WO2006018815A1

WO2006018815A1 - Piperazine derivatives as adrenergic receptor antagonists

Info

Publication number: WO2006018815A1
Application number: PCT/IB2005/052706
Authority: WO
Inventors: Mohammad Salman; Nitya Anand; Somesh Sharma; Gobind Singh Kapkoti; Anita Chugh; Kamna Nanda
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-08-16
Filing date: 2005-08-16
Publication date: 2006-02-23

Abstract

The present invention relates to alpha la and/or alpha id adrenergic receptor antagonists of formula (I). Compounds described herein can function as alpha la and/or alpha id adrenergic receptor antagonists and can be used to treat. diseases or disorders mediated through alpha la and/or alpha id adrenergic receptors. Compounds described herein can also be used to treat benign prostatic hyperplasia or related symptoms thereof. Compounds described herein can also be used to treat lower urinary tract symptoms associated with or without benign prostatic hyperplasia. Also described herein are processes to prepare the described compounds, as well as pharmaceutical compositions thereof and methods of treating benign prostatic hyperplasia or related symptoms thereof.

Description

PIPERAZINE DERIVATIVES AS ADRENERGIC RECEPTOR ANTAGONISTS

[1] Field of the Invention

[2] The present invention relates to alpha Ia and/or alpha Id adrenergic receptor an¬ tagonists. Compounds described herein can function as alpha Ia and/or alpha Id adrenergic receptor antagonists and can be used to treat diseases or disorders mediated through alpha Ia and/or alpha Id adrenergic receptors. Compounds described herein can be used to treat benign prostatic hyperplasia or related symptoms thereof. Compounds described herein can also be used to treat lower urinary tract symptoms associated with or without benign prostatic hyperplasia. Also described herein are processes to prepare the described compounds, as well as, pharmaceutical composition thereof and methods of treating benign prostatic hyperplasia or related symptoms thereof.

[3] Background of the Invention

[4] Benign prostatic hyperplasia (BPH) is a condition involving benign overgrowth of stromal and epithelial elements of the prostate, which typically occurs with aging in elderly males. 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. Con¬ sequences of BPH can involve hypertrophy of bladder smooth muscle, a de¬ compensated bladder and an increased incidence of urinary tract infection.

[5] There are two components of BPH, a static and a dynamic component. The static component is caused by 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 caused by increased smooth muscle tone of the bladder neck and prostate itself and is regulated by alpha- 1 adrenergic receptor.

[6] Currently, the typical treatment for BPH is a surgical procedure known as transurethral resection of the prostate (TURP), which removes obstructing tissue (C. Chappie, Br. Med. Journal, 304:1198-1199, (1992)). TURP is directed to the static and dynamic components of BPH. However, TURP is associated with rates of mortality (1 %) and adverse events (incontinence 2-4 %, infection 5-10 %, and impotence 5-10 %). A noninvasive alternative treatment is therefore highly desirable.

[7] Some drug therapies address the static component of BPH. Administration of fi¬ nasteride is one such therapy, which is indicated for the treatment of symptomatic BPH. Finasteride is a competitive inhibitor of the enzyme 5 alpha-reductase that is re¬ sponsible 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 alpha-reductase, reduce the size of the prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5-alpha 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. [8] 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 alpha 1 a AR antagonists, for example, terazosin, doxazosin, prazosin, alfuzosin and tamsulosin, have been investigated for the treatment of symptomatic bladder outlet obstruction due to BPH. However, these drugs are associated with vascular side effects (e.g., postural hypertension, syncope, dizziness, headache etc.) due to lack of selectivity of action between prostatic and vascular alpha 1 adrenoceptors. Evidence suggests that selectivity for alpha 1 a adrenoceptor over alpha Ib adrenoceptor results in relative absence of vascular side effects, thus lead to better tolerability. Mice deficient in alpha Ib adrenoceptors show diminished blood pressure response to phenylephrine injection compared to homozygous controls (Decreased blood pressure response in mice deficient of alpha Ib adrenergic receptor ( Proc. Natl. Acad. ScL, USA, 94: 11589-11594 (1997)). Also reported were in-vivo studies in healthy subjects, which compared alpha la/alpha Id selective antagonists (for example, tamsulosin) or alpha Ia 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. (Eur. J. Clin. Pharmacol., 49:371-375 (1996); Naunyn Schmiedeberg, Arch Pharmacol, 354:557-561 (1996); Jpn J Pharmacol, 80:209-215 (1999); Br J CHn Pharmacol, 4,1:61-14 (1999)). These studies reported that an antagonist with high affinity for alpha Ia or alpha la/alpha Id can cause some degree of vasodilation, but to a lesser extent than with non-subtype-selective alpha Ia adrenoceptor antagonists. Further, there is increased vascular alpha Ib adrenoceptor expression in elderly patients and thus alpha la/alpha Id selective agents with se¬ lectivity over alpha 1 b adrenoceptor subtype can be useful in treating benign prostatic hyperplasia. Antagonism of both alpha Ia adrenoceptors and alpha Id adrenoceptors can relieve lower urinary tract symptoms especially associated (or suggestive of) with BPH. Targeting alpha Ia adrenoceptors with antagonists can relax prostate smooth muscle and relieve bladder outlet obstruction whereas alpha Ia adrenoceptor antagonism can target irritative symptoms. [9] Significant research efforts have been directed to developing selective alpha 1 a adrenoreceptor antagonists for benign prostatic hyperplasia, which avoid car¬ diovascular side effects associated with currently used drugs. Many selective an¬ tagonists have been described by Hieble et al., Exp. OpIn. Invest. Drugs., 6:367-387 (1997) and by Kenny et al, J. Med. Chem., 40:1293-1325 (1995). Structure-activity re¬ lationships in many of these structural series have been studied in details and numerous highly selective compounds have been identified. Pharmacological activities associated with phenyl piperazines have been disclosed, for example, Eur. J. Med. Chem.- Chimica Therapeutica, 12:173-176 (1977) discloses substituted trifluoromethyl phenyl piperazines having cyclo-imido alkyl side chains shown below.

[11] Other related compounds which have been prepared as anxiolytic, neuroleptic, anti¬ diabetic and anti-allergic agents have been described (PCT Application No. WO 98/37893; Steen et al.,J. Med. Chem., 38:4303-4308 (1995); Ishizumi et al, Chem. Pharm. Bull, 39(9):2288-2300 (1991); Kitaro et al, Japanese Patent Publication No. JP 02-235865 (1990), Ishizumi et al, U.S. Patent No. 4,598,078 (1986), New et al.J. Med. Chem., 29:1476-1482 (1986), Shigeru et al, Japanese Patent Publication No. JP 60-204784 (1985), New et al, U.S. Patent No. 4,524, 206 (1985), Korgaonkar et al.J. Indian Chem. Soc, 60:874-876 (1983)). However, none of these references disclose or suggest the a subtype selectivity profile of the compounds disclosed therein, much less their usefulness in the treatment of symptoms of benign prostate hyperplasia.

[12] The synthesis of l-(4-arylpiperazin-l-yl)-omega-[N- (alpha, omega-dicarboximido)

]-alkanes, which are useful as uro-selective alpha -adrenoceptor blockers, are disclosed in U.S. Patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,559 and 6,420,366, U.S. Patent Application No. 2002/0156085 and PCT Publication Nos. WO 02/44151 and WO 00/05206. These compounds reportedly possess good alpha -adrenergic blocking activity and selectivity.

[13] Alpha Ia adrenoceptor antagonists are also disclosed in U.S. Patent Nos. 6,376,503,

6,319,932, 6,339,090, European Patent No. 711757, and PCT Publication Nos. 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.

[14] However, there remains a need for novel alpha Ia and alpha Id adrenergic receptor antagonists, which can be used, for example, to treat BPH or associated symptoms, as well as LUTS with or without BPH.

[15] Summary of the Invention

[16] The present invention provides novel alpha Ia and/or alpha Id adrenergic receptor antagonists, which can be used to treat benign prostatic hyperplasia (BPH) or related symptoms thereof or lower urinary tract symptoms (LUTS) with or without BPH, and processes for the synthesis of compounds described herein.

[17] Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxide of such compounds having the same type of activity are also provided. Pharmaceutical composition containing one or more described compounds, and which may also contain pharmaceutically acceptable carriers, excipients or diluents, which can be used to treat BPH or related symptoms thereof or LUTS with or without BPH.

[18] In one aspect, provided herein are compounds having the structure of Formula I,

[20] pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof, wherein:

[22] wherein:

[23] R and R can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NR R , wherein

^J 1 1 12

[24] R and R can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cy- cloalkenyl, aryl or heterocycle;

[25] R and R can independently be hydrogen, alkyl or phenyl;

[26] R can be hydrogen, alkyl, phenyl, hydroxy or alkoxy;

6

[27] R and R can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,

7 8 heterocycle, aralkyl, (heterocycle)alkyl or R -Q-(CH ) -, or R and R together can be

9 2 m 7 8 cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle, wherein [28] m can be an integer from 0 to 3; R can be alkyl, alkenyl, alkynyl, cycloalkyl, cy- cloalkenyl, aryl or heterocycle; and Q can be oxygen, sulfur, carbonyl, carboxyl or -

N(R )-W, wherein [29] W can be no atom, carbonyl, carboxylic or amide; and R can be hydrogen, alkyl, aryl or heterocycle; [30] can be optional double bond;

[31] Z can be CH₂, CH₂CH₂ or O;

[32] X and Y can independently be methylene or carbonyl;

[33] R can be hydrogen or methyl;

[34] R can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or

(heterocycle)alkyl; and [35] n can be an integer of from 1 to 3.

[36] These compounds can include one or more of the following embodiments. For example in one embodiment, R can be aryl; n can be an integer of from 1 to 3; both X and Y can be methylene; R can be hydrogen;

[38] In another aspect, provided herein are compounds selected from:

[39] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-4-yl)-3-[4-(2-methoxyphenyl

)-piperazin- 1 -yl]-propionamide, [40] N-(l,3-Dioxo-l,3,3a,4,7,7 a- hexahydro-isoindol-2-yl)-3-[4-(2-methoxyphenyl)-piperazin-l-yl)-propionamide, [41] 3-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

- 1 -yl)-propionamide, [42] N-(2,6-Dioxo-piperidin- 1 -yl)-3-[4-(2-methoxyphenyl)-piperazin- 1 -yl]-propionamid e, [43] N-( 1 ,3-Dioxo- 1 ,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-3-[4-(2-isopropoxyphenyl)-pi perazin- 1 -yi]-propionamide, [44] N-(3,4-Dimethyl-2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-3-[4-(2-isopropoxyphenyl)-pip erazin-l-yl]-propionamide, [45] 4-[4-(2-Methoxyphenyl)-piperazin- 1 -yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

-l-yl)-butyramide, [46] 2-[4-(2-Methoxyphenyl)-piperazin- 1 -yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

-l-yl)-acetamide, [47] N-(3,4-Dimethyl-2,5-dioxo-2,5-dihylro-pyrrol- 1 -yl)-2-[4-(2-methoxyphenyl)-pipera zin- 1 -yl]-acetamide, [48] N-(2,6-Dioxo-piperidin- 1 -yl)-2-[4-(2-methoxyphenyl)-piperazin- 1 -yl]-acetamide,

[49] 3-[4-(2-Isopropoxyphenyl)-piperazin- 1 -yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrr ol- 1 -yl)-propionamide,

[50] N-(2,6-Dioxo-piperidin-l-yl)-2-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-acetamide,

[51] N-(3,5-Dioxo-10-oxa-tricyclo[5.2.1, 0*2,6*] dec-

8-en-4-yl)-2-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-acetamide, [52] N-(3,4-Dimethyl-2,5-dioxo-cyclopent-3-enyl)-2-[4-(2-isopropoxyphenyl)-piperazin

-l-yl]-acetamide, [53] 2-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-cyclopent-3-enyl

)-acetamide, [54] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*,6*]dec-8-en-4-yl)-3-[4-(2-isopropoxy phenyl)-piperazin- 1 -yl]-propionamide, [55] N-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-2-[4-(2-methoxyphenyl)-pipe razin-l-yl]-acetamide, [56] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-8-en-4-yl)-2-[4-(2-methoxyp henyl)-piperazin- 1 -yl]-acetamide, [57] N-(l,3-Dioxo-2,3,3a,4,7,7a-hexahydro-lH-inden-2-yl)-2-[4-(2-isopropoxyphenyl)- piperazin- l-yl]-acetamide, [58] N-(3,5-Dioxo-4-aza-tricyclo[5.2.2.0*2,6*]undec-8-en-4-yl)-3-[4-(2-ethoxyphenyl)- piperazin- 1 -yl]-propionamide, [59] 3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-N-(3,5-dioxo-4-aza-tricyclo

[5.2.1.0*2,6*]dec-8-en-4-yl)-propionamide, [60] N-(3-Benzyl-2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-3-(4-phenyl-piperazin-l-yl)-propio namide, [61] N-(3,5-Dioxo-4-aza-tricyclo[5.2.2.0*2,6*]undec-8-en-4-yl)-3-{4-[2-(3,3,3-trifluoro

-propoxy)-phenyl]-piperazin- 1 -yl } -propionamide, [62] N-(3,3-Dimethyl-2,6-dioxo-piperidin- 1 -yl)-3-[4-(2-methoxyphenyl)-3-oxo-piperazi n-l-yl]-propionamide, [63] 3-(2,3-Dioxo-4-phenyl-piperazin- 1 -yl)-N-(2,6-dioxo-4-phenyl-piperidin- 1 -yl)-propi onamide, [64] 2-[4-(2-Isopropoxyphenyl)-2,3-dimethyl-piperazin- 1 -yl]-N-(3-methyl-2,6-dioxo-pip eradin-l-yl)-acetamide, or [65] pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof. [66] In another aspect, provided herein are compounds selected from:

[67] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-4-yl)-3-[4-(2-methoxyphenyl

)-piperazin-l-yl]-propionamide hydrochloride salt, [68] N-(l,3-Dioxo-l,3,3a,4,7,7 a- hexahydro-isoindol-2-yl)-3-[4-(2-methoxyphenyl)-piperazin-l-yl)-propionamide hy¬ drochloride salt, [69] 3-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

-l-yl)-propionamide hydrochloride salt, [70] N-(2,6-Dioxo-piperidin- 1 -yl)-3-[4-(2-methoxyphenyl)-piperazin- 1 -yl]-propionamid e hydrochloride salt, [71] N-(1 ,3-Dioxo- 1 ,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-3-[4-(2-isopropoxyphenyl)-pi perazin-l-yl]-propionamide hydrochloride salt, [72] N-(3,4-Dimethyl-2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-3-[4-(2-isopropoxyphenyl)-pip erazin-l-yl]-propionamide hydrochloride salt, [73] 4-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

-l-yl)-butyramide hydrochloride salt, [74] 2-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

-l-yl)-acetamide hydrochloride salt, [75] N-(3,4-Dimethyl-2,5-dioxo-2,5-dihylro-pyrrol- 1 -yl)-2-[4-(2-methoxyphenyl)-pipera zin-l-yl]-acetamide hydrochloride salt, [76] N-(2,6-Dioxo-piperidin-l-yl)-2-[4-(2-methoxyphenyl)-piperazin-l-yl]-acetamide hydrochloride salt, [77] 3-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrr ol-l-yl)-propionamide hydrochloride salt, [78] N-(2,6-Dioxo-piperidin- 1 -yl)-2-[4-(2-isopropoxyphenyl)-piperazin- 1 -yl]-acetamide hydrochloride salt, [79] N-(3,5-Dioxo-10-oxa-tricyclo[5.2.1, 0*2,6*] dec-

8-en-4-yl)-2-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-acetamide hydrochloride salt, [80] N-(3,4-Dimethyl-2,5-dioxo-cyclopent-3-enyl)-2-[4-(2-isopropoxyphenyl)-piperazin

-l-yl]-acetamide hydrochloride salt, [81] 2-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-cyclopent-3-enyl

)-acetamide hydrochloride salt, [82] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*,6*]dec-8-en-4-yl)-3-[4-(2-isopropoxy phenyl)-piperazin-l-yl]-propionamide hydrochloride salt, [83] N-( 1 ,3-Dioxo- 1 ,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-2-[4-(2-methoxyphenyl)-pipe razin-l-yl]-acetamide hydrochloride salt, [84] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-8-en-4-yl)-2-[4-(2-methoxyp henyl)-piperazin-l-yl]-acetamide hydrochloride salt, [85] N-( 1 ,3-Dioxo-2,3,3a,4,7,7a-hexahydro- 1 H-inden-2-yl)-2-[4-(2-isopropoxyphenyl)- piperazin-l-yl]-acetamide hydrochloride salt, [86] N-(3,5-Dioxo-4-aza-tricyclo[5.2.2.0*2,6*]undec-8-en-4-yl)-3-[4-(2-ethoxyphenyl)- piperazin-l-yl]-propionamide hydrochloride salt, [87] 3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-N-(3,5-dioxo-4-aza-tricyclo

[5.2.1.0*2,6*]dec-8-en-4-yl)-propionamide hydrochloride salt,

[88] N-(3-Benzyl-2,5-dioxo-2,5-dihydro-pyrrol- 1 -yl)-3-(4-phenyl-piperazin- 1 -yl)-propio namide hydrochloride salt,

[89] N-(3,5-Dioxo-4-aza-tricyclo[5.2.2.0*2,6*]undec-8-en-4-yl)-3-{4-[2-(3,3,3-trifluoro

-propoxy)-phenyl]-piperazin- 1 -yl } -propionamide hydrochloride salt,

[90] N-(3,3-Dimethyl-2,6-dioxo-piperidin-l-yl)-3-[4-(2-methoxyphenyl)-3-oxo-piperazi n-l-yl]-propionamide hydrochloride salt,

[91 ] 3-(2,3-Dioxo-4-phenyl-piperazin- 1 -yl)-N-(2,6-dioxo-4-phenyl-piperidin- 1 -yl)-propi onamide hydrochloride salt, or

[92] 2-[4-(2-Isopropoxyphenyl)-2,3-dimethyl-piperazin-l-yl]-N-(3-methyl-2,6-dioxo-pip eradin-l-yl)-acetamide hydrochloride salt.

[93] In yet another aspect, provided herein are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds described herein optionally together with one or more pharmaceutically acceptable carriers, excipients or diluents. Such pharmaceutical compositions can further comprise one or more therapeutic agents selected from one or more muscarinic receptor antagonists, one or more testosterone 5 alpha-reductase inhibitors, one or more endothelin antagonists, one or more melanocortin receptor agonists, one or more cGMP elevators, one or more HMG-Co-A reductase inhibitors, 5-HT receptor antagonists or mixtures thereof.

[94] In yet another aspect, provided herein are methods for treating a patient suffering from diseases or disorders mediated through alpha Ia and/or alpha Id adrenergic receptor, comprising administering to a patient in need thereof therapeutically effective amounts of one or more compounds described herein. These methods can include one or more of the following embodiments. For example, the method can be for treating benign prostatic hyperplasia (BPH) or lower urinary tract symptoms (LUTS).

[95] In yet another aspect, provided herein are methods for treating a patient suffering from diseases or disorders mediated through alpha Ia and/or alpha Id adrenergic receptor, comprising administering to a patient in need thereof therapeutically effective amounts of one or more pharmaceutical compositions described herein. These methods can include one or more of the following embodiments. For example, the method can be for treating benign prostatic hyperplasia (BPH) or lower urinary tract symptoms (LUTS).

[96] In another aspect, provided herein are processes of preparing compounds of

Formula VIII,

[97]

(FORMULA I, wherein X=Y=C^ Rj=H )

[98] or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof, wherein:

[100] wherein: [101] R₅ and R can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocy ^Jcle or -NR 1 1 R 12 ,

[102] wherein R and R can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle,

[103] R 4 and R 5 can independently be hydrogen, alkyl or phenyl, [104] R 6 can be hydrogen, alkyl, phenyl, hydroxy or alkoxy, [105] R 7 and R 8 can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl, (heterocycle)alkyl or R 9 -Q-(CH 2 ) m -,

[106] wherein m can be an integer of from 0 to 3, R can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle, Q can be oxygen, sulfur, carbonyl, carboxyl or -N(R 10 )-W, or R 7 and R 8 together can be cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle,

[107] wherein W can be no atom, carbonyl, carboxylic or amide, R can be hydrogen, alkyl, aryl or heterocycle;

[108] can be optional double bond, Z can be CH , CH CH or O; [109] R can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or (heterocycle)alkyl; and

[HO] n can be an integer of from 1 to 3; [111] the methods comprising the steps of: [112] a) reacting compounds of Formula II [113] R-N N-H

Formula II

[I H] with compounds of Formula III

Formula III

[116] to form compounds of Formula IV,

Formula IV

[118] b) compounds of Formula IV can be hydrolyzed to form compounds of Formula V,

Formula V

[120] c) compounds of Formula V can be treated with tert-butylcarbazate to form compounds of Formula VI,

[122] d) compounds of Formula VI can be hydrolyzed to form compounds of Formula VII,

Formula VII

[124] e) compounds of Formula VII can be treated with compounds of Formula K to

V form compounds of Formula VIII.

[125] Detailed Description of the Invention [126] Provided are compounds having the structure of Formula I,

[128] pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof, wherein:

[130] wherein:

[131] R and R can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocy ^Jcle or -NR 1 1 R 12 ,

[132] wherein R and R can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle, [133] R 4 and R 5 can independently be hydrogen, alkyl or phenyl,

[134] R 6 can be hydrogen, alkyl, phenyl, hydroxy or alkoxy,

[135] R and R can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,

7 8 heterocycle, aralkyl, (heterocycle)alkyl or R 9 -Q-(CH 2 ) m -, or, R 7 and R 8 together can be cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle, [136] wherein m can be an integer of from 0 to 3; R can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle; Q can be oxygen, sulfur, carbonyl, carboxyl or -N(R )-W, [137] wherein W can be no atom, carbonyl, carboxylic or amide, R can be hydrogen, alkyl, aryl or heterocycle; and [138] ^^ can be optional double bond, Z can be CH , CH CH or O;

[139] X and Y can independently be methylene or carbonyl;

[140] R can be hydrogen or methyl;

[141] R can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or

(heterocycle)alkyl; and

[142] n can be an integer of from 1 to 3.

[143] Also provided are compounds having the structure of Formula I, wherein:

[144] R can be aryl;

[145] n can be an integer of from 1 to 3; [146] X and Y can be methylene;

[147] R can be hydrogen; and

[149] Also provided are methods for treating a patient suffering from diseases or disorders mediated through alpha Ia and/or alpha Id adrenergic receptor comprising administering to a patient in need thereof therapeutically effective amounts of one or more compounds described herein.

[150] Also provided are methods for treating a patient suffering from benign prostatic hy¬ perplasia (BPH) or related symptoms comprising administering to a patient in need thereof therapeutically effective amounts of one or more compounds described herein.

[151] Also provided herein are methods for treating a patient suffering from lower urinary tract symptoms (LUTS) with or without BPH comprising administering to a patient in need thereof therapeutically effective amounts of one or more compounds described herein. LUTS may include, for example, irritative symptoms (e.g., frequent urination, urgent urination, nocturia and unstable bladder contractions); obstructive symptoms ( e.g., hesitancy, poor stream, prolonged urination, and feelings of incomplete emptying).

[152] Also provided herein is a process for preparing compounds described herein.

[153] Also provided herein are methods for treating a patient suffering from BPH or

LUTS with or without BPH comprising administering to a patient in need thereof ther¬ apeutically effective amounts one or more compounds (or compositions) described herein in combination with one or more therapeutic agents, for example, muscarinic receptor antagonists^. g., bladder selective muscarinic receptor antagonists), testosterone 5 alpha-reductase inhibitors, endothelin antagonists, melanocortin receptor agonists, cGMP elevators, HMG-CoA reductase inhibitors (e.g. statin), 5-HT antag onists or combinations thereof.

[154] Receptor binding studies described below indicated that the compounds described herein possess selective alpha Ia adrenoceptor antagonistic activity over the alpha Ib adrenoceptors. The examples presented below describe a method to treat BPH in a patient wherein the test compounds alleviated pressure at dosages, which did not result, in significant change in blood pressure. Additionally, compounds described herein can be used for relaxing lower urinary tract tissues and thus alleviating irritative symptoms in-patient. Therefore, the present invention provides pharmaceutical compositions for treating a disease or disorder mediated through alpha Ia adrenoceptor. In particular, compounds described herein can also be used for treating lower urinary tract symptoms. Compounds and compositions described herein can be administered orally, parenterally, subcutaneously, transdermally, topically or other routes. [155] The term 'alkyl,¹ unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. Alkyl groups can be optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, a phenylene, sulfinyl, sulfonyl group or -NR a -, wherein R a can be hydrogen, alkyl, alkenyl, alkynyl cycloalkyl or aryl. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may be substituted further (referred herein as substituted alkyl') with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, -NHC(=O)R , -NR R , - C(=O)NR R , -NHC(=O)NR R , -C(=O)heteroaryl, C(=O)heterocyclyl, -O-C(=O)NR p q P q. p

R {wherein R and R are independently selected fromalkyl, alkenyl, cycloalkyl, cy- q p q cloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, hydroxyamino, alkoxyamino or S(O) m R 13 (wherein m is an integer from 0-2 and

R is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, het¬ eroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, -NR p Rq , -C(=0)NR p Rq , -OC(=O) NR p Rq . -NHQ=O)NR fp Rq

(wherein R p and R q are the same as defined earlier), hydroxy, alkoxy, halogen, CF 3 , cyano, and S(O) R (wherein m is an integer from 0-2 and R are the same as defined earlier); or an alkyl group also may be interrupted by 1-5 atoms of groups inde¬ pendently selected from oxygen, sulfur or -NR a - { wherein R a is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl, - C(=O)OR p (wherein Rp is the same as defined earlier), S(O) m R 13 (wherein m is an integer from 0-2 and R is as defined earlier), or -C(=O)NR R (wherein R and R are

13 p q p q as defined earlier)}. Unless otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, carboxy, car¬ boxyalkyl, -NR R , -C (=0)NR R , -O-C(=O)NR R (wherein R and R are the same p q p q p q p q as defined earlier) hydroxy, alkoxy, halogen, CF 3 , cyano, and S(O) m R 13 (wherein m is an integer from 0-2 and R 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.

[156] 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. It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulfinyl, sulfonyl and -NR a -, wherein R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. 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 (referred to herein as 'substituted alkenyl') with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, -NHC(=O)R , - NR p Rq , -C(=O)NR p Rq , -NHC(=O)NR p Rq , -O-C(=O)NR p Rq (wherein R p and Rq are' the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, keto, carboxyalkyl, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino, alkoxyamino, hydroxyamino, alkoxyamino, nitro, or SO R (wherein R are is same as defined earlier). Unless otherwise constrained by the definition, alkenyl substituents optionally may be substituted further by 1-3 sub¬ stituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, -CF , cyano, -NR R , -Q=O)NR p R q , -O-C(=O)NR p R q (wherein R p and R q are the same as defined earlier) and -SO R (where R is same as defined earlier). Groups such as ethenyl or vinyl (CH=CH ), 1 -propylene or allyl (-CH₂CH=CH₂), iso-propylene (-C(CH )=CH ), bicyclo[2.2.1]heptene, and the like, exemplify this term. The term 'alkynyl,' unless otherwise specified, refers to a monoradical of an un¬ saturated hydrocarbon, having from 2 to 20 carbon atoms. It can be optionally in¬ terrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulfinyl, sulfonyl and -NR a -, where R a can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. 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 (referred to herein as 'substituted alkynyl') with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxy¬ carbonylamino, azido, cyano, halogen, hydroxy, keto, oxo, thiocarbonyl, carboxy, car¬ boxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocar¬ bonylamino, hydroxyamino, alkoxyamino, nitro, heterocyclyl, heteroaryl, heterocy- clylalkyl, heteroarylalkyl, -NHC(=O)R -NR R , -NHC(=O)NR R , -Q=O)NR R , - p. p q p q p q

0-Q=O)NR p R q (wherein R p and R q are the same as defined earlier), S(O) 111 R 13 (wherein m is an integer from 0-2 and R is as defined earlier). Unless otherwise constrained by the definition, alkynyl substituents optionally may be substituted further by 1-3 sub¬ stituents selected from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF , - NR p Rq , -Q=O)NR p Rq , -NHQ=O)NR p Rq , -Q=O)NR p Rq (wherein R p and Rq are the same as defined earlier), cyano, or S(O) m R 13 (wherein m is an integer from 0-2 and R 13 is same as defined earlier). Groups such as ethynyl, (-C ^s CH), propargyl (or propynyl, -CH C ^≡ CH), and the like exemplify this term.

[158] 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 R , - NHC(=O) NR p Rq , -NHC(=O) R p , -C(=O) NR p Rq , -O-C (=O)NR p Rq (wherein R p and Rq are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, het- eroarylalkyl, or S(O) m R 13 (wherein m is an integer from 0-2 and R 13 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, CF 3 , -NR p R q , -C(=O)NR p R q , -NHC(=O)NR p R q , -

O-C(=O)NR R (wherein R and R are the same as defined earlier), cyano or S(O) R p q p q m 13

(wherein m is an integer from 0-2 and R is same as defined earlier). [159] As used herein, the term 'cycloalkenyl,¹ unless otherwise specified, refers to un¬ saturated 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 -NR R , wherein R and R are selected from hydrogen and alkyl. Examples of cycloalkenyl include, but are not limited to, cyclopropenyl or cyclobutenyl, and the like. Multiple cyclic structures are also included. Unless otherwise constrained by the definition, cy¬ cloalkenyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, CF 3 , -NR p R q , -C(=O)NR p R q , -

NHC(=O)NR p R q , -O-C(=O)NR p R q (wherein R p and R q are the same as defined earlier), cyano or S(O) R (wherein m is an integer from 0-2 and R is same as defined earlier). The term 'halogen,' unless otherwise specified,' refers to fluorine, chlorine, bromine or iodine.

[160] The term 'hydroxy,' unless otherwise specified, refers to -OH.

[161] The term 'alkoxy,' unless otherwise specified, refers to the group O-alkyl, wherein alkyl is the same as defined above. [162] The term 'cycloalkoxy,' unless otherwise specified, refers to -O-cycloalkyl, wherein cycloalkyl is the same as defined above.

[163] The term 'haloalkoxy,' unless otherwise specified, refers to alkoxy wherein one or more hydrogen atom(s) of alkyl group are replaced by halogen atom(s).

[164] The term 'aryl,' unless otherwise specified, herein refers to aromatic system having

6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups. For example, aryl groups include, but are not limited to, phenyl, biphenyl, anthryl or naphthyl ring and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF , cyano, nitro, COOR (wherein R is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=0)R p , -NRp Rq , -C(=O)NR p Rq , -NHC(=0)NR p Rq , -O-C(=O)NR p Rq (wherein R p and R q are the same as defined earlier), S(O) m R 13 (wherein m is an integer from 0-2 and

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. Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.

[165] 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.

[166] The terms 'heterocycle' or '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, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -O-C(=O)R , -O-C(=O)OR - C(=0)NR R , S(O) R , -0-C(=0)NR R , -NHC(=O)NR R , -NR R (wherein m, R R p q m 13 P q P 9 P 9 '3, and R are as defined earlier) or guanidine. Carbonyl or sulfonyl group can replace p q carbon atom(s) of heterocyclyl. 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 azabi- cyclohexyl, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, ben- zoxazolyl, benzoxazinyl, benzthiazinyl, benzothiazolyl, benzothienyl, carbaxolyl, dihy- drobenzofuryl, dihydroimidazolyl, dihydroindolyl, dihydropyranyl, dihydrofuranyl, di- hydroisoxazolyl, dihydropyridinyl, dioxanyl, dioxolanyl, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoindole 1,3-dione, iso- quinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, moφholinyl, napthyridinyl, oxazolidinyl, oxazolyl, phenoxazinyl, phenothiazinyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyridinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thia- zolidinyl, thiazolyl, or thienyl, and the like.

[167] The term '(heterocycle)alkyl' or '(heterocyclyl)alkyl,¹ unless otherwise specified,¹ refers to heterocycle which is bonded to an alkylene chain. Examples of (heterocycle)alkyl include, but are not limited to, isothiazolidinyl ethyl, isothiazolyl propyl, pyrazinyl methyl, pyrazolinyl propyl or pyridyl butyl, and the like.

[168] Aryl or heterocycle may optionally be substituted with one or more substituent(s) independently selected from halogen, hydroxy, nitro, mercapto, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, thioalkyl, cycloalkoxy, -NR R , -CONR R , -COOR

15 , -CONHR 15 , -OCOR 15 , -COR 15 , -NHSO 2 R 15 and -SO 2 NHR 15, wherein R 14 and R 15 are independently selected from hydrogen or alkyl.

[169] The term 'pharmaceutically acceptable salts' refers to derivatives of compounds that can be modified by forming their corresponding non-toxic inorganic or organic acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts of basic residues (such as amines), or alkali or organic salts of acidic residues (such as carboxylic acids), and the like. Examples of inorganic acids used to prepare inorganic acid salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous, nitric, carbonic, sulfuric, phosphoric acid, and the like. Examples of organic acids used to prepare organic acid salts include, but are not limited to aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methansulfonic, ethanesulfonic, benzenesulfonic, panthenic, toluenesulfonic or 2-hydroxyethanesulfonic acid, and the like.

[170] The term 'pharmaceutically acceptable solvates' refers to solvates with waters (i.e., hydrates, hemihydrates or sesquihydrates) or pharmaceutically acceptable organic solvents. Such solvates are also encompassed within the scope of the present invention. Further, some crystalline forms of the compounds described herein may exist as polymorphs and as such are encompassed by the present invention.

[171] The present invention also encompasses prodrugs of compounds described herein.

In general, such 'prodrugs' are functional derivatives, which can be readily converted in vivo into the required compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in 'design of prodrugs', ed. H Bundgaard and, Elsevier, 1985.

[172] The present invention also encompasses metabolites, which become active upon in¬ troduction into the biological system. Crystalline or amorphous forms of compounds described herein may exist as polymorphs and as such are intended to be included in the present invention.

[173] The compounds of present invention include stereoisomers. The term 'stereoisomer' refers to compounds having identical chemical composition or molecular formula (i.e., having the same atoms bonded to each other), but differing in the spatial arrangement of the atoms or functional groups of the chemical structure. Stereoisomers include enantiomers, diastereomers, geometrical isomers, atropisomer or comformational isomers. Geometric isomers are chemical compounds having the same molecular formula as another, but a different configuration, as when atoms or groups of atoms are attached in different spatial arrangements on either side of a double bond or other rigid bond. An enantiomer is a stereoisomer of a reference molecule that is a nonsuper- imposable mirror image of the reference molecule. Diastereomers are stereoisomers that are not the mirror images of each other. An atropisomer is a conformational isomer of a reference compound that converts to the reference compound only slowly on the NMR or laboratory time scale. Conformational isomers (or conformers or rotational isomers or rotamers) are stereoisomers produced by rotation about sigma bonds, and are often rapidly interconverting at room temperature. Racemic mixtures are also encompassed within the scope of this invention.

[174] The compounds described herein may be prepared by techniques well known in the art and familiar to one of ordinary skill in the art. In addition, the compounds described herein may be prepared by the following reaction sequence as depicted in Scheme I

[175]

SCHEME I

[176] Thus, compounds of Formula II can be reacted with compounds of Formula III to form compounds of Formula IV (wherein R and n are the same as defined earlier). Compounds of Formula IV can be hydrolyzed to form compounds of Formula V. Compounds of Formula V can be treated with terr-butylcarbazate to form compounds of Formula VI. Compounds of Formula VI can be hydrolyzed to form compounds of Formula VII. Finally, compounds of Formula VII can be treated with compounds of

Formula S to form compounds of Formula VIII.

V

[177] The reaction of compounds of Formula II with compounds Formula III can be carried out in one or more solvents, for example, acetonitrile, acetone, tetrahydrofuran, cyclohexane, hexamethyl phosphoramide, dimethylformamide, dimethylsulfoxide or mixtures thereof. This reaction can also be carried out in the presence of one or more inorganic bases, for example, potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.

[178] The hydrolysis of compounds of Formula IV can be carried out in one or more solvents, for example, methanol, isopropanol, ethanol, chloroform, acetone, dichloromethane, acetonitrile, tetrahydrofuran or mixtures thereof. The hydrolysis can also be carried out in the presence of one or more acids, for example, hydrochloric, acetic, benzoic, difluoroacetic, or trifluoroacetic acids or mixtures thereof. [179] The reaction of compounds of Formula V with tert-butylcarbazate can be carried out in one or more solvents, for example, dichloromethane, tetrahydrofuran, dimethyl- formamide or mixtures thereof. This reaction can also be carried out in the presence of one or more reagents, for example, dicyclohexylcarbodiimide, l-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride, hydroxybenzotrizole or mixtures thereof.

[180] The hydrolysis of compounds of Formula VI can be carried out in one or more solvents, for example, ethanol, ethyl acetate, methanol, isopropanol, dichloromethane or mixtures thereof. The hydrolysis can also be carried out in the presence of one or more acids, for example, hydrochloric, acetic, benzoic, difluoroacetic, trifluoroacetic acid or mixtures thereof.

[181] The reaction of compounds of Formula VII with a compound of Formula £ can

be carried out in one or more solvents, for example, toluene, tetrahydrofuran, acetic anhydride, pyridine, acetonitrile, xylene or mixtures thereof. [182] In the above schemes, where specific reagents, for example, solvents, bases, acids, and other reagents, are described, it is to be understood that other reagents, e.g., solvents, bases, acids and other reagents known to one of ordinary skill in the art, may be used. Similarly, reaction temperatures and durations may be adjusted according to the desired needs without undue experimentation and well within the abilities of one of ordinary skill in the art.

[183] Specific compounds can include, for example:

[184] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-4-yl)-3-[4-(2-methoxyphenyl

)-piperazin-l-yl]-propionamide (Compound No. 1), [185] N-(l,3-Dioxo-l,3,3a,4,7,7 a- hexahydro-isoindol-2-yl)-3-[4-(2-methoxyphenyl)-piperazin-l-yl)-propionamide

(Compound No. 2), [186] 3-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

-l-yl)-propionamide (Compound No. 3), [ 187] N-(2,6-Dioxo-piperidin- 1 -yl)-3-[4-(2-methoxyphenyl)-piperazin- 1 -yl]-propionamid e (Compound No. 4), [188] N-(1 ,3-Dioxo- 1 ,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-3-[4-(2-isopropoxyphenyl)-pi perazin-l-yl]-propionamide (Compound No. 5), [189] N-(3,4-Dimethyl-2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-3-[4-(2-isopropoxyphenyl)-pip erazin-l-yl]-propionamide (Compound No. 6), [190] 4-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

-l-yl)-butyramide (Compound No. 7), [191] 2-[4-(2-Methoxyphenyl)-piperazin- 1 -yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

-l-yl)-acetamide (Compound No. 8), [192] N-(3,4-Dimethyl-2,5-dioxo-2,5-dihylro-pyrrol-l-yl)-2-[4-(2-methoxyphenyl)-pipera zin-l-yl]-acetamide (Compound No. 9), [193] N-(2,6-Dioxo-piperidin- 1 -yl)-2-[4-(2-methoxyphenyl)-piperazin- 1 -yl]-acetamide

(Compound No. 10), [194] 3-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrr ol-l-yl)-propionamide (Compound No. 11), [ 195] N-(2,6-Dioxo-piperidin- 1 -yl)-2-[4-(2-isopropoxyphenyl)-piperazin- 1 -yl]-acetamide

(Compound No. 12), [196] N-(3,5-Dioxo-10-oxa-tricyclo[5.2.1, 0*2,6*] dec-

8-en-4-yl)-2-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-acetamide (Compound No. 13), [197] N-(3,4-Dimethyl-2,5-dioxo-cyclopent-3-enyl)-2-[4-(2-isopropoxyphenyl)-piperazin

-l-yl]-acetamide (Compound No. 14), [198] 2-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-cyclopent-3-enyl

)-acetamide (Compound No. 15), [199] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*,6*]dec-8-en-4-yl)-3-[4-(2-isopropoxy phenyl)-piperazin-l-yl]-propionamide (Compound No. 16), [200] N-( 1 ,3-Dioxo- 1 ,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-2-[4-(2-methoxyphenyl)-pipe razin-l-yl]-acetamide (Compound No. 17), [201] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-8-en-4-yl)-2-[4-(2-methoxyp henyl)-piperazin-l-yl]-acetamide (Compound No. 18), [202] N-(l,3-Dioxo-2,3,3a,4,7,7a-hexahydro-lH-inden-2-yl)-2-[4-(2-isopropoxyphenyl)- piperazin-l-yl]-acetamide (Compound No. 19), [203] N-(3,5-Dioxo-4-aza-tricyclo[5.2.2.0*2,6*]undec-8-en-4-yl)-3-[4-(2-ethoxyphenyl)- piperazin-l-yl]-propionamide (Compound No. 20), [204] 3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-N-(3,5-dioxo-4-aza-tricyclo

[5.2.1.0*2,6*]dec-8-en-4-yl)-propionamide (Compound No. 21), [205] N-(3-Benzyl-2,5-dioxo-2,5-dihydro-pyrrol- 1 -yl)-3-(4-phenyl-piperazin- 1 -yl)-propio namide (Compound No. 22), [206] N-(3,5-Dioxo-4-aza-tricyclo[5.2.2.0*2,6*]undec-8-en-4-yl)-3-{4-[2-(3,3,3-trifluoro

-propoxy)-phenyl]-piperazin-l-yl}-propionamide (Compound No. 23), [207] N-(3,3-Dimethyl-2,6-dioxo-piperidin-l-yl)-3-[4-(2-methoxyphenyl)-3-oxo-piperazi n-l-yl]-propionamide (Compound No. 24), [208] 3-(2,3-Dioxo-4-pheny 1-piperazin- 1 -yl)-N-(2,6-dioxo-4-phenyl-piperidin- 1 -yl)-propi onamide (Compound No. 25), [209] 2-[4-(2-Isopropoxyphenyl)-2,3-dimethyl-piperazin-l-yl]-N-(3-methyl-2,6-dioxo-pip eradin-l-yl)-acetamide (Compound No. 26) or [210] pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof. [211] Specific compounds can also be, for example:

[212] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-4-yl)-3-[4-(2-methoxyphenyl

)-piperazin-l-yl]-propionamide hydrochloride salt (Compound No. 27), [213] N-(l,3-Dioxo-l,3,3a,4,7,7 a- hexahydro-isoindol-2-yl)-3-[4-(2-methoxyphenyl)-piperazin-l-yl)-propionamide hy¬ drochloride salt (Compound No. 28), [214] 3-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

-l-yl)-propionamide hydrochloride salt (Compound No. 29), [215] N-(2,6-Dioxo-piperidin- 1 -yl)-3-[4-(2-methoxyphenyl)-piperazin- 1 -yl]-propionamid e hydrochloride salt (Compound No. 30), [216] N-( 1 ,3-Dioxo- 1 ,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-3-[4-(2-isopropoxyphenyl)-pi perazin-l-yl]-propionamide hydrochloride salt (Compound No. 31), [217] N-(3,4-Dimethyl-2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-3-[4-(2-isopropoxyphenyl)-pip erazin-l-yi]-propionamide hydrochloride salt (Compound No. 32), [218] 4-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

-l-yl)-butyramide hydrochloride salt (Compound No. 33), [219] 2-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

-l-yl)-acetamide hydrochloride salt (Compound No. 34), [220] N-(3,4-Dimethyl-2,5-dioxo-2,5-dihylro-pyrrol-l-yl)-2-[4-(2-methoxyphenyl)-pipera zin-l-yl]-acetamide hydrochloride salt (Compound No. 35), [221 ] N-(2,6-Dioxo-piperidin- 1 -yl)-2- [4-(2-methoxyphenyl)-piperazin- 1 -yl]-acetamide hydrochloride salt (Compound No. 36), [222] 3-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrr ol-l-yl)-propionamide hydrochloride salt (Compound No. 37), [223] N-(2,6-Dioxo-piperidin-l-yl)-2-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-acetamide hydrochloride salt (Compound No. 38), [224] N-(3,5-Dioxo-10-oxa-tricyclo[5.2.1, 0*2,6*] dec-

8-en-4-yl)-2-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-acetamide hydrochloride salt

(Compound No. 39), [225] N-(3,4-Dimethyl-2,5-dioxo-cyclopent-3-enyl)-2-[4-(2-isopropoxyphenyl)-piperazin

-l-yl]-acetamide hydrochloride salt (Compound No. 40), [226] 2-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-cyclopent-3-enyl

)-acetamide hydrochloride salt (Compound No. 41), [^•227] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*,6*]dec-8-en-4-yl)-3-[4-(2-isopropoxy phenyl)-piperazin-l-yl]-propionamide hydrochloride salt (Compound No. 42), [228] N-( 1 ,3-Dioxo- 1 ,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-2-[4-(2-methoxyphenyl)-pipe razin-l-yl]-acetamide hydrochloride salt (Compound No. 43),

[229] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6^:f!]dec-8-en-4-yl)-2-[4-(2-methoxyp henyl)-piperazin-l-yl]-acetamide hydrochloride salt (Compound No. 44),

[230] N-(l,3-Dioxo-2,3,3a,4,7,7a-hexahydro-lH-inden-2-yl)-2-[4-(2-isopropoxyphenyl)- piperazin-l-yl]-acetamide hydrochloride salt (Compound No. 45),

[231] N-(3,5-Dioxo-4-aza-tricyclo[5.2.2.0*2,6*]undec-8-en-4-yl)-3-[4-(2-ethoxyphenyl)- piperazin-l-yl]-propionamide hydrochloride salt (Compound No. 46),

[232] 3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-N-(3,5-dioxo-4-aza-tricyclo

[5.2.1.0*2,6*]dec-8-en-4-yl)-propionamide hydrochloride salt (Compound No. 47),

[233] N-(3-Benzyl-2,5-dioxo-2,5-dihydro-pyrrol- 1 -yl)-3-(4-phenyl-piperazin- 1 -yl)-propio namide hydrochloride salt (Compound No. 48),

[234] N-(3,5-Dioxo-4-aza-tricyclo[5.2.2.0*2,6*]undec-8-en-4-yl)-3-{4-[2-(3,3,3-trifluoro

-propoxy)-phenyl]-piperazin-l-yl}-propionamide hydrochloride salt (Compound No. 49),

[235] N-(3,3-Dimethyl-2,6-dioxo-piperidin-l-yl)-3-[4-(2-methoxyphenyl)-3-oxo-piperazi n-l-yl]-propionamide hydrochloride salt (Compound No. 50),

[236] 3-(2,3-Dioxo-4-phenyl-piperazin- 1 -yl)-N-(2,6-dioxo-4-phenyl-piperidin- 1 -yl)-propi onamide hydrochloride salt (Compound No. 51),

[237] 2-[4-(2-Isopropoxyphenyl)-2,3-dimethyl-piperazin-l-yl]-N-(3-methyl-2,6-dioxo-pip eradin-l-yl)-acetamide hydrochloride salt (Compound No. 52).

[238] Compounds described herein are pharmacologically active and thus may be ad¬ ministered to an animal for treatment orally, parenterally, topically, rectally, in- ternasally, subcutaneously or transdermally. Pharmaceutical compositions described herein comprise therapeutically effective amounts of one or more compounds described herein formulated together with one or more pharmaceutically acceptable carriers.

[239] The term 'pharmaceutically acceptable carriers,' as used herein, refers to non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Solid form preparations for oral administration include capsules, tablets, pills, powder, granules, cachets and suppository. For solid form preparations, active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carriers (for example, sodium citrate, dicalcium phosphate or mixtures thereof) and/or one or more fillers or extenders (for example, starch, lactose, sucrose, glucose, mannitol, silicic acid or mixtures thereof); binders (for example, car- boxymethylcellulose, alginates, gelatins, poly vinylpyrolidinone, sucrose, acacia or mixtures thereof); disintegrating agents (for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates, sodium carbonate or mixtures thereof); absorption accelerators (for example, quaternary ammonium compounds); wetting agents (for example, cetyl alcohol, glycerol, monostearate or mixtures thereof); adsorbents (for example, kaolin); lubricants (for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulfate or mixtures thereof) or mixtures thereof.

[240] Capsules, tablets, or pills may also comprise buffering agents.

[241] Tablets, capsules, pills, or granules can be prepared with one or more coatings or shells, for example, enteric coatings or other coatings known to one of ordinary skill in the art.

[242] Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In such liquid form preparations, active compounds can be mixed with water or one or more other solvents, solubilizing agents or emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils {e.g., cottonseed, groundnut, corn, germ, olive, castor, sesame oil or mixtures thereof), glycerol, fatty acid esters of sorbitan or mixtures thereof. Oral liquid form preparations can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or mixtures thereof.

[243] Injectable preparations (for example, sterile injections, aqueous or oleaginous suspensions) may be formulated according to methods known to one of ordinary skill in the art, and in particular, using one or more suitable dispersing or wetting and suspending agents. Acceptable vehicles and solvents that may be employed include one or more of water, Ringer's solution, isotonic sodium chloride or mixtures thereof.

[244] Dosage forms for topical or transdermal administration include ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhalants or patches. Active compounds can be admixed under sterile conditions with one or more pharmaceutically acceptable carriers, and optionally any preservative or buffer as may be required. Ophthalmic for¬ mulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.

[245] Pharmaceutical preparations may be in unit dosage form. In unit dosage form, phar¬ maceutical preparations may be subdivided into unit doses containing appropriate quantities of active ingredients. Unit dosage forms can be packaged preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, cachets, tablets, gel creams or any combination and number of such packaged forms.

[246] Formulations described herein may be formulated to provide immediate, sustained, or delayed release of active ingredients after administration to patients by employing procedures well known to one of ordinary skill in the art.

[247] Dosages of compounds described herein, bladder selective muscarinic receptor an- tagonists or 5 alpha-reductase inhibitors can be adjusted accordingly when formulated in any combination to achieve desired effects. As one of ordinary skill in the art will appreciate, dosages of compounds described herein, bladder selective muscarinic receptor antagonists or 5 alpha-reductase inhibitors may be independently optimized and combined to achieve synergistic results, such that the pathology is reduced more than it would be if each agent are used alone, i.e., the cumulative effect are greater than when each agent are used alone. In accordance with the formulations and methods described herein, individual components in any combination can be administered con¬ currently in divided or single combination forms or sequentially in any order and at different times during the course of therapy.

[248] While the present invention has been described in terms of its specific em¬ bodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

[249] Examples

[250] Example 1: Preparation of 2-[4-(2-Methoxyphenyl)-piperazin-l-yl1 -

N-(3-methyl-2.5-dioxo-2.5-dihydro-pyrrol-l-yl)-acetamide hydrochloride salt (Compound No. 34)

[251] Step 1: Preparation of [4-(2-Methoxyphenyl)-piperazin-l-yl] -acetic acid tert-butyl ester

[252] A mixture of 2-methoxy phenyl piperazine monohydrochloride (5.0 g, 21.88 mmol, commercially available, Lancaster), ter/-butylbromoacetate (5.12 g, 26.25 mmol), and anhydrous potassium carbonate (6.0 g, 43.47 mmol) in acetone (30 mL) was stirred at ambient temperature for 12 to 18 hours. The reaction mixture was filtered through a celite pad, washed with acetone and the filtrate was concentrated to yield a viscous residue. The residue was suspended in water and extracted with ethyl acetate. The resulting organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to yield [4-(2-Methoxyphenyl)-piperazin-l-yl]-acetic acid tert-butyl ester.

[253] Yield: 5.10 g (77 %)

[254] Step 2: Preparation of [4-(2-methoxyphenyl)-piperazin-l-yl]-acetic acid

[255] Trifluoroacetic acid was added to a solution of

[4-(2-methoxyphenyl)-piperazin-l-yl]-acetic acid te>t-butyl ester (5.0 g, 16 mmol, from Step 1) in dichloromethane and the reaction mixture was stirred for 5 to 10 hours. After completion of the reaction, the reaction mixture was concentrated by evaporating the solvent to form a residue. Toluene was added to the residue and rotary evaporated to yield [4-(2-methoxyphenyl)-piperazin-l-yl]-acetic acid. [256] Yield: 4.0 g (98 %)

[257] Step 3: Preparation of l-(2-methoxyphenyl)-piperazine-N'-Propionyl-hydrazine carboxylic acid tert-butyl ester

[258] 7eλt-butylcarbazate (1.056 g, 8 mmol) was added to a solution of

[4-(2-methoxyphenyl)-piperazin-l-yl]-acetic acid (2.0 g, 8 mmol, from Step 2), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.5 g, 7.85 mmol), hydroxybenztriazole (0.936 g, 8 mmol) and N-methyl morpholine (0.80 g, 8 mmol) in dimethylformamide at 0 ⁰C to 10 ⁰C and the reaction mixture was stirred for 12 to 18 hours. The reaction mixture was quenched by adding water and extracted with ethyl acetate. The resulting organic layer washed with water, dried over anhydrous sodium sulfate and concentrated to yield l-(2-methoxyphenyl)-piperazine-N'-Propionyl-hydrazine carboxylic acid tert-butyl ester.

[259] Yield: 2.25 g (77 %)

[260] Step 4: Preparation of [4-(2-Methoxyphenyl)-piperazin-l-yl] acetic acid hydrazide

[261] Ethanolic hydrochloric acid (1.5 N) was added to a solution of l-(2-Methoxyphenyl)-piperazine-N'-propionyl-hydrazine carboxylic acid tert-butyl ester (2.0 g, 5.40 mmol, from Step 3) in ethanol and the reaction mixture stirred for 8 to 10 hours. Solid sodium bicarbonate was added to reaction mixture until the pH was neutral. The reaction mixture was filtered though a celite pad and washed with ethanol. The filtrate was concentrated to yield a crude product, which was then purified on silica gel (60-120 mesh) column using dichloromethane-methanol (9.2:0.8) as eluent to yield the title compound.

[262] Yield: 1.0 g (69 %)

[263] Step 5: 2-[4-(2-Methoxyphenyl)-piperazin-l-yl] -

N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-acetamide (Compound No. 8)

[264] [4-(2-Methoxyphenyl)-piperazin-l-yl] acetic acid hydrazide (0.5 g, 1.89 mmol, from Step 4) and citraconic anhydride (0.212 g, 1.89 mmol) were dissolved in toluene and the reaction mixture refluxed for 1 to 5 hours. Solvent was removed by evaporation under vacuum to yield 2-[4-(2-Methoxyphenyl)-piperazin-l-yl] - N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol- 1 -yl)-acetamide.

[265] The following compounds were also prepared following the above procedures using the appropriate corresponding reagents:

[266] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-4-yl)-3-[4-(2-methoxypenyl)- piperazin-l-yl]-propionamide (Compound No. 1)

[267] N-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-3-[4-(2-methoxyphenyl)-pipe razin-l-yl)-propionamide(Compound No. 2)

[268] 3-[4-(2-Methoxyphenyl)-piperazin- 1 -yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol -l-yl)-propionamide(Compound No. 3) [269] N-(2,6-Dioxo-piperidin-l-yl)-3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propionamid e(Compound No. 4) [270] N-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-3-[4-(2-isopropoxyphenyl)-pi perazin-l-yl]-propionamide(Compound No. 5) [271] N-(3,4-Dimethyl-2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-3-[4-(2-isopropoxyphenyl)-pip erazin-l-yl]-propionamide(Compound No. 6) [272] 4-[4-(2-Methoxyphenyl)-piperazin- 1 -yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol

-l-yl)-butyramide(Compound No. 7) [273] N-(3,4-Dimethyl-2,5-dioxo-2,5-dihylro-pyrrol-l-yl)-2-[4-(2-methoxyphenyl)-pipera zin-l-yl]-acetamide(Compound No. 9) [274] N-(2,6-Dioxo-piperidin- 1 -yl)-2-[4-(2-methoxyphenyl)-piperazin- 1 -yl]-acetamide(C ompound No. 10) [275] 3-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrr ol-l-yl)-propionamide(Compound No. 11) [276] N-(2,6-Dioxo-piperidin- 1 -yl)-2-[4-(2-isopropoxyphenyl)-piperazin- 1 -yl]-acetamide

(Compound No. 12) [277] N-(3,5-Dioxo-10-oxa-tricyclo[5.2.1,0*2,6*]dec-8-en-4-yl)-2-[4-(2-isopropoxyphen yl)-piperazin-l-yl]-acetamide(Compound No. 13) [278] N-(3,4-Dimethyl-2,5-dioxo-cyclopent-2-enyl)-2-[4-(2-isopropoxyphenyl)-piperazin

-l-ylj-acetamideCCompound No. 14) [279] 2-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-cyclopent-3-enyl

)-acetamide(Compound No. 15) [280] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*,6*]dec-8-en-4-yl)-3-[4-(2-isopropoxy phenyl)-piperazin-l-yl]-propionamide(Compound No. 16) [281] N-(1 ,3-Dioxo- 1 ,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-2-[4-(2-methoxyphenyl)-pipe razin-l-yl]-acetamide(Compound No. 17) [282] N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6^!|:]dec-8-en-4-yl)-2-[4-(2-methoxyp henyl)-piperazin-l-yl]-acetamide(Compound No. 18) [283] N-( 1 ,3-Dioxo-2,3,3a,4,7,7a-hexahydro- 1 H-inden-2-yl)-2-[4-(2-isopropoxyphenyl)- piperazin-l-yl]-acetamide(Compound No. 19)

[284] The following compounds can also be prepared following the above procedures:

[285] N-(3,5-Dioxo-4-aza-tricyclo[5.2.2.0*2,6*]undec-8-en-4-yl)-3-[4-(2-ethoxyphenyl)- piperazin-l-yl]-propionamide (Compound No. 20) [286] 3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-N-(3,5-dioxo-4-aza-tricyclo

[5.2.1.0*2,6*]dec-8-en-4-yl)-propionamide (Compound No. 21) [287] N-(3-Benzyl-2,5-dioxo-2,5-dihydro-pyrrol- 1 -yl)-3-(4-phenyl-piperazin- 1 -yl)-propio namide (Compound No. 22) [288] N-(3,5-Dioxo-4-aza-tricyclo[5.2.2.0*2,6*]undec-8-en-4-yl)-3-{4-[2-(3,3,3-trifluoro

-propoxy)-phenyl]-piperazin-l-yl}-propionamide (Compound No. 23) [289] N-(3,3-Dimethyl-2,6-dioxo-piperidin-l-yl)-3-[4-(2-methoxyphenyl)-3-oxo-piperazi n-l-yl]-propionamide (Compound No. 24) [290] 3-(2,3-Dioxo-4-phenyl-piperazin- 1 -yl)-N-(2,6-dioxo-4-phenyl-piperidin- 1 -yl)-propi onamide (Compound No. 25) [291] 2-[4-(2-Isopropoxyphenyl)-2,3-dimethyl-piperazin-l-yl]-N-(3-methyl-2,6-dioxo-pip eradin-l-yl)-acetamide (Compound No. 26) [292] Step 6: Preparation of 2-[4-(2-Methoxyphenyl)-piperazin-l-yl] -

N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol- 1 -yl)-acetamide hydrochloride salt [293] An equimolar quantity of isopropyl alcohol and hydrochloric acid was added to

2-[4-(2-methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyrrol-l- yl)-acetamide. A solid precipitated and was filtered to yield the title compound. [294] Yield 0.570 g (85 %)

[295] IR (KBr): 1739.6 (CO), 1696.1 (co) cm^"1; ¹H NMR (300 MHz, DMSO-d₆):d2.07 (s,

3H), 3.06 (brs, 2H), 3.38 (brs, 6H), 3.79 (s, 3H), 4.35 (brs, 2H), 6.87 (s, IH), 6.90-7.05

(m, 4H), 10.70 (brs, IH), 11.47 (brs, IH); Mass (m/z): 359 (M⁺+l). [296] The following compounds were prepared following the above procedure of

Example 1, step 6: [297] N-(3.5-Dioxo-10-oxa-4-aza-tricvclor5.2.1.0*2.6*1 dec-

4-yl)-3-r4-(2-methoxypenyl)-piperazin-l-yl1-propionamide hydrochloride salt

(Compound No. 27) [298] IR (KBr): 1725 (CO) cm^"1; ¹H NMR (300 MHz, DMSO-d₆):d2.85-2.87 (m, 2H),

3.08 (m, 4H), 3.39-3.41 (m, 8H), 3.80 (s, 3H), 6.59 (brs, 2H), 6.94-7.05 (m, 4H), 11.20

(brs, IH); Mass (m/z): 427.1 (M⁺+l). [299] N-

(1.3-Dioxo-1.3.3a.4.7.7a-hexahvdro-isoindol-2-yl)-3-r4-(2-methoxyphenylVpiperazin- l-yl)-propionamidehydrochloride salt (Compound No. 28) [300] IR (KBr): 3489.0, 1727.4 cm^"1; ¹H NMR (300 MHz, CDCy:d2.26-2.31 (d, 2H),

2.52-2.58 (d, 2H), 3.15-3.29 (m, 6H), 3.47-3.60 (m, 8H), 3.86 (s, 3H), 5.93 (d, 2H),

6.86-7.08 (m, 4H), 10.52 (brs, IH); Mass (m/z): 412.8 (M⁺+l). [301] 3- r4-(2-Methoxyphenyl)-piperazin- 1 -y 1] -

N-(3-methyl-2.5-dioxo-2.5-dihydro-pyrrol- 1 -yP-propionamidehydrochloride salt

(Compound No. 29) [302] IR (KBr): 1734.3 cm^"1; ¹H NMR (300 MHz, DMSO-d ):d2.04 (s, 3H), 2.94-3.59 (m,

12H), 3.78 (s, 3H), 6.80 (s, IH), 6.89-7.01 (m, 4H), 10.85 (s, IH), 11.32 (brs, IH);

Mass (m/z): 373.0 (M⁺+ 1). [303] N-(2.6-Dioxo-piperidin- 1 -yl)-3-r4-(2-methoxyphenyD-piperazin- 1 -yll - propionamidehydrochloride salt (Compound No. 30^*) [304] IR (KBr): 1734.3 cm ¹; ¹H NMR (300 MHz, DMSO-d₆):dl .86-1.90 (m, 2H),

2.73-2.75 (m, 4H), 2.87-2.90 (m, 2H), 2.92-3.49 (m, 10H), 3.79 (s, 3H), 6.91-7.03 (m,

4H), 10.53 (s, IH), 10.83 (brs, IH); Mass (m/z): 375 (M⁺+l). [305] N-

(l,3-Dioxo-1.3.3a.4.7.7a-hexahydro-isoindol-2-yl)-3-f4-(2-isopropoxyphenyl^')-piperazi n-l-yll -propionamidehydrochloride salt (^"Compound No. 31^*) [306] IR (KBr): 1727.8, 1700.6 cm^"1; ¹H NMR (300 MHz, DMSO-d₆):dl.27-1.29 (d, 6H),

2.23-2.50 (m, 4H), 2.87-3.23 (m, 10H), 3.52-3.56 (m, 4H), 4.60-4.64 (m, IH), 5.88

(brs, 2H), 6.89-6.96 (m, 4H), 11.21 (m, 2H); Mass (m/z): 441.2 (M⁺+l). [307] N-

(3.4-Dimethyl-2.5-dioxo-2.5-dihydro-pyrrol-l-yI^*)-3-r4-(2-isopropoxyphenyl)-piperazi n-l-yli-propionamidehydrochloride salt (Compound No. 32^*) [308] IR (KBr): 1723.5, 1702.2 cm^'1; ¹H NMR (300 MHz, DMSO-d₆):dl.27-1.29 (d, 6H),

1.96 (s, 6H), 2.95-3.16 (m, 8H), 3.52-3.56 (m, 4H), 4.62 (m, IH), 6.89-6.96 (m, 4H),

10.82-11.00 (m, 2H). [309] 4-r4-(2-Methoxyphenyl^*)-piperazin-l-vn -

N-(3-methyl-2.5-dioxo-2.5-dihydro-pyrrol-l-yl)-butyramidehydrochloride salt

(Compound No. 33) [310] IR (KBr): 1738.0 cm^'1; ¹H NMR (300 MHz, CDCl ):dl .68 (s, 3H), 2.39 (m, 2H),

3.14-3.51 (m, 8H), 3.67 (m, 2H), 3.87 (s, 3H), 4.32 (m, 2H), 6.43 (m, IH), 6.87-7.10

(m, 4H), 8.08 (brs, IH), 12.25 (brs, IH). [311] N-

(3.4-Dimethyl-2.5-dioxo-2.5-dihylro-pyrrol- 1 -ylV 2-r4-(2-methoxyphenyl^*)-piperazin- 1

-yli-acetamidehydrochloride salt (Compound No. 35^*) [312] IR (KBr): 1737.4, 1700.2 cm^"'; ¹H NMR (300 MHz, DMSO-d₆):dl.97 (s, 6H),

3.19-3.41 (m, 4H), 3.80 (s, H), 4.21 (brs, 2H), 6.93-7.07 (m, 4H), 10.50 (brs, IH),

11.29 (brs, IH); Mass (m/z): 373 (M⁺+l). [313] N-(2.6-Dioxo-piperidin-l-yl)-2-[4-(2-methoxyphenylVpiperazin-l-yll - acetamidehydrochloride salt (Compound No. 36) [314] IR (KBr): 3441.5, 1706.4 cm ¹; ¹H NMR (300 MHz, CDCl ):d2.00-2.05 (m, 2H),

2.79 (brs, 4H), 3.53-3.86 (m, HH), 4.01 (brs, 2H), 6.88-7.08 (m, 4H), 11.00 (brs, IH);

Mass (m/z): 361.0 (M⁺+l). [315] 3-r4-(2-IsopropoxyphenylVpiperazin-l-yll-N-(3-meth yl-

2.5-dioxo-2.5-dihydro-pyrrol-l-yl^*)-propionamidehydrochloride salt (Compound No. in

[316] IR (KBr): 1733.4, 1636.2 cm^"1; ¹H NMR (300 MHz, DMSO-d ):dl.27-1.29 (d, 6H),

2.95-3.05 (m, 4H), 3.17-3.20 (m, 2H), 3.53-3.57 (m, 6H), 4.60-4.64 (m, IH), 6.82 (s, IH), 6.89-6.96 (m, 4H), 10.83-11 (brs, 2H); Mass (m/z): 401.2 (M⁺+l). [317] N-(2.6-Dioxo-piperidin- 1 -yl)-2-r4-(2-isopropoxyphenyl)-piperazin- 1 -yl^"| - acetamidehydrochloride salt (Compound No. 38^") [318] IR (KBr): 1758.4, 1713.0 cm^"1; ¹H NMR (300 MHz, DMSO-d₆):dl.28-1.30 (d, 6H),

1.93 (m, 2H), 2.79 (m, 4H), 3.46 (m, 8H), 4.22 (s, 2H), 4.60-4.62 (m, IH), 6.95-7.03

(m, 4H); Mass (m/z): 389 (M⁺+l). [319] N-(3.5-Dioxo-10-oxa-tricvclor5.2.1.0*2.6*l dec-

8-en-4-yl)-2-r4-(2-isopropoxyphenyl)-piperazin-l-yl1-acetamidehydrochloride salt

(Compound No. 39) [320] IR (KBr): 1735.6, 1708 cm^"1; ¹H NMR (300 MHz, DMSO-d₆):d3.11-3.43 (m, 12H),

5.22 (brs, 2H), 6.60 (brs, 2H), 6.96 (m, 4H); Mass (m/z): 441.3 (M⁺+l). [321] N-

(3.4-Dimethyl-2.5-dioxo-cyclopent-2-enyl^*)-2-r4-(2-isopropoxyphenyD-piperazin-l-yll

-acetamidehydrochloride salt (Compound No. 40) [322] IR (KBr): 1738.9, 1709.2 cm^'1; ¹H NMR (300 MHz, DMSO-d₆):dl.28 (s, 6H), 1.97

(s, 6H), 3.28-3.42 (m, 8H), 4.62 (m, 2H), 6.96-7.01 (m, 4H); Mass (m/z): 400.9 (M⁺

+1). [323] 2-r4-(2-Isopropoxyphenyl^')-piperazin-l-yn -

N-(3-methyl-2.5-dioxo-cyclopent-3-enyO-acetarnidehydrochloride salt (Compound

No. 41) [324] IR (KBr): 1745.9, 1700.8 cm^"1; ¹H NMR (300 MHz, DMSO-d₆):dl.28-1.30 (d, 6H),

2.08 (s, 3H), 3.29-3.44 (m, 8H), 4.27 (m, 2H), 4.62 (m, IH), 6.81 (s, IH), 6.91-7.03

(m, 4H), 11.44 (brs, IH); Mass (m/z): 387 (M⁺+l). [325] N-(3.5-Dioxo- 10-oxa-4-aza-tricvclor5.2.1.0*.6*1 dec-

8-en-4-yl)-3-r4-(2-isopropoxyphenyl)-piperazin-l-yl]-propionamidehydrochloride salt

(Compound No. 42) [326] IR (KBr): 1730.5, 1719.4 cm^"1; ¹H NMR (300 MHz, DMSO-d ):dl.27-1.29 (d, 6H),

2.93-3.20 (m, 10H), 3.53-3.56 (m, 4H), 4.60-4.64 (m, IH), 5.20 (brs, 2H), 6.58 (s, 2H),

6.89-6.96 (m, 4H), 10.8-11.2 (m, 2H); Mass (m/z): 455.2 (M⁺+l). [327] N-

(1.3-Dioxo-1.3.3a.4.7.7a-hexahydro-isoindol-2-yl)-2-r4-(2-methoxyphenyl)-piperazin- l-yl^"|-acetamidehydrochloride salt (Compound No. 43) [328] IR (KBr): 1725.7 cm^"1; ¹H NMR (300 MHz, DMSO-d₆):d2.25-2.43 (m, 4H),

3.07-3.45 (m, 8H), 3.79 (brs, 5H), 4.31 (s, 2H), 5.90 (brs, 2H), 6.88-7.06 (m, 4H),

1 1.42 (brs, IH); Mass (m/z): 399 (M⁺+l). [329] N-(3.5-Dioxo- 10-oxa-4-aza-tricvclor5.2.1.0*2.6*1 dec-

8-en-4-yl)-2-[4-(2-methoxyphenyl)-piperazin- 1 -yll-acetamidehydrochloride salt

(Compound No. 44) [330] IR (KBr): 1729.4 cm^"1; ¹H NMR (300 MHz, DMSO-d ):d3.09-3.42 (m, 8H), 3.80

(brs, 5H), 4.32 (brs, 2H), 5.22 (brs, 2H), 6.59 (s, 2H), 6.88-7.23 (m, 4H), 11.55 (brs,

IH); Mass (m/z): 413.1 (M⁺+l). [331] N-

(1.3-Dioxo-2.3.3a.4.7.7a-hexahydro-lH-inden-2-yl)-2-r4-(2-isopropoxyphenyl)-pipera zin-1-yli-acetamidehydrochloride salt (Compound No. 45) [332] IR (KBr): 1734 cm^"1; ¹H NMR (300 MHz, DMSO-d₆):dl.28-1.30 (d, 6H), 2.26-2.44

(m, 4H), 3.33-3.44 (m, 10H), 4.21 (m, 2H), 4.62 (m, IH), 5.90 (brs, 2H), 6.96-7.02 (m,

4H), 10.75 (brs, IH), 11.60 (brs, IH); Mass (m/z): 427.1 (M⁺+l). [333] The following compounds can also be prepared following the above procedures using the appropriate corresponding reagents: [334] N-(3,5-Dioxo-4-aza-tricyclo[5.2.2.0*2,6*]undec-8-en-4-yl)-3-[4-(2-ethoxyphenyl)- piperazin-l-yl]-propionamide hydrochloride salt (Compound No. 46) [335] 3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-N-(3,5-dioxo-4-aza-tricyclo

[5.2.1.0*2,6*]dec-8-en-4-yl)-propionamide hydrochloride salt (Compound No. 47) [336] N-

(3-Benzyl-2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-3-(4-phenyl-piperazin-l-yl)-propionami de hydrochloride salt (Compound No. 48) [337] N-(3,5-Dioxo-4-aza-tricyclo[5.2.2.0*2,6*] undec-

8-en-4-yl)-3-{4-[2-(3,3,3-trifluoro-propoxy)-phenyl]-piperazin-l-yl}-propionamide hydrochloride salt (Compound No. 49) [338] N-

(3,3-Dimethyl-2,6-dioxo-piperidin-l-yl)-3-[4-(2-methoxyphenyl)-3-oxo-piperazin-l-yl

]-propionamide hydrochloride salt (Compound No. 50) [339]

3-(2,3-Dioxo-4-phenyl-piperazin- 1 -yl)-N-(2,6-dioxo-4-phenyl-piperidin- 1 -yl)-propion amide hydrochloride salt (Compound No. 51) [340] 2-[4-(2-Isopropoxyphenyl)-2,3-dimethyl-piperazin-l-yl] -

N-(3-methyl-2,6-dioxo-piperadin-l-yl)-acetamide hydrochloride salt (Compound No.

52)

[341] Example 2: Pharmacological testing

[342] Receptor binding assays were performed using native alpha- 1 adrenoceptors. The affinity of different compounds for alpha Ia and alpha Ia 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. [343] Submaxillary glands were isolated immediately after sacrifice. The liver was perfused with buffer (Tris HCl 50 mM, NaCl 100 niM, 10 mM EDTA pH 7.4). The tissues were homogenized in 10 volumes of buffer (Tris HCl 50 mM, NaCl 100 mM, EDTA 10 mM, pH 7.4). The homogenate was filtered through two layers of wet gauze and the filtrate was centrifuged at 500g for 10 minutes. The supernatant was sub¬ sequently centrifuged at 40,00Og for 45 minutes. The pellet thus obtained was re- suspended in an equivolume of assay buffer (Tris HCl 50 mM, EDTA 5 mM, pH 7.4) and were stored at -7O⁰C until the time of assay.

[344] The membrane homogenates (150-250 mg protein) were incubated in 250 mL 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 IC 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 the Cheng and Prusoff equation (Cheng and Prusoff, Biochem. Pharmacol, 22:3099-3108 (1973))

[345] Ki = IC₅₀ /(1+UKd)

[346] where L is the concentration of [ H] prazosin used in the particular experiment.

[347] The Ki values for compounds described herein range as follows:

[348] a) alpha Ia Ki (nM) for compounds described herein were between about 41 nM to greater than about 1000 nM, as well as between about 190 nM to about 363 nM.

[349] b) alpha Ia Ki (nM) for compounds described herein were between about 252 nM to greater than about 1000 nM, as well as between about 310 nM to greater than about 1000 nM.

Claims

[1] Compounds having the structure of Formula I,

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof, wherein: A is

wherein:

R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NR R

11 12 wherein R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle,

R and R are independently hydrogen, alkyl or phenyl,

4 5

R is hydrogen, alkyl, phenyl, hydroxy or alkoxy,

6

R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,

7 8 heterocycle, aralkyl, (heterocycle)alkyl or R -Q-(CH ) -, or R and R together

9 2 m 7 8 form cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle, wherein m is an integer of from 0 to 3, R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle, Q is oxygen, sulfur, carbonyl, carboxyl or - N(R )-W, wherein W is no atom, carbonyl, carboxylic or amide, R is hydrogen, alkyl, aryl or heterocycle, ϋ^ is optional double bond, Z is CH , CH CH or O;

X and Y are independently methylene or carbonyl;

R is hydrogen or methyl;

R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or (heterocycle)alkyl; and n is an integer of from 1 to 3.

[2] The compound of claim 1, wherein R is aryl; n is an integer of from 1 to 3; X and

Y are methylene; R is hydrogen; and A is

[3] A compound selected from:

N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-4-yl)-3-[4-(2-methoxyphe nyl)-piperazin- 1 -yl]-propionamide,

N-(l,3-Dioxo-l,3,3a,4,7,7 a- hexahydro-isoindol-2-yl)-3-[4-(2-methoxyphenyl)-piperazin-l-yl)-propionamide,

3-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyr rol- 1 -yl)-propionamide,

N-(2,6-Dioxo-piperidin-l-yl)-3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propiona mide,

N-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-3-[4-(2-isopropoxyphenyl)

-piperazin- 1 -yl]-propionamide,

N-(3,4-Dimethyl-2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-3-[4-(2-isopropoxyphenyl)- piperazin- 1 -yl] -propionamide,

4-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyr rol- 1 -yl)-butyramide,

2-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyr rol- 1 -yl)-acetamide,

N-(3,4-Dimethyl-2,5-dioxo-2,5-dihylro-pyrrol-l-yl)-2-[4-(2-methoxyphenyl)-pip erazin- 1 -yl]-acetamide,

N-(2,6-Dioxo-piperidin- 1 -yl)-2-[4-(2-methoxyphenyl)-piperazin- 1 -yl]-acetamide

>

3-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-p yrrol- 1 -yl)-propionamide,

N-(2,6-Dioxo-piperidin-l-yl)-2-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-acetami de,

N-(3,5-Dioxo-10-oxa-tricyclo[5.2.1, 0*2,6*] dec-

8-en-4-yl)-2-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-acetamide,

N-(3,4-Dimethyl-2,5-dioxo-cyclopent-3-enyl)-2-[4-(2-isopropoxyphenyl)-pipera zin- 1 -yl]-acetamide, 2-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-cyclopent-3-e nyl)-acetamide,

N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*,6*]dec-8-en-4-yl)-3-[4-(2-isopropo xyphenyl)-piperazin- 1 -yl] -propionamide,

N-( 1 ,3-Dioxo- 1 ,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-2-[4-(2-methoxyphenyl)-pi perazin- 1 -yl]-acetamide,

N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-8-en-4-yl)-2-[4-(2-methox yphenyl)-piperazin- 1 -yl]-acetamide,

N-(l,3-Dioxo-2,3,3a,4,7,7a-hexahydro-lH-inden-2-yl)-2-[4-(2-isopropoxyphenyl )-piperazin-l-yl]-acetamide, or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites. [4] A compound selected from:

N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-4-yl)-3-[4-(2-methoxyphe nyl)-piperazin-l-yl]-propionamide hydrochloride salt,

N-(l,3-Dioxo-l,3,3a,4,7,7 a- hexahydro-isoindol-2-yl)-3-[4-(2-methoxyphenyl)-piperazin-l-yl)-propionamide hydrochloride salt,

3-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyr rol-l-yl)-propionamide hydrochloride salt,

N-(2,6-Dioxo-piperidin- 1 -yl)-3-[4-(2-methoxyphenyl)-piperazin- 1 -yl]-propiona mide hydrochloride salt,

N-(l,3-Dioxo-l,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-3-[4-(2-isopropoxyphenyl)

-piperazin-l-yl]-propionamide hydrochloride salt,

N-(3,4-Dimethyl-2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-3-[4-(2-isopropoxyphenyl)- piperazin-l-yl]-propionamide hydrochloride salt,

4-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyr rol-l-yl)-butyramide hydrochloride salt,

2-[4-(2-Methoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-pyr rol-l-yl)-acetamide hydrochloride salt,

N-(3,4-Dimethyl-2,5-dioxo-2,5-dihylro-pyrrol-l-yl)-2-[4-(2-methoxyphenyl)-pip erazin-l-yl]-acetamide hydrochloride salt,

N-(2,6-Dioxo-piperidin- 1 -yl)-2-[4-(2-methoxyphenyl)-piperazin- 1 -yl]-acetamide hydrochloride salt,

3-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-2,5-dihydro-p yrrol-l-yl)-propionamide hydrochloride salt,

N-(2,6-Dioxo-piperidin- 1 -yl)-2-[4-(2-isopropoxyphenyl)-piperazin- 1 -yl]-acetami de hydrochloride salt, N-O.S-Dioxo-lO-oxa-tricyclotS^.l, 0*2,6*] dec-

8-en-4-yl)-2-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-acetamide hydrochloride salt,

N-(3,4-Dimethyl-2,5-dioxo-cyclopent-3-enyl)-2-[4-(2-isopropoxyphenyl)-pipera zin-l-yl]-acetamide hydrochloride salt,

2-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-N-(3-methyl-2,5-dioxo-cyclopent-3-e nyl)-acetamide hydrochloride salt,

N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*,6*]dec-8-en-4-yl)-3-[4-(2-isopropo xyphenyl)-piperazin-l-yl]-propionamide hydrochloride salt, N-( 1 ,3-Dioxo- 1 ,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-2-[4-(2-methoxyphenyl)-pi perazin-l-yl]-acetamide hydrochloride salt,

N-(3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.0*2,6^:|:]dec-8-en-4-yl)-2-[4-(2-methox yphenyl)-piperazin-l-yl]-acetamide hydrochloride salt, or N-(l,3-Dioxo-2,3,3a,4,7,7a-hexahydro-lH-inden-2-yl)-2-[4-(2-isopropoxyphenyl )-piperazin-l-yl]-acetamide hydrochloride salt.

[5] A pharmaceutical composition comprising therapeutically effective amounts of one or more compounds having the structure of Formula I,

wherein:

R R 2 a anndd R R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NR R

1 1 12 wherein R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle,

R 4 and R 5 are independently hydrogen, alkyl or phenyl, R 6 is hydrogen, alkyl, phenyl, hydroxy or alkoxy,

R 7 and R 8 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl, (heterocycle)alkyl or R 9 -Q-(CH 2 ) m -, or R 7 and R 8 together form cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle, wherein m is an integer of from 0 to 3, R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle, Q is oxygen, sulfur, carbonyl, carboxyl or - N(R )-W, wherein W is no atom, carbonyl, carboxylic or amide, R is hydrogen, alkyl, aryl or heterocycle, ^ is optional double bond, Z is CH , CH CH or O;

X and Y are independently methylene or carbonyl;

R is hydrogen or methyl;

R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or

(heterocycle)alkyl; and n is an integer of from 1 to 3; optionally together with one or more pharmaceutically acceptable carriers, excipients or diluents.

[6] The pharmaceutical composition of claim 5, further comprising one or more therapeutic agents selected from one or more muscarinic receptor antagonists, one or more testosterone 5 alpha-reductase inhibitors, one or more endothelin an¬ tagonists, one or more melanocoitin receptor agonists, one or more cGMP elevators, one or more HMG-Co-A reductase inhibitors, 5-HT receptor an¬ tagonists or mixtures thereof.

[7] A method for treating a patient suffering from a disease or disorder mediated through alpha Ia and/or alpha Id adrenergic receptors comprising administering to a patient in need thereof therapeutically effective amounts one or more compounds having the structure of Formula I,

wherein:

R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NR R , wherein R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle,

R 4 and R 5 are independently hydrogen, alkyl or phenyl,

R 6 is hydrogen, alkyl, phenyl, hydroxy or alkoxy,

R 7 and R 8 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl, (heterocycle)alkyl or R 9 -Q-(CH 2 ) πi -, or R 7 and R 8 together form cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle, wherein m is an integer of from 0 to 3, R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle, Q is oxygen, sulfur, carbonyl, carboxyl or - N(R )-W, wherein W is no atom, carbonyl, carboxylic or amide, and R is hydrogen, alkyl, aryl or heterocycle, is optional double bond, Z is CH , CH CH or O;

X and Y are independently methylene or carbonyl;

R is hydrogen or methyl;

R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or

(heterocycle)alkyl; n is an integer of from 1 to 3.

[8] The method of claim 7, wherein a disease or disorder is benign prostatic hy¬ perplasia (BPH) or lower urinary tract symptoms (LUTS).

[9] The method of claim 7, wherein compound causes minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.

[10] A method for treating a patient suffering from a disease or disorder mediated through alpha Ia and/or alpha Id adrenergic receptors comprising administering to a patient in need thereof therapeutically effective amount one or more phar¬ maceutical compositions comprising therapeutically effective amounts of one or more compounds having the structure of Formula I,

wherein:

R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocy ^Jcle or -NR I l R 12 wherein R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle,

R 4 and R 5 are independently hydrogen, alkyl or phenyl,

R 6 is hydrogen, alkyl, phenyl, hydroxy or alkoxy,

R 7 and R 8 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl, (heterocycle)alkyl or R 9 -Q-(CH 2 ) m -, or R 7 and R 8 together form cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle, wherein m is an integer of from 0 to 3, R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle, Q is oxygen, sulfur, carbonyl, carboxyl or -

wherein W is no atom, carbonyl, carboxylic or amide, R is hydrogen, alkyl, aryl or heterocycle, is optional double bond, Z is CH , CH CH or O;

X and Y are independently methylene or carbonyl;

R is hydrogen or methyl;

R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or

[H] The method of claim 10, wherein a disease or disorder is benign prostatic hy¬ perplasia (BPH) or lower urinary tract symptoms (LUTS). [12] The method of claim 10, wherein compound causes minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.

[13] A process of preparing compounds having the structure of Formula VIII,

(FORMULA I, wherein

Rl=H ) pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof, wherein: A is

wherein: R R 2 a anndd R R 3 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NR I l R 12 , wherein R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle,

R and R are independently hydrogen, alkyl or phenyl,

R 6 is hydrogen, alkyl, phenyl, hydroxy or alkoxy,

R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,

7 8 heterocycle, aralkyl, (heterocycle)alkyl or R 9 -Q-(CH 2 ) m -, or R 7 and R 8 together form cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle, wherein m is an integer of from 0 to 3, R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle, Q is oxygen, sulfur, carbonyl, carboxyl or -

wherein W is no atom, carbonyl, carboxylic or amide, R 10 is hydrogen, alkyl, aryl or heterocycle; is optional double bond, Z is CH , CH CH or O;

R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or

(heterocycle)alkyl; n is an integer of from 1 to 3; the method comprising the steps of: a) reacting compounds of Formula II with compounds of Formula III

R-N N-H

Formula II

Formula HI to form compounds of Formula IV,

Formula IV b) the compound of Formula IV is hydrolyzed to form compounds of Formula V,

Formula V c) the compound of Formula V is treated with tert-butylcarbazate to form compounds of Formula VI,

Formula VI d) the compound of Formula VI is hydrolyzed to form compounds of Formula VII,

Formula VII e) the compound of Formula VII is treated with compounds of Formula ?. to

V form compounds of Formula VIII.