WO2008097924A2 - Compositions pharmaceutiques comprenant des analogues du dextrométhorphane pour le traitement de troubles neurologiques - Google Patents

Compositions pharmaceutiques comprenant des analogues du dextrométhorphane pour le traitement de troubles neurologiques Download PDF

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WO2008097924A2
WO2008097924A2 PCT/US2008/052949 US2008052949W WO2008097924A2 WO 2008097924 A2 WO2008097924 A2 WO 2008097924A2 US 2008052949 W US2008052949 W US 2008052949W WO 2008097924 A2 WO2008097924 A2 WO 2008097924A2
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compound
pain
disease
group
injury
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WO2008097924A3 (fr
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Jagadish Sircar
Kc Sunil Kumar
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Avanir Pharmaceuticals
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • compositions and methods for treating neurological disorders are provided.
  • the compositions comprise dextromethorphan analogs.
  • Dementia is a neurological disease that results in loss of mental capacity and is associated with widespread reduction in the number of nerve cells and brain tissue shrinkage.
  • Memory is the mental capacity most often affected by dementia.
  • the memory loss may first manifest itself in simple absentmindedness, a tendency to forget or misplace things, or to repeat oneself in conversation. As the dementia progresses, the loss of memory broadens in scope until the patient can no longer remember basic social and survival skills and function independently. Dementia can also result in a decline in the patient's language skills, spatial or temporal orientation, judgment, or other cognitive capacities. Dementia tends to run an insidious and progressive course.
  • AD Alzheimer's disease
  • brain a degenerative brain disorder presented clinically by progressive loss of memory, cognition, reasoning, judgment, and emotional stability that gradually leads to profound mental deterioration and ultimately death.
  • Individuals with AD exhibit characteristic beta amyloid deposits in the brain (beta amyloid plaques) and in cerebral blood vessels (beta amyloid angiopathy) as well as neurofibrillary tangles.
  • beta amyloid plaques in the brain
  • brain blood vessels beta amyloid angiopathy
  • neurofibrillary tangles On autopsy of AD patients, large numbers of these lesions, which are believed to be a causative precursor or factor in the development of disease, are generally found in areas of the human brain important for memory and cognitive function. Smaller numbers are found in the brains of most aged humans not showing clinical symptoms of AD.
  • Beta amyloid plaques and beta amyloid angiopathy also characterize the brains of individuals with Down's syndrome (Trisomy 21) and Hereditary Cerebral Hemorrhage with Beta amyloidosis of the Dutch-Type, and other such disorders.
  • Vascular Dementia is defined as the loss of cognitive function resulting from ischemic, ischemic-hypoxic, or hemorrhagic brain lesions as a result of cardiovascular diseases and cardiovascular pathologic changes.
  • VaD is a chronic disorder and the symptoms of VaD include cognitive loss, headaches, insomnia and memory loss.
  • VaD may be caused by multiple strokes (MID or post-stroke dementia) but also by single strategic strokes, multiple lacunes, and hypoperfusive lesions such as border zone infarcts and ischemic periventricular leukoencephalopathy (Binswanger's disease).
  • IEED Involuntary Emotional Expression Disorder
  • emotional lability and pseudobulbar affect are used by psychiatrists and neurologists to refer to a set of symptoms that are often observed in patients who have suffered a brain insult such as a head injury, stroke, brain tumor, or encephalitis, or who are suffering from a progressive neurodegenerative disease such as Amyotrophic Lateral Sclerosis (ALS, also called motor neuron disease or Lou Gehrig's disease), Parkinson's disease, Alzheimer's disease, or multiple sclerosis (MS).
  • ALS Amyotrophic Lateral Sclerosis
  • MS multiple sclerosis
  • emotional lability occurs in patients who have bilateral damage (damage which affects both hemispheres of the brain) involving subcortical forebrain structures.
  • IEED is distinct from clinical forms of reactive or endogenous depression, and is characterized by intermittent spasmodic outbursts of emotion, such as anger, or expressions of irritability or frustration at inappropriate times or in the absence of any particular provocation.
  • the feelings that accompany emotional lability are often described in words such as "disconnectedness," since patients are fully aware that an outburst is not appropriate in a particular situation, but they do not have control over their emotional displays.
  • IEED is also referred to by the terms emotionalism, emotional incontinence, emotional discontrol, excessive emotionalism, and pathological laughing and crying.
  • Emotional lability or pseudobulbar affect becomes a clinical problem when the inability to control emotional outbursts interferes in a substantial way with the ability to engage in family, personal, or business affairs.
  • a businessman suffering from early-stage ALS or Parkinson's disease might become unable to sit through business meetings, or a patient might become unable to go out in public, such as to a restaurant or movie, due to transient but intense inability to keep from crying or laughing at inappropriate times in front of other people.
  • These symptoms can occur even though the patient still has more than enough energy and stamina to do the physical tasks necessary to interact with other people.
  • Depression is defined by a constellation of chronic symptoms that include sleep problems, appetite problems, anhedonia or lack of energy, feelings of worthlessness or hopelessness, difficulty concentrating, suicidal thoughts, mood swings (feelings of sadness, abandonment, humiliation, devaluing), psychomotor inhibition (fatigue, daily powerlessness, difficulty in concentration), manifest anxiety (often in the foreground), and quasi-constant somatic difficulties (oppression, spasms, disturbed sleep, loss of appetite, sexual dysfunction).
  • Bipolar Disorder involves major depressive episodes alternating with high- energy periods of rash behavior, poor judgment, and grand delusions. An estimated one percent of the American population experiences Bipolar Disorder annually.
  • TCA Tricyclic antidepressants
  • IMAO monoamine oxydase
  • phenelzine hydrozine
  • pargyline class of acetylenics
  • iproniazude Marsilid
  • SSRIs Selective serotonin reuptake inhibitors
  • SSRIs have become first choice therapeutics in the treatment of depression, certain forms of anxiety and social phobias, because they are effective, well tolerated and have a favorable safety profile compared to the classic tricyclic antidepressants. Since the introduction of SSRIs, many patients have been effectively treated with anti-depressant medication. However, clinical studies on depression and anxiety disorders indicate that non-response to SSRIs is substantial, up to 30%. Another, often neglected, factor in antidepressant treatment is compliance, which has a rather profound effect on the patient's motivation to continue pharmacotherapy. First of all, there is the delay in therapeutic effect of SSRIs.
  • the serotoninergic syndrome often misunderstood, is associated with certain overdoses or interactions and justifies an immediate halt to treatment. It can cause hospitalization, and in exceptional circumstances the involvement of vital prognosis. It links a set of symptoms of digestive order (diarrhea), vegetative: (sweating, thermal deregulation, hypo- or hypertension), motor (myoclonia, trembling), neuropsychic (confusion, agitation, even coma). New medications to treat depression are introduced almost every year, and research in this area is ongoing.
  • Anxiety is an emotional condition characterized by feelings such as apprehension and fear accompanied by physical symptoms such as tachycardia, increased respiration, sweating and tremor. It is a normal emotion but when it is severe and disabling it becomes pathological.
  • Anxiety disorders are generally treated using benzodiazepine sedative- antianxiety agents.
  • Potent benzodiazepines are effective in panic disorder as well as in generalized anxiety disorder, however, the risks associated with the drug dependency may limit their long-term use, 5-H1A receptor partial agonists also have useful anxiolytic and other pyschotropic activity, and less likelihood of sedation and dependence.
  • a method of treating emotional lability, pseudobulbar affect, and other conditions in human patients who are in need of such treatment, without oversedation or otherwise significantly interfering with consciousness or alertness is provided.
  • the treatment involves administering dextromethorphan analogs to a patient in need thereof.
  • dextromethorphan analogs in the treatment of emotional lability, pseudobulbar affect and other conditions are advantageous in that the metabolism to dextrorphan can be prevented or greatly reduced.
  • a method of treating dementia, Alzheimer's disease, emotional lability, pseudobulbar affect, and other chronic conditions in human patients who are in need of such treatment, without oversedation or otherwise significantly interfering with consciousness or alertness is provided.
  • the treatment involves administering a dextromethorphan analog.
  • Methods of treatment of depression and/or anxiety that can provide one or more of these benefits involve administering dextromethorphan analogs.
  • the methods and compositions of the preferred embodiments are also useful for treating social anxiety disorder, posttraumatic stress disorder (PTSD), panic disorder, eating disorders (anorexia, bulimia), obsessive-compulsive disorder (OCD), and premenstrual dysphoric disorder (PMDD).
  • PTSD posttraumatic stress disorder
  • panic disorder anxiety disorders
  • eating disorders anorexia, bulimia
  • OCD obsessive-compulsive disorder
  • PMDD premenstrual dysphoric disorder
  • IEED involuntary emotional expression disorder
  • pseudobulbar affect or emotional lability also known as pseudobulbar affect or emotional lability
  • neuropathic pain comprising administering to a patient in need thereof a compound of Formula (I):
  • each Ri is independently selected from the group consisting Of C 1 -C 1 O alkyl, C 2 -CJ O alkenyl, C 2 -C 10 alkynyl, C 6 -C] 2 aryl, C 7 -C] 3 arylalkyl, C 3 -CiO cycloalkyl, C 2 -CiO heterocycle, C 3 -C] 0 heterocyclealkyl, C 3 -Ci 2 heteroaryl, C 4 -Ci 2 heteroarylalkyl, alkylamino and dialkylamino, wherein each hydrogen is optionally substituted with a lower alkyl, an alkoxy or a halogen.
  • the compound has the formula:
  • the compound has the formula:
  • the method can further comprise administering a compound to treat pain.
  • Suitable compounds include but are not limited to amitriptyline, proptriptyline, imipramine, desipramine, doxepin, nortriptyline, trimipramine, amoxapine, clomipramine, fluoxetine, paroxetine, venlafaxine, sertraline, escitalopram and citalopram and fluvoxamine.
  • the method can further comprise administering an antipsychotic compound.
  • Suitable compounds include but are not limited to clozapine, olanzapine, respiradone, quetiapine, aiprasidone and aripiprazole.
  • the method can further comprise administering a compound to treat neuropathic pain.
  • Suitable compounds include but are not limited to carbamazepine, gabapentin, pregabalin, duloxetine, lidocaine, tiagabine, lamotrigine, levetiracetam, oxcarbazepine, topiramte and zonisamide.
  • IEED involuntary emotional expression disorder
  • pseudobulbar affect or emotional lability also known as pseudobulbar affect or emotional lability
  • neuropathic pain comprising administering to a patient in need thereof a compound of Formula (II):
  • Ri is selected from the group consisting of hydrogen, Ci-Ci 0 alkyl, C 2 -Ci 0 alkenyl, C 2 -Ci 0 alkynyl, C 6 -Ci 2 aryl, C 7 -C] 3 arylalkyl, Cs-C] 0 cycloalkyl, C 2 -Cj 0 heterocycle, C 3 -C 10 heterocyclealkyl, C 3 - Ci 2 heteroaryl, C 4 -Cj 2 heteroarylalkyl, alkylamino and dialkylamino, wherein each hydrogen is optionally substituted with a lower alkyl, an alkoxy or a halogen; and R 2 is selected from the group consisting C 2 -C] 0 alkyl, C 2 -Ci 0 alkenyl, C 2 -Ci 0 alkynyl, C 6 -Cj 2 aryl, C7-C
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is [0030] In another aspect of the second embodiment, wherein the compound is
  • the method can further comprise administering a compound to treat pain.
  • Suitable compounds include but are not limited to amitriptyline, proptriptyline, imipramine, desipramine, doxepin, nortriptyline, trimipramine, amoxapine, clomipramine, fluoxetine, paroxetine, venlafaxine, sertraline, escitalopram and citalopram and fluvoxamine.
  • the method can further comprise administering an antipsychotic compound.
  • Suitable compounds include but are not limited to clozapine, olanzapine, respiradone, quetiapine, aiprasidone and aripiprazole.
  • the method can further comprise administering a compound to treat neuropathic pain.
  • Suitable compounds include but are not limited to carbamazepine, gabapentin, pregabalin, duloxetine, lidocaine, tiagabine, lamotrigine, levetiracetam, oxcarbazepine, topiramte and zonisamide.
  • IEED involuntary emotional expression disorder
  • pseudobulbar affect or emotional lability also known as pseudobulbar affect or emotional lability
  • neuropathic pain comprising administering to a patient in need thereof a compound of Formula (III):
  • each R] is independently selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 2 -Ci 0 alkenyl, C 2 -Ci O alkynyl, C 6 -C) 2 aryl, C7-Q3 arylalkyl, C 3 -Ci O cycloalkyl, C 2 -C 10 heterocycle, C3-C 10 heterocyclealkyl, C3-C12 heteroaryl, C4-C 1 2 heteroarylalkyl, alkylamino and dialkylamino, wherein each hydrogen is optionally substituted with a lower alkyl, an alkoxy or a halogen; and R 2 is selected from the group consisting of -SR],
  • the compound is:
  • the compound is:
  • the compound is:
  • the method can further comprise administering a compound to treat pain.
  • Suitable compounds include but are not limited to amitriptyline, proptriptyline, imipramine, desipramine, doxepin, nortriptyline, trimipramine, amoxapine, clomipramine, fluoxetine, paroxetine, venlafaxine, sertraline, escitalopram and citalopram and fluvoxamine.
  • the method can further comprise administering an antipsychotic compound.
  • Suitable compounds include but are not limited to clozapine, olanzapine, respiradone, quetiapine, aiprasidone and aripiprazole.
  • the method can further comprise administering a compound to treat neuropathic pain.
  • Suitable compounds include but are not limited to carbamazepine, gabapentin, pregabalin, duloxetine, lidocaine, tiagabine, lamotrigine, levetiracetam, oxcarbazepine, topiramte and zonisamide.
  • a compound of the Formula (I): or a stereoisomer or pharmaceutically acceptable salt thereof wherein each Rj is independently selected from the group consisting of Ci-Ci o alkyl, C 2 -CiO alkenyl, C 2 -CiO alkynyl, C 6 -C 12 aryl, C 7 -Ci 3 arylalkyl, C 3 -Ci O cycloalkyl, C 2 -Ci O heterocycle, C 3 -Ci O heterocyclealkyl, C 3 -C] 2 heteroaryl, C 4 -Ci 2 heteroarylalkyl, alkylamino and dialkylamino, wherein each hydrogen is optionally substituted with a lower alkyl, an alkoxy or a halogen.
  • the compound has the formula:
  • the compound has the formula:
  • a compound of the Formula (II): or a stereoisomer or pharmaceutically acceptable salt thereof wherein: Ri is selected from the group consisting of hydrogen, Ci-Qo alkyl, C 2 -Ci O alkenyl, C 2 -Ci O alkynyl, C(,- C]2 aryl, C 7 -Ci 3 arylalkyl, C3-C10 cycloalkyl, C2-C10 heterocycle, C 3 -CiO heterocyclealkyl, C 3 -Cj 2 heteroaryl, C 4 -C 12 heteroarylalkyl, alkylamino and dialkylamino, wherein each hydrogen is optionally substituted with a lower alkyl, an alkoxy or a halogen; and R 2 is selected from the group consisting C 3 linear alkyl, C 4 -C 10 linear or branched alkyl, C 2 -Ci O alkenyl, C2-C10 alkyny
  • the compound is:
  • the compound is: [0048] In another aspect of the fifth embodiment, the compound is:
  • each Ri is independently selected from the group consisting of hydrogen, C 1 -Ci O alkyl, C 2 -Ci O alkenyl, C 2 -CiO alkynyl, C 6 -Ci 2 aryl, C 7 -C] 3 arylalkyl, C 3 -C) O cycloalkyl, C 2 -Ci O heterocycle, C 3 -Cj O heterocyclealkyl, C 3 -Ci 2 heteroaryl, C 4 -Cj 2 heteroarylalkyl, alkylamino and dialkylamino, wherein each hydrogen is optionally substituted with a lower alkyl, an alkoxy or a halogen; and R 2 is selected from the group consisting of -SRi,
  • the compound is:
  • the compound is:
  • the compound is:
  • kits comprising at least one unit dosage form of the compound of Formula (I) and directions for administering the unit dosage form to treat pseudobulbar affect of emotional liability.
  • kits comprising at least one unit dosage form of the compound of Formula (II) and directions for administering the unit dosage form to treat pseudobulbar affect of emotional liability.
  • a pharmaceutical kit comprising at least one unit dosage form of the compound of Formula (III) and directions for administering the unit dosage form to treat pseudobulbar affect of emotional liability.
  • a method of treating a disorder, disease, or condition or imparting a therapeutic effect by administering a compound of Formula (I), (II), or (III) in combination with a compound selected from the group consisting of an anti-dementia agent, an anti-inflammatory agent, an anti-infective agent, an anesthetic compound, an agent for treating neuropathic pain, an antitussive, an expectorant, an agent for treating Parkinson's disease and an agent for treating Alzheimer's disease.
  • Emotional lability or pseudobulbar affect is associated with a number of neurological diseases, such as stroke (House et al., BMJ, 1989; 298:991-4), multiple sclerosis (MS) (Cotrell et al., J. Neurol. Psychopathol., 1926; 7:1-30; Feinstein et al., Arch. Neurol, 1997; 54:1116-21), amyotrophic lateral sclerosis (ALS) (Miller et al., Neurol., 1999; 52:1311-23; Jackson et al., Semin. Neurol. 1998; 18:27-39; Poeck, K., Pathophysiology of emotional disorders associated with brain damage.
  • stroke House et al., BMJ, 1989; 298:991-4
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • PJ Vinken
  • Emotional lability or pseudobulbar affect in the context of neurological injury can be considered a disconnection syndrome resulting from loss of cortical communication with the brainstem or cerebellum (Wilson S.A.K., J. Neurol. Psychopathol., 1924; IV:299-333; Parvivzi et al., Brain, 2001;124:1708-19).
  • disruptions of ascending and descending serotonergic pathways arising in the brainstem, and dysregulation of dopaminergic projections to the striatum and cortex have been implicated (Andersen et al., Stroke, 1994; 25:1050-2; Ross et al., J. Nerv. Ment. Dis., 1987; 175:165-72; Shaw et al., Brain Sciences in Psychiatry, London: Butterworth, 1982; Udaka et al., Arch. Neurol. 1984;41 :1095-6).
  • ALS is a neurodegenerative disease produced by progressive loss of upper and lower motor neurons. Up to 50 percent of patients with ALS exhibit emotional lability, and it is more prevalent in those with the bulbar form of ALS (Gallagher JP, Acta Neurol. Scand., 1989; 80: 114-7).
  • a number of chronic disorders other than emotional lability also have symptoms which are known to be very difficult to treat, and often fail to respond to safe, non-addictive, and non-steroid medications.
  • Disorders such as intractable coughing fail to respond to conventional medicines and are typically treated by such drugs as codeine, morphine, or the anti-inflammatory steroid prednisone. These drugs are unacceptable for long-term treatment due to dangerous side effects, long-term risks to the patient's health, or the danger of addiction.
  • Neuropathic pain includes, for example, diabetic neuropathy, postherpetic neuralgia, phantom limb pain, trigeminal neuralgia, and sciatica.
  • Postherpetic neuralgia is a complication of shingles and occurs in approximately ten percent of patients with herpes zoster. The incidence of PHN increases with age.
  • Diabetic neuropathy is a common complication of diabetes which increases with the duration of the disease.
  • the pain for these types of neuropathies has been described as a burning steady pain often punctuated with stabbing pains, pins and needles pain, and toothache-like pain.
  • the skin can be sensitive with dysesthetic sensations to even light touch and clothing.
  • the pain can be exacerbated by activity, temperature change, and emotional upset.
  • the pain can be so severe as to preclude daily activities or result in sleep disturbance or anorexia.
  • the mechanisms involved in producing pain of these types are not well understood, but may involve degeneration of myelinated nerve fibers. It is known that in diabetic neuropathy, both small and large nerve fibers deteriorate resulting in reduced thresholds for tolerance of thermal sensitivity, pain, and vibration. Dysfunction of both large and small fiber functions is more severe in the lower limbs when pain develops. Most of the physiological measurements of nerves that can be routinely done in patients experiencing neuropathic pain demonstrate a slowing of nerve conduction over time. To date, treatment for neuropathic pain has been less than universally successful. Chronic pain is
  • Tinnitus is a syndrome characterized by a high pitched ringing in the ears. Tinnitus can be intermittent or constant with single or multiple tones and the perceived volume can range from subtle to shattering. Of the 50 million individuals who experience tinnitus to some degree, about two million are seriously debilitated to the point they cannot function normally on a day- to-day basis.
  • Affective lability is characterized by unstable, rapidly changing emotions within a very short period of time, and without appropriate external reasons. Affective lability is most common among individuals with borderline personality disorders, attention deficit/hyperactivity disorder and women with premenstrual dysphoric disorder. However, longer periods of symptoms of affective lability are typical for organic brain disorders and severe psychiatric disorders such as schizophrenia.
  • Symptoms associated with depression and anxiety can also be treated by the compounds of preferred embodiments.
  • Dextromethorphan is widely used as a cough syrup, and it has been shown to be sufficiently safe in humans to allow its use as an over-the-counter medicine. It is well tolerated in oral dosage form, either alone or with quinidine, at up to 120 milligrams (mg) per day, and a beneficial effect may be observed when receiving a substantially smaller dose (e.g., 30 mg/day) (U.S. 5,206,248 to Smith).
  • An increasing body of evidence indicates dextromethorphan has therapeutic potential for treating several neuronal disorders (Zhang et al., Clin. Pharmacol. Ther. 1992; 51 : 647-655; Palmer GC, Curr. Drug Targets, 2001 ; 2: 241-271 ; and Liu et al, J. Pharmacol. Exp. Ther. 2003; 21 : 21 ; Kim et al., Life Sci., 2003; 72: 769-783).
  • Dextromethorphan is the common name for (+)-3-methoxy-N- methylmorphinan. It is one of a class of molecules that are dextrorotatory analogs of morphine-like opioids.
  • opioid refers to drugs that are derived from opium, such as morphine and codeine.
  • opioid is broader. It includes opiates, as well as other drugs, natural or synthetic, which act as analgesics and sedatives in mammals.
  • the carbon atoms are conventionally numbered as shown, and the wedge-shaped bonds coupled to carbon atoms 9 and 13 indicate that those bonds rise out of the plane of the three other rings in the morphinan structure.
  • Many analogs of this basic structure are pentacyclic compounds that have an additional ring formed by a bridging atom (such as oxygen) between the number 4 and 5 carbon atoms.
  • dextrorotatory analogs of morphine are much less addictive than the levorotatory compounds.
  • Some of these dextrorotatory analogs, including dextromethorphan and dextrorphan, are enantiomers of the morphinan structure. In these enantiomers, the ring that extends out from carbon atoms 9 and 13 is oriented in the opposite direction from that depicted in the above structure.
  • dextromethorphan is known to have at least three distinct receptor activities which affect central nervous system (CNS) neurons. First, it acts as an antagonist at N-methyl-D- aspartate (NMDA) receptors. NMDA receptors are one of three major types of excitatory amino acid (EAA) receptors in CNS neurons. Since activation of NMDA receptors causes neurons to release excitatory neurotransmitter molecules (primarily glutamate, an amino acid), the blocking activity of dextromethorphan at these receptors reduces the level of excitatory activity in neurons having these receptors.
  • NMDA N-methyl-D- aspartate
  • Dextromethorphan is believed to act at the phencyclidine (PCP) binding site, which is part of the NMDA receptor complex. Dextromethorphan is relatively weak in its NMDA antagonist activity, particularly compared to drugs such as MK-801 (dizocilpine) and phencyclidine. Accordingly, when administered at approved dosages, dextromethorphan is not believed to cause the toxic side effects (discussed in U.S. Pat. No. 5,034,400 to Olney) that are caused by powerful NMDA antagonists such as MK-801 or PCP.
  • DM is a non-competitive NMDA antagonist that has neuroprotective, anticonvulsant and antinociceptive activities in a number of experimental models (Desmeules et al., J. Pharmacol. Exp. Ther., 1999; 288: 607-612).
  • Dextromethorphan also may function as an agonist at certain types of inhibitory receptors; unlike EAA receptors, activation of inhibitory receptors suppresses the release of excitatory neurotransmitters by affected cells. Initially, these inhibitory receptors were called sigma opiate receptors. However, questions have been raised as to whether they are actually opiate receptors, so they are now generally referred to as sigma ( ⁇ ) receptors. Binding studies suggest DM is a ligand at the high affinity sigma 1 site, where it initially was proposed to act as an antagonist (Tortella et al., TiPS, 1989; 10:501- 7) but more recently as an agonist (Maurice et al., Brain Res. Brain Res.
  • dextromethorphan also binds to another class of inhibitory receptors that are closely related to, but distinct from, sigma receptors.
  • the evidence, which indicates that non-sigma inhibitory receptors exist and are bound by dextromethorphan, is that certain molecules which bind to sigma receptors are not able to completely block the binding of dextromethorphan to certain types of neurons that are known to have inhibitory receptors (Musacchio et al, Cell MoI.
  • the phrase "dextromethorphan- binding inhibitory receptors" includes both sigma and non-sigma receptors which undergo affinity-binding reactions with dextromethorphan and which, when activated by dextromethorphan, suppress the release of excitatory neurotransmitters by the affected cells (Largent et al., MoI. Pharmacol., 1987 Dec, 32(6):772-84).
  • Dextromethorphan also decreases the uptake of calcium ions (Ca ++ ) by neurons.
  • Calcium uptake which occurs during transmission of nerve impulses, involves at least two different types of channels, known as N-channels and L-channels.
  • Dextromethorphan suppressed calcium uptake fairly strongly in certain types of cultured neurons (synaptosomes) which contain N-channels; it also suppressed calcium uptake, although less strongly, in other cultured neurons (PC 12 cells) which contain L-channels (Carpenter et al., Brain Res., 1988 Jan. 26, 439(l-2):372-5).
  • dextromethorphan and its analogs have little or no agonist or antagonist activity at various other opiate receptors, including the mu ( ⁇ ) and kappa (K) classes of opiate receptors. This is highly desirable, since agonist or antagonist activity at those opiate receptors can cause undesired side effects such as respiratory depression (which interferes with breathing) and blockade of analgesia (which reduces the effectiveness of pain-killers).
  • emotional lability or pseudobulbar affect can be treated in at least some patients by means of administering a drug which functions as an antagonist at NMDA receptors and as an agonist at dextromethorphan-binding inhibitory receptors, and wherein the drug is also characterized by a lack of agonist or antagonist activity at mu or kappa opiate receptors, namely, dextromethorphan and its analogs.
  • dextromethorphan and its analogs can reduce the internal feelings and external symptoms of emotional lability or pseudobulbar affect in some patients suffering from progressive neurological disease suggest that dextromethorphan and its analogs are also likely to be useful for helping some patients suffering from emotional lability due to other causes, such as stroke or other ischemic (low blood flow) or hypoxic (low oxygen supply) events which led to neuronal death or damage in limited regions of the brain, or head injury or trauma as might occur during an automobile, motorcycle, or bicycling accident or due to a gunshot wound.
  • stroke or other ischemic (low blood flow) or hypoxic (low oxygen supply) events which led to neuronal death or damage in limited regions of the brain, or head injury or trauma as might occur during an automobile, motorcycle, or bicycling accident or due to a gunshot wound.
  • dextromethorphan and its analogs are likely to be useful for treating some cases of emotional lability which are due to administration of other drugs.
  • various steroids such as prednisone
  • prednisone are widely used to treat autoimmune diseases such as lupus.
  • prednisone has adverse events on the emotional state of many patients, ranging from mild but noticeably increased levels of moodiness and depression, up to severely aggravated levels of emotional lability that can impair the business, family, or personal affairs of the patient.
  • the metabolic pathway that converts DM to DX is dominant in the majority of the population and is the principle for using DM as a probe to phenotype individuals as CYP2D6 extensive and poor metabolizers (Kupfer et al., Lancet 1984; 2: 517-518; Guttendorf et al., Ther. Drug Monit., 1988; 10: 490-498).
  • a subset of the population, 5 to 10% of Caucasians, has reduced activity of this enzyme while the incidence of poor metabolizer phenotype in Chinese and Black African populations is lower (Hildebrand et al., Eur. J. Clin.
  • alkyl means any unbranched or branched, substituted or unsubstituted, saturated hydrocarbon.
  • the alkyl moiety may be branched or linear chain.
  • the alkyl group may have 1 to 10 carbon atoms (whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; e.g., "1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • substituted has its ordinary meaning, as found in numerous contemporary patents from the related art. See, for example, U.S. Patent Nos. 6,509,331 ; 6,506,787; 6,500,825; 5,922,683; 5,886,210; 5,874,443; and 6,350,759; all of which are incorporated herein in their entireties by reference. Specifically, the definition of substituted is as broad as that provided in U.S. Patent No.
  • substituted alkyl such that it refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl,
  • cycloalkyl refers to any non-aromatic hydrocarbon ring, preferably having five to twelve atoms comprising the ring.
  • heterocycle or “heterocyclic” refer to any to non-aromatic hydrocarbon rings in which at least one heteroatom, e.g., oxygen, sulfur, or nitrogen atom, is in the ring along with at least one carbon atom.
  • alkenyl means any unbranched or branched, substituted or unsubstituted, unsaturated hydrocarbon containing a double bond between two carbons.
  • alkynyl means any unbranched or branched substituted or unsubstituted, unsaturated hydrocarbon containing a triple bond between two carbons.
  • aryl and heteroaryl refer to aromatic hydrocarbon rings, preferably having five, six, or seven atoms, and most preferably having six atoms comprising the ring.
  • Heteroaryl refers to aromatic hydrocarbon rings in which at least one heteroatom, e.g., oxygen, sulfur, or nitrogen atom, is in the ring along with at least one carbon atom.
  • heterocycle or “heterocyclic” refer to any cyclic compound containing one or more heteroatoms. The aryls, heterocycles and heteroaryls can be substituted with any substituent, including those described above and those known in the art.
  • R refers to a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclyl (bonded through a ring carbon).
  • aminoalkyl refers to a substituent selected from the group consisting of -RNR'R", -RNHR', and -RNH 2 , with R, R', and R" independently being as R is defined herein.
  • halogen atom means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
  • alkoxy refers to any unbranched, or branched, substituted or unsubstituted, saturated or unsaturated ether, with Ci-C 6 unbranched, saturated, unsubstituted ethers being preferred, with methoxy being preferred, and also with dimethyl, diethyl, methyl-isobutyl, and methyl-tert-butyl ethers also being preferred.
  • the hydrogen at the 2-position of the aryl ring, Ri can be replaced with a bulkier group.
  • the term "bulky” or “bulkier” refers to a substituent with a larger cone angle than hydrogen. Suitable substituents include but are not limited to C 1 -C 10 alkyl, C 2 -Ci 0 alkenyl, C 2 -Ci 0 alkynyl, C 6 -Ci 2 aryl, C 7 -C n arylalkyl, C 3 -C 10 cycloalkyl, C 2 -Ci 0 heterocycle, C 3 -Cj 0 heterocyclealkyl, C 3 -C 12 heteroaryl, C 4 -Cj 2 heteroarylalkyl, alkylamino and dialkylamino, wherein each hydrogen is optionally substituted with a lower alkyl, an alkoxy, or a halogen.
  • a bulkier group at 2-position may block CYP2D6 from initiating the catalytic process that converts dextromethorphan to dextrorphan and other metabolites.
  • the rapid metabolism of the dextromethorphan analogs may be prevented or drastically reduced.
  • a f-butyl alkyl group with its relatively large cone angle, may protect the methyl group bonded to the oxygen and prevent the O- demethylation of dextromethorphan.
  • the bulky group contains a basic nitrogen, the presence of such a nitrogen 5 to 7 angstroms away from the methoxy group may prevent oxidation by inhibiting CYP2D6.
  • Suitable DM analogs with bulky groups at the 2-positions include compounds (1-1) and (1-2), shown below.
  • the methoxy group at the 3-position may be substituted with a bulkier group, OR 2 .
  • Suitable substituents include but are not limited to the following: Ri is selected from the group consisting of hydrogen, Cj-Cio alkyl, C 2 -CiO alkenyl, C2-C10 alkynyl, C 6 -Ci 2 aryl, C 7 -CB arylalkyl, C3-C10 cycloalkyl, C 2 -CiO heterocycle, C3-C10 heterocyclealkyl, C3-C 12 heteroaryl, C 4 -Ci 2 heteroarylalkyl, alkylamino and dialkylamino, wherein each hydrogen is optionally substituted with a lower alkyl, an alkoxy or a halogen; and R 2 is selected from the group consisting C 2 -Ci O alkyl, C 2 -Ci 0 alkenyl, C 2 -CiO alkynyl, C O -C] 2 aryl, C 7 -Cn arylalkyl, C 3
  • Suitable DM analogs with bulky -OR 2 group at the 3-position include compounds (II- 1) - (II-4), shown below.
  • the methoxy group at the 3-position may be substituted with a bulkier group that includes a sulfur atom.
  • Suitable substituents include but are not limited to the following: each Ri is independently selected from the group consisting of hydrogen, Ci-Cio alkyl, C 2 -C 10 alkenyl, C 2 -Ci O alkynyl, C 6 -C] 2 aryl, C7-C 1 3 arylalkyl, C3-C 1 0 cycloalkyl, C 2 -CiO heterocycle, C 3 -Ci O heterocyclealkyl, C 3 -Ci 2 heteroaryl, C 4 -C] 2 heteroarylalkyl, alkylamino and dialkylamino, wherein each hydrogen is optionally substituted with a lower alkyl, an alkoxy or a halogen; and R 2 is selected from the group consisting of -SRj,
  • Suitable DM analogs with sulfur containing bulky group at the 3- position include compounds (III- 1 ) - (III-3), shown below.
  • a drug that inhibits CYP2D6 activity such as an antioxidant such as quinidine
  • a CYP2D6 inhibitor such as quinidine
  • quinidine can be used in combination with a DM analog at relative lower concentrations.
  • the chemical structure of quinidine is as follows:
  • Suitable compounds for treating pain include but are not limited to, for example, amitriptyline, proptriptyline, imipramine, desipramine, doxepin, nortriptyline, trimipramine, amoxapine, clomipramine, fluoxetine, paroxetine, venlafaxine, sertraline, escitalopram, citalopram and fluvoxamine.
  • suitable compounds include but are not limited to, for example, carbamazepine, gabapentin, pregabalin, duloxetine, lidocaine, tiagabine, lamotrigine, levetiracetam, oxcarbazepine, topiramte and zonisamide.
  • Suitable anti-psychotic compounds include but are not limited to, for example, clozapine, olanzapine, respiradone, quetiapine, aiprasidone, aripiprazole, pimozide, loxapine, molidone, remoxipride, sertindole, quetiapine and ziprasidone.
  • Suitable anti-dementia agents include but are not limited to acetylcholiesterase inhibitors, rivastigmine and donepezil.
  • Suitable anti-inflammatory agents include but are not limited to, for example, nonsteroidal anti-inflammatory drugs (NSAIDs) such aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potasium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, melenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and tolmetin; and corticosteroids such as cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethesone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, fluni
  • Suitable anti-infective agents may include, but are not limited to, anthelmintics (mebendazole), antibiotics including aminoclycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), beta-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolides (azithromycin, clarithromycin, erythromycin), penicillins (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, ticarcillin), te
  • Suitable anesthetics compounds include, but are not limited to ethanol, bupivacaine, chloroprocaine, levobupivacaine, lidocaine, mepivacaine, procaine, ropivacaine, tetracaine, desflurane, isoflurane, ketamine, propofol, sevoflurane, codeine, fentanyl, hydromorphone, marcaine, meperidine, methadone, morphine, oxycodone, remifentanil, sufentanil, butorphanol, nalbuphine, tramadol, benzocaine, dibucaine, ethyl chloride, xylocaine, meperidine, propoxyphene, levorphanol, oxymorphone, pentazocine, hydrocodone and phenazopyridine.
  • Suitable agents for treating neuropathic pain include but are not limited to tricyclic antidepressants agents such amitriptyline, imipramine, desimipramine, clomipramine, doxepine and trimipramine, anticonvulsants such phenyltoin, carbamazepine, valproid acid, clonazepam, gabapentin and lamotrigine, capsaicin, baclofen, cholecystokinin (CKK) antagonists, membrane stablilisers, ketamine, nerve blocks and clonidine.
  • tricyclic antidepressants agents such amitriptyline, imipramine, desimipramine, clomipramine, doxepine and trimipramine
  • anticonvulsants such phenyltoin, carbamazepine, valproid acid, clonazepam, gabapentin and lamotrigine, capsaicin, baclofen, cholecys
  • Suitable antitussives and expectorants for a cough include but are not limited to codeine and guaifenesin.
  • Suitable agents for treating Parkinson's disease include but are not limited to levodopa alone or in combination with another therapeutic agent, amantadine, COMT inhibitors such as entacapone and tolcapone, dopamine agonists such as bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine and lisuride, Anticholinergic mediations such as biperiden HCl, benztropine mesylate, procyclidine and trihexyphenidyl, and selegiline preparations such as Eldepryl®, Atapryl® and Carbex®.
  • Suitable agents from treating Alzheimer's disease include but are not limited to cholinesterase inhibitors such as donepezil, rivastigmine, galantamine and tacrine, memantine and Vitamin E. Methods of Use
  • the DM analogs or certain other therapeutic agents can be administered in the form of a pharmaceutically acceptable salt, e.g., the trihydrochloride salt.
  • a pharmaceutically acceptable salt e.g., the trihydrochloride salt.
  • pharmaceutically acceptable salts and “a pharmaceutically acceptable salt thereof as used herein are broad terms and are used in their ordinary sense, including, without limitation, to refer to salts prepared from pharmaceutically acceptable, non-toxic acids or bases.
  • Suitable pharmaceutically acceptable salts include metallic salts, e.g., salts of aluminum, zinc, alkali metal salts such as lithium, sodium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts; organic salts, e.g., salts of lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, and tris; salts of free acids and bases; inorganic salts, e.g., sulfate, hydrochloride, and hydrobromide; and other salts which are currently in widespread pharmaceutical use and are listed in sources well known to those of skill in the art, such as, for example, The Merck Index.
  • metallic salts e.g., salts of aluminum, zinc, alkali metal salts such as lithium, sodium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts
  • Any suitable constituent can be selected to make a salt of the DM analogs or other therapeutic agents discussed herein, provided that it is non-toxic and does not substantially interfere with the desired activity.
  • pharmaceutically acceptable precursors and derivatives of the compounds can be employed.
  • Pharmaceutically acceptable amides, lower alkyl esters, and protected derivatives can also be suitable for use in compositions and methods of preferred embodiments.
  • Also suitable for administration are selected therapeutic agents in hydrated form, selected enantiomeric forms of certain therapeutic agents, racemic mixtures of certain therapeutic agents, and the like.
  • the magnitude of a prophylactic or therapeutic dose of a dextromethorphan analog in the treatment and/or management of emotional lability or other chronic conditions can vary with the particular cause of the condition, the severity of the condition, and the route of administration.
  • the dose and/or the dose frequency can also vary according to the age, body weight, and response of the individual patient.
  • the optimal dosage of a DM analog to be administered to a specific patient can be determined by administering various dosages of the DM analog and then (1) analyzing blood samples to determine the concentration of DM analog in the circulating blood, and/or (2) evaluating the patient's progress to determine which dosage provides the best result in effectively suppressing the symptoms being targeted.
  • a recommended dosage of a DM analog is approximately 15 mg/day or less to about 300 mg/day or more.
  • the concentration can be reduced further if the DM analog is administered in conjunction with a second compound which increases blood plasma concentrations. Higher concentrations are desirable if the individual shows no adverse effects at those higher dosages and if the doctor deems it advisable.
  • the total daily dose for DM analog for the conditions described herein is preferably about 15 mg/day to about 120 mg/day; more preferably about 20 or 25 mg/day up to about 50, 55, or 60 mg/day; and still more preferably about 30 or 35 mg/day up to about 40 or 45 mg/day.
  • One of the significant characteristics of the treatments of preferred embodiments is that the treatments function to reduce emotional lability without tranquilizing or otherwise significantly interfering with consciousness or alertness in the patient.
  • "significant interference” refers to adverse events that would be significant either on a clinical level (they would provoke a specific concern in a doctor or psychologist) or on a personal or social level (such as by causing drowsiness sufficiently severe that it would impair someone's ability to drive an automobile).
  • an over-the-counter drug such as a dextromethorphan-containing cough syrup when used at recommended dosages are not regarded as significant interference.
  • compositions of the preferred embodiments comprise a dextromethorphan analog, or pharmaceutically acceptable salts of an analog of dextromethorphan, as the active ingredient and can also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
  • Any suitable route of administration can be employed for providing the patient with an effective dosage of the dextromethorphan analog.
  • oral, rectal, transdermal, parenteral (subcutaneous, intramuscular, intravenous, intraorbital), intrathecal, intraperitoneal, topical, inhalable, and like forms of administration can be employed.
  • Suitable dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
  • Administration of medicaments prepared from the compounds described herein can be by any suitable method capable of introducing the compounds into the bloodstream.
  • Formulations of preferred embodiments can contain a mixture of active compounds with pharmaceutically acceptable carriers or diluents as are known by those of skill in the art.
  • the DM analog and/or other therapeutic agent can be formulated into liquid preparations for, e.g., oral, nasal, anal, rectal, buccal, vaginal, peroral, intragastric, mucosal, perlingual, alveolar, gingival, olfactory, or respiratory mucosa administration. Suitable forms for such administration include suspensions, syrups, and elixirs. If nasal or respiratory (mucosal) administration is desired (e.g., aerosol inhalation or insufflation), compositions may be in a form and dispensed by a squeeze spray dispenser, pump dispenser or aerosol dispenser. Aerosols are usually under pressure by means of a hydrocarbon. Pump dispensers can preferably dispense a metered dose or a dose having a particular particle size.
  • compositions containing a DM analog and/or other therapeutic agent are preferably isotonic with the blood or other body fluid of the patient.
  • the isotonicity of the compositions can be attained using sodium tartrate, propylene glycol or other inorganic or organic solutes.
  • Sodium chloride is particularly preferred.
  • Buffering agents can be employed, such as acetic acid and salts, citric acid and salts, boric acid and salts, and phosphoric acid and salts.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like.
  • Viscosity of the pharmaceutical compositions can be maintained at the selected level using a pharmaceutically acceptable thickening agent.
  • Methylcellulose is preferred because it is readily and economically available and is easy to work with.
  • Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, and the like.
  • the preferred concentration of the thickener can depend upon the thickening agent selected. An amount is preferably used that can achieve the selected viscosity. Viscous compositions are normally prepared from solutions by the addition of such thickening agents.
  • a pharmaceutically acceptable preservative can be employed to increase the shelf life of the pharmaceutical compositions.
  • Benzyl alcohol can be suitable, although a variety of preservatives including, for example, parabens, thimerosal, chlorobutanol, or benzalkonium chloride can also be employed.
  • a suitable concentration of the preservative is typically from about 0.02% to about 2% based on the total weight of the composition, although larger or smaller amounts can be desirable depending upon the agent selected.
  • the DM analog and/or other therapeutic agent can be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, or the like, and can contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. Standard texts, such as “Remington: The Science and Practice of Pharmacy", Lippincott Williams & Wilkins; 20th edition (June 1, 2003) and “Remington's Pharmaceutical Sciences,” Mack Pub. Co.; 18 th and 19 th editions (December 1985, and June 1990, respectively).
  • Such preparations can include complexing agents, metal ions, polymeric compounds such as polyacetic acid, polyglycolic acid, hydrogels, dextran, and the like, liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts or spheroblasts.
  • Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like.
  • the DM analog and/or other therapeutic agent can be provided as a tablet, aqueous or oil suspension, dispersible powder or granule, emulsion, hard or soft capsule, syrup or elixir.
  • Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and can include one or more of the following agents: sweeteners, flavoring agents, coloring agents and preservatives.
  • Aqueous suspensions can contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Formulations for oral use can also be provided as hard gelatin capsules, wherein the DM analog and/or other therapeutic agent are mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules.
  • an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin
  • the active compounds can be dissolved or suspended in suitable liquids, such as water or an oil medium, such as peanut oil, olive oil, fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • Stabilizers and microspheres formulated for oral administration can also be used.
  • Capsules can include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the DM analog and/or other therapeutic agent in an admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • Tablets can be uncoated or coated by known methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time.
  • a time delay material such as glyceryl monostearate can be used.
  • the solid form When administered in solid form, such as tablet form, the solid form typically comprises from about 0.001 wt. % or less to about 50 wt.
  • % or more of active ingredient(s) including the DM analog and/or other therapeutic agent preferably from about 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 wt. % to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 wt. %.
  • Tablets can contain the DM analog and/or other therapeutic agent in admixture with non-toxic pharmaceutically acceptable excipients including inert materials.
  • a tablet can be prepared by compression or molding, optionally, with one or more additional ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • tablets or capsules are provided in a range of dosages to permit divided dosages to be administered.
  • a dosage appropriate to the patient and the number of doses to be administered daily can thus be conveniently selected.
  • it is generally preferred to incorporate the DM analog and/or other therapeutic agent in combination therewith in a single tablet or other dosage form in certain embodiments it can be desirable to provide the DM analog and/or other therapeutic agent in separate dosage forms, e.g., DM analog in a dosage form separate from the other therapeutic agent.
  • Combinations of dosage forms can also be employed, e.g., oral and intravenous.
  • Suitable inert materials include diluents, such as carbohydrates, mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, starch, and the like, or inorganic salts such as calcium triphosphate, calcium phosphate, sodium phosphate, calcium carbonate, sodium carbonate, magnesium carbonate, and sodium chloride.
  • diluents such as carbohydrates, mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, starch, and the like
  • inorganic salts such as calcium triphosphate, calcium phosphate, sodium phosphate, calcium carbonate, sodium carbonate, magnesium carbonate, and sodium chloride.
  • Disintegrants or granulating agents can be included in the formulation, for example, starches such as corn starch, alginic acid, sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite, insoluble cationic exchange resins, powdered gums such as agar, karaya or tragacanth, or alginic acid or salts thereof.
  • starches such as corn starch, alginic acid, sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite, insoluble cationic exchange resins, powdered gums such as agar, karaya or tragacanth, or alginic acid or salts thereof.
  • Binders can be used to form a hard tablet. Binders include materials from natural products such as acacia, tragacanth, starch and gelatin, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, and the like.
  • Lubricants such as stearic acid or magnesium or calcium salts thereof, polytetrafluoroethylene, liquid paraffin, vegetable oils and waxes, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, starch, talc, pyrogenic silica, hydrated silicoaluminate, and the like, can be included in tablet formulations.
  • Surfactants can also be employed, for example, anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate, cationic such as benzalkonium chloride or benzethonium chloride, or nonionic detergents such as polyoxyethylene hydrogenated castor oil, glycerol monostearate, polysorbates, sucrose fatty acid ester, methyl cellulose, or carboxymethyl cellulose.
  • Controlled release formulations can be employed wherein the DM analog and/or other therapeutic agent are incorporated into an inert matrix that permits release by either diffusion or leaching mechanisms. Slowly degenerating matrices can also be incorporated into the formulation.
  • Other delivery systems can include timed release, delayed release, or sustained release delivery systems.
  • Coatings can be used, for example, nonenteric materials such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methylhydroxy-ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, sodium carboxy-methyl cellulose, providone and the polyethylene glycols, or enteric materials such as phthalic acid esters.
  • Dyestuffs or pigments can be added for identification or to characterize different combinations of active compound doses
  • a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils can be added to the DM analog and/or other therapeutic agent.
  • Physiological saline solution, dextrose, or other saccharide solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol are also suitable liquid carriers.
  • the pharmaceutical compositions can also be in the form of oil-in-water emulsions.
  • the oily phase can be a vegetable oil, such as olive or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents include naturally-occurring gums such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate.
  • the emulsions can also contain sweetening and flavoring agents.
  • Pulmonary delivery of the DM analog and/or other therapeutic agent can also be employed.
  • the DM analog and/or other therapeutic agent are delivered to the lungs while inhaling and traverses across the lung epithelial lining to the blood stream.
  • a wide range of mechanical devices designed for pulmonary delivery of therapeutic products can be employed, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
  • These devices employ formulations suitable for the dispensing of DM analog and/or other therapeutic agent.
  • each formulation is specific to the type of device employed and can involve the use of an appropriate propellant material, in addition to diluents, adjuvants, and/or carriers useful in therapy.
  • the DM analog and/or other therapeutic agent, and/or other optional active ingredients are advantageously prepared for pulmonary delivery in particulate form with an average particle size of from 0.1 ⁇ m or less to 10 ⁇ m or more, more preferably from about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 ⁇ m to about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, or 9.5 ⁇ m.
  • Pharmaceutically acceptable carriers for pulmonary delivery of DM analog and/or other therapeutic agent include carbohydrates such as trehalose, mannitol, xylitol, sucrose, lactose, and sorbitol.
  • Other ingredients for use in formulations can include DPPC, DOPE, DSPC, and DOPC.
  • Natural or synthetic surfactants can be used, including polyethylene glycol and dextrans, such as cyclodextran.
  • Bile salts and other related enhancers, as well as cellulose and cellulose derivatives, and amino acids can also be used. Liposomes, microcapsules, microspheres, inclusion complexes, and other types of carriers can also be employed.
  • compositions suitable for use with a nebulizer typically comprise the DM analog and/or other therapeutic agent dissolved or suspended in water at a concentration of about 0.01 or less to 100 mg or more of each of DM analog and/or other therapeutic agent per mL of solution, preferably from about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg to about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 mg per mL of solution.
  • the formulation can also include a buffer and a simple sugar (e.g., for protein stabilization and regulation of osmotic pressure).
  • the nebulizer formulation can also contain a surfactant, to reduce or prevent surface induced aggregation of the DM analog and/or other therapeutic agent caused by atomization of the solution in forming the aerosol.
  • Formulations for use with a metered-dose inhaler device generally comprise a finely divided powder containing the active ingredients suspended in a propellant with the aid of a surfactant.
  • the propellant can include conventional propellants, such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, and hydrocarbons.
  • Preferred propellants include trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, 1,1,1,2-tetrafluoroethane, and combinations thereof.
  • Suitable surfactants include sorbitan trioleate, soya lecithin, and oleic acid.
  • Formulations for dispensing from a powder inhaler device typically comprise a finely divided dry powder containing the DM analog and/or other therapeutic agent, optionally including a bulking agent, such as lactose, sorbitol, sucrose, manm ' tol, trehalose, or xylitol in an amount that facilitates dispersal of the powder from the device, typically from about 1 wt. % or less to 99 wt. % or more of the formulation, preferably from about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 wt. % to about 55, 60, 65, 70, 75, 80, 85, or 90 wt. % of the formulation.
  • a bulking agent such as lactose, sorbitol, sucrose, manm ' tol, trehalose, or xylitol in an amount that facilitates dispersal of the powder from the device, typically from about 1 wt. % or less to 99 wt. % or more
  • the DM analog and/or other therapeutic agent When administered by intravenous, cutaneous, subcutaneous, parenteral, or other injection, it is preferably in the form of a pyrogen-free, parenterally acceptable aqueous solution or oleaginous suspension.
  • Suspensions can be formulated according to methods well known in the art using suitable dispersing or wetting agents and suspending agents. The preparation of acceptable aqueous solutions with suitable pH, isotonicity, stability, and the like, is within the skill in the art.
  • a preferred pharmaceutical composition for injection preferably contains an isotonic vehicle such as 1,3-butanediol, water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, dextrose and sodium chloride solution, lactated Ringer's solution, or other vehicles as are known in the art.
  • an isotonic vehicle such as 1,3-butanediol, water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, dextrose and sodium chloride solution, lactated Ringer's solution, or other vehicles as are known in the art.
  • sterile fixed oils can be employed conventionally as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid can likewise be used in the formation of injectable preparations.
  • the pharmaceutical compositions can also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art
  • the duration of the injection can be adjusted depending upon various factors, and can comprise a single injection administered over the course of a few seconds or less to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 54, 60, 66, 72, 78, 84, 90, or 96 hours or more of continuous intravenous administration.
  • the DM analog and/or other therapeutic agent can be administered systematically or locally, via a liquid or gel, or as an implant or device.
  • a "minimum effective therapeutic amount” is that amount which provides a satisfactory degree of inhibition of the rapid elimination of dextromethorphan analog from the body, while producing no adverse effect or only adverse events of an acceptable degree and nature.
  • dextromethorphan analogs can also be extremely effective in formulations for the treatment for other chronic disorders which do not respond well to other treatments.
  • An analog of dextromethorphan can be used to effectively treat severe or intractable coughing, which has not responded adequately to non-addictive, non-steroid medications, with minimal side-effects. Intractable coughing is a consequence of respiratory infections, asthma, emphysema, and other conditions affecting the pulmonary system.
  • a dextromethorphan analog as in the preferred embodiments can also be used in pharmaceutical compositions for treating dermatitis.
  • dermatitis or “eczema” is a skin condition characterized by visible skin lesions and/or an itching or burning sensation on the skin.
  • a dextromethorphan analog can also be used in pharmaceutical compositions for the treatment of chronic pain from conditions such as stroke, trauma, cancer, and pain due to neuropathies such as herpes zoster infections and diabetes.
  • Other conditions that can be treated using a dextromethorphan analog according to the preferred embodiments can include sexual dysfunctions, such as priapism or premature ejaculation, as well as tinnitus.
  • Dextromethorphan analogs can also reduce the external displays or the internal feelings that are caused by or which accompany various other problems such as "premenstrual syndrome” (PMS), Tourette's syndrome, and the outburst displays that occur in people suffering from certain types of mental illness.
  • PMS menstrual syndrome
  • Tourette's syndrome the outburst displays that occur in people suffering from certain types of mental illness.
  • problems may not be clinically regarded as emotional lability, they involve manifestations that appear to be sufficiently similar to emotional lability to suggest that analogs of dextromethorphan can offer an effective treatment for at least some patients suffering from such problems.
  • Dextromethorphan analogs can also be used to treat an acute infectious brain edema due to pertussis bacilli; acute ischemic hemispheric stroke and motor deficit; acute ischemic stroke; acute ischemic stroke in elderly population; acute mild or moderate traumatic brain injury or hemorrhagic stroke; acute stroke; acute traumatic brain injury; age-related neuroendocrine and sleep EEG changes; alcohol craving and subjective dissociative effects (moderate drinkers); alcohol dependence; alcohol tolerance; alcoholism; Alzheimer's disease; aminoglycosides-induced ototoxicity; analgesia; anticonvulsant effect; anti-craving for alcohol; antinociception; antinociception and postoperative pain; antinociception following orthopedic surgery; anxiolytic effect; asphyxia; automatic postural responses; birth asphyxia; brain ischemia; brain ischemic damage protection during cardiopulmonary bypass; brain trauma; burn injury; burn- induced primary hyperalgesia; burn-induced secondary hyperalgesia; cancer
  • D1/D2 balance in basal ganglia toxicity; traumatic brain injury; ulcerprotective activity; vascular disease; visceral pain hypersensitivity; visceral perception in gastric barostat study; voice spasms; vulnerability to alcoholism; Wernicke-Korsakoff syndrome; and wind-up.
  • NMDA receptors are transiently activated by mM concentrations of glutamate (Clements, et al, Science. 1992 Nov 27;258(5087):1498-1501). In order to prevent excessive influx, the ion channel is blocked by a magnesium ion under resting conditions. If the NMDA receptor is activated by glutamate and the postsynaptic neuron is depolarized at the same time, magnesium leaves the ion channel and calcium can flow in, which is important for learning processes. During pathological activation, such as that occurring in Alzheimer's disease, NMDA receptors are likely activated by lower concentrations of glutamate, but more or less continuously.
  • NMDA receptor antagonist such as a dextromethorphan analog
  • NMDA receptor antagonist can provide a neuroprotective effect, and as such can be used to treat dementia, Alzheimer's disease, or other cognitive disorders.
  • compositions of the preferred embodiments are suitable for use in treating or alleviating symptoms of a variety of conditions, including but not limited to alcoholism (craving-withdrawal- tolerance), amyotrophic lateral sclerosis (ALS), anxiety/stress, autism, carpal tunnel syndrome, cerebral palsy, chronic cough, chronic pain, chronic obstructive pulmonary disease (COPD), dementia, agitation in dementia, depression, dermatitis, Epilepsy (e.g., pre-kindling), fibromyalgia, Huntington's disease, impotence, migraine, neuropathic pain (e.g., diabetic neuropathy, experimental wind-up pain, hyperalgsia, central summation, post-herpetic neuralgia), neuroprotection (e.g., for head injury/traumatic brain injury, ischemia, methotrexate neurotoxicity), chronic pain, pain (e.g., nociception, operative, postoperative), Parkinson'
  • compositions of the preferred embodiments can also exhibit a neuroprotective effect (e.g., for head injury/traumatic brain injury, ischemia, methotrexate neurotoxicity), an improvement in bulbar function, and improved cognition, learning and memory (e.g., in aging). Pain
  • compositions of preferred embodiments are effective in providing preemptive or preventative analgesia. They are typically administered prior to or during surgery, usually with anesthetics, opiates, and/or NSAIDs. Clinical trials have demonstrated that dextromethorphan decreases postoperative pain and/or analgesia consumption (opioid use), making it desirable for use in adjunctive therapy. Compositions containing the dextromethorphan analog are believed to be particularly effective when administered pre-operatively or peri-operatively, rather than postoperatively; however, in certain embodiments it can be desirable to administer compositions containing the dextromethorphan analog postoperatively.
  • NMDA receptors Both central sensitization after peripheral tissue injury and the development of opiate tolerance involve activation of NMDA receptors.
  • Experimental studies have demonstrated that peripheral tissue injury may lead to hyperexcitability of nociceptive neurons in the dorsal horn, in part mediated by NMDA receptor mechanisms. Sensitization of dorsal horn neurons may be an important contributor to postoperative pain.
  • DM is a weak noncompetitive NMDA receptor antagonist known to inhibit wind-up and NMDA-mediated nociceptive responses of dorsal horn neurons. DM inhibits spinal cord sensitization in animal models of pain and also inhibits the development of cutaneous secondary hyperalgesia after tissue trauma.
  • NMDA studies reported reduction of nociceptive input through blockade of NMDA receptors.
  • Tissue injury induces central sensitization in spinal cord dorsal horn neurons via mechanisms involving NMDA receptors, leading to secondary hyperalgesia.
  • opioids By an action on NMDA receptors, opioids also induce, in a dose dependent manner, an enhancement of this postoperative hypersensitivity.
  • NMDA receptor antagonists enhance opioid-induced analgesia.
  • drugs commonly used to treat postoperative pain including ketamine, are linked to nitric oxide (NO) in their MOA. Biosynthesis of NO in CNS is tonically involved in nociceptive processing.
  • Nociceptive pain is pain caused by injury or disease outside the nervous system. It can be somatic or visceral, acute or chronic, and is mediated by stimulation of receptors on A-delta and C-fibers and by algogenic substances (e.g., substance P). It involves normal activation of nociceptive system by noxious stimuli. Postoperative and posttraumatic pain are primarily nociceptive in nature, not neuropathic.
  • Neuropathic pain is caused by primary lesion or dysfunction of the nervous system. It is generally chronic and highly unresponsive to traditional analgesics. Symptoms include Hyperalgesia (lowering of pain threshold and increased response to noxious stimuli) and allodynia (evocation of pain by non-noxious stimuli). Multiple pathological mechanisms underlie neuropathic pain, including peripheral and central sensitization, which results in overstimulation and hyperexcitability of nerve paths.
  • Central sensitization including the phenomena of wind-up (progressive increase in the number of action potentials elicited per stimulus that occurs in dorsal horn neurons due to repetitive noxious stimulation of unmyelinated C-fibers) and long-term potentiation (long lasting increase in the efficacy of synaptic transmission that may be precipitated by repetitive episodes of wind-up), involves activation of NMDA receptors.
  • Neuropathic pain is primarily centrally mediated pain involving a process of central sensitization.
  • the compositions of preferred embodiments can be used to treat neuropathic conditions such as diabetic neuropathy.
  • neuropathic conditions such as diabetic neuropathy.
  • Studies have shown an association of NMDA receptors with development of hyperalgesia and 'wind-up', i.e., lasting activation of the polymodal, second-order sensory neurons in the deeper layers of the dorsal horn.
  • Glutamate and aspartate are main neurotransmitters along ascending nociceptive pathways in the spinal cord. Glutamate, aspartate, and their receptors can be detected in particularly high concentrations in the dorsal root ganglia and the superficial laminae of the spinal cord.
  • glutamate receptor antagonists In low doses, glutamate receptor antagonists only slightly elevate the threshold of the physiological pain sensation. However, they suppress the process of pathological sensitization, i.e., lowering of the pain threshold seen upon excessive or lasting stimulation of C-fiber afferents, a process that takes place during inflammation or other kinds of tissue injury. At the electrophysiological level, antagonists of both the NMDA-receptors and AMPA/kainate receptors inhibit wind-up.
  • NMDA antagonists are apparently more potent in experimental models of neuropathic pain. It is hypothesized that low-affinity NMDA channel blockers may have a better therapeutic ratio.
  • NMDA receptors are involved in perception and maintenance of pathological pain in some patients. In others, pain appears to be mediated by NMDA-receptor independent mechanisms.
  • Temporal summation of second pain at least partly reflects temporal summation of dorsal horn neuronal responses, and both have been termed wind-up, a form of nociception-dependent central sensitization. Animal and human experiments have shown that both forms of wind-up depend on NMDA and substance P receptor systems. Wind-up of second pain in patients with fibromyalgia (FM) is enhanced compared with normal control subjects and is followed by exaggerated wind-up of second pain aftersensations and prolonged wind-up of second pain maintenance at low stimulus frequencies. Enhanced wind-up of second pain of FM patients could be related to abnormal endogenous modulation of NDMA receptors. Central mechanisms related to referred muscle pain and temporal summation of muscular nociceptive activity are facilitated in FM syndrome. NMDA-mediated neurotransmission may play an important role in mediating wind-up and related phenomena in pain pathways.
  • compositions of preferred embodiments are efficacious in treating both nociceptive and neuropathic pain.
  • Chronic Cough
  • Chronic cough e.g., cough associated with cancer and respiratory infection
  • Clinical trials demonstrated efficacy of DM, alone or in combination therapy, for treatment of chronic cough.
  • the antitussive effect is seemingly enhanced by Q in a cough model, and a subjective preference for DM indicates a psychotropic CNS action.
  • the antitussive effects of DM were significantly and dose-dependently reduced by pretreatment with rimcazole, a specific antagonist of sigma sites. These results suggest that sigma sites may be involved in the antitussive mechanism of non-narcotic antitussive drugs.
  • compositions of preferred embodiments are useful in treating levodopa-induced dyskinesias and spasticity.
  • Levodopa-related motor response complications occur in most Parkinson's disease patients.
  • Experimental evidence suggests that increased synaptic efficacy of NMDA receptors expressed on basal ganglia neurons may play a role in the pathophysiology of levodopa-induced motor response complications.
  • Motor dysfunction produced by chronic non-physiological stimulation of dopaminergic receptors on striatal medium spiny neurons is associated with alterations in the sensitivity of glutamatergic receptors, including those of the NMDA subtype. Functional characteristics of these ionotropic receptors are regulated by their phosphorylation state.
  • NMDA receptor subunits Lesioning the nigrostriatal dopamine system of rats induces Parkinsonian signs and increases the phosphorylation of striatal NMDA receptor subunits on serine and tyrosine residues.
  • the intrastriatal administration of certain inhibitors of the kinases capable of phosphorylating NMDA receptors produces a dopaminomimetic motor response in these animals. Treating Parkinsonian rats twice daily with levodopa induces many of the characteristic features of the human motor complication syndrome and further increases the serine and tyrosine phosphorylation of specific NMDA receptor subunits.
  • the intrastriatal administration of selective inhibitors of certain serine and tyrosine kinases alleviates the motor complications.
  • striatal dopaminergic receptors differentially activates signal transduction pathways in medium spiny neurons. These in turn modify the phosphorylation state of ionotropic glutamate receptors and consequently their sensitivity to cortical input. These striatal changes contribute to symptom production in Parkinson's disease.
  • glutamate pathways within the basal ganglia become overactive (overactive glutamatergic transmission in cortico-striatal and subthalamo-medial pallidal pathways).
  • glutamate antagonists may possess Antiparkinsonian qualities.
  • Neuroleptic malignant syndrome (NMS) exhibits identical presumed pathogenesis as akinetic Parkinsonian crisis.
  • NMDA receptor antagonists can be used for management of
  • NMS as these drugs are expected to exhibit hypothermic and central muscle relaxant properties.
  • compositions of preferred embodiments can have a beneficial effect in treating senile dementia or for cognitive enhancement in aging.
  • the "modulatory" role of the compositions means that they exert such beneficial effects only when brain functions are perturbed.
  • DM affects CNS serotonergic systems, the probable therapeutic mechanism.
  • Sigma 1 ligands prevent experimental amnesia induced by muscarinic cholinergic antagonists at either the learning, consolidation, or retention phase of the mnesic process.
  • Sigma 1 receptor ligands also attenuate the learning impairment induced by dizocilpine, a non-competitive antagonist of the NMDA receptor, and may relate to the potentiating effect of sigma- 1 ligands on several NMDA receptor-mediated responses. Dementia
  • Alzheimer's disease Symptoms of Alzheimer's disease, vascular disease, mixed dementia, and Wernicke-Korsakoff Syndrome are each amenable to treatment by administration of the compounds of preferred embodiments.
  • Neuroprotection and cognitive improvement can be provided by administration of low affinity, noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency. These compositions have desirable efficacy and safety profiles.
  • Alzheimer's disease, vascular disease, and mixed dementia i.e., coexistence of Alzheimer's disease and vascular disease
  • Alzheimer's disease is an age-related neurodegenerative disease that affects approximately 4.5 million people in the United States, as of 2005.
  • NMDA receptor-mediated glutamate excitotoxicity plays a major role in Abeta-induced neuronal death.
  • glutamate-induced neurotoxicity excitotoxicity
  • the NMDA receptor antagonist memantine may prevent excitatory neurotoxicity in dementia.
  • Memantine acts as a neuroprotective agent in various animal models based on both neurodegenerative and vascular processes as it ameliorates cognitive and memory deficits.
  • Memantine's mechanism of action of symptomatological improvement of cognition in animal models is unclear but might be related to an enhancement of AMPA receptor mediated neurotransmission.
  • NMDA receptor antagonists can be employed to inhibit the pathological functions of NMDA receptors while physiological processes in learning and memory are unaffected.
  • the voltage-dependency of Mg++ is so pronounced that under pathological conditions it leaves the NMDA channel upon moderate depolarization, thus interrupting memory and learning.
  • the NMDA receptor antagonist rapidly leaves the NMDA channel upon transient physiological activation by synaptic glutamate (restoring significant signal transmission), but blocks the sustained activation of low glutamate concentration under pathological conditions, i.e., to protect against excitotoxicity as a pathomechanism of neurodegenerative disorders. Neuroprotection for Ischemia and Head Injury/Traumatic Brain Injury
  • NMDA receptor antagonists such as DM are efficacious in treating ischemia (e.g., focal cerebral ischemia) and provides neuroprotection (e.g., during cardiac surgery) and limited clinical evidence of efficacy.
  • Excitotoxicity is thought to be a primary cause of delayed neuronal injury after ischemia, head injury, traumatic brain injury, spinal cord injury, hypoxia, or asphyxia.
  • the compositions of preferred embodiments are preferably administered as soon as possible after injury, or prophylactically before injury occurs.
  • Visceral hypersensitivity is a common feature of functional gastrointestinal disorders.
  • One speculated mechanism is activity-dependent increase in spinal cord neuronal excitability (central sensitization), dependent on NMDA receptor activation.
  • IBS is a common gastrointestinal disorder characterized by chronic abdominal pain and altered bowel function (diarrhea and/or constipation).
  • visceral hypersensitivity i.e., decreased pain thresholds in response to gut distension
  • IBS i.e., decreased pain thresholds in response to gut distension
  • DM alters reflexes of larynx (voice box), and might change voice symptoms in people with voice disorders due to uncontrolled laryngeal muscle spasms. These include abductor spasmodic dysphonia (breathy voice breaks), adductor spasmodic dysphonia (vowel breaks), muscular tension dysphonia (tight strained voice), and vocal tremor (tremulous voice). In animal studies, DM blocked one of reflexes in larynx that may be associated with spasms in laryngeal muscles.
  • Rett Syndrome Rett syndrome (RTT) is disorder in which nervous system does not develop properly. RTT generally affects girls, but there are some boys who have been diagnosed with RTT. Symptoms of RTT include small brain size, poor language skills, repetitive hand movements, and seizures. Recent studies demonstrate increased brain NMDA receptors in stages 2 and 3 of disease. This age-specific increase in glutamate levels and their receptors contribute to brain damage. Depression
  • Clinical depression can be treated using the compositions of preferred embodiments. Interaction with the sigma-1 receptor may strengthen antidepressant effects of the compositions. For example, the NMDA receptor antagonist ketamine improved clinical postoperative and major depressive symptoms. Multicase evidence showed that that a single IV dose of this NMDA receptor antagonist provided sustained depressive symptom relief.
  • Antidepressant-like effects of NMDA receptor antagonists in animal models implicate the glutamate system in depression and mechanism of action of antidepressants. Certain sex hormones in the brain (neurosteroids) are known to interact with sigma-1 receptors. Sigma-1 receptors regulate glutamate NMDA receptor function and the release of neurotransmitters such as dopamine.
  • sigma-1 receptor ligands The most distinctive feature of the action of sigma-1 receptor ligands is their "modulatory" role. In behavioral studies of depression and memory, they exert beneficial effects only when brain functions are perturbed. Sigma-1 agonists modulate intracellular calcium mobilization and extracellular calcium influx, NMDA-mediated responses, acetylcholine release, and alter monoaminergic systems. A growing body of preclinical research suggests brain glutamate systems may be involved in pathophysiology of major depression and the mechanism of action of antidepressants. Antidepressant-like activity can be produced by agents that affect subcellular signaling systems linked to excitatory amino acid (EAA) receptors (e.g., nitric oxide synthase).
  • EAA excitatory amino acid
  • Ulcerprotective activity of sigma-receptor ligands may be related to their stimulating effect on bicarbonate secretion through interaction with sigma-receptor in the gastrointestinal mucosa.
  • SD Spreading depression
  • a preeminent role is attributed to 'third hyperalgesia', newly observed which is inheritable and can act as a ground for 'chronicization' of migraine, while the role of primary and secondary hyperalgesia is in giving redundance to neuraxial abnormalities. Sleep
  • a growing body of literature implicates interactions between glutamatergic and neostriatal dopaminergic neurotransmitter systems in development and expression of impulsivity, hyperactivity, and stereotypy. Eating disorders are compulsive behavior disease, characterized by frequent recall of anorexic thoughts. Evidence suggests that memory is neocortical neuronal network, excitation of which involves hippocampus, with recall occurring by re-excitement of the same specific network. Excitement of hippocampus by NMDA receptors, leading to long-term potentiation (LTP), can be blocked by ketamine. Continuous block of LTP prevents new memory formation but does not affect previous memories. Opioid antagonists prevent loss of consciousness with ketamine but do not prevent LTP block. Sensorineural/ Nonconductive Smell Disorders
  • Tinnitus is a ringing in the ears.
  • a hypothesis of pathophysiology of inner ear tinnitus is that physiological activity of NMDA and AMPA receptors at subsynaptic membranes of inner hair cell afferents is disturbed. Huntington's Disease
  • NMDA- receptor antagonists for treatment of symptoms associated with Huntington's disease (HD).
  • HD Huntington's disease
  • NMDA receptor supersensitivity on striatal neurons may contribute to choreiform dyskinesias, and excitotoxicity may play a role in the pathogenesis of Huntington's disease.
  • Chorea in HD and in levodopa-induced dyskinesias of Parkinson's disease may be clinically indistinguishable. Alcoholism
  • Ethanol is a NMDA receptor antagonist and ethanol dependence upregulates NMDA receptors.
  • NMDA receptor antagonists are effective for treating craving-withdrawal-tolerance in alcoholism.
  • acamprosate is used for relapse prophylaxis (anti-craving) in weaned alcoholics in Europe, and has been approved by the FDA for this indication in the United States.
  • Acamprosate may impair memory functions in healthy humans, and also acts by antagonizing metabotropic glutamate receptors (mGluR5).
  • mGluR5 metabotropic glutamate receptors
  • NMDA receptor activation may play crucial role in epilepsy.
  • EAA antagonists have anticonvulsant properties.
  • NMDA antagonists as anticonvulsants are especially active in preventing the generalization of behavioral and electrical seizures and display a typical spectrum of in vitro antiepileptiform activities.
  • the drugs should be regarded more as an antiepileptiform than as an anticonvulsant drugs.
  • DM has antiepileptic and neuroprotective properties.
  • DM non-ketotic Hyperglycinemia
  • NKH is a rare and lethal congenital metabolic disease with autosomal recessive inheritance, causing severe, frequently lethal, neurological symptoms in the neonatal period. NKH causes muscular hypotonia, seizures, apnea, and lethargy, and it has a poor prognosis.
  • the metabolic lesion of NKH is in the glycine cleavage system (GCS), a complex enzyme system with four enzyme components: P-, T-, H-, and L- protein.
  • GCS glycine cleavage system
  • GCS expression resembles that of NMDA receptor which has binding site for glycine.
  • Glycine is a co-agonist of glutamate at the NMDA receptor, increasing the affinity of the receptor for the endogenous agonist glutamate. It is, therefore, suggested that the neurological disturbance in NKH may be caused by excitoneurotoxicity through the NMDA receptor allosterically activated by high concentration of glycine. Trials have been carried out with a therapy that diminishes the levels of glycine, benzoate (BZ), and another that blocks the excitatory effect in NMDA receptors (DM).
  • BZ benzoate
  • DM excitatory effect in NMDA receptors
  • NMDA receptor antagonists such as a DM analog can also be employed to provide neuroprotection against methotrexate (MTX) neurotoxicity.
  • MTX methotrexate
  • One potential biochemical pathway for MTX neurotoxicity involves production of excitatory NMDA receptor agonists; the mechanism of action is likely multifactorial.
  • a short course of DM therapy was demonstrated to resolve symptoms of MTX neurotoxicity.
  • Methotrexate-induced neurotoxicity (MTX-Ntox) is frequent complication of MTX therapy for patients with both malignant and inflammatory diseases.
  • Methotrexate (formerly amethopterin) is an antimetabolite used in treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis.
  • Symptoms can present in acute, subacute, or late setting form, and can range from affective disorders, malaise, and headaches, to somnolence, focal neurological deficits, and seizures. While the pathogenesis of MTX-Ntox is likely multifactorial, one potential biochemical pathway leading from MTX to neurotoxicity involves the folate dependent remethylation of homocysteine (Hey). MTX therapy is known to cause elevations of both plasma and CSF Hey. Hey is directly toxic to vascular endothelium and it and its metabolites are excitatory agonists of the NMDA receptor.
  • Hey homocysteine
  • NMDA receptors in cochlea may be involved in ototoxic effects of aminoglycosides in animals.
  • Aminoglycoside antibiotics enhance the function of NMDA receptors by interaction with a polyamine modulatory site.
  • High doses of aminoglycosides may increase calcium entry through NMDA receptor-associated channel and promote degeneration of hair cells and cochlear nerve fibers.
  • Organophosphorus nerve agents are considered as potential threats in both military and terrorism situations. They act as potent irreversible inhibitors of acetylcholinesterase in both CNS and PNS. Numerous studies have shown that glutamate also plays a prominent role in the maintenance of organophosphate-induced seizures and in the subsequent neuropathology especially through overactivation of NMDA receptors. Prion Diseases
  • Apoptotic neuronal cell death is a hallmark of prion diseases.
  • the apoptotic process in neuronal cells is thought to be caused by the scrapie prion protein, PrPSc, and can be experimentally induced by its peptide fragment, PrP 106- 126.
  • Changes in the permeability of blood-brain barrier (BBB) and Ca(2+)-overload may participate in pathogenesis of infectious brain edema. Infectious brain edema is not only cytotoxic brain edema (intracellular edema) but also vasogenic brain edema (extracellular edema) followed by earlier BBB breakdown, so infectious brain edema is complicated with brain edema.
  • NMDA receptor antagonists such as DM can also be employed to provide protection against apoptotic neuronal cell death.
  • neuroprotective molecules such as a DM analog, might favor myelination, and thus be effective in treating symptoms associated with multiple sclerosis.
  • the compounds of this invention can be prepared from readily available starting materials following general methods and procedures. It will be appreciated that where typical or preferred conditions (e.g., reaction temperatures, times, mole ratios or reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • Dextromethorphan is hydrolyzed to form dextrorphan using tribromoborane (BBr 3 ) in dimethylchloride.
  • BBr 3 tribromoborane
  • the reaction mixtures is cooled to -75°C and allowed to warm to room temperature ( ⁇ 25°C) overnight.
  • dextromethorphan may be O-demethylated using hydrobromic acid in water at room temperature ( ⁇ 25°C).
  • the hydrogen of the hydroxy group of dextrorphan may then be replaced via a Grignard reaction using the appropriate alkylhalide to form the desired dextromethorphan analog. This can be accomplished using sodium hydride in dimethylformamide (DMF) at room temperature. If desired, the reaction can be run at elevated temperatures using potassium carbonate in place of sodium hydride.
  • DMF dimethylformamide
  • Dextrorphan and 5-chloro-l -phenyl- lH-tetrazole are mixed along with potassium carbonate in dimethylformamide at room temperature for 18 hours.
  • the resulting ether is then treated with hydrogen gas and palladium on activated carbon at 4O 0 C for 4 days.
  • the product is a dextromethorphan analog with an unsubstituted aryl ring.
  • a -SH group can then be added to the 3-position of the unsubstituted aryl ring via two different routes.
  • an amine group is attached to the 3- position of the aryl ring using nitric acid-acetic acid, hydrogen gas and a palladium on activated carbon.
  • the amine group can then be replaced using lithium aluminum hydride and EtOCS 2 K to form the dextromethorphan analog with a -SH group at the 3 -position.
  • the second route utilizes chlorosulfonic acid (ClSO 2 OH) to form an intermediate which can then treated with lithium aluminum hydride to form the dextromethorphan analog with a -SH group at the 3 -position.
  • the -SH group can be alkylated using sodium hydride and the appropriate alkylhalide. If desired, the resulting alkyl group attached to the sulfur atom may then be oxidized with meta-chloroperbenzoic acid (m-CPBA).
  • m-CPBA meta-chloroperbenzoic acid

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Abstract

L'invention concerne des compositions pharmaceutiques et des procédés servant à traiter des troubles neurologiques en administrant celles-ci. Les compositions comprennent des analogues du dextrométhorphane.
PCT/US2008/052949 2007-02-05 2008-02-04 Compositions pharmaceutiques comprenant des analogues du dextrométhorphane pour le traitement de troubles neurologiques WO2008097924A2 (fr)

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