NZ734071B - Heterocyclylalkyne derivatives and their use as modulators of mglur5 receptors - Google Patents
Heterocyclylalkyne derivatives and their use as modulators of mglur5 receptorsInfo
- Publication number
- NZ734071B NZ734071B NZ734071A NZ73407115A NZ734071B NZ 734071 B NZ734071 B NZ 734071B NZ 734071 A NZ734071 A NZ 734071A NZ 73407115 A NZ73407115 A NZ 73407115A NZ 734071 B NZ734071 B NZ 734071B
- Authority
- NZ
- New Zealand
- Prior art keywords
- group
- optionally substituted
- alkyl
- tricyclic
- acid
- Prior art date
Links
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- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000002633 protecting Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 230000027425 release of sequestered calcium ion into cytosol Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000000717 retained Effects 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229940116353 sebacic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000021317 sensory perception Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(E)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N stearylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000005338 substituted cycloalkoxy group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000000152 swallowing Effects 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 239000000979 synthetic dye Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 108010032623 tetracycline resistance-encoding transposon repressor protein Proteins 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229930003799 tocopherols Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N α-Ketoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N β-D-glucuronic acid Chemical class O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Abstract
This invention relates to compounds of formula (I), their use as allosteric modulators of mGluR5 receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for the treatment and/or prevention of neurological and psychiatric disorders associated with glutamate dysfunction, such as schizophrenia or cognitive decline, dementia or cognitive impairment, or other pathologies that can be related directly or indirectly to glutamate dysfunction. lutamate dysfunction, such as schizophrenia or cognitive decline, dementia or cognitive impairment, or other pathologies that can be related directly or indirectly to glutamate dysfunction.
Description
HETEROCYCLYLALKYNE DERIVATIVES AND THEIR USE AS MODULATORS
OF mGluR5 RECEPTORS
FIELD OF THE INVENTION
This invention relates to heterocyclylalkynes and their use as allosteric
modulators of mGluR5 receptor activity, pharmaceutical compositions comprising such
compounds, and methods of treatment therewith. Compounds of the invention can be used
for the treatment and/or prevention of neurological and psychiatric disorders associated with
glutamate dysfunction such as schizophrenia or cognitive decline, dementia or cognitive
impairment, or other pathologies that can be related either directly or indirectly to glutamate
dysfunction.
BACKGROUND TO THE INVENTION
Glutamate is the primary excitatory amino acid in the mammalian central nervous
system. Neurotransmission mediated by glutamate has been demonstrated to be critical in
many physiological processes, such as synaptic plasticity, long term potentiation involved in
both learning and memory as well as sensory perception (Riedel et al., Behav. Brain Res.
(2003), Vol.140, pp.1-47, in review). Furthermore, it has been demonstrated that an
imbalance of glutamate neurotransmission plays a critical role in the pathophysiology of
various neurological and psychiatric diseases.
The excitatory neurotransmission of glutamate is mediated through at least two
different classes of receptors: ionotropic glutamate receptors such as the N-methyl-D-
aspartate receptor (NMDA), α-aminohydroxymethylisoxazolepropionic acid
receptor (AMPA) or kainate; and the metabotropic glutamate receptors (mGluR). The
ionotropic receptors are ligand gated ion channels and are thought to be responsible for
regulating the rapid neuronal transmission between two neurons. The metabotropic
glutamate receptors are G-protein coupled receptors (GPCRs) which appear to mediate not
only synaptic transmission, but also to regulate the extent of neurotransmitter release as well
as post synaptic receptor activation.
Dysregulation in glutamatergic neurotransmission, for example through altered
glutamate release or post-synaptic receptor activation, has been demonstrated in a variety of
neurological as well as psychiatric disorders. Hypofunction of the NMDA receptor has not
only been demonstrated in Alzheimer's patients, but is increasingly accepted as the putative
cause of schizophrenia (Farber et al., Prog. Brain Res., (1998), Vol.116, pp.421-437, Coyle
et al., Cell. and Mol. Neurobiol., (2006), Vol.26, pp.365-384). This is supported by clinical
studies showing that antagonists of the NMDA receptor induce symptoms indistinguishable
to those suffered by schizophrenia patients (Javitt et al., Am J. Psychiatry, (1991), Vol.148,
pp. 1301-1308; Meltzer HY, Biol. Psychiatry, (1999), Vol.46(10), pp.1321-1327).
Therefore, approaches that could potentiate or normalize NMDA receptor signaling have the
potential to treat neurological and psychiatric disorders. mGluR5, a G protein-coupled
receptor that is encoded by the GRM5 gene, belongs to a superfamily of currently eight
identified Type III GPCRs, which are unique in that the glutamate ligand binds to a large
extracellular amino-terminal protein domain.
This superfamily is further divided into three groups (Groups I, II and III) based
on amino acid homology as well as the intracellular signalling cascades they regulate
(Schoepp et al., Neuropharma, (1999), Vol.38, pp.1431-1476) and pharmacological profile.
mGluR5 belongs to Group I and is coupled to the phospholipase C signalling cascade which
regulates intracellular calcium mobilization.
In the central nervous system (CNS), mGluR5 has been demonstrated to be
expressed mainly in the cortex, hippocampus, nucleus accumbens and the caudate-putamen.
These brain regions are known to be involved in memory formation and cognitive function as
well as emotional response. mGluR5 has been shown to be localized post-synaptically,
adjacent to the post-synaptic density (Lujan et al., Eur. J. Neurosci. (1996), Vol.8, pp.1488-
1500). A functional interaction between mGluR5 and the NMDA receptor has also been
demonstrated, where activation of mGluR5 potentiates the activation state of the NMDA
receptor (Mannaioni et al., NeuroSci., (2001), Vol.21, pp.5925-5924, Rosenbrock et al., Eur.
J. Pharma., (2010), Vol.639, pp.40-46). Furthermore, activation of mGluR5 has been
demonstrated in pre-clinical in vivo models to rescue cognitive impairment as well as
psychotic disturbance induced by NMDA receptor antagonists (Chan et al., Psychopharma.
(2008), Vol.198, pp.141-148). Therefore, activation of mGluR5, and thereby potentiation or
normalization of the NMDA receptor signaling, is a potential mechanism for the treatment of
psychiatric and neurological disorders.
Most agonists of mGluR5 bind the orthosteric glutamate binding site. Since the
glutamate binding site between the mGluR family members is highly conserved, it has been
challenging to develop selective mGluR5 agonists which have acceptable CNS penetration
and demonstrate in vivo activity.
An alternative approach to achieve selectivity between the mGluR family
members is to develop compounds which bind to an allosteric site, which is not as highly
conserved between the family members. These allosteric binding compounds would not
interfere with the natural glutamate binding and signaling, but modulate the receptor
activation state. Allosteric ligands that have agonistic or inverse agonistic activity in the
absence of orthosteric ligands are termed allosteric agonists or antagonists, respectively.
Allosteric ligands lacking effect in the absence of orthosteric ligands are termed modulators
(negative or positive).
Positive allosteric modulators of mGluR5 have recently been identified (O'Brien
et al., Mol. Pharma. (2003), Vol.64, pp.731-740, Lindsley et al., J. Med. Chem. (2004),
Vol.47, pp.5825-5828), where it has been determined that these compounds potentiate
mGluR5 activity in the presence of bound glutamate. In the absence of bound glutamate, the
mGluR5 positive modulators do not demonstrate any intrinsic activity.
Therefore, these compounds potentiate the natural signaling of mGluR5 as
opposed to agonists which activate the receptor in a permanent, unnatural manner. mGluR5
positive allosteric modulators therefore represent an approach to potentiate mGluR5
signaling which in turn potentiates and normalizes the NMDA receptor hypofunction
detected in neurological and psychiatric disorders. mGluR5 negative allosteric modulators
are useful to depress the mGluR5 signaling which in turn decreases and normalizes the
NMDA receptor hyperfunction detected in some neurological, psychiatric disorders and in
more general CNS disorders. Both types of allosteric modulator can also be related to some
rare disease e.g. without any kind of limitation, Fragile-X syndrome, Rett syndrome, Phelan-
McDermid syndrome or tuberous sclerosis.
SUMMARY OF THE INVENTION
The invention provides a compound having the general formula I:
(I),
or an enantiomer, diastereomer, N-oxide, or a pharmaceutically acceptable salt thereof,
wherein:
R is an alkyl group, an optionally substituted mono-, bi- or tricyclic C -C heterocyclic
1 1 13
group containing from 1 to 5 heteroatoms selected from N, O, and S, an optionally
-C aryl group, an optionally substituted C -C
substituted mono-, bi- or tricyclic C
6 14 3 6
cycloalkyl group, an optionally substituted C -C cycloalkenyl group, a bond, or an
optionally substituted CO, CS, CH, CH or SO group;
R is absent, or is an optionally substituted mono- or bicyclic C -C heterocyclic group
2 1 9
containing from 1 to 3 heteroatoms selected from N, O, and S, an optionally substituted
mono-, bi- or tricyclic C -C aryl group, or an optionally substituted group selected from
6 14
alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryloxy, cycloalkyl, cycloalkyloxy, heteroaryloxy,
alkylthio, amino, N-alkylamino, N,N-dialkylamino, N-alkyl-N-alkoxyamino or N-alkyl-N-
alkyloxyamino;
R is an optionally substituted alkyl group, an optionally substituted mono-, bi- or tricyclic
C -C heterocyclic group containing from 1 to 5 heteroatoms selected from N, O, and S, an
1 13
optionally substituted mono-, bi- or tricyclic C -C aryl group, an optionally substituted C -
6 14 3
C cycloalkyl group, or an optionally substituted C -C cycloalkenyl group; and
6 3 6
n is 1-3, with the proviso that said compound of Formula I does not include the following
selection of compounds:
; and
The optional substituents are independently selected from halogen atoms and C -
C alkyl, C -C alkoxy, hydroxy, mercapto, nitro, cyano, oxo, halo(C -C )alkyl, halo(C -
6 1 6 1 6 1
C )alkoxy, C -C alkylthio, C -C alkylsulphonyl, C -C alkylcarbonyl, sulphamoyl, C -C
6 1 6 1 6 1 6 1 6
alkylsulphamoyl, di(C -C)alkylsulphamoyl, (C -C )alkoxycarbonyl and (C -
1 6 1 6 1
C )alkylcarbonyl(C -C )alkyl groups, and from groups of the formulae -NR*R*, -C(=O)-
6 1 6
NR*R*, -A, -O-A, -C(=O)-A, -(CH )q-A, -NR**-A, -C(=O)-NR**-A, -NR**C(=O)-A and -
O-C(=O)-A wherein each R* independently represents a hydrogen atom or a C -C alkyl, C -
1 6 1
C alkoxy, C -C alkylcarbonyl, phenyl or benzyl group, R** represents a hydrogen atom or
6 1 6
a C -C alkyl group, q is an integer from 1 to 6 and A represents a phenyl group or a C -C
1 6 1 8
heterocyclic group containing from 1 to 3 heteroatoms selected from N, O and S; a C -C
cycloalkyl group; each group A being optionally substituted with from 1 to 3 groups
independently selected from halo, hydroxy, cyano, nitro and C -C alkyl, preferably wherein
the optional substituents are selected from the groups consisting of halogen atoms and C -C
alkyl groups.
The most preferred compounds according to the invention are those in which R
represents a CO group and n is 1.
In an embodiment of the invention, R preferably is an optionally substituted
mono- or bicyclic C -C heterocyclic group containing from 1 to 3 heteroatoms selected from
nitrogen, oxygen and sulfur, or an optionally substituted group chosen from cycloalkyl,
alkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, amino, N-alkylamino, N,N-dialkylamino, or
N-alkyl-N-alkoxyamino.
For example, when R represents an optionally substituted mono- or bicyclic C -
C heterocyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and
sulfur, R is preferably a 2-furyl, 5-methylfuryl, 3-furyl, 4-morpholinyl, 4-oxanyl,
piperidinyl, 1-methylpiperidinyl, 4-methylpiperazinyl, 3-(1,5-dimethyl)pyrazolyl, 3-
pyridylamino, pyrrolidinyl or 4-thiazolyl group.
For example, when R represents an optionally substituted cycloalkyl group, R is
preferably a cyclopentyl or 4-(1,1-difluorocyclohexyl) group.
For example, when R represents an optionally substituted alkoxy group, R is
preferably an ethoxy, isopropoxy, 2,2-dimethylpropoxy, t-butoxy or 3-methylbutoxy group.
For example, when R represents an optionally substituted cycloalkyloxy group,
R is preferably a cyclopropylmethoxy or cyclopentoxy group.
For example, when R represents an optionally substituted heteroaryloxy group,
R is preferably a 4-oxanyloxy group.
For example, when R represents an optionally substituted amino group, R is
preferably an isopropylamino, 2,2-dimethylpropylamino, t-butylamino, 3-pentylamino
cyclopentylamino or a 3-pyridylamino group.
For example, when R represents an optionally substituted N-alkylamino, N,N-
dialkylamino, or N-alkyl-N-alkoxyamino group, R is preferably an N,N-dimethyl, N,N-
diethyl, N-ethyl-N-isopropyl, N-methoxy-N-methyl or N-(2-methoxyethyl)-N-methyl group.
In an alternative embodiment of the invention, R preferably represents a group
having the formula:
wherein R is a C -C linear or branched alkyl group, a C -C cycloalkyl group or a C -C
4 1 10 1 10 1 10
heterocyclic group containing at least one heteroatom selected from N or O.
For example, when R is a C -C linear or branched alkyl group, R is preferably
4 1 10 4
an ethyl, isopropyl, 2,2-dimethylpropyl, t-butyl or 3-methylbutyl group so that R is
preferably an ethoxy, isopropoxy, 2,2-dimethylpropoxy, t-butoxy or 3-methylbutoxy group.
For example, when R is a C -C a cycloalkyl group, R is preferably a
4 1 10 4
cyclopropylmethyl or a cyclopentyl group so that R is preferably a cyclopropylmethoxy or
cyclopentoxy group.
For example, when R is a C -C heterocyclic group containing at least one
4 1 10
heteroatom selected from N or O, R is preferably a 4-oxanyl group so that R is a 4-
oxanyloxy group.
In an alternative embodiment of the invention, R preferably is a saturated or
unsaturated, optionally substituted, five or six membered homocyclic group or heterocyclic
group containing at least one heteroatom selected from N or O.
For example, when R is an optionally substituted, five membered homocyclic
group, R is preferably a cyclopentyl group. When R an optionally substituted six
membered homocyclic group, R is preferably a 4-(1,1-difluorocyclohexyl) group.
For example, when R is an optionally substituted, five membered heterocyclic
group containing at least one heteroatom selected from N or O, R is preferably a 2-furyl, 5-
methylfuryl, 3-furyl, 3-(1,5-dimethyl)pyrazolyl, pyrrolidinyl or 4-thiazolyl group. When
R is an optionally substituted, five membered heterocyclic group containing at least one
heteroatom selected from N or O, R is preferably a 4-morpholinyl, 4-oxanyl, piperidinyl, 1-
methylpiperidinyl, 4-methylpiperazinylor 3-pyridylamino group.
In an alternative embodiment of the invention, R preferably represents a group
having the formula:
-NR R
wherein R is a C -C linear or branched alkyl or alkoxy group or hydrogen; R is a C -C
1 10 6 1 10
linear or branched alkyl or alkoxy group, R and R being the same or different; or wherein
R and R together with the nitrogen atom form a five or six membered heterocyclic ring.
For example, when R or R is a C -C linear or branched alkyl group, R or R is
6 1 10 5 6
preferably a methyl, ethyl, isopropyl, 2,2-dimethylpropyl, t-butyl or 3-pentyl group and R is
preferably an N,N-dimethyl, N,N-diethyl, N-ethyl-N-isopropyl, isopropylamino, t-
butylamino, 3-pentylamino or 2,2-dimethylpropylamino group.
For example, when R or R is a C -C linear or branched alkoxy group, R or R
6 1 10 5 6
is preferably a methoxy or 2-methoxyethyl group and R is preferably an N-methoxy-N-
methyl or N-(2-methoxyethyl)-N-methyl group.
For example, when R and R together with the nitrogen atom form a five or six
membered heterocyclic ring, R is preferably a 4-methylpiperazinyl, 4-morpholinyl,
piperidinyl or pyrrolidinyl group.
In an embodiment of the invention, R preferably is an optionally substituted
mono-, bi- or tricyclic C -C aryl group, an optionally substituted, five or six membered
6 14
heterocyclic group containing at least one heteroatom selected from N or O, an optionally
substituted C -C cycloalkyl group, or an optionally substituted C -C cycloalkenyl group.
3 6 3 6
For example, when R is an optionally substituted mono-, bi- or tricyclic C -C aryl group,
3 6 14
R is preferably a phenyl group. When R is an optionally substituted, five or six membered
heterocyclic group containing at least one heteroatom selected from N or O, R is preferably
a pyridyl group.
In an alternative embodiment of the invention, R is most preferably an optionally
substituted phenyl or pyridyl group, with said optional substituents being selected from a C -
C alkyl group or a halide group. For example, R represents a phenyl, 3-methylphenyl, 3-
3
bromophenyl, 3-chlorophenyl, 3-fluorophenyl or 6-methylpyridyl group.
In an alternative embodiment of the invention, R represents an optionally
substituted CO group, R is absent, R represents a phenyl, 3-bromophenyl, 3-chlorophenyl,
3-fluorophenyl, 3-methylphenyl or a 6-methylpyridyl group and n is 1.
In a highly preferred embodiment of the invention, R represents a CO group, R
represents a 4-morpholinyl group, R represents a 3-chlorophenyl, 3-fluorophenyl or a 3-
methylphenyl group and n is 1.
In a further highly preferred embodiment of the invention, R represents a CO
group, R represents a 2,2-dimethylpropoxy, t-butylamino, 3-methylbutoxy or a
cyclopentylamino group, R represents a 3-chlorophenyl group and n is 1.
In an embodiment of the invention, a compound, or an enantiomer, diastereomer,
N-oxide, or a pharmaceutically acceptable salt, is provided according to general formula I
selected from:
In a further embodiment of the invention, a pharmaceutical composition is
preferably provided comprising a compound of Formula I,
(I),
or an enantiomer, diastereomer, N-oxide, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier, wherein R is an alkyl group, an optionally substituted
mono-, bi- or tricyclic C -C heterocyclic group containing 1 to 5 heteroatoms selected from
1 13
N, O, and S; an optionally substituted mono-, bi- or tricyclic C -C aryl group, an optionally
6 14
substituted C -C cycloalkyl group, or an optionally substituted C -C cycloalkenyl group; or
3 6 3 6
a bond, CO, CS, CH, CH , SO group optionally substituted by one or more R group or
2 2 2
substituent; R is absent or is an optionally substituted mono- or bicyclic C -C heterocyclic
2 1 9
group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, an
optionally substituted mono-, bi- or tricyclic C -C aryl group, or an optionally substituted
6 14
group chosen from alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryloxy, heteroaryloxy,
alkylthio, amino, N-alkylamino, N,N-dialkylamino or N-alkyl-N-alkoxyamino; R is an
optionally substituted alkyl group, an optionally substituted mono-, bi- or tricyclic C -C
1 13
heterocyclic group containing 1 to 5 heteroatoms selected from N, O, and S; an optionally
substituted mono-, bi- or tricyclic C -C aryl group, an optionally substituted C -C
6 14 3 6
cycloalkyl group, or an optionally substituted C -C cycloalkenyl group; and
n is 1-3, with the proviso that said compound of Formula I does not include the following
selection of compounds:
; and
In another embodiment of the invention, use of a compound of Formula I,
(I),
or an enantiomer, diastereomer, N-oxide, or a pharmaceutically acceptable salt thereof, in the
manufacture of a medicament the treatment and/or prevention of a neurological disorder,
psychotic disorder, or a psychiatric disorder associated with glutamate dysfunction is
preferably provided, wherein R is an alkyl group, an optionally substituted mono-, bi- or
tricyclic C -C heterocyclic group containing 1 to 5 heteroatoms selected from N, O, and S;
1 13
an optionally substituted mono-, bi- or tricyclic C -C aryl group, an optionally substituted
6 14
C -C cycloalkyl group, or an optionally substituted C -C cycloalkenyl group; or a bond,
3 6 3 6
CO, CS, CH, CH , SO group optionally substituted by one or more R group or substituent;
2 2 2
R is absent or is an optionally substituted mono- or bicyclic C -C heterocyclic group
2 1 9
containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, an optionally
substituted mono-, bi- or tricyclic C -C aryl group, or an optionally substituted group
6 14
chosen from alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, alkylthio,
amino, N-alkylamino, N,N-dialkylamino or N-alkyl-N-alkoxyamino; R is an optionally
substituted alkyl group, an optionally substituted mono-, bi- or tricyclic C -C heterocyclic
1 13
group containing 1 to 5 heteroatoms selected from N, O, and S; an optionally substituted
mono-, bi- or tricyclic C -C aryl group, an optionally substituted C -C cycloalkyl group, or
6 14 3 6
an optionally substituted C -C cycloalkenyl group; and n is 1-3, with the proviso that said
compound of Formula I does not include the following selection of compounds:
; and
In an embodiment of the invention, a compound according to Formula I is used in
the treatment and/or prevention of a neurological disorder, psychotic disorder, or a
psychiatric disorder associated with glutamate dysfunction.
Preferably the neurological disorder, psychotic disorder, or psychiatric disorder
associated with glutamate dysfunction is schizophrenia, schizoaffective disorder, substance
induced psychotic disorder, age-associated learning and memory impairments or losses, post
stroke dementia, deficits in concentration, mild cognitive impairment, cognitive dysfunction
in Alzheimer’s disease, cognitive dysfunction of schizophrenia, cognitive decline, dementia
or cognitive impairment.
More preferably the disorder is Fragile-X syndrome, Rett syndrome, Phelan-
McDermid syndrome, or tuberous sclerosis.
Terms and Definitions Used
Except where stated otherwise, the following definitions apply throughout the
present specification and claims. These definitions apply regardless of whether a term is
used by itself or in combination with other terms. For example, the definition of “alkyl”
applies not only to alkyl groups per se, but also to the alkyl portions of alkoxy, alkylamino,
alkylthio or alkylcarbonyl groups etc. Furthermore all ranges described for a chemical
group, for example “from 1 to 13 carbon atoms” or “C -C alkyl” include all combinations
and sub-combinations of ranges and specific numbers of carbon atoms therein.
“Alkyl” means a straight chain or branched chain aliphatic hydrocarbon group
having from 1 to 20 carbon atoms in the chain. Preferred alkyl groups have from 1 to 12
carbon atoms in the chain. More preferred alkyl groups have from 1 to 6 carbon atoms in the
chain. “Lower alkyl” means an alkyl group having about 1 to about 6 carbon atoms in the
chain which may be straight or branched. Examples of suitable alkyl groups include methyl,
ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, and t-butyl.
“Alkenyl” means a straight chain or branched chain aliphatic hydrocarbon group
having at least one carbon-carbon double bond and having from 2 to 15 carbon atoms in the
chain. Preferred alkenyl groups have from 2 to 12 carbon atoms in the chain. More
preferred alkenyl groups have from 2 to 6 carbon atoms in the chain. “Lower alkenyl” means
an alkenyl group having 2 to about 6 carbon atoms in the chain, which may be straight or
branched. Examples of suitable alkenyl groups include ethenyl, propenyl, isopropenyl, n-
butenyl, 1-hexenyl and 3-methylbutenyl.
“Alkynyl” means a straight chain or branched chain aliphatic hydrocarbon group
having at least one carbon-carbon triple bond and having from 2 to 15 carbon atoms in the
chain. Preferred alkynyl groups have from 2 to 12 carbon atoms in the chain. More
preferred alkynyl groups have from 2 to 6 carbon atoms in the chain. “Lower alkynyl”
means an alkynyl group having 2 to about 6 carbon atoms in the chain, which may be straight
or branched. Examples of suitable alkynyl groups include ethynyl, propynyl and 2-butynyl.
“Mono-, bi-, or tricyclic heterocyclic” means an aromatic or non-aromatic
saturated mono- bi- or tricyclic ring system having from 2 to 14 ring carbon atoms, and
containing from 1 to 5 ring atoms selected from N, O and S, alone or in combination. Bi-
and tricyclic heterocyclic groups are fused at 2 or 4 points or joined at one point via a bond
or a heteroatom linker (O, S, NH, or N(C -C alkyl). The “mono- bi- or tricyclic
heterocyclic” can be optionally substituted on the ring by replacing an available hydrogen on
the ring by one or more substituents which may be the same or different. The nitrogen or
sulphur atom of the heterocyclic can be optionally oxidized to the corresponding N-oxide, S-
oxide or S-dioxide. Examples of suitable heterocyclics include furanyl, imidazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl,
triazolyl, tetrazolyl, thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl,
quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl,
isoindolyl, acridinyl and benzoisoxazolyl, aziridinyl, piperidinyl, pyrrolidinyl, piperazinyl,
tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl and
thiomorpholinyl.
Heterocyclics with aromatic characteristics may be referred to as heteroaryls or
heteroaromatics. Examples of suitable heteroaromatics include furanyl, imidazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl,
triazolyl, tetrazolyl, thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl,
quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl,
isoindolyl, acridinyl, benzoisoxazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 3-
phenylpyridine, 3-cyclohexylpyridine, 3-(pyridinyl) morpholine, 3-phenylisoxazole and 2-
(piperidinyl)pyrimidine.
“Mono-, bi- or tricyclic aryl” means an aromatic monocyclic, bicyclic or tricyclic
ring system comprising 6 to 14 carbon atoms. Bi- and tricyclic aryl groups are fused at 2 or 4
points or joined at one point via a bond or a heteroatom linker (O, S, NH, or N(C -C alkyl)
(e.g., biphenyl, 1-phenylnapthyl). The aryl group can be optionally substituted on the ring
with one or more substituents, preferably 1 to 6 substituents, which may be the same or
different. Examples of suitable aryl groups include phenyl and naphthyl.
“Cycloalkyl” means a monocyclic or bicyclic carbon ring system having from 3 to
14 carbon atoms, preferably from 3 to 6 carbon atoms. The cycloalkyl can be optionally
substituted on the ring by replacing an available hydrogen on the ring by one or more
substituents which may be the same or different. Examples of suitable monocyclic
cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of
suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl and adamantyl.
“Cycloalkenyl” has a meaning corresponding to that of cycloalkyl, but with one
or two double bonds within the ring (e.g., cyclohexenyl, cyclohexadiene).
“Amines” are derivatives of ammonia, wherein one or more hydrogen atoms have
been replaced by a substituent such as an alkyl or aryl group. These may respectively be
called alkylamines and arylamines; amines in which both types of substituent are attached to
one nitrogen atom may be called alkylarylamines.
Amines can be further organized into four sub-categories. Primary amines arise
when one of the three hydrogen atoms in ammonia is replaced by an alkyl or aromatic group
(an N-alkylamino or N-arylamino respectively). Examples of suitable primary alkyl amines
include methylamine or ethanolamine, or aniline (phenylamine) as an example of an aromatic
amine. Secondary amines have two organic substituents (independently alkyl or aryl groups)
bound to the nitrogen atom together with one hydrogen (or no hydrogen if one of the
substituent bonds is double). Examples of suitable secondary amines include dimethylamine
and methylethanolamine, while an example of an aromatic amine would be diphenylamine.
Such compounds may also be referred to as “N,N-dialkylamino”, “N,N-diarylamino” or
“N,N-alkylarylamino” groups depending on the nature of the substituents. A secondary
amine substituted by an alkoxy group, as defined herein, would be termed an “N-alkyl-N-
alkoxyamino” compound for example. In tertiary amines, all three hydrogen atoms are
replaced by organic substituents, such as trimethylamine. The final sub-category is cyclic
amines which are either secondary or tertiary amines. Examples of suitable cyclic amines
include the 3-member ring aziridine and the six-membered ring piperidine. N-
methylpiperidine and N-phenylpiperidine are suitable examples of cyclic tertiary amines.
“Amides” are compounds with a nitrogen atom attached to a carbonyl group, thus
having the structure R–CO–NR’R’’, with groups R’ and R’’ being independently selected
from alkyl or aromatic groups as defined herein. For example when R’ is hydrogen and R’’
is a 3-pyridyl group, the resulting amide has a 3-pyridylamino substituent. Alternatively
when R’ is hydrogen and R’’ is a cyclopentyl group, the resulting amide has a
cyclopentylamino substituent.
“Halogen”, “halide” or “halo” means fluorine, chlorine, bromine or iodine.
Preferred halogens are fluorine, chlorine or bromine, and most preferred are fluorine and
chlorine.
The term “acyl”, whether used alone, or within a term such as “acylamino”,
denotes a radical provided by the residue after removal of hydroxyl from an organic acid.
The term “acylamino” refers to an amino radical substituted with an acyl group. An example
of an “acylamino” radical is CH C(=O)-NH- where the amine may be further substituted
with alkyl, aryl or aralkyl groups.
An asterisk may be used in sub-formulas to indicate the bond which is connected
to a parent or core molecule as defined herein.
Stereochemistry
Unless specifically indicated, throughout the specification and claims, a given
chemical formula or name shall encompass tautomers and all stereo, optical and geometrical
isomers (e.g. enantiomers, diastereomers, E/Z isomers etc.) and racemates thereof. This
includes mixtures in different proportions of the separate enantiomers, mixtures of
diastereomers, or mixtures of any of the foregoing forms where such isomers and
enantiomers exist, as well as salts, including pharmaceutically acceptable salts and solvates
thereof such as hydrates, solvates of the free compounds or solvates of a salt of the
compound.
Derivatives of Compounds of the Invention
The invention further encompasses salts, solvates, hydrates, N-oxides, produgs
and active metabolites of the compounds of formula I.
The phrase “pharmaceutically acceptable” is employed herein to refer to those
compounds, materials, compositions, and/or dosage forms which are, within the scope of
sound medical judgment, suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response, or other problem or
complication, and commensurate with a reasonable benefit/risk ratio.
As used herein, “pharmaceutically acceptable salts” refers to derivatives of the
disclosed compounds wherein the parent compound is modified by making acid or base salts
thereof. Examples of pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic
residues such as carboxylic acids; and the like. For example, such salts include salts from
ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol,
diethanolamine (2,2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-
aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine,
magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-
(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2',2''-
nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2,2-dichloro-acetic acid,
adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid,
2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor
sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid,
dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-
ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid,
glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic
acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid,
lactobionic acid, lauric acid, lysine, maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic
acid, methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid, naphthalene
sulfonic acid, 1-hydroxynaphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic
acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid,
propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,
stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-
toluenesulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be
formed with cations from metals such as aluminium, calcium, lithium, magnesium,
potassium, sodium, zinc and the like (see Pharmaceutical salts, Berge, S. M. et al., J. Pharm.
Sci., (1977), Vol.66, pp.1-19).
Pharmaceutically acceptable salts of the present invention can be synthesized
from the parent compound which contains a basic or acidic moiety by conventional chemical
methods. Generally, such salts can be prepared by reacting the free acid or base forms of
these compounds with a sufficient amount of the appropriate base or acid in water or in an
organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture
thereof.
Salts of other acids than those mentioned above which for example are useful for
purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts),
also comprise a part of the invention.
Typically, a pharmaceutically acceptable salt of a compound of formula I may be
readily prepared by using a desired acid or base as appropriate. The salt may precipitate
from solution and be collected by filtration or may be recovered by evaporation of the
solvent. For example, an aqueous solution of an acid such as hydrochloric acid may be
added to an aqueous suspension of a compound of formula I and the resulting mixture
evaporated to dryness (lyophilized) to obtain the acid addition salt as a solid. Alternatively, a
compound of formula I may be dissolved in a suitable solvent, for example an alcohol such
as isopropanol, and the acid may be added in the same solvent or another suitable solvent.
The resulting acid addition salt may then be precipitated directly, or by addition of a less
polar solvent such as diisopropyl ether or hexane, and isolated by filtration.
The acid addition salts of the compounds of formula I may be prepared by
contacting the free base form with a sufficient amount of the desired acid to produce the salt
in the conventional manner. The free base form may be regenerated by contacting the salt
form with a base and isolating the free base in the conventional manner. The free base forms
differ from their respective salt forms somewhat in certain physical properties such as
solubility in polar solvents, but otherwise the salts are equivalent to their respective free base
for purposes of the invention.
Also included are both total and partial salts, that is to say salts with 1, 2 or 3,
preferably 2, equivalents of base per mole of acid of formula I or salts with 1, 2 or 3
equivalents, preferably 1 equivalent, of acid per mole of base of formula I.
Pharmaceutically acceptable base addition salts are formed with metals or amines,
such as alkali and alkaline earth metals or organic amines. Examples of metals used as
cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable
amines are N,N’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,
dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.
The base addition salts of said acidic compounds are prepared by contacting the
free acid form with a sufficient amount of the desired base to produce the salt in the
conventional manner. The free acid form may be regenerated by contacting the salt form
with an acid and isolating the free acid.
Compounds of the invention may have both a basic and an acidic centre and may
therefore be in the form of zwitterions or internal salts.
Typically, a pharmaceutically acceptable salt of a compound of formula I may be
readily prepared by using a desired acid or base as appropriate. The salt may precipitate
from solution and be collected by filtration or may be recovered by evaporation of the
solvent. For example, an aqueous solution of an acid such as hydrochloric acid may be
added to an aqueous suspension of a compound of formula I and the resulting mixture
evaporated to dryness (lyophilized) to obtain the acid addition salt as a solid. Alternatively, a
compound of formula I may be dissolved in a suitable solvent, for example an alcohol such
as isopropanol, and the acid may be added in the same solvent or another suitable solvent.
The resulting acid addition salt may then be precipitated directly, or by addition of a less
polar solvent such as diisopropyl ether or hexane, and isolated by filtration.
Those skilled in the art of organic chemistry will appreciate that many organic
compounds can form complexes with solvents in which they are reacted or from which they
are precipitated or crystallized. These complexes are known as “solvates”. For example, a
complex with water is known as a “hydrate”. Solvates of the compound of the invention are
within the scope of the invention. The salts of the compound of formula I may form solvates
(e.g., hydrates) and the invention also includes all such solvates. The meaning of the word
“solvates” is well known to those skilled in the art as a compound formed by interaction of a
solvent and a solute (i.e., solvation). Techniques for the preparation of solvates are well
established in the art (see, for example, Brittain. Polymorphism in Pharmaceutical solids.
Marcel Decker, New York, 1999.).
The invention also encompasses N-oxides of the compounds of formulas I. The
term “N-oxide” means that for heterocycles containing an otherwise unsubstituted sp N
atom, the N atom may bear a covalently bound O atom, i.e., -N→O. Examples of such N-
oxide substituted heterocycles include pyridyl N-oxides, pyrimidyl N-oxides, pyrazinyl N-
oxides and pyrazolyl N-oxides.
The invention also encompasses prodrugs of the compounds of formula I, i.e.,
compounds which release an active parent drug according to formula I in vivo when
administered to a mammalian subject. A prodrug is a pharmacologically active or more
typically an inactive compound that is converted into a pharmacologically active agent by a
metabolic transformation. Prodrugs of a compound of formula I are prepared by modifying
functional groups present in the compound of formula I in such a way that the modifications
may be cleaved in vivo to release the parent compound. In vivo, a prodrug readily undergoes
chemical changes under physiological conditions (e.g., are acted on by naturally occurring
enzyme(s)) resulting in liberation of the pharmacologically active agent. Prodrugs include
compounds of formula I wherein a hydroxy, amino, or carboxy group of a formula I
compound is bonded to any group that may be cleaved in vivo to regenerate the free
hydroxyl, amino or carboxy group, respectively. Examples of prodrugs include esters (e.g.,
acetate, formate, and benzoate derivatives) of compounds of formula I or any other derivative
which upon being brought to the physiological pH or through enzyme action is converted to
the active parent drug. Conventional procedures for the selection and preparation of suitable
prodrug derivatives are described in the art (see, for example, Bundgaard. Design of
Prodrugs. Elsevier, 1985).
Prodrugs may be administered in the same manner as the active ingredient to
which they convert or they may be delivered in a reservoir form, e.g., a transdermal patch or
other reservoir which is adapted to permit (by provision of an enzyme or other appropriate
reagent) conversion of a prodrug to the active ingredient slowly over time, and delivery of
the active ingredient to the patient.
The invention also encompasses metabolites. A “metabolite” of a compound
disclosed herein is a derivative of a compound which is formed when the compound is
metabolised. The term “active metabolite” refers to a biologically active derivative of a
compound which is formed when the compound is metabolised. The term “metabolised”
refers to the sum of the processes by which a particular substance is changed in the living
body. In brief, all compounds present in the body are manipulated by enzymes within the
body in order to derive energy and/or to remove them from the body. Specific enzymes
produce specific structural alterations to the compound. For example, cytochrome P450
catalyses a variety of oxidative and reductive reactions while uridine diphosphate
glucuronyltransferases catalyse the transfer of an activated glucuronic-acid molecule to
aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups.
Further information on metabolism may be obtained from The Pharmacological Basis of
Therapeutics, 9th Edition, McGraw-Hill (1996), pages 11-17.
Metabolites of the compounds disclosed herein can be identified either by
administration of compounds to a host and analysis of tissue samples from the host, or by
incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
Both methods are well known in the art.
The term “carrier” refers to a diluent, excipient, and/or vehicle with which an
active compound is administered. The pharmaceutical compositions of the invention may
contain combinations of more than one carrier. Such pharmaceutical carriers can be sterile
liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol
solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such
as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution
saline solutions and aqueous dextrose and glycerol solutions are preferably employed as
carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described
in “Remington’s Pharmaceutical Sciences” by E.W. Martin, 18th Edition.
A “pharmaceutically acceptable excipient” means an excipient that is useful in
preparing a pharmaceutical composition that is generally safe, non-toxic and neither
biologically nor otherwise undesirable, and includes an excipient that is acceptable for
veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable
excipient” as used in the present application includes both one and more than one such
excipient.
The compounds of the invention may be formulated for administration in any
convenient way for use in human or veterinary medicine and the invention therefore includes
within its scope pharmaceutical compositions comprising a compound of the invention
adapted for use in human or veterinary medicine. Such compositions may be presented for
use in a conventional manner with the aid of one or more suitable carriers. Acceptable
carriers for therapeutic use are well-known in the pharmaceutical art, and are described, for
example, in Remington’s Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro
edit. 1985). The choice of pharmaceutical carrier can be selected with regard to the intended
route of administration and standard pharmaceutical practice. The pharmaceutical
compositions may comprise as, in addition to, the carrier any suitable binder(s), lubricant(s),
suspending agent(s), coating agent(s), and/or solubilizing agent(s).
Pharmaceutical Compositions Comprising a Compound of Formula I
While it is possible that a compound I may be administered as the bulk substance,
it is preferable to present the active ingredient in a pharmaceutical formulation, e.g., wherein
the agent is in admixture with a pharmaceutically acceptable carrier selected with regard to
the intended route of administration and standard pharmaceutical practice.
Accordingly, the invention further provides a pharmaceutical composition
comprising a compound of formula I or a solvate, hydrate, enantiomer, diastereomer, N-
oxide or pharmaceutically acceptable salt thereof in admixture with a pharmaceutically
acceptable carrier. The term “carrier” refers to a diluent, excipient, and/or vehicle with
which an active compound is administered.
A compound of formula I may be used in combination with other therapies and/or
active agents. Accordingly, the invention provides, in a further aspect, a pharmaceutical
composition comprising a compound of formula I or a solvate, hydrate, enantiomer,
diastereomer, N-oxide or pharmaceutically acceptable salt thereof, a second active agent, and
a pharmaceutically acceptable carrier.
The pharmaceutical compositions may comprise as, in addition to, the carrier any
suitable binder, lubricant, suspending agent, coating agent and/or solubilizing agent.
Preservatives, stabilizers, dyes and flavouring agents also may be provided in the
pharmaceutical composition. Antioxidants and suspending agents may be also used.
The compounds of the invention may be milled using known milling procedures
such as wet milling to obtain a particle size appropriate for tablet formation and for other
formulation types. Finely divided (nanoparticulate) preparations of the compounds of the
invention may be prepared by processes known in the art, for example see WO02/00196.
Routes of Administration and Unit Dosage Forms
The routes for administration include oral (e.g., as a tablet, capsule, or as an
ingestible solution), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), nasal,
parenteral (e.g., by an injectable form), gastrointestinal, intraspinal, intraperitoneal,
intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal,
intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including
intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual. The
compositions of the invention may be especially formulated for any of those administration
routes. In preferred embodiments, the pharmaceutical compositions of the invention are
formulated in a form that is suitable for oral delivery.
There may be different composition/formulation requirements depending on the
different delivery systems. It is to be understood that not all of the compounds need to be
administered by the same route. Likewise, if the composition comprises more than one
active component, then those components may be administered by different routes. By way
of example, the pharmaceutical composition of the invention may be formulated to be
delivered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol
for inhalation or ingestible solution, or parenterally in which the composition is formulated
by an injectable form, for delivery, by, for example, an intravenous, intramuscular or
subcutaneous route. Alternatively, the formulation may be designed to be delivered by
multiple routes.
Where the agent is to be delivered mucosally through the gastrointestinal mucosa,
it should be able to remain stable during transit though the gastrointestinal tract; for example,
it should be resistant to proteolytic degradation, stable at acid pH and resistant to the
detergent effects of bile. For example, the compound of Formula I may be coated with an
enteric coating layer. The enteric coating layer material may be dispersed or dissolved in
either water or in a suitable organic solvent. As enteric coating layer polymers, one or more,
separately or in combination, of the following can be used; e.g., solutions or dispersions of
methacrylic acid copolymers, cellulose acetate phthalate, cellulose acetate butyrate,
hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate,
polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose,
shellac or other suitable enteric coating layer polymer(s). For environmental reasons, an
aqueous coating process may be preferred. In such aqueous processes methacrylic acid
copolymers are most preferred.
When appropriate, the pharmaceutical compositions can be administered by
inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution,
cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets
containing excipients such as starch or lactose, or in capsules or ovules either alone or in
admixture with excipients, or in the form of elixirs, solutions or suspensions containing
flavouring or colouring agents, or they can be injected parenterally, for example
intravenously, intramuscularly or subcutaneously. For buccal or sublingual administration
the compositions may be administered in the form of tablets or lozenges, which can be
formulated in a conventional manner.
When the composition of the invention is to be administered parenterally, such
administration includes one or more of: intravenously, intraarterially, intraperitoneally,
intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly
or subcutaneously administering the agent; and/or by using infusion techniques.
Pharmaceutical compositions of the invention can be administered parenterally,
e.g., by infusion or injection. Pharmaceutical compositions suitable for injection or infusion
may be in the form of a sterile aqueous solution, a dispersion or a sterile powder that contains
the active ingredient, adjusted, if necessary, for preparation of such a sterile solution or
dispersion suitable for infusion or injection. This preparation may optionally be encapsulated
into liposomes. In all cases, the final preparation must be sterile, liquid, and stable under
production and storage conditions. To improve storage stability, such preparations may also
contain a preservative to prevent the growth of microorganisms. Prevention of the action of
micro-organisms can be achieved by the addition of various antibacterial and antifungal
agents, e.g., paraben, chlorobutanol, or acsorbic acid. In many cases isotonic substances are
recommended, e.g., sugars, buffers and sodium chloride to assure osmotic pressure similar to
those of body fluids, particularly blood. Prolonged absorption of such injectable mixtures
can be achieved by introduction of absorption-delaying agents, such as aluminium
monostearate or gelatin.
Dispersions can be prepared in a liquid carrier or intermediate, such as glycerin,
liquid polyethylene glycols, triacetin oils, and mixtures thereof. The liquid carrier or
intermediate can be a solvent or liquid dispersive medium that contains, for example, water,
ethanol, a polyol (e.g., glycerol, propylene glycol or the like), vegetable oils, non-toxic
glycerine esters and suitable mixtures thereof. Suitable flowability may be maintained, by
generation of liposomes, administration of a suitable particle size in the case of dispersions,
or by the addition of surfactants.
For parenteral administration, the compound is best used in the form of a sterile
aqueous solution which may contain other substances, for example, enough salts or glucose
to make the solution isotonic with blood. The aqueous solutions should be suitably buffered
(preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral
formulations under sterile conditions is readily accomplished by standard pharmaceutical
techniques well-known to those skilled in the art.
Sterile injectable solutions can be prepared by mixing a compound of formula I
with an appropriate solvent and one or more of the aforementioned carriers, followed by
sterile filtering. In the case of sterile powders suitable for use in the preparation of sterile
injectable solutions, preferable preparation methods include drying in vacuum and
lyophilization, which provide powdery mixtures of the aldosterone receptor antagonists and
desired excipients for subsequent preparation of sterile solutions.
The compounds according to the invention may be formulated for use in human
or veterinary medicine by injection (e.g., by intravenous bolus injection or infusion or via
intramuscular, subcutaneous or intrathecal routes) and may be presented in unit dose form, in
ampoules, or other unit-dose containers, or in multi-dose containers, if necessary with an
added preservative. The compositions for injection may be in the form of suspensions,
solutions, or emulsions, in oily or aqueous vehicles, and may contain formulatory agents such
as suspending, stabilizing, solubilizing and/or dispersing agents. Alternatively the active
ingredient may be in sterile powder form for reconstitution with a suitable vehicle, e.g.,
sterile, pyrogen-free water, before use.
The compounds of the invention can be administered (e.g., orally or topically) in
the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain
flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed-or
controlled-release applications.
The compounds of the invention may also be presented for human or veterinary
use in a form suitable for oral or buccal administration, for example in the form of solutions,
gels, syrups, mouth washes or suspensions, or a dry powder for constitution with water or
other suitable vehicle before use, optionally with flavouring and colouring agents. Solid
compositions such as tablets, capsules, lozenges, pastilles, pills, boluses, powder, pastes,
granules, bullets or premix preparations may also be used. Solid and liquid compositions for
oral use may be prepared according to methods well-known in the art. Such compositions
may also contain one or more pharmaceutically acceptable carriers and excipients which may
be in solid or liquid form.
The tablets may contain excipients such as microcrystalline cellulose, lactose,
sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such
as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose
sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone,
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and
acacia.
Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl
behenate and talc may be included.
The compositions may be administered orally, in the form of rapid or controlled
release tablets, microparticles, mini tablets, capsules, sachets, and oral solutions or
suspensions, or powders for the preparation thereof. In addition to the new solid-state forms
of pantoprazole of the invention as the active substance, oral preparations may optionally
include various standard pharmaceutical carriers and excipients, such as binders, fillers,
buffers, lubricants, glidants, dyes, disintegrants, odourants, sweeteners, surfactants, mold
release agents, antiadhesive agents and coatings. Some excipients may have multiple roles in
the compositions, e.g., act as both binders and disintegrants.
Examples of pharmaceutically acceptable disintegrants for oral compositions
include starch, pre-gelatinized starch, sodium starch glycolate, sodium
carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins,
surfactants, effervescent compositions, aqueous aluminum silicates and cross-linked
polyvinylpyrrolidone.
Examples of pharmaceutically acceptable binders for oral compositions include
acacia; cellulose derivatives, such as methylcellulose, carboxymethylcellulose,
hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; gelatin,
glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-
gelatinized starch, tragacanth, xanthane resin, alginates, magnesium−aluminum silicate,
polyethylene glycol or bentonite.
Examples of pharmaceutically acceptable fillers for oral compositions include
lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch,
cellulose (particularly microcrystalline cellulose), dihydro- or anhydro-calcium phosphate,
calcium carbonate and calcium sulphate.
Examples of pharmaceutically acceptable lubricants useful in the compositions of
the invention include magnesium stearate, talc, polyethylene glycol, polymers of ethylene
oxide, sodium lauryl sulphate, magnesium lauryl sulphate, sodium oleate, sodium stearyl
fumarate, and colloidal silicon dioxide.
Examples of suitable pharmaceutically acceptable odourants for the oral
compositions include synthetic aromas and natural aromatic oils such as extracts of oils,
flowers, fruits (e.g., banana, apple, sour cherry, peach) and combinations thereof, and similar
aromas. Their use depends on many factors, the most important being the organoleptic
acceptability for the population that will be taking the pharmaceutical compositions.
Examples of suitable pharmaceutically acceptable dyes for the oral compositions
include synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of
grapefruit peel.
Examples of useful pharmaceutically acceptable coatings for the oral
compositions, typically used to facilitate swallowing, modify the release properties, improve
the appearance, and/or mask the taste of the compositions include
hydroxypropylmethylcellulose, hydroxypropylcellulose and acrylate-methacrylate
copolymers.
Examples of pharmaceutically acceptable sweeteners for the oral compositions
include aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol,
sorbitol, lactose and sucrose.
Examples of pharmaceutically acceptable buffers include citric acid, sodium
citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate
and magnesium hydroxide.
Examples of pharmaceutically acceptable surfactants include sodium lauryl
sulphate and polysorbates.
Solid compositions of a similar type may also be employed as fillers in gelatin
capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or
high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the
agent may be combined with various sweetening or flavouring agents, colouring matter or
dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol,
propylene glycol and glycerin, and combinations thereof.
The compounds of the invention may also, for example, be formulated as
suppositories e.g., containing conventional suppository bases for use in human or veterinary
medicine or as pessaries e.g., containing conventional pessary bases.
The compounds according to the invention may be formulated for topical
administration, for use in human and veterinary medicine, in the form of ointments, creams,
gels, hydrogels, lotions, solutions, shampoos, powders (including spray or dusting powders),
pessaries, tampons, sprays, dips, aerosols, drops (e.g., eye ear or nose drops) or pour-ons.
For application topically to the skin, the agent of the invention can be formulated
as a suitable ointment containing the active compound suspended or dissolved in, for
example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white
petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying
wax, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl
esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Such
compositions may also contain other pharmaceutically acceptable excipients, such as
polymers, oils, liquid carriers, surfactants, buffers, preservatives, stabilizers, antioxidants,
moisturizers, emollients, colourants, and odourants.
Examples of pharmaceutically acceptable polymers suitable for such topical
compositions include acrylic polymers; cellulose derivatives, such as carboxymethylcellulose
sodium, methylcellulose or hydroxypropylcellulose; natural polymers, such as alginates,
tragacanth, pectin, xanthan and cytosan.
Examples of suitable pharmaceutically acceptable oils which are so useful include
mineral oils, silicone oils, fatty acids, alcohols, and glycols.
Examples of suitable pharmaceutically acceptable liquid carriers include water,
alcohols or glycols such as ethanol, isopropanol, propylene glycol, hexylene glycol, glycerol
and polyethylene glycol, or mixtures thereof in which the pseudopolymorph is dissolved or
dispersed, optionally with the addition of non-toxic anionic, cationic or non-ionic surfactants,
and inorganic or organic buffers.
Examples of pharmaceutically acceptable preservatives include sodium benzoate,
ascorbic acid, esters of p-hydroxybenzoic acid and various antibacterial and antifungal agents
such as solvents, for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol,
quaternary ammonium salts, and parabens (such as methyl paraben, ethyl paraben and propyl
paraben).
Examples of pharmaceutically acceptable stabilizers and antioxidants include
ethylenediaminetetraacetic acid (EDTA), thiourea, tocopherol and butyl hydroxyanisole.
Examples of pharmaceutically acceptable moisturizers include glycerine, sorbitol,
urea and polyethylene glycol.
Examples of pharmaceutically acceptable emollients include mineral oils,
isopropyl myristate, and isopropyl palmitate.
The compounds may also be dermally or transdermally administered, for
example, by use of a skin patch.
For ophthalmic use, the compounds can be formulated as micronized suspensions
in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted,
sterile saline, optionally in combination with a preservative such as a benzylalkonium
chloride.
As indicated, the compounds of the invention can be administered intranasally or
by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol
spray presentation from a pressurized container, pump, spray or nebulizer with the use of a
suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA
134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other suitable
gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a
valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may
contain a solution or suspension of the active compound, e.g., using a mixture of ethanol and
the propellant as the solvent, which may additionally contain a lubricant, e.g., sorbitan
trioleate.
Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or
insufflator may be formulated to contain a powder mix of the compound and a suitable
powder base such as lactose or starch.
For topical administration by inhalation the compounds according to the invention
may be delivered for use in human or veterinary medicine via a nebulizer.
The pharmaceutical compositions of the invention may contain from 0.01 to 99%
weight per volume of the active material. For topical administration, for example, the
composition will generally contain from 0.01-10%, more preferably 0.01-1% of the active
material.
The active agents can also be administered in the form of liposome delivery
systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar
vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol,
stearylamine or phosphatidylcholines.
The pharmaceutical composition or unit dosage form of the invention may be
administered according to a dosage and administration regimen defined by routine testing in
the light of the guidelines given above in order to obtain optimal activity while minimizing
toxicity or side effects for a particular patient. However, such fine tuning of the therapeutic
regimen is routine in the light of the guidelines given herein.
The dosage of the active agents of the invention may vary according to a variety
of factors such as underlying disease conditions, the individual’s condition, weight, gender
and age, and the mode of administration. An effective amount for treating a disorder can
easily be determined by empirical methods known to those of ordinary skill in the art, for
example by establishing a matrix of dosages and frequencies of administration and
comparing a group of experimental units or subjects at each point in the matrix. The exact
amount to be administered to a patient will vary depending on the state and severity of the
disorder and the physical condition of the patient. A measurable amelioration of any
symptom or parameter can be determined by a person skilled in the art or reported by the
patient to the physician.
The amount of the agent to be administered can range between about 0.01 and
about 25 mg/kg/day, preferably between about 0.1 and about 10 mg/kg/day and most
preferably between 0.2 and about 5 mg/kg/day. It will be understood that the pharmaceutical
formulations of the invention need not necessarily contain the entire amount of the agent that
is effective in treating the disorder, as such effective amounts can be reached by
administration of a plurality of doses of such pharmaceutical formulations.
In a preferred embodiment of the invention, the compounds according to formula
I are formulated in capsules or tablets, preferably containing 10 to 200 mg of the compounds
of the invention, and are preferably administered to a patient at a total daily dose of 10 to 300
mg, preferably 20 to 150 mg and most preferably about 50 mg.
A pharmaceutical composition for parenteral administration contains from about
0.01% to about 100% by weight of the active agents of the invention, based upon 100%
weight of total pharmaceutical composition.
Generally, transdermal dosage forms contain from about 0.01% to about 100% by
weight of the active agents versus 100% total weight of the dosage form.
The pharmaceutical composition or unit dosage form may be administered in a
single daily dose, or the total daily dosage may be administered in divided doses. In
addition, co-administration or sequential administration of another compound for the
treatment of the disorder may be desirable. To this purpose, the combined active principles
are formulated into a simple dosage unit.
For combination treatment where the compounds are in separate dosage
formulations, the compounds can be administered concurrently, or each can be administered
at staggered intervals. For example, the compound of the invention may be administered in
the morning and the antimuscarinic compound may be administered in the evening, or vice
versa. Additional compounds may be administered at specific intervals too. The order of
administration will depend upon a variety of factors including age, weight, gender and
medical condition of the patient; the severity and aetiology of the disorders to be treated, the
route of administration, the renal and hepatic function of the patient, the treatment history of
the patient, and the responsiveness of the patient. Determination of the order of
administration may be fine-tuned and such fine-tuning is routine in the light of the guidelines
given herein.
DESCRIPTION OF THE INVENTION
Synthesis
Compounds of formula I, and enantiomers, diastereomers, N-oxides, and
pharmaceutically acceptable salts thereof, may be prepared by the general methods outlined
hereinafter, said methods constituting a further aspect of the invention.
The compounds of this invention can be prepared by employing reactions as
shown in the following schemes, in addition to other standard manipulations that are known
in the literature, exemplified in the experimental section or clear to one skilled in the art. The
starting materials which are not described herein are either commercially available or may be
prepared by employing reactions described in the literature or are clear to one skilled in the
art. The following examples are provided so that the invention might be more fully
understood, are illustrative only, and should not be construed as limiting.
It will be appreciated by those skilled in the art that it may be desirable to use
protected derivatives of intermediates used in the preparation of the compounds according to
formula I. Protection and deprotection of functional groups may be performed by methods
known in the art (see, for example, Green and Wuts Protective Groups in Organic Synthesis.
John Wiley and Sons, New York, 1999).
The abbreviation PG describes a “protecting group” which is introduced to a
reactive group before a certain manipulation is carried out, and which is later removed.
Examples of PG’s for protecting a reactive group include: acetyl-, trifluoracetyl-, benzoyl-,
ethoxycarbonyl-, N-tert-butoxycarbonyl- (BOC), N-benzyloxycarbonyl- (Cbz), benzyl-,
methoxybenzyl-, 2,4-dimethoxybenzyl- and for amino groups additionally the phthalyl-
group for amino-alkylamino or imino groups; N-methoxynethyl- (MOM), N-
benzyloxymethyl- (BOM), N-(trimethylsilyl)ethoxymethyl- (SEM), N-tert-butyl-
dimethylsiloxymethyl-, N-tert-butyl-dimethylsilyl- (TBDMS), N-triisopropylsilyl- (TIPS), N-
benzyl-, Nmethoxybenzyl (PMB), N-triphenylmethyl- (Tr), N-tert-butoxycarbonyl-
(BOC), N-benzyloxycarbonyl- (Cbz) or N-trimethylsilylethylsulfonyl- (SES) for amide
groups; methoxy-, benzyloxy-, trimethylsilyl- (TMS), acetyl-, benzoyl-, tert-butyl-, trityl-,
benzyl-, or tetrahydropyranyl (THP) groups for hydroxy groups; or trimethylsilyl- (TMS),
methyl-ethyl-, tert-butyl-, benzyl-, or tetrahydropyranyl (THP) groups for carboxyl groups.
The compounds of the invention are generally prepared according to the
following scheme, wherein groups R , R , R , and n are as previously defined herein:
1 2 3
Scheme 1.
In some cases the final product may be further modified, for example by
manipulation of substituents. These manipulations may include, but are not limited to,
reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly
known to those skilled in the art. In some cases the order of carrying out the foregoing
reaction schemes may be varied in order to facilitate the reaction or to avoid unwanted
reaction products. The following examples are provided so that the invention might be more
fully understood. These examples are illustrative only and should not be constructed as
limiting the invention in any way.
As shown in Scheme 1, silyl protected propargylaldehyde oxime 1 is reacted with
N-protected unsaturated cyclic amines through a 1,3-dipolar cycloaddition, with the previous
formation of the nitrile oxide species via halogenation-elimination (see e.g. Kanemasa, S.;
Nishiuchi, M.; Kamimure, A.; Hori, K. J. Am. Chem. Soc. (1994), Vol.116, pp.2324).
Compounds 2 formed therefrom can be then reacted with an R LG compound directly, or by
deprotection of the alkyne moiety using standard methodologies (e.g., NaOH or Na CO in
MeOH, or tetrabutylammonium fluoride in THF). LG represents a leaving group such as
halogen, mesylate, tosylate, alkylsulphonate, triflate or other without limitation. This
reaction is performed e.g. by carrying out a Sonogashira (Chinchilla et al., Chem. Rev.,
(2007), Vol.107 (3), pp.874–922) or like reaction, with the aid of a palladium catalyst and
copper iodide. Following N-deprotection by standard methods, reaction with an R -R -LG
group follows, where LG is as defined above. This last derivatization procedure can be done
using standard methods such us e.g. Buchwald reactions, acylation reactions, reaction with
alkyl/arylisocyanates, alkyl/ arylchloroformate, chloroformamides, reductive amination,
alkylation or any kind of N-derivatization reaction useful to the aim of forming compounds
according to formula I and very well known to people skilled in the art. This last reaction
can be carried out also by the previous formation of suitable intermediates e.g. a
chlorosulphonyl or chlorocarbonyl N-derivative of intermediate 5.
Alternatively, compounds of the invention can be prepared according to Scheme
Scheme 2.
Following Scheme 2, the R group is introduced at the beginning of the synthetic
pathway by a Sonogashira or Sonogashira-like reaction of the dialkyl or cyclic acetal of
propiolaldehyde with the proper alkylating, arylating or derivatising reagent R -LG where
LG is a leaving group as defined above.
The syntheses of other compounds not currently described in the general
description above are well documented inside the experimental part of this invention which
follows.
The free bases of compounds according to formula I, their diastereomers or
enantiomers can be converted to the corresponding pharmaceutically acceptable salts under
standard conditions well known in the art. For example, the free base is dissolved in a
suitable organic solvent, such as methanol, treated with, for example one equivalent of
maleic or oxalic acid, one or two equivalents of hydrochloric acid or methanesulphonic acid,
and then concentrated under vacuum to provide the corresponding pharmaceutically
acceptable salt. The residue can then be purified by recrystallization from a suitable organic
solvent or organic solvent mixture, such as methanol/diethyl ether.
The N-oxides of compounds according to formula I can be synthesized by simple
oxidation procedures well known to those skilled in the art.
Preparation of Compounds of the General Formula I
Unless otherwise stated, one or more tautomeric forms of compounds of the
examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms
of compounds of the examples described hereinafter should be considered to be disclosed.
The invention is illustrated by way of the following examples, in which the
following abbreviations may be employed:
AcOH acetic acid
AN acetonitrile
BOC tert-butyloxycarbonyl
conc. concentrated
DCM dichloromethane
DIPEA N,N-diisopropylethylamine
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
DPPF 1,1'-bis(diphenyl-phosphino)ferrocene
EI electron ionisation
ESI electrospray ionisation
EtOAc ethyl acetate
EtOH ethanol
HATU 2-(7-aza-1H-benzotriazoleyl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
HCl hydrochloric acid
HCOOH formic acid
HPLC high performance liquid chromatography
HPLC-MS HPLC coupled with mass spectrometry
i.vac. under vacuum
MeOH methanol
MS mass spectrometry
MW molecular weight
NaOH sodium hydroxide
NH OH ammonium hydroxide (30% ammonia in water)
PE petroleum ether
R retention value (from thin layer chromatography)
RT room temperature
R.sub.t retention time (from HPLC)
TBTU 2-(1H-benzotriazoleyl)-1,1,3,3-tetramethyluronium tetrafluoroborate
THF tetrahydrofurane
TEA triethyl amine
TFA trifluoracetic acid
THF tetrahydrofurane.
The following table (Table 1) illustrates some example compounds of the
invention according to general formula I, that were prepared according to Scheme 1 or
Scheme 2. Compounds 21, 25, 28, 29, 33 and 36 do not fall within the scope of the invention:
HPL-MS
Ex. Structure Chemical Name
(M+H)
t-butyl(3-chlorophenylethynyl)-
1 347.11
3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate
3-(3-chlorophenylethynyl)-3a,4,5,6a-
341.77
tetrahydropyrrolo[3,2-d]isoxazolyl-
(furan-2yl)methanone
ethyl(3-chlorophenylethynyl)-
3 319.76
3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate
3-(3-chlorophenylethynyl)-N-ethyl-N-
isopropyl-3a,4,5,6a-
4 360.86
tetrahydropyrrolo[3,2-d]isoxazole
carboxamide
t-butyl[(6-methyl
pyridyl)ethynyl]-3a,4,5,6a-
328.38
tetrahydropyrrolo[3,2-d]isoxazole
carboxylate
3-(3-chlorophenylethynyl)-3a,4,5,6a-
6 360.81
tetrahydropyrrolo[3,2-d]isoxazolyl-
(morpholinyl)methanone
3-(3-chlorophenylethynyl)-N,N-
dimethyl-3a,4,5,6a-
7 318.78
tetrahydropyrrolo[3,2-d]isoxazole
carboxamide
3-(3-chlorophenylethynyl)-3a,4,5,6a-
8 358.84
tetrahydropyrrolo[3,2-d]isoxazolyl-
(piperidinyl)methanone
3-(3-chlorophenylethynyl)-3a,4,5,6a-
9 344.81
tetrahydropyrrolo[3,2-d]isoxazolyl-
(pyrrolidinyl)methanone
t-butyl(3-methylphenylethynyl)-
327.40
3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate
3-(3-methylphenylethynyl)-3a,4,5,6a-
11 324.40
tetrahydropyrrolo[3,2-d]isoxazolyl-
(pyrrolidinyl)methanone
3-(3-methylphenylethynyl)-3a,4,5,6a-
12 338.42
tetrahydropyrrolo[3,2-d]isoxazolyl-
(piperidinyl)methanone
3-(3-methylphenylethynyl)-3a,4,5,6a-
13 340.40
tetrahydropyrrolo[3,2-d]isoxazolyl-
(morpholinyl)methanone
N,N-diethyl(3-
methylphenylethynyl)-3a,4,5,6a-
14 326.41
tetrahydropyrrolo[3,2-d]isoxazole
carboxamide
N-methoxy-N-methyl(3-
methylphenylethynyl)-3a,4,5,6a-
314.36
tetrahydropyrrolo[3,2-d]isoxazole
carboxamide
ethyl(3-methylphenylethynyl)-
16 299.34
3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate
3-[(6-methylpyridyl)ethynyl]-
3a,4,5,6a-tetrahydropyrrolo[3,2-
17 339.42
d]isoxazolyl-(piperidin
yl)methanone
3-[(6-methylpyridyl)ethynyl]-
3a,4,5,6a-tetrahydropyrrolo[3,2-
18 341.37
d]isoxazolyl-(morpholin
yl)methanone
N-methoxy-N-methyl[(6-methyl
pyridyl)ethynyl]-3a,4,5,6a-
19 315.35
tetrahydropyrrolo[3,2-d]isoxazole
carboxamide
ethyl[(6-methylpyridyl)ethynyl]-
300.33
3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate
isopropyl(3-chlorophenylethynyl)-
3a,4,5,6a-tetrahydropyrrolo[3,2- 333.1
d]isoxazolecarboxylate
cyclopropylmethyl(3-
chlorophenylethynyl)-3a,4,5,6a-
345.8
tetrahydropyrrolo[3,2-d]isoxazole
carboxylate
cyclopentyl(3-
chlorophenylethynyl)-3a,4,5,6a- [2M+Na]
tetrahydropyrrolo[3,2-d]isoxazole = 739.4
carboxylate
2,2-dimethylpropyl(3-
chlorophenylethynyl)-3a,4,5,6a- [2M+Na]
tetrahydropyrrolo[3,2-d]isoxazole = 743.6
carboxylate
3-(3-chlorophenylethynyl)-N-(propan-
2-yl)-3a,4,5,6a-tetrahydropyrrolo[3,2- 332.1
d]isoxazolecarboxamide
N-t-butyl(3-chlorophenylethynyl)-
3a,4,5,6a-tetrahydropyrrolo[3,2- 346
d]isoxazolecarboxamide
3-(3-chlorophenylethynyl)-N-
cyclopentyl-3a,4,5,6a-
358.1
tetrahydropyrrolo[3,2-d]isoxazole
carboxamide
3-(3-chlorophenylethynyl)-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolyl- 341.5
(furanyl)methanone
3-(3-chlorophenylethynyl)-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolyl- 355.1
(5-methylfuranyl)methanone
3-(3-chlorophenylethynyl)-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolyl- 343.1
(cyclopentyl)methanone
3-(3-chlorophenylethynyl)-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolyl- 359.1
(oxanyl)methanone
3-(3-chlorophenylethynyl)-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolyl- 373.3
(4-methylpiperazinyl)methanone
4-oxanyl(3-chlorophenylethynyl)-
[2M+Na]
3a,4,5,6a-tetrahydropyrrolo[3,2-
= 771.3
d]isoxazolecarboxylate
3-methylbutyl(3-
chlorophenylethynyl)-3a,4,5,6a- [2M+Na]
tetrahydropyrrolo[3,2-d]isoxazole = 743.3
carboxylate
3-(3-chlorophenylethynyl)-N-(pentan-
3-yl)-3a,4,5,6a-tetrahydropyrrolo[3,2- 360
d]isoxazolecarboxamide
3-(3-chlorophenylethynyl)-N-(pyridin-
3-yl)-3a,4,5,6a-tetrahydropyrrolo[3,2- 367.2
d]isoxazolecarboxamide
3-(3-chlorophenylethynyl)-N-(2,2-
dimethylpropyl)-3a,4,5,6a-
360.2
tetrahydropyrrolo[3,2-d]isoxazole
carboxamide
3-(3-chlorophenylethynyl)-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolyl- 358.1
(thiazolyl)methanone
3-(3-chlorophenylethynyl)-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolyl- [2M+Na]
[4-(1,1- = 807.3
difluorocyclohexyl)]methanone
3-(3-chlorophenylethynyl)-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolyl- 372.3
(1-methyl-piperidinyl)methanone
3-(3-chlorophenylethynyl)-N-(2-
methoxyethyl)-N-methyl-3a,4,5,6a- [2M+Na]
tetrahydropyrrolo[3,2-d]isoxazole = 745.3
carboxamide
3-(3-fluorophenylethynyl)-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolyl- 344.54
(morpholinyl)methanone
3-(3-fluorophenylethynyl)-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolyl- 328.54
(pyrrolidinyl)methanone
3-phenylethynyl-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolyl- 326.55
(morpholinyl)methanone
3-(3-bromophenylethynyl)-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolyl- 389.71
(pyrrolidinyl)methanone
Table 1: Example Compounds of the Invention
H-NMR data for selected compounds above is shown below in Table 2.
Ex. H-NMR
(400 MHz, DMSO-d6) δ ppm 1.44 (s, 9 H) 2.20 (br. s., 2H) 2.90 - 3.09 (m, 1H)
1 3.61 - 3.71 (m, 1H) 4.15 (br. s., 1H) 6.18 - 6.37 (m, 1H) 7.45 - 7.53 (m, 1H) 7.57
- 7.63 (m, 2H) 7.74 (s, 1H)
(400 MHz, CHLOROFORM-d) δ ppm 2.22 (d, 1H) 2.42 (br. s., 1H) 3.33 (br. s.,
1H) 4.11 (br. s., 1H) 4.38 (dd, 1H) 6.56 (dd, 1H) 6.88 (d, 1H) 7.30 (br. s., 1H)
7.32 - 7.38 (m, 1H) 7.41 - 7.49 (m, 2H) 7.56 (t, 1H) 7.61 (s, 1H)
(400 MHz, DMSO-d6) δ ppm 1.22 (t, 3H) 2.23 (br. s., 2H) 2.95 - 3.15 (m, 1H)
3.66 - 3.76 (m, 1H) 4.05 - 4.24 (m, 3H) 6.32 (br. s., 1H) 7.46 - 7.53 (m, 1H) 7.56
- 7.63 (m, 2H) 7.75 (t, 1H)
(400 MHz, CHLOROFORM-d) δ ppm 1.16 (t, 3H) 1.22 (t, 6H) 2.18 (tt, 1H)
4 2.29 (dd, 1H) 3.09 - 3.35 (m, 3H) 3.76 (dd, 1H) 3.92 (t, 1H) 4.13 (spt, 1H) 6.59
(d, 1H) 7.30 - 7.36 (m, 1H) 7.39 - 7.46(m, 2H) 7.54 (t, 1H)
(400 MHz, CHLOROFORM-d) δ ppm 2.10 - 2.23 (m, 1H) 2.30 (dd, 1H) 3.18
6 (td, 1H) 3.43 - 3.50 (m, 4H) 3.73 (m, 4H) 3.87 - 3.98 (m, 2H) 6.57 (d, 1H) 7.33
(dd, 1H) 7.43 (m, 2H) 7.54 (s, 1H)
(400 MHz, CHLOROFORM-d) δ ppm 2.08 - 2.22 (m, 1H) 2.25 - 2.34 (m, 1H)
2.96 (s, 6H) 3.25 (td, 1H) 3.80 (dd, 1H) 3.92 (dd, 1H) 6.60 (s, 1H) 7.30 - 7.37
(m, 1H) 7.38 - 7.47 (m, 2H) 7.54 (t, 1H)
(400 MHz, CHLOROFORM-d) δ ppm 1.49 - 1.71 (m, 6H) 2.09 - 2.22 (m, 1H)
2.23 - 2.32 (m, 1H) 3.21 (td, 1H) 3.37 (m, 4H) 3.82 (dd, 1H) 3.91 (dd, 1H) 6.61
(d, 1H) 7.33 (dd, 1H) 7.38 - 7.47 (m, 2H) 7.54 (t, 1H)
(400 MHz, CHLOROFORM-d) δ ppm 1.80 - 1.98 (m, 4H) 2.11 - 2.24 (m, 1H)
2.31 (dd, 1H) 3.26 (td, 1H) 3.41-3.49 (m, 2H) 3.49 - 3.57 (m, 2H) 3.88 (dd, 1H)
3.94 (dd, 1H) 6.62 (d, 1H) 7.33 (dd, 1H) 7.38 - 7.47 (m, 2H) 7.54 (t, 1H)
(400 MHz, DMSO-d6) δ ppm 1.44 (s, 9 H) 2.09 - 2.29 (m, 2H) 2.33 (s, 3H) 2.86
- 3.09 (m, 1H) 3.57 - 3.72 (m, 1H) 4.14 (br. s., 1H) 6.15 - 6.37(m, 1H) 7.30 -
7.43 (m, 3H) 7.45 (s, 1H)
(400 MHz, CHLOROFORM-d) δ ppm 1.79 - 1.97 (m, 4H) 2.16 (m, 1H) 2.32
11 (dd, 1H) 2.37 (s, 3H) 3.26 (td, 1H) 3.40 - 3.48 (m, 2H) 3.48 - 3.59 (m, 2H) 3.87
(dd, 1H) 3.93 (dd, 1H) 6.59 (d, 1H) 7.20 - 7.31 (m, 2H) 7.31 - 7.40 (m, 2H)
13 (400 MHz, CHLOROFORM-d) δ ppm 2.16 (m, 1H) 2.33 (dd, 1H) 2.38 (s, 3H)
3.19 (td, 1H) 3.43 - 3.50 (m, 4H) 3.68 - 3.77 (m, 4H) 3.86 - 3.99 (m, 2H) 6.54
(d, 1H) 7.21 - 7.32 (m, 2H) 7.34 - 7.41 (m, 2H)
(400 MHz, CHLOROFORM-d) δ ppm 1.19 (t, 6H) 2.10 - 2.23 (m, 1H) 2.32 (dd,
1H) 2.38 (s, 3H) 3.22 (td, 1H) 3.26 - 3.43 (m, 4H) 3.79 (dd, 1H) 3.91 (dd, 1H)
6.57 (d, 1H) 7.21 - 7.31 (m, 2H) 7.33 - 7.40 (m, 2H)
(400 MHz, DMSO-d6 343 K) δ ppm 1.24 (t, 3H) 2.16 - 2.25 (m, 2H) 2.35 (s,
16 3H) 2.99 - 3.10 (m, 1H) 3.65 - 3.76 (m, 1H) 4.14 (q, 2H) 4.06 - 4.31 (m, 1H)
6.30 (d, 1H) 7.28 - 7.42 (m, 3H) 7.42 - 7.46 (m, 1H)
(400 MHz, CHLOROFORM-d) δ ppm 1.58 - 1.70 (m, 6H) 2.08 - 2.21 (m, 1H)
17 2.34 (dd, 1H) 2.61 (s, 3H) 3.19 (td, 1H) 3.32 - 3.43 (m, 4H) 3.81 (dd, 1H) 3.94
(dd, 1H) 6.60 (d, 1H) 7.20 (d, 1H) 7.41 (d, 1H) 7.62 (t, 1H)
(400 MHz, CHLOROFORM-d) δ ppm 2.02 - 2.22 (m, 1H) 2.35 (dd, 1H) 2.58 (s,
18 3H) 3.15 (td, 1H) 3.35 - 3.52 (m, 4H) 3.63 - 3.78 (m, 4H) 3.86 (dd, 1H) 3.96 (dd,
1H) 6.55 (d, 1H) 7.19 (d, 1H) 7.39 (d, 1H) 7.61 (t, 1H)
(400 MHz, CHLOROFORM-d) δ ppm 2.18 (m, 1H) 2.42 (dd, 1H) 2.63 (s, 3H)
3.15 (s, 3H) 3.34 (td, 1H) 3.69 (s, 3H) 3.90 (dd, 1H) 4.01 (dd, 1H) 6.66 (d, 1H)
7.23 (d, 1H) 7.43 (d, 1H) 7.65 (t, 1H)
(400 MHz, CHLOROFORM-d) δ ppm 1.28 - 1.38 (m, 3H) 2.11 - 2.28 (m, 1H)
2.40 (dd, 1H) 2.60 (s, 3H) 3.22 (td, 1H) 3.73 - 3.93 (m, 1H) 3.93 - 4.08 (m, 1H)
4.24 (d, 2H) 6.28 - 6.52 (m, 1H) 7.20 (d, 1H) 7.40 (d, 1H) 7.57 - 7.66 (m, 1H)
Table 2: Selected H-NMR data
The following examples illustrate some of the compounds of general formula I as
described above. These examples are illustrative only and are not intended to limit the scope
of the invention. The reagents and starting materials are readily available to those skilled in
the art.
Example 6 (Method 1 – ref. scheme 2)
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-
(morpholinyl)methanone
1-chloro(3,3-diethoxypropynyl)benzene (Intermediate 6a)
A mixture of 1-chloroiodobenzene (4 g, 16.8 mmol), propargylaldehyde
diethyl acetal (2.66 mL, 18.5 mmol), bis(trifenilphosphine)palladium(II)dichloride (295 mg,
0.42 mmol), cuprous iodide (160 mg, 0.84 mmol) and triethylamine (60 mL) was stirred at
r.t. for 3h. After 4h, the reaction mixture was quenched with H O, extracted with EtOAc,
which was washed with brine, dried over Na SO , and evaporated to dryness in vacuo. The
residue was purified by automated flash chromatography (Horizon TM – Biotage; Petroleum
Ether:EtOAc, 97:3) to give 4 g of the title compound as a fluid yellowish oil. Yield: 100%.
MS: [M+H] = 239.32.
3-(3-chlorophenyl)propynal (Intermediate 6b)
To a solution of Intermediate 6a (4g, 16.7 mmol) in CH Cl (50 mL) was added
38.8 mL of water and 7.7 mL of trifluoroacetic acid. After 4 h of stirring, a further 4 eq. of
trifluoroacetic acid was added. After 24h the conversion was completed; the 2 layers were
separated, the organic layer was washed with water, dried over Na SO and evaporated to
dryness in vacuo to afford the title compound as a yellow-brownish oil, used in the next step
without further purification.
MS: [M+H]+ = 165.35.
3-(3-chlorophenyl)propynal oxime (Intermediate 6c)
A mixture of 3-chlorophenylpropargylaldehyde (22.8 g, 139 mmol),
hydroxylamine hydrochloride (416 mmol, 28.9 g), EtOH (200 mL) and water (50 mL) was
stirred at r.t. for 24h. The reaction mixture was diluted with H O, extracted with
Et O:EtOAc, washed with brine and evaporated to dryness in vacuo affording 24 g of the title
compound (syn:anti 1:1) as a pasty brownish solid. The pale brown residue was used in the
next step without further purification. Yield: 96.4%.
MS: [M+H]+ = 180.16.
t-butyl(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazole
carboxylate (Intermediate 6d)
To a solution of Intermediate 6c (20.68 mmol, 3.72 g) in N,N-dimethylformamide
(40 mL) was added N-chlorosuccinimide (23.64 mmol, 3.16 g) and the mixture was stirred at
room temperature for 2h. Then water was added and the aqueous layer was extracted with
Et O. The organic phase was dried over Na SO , filtered and evaporated. The crude residue
2 2 4
was dissolved in CH Cl (40 mL) and cooled at 0°C, then tert-butyl 2,3-dihydropyrrole
carboxylate (5.91 mmol, 1 g) followed by TEA (17.73 mmol, 1.79 g, 2.47 mL) were added
and the mixture was stirred at room temperature overnight. Afterwards, water was added, the
two phases were separated, the organic layer was washed with water and brine, dried over
Na SO . The solvent was removed in vacuo and the crude residue was purified via
automated flash chromatography (Isolera® Biotage, SNAP100 cartidge) eluting with
EtOAc:Petroleum Ether gradient from 5% to 50% of EtOAc. The title product (1.1 g) was
isolated as a brownish solid.
3-(3-chlorophenylethynyl)-4,5,6,6a-tetrahydropyrrolo[3,2-d]isoxazole
(Intermediate 6e)
Into a solution of tert-butyl 3-[2-(3-chlorophenyl)ethynyl]-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolecarboxylate (intermediate 6d, 2.88 mmol, 1 g) in CHCl3
(40 mL) stirred at 0°C was added dropwise trifluoroacetic acid (28.84 mmol, 3.288 g, 2.208
mL) and the mixture was heated at 60°C for 5 hours. The reaction was checked by LC/MS
showing the correct (M+H)+ peak. The mixture was cooled at 0-5°C and alkalinized with
NaOH to pH=9. Afterwards, water was added, the two phases were separated, the organic
layer was washed with water and brine, dried over Na SO . The solvent was removed in
vacuo affording the title product (0.7 g, 98.4 %) as a brown oil that was used for the next step
without purification.
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-
(morpholinyl)methanone
To a solution of 3-(3-chlorophenylethynyl)-4,5,6,6a-tetrahydropyrrolo[3,2-
d]isoxazole (intermediate 6e, 0.6 g, 2.4 mmol) in dichloromethane (40 mL) and triethylamine
(0.63 mL, 2.8 mmol) was added dropwise 4-morpholinecarbonyl chloride (0.42 mL, 3.6
mmol) and the resulting mixture was stirred overnight at r.t.. Afterwards it was heated at
50°C for 4 h. The reaction mixture was then poured into water, the organic layer was
separated, dried over Na SO and evaporated to dryness in vacuo. The crude product was
purified by flash chromatography (SP1® Biotage) eluting with a gradient petroleum
ether:ethyl acetate 9:1 to 6:4 affording the title compound as a white solid (0.45 g, 51%
yield).
H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.10 - 2.23 (m, 1H) 2.30 (dd, 1H) 3.18 (td,
1H) 3.43 - 3.50 (m, 4H) 3.73 (m, 4H) 3.87 - 3.98 (m, 2H) 6.57 (d, 1H) 7.33 (dd, 1H) 7.43 (m,
2H) 7.54 (s, 1H).
MS: [M+H] = 239.32.
Example 6a
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-
morpholinomethanone less polar enantiomer
Example 6b
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-
morpholinomethanone more polar enantiomer
Example compounds 6a and 6b were obtained by chiral HPLC purification from
the compound of Example 6.
Example 20 (Method 2 – ref. scheme 1)
ethyl[(6-methylpyridyl)ethynyl]-3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate
N-hydroxytrimethylsilyl-propynimidoyl chloride (Intermediate 20a)
To a solution of 3-trimethylsilylpropynal oxime (Carreira, Erick M.; Lohse-
Fraefel, Nina, Organic Letters, (2005), Vol. 7, No.10, pp.2011-2014, 68 g, 11.9 mmol) in
11.9 mL of DMF stirred at r.t. was added N-chlorosuccinimide (1.99 g, 14.8 mmol). After 4
h stirring, the solution was poured into water and extracted with Et O. After the usual work-
up, the residue (2.09 g) was used as it was for the next step.
t-butyl[(trimethylsilyl)ethynyl]-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazole
carboxylate (Intermediate 20b)
A solution of TEA (0.554 mL, 3.85 mmol) in 9.4 mL of dichloromethane was
added dropwise into a solution of Compound 20a (1.67 g, 2.57 mmol) and tert-butyl 2,3-
dihydropyrrolecarboxylate (600 mg, 2.57 mmol) in 42 mL of dichloromethane stirred at
0°C. Afterwards, the reaction mixture was stirred at r.t. for 24 h; then it was diluted with
cold water. The organic layer was washed with brine, dried over Na SO , evaporated to
dryness in vacuo. The crude product was purified by automated flash chromatography
(SP1®TM – Biotage; gradient Petroleum Ether:EtOAc from 5:5 to 0:10) affording 641 mg of
the title product. Yield: 67 %.
t-butyl[(6-methylpyridinyl)ethynyl]-3a,4,5,6a-tetrahydro-pyrrolo[3,2-
d]isoxazolecarboxylate (Intermediate 20c)
To a solution of Intermediate 20b (200 mg, 0.65 mmol) and 2-bromo
methylpyridyne (81.1µl, 0.72 mmol) in N,N-dimethylformamide (4 mL), degassed with a
nitrogen stream for 5 min., were added quickly in the order
tetrakis(triphenylphosphine)palladium(0) (22.5 mg, 0.02 mmol), tetrabutylammonium
fluoride (186 mg, 0.713 mmol) and sodium acetate (106 mg, 1.3 mmol). The mixture was
heated in a microwave oven at 120°C for 10 min. The reaction was poured into water and
extracted with ethyl acetate. The organic layer was dried over Na SO and evaporated to
dryness. The crude product was purified by automated flash chromatography (SP1®TM –
Biotage) with a gradient petroleum ether:ethyl acetate from 8:2 to 3:7. The title product was
isolated as a brownish oil (212mg, 54.2%).
3-[(6-methylpyridinyl)ethynyl]-4,5,6,6a-tetrahydropyrrolo[3,2-d]isoxazole
(Intermediate 20d).
The title compound was synthesized using the method reported above for
Intermediate 6e, but replacing Intermediate 20c for Intermediate 6d. After the usual work-up
procedure the residue was purified by means of automated flash chromatography
(Horizon®TM – Biotage; gradient Petroleum Ether:EtOAc from 98:2 to 9:1) to give the title
compound. Yield: 95.9%.
ethyl[(6-methylpyridyl)ethynyl]-3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate.
To a solution of Intermediate 20d (60 mg, 0.26 mmol) in CH Cl (6 mL) was
added TEA (0.08 mL) and then, dropwise, ethyl chloroformate (38.1 µL, 0.4 mmol). The
reaction mixture was stirred at r.t. for 1 h. Afterwards, it was poured into water and extracted
with ethyl acetate. The organic layer was dried over Na SO and evaporated to dryness. The
crude product was purified by automated flash chromatography (SP1®TM – Biotage) with a
gradient petroleum ether:ethyl acetate from 9:1 to 4:6. The title product was isolated as a
brownish oil which was further purified by preparative HPLC affording the title product.
Yield: 25.3%.
H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 - 1.38 (m, 3H) 2.11 - 2.28 (m, 1H)
2.40 (dd, 1H) 2.60 (s, 3H) 3.22 (td, 1H) 3.73 - 3.93 (m, 1H) 3.93 - 4.08 (m, 1H) 4.24 (d, 2H)
6.28 - 6.52 (m, 1H) 7.20 (d, 1H) 7.40 (d, 1H) 7.57 - 7.66 (m, 1H).
Alternative procedure for the synthesis of Intermediate 20c.
t-butylethynyl-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolecarboxylate
(Intermediate 20e).
To a solution of Intermediate 20b (530 mg, 1.72 mmol) in MeOH (20mL) was
added K CO (713 mg, 5.16 mmol) and the mixture was stirred for 1 h at r.t., checked by
HPLC-MS, poured into water and extracted with EtOAc. The title compound was obtained
by purification with automated flash column chromatography (SP1®TM – Biotage) with a
gradient petroleum ether:ethyl acetate from 7:3 to 6:4. Colourless oil (406 mg, 49.2 %).
t-butyl[(6-methylpyridinyl)ethynyl]-3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate (Intermediate 20c).
To a solution of Intermediate 20e (200 mg, 0.85 mmol) and 2-bromo
methylpyridyne (106 µl, 0.93 mmol) in N,N-dimethylformamide (4 mL) degassed with a
nitrogen stream for 5 min., were added quickly in the order
tetrakis(triphenylphosphine)palladium(0) (29.3 mg, 0.025 mmol) and sodium acetate (139
mg, 1.7 mmol) and the mixture was heated in a microwave oven at 120°C for 10 min. The
reaction was poured into water and extracted with ethyl acetate. The organic layer was dried
over Na SO and evaporated to dryness. The crude product was purified by automated flash
chromatography (SP1®TM – Biotage) with a gradient petroleum ether:ethyl acetate from 8:2
to 3:7. The title product was isolated as a brownish oil (212mg, 54.2%).
Starting from Intermediate 6e (as hydrochloride) the following compounds were
prepared as follows:
Example 21
isopropyl(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazole-
6-carboxylate
Intermediate 6e (30 mg, 0.1 mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (21 µL, 0.15
mmol) followed by isopropyl chloroformate 1.0M in toluene (127 µL, 0.12 mmol) were
added. Stirring was continued at room temperature overnight. Water was added (5 mL) and
the reaction mixture was extracted with DCM (10 mL, 3x). The organic layer was dried over
MgSO and evaporated to dryness under reduced pressure to give 55 mg of crude product.
The crude product was purified by preparative TLC (Hex:EtOAc 6:4), taking up the silica
with 5% MeOH in EtOAc. The filtrate was concentrated under vacuum to give 11.4 mg (38
% yield) of the title product.
MS: [M+H] = 333.1, [2M+Na] = 687.3;
H NMR (400 MHz, DMSO-d ) δ 7.77 – 7.73 (m, 1H), 7.63 – 7.57 (m, 2H), 7.53 – 7.47 (m,
1H), 6.35 – 6.26 (m, 1H), 4.89 – 4.78 (m, 1H), 4.21 – 4.12 (m, 1H), 3.73 – 3.65 (m, 1H), 3.08
– 2.97 (m, 1H), 2.26 – 2.18 (m, 2H), 1.23 (d, 6H).
Example 22
cyclopropylmethyl(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate
Intermediate 6e (30 mg, 0.1 mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0 °C and triethylamine (21 µL, 0.15
mmol) followed by cyclopropylmethyl chloroformate (17 mg, 0.12 mmol)) were added.
Stirring was continued at room temperature overnight. Water was added (5 mL) and the
reaction mixture was extracted with DCM (10 mL, 3x). The organic layer was dried over
MgSO , and evaporated to dryness under reduced pressure to give 48 mg of crude product.
The crude product was purified by preparative TLC (Hex:EtOAc 4:6), taking up the silica
with 5% MeOH in EtOAc. The filtrate was concentrated under vacuum to give 18.6 mg (50
% yield) of the title product.
MS: [M+H] = 345.8
H NMR (400 MHz, DMSO-d ) δ 7.77 – 7.74 (m, 1H), 7.64 – 7.56 (m, 2H), 7.51 (dd, 1H),
6.33 (d, 1H), 4.23 – 4.11 (m, 2H), 3.76 – 3.67 (m, 1H), 3.14 – 2.97 (m, 2H), 2.29 – 2.16 (m,
2H), 1.21 – 1.07 (m, 1H), 0.53 (d, 2H), 0.35 – 0.26 (m, 2H).
Example 23
cyclopentyl(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate
Intermediate 6e (30 mg, 0.11 mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (21 µL, 0.15
mmol)) followed by cyclopentyl chloroformate (16 µL, 0.13 mmol) were added. Stirring
was continued for 1 hour at room temperature. Water was added (5 mL) and the reaction
mixture was extracted with EtOAc (10 mL, 3x). The organic layer was dried over Na SO ,
and evaporated to dryness under reduced pressure to give 54 mg of crude product. The crude
product was purified by flash column chromatography on silica using EtOAc:DCM:Hex
3:1:1 as an eluent. 27 mg of the title compound as a yellow thick oil was obtained (71 %
yield).
MS: [2M+Na] = 739.4
H NMR (400 MHz, DMSO-d6) δ 7.78 – 7.73 (m, 1H), 7.63 – 7.57 (m, 2H), 7.53 – 7.47 (m,
1H), 6.29 (dd, 1H), 5.05 (s, 1H), 4.26 – 4.11 (m, 1H), 3.73 – 3.62 (m, 1H), 3.14 – 2.95 (m,
1H), 2.27 – 2.15 (m, 2H), 1.90 – 1.75 (m, 2H), 1.75 – 1.50 (m, 6H).
Example 24
2,2-dimethylpropyl(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate
Intermediate 6e (30 mg, 0.11 mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (21 µL, 0.15
mmol) followed by neopentyl chloroformate (19 µL, 0.13 mmol) were added. Stirring was
continued for 1 hour at room temperature. Water was added (5 mL) and the reaction mixture
was extracted with EtOAc (10 mL, 4x). The organic layer was dried over Na SO , and
evaporated to dryness under reduced pressure to give 48 mg of crude product. The crude
product was purified by flash column chromatography on silica using EtOAc:DCM:Hex
3:1:1 as an eluent. 33 mg of the title compound as a yellow thick oil was obtained (86 %
yield).
MS: [2M+Na]=743.6
H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.66 – 7.56 (m, 2H), 7.54 – 7.45 (m, 1H),
6.40 – 6.26 (m, 1H), 4.28 – 4.10 (m, 1H), 3.89 – 3.62 (m, 3H), 3.22 – 2.95 (m, 1H), 2.24 (s,
2H), 0.97 – 0.90 (m, 9H).
Example 25
3-(3-chlorophenylethynyl)-N-(propanyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxamide
Intermediate 6e (30 mg, 1.1 mmol) was dissolved in DCM (0.45 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (32 µL, 0.23
mmol)) followed by isopropyl isocyanate (10 µL, 0.11 mmol) were added. Stirring was
continued for 24 hours at room temperature. Water was added (5 mL) and the reaction
mixture was extracted with DCM (10 mL, 3x). The organic layer was dried over MgSO and
evaporated to dryness under reduced pressure to give 41 mg of crude product. The residue
was purified via preparative HPLC to afford 23 mg of the title compound (66% yield).
MS: [M+H] = 332.1
H NMR (400 MHz, DMSO-d6) δ 7.75 (t, 1H), 7.63 – 7.56 (m, 2H), 7.53 – 7.46 (m, 1H),
6.44 (d, 1H), 6.35 (d, 1H), 4.14 – 4.06 (m, 1H), 3.84 – 3.75 (m, 1H), 3.70 – 3.61 (m, 1H),
3.00 – 2.89 (m, 1H), 2.24 – 2.10 (m, 2H), 1.09 (dd, 6H).
Example 26
N-t-butyl(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazole-
6-carboxamide
Intermediate 6e (30 mg, 0.1 mmol) was dissolved in DCM (0.45 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (49 µL, 0.35
mmol) followed by tert-butyl isocyanate (17 µL, 0.14 mmol) were added. Stirring was
continued for 24 hours at room temperature. Water was added (5 mL) and the reaction
mixture was extracted with DCM (10 mL, 3x). The organic layer was dried over MgSO and
evaporated to dryness under reduced pressure to give 45 mg of crude product. The residue
was purified via flash column chromatography on silica eluting with AcOEt:Hex 1:1. The
collected combined fractions were taken up with hexane and finally purified via preparative
TLC (AcOEt:Hex 1:9), taking up the silica with 5% MeOH in EtOAc. The filtrate was
concentrated under vacuum to give 14 mg (33 % yield) of the title product.
MS: [M+H] = 346
H NMR (400 MHz, DMSO-d6) δ 7.75 (t, 1H), 7.62 – 7.57 (m, 2H), 7.53 – 7.47 (m, 1H),
6.48 (d, 1H), 5.82 (s, 1H), 4.14 – 4.05 (m, 1H), 3.69 – 3.60 (m, 1H), 3.03 – 2.90 (m, 1H),
2.22 – 2.11 (m, 2H), 1.29 (s, 9H).
Example 27
3-(3-chlorophenylethynyl)-N-cyclopentyl-3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxamide
Interrmediate 6e (30 mg, 0.1 mmol) was dissolved in DCM (0.45 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (35 µL, 0.25
mmol) followed by cyclopentyl isocyanate (14 µL, 0.12 mmol) were added. Stirring was
continued for 24 hours at room temperature. Water was added (5 mL) and the reaction
mixture was extracted with DCM (10 mL, 3x). The organic layer was dried over MgSO and
evaporated to dryness under reduced pressure to give 48 mg of crude product. The crude
product was purified via flash column chromatography on silica eluting with a gradient from
Hex:EtOAc 9:1 to EtOAc. The collected combined fractions were evaporated to dryness,
taken up with hexane, purified by preparative TLC (Hex:EtOAc 9:1) and finally by
preparative HPLC to afford 14 mg (36% yield) of the title product.
MS:[M+H] =358.1
H NMR (400 MHz, DMSO-d6) δ 7.77 – 7.73 (m, 1H), 7.59 (m, 2H), 7.53 – 7.46 (m, 1H),
6.46 (d, 1H), 6.41 (d, 1H), 4.10 (t, 1H), 4.00 – 3.88 (m, 1H), 3.71 – 3.62 (m, 1H), 3.00 – 2.89
(m, 1H), 2.23 – 2.09 (m, 2H), 1.86 – 1.74 (m, 2H), 1.68 – 1.60 (m, 2H), 1.53 – 1.37 (m, 4H).
Example 28
3-(3-chlorophenyl)ethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-
(furanyl)methanone
Intermediate 6e (30 mg, 0.1 mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (21 µL, 0.14
mmol) followed by furancarbonyl chloride (17 mg, 0.12 mmol) were added. Stirring was
continued at room temperature overnight. Water was added (5 mL) and the reaction mixture
was extracted with DCM (10 mL, 3x). The organic layer was dried over MgSO , and
evaporated to dryness under reduced pressure to give 53 mg of crude product. The crude
product was purified by flash column chromatography on silica followed by preparative TLC
(Hex:EtOAc 2:8) taking up the silica with 5% MeOH in EtOAc. The filtrate was evaporated
under vacuum to give 22.4 mg of the title product (62% yield).
MS: [M+H] = 341.5
H NMR (400 MHz, DMSO) δ 8.30 – 8.14 (m, 1H), 7.86 – 7.74 (m, 2H), 7.66 – 7.57 (m,
2H), 7.51 (t, 1H), 6.85 – 6.78 (m, 1H), 6.69 – 6.54 (m, 1H), 4.36 – 4.07 (m, 2H), 3.14 – 2.98
(m, 1H), 2.38 – 2.15 (m, 2H).
Example 29
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-(5-
methylfuranyl)methanone
Intermediate 6e (30 mg, 0.1 mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (21 µL, 0.14
mmol) followed by 5-methylfurancarbonyl chloride (18 mg, 0.13 mmol) were added.
Stirring was continued for 1 hour at room temperature. Water was added (5 mL) and the
reaction mixture was extracted with EtOAc (10 mL, 3x). The organic layer was dried over
Na SO and evaporated to dryness under reduced pressure to give 50 mg of crude product.
The crude product was purified by flash column chromatography on silica using
EtOAc:DCM:Hex 3:1:1 as an eluent. 30 mg of the title compound as a yellow thick oil was
obtained (80% yield).
MS: [M+H] = 355.1, [2M+Na] = 731.4
H NMR (400 MHz, DMSO-d6) δ 7.78 (t, 1H), 7.66 – 7.56 (m, 2H), 7.55 – 7.46 (m, 1H),
7.11 (d, 1H), 6.81 (s, 1H), 6.33 (dd, 1H), 4.30 (s, 1H), 4.21 – 3.86 (m, 2H), 3.08 (s, 1H), 2.36
(s, 3H), 2.30 (s, 1H).
Example 30
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-
(cyclopentyl)methanone
Intermediate 6e (30 mg, 0.1 mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (37 µL, 0.26
mmol) followed by cyclopentanecarbonyl chloride (15 µL, 0.13 mmol) were added. Stirring
was continued for 1 hour at room temperature. Water was added (5 mL) and reaction
mixture was extracted with DCM (10 mL, 3x). The organic layer was dried over MgSO ,
and evaporated to dryness under reduced pressure to give 46 mg of crude product. The crude
product was purified by flash column chromatography on silica using hexane:EtOAc 7:3 as
an eluent to afford 35 mg of the title product (96% yield).
MS: [M+H] = 343.1
H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 7.78 – 7.75 (m, 1H), 7.64 – 7.58 (m,
2H), 7.50 (t, 1H), 6.60 (d, 1H ), 6.45 (d, 1H ), 4.28 (t, 1H ), 4.13 (t,
major rotamer minor rotamer major rotamer
1H ), 3.92 – 3.82 (m, 1H), 3.24 – 3.14 (m, 1H ), 3.09 – 3.00 (m, 1H
minor rotamer major rotamer minor
), 2.99 – 2.87 (m, 1H), 2.29 – 2.11 (m, 2H), 1.93 – 1.77 (m, 2H), 1.73 – 1.52 (m, 6H).
rotamer
Example 31
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]oxazolyl-(oxan-
4-yl)methanone
Intermediate 6e (30 mg, 0.1 mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (37 µL, 0.26
mmol) followed by tetrahydro-2H-pyrancarbonyl chloride (19 mg, 0.13 mmol) were
added. Stirring was continued for 1 hour at room temperature. Water was added (5 mL) and
reaction mixture was extracted with DCM (10 mL, 3x). The organic layer was dried over
MgSO , and evaporated to dryness under reduced pressure to give 65 mg of crude product.
The crude product was purified by flash column chromatography on silica using a gradient
DCM:EtOAc 8:2 to 6:4 as an eluent. 32 mg of the title compound were obtained (84% yield).
MS:[M+H] = 359.1
H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 7.78 – 7.75 (m, 1H), 7.64 – 7.57 (m,
1H), 7.51 (t, 1H), 6.67 (d, 1H ), 6.46 (d, 1H ), 4.29 (t, 1H ), 4.13
major rotamer minor rotamer major rotamer
(t, 1H ), 3.94 – 3.77 (m, 4H), 3.44 – 3.33 (m, 3H), 3.00 – 2.87 (m, 1H), 2.35 – 2.08
minor rotamer
(m, 2H), 1.71 – 1.52 (m, 4H).
Example 32
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-(4-
methylpiperazinyl)methanone
Intermediate 6e (30 mg, 0.1 mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (37 µL, 0.26
mmol) followed by 4-methylpiperazinecarbonyl chloride (17 µL, 0.13 mmol) were added.
Stirring was continued for 1 hour at room temperature. Water was added (5 mL) and
reaction mixture was extracted with DCM (10 mL, 3x). The organic layer was dried over
MgSO and evaporated to dryness under reduced pressure to give 42 mg of crude product.
The crude product was purified by flash column chromatography on silica using
DCM:MeOH 19:1 as an eluent. 20 mg of the title product were obtained (51% yield).
MS: [M+H] = 373.3
H NMR (400 MHz, DMSO-d6) δ 7.77 – 7.73 (m, 1H), 7.62 – 7.57 (m, 2H), 7.53 – 7.46 (m,
1H), 6.52 (d, 1H), 4.12 (t, 1H), 3.59 (dd, 1H), 3.36 – 3.28 (m, 2H, the signal is partially
covered by water), 3.28 – 3.19 (m, 2H), 3.16 – 3.07 (m, 1H), 2.36 – 2.24 (m, 4H), 2.23 – 2.16
(m, 4H), 2.15 – 2.05 (m, 1H).
Example 33
4-oxanyl(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazole-
6-carboxylate
Intermediate 6e (30 mg, 0.11 mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (21 µL, 15
mmol) followed by oxanyl chloroformate (21 mg, 0.13 mmol) were added. Stirring was
continued for 1.5 hour at room temperature. Water was added (5 mL) and reaction mixture
was extracted with EtOAc (10 mL, 3x). The organic layer was dried over Na SO and
evaporated to dryness under reduced pressure to give 60 mg of crude product. The crude
product was purified by flash column chromatography on silica using EtOAc:DCM 3:1 as an
eluent. After a further flash purification 28 mg of the title compound as a yellow thick oil
were obtained (70% yield).
MS: [2M+Na] = 771.3
H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.65 – 7.56 (m, 2H), 7.53 – 7.47 (m, 1H),
6.35 (t, 1H), 4.83 (s, 1H), 4.20 (s, 1H), 3.87 – 3.63 (m, 3H), 3.50 (d, 2H), 3.05 (s, 1H), 2.24
(s, 2H), 1.87 (s, 2H), 1.59 (s, 2H).
Example 34
3-methylbutyl(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate
Intermediate 6e (30 mg, 0.11mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (21 µL, 0.15
mmol) followed by 3-methylbutyl chloroformate (19 mg, 0.13 mmol) were added. Stirring
was continued for 1 hour at room temperature. Water was added (5 mL) and reaction
mixture was extracted with EtOAc (10 mL, 3x). The organic layer was dried over Na SO ,
and evaporated to dryness under reduced pressure to give 53 mg of crude product. The crude
product was purified by column chromatography on silica using EtOAc:DCM 3:1 as an
eluent. 34 mg of the title product as a yellow thick oil was obtained (89% yield).
MS: [2M+Na] =743.3
H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.64 – 7.56 (m, 2H), 7.55 – 7.46 (m, 1H),
6.37 – 6.23 (m, 1H), 4.24 – 4.14 (m, 1H), 4.16 – 4.05 (m, 2H), 3.77 – 3.61 (m, 1H), 3.12 –
2.97 (m, 1H), 2.22 (m, 2H), 1.79 – 1.58 (m, 1H), 1.49 (dt, 2H), 0.91 (d, 6H).
Example 35
3-(3-chlorophenylethynyl)-N-(pentanyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxamide
Intermediate 6e (40 mg, 0.14 mmol) was dissolved in DCM (0.45 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (54 µL, 0.038
mmol) followed by 2-ethylpropylisocyanate (18mg, 0.15 mmol) were added. Stirring was
continued for 24 hours at room temperature. Water was added (5 mL) and reaction mixture
was extracted with DCM (10 mL, 3x). The organic layer was dried over MgSO and
evaporated to dryness under reduced pressure to give 57 mg of crude product. The crude
product was purified via preparative HPLC to afford 42 mg of the title product (78% yield).
MS: [M+H] = 360.0
H NMR (400 MHz, DMSO-d6) δ 7.75 (t, 1H), 7.63 – 7.56 (m, 2H), 7.54 – 7.46 (m, 1H),
6.48 (d, 1H), 6.19 (d, 1H), 4.17 – 4.07 (m, 1H), 3.73 – 3.62 (m, 1H), 3.50 – 3.41 (m, 1H),
3.03 – 2.92 (m, 1H), 2.24 – 2.13 (m, 2H), 1.52 – 1.31 (m, 4H), 0.83 (td, 6H).
Example 36
3-(3-chlorophenylethynyl)-N-(pyridinyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxamide
Intermediate 6e (40 mg, 0.14 mmol) was dissolved in DCM (0.8 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (47 µL, 0.33
mmol) followed by pyridineisocyanate (19 mg, 0.15 mmol) were added. Stirring was
continued for 24 hours at room temperature. Water was added (5 mL) and the reaction
mixture was extracted with DCM (10 ml, 3x). The organic layer was dried over MgSO , and
evaporated to dryness under reduced pressure to give 61 mg of crude product. The crude
product was purified via flash column chromatography on silica with a gradient hexane to
Hex:EtOAc 1:1 as eluent. The combined collected fractions were evaporated to dryness and
further purified by preparative TLC (Hex:EtOAc 6:4). 40 mg of the title compound were
obtained (77% yield).
MS: [M+H] = 367.2, [2M+Na] = 755.2
H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.70 (d, 1H), 8.22 (dd, 1H), 7.94 (dd, 1H),
7.77 (t, 1H), 7.65 – 7.58 (m, 2H), 7.55 – 7.48 (m, 1H), 7.32 (dd, 1H), 6.60 (d, 1H), 4.24 (t,
1H), 3.91 – 3.82 (m, 1H), 3.21 – 3.10 (m, 1H), 2.37 – 2.24 (m, 2H).
Example 37
3-(3-chlorophenylethynyl)-N-(2,2-dimethylpropyl)-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolecarboxamide
Intermediate 6e (30 mg, 0.1 mmol) was dissolved in DCM (0.45 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (32 µL, 0.24
mmol) followed by 2,2-dimethylpropyl isocyanate (12 mg, 0.1 mmol) were added. Stirring
was continued for 24 hours at room temperature. Water was added (5 mL) and the reaction
mixture was extracted with DCM (10 ml, 3x). The organic layer was dried over MgSO and
evaporated to, dryness under reduced pressure to give 39 mg of crude product. The crude
product was purified via preparative HPLC to yield 23 mg of the title product (60%).
MS: [M+H] = 360.2
H NMR (400 MHz, DMSO-d6) δ 7.75 (t, 1H), 7.63 – 7.56 (m, 2H), 7.53 – 7.47 (m, 1H),
6.53 – 6.45 (m, 2H), 4.16 – 4.09 (m, 1H), 3.71 – 3.64 (m, 1H), 3.07 – 2.96 (m, 2H), 2.78 (dd,
1H), 2.23 – 2.16 (m, 2H), 0.84 (s, 9H).
Example 38
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-(1,5-
dimethyl-1H-pyrazolyl)methanone
Intermediate 6e (50 mg, 0.18 mmol) was suspended in DCM (1 mL) at room
temperature. TEA (52 µl, 37 mmol) was added and the suspension became a clear, yellow
solution. 1,5-dimethyl-1H-pyrazolecarbonyl chloride (28 mg, 18 mmol) as solid was
added. The reaction solution was stirred at room temperature for 2h. The solvent was
removed in vacuo. The by-products were removed by dissolving the crude product in MeOH
and precipitating with Et O. Afterwards, the solvents were removed in vacuo and the residue
was dissolved in 10 mL of EtOAc and washed three times with 1M KHSO to give the
desired product (34 mg, 53 % yield).
MS:[M+H] = 369.1, [2M+H] = 759.2
H NMR (400 MHz, DMSO-d6) δ 7.77 (t, 1H), 7.66 – 7.56 (m, 2H), 7.50 (t, 1H), 7.34 (d,
1H), 6.50 (d, 1H), 4.30 (t, 1H), 4.01 (dd, 1H), 3.80 (d, 3H), 3.06 (td, 1H), 2.36 – 2.10 (m,
5H).
Example 39
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-
(thiazolyl)methanone
Intermediate 6e (50 mg, 18 mmol)) was suspended in DCM (1 mL) at room
temperature. TEA (52 µl, 0.37 mmol)) was added and the suspension became a clear, yellow
solution. Next, 1,3-thiazolecarbonyl chloride (26 mg, 0.18 mmol) as a solid was added.
The reaction solution was stirred at room temperature for 2h. The solvent was removed in
vacuo and the crude product was purified using flash column chromatography Hex:EtOAc
1:1, TLC =0.24). Trituration with Et O increased the product purity from 91 % to 93 %.
Rf 2
The final purification step was performed on the prep. HPLC, which yielded 11 mg of the
desired product (as formate salt) with a purity of 99.7 % (17% yield).
MS : [M+H] = 358.1
H NMR (400 MHz, DMSO-d6) δ 9.30 – 9.16 (m, 1H), 8.44 (d, 1H), 7.78 (t, 1H), 7.61 (tt,
2H), 7.55 – 7.45 (m, 1H), 7.35 (d, 1H), 4.34 – 4.23 (d, 1H), 4.03 (dd, 1H), 3.15 (dd, 1H),
2.32 – 2.22 (m, 2H).
Example 40
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-(4,4-
difluorocyclohexyl)methanone
Intermediate 6e (30 mg, 0.11 mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (37 µL, 26
mmol) followed by 4,4-difluorocyclohexanecarbonyl chloride (23 mg, 0.13 mmol) were
added. Stirring was continued at room temperature overnight. Water was added (5mL) and
the reaction mixture was extracted with DCM (10 mL, 3x). The organic layer was extracted
with brine and evaporated to dryness under reduced pressure. The crude product was
purified by flash column chromatography on silica using DCM:MeOH 95:5 as an eluent to
give 38.0 mg. The obtained product was further purified by preparative TLC, using as an
eluent AcOEt: hexane (1:1) and finally by preparative HPLC to give 17 mg of the title
compound (41% yield).
MS: [2M+Na]+=807.3
H NMR (400 MHz, DMSO-d6) δ 7.78 – 7.75 (m, 1H), 7.64 – 7.58 (m, 2H), 7.54 – 7.48 (m,
1H), 6.65 (d, 1H ), 6.45 (d, 1H ), 4.36 – 4.27 (m, 1H ), 4.17 – 4.10
major rotamer minor rotamer major rotamer
(m, 1H ), 3.96 – 3.89 (m, 1H ), 3.89 – 3.80 (m, 1H ), 2.95 (td,
minor rotamer minor rotamer major rotamer
1H), 2.88 – 2.79 (m, 1H), 2.31 – 2.20 (m, 2H), 2.18 – 2.00 (m, 2H), 1.98 – 1.75 (m, 4H), 1.69
– 1.52 (m, 2H).
Example 41
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-(1-
methyl-piperidinyl)methanone
Intermediate 6e (30 mg, 0.11 mmol) was dissolved in DCM (0.3 mL) under an
argon atmosphere. Catalytic DMF was added, then 1-methylpiperidinecarboxylic acid (30
mg, 0.21 mmol) and DIPEA (55 µL, 32 mmol). Stirring was continued for 15 mins at room
temperature. After 15 min HATU (85 mg, 0.22 mmol) was added and stirring was continued
overnight at room temperature. Sodium bicarbonate saturated aq. solution was added (5mL)
and the reaction mixture was extracted with DCM (10 mL, 3x). The organic layer was
evaporated to dryness under reduced pressured. The crude product was purified by flash
column chromatography on silica using as an eluent DCM:MeOH 9:1 to give 20 mg of solid
title compound (51% yield).
MS: [M+H] = 372.3
H NMR (400 MHz, DMSO-d6) δ 7.78 – 7.74 (m, 1H), 7.64 – 7.58 (m, 2H), 7.54 – 7.47 (m,
1H), 6.64 (d, 1H ), 6.45 (d, 1H ), 4.35 – 4.28 (m, 1H ), 4.18 – 4.11
major rotamer minor rotamer major rotamer
(m, 1H ), 3.96 – 3.80 (m, 1H), 3.27 – 3.00 (m, 3H), 3.00 – 2.89 (m, 1H), 2.84 – 2.71
minor rotamer
(m, 1H), 2.31 – 2.23 (m, 1H), 2.21 – 2.08 (m, 1H), 1.92 – 1.58 (m, 4H), 1.21 – 1.11 (m, 1H).
Signal from CH group covered by DMSO-d
3 6.
Example 42
3-(3-chlorophenylethynyl)-N-(2-methoxyethyl)-N-methyl-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolecarboxamide
3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazole
carbonyl chloride (Intermediate 42a)
Triphosgene (18 mg, 0.06 mmol) was dissolved in dry DCM (0.4 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and pyridyne (14 µL, 0.18
mmol) was added. After 5 min Intermediate 6e (50 mg, 0.18 mmol) dissolved in dry DCM
was added slowly. The reaction mixture was warmed up to room temperature. Stirring was
continued for 2 hours at room temperature. The reaction was quenched with 1M HCl (0.35
mL), extracted 5 x with DCM (10 mL), and washed with a saturated aq. solution of NaHCO
(5mL). The organic layer was dried over Na SO , concentrated and dried under reduced
pressure to give 73 mg of crude product. The crude product was purified by flash column
chromatography using EtOAc:DCM 3:1 as an eluent. 35 mg of a yellow thick oil was
obtained. The product was used immediately in the next step without further purification.
3-(3-chlorophenylethynyl)-N-(2-methoxyethyl)-N-methyl-3a,4,5,6a-
tetrahydropyrrolo[3,2-d]isoxazolecarboxamide
Intermediate 42a (35 mg, 11 mmol) was dissolved in DCM (0.6 mL) under an
argon atmosphere. The reaction mixture was cooled to 0°C and triethylamine (32 µL, 0.23
mmol) followed by (2-methoxyethyl)methylamine (25 µL, 0.23 mmol) were added. Stirring
was continued for 2 hours at room temperature. Water was added (5 mL) and the reaction
mixture was extracted with DCM (10 mL, 3x). The organic layer was dried over Na SO and
evaporated to dryness under reduced pressure to give 53 mg of crude product. The crude
product was purified by flash column chromatography on silica using EtOAc:DCM 3:1 as an
eluent. 25 mg of yellow thick oil was obtained (61 % yield).
MS: [2M+Na] = 745.3
H NMR (400 MHz, DMSO-d6) δ 7.75 (t, 1H), 7.64 – 7.55 (m, 2H), 7.54 – 7.46 (m, 1H),
6.52 (d, 1H), 4.12 (t, 1H), 3.61 – 3.39 (m, 4H), 3.31 – 3.27 (m, 1H), 3.26 (s, 3H), 3.18 – 3.05
(m, 1H), 2.88 (s, 3H), 2.25 – 2.01 (m, 2H).
Example 43
3-(3-fluorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-
morpholinyl-methanone
tert-butyl-(3-trimethylsilylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazole
carboxylate (Intermediate 20b, alternative procedure)
A solution of tert-butyl 2,3-dihydropyrrolecarboxylate (500 mg, 2.95 mmol)
and 3-trimethylsilylpropynal oxime (459.06 mg, 3.25 mmol) in MTBE (15 mL) was
cooled to 0-5°C while stirring. Sodium hypochlorite (2.806 mL, 5.91 mmol) was added
dropwise keeping the reaction temperature below 20°C. The reaction mixture was stirred at
the same temperature for 3 hours; afterwards, it was quenched with Na SO solution; the two
phases were separated, the organic layer was washed with water and brine, dried over
Na SO , filtered and evaporated to dryness in vacuo. The crude residue was purified by
automated flash chromatography (Biotage SP1, cartridge type SNAP25) using a gradient
from petroleum ether:EtOAc 95:5 to 7:3. Further purification by automated flash
chromatography (Isolera Biotage) with a gradient Petroleum Ether:EtOAc from 5:5 to 0:10
afforded 250 mg of the title product. Yield: 27 %.
tert-butyl(3-fluorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazole-
6-carboxylate (Intermediate 43a)
The title compound was synthesized using the method reported above for
Intermediate 20c, but replacing 2-bromomethylpyridyne with 1-fluoroiodo-benzene.
After the usual work-up procedure the residue was purified by automated flash
chromatography (Isolera Biotage; gradient Petroleum Ether:EtOAc from 95:5 to 7:3) to give
the title compound. Yield: 76%.
MS: [M+H] = 331.65
3-(3-fluorophenylethynyl)-4,5,6,6a-tetrahydropyrrolo[3,2-d]isoxazole
(Intermediate 43b)
The title compound was synthesized using the method reported above for
Intermediate 6e, but replacing Intermediate 6d with Intermediate 43a. After the usual work-
up procedure the residue was used for the next step without further purification. Yield: 95%
(crude product).
MS: [M+H] = 231.54
3-(3-fluorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-
morpholinyl-methanone
To a solution of Intermediate 43b (50 mg, 0.21 mmol) in CH Cl (6 mL) was
added TEA (56 µL, 0.43 mmol) and then, dropwise, morpholinecarbonyl chloride (38.1
µL, 0.32 mmol). The reaction was heated at 50°C for 4 h. The reaction mixture was then
poured into water, the organic layer was separated, dried over Na SO and evaporated to
dryness in vacuo. The crude product was purified by flash chromatography (Isolera
Biotage) eluting with a gradient petroleum ether:ethyl acetate 8:2 to 2:8 affording the title
compound as a white solid (0.31 g, 41% yield).
MS: [M+H] = 344.54
H NMR (400 MHz, DMSO-d6) ppm 7.45 - 7.58 (m, 3H) 7.34 - 7.43 (m, 1H) 6.54 (d, 1H)
4.10 - 4.19 (m, 1H) 3.51 - 3.69 (m, 5H) 3.30 - 3.38 (m, 2H) 3.19 - 3.28 (m, 2H) 3.12 (td, 1H)
2.05 - 2.25 (m, 2H)
Example 44
3-(3-fluorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-
(pyrrolidinyl)methanone
The title compound was synthesized using the method reported above for
Example 43, but replacing 4-pyrrolidine carbonyl chloride for morpholinecarbonyl
chloride. After the usual work-up procedure the residue was purified by flash
chromatography (Isolera Biotage) eluting with a gradient petroleum ether:ethyl acetate 8:2
to 2:8 affording the title compound as a white solid (0.20 g, 28% yield).
MS: [M+H] = 328.54
H NMR (400 MHz, DMSO-d6) ppm 7.45 - 7.58 (m, 3H) 7.29 - 7.44 (m, 1H) 6.54 (d, 1H)
4.19 (dd, 1H) 3.68 (dd, 1H) 3.35 - 3.46 (m, 2H) 3.23 - 3.28 (m, 2H) 3.11 (td, 1H) 2.04 - 2.28
(m, 2H) 1.59 - 1.93 (m, 4H)
Example 45
3-phenylethynyl-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-(morpholin
yl)methanone
tert-butyl(2-phenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazole
carboxylate (Intermediate 45a)
The title compound was synthesized using the method reported above for
Intermediate 20c, but replacing 2-bromomethylpyridyne with iodobenzene. After the
usual work-up procedure the residue was purified by means of automated flash
chromatography (Isolera – Biotage; gradient Petroleum Ether:EtOAc from 95:5 to 7:3) to
give the title compound. Yield: 59%.
MS: [M+H] = 313.51
3-(2-phenylethynyl)-4,5,6,6a-tetrahydropyrrolo[3,2-d]isoxazole (Intermediate
45b)
The title compound was synthesized using the method reported above for
Intermediate 6e, but replacing Intermediate 6d with Intermediate 45a. After the usual work-
up procedure the residue was used for the next step without further purification Yield: 98%
(crude product).
MS: [M+H] = 213.54
3-phenylethynyl-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-(morpholin
yl)methanone
The title compound was synthesized using the method reported above for
Example 43, but replacing Intermediate 43b with Intermediate 45b. After the usual work-up
procedure the residue was purified by flash chromatography (Isolera Biotage) eluting with a
gradient petroleum ether:ethyl acetate 8:2 to 2:8 affording the title compound as a white solid
(0.23 g, 25% yield).
MS: [M+H] = 326.55
H NMR (400 MHz, DMSO-d6) ppm 7.59 - 7.66 (m, 2H) 7.43 - 7.56 (m, 3H) 6.53 (d, 1H)
4.13 (dd, 1H) 3.52 - 3.69 (m, 5H) 3.33 - 3.41 (m, 2H) 3.19 - 3.28 (m, 2H) 3.13 (td, 1H) 2.05 -
2.24 (m, 2H)
Example 46
3-(3-bromophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-
(pyrrolidinyl)methanone
tert-Butyl 3-(3-bromophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-
d]isoxazolecarboxylate (Intermediate 46a)
The title compound was synthesized using the method reported above for
Intermediate 20c, but replacing 2-bromomethylpyridyne with 1-bromoiodo-benzene.
After the usual work-up procedure the residue was purified by means of automated flash
chromatography (Isolera – Biotage; gradient Petroleum Ether:EtOAc from 9:1 to 6:4) to give
the title compound. Yield: 42%.
MS: [M+H] = 392.66
3-(3-bromophenylethynyl)-4,5,6,6a-tetrahydropyrrolo[3,2-d]isoxazole
(Intermediate 46b)
The title compound was synthesized using the method reported above for
Intermediate 6e, but replacing Intermediate 6d with Intermediate 46a. After the usual work-
up procedure the residue was used for the next step without further purification Yield: 89%
(crude product).
MS: [M+H] = 292.78
3-(3-bromophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazolyl-
(pyrrolidinyl)methanone
The title compound was synthesized using the method reported above for
Example 43, but replacing Intermediate 43b with Intermediate 46b and 4-pyrrolidine
carbonyl chloride for morpholinecarbonyl chloride. After the usual work-up procedure
the residue was purified by flash chromatography (Isolera Biotage) eluting with a gradient
petroleum ether:ethyl acetate 8:2 to 2:8 affording the title compound as a white solid (0.20 g,
19% yield).
MS: [M+H] = 389.71
H NMR (400 MHz, DMSO-d6) ppm 7.87 (m, 1H), 7.72 (m, 1H), 7.64 (m, 1H), 7.39-7.48
(m, 1H), 6.54 (d, 1H), 4.07-4.18 (m, 1H), 3.60-3.72 (m, 1H), 3.34-3.44 (m, 2H), 3.31 (d, 2H),
3.11 (m, 1H), 2.03-2.30 (m, 2H), 1.64-1.94 (m, 4H)
Biological Assay
Cell lines stably transfected were generated using inducible expression vectors
encoding human mGlu receptor using the Tetracycline-Regulated Expression system (T-
REx system, Invitrogen, Life Technologies). Human mGluR open reading frame (ORF),
comprehensive of the stop codon, were cloned into the pcDNA4/TO/myc-His A vector,
carrying the TetO2. The insertion site was HindIII-PstI for mGluR receptors. The obtained
constructs were then transfected into the T-REx CHO cell line using the FuGENE protocol
(Roche); the CHO T-REx cell line stably expresses the Tet repressor (from the
pcDNA6/TR plasmid) under the selection of blasticidin, 10µg/ml. Stable clones were
obtained selecting with zeocin 1 mg/ml and maintaining in ULTRA CHO medium (LONZA)
supplemented with dialyzed FBS, zeocin, blasticidine, at 37°C, in an atmosphere of 5 % CO .
The expression of h-mGluR receptors was de-repressed with 1 µg/ml tetracycline for 18h
before binding experimentation, while the expression of h-mGluR receptors was derepressed
respectively with 3 ng/ml and 10 ng/ml tetracycline for 18h before calcium fluorescence
experimentation.
Radioligand binding assay at native mGluR and mGluR receptor subtypes
Affinity at transmembrane glutamate metabotropic mGluR receptor subtypes was
evaluated according to the methods of Anderson (Anderson et al., J Pharmacol. Exp. Ther.,
(2002), Vol.303(3), pp.1044-51), with some modifications. Cloned mGluR was obtained by
re-suspending CHO T-REx h-mGluR cells (50 µg/well) in 20 mM HEPES, 2 mM MgCl ,
2mM CaCl , pH 7.4, that then were incubated in a final volume of 1 ml for 60 min at 25 °C
with 4 nM [ H]MPEP in the absence or presence of competing drugs. Non-specific binding
was determined in the presence of 10 μM MPEP. The incubation was stopped by addition of
cold Tris buffer pH 7.4 and rapid filtration through 0.2% polyethyleneimine pretreated
Filtermat 1204-401 (Perkin Elmer) filters. The filters were then washed with cold buffer and
the radioactivity retained on the filters was counted by liquid scintillation spectrometry
(Betaplate 1204 BS-Wallac).
Calcium Fluorescence Measurements
Cells were seeded into black-walled, clear-bottom, 96-well plates at a density of
80000 cell/well, in RPMI (without Phenol Red, without L-glutamine; Gibco
LifeTechnologies, CA) supplemented with 10% dialyzed FBS. Following 18-h incubation
with tetracycline, the cells were loaded with 2 mM Ca - sensitive fluorescent dye Fluo-
4/AM (Molecular Probes) in Hanks’ balanced saline solution (HBSS, Gibco
LifeTechnologies, CA) with 20 μM Hepes (Sigma) and 2.5mM probenecid (Sigma), for 1h at
37°C. The cells were washed three times with HBSS to remove extracellular dye.
Fluorescence signals were measured by using the fluorescence microplate reader Flexstation
III (Molecular Devices) at sampling intervals of 1.5s for 60s.
The antagonist potency was determined using the EC of the quisqualate used as
agonist and the potentiation of mGlu activation was determined using the EC of the agonist
20
(quisqualate or glutamate). The compounds were applied 10 minutes before the application
of the agonist. For binding and calcium assay studies, the compounds were dissolved in
DMSO or demineralized water according to their solubility. All the reported doses were
those of the corresponding salts or bases.
Statistical analysis.
The inhibition curves of the tested compounds at native and cloned mGluR and
mGluR subtypes were determined by nonlinear regression analysis using software Prism 4.0
(Graphpad, San Diego, CA). The IC values and pseudo-Hill slope coefficients were
estimated by the program. The values for the inhibition constant, K, were calculated
according to the equation K = IC /(1 + [L]/K ), where [L] is the concentration of
i 50 d
radioligand and K is the equilibrium dissociation constant of the radioligand-receptor
complex (Cheng et al., Biochem. Pharmacol. (1973), Vol.22, pp.3099–3108).
Selected data for some of the compounds of interest prepared according to the
invention, are shown below in Table 3.
h.c. h.c. Fold Fold
EC50 Fold EC50 Fold
mglu R5 mgluR5 Increase Shift 1
Ex. nM Increase nM Inc.
IC50_n Calcium 1 μM microM
Glutam. Glutam. Quisq. Quisq.
M IC50_nM Glutam. Quisq.
1 3.87 >1000 37.11 1.96 1.8
2 29.6 >1000 0
3 81.5 54.76
4 6.99
707.9 0
6 24.8 95.18 5.1 3.24 132.15 3.3 2.7
6a 4875.5 0.745
6b 57.01 3.98 3.62
7 59.2 211.8 0
8 12.52 >1000
9 15.02 >1000
3.65 >1000 140.7 3.5 2.2
11 17 >1000
12 10.6
13 50.03 >1000 130.7 2.06 3.2
14 14.8 >1000
21.97 21.1
16 151.6
17 >1000 1.27
18 >1000
19 239.4
>1000 0
21 0 0
22 777 4.7 3.11
23 144 2.49 4.73
24 33.94 5.8 8.48
0 0
26 54.58 5.09 2.65
27 96.86 5.11 4.08
28 0 0
29 0 0
108.3 3.69 3.95
31 300.8 5.29 2.14
32 1100 2.92 1.92
34 541.9 3.31 5.6
36 0 0
Table 3: Biological Testing Data
Claims (15)
1. A compound of formula I (I), or an enantiomer, diastereomer, N-oxide, or a pharmaceutically acceptable salt thereof, wherein: R is an alkyl group, an optionally substituted mono-, bi- or tricyclic C -C heterocyclic 1 1 13 group containing 1 to 5 heteroatoms selected from N, O, and S; an optionally substituted mono-, bi- or tricyclic C -C aryl group, an optionally substituted C -C cycloalkyl group, or 6 14 3 6 an optionally substituted C -C cycloalkenyl group; or a bond, CO, CS, CH, CH , SO group 3 6 2 2 optionally substituted by one or more R groups or substituents; R is absent or is an optionally substituted mono- or bicyclic C -C heterocyclic group 2 1 9 containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, an optionally substituted mono-, bi- or tricyclic C -C aryl group, or an optionally substituted group 6 14 chosen from alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, alkylthio, amino, N-alkylamino, N,N-dialkylamino, or N-alkyl-N-alkoxyamino; R is an optionally substituted alkyl group, an optionally substituted mono-, bi- or tricyclic C -C heterocyclic group containing 1 to 5 heteroatoms selected from N, O, and S; an 1 13 optionally substituted mono-, bi- or tricyclic C -C aryl group, an optionally substituted C - 6 14 3 C cycloalkyl group, or an optionally substituted C -C cycloalkenyl group; and 6 3 6 n is 1-3, with the proviso that said compound of Formula I does not include the following selection of compounds: ; and
2. The compound according to claim 1, wherein the optional substituents being independently selected from the group consisting of halogen atoms and C -C alkyl, C -C 1 6 1 6 alkoxy, hydroxy, mercapto, nitro, cyano, oxo, halo(C -C )alkyl, halo(C -C )alkoxy, C -C 1 6 1 6 1 6 alkylthio, C -C alkylsulphonyl, C -C alkylcarbonyl, sulphamoyl, C -C alkylsulphamoyl, 1 6 1 6 1 6 di(C -C)alkylsulphamoyl, (C -C)alkoxycarbonyl and (C -C )alkylcarbonyl(C -C )alkyl 1 6 1 6 1 6 1 6 groups, and from groups of the formulae -NR*R*, -C(=O)-NR*R*, -A, -O-A, -C(=O)-A, - (CH )q-A, -NR**-A, -C(=O)-NR**-A, -NR**C(=O)-A and -O-C(=O)-A wherein each R* independently represents a hydrogen atom or a C -C alkyl, C -C alkoxy, C -C 1 6 1 6 1 6 alkylcarbonyl, phenyl or benzyl group, R** represents a hydrogen atom or a C -C alkyl group, q is an integer from 1 to 6 and A represents a phenyl group or a C -C heterocyclic group containing from 1 to 3 heteroatoms selected from N, O and S; a C -C cycloalkyl group; each group A being optionally substituted with from 1 to 3 groups independently selected from halo, hydroxy, cyano, nitro and C -C alkyl, preferably wherein the optional substituents are independently selected from the groups consisting of halogen atoms and C - C alkyl groups.
3. The compound according to claim 1 or claim 2, wherein n = 1.
4. The compound according to claim 1, wherein R is a CO group.
5. The compound according to any one of claims 1 to 4, wherein R is an optionally substituted mono- or bicyclic C -C heterocyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or an optionally substituted group chosen from cycloalkyl, alkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, amino, N-alkylamino, N,N- dialkylamino, or N-alkyl-N-alkoxy.
6. The compound according to claim 5, wherein R has the formula: where R is a C -C linear or branched alkyl group, a C -C cycloalkyl group or a C -C 4 1 10 1 10 1 10 heterocyclic group containing at least one heteroatom selected from N or O.
7. The compound according to claim 5 wherein R is a saturated or unsaturated, optionally substituted, five or six membered homocyclic group or heterocyclic group containing at least one heteroatom selected from N or O.
8. The compound according to claim 5 wherein R has the formula: -NR R where R is a C -C linear or branched alkyl or alkoxy group or hydrogen; R is a C -C 5 1 10 6 1 10 linear or branched alkyl or alkoxy group, R and R being the same or different; or wherein R and R together with the nitrogen atom form a five or six membered heterocyclic ring.
9. The compound according to any one of the preceding claims, wherein R is an optionally substituted mono-, bi- or tricyclic C -C aryl group, an optionally substituted, five 6 14 or six membered heterocyclic group containing at least one heteroatom selected from N or O, an optionally substituted C -C cycloalkyl group, or an optionally substituted C -C 3 6 3 6 cycloalkenyl group.
10. The compound according to claim 9, wherein R is a phenyl or pyridyl group, said optional substituents being selected from a C -C alkyl group or a halide group. 1 10
11. A compound according to claim 1 selected from:
12. A pharmaceutical composition comprising a compound of Formula I, (I), or an enantiomer, diastereomer, N-oxide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein: R is an alkyl group, an optionally substituted mono-, bi- or tricyclic C -C heterocyclic 1 1 13 group containing 1 to 5 heteroatoms selected from N, O, and S; an optionally substituted mono-, bi- or tricyclic C -C aryl group, an optionally substituted C -C cycloalkyl group, or 6 14 3 6 an optionally substituted C -C cycloalkenyl group; or a bond, CO, CS, CH, CH , SO group 3 6 2 2 optionally substituted by one or more R group or substituent; R is absent or is an optionally substituted mono- or bicyclic C -C heterocyclic group 2 1 9 containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, an optionally substituted mono-, bi- or tricyclic C -C aryl group, or an optionally substituted group 6 14 chosen from alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, alkylthio, amino, N-alkylamino, N,N-dialkylamino or N-alkyl-N-alkoxyamino; R is an optionally substituted alkyl group, an optionally substituted mono-, bi- or tricyclic C -C heterocyclic group containing 1 to 5 heteroatoms selected from N, O, and S; an 1 13 optionally substituted mono-, bi- or tricyclic C -C aryl group, an optionally substituted C - 6 14 3 C cycloalkyl group, or an optionally substituted C -C cycloalkenyl group; and 6 3 6 n is 1-3, with the proviso that said compound of Formula I does not include the following selection of compounds: ; and
13. Use of a compound of Formula I, (I), or an enantiomer, diastereomer, N-oxide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prevention of a neurological disorder, psychotic disorder, or a psychiatric disorder associated with glutamate dysfunction in a patient in need thereof, wherein: R is an alkyl group, an optionally substituted mono-, bi- or tricyclic C -C heterocyclic 1 1 13 group containing 1 to 5 heteroatoms selected from N, O, and S; an optionally substituted mono-, bi- or tricyclic C -C aryl group, an optionally substituted C -C cycloalkyl group, or 6 14 3 6 an optionally substituted C -C cycloalkenyl group; or a bond, CO, CS, CH, CH , SO group 3 6 2 2 optionally substituted by one or more R group or substituent; R is absent or is an optionally substituted mono- or bicyclic C -C heterocyclic group 2 1 9 containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, an optionally substituted mono-, bi- or tricyclic C -C aryl group, or an optionally substituted group 6 14 chosen from alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, alkylthio, amino, N-alkylamino, N,N-dialkylamino or N-alkyl-N-alkoxyamino; R is an optionally substituted alkyl group, an optionally substituted mono-, bi- or tricyclic C -C heterocyclic group containing 1 to 5 heteroatoms selected from N, O, and S; an 1 13 optionally substituted mono-, bi- or tricyclic C -C aryl group, an optionally substituted C - 6 14 3 C cycloalkyl group, or an optionally substituted C -C cycloalkenyl group; and 6 3 6 n is 1-3, with the proviso that said compound of Formula I does not include the following selection of compounds: ; and
14. Use of the compound according to claim 13, wherein the disorder associated with glutamate dysfunction is schizophrenia, schizoaffective disorder, substance induced psychotic disorder, age-associated learning and memory impairments or losses, post stroke dementia, deficits in concentration, mild cognitive impairment, cognitive dysfunction in Alzheimer’s disease, cognitive dysfunction of schizophrenia, cognitive decline, dementia, cognitive impairment, Fragile-X syndrome, Rett syndrome, Phelan-McDermid syndrome, or tuberous sclerosis.
15. Use of the compound according to claim 13, wherein the disorder is Fragile-X syndrome, Rett syndrome, Phelan-McDermid syndrome, or tuberous sclerosis.
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PCT/EP2015/081337 WO2016107865A1 (en) | 2014-12-29 | 2015-12-29 | Heterocyclylalkyne derivatives and their use as modulators of mglur5 receptors |
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