WO2005018643A1

WO2005018643A1 - Metabolites of 1-{3-4`4-(2-methoxyphenyl) piperazin-1-yl!-propyl}-piperidine-2, 6-dione for use in the treatment of benign prostatic hyperplasia

Info

Publication number: WO2005018643A1
Application number: PCT/IB2003/003509
Authority: WO
Inventors: Mohammad Salman; Gyan Chand Yadav; Somesh Sharma; Gobind Singh Kapkoti; Anita Mehta; Sanjay Jain; Neelima Sinha; Anita Chugh; Jyoti Kumar Paliwal; Nitya Anand
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2003-08-25
Filing date: 2003-08-25
Publication date: 2005-03-03
Also published as: AU2003259391A1

Abstract

The present invention relates to the metabolites of 1-{3-[4-(2-Methoxyphenyl) piperazin-1-yl]-propyl}-piperidine-2, 6-dione of Formula (I). The disclosed compounds can function as α1a-adrenceptor antagonists and thus can be used for the treatment of benign prostatic hyperplasia (BPH) and related symptoms thereof. Processes for the preparation of the metabolites, pharmaceutical compositions containing these metabolites and the method of treating BPH and related symptoms thereof are also disclosed.

Description

METABOLITES OF 1- { 3-4 ' 4 - ( 2 -METHOXYPHENYL ) PIPERAZIN- 1-YL ! -PROPYL } - PIPERIDINE-2 , 6-DIONE FOR USE IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA

FIELD OF THE INVENTION The present invention relates to the metabolites of l-{3-[4-(2-Methoxyphenyl) piperazin-l-yl]-propyl}-piperidine-2, 6-dione of Formula I

The disclosed compounds can function as αι_a-adrenceptor antagonists and thus can be used for the treatment of benign prostatic hyperplasia (BPH) and related symptoms thereof. Processes for the preparation of the metabolites, pharmaceutical compositions containing these metabolites and the method of treating BPH and related symptoms thereof are also disclosed.

BACKGROUND OF THE INVENTION cti.-Adrenoceptor antagonists are in clinical use for symptomatic treatment of benign prostatic hyperplasia (BPH) (Oesterling, Drug Therapy, 332(2^:99-1 10, 1995; Chappie, Br. J. Urology, 1:47-55, 1995). Their beneficial effect result from antagonism of noradrenaline induced contraction of prostatic smooth muscle that occurs via _\- adrenoceptors (Hieble et al., European Journal of Pharmacology, 107: 111-117, 1985). However, as cci-adrenoceptors are widely distributed, poor organ selectivity limits therapeutic usefulness for this class of drugs. In recent years, the existence of at least three distinct subtypes of oti-adrenoceptors, designated as αι_a, cti_b and ai_d, has been established. Several studies have indicated that α_la-adrenoceptors can mediate the contraction of human and dog prostatic smooth muscle (Marshall et al, Br. J. Pharmacol, ϋ2:59p, 1992; Forray et al, Molecular Pharmacology, 45:703-708, 1994). It has been suggested that selective αι_a-antagonists can be more efficacious and better-tolerated agents for symptomatic BPH. l-{3-[4-(2-Methoxyphenyl) piperazin-l-yl]-propyl}-piperidine-2, 6-dione is a new αι_a-adrenoceptor antagonist for the treatment of BPH as described in US Patent Nos. 6,083,950; 6,090,809; 6,410,735; 6,420,559 and 6,420,366. The invention relates to metabolites of l-{3-[4-(2-Methoxyphenyl)piperazin-l-yl]-propyl}-piperidine-2, 6-dione, pharmaceutical compositions thereof, processes for preparing them and to method of using the metabolites and the pharmaceutical compositions in the treatment of symptomatic BPH.

BPH also known as benign prostatic hypertropy is highly prevalent in men beyond the age of 50 and increase in severety and incidence with increase age. The incidence is about 70% at 70 years of age and becomes nearly universal with advancing age, reaching about 90% incidence at 80 years of age. BPH is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urine stream, and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and increased incidence of urinary tract infection. Currently, in United States, the method of choice for treating BPH is surgery (Lepor, et al., The Journal of Urology, 143:553-537, 1990). The limitation of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery. Therefore, a medicinal alternative to surgery is clearly very desirable.

SUMMARY OF THE INVENTION The metabolites of l-{3-[4-(2-Methoxyphenyl) piperazin-l-yl]-propyl}-piperidine- 2, 6-dione are provided. These are useful for the safe and effective treatment of BPH or related symptoms thereof. Processes for the synthesis of these metabolites are also provided.

Pharmaceutical compositions containing the metabolites are also provided. Such compositions may also contain pharmaceutically acceptable carriers or diluents.

The pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates, or prodrugs of these metabolites having the same type of activity are also provided, and are useful for the safe and effective treatment of BPH or related symptoms thereof.

Pharmaceutical compositions comprising the metabolites of the present invention, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymoφhs, conjugates, or prodrugs in combination with pharmaceutically acceptable carriers and optionally included excipients are also included, and are useful for the safe and effective treatment of BPH or related symptoms thereof. Other aspects and properties of this subject matter will be set forth in description which follows, and will be apparent from the description or may be learnt by the practice thereof.

In accordance with one aspect, there are provided metabolites of a compound of Formula I,

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates, and prodrugs thereof.

In accordance with a second aspect, there are provided pharmaceutical compositions comprising therapeutically effective amounts of any one of the metabolites described herein and pharmaceutically acceptable carriers. In accordance with third aspect, there are provided methods for the treatment of subjects suffering from a disease or disorder mediated through α_la-andrenoceptors, comprising administering (including directly administering) to a subject in need thereof, therapeutically effective amounts of any of the metabolites described herein. In accordance with a fourth aspect, there are provided methods for treatment of subjects suffering from BPH, comprising administering (such as directly administering) to a subject in need thereof, therapeutically effective amounts of any one of the metabolites described herein.

In accordance with a fifth aspect, there are provided methods for treatment of subjects suffering from high intraocular pressure, disorder associated with high cholesterol, cardiac arrhythmia, impotency, sympathetically mediated pain, or migraine, comprising administering (such as directly administering) to a subject in need thereof, therapeutically effective amounts of any one of the metabolites described herein.

In accordance with a sixth aspect, there are provided processes for preparing metabolites as described herein. DETAILED DESCRIPTION OF THE INVENTION The invention provides metabolites of l-{3-[4-(2-Methoxyphenyl)piperazin-l-yl]- propyl}-piperidine-2, 6-dione (Compound No. 1) of Formula I

wherein the metabolites comprise the desmethylated, hydroxylated, N-oxide and open piperidine-2,6-dione ring derivatives of Formula I.

A desmethylated, hydroxylated or N-oxide metabolite of compound of Formula I is the compound represented by the general Formula II, and pharmaceutically acceptable salts, solvates, polymoφhs, conjugates or prodrugs thereof,

Formula II

wherein

Ri. and R₂ are independently selected from hydrogen, hydroxy, R₃ represents hydrogen, methyl, n represents an integer 0 or 1 with the provisio that when R₃ is methyl and n is 0, Ri. and R₂ simultaneously are not hydrogen. Opened piperidine-2,6-dione ring metabolites of Formula I is the compound represented by the general Formula III, and pharmaceutically acceptable salts, solvates, polymoφhs, conjugates or prodrugs thereof,

Formula III

wherein

Ri and R₂ are independently selected from hydrogen, hydroxy

R represents hydrogen, methyl, n represents an integer 0 or 1

R₄ represents hydrogen, methyl. A metabolite defined herein, but are not limited to, includes l-{3-[4-(2-Hydroxy-phenyl)-piperazin-l-yl]-propyl}-piperidine-2,6-dione (Compound

No.2)

l-{2-Hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-l-yl]-propyl}piperidine-2,6-dione (Compound No. 3), 1 - {3-[ 1 -oxo-4-(2-hydroxy-phenyl)-piperazin- 1 -yl]-propyl}piperidine-2,6-dione (Compound No. 4),

1 - {2-Hydroxy-3- {4-(2-methoxy-phenyl)-piperazin-l -yl} -propyl} -piperidine-2,6-dione (Compound No. 5), l-{3-[4-(5-Hydroxy-2-methoxy-phenyl)-piperazin-l-yl]-propyl}-piperidine-2,6-dione (Compound No. 6), l-{2-Hydroxy-3-[4-(5-hydroxy-2-methoxy-phenyl)-piperazin-l-yl]-propyl}-piperidine- 2,6-dione (Compound No. 7),

1 - {3-[ 1 -oxo-4-(2-methoxy-phenyl)-piperazin- 1 -yl]-propyl} -piperidine-2,6-dione (Compound No. 8),

1 - {2-Hydroxy-3-[ 1 -oxo-4-(5-hydroxy-2-methoxy-phenyl)-piperazin- 1 -yl]-propyl} - piperidine-2,6-dione (Compound No. 9), l-{2-Hydroxy-3-[l-oxo-4-(5-hydroxy-2-methoxy-phenyl)-piperazin-l-yl]-propyl}- piperidine-2,6-dione (Compound 10),

4- {-3-[4-(2-Methoxy-phenyl)-piperazin- 1 -yl]-propylcarbamoyl} -butyric acid (Compound No. 11)

4-{-3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propylcarbamoyl}-butyric acid methyl ester (Compound No. 12)

The term "pharmaceutically acceptable salts" refers to a salt prepared from pharmaceutically acceptable non-toxic inorganic or organic acid. Example of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous, nitric, carbonic, 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 such as, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyurvic, aspartic, glutamic, benzoic, anthralic, mesylic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic, methansulfonic, ethanesulfonic, benzenesulfonic, panthenic, toluenesulfonic, 2-hydroxyethanesulfonic acid and the like. The term "pharmaceutically acceptable solvates" refers to solvates with waters

(i.e., hydrates) or pharmaceutically acceptable organic solvents. Such solvates are also intended to be encompassed herein. Further more, some of the crystalline forms for compounds described herein may exist as polymoφhs and as such are intended to be encompassed herein. Where the metabolites have at least one chiral center, they may accordingly exist as enantiomers. It is to be understood that all such optically active isomers and the racemic mixture therefore are encompassed herein. The conjugates disclosed herein include sulfate or glucuronate derivatives of hydroxylated metabolites. Prodrugs of hydroxylated metabolites are also disclosed. The prodrugs include, but are not limited to, carbamoyl, (Cι-C₄) alkyl carbonyl, aryl carbonyl, alkyl sulfonyl, and the like.

Prodrugs as disclosed herein include, but are not limited to:

Methanesulfonic acid 2-(2,6-dioxo-piperidin- 1 -yl)- 1 -[4-(2-methoxy-phenyl)-piperazin- 1 - yl-methyl] ethyl ester,

Benzenesulfonic acid 2-(2,6-dioxo-piperidin- 1 -yl)- 1 -[4-(2-methoxy-phenyl)-piperazin- 1 - yl-methyl] ethyl ester,

Acetic acid 2-(2,6-dioxo-piperidin- 1 -yl)- 1 -[4-(2-methoxy-phenyl)-piperazin- 1 -yl- methyl] ethyl ester, Propionic acid 2-(2,6-dioxo-piperidin-l-yl)-l-[4-(2-methoxy-phenyl)-piperazin-l-yl- methyl] ethyl ester,

Phenyl acetic acid 2-(2,6-dioxo-piperidin-l-yl)-l-[4-(2-methoxy-phenyl)-piperazin-l-yl- methyl] ethyl ester,

Dimethyl carbamic acid 2-(2,6-dioxo-piperidin-l-yl)-l-[4-(2-methoxy-phenyl)-piperazin- 1 -yl-methyl] ethyl ester,

Methyl-phenyl carbamic acid 2-(2,6-dioxo-piperidin-l-yl)-l-[4-(2-methoxy-phenyl)- piperazin-1 -yl-methyl] ethyl ester,

Diphenyl carbamic acid 2-(2,6-dioxo-piperidin-l-yl)-l-[4-(2-methoxy-phenyl)-piperazin- 1 -yl-methyl] ethyl ester, Methanesulfonic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3- methoxy phenyl ester,

Benzenesulfonic acid 2- {4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl} -3- methoxy phenyl ester,

Acetic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3-methoxy phenyl ester,

Propionic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3-methoxy phenyl ester,

Phenyl acetic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3-methoxy phenyl ester, Dimethyl carbamic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3- methoxy phenyl ester,

Methyl-phenyl carbamic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}- 3-methoxy phenyl ester, Diphenyl carbamic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l -yl}-3- methoxy phenyl ester. Pharmaceutical compositions comprising metabolites of l-{3-[4-(2- Methoxyphenyl)piperazin-l-yl]-propyl}-piperidine-2,6-dione (Formula I), their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymoφhs, conjugates, or prodrugs and pharmaceutically acceptable carrier or excipient are also included herein.

The compositions disclosed herein may contain only one metabolite, but can also contain two or more metabolites in compositions that are suitable for oral, parenteral, topical, transdermal, colonic, buccal, sublingual or intravaginal administration. The compositions may be formulated to provide immediate or sustained release of the therapeutic agents. The agents described herein can be administered alone but will generally be administered as an admixture with a suitable "pharmaceutically acceptable carrier". The term "pharmaceutically acceptable carrier" is intended to include non-toxic, inert solid, semi-solid or liquid filter, diluent, encapsulating material or formulation auxiliary of any type.

Solid form preparations for oral administration may include capsules, tablets, pills, powder, granules and suppositories. For solid form preparations, the metabolite is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate and/or a filter and extender such as starch, lactose, sucrose, glucose, mannitol or silicic acid; binders such as carboxymethyl cellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, or acacia; disintegrating agents such as agar- agar, calcium carbonate, potato starch, or aliginic acid, certain silicates and sodium carbonate; absoφtion accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol, or monostearate; adsorbents such as kaolin; or lubricants such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate or mixtures thereof. In the case of capsules, tablets, or pills, the dosage form may also comprise buffering agents. The solid preparation of tablets, capsules, pills, granules can be prepared with coatings and/or shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.

Liquid form preparations for oral administration may include pharmaceutically acceptable emulsions, solution, suspensions, syrups or elixirs. For liquid form preparation, the metabolite is mixed with water or other solvent, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol or fatty acid ester of sorbitan or mixture thereof.

Besides inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.

Injectable preparations, such as sterile injections, or 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, Ringers solution, U.S.P and isotonic sodium chloride.

Dosage forms for topical or transdermal administration include ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhalants or patches. The metabolite is admixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives or buffer as may be desirable.

The pharmaceutical preparations are desirably in unit dosage form. In such forms, the preparations are subdivided into unit doses containing appropriate quantities of the active metabolite.

The formulations described herein may be formulated so as to provide immediate, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. The term "subject" as used herein refers to an animal, a mammal, or a human, who has been the object of treatment, observation or experiment. The compositions may be administered as a depot formulation that permits sustained release, limits access to general circulation, and increases the prostate and/or bladder-specific localization of the composition. Such a formulation may be provided as a slow release implant, be microencapsulated, or attached to a biodegradable polymers or a prostate-specific immunoglobulin. A sustained release formulation is a preparation that releases the active metabolite over an extended period of time. A sustained release formulation can be prepared by applying a biodegradable, bioerodible or bioabsorbable polymeric formulation that is compatible on the surface of the active metabolite. The effective release of metabolite is regulated by the slow erosion of the polymer. One or more polymer recognized in the art of pharmaceutical compounding for release retarding properties together form the polymer matrix. The drug is entrapped within this polymeric matrix. The rate of release of metabolite for such a system is primarily dependent on rate of water imbibitions, resultant rate of swelling of matrix, drug dissolution and diffusion from the matrix. In addition to the rate controlling polymers, the composition may additionally contain 6 to 50% w/w of other pharmaceutically acceptable excipients such as gas generating component, swelling agent, lubricant and filler. The pharmaceutically acceptable rate controlling polymers used in accordance with the present invention include, but are not limited to, hydroxypropylmethylcellulose (HPMC), hydrogenated vegetable oil (HVO), ethylcellulose, polyvinylpyrrolidione, pyran copolymer, polyhydroxypropylmethacryl - amidephenol, polyhydroxy - ethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, and polycyano acrylates. The composition according to the invention may be formulated as a capsule or tablet. The tablet formulation can be prepared by wet granulation, dry granulation, direct compression or by any other techniques known in the pharmaceutical art. The tablet made may be coated with a layer of rapidly dissolving water soluble polymer or pharmaceutical excipient(s). The term "biodegradable" means that the polymeric formulation degrades overtime by the action of enzymes, by hydrolytic action and/or by other similar mechanisms in the human body. By "bioerodible" it is meant that the polymeric formulation erodes or degrades over time due, at least in part, to contact with substances found in the smrounding tissue fluids or cellular action. By "bioabsorbable", it is meant that the polymeric formulation is broken down and absorbed within the human body, for example, by a cell or tissue. "Biocompatible" means that the polymeric formulation does not cause substantial tissue irritation or necrosis. The metabolites described herein can also be administered in the form of liposome delivery systems, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, for example, cholesterol, stearylamine or phosphatidylcholines. Aqueous parenteral compositions, containing therapeutically effective amounts of metabolite are disclosed herein. Methods of delivery such that intraprostatic injection of therapeutically effective amounts of disclosed compositions result in the relief of the obstructive symptoms associated with benign prostatic hypeφlasia are also provided. Intraprostatic injection can be accomplished by means of a long, fine needle inserted into the prostate under digital rectal control and /or ultrasonic guidance while the subject is under local anesthesia. The injection solution may be diluted with, for example, lidocaine. During the injection, the needle may be frequently relocated in order to obtain the best possible distribution of the composition. Several routes of administration are available for the introduction of the disclosed composition into the prostate. The preferred route of administration is by means of transurethral intraprostatic (intralesional) injection.

Alternatively, the transperineal or transrectal routes of prostatic injection may be used.

The metabolites described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the metabolites described herein may be prepared by the following reaction sequences as depicted in Schemes I, II and III.

The method of preparation can comprise reacting a compound of Formula IV with a compound of Formula V to give a compound of Formula VI wherein R₂ represents hydrogen, hydroxy, R₃ represents hydrogen, methyl, with the provisio that R and R₃ are not hydrogen and methyl, respectively for Formula VI.

The reaction of a compound of Formula IV with a compound of Formula V can be carried out in presence of potassium iodide or sodium iodide and a suitable inorganic base, for example, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, barium carbonate or sodium hydride.

The reaction of the compound of Formula IV with a compound of Formula V can be carried out in a suitable solvent, for example, acetonitrile, acetone, tetrahydrofuran, cyclohexane, toluene, dimethylformamide or dimethylsulfoxide. The reaction of the compound of Formula IV with a compound of Formula V can be carried out at a suitable temperature, for example, ranging from about 75 °C to about

100 ^ϋC.

The reaction of the compound of Formula VI to give a compound of Formula VII can be carried out in presence of a peroxyacid, for example, meta-chloroperbenzoic acid and a suitable solvent, for example, chloroform, dichloromethane, tetrahydrofuran or acetonitrile.

The method of preparation can comprise reacting a compound of Formula VIII with a compound of Formula V to give a compound of Formula IX wherein R₂ represents hydrogen, hydroxy, R₃ represents hydrogen, methyl. The reaction of a compound of Formula VIII with a compound of Formula V can be carried out in a suitable alcoholic solvent, for example, methanol, ethanol, isopropanol or n-butanol.

The reaction of the compound of Formula LX to give a compound of Formula X can be carried out in presence of peroxyacid, for example, meta-chloroperbenzoic acid and a suitable solvent, for example, chloroform, dichloromethane, tetrahydrofuran or acetonitrile. Scheme III

The method of preparation can comprise reacting a compound of Formula II with an inorganic base, for example, sodium hydroxide or potassium hydroxide to give a compound of Formula XI wherein R₂ represents hydrogen, hydroxy, R represents hydrogen, methyl.

The reaction of the compound of Formula XI to give a compound of Formula XII can be carried out in presence of peroxyacid, for example, meta-chloroperbenzoic acid and a suitable solvent, for example, chloroform, dichloromethane, tetrahydrofuran or acetonitrile.

The reaction of a compound of Formula XI to give a compound of Formula XIII can be carried out in the presence of methanol and hydrochloric acid. The reaction of the compound of Formula XIII to give a compound of Formula

XrV can be carried out in presence of peroxyacid, for example, meta-chloroperbenzoic acid and a suitable solvent, for example, chloroform, dichloromethane, tetrahydrofuran or acetonitrile. The prodrugs of hydroxylated metabolites described herein may be prepared by the following reaction sequences as depicted in the schemes IV and V.

Scheme IV

Formula XV

Formula XVI

Scheme V

Formula XVII

SCHEME IV or V The preparation comprises reacting a compound of Formula XV or XVII with a compound of Formula Cl — W— R to give a compound of Formula XVI or XVIII, wherein Ri, R₂ and R₃ are the same as defined earlier, W represents -SO₂-, -CO-, -CONR₅- wherein R₅ represents alkyl of from one to four carbon atoms or aryl, for example, phenyl or naphthyl,

R represents alkyl of from one to four carbon atoms, aryl, for example, phenyl or naphthyl,

n represents an integer 0 or 1.

The reaction of metabolite of Formula XV or XVII with a compound of Formula Cl — W — R to give compound of Formula XVI or XVIII can be carried out in a suitable solvent, for example, tetrahydrofuran or dimethylformamide.

The reaction of metabolite of Formula XV or XVII with a compound of Formula Cl — W — R can be carried out in the presence of an inorganic base, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or sodium hydride.

The examples below demonstrate some illustrative synthetic procedures for preparation of metabolites described herein. The examples are provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention as defined by the claims.

EXPERIMENTAL DETAILS Solvents were dried using well-known literature procedures. IR spectra were recorded as nujol mulls or a thin film on a Perkin Elmer Paragon. Nuclear magnetic resonance spectra were recorded on a Varian XL-200 instrument using tetramethylsilane as internal standard.

Example 1 : Preparation of l-O-chloropropyl) piperadine 2,6-dione A mixture of glutarimide (10 gm, 0.088 mole), l-bromo-3-chloropropane (20.8 gm, 0.132 mole), anhydrous potassium carbonate (18.3 gm, 0.132 mole) and TBAB (0.056 gm 0.0001 mole) in acetone was stined at an ambient temperature for 48 hours. Inorganic were filtered through celite pad, washed with acetone; filterate thus obtained was concentrated on buchi to yield the crude product. The crude product was purified on a column (silica gel, 60-120 mesh) using hexane and ethyl acetate as eluent.

Example 2: Preparation of l-oxiranylmethyl-piperedine-2,6-dione A mixture of glutarimide (10 gm, 0.088 mole) and triethylamine (13.4 gm, 0.132 mole) epichlorohydrin (12.2 gm, 0.132 mole), in ethylmethylketone was refluxed for 6 hours. After completion of reaction, the reaction mixture was concentrated and purified on a column (silica gel, 60-120 mmol) using hexane and ethyl acetate as eluent.

Example 3: Preparation of 5-Hydroxy-2-methoxyphenyl piperazine

Step 1: To a mixture of 1,4-quinol (5.0 gm, 0.04 moles), triethylamine (4.6 gm, 0.045 mole) in dichloromethane was added ethylchloroformate (4.9 gm, 0.045 mole) at 0°C to 10°C and reaction mixture stirred for 4 hours. To the reaction mass was added water after completion of the reaction, extracted with dichloromethane; organic layer was dried over anhydrous sodium sulphate and concentrated to yield the crude product. The crude product was purified on a column (silica gel, 60-120 mesh) using hexane and ethyl acetate as eluent.

Step 2: To a mixture of Step 1 product (5.0 gm, 0.027 moles) in acetic acid was added concentrated nitric acid and reaction mixture heated at 100°C to 103°C for 1 hour.

Reaction was quenched by adding water to it, extracted with ethyl acetate; organic layer was dried over anhydrous sodium sulphate to yield the desired compound as oil.

Step 3: To a solution of Step 2 product (3.0 gm, 0.013 mole) in dimethylformamide was added anhydrous potassium carbonate (3.6 gm, 0.026 mole) and reaction mixture stirred for 1 hour at reaction temperature; followed by addition of methyl iodide (3.7 gm, 0.026) at 10°C to 15°C and reaction mixture stirred for 2 hours. Reaction was quenched by adding water to it; extracted with dichloromethane; organic layer was dried over anhydrous sodium sulphate to yield the required product.

Step 4: To a solution of Step 3 product (2.5 gm, 0.010 mole) in methanol was added sodium bicarbonate (1.74 gm, 0.020 mole) and reaction mixture refluxed till completion of the reaction. The inorganic material was filtered through celite pad; wasted with methanol; filtrate thus obtained was concentrated to yield the required compound

Step 5: To a solution of Step 4 product (1.0 gm, 0.0059 mole) in methanol was added palladium on carbon and reaction mixture hydrogenated at 50 to 55 psi for 1 hour. After completion of the reaction, it was filtered through celite pad, washed with methanol. Filtrate thus obtained was concentrated to yield the desired amine.

Step 6: A mixture of Step 5 product (0.5 gm, 0.0036 mole), triethylamine (0.54 gm, 0.0054 mole) and bis (2-chloroethyl) amine hydrochloride (1.022 gm, 0.0057 mole) in chlorobenze was refluxed for 10 hours. Reaction was quenched by adding chloroform and ammonia under stirring at 10°C to 15°C till pH reaches 10. Solid thus precipitated was filtered, washed with chloroform. Filtrate thus obtained was concentrated to yield the titled compound.

Example 4: Preparation of l-{3-[4-(2-hydroxy-phenyl)-piperazin-l-yl]-propy - piperidine-2,6-dione (Compound No.2) A mixture of l-(3-chloro-propyl)-piperdine-2,6-dione (1.0 gm, 0.005 mole, from Example 1), 2-hydroxyphenyl piperazine monohydrochloride (1.0 gm, 0.004 mole, commercially available from Lancaster), anhydrous potassium carbonate (1.46 gm, 0.01 mole) and potassium iodide (0.017 gm, 0.0001 mole) in dimethylformamide (10 ml) was heated at 75-80°C for 6 to 8 hours. Reaction was quenched by adding water (30 ml) to it, extracting with ethyl acetate (2 15 ml), drying over anhydrous sodium sulphate and concentrating with rotary evaporation. The resulting crude product was purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent, in a yield of 1.12 gm (75%), an ^]H NMR spectrum with peaks at (300 MHz, DMSO-d₆): δ 1.83-1.90 (m, 4H), 2.59-2.63 (m, 4H), 3.00-3.16 (m, 6H), 3.42-3.51 (m, 6H), 6.72-6.90 (m, 4H), 10.47 (brs, 1H); and a mass spectrum peak at (m/z): 332 (M⁺+l).

Example 5: Preparation of l-(2-Hvdroxy-3-[4-(2-hydroxy-phenylVpiperazin-l-yl]- propyl}piperidine-2,6-dione (Compound No. 3) A mixture of l-oxiranylmethyl-piperadine-2,6-dione (1.0 gm, 0.0059 mole, from Example 2), 2-hydroxyphenyl piperazine monohydrochloride (1.14 gm, 0.0053 mole, commercially available from Lancaster) and triethylamine (0.597 gm, 0.0059 mole) in ethanol (10 ml) was refluxed for 4 to 5 hours. After completion of the reaction, it was concentrated, purified on a silica gel (60-120 mesh) column using dichloromethane and methanol as eluent to yield the desired compound in a yield of 1.6 gm (80%), with major IR peaks at (KBr): 1688.3, 1720.0 cm^"1; an 1H NMR spectrum with peaks at (300 MHz, DMSO-d₆): δ 1.86-1.90 (m, 2H), 2.62-2.66 (m, 4H), 3.03-3.11 (m, 6H), 3.17-3.21 (m, 4H), 3.61-3.67 (m, 1H), 4.00-4.15 (m, 2H), 6.78-6.86 (m, 2H), 6.91-6.96 (m, 2H); and a mass spectrum peak at (m/z): 348.2 (M⁺+l). Example 6: Preparation of l-{3-ri-oxo-4-(2-hvdroxy-phenylVpiperazin-l-vι]- propy piperidine-2,6-dione (Compound No. 4) To a solution of l-{3-[4-(2-Hydroxy-phenyl)-piperazin-l-yl]-propyl}-piperidine- 2,6-dione (0.6 gm, 0.0018 mole, from Example 4) in dichloromethane (15 ml) was added meta chloroperbenzoic acid (10.26 gm, 0.0015 mole) at 0°C to 5°C. The reaction mixture was stirred for 4 to 5 hours at this temperature. After completion of the reaction, the mixture was concentrated and purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent, to give the product in a yield of 0.200 gm (32%), with a melting point of 186-190°C with major IR peaks at (KBr): 1667.5, 1721.1, 3500.9 cm^"1; 1H NMR spectrum with peaks at (300 MHz, DMSO-d₆): δ 1.82-1.86 (m, 2H), 2.01 (m, 2H), 2.59-2.63 (m, 4H), 3.05-3.21 (m, 6H), 3.32-3.44 (m, 4H), 3.72-3.75 (m, 2H), 6.74-6.94 (m, 4H), 9.35 (brs, 1H); and a mass spectrum peak at (m/z): 348 (M⁺+l).

Example 7: Preparation of l-{2-Hydroxy-3-{4-(2-methoxy-phenv -piperazin-l-yl|- propyl|-piperidine-2,6-dione (Compound No. 5) A mixture of l-oxiranylmethyl-piperadine-2,6-dione (0.3 gm, 0.00178 mole, from Example 2) and 2-methoxy phenyl piperazine (commercially available from Lancaster) in absolute alcohol (10-12 ml) was refluxed for 4 to 5 hours. Reaction mixture was concentrated, the crude product thus obtained was purified on silica gel (60-120 ml) column using dichloromethane and methanol as eluent, in a yield of 0.32 gm (50%), an Η NMR spectrum with peaks at (300 MHz, D₂O): δ 1.84-1.94 (m, 2H), 2.67-2.71 (m, ' 4H), 3.21-3.76 (m, 10H), 3.84 (s, 3H), 3.91-3.94 (m, 2H), 4.28 (m, 1H), 6.98-7.24 (m, 4H); and a mass spectrum peak at (m/z): 361.9 (M⁺+l). Example 8: Preparation of l-{3-|^"4-(5-Hvdroxy-2-methoxy-phenylVpiperazin-l-yl]- propyl|-piperidine-2.6-dione (Compound No. 6) A mixture of 5-Hydroxy-2-methoxy phenyl piperazine (0.3 gm, 0.0014 mole, from Example 3). l-(3-chloro-propyl)-piperdine-2,6-dione (0.303 gm, 0.0016 mole, from Example 1), anhydrous potassium carbonate (0.221 gm, 0.0016 mole) and potassium iodide (0.017 gm, 0.0001 mole) in dimethylformamide (5 ml) was stirred at 75-80°C for 10 hours. Reaction was quenched by adding water (20 ml) to it, extracted with ethylacetate (2x10 ml), dried over anhydrous sodium sulphate and concentrated to yield crude product; which was purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent to give the required compound as oil, in a yield of 0.468 gm (90%), with major IR peaks at (KBr): 1672.6, 1720.0 cm^"1; an 1H NMR spectrum with peaks at (300 MHz, D₂O): δ 1.90-1.94 (m, 4H), 2.7-2.71 (m, 4H), 2.96-3.00 (m, 2H), 3.17-3.22 (m, 2H), 3.34-3.36 (m, 2H), 3.59-3.73 (m, 4H), 3.78-3.82 (m, 5H), 6.59-6.63 (brd, 2H), 6.91-6.94 (brd, 2H); and a mass spectrum peak at (m/z): 362 (M⁺+l).

Example 9: Preparation of l-{2-Hydroxy-3- 4-(5-hydroxy-2-methoxy-phenyl)-piperazin- l-yl]-propyl|-piperidine-2.6-dione (Compound No. 7) A mixture of l-oxiranylmethyl-piperadine-2,6-dione (2.0 gm, 0.0118 mole, from Example 2), 5-hydroxy 2-methoxy phenyl piperazine (2.2 gm, 0.0105 mole, from Example 3) and triethylamine (1.32 gm, 0.031 mole) in alcohol (20 ml) was refluxed for 4 to 5 hours. After completion of the reaction, the reaction mass was concentrated. The crude product thus obtained was purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent to yield the desired compared, in a yield of 3.5 gm (89%), with a melting point of 220-23°C, with major IR peaks at (KBr): 1672.7, 1720.6, 3377.7 cm^"1; an ^]H NMR spectrum with peaks at (300 MHz, DMSO-d₆): δ 1.86- 1.90 (m, 2H), 2.62-2.66 (m, 4H), 3.03-3.20 (m,6H), 3.48-3.51 (m, 4H), 3.80 (s, 3H), 3.82- 3.87 (m, 2H), 4.13-4.15 (m, 1H), 6.37-6.45 (m, 2H), 6.79-6.82 (d, 1H); and a mass spectrum peak at (m/z): 378.1 (M⁺+l).

Example 10: Preparation of 1 - (3- 1 -oxo-4-(2-methoxy-phenylVpiperazin- 1 -yl]-propy - piperidine-2,6-dione (Compound No. 8) To a solution of l-{3-[4-(2-Methoxyphenyl)piperazin-l-yl]-propyl}-piperidine- 2,6-dione (6.9 gm, 0.02 mole, prepared according to the method given in US Patent No. 6,090,809) in chloroform (35 ml) was added meta chloroperbenzoic acid (6.9 gm, 0.04 mole) at 0-5°C and reaction mixture stined for 4 to 5 hours. Allowed the temperature of the reaction mixture to come at room temperature. After completion of the reaction mixture, it was concentrated and purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent, in a yield of 1.4 gm (19%), with major IR peaks at (DCM): 1668.7, 1720.8 cm^"1; an 1H NMR spectrum with peaks at (300 MHz, CDC1₃): δ 1.95-2.02 (m, 2H), 2.24-2.29 (m, 2H), 2.67-2.76 (m, 4H), 3.29-3.32 (m, 6H), 3.45-3.52 (m, 2H), 3.63-3.70 (m, 2H), 3.89 (s, 3H), 3.93-3.97 (m, 2H), 6.89-7.10 (m, 4H); and a mass spectrum peak at (m z): 362 (M⁺+l).

Example 11: Preparation of l-{2-Hvdroxy-3-ri-oxo-4-(5-hydroxy-2-methoxy-phenyl)- piperazin-l-yl]-propyl}-piperidine-2,6-dione (Compound No. 9) To the solution of l-{2-Hydroxy-3[4-(2-Methoxy-phenyl)]-piperizine-l-yl]- propyl}-piperidine-2,6-dione (0.5 gm, 0.0014 mole, from Example 7) in dichloromethane (10 ml) was added meta chloroperbenzoic acid (0.24 gm, 0.0014 mole) at 0-5°C. The reaction mixture was stirred for 4 to 5 hrs. After completion of the reaction, it was concentrated and then purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent. The product yield was 0.100 gm (19%), with a melting point of 178-82°C, with major IR peaks at (KBr): 1665.4, 1722.4 cm^"1', an 1H NMR spectrum with peaks at (300 MHz, CDC1₃): δ 1.95-2.00 (m, 2H), 2.68-2.73 (m, 4H), 3.23-3.39 (m, 6H) 3.56-3.67 (m, 4H), 3.67-3.86 (m, 4H), 4.03-4.05 (m, 1H), 4.57-4.60 (m, 1H), 6.87-7.06 (m, 4H), and a mass spectrum peak at (m/z): 378.0 (M⁺+l)

Example 12: Preparation of l-{2-Hvdroxy-3-ri-oxo-4-(5-hvdroxy-2-methoxy-phenylV piperazin-l-yl]-propyl|-piperidine-2,6-dione (Compound 101 To a solution of l-{2-Hydroxy-3-[4-(5-hydroxy-2-methoxy-phenyl)-piperazin-l- yl] -propyl }-piperidine-2, 6-dione (1.2 gm, 0.003 mole, from Example 9) in dichloromethane (10 ml) at 0-5°C was added meta chloroperbenzoic acid (0.54 gm, 0.003 mole) and reaction mixture stirred for 4 to 5 hrs. Reaction mixture was concentrated to give the crude product. It was purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent. The product yield was 130 mg (10%), with major IR peaks at (KBr): 1668.0, 1723.0 cm^"1; an 1H NMR spectrum with peaks at (300 MHz, DMSO-d₆): δ 1.87 (brs, 2H), 2.63 (brs, 4H), 3.21-3.24 (m, 8H), 3.48 (brs, 2H), 3.69- 3.80 (m, 5H), 4.40-4.43 (m, 1H), 6.30-6.43 (m, 2H), 6.77-6.80 (brs, 1H), and a mass spectrum peak at (m/z): 394.2 (M⁺+l).

Example 13: Preparation of 4-{-3- 4-(2-Methoxy-phenyl -piperazin-l-yl]- propylcarbamoyll -butyric acid (Compound No. 11) A solution of l-{3-[4-(2-Methoxyphenyl)piperazin-l-yl]-propyl}-piperidine-2,6- dione (0.5 gm, 0.0013 mole, prepared according to the method given in US Patent No. 6,090,809) in 0.1N NaOH was refluxed for 2 to 4 hours. After the completion of the reaction, the reaction mixture was neutralized with glacial acetic acid (pH 7). The resulting mass was concentrated with rotary evaporation, to it toluene (2 x 10 ml) was added and concentrated again to finally yield an oily product. The product yield was 0.41 gm (86%), with major IR peaks at (DCM): 1638.9, 1662.76 cm^"1; an 1H NMR spectrum with peaks at (300 MHz, CDC1₃): δ 1.90-2.02 (m, 4H), 2.26-2.31 (m, 4H), 2.85-2.89 (m, 2H), 3.07-3.48 (m, 10H), 3.86 (s, 3H), 6.40 (brs, 1H), 6.85-7.06 (m, 4H); and a mass spectrum peak at (m/z): 364.3 (M⁺+l).

Example 14: Preparation of 4-(-3-[4-(2-Methoxy-phenyl^')-piperazm-l-yl]- propylcarbamoyll -butyric acid methyl ester (Compound No. 12) To a solution of 4-{3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propyl carbonoyl}- butyric acid (1.0 gm, 0.0027 mole, from Example 13) in methanol (5 ml) was added in methanol-hydrochloride solution at 0-5°C and reaction mixture stirred for 6-10 hours at this temperature. After completion of the reaction, it was neutralized with chloroform- ammonia (pH-7) and concentrated with rotary evaporation. The crude product was purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent. The product yield was 0.600 gm (60%), with 1H NMR signals at (300 MHz,

DMSO-d₆): δ 1.90-1.94 (m, 2H), 2.12 (m, 2H), 2.23-2.28 (m, 2H), 2.34-2.38 (m, 2H), 3.18 (m, 2H), 3.34 (m, 4H), 3.55-3.59 (m, 5H), 3.90 (s, 3H), 6.94-6.96 (m, 2H), 7.12-7.17 (m., 2H), 7.90 (brs, 1H), and a mass spectrum peak at (m/z): 378.3 (M⁺+l).

Example 15: Metabolite identification and quantification

Identification of metabolites of l-{3-[4-(2-Methoxyphenyl)piperazine-l-yl]-propyl}- piperidine-2,6-dione in plasma/urine of human and animal. In Plasma Method 1: To lmL plasma was added 50 μL of 2-{3-[4-(2-Methoxyphenyl)-piperazin-l- yl]-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3- dione (internal standard) and 0.5 mL of 0.1 M potassium dihydrogen phosphate buffer (pH 5). Vortexed and loaded 1.2 mL on preconditioned drug test cartridge (combination of hydrophilic and hydrophobic cation exchange sorbent, 130 mg/3 cc) [conditioned with 2 mL of methanol followed by 2 mL of 0.1 M phosphate buffer (pH 5)]. The cartridge was washed with 3 mL of 5.75 % acetic acid (v/v), and dried for 2 minutes followed by washing with 3 mL of methanol and drying for 2 minutes. The cartridge was than eluted with 2 mL twice of 2% ammonia in ethyl acetate (v/v). The samples were dried and reconstituted in 150 μL of mobile phase. The molecular ion peak (m/z) , product ion peak (m/z) and retention time (RT) are given in Table I.

Chromatographic conditions Column: Lichrospher RP-Select B 5 μ (4x125 mm) Mobile phase: 8 mM ammonium acetate buffer (pH~6): acetonitrile: :40:60 Flow: 0.3mL/mm Injection volume: 100 μL Instrument: Perkin-Elmer API 3000 LC/MS/MS system with Turbo Ion Spray source Mode: MRM Table I

Method 2: To 750 μL plasma was added 50 μL of 2-{3-[4-(2-Methoxyphenyl)-piperazin- l-yl]-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3- dione (internal standard) and 0.5mL of 0.1M potassium dihydrogen phosphate buffer (pH 3.2). The mixture was vortexed lmL was loaded on a pre-conditioned drug test cartridge (combination of hydrophilic and hydrophobic cation exchange sorbent, 130 mg/3 cc) [conditioned with 2 mL of methanol followed by 2 mL of 0.1 M phosphate buffer (pH 3.2)]. The cartridge was washed with 3 mL of 40%) in methanol in water (v/v) and dried for 2 minutes. The cartridge was then eluted with 2mL of 4% ammonia in methanol (v/v). The samples were dried and reconstituted in 150 μL of mobile phase. The molecular ion peak (m/z) , product ion peak (m/z) and retention time (RT) are given in Table II.

Chromatographic conditions Column: Lichrospher RP-Select B5 μ (4x125 mm) Mobile phase: 8 mM ammonium acetate buffer (pH~6): acetonitrile:: 10:90 Flow: 0.8 mL/min Injection volume: lOOμL Instrument: Perkin-Elmer API 3000 LC/MS/MS system with Turbo Ion spray source Mode: MRM Table II

In Urine Method 1: To 2 mL urine was added 50 μL of 2-{3-[4-(2-Methoxyphenyl)-piperazin-l- yl]-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3- dione (internal standard) and 1 mL of 0.1M potassium dihydrogen phosphate buffer (pH 5). The mixture was vortexed and loaded 2.75 mL on a pre-conditioned drug test cartridge (combination of hydrophilic and hydrophobic cation exchange sorbent, 130 mg/3 cc) [conditioned with 2 mL of methanol followed by 2 mL of 0.1M phosphate buffer (pH 5)]. The cartridge was washed with 3 mL of 5.75% acetic acid (v/v), the dried for 2 minutes followed by washing with 3 mL of methanol and drying for 2 minutes. The cartridge was then eluted with 2 mL twice of 2% ammonia in ethyl acetate (v/v). The samples were dried and reconstituted in 150 μL of mobile phase. The molecular ion peak (m/z) , product ion peak (m/z) and retention time (RT) are given in Table III.

Chromatographic conditions Column: Lichrospher RP-Selct B 5 μ (4x125 mm) Mobile phase: 8 mM ammonium acetate buffer (pH-6): acetonitrile:: 40:60 Flow: 0.3 mL/min Injection volume: 100 μL Instrument: Perkin-Elmer API 3000 LC/MS/MS system with Turbo Ion Spray source

Mode: MRM Table III

Method 2: To 1 mL urine was added 50 μL of 2-{3-[4-(2-Methoxyphenyl)-piperazin-l- yl]-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3- dione (internal standard) and 0.5 mL of 0.1 M potassium dihydrogen phosphate buffer (pH 3.2). The mixture was vortexed and loaded 1 mL on pre-conditioned drug test cartridge (combination of hydrophilic and hydrophobic cation exchange sorbent, 130 mg/3 cc) [conditioned with 2 mL of methanol followed by 2 mL of 0.1 M phosphate buffer (pH 3.2)]. The cartridge was washed with 3 mL of 4% methanol in water (v/v) and dried for 2 minutes. The samples were dried and reconstituted in 150 μL of mobile phase. Chromatographic conditions: Column: Lichrospher RP-Select B 5 μ (4 125 mm) Mobile phase: 8 mM ammonium acetate buffer (pH-6): acetonitrile:: 10:90 Flow: 0.8 mL/min

Injection volume: 100 μL

Instrument Perkin-Elmer API 3000 LC/MS/MS system with Turbo Ion Spray source

Mode: MRM

Table IV

Example 16: Estimation of l-{3-[4-(2-Methoxyphenyl piperazine- 1 -yl] -propyl }- piperidine-2,6-dione (free base) and its metabolites in plasma by LC/MS/MS Method (By Solid phase extraction): To 750 μL of plasma, 350 μL of potassium dihydrogen phosphate buffer (0.1 M, pH 4.0 ± 0.1) and 50 μL of solution of 2-{3-[4-(2- Methoxyphenyl)-piperazin- 1 -yl] -propyl} -3 a,4,7,7a-tetrahydro-isoindole- 1 ,3 -dione (Internal Standard) was added and vortexed to ensure poφer mixing. Cι₈ cartridges (100 mg) were used for processing the samples. The cartridges were conditioned on a vacuum manifold at constant pressure using 2 mL methanol and 2 mL potassium dihydrogen phosphate buffer (0.1 M, pH 4.0 ± 0.1) followed by loading of 1 mL of plasma sample. The cartridges were washed using 3 mL of potassium dihydrogen phosphate buffer (0.1 M, pH 4.0 ± 0.1) and dried for 2 minutes under vacuum washed again with 3 mL of water and dried for 2 minutes under vacuum. Finally l-{3-[4-(2-Methoxyphenyl)piperazine-l-yl]- propyl}-piperidine-2,6-dione (Compound No.l) and its metabolites were eluted twice with 2 mL each of elution solution (2% ammoniated methanol). The eluate was dried at 50°C under 10 psi of nitrogen. The residue was reconstituted in 350 μL of mobile phase and 100 μL of this solution was injected on LC/MS/MS for analysis. The molecular ion peak (m/z), product ion peak (m/z) and retention time (RT) are given in Table V. Chromatographic Conditions

Column Novapak-phenyl, 4μm, 3.9 x 125 mm Mobile Phase 8mM ammonium acetate buffer(pH5.0±0.1): Acetonitrile ::70:30 Flow rate 0.75 ml/min Injection Volume 100 μL Sample Cooler Temp : 12°C Ion source : Turbo Ion Spray Sample Preparation Table V

Example 17: Estimation of l-(3-[4-(2-Methoxyphenyl piperazine-l-yl1-propy - piperidine-2,6-dione (free base) and its metabolites in urine by LC/MS/MS Method (By solid phase extraction): To 950 μL of urine, 500 μL of potassium dihydrogen phosphate buffer (0.1 M, pH 4.7±0.1) and 50 μL of solution of 2-{3-[4-(2- Methoxyphenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione (Internal Standard) was added and vortexed to ensure proper mixing. Drug test cartridges (130mg) were used for processing the samples. The cartridges were conditioned on vacuum manifold at constant pressure using 2 mL methanol and 2 mL potassium dihydrogen phosphate buffer (0.1 M, pH 4.7±0.1) followed by loading of 1.4 mL of urine sample. The cartridges were washed using 3 mL of 5.75% acetic acid and dried for 2 minutes under vacuum. Washed again with 3 mL of methanol and dried for 2 minutes under vacuum. Finally l-{3-[4-(2-Methoxyphenyl)piperazine-l-yl]-propyl}-piperidine- 2,6-dione (Compound No.l) and its metabolites were eluted with 3 mL each of elution solution (2% ammoniated ethyl acetate). The eluate was dried at 50°C under 10 psi of nitrogen. The residue was reconstituted in 200 μL of mobile phase 20 μL of this solution was injected on LC/MS/MS for analysis. The molecular ion peak (m z), product ion peak (m/z) and retention time (RT) are given in Table VI. Chromatographic Conditions Column : Novapak-phenyl, 4μm, 3.9 x 125 mm Mobile Phase : 8mM ammonium acetate buffer(pH 5.0±0.1): Acetonitrile ::70:30 Flow rate : 0.8 ml/min Injection Volume : 20 μL Sample Cooler Temp : 12°C Ion source : Turbo Ion Spray

Table VI

Example 18: Estimation of Compound No. 9 and Compound No. 11 in urine by LC/MS/MS Method (By Solid phase extraction): To 950 μL of urine, 500 μL of potassium dihydrogen phosphate buffer (0.1 M, pH 3.510.1) and 50 μL of solution of 2-{3-[4-(2- Methoxyphenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione (Internal Standard) was added and vortexed to ensure proper mixing. Drug test cartridges (130mg) were used for processing the samples. The cartridges were conditioned on vacuum manifold at constant pressure using 2 mL methanol and 2 mL potassium dihydrogen phosphate buffer (0.1 M, pH 3.510.1) followed by loading of 1.4 mL of urine sample. The cartridges were washed using 3 mL of potassium dihydrogen phosphate buffer (0.1 M, pH 3.510.1) and dried for 2 minutes under vacuum washed again with 3 mL of water and dried for 2 minutes under vacuum. Finally l-{2-Hydroxy-3-[l-oxo-4-(2- methoxy-phenyl)-piperazin-l-yl]-propyl}-piperidine-2,6-dione (Compound No.9) and 4-{- 3-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-propylcarbamoyl}-butyric acid (Compound No. 11) were eluted with 3 mL each of elution solution (4% ammoniated methanol). The eluate was dried at 50°C under 10 psi of nitrogen. The residue was reconstituted in 250 μL of mobile phase and 20 μL of his solution was injected on LC/MS/MS for analysis. The molecular ion peak (m/z), product ion peak (m/z) and retention time (RT) are given in Table VIII. Chromatographic Conditions Column : Novapak-phenyl, 4μm, 3.9 x 125 mm Mobile Phase : 8mM ammonium acetate bufferψH 5.010.1): Acetonitrile ::70:30 Flow rate : 0.8 ml/min Injection Volume : 20 μL Sample Cooler Temp : 12°C Ion source : Turbo Ion Spray

Table VII

Example 19: Pharmacological activity - Radioligand binding assay The affinities of metabolites of l-[4-(2-Methoxy phenyl)piperazin-l-yl}-3-(2-,5- dioxopyrrolidin-l-yl)propane for αι_a and αn,-adrenceptor subtype were evaluated by studying their ability to displace specific [³H] prazosin binding from the membrane of rat submaxillary and liver respectively (Michel et al., 1989). These tissues are reported to have a homogeneous population of respective αpadrenceptor subtype (Forel et al., 1994). The binding assays were performed according to U' (Prichard et al., 1978) with minor modifications.

Submaxillary glands were isolated immediately after sacrifice. The liver was perfused with buffer (Tris HCl 50 mM, pH 7.4). the tissues were homogenized 10 volume of buffer (Tris HCL 50 mM, NaCl 100 mM, EDTA ImM, pH 7.4) with a polytron. The homogenate was filtered through two layers of wet guaze and filtrate was centrifuged at 3000g for 10 min. The supernatant was subsequently centrifuged at 60,000g for 45 min. The pellet thus obtained was resuspended in same volume of assay buffer (Tris HCl 50 mM, EDTA ImM, pH 7.4) and were stored at -70°C until the time of assay. The membrane homogenates (150-250 μg protein) were incubated in titre plates in 250 μl of assay buffer (Tris HCl 50 mM, EDTAi mM, pH 7.4) at 24-25°C for 1 hour. Non-specific binding was determined in the presence of 300 mM prazosin or 10 μM terazosin. The in cubation was terminated by vaccum filtration over 0.5% polyethylenimine pre-treated GF/B fibers using skatron cell harvester. The filters were then washed with ice coed 50 mM Tris HCl buffer (pH 7.4). the filtermates were dried and transferred to 24 well plates (PET A No cross talk). Radio activity retained on filters was counted in 600 μl of supermix in microbeta with a counting efficiency of 46%. IC₅₀ value was determined using the non-linear curve fiting program using G pad prism software. Saturation binding assays were used to determined Kd (apparent dissociation constant) for [³H] prazosin. The value of inhibition constant Ki was calculated from competitive binding studies by using Cheng and prusoff equation (Cheng and Prusoff, 1973), Ki = IC₅₀ L (i+ — ) wherein L is the concentration of [ H] prazosin used in the particular experiment. Ka Subtype selective by (α_la Vs α^) is expressed as ratio of mean Ki at αi_b receptors to mean Ki at αi_a receptors (Table VIII).

Table VIII

Example 20: Preparation of Methanesulfonic acid 2-(2.6-dioxo-piperidin-l-yl)-l- 4-(2- methoxy-phenvD-piperazin- 1 -yl-methyl]ethyl ester To a solution of l -{2-Hydroxy-3-{ 4-(2-methoxy-phenyl)-piperazin-l-yl} -propyl }- piperidine-2,6-dione (1 equi, from example 7) in dichloromethane (80-100 ml) is added triethylamine (1.5 equi) at 0-5°C and reaction mixture stirred for 15-30 minutes. To the reaction mixture is added methansulfonyl chloride (1.5 equi) at 0 °C to 5 °C for half to one hour. Reaction mixture is poured in 5% sodium bicarbonate solution. Organic layer is separated and washed with water, dried over anhydrous sodium sulphate and solvent is removed under reduced pressure to yield the desired product.

The following prodrugs can be prepared similarly

Benzenesulfonic acid 2-(2,6-dioxo-piperidin-l-yl)-l -[4-(2-methoxy-phenyl)-piperazin-l- yl-methyl]ethyl ester,

Acetic acid 2-(2,6-dioxo-piperidin-l -yl)-l -[4-(2-methoxy-phenyl)-piperazin-l -yl- methyl] ethyl ester,

Propionic acid 2-(2,6-dioxo-piperidin-l -yl)-l-[4-(2-methoxy-phenyl)-piperazin-l -yl- methyl] ethyl ester, Phenyl acetic acid 2-(2,6-dioxo-piperidin-l-yl)-l-[4-(2-methoxy-phenyl)-piperazin-l-yl- methyl] ethyl ester,

Dimethyl carbamic acid 2-(2,6-dioxo-piperidin-l-yl)-l -[4-(2-methoxy-phenyl)-piperazin- 1-yl-mcthyl] ethyl ester,

Methyl-phenyl carbamic acid 2-(2,6-dioxo-piperidin-l-yl)-l-[4-(2-methoxy-phenyl)- pipcrazin-1 -yl-methyl] ethyl ester,

Diphenyl carbamic acid 2-(2,6-dioxo-piperidin-l-yl)-l-[4-(2-methoxy-phenyl)-piperazin- 1 -yl-methyl] ethyl ester.

Example 21: Preparation of Acetic acid 2- -[3-(2,6-dioxo-piperadin-l-yl)-propyl]- piperazin-1-vU -3 -methoxy phenyl ester. To a solution of l-{3-[4-(5-Hydroxy-2-methoxy-phenyl)-piperazin-l-yl]-propyl}- piperidine-2,6-dione (1 equi, from example 8) in dichloromethane (80-100 ml) is added triethylamine (1.5 equi) at 0-5°C and reaction mixture stirred for 15-30 minutes. To the reaction mixture is added ethanoyl chloride (1.5 equi) at 0 °C to 5 °C for half to one hour. The reaction mixture is poured in 5% sodium bicarbonate solution. Organic layer is separated and washed with water, dried over anhydrous sodium sulphate and solvent is removed under reduced pressure to yield the desired product.

The following prodrugs can be prepared similarly

Methanesulfonic acid 2- { 4-[3-(2,6-dioxo-piperadin- 1 -yl)-propyl]-piperazin- 1 -yl} -3- methoxy phenyl ester,

Benzenesulfonic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3- methoxy phenyl ester,

Propionic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3-methoxy phenyl ester, Phenyl acetic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3-methoxy phenyl ester,

Dimethyl carbamic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3- methoxy phenyl ester,

Methyl-phenyl carbamic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}- 3-methoxy phenyl ester,

Diphcnyl carbamic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3- methoxy phenyl ester.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

We Claim

1. A metabolite of compound namely, l-{3-[4-(2-Methoxyphenyl)piperazin-l-yl] propyl} -piperidine-2,6-dione of Formula I,

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymoφhs, conjugates or prodrugs thereof.

2. A metabolite according to claim 1 wherein said metabolite of said compound of Formula I is desmethylated, hydroxylated or N-oxide having the structure of Formula II,

their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers or polymoφhs wherein Ri and R₂ are independently selected from hydrogen, hydroxy, R₃ represents hydrogen, methyl, n represents an integer 0 or 1 , with the proviso that when R₃ is methyl and n is 0, Ri and R₂ simultaneously are not hydrogen.

3. A metabolite according to claim 1 wherein said metabolite of said compound of Formula I is opened piperidine-2,6-dione derivative having the structure of Formula III,

Formula III their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers or polymoφhs wherein Ri. and R₂ are independently selected from hydrogen, hydroxy, R₃ represents hydrogen, methyl, R₄ represents hydrogen, methyl.

4. A metabolite according to claim 1 wherein said metabolite of said compound of Formula I is a desmethylated or hydroxylated derivative or its conjugate or prodrug.

5. A conjugate according to claim 4 selected from sulfate, phosphate and glucuronate.

6. A prodrug according to claim 4 selected from carbamoyl, alkyl (Cι-C₄) carbonyl, aryl carbonyl and alkyl (Cι-C₄) sulfonyl.

7. The desmethylated metabolite l-{3-[4-(2-Hydroxy-phenyl)-piperazin-l-yl]- propyl} -piperidine-2,6-dione, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymoφhs, conjugates or prodrugs.

8. A metabolite according to claim 7 eluted off from Lichrospher RP-select B 5μ (4 x 125 mm) column using a flow rate of 0.3 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 6) and acetonitrile (40:60), at 15.5-16.6 minutes, and has a molecular ion peak m/z 332.

9. A metabolite according to claim 7 eluted off from Novapak-phenyl 4 μm (3.9 x 125 mm) column using a flow rate of 0.8 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 5 1 0.1) and acetonitrile (70:30), at 3.7-4.6 minutes, and has a molecular ion peak m/z 332.

10. The hydroxylated metabolite l-{2-Hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-l- yl]-propyl}piperidine-2,6-dione, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymoφhs, conjugates or prodrugs.

11. A metabolite according to claim 10 eluted off from Lichrospher RP-select B 5μ (4 x 125 mm) column using a flow rate of 0.3 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 6) and acetonitrile (40:60), at 11.5-12.7 minutes, and has a molecular ion peak m/z 348.

12. A metabolite according to claim 10 eluted off from Novapak-phenyl 4 μm (3.9 x 125 mm) column using a flow rate of 0.8 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 5 1 0.1) and acetonitrile (70:30), at 2.4-3.5 minutes, and has a molecular ion peak m z 348.

13. The N-oxide metabolite l-{3-[l-oxo-4-(2-hydroxy-phenyl)-piperazin-l-yl]- propyl} piperidine-2,6-dione, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymoφhs, conjugates or prodrugs.

14. A metabolite according to claim 13 eluted off from Lichrospher RP-select B 5μ (4 x 125 mm) column using a flow rate of 0.3 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 6) and acetonitrile (40:60), at 5.5-6.5 minutes, and has a molecular ion peak m z 348.

15. The hydroxylated metabolite 1 - {2-Hydroxy-3 - {4-(2-methoxy-phenyl)-piperazin- 1 - yl} -propyl} -piperidine-2,6-dione, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymoφhs, conjugates or prodrugs.

16. A metabolite according to claim 15 eluted off from Lichrospher RP-select B 5μ (4 x 125 mm) column using a flow rate of 0.3 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 6) and acetonitrile (40:60), at 13.0-14.4 minutes, and has a molecular ion peak m/z 362.

17. A metabolite according to claim 15 eluted off from Novapak-phenyl 4 μm (3.9 x 125 mm) column using a flow rate of 0.8 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 5 1 0.1) and acetonitrile (70:30), at 3.2-4.5 minutes, and has a molecular ion peak m/z 362.

18. The hydroxylated metabolite l-{3-[4-(5-Hydroxy-2-methoxy-phenyl)-piperazin-l- yl]-propyl}-piperidine-2,6-dione, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymoφhs, conjugates or prodrugs.

19. A metabolite according to claim 18 eluted off from Lichrospher RP-select B 5μ (4 x 125 mm) column using a flow rate of 0.3 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 6) and acetonitrile (40:60), at 13.0-14.2 minutes, and has a molecular ion peak m/z 362.

20. A metabolite according to claim 18 eluted off from Novapak-phenyl 4 μm (3.9 x 125 mm) column using a flow rate of 0.8 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 5 1 0.1) and acetonitrile (70:30), at 3.0-4.2 minutes, and has a molecular ion peak m/z 362.

21. The hydroxylated metabolite l-{2-Hydroxy-3-[4-(5-hydroxy-2-methoxy-phenyl)- piperazin-l-yl]-propyl}-piperidine-2,6-dione, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymoφhs, conjugates, or prodrugs.

22. A metabolite according to claim 21 eluted off from Lichrospher RP-select B 5μ (4 x 125 mm) column using a flow rate of 0.3 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 6) and acetonitrile (40:60), at 10.5-11.6 minutes, and has a molecular ion peak m/z 378.

23. The N-oxide metabolite l-{3-[l-oxo-4-(2-methoxy-phenyl)-piperazin-l-yl]- propyl} -piperidine-2,6-dione, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates or polymoφhs.

24. A metabolite according to claim 23 eluted off from Lichrospher RP-select B 5μ (4 x 125 mm) column using a flow rate of 0.3 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 6) and acetonitrile (40:60), at 7.0-8.2 minutes, and has a molecular ion peak m/z 362.

25. A metabolite according to claim 23 eluted off from Novapak-phenyl 4 μm (3.9 x 125 mm) column using a flow rate of 0.8 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 5 1 0.1) and acetonitrile (70:30), at 1.7-2.6 minutes, and has a molecular ion peak m/z 362.

26. The N-oxide metabolite 1 - {2-Hydroxy-3-[ 1 -oxo-4-(5-hydroxy-2-methoxy-phenyl)- piperazin-l-yl]-propyl}-ρiperidine-2,6-dione, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymoφhs, conjugates or prodrugs.

27. A metabolite according to claim 26 eluted off from Lichrospher RP-select B 5μ (4 x 125 mm) column using a flow rate of 0.3 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 6) and acetonitrile (40:60), at 4.5-5.4 minutes, and has a molecular ion peak m/z 378.

28. The N-oxide metabolite l-{2-Hydroxy-3-[l-oxo-4-(5-hydroxy-2-methoxy-ρhenyl)- piperazin-l-yl]-propyl}-ρiperidine-2,6-dione, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymoφhs, conjugates or prodrugs.

29. A metabolite according to claim 28 eluted off from Lichrospher RP-select B 5μ (4 x 125 mm) column using a flow rate of 0.3 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 6) and acetonitrile (40:60), at 3.6-4.8 minutes, and has a molecular ion peak m z 394.

30. The opened piperidine-2,6-dione ring metabolite 4-{-3-[4-(2-Methoxy-phenyl)- piperazin-l-yl]-propylcarbamoyl} -butyric, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates or polymoφhs.

31. A metabolite according to claim 30 eluted off from Lichrospher RP-select B 5μ (4 x 125 mm) column using a flow rate of 0.8 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 6) and acetonitrile (40:60), at 1.5-2.7 minutes, and has a molecular ion peak m/z 364.

32. A metabolite according to claim 30 eluted off from Novapak-phenyl 4 μm (3.9 x 125 mm) column using a flow rate of 0.8 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 5 1 0.1) and acetonitrile (70:30), at 1.5-2.5 minutes, and has a molecular ion peak m/z 364.

33. The opened piperidine-2,6-dione ring metabolite 4- {-3-[4-(2-Methoxy-phenyl)- piperazin-l-yl]-propylcarbamoyl}-butyric acid methyl ester, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates or polymoφhs.

34. A metabolite according to claim 33 eluted off from Lichrospher RP-select B 5μ (4 x 125 mm) column using a flow rate of 0.3 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 6) and acetonitrile (40:60), at 18.0-19.5 minutes, and has a molecular ion peak m/z 378.

35. A metabolite according to claim 33 eluted off from Novapak-phenyl 4 μm (3.9 x 125 mm) column using a flow rate of 0.8 mL/min and a solvent system 8 nM ammonium acetate buffer (pH 5 1 0.1) and acetonitrile (70:30), at 3.5-4.5 minutes, and has a molecular ion peak m/z 378.

36. A pharmaceutical composition comprising a therapeutically effective amount of a metabolite of any one of the preceding claims, its pharmaceutically acceptable salts, solvates, enantiomers, polymoφhs, conjugates or prodrugs and a pharmaceutically acceptable carrier.

37. A method for treatment of a subject suffering from a disease or disorder mediated through αι_a-adrenceptor, comprising administering to said subject a therapeutically effective amount of a metabolite according to claim 1 or 2.

38. A method for treatment of a subject suffering from a disease or disorder selected from the group comprising of high intraocular pressure, disorder associated with high cholesterol, cardiac arrhythmia, impotency, sympathetically mediated pain and migraine, comprising administering to said subject a therapeutically effective amount of a metabolite according to claim 1 or 2.

39. A method for the treatment of a subject suffering from benign prostatic hypeφlasia, comprising administering to said subject a therapeutically effective amount of a metabolite according to claim 1 or 2.

40. The method according to claim 39 wherein metabolite additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hypeφlasia.

41. The method according to claim 39 wherein the metabolite treats benign prostatic hypeφlasia by relaxing lower urinary tract tissue.

42. The method according to claim 41 wherein lower urinary tract tissue is prostate smooth muscle.

43. A method for treatment of a subject suffering from a disease or disorder mediated through αι_a-adrenceptor, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition according to claim 36.

44. A method for treatment of a subject suffering from a disease or disorder selected from the group comprising of high intraocular pressure, disorder associated with high cholesterol, cardiac arrhythmia, impotency, sympathetically mediated pain and migraine, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition according to claim 36.

45. A method for the treatment of a subject suffering from benign prostatic hypeφlasia, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition according to claim 36.

46. The method according to claim 45 wherein pharmaceutical composition additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hypeφlasia.

47. The method according to claim 45 wherein pharmaceutical composition treats benign prostatic hypeφlasia by relaxing lower urinary tract tissue.

48. The method according to claim 47 wherein lower urinary tract tissue is prostate smooth muscle.

49. A process for the preparation of a metabolite of Formula VI,

its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymoφhs, conjugates or prodrugs, wherein R represents hydrogen, hydroxy, R₃ represents, hydrogen, methyl, with the proviso that R₂ and R₃ are not hydrogen and methyl, respectively, which method comprises reacting a compound of Formula IV with a compound of Formula V to give a compound of Formula VI,

50. The process according to claim 49 wherein the reaction of a compound of Formula IV with a compound of Formula V to give a compound of Formula VI is carried out in a solvent selected from acetonitrile, acetone, tetrahydrofuran, cyclohexane, dimethylformamide and dimethylformamide.

51. The process according to claim 50 wherein the reaction is carried out in dimethylformamide.

52. The process according to claim 49 wherein the reaction of a compound of Formula IV with a compound of Formula V is carried out in the presence of potassium iodide or sodium iodide and a suitable inorganic base selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, barium carbonate and sodium hydride.

53. The process according to claim 52 wherein the reaction is carried out in the presence of potassium carbonate.

54. A process for the preparation of a metabolite of Formula VII,

its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymoφhs, conjugates or prodrugs, wherein R₂ represents hydrogen, hydroxy, R represents hydrogen, methyl, which method comprises reacting a compound of Formula VI with peroxyacid to give a compound of Formula VII.

55. The process according to claim 54 wherein the reaction of a compound of Formula VI to give a compound of Formula VII is carried out in a solvent selected from chloroform, dichloromethane, tetrahydrofuran and acetonitrile.

56. The process according to claim 54 wherein peroxyacid is meta-perchlorobenzoic acid.

57. A process for the preparation of a metabolite of Formula IX,

its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymoφhs, conjugates or prodrugs, wherein R₂ represents hydrogen, hydroxy, R represents hydrogen, methyl, which method comprises reacting a compound of Formula VIII with a compound of Formula V to give a compound of Formula IX.

Formula VIII

58. The process according to claim 57 wherein the reaction of a compound of Formula VIII with a compound of Formula V is carried out in the presence of an alcohol selected from methanol, ethanol, isopropanol and butanol.

59. The process according to claim 58 wherein the reaction is carried out in ethanol.

60. A process for the preparation of a metabolite of Formula X,

its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers and polymoφhs, conjugates, or prodrugs, wherein R₂ represents hydrogen, hydroxy, R₃ represents hydrogen, methyl, which method comprises reacting a compound of Formula IX with peroxyacid to give a compound of Formula X.

61. The process according to claim 60 wherein the reaction of a compound of Formula IX to give a compound of Formula X is carried out in a solvent selected from chloroform, dichloromethane, tetrahydrofuran and acetonitrile.

62. The process according to claim 60 wherein peroxyacid is meta-perchlorobenzoic acid.

63. A process for the preparation of a metabolite of Formula XI,

its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymoφhs, conjugates or prodrugs, wherein Ri represents hydrogen, hydroxy, R₂ represents hydrogen, hydroxy, R₃ represents hydrogen, methyl, which method comprises reacting a compound of Formula II with an inorganic base to give a compound of Formula XI.

64. The process according to claim 63 wherein the inorganic base is selected from potassium hydroxide and sodium hydroxide.

65. The process according to claim 64 wherein the inorganic base is sodium hydroxide.

66. A process for the preparation of a metabolite of Formula XIII,

its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymoφhs, enantiomers, conjugates or prodrugs, wherein Ri represents hydrogen, hydroxy, R₂ represents hydrogen, hydroxy, R₃ represents hydrogen, methyl, which method comprises reacting a compound of Formula XI with methanol to give a compound of Formula XIII.

67. The process according to claim 66 wherein the reaction of a compound of Formula XI to give a compound of Formula XIV is carried out in the presence of hydrochloric acid.

68. A prodrug having the structure of Formula XVI,

wherein W represents -SO₂-, -CO-, -CONR₅- wherein R₅ represents alkyl of from one to four carbon atoms or aryl selected from phenyl and naphthyl, R represents alkyl of from one to four carbon atoms, aryl, aralkyl, n represents an integer 0 or 1.

69. A prodrug having the structure of Formula XVIII,

70. A prodrug according to claim 68 or 69 wherein aryl is phenyl or naphthyl.

71. A prodrug according to claim 68 or 69 wherein aralkyl is benzyl.

72. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, SO , 0 and alkyl of from one to four carbon atoms.

73. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, SO₂, 0 and methyl.

74. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, SO₂, 0 and aryl.

75. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, SO , 0 and phenyl.

76. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, CO, 0 and alkyl of form one to four carbon atoms.

77. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, CO, 0 and methyl.

78. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, CO, 0 and ethyl.

79. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, CO, 0 and aralkyl.

80. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, CO, 0 and benzyl.

81. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, CONR₅, 0 and alkyl of from one to four carbon atoms, wherein R₅ is alkyl of from one to four carbon atoms.

82. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, CONR₅, 0 and methyl, wherein R₅ methyl.

83. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, CONR₅, 0 and aryl, wherein R₅ is alkyl of from one to four carbon atoms.

84. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, CONR₅, 0 and phenyl, wherein R₅ is methyl.

85. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, CONR₅, 0 and aryl, wherein R₅ is aryl.

86. A prodrug according to claim 68 or 69 wherein W, n and R are respectively, CONR₅, 0 and phenyl, wherein R₅ is phenyl.

87. A prodrug, namely: Methanesulfonic acid 2-(2,6-dioxo-piperidin- 1 -yl)- 1 -[4-(2-methoxy-phenyl)- piperazin-l-yl-methyl]ethyl ester, Benzenesulfonic acid 2-(2,6-dioxo-piperidin- 1 -yl)- 1 -[4-(2-methoxy-phenyl)- piperazin- 1 -yl-methyl] ethyl ester, Acetic acid 2-(2,6-dioxo-piperidin- 1 -yl)- 1 -[4-(2-methoxy-phenyl)-piperazin- 1 -yl- methyl] ethyl ester, Propionic acid 2-(2,6-dioxo-piperidin- 1 -yl)- 1 -[4-(2-methoxy-phenyl)-piperazin- 1 - yl-methyl] ethyl ester, Phenyl acetic acid 2-(2,6-dioxo-piperidin- 1 -yl)- 1 -[4-(2-methoxy-phenyl)- piperazin- 1 -yl-methyl] ethyl ester, Dimethyl carbamic acid 2-(2,6-dioxo-piperidin- 1 -yl)- 1 -[4-(2-methoxy-phenyl)- piperazin- 1 -yl-methyl] ethyl ester, Methyl-phenyl carbamic acid 2-(2,6-dioxo-piperidin-l-yl)-l-[4-(2-methoxy- phenyl)-piperazin-l -yl-methyl] ethyl ester, Diphenyl carbamic acid 2-(2,6-dioxo-piperidin- 1 -yl)- 1 -[4-(2-methoxy-phenyl)- piperazin- 1 -yl-methyl] ethyl ester, Methanesulfonic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}- 3 -methoxy phenyl ester, Benzenesulfonic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}- 3 -methoxy phenyl ester, Acetic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3-methoxy phenyl ester, Propionic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3- methoxy phenyl ester, Phenyl acetic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l-yl}-3- methoxy phenyl ester, Dimethyl carbamic acid 2- {4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l- yl} -3-methoxy phenyl ester, Methyl-phenyl carbamic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]- piperazin- 1 -yl} -3-methoxy phenyl ester, Diphenyl carbamic acid 2-{4-[3-(2,6-dioxo-piperadin-l-yl)-propyl]-piperazin-l- yl } -3 -methoxy phenyl ester.

88. A process for the preparation of a prodrug of Formula XVI,

Formula XVI which method comprises reacting a compound Formula XV

Formula XV with a compound of Formula Cl — W — R to give a prodrug of Formula XVI, wherein W represents -SO₂-, -CO-, -CONR5- wherein R₅ represents alkyl of from one to four carbon atoms or aryl selected from phenyl and naphthyl, R represents alkyl of from one to four carbon atoms, aryl, aralkyl, n represents an integer 0 or 1.

89. The 'process according to claim 88 wherein the reaction of a compound of Formula XV with a compound of Formula Cl — W— R to give a prodrug of Formula XVI is carried out in a solvent selected from tetrahydrofuran and dimethylformamide.

90. The process according to claim 88 wherein the reaction of a compound of Formula XV with a compound of Formula Cl — W — R is carried out in the presence of an inorganic base selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and sodium hydride.

91. A process for the preparation of a prodrug of Formula XVIII,

Formula XVIII which method comprises reacting a compound Formula XVII

Formula XVII with a compound of Formula Cl — W — R to give compound of Formula XVIII, wherein W represents -SO₂-, -CO-, -CONR - wherein R₅ represents alkyl of from one to four carbon atoms or aryl selected from phenyl and naphthyl, R represents alkyl of from one to four carbon atoms, aryl, aralkyl, n represents an integer 0 or 1.

92. The process according to claim 91 wherein the reaction of a compound of Formula XV with a compound of Formula Cl — W— R to give a compound of Formula XVI is carried out in a solvent selected from tetrahydrofuran and dimethylformamide.

93. The process according to claim 91 wherein the reaction of a compound of Formula XV with a compound of Formula Cl — W— R is carried out in the presence of an inorganic base selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and sodium hydride.