NZ509388A

NZ509388A - Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers

Info

Publication number: NZ509388A
Application number: NZ509388A
Authority: NZ
Inventors: Sanjay Jain; Anita Mehta; Anil Kumar Saxena; Jang Bahadur Gupta; Nitya Anand; Neelima Sinha
Original assignee: Ranbaxy Lab Ltd
Priority date: 1998-07-21
Filing date: 1999-07-16
Publication date: 2003-12-19
Also published as: AU763541B2; PL345562A1; BR9912318A; EP1097134A1; MXPA01000637A; AU4641099A; HUP0102980A3; CA2338317A1; HUP0102980A2; SK932001A3; WO2000005205A1

Abstract

Compounds of formula (I), wherein: Y is O, Q is CH, X, Z and Z' are independently CH or N, m is 0-3, n is 0-4, R1 and R2 are independently H, F, CL, Br, OCH3, OC2H5, OCH2CF3, CH3, C2H5, CF3, isopropyloxy, or cyclopropyl, R3 is H, R4 and R5 are H or phenyl. The compounds are used in the manufacture of medicaments for the treatment of vascular disease, congestive heart failure or hypertension.

Description

New Zealand Paient Spedficaiion for Paient Number 509388 5093 88 ARYLPIPERAZINE DERIVATIVES USEFUL AS UROSELECTIVE ALPHA 1-ADRENOCEPTOR BLOCKERS L. Field of the Invention The present invention relates to certain novel piperazine derivatives having protracted uro-selective a,-adrenoceptor antagonistic activity exceeding those of previously described compounds. The compounds of the present invention hold promise for treating benign prostatic hyperplasia (BPH). This invention also relates to methods for making the novel 10 compounds, pharmaceutical compositions containing the compounds, and methods of treating benign prostatic hyperplasia using the compounds. 2. Description of the Related Art A review in J.Med.Chem.. 1997, V.40, No.9, pp.1292-1315, describes the most important 15 pharmacological options available at present in the treatment of benign prostatic hyperplasia. The two most successful therapies are based on a-adrenergic receptor antagonism and androgen levels modulation by 5a-reductase inhibitors. 5a-reductase inhibitors are of limited effectiveness in terms of immediate symptomatic and urodynamic relief, a,-antagonists appear to be much more effective and provide immediate subjective symptomatic improvements and are therefore the 20 preferred modalities of treatment in the control of benign prostrate hypertrophy. a,-adrenoceptors are also present in blood vessels and play an important role in the regulation of blood pressure.

CONFIRMATION COPY Thus, a,-adrenoceptor antagonists are of particular importance as they were originally developed as antihypertensive agents and are likely also to have a beneficial effect on lipid dysfunction and insulin resistance, which are commonly associated with essential hypertension.

The more important of the a,-adrenoceptor antagonists which are currently used in the management of BPH are shown below.

NH, oc/OO TERAZOSIN (RK-)-TAMSULOSIN NH, ALFUZOSIN However, most of these known drugs are associated with vascular side effects (e.g., postural hypertension, syncope, dizziness, headaches, etc.) due to lack of selectivity of action between prostatic and vascular ai-adrenoceptors. Clearly, ai-adrenoceptor antagonists which have inherently greater selectivity for prostatic oc,-adrenoceptors offer the potential of increased urodynamic benefits. This underscores the importance of the discovery of prostate-selective ar adrenoceptor antagonists which will confer urodynamic improvement without the side effects associated with existing drugs.

Recently, it has been demonstrated that the prostate tissue of higher species like man and dog is overvalued by low affinity aiA-adrenoceptor subtype. This makes it possible to develop 10 agents with selective action against these pathological urodynamic states. The present invention is directed to the development of novel oa-antagonists, namely, a new class of piperazine compounds, with greater selectivity of action against ocia adrenoceptors and which would thus offer selective relief for prostate hypertrophy as well as essential hypertension.

There are many descriptions in the literature of the pharmacological activities associated 15 with phenyl piperazines. Eur. J. Med. Chem.-Chimica Therapeutica , 1977, V. 12, No. 2, pp. 173-176, describes substituted trifluoromethyl phenyl piperazines having cyclo-imido alkyl side chains shown below as anorectic agents with no CNS side effects.

O R N V N—(CH^n-N y V GF3 The synthesis and pharmacology of some 2-[3-(4-aryl-l-piperazinyl)propyl]-l//-benzrde1isoquinolin-1.3-f2//)-diones/2.5-pvrrolidinediones (J. Indian Chem. Soc.. 1986, V. LXIII, pp. 529-530), ofN-(N4-aryl-N'-piperozinylmethyl)-4-(4'-methoxyphenyl)piperidine-2,6-diones (J. Indian Chem. Soc.. 1978, v. LV, pp.819-821), and of N-(N4-aryipiperazinylalkyl)- phthalimides 5 (J. Indian Chem. Soc.. 1979, V. LVI, pp. 1002-1005), as shown below, have been reported. The compounds were shown to exhibit antihypertensive and CNS depressant activity in experimental animals.

However, in those papers there is no mention of the adrenoceptor blocking activity of 20 these compounds, and thus their usefulness in the treatment of benign prostate hyperplasia did not arise. 4 The earlier synthesis of various l-(4-aryl-piperazin-l-yl)-3-(2-oxo-pyrrolidin-l-yl/piperidin-l-yl) alkanes and their usefulness as hypotensive and antischemic agents is disclosed in unpublished Indian patent applications DEL 496/95 (March 3, 1995), DEL/500/95 (March 21, 1995) and DEL/96/96 (March 29, 1996) by the inventors herein. These compounds had low a(-5 adrenergic blocking activity (pKi - 6 as compared to >8 of the known a,-antagonists such as prazosin), and practically no adrenoceptor sub-class selectivity for a1A vs. a1B or a1D adrenoceptors. It has now been discovered that structural modification of these compounds from lactam to dioxo compounds, i.e., from 2-oxopyrrolidin to 2,5- dioxopyrrolidin and 2,6-dioxopiperidine, enhances the adrenoceptor blocking activity, and also greatly increases the 10 selectivity for a,A in comparison to aIB-adrenoceptor blocking activity, an essential requirement for compounds to be good candidates for treatment of BPH. 3i Objects of the Invention An object of the present invention, therefore, is to provide novel arylpiperazine 15 derivatives that exhibit significantly greater a,A- adrenergic blocking potency than available with the known compounds in order to provide specific treatment for benign prostatic hyperplasia.

It is also an object of the invention to provide a method for synthesis of the novel compounds.

It is a further object of the invention to provide compositions containing the novel 20 compounds which are useful in the treatment of benign prostatic hyperplasia. 4. Summary of the Invention The above-mentioned objectives are achieved by a novel class of piperazine derivatives of general Formula I below I (Cfiyn—CH- r3 -CH2—N X \ / Tiff Ri r2 wherein Y is O or S; Q, X, Z and Z' are independently CH or N; m=0-3; n= 0-4; R„ R2 are independently selected from: H, F, CI, Br, OCH3, OCjHj, OCH2CF3, SCF3, CH3, CjHj, CF3, isopropyloxy, and cyclopropyl; R3 is H, R^, OH or OR<; R^ is a substituted or unsubstituted alkyl chain containing 1-6 carbon atoms; and R^, R^ are H, C,.3 alkyl, substituted or unsubstituted phenyl, or a 5-membered spiro ring. Preferably, R, is H, R2 is H, CI or CF3, R3, R,, and Rj = H, Y = O and Q = CH when m=0 and n=l; or R, is H, R2 is OCH3, R3, R, and Rs = H, Y = O and Q = CH when m = 0 and n = 2.

Compounds within the scope of Formula I but having the structure of Formula II below 6 wherein n, X, Z, Z', R'i, R2 and R3 are as defined for Formula I and wherein m' = 1-4, are preferred as selective and potent aw-adrenoceptor antagonistic activity over the am- and aiD-adrenoceptors. In Formula II, preferably Ri is H, R2 is H, CI or CF3, and R3 is H when m' = 1 and n = 1; or Ri is H, R2 is OCH3, and R3 is H when m' = I and n = 2.

The present invention also provides pharmaceutical compositions for the treatment of benign prostatic hyperplasia. These compositions comprise an effective amount of at least one of the above compounds of Formula I, or preferably of Formula n, and/or an effective amount of at least one physiologically acceptable acid addition salt thereof, with a phaimaceutically acceptable carrier.

An illustrative list of particular compounds of the invention is given below: Compound Chemical Name No. 1. l-[4-(4-FluorophenyI)piperazin-l-yl]-3-(2,5-dioxopyrrolidin-l-yl)propane 2. l-[4-(2-MethoxyphenyI)piperazm-l-yl]-3-(2,5-dioxopyrrolidin-l-yl)propane 3. l-[4-(3-Trifluoromethylphenyl)piperazin-l-yl]-3-(2,5-dioxopyrroIidin-l-yl)propane 4. l-[4-(2-PyridyI)piperazin-l-yl]-3-(2,5-dioxopyrroIidin-l-yl)propane . l-[4-(3-ChlorophenyI)piperazm-l-yl]-3-(2,5-dioxopyrrolidin-l-yl)propane 6. l-[4-(2-Pyrimidyl)piperazin-l-yl]-3-(2,5-dioxopyrroIidin-l-yl)propane 7. l-[4-(3,4-Dimethylphenyl)piperazin-l-yl]-3-(2,5-dioxopyrroIidin-l-yl)propane 8. l-[4-(Phenylpiperazin)-l-yl]-3-(2,5-dioxopyrroIidin-l-yI)propane 9. l-[4-(2-MethoxyphenyI)piperazin-l-yI]-4-(2,5-dioxopyrroIidin-l-yI)butane . l-[4-(2-MethoxyphenyI)piperazin-l-yI]-2-(2,5-dioxopyrroIidiii-l-yl)ethane 11. l-[4-(3-MethoxyphenyI)piperazin-l-yI]-3-(2,5-dioxopyrroIidin-l-yI)propane 12. l-[4-(4-MethoxyphenyI)piperazin-l-yI]-3-(2,5-dioxopyrroIidin-l-yI)propane 13. l-[4-(2-Methoxyphen.yl)piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yl)propane 14. l-l4-(4-Fluorophenyl)piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yl)propane . l-[4-(4-Chlorophenyl)piperazin-l-yl]-3-(2,6-dioxopiperidm-l-yl)propane 16. l-[4-(3-TrifluoromethyIphenyI)piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yI)propane 17. l-[4-(2-FIuorophenyI)piperaziii-l-yI]-3-(2,6-dioxopiperidm-l-yl)propane 18. l-[4-(2-MethylphenyI)piperazin-l-yI]-3-(2,6-dioxopiperidin-l-yl)propane 19. l-[4-(2-Pyridyl)piperaziii-l-yI)-3-(2,6-dioxopiperidm-l-yl)propaiie . l-[4- (3-Chlorophenyl)piperazin -l-yI]-3-(2,6-dioxopiperidin-l-yI)propane 21. l-[4-(3,4-DimethyIphenyI)piperaziii-l-yII-3-(2,6-dioxopiperidin-l-yI)propane 22. l-[4-(2-Pyrimidyl)piperaziii-l-yI]-3-(2,6-dioxopiperidin-l-yl)propaae 23. l-[4-(3-Methoxyphenyl)piperaziii-l-yI]-3-(2,6-dioxopiperidin-l-yl)propane 24. l-[4-(4-MethoxyphenyI)piperaziii-l-yI]-3-(2,6-dioxopiperidm-l-yI)propaiie . l-[4-(2-MethoxyphenyI)piperazin-l-yI]-4-(2,6-dioxopiperidin-l-yI)butane 26. l-[4-(2-MethoxyphenyI)piperazm-l-yI]-3-[2,5-dioxo-3-phenyI-pyroIidin-l-yl] propane 27. l-[4-(PhenyI)piperidm-l-yI]-3-[2,5-dioxopyrolidin-l-yljpropane fL Detailed Description of the Invention 5a. Synthesis of the compounds of the invention The compounds of the present invention may be prepared by one of the reaction 5 sequences (Schemes I, II & III) shown below to yield compounds of Formula II with the R„ R2, R3, R,, 1^, R^, m, n, Z, Z', Q and Y groups as defined above. The starting materials for Schemes I, II and III may be suitably adapted to produce the more general compounds of Formula I.

Scheme - I Scheme-I shows the synthesis of compounds of the Formula II in which Rj, R2, R3, R4, R5, R^j m\ n, Z, Z\ Q, X, and Y are as defined earlier. The preparation comprises condensing a,eo-dicarboximides of Formula III with l-(4-arylpiperazin-l-yl)-<B-chioroalkanes of Formula IV, 15 in the presence of a base and an organic solvent at a temperature ranging from 80-150°C for a period varying between 8-24 hours to produce the corresponding l-(4-aiylpiperazin-l-yl)-oo-[N-(a,e>-dicarboximido)]alkanes of the Formula II where Rj and R2 have the meanings given above. Phase transfer catalysts, preferably tetrabutylammonium bromide, are particularly useful in catalysing the reaction. 9 PCMB99/01296 (CH2)m- O^N^o H on) a—(ch2)n—ch-ch2—n R3 (iv) f-VR> z^R2 (012)111*—I 0 Y 0 /• vR' Scheme-I WO 00/05205 PCT/IB99/01296 Scheme - II The compounds of Formula II can also be prepared by condensation of the piperazines of the Formula V with the anhydrides of Formula VI wherein Rj, R2, R3, Y, Z, Z\ X, and m' 5 are as defined above.

(CH2)m'~ -O-O' 0 O (VD H2N—(CH2)n—CH-ch2—N R3 (V) X T~vRi -O r2 (CH2)m'—| o / (CH2)n—CH—CH2—N R3 \ /z,—VR1 (H) Scheme-II 11 Scheme-Ill The compounds of Formula II can also be prepared by alkylation of the a,co-dicarboximide moiety with a,co-dihaloalkanes followed by condensation of l-(co-haloalkyl)dicarboximide thus obtained (Formula VII) with 1-arylpiperazines (Formula VIII) as 5 shown below, wherein Rj, R.2, R3, Y, Z, Z\ X, m' and n are as defined above. The reaction is preferably carried out in the presence of a base and an organic solvent at a temperature ranging from 60-100°C for a period varying between 10-24 hours to produce the corresponding l-(4-arylpiperazin-l-yl)-to-[N-(a,co-dicarboximido)]alkanes of Formula II. Phase transfer catalysts, more preferably tetrabutylammonium bromide and potassium iodide, are useful in catalysing the 10 reaction.

T'l ^ + H—N X—/ * O (CH^n—CH-CH2—a R3 z^^R2 (VIED (vn) (CH2)m'—| O^N^O /'-vRi (CH2)n—CH—CH2—N X—^ ^ i Z=/~R2 (n) Scheme-IH 12 In the above Schemes, where specific bases, acids, solvents, phase transfer catalysts, etc., are mentioned, it is to be understood that other acids, bases, solvents, phase transfer catalysts, etc., known to those skilled in the art may also be used. Similarly, the reaction temperature and duration of the reactions may be adjusted according to the desired needs.

The starting piperazines of the Formulas IV, V and VIII are known in the art and may be synthesized by the procedures described in Kiritzy, J.A., et al., J. Med. Ch^m- 1978, V. 21, p. 1301 ; U.S. Patent No. 3,637,705 (Abbott, 1972); FR 2,179,491 (1973); Aggarwal S.K., et al., Ind. J. Chem.. 1982, V.21B, pp. 435-439; and U.S. Patent No. 2,922,788 (Parcell, 1960). 5b. Pharmacological Testing Results The affinity of the compounds of the invention for each subtype of a-adrenoceptor can be assessed by receptor binding assays (RBA's) described in the examples given below. It should be noted that the identification and characterization of the foregoing receptors is still in progress and that their types and subtypes are subject to review and refinement.

Receptor binding and in vitro functional assay studies described below indicated that the compounds of the present invention possess selective and potent a1A adrenoceptor antagonistic activity over the a,B and a1D adrenoceptors. The present invention also provides a method to demonstrate the selective affinity of the compounds for prostatic tissues over vascular tissues. Further, the examples presented below describe a method to treat BPH in mammals wherein the test compounds alleviated pressure at dosages which did not result in significant change in blood pressure. Several of the compounds of present invention demonstrated manifest selectivity for prostatic tissues in comparison to known compounds, such as terazosin, doxazosin, etc. The compounds of the present invention also lowered the blood pressure with prolonged duration of action. The compounds of the present invention have been demonstrated to be useful for treating warm blooded animals and mammals. These compounds can be administered orally or parenterally in suitable pharmaceutical compositions.

Preferred compounds of the invention are l-[4-(2-methoxyphenyl)piperazin-l-yl]-3-(2,5-dioxopyrrolidin-l-yl)propane (Compound No. 2), l-[4-(2-methoxyphenyl)piperazin-l-yI]-4-(2,5-dioxopyrrolidin-l-yl)butane (Compound No. 9), and 1 -[4-(2-methoxyphenyI)piperazin-1 -yl]-3-(2,6-dioxopiperidin-l-yl)propane (Compound No. 13).

Pharmaceutically acceptable, non-toxic, acid addition salts of the compounds of the present invention having the utility of the free bases of Formulas I and II may be formed with inorganic or organic acids, by methods well known in the art and may be used in place of the free bases. Representative examples of suitable acids for formation of such acid addition salts are malic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene salicylic, methanesulfonic, ethane disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfamic, phosphoric, hydrobromic, sulfuric, cyclohexylsulfamic, hydrochloric and nitric acids.

The present invention also includes within its scope prodrugs of the compounds of Formulas I and II. In general, such prodrugs will be functional derivatives of these compounds which are readily converted in vivo into the defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known. 14 The invention also includes the enantiomers, diastereomers, N-oxides and pharmaceutical^ acceptable salts of these compounds, as well as metabolites having the same type of activity. The invention further includes pharmaceutical compositions comprising the molecules of Formula I and II, or prodrugs, metabolites, enantiomers, diastereomers, N-oxides, or pharmaceutical^ 5 acceptable salts thereof, in combination with a pharmaceutical^ acceptable carrier and optionally included excipients.

In yet another aspect, the invention is directed to methods for selectively blocking a,A receptors by delivering in the environment of said receptors, e.g., to the extracellular medium (or by administering to a mammal possessing said receptors), an effective amount of the compounds 10 of the invention.

The invention will now be illustrated by the following non-limiting examples.

Preparation of l-[4-(4-FIuorophenyI)piperazin-l-yI]-3-[2,5-dioxopyrroIidin-l-yl]propane 15 (Compound No. 1) Scheme-I: A mixture of 2,5-dioxopyrrolidine (0.500 g, 5 mmol), l-[4-(4-fluorophenyl)-piperazin-l-yI]-3-chloropropane (1.28 g, 5 mmol), potassium carbonate (0.502 g, 3.75 mmol) and tetrabutylammonium bromide (0.322 g, 1 mmol) in acetone (25 ml) was refluxed for 16 hours 20 at 80°C with stirring. The solvent was evaporated off in vacuo and the residue was suspended in water (80 ml). The aqueous solution was extracted with chloroform (3x50 ml), and the organic layers combined, washed with water (2x50 ml), dried over Na2SC>4 and evaporated in vacuo to give the title compound. The product was purified by column chromatography over flash silica gel using chloroform-methanol (98:2) as eluent; yield 1.00 g (65%), oil.

Scheme-H; l-amino-3-[4-(4-fluorophenyl)piperazin-l-yl]propane (0.700 g, 2.95 mmol) and succinic anhydride (0.295 g, 2.95 mmol) were refluxed in pyridine (10 ml) for 10 hours. Acetic anhydride (2 ml, excess) was added and the mixture was further refluxed for 5 hours. Solvent was removed in vacuo and the residue was suspended in water and extracted with chloroform (2x25 ml). Organic layers were combined, washed with water (2x25 ml), dried over 10 Na2S04 and concentrated. The compound was purified by column chromatography over flash silica gel using chloroform-methanol (98:2) as eluent; yield 0.436 g (46%), oil.

Scheme-IP; A mixture of l-chloro-3-(2,5-dioxopyrrolidin-l-yl) propane (1.54 g, 8.80 mmol), l-(4-fluorophenyl)piperazine (1.58 g, 8.80 mmol), potassium carbonate (1.21 g, 8.80 15 mmol) and potassium iodide (0.146g, 0.88 mmol) in N,N-dimethylformamide (25 ml) was heated at 100°C for 18 hours. Solvent was evaporated under reduced pressure. Residue was shaken with water (25 ml), extracted with chlorofonn (2x25 ml), and the organic layers combined, washed with water (2x20 ml), dried over Na2S04 and concentrated to give an oil which was purified by column chromatography over flash silica gel using chloroform-methanol ( 98:2) as eluent; yield 20 2.00g (71%), oil. 16 The hydrochloride salt of l-[4-(4-fluorophenyl)piperazin-l-yl]-3-(2,5-dioxopyrroIidin-l-yl)-propane (Compound No. 1) was formed in quantitative yield by the addition of ethereal hydrogen chloride solution to a methanolic solution of the free base and the resultant precipitate was collected by filtration, m.p 246-247°C.

Preparation of l-[4-(2-methoxyphenyl)piperazm-l-yI]-3-[2,5-dioxopyrroIidin-l-yl]propane (Compound No. 2) Scheme-I: A mixture of 2,5-dioxopyrrolidine (3.68 g, 37.24 mmol), l-[4-(2-methoxyphenyl)-piperazin-l-yl]-3-chloropropane (10.0 g, 37.24 mmol), potassium carbonate (7.70 g, 55.8 mmol) and tetrabutylammonium bromide (2.38 g, 7.4 mmol) in acetone (100 ml) was refluxed for 12 hours at 80°C with stirring. The solvent was evaporated off in vacuo and the residue was taken up in water (80 ml). The aqueous solution was extracted with chloroform (3 x 50 ml) and the organic layers combined, washed with water (2 x 50 ml), dried over Na2S(>4 and evaporated in vacuo to give the title compound. The product was purified by column chromatography over flash silica gel using chloroform-methanol (99:1) as eluent; yield 8.00 g (65%) in oil. The hydrochloride salt was prepared by the method described above; mp 199-202°C. 17 Scheme-II: A mixture of l-chloro-3-(2,5-dioxopyrrolidin-l-yl) propane (28.00 gm, 159.5 mmol), l-(2-methoxyphenyl)piperazin hydrochloride (36.45 g, 159.5 mmol), potassium carbonate (44.03 g, 319.0 mmol) and potassium iodide (1.58 g, 9.57 mmol) in N,N-dimethylformamide (115 ml) was heated at 80°C for 17 hours and the solvent was evaporated under reduced pressure. Residue 5 was suspended in ethyl acetate (600 ml), washed with water (5 x 100 ml.) and dried over Na2SC>4 and concentrated to give an oil which was purified by column chromatography over silica gel (100-200 mesh) using chloroform-methanol (99:2) as eluent; yield 55.1 g, (80%), oil. The hydrochloride salt of this product was formed in the manner described above; mp 199-202°C. l-Chloro-3-(2,5-dioxopyrrolidin-l-yl)propane can be prepared by the reaction of 2,5-dioxopyrrolidine and l-bromo-3-chloropropane in the presence of potassium carbonate and tetrabutylammonium bromide in acetone.

Preparation of l-[4-(2-methoxyphenyl)piperazin-l-yl]-4-[2,5-dioxopyrroIidin-l-yl]butane 15 (Compound No. 9) Scheme-HI: A mixture of l-cMoro-4-(2,5-dioxopyrrolidin-l-yl)butane (11.0 g, 58.04 mmol), l-(2-methoxyphenyl)piperazine hydrochloride (12.99 g, 56.85 mmol), potassium carbonate (16.02 g, 116.09 mmol) and potassium iodide (0.577 g, 3.48 mmol) in N,N-dimethylformamide 20 (45 ml) was stirred at 100°C for 18 hours. N,N-dimethylformamide was evaporated at reduced pressure and the residue was taken up in water (100 ml) and extracted with chloroform (2x100 ml). The extracts were dried over Na2S04 and concentrated under reduced pressure to give 1- 18 [4-(2-methoxyphenyl)piperazin-l-yl]-4-(2,5-dioxopyrrolidin-l-yl)butane as an oil which was purified by column chromatography over silica gel (230-400 mesh) using chloroform-methanol (98:2) as eluent; yield 18.00 g, (92%), oil. Hydrochloride salt was prepared by the method described above; mp 218-220°C. l-Chloro-4-(2,5-dioxopyrrolidin-l-yl)butane can be prepared by the reaction of 2,5-dioxopyrrolidine and l-bromo-3-chlorobutane in the presence of potassium carbonate and tetrabutylammonium bromide in acetone.

Preparation of l-[4-(2-methoxyphenyl)piperazin-l-yl]-3-[2,6-dioxopiperidin-l-yl)propane (Compound No. 13) Scheme-I: A mixture of 2,6-dioxopiperidine (2.60 g, 23.02 mmol), l-[4-(2-methoxyphenyl)-piperazin-l-yl]-3-chloropropane (6.18 g, 23.02 mmol), potassium carbonate (2.38 g, 17.27 mmol) 15 and tetrabutylammonium bromide (1.48 g, 4.60 mmol) in acetone (80 ml) was refluxed for 16 hours at 80°C with stirring. The solvent was evaporated off in vacuo and the residue suspended in water (60 ml), extracted with chlorofonn (3x40 mmol) and the organic layers combined, washed with water (2.40 ml), dried over anhydrous NaiSQt and evaporated in vacuo to give the title compound. The product was purified by column chromatography over flash silica gel (230-400 20 mesh) using chloroform-methanol (98:1) as eluent; yield 3.58 g (45%), oil. 19 The hydrochloride salt was prepared in the quantitative yield by the method described above; m.p. 206-210°C.

Scheme-Ill: A mixture of l-chloro-3-(2,6-dioxopiperidin-l-yl)propane (22.06 gm, 116.40 mmol), 5 l-(2-methoxyphenyl)piperazine (21.90 g, 114.06 mmol), potassium carbonate (16.06g, 116.40 mmol) and potassium iodide (1.16g, 6.98 mmol) in N,N-dimethylformamide (90 ml), was heated at 80°C for 17 hrs. and the solvent was evaporated under reduced pressure. Residue was dissolved in ethyl acetate (400 ml), washed with water (5 x 100 ml) and dried over NajSO^ and concentrated to given an oil which was purified by column 10 chromatography over silica gel (100-200 mesh) using chloroform-methanol (99:1) as eluent; yield 33.8 g, (86%), oil. The hydrochloride salt was prepared in the quantitative yield by the addition of excess ethereal hydrogen chloride solution to a methanolic solution of the free base and collected by filtration of the resultant precipitate; m.p. 206-210°C.

An illustrative list of the compounds of the invention which were synthesized by one or more of the above described methods is now given. l-[4-(4-Fluorophenyl)piperazin-l-yl]-3-(2,5-dioxopyrroIidin-l-yI)propane hydrochloride; m.p. 246-247°C. l-[4-(2-Methoxyphenyl)piperazin-l-yl]-3-(2,5-dioxopyrroIidin-l-yI)propane hydrochloride; m.p. 199-202°C. l-[4-(3-TrifluoromethylphenyI)piperazin-l-yl]-3-(2,5-dioxopyrroIidin-l-yI)propane hydrochloride; m.p. 218-220°C. l-[4-(2-PyridyI)piperazin-l-yI]-3-(2,5-dioxopyrroIidin-l-yl)propane hydrochloride; m.p. 261-262°C. l-[4-(3-Chlorophenyl)piperazin-l-yI]-3-(2,5-dioxopyrroIidin-l-yl)propane hydrochloride; m.p. 230-231°C. l-[4-(2-Pyrimidyl)piperazin-l-yI]-3-(2,5-dioxopyrroiidin-l-yl)propane hydrochloride; m.p. 196-198°C. l-[4-(3,4-Dimethylphenyl)piperazin-l-yI]-3-(2,5-dioxopyrrolidin-l-yl) propane hydrochloride; m.p. 244-246°C. l-[4-(PhenyI)piperazin-l-yl]-3-(2,5-dioxopyrroIidin-l-yl)propane hydrochloride; m.p. 258-259°C. l-[4-(2-Methoxyphenyl)piperazin-l-yl]-4-(2,5-dioxopyrrolidin-l-yl)butane hydrochloride; m.p. 20 218-220°C. 21 l-[4-(2-Methoxyphenyl)piperazin-l-yl]-2-(2,5-dioxopyrrolidiii-l-yl)ethane hydrochloride; m.p. 232-234°C. l-[4-(3-MethoxyphenyI)piperazin-l-yl]-3-(2,5-dioxopyrroIidin-l-yl)propaiie hydrochloride; 5 m.p. 199-201°C. l-[4-(4-MethoxyphenyI)piperazin-l-yI]-3-(2,5-dioxopyrrolidin-l-yl)propaae hydrochloride; m.p. 240-242°C. l-[4-(2-MethoxyphenyI)piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yI)-propane hydrochloride; m.p. 206-210°C. l-[4-(4-FluorophenyI)piperazin-l-yI]-3-(2,6-dioxopiperidin-l-yI)propane; m.p. 200-202°C. l-[4-(4-ChIorophenyI)piperazin-l-yI]-3-(2,6-dioxopiperidin-l-yI)propane hydrochloride; m.p. 206-208°C. l-[4-(3-Trifluoromethylphenyl)piperazin-l-yI]-3-(2,6-dioxopiperidin-l-yI)propane hydrochloride; m.p. 228-229°C. l-[4-(2-FiuorophenyI)piperazm-l-yI]-3-(2,6-dioxopiperidin-l-yl)propane hydrochloride; m.p. 215-216°C. 22 l-[4-(2-Methylphenyl)piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yI)propane hydrochloride; m.p. 206-207°C. l-[4-(2-Pyridyl)piperazin-l-yI)-3-(2,6-dioxopiperidin-l-yl)propane hydrochloride; m.p. 244-245° C. l-[4-(3-Chlorophenyl)piperazin -l-yI]-3 -(2, 6-dioxopiperidin -l-yI)propane hydrochloride; m.p. 214-215°C. l-[4-(3,4-DimethyIphenyI)piperazin-l-yI]-3-(2,6-dioxopiperidin-l-yl)propane hydro chloride; low melting hygroscopic. l-[4-(2-PyrimidyI)piperazin-l-yI|-3-(2,6-dioxopiperidin-l-yI)propane hydrochloride; m.p. 195-196°C. l-[4-(3-MethoxyphenyI)piperazin-l-yI]-3-(2,6-dioxopiperidin-l-yl)propane hydrochloride; m.p. 196-197°C. !-[4-(4-MethoxyphenyI)piperazin-l-yI]-3-(2,6-dioxopiperidin-l-yl)propane hydrochloride; 20 m.p. 218-220°C. 23 l-[4-(2-Methoxyphenyl)piperazin-l-yIl-4-(2,6-dioxopiperidin-l-yl)fautane hydrochloride; m.p. 190-192 °C. l-[4-(2-MethoxyphenyI)piperazia-l-yI]-3-(2,5-dioxo-3-phenylpyrroLidin-l-yl]propane 5 hydrochloride; m.p. 171-172°C. l-[4-(Phenyl)piperadin-l-yl]-3-(2,5-dioxopyrroIidia-l-yI]propaae hydrochloride; m.p. 208-209 °C.

All the melting points reported above are uncorrected and measured by an open capillary method using Buchi 535.

Receptor Binding Assay In vitro receptor binding Receptor binding assays (RBA's) were performed for native a \-adrenoceptors. Rat submaxillary and rat liver membrane preparations were used to assess the affinity for a1A and a,B subtypes, respectively. Aliquots of membrane protein (100 - 200 mg) were incubated in a final 20 volume of 250 ml assay buffer (50 mM Tris, 0.5 mM EDTA at pH 7.4) with 0.5 nM [^H] prazosin for 60 mins at 28°C. Reaction was stopped by rapid filtration on Millipore filters. Filters were dried and bound radioactivity counted. Non-specific binding was determined in the presence 24 of 0.3 mM prazosin. Protein was assayed according to the method of protein estimation by Lowry, O.H. et al., J. Biol. Chem.. V. 193, pp. 265-275 (1951). Results are listed in Table 1.

Table 1 Compound No.

RBA (Ki nM) In Vitro Functional Assay (pKB) In Vivo BP fflA "IB <*1A fflB alD Fall in mmHg Duration in min.

Compound 1 >2500 1000 7.1 7.0 6.8 .0 .0 Compound 2 19 244 8.7 7.6 7.3 120.0 Compound 3 1500 1000 - 7.2 .0 - Compound 4 1660 2100 - .6 - _ Compound 5 106 175 .3 .3 7.0 - - Compound 6 1140 >250 0 4.7 .3 6.5 Compound 7 450 282 6.4 6.7 6.5 - - Compound 8 57 590 7.5 - 6.6 - - Compound 9 1 9.0 8.0 8.3 46 >180 Compound 10 1600 2350 6.9 6.7 6.9 - - Compound 11 >2500 >250 0 Compound 12 >2500 >250 0 Compound 13 3 168 8.6 8.0 7.9 50.0 >180 Compound 14 67 192 8.4 7.4 7.1 .0 60.0 Compound 15 520 201 6.7 6.0 6.2 - - Compound 16 345 765 6.5 - 6.9 - - Compound 17 21 396 8.0 7.1 7.9 50.0 120.0 Compound 18 9 267 8.2 .5 8. 5 40.0 >150 Compound 19 164 >250 0 6.4 6.7 Compound 20 22 113 7.5 - 7.6 - - Compound 21 2130 176 6.5 6.7 6.5 - - Compound 22 >2500 >250 0 6.4 - 7.0 - Compound 23 2170 940 - - - - Compound 24 <2500 >250 0 - - - - _ Compound 25 1.6 7.5 - - - - _ Compound 26 600 - - - - - Compound 27 1300 2000 26 In vitro Functional Studies In vitro ai -Adrenoceptor selectivity In order to study selectivity of action of the present compounds towards different a-adrenoceptor subtypes, the ability of these compounds to antagonize oq-adrenoceptor agonist induced contractile response of aorta (a1D), prostate (a1A) and spleen (a1B) was studied. Aorta, prostate and spleen tissues were isolated from urethane anaesthetized (1.5 gm/kg) male wistar rats. 10 Isolated tissues were mounted in organ bath containing Krebs Henseleit buffer of the following composition (mM): NaCl 118; KC14.7; CaCl2 2.5; MgSO< • 7H20 1.2; NaHC03 25; KKJC^ 1.2; glucose 11.5. Buffer was maintained at 37°C and aerated with a mixture of 95 % 02 and 5 % CO. A resting tension of 2g (aorta) or 1 g (spleen and prostate) was applied to tissues. Contractile response was monitored using a force displacement transducer and recorded on chart recorders. 15 Tissues were allowed to equilibrate for 2 hours. At the end of equilibration period, concentration response curves to norepinephrine (aorta) and phenylephrine (spleen and prostate) were obtained in the absence and presence of the tested compound (at concentrations of 0.1, 1 and 10 jxM). Antagonist affinity was calculated and expressed as pKg values in Table 1.

In vitro Receptor Selectivity Selectivity of action of the present componds was tested against a range of different receptors, e.g., and ocj-adrenergic, muscarinic cholinergic, serotoninergic (5-HT2A), histaminergic (H,), angiotensin II, endothelin (ETA and B>), as well as calcium and potassium •channels. Rat aorta was used to study the effect of the compounds on 5-HT2A,-ETA, calcium 27 and potassium channels. Angiotensin II receptor antagonistic activity was studied in rabbit aorta. Muscarinic cholinergic receptor and ETg receptor antagonistic activity was studied in rat trachea, while guinea pig trachea was used to study Hj receptor antagonistic activity. Electrically stimulated rat vas deferens was used to investigate the effect of a2-adrenoceptors, while fir adrenoceptor antagonistic activity was studied using electrically stimulated rat ventricular strips. Results of this selectivity study is shown in (Table 2).

Table 2 Selectivity Study Receptor Type pK^ Compound 2 ComDound 9 Comnound 13 ocj-adrenergic NE NE NE fl-adrenergic 4.2 - .1 Muscarinic .0 .0 .5 H i -Histaminergic .3 .4 .7 -HT2A 7.6 7.9 8.0 eta - 4.3 4.3 etb - .4 4.9 Angiotensin II - .6 .3 Calcium Channel NE NE NE Potassium Channel NE NE NE : No effect (-): Not tested 28 In vivo Antihypertensive Effect Antihypertensive effect of selected compounds according to the invention were studied for their ability to lower blood pressure in anaesthetized and conscious normotensive and spontaneously hypertensive rats via intravenous, oral and intraduodenal routes. Results are shown in Tables 1 and 3.

Anaesthetized Normotensive Rats Intravenous Route Male wistar rats were anaesthetized with urethane (2.5 g/kg). Femoral vein and carotid artery were cannulated. Blood pressure and heart rate were recorded using Statham pressure transducer. Data was recorded on Grass polygraph as well as using online data acquisition system (Buxco AT). Intravenously administered compounds of the invention were initially tested at 0.3 mg/kg over a period of 3 hours for their effect on blood pressure and the results are shown in Table 1. For a select few of the compounds, the blood pressure lowering effect upon intravenous administration was also studied at dosages of 0.03, 0.1, 0.3, and 1 mg/kg.

Intraduodenal Route Male wistar rats were fasted for 18 hours. Rats were anaesthetized with urethane. Femoral vein and carotid artery were cannulated. A catheter was placed in the duodenum following lapratomy. The compounds of the present invention (at dosages of 0.3, 1,3 and 10 mg/kg) were administered in the duodenum and blood pressure was monitored for 3 hours. Results are recorded in Table 3. 29 Table 3 Effect on mean arterial pressure in anaesthetized normotensive rats.

Compound No.

Dose (mg/kg) Mean Arterial Pressure (% Change from basal) Duration of Action Compound 2 1 -19 > 2.5 hr 3 -43 > 2.5 hr -42 > 2.5 hr Compound 9 1 -19 > 3.0 hr 3 -53 > 3.0 hr -57 > 3.0 hr Compound 13 1 -32 < 3.0 hr 3 -40 > 3.0 hr -42 > 3.0 hr Conscious Normotensive Rats Femoral artery of normotensive male wistar rats, maintain^ on an overnight light diet, were catheterized under pentobarbitone anaesthesia (35 mg/kg). Femoral artery catheter was exteriorized through the neck region for blood pressure recording. Compounds of the present 30 invention (at dosages of 0.1, 0.3 and 1 mg/kg) were administered 24 hours following surgery through oral route in the form of gavage to overnight fasted rats. Blood pressure and heart rate were recorded with the help of Statham pressure transducer on a Grass polygraph and the results are shown in Table 4.

Table 4 Effect on systolic blood pressure in conscious spontaneously hypertensive rats Compound No. Dose Systolic Pressure (mg/kg) (% Change from basal) (at 6 hours) Compound 2 1 -7.0 3 - 12.0 - 13.0 - 17.0 Compound 9 1 -0.4 3 -7.0 -24.0 -25.0 Compound 13 1 - 7.0 3 - 18.0 - 19.0 - 14.0 Conscious Spontaneously Hypertensive Rats Spontaneously hypertensive rats weighing between 250 - 300 g were used in this study. Rats were fasted overnight. Blood pressure was monitored from tail artery using semi-automatic noninvasive blood pressure monitoring apparatus. Compounds of the present invention (at 35 dosages of 1, 3,10, and 30 mg/kg) were administered orally. Blood pressure was monitored prior to and 1.5, 4, 6 and 24 hours after drug administration. Results are shown in Table 5. 31 Table 5 Effect on mean arterial blood pressure in conscious freely moving normotensive rats.

Compound No.

Dose (mg/kg) Mean Arterial Pressure (% Change from basal) Compound 2 3 -14 -10 Compound 9 1 -4 -11 Compound 13 1 -5 3 -10 in Vivo Selectivity Study Male mongrel dogs (12 - 20 Kg) were anaesthetized with pentobarbitone sodium (35 25 mg/kg, iv). Trachea was intubated for artificial respiration. Femoral artery and femoral vein were cannulated for recording blood pressure and for administration of drug solutions, respectively. Blood pressure was recorded on a polygraph through a pressure transducer. A paramedian incision was made lateral to the penis and the bladder was exposed. Urine was drained through a cannula put directly into the bladder and it was guided into the urethra gently 30 and was placed at the prostatic urethra. Balloon was inflated with 2 cc air and its placement was confirmed by digital pressure. Intraurethral pressure was recorded on the polygraph through a pressure transducer. Graded dose response relationship of phenylephrine (1-16 (xg/kg, iv) was obtained on prostatic pressure and blood pressure, prior to administration of the compounds of 32

Claims

WO 00/05205 PCT/IB99/01296 10 15 20 the present invention. Compounds 2, 9, and 13 (at dosages of 0.01, 0.03, 0.1, and 0.3 mg/kg) were administered intravenously 10 min before obtaining phenylephrine dose response curves. Results were analyzed and pseudo pKu values were calculated as described in Kenny et al (1996). Results are shown in Table 6. Table 6 Effect on blood pressure and intraurethral pressure in anaesthetized dogs pseudo pKB Compound 2 Compound 9 Compound 13 Blood Pressure 6.9 7.4 7.1 Intraurethral Pressure 7.60 7.9 8.1 25 While the invention has been described by reference to specific embodiments, this was for purposes of illustration only. Numerous alternative embodiments will be apparent to those skilled 30 in the art and are deemed to be within the scope of the invention. 33 1. A compound having the structure of Formula I 509388 (CHzJn—CH—CH2—N I ^ Rj (I) 4. 5. 6. 7. its pharmaceutically acceptable salts, esters, enantiomers, diastereomers, N-oxides, amides, prodrugs, or metabolites, wherein Y is O; Q is CH; X, Z, and Z' are independently CH or N; m=0-3; n=0-4; R1f R2 are independently selected from: H, F, CI, Br, OCH3, OC2H5, OCH2CF3, CH3, C2H5, CF3, isopropyloxy, and cyclopropyl; R3 is H; R4, R5 are H, or phenyl, except that Rt is H, R2 is H, CI or CF3, R3, R4 and R5 = H, Y = O and Q = CH when m=0 and n=1; and also except that Rt is H, R2 is OCH3, R3, R4 and R5; = H, Y=0, Q=CH when m=0 and n=2. The compound of claim 1 having the structure of Formula II wherein n, X, Z, Z', Ri, R2 and R3 are as defined for Formula I and m' = 1-4, except that Ri is H, R2 is H, CI or CF3 and R3 is H when m' = 1 and n = 1; and also except that R! is H, R2 is OCH3 and R3 is H when m' = 1 and n = 2. The compound of claim 1 which is 1-[4-(4-fluorophenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(2-methoxyphenyl)piperazin-1-yl] -3-(2,5-dioxopyrrolidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(2-pyridyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(2-pyrimidyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(3,4-dimethylphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1 -yl)propane or its hydrochloride salt. The compound of claim 1 which is 1- [4-(2-methoxyphenyl)piperazin-1-yl]-2-(2,5-dioxopyrrolidin-1-yl)ethane or its hydrochloride salt. 34 9. 10 11 12 13, 14. 15. 16, 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 509388 The compound of claim 1 which is 1-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(4-methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(4-fluorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1 -yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(4-chlorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(3-trifluoromethylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(2-fluorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(2-methylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(2-pyridyl)piperazin-1-yl)-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(3-chlorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(3,4-dimethylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(2-pyrimidyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1 -yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(4-methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(2-methoxyphenyl)piperazin-1-yl]-4-(2,6-dioxopiperidin-1-yl)butane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(2-Methoxyphenyl)piperazin-1-yl]-3- [2,5-dioxo-3-phenyl-pyrolidin-1-yl]propane or its hydrochloride salt. The compound of claim 1 which is 1-[4-(Phenyl)piperidin-1-yl]-3-[2,5-dioxopyrolidin-1-yl]propane or its hydrochloride salt. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 35 50938 27. Use of a compound having the structure of Formula I its pharmaceutically acceptable salts, esters, amides, enantiomers, diastereomers, N- oxides, amides, prodrugs, or metabolites, wherein Y is O or S; Q is CH; X, Z, and Z' are independently CH or N; m=0-3; n= 0-4; R1t R2 are independently selected from: H, F, CI, Br, OCH3, OC2H5, OCH2CF3, SCF3, CH3, C2H5, CF3, isopropyloxy, and cyclopropyl; R3, R4, R5i are H, C1.3 alkyl, substituted or unsubstituted phenyl for making a medicament for selectively antagonizing a!-adrenergic receptors. 28. The method of claim 27 wherein said compound has the structure of Formula II |N O yT—y (CHaJn—CH—CH2—N X I \ / Rj (id wherein n, X, Z, Z', R^ R2 and R3 are as defined for Formula I and m' = 1-4. 29. The method of claim 28 wherein said compound is 1-[4-(2-methoxy-phenyl)piperazin-1yl]-3-(2,5-dioxopyrrolidin-1-yl)propane or its hydrochloride salt. 30. The method of claim 28 wherein said compound is 1 -[4-(2-methoxyphenyl)piperazin-1 -yl]4-(2,5-dioxopyrrolidin-1-yl)butane or its hydrochloride salt. 31. The method of claim 28 wherein said compound is 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. 32. Use of a compound of the structure of Formula I (CHz)m R4--Q' y—Ks (CH2)n—p—CH2—N X Rj (d its pharmaceutically acceptable salts, esters, amides, enantiomers, diastereomers, N-oxides, amides, prodrugs, or metabolites, wherein Y is O or S; Q is CH; X Z, and Z' are independently CH or N; m=0-3; n=0-4; Ru R2 are independently selected from: H, F, CI, Br, OCH3, OC2H5, OCH2CF3, SCF3, CH3, C2H5, CF3, isopropyloxy, and cyclopropyl; R3, 36 50 938b R4, R5i are H, C1.3 alkyl, substituted or unsubstituted phenyl for making a medicament for the treatment of benign prostatic hypertrophy. 33. The method of claim 32 wherein said compound has the structure of Formula II wherein n, X, Z, Z', R^ R2 and R3 are as defined for Formula I and m'= 1-4. 34. The method of claim 33 wherein said compound is 1 -[4-(2-methoxyphenyl)piperazin-1 -yl]- 3-(2,5-dioxopyrrolidin-1-yl)propane or its hydrochloride salt. 35. The method of claim 33 wherein said compound is 1 -[4-(2-methoxyphenyl)piperazin-1 -yl]- 4-(2,5-dioxopyrrolidin-1-yl)butane or its hydrochloride salt. 36. The method of claim 33 wherein said compound is 1 -[4-(2-methoxyphenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. 37. Use of a compound of the structure of Formula I its pharmaceutically acceptable salts, esters, amides, enantiomers, diastereomers, N-oxides, amides, prodrugs, or metabolites, wherein Y is 0 or S; Q is CH; X, Z, and Z' are independently CH or N; m=0-3; n= 0-4; R^ R2 are independently selected from: H, F, CI, Br, OCH3, OC2H5, OCH2CF3, SCF3, CH3, C2H5, CF3, isopropyloxy, and cyclopropyl; R3, R4, R5 are H, C^ alkyl, substituted or unsubstituted phenyl, or a 5-membered spiro ring for making a medicament for the treatment of vascular disease, congestive heart failure or hypertension. (d 37 38. The method of claim 37 wherein said compound has the structure of Formula II (CH^m4—i (cha)n—ch—ch2— n x- y / m Rj Z-^ ^ wherein n, X, Z, Z', R1t R2 and R3 are as defined for Formula I and m' = 1-4. 39. The method of claim 38 wherein said compound is 1- [4- (2-methoxyphenyl) piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1 -yl)propane or its hydrochloride salt. 40. The method of claim 33 wherein said compound is 1 -[4-(2-methoxyphenyl)piperazin-1 -yl] 4-(2,5-dioxopyrrolidin-1-yl)butane or its hydrochloride salt. 41. The method of claim 33 wherein said compound is 1 -[4-(2-methoxyphenyl)piperazin-1 -yl] 3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt. 42. A method for making a compound having the structure of Formula I „ (CH^m 'm—Q- y-Rj Y^N^y y y /~VRI /-R © R3 NR2 its pharmaceutically acceptable salts, esters, amides, enantiomers, diastereomers, N-oxides, amides, prodrugs, or metabolites, wherein Y is O or S; Q is CH; X, Z and Z' are independently CH or N; m=0-3; n=0-4; R,, R2 are independently selected from: H, F, CI, Br, OCH3, OC2H5, OCH2CF3, SCF3, CH3, C2H5i CF3, isopropyloxy, and cyclopropyl; R3 is H; R4 and R5 are H, C^ alkyl, substituted or unsubstituted phenyl, which comprises reacting a compound having the structure of Formula III' ^Q' Y^N I H W) 38 50 9 3 B ^ with a compound having the structure of Formula IV in the presence of a base and acetone solvent at about 80°C CI—(CHa)n—m-CH2— N X- l3 / Z- (IV) thereby to produce the compound of Formula I. 43. The method of claim 42 for producing a compound having the structure of Formula II (Oym"—| o J* O y—Z' \ Rt wherein n, X, Z, Z', R1f R2 and R3 are as defined for Formula I and m'=1-4, which comprises reacting a compound having the structure of Formula III (CH^m'—s H m with said compound of Formula IV. 39 50 9 "5 B 44. A method for making a compound having the structure of Formula I A (CH2)n—CH-CH-!—N % 0) its pharmaceutically acceptable salts, esters, amides, enantiomers, diastereomers, N-oxides, amides, prodrugs, or metabolites, wherein Y is O or S; Q is CH; X, Z and Z' are independently CH or N; m=0-3; n=0-4; R2 are independently selected from: H, F, CI, Br, OCH3, OC2H5, OCH2CF3, SCF3, CH3, C2H5, CF3, isopropyloxy, and cyclopropyl; R3 is H; R4 and R5 are H, Ci.3 alkyl, substituted or unsubstituted phenyl, which comprises reacting a compound having the structure of Formula VI' with a compound having the structure of Formula V in pyridine at reflux temperature followed by reflux in the presence of acetic anhydride, hsn—ch-chr-n ; I \ / (V) thereby to produce the compound of Formula I. 45. The method of claim 44 for producing a compound having the structure of Formula (QEyat'—| 0 / \ (CH^n—CH—CH2—\ ^ wherein n, X, Z, Z', R1( R2 and R3 are as defined for Formula I and m' = 1-4, 40 50938 which comprises reacting a compound having the structure of Formula VI 46. <VQ with said compound of Formula V. A method for making a compound having the structure of Formula I n (CH^m p (CHila—CH—CH2—N Rj (0 its pharmaceutically acceptable salts, esters, amides, enantiomers, diastereomers, N-oxides, amides, prodrugs, or metabolites, wherein Y is O or S; Q is CH; X, Z and Z' are independently CH or N; m=0-3 ; n=0-4; R2 are independently selected from: H, F, CI, Br, OCH3, OC2H5, OCH2CF3, SCF3, CH3, C2H5i CF3i isopropyloxy, and cyclopropyl; R3 is H; R4 and R5; are H, Ci.3 alkyl, substituted or unsubstituted phenyl, which comprises reacting a compound having the structure of Formula VII' (CHaJta _ Rr--Q' v—Rj (Cf%)tt——CHj—ci Rj (vno with a compound having the structure of Formula VIII H—N (VHD thereby to produce the compound of Formula I. 41 The method of claim 46 for producing a compound having the structure of Formula II wherein n, X, Z, Z', R2 and R3 are as defined for Formula I and m' = 1-4, which comprises reacting a compound having the structure of Formula VII CVH) with said compound of Formula VIII. RANBAXY LABORATORIES LIMITED by their authorised agents JAMES & WELLS Intellectual Property Office of NZ