NZ718978B2 - Novel treatments for attention and cognitive disorders, and for dementia associated with a neurodegenerative disorder - Google Patents

Abstract

The present invention provides a method of treating or preventing an attention and/or cognitive disorder in a subject in need thereof, comprising administering to the subject a compound of formula (I). The present invention further provides a method of treating or preventing dementia associated with a neurodegenerative disorder in a subject in need thereof, comprising administering to the subject a compound useful within the invention. a neurodegenerative disorder in a subject in need thereof, comprising administering to the subject a compound useful within the invention.

Description

(12) Granted patent caon (19) NZ (11) 718978 (13) B2 (47) Publicaon date: 2.24 (54) NOVEL TREATMENTS FOR ATTENTION AND COGNITIVE DISORDERS, AND FOR DEMENTIA ASSOCIATED WITH A NEURODEGENERATIVE DISORDER (51) Internaonal Patent Classificaon(s): A61K 31/4184A61K 31/4045 (22) Filing date: (73) Owner(s): 2014.10.28 DREXEL UNIVERSITY (23) Complete specificaon filing date: (74) Contact: 2014.10.28 Pizzeys Patent and Trade Mark Attorneys P ty Ltd (30) Internaonal Priority Data: US 61/896,173 2013.10.28 (72) Inventor(s): KORTAGERE, a (86) Internaonal Applicaon No.: (87) Internaonal Publicaon number: WO/2015/066019 (57) Abstract: The present invenon provides a method of treang or prevenng an aenon and/or cognive disorder in a subject in need thereof, comprising stering to the subject a compound of formula (I). The present invenon further es a method of treang or prevenng demena associated with a neurodegenerave disorder in a subject in need f, comprising administering to the t a compound useful within the invenon. 718978 B2 TITLE OF THE INVENTION NOVEL TREATMENTS FOR ATTENTION AND COGNITIVE DISORDERS, AND FOR DEMENTIA ATED WITH A EGENERATIVE DISORDER CROSS-REFERENCE TO D APPLICATIONS The present application claims priority under 35 U.S.C. § 119(e) to US.

Provisional Patent Application No. 61/896,173, filed October 28, 2013, which application is incorporated herein by reference in its ty.

BACKGROUND OF THE INVENTION The family of ein coupled receptors ) is one of the most important classes of proteins from both functional and structural standpoints. The human genome contains nearly 950 genes coding for GPCRs, of which nearly 450 genes have been implicated as therapeutic s. Ligand binding to GPCRs induces le receptor conformations and different ligands may stabilize distinct receptor conformations (Kenakin & Miller, 2010, Pharmacol. Rev. 265—304). The concept of functional selectivity is based on the hypothesis that distinct receptor conformations recruit distinct signaling proteins, leading to ential activation of one ing pathway over another (Mailman, 2007, Trends Pharmacol. Sci. 28(8):390—396). In on to selecting the signaling pathways, agonist—induced receptor conformations can also potentially affect or signaling properties.

Among the GPCRs, the subfamily of dopamine receptors has attracted attention from biologists and pharmacologists. In the central nervous system, dopamine receptors are widely expressed and involved in the control of locomotion, cognition, emotion and neuroendocrine secretion. In the peripheral system, ne receptors are present more prominently in kidney, vasculature and pituitary, where they affect mainly sodium homeostasis, vascular tone, and hormone secretion. While there are numerous examples of functionally—selective s that activates one signaling cascade preferentially over others, functionally—selective ligands that alter receptor signaling properties are rare and have not been described for dopamine receptors.

The neurotransmitter dopamine controls a wide variety of physiological and behavioral functions in mammals via five major subtypes of dopamine receptors. They are broadly classified into the “D1—like” and “DZ—like” dopamine receptors based on 2014/062644 pharmacology and function. The D1—like receptors consist of D1 and D5 ors, while the DZ—like receptors consist of D2, D3 and D4 receptors.

The D3 receptor primarily couples to the pertussis toxin—sensitive Gog—proteins (Gi/GO) (Ahlgren—Beckendorf & Levant, 2004, J. . Signal Transduct. Res. 24(3):117— 130). When transfected into different cell lines, the D3 receptor couples to adenylyl e V isoform (Robinson & Caron, 1997, Mol. Pharmacol. 52:508—514) and initiates signaling events including phosphorylation of mitogen—activated protein (MAP) kinases (Cussac et al., 1999, Mol. Pharmacol. 56(5):1025—103). D2 and D3 dopamine receptors also modulate potassium and m channel function (Seabrook et al., 1994, Br. J. Pharmacol. 111:391— 393; Werner et al., 1996, Mol. Pharmacol. 49:656—661). Transfected D3 receptors couple robustly to natively expressed G—protein coupled inward rectifier potassium (GIRK) and voltage—gated P/Q type calcium channels, and inhibit firing of spontaneous action potentials and secretory activity in the AtT—20 ndocrine cell line kandathil & Oxford, 1999, J. Neurosci. 19(5):1698—1707; Kuzhikandathil & Oxford, 2000, J. Gen. Physiol. 115 :697—706; Kuzhikandathil et al., 1998, Mol. Cell Neurosci. 12:390—402). The D3 receptor further couples to natively expressed adenylyl cyclase V (Kuzhikandathil & Bartoszyk, 2006, harm. 51:873—884), MAP kinases (Westrich & Kuzhikandathil, 2007, Biochim.

Biophys. Acta—MCR 1773:1747—1758) and ion channels kandathil & Oxford, 1999, J.

Neurosci. 19(5):1698—1707; Kuzhikandathil & , 2000, J. Gen. l. 115:697—706; Kuzhikandathil et al., 1998, Mol. Cell Neurosci. 12:390—402; Kuzhikandathil et al., 2004, Mol. Cell Neurosci. 26:144—155) in AtT—20 cells.

Dopamine receptors are targets for the treatment of s neurological and psychiatric disorders, such as Parkinson’s Disease, schizophrenia, drug addiction, depression, bipolar disorder, ion deficit hyperactivity syndrome, Tourette’s Syndrome, Huntington’s Disease and migraine.

Norepinephrine, also known as noradrenaline or 4—[(1R)—2—amino—1—hydroxy ethyl]benzene—1,2—diol, is a olamine that acts as a hormone and a neurotransmitter.

Norepinephrine is the hormone and neurotransmitter most sible for concentration, in contrast to the chemically similar hormone dopamine, also known as 4—(2—aminoethyl) benzene—1,2—diol), which is most responsible for alertness. Areas of the body that produce or are affected by norepinephrine are described as noradrenergic.

Norepinephrine has an important role as the neurotransmitter released from the sympathetic neurons to increase the rate of contractions in the heart. As a stress hormone, norepinephrine affects parts of the brain, such as the la, where attention and responses are controlled. Along with epinephrine (also known as adrenaline or (R)—4—(l—Hydroxy—2— (methylamino)ethyl)benzene—l,2—diol), nephrine underlies the fight—or—flight response, ly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to al muscle. It increases the brain's oxygen supply, and may also suppress neuro—inflammation when released diffusely in the brain from the locus eus. As a drug, norepinephrine increases blood re by increasing vascular tone (tension of vascular smooth muscle) h (x—adrenergic receptor activation.

Norepinephrine has potentially beneficial effects on attention deficit/ hyperactivity disorder, depression and hypotension, but, as with other catecholamines, it cannot be used in the clinic because it does not cross the blood—brain barrier. However, drugs that inhibit nephrine transporter in the ntal cortex (PFC), such as methylphenidate (MPH, also known as methyl phenyl(piperidin—2—yl)acetate), increase extracellular concentrations of norepinephrine in brain tissue and increase rodent performance in a sustained attention task.

Non—norepinephrine drugs such as amphetamines are used to stimulate brain activity levels. For people with attention—deficit/hyperactivity disorder (ADHD), psychostimulant medications such as amphetamines (ADDERALL® or DESOXYN®) are prescribed to increase both levels of norepinephrine and dopamine. phenidate (RITALIN® or CONCERTA®, a dopamine ke inhibitor) and atomoxetine (STRATTERA® or (3R)—N—methyl—3—(2—methylphenoxy)—3—phenylpropan—l—amine; a selective norepinephrine reuptake inhibitor) increase both norepinephrine and dopamine in the prefrontal cortex equally, but only dopamine (in the case of methylphenidate) and norepinephrine (in the case of atomoxetine) elsewhere in other parts of the brain. Other serotonin—norepinephrine reuptake inhibitors (SNRIs) currently approved as antidepressants are also used off—label for treatment of ADHD. The few medications ble to treat ADHD, such as MPH, have been illegally used by students and teenagers as a stimulant to boost their grades.

In addition to its neurotransmitter role, the norepinephrine from locus coeruleus cells y diffuses from “varicosities,” providing an endogenous anti— inflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus. Up to 70% of norepinephrine projecting cells are lost in Alzheimer’s Disease. Norepinephrine stimulates mouse microglia to suppress AB— induced production of nes and their ytosis of AB, suggesting this loss might have a role in causing this disease. There are currently no medications that may be used to treat dementia associated with a neurodegenerative disorder such as Parkinson's Disease and Alzheimer's Disease.

There is a need in the art for novel methods of treating or preventing an attention disorder and/or cognitive disorder in a subject in need thereof. Further, there is a need in the art for novel methods of treating or ting dementia associated with a neurodegenerative disorder in a subject in need thereof. The present invention fulfills these needs.

BRIEF SUMMARY OF THE INVENTION The invention includes a method of treating or preventing an attention disorder or a cognitive disorder in a subject in need thereof. The invention further includes a method of treating or preventing dementia associated with a neurodegenerative disease in a subject in need thereof.

In certain embodiments, the method ses stering to the subject a therapeutically ive amount of at least one compound ed from the group consisting R4\ R1 NH X/\I_R2 \ \J3 n R a nd of formula (I): (I), wherein in (I): R1, R2 and R3 are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C1_6 alkyl, substituted C1_6 alkyl, heteroalkyl, heterocyclyl, tuted heterocyclyl, aryl, tuted aryl, aryl—(C1_3)alkyl, substituted aryl— (C1_3)alkyl, carboxy, alkylcarboxy, formyl, alkyl—carbonyl, aryl—carbonyl, and heteroaryl—carbonyl; R4 and R5 are independently selected from the group consisting of H, C1_6 alkyl, substituted C1_6 alkyl, alkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl—(C1_3)alkyl, and substituted C1_3)alkyl; and, nis2,3,4or5; HN—R5 R1 m / R4 R2£ ‘ \ \ N a compound of formula (II): R3 (II), wherein in (II): R1 and R2 are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C1_6 alkyl, substituted C1_6 alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl—(C1_3)alkyl, substituted aryl— (C1_3)alkyl, carboxy, alkylcarboxy, forrnyl, alkyl—carbonyl, arbonyl, and aryl—carbonyl; R3 and R4 are independently selected from the group consisting of H, C1_6 alkyl, and substituted C1_6 alkyl; R5 is selected from the group consisting of H, C1_6 alkyl, substituted C1_6 alkyl, heteroalkyl, cyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl—(C1_3)alkyl, and substituted C1_3)alkyl; and, m is l, 2, or 3; 2,7—diamino—5—(4—fluorophenyl)—4—oxo—3,4,5,6—tetrahydropyrido[2,3—d]pyrimidine—6— carbonitrile; (Z)—2—(lH—benzo[d]imidazol—2—yl)—N'—hydroxy—3—(4—methoxyphenyl)propanimidamide; a pharmaceutically acceptable salt or solvate thereof, and any mixtures thereof.

In certain embodiments, the ion or cognitive disorder comprises ADD or ADHD. In other embodiments, administration of the compound improves cognitive flexibility in the subject. In yet other embodiments, administration of the compound improves sustained attention in the subject.

In certain embodiments, the neurodegenerative disease ses at least one ed from the group consisting of Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, transmissible spongiforrn alopathies, chronic traumatic encephalopathy (CTE) resulting from repeated traumatic brain injuries, and amyotrophic lateral sclerosis.

In certain embodiments, in formula (I) R1, R2 and R3 are independently selected from the group consisting of H, cyano, halo, , nitro, C1_6 alkyl, and carboxy.

In other embodiments, in formula (I) R4 and R5 are independently selected from the group consisting of H, C1_6 alkyl, and tuted C1_6 alkyl. In yet other embodiments, in formula (I) n is 2. In yet other embodiments, in formula (II) m is l.

In certain embodiments, the at least one compound is selected from the group consisting of: 2—amino—4—(2—chlorophenyl)butan—l—ol; 2—(3—aminohexyl)phenol; hlorophenyl)—2—methylamino—butane; 4—(2—fluorophenyl)butan—2—amine; 4—(2— bromophenyl)butan—2—amine; 4—(2—iodophenyl)butan—2—amine; 4—(2—methoxyphenyl)butan—2— amine; 2—(3—aminobutyl)phenol; —diethoxyphenyl)propan—l—amine; 4—(4— chlorophenyl)butan—2—amine; ethoxyphenyl)butan—2—amine; 2—(5—chloro— l—methyl— lH— indol—3—yl)ethanamine; l—(5—fluoro—l—methyl—lH—indol—3—yl)propan—2—amine; l—(5—methoxy— l—methyl—lH—indol—3—yl)propan—2—amine; 2,7—diamino—5—(4—fluorophenyl)—4—oxo—3,4,5,6— tetrahydropyrido[2,3—d]pyrimidine—6—carbonitrile; (Z)—2—(lH—benzo[d]imidazol—2—yl)—N'— hydroxy—3—(4—methoxyphenyl)propanimidamide; a pharmaceutically acceptable salt or solvate, and mixtures thereof.

In certain ments, the composition further ses at least one drug selected from the group consisting of methylphenidate, amphetamine, dextroamphetamine—amphetamine, lisdexamfetamine, ADHD medication, antidepressants, clonidine, guanfacine, and a salt or solvate thereof.

In certain embodiments, the subject is a mammal. In other embodiments, the subject is human.

BRIEF DESCRIPTION OF THE DRAWINGS For the purpose of illustrating the invention, there are ed in the drawings certain embodiments of the present invention. However, the invention is not limited to the precise arrangements and instrumentalities of the ments depicted in the drawings.

Fig. l is a graph illustrating the effect of SK609 (also known as 4—(2— phenyl)—butan—2—amine or a salt thereof) on the effluX of the various monoamine neurotransmitters measured as a percentage of the vehicle. The IC50 value for hSERT was .85 uM, for hDAT was 8.5 uM, and for hNET was 290 nM.

Fig. 2 is a schematic illustration of the experimental set—up sustained attention task animal study described herein.

Fig. 3 is a set of pictures illustrating the sustained attention task apparatus described herein. Operant conditioning chambers pictured with presentation lights, levers and water reward mechanism. The t chambers are contained in an air—circulated and sound—isolated cabinet.

Fig. 4 is a graph rating vigilance indeX (VI) scores against varying doses of SK609 (doses of 2, 4, 8, 10 and 20 mg/kg at 1 ml/kg weight) in a sustained attention task.

A typical inverted—U shaped mance was observed with SK609 treatment; a peak dose of 8 mg/kg was completely abrogated by pre—treatment with prozosin and tely by D2— like antagonist raclopride. The peak dose mance of SK609 was similar to the performance of MPH.

Fig. 5 is a bar graph illustrating the % omission as a on of SK609 dose.

IP administration of SK609 at high doses increased the % of omissions for the .

Fig. 6 is a bar graph illustrating the finding that administration of prazosin (IP, 0.25 mg/kg) blocked the effects of administration of SK609 (IP, 4.0 mg/kg) in rats (n=6, *p=0.07). Prazosin had similar ng effect with MPH administration.

Fig. 7 is an illustration of a cross maze used to test compounds of the present invention.

Fig. 8 is a bar graph that illustrates the effect of raclopride on SK609 and MPH in a vigilance index (VI) score experiment.

Fig. 9 is a bar graph that illustrates the effect of SK609 and raclopride in a set— shifting task.

Fig. 10, comprising Figs. 10A—10B, rates the effect of SK609 in a cross— maze task. Fig. 10A illustrates number of trials to reach the criterion, and Fig. 10B illustrates overall performance upon administration of saline or SK609.

DETAILED DESCRIPTION OF THE INVENTION The t invention relates to the unexpected identification of compounds that are useful to treat or prevent an attention and/or cognitive disorder, such as but not limited to attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD). The present invention further relates to the unexpected fication of compounds that are useful to treat or prevent dementia associated with a neurodegenerative disorder.

In certain embodiments, the neurodegenerative disorder comprises at least one selected from the group consisting of Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), transmissible spongiform encephalopathies (TSEs), and amyotrophic lateral sclerosis (ALS).

In certain embodiments, the compound useful within the invention is a selective D3 receptor t and a ive norepinephrine orter (NET) inhibitor. In other embodiments, the compounds useful within the invention are not selective activators of the dopamine transporter or serotonin transporter. In yet other embodiments, the compounds useful within the invention are not selective inhibitors of the dopamine transporter or serotonin transporter. Without g to be limited by any theory, a nd that is a selective D3 receptor t and a selective norepinephrine transporter tor blocks NET, increases extracellular norepinephrine, and improves performance in a sustained attention task.

In certain embodiments, the compounds of the present invention improve cognitive flexibility in a subject. In other embodiments, the compounds of the present invention improve sustained attention in a t. In yet other embodiments, the compounds of the present invention improve cognitive lity and sustained attention in a subject.

Without wishing to be limited by any theory, these improvement are mediated ically through the targets dopamine D3 receptor and NET. In certain embodiments, the improvement in sustained attention can be blocked by the use of a D3 receptor antagonist and (11 adrenergic receptor antagonist, suggesting the target ment by the compounds of present invention.

As demonstrated , SK609, an atypical ive t of the D3 receptor, was characterized against a panel of monoamine neurotransmitter transporters and other G—protein coupled receptors, and these studies revealed novel armacological effects that contribute significantly to its atypical profile. In addition to its highly selective D3 agonist activity, SK609 exhibited selective NET antagonism. Further, SK609 had no effect on dopamine transporters (DAT) or serotonin transporters (SERT), and likely does not produce the stimulant effects as seen with amphetamine compounds.

The results described herein demonstrate that SK609 increased male Sprague— Dawley rat performance in the sustained attention task in a dose dependent manner with a peak effect at 8 mg/kg. SK609—induced changes in performance followed an inverted—U curve, which is the same dose—response relationship noted previously for MPH. In addition, eatment with the OLl—adrenergic or antagonist prazosin reversed the attention— enhancing effects of SK609 and MPH completely, while the dopamine DZ—like receptor antagonist raclopride had complete tion, suggesting a role for norepinephrine and dopaminergic modulation in the action of these compounds and PFC—related cognitive tasks.

Definitions As used , each of the ing terms has the meaning associated with it in this section.

Unless d otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in animal physiology, pharmacology, organic chemistry, and peptide chemistry are those well known and commonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more than one (i. e. to at least one) of the grammatical object of the article. By way of e, “an element” means one element or more than one element.

As used , the term “about” will be understood by s of ordinary skill in the art and will vary to some extent on the context in which it is used.

As used herein, the term “atomoxetine” refers to (3R)—N—methyl—3—(2— methylphenoxy)—3—phenylpropan—l—amine, or a salt or solvate thereof.

The term “container” includes any receptacle for holding the pharmaceutical composition. For example, In certain embodiments, the ner is the packaging that contains the pharmaceutical composition. In other embodiments, the container is not the packaging that contains the pharmaceutical ition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition.

Moreover, packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical ition may be contained on the packaging ning the pharmaceutical composition, and as such the instructions form an sed functional onship to the packaged product. However, it should be understood that the instructions may contain information pertaining to the compound’s ability to perform its intended function, e.g., treating, preventing, or reducing a disease or disorder in a t.

As used herein, the term “DAT” refers to dopamine transporter.

As used herein, the term “L—DOPA” refers to levodopa, also known as L—3,4— dihydroxyphenylalanine, or a salt or solvate thereof.

As used herein, the terms “effective amount,77 4‘pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological . An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine mentation.

As used , the term “E8609” or “E80609” refers to 4—(2—chlorophenyl)— 2—amine, or a salt or solvate thereof.

“Instructional material” as that term is used herein includes a ation, a recording, a diagram, or any other medium of expression that may be used to communicate the usefulness of the compounds of the t invention. In some instances, the instructional material may be part of a kit useful for effecting alleviating or treating the various es or disorders recited herein. Optionally, or alternately, the instructional material may describe one or more methods of alleviating the diseases or disorders in a cell or a tissue of a mammal.

The instructional material of the kit may, for example, be affixed to a container that ns the compounds of the present invention or be shipped together with a container that contains the nds. Alternatively, the instructional material may be shipped separately from the container with the intention that the recipient uses the instructional material and the compound cooperatively. For example, the instructional al is for use of a kit; instructions for use of the compound; or instructions for use of a formulation of the compound.

As used herein, the term “MPH” refers to phenidate or methyl phenyl(piperidin—2—yl)acetate, or a salt or solvate thereof.

As used herein, the term “NET” refers to norepinephrine orter.

As used herein, the term “patient,” “individual” or “subject” refers to a human or a non—human mammal. Non—human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. In certain embodiments, the patient, individual or subject is human.

As used herein, the term “PFC” refers to prefrontal cortex.

As used herein, the term “polypeptide” refers to a polymer composed of amino acid residues, related lly occurring structural variants, and synthetic non—naturally occurring s thereof linked via peptide bonds. Synthetic polypeptides may be sized, for example, using an automated polypeptide synthesizer. As used herein, the term “protein” typically refers to large polypeptides. As used herein, the term “peptide” typically refers to short polypeptides. Conventional notation is used herein to represent polypeptide sequences: the and end of a polypeptide sequence is the amino—terminus, and the right—hand end of a polypeptide sequence is the carboxyl—terminus.

As used herein, amino acids are represented by the full name thereof, by the three letter code corresponding thereto, or by the one—letter code corresponding thereto, as indicated below: Aspartic Acid, Asp, D; Glutamic Acid, Glu, E; Lysine, Lys, K; Arginine, Arg, R; Histidine, His, H; ne, Tyr, Y; Cysteine, Cys, C; Asparagine, Asn, N; WO 66019 Glutamine, Gln, Q; Serine, Ser, S; Threonine, Thr, T; Glycine, Gly, G; Alanine, Ala, A; Valine, Val, V; Leucine, Leu, L; Isoleucine, Ile, I; Methionine, Met, M; Proline, Pro, P; Phenylalanine, Phe, F; Tryptophan, Trp, W.

As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is vely non—toxic, i.e. the al may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used , the phrase aceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non—toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. ceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, cation or formulation of compounds useful within the methods of the present invention. Salts may be comprised of a fraction of one, one or more than one molar equivalent of acid or base with t to any compound of the present invention.

Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include sulfate, hydrogen e, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and oric acids (including hydrogen ate and dihydrogen phosphate). Organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic s of c acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, , ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4—hydroxy benzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2—hydroxyethanesulfonic, p—toluene sulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, B—hydroxybutyric, salicylic, galactaric, galacturonic acid, glycerophosphonic acids and saccharin (e.g., saccharinate, saccharate). le pharmaceutically acceptable base addition salts of compounds of the present invention include, for example, ammonium salts, ic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for e, N,N’—dibenzylethylene— diamine, chloroprocaine, e, diethanolamine, ethylenediamine, meglumine (N—methyl ine) and procaine. All of these salts may be ed from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.

As used herein, the term “pharmaceutical ition” or “composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, l, parenteral, ophthalmic, ary and topical administration.

As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, sing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating al, involved in carrying or transporting a nd useful within the invention within or to the t such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as ceutically able carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium ide and aluminum hydroxide; e active agents; alginic acid; pyrogen—free water; isotonic saline; ’s solution; ethyl alcohol; phosphate buffer solutions; and other non—toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also es any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the ion, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may r include a pharmaceutically acceptable salt of the compound useful within the invention.

Other additional ingredients that may be included in the pharmaceutical itions used in the ce of the present invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

As used herein, the term “prazosin” refers to 2—[4—(2—furoyl)piperazin—l—yl]— 6,7—dimethoxyquinazolin—4—amine, or a salt or solvate thereof.

As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or e. Also considered is the ability of one to prevent some or all of the symptoms ated with the disorder or disease.

As used herein, the term “raclopride” refers to 3,5 —dichloro—N—{ [(ZS)—l— yrrolidin—2—yl]methyl}—2—hydroxy—6—methoxybenzamide, or a salt or solvate thereof.

As used herein, the term “SERT” refers to serotonin transporter.

As used herein, the term “SRT property” or “slow response termination” as ng to the D3 receptor refers to the increase in time taken to terminate the signaling function of the D3 receptor, after removal of the agonist.

As used herein, the term “tolerance property” as applying to the D3 receptor refers to the progressive decrease in receptor signaling function upon repeated ation by classical agonists, including dopamine.

As used herein, the term “treatment” or ing” is defined as the application or administration of a eutic agent, i.e., a compound useful within the invention (alone or in combination with another ceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder, a symptom of a e or disorder or the potential to develop a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, , ameliorate, improve or affect the e or disorder, the symptoms of the disease or disorder, or the potential to develop the disease or disorder. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

As used , the term “VI” refers to vigilante index.

Throughout this disclosure, various aspects of the present invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible tion on the scope of the present invention. Accordingly, the description of a range should be ered to have specifically disclosed all the possible nges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub—ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.1, 5.3, 5.5, and 6. This applies regardless of the breadth of the range.

Compounds The compounds useful within the invention may be synthesized using techniques well—known in the art of organic sis.

In one aspect, the compounds useful within the invention are selective D3 receptor ts and selective norepinephrine transporter (NET) antagonists. In another aspect, the compounds useful within the invention are not agonists of the dopamine transporter or serotonin transporter. In yet another aspect, the compounds useful within the invention are not an antagonist of the ne transporter or serotonin transporter.

In another aspect, the compound useful within the present invention has the NH RLKK//\:_R2 \ \J3 formula (I): n R (I), n in (I): R1, R2 and R3 are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C1_6 alkyl, tuted C1_6 alkyl, heteroalkyl, heterocyclyl, tuted heterocyclyl, aryl, substituted aryl, aryl—(C1_3)alkyl, substituted aryl— (C1_3)alkyl, carboxy, alkylcarboxy, formyl, alkyl—carbonyl, aryl—carbonyl, and heteroaryl—carbonyl; R4 and R5 are independently selected from the group ting of H, C1_6 alkyl, substituted C1_6 alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl—(C1_3)alkyl, and substituted aryl—(C1_3)alkyl; and, n is 2, 3, 4 or 5; or a pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, R1, R2 and R3 are ndently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C1_6 alkyl, substituted C1_6 alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, carboxy, alkylcarboxy, formyl, alkyl—carbonyl, arbonyl, and heteroaryl—carbonyl. In other embodiments, R1, R2 and R3 are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, , nitro, C1_6 alkyl, substituted C1_6 alkyl, heteroalkyl, carboxy, alkylcarboxy, formyl, and carbonyl. In yet other embodiments, R1, R2 and R3 are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C1_6 alkyl, tuted C1_6 alkyl, alkyl, and carboxy. In yet other embodiments, R1, R2 and R3 are independently selected from the group consisting of H, cyano, hydroxyl, amino, ido, halo, alkoxy, nitro, C1_6 alkyl, and y. In yet other embodiments, R1, R2 and R3 are independently selected from the group consisting of H, cyano, halo, alkoxy, nitro, C1_6 alkyl, and carboxy. In yet other embodiments, R1 and R2 are H, and R3 is . In yet other embodiments, R1, R2 and R3 are either independently or in combination selected from the group consisting of H, fluoro, chloro, bromo, iodo, methoxy, ethoxy, hydroxyl, methyl, ethyl or other lower alkyl or aryl groups .

In certain embodiments, n is 2, 3 or 4. In other embodiments, n is 2 or 3. In yet other embodiments, n is 2.

In certain embodiments, R4 and R5 are independently selected from the group consisting of H, C1_6 alkyl, substituted C1_6 alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, and substituted aryl. In other embodiments, R4 and R5 are independently selected from the group consisting of H, C1_6 alkyl, substituted C1_6 alkyl, heteroalkyl, cyclyl, and substituted heterocyclyl. In yet other embodiments, R4 and R5 are independently ed from the group consisting of H, C1_6 alkyl, substituted C1_6 alkyl, and heteroalkyl. In yet other embodiments, R4 and R5 are independently selected from the group consisting of H, C1_6 alkyl, and substituted C1_6 alkyl. In yet other ments, R4 and R5 are methyl. In yet other embodiments, R5 is H, methyl, ethyl, prop—l—yl, prop—2—yl, hydroxymethyl, l—hydroxy—ethyl, 2—hydroxy—ethyl, l—hydroxy—prop—l—yl, 2—hydroxy—prop—l— yl, 3—hydroxy—prop—l—yl, l—hydroxy—prop—2—yl or 2—hydroxy—prop—2—yl.

In certain embodiments, the compound useful within the invention is selected from the group consisting of: 2—amino—4—(2—chlorophenyl)butan— l—ol ; HogNH2 2—(3—amin0hexy1)phenol ; 4—(2—chlor0pheny1)—2—methy1amino—butane (also known as 4—(2—chloropheny1)—N—methy1 butan—Z—amine) ' F5NH2 4—(2—flu0r0pheny1)butan—2—amine ' BréNH2 4—(2—brom0pheny1)butan—2—amine ; 5NH2 4—(2—iodopheny1)butan—2—amine ; MeOéN H2 eth0xypheny1)butan—2—amine ; HOSNH2 2—(3—aminobuty1)phenol 3 3—(3,4—diethoxyphenyl)propan— l —amine OEt ; 4—(4—chlorophenyl)butan—2—amine Cl ; 4—(4—methoxyphenyl)butan—2—amine OMe ; mixtures thereof, or a pharmaceutically acceptable salt or solvate f.

In yet another aspect, the compound useful within the invention has the formula (II): HN—R5 R1 m R4 R23/ ‘ \ \ N\ R3 (11), wherein in (II): R1 and R2 are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C1_6 alkyl, tuted C1_6 alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl—(C1_3)alkyl, substituted aryl— alkyl, y, alkylcarboxy, formyl, alkyl—carbonyl, aryl—carbonyl, and heteroaryl—carbonyl; R3 and R4 are independently selected from the group consisting of H, C1_6 alkyl, and substituted C1_6 alkyl or aryl or heteroaryl; R5 is selected from the group consisting of H, C1_6 alkyl, substituted C1_6 alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl—(C1_3)alkyl, and substituted aryl—(C1_3)alkyl; and, m is l, 2, or 3; or a pharmaceutically acceptable salt or e thereof. 2014/062644 In certain embodiments, R1 and R2 are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C1_6 alkyl, substituted C1_6 alkyl, carboxy, alkylcarboxy, forrnyl, carbonyl, aryl—carbonyl, and heteroaryl—carbonyl. In other embodiments, R1 and R2 are independently selected from the group consisting of H, cyano, hydroxyl, halo, and alkoxy, C1_6 alkyl, and substituted C1_6 alkyl.

In certain embodiments, R3 and R4 are independently selected from the group consisting of H, and C1_6 alkyl.

In certain embodiments, R5 is selected from the group consisting of H, C1_6 alkyl, and substituted C1_6 alkyl.

In certain embodiments, m is l, or 2.

In certain embodiments, the compound useful within the invention is selected from the group consisting of 2—(5—chloro— l—methyl— lH—indol—3—yl)ethanamine CH3 ; l—(S—fluoro— 1 —methyl— lH—indol—3—yl)propan—2—amine CH3 ; l—(5—methoxy— l—methyl— lH—indol—3—yl)propan—2—amine CH3 ; es f, or a pharmaceutically acceptable salt or e thereof.

In yet another aspect, the compound useful within the invention is selected from the group consisting of: 2,7—diamino—5—(4—fluorophenyl)—4—oxo—3,4,5,6—tetrahydropyrido[2,3—d]pyrimidine—6— carbonitrile, (Z)—2—(lH—benzo[d]imidazol—2—yl)—N'—hydroxy—3—(4—methoxyphenyl)propanimidamide, @\NN OMe H N/ mixtures thereof, or a pharrnaceutically acceptable salt or solvate thereof.

Methods In one aspect, the invention includes a method of treating or preventing an attention disorder or cognitive disorder in a subject in need thereof. In certain embodiments, the ion disorder or cognitive disorder comprises ADD or ADHD.

In another aspect, the invention includes a method of treating or preventing dementia ated with a neurodegenerative disorder in a subject in need thereof. In certain embodiments, the neurodegenerative disorder ses at least one selected from the group consisting of Alzheimer’s Disease (AD), son’s Disease (PD), Huntington’s Disease (HD), transmissible spongiform encephalopathies (TSEs), chronic traumatic encephalopathy (CTE) resulting from repeated traumatic brain injuries, and ophic lateral sclerosis (ALS).

In certain embodiments, the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the present ion.

In certain ments, the compounds of the present invention improve cognitive flexibility in a subject. In other embodiments, the nds of the t ion do not improve cognitive flexibility in a subject. In yet other embodiments, the compounds of the present invention improve sustained attention in a subject. In yet other embodiments, the compounds of the present ion do not improve sustained attention in a subject.

In certain embodiments, the compound useful within the invention is selected from the group consisting of: 2—amino—4—(2—chlorophenyl)butan—1—ol; 2—(3—aminohexyl) phenol; hlorophenyl)—2—methylamino—butane (also known as 4—(2—chlorophenyl)—N— methylbutan—2—amine); 4—(2—fluorophenyl)butan—2—amine; 4—(2—bromophenyl)butan—2—amine; 4—(2—iodophenyl)butan—2—amine; 4—(2—methoxyphenyl)butan—2—amine; 2—(3—aminobutyl) phenol; 3—(3,4—diethoxyphenyl)propan—1—amine; 4—(4—chlorophenyl)butan—2—amine; 4—(4— yphenyl)butan—2—amine; 2—(5—chloro—1—methyl—1H—indol—3—yl)ethanamine; 1— (5—fluoro— 1—methyl—1H—indol—3—yl)propan—2—amine; 1—(5—methoxy—1—methyl—1H—indol—3—yl)propan—2— amine; 2,7—diamino—5—(4—fluorophenyl)—4—oxo—3,4,5,6—tetrahydropyrido[2,3—d]pyrimidine—6— itrile; (Z)—2—(1H—benzo[d]imidazol—2—yl)—N'—hydroxy—3—(4—methoxyphenyl) propanimidamide; mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, the t is human.

Combination Therapies The compounds of the present invention are intended to be useful in the methods of present invention in combination with one or more additional compounds useful for treating the diseases or disorders contemplated within the invention. These additional compounds may comprise compounds of the present invention or compounds, e.g., commercially available compounds, known to treat, prevent, or reduce the symptoms of the diseases or disorders contemplated within the invention.

In non—limiting examples, the compounds of the present invention may be used in combination with one or more of the following drugs: methylphenidate (CONCERTA®, METADATE®, and RITALIN®), dextroamphetamine (DEXEDRINE®), dextroamphetamine—amphetamine (ADDERALL XR®), lisdexamfetamine (VYVANSE®), ADHD medication such as atomoxetine (STRATTERA®), antidepressants such as bupropion UTRIN®) and desipramine (NORPRAMIN®), ine RES®), guanfacine (INTUNIV®, TENEX®), a salt or solvate thereof and es thereof.

A synergistic effect may be ated, for example, using suitable methods such as, for example, the Sigmoid—Emax equation (Holford & Scheiner, 19981, Clin.

Pharmacokinet. 6: 429—453), the equation of Loewe vity (Loewe & nek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313—326) and the median—effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22: 27—55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration—effect curve, isobologram curve and combination index curve, respectively.

Administration/Dosage/Formulations The n of stration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the patient either prior to or after the onset of a disease or disorder. r, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as ted by the exigencies of the therapeutic or prophylactic situation.

Administration of the compositions useful within the present invention to a patient, preferably a mammal, more ably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the e or disorder in the t; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease or disorder in the patient. Dosage regimens may be adjusted to e the optimum eutic response. For example, several divided doses may be administered daily or the dose may be proportionally d as indicated by the exigencies of the therapeutic situation. A non—limiting example of an effective dose range for a therapeutic nd of the present invention is from about 1 and 5,000 mg/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

In particular, the selected dosage level will depend upon a variety of s including the activity of the particular compound employed, the time of administration, the rate of excretion of the nd, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, , condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may y determine and prescribe the effective amount of the pharmaceutical composition required. For e, the physician or veterinarian could start doses of the nds of the present invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually se the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to ate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the present invention are dictated by and ly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of nding/formulating such a therapeutic compound for the treatment of a disease or disorder in a patient.

In certain embodiments, the compositions useful within the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions of the t invention comprise a therapeutically effective amount of at least one compound useful within the invention and a pharmaceutically acceptable carrier.

The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, ol, propylene , and liquid polyethylene , and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a g such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various cterial and antifungal , for example, parabens, chlorobutanol, phenol, ascorbic acid, osal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

In certain embodiments, the itions useful within the invention are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions useful within the invention are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It will be readily apparent to one skilled in the art that the frequency of administration of the various combination compositions useful within the invention will vary from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the ion should not be construed to be limited to any ular dosage regime and the precise dosage and composition to be administered to any patient will be determined by the attending physical taking all other factors about the patient into account.

Compounds for stration may be in the range of from about 1 ug to about 10,000 mg, about 20 ug to about 9,500 mg, about 40 ug to about 9,000 mg, about 75 ug to about 8,500 mg, about 150 ug to about 7,500 mg, about 200 ug to about 7,000 mg, about 3050 pg to about 6,000 mg, about 500 ug to about 5,000 mg, about 750 ug to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 75 mg to about 900 mg, about 100 mg to about 800 mg, about 250 mg to about 750 mg, about 300 mg to about 600 mg, about 400 mg to about 500 mg, and any and all whole or partial increments therebetween.

In some embodiments, the dose of a compound is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound of the present ion used in compositions bed herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound (i.e., a drug used for treating a disease or disorder) as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

In certain embodiments, the present invention is directed to a packaged ceutical ition comprising a container holding a therapeutically effective amount of a compound of the present invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder in a patient.

Formulations may be ed in admixtures with conventional ents, i. 6., pharmaceutically acceptable organic or nic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other le mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., ants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.

Routes of administration of any of the compositions of the present invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the ion may be formulated for administration by any le route, such as for oral or parenteral, for e, ermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, l (e.g., trans— and perivaginally), (intra)nasal and (trans)rectal), esical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, uscular, intradermal, intra—arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for tion, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the t invention are not limited to the particular formulations and compositions that are described herein.

Oral Administration For oral ation, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may 2014/062644 be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group ting of inert, non—toxic pharmaceutically excipients which are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.

The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

For oral administration, the compounds may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl cellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If d, the tablets may be coated using suitable methods and g materials such as OPADRYTM film coating systems available from Colorcon, West Point, Pa. (e.g., TM OY Type, OYC Type, Organic Enteric OY—P Type, Aqueous Enteric OY—A Type, OY—PM Type and OPADRYTM White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically able ves such as suspending agents (e.g., ol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non—aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p—hydroxy benzoates or sorbic acid).

Granulating techniques are well known in the ceutical art for modifying starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free—flowing agglomerates or granules referred to as a “granulation.” For example, solvent—using “wet” granulation processes are generally characterized in that the powders are combined with a binder material and ned with water or an c solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.

Melt granulation generally consists in the use of materials that are solid or semi—solid at room temperature (i. 6. having a relatively low softening or melting point range) to promote ation of powdered or other materials, essentially in the e of added water or other liquid ts. The low melting solids, when heated to a temperature in the melting point range, y to act as a binder or granulating medium. The liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound er. The resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active (i.e. drug) by forming a solid dispersion or solid solution.

US. Patent No. 5,169,645 discloses directly compressible wax—containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by g and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and ves(s), and in other cases both the ) and the additives(s) will melt.

The present invention also includes a multi—layer tablet comprising a layer providing for the delayed release of one or more nds of the present invention, and a further layer ing for the immediate release of a medication for treatment of a disease or disorder. Using a wax/pH—sensitive r mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its d release.

Parenteral Administration For parenteral administration, the compounds may be formulated for injection or infusion, for example, intravenous, uscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or sing agents may be used.

Additional Administration Forms onal dosage forms of this invention include dosage forms as described in US. Patents Nos. 6,340,475, 6,488,962, 6,451,808, 5,972,389, 837, and ,007,790. Additional dosage forms of this invention also include dosage forms as described in US. Patent Applications Nos. 20030147952, 04062, 20030104053, 20030044466, 20030039688, and 51820. Additional dosage forms of this invention also include dosage forms as described in PCT Applications Nos. WO 03/35041, WO 03/35040, WO 03/35029, WO 03/35177, WO 03/35039, WO 02/96404, WO 02/32416, WO 01/97783, WO 01/56544, WO 01/32217, WO 98/55107, WO 98/11879, WO 97/47285, WO 93/18755, and WO 90/11757.

Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the formulations of the present invention may be, but are not limited to, short—term, offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.

The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially nt blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.

For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic al which provides sustained release properties to the compounds. As such, the compounds for use the method of the present ion may be administered in the form of microparticles, for example, by ion or in the form of wafers or discs by implantation.

In certain embodiments of the present invention, the compounds of the present invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a ned e formulation.

The term delayed e is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.

The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.

As used herein, short—term refers to any period of time up to and ing about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 s, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug stration after drug administration.

As used herein, rapid—offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.

Dosing The therapeutically effective amount or dose of a compound will depend on the age, sex and weight of the patient, the current medical condition of the patient and the progression of Parkinson’s Disease in the t being treated. The skilled artisan will be able to determine appropriate dosages ing on these and other factors.

A suitable dose of a compound of the present invention may be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day.

The dose may be administered in a single dosage or in multiple dosages, for e from 1 to 4 or more times per day. When multiple s are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12—hour interval between doses.

It is understood that the amount of compound dosed per day may be administered, in non—limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.

The compounds for use in the method of the present invention may be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units le as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic , optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such lents were considered to be within the scope of this invention and d by the claims ed hereto. For example, it should be understood, that modifications in reaction conditions, including but not d to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, heric conditions, e.g., nitrogen atmosphere, and ng/oxidizing agents, with art— recognized alternatives and using no more than routine experimentation, are within the scope of the present ation.

It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the t invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

The following examples further illustrate aspects of the present invention.

However, they are in no way a limitation of the teachings or disclosure of the present invention as set forth .

The invention is now described with reference to the following Examples.

These Examples are provided for the purpose of illustration only, and the invention is not limited to these Examples, but rather encompasses all variations that are evident as a result of the teachings provided herein.

Example 1: Stimulus and Non-Stimulus Trials.

The nce index (VI) of rats d with SK609 was evaluated using the following ol. Substantively, eight water restricted male Sprague—Dawley rats were trained in an operant task of sustained ion (McGaughy & Sarter, 1995, Psychopharm. 117:340—357). In response to both signal and non—signal conditions, a water reward was given for correct responses as a positive reinforcer. Rats were first trained by successive approximation to establish lever pressing behavior. Subjects were then trained to criterion performance on the sustained attention task with a 1,000 msec light stimulus duration and then erred to 15 msec stimulus duration.

Performance was determined based on a rat’ s calculated V1: VI = (h — f) / [2*(h + f)- (h + DZ], wherein h (relative hits) 2 #Hits / (#Hits + #Misses), and f (relative misses) = #False Alarms / (#False Alarms + #Correct ions).

VI of 1 indicates complete vigilance; VI of 0.35 indicates above chance vigilance; and VI of —1 indicates no vigilance.

Testing ed over a 45 min session of randomly ted signal and non— signal trials. Criterion performance required a rat to achieve greater than 59% signal and non—signal trials, a VI greater than 0.35 and less than 25% ons per day for three consecutive days. Once subjects stabilized at a baseline, their responses are no longer considered random.

SK609 was administered intraperitoneally (IP) at various doses 15 min prior to beginning the task. Prazosin was administered IP 30 min prior, and SK609 15 min prior to beginning the task. Data are presented as difference scores for V1 from an average baseline (Figs. 4-6).

As illustrated in Figs. 4—5, SK609 enhanced sustained attention at a dose of 8 mg/kg, without sing omissions. However, higher doses increased omissions. As illustrated in Fig. 6, the 061 rgic receptor antagonist prazosin reversed the enhancement of ned attention, similar to its reversal of MPH.

Taken together, these results indicate that the norepinephrine system is important for sustained attention. In certain embodiments, the effects of SK609 may be ed through a repetition of doses as well as the use of additional dopamine and norepinephrine antagonists.

The nds of the present invention may be tested in rodent models for AD and PD. The compounds of the t invention may also be tested for self administration in rodents and conditional place preference tests, which are among the most tested paradigm for drugs of abuse. Additional cognitive models, such as set shifting, five— choice serial reaction time task, radial maze and water maze in healthy and animals with neuronal disorders may also be employed.

Example 2: Prefrontal Cortex (PFC) Mediated Tasks.

Catecholamines, particularly norepinephrine and ne, strongly modify cognitive functions. As demonstrated herein, in rodent models of ive flexibility, SK609 showed no drug effect in the set—shifting task, but improved performance in cross maze. Use of the DZ/D3—like receptor antagonist raclopride still demonstrated ability to inhibit cognitive performance. When these results were ed to previous studies on methylphenidate dge, et al., 2012, Biol. Psych. 7l(5):567—73), SK609 performed comparable to MPH in cross—maze but not in set—shifting.

Taken together, our results te that PFC—mediated tasks of sustained attention and working memory may be mediated by different mechanisms. Sustained attention appears to be mediated by both norepinephrine and dopamine.

WO 66019 Methods (a) Sustained Attention: The operant conditioning chambers contained a house light (2.8W), a stimulus light (2.8W), a pair of retractable levers and water reward apparatus. Eight water—restricted male Sprague—Dawley rats were trained in an operant task of sustained attention. In response to both signal and non—signal conditions, a water reward was given for correct responses as a positive reinforcer.

Rats were first trained by successive approximation to ish lever pressing behavior. Subsequently, the rats were trained to criterion performance. Criterion performance required a rat to e greater than 59% signal and non—signal trials, a VI r than 0.35 and less than 25% omissions per day for three consecutive days.

MPH (2.0 mg/kg) or SK609 (4.0 mg/kg; this dose for a younger cohort was found to be comparable to the dose of 8.0 mg/kg in older animals) was administered (lP) at various doses 15 min prior to beginning the task. Prazosin (0.25 mg/kg) and raclopride (0.05 mg/kg) were administered (IP) 30 min prior to the experiment followed by either SK609 (4.0 mg/kg) or MPH (2.0 mg/kg) 15 min prior to beginning the task. Performance was determined based on a rat’s calculated Vigilance Index (VI). Data are presented as difference scores for VI from an average baseline. (b) Set-Shifting: Sixteen food—restricted male Sprague—Dawley rats were trained to minate between a pair of small ceramic pots in order to retrieve a food reward buried within one of the pots. A pair of pots differed from each other along three le dimensions: scent, digging medium, or al covering the outer surface of the pot.

Simple discriminations (SD) were made between pots ing from each other along one dimension. Compound minations (CD) were made between pots differing along two dimensions. Intra—dimensional Shifts (IDS) were changes made within a previously tested dimension. Extra—Dimensional Shifts (EDS) were changes made to a previously untested dimension.

Animals were tested on their y to form an attentional set by attending to the dimension that predicts the food reward. Animals were then tested on their ability to make an IDS, EDS, or reversal by responding only to the new salient dimension while suppressing the urge to respond to the previously salient stimulus. 0.9% saline (1 mg/kg), raclopride (0.05 mg/kg ) or SK609 (4 mg/kg) were administered (IP) 30 prior to the ment followed by 0.9% saline (1 mg/kg) 15 min prior to beginning the task. Animals were tested to criterion performance of 5 consecutive t trials. (0) Cross Maze: The experimental design for cross maze task was adapted from Stefani et al, 2003, Behav. Neurosci. ll7(4):728—37 (Fig. 7). Ten food—restricted male Sprague—Dawley rats were acclimated to a cross maze whose arms differed by color (red vs blue) or texture (smooth vs rough). A food reward was placed in a food well located at the end of the arm.

Rats were trained to form a mental set by associating a food reward with one feature of one dimension. Rats were subsequently tested on their ability to predict the food reward based on one feature of the alternative ion. 0.9% saline (1 mg/kg), raclopride (0.05 mg/kg ) or SK609 (4 mg/kg) were administered (IP) 30 prior to the experiment, followed by 0.9% saline (1 mg/kg) 15 min prior to beginning the task. Animals were tested to criterion performance of 8 consecutive correct trials.

The results of the experiments are now illustrated. ned Attention: Fig. 4 illustrates the dose—dependent response of SK609, which showed an inverted—U dose response relationship, with a peak dose at 8 mg/kg.

Fig. 6 illustrates the effect of prazosin on SK609 and MPH (as positive l). IP prazosin (0.25 mg/kg) d the effects of IP administration of MPH (2.0 mg/kg) in rats (n=8).

Fig. 8 illustrates the effect of raclopride on SK609 and MPH (as ve control). IP raclopride (0.05 mg/kg) blocked the effects of IP administration of SK609 (4.0 mg/kg) in rats (n=7).

Set-Shifting Task: SK609, a D3 agonist and NET tor that improves cognitive performance in sustained attention, was used to test the roles of catecholamines in cognitive flexibility using the set—shifting task. Rats (n=4) given IP administration of SK609 (4.0 mg/kg) did not differ significantly from saline (n=4) in Extra—Dimensional Shifts (EDS), Intra—Dimensional Shifts (IDS), or compound discriminations (CD) (Fig. 9). Additionally, rats (n=8) given IP injections of the D2/D3 antagonist raclopride (0.05 mg/kg) demonstrated impairments in performance ve to controls (p—value = 0.04).

Cross-Maze: Effects seen in ifting were tested in the Cross Maze, an alternative to task that also tests cognitive flexibility. In this task, 1P administration of SK609 (4.0 mg/kg) in rats (n25) improved performance relative to saline (n22) (p—value = 0.027) (Fig. 10A).

Performance was analyzed in 8 trial increments over a total of 80 trials. SK609 improved performance faster and maintained improvements better than saline (p—value = 0.008) (Fig. 10B).

Taken together, the present results indicated that sustained attention is mediated by both dopamine and norepinephrine. SK609—enhanced performance was ed by pretreatment with the DZ/D3 antagonist raclopride, suggesting a role for DA in PFC— ed cognition. SK609—enhanced performance was reversed by pretreatment with the OL rgic receptor antagonist in, but an increase in omissions was also observed. In models of cognitive flexibility, SK609 did not enhance performance in set—shifting tasks, but showed significant improvement in cross—maze.

Different molecular mechanisms may govern cognitive lity and sustained attention. The mechanisms governing sustained attention involves both nephrine and dopamine.

The disclosures of each and every patent, patent ation, and publication cited herein are hereby orated herein by reference in their entirety.

While the invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the t invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims (15)

1. Use of a compound in the manufacture of a medicament for the treatment or prevention of an attention disorder or a cognitive disorder in a human subject in need thereof, wherein the compound is a compound of formula (I) R4 R1 R5 n R3 (I), wherein in (I): R1, R2 and R3 are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C1-6 alkyl, heteroalkyl, heterocyclyl, aryl, aryl-(C1-3)alkyl, y, alkylcarboxy, formyl, alkyl-carbonyl, arbonyl, and heteroaryl-carbonyl; R4 and R5 are independently selected from the group consisting of H, C1-6 alkyl, C1-6 hydroxyalkyl, heteroalkyl, heterocyclyl, aryl, and aryl-(C1-3)alkyl; and, n is 2, 3, 4 or 5; a pharmaceutically acceptable salt or solvate thereof, or any mixtures thereof.

2. The use of claim 1, wherein the attention or cognitive er comprises ADD or ADHD.

3. The use of claim 1, wherein administration of the compound improves cognitive flexibility in the subject.

4. The use of claim 1, n administration of the compound es sustained ion in the subject.

5. The use of claim 1, wherein R1, R2 and R3 are independently selected from the group consisting of H, cyano, halo, , nitro, C1-6 alkyl, and carboxy.

6. The use of claim 1, wherein R4 and R5 are independently selected from the group consisting of H, C1-6 alkyl, and C1-6 hydroxyalkyl.

7. The use of claim 1, n in formula (I) n is 2.

8. The use of claim 1, wherein the compound is selected from the group consisting of: 2-amino(2-chlorophenyl)butanol; 2-(3-aminohexyl)phenol; hlorophenyl)methylamino-butane; 4-(2-chlorophenyl)-butanamine; 4-(2- fluorophenyl)butanamine; 4-(2-bromophenyl)butanamine; 4-(2-iodophenyl)butan amine; 4-(2-methoxyphenyl)butanamine; 2-(3-aminobutyl)phenol; 3-(3,4- diethoxyphenyl)propanamine; 4-(4-chlorophenyl)butanamine; 4-(4- methoxyphenyl)butanamine; a pharmaceutically acceptable salt or solvate, and mixtures thereof.

9. The use of claim 1, wherein the subject is to be further administered at least one drug selected from the group consisting of methylphenidate, dextroamphetamine, dextroamphetamine-amphetamine, lisdexamfetamine, ADHD medication, pressants, clonidine, guanfacine, and a salt or solvate thereof.

10. Use of a compound in the preparation of a medicament for the treatment or prevention of dementia associated with a neurodegenerative disease in a human subject in need thereof, n the neurodegenerative disease comprises at least one selected from the group consisting of Alzheimer’s Disease (AD), Huntington’s Disease, transmissible spongiform encephalopathies (TSEs), c traumatic alopathy (CTE) resulting from repeated traumatic brain injuries, and amyotrophic lateral sclerosis (ALS); wherein the compound is a compound of formula (I): R4 R1 R5 n R3 (I), wherein in (I): R1, R2 and R3 are independently selected from the group consisting of H, cyano, yl, amino, acetamido, halo, , nitro, C1-6 alkyl, heteroalkyl, heterocyclyl, aryl, aryl-(C1-3)alkyl, carboxy, alkylcarboxy, formyl, alkyl-carbonyl, aryl-carbonyl, and heteroaryl-carbonyl; R4 and R5 are independently selected from the group consisting of H, C1-6 alkyl, C1-6 hydroxyalkyl, heteroalkyl, heterocyclyl, aryl, and aryl-(C1-3)alkyl; and, n is 2, 3, 4 or 5; a pharmaceutically acceptable salt or solvate thereof, or any mixtures thereof.

11. The use of claim 10, wherein R1, R2 and R3 are independently selected from the group consisting of H, cyano, halo, , nitro, C1-6 alkyl, and carboxy.

12. The use of claim 10, wherein R4 and R5 are ndently selected from the group consisting of H, C1-6 alkyl, and C1-6 hydroxyalkyl.

13. The use of claim 10, wherein in formula (I) n is 2.

14. The use of claim 10, wherein the compound is selected from the group consisting of: 2-amino(2-chlorophenyl)butanol; 2-(3-aminohexyl) phenol; 4-(2-chlorophenyl)methylamino-butane (also known as 4-(2-chlorophenyl)-N- methylbutanamine); 4-(2-chlorophenyl)-butanamine; 4-(2-fluorophenyl)butanamine; 4-(2-bromophenyl)butanamine; 4-(2-iodophenyl)butanamine; 4-(2- methoxyphenyl)butanamine; 2-(3-aminobutyl) phenol; 3-(3,4-diethoxyphenyl)propan amine; 4-(4-chlorophenyl)butanamine; 4-(4-methoxyphenyl)butanamine; a pharmaceutically able salt thereof, and any mixtures thereof.

15. The use of claim 10, wherein the subject is to be further administered at least one drug selected from the group consisting of phenidate, dextroamphetamine, amphetamine-amphetamine, lisdexamfetamine, ADHD tion, antidepressants, clonidine, guanfacine, and a salt or solvate thereof.