MX2007002790A - Combination of a 5-ht(1) receptor agonist and an alpha-2-delta ligand for the treatment of migraine. - Google Patents

Combination of a 5-ht(1) receptor agonist and an alpha-2-delta ligand for the treatment of migraine.

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Publication number
MX2007002790A
MX2007002790A MX2007002790A MX2007002790A MX2007002790A MX 2007002790 A MX2007002790 A MX 2007002790A MX 2007002790 A MX2007002790 A MX 2007002790A MX 2007002790 A MX2007002790 A MX 2007002790A MX 2007002790 A MX2007002790 A MX 2007002790A
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pain
alpha
acid
combination
agonist
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MX2007002790A
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Jayasena Hettiarachchi
Iradj Haji Mohamad Reza
Carolyn Rose Sikes
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Pfizer
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Priority claimed from GBGB0419849.5A external-priority patent/GB0419849D0/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents

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  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Neurology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention relates to a combination of 5-HT1B, 5-HT1D or 5-HT1F agonist and an alpha-2-delta ligand. Such a combination is useful in the treatment of pain, particularly the pain arising from migraine.

Description

COMBINATION OF A RECEPTOR AGONIST 5- HYDROXITRIPTAMINE (I) AND A LINKED ALPHA-2-DELTA FOR THE TREATMENT OF MIGRAINE DESCRIPTIVE MEMORY The present invention relates to a combination of a 5-HT1B, 5-HT1D or d-HT2 receptor agonist and an alpha-2-delta ligand, as well as to pharmaceutical compositions comprising such combination and to the uses of such combination in the treatment of pain and other combinations, especially in the treatment of migraine. Serotonin (5-hydroxytryptamine, 5-HT) acts on a number of membrane-bound receptors known as 5-HT receptors. These heterogeneous receptors belong to the superfamily of receptors coupled to the G protein and have been divided into six broad classes (5-HTL 5-HT2, 5-HT4, 5-HT5, 5-HT6 and 5-HT7). Some of these classes may be further subdivided. The 5-HT class ?, for example, comprises five subtypes of receptors, all of which have a nanomolar affinity for serotonin. The 5-HT? A, 5-HT? B and 5-HT1 subtypes are characterized by a high affinity for 5-carboxamidotriptamine while the 5-HT? E and 5-HT1 F subtypes are characterized by a low affinity for this agonist synthetic. See Lanfumey and Hamon in Current Drug Targets - CNS & Neurological Disorders, 2004, 3 (1), 1-10 for additional information.
A number of indole 5-HTt agonists (commonly known as triptans) have been identified that act most potentially in the 5-HT1 B and 5-HT1D receptor subtypes and have efficacy in the treatment of migraine. These include sumatriptan, anratriptan, zolmitriptan, rizatriptan, frovotriptan, almotriptan and eletriptan. Ergotamine and dihydroergotamine are also potent agonists of the 5-HT1 B and 5-HT1D receptors. More recently, selective 5-l-pv receptor agonists (such as LY334370 and LY34484) have been discovered and shown to be effective in preclinical models of migraine (see Phebus et al., Society for Neuroscience, 1996, 22, 1331 and Life Sci., 1997, 61, 2117). An alpha-2-delta ligand (also known as a GABA analogue) is a compound that selectively shifts 3H-gabapentin from brain membranes (eg, porcine or human brain membranes) and thus has a high affinity interaction with the alpha-2-delta subunit (a2d) of the calcium channels activated by tension. The alpha-2-delta ligands act on voltage-activated calcium channels to attenuate excessive neuronal activity by reducing movement induced by the depolarization of calcium ions at the presynaptic terminals and reducing the subsequent release of neurotransmitters such as glutamate , noradrenaline and substance P. Alpha-2-delta ligands are useful in the treatment of a number of conditions. The most known alpha-2-delta ligand, gabapentin (NEURONTIN ®, l - (aminomethyl) -cyclohexylacetic acid) was first described in the family of patents comprising document 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 effective in migraine prophylaxis, there are no reviews showing efficacy in the acute (abortive) treatment of migraine. A second alpha-2-delta ligand, pregabalin (LYRICA ® (S) - (+) - 4-amino-3- (2-methylpropyl) butanoic acid), is described in EP-A-0641330 and a useful anticonvulsant in the treatment of epilepsy. The use of pregabalin in the treatment of pain is described in EP-A-0934061. Pregabalin easily crosses the blood-brain barrier through the L-amino acid transporter of cell membranes, thus reaching its lianas in the brain and spinal cord. There is an ongoing need to provide better pain treatments (eg, migraine headaches) that are, for example, more effective at lower doses, effectiveness against a wider spectrum of painful conditions, less susceptible to side effects, faster acting and more lasting performance. A lower rate of recurrence in certain painful conditions (eg, migraine) is also desirable. The use of a 5-HT1B, 5-HT? D or 5-HT1F receptor agonist (particularly a tryptophan) in the treatment of migraine is somewhat limited by the need for early administration in order to achieve optimal pain relief and for potential unwanted side effects at doses therapeutic Migraine is a disorder of the primary brain in which neural episodes result in both dilation and inflammation of the cranial blood vessels and neurological inflammation in the brain. There is increased sensitivity and excitability resulting in peripheral sensitization after central sensitization. Central sensitization is an increase in the excitability of neurons within the central nervous system, so that it could normally evoke a soft sensation or none now produces an exaggerated response (for example, tactile allodynia in which a painful response is evoked by brushing light skin). Recent evidence indicates that triptans are more effective if provided at the beginning of the attack, before peripheral neurons sensitize central neurons that lead to central sensitization and that are unable to reverse the ongoing peripheral or central sensitization. Surprisingly it has now been found that combination therapy with a 5-HT1B, 5-HT1 or 5-HT1F receptor agonist and an alpha-2-delta ligand offers significant benefits in the treatment of pain, particularly in the treatment of pain. migraine. Such a combination therapy is particularly advantageous when compared to the therapy used by any agent alone. Such a combination of a 5-HT1B) 5-HT1 or 5-HT1F receptor agonist and an alpha-2-delta ligand unexpectedly results in a synergistic effect, resulting in an efficiency greater than that which would be obtained using any kind of agent only. In particular, the dose of a 5-HT1B, 5-HT1 D or 5-HT1F receptor agonist (particularly a triptan) necessary to treat a migraine attack is reduced, potentially leading to fewer side effects. In addition, the efficacy of such a compound, when administered in the later stages of an attack, at a time when peripheral sensitization has already begun, is considerably greater when administered in combination with an alpha-2-delta ligand. Therefore, the invention provides a combination of a 5-HT1B, 5-HT ?D or 5-HT1 F receptor agonist and an alpha-2-delta ligand. In addition, the invention provides a pharmaceutical composition comprising a 5-HT1B, 5-HT1D or 5-HT-? F receptor agonist, an alpha-2-delta ligand and a pharmaceutically acceptable excipient, diluent or carrier. In addition, the invention provides a combination of a 5-HT1B, 5-HTID O 5-HT1 F receptor agonist and an alpha-2-delta ligand for use as a medicament. In addition, the invention provides the use of a 5-HT? B, 5-HT? D or 5-HT? F receptor agonist or an alpha-2-delta ligand in the manufacture of a medicament for simultaneous, sequential administration or separated from both agents in the treatment of pain (especially migraine). In addition, the invention provides a combination of a 5-HTβ, 5-HT1D or 5-HT1F receptor agonist or an alpha-2-delta ligand for the simultaneous, sequential or separate administration of both agents in the treatment of pain (especially migraine). In addition, the invention provides a method of treating pain (especially migraine) comprising the simultaneous, sequential or separate administration to a mammal in need of such treatment of an effective amount of a 5-HT1B, 5-HT1 receptor agonist. or 5-HT1F and an alpha-2-delta ligand. In addition, the invention provides a kit comprising a 5-HT1B, 5-HT1D or 5-HT? F receptor agonist, an alpha-2-delta ligand and means for containing said compounds. In addition, the invention provides a product that contains a 5-HT? B receptor agonist, 5-HT1D or 5-HT? F 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 the danger of potentially harmful stimuli from the external environment. The system operates through a specific set of primary sensory neurons and is activated by noxious stimuli by peripheral transduction mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review). These sensory fibers are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimuli and by virtue of its topographically organized projection to the spinal cord, the location of the stimulus. Nociceptors are found in nociceptive nerve fibers of which there are two main types, A-delta fibers (myelinated) and C fibers (unmyelinated). The activity generated by the nociceptor inputs is transferred, after the complex processing in the dorsal horn, either directly, or by nuclei of transmission of the brainstem, to the ventrobasal thalamus and later on the cortex, where the sensation of pain is generated. Pain can usually be classified as acute or chronic. Acute pain starts 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 acute and severe. It is the type of pain that can occur after specific injuries that result from surgery, dental work, sprain, or sprain. Acute pain usually does not result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persistent for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (eg, painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain. When a substantial injury to the body tissue occurs, through disease or trauma, the characteristics of the activation of nociceptors are altered and there is sensitization in the periphery, locally around the lesion and centrally where the nociceptors end. These effects lead to an increased feeling of pain. In acute pain these mechanisms can be useful, in promoting protective behaviors that can allow the repair processes that take place. The normal expectation would be that the sensitivity returns to normal value once the injury has healed. However, in many states of chronic pain, hypersensitivity lasts longer than the healing process and is often due to injury to the nervous system. This injury often leads to abnormalities in the sensory nerve fibers associated with maladaptation and aberrant activity (Woolf and Salter, 2000, Science, 288, 1765-1768). Clinical pain is present when a feeling of discomfort and abnormality stands out among the patient's symptoms. Patients tend to be quite heterogeneous and may exhibit various pain symptoms. Such symptoms include: 1) spontaneous pain that may be dull, burning, or throbbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia - Meyer et al., 1994, Texbook 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. Therefore, the pain can also be divided into a number of different subtypes according to different pathophysiology, including nociceptive, inflammatory and neuropathic pain. Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by the transduction of stimuli by the nociceptors at the site of injury and activate spinal cord neurons at the level of their termination. This is then transmitted over the spinal tract to the brain where the pain is perceived (Meyer et al., 1994 Textbook of Pain 13 -44). The activation of the nociceptors activates two types of afferent nerve fibers. The delta A myelinated fibers are rapidly transmitted and are responsible for the sharp and throbbing sensations of pain, whereas unmyelinated C fibers are transmitted at a slower rate and lead to dull or painful pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, sprains / strains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain that follows any type of surgical procedure), post-traumatic pain, renal colic, cancer pain and back pain. The pain of cancer may be chronic pain such as tumor-related pain (eg, bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (eg, syndromes after chemotherapy, pain syndromes) after chronic surgery or syndromes after radiation). Cancer pain can also occur in response to chemotherapy, immunotherapy, therapy hormonal or radiotherapy. Back pain may be due to herniated or broken intervertebral discs or abnormalities of the lumbar facet joints, sacroiliac joints, paraspinal muscles or the longitudinal posterior ligament. Back pain can be resolved naturally but in some patients, where it lasts for more than 12 weeks, it becomes a chronic condition that can be particularly debilitating. Neuropathic pain is currently defined as pain initiated or caused by a lesion or primary dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and so the term 'neuropathic pain' encompasses many disorders with various etiologies. 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, pain after central stroke, and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological because it has no protective role. It is often present long after the original cause has dissipated, commonly lasting for years, significantly lowering patients' quality of life (Woolf and Mannion 1999 Lancet 353: 1959-1964). The symptoms of neuropathic pain are difficult to treat, since they are often heterogeneous even among patients with the same disease (Woolf and Decosterd 1999 Pain Supp. 6: S141 - S147; Woolf and Mannion 1999 Lancet 353: 1959 - 1964). They include spontaneous pain, which may be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally harmless stimulus). The inflammatory process is a complex series of biochemical and cellular processes activated in response to tissue injury or the presence of foreign substances, which result 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 most common chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact etiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan and Jayson 1994 Textbook of Pain 397-407). It has been estimated that nearly 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of which are above 60 years of age, and this is expected to increase to 40 million as age increases. of the population increases, making this a public health problem of enormous magnitude (Houge and 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 the psychosocial and physical function and it is known to be the main cause of disability in old age. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies between intermittent episodes of back pain that occur throughout life to a serious chronic disease that attacks the spine, peripheral joints and other organs of the body. Another type of inflammatory pain is visceral pain that includes pain associated with inflammatory bowel disease (IBD). Visceral pain is the pain associated with the viscera, which encompasses the organs of the abdominal cavity. These organs include the sexual organs, spleen and part of the digestive system. The pain associated with the viscera can be divided into visceral digestive pain and non-digestive visceral pain. Gastrointestinal (Gl) disorders commonly found to cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These Gl disorders include a wide range of disease states that are currently only moderately controlled, including, with respect to FBD, gastroesophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and with respect to IBD, Crohn's disease, ileitis, and ulcerative colitis, all of which produce regularly visceral pain. Other types of visceral pain include pain associated with dysmenorrhea, cystitis and pancreatitis, and pelvic pain. It should be noted that some types of pain have multiple etiologies and thus can be classified into more than one area, for example pain of Cancer pain and back have both nociceptive and neuropathic components. Other types of pain include: • pain produced by musculoskeletal disorders including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-joint rheumatism, dystrophinopathy, glycogenolysis, polymyositis, and pyomyositis; • cardiac and vascular pain including pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, sclerodoma, and skeletal muscle ischemia; • headache such as migraine (including migraine with aura and migraine without aura), cluster headache, headache of mixed celale tension type and headache associated with vascular disorders; and • orofacial pain, including dental pain, earache, burning mouth syndrome, and temporomandibular myofacial pain. The combination of the present invention is potentially useful in the treatment of all types of pain, particularly headache, most notably migraine, tension-type headaches and cluster headaches. All types of migraine can 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 in the prevention of migraine recurrence. 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 can be useful in the treatment of overactive bladder, premature ejaculation, chronic paroxysmal hemicrania, depression, drug abuse, emesis, eating disorders, hypertension, post-traumatic cranial and neck injury and obesity and as a vasodilator or antimicrobial agent. The combination of the present invention may also be useful in the treatment of epilepsy, fading attacks, hypokinesia, cranial disorders, neuropathological 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 brain injury include stroke, cephalic trauma, and asphyxia. Stroke, which refers to a cerebrovascular disease is also known as stroke, includes acute thromboembolic stroke and both focal and global ischemia. Transient cerebral ischemic attacks and other cerebral vascular problems accompanied by cerebral ischemia are also included. These vascular disorders may occur in a patient suffering from carotid endarterectomy specifically or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures including cerebral angiography and the like. Other incidents Related are cranial trauma, spinal cord trauma, or general anoxia injury, hypoxia, hypoglycaemia, hypotension as well as similar injuries observed during embolism, hyperfusion, and hypoxia procedures. 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 epileptic states. The combination of the present invention may also be useful in the treatment of depression (eg, major depressive disorders of a single or recurrent episode, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, awakening early in the morning or psychomotor retardation, atypical depression or reactive depression, including increased appetite, hyperinsomnia, psychomotor agitation or irritability, seasonal affective disorder, minor depression and pediatric depression), bipolar disorders or manic depression (for example, bipolar I disorder) bipolar II 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 with no history of panic disorder, specific phobias such as specific animal phobias, social anxiety, social phobia including social anxiety disorder, obsessive-compulsive disorder and related spectrum disorders and disorders generalized anxiety), stress disorder (including post-traumatic stress disorder, acute stress disorder and chronic stress disorder), borderline personality disorder, schizophrenia and other psychotic disorders, schizophreniform disorders, schizoaffective disorders, hallucinatory disorders, brief psychotic disorders, disorders shared psychotics, psychotic disorders with delusions and hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic smoke disorders (such as severe major depressive disorder), mood disorders associated with psychotic disorders (such as acute mania and depression associated with disorder bipolar), mood disorders associated with schizophrenia, delirium, dementia, senile dementia, memory disorders, loss of executive function, vascular dementia, movement disorder (such as akinesia, dyskinesia, including familial paroxysmal dyskinesias, spasticities, d e Scout, PALSYS and akinetic rigid syndrome), extrapyramidal movement disorders (such as medication-induced movement disorders, eg, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, acute neuroleptic-induced dystonia, acute neuroleptic-induced akatisia, dyskinesia delayed neuroleptic-induced tremor), addictive disorders and withdrawal syndrome, chemical dependencies and addictions (eg, dependence on, or addictions to, alcohol, heroin, cocaine, benzodiazepines, psychoactive substances, nicotine, or phenobarbitol), behavioral addictions (such as gambling addiction), eye disorders (such as glaucoma and ischemic retinopathy), abstinence, disorder of juste (including depressive mood, anxiety, mixed anxiety and depressive mood, behavior alteration, and mixed alteration of behavior and mood), learning associated with age and mental disorders, anorexia nervosa, apathy, attention deficit disorder (or other cognitive) due to general medical conditions (including attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD) and its recognized subtypes), bulimia nervosa, chronic fatigue syndrome, somatoform disorders (including of somatization, conversion disorder, hypochondriasis, body dysmorphic disorder, undifferentiated somatoform disorder and somatoform NOS), incontinence (eg, stress incontinence, genuine stress incontinence and mixed incontinence), urinary disorders, premature ejaculation, inhalation disorders, obesity (for example, weight reduction of obese or overweight patients), Oppositional defiant disorder, premenstrual dysphoric disorder (eg premenstrual syndrome and luteal phase dysphoric disorder), sleep disorders (such as narcolepsy, insomnia and enuresis), specific developmental disorders, "failure after a satisfactory response" syndrome to the selective inhibition of serotonin reuptake (SSRI) (where a patient does not maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response) and ICT derangement (eg, 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 100 nM, preferably less than 10 nM) and selective. In the context of the present invention, a selective alpha-2-delta ligand is a compound that binds to the gabapentin binding site of the alpha-2-delta subunit (a2d) of voltage-activated calcium channels more potentially than it binds to any other physiologically important receptor. Such selectivity is preferably at least 2 times; more preferably at least 10 times, most preferably at emnos 100 times. Examples of the alpha-2-delta ligands suitable for use with the present invention are those compounds generally or specifically described in US-B-4., 024,175 (particularly gabapentin), EP-A-641330 (particularly pregabalin) document US-B-5,563,175, WO-A-97/33858, WO-A-97/33859, WO-A-99/31057 , WO-A-99/31074, WO-A-97/29101, WO-A-02/085839 (particularly (1R, 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-dimethylcyclopentyl) acetic acid, WO-A-01/90052, WO-A-01/28978 (particularly (1a, 3a, 5a) (3-aminomethylbicyclo [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-acid Methyloctanoic, WO-A-03/082807 (particularly (3S, 5R) -3-amine-5-methylheptanoic acid and (3S, 5R) -3-amino-5-methylnonanoic acid and (3S, 5R) -3 acid -amino-5-methyloctanoic acid), EP-A-1178034, EP1201240, 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-02 100347, WO-A-02/42414, WO-A-02/32736, WO-A-02/28881, and WO-A- 03/082807 (especially 2-aminomethyl-4-ethylhexanoic acid) and the pharmaceutically acceptable salts and solvates thereof. Other cyclic alpha-2-delta ligands useful for use in the present invention can be shown by the following formula (I): wherein X is a carboxylic acid or bioisostere of the carboxylic acid; n is 0, 1 or 2; and R1, R a, R 2a, R 3, R 3a, R 4 and R 4a are independently selected from H and C 1 -C 7 alkyl, or R 1 and R 2 or R 2 and R 3 are taken together to form a C 3 -C 7 cycloalkyl ring, which is optionally substituted with one or two substituents selected from Ci-C6 alkyl; or a pharmaceutically acceptable salt or solvate thereof. In formula (I), suitably R1, R1a, R2a, R3a, R4 and R4a are H and R2 and R3 are independently selected from H and methyl, or R1a, R a, R3a and R4a are H and R1 and R2 or R2 and R3 are taken together to form a C3-C cycloalkyl ring, which is optionally substituted with one or two methyl substituents. A suitable bioisostere of the carboxylic acid is selected from tetrazolyl and oxadiazolyl. X is preferably a carboxylic acid. In the formula (I), preferably R1, R1a, R2a, R3a, R4 and R4a are H and R2 and R3 are independently selected from H and methyl, or R1a, R2a, p3a and R4a are H and R1 and R2 or R2 and R3 are taken together to form a C4-C5 cycloalkyl ring, or when n is 0, R1, R1a, R2a, R3a, R4 and R4a are H and R2 and R3 form a cyclopentyl ring, or, when n is 1, R1, R1a, R2a, R3a, R4 and R4a are H and R2 and R3 are both methyl or R1, R1a, R2a, R3a, R4 and R a are H and R2 and R3 form a cyclobutyl ring, or, when n is n 2, R1 , R1a, R2a, 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. Additional useful acyclic alpha-2-delta ligands for use in the present invention can be shown by the following formula (II): wherein n is 0 or 1, R1 is hydrogen or (Ci-C6) alkyl; R2 is hydrogen or (Ci-C6) alkyl; R3 is hydrogen or (Ci-C6) alkyl; R4 is hydrogen or (Ci-C6) alkyl; R5 is hydrogen or (Ci-C6) alkyl and R2 is hydrogen or alkyl (Ci-Ce), or a pharmaceutically acceptable salt or solvate thereof. According to formula (II), suitably R1 is alkyl (Ci-Ce), R2 is methyl, R3-R6 is hydrogen and n is 0 or 1. R1 is more preferably methyl, ethyl, n-propyl or n-butyl, R 2 is methyl, R 3 -R 6 is hydrogen and n is 0 or 1. When R 2 is methyl R 3 - R 6 is hydrogen and n is 0, R 1 is suitably ethyl, n-propyl or n-butyl. When R2 is methyl, R3-R6 is hydrogen and n is 1, R1 is suitably methyl or n-propyl. The 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, [(1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl] acid] acetic acid), 3- (1-aminomethylcyclohexylmethyl) -4H- [1, 2,4] oxadiazol-5-one, C- [1 - (1 H -tetrazol-5-ylmethyl) cycloheptyl] methylamine, acid (3S) , 4S) - (1-Aminomethyl-3,4-dimethylcyclopentyl) acetic acid, (1a, 3a, 5a) (3-aminomethylbicyclo [3.2.0] hept-3-yl) acetic acid, (3S, 5R) -3 acid -amino-5-methyloctanoic acid, (3S, 5R) -3-amino-5-methylheptanoic acid, (3S, 5R) -3-amino-5-methylnonanoic acid, (3S, 5R) -3-amino-5-acid methyloctanoic acid), (2S, 4S) -4- (3- (chlorophenoxy) proline and (2S, 4S) -4- (3-fluorobenzyl) proline and the pharmaceutically acceptable salts and solvates thereof is particularly preferred.
Additional preferred alpha-2-delta ligands are (3R, 4R, 5R) -3-amino-4,5-dimethylheptanoic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyloctanoic acid) and the pharmaceutically acceptable salts and solvates thereof. One of these compounds can be prepared using the following procedures and the other compounds can be prepared by analogous methods.
(R) -3 - ((R) -3-Methyl-hexanoyl) -4-phenyl-oxazolidin-2-one To a complex of copper (I) dimethylsulfoxide bromide (13.34 g, 64.87 mmole) in Dry tetrahydrofuran (150 ml) at -30 ° C under nitrogen was added a solution in 2M ether of propylmagnesium chloride (64.87 ml, 129.7 mmoles). The reaction mixture was stirred for 20 minutes. A solution of (R) -3-but-2-enoyl-4-phenyl-oxazolidin-2-one (15.0 g, 64.87 mmol) in tetrahydrofuran (60 ml) was added over a period of 15 minutes at -35 ° C. and the reaction mixture was allowed to warm slowly to room temperature for 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 yielding the title compound (13.34 g, 100%) as a white solid. 1 H NMR (CDCl 3, 400 MHz) 6 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 - ((2R, 3R) -2,3-dimethyl-hexanoyl) -4-phenyl-oxazolidin-2-one To a 1 M solution of sodium hexamethyldisilylamide (16.2 g, 88. 3 mmol) in tetrahydrofuran at -78 ° C was added, via cannula, at 0 ° C a solution of in nitrogen was added a solution of (R) -3 - ((R) -3-Methyl-hexanoyl) -4- phenyl-oxazolidin-2-one (18.7 g, 67.9 mmol) in 70 ml of dry tetrahydrofuran. The resulting solution was stirred at -78 ° C for 30 minutes. Methyl iodide (48.2 g, 339.5 mmol) was added and stirring was continued at -78 ° C for 4 hours. The reaction mixture was quenched with saturated ammonium sodium chloride, extracted with CH 2 Cl 2 and washed with 1 M sodium bisulfite. The solution was dried over MgSO 4, concentrated and chromatographed in 10% ethyl acetate in hexane to provide the compound of the title (11.1 g, 56.5%) in the form of an oil. 1 H NMR (CDCl 3) 400 MHz) d ppm 0.8 (t, J = 7.0 Hz, 3 H) 0.9 (d, J = 6.6 Hz, 3 H), 1.0 (d, J = 6.8 Hz, 3 H) 1.0 (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 = 87, 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%]. (2R, 3R) -2,3-dimethyl-hexan-1-ol A 1 M solution of lithium aluminum hydride was added tetrahydrofuran (95.9 ml, 95.9 mmol) to a solution of (R) -3 - ((2R, 3R) -2,3-dimethyl-hexanoyl) -4-phenyl-oxazolidin-2-one in tetrahydrofuran (300 ml) in nitrogen at -78 ° C. The reaction mixture was stirred for 3 hours at that temperature. Water was added dropwise to inactivate the excess lithium aluminum hydride and the reaction mixture was then poured into a mixture of ice in water. The resulting mixture was extracted into ether and washed with water and dried over MgSO4. The solution was concentrated followed by the addition of an excess of hexane. The resulting white precipitate was filtered and washed with hexane. The filtrate was concentrated to yield the title compound. 1 H NMR (CDCl 3, 400 MHz) d 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 (37.35 g, 126.9 mmol) and neutral alumina (96 g, 3.5 g per gram of pyridinium chlorochromate) in dry dichloromethane (200 ml) was stirred. ) under nitrogen for 0.25 h. (2R, 3R) -2,3-dimethyl-hexan-1-ol (5.0 g, 38.46 mmol) in dichloromethane (60 ml) was added and the resulting dark suspension was stirred at room temperature for 3 hours, the suspension was filtered through a short silica pad eluting with excess dichloromethane. Evaporation of the solvent afforded the title compound (4.1, 84%) as an oil. 1 H NMR (CDCl 3, 400 MHz) d 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 (sm, 1 H). ((2R, 3R) -2,3-Dimethyl-hexylidene) -amide of 4-methyl-benzenesulfinic acid Titanium (IV) ethoxide (5.16 g, 22.6 mmol) and (S) - (+) - p- were added toluenesulfinamide (7.02 g, 45.2 mmol) to (2R, 3R) -2,3-dimethyl-hexanal (2.9 g, 22.6 mmol) in tetrahydrofuran (30 mL). The resulting mixture was stirred at room temperature for 18 hours and poured into a brine solution (40 ml). The resulting suspension was stirred rapidly 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 buffer, eluting with 50/50 hexane / ethyl acetate solution affording the title compound (3.1, 51.6%) as an oil. 1 H NMR (CDCl 3 | 400 MHz) d ppm 0.8 (m, 6 H) 1.1 (m, 3 H) 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) EM, 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 (26.3 ml, 42.04 mmol) was added to a solution of diisopropylamine ( 4.6 g, 45.6 mmol) in dry tetrahydrofuran (40 ml) 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, 35.0 mmol) and stirred at that temperature for 45 minutes. Chlorotitanium triisopropoxide (9.4 g, 36.2 mmol) was added dropwise and stirring was continued at -78 ° C for 30 minutes. A solution of 4-methyl-benzenesulfinic acid ((2R, 3R) -2, 3-dimethyl-hexylidene) -amide (3.1 g, 1.7 mmol) in dry tetrahydrofuran (10 mL) was added to the reaction and the mixture The resulting mixture was stirred at -78 ° C for 4 hours. The reaction was quenched with a saturated solution of NaH2P04 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 (2.4 g, 53.9%) as a white solid. 1 H NMR (CDCl 3, 400 MHz) d 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 (CH 3) 3, 50%].
Acid (3R, 4R. 5R) -3-amino-4,5-dimethyl-octanec To a solution of the tert-butyl ester of (4R, 5R) -4,5-dimethyl- (R) -3- acid (toluene-4-sulfinylamino) -octanoic acid (1.8 g, 4.71 mmol) in dry methanol (30 ml) at 0 ° C under nitrogen was added excess trifluoroacetic acid (25 ml) and the reaction mixture was stirred for 2 hours at room temperature. The solution was concentrated to dryness followed by the addition of dry dichloromethane (20 ml) and trifluoroacetic acid (20 ml). 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 a constant pH of 6.5. The resin was then eluted with a 1: 1 solution of methanol and 10% solution of ammonium hydroxide. The sodium hydroxide solution was evaporated and the residue was crystallized with methanol-acetonitrile mixture to afford the title compound (0.717 g, 81.2%) as a white solid. 1 H NMR (CD 3 OD, 400 MHz) d ppm 0.9 (m, 1 1 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-HT 1 B, 5-HT 6 D or 5-HT 1 F agonist is a compound that binds sensitively to one or more of these receptors and activates it to some degree (preferably by binding to an affinity of less than 100 nM, most preferably less than 100 nM). Preferably, a 5-HT1B, 5-HT1D or 5-HT1 F agonist selected for use in the combination provided by the present invention is a selective 5-HT ?B, 5-HTID or 5-HT ?F agonist. A selective agonist can be defined as a compound having a high binding affinity (measured by a KD value) for one or more of the 5-HT ?B, 5-HT1D and 5-HT1F receptors. selectivity on 5-HT? A) 5-HT2A, 5-HT2c, 5-HT3, 5- receptors HT4, 5-HT5A and 5-HT6. The level of selectivity on these receptors is preferably at least 2 times, more preferably at least 4 times, more preferably still at least 10 times and most preferably at least 100 times. The 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 5-HT1B agonist, 5-HT1D or 5-HT? F particularly preferred for use in the invention is a compound that is an agonist (preferably a selective agonist, as defined above) of both the 5-HT1 B receptor and the 5-HT1 D receptor (known as a 5-HT1 B / 1D agonist). Such compounds include the indole-containing antimigraine drugs known as triptans, for example, almotriptan, alnatriptan, avitriptan, donitriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan and the pharmaceutically acceptable salts and solvates thereof. The most preferred 5-HT? B, 5-HT1D or 5-HT? F agonist for use in the invention is eletriptan and pharmaceutically acceptable salts and solvates thereof, particularly eletriptan hydrobromide and eletriptan hemisulfate, most particularly the a-polymorphic form of eletriptan hydrobromide described in WO-A-96/06842 and the form I polymorph of eletriptan hemisulfate described in WO-A-01/23377. Selective 5-HT 1 F receptor agonists (such as LY334370 ((5- (4-fluorobenzoyl) amino-3- (1 - methylpiperidin-4-yl) -1 H-indole) and LY344864). See Phebus et al., Life Sciences., 1997, 61, 2117 and Remandan et al., Cephalagia, 2003, 23, 776. Other suitable 5-HT1B, 5-HT1D or 5-HT? F 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 serotonin-O-carboxymethyl-glycyl-tyrosinamide In one embodiment, the invention provides a combination of a 5-HT ?B agonist (preferably a selective agonist, as defined above) and a alpha-2-delta ligand In another embodiment, the invention provides a combination of a 5-HT ?D agonist (preferably a selective agonist, as defined above) and an alpha-2-delta ligand. 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 a combination of a 5-HTI B ID 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 / 1 F 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 / IF agonist (preferably a selective agonist, as has been defined above) and an alpha-2-delta ligand. In another embodiment, the invention provides a combination of a 5-HTIB 1 D / IF 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 an antimigraine triptan drug and an alpha-2-delta ligand. Another preferred combination according to the invention is a combination of eletriptan, or a pharmaceutically acceptable salt or solvate thereof and an alpha-2-delta ligand. Another preferred combination according to the invention is a combination of a 5-HT 1B, 5-HT 5 agonist. or 5-HT1 F and an alpha-2-delta ligand selected from gabapentin, pregabalin, [(1R, 5R, 6S) -6- (aminomethyl) bicyclo [3,2,0] hept-6-yl] acetic acid ), 3- (1-aminomethylcyclohexylmethyl) -4H- [1, 2,4] oxadiazol-5-one, C- [1- (1 H-tetrazol-5-ylmethyl) cycloheptyl] methylamine, (3S, 4S) - (1-Aminomethyl-3,4-dimethylcyclopentyl) acetic acid, (1a, 3a, 5a) (3-aminomethylbicyclo [3,2,0] hept-3-yl) acetic acid, (3S, 5R) -3-amino-5-methyloctanoic acid, (3S, 5R) -3-amino-5-methylheptanoic acid, (3S, 5R) -3-amino-5-methylnonanoic acid, (3S, 5R) -3- amino-5-methyloctanoic), (2S, 4S) -4- (3- (chlorophenoxy) proline, (2S, 4S) -4- (3-fluorobenzyl) proline, (3R, 4R, 5R) -3-amino acid 4,5-dimethylheptanoic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyloctanoic acid and the pharmaceutically acceptable salts and solvates thereof Another preferred combination according to the invention is a combination of a 5-HT1B, 5-HT1 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-aminomethylcyclohexylmethyl) -4H- [1, 2,4] oxadiazol-5-one, C- [1 - (1 H-tetrazole-5 ylmethyl) cycloheptyl] methylamine, (3S, 4S) - (1-aminomethyl-3,4-dimethylcyclopentyl) acetic acid, (1a, 3a, 5a) (3-aminomethylbicyclo [3,2,0] hept-3-yl) acetic acid , (3S, 5R) -3-amino-5-methyloctanoic acid, (3S, 5R) -3-amino-5-methylheptanoic acid, (3S, 5R) -3-amino-5-methylnonanoic acid, (3S, 5R) -3-amino-5-methyloctanoic), (2S, 4S) -4- (3- (chlorophenoxy) proline, (2S, 4S) -4- (3-fluorobenzyl) proline, acid (3R, 4R, 5R ) -3-amino-4,5-dimethylheptanoic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyloctanoic acid and the pharmaceutically acceptable salts and solvates thereof Another preferred combination according to the invention is a combination of a drug antimigraine of triptan and pregabalin or a pharmaceutically acceptable salt or solvate thereof. Another preferred combination according to the invention is a combination of a 5-HT? B 1D agonist (preferably a selective agonist, as defined above) and an alpha-2-delta ligand selected from gabapentin, pregabalin, acid [( 1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl] acetic), 3- (1-aminomethylcyclohexylmethyl) -4H- [1, 2,4] oxadiazol-5-one, C- [1 - (1 H -tetrazol-5-ylmethyl) cycloheptyl] methylamine, (3S, 4S) - (1-aminomethyl-3,4-dimethylcyclopentyl) acetic acid, (1a, 3a, 5a) (3-aminomethylbicyclo [3.2.0] hept-3-yl) acetic acid, (3S, 5R) -3-amino-5-methyloctanoic acid, (3S, 5R) -3 acid -amino-5-methylheptanoic acid, (3S, 5R) -3-amino-5-methylnonanoic acid, (3S, 5R) -3-amino-5-methyloctanoic acid), (2S, 4S) -4- (3- ( chlorophenoxy) proline, (2S, 4S) -4- (3-fluorobenzyl) proline, (3R, 4R, 5R) -3-amino-4,5-dimethylheptanoic acid and (3R, 4R, 5R) -3-amino acid 4,5-dimethyloctanoic acid and the pharmaceutically acceptable salts and solvates thereof Another preferred combination according to the invention is a combination of a 5-HT 1B agonist 1D and pregabalin or a pharmaceutically acceptable salt or solvate thereof. Preferred according to the invention is the combination of eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and gabapantin or a pharmaceutical salt or solvate only acceptable of it. 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-aminomethylcyclohexylmethyl) -4H- [1, 2,4] oxadiazol-5-one, 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 C- [1- (1 H-tetrazol-5-ylmethyl) cycloheptyl] methylamine, or a salt or solvate pharmaceutically acceptable 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-dimethylcyclopentyl) acetic acid, or a pharmaceutically acceptable salt or solvate acceptable of it. A preferred specific combination according to the invention is the combination of eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and (1a, 3a, 5a) (3-aminomethyl-cyclo [3,2,0] hept-3) acid. -yl) acetic acid, or a pharmaceutically acceptable salt or solvate thereof. A specific preferred combination according to the invention is the combination of eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and (3S, 5R) -3-amino-5-methyloctanoic 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-methylheptanoic 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-methylnonanoic 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-methyloctanoic 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- (chlorophenoxy) proline, or a pharmaceutically acceptable salt or solvate of the A specific preferred combination according to the invention is the combination of eletriptan, or a pharmaceutically acceptable salt or solvate thereof, and 2-aminomethyl-4-ethylhexanoic 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-dimethylheptanoic acid, or a salt or solvate pharmaceutically acceptable 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-dimethyloctanoic acid, or a salt or solvate pharmaceutically acceptable thereof. A 5-HT1B, 5-HT1D or 5-HT1F 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') can be used in the form of a pharmaceutically acceptable salt, for example an acid or basic addition salt. Suitable acid addition addition salts are formed from acids that form non-toxic salts. Examples include acetate salts, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybienate, hydrochloride / chloride, hydrobromide / bromide, iodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylisulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, stearate, succinate, tartrate, tosylate and trifluoroacetate. Suitable basic salts are formed from bases that form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. The hemispheres of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). The pharmaceutically acceptable salts of a compound for use in the invention can be prepared by one or more of three methods: (i) by reacting the compound with the desired acid or base; (ii) removing an acid or base labile protecting group from a suitable precursor of the compound or opening the ring of a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base, or (iii) converting a salt of the compound in another by reaction with an appropriate acid or base or by a suitable ion exchange column. The three reactions are typically carried out in solution. The resulting salt can be precipitated and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized.
A compound for use in the invention can exist in both unsolvated and solvated forms. The term 'solvate' is used in this specification 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 used when said solvent is water. A compound for use in the invention can form a complex such as clathrate, a drug-host inclusion complex in which, unlike 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 that may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized.
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 can be used in the form of a prodrug. Thus, certain derivatives of a compound that may have little or no pharmacological activity themselves may, when administered in or on the body, be converted into compounds having the desired activity, for example, by hydrolytic cleavage. Such derivatives are called 'profaramcos'. Additional information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. Roche, American Pharmaceutical Association). The proframas may for example be produced by replacing appropriate functionalities with certain residues known to those skilled in the art as 'pro-residues' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985). A compound for use in the invention can also form active metabolites when administered to a patient, primarily by oxidative methods. Hydroxylation by enzymes of the liver is of particular interest. A compound for use in the invention that contains one or more asymmetric carbon atoms may exist in the form of two or more stereoisomers. When a compound contains an alkenyl or alkenylene group, the cis / trian geometric isomers (or TJE) are possible. When structural isomers are interconvertible by a low energy barrier, tautomeric isomerism ('tautomerism') can be produced. This can take the form of proton tautomerism in compounds containing, for example, an imino, keto, or oxime group, or also called valence tautomerism in compounds containing an aromatic moiety. From this it follows that an individual compound may exhibit more than one type of isomerism. The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. 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, high pressure liquid chromatography (HPLC). ) chiral. Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, in the case in which the compound contains an acid or basic moiety, an acid or base such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and one or both of the diastereomers can be converted to the corresponding enantiomer (s) by means well known to those skilled in the art. The chiral compounds of the invention (and chiral precursors thereof) can 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 between 0 and 50% isopropanol, typically between 2 and 20%, and between 0 and 5% of an alkylamine , typically 0.1% of diethylamine. The concentration of the eluate produces the enriched mixture. The stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994). A compound for use in the invention can be isotopically labeled in which 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 that predominates in nature. Examples of such isotopes include isotopes of hydrogen, such as 2H and 3H, carbon, such as 1 C, 13C and 14C, chloro, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen such such as 13N and 15N, oxygen such as 150, 170 and 180, phosphorus such as 32P and sulfur such as 35S. Certain isotopically-labeled compounds, for example, those that incorporate a radioactive isotope, are useful in distribution studies in drug tissues and / or substrates. The radioactive isotopes tritium, ie 3H, and carbon-14, ie 14C, are particularly useful for this purpose in view of their easy incorporation and easy means of detection.
Substitution with heavier isotopes such as deuterium, i.e. H, can produce certain therapeutic advantages that result from increased metabolic stability, for example, increased half-life in vivo or decreased dosing requirements, and therefore It can be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, may be useful in positron emission tomography (PET) studies to examine the occupation of substrate receptors. The pharmaceutically acceptable solvates include those in which the crystallization solvent can be isotopically substituted, for example D 0, d 6 -acetone, d 6 -DMSO. A compound for use in the invention can be administered in the form of a crystalline or amorphous product. It can be obtained, for example, in the form of an obturator, powder, or solid film by processes such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radiofrequency drying can be used for this purpose. A compound for use in the invention can be administered alone but more likely will be administered in the form of a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used in this specification to describe any ingredient other than the compound for use in the invention. The choice of excipient will depend to a large extent on factors such as particular mode of administration, the effect of the excipient on the solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the distribution of the compounds of the present invention and methods for the preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th edition (Mack Publishing Company, 1995). A compound for use in the invention can be administered orally. Oral administration which may involve ingestion may be employed, such that the compound enters the gastrointestinal tract, or buccal or sublingual administration whereby the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particles, liquids, or powders, dragees (including those loaded with liquid), chewing gums, multi and nanoparticles, gels, solid solution, liposome, films, ovules, sprays and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can 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 can also be prepared by reconstituting a solid, for example, from an envelope. A compound for use in the invention can also be used in rapidly dissolving, rapid disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen, (2001). For dosage forms of tablets, depending on the dose, the drug can reach up to between 1 and 80% by weight of the dosage form, more typically between 5% by weight and 60% by weight of the dosage form. In addition, the tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, methyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with lower alkyl, starch, pregelatinized starch and sodium alginate. In general, the disintegrant will comprise between 1% by weight and 25% by weight, preferably between 5 and 20% by 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, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diluents, such as lactose (monohydrate, monohydrate spray dried, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. The tablets may also optionally comprise surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactants may comprise between 0.2% by weight and 5% by weight of the tablet, and sliders can comprise between 0.2% and 1% by weight of the tablet. The tablets in general also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants in general comprise between 0.25% by weight and 10% by weight, preferably between 0.5% by weight and 3% by weight of the tablet. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents. Exemplary tablets contain up to about 80% of drug, between about 10% by weight and about 90% by weight of binder, between about 0% by weight and about 85% by weight of diluent, between about 2% by weight and about 10% by weight. % by weight of disintegrant, and between approximately 0.25% by weight and approximately 10% by weight of lubricant.
The tablet mixtures can be compressed directly or by a roller to form tablets. Mixtures of tablets or portions of mixtures may alternatively be granulated wet, dry, or in the molten state, coagulated in the molten state, or extruded prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; they can even be encapsulated. The formulations of the tablets are described in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N. Y., N. Y., 1980). Oral films consumable for human or veterinary use are typically thin-film, water-soluble or swellable flexible water-fast dispensing forms, or mucoadhesive, and typically comprise a compound for use in the invention, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifying agent and a solvent. Some components of the formulation can perform more than one function. A compound for use in the invention can be soluble or insoluble in water. A water-soluble compound typically comprises between 1% by weight and 80% by weight, more typically between 20% by weight and 50% by weight of the solutes. The less soluble compounds may comprise a greater proportion of the composition, typically up to 88% by weight of Iso solutes. Alternatively, a compound for use in the invention may be in the form of multiparticulate beads. The film-forming polymer can be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is typically present in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight. Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, antifoaming agents, surfactants and flavor masking agents. The films are typically prepared by evaporative drying of the thin aqueous films coated on a release backing support or paper. This can be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze drying or vacuum drying. Solid formulations for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. Modified release formulations suitable for the purposes of the invention are described in U.S. Patent No. 6,106,864. The details of other suitable release technologies such as high energy dispersions and coated and osmotic particles are found in Verma et al., Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). The use of chewing gums to achieve controlled release is described in WO 00/35298. A compound for use in the invention can also be administered directly into the blood stream, into the muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrathecal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle injectors (including microneedle, needleless injectors, and infusion techniques.) Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably up to a pH of 3 and 9), but, for some applications, they may be more adequately formulated as a sterile non-aqueous solution or as a dry 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 lyophilization, they can be easily carried out using conventional pharmaceutical techniques well known to those skilled in the art.The solubility of a compound used in the preparation of parenteral solutions can be increased by the use of suitable formulations, such as the incorporation of solubility enhancing agents. Formulations for use with needleless injection comprise a compound of the invention in powder form together with a suitable vehicle such as sterile, pyrogen-free water. Formulations for parenteral administration can be formulated to be immediate and / or controlled release. Controlled release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. Thus, a compound for use in the invention can be formulated as a solid, semi-solid or thixotropic liquid for administration as an implanted reservoir that provides modified release of the active compound. Examples of such formulations include drug coated extenders and poly (dl-lactic-coglycolic) acid microspheres (PGLA). A compound for use in the invention can also be administered topically to the skin or mucosa, specifically, dermal or transdermal. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusts, bandages, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J. Pharm. Sci., 88 (10), 955-958, by Finnin and Morgan (October 1999). The administration Topical can also be achieved using a patch, such as a transdermal iontophoretic patch. Other means of topical administration include electroporation distribution, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection (e.g., Powderject ™, Bioject ™, etc.). Formulations for topical administration can be formulated to be immediate and / or controlled release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. A compound for use in the invention may 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 mixture with lactose, or as a particle of mixed components, for example, mixing with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1,1,1,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurized container, pump, sprayer, atomizer, or nebulizer contains a solution or suspension of a compound for use in the invention comprising, for example, ethanol, aqueous ethanol, or an alternative agent suitable for dispersing, solubilizing or extending the release of the active ingredient, a propellant (s) as a solvent and an optional surfactant, such as sorbitan trioleate , oleic acid, or an oligoláctico acid. Before use in a dry powder or suspension formulation, the drug product is micronized to a suitable size to be distributed by inhalation (typically less than 5 microns). This can be achieved by any suitable grinding process, such as spiral injection grinding, fluid bed injection grinding, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. Capsules (made, for example, of gelatin or hydroxypropylmethylcellulose), blister packs and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-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 solution formulation suitable for use in an atomizer that uses electrohydrodynamics to produce a fine mist may contain between 1 μg and 20 mg of the compound of the invention per actuation and the actuation volume may vary between 1 μl and 100 μl. A typical formulation can comprising a compound of formula I, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin, or sodium saccharin, can be added to those formulations of the invention proposed for intranasal inhaled administration. Formulations for inhaled / intranasal administration can be formulated to be immediate release and / or modified using, for example, PGLA. Controlled release formulations include, delayed, sustained, pulsed, controlled, directed and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that distributes a measured quantity. The units according to the invention are typically arranged to administer a measured or "puffed" dose. The global daily dose will typically be administered in a single dose or, more usually, in the form of divided doses throughout the day. A compound for use in the invention can also 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.
Formulations for rectal / vaginal administration can be formulated for be of immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. A compound for use in the invention can also be administered directly to the eye or ear, typically in the form of droplets of a suspension or micronized 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 crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gellan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Said formulations can also be administered by iontophoresis. Formulations for ocular / and aural administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed or programmed release. A compound for use in the invention can be combined with soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polymers containing polyethylene glycol for improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the aforementioned modes of administration. For example, the drug-cyclodextrin complexes are found to be generally useful for most dosage forms and routes of administration. The complexes can be used, both inclusion and non-inclusion complexes. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. The most commonly used for these purposes are the alpha, beta and gamma cyclodextrins, examples of which can be found in International Patent Applications Nos. WO / 91/11172, WO 94/02518 and WO 98/55148. The two components of the present combination of the invention (ie, the 5-HT1B, 5-HT1D or 5-HT? F agonist and the alpha-2-delta ligand) can be administered simultaneously, sequentially or separately with in order to have the benefits of the combination therapy provided by the present invention. Each component can be administered by itself but is more usually administered in association with one or more excipients in the form of a uan of the pharmaceutical compositions described above. Usually, both components will be administered by the same route (for example, the oral route). However, there may be circumstances when it is preferable to administer each component by a different route (for example, a component through the oral route and a component through the parenteral route). For simultaneous administration, the two components preferably form part of the same pharmaceutical composition and are, therefore, administered by the same route. Oral administration is preferred for both components of the administration for. Most preferably, the two components are administered simultaneously by the oral route, for example in the form of a tablet. The two components of the present invention can be conveniently combined in the form of a kit. Such a kit comprises a 5-HT1B, 5-HT1D or 5-HT1 F agonist and an alpha-2-delta ligand, each usually in the form of one of the pharmaceutical compositions described above., and means for retaining them separately, such as a container, divided bottle, or package of divided sheets. An example of such a kit is the family 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 the separate compositions at different dosage intervals, or for evaluating the compositions separated from each other. To improve acceptance, the kit typically comprises instructions for administration and can be provided with a so-called reminder. For administration to human patients, the optimal total daily dose of the 5-HT ?B, 5-HT1D or 5-HT1 F agonist and the alpha-2-delta ligand administered according to the present invention will vary considerably according to the particular compounds chosen. Such optimal doses are readily determined by those skilled in the art in accordance with standard pharmaceutical practice using dose variation studies. As an example, in the case where the 5-HT? B, 5-HT.sub.1 D or 5-HT.sub.1 F agonist is eletriptan, the total daily dose is typically in the range of 20 mg to 80 mg. The administration of one or two doses of 40 mg is particularly preferred. In the case where the alpha-2-delta ligand is pregabalin, the total daily dose is usually between 150 and 600 mg, taken as two or three doses. The total daily dose of any component may be administered in single or divided doses and may, at the discretion of the physician, fall outside the typical ranges described above. To avoid any doubt, references to "treatment" include references to curative, palliative and prophylactic treatment. Some of the advantages of the combination provided by the present invention can be seen in preclinical models (especially preclinical models of migraine pathophysiology or central sensitization). Such models include: • The rat model for cutaneous allodynia induced by intracranial pain described by Burnstein 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 Status of America, 2003, 101 (12), 4274-9; • the rat model described by Bumstein and with in Journal of Neurophysiology, 1999, 81 (2), 479-93; and • the rat model described by Burnstein and with the Journal of Neurophysiology, 1998, 79 (2), 964-82. The advantages of the combination provided by the present invention will also be apparent from clinical efficacy measurements. In the case of migraine headache such advantages can be seen as improved efficacy (for example, the rate of migraine resolution) and as an improved safety profile (for example, in the reduction of adverse events). A combination of eletriptan and pregabalin has been tested in the migraine rat model developed by Burnstein and described in the references of the Journal of Neurophysiology 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"3 M, histamine, 10'3, prostaglandin E2, 10" 4 and bradykin 10'3) are applied in a combined preparation called inflammatory broth. The progress of the headache is controlled using the electrophysiology of a 2nd sensory neuron in the trigeminal caudal nucleus (TNC). In this model, once sensitization has been induced, it is not reversed by the actions of triptans (including eletriptan). Therefore this model reflects the clinical observation that after Since the symptoms of allodynia have developed during a migraine attack, triptans often do not alleviate all the pains of the patient. A control animal was treated with the inflammatory broth in the dura at time 0 and then with saline 3 hours later. This animal showed a strong sensitization of its responses to sensory stimuli such as brush and pin. Receiving 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 broth, the sensitization was stable and an increase in the magnitude of the response to the sensory stimuli was maintained. The animals treated with inflammatory broth in the dura followed by eletriptan at 3 hours showed a strong sensitization of their response at 2.5 hours to sensory stimuli such as brush and pin and the eletriptan did not reverse the sensitization even as much as 5.5 hours after the sensitization. This is in agreement with clinical studies of the effects of triptans on sensitization and allodynia in patients, who have shown that in approximately 80% of patients who experience allodynia during their migraine, triptans are much more effective if treatment is delayed until after sensitization manifests. The animals treated with inflammatory broth in the dura followed by pregabalin (30 mg / kg) at 3 hours showed sensitization of their responses at 2.5 hours to sensory stimuli such as brush and pin and pregabalin moderately reversed the sensitization in the moments 4.5 hours after 4.5 hours 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 and 4.5 hour moments. However, in animals treated with inflammatory broth over dura followed by a combination of pregabalin (30 mg / kg) and eletriptan (0.2 mg / kg) at 3 hours, the combination of drugs reversed the sensitization and the number of tips in response to the same sensory stimulus at 4.5 hours after sensitization was less than before the application of the broth. The data show, in a migraine rat model, that although triptans alone do not reverse the sensitization of trigeminal transmission neurons in the TCN, a combination of triptan eletriptan and the ligand alpha-2-delta pregabalin is effective. A combination of the present invention can 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 compound of the present invention, in its broadest sense or in any of the above preferred aspects, can be administered, simultaneously, sequentially or separately in combination with one or more agents selected from: • an opioid analgesic, for example , morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine; • a non-steroidal anti-inflammatory drug (NSAID), for example, 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, tolmentine or zomepirac; • a sedative barbiturate, for example, amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metarbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, teamilal or thiopental; • a benzodiazepine having sedative action, for example, chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam; • a Hi antagonist having a sedative action, for example, diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; • a sedative such as glutethimide, meprobamate, metaqualone or dichloralphenazone; • a skeletal muscle relaxant, for example, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orfrenadine; an NMDA receptor antagonist, for example, dextromethorphan ((+) - 3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+) - 3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4- (phosphonomethyl) -2- piperidinecarboxylic, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, for example, 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, for example, doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1, 2,3,4-tetrahydroisoquinol-2) -yl) -5- (2-pyridyl) quinazoline; • a tricyclic antidepressant, for example, desipramine, imipramine, amitriptyline or nortriptyline; • an anticonvulsant, for example, carbamazepine, lamotrigine, topiratmate or valproate; • a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, for example, (Ar, 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-tñazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3 - [[2-methoxy-5- (trifluoromethoxy) phenyl] methylamino] -2 -phenylpipehdine (2S.3S); • a muscarinic antagonist, for example, oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverina and ipratropium; • a selective COX-2 inhibitor, eg, celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; • an analgesic of coal tar, in particular paracetamol; • a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine , lurasidone, amisulpride, balaperidone, palindora, eplivanserin, osanetant, ñmonabant, meclinertant, Miraxion ® or sarizotan; "An agonist (e.g., resinferatoxin) or antagonist (e.g., capsazepine) of a vanilloid receptor; • an adrenergic beta such as propranolol; • a local anesthetic such as mexiletine; • a corticosteroid such as dexamethasone; • a 5-HT2A receptor antagonist such as R (+) - alpha- (2,3-dimethoxyphenyl) -1 - [2- (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 ®; • a PDEV inhibitor, such as 5- [2-ethoxy-5- (4-methyl-1-piperazinyl-sulfonyl) 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- ethylpiperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7- propyl-3H-imiadzo [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-d] pyrimidin-7-one, 5- ( 5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, - [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) 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-6J-dihydro-1 H -pyrazolo [4,3-d] pyrimidin-5-yl) -N- [2- (1 - methylpyrrolidin-2-yl) ethyl] -4-propoxybenzenesulfonamide; • a cannabinoid; • a metabotropic glutamate subtype 1 receptor antagonist (mGluRI); «A serotonin reuptake inhibitor such as sertraline, sertraline metabolite desmethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, metabolite of citalopram, desmethylcitalopram, escitalopram, d, l-fenfluramine, femoxetine, ifoxetine, cyanodotiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone; • a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramin, mirtazepine, oxaprotiline, phezolamine, tomoxetine, mianserin, buproprion, bupropion metabolite hydroxybuproprion, nomifensin and viloxazine (Vivalan ®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S.S) -reboxetine; • a dual inhibitor of serotonin reuptake -noradrenaline such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran, and imipramine; • inducible nitric oxide synthase (NOS) 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, 2- [[(1 R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -5-chloro-3-pyridinecarbonitrile; 2 - [[(1 R, 3 S) -3-amino-4-hydroxy-1 - (5-thiazolyl) butyl] thio] -4-chlorobenzonitim, (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-piñdincarbonitrile, 2 - [[(1 R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -5-chlorobenzonitrile, N- [4- [2 - (3-chlorobenzylamino) ethyl] phenyl] thiophene-2-carboxamidine, or guanidinoethyldisulfide; • an acetylcholinesterase inhibitor such as donepezil; • an antagonist of subtype 4 of prostaglandin E2 (EP4) such as N- [(. {2- [4- (2-ethyl-4,6-dimethyl-1 H-imidazo [4,5-c] pyridine- 1-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-) acid ilmethyl-4-hydroxy-chroman-7-yl) cyclopentanecarboxylic acid (CP-105696), 5- [2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl) -5E-hexenyl] oxyphenoxy] valéñco acid ( ONO-4057) or DPC-11870, • an inhibitor of 5-lipoxygenase, such as zileuton, 6 - [(3-fluoro-5- [4-methoxy-3,4,5,6-tetrahydro-2H-pyran -4-yl]) phenoxymethyl] -1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6- (3-pyridylmethyl) -1, 4-benzoquinone (CV-6504); • a sodium channel blocker, such as lidocaine; • a 5-HT3 antagonist, such as ondansetron; and the pharmaceutically acceptable salts and solvates thereof.

Claims (12)

NOVELTY OF THE INVENTION CLAIMS
1. - A combination of a 5-HT1B, 5-HT? D or 5-HT1F agonist and an alpha-2-delta ligand.
2. The combination according to claim 1, further characterized in that the 5-HT1B, 5-HT1D or 5-HT1 F agonist is a 5-HT1 B /? D agonist.
3. The combination according to claim 2, further characterized in that the 5-HT? B / 1 D agonist is a triptan antimigraine drug.
4. The combination according to claim 3, further characterized in that the antimigraine drug triptan is eletriptan, or a pharmaceutically acceptable salt or solvate thereof.
5. The combination according to any of claims 1 to 4, further characterized in that the alpha-2-delta ligand is pregabalin, or a pharmaceutically acceptable salt or solvate thereof.
6. The combination according to any of claims 1 to 5 for use as a medicine.
7. A pharmaceutical composition comprising a combination according to any of claims 1 to 5 and a pharmaceutically acceptable excipient, diluent or carrier.
8. - The use of a 5-HT? B, 5-HT? D or 5-HT? F agonist and an alpha-2-delta ligand in the manufacture of a medicament useful in the treatment of pain, wherein said agonist 5-HT1B, 5-HT1D or 5-HT? F and said alpha-2-delta ligand are adapted to be administrable simultaneously, sequentially or separately.
9. The use claimed in claim 8, wherein the pain is migraine pain.
10. The use claimed in claim 8, wherein the 5-HT1B, 5-HT1 D or 5-HT? F agonist is eletriptan or a pharmaceutically acceptable salt or solvate thereof.
11. The use claimed in claim 8, wherein the alpha-2-delta ligand is pregabalin or a pharmaceutically acceptable salt or solvate thereof.
12. A kit comprising a 5-HT1B, 5-HTID or 5-HT? F receptor agonist, an alpha-2-delta ligand and means for containing said compounds.
MX2007002790A 2004-09-07 2005-08-27 Combination of a 5-ht(1) receptor agonist and an alpha-2-delta ligand for the treatment of migraine. MX2007002790A (en)

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