NZ614688B2 - Ethynyl derivatives as positive allosteric modulators of the mglur5 - Google Patents
Ethynyl derivatives as positive allosteric modulators of the mglur5 Download PDFInfo
- Publication number
- NZ614688B2 NZ614688B2 NZ614688A NZ61468812A NZ614688B2 NZ 614688 B2 NZ614688 B2 NZ 614688B2 NZ 614688 A NZ614688 A NZ 614688A NZ 61468812 A NZ61468812 A NZ 61468812A NZ 614688 B2 NZ614688 B2 NZ 614688B2
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- NZ
- New Zealand
- Prior art keywords
- pyridinyl
- phenylethynyl
- methyl
- hydrogen
- compound
- Prior art date
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- 230000000051 modifying Effects 0.000 title abstract description 18
- 230000003281 allosteric Effects 0.000 title abstract description 16
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 146
- -1 pyridinyl ethynyl Chemical class 0.000 claims abstract description 125
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- 125000000217 alkyl group Chemical group 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- 239000001257 hydrogen Substances 0.000 claims description 47
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- 238000007792 addition Methods 0.000 claims description 22
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- 125000004076 pyridyl group Chemical group 0.000 claims description 18
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Abstract
Disclosed are phenyl and pyridinyl ethynyl derivatives of formula I where the substituents are as defined hererin. Examples of the compounds of the present invention are (RS)-1,5,5-trimethyl-3-(5-(phenylethynyl)pyridin-2-yl)pyrrolidin-2-one and (RS)-benzyl 1,5,5-trimethyl-2-oxo-3-(5-(phenylethynyl)pyrimidin-2-yl)pyrrolidine-3-carboxylate. The compounds of general formula I are positive allosteric modulators (PAM) of the metabotropic glutamate receptor subtype 5 (mGluR5). They may be used for the treatment of schizophrenia or cognitive disorders. yrimidin-2-yl)pyrrolidine-3-carboxylate. The compounds of general formula I are positive allosteric modulators (PAM) of the metabotropic glutamate receptor subtype 5 (mGluR5). They may be used for the treatment of schizophrenia or cognitive disorders.
Description
Case 27434
ETHYNYL DERIVATIVES AS POSITIVE ALLOSTERIC MODULATORS OF THE
MGLUR5
The present invention relates to ethynyl derivatives of formula I
6 ()
wherein
X is N or C-R, wherein R is hydrogen or halogen;
G is N or CH;
with the proviso that maximum one of G or X can be nitrogen;
R is phenyl or pyridinyl, which are optionally substituted by halogen;
R is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl;
3 3’ 4 4’ 6 6’
R ,R , R , R , R , R are independently from each other hydrogen or lower alkyl;
or R and R may form together with the carbon atom to which they are attached a
C -cycloalkyl ring, if m is 0 and n is 1 or 2;
R is hydrogen or lower alkyl;
n is 0, 1 or 2;
m is 0 or 1; with the proviso that n and m are not simultaneously 0;
or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its
corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
It has now surprisingly been found that the compounds of general formula I are positive
allosteric modulators (PAM) of the metabotropic glutamate receptor subtype 5 (mGluR5).
In the central nervous system (CNS) the transmission of stimuli takes place by the
interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in
a variety of central nervous system (CNS) functions. The glutamate-dependent stimulus
receptors are divided into two main groups. The first main group, namely the ionotropic
Pop/01.02.2012
receptors, forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR)
belong to the second main group and, furthermore, belong to the family of G-protein coupled
receptors.
At present, eight different members of these mGluR are known and of these some even
have sub-types. According to their sequence homology, signal transduction mechanisms and
agonist selectivity, these eight receptors can be sub-divided into three sub-groups:
mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and
mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for
the treatment or prevention of acute and/or chronic neurological disorders such as psychosis,
epilepsy, schizophrenia, Alzheimer’s disease, cognitive disorders and memory deficits, as well as
chronic and acute pain.
Other treatable indications in this connection are restricted brain function caused by bypass
operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries,
hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications
are ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by
AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by
medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g.
muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction,
anxiety, vomiting, dyskinesia and depressions.
Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic
degenerative processes of the nervous system, such as Alzheimer’s disease, senile dementia,
Parkinson’s disease, Huntington’s chorea, amyotrophic lateral sclerosis and multiple sclerosis,
psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency
(Expert Opin. Ther. Patents (2002), 12, (12)).
A new avenue for developing selective modulators is to identify compounds which act
through allosteric mechanism, modulating the receptor by binding to site different from the
highly conserved orthosteric binding site. Positive allosteric modulators of mGluR5 have
emerged recently as novel pharmaceutical entities offering this attractive alternative. Positive
allosteric modulators have been described, for example in WO2008/151184, WO2006/048771,
WO2006/129199 and WO2005/044797 and in Molecular Pharmacology, 40, 333 – 336, 1991;
The Journal of Pharmacology and Experimental Therapeutics, Vol 313, No. 1, 199-206, 2005;
Positive allosteric modulators are compounds that do not directly activate receptors by
themselves, but markedly potentiate agonist-stimulated responses, increase potency and
maximum of efficacy. The binding of these compounds increase the affinity of a glutamate-site
agonist at its extracellular N-terminal binding site. Positive allosteric modulation is thus an
attractive mechanism for enhancing appropriate physiological receptor activation. There is a
scarcity of selective positive allosteric modulators for the mGluR5 receptor. Conventional
mGluR5 receptor modulators typically lack satisfactory aqueous solubility and exhibit poor oral
bioavailability. Therefore, there remains a need for compounds that overcome these deficiencies
and that effectively provide selective positive allosteric modulators for the mGluR5 receptor.
Compounds of formula I are distinguished by having valuable therapeutic properties. They
can be used in the treatment or prevention of disorders, relating to positive allosteric modulators
for the mGluR5 receptor.
The most preferred indications for compounds which are positive allosteric modulators are
schizophrenia and cognition.
The present invention relates to compounds of formula I and to their pharmaceutically
acceptable salts, to these compounds as pharmaceutically active substances, to the processes for
their production as well as to the use of the compounds for the manufacture of medicaments for
the treatment or prevention of disorders, relating to positive allosteric modulators for the
mGluR5 receptor, such as schizophrenia, tuberous sclerosis, and cognition, and to
pharmaceutical compositions containing the compounds of formula I.
The following definitions of the general terms used in the present description apply
irrespective of whether the terms in question appear alone or in combination.
As used herein, the term "lower alkyl" denotes a saturated, i.e. aliphatic hydrocarbon group
including a straight or branched carbon chain with 1 – 4 carbon atoms. Examples for “alkyl” are
methyl, ethyl, n-propyl, and isopropyl.
The term “alkoxy” denotes a group -O-R’ wherein R’ is lower alkyl as defined above.
The term “halogen” denotes fluoro, chloro, bromo or iodo.
The term "pharmaceutically acceptable salt" or “pharmaceutically acceptable acid addition
salt” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid,
sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid,
succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
One embodiment of the invention are compounds of formula IA
6' R
wherein
R is phenyl or pyridinyl, which are optionally substituted by halogen;
R is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl;
4 4’ 6 6’
R , R , R , R are independently from each other hydrogen or lower alkyl;
or R and R may form together with the carbon atom to which they are attached a
C -cycloalkyl ring;
R is hydrogen or lower alkyl;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding
enantiomer and/or optical isomer and/or stereoisomer thereof.
Examples from this group of compounds are
(RS)-1,5,5-trimethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone
(RS)-1,5,5-trimethyl(5-(pyridinylethynyl)pyridinyl)pyrrolidinone
(RS)(5-((3-chlorophenyl)ethynyl)pyridinyl)-1,5,5-trimethylpyrrolidinone
(RS)(5-((3-fluorophenyl)ethynyl)pyridinyl)-1,5,5-trimethylpyrrolidinone
(RS)hydroxy-1,5,5-trimethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone
(RS)methoxy-1,5,5-trimethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone
(RS)-1,3,5,5-tetramethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone
(3RS,3aSR,6aSR)methyl(5-phenylethynyl-pyridinyl)-hexahydro-cyclopenta[b]pyrrol
(3R,3aS,6aS) or (3S,3aR,6aR)methyl(5-phenylethynyl-pyridinyl)-hexahydro-
cyclopenta[b]pyrrolone
(3RS,3aSR,6aSR)[5-(4-fluoro-phenylethynyl)-pyridinyl]methyl-hexahydro-
cyclopenta[b]pyrrolone
(3RS,3aSR,6aSR)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-hexahydro-
cyclopenta[b]pyrrolone
(3R,3aS,6aS) or (3S,3aR,6aR)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-hexahydro-
cyclopenta[b]pyrrolone
(3S,3aR,6aR) or (3R,3aS,6aS)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-hexahydro-
cyclopenta[b]pyrrolone
(3RS,6SR,7SR)methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone
(3SR,6SR,7SR)methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone
(3R,6S,7S)methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone and (3S,6R,7R)
Methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone
(3RS,6SR,7SR)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone
(3SR,6SR,7SR)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone
(3R,6S,7S)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone
(3S,6R,7R)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone
(3R,6S,7S)[5-(4-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone
(3S,6R,7R)[5-(4-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone
(RS)[5-(2-chloro-pyridinylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrrolidinone
(S) or (R)[5-(2-chloro-pyridinylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrrolidinone or
(R) or (S)[5-(2-chloro-pyridinylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrrolidinone.
One embodiment of the invention are compounds of formula IB
6' R
wherein
X is N or C-R, wherein R is halogen;
R is phenyl or pyridinyl, which are optionally substituted by halogen;
R is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl;
4 4’ 6 6’
R , R , R , R are independently from each other hydrogen or lower alkyl;
or R and R may form together with the carbon atom to which they are attached a
C -cycloalkyl ring,;
R is hydrogen or lower alkyl;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding
enantiomer and/or optical isomer and/or stereoisomer thereof.
Examples from this group of compounds are
(RS)-benzyl 1,5,5-trimethyloxo(5-(phenylethynyl)pyrimidinyl)pyrrolidine
carboxylate
(RS)-1,5,5-trimethyl(5-(phenylethynyl)pyrimidinyl)pyrrolidinone
(RS)(5-((3-fluorophenyl)ethynyl)pyrimidinyl)-1,5,5-trimethylpyrrolidinone
(RS)(5-((4-fluorophenyl)ethynyl)pyrimidinyl)-1,5,5-trimethylpyrrolidinone or
(3RS,3aSR,6aSR)methyl(5-phenylethynyl-pyrimidinyl)-hexahydro-cyclopenta[b]pyrrol-
2-one.
One embodiment of the invention are compounds of formula IC
R 4'
wherein
R is phenyl or pyridinyl, which are optionally substituted by halogen;
R is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl;
4 4’ 6 6’
R , R , R , R are independently from each other hydrogen or lower alkyl;
or R and R may form together with the carbon atom to which they are attached a
C -cycloalkyl ring;
R is hydrogen or lower alkyl;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding
enantiomer and/or optical isomer and/or stereoisomer thereof.
Examples from this group of compounds are
(RS)(6-((3-fluorophenyl)ethynyl)pyridazinyl)-1,5,5-trimethylpyrrolidinone
(RS)(6-((4-fluorophenyl)ethynyl)pyridazinyl)-1,5,5-trimethylpyrrolidinone or
(RS)(6-(phenylethynyl)pyridazinyl)-1,5,5-trimethylpyrrolidinone.
One embodiment of the invention are compounds of formula ID
wherein
R is phenyl or pyridinyl, which are optionally substituted by halogen;
R is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl;
3 3’ 4 4’ 6 6’
R ,R , R , R , R , R are independently from each other hydrogen or lower alkyl;
R is hydrogen or lower alkyl;
n is 1 or 2;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding
enantiomer and/or optical isomer and/or stereoisomer thereof.
Examples from this group of compounds are
(RS)-1,6,6-trimethyl(5-(phenylethynyl)pyridinyl)piperidinone
(RS)(5-((3-fluorophenyl)ethynyl)pyridinyl)-1,6,6-trimethylpiperidinone
(RS)(5-((4-fluorophenyl)ethynyl)pyridinyl)-1,6,6-trimethylpiperidinone
(RS)methyl(5-phenylethynyl-pyridinyl)-azepanone
(RS)[5-(4-fluoro-phenylethynyl)-pyridinyl]methyl-azepanone
(RS)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-azepanone
(S or R)methyl(5-phenylethynyl-pyridinyl)-azepanone or
(R or S)methyl(5-phenylethynyl-pyridinyl)-azepanone.
One embodiment of the invention are compounds of formula IE
6' 4'
wherein
R is phenyl or pyridinyl, which are optionally substituted by halogen;
R is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl;
3 3’ 4 4’ 6 6’
R ,R , R , R , R , R are independently from each other hydrogen or lower alkyl;
R is hydrogen or lower alkyl;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding
enantiomer and/or optical isomer and/or stereoisomer thereof.
Examples from this group of compounds are
(RS)-1,6,6-trimethyl(5-(phenylethynyl)pyrimidinyl)piperidinone
(RS)(5-((4-fluorophenyl)ethynyl)pyrimidinyl)-1,6,6-trimethylpiperidinone or
(RS)(5-((3-fluorophenyl)ethynyl)pyrimidinyl)-1,6,6-trimethylpiperidinone.
A further embodiment of the invention are compounds of formula
Q ()
wherein
X is N or C-R, wherein R is hydrogen, methyl or halogen;
G and A are independently N or CH;
with the proviso that maximum one of G, A or X can be nitrogen;
9 6 6’
Q is O, N-R or -CR R -;
R is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl
or lower alkoxy;
R is hydrogen, lower alkyl, hydroxy, lower alkoxy, C(O)O-benzyl, C(O)O-lower
alkyl or CONR R ;
3 3’ 4 4’ 6 6’
R ,R , R , R , R , R are independently from each other hydrogen, lower alkyl, alkoxy,
hydroxy or CH -lower alkoxy;
or R and R may form together with the carbon atom to which they are attached a
C -cycloalkyl ring;
R is hydrogen, lower alkyl, or may form together with R a C -C -cycloalkyl;
7 8 7 8
R , R are independently hydrogen, lower alkyl, or R can form with R a C -C -
cycloalkyl ring;
R is hydrogen or lower alkyl;
n is 0, 1 or 2;
m is 0 or 1;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding
enantiomer and/or optical isomer and/or stereoisomer thereof.
In another aspect, the invention relates to a process for preparing compounds of formula I,
comprising a) reacting a compound of formula
wherein X is halogen,
with a compound of formula
in the presence of Bis-(tpp)-Pd(II)Cl , Et N, TPP, CuI and THF or DMF at 70°C,
to a compound of formula
R 4'
wherein the definitions are as described above.
The preparation of compounds of formula I of the present invention may be carried out in
sequential or convergent synthetic routes. Syntheses of the compounds of the invention are
shown in the following scheme 1. The skills required for carrying out the reaction and
purification of the resulting products are known to those skilled in the art. The substituents and
indices used in the following description of the processes have the significance given herein
before.
The compounds of formula I can be manufactured by the methods given below, by the
methods given in the examples or by analogous methods. Appropriate reaction conditions for the
individual reaction steps are known to a person skilled in the art. The reaction sequence is not
limited to the one displayed in the schemes, however, depending on the starting materials and
their respective reactivity the sequence of reaction steps can be freely altered. Starting materials
are either commercially available or can be prepared by methods analogous to the methods given
below, by methods described in references cited in the description or in the examples, or by
methods known in the art.
The present compounds of formula I and their pharmaceutically acceptable salts may be
prepared by methods, known in the art, for example by the process variants described below,
which process comprises
a) reacting a compound of formula
wherein X is halogen
with a compound of formula
to a compound of formula
wherein the definitions are as described above or
b) reacting a compound of formula
wherein X is halogen
with a compound of formula
to form a compound of formula
R 4'
wherein the definitions are as described above, or, if desired, converting the compounds obtained
into pharmaceutically acceptable acid addition salts.
The preparation of compounds of formula I is further described in more detail in schemes 1 to 4
and in examples 1 – 46.
Scheme 1
3' 3'
6' R R
R 4 4
() ()
N X' 6
4' N 4'
R Base
G ()
X 5 5
R R R
X= Br, I
X'= F, Cl R
Bis-(tpp)-Pd(II)Cl
Et N, TPP, CUI
THF or DMF, 2-16h, 70°
An acetylenic compound of formula I can be obtained for example by reaction of a para-
dihalo disubstituted heterocyclic derivative 1 with an appropriately substituted cyclic amide 2 in
the presence of a strong base such as sodium hydride, sodium hexamethyldisilylamide
(NaHMDS), lithium diisopropylamide (LDA), or in an inert solvent like toluene, DMF, DMSO
or THF; or sodium alkoxide in a corresponding alcohol as solvent to form the corresponding 3-
heteroaryl lactam derivatives 3. Sonogashira coupling of the lactams 3 with an appropriately
substituted arylacetylene 4 yield the desired ethynyl compounds of general formula I (scheme 1).
Scheme 2
3 6'
R m R
R 4'
NaOH ()
6' R
R ()
H O, EtOH
I (R is C(O)O-benzyl or C(O)O-lower alkyl)
R is COOH
R ()
I (R is H)
An acetylenic compound of formula I can be obtained for example when
R = COO-benzyl or COO-lower alkyl by hydrolysis of the ester group using for example,
aqueous sodium of potassium hydroxide in a solvent such as methanol or ethanol followed by
decarboxylation of the acid formed to yield a compound of general formula I where R is
hydrogen (scheme 2).
Scheme 3
6 6'
R R ()
NaOH
R ()
H O, EtOH
X O
R = COOH
2 -CO
R = C(O)O-benzyl or C(O)O-lower alkyl
R R 4
Bis-(tpp)-Pd(II)Cl
6 2 R
m Et N, TPP, CUI
R ()
3 R R
THF or DMF, 2-16h, 70°
N N R
R = H
The latter procedure can also be used to modify a compound of formula 3 where R is an
ester to form a compound of formula 3 where R is hydrogen. Sonogashira coupling of the
lactams 3 with appropriately substituted arylacetylenes 4 yield the desired ethynyl compounds of
general formula I where R is hydrogen (scheme 3).
Scheme 4
Bis-(tpp)-Pd(II)Cl2 R 4
Et3N, TPP, CUI
N X 4'
R ()
THF or DMF, 2-16h, 70°
X= Br, I, F, Cl
X' = Br, I
Base
formula I can also be modified in certain cases, for example by first running the
Sonogashira coupling to form an appropriately substituted aryl- or heteroaryl-ethynyl derivative
followed by reaction with a lactam of formula 2 using procedures similar to those described in
schemes 1 to 3 (scheme 4).
Biological Assay and Data:
Intracellular Ca mobilization assay
A monoclonal HEK-293 cell line stably transfected with a cDNA encoding for the human
mGlu5a receptor was generated; for the work with mGlu5 Positive Allosteric Modulators
(PAMs), a cell line with low receptor expression levels and low constitutive receptor activity was
selected to allow the differentiation of agonistic versus PAM activity. Cells were cultured
according to standard protocols (Freshney, 2000) in Dulbecco’s Modified Eagle Medium with
high glucose supplemented with 1 mM glutamine, 10% (vol/vol) heat-inactivated bovine calf
serum, Penicillin/Streptomycin, 50 μg/ml hygromycin and 15 μg/ml blasticidin (all cell culture
reagents and antibiotics from Invitrogen, Basel, Switzerland).
About 24 hrs before an experiment, 5x10 cells/well were seeded in poly-D-lysine coated,
black/clear-bottomed 96-well plates. The cells were loaded with 2.5 µM Fluo-4AM in loading
buffer (1xHBSS, 20 mM HEPES) for 1 hr at 37°C and washed five times with loading buffer.
The cells were transferred into a Functional Drug Screening System 7000 (Hamamatsu, Paris,
France), and 11 half logarithmic serial dilutions of test compound at 37°C were added and the
cells were incubated for 10-30 min. with on-line recording of fluorescence. Following this pre-
incubation step, the agonist L-glutamate was added to the cells at a concentration corresponding
to EC (typically around 80 μM) with on-line recording of fluorescence; in order to account for
day-to-day variations in the responsiveness of cells, the EC of glutamate was determined
immediately ahead of each experiment by recording of a full dose-response curve of glutamate.
Responses were measured as peak increase in fluorescence minus basal (i.e. fluorescence
without addition of L-glutamate), normalized to the maximal stimulatory effect obtained with
saturating concentrations of L-glutamate. Graphs were plotted with the % maximal stimulatory
using XLfit, a curve fitting program that iteratively plots the data using Levenburg Marquardt
algorithm. The single site competition analysis equation used was y = A + ((B-A)/(1+((x/C)D))),
where y is the % maximal stimulatory effect, A is the minimum y, B is the maximum y, C is the
EC , x is the log10 of the concentration of the competing compound and D is the slope of the
curve (the Hill Coefficient). From these curves the EC (concentration at which half maximal
stimulation was achieved), the Hill coefficient as well as the maximal response in % of the
maximal stimulatory effect obtained with saturating concentrations of L-glutamate were
calculated.
Positive signals obtained during the pre-incubation with the PAM test compounds (i.e. before
application of an EC concentration of L-glutamate) were indicative of an agonistic activity, the
absence of such signals were demonstrating the lack of agonistic activities. A depression of the
signal observed after addition of the EC concentration of L-glutamate was indicative of an
inhibitory activity of the test compound.
In the table below are shown the prepared compounds 1 – 46 with corresponding results (EC in
nM).
List of Examples:
Ex. Structure Name EC (nM) Eff. (%)
mGlu5
(RS)-1,5,5-trimethyl(5-
1 (phenylethynyl)pyridin
60 111
yl)pyrrolidinone
(RS)-1,5,5-trimethyl(5-
2 (pyridinylethynyl)pyridin
981 107
yl)pyrrolidinone
(RS)(5-((3-
chlorophenyl)ethynyl)pyridin-
38 81
2-yl)-1,5,5-
trimethylpyrrolidinone
(RS)(5-((3-
fluorophenyl)ethynyl)pyridin-
61 103
F 2-yl)-1,5,5-
trimethylpyrrolidinone
(RS)-benzyl 1,5,5-trimethyl
oxo(5-
528 48
(phenylethynyl)pyrimidin
yl)pyrrolidinecarboxylate
(RS)-1,5,5-trimethyl(5-
6 (phenylethynyl)pyrimidin
130 90
yl)pyrrolidinone
(RS)(5-((3-
fluorophenyl)ethynyl)pyrimidi
137 85
nyl)-1,5,5-
trimethylpyrrolidinone
3-(5-((4-
fluorophenyl)ethynyl)pyrimidi
O 390 105
nyl)-1,5,5-
trimethylpyrrolidinone
3-(6-((3-
N fluorophenyl)ethynyl)pyridazi
34 88
nyl)-1,5,5-
trimethylpyrrolidinone
3-(6-((4-
fluorophenyl)ethynyl)pyridazi
247 99
nyl)-1,5,5-
trimethylpyrrolidinone
(RS)-1,5,5-trimethyl(6-
11 (phenylethynyl)pyridazin
O 58 115
yl)pyrrolidinone
(RS)-1,6,6-trimethyl(5-
12 (phenylethynyl)pyridin
113 103
yl)piperidinone
(RS)(5-((3-
fluorophenyl)ethynyl)pyridin-
O 98 90
2-yl)-1,6,6-trimethylpiperidin-
2-one
(RS)(5-((4-
fluorophenyl)ethynyl)pyridin-
212 96
2-yl)-1,6,6-trimethylpiperidin-
F 2-one
(RS)-1,6,6-trimethyl(5-
(phenylethynyl)pyrimidin
179 91
yl)piperidinone
(RS)(5-((4-
fluorophenyl)ethynyl)pyrimidi
573 96
nyl)-1,6,6-
trimethylpiperidinone
(RS)(5-((3-
fluorophenyl)ethynyl)pyrimidi
132 80
nyl)-1,6,6-
trimethylpiperidinone
(RS)hydroxy-1,5,5-
trimethyl(5-
414 126
(phenylethynyl)pyridin
yl)pyrrolidinone
(RS)methoxy-1,5,5-
N trimethyl(5-
96 108
(phenylethynyl)pyridin
yl)pyrrolidinone
(RS)-1,3,5,5-tetramethyl(5-
(phenylethynyl)pyridin
90 109
yl)pyrrolidinone
(RS)(3-fluoro((3-
fluorophenyl)ethynyl)pyridin-
O 188 91
2-yl)-1,5,5-
trimethylpyrrolidinone
(RS)Methyl(5-
22 O phenylethynyl-pyridinyl)-
59 59
azepanone
(RS)[5-(4-Fluoro-
23 phenylethynyl)-pyridinyl]-
90 61
1-methyl-azepanone
(RS)[5-(3-Fluoro-
24 O phenylethynyl)-pyridinyl]-
39 69
1-methyl-azepanone
Chiral
(S or R)Methyl(5-
Chiral
phenylethynyl-pyridinyl)-
70
azepanone
Chiral
(R or S)Methyl(5-
Chiral
26 phenylethynyl-pyridinyl)-
265 69
azepanone
(3RS,3aSR,6aSR)Methyl
(5-phenylethynyl-pyridin
27 H
47 53
yl)-hexahydro-
cyclopenta[b]pyrrolone
Chiral
(3S,3aR,6aR) or (3R,3aS,6aS)-
1-Methyl(5-phenylethynyl-
Chiral
28 H
24 58
pyridinyl)-hexahydro-
cyclopenta[b]pyrrolone
(3RS,3aSR,6aSR)[5-(4-
Fluoro-phenylethynyl)-
29 pyridinyl]methyl-
78 53
hexahydro-
cyclopenta[b]pyrrolone
(3RS,3aSR,6aSR)[5-(3-
Fluoro-phenylethynyl)-
pyridinyl]methyl-
33 57
hexahydro-
cyclopenta[b]pyrrolone
Chiral
(3R,3aS,6aS) or (3S,3aR,6aR)-
3-[5-(3-Fluoro-phenylethynyl)-
Chiral
31 pyridinyl]methyl-
51
hexahydro-
cyclopenta[b]pyrrolone
Chiral
(3S,3aR,6aR) or (3R,3aS,6aS)-
3-[5-(3-Fluoro-phenylethynyl)-
Chiral
32 pyridinyl]methyl-
48 68
hexahydro-
cyclopenta[b]pyrrolone
(3RS,3aSR,6aSR)Methyl
(5-phenylethynyl-pyrimidin
33 H
O 52 52
yl)-hexahydro-
cyclopenta[b]pyrrolone
(3RS,6SR,7SR)Methyl
34 (5-phenylethynyl-pyridin
O 185 82
yl)-octahydro-indolone
(3SR,6SR,7SR)Methyl
(5-phenylethynyl-pyridinyl)
101 60
octahydro-indolone
(3R,6S,7S)Methyl(5-
36 phenylethynyl-pyridinyl)-
84 92
octahydro-indolone
(3S,6R,7R)Methyl(5-
37 phenylethynyl-pyridinyl)-
84 49
octahydro-indolone
(3RS,6SR,7SR)[5-(3-
Fluoro-phenylethynyl)-
69 60
pyridinyl]methyl-
octahydro-indolone
(3SR,6SR,7SR)[5-(3-
Fluoro-phenylethynyl)-
141 61
pyridinyl]methyl-
octahydro-indolone
H (3R,6S,7S)[5-(3-Fluoro-
phenylethynyl)-pyridinyl]-
89 68
1-methyl-octahydro-indol
(3S,6R,7R)[5-(3-Fluoro-
phenylethynyl)-pyridinyl]-
68 56
1-methyl-octahydro-indol
(3R,6S,7S)[5-(4-Fluoro-
N phenylethynyl)-pyridinyl]-
57 63
1-methyl-octahydro-indol
(3S,6R,7R)[5-(4-Fluoro-
phenylethynyl)-pyridinyl]-
43 H
O 146 53
1-methyl-octahydro-indol
(RS)[5-(2-Chloro-pyridin
44 ylethynyl)-pyridinyl]-1,5,5-
88 32
trimethyl-pyrrolidinone
Chiral
(S) or (R)[5-(2-Chloro-
pyridinylethynyl)-pyridin
Chiral
65 36
yl]-1,5,5-trimethyl-pyrrolidin-
2-one
Chiral
(R) or (S)[5-(2-Chloro-
pyridinylethynyl)-pyridin
Chiral
103 40
yl]-1,5,5-trimethyl-pyrrolidin-
2-one
The compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as
medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations
can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft
gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be
effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection
solutions.
The compounds of formula (I) and pharmaceutically acceptable salts thereof can be
processed with pharmaceutically inert, inorganic or organic carriers for the production of
pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its
salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées
and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable
oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active
substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable
carriers for the production of solutions and syrups are, for example, water, polyols, sucrose,
invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils
and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of
formula (I), but as a rule are not necessary. Suitable carriers for suppositories are, for example,
natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical preparations can contain preservatives, solubilizers,
stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the
osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other
therapeutically valuable substances.
As mentioned earlier, medicaments containing a compound of formula (I) or
pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an aspect
of the present invention, as is a process for the production of such medicaments which comprises
bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and,
if desired, one or more other therapeutically valuable substances into a galenical dosage form
together with one or more therapeutically inert carriers.
As further mentioned earlier, the use of the compounds of formula (I) for the preparation of
medicaments useful in the prevention and/or the treatment of the above recited diseases is also an
aspect of the present invention.
The dosage can vary within wide limits and will, of course, be fitted to the individual
requirements in each particular case. In general, the effective dosage for oral or parenteral
administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being
preferred for all of the indications described. The daily dosage for an adult human being
weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg
per day.
Preparation of pharmaceutical compositions comprising compounds of the invention:
Example A
Tablets of the following composition are produced in a conventional manner:
mg/Tablet
Active ingredient 100
Powdered. lactose 95
White corn starch 35
Polyvinylpyrrolidone 8
Na carboxymethylstarch 10
Magnesium stearate 2
Tablet weight 250
Example 1
(RS)-1,5,5-Trimethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone
Step 1: (RS)(5-Iodo-pyridinyl)-1,5,5-trimethyl-pyrrolidinone
A solution of 2-fluoroiodopyridine (260 mg, 1.17 mmol) and 1,5,5-trimethyl-pyrrolidinone
(148 mg, 1.17 mmol) in 6 ml of dry toluene was purged with Argon and cooled to -4°C. A 1M
solution of sodium hexamethyldisilylamide (NaHMDS) in toluene (2.33 ml, 2.33 mmol) was
added dropwise maintaining the temperature below 0°C. The red solution was stirred for 2h at
0°C, quenched by addition of 5 ml of saturated ammonium chloride solution. After extraction
with ethyl acetate/water, drying over sodium sulfate and concentration; the residue (400 mg) was
taken up in ethyl acetate, adsorbed onto 5 g of silicagel which was loaded onto a 20 g prepacked
flash chromato-graphy column. After elution with a 0% to 75% ethyl acetate in heptane gradient,
the fractions containing the desired product were collected to yield 145 mg (38%) of the title
compound as a yellow viscous oil, MS: m/e = 331.0 (M+H ).
Step 2: (RS)-1,5,5-Trimethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone
A solution of (RS)(5-iodopyridinyl)-1,5,5-trimethylpyrrolidinone (140mg, 0.42 mmol),
ethynylbenzene (65.0 mg, 69.9 µl, 0.64 mmol), triethylamine (129 mg, 177 µl, 1.27 mmol),
bis(triphenylphosphine)palladium (II) chloride (17.9 mg, 25.4 µmol) and triphenylphosphine
(3.34 mg, 12.7 µmol) in 4 ml of THF was purged with argon. Then copper (I) iodide (2.42 mg,
12.7 µmol) was added and the reaction was heated for 3h at 60°C. After extraction with ethyl
acetate/water, drying over sodium sulfate and concentration; the residue was taken up in ethyl
acetate, adsorbed onto 3 g of silicagel which was loaded onto a 20 g prepacked flash chromato-
graphy column. After elution with a 0% to 65% ethyl acetate in heptane gradient, the fractions
containing the desired product were collected to yield 103 mg (72%) of the title compound as an
amorphous yellow solid, MS: m/e = 305.2 (M+H ).
Example 2
(RS)-1,5,5-Trimethyl(5-(pyridinylethynyl)pyridinyl)pyrrolidinone
The title compound was obtained as an amorphous yellow solid, MS: m/e = 306.2 (M+H ), using
chemistry similar to that described in Example 1, step 2 from (RS)(5-iodopyridinyl)-1,5,5-
trimethylpyrrolidinone (Example 1, step 1) and 3-ethynyl-pyridine.
Example 3
(RS)(5-((3-Chlorophenyl)ethynyl)pyridinyl)-1,5,5-trimethylpyrrolidinone
The title compound was obtained as a yellow viscous oil, MS: m/e = 339.1,
341.1 (M+H ), using chemistry similar to that described in Example 1, step 2 from (RS)(5-
iodopyridinyl)-1,5,5-trimethylpyrrolidinone (Example 1, step 1) and 3- ethynylchloro-
benzene.
Example 4
(RS)(5-((3-Fluorophenyl)ethynyl)pyridinyl)-1,5,5-trimethylpyrrolidinone
The title compound was obtained as a yellow viscous oil, MS: m/e = 323.3 (M+H ), using
chemistry similar to that described in Example 1, step 2 from (RS)(5-iodopyridinyl)-1,5,5-
trimethylpyrrolidinone (Example 1, step 1) and 1-ethynylfluoro-benzene.
Example 5
(RS)-Benzyl 1,5,5-trimethyloxo(5-(phenylethynyl)pyrimidinyl)pyrrolidine
carboxylate
Step 1: (RS)-1,5,5-Trimethyloxo-pyrrolidinecarboxylic acid benzyl ester
In a flame-dried 50 ml three necked flask under argon atmosphere were dissolved 1.27 g (10.0
mmol) of 5,5-dimethylpyrrolidinone in 10 ml of dry THF. After cooling to
-75°C, a 2 M solution of lithium diisopropylamide in THF (10.5 ml, 10.5 mmol) was added
dropwise maintaining the temperature below -73°C. The solution was stirrred for 1h at -75°C
Then a solution of dibenzyl carbonate (2.72 g, 11.0 mmol) in 5 ml of THF was added dropwise
at -75°C, allowed to warm up to r.t. and stirred for 1h. The reaction was quenched by addition of
ml of saturated ammonium chloride solution. After extraction with ethyl acetate/water, drying
over sodium sulfate and concentration; the residue was loaded onto a 50 g prepacked flash
chromatography column. After elution with a 10% to 70% ethyl acetate in heptane gradient, the
fractions containing the desired product were collected to yield 1.07 g (41%) of the title
compound as a light yellow oil, MS: m/e = 262.2 (M+H ).
Step 2: (RS)-Benzyl 1,5,5-trimethyloxo(5-(phenylethynyl)pyrimidin-2yl)-pyrrolidine
carboxylate
A solution of (RS)-benzyl 1,5,5-trimethyloxopyrrolidinecarboxylate (206 mg, 787 µmol) in
4 ml of dry DMF was purged with argon and cooled to 0°C. Then a 60% suspension of sodium
hydride (31.5 mg, 0.79 mmol) was added and the mixture was stirred for 40 min at room
temperature whereby a white suspension was formed. Then 2-chloro
(phenylethynyl)pyrimidine (CAS: [10513889]) (130 mg, 606 µmol) was added, the mixture
was stirred for 30 min at 80°C, and then quenched by addition of 1 ml of saturated ammonium
chloride solution. After extraction with ethyl acetate/water, drying over sodium sulfate and
concentration; the residue (440 mg, yellow oil) was taken up in ethyl acetate, adsorbed onto 3 g
of silicagel and loaded onto a 20 g prepacked flash chromatography column. After elution with a
10% to 60% ethyl acetate in heptane gradient, the fractions containing the desired product were
collected to yield 212 mg (80%) of the title compound as a light yellow waxy solid, MS: m/e =
440.3 (M+H ).
Example 6
(RS)-1,5,5-Trimethyl(5-(phenylethynyl)pyrimidinyl)pyrrolidinone
To a solution of (RS)-benzyl 1,5,5-trimethyloxo(5-(phenylethynyl)pyrimidin
yl)pyrrolidinecarboxylate (Example 5, step 2) (205mg, 0.47 µmol) in 3 ml of ethanol was
added 1N sodium hydroxide solution (933 µl, 0.94 mmol). After stirring for 1.5h at room
temperature, the pH was neutralized by addition of 1N HCl, and the solvent was evaporated in
vaccuo. The residue (165 mg, yellow oil) was loaded onto a 20 g prepacked flash
chromatography column. After elution with a 15% to 100% ethyl acetate in heptane gradient, the
fractions containing the desired product were collected to yield 94 mg (66%) of the title
compound as a light yellow crystalline solid, MS: m/e = 306.2 (M+H ).
Example 7
(RS)(5-((3-Fluorophenyl)ethynyl)pyrimidinyl)-1,5,5-trimethylpyrrolidinone
Step 1: (RS)(5-Bromo-pyrimidinyl)-1,5,5-trimethyloxo-pyrrolidinecarboxylic acid
benzyl ester
The title compound was obtained as a colorless viscous oil, MS: m/e = 420.1, 418.2 (M+H ),
using chemistry similar to that described in Example 5, step 2 from (RS)-benzyl 1,5,5-trimethyl-
2-oxopyrrolidinecarboxylate (Example 5, step 1) and 5-bromochloropyrimidine.
Step 2: (RS)(5-Bromo-pyrimidinyl)-1,5,5-trimethyl-pyrrolidinone
The title compound was obtained as a crystalline white solid, MS: m/e = 284.0, 286.0
(M+H ), using chemistry similar to that described in Example 6 from (RS)(5-bromo-
pyrimidinyl)-1,5,5-trimethyloxo-pyrrolidinecarboxylic acid benzyl ester.
Step 3: (RS)(5-((3-Fluorophenyl)ethynyl)pyrimidinyl)-1,5,5-trimethylpyrrolidinone
The title compound was obtained as a crystalline white solid, MS: m/e = 324.2 (M+H ), using
chemistry similar to that described in Example 1, step 2 from (RS)(5-iodopyridinyl)-1,5,5-
trimethylpyrrolidinone and 1-ethynylfluoro-benzene.
Example 8
(RS)(5-((4-Fluorophenyl)ethynyl)pyrimidinyl)-1,5,5-trimethylpyrrolidinone
Step 1: 2-Chloro(4-fluoro-phenylethynyl)-pyrimidine
N Cl
A solution of 2-chloroiodopyrimidine (600 mg, 2.5 mmol), 1-ethynylfluorobenzene (330
mg, 2.75 mmol), triethylamine (556 mg, 761 µl, 5.49 mmol), and bis(triphenyl-
phosphine)palladium (II) chloride (175 mg, 250 µmol) in 7 ml of THF was purged with argon.
Then copper (I) iodide (23.8 mg, 125 µmol) was added and the reaction was heated for 2h at
room temperature. The dark solution was filtered and the solids were washed with THF. The
residue was taken up in ethyl acetate, adsorbed onto 3 g of silicagel which was loaded onto a 50
g prepacked flash chromatography column. After elution with a 0% to 20% ethyl acetate in
heptane gradient, the fractions containing the desired product were collected to yield 505 mg
(87%) of the title compound as an crystalline light yellow solid, MS: m/e = 233.1, 235.1 (M+H ).
Step 2: 3-[5-(4-Fluoro-phenylethynyl)-pyrimidinyl]-1,5,5-trimethyloxo-pyrrolidine
carboxylic acid benzyl ester
The title compound was obtained as a light yellow viscous oil, MS: m/e = 458.3 (M+H ), using
chemistry similar to that described in Example 5, step 2 from (RS)-1,5,5-trimethyloxo-
pyrrolidinecarboxylic acid benzyl ester (Example 5, step 1) and 2-chloro(4-fluoro-
phenylethynyl)-pyrimidine.
Step 3: (RS)(5-((4-Fluorophenyl)ethynyl)pyrimidinyl)-1,5,5-trimethylpyrrolidinone
The title compound was obtained as a white waxy solid, MS: m/e = 324.2 (M+H ), using
chemistry similar to that described in Example 6 from 3-[5-(4-fluoro-phenylethynyl)-pyrimidin-
2-yl]-1,5,5-trimethyloxo-pyrrolidinecarboxylic acid benzyl ester.
Example 9
(RS)(6-((3-Fluorophenyl)ethynyl)pyridazinyl)-1,5,5-trimethylpyrrolidinone
Step 1: 3-Chloro(3-fluoro-phenylethynyl)-pyridazine
N Cl
The title compound was obtained as a crystalline light yellow solid, MS: m/e = 233.1, 235.0
(M+H ), using chemistry similar to that described in Example 8, step 1 from 3-chloro
iodopyridazine and 1-ethynylfluorobenzene.
Step 2: (RS)[6-(3-Fluoro-phenylethynyl)-pyridazinyl]-1,5,5-trimethyloxo-pyrrolidine
carboxylic acid benzyl ester
The title compound was obtained as a yellow gum, MS: m/e = 458.3 (M+H ), using chemistry
similar to that described in Example 5, step 2 from (RS)-1,5,5-trimethyloxo-pyrrolidine
carboxylic acid benzyl ester (Example 5, step 1) and 3-chloro(3-fluoro-phenylethynyl)-
pyridazine.
Step 3: (RS)(6-((3-fluorophenyl)ethynyl)pyridazinyl)-1,5,5-trimethylpyrrolidinone
The title compound was obtained as a colorless viscous oil, MS: m/e = 324.2 (M+H ), using
chemistry similar to that described in Example 6 from (RS)[6-(3-fluoro-phenyl-ethynyl)-
pyridazinyl]-1,5,5-trimethyloxo-pyrrolidinecarboxylic acid benzyl ester.
Example 10
(RS)(6-((4-Fluorophenyl)ethynyl)pyridazinyl)-1,5,5-trimethylpyrrolidinone
Step 1: 3-Chloro(4-fluoro-phenylethynyl)-pyridazine
N Cl
The title compound was obtained as a crystalline light yellow solid, MS: m/e = 233.1, 235.1
(M+H ), using chemistry similar to that described in Example 8, step 1 from 3-chloro
iodopyridazine and 1-ethynylfluorobenzene.
Step 2: (RS)[6-(3-Fluoro-phenylethynyl)-pyridazinyl]-1,5,5-trimethyloxo-pyrrolidine
carboxylic acid benzyl ester
The title compound was obtained as a yellow viscous oil, MS: m/e = 458.3 (M+H ), using
chemistry similar to that described in Example 5, step 2 from (RS)-1,5,5-trimethyloxo-
pyrrolidinecarboxylic acid benzyl ester (example 5, step 1) and 3-chloro(4-fluoro-
phenylethynyl)-pyridazine.
Step 3: (RS)(6-((3-Fluorophenyl)ethynyl)pyridazinyl)-1,5,5-trimethylpyrrolidinone
The title compound was obtained as a colorless viscous oil, MS: m/e = 324.2 (M+H ), using
chemistry similar to that described in Example 6 from (RS)[6-(4-fluoro-phenyl-ethynyl)-
pyridazinyl]-1,5,5-trimethyloxo-pyrrolidinecarboxylic acid benzyl ester.
Example 11
(RS)(6-(Phenylethynyl)pyridazinyl)-1,5,5-trimethylpyrrolidinone
Step 1: 3-Chloro(phenylethynyl)-pyridazine
N Cl
The title compound was obtained as a crystalline light yellow solid, MS: m/e = 215.2, 217.2
(M+H ), using chemistry similar to that described in Example 8, step 1 from 3-chloro
iodopyridazine and 1-ethynyl-benzene.
Step 2: (RS)[6-(Phenylethynyl)-pyridazinyl]-1,5,5-trimethyloxo-pyrrolidine
carboxylic acid benzyl ester
The title compound was obtained as a light yellow oil, MS: m/e = 440.2 (M+H ), using
chemistry similar to that described in Example 5, step 2 from (RS)-1,5,5-trimethyloxo-
pyrrolidinecarboxylic acid benzyl ester (Example 5, step 1) and 3-chloro(phenylethynyl)-
pyridazine.
Step 3: (RS)(6-(Phenylethynyl)pyridazinyl)-1,5,5-trimethylpyrrolidinone
The title compound was obtained as a yellow waxy solid, MS: m/e = 306.3 (M+H ), using
chemistry similar to that described in Example 6 from (RS)[6-(phenylethynyl)-pyridazin
yl]-1,5,5-trimethyloxo-pyrrolidinecarboxylic acid benzyl ester.
Example 12
(RS)-1,6,6-Trimethyl(5-(phenylethynyl)pyridinyl)piperidinone
Step 1: 3 to 1 Mixture of 6,6-dimethyl-piperidinone and 3,3-dimethyl-piperidinone:
To 9.97 g (88.9 mmol) of 2,2,-dimethylcyclopentanone were added 70 ml of 98% formic acid
with stirring. To this clear solution was added 15.1 g (133 mmol) of hydroxylamine-O-sulfonic
acid in portions, maintaining the temeprature between 15-20°C using an ice-bath. After stirring
for 5 min the white suspension became a clear solution. The mixture was then refluxed for 4h
(100°C) and allowed to cool overnight. The resulting yellow solution was concentrated in
vaccuo. The light orange resinous residue was taken up in 30 ml of water, 40 ml of 1N sodium
hydroxide solution and 100 ml of chloroform and vigourously stirred until dissolution was
complete. The pH of the aqueous phase was adjusted to 8 by addition of 25% NaOH solution.
The organic phase was separated. The aqueous phase was extracted five times with 30 ml of
chloroform. The combined organic phases were washed with 10 ml of water. The combined
organic phases were concentrated in vaccuo to yield 9.9 g of a light orange semi-solid which was
purified by chromatography over silicagel (ethyl acetate/methanol 9:1). Fractions containing the
two isomers were collected to yield 4.72 g (41.8%) of a white solid which was directly used in
the next step.
Step 2: 1,6,6-Trimethyl-piperidinone
To a solution of a 3 to 1 mixture of 3,3-dimethylpiperidinone and 6,6-dimethylpiperidinone
(4.72 g, 37.1 mmol) in 60ml of THF was added 60% sodium hydride suspension (1.93g, 48.2
mmol). The grey reaction mixture was stirred at room temperature for 30 minutes. Then methyl
iodide (3.02 ml, 48.2 mmol) was added and the reaction mixture was stirred at room temperature
overnight. The reaction mixture was quenched with water, and worked up with ethyl
acetate/water. The orange oil was chromatographed over a prepacked 70g silica column After
elution with a 50% to 100% ethyl acetate in heptane gradient, the fractions containing the desired
product were collected to yield 2.46 g (47%) of the title compound as a light yellow solid; and
0.91 g (17%) of isomeric 1,3,3-trimethyl-piperidinone as a yellow oil.
Step 2: (RS)Iodo-1',6',6'-trimethyl-3',4',5',6'-tetrahydro-1'H-[2,3']bipyridinyl-2'-one
The title compound was obtained as a colorless viscous oil, MS: m/e = 345.1 (M+H ), using
chemistry similar to that described in Example 1, step 1 from 1,6,6-trimethyl-piperidinone and
2-fluoroiodopyridine.
Step 3: 5 (RS)-1,6,6-Trimethyl(5-(phenylethynyl)pyridinyl)piperidinone
The title compound was obtained as a light yellow viscous oil, MS: m/e = 319.2 (M+H ), using
chemistry similar to that described in Example 1, step 2 from (RS)iodo-1',6',6'-trimethyl-
3',4',5',6'-tetrahydro-1'H-[2,3']bipyridinyl-2'-one and 3-ethynyl-pyridine.
Example 13
(RS)(5-((3-Fluorophenyl)ethynyl)pyridinyl)-1,6,6-trimethylpiperidinone
The title compound was obtained as a light yellow viscous oil, MS: m/e = 337.2 (M+H ), using
chemistry similar to that described in Example 1, step 2 from (RS)iodo-1',6',6'-trimethyl-
3',4',5',6'-tetrahydro-1'H-[2,3']bipyridinyl-2'-one and 1-ethynylfluoro-benzene.
Example 14
(RS)(5-((4-Fluorophenyl)ethynyl)pyridinyl)-1,6,6-trimethylpiperidinone
The title compound was obtained as a light yellow waxy solid, MS: m/e = 337.2 (M+H ), using
chemistry similar to that described in Example 1, step 2 from (RS)iodo-1',6',6'-trimethyl-
3',4',5',6'-tetrahydro-1'H-[2,3']bipyridinyl-2'-one and 1-ethynylfluoro-benzene.
Example 15
(RS)-1,6,6-Trimethyl(5-(phenylethynyl)pyrimidinyl)piperidinone
Step 1: (RS)-1,6,6-Trimethyloxo-piperidinecarboxylic acid benzyl ester
The title compound was obtained as a light yellow oil, using chemistry similar to that described
in Example 5, step 1 from 1,6,6-trimethyl-piperidinone and dibenzyl carbonate.
Step 2: (RS)-1,6,6-Trimethyloxo(5-phenylethynyl-pyrimidinyl)-piperidine
carboxylic acid benzyl ester
The title compound was obtained as a yellow oil, using chemistry similar to that described in
Example 5, step 2 from (RS)-1,6,6-trimethyloxo-piperidinecarboxylic acid benzyl ester and
2-chloro(phenylethynyl)pyrimidine (CAS: [10513889]).
Step 3: (RS)-1,6,6-Trimethyl(5-(phenylethynyl)pyrimidinyl)piperidinone
The title compound was obtained as a light yellow solid, MS: m/e = 320.2 (M+H ), using
chemistry similar to that described in Example 6 from (RS)-1,6,6-trimethyloxo(5-
phenylethynyl-pyrimidinyl)-piperidinecarboxylic acid benzyl ester.
Example 16
(RS)(5-((4-Fluorophenyl)ethynyl)pyrimidinyl)-1,6,6-trimethylpiperidinone
Step 1: (RS)-1,6,6-Trimethyloxo(5-((4-fluorophenyl)ethynyl)-pyrimidinyl)-piperidine-
3-carboxylic acid benzyl ester
The title compound was obtained as an orange oil, using chemistry similar to that described in
Example 5, step 2 from (RS)-1,6,6-trimethyloxo-piperidinecarboxylic acid benzyl ester and
2-chloro(4-fluoro-phenylethynyl)-pyrimidine (Example 8, step 1).
Step 2: (RS)(5-((4-Fluorophenyl)ethynyl)pyrimidinyl)-1,6,6-trimethylpiperidinone
The title compound was obtained as an off-white solid, MS: m/e = 338.2 (M+H ), using
chemistry similar to that described in Example 6 from (RS)-1,6,6-trimethyloxo(5-((4-
fluorophenyl)ethynyl)-pyrimidinyl)-piperidinecarboxylic acid benzyl ester.
Example 17
(RS)(5-((3-Fluorophenyl)ethynyl)pyrimidinyl)-1,6,6-trimethylpiperidinone
Step 1: 2-Chloro(3-fluoro-phenylethynyl)-pyrimidine
N Cl
The title compound was obtained as a yellow solid, MS: m/e = 233.0, 234.9 (M+H ), using
chemistry similar to that described in Example 8, step 1 from 2-chloroiodopyrimidine and 1-
ethynylfluorobenzene.
Step 2: (RS)-1,6,6-Trimethyloxo(5-((3-fluorophenyl)ethynyl)-pyrimidinyl)-piperidine-
3-carboxylic acid benzyl ester
The title compound was obtained as a yellow oil, using chemistry similar to that described in
example 5, step 2 from (RS)-1,6,6-trimethyloxo-piperidinecarboxylic acid benzyl ester and
2-chloro(3-fluoro-phenylethynyl)-pyrimidine (Example 8, step 1).
Step 3: (RS)(5-((4-Fluorophenyl)ethynyl)pyrimidinyl)-1,6,6-trimethylpiperidinone
The title compound was obtained as a light brown solid, MS: m/e = 338.2 (M+H ), using
chemistry similar to that described in Example 6 from (RS)-1,6,6-trimethyloxo(5-((3-
fluorophenyl)ethynyl)-pyrimidinyl)-piperidinecarboxylic acid benzyl ester.
Example 18
(RS)Hydroxy-1,5,5-trimethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone
The title compound was obtained as byproduct in the synthesis of Example 1 as a light brown
oil, MS: m/e = 321.2 (M+H ).
Example 19
(RS)Methoxy-1,5,5-trimethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone
The title compound was obtained as a light yellow oil, MS: m/e = 335.2 (M+H ), using
chemistry similar to that described in Example 12, step 2 from (RS)hydroxy-1,5,5-trimethyl-
3-(5-(phenylethynyl)pyridinyl)pyrrolidinone (Example 18) and iodomethane.
Example 20
(RS)-1,3,5,5-Tetramethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone
Step 1: (RS)(5-Iodo-pyridinyl)-1,3,5,5-tetramethyl-pyrrolidinone
The title compound was obtained as a white solid, MS: m/e = 345.0 (M+H ), using chemistry
similar to that described in Example 12, step 2 from (RS)(5-iodo-pyridinyl)-1,5,5-
trimethyl-pyrrolidinone (Example 1, step 1) and iodomethane.
Step 2: (RS)-1,3,5,5-Tetramethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone
The title compound was obtained as a light brown oil, MS: m/e = 319.1 (M+H ), using chemistry
similar to that described in Example 1, step 2 from (RS)(5-iodo-pyridinyl)-1,3,5,5-
tetramethyl-pyrrolidinone (Example 20, step 1) and phenylacetylene.
Example 21
(RS)(3-fluoro((3-fluorophenyl)ethynyl)pyridinyl)-1,5,5-trimethylpyrrolidinone
Step 1: (RS)(3-Fluoroiodo-pyridinyl)-1,5,5-trimethyl-pyrrolidinone
The title compound was obtained as a light brown solid, MS: m/e = 349.0 (M+H ), using
chemistry similar to that described in Example 1, step 1 from 2,3-difluoroiodopyridine and
1,5,5-trimethyl-pyrrolidinone.
Step 2: (RS)(3-fluoro((3-fluorophenyl)ethynyl)pyridinyl)-1,5,5-trimethylpyrrolidin
The title compound was obtained as a light brown oil, MS: m/e = 319.1 (M+H ), using chemistry
similar to that described in example 1, step 2 from (RS)(3-fluoroiodo-pyridinyl)-1,5,5-
trimethyl-pyrrolidinone (Example 21, step 1) and 1-ethynylfluorobenzene.
Example 22
(RS)Methyl(5-phenylethynyl-pyridinyl)-azepanone
Step 1: (RS)(5-Iodo-pyridinyl)methyl-azepanone
The title compound was obtained as a light yellow solid, MS: m/e = 331.0 (M+H ), using
chemistry similar to that described in Example 1, step 1 from 2-fluoroiodopyridine and 1-
methyl-azepanone.
Step 2: (RS)Methyl(5-phenylethynyl-pyridinyl)-azepanone
The title compound was obtained as an orange solid, MS: m/e = 305.1 (M+H ), using chemistry
similar to that described in example 1, step 2 from (RS)(5-iodo-pyridinyl)methyl-
azepanone (Example 22, step 1) and phenylacetylene.
Example 23
(RS)[5-(4-Fluoro-phenylethynyl)-pyridinyl]methyl-azepanone
The title compound was obtained as a light yellow solid, MS: m/e = 323.1 (M+H ), using
chemistry similar to that described in example 1, step 2 from (RS)(5-iodo-pyridinyl)
methyl-azepanone (Example 22, step 1) and 1-ethynylfluoro-benzene.
Example 24
(RS)[5-(3-Fluoro-phenylethynyl)-pyridinyl]methyl-azepanone
The title compound was obtained as a light brown solid, MS: m/e = 323.1 (M+H ), using
chemistry similar to that described in example 1, step 2 from (RS)(5-iodo-pyridinyl)
methyl-azepanone (Example 22, step 1) and 1-ethynylfluoro-benzene.
Example 25
(S or R)Methyl(5-phenylethynyl-pyridinyl)-azepanone
Chiral Chiral
The title compound, a light yellow oil, MS: m/e = 305.1 (M+H ), was prepared by separation of
(RS)methyl(5-phenylethynyl-pyridinyl)-azepanone (Example 22) using a chiral
column (Reprosil Chiral NR with heptane:ethanol 60:40 as solvent).
Example 26
(R or S)Methyl(5-phenylethynyl-pyridinyl)-azepanone
Chiral Chiral
O or O
The title compound, a light yellow oil, MS: m/e = 305.1 (M+H ), was prepared by separation of
(RS)methyl(5-phenylethynyl-pyridinyl)-azepanone (Example 22) using a chiral
column (Reprosil Chiral NR with heptane:ethanol 60:40 as solvent).
Example 27
(3RS,3aSR,6aSR)Methyl(5-phenylethynyl-pyridinyl)-hexahydro-
cyclopenta[b]pyrrolone
Step 1: (3RS,3aSR,6aSR)(5-Iodo-pyridinyl)methyl-hexahydro-cyclopenta[b]pyrrol
The title compound was obtained as a yellow oil, MS: m/e = 342.9 (M+H ), using chemistry
similar to that described in Example 1, step 1 from 2-fluoroiodopyridine and cismethyl-
hexahydro-cyclopenta[b]pyrrolone (CAS 1696886).
Step 2: (3RS,3aSR,6aSR)Methyl(5-phenylethynyl-pyridinyl)-hexahydro-
cyclopenta[b]pyrrolone
The title compound was obtained as a brown oil, MS: m/e = 317.1 (M+H ), using chemistry
similar to that described in example 1, step 2 from (3RS,3aSR,6aSR)(5-iodo-pyridinyl)
methyl-hexahydro-cyclopenta[b]pyrrolone (Example 27, step 1) and phenylacetylene.
Example 28
(3R,3aS,6aS) or (3S,3aR,6aR)Methyl(5-phenylethynyl-pyridinyl)-hexahydro-
cyclopenta[b]pyrrolone
Chiral Chiral
The title compound, a light yellow oil, MS: m/e = 317.1 (M+H ), was prepared by separation of
(3RS,3aSR,6aSR)methyl(5-phenylethynyl-pyridinyl)-hexahydro-cyclopenta[b]pyrrol
one (Example 27) using a chiral column (Chiralpak AD with heptane:isopropanol 60:40 as
solvent).
Example 29
(3RS,3aSR,6aSR)[5-(4-Fluoro-phenylethynyl)-pyridinyl]methyl-hexahydro-
cyclopenta[b]pyrrolone
The title compound was obtained as a light brown oil, MS: m/e = 335.1 (M+H ), using chemistry
similar to that described in example 1, step 2 from (3RS,3aSR,6aSR)(5-iodo-pyridinyl)
methyl-hexahydro-cyclopenta[b]pyrrolone (Example 27, step 1) and 1-ethynylfluoro-
benzene.
Example 30
(3RS,3aSR,6aSR)[5-(3-Fluoro-phenylethynyl)-pyridinyl]methyl-hexahydro-
cyclopenta[b]pyrrolone
The title compound was obtained as a light brown oil, MS: m/e = 335.1 (M+H ), using chemistry
similar to that described in example 1, step 2 from (3RS,3aSR,6aSR)(5-iodo-pyridinyl)
methyl-hexahydro-cyclopenta[b]pyrrolone (Example 27, step 1) and 1-ethynylfluoro-
benzene.
Example 31
(3R,3aS,6aS) or (3S,3aR,6aR)[5-(3-Fluoro-phenylethynyl)-pyridinyl]methyl-
hexahydro-cyclopenta[b]pyrrolone
Chiral
Chiral
or H
The title compound, a light yellow oil, MS: m/e = 335.1 (M+H ), was prepared by separation of
(3RS,3aSR,6aSR)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-hexahydro-
cyclopenta[b]pyrrolone (Example 30) using a chiral column (Reprosil Chiral NR with
heptane:ethanol 60:40 as solvent).
Example 32
(3S,3aR,6aR) or (3R,3aS,6aS)[5-(3-Fluoro-phenylethynyl)-pyridinyl]methyl-
hexahydro-cyclopenta[b]pyrrolone
Chiral Chiral
or H
The title compound, a light yellow oil, MS: m/e = 335.1 (M+H ), was prepared by separation of
(3RS,3aSR,6aSR)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-hexahydro-
cyclopenta[b]pyrrolone (Example 30) using a chiral column (Reprosil Chiral NR with
heptane:ethanol 60:40 as solvent).
Example 33
(3RS,3aSR,6aSR)Methyl(5-phenylethynyl-pyrimidinyl)-hexahydro-
cyclopenta[b]pyrrolone
The title compound was obtained as a white solid, MS: m/e = 318.1 (M+H ), using chemistry
similar to that described in example 5 and example 6 starting from cismethyl-hexahydro-
cyclopenta[b]pyrrolone (CAS 1696886) instead of 5,5-dimethylpyrrolidinone.
Examples 34 and 35
(3RS,6SR,7SR)Methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone and
(3SR,6SR,7SR)Methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone
Step 1: 7:1-mixture of (3RS,5SR,6SR)(5-Iodo-pyridinyl)methyl-octahydro-indolone
and (3SR,5SR,6SR)(5-Iodo-pyridinyl)methyl-octahydro-indolone
The title compound mixture was obtained as a yellow solid, MS: m/e = 357.1 (M+H ), using
chemistry similar to that described in Example 1, step 1 from 2-fluoroiodopyridine and
racemic cis-octahydromethyl-2H-indolone (CAS 1167251).
Step 2: (3RS,6SR,7SR)Methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone and
(3SR,6SR,7SR)Methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone
The title compound (3RS,6SR,7SR)methyl(5-phenylethynyl-pyridinyl)-octahydro-indol-
2-one (147 mg, major isomer, exo-adduct) was obtained as a light brown solid, MS: m/e = 331.2
(M+H ), and the minor isomer (3SR,6SR,7SR)methyl(5-phenylethynyl-pyridinyl)-
octahydro-indolone (22 mg) was obtained as a brown gum, MS: m/e = 331.2 (M+H ), using
chemistry similar to that described in example 1, step 2 from a 7:1-mixture of (3RS,6SR,7SR)
(5-iodo-pyridinyl)methyl-octahydro-indolone and (3SR,6SR,7SR)(5-iodo-pyridin
yl)methyl-octahydro-indol-2one (Example 34, step 1) and phenylacetylene.
Example 36 and 37
(3R,6S,7S)Methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone and
(3S,6R,7R)Methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone
(3R,6S,7S)Methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone (56 mg, colorless
gum), MS: m/e = 331.2 (M+H ), and (3S,6R,7R)methyl(5-phenylethynyl-pyridinyl)-
octahydro-indolone, (62 mg, light yellow gum), MS: m/e = 331.2 (M+H ), were prepared by
separation of racemic (3RS,3aSR,7aSR)methyl(5-phenylethynyl-pyridinyl)-octahydro-
indolone (Example 34) using a chiral column (Reprosil Chiral NR with heptane:ethanol 80:20
as solvent).
Examples 38 and 39
(3RS,6SR,7SR)[5-(3-Fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indol
one and (3SR,6SR,7SR)[5-(3-Fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-
indolone
The title compound (3RS,6SR,7SR)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-
octahydro-indolone (187 mg, major isomer, exo-adduct) was obtained as a yellow oil, MS:
m/e = 349.3 (M+H ), and the minor isomer (3SR,6SR,7SR)[5-(3-fluoro-phenylethynyl)-
pyridinyl]methyl-octahydro-indolone (25 mg) was obtained as a light brown gum, MS:
m/e = 349.3 (M+H ), using chemistry similar to that described in example 34 and 35, step 2 from
a 7:1-mixture of (3RS,3aSR,7aSR)(5-iodo-pyridinyl)methyl-octahydro-indolone and
(3SR,3aSR,7aSR)(5-iodo-pyridinyl)methyl-octahydro-indol-2one (Example 34, step 1)
and 3-fluorophenylacetylene.
Example 40 and 41
(3R,6S,7S)[5-(3-Fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone
and (3S,6R,7R)[5-(3-Fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indol
(3R,6S,7S)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone (66 mg,
colorless gum), MS: m/e = 349.3 (M+H ), (3S,6R,7R)[5-(3-fluoro-phenylethynyl)-pyridin
yl]methyl-octahydro-indolone (63 mg, colorless gum), MS: m/e = 349.3 (M+H ), were
prepared by separation of racemic (3RS,6SR,7SR)[5-(3-fluoro-phenylethynyl)-pyridinyl]-
1-methyl-octahydro-indolone (Example 38) using a chiral column (Reprosil Chiral NR with
heptane:ethanol 60:40 as solvent).
Example 42 and 43
(3R,6S,7S)[5-(4-Fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone
and (3S,6R,7R)[5-(4-Fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indol
Step 1: (3RS,6SR,7SR)[5-(4-Fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indol-
2-one§
The title compound, racemic (3RS,6SR,7SR)[5-(4-fluoro-phenylethynyl)-pyridinyl]
methyl-octahydro-indolone (189 mg, major isomer, exo-adduct) was obtained as a light brown
oil, MS: m/e = 349.3 (M+H ), using chemistry similar to that described in example 34, step 2
from a 7:1-mixture of (3RS,3aSR,7aSR)(5-iodo-pyridinyl)methyl-octahydro-indol
one and (3SR,3aSR,7aSR)(5-iodo-pyridinyl)methyl-octahydro-indol-2one (Example 34,
step 1) and 4-fluorophenylacetylene. The minor isomer was not isolated.
(3R,6S,7S)[5-(4-Fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone (78
mg, light yellow gum), MS: m/e = 349.3 (M+H ), (3S,6R,7R)[5-(4-fluoro-phenylethynyl)-
pyridinyl]methyl-octahydro-indolone (75 mg, light yellow gum), MS: m/e = 349.3
(M+H ), were prepared by separation of racemic (3RS,6SR,7SR)[5-(4-fluoro-phenylethynyl)-
pyridinyl]methyl-octahydro-indolone (Example 42) using a chiral column (Reprosil
Chiral NR with heptane:ethanol 60:40 as solvent).
Example 44
(RS)[5-(2-Chloro-pyridinylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrrolidinone
The title compound was obtained as a light yellow oil, MS: m/e = 340.3/342.4 (M+H ), using
chemistry similar to that described in Example 1, step 2 from (RS)(5-iodopyridinyl)-1,5,5-
trimethylpyrrolidinone (Example 1, step 1) and 2-chloroethynyl-pyridine (CAS 945717
Example 45
(S) or (R)[5-(2-Chloro-pyridinylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrrolidin
one
Chiral Chiral
O or
The title compound, a yellow solid, MS: m/e = 340.4/342.4 (M+H ), was prepared by separation
of (RS)[5-(2-chloro-pyridinylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrrolidinone
(Example 44) using a chiral column (Chiralpak AD with heptane:isopropanol 60:40 as solvent).
Example 46
(R) or (S)[5-(2-Chloro-pyridinylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrrolidin
Chiral Chiral
or O
The title compound, a light yellow solid, MS: m/e = 340.4/342.4 (M+H ), was prepared by
separation of (RS)[5-(2-chloro-pyridinylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrrolidin-
2-one (Example 44) using a chiral column (Chiralpak AD with heptane:isopropanol 60:40 as
solvent).
Claims (18)
1. A compound of formula 6 () wherein 5 X is N or C-R, wherein R is hydrogen or halogen; G is N or CH; with the proviso that maximum one of G or X can be nitrogen; R is phenyl or pyridinyl, which are optionally substituted by halogen; R is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl; 3 3’ 4 4’ 6 6’ 10 R ,R , R , R , R , R are independently from each other hydrogen or lower alkyl; or R and R may form together with the carbon atom to which they are attached a C -cycloalkyl ring, if m is 0 and n is 1 or 2; R is hydrogen or lower alkyl; n is 0, 1 or 2; 15 m is 0 or 1; with the proviso that n and m are not simultaneously 0; or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
2. A compound of formula IA according to claim 1, 6' R 20 IA wherein R is phenyl or pyridinyl, which are optionally substituted by halogen; R is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl; 4 4’ 6 6’ R , R , R , R are independently from each other hydrogen or lower alkyl; or R and R may form together with the carbon atom to which they are attached a C -cycloalkyl ring; 5 R is hydrogen or lower alkyl; or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
3. A compound of formula IA according to any one of claims 1 or 2, which compounds 10 are (RS)-1,5,5-trimethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone (RS)-1,5,5-trimethyl(5-(pyridinylethynyl)pyridinyl)pyrrolidinone (RS)(5-((3-chlorophenyl)ethynyl)pyridinyl)-1,5,5-trimethylpyrrolidinone (RS)(5-((3-fluorophenyl)ethynyl)pyridinyl)-1,5,5-trimethylpyrrolidinone 15 (RS)hydroxy-1,5,5-trimethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone (RS)methoxy-1,5,5-trimethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone (RS)-1,3,5,5-tetramethyl(5-(phenylethynyl)pyridinyl)pyrrolidinone (3RS,3aSR,6aSR)methyl(5-phenylethynyl-pyridinyl)-hexahydro-cyclopenta[b]pyrrol 20 (3R,3aS,6aS) or (3S,3aR,6aR)methyl(5-phenylethynyl-pyridinyl)-hexahydro- cyclopenta[b]pyrrolone (3RS,3aSR,6aSR)[5-(4-fluoro-phenylethynyl)-pyridinyl]methyl-hexahydro- cyclopenta[b]pyrrolone (3RS,3aSR,6aSR)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-hexahydro- 25 cyclopenta[b]pyrrolone (3R,3aS,6aS) or (3S,3aR,6aR)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-hexahydro- cyclopenta[b]pyrrolone (3S,3aR,6aR) or (3R,3aS,6aS)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-hexahydro- cyclopenta[b]pyrrolone 30 (3RS,6SR,7SR)methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone (3SR,6SR,7SR)methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone (3R,6S,7S)methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone and (3S,6R,7R) Methyl(5-phenylethynyl-pyridinyl)-octahydro-indolone (3RS,6SR,7SR)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone (3SR,6SR,7SR)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone (3R,6S,7S)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone (3S,6R,7R)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone 5 (3R,6S,7S)[5-(4-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone (3S,6R,7R)[5-(4-fluoro-phenylethynyl)-pyridinyl]methyl-octahydro-indolone (RS)[5-(2-chloro-pyridinylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrrolidinone (S) or (R)[5-(2-chloro-pyridinylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrrolidinone or (R) or (S)[5-(2-chloro-pyridinylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrrolidinone. 10 4. A compound of formula IB according to claim 1 wherein X is N or C-R, wherein R is halogen; R is phenyl or pyridinyl, which are optionally substituted by halogen; 15 R is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl;
4 4’ 6 6’ R , R , R , R are independently from each other hydrogen or lower alkyl; or R and R may form together with the carbon atom to which they are attached a C -cycloalkyl ring,; R is hydrogen or lower alkyl; 20 or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
5. A compound of formula IB according to any one of claims 1 or 4, which compounds are 25 (RS)-benzyl 1,5,5-trimethyloxo(5-(phenylethynyl)pyrimidinyl)pyrrolidine carboxylate (RS)-1,5,5-trimethyl(5-(phenylethynyl)pyrimidinyl)pyrrolidinone (RS)(5-((3-fluorophenyl)ethynyl)pyrimidinyl)-1,5,5-trimethylpyrrolidinone (RS)(5-((4-fluorophenyl)ethynyl)pyrimidinyl)-1,5,5-trimethylpyrrolidinone or (3RS,3aSR,6aSR)methyl(5-phenylethynyl-pyrimidinyl)-hexahydro-cyclopenta[b]pyrrol- 2-one. 5
6. A compound of formula IC according to claim 1 wherein R is phenyl or pyridinyl, which are optionally substituted by halogen; R is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl; 4 4’ 6 6’ 10 R , R , R , R are independently from each other hydrogen or lower alkyl; or R and R may form together with the carbon atom to which they are attached a C -cycloalkyl ring; R is hydrogen or lower alkyl; or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding 15 enantiomer and/or optical isomer and/or stereoisomer thereof.
7. A compound of formula IC according to any one of claims 1 or 6, wherein the compounds are (RS)(6-((3-fluorophenyl)ethynyl)pyridazinyl)-1,5,5-trimethylpyrrolidinone 20 (RS)(6-((4-fluorophenyl)ethynyl)pyridazinyl)-1,5,5-trimethylpyrrolidinone or (RS)(6-(phenylethynyl)pyridazinyl)-1,5,5-trimethylpyrrolidinone.
8. A compound of formula ID according to claim 1 6 R 4 6' n wherein R is phenyl or pyridinyl, which are optionally substituted by halogen; R is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl; 3 3’ 4 4’ 6 6’ 5 R ,R , R , R , R , R are independently from each other hydrogen or lower alkyl; R is hydrogen or lower alkyl; n is 1 or 2; or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
9. A compound of formula ID according to any one of claims 1 or 8, wherein the compounds are (RS)-1,6,6-trimethyl(5-(phenylethynyl)pyridinyl)piperidinone (RS)(5-((3-fluorophenyl)ethynyl)pyridinyl)-1,6,6-trimethylpiperidinone 15 (RS)(5-((4-fluorophenyl)ethynyl)pyridinyl)-1,6,6-trimethylpiperidinone (RS)methyl(5-phenylethynyl-pyridinyl)-azepanone (RS)[5-(4-fluoro-phenylethynyl)-pyridinyl]methyl-azepanone (RS)[5-(3-fluoro-phenylethynyl)-pyridinyl]methyl-azepanone (S or R)methyl(5-phenylethynyl-pyridinyl)-azepanone or 20 (R or S)methyl(5-phenylethynyl-pyridinyl)-azepanone.
10. A compound of formula IE according to claim 1 6' 4' wherein R is phenyl or pyridinyl, which are optionally substituted by halogen; R is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl; 3 3’ 4 4’ 6 6’ 5 R ,R , R , R , R , R are independently from each other hydrogen or lower alkyl; R is hydrogen or lower alkyl; or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof. 10
11. A compound of formula IE according to any one of claims 1 or 10, which compounds are (RS)-1,6,6-trimethyl(5-(phenylethynyl)pyrimidinyl)piperidinone (RS)(5-((4-fluorophenyl)ethynyl)pyrimidinyl)-1,6,6-trimethylpiperidinone or (RS)(5-((3-fluorophenyl)ethynyl)pyrimidinyl)-1,6,6-trimethylpiperidinone.
12. A process for preparation of a compound of formula I as described in any one of claims 1 - 11, comprising: a) reacting a compound of formula 20 wherein X is halogen, with a compound of formula in the presence of Bis-(tpp)-Pd(II)Cl , Et N, TPP, CuI and THF or DMF at 70°C, to a compound of formula wherein the definitions are as described in claim 1.
13. A compound according to any one of claim 1 -11, whenever prepared by a process as claimed in claim 12.
14. A compound according to any one of claims 1 –11 for use as therapeutically active substance.
15. A pharmaceutical composition comprising a compound in accordance with any one of 15 claims 1 –11 and a therapeutically active carrier.
16. The use of a compound as claimed in any one of claims 1-11 for the manufacture of a medicament for the treatment of schizophrenia or cognitive diseases. 20
17. A compound according to any one of claims 1 –11 for the treatment of schizophrenia or cognitive diseases.
18. A pharmaceutical composition according to claim 15 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP11163683.3 | 2011-04-26 | ||
EP11163683 | 2011-04-26 | ||
PCT/EP2012/057335 WO2012146551A1 (en) | 2011-04-26 | 2012-04-23 | Ethynyl derivatives as positive allosteric modulators of the mglur5 |
Publications (2)
Publication Number | Publication Date |
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NZ614688A NZ614688A (en) | 2015-09-25 |
NZ614688B2 true NZ614688B2 (en) | 2016-01-06 |
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