WO2012129262A1

WO2012129262A1 - Treatment of attention deficit/hyperactivity disease

Info

Publication number: WO2012129262A1
Application number: PCT/US2012/029879
Authority: WO
Inventors: Merouane Bencherif; Geoffrey Charles Dunbar; David A. Hosford; Gregory J. Gatto; Terry Hauser; Kristen G. Jordan; Anthony Carl SEGRETI
Original assignee: Targacept, Inc.
Priority date: 2011-03-23
Filing date: 2012-03-21
Publication date: 2012-09-27
Also published as: TW201244717A; AR085483A1

Abstract

The present invention relates to methods and uses for 2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof.

Description

TREATMENT OF ATTENTION DEFICIT/HYPERACTIVITY DISEASE

FIELD OF THE INVENTION

The present invention relates to methods and uses for (2S,3R)-N-(2-((3- pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof.

BACKGROUND

The compound (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3- yl)benzofuran-2-carboxamide, is described, including methods of synthesis, in published U.S. Patent Application No. 12/184,312 (Publication No. US 2009/0048290 A1 ), and is part of a genus described in U.S. Pat. No. 6,953,855, both of which are fully incorporated herein by reference. The compound may be referred to as TC-5619.

Attention deficit hyperactivity disorder (ADHD or AD/HD or ADD) is a neurobehavioral developmental disorder. ADHD is primarily characterized by the co-existence of problems with attention and hyperactivity, with each behavior occurring infrequently alone. ADHD is a chronic disorder with 30 to 50 percent of those individuals diagnosed in childhood continuing to have symptoms into adulthood. Adolescents and adults with ADHD tend to develop coping mechanisms to compensate for some or all of their impairments. ADHD is diagnosed via a psychiatric assessment; to rule out other potential causes or co-morbidities, physical examination, radiological imaging, and laboratory tests may be used.

In North America, the DSM criteria are often the basis for a diagnosis, such as the criteria laid down by the American Psychiatric Association in their Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 4th edition. Based on the DSM-IV criteria listed below, three types of ADHD are classified currently: (i) ADHD, Combined Type; (ii) ADHD

Predominantly Inattentive Type; and (iii) ADHD, Predominantly Hyperactive-Impulsive Type. The previously used phrase ADD (Attention Deficit Disorder) expired with the most recent revision of the DSM. Consequently, ADHD is the current nomenclature used to describe the disorder as one distinct disorder which can manifest itself as being a primary deficit resulting in hyperactivity/impulsivity (ADHD, predominately hyperactive-impulsive type) or inattention (ADHD predominately inattentive type) or both (ADHD combined type). In the tenth edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) the signs of ADHD are given the name "Hyperkinetic disorders". When a conduct disorder (as defined by ICD-10) is present, the condition is referred to as "Hyperkinetic conduct disorder". Otherwise the disorder is classified as "Disturbance of Activity and Attention", "Other Hyperkinetic Disorders" or "Hyperkinetic Disorders, Unspecified". The latter is sometimes referred to as, "Hyperkinetic Syndrome". Each of the DSM-IV and the ICD-10 are herein incorporated by reference with regard to such diagnosis, symptoms, and terminology for these disorders. Regardless of the terminology, the present invention is directed to treatments associated with these disorders.

With reference to the DSM-IV, a diagnosis of the predominantly inattentive subtype of ADHD is available if the individual presents six or more of a defined series of symptoms of inattention for at least six months to a point that is considered disruptive and inappropriate. Similarly, a diagnosis of predominantly hyperactive-impulsive subtype of ADHD is available if the individual presents six or more of a defined battery of a defined series of symptoms of hyperactivity/impulsivity for at least six months prior to a point that is considered disruptive and inappropriate. A diagnosis of combined type, likewise, is available when an individual presents both series of symptoms.

Stimulants, whether long-acting or short-acting work relatively quickly (same day) with effect sizes, namely the magnitude of treatment effect, of approximately 0.8 to 0.9. Such agents present a high liability for abuse and often are scheduled drugs. In addition, such agents often are accompanied by a less-than ideal tolerability profile, including hypertension, tachycardia, insomnia, weight effects, irritability, or mood swings. Non-stimulants take effect more slowly, with effect sizes of approximately 0.5. While the potential for abuse is addressed, the tolerability profile is similar to that of stimulants. A relatively quick onset agent with minimal abuse liability and favorable tolerability profile would greatly benefit patients with ADHD.

SUMMARY OF THE INVENTION

The present invention includes methods of treatment of ADHD by the administration of a therapeutically effective amount of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3- yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof.

The present invention includes a method of treating patients diagnosed with an inattentive subtype of ADHD comprising administering a therapeutically effective amount of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof.

The present invention includes a method of improving attention in a subject in need thereof comprising administering a therapeutically effective amount of (2S,3R)-N-(2-((3- pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof. One aspect of the present invention includes a method of treating inattention comprising administering a therapeutically effective amount of (2S,3R)-N-(2-((3- pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof.

The present invention includes early onset effect, namely within one week on drug, of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof on symptoms associated with ADHD, including but not limited to total performance on Conners Adult ADHD Rating Scale (CAARS), hyperactivity, impulsivity, and ADHD Index sub-scales..

The present invention includes continued effect, namely maintained at 4 or more weeks on drug, of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2- carboxamide or a pharmaceutically acceptable salt thereof on symptoms associated with ADHD, including but not limited to hyperactivity, inattention, self-concept, anger, hostility, confusion, and bewilderment.

The present invention includes a combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, or another a 7 agonist, with one or more stimulant agent to treat ADHD of the combined, inattentive, or hyperactive/impulsive type. The present invention includes a combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, or another al agonist, with one or more

antidepressant agent to treat ADHD of the combined, inattentive, or hyperactive/impulsive type. The present invention includes a combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, or another al agonist, with one or more antihypertensive agent to treat ADHD of the combined, inattentive, or hyperactive/impulsive type. The present invention includes a combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2- carboxamide or a pharmaceutically acceptable salt thereof, or another al agonist, with one or more of one or more stimulant agent, one or more antidepressant agent, and one or more antihypertensive to treat ADHD of the combined, inattentive, or hyperactive/impulsive type. In this regard, the present invention includes a combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof with another therapeutic agent for treating ADHD, including of the combined, inattentive, or hyperactive/impulsive type. Various terms used herein, not otherwise defined, may be defined with reference to the Protocol.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is a graphical depiction of statistically significant results of (2S,3R)-N-(2-((3- pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof in several outcome measures associated with ADHD in an inattentive subpopulation. As illustrated, (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3- yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof demonstrated statistically significant improvement across a number of scales, including CGI-Global

Improvement, CAAR-S: ADHD Index, and CAARS-lnv: ADHD Index.

Figure 2 is a graphical depiction of the multiple rising dose study to assess

pharmacokinetic and pharmacodynamic profiles of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof at increasing dose levels. As illustrated, (2S,3R)-N-(2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof demonstrated a significant improvement in attention as compared to placebo.

DETAILED DESCRIPTION OF THE INVENTION

(2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, (2S,3R)-N-(2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide, is described, including methods of synthesis, in U.S. Patent No. 7,981 ,906 (previously published as Publication No. US

2009/0048290 A1 ), and is part of a genus described in U.S. Pat. No. 6,953,855, both of which are fully incorporated herein by reference.

(2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof is a selective alpha7 NNR agonist. (2S,3R)-N-(2- ((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a

pharmaceutically acceptable salt thereof had efficacy in preclinical models of memory and was generally well tolerated in phase 1 trials in healthy volunteers, who demonstrated a robust improvement in attention when 6.7mg (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct- 3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof was administered. See, Hauser TA, Kucinski A, Jordan KG, Gatto GJ, Lippiello PM, Bencherif M: (2S,3R)-N-(2-((3- pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof: An a7 NNR selective agonist that demonstrates efficacy in animal models of schizophrenia, Biochem. Pharmacol. 1009; 78: 803-812, herein incorporated by reference.

The present invention results from a clinical trial conducted to test the effect of (2S,3R)- N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof in adults with ADHD. The study randomized 135 male or female adults (ages 18 - 65 years) with ADHD from sites in the US, diagnosed per DSM-IV- TR criteria. Subjects were randomized to 12 weeks of treatment using either placebo (n = 67) or (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof (n = 68: 1 mg po qd for 4weeks, then 5mg po qd for 4 weeks, and finally 25mg po qd for 4 weeks).

The primary outcome measure (Conners Adult ADHD Rating Scale - Investigator

[CAARS-lnv] total score) showed no statistically significant benefit (p < 0.10) favoring (2S,3R)- N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof at Weeks 4, 8, or 12; and so the study did not meet predefined success criteria. The CAARS-lnv, however, did show significant benefit favoring (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof at Week 1 (p = 0.0191 ). In secondary outcome measures, (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2- carboxamide or a pharmaceutically acceptable salt thereof showed statistically significant benefit at various times in: CAARS-lnv Hyperactivity-lmpulsivity scale; CAARS-subject (CAARS- S) ADHD Index, Hyperactivity scale, Inattentive scale, and Problems with Self-Concept scale; objective measures in the CogState ADHD Test Battery [CATB: Stop Signal Reaction Time (a test of behavioral inhibition), Groton Maze Learning Test (GMLT), Detection task (a test of psychomotor processing), and the International Shopping List Task (a test of verbal learning]; overall clinical global impression (CGI) in the CGI-Severity (CGI-S) and CGI-lmprovement (CGI- I) scales; and behavioral items in the Profile of Mood States (POMS) for anger-hostility and confusion-bewilderment.

In a post hoc analysis examining the subtypes of ADHD, the inattentive type (n = 30) was found to not only drive the significant benefit favoring (2S,3R)-N-(2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof but to also significantly improve CAARS-ln total score.

Thus, although the primary outcome measure did not show benefit favoring (2S,3R)-N- (2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof at Weeks 4, 8 or 12, positive benefit favoring the compound was observed in a variety of CAARS-lnv and CAARS-S scales, CATB items, CGI-S, CGI-I, and POMS items. Moreover, a post hoc analysis in subjects with the predominantly inattentive type of ADHD showed statistically significant benefit favoring (2S,3R)-N-(2-((3- pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof on not only the primary outcome measure (CAARS-ln total score), but also on a variety of secondary outcome measures. Together, these results indicate that (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof produced cognitive and clinical benefit in adults with ADHD.

I. Compound

The compound of the present invention is (2S,3R)-N(2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide, represented as Compound A below, or a pharmaceutically acceptable salt forms of Compound A.

Compound A

(2S,3R)-N(2-((3-Pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide (Compound A) is a highly selective, full agonist at the a7 NNR receptor with a remarkably low EC₅o (for activation) value and a good separation between EC₅o and the IC₅o (for residual inhibition), providing functional agonism over a broad range of therapeutically useful concentrations.

II. Scalable synthesis of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1 -azabicyclo[2.2.2]oct-3- yl)benzofuran-2-carboxamide Particular synthetic steps vary in their amenability to scale-up. Reactions are found lacking in their ability to be scaled-up for a variety of reasons, including safety concerns, reagent expense, difficult work-up or purification, reaction energetics (thermodynamics or kinetics), and reaction yield.

The synthesis of (2S,3R)-N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3- yl)benzofuran-2-carboxamide described herein has been used to produce kilogram quantities of material, and the component reactions have been carried out on multi-kilogram scale in high yield.

The scalable synthesis utilizes both the dynamic resolution of a racemizable ketone (2- ((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one) and the stereoselective reduction of the (R)-a-methylbenzylamine imine derivative (reductive amination) of the resolved ketone. The synthetic sequences reported herein are readily scalable and avoid chromatographic

purifications.

III. Preparation of Salt forms of (2S,3R)-N-(2-((3-pyridinyl)methyl-1 - azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide

(2S,3R)-N-(2-((3-Pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide as a free base is an amorphous powder with very limited water solubility. The free base will react with both inorganic and organic acids to make certain acid addition salts that have physical and chemical properties that are advantageous for the preparation of pharmaceutical compositions, including but not limited to crystallinity, water solubility, and stability. The stoichiometry of the salts of the present invention can vary.

Depending upon the manner by which the salts described herein are formed, the salts can have crystal structures that occlude solvents that are present during salt formation. Thus, the salts can occur as hydrates and other solvates of varying stoichiometry of solvent relative to the (2S,3R)-N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide.

The method for preparing the salt forms can vary. The preparation of (2S,3R)-N-(2-((3- pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide salt forms generally involves: (i) mixing the free base or a solution of the free base, namely (2S,3R)-N-(2-((3- pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide in a suitable solvent with an acid neat, or as a solution of an acids in a suitable solvent; (iia) cooling the resulting salt solution, if necessary to cause precipitation; or (iib) adding a suitable anti-solvent to cause precipitation; or (iic) evaporating the first solvent and adding a new solvent and repeating either steps (iia) or step (iib); and (iii) filtering and collecting the resulting salt. The stoichiometry, solvent mix, solute concentration, and temperature employed can vary. Representative solvents that can be used to prepare or recrystallize the salt forms include, without limitation, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate, and acetonitrile.

Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts such as chloride, bromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; and salts with amino acids such as aspartate and glutamate. The salts may be in some cases hydrates or ethanol solvates. Representative salts are provided as described in U.S. Patent Nos. 5,597,919 to Dull et al., 5,616,716 to Dull et al. and 5,663,356 to Ruecroft et al, each of which is incorporated by reference. Salt screening for the free base (2S,3R)-N-(2-((3-pyridinyl)methyl-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide revealed that, while many salts of pharmaceutically acceptable acids could be formed, only a few of these salts had acceptable properties for commercial manufacture. The ability to predict the characteristics exemplified by a commercially viable salt, therefore, does not exist. Acids that provided salts that were crystalline, namely salts that demonstrate some degree of crystallinity, dependent upon the method by which they are prepared, include hydrochloric acid, sulfuric acid, phosphoric acid, p- toluenesulfonic acid, galactaric (mucic) acid, D-mandelic acid, D-tartaric acid, methanesulfonic acid, R- and S-10-camphorsulfonic acids, maleic acid, ketoglutaric acid and hippuric acid. Of these salts, the hydrochloric acid, phosphoric acid, maleic acid and p-toluenesulfonic acid salts each exhibited additional desirable properties, including high melting points, good water solubility, and low hygroscopicity. These characteristics in these salts were unexpected.

IV. Pharmaceutical Compositions

The pharmaceutical compositions of the present invention include the salts described herein, in the pure state or in the form of a composition in which the compounds are combined with any other pharmaceutically compatible product, which can be inert or physiologically active. The resulting pharmaceutical compositions can be used to prevent a condition or disorder in a subject susceptible to such a condition or disorder, and/or to treat a subject suffering from the condition or disorder. The pharmaceutical compositions described herein include the compound of the present invention and/or pharmaceutically acceptable salts thereof.

The manner in which the compounds are administered can vary. The compositions are preferably administered orally (e.g., in liquid form within a solvent such as an aqueous or nonaqueous liquid, or within a solid carrier). Preferred compositions for oral administration include pills, tablets, capsules, caplets, syrups, and solutions, including hard gelatin capsules and time- release capsules. Standard excipients include binders, fillers, colorants, solubilizers, and the like. Compositions can be formulated in unit dose form, or in multiple or subunit doses.

Preferred compositions are in liquid or semisolid form. Compositions including a liquid pharmaceutically inert carrier such as water or other pharmaceutically compatible liquids or semisolids can be used. The use of such liquids and semisolids is well known to those of skill in the art.

The compositions can also be administered via injection, i.e., intravenously,

intramuscularly, subcutaneously, intraperitoneally, intraarterially, intrathecally; and

intracerebroventricularly. Intravenous administration is the preferred method of injection.

Suitable carriers for injection are well known to those of skill in the art and include 5% dextrose solutions, saline, and phosphate-buffered saline. The drug product can also be administered as an infusion or injection (e.g., as a suspension or as an emulsion in a pharmaceutically acceptable liquid or mixture of liquids).

The formulations can also be administered using other means, for example, rectal administration. Formulations useful for rectal administration, such as suppositories, are well known to those of skill in the art. The drug product can also be administered by inhalation (e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Patent No. 4,922,901 to Brooks et al., the disclosure of which is incorporated herein in its entirety); topically (e.g., in lotion form); transdermal^ (e.g., using a transdermal patch) or iontophoretically; or by sublingual or buccal administration. Although it is possible to administer a compound in the form of a bulk active chemical, it is preferred to present a drug product in the form of a pharmaceutical composition or formulation for efficient and effective administration.

Exemplary methods for administering compounds will be apparent to the skilled artisan. The usefulness of these formulations can depend on the particular composition used and the particular subject receiving the treatment. These formulations can contain a liquid carrier that can be oily, aqueous, emulsified or contain certain solvents suitable to the mode of

administration.

The compositions can be administered intermittently or at a gradual, continuous, constant or controlled rate to a warm-blooded animal (e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey), but advantageously are administered to a human being. In addition, the time of day and the number of times per day that the pharmaceutical formulation is administered can vary. Other suitable methods for administering the compounds of the present invention are described in U.S. Patent No. 5,604,231 to Smith et al., the contents of which are hereby incorporated by reference.

In an embodiment of the present invention and as will be appreciated by those skilled in the art, the compound of the present invention may be administered in combination with other therapeutic compounds. For example, one aspect of the present invention includes a combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2- carboxamide or a pharmaceutically acceptable salt thereof, or another a 7 agonist, with one or more stimulant agent to treat ADHD of the combined, inattentive, or hyperactive/impulsive type. Another aspect includes a combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, or another a 7 agonist, with one or more antidepressant agent to treat ADH D of the combined, inattentive, or hyperactive/impulsive type. Another aspect includes a combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, or another al agonist, with one or more

antihypertensive agent to treat ADHD of the combined, inattentive, or hyperactive/impulsive type. Yet another aspect includes a combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, or another al agonist, with one or more of one or more stimulant agent, one or more antidepressant agent, and one or more antihypertensive to treat ADHD of the combined, inattentive, or hyperactive/impulsive type.

There are many stimulants available to treat ADHD. Common stimulants include but are not limited to: Adderall®, racemic amphetamine aspartate monohydrate, racemic amphetamine sulfate, dextroamphetamine saccharide, and dextroamphetamine sulfate; Concerta®, methylphenidate; Dexedrine®, dextroamphetamine, Metadate®, methylphenidate; Methylin®, methylhenidate; Ritalin®, methylphenidate; or Vyvanse®, lisdexamfetamine. Additionally, agents such as Provigil®, modafinil and Nuvigil®, armodafinil, whose prcise mechanism of action is not known but provides action similar to sympathomimetic agents, should be considered within the scope of the present invention.

Antihypertensives used to treat ADHD include but are not limited to: Catapres®, clonidine; and Tenex®, guanfacine. The use of such medications is often directed toward symptoms of aggression and impulsivity that may not be controlled by other ADHD medicines. Antidepressants used to treat ADHD include but are not limited to: Wellbutrin®, bupropion; tricyclic antidepressants, such as Pamelor®, nortriptyline, Aventyl®, nortiptyline, Tofranil®, imipramine; and Norpramin®, desipramine; Effexor®, venlafaxine; monoamine oxidase (MAO) inhibitors, including Nardil®, phenelzine, or Parnate®, tranylcypromine; and selective norepinephrine reuptake inhibitors, such as Strattera®, atomoxetine.

The compounds of the present invention may be employed alone or in combination with other therapeutic agents. Such a combination of pharmaceutically active agents may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compounds or agents and the relative timings of administration will be selected in order to achieve the desired therapeutic effect. The administration in combination may be by administration concomitantly in: (1 ) a unitary pharmaceutical composition including multiple compounds; or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time. The compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions.

The appropriate dose of the compound is that amount effective to prevent occurrence of the symptoms of the disorder or to treat some symptoms of the disorder from which the patient suffers. As noted, by "effective amount", "therapeutic amount" or "effective dose" is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disorder.

When treating a CNS disorder such as ADHD, an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject and to modulate the activity of relevant NNR subtypes (e.g., provide neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder). An example of prevention of a disorder is manifested by delaying the onset of the symptoms of the disorder. An example of treatment of a disorder is manifested by a decrease in the symptoms associated with the disorder or an amelioration of the recurrence of the symptoms of the disorder. Preferably, the effective amount is sufficient to obtain the desired result, but insufficient to cause appreciable side effects. The effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered. For human patients, the effective dose of typical compounds generally requires administering the compound in an amount sufficient to modulate the activity of relevant NNRs, but the amount should be insufficient to induce effects on skeletal muscles and ganglia to any significant degree. The effective dose of compounds will of course differ from patient to patient, but in general includes amounts starting where CNS effects or other desired therapeutic effects occur but below the amount where muscular effects are observed.

The compounds described herein, when employed in effective amounts in accordance with the methods described herein, can provide some degree of prevention of the progression of, ameliorate symptoms of, or ameliorate, to some degree, the recurrence of CNS or other disorders. The effective amounts of those compounds are typically below the threshold concentration required to elicit any appreciable side effects, for example those effects relating to skeletal muscle or ganglia. The compounds can be administered in a therapeutic window in which certain CNS and other disorders are treated and certain side effects are avoided. Ideally, the effective dose of the compounds described herein is sufficient to provide the desired effects upon the disorder but is insufficient (i.e., is not at a high enough level) to provide undesirable side effects. Preferably, the compounds are administered at a dosage effective for treating the CNS or other disorders but less than, often less than 1/5, and often less than 1/10, the amount required to elicit certain side effects to any significant degree.

Most preferably, effective doses are at very low concentrations, where maximal effects are observed to occur, with a minimum of side effects. Typically, the effective dose of such compounds generally requires administering the compound in an amount of less than 5 mg/kg of patient weight. Often, the compounds of the present invention are administered in an amount from less than about 1 mg/kg patent weight and usually less than about 100 μg/kg of patient weight, but frequently between about 10 μg to less than 100 μg/kg of patient weight. The foregoing effective doses typically represent that amount administered as a single dose, or as one or more doses administered over a 24-hour period. For human patients, the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1 , at least about 10, and at least about 100 mg/ 24 hr/ patient. For human patients, the effective dose of typical compounds requires administering the compound which generally does not exceed about 500, often does not exceed about 400, and frequently does not exceed about 300 mg/ 24 hr/ patient. In addition, the compositions are advantageously administered at an effective dose such that the concentration of the compound within the plasma of the patient normally does not exceed 50 ng/mL, often does not exceed 30 ng/mL, and frequently does not exceed 10 ng/mL. In one embodiment of the present invention, an effective dose is between about 1 mg and 50 mg in a 24-hour period.

Method of Using Pharmaceutical Compositions

As used herein, "intrinsic activity" or "efficacy" relates to some measure of biological effectiveness of the binding partner complex. With regard to receptor pharmacology, the context in which intrinsic activity or efficacy should be defined will depend on the context of the binding partner (e.g., receptor/ligand) complex and the consideration of an activity relevant to a particular biological outcome. For example, in some circumstances, intrinsic activity may vary depending on the particular second messenger system involved. See Hoyer, D. and Boddeke, H., Trends Pharmacol. Sci. 14(7): 270-5 (1993), herein incorporated by reference with regard to such teaching. Where such contextually specific evaluations are relevant, and how they might be relevant in the context of the present invention, will be apparent to one of ordinary skill in the art.

As used herein, neurotransmitters whose release is mediated by the compounds described herein include, but are not limited to, acetylcholine, dopamine, norepinephrine, serotonin, and glutamate, and the compounds described herein function as modulators at the a7 subtype of the CNS NNRs.

As used herein, the terms "prevention" or "prophylaxis" include any degree of reducing the progression of or delaying the onset of a disease, disorder, or condition. The term includes providing protective effects against a particular disease, disorder, or condition as well as amelioration of the recurrence of the disease, disorder, or condition. Thus, in another aspect, the invention provides a method for treating a subject having or at risk of developing or experiencing a recurrence of a NNR or nAChR mediated disorder. The compounds and pharmaceutical compositions of the invention may be used to achieve a beneficial therapeutic or prophylactic effect, for example, in a subject with a CNS dysfunction.

As noted above, the free base and salt compounds of the present invention modulates the a7 NNR subtype, characteristic of the CNS, and can be used for preventing or treating various conditions or disorders, including those of the CNS, in subjects which have or are susceptible to such conditions or disorders, by modulation of the a7 NNR. The compounds have the ability to selectively bind to the a7 NNR and express nicotinic pharmacology, for example, to act as agonists, partial agonists, antagonists, as described. For example, compounds of the present invention, when administered in effective amounts to patients in need thereof, provide some degree of prevention of the progression of the CNS disorder, namely, providing protective effects, amelioration of the symptoms of the CNS disorder, or amelioration of the reoccurrence of the CNS disorder, or a combination thereof.

The compounds of the present invention can be used to treat or prevent those types of conditions and disorders for which other types of nicotinic compounds have been proposed or are shown to be useful as therapeutics. See, for example, the references previously listed hereinabove, as well as Williams et al., Drug News Perspec. 7(4): 205 (1994), Arneric et al., CNS Drug Rev. 1 (1 ): 1-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1 ): 79-100 (1996), Bencherif et al., J. Pharmacol. Exp. Ther. 279: 1413 (1996), Lippiello et al., J. Pharmacol. Exp. Ther. 279: 1422 (1996), Damaj et al., J. Pharmacol. Exp. Ther. 291 : 390 (1999); Chiari et al., Anesthesiology 91 : 1447 (1999), Lavand'homme and Eisenbach, Anesthesiology 91 : 1455 (1999), Holladay et al., J. Med. Chem. 40(28): 4169-94 (1997), Bannon et al., Science 279: 77 (1998), PCT WO 94/08992, PCT WO 96/31475, PCT WO 96/40682, and U.S. Patent Nos. 5,583, 140 to Bencherif et al., 5,597,919 to Dull et al., 5,604,231 to Smith et al. and 5,852,041 to Cosford et al., the disclosures of which are incorporated herein by reference with regard to such therapeutic teaching.

The compounds and their pharmaceutical compositions are useful in the treatment or prevention of a variety of CNS disorders, including cognitive deficits and dysfunctions, age- related and otherwise and attentional disorders and, in particular ADHD. The American

Psychiatric Association's Diagnostic and Statistical Manual-IV, Text Revision (DSM-IV-TR) is used by mental health professionals to help diagnose ADHD. This diagnostic standard helps ensure that people are appropriately diagnosed and treated for ADHD. Using the same standard across communities will help determine the prevalence and public health impact of ADHD. As noted hereinabove, three types of ADHD are identified: ADHD, Combined Type: if specified criteria for inattentive and hyperactivity/impulsivity are met for the past 6 months; ADHD, Predominantly Inattentive Type: if criterion for inattentive is met but criterion for hyperactivity/impulsivity is not met for the past six months; and ADHD, Predominantly

Hyperactive-Impulsive Type: if criterion for hyperactivity/impulsivity is met but criterion for inattentive is not met for the past six months. The above conditions and disorders are discussed in further detail, for example, in the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, Washington, DC, American

Psychiatric Association, 2000; incorporated herein by reference with regard to defining such conditions and disorders. This Manual may also be referred to for greater detail on the symptoms and diagnostic features.

Preferably, the treatment or prevention of diseases, disorders, and conditions occurs without appreciable adverse side effects, including, for example, significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and significant effects upon skeletal muscle.

The compounds of the present invention, when employed in effective amounts, are believed to modulate the activity of the a 7 NNR without appreciable interaction with the nicotinic subtypes that characterize the human ganglia, as demonstrated by a lack of the ability to elicit nicotinic function in adrenal chromaffin tissue, or skeletal muscle, further demonstrated by a lack of the ability to elicit nicotinic function in cell preparations expressing muscle-type nicotinic receptors. Thus, these compounds are believed capable of treating or preventing diseases, disorders, and conditions without eliciting significant side effects associated activity at ganglionic and neuromuscular sites. Thus, administration of the compounds is believed to provide a therapeutic window in which treatment of certain diseases, disorders, and conditions is provided, and certain side effects are avoided. That is, an effective dose of the compound is believed sufficient to provide the desired effects upon the disease, disorder, or condition, but is believed insufficient, namely is not at a high enough level, to provide undesirable side effects.

Thus, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in therapy, such as a therapy described above.

V. Synthetic Examples

The following synthetic examples are provided to illustrate the present invention and should not be construed as limiting the scope thereof. In these examples, all parts and percentages are by weight, unless otherwise noted. All solutions are aqueous unless otherwise noted.

Example 1 : Small scale synthesis of (2S, 3R)-N-(2-((3-pyridinyl)methyl)-1 - azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide (Compound A) and its enantiomer, (2R, 3S)-N-(2-((3-pyridinyl)methyl)-1 -azabicyclo[2.2.2]octan-3-yl)benzofuran-2- carboxamide

2-((3-Pyridinyl)methylene)-1-azabicvclor2.2.2loctan-3-one

Potassium hydroxide (56 g, 0.54 mole) was dissolved in methanol (420 ml_). 3- Quinuclidinone hydrochloride (75 g, 0.49 mole) was added and the mixture was stirred for 30 min at ambient temperature. 3-Pyridinecarboxaldehyde (58 g, 0.54 mole) was added and the mixture stirred for 16 h at ambient temperature. The reaction mixture became yellow during this period, with solids caking on the walls of the flask. The solids were scraped from the walls and the chunks broken up. With rapid stirring, water (390 mL) was added. When the solids dissolved, the mixture was cooled at 4°C overnight. The crystals were collected by filtration, washed with water, and air dried to obtain 80 g of yellow solid. A second crop (8 g) was obtained by concentration of the filtrate to -10% of its former volume and cooling at 4°C overnight. Both crops were sufficiently pure for further transformation (88 g, 82% yield).

2-((3-Pyridinyl)methyl)-1-azabicvclor2.2.2loctan-3-one

2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (20 g, 93 mmol) was suspended in methanol (200 mL) and treated with 46 mL of 6 M hydrochloric acid. 10% Palladium on carbon (1.6 g) was added and the mixture was shaken under 25 psi hydrogen for 16 h. The mixture was filtered through diatomaceous earth, and the solvent was removed from the filtrate by rotary evaporation. This provided crude 2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]octan-3-one hydrochloride, as a white gum (20 g), which was subsequently treated with 2 M sodium hydroxide (50 mL) and chloroform (50 mL) and stirred for an hour. The chloroform layer was separated, and the aqueous phase was treated with 2 M sodium hydroxide (~5 mL, enough to raise the pH to 10) and saturated aqueous Sodium chloride (25 mL). This aqueous mixture was extracted with chloroform (3 x 10 mL), and the combined chloroform extracts were dried (anhydrous magnesium sulfate) and concentrated by rotary evaporation. The residue (18 g) was dissolved in warm ether (320 mL) and cooled to 4°C. The white solid was filtered off, washed with a small portion of cold ether and air dried. Concentration of the filtrate to -10% of its former volume and cooling at 4°C produced a second crop. A combined yield 16 g (79%) was obtained.

3-Amino-2-((3-pyridinyl)methyl)-1-azabicvclor2.2.2loctane

To a stirred solution of 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one (3.00 g, 13.9 mmol) in dry methanol (20 mL), under nitrogen, was added a 1 M solution of zinc chloride in ether (2.78 mL, 2.78 mmol). After stirring at ambient temperature for 30 min, this mixture was treated with solid ammonium formate (10.4 g, 167 mmol). After stirring another hour at ambient temperature, solid sodium cyanoborohydride (1.75 g, 27.8 mmol) was added in portions. The reaction was then stirred at ambient temperature overnight and terminated by addition of water (~ 5 mL). The quenched reaction was partitioned between 5 M sodium hydroxide (10 mL) and chloroform (20 mL). The aqueous layer was extracted with chloroform (20 mL), and combined organic layers were dried (sodium sulfate), filtered and concentrated. This left 2.97 g of yellow gum. GCMS analysis indicated that the product was a 1 :9 mixture of the cis and trans amines, along with a trace of the corresponding alcohol (98% total mass recovery).

(2R.3S) and (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicvclor2.2.2loctane

Di-p-toluoyl-D-tartaric acid (5.33 g, 13.8 mmol) was added to a stirred solution of crude

3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (6.00 g, 27.6 mmol of 1 :9 cis/trans) in methanol (20 mL). After complete dissolution, the clear solution was then concentrated to a solid mass by rotary evaporation. The solid was dissolved in a minimum amount of boiling methanol (~5 mL). The solution was cooled slowly, first to ambient temperature (1 h), then for ~ 4 h at 5°C and finally at -5°C overnight. The precipitated salt was collected by suction filtration and recrystallized from 5 mL of methanol. Air drying left 1.4 g of white solid, which was partitioned between chloroform (5 mL) and 2 M sodium hydroxide (5 mL). The chloroform layer and a 5 mL chloroform extract of the aqueous layer were combined, dried (anhydrous sodium sulfate) and concentrated to give a colorless oil (0.434 g). The enantiomeric purity of this free base was determined by conversion of a portion into its N-(tert-butoxycarbonyl)-L-prolinamide, which was then analyzed for diastereomeric purity (98%) using LCMS.

The mother liquor from the initial crystallization was made basic (~ pH 11 ) with 2 M sodium hydroxide and extracted twice with chloroform (10 mL). The chloroform extracts were dried (anhydrous sodium sulfate) and concentrated to give an oil. This amine (3.00 g, 13.8 mmol) was dissolved in methanol (10 mL) and treated with di-p-toluoyl-L-tartaric acid (2.76 g, 6.90 mmol). The mixture was warmed to aid dissolution and then cooled slowly to -5°C, where it remained overnight. The precipitate was collected by suction filtration, recrystallized from methanol and dried. This left 1.05 g of white solid. The salt was converted into the free base (yield = 0.364 g), and the enantiomeric purity (97%) was assessed using the prolinamide method, as described above for the other enantiomer.

Trans enantiomer A of N-(2-((3-pyridinyl)methyl)-1-azabicvclor2.2.2loctan-3-yl)benzofuran-2- carboxamide

Diphenylchlorophosphate (0.35 mL, 0.46 g, 1.7 mmol) was added drop-wise to a solution of benzofuran-2-carboxylic acid (0.28 g, 1.7 mmol) and triethylamine (0.24 mL, 0.17 g, 1.7 mmol) in dry dichloromethane (5 mL). After stirring at ambient temperature for 30 min, a solution of (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (0.337 g, 1.55 mmol) (that derived from the di-p-toluoyl-D-tartaric acid salt) and triethylamine (0.24 mL, 0.17 g, 1.7 mmol) in dry dichloromethane (5 mL) was added. The reaction mixture was stirred overnight at ambient temperature, and then treated with 10% sodium hydroxide (1 mL). The biphasic mixture was separated, and the organic layer was concentrated on a Genevac centrifugal evaporator. The residue was dissolved in methanol (6 mL) and purified by HPLC on a C18 silica gel column, using an acetonitrile/water gradient, containing 0.05% trifluoroacetic acid, as eluent. Concentration of selected fractions, partitioning of the resulting residue between chloroform and saturated aqueous sodium bicarbonate, and evaporation of the chloroform gave 0.310 g (42% yield) of white powder (95% pure by GCMS). ¹H NMR (300 MHz, CDCI₃) δ 8.51 (d, 1 H), 8.34 (dd, 1 H), 7.66 (d, 1 H), 7.58 (dt, 1 H), 7.49 (d, 1 H), 7.44 (s, 1 H), 7.40 (dd, 1 H), 7.29 (t, 1 H), 7.13 (dd, 1 H), 6.63 (d, 1 H), 3.95 (t, 1 H), 3.08 (m, 1 H), 2.95 (m, 4H), 2.78 (m, 2H), 2.03 (m, 1 H), 1.72 (m, 3H), 1.52 (m, 1 H).

This material (trans enantiomer A) was later determined to be identical, by chiral chromatogrphic analysis, to material whose absolute configuration is 2S,3R (established by x- ray crystallographic analysis).

Trans enantiomer B of N-(2-((3-pyridinyl)methyl)-1-azabicvclor2.2.2loctan-3-yl)benzofuran-2- carboxamide

Diphenylchlorophosphate (96 μί, 124 mg, 0.46 mmol) was added drop-wise to a solution of the benzofuran-2-carboxylic acid (75 mg, 0.46 mmol) and triethylamine (64 μί, 46 mg, 0.46 mmol) in dry dichloromethane (1 mL). After stirring at ambient temperature for 45 min, a solution of (2R,3S)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (0.10 g, 0.46 mmol) (that derived from the di-p-toluoyl-L-tartaric acid salt) and triethylamine (64 μί, 46 mg, 0.46 mmol) in dry dichloromethane (1 mL) was added. The reaction mixture was stirred overnight at ambient temperature, and then treated with 10% sodium hydroxide (1 mL). The biphasic mixture was separated, and the organic layer and a chloroform extract (2 mL) of the aqueous layer was concentrated by rotary evaporation. The residue was dissolved in methanol and purified by HPLC on a C18 silica gel column, using an acetonitrile/water gradient, containing 0.05% trifluoroacetic acid, as eluent. Concentration of selected fractions, partitioning of the resulting residue between chloroform and saturated aqueous sodium bicarbonate, and evaporation of the chloroform gave 82.5 mg (50% yield) of a white powder. The NMR spectrum was identical to that obtained for the 2S,3R isomer. Since the immediate precursor of this material (trans enantiomer B) is enantiomeric to the immediate precursor of 2S,3R compound (trans enantiomer A), the absolute configuration of trans enantiomer B is presumed to be 2R,3S. Example 2: Large scale synthesis of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1 - azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide and (2S,3R)-N-(2-((3- pyridinyl)methyl)-1 -azabicyclo[2.2.2]oct-3-yl)-1 -benzofuran-2-carboxamide p- toluenesulfonate salt

2-((3-Pyridinyl)methylene)-1-azabicvclor2.2.2loctan-3-one

3-Quinuclidinone hydrochloride (8.25 kg, 51.0 mol) and methanol (49.5 L) were added to a 100 L glass reaction flask, under an nitrogen atmosphere, equipped with a mechanical stirrer, temperature probe, and condenser. Potassium hydroxide (5.55 kg, 99.0 mol) was added via a powder funnel over an approximately 30 min period, resulting in a rise in reaction temperature from 50°C to 56°C. Over an approximately 2 h period, 3-pyridinecarboxaldehyde (4.80 kg, 44.9 mol) was added to the reaction mixture. The resulting mixture was stirred at 20°C ± 5°C for a minimum of 12 h, as the reaction was monitored by thin layer chromatography (TLC). Upon completion of the reaction, the reaction mixture was filtered through a sintered glass funnel and the filter cake was washed with methanol (74.2 L). The filtrate was concentrated, transferred to a reaction flask, and water (66.0 L) was added. The suspension was stirred for a minimum of 30 min, filtered, and the filter cake was washed with water (90.0 L) until the pH of the rinse was 7-9. The solid was dried under vacuum at 50°C ± 5°C for a minimum of 12 h to give 8.58 kg (89.3%) of 2-((3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one.

(2S)-2-((3-pyridinyl)methyl)-1-azabicvclor2.2.2loctan-3-one di-p-toluoyl-D-tartrate salt

2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (5.40 kg, 25.2 mol) and methanol (40.5 L) were added to a 72 L reaction vessel under an inert atmosphere equipped with a mechanical stirrer, temperature probe, low-pressure gas regulator system, and pressure gauge. The headspace was filled with nitrogen, and the mixture was stirred to obtain a clear yellow solution. To the flask was added 10% palladium on carbon (50% wet) (270 g). The atmosphere of the reactor was evacuated using a vacuum pump, and the headspace was replaced with hydrogen to 10 to 20 inches water pressure. The evacuation and pressurization with hydrogen were repeated 2 more times, leaving the reactor under 20 inches water pressure of hydrogen gas after the third pressurization. The reaction mixture was stirred at 20°C ± 5°C for a minimum of 12 h, and the reaction was monitored via TLC. Upon completion of the reaction, the suspension was filtered through a bed of Celite^®545 (1.9 kg) on a sintered glass funnel, and the filter cake was washed with methanol (10.1 L). The filtrate was concentrated to obtain a semi-solid which was transferred, under an nitrogen atmosphere, to a 200 L reaction flask fitted with a mechanical stirrer, condenser, and temperature probe. The semi-solid was dissolved in ethanol (57.2 L), and di-p-toluoyl-D-tartaric acid (DTTA) (9.74 kg, 25.2 mol) was added. The stirring reaction mixture was heated at reflux for a minimum of 1 h, and for an additional minimum of 12 h while the reaction was cooled to between 15°C and 30°C. The suspension was filtered using a tabletop filter, and the filter cake was washed with ethanol (1 1.4 L). The product was dried under vacuum at ambient temperature to obtain 1 1.6 kg (76.2% yield, 59.5% factored for purity) of (2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one di-p-toluoyl-D-tartrate salt.

(2S,3R)-3-Amino-2-((3-pyridinyl)methyl)-1-azabicvclor2.2.2loctane di-p-toluoyl-D-tartrate salt Water (46.25 L) and sodium bicarbonate (4.35 kg, 51.8 mol) were added to a 200 L flask. Upon complete dissolution, dichloromethane (69.4 L) was added. (2S)-2-((3-

Pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one di-p-toluoyl-D-tartrate salt (1 1.56 kg, 19.19 mol) was added, and the reaction mixture was stirred for between 2 min and 10 min. The layers were allowed to separate for a minimum of 2 min (additional water (20 L) was added when necessary to partition the layers). The organic phase was removed and dried over anhydrous sodium sulfate. Dichloromethane (34.7 L) was added to the remaining aqueous phase, and the suspension was stirred for between 2 min and 10 min. The layers were allowed to separate for between 2 min and 10 min. Again, the organic phase was removed and dried over anhydrous sodium sulfate. The extraction of the aqueous phase with dichloromethane (34.7 L) was repeated one more time, as above. Samples of each extraction were submitted for chiral HPLC analysis. The sodium sulfate was removed by filtration, and the filtrates were concentrated to obtain (2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one (4.0 kg) as a solid.

The (2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one (3.8 kg) was transferred to a clean 100 L glass reaction flask, under a nitrogen atmosphere, fitted with a mechanical stirrer and temperature probe. Anhydrous tetrahydrofuran (7.24 L) and (+)-(R)-o

methylbenzylamine (2.55 L, 20.1 mol) were added. Titanium(IV) isopropoxide (6.47 L, 21.8 mol) was added to the stirred reaction mixture over a 1 h period. The reaction was stirred under a nitrogen atmosphere for a minimum of 12 h. Ethanol (36.17 L) was added to the reaction mixture. The reaction mixture was cooled to below -5°C, and sodium borohydride (1.53 kg, 40.5 mol) was added in portions, keeping the reaction temperature below 15°C (this addition took several hours). The reaction mixture was then stirred at 15°C ± 10°C for a minimum of 1 h. The reaction was monitored by HPLC, and upon completion of the reaction (as indicated by less than 0.5% of (2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one remaining), 2 M sodium hydroxide (15.99 L) was added and the mixture was stirred for a minimum of 10 min. The reaction mixture was filtered through a bed of Celite 545 in a tabletop funnel. The filter cake was washed with ethanol (15.23 L), and the filtrate was concentrated to obtain an oil.

The concentrate was transferred to a clean 100 L glass reaction flask equipped with a mechanical stirrer and temperature probe under an inert atmosphere. Water (1 L) was added, and the mixture was cooled to 0°C ± 5°C. 2 M Hydrochloric acid (24 L) was added to the mixture to adjust the pH of the mixture to pH 1. The mixture was then stirred for a minimum of 10 min, and 2 M sodium hydroxide (24 L) was slowly added to adjust the pH of the mixture to pH 14. The mixture was stirred for a minimum of 10 min, and the aqueous phase was extracted with dichloromethane (3 x 15.23 L). The organic phases were dried over anhydrous sodium sulfate (2.0 kg), filtered, and concentrated to give (2S,3R)-N-((1 R)-phenylethyl)-3-amino-2-((3- pyridinyl)methyl) )-1-azabicyclo[2.2.2]octane (4.80 kg, 84.7% yield).

The (2S,3R)-N-((1 R)-phenylethyl)-3-amino-2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]octane was transferred to a 22 L glass flask equipped with a mechanical stirrer and temperature probe under an inert atmosphere. Water (4.8 L) was added, and the stirring mixture was cooled to 5°C ± 5°C. Concentrated hydrochloric acid (2.97 L) was slowly added to the reaction flask, keeping the temperature of the mixture below 25°C. The resulting solution was transferred to a 72 L reaction flask containing ethanol (18 L), equipped with a mechanical stirrer, temperature probe, and condenser under an inert atmosphere. To the flask was added 10% palladium on carbon (50% wet) (311 .1 g) and cyclohexene (14.36 L). The reaction mixture was heated at near-reflux for a minimum of 12 h, and the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to below 45°C, and it was filtered through a bed of Celite^®545 (1.2 kg) on a sintered glass funnel. The filter cake was rinsed with ethanol (3 L) and the filtrate was concentrated to obtain an aqueous phase. Water (500 ml.) was added to the concentrated filtrate, and this combined aqueous layer was washed with methyl tert-butyl ether (MTBE) (2 x 4.79 L). 2 M Sodium hydroxide (19.5 L) was added to the aqueous phase to adjust the pH of the mixture to pH 14. The mixture was then stirred for a minimum of 10 min. The aqueous phase was extracted with chloroform (4 x 1 1.96 L), and the combined organic phases were dried over anhydrous sodium sulfate (2.34 kg). The filtrate was filtered and concentrated to obtain (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]octane (3.49 kg, > quantitative yield) as an oil.

The (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane was transferred to a clean 100 L reaction flask equipped with a mechanical stirrer, condenser, and temperature probe under an inert atmosphere. Ethanol (38.4 L) and di-p-toluoyl-D-tartaric acid (3.58 kg, 9.27 mol) were added. The reaction mixture was heated at gentle reflux for a minimum of 1 h. The reaction mixture was then stirred for a minimum of 12 h while it was cooled to between 15°C and 30°C. The resulting suspension was filtered, and the filter cake was washed with ethanol (5.76 L). The filter cake was transferred to a clean 100 L glass reaction flask equipped with a mechanical stirrer, temperature probe, and condenser under an inert atmosphere. A 9:1 ethanol/water solution (30.7 L) was added, and the resulting slurry was heated at gentle reflux for a minimum of 1 h. The reaction mixture was then stirred for a minimum of 12 h while cooling to between 15°C and 30°C. The mixture was filtered and the filter cake was washed with ethanol (5.76 L). The product was collected and dried under vacuum at 50°C ± 5°C for a minimum of 12 h to give 5.63 kg (58.1 % yield) of (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]octane di-p-toluoyl-D-tartrate salt.

(2S,3R)-N-(2-((3-Pyridinyl)methyl)-1-azabicvclor2.2.2loctan-3-yl)benzofuran-2-carboxamide

(2S,3R)-3-Amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane di-p-toluoyl-D-tartrate salt (3.64 kg, 5.96 mol) and 10% aqueous sodium chloride solution (14.4 L, 46.4 mol) were added to a 72 L glass reaction flask equipped with a mechanical stirrer under an inert atmosphere. 5 M Sodium hydroxide (5.09 L) was added to the stirring mixture to adjust the pH of the mixture to pH 14. The mixture was then stirred for a minimum of 10 min. The aqueous solution was extracted with chloroform (4 x 12.0 L), and the combined organic layers were dried over anhydrous sodium sulfate (1.72 kg). The combined organic layers were filtered, and the filtrate was concentrated to obtain (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]octane (1.27 kg) as an oil.

The (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane was transferred to a 50 L glass reaction flask equipped with a mechanical stirrer under an inert atmosphere. Dichloromethane (16.5 L), triethylamine (847 ml_, 6.08 mol), benzofuran-2-carboxylic acid (948 g, 5.85 mol) and 0-(benzotriazol-1-yl)-N,N,N,1-tetramethyluronium hexafluorophosphate

(HBTU) (2.17 kg, 5.85 mol) were added to the reaction mixture. The mixture was stirred for a minimum of 4 h at ambient temperature, and the reaction was monitored by HPLC. Upon completion of the reaction, 10% aqueous potassium carbonate (12.7 L, 17.1 mol) was added to the reaction mixture and the mixture was stirred for a minimum of 5 min. The layers were separated and the organic phase was washed with 10% brine (12.7 L). The layers were separated and the organic phase was cooled to 15°C ± 10 °C. 3 M Hydrochloric acid (8.0 L) was slowly added to the reaction mixture to adjust the pH of the mixture to pH 1. The mixture was then stirred for a minimum of 5 min, and the layers were allowed to partition for a minimum of 5 min. The solids were filtered using a table top filter. The layers of the filtrate were separated, and the aqueous phase and the solids from the funnel were transferred to the reaction flask. 3 M Sodium hydroxide (9.0 L) was slowly added to the flask in portions to adjust the pH of the mixture to pH 14. The aqueous phase was extracted with dichloromethane (2 x 16.5 L). The combined organic phases were dried over anhydrous sodium sulfate (1.71 kg). The mixture was filtered, and the filtrate was concentrated to give (2S,3R)-N-(2-((3- pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide (1 .63 kg, 77.0% yield) as a yellow solid.

(2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicvclor2.2.2loct-3-yllbenzofuran-2-carboxamide p- toluenesulfonate

(2S,3R)-N-(2-((3-Pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)benzofuran-2- carboxamide (1.62 kg, 4.48 mol) and dichloromethane (8.60 kg) were added into a carboy. The weight/weight percent of the material in solution was determined through HPLC analysis. The solution was concentrated to an oil, acetone (4 L) was added, and the mixture was concentrated to an oily solid. Additional acetone (12 L) was added to the oily solid in the rotary evaporator bulb, and the resulting slurry was transferred to a 50 L glass reaction flask with a mechanical stirrer, condenser, temperature probe, and condenser under an inert atmosphere. The reaction mixture was heated to 50°C ± 5°C. Water (80.7 g) was added to the solution, and it was stirred for a minimum of 10 min. p-Toluenesulfonic acid (853 g, 4.44 mol) was added to the reaction mixture in portions over approximately 15 min. The reaction mixture was heated to reflux and held at that temperature for a minimum of 30 min to obtain a solution. The reaction was cooled to 40°C ± 5°C over approximately 2 h. Isopropyl acetate (14.1 L) was added over approximately 1.5 h. The reaction mixture was slowly cooled to ambient temperature over a minimum of 10 h. The mixture was filtered and the filter cake was washed with isopropyl acetate (3.5 L). The isolated product was dried under vacuum at 105°C ± 5°C for between 2 h and 9 h to give 2.19 kg (88.5% yield) of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2- carboxamide p-toluenesulfonate, mp 226-228°C. ¹H NMR (500 MHz, D₂0) δ 8.29 (s, 1 H), 7.78 (m, J = 5.1 , 1 H), 7.63 (d, J = 7.9, 1 H), 7.54 (d, J = 7.8, 1 H), 7.49 (d, J = 8.1 , 2H), 7.37 (m, J = 8.3, 1 H), 7.33 (m, J = 8.3, 6.9, 1.0, 1 H), 7.18 (m, J = 7.8, 6.9, 1.0, 1 H), 7.14 (d, J = 8.1 , 2H), 7.09 (s, 1 H), 6.99 (dd, J = 7.9, 5.1 , 1 H), 4.05 (m, J = 7.7, 1 H), 3.74 (m, 1 H), 3.47 (m, 2H), 3.28 (m, 1 H), 3.22 (m, 1 H), 3.15 (dd, J = 13.2, 4.7, 1 H), 3.02 (dd, J = 13.2, 1 1.5, 1 H), 2.19 (s, 3H), 2.02 (m, 2H), 1.93 (m, 2H), 1.79 (m, 1 H). ¹³C NMR (126 MHz, D₂0) δ 157.2, 154.1 , 150.1 , 148.2, 146.4, 145.2, 138.0, 137.0, 130.9, 128.2 (2), 126.9, 126.8, 125.5 (2), 123.7, 123.3, 122.7,

11 1.7, 100.7, 61.3, 50.2, 48.0, 40.9, 33.1 , 26.9, 21.5, 20.8, 17.0.

Samples of this material were converted into Compound A free base (for use in salt selection studies) by treatment with aqueous sodium hydroxide and extraction with chloroform. Thorough evaporation of the chloroform left an off-white powder, mp 167-170°C, with the following spectral characteristics: Positive ion electrospray MS [M+H]⁺ ion m/z = 362. ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (d, J = 7.6 Hz, 1 H), 8.43 (d, J = 1.7 Hz, 1 H), 8.28 (dd, J = 1.6, 4.7 Hz, 1 H), 7.77 (d, J = 7.7 Hz, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.63 (dt, J = 1.7, 7.7 Hz, 1 H), 7.52 (s, 1 H), 7.46 (m, J = 8.5, 7.5 Hz, 1 H), 7.33 (m, J = 7.7, 7.5 Hz, 1 H), 7.21 (dd, J = 4.7, 7.7 Hz, 1 H), 3.71 (m, J = 7.6 Hz, 1 H), 3.1 1 (m, 1 H), 3.02 (m, 1 H), 2.80 (m, 2H), 2.69 (m, 2H), 2.55 (m, 1 H), 1.80 (m, 1 H), 1.77 (m, 1 H), 1.62 (m, 1 H), 1.56 (m, 1 H), 1.26 (m, 1 H). ¹³C NMR (126 MHz, DMSO-d₆) 5 158.1 , 154.1 , 150.1 , 149.1 , 146.8, 136.4, 135.4, 127.1 , 126.7, 123.6, 122.9, 122.6,

11 1.8, 109.3, 61.9, 53.4, 49.9, 40.3, 35.0, 28.1 , 26.1 , 19.6.

The monohydrochloride salt of Compound A (see Example 3) was submitted for x-ray crystallographic analysis. The resulting crystal structure established the 2S,3R absolute configuration of Compound A.

Example 3: Synthesis of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1 -azabicyclo[2.2.2]oct-3- yl)benzofuran-2-carboxamide hydrochloride salts

Monohydrochloride: A hydrochloric acid/THF solution was prepared by adding of concentrated hydrochloric acid (1.93 mL of 12M, 23.2 mmol) drop-wise to 8.5 mL of chilled THF. The solution was warmed to ambient temperature. To a round bottom flask was added (2S,3R)- N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide (8.49 g, 23.5 mmol) and acetone (85 mL). The mixture was stirred and heated at 45-50°C until a complete solution was obtained. The hydrochloric acid/THF solution prepared above was added drop- wise over a 5 min period, with additional THF (1.5 mL) used in the transfer. Granular, white solids began to form during the addition of the acid solution. The mixture was cooled to ambient temperature, and stirred overnight (16 h). The solids were collected by suction filtration, the filter cake was washed with acetone (10 mL), and the solid was air-dried with suction for 30 min. The solid was further dried in a vacuum oven at 75°C for 2 h to give 8.79 g of the fine white crystals (94% yield), mp 255-262°C. Chiral LC analysis gave a purity of 98.8% (270 nm). ¹H- NMR (DMSO-d₆) shows no residual solvents and confirms mono stoichiometry. ¹H NMR (300 MHz, DMSO-de) δ 10.7 (broad s, 1 H - quaternary ammonium), 8.80 (broad s, 1 H - amide H), 8.54 (s, 1 H), 8.23 (d, 1 H), 7.78 (d, 1 H), 7.74 (d, 1 H), 7.60 (d, 1 H), 7.47 (m, 2H), 7.33 (m, 1 H), 7.19 (m, 1 H), 4.19 (m, 1 H), 4.08 (m, 1 H), 3.05-3.55 (m, 6H), 2.00-2.10 (m, 3H), 1.90 (m, 1 H), 1.70 (m, 1 H). An x-ray crystallographic analysis of this salt established stereochemical assignment and stoichiometry.

Dihydrochloride: Hydrogen chloride gas was slowly bubbled into a ice cooled solution of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide (1.9 g, 5.3 mmol) in anhydrous ether (25 ml_). The volatiles were removed, first in a nitrogen stream and then with high vacuum (sodium hydroxide scrubber in high vacuum line). The residue was triturated several times with small volumes of anhydrous ether (discarded), and the remaining solid was dried under high vacuum. This gave 2.17 g (94% yield) of off-white powder, mp 210- 212 °C (hygroscopic). Chiral LC analysis gave a purity of 93.7% (270 nm). Positive ion electrospray MS [M+H]⁺ ion m/z = 362. ¹H NMR (300 MHz, CD₃OD) δ 9.15 (s, 1 H), 8.84 (d, 1 H), 8.63 (d, 1 H), 7.97 (t, 1 H), 7.75 (d, 1 H), 7.61 (d, 1 H), 7.52 (m, 2H), 7.35 (t, 1 H), 4.50 (m, 1 H), 4.32 (m, 1 H), 3.40-3.85 (m, 6H), 1.95-2.40 (m, 5H).

VI. A Double-blind, Randomized, Placebo-Controlled, Multicenter, Fixed Dose Titration Study to Assess Efficacy, Safety, and Tolerability of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1 - azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof in Adults with Attention Deficit/Hyperactivity Disease (ADHD)

Efficacy Results

The present invention results from a trial conducted to test the effect of (2S,3R)-N-(2-((3- pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof in adults with ADHD. The study randomized 135 male or female adults (ages 18 - 65 years) with ADHD from sites in the US, diagnosed per DSM-IV-TR criteria.

Subjects were randomized to 12 weeks of treatment using either placebo (n = 67) or (2S,3R)-N- (2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a

pharmaceutically acceptable salt thereof (n = 68: 1 mg po qd for 4weeks, then 5mg po qd for 4 weeks, and finally 25mg po qd for 4 weeks).

The following Clinical Study Protocol No. TC-5619-238-CRD-002 provides a detailed description.

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The primary outcome measure (Conners Adult ADHD Rating Scale - Investigator

Thus, although the primary outcome measure did not show benefit favoring (2S,3R)-N- (2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a

pharmaceutically acceptable salt thereof at Weeks 4, 8 or 12, positive benefit favoring the compound was observed in a variety of CAARS-lnv and CAARS-S scales, CATB items, CGI-S, CGI-I, and POMS items. Moreover, a post hoc analysis in subjects with the predominantly inattentive type of ADHD showed statistically significant benefit favoring (2S,3R)-N-(2-((3- pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof on not only the primary outcome measure (CAARS-ln total score), but also on a variety of secondary outcome measures. Together, these results indicate that (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof produced cognitive and clinical benefit in adults with ADHD.

Efficacy results are presented in Tables 1 - 10.

Summary of Efficacy

Although (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2- carboxamide or a pharmaceutically acceptable salt thereof failed to separate from placebo on the primary outcome measure (CAARS-lnv Total) at Weeks 4, 8 and 12 in the total population, (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof did separate in the Inattentive subtype.

An effect was seen at Week 1 on the CAARS-lnv Total, Hyperactivity / Impulsivity, and ADHD Index sub-scales in the total population, but this effect was quickly lost. A similar profile was seen with the CGI-S and CGI-I.

The effect on CAARS-lnv was more long-lasting in the Inattentive subtype.

A consistent signal was seen on subject ratings (CAARS-S: ADHD Index, Hyperactivity, Inattention and Problems with Self Concept at Week 12), and this was supported by positive signals in POMS self-ratings (anger/hostility at Week 8 and confusion/bewilderment at Weeks 4 and 12).

Qualitatively similar profiles were seen in the Inattentive subtype.

(2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof separated sporadically on some objective tests of cognitive function including GMLT, International Shopping List, Detection, and Stop Signal Reaction Time.

Overall, (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2- carboxamide or a pharmaceutically acceptable salt thereof was statistically significant in 22 scales or items in the total population, vs. 3 for placebo.

The specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with practice of the present invention.

Although specific embodiments of the present invention are herein illustrated and described in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.

Claims

What is claimed is:

1. A method of treating of ADHD, comprising administering a therapeutically effective amount of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2- carboxamide or a pharmaceutically acceptable salt thereof.

2. A method of treating inattentive subtype ADHD, comprising administering a

therapeutically effective amount of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof.

3. A method of improving attention in a subject in need thereof comprising administering a therapeutically effective amount of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1- azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof.

4. A method of treating inattention, comprising administering a therapeutically effective amount of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2- carboxamide or a pharmaceutically acceptable salt thereof.

5. A method of treating one or more symptoms associated with ADHD, comprising

administering (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran- 2-carboxamide or a pharmaceutically acceptable salt thereof.

6. The method of claim 5, wherein the one or more symptoms is selected from the group consisting of total performance on Conners Adult ADHD Rating Scale (CAARS), hyperactivity, impulsivity, and ADHD Index sub-scales.

7. The method of claim 6, wherein the treatment provides early onset effect.

8. The method of claim 5, wherein the one or more symptoms is selected from the group consisting of hyperactivity, inattention, self-concept, anger, hostility, confusion, and bewilderment.

9. The method of claim 8, wherein the treatment provides continued effect .

10. A combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3- yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, or another a7 agonist, with one or more stimulant agent to treat ADHD.

11. The combination of claim 10, wherein the ADHD is of the combined, inattentive, or hyperactive/impulsive type.

12. A combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3- yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, or another a7 agonist, with one or more antidepressant agent to treat ADHD.

13. The combination of claim 12, wherein the ADHD is of the combined, inattentive, or

hyperactive/impulsive type.

14. A combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3- yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, or another a7 agonist, with one or more antihypertensive agent to treat ADHD.

15. The combination of claim 14, wherein the ADHD is of the combined, inattentive, or

hyperactive/impulsive type.

16. A combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3- yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, or another a7 agonist, with one or more of one or more stimulant agent, one or more antidepressant agent, and one or more antihypertensive to treat ADHD of the combined, inattentive, or hyperactive/impulsive type.

17. A combination of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3- yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof with another therapeutic agent for treating ADHD.

18. The combination of claim 17, wherein the ADHD is of the combined, inattentive, or

hyperactive/impulsive type.