Title of Invention

METHYL INDOLES AND METHYL PYRROLOPYRIDINES AS ALPHA-1 ADRENERGIC AGONISTS AND A PROCESS FOR PREPARING THE SAME

Abstract

This invention relates to compounds which are alpha- 1 receptor agonists, preferably alpha-1A/L receptor agonists, and which are represented by Formula (I), wherein m, A, X, Y, R<SUP>1</SUP>, R<SUP>2</SUP>, R<SUP>3</SUP>, R<SUP>4</SUP> and R<SUP>5</SUP> are as defined in the specification; or individual isomers, racemic or non racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof. The invention further relates to pharmaceutical compositions containing such compounds, methods for their use as therapeutic agents, and methods of preparation thereof.

Full Text

This invention relates to substituted indoles which are alpha-1 adrenergic agonists, prefer¬ably alpha- 1A/L adrenergic agonists, and associated pharmaceutical compositions, methods for use as therapeutic agents, and methods of preparation thereof. Alpha-1 adrenergic receptors (interchangeably named alpha-1 adrenoceptors) are G-pro-tein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine and norepineph¬rine (NE). Currently, several subtypes of the alpha-1 adrenergic receptors are known to exist for which the genes have been cloned: alpha-lA (previously known as alpha-lC), alpha-IB and alpha-ID. Recently the existence of a low affinity alpha-1 adrenoceptor for prazosin named alpha-IL, in human prostate has been determined. However, thegene for the alpha-lL adrenergic receptor subtype has yet to be cloned. The alpha^l adrenoceptor plays a part in the sympathetic maintenance of smooth muscle tone and alpha-1 adrenergic agonists are known to increase muscle tone in the lower urinary tract necessary for urine storage and urine emptying thus making adrenergic receptors important targets for drug development in urinary dysfunction [Testa, Eur.J.Pharmacol. 249:307-315 (1993)]. Phar¬macological studies resulting in the subdivision of alpha-1 adrenergic receptors have let to the suggestion that development of subtype-selective compounds may allow improved treatment with a lower incidence of side effects, and Tanaguchi et al. [Eur. J. Pharmacol. 318:117-122 (1996)], have reported that compounds with selectivity for the alpha- 1A. receptor and to a lessen extent to the alpha-IL receptor over the alpha-IB and alpha-ID subtypes have selectivity for urethral over vascular tissue. Certain alpha-1A agonists are known and are indicated to be useful in treating Various di¬sease states including urinary incontinence, nasal congestion, sexual dysfunction such as ejaculation disorders and priapism, and CNS disorders such as depression, anxiety, de¬mentia, senility, Alzheimer"s, deficiencies in attentiveness and cognition, and eating dis¬orders such as obesity, bulimia, and anorexia, see, e.g., US 5,952,362 which discloses a variety of alpha- 1A/L agonists including some 2-imidazoline, 2-oxazoline, 2-thiazoline and 4-imidazole derivatives. Urinary incontinence is a condition defined as trie involuntary loss of urine to such an ex¬tent as to become a hygienic or social concern to the patient Stress urinary incontinence (SUI) occurs when the internal sphincter does not close completely. The primary symptom is minor leakage from activities, such as coughing, sneezing, laughing, running, lifting, or even standing, that apply pressure to a full bladder. Leakage stops when the activity stops. SUI is most common in women between the ages of 25 and 50, and many regularly exer¬cising women have some degree of SUI. The methods presently available to treat SUI include physiotherapy and surgery. Treat¬ment with pharmaceuticals is limited to the use of non-selective adrenergic agonists. Only a limited number of pharmaceutical agents have been employed, with varying success, to treat stress incontinence. Phenylpropanolamine, pseudoephrine and midodrine are considered first-line therapy for mild to moderate stress incontinence [Lundberg (ed.), JAMA 261:2685-2690 (1989)]. These agents are believed to work both by direct activation of alpha-1 adrenoceptors and indirectly by displacement of endogenous norepinephrine from sympathetic neurons following uptake into the nerve terminal [Andersson and Sjogren, Progress in Neuro¬biology 71-89 (1982)]. Activation of alph.a-1 adrenoceptors located on the smooth muscle cells of the proximal urethra and bladder neck [Sourander, Gerontology 36:19-26 (1990)] evokes contraction and an increase in urethral closure pressure. The utility of phenylpropanolamine, pseudoephrine, and midodrine is limited by a lack of selectivity among the alpha-1 adrenoceptor subtypes and by the indirect action of these agents (i.e. activation of alpha-1, alpha-2, and beta-adrenoceptors in the central nervous system and periphery). As a result, any desired therapeutic effect of these agents maybe accompanied by undesirable side effects such as an increase in blood pressure. The in¬crease in blood pressure is dose-dependent and therefore limits the ability to achieve thera¬peutically effective circulating concentrations of these agents. Furthermore, in some patients these agents produce insomnia, anxiety and dizziness as a result of their central nervous system stimulant actions. Due to side effects and /or limited efficacy associated with the current available medica¬ments, there is an unmet medical need for useful compounds. A compound having the desired alpha-1A/L adrenergic agonist profile is desirable. Those skilled in the art will recognize that stereoisomers exist in some compounds of for¬mula I. Accordingly, the present invention includes all possible stereoisomers, and geome¬tric isomers and includes not only racemic compounds but also the optically active com¬pounds as well. Additionally when tautomers of the compounds of formula I are possible, the present invention is intended to include all tautomeric forms of the compounds. The invention further relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula I, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with at least one suitable carrier. la another embodiment the method of treating a subject comprises administering to a sub¬ject having a disease state which is alleviated by treatment with an alpha-1A/L receptor agonist, a therapeutically effective amount of one or more compounds of formula I. In another embodiment, the method of treating a subject comprises administering to a subject having a disease state which is alleviated by treatment with an alpha- 1A/L receptor agonist, a pharmaceutically effective amount of the pharmaceutical composition contain¬ing at least one compound of formula I. The disease state may comprise urinary inconti¬nence, nasal congestion, sexual dysfunction such as ejaculation disorders and priapism, and central nervous system (CNS) disorders such as depression, anxiety, dementia, senility, Alzheimer"s, deficiencies in attentiveness and cognition., and eating disorders such as obesity, bulimia, and anorexia. In another embodiment the disease state maybe selected from urge incontinence, stress incontinence, overflow incontinence and functional incontinence. In another embodiment the disease may comprise-nasal congestion associated with aller¬gies, colds, and other nasal disorders, as well as the sequelae of congestion of the mucous membranes (e.g., sinusitis and otitis media). Another aspect of this invention involves methods for preventing or treating nasal congestion by administering a safe and effective amount of a subject compound to a mammal experiencing or at risk of experiencing nasal congestion. Such nasal congestion may be associated with human diseases or disorders i which include, but are not limited to, seasonal allergic rhinitis, acute upper respiratory viral infections, sinusitis, perennial rhinitis, and vasomotor rhinitis. In addition, other dis¬orders can be generally associated with mucous membrane congestion (e.g., otitis media and sinusitis). Unless otherwise stated, the following terms used in this Application, including the specifi¬cation and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an," and "the" include plural referents unless the context clearly dictates otherwise. "Alky!" means the monovalent linear, branched or cyclic saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms inclusive, unless otherwise indicated. Examples of alkyl radicals include, but are not limited to, methyl, ethyl,"propyl, cyclopropyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyi, and the like. "Lower alkyl" means the monovalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms in¬clusive, unless otherwise indicated. Examples of lower alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, and the like. "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms. C2-C3 alkylenes include, by way of example, methylene, ethylene, 2,2-dim ethyl ethylene, propylene, 2-methylpropylene, and the like. "Alkoxy" means the radical -OR, wherein R is a lower alkyl radical as defined herein. Examples of alkoxy radicals include, but are not limited to, raethoxy, ethoxy, isopropoxy, isobutoxy and the like. "Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g„ ethenyl, propenyl, allyl and the like. "Aryl" means the monovalent cyclic aromatic hydrocarbon radical consisting of one or more fused rings in which at least one ring is aromatic in nature, which can optionally be substituted with hydroxy, cyano, lower alkyl, lower alkoxy, alkylthio, halo, haloalfcyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylarnino, nitro, and/or alkylsulphonyl, unless otherwise indicated. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, biphenyl, indanyl, anthraquinolyl, and the like. "Heteroaryi" means the monovalent aromatic carbocyclic radical having one or more rings incorporating one, two, or three heteroatoms within the ring (chosen from nitrogen, oxy¬ gen, or sulfur) which can optionally be substituted with hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, arninosulfonyl, sulfonylarnino and/or alkyl- sulfonyl, unless otherwise indicated. Examples of heteroaryi radicals include, but are not limited to, imidazolyl, oxazolyl, thiazolyl, pyrazinyl, thioplienyl, furanyl, pyranyl, pyridmyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, ben2imidazolyl, benzooxazolyl, benzothiazolyl, benzopyranyl, indazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, quinuclidinyl, naphtyridinyi, and the hke, .....". . "Arylsulfonyl" means a radical -SfCOjR where R is an aryl group as defined herein. "Cycloalkyl" means a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons. The cycloalkyl may be optionally substituted independently with one, two, or three substituents selected from alkyl, optionally substituted phenyl, or -C(0)R (where R is hydrogen, alkyl, haloalkyl, amino, acylamino, roono-alkylamino, di-alkylamino, hydroxy, alkoxy, or optionally substituted phenyl). More specifically, the term cycloalkyl includes, e.g., cyclopropyl, cyclohexyl, phenylcyclohexyl, 4-carboxycyclohexyl, 2-carboxamido-cyclohexyl, 2-dimethyIaminocarbonyI-cycIoh.exyI, and the like. "Cycloalkylalkyl" means a radical -RaR where Ra is an alkylene group and R is a cycloalkyl group as denned herein, e.g., cyclopropylmethyl, cyclopropylediyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylpropyl, 3-cyclohexyI-2-methylpropyl; and the Hke. "Halogen" or "halo" means the radical fiuoro, bromo, chloro, and/or iodo. "Haloalkyl" means the lower alkyl radical as defined herein substituted in any position with one or more halogen atoms as defined herein. Examples of haloalkyl radicals include, but are not limited to, 1,2-difhiOTopropyl, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 2,2,2-trichloroethyl, and the like. "Alkylthio" means the radical -SR, wherein R is a lower alkyl radical as defined herein. Examples of alkyithio radicals include, but axe not limited to, methylthio, butylthio, and the like. "Alkylamino" means the radical -NHR, wherein R is a lower alkyl radical as defined herein. Examples of alkylamino radicals include, but are not limited to, methylamino, (1-ethyl-ethyl)amino, and the like. "Dialkylamino" means the radical -NR"R", wherein R" and R" are each independently lower alkyl radicals as defined herein. Examples of dialkylamino radicals include, but are not limited to, dimethylamino, methylethylarnino, diethylamino, di(l-methylethyl)amino, and the like. "Alkylaminosulfonyl" means the radical -StO^NR"R", wherein R" is lower alkyl as defined herein, and R" is hydrogen or lower alkyl as defined herein. Examples of alkylaminosulfon¬ yl include, hut are not limited to methylaminosulfonyl, cHmemylaminosulfonyl, and the like. ■"■ " "Alkylsulfonylamino" means the radical -N S(0)2R", wherein R" is lower alkyl as defined herein. Examples of alkylsulfonylamino include, but are not limited to methylsulfonyl-amino, ethylsulfonyiamino, and the like. "Hydroxyalkyr means an alkyl radical as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not zaxiy more than one hydroxy group. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylprop-pl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-l-iydroxymethylethyl,2,3-dihydroxyfautyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-lydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and l-(hydroxymethyl)-2-lydroxyethyl. "Hydjoxyalkylamino means a radical -NRR1 wherein R is hydrogen, alkyl or hydroxyalkyl, ind R" is hydroxyalkyl as defined herein. "Heterocyclyl11 means a monovalent saturated moiety, consisting of one to three rings, in-:orporating one, two, or three heteroatoms (chosen from nitrogen, oxygen or sulfur). The leterocyclyl rmg may be optionally substituted as defined herein. Examples of heterocyclyl noieties include, but are not limited to, piperidinyl, piperazinyl, azepinyl, pyrrolidinyl, jyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazoli-. - dinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isotiiiazolidinyi, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl, di-hydrofuryl, tetrahydroniryl, dihydropyranyl, tetrahydropyranyl, tbiamorpholinyl, thiamor-pholinylsulfoxide, thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquraolinyl, tetra-hydroquinolinyl, tetrahydriso quinolinyl, and the like. i It is to be understood that the double bond in 2-imidazoline and 2-imidazolinylmethyi may assume other resonance forms. The terms 2-imidazoline 2-imida2olinylmethyl in¬clude all such resonance forms. "Isomerism" means compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereo7 isomers". Stereoisomers that are not mirror images of one another are termed "diastereo-isomers", and stereoisomers that are non-superimposable mirror images are termed "enan-tiomers", or sometimes optical isomers. A carbon atom bonded to four nonidenrical sub-stituents is termed a "chiral center". "Chiral compound" means a compound with one or more chiral center. It has two enantio¬meric forms of opposite chirality and may exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture". A compound that has more than one chiral center has 2n_I enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereo-mer or as a mixture of diastereomers, termed a "diastereomeric mixture". When chiral cen¬ters are present, the stereoisomers maybe characterized by the absolute configuration (R or S ) of the chiral centers. Absolute configuration refers to the arrangement in space of the substituents attached to a chiral center. The substituents attached to a chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. [Cahn et al., Angew. Chem. Inter. Edit 5:385; errata 511 (1966); Cahn et al., Angew. Chem. 78:413 (1966); Cahn and Ingold, J. Chem. Soc. (London) 612 (1951); Cahn et al., Experien-tia 12:81 (1956); Cahn, J. Chem.Educ. 41:116 (1964)]. "Tautomers" refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium. Compounds of Formula I contain groups that may exist in tautomeric equilibrium. It is to be understood that compounds of Formula I maybe depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any tautomer form. "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not For example, "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds. "Optionally substituted", when used in association with "aryl", phenyl", "benzyl", "benzoyl", "heteroaryl", or "heterocyclyl", means an aryl, phenyl, benzyl, benzoyl, heteroaryl, or heterocyclyl which is optionally substituted independently with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, hetero-alkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkyl-amino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), -(CR"R")n-COOR (where n is an integer from 0 to 5, R" and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkyl¬alkyl, phenyl or phenylalkyl), or -(CR"R")n-CONRaRb (where n is an integer from 0 to 5, R" and R" are independently hydrogen or alkyl, and Ra and R are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl. "Leaving group" means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating condi¬tions. Examples of leaving groups include, but are not limited to, halogen, alkane- or aryl-enesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulf- onyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyl-oxy, isopropyloxy, acyloxy, and the like. "Inert organic solvent" or "inert solvent" means the solvent inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimetbyiformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, terf-butanol, dioxane, pyridine, and the like. Unless spedfied to the contrary, the solvents used in the reactions of the pre¬sent invention are inert solvents. "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise un¬desirable and includes that which is acceptable for veterinary as well as human pharmaceu¬tical use. "Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically - . acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts indude: (1) add addition salts formed with inorganic acids such as hydrochloric add, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic adds such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, dtric acid, ethanesulfonic add, fumaric acid, glucoheptonic add, gluconic add, glutamic acid, glycolic add, hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic add, maleic add, malic add, malonic add, mandelic add, methanesulfonic acid, muconic add, 2-naphthalene-sulfonic acid, propionic acid, salicylic add, succinic acid, tartaric add, p-toluenesulfonic acid, trimethylacetic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound tither is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or co¬ordinates with an organic or inorganic base. Acceptable organic bases include diethanol-amine, ethanolarnine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, caldum hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. It should be understood mat all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as denned herein, of the same add addition salt. The preferred pharmaceutically acceptable salts are the salts formed from acetic acid, hydrochloric acid, sulphuric add, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium. "Solvates" means solvent additions forms that contain eidier stoichiometric or non stoi¬chiometric amounts of solvent Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H20, such com¬bination being able to form one or more hydrate. "Prodrug" or "pro-drug" means a pharmacologically inactive form of a compound which must be metabolized in vivo, e.g., by biological fluids or enzymes, by a subject after ad¬ministration into a pharmacologically active form of the compound in order to produce the desired pharmacological effect. Prodrugs of a compound of Formula I are prepared by modifying one or more functional group(s) present in the compound of Formula I in such a way that the modification(s) maybe cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula I wherein a hydroxy, amino, sulfhydryi, carboxy or carbonyl group in a compound of Bormula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy!, amino, sulfhydryi, carboxy or carbonyl group res¬pectively. Examples of prodrugs include, but are not limited to, esters (e.g. acetate, dialkyl-aminoacetates, formates, phosphates, sulfates and benzoate derivatives) and carbamates of hydroxy functional groups ( e.g. N.JV-dimethyl-carbonyl), esters of carboxyl functional groups (e.g. ethyl esters, morpholinoethanol esters), N-acyl derivatives (e.g. N-acetyl), N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals, and enol esters of ketones and aldehyde functional groups in compounds of Formula I, and the like. The prodrug can be metabolized before absorption, during absorption, after absorption, or at a specific site. Although metabolism occurs for many compounds primarily in the liver, almost all other tissues and organs, especially the lung, are able to carry out varying degrees . of metabolism. Prodrug forms of compounds maybe utilized, e.g., to improve bioavail¬ability, improve subject acceptability such as by masking or reducing unpleasant characte¬ristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intra¬venous use, provide for prolonged or sustained release or delivery, improve ease of formu¬lation, or provide site-specific delivery of the compound. Reference to a compound herein includes prodrug forms of a compound. Prodrugs are described in Silverman [The Organic Chemistry of Drug Design and Drug Action, Academic Press, San Diego, pp .352-401 (1992)], Bundgaard [(Ed.) Design of Prodrugs, Elsevier Science, Amsterdam (1985)], Roche [(Ed.) Design of Biopharmaceutical Properties through Prodrugs and Analogs, American Pharmaceutical Association, Washington (1977)] and Juliano [(Ed.) Drug Delivery Systems, Oxford Univ. Press, Oxford (1980")]. "Subject" means mammals and non-mammals. Mammals means any member of the Mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and die like. The term "subject" doe not denote a particular age or sex. "Therapeutically effective amount" means an amount of a compound that, when admini¬stered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on die com¬pound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attendii medical or veterinary practitioner, and other factors. "Pharmacological effect" as used herein encompasses effects produced in the subject that achieve the intended purpose of a therapy. For example, a pharmacological effect would one that results in the prevention, alleviation or reduction of urinary incontinence in a treated subject "Disease state" means any disease, condition, symptom, or indication. "Treating" or "treatment" of a disease state includes: (1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state; (2) inhibiting the disease state, ie., arresting the development of die disease state or its clinical symptoms; or (3) relieving the disease state , i.e., causing temporary or permanent regression of the disease state or its clinical symptoms. "ai-adrenergic receptors"," a ^-adrenergic receptors" (previously known as " a ic-adren-ergic receptors"), or" a ^-adrenergic receptors", used interchangeably with " ai-adreno- ceptors"," a iA-adrenoceptors" (previously known as " a iC-adrenoceptors receptors"), or "aiL-adienoceptors", respectively, refers to a molecule conforming to the seven membrane-spanning G-protein receptors, which under physiologic conditions mediate various actions, e.g., in the central and/or peripheral sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine. "Agonist" means a molecule, such as a compound, a drug, an enzyme activator, or a hor¬mone, that enhances the activity of another molecule or receptor site. "Urinary Incontinence" is a condition characterized by the involuntary loss of urine, which is objectively demonstrable. It is both a social and hygienic problem. Stated simply, in¬continence results from the failure of the bladder and/or the urethra to work properly, or when the coordination of their functions is defective. It is estimated that at least ten million Americans suffer from incontinence. While the prevalence of incontinence is two¬fold higher in females, with the greatest incidence in postmenopausal women, it also affects males. Urinary incontinence can be classified into four basic types: urge, stress, overflow and functional, and as used herein the term "urinary incontinence" encompasses all four types. Urge incontinence (detrusor instability) is the involuntary loss of urine associated with a strong urge to void. This type of incontinence is the result of either an overactive or hypersensitive detrusor muscle. The patient with detrusor overactivity experiences in¬appropriate detrusor contractions and increases in intravesical pressure during bladder filling. Detrusor instability resulting from a hypersensitive detrusor (detrusor hyper-reflexia) is most often associated with a neurological disorder. Genuine stress incontinence (outlet incompetence) is the involuntary loss of urine occur¬ring when increases in intra-abdominal pressure cause a rise in intravesical pressure which exceeds the resistance offered by urethral closure mechanisms. Stress incontinent episodes can result from normal activities such as laughing, coughing, sneezing, exercise, or, in severe stress incontinent patients, standing or walking. Physiologically, stress incontinence is often characterized by a descensus of the bladder neck and funneling of the bladder out¬let. This type of incontinence is most common in multiparous women, as pregnancy and vaginal delivery can cause loss of the vesicourethral angle and damage to the external sphincter. Hormonal changes associated with menopause may exacerbate this condition. Overflow incontinence is an involuntary loss of urine resulting from a weak detrusor or from the failure of the detrusor to transmit appropriate signals (sensory) when the bladder is full. Overflow incontinent episodes are characterized by frequent or continuous dribbling of urine and incomplete or unsuccessful voiding. Functional incontinence, in contrast to the types of incontinence described above, is not defined by an underlying physiological dysfunction in the bladder or urethra. This type of incontinence includes the involuntary loss of urine resulting from such factors as decreased mobility, medications (e.g., diuretics, muscarinic agents, or alpha-1 adrenoceptor ant¬agonists), or psychiatric problems such as depression or cognitive impairment "A method of treating or preventing incontinence" refers to the prevention of or relief from the symptoms of incontinence including involuntary voiding of feces or urine, and dribbling or leakage of feces or urine which may be due to one or more causes including, but not limited to, pathology altering sphincter control, loss of cognitive function, over-distention of the bladder, hyper- reflexia and/or involuntary urethral relaxation, weakness of the muscles associated with the bladder, or neurologic abnormalities. . In general,- the nomenclature used in this Application is based on AUTONOM v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomen¬clature. The numbering of the indole ring system as used herein is shown by the formula: Chemical structures shown herein are prepared using ISIS v. 4.0. Ajiy open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen. In one embodiment the present invention provides a compound of formula I wherein p is 0. In one embodiment the present invention provides a compound of formula I wherein R3, R4, R5 and R6 are hydro gen. i In one embodiment the present invention provides a compound of formula I wherein R3 is located at the 2- position of the indole ring system. In one embodiment the present invention provides a compound of formula I wherein Y is of the formula i. In one embodiment the present invention provides a compound of formula I wherein X is carbon. In another embodiment the present invention provides a compound of formula I wherein X is nitrogen. In one embodiment the present invention provides a compound of formula I wherein A is -S02-. In another embodiment the present invention provides a compound of formula I wherein A is -C(O)-. In one embodiment the present invention provides a compound of formula I wherein R: is alkyl. In another embodiment the present invention provides a compound of formula I wherein R is methyl, ethyl or isopropyl. In another embodiment the present invention provides a compound of formula I wherein R2 is -(CH3)p-NRcR . In one embodiment the present invention provides a compound of formula 1 wherein R2 is - (CH;0p-NRcR , wherein Rc and R are hydrogen. In another embodiment the present in¬vention provides a compound of formula I wherein R2 is -(CH2)P-NR";Rd, wherein Rc and R are alkyl. In another embodiment the present invention provides a compound of for- . mula I wherein R2 is -(CHiJp-NRcRd, wherein one of Rc and Rd is hydrogen and the other is alkyl. In another embodiment the present invention provides a compound of formula I wherein R2 is -(CH2)p-NR,:Rd, wherein Rc and Rd are methyl. In another embodiment the present invention provides a compound of formula I wherein R is -(CH2)P-NRCR , where¬in one of Rc and R is hydrogen and the other is methyl. In one embodiment the present invention provides a compound of formula I wherein R4 and R5 are hydrogen. In one embodiment the present invention provides a compound of formula I wherein R is hydrogen. In one embodiment the present invention provides a compound of formula I wherein m is from 0 to 2, and each R1 independently is halogen, alkyl or alkoxy. In one embodiment the present invention provides a compound of formula I wherein R3 is hydrogen. In another embodiment the present invention provides a compound of formula I wherein R3 is alkyl. In one embodiment the present invention provides a compound of formula I wherein A is -(c=o)-. In one embodiment the present invention provides a compound of formula I selected from: 3-(4,5-cUhydro-lH-imidazol-2-ylmethyl)-l-methanesulfon7l-lH-indole; 5-chloro-3-(415-dihydro-lH-in3idazol-2-ylmethyl)-l-methanesulfonyl-lH-mdoIe;3-(4,5-dmydro-lH-irnidazol-2-ylmemyl)-4-fluoro-l-methanesulfonyl-lH-indole; 3-(4,5-dihyclro-lH-imidazol-2-ylmetiyl)-5-nuoro-l-meflianesulfonyl-lH-indole; and 4-chloro-3-(4,5-di-riydro-lH-mTidazoi-2-ylme1iyI)-l-methanesLilfonyi--2-methyl-lH-indole. Where any of R1, R2, R3, R4, R5, R6, Ra, Rb, Rc and Rd are altyl, they are preferably lower alkyl, i.e. Ci-Cgalkyl, and more preferably Q-C4alkyl. Compounds of the present invention maybe made by the methods depicted in the illustra¬tive synthetic reaction schemes shown and described below. The starting materials and reagents used in preparing these compounds generally are either 5 available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser andFieser"s Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd"s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. Where necessary, conventional protecting group techniques were used as described by Greene et al., Protecting Groups in Organic Synthesis, 3rd Ed., Wiley Inter- . science, 1999. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention may be synthesized, and vari¬ous modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application. The starting materials and the intermediates of the synthetic reaction schemes may be iso¬lated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data. Unless specified to the contrary, the reactions described herein preferably take place at atmospheric pressure over a temperature range from about -78°C to about 150DC, more preferably from about 0°C to about 125°C, and most preferably and conveniently at about room (or ambient) temperature (hereinafter: RT), e.g., about 20DC. Schemes A through F describe general methods for preparation of compounds of formula I. Schemes A and B illustrate synthetic routes to indole compounds usable in preparation of compounds of formula I. Schemes C and D show methods of preparing compounds of formula Ithat fall within the embodiments of formula in above. Scheme E relates a proce¬dure for preparation of compounds of formula Ijhat fall within the embodiments of for¬mula IV above. Scheme F illustrates a procedure that maybe used in the preparation of 7-azaindole compounds of formula I wherein X is nitrogen. Specific examples in accordance with Schemes A-B are provided below in the Experimental portion of this disclosure. In step 1 of Scheme B, an ortho nitrotoluene b is subject to reduction via treatment with SnCl2, H2/Pd or other reducing reagent to afford an aniline compound (not shown), which is then protected by BOC or other suitable amine protection chemistry to provide pro¬tected aniline f. Compound b maybe prepared as described in Scheme A or obtained commercially. The protected aniline f is alkylated by treatment with alkyl lithium or other strong base, and then reaction witb an N-alkyl-N-alkoxy amide g to yield a keto-substitu-ted compound h. The keto-compound h may then be treated with acid to effect deprotec-tion and cyclization to provide indole compound e. In step 2, the aminoalkyl indole compound k is converted to a nitrile compound 1 via heating with alkalai metal cyanide such as NaCN in a polar aprotic solvent system. The nitrile compound 1 may then be treated with alkalai metal hydride or like base, followed by an alkylsulfonyl halide reagent m to provide an alkylsulfonylated nitrile com¬pound n. Where R7 is methyl, reagent rn may comprise, e.g., methanesulfonyl chloride. The alkylsulfonylation of step 3 may be performed under dry polar aprotic solvent con¬ditions. In step 4, the alkylsulfonylated nitrite compound n of step 3 is exposed to acid and EtOH to form an imidate, and then treated with ethylene diamine to effect cyclization to form an imidazolinyl group and provide a compound of formula HI, which represents specific em¬bodiments of compounds of formula las described above. Several variations on the procedure of Scheme C may be used to provide various embodi¬ ments compounds of the invention. In one such variation, the allcylsulfonylated nitrile compound n of step 3 may, after acid treatment, be reacted with aminoacetaldehyde di¬ methyl acetal instead of ethylene diamine, to afford an imidazol group (i.e., a group of formula u) instead of the imidazolinyl group shown in Scheme C. In other variations of Scheme C, the indole nitrogen of compound e or k may be protected to allow aromatic substitution (s) at positions 4-7 of the indole ring, and then subsequently deprotected to allow alkylsulfonylation in step 3. Thealkylsulfonylationofstep 3 may be carried out prior to nitrile formation when the indole nitrogen is suitably protected. Other variations on the procedures of Scheme C and the other reaction schemes herein will suggest themselves to those skilled in the art. .■:-.- SCHEMED In step 1 of Scheme D, a phenyl hydrazine D. is reacted with a beta keto ester tj under acidic conditions to provide a carboxyester indole r. The carboxyester indole compound r may then in step 2 be treated with base and reacted with an alkylsulfonyl halide m, in the manner described above in Scheme Q to yield an alkylsulfonylated compound s. In step 3, carboxyester compound s is subject to reduction to afford a hydroxymethyl indole t This reduction may be performed using a dialkylaluminum hydride reducing agent such as "DIBAL" under dry, polar aprotic solvent conditions with reduced tempera¬ture and inert atmosphere. In step 4 a bromination or other halogenation is carried out to convert the hydroxymethyl indole t of step 3 to a bromomethyl indole compound u. Bromination in this case may be performed using phosphorus tribromide and dry, polar aprotic solvent conditions at re- . duced temperature. The bromomethyl indole compound u is then used to prepare a cyanomelhyl indole com¬pound v in step 5 by reaction with alkalai metal nitrile salt in the manner described above for Scheme C. Step 6 of Scheme D involves a cyclization by reaction of the cyanomethyl indole v of step 5 with ethylene diamine as described in Scheme C, to provide a compound of formula III. As in the case of Scheme C, many variations on the procedure of Scheme D are possible and may be used to provide compounds in accordance with the invention. For example, aUcylsulfonylation may be carried out prior to nitrile formation in cases where the indole nitrogen is suitably protected. Ajninoacetaldehyde dimethyl acetal may be used in place of ethylene diamine in step 6 to provide an imidazol group instead of an imidazolinyl group as noted above. Referring now to Scheme E, there are shown reaction procedures for preparation of com¬pounds of the invention that correspond to formula IV, wherein m, R3, R4, R5; Rc and Rd are as described herein. Step 1 of Scheme E diverges along three paths shown as steps la, lb and 1c which respectively correspond to embodiments where Rc and R are both hydro-l gen, where Rc is hydrogen and R is alkyl, and where both where Rc and R are alkyl. SCHEME E In step la of Scheme E, a cyanoalkyl indole compound k, which may be prepared as described above in Scheme C, is reacted with a chlorosulfonyl isocyanate n under dry,. polar aprotic solvent conditions to form carboxylic acid amide compound o. Alternatively, cyanoalkyl indole compound k may be treated with an alkyl Hthium reagent followed by an alkyl isocyanate £ under dry, polar aprotic solvent conditions in step lb to yield a carb¬oxylic acid alkyiamide compound (j. Step 1c provides yet another alternative in which cyanoalkyl indole compound k is reacted with an alkyl lithium reagent followed by a N,N-dialkyl carbamyl chloride r under dry, polar aprotic solvent conditions to provide a carb¬oxylic acid dialkylamide compound s. In steps 2a-2c, the carboxylic amide compounds o, In step I of Scheme F, a 7-azaindoIe compound v is alkylated by heating with hexameth-ylenetetramine under acidic conditions to provide an azaindole aldehyde compound w. The aldehyde compound w. is then treated with an alkalai metal hydride or like base under polar protic solvent conditions, followed by reaction with an alkylsulfonyl halide m to pro¬vide an alkylsulfonylated azaindole x. In step 3, alkylsulfonyl halide m is treated with a mild oxidizing agent such as a perben2oic acid, in polar aprotic solvent, to afford a pyrrolopyridinone compound y_. ) A nitrile formation reaction may then be carried out in step 4 by reaction of pyrrolopyri¬dinone compound y. with a dialkoxycyanomethyl phosphonate (not shown) to afford a cyanomethyl azaindole compound z. The cyanomethyl azaindole compound z may be treated with HCl/EtOH followed by ethylene diamine, in the manner described in step 4 of Scheme C above, to form an imid- azolinyl group and yield a compound of formula V, which represents a specific embodi¬ment of compounds of formula I. As noted above many variations on the procedure of Scheme F may be used as required to prepare different embodiments of the subject compounds. In step 2, e.g., alkylsulfonyla-tion may instead be replaced by reaction with a chlorosulfonyl isocyanate, alkyl isocyanate or N,N-dialkyl carbamyl compound as shown in Scheme E above to provide corresponding carboxylic acid amide compounds. The compounds of the present invention have selective alpha-lA/L adrenergic selective activity and as such are expected to be useiiil in the treatment of various disease states, such as urinary incontinence; nasal congestion; sexual dysfunction, such as ejaculation disorders and priapism; CNS disorders such as depression, anxiety, dementia, senility, Alzheimer"s, deficiencies in attentiveness and cognition, and eating disorders such as obesity, bulimia, and anorexia. Urinary incontinence (UI) is a condition defined as the involuntary loss of urine to such an extent as to become a hygienic or social concern to the patient. Involuntary loss of urine occurs when pressure inside the bladder exceeds retentive pressure of the urethral sphinc¬ters (intraurethral pressure). Four major types of urinary incontinence have been defined based on symptoms, signs and condition: stress, urge, overflow and functional incon¬tinence. Stress urinary incontinence (SUI) is the involuntary loss of urine during coughing, sneez¬ing, laughing, or other physical activities. The present methods to treat SUI include physiotherapy and surgery. Treatment with pharmaceutical agents is limited to the use of non selective-adrenergic agonists like phenylproanolamine and midodrine. The rationale for the use of adrenergic agonists for the treatment of SUI is based on physiological data indicating an abundant noradrenergic input to smooth muscle of the urethra. Urge incontinence (detrusor instability) is the involuntary loss of urine associated with a strong urge to void. This type of incontinence is the result of either an overactive or hypersensitive detrusor muscle. The patient with detrusor overactivity experiences inap¬propriate detrusor contractions and increases in intravesical pressure during bladder i filling. Detrusor instability resulting from a hypersensitive detrusor (detrusor hyper-reflexia) is most often associated with a neurological disorder. Overflow incontinence is an involuntary loss of urine resulting from a weak detrusor or from the failure of the detrusor to transmit appropriate signals (sensory) when the bladder is full. Overflow incontinent episodes are characterized by frequent or continuous dribbl¬ing of urine and incomplete or unsuccessful voiding. Functional incontinence, in contrast to the types of incontinence described above, is not defined by an underlying physiological dysfunction in the bladder or urethra. This type of incontinence includes the involuntary loss of urine resulting from such factors as decreased mobility, medications (e.g., diuretics, muscarinic agents, or alpha-1 adrenoceptor ant¬agonists), or psychiatric problems such as depression or cognitive impairment The compounds of this invention are also particularly useful for the treatment of nasal congestion associated with allergies, colds, and other nasal disorders, as well as the sequelae of congestion of the mucous membranes (e.g., sinusitis and otitis media), with less or no undesired side effects. These and other therapeutic uses are described, e.g., in Goodman & Gilman"s, The Phar¬macological Basis of Titerapeutks, ninth edition, McGraw-Hill, New York, 1996, Chapter 26:601-616; and Coleman, -R.A., Pharmacological Review"s, 1994,46:205-229.1 General Strategy for Identifying Alpha-1A/L-adrenoceptor Agonists: In Vitro: The inhibitory activity of compounds of this invention in vitro was examined using fluores¬cent dye determination of intracellular calcium concentrations as described in the Exam¬ples below. Alpha-1A/L-adrenoceptor agonist activity was determined in vitro and in vivo. i In Vitro: The activity of potential alpha- 1A/L activity in vitro was determined by evaluating the potency and relative intrinsic activity (relative to norepinephrine or phenylephrine) of standard and novel compounds to contract isolated rabbit bladder neck strips (alpha-1 A/L-adrenoceptor) and isolated rat aortic rings (alpha-ID adrenoceptor). > In Viva: Standard and novel compounds which selectively contracted rabbit bladder neck strips were subsequently evaluated in vivo in anesthetized female micropigs to assess urethral activity relative to diastolic blood pressure effects. Compounds with the desired activity in anesthetized pigs were evaluated in conscious female micropigs instrumented with tele- ) metry to measure diastolic blood pressure and a strain-gage transducer to measure urethral tension. The present invention includes pharmaceutical compositions comprising at least one com¬pound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophy¬lactic ingredients. In general, the compounds of the present invention will be administered in a therapeuti¬cally effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary sldll in the art of treating such diseases will be able, without un¬due experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertains therapeutically effective amount of the compounds of the pre-r sent invention for a given disease. In general, compounds of the present invention will be aclministered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for ad¬ministration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. A compound or compounds of tlie present invention, together with one or more conven¬tional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical com¬positions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formula¬tions, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms. The compounds of the present invention may be formulated in a wide variety of oral ad¬ministration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier maybe one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and com¬pacted in the shape and size desired. The powders and tablets preferably contain from about-one (1-) to about seventy (70) percentof the active compound. Suitable carriers in-, - . . elude but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin., tragacanth, methylceUulose, sodium carboxymethylcellu-lose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration. Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form prepara¬tions which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, e.g., in aqueous propylene glycol solutions or may contain emulsifying agents, e.g., such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylceUulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspen¬sions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The compounds of the present invention maybe formulated for parenteral administration (&%•■> by injection, e.g., bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspen¬sions, solutions, or emulsions in oily or aqueous vehicles, e.g., solutions in aqueous poly¬ethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles in¬clude propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g.-, sterile, pyrogen-free water. The compounds of the present invention may be formulated for topical administration to the epidermis as ointments., creams or lotions, or as a transdermal patch. Ointments and creams may, e.g., be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dis¬persing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouth¬washes comprising the active ingredient in a suitable liquid carrier. The compounds of the present invention maybe formulated for administration as suppo¬sitories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, e.g., by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to coc and to solidify. 1 The compounds of the present invention maybe formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, e.g., with a dropper, pipette or spray. The formulations maybe provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved, e.g., by means of a metering atomizing spray pump. The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The com¬pound will generally have a small particle size, e.g., of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, e.g., by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), e.g., dichlorodifluoromethane, trichlorofiuoromethane, or di-chlorotetraffuoroethane, or carbon dioxide or other suitable gas. The aerosol may con-veniendy also contain a-surfactant such as lecithin. The dose of drugmaybexontrolledby... a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, e.g., a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (FVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form e.g., in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler. When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery de¬vices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (l-dodecylaza-cycloheptan-2-one). Sustained release delivery systems are inserted sub-cutaneously into to the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a bio¬degradable polymer, e.g., polyactic acid. The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Representative pharmaceutical formulations contain¬ing a compoundof the present invention are described in Example 5. The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be con¬sidered as limiting the scope of the invention, but merely as being illustrative and repre¬sentative thereof. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be "allowed for as well as due to "differences such "as," e.g., in calibration, rounding, of numbers, . and the like. EXAMPLES The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice trie present invention. They should not be con¬sidered as limiting the scope of the invention, but merely as being illustrative and repre¬sentative thereof. sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 2 to 3% ethyl acetate in hexanes give l-Bromo-2-Euoro-4-methyl-5-nitro-benzene as a white solid (5.21g, 78%). !H NMR (CDCh) d:2.60 (s, 3H), 7.11 (d, 1H, J=8.6 Hz ), 8.28 (d, 1H, J=6.4 Hz). Synthesis of 6-Bromo-5-fluoroindole was carried out in this step according to the pro¬cedure reported by Batcho and Leimgruber [Org. Synth. 63:214 (1985)]. A mixture of hydrazine hydrate (1.30 ml, 26.8 mmoles), crude [2-(4-Bromo-5-fluoro-2-nitro-phenyl)-vinyl] -dirnethyl-ainine as from step 2 and Raney ruckle in tetrahydrofuran (30 ml) and methanol (30 ml) was stirred at RT over night. The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 0.1N hydrogen chloride solution. The organic ex¬tract was washed with brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 10% ethyl acetate in hexane to give 6-Bromo-5-fiuoro-lH-indole as a light green solid (0.865 g, 61%). *H NMR (CDC13) d: 6A9-6.51 (m, 1H), 7.23-7.26 (m, 1H), 7.36 (d, 1H, J=9.2 Hz),7.56 (dd, 1H, J=5.6 Hz, 0.9 Hz), 8.14 (bs, 1H). To a solution of 6-bromo-5-fluoro-lH-indole (0.86g, 4.02 mmol) in CH2C12 (30ml) was added N,N-dimethyl mediyleneiminium chloride (0.5g, 5.34 mmol). The mixture was stirred at RT overnight and a aqueous sodium hydroxide (0.22g, 5.50mmol, 100ml water) was added. The aqueous solution was extracted into ethyl acetate. The organic extract was dried (anhydrous sodium sulfate) and concentrated under reduced pressure to give (6-bromo-5-fluoro-lH-indol-3-ymiediyl)-dmiethyl-aniine as alight green solid (l-06g), H NMR (DMSO) d: 2.12 (s, 6H), 3.48 (s, 2H), 7.34 {s, 1H), 7.50(d, 1H; J=9.9 Hz ), 7.62 (d, lH,J=6.0Hz). M-H:269. A mixture of (6-bromo-5-fiuoro-lH-mdol-3-ylmethyl)-cUmethyl-amine (l.Og ) and sodium cyanide (0.54g, 11.02 mmol) hi ethyl acetate (1.8 ml) and methyisulfoxide (16 ml) was heated at 80°C for 24 hrs then partitioned between ethyl acetate and water. The organic extract was washed with brine, dried (anhydrous sodium sulfate), concentrated under reduced pressure. The residue was purified by Sash column chromatography over silica gel eluting with 20% ethyl acetate in hexane to give (6-Bromo-5-£Iuoro-lH-indol-3-yl)~acetonitiile as ayellowsolid (0.41 g, 44%). :H NMR(CDC13) d: 3.78 (d, 2H, J=1.0 Hz), 7.27 (dd, 1H, J=1.2 Hz), 7.31 (d, 1H, J=S:S Hz, 7.58 (d, 1H, J=5.5 Hz), 8.23 (bs, 1H). i To a solution of (6-Bromo-5-fluoro-lH-indo2-3-yl)-acetoniIriIe (0.205g, QMmmol) in an¬hydrous tetrahydrofuran (lOml), was added sodium hydride (O.lg,, 2.5 mmol, 60% in mineral oil) at 0°C. After stirring for lOminutes, methanesulfonyi chloride (0.13 ml, 1.68 mmol) was added dropwise. The reaction mixture was stirred at RT for 24 h then parti¬tioned between ethyl acetate and water. The organic extract was washed with brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 30% ethyl acetate in hexane to give (6-Bromo-5-fluoro-l-methanesulfonyl-lH-indol-3--yl)--acetonitrile as a yellow solid, (0.22g, 82%). LH NMR (CDCl3) d: 3.59 (s, 3H), 4.15 (d, 2H, J-l.l Hz), ■ 7.75(s, 1H), 7.79 (d, 1H, J=9.0 Hz) 8.11 (d, 1H, J=5.8 Hz). Hydrogen chloride gas was bubbled through a cold (0°C) suspension of (6-bromo-5-fiuoro-l-methanesulfonyl-lH-indol-3-yl)-acetonitrile (0.215g, 0.65 mmol) in anhydrous ethanol (20 ml) for 15 minutes. The reaction mixture was refrigerated for 72 hours and the solvent was removed under reduced pressure. The solid residue was re-dissolved in an¬hydrous methanol (10 ml), and ethylene diamine (0.05 ml, 0.77mmol) was added. The reaction mixture was heated to reflux for 24 hours and the solvent was removed under re¬duced pressure. The resulting residue was purified by flash column chromatography over silica gel eluting with 7% methanol in dichloromethane with 0.1% concentrated ammoni¬um hydroxide to give6-Bromo-3-(4,5-dmydro-lH-imidazol-2-yLmethyl)-5-fluoro-l-methanesulfonyl-lH-indole, which was recrystallized from methanol and ether (0.133 g, 55%). lH NMR (DMSO) d: 3.56 (s, 3H), 3.82(s, 4H), 4.07 (s, 2H), 7.84 (s, 1H), 7.90 (d, 1H, 1=9.1 Hz), 8.10 (d, 1H, J=5.8 Hz), 10.23 (bs,lH). M+H: 374. The following compounds were also synthesized by the procedure of Example 1: 4-Cbdoro-3-(4,5-o%ydro-lH-irrddazol-2-yhiiethyl)-l-memanesulforiyl-lH-iridole; 5-Cbloro-3- (4,5-dihydro- lH-imidazol-2 -yimethyl) -1 -methanesulfonyi- lH-indole; 6-CMoro-3-(4,5-dihydro-lH-irnidazol-2-ylmethyl)-l-methanesuifonyi-lH-indole; 7-Cbloro-3-(4,5-dihydro-lH4midazol-2-ylmethyl)-l-methanesulfonyl-lH-jndole; 4~Brorno-3-(4,5-dihydro-1 H-imidazol-2 -yimethyl)-1 -methanesulfony]-lH-indole; 3-(4,5-Dmydro-lH4midazol-2-yhnethyl)-4-fluoro-l-methanesulfonyl-lH-indole; 3-(4,5-Dihydro-lH-imidazol-2-ylraethyl)-5-fluoro-l-methanesulfonyl-lH-indoIe; 3-(4,5-Dihydro-lH-imidazol-2-ylmethyl)-6-fluoro-l-methajiesulfonyI-lH-indole; 3-(4,5-Dmydro-lH-inuda2ol-2-yimethyl)-l-methanesulfonyl-4-metiyl-lH-iridole; 3-(4,5-Dmydro-lH-kmdazol-2-ybiietiiyI)-l-methanesulfonyl-6-methoxy-lH-indole; and 3-(4,5-Dihydro-lH-unidazol-2-ylme&yl)-l-methanesulfonyl-4-methoxy-lH-iiidole. Using a similai procedure to that described above, but replacing methanesulfonyl chloride in step 6 with the appropriate alkylsulfonyl chloride, 4-chloro-3-(4,5-dihydro-lH-imid-azol-2-ylmethyl)-l-ethanesulfonyi-lH-indole was prepared. Example 2: 4-Chloro-3- (4,5-dihydro-lH-imidazol-2-ylmethyl)-l -methanesulfonyl-2-methyl- lH-indole To a cold solution of (3-chloro-2-methyl-phenyl)-carbarnic acid tert-butyl ester (5.0 g, 20.7 mmol) in anhydrous tetrahydrofuran (100 ml) at -40°C under N2, was added a solu¬tion of s-butyi Hthium (40 ml, 52 mmol, 1.3 M in cyclohexane) dropwise and maintained the reaction temperature below -30°C. To the bright yellow solution at -50°C was added a solution of N-methoxy N-methylacetamide (2.33 g, 22.6 mmol) in anhydrous tetrahydro¬furan (40 ml) dropwise and maintained the reaction temperature between ~50°C to -40°C. The mixture was allowed to warm to -10°C over a period of 35 minutes and was then par¬titioned between diethyl ether and 0.3 N hydrochloric acid solution. The organic extract was washed with water and brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 20% ethyl acetate in hexane to give crude [3-ChIoro-2-(2-oxo-prop-yl)-phenyl]-carbamic acid tert-butyl ester (5.21 g) as a colorless oil. To a solution of the crude [3-CHoro-2-(2-oxo-propyl)-phenyl]-carbamic acid tert-butyl ester (5.21g) in dicbloromethane (180 ml) was added trifiuoroacetic acid (20 ml). The reaction mixture was stirred at RT for 5 days and then partitioned between dichloro-methane and 5% sodium bicarbonate solution. The organic extract was washed with brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure to give 4-Chloro-2-methyl-lH-indole and 3-Chloro-2-methyl-phenylamine as a mixture. (2.6g mixture, 69% yield of 4-Chloro-2-methyl-lH-indole). JH NMR (CDC13) d: 2.45 (s, 3H), 6.32-6.33 (m, 1H), 6.98-7.18 (m, 3H), 7.96 (bsf 1H), M-H: 164. Steps 3-5 Steps 3-5 were carried out as described above for Steps 4-6 of Example 1, to yield 4-chloro-l-methanesulfonyl-lH-mdoI-3-yl)-acetonitrile (1.156g, 4.30 mmol). Hydrogen chloride gas was bubbled to a cold (0QC) suspension of 4-chloro-l-methane-sulfonyl-lH-indol-3-yl)-acetonitrile (1.156g, 4.30 mmol) in absolute ethanol (50 ml) for 15 minutes. The reaction mixture was kept in refrigerator for 3.5 days. Solvent was re¬moved under reduced pressure. The solid residue was resuspended in dry ethylene glycol dimethyl ether (20 ml). To this mixture was added aminoacetalaldehyde dimethyl acetal (0,52 ml, 1.07 mmole) at 0°C diopwise. After stirring vigorously at RT overnight, glacial acetic acid (99.5%, 40ml) was added and followed by bubbling hydrogen chloride gas through the resulting mixture for 2 minutes. The rruxture was heated at 50°C for 24 hours, cooled to RT and poured into ether. The insoluble residue obtained after decanting the supernatant was washed with ether and redissolved in a solution of concentrated am¬monium hydroxide (0.5 ml) in methanol (50 ml). Solvent was then removed under re¬duced pressure. The residue was purified by flash column chromatography over silica gel eluting with 3 to 5% methanol in methylene chloride with 0.1% concentrated ammonium hydroxide to give 4-Cliloro-3-(lH-iniidazol-2-ylmethyl)-l-memanesulfonyl-lH-indole as a cream solid (0.55g, 41%). lH NMR (DMSO) 5: 3.46 (s, 3H), 4.34 (d, 2H, J=1.0 Hz), 6.84 (bs, 1H), 7.02 (bs, 1H) 7.32-7.45 (m, 3H), 7.84 (dd, 1H,>7.8 Hz, 1.4 Hz ), 11.73 (bs, 1H). M+H: 310. Step 2 was carried out according to the procedure described by Iwao et al. [Tetrahedron 54: 8999(1998)}. To a solution of (6-memoxy-lH-mdo]-3-ylmemyl)-dimethyl-ambe (0.0.76g, 3.73mmol) in anhydrous tetrahydrofuran (10ml), was added sodium hydride (0.22g,, 5.59 mmol, 60% in mineral oil) at 0 °C. After stirring for ID minutes, triisopropyl-silyl chloride (0.82g, 4.10 mmol) was added dropwise over 20 rnin. The reaction mixture was stored at 0°C for 16 hours and then quenched with water. The aqueous solution was extracted into ether. The ether extract was washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was triturated with hexanes and the insoluble material was removed by filtration. The nitrate was concentrated under reduced pressure to give (6-methoxy-l-tri-tert-butylsilanyl-lH-indol-3-ylmethyl)-di-methylamine as an oil (0.76g, 56.7%). XH NMR To a solution of (4-CMoro-6-methoxy-l-tri-tert-butylsflanyI-lH-indol-3-ylmethyl)-di-methyl-amine (0.73g, 1.85mmol) in benzene (20ml) was added methyl iodide (0.52g, 3.71mmoi). After stirring at ambient temperature for 16 hours, the solvent was removed under reduced pressure. The residue was suspended in anhydrous tetrahydrofuran (10ml). To this solution was added, sequentially, trimethylsilyi cyanide (0.27g, 2.78mmol) and tetrabutylammonium fluoride (1.45g, 5.56mmol, 1M in tetrahydrofuran, after which the solution was stirred for an hour. After solvent was removed under reduced pressure, the residue was partitioned between water and ether. The ether extract was dried (anhydrous sodium sulfate) and concentrated under reduced pressure to give (4~Chloro-6-methoxy-lH-indoI-3-yi)-acetonitriIe as solid (0.41g, quantitative). JH NMR (CDC13) S: 3.82 (s, 3H), 4.10 (d, 2H, J+ 1.17Hz), 6.79 (d, 1H, J= 2.07Hz), 6.79 (d, 1H, J= 2.07), 7.16 (m, 1H), 8.11 OUH). Step 5 was carried out as described in step 6 of Example 1 to provide (4-chloro-l-methane-sulfonyI-6-methoxy-lH-indol-3-yl)-acetonitrile, M+H = 298. Step 6: 4-Chloro-3-(4,5-dihydro-lK-imida7ol-2-ylmethyl)-l-mel±ianesuIfonjl-6-methoxy-i lH-indole Step 6 was carried out as described in step 7 of Example 1 to provide 4-Chloro-3-(4,5-di-hydro-lH4midazol-2-ylme1iyl)-l-methanesulfonyl-6-methoxy-lH-mdole)M+H=342. Also prepared in the manner described above in Example 3 were the following compounds: 4-chloro-3- (4,5-dihydro- lH-imidazol-2-ylmethyl) - 6-fluoro-1 -medianesulfonyl- 1H-) indole; and 4-cMoro-3-(4,5-dmydro-lH-imidazol-2-ylmethyl)-5-fluoro-l-rnethanesulfonyl-lH- indole. Step 2 of this Example was carried out according to the procedure described in Step 6 of Example 1, to provide l-me1h.anesulfonyl"5-methoxy_-2-methyl-lH"--indole-3--carboxylic acid ethyl ester, M+H = 312. Dhsobutylaluminurn hydride (6 ml, 6 mmol, 1M in dichloromethane) was added slowly at -78°C under N2 to a solution of l-methanesulfonyl-5-methoxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.4 g, 1.29 mmol) in anhydrous tetrahydrofuran (10ml). The reaction mixture was stirred at -78°C for 1.5 hours and then kept at 4DC for 16 hours. The reaction was quenched with water and stirred for 0.5 hour. The insoluble material was re¬moved by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography over silica gel eluting with 50 to 70% ethyl acetate in hexane to give (l-methanesulfonyl-5-methoxy-2-methy3-lH-indol-3-yl)-mefhanol as a white solid, (0.26g, 75.2%). lB NMR (CDC13) 5: 2.59 (s, 3H), 3.00 (s, 3H), 3.87 (s, 3H), 4.79 (bs, 2H), 6.91 (dd, 1H, J=9.1 Hz, 2.6 Hz), 7.11 (d, 1H, J=2.6 Hz), 7.89 (dd, 1H, J=9.1 Hz, 0.3 Hz). To a solution of (l-Memanesulfonyl-5-methoxy-2-methyl-lH-indol-3-yl)-methanol (1.53 g, 5.68 mmol) in anhydrous ethyl ether (50 ml) and tetrahydrofuran (20 ml) at 0QC under N2 was added a solution of phosphorus tribromide (7.5 ml, 1 M in dichloromethane,). The mixture was stirred at RT for S hours and concentrated under reduced pressure to give 3-bromomethyl-l-methane sulfonyl- 5 -methoxy-2 -methyl- lH-indole as white solid. H NMR (CDCI3) 5:2.57 (s, 3H), 3.04(s, 3H), 3.89 (s, 3H), 4.63 (s, 2H), 6.93 (dd, 1H, J=9.1 Hz, 2.5 Hz), 7.04 (d, 1H, J=2.5 Hz), 7.89 (d, 1H, 1=9.1 Hz). To a suspension of potassium cyanide (3.0 g, 46.1 mmol) in methyl sulfoxide (16 ml) and tetrahydrofuran (4 ml) at G°C was added a solution of (l-methanesulfonyl-5-methoxy-2-methyl-lH-indol-3-yl)-methanol (0.26g,) in tetrahydrofuran (20 ml) at 0°C. The reaction mixture was stirred at RT for 8 hours and then kept at 4°C for 72 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 50 to 70% ethyl acetate in hexane) to give (I-methanesiiifonyI-5-methoxy-2-metbyI-lH-in.doE-3-yl)-acetonitrile as a white solid, (0.2 g, 13% in 2 steps). "H NMR (CDC13) 8: 2.58 (s, 3H), 3.03 (s, 3H), 3.71 (s, 2H), 3.S8 (s, 3H), 6.93-6.99 (m, 2H), 7.91 (dd, 1H, J=8.9 Hz, 0.6 Hz). (4-Chloro-lH-indol-3-yl)-acetonitrile used in step 1 was prepared from commercially ob¬tained 4-chioro-lH-indoIe (Aldrich Chemical Co. Cat No. 24,622-0) using the procedure of steps 4 and 5 of Example 1. The indole N-acylation in step 1 was carried out according to the procedure described by Curtin and Davidsen [J. Med. Chem. 41:74-95 (2998)]. To a solution of (4-cHoro-lH-indol-3-yl)-acetonitrile (200 mg, 1.05 mmol) dissolved in an¬hydrous tetrahydrofuran (5ml) at 0DC was added sodium"hydride (63 mg, 1.57 mmol, 60% dispersion in mineral oil). After 20 minutes at 0DC, the ice bath was removed and dimethyl carbamyi chloride (0.12 mL, 1.26 mmol) was slowly added. After one hour, the reaction was partitioned between ethyl acetate (100 mL) and saturated sodium chloride solution (2.5 mL). The ethyl acetate extract was dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure. The resulting material was purified by flash column chromatography over silica gel eluting with 40% ethyl acetate in hexane to give 4-Chloro-3-cyanomerayl-indole-l-carboxylic acid dimethylamide as a white solid (239 mg, 87%). LH NMR (CDClj) 5: 3.10 (s, 6H), 4.16 (br s, 2H), 7.22 (m, 2H), 7.42 (br s, 1H), 7.57 (m, 1H); M+H 262 The (4-chloro-lH-indol-3-yl)-acetonitrile used in step 1 was prepared from commercially obtained 4-chloro-lH-indoIe (Aldrich Chemical"Co. Cat. No. 24,622-0) using the proce¬dure of steps 4 and 5 of Example 1. The indole N-acylation in step I was carried out according to the procedure described by Sheppard and Pireh [J.Med. Chem. 37:2011-2032 (1994)]. To a solution of 2,2,6,6-tetramethyl piperidine (0.18 ml, 1.05 mrnol) dissolved in anhydrous tetrafiydrofuran (5 ml) was added butyllithium (2.5M in hexanes; 0A2 ml, 1.05 mmol). The reaction was cooled to-78°C and a solution of (4~chloro-lH-indol-3-yl)-acetonitrile (200 mg, 1.05 mmol) in anhydrous tetrahydrofuran (5 ml) was added, main¬taining the temperature between -78°C and ~72°C, After 5 minutes, methyl isocyanate (0.06 mlf 1.05 mmol) was added. The dry ice bath was -removed after 15 minutes and the reaction was allowed to stir overnight. After the solvent was removed under reduced pressure , the residue was partitioned between dichloromethane(100 ml) and saturated sodium chloride solution (5 ml). The organic extract was dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography over silica gel eluting with 30% ethyl acetate in hexane to give 4-chloro-3-cyanomethyl-indole-1-carbosyhc acid methylamide as a white solid (54 mg, 21%). !H NMR (CDQO 5: 3.07 (d, 3H, J=4.7 Hz), 4.17 (s, 2H), 7.24 (m, 2H), 7.50 (s, 1H), 8.14 (m, 1H) M+ 247. Step 2: 4-Chloro-3-(4.5-dihydro-l-H-imidazol-2-ylmethyl-)-indole-l-cafboxylic acid diethylamide The (4-chloro-lH-indol-3-yl)-acetonitrile used in step 1 was prepared from commercially obtained 4-chloro-LH-indole (Aldrich Chemical Co. Cat. No. 24,622-0) using the proce¬dure of steps 4 and 5 of Example 1. To (4-chIoro-lH~indol-3-yl)-acetonitrile (500 mg, 2.62 mtnol) dissolved in anhydrous dichloromethane (10 mL) was added chlorosulfonyl isocyanate (0.92 mL, 10.50 mmol). After 1.5 hours, the reaction was filtered and the re¬sulting solid was washed with dichloromethane. The solid was then dissolved in acetone and water (2.5 mL) was added. The reaction mixture was concentrated to dryness to yield 4-Chloro-3-cyano methyl-indole-1-carboxylic acid amide as a pale pink solid (377 mg, 62%).^ NMR (DMSO-d6) 5: 4.27 (br s, 2H), 7.28 (m, 2H), 7.78 (br s, 2H), 7.98 (s, 1H), 8.28 (m, 1H); M+ 233. ) Step 2: 4-Chloro-3-(4,5-dihydro-l-H-iniidazol-2-vlmethvl1-mdole-l-carboxviic acid amide 4-CHoro-3-(4,5-ch1iydro-l-H-irriidazol-2-ylmethyI)-mdole-l-carboxy[ic acid "amide was obtained from the nitrile compound of step 1 using the procedure of step 7 of Example 1. 7-AzaindoIe-2-carboxaldehyde (2.31 g, 15.8 mmoles) from step 1 was dissolved in DMF (50 ml). Sodium hydride (0.76 g, 19 mmol) was added and the reaction was stirred at RT for 15 min. Methanesulfonyl chloride (1.8 ml, 24 mmoles) was added and the reaction was stirred for 3 h. The reaction mixture was diluted with ethyl acetate and washed trice with 5% lithium chloride solution, then brine. The organic layer was dried (magnesium sulfate) and concentrated to provide l-methanesulfonyl-lH-pyTrolo[2,3-b]pyridine-3-carbalde-hyde (2.84g, 80% yield). !H NMR (CDC13) 5: 3.71 (3H, s), 7.42 (1H, dd, J = 4.7Hz, 8.1 Hz), S.30 (1H, s), 8.57 (1H, dd, J = 1.7 Hz, 4.7 Hz), 8.63 (1H, dd, J = 1.7 Hz, 8.1 Hz), 10.07 (s, 1H). Diethyi(cyanomethyI)phosph.onate (0.47 ml, 3.1 mmol) was dissolved in tetrahydrofiiran (5 ml) and cooled to 0°C. Sodium hydride (0.12 g, 3.1 mmol) was added portionwise and the reaction was stirred for 10 min. l-Methanesiilfon>"l-l,2-dihydro-pvrro]o[2r3-b]p7ridin-3-one (0.332 g, 1.57 mmoles) suspended in tetrahydrofiiran (3 ml) was added dropwise, whereupon it immediately dissolved. The reaction was stirred at RT for 2h. The reaction mixture was diluted with water and neutralized with 1M hydrochloric acid The aqueous solution was extracted with ethyl acetate. The organic extract was washed with brine, dried (sodium sulfate) and concentrated under reduced pressure. The crude product was chro-matographed over silica gel eluting with 50% ethyl acetate in hexane to provide pure (l-methanesuIfonyI-lH-pyrroio[2,3-b]pyridin-3-yI)-acetonitrile (0.30 g, 45 %). ]H NMR : (CDC13) 5: 3.61 (3H, s), 3.81 (2H, s), 7.34 (1H, dd, J = 4.8 Hz, 7.9 Hz), S.02 (1H, dd, J = 1.6 Hz, 7.9 Hz), S.54 (1H, dd, J = 1.6 Hz, 4.8 Hz). (4-Chloro-l-methanesulfonyl-lH-indol-3-yl)-acetontrile (1.156 g. 4.30 mmol) was sus¬pended in absolute ethanol (50 mL), cooled to 0°C, and hydrogen chloride gas was bubbled therethrough for 15 minutes. The reaction mixture was then kept in refrigerator for 3.5 days, after which solvent was removed under reduced pressure. The solid residue was re-suspended in dry ethylene glycol dimethyl ether (20 ml). To this mixture was added aminoacetalaldehyde dimethyl acetal (0.52 ml, 1.07 mmole) at 0°C drbpwise. After stirring vigorously at RT overnight, glacial acetic acid (99.5%, 40ml) was added and followed by bubbling hydrogen chloride gas through the resulting mixture for 2 minutes. The mixture was heated at 50°C for 24 hours, cooled to RT, and poured into ether. The insoluble resi- due obtained after decanting the supernatant was washed with ether and redissolved in a solution of concentrated ammonium hydroxide (0.5 ml) in methanol (50 ml). Solvent was then removed under reduced pressure. The residue was purified by flash column chroma¬tography over silica gel eluting with 3 to 5% methanol in methylene chloride with 0.1% concentrated ammonium hydroxide to give 4-ChJoro-3-(lH-imida2ol-2-ylmethyl)-l-methanesulfonyl-lH-indole as a cream solid (0.55g, 41%). :H NMR (DMSO) 5:3.46 (s, 3H), 4.34 (d, 2H, J=1.0 Hz), 6.84 (bs, 1H), 7.02 (bs, 1H) 7.32-7.45 (m, 3H), 7.84 (dd, 1H, J=7.8 Hz, 1.4 Hz ), 11.73 (bs, 1H). M+H: 310. Example 10: Pharmaceutical Formulations Pharmaceutical compositions of the subject Compounds for administration via several routes were prepared as described in this Example. Composition for Oral Administration (A) All of the ingredients, except water, are combined and heated to about 60°C with stirring. A sufficient quantity of water at about 60°C is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. about 100 g. Nasal Spray Formulations Several aqueous suspensions containing from about 0.025-0.5 percent active compound are prepared as nasal spray formulations. The formulations optionally contain inactive in¬gredients such as, e.g., microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid may be added to adjust pH. The nasal spray formulations may be delivered via a nasal spray metered pump typically delivering about 50-100 micro-hters of formulation per actuation. A typical dosing schedule is 2-4 sprays every 4-12 . hours. Example 11: Functional Assay for alpha-lA/L agonist activity The inhibitory activity of compounds of this invention in vitro was examined using fluorescent dye determination of intracellular calcium concentrations. FIuo-3 loaded cell preparation: Chinese hamster ovary cells CHO-Kl expressing the alpha-1A adrenoceptors (clone 13) are washed 4 times (approx. 300 uL/well) with fluorometric imaging plate reader (FLIPR) buffer (Hank"s buffered saHne solution (HBSS), 2mM CaCl2,10 mM HEPES, 2,5 mM probenecid, 100 uM ascorbic acid), with a final volume of 150[iL/well. Cells are loaded with 50 uL/well of 8 JJ,M Fluo-3 AM (Molecular Probes, Eugene, OR), for a final concen¬tration of 2 uM Huo-3 AM. Cells are then incubated for 60 min at 37°C. Following dye loading , cells are washed 4 times (approx. 300uI7well) with FLIPS, buffer with a final volume of 150 ul/well. Agonist Assay The Test compound, control compound and reference compound are run in quadrupli¬cate, 8-point curves on each plate with a final assay concentration range of lO^M to 10"UM for each compound. All compounds are dissolved in DMSO at lOmM, and serially diluted in FLIPR buffer. The assay plate is placed in the FLIPR incubation chamber and a baseline fluorescence measurement (excitation @ 488 nm and emission @ 510-570 nm) is obtained (15 sec inter¬val). An experimental run is then commenced. The reaction is started with the addition of 50 [iL/well (at 4x final concentration) of test, control, or reference compound solution from the agonist plate to the assay plate to all 96 wells simultaneously. Fluorescence is measured for 120 sec at 1 sec intervals. Then, a second addition of 5 uM ionomycin (50 uL/well from 5 x concentration ionomycin plate) is added to the assay plate. Fluorescence is measured for 30 sec at 1 sec intervals. All experiments are conducted at RT. Measurements For each assay plate, responses (increase in peak fluorescence) in each well following addition of agonist (test, control and reference) are determined. These responses may be expressed as raw CFU (Corrected Fluorescence Units), as a % maximum ionomycin response or other unit as determined by the investigator. Statistics For test compound, control compound (Noerepinephrine (NE) bitartrate), and reference compound) the concentration producing a 50% increase in control response (EC5o) is determined using iterative curve-fitting methods. Excel spreadsheet or Kaleidagraph soft¬ware are used to fit data to the general logistic function (E = B + Emas ■ A1^ / A^ + ECso^), where B is the corrected baseline fluorescence units (defined as zero), A is the concentra¬tion of agonist added and nH is the Hill slope (constrained to unity). EC50 values and maxima (Emai) for each curve can be estimated objectively using this software. In addition the intrinsic activity (a) is determined. Intrinsic activity is defined as the maxi-l mum response to test agonist divided by the maximum response to a full agonist acting through the same receptor. For these experiments, the full agonist is defined as Norepi¬nephrine (NE) bitartrate (control). As used herein an agonist is a compound that elicits a maximal response greater than 50% of that of norepinephrine with a pEC5o>5.5. j The compounds prepared in the above examples are alpha-1A/L agonists. Example 12: Assays for Alpha- 1A/L Adrenoceptor Activity Compounds used in this example were from Sigma Chemical Co., St Louis, MO, U.S.A.) unless specified otherwise. In Vitro: Male white New Zealand rabbits (3-3.5 kg) and Sprague-Dawley rats (250-400 g) were euthanized by C02 asphyxiation. The bladder (rabbit) or aorta (rat) were removed, extra¬neous tissue was dissected away, and tissues were placed in oxygenated Krebs" solution (mM: NaO, H8.5; NaHCO,, 25; dextrose, 5: KC1,4.8; CaCl2, 2.5; MgS04, 1.2 and KH2P04, 1.2). Cocaine (30 uM), corticosterone (30 uM), ascorbic acid (100 uM), indomethacin (10 uM) and propranolol (1 uM) were added to the Krebs" solution to block neuronal uptake, extxaneuronal uptake, auto-oxidation of catecholamines, prostanoid synthesis, beta-adre-noceptors, respectively. The alpha-2 adrenoceptor antagonist idazoxan (0.3 uM, Research Biochemicals, Inc., Natick, MA, U.S.A.) and the calcium channel antagonist nitrendipine (1 uM, Research Biochemico International, Natick, MA, U.S.A.) were added the Krebs" solution for rabbit and. rat experiments, respectively. Strips of bladder neck (rabbit)" .. . approximately 0.8-1.2 cm in length and 2-3 mm in width and aortic rings (2-4 per rat) approximately 3 mm in width, cut as near the heart as possible, were suspended in water-jacketed tissue baths at a resting tension of 1. Tissues were maintained at 34°C and bubbled continuously with an oxygen/carbon dioxide mixture. Tissues were primed with norepinephrine (10 uM) and washed for 60 minutes before con¬structing a first cumulative concentration-effect to norepinephrine. Tissues were then washed for 60 minutes before constructing a second concentration-effect curve to a test agonist. The concentration producing the half maximal response (pEC50) and the intrinsic activity (relative to norepinephrine) were recorded. Results for standards and representa¬tive compounds of the present invention were determined. Representative compounds of the invention showed activity in this assay. In Vivo: Anesthetized Pig Urethra/Blood Pressure Model: Female Yucatan micropigs (12-35 kg; >10 months old) were anesthetized with ketamine (Aveco Co., Ft. Dodge, IA, U.S.A.) followed by pentobarbital (Schering Plough Animal Health Corp., Kenilworth, N.J., U.S.A.). A cuffed endotracheal tube was placed in the trachea and the pig mechanically ventilated with room air under positive pressure. The right or left femoral artery and vein were isolated and cannulated. One of the two cannulae inserted into the femoral vein was used to infuse pentobarbital (5-20 mg/kg/hr) via an in¬fusion pump. The second cannula was used to administer test compounds. The cannula inserted into the femoral artery was connected to a blood pressure transducer (Gould/-Statham Spiectamed P23 series) for the measurement of aortic blood pressure. Needle electrodes were placed subcutaneously to record a limb lead II ECG and heart rate was monitored by a tachometer triggered by the R-wave of the ECG. Body heat was main¬tained with an Aquamatic hot water blanket, model K-2Q, and rectal temperature was con¬tinuously monitored with a YSI TeleThermometer, model 43TA. Following a ventral midline laparotomy, both ureters were cannulated for the exterioriza¬tion of urine. The bladder was emptied and a water-filled balloon catheter (reservoir tip of a latex condom attached to PE-190 tubing) attached to an external pressure transducer was inserted through the bladder via a stab incision. The balloon catheter was advanced into the urethra and secured with silk ligatures. Correct placement of the balloon was verified by palpating the urethra when inflating and deflating the balloon. Following the surgical preparation, blood gases (analyzed by a Nova Stat Profile 3 blood gas analyzer) and pH were adjusted to within normal limits by adjusting respiratory rate, tidal volume, and/or positive-end expiratory pressure. Intraurethrai pressure was adjusted to an appropriate baseline (20-40 cml^O) by inflating or deflating the balloon. Following a 30 minute stabilization period, the pig was pretreated with a beta-adrenoceptor ant¬agonist (propranolol; 100 ug/kg, iv), a non-selective alpha-2 adrenoceptor antagonist [8aR-(8aa,12aa,13aa)]-N-[3-[(53a,9,1041,12a,13,13a~octahycb-o-3-methoxy-6H-isoqumol[2,l-g] [l,3]naphtbyridin-12(8H)-yl)-sulfonyl]propyl]-methanesuifonamide (e.g., prepared by procedures described in EP 524,004 for compounds according to the present invention) (300 ug/kg, iv) and a ganglionic antagonist (chlorisondamine; 200 ug/kg, iv, prepared according to the procedure described in US 3,025,294). A single phenylephrine challenge (10 ug/kg, iv) was given to verify intraurethrai and blood pressure responses. After the response returned to baseline, multiple escalating doses of agonists were administered intravenously and maximal intraurethrai and diastolic blood pressure responses following each dose were recorded. Intervals between doses varied from 5-120 minutes to allow responses to return to baseline before giving the nest dose. At the end of each experiment, pigs were euthanized by a lethal injection of pentobarbital. The maximum responses for intraurethrai and diastolic blood pressure for standards and representative compounds of the invention were determined. Representative compounds of the invention showed l activity in this assay. In Vivo: Conscious Pig Urethra/Blood Pressure Model: Female Yucatan micropigs (12-35 kg; >10 months old) were trained to rest quietly in a sling for a week prior to surgery. Only those pigs which acclimated to the sling were used for the study. Figs were surgically instrumented under aseptic conditions, A telemetry 5 device (Data Science International, St Paul, MN, U.S.A., model TA11PAD-70) was im¬planted into the pig with the cannula portion of the device inserted into the right external iliac artery and advanced into the abdominal aorta. Ine transmitter puruon 01 uic uevn_e was placed in a pocket created under the skin in close proximity to the insertion point of tie cannula. A vascular access port (Sims Deltec, St Paul, MN, U.S.A.) with a silicon catheter was implanted for intravenous administration of test compounds. The catheter portion was inserted into the Jeft or right jugular vein with the port under the skin in the shoulder area. A strain-gauge transducer (SP Products, Madison, Wl, U.S.A.) was sutured to the urethra and the wire exteriorized dorsally. Pigs were allowed at least one week to recover from surgery. On each experimental day, pigs were placed in the sling and allowed to stabilize before ad¬ministering a phenylephrine prime (10 ug/kg, iv) to verify the placement of the needle in the vascular access port and calibration of the telemetry and strain-gauge probes. After urethral tension and blood pressure returned to baseline values, a non-cumulative dose-response curve to phenylephrine was constructed. Intervals between doses varied form 5-120 minutes to allow blood pressure to return to baseline levels. Sixty minutes after the last phenylephrine dose returned to baseline, a second non-cumulative curve to test compound was constructed. Responses to test compounds were expressed as a percentage of the maxi¬mum response obtained with phenylephrine. Representative compounds of the invention showed activity in this assay. While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. WE CLAIM : 1. A compound of the formula I or a phaimaceutically acceptable salt. 5. The compound of formula I according to claim 1 selected from 3-(4,5-dihycko-lH-imida2ol-2-7lmeth^)-l-metrianesulfon7l-lH-mdole; 5-chloro-3- (4,5-dmydro-lH-imidazol-2-ylmethyi) -1 -median esulfonyl- lH-indole; 3-(4,5-dmydro-lH-irmdazol-2-ylmemyl)-4-fluoro-l-meliiaiiesulfonyl-lH-indole;" 3-(4,5-dmydro-lH-imida2ol-2-yImemyI)-5-fluoro-l-methanesulfonyi-lH-indole;and 4-chIoro-3-(4,5-dihydro- lH-imidazol-2-ylniethyl)- l-methanesultoDyl-2-aiethyl- 1H-indole. 6. A compound of formula I according to claim 1 for use as therapeutic active substance. 7. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 together with a pharcaaceuticaHy acceptable carrier.

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