WO2005118591A1 - Condensed piperidine compounds acting as adrenergic receptor antagonists useful in the treatment of prostatic hyperplasia and lower urinary symptoms - Google Patents

Abstract

The present invention relates to α1a and/or α1d adrenergic receptor antagonists. Compounds provided herein can function as α1a and/or α1d adrenergic receptor antagonist and can be used for the treatment of a disease or disorder mediated through α1a and/or α1d adrenergic receptor. Compounds provided herein can be used for the treatment of benign prostatic hyperplasia (BPH) and the related symptoms thereof, lower urinary tract symptoms (LUTS) associated with or without BPH. Processes for the preparation of the provided compounds, as well as, pharmaceutical composition containing the provided compounds, and methods of treating benign prostatic hyperplasia or related symptoms thereof are provided herein.

Description

CONDENSED PIPERIDINE COMPOUNDS ACTING AS ADRENERGIC RECEPTOR ANTAGONISTS USEFUL IN THE TREATMENT OF PROSTATIC HYPERPLASIA AND LOWER URINARY SYMPTOMS Field of the Invention

The present invention relates to αj_a and/or ai_d adrenergic receptor antagonists. Compounds provided herein can function as αι_a and/or α^ adrenergic receptor antagonist and can be used for the treatment of a disease or disorder mediated through αι_a and/or α^ adrenergic receptor. Compounds provided herein can be used for the treatment of benign prostatic hyperplasia (BPH) and the related symptoms thereof, lower urinary tract symptoms (LTJTS) associated with or without BPH. Processes for the preparation of the provided compounds, as well as, pharmaceutical composition containing the provided compounds, and methods of treating benign prostatic hyperplasia or related symptoms thereof are provided herein.

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, a static component 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 an increased smooth muscle tone of the bladder neck and prostate itself and is regulated by cci 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 5α- 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 that inhibit 5α- reductase reduce the size of the prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5 -reductase inhibitor and causes a marked decrease in serum and tissue concentrations of dihydrotestosterone, it is only 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 αι_a 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 oci adrenoceptor. There are several lines of evidence to suggest that selectivity for αj_a adrenoceptor over ocι_D adrenoceptor will result in relative lack of vascular side effects, and thus lead to better tolerability. Mice deficient in cti_b adrenoreceptors show diminished blood pressure response to phenylephrine injection compared to homozygous controls (Proc. Nal. Acad. Sci. USA 1997, 94, 11589-11594). In-vivo comparison in healthy subjects of α,ι_a / ai_d selective antagonists (for example, tamsulosin) or αι_a 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 has been reported. (Eur. Clin. Pharmaco.l, 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 αι_a or αι_a/αi_d can cause some degree of vasodilation but that it is much smaller than with non-subtype-selective αι_a adrenoceptor antagonist. Further, there is increased vascular α^ adrenoceptor expression in elderly patients and thus α_la/αιa selective agents with selectivity over αi_b adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia, which is generally a disease of old age. Antagonism of both αι_a adrenoceptor and α^ adrenoceptor is important to relieve lower urinary tract symptoms especially associated with (suggestive of) BPH. Targeting α_la adrenoceptor with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction whereas α^ adrenoceptor antagonism is believed important to target irritative symptoms.

Over the past decade, there has been an intensive search for selective αι_a adrenoceptor antagonists for benign prostatic hyperplasia, which would avoid the cardiovascular side effects associated with currently used drugs. Selective antagonists 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 detail and some highly selective compounds have been identified. The literature describes the pharmacological activities associated with phenyl piperazines. Eur. J. Med. Chem. - Chimica Therapeutica, 12, 173- 176 (1977) describes substituted trifluoromethyl phenyl piperazines having cyclo-imido alkyl side chains such as shown below.

Other 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, Ishizumi et al., U.S. Patent No. 4,598,078, New et. al., J. Med. Chem., 29, 1476-1482 (1986), Shigeru et. al., JP 60-204784, New et al., U.S. Patent No. 4,524, 206, Korgaonkar et al., J. Indian Chem. Soc, 60, 874-876 (1983).

However, none of the above mentioned references disclose or suggest the α 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)-ω-[N- (α, ω-dicarboximido)]-alkanes useful as uro-selective αi -adrenoceptor blockers are disclosed in U.S. Patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,559, 6,420,366, WO 00/05206, U.S. Patent Appl. 2002/0156085 and WO 02/44151. These compounds had good αi-adrenergic blocking activity and selectivity.

Other reports describing selective αι_a adrenoceptor antagonists are U.S. Patent No. 6,376,503, U.S. Patent No. 6,319,932, U.S. Patent No. 6,339,090, EP 711 757, 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. Summary of the Invention

The present invention provides αι_a and/or α^ 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 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 compositions containing the 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 are also provided.

Other aspects will be set forth in accompanying description which follows, and will be apparent from the description or may be learnt by the practice of the invention. In one aspect, there are provided compounds having the structure of Formula I,

and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs or metabolites, wherein:

A can be

wherein,

R and R can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NRπR₁₂ (wherein Rn and R₁₂ can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocycle); R₄ and R₅ can be independently hydrogen, alkyl or phenyl;

R can be hydrogen, alkyl, phenyl, hydroxy or alkoxy;

— can be an optional single or double bond;

R₇ and R₈ can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, aralkyl, (heterocyclyl)alkyl or Re, — Q — (CH₂)m — [wherein m can be an integer of from 0 to 3, R₉ can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl, and Q can be oxygen, sulphur, carbonyl, carboxyl or ^^~w (wherein W can be carbonyl, carboxyl, amide or no atom, Rι₀ can be hydrogen, alkyl, aryl or heterocyclyl)], or R₇ and R₈ together can be cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle;

R can be hydrogen, alkyl;

n can be an integer of from 1 to 2; and X can be oxygen, sulphur, CH₂ or NRι₃ (wherein Rι₃ can be alkyl).

In a second aspect, there is provided a method for the treatment of a patient suffering from a disease or disorder mediated through α_]a and/or α^ adrenergic receptor, comprising administering a therapeutically effective amount ofa compound disclosed herein to a patient.

In 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 a therapeutically effective amount of a compound disclosed herein to a patient.

In 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 a therapeutically effective amount of a compound disclosed herein to a patient. In a fifth aspect, there is provided a process for the preparation of the compounds described herein.

In 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 a therapeutically effective amount ofa compound (or composition) described herein to a patient in combination with a bladder selective muscarinic receptor antagonist.

In 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 a therapeutically effective amount of a compound (or composition) described herein to a patient in combination with a testosterone 5 α-reductase inhibitor. In 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 a therapeutically effective amount of a compound (or composition) described herein to a patient in combination with a bladder selective muscarinic receptor antagonist and an optionally included testosterone 5 α reductase inhibitor.

Receptor binding assay studies described below indicated that the compounds disclosed herein possess selectivity towards αj_a 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 αι_a 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," unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may be substituted further with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, -NHC(=O)R_f, -NR_fRq, -C(=O)NR_fR_q, -NHC(=O)NR_fRq,, -C(=O)heteroaryl, C(=O)heterocyclyl, -O-C(=O)NR_fR_q {wherein R_f and R_q are independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, or -SO₂R_<5 (wherein Rβ is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1-3 substituents selected from alkyl, carboxy, -NR_fRq, -C(=O)NR_fRq, -OC(=O) NRfRq , -NHC(=O)NR_fRq (wherein R_f and R_q are the same as defined earlier), hydroxy, alkoxy, halogen, CF , cyano, and -SO Rό, (wherein R_ό are the same as defined earlier); or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NR_a- {wherein R_a is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=O)ORf (wherein Rf is the same as defined earlier), SO₂R_ό (where R₆ is as defined earlier), or -C(=O)NRfR_q (wherein R_f and R_q are as defined earlier)}. Unless otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, carboxy, -NR_fR_q, -C (=O)NR_fR_q, -O-C(=O)NR_fR_q (wherein R_f and R_q are the same as defined earlier) hydroxy, alkoxy, halogen, CF , cyano, and -SO₂R_ό (where Re is same as defined earlier); or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above. The term "alkylene," as used herein, refers to -(CH)_n- wherein n can be an integer of from 0 to 4 and one or more hydrogen can optionally be substituted with alkyl, hydroxy, halogen or oximes. Alkylene can also be optionally interrupted by -CONH-, -C=O or -C=NOH. The term "alkenyl," unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or geminal geometry. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom. Alkenyl groups may be substituted further with one or more substituents selected from alkyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, -NHC (=O)R_f, -NR_fR_q, -C(=O)NR_fR_q, -NHC(=O)NR_fR_q, -O-C(=O)NR_fR_q (wherein R_f and R_q are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino, alkoxyamino, nitro, or SO₂R<₅ (wherein R₆ are is same as defined earlier). Unless otherwise constrained by the definition, alkenyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, -CF₃, cyano, -NR_fR_q, - C(=O)NR_fRq, -O-C(=O)NR_fR_q (wherein R_f and R_q are the same as defined earlier) and - SO₂Re( where R_ό is same as defined earlier). The term "alkynyl," unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -NHC(=O)R_f) -NR_fRq, -NHC(=O)NR_fR_q , -C(=O)NR_fRq, -O-C(=O)NR_fRq (wherein R_f and Rq are the same as defined earlier), or -SO₂R_ό (wherein R$ is as defined earlier). Unless otherwise constrained by the definition, alkynyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF₃, -NR_fR_q, -C(=O)NR_fR_q, -NHC(=O)NR_fR_q , -C(=O)NR_fR_q (wherein R_f and Rq are the same as defined earlier), cyano, or -SO₂R₆ (where R_ό is same as defined earlier). The term "cycloalkyl," unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like. Spiro and fused ring structures can also be included. Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, -NR_fR_q, -NHC (=O) NRfRq, -NHC (=O) R_f, -C (=O) NR_fR_q, -O-C (=O)NR_fR_q (wherein R and Rq are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or SO₂-Rδ (wherein R₆ is same as defined earlier). Unless otherwise constrained by the definition, cycloalkyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, CF₃, -NR_fRq, -C(=O)NR_fR_q, -NHC(=O)NR_fR_q , -OC(=O)NRfRq (wherein R_f and Rq are the same as defined earlier), cyano or -SO₂R_δ (where R^ is same as defined earlier). "Cycloalkylalkyl" refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier.

As used herein, the term "cycloalkenyl" refers to unsaturated carbocyclic ring having three to seven carbon atoms. One or more hydrogen of said alkenyl or alkynyl can be replaced by halogen, hydroxy, cyano, or -NR₅R_ό, wherein R₅ and R₆ are selected from hydrogen and alkyl. Examples of cycloalkenyl include, but are not limited to, cyclopropenyl and cyclobutenyl, and the like. Multiple cyclic structures are also included. The "cycloalkyl" or "cycloalkenyl" may optionally be substituted with halogen. The term "halogen" refers to fluorine, chlorine, bromine or iodine. The term "aryl," unless otherwise specified, refers to carbocyclic aromatic groups, for example, phenyl, biphenyl or napthyl ring and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF₃, cyano, nitro, COOR_e (wherein R_e is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=O)R_f, -NR_fR_q, -C(=O)NR_fR_q, -NHC(=O)NR_fR_q , -O-C(=O)NR_fRq (wherein R_f and R_q are the same as defined earlier), -SO₂R_ό (wherein R^ is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino. The aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S. The term "aralkyl," unless otherwise specified, refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined below. Examples of aralkyl groups include benzyl, ethylphenyl and the like. The term "alkoxy" denotes the group O-alkyl wherein alkyl is the same as defined above.

The term 'heterocyclyl," unless otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -O-C(=O)R_f, -O-C(=O)OR_f, -C(=O)NR_fR_q, SO₂R₆, -O-C(=O)NR_fR_q, -NHC(=O)NR_fRq, -NR_fRq (wherein Rό, R_f and R_q are as defined earlier) or guanidine. Heterocyclyl can optionally include rings having one or more double bonds. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s). Examples of heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl or piperazinyl. 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 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, -NHSO₂R² and -SO₂NHR² wherein R¹ and R² 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 sequences as shown in Scheme I. Scheme I

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 can give a compound of Formula IN (wherein R, n and X are the same as defined earlier), which on reduction can give a compound of Formula V, which on treatment with a compound of Formula VI can give a compound of Formula I (wherein A is the same as defined earlier) which can then be further, converted to any pharmaceutically acceptable salt known to one of ordinary skilled in the 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 TV 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 provided herein is given below: l-[3-(3,4,10,10a-Tetrahydro-lH-9-oxa-2,4a-diaza-phenanthren-2-yl)-propyl]-piperidine- 2,6-dione (Compound No. 1), l-[3-(3,4,10,10a-Tetrahydro-lH-9-oxa-2,4a-diaza-phenanthren-2-yl)-propyl]-piperidine- 2,6-dione hydrochloride salt (Compound No.2),

2-[3-(3,4,10, 10a-Tetrahydro-lH-9-oxa-2,4a-diaza-phenanthren-2-yl)-propyl]-3a,4,7,7a- tetrahydro-isoindole-l,3-dione (Compound No. 3), l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-piperidine-2,6-dione (Compound No. 4),

2-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3a,4,7,7a-tetrahydro- isoindole-l,3-dione (Compound No. 5),

2-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,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), l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-pyrrole-2,5-dione (Compound No. 8), l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3,3-dimethyl- piperidine-2,6-dione (Compound No. 9), l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,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), 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-l,2,4,4a,5,6-hexahydro-pyrazino[l,2-a]quinoxalin-3-yl)- propyl]-pyrrole-2,5-dione (Compound No. 14),

2-[3-(6-Methyl-l,2,4,4a,5,6-hexahydro-pyrazino[l,2-a]quinoxalin-3-yl)-propyl]-5-phenyl- 3a,4,7,7a-tetrahydro-isoindole-l,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-l,3-dione (Compound No. 16), l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,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-lH-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), l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-4-phenyl-piperidine- 2,6-dione (Compound No. 20).

The compounds described herein are basic and can form organic or inorganic acid addition salts, which are within the scope of sound medical judgment 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 therapeutic compositions. 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 solution of the resulting salt can be subjected to rotary evaporation under diminished pressure to the volume necessary to ensure precipitation of the salt upon cooling, which can then be 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 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 can be stripped off 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 pharmacological activity, and 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 pharmaceutically effective amount of a compound provided herein 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 fillers, diluents, encapsulating materials or formulation auxiliaries of any type. Solid form preparations for oral administrations, include capsules, tablets, pills, powder, granules, cathets and suppositories. For solid form preparations, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, or dicalcium phosphate and/or a filler or extender such as starch, lactose, sucrose, glucose, mannitol or silicic acid; binder such as carboxymethylcellulose, alginates, gelatins, polyvinylpyrolidinone, sucrose, or acacia; disintegrating agent such as a agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates or sodium carbonate; absorption accelator such as quaternary ammonium compounds; wetting agent such as cetyl alcohol, glycerol, or a monostearate; adsorbent such as kaolin; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, or sodium lauryl sulphate and mixture thereof.

In case of capsules, tablets, and pills, the dosage form may also comprise buffering agents. The solid preparation of tablets, capsules, pills, or 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, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol and fatty acid esters of sorbitan and mixtures 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 forms for topical or transdermal administration of a compound provided herein 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 forms, the preparation may be subdivided into unit doses containing appropriate quantities of the active component. The unit dosage forms can be packaged preparations, the package containing discrete capsules, powders, in vials or ampoules and ointments, capsules, cachets, tablets, gel cream, 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 provided herein, bladder selective muscarinic receptor antagonist and 5α.reductase inhibitor are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the compounds provided herein, bladder selective muscarinic receptor antagonist and 5α.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 components 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.

Examples

Example 1: Preparation of 2-^3- l,2A4a,5,6-Hexahydro-p azino^l.2-a]quinolin-3-yl - propyl^-3aA7,7a-tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 6)

Step 1: Preparation of 3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-y.)- propionitrile

To a solution of 2,3,4,4a,5,6-Hexahydro-lH-pyrazino[l,2-a]quinoline (1 gm, 5.3 mmole, S. P. Gupta et al., Indian J. of Chem., L3, 462-467 (1975)) in methanol was added acrylonitrile (0.56 gm, 10.6 mmole) and reaction mixture stirred. Excess solvent was removed on buchi to give the crude product. The crude product was purified on silica gel column using dichloromethane as eluent. Yield: 1.0 gm (78%)

Step 2: Preparation of 3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinoIin-3-yl)- propylamine To a solution 3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,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-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)- propyl]-3a,4,7,7a-tetrahydro-isoindole-l,3-dione To a solution of 3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)- propylamine (0.5 gm, 2.0 mmole, from step 2) in toluene was added cis-l, 2,3,6- tetrahydrophthalimide and reaction mixture was reflux ed. 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-l,3-dione IR (KBr): 1703.3 cm^"1; Η NMR (300 MHz, CDC1₃): δ 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 (m, 3H), 5.81 (s, 2H), 6.72-6.83 (m, 4H), 13.35 (brs, IH); Mass (m/z): 382.2 (M⁺+l)

Compound No. 4: l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]- piperidine-2,6-dione

LR (KBr): 1673.4 cm^'1; 1H NMR (300 MHz, CDC1₃): δ 1.79 (m, IH), 1.99 (m, 3H), 2.20 (m, 2H), 2,70 (m, 6H), 2.88-3.04 (m, 4H), 3.48-3.51 (m, IH), 3.66-3.73 (m, 2H), 3.90-4.02 (m, 4H), 6.81-7.39 (m, 4H), 12.97 (brs, IH); Mass (m/z): 342.3 (M⁺+l)

Compound No. 7: l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]- 3,4-dimethyl-pyrrole-2,5-dione

LR (KBr): 1710.0 cm^'1; 1H NMR (300 MHz, CDC1₃): δ 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, IH), 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, IH); Mass (m z): 354.4 (M⁺+l) Compound No. 8: l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]- pyrrole-2,5-dione

IR (KBr): 1705.8 cm^-1; Η NMR (300 MHz, CDCI₃): δ 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), 6.75-7.11 (m, 6H), 13.06 (brs, IH); Mass (m/z): 326.5 (M⁺+l) Compound No. 9: l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-

3,3-dimethyl-piperidine-2,6-dione

LR (KBr): 1672.9 cm^"1; Η NMR (300 MHz, CDCI₃): δ 1.26-1.29 (m, 6H), 1.81-1.86 (m, 3H), 2.01 (m, IH), 2.15 (m, 2H), 2.71-2.75 (m, 4H), 2.91-3.01 (m, 4H), 3.46 (m, IH), 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, IH); Mass (m/z): 370.5 (M⁺+l)

Compound No. 12: l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3- methyl-pyrrole-2 , 5 -dione

IR (KBr): 1704.7 cm^"1; Η NMR (300 MHz, CDCI₃): δ 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, IH), 3.63-3.74 (m, 4H), 3.89-3.99 (m, 2H), 6.35 (brs, IH), 6.78-6.83 (m, 2H), 7.00-7.14 (m, 2H); Mass (m/z): 340.4 (M⁺+l)

Step 4: Preparation of 2-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)- propyl]-3a,4,7,7a-tetrahydro-isoindole-l ,3-dione hydrochloride salt

To a solution of 2-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,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: 0.6 lgm (89%)

IR (KBr): 1697.2 cm^"1; Η NMR (300 MHz, CDC1₃): δ 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: l-[3-(3,4,10,10a-Tetrahydro-lH-9-oxa-2,4a-diaza-phenanthren-2-yl)- propyl]-piperidine-2,6-dione hydrochloride salt

IR (DCM): 1653.7 cm^"1; 1H NMR (300 MHz, CDC1₃): δ 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, IH); Mass (m/z): 344.3 (M⁺+l)

Compound No. 11 : 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

IR (KBr): 1697.3 cm^"1; 1H NMR (300 MHz, CDCI₃): δ 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, IH), 3.45-3.70 (m, 4H), 3.91 (m, IH), 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-Hexahvdro-pyrazinori,2-a1quoinolin-3-yl)- propyl1-3-phenyl-pyrrole-2.5-dione (Compound No. 13)

To a solution of 3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)- propylamine (0.5 gm, 2.0 mmole, from Example 1, Step 2) in toluene is added 3-phenyl- furan-2,5-dione and reaction mixture is refiuxed. 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-l-[3-(6-methyl-l,2,4,4a,5,6-hexahydro-pyrazino[l,2-a]quinoxalin-3-yl)- propyl]-pyrrole-2,5-dione (Compound No. 14)

-2-[3-(6-Methyl-l ,2,4,4a,5,6-hexahydro-pyrazino[l ,2-a]quinoxalin-3-yl)-propyl]-5- phenyl-3a,4,7,7a-tetrahydro-isoindole-l,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-l,3-dione (Compound No. 16)

-l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,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-lH-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)

-l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-4-phenyl-piperidine- 2,6-dione (Compound No. 20)

Example 3: Pharmacological testing - Receptor Binding Assay Receptor binding assays were performed using native αi adrenoceptors. The affinity of different compounds for αι_a and α^ adrenoceptor subtypes was evaluated by studying 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 hydrochloric acid (HCl) 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 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 40,000g for 45 min. The pellets thus obtained were 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 1 hour. Non-specific 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 HCl 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), K = IC₅₀ /(1+L/Kd) where L is the concentration of [³H] prazosin used in the particular experiment. The affinity at _la adrenoreceptor expressed in terms of K, (nM) for all compounds ranged from low nanomolar (K, = 0.14 nM) to high nanomolar (K, = 4098 nM) in comparison to terazosin (K, =7.5 nM). For example, the _la affinity ranged from K, of about 115 nM to about 0.14 nM, or from about 43 nM to about 0.14 nM, or from about 5 nM to about 0.14 nM.

The affinity at αi_b expressed as K, (nM) for all compounds was ranged from low nano molar (K, = 96.3 nM) to high nano molar (K, =3279 nM) in comparison to terazosin with a K, value of 5.5 nM. For example, the oiib affinity ranged from K, of about 280 nM to about 96.3 nM, or from about 186 nM to about 96.3 nM. The fold selectivity of ι_a over i_b adrenoreceptor for all compounds ranged from

0.80 fold to 3936 fold compared to 0.73 selectivity for terazosin. For example, the fold selectivity ranged from about 2.3 fold to about 3936 fold, or from about 15 fold to about 3936 fold, or from about 21 fold to about 3936 fold. Thus, compounds of the present invention are relatively more selective for a ι_a over π, adrenoreceptors compared to terazosin.

Example 4: In vitro functional studies - In vitro a , Adrenoceptor selectivity

In order to study selectivity of action of the present compounds towards different αι_a adrenoreceptor subtypes, the ability of these compounds to antagonize ι_a adrenoreceptor agonist induced contractile response of aorta (α^), prostate (αι_a ) and spleen ( α^) 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 (NaCl) 118; potassium chloride (KC1) 4.7; calcium chloride (CaCl₂) 2.5; magnesium sulphate hepta hydrate (MgSO₄. 7H₂O) 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 (CO₂). 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).

Claims

We Claim: 1. A compound having the structure of Formula I,

and its pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs or metabolites, wherein, A is wherein

R₂ and R₃ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NRi ιR]₂ (wherein Ri i and R]₂ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocycle); R₄ and R₅ are independently hydrogen, alkyl or phenyl; R₆ are hydrogen, alkyl, phenyl, hydroxy or alkoxy; — is an optional single or double bond; R₇ and R₈ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, aralkyl, (heterocyclyl)alkyl or ^ ^Q iP ihn. [wherein m is an integer of from 0 to 3, R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl N— W or heterocyclyl, and Q is oxygen, sulphur, carbonyl, carboxyl or 1 (wherein ^Rιo W is carbonyl, carboxyl, amide or no atom, and Rio is hydrogen, alkyl, aryl or heterocyclyl)], or R₇ and R₈ together are cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle; R is hydrogen or alkyl; n is an integer of from 1 to 2; and X is oxygen, sulphur, CH₂ or NR₁₃ (wherein Rι₃ is alkyl).

2. The compound according to claim 1 wherein A is

n is 1 , R is hydrogen, X is O or CH₂.

3. A compound, which is: l-[3-(3,4,10,10a-Tetrahydro-lH-9-oxa-2,4a-diaza-phenanthren-2-yl)-propyl]- piperidine-2,6-dione, l-[3-(3,4,10,10a-Tetrahydro-lH-9-oxa-2,4a-diaza-phenanthren-2-yl)-propyl]- piperidine-2,6-dione hydrochloride salt, 2-[3-(3,4,10, 10a-Tetrahydro-lH-9-oxa-2,4a-diaza-phenanthren-2-yl)-propyl]- 3a,4,7,7a-tetrahydro-isoindole-l,3-dione, l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-piperidine- 2,6-dione, 2-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3a,4,7,7a- tetrahydro-isoindole- 1 ,3-dione, 2-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3a,4,7,7a- tetrahydro-isoindole- 1, 3 -dione hydrochloride salt, l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3,4-dimethyl- pyrrole-2,5-dione, l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-pyrrole-2,5- dione, l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3,3-dimethyl- piperidine-2,6-dione, l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3-phenyl- pyrrolidine-2,5-dione, 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, l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3-methyl- pyrrole-2,5-dione, l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quoinolin-3-yl)-propyl]-3-phenyl- pyrrole-2,5-dione, 3,4-Dimethyl- 1 -[3-(6-methyl-l ,2,4,4a,5,6-hexahydro-pyrazino[ 1 ,2-a]quinoxalin-3- yl)-propyl]-pyrrole-2,5-dione, 2-[3-(6-Methyl-l,2,4,4a,5,6-hexahydro-pyrazino[l,2-a]quinoxalin-3-yl)-propyl]-5- phenyl-3a,4,7,7a-tetrahydro-isoindole-l,3-dione, 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, l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-3-pyridin-2- yl-pyrrole-2,5-dione, 5-Phenyl-2-[3-(3,4, 10, 10a-tetrahydro-lH-9-oxa-2,4a-diaza-phenanthren-2-yl)- propyl]-3a,4,7,7a-tetrahydro-isoindole-l ,3-dione, 3-Methyl-l-[3-(3,4,10,10a-tetrahydro-lH-9-oxa-2,4a-diaza-phenanthren-2-yl)- propyl]-piperidine-2,6-dione, l-[3-(l,2,4,4a,5,6-Hexahydro-pyrazino[l,2-a]quinolin-3-yl)-propyl]-4-phenyl- piperidine-2,6-dione or their pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs or metabolites

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 optionally together with pharmaceutically acceptable carriers, excipients or diluents.

5. A method for treatment of a patient suffering from a disease or disorder mediated through α_]a and/or α^ adrenergic receptor, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or pharmaceutical composition of claim 4.

6. The method according to claim 5 wherein a disease or disorder is benign prostatic hyperplasia or lower urinary tract symptoms.

7. The method according to claim 5 wherein compound causes minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. A method for the preparation ofa compound of Formula I,

pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof, wherein A is ^*" - ^• , ^or _R X ^wherein ^ R₂ and R₃ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NRnR_]2 (wherein Rπ and Rι₂ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocycle); R and R₅ are independently hydrogen, alkyl or phenyl;

R_ό are hydrogen, alkyl, phenyl, hydroxy or alkoxy;

— is an optional single or double bond;

R₇ and R₈ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, aralkyl, (heterocyclyl)alkyl or R9 — Q — (CH₂)m — [wherein m is an integer of from 0 to 3, R₉ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl — — W or heterocyclyl, and Q is oxygen, sulphur, carbonyl, carboxyl or 1 (wherein ^Rιo W is carbonyl, carboxyl, amide or no atom, and Rio is hydrogen, alkyl, aryl or heterocyclyl)], or R₇ and R₈ together are cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle;

R is hydrogen or alkyl;

n is an integer of from 1 to 2; and X is oxygen, sulphur, CH₂ or NR₁₃ (wherein R₎₃ is alkyl), which method comprises:

(a) reacting a compound of Formula II with a compound of Formula III,

Formula II Formula III to give a compound of Formula IN,

Formula IV

(b) reducing the compound of Formula IV to give a compound of Formula V,

Formula V

(c) treating the compound of Formula V with a compound of Formula VI,

Formula VI to give a compound of Formula I.