMF (140 ml) and
the mixture was heated at 110.degree. C. for 1 hour. After cooling
in an ice bath the solution was partitioned between water and
EtOAc. After three extractions with EtOAc, the combined organic
fractions were dried (Na.sub.2SO.sub.4) and the solvent was
evaporated in vacuo. The crude product was purified by column
chromatography (silica gel; DCM as eluent). The desired fractions
were collected and evaporated in vacuo to yield intermediate D3
(1.82 g, 93%).
Description 7
4-Bromo-1-(3-methylbutyl)-1H-pyridin-2-one (D7)
##STR00025##
[0107] Intermediate D7 was prepared following the same procedure
implemented for the synthesis of D3, using
4-hydroxy-1-(3-methylbutyl)-1H-pyridin-2-one as starting material,
which was prepared by the same method used for the synthesis of
intermediate D2, by reaction of 4-benzyloxy-1H-pyridin-2-one with
1-bromo-3-methylbutane.
Description 4
4-Benzyloxy-1-butyl-1H-pyridin-2-one (D4)
##STR00026##
[0109] 1-Bromobutane (3.75 g, 27.33 mmol) and potassium carbonate
(10.3 g, 74.52 mmol) were added to a solution of
4-benzyloxy-1H-pyridin-2-one (5.0 g, 24.84 mmol) in acetonitrile
(200 ml) and the mixture was heated at reflux for 16 hours. The
reaction mixture was filtered through diatomaceous earth and
concentrated in vacuo. The crude residue was then triturated with
diethylether to yield pure D4 (6.26 g, 98%) as a white solid.
Description 5
1-Butyl-4-hydroxy-1H-pyridin-2-one (D5)
##STR00027##
[0111] A mixture of intermediate D4 (2.01 g, 7.83 mmol) and a
catalytic amount of 10% palladium on activated carbon in ethanol
(300 ml) was stirred under a hydrogen atmosphere for two hours. The
mixture was filtered through diatomaceous earth and the solvent was
evaporated in vacuo to yield intermediate D5 (1.3 g, 100%) that was
used without further purification.
Description 6
4-Bromo-1-butyl-1H-pyridin-2-one (D6)
##STR00028##
[0113] Phosphorus oxybromide (5.4 g, 18.9 mmol) was added to a
solution of intermediate D5 (1.44 g, 8.6 mmol) in DMF (140 ml) and
the mixture was heated at 110.degree. C. for 1 hour.
[0114] After cooling in an ice bath, the solution was partitioned
between water and EtOAc. After three extractions with EtOAc, the
combined organic fractions were dried (Na.sub.2SO.sub.4) and the
solvent evaporated in vacuo. The crude product was purified by
column chromatography (silica gel; DCM as eluent). The desired
fractions were collected and evaporated in vacuo to yield
intermediate D6 (1.82 g, 93%).
Description 8
1-Butyl-3-chloro-4-hydroxy-1H-pyridin-2-one (D8)
##STR00029##
[0116] N-Chlorosuccinimide (1.6 g, 11.96 mmol) was added to a
solution of intermediate D5 (2.0 g, 11.96 mmol) in DMF (30 ml). The
reaction was stirred at room temperature overnight and then it was
concentrated in vacuo. The crude product was purified by column
chromatography (silica gel; 0-5% methanol/DCM as eluent) to yield
intermediate D8 (2.0 g, 83%).
Description 9
Trifluoro-methanesulfonic acid
1-butyl-3-chloro-2-oxo-1,2-dihydropyridin-4-yl ester (D9)
##STR00030##
[0118] Pyridine (1.60 ml, 19.8 mmol) was added to a cooled
(-78.degree. C.) solution of intermediate D8 (2.0 g, 9.92 mmol) in
DCM (80 ml). The resulting solution was stirred for 10 minutes
after which trifloromethanesulfonic anhydride (1.90 ml, 10.9 mmol)
was added, and the resulting solution was stirred at -78.degree. C.
for 3 hours. Then the mixture was warmed to room temperature and
was quenched by the addition of aqueous saturated ammonium
chloride. The mixture was diluted with water, extracted with DCM,
dried (Na.sub.2SO.sub.4) and the solvent evaporated in vacuo,
yielding intermediate D9 (3.31 g, 100%) as a crude that was used
without further purification.
Description 10
4-Benzyloxy-1-cyclopropylmethyl-3-iodo-1H-pyridin-2-one (D10)
##STR00031##
[0120] N-Iodosuccinimide (2.64 g, 11.74 mmol) was added to a
solution of intermediate D1 (3.0 g, 11.74 mmol) in acetic acid (40
ml). The reaction mixture was stirred at room temperature for 1
hour, after which it was concentrated in vacuo, purified by flash
chromatography (silica gel; 0-3% methanol/DCM as eluent) and
finally recrystallized from diethyl ether to afford intermediate
D10 (4.12 g, 92%) as a solid.
Description 11
4-Benzyloxy-1-cyclopropylmethyl-3-trifluoromethyl-1H-pyridin-2-one
(D11)
##STR00032##
[0122] Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.67 ml, 5.24
mmol) and intermediate D10 (1.0 g, 2.63 mmol) were added to a
solution of copper(I) iodide (0.99 g, 5.24 mmol) in DMF (30 ml).
The mixture was then heated at 100.degree. C. for 5 hours, after
which it was filtered through diatomaceous earth and the filtrate
was concentrated in vacuo. The residue was purified by column
chromatography (silica gel; DCM as eluent) to yield intermediate
D11 (0.76 g, 89%).
Description 12
1-Cyclopropylmethyl-4-hydroxy-3-trifluoromethyl-1H-pyridin-2-one
(D12)
##STR00033##
[0124] A mixture of intermediate D11 (2.0 g, 6.19 mmol), a
catalytic amount of 10% palladium on activated carbon and ethanol
(60 ml) was stirred under hydrogen atmosphere for 2 hours. The
mixture was filtered through diatomaceous earth and the solvent was
evaporated in vacuo to yield crude intermediate D12 (1.45 g, 100%)
that was used without further purification.
Description 13
4-Bromo-1-cyclopropylmethyl-3-trifluoromethyl-1H-pyridin-2-one
(D13)
##STR00034##
[0126] Phosphorus oxybromide (7.03 g, 24.5 mmol) was added to a
solution of intermediate D12 (2.60 g, 11.1 mmol) in DMF (50 ml) and
the mixture was heated at 110.degree. C. for 1 hour. After cooling
in an ice bath the solution was partitioned between water and
EtOAc. After three extractions with EtOAc, the combined organic
fractions were dried (Na.sub.2SO.sub.4) and the solvent evaporated
in vacuo. The crude product was purified by column chromatography
(silica gel; DCM as eluent). The desired fractions were collected
and evaporated in vacuo to yield intermediate D13 (1.38 g,
42%).
Description 14
4-Benzyloxy-1-(4-trifluoromethoxy-benzyl)-1H-pyridin-2-one
(D14)
##STR00035##
[0128] 1-Bromomethyl-4-trifluoromethoxybenzene (3.32 g, 13.04 mmol)
and potassium carbonate (3.51 g, 25.46 mmol) were added to a
mixture of 4-benzyloxy-1H-pyridin-2-one (2.5 g, 12.42 mmol) in
acetonitrile (10 ml). The reaction mixture was heated at reflux
temperature for 24 hours. After cooling to room temperature, it was
filtered through diatomaceous earth, the solid residues were washed
with methanol and the combined organic extracts were evaporated in
vacuo. The crude residue thus obtained was precipitated with DIPE
to yield intermediate D14 (4.5 g, 96%) as a white solid.
Description 15
4-Benzyloxy-3-chloro-1-(4-trifluoromethoxy-benzyl)-1H-pyridin-2-one
(D15)
##STR00036##
[0130] N-Chlorosuccinimide (1.68 g, 12.61 mmol) was added to a
solution of intermediate D14 (4.31 g, 11.47 mmol) in DMF (30 ml)
and the mixture was stirred at room temperature for 24 hours. The
solvent was evaporated and the solid residue was washed with water
(4.times.25 ml). The crude solid was washed with DIPE to yield
intermediate D15 (4.5 g, 95%) as a white solid.
Description 16
3-Chloro-4-hydroxy-1-(4-trifluoromethoxy-benzyl-1H-pyridin-2-one
(D16)
##STR00037##
[0132] Hydrobromic acid (0.1 ml) was added to a mixture of
intermediate D15 (4.5 g, 10.98 mmol) in acetic acid (20 ml). The
solution was heated at 130.degree. C. for 30 minutes under
microwave irradiation. After cooling to room temperature, the
solvent was evaporated in vacuo and the residue was treated with an
aqueous saturated solution of NaHCO.sub.3 until the solution
reached a pH of approximately 8. The white solid that precipitated
was collected by filtration and washed with cold DIPE to yield
intermediate D16 (1.1 g, 31%).
Description 17
4-Bromo-3-chloro-1-(4-trifluoromethoxy-benzyl)-1H-pyridin-2-one
(D17)
##STR00038##
[0134] Phosphorus oxybromide (1.05 g, 3.75 mmol) was added to a
solution of intermediate D16 (1.0 g, 3.13 mmol) in DMF (5 ml) and
the mixture was heated at 115.degree. C. for 4 hours. The solvent
was evaporated in vacuo and the crude residue was treated with an
aqueous saturated solution of NaHCO.sub.3. The mixture was
extracted with DCM (3.times.5 ml), the organic fractions were dried
(Na.sub.2SO.sub.4) and the solvent was evaporated in vacuo. The
crude product was purified by column chromatography (silica gel;
diethyl ether as eluent). The desired fractions were collected and
evaporated in vacuo to yield intermediate D17 (0.21 g, 18%) as a
yellow oil.
Description 18
1'-Cyclopropylmethyl-4-phenyl-3,4,5,6-tetrahydro-2H,1
`H-[1,4]bipyridinyl-2`-one (D18)
##STR00039##
[0136] 4-Phenylpiperidine (0.45 g, 2.78 mmol), palladium(II)
acetate (0.016 g, 0.069 mmol), sodium tert-butoxide (0.34 g, 3.5
mmol) and BINAP (0.065 g, 0.104 mmol) were added to a solution of
intermediate D3 (0.32 g, 1.39 mmol) in toluene (5 ml). The reaction
mixture was heated at 100.degree. C. for 16 hours in a sealed tube,
after which it was cooled to room temperature, diluted with water
(5 ml) and then extracted with EtOAc (3.times.5 ml).
[0137] The combined organic fractions were dried (Na.sub.2SO.sub.4)
and the solvent evaporated in vacuo. The crude product was purified
by column chromatography (silica gel; 0-4% methanol/DCM as eluent).
The desired fractions were collected and evaporated in vacuo to
yield intermediate D18 (0.33 g, 78%).
Description 19
1'-Butyl-4-phenyl-3,4,5,6-tetrahydro-2H,1'H-[1,4]bipyridinyl-2'-one
(D19)
##STR00040##
[0139] 4-Phenylpiperidine (0.45 g, 2.78 mmol), palladium(II)
acetate (0.016 g, 0.069 mmol), sodium tert-butoxide (0.34 g, 3.5
mmol) and BINAP (0.065 g, 0.104 mmol) were added to a solution of
intermediate D6 (0.32 g, 1.39 mmol) in toluene (5 ml). The reaction
mixture was heated at 100.degree. C. for 16 hours in a sealed tube,
after which it was cooled to room temperature and then diluted with
water (5 ml) and extracted with EtOAc (3.times.5 ml). The combined
organic fractions were dried (Na.sub.2SO.sub.4) and the solvent
evaporated in vacuo. The crude product was purified by column
chromatography (silica gel; 0-4% methanol/DCM as eluent). The
desired fractions were collected and evaporated in vacuo to yield
intermediate D19 (0.38 g, 89%).
Description 20
1'-Cyclopropylmethyl-2'-oxo-4-phenyl-3,4,5,6,1',2'-hexahydro-2H-[1,4']bipy-
ridinyl-4-carbonitrile (D20) JNJ-38818468
##STR00041##
[0141] 4-Cyano-4-phenylpiperidine hydrochloride (0.314 g, 1.41
mmol), palladium(II) acetate (0.013 g, 0.059 mmol) sodium
tert-butoxide (0.347 g, 3.54 mmol) and BINAP (0.051 g, 0.08 mmol)
were added to a stirred solution of intermediate D3 (0.27 g, 1.18
mmol) in toluene (5 ml). The reaction mixture was heated at
100.degree. C. for 16 hours in a sealed tube. After cooling to room
temperature the mixture was diluted with water and extracted with
EtOAc. The combined organic phase was dried (Na.sub.2SO.sub.4) and
the solvent evaporated in vacuo. The crude product was purified by
column chromatography (silica gel; 10% ammonia in methanol (7M)/DCM
as eluent). The desired fractions were collected and evaporated in
vacuo to yield D20 (0.35 g, 87%) as a pale yellow oil.
Description 21
4-Hydroxy-4-phenylpiperidine-1-carboxilic acid tert-butyl ester
(D21)
##STR00042##
[0143] Methyl 2-bromobenzoate (1.816 ml, 12.936 mmol) [CAS
610-94-6] was added to a solution of
1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridi-
ne (4 g, 12.936 mmol) [CAS 375853-82-0] (synthesis described in WO
2004072025 A2 20040826) in 1,4-dioxane (28 ml) and an aqueous
saturated solution of NaHCO.sub.3 (24 ml). The resulting solution
was degassed using a stream of nitrogen and Pd(PPh.sub.3).sub.4
(0.747 g, 0.647 mmol) was added to this solution. The reaction was
then microwaved in a sealed tube at 140.degree. C. for 5 minutes.
The resulting cooled reaction mixture was then diluted with EtOAc
and filtered through a pad of diatomaceous earth. The filtrate was
collected, dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
The crude reaction mixture was then purified by column
chromatography (silica gel; DCM to DCM/EtOAc up to 6% as eluent).
The desired fractions were collected and evaporated in vacuo to
yield D21 (4.04 g, 98%).
Description 22
4-(2-Fluoro-4-methoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester (D22)
##STR00043##
[0145] Methyl 4-bromo-3-fluorobenzoate (2.261 g, 9.702 mmol) [CAS
849758-12-9] was added to a solution of
1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridi-
ne (3 g, 9.702 mmol) [CAS 375853-82-0] (synthesis described in WO
2004072025 A2 20040826) in 1,4-dioxane (21 ml) and an aqueous
saturated solution of NaHCO.sub.3 (18 ml). The resulting solution
was degassed using a stream of nitrogen and Pd(PPh.sub.3).sub.4
(0.561 g, 0.485 mmol) was added to this solution. The reaction was
then microwaved in a sealed tube at 150.degree. C. for 5 minutes.
The resulting cooled reaction mixture was then diluted with EtOAc
and filtered through a pad of diatomaceous earth. The filtrate was
collected, dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
The crude reaction mixture was then purified by column
chromatography (silica gel; DCM to DCM/EtOAc up to 6% as eluent).
The desired fractions were collected and evaporated in vacuo to
yield D22 (2.107 g, 65%).
Description 23
4-(2-Fluoro-4-methoxycarbonyl-phenyl)-piperidine-1-carboxylic acid
tent-butyl ester (D23)
##STR00044##
[0147] A solution of intermediate D22 (2.81 g, 8.379 mmol) in
methanol (120 ml) was hydrogenated at room temperature in the
presence of palladium 10% on activated carbon (0.588 g) until the
reaction was completed. The solids were filtered off and the
filtrate was evaporated in vacuo to give D23 (2.73 g, 97%).
Description 24
4-[2-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-piperidine-1-carboxylic
acid tert-butyl ester (D24)
##STR00045##
[0149] A 1.4 M solution of methylmagnesium bromide in toluene/THF
(17.339 ml, 24.274 mmol) was added dropwise to a cooled (0.degree.
C.) solution of intermediate D23 (2.73 g, 8.091 mmol) in
diethylether (150 ml) under nitrogen atmosphere. The resulting
reaction mixture was then stirred at 50.degree. C. for 2 hours.
After cooling in an ice bath the mixture was carefully quenched
with a saturated aqueous solution of ammonium chloride, and then
was extracted with EtOAc. The combined organic phase was dried
(Na.sub.2SO.sub.4) and the solvent evaporated in vacuo to yield D24
(3.16 g, 100%).
Description 25
2-(3-Fluoro-4-piperidin-4-yl-phenyl)-propan-2-ol (D25)
##STR00046##
[0151] A mixture of intermediate D24 (3.067 g, 7.852 mmol) and KOH
(2.54 g, 45.268 mmol) in isopropyl alcohol (13.5 ml) and water (27
ml) was microwaved in a sealed tube at 180.degree. C. for 60
minutes. The resulting cooled reaction mixture was then diluted
with water and brine and extracted with dichloromethane. The
combined organic extracts were dried (Na.sub.2SO.sub.4) and the
solvent was evaporated in vacuo. The residue was treated with
dichloromethane giving rise to a solid that was filtered off to
yield 1.03 g intermediate D25. The filtrate was evaporated in vacuo
and the residue thus obtained was then purified by column
chromatography (silica gel; DCM/(NH.sub.3 7 N solution in MeOH)
gradient up to 10% as eluent). The desired fractions were collected
and evaporated in vacuo to yield a second batch of 0.5 g of D25
(total amount=1.53 g, 82%). M.P. 151.degree. C.
Description 26
4-(2-Methoxycarbonyl-phenyl)-piperidine-1-carboxylic acid
tert-butyl ester (D26)
##STR00047##
[0153] A solution of intermediate D21 (4.04 g, 12.729 mmol) in
methanol (120 ml) was hydrogenated at room temperature in the
presence of palladium 10% on activated carbon (0.846 g) until the
reaction was completed. The solids were filtered off and the
filtrate was evaporated in vacuo to give D26 as white solid (3.67
g, 90%).
Description 27
4-[2-(1-Hydroxy-1-methyl-ethyl)-phenyl]-piperidine-1-carboxylic
acid tert-butyl ester (D27)
##STR00048##
[0155] A 1.4 M solution of methylmagnesium bromide in toluene/THF
(17.443 ml, 24.421 mmol) was added dropwise to a cooled (0.degree.
C.) solution of intermediate D26 (2.6 g, 8.14 mmol) in diethylether
(150 ml) under nitrogen atmosphere. The resulting reaction mixture
was stirred at 45.degree. C. for 2 hours. After cooling in an ice
bath, the mixture was carefully quenched with a saturated aqueous
solution of ammonium chloride, and then extracted with EtOAc. The
combined organic phase was dried (Na.sub.2SO.sub.4) and the solvent
evaporated in vacuo to yield D27 (2.77 g, 69%).
Description 28
2-(2-Piperidin-4-yl-phenyl)-propan-2-ol (D28)
##STR00049##
[0157] A mixture of intermediate D27 (2.77 g, 5.636 mmol) and KOH
(2.43 g, 43.357 mmol) in isopropyl alcohol (13.5 ml) and water (27
ml) was microwaved in a sealed tube at 180.degree. C. for 60
minutes. The resulting cooled reaction mixture was then diluted
with water and brine and extracted with dichloromethane. The
residue was treated with dichloromethane giving rise to a solid
that was filtered off Yield: 0.737 g of intermediate D28. The
filtrate was evaporated in vacuo and the residue was then purified
by column chromatography (silica gel; DCM/(NH.sub.3 7 N solution in
MeOH) gradient up to 10% as eluent). The desired fractions were
collected and evaporated in vacuo to yield a second batch of 0.306
g of intermediate D28 (total amount=1.04 g, 84%). M.P.
219.5.degree. C.
Description 29
4-Hydroxy-4-phenylpiperidine-1-carboxilic acid tert-butyl ester
(D29)
##STR00050##
[0159] Di-tert-butyl dicarbonate (2.95 g, 13.53 mmol) was added to
a solution of 4-hydroxy-4-phenylpiperidine (2 g, 11.28 mmol) in DCM
(50 ml). The reaction was stirred at room temperature for 5 hours.
The solvent was removed in vacuo, affording the desired
intermediate D29 (3.12 g, 100%) as a crude that was used without
further purification.
Description 30
4-fluoro-4-phenylpiperidin-1-carboxilic acid tert-butyl ester
(D30)
##STR00051##
[0161] A solution of (diethylamino)sulfur trifluoride (0.74 ml,
5.67 mmol) in dry DCM (q.s.) was added to a cooled (-78.degree. C.)
solution of D29 (1.5 g, 5 4 mmol) in dry DCM (30 ml) under N.sub.2
atmosphere. After the addition was complete, the reaction mixture
was stirred at -78.degree. C. for 1 hour and then allowed to reach
room temperature and stirred for a further 30 minutes. An aqueous
saturated NaHCO.sub.3 solution (90 ml) was added and the mixture
was stirred for 15 minutes, then the organic layer was separated.
After this, 3-chloroperoxybenzoic acid (0.2 g, 1.18 mmol) was added
and the reaction stirred at room temperature for 30 minutes. The
reaction mixture was washed with aqueous saturated NaHCO.sub.3,
H.sub.2O and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo affording the desired intermediate D30 (1.48
g, 98%) as a crude that was used without further purification.
Description 31
4-fluoro-4-phenylpiperidine hydrochloride (D31)
##STR00052##
[0163] D30 (1.48 g, 5.29 mmol) was dissolved in 4N HCl in dioxane.
The reaction was stirred at room temperature for 2 hours. The
solvent was removed. The crude was triturated with diethyl ether
and dried in vacuo to afford the desired intermediate D31 (1.10 g,
97%) as a chlorohydrate that was used without further
purification.
Description 32
1'-Butyl-4-fluoro-4-phenyl-3,4,5,6-tetrahydro-2H,1'H-[1,4]bipyridinyl-2-on-
e (D32)
##STR00053##
[0165] D31 (0.2 g, 0.94 mmol), palladium(II) acetate (0.009 g, 0.04
mmol) sodium tert-butoxide (0.25 g, 2.58 mmol) and BINAP (0.037 g,
0.06 mmol) were added to a stirred solution of intermediate D6
(0.20 g, 0.86 mmol) in toluene (5 ml). The reaction mixture was
heated at 100.degree. C. for 16 hours in a sealed tube. After
cooling to room temperature the mixture was diluted with water and
extracted with EtOAc. The combined organic phase was dried
(Na.sub.2SO.sub.4) and the solvent evaporated in vacuo. The crude
product was purified by column chromatography (silica gel; 10%
ammonia in methanol (7N)/DCM as eluent). The desired fractions were
collected and evaporated in vacuo to yield D32 (0.21 g, 87%) as a
pale yellow oil.
Description 33
4-Benzyloxy-3-bromo-1-cyclopropylmethyl-1H-pyridin-2-one (D33)
##STR00054##
[0167] A solution of intermediate D1 (3.0 g, 11.7 mmol) and
N-bromosuccinimide (2.09 g, 11.7 mmol) in DCM (100 ml) was stirred
at room temperature for 1 hour. The solvent was evaporated in vacuo
and the crude residue was purified by column chromatography (silica
gel; DCM as eluent). The desired fractions were collected and
evaporated in vacuo yielding D33 (3.56 g, 91%).
Description 34
4-Benzyloxy-3-cyclopropyl-1-cyclopropylmethyl-1H-pyridin-2-one
(D34)
##STR00055##
[0169] NaHCO.sub.3 (1.0 g, excess), cyclopropylboronic acid (0.74
g, 8.93 mmol), potassium carbonate (1.23 g, 8.93 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)--DCM
complex (0.36 g, 0.45 mmol) were added to a solution of
intermediate D10 (1.0 g, 2.98 mmol) in 1,4-dioxane (10 ml). The
resulting mixture was heated at 175.degree. C. for 20 minutes under
microwave irradiation, after which it was filtered through
diatomaceous earth and the solvent was evaporated in vacuo. The
crude residue was purified by column chromatography (silica gel;
0-3% methanol/DCM as eluent). The desired fractions were collected
and evaporated in vacuo yielding D34 (0.6 g, 69%).
Description 35
3-Cyclopropyl-1-cyclopropylmethyl-4-hydroxy-1H-pyridin-2-one
(D35)
##STR00056##
[0171] A mixture of intermediate D34 (1.0 g, 3.38 mmol) and a
catalytic amount of 10% palladium on activated carbon in ethanol
(150 ml) was stirred under a hydrogen atmosphere for 2 hours. The
mixture was filtered through diatomaceous earth and the solvent was
evaporated in vacuo to yield intermediate D35 (0.69 g, 100%) that
was used without further purification.
Description 36
4-Bromo-3-cyclopropyl-1-cyclopropylmethyl-1H-pyridin-2-one
(D36)
##STR00057##
[0173] Phosphorus oxybromide (2.4 g, 8.28 mmol) was added to a
solution of intermediate D35 (0.85 g, 4.14 mmol) in DMF (60 ml),
and the mixture was heated at 110.degree. C. for 1 hour. After
cooling in an ice bath, the solution was partitioned between water
and EtOAc. The mixture was extracted with EtOAc (3.times.200 ml),
the combined organic fractions were dried (Na.sub.2SO.sub.4) and
the solvent evaporated in vacuo. The crude product was purified by
column chromatography (silica gel; DCM as eluent). The desired
fractions were collected and evaporated in vacuo to yield
intermediate D36 (0.99 g, 89%).
Description 37
4-(1'-Cyclopropylmethyl-2'-oxo-3,4,5,6,1',2'-hexahydro-2H-[1,4]bipyridinyl-
-4-yl)-benzoic acid (D37)
##STR00058##
[0175] 4-Piperidin-4-ylbenzoic acid methyl ester (0.40 g, 1.81
mmol), palladium(II) acetate (0.015 g, 0.069 mmol) sodium
tert-butoxide (0.34 g, 3.44 mmol) and BINAP (0.06 g, 0.096 mmol)
were added to a stirred solution of intermediate D3 (0.31 g, 1.37
mmol) in toluene (10 ml). The reaction mixture was heated at
100.degree. C. for 16 hours in a sealed tube. After cooling to room
temperature the mixture was diluted with EtOAc and then filtered
through diatomaceous earth, after which the solvent was evaporated
in vacuo. The crude residue was treated with a mixture of
DCM/methanol and then filtered off. The filtrate was evaporated to
dryness in vacuo to yield crude D37 (0.48 g, 100%) that was used
without further purification.
Description 38
4-(1'-Cyclopropylmethyl-2'-oxo-3,4,5,6,1',2'-hexahydro-2H-[1,4]bipyridinyl-
-4-yl)-benzoic acid methyl ester (D38)
##STR00059##
[0177] A mixture of intermediate D37 (0.43 g, 1.23 mmol), DBU (0.18
g, 1.23 mmol), dimethyl carbonate (4.5 ml, excess, 93 mmol), and
acetonitrile (5 ml) was heated at 160.degree. C. for 20 minutes
under microwave irradiation. The cooled crude mixture was diluted
with water and EtOAc was added, after which the organic layer was
washed with an aqueous 10% citric acid solution, dried
(Na.sub.2SO.sub.4) and the solvent evaporated in vacuo. The crude
residue was purified by column chromatography (silica gel; 0-3%
methanol/DCM as eluent). The desired fractions were collected and
evaporated in vacuo to yield D38 (0.19 g, 38%).
Description 39
1-Cyclopropylmethyl-4-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3,4,5,6-tetrah-
ydro-2H,1'H-[1,4']bipyridinyl-2'-one (D39)
##STR00060##
[0179] A 1.4 M solution of methylmagnesium bromide in toluene/THF
(1.12 ml, 1.57 mmol) was added dropwise to a cooled (0.degree. C.)
solution of intermediate D38 (0.19 g, 0.52 mmol) in THF (20 ml)
under nitrogen atmosphere. The resulting reaction mixture was
stirred at 45.degree. C. for 2 hours. After cooling in an ice bath
the mixture was carefully quenched with a saturated aqueous
solution of ammonium chloride, and then was extracted with EtOAc.
The combined organic phase was dried (Na.sub.2SO.sub.4) and the
solvent evaporated in vacuo. The residue was purified by column
chromatography (silica gel; 0-5% methanol/DCM as eluent). The
desired fractions were collected and evaporated in vacuo to yield
D39 (0.077 g, 40%) as an oil.
Example 1
3'-Chloro-1'-cyclopropylmethyl-4-phenyl-3,4,5,6-tetrahydro-2H,1'H-S[1,4']b-
ipyridinyl-2'-one (E1)
##STR00061##
[0181] A solution of intermediate D18 (0.2 g, 0.65 mmol) and
N-chlorosuccinimide (0.09 g, 0.65 mmol) in DCM (10 ml) was stirred
at room temperature for 1 hour. The solvent was evaporated in vacuo
and the crude product was purified by column chromatography (silica
gel; 0-3% methanol/DCM as eluent). The desired fractions were
collected and evaporated in vacuo and the resulting solid was
recrystallized from diethyl ether to yield compound E1 (0.10 g,
47%) as a white solid.
[0182] Melting point: 170.8.degree. C.
[0183] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.35-0.42 (m,
2H), 0.57-0.64 (m, 2H), 1.19-1.33 (m, 1H), 1.85-2.00 (m, 4H),
2.64-2.76 (m, 1H), 2.85-2.99 (m, 2H), 3.76-3.87 (m, 4H), 6.05 (d,
J=7.6 Hz, 1H), 7.19-7.29 (m, 4H), 7.29-7.38 (m, 2H).
Example 2
1'-Butyl-3'-chloro-4-phenyl-3,4,5,6-tetrahydro-2H,1
'H-[1,4']bipyridinyl-2'-one (E2)
##STR00062##
[0185] A solution of intermediate D19 (0.43 g, 1.40 mmol) and
N-chlorosuccinimide (0.19 g, 1.40 mmol) in DCM (10 ml) was stirred
at room temperature for 1 hour. The solvent was evaporated in vacuo
and the crude product was purified by column chromatography (silica
gel; 0-3% methanol/DCM as eluent). The desired fractions were
collected and evaporated in vacuo and the resulting solid was
recrystallized from diethyl ether to yield compound E2 (0.39 g,
82%) as a white solid.
[0186] Melting point: 149.4.degree. C.
[0187] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.95 (t, J=7.3
Hz, 3H), 1.31-1.42 (m, 2H), 1.68-1.78 (m, 2H), 1.85-1.98 (m, 4H),
2.64-2.73 (m, 1H), 2.87-2.96 (m, 2H), 3.82 (br d, J=12.1 Hz, 2H),
3.93 (t, J=7.3 Hz, 2H), 6.03 (d, J=7.6 Hz, 1H), 7.10 (d, J=7.6 Hz,
1H), 7.19-7.28 (m, 3H), 7.29-7.37 (m, 2H).
Example 3
3'-Bromo-r-cyclopropylmethyl-4-phenyl-3,4,5,6-tetrahydro-2H,1'H-[1,4]bipyr-
idinyl-2'-one (E3)
##STR00063##
[0189] N-Bromosuccinimide (0.145 g, 0.82 mmol) was added to a
solution of intermediate D18 (0.25 g, 0.82 mmol) in DCM (10 ml).
The reaction mixture was stirred at room temperature for 1 hour.
Subsequently, the solvent was evaporated in vacuo and the crude
residue was purified by column chromatography (silica gel; 0-3%
methanol/DCM as eluent). The desired fractions were collected and
evaporated in vacuo to yield compound E3 (0.20 g, 64%) as a white
solid.
[0190] Melting point: 150.degree. C.
[0191] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 0.34-0.40
(m, 2H), 0.44-0.50 (m, 2H), 1.16-1.26 (m, 1H), 1.77 (qd, J=12.38,
3.61 Hz, 2H), 1.88 (br d, J=12.1 Hz, 2H), 2.68-2.78 (m, 1H), 2.91
(br t, J=11.9 Hz, 2H) 3.69 (br d, J=12.1 Hz, 2H), 3.74 (d, J=7.2
Hz, 2H), 6.21 (d, J=7.5 Hz, 1H), 7.19-7.25 (m, 1H), 7.27-7.36 (m,
4H), 7.69 (d, J=7.5 Hz, 1H).
Example 4
[0192]
1-Cyclopropylmethyl-4-phenyl-3'-trifluoromethyl-3,4,5,6-tetrahydro--
2H,1'H-[1,4]bipyridinyl-2'-one (E4)
##STR00064##
[0193] 4-Phenylpiperidine (0.33 g, 2.02 mmol), palladium(II)
acetate (0.012 g, 0.05 mmol), sodium tert-butoxide (0.24 g, 2.52
mmol) and BINAP (0.05 g, 0.08 mmol) were added to a solution of
intermediate D13 (0.3 g, 1.01 mmol) in toluene (7 ml). The reaction
mixture was heated at 100.degree. C. for 16 hours in a sealed tube,
after which it was cooled to room temperature and then it was
diluted with water (5 ml) and extracted with EtOAc (3.times.5 ml).
The combined organic fractions were dried (Na.sub.2SO.sub.4) and
the solvent evaporated in vacuo. The crude product was purified by
column chromatography (silica gel; 0-4% methanol/DCM as eluent).
The desired fractions were collected and evaporated in vacuo to
yield compound E4 (0.11 g, 31%) as a white solid. Melting point:
177.2.degree. C.
[0194] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 0.33-0.38
(m, 2H), 0.45-0.50 (m, 2H), 1.13-1.22 (m, 1H), 1.64-1.75 (m, 2H),
1.84 (br d, J=11.0 Hz, 2H), 2.72-2.80 (m, 1H), 3.14 (br t, J=12.1
Hz, 2H), 3.59 (br d, J=13.0 Hz, 2H), 3.65 (d, J=7.2 Hz, 2H), 6.21
(d, J=7.8 Hz, 1H), 7.19-7.23 m, 1H), 7.24-7.29 (m, 2H), 7.29-7.34
(m, 2H), 7.73 (d, J=7.8 Hz, 1H).
Example 5
3'-Chloro-4-phenyl-P-(4-trifluoromethoxybenzyl)-3,4,5,6-tetrahydro-2H,1'H--
[1,4']bipyridinyl-2'-one (E5)
##STR00065##
[0196] A mixture of intermediate D17 (0.2 g, 0.52 mmol),
4-phenylpiperidine (0.1 g, 0.62 mmol),
2-(2'-Di-tert-butylphosphine)biphenylpalladium(II) acetate (0.01 g,
0.026 mmol) and potassium phosphate (0.23 g, 1.1 mmol) in
1,4-dioxane (3 ml) was stirred at 90.degree. C. for 35 hours. The
mixture was filtered through diatomaceous earth, and the filtrate
was evaporated to dryness after washing with more 1,4-dioxane. The
crude product was purified by column chromatography (silica gel;
heptane/diethyl ether 1:1 as eluent). The desired fractions were
collected and evaporated in vacuo to yield compound E5 (0.075 g,
31%) as a white solid.
[0197] Melting point: 168.6.degree. C.
[0198] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.83-1.98 (m,
4H), 2.65-2.75 (m, 1H), 2.89-2.98 (m, 2H), 3.84 (br d, J=12.2 Hz,
2H), 5.12 (s, 2H), 6.06 (d, J=7.6 Hz, 1H), 7.14 (d, J=7.6 Hz, 2H),
7.15-7.28 (m, 5H), 7.29-7.40 (m, 4H).
Example 6
3'-Chloro-r-cyclopropylmethyl-2'-oxo-4-phenyl-3,4,5,6,1',2'-hexahydro-2H-[-
1,4]bipyridinyl-4-carbonitrile (E6)
##STR00066##
[0200] A solution of intermediate D20 (0.35 g, 1.03 mmol) and
N-chlorosuccinimide (0.14 g, 1.03 mmol) in DCM (25 ml) was stirred
at room temperature for 1 hour. After addition of more DCM, the
solution was washed with brine, dried (Na.sub.2SO.sub.4) and the
solvent evaporated in vacuo. The crude product was purified by
column chromatography (silica gel; 10% ammonia in methanol (7N)/DCM
as eluent) and further purified by preparative HPLC. The desired
fractions were collected and evaporated in vacuo to yield compound
E6 (0.17 g, 47%) as a white solid.
[0201] Melting point: 173.7.degree. C.
[0202] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.17-0.23
(m, 2H), 0.26-0.33 (m, 2H), 0.97-1.09 (m, 1H), 1.91-2.02 (m, 2H),
2.11 (br d, J=12.9 Hz, 2H) 2.98 (br t, J=12.4 Hz, 2H), 3.54-3.63
(m, 4H), 6.14 (d, J=7.4 Hz, 1H), 7.20-7.26 (m, 1H), 7.27-7.35 (m,
2H), 7.40-7.44 (m, 2H), 7.52 (d, J=7.4 Hz, 1H).
Example 7
1'-Butyl-3-chloro-4-fluoro-4-phenyl-3,4,5,6-tetrahydro-2H,1'H-[1,4]bipyrid-
inyl-2-one (E7)
##STR00067##
[0204] A solution of intermediate D32 (0.21 g, 0.66 mmol) and
N-chlorosuccinimide (0.08 g, 0.66 mmol) in DCM (30 ml) was stirred
at room temperature for 10 minutes. After addition of more DCM the
solution was washed with brine, dried (Na.sub.2SO.sub.4) and the
solvent evaporated in vacuo. The crude product was purified by
column chromatography (silica gel; 10% ammonia in methanol (7M)/DCM
as eluent) and further purified by preparative HPLC. The desired
fractions were collected and evaporated in vacuo to yield compound
E7 (0.065 g, 27%) as a white solid.
[0205] Melting point: 136.7.degree. C.
[0206] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.89 (t,
J=7.4 Hz, 3H), 1.21-1.32 (m, 2H), 1.54-1.64 (m, 2H), 2.03 (t,
J=11.8 Hz, 2H), 2.16 (td, J=13.9, 4.6 Hz, 1H), 2.26 (td, J=13.6,
4.6 Hz, 1H), 3.17 (dd, J=12.3, 11.1 Hz, 2H), 3.54-3.64 (m, 2H),
3.87 (t, J=7.2 Hz, 2H), 6.26 (d, J=7.6 Hz, 1H), 7.32-7.38 (m, 1H),
7.42 (t, J=7.4 Hz, 2H), 7.45-7.51 (m, 2H), 7.62 (d, J=7.4 Hz,
1H).
Example 8
3'-Cyclopropyl-1'-cyclopropylmethyl-4-phenyl-3,4,5,6-tetrahydro-2H,1'H-[1,-
4]bipyridinyl-2'-one (E8)
##STR00068##
[0208] 4-Phenylpiperidine (0.22 g, 1.34 mmol), palladium(II)
acetate (0.008 g, 0.034 mmol), sodium tert-butoxide (0.16 g, 1.68
mmol) and BINAP (0.032 g, 0.05 mmol) were added to a solution of
intermediate D36 (0.18 g, 0.67 mmol) in toluene (5 ml). The
reaction mixture was heated at 100.degree. C. for 16 hours in a
sealed tube, after which it was cooled to room temperature and then
diluted with water (5 ml) and extracted with EtOAc (3.times.5 ml).
The combined organic fractions were dried (Na.sub.2SO.sub.4) and
the solvent evaporated in vacuo. The crude product was purified by
column chromatography (silica gel; 0-4% methanol/DCM as eluent).
The desired fractions were collected and evaporated in vacuo to
yield compound E8 (0.18 g, 77%) as a white solid.
[0209] Melting point: 201.9.degree. C.
[0210] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 0.30-0.35
(m, 2H) 0.41-0.47 (m, 2H) 0.74-0.80 (m, 2H), 0.86-0.92 (m, 2H),
1.11-1.21 (m, 1H), 1.60-1.67 (m, 1H), 1.73-1.89 (m, 4H), 2.63-2.72
(m, 1H), 2.87 (br t, J=11.1 Hz, 2H), 3.57-3.65 (m, 4H), 6.07 (d,
J=7.5 Hz, 1H), 7.19-7.24 (m, 1H), 7.26-7.37 (m, 4H), 7.46 (d, J=7.5
Hz, 1H).
Example 9
3'-Chloro-1'-cyclopropylmethyl-4-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3,4-
,5,6-tetrahydro-2H,1'H-[1,4']bipyridinyl-2'-one (E9)
##STR00069##
[0212] A solution of intermediate D39 (0.077 g, 0.21 mmol) and
N-chlorosuccinimide (0.03 g, 0.21 mmol) in DCM (8 ml) was stirred
at room temperature for 5 minutes. The crude mixture was washed
with a saturated NaHCO.sub.3 solution, then it was extracted with
DCM, the combined organic fractions were dried (Na.sub.2SO.sub.4)
and the solvent evaporated in vacuo. The crude residue was purified
by column chromatography (silica gel; 0-5% methanol/DCM as eluent).
A second chromatography was performed (silica gel; DCM/EtOAc 1:1,
and finally 100% EtOAc as eluents). The desired fractions were
collected and evaporated in vacuo and the resulting solid was
crystallized from diethyl ether to yield compound E9 (0.06 g, 71%)
as a white solid.
[0213] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.35-0.41 (m,
2H), 0.56-0.64 (m, 2H), 1.19-1.30 (m, 1H), 1.59 (s, 6H), 1.73 (s,
1H), 1.85-1.99 (m, 4H), 2.65-2.76 (m, 1H), 2.87-2.97 (m, 2H),
3.78-3.87 (m, 4H), 6.05 (d, J=7.6 Hz, 1H), 7.21-7.26 (m, 3H), 7.45
(d, J=8.3 Hz, 2H).
Example 20
3'-Chloro-P-cyclopropylmethyl-4-(2-fluoro-ethoxy)-4-phenyl-3,4,5,6-tetrahy-
dro-2H,1'H-[1,4]bipyridinyl-2'-one (E20)
##STR00070##
[0215] A solution of compound E31 (0.164 g, 0.46 mmol) in
1,2-dimethoxyethane (3 ml) was added dropwise to a mixture of
sodium hydride (0.023 g, 0.58 mmol) in 1,2-dimethoxyethane (0.5 ml)
at 0.degree. C. The reaction mixture was stirred at room
temperature for 15 minutes and subsequently a solution of
2-fluoroethyl tosylate [CAS: 383-50-6] (0.222 g, 1 mmol) in
1,2-dimethoxyethane (1 ml) was added. The reaction mixture was
microwaved into a sealed tube at 180.degree. C. for 20 minutes. The
mixture was cooled to room temperature and an additional amount of
sodium hydride (0.023 g, 0.58 mmol) was added. The mixture was the
heated at 180.degree. C. for 20 minutes under microwave
irradiation. After cooling to room temperature, an aqueous
saturated ammonium chloride solution was added and the mixture was
extracted with EtOAc. The organic layer was separated, dried
(Na.sub.2SO.sub.4) and the solvent was evaporated. The crude
product was purified first by column chromatography (silica gel;
eluent: DCM/EtOAc from 100/0 to 90/10). The desired fractions were
collected and evaporated in vacuo to yield compound E20 (0.041 g,
18%).
[0216] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.36-0.40 (m,
2H), 0.58-0.62 (m, 2H), 1.22-1.28 (m, 1H), 2.12-2.21 (m, 4H),
3.27-3.36 (m, 4H), 3.57 (br d, J=12.1 Hz, 2H), 3.80 (d, J=7.2 Hz,
2H), 4.51 (dm, J=47.7 Hz, 2H), 6.08 (d, J=7.5 Hz, 1H), 7.23 (d,
J=7.5 Hz, 1H), 7.29-7.32 (m, 1H), 7.37-7.41 (m, 2H), 7.44-7.46 (m,
2H).
Example 21
3'-Chloro-1'-cyclopropylmethyl-4-fluoromethyl-4-phenyl-3,4,5,6-tetrahydro--
2H,1'H-[1,4]bipyridinyl-2'-one (E21)
##STR00071##
[0218] (Diethylamino)sulfur trifluoride (0.046 ml, 0.35 mmol) was
added to a cooled (-78.degree. C.) solution of compound E30 (0.119
g, 0.32 mmol) in DCM (1 ml). The reaction mixture was stirred at
-78.degree. C. for 3 hours and then additional for 2 hours at
0.degree. C. Subsequently, additional (diethylamino)sulfur
trifluoride (0.046 ml, 0.35 mmol) was added and the mixture was
further stirred for 1 hour at room temperature. Na.sub.2CO.sub.3
(aqueous saturated solution) was added and the mixture was diluted
with DCM. The organic layer was separated, dried (Na.sub.2SO.sub.4)
and evaporated till dryness. The crude product was purified by
column chromatography (silica gel; eluent: DCM/EtOAc from 100/0 to
80/20). The desired fractions were collected, evaporated in vacuo
and finally freeze dried to yield compound E21 (0.019 g, 16%) as a
white foam.
[0219] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.33-0.40 (m,
2H), 0.52-0.65 (m, 2H), 1.17-1.29 (m, 1H), 1.74-1.96 (m, 4H), 2.96
(d, J=22.7 Hz, 2H), 3.06 (dt, J=11.6, 3.7 Hz, 2H), 3.45-3.52 (m,
2H), 3.79 (d, J=7.2 Hz, 2H), 6.01 (d, J=7.6 Hz, 1H), 7.20-7.36 (m,
6H).
Example 22
[0220]
1-Butyl-3'-chloro-4-hydroxymethyl-4-phenyl-3,4,5,6-tetrahydro-2H,1'-
H-[1,4]bipyridinyl-2'-one (E22)
##STR00072##
[0221] 4-Hydroxymethyl-4-phenylpiperidine (0.172 g, 0.9 mmol),
palladium(II) acetate (0.007 g, 0.03 mmol), cesium carbonate (0.391
g, 1.2 mmol) and Xantphos (0.035 g, 0.06 mmol) were added to a
solution of intermediate D9 (0.2 g, 0.6 mmol) in
trifluoromethylbenzene (2 ml). The reaction mixture was heated at
100.degree. C. for 24 hours in a sealed tube, after which it was
cooled to room temperature. Subsequently, it was diluted with DCM,
H.sub.2O (5 ml) and extracted with EtOAc (3.times.5 ml). The
mixture was filtered through diatomaceous earth, and the filtrate
was evaporated to dryness. The crude product was purified first by
column chromatography (silica gel; eluent: DCM/EtOAc from 90/10 to
0/100) and then by reversed phase HPLC. The desired fractions were
collected, evaporated in vacuo and finally freeze dried to yield
compound E22 (0.041 g, 18%) as a white foam.
[0222] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.93 (t, J=7.3
Hz, 3H), 1.13 (br t, J=6.7 Hz, 1H), 1.28-1.40 (m, 2H), 1.64-1.75
(m, 2H), 1.98-2.08 (m, 2H), 2.31-2.40 (m, 2H), 2.98-3.10 (m, 2H),
3.41-3.51 (m, 2H), 3.63 (d, J=6.5 Hz, 2H), 3.90 (t, J=7.3 Hz, 2H),
5.92 (d, J=7.5 Hz, 1H), 7.04 (d, J=7.5 Hz, 1H), 7.27-7.33 (m, 1H),
7.36-7.46 (m, 4H).
Example 28
1'-Butyl-3'-chloro-4-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-3,4,5,6-tetrahy-
dro-2H,1'H-[1,4']bipyridinyl-2'-one (E28)
##STR00073##
[0224] A mixture of intermediate D9 (0.254 g, 0.76 mmol),
intermediate D28 (0.2 g, 0.912 mmol) and diisopropylethylamine
(0.199 ml, 1.114 mmol) in acetonitrile (11 ml) was heated at
180.degree. C. for 5 minutes under microwave irradiation. The
cooled crude mixture was evaporated in vacuo. The crude residue was
purified by column chromatography (silica gel; DCM/EtOAc/MeOH as
eluent). The desired fractions were collected and evaporated in
vacuo. The solid residue obtained was treated with
diisopropylether. The solid was filtered to yield compound E28
(0.183 g, 61%).
[0225] M.P. 182.degree. C.
[0226] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.95 (t, J=7.3
Hz, 3H), 1.32-1.42 (m, 2H), 1.70 (s, 6H), 1.71-1.77 (m, 2H), 1.79
(s, 1H), 1.82-1.90 (m, 2H), 1.91-2.05 (m, 2H), 2.88-2.98 (m, 2H),
3.76-3.87 (m, 3H), 3.93 (t, J=7.3 Hz, 2H), 6.03 (d, J=7.5 Hz, 1H),
7.11 (d, J=7.5 Hz, 1H), 7.16 (td, J=7.8, 1.4 Hz, 1H), 7.28 (td,
J=7.4, 1.4 Hz, 1H), 7.41 (dd, J=7.7, 1.6 Hz, 1H), 7.42 (dd, J=7.6,
1.7 Hz, 1H).
Example 29
1'-Butyl-3'-chloro-4-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3,4,5,-
6-tetrahydro-2H,1'H-[1,4']bipyridinyl-2'-one (E29)
##STR00074##
[0228] A mixture of intermediate D9 (0.261 g, 0.781 mmol),
intermediate D25 (0.223 g, 0.938 mmol) and diisopropylethylamine
(0.204 ml, 1.172 mmol) in acetonitrile (11 ml) was heated at
180.degree. C. for 5 minutes under microwave irradiation. The
cooled crude mixture was evaporated in vacuo. The crude residue was
purified by column chromatography (silica gel;
DCM/EtOAc/MeOH/NH.sub.3 as eluent). The desired fractions were
collected and evaporated in vacuo. The solid residue obtained was
treated with diisopropylether. The solid was filtered to yield
compound E29 (0.239 g, 73%). M.P. 150.5.degree. C.
[0229] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.95 (t, J=7.3
Hz, 3H), 1.31-1.43 (m, 2H), 1.57 (s, 6H), 1.68-1.76 (m, 2H), 1.77
(s, 1H), 1.87-1.96 (m, 4H), 2.86-2.98 (m, 2H), 2.98-3.09 (m, 1H),
3.81 (br d, J=12.0 Hz, 2H), 3.93 (t, J=7.3 Hz, 2H), 6.03 (d, J=7.5
Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 7.16-7.25 (m, 3H).
Example 32
1-butyl-3-chloro-4-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl)pyridi-
n-2(1H)-one (E32)
##STR00075##
[0231] A mixture of intermediate D9 (0.15 g, 0.45 mmol),
3H-spiro[2-benzofuran-1,4'-piperidine] (0.102 g, 0.54 mmol) and
diisopropylethylamine (0.097 ml, 0.056 mmol) in acetonitrile (4 ml)
was heated at 180.degree. C. for 5 minutes under microwave
irradiation. The cooled crude mixture was evaporated in vacuo. The
crude residue was purified by column chromatography (silica gel;
DCM/EtOAc/MeOH/NH.sub.3 as eluent). The desired fractions were
collected and evaporated in vacuo. The solid residue obtained was
treated with diisopropylether. The solid was filtered to yield
compound E32 (0.14 g, 84%).
[0232] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.95 (t, J=7.3
Hz, 3H), 1.30-1.43 (m, 2H), 1.67-1.79 (m, 2H), 1.85 (dd, J=13.8,
2.20 Hz, 2H), 2.12 (dt, J=13.0, 4.7 Hz, 2H), 3.25 (dt, J=12.4, 2.31
Hz, 2H), 3.57-3.68 (m, 2H), 3.94 (t, J=7.3 Hz, 2H), 6.06 (d, J=7.4
Hz, 1H), 7.12 (d, J=7.4 Hz, 1H), 7.16-7.34 (m, 7H).
Example 33
1-butyl-3-chloro-4-(1'H-spiro[1-benzofuran-3,4'-piperidin]-1'-yl)pyridin-2
(1H)-one (E33)
##STR00076##
[0234] A mixture of intermediate D9 (0.15 g, 0.45 mmol),
spiro[1-benzofuran-3,4'-piperidine] (0.102 g, 0.54 mmol) and
diisopropylethylamine (0.097 ml, 0.056 mmol) in acetonitrile (4 ml)
was heated at 180.degree. C. for 5 minutes under microwave
irradiation. The cooled crude mixture was evaporated in vacuo. The
crude residue was purified by column chromatography (silica gel;
DCM/EtOAc/MeOH/NH.sub.3 as eluent). The desired fractions were
collected and evaporated in vacuo. The solid residue obtained was
treated with diisopropylether. The solid was filtered to yield
compound E33 (0.116 g, 84%).
[0235] .sup.1H NMR (500 MHz, CDCl3) .delta. ppm 0.95 (t, J=7.4 Hz,
3H), 1.30-1.43 (m, 2H), 1.66-1.79 (m, 2H), 1.86 (d, J=13.3 Hz, 2H),
2.05-2.19 (m, 2H), 2.84-2.97 (m, 2H), 3.68 (d, J=12.7 Hz, 2H), 3.94
(t, J=7.4 Hz, 2H), 4.44 (s, 2H), 6.01 (d, J=7.5 Hz, 1H), 6.83 (d,
J=7.8 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 7.07-7.24 (m, 3H).
[0236] Compounds E10, E11, E12, E13, E14, E15, E16, E17, E18, E19,
E23, E24, E25 and E26 were prepared according to the reaction
procedure described in Example 1. Compound E27 was prepared
according to the reaction procedure described in Example 9.
[0237] Compound E30 and compound E31 were prepared according to the
reaction procedure described in Example 22.
Physico-Chemical Data
LCMS--General Procedure
[0238] The HPLC measurement was performed using a HP 1100 from
Agilent Technologies 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 below.
Flow from the column was split to a MS spectrometer. The MS
detector was configured with an electrospray ionization source.
Nitrogen was used as the nebulizer gas. The source temperature was
maintained at 140.degree. C. Data acquisition was performed with
MassLynx-Openlynx software.
[0239] LCMS Method: For all examples, except for Examples E5, E18,
E25, E27, E28, E29, E30 and E31, the following method was used.
[0240] In addition to the general procedure: Reversed phase HPLC
was carried out on an XDB-C18 cartridge (1.8 .mu.m, 2.1.times.30
mm) from Agilent, with a flow rate of 1 ml/min, at 60.degree. C.
The gradient conditions used are: 90% A (0.5 g/1 ammonium acetate
solution), 5% B (acetonitrile), 5% C (methanol) to 50% B and 50% C
in 6.5 minutes, to 100% B at 7 minutes and equilibrated to initial
conditions at 7.5 minutes until 9.0 minutes. Injection volume 2
.mu.l. High-resolution mass spectra (Time of Flight, TOF) were
acquired only in positive ionization mode by scanning from 100 to
750 in 0.5 seconds using a dwell time of 0.1 seconds. The capillary
needle voltage was 2.5 kV and the cone voltage was 20 V.
Leucine-Enkephaline was the standard substance used for the lock
mass calibration.
LCMS Method: This Method was Used for Examples ES and E18.
[0241] In addition to the general procedure: Reversed phase HPLC
was carried out on an ACE-C18 column (3.0 .mu.m, 4.6.times.30 mm)
from Advanced Chromatography Technologies, with a flow rate of 1.5
ml/min, at 40.degree. C. The gradient conditions used are: 80% A
(0.5 g/1 ammonium acetate solution), 10% B (acetonitrile), 10% C
(methanol) to 50% B and 50% C in 6.5 minutes, to 100% B at 7
minutes and equilibrated to initial conditions at 7.5 minutes until
9.0 minutes. Injection volume 54 High-resolution mass spectra (Time
of Flight, TOF) were acquired only in positive ionization mode by
scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.1
seconds. The capillary needle voltage was 2.5 kV for positive
ionization mode and the cone voltage was 20 V. Leucine-Enkephaline
was the standard substance used for the lock mass calibration.
LCMS Method: This Method was Used for Example E25.
[0242] In addition to the general procedure: Reversed phase HPLC
was carried out on a XDB-C18 cartridge (1.8 .mu.m, 2.1.times.30 mm)
from Agilent, with a flow rate of 0.8 ml/min, at 60.degree. C. The
gradient conditions used are: 90% A (0.5 g/1 ammonium acetate
solution), 10% B (mixture of Acetonitrile/Methanol, 1/1), to 100% B
in 6.0 minutes, kept till 6.5 minutes and equilibrated to initial
conditions at 7.0 minutes until 9.0 minutes. Injection volume
2.sub.1.1.1. Low-resolution mass spectra (SQD detector; quadrupole)
were acquired only in positive ionization mode by scanning from 100
to 1000 in 0.1 seconds using an inter-channel delay of 0.08 second.
The capillary needle voltage was 3 kV and the cone voltage was 20
V.
LCMS Method: This Method was Used for Example E27.
[0243] 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/1 ammonium acetate
solution+5% of acetonitrile), 2.5% B (acetonitrile), 2.5% C
(methanol) to 50% B and 50% C in 6.5 minutes, kept till 7 minutes
and equilibrated to initial conditions at 7.3 minutes until 9.0
minutes. Injection volume 2 .mu.l. High-resolution mass spectra
(Time of Flight, TOF) were acquired by scanning from 100 to 750 in
0.5 seconds using a dwell time of 0.3 seconds. The capillary needle
voltage was 2.5 kV for positive ionization 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.
LCMS Method: This Method was Used for Example E28, E29, E32 and
E33.
[0244] 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.
without split to the MS detector. The gradient conditions used are:
95% A (0.5 g/1 ammonium acetate solution+5% acetonitrile), 5% B
(mixture of acetonitrile/methanol, 1/1), to 20% A, 80% B in 4.9
minutes, to 100% B in 5.3 minutes, kept till 5.8 minutes and
equilibrated to initial conditions at 6.0 minutes until 7.0
minutes. Injection volume 0.5 .mu.l. Low-resolution mass spectra
(SQD detector; quadrupole) were acquired by scanning from 100 to
1000 in 0.1 seconds using an inter-channel delay of 0.08 second.
The capillary needle voltage was 3 kV. The cone voltage was 20 V
for positive ionization mode and 30 V for negative ionization
mode.
LCMS Method: This Method was Used for Examples E30 and E31.
[0245] In addition to the general procedure: Reversed phase HPLC
was carried out on an XDB-C18 cartridge (1.8 .mu.m, 2.1.times.30
mm) from Agilent, with a flow rate of 1 ml/min, at 60.degree. C.
The gradient conditions used are: 90% A (0.5 g/1 ammonium acetate
solution), 5% B (acetonitrile), 5% C (methanol), kept 0.2 minutes,
to 50% B, 50% C in 3.5 minutes, kept till 3.65 minutes and
equilibrated to initial conditions at 3.8 minutes until 5.0
minutes. Injection volume 2 .mu.l. High-resolution mass spectra
(Time of Flight, TOF) were acquired by scanning from 100 to 750 in
0.5 seconds using a dwell time of 0.3 seconds. The capillary needle
voltage was 2.5 kV for positive ionization 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.
Melting Points
[0246] For a number of compounds, melting points were determined in
open capillary tubes on a Mettler FP62 apparatus. Melting points
were measured with a temperature gradient of 3 or 10.degree.
C./minute. Maximum temperature was 300.degree. C. The melting point
was read from a digital display and were obtained with experimental
uncertainties that are commonly associated with this analytical
method.
Nuclear Magnetic Resonance (NMR)
[0247] .sup.1H NMR spectra were recorded either on Bruker DPX400 or
Bruker AV-500 spectrometers operating at 400 and 500 MHz
respectively. All reported chemical shifts (.delta.) are expressed
in ppm relative to tetramethylsilane.
[0248] Table 1 lists compounds of Formula (I) that were prepared
according to one of the above Examples.
TABLE-US-00001 TABLE 1 ##STR00077## M.P. RT Ex. Ar R.sup.1 R.sup.2
R.sup.3 (.degree. C.) MH+ (min) E1 Ph ##STR00078## Cl H 170.8 343
4.67 E2 Ph ##STR00079## Cl H 149.4 345 4.92 E3 Ph ##STR00080## Br H
150.2 387 4.81 E4 Ph ##STR00081## CF.sub.3 H 180.6 377 4.90 E5 Ph
##STR00082## Cl H 168.6 463 5.71 E6 Ph ##STR00083## Cl CN 173.7 368
4.01 E7 Ph ##STR00084## Cl F 136.7 363 4.83 E8 Ph ##STR00085##
##STR00086## H 201.9 349 5.17 E9 ##STR00087## ##STR00088## Cl H
142.7 401 4.20 E10 Ph ##STR00089## Cl H 244.6 357 4.97 E11 Ph
##STR00090## Cl H nd 359 5.29 E12 ##STR00091## ##STR00092## Cl H nd
361 4.76 E13 ##STR00093## ##STR00094## Cl H nd 428 4.47 E14
##STR00095## ##STR00096## Cl H 188.3 379 4.84 E15 ##STR00097##
##STR00098## Cl H 145.9 377 5.06 E16 ##STR00099## ##STR00100## Cl H
121.9 411 5.10 E17 Ph ##STR00101## Cl F 195.3 361 4.55 E18 Ph
##STR00102## Cl H 147.3 359 5.41 E19 Ph ##STR00103## Cl H nd 345
4.87 E20 Ph ##STR00104## Cl ##STR00105## nd 405 4.51 E21 Ph
##STR00106## Cl ##STR00107## nd 375 4.68 E22 Ph ##STR00108## Cl
##STR00109## nd 375 3.88 E23 Ph ##STR00110## Cl F 140.4 377 5.07
E24 ##STR00111## ##STR00112## Cl H nd 395 5.31 E25 ##STR00113##
##STR00114## Cl H nd 381 5.10 E26 Ph ##STR00115## Cl F nd 375 4.79
E27 ##STR00116## ##STR00117## Cl H 144.4 403 4.56 E28 ##STR00118##
##STR00119## Cl H 182.0 403 3.60 E29 ##STR00120## ##STR00121## Cl H
150.5 421 3.65 E30 Ph ##STR00122## Cl ##STR00123## nd 373 2.82 E31
Ph ##STR00124## Cl OH nd 359 2.92 nd: not determined
TABLE-US-00002 TABLE 2 ##STR00125## Ex. R.sup.1 R.sup.2
##STR00126## M.P. (.degree. C.) MH+ RT (min) E32 ##STR00127## Cl
##STR00128## 133.1 373 3.68 E33 ##STR00129## Cl ##STR00130## 156.5
373 3.67
D. Pharmacological Examples
[0249] The compounds provided in the present invention are positive
allosteric modulators of mGluR2. These compounds appear to
potentiate glutamate responses by binding to an allosteric site
other than the glutamate binding site. The response of mGluR2 to a
concentration of glutamate is increased when compounds of Formula
(I) are present. Compounds of Formula (I) are expected to have
their effect substantially at mGluR2 by virtue of their ability to
enhance the function of the receptor. The behaviour of positive
allosteric modulators tested at mGluR2 using the
[.sup.35S]GTP.gamma.S binding assay method described below and
which is suitable for the identification of such compounds, and
more particularly the compounds according to Formula (I), are shown
in Table 3.
[.sup.35S]GTP.gamma.S Binding Assay
[0250] The [.sup.35S]GTP.gamma.S binding assay is a functional
membrane-based assay used to study G-protein coupled receptor
(GPCR) function whereby incorporation of a non-hydrolysable form of
GTP, [.sup.35S]GTP.gamma.S (guanosine 5'-triphosphate, labelled
with gamma-emitting .sup.35S), is measured. The G-protein a subunit
catalyzes the exchange of guanosine 5'-diphosphate (GDP) by
guanosine triphosphate (GTP) and on activation of the GPCR by an
agonist, [.sup.35S]GTP.gamma.S, becomes incorporated and cannot be
cleaved to continue the exchange cycle (Harper (1998) Current
Protocols in Pharmacology 2.6.1-10, John Wiley & Sons, Inc.).
The amount of radioactive [.sup.35S]GTP.gamma.S incorporation is a
direct measure of the activity of the G-protein and hence the
activity of the agonist can be determined MGluR2 receptors are
shown to be preferentially coupled to G.alpha.I-protein, a
preferential coupling for this method, and hence it is widely used
to study receptor activation of mGluR2 receptors both in
recombinant cell lines and in tissues (Schaffhauser et al 2003,
Pinkerton et al, 2004, Mutel et al (1998) Journal of
Neurochemistry. 71:2558-64; Schaffhauser et al (1998) Molecular
Pharmacology 53:228-33). Here we describe the use of the
[.sup.35S]GTP.gamma.S binding assay using membranes from cells
transfected with the human mGluR2 receptor and adapted from
Schaffhauser et al ((2003) Molecular Pharmacology 4:798-810) for
the detection of the positive allosteric modulation (PAM)
properties of the compounds of this invention.
Membrane Preparation
[0251] CHO-cells were cultured to pre-confluence and stimulated
with 5 mM butyrate for 24 hours, prior to washing in PBS, and then
collected by scraping in homogenisation buffer (50 mM Tris-HCl
buffer, pH 7.4, 4.degree. C.). Cell lysates were homogenized
briefly (15 s) using an ultra-turrax homogenizer. The homogenate
was centrifuged at 23 500.times.g for 10 minutes and the
supernatant discarded. The pellet was resuspended in 5 mM Tris-HCl,
pH 7.4 and centrifuged again (30 000.times.g, 20 min, 4.degree.
C.). The final pellet was resuspended in 50 mM HEPES, pH 7.4 and
stored at -80.degree. C. in appropriate aliquots before use.
Protein concentration was determined by the Bradford method
(Bio-Rad, USA) with bovine serum albumin as standard.
[.sup.35S]GTP.gamma.S Binding Assay
[0252] Measurement of mGluR2 positive allosteric modulatory
activity of test compounds in membranes containing human mGluR2 was
performed using frozen membranes that were thawed and briefly
homogenized prior to pre-incubation in 96-well microplates (15
.mu.g/assay well, 30 minutes, 30.degree. C.) in assay buffer (50 mM
HEPES pH 7.4, 100 mM NaCl, 3 mM MgCl.sub.2, 50 .mu.M GDP, 10
.mu.g/ml saponin,) with increasing concentrations of positive
allosteric modulator (from 0.3 nM to 50 .mu.M) and either a minimal
pre-determined concentration of glutamate (PAM assay), or no added
glutamate. For the PAM assay, membranes were pre-incubated with
glutamate at EC.sub.25 concentration, i.e. a concentration that
gives 25% of the maximal response glutamate, and is in accordance
to published data (Pin et al. (1999) Eur. J. Pharmacol.
375:277-294). After addition of [.sup.35S]GTP.gamma.S (0.1 nM,
f.c.) to achieve a total reaction volume of 200 .mu.l, microplates
were shaken briefly and further incubated to allow
[.sup.35S]GTP.gamma.S incorporation on activation (30 minutes,
30.degree. C.). The reaction was stopped by rapid vacuum filtration
over glass-fibre filter plates (Unifilter 96-well GF/B filter
plates, Perkin-Elmer, Downers Grove, USA) microplate using a
96-well plate cell harvester (Filtermate, Perkin-Elmer, USA), and
then by washing three times with 300 .mu.l of ice-cold wash buffer
(Na.sub.2PO.sub.4.2H.sub.2O 10 mM, NaH.sub.2PO.sub.4.H.sub.2O 10
mM, pH=7.4). Filters were then air-dried, and 40 .mu.l of liquid
scintillation cocktail (Microscint-O) was added to each well, and
membrane-bound [.sup.35S]GTP.gamma.S was measured in a 96-well
scintillation plate reader (Top-Count, Perkin-Elmer, USA).
Non-specific [.sup.35S]GTP.gamma.S binding is determined in the
presence of cold 10 .mu.M GTP. Each curve was performed at least
once using duplicate sample per data point and at 11
concentrations.
Data Analysis
[0253] The concentration-response curves of representative
compounds of the present invention in the presence of added
EC.sub.25 of mGluR2 agonist glutamate to determine positive
allosteric modulation (PAM), were generated using the Prism
GraphPad software (Graph Pad Inc, San Diego, USA). The curves were
fitted to a four-parameter logistic equation
(Y=Bottom+(Top-Bottom)/(1+10 ((Log EC.sub.50-X)*Hill Slope)
allowing determination of EC.sub.50 values. The EC.sub.50 is the
concentration of a compound that causes a half-maximal potentiation
of the glutamate response. This is calculated by subtracting the
maximal responses of glutamate in presence of a fully saturating
concentration of a positive allosteric modulator from the response
of glutamate in absence of a positive allosteric modulator. The
concentration producing the half-maximal effect is then calculated
as EC.sub.50.
TABLE-US-00003 TABLE 3 Pharmacological data for compounds according
to the invention. All compounds were tested in presence of mGluR2
agonist, glutamate at a predetermined EC.sub.25 concentration, to
determine positive allosteric modulation (GTP.gamma.S-PAM). Values
shown are averages of duplicate values of 11-concentration response
curves, from at least one experiment. All tested compounds showed a
pEC.sub.50 (-logEC.sub.50) value of more than 5.0, from 6.05 to
7.20. The error of determination of a pEC.sub.50 value for a single
experiment is estimated to be about 0.3 log-units. Comp. No. GTPgS
- hR2 PAM pEC.sub.50 1 6.53 2 6.74 3 6.88 4 6.45 5 6.90 6 6.34 7
6.62 8 6.04 9 6.57 10 6.88 11 7.11 12 7.03 13 6.64 14 6.92 15 7.00
16 7.12 17 6.57 18 7.20 19 6.71 20 6.91 21 6.25 22 6.05 23 6.58 24
6.91 25 6.83 26 6.41 27 6.46 28 7.06 29 6.88 30 nd 31 nd 32 nd 33
nd nd = not determined
E. Composition Examples
[0254] "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. Typical examples of recipes for the
formulation of the invention are as follows:
1. Tablets
TABLE-US-00004 [0255] 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
[0256] 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
[0257] 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
[0258] 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-00005 [0259] Active ingredient 5 to 1000 mg Stearyl
alcohol 3 g Lanoline 5 g White petroleum 15 g Water ad 100 g
[0260] 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.
[0261] 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.
* * * * *