WO2014181101A1 - Composés 2-acyl-4-oxy-1,2-dihydropyrrol-5-one destinés à améliorer la mémoire et les fonctions cognitives - Google Patents

Composés 2-acyl-4-oxy-1,2-dihydropyrrol-5-one destinés à améliorer la mémoire et les fonctions cognitives Download PDF

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WO2014181101A1
WO2014181101A1 PCT/GB2014/051391 GB2014051391W WO2014181101A1 WO 2014181101 A1 WO2014181101 A1 WO 2014181101A1 GB 2014051391 W GB2014051391 W GB 2014051391W WO 2014181101 A1 WO2014181101 A1 WO 2014181101A1
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compound according
nhr
independently
alkyl
groups
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PCT/GB2014/051391
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Stephen Hilton
Arnaud RUIZ
Blanka SZULC
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Ucl Business Plc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones
    • 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

Definitions

  • the present invention pertains generally to the field of therapeutic compounds, and more specifically to certain compounds (for convenience, collectively referred to herein as "2-acyl-4-oxy-1 ,2-dihydropyrrol-5-one compounds” and "DHP compounds"), which, inter alia, are useful in methods of improving memory and/or cognitive function, and in the treatment of memory-related disorders and cognitive decline.
  • the present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions in the treatment of central nervous system (CNS) disorders such as memory deficit, memory-related disorders, disorders associated with cognitive decline, and cognitive impairment, including, for example, mild cognitive impairment (MCI), dementia, and Alzheimer's disease.
  • CNS central nervous system
  • Alzheimer's disease is the most common form, affecting 62% of those living with dementia.
  • Many of these people have a mixed pattern of dementia, with the second most common type, vascular dementia, also contributing to their condition.
  • acetylcholinesterase inhibitors such as donepezil
  • NMDA N- methyl-D-aspartate receptor blockers
  • memantine may be of benefit, but the evidence is less conclusive than for AChEls. Due to their differing mechanisms of action, memantine and AChEls can be used in combination. However, the benefit of using such a combination is slight.
  • Nootropic drugs also known as memory enhancers, smart drugs, and cognitive enhancers, are drugs that improve cognitive function, memory, and concentration. Their action alters the availability and balance of brain neurotransmitters, hormones, and enzymes, but the mechanisms by which they improve learning and memory are not fully understood.
  • One plausible mode of action is that they strengthen inter-synaptic communication between neurons and brain circuits that are important for learning and memory.
  • nootropic drugs facilitate the induction of long-term potentiation (LTP) in the hippocampus, a phenomenon leading to synapse reinforcement which is thought to underlie memory storage and recall in this brain structure.
  • LTP long-term potentiation
  • one candidate mechanism by which a drug could prove beneficial for treating the progressive decline typical of these disorders would be by lowering the threshold for long- term potentiation (LTP) induction in the hippocampus.
  • LTP long- term potentiation
  • the hippocampal formation is a region of the brain that plays a central role in learning and memory. It takes the form of an elongated C-shaped structure with a long axis (also known as the "septotemporal axis"), spanning rostro-dorsally from the septal nuclei near the midline of the brain to caudo-ventrally behind the thalamus of the temporal lobe, and a transverse axis, spanning the width of the formation. See, e.g., Amaral et al., 1989.
  • hippocampal formation refers to six regions which are functionally connected in a uni- or bi-directional fashion: the dentate gyrus, the CA regions (also termed hippocampus) consisting of CA1 , CA2, and CA3, the subiculum, the presubiculum, the parasubiculum, and the entorhinal cortex.
  • the term was used to refer to a uni-directional "trisynaptic" loop between the entorhinal cortex, dentate gyrus, CA3 and CA1 (see, e.g., Andersen et al., 1971).
  • use of the term has changed because the subiculum and its adjacent parts (the pre- and para-subiculum) also play important roles in learning and memory, and because the different regions are interconnected.
  • Granule cells within the dentate gyrus project a thin unmyelinated axon that forms a single parent fibre into the hippocampus proper, where it makes synaptic contacts onto CA3 pyramidal cells and various types of interneurones (see, e.g., Ascady et al., 1998).
  • These unusual axons (referred to as "mossy fibres") provide one of the most powerful glutamatergic inputs in the brain, amid the low basal firing rate observed in granule cells in vivo ( ⁇ 0.5 Hz) and the inability of granule cells to fire action potentials for extended periods of time (see, e.g., Henze et al., 2002).
  • Mossy fibre-CA3 synapses display a unique form of frequency-dependent facilitation of transmitter release consecutive to modest increases in presynaptic firing frequency (e.g., from 0.1 to 1 Hz), hence driving CA3 network activity very efficiently (see, e.g., Salin et al., 1996).
  • mossy fibre-CA3 synapses display a presynaptic form of LTP that is expressed by persistent changes in the probability of glutamate release.
  • ionotropic receptors i.e., receptors permeable to ions
  • ion channels localised in presynaptic membranes, in mossy fibres themselves, or in postsynaptic densities in CA3 pyramidal neurons (see, e.g., Ruiz et al., 2013).
  • Compounds that interact with pre- or post-synaptic receptor function thus represent powerful modulators of excitatory connections at the interface between neocortical and dentate structures and the hippocampus itself, where memory formation and information recall occurs.
  • LTP is impaired in the CA1 and CA3 areas (see, e.g., Francis et al., 2009; Simmons et al., 2009; Chong et al., 2011). This translates into a form of LTP having a magnitude that is much less than that which occurs in healthy individuals. However, little is known about changes occurring in CA3, where LTP is thought to be mainly expressed as a change in presynaptic release probability.
  • Excitatory synapses generally express both AMPA (2-amino-3-(3-hydroxy-5-methyl- isoxazol-4-yl)propanoic acid) and NMDA (N-methyl-D-aspartate) receptors, with AMPA receptors mediating the major component of the synaptic response (see, e.g., Zucker et al., 1998).
  • NMDA receptors are permeable to calcium as well as sodium and potassium, but they are blocked by magnesium at resting membrane potential.
  • repetitive activation of AMPA receptors can cause sufficient depolarisation to relieve the magnesium block, enabling a slower NMDA-receptor-mediated component of the response that is associated with calcium influx into the post-synaptic neuron.
  • This influx triggers various forms of synaptic plasticity, including LTP, which results from the activation of calcium- dependent signal transduction cascades that cause trafficking of AMPA receptors into the synapse, thus strengthening synaptic signalling.
  • NMDA receptors are the switches that trigger LTP, which is expressed and maintained by the presence of an increased number of active AMPA receptors at the potentiated synapse.
  • compounds that modulate AMPA receptor function may prove good candidates to strengthen excitatory synapses in diseases affecting memory binding and information recall as in the demented brain.
  • An alternative route by which compounds may enhance synaptic transmission and lower the threshold for LTP induction is by modulating presynaptic Ca 2+ channel function.
  • Voltage-gated Ca 2+ channels are a group of ion channels that are involved in a variety of processes including neurotransmitter exocytosis, synaptic plasticity, and gene expression. VGCCs are classified according to their a1 subunit. High-voltage activated channels consist of the Cav1 and Cav2 sub-families and include L-type (Cav1.1-1.4), P/Q-type (Cav2.1), N-type (Cav2.2) and R-type (Cav2.3) VGCCs. In contrast, low- voltage activated channels carry the Cav3 sub-family, consisting of the T-type
  • P/Q- and N-type VGCCs ensure efficient and rapid exocytosis and account for more than 90% of all VGCCs.
  • the remaining fraction consists of R-type VGCCs, which have been shown to be important for short-term plasticity and LTP at these synapses.
  • L-type VGCCs expressed at postsynaptic membranes are also important for LTP at the mossy fibre-CA3 synapse.
  • a compound that enhances one of the most powerful synapses in the brain is likely to be useful in methods of reducing memory deficits and improving the cognitive faculties of patients suffering from neurodegenerative disorders, such as dementia (and including, for example, senile dementia, vascular dementia, fronto-temporal dementia, and milder forms of dementia), Parkinson's disease, Huntington's disease, and other basal ganglia- related disorders where progressive memory decline is often symptomatic.
  • dementia and including, for example, senile dementia, vascular dementia, fronto-temporal dementia, and milder forms of dementia
  • Parkinson's disease Huntington's disease
  • basal ganglia- related disorders where progressive memory decline is often symptomatic.
  • the present invention provides novel compounds, as described herein, which provide surprising and unexpected activity, for example, as potentiators of excitatory synaptic transmission, enhancers of glutamatergic synapses, and/or positive modulators of AMPA receptors, and which may be useful in the treatment of such diseases and disorders.
  • Racetams are a class of nootropic drugs that share a pyrrolidone core. Piracetam was the first racetam to be discovered and is currently sold across the world under a variety of brand names (e.g., Nootropyl, Nootropil, Lucetam, Oikamid, Smart, Geratam, Biotropil). It is used for a wide range of applications including, for example, applications which rely on its nootropic properties, and treatment of myoclonus (involuntary twitching of a muscle or a group of muscles).
  • Nootropyl Nootropil
  • Lucetam Oikamid, Smart
  • Geratam Biotropil
  • myoclonus involuntary twitching of a muscle or a group of muscles.
  • Several related nootropic compounds including I eveti racetam, oxiracetam, nefiracetam, aniracetam, and pramiracetam, have also been described.
  • Clausenamide is a pyrrolidone-based compound which has been found to possess 50- 100 times greater nootropic activity than piracetam, and to enhance long-term potentiation (see, e.g., Feng et al., 2009). It is a naturally occurring compound which is isolated from extracts of dry leaves of Clausena Lansium, which is used in Chinese folk medicine. Clausenamide has four chiral centres, giving rise to sixteen stereoisomers (eight pairs of enantiomers). In nature, however, the compound appears as a racemate of (-)-clausenamide and (+)-clausenamide.
  • One aspect of the invention pertains to certain 2-acyl-4-oxy-1 ,2-dihydropyrrol-5-one compounds (also referred to herein as DHP compounds), as described herein.
  • compositions e.g., a pharmaceutical composition
  • a pharmaceutical composition comprising a DHP compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • a method of preparing a composition comprising the step of mixing a DHP compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the present invention pertains to a DHP compound, as described herein, for use in a method of improving memory and/or cognitive function in a patient.
  • Another aspect of the present invention pertains to use of a DHP compound, as described herein, in the manufacture of a medicament for improving memory and/or cognitive function in a patient.
  • Another aspect of the present invention pertains to a method of improving memory and/or cognitive function comprising administering to a patient in need of improved memory and/or cognitive function a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention pertains to a DHP compound, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein.
  • a disorder e.g., a disease
  • Another aspect of the present invention pertains to use of a DHP compound, as described herein, in the manufacture of a medicament for treatment, for example, treatment of a disorder (e.g., a disease) as described herein.
  • Another aspect of the present invention pertains to a method of treatment, for example, of a disorder (e.g., a disease) as described herein, comprising administering to a patient in need of treatment a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition.
  • kits comprising (a) a DHP compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
  • Another aspect of the present invention pertains to a DHP compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to a DHP compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
  • Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
  • Figure 1 shows that DHP-001 facilitates excitatory synaptic transmission from the dentate gyrus to CA3.
  • Panel A, top Example traces of excitatory synaptic potentials
  • field-EPSPs recorded with an extracellular electrode (each trace is an average of 20 consecutive field-EPSPs taken at 5 second intervals) before (BASELINE) and following superfusion with DHP-001 (100 ⁇ ) are shown.
  • the right-most trace shows field-EPSPs in the presence of DMSO (100 ⁇ , VEHICLE).
  • Figure 2 shows that superfusion with DHP-001 does not alter the input resistance of dentate granule cells.
  • Panel A Sample traces from a granule cellrecording showing the l-V relationship (membrane potential is -81 mV).
  • Panel B A plot of the l-V relationship (voltage in mV versus current in pA) before and after superfusion with DHP-001 (100 ⁇ ). No difference was found.
  • Panel C A bar graph of R in put ( ⁇ ) for control and DHP-001 , for pooled data from 5 neurons.
  • Figure 3 is a set of graphs illustrating the effect of DHP-001 on evoked AMPA currents in CA3 pyramidal neurons.
  • Bottom left Plot of normalised EPSC amplitude against time showing an increase upon superfusion with DHP-001 (100 ⁇ ) and depression by the group II metabotropic glutamate receptor agonist DCG-IV (1 ⁇ ).
  • Top Representative examples for each condition are shown (data from one CA3 pyramidal neuron).
  • Figure 4 is a concentration-facilitation curve for DHP-001. Each concentration was tested in at least 3 neurons. A logistic function was used to fit the data and each point represents the mean ⁇ S.E.M. The EC 50 inferred from the fit of the concentration- facilitation curve is 12 ⁇ .
  • One aspect of the present invention relates to certain compounds which are related to 2,5-dihydro-1 H-pyrrole, more specifically 1 ,2-dihydropyrrol-5-one:
  • one aspect of the present invention is a compound of the following formula, or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of the foregoing, wherein -J, -Q, -V, and -T are as defined herein (for convenience, collectively referred to herein as "2-acyl-4-oxy-1 ,2-dihydropyrrol-5-one compounds” and "DHP compounds”):
  • -J is independently -OH, -OR JE , -NH 2 , -NHR JN , -NR JN R JN2 , or -NR JN3 R'
  • Ci -6 alkyl is linear or branched saturated Ci -6 alkyl
  • -R JE2 is linear or branched C 2 - 6 alkenyl
  • -R JE3 is linear or branched C 2 - 6 alkynyl
  • each -R JE4 is saturated C 3 . 6 cycloalkyl
  • each -R JE5 is C 3 . 6 cycloalkenyl
  • each -R JE6 is non-aromatic C 3 . 7 heterocyclyl
  • each -R JE7 is independently phenyl or naphthyl
  • each -R JE8 is C 5 .i 0 heteroaryl
  • each -L JE - is linear or branched saturated Ci_ 4 alkylene; wherein: each -R K1C is independently: -F, -CI, -Br, -I,
  • each -R K2C is independently:
  • each -R c is independently: -R KK ,
  • each -R K2N and each -R K3N is independently: -R KK ,
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR KKK , -NH 2 , -NHR KKK , and -NR KKK 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R KKK , -CF 3 , -OH, -OR KKK , -OCF 3 , -NH 2 , -NHR KKK , and -NR KKK 2 ;
  • each -R KKK is linear or branched saturated Ci -4 alkyl
  • each -R JN is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L JN -phenyl;
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR JN A , -NH 2 , -NHR JN A , and -NR JN A 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R JN A , -CF 3 , -OH, -OR JN A , -OCF 3 , -NH 2 , -NHR JN A , and -NR JN A 2 ;
  • each -R JN A is linear or branched saturated C -4 alkyl
  • _ JN - is linear or branched saturated Ci_ 3 alkylene; each -R JN2 is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L JN2 -phenyl;
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR JN2A , -NH 2 , -NHR JN2A , and -NR JN2A 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R JN2A , -CF 3 , -OH, -OR JN2A , -OCF 3 , -NH 2 , -NHR JN2A , and -NR JN2A 2 ;
  • each -R JN2A is linear or branched saturated C -4 alkyl
  • _ JN2 - is linear or branched saturated Ci_ 3 alkylene
  • -Q is independently -H, -Q A , or -Q B ;
  • -Q A is independently:
  • -R QA2 is linear or branched C ⁇ alkenyl
  • -R QA3 is linear or branched C ⁇ alkynyl
  • each -R 0 ⁇ 4 is saturated C 3 . 6 cycloalkyl
  • each -R 0 ⁇ 5 is C 3 . 6 cycloalkenyl
  • each -R 0 ⁇ 6 is non-aromatic C 3 . 7 heterocyclyl
  • each -R ⁇ 7 is independently phenyl or naphthyl
  • each -R 0 ⁇ 8 is C 5 .i 0 heteroaryl
  • each -L QA - is linear or branched saturated Ci_ 4 alkylene; wherein: each -R S C is independently: -F, -CI, -Br, -I,
  • each -R S2C is independently:
  • R is independently:
  • two adjacent groups -R S3C may together form: -0-CH 2 -0- or -0-CH 2 CH 2 -0-;
  • R S2N and each -R S3N is independently:
  • Ci_ 4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR sss , -NH 2 , -NHR SSS , and -NR SSS 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R sss , -CF 3 , -OH, -OR sss , -OCF 3 , -NH 2 , -NHR SSS , and -NR sss 2 ;
  • each -R sss is linear or branched saturated Ci -4 alkyl
  • -Q B is independently -Q B , -Q B2 , -Q B3 , -Q B4 , -Q B5 , -Q B6 , or -Q B7 ;
  • -Q B is independently -OH or -OR QB ;
  • -Q B2 is independently -NH 2 , -NHR QB , -NR QB 2 , or -NR QB2 R QB3 ;
  • -Q B6 is -N0 2 ;
  • -Q B7 is independently -F, -CI, -Br, or -I; each -R QB is independently linear or branched saturated C -4 alkyl, phenyl, or -L QB -phenyl;
  • Ci_ 4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR QBB , -NH 2 , -NHR QBB , and -NR QBB 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R QBB , -CF 3 , -OH, -OR QBB , -OCF 3 , -NH 2 , -NHR QBB , and -NR QBB 2 ;
  • each -R QBB is linear or branched saturated Ci -4 alkyl; -NR Q R Q is independently azetidino, pyrrolidino, piperidino, piperizino,
  • -T is independently -H or -R T ;
  • -R T is independently:
  • -R TA is independently linear or branched saturated Ci -4 alkyl, phenyl, or
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR TAA , -NH 2 , -NHR TAA , and -NR TAA 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R TAA , -CF 3 , -OH, -OR TAA , -OCF 3 , -NH 2 , -NHR TAA , and -NR TAA 2 ;
  • each -R TAA is linear or branched saturated Ci -4 alkyl
  • each -R TB is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L TB -phenyl
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR TBB , -NH 2 , -NHR TBB , and -NR TBB 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R TBB , -CF 3 , -OH, -OR TBB , -OCF 3 , -NH 2 , -NHR TBB , and -NR TBB 2 ;
  • each -R TBB is linear or branched saturated Ci -4 alkyl
  • each -R TN is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L TN -phenyl
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR TN A , -NH 2 , -NHR TN A , and -NR TN A 2 ; wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I , -R TN A , -CF 3 , -OH, -OR TN A , -OCF 3 , -NH 2 , -NH R TN A , and -NR TN A 2 ;
  • each -R TN A is linear or branched saturated d_ 4 alkyl
  • -R TN2 is linear or branched saturated Ci -4 alkyl
  • -V is independently -H or -R v ;
  • Ci -4 alkyl is linear or branched saturated Ci -4 alkyl.
  • -Q and -O-V together form a ring fused to the ring to which they are attached.
  • the carbon atom at this position may be in either (R) or (S) configuration.
  • a reference to one enantiomer/diastereomer is intended to be a reference to both enantiomers/all diastereomers.
  • R 4 when R 4 is -H, the compound may form the corresponding tautomer, for example, as shown below. Unless otherwise stated, a reference to one tautomer is intended to be a reference to both tautomers:
  • C3. 7 heterocyclyl refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., N, O, S).
  • pyridyl is an example of a
  • heteroaryl refers to a group that is attached to the rest of the molecule by an atom that is part of an aromatic ring, wherein the aromatic ring is part of an aromatic ring system, and the aromatic ring system has one or more heteroatoms (e.g., N, O, S).
  • heteroatoms e.g., N, O, S.
  • pyridyl is an example of a C 6 heteroaryl group
  • quinolyl is an example of a Cioheteroaryl group.
  • heterocyclyl refers to a group that is attached to the rest of the molecule by a ring atom that is not part of an aromatic ring (i.e., the ring is partially or fully saturated), and the ring contains one or more heteroatoms (e.g., N, O, S).
  • heteroatoms e.g., N, O, S.
  • piperidino is an example of a C 6 heterocyclyl group.
  • substituted on carbon is intended to refer to a substituent which is attached to a carbon ring atom.
  • substituted on secondary nitrogen is intended to refer to a substituent which is attached to a nitrogen ring atom which, in the absence of the substituent, would be a secondary nitrogen ring atom (i.e., -NH-). Consequently, a pyridyl group may only have “substituents on carbon", whereas 1 H-pyrrole may have both "substituents on carbon” and a “substituent on secondary nitrogen", as illustrated below. a substituent on carbon
  • a piperidino group may only have “substituents on carbon”, whereas piperizino may have both “substituents on carbon” and a “substituent on secondary nitrogen”, as illustrated below.
  • a substituent on carbon a substituent on secondary nitrogen a substituent on secondary nitrogen
  • -R JE if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • the Group -R JE4 (44) A compound according to any one of (1) to (43), wherein each -R JE4 , if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted with one or more groups -R K2C .
  • each -R JE4 if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each -R JE5 is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, and is optionally substituted with one or more groups -R K2C .
  • each -R JE5 if present, is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • the Group -R' is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • each -R is independently oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, or diazepanyl,
  • each -R JE6 is independently tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
  • each -R JE6 if present, is independently tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl,
  • each -R JE6 is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
  • each -R JE7 if present, is phenyl, and is optionally substituted with one or more groups -R K3C .
  • each -R JE7 if present, is naphthyl, and is optionally substituted with one or more groups -R K3C .
  • each -R JE8 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzoimidazolyl, indazolyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl,
  • each -R if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl,
  • each -R JE8 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, or isothiazolyl,
  • each -R JE8 is independently pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl,
  • the Group -L JE - (58) A compound according to any one of (1) to (57), wherein each -L JE -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • each -L JE - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • each -L JE -, if present, is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • (61) A compound according to any one of (1) to (57), wherein each -L JE -, if present, is independently -CH 2 - or -CH 2 CH 2 -.
  • each -L - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 -.
  • each -L -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • each -L -, if present, is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • each -R if present, is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L KK -phenyl, wherein said Ci_ 4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • each -R KK if present, linear or branched saturated C -4 alkyl, wherein said C -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR KKK , -NH -NHR KKK , and -NR 2 .
  • each -R if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is unsubstituted.
  • each -R if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R KK if present, is independently -Me, -Et, -nPr, or -iPr.
  • each -R is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • the Group -L KK - (92) A compound according to any one of (1) to (91), wherein -L KK -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • each -R if present, is independently pyrrolidino, piperidino, piperizino, (N-Ci_ 4 alkyl)-piperizino,
  • each -R JN if present, is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L JN -phenyl, wherein said Ci_ 4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • each -R JN if present, is linear or branched saturated C -4 alkyl, wherein said C -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR JN A , -NH 2 , -NHR JN A , and -NR JN A 2 .
  • each -R JN if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is unsubstituted.
  • each -R JN is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • the Group -L JN - (1 14) A compound according to any one of (1) to (113), wherein -L JN1 -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR JN2A , -NH 2 , -NHR JN2A , and -NR JN2A 2 .
  • each -R JN2A is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R JN2A if present, is independently -Me, -Et, -nPr, or -iPr.
  • -L JN2 - if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • (132) A compound according to any one of (1) to (129), wherein -L -, if present, is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • (133) A compound according to any one of (1) to (129), wherein -L JN2 -, if present, is independently -CH 2 - or -CH 2 CH 2 -.
  • a compound according to any one of (1) to (134), wherein -NR JN3 R JN4 , if present, is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci. 4 alkyl)-piperizino, (N-Ci- 4 alkyl-C( 0))-piperizino, or morpholino; and is optionally substituted with one or more groups selected from linear or branched saturated Ci -4 alkyl.
  • (141) A compound according to any one of (1) to (140), wherein -Q A , if present, is independently -R QM , -R ⁇ 5 , -R QA6 , -R QA7 , or -R QA8 .
  • QA7 (145) A compound according to any one of (1) to (140), wherein -Q A , i present, is -R (
  • QA5 150
  • the Group -R (159) A compound according to any one of (1) to (158), wherein -R QA , if present, is linear or branched saturated Ci -6 alkyl. (160) A compound according to any one of (1) to (158), wherein -R , if present, is linear or branched saturated d_ 4 alkyl, and is optionally substituted with one or more groups
  • each -R QM is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted with one or more groups -R S2C .
  • each -R if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each -R QA5 if present, is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, and is optionally substituted with one or more groups -R S2C .
  • each -R QA5 if present, is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • the Group -R QAS is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • each -R QA6 is independently oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, or diazepanyl,
  • each -R QA6 is independently tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
  • each -R QA6 if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
  • each -R QA7 if present, is phenyl, and is optionally substituted with one or more groups -R S3C .
  • each -R QA7 if present, is naphthyl, and is optionally substituted with one or more groups -R S3C .
  • the Group -R QA8
  • each -R QA8 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzoimidazolyl, indazolyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl,
  • each -R Q is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl,
  • each -R QA8 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, or isothiazolyl,
  • each -R QA8 is independently pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl,
  • each -L - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • each -L -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • each -L -, if present, is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • each -R S2N and each -R S3N is independently -R ss .
  • each -L s - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • each -L s - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • each -L s - is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • each -R if present, is independently linear or branched saturated d_ 4 alkyl, phenyl, or -L ss -phenyl, wherein said Ci_ 4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • each -R if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR sss , -NH 2 , -NHR SSS , and -NR SSS 2 .
  • each -R ss if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is unsubstituted.
  • each -R sss is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R SM if present, is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci. 4 alkyl)-piperizino,
  • each -R SM if present, is independently pyrrolidino, piperidino, piperizino, (N-Ci_ 4 alkyl)-piperizino,
  • each -R if present, is independently linear or branched saturated d_ 4 alkyl, phenyl, or -L QB -phenyl, wherein said Ci_ 4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • each -R if present, linear or branched saturated C -4 alkyl, wherein said C -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR QBB , -NH 2 , -NHR QBB , and -NR QBB 2 .
  • each -R if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is unsubstituted.
  • each -R if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R if present, is independently -Me, -Et, -nPr, or -iPr.
  • each -R QB if present, is independently -Me or -Et.
  • (260) A compound according to any one of (1) to (259), wherein -L QB -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • each -R QBB is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • (280) A compound according to any one of (1) to (279), wherein -R , if present, is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L TA -phenyl, wherein said Ci -4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from from -OH, -OR TAA , -NH 2 , -NHR TAA , and
  • each -R TAA is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R TB if present, is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L TN -phenyl, wherein said Ci_ 4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • each -R TB if present, is linear or branched saturated C -4 alkyl, wherein said C -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR TBB , -NH 2 , -NHR TBB , and -NR TBB 2 .
  • each -R TB if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is unsubstituted.
  • each -R TB is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R TB is independently -Me, -Et, -nPr, or -iPr.
  • each -R TBB is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R TBB is independently -Me, -Et, -nPr, or -iPr.
  • the Group -L TB - (309) A compound according to any one of (1) to (308), wherein -L TB -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • (311) A compound according to any one of (1) to (308), wherein -L TB -, if present, is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • (312) A compound according to any one of (1) to (308), wherein -L TB -, if present, is independently -CH 2 - or -CH 2 CH 2 -.
  • each -R TN if present, is independently linear or branched saturated d_ 4 alkyl, phenyl, or -L TN -phenyl, wherein said Ci_ 4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • each -R TN if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl is optionally substituted with one or more groups independently selected from -OH, -OR TN A , -NH 2 , -NHR TN A , and -NR TN1A 2 .
  • each -R TN if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is unsubstituted.
  • each -R TN is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R TN A is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R TN A is independently -Me, -Et, -nPr, or -iPr.
  • the Group -R TN2 The Group -R TN2
  • a compound according to any one of (1) to (334), wherein -NR TN3 R TN4 , if present, is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci_ 4 alkyl)-piperizino, (N-Ci- 4 alkyl-C( 0))-piperizino, or morpholino; and is optionally substituted with one or more groups selected from linear or branched saturated C -4 alkyl.
  • each -L T - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • each -L T - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, or -CH 2 CH(CH 3 )-.
  • each -L T - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or -CH 2 CH(CH 3 )-.
  • each -L T - is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • Substantially Purified Forms One aspect of the present invention pertains to DHP compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.
  • the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
  • substantially purified form refers to the compound in any
  • the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one
  • the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
  • the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1 % by weight.
  • the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
  • the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer(s) or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
  • 60% optically pure i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer(s) or enantiomer
  • at least 70% optically pure e.g., at least 80% optically pure, e.g., at least 90%
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., Ci -7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • reference to a specifc group or substitution pattern is not intended to include other structural (or constitutional isomers) which differ with respect to the connections between atoms rather than by positions in space.
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a
  • ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,
  • H may be in any isotopic form, including H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 2 C, 3 C, and 4 C; O may be in any isotopic form, including 6 0 and 8 0; and the like.
  • a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof.
  • Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • Salts It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • suitable substituted ammonium ions are those derived from:
  • ethylamine diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • Examples of some preferred salts suitable for amines include: chloride, sulfate, bromide, mesylate, maleate, citrate, tartrate, phosphate, acetate, and iodide.
  • a reference to a particular compound also includes salt forms thereof.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • a reference to a particular compound also includes solvate and hydrate forms thereof.
  • chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like).
  • specified conditions e.g., pH, temperature, radiation, solvent, and the like.
  • well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • a hydroxy group may be protected as an ether (-OR) or an ester
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a
  • benzyloxycarbonyl amide (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxycarbonyl amine (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxycarbonyl amine
  • 2-trimethylsilylethyloxycarbonyl amine (-NH-Teoc), as a 2,2,2-trichloroethyloxycarbonyl amine (-NH-Troc), as an allyloxycarbonyl amine (-NH-Alloc), as a
  • a carboxylic acid group may be protected as an ester for example, as: a Ci- 7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci_ 7 haloalkyl ester (e.g., a C -7 trihaloalkyl ester); a triCi. 7 alkylsilyl-Ci. 7 alkyl ester; or a C 5 _ 2 oaryl-Ci_ 7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • a Ci- 7 alkyl ester e.g., a methyl ester; a t-butyl ester
  • a Ci_ 7 haloalkyl ester e.g., a C -7 trihaloalkyl ester
  • prodrug refers to a compound which, when metabolised (e.g., in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
  • DHP compounds having a 2-carboxylate group may be prepared by a method that involves Lewis acid mediated cyclisation of an amide (7) to give the corresponding DHP compound (8).
  • a range of Lewis acids may be used to achieve this, for example, boron trifluoride dietherate and titanium tetrachloride.
  • the amides (7) may be prepared, for example, by reaction of the corresponding dehydro- compounds (6) with diacetoxy acetyl chloride, for example, in a method analogous to that described in Cook et al., 2009, where the amine is reacted with the acid chloride using a biphasic mixture of water and an organic solvent in the presence of a base.
  • the dehydro compounds (6) may be prepared, for example, from the amino derivative (5) by reaction with a halogenating agent, such as N-chlorosuccinimide or tert-butyl hypochlorite and a base, such as DABCO or DBU, or an oxidant, such as DDQ, for example, in a method analogous to that described in Shimohiagashi et al., 1983.
  • a halogenating agent such as N-chlorosuccinimide or tert-butyl hypochlorite
  • a base such as DABCO or DBU
  • an oxidant such as DDQ
  • the amine (5) may be prepared from the protected amine (4), for example, using known deprotection methods, for example, by reaction of the tert-butyl carbamate protected amine with an acid, as described in Dutton et al., 2003.
  • the protected amine (4) may be prepared, for example, by reaction of the protected amine (3) using a base and a suitable alkyi halide or halo substituted alkyi derivative, for example, as described in Ohmura et al., 2008. In this reaction, the tert-butyl carboxamide group is preferred, but alternative protecting groups such as carboxybenzyl may also be used.
  • the protected amine (3) may be obtained from commercial sources, or may be prepared, for example, from the corresponding amine or protonated amine salt (2) using well known conditions for the protection of amines, for example, as described in Ohmura et al., 2008.
  • An example of such a method is illustrated in the following scheme, wherein (P) denotes a protecting group.
  • the amine (2) may be obtained from commercial sources, or may be prepared from the amino acid using well known esterification techniques, for example, as described in Ohmura et al., 2008.
  • the amine (5) may be prepared by reductive amination, for example, in a manner similar to the method described by Fitch et al., 2005, where the amine is reacted with a range of aldehydes, followed by treatment with a suitable reducing agent, such as sodium borohydride.
  • a suitable reducing agent such as sodium borohydride.
  • the ester (8) may be hydrolysed under basic conditions with a suitable base, such as an aqueous solution of sodium hydroxide, followed by acidic workup to obtain the carboxylic acid, for example as described in Krasnov et al., 2008.
  • a suitable base such as an aqueous solution of sodium hydroxide
  • the amide (10) may be obtained by reaction of the ester (8) with ammonia, or by reaction of the acid with a suitable amine using well-known coupling conditions, for example, as described in Feng et al., 2010.
  • the ether (11 ) may be obtained from the alcohol (9) by reaction with an alky halide, such as methyl iodide, using, for example, mild basic conditions, for example, as described in Devert et al., 2010.
  • an alky halide such as methyl iodide
  • the corresponding N-unsubstituted amide (12) may be reacted with a suitable Lewis acid, such as titanium tetrachloride, to give the corresponding amide (13).
  • a suitable Lewis acid such as titanium tetrachloride
  • the amide (12) may be prepared from the corresponding amine (14), for example, by reaction with diacetoxy acetyl chloride under basic conditions, for example, as described in Cook et al., 2009.
  • the amine (14) may be prepared from the ester (15) by the use of dehydrogenation conditions, for example, as described in Shimohiagashi et al., 1983.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising a DHP compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the composition further comprises one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein.
  • Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing a DHP compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising admixing a DHP compound, as described herein; one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein; and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the DHP compounds described herein are useful, for example, in methods of improving memory and/or cognitive function, and in the treatment of memory-related disorders and cognitive decline.
  • DHP compounds described herein are useful as nootropic agents (e.g., memory enhancers; cognitive enhancers), for example, to improve memory and/or cognitive function in a patient.
  • nootropic agents e.g., memory enhancers; cognitive enhancers
  • one aspect of the present invention pertains to a DHP compound, as described herein, for use in a method of improving memory and/or cognitive function in a patient.
  • Another aspect of the present invention pertains to use of a DHP compound, as described herein, in the manufacture of a medicament for improving memory and/or cognitive function in a patient.
  • Another aspect of the present invention pertains to a method of improving memory and/or cognitive function comprising administering to a patient in need of improved memory and/or cognitive function a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition.
  • a DHP compound as described herein, preferably in the form of a pharmaceutical composition.
  • the DHP compounds described herein are useful in methods of:
  • Such methods may, for example, comprise the step of contacting a neuron or neurons with an effective amount of a DHP compound, as described herein.
  • the method is performed in vitro.
  • the method is performed in vivo.
  • the DHP compound is provided in the form of a pharmaceutically acceptable composition.
  • Another aspect of the present invention pertains to a DHP compound, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein.
  • Another aspect of the present invention pertains to a DHP compound, as described herein, in combination with one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein.
  • Another aspect of the present invention pertains to use of a DHP compound, as described herein, in the manufacture of a medicament for treatment, for example, treatment of a disorder (e.g., a disease) as described herein.
  • a disorder e.g., a disease
  • the medicament comprises the DHP compound.
  • Another aspect of the present invention pertains to use of a DHP compound, as described herein, and one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, in the manufacture of a medicament for treatment, for example, treatment of a disorder (e.g., a disease) as described herein.
  • a disorder e.g., a disease
  • the medicament comprises the DHP compound and the one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents.
  • Another aspect of the present invention pertains to a method of treatment, for example, of a disorder (e.g., a disease) as described herein, comprising administering to a patient in need of treatment a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition.
  • a disorder e.g., a disease
  • a DHP compound as described herein, preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention pertains to a method of treatment, for example, of a disorder (e.g., a disease) as described herein, comprising administering to a patient in need of treatment a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition, and one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, preferably in the form of a pharmaceutical composition.
  • a disorder e.g., a disease
  • the treatment is treatment of a central nervous system (CNS) disorder.
  • CNS central nervous system
  • the treatment is treatment of a neurodegenerative disorder of the central nervous system (CNS). See, e.g., O'Neill et al., 2004.
  • CNS central nervous system
  • the treatment is treatment of memory deficit, for example, deficient memory binding and/or deficient information recall. ln one embodiment, the treatment is treatment of a memory-related disorder.
  • the treatment is treatment of a disorder associated with cognitive decline.
  • the treatment is treatment of cognitive impairment, for example, mild cognitive impairment (MCI).
  • MCI mild cognitive impairment
  • the treatment is treatment of dementia. See, e.g., Akhondzadeh, 1999; Addae et al., 2003; Fitzjohn et al., 2008.
  • the treatment is treatment of: senile dementia (see, e.g., Shi-Lei et al., 2002; Palop et al., 2006; Zhang et al., 2008); vascular dementia (see, e.g., Chang et al., 1997; Xu et al., 2012); fronto-temporal lobe dementia (see, e.g., Chang et al., 1997), etc.
  • senile dementia see, e.g., Shi-Lei et al., 2002; Palop et al., 2006; Zhang et al., 2008
  • vascular dementia see, e.g., Chang et al., 1997; Xu et al., 2012
  • fronto-temporal lobe dementia see, e.g., Chang et al., 1997), etc.
  • the treatment is treatment of Alzheimer's disease (see, e.g., Harrison et al., 1990; Ikonomovic et al., 1995; Armstrong et al., 1996; Jacob et al., 2007; Chen et al., 2010; Chong et al., 2011).
  • the treatment is treatment of a movement disorder. See, e.g., Calabresi et al., 1997.
  • the treatment is treatment of Huntington's disease (see, e.g., Gibson et al., 2005; Andre et al., 2006; Maheshwari et al., 2012).
  • the treatment is treatment of Parkinson's disease (see, e.g., Parkinson's disease (see, e.g., Parkinson's disease).
  • the treatment is treatment of a mental disability disorder.
  • the treatment is treatment of an autism spectrum disorder (see, e.g., Moretti et al., 2006; Bozdagi et al., 2010); fragile-X syndrome; or Rett syndrome (see, e.g., Ivanco et al., 2002; Yun et al., 2011 ; Lanore et al., 2012).
  • an autism spectrum disorder see, e.g., Moretti et al., 2006; Bozdagi et al., 2010
  • fragile-X syndrome see, e.g., Ivanco et al., 2002; Yun et al., 2011 ; Lanore et al., 2012.
  • the treatment is treatment of a mood disorder.
  • the treatment is treatment of a depression disorder (see, e.g., O'Neill et al., 2007), for example, major depressive disorder (see, e.g., Holderbach et al., 2007; Gao et al., 201 1).
  • the treatment is treatment of a basal-ganglia-related disorder, for example, a basal-ganglia-related disorder where progressive memory decline is symptomatic.
  • the treatment is treatment of a disease which is ameliorated by inhibiting acetylcholinesterase.
  • the treatment is treatment of a disease which is ameliorated by inhibition of methyl-D-aspartate (NMDA).
  • NMDA methyl-D-aspartate
  • the treatment is treatment of: a disease which is ameliorated by potentiating excitatory synaptic transmission; a disease which is ameliorated by directly regulating excitatory synapses; a disease which is ameliorated by induction of long-term potentiation; a disease which is ameliorated by lowering the threshold for long-term potentiation induction; a disease which is ameliorated by induction of long-term
  • potentiation in the CA1 a disease which is ameliorated by induction of long-term potentiation in the CA3; a disease which is ameliorated by enhancing glutamatergic synapses; a disease which is ameliorated by modulating AMPA receptor function; a disease which is ameliorated by positively modulating AMPA receptor function; a disease which is ameliorated by indirectly modulating signalling cascades initiated by endogenous growth factors; a disease which is ameliorated by indirectly modulating signalling cascades initiated by BDNF; a disease which is ameliorated by indirectly modulating signalling cascades initiated by NGR; a disease which is ameliorated by modulating presynaptic Ca 2+ channel function; a disease which is ameliorated by modulating R-type voltage-gated Ca 2+ channels; or a disease which is ameliorated by modulating L-type voltage-gated Ca 2+ channels.
  • treatment refers generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e. , prophylaxis
  • treatment use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment”.
  • treatment of dementia includes the prophylaxis of dementia, reducing the incidence of dementia, reducing the severity of dementia, alleviating the symptoms of dementia, etc.
  • therapeutically-effective amount pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, anti-cholinesterase agents, NMDA receptor antagonists, L-dopamine, etc.
  • treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.
  • One aspect of the present invention pertains to a compound as described herein, in combination with one or more additional therapeutic agents, as described below.
  • the particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.
  • the agents may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes.
  • the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
  • agents i.e., the compound described here, plus one or more other agents
  • the agents may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use. Additional Therapeutic Agents For Use In Combination Therapy
  • Drugs which are known to be useful for therapy of the disorders ⁇ e.g., diseases) discussed above may be used in combination therapy with a DHP compound as described herein.
  • cholinesterase inhibitors e.g., donepezil hydrochloride (Aricept), rivastigmine (Exelon), galantamine (Reminyl)), NM DA receptor antagonists (e.g., memantine (Ebixa)
  • non-steroidal anti-inflammatory drugs e.g., salicylates (such as aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (such as indomethacin, tolmetin, sulindac, etodolac, keto
  • mefenamic acid meclofenamic acid, flufenamic acid, tolfenamic acid
  • selective COX-2 inhibitors such as celecoxib, parecoxib, lumiracoxib, sulphonanilides, nimesulide), licofelone, lysine clonixinate.
  • Known drugs for the treatment of Huntington's disease may be used in combination therapy with a DPH compound as described herein.
  • examples of such drugs include: tetrabenazine, haloperidol, olanzapine, risperidone, andquetiapine, pimozide, clonidine, sulpiride, propranolol (or another beta-adrenoceptor blocking drug), piracetam, riluzole.
  • dopaminergic drugs for the treatment of Parkinson's disease may be used in combination therapy with a DPH compound as described herein.
  • examples of such drugs include: dopamine-receptor agonists (e.g., apomorphine hydrochloride,
  • bromocriptine cabergoline, pergolide, pramipexole, ropinirole, rotigotine, levodopa
  • monoamine-oxidase-B inhibitors e.g., rasagiline, selegiline hydrochloride
  • catechol- O-methyltransferase inhibitors e.g., entacapone, tolcapone, amantadine
  • Antipsychotic drugs may be used in the treatment of behavioural and psychological symptoms of dementia, and as such may be used in combination with a DHP compound to give an additive therapeutic benefit.
  • antipsychotic drugs include: first generation antipsychotic drugs (e.g., chlorpromazine, levomepromazine, promazine, pericyazine pipotiazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine) and second generation antipsychotic drugs (e.g., amisulpride, clozapine, olanzapine, paliperidone, quetiapine, risperidone, aripiprazole).
  • first generation antipsychotic drugs e.g., chlorpromazine, levomepromazine, promazine, pericyazine pipotiazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine
  • second generation antipsychotic drugs e.g.,
  • Antidepressants and anticonvulsants may be used in the treatment of behavioural and psychological symptoms of dementia, and as such may be used in combination with a DHP compound to give an additive therapeutic benefit.
  • antidepressants and anticonvlusants include: tricyclic antidepressants (e.g., amitriptyline hydrochloride, clomipramine hydrochloride, dosulepine hydrochloride, doxepin, imipramine
  • hydrochloride lofepramine, nortriptyline, trimipramine
  • tricyclic-related antidepressants e.g., mianserin hydrochloride, trazodone hydrochloride
  • MAOIs monoamine-oxydase inhibitors
  • SSRIs selective serotonin re-uptake inhibitors
  • Hypnotics may be used in the treatment of behavioural and psychological symptoms of dementia, and as such may be used in combination with a DHP compound to give an additive therapeutic benefit.
  • hypnotics include: benzodiazepines (diazepam, alprazolam, chlordiazepoxide hydrochloride, lorazepam, oxazepam), Z-drugs (zaleplon, Zolpidem, zopiclone), clomethiazole, antihistamines, ethyl alcohol, sodium oxybate, and melatonin.
  • Anxiolytics may be used in the treatment of behavioural and psychological symptoms of dementia, and as such may be used in combination with a DHP compound to give an additive therapeutic benefit.
  • Examples of anxiolytics include: diazepam, alprazolam, chlordiazepoxide hydrochloride, buspirone, and meprobamate.
  • the DHP compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • the DHP compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other cognitive enhancers, other anti-dementia agents, etc.
  • kits comprising (a) a DHP compound as described herein, or a composition comprising a DHP compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
  • the kit further comprises one or more ⁇ e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein.
  • the written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
  • the DHP compound or pharmaceutical composition comprising the DHP compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral ⁇ e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal ⁇ e.g., by nasal spray, drops or from an atomiser or dry powder delivery device); ocular ⁇ e.g., by eyedrops); pulmonary ⁇ e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through the mouth or nose); rectal ⁇ e.g., by suppository or enema); vaginal ⁇ e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intra
  • the subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial ⁇ e.g., kangaroo, wombat), a rodent ⁇ e.g., a guinea pig, a hamster, a rat, a mouse), murine ⁇ e.g., a mouse), a lagomorph ⁇ e.g., a rabbit), avian ⁇ e.g., a bird), canine ⁇ e.g., a dog), feline ⁇ e.g., a cat), equine ⁇ e.g., a horse), porcine ⁇ e.g., a pig), ovine ⁇ e.g., a sheep), bovine ⁇ e.g., a cow), a primate, simian ⁇ e.g., a monkey or ape), a monkey
  • the subject/patient may be any of its forms of development, for example, a foetus.
  • the subject/patient is a human.
  • the DHP compound While it is possible for the DHP compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one DHP compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one DHP compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
  • pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

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Abstract

La présente invention a trait généralement au domaine des composés thérapeutiques, et plus spécifiquement à certains composés répondant à la formule ci-après (appelés collectivement ici, pour des raisons pratiques, « composés 2-acyl-4-oxy-1,2-dihydropyrrol-5-one » et « composés DHP »), lesdits composés étant, entre autres<i />, utiles dans des méthodes pour améliorer la mémoire et/ou des fonctions cognitives, ainsi que pour traiter les troubles liés à la mémoire et le déclin cognitif. La présente invention concerne également des compositions pharmaceutiques comprenant de tels composés, ainsi que l'utilisation de ces composés et compositions pour traiter des troubles du système nerveux central (SNC) tels que le déficit de mémoire, les troubles de la mémoire, les troubles associés au déclin cognitif, les déficiences cognitives, y compris par exemple une déficience cognitive légère (MCI), la démence et la maladie d'Alzheimer.
PCT/GB2014/051391 2013-05-08 2014-05-07 Composés 2-acyl-4-oxy-1,2-dihydropyrrol-5-one destinés à améliorer la mémoire et les fonctions cognitives WO2014181101A1 (fr)

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