Field of the Invention This invention relates to use of a compound of Formula I,
(Figure Remove)
in the manufacture of pharmaceutical compositions for treating or preventing disease or disorder mediated through aia and/or aid adrenergic receptors, particularly benign prostatic hyperplasia (BPH) or lower urinary tract symptoms associated with or without BPH. This invention further relates to a process for preparing compounds of Formula I.
Background of the Invention
Benign prostatic hyperplasia (BPH) is a condition, which develops in elderly males and refers to the benign overgrowth of the stromal and epithelial elements of the prostate with aging. The symptoms of BPH vary, but the most common ones involve changes or problems with urination, such as hesitant, interrupted, weak stream or urgency and leaking or dribbling or more frequent urination, especially at night. Consequences of BPH can involve hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection.
There are two components of BPH, static and a dynamic component. The static component is due to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of the urine from the bladder. The dynamic component is due to increased smooth muscle tone of the bladder neck and prostate itself and is regulated by a i adrenergic receptor.
Currently, the most effective treatment for BPH is the surgical procedure of transurethral resection of the prostate (TURP), since it removes the obstructing tissue (C. Chappie's Br. Med. Journal 304: 1198-1199, 1992). It is a treatment, which is directed to the static and dynamic components of the BPH. However this surgical treatment is associated with rates of mortality (1%) and adverse event (incontinence, 2-4%), infection (5-10 %) and impotence (5-10%). A noninvasive alternative treatment is therefore highly desirable. There are some drug therapies, which address the static component of this condition. Administration of fmasteride is one such
therapy, which is indicated for the treatment of symptomatic BPH. This drug is a competitive inhibitor of the enzyme 5 a-reductase that is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland. Dihydrotestosterone appears to be the major mitogen for prostate growth, and agents, which inhibit 5-a reductase reduce the size of the prostate and improve urine flow through the prostatic urethra. Although fmasteride is a potent 5-a reductase inhibitor and causes a marked decrease in serum and tissue concentrations of dihydrotestosterone, it is moderately effective in the treatment of symptomatic BPH. The effects of fmasteride take 6-12 months to become evident and for many men the clinical development is minimal.
The dynamic component of BPH has been addressed by the use of adrenergic receptor blocking agents, which act by decreasing the smooth muscle tone within the prostate gland. A variety of cti AR antagonists, for example,terazosin, doxazosin, prazosin, alfuzosin and tamsulosin have been investigated for the treatment of symptomatic bladder outlet obstruction due to BPH. However, these drugs are associated with vascular side effects (e.g. postural hypertention, syncope, dizziness, headache etc) due to lack of selectivity of action between prostatic and vascular oti adrenoceptor. There are several lines of evidence to suggest that selectivity for aia adrenoceptor over otib adrenoceptor will result in relative lack of vascular side effects, thus lead to a better tolerability. Mice deficient in aib adrenoreceptors show diminished blood pressure response to phenylephrine injection compared to homozygous controls (Decreased blood pressure response in mice deficient of a^ adrenergic receptor. (Proc Natl Acad Sci USA 1997,94,11589-11594). In-vivo studies in healthy subjects comparison of aia / aid selective antagonists (for example, tamsulosin) or aia selective antagonists (for example, urapidil) with non selective antagonists (for example,doxazosin, prazosin, or terazosin) under a variety of experimental conditions (e.g. involving the administration of exogenous agonist or release of endogenous agonist by cold stimulation) in several vascular beds including the skin circulation in finger tips, the dorsal hand vein, or with total peripheral resistance have been reported (Eur J Clin Pharmacol, 1996, 49, 371-375; Naunyn Schmiedeberg's Arch Pharmacol 1996, 354, 557-561; Jpn J Pharmacol 1999, 80, 209-215; Br J Clin Pharmacol 1999, 47, 67-74). These studies have reported that an antagonist with high affinity for aia or aia/aid can cause some degree of vasodilation but that it is much smaller than with non-subtype-selective aia adrenoceptor antagonist. Further, there is increased vascular aib adrenoceptor expression in elderly patients and thus aia/aid selective agents with selectivity over aib adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia, which is generally a disease of old age. Antagonism of both aia adrenoceptor and aid adrenoceptor is important to relieve lower urinary

tract symptoms especially associated (suggestive of) with BPH. Targeting o.ia adrenoceptor with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction whereas aid adrenoceptor antagonism is important to target irritative symptoms.
The synthesis of l-(4-arylpiperazin-l-yl)-co-[N- (a, co-dicarboximido)]-alkanes useful as uro-selective ai-adrenoceptor blockers are described in U.S. patent Nos. 6,083,950; 6,090,809; 6,410,735; 6,420,559; 6,420,366, U.S. Publication No. 2002/0156085; PCT Publication Nos. WO 02/44151 and WO 00/05206. These compounds had good aj-adrenergic blocking activity and selectivity; all these patents are incorporated by reference herein in their entirety.
The PCT Publication No. WO 02/055496 discloses aryl piperidine and aryl piperazine, which are used in the manufactured of medicaments for the treatment of diseases ameliorated by LDL-R upregulation. The U.S. Patent No. 3,933,824 discloses central nervous system active butyrophenone derivatives. The U. S. Patent No. 2,997,472 discloses piperazine derivatives, which are depressants of the central nervous system. They are also barbiturate potentiators and analgesic agents. The European Publication No. 0 661 266 discloses substituted cyclic amine derivatives, which are used for circulatory organ. PCT Publication No. application WO 96/02250 discloses haloperidol analogs as subtype-selective NMDA receptor ligands and the use thereof for treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases. The U.S. Patent Publication No. 2002/0099216 discloses aryl piperidine derivatives, which are useful in the prophylaxis and in the treatment of diseases mediated by opiate receptor, such as pruritus.
Summary of the Invention
In one aspect, provided herein the use of a compound of Formula I in the manufacture of pharmaceutical compositions for treating or preventing a disease or disorder mediated through and/or a^ adrenergic receptors, wherein compound of Formula I is:

0
Formula I pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers,
polymorphs, N-oxide, prodrugs or metabolites thereof, wherein:

RI, Ra and Ra can be independently halogen, alkyl, cycloalkyl or alkoxy;
Rj and RS can be independently hydrogen, halogen, cyano, alkyl, alkoxy OR6, SRe or NR6R7;
Re and Rj can be independently hydrogen, alkyl or aryl; X can be N or CR;
R can be hydrogen, hydroxy or alkoxy; n can be an integer of from 2 to 5.
The use may involve one or more of the following features. For example,
The disease or disorder may be benign prostate hyperplasia. In another feature, compound causes minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. In another feature, the disease or disorder is lower urinary tract symptoms associated with or without BPH. LUTS may include, for example, irritative symptoms such as frequent urination, urgent urination, nocturia and unstable bladder contractions, obstructive symptoms such as hesitancy, poor stream, prolong urination, or feelings of incomplete emptying.
In another aspect, provided herein pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds of Formula I, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, polymorphs, N-oxide, prodrugs or metabolites thereof, optionally together with one or more pharmaceutically acceptable carriers, exipients, diluents or mixture thereof.
In another aspect, provided herein methods for treating or preventing a patient suffering from a disease or disorder mediated through ctia and/or aid adrenergic receptors, comprising administering to a patient therapeutically effective amounts of one or more compounds of Formula I.
In another aspect, provided herein methods for the prophylaxis and/or treatment of a patient suffering from benign prostatic hyperplasia (BPH) and related symptoms comprising administering to a patient therapeutically effective amounts of one or more compounds of Formula I.
In another aspect, provided herein methods for treating a patient suffering from lower urinary tract symptoms (LUTS) with or without BPH comprising administering to a patient therapeutically effective amounts of one or more compounds of Formula I.

In another aspect, provided herein are methods for treating a patient suffering from benign prostatic hyperplasia or lower urinary tract symptoms with or without benign prostatic hyperplasia comprising administering to a patient therapeutically effective amounts of one or more compounds (or compositions) described herein in combination with one or more other therapeutic agents selected from muscarinic receptor antagonists, bladder selective muscarinic receptor antagonists, testosterone 5 alpha-reductase inhibitors, endothelin antagonists, melanocortin receptor agonists, cGMP elevators, HMG-CoA reductase inhibitors, 5-HT antagonists or combination thereof. In one embodiment, provided herein are methods for treating a patient suffering from benign prostatic hyperplasia or lower urinary tract symptoms with or without benign prostatic hyperplasia comprising administering to a patient therapeutically effective amounts of one or more compounds (or compositions) described herein in combination with one or more solifenacin, darifmacin, RBx-9841, 10416, dutasteride, finasteride, pravastatin, simvastatin, atorvastatinRBx-10558, 11901 or combination thereof.
The following definitions apply for the terms used herein:
The term "alkyl," unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may be substituted further with one or more substituents selected from halogen, hydroxy, alkoxy, cycloalkyl, or -NRsR?, wherein Rg and Ry are independently hydrogen or alkyl.
The term "aryl," unless otherwise specified, refers to carbocyclic aromatic groups, for example, phenyl, biphenyl or napthyl ring and the like, optionally substituted with one or more substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CFs, cyano, nitro, carboxy or ester. The aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
The term "cycloalkyl," unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group,
for example, indane, and the like. Spiro and fused ring structures can also be included. Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, animo, or substituted amino.
The term "alkoxy" stands for a radical represented by Formula O-alkyl or O-cycloalkyl, wherein alkyl and cycloalkyl are the same as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, isopropoxy, cyclopentyloxy, and the like.
The term "pharmaceutically acceptable salts" refers to derivatives of compounds that can be modified by forming their corresponding acid salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts, for example, hydrochlorate, sulfate, phosphate, or organic acids salts, for example, acetate, succinate, glycolate, gluconate, lactate, maleate, tartarate, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilate, mesylate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, 2-hydroxyethanesulfonate. These salts may be prepared by the useful prior art techniques.
The term "pharmaceutically acceptable solvates" refers to solvates with waters (i.e hydrates) or pharmaceutically acceptable organic solvents. Such solvates are also encompassed within the scope of this invention. The present invention also includes within its scope prodrugs of these agents. In general, such "prodrugs" will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound. Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example, in "design of prodrugs", ed. H Bundgaard and, Elsevier, 1985. The present invention also includes metabolites, which become active upon introduction into the biological system. The crystalline or amorphous forms of compounds described herein may exist as polymorphs and as such are intended to be included in the present invention. The compounds of present invention include stereoisomers. The term "stereoisomer" refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. These include enantiomers, diastereomers, geometrical isomers, atropisomer and conformational isomers. Geometric isomers may occur when a compound contains a double bond or some other feature that gives the molecule a certain amount of structural rigidity. An enantiomer is a stereoisomer of a reference molecule that is the nonsuperimposable mirror image of the reference molecule. A diastereomer is

a stereoisomer of a reference molecule that has a shape that is not the mirror image of the reference molecule. An atropisomer is a conformational of a reference compound that converts to the reference compound only slowly on the NMR or laboratory time scale. Conformational isomers (or conformers or rotational isomers or rotamers) are stereoisomers produced by rotation about a bonds, and are often rapidly interconverting at room temperature. Racemic mixtures are also encompassed within the scope of this invention.
Detailed Description of the Invention
The compounds described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds of the present invention may be prepared by the following reaction sequences as depicted in Scheme I.
(Figure Remove)
Compounds of Formula I can be prepared according to Scheme I. Thus compound of Formula II can be reacted with a compound of Formula III to form a compound of Formula I.
The reaction of a compound of Formula II can be carried out in the presence of potassium carbonate in a solvent, for example, dimethylformamide, dimethylsulfoxide or tetrahydrofuran. This reaction can also be carried out in the presence of an organic base, for example, trimethylamine, dimethylamine or triethylamine.
An illustrated list of compounds of particular embodiment is given below: l-(2,4-Difluorophenyl)-4-[4-(2-ethoxyphenyl)-piperazin-l-yl]-butan-l-one (CompoundNo. 1),
1 -(2,4-Difluorophenyl)-4-[4-(2-ethoxyphenyl)-piperazin-1 -yl]-butan-1 -one hydrochloride salt (Compound No. 2),
1 -(2,4-Difluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-1 -yl]-propan-1 -one (Compound No.
3),
1 -(2,4-Difluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-1 -yl]-propan-1 -one hydrochloride salt (Compound No. 4),
l-(2,4-Difluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-l-yl]-butan-l-one (CompoundNo. 5),
1 -(2,4-Difluorophenyl)-4- [4-(2-methoxyphenyl)-piperazin-1 -yl] -butan-1 -one hydrochloride salt (Compound No. 6),
l-(2,4-Difluorophenyl)-4-[4-(2-isopropxyphenyl)-piperazin-l-yl]-butan-l-one (Compound No. 7),
1 -(2,4-Difluorophenyl)-4-[4-(2-isopropxyphenyl)-piperazin-1 -yl]-butan-1 -one hydrochloride salt (Compound No. 8),
4-[4-(2-cyclopentyloxyphenyl)-piperazin-1 -yl]-1 -(4-fluorophenyl)-butan-1 -one (Compound No. 9),
4- [4-(2-cyclopentyloxyphenyl)-piperazin-1 -yl] -1 -(4-fluorophenyl)-butan-1 -one hydrochloride salt (Compound No. 10),
4-[4-(2-cyclopentyloxyphenyl)-piperazin-1 -yl]-1 -(2,4-difluorophenyl)-butan-1 -one (Compound No. 11),
4-[4-(2-cyclopentyloxyphenyl)-piperazin-1 -yl]-1 -(2,4-difluorophenyl)-butan-1 -one hydrochloride salt (Compound No. 12),
l-(4-Fluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-l-yl]-butan-l-one (Compound No. 13),
1 -(4-Fluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-1 -yl]-butan-1 -one hydrochloride salt (Compound No. 14),
4-[4-(2-ethoxyphenyl)-piperazin-l-yl]-l-(4-fluorophenyl)-butan-l-one (Compound No. 15),
4- [4-(2-ethoxyphenyl)-piperazin-1 -yl] -1 -(4-fluorophenyl)-butan-1 -one hydrochloride salt (Compound No. 16),
l-(4-Fluorophenyl)-4-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-butan-l-one (Compound No. 17),
1 -(4-Fluorophenyl)-4-[4-(2-isopropoxyphenyl)-piperazin-1 -yl]-butan-1 -one hydrochloride salt (Compound No. 18),
l-(4-Fluorophenyl)-4-[4-(2-methoxyphenyl)-piperidin-l-yl]-butan-l-one (CompoundNo. 19),
1 -(4-Fluorophenyl)-4-[4-(2-methoxyphenyl)-piperidin-1 -yl]-butan-1 -one hydrochloride salt (Compound No. 20),
1 -(4-Fluorophenyl)-4-[4-hydroxy-4-(2-methoxyphenyl)-piperidin-1 -yl]-butan-1 -one (Compound No. 21),
1 -(4-Fluorophenyl)-4-[4-hydroxy-4-(2-methoxyphenyl)-piperidin-1 -yl] -butan-1 -one hydrochloride salt (Compound No. 22),
l-(4-Fluorophenyl)-4-[4-(2-propoxyphenyl)-piperazin-l-yl]-butan-1-one (Compound No. 23),
l-(4-Fluorophenyl)-4-[4-(2-propoxyphenyl)-piperazin-l-yl]-butan-l-one hydrochloride salt (Compound No. 24),
4-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-1 -yl]-1 -(4-fluorophenyl)-butan-1 -one (Compound
No. 25),
4- [4-(5 -Fluoro-2-isopropoxyphenyl)-piperazin-1 -yl] -1 -(4-fluorophenyl)-butan-1 -one hydrochloride salt (Compound No. 26), or
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, polymorphs, N-oxide, prodrugs or metabolites.
The compounds described herein may be administered to an animal for treatment orally, parenterally, topically, rectally, internasally, subcutaneously or by transdermally. The pharmaceutical compositions of the present invention comprise a pharmaceutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filter, diluent, encapsulating material or formulation auxiliary of any type. Solid form preparation for oral administrations, include capsules, tablets, pills, powder, granules cathets and suppository. For solid form preparation, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate and/or a filler or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid; binders such as carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, acacia; disintegrating agents such as a agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates and sodium carbonate, absorption accelators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol, monostearate; adsorbents such as kaolin; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate and mixture thereof.
In case of capsules, tablets, pills, the dosage form may also comprise buffering agents.
The solid preparation of tablets, capsules, pills, granules can be prepared with coating and shells such as enteric coating and other coatings well known in the pharmaceutical formulating art.
Liquid form preparation for oral administration includes pharmaceutically acceptable emulsions, solution, suspensions, syrups and elixirs. For liquid form preparation, the active compound is mixed with water or other solvent, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed, groundnut, corn, germ, olive, castor and Sesamie oil), glycerol, and fatty acid esters of sorbitan and mixture thereof. Besides inert diluents, the oral composition can also include adjuvant such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.
Injectable preparations such as sterile injections, aqueous or oleaginous suspensions may be formulated according to the art using suitable dispersing or wetting and suspending agents. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride.
Dosage form for tropical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhalants or patches. The active compound is admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservative or buffer as may be required. Ophthalmic formulation, eardrops, eye ointments, powder and solution are also contemplated as being within the scope of this invention.
The pharmaceutical preparation may be in unit dosage form. In such form, the preparation may be subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be packaged preparation, the package containing discrete capsules, powders, in vials or ampoules and ointments, capsules, cachet, tablet, gel cream itself or it can be the appropriate number of any of there packaged forms.
The formulation of the present invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known to the art.
The dosages of the compounds described herein, bladder selective muscarinic receptor antagonist, 5 alpha-reductase inhibitor or atorvastatin are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the compounds described
herein, bladder selective muscarinic receptor antagonist, 5 alpha-reductase inhibitor or atorvastatin may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent is used alone. In accordance with the method of this invention, the individual component of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.
Examples
Example 1: Preparation of l-(2.4-Difluorophenvl')-4-[4-(2-methoxvphenvl)-piperazin-l-vl]-propan-1-one (Compound No. 3)
Step a: Preparation of 3-chloro-l-(2,4-difluorophenyl)-propan-l-one
To a solution of 1,3-difluorobenzene (1 equiv.) and anhydrous aluminium chloride (1.5 equiv.) in dichloromethane was added chloropropionyl chloride dropwise at about 0-5 °C. Reaction mixture was gradually brought to about 40 °C and heated at that temperature under stirring till the evolution of hydrochloride gas was stopped. Reaction mixture was poured on to ice cold hydrochloride under stirring and extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated to get the desired product.
Step b: Preparation of l-(2,4-Difluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-l-yl]-propan-l-one
A solution of 3-chloro-l-(2,4-difluorophenyl)-propan-l-one (1 equiv., step a), l-(2-methoxyphenyl)-piperazine mono hydrochloride (1 equiv.), triethylamine (2 equiv.) and potassium iodide (2 mole%) in dimethylformamide was heated at about 55-60 °C for about 12 hours. Reaction was quenched by adding water, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulphate and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate in hexane as solvent.
The following compounds were prepared similarly l-(2,4-Difluorophenyl)-4-[4-(2-ethoxyphenyl)-piperazin-l-yl]-butan-l-one (Compound No. 1)
l-(2,4-Difluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-l-yl]-butan-l-one (Compound No. 5) l-(2,4-Difluorophenyl)-4-[4-(2-isopropxyphenyl)-piperazin-l-yl]-butan-l-one (Compound No. 7)
4-[4-(2-cyclopentyloxyphenyl)-piperazin-1 -ylj-1 -(4-fluorophenyl)-butan-1 -one (Compound No. 9)
4-[4-(2-cyclopentyloxyphenyl)-piperazin-1 -yl]-l-(2,4-difluorophenyl)-butan-1 -one (Compound No. 11)
l-(4-Fluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-l-yl]-butan-l-one (Compound No. 13) 4-[4-(2-ethoxyphenyl)-piperazin-l-yl]-l-(4-fluorophenyl)-butan-l-one (Compound No. 15) l-(4-Fluorophenyl)-4-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-butan-l-one (CompoundNo. 17) l-(4-Fluorophenyl)-4-[4-(2-propoxyphenyl)-piperazin-l-yl]-butan-l-one (Compound No. 23)
4-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-1 -yl]-1 -(4-fluorophenyl)-butan-1 -one (Compound
No. 25)
Example 2: Preparation of l-(2.4-Difluorophenvl)-4-[4-(2-methoxvphenvl)-piperazin-l-vl]-propan-1-one hydrochloride salt (Compound No. 4)
An equimolar quantity of isopropyl alcohol-hydrochloric acid was added to a solution of l-(2,4-Difluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-l-yl]-propan-l-one in dichloromethane at about 0-5°C to get the desired product.
IR(KBr): 1604cm'1
'H NMR (300 MHz, CDC13): 5 3.07-3.19 (6H, m), 3.71-3.88 (6H, m), 3.97 (3H, s), 6.43-7.84 (8H,
m).
Mass (M++l): 361.0, Hygrosopic
The following compounds were prepared similarly
1 -(2,4-Difluorophenyl)-4-[4-(2-ethoxyphenyl)-piperazin-1 -yl]-butan-1 -one hydrochloride salt (Compound No. 2)
IR(KBr): 1612.2cm"1
'H NMR (300 MHz, CDC13): 8 1.25 (3H, m), 1.61 (2H, m), 2.00-2.23 (2H, m), 3.08 (2H, m),
3.65-3.76 (4H, m), 3.99-4.14 (6H, m), 6.54-7.93 (8H, m).
Mass:389(M++l)
Hygrosopic
1 -(2,4-Difluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-1 -yl]-butan-1 -one hydrochloride salt (Compound No. 6)
IR(KBr): 1614.1cm'1
'H NMR (300 MHz, CDC13): 8 1.96-2.01 (2H, m), 3.19-3.22 (6H, m), 3.45-3.55 (4H, m), 9.70-3.88 (2H, m), 3.90 (3H, s), 6.50-7.86 (8H, m). Mass (M++l): 375 (M++l), Hygrosopic
1 -(2,4-Difluorophenyl)-4-[4-(2-isopropxyphenyl)-piperazin-1 -yl]-butan-1 -one hydrochloride salt (Compound No. 8)
IR(KBr): 1670cm'1
'H NMR (300 MHz, CDC13): 8 1.36-1.38 (6H, m), 1.98-2.20 (2H, m), 3.06-3.12 (2H, m), 3.23
(4H, brs), 3.51 (4H, brs), 3.64-3.74 (2H, m), 4.58-4.64 (1H, m), 6.50-6.56 (1H, m), 6.70-6.73 (1H,
m), 6.89-6.95 (4H, m), 7.83-7.89 (1H, m), 12.58 (1H, brs).
Mass (M++l): 403.2
m.p: 102-105°C
4-[4-(2-cyclopentyloxyphenyl)-piperazin-l-yl]-l-(4-fluorophenyl)-butan-l-one hydrochloride salt (Compound No. 10)
IR(KBr): 1685.7cm'1, 1597.0cm'1
'HNMR (300 MHz, CDC13): 8 1.68-1.83 (4H, m), 1.90-1.97 (4H, m), 2.40 (2H, brs), 3.09-3.17 (4H, m), 3.26-3.30 (2H, m), 3.53-3.62 (4H, m), 3.66 (2H, m), 4.81-4.83 (1H, m), 6.85-6.93 (3H, m), 7.00-7.02 (1H, m), 7.13-7.19 (2H, m), 7.99-8.04 (2H, m), 12.58 (1H, brs). Mass(M++l):411.2 m.p: 182-85°C
4-[4-(2-cyclopentyloxyphenyl)-piperazin-l-yl]-l-(2,4-difluorophenyl)-butan-l-one hydrochloride salt (Compound No. 12)
IR(KBr): 1668.9,1610.8cm'1
'HNMR (300 MHz, CDC13): S 1.67-2.01 (10H, m), 3.03-3.05 (2H, m), 3.20-3.31 (4H, m), 3.50
(4H, m), 3.63-3.73 (2H, m), 4.80 (1H, m), 6.50-6.55 (1H, m), 6.70-6.74 (1H, m), 6.70-6.74 (5H,
m), 7.83-7.89 (1H, m), 12.8 (1H, brs).
Mass (M++l): 429
m.p: 116-20°C
1 -(4-Fluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-1 -yl]-butan-1 -one hydrochloride salt (Compound No. 14)
IR (KBr): 1687.6 cm'1, 1637.0 cm'1
'HNMR (300 MHz, CDC13): S 2.39 (2H, m), 3.14-3.19 (4H, m), 5.25-3.29 (2H, m), 3.53 (4H, m),
3.63 (2H, m), 3.88 (3H, s), 6.88-6.98 (3H, m), 7.05-7.18 (3H, m), 7.99-8.04 (2H, m), 12.6 (1H,
brs).
Mass (M++l): 357
m.p: 226-28°C
4-[4-(2-ethoxyphenyl)-piperazin-1 -yl]-1 -(4-fluorophenyl)-butan-1 -one hydrochloride salt (Compound No. 16)
IR (KBr): 1688.7 cm", 1638.3 cm
'HNMR (300 MHz, CDC13): 5 1.44-1.49 (3H, m), 2.40 (2H, m), 3.16 (4H, m), 3.26-3.30 (2H, m), 3.56-3.67 (6H, m), 4.05-4.12 (2H, m), 6.86-7.19 (6H, m), 7.99-8.04 (2H, ml, 12.57) (1H, brs) Mass(M++l):371.19 m.p: 170-73°C
1 -(4-Fluorophenyl)-4- [4-(2-isopropoxyphenyl)-piperazin-1 -yl] -butan-1 -one hydrochloride salt (Compound No. 18)
IR(KBr): 1688.0 cm'1
'HNMR(300 MHz, CDC13): 8 1.38-1.40 (6H, d), 2.39 (2H, m), 3.19-3.30 (6H, m), 3.49-3.74
(6H, m), 4.58-4.66 (1H, m), 6.88-6.94 (2H, m), 7.04-7.18 (4H, m), 7.99-8.04 (2H, m), 12.66 (1H,
brs).
Mass (M++l): 385.5
m.p: 173-77°C
1 -(4-Fluorophenyl)-4- [4-(2-propoxyphenyl)-piperazin-1 -yl] -butan-1 -one hydrochloride salt (Compound No. 24)
IR(KBr): 1684.4,1596.4cm'1
'H NMR (300 MHz, CDC13): 8 1.04-1.09 (3H, m), 1.83-1.90 (2H, m), 2.29-2.34 (2H, m), 3.09-
3.14 (6H, m), 3.20-3.24 (4H, m), 3.48-3.52 (4H, m), 3.74-3.79 (2H, m), 3.99 (2H, m), 6.86-7.18
(6H, m), 7.98-8.02 (2H, m), 12.5 (1H, brs).
Mass (M++l): 385
m.p: 160-165°C
4-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-1 -yl] -1 -(4-fluoropheny l)-butan-1 -one hydrochloride salt (Compound No. 26)
IR(KBr): 1688.4,1598.2cm'1
'H NMR (300 MHz, CDC13): 8 1.33-1.35 (6H, d), 2.37-2.42 (2H, m), 3.06-3.29 (6H, m), 3.57-
3.66 (6H, m), 4.48-4.52 (1H, m), 6.63-6.82 (3H, m), 7.13-7.18 (2H, m), 7.99-8.03 (2H, m).
Mass (M++l): 403
m.p: 186-189°C
Example 3: Preparation of l-(4-FluorophenvlM-[4-hvdroxv-4-(2-methoxyphenylVpiperidin-l-yl]-butan-1-one (Compound No. 21)
A solution of 4-chloro-l-(4-fluorophenyl)-butan-l-one (1 equiv.), 4-(2-methoxyphenyl)-piperidin-4-ol (1 equiv., Chem.Pharm.Bull., 2000, 48(12), 1978), triethylamine (2 equiv.) and potassium iodide (2 mole) in dimethylformamide was heated at about 55-60 °C for about 12 hours. Reaction was quenched by adding water, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulphate and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate in hexane as solvent.
The following compounds can also be prepared similarly l-(4-Fluorophenyl)-4-[4-(2-methoxyphenyl)-piperidin-l-yl]-butan-l-one (Compound No. 19)
Example 4: Preparation of l-(4-Fluorophenvl)-4-[4-hvdroxy-4-(2-methoxyphenyl)-piperidin-l-yi]-butan-l-one hydrochloride salt (Compound No. 22}
An equimolar quantity of isopropyl alcohol-hydrochloric acid was added to a solution of l-(4-Fluorophenyl)-4-[4-hydroxy-4-(2-methoxyphenyl)-piperidin-l-yl]-butan-l-one in dichloromethane at about 0-5°C to get the desired product.
IR(KBr): 1638.9cm"1
'H NMR (300 MHz, DMSO-d6): 8 2.24-2.28 (2H, m), 2.49 (2H, m), 3.11-3.15 (2H, m), 3.57-3.59
(4H, m), 3.68-3.87 (4H, m), 4.23 (3H, s), 7.39-7.46 (2H, m), 7.70-7.75 (3H, m), 7.87-7.90 (1H,
m), 8.45-8.49 (2H, m).
Mass (M++l): 372.28
m.p: 205-208°C
The following compounds can also be prepared similarly
1 -(4-Fluorophenyl)-4- [4-(2-methoxyphenyl)-piperidin-1 -yl] -butan-1 -one hydrochloride salt (Compound No. 20)
IR(KBr): 1597.0cm'1
'H NMR (300 MHz, DMSO-d6): 6 2.23-2.39 (6H, m), 3.37-3.57 (7H, m), 3.95-3.99 (2H, m), 4.13
(3H, s), 7.32-7.36 (2H, m), 7.53-7.67 (4H, m), 8.37-8.41 (2H, m).
Mass (M++l): 356.2
m.p: 207-212°C
Example 5: Pharmacological testing
Receptor Binding Assay: Receptor binding assays were performed using native a-1 adrenoceptors. The affinity of different compounds for aia and ctib adrenoceptor subtypes was evaluated by studing their ability to displace specific [3H]prazosin binding from the membranes of rat submaxillary and liver respectively (Michel et al, Br J Pharmacol, 98, 883-889 (1989)). The binding assays were performed according to U'Prichard et al. (Eur J Pharmacol, 50:87-89 (1978) with minor modifications.
Submaxillary glands were isolated immediately after sacrifice. The liver was perfused with buffer (Tris HC1 50 mM, NaCl 100 mM, 10 mM EDTA pH 7.4). The tissues were homogenized in 10 volumes of buffer (Tris HC1 50 mM, NaCl 100 mM, EDTA 10 mM, pH 7.4). The homogenate was filtered through two layers of wet guaze and filtrate was centrifuged at 500g for 10 min. The supernatant was subsequently centrifuged at 40, OOOg for 45 min. The pellet thus obtained was resuspended in the same volume of assay buffer (Tris HC1 50 mM, EDTA 5 mM, pH 7.4) and were stored at -70 °C until the time of assay.
The membrane homogenates (150-250 u,g protein) were incubated in 250 ul of assay buffer (Tris HC1 50 mM, EDTA 5 mM, pH 7.4) at 24-25 °C for I hour. Non-specific binding was determined in the presence of 300 nM prazosin. The incubation was terminated by vaccum filtration over GF/B fibre filters. The filters were then washed with ice cold 50 mM Tris HC1 buffer (pH 7.4). The filtermats were dried and bounded radioactivity retained on filters was counted. The ICso and Kd were estimated by using the non-linear curve-fitting program using G pad prism software. The value of inhibition constant Ki was calculated from competitive binding studies by using Cheng and Prusoff equation (Cheng and Prusoff, Biochem Pharmacol, 1973, 22:3099-3108), Ki = IC50 /(1+L/Kd) where L is the concentration of [3H] prazosin used in the particular experiment. The selectivity value for alpha la verses alpha Ib is 0.59 (Ki in nM) or more. The Ki (nM) values for alpha la and alpha Ib subtype adrenergic receptors range from 1,6 to 224 and 3.2 to 504, respectively.

WE CLAIM:
1. Use of a compound of Formula I in the manufacture of pharmaceutical compositions for treating or preventing a disease or disorder mediated through a\a and/or aid adrenergic receptors, wherein compound of Formula I is:

(Figure Remove)
pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, prodrugs, polymorphs or metabolites thereof, wherein: RI, RI and Ra are independently halogen, alkyl, cycloalkyl or alkoxy; RI and RS are independently hydrogen, halogen, cyano, alkyl, alkoxy, ORe, SRe or NR6R7;
Re, R? are independently hydrogen, alkyl or aryl; X is N or CR;
R is hydrogen, hydroxy or alkoxy; n is an integer of from 2 to 5.
2. The use of claim 1, wherein pharmaceutical composition further comprises one or more
pharmaceutically acceptable carriers, excipients, diluents or mixture thereof.
3. The use of claim 1, wherein disease or disorder is benign prostatic hyperplasia.
4. The use of claim 1, wherein disease or disorder is lower urinary tract symptoms associated
with or without BPH.
5. The use of claim 1, wherein compound causes minimal fall or no fall in blood pressure at
dosages effective to alleviate benign prostatic hyperplasia.
6. The use of claim 1, wherein:
RI, R2 and RT, are independently hydrogen or halogen; n is an integer of from 2 to 5; X is N, CH or COH; R4 is alkoxy; RS is hydrogen or 4-F.
7. The use of claim 1, wherein compound of Formula I is selected from:
l-(2,4-Difluorophenyl)-4-[4-(2-ethoxyphenyl)-piperazin-l-yl]-butan-l-one,
1 -(2,4-Difluorophenyl)-4- [4-(2-ethoxyphenyl)-piperazin-1 -yl] -butan-1 -one hydrochloride salt,
1 -(2,4-Difluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-1 -yl] -propan-1 -one,
1 -(2,4-Difluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-1 -yl] -propan-1 -one hydrochloride salt,
1 -(2,4-Difluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-1 -yl]-butan-1 -one,
1 -(2,4-Difluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-1 -yl]-butan-1 -one hydrochloride salt,
1 -(2,4-Difluorophenyl)-4- [4-(2-isopropxyphenyl)-piperazin-1 -yl] -butan-1 -one,
1 -(2,4-Difluorophenyl)-4-[4-(2-isopropxyphenyl)-piperazin-1 -yl] -butan-1 -one hydrochloride salt,
4- [4-(2-cyclopentyloxyphenyl)-piperazin-1 -yl] -1 -(4-fluorophenyl)-butan-1 -one,
4-[4-(2-cyclopentyloxyphenyl)-piperazin-1 -yl]-1 -(4-fluorophenyl)-butan-1 -one hydrochloride salt,
4-[4-(2-cyclopentyloxyphenyl)-piperazin-1 -yl]-1 -(2,4-difluorophenyl)-butan-1 -one,
4-[4-(2-cyclopentyloxyphenyl)-piperazin-1 -yl]-1 -(2,4-difluorophenyl)-butan-1 -one hydrochloride salt,
1 -(4-Fluorophenyl)-4-[4-(2-methoxyphenyl)-piperazin-1 -yl]-butan-1 -one,
1 -(4-Fluorophenyl)-4- [4-(2-methoxyphenyl)-piperazin-1 -yl] -butan-1 -one hydrochloride salt,
4-[4-(2-ethoxyphenyl)-piperazin-1 -yl] -1 -(4-fluorophenyl)-butan-1 -one,
4-[4-(2-ethoxyphenyl)-piperazin-1 -yl] -1 -(4-fluorophenyl)-butan-1 -one hydrochloride salt,
1 -(4-Fluorophenyl)-4-[4-(2-isopropoxyphenyl)-piperazin-1 -yl] -butan-1 -one,
1 -(4-Fluorophenyl)-4-[4-(2-isopropoxyphenyl)-piperazin-1 -yl]-butan-1 -one hydrochloride salt,
1 -(4-Fluorophenyl)-4-[4-(2-methoxyphenyl)-piperidin-l -yl]-butan-1 -one, 1 -(4-Fluorophenyl)-4-[4-(2-methoxyphenyl)-piperidin-1 -yl]-butan-1 -one hydrochloride salt,
l-(4-Fluorophenyl)-4-[4-hydroxy-4-(2-methoxyphenyl)-piperidin-l-yl]-butan-l-one,
1 -(4-Fluorophenyl)-4-[4-hydroxy-4-(2-methoxyphenyl)-piperidin-1 -yl]-butan-1 -one hydrochloride salt,
1 -(4-Fluorophenyl)-4-[4-(2-propoxyphenyl)-piperazin-1 -yl] -butan-1 -one,
1 -(4-Fluorophenyl)-4-[4-(2-propoxyphenyl)-piperazin-1 -yl]-butan-1 -one hydrochloride salt,
4-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-l-(4-fluorophenyl)-butan-l-one,
4- [4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-1 -yl] -1 -(4-fluorophenyl)-butan-1 -one hydrochloride salt or
pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, prodrugs, polymorphs or metabolites thereof.
8. A method for preparing a compound of Formula I,

(Figure Remove)
pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, prodrugs, polymorphs or metabolites, wherein:
RI, RI and RS are independently halogen, alkyl, cycloalkyl or alkoxy;
R4 and RS are independently hydrogen, halogen, cyano, alkyl, alkoxy, ORe, SRe or
NR6R7;
Re, R? are independently hydrogen, alkyl or aryl; X is N or CR;
R is hydrogen, hydroxy or alkoxy; n is an integer of from 2 to 5.
which method comprises: