WO2006051374A2 - Arylpiperazines useful as adrenergic receptor antagonists - Google Patents

Abstract

The present invention relates to compounds of formula (I), wherein A can be Formula (II), (III) or (IV), as α1a and/or α1d adrenergic receptor antagonists, which can be used to treat a disease or disorder mediated through α1a and/or α1d adrenergic receptors. Compounds and pharmaceutical compositions disclosed herein can be used to treat benign prostatic hyperplasia (BPH) and related symptoms thereof. Further, such compounds can be used to treat lower urinary tract symptoms that may or may not be associated with BPH. The present invention also relates to processes to prepare the disclosed compounds, pharmaceutical compositions thereof, and methods of treating BPH or related symptoms thereof.

Description

ADRENERGICRECEPTORANTAGONISTS

Field of the Invention

The present invention relates to α_la and/or α₁₍j adrenergic receptor antagonists, which can be used to treat a disease or disorder mediated through α_la and/or α₁₍i adrenergic receptors. Compounds and pharmaceutical compositions disclosed herein can be used to treat benign prostatic hyperplasia (BPH) and related symptoms thereof. Further, such compounds can be used to treat lower urinary tract symptoms that may or may not be associated with BPH. The present invention also relates to processes to prepare the disclosed compounds, pharmaceutical compositions thereof, and methods of treating BPH or related symptoms thereof.

Background of the Invention

Benign prostatic hyperplasia (BPH) is a condition that typically develops in elderly males. BPH causes benign overgrowth of the stromal and epithelial elements of the prostate with aging. Symptoms of BPH can vary and commonly involve changes or problems with urination, such as hesitation, interruption, weak stream, urgency, leaking, dribbling or increased frequency, particularly at night. BPH can consequently cause hypertrophy of bladder smooth muscle, a decompensated bladder or an increased incidence of urinary tract infection.

The symptoms of BPH are a result of two pathological components affecting the prostate gland: a static component and a dynamic component. The static component is related 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 related to increased smooth muscle tone of the bladder neck and prostate itself and is regulated by α-1 adrenergic receptor. Currently, the most effective treatment for BPH is a surgical procedure known as transurethral resection of the prostate (TURP), which involves removing obstructing tissue (C. Chappie, Br. Med. Journal, 304:1198-1199 (1992)). TURP is directed both to the static and dynamic components of the BPH. However, TURP is associated with mortality (1 %), adverse events, e.g., incontinence (2-4 %), infection (5-10 %), and impotence (5-10 %). Therefore, noninvasive alternative treatments are highly desirable. Some drag therapies address the static component of BPH. Administration of finasteride is one such therapy, which is indicated for the treatment of symptomatic BPH. This drag is a competitive inhibitor of the enzyme 5-α reductase that is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland. Dihydrotestosterone appears to be the major mitogen for prostate growth and agents, which inhibit 5-α reductase, reduce the size of the prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5-α reductase inhibitor that causes a marked decrease in serum and tissue concentrations of dihydrotestosterone, it is moderately effective in the treatment of symptomatic BPH. The effects of finasteride take 6-12 months to become evident and for many men the clinical development is minimal.

The dynamic component of BPH has been addressed by the use of adrenergic receptor blocking agents, which act by decreasing the smooth muscle tone within the prostate gland. A variety of α_la 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 drags 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 αi adrenoceptors. There are several lines of evidence suggesting that selectivity for α_la adrenoceptor over a^ adrenoceptor will result in relative lack of vascular side effects, thus lead to better tolerability. Mice deficient in an, adrenoreceptors show diminished blood pressure response to phenylephrine injection when compared to homozygous controls (decreased blood pressure response in mice deficient of a^ adrenergic receptor. (Proc. Nat 'I Acad. ScL USA, 94:1589-11594 (1997)). In-vivo studies in healthy subjects comparison of α_la/α₁₍i selective antagonists (e.g., tamsulosin) or α_la selective antagonists (e.g., urapidil) with non selective antagonists (e.g., doxazosin, prazosin, or terazosin) under a variety of experimental conditions (e.g., involving the administration of exogenous agonist or release of endogenous agonist by cold stimulation) in several vascular beds including the skin circulation in finger tips, the dorsal hand vein, or with total peripheral resistance have been reported. (Eur. J. Clin. Pharmacol, 49:371-375 (1996); N. Schmiedeberg, Arch. Pharmacol, 354:557-561 (1996); Jpn. J. Pharmacol, 80:209-215 (1999); Br. J. CHn.

Pharmacol, 47:67-74 (1999)). These studies reported that an antagonist with high affinity for α_la or α_la/α_lci receptors can cause some degree of vasodilation, although it is much lower than with non-subtype-selective α_la adrenoceptor antagonists. Further, there is increased vascular a^ adrenoceptor expression in elderly patients and thus α_la/α₁₍j- selective agents with selectivity over α_ll3 adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia. Antagonism of both α_la adrenoceptor and α_lcj adrenoceptor is important to relieve lower urinary tract symptoms especially associated with BPH. Targeting α_la adrenoceptors with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction, whereas α₁₍j adrenoceptor antagonism is important to target irritative symptoms.

In the past decade, there were significant efforts in discovering selective α_la adrenoceptor antagonists suitable for treating benign prostatic hyperplasia while avoiding cardiovascular side effects that are associated with current drugs. Selective antagonists have been disclosed in, for example, Exp. Opin. Invest. Drugs, 6:367-387 (1997) and in J. Med. Chetn., 40:1293-1325 (1995). Structure-activity relationships in many of these structural series have been studied in details and numerous highly selective compounds have been identified. There are many description in the literature about the pharmacological activities associated with phenyl piperazines, Eur. J. Med. Chem. - Chimica Therapeutica, 12:173-176 (1977), discloses substituted trifluoromethyl phenyl piperazines having cyclo-imido alkyl side chains shown below.

Other related compounds, which have been prepared as anxiolytic, neuroleptic, anti-diabetic and anti-allergic agents, are disclosed 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. BuIt; 39(9):2288-2300 (1991), Kitaro et al; JP 02-235865 (1990), Ishizumi et al; US Patent No. 4,598,078 (1086), New et al.; J. Med. Chem., 29:1476-1482 (1986), Shigeru et al; JP 60-204784 (1985), New et al, US Patent No. 4,524, 206 (1985), Korgaonkar et al; J. Indian Chem. Soc, 60:874-876 (1983). However, Oc₁ subtype selectivity of the compounds, such as those disclosed in the above-identified references, as well as their usefulness in the treatment of symptoms of benign prostate hyperplasia, were not disclosed in the above references.

The synthesis of l-(4-arylpiperazin-l-yl)-ω-[N- (α, ω-dicarboximido)]-alkanes useful as uro-selective Oc₁ -adrenoceptor blockers are disclosed in US Patent Nos.

6,083,950, 6,090,809, 6,410,735, 6,420,559 and 6,420,366, WO 00/05206, US Patent Appl. No. 2002/0156085 and WO 02/44151. These compounds are described as exhibiting Oc₁ -adrenergic blocking activity and selectivity.

Other disclosures of selective α_la adrenoceptor antagonists include US Patent Nos. 6,376,503, 6,319,932 and 6,339,090, EP 711757, WO 99/42448, WO 99/42445, WO 98/57940, WO 98/57632, WO 98/30560 WO 97/23462, WO 03/084928 and WO 03/084541.

Summary of the Invention

The present invention provides α_la and/or oc₁₍j adrenergic receptor antagonists, which can be used to treat a disease or disorder mediated through α_la and/or α₁₍j adrenergic receptors, and processes for the synthesis of these compounds. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, polymorphs or N- oxide of these compounds having the same type of activity are also provided. Pharmaceutical composition containing the compounds described herein, optionally together with one or more pharmaceutically acceptable carriers, excipients, diluents or mixture thereof, which can be used to treat BPH or related symptoms thereof or LUTS with or without BPH.

Thus, provided herein are compounds having the structure of Formula I,

pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof, wherein:

R₁ and R₂ can be independently hydrogen, C_1-4 alkyl, halogenated C_1-4 alkyl, aryl optionally substituted with one or more substituent(s) selected from halogens, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4 alkoxy, mercapto or C_1-4thioalkyl;

R₃ can be hydrogen, C_1-4 alkyl, C_3-6 alkylene linked to 3a and 7a carbon atoms of isoindole ring; with the proviso that both the R₃ linked to 3 a and 7a carbon atoms of isoindole ring can not be simultaneously hydrogen;

R₄ and R₅ can be independently hydrogen or C_1-4 alkyl; Z can be no atom, oxygen, sulphur, nitrogen, or -(CH₂)_P-; p can be an integer of from 0 to 4; with the proviso that, when Z is no atom, then either OfR₄ and R₅ is C_1-4 alkyl; can be optional double bond; n can be an integer of from 2 to 6; R can be non-aromatic or aromatic ring system having 0 to 4 heteroatom(s) optionally substituted with substituent(s) selected from halogen(s), C_1-4 alkyl, halogenated C_1-4 alkyl, cyano, hydroxy, C_1-4 alkoxy, C_3-6 cycloalkoxy, mercapto, C_1-4 thioalkyl, NR₆R₇ or CONR₆R₇;

R₆ and R₇ can be independently hydrogen or alkyl; and R can also be aralkyl.

These compounds may involve one or more of the following features. For example, R₁ and R₂ can be independently hydrogen or C_1-4 alkyl; R₃ linked to 3a and 7a can be respectively hydrogen or C_1-4 alkyl; Z can be no atom; R₄ and R₅ can be respectively hydrogen and C_1-4 alkyl; Z can be oxygen; R can be substituted monocyclic aromatic ring.

In another embodiment, R₁ and R₂ can be independently hydrogen or methyl; R₃ linked to 3a and 7a carbons of isoindole ring can be respectively hydrogen and methyl, both can be methyl or together can form a cyclohexyl ring; Z can be no atom or oxygen; R₄ and R₅ can be respectively methyl or hydrogen; R can be 2-isopropoxyphenyl.

Also provided herein are compounds selected from:

(R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl-3a,4,7,7a- tetrahydro-isoindole- 1 ,3 -dione,

(R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl-3a,4,7,7a- tetrahydro-isoindole- 1,3 -dione hydrochloride salt, (R or S) 2-{3-[4-(2-Isopropoxy- phenyl)-piperazin- 1 -yl] -propyl} -3 a-methyl-3 a,4,7,7a-tetrahydro-isoindole- 1 ,3-dione, (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl-3a,4,7,7a- tetrahydro-isoindole-l,3-dione hydrochloride salt,

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a- tetrahydro-isoindole- 1 ,3-dione,

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a- tetrahydro-isoindole- 1,3 -dione hydrochloride salt,

12-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-12-aza- tricyclo[4.4.3.0* 1 ,6*]tridec-3-ene-l 1 ,13-dione,

12- {3-[4-(2-Isopropoxy-phenyl)-piperazin- 1 -yl] -propyl} - 12-aza- tricyclo[4.4.3.0*l,6*]tridec-3-ene-ll,13-dione hydrochloride salt, 2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a-tetrahydro- isoindole- 1 ,3 -dione,

2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a-tetrahydro- isoindole- 1,3 -dione hydrochloride salt,

3a-Methyl-2-[3-(4-phenyl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole-l,3- dione,

3a-Methyl-2-[3-(4-phenyl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole-l,3- dione hydrochloride salt,

3a-Methyl-2-[3-(4-pyridin-2-yl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole- 1,3-dione, 3a-Methyl-2-[3-(4-pyridin-2-yl-piρerazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole- 1,3-dione hydrochloride salt,

2-{3-[4-(2-Isopropoxy-ρhenyl)-piperazin-l-yl]-propyl}-5,6,-dimethyl-3a,4,7,7a- tetrahydro-isoindole- 1,3-dione,

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6,-dimethyl-3a,4,7,7a- tetrahydro-isoindole- 1,3-dione hydrochloride salt, 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-hexahydro- isoindole-l,3-dione,

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-hexahydro- isoindole- 1,3-dione hydrochloride salt,

(R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10-oxa-4- aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione,

(R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10-oxa-4- aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione hydrochloride salt,

(R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10-oxa-4- aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione, (R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10-oxa-4- aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione hydrochloride salt,

2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-3a,4,7,7a-tetrahydro- isoindole-l,3-dione,

2- {3 -[4-(2-Methoxy-phenyl)-piperazin- 1 -yl] -propyl} -5,6-dimethyl-3 a,4,7,7a-tetrahydro- isoindole- 1,3-dione hydrochloride salt,

4-[3-(4-(2-Methoxy-phenyl)-piperazin-l-yl)-propyl]-4-aza-tricyclo[5.2.1.0*2,6*]decane- 3,5-dione,

4-[3-(4-(2-Methoxy-phenyl)-piperazin-l-yl)-propyl]-4-aza-tricyclo[5.2.1.0*2,6*]decane- 3,5-dione hydrochloride salt, 6- {3-[4-(2-Isopropoxy-phenyl)-piperazin- 1 -yl]-propyl} -2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione,

6- {3-[4-(2-Isopropoxy-phenyl)-piperazin- 1 -yl]-propyl} -2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride salt,

6- {3-[4-(2-Isopropoxy-phenyl)-piperazin- 1 -yl]-propyl}-hexahydro-[ 1 ,3]dioxolo[4,5- fjisoindole-5,7-dione, 6- {3-[4-(2-Isopropoxy-phenyl)-ρiperazin- l-yl]-propyl} -hexahydro-[ 1 ,3]dioxolo[4,5- f]isoindole-5,7-dione hydrochloride salt,

6-{3-[4-(2-Methoxy-ρhenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione,

6-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride salt, 2,2-Dimethyl-6- {3-[4-phenyl-piperazin-l -yl]-propyl} -hexahydro-[ 1 ,3]dioxolo[4,5- f]isoindole-5,7-dione,

2,2-Dimethyl-6- {3-[4-phenyl-piperazin-l -yl]-propyl} -hexahydro-[ 1 ,3]dioxolo[4,5- f]isoindole-5,7-dione hydrochloride salt,

6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]prόpyl}tetrahydro-3aH- [l,3]dioxolo[4,5-/]isomdole-2,5,7(4H,6H)-trione,

6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}tetrahydro-3aH- [l,3]dioxolo[4,5-/]isomdole-2,5,7(4H,6H)-trione hydrochloride salt,

6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}tetrahydro-3aH- [l,3]dioxolo[4,5-/]isomdole-5,7(4H,6H)-dione, 6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}tetrahydro-3aH- [l,3]dioxolo[4,5-/]isoindole-5,7(4/J,6H)-dione hydrochloride salt,

6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}-2,2-dimethyltetrahydro- 3aH-[l,3]dioxolo[4,5-/|isoindole-5,7(4H,6H)-dione hydrochloride salt,

6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}-2,2-dimethyltetrahydro- 3aH-[l,3]dioxolo[4,5-/|isomdole-5,7(4H,6H)-dione hydrochloride salt, or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs or metabolites. Also provided herein are methods for treating a disease or disorder mediated through α_la and/or α_lti adrenergic receptors, comprising administering to patient in need thereof therapeutically effective amounts of one or more compounds described herein, optionally one or more pharmaceutically acceptable carriers, excipients, diluents or mixture thereof. These methods can encompass one or more of the following features. For example, the disease or disorder can be benign prostatic hyperplasia. In another example, the compound causes minimal decrease or no decrease in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.

Also provided herein are methods for treating lower urinary tract symptoms associated with or without benign prostatic hyperplasia, comprising administering to a patient in need thereof therapeutically effective amounts of one or more compounds described herein, optionally one or more pharmaceutically acceptable carriers, excipients, diluents or mixture thereof.

Also provided herein are methods for treating a patient suffering from benign prostatic hyperplasia or lower urinary tract symptoms with or without benign prostatic hyperplasia comprising administering to a patient therapeutically effective amounts of one or more compounds (or compositions) described herein in combination with one or more other therapeutic agents selected from muscarinic receptor antagonists, bladder selective muscarinic receptor antagonists, testosterone 5 alpha-reductase inhibitors, endothelin antagonists, melanocortin receptor agonists, cGMP elevators, HMG-CoA reductase inhibitors, 5-HT antagonists or combination thereof.

Also provided herein are methods for treating a patient suffering from benign prostatic hyperplasia or lower urinary tract symptoms with or without benign prostatic hyperplasia comprising administering to a patient therapeutically effective amounts of one or more compounds (or compositions) described herein in combination with one or more solifenacin, darifmacin, PCT/IB2003/001367, PCT/IB2004/, dutasteride, finasteride, pravastatin, simvastatin, atorvastatin RBx-10558, 11901 or combination thereof.

Also provided herein are methods for preparing compounds of Formula IV,

Formula IV

pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof, wherein:

R₃ can be hydrogen, C_1-4 alkyl, C_3-6 alkylene linked to 3a and 7a carbon atoms of isoindole ring; with the proviso that both the R₃ linked to 3a and 7a carbon atoms of isoindole ring can not be simultaneously hydrogen; n can be an integer of from 2 to 6;

R can be non-aromatic or aromatic ring system having 0 to 4 heteroatom(s) optionally substituted with substituent(s) selected from halogen(s), C_1-4 alkyl, halogenated C_1-4 alkyl, cyano, hydroxy, C_1-4 alkoxy, C_3-6 cycloalkoxy, mercapto, C_1-4thioalkyl, NR₆R₇ or CONR₆R₇;

R₆ and R₇ can be independently hydrogen or alkyl; R can also be aralkyl; which method comprises : reacting a compound of Formula II with a compound of Formula III (or XR₃X)

III

Formula II

wherein X is halogen, to form a compound of Formula IV.

Also provided herein are the methods for preparing compounds of VII,

Formula VII pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof, wherein: R₄ and R₅ can be independently hydrogen or C_1-4 alkyl;

Z can be no atom, oxygen, sulphur, nitrogen, or -(CH₂)_P-; p can be an integer of from 0 to 4; with the proviso that, when Z is no atom, then either OfR₄ and R₅ is C_1-4 alkyl; n can be an integer of from 2 to 6;

R can be non-aromatic or aromatic ring system having 0 to 4 heteroatom(s) optionally substituted with substituent(s) selected from halogen(s), C_1-4 alkyl, halogenated C_1-4 alkyl, cyano, hydroxy, C_1-4 alkoxy, C_3-6 cycloalkoxy, mercapto, C_1-4 thioalkyl, NR₆R₇ or CONR₆R₇;

R₆ and R₇ can be independently hydrogen or alkyl; R can also be aralkyl; which method comprises :

(a) reacting a compound of Formula V with a compound of Formula VI

to form a compound of Formula VII.

Also provided herein are the methods for preparing compounds of IX,

Formula IX

pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, polymorphs and metabolites thereof wherein:

R₁ and R₂ can be independently hydrogen, C_1-4 alkyl, halogenated C_1-4 alkyl, aryl optionally substituted with one or more substituent(s) selected from halogens, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4 alkoxy, mercapto or C_1-4 thioalkyl; n can be an integer of from 2 to 6;

R can be non-aromatic or aromatic ring system having 0 to 4 heteroatom(s) optionally substituted with substituent(s) selected from halogen(s), C_1-4 alkyl, halogenated C_1-4 alkyl, cyano, hydroxy, C_1-4 alkoxy, C_3-6 cycloalkoxy, mercapto, C_1-4 thioalkyl, NR₆R₇ or CONR₆R₇;

R₆ and R₇ can be independently hydrogen or alkyl; R can also be aralkyl;

(a) oxidizing a compound of Formula II

Formula II to form a compound of Formula VIII,

Formula Vm

(b) treating the compound of Formula VIII with a compound of Formula

to form a compound of Formula IX.

Detailed Description of the Invention

In one aspect, there are provided compounds having the structure of Formula I,

pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof, wherein:

R₁ and R₂ can be independently hydrogen, C_1-4 alkyl, halogenated C_1-4 alkyl, aryl optionally substituted with one or more substituent(s) selected from halogens, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4 alkoxy, mercapto or C_1-4 thioalkyl;

R₃ can be hydrogen, Ci_-4 alkyl, C_3-6 alkylene linked to 3a and 7a carbon atoms of isoindole ring; with the proviso that both the R₃ linked to 3a and 7a carbon atoms of isoindole ring can not be simultaneously hydrogen;

R₄ and R₅ can be independently hydrogen or Ci_-4 alkyl; Z can be no atom, oxygen, sulphur, nitrogen, or -(CH₂)_P-; p can be an integer of from 0 to 4; with the proviso that, when Z is no atom, then either OfR₄ and R₅ is C_1-4 alkyl; can be optional double bond; n can be an integer of from 2 to 6; R can be non-aromatic or aromatic ring system having 0 to 4 heteroatom(s) optionally substituted with substituent(s) selected from halogen(s), C_1-4 alkyl, halogenated C_1-4 alkyl, cyano, hydroxy, C_1-4 alkoxy, C_3-6 CyClOaIkOXy, mercapto, C_1-4thioalkyl, NR₆R₇ or CONR₆R₇; R₆ and R₇ can be independently hydrogen or alkyl;

R can also be aralkyl.

In one embodiment, there are provided compounds of Formula I, wherein R₁ and R₂ can be independently hydrogen or C_1-4 alkyl; R₃ linked to 3 a and 7a can be respectively hydrogen or C_1-4 alkyl; Z can be no atom; R₄ and R₅ can be respectively hydrogen and C_1-4 alkyl; Z can be oxygen; R can be substituted monocyclic aromatic ring. In another embodiment, there are provided compounds of Formula I, wherein R₁ and R₂ can be independently hydrogen or methyl; R₃ linked to 3 a and 7a carbons of isoindole ring can be respectively hydrogen and methyl, both can be methyl or together can form a cyclohexyl ring; Z can be no atom or oxygen; R₄ and R₅ can be respectively methyl or hydrogen; R can be 2-isopropoxyphenyl.

In another aspect, there are provided compounds selected from:

(R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl-3a,4,7,7a- tetrahydro-isoindole-l,3-dione (Compound No. 1), (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl-3a,4,7,7a- tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 2),

(R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl-3a,4,7,7a- tetrahydro-isoindole-l,3-dione (Compound No. 3),

(R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl-3a,4,7,7a- tefrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 4),

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a, 4,7,7a- tetrahydro-isoindole-l,3-dione (Compound No. 5),

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a- tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 6), 12-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-12-aza- tricyclo[4.4.3.0*l,6*]tridec-3-ene-ll,13-dione (Compound No. 7), 12-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-12-aza- Mcyclo[4.4.3.0*l,6*]tridec-3-ene-ll,13-dione hydrochloride salt (Compound No. 8),

2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a-tetrahydro- isoindole-l,3-dione (Compound No. 9),

2- {3- [4-(2-Methoxy-phenyl)-piperazin- 1 -yl] -propyl} -3 a,7a-dimethyl-3 a,4,7,7a-tetrahydro- isoindole-l,3-dione hydrochloride salt (Compound No. 10), 3a-Methyl-2-[3-(4-phenyl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetraliydro-isoindole-l,3- dione (Compound No. 11),

3a-Methyl-2-[3-(4-phenyl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole-l,3- dione hydrochloride salt (Compound No. 12),

3a-Methyl-2-[3-(4-pyridin-2-yl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole- 1, 3 -dione (Compound No. 13),

3a-Methyl-2-[3-(4-pyridin-2-yl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole- 1,3-dione hydrochloride salt (Compound No. 14),

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6,-dimethyl-3a,4,7,7a- tetrahydro-isoindole- 1,3 -dione (Compound No. 15), 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6,-dimethyl-3a,4,7,7a- tetrahydro-isoindole- 1,3 -dione hydrochloride salt (Compound No. 16),

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-hexahydro- isoindo Ie- 1,3-dione (Compound No. 17),

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-hexahydro- isoindole- 1,3 -dione hydrochloride salt (Compound No. 18),

(R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10-oxa-4- aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione (Compound No. 19),

(R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10-oxa-4- aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione hydrochloride salt (Compound No. 20), (R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10-oxa-4- aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione (Compound No. 21),

(R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10-oxa-4- aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione hydrochloride salt (Compound No. 22),

2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-3a,4,7,7a-tetrahydro- isoindole- 1,3 -dione (Compound No. 23), 2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-3a,4,7,7a-tetrahydro- isoindole-l,3-dione hydrochloride salt (Compound No. 24),

4-[3.(4-(2-Methoxy-phenyl)-piperazin-l-yl)-propyl]-4-aza-tricyclo[5.2.1.0*2,6*]decane- 3,5-dione (Compound No. 25),

4-[3_(4-(2-Methoxy-phenyl)-piperazin-l-yl)-propyl]-4-aza-tricyclo[5.2.1.0*2,6*]decane- 3,5-dione hydrochloride salt (Compound No. 26), 6- {3 -[4-(2-Isopropoxy-phenyl)-piperazin- 1 -yl] -propyl} -2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione (Compound No. 27),

6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride salt (Compound No. 28),

6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-[l,3]dioxolo[4,5- f]isoindole-5,7-dione (Compound No. 29),

6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-[l,3]dioxolo[4,5- f]isoindole-5,7-dione hydrochloride salt (Compound No. 30),

6-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione (Compound No. 31), 6-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride salt (Compound No. 32),

2,2-Dimethyl-6-{3-[4-phenyl-piperazin-l-yl]-propyl}-hexahydro-[l,3]dioxolo[4,5- f]isoindole-5,7-dione (Compound No. 33),

2,2-Dimethyl-6- {3-[4-phenyl-piperazin- 1 -yl]-propyl} -hexahydro-[ 1 ,3]dioxolo[4,5- f]isoindole-5,7-dione hydrochloride salt (Compound No. 34),

6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}tetrahydro-3aH- [l,3]dioxolo[4,5-/]isomdole-2,5,7(4H,6H)-trione (Compound No. 35),

6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}tetrahydro-3aH- [l,3]dioxolo[4,5-/Jisoindole-2,5,7(4H,6H)-trione hydrochloride salt (Compound No. 36), 6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}tetrahydro-3aH- [l,3]dioxolo[4,5-/]isoindole-5,7(4H,6H)-dione (Compound No. 37),

6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}tetrahydro-3aH- [l,3]dioxolo[4,5-/|isoindole-5,7(4/i,6H)-dione hydrochloride salt (Compound No. 38),

6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}-2,2-dimethyltetrahydro- 3aH-[l,3]dioxolo[4,5-/Jisoindole-5,7(4H,6H)-dione hydrochloride salt (Compound No. 39), 6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}-2,2-dimethyltetrahydro- 3aH-[l,3]dioxolo[4,5-/]isoindole-5,7(4H,6H)-dione hydrochloride salt (Compound No. 40), or pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof. hi another aspect, there are provided pharmaceutical compositions comprising one or more compounds of Formula I, optionally together with one or more pharmaceutically acceptable carriers, excipients, diluents or mixture thereof. In another aspect, provided are methods for treating a disease or disorder mediated through α_la and/or α₁₍₁ adrenergic receptors comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein. hi another aspect, there are provided methods for treating benign prostatic hyperplasia (BPΗ) or related symptoms comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein. hi another aspect, there are provided methods for treating lower urinary tract symptoms (LUTS) with or without BPΗ comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition disclosed 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, prolong urination, and feelings of incomplete emptying). hi another aspect, there are provided methods for treating a patient suffering from benign prostatic hyperplasia or lower urinary tract symptoms with or without benign prostatic hyperplasia comprising administering to a patient therapeutically effective amounts of one or more compounds (or compositions) described herein in combination with one or more other therapeutic agents selected from muscarinic receptor antagonists, bladder selective muscarinic receptor antagonists, testosterone 5 alpha-reductase inhibitors, endothelin antagonists, nielanocortin receptor agonists, cGMP elevators, HMG-CoA reductase inhibitors, 5 -HT antagonists or combination thereof. In another aspect, there are provided methods for treating a patient suffering from benign prostatic hyperplasia or lower urinary tract symptoms with or without benign prostatic hyperplasia comprising administering to a patient therapeutically effective amounts of one or more compounds (or compositions) described herein in combination with one or more solifenacin, darifinacin, international application numbers PCT/IB2003/001367, PCT/IB2004/000008, dutasteride, finasteride, pravastatin, simvastatin, atorvastatin international application number PCT/IB2004-001761 or combination thereof. hi yet another aspect, there are provided processes for preparing compounds described herein.

Compounds described herein possess selective and potent α_la adrenoceptor antagonistic activity over the a^ adrenoceptors. This invention provides 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, 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 α_la 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 definition apply to terms as used herein:

The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

The term "aryl," unless otherwise specified, refers to carbocyclic aromatic groups, for example, 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, CF₃, cyano, nitro, COOR_e (wherein R_e is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=0)R₁₄, -NRi₄Rl 5, -C(K⁾)NR₁₄R₁₅, -NHC(=O)NR₁₄R₁₅,

(wherein R₁₄ and R₁₅ are the same as defined earlier), S(O)_mR_h (wherein m is an integer from 0-2 and R₆ 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 hetero atoms selected from O, N or S.

The term "aralkyl" unless otherwise specified, refers for an aryl radical having 7 to 14 carbon atoms which is bonded to an alkylene chain, for example, benzyl, naphthylmethyl, phenethyl and phenylpropyl, and the like.

The term "non-aromatic ring system" unless otherwise specified, refers to cycloalkyl having 0 to 4 heteroatom(s) wherein the said heteroatom refers to nitrogen, sulphur or oxygen, and the term ring system refers to mono or bicyclic, example of non- aromatic, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and the like.

The term "aromatic ring system" unless otherwise specified, stands for aryl having 0 to 4 heteroatom(s) wherein the said heteroatom refers to nitrogen, sulphur or oxygen, and the term ring system includes mono, bi or tricyclic, example of aromatic, but are not limited to, phenyl, naphthyl, anthryl, biphenyl, thienyl, furyl, pyrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, thiazolyl, benzthiazolyl, isothiazolyl, oxazolyl, benoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl, indolyl and isoindolyl and the like.

The term "pharmaceutically acceptable salts" refer to a salt prepared from pharmaceutically acceptable non-toxic inorganic or organic acid. Examples of such inorganic acids include, but are not limited to, hydrochloric, sulfuric, phosphoric acid, and the like. Appropriate organic acids include, but are not limited to aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methansulfonic, ethanesulfonic, benzenesulfonic, panthenic, toluenesulfonic and 2-hydroxyethanesulfonic acid, and the like. These salts may be prepared by the useful prior art techniques.

The term "pharmaceutically acceptable solvates" refers to solvates with waters (i.e hydrates) or pharmaceutically acceptable organic solvents. Such solvates are also encompassed within the scope of this invention. The present invention also includes within its scope prodrugs of these compounds. In general, such "prodrugs" will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound. Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example, in "design of prodrugs", ed. H Bundgaard and, Elsevier, 1985.

The present invention also includes metabolites, which become active upon introduction into the biological system.

The crystalline or amorphous forms of compounds disclosed herein may exist as polymorphs and as such are intended to be included in the present invention. The compounds of present invention include stereoisomers. The term

"stereoisomer" refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. These include enantiomers, diastereomers, geometrical isomers, atropisomer and comformational isomers. Geometric isomers may occur when a compound contains a double bond or some other feature that gives the molecule a certain amount of structural rigidity. An enantiomer is a stereoisomer of a reference molecule that is the nonsuperimposable mirror image of the reference molecule. A diastereomer is a stereoisomer of a reference molecule that has a shape that is not the mirror image of the reference molecule. An atropisomer is a conformational of a reference compound that converts to the reference compound only slowly on the NMR or laboratory time scale. Conformational isomers (or conformers or rotational isomers or rotamers) are stereoisomers produced by rotation about σ bonds, and are often rapidly interconverting at room temperature. Racemic mixtures are also encompassed within the scope of this 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 reaction sequence as shown in Schemes I, II and III. Scheme I

Formula IV

Compounds of Formula IV can be prepared according to Scheme I. Thus compounds of Formula II can be reacted with compounds of Formula R₃X or XR₃X (wherein X is halogen, for example iodine) to form compounds of Formula IV, wherein n, R and R₃ have the same meaning as defined earlier.

Compounds of Formula II can be reacted in the presence of one or more bases, for example, lithium diisopropylamine, n-butyl lithium or mixture thereof, in one or more solvents, for example, aprotic polar solvents (e.g., acetonitrile, propionitrile, dimethylformamide, dimethylsulfoxide, or dimethylacetamide), ethers (e.g., tetrahydrofuran, diethylether or dioxane) or mixture thereof.

Scheme II

Compounds of Formula VII can be prepared according to Scheme II. Thus, compounds of Formula V can be reacted to form compounds of Formula VII, wherein n, R, R₄ and R₅ have the same meaning as defined earlier.

Compounds of Formula V can be reacted in one or more solvents, for example, non-polar solvents (e.g., xylene, toluene or benzene), aprotic polar solvents (e.g., tetrahydrofuran, acetonitrile, dimethylformamide or dimethylsulfoxide) or mixtures thereof.

Scheme III

Formula VIII

Compounds of Formula IX can be prepared according to Scheme III. Thus, compounds of Formula II, wherein n and R have the same meaning as defined earlier, can be reacted with an oxidizing agent to form compounds of Formula VIII. Compounds of

Formula VIII can be reacted with compounds of Formula R₁. to form compounds of Formula IX. R/ Compounds of Formula II can be reacted with one or more oxidizing agent, for example, potassium permanganate, potassium dichromate or mixtures thereof in one or more alcoholic solvents (e.g., methanol, ethanol or isopropanol).

Compounds of Formula VIII can be reacted in the presence of one or more organic or inorganic acid, for example, p-toluene sulphonic acid, borontrifluoride,hydrochloric acid or mixtures thereof.

Pharmaceutically acceptable salts can be prepared following the methods well known to one of ordinary skilled in the art. hi the above scheme, where the specific oxidizing agents, acids, solvents, etc., are mentioned, it is to be understood that other oxidizing agents, acids, 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.

Compounds described herein can be administered to a patient (e.g., human or animal) orally, parenterally, topically, rectally, internasally, subcutaneously or transdermally. Pharmaceutical compositions of the present invention can comprise pharmaceutically effective amounts of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers.

The term "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filter, diluent, encapsulating material or formulation auxiliary of any type.

Solid form preparations for oral administration, include capsules, tablets, pills, powder, granules, cachets or suppositories. For solid form preparations, one or more active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carriers, for example, sodium citrate, dicalcium phosphate and/or one or more fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol, silicic acid or mixtures thereof; one or more binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrolidinone, 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 accelators, 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.

For capsules, tablets or pills, dosage forms can also comprise one or more buffering agents. Solid preparations of tablets, capsules, pills or granules can also be prepared with one or more coatings and/or shells, for example, enteric coating and other coatings well known in the pharmaceutical formulating art.

Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. For liquid form preparations, one or more active compounds can be mixed with water and/or other solvent(s), one or more 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 or sesame oil), glycerol, fatty acid esters of sorbitan or mixtures thereof. In addition to inert diluents, oral compositions can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or mixtures thereof.

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

Dosage forms for topical or transdermal administration includes ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhalants or patches. Active compound can be admixed under sterile conditions with one or more pharmaceutically acceptable carriers, as well as any preservatives or buffers as may be required. Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.

Pharmaceutical preparations may be in unit dosage form. In particular, preparations may be subdivided into unit dosage forms containing appropriate and therapeutically effective quantities of one or more active ingredients. Unit dosage forms can be packaged preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, cachets, tablets, gels, creams, or any combination thereof and in appropriate numbers of unit dosages.

Formulations of the present invention may be formulated by methods known to one of ordinary skill in the art to provide immediate release, as well as sustained- or delayed-release of active ingredients after administration to a patient.

Compounds described herein, bladder selective muscarinic receptor antagonists and/or 5α reductase inhibitors can be formulated in combination to achieve desired therapeutic effects, i.e., combination therapies. As such, the dosage amounts of such active ingredients can be adjusted accordingly, without undue experimentation and well within the abilities of one of ordinary skill in the art. As one of ordinary skill in the art can appreciate, dosage amounts of compounds described herein, bladder selective muscarinic receptor antagonists and/or 5α reductase inhibitors maybe independently optimized and combined to achieve a synergistic therapeutic result, hi accordance with methods encompassed herein, individual components of any combination can be administered separately in any sequence at the same or different times during the course of therapy, or concurrently in divided or single combination forms.

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

Experimental

Example 1: Preparation of (R or S) 2-{3-[4-(2-Isopropoxy-phenvD-piperazin-l-yl^'|- propyl) -3 a-methyl-3 a A7,7a-tetøhydro-isoindole- 1 ,3-dione hydrochloride salt (Compound No. 2)

Step 1: Preparation of (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a- methyl-3a,4, 7, 7a-tetrahydro-isoindole-l,3-dione (Compound No. 1)

To a solution of lithium diisopropylamine (0.286 gm, 2.68 mmole) in dry tetrahydrofuran (10 mL) at -78⁰C under N₂ atmosphere was added dropwise 2-[3-{4-(2- isopropoxyphenyl)piperazin- 1 -yl]propyl]-3a,4,7,7a-tetrahydro- lH-isondole- 1 ,3(2H) dione (1.0 gm, 2.4 mmole) dissolved in dry tetrahydrofuran (5 mL). Reaction mixture was stirred for 2 to 4 hours. The reaction mixture was allowed to attain at an ambient temperature. The reaction mixture was cooled again to -78 ⁰C, to it methyl iodide (0.345 gm, 2.4 mmole) was added dropwise and reaction mixture stirred for 2 to 4 hours. The reaction mixture was allowed to attain at an ambient temperature. Reaction was quenched by adding water (25 mL); extracted with ethyl acetate (2x15 mL); dried over anhydrous sodium sulphate and concentrated to yield the crude residue of desired compound. The crude product was then purified on silica gel (60-120 mesh) column using dichloromethane methanol as eluent.

The following compounds were prepared following procedures of Example 1, step 1 : (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl-3a,4,7,7a- tetrahydro-isoindole-l,3-dione (Compound No. 3),

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a- tetrahydro-isoindole-l,3-dione (Compound No. 5),

12-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-12-aza-tricyclo[4.4.3.0*1,6*] tridec-3-ene-ll,13-dione (Compound No. 7),

The following compounds are prepared following procedures of Example 1, step 1:

2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a-tetrahydro- isoindole-l,3-dione (Compound No. 9),

3a-Methyl-2-[3-(4-phenyl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole-l,3- dione (Compound No. 11),

3a-Methyl-2-[3-(4-pyridin-2-yl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole- 1,3-dione (Compound No.13),

Step 2: Preparation of (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a- methyl-3a,4, 7, 7a-tetrahydro-isoindole-l,3-dione hydrochloride salt

To a solution of (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}- 3a-methyl-3a,4,7,7a-tetrahydro-isoindole-l,3-dione in isopropyl alcohol was added isopropyl alcohol/hydrochloric acid at 10-15 ⁰C and the reaction mixture was stirred for about 1 hr. A solid precipitate was filtered, dried and weighed to yield 2-{3-[4-(2- Isopropoxy-phenyl)-piperazin- 1 -yl] -2-oxo-propyl} -Sa^^^a-tetrahydro-isoindole- 1,3- dione hydrochloride salt. Yield: 0.56 gm (54%) IR (KBr): 1692.2 cm-^{1 1}H NMR (300 MHz, CDCl₃): δ 1.38-1.39 (m, 9H), 1.88-1.93 (dd, IH), 2.23-2.25 (m, 3H), 2.59-2.75 (m, 3H), 2.97-3.07 (m, 4H), 3.54-3.61 (m, 8H), 4.59-4.63 (m, IH), 5.94 (brs, 2H), 6.87-7.05 (m, 4H), 12.89 (brs, IH)

Mass (m/z): 426.6 (M⁺+ 1), The following compounds were prepared following the previously disclosed procedure of Example 1, Step 2:

(R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl-3a,4,7,7a- tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 4)

IR (KBr): 1689.9 cm^{"1 1}H NMR (300 MHz, CDCl₃): δ 1.26 (s, 3H), 1.34-1.36 (d, 6H), 1.87-1.92 (dd, 2H), 2.21- (m, 2H), 2.58-2.63 (dd, 2H), 2.71 (brs, IH), 2.94 (m, 4H), 3.43-3.58 (m, 8H), 4.56-4.60 (m, IH), 5.91 (d, 2H), 6.84-7.00 (m, 4H), 12.83 (brs, IH)

Mass (m/z): 426.2 (M⁺+l),

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a- tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 6)

IR (KBr): 1689.6 cm^{"1 1}H NMR (300 MHz, CDCl₃): δ 1.28 (s, 6H), 1.35-1.37 (d, 6H), 1.89-1.93 (d, 2H), 2.22 (m, 2H), 2.59-2.64 (dd, 2H), 2.95 (m, 4H), 3.44-3.59 (m, 8H), 4.57-4.61 (m, IH), 5.92 (m, 2H), 6.85-7.03 (m, 4H), 12.75 (brs, IH). Mass (m/z): 440 (M⁺+l),

12-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-12-aza-tricyclo[4.4.3.0*l,6*] tridec-3-ene-l 1,13-dione hydrochloride salt (Compound No. 8)

IR (KBr): 1696.7 cm^"1

¹H NMR (300 MHz, CDCl₃): δ 1.36-1.46 (m, 8H)₅ 1.59 (m, 4H), 1.84-1.88 (m, 2H), 1.96- 2.01 (d, 2H), 2.23 (m, 2H), 2.51-2.56 (m, 2H), 3.03 (m, 2H), 3.47-3.64 (m, 8H), 4.11 (m, 2H), 4.67 (m, IH), 5.87 (m, 2H), 6.92-7.19 (m, 4H), 13.5 (brs, IH).

Mass (m/z): 466.2 (M⁺+l),

The following compounds are prepared following the previously disclosed procedure of Example 1, Step 2:

2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a-tetrahydro- isoindole-l,3-dione hydrochloride salt (Compound No. 10),

3a-Methyl-2-[3-(4-phenyl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole-l,3- dione hydrochloride salt (Compound No. 12), 3a-Methyl-2-[3-(4-pyridin-2-yl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole- 1,3-dione hydrochloride salt (Compound No.14),

Example 2: Preparation of 2-{3-r4-f2-Isopropoxy-phenvD-piperazin-l-yrj-propyl)-5,6,- dimethyl-3aA7,7a-tetrahvdro-isomdole-1.3-dione hydrochloride salt (Compound No. 16) Step 1: Preparation of 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl] -propyl}-5 ,6,- dimethylSa, 4, 7, 7a-tetrahydro-isoindole-l , 3-dione (Compound No. 15)

A mixture of 2,3-dimethylbutadiene (0.216 gm, 3.08 mmole) and l-[3-{4-(2- isopropoxyphenyl)-piperazin-l-yl]-propyl]-pyrrole-2,5-dione (1 gm, 2.8 mmole) in toluene (15 mL) was refluxed for 5 to 8 hours. Reaction was concentrated on buchi to thick residue, which was purified on silica gel (60-120 mesh) column using dichloromethane-methanol as eluent to form the desired compound.

The following compounds were prepared following the procedures of Example 2, step 1:

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-hexahydro- isoindole-1, 3-dione (Compound No. 17),

(R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10-oxa-4- aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione (Compound No.19),

(R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10-oxa-4- aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione (Compound No.21),

The following compounds are prepared following the procedures of Example 2, step 1:

2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-3a,4,7,7a-tetrahydro- isoindole- 1,3-dione (Compound No. 23),

4-[3-(4-(2-Methoxy-phenyl)-piperazin-l-yl)-propyl]-4-aza-tricyclo[5.2.1.0^:!:2,6*]decane- 3,5-dione (Compound No. 25),

Step 2: Preparation of2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6,- dimethyl-3a,4, 7, 7a-tetrahydro-isoindole-l, 3-dione hydrochloride salt (Compound No. 8)

To a solution of (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazm-l-yl]-propyl}- 5,6,-dimethyl-3a,4,7,7a-tetrahydro-isoindole-l,3-dione in isopropyl alcohol was added isopropyl alcohol/hydrochloric acid at 10-15 ⁰C and the reaction mixture was stirred for about 1 hr. A solid precipitate was filtered, dried and weighed to yield 2-{3-[4-(2- Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3- dione hydrochloride salt.

Yield: l.l gm (92%) IR (KBr): 1695.9 cm^{"1 1}H NMR (SOO MHz, DMSO-d₆): δ 1.25-1.27 (d, 6H), 1.62 (s, 6H), 1.91 (m, 2H), 2.22 (brs, 4H), 3.01-3.09 (m, 8H), 3.39-3.52 (m, 6H), 4.55-4.64 (m, IH)₃ 6.87-6.95 (m, 4H), 10.4 (brs, IH)

Mass (m/z): 440.1 (M⁺+l), The following compounds were prepared following the procedure of Example 2, step 2:

2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-hexahydro- isoindole-l,3-dione hydrochloride salt(Compound No. 18)

IR (KBr)I nOCo Cm^{"1 1}H NMR (300 MHz, DMSOd₆): δ 0.79-0.81 (m, 3H), 0.91-0.96 (m, 3H), 1.32-1.34 (d, 6H), 1.59-1.77 (m, 8H), 3.00-3.17 (m, 8H), 3.57-3.60 (m, 4H), 4.66-4.69 (m, IH), 6.97- 7.02 (m, 4H), 10.30 (brs, IH) Mass (m/z): 442.2 (M⁺+!),

(R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10-oxa-4- aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione hydrochloride salt (Compound No.20)

IR (KBr): 1696.8 cm^"1

¹H NMR (300 MHz, CDCl₃): δ 1.37-1.39 (d, 6H), 1.70 (s, 6H), 2.24-2.28 (m, 2H), 2.90 (s, 2H), 3.02 (m, 2H), 3.46-3.57 (m, 6H), 3.63-3.67 (m, 4H), 4.59-4.63 (m, IH), 6.30-6.32 (d, 2H), 6.87-7.09 (m, 4H), 12.78 (brs, IH) Mass (m/z): 454.1 (M⁺+l),

(R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10-oxa-4- aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione hydrochloride salt (Compound No.22)

IR (KBr): 1699.1 cm^"1

¹H NMR (300 MHz, CDCl₃): δ 1.41-1.43 (d, 6H), 1.71 (s, 6H), 2.15-2.16 (m, 2H), 3.01 (m, 2H), 3.29 (m, 2H), 3.47-3.74 (m, 8H), 3.93-3.96 (m, 2H), 4.67 (m, IH), 6.30 (brs, 2H), 6.75-7.14 (m, 4H), 13.22 (brs, IH) Mass (m/z): 454.2 (M⁺+l),

The following compounds are prepared similarly following the procedure of Example 2, step 2: 2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-3a,4,7,7a-tetrahydro- isoindole-l,3-dione hydrochloride salt (Compound No. 24),

4-[3-(4-(2-Methoxy-phenyl)-piperazin-l-yl)-propyl]-4-aza-tricyclo[5.2.1.0^!|:2,6*]decane- 3,5-dione hydrochloride salt (Compound No. 26),

Example 3: Preparation of 6-(3-[^'4-(^'2-Isopropoxy-phenylVpiperazin-l-yll-propyl>-2,2- dimethyl-hexahvdro-ri,31dioxolor4,5-flisoindole-5,7-dione (Compound No. 28^*) Step 1: Preparation of5,6-Dihydroxy-2-{3-[4-(2-isopropoxy-phenyl)-piperazin-l-ylJ- propyl}-hexahydro-isoindole-l,3-dione

To a solution of 2-[3-{4-(2-Isopropoxy-phenyl)-piperazin-l-yl}propyl]-3a,4,7,7a- tetrahydro-isoindole-1,3 dione (2.0 gm, 4.8 mmole) in ethanol (20 mL) was added potassium permanganate solution dropwise (1.54 gm, 9.7 mmole) at 0°C to 10°C. The reaction mixture was stirred for 5 to 10 hours. After the reaction was over the reaction mixture was filtered through celite pad; washed with ethanol (2x5 mL). Filtrate was concentrated on buchi; the residue thus obtained was purified on silica gel (60-120 mesh) column using dichloromethane-methanol mixture as eluent. Yield: 1.0 gm (48%)

Step 2: Preparation of 6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl] -propyl}-2,2- dimethyl-hexahydro-[l ,3] dioxolo[4,5-f]isoindole-5, 7 -dione (Compound No. 27)

To a solution of 5,6-Dihydroxy-2-{3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]- propyl}-hexahydro-isoindole-l,3-dione (0.6 gm, 1.34 mmole) in acetone (25 mL) was added p-toluene sulfonic acid monohydrate (0.025 gm, 0.13 mmole) and reaction mixture refluxed for 4 to 8 hours. Reaction mixture was concentrated on buchi to thick residue; water (20 mL) was added; extracted with ethyl acetate (2x15 mL). Combined organic layer was dried over anhydrous sodium sulphate; concentrated on buchi under vacuum to yield the crude product. The crude product was then purified on silica gel (60-120 mesh) column using dichloromethane-methanol mixture as eluent.

The following compound was prepared following the procedure of Example 3, step 2:

6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-[l,3]dioxolo[4,5- f]isoindole-5,7-dione (Compound No. 29) The following compounds are prepared following the procedure of Example 3, step 2:

6-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hex^'ahydro- [l,3]dioxolo[4,5-fjisoindole-5,7-dione (Compound No. 31)

2,2-Dimethyl-6-{3-[4-phenyl-piperazin-l-yl]-propyl}-hexahydro-[l,3]dioxolo[4,5- f]isoindole-5,7-dione (Compound No. 33)

Step 3: Preparation of 6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl] -propyl}-2,2- dimethyl-hexahydro-[l,3]dioxolo[4,5-f/isoindole-5, 7 -dione hydrochloride salt

To a solution of 6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-2,2- dimethyl-hexahydro-[l,3]dioxolo[4,5-fjisoindole-5,7-dione in isopropyl alcohol was added isopropyl alcohol/hydrochloric acid at 10-15 ⁰C and the reaction mixture was stirred for about 1 hr. A solid precipitate was filtered, dried and weighed to yield 2-{3-[4-(2- Isopropoxy-phenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3- dione hydrochloride salt.

Yield: 0.4 gm (61%) IR (KBr): 1698.6 cm^"1

¹H NMR (300 MHz, CDCl₃): δ 1.45-1.66 (m, 12H), 1.84 (m,2H), 2.26-2.33 (m, 4H), 3.09 (brs, 6H), 3.54-3.64 (m, 8H), 4.49-4.60 (m, 3H), 6.89-7.04 (m, 4H), 12.72 (brs, IH).

Mass (m/z): 486.4 (M⁺+!)

The following compound was prepared similarly following the procedure of Example 3, step 3:

6- {3-[4-(2-Isopropoxy-phenyl)-piperazin- 1 -yl]-propyl} -hexahydro-[ 1 ,3]dioxolo[4,5- fJisoindole-5,7-dione hydrochloride salt (Compound No. 30)

IR (KBr): 1766.3, 1694.3 cm^"1

¹H NMR (300 MHz, CDCl₃): δ 1.35-1.37 (d, 6H), 1.70-1.78 (m, 2H), 2.22-2.24 (m, 2H), 2.40-2.44 (m, 2H), 3.04-3.10 (m, 6H), 4.29 (s, 2H), 4.57-4.66 (m, 2H), 5.10 (s, IH), 6.85- 7.05 (m, 4H), 13.51 (brs, IH). Mass (m/z): 458 (M⁺+l)

The following compounds are prepared following the procedure of Example 3, step 3:

6-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride salt (Compound No. 32)

2,2-Dimethyl-6-{3-[4-phenyl-piperazin-l-yl]-propyl}-hexahydro-[l,3]dioxolo[4,5- fjisoindole-5,7-dione hydrochloride salt (Compound No. 34)

Example 4: Pharmacological Testing Receptor Binding Assay:

Receptor binding assays were performed using native α-1 adrenoceptors. The affinity of different compounds for α_la and oci_b 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 HCl 50 mM, NaCl 100 mM, 10 mM EDTA pH 7.4). The tissues were homogenized in 10 volumes of buffer (Tris HCl 50 mM, NaCl 100 mM, EDTA 10 mM, pH 7.4). The homogenate was filtered through two layers of wet guaze and filtrate was centrifuged at 50Og for 10 min. The supernatant was subsequently centrifuged at 40, 00Og for 45 min. The pellet thus obtained was resuspended in the same volume of assay buffer (Tris HCl 50 mM, EDTA 5 mM, pH 7.4) and were stored at -70 ⁰C 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 ⁰C for I hour. Non-specific binding was determined in the presence of 300 nM prazosin. The incubation was terminated by vaccum filtration over GF/B fibre filters. The filters were then washed with ice cold 50 mM Tris HCl buffer (pH 7.4). The filtermats were dried and bounded radioactivity retained on filters was counted. The IC₅₀ and Kd were estimated by using the non-linear curve- fitting program using G pad prism software. The value of inhibition constant Ki was calculated from competitive binding studies by using Cheng and Prusoff equation (Cheng and Prusoff, Biochem Pharmacol, 1973, 22:3099-3108), Ki = IC₅₀ /(1+L/Kd) where L is the concentration of [³H] prazosin used in the particular experiment.

The Ki (nM) values for α_la subtype adrenoceptors (Compound Nos. 1-10 tested) ranged from about 0.34 nM to about 8.6 nM, for example from about 0.34 nM to about 1.65 nM, or from about 0.34 nM to about 0.55 nM, while terazosin had a value of about 2.3 nM. The Ki (nM) values for Cc₁₁, subtype adrenoceptors (Compound Nos. 1-10 tested) ranged from about 33 nM to about 119 nM, or from about 33 nM to about 74 nM, or from about 33 nM to about 58 nM, while terazosin had a value of about 1.6 nM. Selectivity of cήbMa ranged from about 10 to about 119, for example from about 18 to about 119, or from about 58 to about 119, while terazosin had selectivity of about 0.7.

In vitro functional studies (In vitro alpha- 1 Adrenoceptor selectivity):

In order to study selectivity of action of the present compounds towards different alpha-1 adrenoceptor subtypes, the ability of Compound Nos. 5, 7, and 8 to antagonize alpha-1 adrenoceptor agonist induced contractile response of aorta (alpha-Id), prostate (alpha- Ia) and spleen (alpha- Ib) was studied. Aorta, prostate and spleen tissue were isolated from thipentane anaesthetized (« 300 mg/Kg) male wistar rats. Isolated tissues were mounted in organ bath containing Krebs Henseleit buffer of the following composition (mM): NaCl 118; KCl 4.7; CaCl₂ 2.5; MgSO₄. 7H₂O 1.2; NaHCO₃ 25; KH₂PO₄ 1.2; glucose 11.1. Buffer was maintained at 37 ⁰C and aerated with a mixture of 95% O₂ and 5% CO₂. A resting tension of 2 g (aorta and spleen) or 1 g (prostate) was applied to tissues. Contractile response was monitored using a force displacement transducer and recorded on chart recorders. Tissues were allowed to equilibrate for 1 and 1/2 hours. At the end of equilibration period, concentration response curves to norepinephrine (aorta) and phenylephirine (spleen and prostate) were obtained in the absence and presence of the tested compound (at concentration of 0.1, 1 and 10 μM). The pKβ values for α_la and α₁₍₁ subtype adrenoceptors ranged from about 8.67 to about 9.53 and about 7.82 to about 8.74, respectively.

Claims

We Claim:

1. Compounds having the structure of Formula I,

pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs and metabolites thereof, wherein:

R₁ and R₂ are independently hydrogen, C_1-4 alkyl, halogenated C_1-4 alkyl, aryl optionally substituted with one or more substituent(s) selected from halogens, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4 alkoxy, mercapto or C_1-4thioalkyl;

R₃ is hydrogen, C_1-4 alkyl, C_3-6 alkylene linked to 3a and 7a carbon atoms of isoindole ring; with the proviso that both the R₃ linked to 3a and 7a carbon atoms of isoindole ring are not simultaneously hydrogen;

R₄ and R₅ are independently hydrogen or C_1-4 alkyl; Z is no atom, oxygen, sulphur, nitrogen, or -(CH₂)_P-; p is an integer of from 0 to 4; with the proviso that, when Z is no atom, then either OfR₄ and R₅ is C_1-4 alkyl; is optional double bond; n is an integer of from 2 to 6; R is non-aromatic or aromatic ring system having 0 to 4 heteroatom(s) optionally substituted with substituent(s) selected from halogen(s), C_1-4 alkyl, halogenated C_{1- 4} alkyl, cyano, hydroxy, C_1-4 alkoxy, C_3-6 cycloalkoxy, niercapto, C_1-4 thioalkyl, NR₆R₇ or CONR₆R₇; R₆ and R₇ are independently hydrogen or alkyl; R is also aralkyl. 2. A compound of claim 1, wherein: R₁ and R₂ are independently hydrogen or C_1-4 alkyl; R₃ linked to 3a and 7a are hydrogen, C_1-4 alkyl or are a C_3-6 alkylene group; Z is no atom or oxygen; R₄ and R₅ are hydrogen or C_1-4 alkyl; and R is substituted monocyclic aromatic ring with C_1-4 alkoxy. 3. A compound of claim 1, wherein: R₁ and R₂ are independently hydrogen or methyl; R₃ linked to 3 a and 7a carbons of isoindole ring are hydrogen, methyl, or together form a cyclohexyl ring; Z is no atom or oxygen; R₄ and R₅ are hydrogen or methyl; and R is 2-isoproρoxyphenyl. 4. A compound selected from: (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl- 3a,4,7,7a-tefrahydro-isoindole-l,3-dione, (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl- 3a,4,7,7a-tetxahydro-isomdole-l,3-dione hydrochloride salt, (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl- 3a,4,7,7a-tetrahydro-isoindole- 1 ,3-dione, (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl- 3a,4,7,7a-tetrahydro-isoindole-l,3-dione hydrochloride salt, 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a- tetrahydro-isoindole-l,3-dione, 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a- tetrahydro-isoindole- 1 ,3-dione hydrochloride salt, 12-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-12-aza- tricyclo[4.4.3.0*l,6*]tridec-3-ene-ll,13-dione, 12-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-12-aza- tricyclo[4.4.3.0*l,6*]tridec-3-ene-l 1,13-dione hydrochloride salt, 2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a- tetrahydro-isoindole- 1 ,3-dione, 2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a- tetrahydro-isoindole- 1 ,3-dione hydrochloride salt, 3a-Methyl-2-[3-(4-phenyl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole- 1,3-dione, 3 a-Methyl-2-[3 -(4-phenyl-piperazin- 1 -yl)-propyl]-3 a,4,7,7a-tetrahydro-isoindole- 1 ,3-dione hydrochloride salt, 3a-Methyl-2-[3-(4-pyridin-2-yl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro- isoindole- 1,3-dione, 3 a-Methyl-2- [3-(4-pyridin-2-yl-piperazin- 1 -yl)-propyl]-3 a,4,7,7a-tetrahydro- isoindole- 1 ,3 -dione hydrochloride salt, 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6,-dimethyl-3a,4,7,7a- tetraliydro-isoindole-l,3-dione, 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6,-dimethyl-3a,4,7,7a- tetrahydro-isoindole- 1 ,3-dione hydrochloride salt, 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-hexahydro- isoindole- 1 ,3-dione, 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-hexahydro- isoindole- 1 ,3-dione hydrochloride salt, (R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10- oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione, (R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10- oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione hydrochloride salt, (R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piρerazin-l-yl]-propyl}-l,7-dimethyl-10- oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione, (R or S) 4-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-l,7-dimethyl-10- oxa-4-aza-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione hydrochloride salt, 2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-3a,4₅7,7a- tetrahydro-isoindole-l,3-dione, 2- {3 -[4-(2-Methoxy-phenyl)-piperazin- 1 -yl] -propyl} -5,6-dimethyl-3 a,4,7,7a- tetrahydro-isoindole- 1 ,3 -dione hydrochloride salt, 4-[3-(4-(2-Methoxy-phenyl)-piperazin-l-yl)-propyl]-4-aza- tricyclo[5.2.1.0*2,6*]decane-3,5-dione, 4-[3-(4-(2-Methoxy-phenyl)-piperazin-l-yl)-propyl]-4-aza- tricyclo[5.2.1.0*2,6*]decane-3,5-dione hydrochloride salt, 6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione, 6- {3-[4-(2-Isopropoxy-phenyl)-piperazin- 1 -yl]-propyl} -2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f|isoindole-5,7-dione hydrochloride salt, 6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro- [l,3]dioxolo[4,5-fjisoindole-5,7-dione, 6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride salt,

6-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione, 6-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hexahydro- [l,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride salt, 2,2-Dimethyl-6-{3-[4-phenyl-piperazin-l-yl]-propyl}-liexahydro-[l,3]dioxolo[4,5- f]isoindole-5,7-dione, 2,

2-Dimethyl-6-{3-[4-phenyl-piperazin-l-yl]-propyl}-hexahydro-[l,3]dioxolo[4,5- f]isoindole-5,7-dione hydrochloride salt, 6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}tetrahydro-3aH- [l,3]dioxolo[4,5-/]isomdole-2,5,7(4H^",6H)-trione, 6- {3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l -yl]propyl}tetrahydro-3aH- [l,3]dioxolo[4,5-/]isoindole-2,5,7(4/i^',6H)-trione hydrochloride salt, 110 6-{3-[4-(5-fluoro-2-isopropoxyphenyl)ρiperazin-l-yl]propyl}tetrahydro-3aH-

111 [l,3]dioxolo[4,5-/Jisoindole-5,7(4H,6H)-dione, 112

113 6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}tetrahydro-3aH-

114 [l,3]dioxolo[4,5-/Jisoindole-5,7(4H,6H)-dione hydrochloride salt, 115

116 6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}-2,2-

117 dimethyltetrahydro-3aH-[l,3]dioxolo[4,5-/]isoindole-5,7(4H,6H)-dione

118 hydrochloride salt, 119

120 6-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}-2,2-

121 dimethyltetrahydro-3aH-[l,3]dioxolo[4,5-/Jisoindole-5,7(4H,6H)-dione

122 hydrochloride salt, or 123

124 their pharmaceutically acceptable salts, pharmaceutically acceptable solvates,

125 enantiomers, diastereomers, N-oxides, prodrugs, polymorphs or metabolites.

1 5. A pharmaceutical composition comprising therapeutically effective amounts of one

2 or more compounds of claim 1, optionally together with one or

3 morepharmaceutically acceptable carriers, excipients, diluents or mixture thereof.

1 6. A method for treating a patient suffering from a disease or disorder mediated

2 through α_la and/or α₁₍₁ adrenergic receptor antagonists comprising administering to

3 said patient therapeutically effective amounts of one or more compounds of claim

4 1, optionally together one or more pharmaceutically acceptable carriers, excipients,

5 diluents or mixture thereof.

1 7. The method according to claim 6 wherein a disease or disorder is benign prostatic

2 hyperplasia (BPΗ) or lower urinary tract symptoms associated with or without

3 BPΗ.

1 8. The method according to claim 6 wherein compound causes minimal fall or no fall

2 in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.

1 9. A process for preparing a compound of Formula IV,

Formula IV pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, polymorphs or metabolites thereof, wherein:

R₃ is hydrogen, C_1-4 alkyl, C_3-6 alkylene linked to 3a and 7a carbon atoms of isoindole ring; with the proviso that both the R₃ linked to 3 a and 7a carbon atoms of isoindole ring are not simultaneously hydrogen; n is an integer of from 2 to 6;

R is non-aromatic or aromatic ring system having 0 to 4 heteroatom(s) optionally substituted with substituent(s) selected from halogen(s), C_1-4 alkyl, halogenated C_{1- 4} alkyl, cyano, hydroxy, C_1-4 alkoxy, C_3-6 cycloalkoxy, mercapto, Ci_-4thioalkyl, NR₆R₇ or CONR₆R₇;

R₆ and R₇ are independently hydrogen or alkyl; R is also aralkyl; which method comprises: reacting a compound of Formula II with a compound of Formula III (or XR₃X), wherein X is halogen,

III

Formula II

to form a compound of Formula IV.

10. A process for preparing a compound of Formula VII,

Formula VII pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites thereof, wherein: R₄ and R₅ are independently hydrogen or C_1-4 alkyl; Z is no atom, oxygen, sulphur, nitrogen, or -(CH₂)_P-; p is an integer of from 0 to 4; with the proviso that, when Z is no atom, then either OfR₄ and R₅ is C_1-4 alkyl; n is an integer of from 2 to 6; R is non-aromatic or aromatic ring system having 0 to 4 heteroatom(s) optionally substituted with substituent(s) selected from halogen(s), C_1-4 alkyl, halogenated C_{1- 4} alkyl, cyano, hydroxy, C_1-4 alkoxy, C_3-6 cycloalkoxy, mercapto, C_1-4 thioalkyl, NR₆R₇ or CONR₆R₇; R₆ and R₇ are independently hydrogen or alkyl; R is also aralkyl which method comprises: reacting a compound of Formula V with a compound of Formula VI

Formula V

to form a compound of Formula VII.

11. A process for preparing a compound of Formula IX,

Formula IX pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, polymorphs or metabolites thereof, wherein: R₁ and R₂ are independently hydrogen, C_1-4 alkyl, halogenated C_1-4 alkyl, aryl optionally substituted with one or more substituent(s) selected from halogens, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4 alkoxy, mercapto or C_1-4thioalkyl; n is an integer of from 2 to 6; R is non-aromatic or aromatic ring system having 0 to 4 heteroatom(s) optionally substituted with substituent(s) selected from halogen(s), C_1-4 alkyl, halogenated C_1- 4 alkyl, cyano, hydroxy, C_1-4 alkoxy, C_3-6 cycloalkoxy, mercapto, C_1-4 thioalkyl, NR₆R₇ Or CONR₆R₇; R₆ and R₇ are independently hydrogen or alkyl; R is also aralkyl; which method comprises: (a) oxidizing a compound of Formula II

o form a compound of Formula VIII,

Formula VIE

(b) treating the compound of Formula VIII with a compound of Formula _R2 >~ to form a compound of Formula IX.