Ligands for monoamine receptors and transporters, and methods of use thereof Number:7,132,551 from the United States Patent and Trademark Office (PTO) owispatent

Title: Ligands for monoamine receptors and transporters, and methods of use thereof

Abstract: One aspect of the present invention relates to heterocyclic compounds. A second aspect of the present invention relates to the use of the heterocyclic compounds as ligands for various mammalian cellular receptors, including dopamine, serotonin, or norepinephrine transporters. The compounds of the present invention will find use in the treatment of numerous ailments, conditions and diseases which afflict mammals, including but not limited to addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, Alzheimer's disease, obesity, emesis, psychosis, schizophrenia, Parkinson's disease, inflammatory pain, neuropathic pain, Lesche-Nyhane disease, Wilson's disease, and Tourette's syndrome. An additional aspect of the present invention relates to the synthesis of combinatorial libraries of the heterocyclic compounds, and the screening of those libraries for biological activity, e.g., in assays based on dopamine transporters.

Patent Number: 7,132,551 Issued on 11/07/2006 to Aquila,   et al.

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Inventors:	Aquila; Brian M. (Marlborough, MA), Bannister; Thomas D. (Northborough, MA), Cuny; Gregory D. (Hudson, MA), Hauske; James R. (Concord, MA), Holland; Joanne M. (Brookline, MA), Persons; Paul E. (Westborough, MA), Radeke; Heike S. (South Grafton, MA), Wang; Fengjiang (Northborough, MA), Shao; Liming (Lincoln, MA)
Assignee:	Sepracor Inc. (Marlborough, MA)
Appl. No.:	10/607,457
Filed:	June 26, 2003

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Current U.S. Class:	548/530 ; 548/531; 548/539; 548/570
Current International Class:	C07D 207/00 (20060101)
Field of Search:	548/530,539,531,570 514/423,428

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References Cited [Referenced By]

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U.S. Patent Documents

	3806595		April 1974		Jaggers et al.
	3876769		April 1975		Mallion et al.
	3959273		May 1976		Mallion et al.
	4033951		July 1977		Maiser
	4241059		December 1980		Hauck et al.
	4593036		June 1986		Lassen et al.
	4605654		August 1986		Cousse et al.
	5328917		July 1994		Jakobsen et al.
	5521180		May 1996		Fujii et al.
	6110937		August 2000		Loughhead et al.
	6124317		September 2000		Bigge et al.
	6124323		September 2000		Bigge et al.
	6653478		November 2003		Urbanski et al.
	6703508		March 2004		Aquila et al.

Foreign Patent Documents

	0 000 693		Feb., 1979		EP
	0 076 089		Apr., 1983		EP
	0 080 940		Jun., 1983		EP
	0 138 716		Apr., 1985		EP
	0 229 623		Jul., 1987		EP
	0 266 574		May., 1988		EP
	0 290 958		Nov., 1988		EP
	0 639 568		Feb., 1995		EP
	1.221.294		Jun., 1960		FR
	2 248 049		May., 1975		FR
	2 471 378		Jun., 1981		FR
	2 534 915		Apr., 1984		FR
	2 553 411		Apr., 1985		FR
	2 564 462		Nov., 1985		FR
	1138405		Jan., 1969		GB
	1184023		Mar., 1970		GB
	1 260 886		Jan., 1972		GB
	1 382 526		Feb., 1975		GB
	1 382 965		Feb., 1975		GB
	1 452 701		Oct., 1976		GB
	1 501 321		Feb., 1978		GB
	111542		Jun., 1965		NR
	WO 91/09032		Jun., 1991		WO
	WO 92/01672		Feb., 1992		WO
	WO 92/02502		Feb., 1992		WO
	WO 93/15052		Aug., 1993		WO
	WO 94/13291		Jun., 1994		WO
	WO 95/03302		Feb., 1995		WO
	WO 95/25732		Sep., 1995		WO
	WO 95/33722		Dec., 1995		WO
	WO 95/33723		Dec., 1995		WO
	WO 98/51668		Nov., 1998		WO
	WO 99/65487		Dec., 1999		WO
	WO 00/09491		Feb., 2000		WO
	WO 0071518		Nov., 2000		WO
	WO 01/32178		May., 2001		WO
	WO 01/68604		Sep., 2001		WO
	WO 01/92226		Dec., 2001		WO

Other References

Nagahara et al., 1994, CAS: 120:323168. cited by examiner . Kutsuki et al., 1990, CAS: 112: 7363. cited by examiner . Andersson et al., 2001, CAS: 135:242140. cited by examiner . Brown et al., 1990, CAS:112:35578. cited by examiner . Engelstoft and Hansen; "Synthesis and 5HT Modulating Activity of Stereoisomers of 3-Phenoxymethyl-4-Phenylpiperidines" Acta Chemica Scandinavica 50:164-169, (1996). cited by other . O'Neill et al.; "Effect of Ca2+ and Na+ Channel Inhibitors in Vitro and In Global Cerebral Ischaemia in Vivo", European Journal of Pharmocology 332: 121-131, (1997). cited by other . Balsamo et al., "3-[(2-Ethoxyphenoxy)methyl]piperidine Derivatives. Synthesis and Antidepressant Activity," J. Med. Chem., 30:222-225 (1987). cited by other . Jones et al., "The Medical Benefit of 5-HT Research," Pharmacology, Biochemistry and Behavior 71:555-568 (2002). cited by other.

Primary Examiner: Saeed; Kamal A.
Assistant Examiner: Shiao; Robert
Attorney, Agent or Firm: Gordon; Dana M. Foley Hoag LLP

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Parent Case Text

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RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No. 09/951,130, filed Sep. 12, 2001; which claims the benefit of priority to: U.S. Provisional Patent Application Ser. No. 60/231,667, filed Sep. 11, 2000; U.S. Provisional Patent Application Ser. No. 60/273,530, filed Mar. 5, 2001; and U.S. Provisional Patent Application Ser. No. 60/298,057, filed Jun. 13, 2001.

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Claims

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What is claimed is:

1. A compound represented by C: ##STR00277## wherein Z represents C(R.sub.3).sub.2, C(O), O, NR, NC(O)OR, S, SO, or SO.sub.2; m is 1, 2, 3, 4 or 5; p is 0, 1, 2, or 3; y is 0, 1 or 2; R represents alkyl, cycloalkyl, aryl, or aralkyl; R.sub.1 represents alkyl, aryl, or aralkyl; R and R.sub.1 may be connected through a covalent bond; R.sub.2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, or cycloalkyl; R.sub.3 represents independently for each occurrence H, alkyl, aryl, OR.sub.2, OC(O)R.sub.2, CH.sub.2OR.sub.2, or CO.sub.2R.sub.2; R.sub.4 represents independently for each occurrence H, alkyl, cycloalkyl, aryl, alkenyl, or OR; R.sub.5 and R.sub.6 are selected independently for each occurrence from the group consisting of H, alkyl, (CH.sub.2).sub.pY, aryl, F, OR.sub.2, and OC(O)R.sub.2; or an instance of CR.sub.5R.sub.6 taken together is C(O); R.sub.8 and R.sub.9 are selected independently for each occurrence from the group consisting of H, alkyl, (CH.sub.2).sub.pY, aryl, F, OR.sub.2, and OC(O)R.sub.2; or an instance of CR.sub.8R.sub.9 taken together is C(O); Y represents independently for each occurrence OR.sub.2, N(R.sub.2).sub.2, SR.sub.2, S(O)R.sub.2, S(O).sub.2R.sub.2, or P(O)(OR.sub.2).sub.2; any two instances of R.sub.2 may be connected through a covalent bond; a covalent bond may connect R.sub.4 and an instance of R.sub.5 or R.sub.6; any two instances of R.sub.5 and R.sub.6 may be connected through a covalent bond; any two geminal or vicinal instances of R.sub.8 and R.sub.9 may be connected through a covalent bond; and the stereochemical configuration at any stereocenter of a compound represented by C is R or S, or a mixture of these configurations.

2. The compound of claim 1, wherein Z is O or NR.

3. The compound of claim 1, wherein m is 3.

4. The compound of claim 1, wherein y is 1.

5. The compound of claim 1, wherein R.sub.1 represents aryl.

6. The compound of claim 1, wherein R.sub.3 represents independently for each occurrence H or alkyl.

7. The compound of claim 1, wherein R.sub.4 represents cycloalkyl, or aryl.

8. The compound of claim 1, wherein R.sub.5 and R.sub.6 are selected independently for each occurrence from the group consisting of H, alkyl, OR.sub.2, aryl, and F.

9. The compound of claim 1, wherein R.sub.8 and R.sub.9 are selected independently for each occurrence from the group consisting of H, alkyl, OR.sub.2, aryl, and F.

10. The compound of claim 1, wherein Z is O or NR; and m is 3.

11. The compound of claim 1, wherein Z is O or NR; and y is 1.

12. The compound of claim 1, wherein Z is O or NR; m is 3; and y is 1.

13. The compound of claim 1, wherein Z is O or NR; m is 3; y is 1; and R.sub.1 is aryl.

14. The compound of claim 1, wherein Z is O or NR; m is 3; y is 1; R.sub.1 is aryl; and R.sub.3 is H or alkyl.

15. The compound of claim 1, wherein Z is O or NR; m is 3; y is 1; R.sub.1 is aryl; R.sub.3 is H or alkyl; and R.sub.4 is cycloalkyl, or aryl.

16. The compound of claim 1, wherein Z is O or NR; m is 3; y is 1; R.sub.1 is aryl; R.sub.3 is H or alkyl; R.sub.4 is cycloalkyl, or aryl; and R.sub.5 and R.sub.6 are selected independently for each occurrence from the group consisting of H, alkyl, OR.sub.2, aryl, and F.

17. The compound of claim 1, wherein Z is O or NR; m is 3; y is 1; R.sub.1 is aryl; R.sub.3 is H or alkyl; R.sub.4 is cycloalkyl, or aryl; R.sub.5 and R.sub.6 are selected independently for each occurrence from the group consisting of H, alkyl, OR.sub.2, aryl, and F; and R.sub.8 and R.sub.9 are selected independently for each occurrence from the group consisting of H, alkyl, OR.sub.2, aryl, and F.

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Description

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BACKGROUND OF THE INVENTION

Dopamine, norepinephrine and serotonin are mammalian monoamine neurotransmitters that play important roles in a wide variety of physiological processes. Therefore, compounds that selectively modulate the activity of these three neurotransmitters, either individually, in pairs, or as a group, promise to serve as agents effective in the treatment of a wide range of maladies, conditions and diseases that afflict mammals due to atypical activities of these neurotransmitters.

For example, depression is believed to result from dysfunction in the noradrenergic, dopaminergic, or serotonergic systems. Furthermore, the noradrenergic system appears to be associated with increased drive, whereas the serotonergic system relates more to changes in mood. Therefore, it is possible that the different symptoms of depression may benefit from drugs acting mainly on one or the other of these neurotransmitter systems. On the other hand, a single compound that selectively affects both the noradrenergic and serotonergic systems should prove effective in the treatment of depression comprising symptoms related to dysfunction in both systems.

Dopamine plays a major role in addiction. Many of the concepts that apply to dopamine apply to other neurotransmitters as well. As a chemical messenger, dopamine is similar to adrenaline. Dopamine affects brain processes that control movement, emotional response, and ability to experience pleasure and pain. Regulation of dopamine plays a crucial role in our mental and physical health. Neurons containing the neurotransmitter dopamine are clustered in the midbrain in an area called the substantia nigra. In Parkinson's disease, the dopamine-transmitting neurons in this area die. As a result, the brains of people with Parkinson's disease contain almost no dopamine. To help relieve their symptoms, these patients are given L-DOPA, a drug that can be converted in the brain to dopamine.

Certain drugs are known as dopamine agonists. These drugs bind to dopamine receptors in place of dopamine and directly stimulate those receptors. Some dopamine agonists are currently used to treat Parkinson's disease. These drugs can stimulate dopamine receptors even in someone without dopamine-secreting neurons. In contrast to dopamine agonists, dopamine antagonists are drugs that bind but don't stimulate dopamine receptors. Antagonists can prevent or reverse the actions of dopamine by keeping dopamine from activating receptors.

Dopamine antagonists are traditionally used to treat schizophrenia and related mental disorders. A person with schizophrenia may have an overactive dopamine system. Dopamine antagonists can help regulate this system by "turning down" dopamine activity.

Cocaine and other drugs of abuse can alter dopamine function. Such drugs may have very different actions. The specific action depends on which dopamine receptors and brain regions the drugs stimulate or block, and how well the compounds mimic dopamine. Drugs such as cocaine and amphetamine produce their effects by changing the flow of neurotransmitters. These drugs are defined as indirect acting because they depend on the activity of neurons. In contrast, some drugs bypass neurotransmitters altogether and act directly on receptors.

Use of these two types of drugs can lead to very different results in treating the same disease. As mentioned earlier, people with Parkinson's disease lose neurons that contain dopamine. To compensate for this loss, the body produces more dopamine receptors on other neurons. Indirect agonists are not very effective in treating the disease since they depend on the presence of dopamine neurons. In contrast, direct agonists are more effective because they stimulate dopamine receptors even when dopamine neurons are missing.

Certain drugs increase dopamine concentrations by preventing dopamine reuptake, leaving more dopamine in the synapse. An example is the widely abused stimulant drug, cocaine. Another example is methylphenidate, used therapeutically to treat childhood hyperkinesis and symptoms of narcolepsy.

Sensitization or desensitization normally occurs with drug exposure. However, addiction or mental illness can tamper with the reuptake system. This disrupts the normal levels of neurotransmitters in the brain and can lead to faulty desensitization or sensitization. If this happens in a region of the brain that serves emotion or motivation, the individual can suffer severe consequences. For example, cocaine prevents dopamine reuptake by binding to proteins that normally transport dopamine. Not only does cocaine "bully" dopamine out of the way, it also hangs on to the transport proteins much longer than dopamine does. As a result, more dopamine remains to stimulate neurons, which causes a prolonged feelings of pleasure and excitement. Amphetamine also increases dopamine levels. Again, the result is over-stimulation of these pleasure-pathway nerves in the brain.

Dopamine activity is implicated in the reinforcing effects of cocaine, amphetamine and natural rewards. However, dopamine abnormalities are also believed to underlie some of the core attention deficits seen in acute schizophrenics.

Norepinephrine, also called noradrenaline, is a neurotransmitter that also acts as a hormone. As a neurotransmitter, norepinephrine helps to regulate arousal, dreaming, and moods. As a hormone, it acts to increase blood pressure, constrict blood vessels and increase heart rate--responses that occur when we feel stress.

Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in animals and plants, occurring in vertebrates, fruits, nuts, and venoms. A number of congeners of serotonin are also found in nature and have been shown to possess a variety of peripheral and central nervous system activities. Serotonin may be obtained from a variety of dietary sources; however, endogenous 5-HT is synthesized in situ from tryptophan through the actions of the enzymes tryptophan hydroxylase and aromatic L-amino acid decarboxylase. Both dietary and endogenous 5-HT are rapidly metabolized and inactivated by monoamine oxidase and aldehyde dehydrogenase to the major metabolite, 5-hydroxyindoleacetic acid (5-HIAA).

Serotonin is implicated in the etiology or treatment of various disorders, particularly those of the central nervous system, including anxiety, depression, obsessive-compulsive disorder, schizophrenia, stroke, obesity, pain, hypertension, vascular disorders, migraine, and nausea. Recently, understanding of the role of 5-HT in these and other disorders has advanced rapidly due to increasing understanding of the physiological role of various serotonin receptor subtypes.

It is currently estimated that up to 30% of clinically diagnosed cases of depression are resistant to all forms of drug therapy. To achieve an effective therapy for such patients, it is logical to develop drugs that possess reuptake inhibition profiles different from those of drugs currently available on the market. For example, the exact role of dopamine in depressive illness is far from clear; however, intervention in the dopamine system may hold promise for the treatment of a subset of major depression.

SUMMARY OF THE INVENTION

One aspect of the present invention relates to heterocyclic compounds. A second aspect of the present invention relates to the use of the heterocyclic compounds as ligands for various mammalian cellular receptors, including dopamine, serotonin, or norepinephrine transporters. The compounds of the present invention will find use in the treatment of numerous ailments, conditions and diseases which afflict mammals, including but not limited to addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, Alzheimer's disease, obesity, emesis, psychosis, analgesia, schizophrenia, Parkinson's disease, restless leg syndrome, sleeping disorders, attention deficit hyperactivity disorder, irritable bowel syndrome, premature ejaculation, menstrual dysphoria syndrome, urinary incontinence, inflammatory pain, neuropathic pain, Lesche-Nyhane disease, Wilson's disease, and Tourette's syndrome. An additional aspect of the present invention relates to the synthesis of combinatorial libraries of the heterocyclic compounds, and the screening of those libraries for biological activity, e.g., in assays based on dopamine transporters.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts an ORTEP drawing of compound 124, which was the basis for the assignment of its absolute stereochemistry.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides heterocyclic compounds, and combinatorial libraries thereof. Furthermore, the present invention provides heterocyclic compounds that are ligands for dopamine, serotonin, or norepinephrine receptors or transporters, and methods of use thereof for the treatment of numerous ailments, conditions and diseases which afflict mammals, including but not limited to addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, Alzheimer's disease, obesity, emesis, psychosis, analgesia, schizophrenia, Parkinson's disease, restless leg syndrome, sleeping disorders, attention deficit hyperactivity disorder, irritable bowel syndrome, premature ejaculation, menstrual dysphoria syndrome, urinary incontinence, inflammatory pain, neuropathic pain, Lesche-Nyhane disease, Wilson's disease, and Tourette's syndrome. The present invention also relates to pharmaceutical formulations of the heterocyclic compounds.

In certain embodiments, compounds of the present invention are ligands for mammalian receptors for dopamine, norepinephrine, serotonin, any two of these three neurotransmitters or all of them. In certain embodiments, compounds of the present invention are ligands for mammalian transporters of dopamine, norepinephrine, serotonin, any two of these three neurotransmitters or all of them. In certain embodiments, compounds of the present invention are agonists of mammalian receptors for dopamine, norepinephrine, serotonin, any two of these three neurotransmitters or all of them. In certain embodiments, compounds of the present invention are antagonists or inverse agonists of mammalian receptors for dopamine, norepinephrine, serotonin, any two of these three neurotransmitters or all of them. In certain embodiments, compounds of the present invention are agonists of mammalian transporters of dopamine, norepinephrine, serotonin, any two of these three neurotransmitters or all of them. In certain embodiments, compounds of the present invention are antagonists or inverse agonists of mammalian transporters of dopamine, norepinephrine, serotonin, any two of these three neurotransmitters or all of them.

In certain embodiments, compounds of the present invention are ligands for mammalian dopamine receptors. In certain embodiments, compounds of the present invention are ligands for mammalian dopamine transporters. In certain embodiments, compounds of the present invention are agonists of mammalian dopamine receptors. In certain embodiments, compounds of the present invention are antagonists or inverse agonists of mammalian dopamine receptors. In certain embodiments, compounds of the present invention are agonists of mammalian dopamine transporters. In certain embodiments, compounds of the present invention are antagonists or inverse agonists of mammalian dopamine transporters.

The mammalian dopamine receptor and transporter are members of a family of cell surface proteins that permit intracellular transduction of extracellular signals. Cell surface proteins provide eukaryotic and prokaryotic cells a means to detect extracellular signals and transduce such signals intracellularly in a manner that ultimately results in a cellular response or a concerted tissue or organ response. Cell surface proteins, by intracellularly transmitting information regarding the extracellular environment via specific intracellular pathways induce an appropriate response to a particular stimulus. The response may be immediate and transient, slow and sustained, or some mixture thereof. By virtue of an array of varied membrane surface proteins, eukaryotic cells are exquisitely sensitive to their environment.

Extracellular signal molecules, such as growth hormones, vasodilators and neurotransmitters, exert their effects, at least in part, via interaction with cell surface proteins. For example, some extracellular signal molecules cause changes in transcription of target gene via changes in the levels of secondary messengers, such as cAMP. Other signals, indirectly alter gene expression by activating the expression of genes, such as immediate-early genes that encode regulatory proteins, which in turn activate expression of other genes that encode transcriptional regulatory proteins. For example, neuron gene expression is modulated by numerous extracellular signals, including neurotransmitters and membrane electrical activity. Transsynaptic signals cause rapid responses in neurons that occur over a period of time ranging from milleseconds, such as the opening of ligand-gated channels, to seconds and minutes, such as second messenger-mediated events. Genes in neural cells that are responsive to transsynaptic stimulation and membrane electrical activity, include genes, called immediate early genes, whose transcription is activated rapidly, within minutes, and transiently (see, e.g., Sheng et al. (1990) Neuron 4: 477 485), and genes whose expression requires protein synthesis and whose expression is induced or altered over the course of hours.

Cell surface receptors and ion channels are among the cell surface proteins that respond to extracellular signals and initiate the events that lead to this varied gene expression and response. Ion channels and cell surface-localized receptors are ubiquitous and physiologically important cell surface membrane proteins. They play a central role in regulating intracellular levels of various ions and chemicals, many of which are important for cell viability and function.

Cell surface-localized receptors are membrane spanning proteins that bind extracellular signalling molecules or changes in the extracellular environment and transmit the signal via signal transduction pathways to effect a cellular response. Cell surface receptors bind circulating signal polypeptides, such as neurotransmitters, growth factors and hormones, as the initiating step in the induction of numerous intracellular pathways. Receptors are classified on the basis of the particular type of pathway that is induced. Included among these classes of receptors are those that bind growth factors and have intrinsic tyrosine kinase activity, such as the heparin binding growth factor (HBGF) receptors, and those that couple to effector proteins through guanine nucleotide binding regulatory proteins, which are referred to as G protein coupled receptors and G proteins, respectively.

The G protein transmembrane signaling pathways consist of three proteins: receptors, G proteins and effectors. G proteins, which are the intermediaries in transmembrane signaling pathways, are heterodimers and consist of alpha, beta and gamma subunits. Among the members of a family of G proteins the alpha subunits differ. Functions of G proteins are regulated by the cyclic association of GTP with the alpha subunit followed by hydrolysis of GTP to GDP and dissociation of GDP.

G protein coupled receptors are a diverse class of receptors that mediate signal transduction by binding to G proteins. Signal transduction is initiated via ligand binding to the cell membrane receptor, which stimulates binding of the receptor to the G protein. The receptor G protein interaction releases GDP, which is specifically bound to the G protein, and permits the binding of GTP, which activates the G protein. Activated G protein dissociates from the receptor and activates the effector protein, which regulates the intracellular levels of specific second messengers. Examples of such effector proteins include adenyl cyclase, guanyl cyclase, phospholipase C, and others.

G protein-coupled receptors, which are glycoproteins, are known to share certain structural similarities and homologies (see, e-g., Gilman, A. G., Ann. Rev. Biochem. 56: 615 649 (1987), Strader, C. D. et al. The FASEB Journal 3: 1825 1832 (1989), Kobilka, B. K., et al. Nature 329:75 79 (1985) and Young et al. Cell 45: 711 719 (1986)). Among the G protein-coupled receptors that have been identified and cloned are the substance P receptor, the angiotensin receptor, the alpha- and beta-adrenergic receptors and the serotonin receptors. G protein-coupled receptors share a conserved structural motif. The general and common structural features of the G protein-coupled receptors are the existence of seven hydrophobic stretches of about 20 25 amino acids each surrounded by eight hydrophilic regions of variable length. It has been postulated that each of the seven hydrophobic regions forms a transmembrane alpha helix and the intervening hydrophilic regions form alternately intracellularly and extracellularly exposed loops. The third cytosolic loop between transmembrane domains five and six is the intracellular domain responsible for the interaction with G proteins.

G protein-coupled receptors are known to be inducible. This inducibility was originally described in lower eukaryotes. For example, the cAMP receptor of the cellular slime mold, Dictyostelium, is induced during differentiation (Klein et al., Science 241: 1467 1472 (1988). During the Dictyostelium discoideum differentiation pathway, cAMP, induces high level expression of its G protein-coupled receptor. This receptor transduces the signal to induce the expression of the other genes involved in chemotaxis, which permits multicellular aggregates to align, organize and form stalks (see, Firtel, R. A., et al. Cell 58: 235 239 (1989) and Devreotes, P., Science 245: 1054 1058 (1989)).

Definitions

For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

The term "cell surface proteins" includes molecules that occur on the surface of cells, interact with the extracellular environment, and transmit or transduce information regarding the environment intracellularly.

The term "extracellular signals" includes a molecule or a change in the environment that is transduced intracellularly via cell surface proteins that interact, directly or indirectly, with the signal. An extracellular signal is any compound or substance that in some manner specifically alters the activity of a cell surface protein. Examples of such signals include, but are not limited to, molecules such as acetylcholine, growth factors, hormones and other mitogenic substances, such as phorbol mistric acetate (PMA), that bind to cell surface receptors and ion channels and modulate the activity of such receptors and channels. Extracellular signals also includes as yet unidentified substances that modulate the activity of a cell surface protein and thereby affect intracellular functions and that are potential pharmacological agents that may be used to treat specific diseases by modulating the activity of specific cell surface receptors.

The term "Ed.sub.50" means the dose of a drug which produces 50% of its maximum response or effect. Alternatively, the dose which produces a pre-determined response in 50% of test subjects or preparations.

The term "LD.sub.50" means the dose of a drug which is lethal in 50% of test subjects.

The term "therapeutic index" refers to the therapeutic index of a drug defined as LD.sub.50/ED.sub.50.

The term "structure-activity relationship (SAR)" refers to the way in which altering the molecular structure of drugs alters their interaction with a receptor, enzyme, etc.

The term "agonist" refers to a compound that mimics the action of natural transmitter or, when the natural transmitter is not known, causes changes at the receptor complex in the absence of other receptor ligands.

The term "antagonist" refers to a compound that binds to a receptor site, but does not cause any physiological changes unless another receptor ligand is present.

The term "inverse agonist" refers to a compound that binds to a constitutively active receptor site and reduces its physiological function.

The term "competitive antagonist" refers to an antagonist, the effects of which can be overcome by increased concentration of an agonist.

The term "partial agonist" refers to a compound that binds to a receptor site but does not produce the maximal effect regardless of its concentration.

The term "ligand" refers to a compound that binds at the receptor site.

The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term "electron-withdrawing group" is recognized in the art, and denotes the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms. A quantification of the level of electron-withdrawing capability is given by the Hammett sigma (.sigma.) constant. This well known constant is described in many references, for instance, J. March, Advanced Organic Chemistry, McGraw Hill Book Company, New York, (1977 edition) pp. 251 259. The Hammett constant values are generally negative for electron donating groups (.sigma.[P]=-0.66 for NH.sub.2) and positive for electron withdrawing groups (.sigma.[P]=0.78 for a nitro group), .sigma.[P] indicating para substitution. Exemplary electron-withdrawing groups include nitro, acyl, formyl, sulfonyl, trifluoromethyl, cyano, chloride, and the like. Exemplary electron-donating groups include amino, methoxy, and the like.

The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C.sub.1 C.sub.30 for straight chain, C.sub.3 C.sub.30 for branched chain), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 3 10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.

Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.

The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

The term "aryl" as used herein includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics." The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, --CF.sub.3, --CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10-membered ring structures, more preferably 3- to 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, --CF.sub.3, --CN, or the like.

The terms "polycyclyl" or "polycyclic group" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, --CF.sub.3, --CN, or the like.

As used herein, the term "nitro" means --NO.sub.2; the term "halogen" designates --F, --Cl, --Br or --I; the term "sulfhydryl" means --SH; the term "hydroxyl" means --OH; and the term "sulfonyl" means --SO.sub.2--.

The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:

##STR00001## wherein R.sub.9, R.sub.10 and R'.sub.10 each independently represent a group permitted by the rules of valence.

The term "acylamino" is art-recognized and refers to a moiety that can be represented by the general formula:

##STR00002## wherein R.sub.9 represents a group permitted by the rules of valence, and R'.sub.11 represents hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.

The term "amido" is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:

##STR00003## wherein R.sub.9, R.sub.10 are as defined above. Preferred embodiments of the amide will not include imides which may be unstable.

The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In preferred embodiments, the "alkylthio" moiety is represented by one of --S-alkyl, --S-alkenyl, --S-alkynyl, and --S--(CH.sub.2).sub.m--R.sub.8, wherein m is an integer less than or equal to ten, and R.sub.8 is alkyl, cycloalkyl, alkenyl, aryl, or heteroaryl. Representative alkylthio groups include methylthio, ethyl thio, and the like.

The term "carbonyl" is art recognized and includes such moieties as can be represented by the general formula:

##STR00004## wherein X is a bond or represents an oxygen or a sulfur, and R.sub.11 represents a hydrogen, an alkyl, an alkenyl, --(CH.sub.2).sub.m--R.sub.8 or a pharmaceutically acceptable salt, R'.sub.11 represents a hydrogen, an alkyl, an alkenyl or --(CH.sub.2).sub.m--R.sub.8, where m and R.sub.8 are as defined above. Where X is an oxygen and R.sub.11 or R'.sub.11 is not hydrogen, the formula represents an "ester". Where X is an oxygen, and R.sub.11 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R.sub.11 is a hydrogen, the formula represents a "carboxylic acid". Where X is an oxygen, and R'.sub.11 is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X is a sulfur and R.sub.11 or R'.sub.11 is not hydrogen, the formula represents a "thiolester." Where X is a sulfur and R.sub.11 is hydrogen, the formula represents a "thiolcarboxylic acid." Where X is a sulfur and R.sub.11' is hydrogen, the formula represents a "thiolformate." On the other hand, where X is a bond, and R.sub.11 is not hydrogen, the above formula represents a "ketone" group. Where X is a bond, and R.sub.11 is hydrogen, the above formula represents an "aldehyde" group.

The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of --O-alkyl, --O-alkenyl, --O-alkynyl, --O--(CH.sub.2).sub.m--R.sub.8, where m and R.sub.8 are described above.

The term "sulfonate" is art recognized and includes a moiety that can be represented by the general formula:

##STR00005## in which R.sub.41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.

The term "sulfate" is art recognized and includes a moiety that can be represented by the general formula:

##STR00006## in which R.sub.41 is as defined above.

The term "sulfonylamino" is art recognized and includes a moiety that can be represented by the general formula:

##STR00007##

The term "sulfamoyl" is art-recognized and includes a moiety that can be represented by the general formula:

##STR00008##

The term "sulfonyl", as used herein, refers to a moiety that can be represented by the general formula:

##STR00009## in which R.sub.44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

The term "sulfoxido" as used herein, refers to a moiety that can be represented by the general formula:

##STR00010## in which R.sub.44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

A "selenoalkyl" refers to an alkyl group having a substituted seleno group attached thereto. Exemplary "selenoethers" which may be substituted on the alkyl are selected from one of --Se-alkyl, --Se-alkenyl, --Se-alkynyl, and --Se--(CH.sub.2).sub.m--R.sub.8, m and R.sub.8 being defined above.

Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

As used herein, the definition of each expression, e.g. alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

The phrase "protecting group" as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2.sup.nd ed.; Wiley: New York, 1991).

Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Further, mixtures of stereoisomers may be resolved using chiral chromatographic means.

Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof, wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in binding to monoamine transporters. In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.

For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986 87, inside cover. Also for purposes of this invention, the term "hydrocarbon" is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted.

Compounds of the Invention

In certain embodiments, a compound of the present invention is represented by A:

##STR00011## wherein

X represents C(R.sub.3).sub.2, O, S, SO, SO.sub.2, NR.sub.2, NC(O)R.sub.7, NC(O)OR.sub.2, NS(O).sub.2R.sub.7, or C.dbd.O;

Z represents C(R.sub.3).sub.2, C(O), O, NR, NC(O)OR, S, SO, or SO.sub.2;

m is 1, 2, 3, 4 or 5;

n is 1 or 2;

p is 0, 1, 2, or 3;

y is 0, 1, or 2;

R represents H, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

R.sub.1 represents H, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

R and R.sub.1 may be connected through a covalent bond;

R.sub.2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;

R.sub.3 represents independently for each occurrence H, alkyl, aryl, OR.sub.2, OC(O)R.sub.2, CH.sub.2OR.sub.2, or CO.sub.2R.sub.2; wherein any two instances of R.sub.3 may be connected by a covalent tether whose backbone consists of 1, 2, 3, or 4 carbon atoms;

R.sub.4 represents independently for each occurrence H, alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, or OR;

R.sub.5 and R.sub.6 are selected independently for each occurrence from the group consisting of H, alkyl, (CH.sub.2).sub.pY, aryl, heteroaryl, F, OR.sub.2, and OC(O)R.sub.2; or an instance of CR.sub.5R.sub.6 taken together is C(O);

R.sub.7 represents alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

R.sub.8 and R.sub.9 are selected independently for each occurrence from the group consisting of H, alkyl, (CH.sub.2).sub.pY, aryl, heteroaryl, F, OR.sub.2, and OC(O)R.sub.2; or an instance of CR.sub.8R.sub.9 taken together is C(O);

Y represents independently for each occurrence OR.sub.2, N(R.sub.2).sub.2, SR.sub.2, S(O)R.sub.2, S(O).sub.2R.sub.2, or P(O)(OR.sub.2).sub.2;

any two instances of R.sub.2 may be connected through a covalent bond;

a covalent bond may connect R.sub.4 and an instance of R.sub.5 or R.sub.6;

any two instances of R.sub.5 and R.sub.6 may be connected through a covalent bond;

any two geminal or vicinal instances of R.sub.8 and R.sub.9 may be connected through a covalent bond; and

the stereochemical configuration at any stereocenter of a compound represented by A is R, S, or a mixture of these configurations.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R.sub.3).sub.2, O, or NR.sub.2.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R.sub.3).sub.2.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein Z is O or NR.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein m is 2 or 3.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein n is 1.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein y is 1.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein R.sub.1 represents aryl.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein R.sub.3 represents independently for each occurrence H or alkyl.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein R.sub.4 represents cycloalkyl, aryl, or heteroaryl.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein R.sub.5 and R.sub.6 are selected independently for each occurrence from the group consisting of H, alkyl, OR.sub.2, aryl, heteroaryl, and F.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein R.sub.8 and R.sub.9 are selected independently for each occurrence from the group consisting of H, alkyl, OR.sub.2, aryl, heteroaryl, and F.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R.sub.3).sub.2, O, or NR.sub.2; and Z is O or NR.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R.sub.3).sub.2, O, or NR.sub.2; Z is O or NR; and m is 2 or 3.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R.sub.3).sub.2, O, or NR.sub.2; Z is O or NR; and n is 1.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R.sub.3).sub.2, O, or NR.sub.2; Z is O or NR; and y is 1.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R.sub.3).sub.2, O, or NR.sub.2; Z is O or NR; m is 2 or 3; n is 1; and y is 1.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R.sub.3).sub.2, O, or NR.sub.2; Z is O or NR; m is 2 or 3; n is 1; y is 1; and R.sub.1 is aryl.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R.sub.3).sub.2, O, or NR.sub.2; Z is O or NR; m is 2 or 3; n is 1; y is 1; R.sub.1 is aryl; and R.sub.3 is H or alkyl.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R.sub.3).sub.2, O, or NR.sub.2; Z is O or NR; m is 2 or 3; n is 1; y is 1; R.sub.1 is aryl; R.sub.3 is H or alkyl; and R.sub.4 is cycloalkyl, aryl, or heteroaryl.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R.sub.3).sub.2, O, or NR.sub.2; Z is O or NR; m is 2 or 3; n is 1; y is 1; R.sub.1 is aryl; R.sub.3 is H or alkyl; R.sub.4 is cycloalkyl, aryl, or heteroaryl; and R.sub.5 and R.sub.6 are selected independently for each occurrence from the group consisting of H, alkyl, OR.sub.2, aryl, heteroaryl, and F.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R.sub.3).sub.2, O, or NR.sub.2; Z is O or NR; m is 2 or 3; n is 1; y is 1; R.sub.1 is aryl; R.sub.3 is H or alkyl; R.sub.4 is cycloalkyl, aryl, or heteroaryl; R.sub.5 and R.sub.6 are selected independently for each occurrence from the group consisting of H, alkyl, OR.sub.2, aryl, heteroaryl, and F; and R.sub.8 and R.sub.9 are selected independently for each occurrence from the group consisting of H, alkyl, OR.sub.2, aryl, heteroaryl, and F.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is CH.sub.2; Z is O; m is 2; n is 1; y is 1; R.sub.1 is 4-trifluoromethylphenyl or 3,4-methylenedioxyphenyl; R.sub.3 is H; R.sub.4 is 4-chlorophenyl; R.sub.5 and R.sub.6 are selected independently for each occurrence from the group consisting of H and alkyl; and R.sub.8 and R.sub.9 are H.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is CH.sub.2; Z is O; m is 3; n is 1; y is 1; R.sub.1 is 4-trifluoromethylphenyl; R.sub.3 is H; R.sub.4 is 4-chlorophenyl; R.sub.5 and R.sub.6 are selected independently for each occurrence from the group consisting of H, OH, and alkyl; and R.sub.8 and R.sub.9 are H.

In assays based on mammalian dopamine, serotonin, or norepinephrine receptors or transporters, certain compounds according to structure A have EC.sub.50 values less than 1 .mu.M, more preferably less than 100 nM, and most preferably less than 10 nM.

In assays based on mammalian dopamine receptors or transporters, certain compounds according to structure A have EC.sub.50 values less than 1 .mu.M, more preferably less than 100 nM, and most preferably less than 10 nM.

In assays based on mammalian dopamine, serotonin, or norepinephrine receptors or transporters, certain compounds according to structure A have IC.sub.50 values less than 1 .mu.M, more preferably less than 100 nM, and most prefera