ADRENERGIC RECEPTOR ANTAGONISTS
Field of the Invention
The present invention relates to alpha la and/or alpha Id adrenergic receptor antagonists.
Compounds disclosed herein can function as alpha la and/or alpha Id adrenergic receptor antagonist and can be used for the treatment of a disease or disorder mediated through alpha la and/or alpha Id adrenergic receptor.
Compounds disclosed herein can be used for the treatment of benign prostatic hyperplasia and the related symptoms thereof
Compounds disclosed herein can be used for the treatment of lower urinary tract symptoms associated with or without benign prostatic hyperplasia. Processes for the preparation of the disclosed compounds, as well as, pharmaceutical composition containing the disclosed compounds, and the methods of treating benign prostatic hyperplasia or related symptoms thereof
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 urinationrespecially 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 -1 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 finasteride 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 finasteride 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 finasteride 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 α1a AR antagonists, for example, terazosin, doxazosin, prazosin, alfuzosin and tamulosin 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 α1 adrenoceptor. There are several lines of evidence to suggest that selectivity for α1a adrenoceptor over a1b adrenoceptor will result in relative lack of vascular side effects, thus lead to a better tolerability. Mice deficient in a1b adrenoreceptors show diminished blood pressure response to phenylephrine injection compared to homozygous controls (Decreased blood pressure response in mice deficient of a1b adrenergic receptor. (Proc Natl Acad Sci USA 1997,94,11589-11594). In-vivo studies in healthy subjects comparison of α1a / α1d selective antagonists (for example, tamsulosin) or α1a 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 au or a\Ja\d can cause some degree of vasodilation but that it is much smaller than with non-subtype-selective α1a adrenoceptor antagonist. Further, there is increased vascular α1b adrenoceptor expression in elderly patients and thus α1a/α1d selective agents with selectivity over α1b adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia, which is generally a disease of old age. Antagonism of both au adrenoceptor and α1d adrenoceptor is important to relieve lower urinary tract symptoms especially associated (suggestive of) with BPH. Targeting α1a adrenoceptor with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction whereas α1d adrenoceptor antagonism is important to target irritative symptoms.
Over the past decade, there has been an intensive search for selective α1a adrenoceptor antagonists for benign prostatic hyperplasia, which would avoid the cardiovascular side effects, associated with currently used drugs. Many selective antagonist have been described by Hieble et al in Exp opin Invest Drugs; 6, 367-387 (1997) and by Kenny et al., in J. Med. Chem.; 40, 1293-1325 (1995). Structure activity relationships in many of these structural series have been studied in details and numerous highly selective compounds have been identified. There are many description in the literature about the pharmacological activities associated with phenyl piperazines, Eur. J. Med. Chem. - Chimica Therapeutica, 12, 173-176 (1977), describes substituted trifluorometyl phenyl piperazines having cyclo-imido alkyl side chains shown below.
(Formula Removed)
Other related compounds which have been prepared as anxiolytic, neuroleptic, antidiabetic and anti-allergic agents are described in the following references:Yukihiro et al; PCT Appl. WO 98/37893 (1998),Steen et al; J. Med. Chem., 38, 4303-4308 (1995),Ishizumi et al. Chem. Pharm. Bult; 39 (9), 2288-2300 (1991),Kitaro et al; JP 02-235865 (1990),lshizumi et al; US 4,598,078 (1086),New et. al; J. Med. Chem. 29, 1476-1482 (1986),Shigeru et. al; JP 60-
204784 (1985),New et al, US 4,524, 206 (1985),Korgaonkar et al; J. Indian Chem. Soc, 60, 874-876(1983).
However, none of the above mentioned references disclose or suggest the α1 subtype selectivity profile of the compounds disclosed therein and thus their usefiilness in the treatment of symptoms of benign prostate hyperplasia did not arise.
The synthesis of l-(4-arylpiperazin-l-yl)- -[N- (α, co-dicarboximido)]-alkanes useful as uro-selective α1-adrenoceptor blockers are disclosed in US patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,559, 6,420,366, WO 00/05206, US patent appl. 2002/0156085 and WO 02/44151. These compounds had good α1 -adrenergic blocking activity and selectivity.
Other reports describing selective a1a adrenoceptor antagonists are US 6,376,503, US 6,319,932, US 6,339,090, EP 711757, WO 99/42448, WO 99/42445, WO 98/57940, WO 98/57632, WO 98/30560 WO 97/23462, WO 03/084928 and WO 03/084541 all these patents are incorporated by reference herein in their entirety.
Summary of the Invention
The present invention provides alpha la and/or alpha Id adrenergic receptor antagonists, which can be used for treatment of benign prostatic hyperplasia (BPH) or related symptoms thereof or lower urinary tract symptoms (LUTS) with or without BPH, and processes for the synthesis of these compounds.
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxide of these compounds having the same type of activity are also provided.
Pharmaceutical composition containing the disclosed compounds, and which may also contain pharmaceutically acceptable carrier, excipients or diluents, which can be used for the treatment of BPH or related symptoms thereof or LUTS with or without BPH.
Other objects will be set forth in accompanying description, which follows and in the part will be apparent from the description or may be learnt by the practice of the invention.
In accordance with one aspect, there are provided compounds having the structure of Formula I, as shown in the accompanied drawings, their pharmaceutically acceptable salts.
pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs, prodrugs or metabolites, wherein: A can be

(Formula Removed)
wherein R2, R3, R4 and R5 can be independently hydrogen, alkyl or phenyl, R6 can be hydrogen,
alkyl, phenyl, hydroxy or alkoxy, R7 and R8 can be independently alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heterocycle, aralkyl, (heterocycle)alkyl or R9—Q—(CH2)m— wherein m can be
an integer of from 0 to 3, R9 can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
heterocycle, Q can be oxygen, sulphur, carbonyl, carboxylic or wherein W can be no atom, carbonyl, carboxylic, amide, R10 can be hydrogen, alkyl, aryl, heterocyclic, R7 and R8
together can represent cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl,
heterocycle, R2 can also be wherein R11 and R12 can be independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NR13R14 wherein R13 and R14 can be
independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycle; X
and Y can be independently methylene or carbonyl; Rj can be hydrogen or methyl; R can be
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or (heterocycle)alkyl; n can be an
integer of from 1 to 3; can be optional double bond.
In accordance with a second aspect, there is provided a method for the treatment of a patient suffering from a disease or disorder mediated through alpha la and/or alpha Id adrenergic receptor, comprising administering to a patient, a therapeutically effective amount of a compound disclosed herein.
In accordance with a third aspect, there is provided a method for the treatment of a patient suffering from benign prostatic hyperplasia (BPH) and related symptoms, comprising administering to a patient, a therapeutically effective amount of a compound disclosed herein.
In accordance with a fourth aspect, there is provided a method for the treatment of a patient suffering from lower urinary tract symptoms (LUTS) 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, and feelings of incomplete emptying, comprising administering to a patient, a therapeutically effective amount of a compound disclosed herein.
In accordance with a fifth aspect, there are provided processes for the preparation of the compounds described herein.
In accordance with a sixth aspect, there is provided a method for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient, a therapeutically effective amount of a compound (or composition) described herein in combination with a bladder selective muscarinic receptor antagonist.
In accordance with a seventh aspect, there is provided a method for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient, a therapeutically effective amount of a compound (or composition) described herein in combination with a testosterone 5 alpha-reductase inhibitor.
In accordance with a eighth aspect, there is provided a method for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient, a therapeutically effective amount of a compound (or composition) described herein in combination with a bladder selective muscarinic receptor antagonist and optionally included testosterone 5 alpha-reductase inhibitor.
Receptor binding studies described below indicated that the compounds disclosed herein possess selective and potent α1a adrenoceptor antagonistic activity over the α1b adrenoceptors. The examples presented below describe a method to treat BPH in a patient wherein the test compounds alleviated pressure at dosages, which did not result, in significant change in blood pressure. Several of the disclosed compounds demonstrated manifest selectivity for prostatic tissues in comparison to known compounds. Additionally, the disclosed compounds can be used for relaxing lower urinary tract tissues and thus alleviating irritative symptoms in-patient.
Therefore, the present invention provides pharmaceutical compositions for treatment of a disease or disorder mediated through α1a adrenoceptor. Moreover, the disclosed compounds of the present invention can also be used for treatment of lower urinary tract symptoms. Compounds and compositions described herein can be administered orally, parenterally, subcutaneously, transdermally or topically. The following definitions apply to terms as used herein:
The term "alkyl" refers to straight or branched saturated hydrocarbon having one to six carbon atom (s). One or more hydrogen atom (s) of sα1d alkyl can optionally be replaced by halogen, hydroxy, cycloalkyl, cycloalkenyl or -NR7R8, wherein R7 and R8 are selected from hydrogen and alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl and butyl, and the like.
The term "alkenyl or alkynyl" stands for unsaturated hydrocarbon having two to six carbon atoms. One or more hydrogen of sα1d alkenyl or alkynyl can be replaced by halogen. Examples of alkenyl and alkynyl include, but are not limited to, ethylene, propylene, ethynyl and propynyl, and the like.
The term "cycloalkyl" refers to saturated carbocyclic ring having three to seven carbon atoms. Examples of cycloakyl include, but are not limited to, cyclopropyl, cyclobutyl and cyclopentyl, and the like.
The term "cycloalkenyl refers to unsaturated carbocyclic ring having three to seven carbon atoms. Examples of cycloakenyl include, but are not limited to, cyclopropenyl and cyclobutenyl, and the like.
The sα1d "cycloalkyl" or "cycloalkenyl" may optionally be substituted with halogen.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "aryl" stands for an aromatic radical having 6 to 14 carbon atoms. Examples of aryl include, but are not limited to, phenyl, napthyl, anthryl and biphenyl, and the like.
The term "aralkyl" stands for an aryl radical having 7 to 14 carbon atoms, which is bonded to an alkylene chain. Examples of aralkyl include, but are not limited to, benzyl, napthylmethyl, phenethyl and phenylpropyl, and the like.
The term "heterocycle" refers to non-aromatic or aromatic ring system having one or more heteroatom (s) wherein the sα1d hetero atom (s) is/ are selected from the group comprising of nitrogen, sulphur and oxygen and the ring system includes mono, bi or tricyclic. Examples of heterocycles include, but not limited to, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothieenyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, napthyridinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, thiazolyl, and thienyl, and the like.
The term "(heterocycle)alkyl" stands for heterocycle which is bonded to an alkylene chain. Examples of (heterocycle)alkyl include, but are not limited to, isothiazolidinyl ethyl, isothiazolyl propyl, pyrazinyl methyl, pyrazolinyl propyl and pyridyl butyl, and the like.
The sα1d aryl and heterocycle may optionally be substituted with one or more substituent(s) independently selected from the group consisting of halogen, hydroxy, nitro, mercapto, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, thioalkyl, cycloalkoxy, -NR1R2, -CONR1R2 -COOR2 -CONHR2 -OCOR2 -COR2 -NHSO2R2 and -SOzNHR2 wherein R1 and R2 are independently selected from hydrogen or alkyl.
The term "pharmaceutically acceptable salts" refer to a salt prepared from pharmaceutically acceptable non-toxic inorganic or organic acid. Example of such inorganic acids include, but are not limited to, hydrochloric, sulfuric, phosphoric acid, and the like. Appropriate organic acids include, but are not limited to aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methansulfonic, ethanesulfonic, benzenesulfonic, panthenic.
toluenesulfonic and 2-hydroxyethanesulfonic acid, and the like. These sahs 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 compounds. 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 disclosed 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 comformational 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 described herein may be prepared by the following reaction sequence as depicted in schemes I and II, as shown in the accompanied drawings.
The compound of Formula VI can be prepared according to the scheme I, as shown in the accompanied drawings. Thus, reacting a compound of Formula II with a compound of Formula III to give a compound of Formula IV (wherein A and n are the same as defined earlier), which on reaction with a compound of Formula V gives a compound of Formula VI.
The reaction of a compound of Formula II with a compound of Formula III is carried out in a suitable solvent such as acetonitrile, acetone, tetrahydrofuran, dimethylformamide or dimethylsulfoxide.
The reaction of a compound of Formula II with a compound of Formula III is carried out in the presence of tetrabutyl ammonium chloride and an inorganic base such as barium carbonate, cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate or sodium bicarbobnate.
The reaction of a compound of Formula IV with a compound of Formula V to give a compound of Formula VI is carried out in a suitable solvent such as acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or acetonitrile.
The reaction of a compound of Formula IV with a compound of Formula V is carried out in the presence of potassium iodide and an inorganic base such as potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium hydride, sodium carbonate or sodium bicarbonate.
The compound of Formula IX can be prepared according to scheme II. Thus, reacting a compound of Formula IV with a compound of Formula VII to give a compound of Formula VIII (wherein A, n and R1 are the same as defined earlier), which on treatment with oxalyl chloride gives a compound of Formula IX.
The reaction of a compound of Formula IV with a compound of Formula VII is carried out in the presence of an inorganic base such as barium carbonate, potassium carbonate, calcium carbonate, sodium carbonate or sodium bicarbonate.
The reaction of a compound of Formula VIII with oxalyl chloride to give a compound of Formula IX is carried out in a suitable solvent such as acetone, dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or acetonitrile.
The reaction of a compound of Formula VIII with oxalyl dichloride is carried out in the presence of an organic base such as triethylamine, diethylamine, 4-dimethylamino pyridine or N-methylpyrrolidone.
In the above Schemes, where the specific base, solvents, etc., are mentioned, it is to be understood that other bases, solvents, etc., known to those skilled in the art may be used. Similarly, the reaction temperature and duration may be adjusted according to the desired needs.
An illustrative list of compounds of the invention are listed below (also shown in Table I):
l-{4-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione (Compound No. 1),
l-{4-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione (Compound No. 2) hydrochloride salt,
l-{4-[4-(2-Ethoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione (Compound No. 3),
l-{4-[4-(2-Ethoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione hydrochloride salt (Compound No. 4),
l-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione (Compound
No. 5),
l-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione hydrochloride salt (Compound No. 6),
1 - {4-[4-(2-Cyclopentyloxy-phenyl)-piperazin-1 -yl] -but-2-ynyl} -piperidine-2,6-dione (Compound No. 7),
l-{4-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione hydrochloride sah (Compound No. 8),
l-(4-{4-[2-(2,2,2-Trifluoro-ethoxy)-phenyl]-piperazin-l-yl}-but-2-ynyl)-piperidine-2,6-dione (Compound No. 9),
l-(4-{4-[2-(2,2,2-Trifluoro-ethoxy)-phenyl]-piperazin-l-yl}-but-2-ynyl)-piperidine-2,6-dione hydrochloride salt (Compound No. 10),
l-[4-(4-Biphenyl-2-yl-piperazin-l-yl)-but-2-ynyl]-piperidine-2,6-dione (Compound No. 11),
1 -[4-(4-Biphenyl-2-yl-piperazin-1 -yl)-but-2-ynyl]-piperidine-2,6-dione hydrochloride salt (Compound No. 12),
l-[4-(4-Biphenyl-2-yl-piperazin-l-yl)-but-2-ynyl]-3,4-dimethyl-pyrrole-2,5-dione (Compound No. 13),
3-Benzyl-l-{4-[4-(2-methoxy-phenyl)-piperazin-I-yl]-but-2-ynyl]-pyrrole-2,5-dione (Compound No. 14),
2-{4-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl)-but-2-ynyl]-3a,4,7,7a-tetrahydro-isoindole-1,3-dione (Compound No. 15),
2-{4-[4-(2-Trifluoromethyl-phenyl)-piperazin-l-yl)-but-2-ynyl]-isoindole-I,3-dione (Compound No. 16),
l-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-3-methyl-4-pyridin-2-yl-pyrrole-2,5-dione (Compound No. 17),
2-{4-[4-(2-Ethoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-5-methyl-3a,4,7,7a-tetrahydro-sioindole-1,3-dione (Compound No. 18),
1 -[4-(2,6-Dioxo-4~piperidin-1 -yl)-but-2-ynyl]-4-(2-methoxy-phenyl)-piperazine-2,3-dione (Compound No. 19),
l-[4-(3,3-Dimethyl-2,6-dioxo-piperidin-l-yl)-but-2-ynyl]-4-(2-methoxy-phenyl)-5,6-dimethyl-piperazine-2,3-dione (Compound No. 20),
l-(2-Cyclopentyloxy-phenyl)-4-[4-(3,5-dimethyl-2,6-dioxo-piperidin-l-yl)-but-2-ynyl]-5,6-dimethyl-piperazine-2,3-dione (Compound No. 21),
l-[4-(2,6-Dioxo-4-phenyl-piperidin-l-yl)-but-2-ynyl]-4-phenyl-piperazine-2,3-dione (Compound No. 22), or
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs, prodrugs or metabolites.

Table I: (Formula I, wherein n=l)

(Table Removed)
The compounds described herein have got pharmacological activity, therefore may be administered to an animal for treatment orally, parenterally, topically, rectally, intemasally, 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, polyvinylpyrolidinone, 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, com, 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 and 5 alpha-reductase inhibitor 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 and 5 alpha-reductase inhibitor may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were 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.
Examples set forth below demonstrates the general synthetic procedure for the preparation of the representative compounds. The examples are provided to illustrate particular aspect of the disclosure and do not constrained the scope of the present invention as defined by the claims.

Experimental details
EXAMPLE 1
Preparation of 2-(2-methoxyaniline)ethylamine
To a solution of 2-methoxyaniline (5.0 gm, 0.04 mole) in acetone was added anhydrous potassium carbonate (2.8 gm, 0.02 mole), followed by addition of 2-bromoethylamine (12.49 gm, 0.06 mole) and reaction mixture refluxed. After completion of reaction, the inorganic were filtered through celite pad, filtrate thus obtained was concentrated to yield the crude product. Finally the crude product was purified by silica gel column chromatography using ethyl acetate and methanol as eluent.
EXAMPLE 2
Preparation of 1 - {4-[4-(2-Methoxv-phenvl)-piperazin-1 -vl]-but-2-vnvli -piperidine-2,6-dione hydrochloride salt (Compound No. 2)
Step 1: Preparation of l-(4-Chloro-but-2-ynyl)-piperadine-2,6-dione
A mixture of glutarimide (2.0 gm, 17.7 mmole), 1,4-dichloro-2-butyne (4.35 gm, 35.4 mmole), potassium carbonate (7.32 gm, 53.1 mmole) and tetrabutylammonium iodide (1.3 gm, 3 mmole) in acetone was heated at 40°C to 60°C for 8 to 12 hours under stirring. Inorganic salts were filtered, washed with acetone, solvent thus obtained was removed under reduced pressure and residue suspended in water. The aqueous solution was extracted with ethyl acetate. Organic layer washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo to give the crude product. The product was purified by silica gel (60-120 mesh) column chromatography using dichloromethane as eluent. Yield: 2.5 gm (71%)
Step 2: Preparation of l-{4-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione (Compound No. 1)
A mixture of l-(4-Chloro-but-2-ynyl)-piperadine-2,6-dione (2.0 gm, 10 mmole, from step 1), 2-methoxy phenyl piperazine monohydrochloride (2.29 gm, 10 mmole, commercially available, Lancaster), potassium carbonate (2.76 gm, 20 mmole) in dimethylformamide was heated at 80°C to 95°C for 8 to 12 hours. After cooling reaction to an ambient temperature.

water was added to the reaction mass, extracted with ethyl acetate. Organic layer washed with
water, dried over anhydrous sodium sulphate and concentrated. The compound was purified by
silica gel (60-120 mesh) column chromatography using dichloromethane - methanol (98:2) as
eluent.
The following compounds were prepared similarly,
l-{4-[4-(2-Ethoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione (Compound No. 3)
1 - {4-[4-(2-lsopropoxy-phenyl)-piperazin-1 -yl] -but-2-ynyl} -piperidine-2,6-dione (Compound
No. 5)
l-{4-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione (Compound No. 7)
l-(4-{4-[2-(2,2,2-Trifluoro-ethoxy)-phenyl]-piperazin-l-yl}-but-2-ynyl)-piperidine-2,6-dione (Compound No. 9)
l-[4-(4-Biphenyl-2-yl-piperazin-l-yl)-but-2-ynyl]-piperidine-2,6-dione (Compound No. 11)
Step 3: Preparation of l-{4-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione hydrochloride salt
An equimolar quantity of isopropyl alcohol and hydrochloric acid was added l-{4-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione. The solid, which precipitates, was then filtered.
Yield: 1.8 gm (51.4%)
IR(KBr): 1673.0 cm''
'H NMR (300 MHz, CDCI3): §1.97-2.04 (m, 2H), 2.71-2.75 (m, 4H), 3.31-3.49 (m, 8H), 3.81-
3.84 (m, 2H), 3.88 (s, 3H), 4.61 (s, 2H), 6.87-7.4 (m, 4H), 13.50 (IH, brs).
The following compounds were prepared following the above procedure
Compound No. 4: l-{4-[4-(2-Ethoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione hydrochloride salt
IR(KBr): 1671.6 cm"'
'H NMR (300 MHz, CDCI3): 6 1.46-1.51 (m, 3H), 1.96-2.04 (m, 2H), 2.71-2.76 (m, 4H), 3.41-3.53 (m, 8H), 3.89 (s, 2H), 4.06-4.13 (m, 2H), 4.61 (s, 2H), 6.86-7.04 (m, 4H), 13.70 (brs, IH) Mass(m/z): 370.3 (M++1)
Compound No. 6: l-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione hydrochloride salt
IR(KBr): 1687.3 cm-1
'H NMR (300 MHz, CDCI3): 5 1.38-1.40 (d, 6H), 1.96-2.02 (m, 2H), 2.72-2.76 (m, 4H), 3.39-3.55 (m, 8H), 3.87 (s, 2H), 4.58-4.61 (m, 3H), 6.87-7.02 (m, 4H), 13.50 (brs, IH). Mass(m/z): 384.4 (M++l)
Compound No. 8: l-{4-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione hydrochloride salt
IR(KBr): 1681.6 cm"'
'H NMR (300 MHz, CDCl3): § 1.68-2.02 (m, lOH), 2.71-2.76 (m, 4H), 3.39-3.53 (m, 8H), 3.86
(s, 2H), 4.61 (s, 2H), 4.82-4.83 (m, IH), 6.86-7.04 (m, 4H), 13.35 (brs, IH)
Mass (m/z): 410.4 (M++1)
Compound No. 10: l-(4-{4-[2-(2,2,2-Trifluoro-ethoxy)-phenyl]-piperazin-l-yl}-but-2-ynyl)-piperidine-2,6-dione hydrochloride salt
IR(KBr): 1682.0 cm-1
'H NMR (300 MHz, CDCl3): 5 1.93-2.00 (m, 2H), 2.69-2.73 (m, 4H), 3.36-3.50 (m, 8H), 3.84 (s,
2H), 4.35-4.43 (m, 2H), 4.59 (s, 2H), 6.84-7.05 (m, 4H), 13.50 (brs, IH)
Mass (m/z): 424.1 (M++l)
Compound No. 12: l-[4-(4-Biphenyl-2-yl-piperazin-l-yl)-but-2-ynyl]-piperidine-2,6-dione hydrochloride salt
IR(KBr): 1685.3 cm-1
'H NMR (300 MHz, CDCI3): 5 1.97-2.06 (m, 2H), 2.73-2.77 (m, 4H), 3.01-3.49 (m, 8H), 3.77
(m, 2H), 4.64 (s, 2H), 7.05-7.61 (m, 9H), 13.4 (brs, IH).
Mass (m/z): 402.4 (M++1)
The following compounds can also be prepared following the above procedure
1 -[4-(4-Biphenyl-2-yl-piperazin-1 -yl)-but-2-ynyl]-3,4-dimethyl-pyrrole-2,5-dione (Compound No. 13) and its hydrochloride sah
3-Benzyl-l-{4-[4-(2-methoxy-phenyl)-piperazin-l-yl]-but-2-ynyl]-pyrrole-2,5-dione (Compound No. 14) and its hydrochloride salt
2-{4-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl)-but-2-ynyl]-3a,4,7,7a-tetrahydro-isoindole-1,3-dione (Compound No. 15) and its hydrochloride salt
2- {4-[4-(2-Trifluoromethyl-phenyl)-piperazin-1 -yl)-but-2-ynyl]-isoindole-1,3-dione (Compound No. 16) and its hydrochloride salt
l-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-3-methyl-4-pyridin-2-yl-pyrrole-2,5-dione (Compound No. 17) and its hydrochloride salt
2-{4-[4-(2-Ethoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-5-methyl-3a,4,7,7a-tetrahydro-sioindole-1,3-dione (Compound No. 18) and its hydrochloride salt
EXAMPLE 3
Preparation of l-[4-(2,6-Dioxo-4--piperidin-l-yl)-but-2-ynyl]-4-(2-methoxy-phenyl)-piperazine-2,3-dione (Compound No. 19) and its hydrochloride salt
Step 1: Preparation of l-{4-[2-(2-Methoxy-phenylamine)-ethylamino]-but-2-ynyl}-piperidine-2,6-dione
A mixture of l-(4-Chloro-but-2-ynyl)-piperadine-2,6-dione (5.0 g, 25 mmole, from example 2, step 1), 2-(2-methoxyaniline)ethylamine (4.024 g, 25 mmole, from example 1), potassium carbonate (6.95 g, 50 mmole) in dimethyl formamide is stirred at an ambient temperature for 8 to 12 hours. Water is added to the reaction mass, extracted with ethyl acetate. Organic layer is washed with water, dried over anhydrous sodium sulphate, and concentrated. The compound was purified by silica gel (60-120 mesh) column chromatography using dichloromethane-methanol (98:2) as eluent.
Step 2: Preparation of l-[4-(2,6-Dioxo-4--piperidin-l-yl)-but-2-ynyl]-4-(2-methoxy-phenyl)-piperazine-2,3 -dione
A mixture of l-{4-[2-(2-Methoxy-phenylamine)-ethylamino]-but-2-ynyl}-piperidine-2,6-dione (1.0 g, 3 mmole, from step 1), triethylamine (0.161 g, 6 mmole) in dichloromethane is cooled at 0 °C to 5 °C and dropwise added oxalyl chloride (0.39 g, 3 mmole) at 0 °C to 5 °C. After stirring 30 min at 0 °C to 5°C, water is added to the reaction mixture. Organic layer is washed with water, dried over anhydrous sodium sulphate and concentrated. The compound is purified by silica gel (60-120 mesh) column chromatography using dichloromethane-methanol (98:2) as eluent. The hydrochloride salt can be prepared by adding an equimolar quantity of isopropyl alcohol and hydrochloric acid to l-[4-(2,6-Dioxo-4-piperidin-l-yl)-but-2-ynyl]-4-(2-methoxy-phenyl)-piperazine-2,3-dione. The solid, which precipitates, is then filtered. The following compounds are prepared following the above procedure
l-[4-(3,3-Dimethyl-2,6-dioxo-piperidin-l-yl)-but-2-ynyl]-4-(2-methoxy-phenyl)-5,6-dimethyl-piperazine-2,3-dione (Compound No. 20) and its hydrochloride salt
l-(2-Cyclopentyloxy-phenyl)-4-[4-(3,5-dimethyl-2,6-dioxo-piperidin-l-yl)-but-2-ynyl]-5,6-dimethyl-piperazine-2,3-dione (Compound No. 21) and its hydrochloride salt
l-[4-(2,6-Dioxo-4-phenyl-piperidin-l-yl)-but-2-ynyl]-4-phenyl-piperazine-2,3-dione (Compound No. 22) and its hydrochloride salt
Pharmacological testing
Receptor Binding Assay: Receptor binding assays were performed using native a-1 adrenoceptors. The affinity of different compounds for α1a and α1b adrenoceptor subtypes was evaluated by shading 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 HCl 50 mM, NaCl 100 mM, 10 mM EDTA pH 7.4). The tissues were homogenized in 10 volumes of buffer (Tris HCl 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 HCl 50 mM, EDTA 5 mM, pH 7.4) and were stored at -70 °C until the time of assay.
The membrane homogenates (150-250 µg protein) were incubated in 250 µl of assay buffer (Tris HCl 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 HCl buffer (pH 7.4). The fihermats were dried and bounded radioactivity retained on filters was counted. The IC50 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.
In vitro functional studies
In vitro alpha-1 Adrenoceptor selectivity: In order to study selectivity of action of the present compounds towards different alpha-1 adrenoceptor subtypes, the ability of these compounds to antagonize alpha-1 adrenoceptor agonist induced contractile response of aorta (alpha-Id), prostate (alpha-la) and spleen (alpha-lb) was studied. Aorta, prostate and spleen tissue were isolated from thipentane anaesthetized (~ 300 mg/Kg) male wistar rats. Isolated tissues were mounted in organ bath containing Krebs Henseleit buffer of the following composition (mM): NaCl 118; KCl 4.7; CaCb 2.5; MgSO4. 7H2O 1.2; NaHCOs 25; KH2PO4 1.2; glucose 11.1. Buffer was maintained at 37 °C. and aerated with a mixture of 95% 02 and 5% CO2. A resting tension of 2 g (aorta and spleen) or 1 g (prostate) was applied to tissues. Contractile response was monitored using a force displacement transducer and recorded on chart recorders. Tissues were allowed to equilibrate for 1 and 1/2 hours. At the end of equilibration period, concentration response curves to norepinephrine (aorta) and phenylephirine (spleen and prostate) were obtained in the absence and presence of the tested compound (at concentration of 0.1, 1 andl0µM).
Results: The affinity at alpha la adrenoceptors expressed in terms of Ki (nM) for all compounds ranged from low nanomolars to high nanomolars in comparison to terazosin 9Ki=6.17nM). The affinity at alpha lb expressed as Ki (nM) for all compounds was greater than 900 nM in comparison to terazosin with a Ki value of 2.84 nM. The fold selectivity of alpha la over alpha lb adrenoceptor for all compounds ranged from 0.75 to 120, compared to 0.5 fold selectivity for terazosin. Thus, compounds of the invention are relatively more selective for alpha la over alpha lb adrenoceptors compared to terazosin.

WE CLAIM:
Compounds having the structure of Formula I, as shown in the accompanied drawings, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs, prodrugs or metabolites wherein: A represents
(Formula Removed)
wherein R2R3, R4 and R5 are independently hydrogen, alkyl or phenyl, R6 is hydrogen,
alkyl, phenyl, hydroxy or alkoxy, R7 and R8 are independently alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heterocycle, aralkyl, (heterocycle)alkyl or R9—Q—(CH2)m—wherein m is
an integer of from 0 to 3, R9 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
heterocycle, Q is oxygen, sulphur, carbonyl, carboxylic or wherein W is no atom, carbonyl, carboxylic, amide, R10 is hydrogen, alkyl, aryl, heterocyclic, R7 and R8
together represent cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl, or
heterocycle, R2 is also wherein R11 and R12 are independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NR13R14 wherein R13 and R14 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle; X and Y are independently methylene or carbonyl; R1 is hydrogen or methyl; R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or (heterocycle)alkyl; n is an integer of from 1 to 3; is optional double bond.
are the same as defined earlier.
3. A compound according to claim 1 wherein A is
4. A compound according to claim 1 wherein X and Y are methylene.
5. A compound according to claim 1 wherein R1 is hydrogen.
6. A compound according to claim 1 wherein R is substituted aryl, the substituent is selected from the group comprising of alkoxy, cycloalkoxy and phenyl.
7. A compound according to claim 1 wherein R is 2-methoxyphenyl.
8. A compound according to claim 1 wherein R is 2-ethoxyphenyl.
9. A compound according to claim 1 wherein R is 2-isopropoxyphenyl.
10. A compound according to claim 1 wherein R is 2-cyclopentoxyphenyl.
11. A compound according to claim 1 wherein R is 2-trifluoroethoxyphenyl.
12. A compound according to claim 1 wherein R is biphenyl.
13. A compound namely l-{4-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione,
l-{4-[4-(2-Ethoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione,
l-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione,
l-{4-[4-(2-Cyclopentyloxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione,
l-(4-{4-[2-(2,2,2-Trifluoro-ethoxy)-phenyl]-piperazin-l-yl}-but-2-ynyl)-piperidine-2,6-dione,
l-[4-(4-Biphenyl-2-yl-piperazin-l-yl)-but-2-ynyl]-piperidine-2,6-dione, or
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, polymorphs or metabolites.
14. A compound namely
l-{4-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione hydrochloride salt,
l-{4-[4-(2-Ethoxy-phenyl)-piperazin-l-yl]-but-2-ynyl}-piperidine-2,6-dione hydrochloride salt,
1 - {4-[4-(2-Isopropoxy-phenyl)-piperazin-1 -yl] -but-2-ynyl} -piperidine-2,6-dione hydrochloride salt,
1 - {4-[4-(2-Cyclopentyloxy-phenyl)-piperazin-1 -yl]-but-2-ynyl} -piperidine-2,6-dione hydrochloride salt,
l-(4-{4-[2-(2,2,2-Trifluoro-ethoxy)-phenyl]-piperazin-l-yl}-but-2-ynyl)-piperidine-2,6-dione hydrochloride salt,
l-[4-(4-Biphenyl-2-yl-piperazin-l-yl)-but-2-ynyl]-piperidine-2,6-dione hydrochloride salt.
15. A pharmaceutical composition comprising a therapeutically effective amount of the
compound as defined in the preceding claims optionally together with pharmaceutically acceptable carriers, excipients or diluents.
16. A method for treatment of a patient suffering from a disease or disorder mediated through alpha la and/or alpha Id adrenergic receptor, comprising administering to said patient a therapeutically effective amount of a compound of any one of the claim 1-14.
17. A method for treatment of a patient suffering from disease or disorder mediated through alpha la and/or alpha Id adrenergic receptor, comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition according to claim 15.
18. The method according to claim 16 or 17 wherein a disease or disorder is benign prostatic hyperplasia.
19. The method according to claim 16 or 17 wherein compound causes minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
20. A method for the preparation a compound having the structure of Formula VI, as shown in scheme I of the accompanied drawings, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs, prodrugs or metabolites, which method comprises:
reacting a compound of Formula II with a compound of Formula III
(Formula Removed)
to give a compound of Formula IV (wherein A and n are the same as defined earlier),
(Formula Removed)
which on treatment with a compound of Formula V
(Formula Removed)
gives a compound of Formula VI (wherein R is the same as defined earlier)
21. The process according to claim 20 wherein the reaction of a compound of Formula II with a compound of Formula III is carried out in a suitable solvent selected from the group comprising of methanol, chloroform, dichloromethane, acetonitrile, acetone and tetrahydrofuran.
22. The process according to claim 21 wherein the reaction is carried out in acetone.
23. The process according to claim 20 wherein the reaction of a compound of Formula II with a compound of Formula III is carried out in presence of tetrabutylammonium iodide and an inorganic base selected from the group comprising of potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate and sodium bicarbonate.
24. The process according to claim 23 wherein the reaction is carried out in the presence of potassium carbonate.
25. The process according to claim 20 wherein the reaction of a compound of Formula IV with a compound of Formula V to give a compound of Formula VI is carried out in a suitable solvent selected from the group comprising of methanol, ethanol, acetone, acetonitrile, chloroform, dimethylformamide and dimethylsulfoxide.
26. The process according to claim 25 wherein the reaction is carried out in dimethylformamide.
27. The process according to claim 20 wherein the reaction of a compound of Formula IV with a compound of Formula V is carried out in the presence of potassium iodide and an inorganic base selected from the group comprising of potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate and sodium bicarbonate.
28. The process according to claim 27 wherein the reaction is carried out in the presence of potassium carbonate.
29. The process for the preparation of compounds of Formula VI substantially as herein described and illustrated by example herein.