NZ758086B2 - Synergistic compositions comprising (r)-dimiracetam (1) and (s)-dimiracetam (2) in a non-racemic ratio - Google Patents
Synergistic compositions comprising (r)-dimiracetam (1) and (s)-dimiracetam (2) in a non-racemic ratio Download PDFInfo
- Publication number
- NZ758086B2 NZ758086B2 NZ758086A NZ75808618A NZ758086B2 NZ 758086 B2 NZ758086 B2 NZ 758086B2 NZ 758086 A NZ758086 A NZ 758086A NZ 75808618 A NZ75808618 A NZ 75808618A NZ 758086 B2 NZ758086 B2 NZ 758086B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- dimiracetam
- sensory neuropathy
- peripheral
- composition
- peripheral sensory
- Prior art date
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Abstract
The present invention relates to a composition of enantiomers of 3,6,77a-tctrahydro-1H- pyrrolo[1,5-a]imidazole-2,5-dione and pharmaceutically acceptable solvates or co-crystals thereof in a certain ratio, a pharmaceutical composition comprising said composition, its use as a medicament and the use of the inventive compositions or pharmaceutical compositions in the treatment and/or prevention of a disease or disorder typically and preferably selected from peripheral sensory neuropathy, preferably peripheral neuropathic pain; seizure; depression; or cognitive impairment. of the inventive compositions or pharmaceutical compositions in the treatment and/or prevention of a disease or disorder typically and preferably selected from peripheral sensory neuropathy, preferably peripheral neuropathic pain; seizure; depression; or cognitive impairment.
Description
Synergistic compositions comprising (R)~din1iracetam (1) and (S)-
dimiracetam (2) in a non—racemic ratio
Cross-Reference to d Application
l0 This ation claims the benefit of priority to European Patent Application No.
171 73760.4, filed May Si, 20} 79 which is incorporated herein by reference in its entirety.
Field
The present invention relates to compositions and kits comprising (R)—3,6,7,7a-
ydro~lH~pyrrolo[l,5»a]imidazole-2,5«dione ((R)~dimiracetam (1)) and 6,?,7a~
tetrahydro-lanyrroloU,Swat]imidazole—Zfiwdione ((Q—dimiracetam (2)) in a certain range of
ratios and ceutically able solvates or co—crystals f, pharmaceutical
compositions sing said compositions, their use as a medicament and the uses of the
inventive compositions or pharmaceutical compositions or kits for the treatment and/or
prevention of a disease or disorder typically and ably selected from peripheral sensory
neuropathy, preferably peripheral neuropathic pain and other symptoms of peripheral sensory
athy; and neuropsychiatric conditions, such as seizure; depression; or cognitive
impairment; and motoneuron diseases, such as amyotrophic lateral sclerosis.
Background
Glutamic acid is an excitatory neurotransmitter that is Widely present in the brain. The
first indication of its role as an tory messenger emerged in the l950’s, when it was
observed that intravenous administration of glutamate induces convulsions. However, the
detection of the entire glutamatergic neurotransmitter system, with biosynthetic and catabolic
enzymes, cellular uptake mechanisms, intracellular storage and release systems, and its cell-
surface ion ls and G protein-coupled receptors, did not take place until the l970’s and
l980’s, when suitable pharmacological tools were first identified. It was in the 1990’s that the
newly emergent tools of molecular biology provided means for the molecular identification
and classification of glutamatergic ion channels, receptors? transporters, etc.
The membrane-bound ion channels that are gated by the excitatory amino acids
glutamate and glycine, and that also respond to the xenobiotic compound N~inethyl-D—
aspartate (NMDA), control the flow of both divalent and monovalent cations into pre- and
post~synaptic neural cells (see Foster et al., Nature l987, 329395—396; Mayer et al., Trends in
Pharmacol. Sci. 1990, llz254'260). They are molecularly, electrophysiologically, and
pharmacologically distinct from the glutamate-gated, cation—conducting ion channels that
respond to the xenobiotic agents kainate or amino—3«hydroxy~5~n1ethyl~4~
isoxazolepropionic acid (AMPA); and they are similarly distinct from the family of
glutamate—gated G protein-coupled receptors, the so—called metabotropic glutamate receptors.
The referring glutamate—gated ion channel has a hetero-tetrameric structural
basis: two obligatory GluNl units and two variable GluNZ receptor subunits encoded by the
GRINl gene and one of four GRINZ genes, respectively. One or both GluNiZ subunits can be
potentially ed by a GluNBA or a GluN3B subunit. The GRlNl gene product has 8 splice
variants while there are 4 different GRINZ genes (GRI’N’ZA-D) encoding four ct GluN2
ts, The glycine binding site is present on the GluN l subunit and the glutamate binding
site is t on the GluNZ subunit (Paoletti P et al., Nat Rev Neurosci. 2013; l4(6):383~
400).
Multiple classes of positive or negative eric modulators of glutamategated ion
channels have been described; they bind glutamate-gated ion channels at the interasubunit
interface of the ligand—binding domains ) of the respective ion channels, a site that is
distinct from the glutamate or the glycine-binding sites t Within the LED (Sun et al.,
2002; Jin et al., 2005; Hackos et al., 2016). Allosteric modulators have also been described
(Wang et al. 20l7) that bind to the trans-membrane domain of the NMDA-type glutamate-
gated ion channel, where a highly~conscrvcd structural motif (the so—called “Lurcher
domain”) cts ionic flow through the pore when the ion channel is in the closed or
deactivated state (Karakas and Furukawa, 2014; Lee et al., 2014; Ogden and Traynelis, 2013).
Ailosteric modulators of glutamate—gated ion channels have therapeutic potential, and
even utility in healthy individuals, in diverse fields, such as learning, memory processing,
mood, attention, emotion, motoneuron e, peripheral sensory neuropathy and pain
tion (C‘ull~Candy S ct al., Curr Opin Neurobiol. 2001; l l(3):327—35).
Compounds that modulate NMDA receptor function can be useful in treatment of many
neurological and psychiatric disorders including but not limited to bipoiar disorder (Martucei
L et al, Schizophrenia Res, 2006; 84(2—3):214~21), major sive disorder (Li N et al.,,
Biol Psychiatry. 2011; 69(8):754-61), treatment—resistant depression (Preskorn SH et al. J
Clin Psychopharmacol. 2008; 28(6):631-7) and other mood disorders (including
schizophrenia (Grimwood S et 211.3 Neuroreport. 1999; 10(3):461’S), ante“ and
rtum depression (Weickert CS et al. Molecular Psychiatry (2013) 18, 92),
seasonal ive disorder, and the like; Aizheimer’s e (Hanson JE et 211., iol
Dis. 20l5; 74:254» 62; Li S et al., J Neurosci. 2011; 31(18):6627~38) and other dementias
(Orgogozo JM et a1. Stroke 2002, 33: 18344 839), Parkinson’s disease (Duty S, CNS Drugs.
2012; 26(12):1017~—32; Steece—Collier K et 211., Exp . 2000; 163(1):239-43; beaver KR
et a1. Clin Exp Pharmacol Physiol. 2008; 35(1 ”1388—94), gton’s ehorea (Tang TS et
31., Pros Natl Acad Sci USA. 2005; 102(7):2602~7; Li L et at, J hysiol. 2004;
92(5):2’?38-46), multiple sclerosis (Grasselli G et al., Br J Pharmacol. 2013; 168(2):502-17),
cognitive impairment (Wang D et al. 2014, Expert Opin Ther Targets 2014; 18(10):} 121~30),
head injury (Bullock MR et al.., Am: N Y Acad Sci. 1999; 890:51—8), spinal cord injury, stroke
(Yang Y et al., J Neurosurg. 2003; 98(2):397—403), sy (Naspolini AP et at“? Epilepsy
Res. 2012 Jun; 100(1—2):l2-9)3 movement disorders (eg. dyskinesias) (Morissette M et at,
Mov Disord. 2006; 21(1):9-l 7), various neurodegenerative diseases (eg. amyotrophic lateral
sis (Fuller Pl et al., Neurosez' Left. 2006; 399(l~2):157—61) or neurodegeneration
associated with ial or chronic infections, glaucoma (Naskar R et a1. 59min Ophthalmoi.
1999 Sep; 14(3):152-8 ), pain (eg. chronic, cancer, post-operative and neuropathie pain (Wu
L} and Zhuo M, iiempeuz‘ics. 2009; 6(4):693~702), diabetic neuropathy, migraine
(Peeters M et al., J Pharmacol Exp Ther. 2007; 321(2):564— 72), cerebral isehemia (Yuan H et
a1“ Neuron. 2015; 85(6):1305—18)3 encephalitis u J. et 31., Lancet Neurol. 2008;
7(12)11091«8.), autism and autism spectrum disorders (Won H. et 31., Nature. 2012;
486(7402):261-5), memory and learning disorders (Tang, Y. P. et al., Nature, 1999;
401(6748):63-9), obsessive compulsive disorder (Arnold PD et al,, Psychiafzy Res. 2009;
l72(2):136—9.)3 attention deficit ctivity disorder (ADHD) (Dorval KM et 211., Genes
Brain 8:2};th 2007; 6(5):444—52), PTSD (Haller J et al. Behav Pharmacol. 2011; 22(2):l 13»
21; Leaderbrand K et al. Neurobiol Learn Mem, 2014; l 13:35— 40), tinnitus (Guitton MJ, and
Dudai Y, Neural? Plasz;2007; 80904; Hu SS et al. 2016; 273(2): 325-332), sleep disorders (like
narcolepsy or excessive daytime sleepiness, patent A1), vertigo and
nystagmus (Straube A. et al., Curr Opin Neurol. 2005; 18(1):l 1—4; Starck M et al. J Neural.
1997 Jan; 244(l):9-l6), anxiety, autoiinmunological disorders like neuropsychiatric systemic
lupus erythematosus {Kowal C et al. Proc. Natl. Acad. Sci. USA, 2006', 103, l9854~l9859)
and addictive illnesses (eg. alcohol addiction, drug addiction) (Nagy l, 2004, Curr Drug
Targets CNS Neural Disord. 2004; 3(3):169—79.; Shen H et al., Proc Nari Acad Sci USA.
2011; 108(48):l9407—l2).
The symptoms of peripheral sensory neuropathy, including one of the most prominent
symptoms, peripheral neuropathic pain (Zilliox LA, 20l7), are frequently encountered al
conditions: the prevalence in the general population has been estimated to be between 7% and
l0% (van Hecke O et (21., 2014). in the United States, painful diabetic peripheral neuropathy
alone is ted to affect approximately 10 million people. Peripheral sensory neuropathy is
often resistant to ent and is associated with poor patient satisfaction of their treatment.
Several medications have been shown to be effective in treating peripheral sensory
neuropathy ated with ic neuropathy and post-herpetic neuralgia, and these
medications are often used to treat neuropathic pain associated with other conditions as well.
These treatments often have unwanted adverse effects and discontinuation of treatment may
be problematic. It is important to recognize that peripheral sensory neuropathy affects many
aspects of daily life and is associated with poor l health, reduction in quality of life,
poor sleep, and higher anxiety and depression. In fact, measures of quality of life in people
with chronic peripheral sensory neuropathy were rated as low as for patients with clinical
depression, coronary artery e, recent myocardial tion, or poorly controlled
diabetes tus (Smith SH 63 al., 2007).
The American Academy of Neurology has hed practice guidelines on the
treatment of painful diabetic neuropathy (Bril V e: at, 201i), post-herpetic neuralgia
(Dubinsky RM er al., 2004), and trigeminal neuralgia (Gronseth G et (12., 2008), Several other
clinical practice guidelines for the treatment of neuropathic pain also have been published
(Attal N at 011., 2010; Moulin D, et at, 2014).
Sensory neuropathy is ly fied as l or peripheral, ing on the
site of the lesion that is g the symptoms. Examples of conditions associated with
peripheral sensory neuropathy are diabetic neuropathy, human immunodeficiency virus“
associated ne‘uropathy, chemotherapy-induced peripheral neuropathy, post—herpetic neuralgia,
trigeminal neuralgia, complex, regional pain me, compressive mononeuropathies,
radiculoneuropathies, inflammatory neuropathies (acute and c inflammatory
demyelinating polyneuropathy), post—traumatic neuropathy, or phantom liinh neuropathy.
Typically, peripheral sensory neuropathy has both positive and negative symptoms.
ve symptoms include ng ("pins and s"), prickling, lightening—like or
lancinating sensations, aching, knife—like, pulling or tightening-like symptoms3 burning— or
g—like, or electrical pain. Negative symptoms include numbness, ss, or the
feeling of wearing socks, Some unique aspects of peripheral sensory neuropathy include
hyperalgesia (an increased response to a stimulation is normally painful); allodynia (pain due
to a stimulus that typically does not provoke pain); hyperestliesia (an increased sensitivity to
ation); paresthesia (abnormal sensation, Whether provoked or spontaneous); dysesthesia
(unpleasant abnonnal ion); hypoesthesia (diminished pain in response to a ly
ll) painful stimulus); analgesia (loss of pain sensation); and hesia (loss of sensation). The
positive signs or symptoms are thought to ent excessive activity in a sensory y
due to a lowered threshold or heightened excitability. ve signs and symptoms are
experienced as diminished or absent feeling and are due to a loss of sensory function.
While some pharmacological agents have been found to be effective in the treatment of
symptoms of peripheral sensory ne‘uropathy (Finnerup NB at all, ZOlS), only a minority of
patients suffering from neuropathic pain show a complete response to drug y. For the
majority of patients, it is reasonable to expect that treatment will make the pain tolerable, in
general, a 30% reduction of a pain on an ll—point numerical rating scale is considered
clinically important and constitutes ”moderate relief“ or "much improved." It is also important
2O to recognize and treat comorbidities, such as anxiety and depression, and secondary treatment
goals may e improving sleep, advancing function, and enhancing overall quality of life,
These goals are best achieved when pharmacologic therapy is one component of a multi~
disciplinary approach to treatment.
Neuropathic pain medications approved by the US Food and Drug Administration are
carhamazepine, duloxetinc, alin, gabapentin, topical lidocaine, and topical capsaicin,
Tramadol and opioid analgesics are effective in different types of athic pain but are
generally not recommended as first—line treatments because of concerns about longterrn
safety. However, they are recommended as first~line treatments in acute neuropathic pain,
neuropathic pain due to cancer, and episodic exacerbations of severe neuropathic pain. The
use of strong opioids (codeine, morphine, oxycodone and fentanyl) in the treatment of a
variety of neuropathic pain conditions is controversial and a public health n given the
rising number of deaths related to iption opioids. The serious risks of overdose,
dependence, and ion which these drugs carry may outweigh the potential benefits,
Thus, there remains an urgent and ant medical need for the development of novel:
orally—effective therapies for peripheral sensory neuropathy and peripheral athic pain
that are toxicologically benign and devoid of the potential for ence and addiction
phenomena.
There also remains an important l need for the pment of novel, orally—
effective therapies for neuropsychiatric diseases, such as those described in the S:h version of
the Diagnostic and Statistical Manual of Mental Disorders (DEM-5); and for the treatment of
motoneuron diseases, such as amyotrophic lateral sclerosis.
cetam (2,5-dioxohexahydro—lH—pyrrolo[l,Z-alimidazole ~ IUPAC name: (RS)-
3,6,7,7a—tetrahydro~lH-—pyrrolo[l,5~a]imidazole~2,5-dione) is a bicyclic 2—pyrrolidinone
derivative and a nootropic member of the racetam family:
AU 2012/201853 discloses the use of diiniracetaim or a pharmaceutically acceptable
solvate thereof, alone or in association with other active principles, in the manufacture of a
medicament useful for the treatment and/or tion of chronic pain.
WO 93/09120 relates to certain processes for preparing certain fused imidazole
derivatives and in particular for preparing chiral fused imidazole derivatives.
US 406 mentions that dimiracetam may be useful in restoring learning and
treating memory difficulties. One example of a disease to be treated with cetam is
Alzheimer’s disease.
Dimiracetam was originally developed as a cognition enhancer and has been shown to
be able to improve learning and memory in rats (Pinza M et all, 1993; EP 3 354 83). In single-
dose healthy human volunteer studies (Torchio L et 61]., P995), dimiracetam was found to
ameliorate, versus placebo, certain es of the transient decline in cognitive perfonnance
induced by injection of scopolamine. Further medical uses of dimiracetam have been
described including in particular its broad efficacy in rodent models of neuropathic pain. The
efficacy of dimiracetam in the treatment of neuropathic pain of different origin has been
3O documented in established models of neuropathic pain d by nerve injury,
chemotherapy, or mono—iodoacctate (MIN-induced osteoarthritis (Fariello R at all, 2014); Di
Cesare Mannclli L at 61]., 2015a; Di Cesare Mannelli L at at, 2015b; ; EP 2
857 0}? Bl, US BOW/0125096; ). The chemotherapy-induced symptoms of
neurotoxicity are responsive to dimiracetam, regardless of which herapeutic agent is
used; dideoxycytidine— (ddC-), oxaliplatim, vincristine—, paclitaxelw, and nib—derived
models all respond to the effects of dimiracetain; and dimiracetam has been shown to be
effective not only in treating, but also in preventing the symptoms brought on by
administration of these chemotherapeutic agents. A single oral administration of dimiracetarn
can completely, but transiently, revert hyperalgesia and allodynia hack to the level of healthy
l0 controls. With repeated twiccudaily oral administration, the maximal effect s
sustained, without evidence of tachyphylaxis, or tolerance, despite dose diminution and
increased inter-dose interval to once~daily oral administration. Furthermore, the effects of
dimiracetain are diseasewspecific: in a eral chronic constriction injury (031) model,
where rats develop a state of peripheral neuropathic pain in one hind—limb subjected to
l5 surgical placement of a ligature around the sciatic nerve, but not in the other limb subjected to
sham surgery, a single oral dose of dimiracetam d the pain response only in the nerve-
ligated limb, without affecting algesia or allodynia in the perated limb; this profile is
markedly distinct from effects of, for example, opiates, which affect both limbs in this model
(Christensen 1) et all, 1998).
The mechanism of dimiracetam’s phannacologieal actions have been explored using
synaptosornal ations of the hippocampus and the spinal cord. This assay is intended to
phannacologically mimic the physiological process of glutamate-triggered glutamate release;
its pH-g, anl- and ifcnprodil-sensitivitics suggest involvement of an NMDA-receptor isoform
containing pH~scnsitive GluNl and GluNZA subunits (Fan'ello at at, 2014). Inhibition of
glutamate signaling is an established basis for the prevention or the treatment of neuropathic
pain (Latrcmoliere and Woolf, 2009). in the spinal cord, at the junction where peripheral
sensory afferents make their first and only synaptic connection to the interneurons of the
central nervous system (Marieba Wilhelm and Mallat, 2017), ate—induced glutamate
release is a ent of the upwregulated, or “sensitized" signaling which s from a
3O damaged peripheral nerve (Latremolier and Woolf, 2009).
In osornal preparations of the hippocampus, dimiracetam is a, tely potent
tor with an K350 of approximately 3 uM for inhibiting NMDA—plusglycinewtriggered
release of [3Hl—D~aspartate usly loaded into the osomal preparation. In
synaptosomal preparations of the spinal cord, however, dimiracetam is much more potent,
with an ngg of approximately 20 nM for inhibiting the NMDA—plus—glycine—triggered [3H]—
D—aspartate release (Fariello R et at, 2014).
cetam’s ability to block glutamate—triggered glutamate release in the spinal cord
underlies its y in the prevention or treatment of peripheral sensory neuropathies; other
mechanisms in the brain may underlie its efficacy in the treatment of sion in rats
(Farielio er al., 2011; WO 2015/010217); and its efficacy in rat and human models of
scopolamine~induced ive impairment (Pinza at all, 1993).
Dimiracetain is a chiral compound with a single stereocenter, but it has undergone
clinical development as a racemic mixture of its (R)- and (S)~enantiomers. This was done even
if) though (.R)—dimiracetam is the more active enantiomer (), because the
racemate of cetam has been found to be even more potent than either of the single
enantiomers. For example, in rats pre-treated with 2',3’-didcoxycytidine (ddC, zalcitabine), a
single oral dose of (R)»dimiracetam resulted in partial y response, While the (S)—
enantiomer resulted in a smaller response than the corresponding dose of the antiomer.
On the other hand, racemic dimiracetani gave a superior response compared to either (R)- or
(fi—diniirace’tam alone (). This rank order of potency of (3)3 (R)—, and
racemic dimiracetam is also seen in the effect of dimiracetarn on reverting MIA—induced
hyperalgesia (WC) 2008/ i .
Summary
It has now been surprisingly and unexpectedly found that compositions ot‘(R)— and (S)-
enantiomers of dimiracetam having an enantiomeric excess (cc) of the (R)-—dimiracetam (1)
greater than or equal to 30% and lower than or equal to 60% exhibit greater pharmacological
potency than the ponding dual enantiomers or even than the racemate and thus
provide a synergistic effect that could not have been predicted based on the potency of the
individual enantiomers or the racemate. These compositions preferably inhibit NMDA plus
glycine—evoked [3H}-Dnaspartic acid release from rat spinal synaptosomes by at least about
40%, preferably at least about 45%, at a tration of about 10 anL
Thus, it has been surprisingly and unexpectedly found that the preferred inventive
composition with an enantiomeric excess of (R)ndiiniracetam of 33% (corresponding to a 2:1
(R):(S) ratio of the dimiracetam enantiomers) inhibits NMDA plus glycine—evoked {3H]»D~
aspartic acid release from rat spinal osomes by about 50% at a concentration of 10 nM
(Fig. 1A, Table l). The further preferred inventive ition with an enantiomeric excess
of (Rydimiracetam of 50% (corresponding to a 3:1 (R):(S) ratio of the dimiracetam
enantiomers) even ts NMDA plus glycine—evoked ~aspartic acid release from rat
spinal synaptosomes by 52% at a concentration of 1 nM (Fig. lB, Table 1). In comparison,
c dimiracetam ts NMDA plus glycine-evoked [3H]»D~aspartic acid release from
U! rat spinal synaptosorncs by 36% at a concentration of 10 nM, corresponding to an estimated
1C50 of 15 11M (Fig. 1C; Table l); (R)—dimiracetarn has an estimated ngo of 123 nM (); and ($«diiniracetam has an estimated 1C5n of 418 nM (FIG. lE).
These surprising results are confirmed in further different rat models of peripheral
neuropathic pain, such as the MIA—induced knee arthritis model or the oxaliplatin-induced
model of neuropathic pain. Thus, the ive compositions with an enantiomeric excess of
(R)-dimiracetam are much more efficient than the racemic mixture ofdimiracetam in reducing
eral neuropathic pain in the paw—pressure test after administration of sodium
monoiodoacetatc (MIA; } or in the prevention of oxaliplatiminduced peripheral
neuropathic pain (. The ive compositions with an enantiorneric excess of (R)-
dimiracetam are also much more efficient than itions in which an excess of the (S)-
enantiorner of dimiracetam is present (.
Therefore, the inventive compositions of (R)- and (S)-enantiomers of dimiracetam
having an enantiomeric excess (cc) of (R)—dirniracetarn higher than or equal to 30% and lower
than or equal to 60% are pharmacologically more effective at a given dose, as compared to
either the pure enantiomers alone or to raceinic dimiracetam. The tenn racemic dimiracetani
refers to a 1:1 by weight mixture of (R)— and (S—enantiomers, which thus has an enantiomeric
excess (cc) of (R)-dimiracetarn of 0%. Thus? the effect associated with the present invention is
a synergistic effect that surprisingly results from a specific range of ratios hetween (R)~
dimiracetam and (S)~dimiracetam.
Since rat plasma tratiomtime profiles after oral administration of either (R)— or
(53—dirniracetarn are identical, and the (1%)» and (S)-enantioiners do not to interconvert in viva
(FlG. 4A and , respectively), the behavior of the ive compositions of
enantioiners is not explained by pharmacokinetics or metabolism of the enantiomers. The fact
that the (R)— and (5’)»enantiomers are both individually effective (albeit With different
y), and that when combined in an riate ratio their phannacological potency is
greater than that of the racernate, shows that they share with racemic cetam the same
pharmacological mechanism and suitability for the treatment of the same medical indications
Therefore, the inventive compositions are beneficial and can be used for the treatment and/or
prevention of a large number of diseases and disorders as set out in the detailed description
The diseases or disorders are typically and preferably selected from eral sensory
athy, preferably peripheral neuropathic pain and other symptoms of peripheral sensory
neuropathy; and nenropsychiatric ions, such as seizure; depression; or cognitive
impairment; and motoneuron diseases, such as ainyotrophic lateral sclerosis, More preferably,
the disease or disorder is typically ed from peripheral sensory neuropathy, preferably
peripheral neuropathic pain; seizure; depression; or cognitive impairment.
In a first aspect, the invention provides for a ition comprising (R)-3,6,7,7a~
tetrahydro-alyrrolofl,5-a}imidazole-2,S~dione imiracetani (1)) and (S)—3,6,7,7a-
tetrahydro— l H-pyrrolo{ l ,5-a]iinidazole—2,Swdione ((S-dimiracetam (2)),
H H
H / 2t /
N N
and/or phannaceutically acceptable es or co—crystals f,
wherein the enantiomeric excess (ee) of said miracetam (I) is equal to or higher than
% and lower than or equal to 60%.
l5 One specific example of such a composition according to the present invention is a non—
racemic mixture of 3,6,7,7a~tetrahydro~lH—pyrrolo[l,5-a]imidazole-2,5~dione (dimiracetam)
and pharmaceutically acceptable solvates or co—crystals thereof, wherein said non-racemic
mixture comprises (_R)~3,6,7,7a—tetrahydro-lH-«pyrrolo[i,5-a]imidazole~2,5—dione ((1?)-
diiniracctarn (1)) and (S)~3,6,7,7a—tetrahydro-1H»pyrrolo[l,5-a]imidazoie~2,5—dione ((5‘)—
dimiracetain (2)) in an enantiorneric excess (ee) of said (R)«dimiracetam (I) of higher than or
equal to 30% and lower than or equal to 60%.
H /
o (1) (2)
in a further aspect, the invention provides for a pharmaceutical composition comprising
the composition of the present ion, eg. the non—racemic mixture of the invention, and a
pharmaceutically acceptable carrier.
In again a further aspect, the invention provides for a kit of parts comprising (R)—
dimiracetam (l) and (S)-dimiracetam (2) and instructions for combining (R)-dimiracetam (l)
and (Sjudiiniracetarn (2) to obtain an enantiomeric excess (cc) of said (R)~dimiracetam (l) of
equal to or higher than 30% and lower than or equal to 60%. In this aspect, the same preferred
ranges of the enantiomeric excess (cc) of said (R)—dimiracetam (l) and enantiomeric ratios of
(R)—dimiracetam (l) to (S—dimiracetam (2) as set out herein with respect to the composition
apply.
in again a further , the invention provides for the composition of the ion or
the pharmaceutical composition of the invention or the kit of the invention for use as a
lO medicament.
in again a, r aspect, the invention es for the ition of the invention or
the phannaceutical composition of the invention or the kit of the invention for use in the
treatment or prevention of a disease or disorder, wherein the disease or disorder is typically
and preferably ed from peripheral sensory neuropathy, preferably peripheral neuropathic
l5 pain and other symptoms of peripheral, y neuropathy; and neuropsychiatric conditions,
such as seizure; depression; or cognitive impairment; and motoneuron diseases, such as
amyotrophic lateral sclerosis.
in again a further aspect, the invention provides for a method for the treatment and/or
prevention of a disease or er of an animal, preferably of a human, wherein the disease
or disorder is typically and preferably ed from peripheral sensory athy, preferably
peripheral neuropathic pain and other symptoms of peripheral sensory neuropathy; and
neoropsychiatric conditions, such as seizure; depression; or cognitive impairment; and
motoneuron diseases, such as amyotrophic lateral sis, wherein said method comprises
administration of the composition of the invention or the pharmaceutical composition of the
ion or the kit of the invention to an animal, preferably to a human.
In again a further aspect, the invention provides for the use of the composition of the
invention or the phannaceutical composition of the invention or the kit of the invention in the
manufacture of a medicament for the treatment and/or prevention of a disease or er,
wherein the disease or disorder is typically and preferably selected from peripheral sensory
3O nenropathy, preferably peripheral neuropathic pain and other symptoms ofperipherai sensory
neuropathy; and neuropsychiatric conditions, such as seizure, depression, or cognitive
impairment; and motoneuron diseases, such as ophic lateral sclerosis.
in again a further aspect, the ion es for an article of manufacture
comprising the composition of the invention or the pham‘iaceutical composition of the
invention, a container or package and a written description and stration instruction
such as a package insert.
It is to be understood that the composition of the present application asses the
cemic mixture of the present invention, so that any reference to the composition of the
present invention is also to be understood as a reference to the non—racemic mixture of the
present invention.
Further aspects and embodiments of the t invention will he become apparent as
this description continues.
Description of Figures
FIG. lA: Effects of increasing molar concentrations of the inventive ition with an
enantiomeric excess of (R)—dimiracetam of 33.3% (corresponding to a 2:1 (.R):(S)
ratio of the enantiomers) on NMDA (l0 uM) plus glycine~ (1 uM) stimulateti
i5 release of —Asp from pro—loaded spinal cord synaptosomcs.
FIG. lB: Effects of increasing molar concentrations of the inventive composition with an
enantiomeric excess of (R)—dimiracetam of 50% (corresponding to a 3:1 (R):(Sj
ratio of the enantiomers) on NMDA (it) uM) plus glycine— (1 uM) stimulated
release of [3H]—D~Asp from lore-«loaded spinal cord synaptosomes.
: Effects of sing molar concentrations of dimiracetam racematc on NMDA
(10 ulVl) plus glycine- (1 pM) ated release of {3H]~D~Asp from preloaded
spinal cord synaptosomes.
FIG. lD: Effects of increasing molar concentrations of miracetam on NMDA (i0 51M)
plus glycine— (1 nM) stimulated release of [3H]—D-Asp from pie—loaded spinal
Ix) U! cord osomes.
FIG. IE: Effects of increasing molar concentrations of (‘Sndimiracetam on NMDA (10 nM)
plus glycine (1 HM) stimulated release of {3H]~D—Asp from preloaded spinal
cord synaptosomes.
In Fig. lA-E, results are expressed as % increase of basal release, and data are
means i S.E.M. of 6 experiments that were run in triplicate.
Antihyperalgesic effect of a single dose of the inventive composition with an
omeric excess of (R)—dimiracetam of 50% sponding to a 3:1 (R):(S)
ratio of the enantiomcrs) in comparison with dimiracetam racemate and a
composition with an excess of the (S)~enantiomer of dimiracetam of 1:3 (R):(S) in
a model of MIA—induced osteoarthritis in rats. Pain threshold was assessed by a
l & Selitto analgesymeter. Results are expressed as grams and each value
ents the mean i S,E.M, of20 rats. M: P < 0.01 versus vehicle-MIA.
FlG.3: Effect of repeated oral administration of the inventive composition with an
enantiomeric excess of (R)-dimiracetam of 50% (corresponding to a 3:1 (R):(S)
ratio of the enantiomers) and dimiracetam racemate on oxaliplatin-induced
mechanical hyperalgesia, Pain threshold was assessed by a Randall 84: Selitto
analgesymeter before the morning administration and each value represents the
mean i S.E.M. of 6 rats. *P<0.05 and **P<0.01 and vs oxaliplatin 4“ vehicle
treated animals; °P<0.05 and t}l vs oxaliplatin + dimiracetam 15 mg/kg;
#P<0.05 and ##P<0,0l vs latin + dimiracetam 50 trig/kg.
: Comparison of the plasma concentration—time profiles of the (R)—enantiomer after
oral administration of miracetam (75 mg/kg) and after oral administration of
racemic dimiracctam (150 mg/kg)
: Comparison of the plasma concentration—time es of the (S)~enantiorner after
oral administration of (Swdimiracetam (2) (75 trig/kg) and after oral administration
ot‘racemic dimiracetam (150 mg/kg).
s 4A and 4B demonstrate that the in viva pharmacological superiority of the
inventive compositions is not attributable to phannacokinetio differences.
FIGS: inhibition of NMDA+glycine—induced [3H]-D—aspartate release e) by
racemic dimiracetam (circle) and five ent enantiomeric mixtures es with
an R to S ratio from 2:1 to 4:1). This data was obtained in e 5.
: Passive avoidance test. Bnantiomeric mixtures of dimiracetam with three ditlerent
R13 ratios (1:1, 2:1 and 3:1) were administered orally at 3, 10 or 30 nag/kg, 39 min
before the training test on day l. Scopolamine (1.5 mg/kg i.p.) was injected
immediately after the punishment on day l. The latency time ed during the
training session was comparable for all groups, (ca. 15 3). On day 2, the retention
session was performed and the latency times are reported in bars. Data are
expressed as mean :t S.B.M. of 12 mice analyzed in 2 different experimental sets.
Ol vs vehicle + vehicle (vehicle); *P<0.05 and **P<0.01 vs scopolamine +
vehicle (scopolamine)
1316.7: Forced swimming test. Enantiomeric mixtures of dimiracetam with three different
12:5 ratios (1:1, 2:1 and 3:1) were administered orally at It)? 30 or 1th mg/kg, 25
min before the test. Mice were placed in water containing glass cylinders for 6
min, the duration of mobility was recorded during the last 4 min. Data are
expressed as mean :t: S.E.M. of 12 mice analyzed in 2 different experimental sets.
*P<0.05 and **P<0.0l vs vehicle + e (vehicle) (indicting that animals were
treated with vehicle instead of scopolainine and, subsequently, were again treated
with vehicle instead of the test compound).
ed Description
Unless defined otherwise, all technical and scientific terms used herein have the same
meanings as commonly understood by one of ordinary skill in the art to which this invention
The term “about" where used to characterize an enantiorneric excess means filo/o
referring to the given numeric value, if not indicated otherwise. In each of the invention
embodiments, "about" can be deleted.
l5 The term “preferably" is used to describe features or ments which are not
required in the present invention but may lead to improved technical effects and are thus
desirable but not ial.
With respect to the numerical values mentioned herein, unless explicitly stated
otherwise, the last decimal place of a numerical value preferably indicates its degree of
accuracy. Thus, unless other error margins are given, the maximum margin is ably
ascertained by ng the rounding—off convention to the last decimal place. Thus, a value
of2.f5 preferably has an error margin of 2.45 to 2.54.
The present ion relates to compositions comprising o,7,7a«tetrahydro-lH-
pyrrololl,5-alimidazole~2,5~dione ((R)-dimiracetarn (1)) and (S)»3,6,7,?a~tetrahydronlH—
(“Q U} pyrrololl,5~a]irnidazole~2,S—dione ((S)«dimiracetarn (2)) in a certain ratio. It is to be
understood that the term ”composition" does not require that the (R)-dimiracetam (l) and (S)—
diiniracetani (2) have to be mixed. They can be ated jointly or separately and be
stered simultaneously or subsequently, provided that the ratio of (R)-diiniracetam (l)
and (S)~dirniracetam (2) achieved in the subject to be treated is as required by the present
invention. Preferably. the inventive composition is a mixture of (thimiracetarn (l) and (S)-«
diiniracetam (‘2), but the inventive composition may also encompass a ation of one or
more es containing (Rydimiracetarn (l) and one or more articles containing (S)—
diiniracetam (2), or a combination of one or more articles containing (R)vdiiniracetam (l) and
one or more articles containing dimiracetarn racemate.
Furthermore, the dimiracetam ned in the composition of the present ion has
to be present in the overall range of ratios of (R)-dimiracetarn (l) and (S—dimii'acetam (2),
alternatively expressed as the enantiomeric excess of (R)—dimiracetain (1), required in the
present invention. In other words, it is against the gist of the present invention to theoretically
split a composition containing equal amounts of miracetarn (l) and (fi—dimiracetam (2)
into a component containing an excess of (R)-dirniracetam (l) and another component
ning an excess of iracetam (2). Thus, in whichever physical form the
composition of the t ion is, the composition as a Whole has to fulfill the
requirements regarding the range of ratios of (R)—dimiracetain (l) and (S-diiniracetam (2),
l0 alternatively expressed as the omeric excess of (R)~dimiracetam (l), of the present
invention. It is to he understood that the ratios of miracetam (l) and (S—dimiracetam
(2), alternatively expressed as the enantiomcric excess of (R)~dimiracetam ( l), are based on a
statistically meaningful number of dimiracetam molecules, which typically exceeds 1000
dimiracetam molecules. In the present ion, the relative amounts of (R)-dimiracetam (l)
l5 and (S)~diiniracetam (2) are expressed either in terms of the ratio of (R)-dimiracetam (l) and
(S—dimiracetam (2) or in terms of the enantiomeric excess of(R)—diiniracetam (l ).
it is to be understood that the “ratio" of (R)~dimiracetam (l) and (S)—dimiracetam (2) as
used herein refers to the weight ratio of (R)—dimiracetarn (l) and (S—dimiracetam (2), unless
explicitly stated otherwise. If solvates of (R)~dimiracetam (1) and/or (S)—dimiracetam (2) are
2O used, the solvent is thus to be disregarded in this calculation. In other words, the "ratio of (R)~
dimiracetam (l) and (S)«-dimiracetam (2) is calculated as s:
Ratio of (R)~dimiracetam (l) and amount of(R)~dimiracetam (l) by weight
miracetam (2) amount of (5')»dirniracetam (2) by weight
As known by the skilled person in the art, the ratio of compounds differing only in
chirality, such as in the case of (R)»dimiracetam (l) and (.S’)—dimiracetam (2), can be
determined in a number of ways known in the art, including but not limited to
chromatography using a chiral support, polanmetric measurement of the rotation of polarized
light, nuclear magnetic resonance spectroscopy using chiral shift reagents? or derivatization of
3O a compound using a chiral compound such as Mosher’s acid followed by chromatography or
nuclear magnetic resonance spectroscopy. Enantioiners can further be isolated from mixtures
by methods known to those skilled in the art, ing chiral highnpressure liquid
chromatography (HPLC) and direct fractional crystallization of the te, Le,
dimiracetam, by chiral co—erystallization techniques, which exploit the ion of specific
hydrogen bonding interactions present in co~crystals (sec Springuel GR, 6! £22., 2012; and US
Patent 6,570,036). Useful co-crystallization partners e enantiomers of mandelic acid,
malic acid, tartaric acid and its derivatives; or enantiorners can be prepared by asymmetric
syntheses. See, for example, Eliel and Wilen, 1994*
The ratio of (R)—dimiracetam (l) and (S)~di1niracetam (2) (which may also be referred to
as the chiral purity) of the inventive ition such as the non—racemic e can also be
expressed in terms of its omeric excess (ee), typically and preferably as determined by
chiral HPLC (see Examples for details), and calculated by the equation:
co = (AR m Ala/(AR + As) >< l00%,
wherein AR is the area of the peak of (R)—3,6,7,7a—tetrahydro~lH—pyrrolo[l,5—a]imidazole—2,5—
dione, i.e. (R)~enantiorner (1) of dimiracetam, in the HPLC chromatogram of the sample
solution and A3 is the area of the peak of (S)-3i6,7,7a-tetrahydro-lH—pyn‘olo[l ,S—alimidazolo
2,5—dione, i.e. (S)—enantiorner (2) of dimiracetam, in the HPLC chromatogram of the sample
solution.
In this respect, it is noted that, although chiral ”purity” is mentioned above, the gist of
the present invention is not achieving a high chiral purity of (R)-dirniracetam (l) or (S)—
dimiracetam (2). instead, the gist of the present invention is that a n range of ratios
between (R)~dimiracetam (l) or (S-dimiracetam (2) leads to a particularly synergistic effect.
As opposed to cases in which merely the purity of a compound is to be improved, i.e. where
the objective is known, namely one specific compound is to be obtained in a purity of ideally
l00%, the t invention is based on a usly unknown ratio of two compounds,
namely (R)—dimiracetam (l) and (Q—dimiracetam (2).
The term "pharmaceutically acceptable“ indicates that the compound or ition,
typically and preferably the solvates, co—crystals or carrier, must be compatible chemically or
toxicologically with the other ingredient(s), typically and ably with the inventive
ition, when typically and preferably used in a formulation or when typically and
ably used for treating the animal, preferably the human, therewith. Preferably, the term
3O "phannaceutically acceptable" indicates that the compound or ition, typically and
preferably the solvates, co-crystals or carrier, must be compatible chemically and
toxicologically with the other ingredient(s), typically and preferably with the inventive
composition, when typically and preferably used in a formulation or when typically and
preferably used for treating, the animal, preferably the human, therewith. It is noted that
pharmaceutical compositions can be formulated by ques known to the person skilled in
the art, such as the techniques published in “Remington: The Science and Practice of
Pharmacy", Pharmaceutical Press, 22“d edition.
A "soivate" refers to an association or complex of one or more solvent molecules and
either the (R)—enantiorner (1) of dimiracetarn or the (S)-enantiorner (2) of dimiracetam.
Examples of solvents that form solvates e, but are not limited to, water, isopropanol,
ethanol, methanol, diinethyl sulfoxide (DMSO), ethyl acetate, acetic acid, and ethanolamine.
The term te" refers to the complex where the solvent molecule is water,
A "co—crystal" refers to a crystalline structure that contains at least two different
nds that are solid in their pure form under t conditions. The at least two
ent compounds may include (R)-dirniracetam (1) and/or (S)~dimiracetam (2) and/or any
further components of the composition or excipients of the phannaceutical composition. C0-
crystals are made from neutral molecular species, and all species remain neutral after
crystallization; further, typically and preferably, they are crystalline homogeneous phase
materials where two or more ng compounds are present in a defined stoichiometric
ratio. See hereto Wang Y and Chen A, 20l3; and Springuel GR, at all, 2012; and US Patent
6,570,036. It to be understood that the (R)~dimiracetam (l) and/or (S-dimiracetam (2) may be
in the form of any polymorph. A variety of co-crystals and techniques for ing such cos
crystals are described in RSC Drug Discovery, Pharmaceutical Salts and (fie-crystals,
published in 2012 by the Royal Society of Chemistry and edited by Johan Wouters and Luc
Queré, in particular in chapters 15 and 16. red examples of the co—crystal formers are
those disclosed in Table it‘ll of this reference. Even more preferred stals include co—
ls of d—ltydroxy acids, d-keto acids and/or a~keto amides with the dimiracetam
enantionaers in the (R) to tios as disclosed herein. Examples of d—hydroxy acids include
atrolactic acid, henzilic acid, 4—chlorornandelic acid, citric acid, 3,4—dihydroxyrnandelic acid,
ethyl pyruvate, galacturonic acid, gluconolactone, glucuronic acid, glucuronolactone, glycolic
acid, oxyhutanoic acid, 2—hydroxypentanoic acid, thydroxyhexanoic acid, 2»-
hydroxyheptanoic acid, 2-«hydroxyactanoic acid, 2whydroxynonanoic acid, 2-hydroxydecanoic
acid, 2-«hydroxyundecanoic acid, 4whydroxymandelic acid, 3~hydroxyw4~methoxyanandelic
3O acid, 4—hydroxy—3—1nethoxymandelic acid, anhydroxyarachidonic acid, xyhutyric acid,
a—hydroxyisohutyric acid, a—hydroxylauric acid, whydroxyniyristic acid, d—hydroxypalmitic
acid, ofihydroxystearic acid, 3~(2’-hydroxyphenyl)lactic acid, 3-(4’~hydroxyphenyl)lactic acid,
lactic acid, malic acid, mandelic acid, methyllaetic acid, pyruvate, mucic acid, a-
phenylacetic acid, onphenylpyruvic acid, pyruvic acid, saccharic acid, tartaric acid and
tartronie acid. Examples of a-keto acids include ethanoic acid (glyoxylic acid), methyl
2—ketoethanoate, Z—ketopropanoic acid (pyruvic acid), methyl Zaketopropanoate (methyl
pyruvate), ethyl 2-ketopropanoate (ethyl pyruvate), propyl 2~ketopropanoate (propyl
pyruvate), 2~phenyl—2-ketoethanoic acid (benzoylformic acid), methyl 2—phenyl—2—
ketoethanoate (methyl benzoylfonnate), ethyl 2—phenyl-‘2-ketoethanoate (ethyl
benzoylformate) acid (phenylpyruvic acid), methyl 3—phenyl-2~
, 3—phenyl—2-ketopropanoic
opanoatc (methyl phenylpyruvate), ethyl 3~phenyl—2~ketopropanoate (ethyl
phenylpyruvate) 2-ketobntanoic acid, Zaketopentanoic acid, Z—ketohexanoic
, acid, 2—
ketoheptanoic acid, 2—ketooctanoic acid, dodecanoic acid and methyl octanoate.
Examples of d—keto amides include any nds obtainable by reacting any one of the
above examples ofn—keto acids with primary or secondary amines.
In a first aspect, the ion provides for a composition comprising (R)m3,6,7,7a-
tetrahydro-lH~pyrroio[l,5-a]imidazole~2,5-dione ((R)-dimiracetam (1)) and (S)«3,6,7,7a«
tetrahydro- l H-pyrrolo[ l ,5»a}imidazole—2,5—dione ((S-dimiracetam (2)),
H,“ I‘d/H
$0 0:0
0 0
l5 <1) (2)
and/or phannaceutically acceptable solvates or co-crystals thereof,
wherein the enantiomeric excess (cc) of said (R)-dimiracetam (l) is equal to or higher than
% and lower than or equal to 60%. This composition, as well as any other compositions and
pharmaceutical compositions according to the present invention, preferably inhibits NMDA
plus giycine~evoked [3H]—D—aspartic acid release from rat spinal synaptosomes by at least
about 36%, preferably at least about 40%, more preferably at least about 45%, even more
preferably about 50%, at a concentration of about 10 nM. An assay for measuring this
parameter is set out in Example 5.
One example of such a composition is a non~racemic mixture of 3,6,7,7a—tetrahydro~
lH—pyn‘olofl ,S-a]imidazole—Z,S—dione and ceutically acceptable solvates or stals
thereof, wherein said cemic e ses (R)—3,6,7,7a—tetrahydro—lH~pyrrolo[l,5-
a]imidazoie~2,5ndione ((R)—dimiracetam (1)) and (S)-3,6,7,7avtetrahydro—lHprrrolofl,5—
a]imidazole-2,S-dione ((Sndimiracetam (2)) in an enantiomeric excess (cc) of said (R)—
dlmiracetam l of higher than or equal to 30% and lower than or equal to 60%.
O O
(I) (2)
Typically; the non—solvated or non-co—crystallized compositions are preferred. Further
preferred are the non-solvated and non~eo—erystallized compositions.
Thus, in a r aspect, the invention provides for a composition of 3,6,7,7a-
tetrahydro—lH-pyrrolo[l,S'alimidazole-2,5—dione, wherein said composition comprises (R)—
396,7,7a—tetrahydro«lH-pyrrolo[l,S—a]imidazole~2,5~dione ((R)—dimiracetam (1)) and (5)»
3,6,77,7a—tetrahydro—lH—pyrrolo[l,5~a]imidazole«2,5~dione iniracetam (2)) in an
enantionieric excess (ee) of said (R)-dimiracetam (1) of higher than or equal to 30% and lower
than or equal to 60%.
More preferably, said enantiomerie excess (ee) of said (R)—dirniracetam (1) is higher
than or equal to 30% and lower than or equal to about 54%. Even more preferably, said
enantiorneric excess (ee) of said (R)—dimiraeetam (1) is higher than or equal to 30% and lower
than or equal to 54%,
More preferably, said enantionieric excess (ee) of said (R)—dimiracetarn (1) is higher
than or equal to about 33% and lower than or equal to about 54%. Even more preferably, said
enantiomeric excess (ee) of said (thimiraeetam (1) is higher than or equal to 33% and lower
than or equal to 54%.
More preferably, said enantiomeric excess (ee) of said miracetain (I) is higher
than or equal to 30% and lower than or equal to about 53%. Even more ably, said
enantiomeric excess (ee) of said (R)—dimiracetam (1) is higher than or equal to 30% and lower
than or equal to 53%.
More preferably, said enantiorherie excess (ee) of said (R)—dirniracetarn (l) is higher
than or equal to about 33% and lower than or equal to about 53%. Even more preferably, said
enantioineric excess (ee) of said (R)~dimiraeetam (1) is higher than or equal to 33% and lower
than or equal to 53%.
Still more preferably, said enantiomeric excess (ee) of said (R)-dimiraeetam (I) is
higher than or equal to about 33% and lower than or equal to about 50% Still more
preferably, said enantiomeric excess (ee) of said miraeetam (1) is higher than or equal to
33% and lower than or equal to 50%.
More preferably, said enantiorneric excess (ee) of said (R)-dimiraeetani (1) is higher
than or equal to about 30% and lower than or equal to about 50%. Even more preferably, said
enantiomeric excess (cc) of said (R)—dirniracetam (l) is higher than or equal to 30% and lower
than or equal to 50%.
More preferably, said enantiomeric excess (ee) of said (R)~dimiraeetam (1) is higher
than or equal to about 35% and lower than or equal to about 54%, and preferably lower than
or equal to about 53%. Even more preferably, said enantiorneric excess (ee) of said (R)—
dimiracetam (1) is higher than or equal to 35% and lower than or equal to 54%, and
preferably lower than or equal to 53%.
More preferably, said enantiomerie excess (cc) of said (Rlvdimiracetarn (1) is higher
than or equal to about 40% and lower than or equal to about 54%, and preferably lower than
or equal to about 53%. Even more preferably, said enantiomerie excess (ee) of said (R)—-
diiniracetain (1) is higher than or equal to 40% and lower than or equal to 54%, and
preferably lower than or equal to 53%.
More preferably, said omeric excess (ee) of said (R)—dimiracetarn (1) is higher
than or equal to about 45% and lower than or equal to about 54%, and preferably lower than
or equal to about 53%. Even more preferably, said enantiornerie excess (ee) of said (R)-
dimiracctam (1) is higher than or equal to 45% and lower than or equal to 54%, and
preferably lower than or equal to 53%.
Still more preferably, said enantiornerie excess (ee) of said (R)~dimiracetarn (1) is
ed from about 33% about 35%, about 37%, about 39%, about 41%, about 43%, about
45%, about 47% about 50% and about 53%. Still more preferably, said enantiomerie excess
(cc) of said (R)~dimiracetam (I) is selected from 33%, 35%, 37%, 39%, 41%, 43%, 45%,
47%, 50% and 53%.
Even still more preferably, said enantiomeric excess (cc) of said (R)~dimiracetarn (1) is
selected from about 50%.
Even still more ably, said enantiorneric excess (cc) of said (R)-dirniracetam (1) is
50%.
As known to the skilled person, instead of the enantiomeric , the ratio of {It}
dimiracetam (1) to (S-dirniracetam (2) may be referred to. red ranges for the ratio of
(R)~dimiracetarn (1) to (Stadimiracetam (2) are 2:l to 3.521, preferably 2:l to 33:1, more
preferably 2.0110 to 3,331.0, even more preferably 2.00:l.00 to 3.30:1.00. Further preferred
ranges are 2.0:l.0 to 32521.0, 2.00:1.00 to 3.25:1.00, 2:1 to 3:1, 0 to 30:10 and
2.002l .00 to 30021.00. Further preferred ranges include 2.321 to 33:1, 2.6:l to 3.311, 2.721 to
32:1, 2.8:l to 3.2:l, 2.9:l to 31:1 as well as 3:1 and 0. Other preferred ranges include
21:1 to 29:1, 2.211 to 2.8:l, 2.3:1 to 2.721, 24:1 to 2.6:l, as well as 2.5:] and 2511.0.
in a further , the invention provides for a phannaceutical composition comprising
the composition of the invention and a pharmaceutically acceptable carrier.
In a further aspect, the ion provides for a kit of parts comprising (R)—dimiracetam
(l) and (S)—dimiracetam (2) and instructions for combining (R)—dimiracetam (l) and (S)—
dimiracetam (2) to obtain an enantiomeric excess (cc) of said (R)-dimiracetam (l) of equal to
or higher than 30% and lower than or equal to 60%. In the following, it is to he tood
that the kit according to the present invention may alternatively be used, whenever the use of
the composition of the present invention is described. The skilled person will understand that
the components of the kit may be combined before administration, which is preferred, or the
components of the kit may be stered separately. In the latter case, the components of
the kit are typically to be administered within a time range of at most 30 minutes in order to
achieve the effects of the present invention.
In again a further aspect, the invention provides for the composition of the invention or
the pharmaceutical composition of the ion or the kit of the invention for use as a
ment.
In again a further aspect, the ion provides for the composition of the invention or
the pharmaceutical composition of the invention or the kit of the invention for use in the
treatment or prevention of a large number of es and disorders such as set out in the
following:
a) for the prevention or the treatment of positive symptoms of peripherai neuropathy,
including COideSEflSilZiVliy, tingling, burning, or aching sensations, such as those associated
with chemotherapy, antiblastic therapy, viral ion and viral treatment, post~herpetic
neuralgia, osteonecrosis, trigeminal neuralgia, or diabetic peripheral neuropathy, to include
the y allodynia, secondary allodynia, or other pains or discomforts associated with
sensitization of the spinal cord or higher brain structures or neuronal pathways;
’0) for the prevention or the ent of pain, including bone and joint pain, osteonecrosis
pain, repetitive motion pain, dental pain, dysmenorrheal pain, cancer pain, myofascial pain,
surgical pain, perioperative pain, and postsurgical pain syndromes such as postamastectomy
me, post-thoracotomy syndrome, or stump pain, as well as pain associated with angina,
neuroma pain, complex regional pain me, chronic pelvic pain, chronic lower back pain;
c) for the prevention or the treatment of inflammatory pain, such as rthritis, rheumatoid
tis, rheumatic disease, chronic arthritic pain and related neuralgias, teno—synovitis and
gout;
d) for the prevention or the treatment of neuropathic pain, such as chemotherapy—induced
pain, post~traumatic injury pain, crush pain, painful traumatic mononeuropathy, painful
polynonropathy, pain resulting from spinal injury, lumbago, nerve compression or
ment, sacral pain, trigeminal gia, ne and migraine headache, postwherpetic
neuralgia, phantom limb pain, post—herpetic pain, diabetic neuropathy, central pain syndrome
caused a lesion at any level of the eral nervous system;
e) for the prevention or the treatment of sychiatric disorders. Examples of
neuropsychiatric disorders include schizophrenia, psychosis including schizophrenia,
phrenitbrm disorder, schizoaffective disorder, delusional disorder, brief psychotic
disorder, substancexrelated disorder, paranoid schizophrenia, disorganized schizophrenia,
catatonic schizophrenia or undifferentiated schizophrenia, substance— induced psychotic
disorder, substance-related disorders and addictive behaviors;
t) epilepsy and other seizures, both focal and generalized;
g) obesity or other eating disorders associated with excessive food , bulimia nervosa;
h) cerebral deficits subsequent to stroke, brain edema, cerebral ia, cerebral
hemorrhage, neurodegenerative diseases, cardiac bypass surgery and grafting, perinatal
hypoxia, cardiac arrest, and hypoglycemic cerebral damage;
i) sleep disorders, such as insomnia, narcolepsy, or restless leg disorder;
j) anxiety disorders, such as affective disorder, panic attacks, panic disorder, acute stress
disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, post-
traumatic stress er, tion anxiety disorder, social , specific phobia,
substance-induced anxiety disorder;
k) mood disorders, such as depression, anhedonia, unipolar depression, bipolar disorder,
psychotic depression;
l) substance addiction, drug dependence, tolerance, dependence or withdrawal from
nces including alcohol, amphetamines, cannabis, cocaine, inogens, inhalants,
nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolyties;
or) impaired cognitive function, such as age related cognitive decline or cognitive disorders
such as the ent types of dementia associated with Alzheimer’s disease, ischemia, trauma,
l0 vascular problems or stroke, HIV disease, Parkinson's disease, Huntington‘s disease, Pick's
disease, Creutzfeldt— Jacob disease, chemotherapy, tal hypoxia, other general medical
conditions or substance abuse;
n) Parkinson's disease, including drug—induced parkinsonisni, or post—encephalitic
parkinsonisrn;
e) attention deficit disorders, such as ion—deficit hyperactivity disorder (ADHD),
obsessive-compulsive disorder, , posttranmatic stress syndrome, autism and autism-
spectrum disorders, impulse control disorder;
p) us, presbycusis;
q) to enhance learning and memory;
r) for the prevention or for the treatment of inherited or sporadic motor neuron disorders.
Examples thereof include amyotrophic lateral sclerosis, primary lateral sclerosis, progressive
muscular atrophy, progressive bulbar palsy, Friedrich’s ataxia, fragile X syndrome;
3) for the prevention or for the treatment of movement disorders. Examples thereof e
ia, chorea, including Huntington’s chorea, Parkinson’s—related dystonia, Creutzfeldt—
Jakob disease, ssive supranuelear palsy, multiple system y, corticobasal
degeneration, basal a calcification;
t) for akinesias such as akinetic-rigid syndromes,
u) for dyskinesias such as medication—induced parkinsonism such as neuroleptic-induced
parkinsonism, neuroleptic malignant syndrome, neurolepticminduced acute dystonia,
neuroleptic-induced acute akathisia, eptic- induced e dyskinesia and medication—
induced postural tremor, ing rest tremor, postural tremor and intention tremor, chorea
(such as Sydenham‘s chorea, Huntington’s disease, benign hereditary chorea,
neuroacanthocytosis, symptomatic chorea, drug—induced chores and heini‘oallism},
generalized or focal myoelonus, tics (including simple tics, complex tics and symptomatic
tics), and dystonia (including generalised dystonia such as iodiopathic dystonia, drug—induced
dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as
blepharospasm, oromandibular dystonia, spasmodic nia, spasmodic torticollis, axial
dystonia, dystonic writer's cramp and hemiplegic dystonia), muscular spasms and disorders
ated with muscular spasticity or weakness including tremors;
l5 v) and for urinary incontinence, multiple system atrophy, tuberous sclerosis, olive-ponto~
cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic
pathy, glaucoma, spasticity, myoclonus, and Tourette's syndrome~associated
dyskinesias.
It is to be understood that the above list of diseases is only given as ic examples
and is not to be interpreted as limiting the present invention. Among the shove, red are
one or more selected from a), e), q), r), and s).
The disease or disorder is typically and preferably ed from peripheral sensory
neuropathy, preferably eral neuropathic pain and other symptoms of peripheral sensory
neuropathy; and neuropsychiatric conditions, such as seizure; depression; or cognitive
impairment; and motoneuron diseases, such as amyotrophic lateral sclerosis.
Furthermore, the compositions of the present ion can also he used to enhance
ng and memory in healthy subjects, e.g. in the form of a erapeutie use.
3O in again a further aspect, the invention provides for a method for the treatment and/or
prevention of a disease or disorder, wherein the disease or disorder is typically and preferably
selected from peripheral sensory neuropathy, preferably peripheral athic pain and other
symptoms of peripheral sensory neuropathy; and neuropsychiatric conditions, such as seizure;
depression; or cognitive impairment; and motoncuron diseases, such as amyotrophic lateral
sclerosis, wherein said method comprises administration of the composition of the invention
or the pharmaceutical composition of the invention or the kit of the ion.
It is also part of the invention to provide a method for the treatment of a disease or
disorder, n a therapeutically effective amount of the composition of the ion or the
ceutical composition of the invention or the kit of the ion is administered to an
, preferably human, in need thereof. The term "therapeutically effective amount" here
refers to that amount sufficient to modulate one or more of the symptoms of the condition or
disease being treated, ably between 10 mg and 3000 mg per administration given once
daily or twice daily or three times daily by the oral route. It is furthermore also a part of the
ll) invention to provide a method for the tion of a disease or disorder, wherein a
therapeutically effective amount of the composition of the invention or the pharmaceutical
ition of the invention or the kit of the invention is administered to an animal,
preferably human, reasonably expected to be in need thereof. The term "therapeutically
effective amoun " here refers to that amount sufficient to modulate one or more of the
ed symptoms of the ion or disease to be avoided, preferably between it) mg and
3000 mg per administration given once daily or twice daily or three times daily by the oral
route.
ln again a further aspect, the invention provides for the use of the composition of the
invention or the pharmaceutical composition of the invention or the kit of the ion in the
manufacture of a medicament for use in the treatment and/or prevention of a disease or
disorder, wherein the disease or disorder is typically and preferably selected from peripheral
sensory neuropathy, preferably peripheral neuropathic pain and other symptoms of peripheral
sensory neuropathy; and neuropsychiatric conditions, such as seizure; depression; or ive
impairment; and motoneuron diseases, such as amyotrophic lateral sclerosis.
it is also part of the present invention to administer the inventive composition or the
ive pharmaceutical ition in association with active principles and active agents,
respectively, which present as side effects the insurgence of peripheral neuropathic pain and
other symptoms of peripheral neuropathy, in particular with antitumor and antiviral drugs.
The composition or the phannaceutieal composition or the kit is preferably used alone or with
at least one antitumor drug or at least one antiviral drug. More preferably, the composition or
the pharmaceutical composition or the kit is used alone. More preferably, the composition or
the pharmaceutical composition or the kit is used with at least one antitumor drug.
Alternatively, preferably the composition or the pharmaceutical composition or the kit is used
with at least one antiviral drug.
It is furthermore preferred that the composition or the pharmaceutical composition or
the kit is administered in association with at least one rnor drug or with at least one
ral drug, wherein said associated administration of said composition or said
pharmaceutical composition with said at least one antitumor drug or with said at least one
ral drug is concurrent? simultaneous, sequential or separate.
Non~limiting examples of such antitumor drugs are ed from the group consisting
of a kinase inhibitor, a proteasome inhibitor, a , a vinca alkaloid, and a platinum salt.
Non—limiting es of such antiviral drugs are selected from a nucleoside analog or a
nucleotide analog. It is fiirthern'iore preferred that said antitumor drug is selected from the
group consisting of a kinase inhibitor, a proteasorne inhibitor, a tasane, a vinca alkaloid, and a
platinum salt. Said antituinor drug is preferably selected from sorafenib, nib, afatinib,
axitinih, vandetanib, yemurafenib; ixazomibi bortezomib, paclitaxel, xel, cabazitaxel,
Vincristine, vinblastine, vindesine, vinorelbine, nedaplatin, lobaplatin, picoplatin, satraplain,
cisplatin, carboplatin, and oxaliplatin. Said antiviral drug is preferably selected from
zalcitabine, sine, stavudine and zidovudine.
The composition or the phannaceutical composition or the kit is preferably used with at
least one antiviral drug, wherein preferably said antiviral drug is selected from a nucleoside or
nucleotide? and wherein Further preferably said antiviral drug is selected from abiney
didanosine, ine or zidovudine,
Said disease or disorder is preferably seizure. Alternatively, said disease or disorder is
preferably depression. Further preferably, said disease or disorder is cognitive impairment.
Even more preferably, said disease or disorder is peripheral sensory neuropathy. Still more
preferably, said disease or disorder is peripheral neuropathie pain.
Said disease or disorder is more preferably peripheral sensory neuropathy, wherein said
peripheral sensory athy is selected from the group ting of (i) diabetic neuropathy
(ii) postmherpctic neuropathy, (iii) luinhago, (iv) sacral pain, (V) surgical pain, (Vi) crush
injury, (Vii) spinal injury, (viii) complex al pain syndrome, (ix) phantom limb
sensations, (x) peripheral sensory neuropathy associated with osteoarthritis, (xi) peripheral
sensory neuropathy associated with rheumatoid tis, (xii) peripheral sensory neuropathy
associated with autoimmune osteoarthrosis, (xiii) eephalea (xiv) librornyalgia, (xv) eral
sensory neuropathy induced by antiblastic therapies, (xvi) eral sensory ne‘uropathy
induced by a chemotherapeutic agent, (xvii) peripheral sensory neuropathy ated with
visceral injury) (xviii) peripheral sensory athy associated with osteonecrosis, (xix)
peripheral sensory neuropathy associated with human immunodeficiency Virus infection and
(Kit) peripheral sensory neuropathy induced by an antiviral agent,
Said disease or disorder is preferably peripheral sensory athy, wherein said
peripheral y neuropathy is selected from the group consisting of (i) ic neuropathy,
(ii) post~herpetic neuropathy, (iii) lumbago, (iv) sacral pain, (v) surgical pain, (Vi) crush
injury, (vii) spinal injury, (viii) complex regional pain syndrome, (ix) phantom limb
sensations, (X) peripheral y athy associated with osteoarthritis, (xi) peripheral
sensory neuropathy associated with rheumatoid arthritis, (xii) peripheral sensory neuropathy
associated with autoimmune osteoarthrosis, (xiii) cephalea (xiv) fibroniyalgia, (XV) peripheral
sensory neuropathy induced by antiblastic therapies, (xvi) peripheral y neuropathy
induced by a chemotherapeutic agentr (xvii) peripheral sensory neuropathy associated with
visceral injury, ) peripheral sensory neuropathy associated with osteonecrosis, (xix)
peripheral sensory athy associated with human innnunodeficieney Virus infection, (XX)
peripheral sensory neuropathy induced by an antiviral agent and (xxi) peripheral athic
l5 pain.
Said e or disorder is further preferably peripheral sensory neuropathy, wherein
said peripheral sensory neuropathy is diabetic athy. Said disease or disorder is even
more preferably peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is
post—herpetic neuropathy. Said disease or disorder is preferably peripheral sensory
athy, wherein said eral sensory neuropathy is lumbago. Said e or disorder
is further preferably eral sensory neuropathy, wherein said peripheral sensory
neuropathy is sacral pain. Said disease or disorder is further preferably peripheral sensory
neuropathy, wherein said peripheral sensory athy is surgical pain. Said disease or
disorder is further preferably peripheral sensory neuropathy, wherein said peripheral sensory
neuropathy is crush injury. Said disease or disorder is further preferably peripheral sensory
neuropathy, wherein said eral sensory neuropathy is spinal injury. Said disease or
disorder is further preferably peripheral sensory neuropathy, wherein said peripheral sensory
neuropathy is complex regional pain me. Said disease or disorder is further preferably
peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is phantom limb
3O sensations. Said disease or disorder is further preferably eral sensory neuropathyt
wherein said peripheral sensory neuropathy is peripheral sensory athy associated with
osteoarthritis. Said disease or er is further preferably peripheral sensory neuropathy,
wherein said peripheral sensory neuropathy is peripheral sensory neuropathy associated with
rheumatoid arthritis, Said disease or er is r preferably peripheral sensory
neuropathy, wherein said peripheral sensory neuropathy is peripheral sensory neuropathy
associated with autoimmune osteoarthrosis, Said disease or disorder is further ably
peripheral sensory neuropathy, wherein said peripheral y neuropathy is cephalea. Said
e or disorder is further preferably peripheral sensory neuropathy, wherein said
U‘I peripheral sensory neuropathy is fibrornyalgia. Said e or disorder is still more
ably peripheral sensory neuropathy, wherein said peripheral y neuropathy is
peripheral sensory neuropathy induced by antiblastic therapies. Said disease or disorder is still
more preferably peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is
peripheral sensory athy induced by a chemotherapeutic agent. Said disease or disorder
is still more preferably eral sensory athy, wherein said peripheral sensory
neuropathy is eral sensory neuropathy associated with Visceral injury. Said disease or
disorder is still more preferably peripheral sensory neuropathyj n said peripheral
sensory neuropathy is peripheral sensory neuropathy associated with osteonecrosis. Said
disease or disorder is still more preferably peripheral sensory neuropathy, wherein said
l5 peripheral sensory neuropathy is peripheral sensory neuropathy associated with human
immunodeficiency Virus infection. Said disease or disorder is still more preferably peripheral
sensory ne‘uropathy, n said peripheral sensory neuropathy is peripheral sensory
neuropathy induced by an antiviral agent. Said disease or disorder is further ably
peripheral sensory neuropathy, wherein said eral sensory neuropathy is peripheral
2O neuropathic pain.
Said peripheral sensory neuropathy is preferably selected from peripheral y
neuropathy induced by a chemotherapeutic agent or peripheral sensory neuropathy induced by
an antiviral agent.
Said disease or disorder is still more preferably peripheral sensory neuropathy d
by a chemotherapeutic agent, wherein typically and preferably said chemotherapeutic agent is
selected from the group consisting of a kinase inhibitor, a proteasome inhibitor, a taxane, a
vinca id and a platinum salt. Still more preferably, said disease or disorder is peripheral
sensory neuropathy induced by a chemotherapeutic agent, wherein said chemotherapeutic
agent is selected from the group consisting of a kinase inhibitor, a proteasome inhibitor, a
taxane, a Vinca alkaloid and a platinum salt. Still more preferably, said disease or disorder is
peripheral sensory neuropathy induced by a chemotherapeutic agent, wherein said
herapeutic agent is selected from the group consisting of sorafenib, sunltinib, afatinib,
axitinib, vandetanib, veinurafenib, ixazomib, bortezomib, paclitaxel, docetaxel, cabazitaxel,
vincristinea stine, ine, Vinorclbine, nedaplatini lobaplating picoplatin, satraplain,
cisplatin, carhoplatin, or oxaliplatin. Said disease or disorder is still more preferably
eral sensory neuropathy induced by a chemotherapeutic agent, wherein said
chemotherapeutic agent is selected from the group consisting of sorafenib, stine,
paclitaxel, or oxaliplatin. Very preferably, said peripheral sensory neuropathy is induced by a
chemotherapeutic agent, wherein said chemotherapeutic agent is sorafenib, paclitaxel,
vincristine, cisplatin, carboplatin or oxaliplatin.
r preferably, said disease or disorder is peripheral sensory neuropathy induced by
an antiviral agent, wherein preferably said antiviral agent is a nucleoside reverse transcriptase
inhibitor. Still more preferably, said e or disorder is peripheral sensory neuropathy
l0 induced by an antiviral agent, wherein said antiviral agent is selected from zalcitabine,
didanosine, stavudine or zidovudine. Still more preferably, said disease or disorder is
peripheral sensory neuropathy induced by zalcitabine
Preferably, said herapy/«induced peripheral sensory neuropathy entails symptoms
of allodynia or dysesthesia, more preferably allodynia or dysesthesia of the hands or feet, and
further preferably nia or dysesthesia of the hands or feet induced by sorafenib, by
vincristine, by paclitaxel, or by carboplatin, cisplatin, or oxaliplatin.
Still more preferably, said peripheral sensory athy is associated with pain,
paresthesias, dysesthesias or allodynia,
Further preferably, the inventive composition or the inventive pharmaceutical
composition may be administered prophylactically, starting before the antituirtoral
chemotherapeutic ple has induced peripheral sensory athy and its attendant
Further preferably, the inventive composition or the inventive pharmaceutical
composition may be administered intennittently. Furthermore it is a preferred in the present
invention that the inventive composition or the inventive pharmaceutical ition may be
administered in synchrony with repeated cycles of an antitumoral chemotherapeutic principle.
The dosage will depend on the route of administration, the severity of the disease, age
and weight of the patient or subject and other factors normally considered by the attending
physician, when detennining, the dual n and dosage level for a particular patient
or subject.
The composition or pharmaceutical composition of the invention may be administered
via any route, including oral, intramuscular, subcutaneous, topical, transdennal, intranasal,
intravenoust sublingual or ectal administration. Typically and preferably, the
pharmaceutical ition of the ion is administered in a single dosage unit oncc~
daily, twice-daily or three times-daily via the oral route, and most preferably once—daily or
twice—daily. in the most preferred embodiment, the composition or pharmaceutical
composition of the ion is administered twice daily.
Typically and preferably, the oral dose of the inventive composition or the inventive
pharmaceutical composition is between l0 mg and 3000 mg per stration, more
preferably between 20 mg to 2000 mg per stration, again more preferably between 50
mg and l000 mg per administration. Typically and preferably, said composition or said
ceutical ition is administered orally twice daily in a dose of between 10 mg
and 3000 mg per administration, more preferably between 20 mg to 2000 mg per
l0 administration, again more preferably between 50 mg and 1000 mg per administration.
The pharmaceutical composition of the invention may be prepared by mixing suitably
selected and pharmaceutically acceptable excipients, vehicles, adjuvants, ves,
surfactants, desiccants or diluents known to those well—skilled in the art, and can be suitably
d for oral, parenteral or topical administration. Typically and preferably the
l5 pharmaceutical composition of the invention is administered in the form of a , capsule,
sachets, powder, granule, pellet, oral or parenteral solution, suspension, suppository,
nt, cream, lotion, gel, paste and/or may contain liposomes, micelles and/or
microspheres.
The pharmaceutically acceptable r of the pharmaceutical composition of the
invention is without limitation any pharmaceutically acceptable excipient, vehicle, adjuvant,
additive, surfactant, desiccant or diluent. Suitable phannaceutically acceptable carriers are
magnesium ate, magnesium te, talc, lactose, sugar, pectin, dextrin, starch,
tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a lting wax, cocoa
butter. Pharmaceutically able carriers of the invention can be solid, sentimsolid or liquid.
Tablets, capsules or sachets for oral administration are usually supplied in dosage units
and may contain conventional excipients, such as binders, fillers, diluents, tableting agents,
ants, detergents, disintegrants, colorants, flavors and wetting agents. Tablets may be
coated in accordance to methods well known in the art. Suitable tillers include or are
preferably cellulose, mannitol, lactose and similar agents. le disintegrants include or are
preferably starch, polyvinyl pyrrolidone and starch derivatives such as sodium starch
glycolate. Suitable lubricants e or are preferably, for example, ium stearate.
Suitable wetting agents include or are preferably sodium lauryl sulfate. These solid oral
compositions can be prepared with conventional mixing, filling or tableting methods. The
mixing operations can be repeated to disperse the active agent in compositions containing
large quantities of fillers. These operations are conventional.
The oral liquid compositions can be provided in the form of, for example, aqueous
solutions, emulsions, syrups or chairs or in the form of a dry product to be tituted with
water or with a suitable liquid carrier at the time of use. The liquid compositions can contain
conventional additives, such as suspending agents, for example sorbitol, syrup,
rnethylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate
gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan
monooleate, or acacia; non aqueous carriers (which can include edible oil), for example
lO almond oil, fractionated coconut oil, oily esters, such as glycerin esters, propylene glycol or
ethyl alcohol; vatives, for example methyl or propyl p-hydroxyhenzoate or sorbic acid
and if desired, conventional flavors or nts. Oral formulations may also include or may
be formulated as tional ations, such as tablets or granules. For parenteral
administration, liquid dosage units can be prepared containing the inventive composition and
l5 a sterile carrier.
Oral ations may optionally further include taste-masking components to optimize
the taste perception of the oral formulation. Examples of such taste—masking components may
be citrusu, ce, mint—, grape», black currant~ or eucalyptuswbased flavorants known to
those well—skilled in the art.
The parenteral solutions are normally prepared by dissolving the compound in a carrier
and sterilizing by filtration, before filling suitable vials or ampoules and sealing.
Adjuvants, such as local anesthetics, preservatives and ing agents can he added to
the pharmaceutical composition. In order to increase stability, the composition can be frozen
after filling the vial and the water d under vacuum. A surfactant or humectant can be
advantageously included in the pharmaceutical ition in order to facilitate uniform
distribution of the inventive composition.
Topical formulations include or are preferably nts, creams, lotions, gels, gums,
solutions, pastes or may contain liposomes, micelles or microspheres.
Subjects to be treated by the composition or pharmaceutical composition of the
invention are humans and animals. Preferred animals are domestic and farm s,
including but not limited to guinea pig, rabbit, horse, donkey, camel, cow, sheep, goat, pig,
cat, dog and parrot. More preferred ts are mammals, again more preferably humans,
in again a r , the invention provides for an article of manufacture
comprising the composition of the invention or the pharmaceutical composition of the
invention or the kit of the invention, a container or e and a written description and
stration instruction such as a package insert.
It is further envisaged that compositions of (R)-diiniracetam or (Sh—dimiracetam with
other racetams such as aniracetarn, brivaracetam, ceharacetam, coluracetarn, doliracetam,
dupracetam, etiracetam/leve’tiracetam, fasoracetarn, imuracetam, methylphenylpiracetarn,
nebracetarn, nefiracetam, omheracetarn (Noopept), oxiracetam, phenylpiracetarn,
piracetam hydrazide, piracetain, pramiracetani, ain, roiziracetain and/or
acetarn may also be used to prepare synergistic mixtures and compositions, in particular
if the ratio of (R)—dimiracetam or (S)~dirniraeetarn and the other racetam, or an enantiomer of
l0 the other racetani, are chosen within the ranges disclosed herein for the mixtures of (R)-
dirniracetarn and (53—dimiracetam.
It is further envisaged that compositions of (R)—dimiracetam or (Sh-diiniracetam with
other derivatives of dimiraeetarn, such as those disclosed in US 7544705 or in US 6,
may also he used to prepare synergistic mixtures and compositions, in particular if the ratio of
l5 (Rydimiracetam and the dimiracetamdike nd, or an enantiomer of the dimiraeetain—
like compound, are chosen within the ranges disclosed herein for the mixtures of {R}
dimiracetam and (S-dimiracetarn.
The present invention also relates to a method of treating and/or preventing a disease,
injury, or disorder, sing: administering to a subject the composition of claim l, wherein
the disease, injury, or disorder is peripheral sensory neuropathy, seizure, depression, or
ive iinpainnent. in this method, the e, injury, or disorder is preferably eral
sensory neuropathy, a neuropsychiatrie disorder, a inotoneuron disorder, or a movement
er. More preferably, the disease, injury, or disorder is peripheral sensory neuropathy,
The peripheral sensory neuropathy is preferably peripheral neuropathic pain. The peripheral
sensory neuropathy is preferably selected from diabetic neuropathy, post'herpetic neuropathy,
lumbago, sacral pain, surgical pain, crush injury, spinal injury, complex regional pain
syndrome, m limb sensations, peripheral sensory neuropathy associated with
osteoarthritis, peripheral sensory athy associated with rheumatoid arthritis, peripheral
sensory neuropathy associated with autoimmune rthrosis, cephalea, fibromyalgia,
peripheral sensory neuropathy induced by antiblastic ies, peripheral sensory neuropathy
induced by a chemotherapeutic agent, peripheral sensory neuropathy associated with Visceral
injury, peripheral sensory neuropathy associated with osteonecrosis, peripheral sensory
athy ated with human deficiency Virus infection, peripheral neuropathic
pain, or peripheral sensory neuropathy induced by an antiviral agent. in some instances, the
peripheral sensory neuropathy is peripheral sensory neuropathy induced by a
chemotherapeutic agent or peripheral sensory neuropathy induced by an antiviral agent. In
certain ces, the peripheral sensory neuropathy is peripheral sensory neuropathy induced
by a chemotherapeutic agent, wherein the chemotherapeutic agent is selected from the group
consisting of a kinase inhibitor, a proteasome inhibitor, a taxane, a vinca id, and a
platinum salt, and wherein preferably the herapeutic agent is selected from sorafenib,
sunitinib, afatinib, axitinib, vandetanib, vemurafenib, ixazomib, bortezomib, paclitaxel,
docetaxel, cabazitaxel, vincristine, vinblastine, vindesine, vinorelbine, nedaplatin, lobaplatin?
picoplatin, satraplain, cisplatin, carboplatin, and oxaliplatin. In some instances, the peripheral
sensory neuropathy is peripheral sensory athy d by an antiviral agent, wherein
the antiviral agent is a nucleoside reverse transcriptase inhibitor. in some instances, the
nucleoside reverse transcriptase inhibitor is zalcitabine, didanosine, stavudine, or zidovudine.
In some instances, the method r comprises administering an antitumor drug,
wherein the antitumor drug is selected from the group ting of" a kinase inhibitor, a
proteasome inhibitor, a taxane, a vinca id, and a platinum salt. In some instances, the
antitumor drug is selected from the group consisting of soraienib, nib, afatinib, axitinib,
vandetanib, vemurafenib, ixazomib, omib, paclitaxel, docetaxel, cabazitaxel,
vincristine, vinblastine, vindesine, vinorclbine, neclaplatin, atin, picoplatin, satraplain,
cisplatin, carboplatin, and oxaliplatin. In some instances, the method further comprises
stering an antiviral drug, wherein the antiviral drug is a side or a nucleotide. In
some instances, the antiviral drug is zalcitabine, didanosine, stavudine, or zidovndine. In
some instances, the ition is administered orally twice daily in a dose ofbetween it) mg
and 3000 mg per administration, between 20 mg to 2000 mg per administration, or between
50 mg and 1000 mg per administration.
The t invention furthermore relates to a method of enhancing learning and
memory, comprising administering to a subject the composition of the present invention as
described herein. In some instances of this , the subject is a healthy subject.
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EXAMPLES
Examples of the present invention are purely for illustrative and non-limiting purposes.
Samples of racemic dimiracctam, (R)~dimiracetam, and (Swdiiniracetain can be syntheaized
using commercially available starting materials, namely:
Preparation ofRfl—dimiracetam as described in US 5,200,406:
Supplier Purity
2—Chloroacetamide Sigma h 98%
Benzyiamine Sigma Aldrich
Ethyl trans-4*oxo—2-butenoate nt 98.5%
Ethyl acetate Sigma Aldrich 99.8%
Sodium hydroxide Sigma Aldrich
Toluene Sigma Aldrich
ium on charcoal Sigma Aldrich
Methanol Sigma Aldrich 98%
Ammonium hydroxide Sigma Aldrich 30%
Preparation ofR,S~Dimiracetam as described in :
l Glycinamide hloride Sigma Aldrich 98% j
Ethyl 4-«0xo—2-butenoate Clariant
Palladium on charcoal Sigma Aldrich
Ethyl acetate Sigma Aldrich
Sodium carboiiate Sigma Aldrich
I Isopropanol Sigma Aldrich
Preparation of racetam as described in W0 93/09l 20:
bethanolR—pyroglutamic acid Sichuan Tongsheng Amino Acid Co. 98%
Sigma Aldrich
Methaneaulfonic acid Sigma Aldrich 99%
Triethylamine Sigma Aldrich 99%
Ethyl acetate Sigma Aldrich
Toluene Sigma Aldrich
Sodium hydryde in oil Sigma Aldrich
t—Butyl cetate LYancheng Longshen Chemical Co 98.5%
Acetic acid Sigma Aldrich
Ammonium hydroxide {Sigma Aldrich
Acetic anhydride Sigma Aldrich
Sodium acetate Sigma Aldrich 99%
Dicioromethane' We: h 98%
Sodium hydrogen ate Sigma Aldrich
lsopropanol Sigma h
Hydrochloric acid LSigma Aldrich 32%
Preparation of S—Dimiracetam as described in WO 93/99120:
S—pyroglutamic acid W 98%
Methanol E Sigma Aldrich 98%
Methanesulfonic acid Sigma Aldrich 99%
Triethylamine Sigma Aldrich 99%
Ethyl acetate Sigma Aldrich 99.8%
e Sigma Aldrich
Sodium e in oil i Sigma Aldrich
t~Butyl bromoacetate Yancheng Longshen Chemical Co 98.5%
Acetic acid Sigma Aldrich 99%
Ammonium hydroxide Sigma Aldrich 30%
Acetic aliiiiydaaSWnga Aldrich 98%
Sodium acetate Sigma Aldrich
Dicloromethane Sigma Aldrich
Sodium en carbonate Sigma Aldrich
Isopropanol i—§gma Aidrich
Hydrochloric acid Sigma Aldrich
These cial es can he used as received from the supplier witheut further
purification, using s and techniques of preparative sis well kncwn to those
skilled in the art.
EXAMPLE 1: Synthesis of the composition of dimiracetam
(R)— and iracetam as well as the racemic mixture of dimiracetam were prepared
in accordance with methods described in WO 93/09120; Pinza at all, 1993; and WO
13640 as well as in Camilleri et at, 1993. The enantiomeric excess of the synthesized
(R)— and (Sudiiniracetain was determined as described in Camilleri at all”, 1993. The
enantiomeric excess of (R)« and (S-dimiracetam, when used separately for preparing the
compesition of the present invention, was equal to or greater than 96% for each enantiomer.
For achieving the d enantiomcric excess of equal to or higher than 30% ee (excess
(RD and less than or equal to 60% ee (excess (RD, as well as other desired specific
compositions in accerdance with the present invention” several methods known to the skilled
person in the art can be applied. For example said compositions were prepared either by
mixing the dual enantiomers or by mixing the racemate of dimiracetam with the
respective quantities of (R)-dimiracetam. Furthermore starting from racemic dimiracetam,
part or all of the (S—enantiomer can he removed by preparative chiral column
chromatography.
EXAMHJE 2: Inhibition of NMDA + glycine—induced glutamate release from rat spinal
synaptosomes
Neurotransmitter release experiments
Rat spinal synaptosomes, free frcm glial contaminants, were prepared according to the
method ofPaluzzi S, at al, 2007, a medificatioa of the method ot‘Nal-iamura at all, 1993, as
follows,
3O Sprague-Dawley rats aged between 90 to ISO days were used. Animals were housed at
constant temperature (22 :l: 10C) and relative humidity (50%) under a regular light—dark
le (lights 7.00 am - 700 pm). Food and water were freely available.
Rats were sacrificed by tation and the whole spinal cord was rapidly removed and
maintained at 40C. Rat spinal cord was homogenized (90 rpm; 24 n strokes in 2 min)
in 10 volumes (1 g tissue in 10 ml) of ice cold 0.32 M sucrose, buffered at pH 7.4 using a
glass—teflon tissue grinder (clearance 0.25 min). The homogenate was centriiiiged (5 min,
l000 g at 40C) to remove nuclei and debris, and the supernatant was gently stratified at 0~40C
on a discontinuous Percoll® (Sigma h, St Louis, MO, USA) gradient (2, 6, l0 and 20%
VA? in Trisvbuffered sucrose) and centrifuged at 33,500 g for 5 min. The layer between l0 and
% l (i.e. the osornal fraction) was collected and washed by centrifugation in
physiological medium having the following ition (mM): NaCl, 140; KCl, 3; MgSOa
l.2; NaHzPO4, 1.2; NaHC03 5; CaC12 1.2; HBPES 10; e, 10; pH 7.4. Protein content
was measured according to Bradford MM, l976 using bovine serum albumin as a standard.
Synaptosomes (about 70 pg protein) were ted at 370C for 15 min in 2.5 ml. of
0.05 pM [3H]-D—aspartate ([3fil—D—Asp; Perkin Elmer ltalia, Monza, Milano, Italy). Then, the
suspension was diluted to 122.5 mL with physiological medium maintained at 37DC and 5 mt.
aliquots of the synaptosomal suspension were layered on microporous filters placed at the
bottom of a set of 24 parallel 25 mL superfusion rs maintained at 370C fusion
l5 system, Ugo Basile, Comerio, Varese, Italy). Superfusion was then started with physiological
medium at a rate of 0.5 n, and was continued for 46 min. Starting at t x 37 min, nine
consecutive l—min filtrate samples were collected. NMDA (10 MM) and glycine (l old) were
introduced at the end of the first sample ted and maintained until the end of the
experiment.
The radioactivity contained in each filtrate sample was measured by scintillographic
methods, using a Ultima Gold scintillation fluid (PerkinmElmer Milan, Italy). Each whole 0.5
mL sample was counted for radioactivity by adding 3 inL of scintillation fluid.
Tritium content measured in each sample was expressed as fractional percent (Le.
percent content of each sample with respect to total [3H] content at the onset of the respective
collection period). Drug effects were ted by calculating the ratio between the effluxes
in the seventh fraction collected (in which the maximum effect of NMDA was reached) and
that of the first on (basal release, prior to ation of NMDA+glycine). This ratio was
compared to the same seventh— and first~fraction ratio obtained under control conditions.
Effects on NMDA—induced glutamate release in synaptosonial fractions
The possible effects of racemic and non-raceinic dimiracetam mixtures on NMDA plus
glycinewinduced neurotransmitter release from rat spinal cord synaptosomes were assessed.
The inventive composition with an enantiomeric excess of (.R)—dirniracetam of 33.3%
corresponding to a 2:1 (R):(S) ratio of the cctam enantiomers inhibits NMDA plus
glycine~evoked [3H]-D—aspartic acid release from rat spinal synaptosomes with an ted
K350 of 10 nM (Fig. 1A)? wherein the inventive composition with an enantiomeric excess of
(R)-dimiracetam of 50% corresponding to a 3:1 (R):(S) ratio of the cetam omers
inhibits NMDA plus glycine-evoked [3fll-D—aspartic acid release from rat spinal
synaptosomes with an estimated IC50 of less than l nM (Fig. 1B). in comparison, the c
dimiraeetam, i.e. lzl (R):(S), inhibits NMDA plus glycine~evoked [3Hl—D—aspartic acid release
from rat spinal synaptosemes with an estimated lC5g of l4.6 11M (Fig. 10; Table 1), whereas
the (R)«dirniracetam has an estimated 1059 of 123 nM ()) and the (‘S-dimiracetam an
ll} estimated leg of 418 nM (3).
A further set of confirming experimental data is represented in Table l‘
Table 1: Inhibition by racemic dimiraeetam and preferred inventive non-raceniic
dimiracetam mixtures on [3Hl-D—Asp release induced by 10 pM NMDA plus 1 pM glycine, in
osonies from rat spinal cord. Results are expressed as % inhibition of NMDA plus
glycine—stimulated release. Data are means :l: ELEM. of 3 to 6 experiments that run in
cate.
Dimiracetam enantiomeric Percent inhibition of NM‘DA + glycinewinduced
mixtures glutamate release from rat spinal synaptosomes
Enantiomeric
(R):(S) ratio excess of (R)- 0.l nM l 31M l0 11M
dimiracetam
0% 93:130/0 29:}:3%
2:1 33% 2:}:170/0 -3.i:tl% 49e7%
3:1 50% 2lil7% 49i10% 54e5%
EXAMPLE 3: Rat models of induced peripheral neuropathic pain
Evaluation of pain responses
At the peak of the pain se according to the model under tion, the effects of
a single dose of the test nds, vehicles and comparators were evaluated. Thereafter, to
assess the possible development of tolerance, repeated administrations of racemic and non»
racemic dimitacetam mixtures were studied. Both hyperalgesia and allodynia were assessed.
All y evaluations were carried out by investigators blinded to the rats’ treatment
allocation.
Paw pressure test ghmeralgesia)
Paw mechanical sensitivity was determined using a Randail & Selitto tus
(Randall and Selitto, 1957) exerting a force that increases at constant rate (32 $3). The
stimulus causing paw withdrawal was evaluated before and at different times after treatment.
Results represent the mean of mechanical thresholds for paw withdrawal expressed as grams.
To avoid possible damage to the rat paw the maximum applied force was set at 240 g. In the
single administration protocol, paw pressure tests were performed before (pro—dose) and at
r intervals after treatment.
Knee osteoarthritis model
A single intra—artieular injection of sodium monoiodoaeetate (MIA) was introduced into
the knee joint of rats according to the method described by Femihough 5 at 61.1., 2004. Sodium
inonoiodoacetate (MIA) inhibits ocyte metabolism leading to cartilage degradation in
form of osteoarthritic-like focal lesions in the cartilage ated with subchondral hone
thickening 14 days after administration (Guingamp e! mi, l997). This model therefore can
easily and quickly reproduce osteoarthritic—like lesions and functional impairment in rats,
similar to that observed in human disease (Guzman at at, 2003). Alter 7 days post-injection;
the inflammatory component subsides and the remaining pain is considered neuropathic in
nature. Briefly, rats were deeply hetized with diethyl ether, Following abolition of the
hind paw pinch withdrawal reflex, a ge needle was introduced into the joint cavity
between the tibial plateau and l eondyles. Once in place, 2 mg of NBA were diluted in
a volume of 25 mL of 1% CMC (carboanethylccllulose in water, Sigma—Aldrich, Italy) and
injected into one knee joint and the rat was allowed to recover for 14 days prior to pain
assessment.
Animals received a single stration of racemic dimiracetam (150 and 300 mg/kg
no.) or compositions of (R) and (S) enantiomers of dimiracetam at 150 and 300 nag/kg in a
3O ratio of 32l (R):(S) and 1:3 ) at day 16 after MIA injection. Control rats were treated
with an equal volume of saline.
Chemotherapy induced peripheral sensory neuropathy ~ Oxaliplatin model
Peripheral sensory neuropathy was induced in adult rats, by administration of
oxaliplatin (Tocris) at 2.4 mg/kg in. in saline once daily for 5 consecutive days every week
for three weeks (cumulative dose 36 reg/kg) according to Cavaletti er a!” 2001. Starting from
day 21 after the first oxaliplatin administration, the effect of repeated oral administration of
racemic dimiraeetam or the preferred inventive composition with an enantiomeric excess of
(R)-dimiraeetam of 50% corresponding to a 3:1 (R):(S) ratio of the enantiomers on
oxaliplatin—indueed mechanical hyperalgesia was assessed.
EXAMPLE 4: Results of experiments in rat models of peripheral neuropathic pain
1. Knee rthritis model
ce of racemio eetam and various compositions of non~raeemie es of
dimiracetam enantiomers on eral neuropathic pain was assessed by paw-«pressure test
after a, single intro-articular injection of sodium monoiodoaeetate (MIA) into rat knee joint
(knee osteoarthritis model) as described above.
Figure 2 shows the results obtained in the paw-pressure test after —dose oral
administration of the racemie mixture of dimiraeetam and ent nonuraeemic es of
(R)—dimiracetam and (S)~dimiraeetam, namely the preferred inventive composition with an
2O enantiomerie excess of (R)~dimiracetam of 50% corresponding to a 3:1 (R):(S) ratio of the
enantiomers, and a composition of 1:3 (R):(S). The red inventive composition with an
omeric excess of (R)~dimiracetam of 50% is more efficient in reducing peripheral
neuropathie pain in the paw-pressure test after injection of sodium monoiodoaeetate (MIA)
than the racemie mixture of dimiraeetam or a mixture with an excess of the (fi—enantiomer of
dimiraeetam [l :3 (R):(S)].
2. Oxaliplatin model
After repeated oral administration of either racemie dimiracetam or the preferred
inventive composition with an enantiomeric excess of (R)-dimiracetam of 50%, oxaliplatin—
induced ical hyperalgesia was measured. Pain threshold was assessed by a Randall &
Selitto analgesymeter before the morning administration. The preferred inventive composition
with an enantiomerie excess of miraeetam of 50% is more potent than racemie
dimiraeetam in reducing latin~induced hyperalgesia (Figure 3A), allodynia (Figure 3B),
and cold—sensitivity (Figure 3C). Thus, also in this model of ohemotherapeutiwily—induced
peripherai y neuropathy, the inventive composition with an excess of the (R)
enantiomer of dimiraeetam is more efficient in reducing peripheral neuropathie pain than the
same amount of the racemic mixture of dimiraeetam. pment of nce was not
EXAMPLE 5: In vitro inhibition of pro—loaded {SHI-D-aspartate reiease induced by
added NMDA+glycine in rat spinal cord osomes
to order to establish the range of (R):(S) ratios of enantiomerie es of dimiracetam
enantiomers providing an inhibitory potency superior to that of raeemic dimiracetam, a
number of mixtures between 2:1 to 4:1 (R):(S) were tested at 10 nM. These experiments were
performed following the previously published methodology llo et al.
Neuropharmacology. 20M, (81), 85—94) and the results are shown in Fig. 5.
Furthermore, the data can be summarized as shown in the following Table 2:
Table 2
% inhibition
(mean)
wherein s.d. is standard deviation and so. is the standard error of the mean.
As can be seen from this data, the compositions according to the present invention, in
particular those having a ratio of 2:1 to 3,321 (R):(S)3 or in between said values, show a
markedly improved inhibitory potency that is Clearly superior to the inhibitory potency of
racemic dimiraeetam.
EXAMPLE 6: In vivo anti-amnestic activity in a e nce paradigm in mice
Racemic dimiraeetam and two different mixtures of its R and S enantiomers (2:1 (R):(S) and
3:1 (R):(S“), respectively) were tested in a passive avoidance test in mice at doses of 3, 10 and
mg/kg, 30 min alter oral administration.
Methods. The test was performed according to the step-through method described by larvik
ME ad Kopp R, Psychol Rep, 21:221—224, 1967. The apparatus consisted of a two—
compartment acrylic box, with a lighted compartment connected to a darkened one by a
guillotine door. Mice receive a punishing electrical shock (0.3 mA, l s) as soon as they
entered the dark compartment. The test was performed on two consecutive days. Mice were
placed in the light side of the two-compartment box: the latency times for entering the dark
compartment were ed in the training session on the first day: and after 24 h in the
retention session on the second day. Mice received the punishment when entering the dark
l5 room in the training session and remembered it in the session on the following day, unless
their memory was impaired by the amnesic drug. In the training session, mice which had not
entered the dark compartment after 60 s latency were excluded from the remainder of the
experiment; about 20—30% of mice were excluded from each group. All investigated drugs
were administered orally 30 min prior to the training session; for memory disruption, mice
were injected with the amnesic drug amine (1.5 mg/kg ip.) ately alter
completion of the ng session.
Vehiclemtreated mice received an i.p. injection of saline immediately after the ng session,
as control of the scopolamine injection. After 24 h, the test was ed (retention session);
during the second day no drug was administered. The maximum entry latency allowed in the
retention session was 180 s. The results are shown in Fig‘ 6.
ingly, it can be seen that the latencies observed in the cases where a 3:1 ratio or a 2:1
ratio of R15 enantiomers was used, were much higher than in the case where the racemate of
dimiracetam was used.
EXAMPLE 7 : Antidepressant ty in the forced swimming (Porsolt) test in mice
c dimiracetam and two mixtures of its R and S enantiomers (2:1 and 3:1, respectively)
were tested in forced swimming (Porsolt) test in mice at doses of 10, 30 and i0() nag/kg, 25
min after oral administration.
Methods. The forced swimming test used was the same as that described in Porsolt RD,
Bertin A, Jalfre Ma Arch. Int Pharmacoeim. Titer. 19771 2.292323% 336. Briefly, mice were
placed individually into glass cylinders (height: 25 cm, diameter: 10 cm) ning 12 cm of
water maintained at 22m23 OC and were left there for 6 min. A mouse was judged to be
le if it floated in the water, in an upright position, and made only small movements to
keep its head above water, The duration of mobility was recorded during the last 4 min of the
6 min test. An increase in the duration of mobility was taken to be an indication of an
antidepressantdike effect. The results are shown in Fig. 7.
ingly, it can be seen that the mobility of the mice that was achievable by the use of a
3:1 ratio or a 2:1 ratio of R15 enantiomers of dimiracetam was markedly higher that in the
case of the racemate of dimiracetam.
In View of the above, it can be seen that the effects of the claimed ratios ofRzS enantiomers of
dimiracetarn lead to reduced glutamate release from rat spinal synaptosomes, d
peripheral neuropathic pain, anti-amnestic effects and anti—«depressant effects that are clearly
hotter than in the case where the te of dimiracetam was used.
EXAMPLE 8: Paw pressure test, Von Frey test and cold plate test in oxaliplatin model
in rats
After repeated oral administration of either racemic dimiracetam or the red
inventive composition with an enantiomeric excess of (R)-dimiraeetam of 50%, oxaliplatin-
induced mechanical hyperalgesia was measured. Pain threshold was assessed by a Randall &
Selitto analgesymeter ton et al. Br. J. Pharmacol. 93:553-560, 1988) before the
g administration. in the morning of day 28, also mechanical allodynia (Sakurai et al.
Pain 14 7 :165— 74‘, 2009) and cold sensitivity were assessed, using the von Frey and cold plate
tests (Di Cesare Mannelli et al. Exp Neurol 261 .2233, 2014), respectively. As shown in
Figure 3 and Table 3, the preferred inventive composition with an enantiomeric excess of (R)~
dimiracetam of 50% is more potent in reducing oxaliplatin-induced hyperalgesia, allodynia
and cold sensitivity; Thus, also in this model of herapeutically induced peripheral
sensory neuropathy, the ive composition with an excess of the (R)—enantiomer of
dimiracetam is more efficient in reducing peripheral neuropathie pain than the racemic
mixture ot‘dimiracetani. Development of tolerance was not observed.
Table 3. Effect of racemic dimiracetam and invention mixture (R:S 3:1)
Randall & Selitto, paw Von Frey paw,
Treatment
, Cold plate, licking latency, s
Dose pressure, g Withdrawal, g
m k {3.14}, t: Day 28 Pro—test Day 28 Protest Day 28
saline 65.8 i l.8 65.2 :t 0.9 23 .0 :l: 0.8 26.3 i 0.8 22.5 i 0.9 20.5 i 0.7
oxaliplatin 68.5 a: 1.1 5L7 :l: 1.9 M 20.6 i 0.9 15.9 :1: 1.0 M 23.5 :1: 0.6 14.2 i 0.6 ’V‘
Rlezi 15 68.11212 48.72%:25 21.4i10 loll-3:15 21.5:t10 14.8il5
R:S3:1 15 65.23% 1.7 62.5 i 1.8 ** 0° 25.121: 0.5 24.7 i 1.5 ** 00 20.8 :1: 1.3 18.7 :t: 0.7 ** 0"
R:Sl:150 67.1:l:0.8 55.2i10 21.4i05 18.5:t23 22.0:lz08 15.4i10
12:53:150 65.4.5.2 65.6:t12 MW 21.22am sums *ro 21.9i2.1 19.63417 **W
Oxaliplatin (2.4 nag/kg i.p.) was administered daily on weekdays from day l to day 15 (ll injections in
total). The two mixtures of dimiraeetam omers (R23 1:1 and R:S 3:1) were administered daily from
day 1 until day 27.
l5 oral measurements were perfonned in the morning of day 28 and represent the mean a: sem of 6
rats. MP<001 vs saline; **P<0.01 vs oxaliplatin; °P<0.05 and 00P<0.01 vs raccmate 15 mgx’kg; 5
and Wl3‘<0.0l vs racemate 50 mg/kg
The paw pressure test, Von Frey test and cold plate test were conducted as s:
Paw pressure test
Paw ical sensitivity was determined using a Randall & Selitto apparatus exerting a
force that increases at constant rate (32 g/s). The stimulus at which rats withdrew the paw was
evaluated before and at different times after ent. s represent the mean of
mechanical thresholds expressed as grains. To avoid any possible damage to the animal paw
the m applied force was fixed at 240 g (Leighton et al. Br. J. Pharmacol. 93:553—560.
1988).
Von Frey test
The animals were placed in 20 cm X 20 cm Plexiglas boxes equipped with a metallic mesh
floor, 20 cm above the bench. Animals were d to habituate themselves to their
environment for 15 min before the test. An electronic Von Frey hair unit (Ugo Basile, ,
Italy) was used: the withdrawal old was evaluated by applying forces ranging from O to
50 g with a 0.2 g cy. Punet’uate stimulus was delivered to the mid-plantar area of each
anterior paw from below the mesh floor through a plastic tip and the withdrawal old
was automatically displayed on the screen. The paw sensitivity threshold was defined as the
minimum force required to elicit a robust and immediate Withdrawal reflex of the paw.
Voluntary movements associated with locomotion were not considered as a withdrawal
response. Stimuli were applied to each posterior paw at 5 8 intervals. Measurements were
repeated 5 times and the final value was obtained by averaging the 5 measurements (Sakurai
et 31. Pain [47 :165w74, 2009).
Cold plate test
The animals were placed in a stainless box (12 cm >< 20 em >< 10 cm) with a cold plate as
floor. The temperature of the cold plate was kept constant at 49C :1: 10C. Pain—related
behaviors (i.e. lifting and licking of the hind paw) were observed and the time (s) of the first
sign was recorded. The cut—off time of the latency ot‘paw lifiing or g was set at 60 s (Di
Cesare li et al. Exp Neurol 26] :22—33, 2014).
All patents, publications? and abstracts cited above are incorporated herein by reference in
their entireties. Various embodiments of the invention have been described in fulfillment of
the various objectives of the invention. It should be recognized that these embodiments are
merely illustrative of the ples of the present invention. Numerous modifications and
ons thereof will be readily apparent to those skilled in the art without departing from the
spirit and scope of the present invention as defined in the ing claims.
Claims (26)
1. A composition sing (R)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5- dione ((R)-dimiracetam (1)) and (S)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole- 2,5-dione ((S)-dimiracetam (2)), and/or pharmaceutically acceptable solvates or co-crystals thereof wherein an enantiomeric excess (ee) of the (R)-dimiracetam (1) is equal to or higher than 33% and lower than or equal to 54%.
2. The ition of claim 1, wherein a ratio of (R)-dimiracetam (1) to miracetam (2) is 2:1 to 3.3:1.
3. The composition of claim 1 or claim 2, wherein the (R)-dimiracetam (1) and/or ceutically acceptable solvates or co-crystals thereof (S)-dimiracetam (2) and/or pharmaceutically acceptable solvates or co-crystals thereof are packaged separately.
4. The composition of claim 1, wherein the composition is a non-racemic mixture of 3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione (dimiracetam) and pharmaceutically acceptable solvates or co-crystals f, wherein the non-racemic mixture comprises (R)-dimiracetam (1) to (S)-dimiracetam (2) in an enantiomeric excess (ee) of the (R)-dimiracetam (1) of equal to or higher than 33% and lower than or equal to 54%.
5. A pharmaceutical composition comprising the composition of any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
6. Use of a composition of any one of claims 1 to 4 in the manufacture of a medicament for treating a disease, injury, or disorder, wherein the disease, injury, or disorder is eral sensory neuropathy, seizure, depression, or cognitive impairment
7. The use of claim 6, wherein the disease, injury, or disorder is peripheral sensory athy, a neuropsychiatric disorder, a motoneuron disorder, or a movement
8. The use of claim 6, wherein the disease, injury, or er is peripheral sensory neuropathy.
9. The use of claim 8, wherein the peripheral sensory neuropathy is peripheral neuropathic pain.
10. The use of any one of claims 6 to 8, wherein the peripheral sensory neuropathy is diabetic neuropathy, post-herpetic neuropathy, lumbago, sacral pain, surgical pain, crush injury, spinal injury, complex al pain syndrome, phantom limb sensations, peripheral y neuropathy associated with osteoarthritis, peripheral sensory neuropathy associated with rheumatoid arthritis, peripheral y neuropathy associated with autoimmune osteoarthrosis, cephalea, fibromyalgia, peripheral sensory neuropathy induced by antiblastic therapies, peripheral sensory neuropathy induced by a chemotherapeutic agent, peripheral y neuropathy associated with visceral , peripheral sensory neuropathy associated with osteonecrosis, peripheral y neuropathy associated with human immunodeficiency virus infection, peripheral neuropathic pain, or peripheral sensory neuropathy induced by an ral agent.
11. The use of any one of claims 6 to 8, wherein the peripheral sensory neuropathy is eral sensory neuropathy induced by a chemotherapeutic agent or peripheral sensory neuropathy induced by an antiviral agent.
12. The use of claim 11, n the peripheral sensory neuropathy is peripheral sensory neuropathy induced by a chemotherapeutic agent, wherein the chemotherapeutic agent is selected from the group ting of a kinase inhibitor, a some inhibitor, a , a vinca alkaloid, and a platinum salt, and wherein preferably the chemotherapeutic agent is selected from sorafenib, sunitinib, afatinib, axitinib, vandetanib, vemurafenib, ixazomib, bortezomib, paclitaxel, docetaxel, cabazitaxel, vincristine, vinblastine, ine, vinorelbine, nedaplatin, lobaplatin, picoplatin, satraplain, cisplatin, carboplatin and oxaliplatin.
13. The use of claim 11, wherein the eral sensory neuropathy is peripheral sensory neuropathy induced by an antiviral agent, n the antiviral agent is a nucleoside reverse transcriptase inhibitor.
14. The use of claim 13, wherein the nucleoside reverse riptase inhibitor is zalcitabine, didanosine, ine, or zidovudine.
15. The use of any one of claims 6 to 8, 11 and 12, wherein the medicament is formulated for administration with an antitumor drug, wherein the wherein the mor drug is selected from the group consisting of a kinase inhibitor, a proteasome inhibitor, a taxane, a vinca alkaloid, and a platinum salt.
16. The use of claim 15, wherein the antitumor drug is selected from the group consisting of sorafenib, sunitinib, afatinib, axitinib, vandetanib, vemurafenib, ixazomib, bortezomib, paclitaxel, docetaxel, cabazitaxel, vincristine, vinblastine, vindesine, vinorelbine, atin, lobaplatin, picoplatin, satraplain, cisplatin, carboplatin, and oxaliplatin.
17. The use of claim 6 to 8, 11, 13 and 14, wherein the medicament is formulated for administration with an antiviral drug, wherein the antiviral drug is a nucleoside or a nucleotide.
18. The use of claim 17, wherein the antiviral drug is of zalcitabine, sine, stavudine, or zidovudine.
19. The use of claim 6 to 18, wherein the medicament is formulated for administration orally twice daily in a dose of between 10 mg and 3000 mg per administration, n 20 mg to 2000 mg per administration, or between 50 mg and 1000 mg per administration.
20. Use of a composition of claim 1 in the manufacture of a medicament for ing learning and memory.
21. The use of claim 20, wherein the medicament is ated for administration to a healthy subject.
22. A method for preparing a composition of claim 1, comprising combining (R)-dimiracetam (1) and (S)-dimiracetam (2), or (R)-dimiracetam (1) and a racemate of dimiracetam.
23. A composition as d in any one of claims 1 to 4 ntially as herein described with reference to any one or more of the examples but excluding comparative examples.
24. A pharmaceutical composition as claimed in claim 5 substantially as herein described with reference to any one or more of the examples but excluding comparative es.
25. Use of a composition as claimed in any one of claims 6 to 21 substantially as herein described with reference to any one or more of the examples but excluding comparative examples.
26. A method as claimed in claim 22 substantially as herein described with reference to any one or more of the examples but excluding comparative examples
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP17173760.4 | 2017-05-31 | ||
EP17173760 | 2017-05-31 | ||
PCT/EP2018/064125 WO2018219977A1 (en) | 2017-05-31 | 2018-05-30 | Synergistic compositions comprising (r)-dimiracetam (1) and (s)-dimiracetam (2) in a non-racemic ratio |
Publications (2)
Publication Number | Publication Date |
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NZ758086A NZ758086A (en) | 2020-12-18 |
NZ758086B2 true NZ758086B2 (en) | 2021-03-19 |
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