阅读说明：本技术 用于治疗痴呆中的激越行为的包含右美沙芬化合物和奎尼丁的药物组合物 (Pharmaceutical composition comprising dextromethorphan compound and quinidine for the treatment of catastrophe in dementia ) 是由 J.西弗特 于 2015-09-14 设计创作，主要内容包括：本发明涉及在患有痴呆(包括与阿尔茨海默症相关的痴呆)的受试者中治疗激越行为和/或攻击行为和/或相关症状的方法。该方法包括向有需要的受试者给药右美沙芬化合物或其药学上可接受的盐与奎尼丁或其药学上可接受的盐的组合。本发明在某些方面还涉及用于在患有阿尔茨海默症的受试者中治疗激越行为和/或攻击行为和/或相关症状的组合物。(The present invention relates to methods of treating aggressive behavior and/or associated symptoms in subjects suffering from dementia, including dementia associated with alzheimer's disease. The method comprises administering to a subject in need thereof a dextromethorphan compound, or a pharmaceutically acceptable salt thereof, in combination with quinidine, or a pharmaceutically acceptable salt thereof. The invention also relates in certain aspects to compositions for treating aggressive behavior and/or associated symptoms in a subject suffering from alzheimer's disease.)

1. Use of deuterated dextromethorphan and quinidine for the preparation of a medicament for the treatment of catatonic and/or aggressive behavior and/or associated symptoms in a subject suffering from dementia.

2. The use according to claim 1, wherein the dementia is of the alzheimer's type.

3. Preparation of a compound in which R is¹Is not CH₃A process for preparing a compound of formula (I) comprising the steps of:

HBr salt 10, in NH₄After OH treatment, N-demethylation to give 11;

acylation of amine 11 with ethyl chloroformate to afford carbamate 12, which is then used with BBr₃O-demethylation to give alcohol 13; and is

Treating compound 13 with appropriately deuterated iodomethane in the presence of a base to give ether 14, which is reduced with Lithium Aluminum Deuteride (LAD) to give a compound wherein R is²═CD₃Or reduced with Lithium Aluminium Hydride (LAH) to give compounds of formula I wherein R is²═CH₃The compound of (1).

Technical Field

The present invention relates to the treatment of behavioral disorders such as agitation behavior and/or aggression behavior and/or associated symptoms associated with Central Nervous System (CNS) disorders such as alzheimer's disease. Methods related to the invention include administering a dextromethorphan compound alone or in combination with a CYP2D6 inhibitor, such as quinidine (Q), to a subject having a Central Nervous System (CNS) disorder, such as aggressive behavior and/or aggressive behavior in alzheimer's disease and/or associated symptoms. The present invention also relates to pharmaceutical combinations comprising dextromethorphan compound alone or in combination with a CYP2D6 inhibitor, such as quinidine (Q).

Background

Alzheimer's disease is a progressive neurodegenerative disease that ultimately leads to death. It is estimated that 540 million americans suffer from alzheimer's disease. This data has doubled since 1980; it is expected that by 2050, the number of patients will be as high as 1600 million (Brookmeyer et al, Alzheimer's details.2011; 7(1): 61-73). The prevalence of dementia is estimated to be 5% to 15% among adults over 65 years of age in the United states, with Alzheimer's disease being the most common type of dementia (Kaplan and Sadock's Synopsis of Psychiatry: Behavior Sciences, 1998; Evans et al, JAMA.1989; 262(18): 2551-6; Losonczy et al, Public Health reports, 1998; 113: 273-80).

It is widely recognized that aggressive behavior is a common and important clinical feature of Alzheimer's disease and other forms of dementia (Ballard CG et al, Nat Rev neurol.2009; 5(5): 245-. Although clinicians and caregivers can readily identify aggressive behavior in dementia, until recently a consensus definition was drawn by the international association for the definition of aggressive behavior (ADWG) of the international association for the psychiatry of the aged (IPA) with the following criteria: "1) occurs in a patient suffering from cognitive impairment or dementia syndrome; 2) the behavior presented is consistent with emotional distress; 3) exhibit excessive motion activity, speech, or physical aggression; and 4) overt behavior that results in excessive impairment to the relationship and/or daily activities, and is not entirely attributable to another disorder (psychiatric, medical, or psychoactive substance-related disorder) (Cummings J et al, int. Psychogeriatr.2014: 1-11). It is estimated that up to about 80% of dementia patients are affected by aggressive and/or aggressive behavior (Ryu S-H et al, Am J Geriatr Psychiatry.2005; 13(11): 976-.

The aggressive behavior of dementia patients is accompanied by: increased dysfunction (Rabins P V et al, Alzheimer's resolution.2013; 9(2): 204-; the quality of life is worse (Gonz lez-Salvador T et al, Int J Geriator Psychiatry.2000; 15(2): 181-189); earlier hospital placement (Steele C et al, Am JPsychiatry. 1990; 147(8):1049- & 1051); increase the burden on the caregiver (Rabins PV et al, Alzheimer's resolution.2013; 9(2): 204-); increase medical costs (Murman DL et al, neurology.2002; 59(11): 1721-; the shorter time required to develop severe dementia (Peters ME et al, Am J Geriaatr Psychiatry. 2014; 22(3): S65-S66); and accelerated death (Peters ME et al, Am J Geriaatr Psychiatry. 2014; 22(3): S65-S66). For these reasons, aggressive and aggressive behavior are the neuropsychiatric symptoms most likely to require drug intervention in Alzheimer's disease patients (Ballard CG et al, Nat Rev neurol.2009; 5(5): 245-.

However, there are currently no FDA-approved drugs for the treatment of catastrophe in Alzheimer's disease, and clinicians can ultimately only attempt to control symptoms by means of off-target uses of antipsychotics, sedatives/hypnotics, anxiolytics, antidepressants (Maher AR et al JAMA. 2011; 306(12): 1359-. Unfortunately, the effectiveness of these treatments is limited and only small therapeutic effects are offset by relatively poor compliance, safety and tolerability (Ballard CG et al, Nat Rev neurol.2009; 5(5): 245-. Thus, there is an urgent need to develop safe and effective pharmaceutical interventions for the treatment of aggressive behavior in dementia. This treatment can have profound effects on patient care, reducing the burden on the caregiver, and potentially improving overall disease prognosis.

Since there is no treatment for Alzheimer's disease-related behavioral symptoms approved by the United states Food and Drug Administration (FDA), it has been common to treat symptoms such as aggression and agitation by off-target use of antipsychotic prescriptions (Salzman et al, J.Clin.Psychiatry.2008; 69(6): 889-98; Levenson and Crecelius, AMDA: Publications-Caring for the Ages., 2003; 4(6):31, 34-35). Short-term treatment (6 to 12 weeks) of atypical antipsychotics has a small effect on aggressive behavior, but the benefit of longer-term treatment is limited because adverse effects tend to offset the potential therapeutic effects (Scheider et al, n.engl.j.med.2006; 355(15): 1525-38). The benefit for other symptoms such as aggressive behavior is less pronounced (Sultzer et al, am.J. Psychiatry.2008; 165(7): 844-54). In addition, the possibility of serious adverse outcomes from the use of antipsychotics is also of serious concern, including the onset of stroke and increased mortality (Hybrechts et al, BMJ.2012; 344: e 977). Antipsychotic psychiatric drugs have also been studied for their use in symptom relief and as secondary prevention, but with minimal success (Tariot et al, Arch. Gen. Psychiatry.2011; 68(8): 853-61). Therefore, careful consideration of other pharmacological and non-pharmacological approaches for treating The aggressive and aggressive behaviors in Alzheimer's disease patients is imperative (Ballard et al, curr. Opin. Psychiatry. 2009; 22(6): 532-40; Lyketsos et al, The Journal of Alzheimer's Association.2011; 7(5): 532-9).

Dextromethorphan is the common name for (+) -3-methoxy-N-methyl morphinan. Which is one of the molecular types of dextrorotatory analogs of morphine-like opioids. Dextromethorphan is known to have at least three distinct receptor activities affecting central nervous system neurons. Although the pharmacological properties of dextromethorphan point to clinical efficacy for several indications, its efficacy is disappointing when dextromethorphan is administered alone compared to placebo.

It has long been known that dextromethorphan undergoes extensive O-demethylation in the liver to dextrorphan in most humans (estimated to cover about 90% of the general population of the United states), which is catalyzed by CYP2D6 and rapidly excreted (Ramachender et al, J.pharm.Sci.1977; 66(7): 1047-8; and Vetticaden et al, pharm.Res.1989; 6(1): 13-9). CYP2D6 is a member of the type of oxidase present in high concentrations in the liver and is called cytochrome P450 enzyme (Kronbach et al, anal. biochem. 1987; 162(1): 24-32; and Dayer et al, Clin. Pharmacol. The.1989; 45(1): 34-40).

In addition to metabolism of dextromethorphan, CYP2D6 is also responsible for polymorphic isoquinolinium hydroxylation in humans (Schmid et al, Clin. Pharmacol. Ther.1985; 38: 618-. An alternative pathway is mediated primarily by CYP3A4 and N-demethylation to form 3-methoxy morphinans (Von Moltke et al, J.Pharm.Pharmacol., 1998; 50: 997-1004). Both dextrorphan and 3-methoxy morphinans may be further demethylated to 3-hydroxy morphinans, which are then subject to glucuronidation. In most humans, the pathway for the conversion of dextromethorphan to dextrorphan is the major metabolic pathway, which is also the principle behind the phenotype of individuals classified into CYP2D6 pan-metabolizers and poor metabolizers using dextromethorphan as a probe (Kupfer et al, Lancet. 1984; 2: 517-518; Guttendorf et al, ther. drug Monit. 1988; 10: 490-498). Approximately 7% of caucasians exhibit the phenotype of undesirable metabolites, and the incidence of undesirable metabolite phenotypes among Huans and African blacks is even lower (Droll et al, Pharmacogenetics.1998; 8: 325-. In a study examining the ability of dextromethorphan to increase pain thresholds in both pan-and mal-metabolizers, it was found that the analgesic effect of dextromethorphan was significant in mal-metabolizers, but not in pan-metabolizers (Desmeules et al, J.Pharmacol. exp. Ther.1999; 288:607- & 612). These results are consistent with the direct effect of the parent dextromethorphan (rather than the dextrorphan metabolite) on neuromodulation.

Disclosure of Invention

As noted above, there remains a pressing need for other or improved forms of treatment for aggressive behavior, and/or associated symptoms in alzheimer's patients. The present invention provides methods of treating aggressive behavior and/or associated symptoms in alzheimer's disease patients without increasing the risk of serious adverse effects.

A first aspect of the invention provides a method for treating aggressive behavior and/or associated symptoms in a demented subject by administering a dextromethorphan compound in combination with a CYP2D6 inhibitor, such as quinidine (Q). The invention also encompasses the use of pharmaceutically acceptable salts of either or both dextromethorphan compound and quinidine in such methods. Analogs or derivatives of quinidine may also be used in the methods described herein. In one embodiment, the dementia is of the alzheimer's type.

A second aspect of the present invention relates to a combination of a dextromethorphan compound and a CYP2D6 inhibitor, such as quinidine. The invention also encompasses the use of pharmaceutically acceptable salts of either or both dextromethorphan compound and quinidine in such combinations. The combination is useful for treating aggressive behavior and/or associated symptoms in a subject with dementia. Analogs or derivatives of quinidine may also be used in this combination. In one embodiment, the dementia is of the alzheimer's type.

In some embodiments, according to the first and second aspects of the invention, the dextromethorphan compound is administered in an amount of about 10mg per day to about 200mg per day, and the quinidine is administered in an amount of about 0.05mg per day to less than about 50mg per day.

In some embodiments, quinidine is administered in an amount or dose of from about 4.75mg per day to about 20mg per day. In some embodiments, the dextromethorphan compound is administered in an amount or dose of about 10mg per day to about 90mg per day.

In some embodiments, either or both of the quinidine and dextromethorphan compounds are in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts according to the present invention include alkali metal salts, lithium salts, sodium salts, potassium salts, alkaline earth metal salts, calcium salts, magnesium salts, lysine salts, N' dibenzylethylenediamine salts, chloroprocaine salts, choline salts, diethanolamine salts, ethylenediamine salts, meglumine salts, procaine salts, Tris salts, salts of free acids, salts of free bases, inorganic salts, sulfates, hydrochlorides and hydrobromides. In some embodiments, the dextromethorphan compound is in the form of dextromethorphan hydrobromide or deuterated dextromethorphan hydrobromide. In some embodiments, the quinidine is in the form of quinidine sulfate.

In some embodiments, the dextromethorphan compound and quinidine are administered or used in a unit dosage form. In some embodiments, the unit dosage form comprises about 4.75mg, 4.9mg, 9mg, or 10mg quinidine (e.g., quinidine sulfate) and about 45mg, 34mg, 30mg, 28mg, 24mg, 23mg, 20mg, 18mg, 15mg, or 10mg dextromethorphan compound (e.g., deuterated dextromethorphan hydrobromide or dextromethorphan hydrobromide). In one embodiment, the unit dosage form comprises about 10mg quinidine (e.g., quinidine sulfate) and about 20mg or 30mg dextromethorphan compound (e.g., dextromethorphan hydrobromide or deuterated dextromethorphan hydrobromide). In another embodiment, the unit dosage form comprises about 9mg quinidine (e.g., quinidine sulfate) and about 15mg or 23mg dextromethorphan compound (e.g., dextromethorphan hydrobromide or deuterated dextromethorphan hydrobromide). In another embodiment, the unit dosage form comprises about 4.9mg quinidine (e.g., quinidine sulfate) and about 18mg, 24mg, 28mg, 30mg, or 34mg dextromethorphan compound (e.g., dextromethorphan hydrobromide or deuterated dextromethorphan hydrobromide). In another embodiment, the unit dosage form comprises about 4.75mg quinidine (e.g., quinidine sulfate) and about 18mg, 24mg, 28mg, 30mg, or 34mg dextromethorphan compound (e.g., dextromethorphan hydrobromide or deuterated dextromethorphan hydrobromide). In some embodiments, the unit dosage form of the dextromethorphan compound and quinidine is in the form of a tablet or capsule.

In some embodiments, the dextromethorphan compound and quinidine are administered or used in a combined dose or in separate doses, wherein the weight ratio of dextromethorphan compound to quinidine is about 1:1 or less. In some embodiments, the weight ratio is about 1:1, 1:0.95, 1:0.9, 1:0.85, 1:0.8, 1:0.75, 1:0.7, 1:0.65, 1:0.6, 1:0.55, or 1:0.5 or less. Also, in certain embodiments, the dose has a weight ratio of dextromethorphan compound to quinidine of less than about 1:0.5, e.g., about 1:0.45, 1:0.4, 1:0.35, 1:0.3, 1:0.25, 1:0.2, 1:0.15, or 1:0.1, 1:0.09, 1:0.08, 1:0.07, 1:0.06, 1:0.05, 1:0.04, 1:0.03, 1:0.02, or 1:0.01 or less. The weight ratio may be, for example, about 1:0.75, about 1:0.68, about 1:0.6, about 1:0.56, about 1:0.5, about 1:0.44, about 1:0.39, about 1:0.38, about 1:0.31, about 1:0.30, about 1:0.29, about 1:0.28, about 1:0.27, about 1:0.26, about 1:0.25, about 1:0.24, about 1:0.23, about 1:0.22, about 1:0.21, about 1:0.20, about 1:0.19, about 1:0.18, about 1:0.17, 1:0.16, about 1:0.15, about 1:0.14, about 1:0.13, about 1:0.12, about 1:0.11, and about 1: 0.10. In some embodiments, the weight ratio of dextromethorphan free base to quinidine free base is about 1:0.68, about 1:0.56, about 1:0.44, about 1: 0.38. In certain other embodiments, the weight ratio of d 6-deuterated dextromethorphan free base to quinidine free base is from about 1:0.30, about 1:0.22, about 1:0.19, about 1:0.18, about 1:0.16, and about 1: 0.15.

The dextromethorphan compound and quinidine may be administered or used in one combined dose per day or in at least two combined doses per day. In one embodiment the dextromethorphan compound and quinidine are administered in combination.

In some embodiments, the improvement obtained in the aggressive behavior and/or associated symptoms in alzheimer's disease subjects by treatment with a dextromethorphan compound in combination with quinidine, may be measured by improvement in one or more of the following scores:

the horror/aggressor field of neuropsychiatric symptom questionnaires (NPIs);

NPI total score;

a composite score of NPI excitatory/aggressive, irritability/instability, abnormal motor behaviour and anxiety domains (NPI 4A);

a composite score of NPI excitatory/aggressive, irritability/instability, abnormal motor behaviour and fields of disinhibition (NPI 4D);

puzzles of NPI caregivers-the area of aggressive/aggressive behavior;

modified alzheimer cooperative study-clinical global impression change for aggressive behavior (ADCS-CGIC) score; and/or

Patient global impression change (PGI-C) score for aggressive behavior.

In one embodiment, the subject has a reduction in the aggressive/aggressive behavior NPI score of at least 1.5 compared to an untreated subject or a subject administered a placebo.

In one embodiment, the subject has a reduction in NP14A score of at least 2.4 compared to an untreated subject or a subject administered a placebo.

In one embodiment, the subject has a decreased NP14D score of at least 3.0 compared to an untreated subject or a subject administered a placebo.

In one embodiment, the subject's ADCS-CGIC score for aggressive behavior is improved by at least 0.5 compared to untreated subjects or subjects administered placebo.

In one embodiment, the subject's PGI-C score for aggressive behavior is improved by at least 0.6 compared to untreated subjects or subjects administered placebo.

The pharmaceutical formulations disclosed herein may optionally include a pharmaceutically acceptable carrier, adjuvant, filler, or other pharmaceutical composition, and may be administered in any of a variety of forms or routes known in the art.

The methods disclosed herein may also optionally include administering the dextromethorphan compound with a CYP2D6 inhibitor such as quinidine, along with other therapeutic agents such as, for example, one or more therapeutic agents known or identified for the treatment of alzheimer's disease.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further non-limiting illustrations of the invention.

Brief Description of Drawings

Fig. 1 shows the chemical structure of one embodiment of the dextromethorphan compound of the present invention, i.e., d 6-deuterium-modified dextromethorphan.

Figure 2 provides a study design for a clinical study of aggressive behavior in alzheimer's disease. "dextromethorphan/quinidine 20/10" refers to a dosage of 20mg dextromethorphan and 10mg quinidine. QD and BHD refer to the once daily and twice daily doses, respectively. Asterisks indicate that participants terminated prior to week 1 visit, and thus there was no post-baseline data available for primary efficacy endpoints.

Figure 3 provides a schematic representation of a unified standards for reporting test (CONSORT) patient flow chart for a transient behavior clinical study in alzheimer's disease as described herein. Is marked with

The population of (a) represents those included in a Sequential Parallel Comparison Design (SPCD).

Figure 4 illustrates the mean NPI aggressive behavior/aggressive behavior scores in the first phase for subjects included in the clinical study of aggressive behavior in alzheimer's disease described herein, using a serial parallel comparison design (or SPCD). P values for each visit are shown, calculated from an analytical covariance (ANCOVA) model (with treatment as the fixed effect and baseline as the covariate).^aAs observed.

Figure 5 illustrates the mean NPI transient behavior/aggression scores in a second phase for subjects involved in a transient behavior clinical study (using SPCD) in alzheimer's disease. P values for each visit are shown, calculated from the ANCOVA model (with treatment as the fixed effect and baseline as the covariate).^aAs observed.

Figure 6 illustrates the mean NPI aggressive behavior/aggressive behavior score in a 10-week secondary analysis of an aggressive behavior clinical study in alzheimer's disease as described herein. Secondary analyses for 10 weeks included only subjects who had been assigned the same treatment throughout the study, i.e., subjects who received only dextromethorphan/quinidine or only placebo, via random assignment throughout the study, thereby mimicking a parallel design. P-values for each visit are shown, calculated from the ANCOVA model (with treatment as the fixed effect and baseline as the covariate).^aAs observed.

Figure 7 shows the mean plasma concentrations of paroxetine and AVP-786-group 1 treatments over time.

Figure 8 shows the mean plasma concentrations of paroxetine and AVP-786-group 2 treatment over time.

Figure 9 shows mean plasma concentrations of duloxetine and AVP-786-group 3 treatments over time.

Figure 10 shows mean plasma concentrations of duloxetine and AVP-786-group 4 treatments over time.

Detailed Description

The following detailed description and examples illustrate certain embodiments of the invention. Those skilled in the art will recognize that there are numerous variations and modifications of the present invention, which are included within the scope of the present invention. Therefore, the description of specific embodiments should not be taken as limiting the scope of the invention.

All references, including but not limited to published and unpublished applications, patents, and literature references, cited in this application are hereby incorporated by reference in their entirety and are hereby incorporated by reference into this specification.

Definition of

The terms "improving" and "treating" are used interchangeably and include therapeutic treatment. The terms refer to ameliorating, reducing, inhibiting, attenuating, alleviating, suppressing, or stabilizing a disease (e.g., a disease or disorder described herein) or the development or progression of a single symptom or a group of symptoms of a disease (e.g., a syndrome). As used herein, "treating" or "treatment" refers to alleviating or alleviating at least one symptom of a disease in a subject. For example, with respect to behavior disorders, "treating" may refer to alleviating or reducing any combination of excitatory and/or aggressive behavior and/or associated symptoms and manifestations thereof (e.g., hitting, cursing, beating, pacing, repelling, etc.) and associated behavior (e.g., irritability, anxiety, etc.). Within the meaning of the present invention, the term "treatment" also means to halt, delay the onset of (i.e. the period of the disease before clinical manifestation), and/or reduce the risk of the disease occurring or worsening.

"disease" refers to any condition or disorder that impairs or interferes with the normal function of a cell, tissue, organ or organism.

The term "dementia" refers to the overall deterioration of mental functioning due to either organic or psychological factors; characterized by directional force impairment; impaired memory, judgment and intelligence; and a superficial and unstable mood. Dementia in the present application includes vascular dementia, Ischemic Vascular Dementia (IVD), frontotemporal dementia (FTD), dementia with lewy bodies, Alzheimer's dementia, and the like. The most common form of dementia is associated with Alzheimer's Disease (AD).

"Alzheimer's Disease (AD)" refers to progressive deterioration of mental performance, which manifests as memory loss, confusion and disorientation, typically occurring in later years, and usually resulting in death between 5 and 10 years. Alzheimer's disease can be diagnosed by a skilled neurologist or clinician. In one embodiment, a subject with alzheimer's disease will meet the national neurological disorders and communication impairment and stroke institute/alzheimer's and related diseases institute (NINCDS/ADRDA) criteria for the presumed presence of alzheimer's disease.

The term "analog" or "derivative" is used herein in the conventional pharmaceutical sense to refer to a molecule that is structurally similar to a reference molecule (such as dextromethorphan, deuterated dextromethorphan, or quinidine), but has replaced one or more particular substituents of the reference molecule with substitute substituents in a targeted and controlled manner such that a molecule is produced that is structurally similar to the reference molecule. The synthesis and screening of analogs (e.g., using structural and/or biochemical analysis) to identify slightly modified versions of known compounds that may have improved or biased properties (such as higher potency and/or higher selectivity for a particular targeted receptor type, higher ability to penetrate the blood-brain barrier of a mammal, fewer side effects, etc.) is a drug design approach well known in pharmaceutical chemistry. In addition, using methods known to those skilled in the art, analogs and derivatives of the compounds of the present invention may be produced that have enhanced therapeutic efficacy, i.e., higher potency and/or greater selectivity for a particular targeted receptor type, greater or lesser ability to penetrate the blood-brain barrier of a mammal (e.g., greater or lesser blood-brain barrier permeability), fewer side effects, longer residence in a subject, etc.

The term "aggressive behavior" as used in the present invention is a generic term that may refer to a range of behavioral disorders or obstacles, including aggressive behavior, fighting and hyperactivity. For the purposes of the present invention, this definition includes the aggressive behavior as follows: cummings et al International Psychogeriatrics; volume 27; issue 01; month 1 of 2015, pp 7-17. In a broad sense, Cummings et al define the aggressive behavior as: 1) occurs in patients with cognitive impairment or dementia syndromes; 2) the behavior presented is consistent with emotional distress; 3) exhibit excessive motion activity, speech, or physical aggression; and 4) overt behavior that results in an excessive disorder and is not entirely attributable to another disorder (psychiatric, medical or psychoactive substance related). The term aggressive behavior also includes:

1) excessive motor activity associated with a feeling of internal stress. This activity is often futile and repetitive, and consists of activities such as failing to sit motionless, pacing, twisting both hands, and pulling on clothing;

2) inappropriate speech, sound or action activity that cannot be interpreted in terms of demand or confusion (fusion) itself. Including such activities as wandering, pacing, cursing, screaming, biting, and fighting;

3) sounds or actions in a particular environment that are disruptive, unsafe, or interfere with the progress of care. It includes four areas of behavior, such as voice production, movement disorders, aggression, and resistance to care;

4) informing others that the individual is experiencing an unpleasant agitation condition and that the behavior remains unchanged after the intrinsic and extrinsic stimuli with reduced intervention, including treatment of resistance, alleviation of aversive physical signs, reduction of sources of accumulated stress; and

5) the individual refuses to collaborate, is helpless, or has difficult to handle.

The term "associated symptoms" as used herein refers to symptoms associated with a patient who meets the criteria for cognitive impairment or dementia syndrome (e.g., alzheimer's disease, frontotemporal dementia, dementia with lewy bodies, vascular dementia, other dementias, a pre-dementing cognitive impairment syndrome such as mild cognitive impairment or other cognitive disorders). The associated symptoms include, for example, behaviors associated with observed or inferred evidence of emotional distress, such as rapid changes in mood, irritability, and an outbreak of splenic qi. In some cases, the behavior is persistent or recurrent at least for a period of two weeks, and represents a behavior different from that of the patient at ordinary times. The term "associated symptoms" also includes excessive motion activity (examples include pacing, swinging back and forth, gesturing, pointing, fidgeting, performing repetitive gestures); verbal attacks (e.g., screaming, speaking with too much voice, abusing, screaming, shouting); personal attacks (e.g., grabbing, pushing, repelling, hitting someone else, kicking an object or person, scratching, biting, throwing an object, hitting oneself, throwing a door, tearing something, and destroying property).

The term "combination" as used in relation to the active ingredients is used herein to define a single pharmaceutical composition (formulation) comprising two agents of the invention (i.e. a dextromethorphan compound and quinidine), or to define two separate pharmaceutical compositions (formulations) to be co-administered, each of which comprises one agent of the invention (i.e. a dextromethorphan compound or quinidine).

Within the meaning of the present invention, the term "co-administration" is used to refer to the simultaneous administration of a dextromethorphan compound and quinidine in one composition, or in different compositions, or sequentially. For sequential administration, which is considered "co-administration," the dextromethorphan compound and quinidine are administered at a time interval that produces a beneficial effect in treating, preventing, suppressing, delaying the onset and/or reducing the risk of worsening a related behavioral disorder in a subject for a Central Nervous System (CNS) disorder. For example, in some embodiments, the dextromethorphan compound and quinidine are administered on the same day (e.g., once or twice each day).

As described herein, the total NPI score is a composite score of the standard 12-item NPI domain. NPI is a validated clinical tool for assessing psychopathology in a variety of disease states, including dementia. NPI is a retrospective caregiver-respondent interview covering the 12 areas of neuropsychiatric symptoms: delusions, hallucinations, aggressive/aggressive behavior, irritability/depression, anxiety, euphoria/elation, apathy/indifference, disinhibition behavior, irritability/instability, abnormal motor behavior, nocturnal behavior disorders and appetite/eating disorders. The finalized NPI interview includes comprehensive screening questions for each symptom domain; when a screening question elicits a positive response, there is a series of questions to be raised next regarding the domain-specific behavior. Neuropsychiatric performance in one field is scored by the caregiver on both frequency (0 to 4) and severity (1 to 3) to obtain a composite (frequency x severity) symptom field score of 1 to 12 for each field deemed positive. Anchor points have been defined in frequency and severity scoring tables to improve the confidence of the caregiver's responses. The caregiver's distress score was rated for each positive neuropsychiatric symptom field on a scale located by a score of 0 (no distress) to 5 (highly distress). As used herein, NPI4A scores are composite scores comprising fields of NPI aggression/aggression, abnormal motor behavior, irritability/instability, and anxiety. As used herein, NPI4D scores are composite scores comprising the fields of NPI aggressive/aggressive behavior, abnormal behaviours, irritability/instability, and disinhibition behavior.

The term "therapeutically effective" when used in reference to a dose or amount refers to an amount of a compound or pharmaceutical composition that is sufficient to produce the desired activity when administered to a subject in need thereof. In the present application, the term "therapeutically effective amount/dose" when used in a pharmaceutical composition comprising a dextromethorphan compound is used interchangeably with the term "neurologically effective amount/dose" and refers to an amount/dose of a compound or pharmaceutical composition sufficient to produce an effective neurological response, i.e., to ameliorate a behavioral disorder associated with a central nervous system disorder, when administered to a subject.

The term "pharmaceutically acceptable" as used in connection with the compositions of the invention, means that the molecular entities and other ingredients of the composition are physiologically tolerable and do not normally produce adverse reactions when administered to a subject, such as a human. In some embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia as suitable for use in mammals, and more particularly in humans.

The term "carrier" as used in the pharmaceutical compositions of the present invention refers to a diluent, excipient or vehicle with which the active compound (e.g., dextromethorphan compound or quinidine) is administered. The pharmaceutical carrier can be a sterile liquid, such as water, saline solution, aqueous dextrose solution, aqueous glycerol solution; and oils, including those from petroleum, animal, vegetable or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Suitable pharmaceutical carriers are described in e.w. martin, 18 th edition of "Remington's pharmaceutical Sciences".

The term "subject" as used herein includes mammals (e.g., rodents such as mice or rats). In some embodiments, the term refers to a human presenting a behavioral disorder associated with a central nervous system disorder, such as aggressive behavior and/or aggressive behavior. The term "subject" also includes humans exhibiting neuropsychiatric or behavioral symptoms of dementia.

It will be appreciated that there are some variations in the abundance of natural isotopes in the compounds synthesized, depending on the source of the chemical starting materials used in the synthesis. Thus, a formulation of dextromethorphan will inherently contain a small amount of deuteration and/or contain¹³Isotopologue of C. Despite this variation, the concentration of naturally abundant stable hydrogen and carbon isotopes is minor and inconsequential compared to the stable degree of isotopic substitution of the compounds of the present invention. See, e.g., Wada E et al, Seikagaku1994, 66: 15; ganes L Z et al, Comp Biochem Physiol A Mol Integr Physiol 1998, 119: 725. In the compounds of the present invention, when a particular position is designated as having deuterium, it is understood that the abundance of deuterium at that position is significantly greater than the natural abundance of deuterium (typically about 0.015%). The position designated as having deuterium typically has a lowest isotopic enrichment factor of at least 3000 (45% incorporation of deuterium) at each atom designated as deuterium in the compound.

The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.

In other embodiments, the compounds of the invention have isotopic enrichment factors for each designated deuterium atom of at least 3500 (52.5% deuterium incorporated at each designated deuterium atom), at least 4000 (60% deuterium incorporated), at least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated), at least 6466.7 (97% deuterium incorporated), at least 6600 (99% deuterium incorporated), or at least 6633.3 (99.5% deuterium incorporated).

In the compounds of the present invention, any atom not specifically designated as a specific isotope means any stable isotope representing the atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," it is understood that the position has hydrogen in its natural abundance isotopic composition.

The term "isotopologues" refers to substances having the same chemical structure as the chemical formula and the particular compounds of the present invention, except for the isotopic composition (e.g., hydrogen versus deuterium) at one or more positions. Thus, isotopologues differ from the specific compounds of the present invention only in their isotopic composition.

The term "compound" as used herein is intended to include any salt, solvate or hydrate thereof. For convenience of use in this application, the term "dextromethorphan compound" will include the following terms: dextromethorphan; or deuterated dextromethorphan; or an analog or derivative of dextromethorphan; or an analog or derivative of deuterated dextromethorphan.

Generally, the dextromethorphan compounds of the present invention have four molecular rings in a configuration referred to as the "morphinan" structure, which is shown below:

in this figure, the carbon atoms are numbered in a conventional manner, while the wedge-shaped bonds coupled to carbon atoms 9 and 13 indicate that these bonds are convex in the plane of the other three rings in the morphinan structure.

Salts of the compounds of the present invention are formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide (hydrogenbisufide), hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid (bitartaric acid), ascorbic acid, maleic acid, benzenesulfonic acid (besylic acid), fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. The pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate (decanoate), octanoate, acrylate, formate, isobutyrate, decanoate (caprate), heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phenylpropionates, phenylbutyrates, citrates, lactates, beta-hydroxybutyrate, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids (e.g., hydrochloric and hydrobromic acids) and include those formed with organic acids such as maleic acid.

In some embodiments, the pharmaceutically acceptable salts include alkali metal salts, lithium salts, sodium salts, potassium salts, alkaline earth metal salts, calcium salts, magnesium salts, lysine salts, N' dibenzylethylenediamine salts, chloroprocaine salts, choline salts, diethanolamine salts, ethylenediamine salts, meglumine salts, procaine salts, Tris salts, salts of free acids, salts of free bases, inorganic salts, sulfates, hydrochlorides, and hydrobromides.

Unless otherwise indicated, the dosages described herein refer to the dextromethorphan compound and the hydrobromide and sulfate salt forms of quinidine, respectively. Based on this information, the skilled person can calculate the corresponding dose of the respective free acid or free base of the active ingredient. One skilled in the art can calculate the molecular weight of the dextromethorphan salt and the molecular weight of the dextromethorphan free base, and use this ratio to calculate the appropriate dosage of the free base and the salt. For example, dextromethorphan hydrobromide (of formula C) in an amount of 15mg can be administered or administered₁₈H₂₅NO.HBr.H₂O) and 9mg of quinidine sulfate (having the formula (C)₂₀H₂₄N₂O₂)₂.H₂SO₄.2H₂O), which corresponds to about 11mg of dextromethorphan and 7.5mg of quinidine. Other doses include, for example, 23mg of dextromethorphan hydrobromide with 9mg of quinidine sulfate (corresponding to about 17mg of dextromethorphan with about 7.5mg of quinidine); 20mg of dextromethorphan hydrobromide with 10mg of quinidine sulfate (corresponding to about 15mg of dextromethorphan with 8.3mg of quinidine); 30mg of dextromethorphan hydrobromide with 10mg of quinidine sulfate (corresponding to about 22mg of dextromethorphan with 8.3mg of quinidine).

The dose of 24mg of d 6-deuterated dextromethorphan hydrobromide (having the formula C)₁₈H₁₉D₆NO.HBr.H₂O) and 4.75mg quinidine sulfate (of formula (C)₂₀H₂₄N₂O₂)₂.H₂SO₄.2H₂O) (corresponding to about 18mg dextromethorphan and 3.96mg quinidine). Other doses of d 6-deuterated dextromethorphan include, for example, 34mg d 6-dextromethorphan hydrobromide and 4.75mg quinidine sulfate (corresponding to about 25.18mg d 6-dextromethorphan and about 3.96mg quinidine); 18mg of d 6-dextromethorphan hydrobromide and 4.9mg of quinidine sulfate (corresponding to about 13.33mg of d 6-dextromethorphan and 4.08mg of quinidine); 24mgd 6-dextromethorphan hydrobromide and 4.9mg quinidine sulfate (corresponding to about 17.78mg d 6-dextromethorphan and 4.08mg quinidine); 28mg of d 6-dextromethorphan hydrobromide and 4.9mg of quinidine sulfate (corresponding to about 20.74mg of d 6-dextromethorphan and 4.08mg of quinidine); 30mg of d 6-dextromethorphan hydrobromide and 4.9mg of quinidine sulfate (corresponding to about 22.22mg of d 6-dextromethorphan and 4.08mg of quinidine); 34mg of d 6-dextromethorphan hydrobromide and 4.9mg of quinidine sulfate (corresponding to about 25.18mg of d 6-dextromethorphan and 4.08mg of quinidine).

As used herein, the term "hydrate" refers to a compound that further comprises stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

As used herein, the term "solvate" refers to a compound that further comprises a stoichiometric or non-stoichiometric amount of a solvent (e.g., water, acetone, ethanol, methanol, dichloromethane, 2-propanol, etc.) bound by non-covalent intermolecular forces.

The compounds of the present invention (e.g., compounds of formula I below) may contain an asymmetric carbon atom due to, for example, deuterium substitution or other reasons. Thus, the compounds of the present invention can exist as individual enantiomers or as mixtures of two enantiomers. Thus, the compounds of the present invention will include racemic mixtures as well as individual stereoisomers, which are substantially free of another possible stereoisomer. The term "substantially free of other stereoisomers" as used herein, means that less than 25% of the other stereoisomers are present; in some embodiments, less than 10% of the other stereoisomers are present; in some embodiments, less than 5% of the other stereoisomers are present; and in some embodiments less than 2% other stereoisomers are present, or less than "X"% (where X is a number from 0 to 100 and includes 0 and 100) are present. Methods for obtaining or synthesizing individual enantiomers of a particular compound are well known in the art and may be applied to the final compound or starting materials or intermediates as the case may be.

The term "stable compound" as used herein refers to a compound that has sufficient stability to facilitate its manufacture and to maintain the integrity of the compound for a sufficient period of time to render it suitable for the purposes detailed herein (e.g., formulation into a therapeutic product, intermediate for the manufacture of a therapeutic compound, an intermediate compound that may be isolated or stored; for the treatment of a disease or condition responsive to a therapeutic agent).

"D" refers to deuterium.

"stereoisomers" refers to both enantiomers and diastereomers.

In this specification, a variable may be broadly designated (e.g., "each R") or may be specifically designated (e.g., R)¹Or R²). Unless otherwise indicated, when a variable is generally referred to, it is intended to include all specific embodiments of that particular variable.

As used herein, the term "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional unrecited elements or method steps.

It is to be understood that all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated otherwise, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

Therapeutic compounds

Dextromethorphan (DM) is a non-opioid d-isomer of the codeine analog levorphanol, and has been widespread in the past about 50 yearsIt is widely used as an over-the-counter (OTC) antitussive. Dextromethorphan is pharmacologically complex, having binding affinities for several different receptors, while its primary activity is directed towards the Central Nervous System (CNS). Dextromethorphan is well known for its activity as a weak non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist (K)_i1500nM), (Tortella et al trends pharmacol sci.1989; 10, (12) 501-7; chou YC et al, Brain Res.1999; 821(2) 516-9; netzer R et al, Eur J Pharmacol.1993; 238(2-3) is 209-16; jaffe DB et al, NeurosciLett.1989; 105(1-2): 227-32), and has the associated potential for anti-glutamate excitatory activity. Dextromethorphan is also a potent Sigma-1 agonist (Zhou GZ et al, Eur J Pharmacol.1991; 206(4): 261-9; Maurice T et al, Brain Res Rev.2001; 37(1-3): 116-32; Cobos EJ et al, CurrNeuropharmacol.2008; 6(4): 344-66), (K)_i200nM) and binds with high affinity to the 5-hydroxytryptamine transporter (SERT; k_i40 nM). Although the affinity of dextromethorphan for the norepinephrine carrier is only moderate (K)_i13 μ M), but it is effective in inhibiting norepinephrine uptake (K)_i240nM) (Codd EE et al, J Pharmacol expther.1995; 274(3):1263-70). Dextromethorphan is an antagonist of the α 3 β 4 nicotinic acetylcholine receptor and an IC50 value (the concentration that produces 50% inhibition) of 0.7 μ M has been reported (Damaj et al, J Pharmacol Exp ther.2005; 312(2): 780-5).

Dextromethorphan reduces potassium-stimulated glutamate release as a result of one or more of these interactions (Annels SJ et al Brain res.1991; 564(2): 341-3), and regulates monoamine (5-hydroxytryptamine, norepinephrine, and dopamine) neurotransmission (Codd EE et al J Pharmacol Exp heat.1995; 274(3): 1263-70; Maurice T et al Pharmacol heat.2009; 124(2): 195- "206; Maurice T et al ProgNeuropsychopharmacol Biol psychiatry 1997; 21(1): 69-102). The antagonism of dextromethorphan at the α 3 β 4 nicotinic acetylcholine receptors (Damaj MI et al, J Pharmacol Exp ther.2005; 312(2): 780-5) has application in certain CNS dyskinesias and addictions (Silver AA et al, J Am Acad Child Adolesc Psychiatry.2001; 40(9): 1103-10). When administered alone, dextromethorphan is rapidly metabolized in the liver to Dextrorphan (DX), resulting in a low bioavailability and thus limited exposure of the central nervous system. Although some receptors that interact with dextrorphan are identical to dextromethorphan, but differ in affinity for key receptors, they rapidly undergo glucuronide conjugation, which largely prevents their passage across the blood-brain barrier, thus reducing the effect of the prescribed dose on the central nervous system (Churchj et al, Eur J Pharmacol.1985; 111(2): 185-90; Franklin PH et al, Mol Pharmacol.1992; 41(1): 134-46).

The present invention provides compounds of formula I, including pharmaceutically acceptable salts, solvates, and hydrates thereof:

wherein R is¹Is selected from CH₃、CH₂D、CHD₂And CD₃(ii) a And R is²Is selected from CH₃、CH₂D、CHD₂And CD₃。

All compounds of formula I having at least one deuterium are referred to as deuterated dextromethorphan. In one embodiment R¹And R²Are all CD₃. The compound is also known as d 6-dextromethorphan or d 6-DM. In another embodiment, R¹And R²Only one of them is CD₃。

In another embodiment, the compound is selected from any one of the compounds shown in table 1.

Table 1: exemplary Compounds of formula I

Compound numbering	R1	R2
			100	CD3	CH3
101	CD3	CD3
			102	CD2H	CD3
103	CD3	CD2H
			104	CH3	CD3
105	CH2D	CH2D
			106	CH2D	CD3
107	CD3	CH2D
			108	CH3	CH3

In another set of embodiments, any atom in any of the above or below embodiments that is not designated as deuterium is present at its natural isotopic abundance.

In another group of embodiments, the compound of formula I is isolated or purified, e.g., the compound of formula I is present in a purity of at least 50% by weight (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, or 99.9%) of the total amount of isotopologues of formula I present, respectively. Thus, in some embodiments, a composition comprising a compound of formula I may comprise a distribution of isotopologues of the compound, with the proviso that at least 50% by weight of the isotopologues are said compound.

In some embodiments, any position in the compound of formula I designated as having deuterium has at least 45% (e.g., at least 52.5%, at least 60%, at least 67.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 99%, or at least 99.5%) of minimal deuterium incorporation at the designated position in the compound of formula I. Thus, in some embodiments, a composition comprising a compound of formula I can include a distribution of isotopologues of the compound, provided that at least 45% of the isotopologues include deuterium at the designated position.

In some embodiments, a compound of formula I is "substantially free" of other isotopologues of the compound, e.g., less than 50%, less than 25%, less than 10%, less than 5%, less than 2%, less than 1%, or less than 0.5% of other isotopologues are present.

The synthesis of the compounds of formula I is readily accomplished by ordinary synthetic chemists. Related procedures and intermediates are disclosed, for example, in Kim H C et al, Bioorg Med Chem Lett 2001, 11:1651 and Newman A H et al, J Med Chem1992, 35: 4135.

These methods can be performed using the corresponding deuterated and optionally other isotopically-containing reagents and/or intermediates, or by employing standard synthetic protocols known in the art for introducing isotopic atoms into chemical structures, to synthesize the compounds described herein.

Deuterated (d6) -dextromethorphan (d6-DM) (fig. 1) is a deuterated isotope of dextromethorphan wherein 6 hydrogen atoms at specific positions are replaced with deuterium. Deuterium is a stable, non-radioactive isotope of hydrogen and is ubiquitous in the environment, including ubiquitous in water. Stable isotopes are often used in medical research and have a long history of use in people of all ages, from newborns to adults. Deuterium is most commonly used at tracer levels in PK and metabolic studies. Expected exposure levels during long-term administration of deuterated therapeutic drugs are also expected to be relatively low compared to daily exposure from natural sources such as water. For example, exposure from a 30mg dose of d 6-dextromethorphan is estimated to be about equivalent to 20 milliliters (0.7 ounces) of water. This is based on the natural abundance of deuterium in water being 0.0156% and the assumption that all doses of d 6-dextromethorphan (MW 277.43) ingested will be metabolized to d 3-dextrorphan (d3-DX) and deuterated water (MW 20.03) liberated. The latter assumption overestimates the amount of deuterated water released, but provides a concept with respect to the comparative amount of deuterium consumed.

Pharmacological studies conducted by the present inventors with deuterated dextromethorphan show that the basic pharmacology of dextromethorphan is not altered by deuteration. PK and drug metabolism studies indicate that the metabolic pathway of d 6-dextromethorphan is the same as that of dextromethorphan. The inhibition of metabolism by CYP2D6 is most likely allowed by the substitution effect of deuterium. In vitro metabolism studies also indicate that d 6-dextromethorphan produces the same metabolite as dextromethorphan (by metabolism of different species, including humans), i.e. d 6-dextromethorphan is not recognized to produce any unique metabolite compared to dextromethorphan. Tissue distribution studies showed that¹⁴C-labelled d 6-dextromethorphan (¹⁴C-d6-DM) with a compound derived from¹⁴C-labelled dextromethorphan (¹⁴C-DM) was similar. Toxicology studies using d 6-dextromethorphan showed dose limiting of d 6-dextromethorphan with dextromethorphan at comparable exposuresSexual toxicity (DLT) is comparable and is based on adverse clinical signs associated with central nervous system effects. In a 13-week toxicity study using d 6-dextromethorphan/quinidine (which included a high dose of dextromethorphan/quinidine for comparison), the toxicity measurements evaluated showed that d 6-dextromethorphan/quinidine gave similar results to the study with non-deuterated dextromethorphan/quinidine.

Exemplary Synthesis

A convenient method of synthesizing the compound of formula I replaces the appropriate deuterated intermediates and reagents in the synthetic methods used in the preparation of dextromethorphan. Such methods are described, for example, in U.S. patent No. 7,973,049, which is incorporated herein by reference in its entirety. The compounds of formula I may be prepared from one of the known intermediates X, XI and XII shown below, and may be prepared from related intermediates that are readily available from known procedures.

Scheme 1 shows the general pathway for compounds of formula I.

Scheme 1 shows the preparation of wherein R¹Is not CH₃General route to compounds of formula I. HBr salt 10, in NH₄After OH treatment, N-demethylation was performed to give 11. Acylation of amine 11 with ethyl chloroformate to afford carbamate 12, which is then used with BBr₃O-demethylation is performed to give alcohol 13. Treating compound 13 with appropriately deuterated iodomethane in the presence of a base to give ether 14, which is reduced with Lithium Aluminum Deuteride (LAD) to give a compound wherein R is²═CD₃Or reduced with Lithium Aluminium Hydride (LAH) to give compounds of formula I wherein R is²═CH₃The compound of (1). For itIn R¹Is CH₃Of carbamate 12 directly treated with LAD to prepare a compound of formula (i) wherein R²Is a CD₃The compound of (1).

The particular methods and compounds shown above are not intended to be limiting. The variables described by chemical structures in the schemes herein are defined herein as being commensurate with the chemical group definitions (moiety, atom, etc.) of the corresponding positions in the compound formulae of the present application, whether identified by the same variable name (i.e., R) or not (i.e., R is defined as a group with a group having a lower degree of identity)¹Or R²) Or not. The suitability of a chemical group in a compound structure for use in the synthesis of another compound falls within the knowledge of one skilled in the art.

Other methods of synthesizing compounds of formula I and their synthetic precursors, including those in pathways not explicitly shown in the schemes of the present application, are within the purview of chemists of ordinary skill in the art. Synthetic chemical transformations and protecting group methods (protection and deprotection) suitable for synthesizing applicable compounds are known in the art and include, for example, those described below: larock R, Comprehensive Organic Transformations, VCH Publishers (1989); greene T W et al, Protective Groups in Organic Synthesis, 3^rdEd, John Wileyand Sons (1999); fieser L et al, Fieser and Fieser's Reagents for organic Synthesis, John Wiley and Sons (1994); and Paquette L, ed., Encyclopedia of Reagentsfor Organic Synthesis, John Wiley and Sons (1995); and their subsequent versions.

Combinations of substituents and variables contemplated by the present invention are those that result in the formation of stable compounds.

Deuterated dextromethorphan and dextromethorphan analogs or derivatives

It is to be understood that the dextromethorphan compounds used in the methods and combinations of the present invention include analogs or derivatives of both dextromethorphan and deuterated dextromethorphan. For example, in one embodiment, the combination or method according to the present invention comprises deuterated dextromethorphan, and in another embodiment, the combination and method comprises an analog or derivative of deuterated dextromethorphan. Similarly, in another embodiment, the combination or method according to the invention comprises dextromethorphan, and in another embodiment, the combination or method comprises an analog or derivative of dextromethorphan.

The term "alkyl", as used herein, refers to any unbranched or branched, substituted or unsubstituted saturated hydrocarbon. The alkyl moiety may be branched or straight chain. An alkyl group may have 1 to 10 carbon atoms (whenever appearing herein, a numerical range such as "1 to 10" refers to each integer within 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 encompasses the term "alkyl" where no numerical range is specified).

The term "substituted" has its usual meaning as found in many modern patents in the relevant art. See, for example, U.S. patent nos. 6,509,331; 6,506,787, respectively; 6,500,825, respectively; 5,922,683, respectively; 5,886,210, respectively; 5,874,443, respectively; and 6,350,759; all of which are incorporated herein by reference in their entirety. Specifically, the definition of "substituted" is as broad as provided in U.S. patent No.6,509,331, the term "substituted alkyl" as defined herein refers to an alkyl group, which in some embodiments has from 1 to 10 carbon atoms and from 1 to 5 substituents, and in some embodiments from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamido, cyano, halogen, hydroxy, carboxy, carboxyalkyl, keto, thioketo, mercapto, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, hydroxyl, carboxyl, carboxyalkyl, keto, thioketo, mercapto, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, substituted alkylthioalkoxy, and mixtures thereof, Nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO₂-alkyl, -SO₂-substituted alkyl, -SO₂-aryl and-SO₂-a heteroaryl group. Other patents, as listed above, also provide standard definitions of the term "substituted" as would be well understood by one skilled in the art.

The term "cycloalkyl" refers to any non-aromatic hydrocarbon ring, in some embodiments having from 5 to 12 atoms that make up the ring. The term "heterocycle" or "heterocyclic" refers to any non-aromatic hydrocarbon ring having at least one heteroatom such as an oxygen, sulfur or nitrogen atom and at least one carbon atom in the ring.

The term "alkenyl", as used herein, refers to any unbranched or branched, substituted or unsubstituted, unsaturated hydrocarbon containing a double bond between two carbons. The term "alkynyl", as used herein, refers to any unbranched or branched, substituted or unsubstituted, unsaturated hydrocarbon containing a triple bond between two carbons.

The terms "aryl" and "heteroaryl" as used herein refer to an aromatic hydrocarbon ring, in some embodiments the ring has 5, 6, or 7 atoms, and in other embodiments the ring has 6 atoms. "heteroaryl" refers to an aromatic hydrocarbon ring having at least one heteroatom such as oxygen, sulfur or nitrogen atom in the ring and at least one carbon atom. The term "heterocycle" or "heterocyclic" refers to any cyclic compound containing one or more heteroatoms. The aryl, heterocyclic and heteroaryl groups may be substituted with any of the substituents, including those described above and known in the art.

Substituent "R", which is present alone and without the indicated number, refers to a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon).

The term "aminoalkyl" refers to a radical selected from the group consisting of-RNR 'R ", -RNHR', and-RNH₂Wherein R, R' and R "are each independently R as defined herein.

The term "halogen atom", as used herein, refers to any one of the radio-stable atoms in column seven of the periodic Table of elements, such as fluorine, chlorine, bromine or iodine.

The term "alkoxy" refers to any unbranched or branched, substituted or unsubstituted, saturated or unsaturated ether, such as C₁-C₆Unbranched saturated unsubstituted ethers, methoxy, and dimethyl ethers, diethyl ethers,Methyl-isobutyl ether, and methyl-tert-butyl ether.

Several analogues of dextromethorphan have been found to slow or prevent the metabolism of dextromethorphan. In some embodiments, the hydrogen at the 2-position of the aryl ring may be replaced with a bulky group, i.e., R₁。

As used herein, the term "bulky" or "voluminous" refers to substituents having a cone angle greater than hydrogen. Suitable substituents include, but are not limited to, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₆-C₁₂Aryl radical, C₇-C₁₃Arylalkyl radical, C₃-C₁₀Cycloalkyl radical, C₂-C₁₀Heterocycle, C₃-C₁₀Heterocycloalkyl radical, C₃-C₁₂Heteroaryl group, C₄-C₁₂Heteroarylalkyl, alkylamino and dialkylamino wherein each hydrogen is optionally substituted by lower alkyl, alkoxy or halogen.

Without wishing to be bound by any particular theory, it is believed that when bulky groups are introduced, CYP2D6 is blocked from initiating the catalytic action of converting dextromethorphan compounds to dextrorphan and other metabolites. Thus, rapid metabolism of dextromethorphan analogs (including deuterated analogs) can be prevented or substantially reduced. For example, tert-butyl alkyl groups, by virtue of their relatively large cone angle, may protect methyl groups bonded to oxygen and prevent O-demethylation of dextromethorphan or deuterated dextromethorphan. Alternatively, if the bulky group contains a basic nitrogen, which is present 5 to 7 angstroms from the methoxy group, oxidation may be prevented by inhibition of CYP2D 6.

Suitable analogs having bulky groups at the 2-position include compounds (1-1) and (1-2), as shown below.

In other embodiments, the methoxy group at the 3-position may be replaced by a larger group OR₂And (4) substitution.

Suitable substituents include, but are not limited to, the following: r₁Selected from hydrogen, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₆-C₁₂Aryl radical, C₇-C₁₃Arylalkyl radical, C₃-C₁₀Cycloalkyl radical, C₂-C₁₀Heterocycle, C₃-C₁₀Heterocycloalkyl radical, C₃-C₁₂Heteroaryl group, C₄-C₁₂Heteroarylalkyl, alkylamino and dialkylamino wherein each hydrogen is optionally substituted with lower alkyl, alkoxy or halogen; and R is₂Is selected from C₂-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₆-C₁₂Aryl radical, C₇-C₁₃Arylalkyl radical, C₃-C₁₀Cycloalkyl radical, C₂-C₁₀Heterocycle, C₄-C₁₀Heterocycloalkyl radical, C₃-C₁₂Heteroaryl group, C₄-C₁₂Heteroarylalkyl, alkylamino and dialkylamino wherein each hydrogen is optionally substituted by lower alkyl, alkoxy or halogen. When R is₁Is hydrogen, R₂Hydrogen or methyl cannot be excluded to exclude dextromethorphan and dextrorphan.

-OR with a large volume at position 3₂Suitable analogues of the groups include compounds (II-1) to (II-4), as shown below.

In other embodiments, the methoxy group in the 3-position may be substituted with a larger group containing a sulfur atom.

Suitable substituents include, but are not limited to, the following: each R₁Independently selected from hydrogen, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₆-C₁₂Aryl radical, C₇-C₁₃Arylalkyl radical, C₃-C₁₀Cycloalkyl radical, C₂-C₁₀Heterocycle, C₃-C₁₀Heterocycloalkyl radical, C₃-C₁₂Heteroaryl group, C₄-C₁₂Heteroarylalkyl, alkylamino and dialkylamino wherein each hydrogen is optionally substituted by lower alkyl, alkoxy or halogen; and R is₂Is selected from-SR₁，

Suitable analogs having a sulfur-containing bulky group at the 3-position include compounds (III-1) - (III-3), as shown below.

Without wishing to be bound by any particular theory, it is believed that the introduction of a bulky group containing an oxygen or sulfur atom at the 3-position improves the half-life (t) of dextromethorphan or deuterated dextromethorphan_1/2). By increasing the half-life, blood levels of the dextromethorphan analog can be increased for a longer period of time before it is metabolized to dextrorphan. Alternative substituents and substitutions are also within the spirit and scope of the present invention. In particular, substituents and substitutions comprising one or more deuterium atoms (e.g., d6DM) are within the scope of the present invention. One of ordinary skill in the art will know how to perform the modifications of the dextromethorphan analogs of the present invention to provide deuterated dextromethorphan analogs.

Also included within the scope of the present invention are Newman et al, J Med chem.1992, 30/10; 35(22) 4135-42. Newman determined that these compounds exhibited anticonvulsant activity in a variety of in vitro and in vivo models of convulsant action.

CYP2D6 inhibitor

The present invention contemplates the use of dextromethorphan compounds in conjunction with CYP2D6 inhibitors such as quinidine. While quinidine is most commonly used for co-administration, other antioxidants, such as Inaba et al, Drug Metabolism and disposition.1985; 443-447, Forme-Pfister et al, biochem, Pharmacol, 1988; 3829-3835, and Broly et al, biochem. Pharmacol.1990; 39:1045-1053, may also be co-administered with dextromethorphan compounds to reduce their metabolic effects. As reported by Inaba et al, CYP2D6 inhibitors having a Ki value (Michaelis-Menton inhibition value) of 50 micromolar or less include nortriptyline, chlorpromazine, domperidone, haloperidol, pipamperone, labetalol, metoprolol, oxprenolol, propranolol, timolol, mexiletine, quinine, diphenhydramine, ajmaline, lobeline, papaverine, and yohimbine. Compounds having particularly potent inhibitory activity include yohimbine, haloperidol, ajmaline, lobeline and pipamperone, which have a K_iThe value ranges from 4 to 0.33. mu.M. In addition to the antioxidants reported above, Eli Lilly and Co, also found under the trade name

Fluoxetine is sold which has utility in some people to increase the concentration of dextromethorphan in the blood. In addition, any of the following compounds may be used to inhibit CYP2D 6: terbinafine, cinacalcet, buprenorphine, imipramine, bupropion, ritonavir, sertraline, duloxetine, thioridazine, metoclopramide, paroxetine, or fluvoxamine. The dosage of other antioxidants will vary depending on the antioxidant and will be determined on an individual basis.

It has been unexpectedly found that subjects suffering from aggressive and/or aggressive behavior in alzheimer's disease can be treated with a combination of a dextromethorphan compound and an amount of quinidine that is significantly lower than the minimum amount previously thought to be required to provide a significant therapeutic effect.

The metabolic effects of dextromethorphan, or deuterated forms thereof, can be further circumvented by co-administration of a CYP2D6 inhibitor in conjunction with dextromethorphan. Quinidine is a potent CYP2D6 inhibitor, and specific studies have been conducted on this use (U.S. patent 5,206,248 to Smith). The chemical structure of quinidine is as follows:

quinidine co-administration has at least two distinct beneficial effects. First, it greatly increases the circulating amount of dextromethorphan compound in blood. In addition, it also produces more consistent and predictable concentrations of dextromethorphan. Studies involving co-administration of dextromethorphan or quinidine and dextromethorphan, as well as studies of the effect of quinidine on plasma concentrations, are described in the patent literature (see, e.g., U.S. patent 5,166,207, U.S. patent 5,863,927, U.S. patent 5,366,980, U.S. patent 5,206,248, U.S. patent 5,350,756, and U.S. patent 7,973,049).

Quinidine administration can shift individuals with a pan-metabolizer phenotype to a poor metabolizer phenotype (Inaba et al, Br. J. Clin. Pharmacol. 1986; 22: 199-200). Dextromethorphan levels in the blood increase linearly with dextromethorphan dose when co-administered with quinidine, but dextromethorphan is not detectable in most subjects even at high doses when administered alone (Zhang et al, clin. pharmac. & thermap. 1992; 51: 647-55). Thus, the plasma levels observed in the fast metabolizer after co-administration of right methamphetamine with quinidine were similar to those observed in the poor metabolizer. Thus, the physician should take care to see the administration of quinidine in subjects who may be undesirable metabolizers.

Pharmaceutical composition

One of the features of the disclosed methods and combinations is that they have the ability to reduce aggressive behavior and/or aggressive behavior in alzheimer's patients. In some cases, this reduction is achieved without sedation or otherwise significantly intervening in consciousness or alertness, and/or without increasing the risk of serious adverse effects. As used herein, "significant intervention" refers to adverse events that are significant at the clinical level (e.g., they would be of particular interest to a physician or psychologist), or significant at the personal or social level (such as by inducing lethargy, which is severe enough to impair an individual's ability to drive a vehicle). Conversely, the very slight type of side effects that may be caused by over-the-counter medications, such as dextromethorphan-containing cough syrup, when used at the recommended dose, are not considered significant interventions.

The therapeutic dose of dextromethorphan compound in combination with quinidine for short or long term management of the aggressive behavior and/or aggressive behavior of subjects with alzheimer's disease may vary depending on factors such as the specific cause of the condition, the severity of the condition and the route of administration. The dosage and/or frequency of administration may also vary depending on the age, weight and response of the individual subject.

In one embodiment, the dextromethorphan compound and quinidine are administered in a combined dose, or in separate doses. The separate doses may be administered substantially simultaneously. In one embodiment, the weight ratio of dextromethorphan compound to quinidine is about 1:1 or less. In some embodiments, the weight ratio is about 1:1, 1:0.95, 1:0.9, 1:0.85, 1:0.8, 1:0.75, 1:0.7, 1:0.65, 1:0.6, 1:0.55, or 1:0.5 or less. Also, in certain embodiments, the dose has a weight ratio of dextromethorphan compound to quinidine of less than about 1:0.5, e.g., about 1:0.45, 1:0.4, 1:0.35, 1:0.3, 1:0.25, 1:0.2, 1:0.15, or 1:0.1, 1:0.09, 1:0.08, 1:0.07, 1:0.06, 1:0.05, 1:0.04, 1:0.03, 1:0.02, or 1:0.01, or less. The weight ratio may be, for example, about 1:0.75, about 1:0.68, about 1:0.6, about 1:0.56, about 1:0.5, about 1:0.44, about 1:0.39, about 1:0.38, about 1:0.31, about 1:0.30, about 1:0.29, about 1:0.28, about 1:0.27, about 1:0.26, about 1:0.25, about 1:0.24, about 1:0.23, about 1:0.22, about 1:0.21, about 1:0.20, about 1:0.19, about 1:0.18, about 1:0.17, 1:0.16, about 1:0.15, about 1:0.14, about 1:0.13, about 1:0.12, about 1:0.11, and about 1: 0.10. In some embodiments, the weight ratio of dextromethorphan free base to quinidine free base is about 1:0.68, about 1:0.56, about 1:0.44, about 1: 0.38. In certain other embodiments, the weight ratio of d 6-deuterated dextromethorphan free base to quinidine free base is from about 1:0.30, about 1:0.22, about 1:0.19, about 1:0.18, about 1:0.16 and about 1: 0.15.

In certain embodiments, less than 50mg of quinidine is administered at any one time when the dextromethorphan compound and quinidine are administered at a weight ratio of 1:1 or less. For example, in certain embodiments, quinidine is administered at about 30mg, 25mg, or 20mg or less. In other embodiments, quinidine is administered at about 15mg, 10mg, 9.5mg, 9.0mg, 8.5mg, 8.0mg, 7.5mg, 7.0mg, 6.5mg, 6.0mg, 5.5mg, 5.0mg, or less. In other embodiments, quinidine is administered at about 5.00mg, 4.95mg, 4.90mg, 4.85mg, 4.80mg, 4.75mg, 4.70mg, 4.65mg, 4.60mg, 4.55mg, 4.50mg, 4.45mg, 4.40mg, 4.35mg, 4.30mg, 4.25mg, 4.20mg, 4.15mg, 4.10mg, 4.05mg, 4.00mg, 3.95mg, 3.90mg, 3.85mg, 3.80mg, 3.75mg, 3.70mg, 3.65mg, 3.60mg, 3.55mg, 3.50mg, 3.45mg, 3.40mg, 3.35mg, 3.30mg, 3.25mg, 3.20mg, 3.15mg, 3.10mg, 3.05mg, 3.00mg, 2.90mg, 2.40mg, 2.35mg, 1.50mg, 1.5mg, 2.45mg, 1.45mg, 1.5mg, 1.50mg, 1.5mg, 2.65mg, 2.5mg, 1.5mg, 2.45mg, 1.5mg, 1.65mg, 2.5mg, 1.5mg, 2.65mg, 1.5mg, 2.5mg, 1.5mg, 2.55mg, 1.5mg, 2.55mg, 2.5mg, 1.5mg, 1.85mg, 1.5mg, 2.5mg, 1.5mg, 2.5.5.5.5.5 mg, 1.5mg, 1.5.5 mg, 2.5mg, 2.55mg, 2.5mg, 2., 0.95mg, 0.90mg, 0.85mg, 0.80mg, 0.75mg, 0.70mg, 0.65mg, 0.60mg, 0.55mg, 0.50mg, 0.45mg, 0.40mg, 0.35mg, 0.30mg, 0.25mg, 0.20mg, 0.15mg, 0.10mg, or 0.05mg, or less.

In some embodiments, a combination dose (or separate doses administered simultaneously) in a weight ratio of 1:1 or less is administered once a day, twice a day, three times a day, four times a day, or more frequently to provide a dosage level to the subject per day, for example: 60mg quinidine and 60mg dextromethorphan compound per day, provided in two doses, each dose comprising 30mg quinidine and 30mg dextromethorphan compound; 50mg quinidine and 50mg dextromethorphan compound per day, provided in two doses, each dose comprising 25mg quinidine and 25mg dextromethorphan compound; 40mg quinidine and 40mg dextromethorphan compound per day, provided in two doses, each dose comprising 20mg quinidine and 20mg dextromethorphan compound; 30mg quinidine and 30mg dextromethorphan compound per day, provided in two doses, each dose comprising 15mg quinidine and 15mg dextromethorphan compound; or 20mg quinidine and 20mg dextromethorphan compound per day, provided in two doses, each dose comprising 10mg quinidine (i.e., about 9mg quinidine free base) and 10mg dextromethorphan compound. In some embodiments, the total amount of dextromethorphan compound and quinidine in the combined dose may be adjusted according to the number of doses administered per day to provide a total daily dose suitable for the subject while maintaining a weight ratio of 1:1 or less.

In some embodiments, the total daily dose of a combination of dextromethorphan compound and quinidine for treating aggressive and/or aggressive behavior in a subject with alzheimer's disease is from about 10mg or less to about 200mg or more of dextromethorphan compound in combination with about 0.05mg or less to about 60mg or more of quinidine. In some embodiments, the daily dose for treating aggressive behavior and/or aggressive behavior in a subject with alzheimer's disease is from about 10mg to about 90mg of dextromethorphan compound in combination with about 2.5mg to about 60mg of quinidine, as a single or separate dose. In some embodiments, the total daily dose of dextromethorphan compound is about 15mg, 16mg, 17mg, 18mg, 19 or 20mg, combining about 15mg, 10mg, 9.5mg, 9.0mg, 8.5mg, 8.0mg, 7.5mg, 7.0mg, 6.5mg, 6.0mg, 5.5mg, 5.00mg, 4.95mg, 4.90mg, 4.85mg, 4.80mg, 4.75mg, 4.70mg, 4.65mg, 4.60mg, 4.55mg, 4.50mg, 4.45mg, 4.40mg, 4.35mg, 4.30mg, 4.25mg, 4.20mg, 4.15mg, 4.10mg, 4.05mg, 4.00mg, 3.95mg, 3.90mg, 3.85mg, 3.80mg, 3.75mg, 3.70mg, 3.15mg, 2.10mg, 2.5mg, 3.5 mg, 4.5 mg, 4.80mg, 4.45mg, 2.5mg, 3.5 mg, 4.80mg, 3.45mg, 3.65mg, 2.5mg, 3.5 mg, 2.5mg, 4.5 mg, 4.45mg, 2.45mg, 3.65mg, 2.5mg, 3.55mg, 2.5mg, 2.55mg, 3.5 mg, 2.55mg, 2.5mg, 3.5 mg, 3.45mg, 2.5mg, 3.5 mg, 3, 2.00mg, 1.95mg, 1.90mg, 1.85mg, 1.80mg, 1.75mg, 1.70mg, 1.65mg, 1.60mg, 1.55mg, 1.50mg, 1.45mg, 1.40mg, 1.35mg, 1.30mg, 1.25mg, 1.20mg, 1.15mg, 1.10mg, 1.05mg, 1.00mg, 0.95mg, 0.90mg, 0.85mg, 0.80mg, 0.75mg, 0.70mg, 0.65mg, 0.60mg, 0.55mg, 0.50mg, 0.45mg, 0.40mg, 0.35mg, 0.30mg, 0.25mg, 0.20mg, 0.15mg, 0.10mg, or 0.05mg of quinidine or less.

In some embodiments, the daily dose for treating aggressive and/or aggressive behavior in a subject with alzheimer's disease is about 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, or 30mg of dextromethorphan compound, combining about 15mg, 10mg, 9.5mg, 9.0mg, 8.5mg, 8.0mg, 7.5mg, 7.0mg, 6.5mg, 6.0mg, 5.5mg, 5.00mg, 4.95mg, 4.90mg, 4.85mg, 4.80mg, 4.75mg, 4.70mg, 4.65mg, 4.60mg, 4.55mg, 4.50mg, 4.45mg, 4.40mg, 4.35mg, 4.30mg, 4.25mg, 4.20mg, 4.15mg, 4.10mg, 4.90mg, 3.50mg, 3.45mg, 3.40mg, 3.35mg, 3.50mg, 3.5 mg, 3.95mg, 3.5 mg, 3.80mg, 3.5 mg, 3.80mg, 3.95mg, 3.80mg, 3.5, 2.70mg, 2.65mg, 2.60mg, 2.55mg, 2.50mg, 2.45mg, 2.40mg, 2.35mg, 2.30mg, 2.25mg, 2.20mg, 2.15mg, 2.10mg, 2.05mg, 2.00mg, 1.95mg, 1.90mg, 1.85mg, 1.80mg, 1.75mg, 1.70mg, 1.65mg, 1.60mg, 1.55mg, 1.50mg, 1.45mg, 1.40mg, 1.35mg, 1.30mg, 1.25mg, 1.20mg, 1.15mg, 1.10mg, 1.05mg, 1.00mg, 0.95mg, 0.90mg, 0.85mg, 0.80mg, 0.75mg, 0.70mg, 0.65mg, 0.60mg, 0.55mg, 0.45mg, 0.05mg, 0.45mg, 0.35mg, 0.0.45 mg, 0.45mg or less quinidine; or about 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, or 40mg dextromethorphan compound in combination with about 15mg, 10mg, 9.5mg, 9.0mg, 8.5mg, 8.0mg, 7.5mg, 7.0mg, 6.5mg, 6.0mg, 5.5mg, 5.00mg, 4.95mg, 4.90mg, 4.85mg, 4.80mg, 4.75mg, 4.70mg, 4.65mg, 4.60mg, 4.55mg, 4.50mg, 4.45mg, 4.40mg, 4.35mg, 4.30mg, 4.25mg, 4.20mg, 4.15mg, 4.10mg, 4.05mg, 4.00mg, 3.95mg, 3.90mg, 3.85mg, 3.80mg, 3.65mg, 3.25mg, 3.20mg, 3.15mg, 2.50mg, 2.5mg, 3.45mg, 3.55mg, 3.45mg, 2.5mg, 3.55mg, 2.5mg, 3.45mg, 3.5 mg, 3.65mg, 3.5 mg, 3.55mg, 2.55mg, 3.0 mg, 2.5mg, 3.5 mg, 3.65mg, 3.55mg, 2.5mg, 3.5 mg, 3.55mg, 2.5mg, 3.5 mg, 3.55mg, 2.5mg, 3.5.5 mg, 3.5 mg, 2., 2.00mg, 1.95mg, 1.90mg, 1.85mg, 1.80mg, 1.75mg, 1.70mg, 1.65mg, 1.60mg, 1.55mg, 1.50mg, 1.45mg, 1.40mg, 1.35mg, 1.30mg, 1.25mg, 1.20mg, 1.15mg, 1.10mg, 1.05mg, 1.00mg, 0.95mg, 0.90mg, 0.85mg, 0.80mg, 0.75mg, 0.70mg, 0.65mg, 0.60mg, 0.55mg, 0.50mg, 0.45mg, 0.40mg, 0.35mg, 0.30mg, 0.25mg, 0.20mg, 0.15mg, 0.10mg, or 0.05mg or less of quinidine; or about 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, or 50mg dextromethorphan compound in combination with about 15mg, 10mg, 9.5mg, 9.0mg, 8.5mg, 8.0mg, 7.5mg, 7.0mg, 6.5mg, 6.0mg, 5.5mg, 5.00mg, 4.95mg, 4.90mg, 4.85mg, 4.80mg, 4.75mg, 4.70mg, 4.65mg, 4.60mg, 4.55mg, 4.50mg, 4.45mg, 4.40mg, 4.35mg, 4.30mg, 4.25mg, 4.20mg, 4.15mg, 4.10mg, 4.05mg, 4.00mg, 3.95mg, 3.90mg, 3.85mg, 3.80mg, 3.65mg, 3.25mg, 3.20mg, 3.15mg, 2.50mg, 2.5mg, 3.55mg, 3.45mg, 3.55mg, 2.5mg, 3.55mg, 3.45mg, 2.5mg, 3.55mg, 3.5 mg, 3.65mg, 3.5 mg, 3.55mg, 2.55mg, 2.5mg, 3.65mg, 3.5 mg, 2.55mg, 2.5mg, 3.5 mg, 3.55mg, 2.5mg, 3.5 mg, 3.55mg, 2.5mg, 3.5.5 mg, 3.5 mg, 3., 2.00mg, 1.95mg, 1.90mg, 1.85mg, 1.80mg, 1.75mg, 1.70mg, 1.65mg, 1.60mg, 1.55mg, 1.50mg, 1.45mg, 1.40mg, 1.35mg, 1.30mg, 1.25mg, 1.20mg, 1.15mg, 1.10mg, 1.05mg, 1.00mg, 0.95mg, 0.90mg, 0.85mg, 0.80mg, 0.75mg, 0.70mg, 0.65mg, 0.60mg, 0.55mg, 0.50mg, 0.45mg, 0.40mg, 0.35mg, 0.30mg, 0.25mg, 0.20mg, 0.15mg, 0.10mg, or 0.05mg or less of quinidine; or about 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, or 60mg dextromethorphan compound in combination with about 15mg, 10mg, 9.5mg, 9.0mg, 8.5mg, 8.0mg, 7.5mg, 7.0mg, 6.5mg, 6.0mg, 5.5mg, 5.00mg, 4.95mg, 4.90mg, 4.85mg, 4.80mg, 4.75mg, 4.70mg, 4.65mg, 4.60mg, 4.55mg, 4.50mg, 4.45mg, 4.40mg, 4.35mg, 4.30mg, 4.25mg, 4.20mg, 4.15mg, 4.10mg, 4.05mg, 4.00mg, 3.95mg, 3.90mg, 3.85mg, 3.80mg, 3.65mg, 3.25mg, 3.20mg, 3.15mg, 2.50mg, 2.5mg, 3.45mg, 2.5mg, 3.55mg, 2.65mg, 3.5 mg, 3.45mg, 2.5mg, 3.55mg, 2.5mg, 3.65mg, 3.5 mg, 3.65mg, 2.5mg, 3.5 mg, 2.5mg, 3.5 mg, 3.55mg, 2.5mg, 3.5 mg, 2.5mg, 2.5.5.5.5.5 mg, 3.5 mg, 3, 2.00mg, 1.95mg, 1.90mg, 1.85mg, 1.80mg, 1.75mg, 1.70mg, 1.65mg, 1.60mg, 1.55mg, 1.50mg, 1.45mg, 1.40mg, 1.35mg, 1.30mg, 1.25mg, 1.20mg, 1.15mg, 1.10mg, 1.05mg, 1.00mg, 0.95mg, 0.90mg, 0.85mg, 0.80mg, 0.75mg, 0.70mg, 0.65mg, 0.60mg, 0.55mg, 0.50mg, 0.45mg, 0.40mg, 0.35mg, 0.30mg, 0.25mg, 0.20mg, 0.15mg, 0.10mg, or 0.05mg or less of quinidine; or about 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, or 70mg dextromethorphan compound, in combination with about 15mg, 10mg, 9.5mg, 9.0mg, 8.5mg, 8.0mg, 7.5mg, 7.0mg, 6.5mg, 6.0mg, 5.5mg, 5.00mg, 4.95mg, 4.90mg, 4.85mg, 4.80mg, 4.75mg, 4.70mg, 4.65mg, 4.60mg, 4.55mg, 4.50mg, 4.45mg, 4.40mg, 4.35mg, 4.30mg, 4.25mg, 4.20mg, 4.15mg, 4.10mg, 4.05mg, 4.00mg, 3.95mg, 3.90mg, 3.85mg, 3.80mg, 3.65mg, 3.25mg, 3.20mg, 3.15mg, 2.5mg, 3.55mg, 3.45mg, 3.55mg, 2.5mg, 3.55mg, 3.45mg, 3.5 mg, 3.55mg, 3.5 mg, 3.65mg, 2.5mg, 3.5 mg, 3.55mg, 2.5mg, 3.5 mg, 3.55mg, 2.5mg, 3.5 mg, 2.5.5.5.5 mg, 3.5.5 mg, 2.00mg, 1.95mg, 1.90mg, 1.85mg, 1.80mg, 1.75mg, 1.70mg, 1.65mg, 1.60mg, 1.55mg, 1.50mg, 1.45mg, 1.40mg, 1.35mg, 1.30mg, 1.25mg, 1.20mg, 1.15mg, 1.10mg, 1.05mg, 1.00mg, 0.95mg, 0.90mg, 0.85mg, 0.80mg, 0.75mg, 0.70mg, 0.65mg, 0.60mg, 0.55mg, 0.50mg, 0.45mg, 0.40mg, 0.35mg, 0.30mg, 0.25mg, 0.20mg, 0.15mg, 0.10mg, or 0.05mg or less of quinidine; or about 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79 mg or 80mg dextromethorphan compound, in combination with about 15mg, 10mg, 9.5mg, 9.0mg, 8.5mg, 8.0mg, 7.5mg, 7.0mg, 6.5mg, 6.0mg, 5.5mg, 5.00mg, 4.95mg, 4.90mg, 4.85mg, 4.80mg, 4.75mg, 4.70mg, 4.65mg, 4.60mg, 4.55mg, 4.50mg, 4.45mg, 4.40mg, 4.35mg, 4.30mg, 4.25mg, 4.20mg, 4.15mg, 4.10mg, 4.05mg, 4.00mg, 3.95mg, 3.90mg, 3.85mg, 3.80mg, 3.65mg, 3.70mg, 3.20mg, 3.15mg, 2.10mg, 2.5mg, 3.55mg, 2.55mg, 3.45mg, 2.55mg, 3.55mg, 2.5mg, 3.50mg, 3.45mg, 3.5 mg, 3.65mg, 3.5 mg, 3.55mg, 3.65mg, 2.5mg, 3.5 mg, 3.55mg, 3.65mg, 3.55mg, 2.5mg, 3.5 mg, 3.55mg, 2.55mg, 3.55mg, 2.55mg, 2.5mg, 3.55mg, 3.5 mg, 3., 2.00mg, 1.95mg, 1.90mg, 1.85mg, 1.80mg, 1.75mg, 1.70mg, 1.65mg, 1.60mg, 1.55mg, 1.50mg, 1.45mg, 1.40mg, 1.35mg, 1.30mg, 1.25mg, 1.20mg, 1.15mg, 1.10mg, 1.05mg, 1.00mg, 0.95mg, 0.90mg, 0.85mg, 0.80mg, 0.75mg, 0.70mg, 0.65mg, 0.60mg, 0.55mg, 0.50mg, 0.45mg, 0.40mg, 0.35mg, 0.30mg, 0.25mg, 0.20mg, 0.15mg, 0.10mg, or 0.05mg or less of quinidine; or about 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg dextromethorphan compound, in combination with about 15mg, 10mg, 9.5mg, 9.0mg, 8.5mg, 8.0mg, 7.5mg, 7.0mg, 6.5mg, 6.0mg, 5.5mg, 5.00mg, 4.95mg, 4.90mg, 4.85mg, 4.80mg, 4.75mg, 4.70mg, 4.65mg, 4.60mg, 4.55mg, 4.50mg, 4.45mg, 4.40mg, 4.35mg, 4.30mg, 4.25mg, 4.20mg, 4.15mg, 4.10mg, 4.05mg, 4.00mg, 3.95mg, 3.90mg, 3.85mg, 3.80mg, 3.65mg, 3.70mg, 3.20mg, 3.15mg, 2.50mg, 3.5 mg, 3.45mg, 2.5mg, 3.55mg, 2.5mg, 3.55mg, 3.45mg, 2.5mg, 3.5 mg, 3.65mg, 3.5 mg, 3.55mg, 2.5mg, 3.65mg, 3.5 mg, 3.65mg, 2.5mg, 3.5 mg, 3.55mg, 2.55mg, 2.5mg, 3.5 mg, 3.55mg, 3.5 mg, 3.5.5 mg, 3.5 mg, 3, 2.00mg, 1.95mg, 1.90mg, 1.85mg, 1.80mg, 1.75mg, 1.70mg, 1.65mg, 1.60mg, 1.55mg, 1.50mg, 1.45mg, 1.40mg, 1.35mg, 1.30mg, 1.25mg, 1.20mg, 1.15mg, 1.10mg, 1.05mg, 1.00mg, 0.95mg, 0.90mg, 0.85mg, 0.80mg, 0.75mg, 0.70mg, 0.65mg, 0.60mg, 0.55mg, 0.50mg, 0.45mg, 0.40mg, 0.35mg, 0.30mg, 0.25mg, 0.20mg, 0.15mg, 0.10mg, or 0.05mg or less of quinidine; either as single or divided doses.

In some embodiments, the daily dose of dextromethorphan compound and quinidine is 30mg dextromethorphan hydrobromide and 30mg quinidine sulfate. Other doses include, for example, 15mg of dextromethorphan hydrobromide and 9mg of quinidine sulfate (corresponding to about 11mg of dextromethorphan and about 7.5mg of quinidine); 23mg of dextromethorphan hydrobromide and 9mg of quinidine sulfate (corresponding to about 17mg of dextromethorphan and about 7.5mg of quinidine); 20mg of dextromethorphan hydrobromide and 10mg of quinidine sulfate (corresponding to about 15mg of dextromethorphan and 8.3mg of quinidine); 30mg of dextromethorphan hydrobromide and 10mg of quinidine sulfate (corresponding to about 22mg of dextromethorphan and 8.3mg of quinidine).

30mg of d 6-dextromethorphan hydrobromide (molecular formula C) can be administered or used₁₈H₁₉D₆NO.HBr.H₂O) and 30mg of quinidine sulfate (molecular formula is (C)₂₀H₂₄N₂O₂)₂.H₂SO₄.2H₂O) (corresponding to about 22.22mg dextromethorphan and 25mg quinidine). Other doses of d 6-deuterated dextromethorphan include, for example, 24mg d 6-dextromethorphan hydrobromide and 4.75mg quinidine sulfate (corresponding to about 18mg d 6-dextromethorphan and about 3.96mg quinidine); 34mg of d 6-dextromethorphan hydrobromide and 4.75mg of quinidine sulfate (corresponding to about 25.18mg of d 6-dextromethorphan and about 3.96mg of quinidine); 18mg of d 6-dextromethorphan hydrobromide and 4.9mg of quinidine sulfate (corresponding to about 13.33mg of d 6-dextromethorphan and 4.08mg of quinidine); 24mgd 6-dextromethorphan hydrobromide and 4.9mg quinidine sulfate (corresponding to about 17.78mg d 6-dextromethorphan and 4.08mg quinidine); 28mg of d 6-dextromethorphan hydrobromide and 4.9mg of quinidine sulfate (corresponding to about 20.74mg of d 6-dextromethorphan and 4.08mg of quinidine)(ii) a 30mg of d 6-dextromethorphan hydrobromide and 4.9mg of quinidine sulfate (corresponding to about 22.22mg of d 6-dextromethorphan and 4.08mg of quinidine); 34mg of d 6-dextromethorphan hydrobromide and 4.9mg of quinidine sulfate (corresponding to about 25.18mg of d 6-dextromethorphan and 4.08mg of quinidine).

In some embodiments, the treatment is initiated at a lower daily dose, for example about 18 or 30mg dextromethorphan compound combined with about 2.5 to 10mg quinidine per day, and increased to about 90mg dextromethorphan compound combined with about 10 to 20mg quinidine or higher, depending on the overall response of the subject. In some embodiments, infants, children, individuals over 65 years of age, and those with impaired renal or hepatic function, initially receive lower doses, which are determined based on individual responses and blood levels. In general, most individuals are well-tolerated by daily doses of 18 to 90mg of dextromethorphan compound and 4.75 to 20mg of quinidine.

As will be apparent to those skilled in the art, doses outside of these disclosed ranges may be administered in some instances. Furthermore, it should be noted that a clinician or attending physician of ordinary skill will understand when to interrupt, adjust or terminate therapy based on individual responses.

Any suitable route of administration may be employed to provide the subject with an effective dose of a combination of dextromethorphan compound and quinidine for treating the aggressive behavior and/or aggressive behavior in a subject with alzheimer's disease. For example, oral, rectal, transdermal, parenteral (subcutaneous, intramuscular, intravenous), intrathecal, topical, inhalation, and the like may be employed. Suitable dosage forms include tablets, dragees, dispersions, suspensions, solutions, capsules, patches and the like. Administration of the medicaments prepared from the compounds described herein is carried out by any suitable method by which such compounds can be introduced into the bloodstream. In some embodiments, the formulations may contain a mixture of the active compound and a pharmaceutically acceptable carrier or diluent known to those skilled in the art.

The pharmaceutical compositions disclosed herein comprise a combination of a dextromethorphan compound and a CYP2D6 inhibitor, such as quinidine, or a pharmaceutically acceptable salt of the dextromethorphan compound and/or quinidine, as an active ingredient, and may further comprise a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt prepared from a pharmaceutically acceptable, non-toxic acid or base. Suitable pharmaceutically acceptable salts include metal salts, for example, 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, for example, lysine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine and Tris salts; salts of free acids and bases; inorganic salts such as sulfate, hydrochloride and hydrobromide; and other salts currently widely used in pharmacy and listed in sources well known to those skilled in The art, such as The Merck Index.

Any suitable components may be selected to produce the salts of the active agents described herein, provided that they are non-toxic and do not substantially interfere with the desired activity. In addition to salts, pharmaceutically acceptable precursors and derivatives of these compounds may also be employed. Pharmaceutically acceptable amides, lower alkyl esters, and protected derivatives of deuterated dextromethorphan and/or quinidine are also suitable for use in the compositions and methods disclosed herein. In certain embodiments, deuterated dextromethorphan is administered as deuterated dextromethorphan hydrobromide, dextromethorphan is administered as dextromethorphan hydrobromide, and quinidine is administered as quinidine sulfate.

The compositions can be prepared in any desired form, for example, tablets, powders, capsules, injectables, suspensions, sachets, cachets, patches, solutions, elixirs and aerosols. Carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used for the oral solid preparation. In certain embodiments, the compositions are prepared as oral solid formulations (e.g., powders, capsules, and tablets). In certain embodiments, the composition is prepared as an oral liquid formulation. In some embodiments, the oral solid formulation is a tablet. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques.

In addition to the above dosage forms, the compounds disclosed herein may also be administered via sustained, delayed or controlled release compositions and/or delivery devices, e.g., as described in U.S. Pat. nos. 3,845,770; 3,916,899; 3,536,809, respectively; 3,598,123, respectively; and 4,008,719.

Pharmaceutical compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, sachets, patches, injectables, tablets, and aerosols, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. These compositions may be prepared by any conventional pharmaceutical method, but most of these methods generally involve the step of bringing into association the active ingredient with the carrier which constitutes one or more of the ingredients. In general, these compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, finely divided solid carriers, or both, and then optionally shaping the product to give the desired appearance.

Tablets may be prepared, for example, by compression or moulding, optionally together with one or more additional ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

In some embodiments, each tablet comprises about 30mg dextromethorphan hydrobromide and 30mg quinidine sulfate. The tablet may comprise, for example, 15mg of dextromethorphan hydrobromide and 9mg of quinidine sulfate (corresponding to about 11mg of dextromethorphan and about 7.5mg of quinidine); 23mg of dextromethorphan hydrobromide and 9mg of quinidine sulfate (corresponding to about 17mg of dextromethorphan and about 7.5mg of quinidine); 20mg of dextromethorphan hydrobromide and 10mg of quinidine sulfate (corresponding to about 15mg of dextromethorphan and 8.3mg of quinidine); 30mg of dextromethorphan hydrobromide and 10mg of quinidine sulfate (corresponding to about 22mg of dextromethorphan and 8.3mg of quinidine).

The tablet may contain 30mg of d 6-dextromethorphan hydrobromide (molecular formula C)₁₈H₁₉D₆NO.HBr.H₂O) and 30mg of quinidine sulfate (molecular formula is (C)₂₀H₂₄N₂O₂)₂.H₂SO₄.2H₂O) (corresponding to about 22.22mg dextromethorphan and 25mg quinidine). The tablet may contain other doses, for example, 24mg of d 6-dextromethorphan hydrobromide and 4.75mg of quinidine sulfate (corresponding to about 18mg of d 6-dextromethorphan and about 3.96mg of quinidine); 34mg of d 6-dextromethorphan hydrobromide and 4.75mg of quinidine sulfate (corresponding to about 25.18mg of d 6-dextromethorphan and about 3.96mg of quinidine); 18mg of d 6-dextromethorphan hydrobromide and 4.9mg of quinidine sulfate (corresponding to about 13.33mg of d 6-dextromethorphan and 4.08mg of quinidine); 24mg of d 6-dextromethorphan hydrobromide and 4.9mg of quinidine sulfate (corresponding to 17.78mg of d 6-dextromethorphan and 4.08mg of quinidine); 28mg of d 6-dextromethorphan hydrobromide and 4.9mg of quinidine sulfate (corresponding to about 20.74mg of d 6-dextromethorphan and 4.08mg of quinidine); 30mgd 6-dextromethorphan hydrobromide and 4.9mg quinidine sulfate (corresponding to about 22.22mg d 6-dextromethorphan and 4.08mg quinidine); 34mg of d 6-dextromethorphan hydrobromide and 4.9mg of quinidine sulfate (corresponding to about 25.18mg of d 6-dextromethorphan and 4.08mg of quinidine).

As used herein, a "minimum therapeutically effective amount" is an amount that produces a satisfactory degree of inhibition for rapid elimination of the dextromethorphan compound from the body, while not eliciting an adverse reaction, or eliciting an adverse event to an acceptable degree and nature. More specifically, in some embodiments, the therapeutically effective amount is a range from about 9, 10, 18, 20, 25, or 30mg to about 90mg of dextromethorphan compound and less than about 50mg of quinidine per day. In some embodiments, the therapeutically effective amount is a range from about 20 or 30mg to about 90mg of dextromethorphan compound and about 0.5mg to about 30mg of quinidine per day. In some embodiments, the amount is based on the plasma half-life of the dextromethorphan compound, administered in divided doses. For example, in one embodiment, deuterated dextromethorphan and quinidine are administered in specified milliincrements to achieve a target concentration of deuterated dextromethorphan at a specific level in μ g/mL plasma, wherein the maximum specified dose of deuterated dextromethorphan and quinidine is based on body weight. In some embodiments, the target dose is administered once every 12 hours. In some embodiments, the target dose is administered once daily. In some embodiments, minimizing the levels of quinidine, and reducing or eliminating the side effects observed at high doses of quinidine, provides a significant benefit over compositions containing dextromethorphan compounds and higher levels of quinidine.

In some embodiments, the additional therapeutic agent is administered in combination with the dextromethorphan compound and quinidine. For example, dextromethorphan compounds and quinidine may be administered in combination with compounds to treat depression or anxiety.

In some embodiments, the dextromethorphan compound and quinidine act as adjuvants to known therapeutic agents for the treatment of symptoms of alzheimer's disease. Drugs that treat the symptoms of alzheimer's disease include, but are not limited to, cholinesterase inhibitors such as donepezil, rivastigmine, galantamine and tacrine, memantine, and vitamin E.

Examples