ADRENERGIC RECEPTOR ANTAGONISTS
Field of the Invention
The present invention relates to alpha la and/or alpha Id adrenergic receptor antagonists. Compounds disclosed herein can function as alpha la and/or alpha Id adrenergic receptor antagonist and can be used for the treatment of a disease or disorder mediated through alpha 1a and/or alpha 1d adrenergic receptors, benign prostatic hyperplasia and the related symptoms thereof, and lower urinary tract symptoms associated with or without benign prostatic hyperplasia. Processes for the preparation of the disclosed compounds, pharmaceutical composition containing the disclosed compounds, and the methods of treating benign prostatic hyperplasia or related symptoms thereof, are also provided.
Background of the Invention
Benign prostatic hyperplasia (BPH) is a condition, which develops in elderly males and refers to the benign overgrowth of the stromal and epithelial elements of the prostate with aging. The symptoms of BPH vary, but the most common ones involve changes or problems with urination, such as hesitant, interrupted, weak stream or urgency and leaking or dribbling or more frequent urination, especially at night. Consequences of BPH can involve hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection.
There are two components of BPH, static and a dynamic component. The static component is due to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of the urine from the bladder. The dynamic component is due to increased smooth muscle tone of the bladder neck and prostate itself and is regulated by a -1 adrenergic receptor.
Currently, the most effective treatment for BPH is the surgical procedure of transurethral resection of the prostate (TURP), since it removes the obstructing tissue (C. Chappie's Br. Med. Journal 304: 1198-1199, 1992). It is a treatment, which is directed to the static and dynamic components of the BPH. However this surgical treatment is associated with rates of mortality (1%) and adverse event (incontinence 2-4%) infection 5-10 %, and impotence 5-10%. A noninvasive alternative treatment is therefore highly desirable. There are some drug therapies, which address the static component of this condition. Administration of finasteride is one such therapy, which is indicated for the treatment of symptomatic BPH.
This drug is a competitive inhibitor of the enzyme 5 a-reductase that is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland. Dihydrotestosterone appears to be the major mitogen for prostate growth, and agents, which inhibit 5 a-reductase reduce the size of the prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5-a reductase inhibitor and causes a marked decrease in serum and tissue concentrations of dihydrotestosterone, it is moderately effective in the treatment of symptomatic BPH. The effects of finasteride take 6-12 months to become evident and for many men the clinical development is minimal.
The dynamic component of BPH has been addressed by the use of adrenergic receptor blocking agents, which act by decreasing the smooth muscle tone within the prostate gland. A variety of α1a AR antagonists, for example, terazosin, doxazosin, prazosin, alfuzosin and tamulosin have been investigated for the treatment of symptomatic bladder outlet obstruction due to BPH. However, these drugs are associated with vascular side effects (e.g. postural hypertention, syncope, dizziness, headache etc) due to lack of selectivity of action between prostatic and vascular α1 adrenoceptor. There are several lines of evidence to suggest that selectivity for α1a adrenoceptor over α1b adrenoceptor will result in relative lack of vascular side effects, thus lead to a better tolerability. Mice deficient in α1b adrenoreceptors show diminished blood pressure response to phenylephrine injection compared to homozygous controls (Decreased blood pressure response in mice deficient of α1b adrenergic receptor. (Proc Natl Acad Sci USA 1997,94,11589-11594). In-vivo studies in healthy subjects comparison of α1a / α1d selective antagonists (for example, tamsulosin) or α1a selective antagonists (for example, urapidil) with non selective antagonists (for example,doxazosin, prazosin, or terazosin) under a variety of experimental conditions (e.g. involving the administration of exogenous agonist or release of endogenous agonist by cold stimulation) in several vascular beds including the skin circulation in finger tips, the dorsal hand vein, or with total peripheral resistance have been reported. (Eur J Clin Pharmacol, 1996, 49, 371-375; Naunyn Schmiedeberg's Arch Pharmacol 1996, 354, 557-561; Jpn J Pharmacol 1999, 80, 209-215; Br J Clin Pharmacol 1999, 47, 67-74). These studies have reported that an antagonist with high affinity for α1a or α1a/α1d can cause some degree of vasodilation but that it is much smaller than with non-subtype-selective α1a adrenoceptor antagonist. Further, there is increased vascular α1b adrenoceptor expression in elderly patients and thus α1a/α1d selective agents with selectivity over α1b adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia, which is generally a disease of old age.
Antagonism of both α1a adrenoceptor and α1d adrenoceptor is important to relieve lower urinary tract symptoms especially associated (suggestive of) with BPH. Targeting α1a adrenoceptor with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction whereas α1d adrenoceptor antagonism is important to target irritative symptoms.
Over the past decade, there has been an intensive search for selective α1a adrenoceptor antagonists for benign prostatic hyperplasia, which would avoid the cardiovascular side effects, associated with currently used drugs. Many selective antagonist have been described by Hieble et al in Exp opin Invest Drugs; 6, 367-387 (1997) and by Kenny et al., in J. Med. Chem.; 40, 1293-1325 (1995). Structure activity relationships in many of these structural series have been studied in details and numerous highly selective compounds have been identified. There are many description in the literature about the pharmacological activities associated with phenyl piperazines, Eur. J. Med. Chem. - Chimica Therapeutica, 12, 173-176 (1977), describes substituted trifluorometyl phenyl piperazines having cyclo-imido alkyl side chains shown below.
(Formula Removed)
Other related compounds which have been prepared as anxiolytic, neuroleptic, antidiabetic and anti-allergic agents are described in the following references:Yukihiro et al; PCT Appl. WO 98/37893 (1998),Steen et al; J. Med. Chem., 38, 4303-4308 (1995),Ishizumi et al. Chem. Pharm. Bult; 39 (9), 2288-2300 (1991),Kitaro et al; JP 02-235865 (1990),Ishizumi et al; US 4,598,078 (1086),New et. al; J. Med. Chem. 29, 1476-1482 (1986),Shigeru et. al; JP 60-204784 (1985),New et al, US 4,524, 206 (1985),Korgaonkar et al; J. Indian Chem. Soc, 60, 874-876 (1983).
However, none of the above mentioned references disclose or suggest the ai subtype selectivity profile of the compounds disclosed therein and thus their usefulness in the treatment of symptoms of benign prostate hyperplasia did not arise.
The synthesis of l-(4-arylpiperazin-l-yl)-co-[N- (a, co-dicarboximido)]-alkanes useful as uro-selective a,-adrenoceptor blockers are disclosed in US patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,559, 6,420,366, WO 00/05206, US patent appl. 2002/0156085
and WO 02/44151. These compounds had good α1-adrenergic blocking activity and selectivity.
Other reports describing selective α1a adrenoceptor antagonists are US 6,376,503, US 6,319,932, US 6,339,090, EP 711757, WO 99/42448, WO 99/42445, WO 98/57940, WO 98/57632, WO 98/30560 WO 97/23462, WO 03/084928 and WO 03/084541 all these patents are incorporated by reference herein in their entirety.
SUMMARY OF THE INVENTION
The present invention provides alpha la and/or alpha Id adrenergic receptor antagonists, which can be used for treatment of benign prostatic hyperplasia (BPH) or related symptoms thereof or lower urinary tract symptoms (LUTS) associated with or without BPH, 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 disclosed compounds and which may also contain pharmaceutically acceptable carrier, excipients or diluents, which can be used for the treatment of BPH or related symptoms thereof or LUTS with or without BPH.
Other objects will be set forth in accompanying description, which follows and in the part will be apparent from the description or may be learnt by the practice of the invention.
In accordance with one aspect, there are provided compounds having the structure of Formula I, ts pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites wherein:
A can be
R1 and R2 can be independently hydrogen, C1-4 alkyl, halogenated C1-4 alkyl, aryl optionally
substituted with one or more substituent(s) selected from halogens, C1-4 alkyl, halogenated
C1-4 alkyl, hydroxy, C1-4 alkoxy, mercapto or C1-4 thioalkyl, R3 can be hydrogen, C1-4 alkyl,
C6.7 cycloalkyl linked to 3a and 7a carbon atoms of isoindole ring with the provisio 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 C1-4 alkyl, X can be no atom, oxygen,
sulphur, nitrogen, or -(CH2)P- (wherein p is 0 to 4) with the provisio that, when X is no atom,
either ofR4 and R5 is C1-4 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), C1-4 alkyl, halogenated C1-4 alkyl, cyano, hydroxy, C1-4 alkoxy, C3-6 cycloalkoxy, mercapto, C1-4 thioalkyl, NR6R7 or CONR6R7 (wherein R6 and R7 are independently hydrogen or alkyl), R can also be aralkyl.
In accordance with a second aspect, there is provided a method for the treatment of a patient suffering from a disease or disorder mediated through alpha 1a and/or alpha 1d adrenergic receptor, comprising administering to a patient, a therapeutically effective amount of a compound disclosed herein.
In accordance with a third aspect, there is provided a method for the treatment of a patient suffering from benign prostatic hyperplasia (BPH) and related symptoms, comprising administering to a patient, a therapeutically effective amount of a compound disclosed herein.
In accordance with a fourth aspect, there is provided a method for the treatment of a patient suffering from lower urinary tract symptoms (LUTS) with or without BPH. LUTS may include, for example, irritative symptoms such as frequent urination, urgent urination, nocturia and unstable bladder contractions, obstructive symptoms such as hesitancy, poor stream, prolong urination, and feelings of incomplete emptying, comprising administering to a patient, a therapeutically effective amount of a compound disclosed herein.
In accordance with a fifth aspect, there is provided a process for the preparation of the compounds described herein.
In accordance with a sixth aspect, there is provided a method for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient, a therapeutically effective amount of a compound (or composition) described herein in combination with a bladder selective muscarinic receptor antagonist.
In accordance with a seventh aspect, there is provided a method for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient, a therapeutically effective amount of a compound (or composition) described herein in combination with a testosterone 5 alpha-reductase inhibitor.
In accordance with a eighth aspect, there is provided a method for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient, a therapeutically effective amount of a compound (or composition) described herein in combination with a bladder selective muscarinic receptor antagonist and optionally included testosterone 5 alpha-reductase inhibitor.
Compounds disclosed herein possess selective and potent α1a adrenoceptor antagonistic activity over the α1b 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 inpatient. Therefore, the present invention provides pharmaceutical compositions for treatment of a disease or disorder mediated through α1a adrenoceptor. Moreover, the disclosed compounds of the present invention can also be used for treatment of lower urinary tract symptoms. Compounds and compositions described herein can be administered orally, parenterally, subcutaneously, transdermally or topically.
The following definition apply to terms as used herein:
The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
The term "aryl" as used herein stands for an aromatic radical having 6 to 14 carbon atoms, example of aryl, but are not limited to, phenyl, naphthyl, anthryl and biphenyl, and the like.
The term "aralkyl" as used herein stands for an aryl radical having 7 to 14 carbon atoms which is bonded to an alkylene chain, example of aralkyl, but are not limited to, benzyl, naphthylmethyl, phenethyl and phenylpropyl, and the like.
The term "non-aromatic ring system" as used herein stands for 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" as used herein 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 a bonds, and are often rapidly interconverting at room temperature. Racemic mixtures are also encompassed within the scope of this invention.
Detailed Description of the Invention
The compounds described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds described herein may be prepared by the reaction sequence as shown in Schemes I, II and III of the accompanied drawings.
The compound of Formula IV can be prepared according to Scheme I, as shown in the accompanied drawings. Thus, a compound of Formula II is reacted with a compound of Formula R3X to give a compound of Formula IV (wherein n, R and R3 are the same as defined earlier).
The reaction of a compound of Formula II with a compound of Formula III can be carried out in a suitable solvent, for example, acetonitrile or tetrahydrofuran.
The reaction of a compound of a Formula II with a compound of Formula III can be carried out in the presence of a base, for example, lithium diisopropylamine or n-butyl lithium.
The compound of Formula VII can be prepared according to Scheme II, as shown in the accompanied drawings. Thus, a compound of Formula V is reacted with a compound of Formula VI to give a compound of Formula VII (wherein n, R, R4 and R5 are the same as defined earlier).
The reaction of a compound of Formula V with a compound of Formula VI to give a compound of Formula VII can be carried out in a suitable solvent, for example, xylene, toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile or benzene.
The compound of Formula IX can be prepared according to Scheme III, as shown in the accompanied drawings. Thus, a compound of Formula II is reacted with a suitable
oxidizing agent (wherein n and R are the same as defined earlier) to give a compound of
Formula VIII, which on reaction with a compound of Formula gives a compound of
Formula IX.
The reaction of a compound of Formula II with a suitable oxidizing agent, for example, potassium permangnate or potassium dichromate to give a compound of Formula VIII can be carried out in a suitable solvent, for example, methanol, ethanol or isopropanol.
The reaction of a compound of Formula VIII with a compound of Formula to
give a compound of Formula IX can be carried out in the presence of a suitable organic inorganic acid, for example, p-toluene sulphonic acid, borontrifluoride or hydrochloric acid.
In 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.
An illustrative list of compounds of the invention are listed below (also shown in Table I):
(R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl-3a,4,7,7a-tetrahydro-isoindole-l,3-dione (CompoundNo. 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-tetrahydro-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-l 1,13-dione (Compound No. 7),
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),
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-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 (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-l,3-dione (Compound No. 13),
3a-Methyl-2-[3-(4-pyridin-2-yl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole-l,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-l,3-dione (CompoundNo. 15),
2-{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. 16),
2 - {3 -[4-(2-Isopropoxy-phenyl)-piperazin-1 -yl] -propyl} -5,6-dimethyl-hexahydro-isoindole-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),
Table 1: wherein n = 3

(Table Removed)
(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-l,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-1 -yl]-propyl} -2,2-dimethyl-hexahydro-[l,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride salt (CompoundNo. 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-1 -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-1 -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-l-yl]-propyl}-hexahydro-[l,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride salt (Compound No. 34), or
their pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites.
(Table Removed)
The compounds described herein have got pharmacological activity, therefore may be administered to an animal for treatment orally, parenterally, topically, rectally, internasally, subcutaneously or by transdermally. The pharmaceutical compositions of the present invention comprise a pharmaceutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filter, diluent, encapsulating material or formulation auxiliary of any type. Solid form preparation for oral administrations, include capsules, tablets, pills, powder, granules cathets and suppository. For solid form preparation, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate and/or a filler or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid; binders such as carboxymethylcellulose, alginates, gelatins, polyvinylpyrolidinone, sucrose, acacia; disintegrating agents such as a agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates and sodium carbonate, absorption accelators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol, monostearate; adsorbents such as kaolin; lubricants such as talc, calcium

(Table Removed)
Table 2: wherein n = 3

(Table Removed)
stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate and mixture thereof.
In case of capsules, tablets, pills, the dosage form may also comprise buffering agents. The solid preparation of tablets, capsules, pills, granules can be prepared with coating and shells such as enteric coating and other coatings well known in the pharmaceutical formulating art.
Liquid form preparation for oral administration includes pharmaceutically acceptable emulsions, solution, suspensions, syrups and elixirs. For liquid form preparation, the active compound is mixed with water or other solvent, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed, groundnut, corn, germ, olive, castor and Sesamie oil), glycerol, and fatty acid esters of sorbitan and mixture thereof. Besides inert diluents, the oral composition can also include adjuvant such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.
Injectable preparations such as sterile injections, aqueous or oleaginous suspensions may be formulated according to the art using suitable dispersing or wetting and suspending agents. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride.
Dosage form for tropical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhalants or patches. The active compound is admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservative or buffer as may be required. Ophthalmic formulation, eardrops, eye ointments, powder and solution are also contemplated as being within the scope of this invention.
The pharmaceutical preparation may be in unit dosage form. In such form, the preparation may be subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be packaged preparation, the package containing discrete capsules, powders, in vials or ampoules and ointments, capsules, cachet, tablet, gel cream itself or it can be the appropriate number of any of there packaged forms.
The formulation of the present invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known to the art.
The dosages of the compounds described herein, bladder selective muscarinic receptor antagonist and 5 alpha-reductase inhibitor are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the compounds described herein, bladder selective muscarinic receptor antagonist and 5 alpha-reductase inhibitor may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In accordance with the method of this invention, the individual component of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
Examples set forth below demonstrates the general synthetic procedure for the preparation of the representative compounds. The examples are provided to illustrate particular aspect of the disclosure and do not constrained the scope of the present invention as defined by the claims.
Experimental Details
Example 1: Preparation of (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-vl"|-propyl|-3a-methyl-3a,4J,7a-tetrahydro-isoindole-l,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 -78°C under N2 atmosphere was added dropwise 2-[3-{4-(2-isopropoxyphenyl)piperazin-l-yl]propyl]-3a,4,7,7a-tetrahydro-lH-isondole-l,3(2H) dione (1.0 gm, 2.4 mmole) dissolved in 5 ml dry tetrahydrofuran. Reaction mixture was stirred for 2 to 4 hours (allow the temperature to come at an ambient temperature). The reaction mixture was cooled again to -78 °C, to it methyl iodide (0.345 gm, 2.4 mmole) was added dropwise and reaction mixture stirred for 2 to 4 hours (allow the temperature of reaction mixture to come 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. It was purified on silica gel (60-120 mesh) column using dichloromethane
methanol as eluent.
The following compounds were prepared
(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*l,6*] tridec-3-ene-ll,13-dione (Compound No. 7)
The following compounds are prepared
2-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-3a,7a-dimethyl-3a,4,7,7a-tetrahydro-isoindole-l,3-chone (CompoundNo. 9)
3a-Methyl-2-[3-(4-phenyl-piperazin-l-yl)-propyl]-3a,4,7,7a-tetrahydro-isoindole-l,3-dione (Compound No. 11)
3 a-Methyl-2- [3 -(4-pyridin-2-yl-piperazin-1 -yl)-propyl]-3 a,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
An equimolar quantity of isopropyl alcohol and hydrochloric acid was added to (R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl-3a,4,7,7a-tetrahydro-isoindole-l,3-dione. The solid, which precipitates, was then filtered.
Yield: 0.56 gm (54%)
IR(KBr): 1692.2 C1-4"1
'H NMR (300 MHz, CDC13): 8 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++l)
The following compounds were prepared similarly
(R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-mefhyl-3a,4,7,7a-tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 4)
IR(KBr): 1689.9 C1-4"1
'H NMR (300 MHz, CDC13): 5 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 (NT+1)
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 C1-4"1
'H NMR (300 MHz, CDC13): 5 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 C1-4"1
'H NMR (300 MHz, CDC13): 5 1.36-1.46 (m, 8H), 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 similarly
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-l,3-dione hydrochloride salt (Compound No. 14)
Example 2: Preparation of 2-{3-[4-(2-Isopropoxv-phenyl)-piperazin-l-yl]-propyl}-5,6,-dimethyl-3aA7Ja-tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 16)
Step 1: Preparation of 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yI]-propyl}-5,6,-dimethyl-3a,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 and was purified on silica gel (60-120 mesh) column using dichloromethane- methanol as eluent.
The following compounds were prepared
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
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 of 2-{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)
An equimolar quantity of isopropyl alcohol and hydrochloric acid was added to 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6,-dimethyl-3a,4,7,7a-tetrahydro-isoindole-1,3-dione. The solid, which precipitates, was then filtered.
Yield: l.lgm(92%)
IR(KBr): 1695.9 C1-4"1
'H NMR (300 MHz, DMSO-d6): § 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), 6.87-6.95 (m, 4H), 10.4 (brs,
IH)
Mass(m/z): 440.1 (M++l)
The following compounds were prepared similarly
2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6-dimethyl-hexahydro-isoindole-1,3-dione hydrochloride salt(Compound No. 18)
IR(KBr): 1700.6 C1-4"1
'H NMR (300 MHz, DMSO-d6): 5 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++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.20)
IR(KBr): 1696.8 C1-4"1
'H NMR (300 MHz, CDCI3): 8 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 C1-4"1
'H NMR (300 MHz, CDC13): 5 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
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-Isopropoxv-phenvl)-piperazin-l-vl"|-propvl|-2,2-dimethyl-hexahydro-[l,31dioxolo[4,5-f|isoindole-5,7-dione (Compound No. 28)
Step 1: Preparation of 5,6-Dihydroxy-2-{3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-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: 1.0gm(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 compound was purified on silica gel (60-120 mesh) column using dichloromethane-methanol mixture as eluent. The following compound was prepared
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
6-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hexahydro-[l,3]dioxolo[4,5-f]isoindole-5,7-dione (CompoundNo. 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-[ 1,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride salt
An equimolar quantity of isopropyl alcohol and hydrochloric acid was added to 6-{3-
[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hexahydro-[l,3]dioxolo[4,5-
f]isoindole-5,7-dione. The solid, which precipitates, was then filtered.
Yield: 0.4gm(61%)
IR(KBr): 1698.6 C1-4"'
'H NMR (300 MHz, CDC13): 5 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, 1H).
Mass (m/z): 486.4 (M++l)
The following compound was prepared similarly
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)
IR(KBr): 1766.3, 1694.3 C1-4"1
'H NMR (300 MHz, CDC13): 5 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, 1H), 6.85-7.05 (m,4H), 13.51 (brs, 1H).
Mass (m/z): 458 (M +1)
The following compounds are prepared similarly
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 hydrochloride salt (Compound No. 34)
Pharmacological testing
Receptor Binding Assay: Receptor binding assays were performed using native α-1 adrenoceptors. The affinity of different compounds for α1a and α1b 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 HC1 50 mM, NaCl 100 mM, 10 mM EDTA pH 7.4). The tissues were homogenized in 10 volumes of buffer (Tris HC1 50 mM, NaCl 100 mM, EDTA 10 mM, pH 7.4). The homogenate was filtered through two layers of wet guaze and filtrate was centrifuged at 500g for 10 min. The supernatant was subsequently centrifuged at 40, OOOg for 45 min. The pellet thus obtained was resuspended in the same volume of assay buffer (Tris HC1 50 mM, EDTA 5 mM, pH 7.4) and were stored at -70 °C until the time of assay.
The membrane homogenates (150-250 µg protein) were incubated in 250 u.1 of assay buffer (Tris HC1 50 mM, EDTA 5 mM, pH 7.4) at 24-25 °C for I hour. Non-specific binding was determined in the presence of 300 nM prazosin. The incubation was terminated by vaccum filtration over GF/B fibre filters. The filters were then washed with ice cold 50 mM Tris HC1 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 [ H] prazosin used in the particular experiment. The Ki (nM) values for α1a and otib subtype adrenoceptors range from 0.34 to 8.6 and 33 to 119, respectively.
In vitro functional studies (In vitro alpha-1 Adrenoceptor selectivity): In order to study selectivity of action of the present compounds towards different alpha-1 adrenoceptor subtypes, the ability of these compounds to antagonize alpha-1 adrenoceptor agonist induced contractile response of aorta (alpha-Id), prostate (alpha-la) and spleen (alpha-lb) was studied. Aorta, prostate and spleen tissue were isolated from thipentane anaesthetized (~ 300 mg/Kg) male wistar rats. Isolated tissues were mounted in organ bath containing Krebs Henseleit buffer of the following composition (mM): NaCl 118; KC1 4.7; CaCl2 2.5; MgS04. 7H20 1.2; NaHC03 25; KH2P04 1.2; glucose 11.1. Buffer was maintained at 37 °C and aerated with a mixture of 95% 02 and 5% C02. 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 uM). The pKe values for ct]a and aid subtype adrenoceptors range from 8.67 to 9.53 and 7.82 to 8.74, respectively.

WE CLAIM:
1. A compound having the structure of Formula I, its pharmaceutically acceptable acid
addition salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides,
polymorphs or metabolite, wherein:
A can be
(Formula Removed)
R1 and R2 are independently hydrogen, C1-4 alkyl, halogenated C1-4 alkyl, aryl
optionally substituted with one or more substituent(s) selected from halogens, C1-4
alkyl, halogenated C1-4 alkyl, hydroxy, C1-4 alkoxy, mercapto or C1-4 thioalkyl, R3 is
hydrogen, C1-4 alkyl, C6-7 cycloalkyl linked to 3a and 7a carbon atoms of isoindole
ring with the provisio that both the R3 linked to 3a and 7a carbon atoms of
isoindole ring can not be simultaneously hydrogen, R4 and R5 are independently
hydrogen or C1-4 alkyl, X is no atom, oxygen, sulphur, nitrogen, or -(CH2)P-
(wherein p is 0 to 4) with the provisio that, when X is no atom, either of R4 and R5 is
C1-4 alkyl, is optionaldouble 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 substiruent(s) selected from halogen(s), C1-4 alkyl, halogenated C1-4 alkyl, cyano, hydroxy, C1-4 alkoxy, C3-6 cycloalkoxy, mercapto, C1-4 thioalkyl, NR6R7 or CONR6R7 (wherein R6 and R7 are independently hydrogen or alkyl), R can also be aralkyl.
2. A compound according to claim 1 wherein R1 and R2 are both hydrogen.
3. A compound according to claim 1 wherein R1 and R2 are C1-4 alkyl.
4. A compound according to claim 1 wherein R1 and R2 are both methyl.
5. A compound according to claim 1 wherein R3 linked to 3a and 7a is hydrogen and C1-4 alkyl.
6. A compound according to claim 1 wherein R3 linked to 3a and 7a carbons of isoindole ring are, respectively hydrogen and methyl.
7. A compound according to claim 1 wherein R3 linked to 3 a and 7a carbons of isoindole ring are both methyl.
8. A compound according to claim 1 wherein R3 linked to 3 a and 7a carbons of isoindole ring together form a cyclohexyl ring.
9. A compound according to claim 1 wherein X is no atom, either of R4 and R5 is C1-4 alkyl.
10. A compound according to claim 1 wherein X is no atom, R4 and R5 are respectively, methyl and hydrogen.
11. A compound according to claim 1 wherein X is oxygen, R4 and R5 are respectively, hydrogen and C1-4 alkyl.
12. A compound according to claim 1 wherein X is oxygen, R4 and R5 are respectively, hydrogen and methyl.
13. A compound according to claim 1 wherein R is aromatic ring substituted with C1-4 alkoxy.
14. A compound according claim 1 wherein R is monocyclic aromatic ring substituted with C1-4 alkoxy.
15. A compound according to claim 1 wherein R is 2-isopropoxyphenyl.
16. A compound namely:
(R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-methyl-3a,4,7,7a-tetrahydro-isoindole-l,3-dione,
(R or S) 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a-mefhyl-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,
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,
2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6,-dimethyl-3a,4,7,7a-tetrahydro-isoindole-1,3-dione,
2- {3 -[4-(2-Isopropoxy-phenyl)-piperazin-1 -yl] -propyl} -5,6-dimethyl-hexahydro-isoindole-1,3-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,
(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,
6-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-2,2-dimethyl-hexahydro-[l,3]dioxolo[4,5-f]isoindole-5,7-dione, or
6- {3 - [4-(2-Isopropoxy-phenyl)-piperazin-1 -yl]-propyl} -hexahydro-[l,3]dioxolo[4,5-f]isoindole-5,7-dione, or
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, N-oxides, polymorphs or metabolites.
A compound namely:
(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,
(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 hydrochloride salt,
12- {3 -[4-(2-Isopropoxy-phenyl)-piperazin-1 -yl] -propyl} -12-aza-tricyclo[4.4.3.0*l,6*]tridec-3-ene-l 1,13-dione hydrochloride salt,
2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-propyl}-5,6,-dimethyl-3a,4,7,7a-tetrahydro-isoindole-l,3-dione hydrochloride salt,
2- {3 -[4-(2-Isopropoxy-phenyl)-piperazin-1 -yl] -propyl} -5,6-dimethyl-hexahydro-isoindole-l,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 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 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 hydrochloride salt, or
6- {3 -[4-(2-Isopropoxy-phenyl)-piperazin-1 -yl] -propyl} -hexahydro-[l,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride salt.
A pharmaceutical composition comprising a therapeutically effective amount of the compound as defined in the preceding claims optionally together with pharmaceutically acceptable carriers, excipients or diluents.
19. A method for treatment of a patient suffering from a disease or disorder mediated through alpha la and/or alpha 1d adrenergic receptor, comprising administering to said patient a therapeutically effective amount of a compound of any one of the claim 1-17.
20. A method for treatment of a patient suffering from disease or disorder mediated through alpha 1a and/or alpha 1d adrenergic receptor, comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition according to claim 18.
21. The method according to claim 19 or 20 wherein a disease or disorder is benign prostatic hyperplasia.
22. The method according to claim 19 or 20 wherein compound causes minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
23. A method for the preparation of a compound having the structure of Formula IV,
(Formula Removed)
its pharmaceutically acceptable acid addition salts, pharmaceutically acceptable
solvates, enantiomers, diastereomers, N-oxides, polymorphs or metabolites, which
method comprises:
reacting a compound of Formula II with a compound of Formula III o
(Formula Removed)
to give a compound of Formula IV (wherein n, R3 are R are the same as defined in claim 1)
24. The method according to claim 23 wherein the reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IV is carried out in a suitable solvent selected from the group comprising of acetonitrile and tetrahydrofuran.
25. The method according to claim 24 wherein the reaction is carried out in tetrahydrofuran.
26. The method according to claim 23 wherein the reaction of a compound of a Formula II with a compound of Formula III is carried out in the presence of a strong base selected from the group comprising of lithium diisopropylamine and n-butyl lithium.
27. The method according to claim 26 wherein the reaction is carried out in the presence of lithium diisopropylamine.
28. A method for the preparation of a compound having the structure of Formula VII,
(Formula Removed)
its pharmaceutically acceptable acid addition salts, pharmaceutically acceptable
solvates, stereoisomers, N-oxides, polymorphs or metabolites which method
comprises:
reacting a compound of Formula V with a compound of Formula VI
(Formula Removed)
to give a compound of Formula VII (wherein R4, R5, X, n and R are the same as defined in claim 1)
29. The method according to claim 28 wherein the reaction of a compound of Formula V with a compound of Formula VI to give a compound of Formula VII is carried out in a suitable solvent selected from the group comprising of xylene, toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile and benzene.
30. The method according to claim 29 wherein the reaction is carried out in toluene.
A method for the preparation of a compound having the structure of Formula IX,(Formula Removed)

its pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, polymorphs or metabolites, which method comprises: oxidizing a compound of Formula II to give a compound of Formula
(Formula Removed)
which on treatment with a compound of Formula gives a compound of Formula IX (wherein R1, R2 n and R ate the same as defined in claim 1).
32. The method according to claim 31 wherein the reaction of a compound of Formula II to give a compound of Formula VIII is carried out with an oxidizing agent selected from the group consisting of potassium permanganate or potassium dichromate.
33. The method according to claim 32 wherein the reaction is carried out with potassium permanganate.
34. The method according to claim 31 wherein the reaction of a compound of Formula II is carried out in a suitable solvent selected from the group consisting of methanol, ethanol and isopropanol.
35. The method according to claim 34 wherein the reaction is carried out in ethanol.
36. The method according to claim 31 wherein the reaction of a compound of
Formula VIII with a compound of Formula is carried out in the presence of an organic or inorganic acid selected from the group comprising of p-toluene sulphonic acid, borontrifluoride and hydrochloric acid.
37. The method according to claim 36 wherein the reaction is carried out in the presence of p-toluene sulphonic acid.
38. The methods for the preparation of compounds of Formula IV, VII and IX substantially as herein described and illustrated by example herein.