WO2005113498A1

WO2005113498A1 - Adrenergic receptor antagonists

Info

Publication number: WO2005113498A1
Application number: PCT/IB2004/001641
Authority: WO
Inventors: Mohammad Salman; Somesh Sharma; Gobind Singh Kapkoti; Nitya Anand; Anita Chugh
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-05-19
Filing date: 2004-05-19
Publication date: 2005-12-01

Abstract

This invention relates to α1a and/or α1d adrenergic receptor antagonists. Compounds disclosed herein can function as α1a and/or α1d adrenergic receptor antagonist and can be used for the treatment of diseases or disorder mediated through α1a and/or α1d adrenergic receptors. Compounds disclosed herein can be used for the treatment of benign prostatic hyperplasia and the related symptoms thereof. Compounds disclosed herein can be used for the treatment of lower urinary tract symptoms associated with or without benign prostatic hyperplasia. Processes for the preparation of compounds disclosed herein, pharmaceutical compositions containing the compounds disclosed herein, and methods of treating benign prostatic hyperplasia or related symptoms thereof are also provided. Formula (I) Its pharmaceutically acceptable acid addition salts,pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, polymorphs or metabolites,wherein; A represents a Formula (F.a or ,F.b or F.c wherein) N represents 1 or 2; Y represents cycloalkyl (C5-C7) group; optionally substituted with halogen atom(s) or lower alkyl (C1-C4) group; and R is selected from optionally substituted non&lowbar;aromatic or aromatic monocyclic or bicyclic ring system having 0 to 4 heteroatom(s),the substituent(s) may be selected from the group consisting of halogen, lower alkyl (C1-C4),halogenated lower alkyl (C1-c4),cyano, hydroxy, lower alkoxy (C1-C4),cycloalkoxy (C3-C6),amino,lower alkylamino (C1-C4) and lower alkylamino (C1-C4) carbonyl group.

Description

ADRENERGIC RECEPTOR ANTAGONISTS

Field of the Invention

This invention relates to α_la and/or α₁₍ι adrenergic receptor antagonists. Compounds disclosed herein can function as α_la and/or α₁₍₁ adrenergic receptor antagonist and can be used for the treatment of diseases or disorder mediated through α_la and/or au adrenergic receptors. Compounds disclosed herein can be used for the treatment of benign prostatic hyperplasia and the related symptoms thereof. Compounds disclosed herein can be used for the treatment of lower urinary tract symptoms associated with or without benign prostatic hyperplasia. Processes for the preparation of compounds disclosed herein, pharmaceutical compositions containing the compounds disclosed herein, and methods of treating benign prostatic hyperplasia or related symptoms thereof are also provided.

Background of the Invention

Benign prostatic hyperplasia (BPH) is a condition which develops in elderly males and refers to the benign overgrowth of the stromal and epithelial elements of the prostate associated with aging. The symptoms of BPH vary, but the most common ones involve changes or problems with urination, such as a hesitant, interrupted, weak stream or urgency and leaking or dribbling or more frequent urination, especially at night. Consequences of BPH can involve hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection.

There are two components of BPH, static and a dynamic component. The static component is due to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of urine from the bladder. The dynamic component is due to increased smooth muscle tone of the bladder neck and prostate itself and is regulated by α- 1 adrenergic receptor.

Currently, the most effective treatment for BPH is the surgical procedure of transurethral resection of the prostate (TURP), since it removes the obstructing tissue (C. Chappie's Br. Med. Journal 304: 1198-1199, 1992). It is a treatment, which is directed to the static and dynamic components of the BPH. However this surgical treatment is associated with rates of mortality (1%) and adverse event (incontinence 2-4%) infection 5-10 %, and impotence 5-10%. A non invasive alternative treatment is therefore highly desirable. There are some drug therapies, which address the static component of this condition. Administration of finasteride is one such therapy, which is indicated for the treatment of symptomatic BPH. This drug is a competitive inhibitor of the enzyme 5α- reductase which is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland. Dihydrotestosterone appears to be the major mitogen for prostate growth, and agents which inhibit 5αreductase reduce the size of the prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5αreductase inhibitor and causes a marked decrease in serum and tissue concentrations of dihydrotestosterone, it is only moderately effective in the treatment of symptomatic BPH. The effects of finasteride take 6-12 months to become evident, and for many men the clinical development is minimal.

The dynamic component of BPH has been addressed by the use of adrenergic receptor blocking agents, which act by decreasing the smooth muscle tone within the prostate gland. A variety of a._\ adrenergic receptor antagonists such as terazosin, doxazosin, prazosin, alfuzosin and tamulosin have been investigated for the treatment of symptomatic bladder outlet obstruction due to BPH. However, these drugs are associated with vascular side effects (e.g. postural hypertention, syncope, dizziness, headache etc) due to lack of selectivity of action between prostatic and vascular αii-adrenoceptors. There are several lines of evidence to suggest that selectivity for α_la adrenoceptor over oii_b adrenoceptor will result in relative lack of vascular side effects, thus lead to a better tolerability. In- vivo studies in healthy subjects comparison

selective antagonists (e.g., tamsulosin) or α_la selective antagonists (e.g., urapidil) with non selective antagonists (e.g., doxazosin, prazosin, or terazosin) under a variety of experimental conditions (e.g., involving the administration of exogenous agonist or release of endogenous agonist by cold stimulation) in several vascular beds including the skin circulation in finger tips, the dorsal hand vein, or with total peripheral resistance have been reported. (Eur. J. Clin. Pharmacol, 1996, 49, 371-375; Naunyn Schmiedeberg's Arch. Pharmacol. 1996, 354, 557-561; Jpn. J. Pharmacol. 1999, 80, 209-215; BrJ Clin. Pharmacol. 1999, 47, 67-74). These studies have reported that an antagonist with high affinity for α_la or _\ au can cause some degree of vasodilation but that it is much smaller than with non-subtype-selective a_\ adrenoceptor antagonist. Further, there is increased vascular a_\\, adrenoceptor expression in elderly patients and thus aγ au selective agents with selectivity over a^ adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia, which is generally a disease of old age. Antagonism of both cϋ_la adrenoceptor and an adrenoceptor is believed important to relieve lower urinary tract symptoms especially associated (suggestive of) with BPH. Targeting α_la adrenoceptor with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction whereas

adrenoceptor antagonism is important to target irritative symptoms.

Over the past decade, there has been an intensive search for selective a_\ adrenoceptor antagonists for benign prostatic hyperplasia which would avoid the cardiovascular side effects associated with currently used drugs. Selective antagonists have been described by Hieble et al in Exp. Opin. Invest. Drugs; 6, 367-387 (1997) and by Kenny et al., in J. Med. Chem.; 40, 1293-1325 (1995). Pharmacological activities associated with phenyl piperazines have been studied in, Eur. J. Med. Chem. — Chimica Therapeutica, 12, 173-176 (1977), which describes substituted trifluorometyl phenyl piperazines having cyclo-imido alkyl side chains shown below.

Other compounds which have been prepared as anxiolytic, neuroleptic, anti- diabetic and anti-allergic agents are described in the following references: Yukihiro et al; PCT Appl. WO 98/37893 (1998), Steen et al; J. Med. Chem., 38, 4303-4308 (1995), Ishizumi et al. Chem. Pharm. Bull; 39 (9), 2288-2300 (1991), Kitaro et al; JP 02-235865 (1990), Ishizumi et al; U.S. Patent No. 4,598,078 (1986), New et. al; J Med. Chem. 29, 1476-1482 (1986), Shigeru et. al; JP 60-204784 (1985), New et al, U.S. Patent No. 4,524, 206 (1985), Korgaonkar et al; J. Indian Chem. Soc, 60, 874-876 (1983).

However, none of the above mentioned references disclose or suggest the ctι subtype selectivity profile of the compounds disclosed therein and thus their usefulness in the treatment of symptoms of benign prostate hyperplasia did not arise.

The synthesis of l-(4-arylpiperazin-l-yl)-ω-[N-(α, ω-dicarboximido)]-alkanes useful as uro-selective αi-adrenoceptor blockers are disclosed in U.S. Patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,559 and 6,420,366. These compounds have good α i -adrenergic blocking activity and selectivity. Other reports describing selective a adrenoceptor antagonists are U.S. Patent

Nos. 6,376,503, 6,319,932, and 6,339,090, EP 711757, WO 02/44151; 99/42448, 99/42445, 98/57940, 98/57632, 98/30560 and WO 97/23462, and all these patents are incorporated by reference herein in their entirety.

Summary of the Invention Provided herein are α_la and/or α_lcι adrenergic receptor antagonists, which are useful for safe and effective treatment of benign prostatic hyperplasia or related symptoms thereof, and methods for the syntheses of these compounds.

Also provided herein are pharmaceutical compositions containing the compounds, which may also contain pharmaceutically acceptable carriers, excipients or diluents, which are useful for the treatment of benign prostatic hyperplasia or related symptoms thereof. Also provided are the enantiomers, diastereomers, pharmaceutically acceptable salts, solvates, polymorphs, N-oxide or metabolites of these compounds having the same type of activity. Further provided are pharmaceutical compositions comprising compounds disclosed herein, their enantiomers, polymorphs, pharmaceutically acceptable acid addition salt, solvates, N-oxides or metabolites, in combination with pharmaceutically acceptable carriers and optionally included excipients. Other aspects of the invention will be set forth in description, which follows and in the part will be apparent from the description or may be learnt by the practice of the invention.

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

its pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, polymorphs or metabolites, wherein;

A can represent

wherein

n represents 1 or 2; and Rι, R₂ and R₃ can be independently selected from hydrogen, lower alkyl ( -

C₄), phenyl and benzyl, wherein phenyl and benzyl may be substituted with halogen (F, CI, Br or I), lower alkyl (Cι-C₄), halogenated (F, CI, Br or I) lower alkyl (d-C₄), hydroxy, alkoxy (Ci-C₄), amino and alkylamino (Cι-C₄) group.

The notation — in the ring represents either no bond or a single bond.

R* and R₅ can be independently selected from a) hydrogen, b) optionally substituted alkyl (Cι-C₆) [wherein the substituents are selected from the group consisting of halogen (F, CI, Br or I), cycloalkyl, cycloalkenyl (C₃-C ), optionally substituted phenyl (wherein the substituent(s) for phenyl may be selected from the group consisting of halogen (F, CI, Br or I), lower alkyl (Cι-C₄), halogenated (F, CI, Br or I) lower alkyl (Cι-C₄), hydroxy, lower alkoxy ( - ), amino and lower alkylamino (C1-C₄) group)]; c) alkenyl, d) alkynyl (C₂-C₇), e) cycloalkyl (C₃-C₇) group optionally substituted with halogen (F, CI, Br or I) atom(s) and f) optionally substituted non-aromatic or aromatic monocyclic or bicyclic ring system having 0 to 4 heteroatom(s) independently selected from the group consisting of nitrogen, sulphur and oxygen, the substituent(s) may be selected from the group consisting of halogen (F, CI, Br or I) atom(s), lower alkyl (Cι-C₄), halogenated (F, CI, Br or I) lower alkyl (Cι-C₄), cyano, hydroxy, lower alkoxy (Cι-C₄), cycloalkoxy (C₃-C₆), amino, lower alkylamino (Cι-C ) and lower alkylamino (C₁-C₄) carbonyl group.

Y can represent cycloalkyl (C₅-C₇) group optionally substituted with halogen or lower alkyl (Cι-C ) group.

R can be selected from optionally substituted non-aromatic or aromatic monocyclic or bicyclic ring systems having 0 to 4 heteroatom(s) independently selected from nitrogen, sulphur and oxygen. The substituent(s) may be selected from halogen, lower alkyl (Cι-C₄), halogenated lower alkyl (CrC₄), cyano, hydroxy, lower alkoxy ( - C₄), cycloalkoxy (C₃-C₆), amino, lower alkylamino ( -C₄) and lower alkylamino (d-C₄) carbonyl group.

In accordance with a second aspect, there is provided a method for the treatment of a patient suffering from a disease or disorder mediated through α_la and/or α₁₍₁ adrenergic receptors, comprising administering to a patient in need thereof an effective amount of compounds as described above. In accordance with a third aspect, there is provided a method for the treatment of a patient suffering from benign prostatic hyperplasia (BPH) and related symptoms, comprising administering to a patient in need thereof an effective amount of compounds as described above. In accordance with a fourth aspect, there is provided a method for the treatment of a patient suffering from lower urinary tract symptoms (LUTS) with or without BPH. LUTS may include, for example, irritative symptoms such as frequent urination, urgent urination, nocturia and unstable bladder contractions, obstructive symptoms such as hesitancy, poor stream, prolong urination, and feelings of incomplete emptying, comprising administering to a patient in need thereof, an effective amount of compounds as described above.

In accordance with a fifth aspect, there are provided processes for preparing the compounds as described above.

In accordance with a sixth aspect, there is provided a method for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient in need thereof, an effective amount of a compound (or composition) described above in combination with a selective muscarinic receptor antagonist.

In accordance with a seventh aspect, there is provided a method for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient in need thereof, an effective amount of a compound (or composition) described above in combination with and a testosterone 5 alpha-reductase inhibitor.

In accordance with an eight aspect, there is provided a method for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient in need thereof, an effective amount of a compound (or composition) described above in combination with a selective muscarinic receptor antagonist and optionally included a testosterone 5 alpha-reductase inhibitor. Receptor binding and in vitro functional assay studies described below indicated that the compounds disclosed herein possess selective and potent α_la adrenoceptor antagonistic activity over the αi_b and/or i_d adrenoceptors. The examples presented below describe a method to treat BPH in a patient wherein the test compounds alleviated pressure at dosages which did not result in significant change in blood pressure. Several of the compounds of the present invention demonstrated manifest selectivity for prostatic tissues in comparison to known compounds. Additionally, the compounds of the present invention are also useful for relaxing lower urinary tract tissues and thus alleviating irritative symptoms in-patient. Therefore, pharmaceutical compositions for treatment of a disease or disorder mediated through α_la adrenoceptors are provided. Moreover, compounds of the present invention can also be used for treatment of lower urinary tract symptoms. Compounds and compositions described herein can be administered orally, parenterally or topically.

Detailed Description of the Invention The compounds described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds described herein may be prepared by the following reaction sequence as depicted in Scheme I.

Scheme I R Nθ₂ Formula II

R NH₂ Formula III H πOu> ^vOH R— N OH Formula IV

R— N OMs \ ^OMs Formula V H2H-Y-NH₂

H₂H-Y-N N— R

The preparation scheme includes hydrogenating a compound of Formula II with a suitable hydrogenating agent wherein R is selected from optionally substituted non- aromatic or aromatic monocyclic or bicyclic ring system having 0 to 4 heteroatom(s) independently selected from nitrogen, sulphur and oxygen, the substituent(s) may be selected from halogen (F, CI, Br or I) atom(s), lower alkyl ( -C₄), halogenated (F, CI, Br or I) lower alkyl (Cι-C₄), cyano, hydroxy, lower alkoxy (Cι-C₄), cycloalkoxy (C₃-C₆), amino, lower alkylamino (Cι-C₄) and lower alkylamino (Cι-C₄) carbonyl group.

The reaction of a compound of Formula II to give a compound of Formula III can be carried out with a hydrogenating agent, for example, palladium-carbon and hydrogen, Raney-Nickel and hydrogen or stannous chloride and hydrochloric acid.

The reaction of a compound of Formula III with 2-chloroethanol to yield a compound of Formula IV can be carried out in a solvent, for example, chlorobenzene, xylene, dioxane, dimethylformamide or toluene.

The reaction of a compound of Formula III with 2-chloroethanol can be carried out in presence of a organic base, for example, triethylamine, pyridine, 4- dimethylaminopyridine, or an inorganic base, for example, potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate.

The reaction of a compound of Formula IV with mesityl chloride to afford a compound of Formula V can be carried out in a solvent, for example, chloroform, dichloromethane, toluene, acetonitrile or tetrahydrofuran. The reaction of a compound of Formula IV with mesityl chloride can be carried out in presence of a base, for example, diethylamine, triethylamine, pyridine or 4-dimethylaminopyridine. The reaction of a compound of Formula IV with mesityl chloride can be carried out at a temperature ranging from about 0°C to about 15°C. The reaction of a compound of Formula V with a compound of Formula H₂N-Y-

NH₂ (wherein Y is as defined earlier) to give a compound of Formula VI can be carried out in a solvent, for example, chloroform, dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide or dimethylsulfoxide. The reaction of a compound of Formula VI with a compound of Formula

(wherein A is the same as defined earlier) can be carried out in acetic anhydride, toluene or xylene by aziotropic water separation.

Representative compounds according to the invention and capable of being produced by the Scheme I and shown in Table I include:

2-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-cyclohexyl}-3a,4,7,7a-tetrahydro- isoindole-l,3-dione (Compound No. 1)

1 - {4-[4-(2-Isopropoxy-phenyl)-piperazin- 1-yl} -cyclohexyl} -piperidine-2,6-dione (Compound No. 2)

1 - {4-[4-(2-Isopropoxy-phenyl)-piperazin- 1 -yl] -cyclohexyl} -3,3-dimethyl-piperidine-2,6- dione (Compound No. 3) 1- {4-[4-(2-Isopropoxy-phenyl)-piperazin- 1 -yl]-cyclohexyl} -3-phenyl-pyrolidine-2,5- dione (Compound No. 4) l-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-cyclohexyl}-pyrrole-2,5-dione (Compound No. 5) l-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-cyclohexyl}-3-methyl-pyrrole-2,5-dione (Compound No. 6)

1 - {4-[4-(2-Isopropoxy-phenyl)-piperazin- 1 -yl] -cyclohexyl} -3-phenyl-pyrole-2,5-dione (Compound No. 7)

1 - {4-[4-(2-Methoxy-phenyl)-piperazin- 1 -yl]-cyclohexyl} -3,4-dimethyl-pyrrole-2,5-dione (Compound No. 8) 3-Benzyl-l-{4-[4-(2-trifluoromethyl-phenyl)-piperazin-l-yl]-cyclohexyl}-pyrrole-2,5- dione (Compound No. 9)

Table 1

The compounds described herein are basic, and form organic or inorganic acid addition salts, which are within the scope of sound medical judgment suitable for use in contact with the tissue of humans and lower animals without undue toxicity, irritation, allergic response and the like. The resulting salts are useful by themselves and in the therapeutic compositions. These salts may be prepared by prior art techniques, such as suspending the compound in water and then adding one equivalent of an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, adipic acid, ascorbic acid, camphoenic acid, nicotinic acid, butyric acid, lactic acid, glucuronic acid, or inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, boric acid and perchloric acid.

The solution of the resulting salt is subjected to rotary evaporation under vacuum to the volume necessary to ensure precipitation of the salt upon cooling, which is then filtered and dried. The salts of the present invention may also be prepared under strictly non-aqueous conditions. For example, dissolving free base in a suitable organic solvent such as ethanol, methanol, isopropanol, dichloromethane or diethyl ether adding exactly one equivalent of the desired acid to the same solvent and stirring the solution at 0°C to 5°C, causes the precipitation of the acid addition salt, which is then filtered, washed the solvent, and dried.

Alternatively, the solvent is stripped of completely to obtain the desired salt. These salts may be suitable for use in formulating therapeutic compositions described herein because they can be crystalline or amorphous, and certain of these forms may be more stable or water soluble, for example.

The compounds described herein have pharmacological activity, and therefore may be administered to an animal for treatment orally, topically, rectally, internasally, or by parenteral route. The pharmaceutical compositions described herein comprise a pharmaceutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. Asused herein, the term "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi- solid or liquid filter, diluent, encapsulating material or formulation auxiliary of any type. Solid form preparation for oral administrations, include capsules, tablets, pills, powders, granules, cathets and suppositories. For solid form preparations, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate and/or a filler or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid; binders such as carboxymethylcellulose, alginates, gelatins, polyvinylpyrolidinone, sucrose, acacia; disintegrating agents such as agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates and sodium carbonate, absorption accelators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol, monostearate; adsorbents such as kaolin; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate and mixtures thereof.

In case of capsules, tablets, pills, the dosage form may also comprise buffering agents. Solid preparations of tablets, capsules, pills, granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.

Liquid form preparations for oral administration can include pharmaceutically acceptable emulsions, solution, suspensions, syrups and elixirs. For liquid form preparations, the active compound can be mixed with water or other solvent, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed, groundnut, corn, germ, olive, castor and Sesamie oil), glycerol, and fatty acid esters of sorbitan and mixture thereof. Besides inert diluents, the oral composition can also include adjuvant such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.

Injectable preparations such as sterile injections, aqueous or oleaginous suspensions may be formulated according to the art using suitable dispersing or wetting and suspending agents. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride. Dosage forms for tropical or transdermal administration of compound described herein include ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhalants or patches. The active compound can be admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservative or buffer as may be required. Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also provided herein.

The pharmaceutical preparation may be in unit dosage form. In such form, the preparation may be subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be packaged preparation, the package containing discrete capsules, powders, in vials or ampoules and ointments, capsules, cachet, tablet, gel cream itself or it can be the appropriate number of any of the packaged forms.

Formulations described herein may be prepared so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known to the art.

The dosages of the compounds described herein, muscarinic receptor antagonist and 5 alpha-reductase inhibitor are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the compounds described herein, muscarinic receptor antagonist and 5 alpha-reductase inhibitor may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In accordance with the method of the present invention, the individual component of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. Examples mentioned below demonstrate general synthetic procedures for the preparation of representative compounds. 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

Various solvents, such as methanol, ethanol, chloroform etc., were dried using various drying reagents according to procedures well known in the literature. IR spectra were recorded as nujol mulls or a thin film on a Perkm Elmer Paragon, Nuclear Magnetic Resonance were recorded on a Varian XL-200 instrument using tetramethylsilane as internal standard.

Example 1 : Preparation of 2- (4- [4-f 2-Isopropoxy-phenyl -piperazin- 1 - yl] - cyclohexyl|-3a,4 ,7a-tetrahydro-isoindole- 3-dione fCompound No. 1)

Step 1: Preparation of 2-Isopropoxy-phenylamine To a solution of l-Isopropoxy-2-nitro-benzene (10 gm, 0.055 mole) in methanol

(40 ml) was added Palladium-carbon (50% wet), 2.0 g and reaction mass hydrogenated at 50-60 psi for 4 to 8 hours. After completion of the reaction, the reaction mass filtered through a celite bed, and washed with methanol (2x 15 ml). The filtrate thus obtained was concentrated to yield the desired amine. Yield: 7.0 gm (84%)

Step 2: preparation of 2-[(2-Hydroxy-ethyl)-(2-isopropoxy-phenyl)-amino]-ethanol

2-Isopropoxy-phenylamine (5 gm, 0.033 mole) was dissolved in chlorobonzene (25 ml) and to reaction mixture was added triethylamine (16.7 gm, 0.165 mole) under stirring. After this, 2-chloroethanol (13.25 gm, 0.165 mole) was added and reaction mixture refluxed for 12 to 15 hours. The reaction was quenched by adding water (50 ml) to it and extracted with dichloromethane (3x50 ml). The organic layer dried over anhydrous sodium sulphate (Na SO₄) and concentrated to give the crude product. The crude product thus obtained was purified on a silica gel (60-120 mesh) column using dichloromethane-methanol as eluent. Yield: 5.8 gm (73%)

Step 3: Preparation of methane sulfonic acid-2-[(2-isopropoxy-phenyl)-(2- methanesulfony!oxy-ethyl]-amine ethyl ester 2-[(2-Hydroxy-ethyl)-(2-isopropoxy-phenyl)-amino]-ethanol (5 gm, 0.021 mole) was dissolved in dichloromethane (25 ml) and reaction mass cooled to about 0°C to 10°C. At this temperature, triethylamine (6.3 gm, 0.0627 mole) and methanosulphonyl chloride (7.18 gm, 0.0627 mole) were added to the reaction mixture under stirring. The reaction mixture was stirred for 30 minutes; and reaction was stopped by adding water (50 ml) to it, extracted with dichloromethane (2x20 ml). The organic layer washed with water (40 ml), dried over anhydrous sodium sulphate and concentrated to give the required compound. Yield; 7.5 gm (91%)

Step 4: Preparation of 4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-cyclohexylamine

To a solution of 1,4-diaminocyclohexane (7.2 gm, 0.063 mole) in dimethylformamide (40 ml) was added methane sulfonic acid-2-[(2-isopropoxy-phenyl)- (2-methanesulfonyloxy-ethyl]-amine ethyl ester (5 gm, 0.012 mole) at about 10°C to 25°C and reaction mixture then stirred at an ambient temperature for 12 to 15 hours. To the reaction mixture was added water (200 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layer washed with water (200 ml), dried over anhydrous sodium sulphate and concentrated to yield the required compound. Yield: 2.5 gm (63%)

Step 5: Preparation of 2-{4-[4-(2-Isopropoxy-phenyI)-piperazin-l-yl]-cycIohexyl}- 3a,4,7,7a-tetrahydro-isoindole-l,3-dione. A solution of 4-[4-(2-Isopropoxy-phenyl)-piρerazin-l-yl]-cyclohexylamine (2 gm, 0.006 mole) and cis-l,2,3,6-tetrahydrophthalicanhydride (1.05 gm, 0.0069 mole) in xylene (10 ml) was refluxed for 4 to 8 hours followed by cooling at an ambient temperature and to a reaction mixture was added water (20 ml) and extracted with ethyl acetate (2 x 15 ml). Combined organic layer washed with water (15 ml), dried over anhydrous sodium sulphate and concentrated to yield the desired compound Yield: 2.27 gm (81%); IR (KBr): 1695.3 cm^-1; 1HNMR (300 MHz, CDC1₃): δ 1.35-1.37 (d, 6H), 1.73-1.77 (m, 4H), 2.23-2.35 (m, 4H), 2.45-2.56 (m, 4H), 2.61-3.14 (m, 5H), 3.48-3.56 (m, 6H), 4.00 (m, IH), 4.57-4.61 (m, IH), 5.80-5.88 (m, 2H), 6.85-7.01 (m, 4H), 12.50 (brs, IH); Mass (m/z) : 452.4 (M⁺+l) The following compounds were prepared analogously.

Compound No. 2: l-(4-[^"4-(2-Isopropoxy-phenylVpiperazin-l-yll-cyclohexyl>- piperidine-2.6-dione

IR (KBr): 1668.0 cm-¹

1H NMR (300 MHz, CDC1₃): δ 1.57-1.59 (d, 6H), 1.90-1.94 (m, 2H), 2.45-2.53 (m, 4H), 2.62-2.66 (m, 4H), 3.49 (m, IH), 3.52 (m, 2H), 3.63-3.67 (m, 2H), 4.60-4.93 (m, 6H), 6.98-7.08 (m, 2H), 7.38-7.43 (m, IH), 8.14-8.16 (d, IH).

Mass (m z) : 414.4 (M⁺+l)

Compound No. 3: l-{4-[4-f2-Isoproρoxy-phenviypiperazin-l-yl]-cvclohexyl}-3,3- dimethyl-piperidine-2,6-dione

TR (KBr): 1671.0 cm^-1

1H NMR (300 MHz, CDC1₃): δ 1.24 (brs, 2H), 1.45 (brs, 6H), 1.74-1.76 (m, 6H), 2.35- 2.67 (m, 6H), 3.26-3.74 (m, 6H), 4.55-4.98 (m, 6H), 7.00-7.08 (m, 2H), 7.39-7.41 (m, IH), 8.19 (brs, IH), 13.48 (brs, IH).

Mass (m/z): 442.5 (M⁺+l)

Compound No. 4: l-{4-|^"4-(2-Isopropoxy-phenylVpiperazin-l-yl]-cyclohexyll-3-phenyl- p yrolidine-2, 5 -dione

IR (KBr): 1695.2 cm^"1

1H NMR (300 MHz, CDE1₃): δ 1.43-1.44 (d, 6H), 1.87-2.00 (m, 4H), 2.43-2.53 ( , 4H), 2.75-2.81 (m, IH), 3.13-3.22 (m, 2H), 3.46-3.58 (m, 5H), 3.70-4.12 (m, 4H), 4.67 (m, IH), 6.92-6.94 (m, 2H), 7.17-7.37 (m, 7H), 12.90 (brs, IH).

Mass (m/z): 476.5 (M⁺+l)

Compound No. 5: l-{4-[^"4- 2-Isopropoxy-phenylVpiperazin-l-yl]-cvclohexyl} -pyrrol e- 2,5-dione IR (KBr): 1709.4 cm^-1 1HNMR (300 MHz, CDC1₃): δ 1.35-1.37 (d, 6H), 1.75-1.92 (m, 4H), 2.26-2.35 (m, 2H), 2.48-2.52 (m, 2H), 3.11-3.19 (m, 4H), 3.46-3.63 (m, 5H), 4.01 (m, IH), 4.56-4.62 (m, IH), 6.66 (brs, 2H), 6.35-7.04 (m, 4H), 12.94 (brs, IH).

Mass (m/z): 398.3 (M⁺+l)

Compound No. 6: l-|4-r4-r2-Isopropoxy-phenyl)-piperazin-l-yll-cvclohexyll-3-methyl- pyrrole-2,5-dione

IR (KBr): 1705.1 cm^-1

1H NMR (300 MHz, CDC1₃): δ 1.36-1.38 (d, 6H), 1.74-1.90 (m, 4H), 2.06 (s, 3H), 2.21- 2.29 (m, 2H), 2.3-2.35 (m, 2H), 3.16-3.19 (m, 3H), 3.53-3.69 (m, 6H), 3.98-3.99 (m, IH), 4.56-4.64 (m, IH), 6.28 (brs, 2H), 6.85-7.05 (m, 4H), 13.64 (brs, IH)

Mass (m/z): 412.4 (M⁺+l)

The following compounds, for example, can be prepared analogously.

l-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-cyclohexyl}-3-phenyl-pyrole-2,5-dione (Compound No. 7)

1 - {4-[4-(2-Methoxy-phenyl)-piperazin- l-yl]-cyclohexyl} -3 ,4-dimethyl-pyrrole-2,5-dione (Compound No. 8)

3 -Benzyl- 1 - {4-[4-(2-trifluoromethyl-phenyl)-piperazin- 1 -yl] -cyclohexyl} -pyrrole-2,5- dione (Compound No. 9)

Example 2: Pharmacological testing: Receptor Binding Assay Receptor binding assays were performed using native α-1 adrenoceptors. The affinity of different compounds for α_la and α^ adrenoceptor subtypes was evaluated by studying their ability to displace specific [ H]prazosin binding from the membranes of rat submaxillary and liver respectively (Michel et al., Br. J. Pharmacol, 98, 883-889 (1989)). The binding assays were performed according to U'Prichard et al. (Eur. J. Pharmacol., 50:87-89 (1978) with minor modifications. Submaxillary glands were isolated immediately after sacrifice. The liver was perfused with buffer (Tris HC1 50 mM, NaCl 100 mM, 10 mM EDTA pH 7.4). The tissues were homogenized in 10 volumes of buffer (Tris HC1 50 mM, NaCl 100 mM, EDTA 10 mM, pH 7.4). The ho ogenate was filtered through two layers of wet guaze and filtrate was centrifuged at 500g for 10 min. The supernatant was subsequently centrifuged at 40, OOOg for 45 min. The pellet thus obtained was resuspended in the same volume of assay buffer (Tris HC1 50 mM, EDTA 5 mM, pH 7.4) and were stored at -70 °C until the time of assay.

The membrane homogenates (150-250 μg protein) were incubated in 250 μl of assay buffer (Tris HC1 50 mM, EDTA 5 mM, pH 7.4) at 24-25 °C for 1 hour. Nonspecific binding was determined in the presence of 300 nM prazosin. The incubation was terminated by vaccum filtration over GF/B fibre filters. The filters were then washed with ice cold 50 mM Tris HC1 buffer (pH 7.4). The filtermats were dried and bounded radioactivity retained on filters was counted. The IC₅₀ and K_d were estimated by using the non-linear curve-fitting program using G pad prism software. The value of the inhibition constant K; was calculated from competitive binding studies by using Cheng and Prusoff equation (Cheng and Prusoff, Biochem. Pharmacol, (1973), 22:3099-3108), K; = IC₅₀ /(1+L/K_d) where L is the concentration of [³H] prazosin used in the particular experiment. The affinity at alpha la adrenoceotprs expressed in terms of Ki (nM) for all compounds ranged from greater than 100 nM to 2.2 nM as compared to terazosin (Ki = 6.17). The affinity at alpha lb adrenoceptors expressed in terms of Ki (nM) for all compounds ranged from 120 nM to 23 nM in comparison to terazosin with a Ki value of 2.84 nM. The fold selectivity of alpha la over alpha lb adrenoceptors for all compounds ranged from 0.34 to 14.3, compared to 0.46 fold selectivity for terazosin. Thus, compounds disclosed herein are several folds more selective for alpha la over alpha lb adrenoceptors compared to terazosin. Example 3: In vitro functional studies: In vitro alpha-1 Adrenoceptor selectivity

In order to study selectivity of action of the present compounds towards different α-1 adrenoceptor subtypes, the ability of these compounds to antagonize α-1 adrenoceptor agonist induced contractile response of aorta ( u), prostate ( _la) and spleen (cti_b) was studied. Aorta, prostate and spleen tissue were isolated from thipentane anaesthetized (« 300 mg/Kg) male wistar rats. Isolated tissues were mounted in an organ bath containing Krebs Henseleit buffer of the following composition (mM): NaCl 118; KC1 4.7; CaCl₂ 2.5; MgSO₄. 7H₂O 1.2; NaHCO₃ 25; KH₂PO₄ 1.2; glucose 11.1. Buffer was maintained at 37 °C. and aerated with a mixture of 95% 02 and 5% CO₂. A resting tension of 2 g (aorta and spleen) or 1 g (prostate) was applied to tissues. Contractile response was monitored using a force displacement transducer and recorded on chart recorders. Tissues were allowed to equilibrate for 1 and 1/2 hours. At the end of equilibration period, concentration response curves to norepinephrine (aorta) and phenyl ephirine (spleen and prostate) were obtained in the absence and presence of the tested compound (at concentration of 0.1, 1 and 10 μM). Antagonist affinity was calculated and expressed as pKβ values and compared with terazosin. The potency of compounds expressed as pKβ at rat alpha-1 A adrenoceptors ranged from about 7.9 to about 8.7 compared to terazosin with 8.5. The pKβ for all compounds tested at rat alpha-ID adrenoceptors ranged from about 8.4 to about 8.9 compared to terazosin with pKβ 8.8. The fold selectivity of alpha-1 A over alpha- ID adrenoceptors for all compounds ranged from about 0.3 to 0.6 compared to 0.5 fold selectivity for terazosin. Thus, like terazosin, the compounds disclosed herein are non- selective for alpha-lA over alpha-ID adrenoceptors.

Claims

We Claim: 1. A compound having the structure of Formula I,

its pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, polymorphs or metabolites, wherein; A represents a Formula

wherein

n represents 1 or 2; Rι, R₂ and R₃ are independently selected from hydrogen, lower alkyl (Cι-C₄), phenyl and benzyl, wherein phenyl and benzyl are optionally substituted with halogen, lower alkyl (Cι-C₄), halogenated lower alkyl (Cι-C₄), hydroxy, alkoxy (Cι-C₄), amino or alkylamino (Cι-C₄); — represents no bond or single bond; Rij and R₅ are independently selected from a) hydrogen, b) optionally substituted alkyl (Cι-C₆) [wherein the substituents are selected from the group consisting of halogen (F, CI, Br or I), cycloalkyl, cycloalkenyl (C₃-C₇), optionally substituted phenyl (wherein the substituent(s) for phenyl may be selected from the group consisting of halogen (F, CI, Br or I), lower alkyl (Cι-C₄), halogenated (F, CI, Br or I) lower alkyl (Cι-C ), hydroxy, lower alkoxy (Ct-C₄), amino and lower alkylamino (Cι-C₄) group)]; c) alkenyl, d) alkynyl (C₂-C₇), e) cycloalkyl (C₃-C₇) group optionally substituted with halogen (F, CI, Br or I) atom(s) and f) optionally substituted non-aromatic or aromatic monocyclic or bicyclic ring system having 0 to 4 heteroatom(s) independently selected from the group consisting of nitrogen, sulphur and oxygen, the substituent(s) may be selected from the group consisting of halogen (F, CI, Br or I) atom(s), lower alkyl (Cι-C₄), halogenated (F, CI, Br or I) lower alkyl (Cτ-C₄), cyano, hydroxy, lower alkoxy (Cι-C₄), cycloalkoxy (C₃-C₆), amino, lower alkylamino (Cι-C ) and lower alkylamino (Cι-C₄) carbonyl group; Y represents cycloalkyl (C₅-C7) group optionally substituted with halogen atom(s) or lower alkyl (Cι-C₄) group; and R is selected from optionally substituted non-aromatic or aromatic monocyclic or bicyclic ring system having 0 to 4 heteroatom(s), the substituent(s) may be selected from the group consisting of halogen, lower alkyl ( -C ), halogenated lower alkyl (Cι-C₄), cyano, hydroxy, lower alkoxy (Cι-C₄), cycloalkoxy (C₃-C₆), amino, lower alkylamino (Cι-C₄) and lower alkylamino (d-C₄) carbonyl group. 2. A compound selected from: 2-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-cyclohexyl}-3a,4,7,7a-tetrahydro- isoindole-l,3-dione (Compound No. 1) 1- {4-[4-(2-Isopropoxy-phenyl)-piperazin- 1 -yl} -cyclohexyl} -piperidine-2,6-dione (Compound No.

2) l-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-cyclohexyl}-3,3-dimethyl- piperidine-2,6-dione (Compound No. 3) l-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-cyclohexyl}-3-phenyl-pyrolidine- 2,5-dione (Compound No. 4) 1- {4-[4-(2-Isopropoxy-phenyl)-piperazin- 1 -yl]-cyclohexyl} -pyrrole-2,5-dione (Compound No. 5) l-{4-[4-(2-Isopropoxy-phenyl)-piperazin-l-yl]-cyclohexyl}-3-methyl-pyrrole- 2,5-dione (Compound No. 6)

3. A pharmaceutical composition comprising a therapeutically effective amount of the compound as defined in the preceding claims optionally together with pharmaceutically acceptable carriers, excipients or diluents.

4. A method for treatment of a patient suffering from a disease or disorder mediated through _la and/or αu adrenergic receptor, comprising administering to said patient a therapeutically effective amount of a compound having the structure of Formula I,

its pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, polymoφhs or metabolites, wherein;

wherein

n represents 1 or 2;

Rι, R₂ and R₃ are independently selected from hydrogen, lower alkyl (Cι-C₄), phenyl and benzyl, wherein phenyl and benzyl are optionally substituted with halogen, lower alkyl (Cι-C₄), halogenated lower alkyl (C_t-C₄), hydroxy, alkoxy (Cι-C₄), amino or alkylamino (Cι-C₄);

— represents no bond or single bond; i and R₅ are independently selected from

a) hydrogen,

b) optionally substituted alkyl (Cι-C₆) [wherein the substituents are selected from the group consisting of halogen (F, CI, Br or I), cycloalkyl, cycloalkenyl (C₃-C₇), optionally substituted phenyl (wherein the substituent(s) for phenyl may be selected from the group consisting of halogen (F, CI, Br or I), lower alkyl (Cι-C₄), halogenated (F, CI, Br or I) lower alkyl ( - ), hydroxy, lower alkoxy ( -C₄), amino and lower alkylamino (Cι-C₄) group)];

c) alkenyl,

d) alkynyl (C₂-C₇),

e) cycloalkyl (C₃-C₇) group optionally substituted with halogen (F, CI, Br or I) atom(s) and

f) optionally substituted non-aromatic or aromatic monocyclic or bicyclic ring system having 0 to 4 heteroatom(s) independently selected from the group consisting of nitrogen, sulphur and oxygen, the substituent(s) may be selected from the group consisting of halogen (F, CI, Br or I) atom(s), lower alkyl (C₁-C₄), halogenated (F, CI, Br or I) lower alkyl (Cτ-C ), cyano, hydroxy, lower alkoxy (Cι-C₄), cycloalkoxy (C₃-C₆), amino, lower alkylamino (Cι-C₄) and lower alkylamino (Cι-C₄) carbonyl group; Y represents cycloalkyl (C₅-C₇) group optionally substituted with halogen atom(s) or lower alkyl (Cι-C₄) group; and R is selected from optionally substituted non-aromatic or aromatic monocyclic or bicyclic ring system having 0 to 4 heteroatom(s), the substituent(s) may be selected from the group consisting of halogen, lower alkyl ( - ), halogenated lower alkyl (Cι-C₄), cyano, hydroxy, lower alkoxy (Cι-C₄), cycloalkoxy (C₃-C₆), amino, lower alkylamino (Cι-C₄) and lower alkylamino (Cι-C₄) carbonyl group.

5. The method according to claim 4 wherein a disease or disorder is benign prostatic hyperplasia.

6. The method according to claim 4 wherein compound causes minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.

7. A method for treatment of a patient suffering from disease or disorder mediated through α_la and/or n adrenergic receptor, comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition according to claim 3.

8. The method according to claim 7 wherein a disease or disorder is benign prostatic hyperplasia.

9. The method according to claim 7 wherein pharmaceutical composition causes minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.

10. A process of preparing a compound having the structure of Formula I,

and its pharmaceutically acceptable acid addition salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, polymorphs or metabolites, wherein;

A represents a Formula

wherein

n represents 1 or 2;

Ri, R₂ and R₃ are independently selected from hydrogen, lower alkyl (C₁-C₄), phenyl and benzyl, wherein phenyl and benzyl are optionally substituted with halogen, lower alkyl (d-C₄), halogenated lower alkyl (Cι-C₄), hydroxy, alkoxy (C_ι-C₄), amino or alkylamino (Cι-C₄);

— represents no bond or single bond;

R₄ and R₅ are independently selected from

a) hydrogen,

b) optionally substituted alkyl (Cι-C₆) [wherein the substituents are selected from the group consisting of halogen (F, CI, Br or I), cycloalkyl, cycloalkenyl (C₃-C ), optionally substituted phenyl (wherein the substituent(s) for phenyl may be selected from the group consisting of halogen (F, CI, Br or I), lower alkyl (Cι-C₄), halogenated (F, CI, Br or I) lower alkyl (C₁-C₄), hydroxy, lower alkoxy (Cι-C ), amino and lower alkylamino (Cι-C₄) group)];

c) alkenyl,

d) alkynyl (C₂-C₇), e) cycloalkyl (C₃-C₇) group optionally substituted with halogen (F, CI, Br or I) atom(s) and

f) optionally substituted non-aromatic or aromatic monocyclic or bicyclic ring system having 0 to 4 heteroatom(s) independently selected from the group consisting of nitrogen, sulphur and oxygen, the substituent(s) may be selected from the group consisting of halogen (F, CI, Br or I) atom(s), lower alkyl (Q-Q), halogenated (F, CI, Br or I) lower alkyl (Cι-C₄), cyano, hydroxy, lower alkoxy (Cι-C₄), cycloalkoxy (C₃-C₆), amino, lower alkylamino (Cι-C₄) and lower alkylamino (Cι-C₄) carbonyl group;

Y represents cycloalkyl (C₅-C₇) group optionally substituted with halogen atom(s) or lower alkyl (Cι-C₄) group; and

R is selected from optionally substituted non-aromatic or aromatic monocyclic or bicyclic ring system having 0 to 4 heteroatom(s), the substituent(s) may be selected from the group consisting of halogen, lower alkyl (Cι-C₄), halogenated lower alkyl (Cι-C₄), cyano, hydroxy, lower alkoxy (Cι-C₄), cycloalkoxy (C₃-C₆), amino, lower alkylamino (Cr-C₄) and lower alkylamino (Cι-C₄) carbonyl group,

which method comprises hydrogenating a compound of Formula II with a hydrogenating agent to give a compound of Formula III; R— NO2 R— NH2 Formula II Formula III

treating the compound of Formula III with 2-chloroethanol in a solvent to give a compound of Formula IV;

Formula IV

treating the compound of Formula IV with mesityl chloride to give a compound of Formula V;

Formula V treating the compound of Formula V with a compound of Formula H₂N-Y-NH₂ (wherein Y is as defined earlier) to give a compound of Formula VI; and / \ H₂N-Y-N N-R Formula VI treating the compound of Formula VI with a compound of Formula

(wherein A is as defined earlier) to give a compound of Formula I.

11. The process according to claim 10 wherein the hydrogenation of a compound of Formula II to give a compound of Formula III is carried out in presence of a hydrogenating agent selected from palladium-carbon and hydrogen, Raney Nickel and hydrogen and stannous chloride and hydrochloric acid.

12. The reaction according to claim 11 is carried out in presence of palladium-carbon and hydrogen.

13. The process according to claim 10 wherein the reaction of a compound of Formula III with 2-chloroethanol is carried out in a solvent selected from chlorobenzene, xylene, dioxane, dimethylformamide and toluene.

14. The reaction according to claim 13 is carried out in chlorobenzene.

15. The process according to claim 10 wherein the reaction of a compound of Formula III with 2-chloroethanol is carried out in presence of an organic or inorganic base selected from triethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate.

16. The reaction according to claim 15 is carried out in presence of triethylamine.

17. The process according to claim 10 wherein the reaction of a compound of Formula IV with mestyl chloride is carried out in presence of an organic base selected from triethylamine, pyridine and 4-dimethylaminopyridine.

18. The reaction according to claim 17 is carried out in presence of triethylamine.

19. The process according to claim 10 wherein the reaction of a compound of Formula V with a compound of Formula H₂N-Y-NH₂ (wherein Y is as defined earlier) is carried out in a suitable solvent selected from methanol, ethanol, chloroform, dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide and dimethylsulfoxide.

20. The reaction according to claim 19 is carried out in dichloromethane.

21. The process according to claim 10 wherein the reaction of a compound of Formula VI with a compound of Formula out in acetic

anhydride, toluene or xylene by aziotropic water separation.

22. The reaction according to claim 21 is carried out in presence of acetic anhydride.