WO2009020578A1 - Alpha2c adrenoreceptor agonists - Google Patents

Abstract

In its many embodiments, the present invention provides a novel class of compounds of formula I that are useful as inhibitors of alpha2C adrenergic receptor agonists, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more conditions associated with the alpha2C adrenergic receptors using such compounds or pharmaceutical compositions. wherein: J is: Z is -[C(RC)(RC)]X; A is a 5-membered heteroaryl, heterocyclyl or heterocyclenyl ring containing 1- 3 heteroatoms, preferably selected from the group consisting of -O-, -S- and -N-, and is optionally substituted with at least one R5 and/or 1 or 2 (=O) (carbonyl) groups; and the rest of the variables are as specified in claim 1.

Description

ALPHA2C ADRENORECEPTOR AGONISTS

Related Applications

This application claims the benefit of provisional application USSN 60/954,151 , filed August 6, 2007, herein incorporated by reference.

Field of the Invention The present invention relates to compounds useful as α2C adrenergic receptor agonists, methods for making the compounds, pharmaceutical compositions containing the compounds, and methods of treatment and prevention using the compounds and compositions to treat disease states such as congestion (including nasal), migraine, congestive heart failure, cardiac ischemia, glaucoma, pain and psychotic disorders. Background of the Invention

The initial classification of adrenergic receptors into α- and β-families was first described by Ahlquist in 1948 (Ahlquist RP, "A Study of the Adrenergic Receptors," Am. J. Physiol. 153:586-600 (1948)). Functionally, the α-adrenergic receptors were shown to be associated with most of the excitatory functions (vasoconstriction, stimulation of the uterus and pupil dilation), β-adrenergic receptors were implicated in vasodilation, bronchodilation and myocardial stimulation (Lands et al., "Differentiation of Receptor Systems Activated by Sympathomimetic amines," Nature 214:597-598 (1967)). Since this early work, α-adrenergic receptors have been subdivided into α1 - and α2-adrenergic receptors. Cloning and expression of α-adrenergic receptors have confirmed the presence of multiple subtypes of both α1 -(α1 A, α1 B, α1 D) and α2-(α2A, α2B, α2C) adrenergic receptors (Michel et al., "Classification of αi -Adrenoceptor Subtypes," Naunyn-Schmiedeberg's Arch. Pharmacol, 352:1 -10 (1995); Macdonald et al., "Gene Targeting-Homing in on α₂-Adrenoceptor-Subtype Function," TIPS, 18:211 - 219 (1997)). Current therapeutic uses of α-2 adrenergic receptor drugs involve the ability of those drugs to mediate many of the physiological actions of the endogenous catecholamines. There are many drugs that act on these receptors to control hypertension, intraocular pressure, eye reddening and nasal congestion and induce analgesia and anesthesia. α2 adrenergic receptors can be found in the rostral ventrolateral medulla, and are known to respond to the neurotransmitter norepinephrine and the antihypertensive drug clonidine to decrease sympathetic outflow and reduce arterial blood pressure (Bousquet et al., "Role of the Ventral Surface of the Brain Stem in the Hypothesive Action of Clonidine," Eur. J. Pharmacol., 34:151 -156 (1975); Bousquet et al., "Imidazoline Receptors: From Basic Concepts to Recent Developments," 26:S1-S6 (1995)). Clonidine and other imidazolines also bind to imidazoline receptors (formerly called imidazoline-guanidinium receptive sites or IGRS) (Bousquet et al., "Imidazoline Receptors: From Basic Concepts to Recent Developments," 26:S1-S6 (1995)). Some researchers have speculated that the central and peripheral effects of imidazolines as hypotensive agents may be related to imidazoline receptors (Bousquet et al., "Imidazoline Receptors: From Basic Concepts to Recent Developments," 26:S1-S6

(1995); Reis et al., "The Imidazoline Receptor: Pharmacology, Functions, Ligands, and Relevance to Biology and Medicine," Ann. N.Y. Acad. Sci., 763:1 -703 (1995).

Compounds having adrenergic activity are well-known in the art, and are described in numerous patents and scientific publications It is generally known that adrenergic activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having an adrenergic compound or compounds as the active ingredient are useful for treating, among other things, glaucoma, chronic pain, migraines, heart failure, and psychotic disorders (e.g., schizophrenia).

For example, published PCT application WO 02/076950 discloses compounds having α2 agonist activity of the following general formula:

Other publications disclosing similar compounds includes WO 01/00586, WO 99/28300, US 6,841 ,684 B2 and US 2003/0023098 A1.

Another class of compounds having α2-agonist properties is disclosed in U.S. Patent No. 5,658,938, and has the following general formula:

wherein n=1 -2, R¹-R³ represent hydrogen, halogen hydroxy, alkyl or alkoxy, and R⁵ is hydrogen or alkyl.

Another class of compounds reported to have affinity for α2 receptors includes the following two compounds (Bagley et.al., Med. Chem. Res. 1994, 4:346-364):

It is also known that compounds having adrenergic activity, such as α2A agonists, may be associated with undesirable side effects. Examples of such side effects include hyper-and hypotension, sedation, locomotor activity, psychotic disorders (e.g., schizophrenia).

Another class of compounds reported to have affinity for α2 receptors includes the following two compounds (Miller et.al., J. Med. Chem. 1994, 37:2328-2333; J. Med. Chem. 1996, 39:3001 -3013; J. Med. Chem. 1997, 37:3014-3024):

Another class of indane and tetrahyrdonaphthalene type compounds having α2- agonist properties is disclosed in PCT application WO 97/12874 and WO20040506356 This class has the following general formula:

wherein n = 0-1 , X is 1 or 2 carbon units, R₄ is H, OH, alkyl, or alkoxy, R₅ may be taken together with R⁴ to form a carbonyl, and R⁶-R⁸ = H, OH, SH, alkyl, alkenyl, cycloalkyl, alkoxy, hydroxyalkyl, alkylthio, alkylthiol, halo, CF₃, NO₂, or alkylamino. This class specifically includes MPV-2426 (fadolmidine) and its prodrug esters:

wherein R is optionally substituted lower alkyl, aryl, cycloalkyl, heteroaryl, lower alkylamino, and saturated 5- or 6-membered heterocyclic groups containing 1 or 2 N atoms. Further, other classes of compounds that exhibit activity functional selectivity for the alpha-2C receptor have been discovered. Application USSN 11/508,458, filed August 23, 2006, discloses indoline compounds that possess this activity and application USSN 11/508,467, filed on the same date, describes morpholine compounds that are active or functionally selective of the alpha-2C receptor. CIP applications of these applications have been filed; the Ser. Nos. are 11/705,673 and 11/705,683, both filed on February 13, 2007.

Additional applications which have been filed that disclose alpha2C receptor agonists are application USSN , which claims priority to provisional application

USSN 60/901 ,045, (AL06619), application USSN , which claims priority to provisional applications USSN 60/901 ,071 and 60/972,892, (AL06620) and application

USSN , which claims priority to provisional application USSN 60/901 ,064,

(AL06621 ).

U.S. Patent 6,673,337 describes and claims an ophthalmic composition comprising an alpha-2C agonist component and a solubility enhancing component other than cyclodextrin.

It has been discovered in accordance with the present invention that adrenergic compounds that act as agonists of the α2C receptor subtypes possess desirable therapeutic properties.

There is a need for new compounds, formulations, treatments and therapies to treat diseases and disorders associated with α2C adrenergic receptor. It is, therefore, an object of this invention to provide compounds useful in the treatment or prevention or amelioration of such diseases and disorders associated with the α2C adrenergic receptor. Summary of the Invention

In its many embodiments, the present invention provides a novel class of heterocyclic compounds that function as α2C adrenergic receptor agonists, or metabolites, stereoisomers, salts, solvates or polymorphs thereof, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more conditions associated with α2C receptors using such compounds or pharmaceutical compositions.

In one aspect, the present application discloses a compound, or pharmaceutically acceptable salts or metabolites, solvates, prodrugs or polymorphs of said compound, said compound having the general structure shown in Formula I

wherein:

J is :

Z is -[C(R^C)(R^C)]_X- ;

A is a 5-membered heteroaryl, heterocyclyl or heterocyclenyl ring containing 1 - 3 heteroatoms, preferably selected from the group consisting of -O-, -S- and -N-, and is optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) R⁵ and/or 1 or 2 (=0) (carbonyl) groups;

X is -O- , -S(O)p- , or -N(R²);

R¹ is selected from the group consisting of H, -CN, -[C(R^a)(R^b)]_qYR^7>, -[C(R^a)(R^b)]_qN(R⁶)YR^7' , or -[C(R^a)(R^b)]_qOYR^7' , and -[C(R^a)(R^b)]_qON=CR⁷R^7';

Y is selected from the group consisting of a bond, -C(=O)-, -C(=O)NR⁷-, -C(=O)O-, -C(=O)-[C(R^a)(R^b)]_n-O-C(=O)-, -C(=O)N(R^C)-O-, -C(=NR⁷)-, -C(=NOR⁷)-, - C(=NR⁷)NR⁷-, -C(=NR⁷)N(R^C)O-, -S(O)_P-, -SO₂NR⁷-, and -C(=S)NR⁷-; wherein R^a and R^b are independently selected from the group consisting of H, alkyl, alkoxy, and halo, and R^c is H or alkyl;

R² is independently selected from the group consisting of H and alkyl; R³ is independently selected from the group consisting of H, halo, and (=O), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) R⁵, provided that when w is 3, no more than 2 of the R³ groups may be (=O);

R⁴ is independently selected from the group consisting of H, halo, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) R⁵;

R⁵ is independently selected from the group consisting of H, halo, -OH, -CN, -NO₂, -NR⁷R⁷ , and -S(O)_PR⁷, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) of halo, -OH, -CN, -NO₂, -NR⁷R^7', and - S(O)_PR⁷ substituents and/or 1 or 2 (=0); R⁶ is H;

R⁷ is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted one or more times (preferably 1 to 5, more preferably 1 to 3) by R¹²;

R⁷ is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted one or more times (preferably 1 to 5, more preferably 1 to 3) by R¹²; or a) when a variable is -NR⁷R^7', -[C(R^a)(R^b)]_qYR^7', -C(R^a)(R^b)]_qNR⁷R^7', - [C(R^a)(R^b)]_qOYR⁷V -(CH₂)_qNR⁷R^7', -C(O)NR⁷R^7' Or -SO₂NR⁷R^7', R⁷ and R^7' together with the nitrogen atom to which they are attached independently form a 3- to 8-membered heterocyclyl, heterocyclenyl or heteroaryl ring having, in addition to the N atom, 1 or 2 additional hetero atoms independently selected from the group consisting of O, N, -N(R⁹)- and S, wherein said rings are optionally substituted by 1 to 5 independently selected R⁵ moieties and/or 1 or

2 (=0), or b) when a variable is -(CH₂)_qON=CR⁷R^7' or -[C(R^a)(R^b)]_qON=CR⁷R^7', R⁷ and R⁷ together with the carbon atom to which they are attached independently form a 3- to 8-membered cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl or heteroaryl ring, wherein said hetroacyclyl, heterocyclenyl or heteroaryl rings have 1 -3 heteroatoms which are independently selected from the group consisting of O, N, -N(R⁹)- and S, wherein said rings are optionally substituted by 1 to 5 independently selected R⁵ moieties and/or 1 or 2 (=0); R⁹ is independently selected from the group consisting of H, -C(O)-R¹⁰, -C(O)- OR¹⁰, and -S(O)_P-OR¹⁰ and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) of halo, -OH, -CN, -NO₂, -N(R¹¹)_2> and -S(O)_pR¹¹substituents and/or 1 or 2 (=0);

R¹⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) of halo, -OH, - CN, -NO₂, -N(R¹¹)_2> and -S(O)_PR¹¹ substituents and/or 1 or 2 (=0);

R¹¹ is a moiety independently selected from the group consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each of which is optionally substituted by at least one (preferably 1 to 5, more preferably 1 to 3) substituent independently selected from the group consisting of halo, -OH, -CN, -NO₂, -N(R¹¹ J₂, and -S(O)_PR¹¹ substituents and/or 1 or 2 (=0);

R¹¹ is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R¹² is independently selected from the group consisting of H, halo, -OH, -CN, -NO₂, -N(R¹¹)₂ , and -S(O)_PR¹¹, and/or 1 or 2 (=0), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl, heterocyclenyl, heterocyclenyloxy, heterocyclylalkyl, heterocyclenylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, and heterocyclenylalkoxy groups, each of which in turn is optionally substituted by at least once (preferably 1 to 5, more preferably 1 to 3) by a substituent selected from the group consisting of H, alkyl, haloalkyl, halo, -OH, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy, optionally substituted heterocyclenyloxy, -CN, -NO₂, -N(R¹¹)₂, and -S(O)_PR¹¹ and/or 1 or 2 (=O), wherein said optionally substituted alkoxy, aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy, and heterocyclenyloxy when substituted are substituted one or more (preferably 1 to 5, more preferably 1 to 3) times by R¹¹; n is O, 1 or 2; w is O, 1 , 2, 3, or 4; p is independently 0, 1 or 2; q is independently and integer from 0-10; and x is 1 , 2, or 3.

The compounds of Formula I can be useful as α2C adrenergic receptor agonists, which can be useful in the treatment and prevention of allergic rhinitis, congestion (including, but not limited to nasal congestion), migraine, congestive heart failure, cardiac ischemia, glaucoma, stress-induced urinary incontence, neuronal damage from ischemia, attention deficit disorder (ADD) and psychotic disorders (e.g., schizophrenia). Further, the compounds of Formula I can be useful in the treatment of pain (both chronic and acute), such as pain that is caused by inflammation, neuropathy, arthritis (including osteo and rheumatoid arthritis), diabetes (e.g., diabetes mellitus or diabetes insipidus) or pain of an unknown origin. Examples of neuropathic pain may include but not limited to; diabetic neuropathy, neuralgia of any etiology (e.g. post-herpetic, trigeminal), chemotherapy-induced neuropathy, HIV, lower back pain of neuropathic origin (e.g. sciatica), traumatic peripheral nerve injury of any etiology, central pain (e.g. post-stroke, thalamic, spinal nerve injury). Other pain that can be treated is nociceptive pain and pain that is visceral in origin or pain that is secondary to inflammation or nerve damage in other diseases or diseases of unknown origin. Detailed Description

In an embodiment, the present invention discloses certain heterocyclic compounds which are represented by structural Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein the various moieties are as described above.

In another embodiment A is unsubstituted imidazole.

In another embodiment, n is 1.

In another embodiment, p is 0-2.

In another embodiment, q is 0-3.

In another embodiment, the present invention discloses compounds which are represented by structural formulae II, III, or IV or a pharmaceutically acceptable salt, solvate or ester thereof,

Formula Il Formula or

Formula IV

wherein the individual variables are defined above.

An embodiment of compounds of formulae Il and III are those wherein: A is

X is -O-;

R¹ is H or -(CH₂)_qNH(Y)R⁷;

Y is a bond, -C(=O)O- or -C(=O)NR⁷; and n is 1.

As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

"Patient" includes both human and animals. "Mammal" means humans and other mammalian animals.

"Congestion" refers to all type of congestion including, but not limited to, congestion associated with perennial allergic rhinitis, seasonal allergic rhinitis, non- allergic rhinitis, vasomotor rhinitis, rhinitis medicamentosa, sinusitis, acute rhinosinusitis, or chronic rhinosinusitis or when the congestion is caused by polyps or is associated with the common cold.

"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. The term "substituted alkyl" means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)₂₎ carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.

"Aryl" means an aromatic monocyclic or multicyclic ring system, in which at least one of the multicyclic rings is an aryl ring, comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. Non-limiting examples of aryl multicyclic ring systems include:

"Heteroaryl" means an aromatic monocyclic or multicyclic ring system, in which at least one of the multicyclic rings is aromatic, comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1 -b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazolyl and the like.

Non-limiting examples of hetreroaryl multicyclic ring systems include:

"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.

"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.

"Halogen" and "Halo" mean fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine. "Ring system substituent" means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, Y₁Y₂N-, YiY₂N-alkyl-, YiY₂NC(O)- and YiY₂NSO₂-, wherein Yi and Y₂ may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl.

"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protected moieties are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S₁S- dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like.

Compounds of Formula I and salts, esters, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. Non- limiting examples of tautomeric forms that are part of this invention are as follows:

It should be noted that in saturated heterocyclyl containing systems of this invention, there are no hydroxyl, amino, or thiol groups on carbon atoms adjacent to a N, O or S atom. Thus, for example, in the ring:

there is no -OH attached directly to carbons marked 2 and 5. It should also be noted that this definition does not preclude (=O), (=S), or (=N) substitutions, or their tautomeric forms, on C atoms adjacent to a N, O or S. Thus, for example, in the above ring, (=O) substitution on carbon 5, or its imino ether tautomer is allowed. Non-limiting examples which illustrate the present invention are as follows:

The following non-limiting examples serve to illustrate radicals not contemplated by the present invention:

"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.

"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

"Heterocyclylalkyl" means a heterocyclyl-alkyl group in which the heterocyclyl and the alkyl are as previously described. Preferred heterocyclylalkyls contain a lower alkyl group. Non-limiting examples of suitable heterocyclylalkyl groups include piperidylmethyl, piperidylethyl, pyrrolidylmethyl, morpholinylpropyl, piperazinylethyl, azindylmethyl, azetidylethyl, oxiranylpropyl and the like. The bond to the parent moiety is through the alkyl group. "Heterocyclenyl" (or "heterocycloalkeneyl") means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon- nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1 ,2,3,4- tetrahydropyridyl, 1 ,2-dihydropyridyl, 1 ,4-dihydropyridyl, 1 ,2,3,6- tetrahydropyridyl, 1 ,4,5,6-tetrahydropyrimidyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 2-oxazolinyl, 2-thiazolinyl, and the like. Non-limiting examples of suitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. Non-limiting example of a suitable multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitable monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.

"Heterocyclenylalkyl" means a heterocyclenyl-alkyl group in which the heterocyclenyl and the alkyl are as previously described.

"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Acyl" means an organic acid group in which the -OH of the carboxyl group is replaced by some other substituent. Suitable non-limiting examples include H-C(O)-, alkyl-C(O)- , cycloalkyl-C(O)-, heterocyclyl-C(O)-, and heteroaryl-C(O)- groups in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.

"Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1 -naphthoyl.

"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.

"Aralkyloxy" or "arylalkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1 - or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.

"Heteroarylalkoxy" means a heteroarylalkyl-O-group in which the heteroarylalkyl group is as previously described.

"Heterocyclylalkoxy" means a heterocyclylalkyl-0 group in which the hetrocyclylalkyl group is as previously described.

"Heterocyclenylalkoxy" means a heterocyclenylalkyl-0 group in which the heterocyclenylalkyl group is as previously described.

"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.

"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.

"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.

"Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl. "Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Alkylsulfonyl" means an alkyl-S(O₂)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl. "Arylsulfonyl" means an aryl-S(O₂)- group. The bond to the parent moiety is through the sulfonyl.

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. It is noted that carbons of Formula I can be replaced with 1-3 silicon atoms, provided all valency requirements are satisfied.

The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

The straight line as a bond generally indicates a mixture of, or either of, the possible isomers, non-limiting example(s) include, containing (R)- and (S)- stereochemistry. For example,

means containing both and

A dashed line ( ) represents an optional bond.

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of the substitutable ring atoms, non-limiting examples include carbon, nitrogen and sulfur ring atoms.

As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:

It should also be noted that any heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the hydrogen atom to satisfy the valences.

When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more than one time in any constituent or formula, its definition on each occurrence is independent of its definition at every other occurrence. Unless defined otherwise, all definitions for the variables follow the convention that the group to the right forms the point of attachement to the molecule; i.e., if a definition is arylalkyl, this means that the alkyl portion of the definition is attached to the molecule.

Further, all divalent variable are attached from left to right. For example when R¹ is -(CH₂)_qN(R⁶)YR^7', and Y is -C(=O)NR⁷-, then R¹ forms the group -(CH₂)_qN(R⁶) - C(=O)N(R⁷)(R⁷) .

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto. For example, if a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C₈)alkyl, (C₂- Ci₂)alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl-1 -(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1 -(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl), carbamoyl-^ -C₂)alkyl, N,N-di (Ci-C₂)alkylcarbamoyl-(C1 - C2)alkyl and piperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of of Formula I contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (CrC₆)alkanoyloxymethyl, 1 -((Ci- C₆)alkanoyloxy)ethyl, 1 -methyl-1 -((Ci-C₆)alkanoyloxy)ethyl, (Ci- C-₆)alkoxycarbonyloxymethyl, N-(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (Cr C₆)alkanoyl, α-amino(CrC₄)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α- aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, -P(O)(OH)₂, -P(O)(O(Ci -C₆)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.

If a compound of of Formula I incorporates -NH- functional group, such as in a primary or secondary amine or in a nitrogen-containing heterocycle, such as imidazole or piperazine ring, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (Ci-Ci_O)alkyl, (C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, -C(OH)C(O)OY¹ wherein Y¹ is H, (C_rC₆)alkyl or benzyl, -C(OY²) Y³ wherein Y² is (Ci-C₄) alkyl and Y³ is (Ci-Cβ)alkyl, carboxy (Ci-Cβ)alkyl, amino(Ci-C₄)alkyl or mono-N- or di-N, N-(Ci- C₆)alkylaminoalkyl, -C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵ is mono-N- or di-N, N- (CrCβJalkylamino morpholino, piperidin-1 -yl or pyrrolidin-1 -yl, and the like.

One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of illustrative solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H₂O. One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical ScL, 93(3), 601 -611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001 ). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

Metabolic conjugates, such as glucuronides and sulfates which can undergo reversible conversion to the compounds of of Formula I are contemplated in the present invention. "Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect.

The terms "purified", "in purified form" or "in isolated and purified form," as used herein, for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

"Capsule" is meant to describe a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.

"Tablet" is meant to describe a compressed or molded solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.

"Oral gels" is meant to describe to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix. "Powders for constitution" refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.

"Diluent" refers to substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%. "Disintegrants" refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include starches; "cold water soluble" modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.

"Binders" refers to substances that bind or "glue" powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.

"Lubricant" is meant to describe a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.

"Glidents" means materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.

"Coloring agents" refers to excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.

"Bioavailability" refers to the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control. Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of granulation produced by compaction, or wet methods or other special procedures. Conventional methods for making other forms for administration such as, for example, capsules, suppositories and the like are also well known.

The compounds of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwittehons ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of Formula I or may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by S. Berge era/, Journal of Pharmaceutical Sciences (1977) 66(1 ) 1 -19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons or sulfurs on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. For example, if a compound of Formula I incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate" "prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds. Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formulae Ia or Ib may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. Polymorphic forms of the compounds of Formula I, and of the salts, solvates and prodrugs of the compounds of Formula I, are intended to be included in the present invention

The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F₁ and ³⁶CI, respectively. Certain isotopically-labelled compounds of Formula I (e.g., those labeled with

³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, lsotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

The compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be useful as α2C adrenoreceptor agonists. A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of the compound of Formula I. An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound.

The compounds of this invention may also be useful in combination (administered together or sequentially) with one or more therapeutic agents such as, for example, glucocorticosteroids, PDE-4 inhibitors, anti-muscarinic agents, cromolyn sodium, H₁ receptor antagonists, 5-HTi agonists, NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin Il receptor agonists, β-blockers, β-agonists (including both long and short acting), leukotriene antagonists, diuretics, aldosterone antagonists, ionotropic agents, natriuretic peptides, pain management/analgesic agents, anti-anxiety agents, anti-migraine agents, and therapeutic agents suitable for treating heart conditions, psychotic disorders, and glaucoma. Suitable steroids include prednisolone, fluticasone (including all ester such as the propionate or furcate esters), triamcinolone, beclomethasone, mometasone (including any ester form such as mometasone furoate), budasamine, ciclesonide betamethasone, dexamethasone, prednisone, flunisolide, and cortisone.

Suitable PDE-4 inhibitors include roflumilast, theophylline, rolipram, piclamilast, cilomilast and CDP-840.

Suitable antiimuscarinic agents include ipratropium bromide and tiatropium bromide.

Suitable Hi antagonists include astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratidine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizeine, fexofenadine, hydroxyzine, ketotifen, loratidine, levocabastine, meclizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or thprolidine.

Suitable anti-inflammatory agents include aspirin, diclofenac, diflunisal, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, and tolmetin.

Suitable aldosterone antagonists include spironolactone. Suitable ionotropic agents include digitalis. Suitable angiotensin Il receptor agonists include irbesartan and losartan.

Suitable diuretics include spironolactone, methyclothiazide, bumetanide, torsemide, hydroflumethiazide, trichlormethiazide, hydroclorothiazide, triamterene, ethacrynic acid, methyclothiazide, hydrochlorothiazide, benzthiazide, hydrochlorothiazide, quinethazone, hydrochlorothiazide, chlorthalidone, furosemide, indapamide, hydroclorothiazide, triamterene, trichlormethiazide, hydrochlorothiazide, amiloride HCI, amiloride HCI, metolazone, trichlormethiazide, bendroflumethiazide, hydrochlorothiazide, polythiazide, hydroflumethiazide, chlorthalidone, and metolazone.

Suitable pain management/analgesic agents include Celecoxib, amitriptyline, ibuprofen, naproxen, gabapentin, tramadol, rofecoxib, oxycodone HCI, acetaminophenoxycodone HCI, carbamazepine, amitriptyline, diclofenac, diclofenac, etodolac, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac tromethamine, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin sodium, valdecoxib, diclofenac/ misoprostol, oxycontin, vicodin, darvocet, percocet, morphine sulfate, dilaudid, stadol, stadol NS, acetaminophen with codeine, acetaminophen with codeine #4, Lidoderm^® patches, ziconotide, duloxetine, roboxetine, gabapentin and pregabalin.

Suitable β-blockers include acebutolol, atenolol, atenolol/chlorthalidone, betaxolol, bisoprolol fumarate, bisoprolol/HCTZ, labetolol, metoprolol tartrate, nadolol, pindolol, propranolol, propranolol/HCTZ, sotalol, and timolol. Suitable β-agonists include dobutamine, ritodrine, salbutamol, levalbuterol, metaprotemol, formoterol, fenoterol, bambuterol, brocaterol, clenbuterol, terbutaline, tulobuterol, epinephrine, isoprenalin, and hexoprenalin.

Suitable leucotriene antagonists include levamisole.

Suitable anti-migraine agents include rovatriptan succinate, naratriptan HCI, rizatriptan benzoate, sumatriptan succinate, zolmitriptan, almothptan malate, methysergide maleate, dihydroergotamine mesylate, ergotamine tartrate, ergotamine tartrate/caffeine, Fioricet^®, Fiorninal^®, Depakene^®, and Depakote^®.

Suitable anti-anxiety and anti-depressant agents include amitriptyline HCI, bupropion HCI, citalopram hydrobromide, clomipramine HCI, desipramine, fluoxetine, fluvoxamine maleate, maprotiline HCI, mirtazapine, nefazodone HCI, nortriptyline, paroxetine HCI, protriptyline HCI, sertraline HCI, doxepin, and trimipramine maleate. Suitable angiotensin converting enzyme inhibitors include Captopril, enalapril, enalapril/HCTZ , lisinopril, lisinopril/HCTZ, and Aceon^®.

The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The exemplified pharmacological assays which are described later have been carried out with the compounds according to the invention and their salts. This invention is also directed to pharmaceutical compositions which comprise at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18^th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.

Liquid form preparations include solutions, suspensions and emulsions. When preparing a liquid preparation, the inclusion of one or more solubility enhancing components is excluded. Solubility enhancing components are described, for example, in U.S. 6,673,337 in colume 2, line 50 to column 3, line 17 and in column 6, line 49 to column 8, line 31 ; US 6,673,337 is expressly incorporated herein by reference. Specific solubility enhancing agents that are excluded in the liquid form preparations include metal carboxymethyl celluloses, metal carboxymethylhydroxy- ethyl celloses, hydroxypropylmethyl celluloses derivative of these compounds, and cyclodextrins. Examples of liquid form preparations include water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions or suspensions for intranasal administration.

An aspect of this invention is that the pharmaceutical composition is in a solid dosage form comprising a compound of Formula I or a pharmaceutical acceptable salt, ester, solvate or prodrug thereof and a least one pharmaceutically acceptable carrier, adjuvant or vehicle.

Another aspect of this invention is a liquid, aqueous pharmaceutical composition is comprising a compound of Formula I or a pharmaceutical acceptable salt, ester, solvate or prodrug thereof and a least one pharmaceutically acceptable carrier, adjuvant or vehicle provided that the adjuvant is not a solubility enhancing component, such as those described in US 6,673,337 (discussed above).

Another aspect of this invention is a liquid, aqueous pharmaceutical composition is comprising a compound of Formula I or a pharmaceutical acceptable salt, ester, solvate or prodrug thereof and a least one pharmaceutically acceptable carrier, adjuvant or vehicle wherein if a solubility enhancement component is present it is cyclodextrin.

Another aspect of this invention is a pharmaceutical formulation that is a nasal spray wherein the pH is equal to or less that about 6.5, more preferably between about 6.1 to 6.2. Another aspect of this invention the formulation is a nasal spray wherein the adjuvants include a suspending agent (e.g., AVICEL (such as AVICIL RC-581 , RC- 591 and CL-611), which are microcrystalline cellulose and carboxymethylcellulose sodium; hydroxypropylmethyl cellulose; methyl cellulose; polyvinyl alcohol; or CARBOPOL) and a humectant (e.g., glycerin, propylene glycol; polyethylene glycol; povidone; or dextrose).

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses. Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and an amount of at least one therapeutic agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect. Yet another aspect of this invention is the compound of Formula I or its pharmaceutically acceptable salt, ester, prodrug or ester in its isolated and purified form.

In general, the compounds in the invention may be produced by a variety of processes know to those skilled in the art and by know processes analogous thereto. The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art. The practitioner is not limited to these methods. One skilled in the art will recognize that one route will be optimized depending on the choice of appendage substituents. Additionally, one skilled in the art will recognize that in some cases the order of steps has to be controlled to avoid functional group incompatability.

The prepared compounds may be anyalyzed for their composition and purity as well as characterized by standard analytical techniques such as, for example, elemental anyalysis, NMR, mass spectroscopy and IR spectra.

One skilled in the art will recognize that reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective equivalents. Hence, when a specific solvent or reagent is mentioned, it is meant to be an illustrative example of the conditions desirable for that particular reaction scheme and in the preparations and examples described below.

Where NMR data are presented, ¹ H spectra were obtained on either a Varian

VXR-400 (400 MHz, ¹ H), Varian Gemini-300 (300 MHz), Varian Mercury VX-400

(400MHz), or Bruker-Biospin AV-500 (500MHz), and chemical shifts are reported as ppm with number of protons and multiplicities indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Applied Biosystems API-100 mass spectrometer and C18 column, 10-95% CH₃CN-H₂O (with 0.05% TFA) gradient.

The observed parent ion is given.

The following solvents and reagents may be referred to by their abbreviations in parenthesis:

Me = methyl; Et = ethyl; Pr = propyl; Bu = butyl; Ph = phenyl, and Ac = acetyl μl = microliters

AcOEt or EtOAc = ethyl acetate AcOH or HOAc = acetic acid

ACN = acetonitrile atm = atmosphere

BINAP = 2,2'-bis(diphenylphosphino)-1 ,1'-bisnaphthyl CAT = catalyst

DEAD = diethylazodicarboxylate

DCM or CH₂CI₂: dichloromethane:

DIPEA = diisopropylethylamine

DMF = dimethylformamide DMS = dimethylsulfide

DMSO = dimethyl sulfoxide g = grams h = hour

LCMS = liquid chromatography mass spectrometry min = minute mg = milligrams ml_ = milliliters mmol = millimoles

MeOH: methanol MS = mass spectrometry

NBS = n-bromosuccimide

NMR = nuclear magnetic resonance spectroscopy

Pyr = pyridine

RT or rt = room temperature (ambient, about 25^QC). TBSCI = t-butyldimethylsilyl chloride

TBS = t-butyldimethyl silyl

TEA or Et₃N = triethylamine

TFA = trifluoroacetic acid

THF = tetrahydrofuran TLC = thin layer chromatography

TMS = trimethylsilyl

Tos or tosyl = p-toluenesulfonyl

ToI = toluene

Tr = triphenylmethyl EXAMPLES

The compounds of this invention can be prepared through the general approach outlined in the schemes provided below. These schemes are being provided to illustrate the present invention. While group A is exemplified as an imidazole, other optionally substituted heteroaryl, heterocyclyl and heterocyclenyl rings containing one to three heteroatoms may be used in place of imidazole.

The starting materials and reagents used in preparing compounds described are either available from commercial suppliers such as Aldrich Chemical Co. (Wisconsin, USA) and Acros Organics Co. (New Jersey, USA) or were prepared by literature methods known to those skilled in the art.

These examples are being provided to further illustrate the present invention. They are for illustrative purposes only; the scope of the invention is not to be considered limited in any way thereby.

General Synthetic Schemes

The alkenyl imine intermediate G10 can be prepared using the synthetic sequence illustrated in Scheme 1. 3-Methoxythiophene is acylated via Friedel-crafts reaction to provide the dimethoxy ketone compound G2. After demethylation with boron tribromide, the resulting diol G3 is cyclized under the standard Mitsunobu condition to form the cyclized ketone compound G4. This ketone intermediate can be further transformed, after sodium borohydride reduction, protection with TBSCI, and bromination using NBS, to a thienyl bromide G7. Treatment of the thienyl bromide G7 with the Buchwald amination protocol would give the imine-silyl ether intermediate G8. By refluxing G8 in benzene with triphenylphosphine hydrogen bromide, the required phosphine salt G9 is generated. The phosphine salt G9 can be elaborated into the desired alkenyl imine G10 via Wittig reaction. Scheme-1 : Synthesis of Intermediates

a) MeOCH₂CH₂COOH, (CIC=O)₂, CH₂CI₂, DMF (cat); AICI₃, 3-methoxythiophene; b) BBr₃, CH₂CI₂; c) Ph₃P, DEAD, THF; d) NaBH₄, MeOH; e) TBSCI, imidazole, CH₂CI₂; f) NBS, CH₂CI₂; g) Ph₂C=NH, Pd(OAc) ₂, BINAP, Cs₂CO₃, ToI; h) Ph₃P-HBr, benzene J) PhLi₁ THF; 1 -Trityl-4- imidazoleformaldehyde.

Compounds of Formula I can be prepared from the intermediate G10 via the synthetic pathway outlined in Scheme 2. The imine protection is removed using aqueous hydrogen chloride in THF to reveal the amine product G11 , which is to react in situ with a variety of electrophiles such as chloroformate to generate carbamate G12; or isocyanate to form urea G13; or acid chloride to form amide G14, and or sulfonyl chloride to yield sulfonamide G15. Removal of the trityl protection on the imidazole ring furnishes the alkenyl type of Formula I (e.g., compounds of Formula III). The intermediates, G12 - 15, may be alkylated with appropriate halides to install the R^b group when needed. Intermediates G12-15 can be converted to the compounds of Formula I, where J is an alkylene group (e.g., compounds of Formula II) by hydrogenation followed by removal of the trityl protecting group. Scheme-2: Modification of Intermediate G10 to form Urea, Amide, and Sulfonamide Derivatives

j) HCI, THF; k) ROCOCI, Pyr; I) RNCO, pyr; m) RCOCI, pyr; n) RSO₂CI, pyr; o) R^bX, Cs₂CO₃, acetone, heat; Pd mediated hydrogenation; TFA, Et₃SiH. R and R^b are independently any of the variable defined in R⁷.

3-Methoxythiophene G1 can also be converted to dimethoxy ketone intermediate G17 via Friedel-Crafts reaction when a longer chain methoxy-alkyl acid is used (Scheme 3). Upon a further two-step transformation, BBr₃ mediated demethylation and intramolecular Mitsunobu cyclization, cyclic ketone G19 could be obtained. Following the synthetic sequences outlined in both Scheme 1 and Scheme 2, compounds of Formula I, where n>1 , could be prepared from G19.

Scheme-3: Preparation of I (n>1)

(n >1) m) MeOCH₂(CH₂) _nCOOH, (CIC=O) ₂, CH₂CI₂, DMF (cat); AICI₃, 3-methoxythiophene; b) BBr₃, CH₂CI₂; c) Ph₃P, DEAD, THF;

Preparative Example 1 :

Step A

To a stirred solution of 3-methoxypropionic acid (7 ml_, 74.50 mmol) in 150 ml_ of anhydrous CH₂CI₂ at room temperature was added oxalyl chloride (6.5 ml_, 74.50 mmol) dropwise. A catalytic amount of Λ/,Λ/-dimethylformamide (0.1 ml_) was added.

After 1.5h, the mixture was cooled in an ice bath, added with 3-methoxythiophene 11

(5 ml_, 50.0 mmol). Anhydrous aluminum chloride (6.67 g, 50.02 mmol) was added.

Reaction was continued at 0⁰C for 1 h, and at room temperature for 3.5 h. The mixture was poured into 300 ml_ of ice / water with stirring. The two layers were separated, and the aqueous layer was extracted with CH₂CI₂ (100 ml_ x 3). The combined organic extracts were washed with H₂O (150 ml_), a sat. NaHCO₃ aqueous solution (150 mL), H₂O (150 ml_), and brine (150 ml_). The organic solution was dried over Na₂SO₄, filtered through a 1 -in silica gel pad, rinsing with excess of CH₂CI₂, then 100 mL of CH₂CI₂-MeOH (100:1 , v/v). The filtrates were concentrated in vacuo to a dark solid, which was purified by column chromatography, eluting with CH₂CI₂ and CH₂CI₂-MeOH (150:1 , v/v). Removal of solvents afforded 5.81 g of dimethoxy ether 12 (58%, MH⁺ = 201.2) as a creamy yellow solid.

Step B Dimethoxy ether I2 (4.06 g, 20.28 mmol) available from step A above was dissolved in 150 mL of CH₂CI₂, and cooled in a -78°C bath. A 1.0 M solution of boron tribromide in CH₂CI₂ (48 mL, 48.0 mmol) was added dropwise. The reaction mixture was stirred over night (15 h) while temperature was increased to room temperature. H₂O (150 mL) was added, stirring was continued for 15 min. The two layers were separated, the aqueous layer was extracted with CH₂CI₂ (100 mL x 2), and the combined organic extracts were washed with brine (100 mL x 2). The organic solution was dried over Na₂SO₄, filtered through a celite pad. The filtrate was concentrated in vacuo to give 3.48 g of diol I3 (100%, MH⁺ = 172.89) as a dark brown oil.

Step C

Triphenyl phosphine (6.10 g, 23.28 mmol) was added to a stirred solution of diethylazodicarboxylate (3.7 mL, 23.50 mmol) in 100 mL of THF at 0⁰C. After 30 min, this solution was taken up in a syringe, and added dropwise to a stirred solution of diol I3 (3.48 g, 20.24 mmol), prepared from step B above, in 100 mL of THF at 0⁰C. Reaction was continued for 1 h. The mixture was concentrated in vacuo to remove the volatiles. The dark brown oily residue (mixed with solids) was dissolved in 50 mL of CH₂CI₂, filtered through a 1 -in silica gel pad, rinsing with CH₂CI₂ (50 mL, 25 mL). The filtrate was concentrated in vacuo to an oil, purified by column chromatography eluting with CH₂CI₂. Removal of solvent afforded 2.43 g of dihydropyranone 14 (78%, MH⁺ = 154.99) as a light yellow oil, solidified on standing. Step D

The dihydropyranone 14 (2.43 g, 15.76 mmol) prepared from step C above was dissolved in 100 ml_ of methanol. Sodium borohydride (0.9 g, 23.78 mmol) was added. The mixture was stirred for 1 h at room temperature. H₂O (50 mL ) was added. Stirring was continued for 15 min, and the mixture was concentrated in vacuo to remove methanol. The aqueous residue was extracted with CH₂CI₂ (50 mL x 3). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to give 2.38 g of alcohol I5 (97%, [MH-H2O]⁺ = 138.99 ) as a near colorless solid.

Step E

Alcohol 15 (0.92 g, 5.89 mmol), available from Step D above, was dissolved in 11 mL of anhydrous benzene at room temperature. Solid triphenylphosphine hydrobromide (2.02 g, 5.89 mmol) was added. The resulting mixture was heated at reflux for 24 h. After cooling, the mixture was diluted with 30 mL of diethyl ether, and filtered through a sintered funnel. The solids were washed successively with diethyl ether (30 mL), acetone (20 mL), and diethyl ether (20 mL), then dried, yielding 2.64 g of the phosphine salt I6 (93%, [M-Br]⁺ = 401.07) as a beige color solid.

Step F

The phosphine salt I6 (0.76 g, 1.57 mmol) from Step E above was suspended in 15 mL of anhydrous THF and cooled in a -78°C bath. A 1.8 M solution of phenyl lithium in dibutyl ether (0.87 mL, 1.57 mmol) was added dropwise. After 30 min, temperature of the cooling bath was increased to -10⁰C. Solid 1 -trityl-4-imidazole carboxaldehyde (0.43 g, 1.26 mmol) was added. The mixture was stirred at -10⁰C for 30 min, and continued at room temperature over night. The mixture was diluted with diethyl ether (30 mL), filtered through a Celite pad, rinsing with CH₂CI₂ (60 mL). The filtrate was concentrated in vacuo to a dark brown oil, separated by preparative TLC (CH₂CI₂ - MeOH = 50:1 , v/v) to afford 368 mg of the alkene product I7 (64%, MH⁺ = 461.12) as a near colorless solid. 3

Step G

Alkene compound 17 (58 mg, 0.126 mmol), prepared in Step F above, was dissolved in 3 mL of CH₂Cb. Trifluoroacetic acid (0.2 ml_, 2.60 mmol) was added followed by triethylsilane (20 μl_, 0.125 mmol). The mixture was stirred at room temperature for 5.5 h, and quenched with a 1.0 M NaOH aqueous solution. The aqueous mixture was extracted with CH₂CI₂ (30 mL x 3). The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated in vacuo to an oily residue, which was purified by preparative TLC (CH₂CI₂ 7N NH₃ in MeOH = 25 :1 , v/v) to give 19.8 mg of the titled product 1 (72%, MH⁺ = 219.1 ) as an off-white solid.

Preparative Example 2:

2

Step A

The alkene compound 17 (75 mg, 0.165 mmol), available from Preparative Example 1 Step F, was dissolved in 3 mL of ethyl acetate and 1.5 mL of ethanol (200 proof). The solution was degassed, and refilled with nitrogen. 10% Palladium on carbon (150 mg, wet -50% H₂O) was added. The mixture was degassed again in vacuo, and refilled with H₂ supplied by a gas balloon. Reaction was continued under the hydrogen atmosphere at room temperature for 5.5 h. The mixture was diluted with CH₂CI₂, filtered through a Celite pad. The filtrate was concentrated in vacuo to give 76 mg of the reduced product I8 (Q₁ MH⁺ = 463.09) as a yellow oil. Step B

Following a similar procedure described in Preparative Example 1 , Step G, thienyl compound I8 prepared from Step A above (76 mg, 0.165 mmol) was converted to 12 mg of the titled product 2 (33%, MH⁺ = 221.1 ) as a light yellow solid.

Preparative Example 3:

Step A

Thienyl-dihydropyranol 15 (2.38 g, 15.24 mmol), available from Preparative Example 1 , Step D, was dissolved in 100 ml_ of CH₂CI₂. Imidazole (1.6 g, 23.50 mmol) and chloro tertbutyldimethylsilane (2.53 g, 16.79 mmol) were added. The mixture was stirred at room temperature for 4.5 h. A sat. NaHCC"₃ aqueous solution (100 ml_) was added. The two layers were separated, and the aqueous layer was extracted with CH₂CI₂ (50 ml_ x 2). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to an oil, further dried on high vacuum, yielding 4.12 g of the TBS-ether product 19 (Q, [MH-TBSOH]⁺= 138.99) as a pale yellow oil. Step B

The TBS-ether compound 19 (4.12 g, 15.24 mmol), prepared in Step A above, was dissolved in 100 ml_ of CH₂CI₂. Λ/-bromosuccinamide (3.0 g, 16.85 mmol) was added. The mixture was stirred for 25 min at room temperature, and quenched with 75 ml_ of a sat. NaHCO₃ aqueous solution. The two layers were separated, the aqueous layer was extracted with CH₂CI₂ (50 ml_ x 2). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered through a 1.5-in silica gel pad, rinsing the pad with additional CH₂CI₂ (50 ml_ x 2). The filtrates were concentrated in vacuo to a yellow oil, further dried on high vacuum for 1 h, providing 5.05 g of the thienyl bromide 110 (95%, [MH-TBSOH]⁺ = 216.79, 218.80) as a yellow oil, used in the next step immediately.

Step C A solid mixture of palladium acetate (0.325 g, 1.45 mmol), (±)-BINAP (1.35 g,

2.17 mmol), and cesium carbonate (9.40 g, 28.85 mmol) was degassed via house vacuum, and refilled with nitrogen. Anhydrous toluene (60 ml_) was added. A solution of the thienyl bromide 110 (5.04 g, 14.43 mmol), prepared in Step B above, in 60 ml_ of anhydrous toluene was added followed by benzophenone imine (3.63 ml_, 21.63 mmol). The resulting mixture was heated at 90⁰C for 56 h. After cooling, the mixture was diluted with 100 ml_ of diethyl ether, filtered through a Celite pad, rinsing with diethyl ether (100 ml. x 2) and a small volume of CH₂CI₂. The filtrate was concentrated in vacuo to a dark brown oil. The oil was dissolved in 100 ml_ of CH₂CI₂, filtered through a 1.5-in silica gel pad rapidly, and quickly rinsing with additional CH₂CI₂ (10O mL x 2). The filtrate was concentrated in vacuo to a dark yellow oil, which was purified by column chromatography eluting with CH₂CI₂. Removal of solvent, further dried on high vacuum, afforded 4.73 g of the thienyl-imine product 111 (73%, MH⁺ = 450.2 ) as a reddish yellow oil. Step D

The thienyl-imine compound 111 (4.67 g, 10.39 mmol), prepared in Step C above, was dissolved in 40 mL of anhydrous benzene. Triphenylphosphine hydrobromide (3.57 g, 10.40 mmol) was added. The mixture was heated to reflux in 20 min, and continued at refluxing for 45 min. After cooling, 60 mL of diethyl ether was added, the mixture was filtered through a sintered funnel. The solids were washed successively with diethyl ether (60 mL), a 1 :1 ratio solution of acetone and diethyl ether (60 mL), and diethyl ether (50 mL x 2). The solids were further dried in vacuo, yielding 6.85 g of phosphine salt 112 (99%, [MH-HBr]⁺ = 580.21 ) as a light bright yellow solid.

Step E

The phosphine salt 112 (6.85 g, 10.37 mmol), prepared from Step D above, was suspended in 80 mL of anhydrous THF and cooled in a -78°C bath. A 1.8 M solution of phenyl lithium in dibutyl ether (7.2 mL, 12.96 mmol) was added dropwise. After 30 min, temperature rose slightly to -65°C. A solution of 1 -trityl-4-imidazole carboxaldehyde in 45 mL of THF was added slowly. Reaction was continued for 4h while temperature was increased to 0⁰C. Diethyl ether (150 mL) was added. The mixture was filtered through a 1.5-in silica gel pad, rinsing with diethyl ether (50 mL x 3) and CH₂CI₂ (50 mL x 2). The combined filtrates were concentrated in vacuo to a reddish brown oily solid, which was purified by column chromatography eluting with CH₂CI₂ to provide 3.41 g of the alkene product 113 (51%, MH⁺ = 640.4) as a bright rusty red solid.

Step F

The alkenyl imine compound 113 (474 mg, 0.74 mmol), available from Step E above, was dissolved in 10 mL of THF, and treated with a 3.0 M HCI aqueous solution (0.74 mL, 2.22 mmol). After 1 h, pyridine (0.71 mL, 8.69 mmol) was added followed by methyl chloroformate (0.34 mL, 4.40 mmol). Reaction was continued for 36 h, quenched with H₂O. The aqueous mixture was extracted with CH₂CI₂ (50 mL x 3).

The combined extracts were washed with brine, dried over Na₂SO₄, and concentrated. The oily residue was separated by preparative TLC (CH₂CI₂ - MeOH = 30 :1 , v/v) to afford 159 mg of the carbamate product 114 (40%, MH⁺ = 534.3) as a creamy yellow solid. Step G

Following a similar procedure described in Preparative Example 1 Step G, the trityl protected compound 114 (57 mg, 0.107 mmol), available from Step F above, was converted to 3.5 mg of the titled product 3 (11%, MH⁺ = 291.84) as a dark yellow solid.

Preparative Example 4:

114 115 Step A

The alkenyl carbamate 114 (126 mg, 0.236 mmol), available from Preparative Example 3 step F, was dissolved in 3.5 ml_ of 200 proof ethanol and 1 ml_ of ethyl acetate. The solution was degased, refilled with N₂, and added with 20% Palladium hydroxide on carbon (126 mg). The suspension was degassed, and refilled with H₂ from a gas balloon. The mixture was stirred over night at room temperature under a hydrogen atmosphere, then diluted with ethyl acetate, filtered through a Celite pad. The filtrate was concentrated in vacuo to give 88 mg of the alkyl product 115 (70%, MH⁺ = 536.28) as a dark yellow oil. Step B

The alkyl compound 115 (98 mg, 0.183 mmol), prepared from Step A above, was dissolved in 3 mL of CH₂CI₂. Trifluoroacetic acid (0.14 mL, 1.82 mmol) and triethylsilane (0.075 mL, 0.47 mmol) were added. The mixture was stirred over night. A sat. NaHCθ₃ aqueous solution was added. The mixture was extracted by CH₂CI₂; and the extracts were washed with brine, dried over Na₂SO₄, concentrated in vacuo to an oil, which was purified by preparative TLC (CH₂CI₂ - 7N NH₃ in MeOH = 20:1 , v/v) to afford 23.4 mg of the titled product 4 (46%, MH⁺ = 294.2).

Preparative Example 5:

Step A

Benzylimine intermediate 113 (400 mg, 0.626mmol), available from Preparative Example 3 step E, was dissolved in 15 mL of THF, and treated with a 3M HCI aqueous solution (0.63 mL, 1.88 mmol). The mixture was stirred for 40 min at room temperature. Pyridine (0.62 mL, 7.56 mmol) was added followed by acetyl chloride (0.27 mL, 3.78 mmol). Reaction was continued over night. Additional amount of pyridine and acetyl chloride were added, and reaction was allowed to continue for 7h. H₂O was added, the aqueous mixture was extracted with CH₂CI₂ (3 x 50 mL), and the combined organic extracts were washed with a sat. NaHCO3 aq. solution, brine, then dried over Na₂SO₄. Removal of solvents gave a crude product, which was separated by preparative TLC eluting with CH₂CI₂-MeOH (30:1 , v/v) to afford 99 mg of the acetamide 116 (MH⁺ = 518.49). Step B

The acetamide 116 (96 mg, 0.185 mmol was dissolved in a mixture of methanol (5 ml_) and acetic acid (0.5 ml_), the resulting mixture was heated at reflux over night, and concentrated in vacuo to an oily residue. This crude product mixture was purified by preparative TLC eluting with CH₂CI₂ - 7N NH₃ in MeOH (30:1 , v/v) to afford 35 mg of the alkene intermediate 117 (MH⁺ = 276.2).

Step C

A nitrogen flushed solution of alkene intermediate 117 (25mg, 0.91 mmol) in 4 ml_ of ethanol and 0.5 ml_ of methanol was treated with 10% palladium on carbon (30 mg). The mixture was degassed via house vacuum, and refilled with H₂ via a gas balloon. Reaction was continued over 1.5d. The mixture was diluted with methanol, and filtered through a celite pad. The filtrate was concentrated in vacuo, purified by preparative TLC (CH₂CI₂ - 7N NH₃ in MeOH = 30:1 , v/v) to afford 9 mg of the titled product 5 (MH⁺ = 278.2).

ASSAY:

Efficacy agonist activity values (Emax, GTPγS assay) for α2C were determined by following the general procedure detailed by Umland et. a/ ("Receptor reserve analysis of the human α_2c-adrenoceptor using [³⁵S]GTPγS and cAMP functional assays" European Journal of Pharmacology 2001 , 411 , 211 -221 ).

The compound of Examples 1 -5 were evaluated and found to be agonists of the α2C receptor subtype.

While the present invention has been described with in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

CLAIMSWhat is claimed is:

1. A compound represented by Formula I:

wherein: J is :

Z is -[C(R^C)(R^C)]_X- ;

A is a 5-membered heteroaryl, heterocyclyl or heterocyclenyl ring containing 1 - 3 heteroatoms, preferably selected from the group consisting of -O-, -S- and -N-, and is optionally substituted with at least one R⁵ and/or 1 or 2 (=O) (carbonyl) groups;

X is -O- , -S(O)p- , or -N(R²);

R¹ is selected from the group consisting of H, -CN, -[C(R^a)(R^b)]_qYR^7', -[C(R^a)(R^b)]_qN(R⁶)YR^r, -[C(R^a)(R^b)]_qOYR^r , and -[C(R^a)(R^b)]_qON=CR⁷R^r;

Y is selected from the group consisting of a bond, -C(=O)-, -C(=O)NR⁷-, -C(=O)O-, -C(=O)-[C(R^a)(R^b)]n-O-C(=O)-, -C(=O)N(R^C)-O-, -C(=NR⁷)-, -C(=NOR⁷)-, - C(=NR⁷)NR⁷-, -C(=NR⁷)N(R^C)O-, -S(O)_P-, -SO₂NR⁷-, and -C(=S)NR⁷-; wherein R^a and R^b are independently selected from the group consisting of H, alkyl, alkoxy, and halo, and R^c is H or alkyl;

R² is independently selected from the group consisting of H and alkyl;

R³ is independently selected from the group consisting of H, halo, and (=O), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R⁵, provided that when w is 3, no more than 2 of the R³ groups may be (=O);

R⁴ is independently selected from the group consisting of H, halo, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R⁵;

R⁵ is independently selected from the group consisting of H, halo, -OH, -CN, -NO₂, -NR⁷R⁷ , and -S(O)_PR⁷, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one of halo, -OH, -CN, -NO₂, -NR⁷R^7', and -S(O)_PR⁷ substituents and/or 1 or 2 (=O); R⁶ is H;

R⁷ is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted one or more times by R¹²;

R⁷ is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted one or more times by R¹²; or a) when a variable is -NR⁷R^7', -[C(R^a)(R^b)]_qYR^7', -C[(R^a)(R^b)]_qNR⁷R^7', - [C(R^a)(R^b)]_qOYR⁷V -(CH₂)_qNR⁷R^7', -C(O)NR⁷R^7' or -SO₂NR⁷R^7', R⁷ and R^7' together with the nitrogen atom to which they are attached independently form a 3- to 8-membered heterocyclyl, heterocyclenyl or heteroaryl ring having, in addition to the N atom, 1 or 2 additional hetero atoms independently selected from the group consisting of O, N, -N(R⁹)- and S, wherein said rings are optionally substituted by 1 to 5 independently selected R⁵ moieties and/or 1 or

2 (=0), or b) when a variable is -(CH₂)_qON=CR⁷R^7' or -[C(R^a)(R^b)]_qON=CR⁷R^7', R⁷ and R⁷ together with the carbon atom to which they are attached independently form a 3- to 8-membered cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl or heteroaryl ring, wherein said hetroacyclyl, heterocyclenyl or heteroaryl rings have 1 -3 heteroatoms which are independently selected from the group consisting of O, N, -N(R⁹)- and S, wherein said rings are optionally substituted by 1 to 5 independently selected R⁵ moieties and/or 1 or 2 (=0); R⁹ is independently selected from the group consisting of H, -C(O)-R¹⁰, -C(O)-

OR¹⁰, and -S(O)_P-OR¹⁰ and alky), alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted with at least one of halo, -OH, -CN, -NO₂, -N(R¹¹)₂, and -S(O)_pR¹¹substituents and/or 1 or 2 (=0); R¹⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted with at least one of halo, -OH, -CN, -NO₂, -N(R¹¹)₂, and -S(O)_PR¹¹ substituents and/or 1 or 2 (=O);

R¹¹ is a moiety independently selected from the group consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each of which is optionally substituted by at least one substituent independently selected from the group consisting of halo, -OH, -CN, -NO₂, -N(R^11')₂, and -S(O)_PR¹¹ substituents and/or 1 or 2 (=O); R¹¹ is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R¹² is independently selected from the group consisting of H, halo, -OH, -CN, -NO₂, -N(R¹¹J₂ , and -S(O)_PR¹¹, and/or 1 or 2 (=0), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl, heterocyclenyl, heterocyclenyloxy, heterocyclylalkyl, heterocyclenylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, and heterocyclenylalkoxy groups, each of which in turn is optionally substituted by at least once by a substituent selected from the group consisting of H, alkyl, haloalkyl, halo, -OH, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy, optionally substituted heterocyclenyloxy, -CN, -NO₂, -N(R¹¹)₂, and - S(O)_PR¹¹ and/or 1 or 2 (=O), wherein said optionally substituted alkoxy, aryloxy, 4

optionally substituted cycloalkoxy, optionally substituted heteroaryloxy, and heterocyclenyloxy when substituted are substituted one or more times by R¹¹; n is O, 1 or 2; w is O, 1 , 2, 3 or 4: p is independently 0, 1 or 2; q is independently 0-10; and x is 1 , 2, or 3 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

2. The compound of claim 1 which has the formula

Il wherein

A is imidazole; X is O; or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

3. The compound of claim 2 which has the formula

or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

4. The compound of claim 2 which has the formula

or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

5. The compound of claim 2 which has the formula

or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

6. The compound according to claim 1 which has the formula

III wherein A is imidazole;

X is O; or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

7. The compound of claim 2 which has the formula

or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

8. The compound of claim 2 which has the formula

or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

9. The compound according to claim 1 which has the formula

IV wherein

A is imidazole; or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

10. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle provided that when the composition is a liquid, aqueous composition, one or more solubility enhancing components are excluded with the exception of cyclodextrin.

11. The pharmaceutical composition of claim 10, further comprising one or more additional therapeutic agents.

12. The pharmaceutical composition of claim 11 , wherein said additional therapeutic agents are selected from the group consisting of steroids, PDE-4 inhibitors, anti- muscarinic agents, cromolyn sodium, H₁ receptor antagonists, 5-HT₁ agonists, NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin Il receptor agonists, β- blockers, β-agonists, leukotriene antagonists, diuretics, aldosterone antagonists, ionotropic agents, natriuretic peptides, pain management agents, anti-anxiety agents, anti-migraine agents, and therapeutic agents suitable for treating heart conditions, psychotic disorders, and glaucoma.

13. A method for treating one or more conditions associated with α2C adrenergic receptors, comprising administering to a mammal in need of such treatment a compound of claim 1 or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.

14. The method of claim 13, wherein the conditions are selected from the group consisting of allergic rhinitis, congestion, pain, diarrhea, glaucoma, congestive heart failure, cardiac ischemia, manic disorders, depression, anxiety, migraine, stress- induced urinary incontinence, neuronal damage from ischemia, attention deficit disorder, and schizophrenia.

15. The method of claim 14, wherein the condition is congestion.

16. The method of claim 15, wherein the congestion is associated with perennial allergic rhinitis, seasonal allergic rhinitis, non-allergic rhinitis, vasomotor rhinitis, rhinitis medicamentosa, sinusitis, acute rhinosinusitis, or chronic rhinosinusitis.

17. The method of claim 15, wherein the congestion is caused by polyps or is associated with the common cold.

18. The method of claim 14, wherein the condition is pain.

19. The method of claim 18, wherein the pain is associated with neuropathy, inflammation, arthritis, diabetes.