Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-11-01
2003-02-18
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S204000, C514S616000, C514S627000
Reexamination Certificate
active
06521790
ABSTRACT:
TECHNICAL FIELD
The present invention relates to alkynyl amides, to the use of these compounds to treat seizures, migraine, and psychiatric disorders, and to the preparation of these compounds.
BACKGROUND OF THE INVENTION
Epilepsy affects roughly 1% of the world's population. Among the drugs employed for control of epileptic seizures is valproic acid. Valproic acid (also referred to as VPA, valproate, di-n-propylacetic acid, DPA, 2-propylvaleric acid or 2-propylpentanoic acid) is an effective anticonvulsant.
Migraine is defined as a periodically occurring vascular headache characterized by pain in the head (usually unilateral), nausea and vomiting, photophobia, phonophobia, vertigo and general weakness. Migraine is the most common type of vascular headache and affects as much as 15% of the world's population. Of the different types of migraines, classical migraine and common migraine are the two most prevalent. The major difference between the two types of migraines is that classical migraines are preceded by the appearance of neurological symptoms before an attack whereas common migraines are not preceded by such symptoms. Migraine is caused by intermittent brain dysfunction. However, the precise pathophysiological mechanisms involved are not understood. The head pain is believed to involve blood vessel dilation.
Analgesics are often used to treat infrequent and mild migraines. Analgesics reduce the pain of a migraine and, in the case of aspirin, also discourage platelet aggregation. However, for moderate to severe migraines, stronger medications such as ergotamine and valproic acid are often necessary. Ergotamine tartrate is a vasoconstrictor which counteracts the painful dilation stage of the headache. When taken during the early stages of an attack, ergotamine tartrate helps to relieve the classic and common migraine symptoms. Valproic acid has been shown to be effective in prevention of migraine, however, its mechanism of anti-migraine action is unclear. It is believed that valproic acid increases brain gamma-aminobutyric acid (GABA) levels and in doing so may activate the GABA receptor and suppresses migraine-related events.
A number of psychiatric disorders may be treated with valproic acid, see: Loscher W., ed. Valproate, Basel Switzerland: Birkhauser Verlag, 1999; Post R. M., In Tasman A., Goldfinger, S. M., Kaufmann, C. A., eds. Review of psychiatry, volume 9, Washington D.C.: American Psychiatric Press, 1990, 170-202; and Jensen R., Brinck T., Olesen J., Neurology 44, 1994, 647. Such psychiatric disorders include: i) Mood Disorders; ii) Anxiety Disorders; iii) Attention-Deficit and Disruptive Behavior Disorders; iv) Behavioral Disturbances associated with dementia; v) Behavioral Disturbances associated with autism; vi) Schizophrenia; vii) Impulse Control Disorders; viii) Personality Disorders; and ix) Substance-related Disorders.
Mood Disorders include, but are not limited to, Depressive Disorders and Bipolar Disorders such as Manic episodes and Mixed episodes. Symptoms associated with Mood Disorders include, but are not limited to, depression, elevated, expansive or irritable mood, insomnia/hypersomnia, agitation and distractability or impulsivity.
Anxiety Disorders include, but are not limited to, Panic Disorder, Posttraumatic Stress Disorder and Generalized Anxiety Disorder. Symptoms associated with Anxiety Disorders include, but are not limited to, anxious mood, panic attacks, irritability, outbursts of anger and exaggerated startle response.
Attention-Deficit and Disruptive Behavior Disorders include, but are not limited to, Attention-Deficit/Hyperactivity Disorder Hyperactive-Impulsive Type, Conduct Disorder, Oppositional Defiant Disorder and Disruptive Behavior Disorder. Symptoms associated with Attention-Deficit and Disruptive Behavior Disorders include, but are not limited to, impulsivity, aggression, anger and loss of temper.
Symptoms associated with Behavioral Disturbances for both dementia and autism include, but are not limited to, verbal and physical agitation and aggression.
Symptoms associated with Substance-related Disorders, include but are not limited to, withdrawal and dependence.
Symptoms associated with schizophrenia, include but are not limited to, positive symptoms, negative symptoms and agitation.
Impulse Control Disorders include, but are not limited to, Intermittent Explosive Disorder. Symptoms associated with Impulse Control Disorders, include but are not limited to, verbal or physical aggressive impulses.
Personality Disorders include, but are not limited to, Borderline Personality Disorder. Symptoms associated with Personality Disorders, include but are not limited to, mood lability, irritability, agitation and aggression.
The symptoms listed for these psychiatric disorders are not an exhaustive description of the diagnostic category or disorder, but merely reflect some of the symptoms that may improve when treated with valproic acid. For Example, valproic acid may be used to treat general agitation or aggression not necessarily associated with any particular psychiatric-disorder.
Further, excitatory neurotransmitters such as glutamate and aspartate, as well as a variety of voltage-gated ion channels, are thought to play a central role in mediating cell death after a variety of cerebral insults including, but not limited to, ischemia, trauma, seizure and hypoglycemia. Many studies have shown that compounds or therapeutic strategies that decrease excitatory neurotransmission, for example, glutamate antagonists, ion channel blockers, anticonvulsants, and the like, elicit a neuroprotective effect in animal models of cerebral insults.
Recently, VPA has been shown to increase the levels of the neuroprotective protein B cell lymphoma protein-2 (bcl-2) in frontal cortex, findings that may have implications for the long-term treatment of various neurodegenerative disorders (Chen G., et al, Journal of Neurochemistry, 1999, 879-882).
Neuropathic pain affects a significant number of patients suffering from disorders of the brain or spinal cord, such as stroke, trauma, multiple sclerosis, and diabetes. Several known anticonvulsant compounds are efficacious in various analgesia models relevant to identifying therapeutic candidates for treating neuropathic pain (Lloyd and Morselli, in Psychopharmacology: The Third Generation of Progress, Raven Press, 1987). The use of anticonvulsants like valproate to treat various pain states has been documented extensively (Swendlow, J. Clin. Neuropharmacol., 7, 1984, 51-82).
Restlessness syndrome denotes a somatic (non-mental) restlessness characterized by involuntary movement of the limbs, as well as by a sense of physical (rather than mental) agitation, which is independent of mood and, hence, is distinguished from restlessness per se, see (Sachdev et al., Austral. New Zealand J. Psychiatry 30, 1996, 38-53.
The genus of restlessness syndromes, inclusive of numerous indications, can be observed in association with many organic and non-organic psychiatric illnesses. For example, drug-induced restlessness (tardive, chronic, and withdrawal akathisias), such as drug-induced extrapyramidal symptoms, is one of the most common side effects of neuroleptic, drug therapy. Also within the restlessness syndrome rubric are the so-called “restless leg syndrome” and “sleep-related periodic leg movements,” pathologies that can be associated with head and/or spinal cord trauma and with lesions of the spinal cord. Idiopathic restless leg syndrome follows an autosomal dominant inheritance, with a variable clinical expression of symptoms.
Diminished GABAergic neurotransmission is implicated in the neurochemical basis of restlessness syndromes. Consistent with this notion, for instance, is the efficacy of drugs such as baclofen, valproate, gabapentin and the benzodiazepines, in the treatment of restless leg syndrome, an important indication, see (O'Keefe, Arch. Intem. Med. 156, 1996, 24348; Danek et al., in Neurological Disorders: Course and Treatment, pages 819-23, Academic Press, 1996; and Mellick and Mellick, Neuro
Kumar Shailendra
Yasger Paul D.
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