Field of the Invention
The present invention relates to αla and/or αld adrenergic receptor antagonists.
Compounds disclosed herein can function as αla and/or αld adrenergic receptor antagonist and can be used for the treatment of a disease or disorder mediated through αla and/or αld 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. Process 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 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: 1198-1 199. 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 ot-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 αla 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 oti adrenoceptor. There are several lines of evidence to suggest that selectivity for αla adrenoceptor over αlb, adrenoceptor will result in relative lack of vascular side effects, thus lead to a better tolerability. Mice deficient in αlbadrenoreceptors show diminished blood pressure response to phenylephrine injection compared to homozygous controls (Decreased blood pressure response in mice deficient of αibadrenergic receptor. (Proc Natl Acad Sci USA 1997,94.1 1589-11594). In-vivo studies in healthy subjects comparison of α1a / α1d selective antagonists (for example, tamsulosin) or αu 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 αld or αld/αld can cause some degree of vasodilation but that it is much smaller than with non-subtype-selective αla adrenoceptor antagonist. Further, there is increased vascular αlb, adrenoceptor expression in elderly patients and thus αla/αld selective agents with selectivity over αlbadrenoceptor subtype would be of particular importance in benign prostatic hyperplasia, which is generally a disease of old age. Antagonism of both αld adrenoceptor and αla adrenoceptor is important to relieve lower urinary tract symptoms especially associated (suggestive of) with BPH. Targeting αld adrenoceptor with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction whereas au adrenoceptor antagonism is important to target irritative symptoms.
Over the past decade, there has been an intensive search for selective αld 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, anti-diabetic 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),Ishizumi et al: US 4.598.078 (1086).New et. al; J. Med. Chem. 29. 1476-
1482 (1986).Shigeru et. al: JP 60-204784 (1985).Ne\v 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 αl subtype selectivity profile of the compounds disclosed therein and thus their usefulness in the treatment of symptoms of benign prostate hyperplasia did not arise.
The synthesis of l-(4-arylpiperazin-l-yl)-(o-[N- (a. co-dicarboximido)]-alkanes useful as uro-selective αl-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 αl-adrenergic blocking activity and selectivity.
Other reports describing selective αa adrenoceptor antagonists are US 6.376,503. US 6.319.932. US 6.339.090. EP 71 1757. 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 ala and/or αldadrenergic 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 process for the synthesis of these compounds.
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers. diastereomers. prodrugs, 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 drawing, and its pharmaceutical^' acceptable salts, pharmaceutical^' acceptable solvates, enantiomers. diastereomers. N-oxides. prodrugs, polymorphs or metabolites, wherein: A represents
(FORMULA REMOVED)

wherein
R2. R3. R4 and R5 are independently selected from
o hydrogen
o alkyl
o phenyl R6 represents
o hydrogen
o alky1
o phenyl
o hydroxy
o alkoxy — represents optional single bond R7 and R8 are independently selected from
o hydrogen
o alky1
o alkenyl
o alkynyl
o cycloalkyl

o lieterocyclyl o aralkyl
o (heterocyclyl)alkyl
(FORMULA REMOVED)

therein m represents an integer 0 to 3
R9 represents
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cycloalkenyl
• aryl

• lieterocyclyl Q represents
• oxygen
• sulphur
• carbonyl
• carboxylic
•
wherein.
represents ♦!♦ no atom
♦ carbonyl
♦ carboxylic
♦ amide Rio represents
♦ hydrogen
♦ alkyl
♦ aryl
♦♦♦ lieterocyclyl R7 and R8 together represent o cycloalkyl o cvcloalkenvl
o bicyclic alkyl o bicyclic alkenyl o aryl

o heterocycle R2 represents " wherein
R11 and R12 are independently selected from
o hydrogen
o alky!
o alken\l
o alkynyl
o cycloalkyl
o aryl
o heterocycle
o -NR13R14 wherein R13 and R]4 are independently selected from
• hydrogen
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cycloalkenyl
• aryl
• heterocycle R represents
o hydrogen
o alkyl n represents an integer 1 to 2 X represents
o -oxygen
o -sulphur

o -CH2
o -NR wherein R represents alkyl.
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 αla and/or αldadrenergic 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 is provided a process 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 a-reductase inhibitor.
In accordance with a eighth aspect, there is provided a method for the treatment of a patient suffering from BPL1 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 a reductase inhibitor.
Receptor binding assay studies described below indicated that the compounds disclosed herein possess selectivity towards ecu, adrenoceptor. 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 aiu 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 said alkyl can optionally be replaced by halogen, hydroxy. cycloalk\l. cycloalkenyl or-NRaRb. wherein Ra and Rb 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 said alkenyl or alkynyl can be replaced by halogen. Examples of alkenyl and alkynyl include, but are not limited to. ethylene, propylene, ethynyl. propynyl, and the like.
The term "cycloalkyl" refers to saturated carbocyclic ring having three to seven carbon atoms. Examples of cycloalkyl 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 cycloalkenyl include, but are not limited to. cyclopropenvl and cyclobutenyl. and the like.
The said "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 "alkoxy" denotes the group O-alkyl wherein alkyl is the same as defined above.
The term "heterocyclyl" refers to non-aromatic or aromatic ring system having one or more heteroatom (s) wherein the said 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-benzodioxolyI. benzoxazolyl. benzothiazolyl. benzothienvl. dihvdroimidazolyi. dihvdropvranyl. dihydrofuranyl. dioxanyl. dioxoianvl. fury I, 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 thienvl. and the like.
The term "(heterocyclyl)alkyl" stands for heterocycle which is bonded to an alkylene chain. Examples of (heterocyclyl)alkyl include, but are not limited to. isothiazolidinyl ethyl, isothiazolyl propyl, pyrazinyl methyl, pyrazolinyl propyl and pyridyl butyl, and the like.
The said 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. -NR'R2. -CONR'R2. -COOR2. -CONHR2. -OCOR2. -COR2. -NHS02R2 and -S02NHR2 wherein R and R' are independently selected from hydrogen or alkyl.
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 compounds of the invention possess two chiral centers, they may. therefore, exist as enantiomers and diastereomers. It is to be understood that all such isomers and racemic mixtures therefore are encompassed within the scope of the present invention.
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.
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 shown in scheme I of the accompanied drawings.
The compound of Formula I can be prepared according to scheme I. Thus, reacting a compound of Formula II with a compound of Formula III to give a compound of Formula IV (wherein R. n and X are the same as defined earlier), which on reduction gives a compound of Formula V. which on treatment with a compound of Formula VI gives a compound of Formula I (wherein A is the same as defined earlier) which can then be further, converted to any pharmaceutical!) acceptable salt known to one ordinary skilled in art.
The reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IV can be carried out in a solvent, for example, chloroform, methanol, ethanol. cyclohexane, n-butylalcohol. acetonitrile. dichloromethane. dimethylformamide or dimethylsulfoxide.
The reaction of a compound of Formula IV to give a compound of Formula V can be carried out in a solvent, for example methanol, ethanol or isopropanol.
The reaction of a compound of Formula IV to give a compound of Formula V can be carried out in the presence of a reducing agent, for example, lithium aluminum hydride or Raney Nickel-hydrogen and ammonia.
The reaction of a compound of Formula V with a compound of Formula VI to give a compound of Formula I can be carried out in a solvent, for example, acetonitrile. toluene, xylene, acetic anhydride or pyridine.
In the above scheme, where the reducing agents, solvents, etc.. are mentioned, it is to be understood that other reducing agents, 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):
-1 -[3-(3.4.10.1 Oa-Tetrahydro I H-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-piperidine-2.6-dione (Compound No. 1).
-1 -[3-(3,4.10.1 Oa-Tetrahydro-1 H-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyI]-piperidine-2,6-dione hydrochloride salt (Compound No.2).
-2-[3-(3.4.10. 1 Oa-Tetrahydro-1 H-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-3a,4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 3).
-l-[3-( 1,2.4,4a.5.6-Hexahydro-pyrazino[1.2-a]quinolin-3-yl)-propyl]-piperidine-2.6-dione (Compound No. 4).
-2-[3-(1.2.4.4a.5.6-Hexahydro-pyrazino[1.2-a]quinolin-3-yl)-propyl]-3a.4.7.7a-tetrahydro-isoindole-l.3-dione (Compound No. 5).
-2-[3-( 1.2.4.4a.5.6-Hexahydro-pyrazino[ 1,2-a]quinolin-3-yl)-propyl]-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 6).
-1-[3-( 1.2.4.4a.5.6-He.xahydro-pyrazino[ 1.2-a]quinolin-3-yl)-propyl]-3,4-dimethyl-pyrrole-2.5-dione (Compound No. 7).
-1-[3-( 1.2.4.4a.5.6-Hexahydro-pyrazino[ 1.2-a]quinolin-3-yl)-propyl]-pyrrole-2.5-dione (Compound No. 8).
-l-[3-(l.2.4.4a.5.6-Hexahydro-p)razino[l.2-a]quinolin-3-yl)-propyl]-3.3-dimethyl-piperidine-2.6-dione (Compound No. 9),
-l-[3-(1.2.4.4a.5.6-Hexahydro-pyrazino[1.2-a]quinolin-3-yl)-propyl]-3-phenyl-pyrrolidine-2.5-dione (Compound No. 10).
-1-[3-( 1.2.4.4a.5.6-Hexahydro-pyrazino[ 1.2-a]quinolin-3-yl)-propyl]-3-phenyl-pyrrolidine-2.5-dione hydrochloride salt (Compound No. 11).
-l-[3-(l.2.4.4a.5,6-Hexahydro-pyrazino[1.2-a]quinolin-3-yl)-propyl]-3-methyl-pyrrole-2.5-dione (Compound No. 12),
-l-[3-(l,2.4.4a.5.6-Hexahydro-pyrazino[l,2-a]quoinolin-3-yl)-propyl]-3-phenyl-pyrrole-2.5-dione (Compound No. 13).
-3.4-Dimethyl-l-[3-(6-methyl-1.2.4.4a.5.6-hexahydro-pyrazino[1.2-a]quinoxalin-3-yl)-propyl]-pyrrole-2.5-dione (Compound No. 14).
-2-[3-(6-Methyl-1.2.4.4a.5.6-hexah)dro-pyrazino[1.2-a]quinoxaIin-3-yl)-propyl]-5-phenyl-3a,4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 15).
-5-Cyclohexylmethyl-2-[3-(3.4,10.1 Oa-tetrahydro-1 H-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 16).
-1 -[3-( 1.2.4.4a.5,6-Hexahydro-pyrazino[ 1,2-a]quinolin-3-yl)-propyl]-3-pyridin-2-yl-pyrro!e-2.5-dione (Compound No. 17).
-5-Phenyl-2-[3-(3,4.10.1 Oa-tetrahydro-1 H-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 18).
-3-Methyl-1 -[3-(3,4.10.1 Oa-tetrahydro-1 H-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-piperidine-2.6-dione (Compound No. 19).
-l-[3-(l,2.4.4a.5.6-Hexahydro-pyrazino[1.2-a]quinolin-3-yl)-propyl]-4-phenyl-piperidine-2.6-dione (Compound No. 20).
Table I (Formula 1, as shown in the accompanied drawings, wherein n=l. R=H)

(TABLE REMOVED)

The compounds described herein are basic and form organic or inorganic acid addition salts, which are within the scope of sound medical judgement suitable for use in contact with the tissue of humans and lower animals without undue toxicity, irritation, allergic response and the like. The resulting salts are useful by themselves and in the therapeutic composition. These salts may be prepared by the useful prior art techniques, such as suspending the compound in water and then adding one equivalent of an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid. malonic acid, adipic acid, ascorbic acid, camphoenic acid, nicotinic acid, butyric acid, lactic acid, glucuronic acid, or inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, boric acid and perchloric acid.
The neutral solution of the resulting salt is subjected to rotary evaporation under diminished pressure to the volume necessary to ensure precipitation of the salt upon cooling, which is then filtered and dried. The salts of the present invention may also be prepared under strictly non-aqueous conditions. For example, dissolving free base in a suitable organic solvent such as ethanol. methanol, isopropanol. dichloromethane or diethyl ether adding exactly one equivalent of the desired acid to the same solvent and stirring the solution at 0°C to 5°C. causes the precipitation of the acid addition salt, which is then filtered, washed with the solvent, and dried.
Alternatively, the solvent is stripped of completely to obtain the desired salt. These salts are often preferred for use in formulating the therapeutic composition of the invention because they are crystalline and relatively more stable and water suitable.
The compounds described herein have got pharmacological activity, therefore may be administered to an animal for treatment orally, parentrally. topically, rectally, internasally. subcutaneously or transdermally. The pharmaceutical compositions of the present invention comprise a pharmaceutical ly 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 nontoxic, 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 tiller or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid; binders such as carboxymethylcellulose. alginates, gelatins, poKvinylpyrolidinone. 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, solutions, 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. eth>I carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate. propylene glycol, 1.3-butylene glycol, dimethylformamide, oils (such as cottonseed. «roundnut, 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(s) 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. U.S.P. 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 these 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 a 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 a 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 demonstrate 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 constrain the scope of the present invention as defined by the claims.
Experimental details
EXAMPLE 1
Preparation of 2-f3-( 1.2.4.4a.5.6-Hexahvdro-pvrazino[ 1.2-a1quinolin-3-yl)-propvll-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt (Compound No. 6)
Step I: Preparation of 3-(1.2.4.4a.5,6-Hexahvdro-pyrazino|4.2-alquinolm-3-yl)-propionitrile
To a solution of 2.3.4.4a,5,6-Hexahydro-l H-pyrazino[1.2-a]quinoline (I gm. 5.3 mmole. S. P. Gupta et al.. Indian .1. of Chein.. 13, 462-467 (1975)) in methanol was added acrylonitrile (0.56 gm. 10.6 mmole) and reaction mixture stirred. Excess of solvent was removed on buchi to give the crude product. The crude product was purified on silica gel column using dichloromethane as eluent. Yield: 1.0gm(78%)
Step 2: Preparation of 3-(l.2.4.4a.5.6-Hexahvdro-pyrazino[l,2-a1quinolin-3-vl)-propylamine
To a solution 3-(1.2.4.4a.5.6-Hexahydro-pyrazino[1.2-a]quinolin-3-yl)-propionitrile (0.8 gm, 33.3 mmole. from step 1) in methanol-ammonia was added Raney-Nickel and reaction mixture was hydrogenated. After the reaction was over, the reaction mixture was filtered through celite pad. washed with methanol. Filtrate was concentrated to yield the desired compound. Yield: 0.79 gm. (97%)
Step 3: Preparation of 2-T3-( l,2.4.4a.5.6-Hexahvdro-pvrazino[l.2-a1quinolin-3-yl)-propyll-3a.4.7.7a-tetrahvdro-isoindole-1.3-dione
To a solution of 3-(1.2.4.4a.5.6-Hexahydro-pyrazino[l,2-a]quinoIin-3-yl)-propylamine (0.5 gm. 2.0 mmole. from step 2) in toluene was added c/.v-l,2.3.6-tetrahydrophthalimide and reaction mixture was refluxed. After completion of the reaction, the reaction mixture was concentrated to yield the crude product, which was purified on silica gel column using dichloromethane and methanol as eluent. Yield: 0.62 gm (80%)
The following compounds were prepared following the above procedure
Compound No. 3: 2-[3-(3,4.10. 10a-Tetrahydro-lH-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-3a.4.7.7a-tetrahydro-isoindole-1.3-dione
IR(KBr): 1703.3 cm"1
'H NMR (300 MHz. CDC13): 8 2.13-2.17 (m, 4H). 2.52-2.58 (m, 4H). 2.86 (m. 2H). 3.08
(m. 2H). 3.36 (m. 2H). 3.43 (m. 2H). 3.79-3.86 (m. 2H). 4.01-4.23 (in, 3H). 5.81 (s. 2H).
6.72-6.83 (m,4H). 13.35 (brs. 1H).
Mass (m/z): 382.2 (M++1)
Compound No. 4: 1 -[3-( 1.2.4.4a.5.6-Hexahydro-pyrazino[ 1,2-a]quinolin-3-yl)-propyl]-piperidine-2.6-dione
IR(KBr): 1673.4 cm"'
'H NMR (300 MHz. CDC13): 5 1.79 (m. 1H). 1.99 (m. 3H). 2.20 (m, 2H). 2.70 (m, 6H).
2.88-3.04 (m. 4H). 3.48-3.51 (m. 1 H). 3.66-3.73 (m. 2H). 3.90-4.02 (m. 4H). 6.81 -7.39
(m. 4H). 12.97 (brs. 1H).
Mass (m/z): 342.3 (M++l)
Compound No. 7: 1 -[3-( 1,2,4.4a.5.6-Hexahydro-pyrazino[ 1.2-a]quinolin-3-yl)-propyl]-3.4-dimethyl-pyrrole-2.5-dione
IR(KBr): 1710.0 cm"1
'H NMR (300 MHz. CDCb): 5 1.71 (brs. 2H). 2.28 (m. 6H). 2.59 (m. 2H). 2.62-2.72 (m. 2H). 2.86-3.01 (m. 4H). 3.43-3.46 (m. 1H). 3.61-3.69 (m. 4H). 3.88-3.93 (m. 2H). 6.75-6.80 (m.2H). 6.99-7.13 (m. 2H). 13.10 (brs. 1H).
Mass (m/z): 354.4 (M++l)
Compound No. 8: l-[3-(1.2,4.4a.5.6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-pyrrole-2.5-dione
IR(KBr): 1705.8 cm"1
'H NMR (300 MHz. CDCI3): 8 1.73-2.01 (m. 2H). 2.32 (m, 2H). 2.67-2.72 (m. 2H). 2.90-
3.04 (m. 4H). 3.48-3.68 (m. 5H). 3.88-3.95 (m. 2H). 6.75-7.1 1 (in. 6H). 13.06 (brs. 1H).
Mass (m/z): 326.5 (M++l)
Compound No. 9: l-[3-(1.2.4.4a.5.6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3.3-dimethyl-piperidine-2.6-dione
IR(KBr): 1672.9 cm"1
'H NMR (300 MHz. CDCh): 5 1.26-1.29 (m. 6H). 1.81-1.86 (m. 3H). 2.01 (m. 1H). 2.15
(m. 2H). 2.71-2.75 (m.4H). 2.91-3.01 (m. 4H). 3.46 (m. 1 H). 3.62-3.71 (m. 2H). 3.86-
3.96 (m, 4H). 6.79-6.84 (m. 2H). 7.01-7.15 (m. 2H). 13.03 (brs. 1H).
Mass (m/z): 370.5 (M++l)
Compound No. 12: 1 -[3-( 1.2.4.4a.5.6-Hexahydro-pyrazino[ 1.2-a]quinolin-3-yl)-propyl]-3-methyl-pyrrole-2,5-dione
IR(KBr): 1704.7 cm"'
'H NMR (300 MHz. CDCb): 5 1.76-2.04 (m, 5H). 2.29 (m. 2H). 2.26-2.73 (m. 2H). 2.86-
3.02 (m. 4H). 3.44-3.47 (m. 1H). 3.63-3.74 (m. 4H). 3.89-3.99 (m. 2H). 6.35 (brs. 1H).
6.78-6.83 (m. 2H). 7.00-7.14 (m. 2H).
Mass (m/z): 340.4 (N/f+1)
Step 4: Preparation of 2-[3-(1.2.4.4a,5.6-Hexahydro-pyrazino[1.2-a]quinolin-3-yl)-propyl]-3a.4.7.7a-tetrahydro-isoindole-1.3-dione hydrochloride salt
To a solution of 2-[3-( 1,2.4.4a.5.6-Hexahydro-pyrazino[ 1.2-a]quinolin-3-yl)-propyl]-3a.4.7.7a-tetrahydro-isoindole-l.3-dione in isopropyl alcohol was added equimolar quantity of isopropyl alcohol - hydrochloride at 10-15 C and the reaction mixture was stirred for about 1 hr. Solid . thus, precipitated was filtered, dried and weighed.
Yield: 0.6Igm (89%) IR(KBr): 1697.2 cm"1
'H NMR (300 MHz. CDC13): 5 1.75-2.01 (m. 2H). 2.21-2.25 (m. 4H), 2.61-2.66 (m. 4H).
2.73-2.95 (m. 4H). 3.18 (m. 2H). 3.46-3.62 (m. 5H). 3.87-3.95 (m. 2H). 5.92 (brs, 2H).
6.78-6.83 (m.2H), 7.00-7.14 (m. 2H). 13.05 (brs. IH).
Mass (m/z): 380.4 (M++l)
Compound No. 2: 1 -[3-(3.4.10.1 Oa-Tetrahydro-1 H-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-piperidine-2,6-dione hydrochloride salt
IR(DCM): 1653.7 cm"'
1H NMR (300 MHz. CDCI3): 5 1.98 (m. 2H). 2.17 (m. 2H). 2.68 (m, 6H). 3.00 (m. 2H).
3.46 (m. 2H). 3.88 (m. 4H). 4.07-4.27 (m. 2H). 6.78-6.89 (m. 4H). 13.10 (brs. 1 H).
Mass (m/z): 344.3 (M++l)
Compound No. 11: l-[3-(1.2.4.4a.5.6-Hexahydro-pyrazino[1.2-a]quinolin-3-yl)-propyl]-3-phenyl-pyrrolidine-2.5-dione hydrochloride salt
IR(KBr): 1697.3 cm"1
'HNMR(300MHz.CDCI3):8 1.71 (m. IH). 1.97-1.98 (m, IH). 2.28-2.30 (m. 2H). 2.71-
2.82 (m, 2H). 2.84-3.05 (m. 5H). 3.26-3.32 (m. I H). 3.45-3.70 (m. 4H), 3.91 (m. 1H).
4.12-4.16 (m. IH). 6.74-7.40 (m.9H). 13.04 (brs. IH).
Mass (m/z): 404.4 (M" + l)
EXAMPLE 2
Preparation of l-[3-(l.2.4.4a.5.6-Hexahydro-pyrazino[1.2-a]quoinolin-3-yl)-propyl]-3-phenyl-pyrrole-2.5-dione (Compound No. 13)
To a solution of 3-(1.2.4.4a.5.6-Hexahydro-pyrazino[1.2-a]quinolin-3-yl)-propylamine (0.5 gm. 2.0 mmole. from example 1. step 2) in toluene is added 3-phenyl-furαlb2.5-dione and reaction mixture is refluxed. After completion of the reaction, the reaction mixture is concentrated to yield the crude product, which is purified on silica gel column using dichloromethane and methanol as eluent. The following compounds are prepared following the above procedure
-3.4-Dimethyl-1 -[3-(6-meth\ 1-1.2.4.4a.5.6-hexahydro-pyrazino[ 1.2-a]quinoxalin-3-yl)-propyl]-pyrrole-2.5-dione (Compound No. 14)
-2-[3-(6-Methyl-l,2,4.4a.5.6-hexah\dro-pyrazino[l.2-a]quinoxalin-3-yl)-propyl]-5-phenyl-3a.4.7,7a-tetrahydro-isoindole-1.3-dione (Compound No. 15)
-5-Cyclohexylmethyl-2-[3-(3.4,10.10a-tetrahydro-lH-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 16)
-1 -[3-( 1.2.4.4a.5.6-Hexahydro-pyrazino[ 1,2-a]quinolin-3-yl)-propyl]-3-pyridin-2-yl-pyrrole-2.5-dione (Compound No. 17)
-5-Phenyl-2-[3-(3.4,10.10a-tetrahydro-l H-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-3a,4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 18)
-3-Methyl-1 -[3-(3,4,10,1 Oa-tetrahydro-1 H-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-piperidine-2.6-dione (Compound No. 19)
-1 -[3-( 1.2.4.4a.5.6-Hexahydro-pyrazino[ 1.2-a]quinolin-3-yl)-propyl]-4-phenyl-piperidine-2.6-dione (Compound No. 20)
Pharmacological testing
Receptor Binding Assay
Receptor binding assays were performed using native ct| adrenoceptors. The affinity of different compounds for αla and αldadrenoceptor subtypes was evaluated by studying their ability to displace specific ['H]prazosin binding from the membranes of rat submaxillary and liver respectively {Michel el 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 hydrochloric acid (HCI) 50 mM, sodium chloride (NaCl) 100 mM, 10 mM . ethylene diamine tetra acetic acid (EDTA) pH 7.4). The tissues were homogenized in 10 volumes of buffer (Tris HCI 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 HCI 50 mM. EDTA 5 mM. pH 7.4) and were stored at-70 °C until the time of assay.
The membrane homogenates (150-250 |ig protein) were incubated in 250 µl of assay buffer (Tris HCI 50 mM. EDTA 5 mM. pH 7.4) at 24-25 °C for 1 hour. Nonspecific binding was determined in the presence of 300 nM prazosin. The incubation was terminated by vacuum filtration over GF/B fiber filters. The filters were then washed with ice-cold 50 mM Tris HCI buffer (pH 7.4). The filtermats 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 = IC5I, /(1+L/Kd) where L is the concentration of ['H] prazosin used in the particular experiment.
The affinity at a iaadrenoreceptor expressed in terms of Ki (nM) for all compounds ranged from low nano molar (Ki = 0.14 nM) to high nano molar (Ki = 4098
nM) in comparison to terazosin (Ki =7.5 nM). The affinity at a ibexpressed as Ki (nM) for all compounds was ranged from low nano molar (Ki = 96.3 nM) to high nano molar (Ki =3279 nM) in comparison to terazosin with a Ki value of 5.5 nM. The fold selectivity of a ia over α lbadrenoreceptor for all compounds ranged from 0.80 to 3936 compared to 0.73 selectivity for terazosin. Thus compounds of the present invention are relatively more selective for α la, over α lb adrenoreceptors compared to terazosin. In vitro functional studies In vitro αld Adrenoceptor selectivit)'
In order to study selectivity of action of the present compounds towards different αla adrenoreceptor subtypes, the abilitv of these compounds to antagonize αldadrenoreceptor agonist induced contractile response of aorta (a)(i). prostate (ctia) and spleen (αlb) is studied. Aorta, prostate and spleen tissue are isolated from thipentane anaesthetized ( 300 mg/Kg) male wistar rats. Isolated tissues are mounted in organ bath containing Krebs Henseleit buffer of the following composition (mM): sodium chloride (NaCI) 118: potassium chloride (KCI) 4.7: calcium chloride (CaCI2) 2.5: magnesium sulphate hepta hydrate (MgSO4. 7H;0) 1.2; sodium bicarbonate (NaHCO3) 25: potassium dihydrogen phosphate (KH2PO4) 1.2: glucose 11.1. Buffer is maintained at 37 ' C and aerated with a mixture of 95% oxygen (O2) and 5% carbon dioxide (CO;). A resting tension of 2 g (aorta and spleen) or 1 g (prostate) is applied to tissues. Contractile response is monitored using a force displacement transducer and recorded on chart recorders. Tissues are allowed to equilibrate for 1 and 1/2 hour. At the end of equilibration period, concentration response curves to norepinephrine (aorta) and phenylepinephrine (spleen and prostate) are obtained in the absence and presence of the tested compound (at concentration of 0.1. 1 and 10 (µM).

WE CLAIM:
1. A compound having the structure of Formula I, as shown in the accompanied drawings, and its pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers. diastereomers. N-oxides. prodrugs, polymorphs or metabolites, wherein: A represents
(FORMULA REMOVED)

wherein
R2. R3, R4 and R5 are independently selected from
o hydrogen
o aIkyI
o phenyl R6 represents
o hydrogen
o alkyl
o phenyl
o hydroxy
o alkoxy — represents optional single bond R7 and R8 are independently selected from
o hydrogen
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocyclyl
o aralkyl

o (heterocyclyl)alkyl
(FORMULA REMOVED)

wherein m represents an integer 0 to 3 R9 represents
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cycloalkenyl
• aryl
• heterocyclyl Q represents

• oxygen
• sulphur
• carbonyl
•carboxylic •
(FORMULA REMOVED)

wherein, w represents *l* no atom
♦ carbonyl
♦ carboxylic
♦ amide R10 represents
♦ hydrogen
♦ alkyl
♦ aryl
♦ heterocyclyl R7 and R8 together represent
o cycloalkyl o cycloalkenyl o bicyclic alkyl o bicyclic alkenyl
o aryl
o heterocycle R2 represents (FORMULA REMOVED) wherein
R11 and Ri2 are independently selected from o hydrogen o alkyl o alkenyl o alkynyl o cycloalkyl o aryl
o heterocycle o -NR13R14 wherein R13 and R11 are independently selected from
• hydrogen
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• cycloalkenyl
• aryl
• heterocycle R represents
o hydrogen
o alkyl n represents an integer I to 2 X represents -oxygen -sulphur -CH2 -NR wherein R represents alkyl.
2. A compound according to claim 1 wherein A is
wherein R2. R3. R4. R5 and R6 are the same as defined in claim
3. A compound according to claim 1 wherein A is
4. A compound according to claim I wherein A is
5. A compound according to claim 1 wherein A is wherein R7 and Rs are the same as defined in claim
6. A compound according to claim 1 wherein A is
7. A compound according to claim 1 wherein A is
|;/^ wherein R7 are R,s are the same as defined in claim
8. A compound according to claim 1 wherein A is
9. A compound according to claim I wherein A is
10. A compound according to claim I wherein A is
11. A compound according to claim 1 wherein A is
12. A compound according to claim I wherein n =1 and R=H.
13. A compound according to claim 1 wherein X is-O-.
14. A compound according to claim I wherein x is -CH2-.
15. A compound, which is:
-1 -[3-(3.4.10.1 Oa-Tetrahydro-1 H-9-oxa-2,4a-diaza-phenanthren-2-yl)-propyl]-piperidine-2.6-dione (Compound No. 1).
-1 -[3-(3.4.10.1 Oa-Tetrahydro-1 H-9-oxa-2,4a-diaza-phenanthren-2-yl)-propyl]-piperidine-2.6-dione hydrochloride salt (Compound No.2),
-2-[3-(3.4.10. 1 Oa-Tetrahydro-1 H-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole-l,3-dione (Compound No. 3).
-1 -[3-( 1,2.4,4a,5,6-Hexahydro-pyrazino[ 1,2-a]qiiinolin-3-yl)-propyl]-piperidine-2,6-dione (Compound No. 4).
-2-[3-(1.2.4.4a.5.6-Hexahydro-pyrazino[1.2-a]quinolin-3-yl)-propyl]-3a.4.7.7a-tetrahydro-isoindole-l,3-dione (Compound No. 5).
-2-[3-( 1,2.4.4a.5,6-Hexahydro-pyrazino[ 1,2-a]quinolin-3-yl)-propyl]-3a,4.7.7a-tetrahydro-isoindole-l.3-dione hydrochloride salt (Compound No. 6).
-l-[3-(l,2,4.4a.5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3,4-dimethyl-pyrrole-2.5-dione (Compound No. 7),
-I -[3-( 1,2.4,4a, 5,6-Hexahydro-pyrazino[ 1,2-a]quinolin-3-yl)-propyl]-pyrroIe-2,5-dione (Compound No. 8),
-l-[3-(l,2.4.4a.5.6-Hexahydro-pyrazino[l,2-a]qumolin-3-yl)-propyl]-3,3-dimethyl-piperidine-2.6-dione (Compound No. 9),
-l-[3-(l,2.4.4a.5,6-Hexahydro-pyrazino[1.2-a]quinolin-3-yl)-propyl]-3-phenyl-pyrrolidine-2.5-dione (Compound No. 10).
-l-[3-(l,2.4,4a.5.6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3-phenyl-pyrrolidine-2.5-dione hydrochloride salt (Compound No. 11),
-l-[3-(l,2,4.4a.5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3-methyl-pyrrole-2,5-dione (Compound No. 12),
-1-[3-( 1,2.4.4a.5,6-Hexahydro-pyrazino[ 1,2-a]quoinol in-3-yl)-propyl]-3-phenyl-pyrrole-2.5-dione (Compound No. 13),
-3,4-Dimethyl-1 -[3-(6-methyl-1,2,4.4a.5.6-hexahydro-pyrazino[ 1,2-a]quinoxalin-3-yl)-propyl]-pyrrole-2,5-dione (Compound No. 14).
-2-[3-(6-Methyl-1,2,4,4a.5.6-hexahydro-pyrazino[ 1,2-a]quinoxalin-3-yl)-propyl]-5-phenyl-3a.4.7.7a-tetrahydro-isoindole-1.3-dione (Compound No. 15),
-5-Cyclohexylmethyl-2-[3-(3,4,10.1 Oa-tetrahydro-1 H-9-oxa-2,4a-diaza-phenanthren-2-yl)-propyl]-3a.4.7,7a-tetrahydro-isoindole-l,3-dione (Compound No. 16),
-l-[3-(l,2.4.4a,5,6-Hexahydro-pyrazino[l,2-a]quinoIin-3-yl)-propyl]-3-pyridin-2-yl-pyrrole-2.5-dione (Compound No. 17).
-5-Phenyl-2-[3-(3,4,10.1 Oa-tetrahydro-1 H-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-3a.4,7,7a-tetrahydro-isoindole-l,3-dione (Compound No. 18),
-3-Methyl-1 -[3-(3,4,10.1 Oa-tetrahydro-1 H-9-oxa-2.4a-diaza-phenanthren-2-yl)-propyl]-piperidine-2.6-dione (Compound No. 19).
-1 -[3-( 1,2.4.4a,5,6-Hexahydro-pyrazino[ 1,2-a]quinolin-3-yl)-propyl]-4-phenyl-piperidine-2.6-dione (Compound No. 20).
their pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers, diastereomers. N-oxides. prodrugs, polymorphs or metabolites
16. 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.
17. A method for treatment of a patient suffering from a disease or disorder mediated through αla and/or αlD adrenergic receptor, comprising administering to said patient a therapeutically effective amount of a compound of any one of the claim 1-15.
18. A method for treatment of a patient suffering from disease or disorder mediated
through αla and/or αlD adrenergic receptor, comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition according to claim 16.
19. The method according to claim I 7 or 18 wherein a disease or disorder is benign prostatic hyperplasia.
20. The method according to claim 17 or 18 wherein compound causes minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
21. A process for the preparation of a compound of Formula I. as shown in scheme I of
the accompanied drawings, its pharmaceutically acceptable acid addition salts.
pharmaceutically acceptable solvates, enantiomers. diastereomers. N-oxides. prodrugs, polymorphs or metabolites wherein: A represents
(FORMULA REMOVED)

wherein
R2. R3, R4 and R5 are independently selected from
o hydrogen
o alkyl
o phenyl R6 represents
o hydrogen
o alkyl
o phenyl
o hydroxy
o alkoxy — represents optional single bond R7 and R8 are independently selected from
o hydrogen
o alkyl
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocyclyl
o aralkyl
o (heterocyclyl)alkyl
(FORMULAR REMOVED)

wherein m represents an integer 0 to
R9 represents
alkyl
alkenyl
alkynyl
cycloalkyl
cycloalkenyl
aryl
heterocycle Q represents
oxygen
sulphur
carbonyl
carboxylic
wherein
represents ♦♦♦ no atom
♦ carbonyl
♦ carboxylic
♦ amide
R10 represents
♦ hydrogen
♦ alkyl
♦ aryl
♦ heterocyclic
R7 and R8 together represent o cycloalkyl o cycloalkenyl o bicyclic alkyl o bicyclic alkenyl o arvl
• heterocycle R2 represents
(FORMULA REMOVED)
wherein
R11 and R12 are independently selected from
o hydrogen
o alky!
o alkenyl
o alkynyl
o cycloalkyl
o aryl
o heterocyclyl
o -NR13R14 wherein R13 and R14 are independently selected from
• hydrogen
• alkyl
• alkenyl

• alkynyl
• cycloalkyl
• cycloalkenyl
• aryl
• heterocyclyl R represents
o hydrogen
o alkyl
n represents an integer 1 to 2 X represents
o -oxygen
o -sulphur
o -CH2
o -NR wherein R represents alkyl.
which method comprises:

reacting a compound of Formula II with a compound of Formula III to give a compound of Formula IV (wherein R. n and X are the same as defined earlier), which on reduction gives a compound of Formula V. which is finally treated with a compound of Formula VI to give a compound of Formula I (wherein A is the same as defined earlier), as shown in the accompanied drawings.
22. The process according to claim 21 wherein the reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IV is carried out in a solvent selected from the group consisting of chloroform, methanol, ethanol. cyclohexane. n-butylalcohol. acetonitrile. dichloromethane. dimethylformamide and dimethylsulfoxide.
23. The process according to claim 22 wherein the reaction is carried out in methanol.
24. The process according to claim 21 wherein the reduction of a compound of Formula IV to give a compound of Formula V is carried out a solvent selected from the group consisting of methanol, ethanol and isopropyl alcohol.
25. The process according to claim 24 wherein the reduction is carried out in methanol.
26. The process according to claim 21 wherein the reduction is carried out in the presence of reducing agent and ammonia selected from the group consisting of lithium aluminum hydride and Raney Nickel-hydrogen and ammonia.
27. The process according to claim 26 wherein the reduction is carried out in the presence of Raney Nickel-hydrogen and ammonia.
28. The process according to claim 21 wherein the reaction of a compound of Formula V with a compound of Formula VI to give a compound of Formula I is carried out in a solvent selected from the group consisting of acetonitrile, toluene, xylene, acetic anhydride and tetrahydrofuran.
29. The process according to claim 28 wherein the reaction is carried out in toluene.
30. The process for the preparation of a compound of Formula I. substantially as herein described and illustrated by example herein.