Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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COMBINATION OF A 5-HT(1) RECEPTOR AGONIST AND AN ALPHA-2-DELTA LIGAND FOR THE
TREATMENT OF MIGRAINE
The present invention relates to a combination of a 5-HT1B, 5-HTID or 5-HTiF
receptor agonist and an alpha-2-delta ligand, as well as to pharmaceutical
compositions comprising such a combination and to the uses of such a
combination
in the treatment of pain and other conditions, especially in the treatment of
migraine.
Serotonin (5-hydroxytryptamine, 5-HT) acts at a number of membrane-bound
receptors known as 5-HT receptors. These heterogeneous receptors belong to the
G-protein coupled receptor supe'rfamily_ and have been divided into six broad
classes (5-HT1, 5-H;T2, 5-HT4, 5-HT5, 5-HT6 and 5-HT7). Some of these classes
can
be further subdivided. The 5-HTi class, for example, comprises five receptor
subtypes, all of whi'ch have a nanomolar affinity for serotonin. The 5-HT1A, 5-
HT1B
and 5-HT1D subtypes are characterized by a high affinity for 5-
carboxamidotryptamine whilst the 5-HT1E and 5-HT1F subtypes are characterized
by
a low affinity for this synthetic agonist. See Lanfumey and Hamon in Current
Drug
Targets - CNS & Neurological Disorders, 2004, 3(1), 1-10 for further
information.
A number of indole 5-HT, agonists (commonly known as triptans) have been
identified which act most potently at the 5-HT1B and 5-HTID receptor subtypes
and
have efficacy in the treatment of migraine. These include sumatriptan,
naratriptan,
zolmitriptan, rizatriptan, frovotriptan, almotriptan and eletriptan.
Ergotamine and
dihydroergotamine are also potent agonists of 5-HTlB and 5-HT1D receptors.
More
recently, selective agonists of the 5-HTiF receptor (such as LY334370 and
LY344864) have been discovered and shown to be effective in preclinical models
of
migraine (see Phebus et al, Society for Neurosceince, 1996, 22, 1331 and Life
Sci.,
1997, 61, 2117).
An alpha-2-delta ligand (also known as a GABA analogue) is a compound which
selectively displaces 3H-gabapentin from brain membranes (e.g. porcine or
human
brain membranes) and consequently has a high affinity interaction with the
alpha-2-
delta ((x28) subunit of voltage-gated calcium channels. Alpha-2-delta ligands
act on
voltage-gated calcium channels to attenuate excessive neuronal activity by
reducing
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the depolarization-induced movement of calcium ions into presynaptic terminals
and
reducing the subsequent release of neurotransmitters such as glutamate,
noradrenalin and substance P.
Alpha-2-delta ligands have utility in the treatment of a number of conditions.
The
best known alpha-2-delta ligand, gabapentin (NEURONTINO, 1-(aminomethyl)-
cyclohexylacetic acid) was first described in the patent family comprising US-
B-
4,024,175. The compound is approved for the treatment of epilepsy and
neuropathic pain. Although recent clinical trials have shown that gabapentin
is
efficacious in migraine prophylaxis, there are no reports showing efficacy in
the
acute (abortive) treatment of migraine.
A second alpha-2-delta ligand, pregabalin (Ll(RICAO, (S)-(+)-4-amino-3-(2-
methylpropyl)butanoic acid), is described in EP-A-0641330 as an anti-
convulsant
useful in the treatment of epilepsy. The use of pregabalin in the treatment of
pain is
described in EP-A-0934061. Pregabalin readily crosses the blood-brain barrier
through the L-amino acid transporter of cell membranes, thereby reaching its
key
targets in the brain and spinal cord.
There is an ongoing need to provide better treatments for pain (e.g. migraine
headaches) that are, for example, more effective at lower doses, effective
against a
wider spectrum of pain conditions, less prone to produce side effects, faster
acting
and longer acting. A lower rate of recurrence in certain painful conditions
(e.g.
migraine) is also desirable.
The use of a 5-HT1B, 5-HTiD or 5-HTiF receptor agonist (particularly a
triptan) in the
treatment of migraine is somewhat limited by the need for early administration
in
order to achieve optimal pain relief and by the potential for unwanted side-
effects at
therapeutic doses. Migraine is a primary brain disorder in which neural events
result
in both dilation and inflammation of cranial blood vessels and neurogenic
inflammation in the brain. An increased sensitivity and excitability is
produced
resulting in peripheral sensitization followed by central sensitization.
Central
sensitization is an increase in the excitability of neurons within the central
nervous
system, so that inputs that would normally evoke a mild or absent sensation
now
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produce an exaggerated response (e.g. tactile allodynia in which a pain
response is
evoked by light brushing of the skin). Recent evidence indicates that triptans
are
more effective if given early in an attack, before peripheral neurons
sensitize central
neurons leading to central sensitization and that they are unable to reverse
ongoing
peripheral or central sensitisation.
It has now been surprisingly found that combination therapy with a 5-HT1B, 5-
HTiD
or 5-HTiF receptor agonist and an alpha-2-delta ligand offers significant
benefits in
the treatment of pain, particularly in the treatment of migraine. Such
combination
therapy is particularly advantageous when compared with therapy using either
agent alone. Such a combination of a 5-HT1B, 5-HT1D or 5-HT1F receptor agonist
and an alpha-2-delta ligand results unexpectedly in a synergistic effect,
resulting in
greater efficacy than would be obtained using either class of agent singly. In
particular, the dose of a 5-HT1B, 5-HTlD or 5-HT1F receptor agonist
(particularly a
triptan) necessary to treat a migraine attack is reduced, potentially leading
to fewer
side-effects. Furthermore, the efficacy of such a compound, when administered
in
the later phases of an attack, at a time when peripheral sensitisation has
already
started, is considerably greater when administered in combination with an
alpha-2-
delta ligand.
The invention therefore provides a combination of a 5-HT1B, 5-HT1 or 5-HTiF
receptor agonist and an alpha-2-delta ligand.
Further, the invention provides a pharmaceutical composition comprising a 5-
HTiB,
5-HT1D or 5-HTiF receptor agonist, an alpha-2-delta ligand and a
pharmaceutically
acceptable excipient, diluent or carrier.
Further, the inventiori provides a combination of a 5-HTiB, 5-HT1D or 5-HTiF
receptor agonist and an alpha-2-delta ligand for use as a medicament.
Further, the invention provides the use of a 5-HT1B, 5-HT1D or 5-HT1F receptor
agonist or an alpha-2-delta ligand in the manufacture of a medicament for
simultaneous, sequential or separate administration of both agents in the
treatment
of pain (especially migraine).
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Further, the invention provides a combination of a 5-HT1B, 5-HT1D or 5-HT1F
receptor agonist and an alpha-2-delta ligand for simultaneous, sequential or
separate administration in the treatment of pain (especially migraine).
Further, the invention provides a method of treating pain (especially
migraine)
comprising administering simultaneously, sequentially or separately, to 'a
mammal
in need of such treatment, an effective amount of a 5-HT1B, 5-HT1D or 5-HT1F
receptor agonist and an alpha-2-delta ligand.
Further, the invention provides a kit comprising a 5-HT1B, 5-HT1D or 5-HTiF
receptor
agonist, an alpha-2-delta ligand and means for containing said compounds.
Further, the invention provides a product containing a 5-HT1B, 5-HTlp or 5-
HTiF
receptor agonist and an alpha-2-delta ligand as a combined preparation for
simultaneous, separate or sequential use in the treatment of pain (especially
migraine).
The combination provided by the present invention is useful in the treatment
of pain,
which is a preferred use. Physiological pain is an important protective
mechanism
designed to warn of danger from potentially injurious stimuli from the
external
environment. The system operates through a specific set of primary sensory
neurones and is activated by noxious stimuli via peripheral transducing
mechanisms
(see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review). These sensory
fibres
are known as nociceptors and are characteristically small diameter axons with
slow
conduction velocities. Nociceptors encode the intensity, duration and quality
of
noxious stimulus and by virtue of their topographically organised projection
to the
spinal cord, the location of the stimulus. The nociceptors are found on
nociceptive
nerve fibres of which there are two main types, A-delta fibres (myelinated)
and C
fibres (non-myelinated). The activity generated by nociceptor input is
transferred,
after complex processing in the dorsal horn, either directly, or via brain
stem relay
nuclei, to the ventrobasal thalamus and then on to the cortex, where the
sensation
of pain is generated.
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Pain may generally be classified as acute or chronic. Acute pain begins
suddenly
and is short-lived (usually twelve weeks or less). It is usually associated
with a
specific cause such as a specific injury and is often sharp and severe. It is
the kind
of pain that can occur after specific injuries resulting from surgery, dental
work, a
5 strain or a sprain. Acute pain does not generally result in any persistent
psychological response. In contrast, chronic pain is long-term pain, typically
persisting for more than three months and leading to significant psychological
and
emotional problems. Common examples of chronic pain are neuropathic pain (e.g.
painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome,
back
pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.
When a substantial injury occurs to body tissue, via disease or trauma, the
characteristics of nociceptor activation are altered and there is
sensitisation in the
periphery, locally around the injury and centrally where the nociceptors
terminate.
These effects lead to a hightened sensation of pain. In acute pain these
mechanisms can be useful, in promoting protective behaviours which may better
enable repair processes to take place. The normal expectation would be that
sensitivity returns to normal once the injury has healed. However, in many
chronic
pain states, the hypersensitivity far outiasts the healing process and is
often due to
nervous system injury. This injury often leads to abnormalities in sensory
nerve
fibres associated with maladaptation and aberrant activity (Woolf & Salter,
2000,
Science, 288, 1765-1768).
Clinical pain is present when discomfort and abnormal sensitivity feature
among the
patient's symptoms. Patients tend to be quite heterogeneous and may present
with
various pain symptoms. Such symptoms include: 1) spontaneous pain which may
be dull, burning, or stabbing; 2.) exaggerated pain responses to noxious
stimuli
(hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia -
Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from
various forms of acute and chronic pain may have similar symptoms, the
underlying
mechanisms may be different and may, therefore, require different treatment
strategies. Pain can also therefore be divided into a number of different
subtypes
according to differing pathophysiology, including nociceptive, inflammatory
and
neuropathic pain.
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Nociceptive pain is induced by tissue injury or by intense stimuli with the
potential to
cause injury. Pain afferents are activated by transduction of stimuli by
nociceptors at
the site of injury and activate neurons in the spinal cord at the level of
their
termination. This is then relayed up the spinal tracts to the brain where pain
is
perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of
nociceptors activates two types of afferent nerve fibres. Myelinated A-delta
fibres
transmit rapidly and are responsible for sharp and stabbing pain sensations,
whilst
unmyelinated C fibres transmit at a slower rate and convey a dull or aching
pain.
Moderate to severe acute nociceptive pain is a prominent feature of pain from
central nervous system trauma, strains/sprains, burns, myocardial infarction
and
acute pancreatitis, post-operative pain (pain following any type of surgical
procedure), posttraumatic pain, renal colic, cancer pain and back pain. Cancer
pain
may be chronic pain such as tumour related pain (e.g. bone pain, headache,
facial
pain or visceral pain) or pain associated with cancer therapy (e.g.
postchemotherapy syndrome, chronic postsurgical pain syndrome or post
radiation
syndrome). Cancer pain may also occur in response to chemotherapy,
immunotherapy, hormonal therapy or radiotherapy. Back pain may be due to
herniated or ruptured intervertabral discs or abnormalities of the lumber
facet joints,
sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament.
Back
pain may resolve naturally but in some patients, where it lasts over 12 weeks,
it
becomes a chronic condition which can be particularly debilitating.
Neuropathic pain is currently defined as pain initiated or caused by a primary
lesion
or dysfunction in the nervous system. Nerve damage can be caused by trauma and
disease and thus the term 'neuropathic pain' encompasses many disorders with
diverse aetiologies. These include, but are not limited to, peripheral
neuropathy,
diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain,
cancer
neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central
post-stroke pain and pain associated with chronic alcoholism, hypothyroidism,
uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy
and
vitamin deficiency. Neuropathic pain is pathological as it has no protective
role. It is
often present well after the original cause has dissipated, commonly lasting
for
years, significantly decreasing a patient's quality of life (Woolf and
Mannion, 1999,
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Lancet, 353, 1959-1964). The symptoms of neuropathic pain are difficult to
treat, as
they are often heterogeneous even between patients with the same disease
(Woolf
& Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet,
353, 1959-1964). They include spontaneous pain, which can be continuous, and
paroxysmal or abnormal evoked pain, such as hyperalgesia (increased
sensitivity to
a noxious stimulus) and allodynia (sensitivity to a normally innocuous
stimulus).
The inflammatory process is a complex series of biochemical and cellular
events,
activated in response to tissue injury or the presence of foreign substances,
which
results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-
56).
Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one
of
the commonest chronic inflammatory conditions in developed countries and
rheumatoid arthritis is a common cause of disability. The exact aetiology of
rheumatoid arthritis is unknown, but current hypotheses suggest that both
genetic
and microbiological factors may be important (Grennan & Jayson, 1994, Textbook
of Pain, 397-407). It has been estimated that almost 16 million Americans have
symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom
are
over 60 years of age, and this is expected to increase to 40 million as the
age of the
population increases, making this a public health problem of enormous
magnitude
(Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al.,
1994, Textbook of Pain, 387-395). Most patients with osteoarthritis seek
medical
attention because of the associated pain. Arthritis has a significant impact
on
psychosocial and physical function and is known to be the leading cause of
disability in later life. Ankylosing spondylitis is also a rheumatic disease
that causes
arthritis of the spine and sacroiliac joints. It varies from intermittent
episodes of back
pain that occur throughout life to a severe chronic disease that attacks the
spine,
peripheral joints and other body organs.
Another type of inflammatory pain is visceral pain which includes pain
associated
with inflammatory bowel disease (IBD). Visceral pain is pain associated with
the
viscera, which encompass the organs of the abdominal cavity. These organs
include the sex organs, spleen and part of the digestive system. Pain
associated
with the viscera can be divided into digestive visceral pain and non-digestive
visceral pain. Commonly encountered gastrointestinal (GI) disorders that cause
pain
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inciude functional bowel disorder (FBD) and inflammatory bowel disease (IBD).
These GI disorders include a wide range of disease states that are currently
only
moderately controlled, including, in respect of FBD, gastro-esophageal reflux,
dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain
syndrome
(FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative
colitis, all of
which regularly produce visceral pain. Other types of visceral pain include
the pain
associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.
It should be noted that some types of pain have multiple aetiologies and thus
can
be classified in more than one area, e.g. back pain and cancer pain have both
nociceptive and neuropathic components;
Other types of pain include:
= pain resulting from musculo-skeletal disorders, including myalgia,
fibromyalgia,
spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular
rheumatism, dystrophinopathy, glycogenolysis, polymyositis and pyomyositis;
= heart and vascular pain, including pain caused by angina, myocardical
infarction,
mitral stenosis, pericarditis, Raynaud's phenomenon, scieredoma and skeletal
muscle ischemia;
= head pain, such as migraine (including migraine with aura and migraine
without
aura), cluster headache, tension-type headache mixed headache and headache
associated with vascular disorders; and
= orofacial pain, including dental pain, otic pain, burning mouth syndrome and
temporomandibular myofascial pain.
The combination of the present invention is potentially useful in the
treatment of all
kinds of pain, particularly head pain, most particularly migraine, tension
type
headaches and cluster headaches. All kinds of migraine may be treated,
including
early migraine, menstrual migraine, migraine in children, mild migraine and
recurrent migraine. The combination is useful both in the treatment of
migraine and
the prevention of migraine recurrence.
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The combination of the present invention is also useful in the treatment of
conditions other than pain. In particular, the combination provided by the
present
invention may be useful in the treatment of overactive bladder, premature
ejacuiation, chronic paroxysmal hemicrania, depression, drug abuse, emesis,
eating
disorders, hypertension, post-traumatic head and neck injury and obesity and
as a
vasodilator or antithrombotic agent.
The combination of the present invention may also be useful in the treatment
of
epilepsy, faintness attacks, hypokinesia, cranial disorders, neuropathalogical
disorders and neurodegenerative disorders. Such neurodegenerative disorders
include, for example, Alzheimer's disease, Huntington's disease, Parkinson's
disease, Amyotrophic Lateral Sclerosis and acute brain injury.
Neurodegenerative
disorders associated with acute brain injury include stroke, head trauma, and
asphyxia. Stroke, which refers to a cerebral vascular disease and is also
known as
a cerebral vascular accident (CVA), includes acute thromboembolic stroke and
both
focal and global ischemia. Also included are transient cerebral ischemic
attacks and
other cerebral vascular problems accompanied by cerebral ischemia. These
vascular disorders may occur in a patient undergoing carotid endarterectomy
specifically or other cerebrovascular or vascular surgical procedures in
general, or
diagnostic vascular procedures including cerebral angiography and the like.
Other
related incidents are head trauma, spinal cord trauma, or injury from general
anoxia,
hypoxia, hypoglycemia, hypotension as well as similar injuries seen during
procedures from embole, hyperfusion and hypoxia. The present invention would
be
useful in the treatment of a range of incidents, for example, during cardiac
bypass
surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia, in
cardiac
arrest and in status epilepticus.
The combination of the present invention may also be useful in the treatment
of
depression (e.g. single episodic or recurrent major depressive disorders,
dysthymic
disorders, depressive neurosis and neurotic depression, melancholic depression
including anorexia, weight loss, insomnia, early morning waking or psychomotor
retardation, atypical depression or reactive depression, including increased
appetite, hypersomnia, psychomotor agitation or irritability, seasonal
affective
disorder, minor depression and pediatric depression), bipolar disorders or
manic
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depression (e.g. bipolar I disorder, bipoiar II disorder and cyclothymic
disorder)
conduct disorder; disruptive behavior disorder, behavioral disturbances
associated
with mental retardation, autistic disorder, conduct disorder; anxiety
disorders (such
as panic disorder with or without agoraphobia, agoraphobia without history of
panic
5 disorder, specific phobias such as specific animal phobias, social anxiety,
social
phobia including social anxiety disorder, obsessive-compulsive disorder and
related
spectrum disorders and generalised anxiety disorders), stress disorders
(including
post-traumatic stress disorder, acute stress disorder and chronic stress
disorder),
borderline personality disorder, schizophrenia and other psychotic disorders,
10 schizophreniform disorders, schizoaffective disorders, delusional
disorders, brief
psychotic disorders, shared psychotic disorders, psychotic disorders with
delusions
or hallucinations, psychotic episodes of anxiety, anxiety associated with
psychosis,
psychotic mood disorders (such as severe major depressive disorder), mood
disorders associated with psychotic disorders (such as acute mania and
depression
associated with bipolar disorder), mood disorders associated with
schizophrenia,
delirium, dementia, senile dementia, memory disorders, loss of executive
function,
vascular dementia, movement disorders (such as akinesias, dyskinesias,
including
familial paroxysmal dyskinesias, spasticities, Scott syndrome, PALSYS and
akinetic-rigid syndrome), extra-pyramidal movement disorders (such as
medication-
induced movement disorders, for example, neuroleptic-induced Parkinsonism,
neuroleptic malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-
induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-
induced postural tremour), addictive disorders and withdrawal syndrome,
chemical
dependencies and addictions (e.g., dependencies on, or addictions to, alcohol,
heroin, cocaine, benzodiazepines, sychoactive substances, nicotine, or
phenobarbitol), behavioural addictions (such as an addiction to gambling),
ocular
disorders (such as glaucoma and ischemic retinopathy), withdrawal syndrome,
adjustment disorders' (including depressed mood, anxiety, mixed anxiety and
depressed mood, disturbance of conduct, and mixed disturbance of conduct and
mood), age-associated learning and mental disorders, anorexia nervosa, apathy,
attention-deficit (or other cognitive) disorders due to general medical
conditions
(including attention-deficit disorder (ADD) and attention-deficit
hyperactivity disorder
(ADHD) and it's recognized sub-types), bulimia nervosa, chronic fatigue
syndrome,
somatoform disorders (including somatization disorder, conversion disorder,
pain
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disorder, hypochondriasis, body dysmorphic disorder, undifferentiated
somatoform
disorder and somatoform NOS), incontinence (e.g. stress incontinence, genuine
stress incontinence and mixed incontinence), urinary disorders, premature
ejaculation, inhalation disorders, obesity (e.g. reducing the weight of obese
or
overweight patients), oppositional defiant disorder, premenstrual dysphoric
disorder
(e.g. premenstrual syndrome and late luteal phase dysphoric disorder), sleep
disorders (such as narcolepsy, insomnia and enuresis), specific developmental
disorders, selective serotonin reuptake inhibition (SSRI) "poop out" syndrome
(wherein a patient fails to maintain a satisfactory response to SSRI therapy
after an
initial period of satisfactory response) and TIC disorders (e.g. Tourette's
Disease).
The alpha-2-delta ligand selected for use in the present invention is
preferably
potent (having a binding affinity of less than 100nM, preferably less than
10nM) and
selective. In context of the present invention, a selective apha-2-delta
ligand is a
compound that binds to the gabapentin binding site of the alpha-2-delta ((X28)
subunit of voltage-gated calcium channels more potently than it binds to any
other
physiologically important receptor. Such selectivity is preferably at least 2
fold, more
preferably at least 10 fold, most preferably at least 100 fold.
Examples of alpha-2-delta ligands suitable for use with the present invention
are
those compounds generally or specifically disclosed in US-B-4,024,175
(particularly
gabapentin), EP-A-641330 (particularly pregabalin), US-B-5,563,175, WO-A-
97/33858, WO-A-97/33859, W O-A-99/31057, W O-A-99/31074, W O-A-97/29101,
WO-A-02/085839 (particularly (1 R,5R,6S)-6-(Aminomethyl)bicyclo[3.2.0]hept-6-
yl]acetic acid), WO-A-99/31075 (particularly 3-(1-Aminomethyl-
cyclohexylmethyl)-
4H-[1,2,4]oxadiazol-5-one and C-[1 -(1 H-Tetrazol-5-ylmethyl)-cycloheptyl]-
methylamine), WO-A-99/21824 (particularly (3S,4S)-(1-Aminomethyl-3,4-dimethyl-
cyclopentyl)-acetic acid), WO-A-01/90052, WO-A-01/28978 (particularly
(1 a,3a,5a)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid), EP-A-
0641330,
WO-A-98/17627, WO-A-00/76958 (particularly (3S,5R)-3-aminomethyl-5-methyl-
octanoic acid), WO-A-03/082807 (particularly (3S,5R)-3-amino-5-methyl-
heptanoic
acid, (3S,5R)-3-amino-5-methyl-nonanoic acid and (3S,5R)-3-Amino-5-methyl-
octanoic acid), EP-A-1 178034, EP-A-1 201240, WO-A-99/31074, WO-A-03/000642,
WO-A-02/22568, WO-A-02/30871, WO-A-02/30881, WO-A-02/100392, WO-A-
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02/100347, WO-A-02/42414, WO-A-02/32736, WO-A-02/28881 and WO-A-
03/082807 (especially 2-aminomethyl-4-ethyl-hexanoic acid) and
pharmaceutically
acceptable saits and solvates thereof.
Other useful cyclic alpha-2-delta ligands for use in the present invention may
be
.
depicted by the following formula (I):
NH2 x
R R4a
R~ a R4) n
Z
R R3a
R2a R3
wherein X is a carboxylic acid or carboxylic acid bioisostere; n is 0, 1 or 2;
and R1,
R'a, R2, R2a, R3, R3a, R4 and R4a are independently selected from H and Ci-C6
alkyl;
or R' and R2 or R2 and R3 are taken together to form a C3-C7 cycloalkyl ring,
which
is optionally substituted with one or two substituents selected from C1-C6
alkyl; or a
pharmaceutically acceptable salt or solvate thereof.
In formula (I), suitably, R', R1a, R2a, R3a R4 and R4a are H and R2 and R3 are
independently selected from H and methyl, or R'a, R2a, R3a and R4a are H and
R'
and R2 or R2 and R3 are taken together to form a C3-C7 cycloalkyl ring, which
is
optionally substituted with one or two methyl substituents. A suitable
carboxylic acid
bioisostere is selected from tetrazolyl and oxadiazolonyl. X is preferably a
carboxylic
acid.
In formula (I), preferably, R1, R'a, R2a, R3a, R4 and R4a are H and R2 and R3
are
independently selected from H and methyl, or R'a, R2a, R3a and R4a are H and
R'
and R2 or R2 and R3 are taken together to form a C4-C5 cycloalkyl ring, or,
when n is
0, R1, R'a, R2a, R3a, R4 and R4a are H and R2 and R3 form a cyclopentyl ring,
or,
when n is 1, R1, R'a, R2a, R3a, R4 and R4a are H and R2 and R3 are both methyl
or
R1, R'a, R2a, R3a, R4 and R4a are H and R2 and R3 form a cyclobutyl ring, or,
when n
is 2, R1, R'a, R2, R2a, R3, R3a, R4 and R4a are H, or, n is 0, R1, R'a, R2a,
R3a, R4 and
R4a are H and R2 and R3 form a cyclopentyl ring.
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13
Further useful acyclic alpha-2-delta ligands for use in the present invention
may be
depicted by the following formula (II):
R4 R5
R3
H2N R6 R2
R'
HOOC (II)
wherein n is 0 or 1, R' is hydrogen or (C1-C6)alkyl; R2 is hydrogen or (C1-
C6)alkyl; R3
is hydrogen or (C1-C6)alkyl; R4 is hydrogen or (Cl-C6)alkyl; R5 is hydrogen or
(C1-
C6)alkyl and R2 is hydrogen or (C1-C6)alkyl, or a pharmaceutically acceptable
salt or
solvate thereof.
According to formula (II), suitably R' is C1-C6 alkyl, R2 is methyl, R3 - R6
are
hydrogen and n is 0 or 1. More suitably R' is methyl, ethyl, n-propyl or n-
butyl, R2 is
methyl, R3 - R6 are hydrogen'and n is 0 or 1. When R2 is methyl, R3 - R6 are
hydrogen and n is 0, R' is suitably ethyl, n-propyl or n-butyl. When R2 is
methyl, R3
- R6 are hydrogen and n is 1, R' is suitably methyl or n-propyl. Compounds of
formula (II) are suitably in the 3S,5R configuration.
Preferred alpha-2-delta ligands for use in the present invention include:
gabapentin,
pregabalin, [(1 R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-
(1-
aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1 -(1 H-tetrazol-5-
ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-
cyclopentyl)-acetic acid, (1 a,3a,5a)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-
acetic
acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-
heptanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-
5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline and (2S,4S)-4-(3-
fluorobenzyl)proline and the pharmaceutically acceptable salts and solvates
thereof.
Pregabalin, or a pharmaceutically acceptable salt or solvate thereof is
particularly
preferred.
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Further preferred alpha-2-delta ligands are (3R,4R,5R)-3-amino-4,5-dimethyl-
heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid and the
pharmaceutically acceptable salts and solvates thereof. One of these compounds
can be made using the following methods and the other compound can be made by
analogous methods.
(R)-3-((R)-3-Methyl-hexanoyl)-4-phenyl-oxazol idi n-2-one
To a copper(I)bromide dimethylsulfide complex (13.34g, 64.87mmol) in dry
tetrahydrofuran (150m1) at -30 C under nitrogen was added a 2M ether solution
of
propylmagnesiumchloride (64.87ml, 129.7mmol). The reaction mixture was stirred
for 20min. A solution of (R)-3-but-2-enoyl-4-phenyl-oxazolidin-2-one (15.0g,
64.87mmol) in tetrahydrofuran (60m1) was added over a 15 minute period at -35
C
and the reaction mixture was allowed to slowly warm to room temperature over 4
hours. The mixture was cooled to 0 C and quenched with saturated ammonium
chloride solution. The resulting suspension was extracted into ether, washed
with
5% ammonium hydroxide solution and brine and dried over MgSO4. The solution
was concentrated under reduced pressure to afford the title compound (13.34g;
100
%) as a white solid. 'H NMR (400 MHz, CDCI3) S ppm 0.8 (m, 6 H) 1.2 (m, 3 H)
1.6
(s, 1 H) 2.0 (m, 1 H) 2.7 (dd, J=16.1, 8.5 Hz, 1 H) 3.0 (dd, J=15.9, 5.4 Hz, 1
H) 4.3
(dd, J=8.9, 3.8 Hz, 1 H) 4.7 (t, J=8.9 Hz, 1 H) 5.4 (dd, J=8.8, 3.9 Hz, 1 H)
5.4 (dd,
J 8.8, 3.9 Hz, 1 H) 7.3 (m, 5 H). MS, m/z (relative intensity): 276 [M+1 H,
100%].
(R)-3-((2 R,3 R)-2,3-Di methyl-hexanoyl)-4-phenyl-oxazol id i n-2-one
To a 1M solution of sodium hexamethyldisylamide (16.2g, 88.3mmol) in
tetrahydrofuran at -78 C was added, via canular, a 0 C solution of (R)-3-((R)-
3-
methyl-hexanoyl)-4-phenyl-oxazolidin-2-one (18.7g, 67.9mmol) in 70m1 of dry
tetrahydrofuran. The resulting solution was stirred at -78 C for 30 min.
Methyl
Iodide (48.2g, 339.5mmol) was added and stirring at -78 C was continued for 4
hours. The reaction mixture was quenched with saturated ammonium chloride
solution, extracted into CH2CI2 and washed with 1 M sodium bisulfite. The
solution
was dried over MgSO4, concentrated and chromatographed in 10% ethylacetate in
hexane to give the title compound (11.1g, 56.5%) as an oil. 'H NMR (400 MHz,
CDCI3)8ppm0.8(t,J=7.0Hz,3H)0.9(d,J=6.6Hz,3H) 1 .0 (d, J=6.8 Hz, 3 H) 1.0
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(d, J=8.5 Hz, 1 H) 1.1 (m, 1 H) 1.4 (m, 1. H) 1.7 (m, 1 H) 3.7 (m, 1 H) 4.2
(dd, J=8.8,
3.4 Hz, 1 H) 4.6 (t, J=8.7 Hz, 1 H) 5.4 (dd, J=8.7, 3.3 Hz, 1 H) 7.2 (m, 2 H)
7.3 (m, 3
H). MS, m/z (relative intensity):290 [M+1 H, 100%].
5 (2R,3R)-2,3-Dimethyl-hexan-1-o1
A 1M solution of lithium aluminium hydride in tetrahydrofuran (95.9m1,
95.9mmol)
was added to a solution of (R)-3-((2R,3R)-2,3-dimethyl-hexanoyl)-4-phenyl-
oxazolidin-2-one in tetrahydrofuran (300m1) under nitrogen at -78 C. The
reaction
mixture was stirred for 3 hours at that temperature. Water was added dropwise
to
10 quench the excess lithium aluminium hydride and the reaction mixture was
then
poured into a mixture of ice and ether. . The resulting mixture was extracted
into
ether which was washed with water and dried over MgSO4. The solution was
concentrated followed by the addition of excess hexane. The resulting white
precipitate was filtered and washed with hexane. The filtrate was concentrated
to
15 afford the title compound (5.05g, 100%) as an oil. 'H NMR (400 MHz, CDCI3)
8
ppm 0.9 (m, 9 H) 1.0 (d, J=6.8 Hz, 1 H) 1.1 (m, 1 H) 1.2 (m, 3 H) 1.6 (m, 2 H)
3.4
(m, 1 H) 3.6 (m, 1 H).
(2R,3R)-2,3-Dimethyl-hexanal
A mixture of pyridinium chlorochromate (27.35g, 126.9mmol) and neutral alumina
(96g, 3.5g per gram of pyridinium chlorochromate) in dry dichloromethane
(200ml)
was stirred under nitrogen for 0.25hr. (2R,3R)-2,3-Dimethyl-hexan-l-ol (5.0g,
38.46mmol) in dichloromethane (60m1) was added and the resulting dark slurry
was
stirred at room temperature for 3 hours. The slurry was filtered through a
short pad
of silica eluting with excess dichloromethane. Evaporation of the solvent
afforded
the title compound (4.1, 84%) as an oil. 1 H NMR (400 MHz, CDCI3) S ppm 0.8
(m, 3
H) 0.9 (d, J=6.6 Hz, 3 H) 1.0 (d, J=6.6 Hz, 3 H) 1.2 (m, 4 H) 1.8 (m, 1 H) 2.2
(m, 1
H) 9.6 (s, 1 H).
4-Methyl-benzenesulfinic acid ((2R,3R)-2,3-dimethyl-hexylidene)-amide
Titanium(IV) ethoxide (5.16g, 22.6mmol) and (S)-(+)-p-toluenesulfinamide
(7.02g,
45.2mmol) were added to (2R,3R)-2,3-dimethyl-hexanal (2.9g, 22.6mmol) in dry
tetrahydrofuran (30m1). The resulting mixture was stirred at room temperature
for
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16
18 hours and poured into a brine solution (40m1). The resulting siurry was
rapidly
stirred for 10 minutes and filtered. The filtrate was extracted into ethyl
acetate, and
the extract was washed with brine and dried over MgSO4. The solvent was
evaporated and the residue was filtered through a silica plug, eluting with
50/50
solution of hexane/ethyl acetate to afford the title compound (3.1 g, 51.6%)
as an oil.
1H NMR (400 MHz, CDCI3) 8 ppm 0.8 (m, 6H) 1.1 (m, 4H) 1.3 (m, 3H) 1.7 (m, 1 H)
2.4 (s, 3 H) 2.5 (m, 1 H) 7.3 (d, J=8.3 Hz, 2 H) 7.5 (d, J=8.1 Hz, 2 H) 8.1
(d, J=5.4
Hz, 1 H). MS, m/z (relative intensity): 266 [M+1 H, 100%].
(4R,5R)-4,5-Dimethyl-(R)-3-(toluene-4-sulfinylamino)-octanoic acid tert-butyl
ester
Butyl lithium (26.3m1, 42.04mmol) was added to a solution of diisopropylamine
(4.6g, 45.6mmol) in dry tetrahydrofuran (40m1) under nitrogen at 0 C and the
resulting mixture was stirred for 20 minutes. The solution was cooled to -78 C
followed by the addition of t-butyl acetate (4.1 g, 35.Ommol) and stirred at
that
temperature for 45 minutes. Chlorotitanium triisopropoxide (9.4g, 36.2mmol)
was
added dropwise and stirring was continued for 30 minutes at -78 C. A-50 C
solution of 4-methyl-benzenesulfinic acid ((2R,3R)-2,3-dimethyl-hexylidene)-
amide
(3.1 g, 11.7mmol) in dry tetrahydrofuran (10mI) was added to the reaction and
the
resulting mixture was stirred at -78 C for 4 hours. The reaction was quenched
with
a saturated solution of NaH2PO4 and extracted into ethyl acetate. The extract
was
dried over MgSO4 and concentrated. The resulting residue was chromatographed
on silica, eluting with 15% ethyl acetate in hexane to give the title compound
(2.4g,
53.9%) as white solid. iH NMR (400 MHz, CDCI3) S ppm 0.9 (m, 6 H) 1.0 (d,
J=6.6
Hz, 3 H) 1.1 (m, 1 H) 1.3 (m, 2 H) 1.4 (m, 9 H) 1.5 (m, 2 H) 2.4 (s, 3 H) 2.6
(m, 2 H)
3.8 (m, 1 H) 4.4 (d, J=10.0 Hz, 1 H) 7.3 (d, J=8.1 Hz, 2 H) 7.6 (d, J=8.1 Hz,
2 H).
MS, m/z (relative intensity): 382 [M+1 H, 100%], 326 [M+1 H-C(CH3)3, 50%].
(3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic acid
To a solution of (4R,5R)-4,5-dimethyl-(R)-3-(toluene-4-sulfinylamino)-octanoic
acid
tert-butyl ester (1.8g, 4.71 mmol) in dry methanol (30m1) at 0 C under
nitrogen was
added excess trifluoroacetic acid (25m1) and the reaction mixture was stirred
for 2
hours at that temperature. The solution was concentrated to dryness followed
by
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the addition of dry dichloromethane (20m1) and trifluoroacetic acid (20m1).
The
resulting mixture was stirred for 2 hours under nitrogen and concentrated to
dryness. The residue was applied to BondElute SCX ion exchange resin and
eluted
with water until the eluent was at constant pH of 6.5. The resin was then
eluted with
a 1:1 solution of methanol and 10% ammonium hydroxide solution. The ammonium
hydroxide solution was evaporated and the residue was crystallized with
methanol-
acetonitrile mixture to afford the title compound (0.717g, 81.2%) as a white
solid. ' H
NMR (400 MHz, CD3QD) 8 ppm 0.9 (m, 11 H) 1.1 (m, 2 H) 1.3 (m, 1 H) 1.4 (m, 1
H)
1.6 (m, 1 H) 1.7 (m, 2 H) 2.3 (dd, J=16.6, 10.0 Hz, 1 H) 2.5 (dd, J=16.7, 3.5
Hz, 1 H)
3.3 (m, 1 H). MS, m/z (relative intensity): 188 [M+1 H, 100%], 186 [M-1 H,
100%].
In the context of this invention, a 5-HT1B, 5-HTlD or 5-HT1F agonist is a
compound
which binds measurably to one or more of these three receptors and activates
it to
some extent (preferably binding with an affinity of less than 100nM, most
preferably
less than 10nM). Preferably, a 5-HT1B, 5-HT1D or 5-HTiF agonist selected for
use in
the combination provided by the present invention is a selective 5-HT1B, 5-
HTlD or
5-HT1F agonist. A selective agonist may be defined as a compound that has a
higher binding affinity (as measured by a KD value) for one or more of the 5-
HT1B, 5-
HT1D and 5-HTiF receptors than for any 5-HT receptor other than the 5-HTiB, 5-
HT1D and 5-HT1F receptors. Selectivity over the 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3,
5-
HT4, 5-HT5A and 5-HT6 receptors is preferred. The level of selectivity over
these
receptors is preferably at least 2 fold, more preferably at least 4 fold, more
preferably still at least 10 fold and most preferably at least 100 fold.
Binding affinity
for one or more of the 5-HT receptors can be measured using the methods
described in European Journal of Pharmacology, 1999, 368, 259 and Life
Sciences,
1997, 61, 2117.
A particularly preferred 5-HT1B, 5-HTlD or 5-HT1F agonist for use in the
invention is a
compound which is an agonist (preferably a selective agonist, as defined
above) of
both the 5-HTi B receptor and the 5-HT1 c receptor (known as a 5-HTi Bi1p
agonist).
Such compounds include the indole-containing antimigraine drugs known as
triptans, e.g. almotriptan, alnatriptan, avitriptan, donitriptan,
frovatriptan, naratriptan,
rizatriptan, sumatriptan and zolmitriptan and the pharmaceutically acceptable
salts
and solvates thereof.
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18
The most preferred 5-HT1B, 5-HT1D or 5-HTlF agonist for use in the invention
is
eletriptan and the pharmaceutically acceptable salts and solvates thereof,
particularly eletriptan hydrobromide and eletriptan hemisulphate, most
particularly
the a-polymorphic form of eletriptan hydrobromide described in WO-A-96/06842
and the form I polymorph of eletriptan hemisulphate described in WO-A-
01/23377.
Also preferred are selective agonists of the 5-HT1F receptor (such as LY334370
((5-
(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1 H-indole fumarate) and
LY344864). See Phebus et al, Life Sciences, 1997, 21, 2117 and Ramandan et al,
Cephalalgia, 2003, 23, 776.
Other suitable 5-HT1B, 5-HT1D or 5-HTiF agonists are PNU-109291 ((S)-(-)-1-[2-
[4-
(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methyl-isochroman-6-carboxamide),
ergotamine, dihydroergotamine, IS-159, L-775606, L-772405, L-741604 and
seroton in-O-carboxymethyl-glycyl-tyrosinamide.
In one embodiment, the invention provides a combination of a 5-HT1B agonist
(preferably a selective agonist, as defined above) and an alpha-2-delta
ligand.
In another embodiment, the invention provides a combination of a 5-HT1D
agonist
(preferably a selective agonist, as defined above) and an alpha-2-delta
ligand.
In another embodiment, the invention provides a combination of a 5-HT1F
agonist
(preferably a selective agonist, as defined above) and an alpha-2-delta
ligand.
In another embodiment, the invention provides a combination of a 5-HT1Bi1D
agonist
(preferably a selective agonist, as defined above) and an alpha-2-delta
ligand.
In another embodiment, the invention provides a combination of a 5-HT1Bi1F
agonist
(preferably a selective agonist, as defined above) and an alpha-2-delta
ligand.
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In another embodiment, the invention provides a combination of a 5-HT1oi1F
agonist
(preferably a selective agonist, as defined above) and an alpha-2-delta
ligand.
In another embodiment, the invention provides a combination of a 5-HT,B/1DnF
agonist (preferably a selective agonist, as defined above) and an alpha-2-
delta
ligand.
A preferred combination according to the invention is a combination of a
triptan
antimigraine drug and an alpha-2-delta ligand.
Another preferred combination according to the invention is a combination of
eletriptan, or a pharmaceutically acceptable sait or solvate thereof and an
alpha-2-
delta ligand.
Another preferred combination according to the invention is a combination of a
5-
HT1Bi 5-HT1p or 5-HT1F agonist and an alpha-2-delta ligand selected from
gabapentin, pregabalin, [(1 R,5R,6S)-6-(aminomethyl)bicycio[3.2.0]hept-6-
yl]acetic
acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1 H-
tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-
dimethyl-cyclopentyl)-acetic acid, (1 cc,3(x,5a)(3-amino-methyl-
bicyclo[3.2.0]hept-3-
yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-
5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-
3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-
(3-
fluorobenzyl)proline, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and
(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid and the pharmaceutically
acceptable salts and solvates thereof.
Another preferred combination according to the invention is a combination of a
5-
HT1B, 5-HT1D or 5-HT1F agonist and pregabalin or a pharmaceutically acceptable
salt or solvate thereof.
Another preferred combination according to the invention is a combination of a
triptan antimigraine drug and an alpha-2-delta ligand selected from
gabapentin,
pregabalin, [(1 R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-
(1-
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aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1 H-tetrazol-5-
ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-
cyclopentyl)-acetic acid, (1 a,3a,5(x)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-
acetic
acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-
5 heptanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-
5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-
fluorobenzyl)proline, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and
(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid and the pharmaceutically
acceptable salts and solvates thereof.
Another preferred combination according to the invention is a combination of a
triptan antimigraine drug and pregabalin or a pharmaceutically acceptable salt
or
solvate thereof.
Another preferred combination according to the invention is a combination of 5-
HTiBi1D agonist (preferably a selective agonist, as defined above) and an
alpha-2-
delta ligand selected from gabapentin, pregabalin, [(1 R,5R,6S)-6-
(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminomethyl-
cyclohexytmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1 H-tetrazol-5-ylmethyl)-
cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-
acetic
acid, (1 cc,3oc,5(x)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,
(3S,5R)-
3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid,
(3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic
acid,
(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)proline,
(3R,4R,5R)-
3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-
octanoic acid and the pharmaceutically acceptable salts and solvates thereof.
Another preferred combination according to the invention is a combination of a
5-
HT1Biio agonist and pregabalin or a pharmaceutically acceptable salt or
solvate
thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and
gabapentin,
or a pharmaceutically acceptable salt or solvate thereof.
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A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and
pregabalin,
or a pharmaceutically acceptable salt or solvate thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and
[(1 R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, or a
pharmaceutically acceptable salt or solvate thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and 3-(1-
aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-orie, or a
pharmaceutically
acceptable salt or solvate thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and G-[1-
(1 H-
tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, or a pharmaceutically
acceptable salt
or solvate thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and
(3S,4S)-(1-
aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, or a pharmaceutically
acceptable salt or solvate thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and
(1 a,3a,5(x)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, or a
pharmaceutically acceptable salt or solvate thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and
(3S,5R)-
3-aminomethyl-5-methyl-octanoic acid, or a pharmaceutically acceptable salt or
solvate thereof.
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A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and
(3S,5R)-
3-amino-5-methyl-heptanoic acid, or a pharmaceutically acceptable salt or
solvate
thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and
(3S,5R)-
3-amino-5-methyl-nonanoic acid, or a pharmaceutically acceptable salt or
solvate
thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and
(3S,5R)-
3-amino-5-methyl-octanoic acid, or a pharmaceutically acceptable salt or
solvate
thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or soivate thereof, and
(2S,4S)-4-
(3-chlorophenoxy)proline, or a pharmaceutically acceptable salt or solvate
thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and 2-
aminomethyl-4-ethyl-hexanoic acid, or a pharmaceutically acceptable salt or
solvate
thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and
(2S,4S)-4-
(3-fluorobenzyl)proline, or a pharmaceutically acceptable salt or solvate
thereof.
A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and
(3R,4R,5R)-
3-amino-4,5-dimethyl-heptanoic acid, or a pharmaceutically acceptable salt or
solvate thereof.
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A preferred specific combination according to the invention is the combination
of
eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and
(3R,4R,5R)-
3-amino-4,5-dimethyl-octanoic, acid, or a pharmaceutically acceptable salt or
solvate
thereof.
A 5-HT1B, 5-HTlp or 5-HTiF agonist or an alpha-2-delta ligand selected for use
in
the combination of the present invention, particularly one of the suitable or
preferred
compounds listed above, (hereinafter referred to as 'a compound for use in the
invention') may be used in the form of a pharmaceutically acceptable salt, for
example an acid addition or base salt.
Suitable acid addition salts are formed from acids which form non-toxic salts.
Examples include the acetate, aspartate, benzoate, besylate,
bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,
edisylate,
esylate, formate, fumarate, gluceptate, gluconate, glucuronate,
hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,
hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate,
methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,
oxalate,
palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,
saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate
salts.
Suitable base salts are formed from bases which form non-toxic salts. Examples
include the aluminium, arginine, benzathine, calcium, choline, diethylamine,
diolamine, glycine, lysine, magnesium, megiumine, olamine, potassium, sodium,
tromethamine and zinc salts.
Hemisalts of acids and bases may also be formed, for example, hemisulphate and
hemicalcium salts.
For a review on suitable salts, see Handbook of Pharmaceutical Salts:
Properties,
Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,
2002).
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24
Pharmaceutically acceptable salts of a compound for use in the invention may
be
prepared by one or more of three methods:
(i) by reacting the compound with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a suitable
precursor of the compound or by ring-opening a suitable cyclic precursor, for
example, a lactone or lactam, using the desired acid or base; or
(iii) by converting one salt of the compound to another by reaction with an
appropriate acid or base or by means of a suitable ion exchange column.
All three reactions are typically carried out in solution. The resulting salt
may
precipitate out and be collected by filtration or may be recovered by
evaporation of
the solvent. The degree of ionisation in the resulting salt may vary from
completely
ionised to almost non-ionised.
A compound for use in the invention may exist in both unsolvated and solvated
forms. The term 'solvate' is used herein to describe a molecular complex
comprising
the compound and a stoichiometric amount of one or more pharmaceutically
acceptable solvent molecules, for example, ethanol. The term 'hydrate' is
employed
when said solvent is water.
A compound for use in the invention may form a complex such as a clathrate, a
drug-host inclusion complexe wherein, in contrast to the aforementioned
solvates,
the drug and host are present in stoichiometric or non-stoichiometric amounts.
A
compound for use in the invention may also contain two or more organic and/or
inorganic components which may be in stoichiometric or non-stoichiometric
amounts. The resulting complexes may be ionised, partially ionised, or non-
ionised.
For a review of such complexes, see J. Pharm. Sci., 64 (8), 1269-1288, by
Haleblian (August 1975).
A compound for use in the invention may be used in the form of a pro-drug.
Thus,
certain derivatives of a compound which may have little or no pharmacological
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activity themselves can, when administered into or onto the body, be converted
into
compounds having the desired activity, for example, by hydrolytic cleavage.
Such
derivatives are referred to as 'prod.rugs'. Further information on the use of
prodrugs
may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium
5 Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design,
Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
Prodrugs can, for example, be produced by replacing appropriate
functionalities
with certain moieties known to those skilled in the art as 'pro-moieties' as
described,
for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
A compound for use in the invention may also form active metabolites when
administered to a patient, mainly by oxidative processes. Hydroxylation by
liver
enzymes is of particular note.
A compound for use in the invention which contains one or more asymmetric
carbon atoms can exist as two or more stereoisomers. Where a compound contains
an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are
possible.
Where structural isomers are interconvertible via a low energy barrier,
tautomeric
isomerism ('tautomerism') can occur. This can take the form of proton
tautomerism
in compounds- containing, for example, an imino, keto, or oxime group, or so-
called
valence tautomerism in compounds which contain an aromatic moiety. It follows
that
a single compound may exhibit more than one type of isomerism.
Cisltrans isomers may be separated by conventional techniques well known to
those skilled in the art, for example, chromatography and fractional
crystallisation.
Conventional techniques for the preparation/isolation of individual
enantiomers
include chiral synthesis from a suitable optically pure precursor or
resolution of the
racemate (or the racemate of a salt or derivative) using, for example, chiral
high
pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a
suitable
optically active compound, for example, an alcohol, or, in the case where the
compound contains an acidic or basic moiety, a base or acid such as 1-
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26
phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be
separated by chromatography and/or fractional crystallization and one or both
of the
diastereoisomers converted to the corresponding pure enantiomer(s) by means
well
known to a skilled person.
Chiral compounds (and chiral precursors thereof) may be obtained in
enantiomerically-enriched form using chromatography, typically HPLC, on an
asymmetric resin with a mobile phase consisting of a hydrocarbon, typically
heptane
or hexane, containing from 0 to 50% by volume of isopropanol, typically from
2% to
20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine.
Concentration of the eluate affords the enriched mixture.
Stereoisomeric conglomerates may be separated by conventional techniques
known to those skilled in the art - see, for example, Stereochemistry of
Organic
Compounds by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994).
A compound for use in the invention may be isotopically-labelled wherein one
or
more atoms are replaced by atoms having the same atomic number, but an atomic
mass or mass number different from the atomic mass or mass number which
predominates in nature.
Examples of such isotopes include isotopes of hydrogen, such as 2H and 3H,
carbon, such as "C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18
F,
iodine, such as1231 and'251, nitrogen, such as'3N and'5N, oxygen, such as'50,
"O
and'$O, phosphorus, such as 32P, and sulphur, such as 35S.
Certain isotopically-labelled compounds, for example, those incorporating a
radioactive isotope, are useful in drug and/or substrate tissue distribution
studies.
The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are
particularly
useful for this purpose in view of their ease of incorporation and ready means
of
detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford
certain
therapeutic advantages resulting from greater metabolic stability, for
example,
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27
increased in vivo half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
Substitution with positron emitting isotopes, such as "C, 18 F, 15O and 13N,
can be
useful in Positron Emission Topography (PET) studies for examining substrate
receptor occupancy.
Pharmaceutically acceptable solvates include those wherein the solvent of
crystallization may be isotopically substituted, e.g. D20, d6-acetone, d6-
DMSO.
A compound for use in the invention may be administered as a crystalline or
amorphous product. It may be obtained, for example, as a solid plug, powder or
film
by methods such as precipitation, crystallization, freeze drying, or spray
drying, or
evaporative drying. Microwave or radio frequency drying may be used for this
purpose.
A compound for use in the invention may be administered alone but will more
likely
be administered as a formulation in association with one or more
pharmaceutically
acceptable excipients. The term 'excipient' is used herein to describe any
ingredient
other than a compound for use in the invention. The choice of excipient will
to a
large extent depend on factors such as the particular mode of administration,
the
effect of the excipient on solubility and stability, and the nature of the
dosage form.
Pharmaceutical compositions suitable for the delivery of a compound for use in
the
invention and methods for their preparation will be readily apparent to those
skilled
in the art. Such compositions and methods for their preparation may be found,
for
example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing
Company, 1995).
A compound for use in the invention may be administered orally. Oral
administration
may involve swallowing, so that the compound enters the gastrointestinal
tract, or
buccal or sublingual administration may be employed by which the compound
enters the blood stream directly from the mouth.
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Formulations suitable for oral administration include solid formulations such
as
tablets, capsules containing particulates, liquids, or powders, lozenges
(including
liquid-filled), chews, multi- and nano-particulates, gels, solid solution,
liposome,
films, ovules, sprays and and liquid formulations.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such
formulations may be employed as fillers in soft or hard capsules and typically
comprise a carrier, for example, water, ethanol, polyethylene glycol,
propylene
glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents
and/or
suspending agents. Liquid formulations may also be prepared by the
reconstitution
of a solid, for example, from a sachet.
A compound for use in the invention may also be used in a fast-dissolving,
fast-
disintegrating dosage form such as one of those described in Expert Opinion in
Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).
For tablet dosage forms, depending on dose, a compound for use in the
invention
will generally make up from 1 weight % to 80 weight % of the dosage form, more
typically from 5 weight % to 60 weight % of the dosage form. In addition,
tablets
generally contain a disintegrant. Examples of disintegrants include sodium
starch
glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose,
croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose,
microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose,
starch,
pregelatinised starch and sodium alginate. Generally, the disintegrant will
comprise
from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of
the
dosage form.
Binders are generally used to impart cohesive qualities to a tablet
formulation.
Suitable binders include microcrystalline cellulose, gelatin, sugars,
polyethylene
glycol, natural and synthetic gums, poiyvinylpyrrolidone, pregelatinised
starch,
hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also
contain diluents, such as lactose (monohydrate, spray-dried monohydrate,
anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol,
microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
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Tablets may also optionally comprise surface active agents, such as sodium
lauryl
suifate and polysorbate 80, and glidants such as silicon dioxide and talc.
When
present, surface active agents may comprise from 0.2 weight % to 5 weight % of
the
tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the
tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium
stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium
stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25
weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the
tablet.
Other possible ingredients include anti-oxidants, colourants, flavouring
agents,
preservatives and taste-masking agents.
Exemplary tablets contain up to about 80% drug, from about 10 weight % to
about
90 weight % binder, from about 0 weight % to about 85 weight % diluent, from
about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight
%
to about 10 weight % lubricant.
Tablet blends may be compressed directiy or by roller to form tablets. Tablet
blends
or portions of blends may alternatively be wet-, dry-, or melt-granulated,
melt
congealed, or extruded before tabletting. The final formulation may comprise
one or
more layers and may be coated or uncoated; it may even be encapsulated.
The formulation of tablets is discussed in Pharmaceutical Dosage Forms:
Tablets,
Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
Consumable oral films for human or veterinary use are typically pliable water-
solubie or water-swellable thin film dosage forms which may be rapidly
dissolving or
mucoadhesive and typically comprise a compound for use in the invention, a
film-
forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser
or
emulsifier, a viscosity-modifying agent and a solvent. Some components of the
formulation may perform more than one function.
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A compound for use in the invention may be water-soluble or insoluble. A water-
soluble compound typically comprises from 1 weight % to 80 weight %, more
typically from 20 weight % to 50 weight '%, of the solutes. Less soluble
compounds
may comprise a greater proportion of the composition, typically up to 88
weight % of
5 the solutes. Alternatively, a compound for use in the invention may be in
the form of
multiparticulate beads.
The film-forming polymer may be selected from natural polysaccharides,
proteins,
or synthetic hydrocolloids and is typically present in the range 0.01 to 99
weight %,
10 more typically in the range 30 to 80 weight %.
Other possible ingredients include anti-oxidants, colorants, flavourings and
flavour
enhancers, preservatives, salivary stimulating agents, cooling agents, co-
solvents
(including oils), emollients, bulking agents, anti-foaming agents, surfactants
and
15 taste-masking agents.
Films are typically prepared by evaporative drying of thin aqueous films
coated onto
a peelable backing support or paper. This may be done in a drying oven or
tunnel,
typically a combined coater dryer, or by freeze-drying or vacuuming.
Solid formulations for oral administration may be formulated to be immediate
and/or
controlled release. Controlled release formulations include delayed-,
sustained-,
pulsed-, controlled-, targeted and programmed release.
Suitable modified release formulations for the purposes of the invention are
described in US Patent No. 6,106,864. Details of other suitable release
technologies such as high energy dispersions and osmotic and coated particles
are
to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al
(2001). The use of chewing gum to achieve controlled release is described in
WO
00/35298.
A compound for use in the invention may also be administered directly into the
blood stream, into muscle, or into an internal organ. Such parenteral
administration
includes intravenous, intraarterial, intraperitoneal, intrathecal,
intraventricular,
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31
intraurethral, intrasternal, intracranial, intramuscular and subcutaneous
administration. Suitable devices for parenteral administration include needle
(including microneedle) injectors, needie-free injectors and infusion
techniques.
Parenteral formulations are typically aqueous solutions which may contain
excipients such as salts, carbohydrates and buffering agents (preferably to a
pH of
from 3 to 9), but, for some applications, they may be more suitably formulated
as a
sterile non-aqueous solution or as powdered a dried form to be used in
conjunction
with a suitable vehicle such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for
example, by
lyophilisation, may readily be accomplished using standard pharmaceutical
techniques well known to those skilled in the art.
The solubility of a compound used in the preparation of parenteral solutions
may be
increased by the use of appropriate formulation techniques, such as the
incorporation of solubility-enhancing agents. Formulations for use with needie-
free
injection administration comprise a compound of the invention in powdered form
in
conjunction with a suitable vehicle such as sterile, pyogen-free water.
Formulations for parenteral administration may be formulated to be immediate
and/or controlled release. Controlled release formulations include delayed-,
sustained-, pulsed-, controlled-, targeted and programmed release. Thus a
compound for use in the invention may be formulated as a solid, semi-solid, or
thixotropic liquid for administration as an implanted depot providing modified
release
of the active compound. Examples of such formulations include drug-coated
stents
and poly(dl-lactic-coglycolic)ac'id (PGLA) microspheres.
A compound for use in the invention may also be administered topically to the
skin
or mucosa, that is, dermally or transdermally. Typical formulations for this
purpose
include gels, hydrogels, lotions, solutions, creams, ointments, dusting
powders,
dressings, foams, films, skin patches, wafers, implants, sponges, fibres,
bandages
and microemulsions. Liposomes may also be used. Typical carriers include
alcohol,
water, mineral oil, liquid petrolatum, white petrolatum, glycerin,
polyethylene glycol
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32
and propylene glycol. Penetration enhancers may be incorporated - see, for
example, J. Pharm. Sci., 88 (10), 955-958, by Finnin and Morgan (October
1999).
Topical administration may also be achieved using a patch, such as a
transdernal
iontophoretic patch. Other means of topical administration include delivery by
electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or
needle-free (e.g. PowderjectT"", BiojectT"', etc.) injection.
Formulations for topical administration may be formulated to be immediate
and/or
controlled release. Controlled release formulations include delayed-,
sustained-,
pulsed-, controlled-, targeted and programmed release.
A compound for use in the invention can also be administered intranasally or
by
inhalation, typically in the form of a dry powder (either alone, as a mixture,
for
example, in a dry blend with lactose, or as a mixed component particle, for
example,
mixed with phospholipids, such as phosphatidylcholine) from a dry powder
inhaler
or as an aerosol spray from a pressurised container, pump, spray, atomiser
(preferably an atomiser using electrohydrodynamics to produce a fine mist), or
nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-
tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the
powder may comprise a bioadhesive agent, for example, chitosan or
cyclodextrin.
The pressurised container, pump, spray, atomizer, or nebuliser contains a
solution
or suspension of a compound for use in the invention comprising, for example,
ethanol, aqueous ethanol, or a suitable alternative agent for dispersing,
solubilising,
or extending release of the active, a propellant(s) as solvent and an optional
surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is
micronised to a size suitable for delivery by inhalation (typically less than
5
microns). This may be achieved by any appropriate comminuting method, such as
spiral jet milling, fluid bed jet milling, supercritical fluid processing to
form
nanoparticles, high pressure homogenisation, or spray drying.
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Capsules (made, for example, frorri gelatin or hydroxypropylmethylcellulose),
blisters and cartridges for use in an inhaler or insufflator may be formulated
to
contain a powder mix of a compound for use in the invention, a suitable powder
base such as lactose or starch and a performance modifier such as /-leucine,
mannitol, or magnesium stearate. The lactose may be anhydrous or in the form
of
the monohydrate, preferably the latter. Other suitable excipients include
dextran,
glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomiser using
electrohydrodynamics to
produce a fine mist may contain from 1 pg to 20mg of the compound for use in
the
invention per actuation and the actuation volume may vary from 1pl to 100p1. A
typical formulation may comprise a compound for use in the invention,
propylene
glycol, sterile water, ethanol and sodium chloride. Alternative solvents which
may be
used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavours, such as menthol and levomenthol, or sweeteners, such as
saccharin or saccharin sodium, may be added to those formulations intended for
inhaled/intranasal administration.
Formulations for inhaled/intranasal administration may be formulated to be
immediate and/or controlled release using, for example, PGLA. Controlled
release
formulations include delayed-, sustained-, pulsed-, controlled-, targeted and
programmed release.
In the case of dry powder inhalers and aerosols, the dosage unit is determined
by
means of a valve which delivers a metered amount. Units are typically arranged
to
administer a metered dose or "puff". The overall daily dose will be
administered in a
single dose or, more u'sually, as divided doses throughout the day.
A compound for use in the invention may be administered rectally or vaginally,
for
example, in the form of a suppository, pessary, or enema. Cocoa butter is a
traditional suppository base, but various alternatives may be used as
appropriate.
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34
Formulations for rectal/vaginal administration may be formulated to be
immediate
and/or controlled release. Controlled release formulations include delayed-,
sustained-, pulsed-, controlled-, targeted and programmed release.
A compound for use in the invention may also be administered directly to the
eye or
ear, typically in the form of drops of a micronised suspension or solution in
isotonic,
pH-adjusted, sterile saline. Other formulations suitable for ocular and aural
administration include ointments, biodegradable (e.g. absorbable gel sponges,
collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and
particulate or vesicular systems, such as niosomes or liposomes. A polymer
such
as crossed-linked poiyacrylic acid, polyvinylalcohol, hyaluronic acid, a
cellulosic
polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or
methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum,
may
be incorporated together with a preservative, such as benzalkonium chloride.
Such
formulations may also be delivered by iontophoresis.
Formulations for ocular/aural administration may be formulated to be immediate
and/or controlled release. Controlled release formulations include delayed-,
sustained-, pulsed-, controlled-, targeted, and programmed release.
A compound for use in the invention may be combined with soluble
macromolecular
entities, such as cyclodextrin and suitable derivatives thereof or
polyethylene glycol-
containing polymers, in order to improve their solubility, dissolution rate,
taste-
masking, bioavailability and/or stability for use in any of the aforementioned
modes
of administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful for
most
dosage forms and 'administration routes. Both inclusion and non-inclusion
complexes may be used. As an alternative to direct complexation with the drug,
the
cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent,
or
solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-
cyclodextrins, examples of which may be found in International Patent
Applications
Nos. WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
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The two components of the present combination invention (i.e. the 5-HT1B, 5-
HT1D
or 5-HT1F agonist and the alpha-2-delta ligand) may be administered
simultaneously, sequentially or separately in order to enjoy the benefits of
the
combination therapy provided by the present invention. Each component may be
5 administered on its own but is more usually administered in association with
one or
more excipients as one of the pharmaceutical compositions described above.
Usually, both components will be administered via the same route (e.g. the
oral
route). However, there may be circumstances where it is preferable to
administer
each component via a different route (e.g. one component via the oral route
and
10 one component via the parenteral route). For simultaneous administration,
the two
components preferably form part of the same pharmaceutical composition and are
therefore administered via the same route.
Oral administration is preferred for both components of the invention. Most
15 preferably, the two components are delivered simultaneously via the oral
route, for
example in the form of a tablet
The two components of the present combination invention may conveniently be
combined in the form of a kit. Such a kit comprises a 5-HT1B, 5-HT1D or 5-HTiF
20 agonist and an alpha-2-delta ligand, each usually in the form of one of the
pharmaceutical compositions described above, and means for separately
retaining
them, such as a container, divided bottle, or divided foil packet. An example
of such
a kit is the familiar blister pack used for the packaging of tablets, capsules
and the
like.
The kit of the invention is particularly suitable for administering different
dosage
forms, for example, oral and parenteral, for administering separate
compositions at
different dosage intervals, or for titrating separate compositions against one
another. To assist compliance, the kit typically comprises directions for
administration and may be provided with a so-called memory aid.
For administration to human patients, the optimal total daily dose of the 5-
HT1B, 5-
HT1D or 5-HT1F agonist and the alpha-2-delta ligand administered according to
the
present invention will vary considerably according to the particular compounds
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36
chosen. Such optimal doses are readily determined by the skilled person in
accordance with normal pharmaceutical practice using dose ranging studies. As
an
example, in the case where the chosen 5-HTiB, 5-HT1D or 5-HTIF agonist is
eletriptan, the total daily oral dose is typically in the range 20 mg to 80
mg. The
administration of one or two 40 mg doses is particularly preferred. In the
case where
the alpha-2-delta ligand is pregabalin, the total daily oral dose is usually
from 150 to
600 mg, taken as two or three doses.
The total daily dose of either component may be administered in single or
divided
doses and may, at the physician's discretion, fall outside of the typical
ranges
described above.
For the avoidance of doubt, references herein to "treatment" include
references to
curative, palliative and prophylactic treatment.
Some of the advantages of the combination provided by the present invention
may
be appreciated in pre-clinical models (especially preclinical models of
migraine
pathophysiology or central sensitisation). Such models include:
= the rat model for cutaneous allodynia induced by intracranial pain described
by Burstein et al in Annals of Neurology, 2004, 55(1), 27-36;
= the animal model of intracranial pain described by Ramadan in Proceedings
of the National Academy of Sciences of the United States of America, 2003,
101(12), 4274-9;
= the rat model described by Burstein et al in Journal of Neurophysiology,
1999, 81(2), 479-93; and
= the rat model described by Burstein et al in Journal of Neurophysiology,
1998, 79(2), 964-82.
The advantages of the combination provided by the present invention will also
be
apparent from clinical measurements of efficacy. In the case of migraine
headache
such advantages can be seen as improved efficacy (e.g. the rate of migraine
resolution) and as an improved safety profile (e.g. in the reduction in the
adverse
events).
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37
A combination of eletriptan and pregabalin has been tested in the rat model of
migraine developed by Burnstein and disclosed in the Journal of
Neurophysiology
references cited above. This sensitization model uses chemical mediators of
inflammation applied to the dura to induce a headache in the rat. The chemical
mediators (serotonin, 10-3M; histamine, 10-3M; prostagiandin E2, 10-4M and
bradykinin 10-3M) are applied in a combined preparation referred to as an
inflammatory soup. The progress of the headache is monitored using
electrophysiology of a 2nd sensory neuron in the trigeminal nucleus caudalis
(TNC).
In this model, once sensitization is induced, it is not reversed by the
actions of
triptans (including eletriptan). This model therefore reflects the clinical
observation
that after allodynic symptoms have developed during a migraine attack, the
triptans
often do not relieve all of the patient's pain.
A control animal was treated with the inflammatory soup on the dura at time 0
and
then with saline solution 3 hours later. This animal showed strong
sensitization of its
responses to sensory stimuli such as brush and pin. The receptive fields
increased
and there was a large increase in the number of action potentials at 2.5 hours
after
sensitization was induced. At 4.5 hours after the application of the
inflammatory
soup, the sensitization was stable and an increase in the magnitude of the
response
to the sensory stimuli was maintained.
Animals treated with inflammatory soup on the dura followed by eletriptan at 3
hours showed strong sensitization of their responses at 2.5 hours to sensory
stimuli
such as brush and pin and the eletriptan did not reverse the sensitization
even as
late as 5.5 hours after sensitization. This is in accordance with clinical
studies of the
effects of triptans on sensitization and allodynia in patients, which have
shown that
in the approximately 80% of patients who experience allodynia during their
migraine, the triptans are much less effective if treatment is delayed until
after
sensitization is manifest.
Animals treated with inflammatory soup on the dura followed by pregabalin
(30mg/kg) at 3 hours showed sensitization of their responses at 2.5 hours to
sensory stimuli such as brush and pin and the pregabalin moderately reversed
the
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38
sensitization at the 4.5 hour time points after sensitization. This change was
not
consistent among the animals tested. There was a large amount of variability
between the animals and they did not show a smooth return to baseline activity
at
the 3.5 hour and the 4.5 hour time points.
However, in animals treated with inflammatory soup on the dura followed by a
combination of pregabalin (30mg/kg) and eletriptan (0.2 mg/kg) at 3 hours, the
combination of drugs reversed sensitization and the number of spikes in
response
to the same sensory stimulus at 4.5 hours after sensitization was less then
before
application of the soup.
The data show, in a rat model of migraine, that although triptans alone do not
reverse sensitization of trigeminal relay neurons in the TNC, a combination of
the
triptan eletriptan and the alpha-2-delta ligand pregabalin is effective.
A combination of the present invention may be further combined with another
pharmacologically active compound, or with two or more other pharmacologically
active compounds, particularly in the treatment of pain, especially migraine.
Thus, a
combination of the present invention, in its broadest sense or in any of the
preferred
aspects presented above, may be administered simultaneously, sequentially or
separately in combination with one or more agents selected from:
= an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone,
levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine,
codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene,
nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol,
nalbuphine or pentazocine;
= a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac,
diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen,
ibuprofen,
indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid,
meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,
oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or
zomepirac;
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39
= a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital,
butabital,
mephobarbital, metharbital, methohexital, pentobarbital, phenobartital,
secobarbital, talbutal, theamylal or thiopental;
= a benzodiazepine having a sedative action, e.g. chlordiazepoxide,
clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or
triazolam;
= an H, antagonist having a sedative action, e.g. diphenhydramine, pyrilamine,
promethazine, chlorpheniramine or chlorcyclizine;
= a sedative such as glutethimide, meprobamate, methaqualone or
dichloralphenazone;
= a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone,
cyclobenzaprine, methocarbamol or orphrenadine;
= an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N-
methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-
methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-
(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231
(MorphiDex , a combination formulation of morphine and
dextromethorphan), topiramate, neramexane or perzinfotel including an
NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3-
fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1 H)-
quinolinone;
= an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine,
dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-
sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
= a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or
nortriptyline;
= an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate or
valproate;
= a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist,
e.g. ((xR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-
5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione
(TAK-637), 5-[[(2R,3S)-2-[(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-
fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-
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869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-
(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);
= a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium
chloride, darifenacin, solifenacin, temiverine and ipratropium;
5= a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib,
valdecoxib,
deracoxib, etoricoxib, or lumiracoxib;
= a coal-tar analgesic, in particular paracetamol;
= a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine,
thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine,
10 olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole,
sonepiprazole, bionanserin, iloperidone, perospirone, raclopride, zotepine,
bifeprunox, asenapine, lurasidone, amisuipride, balaperidone, palindore,
eplivanserin, osanetant, rimonabant, meclinertant, Miraxion or sarizotan;
= a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist (e.g.
15 capsazepine);
= a beta-adrenergic such as propranolol;
= a local anaesthetic such as mexiletine;
= a corticosteroid such as dexamethasone;
= a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-
20 (4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
= a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-
methyl-4-(3-pyridinyl)-3-buten-1 -amine (RJR-2403), (R)-5-(2-
azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
= Tramadol ;
25 = a PDEV inhibitor, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-
sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-
6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1 ]-pyrido[3,4-b]indole-1,4-
dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-
sulphonyl)-
30 phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one
(vardenafil),
5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-
7H-pyrazolo[4,3-c~pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-
2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-4 pyrimidin-7-one, 5-
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41
[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-
methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-
methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-
2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-
dihydro-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-
yl)ethyl]-
4-propoxybenzenesulfonamide;
= a cannabinoid;
= metabotropic glutamate subtype 1 receptor (mGIuR1) antagonist;
= a serotonin reuptake inhibitor such as sertraline, sertraline metabolite
demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl
metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite
desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine,
cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and
trazodone;
= a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline,
lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin,
buproprion, buproprion metabolite hydroxybuproprion, nomifensine and
viloxazine (Vivalan ), especially a selective noradrenaline reuptake inhibitor
such as reboxetine, in particular (S,S)-reboxetine;
= a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine,
venlafaxine metabolite 0-desmethylvenlafaxine, clomipramine, clomipramine
metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;
= an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1-
iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-
4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,
(2S,5Z)-2-amino-2-methyl-7-[(1 -iminoethyl)amino]-5-heptenoic acid, 2-
[[(1 R,3S)-3-amino-4- hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-
pyridinecarbonitrile; 2-[[(1 R,3S)-3-amino-4-hydroxy-1-(5-
thiazolyl)butyl]thio]-
4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-
(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,
2-[[(1 R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl) butyl]thio]-6-(trifluoromethyl)-
3
pyridinecarbonitrile, 2-[[(1 R,3S)-3- amino-4-hydroxy- 1-(5-
thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-
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42
chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, or
guanidinoethyldisulfide;
= an acetylcholinesterase inhibitor such as donepezil;
= a prostagiandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6-
dimethyl-1 H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-
methylbenzenesulfonamide or 4-[(1 S)-1-({[5-chloro-2-(3-
fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;
= a leukotriene B4 antagonist; such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-
chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-
Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid
(ONO-4057) or DPC-11870,
= a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-
3,4,5,6-tetrahydro-2H-pyran-4-yi])phenoxy-methyl]-1-methyl-2-quinolone (ZD-
2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl), 1,4-benzoqui none (CV-6504);
= a sodium channel blocker, such as lidocaine;
= a 5-HT3 antagonist, such as ondansetron;
and the pharmaceutically acceptable salts and solvates thereof.
