RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 61/651 ,714, filed on May 25, 2012 and U.S. Provisional Application No. 61/651 ,723, filed on May 25, 2012. The entire teachings of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Huntington's disease (HD) is a rare, dramatic and fatal disease of high complexity. HD is associated with a broad spectrum of often opposite symptoms affecting motor control, cognitive performance, mental function and mood. Despite the fact that alterations in dopaminergic transmission have been suspected for decades as the mechanistic basis for the underlying pathological manifestations of HD, most prescribed drug treatments targeting dopaminergic transmission, either via blockade of dopamine (DA) receptors (e.g., antipsychotic/neuroleptic agents) or via depletion of DA stores, are far from satisfactory, mainly because they elicit incapacitating side effects or precipitate opposite symptoms.

Tetrabenazine is approved for the treatment of HD. Tetrabenazine not only completely shuts down dopaminergic transmission by depleting DA stores and blocking postsynaptic DA receptors, but also by depleting noradrenaline, adrenaline and serotonin, both in the medium-sized spiny neurons (MSNs) affected in HD, and also throughout the brain and the peripheral nervous system.

Thus, there is an acute need for alternative drugs for treating HD. In particular, there is a need for drugs that can more selectively modulate dopaminergic transmission in MSNs.

SUMMARY OF THE INVENTION

The present invention is related to the unexpected discovery that an averaged affinity for DA D2 receptors characterized by a K _d of about 10 ^"5 to about 10 ^"8 M, and a 5- to 100-fold preferential affinity for pre-synaptic DA D2 receptors versus post-synaptic DA D2 receptors are important determinants of a compound's ability to restore DA homeostasis and thereby treat Huntington's disease (HD) in a mammal. One embodiment of the invention is a method for treating HD in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of any one of Formulas I-III:

or a pharmaceutically acceptable salt thereof, having an affinity for a pre-synaptic DA D2 receptor, an affinity for a post-synaptic DA D2 receptor, and an averaged affinity for DA D2 receptors. The averaged affinity of the compound for DA D2 receptors is characterized by a K _d of about 10 ^"5 to about 10 ^"8 M, and the affinity of the compound for a pre-synaptic DA D2 receptor, as characterized by Kd, is about 5 to about 100 times greater than the affinity of the compound for a post-synaptic DA D2 receptor, as characterized by ¾. The variables and alternative variables for a compound of Formulas (I)-(III) are as described hereinbelow.

Another embodiment of the invention is a compound of any one of Formulas I-III, or a pharmaceutically acceptable salt thereof, having an averaged affinity for DA D2 receptors characterized by a K _d of about 10 ^" to about 10 ^" M, and an affinity for a pre-synaptic DA D2 receptor, as characterized by Kd, that is about 5 to about 100 times greater than the affinity of the compound for a post-synaptic DA D2 receptor, as characterized by Kd, for use in treating HD in a mammal in need thereof.

Another embodiment of the invention is use of a compound of any one of Formulas I-

III, or a pharmaceutically acceptable salt thereof, having an averaged affinity for DA D2 receptors characterized by a Kd of about 10 ^"5 to about 10 ^"8 M, and an affinity for a presynaptic DA D2 receptor, as characterized by K _d , that is about 5 to about 100 times greater than the affinity of the compound for a post-synaptic DA D2 receptor, as characterized by ¾, in the manufacture of a medicament for the treatment of HD.

Another embodiment of the invention is a method for treating HD in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of Formula III, or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of Formula III, or a

pharmaceutically acceptable salt thereof, for use in treating HD in a mammal in need thereof.

Another embodiment of the invention is a use of a compound of Formula III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of HD.

The compounds of Formulas I-III (also referred to herein as benzamide compounds) exhibit a dual, biphasic mode of action due, at least in part, to a preferential affinity for presynaptic D2 receptors versus post-synaptic D2 receptors. At low doses, the benzamide compounds of the present invention are disinhibitory, while at high doses, they act as central depressants. Due to this differential action over a wide range of doses, the compounds are expected to be useful in treating largely opposite symptoms often associated with HD, including cognitive impairment, dementia and depression, and movement disorders, locomotor deficit and chorea, without eliciting the extrapyramidal side effects associated with neuroleptic agents typically used to treat HD or the dopaminergic hyper-excitability thought to cause chorea and some psychotic-like symptoms.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing will be apparent from the following more particular description of example embodiments of the invention, as illustrated in the accompanying drawings. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments of the present invention.

FIG. 1 is a schematic representation of the ultrastructural elements integrated into a computer-based model and illustrates a medium spiny neuron (MSN) and its immediate environment.

FIG. 2 is a schematic representation of the intracellular pathways integrated into the computer-based model and illustrates the complexity of DA signaling in MSNs. FIG. 3 is a three-dimensional graph of cyclic adenosine monophosphate (cAMP) concentration as a function of the concentration of DA acting on the Dl and D2 receptors (D1R and D2R, respectively), and illustrates the relationship between DA concentrations at the Dl and D2 receptors and formation of cAMP.

FIG. 4 is a schematic representation of a pre-synaptic nigrostriatal dopaminergic terminal and illustrates the biological pathway leading to DA release into the synaptic cleft.

FIG. 5 is a graph of predicted DA concentration as a function of time and shows that increasing concentrations of haloperidol, a known D2 receptor antagonist, acting on a presynaptic DA receptor causes an increase in DA release into the synaptic cleft.

FIG. 6 is a graph of post-synaptic cAMP concentration as a function of the concentration of virtual D2 receptor antagonists characterized by a K _d of between 10 ^"9 M and 10 ^"5 M and having a preferential affinity ratio for a pre-synaptic D2 receptor versus a postsynaptic D2 receptor of 1 , and shows that the dose-response curves for the virtual D2 receptor antagonists characterized by a K _d of between 10 ^"8 and 10 ^"5 are non-linear.

FIG. 7 is a graph of post-synaptic cAMP concentration as a function of the concentration of virtual D2 receptor antagonists characterized by a Kd of 10 ^"8 M and having a preferential affinity ratio for a pre-synaptic D2 receptor versus a post-synaptic D2 receptor of between 1 and 100, and shows that the preferential affinity ratio does not affect the dose- response curves of virtual D2 receptor antagonists characterized by a Kd of 10 ^" M.

FIG. 8 is a graph of post-synaptic cAMP concentration as a function of the concentration of virtual D2 receptor antagonists characterized by a Kd of 10 ^"5 M and having a preferential affinity ratio for a pre-synaptic D2 receptor versus a post-synaptic D2 receptor of between 1 and 100, and shows that the preferential affinity ratio profoundly affects the dose- response curves of virtual D2 receptor antagonists characterized by a K _d of 10 ^"5 M.

FIG. 9 is a graph of predicted DA concentration as a function of time and shows that increasing concentrations of a compound of Formula III, acting on a pre-synaptic DA receptor, causes an increase in DA release into the synaptic cleft.

FIG. 10 is a graph of post-synaptic cAMP concentration as a function of the concentration of virtual D2 receptor antagonists characterized by a K _d corresponding to that of a compound of Formula III and having a preferential affinity ratio for a pre-synaptic D2 receptor versus a post-synaptic D2 receptor of between 1 and 100, and shows that the preferential affinity ratio profoundly affects the dose-response curves of virtual D2 receptor antagonists characterized by a K _d of 6 x 10 ^"7 M.

FIG. 1 1 is a graph of post-synaptic cAMP concentration as a function of the concentration of virtual D2 receptor antagonists characterized by a K _d of between 10 ^"9 M and 10 ^"5 M and a preferential affinity ratio for a pre-synaptic D2 receptor versus a post-synaptic D2 receptor of 13, and shows that the dose-response curves for the virtual D2 receptor antagonists characterized by a K _d of between 10 ^"7 and 5 x 10 ^~5 M are non-linear.

DETAILED DESCRIPTION OF THE INVENTION

A description of example embodiments of the invention follows.

One embodiment of the invention is a method for treating HD in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, having an affinity for a pre-synaptic DA D2 receptor, an affinity for a post-synaptic DA D2 receptor, and an averaged affinity for DA D2 receptors. The averaged affinity of the compound for DA D2 receptors is

characterized by a Kd of about 10 ^"5 to about 10 ^"8 M, and the affinity of the compound for a pre-synaptic DA D2 receptor, as characterized by K _d , is about 5 to about 100 times greater than the affinity of the compound for a post-synaptic DA D2 receptor, as characterized by K _d .

The compound of Formula III is characterized by an averaged affinity for DA D2 receptors of about 10 ^"6 to about 10 ^"7 M, more specifically, about 6 x 10 ^"7 M, and an affinity for a pre-synaptic DA D2 receptor, as characterized by K _d , that is about 13 times greater than an affinity of the compound for a post-synaptic DA D2 receptor, as characterized by Kd. Thus, one embodiment of the invention is a method for treating HD in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of Formula III, or a pharmaceutically acceptable salt thereof.

"Averaged affinity," as used herein, refers to a binding interaction between a subclass of receptor types, such as D2 receptors (including pre- and post-synaptic D2 receptors), and a ligand, such as a compound of Formula I. The interaction can be characterized using methods known to those of skill in the art. Typically, the interaction is characterized by a dissociation constant (K _d ), an inhibitor constant (¾; the concentration of competing ligand in a competition assay which would occupy 50% of the receptors if no ligand were present), IC50 (the concentration at which an agent inhibits a biological process by half) or EC50 (the concentration at which an agent induces a response halfway between the baseline and the maximum for a biological process after a specified exposure time). IC50, Kd, Kj and EC50 can be measured using receptor binding techniques, such as saturation binding assays, binding kinetics, or competition, including inhibition and displacement, assays. Other methods for determining IC ₅₀ , Kd, Kj and EC ₅₀ are known to those of skill in the art.

In some embodiments of the invention, the averaged affinity of the compound for DA D2 receptors is characterized by a Kd. Preferably, the Kd is about 10 ^"5 to about 10 ^"8 M. More preferably, the Kd is about 10 ^"6 to about 10 ^"7 M. Alternatively, the Kd is about the Kd of a compound of Formula III .

In some embodiments of the invention, the averaged affinity of the compound for DA D2 receptors is characterized by IC ₅₀ , for example, in a spiperone binding assay. Preferably, the IC ₅ 0 of the compound in a spiperone binding assay is about 10 ^"6 M. A spiperone binding assay is disclosed in Bischoff, S., et al ; Naunyn-Schmiedeberg 's Arch. Pharmacol. (1994) 350:230-238.

The IC50 of a binding interaction between a ligand and a receptor can be converted to Kj using the Cheng-Prussoff equation:

¾ = IC ₅₀ /(l+L*/K _d ),

where L* is the concentration of ligand and Kd is the equilibrium dissociation constant ligand (see Cheng Y., Prusoff, W.H. Biochem. Pharmacol. (1973); Munson, P. J., Rodbard, D. An exact correction to the "Cheng-Prusoff correction. JRecept. Res. 8:533-46 (1988)). In some circumstances, this equation can be approximated:

(i) when L* = Kd, then Kj = IC ₅ o/2; and

(ii) when Kd is significantly greater than L*, L*/Kd approaches zero and Kj = IC ₅₀ . Because the present invention is related, in part, to the discovery that compounds exhibiting a preferential affinity for pre-synaptic D2 receptors versus post-synaptic D2 receptors may be useful for treating HD, it is necessary to discriminate between the affinity of a compound for a sub-class of receptors, such as D2 receptors, and the affinity of the compound for specific types of receptors in a sub-class, such as a pre- or a post-synaptic D2 receptor. Therefore, as used herein, "affinity" refers to a binding interaction between a specific type of receptor, such as a pre- or a post-synaptic D2 receptor, and a ligand, such as a compound of Formula I.

"Preferential affinity" means that a compound or ligand binds to one type of receptor in a sub-class to a greater extent than to another type of receptor in the sub-class (i. e. , the compound exhibits selectivity for one type of receptor over another type of receptor). In some cases, preferential affinity is measured at low concentrations (e.g. , non-saturating concentrations) of the compound. Therefore, in some embodiments, the affinity of a compound of Formula I, II or III, or a pharmaceutically acceptable salt thereof, for a presynaptic DA D2 receptor is about 5 to about 100 times greater than the affinity of the compound for a post-synaptic DA D2 receptor at low concentrations of the compound.

In some embodiments, the affinity of the compound for a pre-synaptic DA D2 receptor, as characterized by Kd, is about 5 to about 100 times greater than the affinity of the compound for a post-synaptic DA D2 receptor, as characterized by ¾. In some

embodiments, the affinity of the compound for a pre-synaptic DA D2 receptor, as

characterized by Kd, is about 5 to about 15, or about 10 to about 15 times greater than the affinity of the compound for a post-synaptic DA D2 receptor, as characterized by ¾. In some embodiments, the preferential affinity of the compound for a pre-synaptic DA D2 receptor versus a post-synaptic DA D2 receptor is about the preferential affinity of a compound of Formula III for a pre-synaptic DA D2 receptor versus a post-synaptic DA D2 receptor (e.g. , the compound is approximately 13 times more selective for a pre-synaptic D2 receptor than for a post-synaptic D2 receptor).

Methods of assessing the averaged affinity of a D2 receptor antagonist, as well as the preferential affinity of a D2 receptor antagonist for D2 _pre versus D2 _post , are disclosed in Bischoff, S., et al. ; Naunyn-Schmiedeberg 's Arch. Pharmacol. (1994) 350:230-238. Methods of determining dissociation constants are known to those of skill in the art.

In some embodiments, the affinity or averaged affinity is the affinity or averaged affinity of a compound of Formula I, II or III for a D2 receptor, such as a pre- or a postsynaptic D2 receptor, or D2 receptors, including pre- and post-synaptic receptors, found in neuronal tissue.

In some embodiments, the compound of Formula I, II or III, or a pharmaceutically acceptable salt or a metabolite thereof, crosses the blood-brain barrier. As used herein, the term "mammal" means a mammal in need of treatment or prevention, e.g. , companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g. , rats, mice, guinea pigs and the like). Typically, the subject is a human in need of the specified treatment.

As used herein, the term "treating" or "treatment" refers to obtaining desired pharmacological and/or physiological effect. The effect can include achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder; delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.

"Effective amount" means that amount of active compound that elicits the desired biological response in a mammal. HD is a progressive, neurodegenerative disease that causes symptoms associated with hyperactive dopaminergic transmission (e.g. , chorea, psychotic states) and hypoactive dopaminergic transmission (e.g. , hypokinesia, Parkinson-like symptoms, depressive states). Thus, in some embodiments, the effective amount of a compound is an effective amount to inhibit dopaminergic transmission. In other

embodiments, the effective amount of a compound is an effective amount to stimulate dopaminergic transmission. In yet other embodiments, the effective amount of a compound is an effective amount to restore DA homeostasis. Alternatively, the effective amount is about 1 to about 150 mg/kg, about 1 to about 25 mg/kg, about 5 to about 15 mg/kg, about 30 to about 100 mg/kg, or about 70 to about 100 mg/kg.

As used herein, "dopamine homeostasis" or "DA homeostasis" refers to the tendency toward equilibrium between the succession of equilibriums or biological processes governing or contributing to physiologically controlled dopaminergic transmission. Dopamine is an important factor in the regulation of many biological processes, from addiction to balance and locomotion and, therefore, its function is tightly regulated. The delicate balance between DA release into the synaptic cleft and post-synaptic receptor transduction in response to DA binding (which together contribute to dopamine homeostasis), is thought to be disrupted in the physiopathology of HD. Thus, "to restore DA homeostasis" means to re-equilibrate the succession of equilibriums or biological processes governing or contributing to

physiologically controlled dopaminergic transmission. To keep the system in equilibrium, the extracellular DA concentration should be maintained in a range that correlates with a cAMP response in the midrange of physiological variation.

The activity state of a neuron and, therefore, whether the neuron is functioning under DA homeostatic conditions, can be measured, for example, as output current, or amount or concentration of released DA. The activity state of the neuron is also referred to herein as the "tone" of the neuron.

The compound of Formula I is represented by the following structural formula:

I),

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is hydrogen, halogen, hydroxy, (Ci-C ₈ )aliphatic-0-, (C3-C ₈ )carbocyclyloxy, (C ₃ -C ₈ )carbocyclyl(Ci-C ₄ )alkoxy, (C,-C ₃ )aliphatic-OC(0)-, (Ci-C ₈ )aliphatic-C(0)0-, (Ci-C ₈ )aliphatic- or N(R ⁸ ) ₂ . Preferably, R ¹ is hydrogen, halogen, hydroxy,

(Ci-Cs)aliphatic-O-, (C ₃ -C ₈ )carbocyclyloxy or (C3-C ₈ )carbocyclyl(C]-C4)alkoxy. More preferably, R ¹ is hydrogen.

R ³ is hydrogen, halogen, hydroxy, (C ₁ -C ₈ )aliphatic-0-, (C3-C ₈ )carbocyclyloxy, (C ₃ -C ₈ )carbocyclyl(Ci-C ₄ )alkoxy, (Ci-C ₈ )aliphatic-OC(0)-, (C ₁ -C ₈ )aliphatic-C(0)0-, (Ci-C ₈ )aliphatic- or N(R ⁸ ) ₂ . Preferably, R ³ is hydrogen, halogen, hydroxy,

(Ci-Cg)aliphatic-O-, (C3-C ₈ )carbocyclyloxy or (C ₃ -C ₈ )carbocyclyl(Ci-C4)alkoxy. More preferably, R ³ is halogen. Yet more preferably, R ³ is fluoro or chloro.

R ⁵ is hydrogen, halogen, hydroxy, (C ₁ -C ₈ )aliphatic-0-, (C ₃ -C ₈ )carbocyclyloxy, (C ₃ -C ₈ )carbocyclyl(Ci-C ₄ )alkoxy, (Ci-Cg)aliphatic-OC(O)-, (Ci-C ₈ )aliphatic-C(0)0-, (Ci-C ₈ )aliphatic- or N(R ⁸ ) ₂ . Preferably, R ⁵ is hydrogen, halogen, hydroxy,

(C ₁ -C ₈ )aliphatic-0-, (C ₃ -C ₈ )carbocyclyloxy or (C ₃ -C ₈ )carbocyclyl(C ₁ -C ₄ )alkoxy. More preferably, R ⁵ is hydroxy, (Ci-C ₈ )aliphatic-0-, (C ₃ -C ₈ )carbocyclyloxy or

(C3-C ₈ )carbocyclyl(C]-C ₄ )alkoxy. Yet more preferably, R ⁵ is (C ₁ -C ₈ )aliphatic-0-. Yet more preferably, R ⁵ is (Ci-C ₈ )alkoxy or (Ci-C ₈ )alkenyloxy. Each aliphatic, carbocyclyl, or alkyl group represented by R ¹ , R ³ and R ⁵ is optionally and independently substituted. Alternatively, each aliphatic, carbocyclyl, or alkyl group represented by R , R and R is unsubstituted.

R is hydrogen, cyano, nitro, (Ci-C ₈ )aliphatic-S(0)- or (C ₁ -C8)aliphatic-S(0)0-. Preferably, R is cyano.

R ⁴ is hydrogen, cyano, nitro, (Ci-C ₈ )aliphatic-S(0)- or (C ₁ -Cg)aliphatic-S(0)0-. Preferably, R ⁴ is hydrogen.

7

R° and R' are each independently hydrogen, (C ₁ -C3o)aliphatic-, carbocyclyl, heterocyclyl, aryl, heteroaryl, aralkyl, or alkylaryl. Preferably, R and R are each

7

independently (Ci-C3o)aliphatic-. More preferably, R and R are each independently

7

(Ci-C ₈ )aliphatic-. Yet more preferably, R and R are each independently (Ci-C8)alkyl-. Yet

(\ 7

more preferably, R and R are each independently (C ₁ -C ₄ )alkyl-.

Alternatively, R ⁶ and R ⁷ are each hydrogen, (C ₁ -C ₃ o)aliphatic-, carbocyclyl, heterocyclyl, aryl, heteroaryl, aralkyl, or alkylaryl. Preferably, R ⁶ and R ⁷ are each

(Ci-C ₃ o)aliphatic-. More preferably, R ⁶ and R ⁷ are each (Ci-C ₈ )aliphatic-. Yet more preferably, R ⁶ and R ⁷ are each (Ci-C ₈ )alkyl-. Yet more preferably, R ⁶ and R ⁷ are each (d-C ₄ )alkyl-.

At least one C in each aliphatic or alkyl group represented by R and R is optionally and independently replaced by a heteroatom selected from oxygen, sulfur and nitrogen.

Each aliphatic, carbocyclyl, heterocyclyl, aryl, heteroaryl, aralkyl and alkylaryl represented by R ⁶ and R ⁷ is optionally and independently substituted. Alternatively, each aliphatic, carbocyclyl, heterocyclyl, aryl, heteroaryl, aralkyl and alkylaryl represented by R ⁶ and R is unsubstituted.

R ⁶ and R ⁷ , together with the N to which they are bound, form a 4-8-membered, optionally substituted heterocyclyl or a 5-12-membered, optionally substituted heteroaryl. Preferably, R ⁶ and R ⁷ , together with the N to which they are bound, form a 4-8-membered, optionally substituted heterocyclyl. More preferably, R ⁶ and R ⁷ , together with the N to which they are bound, form a 5-7-membered, optionally substituted heterocyclyl.

Each R is independently hydrogen or (Ci-C ₈ )aliphatic-. Preferably, each R is independently hydrogen or (Ci-C ₈ )alkyl. More preferably, each R ⁸ is independently hydrogen or (Ci-C ₄ )alkyl. Two R , together with the N to which they are bound, form a 4-8-membered heterocyclyl. Preferably, two R ⁸ , together with the N to which they are bound, form a 5-7- membered heterocyclyl.

An "aliphatic group" is a non-aromatic monovalent radical consisting solely of carbon and hydrogen and can optionally contain one or more units of unsaturation, e.g. , double and/or triple bonds. An aliphatic group can be straight-chained or branched. An aliphatic group can contain between about one and about thirty carbon atoms, between about one and about ten carbon atoms, between about one and about eight carbon atoms, or between about one and about four carbon atoms. Exemplary aliphatic groups include alkyl and alkenyl groups. A "substituted aliphatic group" is substituted at any one or more "substitutable carbon atoms." A "substitutable carbon atom" in an aliphatic, alkyl, alkenyl, carbocyclyl, cycloalkyl, or heterocyclyl group is a carbon in atom that is bonded to one or more hydrogen atoms. The one or more hydrogen atoms can optionally be replaced with a suitable substituent group.

"Alkyl" means a saturated aliphatic branched or straight-chain monovalent hydrocarbon radical. "(Ci-C8)alkyl" means a radical having from 1-8 carbon atoms in a linear or branched arrangement. "(CrCs^lkyl" includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

"Alkylthio" means an alkyl radical attached through a sulfur linking atom.

"Alkylthio" can also be depicted as -S-alkyl.

"Alkylsulfmyl" means an alkyl radical attached through a sulfinyl (i.e., -S(O)-) group. "Alkylsulfmyl" can be depicted as -S(0)-alkyl.

"Alkylsulfonyl" means an alkyl radical attached through a sulfonyl {i.e., -S(0) ₂ -) group. "Alkylsulfonyl" can be depicted as -S(0)2-alkyl.

The term "alkoxy" means an alkyl radical attached through an oxygen linking atom.

"Alkoxy" can be depicted as -O-alkyl. "Hydroxy alkyl" means alkyl substituted with hydroxy; "aralkyl" means alkyl substituted with an aryl group; "alkoxyalkyl" means alkyl substituted with an alkoxy group; "alkylaryl" means aryl substituted with an alkyl group; "cycloalkylalkyl" means alkyl substituted with cycloalkyl; where alkyl, cycloalkyl and aryl are as defined herein. "Carbocyclyl" means a non-aromatic monocyclic or polycyclic ring system consisting solely of carbon and hydrogen. A carbocyclyl can optionally contain one or more units of unsaturation, e.g. , double and/or triple bonds. In some embodiments, a carbocyclyl contains three to ten carbon atoms, three to eight carbon atoms, or three to seven carbon atoms.

The term "carbocyclyloxy" means -O-carbocycylyl; "carbocyclylalkoxy" means

-O-alkyl-carbocyclyl; where carbocyclyl and alkyl are as defined above.

"Cycloalkyl" means a saturated monocyclic or polycyclic carbocyclic ring. In some embodiments, a carbocyclyl includes three to ten carbon atoms, or three to seven carbon atoms.

"Cycloalkoxy" means a cycloalkyl radical attached through an oxygen linking atom.

"Cycloalkoxy" can also be depicted as -O-cycloalkyl.

"Halogen'Or "halo," as used herein, refers to fluorine, chlorine, bromine, or iodine. Preferably, the halogen is fluorine or chlorine. More preferably, the halogen is chlorine.

As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon group that contains one or more double bonds between carbon atoms. Suitable alkenyl groups include, e.g., -butenyl, allyl, and the like. Suitable substituents for an alkenyl group include those for an aliphatic group.

"Aryl" means an aromatic monocyclic or polycyclic (e.g. , bicyclic or tricyclic) carbocyclic ring system. In one embodiment, "aryl" is a 6-12 membered monocylic or bicyclic systems. Aryl systems include, but are not limited to, phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, and anthracenyl. A "substituted aryl group" is substituted at any one or more "substitutable ring atom."

"Hetero" refers to the replacement of at least one carbon atom member in a ring system with at least one heteroatom selected from N, S, and O. When the heteroatom is S, the S can be oxidized (/ ^' . e. , -S(O)- or -S0 ₂ -). A hetero ring system can have 1 , 2, or 3 carbon atom members replaced by a heteroatom.

The term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system in which one or more ring carbons are replaced with a heteroatom independently selected from N, O, and S. In one embodiment, "heteroaryl" is a 5-12-membered, preferably a 5-6- membered ring system. Typically, a heteroaryl contains 1, 2, or 3 heteroatoms. Heteroaryls include, but are not limited to pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole 1,1-dioxide, 1, 3, 4-thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-triazine, 1 ,3,5-triazine, and tetrazole.

The term "heterocyclyl" refers to a non-aromatic monocyclic or polycyclic ring system in which one or more ring carbons, preferably one or two, are each replaced by a heteroatom independently selected from N, O, and S. A heterocyclyl can optionally contain one or more units of unsaturation, e.g. , double and/or triple bonds. In some embodiments, "heterocyclyl" is a 4-12-membered, a 4-8-membered, or a 5-7-membered ring system.

Examples of heterocyclic groups include tetrahydrofuranyl, azetidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, piperazinyl and piperidinyl.

A "substitutable ring atom" in an aromatic group is a ring carbon or nitrogen atom bonded to a hydrogen atom. The hydrogen can optionally be replaced with a suitable substituent group.

Suitable substituent groups for an aliphatic, alkyl, aryl, carbocyclyl, cycloalkyl, heteroaryl and heterocyclyl include, but are not limited to, halogen, hydroxy, nitro, cyano, (Ci-C ₄ )alkyl, (Ci-C ₄ )alkoxy, (C,-C ₄ )alkylthio, (Ci-C ₄ )alkylsulfinyl, (Ci-C ₄ )alkylsulfonyl,

(Ci-C ₄ )alkoxy(Ci-C ₄ )alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, and -N(R ) ₂ , wherein each R ⁸ is independently as described above. Examples of suitable substituents for a substitutable carbon of an aliphatic, alkyl, carbocyclyl, cycloalkyl, and heterocyclyl that is bonded to two or more hydrogen atoms include those listed above and the following: =0 and

S.

In a first embodiment, the compound is represented by Structural Formula I, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ , R ³ and R ⁵ are each independently hydrogen, halogen, hydroxy,

(Ci-Cg^liphatic-O-, (C ₃ -C ₈ )carbocyclyloxy, (C ₃ -Cg)carbocyclyl(C ₁ -C ₄ )alkoxy,

(Ci-Cg)aliphatic-OC(O)-, (C ₁ -C ₈ )aliphatic-C(0)0-, (C _! -C ₈ )aliphatic- or N(R*) ₂ , wherein

each R is independently hydrogen or (Ci-C ₈ )aliphatic-; or

two R ⁸ , together with the N to which they are bound, form a 4-8-membered heterocyclyl; and each aliphatic, carbocyclyl, or alkyl group is optionally and independently substituted;

R ² and R ⁴ are each independently hydrogen, cyano, nitro, (Ci-Cg)aliphatic-S(O)- or (Ci-C ₈ )aliphatic-S(0)0-;

are each independently hydrogen, (C]-C3o)aliphatic-, carbocyclyl, heterocyclyl, aryl, heteroaryl, aralkyl, or alkylaryl, wherein at least one C in each aliphatic or alkyl group is optionally and independently replaced by a heteroatom selected from oxygen, sulfur and nitrogen, and wherein each aliphatic, carbocyclyl, heterocyclyl, aryl, heteroaryl, aralkyl and alkylaryl is optionally and independently substituted; or

6 7

R and R , together with the N to which they are bound, form a 4-8-membered,

optionally substituted heterocyclyl or a 5-12-membered, optionally substituted heteroaryl.

In a first aspect of the first embodiment, R is hydrogen; R is halogen; and R is hydroxy, (C ₁ -C ₈ )aliphatic-0-, (C3-C ₈ )carbocyclyloxy or (C3-C ₈ )carbocyclyl(C ₁ -C ₄ )alkoxy. The values and alternative values for the remaining variables are as described in the first embodiment.

In a second aspect of the first embodiment, R is hydrogen, cyano, nitro,

(Ci-Cg)aliphatic-S(O)- or (Ci-Cg)aliphatic-S(0)0- and R ⁴ is hydrogen. The values and alternative values for the remaining variables are as described in the first embodiment, or first aspect thereof.

In a third aspect of the first embodiment, R is hydrogen and R and R are each independently hydrogen, halogen, hydroxy, (Ci-C8)aliphatic-0-, (C ₃ -C ₈ )carbocyclyloxy or (C ₃ -C ₈ )carbocyclyl(Ci-C4)alkoxy. The values and alternative values for the remaining variables are as described in the first embodiment, or first or second aspect thereof.

In a fourth aspect of the first embodiment, R is cyano and R is halogen. The values and alternative values for the remaining variables are as described in the first embodiment, or first through third aspects thereof.

In a fifth aspect of the first embodiment, R ⁶ and R ⁷ are each (C ₁ -C ₈ )aliphatic. The values and alternative values for the remaining variables are as described in the first embodiment, or first through fourth aspects thereof. In a sixth aspect of the first embodiment, R ⁶ and R ⁷ are each independently (Ci-C _8- )alkyl. The values and alternative values for the remaining variables are as described in the first embodiment, or first through fifth aspects thereof.

In a seventh aspect of the first embodiment, R ⁵ is hydroxy, (Ci-C ₈ )aliphatic-0-, (C ₃ -C ₈ )carbocyclyloxy or (C ₃ -C ₈ )carbocyclyl(Ci-C4)alkoxy. The values and alternative values for the remaining variables are as described in the first embodiment, or first through sixth aspects thereof.

In an eighth aspect of the first embodiment, R ⁵ is (C ₁ -C ₈ )alkoxy or (Ci-C ₈ )alkenyloxy. The values and alternative values for the remaining variables are as described in the first embodiment, or first through seventh aspects thereof.

In a ninth aspect of the first embodiment, R is cyano and R is chloro. The values and alternative values for the remaining variables are as described in the first embodiment, or first through eighth aspects thereof.

In a second embodiment, the compound is represented by Structural Formula II:

or a pharmaceutically acceptable salt thereof. The values and alternative values for the remaining variables are as described in the first embodiment, or any aspect thereof.

In a third embodiment, the compound is represented by Structural Formula III:

or a pharmaceutically acceptable salt thereof.

In a first aspect of the third embodiment, the compound is the hydrochloride salt of the compound of Structural Formula III.

Methods of making a compound of Structural Formulas I-III, as well as exemplary compounds useful in the methods of the invention, are disclosed in U.S. Patent No.

4,772,630.

A pharmaceutically acceptable salt of a compound for use in the methods of the present invention can be obtained, for example, by reacting an amine or other basic group in the compound with a suitable organic or inorganic acid. Examples of salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,

hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts. In some embodiments, the compound of Formula I, II, or III is the hydrochloride salt of the compound of Formula I, II, or III.

Another embodiment of the present invention is a method for treating HD in a mammal in need thereof, comprising administering to the mammal a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and/or diluents and a compound of Formula I, II or III, or a pharmaceutically acceptable salt thereof.

"Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" mean non-therapeutic components that are of sufficient purity and quality for use in the formulation of a composition of the invention that, when appropriately administered to a mammal or human, typically do not produce an adverse reaction, and that are used as a vehicle for a drug substance.

The compositions of the invention include oral, transdermal, topical with or without occlusion, intravenous (both bolus and infusion), and injection (intraperitoneally, subcutaneously, intramuscularly or parenterally) formulations. The composition can be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, parenteral solution or suspension, ampoule, auto-injector device, or suppository; for administration orally, transdermally, topically, or intravenously.

Compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions. The dosage form containing the composition of the invention contains an effective amount of the active ingredient necessary to provide a therapeutic effect. The composition can contain from about 5,000 mg to about 0.5 mg (preferably, from about 1 ,000 mg to about 0.5 mg) of a compound of any one of Formulas I-III, or a salt form thereof, and can be constituted into any form suitable for the selected mode of administration. The composition can be administered about 1 to about 5 times per day. Daily administration or post-periodic dosing can be employed.

For oral administration, the composition is preferably in the form of a tablet or capsule containing, e.g. , 100 to 1 milligrams of the active compound. Dosages will vary depending on factors associated with the symptoms of the particular mammal being treated, the severity of the condition being treated, the mode of administration, and the strength of the preparation.

The oral composition is preferably formulated as a homogeneous composition, wherein the active ingredient is dispersed evenly throughout the mixture, which can be readily subdivided into dosage units containing equal amounts of a compound of Formula I, II or III, or a pharmaceutically acceptable salt thereof. Preferably, the compositions are prepared by mixing a compound of Formula I, II or III, or a pharmaceutically acceptable salt thereof, with one or more optionally present pharmaceutical carriers (such as a starch, sugar, diluent, granulating agent, lubricant, glidant, binding agent, and disintegrating agent), one or more optionally present inert pharmaceutical excipients (such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and syrup), one or more optionally present conventional tableting ingredients (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, and any of a variety of gums), and an optional diluent (such as water).

Binder agents include starch, gelatin, natural sugars (e.g., glucose and beta-lactose), corn sweeteners and natural and synthetic gums (e.g., acacia and tragacanth). Disintegrating agents include starch, methyl cellulose, agar, and bentonite.

Tablets and capsules represent an advantageous oral dosage unit form. Tablets can be sugar-coated or film-coated using standard techniques. Tablets can also be coated or otherwise compounded to provide a prolonged, controlled-release therapeutic effect. The dosage form can comprise an inner dosage and an outer dosage component, wherein the outer component is in the form of an envelope over the inner component. The two components can further be separated by a layer which resists disintegration in the stomach (such as an enteric layer) and permits the inner component to pass intact into the duodenum or a layer which delays or sustains release. A variety of enteric and non-enteric layer or coating materials (such as polymeric acids, shellacs, acetyl alcohol, and cellulose acetate or combinations thereof) can be used.

Compositions for use in the methods of the invention can also be administered via a slow release composition; wherein the composition includes a compound of Formula I, II or III, or a pharmaceutically acceptable salt thereof, and a biodegradable slow release carrier (e.g., a polymeric carrier) or a pharmaceutically acceptable non-biodegradable slow release carrier (e.g., an ion exchange carrier).

Biodegradable and non-biodegradable slow release carriers are well known in the art. Biodegradable carriers are used to form particles or matrices which retain an active agent(s) and which slowly degrade/dissolve in a suitable environment (e.g., aqueous, acidic, basic and the like) to release the agent. Such particles degrade/dissolve in body fluids to release the active compound therein. The particles are preferably nanoparticles or nanoemulsions (e.g., in the range of about 1 to 500 nm in diameter, preferably about 50-200 nm in diameter, and most preferably about 100 nm in diameter). In a process for preparing a slow release composition, a slow release carrier and a compound of Formula I, II or III, or a

pharmaceutically acceptable salt thereof, are first dissolved or dispersed in an organic solvent. The resulting mixture is added into an aqueous solution containing an optional surface-active agent(s) to produce an emulsion. The organic solvent is then evaporated from the emulsion to provide a colloidal suspension of particles containing the slow release carrier and the compound of the invention.

The compound disclosed herein can be incorporated for administration orally or by injection in a liquid form such as aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil and the like, or in elixirs or similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,

methylcellulose, polyvinyl-pyrrolidone, and gelatin. The liquid forms in suitably flavored suspending or dispersing agents can also include synthetic and natural gums. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations, which generally contain suitable preservatives, are employed when intravenous administration is desired.

The compounds can be administered parenterally via injection. A parenteral formulation can consist of the active ingredient dissolved in or mixed with an appropriate inert liquid carrier. Acceptable liquid carriers usually comprise aqueous solvents and other optional ingredients for aiding solubility or preservation. Such aqueous solvents include sterile water, Ringer's solution, or an isotonic aqueous saline solution. Other optional ingredients include vegetable oils (such as peanut oil, cottonseed oil, and sesame oil), and organic solvents (such as solketal, glycerol, and formyl). A sterile, non-volatile oil can be employed as a solvent or suspending agent. The parenteral formulation is prepared by dissolving or suspending the active ingredient in the liquid carrier whereby the final dosage unit contains from 0.005 to 10% by weight of the active ingredient. Other additives include preservatives, isotonizers, solubilizers, stabilizers, and pain-soothing agents. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents and the like can be employed.

The compounds of Formulas I-III, and pharmaceutically acceptable salts thereof, can also be administered topically or enhanced by using a suitable topical transdermal vehicle or a transdermal patch.

EXEMPLIFICATION

Example 1. Validation of the Computer-based Model.

The present invention is related to the identification of specific relationships that govern glutamatergic and dopaminergic homeostasis at the MSN synaptic level using a computer-based model of dopaminergic and glutamatergic interactions designed and developed for that purpose. The computer-based model of a MSN was constructed using data and other information about MSN physiology. Sources of this data include, but are not limited to, reports of human pathophysiology and relevant animal data. FIGS. 1 , 2 and 4 are schematic representations of the structural elements and biochemical pathways incorporated into the computer-based model. Literature references, textbooks, online databases, etc., were used to identify, calibrate and validate the actions and interactions of the elementary components in the simulation. FIGS. 3 and 5 are simulations performed with the computer-based model to validate its ability to accurately reflect experimental data obtained in vitro or in vivo. A discussion of FIGS. 1-5 follows.

FIG. 1 is a schematic representation of the ultrastructural elements accounted for by the computer-based model and illustrates a MSN and its immediate environment. Dendritic spine 1 receives excitatory inputs from cortical afferent 2. Dendritic spine 1 and cortical afferent 2 form an asymmetric glutamatergic synapse. Various glutamatergic receptors, including AMP A, NMD A, and mGluR, are expressed on spine head 3. MSNs also receive dopaminergic inputs from substantia nigra pars compacta 4 in the form of symmetric "en- passant" synapses typically located on neck or shaft 5 of dendritic spine 1. Dopaminergic receptors, including Dl and D2 receptors, are expressed on spine neck or shaft 5.

Dopaminergic receptors (mainly D2 receptors) are also present on pre-synaptic dopaminergic terminal 2 and glutamatergic terminal 4, where their activation leads to changes in neurotransmitter release.

FIG. 2 is a schematic representation of the intracellular pathways integrated into the computer-based model and illustrates the biological pathways involved in cAMP formation and degradation. Nigrostriatal stimulation of a MSN increases cAMP formation by adenylate cyclase by activating a Dl receptor, and also inhibits cAMP formation by adenylate cyclase by activating a D2 receptor. Calcium, whose influx is regulated mainly by NMDA receptor activation, is a potent inhibitory regulator of cAMP signaling and causes a drastic reduction in adenylate cyclase activity. Intracellular cAMP is degraded by phosphodiesterases (PDE).

It is known that Dl -type and D2-type receptors have opposing actions on the activity of adenylyl cyclase in neostriatal neurons; whereas activation of Dl -type receptors increases cAMP formation by adenylyl cyclase, activation of D2 receptors inhibits adenylyl cyclase activity. FIG. 3 is a three-dimensional graph obtained using the computer-based model and illustrates the relationship between DA concentrations at the Dl and D2 receptors and formation of cAMP. FIG. 3 reflects the opposing actions of Dl and D2 receptors on cAMP formation that are observed in MSNs. Another important aspect of DA neurotransmission in the neostriatum is the regulation of DA release by DA autoreceptors. DA release into the synaptic cleft has also been integrated into the computer-based model. FIG. 4 is a schematic representation of a presynaptic nigrostriatal dopaminergic terminal and illustrates the biological pathway leading to DA release into the synaptic cleft.

Haloperidol is a known D2 antagonist that acts on pre-synaptic DA receptors to release DA into the synaptic cleft. The effect of increasing concentrations of haloperidol on DA release into the synaptic cleft as a function of time was simulated using the computer- based model described above. The results are depicted in FIG. 5, which shows that increasing concentrations of haloperidol cause an increase in DA release into the synaptic cleft. The results depicted in FIG. 5 (i. e. , an increase in extracellular DA concentration following acute haloperidol treatment) are similar to those observed in in vitro and in vivo experiments, such as in vitro electrically-stimulated dopamine release experiments

(Robinson, D.L., et al. Clin. Chem. (2003) 49:1763-73) and in vivo microdialysis studies (see Neuropsychopharmacology (1993) 9: 101-9; Osborne, P.G., et al, Brain Res. (1994) 634:20- 30).

Example 2. Identification of the Kinetic Characteristics of a Compound for Treatment of Huntington's Disease.

Virtual D2 antagonists having affinities for D2 ranging from 1 x 10 ^"9 M to 5 x 10 ^~5 M, as characterized by ¾, were used in the computer-based model to probe the relationship between D2 antagonism and intracellular cAMP homeostasis in the MSN spine. In theory, D2 antagonists can act at the same time to: (i) favor DA release into the synaptic cleft by antagonizing D2 pre-synaptic autoreceptors, and (ii) favor DA-induced cAMP formation at the post-synaptic level of the MSN spine.

In silico, the computer-based model unexpectedly revealed that an important feature of MSN integration of glutamatergic and dopaminergic signals is the tone of the

dopaminergic afferent input and the equilibrium between: (i) the activation of pre-synaptic D2 DA receptors (D2 _pre ), leading to a retroactive decrease of DA release and consequently a reduction of the dopaminergic modulation of MSN, and (ii) the activation of post-synaptic D2 DA receptors (D2 _post ), leading to an activation of a positive control of the MSN output in terms of cAMP formation. This complex interaction became highly non-linear for a range of affinity constants between 10 ^"8 and 10 ^"5 M.

FIG. 6 is a graph of post-synaptic cAMP concentration as a function of the

concentration of a virtual D2 receptor antagonist characterized by a ¾ of between 10 ^"9 M and 10 ^"5 M and shows that the dose-response curves for the virtual D2 receptor antagonists characterized by a K _d of between 10 ^"8 and 10 ^"5 are non-linear. FIG. 6 suggests that the action of DA D2 receptor antagonists with a Kd in the range of 10 ^"5 and 10 ^"8 M is highly dependent on the intrasynaptic concentration of DA, and the dynamic competition for D2 receptors between DA D2 receptor antagonists and intrasynaptic DA.

Because the intrasynaptic DA concentration is dependent upon activation of presynaptic D2 receptors by the virtual D2 antagonist and the post-synaptic cAMP concentration is dependent upon activation of post-synaptic D2 receptors, the differential affinity of a DA D2 receptor antagonist for D2 _pre or D2 _post is, in addition to the averaged affinity of the antagonist for D2 receptors, another important parameter of the antagonist. For example, when dopaminergic transmission is impaired, an antagonist exhibiting an affinity higher than that of DA for D2 is less capable of exhibiting a preference for pre-synaptic D2 receptors, as there is not initially competition between the antagonist and DA.

FIG. 7 is a graph of post-synaptic cAMP concentration as a function of the concentration of virtual D2 receptor antagonists characterized by a Kd of 10 ^"8 M and having a preferential affinity ratio for a pre-synaptic D2 receptor versus a post-synaptic D2 receptor of between 1 and 100, and shows that the preferential affinity ratio does not affect the dose- response curve of virtual D2 receptor antagonists characterized by a Kd of 10 ^" M.

FIG. 8 is a graph of post-synaptic cAMP concentration as a function of the concentration of virtual D2 receptor antagonists characterized by a Kd of 10 ^"5 M and having a preferential affinity ratio for a pre-synaptic D2 receptor versus a post-synaptic D2 receptor of between 1 and 100. FIG. 8 shows that, in contrast to the dose-response curves corresponding to D2 receptor antagonists having a Kd of 10 ^"8 M, the dose-response curves of virtual D2 receptor antagonists characterized by a K _d of 10 ^"5 M are profoundly affected by the preferential affinity ratio.

Antagonists with Kd characteristics in the range of 10 ^"5 and 10 ^"8 M that interact differently with D2 _pre and D2 _post , as measured by a preferential affinity ratio of D2 _pre to D2 _post of 5 to 100, impact the dynamic modulation of the dopaminergic control of the MSN differently, resulting in different MSN behaviors. Some symptoms of HD are thought to be related to hyperactive dopaminergic neurotransmission, while other symptoms are attributed to hypoactive dopaminergic neurotransmission. Thus, antagonists that preferentially bind D2 _pre versus D2 _post are expected to have beneficial clinical effects by enabling a clinician to fine tune the balance of activation by DA of D2 _pre versus D2 _pos t.

Example 3. Identification of a Compound for Treatment of Huntington's Disease.

The specific pharmacological requirements identified in Example 2 were applied to known molecules to identify compounds for treatment of Huntington's Disease. Substituted benzamides of Formulas I-III can meet the pharmacological characteristics identified in Example 2.

Compounds of Formula I possess a high electron density at the oxygen of the amide functionality, which can enable them to discriminate between pre-and post-synaptic D2 receptors. The presence of electron- withdrawing groups meta to the amide funtionality and/or electron-donating groups ortho and para to the amide functionality can enhance this effect. Compounds of Formula II are, in some cases, preferred to minimize steric interactions that can cause the benzamide to distort into a non-planar configuration.

In particular, the compound of Formula III was identified as a compound having the specific kinetic requirements of a compound useful for the treatement of HD identified in Example 2 (an affinity for D2 receptors characterized by a ¾ of 10 ^"5 -10 ^"8 M with a pre/post ratio between 5 and 100). In in vitro experiments, the compound of Formula III exhibited an affinity for D2 receptors of about 6 x 10 ^"7 M and preferentially bound D2 _pre versus D2 _post with a preferential affinity ratio of about 13. In in vivo experiments, the compound of Formula III had a dose-dependent dual consequence, inducing a moderate increase of the tone of the dopaminergic modulation of the MSN (e.g. , increased concentration of DA in the synaptic cleft) at low concentrations followed by a blockade of the dopaminergic neurotransmission at higher concentrations. This biphasic effect could restore normal function following disruptions of the pre-/post-synaptic D2 homeostasis due to either a hyperactive or a hypoactive dopaminergic modulatory control of the MSN and, ultimately, strengthen the GABAergic output of an MSN. The experimentally-determined properties of the compound of Formula III were inputted into the computer-based model and the effect of the compound of Formula III on dopamine signaling was modeled. The in silico effect of a virtual compound having the kinetic characteristics of the compound of Formula III on dopaminergic transmission was consistent with the experimental data described above.

FIG. 9 is a graph of predicted DA concentration as a function of time and shows that increasing concentrations of a compound of Formula III, acting on a pre-synaptic DA receptor, cause an increase in DA release into the synaptic cleft. The results depicted in FIG. 9 (z. e. , an increase in extracellular DA concentration following acute treatment with a compound of Formula III) are in accordance with the data disclosed in Bischoff, S., et al. ; Naunyn-Schmiedeberg's Arch. Pharmacol. (1994) 350:230-238.

FIG. 10 is a graph of post-synaptic cAMP concentration as a function of the concentration of virtual D2 receptor antagonists characterized by a K _d corresponding to that of a compound of Formula III and having a preferential affinity ratio for a pre-synaptic D2 receptor versus a post-synaptic D2 receptor of 1, 13 or 100. FIG. 10 shows that the dose- response curve of a virtual D2 receptor antagonist characterized by a K _d of 6 x 10 ^"7 M and a preferential affinity ratio of 13 is non-linear.

FIG. 11 is a graph of post-synaptic cAMP concentration as a function of the concentration of virtual D2 receptor antagonists characterized by a K _d of between 10 ^"9 M and 10 ^"5 M and a preferential affinity ratio for a pre-synaptic D2 receptor versus a post-synaptic D2 receptor of 13, and shows that the dose-response curves for the virtual D2 receptor antagonists characterized by a K _d of between 10 ^"7 and 5 x 10 ^"5 are non- linear.

Methods of making a compound of Formula III are described in U.S. Patent No. 4,772,630 to Storni et al. Methods of assessing the K _d of the compound of Formula III, as well as the preferential affinity of the compound of Formula III for D2 _pre versus D2 _pos t, are disclosed in Bischoff, S., et al ; Naunyn-Schmiedeberg 's Arch. Pharmacol. (1994) 350:230- 238.

The relevant teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety. While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details can be made therein without departing from the scope of the invention encompassed by the appended claims.